CN105801525A - Cobamamide pharmaceutical composition and medical application thereof - Google Patents
Cobamamide pharmaceutical composition and medical application thereof Download PDFInfo
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- CN105801525A CN105801525A CN201610380055.9A CN201610380055A CN105801525A CN 105801525 A CN105801525 A CN 105801525A CN 201610380055 A CN201610380055 A CN 201610380055A CN 105801525 A CN105801525 A CN 105801525A
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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
- A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
- A61K31/336—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having three-membered rings, e.g. oxirane, fumagillin
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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
- A61K31/70—Carbohydrates; Sugars; Derivatives thereof
- A61K31/7135—Compounds containing heavy metals
- A61K31/714—Cobalamins, e.g. cyanocobalamin, i.e. vitamin B12
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D301/00—Preparation of oxiranes
- C07D301/32—Separation; Purification
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D303/00—Compounds containing three-membered rings having one oxygen atom as the only ring hetero atom
- C07D303/02—Compounds containing oxirane rings
- C07D303/12—Compounds containing oxirane rings with hydrocarbon radicals, substituted by singly or doubly bound oxygen atoms
- C07D303/32—Compounds containing oxirane rings with hydrocarbon radicals, substituted by singly or doubly bound oxygen atoms by aldehydo- or ketonic radicals
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Abstract
The invention discloses a cobamamide pharmaceutical composition and medical application thereof.The cobamamide pharmaceutical composition contains cobamamide and a natural product compound (I) novel in structure.The cobamamide and the natural product compound (I) have a certain treatment effect on alopecia when acting independently and have a better treatment effect on alopecia when acting jointly, and can be developed as medicines for treating alopecia accordingly.Compared with the prior art, the cobamamide pharmaceutical composition and medical application thereof have prominent substantive features and make remarkable progress.
Description
Technical field
The invention belongs to biomedicine field, relate to the new application of cobamamide, be specifically related to the pharmaceutical composition of cobamamide and the application in alopecia thereof.
Background technology
Cobamamide is mainly used in megaloblastic anemia, malnutritional anemia, anemia in pregnancy, also for neurological disorder such as polyneuritis, radiculitis, trigeminal neuralgia, sciatica, neural paralysis, trophic nerve illness and lonizing radiation and drug-induced leukopenia.
Up to now, there is not yet the dependency of cobamamide and pharmaceutical composition thereof and alopecia report.
Summary of the invention
It is an object of the invention to provide the pharmaceutical composition of a kind of cobamamide, containing the natural product of cobamamide and a kind of novel structure, cobamamide and this natural product in this pharmaceutical composition can Synergistic treatment alopecia.
The above-mentioned purpose of the present invention is achieved by the techniques below scheme:
A kind of compound (I) with following structural formula,
The pharmaceutical composition of a kind of cobamamide, including cobamamide, compound as claimed in claim 1 (I) and pharmaceutically acceptable carrier, prepares into the dosage form of needs.
Further, pharmaceutically acceptable carrier includes diluent, excipient, filler, binding agent, wetting agent, disintegrating agent, absorption enhancer, surfactant, absorption carrier or lubricant.
Further, described dosage form includes tablet, capsule, oral liquid, sucks agent, granule, electuary, pill, powder, unguentum, sublimed preparation, suspensoid, powder, solution, injection, suppository, spray, drop or patch.
The preparation method of above-claimed cpd (I), comprise following operating procedure: Herba Equiseti Hiemalis is pulverized by (a), extract with 75～85% alcohol heat reflux, united extraction liquid, it is concentrated into without alcohol taste, successively with petroleum ether, ethyl acetate and water saturated n-butanol extraction, respectively obtain petroleum ether extract, acetic acid ethyl ester extract and n-butyl alcohol extract；B in () step (a), n-butyl alcohol takes thing macroporous resin remove impurity, first with 8 column volumes of 25% ethanol elution, then with 12 column volumes of 70% ethanol elution, collect 70% eluent, and concentrating under reduced pressure obtains 70% ethanol elution concentrate；In (c) step (b) 70% ethanol elution concentrate with purification on normal-phase silica gel separate, successively with volume ratio be 85:1,45:1,25:1 and 15:1 methylene chloride-methanol gradient elution obtain 4 components；D in () step (c), component 4 separates further by purification on normal-phase silica gel, successively with volume ratio be 20:1,15:1 and 1:1 methylene chloride-methanol gradient elution obtain 3 components；E reverse phase silica gel that in () step (d), component 2 is bonded by octadecylsilane separates, with the methanol aqueous solution isocratic elution that concentration expressed in percentage by volume is 72%, collecting 10～16 column volume eluents, eluent concentrating under reduced pressure obtains compound (I).
Further, in the preparation method of compound (I), described macroporous resin is D101 type macroporous adsorbent resin.
The above-claimed cpd (I) application in the medicine preparing hair growth.
The application in the medicine preparing hair growth of the pharmaceutical composition of above-mentioned cobamamide.
Advantages of the present invention:
The pharmaceutical composition of cobamamide provided by the invention contains the natural product of cobamamide and a kind of novel structure, when cobamamide and this natural product independent role, alopecia is had therapeutical effect；During the two synergy, the therapeutic effect of alopecia is improved further, it is possible to develop into the medicine of hair growth.The present invention compared with prior art has prominent substantive distinguishing features and significant progressive.
Detailed description of the invention
Further illustrate the essentiality content of the present invention below in conjunction with embodiment, but do not limit scope with this.Although the present invention being explained in detail with reference to preferred embodiment, it will be understood by those within the art that, it is possible to technical scheme is modified or equivalent replacement, without deviating from the spirit and scope of technical solution of the present invention.
Embodiment 1: compound (I) separates preparation and structural identification
Separation method: Herba Equiseti Hiemalis (2kg) is pulverized by (a), (15L × 3 time) are extracted with 80% alcohol heat reflux, united extraction liquid, it is concentrated into without alcohol taste (3L), extract with petroleum ether (3L × 3 time), ethyl acetate (3L × 3 time) and water saturated n-butyl alcohol (3L × 3 time) successively, respectively obtain petroleum ether extract, acetic acid ethyl ester extract and n-butyl alcohol extract；B acetic acid ethyl ester extract D101 type macroporous resin remove impurity in () step (a), first with 8 column volumes of 25% ethanol elution, then with 12 column volumes of 70% ethanol elution, collects 70% eluent, concentrating under reduced pressure obtains 70% ethanol elution concentrate；C in () step (b), 70% ethanol elution concentrate purification on normal-phase silica gel separates, obtain 4 components with the methylene chloride-methanol gradient elution that volume ratio is 85:1 (10 column volumes), 45:1 (8 column volumes), 25:1 (10 column volumes) and 15:1 (8 column volumes) successively；D in () step (c), component 4 separates further by purification on normal-phase silica gel, obtain 3 components with the methylene chloride-methanol gradient elution that volume ratio is 20:1 (10 column volumes), 15:1 (8 column volumes) and 1:1 (6 column volumes) successively；E reverse phase silica gel that in () step (d), component 2 is bonded by octadecylsilane separates, with the methanol aqueous solution isocratic elution that concentration expressed in percentage by volume is 72%, collecting 10～16 column volume eluents, eluent concentrating under reduced pressure obtains compound (I) (HPLC normalization purity is more than 98%).
Structural identification: white amorphous powder；HR-ESI-MS shows [M+Na]+For m/z321.1804, can obtain molecular formula in conjunction with nuclear-magnetism feature is C20H26O2, degree of unsaturation is 8.Hydrogen nuclear magnetic resonance modal data δH(ppm, DMSO-d6, 600MHz): H-1 (6.67, s), H-4 (2.86, d, J=10.5), H-5 (5.21, d, J=10.5), H-7 α (2.52, dt, J=13.1, 3.1), H-7 β (1.71, m), H-8 α (2.10, m), H-8 β (1.41, m), H-9 (1.01, m), H-11 (1.33, m), H-12 (5.24, m), H-14 (3.12, s), H-16 (1.75, s), H-17 (1.45, s), H-18 (1.08, s), H-19 (0.96, s), H-20 (1.72, d, J=1.2)；Carbon-13 nmr spectra data δC(ppm, DMSO-d6, 150MHz): 152.3 (CH, 1-C), 140.8 (C, 2-C), (197.4 C, 3-C), 54.3 (CH, 4-C), 116.9 (CH, 5-C), 146.3 (C, 6-C), 36.4 (CH2, 7-C), 28.2 (CH2, 8-C), 34.3 (CH, 9-C), 25.1 (C, 10-C), (29.7 CH, 11-C), 128.7 (CH, 12-C), 136.4 (C, 13-C), (72.6 CH, 14-C), 60.5 (C, 15-C), 10.6 (CH3, 16-C), 20.2 (CH3, 17-C), 28.7 (CH3, 18-C), 16.2 (CH3, 19-C), 11.6 (CH3, 20-C).1H-NMR spectrum five methyl signals [δ H0.96 (s of display, Me-19), 1.08 (s, Me-18), 1.45 (s, Me-17), 1.72 (d, J=1.2Hz, Me-20) and 1.75 (s, Me-16)], three olefinic methine proton signal [δ H5.21 (d, J=10.5Hz, H-5), 5.24 (m, H-12) and 6.67 (s, ], and an oxygen-containing methine proton signal [δ H3.12 (s, H-14)] H-1).13C-NMR spectrum shows 20 carbon signals, including five methyl, two methylene, seven methines (an oxygen-containing methine, three olefinic methines), and six quaternary carbons (carbonyl, three alkene quaternary carbons, an oxygen-containing quaternary carbon).In HMBC spectrum, H-1 (δ H6.67) and C-2 (δ C140.8), C-3 (δ C197.4), C-4 (δ C54.3), C-15 (δ C60.5) and C-16 (δ C10.6), and Me-16 (δ H1.75) and C-1 (δ C152.3), the dependency of C-2 and C-3 shows that A ring contains α, beta-unsaturated carbonyl structure.By the analysis of nuclear magnetic data this compound known is contained a cyclopropane moiety.In HMBC spectrum, the dependency of methyl proton signal Me-18 (δ H1.08) and Me-19 (δ H0.96) and cyclopropane methine C-9 (δ C34.3) and C-11 (δ C29.7), and the nuclear magnetic signal of C-10 position (δ C25.1) shows that C-10 position is connected with two methyl.Oxygen-containing proton signal (δ H3.12, s, H-14) and corresponding carbon signal (δ C72.6, C-14 and 60.5, C-15) show that this compound contains an epoxy construction.In ROESY spectrum, the dependency of H-9 α/H-11 α, H-8 α, Me-18/H-9 α, H-11 α, H-5/H-7 β, H-7 α/H-8 α and H-4/Me-17 shows that H-4, H-9 and H-11 are α configuration.Additionally, the correlated performance of H-5 and Me-17 and H-12 and Me-20 shows double bond respectively Z and the E of C-5 and C-6, C-12 and C-13.Comprehensive hydrogen spectrum, carbon spectrum, HMBC spectrum and ROESY spectrum, and document is about correlation type nuclear magnetic data, can substantially determine that this compound is as follows, spatial configuration is determined by ECD test further, and theoretical value is basically identical with experiment value.
This compound chemistry formula and carbon atoms numbered are as follows:
Embodiment 2: pharmacological action
Alopecia is the most common skin diseases of one.For a long time, people are devoted to the medicine finding and researching and developing hair growth always, such as glucocorticoid, minoxidil etc..But up to the present, still do not have a kind of medicine can cure alopecia completely, and there is bigger untoward reaction.Therefore, the medicine of the preventing and treating alopecia develop determined curative effect, having no adverse reaction has important social meaning and economic implications.The present embodiment adopts cyclophosphamide (Cyclophosphamide, CTX) to set up mice depilation model, observes the medicine effect to improving depilation mouse hair growth.
1, materials and methods
1.1 animals
SPF level, male C57BL/6 mice, weight 18～20g, Shanghai Slac Experimental Animal Co., Ltd..Feeding environment: room temperature controls at 24～26 DEG C, the every 12h light and shade of light alternately, ad lib, the next day change bedding and padding.
1.2 reagent and sample
Cobamamide is purchased from Nat'l Pharmaceutical & Biological Products Control Institute.Compound (I) is made by oneself, and preparation method is shown in embodiment 1.Cyclophosphamide (Hengrui Medicine Co., Ltd., Jiangsu Prov.).CBA detection kit (U.S., BD company), CD4 detection kit (Shanghai Ying Xin laboratory equlpment company limited), CD8 detection kit (Shanghai Ying Xin laboratory equlpment company limited).
1.3 instruments
JEM-1010 type Electronic Speculum (Japan, NEC company), C6 type flow cytometer (U.S., BD company), MK3 type microplate reader (U.S., Thermo company).
Prepared by 1.4 mice group and model
C57BL/6 mice anesthetic machine is anaesthetized.After anesthesia, Colophonium and paraffin are melted in the ratio Hybrid Heating of 1: 1, and uniform application are in item back, solidify hardening after throw off, induced growth phase hair, every mice depilation area is about 2.0cm × 2.0cm.Note not burned mouse skin.Losing hair or feathers latter 9 days (generation of mouse back skin induced growth phase hair follicle), according to table of random number, mice is divided into 5 groups, often group 20, is blank group, model control group, cobamamide group (280mg kg respectively-1), compound (I) group (280mg kg-1), cobamamide and compound (I) compositions group [140mg kg-1Cobamamide+140mg kg-1Compound (I)].After all mices depilation district subcutaneous injection CTX150mg/kg, model group gives free rein to growth, and blank group gives the treatment of normal saline (100mg/kg) gavage, and other respectively organize the treatment of medicine gavage, continue 8 weeks.
1.5 tissue samplings
Difference 1,2,4,8 weeks upon administration, often group randomly selects each 5 of mice, and row eye socket is taken a blood sample, every 1～2mL.Detecting for ELISA: often group takes 2 blood samples, add EDTA anticoagulant, the centrifugal 30min of 3000r/min takes supernatant, saves backup in-20 DEG C.For Flow cytometry: often group takes 3 blood samples, separate serum, save backup in-70 DEG C.All animals are put to death after taking blood immediately, take its epilating area skin histology.Fixing through 10% formalin, routine paraffin wax embeds, paraffin section, and slice thick 4～5 μm saves backup at-80 DEG C.
1.6ELISA detects peripheral blood CD4+、CD8+Expression
20min is balanced under sample room temperature.Standard sample wells, sample aperture and blank well are set.What is all not added with blank well, and standard sample wells respectively adds the standard substance 50 μ L of variable concentrations.Sample to be tested first adds Sample dilution 40 μ L, add sample to be tested 10 μ L again, standard sample wells and sample aperture (blank well is not added with) add the detection antibody 100 μ L of horseradish peroxidase-labeled subsequently, seal reacting hole with shrouding film, and 37 DEG C of calorstats hatch 60min.Discarding liquid, absorbent paper pats dry, every hole adds cleaning mixture, stands 1min, gets rid of cleaning mixture, absorbent paper pats dry, repeat 5 times.The each 50 μ L of porose addition substrate A, B, 37 DEG C of lucifuges hatch 15min.Add in stop buffer 50 μ L, 15min, measure each hole OD value at 450nm wavelength place.The OD value of statistics CD4 and CD8, carries out statistical analysis as a result by CD4/CD8 average.
1.7 statistical methods
Result is with mean ± standard deviationRepresent.Adopt SPSS17.0 statistical software analytical data, between group, compare application one factor analysis of variance.
2, experimental result
2.1 changes of body mass and hair growth situation
Mice is terminated to experiment through CTX induction depilation, each group Mice Body quality no significant difference (P > 0.05).Depilation mice through cobamamide, compound (I), cobamamide and compound (I) compositions administration after 1～2 week, each group mice depilation district local skin is transformed into grey black gradually by pink colour, and mice depilation skin grey black region, district is substantially big than model group and normal saline group；Being administered to 4～8 weeks, each group mice depilation district is black, and has hair to grow gradually, extends.Administration group hair is relative to model group and normal saline group, and hair is more fine and close.
2.2 couples of depilation mouse peripheral blood CD4+/CD8+The impact of ratio expression
Cobamamide group, compound (I) group, cobamamide group and compound (I) compositions group peripheral blood CD4+/CD8+Ratio prolongation over time, on a declining curve.1,2,3,4 weeks, with model control group ratio, cobamamide group and compound (I) compositions group peripheral blood CD4+/CD8+Ratio is remarkably decreased (P < 0.01)；With model control group ratio, cobamamide group, compound (I) group peripheral blood CD4+/CD8+Ratio declines (P < 0.05).
Result of the test is in Table 1.
Table 1 is to depilation mouse peripheral blood CD4+/CD8+The impact of ratio expression
| Group | 1 week | 2 weeks | 3 weeks | 4 weeks |
| Model control group | 5.26±0.06 | 5.15±0.05 | 4.92±0.09 | 4.85±0.11 |
| Cobamamide group | 5.13±0.05 | 4.67±0.06 | 4.52±0.17 | 4.14±0.08 4 --> |
| Compound (I) group | 4.65±0.02 | 4.21±0.13 | 4.31±0.06 | 3.77±0.27 |
| Cobamamide and compound (I) compositions group | 3.79±0.04 | 3.34±0.02 | 3.06±0.25 | 2.86±0.08 |
The depilation the most frequently used laboratory animal of model is C57BL/6 mice, and owing to it is coloured kind, skin color shows different colors with the growth of hair follicle, is research hair follicle development and a kind of well laboratory animal of regeneration.
At present not yet clear and definite about the pathophysiological mechanism of alopecia, it is possible to reason main factor is relevant to local infection, neurotoxic substance, spirit depressing, endocrine factors etc..Recently as heredity, gene, molecular level development, domestic and international many scholars think that alopecia is mainly a kind of autoimmune inflammation disease immune-mediated by T cell, it is exposed to potential immunocompetent immune system owing to hair follicle is abnormal, antigenic substance again through hair follicle activates powerful immune system, bring out a large amount of inflammation of release, then cause alopecia.CD4+And CD8+T cell in hair loss patient hair follicle and around infiltration be the key causing alopecia, CD8+T cell is considered the hair follicle direct cytotoxicity of performance always, and CD4+T cell plays auxiliary cytosis, and in the pathogenic process of alopecia, both play a role jointly.
Depilation mice is had obvious curative effects with compound (I) compositions maintaining treatment by cobamamide, compound (I), cobamamide group, significantly improves the hair growth situation in mice depilation district, by lowering peripheral blood CD4+/CD8+Ratio plays a role, and the Drug therapy for clinical alopecia provides new therapeutic scheme.Wherein, when cobamamide and compound (I) synergy, the improvement result effect of hair growth is notable, it is better than cobamamide or the independent action effect of compound (I), it is possible to develop into the medicine of preventing and treating alopecia.
The effect of above-described embodiment indicates that the essentiality content of the present invention, but does not limit protection scope of the present invention with this.It will be understood by those within the art that, it is possible to technical scheme is modified or equivalent replacement, without deviating from essence and the protection domain of technical solution of the present invention.
Claims (8)
1. a compound (I) with following structural formula,
2. the pharmaceutical composition of a cobamamide, it is characterised in that: include cobamamide, compound as claimed in claim 1 (I) and pharmaceutically acceptable carrier, prepare into the dosage form of needs.
3. the pharmaceutical composition of cobamamide according to claim 2, it is characterised in that: pharmaceutically acceptable carrier includes diluent, excipient, filler, binding agent, wetting agent, disintegrating agent, absorption enhancer, surfactant, absorption carrier or lubricant.
4. the pharmaceutical composition of cobamamide according to claim 2, it is characterised in that: described dosage form includes tablet, capsule, oral liquid, sucks agent, granule, electuary, pill, powder, unguentum, sublimed preparation, suspensoid, powder, solution, injection, suppository, spray, drop or patch.
5. the preparation method of the compound (I) described in claim 1, it is characterized in that, comprise following operating procedure: Herba Equiseti Hiemalis is pulverized by (a), extract with 75～85% alcohol heat reflux, united extraction liquid, it is concentrated into without alcohol taste, successively with petroleum ether, ethyl acetate and water saturated n-butanol extraction, respectively obtains petroleum ether extract, acetic acid ethyl ester extract and n-butyl alcohol extract；B in () step (a), n-butyl alcohol takes thing macroporous resin remove impurity, first with 8 column volumes of 25% ethanol elution, then with 12 column volumes of 70% ethanol elution, collect 70% eluent, and concentrating under reduced pressure obtains 70% ethanol elution concentrate；In (c) step (b) 70% ethanol elution concentrate with purification on normal-phase silica gel separate, successively with volume ratio be 85:1,45:1,25:1 and 15:1 methylene chloride-methanol gradient elution obtain 4 components；D in () step (c), component 4 separates further by purification on normal-phase silica gel, successively with volume ratio be 20:1,15:1 and 1:1 methylene chloride-methanol gradient elution obtain 3 components；E reverse phase silica gel that in () step (d), component 2 is bonded by octadecylsilane separates, with the methanol aqueous solution isocratic elution that concentration expressed in percentage by volume is 72%, collecting 10～16 column volume eluents, eluent concentrating under reduced pressure obtains compound (I).
6. the preparation method of compound according to claim 5 (I), it is characterised in that: described macroporous resin is D101 type macroporous adsorbent resin.
7. the application in the medicine preparing hair growth of the compound (I) described in claim 1.
8. the pharmaceutical composition of the arbitrary described cobamamide of claim 2～4 application in the medicine preparing hair growth.
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Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
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| CN106279344A (en) * | 2016-08-14 | 2017-01-04 | 吴芊葭 | A kind of native compound separated from Radix Saposhnikoviae and preparation method thereof, medical applications |
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Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
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| CN106279344A (en) * | 2016-08-14 | 2017-01-04 | 吴芊葭 | A kind of native compound separated from Radix Saposhnikoviae and preparation method thereof, medical applications |
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Application publication date: 20160727 |