CN105622563A - Pharmaceutical composition of bromhexine hydrochloride and medical application thereof - Google Patents
Pharmaceutical composition of bromhexine hydrochloride and medical application thereof Download PDFInfo
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- CN105622563A CN105622563A CN201610216945.6A CN201610216945A CN105622563A CN 105622563 A CN105622563 A CN 105622563A CN 201610216945 A CN201610216945 A CN 201610216945A CN 105622563 A CN105622563 A CN 105622563A
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- bromhexine hydrochloride
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- silica gel
- liver
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D311/00—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only hetero atom, condensed with other rings
- C07D311/02—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only hetero atom, condensed with other rings ortho- or peri-condensed with carbocyclic rings or ring systems
- C07D311/04—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring
- C07D311/58—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring other than with oxygen or sulphur atoms in position 2 or 4
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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
- A61K31/13—Amines
- A61K31/135—Amines having aromatic rings, e.g. ketamine, nortriptyline
- A61K31/137—Arylalkylamines, e.g. amphetamine, epinephrine, salbutamol, ephedrine or methadone
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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
- A61K31/35—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having six-membered rings with one oxygen as the only ring hetero atom
- A61K31/352—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having six-membered rings with one oxygen as the only ring hetero atom condensed with carbocyclic rings, e.g. methantheline
Abstract
The invention discloses a pharmaceutical composition of bromhexine hydrochloride and medical application thereof. The pharmaceutical composition of bromhexine hydrochloride contains bromhexine hydrochloride and a novel-structure natural product compound (I) separated from the dried aerial part of oriental wormwood. The bromhexine hydrochloride and compound (I) can enhance the GSH content in mouse hepatic tissues, lower the MDA (malondialdehyde) content, inhibit the accumulation of TG and have certain liver protection functions. The combination of the bromhexine hydrochloride and compound (I) has better treatment effect, and can be developed into liver protection drugs.
Description
Technical field
The invention belongs to biomedicine field, it relates to the novelty teabag of bromhexine hydrochloride, it is specifically related to the pharmaceutical composition of bromhexine hydrochloride and protects the medicinal use of liver.
Background technology
Bromhexine hydrochloride is the crystalline powder of white or off-white color; Without smelly, tasteless. In formic acid easily molten, micro-molten in methyl alcohol, atomic dissolving in second alcohol and water. The fusing point of this product is about 239 DEG C, decomposes during melting simultaneously.
Bromhexine hydrochloride can directly act on bronchial gland body, impels the lysosome of mucous secreting cell to disengage, and makes the sticky sugared fiber differentiation cracking in phlegm; Also can suppress the synthesis of acid glycoprotein in mucous gland and goblet cell, make it to secrete the lower micro-molecule glucoprotein of viscosity, thus the viscosity making phlegm liquid reduces, and is easy to expectoration. In addition, bromhexine hydrochloride causes respiratory tract glandular secretion to increase with also can stimulating stomach mucous membrane reflectivity, and phlegm liquid is diluted. The sticky phlegm not easily expectorations such as bronchitis, asthma, pulmonary emphysema.
Clinically, bromhexine hydrochloride is used for acute and chronic bronchitis, asthma, bronchiectasis, pulmonary emphysema, is especially applicable to the sticky productive cough of white and goes out difficulty person and extensively block the critical acute disease etc. that Bronchiole causes because of phlegm liquid.
At present, there is not yet bromhexine hydrochloride and pharmaceutical composition has the effect report protecting liver.
Summary of the invention
It is an object of the invention to provide the pharmaceutical composition of a kind of bromhexine hydrochloride, this pharmaceutical composition can be worked in coordination with a kind of natural product being separated the novel structure obtained from draft, bromhexine hydrochloride and this natural product containing bromhexine hydrochloride and protect liver.
The above-mentioned purpose of the present invention is achieved by technical scheme below:
A kind of compound (I) with following structural formula,
A pharmaceutical composition for bromhexine hydrochloride, the carrier comprising bromhexine hydrochloride, compound (I) as above and pharmaceutically can accepting.
The preparation method of compound as above (I), comprise following operation steps: the dry aerial parts of oriental wormwood are pulverized by (a), extract with 85��95% alcohol heat reflux, united extraction liquid, concentrate to without alcohol taste, successively with the n-butanol extraction of sherwood oil, ethyl acetate and water saturation, obtain petroleum ether extract, acetic acid ethyl ester extract and n-butyl alcohol extract respectively; B in () step (a), thing macroporous resin removal of impurities got by propyl carbinol, first with 30% ethanol elution, 9 column volumes, then with 90% ethanol elution, 12 column volumes, collect 90% elutriant, and concentrating under reduced pressure obtains 90% ethanol elution enriched material; C in () step (b), 90% ethanol elution enriched material purification on normal-phase silica gel is separated, the methylene chloride-methanol gradient elution being 125:1,65:1,30:1 and 15:1 by volume ratio successively obtains 4 components; D in () step (c), component 3 is separated further by purification on normal-phase silica gel, the methylene chloride-methanol gradient elution being 40:1,30:1 and 10:1 by volume ratio successively obtains 3 components; E in () step (d), component 2 reverse phase silica gel separation, is the methanol aqueous solution isocratic elution of 85% by concentration expressed in percentage by volume, collects 13��17 column volume elutriants, elutriant concentrating under reduced pressure obtains compound (I).
Further, step (a) is extracted with 90% alcohol heat reflux, united extraction liquid.
Further, described macroporous resin is D101 type macroporous adsorbent resin.
Further, described reverse phase silica gel is the reverse phase silica gel of octadecylsilane bonding.
Compound as above (I) protects the application in the medicine of liver in preparation.
The pharmaceutical composition of bromhexine hydrochloride as above protects the application in the medicine of liver in preparation.
The advantage of the present invention:
When the pharmaceutical composition of bromhexine hydrochloride provided by the invention acts on separately with a kind of natural product being separated the novel structure obtained from the dry aerial parts of oriental wormwood, bromhexine hydrochloride and this natural product containing bromhexine hydrochloride, there is hepatoprotective effect; During the two combined action, protect liver effect and improve further, it is possible to be developed to the medicine protecting liver.
Embodiment
The essentiality content of the present invention is described further below in conjunction with embodiment, but does not limit protection domain of the present invention with this. Although the present invention being explained in detail with reference to better embodiment, it will be understood by those within the art that, it is possible to the technical scheme of the present invention is modified or equivalent replacement, and do not depart from essence and the scope of technical solution of the present invention.
Embodiment 1: compound (I) separation preparation and structural identification
Separation method: the dry aerial parts (2kg) of oriental wormwood are pulverized by (a), (15L �� 3 time) are extracted with 90% alcohol heat reflux, united extraction liquid, concentrate to without alcohol taste (3L), extract with the propyl carbinol (3L �� 3 time) of sherwood oil (3L �� 3 time), ethyl acetate (3L �� 3 time) and water saturation successively, obtain petroleum ether extract, acetic acid ethyl ester extract and n-butyl alcohol extract respectively; Acetic acid ethyl ester extract D101 type macroporous resin removal of impurities in (b) step (a), first with 30% ethanol elution, 9 column volumes, again with 90% ethanol elution, 12 column volumes, collecting 90% elutriant, concentrating under reduced pressure obtains 90% ethanol elution enriched material; C in () step (b), 90% ethanol elution enriched material purification on normal-phase silica gel is separated, the methylene chloride-methanol gradient elution being 125:1 (11 column volumes), 65:1 (9 column volumes), 30:1 (9 column volumes) and 15:1 (8 column volumes) by volume ratio successively obtains 4 components; D in () step (c), component 3 is separated further by purification on normal-phase silica gel, the methylene chloride-methanol gradient elution being 40:1 (6 column volumes), 30:1 (8 column volumes) and 10:1 (6 column volumes) by volume ratio successively obtains 3 components; E reverse phase silica gel separation that in () step (d), component 2 is bonded by octadecylsilane, with the methanol aqueous solution isocratic elution that concentration expressed in percentage by volume is 85%, collect 13��17 column volume elutriants, elutriant concentrating under reduced pressure obtains compound (I) (521mg, HPLC normalization method purity is greater than 98%).
Structural identification: HR-ESI-MS shows [M+H]+For m/z419.1821, it is C that syncaryon magnetic feature can obtain molecular formula26H26O5, degree of unsaturation is 14. Hydrogen nuclear magnetic resonance modal data ��H(ppm, CD3OD, 500MHz): H-6 (6.58, s), H-7 (7.92, d, J=16.2Hz), H-8 (6.86, d, J=16.2Hz), H-10 (7.52, d, J=7.5Hz), H-11 (7.33, t, J=7.5Hz), H-12 (7.24, t, J=7.2Hz), H-13 (7.33, t, J=7.5Hz), H-14 (7.52, d, J=7.5Hz), H-1 ' (6.72, d, J=10.2Hz), H-2 ' (5.62, d, J=10.2Hz), H-4 ' (1.42, s), H-5 ' (2.06, m, 2H), H-6 ' (2.87, m, 2H), H-9 ' (1.80, s), H-10 ' (5.76, d, J=4.1Hz), H-10 ' (5.98, d, J=4.1Hz), 3-OMe (3.81, s), carbon-13 nmr spectra data ��C(ppm, CD3OD, 125MHz): 143.5 (C, 1-C), 102.5 (C, 2-C), 160.9 (C, 3-C), 110.3 (C, 4-C), 158.6 (C, 5-C), 108.4 (CH, 6-C), 130.5 (CH, 7-C), 131.4 (CH, 8-C), 138.9 (C, 9-C), 127.4 (CH, 10-C), 129.5 (CH, 11-C), 128.2 (CH, 12-C), 129.5 (CH, 13-C), 127.4 (CH, 14-C), 174.8 (C, 15-C), 117.4 (CH, 1 '-C), 128.9 (CH, 2 '-C), 80.7 (C, 3 '-C), 27.2 (CH3, 4 '-C), 37.1 (CH2, 5 '-C), 32.3 (CH2, 6 '-C), 204.1 (C, 7 '-C), 145.5 (C, 8 '-C), 17.2 (CH3, 9 '-C), 125.4 (CH2, 10 '-C), 62.3 (CH3, 3-OMe). Infrared spectrum shows that this compound contains carbonyl (1765cm-1), aromatic nucleus (1615cm-1, 1563m-1, 1451cm-1) group.13C-NMR, DEPT and hsqc spectrum show 26 carbon signals, comprise three methyl (methoxyl group), three methylene radical (an alkene carbon), ten methyne (four alkene carbon, six aromatic carbon), and ten quaternary carbons (six aromatic carbon, an alkene carbon, two carbonyls); In conjunction with unsaturated number, above functional structure shows that this compound is tricyclic structure again.1H-NMR spectrum exists one group without substituted benzene ring proton signal ��H7.52 (2H, d, J=7.5Hz), 7.33 (2H, t, J=7.5Hz) and 7.24 (1H, t, J=7.2Hz) and one group of trans olefins proton signal ��H7.92 (1H, d, J=16.2Hz) and 6.86 (1H, d, J=16.2Hz) imply there is trans stilbene fragment in structure, one group of cis-double bonds proton signal ��H6.72 (1H, d, J=10.2Hz) and 5.62 (1H, d, J=10.2Hz), one to same carbon olefin proton signal ��H5.76 (1H, d, J=4.1Hz) and 5.98 (1H, d, J=4.1Hz), two methene proton signal ��H2.06 (2H, m) and 2.87 (2H, m), two methyl proton signal ��H1.42 (3H, s) and 1.80 (3H, s), a methoxyl group proton signal ��H3.81 (3H, s). By13The chemical shift �� of C-3 and C-5 in C-NMR spectrumC-3160.9 and ��C-5158.6 known C-3, C-5 are all even oxygen carbon, and during another HMBC composes, the coherent signal of methoxyl group proton and C-3 demonstrates C-3 position and is connected with a methoxyl group, and H-1 ', H-2 ', H3-4����H2-5 ' and C-3 ' there is coherent signal, the chemical shift of C-3 ' is ��C-3��80.7 prompting C-3 ' are also for connecting oxygen carbon. H-1 ' and C-3 ' is there is, H in HMBC in composing3And C-2 ' and C-5 ' ,-4 ' H2And C-2 ', C-4 ' and C-7 ' ,-5 ' H3And C-7 ', C-8 ' and C-10 ' coherent signal ,-9 ' in conjunction with1H-1H-1 ' and H-2 ', H in HCOSY spectrum2-5 ' and H2-6 ' coherent signal, the signal chains of a C-1 '-C-10 ' can be built, the C-1 ' in this signal chains unit can be speculated by above information, phenyl ring C-4 in C-3 ' position and trans stilbene unit, be directly connected by the carbon-carbon respectively cyclisation that is connected with carbon-oxygen-carbon of C-5 position is benzopyran structure. HMBC also confirms the coherent signal of H-6 and C-7 and H-8 and C-1 in composing, thus known and trans stilbene unit mode of connection, H-6 and C-2 and C-15 coherent signal has then known that in structure, carboxyl is connected with C-2. 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 shown below, steric configuration is determined by ECD test further, and theoretical value and experimental value are basically identical.
This compound chemical formula and carbon atoms numbered are as follows:
Embodiment 2: pharmacological action
1, materials and methods
1.1 materials and instrument
Bromhexine hydrochloride is purchased from Nat'l Pharmaceutical & Biological Products Control Institute. Compound (I) is made by oneself, and preparation method is shown in embodiment 1. ICR female small white mouse body weight (25 �� 5) g, Shanghai Si Laike laboratory animal responsibility company limited; Coomassie brilliant G-250, triglyceride test kit, mda testing cassete, glutathione peroxidase test kit, ethanol dehydrogenase measure test kit Nanjing and build up Bioengineering Research Institute; Hai Wangjin cup, ShenZhen,GuangDong Hai Wang pharmaceutcal corporation, Ltd; 56 �� of Red Star strong, colourless liquor distilled from sorghum white wine, Beijing Red Star distillery. Christ company of Alpha-D2 Freeze Drying Equipment Germany; Electronic balance, Shanghai balance equipment factory; UV752N ultraviolet-visible pectrophotometer, Shanghai instrument electric analysis Instrument company limited.
1.2 animal groupings
By 72 ICR mouse in (22 �� 1) DEG C, humidity 40%��60%, 12h alternation of day and night, freely takes food, after adaptability feeds one week when intaking, is divided into six groups at random. Blank group 12: be left intact in experimentation, freely feed; The physiological saline of model group 12: 0.9%; Bromhexine hydrochloride group 12: concentration is 100mg/mL; Compound (I) group 12: concentration is 100mg/mL; Bromhexine hydrochloride and compound (I) composition group 12: concentration is 50mg/mL bromhexine hydrochloride+50mg/mL compound (I); Positive controls 12: concentration is extra large Wang Jin cup solution of 25mg/mL.
1.3 administration
Every Nikkei mouth gavage gives 20mL/kg BW given the test agent. Blank group does not do any gavage, freely takes food, intakes; Model control group gives physiological saline by body weight, successive administration 30d. Weigh weekly once, adjust dosage according to body weight. At the end of giving given the test agent, giving white wine 5mL/kg BW by model control group and each sample group gavage, blank group is to distilled water.
1.4 liver sample preparations
After last administration, water 12h is can't help in fasting, the dislocation of mouse cervical vertebra is put to death, dissects and take out complete liver, and pre-cold saline cleans to washing lotion without, after color, blotting liver surface moisture. Cut and get 0.1g liver organization and be placed in small beaker (in frozen water), prepare 9 times (0.9mL) in liver organization weight 0.9% physiological saline, the physiological saline of transfer total amount 2/3 is in beaker, shred tissue block as early as possible, pour glass homogenizer into, remaining 1/3 normal saline flushing is remained in the broken tissue block in beaker again, pour homogenate tube together into and carry out homogenate, fully make the tissue homogenate of 10% after grinding, with the centrifugal 15min of 2000r/min in whizzer, get supernatant liquor for subsequent use.
1.5 Testing index
Mouse body weight: weigh weekly a mouse body weight, until experiment terminates, to investigate given the test agent to the impact of each group of mouse body weight. Hepatic tissue index determining: GSH, MDA and TG content in each group hepatic tissue, ADH determination of activity carries out according to each test kit specification sheets operation steps.
1.3 data statistics
Data all represent with (mean value �� standard deviation), group difference adopts SPSS16.0 to carry out single factor analysis (ANOVA), determines whether difference has statistical significance with P < 0.05 or P < 0.01.
2, experimental result
2.1 on the impact of gsh, mda content
The total content of liver gsh (GSH) is the important indicator evaluating medicine facilitating alcohol metabolism and protecting liver function. As shown in Table 1, comparing with blank group, model group mouse is after white wine gavage, and liver gsh content extremely significantly reduces (P < 0.01), and this model modeling success is described. Positive controls extremely significantly raises (P < 0.01) with GSH content in compound (I) composition group mouse liver even slurry with bromhexine hydrochloride compared with model group, and in bromhexine hydrochloride group, compound (I) group mouse liver even slurry, GSH content also obviously raises (P < 0.05). Composition can maintain liver gsh content, and the liver GSH that Anti-ethanol damage causes exhausts, it is to increase the ability of body scavenging free radicals, thus is played a protective role by mouse liver. Owing to GSH can stop peroxidatic reaction of lipid in hepatic tissue to a certain extent, and mda (MDA) is one of product of peroxidatic reaction of lipid, and therefore the reduction of GSH concentration can cause the increase of liver MDA content indirectly. As shown in Table 1, comparing with blank group, after model group mouse stomach, liver MDA content extremely significantly raises (P < 0.01), and this model modeling success is described. Positive controls significantly declines compared with model group with bromhexine hydrochloride and MDA content in compound (I) composition group mouse liver even slurry P (< 0.01), bromhexine hydrochloride group, compound (I) group also shows MDA content and obviously declines, significance level (P < 0.05).
Table 1 given the test agent is on the impact of GSH, MDA content in murine liver tissue
| Group | GSH(mmol/L) | MDA(nmol/mgprot) |
| Blank group | 26 | 5.1 |
| Model group | 16 | 11.8 |
| Positive controls | 27 | 5.7 |
| Bromhexine hydrochloride group | 23 | 7.3 |
| Compound (I) group | 23 | 7.5 |
| Bromhexine hydrochloride and compound (I) composition group | 28 | 5.2 |
2.2 on the impact of content of triglyceride
When body takes in a large amount of ethanol, ethanol is oxidized in a large number under the effect of ethanol dehydrogenase so that tricarboxylic acid cycle and metabolism of fat are obstructed so that triglyceride level (TG) is constantly piled up in liver, not only can bring out comparatively serious cardiovascular disorder, also can cause fatty liver. As shown in Table 2, comparing with blank group, model group mouse liver tissue T G content extremely significantly raises (P < 0.01), and this model modeling success is described. Comparing with model group, in bromhexine hydrochloride and compound (I) composition group and positive controls mouse liver even slurry, TG content extremely significantly reduces (P < 0.01). In this experiment; each medicine group all shows and reduces drunk mouse liver TG content, and composition group all reaches pole conspicuous level (P < 0.01), illustrates that this composition can reduce drunk mouse liver tissue T G content; alleviate liver fat to pile up, play the effect of protection liver.
Table 2 given the test agent is on the impact of TG content in murine liver tissue
| Group | TG(mmol/L) |
| Blank group | 0.7��0.04 |
| Model group | 1.6��0.08 |
| Positive controls | 0.7��0.03 |
| Bromhexine hydrochloride group | 1.0��0.05 |
| Compound (I) group | 0.9��0.06 |
| Bromhexine hydrochloride and compound (I) composition group | 0.7��0.04 |
Above-mentioned test shows, bromhexine hydrochloride, compound (I) can improve GSH content in murine liver tissue, reduces MDA content, suppresses the accumulation of TG, has certain hepatoprotective effect; When bromhexine hydrochloride and compound (I) conbined usage, result for the treatment of is better, can be developed into hepatic.
The effect of above-described embodiment is to illustrate 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 the technical scheme of the present invention is modified or equivalent replacement, and do not depart from essence and the protection domain of technical solution of the present invention.
Claims (8)
1. one kind has the compound (I) of following structural formula,
2. the pharmaceutical composition of a bromhexine hydrochloride, it is characterised in that: the carrier comprising bromhexine hydrochloride, compound (I) as claimed in claim 1 and pharmaceutically can accepting.
3. the preparation method of compound according to claim 1 (I), it is characterized in that, comprise following operation steps: the dry aerial parts of oriental wormwood are pulverized by (a), extract with 85��95% alcohol heat reflux, united extraction liquid, concentrate to without alcohol taste, successively with the n-butanol extraction of sherwood oil, ethyl acetate and water saturation, obtaining petroleum ether extract, acetic acid ethyl ester extract and n-butyl alcohol extract respectively; B in () step (a), thing macroporous resin removal of impurities got by propyl carbinol, first with 30% ethanol elution, 9 column volumes, then with 90% ethanol elution, 12 column volumes, collect 90% elutriant, and concentrating under reduced pressure obtains 90% ethanol elution enriched material; C in () step (b), 90% ethanol elution enriched material purification on normal-phase silica gel is separated, the methylene chloride-methanol gradient elution being 125:1,65:1,30:1 and 15:1 by volume ratio successively obtains 4 components; D in () step (c), component 3 is separated further by purification on normal-phase silica gel, the methylene chloride-methanol gradient elution being 40:1,30:1 and 10:1 by volume ratio successively obtains 3 components; E in () step (d), component 2 reverse phase silica gel separation, is the methanol aqueous solution isocratic elution of 85% by concentration expressed in percentage by volume, collects 13��17 column volume elutriants, elutriant concentrating under reduced pressure obtains compound (I).
4. the preparation method of compound according to claim 3 (I), it is characterised in that: step (a) is extracted with 90% alcohol heat reflux, united extraction liquid.
5. the preparation method of compound according to claim 3 (I), it is characterised in that: described macroporous resin is D101 type macroporous adsorbent resin.
6. the preparation method of compound according to claim 3 (I), it is characterised in that: described reverse phase silica gel is the reverse phase silica gel of octadecylsilane bonding.
7. compound according to claim 1 (I) protects the application in the medicine of liver in preparation.
8. the pharmaceutical composition of bromhexine hydrochloride according to claim 2 protects the application in the medicine of liver in preparation.
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| WO2017220044A3 (en) * | 2016-06-23 | 2018-02-15 | 赵吉永 | Bifonazole pharmaceutical composition and liver-protecting effect thereof |
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