CN104758936A - Synthetic small-molecular compound capable of transporting bioactive substances and application thereof - Google Patents
Synthetic small-molecular compound capable of transporting bioactive substances and application thereof Download PDFInfo
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- CN104758936A CN104758936A CN201510105104.3A CN201510105104A CN104758936A CN 104758936 A CN104758936 A CN 104758936A CN 201510105104 A CN201510105104 A CN 201510105104A CN 104758936 A CN104758936 A CN 104758936A
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Abstract
A synthetic small-molecular compound capable of transporting bioactive substances and an application thereof, wherein the synthetic small-molecular compound or any one pharmaceutically acceptable salt thereof has a general formula as follows, wherein A, B and C are substituent groups including, but not limit to the following group: a hydrogen atom, a halogen atom, a C1-C4 saturated alkyl group, a C3-C6 naphthenic alkyl group, an O-C1-C4 saturated alkyl group, an O-C3-C6 naphthenic alkyl group, OH, NH2, CN, NO2, CF3, NHCO(C1-C4 saturated alkyl group, C3-C6 naphthenic alkyl group, C6-C10 aromatic ring or C5-C9 hetero-aromatic ring), or OCF3; the D is O, NH or CH2; and the E is a carboxyl group (COOH), CONHOH, a tetrazole group, OH or a sulfonic group. The n is an integer including 0, 1, 2, 3, 4, 5 and 6.
Description
Technical field
The present invention relates to one and bioactive substance (comprising chemosynthesis active substance) can be delivered to micromolecular compound in organism and application thereof.
Background technology
There is bioactive material be transported in organism by several routes, but which kind of method can reach objective condition when conveying object is often limited by conveying actually.
The clinical conventional route of administration that great majority have bioactive material (as calcitonin, interferon, insulin, special mucopolysaccharide, heparin, hyparinoids from animal organs etc.) is injection solution agent and lyophilized injectable powder, route of administration is more single, and frequent drug administration, patient's poor compliance.At present, the greatest problem of this type of material oral administration be the physics of body, chemistry and biology barriers affect its send.Such as, protein drug cannot adopt oral administration, this is mainly because this kind of medicine is before being rapidly absorbed into blood circulation through digestive tract, often by the hydrolysis of strong gastric acid or degrade by the multiple digestive enzyme of gastrointestinal, thus lose biological activity.Nearly all natural polypeptides, protein, polysaccharide, phospholipid and lipoid etc. are all degraded into junior unit and by intestinal absorption in the intestines and stomach.
Therefore, just must consider these objective condition when design has bioactive molecule oral administration route, the method using some feasible is to reduce the degraded of this kind of medicine in the intestines and stomach.
Conventional method uses penetrating agent, as surfactant, fatty acid or cholate, increases the permeability of rete malpighii and epithelium layer, expand intercellular substance.The most frequently used oral absorption promoter is cholate and fatty acid, and also someone uses sodium salicylate.The disadvantage of such material be non-selectivity act on lipid sur and all small intestine contents compositions may be made to comprise various toxin and bio-pathogen enters blood, also have the toxicity such as potential cellular membrane lysis and local inflammation; Nearly all polypeptide drugs and mucosa transmission all need penetrating agent, its broad categories, and existing problems how to reduce stimulation and whether life-time service affects epithelial integrity, causes coup injury to mucosa, therefore its application is clinically restricted.
Application protease inhibitor can stop gastro-intestinal digestion enzyme to the destruction of insulin etc., conventional enzyme inhibitor has sodium glycocholate, camostat mesilate, bacitracin, aprotinin, Semen sojae atricolor pancreatin inhibitor etc., front 3 kinds of effects are better, the absorption of the large intestinal segment that major effect protease is concentrated.But enzyme inhibitor, while significantly improving protein and peptide drugs oral administration bioavailability, also can bring a lot of untoward reaction.Even if ignore its Systemic reaction, it also can have an impact to digesting and assimilating of Intra-intestinal nutrition support albumen, produces feedback regulation, thus stimulate enzyme secretion to the inhibitory action of gastrointestinal proteases, and long-term treatment also can cause spleen hypertrophy and hypertrophy; Enzyme inhibitor is also easily diluted in intestinal, and therefore use amount just must strengthen, and the excessive toxic reaction causing various system of use amount.
By adjusting close-connected permeability, can improve the percent of pass of macromolecular drug at intercellular substance, result shows, the compact siro spinning technology although a lot of material can relax, significantly improves the permeability of medicine at intercellular substance, but occur safety issue simultaneously.Compact siro spinning technology is once be opened, and except medicine can pass through, some albumen poisonous or harmful in digestive tract also can pass through.Because a lot of biological medicament is all for chronic disease treatment, Long-term absorption deleterious protein is the problem that this approach must be paid close attention to.
The physicochemical property of macromolecular drug being modified, by preparing the method for prodrug or analog, protease or digestive tract other enzymes interior can be avoided the degraded of polypeptide protein class medicine.Such as; medicine is combined with form covalently or non-covalently with a fat-soluble compound by lipophilization, increases the fat-soluble of polypeptide protein class medicine, or combines with Polyethylene Glycol (PEG); the water solublity of medicine can be increased, medicine can be protected from the degraded of digestive system protease.The range of application of polypeptide drugs has been widened in being applied in of prodrug to a great extent, but dressing agent presents multiple polymerization, and selectivity is not high enough, and the medicine Mr distribution after modification is wide, activity is low, stability is sometimes not ideal enough becomes outstanding problem; In addition its structural complexity and the effective synthesis technique of shortage, are all bottlenecks.
Utilize transhipment-carrier molecule, it is combined with polypeptide protein medicine, thus endogenic cell-movement system identified in digested road, the oral administration biaavailability of polypeptide protein class medicine can be improved, this transhipment principle is relevant with the endocytosis of the carrier mediated and receptor modulators on cell membrane, the part that mediation or endocytosis are connected with macromolecular drug can be identified specifically, thus reach the transmembrane transport to macromolecular drug.Such as, medicine is combined with certain dipeptides, this two Toplink by the peptide-Nei on cell membrane flow carrier identify mediation, thus the macromolecular transmembrane transport of realize target, the oral administration biaavailability of macromolecular drug is improved.Outer row's carrier, such as P glycoprotein, can have a strong impact on some macromolecular drugs, as the oral absorption of polypeptide, therefore, adopts P glycoprotein inhibitors, may increase the oral absorption to P glycoprotein substrate to a certain extent.But, generally speaking, the identification mediation of cell membrane carrier can only realize the transmembrane transport of the relatively little molecule of number molecular weight.On the contrary, the cellular endocytosis machinery of receptor modulators is not but substantially by the impact of molecular size.
Cell permeable polypeptide (CPP) may be by carrying out heterozygosis with target substance, thus helps micromolecule, macromole, liposome and nanoparticle etc., through cell or tissue.Have research to think, the mechanism of action of CPP may be lipid bilayer Rotating fields by direct interference cell membrane or endocytosis, by by the substance delivery that transmits in Cytoplasm.But up to the present, also lack Data support in enough bodies to the research of CPP delivering method, they are also indefinite with effect to the delivery mechanism of medicine over the course for the treatment of.
Particulate carrier delivery system can protect the macromolecular drug of easy inactivation in the violent environment of digestive tract, from metabolism and the degraded of enzyme system.When not adding penetrating agent, some particulate carrier can absorb by epithelial cell, or by lymphoid tissue PeyerShi knot (Peyer ' s Patch) absorb.To develop based on hydrogel, nanoparticle, microsphere at present, and the high molecular particle drug-loading system of lipid (such as microemulsion, liposome and solid lipid nanoparticle) etc., and for the oral delivery of macromolecular drug.But in these particulate carrier delivery systems, lipid drug delivery system, for large hydrophilic molecular medicine, can not reach higher envelop rate.In addition, their less stable in digestive tract.Common liposome and microemulsion cannot meet the oral delivery of large hydrophilic molecular medicine substantially.
Although some follow-on lipid carriers, such as through the fusogenic lipid plastid of viral glycoprotein parcel, or the liposome of adhesiveness macromolecular material coating, although they significantly improve the absorption of large hydrophilic molecular medicine in small intestinal, but generally speaking, solid particle, than lipid carrier, has more advantage in the oral delivery of macromolecular drug.
Summary of the invention
The technical problem solved: the object of the invention is to overcome the above-mentioned defect that prior art exists, provides a kind of and bioactive substance effectively can be delivered to micromolecular compound in organism and application thereof.
Technical scheme: the micromolecular compound of the present invention is micromolecular compound or the pharmaceutically useful salt of its any one with following general formula:
In described general formula:
A, B and C are substituent group; Can be but be not limited to hydrogen, halogen, C
1-C
4saturated alkyl, C
3-C
6cycloalkyl, O-C
1-C
4saturated alkyl, O-C
3-C
6cycloalkyl, OH, NH
2,cN, NO
2, CF
3, NHCO (C
1-C
4saturated alkyl, C
3-C
6cycloalkyl, C
6-C
10aromatic ring or C
5-C
9hetero-aromatic ring) or OCF
3;
D is O, NH or CH
2;
E is carboxylic acid group (COOH) ,-CONHOH, tetrazolium, OH ,-SO
3h.
N is integer 0,1,2,3,4,5,6.
Wherein, preferred compound is as shown in the table:
Apply the synthesized micromolecule compound of described energy conveying bioactivator, the preparation containing one or more bioactive substances can be made.
The described preparation containing bioactive substance is the mixture under a specific acid basicity, if its acid-base value characterizes with pH value, then its value can be but is not limited to 2,3,4,5,6,7 or 8.
Described preparation can be liquid, suspension containing solid or solid.
Described have bioactive material and can be protein, polypeptide, polysaccharide, vitamin, rare metal or micromolecule medicine, and the mol ratio of described micromolecular compound and bioactive substance is: 1:0.01-1000.
The preferred molar ratio of described micromolecular compound and bioactive substance is: 1:0.1,1:0.5,1:1,1:5,1:10,1:20,1:50,1:100,1:200,1:500.
Described to have bioactive material be selected from least one in following material: enzyme inhibitor, protease inhibitor, growth hormone, human growth hormone, recombinant human somatropin, heparin, unfraction heparin, low molecular weight heparin, calcitonin, salmon calcitonin see calcimar, eel calcitonin, human calcitonin, insulin, Iletin II (Lilly), bovine insulin, insulin human, recombinant human insulin, prostaglandin, monoclonal antibody, antigen, PYY
3-36, antiinflammatory, antioxidant, antibacterial, antimicrobial, vitamin, and by poly ethyldiol modified various derivants.
Described preparation, can be a kind of unit dosage form, at least one containing in lower material: reinforcing agent, chelating agent, plasticizer, buffer agent, surfactant, acid-base modifier.
Described unit dosage form can be lamellar, capsule, powder, liquid or the suspension containing solid.
If described unit dosage form contains suspension or the liquid of solid, then carrier can be but be not limited to water, ethylene glycol, glycerol.
Beneficial effect: the micromolecular compound of the present invention effectively can be delivered in organism by the approach such as oral cavity, colon by having bioactive material, realize organism administration, namely the stability of medicine can be improved, improve medicine absorbance in the gastrointestinal tract, biomacromolecule is prevented to be degraded very soon in vivo, guarantee that the content of this active substance in vivo exceedes the amount produced needed for biological agent, medicine orientation can also be sent to body target site, and reach slow release long-acting object by the degraded of biodegradable polymers; Oral administration is convenient simultaneously, good patient compliance.
Detailed description of the invention
Below in conjunction with embodiment, the invention will be further described.
Embodiment 1: the preparation of compound
Method one: add EDC (1.0 equivalent) in dichloromethane (30 milliliters) solution being dissolved with chromone-3-formic acid derivates (1.0 equivalent), this solution stirred after 20 minutes at 0 DEG C, dichloromethane (10 milliliters) solution containing amine (1.0 equivalent) and triethylamine (2.0 equivalent) is added in solution, after interpolation, reaction mixture is warmed to room temperature gradually and at room temperature stirs 12 hours.
Solution is proceeded to separatory funnel, use 1 equivalent hydrochloric acid solution (2x 20 milliliters) respectively, water (2X 20 milliliters), saturated charcoal acid hydrogen sodium solution (2X 20 milliliters), saturated brine (40 milliliters) is washed. and with anhydrous magnesium sulfate drying, filter, vacuum concentration. subsequently, residue be dissolved in oxolane (30 milliliters) and add hydrogen-oxygen flower sodium solution (2 equivalent). this mixture at room temperature stirs 5 hours. after vacuum concentration, use 1.0N hcl acidifying. collect the solid formed with filtration under diminished pressure, obtain pure compound with ethanol/water recrystallization.
Compound 1-9 is synthesized by the suitable initiation material of said method.
Embodiment 1: Oral Administration in Rats heparin administration
Heparin is a kind of by glucamine, the mucopolysaccharide sulfuric acid ester that L-idose aldehyde glycosides, N-Acetyl-D-glucosamine and D-Glucose aldehydic acid alternately form.Have anticoagulation, suppress platelet, increase the effects such as the permeability of blood vessel wall, controllable angiogenesis, Adjust-blood lipid, and multiple links that can act on complement system, to suppress system excessive activation.Related to this, heparin also has antiinflammatory, antianaphylactic effect.
Be dissolved in the aqueous solution of propylene glycol of 25% to 1,3,5,8,13,16,26 in each compound listed by claim 2 according to the compound dosage in following table and corresponding heparin amount, and by the sodium hydrate aqueous solution adjust ph to 8.0 of monovalent, make it to become even oral administration mixture with ultrasonic wave concussion subsequently.
It is the male rat fasting 24 hours of 200-250 gram by weight, within 15 minutes, inject ketamine (44mg/kg) to rat muscle before administration, the latex tubing being 5mm by the diameter that connects syringe is subsequently inserted in stomach through rat oral cavity, and oral administration mixture (1ml) is sent in the stomach of rat by syringe through latex tubing; Be interval in rat tails at different time subsequently and get blood.The activity of Oral Heparin was expressed by the part activated thrombin time (APTT).Method of testing according to Henry, J.B. at " method of room carries out clinical diagnosis and management by experiment " (Clinical Diagnosis and Management by Laboratory Methods; Philadelphia, PA; W.B.Saunders 1979) described in method carry out.
Table 1 Oral Administration in Rats heparin administration data
+ represent APTT<30s
++ represent 30<APTT<80s
+++ represent 80<APTT<100s
++++represent APTT>140s
Embodiment 2: Oral Administration in Rats insulin administration
Prepare oral insulin drug-delivery preparation: by compound dissolution in table 2 in the sodium hydrate aqueous solution of equivalent, insulin is then dissolved in appropriate water, these two kinds of solution mixing is also fully stirred subsequently and forms homogeneous phase solution with for subsequent use.
It is the male rat fasting 24 hours of 200-250 gram by weight, anaesthetize within 15 minutes, to before administration rat through lumbar injection pentobarbital sodium 40mg/kg, after anesthesia, animal is fixed on operation plate, the latex tubing being 5mm by the diameter that connects syringe is subsequently inserted in stomach through rat oral cavity, and oral administration mixture (2mL) is sent in the stomach of rat through latex tubing by syringe.Be interval in rat tail point at different time subsequently and get blood, after blood coagulation centrifugal (3000r/min, 15min), get serum, by blood sugar detection requirement, measure blood glucose and reduce level.
Table 2 Oral Administration in Rats insulin data
+ represent blood glucose reduce be less than 5
++ represent blood glucose reduction and be greater than 5 but be less than 10
+++ represent blood glucose and reduce and be greater than 10 and be less than 20
The reduction of ++++represent blood glucose is greater than 20 and is less than 35%.
Claims (10)
1. the synthesized micromolecule compound of energy conveying bioactivator, it is characterized in that, it is micromolecular compound or the pharmaceutically useful salt of its any one with following general formula:
I
In described general formula:
A, B and C are substituent group; A, B, C comprise hydrogen, halogen, C
1-C
4saturated alkyl, C
3-C
6cycloalkyl, O-C
1-C
4saturated alkyl, O-C
3-C
6cycloalkyl, OH, NH
2,cN, NO
2, CF
3, NHCO (C
1-C
4saturated alkyl, C
3-C
6cycloalkyl, C
6-C
10aromatic ring or C
5-C
9hetero-aromatic ring) or OCF
3;
D is O, NH, or CH
2;
E is carboxylic acid group (COOH) ,-CONHOH, tetrazolium, OH ,-SO
3h;
N is integer 0,1,2,3,4,5,6.
2. the synthesized micromolecule compound of energy conveying bioactivator according to claim 1, is characterized in that, is following one or more listed micromolecular compounds:
（1）
；
（2）
；
（3）
；
（4）
；
（5）
；
（6）
；
（7）
；
（8）
；
（9）
。
3. require according to claims the preparation that the synthesized micromolecule compound of the energy conveying bioactivator described in 1 or 2 is made, it is characterized in that, described preparation contains one or more and has bioactive material.
4. according to claim 3 can the preparation made of the synthesized micromolecule compound of conveying bioactivator, it is characterized in that, the pH value of described preparation is 2,3,4,5,6,7 or 8.
5. according to claim 3 can the preparation made of the synthesized micromolecule compound of conveying bioactivator, it is characterized in that, described preparation is liquid, suspension containing solid or solid.
6. according to claim 3 can the preparation made of the synthesized micromolecule compound of conveying bioactivator, it is characterized in that, described to have bioactive material be protein, polypeptide, polysaccharide, vitamin, rare metal or micromolecule medicine, and the mol ratio of described micromolecular compound and bioactive substance is: 1:0.01-1000.
7. according to claim 6 can the preparation made of the synthesized micromolecule compound of conveying bioactivator, it is characterized in that, the mol ratio of described micromolecular compound and bioactive substance is: 1:0.1,1:0.5,1:1,1:5,1:10,1:20,1:50,1:100,1:200,1:500.
8. according to claim 3 can the preparation made of the synthesized micromolecule compound of conveying bioactivator, it is characterized in that, described to have bioactive material be selected from least one in following material: enzyme inhibitor, protease inhibitor, growth hormone, human growth hormone, recombinant human somatropin, heparin, unfraction heparin, low molecular weight heparin, calcitonin, salmon calcitonin see calcimar, eel calcitonin, human calcitonin, insulin, Iletin II (Lilly), bovine insulin, insulin human, recombinant human insulin, prostaglandin, monoclonal antibody, antigen, PYY
3-36, antiinflammatory, antioxidant, antibacterial, antimicrobial, vitamin, and by poly ethyldiol modified various derivants.
9. according to claim 3 can the preparation made of the synthesized micromolecule compound of conveying bioactivator, it is characterized in that, for a kind of unit dosage form, at least one containing in lower material: reinforcing agent, chelating agent, plasticizer, buffer agent, surfactant, acid-base modifier.
10. according to claim 9 can the preparation made of the synthesized micromolecule compound of conveying bioactivator, it is characterized in that, unit dosage form is lamellar, capsule, powder, liquid or the suspension containing solid.
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Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO1998034632A1 (en) * | 1997-02-07 | 1998-08-13 | Emisphere Technologies, Inc. | Compounds and compositions for delivering active agents |
| CN1190893A (en) * | 1995-03-31 | 1998-08-19 | 艾米斯菲尔技术有限公司 | Compound and compositions for delivering active agents |
-
2015
- 2015-03-11 CN CN201510105104.3A patent/CN104758936A/en active Pending
Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1190893A (en) * | 1995-03-31 | 1998-08-19 | 艾米斯菲尔技术有限公司 | Compound and compositions for delivering active agents |
| WO1998034632A1 (en) * | 1997-02-07 | 1998-08-13 | Emisphere Technologies, Inc. | Compounds and compositions for delivering active agents |
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Application publication date: 20150708 |
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