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WO2022080529A1 - Composition pharmaceutique et aliment fonctionnel de santé pour prévenir ou traiter l'hyposalivation - Google Patents

Composition pharmaceutique et aliment fonctionnel de santé pour prévenir ou traiter l'hyposalivation Download PDF

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Publication number
WO2022080529A1
WO2022080529A1 PCT/KR2020/014087 KR2020014087W WO2022080529A1 WO 2022080529 A1 WO2022080529 A1 WO 2022080529A1 KR 2020014087 W KR2020014087 W KR 2020014087W WO 2022080529 A1 WO2022080529 A1 WO 2022080529A1
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Prior art keywords
acid
hyposalivation
pharmaceutical composition
ala
group
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Ceased
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PCT/KR2020/014087
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English (en)
Korean (ko)
Inventor
정정화
김진현
우승훈
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Gyeongsang National University Hospital
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Gyeongsang National University Hospital
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Priority to PCT/KR2020/014087 priority Critical patent/WO2022080529A1/fr
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    • A—HUMAN NECESSITIES
    • A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
    • A23L—FOODS, FOODSTUFFS OR NON-ALCOHOLIC BEVERAGES, NOT OTHERWISE PROVIDED FOR; PREPARATION OR TREATMENT THEREOF
    • A23L33/00—Modifying nutritive qualities of foods; Dietetic products; Preparation or treatment thereof
    • A23L33/10—Modifying nutritive qualities of foods; Dietetic products; Preparation or treatment thereof using additives
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/38—Heterocyclic compounds having sulfur as a ring hetero atom
    • A61K31/385—Heterocyclic compounds having sulfur as a ring hetero atom having two or more sulfur atoms in the same ring
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00

Definitions

  • the present invention relates to a pharmaceutical composition and health functional food for preventing or treating hyposalivation.
  • Saliva is a secretion secreted from the salivary glands into the oral cavity. A normal person produces an average of 1-1.5 L of saliva per day. About 99.5% of saliva is water, and the remaining 0.5% is composed of electrolytes, mucin, glycoproteins, enzymes, and antibacterial substances. Saliva lubricates the oral mucosa, protects oral tissues, and is involved in digestion, taste, and remineralization of teeth. In particular, several proteins present in saliva have a profound effect on the oral microbiota due to their antibacterial, antiviral and antifungal actions.
  • the mechanism of salivation can be divided into protein secretion and fluid and electrolyte secretion.
  • protein secretion the sympathetic neurotransmitter norepinephrine binds to the ⁇ -adrenergic receptor present in the cell membrane at the bottom of the secretory terminal cell, resulting in heterotrimeric G-protein (heterotrimeric).
  • G-protein) and adenylyl cyclase are activated.
  • the formation of cyclic adenosine monophosphate is catalyzed, and when protein kinase A is activated, the secretory granules present in the cell membrane secrete the protein toward the lumen by exocytosis.
  • secretion of liquid and electrolyte mainly occurs by binding of acetylcholine, a parasympathetic neurotransmitter, to muscarinic receptors.
  • an agonist binds to a muscarinic receptor
  • heterotrimeric G-protein and phospholipase C are sequentially activated and ultimately inositol triphosphate , IP3) is promoted.
  • IP3 releases Ca 2+ stored in the cell, and the Cl - channel on the luminal side and K + channel on the bottom side are opened by the increased Ca 2+ concentration to open Na + /K + /2Cl - co-
  • the co-transporter is activated.
  • aquaporin 5 (AQP5) protein present in the vesicle moves to the luminal cell membrane.
  • the increased luminal Cl ⁇ is balanced along with Na + moving into the lumen through the closed junction, resulting in an osmotic gradient.
  • the osmotic gradient moves water from the cell towards the lumen through the closed junction with AQP5.
  • aquaporin as a water channel protein is found in the cornea, kidney, liver, skin, and the like.
  • AQP5 is a major biomarker for salivation.
  • research results have been published that the amount of saliva secretion decreased by more than 60% in AQP5 knockout mice.
  • Xerostomia is the most common clinical symptom associated with salivary glands. Dry mouth is diagnosed when the amount of saliva secreted during non-stimulation is less than 0.1 ml per minute. The causes of dry mouth are mainly side effects caused by drugs such as antidepressants, antidiabetics, and antiallergy. Dry mouth caused by natural aging is caused by a decrease in the parenchymal tissue and replacement by adipose tissue or a decrease in the volume of the alveoli. When the amount of saliva in the oral cavity is reduced, tooth decay, acid erosion, oral candidiasis, dysgeusia, dysphagia, oral dysesthesia, and intraoral halitosis may occur. accompanying
  • Representative treatments for dry mouth currently used include parasympathomimetic pilocarpine, cevimeline, and bethanechol.
  • these treatments have the disadvantage of causing side effects such as sweating, vomiting, vasodilation, diarrhea, and bronchospasm. Therefore, it is a very important task to prevent and treat dry mouth based on natural products with few side effects and high safety features.
  • An object of the present invention is to provide a pharmaceutical composition for preventing or treating hyposalivation, comprising ⁇ -Lipoic acid or a pharmaceutically acceptable salt thereof.
  • Another object of the present invention is to provide a health functional food for preventing or improving hyposalivation, comprising alpha-Lipoic acid or a pharmaceutically acceptable salt thereof.
  • a pharmaceutical composition for preventing or treating hyposalivation comprising ⁇ -Lipoic acid or a pharmaceutically acceptable salt thereof.
  • Health functional food for preventing or improving hyposalivation, including ⁇ -Lipoic acid or a pharmaceutically acceptable salt thereof.
  • the pharmaceutical composition comprising alpha lipoic acid of the present invention can achieve the prevention or treatment effect of hyposalivation by improving the damage to the salivary gland, and the health functional food of the present invention can achieve the prevention or improvement effect of hyposalivation.
  • FIG. 1 is a diagram showing improvement of weight loss and damaged saliva secretion due to radioiodine (RI) treatment.
  • FIG. 2 is a diagram confirming the effect of ALA on thyroid function after RI treatment.
  • 3 and 4 are diagrams confirming the pathological results after RI treatment.
  • 5 and 6 are diagrams confirming the effect of ALA on increased cell death and aging after RI treatment.
  • FIG. 7 is a diagram showing that the administration of ALA improves the radioiodine (RI) treatment-induced decrease in AQP5 expression.
  • FIG 8 and 9 are diagrams showing planar whole body images and dynamics of 99m Tc pertechnetate absorption and excretion.
  • compositions for preventing or treating hyposalivation comprising alpha-lipoic acid or a pharmaceutically acceptable salt thereof.
  • the alpha lipoic acid is a compound represented by the following Chemical Formula 1, the chemical formula is C 8 H 14 O 2 S 2 , the molar mass is 206.33 g/mol, and the IUPAC name is 5-(1,2-dithiolan-3-yl)pentanoic acid am:
  • the alpha lipoic acid may be derived from nature or may be synthesized using a known organic synthesis method.
  • the alpha lipoic acid may be a non-protein compound, a peptide, an extract of a plant-derived tissue or cell, or a product obtained by culturing a microorganism (eg, bacteria or fungi, and particularly yeast).
  • a microorganism eg, bacteria or fungi, and particularly yeast
  • the pharmaceutical composition according to the present invention may be provided as a pharmaceutical composition including an active ingredient alone or one or more pharmaceutically acceptable carriers, excipients or diluents.
  • “Pharmaceutically acceptable” in the present invention means exhibiting a property that is not toxic to cells or humans exposed to the composition.
  • the term “pharmaceutically acceptable salt” refers to a salt prepared using a specific compound according to the present invention and a relatively non-toxic acid or base.
  • base addition salts may be obtained by contacting the neutral form of such compounds with a sufficient amount of the base in neat solution or in a suitable inert solvent.
  • Pharmaceutically acceptable base addition salts include salts of sodium, potassium, calcium, ammonium, organic amines, or magnesium or similar salts.
  • acid addition salts can be obtained by contacting the neutral form of such compounds with a sufficient amount of acid in neat solution or in a suitable inert solvent.
  • Pharmaceutically acceptable acid addition salts include salts of inorganic acids such as hydrochloric acid, hydrobromic acid, nitric acid, carbonic acid, hydrogen carbonate ion, phosphoric acid, phosphate monohydrogen ion, phosphate dihydrogen ion, sulfuric acid, hydrogen sulfate ion, hydroiodic acid or phosphorous acid; and salts of organic acids such as acetic acid, propionic acid, isobutyric acid, maleic acid, malonic acid, benzoic acid, succinic acid, suberic acid, fumaric acid, lactic acid, mandelic acid, phthalic acid, benzenesulfonic acid, p-tolylsulfonic acid, citric acid, tartaric acid, and methanesulfonic acid and salts of amino acids (eg, arginine) and salts of organic acids such as glucuronic acid are also included.
  • inorganic acids such as hydrochloric acid, hydrobromic acid,
  • the pharmaceutically acceptable salt of the present invention can be synthesized from a parent compound containing an acidic or basic moiety by a conventional chemical method.
  • such salts are prepared by reacting the free acid or form of the base of these compounds with a stoichiometrically appropriate amount of the base or acid, in water or in an organic solvent or in a mixture of the two.
  • non-aqueous media such as ether, ethyl acetate, ethanol, isopropanol or acetonitrile are preferred.
  • the pharmaceutical composition of the present invention may be provided by mixing with a conventionally known composition for preventing or treating hyposalivation. That is, the pharmaceutical composition of the present invention may be administered in parallel with a known compound having an effect of preventing or treating hyposalivation.
  • administration means introducing a predetermined substance to an individual by an appropriate method
  • individual means all living things, such as mice, mice, and livestock, including humans, that may have hyposalivation. As a specific example, it may be a mammal including a human.
  • the pharmaceutical composition of the present invention may additionally include a composition having a known preventive or therapeutic effect on hyposalivation.
  • compositions for preventing or treating hyposalivation include Java turmeric ( Curcumaxanthorrhiza ) extract, polyglutamic acid and Aspalathus linearis ( Aspalathus linearis ) extract, Hepatica oleracea extract, warthog extract, and the like, but are limited thereto. not.
  • the route of administration of the pharmaceutical composition is, but not limited to, oral, intravenous, intramuscular, intraarterial, intramedullary, intrathecal, intracardiac, transdermal, subcutaneous, intraperitoneal, intranasal, intestinal, topical, sublingual or rectal.
  • composition of the present invention may be administered orally or parenterally, and when administered parenterally, it is preferable to select an injection method for external application or intraperitoneal injection, intrarectal injection, subcutaneous injection, intravenous injection, intramuscular injection or intrathoracic injection. , but is not limited thereto.
  • the preferred dosage of the composition of the present invention varies depending on the condition and weight of the patient, the degree of disease, the drug form, the route and duration of administration, but may be appropriately selected by those skilled in the art. However, for a desirable effect, the composition is preferably administered at 0.01 to 1000 mg/kg/day, preferably at 0.1 to 500 mg/kg/day, but is not limited thereto. The administration may be administered once a day, or divided into several administrations. The above dosage does not limit the scope of the present invention in any way.
  • Solid preparations for oral administration include tablets, pills, powders, granules, capsules, etc., and such solid preparations include at least one excipient in the extract, for example, starch, calcium carbonate, sucrose. Alternatively, it is prepared by mixing lactose, gelatin, etc. In addition to simple excipients, lubricants such as magnesium stearate and talc are also used.
  • Liquid formulations for oral use include suspensions, solutions, emulsions, syrups, etc.
  • Formulations for parenteral administration include sterile aqueous solutions, non-aqueous solutions, suspensions, emulsions, freeze-dried preparations, and suppositories.
  • Non-aqueous solvents and suspending agents include propylene glycol, polyethylene glycol, vegetable oils such as olive oil, and injectable esters such as ethyl oleate.
  • a suppository base witepsol, macrogol, tween 61, cacao butter, laurin, glycero geratin and the like can be used.
  • the hyposalivation may be caused by various causes, for example, may be caused by damage to the salivary gland, but is not limited thereto.
  • the salivary gland damage may also be caused by various causes, for example, it may be caused by radioiodine treatment, but is not limited thereto.
  • the alpha lipoic acid can increase the amount of salivary secretion by restoring the damage to the salivary glands, specifically, can increase the weight of the salivary glands reduced due to damage to the salivary glands again, and specifically decrease the salivary gland-related factor of aquaporin 5. It may increase expression, but is not limited thereto.
  • the alpha lipoic acid can restore damaged parasympathetic nerves, and specifically can increase the expression of glial cell-derived neurotrophic factor family receptor 2 (GFR2), which is a marker of parasympathetic nerves. and may increase the expression of brain-derived neurotrophic factor (BDNF) and neurturin related to parasympathetic nerves, but is not limited thereto.
  • GFR2 glial cell-derived neurotrophic factor family receptor 2
  • BDNF brain-derived neurotrophic factor
  • neurturin related to parasympathetic nerves but is not limited thereto.
  • the alpha lipoic acid can regenerate the salivary glands, specifically hedgehog (Hedgehog, Hh) signaling related to the regeneration of the salivary gland Sonic hedgehog (Sonic Hedgehog, Shh) and its receptor Patched (Patched, Ptch) It is possible to increase the expression of the gene and may increase the expression of Sca-1, a stem cell-related marker related to regeneration of the salivary gland, but is not limited thereto.
  • the present invention relates to a health functional food for preventing or improving hyposalivation, comprising ⁇ -Lipoic acid or a pharmaceutically acceptable salt thereof.
  • the hyposalivation may be caused by damage to the salivary glands, and the damage to the salivary glands may be caused by radioiodine treatment, but is not limited thereto.
  • the efficacy, mechanism of action, etc. of the alpha lipoic acid may be within the above-mentioned range.
  • food pharmaceutically acceptable means exhibiting a property that is not toxic to cells or humans exposed to the compound.
  • “food pharmaceutically acceptable salt” means a salt prepared using a specific compound according to the present invention and a relatively non-toxic acid or base, and may be within the above-described range for “salt”.
  • the health functional food of the present invention may be formulated into one selected from the group consisting of tablets, pills, powders, granules, powders, capsules, and liquid formulations, further comprising one or more of carriers, diluents, excipients and additives.
  • Foods to which the extract of the present invention can be added include various foods, powders, granules, tablets, capsules, syrups, beverages, gums, tea, vitamin complexes, health functional foods, and the like.
  • Additives that may be further included in the present invention include natural carbohydrates, flavoring agents, nutrients, vitamins, minerals (electrolytes), flavoring agents (synthetic flavoring agents, natural flavoring agents, etc.), coloring agents, fillers (cheese, chocolate, etc.), At least one component selected from the group consisting of facic acid and its salts, alginic acid and its salts, organic acids, protective colloidal thickeners, pH adjusters, stabilizers, preservatives, antioxidants, glycerin, alcohols, carbonation agents, and pulp may be used. .
  • natural carbohydrates examples include monosaccharides such as glucose, fructose and the like; disaccharides such as maltose, sucrose and the like; and polysaccharides such as conventional sugars such as dextrin and cyclodextrin, and sugar alcohols such as xylitol, sorbitol, and erythritol.
  • natural flavoring agents tacartin, stevia extract (eg, rebaudioside A, glycyrrhizin, etc.) and synthetic flavoring agents (saccharin, aspartame, etc.) can be advantageously used.
  • the health functional food of the present invention includes various nutrients, vitamins, minerals (electrolytes), flavoring agents such as synthetic and natural flavoring agents, colorants and thickeners (cheese, chocolate, etc.), pectic acid and its salts, alginic acid and salts thereof, organic acids, protective colloidal thickeners, pH adjusters, stabilizers, preservatives, glycerin, alcohols, carbonation agents used in carbonated beverages, and the like.
  • the composition according to the present invention may contain the pulp for the production of natural fruit juices and vegetable beverages. These components may be used independently or in combination.
  • carrier examples include, but are not limited to, lactose, dextrose, sucrose, sorbitol, mannitol, erythritol, starch, acacia gum, calcium phosphate, alginate, gelatin, calcium phosphate, calcium Silicate, microcrystalline cellulose, polyvinylpyrrolidone, cellulose, polyvinylpyrrolidone, methylcellulose, water, sugar syrup, methylcellulose, methyl hydroxy benzoate, propyl hydroxy benzoate, talc, magnesium stearate and at least one selected from the group consisting of mineral oil is preferably used.
  • the health functional food of the present invention it is prepared using a diluent or excipient such as a filler, extender, binder, wetting agent, disintegrant, and surfactant usually used.
  • a diluent or excipient such as a filler, extender, binder, wetting agent, disintegrant, and surfactant usually used.
  • Salivary function was assessed by measuring salivary secretion. After injection of pilocarpine (0.01 mL/g body weight i.p.; Isopto Carpine; Alcon Korea Ltd., Seoul, Korea), saliva discharge was collected from the mouth for 5 minutes after 8 minutes. After measuring the total body weight of the mice, the total amount and volume of saliva accumulated for 10 minutes after pilocarpine injection into a fresh tube was normalized to body weight. The needle delay time and flow rate were measured. Salivary flow rate (total needle weight divided by collection time) and delay time (time from stimulation to onset of salivation) were calculated.
  • Tissues were fixed in 4% paraformaldehyde in 0.1M PBS, embedded in paraffin, and cut into 5 ⁇ m. Sections were stained with HE. Histopathological damage in HE staining was scored by grading the number of acinar cells with cytoplasmic vacuoles in a ⁇ 200 magnification field. 0, 0-1; 1, 2-5; 2, 5-10; 3, 10-15; 4, 15-20; 5, > 20. Sections were stained with MT (Masson's Trichrome kit, Sigma Diagnostics, St. Louis, MO, USA) to analyze the degree of collagen deposition. Randomly selected SG (salivary gland) fields at 400x magnification were evaluated in each mouse, and the density of trichrome-positive signals was analyzed using NIS-Elements BR 3.2 (Nikon, Japan).
  • SG was immediately put in 4% paraformaldehyde at room temperature, embedded in paraffin, and then cut to a thickness of 5 ⁇ m. SGs were stained with Masson's trichrome (MT) and hematoxylin and eosin (H&E). Apoptosis of submaxillary gland tissues was determined by TUNEL analysis using the ApopTag Plus In Situ Apoptosis Kit (Chemicon Int., Temecula, CA, USA). TUNEL-positive cells were detected at ⁇ 400 magnification, and TUNEL-positive cells were counted in 10 random high-power fields. TUNEL analysis was performed at 30 and 90 days post RI exposure.
  • MT Masson's trichrome
  • H&E hematoxylin and eosin
  • Sections were visualized by light microscopy and digital images were captured and analyzed. Data were analyzed as signal intensity using NIS-Elements BR 3.2 (Nikon, Japan) in 10 random fields and accounted for by fold change. Fold change was calculated as the ratio of the final value of each group to the value of the control group at day 30 (set as "1").
  • Whole-body SPECT images were obtained using a large field-of-view rotating gamma camera equipped with four multi-pinhole collimators. Acquisition parameters are: 24 projections over 360°, circular trajectory, and a total acquisition time of 6 minutes (4 seconds per projection). The tomographic images were reconstructed using an iterative reconstruction algorithm.
  • ALA improves weight loss and impaired salivation due to radioiodine exposure.
  • the average body weight of the RI-treated mouse group was significantly lower than that of the control group at 90 days, and the body weights of the RI+ALA and ALA groups were similar to those of the control group ( FIG. 1A ).
  • the salivary flow rate of the RI+ALA-treated group was higher than that of the RI-only group at 30 and 90 days after RI (Fig. 1B).
  • salivation delay was improved in the RI+ALA group compared to the RI alone group (FIG. 1C).
  • TSH thyroid stimulating hormone
  • HE hematoxylin and eosin
  • MT Masson trichrome
  • Terminal deoxynucleotidyl transferase biotin-dUTP nick end labeling (TUNEL) assay was performed to determine the effect of ALA on RI-induced apoptosis.
  • a faint signal was found in both the control and ALA-only groups at 30 and 90 days after RI treatment; They were more abundant in acinar than ductal cells and more pronounced at 30 days than at 90 days ( Figures 5A, 5B).
  • the positive signal was significantly increased in the RI-only group compared to the control and ALA-only groups.
  • the total number of apoptotic cells was significantly lower in the ALA+RI group compared to the RI alone group at both 30 and 90 days after RI treatment (Fig. 5C).
  • ALA prevents RI-induced cellular senescence in SGs.
  • SA- ⁇ -gal senescence-associated ⁇ -galactosidase
  • ALA restores the radioiodine-induced decrease in AQP5 expression.
  • ALA ameliorates RI-induced acupuncture dysfunction.
  • Acupuncture function was examined after RI treatment using single-photon emission computed tomography (SPECT).
  • SPECT single-photon emission computed tomography
  • the degree of 99m Tc pertechnetate clearance was much lower in the RI alone group at 110 and 120 minutes.
  • the excretion of 99m Tc pertechnetate in the ALA-only group was similar to that of the control group ( FIGS. 8A and 8B ).
  • the level of 99m Tc pertechnetate clearance was significantly lower in the RI-only group compared to the other groups at 70, 90, 100, 110 and 120 min.
  • the excretion of 99m Tc pertechnetate in the ALA-only group was better than in the control group ( FIGS. 9A and 9B ).

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Abstract

La présente invention concerne une composition pharmaceutique et un aliment fonctionnel de santé comprenant de l'acide alpha-lipoïque ou un sel de celui-ci, qui atténuent les dommages causés aux glandes salivaires pour obtenir un effet de prévention ou de traitement de l'hyposalivation, et plus spécifiquement, présentent un excellent effet dans le soulagement des dommages causés aux glandes salivaires par un traitement par l'iode radioactif (RI).
PCT/KR2020/014087 2020-10-15 2020-10-15 Composition pharmaceutique et aliment fonctionnel de santé pour prévenir ou traiter l'hyposalivation Ceased WO2022080529A1 (fr)

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Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4906455A (en) * 1988-04-15 1990-03-06 Wm. Wrigley Jr. Company Method for treating xerostomia employing chewing gum containing relatively insoluble, hydrophobic, food-grade organic acid
KR20120092152A (ko) * 2009-11-12 2012-08-20 아카시아 파마 리미티드 타액선 기능장애의 치료
KR20200083370A (ko) * 2018-12-28 2020-07-08 경상대학교병원 침분비 저하증 예방 또는 치료용 약학적 조성물 및 건강기능식품
KR20200118128A (ko) * 2018-02-05 2020-10-14 셀릭스 바이오 프라이빗 리미티드 항무스카린제 또는 항콜린제 및 리포산의 조합 및 이의 용도

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4906455A (en) * 1988-04-15 1990-03-06 Wm. Wrigley Jr. Company Method for treating xerostomia employing chewing gum containing relatively insoluble, hydrophobic, food-grade organic acid
KR20120092152A (ko) * 2009-11-12 2012-08-20 아카시아 파마 리미티드 타액선 기능장애의 치료
KR20200118128A (ko) * 2018-02-05 2020-10-14 셀릭스 바이오 프라이빗 리미티드 항무스카린제 또는 항콜린제 및 리포산의 조합 및 이의 용도
KR20200083370A (ko) * 2018-12-28 2020-07-08 경상대학교병원 침분비 저하증 예방 또는 치료용 약학적 조성물 및 건강기능식품

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
KIM, J. H. ET AL.: "Protective effects of alpha lipoic acid on radiation-induced salivary gland injury in rats", ONCOTARGET, vol. 7, no. 20, 2016, pages 29143 - 29153, XP055621077, DOI: 10.18632/oncotarget.8661 *

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