CN111686109A - Application of 8-octyl berberine salt in preparation of anti-helicobacter pylori infection medicine - Google Patents

Application of 8-octyl berberine salt in preparation of anti-helicobacter pylori infection medicine Download PDF

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Publication number
CN111686109A
CN111686109A CN202010659071.8A CN202010659071A CN111686109A CN 111686109 A CN111686109 A CN 111686109A CN 202010659071 A CN202010659071 A CN 202010659071A CN 111686109 A CN111686109 A CN 111686109A
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helicobacter pylori
berberine salt
pylori infection
octyl
octyl berberine
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何欢
李滟临
肖亚平
来智慧
刘妍
范金花
周黎明
李学刚
叶小利
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Southwest University
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    • 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
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/4353—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems
    • A61K31/4375—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems the heterocyclic ring system containing a six-membered ring having nitrogen as a ring heteroatom, e.g. quinolizines, naphthyridines, berberine, vincamine
    • 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
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/4164—1,3-Diazoles
    • 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
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/42—Oxazoles
    • A61K31/422—Oxazoles not condensed and containing further heterocyclic rings
    • 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
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/425—Thiazoles
    • A61K31/429—Thiazoles condensed with heterocyclic ring systems
    • A61K31/43—Compounds containing 4-thia-1-azabicyclo [3.2.0] heptane ring systems, i.e. compounds containing a ring system of the formula, e.g. penicillins, penems
    • 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
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
    • A61K31/4439—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems containing a five-membered ring with nitrogen as a ring hetero atom, e.g. omeprazole
    • 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
    • A61K31/70—Carbohydrates; Sugars; Derivatives thereof
    • A61K31/7042—Compounds having saccharide radicals and heterocyclic rings
    • A61K31/7048—Compounds having saccharide radicals and heterocyclic rings having oxygen as a ring hetero atom, e.g. leucoglucosan, hesperidin, erythromycin, nystatin, digitoxin or digoxin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/04—Antibacterial agents

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  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Veterinary Medicine (AREA)
  • Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Epidemiology (AREA)
  • Molecular Biology (AREA)
  • Communicable Diseases (AREA)
  • Oncology (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Organic Chemistry (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

The invention provides an application of 8-octyl berberine salt in preparing a medicament for resisting helicobacter pylori infection. The research of the invention finds that when the 8-octyl berberine salt is used together with antibiotics such as amoxicillin, clarithromycin, metronidazole, furazolidone, omeprazole and the like, the antibacterial activity of the antibiotics can be obviously improved, and the synergistic effect is realized.

Description

Application of 8-octyl berberine salt in preparation of anti-helicobacter pylori infection medicine
Technical Field
The invention relates to medical application of 8-octyl berberine salt, in particular to application of 8-octyl berberine salt in preparation of a helicobacter pylori infection resisting medicine, and belongs to the technical field of new medicine development.
Background
Helicobacter pylori (hereinafter, Hp) is a spiral, micro-anaerobic bacterium that has severe requirements for growth conditions. The first successful isolation from biopsy tissue from the gastric mucosa of patients with chronic active gastritis in 1983 is the only microorganism species currently known to survive in the human stomach. In 2017, 10 and 27, the international cancer research institution of the world health organization publishes a carcinogen list for preliminary reference, and helicobacter pylori (infection) is in a carcinogen list. The helicobacter pylori diseases include gastritis, peptic ulcer, lymphoproliferative gastric lymphoma, etc. caused by helicobacter pylori infection. Clinically, the Hp is killed by antibiotics. The efficacy of antibiotics is decreasing due to resistance problems. In 1998, "triple therapy" (three antibiotics used simultaneously) for clinically treating Hp was approved by FDA in the united states, but by 2018, the fifth national specialist for helicobacter pylori, it was generally considered that the curative effect of the triple therapy could not meet the requirement of clinical treatment, and "quadruple therapy" (four antibiotics used simultaneously) was recommended, resulting in more and more serious side effects. Therefore, the development of new anti-Hp drugs is a very urgent clinical problem.
Disclosure of Invention
In order to solve the problems in the prior art, the invention provides an application of 8-octyl berberine salt in the field of pharmacy.
The 8-octyl berberine is berberine C8 bit long chain alkyl substituted derivative, which has better lipid solubility than berberine and is more beneficial to the absorption of organisms. Research shows that the lipid-lowering activity of 8-octyl berberine is obviously higher than that of berberine. 8-Octyl berberine salt with molecular formula of C28H34O4N.X, the structural formula is as follows:
Figure BDA0002577838360000011
wherein X is halogen, in particular fluorine, chlorine, bromine or iodine.
The purpose of the invention is realized as follows:
the invention provides an application of 8-octyl berberine salt in preparing a medicament for resisting helicobacter pylori infection.
The inventor finds that when the 8-octyl berberine salt is used together with the antibiotic, the anti-Hp activity of the antibiotic can be obviously improved. The antibiotic is selected from one or a combination of several of amoxicillin, clarithromycin, metronidazole, furazolidone and omeprazole.
Furthermore, the invention also provides application of the 8-octyl berberine salt and amoxicillin combined medicine in preparing a medicine for resisting helicobacter pylori infection; the application of the 8-octyl berberine salt and clarithromycin in preparing the anti-helicobacter pylori infection medicine; the application of the 8-octyl berberine salt and metronidazole combined medicine in preparing the anti-helicobacter pylori infection medicine; the application of the 8-octyl berberine salt and furazolidone combination medicine in preparing the anti-helicobacter pylori infection medicine; application of 8-octyl berberine salt and omeprazole in preparation of anti-helicobacter pylori infection medicine.
The present invention also provides a method of treating helicobacter pylori infection in a subject, the method comprising: administering to a patient in need of such treatment an effective amount of 8-octyl berberine salt and an antibiotic.
The purity of the 8-octyl berberine salt used by the invention is better to be more than 99.0 percent in percentage by weight.
The term "treating" as used herein includes limiting, slowing, terminating or reversing the progression or severity of the symptoms or conditions present. The term "patient" as used herein refers to a human.
The term "effective amount" as used herein refers to a dosage of the 8-octyl berberine salt of the invention that, when administered to a patient in single or multiple doses, is capable of providing the desired effect in the patient under diagnosis or treatment. As one skilled in the art, an effective amount can be readily determined by a diagnostician using known techniques and observing the results obtained under analogous circumstances. In determining the effective amount for a patient, the diagnostician will consider a number of factors, including, but not limited to, the type of patient; age and general health; the particular disease or condition involved; the complexity or severity of the disease or disorder; the response of the individual patient; the specific compound administered; a mode of administration; the bioavailability characteristics of the formulation administered; a selected dosage regimen; concomitant medication for use; and other related circumstances.
Preferably, the 8-octyl berberine salts of the present invention are formulated as pharmaceutical compositions to be administered by any route that enables the compound to be bioavailable, including oral, transdermal and parenteral routes. Most preferably, such compositions are administered orally or transdermally, with oral administration being especially preferred. Such pharmaceutical compositions and methods of preparing them are well known in the art, e.g., tablets, pills, powders, granules, capsules, and the like; the injection can be made into powder for injection, lyophilized powder for injection, etc., by conventional method. The above dosage forms are preferably oral capsules, tablets and injections.
The preparation or pharmaceutical composition of the present invention is not particularly limited, and examples thereof include preparations such as tablets, powders, granules, capsules, oral liquids, emulsions, elixirs, lemon water solutions, suspensions, syrups, oral tablets, oral jellies, inhalants, suppositories, injections, ointments, eye drops, nasal drops, ear drops, patches, and external liquids. In the formulation, a commonly used excipient, binder, lubricant, coloring agent, flavoring agent, stabilizer, emulsifier, absorption enhancer, surfactant, pH adjuster, preservative, antioxidant and the like can be used, and the formulation can be prepared by a conventional method by blending components commonly used as raw materials of pharmaceutical preparations. For example, in the production of an oral preparation, the crystalline or amorphous compound of the present invention and an excipient are added and further, as additives, a binder, a disintegrant, a lubricant, a coloring agent, a taste-modifying agent and the like are added as necessary, and then, a powder, a fine granule, a tablet, a coated tablet, a capsule and the like are prepared by a conventional method. Examples of additives include: animal and vegetable oils such as soybean oil, beef tallow, synthetic glyceride, etc.; hydrocarbons such as liquid paraffin, squalane, and paraffin wax; ester oils such as octyldodecyl myristate and isopropyl myristate; higher alcohols such as cetearyl alcohol and behenyl alcohol; a silicone resin; a silicone oil; surfactants such as polyoxyethylene fatty acid esters, sorbitan fatty acid esters, glycerin fatty acid esters, polyoxyethylene sorbitan fatty acid esters, polyoxyethylene hardened castor oil, and polyoxyethylene polyoxypropylene block copolymers; water-soluble polymers such as hydroxyethyl cellulose, hydroxypropyl methylcellulose phthalate, polyacrylic acid, carboxyvinyl polymer, polyethylene glycol, polyvinylpyrrolidone, and methyl cellulose; lower alcohols such as ethanol and isopropanol; polyhydric alcohols such as glycerin, propylene glycol, dipropylene glycol, and sorbitol; sugars such as glucose and sucrose; inorganic powders such as anhydrous silicic acid, magnesium aluminum silicate, etc., purified water, etc. Examples of the excipient include lactose, corn starch, white sugar, glucose, mannitol, sorbitol, crystalline cellulose, and silicon dioxide, examples of the binder include polyvinyl alcohol, polyvinyl ether, methyl cellulose, ethyl cellulose, gum arabic, tragacanth, gelatin, gellan gum, hydroxypropylmethyl cellulose, hydroxypropyl cellulose, polyvinylpyrrolidone, polypropylene glycol/polyoxyethylene block polymer, and meglumine, examples of the disintegrant include starch, agar, gelatin powder, crystalline cellulose, calcium carbonate, sodium hydrogen carbonate, calcium citrate, dextrin, pectin, and carboxymethylcellulose-calcium, examples of the lubricant include magnesium stearate, talc, polyethylene glycol, silicon dioxide, and hardened vegetable oil, examples of the colorant include colorants, colorants permitted to be added to pharmaceuticals, as flavoring agent, cocoa powder, Mentholum, aromatic powder, oleum Menthae Dementholatum, Borneolum Syntheticum, and cortex Cinnamomi Japonici powder can be used. In the case of producing tablets or granules, the tablets or granules may be coated with a sugar coating, and may be appropriately coated as necessary. In addition, in the preparation of syrups, emulsions, elixirs, aqueous lemonades, suspensions, injectable preparations and other liquid formulations, the compounds of the present invention may be formulated by conventional methods by further adding, as required, pH regulators, solubilizers, emulsifiers, dispersants, isotonic agents and the like, cosolvents, stabilizers and the like as additives. The method for producing the external preparation is not limited, and the preparation can be produced by a conventional method. That is, as base materials used for formulation, various materials generally used in pharmaceuticals, quasi drugs, cosmetics, and the like can be used. Specific examples of the base material to be used include animal and vegetable oils, mineral oils, ester oils, waxes, higher alcohols, fatty acids, silicone oils, surfactants, phospholipids, alcohols, polyols, water-soluble polymers, clay minerals, resins, plastics, water-insoluble natural or synthetic polymer compounds such as rubbers, purified water, and the like, and further, pH adjusters, antioxidants, chelating agents, preservatives, antifungal agents, coloring agents, perfumes, and the like may be added as necessary.
Further, components having differentiation inducing activity, blood flow promoters, antiseptics, anti-inflammatory agents, cell activators, vitamins, amino acids, moisturizers, keratolytic agents, and the like may be blended as necessary. The amount of the base material added is an amount to reach a concentration set in the production of a usual external preparation.
Has the advantages that:
the invention provides an application of 8-octyl berberine salt in preparing a medicament for resisting helicobacter pylori infection. The research of the invention finds that when the 8-octyl berberine salt is used together with antibiotics such as amoxicillin, clarithromycin, metronidazole, furazolidone, omeprazole and the like, the antibacterial activity of the antibiotics can be obviously improved, and the synergistic effect is realized.
Detailed Description
The present invention is described in detail below with reference to specific examples, which are given for the purpose of further illustrating the invention and are not to be construed as limiting the scope of the invention, and the invention may be modified and adapted by those skilled in the art in light of the above disclosure. Except for special description, the percentages are mass percentages. The raw materials and reagents used in the invention are all commercial products, wherein the 8-octyl berberine salt is prepared according to ZL 200610095288.0.
Examples
anti-Hp activity test of 8-octyl berberine salt
(ii) experimental materials.
The test drug 8-octyl berberine hydrochloride (O-BBR) is prepared to 1000ppm respectively.
The reference drug, berberine hydrochloride (BBR), was formulated at 1000ppm each.
Antibiotics: amoxicillin (a), clarithromycin (g), metronidazole (a), levofloxacin (a), furazolidone (a) and omeprazole (an), which are respectively configured to be 100 ppm.
Secondly, strain: helicobacter pylori (Hp, 11637)
③ culture medium: MH broth and MH agar are all sold.
④ MIC detection comprises determining MBC of related drugs by dilution method (Chinese medicine basic medicine journal, 2017,23(03):405-407+422) using MH agar medium to obtain 100uL of 3 × 108CFU·mL-1The helicobacter pylori liquid is uniformly coated on MH agar culture medium by a disposable coater, and the test medicines are diluted into concentrations of 400, 200, 100, 50, 25, 12.5, 6.25, 3.1, 1.56, 0.78, 0.39, 0.198, 0.099 and 0.050 ug/ml-1Spreading on MH agar medium, and placing in a three-atmosphere incubator (85% N) with blank medium as control2，10％CO2，5％O2) Culturing for 48-72 h, observing the growth condition of bacteria, and taking the lowest drug concentration of the number of bacteria as the minimum bactericidal concentration (MIC). The results are shown in Table 1.
TABLE 1 MIC (μ g/mL) of drugs against H.pylori (11637)
Medicine MIC Mixed medicine MIC Mixed medicine MIC
BBR 50 ---- ---- ---- ----
O-BBR 0.39 ---- ---- ---- ----
A 0.05 BBR-A 50-0.05 O-BBR-A 0.10-0.025
Keke (Chinese character of 'Keke') 0.1 BBR-g 50-0.10 O-BBR-g 0.20-0.025
First of all 1.56 BBR-A 50-1.56 O-BBR-methyl 0.10-0.39
Left side of 3.1 BBR-left 50-3.1 O-BBR-left 0.39-3.1
Furan (R) 1.56 BBR-furs 50-1.56 O-BBR-furan 0.10-0.39
Ao nationality of Olympic 100 BBR-ao 50-50 O-BBR-ao 0.10-25
As can be seen from table 1: 1) the activity of 8-octyl berberine to resist Hp is more than 100 times higher than that of berberine; 2) the berberine is combined with antibiotics, and has no synergistic effect on other antibiotics except for certain synergistic effect on omeprazole; 3) the 8-octyl berberine and the antibiotic are combined, so that the synergistic effect is strong, the antibacterial activity of the antibiotic can be obviously improved, and the anti-Hp activity of the antibiotic can be improved; however, 8-octyl berberine is compounded with levofloxacin, and no synergistic effect exists.

Claims (7)

1.8 application of octyl berberine salt in preparing medicine for resisting helicobacter pylori infection; the structural formula of the 8-octyl berberine salt is as follows:
Figure FDA0002577838350000011
wherein X is halogen.
2.8 application of a combined drug of octyl berberine salt and amoxicillin in preparing a drug for resisting helicobacter pylori infection.
3.8-octyl berberine salt and clarithromycin are used in the preparation of the anti-helicobacter pylori infection medicine.
4.8-octyl berberine salt and metronidazole are used in the preparation of the anti-helicobacter pylori infection medicine.
5.8-octyl berberine salt and furazolidone are used in the preparation of the anti-helicobacter pylori infection medicine.
6.8-octyl berberine salt and omeprazole are combined to prepare the anti-helicobacter pylori infection drug.
7. Use according to any one of claims 1 to 6, wherein: the raw material purity of the 8-octyl berberine salt is more than 99.0 percent in percentage by weight.
CN202010659071.8A 2020-07-09 2020-07-09 Application of 8-octyl berberine salt in preparation of anti-helicobacter pylori infection medicine Pending CN111686109A (en)

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Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN1974569A (en) * 2006-12-14 2007-06-06 西南大学 8-octyl berberine hydrochloride and its synthesis process and application
CN101367800A (en) * 2008-10-09 2009-02-18 西南大学 Synthesis of tubercle bacillus resistant medicament 3-alkoxyl-8-alkyl -12-R3-jatrorrhizine salt and uses thereof
CN111377913A (en) * 2020-03-19 2020-07-07 西南大学 9-alkoxy berberine salt, synthesis method and application

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN1974569A (en) * 2006-12-14 2007-06-06 西南大学 8-octyl berberine hydrochloride and its synthesis process and application
CN101367800A (en) * 2008-10-09 2009-02-18 西南大学 Synthesis of tubercle bacillus resistant medicament 3-alkoxyl-8-alkyl -12-R3-jatrorrhizine salt and uses thereof
CN111377913A (en) * 2020-03-19 2020-07-07 西南大学 9-alkoxy berberine salt, synthesis method and application

Non-Patent Citations (4)

* Cited by examiner, † Cited by third party
Title
K IWASA ET AL.: "Antibacterial activity and structure-activity relationships of berberine analogs", 《EUR J MED CHEM》 *
XIAOLI YE等: "Study of antihyperlipidemic effect on rabbits of 8-alkylberberine derivatives", 《JOURNAL OF MEDICINAL PLANTS RESEARCH》 *
张俊璇等: "根除幽门螺杆菌治疗药物的研究进展", 《医学综述》 *
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