CN103193772A - Preparation method and application of substituted aryl propionic berberine ion-pair compound - Google Patents
Preparation method and application of substituted aryl propionic berberine ion-pair compound Download PDFInfo
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- CN103193772A CN103193772A CN201310103924XA CN201310103924A CN103193772A CN 103193772 A CN103193772 A CN 103193772A CN 201310103924X A CN201310103924X A CN 201310103924XA CN 201310103924 A CN201310103924 A CN 201310103924A CN 103193772 A CN103193772 A CN 103193772A
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Abstract
The invention relates to a preparation method and an application of a substituted aryl propionic berberine ion-pair compound. The substituted aryl propionic berberine ion-pair compound prepared by adopting the preparation method can be prepared into tablets, capsules, injections and gels and can be also prepared into suppositories applied to one part of the rectum and the vagina and lotions. The medicinal preparation prepared from the substituted aryl propionic berberine ion-pair compound has the effects of resisting bacteria, inflammation, cardiac failure and platelet aggregation, lowering blood pressure and treating hypertension, peptic ulcer and diabetes. The substituted aryl propionic berberine ion-pair compound has the pharmacological effect of the berberine hydrochloride and the pharmacological effect of the aryl propionic anti-inflammatory medicament.
Description
Technical field
The invention belongs to medical technical field, specifically arylprop acids medicine reacts substituted aryl phenoxy propionic acid Berberine ion-pair compound and the purposes made from berberine hydrochloride.
Background technology
Berberine (is Berberine: be Berberine) a kind of quaternary ammonium steroid alkaloid extracted from the plant roots and stems such as the coptis, golden cypress, Root of Chinese Barberry, Mahonia fortunei.Clinically multiplex its hydrochloride (Bererini Hydrochclorium: Berberine Hydrochloride), molecular formula: C20H18ClNO4
.2H2O, molecular weight: 407. 85.Its outward appearance is yellow needle-like crystal or powder, and odorless, flavor are extremely bitter.While being heated to 160-220 ℃, decompose, complete melting in the time of 278-280 ℃, be soluble in hot water, be slightly soluble in cold water or ethanol, the atomic chloroform that is dissolved in, be insoluble to ether (Jiang Biao. extract Bererini Hydrochclorium from golden cypress. guizhou chemical industry .2005,30,56-57.).
Traditional medicine thinks that Berberine is inhibited to Gram-positive, negative bacterium, and clinical application mainly is confined to the treatment of the diseases such as intestinal tract infections that dysentery bacterium, people enterobacteria, streptococcus aureus etc. cause, eye conjunctivitis.In recent years, a large amount of research reports show, Berberine can be used as antidiabetic medicine, compares with common antidiabetic drug and Chinese medicine and at least has drug effect steadily lasting, safe without toxic side effect, not only hypoglycemic but also prevent and treat complication, with other drug, the six large advantages such as good synergy, the single system easy to control the quality of composition, aboundresources be cheap arranged.
Aryl propionic non-steroid antiphlogistic is the anti-inflammation and analgesic drugs of commonly using clinically, has analgesic, analgesia significantly, anti-inflammatory effect, primary treatment sacroiliitis, alleviates broad variety that such as flu, dysmenorrhoea etc. cause slightly and moderate pain.
The diabetic subject is often with non-infectious inflammation.The present invention is combined into prodrug by base phenylpropionic acid NSAID (non-steroidal anti-inflammatory drug) such as Berberine and Ibuprofen BP/EP virtues, resolves in vivo original two parent drugs after administration, synergy occurs, and curative effect is strengthened, and reduces patient's dosage, enlarges clinical application range.And hydrochloride side effect potential risks have been avoided, the security that greatly improves medicine.
Summary of the invention
One of the object of the invention just is to provide a kind of synthetic method of aryl propionic non-steroid antiphlogistic Berberine ion-pair compound.Technique is simple, with low cost, environmental pollution is little, is applicable to industrial production.The present invention be take Berberine as raw material, and respectively with Ibuprofen BP/EP, flurbiprofen, loxoprofen, fenoprofen, Ketoprofen and Naproxen Base salify, its preparation process can be expressed with following reaction formula:
Two of purpose of the present invention is to provide the novel drugs that can be effective to treat diabetes, the present invention is combined into prodrug by non-steroidal arylpropionic acid antiphlogistic drug and two parent drugs of Bererini Hydrochclorium, resolve in vivo original two parent drugs after administration, synergy occurs, make the non-bacterial infection inflammatory patients to obtain medical treatment simultaneously; It is the innovation greatly on the treatment diabetes medicament.
The pharmaceutical preparation of aryl propionic non-steroid antiphlogistic berberine salt of the present invention also has the effects such as antisepsis and anti-inflammation, heart failure resistance, platelet aggregation-against, treatment hypertension, reducing blood-fat, treatment peptide ulceration.
In aryl propionic non-steroid antiphlogistic berberine salt preparation provided by the present invention, can be made into crystalline hydrate, so the aryl propionic non-steroid antiphlogistic berberine salt also comprises its crystalline hydrate.
Aryl propionic non-steroid antiphlogistic berberine salt of the present invention, adopt appropriate auxiliary material and preparation method, can make various pharmaceutical dosage forms, for example injection liquid, gelifying agent, tablet for oral use, capsule, the suppository (rectum and vaginal application) that also can be made into the confession topical application and lotion etc.
Embodiment
By the following examples, aryl propionic non-steroid antiphlogistic Berberine ion-pair compound of the present invention is done further and illustrated, but do not mean that embodiment is limitation of the present invention.
The preparation of embodiment 1 Ibuprofen BP/EP Berberine ion-pair compound
In 2000 mL reaction flasks, add berberine hydrochloride 33.6 g (0.1 mol), add 1500 mL distilled water, heating is dissolved berberine hydrochloride, adds 10% sodium carbonate solution, regulates pH to 8.5-9.0, stirring reaction 1 h; Add Ibuprofen BP/EP, back flow reaction 2 h, crystallisation by cooling, separate out precipitation, suction filtration, recrystallization, dry and get final product, and yield is 95.6%.
The preparation of embodiment 2 Naproxen Base Berberine ion-pair compounds
In 2000 mL reaction flasks, add berberine hydrochloride 16.8 g (0.05 mol), add 750 mL distilled water, be heated to 80 ℃ of left and right berberine hydrochloride is dissolved, add 5% sodium hydroxide solution, to pH 7.5-8.5, stirring reaction 0.5 h; Add Naproxen Base, back flow reaction 2 h, crystallisation by cooling, separate out precipitation, suction filtration, recrystallization, dry and get final product, and yield is 93.3%.
The preparation of embodiment 3 flurbiprofen Berberine ion-pair compounds
In 2000 mL reaction flasks, add berberine hydrochloride 16.8 g (0.05 mol), add 750 mL distilled water, be heated to 80 ℃ of left and right berberine hydrochloride is dissolved, add 5% sodium hydroxide solution, to pH 9.0-9.5, stirring reaction 0.5 h; Add flurbiprofen, back flow reaction 2 h, crystallisation by cooling, separate out precipitation, suction filtration, recrystallization, dry and get final product, and yield is 90.5%.
Embodiment 4 Ibuprofen BP/EP Berberine ion-pair compound suppositorys:
Prescription: Ibuprofen BP/EP Berberine ion-pair compound 5 g
Semi-synthetic fatty acid ester 95 g
Carbomer 0.5 g
Make 100 pieces of suppositorys
Preparation method: Ibuprofen BP/EP 5 g, semi-synthetic fatty acid ester 95 g, carbomer 0.5 g, by after semi-synthetic fatty acid ester heating and melting, adding Ibuprofen BP/EP and carbomer, mix, pour in the bolt mould that scribbles glycerine, put to room temperature, scrape off the outer medicine of mould, take out, obtain Ibuprofen BP/EP Berberine ion-pair compound suppository.
Embodiment 5 ibuprofen for injection Berberine ion-pair compound gelifying agents
Prescription: Ibuprofen BP/EP Berberine ion-pair compound 5.0 g
Ethanol 15 g
Sodium alginate 0.5 g
Poloxamer 20 g
Distilled water to 100 mL
Get Ibuprofen BP/EP Berberine ion-pair compound 5.0 g of above recipe quantity, be dissolved in 95% ethanol of 15 g, add distilled water appropriate, slowly add 0.5 g sodium alginate, the limit edged stirs, and mixture is cooled to 4 ℃; Slowly add 20 g poloxamers, the limit edged stirs again, and distilled water adds to 100 mL.Mixture, in 4 ℃ of placements white mucus of spending the night to obtain, is to Ibuprofen BP/EP Berberine ion-pair compound water-soluable gel.
Embodiment 6 Ibuprofen BP/EP Berberine ion-pair compound injection liquids
Prescription: Ibuprofen BP/EP Berberine ion-pair compound 20 g
Arginine 80 g
Tween 80 is appropriate
Water for injection to 1000 mL
Get arginine 80 g of above recipe quantity, after injecting water to 800 mL arginine being dissolved, to it, add people's 20 g Ibuprofen BP/EP Berberine ion-pair compound and appropriate tween 80s, 60 ~ 80 ℃ of stirrings, after Ibuprofen BP/EP is dissolved fully, with 1 mol/L sodium hydroxide, regulate pH to 7.0-8.0.Add 0.3% needle-use activated carbon (i.e. 3.0 g) by the preparation total amount, 60 ~ 80 ℃ of stirrings are filtered decarburization after 30 min, add water for injection to 1000 mL, stir evenly, embedding in the ampoule of 5 mL, 121 ℃ of pressure sterilizing 15 min, labeling, packing.Every bottle containing Ibuprofen BP/EP Berberine ion-pair compound 100 mg.
Embodiment 7 Ibuprofen BP/EP Berberine ion-pair compound capsules
Prescription: Ibuprofen BP/EP Berberine ion-pair compound 50 g
Microcrystalline Cellulose 100 g
Croscarmellose sodium 5 g
5% polyvidone (K30) aqueous solution is appropriate
After being pulverized, the solid materials of above-mentioned recipe quantity crosses 80 mesh sieves, mix and by povidone solution, make softwood afterwards, by 20 mesh sieve granulation post-dryings, whole grain, divide and be filled in 1000 Capsuleses, obtain every capsule preparations containing 50 mg Ibuprofen BP/EP Berberine ion-pair compounds.
Embodiment 8 Ibuprofen BP/EP Berberine ion-pair compound sheets
Prescription: Ibuprofen BP/EP Berberine ion-pair compound 100 g
Aspartame 12.5 g
Microcrystalline Cellulose 1.5 g
Croscarmellose sodium 7.0 g
Micropowder silica gel 4.5 g
Mint Essence 4.5 g
60% appropriate amount of ethanol
Raw material is crossed to 100 mesh sieves, add aspartame to do sweeting agent, make tackiness agent with 60% ethanol and make softwood, cross 36 mesh sieves and granulate, under 45 ℃ of conditions after dry 2 h with the whole grain of 36 mesh sieves, the Microcrystalline Cellulose that adds directly compressible with outer addition, croscarmellose sodium, micropowder silica gel, essence, after fully mixing, compressing tablet, sheet weighs 0.23 g (content is 0.1 g).
Claims (6)
1. substituted aryl phenoxy propionic acid Berberine ion-pair compound, be arylprop acids Berberine drug salts, and its chemical structural formula is as follows:
It is characterized in that middle B is:
These 6 kinds of arylprop acids Berberine ion-pair compounds are respectively:
(1) Ibuprofen BP/EP berberine salt; (2) flurbiprofen berberine salt; (3) Naproxen Base berberine salt; (4) fenoprofen berberine salt; (5) Ketoprofen berberine salt; (6) loxoprofen berberine salt.
2. according to the Preparation method and use of claim 1 substituted aryl phenoxy propionic acid Berberine ion-pair compound, Berberine ion-pair compound drug salts also comprises its crystalline hydrate.
3. the Preparation method and use of substituted aryl phenoxy propionic acid Berberine ion-pair compound according to claim 1 can adopt the following methods preparation, and its preparation process can be expressed with following reaction formula
Preparation method: berberine hydrochloride is made to solution, with alkali, solution is adjusted to 7.5-10.0 by the pH value, stir 0.5-1 h; Add the substituted aryl propionic acid, back flow reaction 1-2 h, cooling, there is yellow substance to separate out, suction filtration, recrystallization, filter cake is drying to obtain in 80 ℃ of left and right.
4. the Preparation method and use of substituted aryl phenoxy propionic acid Berberine ion-pair compound according to claim 1, its compound prepared is a kind of antisepsis and anti-inflammation, treatment diabetes class medicine, it is characterized in that containing compound claimed in claim 1, or this compound and available auxiliary material pharmaceutically.
5. according to the Preparation method and use of substituted aryl phenoxy propionic acid Berberine ion-pair compound claimed in claim 1, the compound that it prepares, for a kind of anti-arrhythmia, heart failure resistance, platelet aggregation-against, treatment hypertension, reducing blood-fat and treatment digestive ulcer medicament, it is characterized in that containing compound claimed in claim 1, or this compound and available auxiliary material pharmaceutically.
6. according to the Preparation method and use of substituted aryl phenoxy propionic acid Berberine ion-pair compound claimed in claim 1, the compound that it prepares, feature is to adopt appropriate pharmaceutical excipient and preparation method, can be made into acceptable pharmaceutical dosage form on any medicine.
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Cited By (8)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN104292225A (en) * | 2014-09-30 | 2015-01-21 | 中南大学 | Preparation method and use of substituted o-aminobenzoic acid berberine salt |
| CN104327070A (en) * | 2014-09-30 | 2015-02-04 | 中南大学 | Preparation method and application of substituted indole acetic acid berberine salt |
| CN105732612A (en) * | 2016-03-15 | 2016-07-06 | 合肥华方医药科技有限公司 | Preparation and medical application of ACEI (angiotensin converting enzynme inhibitor)-type berberine conjugate |
| CN107188890A (en) * | 2017-06-13 | 2017-09-22 | 闽江学院 | A kind of nothing of crystal form draws moist protocatechuic acid berberine monohydrate |
| CN109020968A (en) * | 2018-07-31 | 2018-12-18 | 南京中医药大学 | Jamaicin crystalline salt and preparation method thereof |
| CN110041325A (en) * | 2018-01-15 | 2019-07-23 | 中国医学科学院药物研究所 | Berberine hydrochloride and brufen eutectic object and preparation method and its composition and purposes |
| CN112010849A (en) * | 2019-05-29 | 2020-12-01 | 北京中医药大学 | Flavonoid glycoside and isoquinoline alkaloid complex for inhibiting multiple drug-resistant staphylococcus aureus and preparation of carrier-free nano-drug thereof |
| WO2023088319A1 (en) * | 2021-11-16 | 2023-05-25 | 温州医科大学附属眼视光医院 | Montelukast berberine quaternary ammonium salt compound and double salt composition, and synthesis method therefor and use thereof |
Citations (2)
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|---|---|---|---|---|
| CN1990487A (en) * | 2005-12-30 | 2007-07-04 | 贾本真 | Berberine ion pair compound, preparing method and drug containing same |
| CN102309483A (en) * | 2010-06-30 | 2012-01-11 | 贾本真 | New application of berberine ion pair compound in tumor resistance |
-
2013
- 2013-03-28 CN CN201310103924XA patent/CN103193772A/en active Pending
Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
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| CN1990487A (en) * | 2005-12-30 | 2007-07-04 | 贾本真 | Berberine ion pair compound, preparing method and drug containing same |
| CN102309483A (en) * | 2010-06-30 | 2012-01-11 | 贾本真 | New application of berberine ion pair compound in tumor resistance |
Cited By (10)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN104292225A (en) * | 2014-09-30 | 2015-01-21 | 中南大学 | Preparation method and use of substituted o-aminobenzoic acid berberine salt |
| CN104327070A (en) * | 2014-09-30 | 2015-02-04 | 中南大学 | Preparation method and application of substituted indole acetic acid berberine salt |
| CN105732612A (en) * | 2016-03-15 | 2016-07-06 | 合肥华方医药科技有限公司 | Preparation and medical application of ACEI (angiotensin converting enzynme inhibitor)-type berberine conjugate |
| CN107188890A (en) * | 2017-06-13 | 2017-09-22 | 闽江学院 | A kind of nothing of crystal form draws moist protocatechuic acid berberine monohydrate |
| CN107188890B (en) * | 2017-06-13 | 2019-03-29 | 闽江学院 | A kind of nothing of crystal form draws moist protocatechuic acid berberine monohydrate |
| CN110041325A (en) * | 2018-01-15 | 2019-07-23 | 中国医学科学院药物研究所 | Berberine hydrochloride and brufen eutectic object and preparation method and its composition and purposes |
| CN110041325B (en) * | 2018-01-15 | 2023-04-11 | 中国医学科学院药物研究所 | Eutectic crystal of berberine hydrochloride and ibuprofen, preparation method, composition and application thereof |
| CN109020968A (en) * | 2018-07-31 | 2018-12-18 | 南京中医药大学 | Jamaicin crystalline salt and preparation method thereof |
| CN112010849A (en) * | 2019-05-29 | 2020-12-01 | 北京中医药大学 | Flavonoid glycoside and isoquinoline alkaloid complex for inhibiting multiple drug-resistant staphylococcus aureus and preparation of carrier-free nano-drug thereof |
| WO2023088319A1 (en) * | 2021-11-16 | 2023-05-25 | 温州医科大学附属眼视光医院 | Montelukast berberine quaternary ammonium salt compound and double salt composition, and synthesis method therefor and use thereof |
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Application publication date: 20130710 |