CN103405777B - Application of HP-beta-CD-GMA-PEI as oral and transpulmonary absorption accelerant - Google Patents
Application of HP-beta-CD-GMA-PEI as oral and transpulmonary absorption accelerant Download PDFInfo
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Abstract
The invention discloses an application of HP-beta-CD-GMA-PEI as an oral and transpulmonary absorption accelerant. The HP-beta-CD-GMA-PEI can obviously promote the oral and transpulmonary absorption of water-soluble macro-molecular difficult-to-absorb drugs as an absorption accelerant; and toxicity investigation results show that the HP-beta-CD-GMA-PEI has no obvious damages to the oral and pulmonary absorption positions, so the HP-beta-CD-GMA-PEI is a safe absorption accelerant, can be applied in the oral and transpulmonary absorption preparations of the macro-molecular drugs, is used for improving the water-soluble macro-molecular difficult-to-absorb drugs, and is especially used for improving the oral and transpulmonary absorption bioavailability of protein peptide drugs.
Description
Technical field
The present invention relates to technical field of medicine, relate to HP-β-CD-GMA-PEI as oral and through the application of lung absorption enhancer.
Background technology
In recent years, along with the raising of the development of biotechnology, the application of combinatorial chemistry and high throughput screening drug, more and more medicine with physiologically active is developed gradually, and wherein, water-soluble macromolecule medicine such as protein, polypeptide drug are wherein classes.But these medicines also also exist limitation while having excellent activity.Protein, polypeptide drug are generally unstable in vivo, the acid in easy body and protease hydrolysis and degrade; Fat-soluble low, molecular weight is large, weak etc. through membranes barriers ability, be difficult to after finally causing these drug administrations be absorbed.Therefore clinical practice is main mainly with injecting pathway, but the body injury that causes of long term frequent drug administration by injection and spirit, economic pressures often make patient be difficult to bear.Therefore great to the Research Significance of such medicine Non-parenteral Delivery Routes.
For a long time, oral administration is because it is easy, good patient compliance, acceptable degree are high and noticeable.Meanwhile, through lung administration due to without first pass effect, the surface area that alveolar surface is huge, numerous advantages such as alveolar epithelial cells envelope barrier is thinner are also applied in Non-parenteral Delivery Routes gradually.
At present, improving macromole difficulty and absorb the drug bioavailability study mainly through following approach: as made prodrug by carrying out suitable structural modification to medicine, or being combined with macromolecular carrier albumen or polymer, to increase the lipotropy of medicine, reduce enzymolysis, thus improve bioavailability; Adopt high molecular polymer as intestinal sweater material, to reduce the destruction of gastric acid and part enzyme, reach the object of location release; Adopt and have significant immunoreation concurrently, the polypeptide drug such as insulin, calcitonin receptor endoenzyme also can be avoided and reduce to microgranule, liposome etc. that the new material of excellent histocompatibility and biological degradability is made degraded, strengthen mucosa penetration, thus greatly water soluble polymer drug bioavailability.But changing the physicochemical characteristics of medicine to increase its fat-soluble and metabolic stability by design and synthesis prodrug, is change medicine after all, there is different research and approval and enter the program that clinical trial applies; Microgranule needs polymer substance as framework material, and biological tissue's compatibility well biodegradable kind of carrier is limited, and the pharmacokinetics of these carriers yet needs further systematic study; Liposome is unstable when temperature is higher, also not high with the combination rate of water soluble polymer medicine, and its liquid form is easy to again be oxidized Sum decomposition, thus limits its extensive use in practice to a certain extent.
Being one of method easy, economic, safe in numerous research method for improving absorb the drug bioavailability and the absorption enhancer research carried out of difficulty, is also a main focus of current Pharmaceutical study.Up to the present, the absorption enhancer of bibliographical information probably can be summarized as following two classes: a class is micromolecule class absorption enhancer, comprises Medium chain fatty acid sodium-salt, cholate, cyclodextrin and derivant thereof, surfactant, chelating agen and other small-molecule substances such as NO and supplies and body, fatty acyl carnitine, bacitracin etc.; Another kind of is polymer class absorption enhancer, comprises cationic polymer, anionic polymer and sulfydryl polymer etc.Numerous result of study shows, above-mentioned absorption enhancer all significantly can improve difficulty and absorb the drug in the absorption of each medicine-feeding part, but along with the enhancing of its absorption enhancement effect, the mucosa injury of these absorption enhancers to absorption site also increases gradually, thus limits the application of these absorption enhancers in pharmaceutical preparation.Therefore, filter out a kind of absorption that significantly can improve difficulty and absorb the drug, the excellent absorption enhancer of damage will be caused to be then current problem demanding prompt solution to absorption site mucosa again.
Summary of the invention
The problem that the present invention solves is to provide HP-β-CD-GMA-PEI as oral and through the application of lung absorption enhancer, not only increase water-soluble macromolecule drug oral and the bioavailability through lung administration, and little to absorption site mucosal toxicity, security performance is high.
The present invention is achieved through the following technical solutions:
HP-β-CD-GMA-PEI in pharmaceutical preparation as oral administration and/or the application of absorption enhancer that absorbs the drug through lung.
Described HP-β-CD-GMA-PEI is as the application of the difficult absorption enhancer that absorbs the drug of water-soluble macromolecule.
Described HP-β-CD-GMA-PEI as oral administration, molecular weight 4000 ~ 10000 the application of drug absorption enhancer.
Described HP-β-CD-GMA-PEI as through lung, molecular weight 4000 ~ 10000 the application of drug absorption enhancer.
Described HP-β-CD-GMA-PEI is as the application of water-solubility protein peptide class macromolecular drug absorption enhancer.
Described HP-β-CD-GMA-PEI improves the bioavailability of medicine as absorption enhancer.
Described HP-β-CD-GMA-PEI promotes drug absorption by opening compact siro spinning technology between cell.
Described HP-β-CD-GMA-PEI, according to the difference of connected PEI molecular weight, comprises following three kinds:
HP-β-CD-GMA-PEI600, HP-β-CD-GMA-PEI1800 and HP-β-CD-GMA-PEI10000.
HP-β-CD-GMA-PEI is preparing the application in oral Preparation.
HP-β-CD-GMA-PEI is in the application of preparation in lung drug-delivery preparation.
Compared with existing absorption enhancer, the present invention has following useful effect:
The present invention is based on the effect that HP-β-CD-GMA-PEI promotes that medicine urgees intestinal absorption at body, short lung absorbs, propose HP-β-CD-GMA-PEI in pharmaceutical preparation as oral administration and/or the application of absorption enhancer that absorbs the drug through lung.
HP-β-CD-GMA-PEI, as absorption enhancer, obviously can promote that water-soluble macromolecule difficulty absorbs the drug oral and absorbs through lung; Simultaneously, Toxicity test result display HP-β-CD-GMA-PEI oral disposition and pulmonary absorption position mucosa are without obvious damage, therefore HP-β-CD-GMA-PEI is safe absorption enhancer, can be applicable to macromolecular drug oral and in lung absorbable preparation, absorb the drug for improving water-soluble macromolecule difficulty, especially albumen peptide medicament (as insulin, calcitonin etc.) bioavailability that is oral and that absorb through lung.
HP-β-CD-GMA-PEI, as absorption enhancer, promotes that the difficult absorption portion that absorbs the drug of macromole is opened compact siro spinning technology mechanism between cell by paracellular pathway and promotes drug absorption; Significantly can improve the absorption that difficulty absorbs the drug, can not cause damage again to absorption site mucosa, be a kind of excellent absorption enhancer.
Accompanying drawing explanation
Fig. 1 is the chemical structural drawing of absorption enhancer HP-β-CD-GMA-PEI.
Fig. 2 is that the HP-β-CD-GMA-PEI of different molecular weight (A) and variable concentrations (B) affects in Rats Intestinal Absorption facilitation FD4.
Fig. 3 is HP-β-CD-GMA-PEI1800(5%) to FD4(A), FD10(B) and FD70(C) to affect in Rats Intestinal Absorption facilitation.
Fig. 4 is that HP-β-CD-GMA-PEI is to intestinal absorption site mucosal toxicity evaluation result.
Fig. 5 is that HP-β-CD-GMA-PEI1800 is respectively to FD4(A), FD10(B) and FD70(C) at rat lung absorption enhancement exercising result.
Fig. 6 is that HP-β-CD-GMA-PEI is to pulmonary absorption position mucosal toxicity evaluation result.
Fig. 7 is that HP-β-CD-GMA-PEI is by opening compact siro spinning technology penetration enhancement authenticate result between cell.
Detailed description of the invention
Below in conjunction with specific embodiment, the present invention is described in further detail, and the explanation of the invention is not limited.
Its structural formula of absorption enhancers HP-β-CD-GMA-PEI(of the present invention as shown in Figure 1), that polymine is connected on hydroxypropyl beta cyclodextrin by glycidyl methacrylate, wherein, hydroxypropyl beta cyclodextrin is basic framework, glycidyl methacrylate is side chain, and polymine is adhesiveness functional groups.
HP-β-CD (HP-β-CD) is a kind of derivant of beta-schardinger dextrin-and 1,2 epoxy prapane condensation, and because on beta-schardinger dextrin-, hydroxyl is replaced by hydroxypropyl, destroy its intramolecular hydrogen bond, compared with beta-schardinger dextrin-, its water solublity significantly improves; It is stablized light and heat, and when HP-β-CD is used for polypeptide drugs, energy protease inhibition, to the decomposition of peptide medicament, improves peptide medicament stability; HP-β-CD is not substantially decomposed metabolism in human body, and also do not accumulate, the oral rear overwhelming majority excretes with feces, and parenterai administration all excretes with urine substantially; Nontoxic to kidney, to muscle and mucosa almost non-stimulated, surface activity is low, and hemolytic activity is low, relative to beta-schardinger dextrin-, uses safer.
Polymine (PEI) is a kind of water-soluble polymer produced by the polymerization of aziridine, and according to the size of its degree of polymerization, its molecular weight is different.PEI is not linear polymer completely, but one comprises primary amine, the part branch polymer of secondary amine and tertiary amine.Owing to containing multiple amino in its structure, so PEI has higher positive charge density, can be combined by electrostatic interaction with the surface of cell membrane of bear electricity, thus strengthen medicine transmembrane transport ability, and then promote difficult absorbing the drug in the absorption of intestinal.
Utilize the HP-β-CD-GMA-PEI of above-mentioned HP-β-CD and the synthesis of PEI feature not only can significantly improve macromole difficulty to absorb the drug bioavailability, and little to absorption site mucosal toxicity, and safety is high, is a kind of safety, efficiently absorption enhancer.
Urge intestinal absorption below in conjunction with HP-β-CD-GMA-PEI, embodiment that short lung absorbs to be to illustrate that HP-β-CD-GMA-PEI is as oral administration, the effect of absorption enhancer that absorbs the drug through lung.
1, HP-β-CD-GMA-PEI urgees rat absorption kinetics
Choose 8-10 male SD rat in age in week (body weight 230-250 gram), test front 16 h fast, can freely drink water, pentobarbital sodium intraperitoneal injection of anesthesia (40mg/kg), being lain on the back by rat is placed on fixing head, cut off along ventrimeson, from jejunum upper end intubate, with PBS(pH7.4) solution flushing intestinal, the other end seals after terminal ileum intubate, from intestinal segment upper end syringe, medicinal liquid is slowly injected, with mosquito forceps sealing, sew up abdominal part opening.Peel off rat jugular vein, get blood 0.25mL respectively at different intervals, be placed in the centrifuge tube of heparinization, centrifugal 5 minutes of 12000rpm, separated plasma, in centrifuge tube, is placed in ice chest to be measured.Adopt above-mentioned absorption kinetics model, respectively with the FDs(dextran labelling Fluorescein isothiocyanate of different molecular weight ranges) comprise FD4, FD10 and FD70(mean molecule quantity is respectively 4400,10000 and 70000) be model drug, investigate variable concentrations (2.5%, 5%, 10%) and variety classes HP-β-CD-GMA-PEI(HP-β-CD-GMA-PEI600, HP-β-CD-GMA-PEI1800, HP-β-CD-GMA-PEI10000) on the impact of above-mentioned model drug FDs at Rats Intestinal Absorption, result is as shown in Figure 2 and Figure 3.
Fig. 2 (A) is variety classes HP-β-CD-GMA-PEI(5%) impact on FD4 intestinal absorption, as shown in Figure 2 (A) shows, compared with the contrast being used alone FD4, three kinds of HP-β-CD-GMA-PEI600,1800,10000 all can improve the absorption of FD4 at small intestinal, wherein, HP-β-CD-GMA-PEI1800 shows the strongest absorption enhancement effect; Then, the HP-β-CD-GMA-PEI1800 choosing absorption enhancement effect the strongest is absorption enhancer, has investigated variable concentrations (2.5%, 5%, 10%) HP-β-CD-GMA-PEI1800 and has promoted ability to FD4 at intestinal absorption;
Fig. 2 (B) is variable concentrations HP-β-CD-GMA-PEI1800(2.5%, 5%, 10%) and on the impact of FD4 at intestinal absorption.Result shows, compared with the contrast being used alone FD4, concentration be 5% HP-β-CD-GMA-PEI1800 show the strongest absorption enhancement effect, be followed successively by 5% > 10% > 2.5%.
For investigating HP-β-CD-GMA-PEI1800 to the absorption enhancement ability of other macromole model drugs, choose FD10(MW10000) and FD70(MW70000) be model drug, to HP-β-CD-GMA-PEI1800(5%) FD10 and FD70 is evaluated in the absorption enhancement effect of small intestinal.Result is as shown in Figure 3, and wherein Fig. 3 (A), Fig. 3 (B), Fig. 3 (C) are respectively FD4, FD10 and FD70 in Rats Intestinal Absorption facilitation; HP-β-CD-GMA-PEI1800(5% can be seen) significantly can strengthen the absorption of FD10 at small intestinal, but to FD70 without obvious absorption enhancement effect.
Result shows that HP-β-CD-GMA-PEI can have absorption enhancement effect to the medicine of molecular weight less than 10000 at small intestinal.
2, HP-β-CD-GMA-PEI is to intestinal mucosa toxicity assessment
Choose 8-10 male SD rat in age in week (body weight 230-250 gram), adopt above-mentioned absorption kinetics experimental model, preparation variable concentrations (2.5%, 5%, 10%) HP-β-CD-GMA-PEI1800 solution gives rat small intestine position, and administration is after 4 hours, with PBS(pH7.4) rinse medicine-feeding part intestinal segment respectively, with total protein in perfusate and lactic acid dehydrogenase (LDH) for Testing index, evaluate HP-β-CD-GMA-PEI to absorption site mucosal toxicity, the results are shown in Figure 4.
As shown in Fig. 4 (A), Fig. 4 (B), compare with negative control group (PBS solution, pH7.4), each administration group HP-β-CD-GMA-PEI1800(2.5%, 5%, 10%) lactic acid dehydrogenase activity (B) and total protein concentration (A) be all without significant difference; Simultaneously, with positive controls (TritonX-100,3%) compare, each administration group tool significant difference (P < 0.01), show HP-β-CD-GMA-PEI1800(2.5%, 5%, 10%) each absorption site mucosa is not obviously damaged, can safety applications in above-mentioned concentration range.
3, HP-β-CD-GMA-PEI rat at body through lung absorption experiment
Choose 8-10 male SD rat in age in week (body weight 230-250 gram), test front 16 h fast, can freely drink water, pentobarbital sodium intraperitoneal injection of anesthesia (40mg/kg), being lain on the back by rat is placed on fixing head, surgical incision trachea, injects medicinal liquid according to 400 μ L/kg dosage microsyringes after tracheal intubation.Peel off rat jugular vein, get blood 0.25mL respectively at different intervals, be placed in the centrifuge tube of heparinization, centrifugal 5 minutes of 12000rpm, get blood plasma 100 μ L, be placed in ice chest to be measured.Adopt above-mentioned at body lung absorption experiment model, respectively with the FDs (FD4 of different molecular weight ranges, FD10 and FD70) be model drug, investigate variable concentrations (2.5%, 5%, 10%) and variety classes HP-β-CD-GMA-PEI (HP-β-CD-GMA-PEI600, HP-β-CD-GMA-PEI1800, HP-β-CD-GMA-PEI10000) impact that above-mentioned model drug is absorbed at rat lung, the results are shown in Figure 5.
Figure 5 shows that variable concentrations (2.5%, 5%, 10%) HP-β-CD-GMA-PEI1800 is respectively to FD4, FD10 and FD70 pulmonary absorption facilitation result, as we can see from the figure, high concentration (5%, 10%) HP-β-CD-GMA-PEI1800 all can improve the pulmonary absorption of FD4, FD10 and FD70, simultaneously, along with the increase of model drug molecular weight, its absorption enhancement effect reduces gradually.In high, normal, basic three concentration of application, concentration be 5% HP-β-CD-GMA-PEI1800 to molecular weight be 4400 FD4 show the strongest absorption enhancement effect at pulmonary absorption, show that such absorption enhancer has good absorption enhancement effect to the macromolecular drug that molecular weight is about 4000.
4, HP-β-CD-GMA-PEI is to pulmonary's mucosal toxicity evaluation experimental
Choose 8-10 male SD rat in age in week (body weight 230-250 gram), adopt above-mentioned through lung absorption experiment model, preparation variable concentrations (2.5%, 5%, 10%) HP-β-CD-GMA-PEI1800 solution, give rat lung administration respectively, administration is after 4 hours, with PBS(pH7.4) rinse pulmonary respectively, collect lung perfusate, with total protein in perfusate and lactic acid dehydrogenase (LDH) for Testing index, evaluate HP-β-CD-GMA-PEI to pulmonary absorption position mucosal toxicity, the results are shown in Figure 6.
As shown in Figure 6, as compared to matched group (PBS solution, pH7.4), each administration group HP-β-CD-GMA-PEI1800(2.5%, 5%, 10%) total protein concentration and lactic acid dehydrogenase activity are all without significant difference, and with positive controls (NaDC, 1%) tool significant difference (P < 0.01), show HP-β-CD-GMA-PEI1800(2.5%, 5%, 10%) pulmonary absorption position mucosa is not significantly damaged, can safety applications in above-mentioned concentration range.
5, HP-β-CD-GMA-PEI absorption enhancement mechanism is investigated
Absorption enhancer promotes that medicine transmembrane transport is generally main and carries out in two ways, one is through cellular pathways, another kind is paracellular pathway, in this experiment, by research HP-β-CD-GMA-PEI to CF(CF 5(6)-Carboxyfluorescein, the model drug of drug absorption is promoted by the compact siro spinning technology opened between cell bypass) absorption enhancement situation, thus confirm whether HP-β-CD-GMA-PEI promotes drug absorption through paracellular pathway.Specific experiment scheme is as follows: choose 8-10 male SD rat in age in week (body weight 230-250 gram), test front 16 h fast, can freely drink water, pentobarbital sodium intraperitoneal injection of anesthesia (40mg/kg), being lain on the back by rat is placed on fixing head, surgical incision trachea, gives CF solution and HP-β-CD-GMA-PEI1800 (5%)-CF solution respectively after tracheal intubation.Peel off rat jugular vein, get blood 0.25mL respectively at different intervals, be placed in the centrifuge tube of heparinization, centrifugal 5 minutes of 12000rpm, separated plasma, is placed in ice chest to be measured, the results are shown in Figure 7.
As seen from Figure 7, compared with matched group (CF solution), HP-β-CD-GMA-PEI1800(5%) administration group plasma drug level significantly improves, HP-β-CD-GMA-PEI1800(5% is described) can greatly strengthen CF at pulmonary absorption, thus prompting HP-β-CD-GMA-PEI promotes that the difficult absorption portion that absorbs the drug of above-mentioned macromole is opened compact siro spinning technology mechanism between cell by paracellular pathway and promotes drug absorption.
Show through above-mentioned five embodiments: HP-β-CD-GMA-PEI, as absorption enhancer, obviously can promote that water-soluble macromolecule difficulty absorbs the drug oral and absorbs through lung; Simultaneously, Toxicity test result display HP-β-CD-GMA-PEI oral disposition and pulmonary absorption position mucosa are without obvious damage, can infer thus, HP-β-CD-GMA-PEI is safe absorption enhancer, can be applicable to macromolecular drug oral and in lung absorbable preparation, absorb the drug for improving water-soluble macromolecule difficulty, especially albumen peptide medicament (as insulin, calcitonin etc.) bioavailability that is oral and that absorb through lung.
So HP-β-CD-GMA-PEI can be applied to prepare oral Preparation;
And HP-β-CD-GMA-PEI can be applied to preparation through lung drug-delivery preparation.
Claims (7)
1.HP-β-CD-GMA-PEI is as oral administration and/or the application of absorption enhancer that absorbs the drug through lung in pharmaceutical preparation, and wherein, HP-β-CD-GMA-PEI can improve the bioavailability of medicine as absorption enhancer; HP-β-CD-GMA-PEI can promote the absorption of water-solubility protein peptide class macromolecular drug as absorption enhancer; Described HP-β-CD-GMA-PEI, according to the difference of connected PEI molecular weight, comprises following three kinds: HP-β-CD-GMA-PEI600, HP-β-CD-GMA-PEI1800 and HP-β-CD-GMA-PEI10000.
2. apply as claimed in claim 1, it is characterized in that, HP-β-CD-GMA-PEI is as the application of the difficult absorption enhancer that absorbs the drug of water-soluble macromolecule.
3. apply as claimed in claim 2, it is characterized in that, HP-β-CD-GMA-PEI as oral administration, molecular weight 4000 ~ 10000 the application of drug absorption enhancer.
4. apply as claimed in claim 2, it is characterized in that, HP-β-CD-GMA-PEI as through lung, molecular weight 4000 ~ 10000 the application of drug absorption enhancer.
5. apply as claimed in claim 1 or 2, it is characterized in that, HP-β-CD-GMA-PEI opens compact siro spinning technology between cell by paracellular pathway and promotes drug absorption.
6. described in claim 1, HP-β-CD-GMA-PEI is preparing the application in oral Preparation.
7. HP-β-CD-GMA-PEI described in claim 1 is in the application of preparation in lung drug-delivery preparation.
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| Cyclodextrin-Modified Polyethylenimine Polymers for Gene Delivery;Pun,et al;《Bioconjugate Chem》;20041231;第15卷;第831-840页 * |
| 环糊精及其衍生物在多肽/蛋白质类药物非注射给药体系中的应用;陈星羽等;《中国生物工程杂志》;20101231;第30卷(第12期);第111-115页 * |
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