CN1593428A - Dextran-aspirin combined medicine and its preparation method - Google Patents
Dextran-aspirin combined medicine and its preparation method Download PDFInfo
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- CN1593428A CN1593428A CNA2004100410939A CN200410041093A CN1593428A CN 1593428 A CN1593428 A CN 1593428A CN A2004100410939 A CNA2004100410939 A CN A2004100410939A CN 200410041093 A CN200410041093 A CN 200410041093A CN 1593428 A CN1593428 A CN 1593428A
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Abstract
The invention discloses a dextran-aspirin combined medicine and its preparation method, wherein the medicament has the structural formula disclosed in the specification, n=120-250. The medicament can reduce the side effects to stomach and intestine, and extend the internal release time.
Description
Technical field:
The present invention relates to a kind of chemical compound with and preparation method thereof, the macromolecule of more specifically saying so articulates medicine and synthetic method.
Background technology:
Aspirin Aspirin has another name called aspirin Acetylsalicylic Acid because its good analgesic, analgesia, antiinflammatory action, low price in addition, so far it be still most widely used in the world analgesic, analgesia and anti-inflammatory agent.In twentieth century latter half, Cimetiere B., (WO03084525) such as Verbeuren T. finds that again aspirin has the characteristic of long-term prevention myocardial infarction, thrombosis, apoplexy, rheumatism and cancer.Robert S., Sandler, (A RandomizedTrial of Aspirin to Prevent Colorectal Adenomas in Patients with PreviousColorectal Cancer.The New England Journal of Medicine.2003 such as M.D, 348:883-890.) report, the life-time service aspirin can reduce esophageal carcinoma, human primary gastrointestinal cancers, colon cancer, rectal cancer prevalence, and aspirin can be used for birth control, suppresses HIV (human immunodeficiency virus) breeding and enhancing immunity.
But gastrointestinal side effect is comparatively obvious when taking aspirin, and is big to the zest of gastric mucosa, easily cause gastric mucosa congestion, erosion or shallow table ulcer or original ulcer is increased the weight of, even perforation.At present, aspirin is the rheumatismal choice drug of treatment, and patient needs long-term large dose oral administration, so, bigger to the zest of gastric mucosa.And accretion rate is very fast in vivo, to eliminate the half-life too short for aspirin, if need frequent drug administration during as diseases such as prevention myocardial infarction, thrombosis, apoplexy, rheumatism and cancers, makes troubles to patient.Therefore, need modify and improve, reducing its gastrointestinal toxic and side effects, and prolong release time in its body, reach slow release, make it can obtain clinical practice more widely aspirin.
For solving these defectives of aspirin, interior in the past few decades people have done a lot of work and have gone to improve.Comprising the structural modification aspect to aspirin, people mainly are by preparation aspirin ester or salt, have been used for clinical Aspirin-arginin, salsalate, two difunisal, benorylate, acetaminophen at present.Hussain, Anwar A. etc., U.S.Pat.4,242,330, synthetic aspirin and α-D-2-deoxidation Glucopyranose.; Gao Lianxun, Gao Zhaobo etc. are in CN02148861.4, salicylate camphane (alcohol)/different camphane (alcohol) ester and derivant thereof, aspirin non-steroid antiinflammatory drugs is carried out the Rational structure transformation, make it to weaken inhibitory action to COX-1, and strengthen inhibitory action, thereby have better therapeutic and littler toxic and side effects to COX-2; Xu Mingxia, Chen Fener is in CN94111849.5, synthetic drug is with new aspirin ester derivant, as ASPA, aspirin-7-hydroxyisoflavone ester, aspirin-4-methylol phenyl ester, aspirin Rhizoma et radix valerianae aldehydo-ester, alleviating it to when being the stimulation of mucosa, have stronger anti thrombotic action, be applicable to and prevent and treat the cardiovascular and cerebrovascular vessel embolism class diseases; Bayer AG, CN01815881.1, the sta-salt of O-aspirin and basic amino acid.Recently, Soldato P.D., (AU766497 such as Garufi M.; CA2361454) again the NO base is incorporated in the aspirin molecule, or with aspirin and COX-2 enzyme in conjunction with (Pharmacia Corp. (US) US2003207846), optionally acts on lesions position, reduces the side effect to gastric mucosa.Yet these improve and all are intended to reduce or remit aspirin
To the stimulation of gastric mucosa, and do not solve relatively short problem of the aspirin time of staying in vivo.
By chemical bond with medicine and the direct combination of polymer, be a kind of method of preparation bioerodable type slow releasing preparation, medicine discharges from polymer lentamente by hydrolysis or enzyme reaction, and rate of releasing drug is more easy to control, and this type of preparation drug loading is very high, and can improve the pharmaceutical property of medicine.As Mitra S., Gaur U., (Journal ofControlled Release such as Ghos.C.h, 74 (2001) 317-323), react with amycin again after dextran handled with sodium metaperiodate, make dextran-amycin complex, prolonged the amycin time of staying in vivo, and avoided the toxic and side effects of amycin heart; Josephson Lee, Groman Ernest, Wu Yongqian etc. at U.S.Pat.5, in 981,507, are articulated to nucleoside medicine on the macromolecular chain such as dextran, with the curative effect that improves nucleoside medicine and reduce its toxicity; Battersby John E., Clark Ross G. etc. be at U.S.Pat.5, in 614,487, polypeptide drugs is chemically bonded on the dextran, and the polypeptide drugs elimination factor in vivo that slows down makes it obtain the effect of slow release or even controlled release; Iwamoto, Kiyoshi etc., U.S.Pat.5,120,719, synthesize glucosan-prostaglandin and articulated medicine, because the prostaglandin medicine is very unstable, easily under conditions such as acid, alkali or heat, degrade, and easily by liver metabolism.After prostaglandin and glucosan synthetic high polymer are articulated medicine, can make prostaglandin be difficult for having been prolonged medicine circulation cycle in blood by liver metabolism.The somebody is by being articulated to medicine on the macromolecular chains such as dextran, to improve the pharmaceutical property of medicine, as Kapa, Prasad etc., U.S.Pat.5,691,304, preparation dextran-polymyxin B complex, the water solublity of increase medicine, strengthen medicine and suppress endotoxin, improve the pharmaceutical properties of medicine; Moreno Carlos is at U.S.Pat.4, in 260,602, synthesized dextran-penicillin complex, improved the biological tolerability of penicillin; Adamson, Gordon J., U.S.Pat.6,500,930, synthetic glucosan-hematochrome articulates thing, strengthens its oxygen carrying capacity; Wang, Denong etc., U.S.Pat.6,287,568, synthetic glucosan-protein; Woiszwillo, James E. etc., U.S.Pat.5,554,730, glucosan-protein.Therefore, dextran (glucosan) is good sustained and controlled release medicament carrier.
Summary of the invention:
The present invention provides dextran-aspirin and articulates medicine and preparation method thereof.By aspirin is modified and is improved, reducing its gastrointestinal toxic and side effects, and prolong release time in its body, reach slow release, make it can obtain clinical practice more widely.
The technical scheme that technical solution problem of the present invention is adopted is:
The characteristics that dextran-aspirin of the present invention articulates medicine are that its structural formula is:
N=120-250 in above structural formula
The characteristics that dextran-aspirin of the present invention articulates medication preparation are to have following steps:
A, make adjacent acetoxyl group Benzenecarbonyl chloride. by the reaction of aspirin and acyl chlorinating agent
B, then, in the presence of catalyst and/or acid binding agent, dextran and adjacent acetoxyl group Benzenecarbonyl chloride. carry out esterification and generate.
Compared with the prior art, beneficial effect of the present invention is embodied in:
Dextran-aspirin of the present invention articulates medicine and is light yellow toner powder, and stable in properties is difficult for suction and oxidation at normal temperatures and pressures; Be insoluble to ethanol, isopropyl alcohol etc., be slightly soluble in water, can be dissolved in dimethyl sulfoxine (DMSO) and N, dinethylformamide (DMF) etc.This chemical compound is more stable under the acid condition of simulated gastric fluid, can avoid medicine a large amount of release and the local concentration that causes is too high in gastric juice, and reduce the stimulation to gastric mucosa.The release in vitro that this dextran-aspirin articulates medicine is the zero level cumulative release, and does not have " burst release " phenomenon, has slow controlled release usefulness.Its release profiles in simulated gastric fluid as shown in Figure 1, as seen from the figure, it is very slow that dextran-aspirin articulates the rate of release of medicine in simulated gastric fluid, and burst size is little.But the release profiles in simulated intestinal fluid such as Fig. 2, medicine slowly discharges medicine with stable rate of release.
Description of drawings:
Fig. 1 articulates the release profiles of medicine in simulated gastric fluid for different carrying drug ratio dextran-aspirin.
Fig. 2 articulates the release profiles of medicine in simulated intestinal fluid for different carrying drug ratio dextran-aspirin.
The specific embodiment:
Dextran-aspirin articulates the structural formula of medicine and is in the present embodiment:
Dextran-aspirin articulates the preparation process of medicine and is in the present embodiment:
A, react in the presence of catalyst by aspirin and acyl chlorinating agent and to make adjacent acetoxyl group Benzenecarbonyl chloride.;
B, in the presence of acid binding agent, dextran and adjacent acetoxyl group Benzenecarbonyl chloride. carry out esterification and generate complex.
In above-mentioned steps a, at first aspirin is dissolved in the organic solvent, add acyl chlorinating agent and catalyst again, under 35～80 ℃ of temperature acyl chloride reaction 2.5-3 hour, adjacent acetoxyl group Benzenecarbonyl chloride.; Wherein, described organic solvent comprises benzene, acetone, normal hexane; Described acyl chlorinating agent is thionyl chloride or Phosphorous chloride.; Described catalyst comprises pyridine, N, dinethylformamide DMF, and the addition of catalyst is to add catalyst 0.01-0.05ml in every gram acetyl bigcatkin willow.
In above-mentioned steps b, under the effect of acid binding agent, adjacent acetoxyl group Benzenecarbonyl chloride. and dissolved dextran were at 35～75 ℃ of following esterification 3-5 hours, separate out precipitation in the reactant liquor impouring cold isopropanol, reuse dehydrated alcohol eluting is 2～3 times behind the recrystallization, places 40～50 ℃ to dry to such an extent that dextran-aspirin articulates medicine.
In concrete the enforcement, in the esterification reaction process of above-mentioned steps b, dextran: the mass ratio of adjacent acetoxyl group Benzenecarbonyl chloride. is 0.27: 1 to 0.90: 1; Acid binding agent comprises triethylamine TEA, pyridine, strong caustic, and its consumption is acid binding agent in molar ratio: adjacent acetoxyl group Benzenecarbonyl chloride .=0.6～1.5: 1; The dextran weight average molecular weight is 2,000～70, and arbitrary between 000 is as weight average molecular weight 5,000,10,000,20,000,40,000 or 70,000; Dissolved dextran is meant, dextran is dissolved in dimethyl sulfoxine DMSO at 75～85 ℃, or dextran is dissolved in N at 85 ℃, dinethylformamide DMF, or in 90～95 ℃ of gelatinizing 1h in a small amount of distilled water.
Method in the present embodiment, also be applicable to chemical compound with the aspirin structural similarity, reaction as salicylic acid, para-aminosalicylic acid (para-aminosalicylate), salsalate (salsalate), diflunisal (dolobid) etc. and other macromolecule polyalcohol, biological polyoses class or their mixture.
Non-limiting examples is described below:
Embodiment 1:
In the 100ml there-necked flask that agitator, reflux condenser, device for recovering tail gas, Dropping funnel, thermometer are housed, the aspirin that adds 10.8g, 0.06mol successively, the organic solvent anhydrous benzene of 30ml, drip N again as catalyst, each 0.2ml of dinethylformamide DMF and pyridine is measured the thionyl chloride SOCl of 13ml, 0.18mol then
2In constant pressure funnel, dripping below 50 ℃, about 10～20min dropwises, and is warming up to 75～80 ℃ then, reacts 2.5 hours.Remove excessive thionyl chloride and benzene then under reduced pressure, get adjacent acetoxyl group Benzenecarbonyl chloride..
Take by weighing 1.62g, 0.01mol dextran T-40 puts into the 250ml there-necked flask, the organic solvent N that adds 80ml then, dinethylformamide DMF solution, heating and be stirred to 85 ℃ treat that it dissolves fully after, after reducing to 40 ℃, add the acid binding agent triethylamine TEA of adjacent acetoxyl group Benzenecarbonyl chloride. of 5.96g, 0.03mol and 3.2ml, then, reactant liquor is incubated 4 hours in 40 ℃.After reaction finishes, reactant liquor poured in the cold isopropyl alcohol separate out flocculent deposit, with dehydrated alcohol eluting 2～3 times, dry carrying drug ratio 7.2% product 0.479g.
Embodiment 2:
The method for preparing adjacent acetoxyl group Benzenecarbonyl chloride. is with embodiment 1.Take by weighing 1.62g, 0.01mol dextran T-40 puts into the 100ml there-necked flask, add 50ml dimethyl sulfoxine DMSO then, heating and be stirred to 80 ℃ treat that it dissolves fully after, reduce to 60～70 ℃, in reactant liquor, add adjacent acetoxyl group Benzenecarbonyl chloride. of 5.96g, 0.03mol and 1ml concentrated sodium hydroxide NaOH solution, then, reactant liquor is incubated 4 hours in 40 ℃.After reaction finishes, reactant liquor poured in the cold isopropyl alcohol separate out flocculent deposit, with dehydrated alcohol eluting 2～3 times, dry carrying drug ratio 6.3% product 0.441g.
Embodiment 3:
The method for preparing adjacent acetoxyl group Benzenecarbonyl chloride. is with embodiment 1.Take by weighing 1.62g, 0.01mol dextran T-20 puts into the 100ml there-necked flask, add 50ml dimethyl sulfoxine DMSO then, heating and be stirred to 80 ℃ treat that it dissolves fully after, in reactant liquor, add adjacent acetoxyl group Benzenecarbonyl chloride. of 5.96g, 0.03mol and 4.2ml pyridine, then reactant liquor is incubated 4 hours in 70 ℃.After reaction finishes, reactant liquor poured in the cold isopropyl alcohol separate out flocculent deposit, with dehydrated alcohol eluting 2～3 times, dry carrying drug ratio 8.9% product 0.508g.
Embodiment 4:
The method for preparing adjacent acetoxyl group Benzenecarbonyl chloride. is with embodiment 1.Take by weighing 1.013g dextran T-20 and put into the 50ml there-necked flask, add the 10ml distilled water then in 90 ℃ of gelatinizing 1h, treat its cooling after, place ice bath, stir on one side,, be incubated 4 hours then Yi Bian add adjacent acetoxyl group Benzenecarbonyl chloride. of 0.01875mol and 3ml triethylamine TEA.After reaction finishes, reactant liquor poured in the cold isopropyl alcohol separate out flocculent deposit, with dehydrated alcohol eluting 2～3 times, dry carrying drug ratio 10.2% product 0.578g.
Figure 1 shows that different carrying drug ratio dextran-aspirin articulate the release profiles of medicine in simulated gastric fluid, wherein RDL represents carrying drug ratio, and r represents the linear dependence of the release profiles of institute's match.As seen from the figure, it is very little that this articulates medicine rate of release in simulated gastric fluid, and the burst size in the unit interval is more constant.Illustrate that this chemical compound is more stable under the acid condition of simulated gastric fluid, can avoid medicine a large amount of release and the local concentration that causes is too high in gastric juice, so reduced stimulation to gastric mucosa.Figure has illustrated that the medicine that articulates described in the present invention has played and avoids the effect of aspirin to the gastric mucosa side effect thus.
Figure 2 shows that different carrying drug ratio dextran-aspirin articulate the release profiles of medicine in simulated intestinal fluid, wherein RDL represents carrying drug ratio, and r represents the linear dependence of the release profiles of institute's match.By linearly dependent coefficient r as can be known, in more than 270 hours release in vitro process, different carrying drug ratios to articulate the rate of release of medicine in simulated intestinal fluid very even, aspirin with a kind of slowly and even velocity from pharmaceutical carrier, discharge, present zero level and discharge, and avoided discharging " burst release " phenomenon of incipient stage.Explanation thus, dextran-aspirin articulates the slow delivery systme that medicine has been a kind of aspirin, medicine can discharge with a kind of stable rate of release that continues, and can keep long release time, be expected to make it as disease medications such as long-term prevention myocardial infarction, thrombosis, apoplexy, rheumatism and cancers.
Annotate: extracorporeal releasing experiment is carried out " People's Republic of China's 5 pharmacopeia " (2000 editions) regulation.
Claims (8)
1, dextran-aspirin articulates medicine, it is characterized in that the structural formula of described medicine is:
N=120-250 in above structural formula
2, the described dextran-aspirin of a kind of claim 1 articulates the preparation method of medicine, it is characterized in that having following steps:
A, react in the presence of catalyst by aspirin and acyl chlorinating agent and to make adjacent acetoxyl group Benzenecarbonyl chloride.;
B, in the presence of acid binding agent, dextran and adjacent acetoxyl group Benzenecarbonyl chloride. carry out esterification and generate.
3, dextran-aspirin according to claim 2 articulates the preparation method of medicine, it is characterized in that in described step a, at first aspirin is dissolved in the organic solvent, add acyl chlorinating agent and catalyst again, under 35～80 ℃ of temperature acyl chloride reaction 2.5-3 hour, adjacent acetoxyl group Benzenecarbonyl chloride.; Wherein, described organic solvent comprises benzene, acetone, normal hexane; Described acyl chlorinating agent is thionyl chloride or Phosphorous chloride.; Described catalyst comprises pyridine, N, dinethylformamide DMF, and the addition of catalyst is to add catalyst 0.01-0.05ml in every gram aspirin.
4, dextran-aspirin according to claim 2 articulates the preparation method of medicine, it is characterized in that in described step b, under the effect of acid binding agent, adjacent acetoxyl group Benzenecarbonyl chloride. and dissolved dextran were at 35～75 ℃ of following esterification 3-5 hours, separate out precipitation in the reactant liquor impouring cold isopropanol, reuse dehydrated alcohol eluting is 2～3 times behind the recrystallization, places 40～50 ℃ to dry to such an extent that dextran-aspirin articulates medicine.
5, dextran-aspirin according to claim 4 articulates the preparation method of medicine, it is characterized in that in the described esterification reaction process dextran: the mass ratio of adjacent acetoxyl group Benzenecarbonyl chloride. is 0.27: 1 to 0.90: 1.
6, dextran-aspirin according to claim 4 articulates the preparation method of medicine, it is characterized in that described acid binding agent comprises triethylamine TEA, pyridine, strong caustic, and its consumption is in molar ratio:
Acid binding agent: adjacent acetoxyl group Benzenecarbonyl chloride .=0.6～1.5: 1.
7, dextran-aspirin according to claim 4 articulates the preparation method of medicine, it is characterized in that described dextran weight average molecular weight is 2,000～70, arbitrary between 000, as weight average molecular weight 5,000,10,000,20,000,40,000 or 70,000.
8, dextran-aspirin according to claim 4 articulates the preparation method of medicine, it is characterized in that described dissolved dextran is meant, dextran is dissolved in dimethyl sulfoxine DMSO at 75～85 ℃, or dextran is dissolved in DMF at 85 ℃, or in 90～95 ℃ of gelatinizing 1h in a small amount of distilled water.
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Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101863934B (en) * | 2009-04-20 | 2014-07-23 | 中国医学科学院药物研究所 | Salicylic acid glucosides methyl compound, and synthesis method and purposes thereof |
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2004
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Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101863934B (en) * | 2009-04-20 | 2014-07-23 | 中国医学科学院药物研究所 | Salicylic acid glucosides methyl compound, and synthesis method and purposes thereof |
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