CN110522921A - A kind of insulin with insulin capturing function transports the synthetic method of system - Google Patents
A kind of insulin with insulin capturing function transports the synthetic method of system Download PDFInfo
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- CN110522921A CN110522921A CN201810506150.8A CN201810506150A CN110522921A CN 110522921 A CN110522921 A CN 110522921A CN 201810506150 A CN201810506150 A CN 201810506150A CN 110522921 A CN110522921 A CN 110522921A
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- Prior art keywords
- insulin
- synthetic method
- chitosan
- beta cyclodextrin
- geniposide
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Classifications
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K38/00—Medicinal preparations containing peptides
- A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
- A61K38/17—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
- A61K38/22—Hormones
- A61K38/28—Insulins
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/50—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
- A61K47/69—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the conjugate being characterised by physical or galenical forms, e.g. emulsion, particle, inclusion complex, stent or kit
- A61K47/6949—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the conjugate being characterised by physical or galenical forms, e.g. emulsion, particle, inclusion complex, stent or kit inclusion complexes, e.g. clathrates, cavitates or fullerenes
- A61K47/6951—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the conjugate being characterised by physical or galenical forms, e.g. emulsion, particle, inclusion complex, stent or kit inclusion complexes, e.g. clathrates, cavitates or fullerenes using cyclodextrin
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P3/00—Drugs for disorders of the metabolism
- A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
- A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
Abstract
Present invention relates particularly to the synthetic methods that a kind of insulin with insulin capturing function transports system, belong to synthesis of medical technical field of pharmaceuticals.The synthetic method is the following steps are included: (1) selects mono amino beta cyclodextrin；(2) using mono amino beta cyclodextrin as the medium for positioning and capturing insulin, mixing is sufficiently stirred in aqueous solution with insulin and makes it combine, form the insulin molecule with capture label；(3) use Geniposide for crosslinking agent, chitosan is backbone, completes the crosslinking of amino, and chitosan captures insulin by being crosslinked with mono amino beta cyclodextrin；Form the nanoparticle with capture insulin；Synthetic method reaction of the invention is common, and feasibility is higher, mild condition, does not destroy the bioactivity of insulin；And the material therefor toxicity of synthetic method is extremely low, Geniposide is genipin, and compared with other common crosslinking agents, toxicity is extremely low；Cyclodextrin, chitosan are also common natural materials, hardly have a bio-toxicity.
Description
[technical field]
The present invention relates to synthesis of medical technical field of pharmaceuticals, and in particular to a kind of insulin with insulin capturing function
Transport the synthetic method of system.
[background technique]
Accumulation in recent years recognizes researchers gradually, and diabetes are a kind of comprehensive endocrine system diseases, it and pancreas
Imbalance, the carbohydrate of body and the metabolism of lipid of the secretion of island element multiple metabolic pathways all relevant to mechanism have related
Property [1], hyperglycemia is one of its significant symptom.There are many cause of disease, including life stress, dietary structure, immune disorders for diabetes
Deng.Diabetic needs prolonged administration of drugs or insulin injection that its blood glucose is maintained to be in appropriate section, and undertakes higher
Complication risk, such as fracture, thyroid function and blood lipid level are abnormal, foot lesion, heart disease etc..So although
Diabetes are not a kind of fatal disease, but it has more serious influence to quality of life, the health index etc. of patient.The whole world
For Disease Spectrum studies have shown that diabetic is more than 4.23 hundred million people, disability adjusts life years (disability-
Adjusted life years, DALY) it is also significantly greater than desired value.Diabetes have become patient people and society and are not sneezed at
Disease Spectrum.
Diabetes are broadly divided into four classes, are a patients with type Ⅰ DM respectively, type-II diabetes, diabetes during pregnancy and other types of
Diabetes.Wherein a type and type-II diabetes account for 90% or more of main number of patients, can only alleviate symptom by drug, it is extremely difficult to
It cures.External supplement insulin is the necessary treatment method of a patients with type Ⅰ DM Yu more serious other class patients with type Ⅰ DM, Neng Gougao
Effect reduces patient blood glucose.Injecting pathway is the external supply approach of existing insulin regular, but will cause trouble since its is invasive
Person's compliance is poor, and circulation in vivo avoids the first pass effect of liver, forms that blood vessel insulin concentration in periphery is excessively high to ask
Topic.Then, seem extremely important using the exploitation that nanostructure transports system as the insulin of carrier, a variety of non-intruding approach.
Effect is loaded and all there is raw material insulin drug in the researchs such as lung inhalation route, buccal absorption approach, oral route
Rate is low, transport drug release it is very fast the problems such as.Even if in the research that closed loop (Close-loop) insulin transports system, though
The release of insulin can preferably be adjusted by so demonstrating such glucose irritability and transporting system, but the synthesis of its system is still
Significantly by synthesis process on the lower influence of raw material insulin utilization rate.In the research for respectively transporting system, researchers
Effort focus primarily upon controllableization, the Intelligent improvement for increasing the modification of the target of drug its absorption efficiency and its release mode
[, and the initial stage is synthesized in system, intelligentized synthetic strategy is temporarily less to be referred to.On the other hand, even if more research is directed to pancreas
The controlled-release effect that island element transports system improves, still it is not difficult to find that insulin too fast release in transporting system is its dimension
Hold hypoglycemic effect, the continual and steady obstruction completing insulin and transporting.So developing a kind of transporting with insulin capturing function
System combines individually or with other transport structures it, will be a kind of from the stage of synthesis, for a variety of systems that transport
Synthesis provides basis, increases the optimisation strategy of each existing combined coefficient for transporting system；It also will be to enhance insulin and transport body
The binding force of system slows down its rate of release, promotes its effective means to glycemic control.
Since insulin releases mouth caused by discharging the common causes such as too fast, system enteric epithelium transmitance is low in alimentary canal
Admit defeat transport the low problem of biological insulin pick-up rate be existing insulin transport system be extended to clinical application major obstacle it
One.It summarizes the insulin delivered and transports architectural study, it is not difficult to find that novel insulin, which transports system, is normally based on one kind newly
The material or design of grain husk, promote system from some specific angle, preferably transport insulin life relatively to have
Object pick-up rate.For example, researcher applies albumen, cell-penetrating egg with targeting enteric epithelium goblet cell (Goblet Cell)
The characteristic of the substances such as white (CPP), vitamin B12, design insulin transport system, have reached and dramatically increased the system of transporting by intestines
The absorptivity of skin, to promote the effect of different blood glucose levels.However, these substances can only play work in specific system
With the versatility in different systems then has biggish limitation, a kind of general component structure is not synthesized, to be unable to shape
At a kind of propagable structural modification, can not systematic propulsion insulin transport system and be total to problematic solution.So this
Project research is developed on the basis of verifying the effect of active principle a kind of more general functional element, is made
Its wide functional promotion that system is transported for oral insulin.
[summary of the invention]
Goal of the invention of the invention is: in view of the above problems, synthetic method reaction of the invention is common, feasible
Higher, the mild condition of property, does not destroy the bioactivity of insulin；And the material therefor toxicity of synthetic method is extremely low, Geniposide is
Genipin, compared with other common crosslinking agents, toxicity is extremely low；Cyclodextrin, chitosan are also common natural materials, several
Do not have bio-toxicity.
To achieve the goals above, The technical solution adopted by the invention is as follows:
A kind of insulin with insulin capturing function of the present invention transports the synthetic method of system, the synthetic method packet
It includes following steps: (1) selecting mono amino beta cyclodextrin, molecular formula are as follows:
(2) it using mono amino beta cyclodextrin as the medium for positioning and capturing insulin, is sufficiently stirred in aqueous solution with insulin
It mixes mixing to make it combine, forms the insulin molecule with capture label；Since mono amino beta cyclodextrin has inner hydrophobic, outside
The hydrophilic property in portion, also there are many hydrophobic groupings on insulin surface, and in aqueous solution, mono amino beta cyclodextrin can active and pancreas islet
Plain surface hydrophobicity group combines.
(3) use Geniposide for crosslinking agent, chitosan is backbone, under conditions of pH=3.8~4.5, in 8~15 DEG C of rings
18~30h is stirred in border, completes the crosslinking of amino, and chitosan captures insulin by being crosslinked with mono amino beta cyclodextrin；Shape
At the nanoparticle with capture insulin；In addition, insulin in acid condition stablize by property, bioactivity is not by shadow
It rings.And Geniposide can also be crosslinked with this condition.
In synthetic method of the invention, crosslinking agent Geniposide described in step (3) first stirs in aqueous solution with chitosan
Polymer is formed, then is mixed with the insulin molecule with capture label, the nanoparticle with capture insulin is formed.
And crosslinking agent Geniposide forms polymer with the first stirring in aqueous solution of chitosan and carries out at room temperature, 2~6h of mixing time.
The present invention will select the derivative and crosslinking agent appropriate of beta cyclodextrin first, make derivative, the crosslinking of beta cyclodextrin
Agent, chitosan three its can react under mild conditions.It is again that the derivative of beta cyclodextrin and insulin is jointly molten
Solution forms the insulin molecule with capture label.Then crosslinking agent Geniposide and chitosan are added under mild conditions, it will
The beta cyclodextrin derivative combined with insulin is crosslinked with the amino in polymer, thus make beta cyclodextrin become positioning,
Capture the medium of insulin
In conclusion by adopting the above-described technical solution, the beneficial effects of the present invention are:
1, synthetic method of the invention combines mono amino beta cyclodextrin sufficiently with insulin, avoids monoamine
Base beta cyclodextrin first with it is chitosan crosslinked, and cause steric hindrance larger, mono amino beta cyclodextrin feelings less in conjunction with insulin
Condition.
2, reaction of the invention is common, and feasibility is higher, mild condition, does not destroy the bioactivity of insulin.
3, synthetic method of the invention can be applied to the medicine-carried system of drug of other surfaces with hydrophobic group
Synthesis in, for increasing the utilization rate of bulk pharmaceutical chemicals.
4, the material therefor toxicity of synthetic method of the present invention is extremely low, and Geniposide is genipin, with other common crosslinkings
Agent is compared, and toxicity is extremely low；Cyclodextrin, chitosan are also common natural materials, hardly have a bio-toxicity.
[Detailed description of the invention]
Fig. 1 is Geniposide molecular formula of the present invention and its mechanism of crosslinking reaction equation with amino.
The schematic diagram of Fig. 2 synthetic method of the present invention.
[specific embodiment]
Below by way of specific embodiments and drawings, the invention will be further described.
Embodiment 1:
As depicted in figs. 1 and 2, a kind of insulin with insulin capturing function of the present invention transports the synthesis side of system
Method, the synthetic method is the following steps are included: (1) selects mono amino beta cyclodextrin, molecular formula are as follows:
(2) it using mono amino beta cyclodextrin as the medium for positioning and capturing insulin, is sufficiently stirred in aqueous solution with insulin
It mixes mixing to make it combine, forms the insulin molecule with capture label；Since mono amino beta cyclodextrin has inner hydrophobic, outside
The hydrophilic property in portion, also there are many hydrophobic groupings on insulin surface, and in aqueous solution, mono amino beta cyclodextrin can active and pancreas islet
Plain surface hydrophobicity group combines.
(3) use Geniposide for crosslinking agent, chitosan is backbone, under conditions of pH=3.8, is stirred in 8 DEG C of environment
18h, completes the crosslinking of amino, and chitosan captures insulin by being crosslinked with mono amino beta cyclodextrin；Being formed has capture pancreas
The nanoparticle of island element；In addition, insulin in acid condition stablize by property, bioactivity is unaffected.And Geniposide
It can be crosslinked with this condition.
In synthetic method of the invention, crosslinking agent Geniposide described in step (3) first stirs in aqueous solution with chitosan
Polymer is formed, then is mixed with the insulin molecule with capture label, the nanoparticle with capture insulin is formed.
And crosslinking agent Geniposide forms polymer with the first stirring in aqueous solution of chitosan and carries out at room temperature, mixing time 2h.
The present invention will select the derivative and crosslinking agent appropriate of beta cyclodextrin first, make derivative, the crosslinking of beta cyclodextrin
Agent, chitosan three its can react under mild conditions.It is again that the derivative of beta cyclodextrin and insulin is jointly molten
Solution forms the insulin molecule with capture label.Then crosslinking agent Geniposide and chitosan are added under mild conditions, it will
The beta cyclodextrin derivative combined with insulin is crosslinked with the amino in polymer, thus make beta cyclodextrin become positioning,
Capture the medium of insulin.
Embodiment 2:
In step (3) under conditions of pH=4.5,30h is stirred in 15 DEG C of environment；And crosslinking agent Geniposide and chitosan
First stirring in aqueous solution forms polymer and carries out at room temperature, and mixing time 6h, other are same as Example 1.
Embodiment 3
In step (3) under conditions of pH=4, stirred for 24 hours in 10 DEG C of environment；And crosslinking agent Geniposide and chitosan are first
Stirring forms polymer and carries out at room temperature in aqueous solution, and mixing time 4h, other are same as Example 1.
Examples 1 to 3, the application intend on the basis of early-stage study, and relatively base existing in research is transported for insulin
Plinth, more specific problem, propose new solution.By the interaction between beta cyclodextrin and the hydrophobic structure of insulin
It for starting point, constructs and transports system with insulin capturing function, transport the innovation in system in insulin for classical material and answer
With the new thinking of offer.At the same time, there is the element of certain versatility by developing, systematic optimization is made to transport system
Efficiency, the solution problematic altogether for promoting difference to transport system on the whole are possibly realized.Research for oral insulin system mentions
For new basis, new possibility also is provided for I type and the research of the clinical treatment of more serious type-2 diabetes mellitus people.
Claims (2)
1. the synthetic method that a kind of insulin with insulin capturing function transports system, which is characterized in that the synthesis side
Method the following steps are included:
(1) mono amino beta cyclodextrin, molecular formula are selected are as follows:
(2) it using mono amino beta cyclodextrin as the medium for positioning and capturing insulin, is sufficiently stirred in aqueous solution with insulin mixed
It is even to make it combine, form the insulin molecule with capture label；
(3) use Geniposide for crosslinking agent, chitosan is backbone, under conditions of pH=3.8~4.5, in 8~15 DEG C of environment
Stir 18~30h；Form the nanoparticle with capture insulin.
2. a kind of insulin with insulin capturing function transports the synthetic method of system according to claim 1, special
Sign is that first stirring forms polymer in aqueous solution for crosslinking agent Geniposide described in step (3) and chitosan, then catches with having
The insulin molecule for obtaining label is mixed, and the nanoparticle with capture insulin is formed.
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| Application Number | Priority Date | Filing Date | Title |
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| CN201810506150.8A CN110522921A (en) | 2018-05-24 | 2018-05-24 | A kind of insulin with insulin capturing function transports the synthetic method of system |
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| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201810506150.8A CN110522921A (en) | 2018-05-24 | 2018-05-24 | A kind of insulin with insulin capturing function transports the synthetic method of system |
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| CN110522921A true CN110522921A (en) | 2019-12-03 |
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Citations (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US20020151467A1 (en) * | 2000-12-21 | 2002-10-17 | Leung Frank K. | Methods and compositions for oral insulin delivery |
| CN101217947A (en) * | 2005-06-02 | 2008-07-09 | 圣地亚哥联合大学 | Nanoparticles comprising chitosan and cyclodextrin |
| CN106310232A (en) * | 2016-10-25 | 2017-01-11 | 南京师范大学 | Stable insulin depolymerizer supramolecular complex and preparation method thereof |
| CN106310230A (en) * | 2016-08-24 | 2017-01-11 | 华南师范大学 | Preparing method and application of oral insulin transport system in layer-by-layer self-assembly structure |
| CN106421807A (en) * | 2015-08-07 | 2017-02-22 | 中国海洋大学 | Preparation method of insulin-supporting carboxymethyl chitosan/chitosan nanometer preparation |
-
2018
- 2018-05-24 CN CN201810506150.8A patent/CN110522921A/en active Pending
Patent Citations (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US20020151467A1 (en) * | 2000-12-21 | 2002-10-17 | Leung Frank K. | Methods and compositions for oral insulin delivery |
| CN101217947A (en) * | 2005-06-02 | 2008-07-09 | 圣地亚哥联合大学 | Nanoparticles comprising chitosan and cyclodextrin |
| US20080220030A1 (en) * | 2005-06-02 | 2008-09-11 | Universidade De Santiago De Compostela | Nanoparticles Comprising Chitosan and Cyclodextrin |
| CN106421807A (en) * | 2015-08-07 | 2017-02-22 | 中国海洋大学 | Preparation method of insulin-supporting carboxymethyl chitosan/chitosan nanometer preparation |
| CN106310230A (en) * | 2016-08-24 | 2017-01-11 | 华南师范大学 | Preparing method and application of oral insulin transport system in layer-by-layer self-assembly structure |
| CN106310232A (en) * | 2016-10-25 | 2017-01-11 | 南京师范大学 | Stable insulin depolymerizer supramolecular complex and preparation method thereof |
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| 朱文杰: "胰岛素/环糊精超分子的制备及其稳定性研究", 《万方学位论文数据库》 * |
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| PB01 | Publication | ||
| PB01 | Publication | ||
| CB02 | Change of applicant information | ||
| CB02 | Change of applicant information |
Address after: 510599 no.1307, Guangzhou Avenue middle, Tianhe District, Guangzhou City, Guangdong Province Applicant after: Institute of health medicine, Guangdong Academy of Sciences Address before: 510599 no.1307, Guangzhou Avenue middle, Tianhe District, Guangzhou City, Guangdong Province Applicant before: GUANGDONG INSTITUTE OF MEDICAL INSTRUMENTS |
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| SE01 | Entry into force of request for substantive examination | ||
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| RJ01 | Rejection of invention patent application after publication | ||
| RJ01 | Rejection of invention patent application after publication |
Application publication date: 20191203 |