CN102847161A - Application of tetrahydropyrimidine and its derivate in preparation of pulmonary absorption enhancer medicine - Google Patents
Application of tetrahydropyrimidine and its derivate in preparation of pulmonary absorption enhancer medicine Download PDFInfo
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- CN102847161A CN102847161A CN2011101808695A CN201110180869A CN102847161A CN 102847161 A CN102847161 A CN 102847161A CN 2011101808695 A CN2011101808695 A CN 2011101808695A CN 201110180869 A CN201110180869 A CN 201110180869A CN 102847161 A CN102847161 A CN 102847161A
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Abstract
The invention discloses a new application of tetrahydropyrimidine and its derivate, i.e. the application of tetrahydropyrimidine and its derivate in preparation of pulmonary absorption enhancer medicine, wherein the tetrahydropyrimidine derivates include 1,4,5,6-tetrahydro-2-methyl-5-hydroxy-4-pyrimdine carboxylic acid. It has good pulmonary delivery effect, has a better effect in a dose of 0.5%-30% drug quantity, and is preferably administered 5-10 min before drug administration. The inventor research indicates that tetrahydropyrimidine and its derivate have great effect in enhancing pulmonary absorption rate and absorption degree to improve the curative effect of drug for pulmonary delivery.
Description
Technical field
The present invention relates to the application in preparation medicine pulmonary receipts promoter of tetrahydropyrimidine and derivant thereof.
Background technology
The human lung has a large amount of alveolars, is enlarged so that lung surface is long-pending, is conducive to contacting of medicine and pulmonary.And the pulmonary vascular distribution is abundant, and blood flow is large, is conducive to the transhipment of medicine.
Study at present and think, medicine enters blood circulation through pulmonary and can avoid liver first-pass effect to the destruction of medicine, is conducive to keep medicine effective blood drug concentration in vivo, is conducive to medicine performance therapeutical effect.
In view of above advantage, pulmonary delivery system is obtaining the extensive concern of field of medicaments in recent years, and various pulmonary delivery systems begin to be applied at field of medicaments, such as spray, and Foradil Aerolizer formoterol fumarate etc.
But because physicochemical property and pulmonary's physiological structure factor of medicine itself, a lot of medicines are difficult to be absorbed in pulmonary, and the drug effect of pulmonary administration is undesirable, such as protein and peptide macromolecular drugs such as insulin, salmon calcitonin see calcimars.In addition, pulmonary has the height lipotropy, and the absorption efficiency of water soluble drug is also very low.
Therefore, the research and development of pulmonary administration drug absorption enhancer become needs one of subject matter that solves.Up to now, existing multiple pulmonary absorption promoter is applied, such as cholate, phospholipid, cyclodextrin, citric acid and surfactant etc.
Wherein cyclodextrin is a kind of newer penetrating agent, and for the mucosa delivery of water-soluble macromolecule, it all has the short effect of oozing at pulmonary, eye and nasal cavity.
These chemical substances may be directly the alveolar epithelium mucosa to be produced to disturb to the short mechanism of absorption of the pulmonary of medicine, can extract lipid and protein on the cell membrane such as cyclodextrin.
Most of existing pulmonary absorption promoter have certain toxic action, can't use in the pulmonary drug preparation by long-term, high-dose.
Tetrahydropyrimidine, English ectoine by name, CAS number is 96702-03-3, chemistry Isosorbide-5-Nitrae by name, 5,6-tetrahydrochysene-2-methyl-4-pyrimidine carboxylic or 2-Methyl-1,4,5,6-tetrahydropyrimidine-4-carboxylic acid or (S)-2-methyl-1,4,5,6-tetra-hydro pyrimidine-4-carboxylic acid or 1,4,5,6-tetrahydro-2-methyl-4-pyrimidine carbonic acid is the amino acid derivativges of finding in 1985, discovered in recent years, it has certain mitigation to allergic disease.In addition tetrahydropyrimidine has been used to cosmetics, uses as moisturizing or sun-proof articles.
Summary of the invention
For above-mentioned prior art, the purpose of this invention is to provide a kind of new purposes of tetrahydropyrimidine and derivant thereof, specifically tetrahydropyrimidine and derivant thereof the application in preparation medicine pulmonary absorption promoter.
For achieving the above object, the technical solution used in the present invention is:
The application in preparation medicine pulmonary absorption promoter of tetrahydropyrimidine and derivant thereof.
Described tetrahydropyrimidinederivatives derivatives is Isosorbide-5-Nitrae, 5,6-tetrahydrochysene-2-methyl-5-hydroxyl-4-pyrimidine carboxylic.
The consumption of described tetrahydropyrimidine and derivant thereof is the 0.5%-30% of drug weight.
Described tetrahydropyrimidine and derivant thereof be use in 5-10 minute before accepting Drug therapy.
Described tetrahydropyrimidine and derivant using method thereof are pulmonary administration.
Under study for action surprised discovery of the present inventor, tetrahydropyrimidine and derivant thereof have unexpected pulmonary absorption facilitation, and safety is higher.
Tetrahydropyrimidine described in the technical scheme of the present invention, English ectoine by name, CAS number is 96702-03-3, chemistry 2-Methyl-1 by name, 4,5,6-tetrahydropyrimidine-4-carboxylic acid or (S)-2-methyl-1,4,5,6-tetra-hydro pyrimidine-4-carboxylic acid or Isosorbide-5-Nitrae, 5,6-tetrahydro-2-methyl-4-pyrimidine carbonic acid.Isosorbide-5-Nitrae, 5,6-tetrahydrochysene-2-methyl-5-hydroxyl-4-pyrimidine carboxylic is commonly called as the hydroxy tetrahydro pyrimidine, and this is that those skilled in the art are known.
Term used herein " pulmonary administration " comprises the modes such as spraying, suction namely through the lung administration, and this is that those skilled in the art are known.
The specific embodiment
Below in conjunction with embodiment the present invention is further explained.Should be understood that, following examples only are used for explaining the present invention, rather than restriction protection scope of the present invention.
Embodiment 1 tetrahydropyrimidine is to the facilitation of macromolecular drug pulmonary absorption
Take macromole hypoglycemic medicine insulin as model drug, research tetrahydropyrimidine and derivant thereof are to the pulmonary absorption facilitation of macromolecular drug
24 of Wistar rats, 200 ~ 400 g are divided into four groups at random, and 6 every group, fasting is 12 hours before the experiment, after pentobarbital anesthesia, rat is lain on the back fixing the surgical incision trachea:
First group from injecting 100mg/ml insulin solutions 40 μ l under the thyroid cartilage between the 5th to the 6th pipe ring;
Second group from injecting 20 mg/ml tetrahydropyrimidine solution, 20 μ l between the 5th to the 6th pipe ring under the thyroid cartilage, after 8 minutes, inject 100mg/ml insulin solutions 20 μ l from this position again;
The 3rd group from injecting 100mg/ml insulin solutions 20 μ l under the thyroid cartilage between the 5th to the 6th pipe ring, injects 10 mg/ml tetrahydropyrimidine solution, 20 μ l after 8 minutes from this position again;
The 4th group from the mixed solution that injects 100mg/ml insulin solutions 20 μ l and 5 mg/ml tetrahydropyrimidine solution, 20 μ l under the thyroid cartilage between the 5th to the 6th pipe ring totally 40 μ l.
With after the last administration the 30th minute, 1 hour, 1.5 hours, 2 hours, 3 hours, 4 hours, from the tail point blood sampling of rat, measure the rat blood insulin level, and calculate the bioavailability of respectively organizing rat insulin respectively.
Each bioavailability of organizing rat insulin sees the following form.
Table 1 is respectively organized the bioavailability of rat insulin
| Group | The bioavailability of insulin |
| First group | 21.7% |
| Second group | 52.2% |
| The 3rd group | 27.3% |
| The 4th group | 44.9% |
By as seen from Table 1, give tetrahydropyrimidine through pulmonary, give insulin after 8 minutes, the bioavailability of insulin significantly improves, and the prompting tetrahydropyrimidine has effective facilitation to the pulmonary absorption of macromolecular drug.And give first to give insulin behind the tetrahydropyrimidine, the raising of insulin bioavailability is more obvious than other dosage regimens.
Embodiment 2 tetrahydropyrimidines and derivant thereof are to the facilitation of water soluble drug pulmonary absorption
Take water solublity antianaphylaxis asthmatic medicament sodium cromoglicate as model drug, research tetrahydropyrimidine and derivant thereof are to the pulmonary absorption facilitation of water soluble drug
36 of Wistar rats, 250 ~ 450 g are divided into six groups at random, and 6 every group, fasting 12 hours before the experiment after pentobarbital anesthesia, is lain on the back rat fixing, the surgical incision trachea, from injection of medicine between the 5th to the 6th pipe ring under the thyroid cartilage:
First group is injected 100mg/ml sodium cromoglicate solution 40 μ l;
Second group is injected 5 mg/ml tetrahydropyrimidine solution, 20 μ l, after 6 minutes, injects 100mg/ml sodium cromoglicate solution 20 μ l from this position again;
The 3rd group is injected 10 mg/ml Isosorbide-5-Nitraes, and 5,6-tetrahydrochysene-2-methyl-5-hydroxyl-4-pyrimidine carboxylic solution 20 μ l after 6 minutes, injects 100mg/ml sodium cromoglicate solution 20 μ l again from this position;
The 4th group is injected 100mg/ml sodium cromoglicate solution 20 μ l, injects 10 mg/ml tetrahydropyrimidine solution, 20 μ l after 5 minutes;
The 5th group is injected 100mg/ml sodium cromoglicate solution 20 μ l, injects 10 mg/ml Isosorbide-5-Nitraes, 5,6-tetrahydrochysene-2-methyl-5-hydroxyl-4-pyrimidine carboxylic solution 20 μ l after 5 minutes;
The 6th group is injected 100mg/ml sodium cromoglicate solution 20 μ l and 20 mg/ml Isosorbide-5-Nitraes, and the mixed solution of 5,6-tetrahydrochysene-2-methyl-5-hydroxyl-4-pyrimidine carboxylic solution 20 μ l is totally 40 μ l.
After the last administration the 30th minute, 1 hour, 1.5 hours, 2 hours, 3 hours, 4 hours, from the tail point blood sampling of rat, measure rat blood sodium cromoglicate level, and calculate the bioavailability of respectively organizing the rat sodium cromoglicate respectively.
Each organizes the peak time (T of rat sodium cromoglicate
Max) and bioavailability see the following form.
Table 2 is respectively organized the peak time (T of rat sodium cromoglicate
Max) and bioavailability
| Group | T max(minute) | Bioavailability (%) |
| First group | ?92 | 12 |
| Second group | ?60 | 77 |
| The 3rd group | ?52 | 83 |
| The 4th group | ?84 | 35 |
| The 5th group | 91 | 42 |
| The 6th group | ?79 | 26 |
By as seen from Table 2, tetrahydropyrimidine and 1,4,5,6-tetrahydrochysene-2-methyl-5-hydroxyl-4-pyrimidine carboxylic pulmonary administration has significant facilitation to the pulmonary absorption of water soluble drug sodium cromoglicate, and tetrahydropyrimidine and 1, give again sodium cromoglicate after 4,5,6-tetrahydrochysene-2-methyl-5-hydroxyl-4-pyrimidine carboxylic administration, the bioavailability of sodium cromoglicate is higher, reach the peak faster, prompting tetrahydropyrimidine and Isosorbide-5-Nitrae, 5,6-tetrahydrochysene-2-methyl-5-hydroxyl-4-pyrimidine carboxylic can improve the pulmonary absorption of sodium cromoglicate and accelerate its infiltration rate.
Claims (5)
1. tetrahydropyrimidine and derivant thereof the application in preparation medicine pulmonary absorption promoter.
2. application according to claim 1 is characterized in that: described tetrahydropyrimidinederivatives derivatives is Isosorbide-5-Nitrae, 5,6-tetrahydrochysene-2-methyl-5-hydroxyl-4-pyrimidine carboxylic.
3. according to claim 1-2 described application is characterized in that: the consumption of described tetrahydropyrimidine and derivant thereof is the 0.5%-30% of drug weight.
4. according to claim 1-2 described application is characterized in that: described tetrahydropyrimidine and derivant thereof be use in 5-10 minute before accepting Drug therapy.
5. according to claim 1-2 described application is characterized in that: described tetrahydropyrimidine and derivant using method thereof are pulmonary administration.
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Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN112813015A (en) * | 2021-02-05 | 2021-05-18 | 深圳大学 | Promoter for increasing dry weight of euglena, euglena culture medium and application thereof |
Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2005002556A1 (en) * | 2003-07-07 | 2005-01-13 | bitop Aktiengesellschaft für biotechnische Optimierung | Use of osmolytes obtained from extremophilic bacteria for the production of inhalable medicaments for the prophylaxis and treatment of pulmonary and cardiovascular diseases and an inhalation device comprising an osmolyte as active agent component |
| CN101878040A (en) * | 2007-10-31 | 2010-11-03 | 扩散药品有限公司 | A new class of therapeutics that enhance small molecule diffusion |
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Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2005002556A1 (en) * | 2003-07-07 | 2005-01-13 | bitop Aktiengesellschaft für biotechnische Optimierung | Use of osmolytes obtained from extremophilic bacteria for the production of inhalable medicaments for the prophylaxis and treatment of pulmonary and cardiovascular diseases and an inhalation device comprising an osmolyte as active agent component |
| CN101878040A (en) * | 2007-10-31 | 2010-11-03 | 扩散药品有限公司 | A new class of therapeutics that enhance small molecule diffusion |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN112813015A (en) * | 2021-02-05 | 2021-05-18 | 深圳大学 | Promoter for increasing dry weight of euglena, euglena culture medium and application thereof |
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Application publication date: 20130102 |