CN101134785B - Colonic microflora degradation material and preparation method and uses thereof - Google Patents
Colonic microflora degradation material and preparation method and uses thereof Download PDFInfo
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- Polysaccharides And Polysaccharide Derivatives (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
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Abstract
The present invention discloses colon flora degraded material and its preparation process and use. The colon flora degraded material as one polyelectrolyte composite comprising sodium cellulose sulfate (NaCS) and chitosan is prepared through mixing water solution of NaCS and acetic acid solution of chitosan, reacting in a reactor under high speed stirring to form homogeneous white emulsion, and further processing to form coated solid product. The colon flora degraded material is insoluble in solution of all pH values and may be degraded by the colon flora secreted enzyme, so that it is hopeful to become new carrier material of colon flora targeting administration system. It has facile material, high biocompatibility, high safety, simple preparation process and other advantages.
Description
Technical field
The present invention relates to a kind of colonic microflora degradation material and its production and use.
Background technology
The solid support material or the correlation technique that suit need be selected by the colon targeting drug administration system, pharmaceutical cpd is transported to human body ileocecus position carries out disintegration or release, thereby make medicine absorb the effect of performance whole body therapeutic, and it is also few to satisfy the material of these needs at present in colon local performance curative effect or per rectum.
Carry out the colon targeting drug administration systematic study and have important actual application value.At first, for treatment inflammatory bowel disease (IBD), as enteropathies such as colitis, ulcerative colitis and Crohn diseases, general oral administration not only can't make medicine be scattered in site of action with high density, and also has bigger side effect.If adopt the colon targeting drug administration technology that hormone, anti-infective or other types of drug are transported to the human body ileocecus, it is discharged and the performance drug effect at large intestine, thereby the partial concn that can improve medicine improve result of treatment.Secondly, genetically engineered drug belongs to protein and polypeptide drug mostly, with synthetic and natural small-molecule drug comparison, they all have its singularity in process and the drug efficacy study in vivo, in whole gi system, the proteolysis enzyme concn at colon position is much smaller than other section of digestive tube, and medicine is grown (can reach more than 48 hours) in this position residence time, colon wall is also little than small intestine to the resistance that macromole penetrates simultaneously, helps the abundant absorption of this type of medicine.Therefore colon targeting drug administration absorbs the place for the protein and peptide drugs oral administration provides an ideal undoubtedly.Moreover in the diseases such as asthma, stenocardia and sacroiliitis of treatment night-time attack, medicine slowly discharges at colon, will bring into play long-acting.In addition, the medicine of the treatment rectum cancer adopts the colon targeting drug administration technology, can reduce when oral chemotherapeutic GI stimulation is improved curative effect thereby improve local drug concentration, can also reduce because the general toxic reaction that the chemotherapeutic gastrointestinal absorption causes.For some vermicides and colon diagnostic reagent, colon targeting drug administration also can reduce dosage and side effect.
In the oral colon-target drug delivery system, it is crucial that solid support material plays a part, and it has decisive role at aspects such as the release of active function composition, guiding.The prerequisite condition of the segmented intestine targeted carrier of ideal is: (1) protection activeconstituents is not destroyed through stomach and small intestine the time or seldom destroys; (2) pharmaceutical cpd can discharge at colon, has good target; (3) good biocompatibility of integral material; (4) biodegradable, and degraded product also must be biocompatible, nontoxic, easy-clear; (5) do not react and change its character with pharmaceutical cpd.
Solid support material can mainly contain three kinds according to the mode of action, and pH dependent form, time-dependent and flora flip-over type are wherein best with flora flip-over type Targeting Performance again, is the focus of studying at present.The segmented intestine targeted solid support material of being paid close attention to of flora flip-over type mainly is divided into two kinds, and a kind of is azo-compound, and a kind of is polysaccharide compound.1986; Saffran etc. adopted vinylbenzene (ST), HEMA, linking agent 4,4 '-divinyl nitrogen benzide or N, N '-two (β-vinylbenzene alkylsulfonyl)-4; 4 '-chrysoidine synthesized multipolymer, used it for capsule and piller that dressing is made Regular Insulin and vassopressin.Show that through experimentation on animals above-mentioned preparation is all disengaged medicine at the colon position by microflora degradation.But azo micromolecular compound is a kind of strong carcinogen, and is bigger to the toxic side effect of human body.
Polysaccharide compound is an a class segmented intestine targeted solid support material newly developed, pays close attention to more at present.This base polymer has multiple derivative, and molecular weight ranges is wide, and chemical constitution is different, and majority has that toxicity is lower, biological degradability is better and stable advantage of higher.But this compounds mostly is water-soluble macromolecule, therefore need transform its structure, under the prerequisite that does not weaken its targeting, improves its hydrophobicity, more effectively to play a role.At present the main method of using is that solid support material is carried out dressing, but this method complex process, in the colonic drug release slowly or shortcoming such as drug release arranged in stomach and intestine.And also there is the biocompatibility of degraded product in coating material itself, and is slow to active function composition release rate, can't avoid upper digestive tract to occur that pharmaceutical cpd is revealed or discharge weak points such as incomplete at the colonic pharmaceutical cpd.
Chitosan is a glycosaminoglycan, is a kind of polycation electrolyte that has positive charge, is the deacetylated product of chitin, often is used as a kind of slow/controlled release material in recent years.Chitosan has good thing consistency, and the glycosidic link in its molecule can be degraded by colonic enzyme, still, chitosan is soluble in acid, and it can't normally pass through the human stomach, can not be as colon dissolved single-material, therefore, chitosan must be modified or other processing.
NaCS (Ushercell) is a kind of water soluble dyes derivative, for having the polyanion polyelectrolyte of negative charge.It is to be raw material with the Mierocrystalline cellulose, and the mixing solutions of sulfuric acid and n-propyl alcohol is a sulphonating agent, and heterogeneous method prepares the Ushercell of water-soluble high-substitution.Concrete steps are as follows: 1) add an amount of n-propyl alcohol in a certain amount of vitriol oil, keep low temperature and stirring, mix, form sulphonating agent.2) by a certain percentage Mierocrystalline cellulose is joined in the sulphonating agent, low temperature is reaction down, keeps stirring.3) after reaction finishes, solid-liquid separation, washed with isopropyl alcohol obtains the cellulose sulfuric acid ester solid.4) add sodium hydroxide solution in the cellulose sulfuric acid ester solid, pH to 9 is regulated in the neutralization while dissolving, and solid-liquid separation is removed solid, obtains the cellulose sulfate sodium solution.5) add an amount of ethanol, be settled out Ushercell, through centrifugal or filter to isolate Ushercell precipitation.6) vacuum-drying obtains the Ushercell solid.
It has advantages such as nontoxic, harmless, good film-forming property.Use more as microencapsulation material in recent years.It can form polyelectrolyte polymers water insoluble and sour, basic solution with chitosan, and this compound polyelectrolyte can be degraded by the secreted enzyme of colonic microflora again, thereby can be used as colon targeting drug administration system solid support material.
Summary of the invention
The purpose of this invention is to provide a kind of colonic microflora degradation material and its production and use.Its molecular structural formula of this colonic microflora degradation material is:
This kind material is Ushercell and the polyelectrolyte material that formed by chitosan, and it has film forming characteristics preferably, has mechanical property preferably after making film, and tensile strength is about 7.03～14.73MPa, and elongation at break is about 29.98～41.62%.Behind its drying and forming-film, be insoluble to the aqueous solution of pH=1.0～14.0, but can be degraded, utilize this specific character, use it for the solid support material of colon targeting drug administration system by the secreted beta-glycosidase of colonic microflora.
The preparation method of colonic microflora degradation material comprises the steps:
1) be 30～800cp with viscosity, it is in 0.5～3% acetum that the chitosan of deacetylation 〉=85% is dissolved in mass volume ratio concentration, is mixed with mass volume ratio concentration and is 0.3～2% chitosan-acetic acid solution, standby;
2) be 100～1000kD with molecular weight, the sulfuric acid substitution value is that mass volume ratio concentration that 0.2～1.0 Ushercell is mixed with is 1～5% cellulose sulfate sodium water solution, and is standby;
3) above-mentioned chitosan-acetic acid solution and cellulose sulfate sodium solution are mixed with the volume ratio of 1:3～3:1, stir, carry out the polyelectrolyte polyreaction and form evenly emulsion liquid of white, stirring velocity is 400～2000r/min, and the reaction times is 1～40min.
Described Ushercell is prepared from through heterogeneous method by the raw material of rich cellulose such as absorbent cotton, linters, Microcrystalline Cellulose, and the sulfuric acid substitution value is 0.2～1.0, and molecular weight is 100～1000kD.The aqueous solution mass volume ratio concentration of Ushercell is preferably 2～4%.Chitosan viscosity is preferably 50～600cp, deacetylation 〉=85%.The chitosan mass volume by volume concentration is preferably 0.5～1.5%, and acetum mass volume ratio concentration is preferably 0.5～2%.Two kinds of solution blending ratio preferred cellulose aqueous sodium persulfate solutions: chitosan-acetic acid solution is 1:2～2:1.Stirring velocity is preferably 800～1800r/min.It is 1～30min that reaction times is preferably.
The present invention compares with present technology, has following beneficial effect:
(1) the present invention is with the compound polyelectrolyte of polymer anion Ushercell and the formation of polymer cation chitosan reaction, it is a kind of novel material of colonic microflora degradation, the carrier candidate material that can be used for the colon targeting drug administration system, this material good biocompatibility, no side effects, cheap and easy to get, preparation technology is simple, mild condition.
(2) novel material of the colonic microflora degradation for preparing of the present invention has better segmented intestine targeted performance and release performance.The capsule for preparing as matrix, and can reach more than 90% in colonic 3h release amount less than 5% at stomach and enteral amount of leakage.
Embodiment
The invention will be further described by the following examples:
Embodiment 1
With viscosity is 50cp, it is in 0.5% acetum that the chitosan of deacetylation 90% is dissolved in mass volume ratio concentration, be mixed with mass volume ratio concentration and be 0.5% solution, (chitosan-acetic acid solution: the volume ratio cellulose sulfate sodium water solution) and molecular weight are 100kD with 2:1 then, the sulfuric acid substitution value is that mass volume ratio concentration that 1.0 Ushercell is mixed with is that 4% aqueous solution is in reactor, stirring velocity is 600r/min, and the reaction times is 30min.To the even emulsion liquid of reaction formation white, then in 45 ℃ of following vacuum-drying film forming.Carry out the external degradation experiment with artificial colonic fluid, (degradation rate is defined as: be 17.8% proper mass * 100% before the quality/degraded of degrading in artificial colonic fluid) to obtain the degradation rate of this material in colon.
Embodiment 2
With viscosity is 600cp, it is in 2% acetum that the chitosan of deacetylation 85% is dissolved in mass volume ratio concentration, be mixed with mass volume ratio concentration and be 1.5% solution, (chitosan-acetic acid solution: the volume ratio cellulose sulfate sodium water solution) and molecular weight are 1000kD with 1:2 then, the sulfuric acid substitution value is that mass volume ratio concentration that 0.2 Ushercell is mixed with is that 2% aqueous solution is in reactor, stirring velocity is 1800r/min, and the reaction times is 1min.To the even emulsion liquid of reaction formation white, then in 45 ℃ of following vacuum-drying film forming.Carry out the external degradation experiment with artificial colonic fluid, obtaining the degradation rate of this material in colon is 22.5%.
Embodiment 3
With viscosity is 800cp, it is in 0.3% acetum that the chitosan of deacetylation 85% is dissolved in mass volume ratio concentration, be mixed with mass volume ratio concentration and be 0.3% solution, (chitosan-acetic acid solution: the volume ratio cellulose sulfate sodium water solution) and molecular weight are 1000kD with 3:1 then, the sulfuric acid substitution value is that mass volume ratio concentration that 0.2 Ushercell is mixed with is that 1% aqueous solution is in reactor, stirring velocity is 2000r/min, and the reaction times is 40min.To the even emulsion liquid of reaction formation white, then in 45 ℃ of following vacuum-drying film forming.Carry out the external degradation experiment with artificial colonic fluid, obtaining the degradation rate of this material in colon is 7.4%.
Embodiment 4
With viscosity is 30cp, it is in 0.5% acetum that the chitosan of deacetylation 99% is dissolved in mass volume ratio concentration, be mixed with mass volume ratio concentration and be 2% solution, (chitosan-acetic acid solution: the volume ratio cellulose sulfate sodium water solution) and molecular weight are 100kD with 1:3 then, the sulfuric acid substitution value is that mass volume ratio concentration that 1.0 Ushercell is mixed with is that 5% aqueous solution is in reactor, stirring velocity is 400r/min, and the reaction times is 40min.To the even emulsion liquid of reaction formation white, then in 45 ℃ of following vacuum-drying film forming.Carry out the external degradation experiment with artificial colonic fluid, obtaining the degradation rate of this material in colon is 11.6%.
Embodiment 5
With viscosity is 300cp, it is in 1% acetum that the chitosan of deacetylation 85% is dissolved in mass volume ratio concentration, be mixed with mass volume ratio concentration and be 1% solution, (chitosan-acetic acid solution: the volume ratio cellulose sulfate sodium water solution) and molecular weight are 900kD with 1:1 then, the sulfuric acid substitution value is that mass volume ratio concentration that 0.28 Ushercell is mixed with is that 4% aqueous solution is in reactor, stirring velocity is 800r/min, and the reaction times is 15min.To the even emulsion liquid of reaction formation white, then in 45 ℃ of following vacuum-drying film forming.Carry out the external degradation experiment with artificial colonic fluid, obtaining the degradation rate of this material in colon is 48.5%.
Embodiment 6
With viscosity is 300cp, it is in 1% acetum that the chitosan of deacetylation 85% is dissolved in mass volume ratio concentration, be mixed with mass volume ratio concentration and be 1% solution, (chitosan-acetic acid solution: the volume ratio cellulose sulfate sodium water solution) and molecular weight are 600kD with 1:1 then, the sulfuric acid substitution value is that mass volume ratio concentration that 0.4 Ushercell is mixed with is that 3% aqueous solution is in reactor, stirring velocity is 800r/min, and the reaction times is 15min.To the even emulsion liquid of reaction formation white, then in 45 ℃ of following vacuum-drying film forming.Carry out the external degradation experiment with artificial colonic fluid, obtaining the degradation rate of this material in colon is 38.6%.
Embodiment 7
With viscosity is 300cp, it is in 1% acetum that the chitosan of deacetylation 85% is dissolved in mass volume ratio concentration, be mixed with mass volume ratio concentration and be 1.5% solution, (chitosan-acetic acid solution: the volume ratio cellulose sulfate sodium water solution) and molecular weight are 300kD with 1:1 then, the sulfuric acid substitution value is that mass volume ratio concentration that 0.4 Ushercell is mixed with is that 3% aqueous solution is in reactor, stirring velocity is 800r/min, and the reaction times is 15min.To the even emulsion liquid of reaction formation white, then in 45 ℃ of following vacuum-drying film forming.Carry out the external degradation experiment with artificial colonic fluid, obtaining the degradation rate of this material in colon is 31.3%.
Claims (9)
1. a colonic microflora degradation material is characterized in that, its molecular structural formula is:
2. the preparation method of colonic microflora degradation material according to claim 1 is characterized in that comprising the steps:
1) be 30～800cp with viscosity, it is in 0.5～3% acetum that the chitosan of deacetylation 〉=85% is dissolved in mass volume ratio concentration, is mixed with mass volume ratio concentration and is 0.3～2% chitosan-acetic acid solution, standby;
2) be 100～1000kD with molecular weight, the sulfuric acid substitution value is that mass volume ratio concentration that 0.2～1.0 Ushercell is mixed with is 1～5% cellulose sulfate sodium water solution, and is standby;
3) above-mentioned chitosan-acetic acid solution and cellulose sulfate sodium solution are mixed with 1: 3～3: 1 volume ratio, stir, carry out the polyelectrolyte polyreaction and form evenly emulsion liquid of white, stirring velocity is 400～2000r/min, and the reaction times is 1～40min.
3. the preparation method of a kind of colonic microflora degradation material according to claim 2, it is characterized in that: described Ushercell is prepared from through heterogeneous method by absorbent cotton, linters, Microcrystalline Cellulose, the sulfuric acid substitution value is 0.2～1.0, and molecular weight is 100～1000kD.
4. the preparation method of a kind of colonic microflora degradation material according to claim 2, it is characterized in that: the aqueous solution mass volume ratio concentration of described Ushercell is 2～4%.
5. the preparation method of a kind of colonic microflora degradation material according to claim 2, it is characterized in that: described chitosan viscosity is 50～600cp.
6. the preparation method of a kind of colonic microflora degradation material according to claim 2, it is characterized in that: described chitosan mass volume by volume concentration is 0.5～1.5%, acetum mass volume ratio concentration is 0.5～2%.
7. the preparation method of a kind of colonic microflora degradation material according to claim 2, it is characterized in that: described two kinds of solution blending ratios are 1: 2～2: 1.
8. the preparation method of a kind of colonic microflora degradation material according to claim 2 is characterized in that: described stirring velocity 600～1800r/min.
9. the preparation method of a kind of colonic microflora degradation material according to claim 2, it is characterized in that: the described reaction times is 1～30min.
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| CN2007100708123A CN101134785B (en) | 2007-08-17 | 2007-08-17 | Colonic microflora degradation material and preparation method and uses thereof |
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| CN1310630A (en) * | 1998-07-23 | 2001-08-29 | 三阳社 | Composition and pharmaceutical dosage form for colonic drug delivery using polysaccharides |
| WO2005027878A1 (en) * | 2003-09-19 | 2005-03-31 | Penwest Pharmaceuticals Co. | Delayed released dosage forms |
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| CN1310630A (en) * | 1998-07-23 | 2001-08-29 | 三阳社 | Composition and pharmaceutical dosage form for colonic drug delivery using polysaccharides |
| WO2005027878A1 (en) * | 2003-09-19 | 2005-03-31 | Penwest Pharmaceuticals Co. | Delayed released dosage forms |
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