CN101366946B - Starch based segmented intestine targeting specific adhesion material, preparation and application thereof - Google Patents

Starch based segmented intestine targeting specific adhesion material, preparation and application thereof Download PDF

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CN101366946B
CN101366946B CN2008101983419A CN200810198341A CN101366946B CN 101366946 B CN101366946 B CN 101366946B CN 2008101983419 A CN2008101983419 A CN 2008101983419A CN 200810198341 A CN200810198341 A CN 200810198341A CN 101366946 B CN101366946 B CN 101366946B
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starch
adhesion material
starch based
targeting specific
specific adhesion
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CN101366946A (en
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李晓玺
陈玲
王雪毓
刘早
李琳
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South China University of Technology SCUT
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Abstract

The invention discloses a starch based colon idiosyncratic adhesion material for coupling concanavalin A and a method for preparing the same. The anti-digestion starch undergoes the activating treatment by glutaraldehyde, couples with the concanavalin A and is subjected to centrifuge washing by phosphate buffer and inactivation by ethanolamine to obtain the starch based colon idiosyncratic adhesion material. The invention also discloses application of the starch based colon targeting idiosyncratic adhesion material in preparing biomacromolecule medicines of polypeptide protein or medicines of treating colon diseases. For the first time, the invention utilizes the characteristics of the idiosyncratic adsorption between the concanavalin A and the colon epithelial cell, successfully prepares the carrier material of the starch based colon idiosyncratic adhesion material by coupling the concanavalin A with the anti-digestion starch molecule by the glutaraldehyde and uses the starch based colon idiosyncratic adhesion material as an oral taking colon targeting control-release carrier material, so that starch based colon idiosyncratic adhesion material and the method have the characteristics of cell adsorption, enzymolysis triggering targeting, good biocompatibility, safety and non-toxin, good targeting slow-release effect, and the like.

Description

Starch based segmented intestine targeting specific adhesion material and its production and application
Technical field
The present invention relates to the research and development field of natural macromolecular material, particularly be used for the starch based segmented intestine targeting specific adhesion material and its production and application of the target controlling and releasing pharmaceutical carrier of oral colon-target controlled-release administrating system at field of medicaments.
Background technology
Bioadhesive material can interact with the body tissue surface, produce adhesive capacity, therefore utilize bioadhesive material that drug-supplying system was prolonged in the biomembranous specific part holdup time, and by means of the adhesion between material and mucosa, make medicine diffuse into the body-internal-circulation system by the mucomembranous surface epithelial cell membrane with certain speed, the action time of prolong drug, thus bioavailability of medicament improved.
The abundantest natural biological of the occurring in nature renewable macromolecule starch of degrading is applied to field of medicaments as excipient, disintegrating agent etc. very early.Because starch has excellent biological compatibility, biodegradable, it is structurally-modified to be easy to, have inexpensive, wide material sources, stability is high, safe, nontoxic and is easy to form good characteristic such as gel, become very potential targeted drug transmission system carrier.Soane R.J. etc. are at " mensuration of bioadhesion System Cleaning characteristic in the human body " (Soane R.J., Frier M., Perkins A.C., etal.Evaluation of the clearance characteristics of bioadhesive systems in human.Int.J.Pharm.1999,178:55) study the spherex nasal-cavity administration with radioactive label in the literary composition, the result shows that spherex has bioadhesion ability preferably, it removes 3 times of aqueous solution that half-life is a chitosan, reaches 68min.Illum L. etc. are at " the collaborative absorbability of polypeptide in nasal cavity that strengthen of starch bioadhesion microsphere and absorption enhancer " (Illum L., Fisher A.N., Jabbal-Gill I., et.al.Bioadhesive starchmicrospheres and absorption enhancing agents act synergistically to enhance thenasal absorption of polypeptides.Int.J.Pharm.2001,222:109-119) in the literary composition by in spherex, adding absorption of insulin promoter by the nasal cavity uelralante of sheep, the absorption of insulin has as a result improved 1.4~5 times.In addition, Ameye D. etc. is " spray-dired
Figure G2008101983419D00011
Starch and The 974P blend adheres to the research of carrier as oral mucosa " (Ameye D., Mus D., Foreman P., et.al.Spray-dried
Figure G2008101983419D00013
Starch/ 974P mixtures asbuccal bioadhesive carriers.Int.J.Pharm.2005 passes through in 301:170-180) Starch with
Figure G2008101983419D00021
Make the adhesion carrier material that is used for mouth mucosa drug administration after the 974P blend, the result demonstrates
Figure G2008101983419D00022
Starch with
Figure G2008101983419D00023
The 974P intermingling material has mucosal adhesive ability preferably.But Witschi C. etc. are at " application in the albumen nasal-cavity administration of external test microsphere and polymer gel " (Witschi C., Mrsuy R.J.In vitro evaluation of microparticles and polymer gelsfor use as nasal platforms for protein delivery.Pharm.Res.1999,16 (3): be model drug with the bovine serum albumin in the literary composition 382), respectively with starch, carbomers etc. are adhesion material, make microgranule by spray drying, estimate adhesive capacity at the polar Calu-3 cell of external use, found that the starch adhesion is relatively poor.
The oral colon-target drug-supplying system becomes at present one of drug-supplying system of tool in the world development prospect owing to being specially adapted to release, absorption and utilization at the medicine of disease such as the asthma, angina pectoris, arthritis of treatment night-time attack and treatment colonic diseases and polypeptide, protein drug.In recent years, the colon targeting drug administration system has obtained remarkable progress at aspects such as galenic pharmacy and target controlling and releasing carrier materials, and it is clinical that some of them have been applied to, and shown gratifying prospect.
The bioadhesion carrier material that is used for the oral colon-target medicine-releasing system must possess: (1) is not degraded at upper digestive tract; (2) in colonic environment, can degrade, and most of medicine can discharge by carrier; (3) material and mucous membrane of colon epithelial cell have specific adhesive capacity; (4) carrier material and its catabolite to mucous membrane of colon non-stimulated and toxic action.Sprouting and rise along with " ecological environment production " and " green consumption " consciousness, the renewable macromolecule of natural biological degraded has become the basis of drug delivery system design, preparation, it is carried out suitable physics, chemistry or bio-modification, can adjust the control drug release behavior of drug-supplying system, obtain ideal drug-supplying system.Because starch is easily degraded by the amylase in the digestive tract, so in research both at home and abroad at present, starch is mainly concentrated on oral mucosa as the application of bioadhesion drug carrier material, can not be used for the oral colon-target medicine-releasing system in parenterai administration such as upper digestive tract and the nasal membrane system, and existing starch-based bio adheres to and all lacks specificity, be that they do not have specificity to corresponding substrate, particularly in gastrointestinal administration, this may cause the too early inactivation of medicine, limit drug is at the time of staying of special absorption site (Gilles Ponchela, Juan-Manuel Irache.Specific andnon-specific bioadhesive particulate systems for oral delivery to the gastrointestinaltract.Adv.Drug Del.Rev.1998,34:191-219).
The carrier material of ideal oral colon-target drug-supplying system not only needs to possess stronger medicine controlled releasing ability, but also should have stronger affinity with target position so that improve bioavailability of medicament, so must have the carrier material of specificity adhesion property by utilization, through controlled-release technology, after making drug oral, not in the upper digestive tract release, have only when transport of drug behind ileocecus, just begin disintegrate or discharge medicine carrying microgranule, and carrier adheres to the mucous membrane of colon surface epithelial cell in the certain hour scope, medicine discharges from carrier inside with given pace, improve medicine whereby in specific part concentration, then improve drug bioavailability, reach targeting drug release and adherent dual purpose.
The research work of relevant starch based segmented intestine targeting specific adhesion carrier material yet there are no report at home and abroad.
Summary of the invention
In order to solve the deficiency of above-mentioned existing starch base adhesion material, primary and foremost purpose of the present invention provides a kind of starch based segmented intestine targeting specific adhesion carrier material.This starch based segmented intestine targeting specific adhesion material has good molecular specificity to colon cell, good biocompatibility, safety non-toxic.
Another object of the present invention provides the preparation method of above-mentioned starch based segmented intestine targeting specific adhesion material.
A further object of the present invention provides the application as carrier material in preparation oral colon-target medicine of above-mentioned starch based segmented intestine targeting specific adhesion material.
Purpose of the present invention realizes by following technical proposals: a kind of starch based segmented intestine targeting specific adhesion material, be resistant starch (ZL 200310112540.0) go up the coupling biologically active concanavalin A and.
The present invention is on the basis of the prepared resistant starch of a patent before the applicant " resistant starch and its production and application (ZL200310112540.0) ", forms by the amido coupling of glutaraldehyde with hydroxyl on the resistant starch molecule and concanavalin A.
The preparation method of above-mentioned starch based segmented intestine targeting specific adhesion material comprises the steps:
Be that 50~80% resistant starch is 20~90 ℃ of temperature with water content, pH is under 2~5 the condition, adding the quality volumetric concentration is the alcoholic extract hydroxyl group of the glutaraldehyde activation starch of 1~10% (g/L is in the resistant starch butt), behind reaction 0.25~6h, after the phosphate buffer washing, the concanavalin A (w/w is in the resistant starch butt) of adding 0.5~5% carries out coupling, and the temperature of coupling reaction is 10~30 ℃, coupling time is 5~30h, obtains starch material after reacting completely; Starch material adds unreacted activated group in the ethanolamine passivation starch material after using the phosphate buffer centrifuge washing then, through centrifuge washing final vacuum drying, obtains starch based segmented intestine targeting specific adhesion material.
The starch based segmented intestine targeting specific adhesion material that the present invention obtains can be used in preparation polypeptide protein class biopharmaceutical macromolecular drug or treatment colonic diseases medicine, the colon targeted adhesive of realizing said medicine discharges, and improves the toxic and side effects of bioavailability of medicament and reduction medicine.
Described starch based segmented intestine targeting specific adhesion material prepares polypeptide protein class biopharmaceutical macromolecular drug or treatment colonic diseases medicine is to carry out as follows: behind polypeptide protein class biopharmaceutical macromolecular drug or treatment colonic diseases medicine and starch based segmented intestine targeting specific adhesion material mixing, with hydroxypropyl methylcellulose (HPMC) aqueous solution is binding agent, makes the starch based segmented intestine targeting specific adhesion tablet of medicine carrying through pelletize, drying, tabletting.
The present invention compared with prior art has following advantage and beneficial effect:
(1) the present invention utilizes the characteristics of concanavalin A and colon epithelial cell specific adsorption first, concanavalin A is successfully prepared the starch based segmented intestine targeting specific adhesion carrier material by the method that glutaraldehyde is coupled on the resistant starch molecule, it is cheap and easy to get to adopt starch based segmented intestine targeting specific adhesion material to have as the carrier material of oral colon-target controlled-release administrating system, good biocompatibility, safety non-toxic own.
(2) the present invention has adopted the compound segmented intestine targeted location technology that cell adhesion and enzymolysis trigger, can significantly improve the segmented intestine targeted property of medicine, guaranteeing under the less prerequisite of the enteral leakage rate of harmonization of the stomach, significantly improved the holdup time of medicine at colon, can make the slow-release time of medicine in colon extend to 30~40h, drug release rate can reach more than 90%, improves bioavailability.
The specific embodiment
Below in conjunction with embodiment, the present invention is described in further detail, but embodiment of the present invention is not limited in this.
Embodiment one
(1) preparation of resistant starch: starch and water are mixed through mechanical agitation at blending tank, making moisture quality percentage composition be controlled between 10~95% (w/w is in the starch butts) back is that 30~140 ℃, pressure limit are that 0.1~4h is handled in modification under 0.5~3MPa in temperature range; With the mass transport after handling in enzyme reactor, with heat-resistant alpha-amylase and the abundant enzymolysis of glucoamylase after centrifugal, washing, the resistant starch that filters, obtain after dry, the pulverizing.
(2) preparation of starch based segmented intestine targeting specific adhesion material: the resistant starch of above-mentioned preparation is scattered in 50% (w/w, in the resistant starch butt) distilled water in, 20 ℃ of temperature, pH is under 2 the condition, adding the quality volumetric concentration is 1% (g/L, in the resistant starch butt) the alcoholic extract hydroxyl group of glutaraldehyde activation resistant starch, behind the reaction 0.25h, behind the phosphate buffer thorough washing, the concanavalin A (w/w is in the resistant starch butt) of adding 0.5% carries out coupling, and the temperature of coupling reaction is 10 ℃, coupling time is 5h, obtains starch material after reacting completely; After starch material is used the phosphate buffer centrifuge washing, add unreacted activated group in the ethanolamine passivation starch material,, obtain the starch based segmented intestine targeting specific adhesion material of white powder through centrifuge washing final vacuum drying.
Embodiment two
The resistant starch of preparation among the weighing embodiment one, be scattered in 80% (w/w, in the resistant starch butt) distilled water in, 90 ℃ of temperature, pH is under 5 the condition, adding the quality volumetric concentration is 10% (g/L, in the resistant starch butt) the alcoholic extract hydroxyl group of glutaraldehyde activation resistant starch, behind the reaction 6h, behind the phosphate buffer thorough washing, add 5% concanavalin A (w/w, in the resistant starch butt) carry out coupling, the temperature of coupling reaction is 30 ℃, and coupling time is 30h, obtains starch material after reacting completely; After starch material is used the phosphate buffer centrifuge washing, add unreacted activated group in the ethanolamine passivation starch material,, obtain the starch based segmented intestine targeting specific adhesion material of white powder through centrifuge washing final vacuum drying.
Embodiment three
The resistant starch of preparation among the weighing embodiment one, be scattered in 60% (w/w, in the resistant starch butt) distilled water in, 50 ℃ of temperature, pH is under 3 the condition, adding the quality volumetric concentration is 6% (g/L, in the resistant starch butt) the alcoholic extract hydroxyl group of glutaraldehyde activation resistant starch, behind the reaction 4h, behind the phosphate buffer thorough washing, add 3% concanavalin A (w/w, in the resistant starch butt) carry out coupling, the temperature of coupling reaction is 20 ℃, and coupling time is 20h, obtains starch material after reacting completely; After starch material is used the phosphate buffer centrifuge washing, add unreacted activated group in the ethanolamine passivation starch material,, obtain the starch based segmented intestine targeting specific adhesion material of white powder through centrifuge washing final vacuum drying.
Embodiment four
With the bovine serum albumin is model drug, with the starch based segmented intestine targeting specific adhesion material of preparation among medicine (bovine serum albumin) and the embodiment one in 1: 9 ratio mixing of mass ratio after mistake 80 mesh sieves, the mass concentration of adding starch based segmented intestine targeting specific adhesion material dry weight 5% behind the triplicate is 10% hydroxypropyl methylcellulose (HPMC) aqueous solution, the system soft material, cross 20 mesh sieve pelletizes, then in 50 ℃ of baking oven inner drying 10min, after 18 mesh sieve granulate, make starch base bovine serum albumin oral colon-target adhesive tablet through tabletting, it is at gastric juice, release performance in intestinal fluid and the colonic fluid is as shown in table 1, illustrates that this starch based segmented intestine targeting specific adhesion material has the effect of oral colon-target controlled release medicine carrying.
Table 1
Embodiment five
With the 5-aminosalicylic acid is model drug, with the starch based segmented intestine targeting specific adhesion material of preparation among medicine (5-aminosalicylic acid) and the embodiment two in 1: 9 ratio mixing after mistake 80 mesh sieves, the mass concentration of adding starch based segmented intestine targeting specific adhesion material dry weight 5% behind the triplicate is 10% hydroxypropyl methylcellulose (HPMC) aqueous solution, the system soft material, cross 20 mesh sieve pelletizes, then in 50 ℃ of baking oven inner drying 10min, after 18 mesh sieve granulate, make starch base 5-aminosalicylic acid oral colon-target adhesive tablet through tabletting, it is at gastric juice, release performance in intestinal fluid and the colonic fluid is as shown in table 2, illustrates that starch based segmented intestine targeting specific adhesion material has the effect of oral colon-target controlled release medicine carrying.
Table 2
Figure G2008101983419D00062
Embodiment six
Be model drug with 5-aminosalicylic acid and bovine serum albumin respectively, with the starch based segmented intestine targeting specific adhesion material of preparation among medicine (5-aminosalicylic acid and bovine serum albumin) and the embodiment three in 1: 9 ratio mixing after mistake 80 mesh sieves, the mass concentration of adding starch based segmented intestine targeting specific adhesion material dry weight 5% behind the triplicate is 10% hydroxypropyl methylcellulose (HPMC) aqueous solution, the system soft material, cross 20 mesh sieve pelletizes, then in 50 ℃ of baking oven inner drying 10min, after 18 mesh sieve granulate, make starch base 5-aminosalicylic acid oral colon-target adhesive tablet and starch base bovine serum albumin oral colon-target adhesive tablet respectively through tabletting, it is at gastric juice, total release rate of intestinal fluid is respectively 9.5% and 10.2%, total release rate reaches 90.1% and 91.6% respectively behind the 40h in the colon, illustrates that starch based segmented intestine targeting specific adhesion material has the effect of oral colon-target controlled release medicine carrying.
The foregoing description is a preferred implementation of the present invention; but embodiments of the present invention are not restricted to the described embodiments; other any do not deviate from change, the modification done under spirit of the present invention and the principle, substitutes, combination, simplify; all should be the substitute mode of equivalence, be included within protection scope of the present invention.

Claims (3)

1. starch based segmented intestine targeting specific adhesion material, it is characterized in that: described starch based segmented intestine targeting specific adhesion material is the concanavalin A of coupling biologically active on resistant starch and getting, and described starch based segmented intestine targeting specific adhesion material is to be prepared from as follows:
Be that 50~80% resistant starch is 20~90 ℃ of temperature with water content, pH is under 2~5 the condition, adding is the alcoholic extract hydroxyl group of 1~10% glutaraldehyde activation starch in resistant starch butt quality volumetric concentration, behind reaction 0.25~6h, after the phosphate buffer washing, adding is carried out coupling in the concanavalin A of resistant starch butt 0.5~5%, the temperature of coupling reaction is 10~30 ℃, coupling time is 5~30h, obtain starch material after reacting completely, after starch material is used the phosphate buffer centrifuge washing; Add unreacted activated group in the ethanolamine passivation starch material then,, obtain starch based segmented intestine targeting specific adhesion material through centrifuge washing final vacuum drying.
2. the described starch based segmented intestine targeting specific adhesion material of claim 1 is as the application of carrier material in preparation polypeptide protein class biopharmaceutical macromolecular drug or treatment colonic diseases medicine.
3. starch based segmented intestine targeting specific adhesion material according to claim 2 is as the application of carrier material in preparation polypeptide protein class biopharmaceutical macromolecular drug or treatment colonic diseases medicine, it is characterized in that: described starch based segmented intestine targeting specific adhesion material prepares polypeptide protein class biopharmaceutical macromolecular drug or treatment colonic diseases medicine is to carry out as follows: behind polypeptide protein class biopharmaceutical macromolecular drug or treatment colonic diseases medicine and starch based segmented intestine targeting specific adhesion material mixing, with the hydroxypropyl methylcellulose aqueous solution is binding agent, through pelletize, dry, tabletting makes the starch based segmented intestine targeting specific adhesion tablet of medicine carrying.
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Citations (2)

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WO2004058343A1 (en) * 2002-12-17 2004-07-15 Concentric Medical, Inc. Soft filament occlusive device delivery system
CN1219072C (en) * 2003-12-12 2005-09-14 华南理工大学 Digestion tolerant starch and its preparation method and uses

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2004058343A1 (en) * 2002-12-17 2004-07-15 Concentric Medical, Inc. Soft filament occlusive device delivery system
CN1219072C (en) * 2003-12-12 2005-09-14 华南理工大学 Digestion tolerant starch and its preparation method and uses

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