CN101601646B - Nasal cavity drop for treating diabetes and preparation method thereof - Google Patents
Nasal cavity drop for treating diabetes and preparation method thereof Download PDFInfo
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- CN101601646B CN101601646B CN2009101817485A CN200910181748A CN101601646B CN 101601646 B CN101601646 B CN 101601646B CN 2009101817485 A CN2009101817485 A CN 2009101817485A CN 200910181748 A CN200910181748 A CN 200910181748A CN 101601646 B CN101601646 B CN 101601646B
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Abstract
The invention discloses a nasal cavity drop for treating diabetes and a preparation method. The nasal cavity drop comprises solvent and accessories, and is characterized in that the solvent contains a compound of calcium phosphate nano particles and exenatide, the weight ratio of the calcium phosphate nano particles to the exenatide in the compound is 1-10:0.1-10, and the content of the exenatide in the solvent is 0.01 to 0.5 milligram per milliliter. The preparation method for the nasal cavity drop comprises the following steps: mixing aqueous solutions of calcium salt, phosphate, citrate and exenatide to form the compound of the calcium phosphate nano particles and the exenatide, adding the accessories which are frequently used for aqueous agent into the mixture, detecting and adjusting the pH of the solution, and finally forming the nasal cavity drop, wherein the weight ratio of the calcium phosphate nano particles to the exenatide in the compound is 1-10:0.1-10, and the content of the diluted exenatide in the solvent is 0.01 to 0.5 milligram per milliliter.
Description
Technical field
The present invention is a kind of nasal cavity drop and preparation method, nasal cavity drop of especially a kind of treatment diabetes that contain Exenatide and preparation method thereof.
Background technology
Diabetes are a kind of common metabolic endocrinopathyes, because of its sickness rate, mortality rate, disability rate height, and the serious harm human health, and be subjected to the extensive concern of medical circle day by day.From the clinical onset situation, wherein the overwhelming majority is a type ii diabetes, and its clinical symptoms is that the glucose content in blood and the urine exceeds normal range.Blood sugar level is regulated by insulin and glucagon mainly.Glucagon is accelerated glycogenolysis by series reaction.Increase concentration of glucose in the body, it is synthetic that opposite insulin is then accelerated glycogen, blood sugar lowering concentration.In vivo, the at first synthetic precursor of glucagon forms glucagon-like peptide GLP-1 and GLP-2 after translation process.Wherein GLP-1 has Beta cell proliferation in the pancreas of promotion, stimulates insulinogenic physiological function.But GLP-1 in vivo can be rapidly by DPP IV (dipeptidy I peptidase IV, DPP IV) degraded inactivation, its half-life less than 2 minutes.So can not give full play to its proper function aspect the clinical treatment type ii diabetes.1992, scientist has separated native peptides (Exendin-4) from Gila monster (Helodermasuspectum) saliva of Southwestern United Stares and Mexico northern territory, exenatide is the synthetic material of Exendin-4, it forms (main component structure: His-Gly-Glu-Gly-Thr-Phe-Thr-Ser-Asp-Leu-Ser-Lys-Gln-Met-Glu-Glu-Glu-Ala-Val-Arg-Leu-Phe-Ile-Glu-Trp-Leu-Lys-Asn-Gly-Gly-Pro-Ser-Ser-Gly-Ala-Pro-Pro-Pro-Ser-NH2) by 39 amino acid residues, not only has identical function with GLP-1, and DPP IV had very height endurability, become treatment type ii diabetes new drug with broad prospect of application.The known pharmacological action of Exenatide (exenatide) comprises: 1. significantly increase glucose dependency insulin secretion accelerating, do not stimulate secretion of insulin in blood sugar level during normal or hypoglycemia.2. suppress type ii diabetes patient glucagon secretion, and when hyperglycemia, reduce glucagon concentration, but do not weaken normal pancreas hyperglycemia hypoglycemic reaction.3. just suppress gastrointestinal tract dynamia and secretory function after the meal, postpone gastric emptying, thereby just help glycemic control after the meal.4. reduction appetite reduces things and takes in.5. stimulate the ripe differentiation of β hyperplasia or embryo's insulin, suppress the β apoptosis, thereby increase the quantity of β cell.6. phase reaction when recovering the insulin the first of type ii diabetes patient forfeiture significantly increases at first o'clock and reaches second o'clock phase secretion of insulin mutually, improves type ii diabetes patient's empty stomach and has dinner the back blood sugar level.
At one by a definite date in the randomized, double-blind placebo-controlled study in 30 weeks, 733 examples are united and are used metformin and sulfonylureas to treat unfavorable type ii diabetes patient [(HbA
1cBaseline values in (8.2 ± 1.0%)], 2 times/day subcutaneous injection Exenatide 5 μ g or placebo at first, metformin treatment group is still kept original dosage, the sulfonylurea treatment group then is divided into effective dose (MAX) and minimum recommended dosage (MIN) group at random.The result shows treatment during 30 weeks, patient HbA
1cSignificantly reduce, curative effect and Exenatide have dose-effect relationship, and 2 dosed administration group weight in patients all significantly alleviate.
At present existing company is developed to injection type-Exenatide (exenatide with it, trade name Byetta), can the effective stimulus insulin secretion, suppress the hyperglycemia secretion and slow down gastric emptying speed, reduce appetite, the minimizing things is taken in and is lost weight, can effectively treat type ii diabetes, be particularly useful for improving and control the treatment that metformin and sulfonylureas are treated unfavorable type ii diabetes patient.This medicine obtains the FDA approval and has gone on the market in 2005.But this a kind of dosage form list marketing is only arranged at present, and administering mode is for being subcutaneous injection.And the malpractice subcutaneous, that intramuscular injection causes is the multiple accident in the nursery work, and main forms has: 1. because the broken needle that operation is unskilled or patient is nervous, mismatch etc. causes.2. the injection site suppurative infection that sterilization of instruments is not thoroughly, surrounding pollutes, the injection site sterilization is not thorough etc. causes.3. the neural paralysis of the improper initiation of injection operation even disable deadly.And diabetes are chronic disease, need long term administration, so persistence misery, inconvenience and potential safety hazard are in use brought to the patient in the commercially available prod.
Summary of the invention
Purpose of the present invention is: at Exenatide (exenatide) as subcutaneous injection in the drawback that treatment exists in the diabetes, the oral drugs and preparation method thereof of the treatment diabetes of a kind of employing Exenatide (exenatide) are provided.
The object of the present invention is achieved like this: a kind of nasal mist for the treatment of diabetes, comprise solvent and adjuvant, it is characterized in that: the complex that contains calcium phosphate nano particle and Exenatide in the solvent, calcium phosphate nano particle and the Exenatide weight ratio in complex is 1～10: 0.1～10, the content of Exenatide is 0.01～0.5mg/ml in the solvent, the pH=6 of solvent～7.
In the present invention: the calcium phosphate nano particle by concentration be the calcium salt soln, phosphate solution, citrate solution of 0.001-1mol/L according to 1～20: 1～20: 1～10 volume ratio is mixed the back and is obtained.
In the present invention: described calcium salt can be calcium salts such as calcium sulfate, calcium chloride, described phosphate can be phosphate such as sodium phosphate, sodium dihydrogen phosphate, sodium hydrogen phosphate, Ammonium biphosphate, described citrate is citrates such as potassium citrate, citrate of magnesia, sodium citrate, and described solution is aqueous solution.
In the present invention: described solvent is a water for injection, adds aqua medicine adjuvant commonly used in the solvent.
A kind of preparation method of above-mentioned nasal mist is characterized in that:
A) with described calcium salt soln, phosphate solution, citric acid salt solution mix, obtain the calcium phosphate nano particle after the supersound process, be that the aqueous solution of 0.01～50mg/mL mixes with Exenatide concentration again;
B) at room temperature stir 1～3 day, supersound process, centrifugal, supernatant discarded, the complex of acquisition calcium phosphate nano particle and Exenatide, calcium phosphate nano particle and the Exenatide weight ratio in complex is 1～10: 0.1～10;
C) complex that the b step is obtained forms drug solvent with the water for injection dilution, and the content of the Exenatide in the drug solvent after the dilution is 0.01～0.5mg/ml;
D) in the drug solvent that the c step obtains, add water preparation adjuvant commonly used, detect pH behind the mix homogeneously, when pH ≠ 6～7, after adjusting by the pH regulator agent, obtain the nasal cavity drop of treatment diabetes medicament.
The preparation method of another kind of above-mentioned nasal mist is characterized in that:
A) with concentration be calcium salt soln, phosphate solution, citrate solution and the concentration of 0.001-1mol/L be the Exenatide aqueous solution of 0.01-50mg/mL according to volume ratio 1～10: mix stir at 1～10: 1～5: 0.01～1;
B) at room temperature stir 1～3 day, supersound process, centrifugal, supernatant discarded, the complex of acquisition calcium phosphate nano particle and Exenatide, the weight ratio of calcium phosphate nano particle and Exenatide is 1-10: 0.1-10 in the complex;
C) complex that the b step is obtained forms drug solvent with the water for injection dilution, and the content of the Exenatide in the drug solvent after the dilution is 0.01～0.5mg/ml;
D) in the drug solvent that the c step obtains, add water preparation adjuvant commonly used, detect pH behind the mix homogeneously, when pH ≠ 6～7, after adjusting by the pH regulator agent, obtain the nasal cavity drop of treatment diabetes medicament.
The invention has the advantages that: by carrier technique carry Exenatide (exenatide) thus seeing through the bronchia mucosal barrier enters blood circulation and plays therapeutical effect, avoid present subcutaneous injection administering mode to the patient bring painful and inconvenient.Simultaneously, phosphate is that skeleton, tooth are mainly led into part with calcium salt in the raw material, is the necessary material of human body, and greatly degree has been avoided because carrier can not be had the potential safety hazard that toxic and side effects is brought to human body by biodegradation or catabolite.
The specific embodiment
Embodiment 1
Precision takes by weighing calcium chloride 1.0g and is dissolved in the 500ml deionized water and makes calcium chloride solution; Precision takes by weighing sodium hydrogen phosphate 1.0g and is dissolved in the 500ml deionized water and makes disodium phosphate soln; Precision takes by weighing sodium citrate 0.4g and is dissolved in the 80ml deionized water and makes liquor sodii citratis, calcium chloride solution, disodium phosphate soln and liquor sodii citratis mixed the back stirring at room 48 hours according to 2: 2: 1 volume ratio, after the supersound process, centrifugal, supernatant discarded, formation contains the calcium phosphate nano particle solution, and the concentration of the calcium phosphate nano particle in the solution is 0.5mg/ml.The calcium phosphate nano particle solution was mixed stirring 2 hours with 20mg/mL Exenatide aqueous solution by weight 1: 1, centrifugal, supernatant discarded, the complex of acquisition calcium phosphate nano particle and Exenatide; Described complex is formed drug solvent with the note dilute with water, and the content of the Exenatide in the drug solvent after the dilution is 0.01～0.5mg/ml; In drug solvent, add aqua medicine following adjuvant commonly used: pyrosulfite, sodium chloride, wherein: the addition of pyrosulfite is a 0.05% (percent by volume of drug solvent, down together), the addition of bromo geramine is 0.01% of a drug solvent, the addition of sodium chloride is 0.9% of a drug solvent, detects pH behind the mix homogeneously, when pH ≠ 6～7, adjust to pH=6～7 by the pH regulator agent, obtain the nasal cavity drop of treatment diabetes medicament.The pH regulator agent can be selected hydrochloric acid, or sodium hydroxide, or triethanolamine, or trometamol.
Embodiment 2
The accurate calcium chloride 1.0g that takes by weighing is dissolved in the 500ml deionized water and makes calcium chloride solution; Precision takes by weighing sodium hydrogen phosphate 1.0g and is dissolved in the 500ml deionized water and makes disodium phosphate soln; Precision takes by weighing sodium citrate 0.4g and is dissolved in the 80ml deionized water and makes liquor sodii citratis, the accurate Exenatide 50mg that takes by weighing is dissolved in and makes the Exenatide aqueous solution in the 5mL deionized water, above-mentioned solution is mixed stirring 48 hours, after the supersound process, centrifugal, supernatant discarded, the complex of acquisition calcium phosphate nano particle and Exenatide; Described complex is formed drug solvent with the note dilute with water, and the content of the Exenatide in the drug solvent after the dilution is 0.01～0.5mg/ml; In drug solvent, add aqua medicine following adjuvant commonly used: pyrosulfite, sodium chloride, wherein: the addition of pyrosulfite is a 0.05% (percent by volume of drug solvent, down together), the addition of bromo geramine is 0.01% of a drug solvent, the addition of sodium chloride is 0.9% of a drug solvent, detects pH behind the mix homogeneously, when pH ≠ 6～7, adjust to pH=6～7 by the pH regulator agent, obtain the nasal cavity drop of treatment diabetes medicament.The pH regulator agent can be selected hydrochloric acid, or sodium hydroxide, or triethanolamine, or trometamol.
Embodiment 3
Nasal cavity drug metabolism experiment
Laboratory animal:
The SD rat, 180～200g, male, 8
The experiment medicine:
Test group: with the nasal cavity drop that embodiment 2 obtains, the Exenatide concentration 16mg/ml in the nasal cavity drop.
Matched group: Exenatide is diluted dilution back active drug Exenatide concentration 16mg/ml with water for injection.
Experimental technique:
Experimental rat precuring 3 days, test fasting the previous day 12h.
Rat is divided into parallel four groups of A, B, C, D, and 2 every group, wherein, A, B, C group are test group, and the D group is matched group, and each only organizes equal intranasal administration 5 μ l/, and dosage is 100 μ g/200g.In each group, 5,10,20,30 minutes eye sockets blood sampling 0.3ml after administration, with blood at 4 ℃, under 3000 rpms of conditions centrifugal 10 minutes, collect upper serum ,-20 ℃ of refrigerators are preserved, to be measured, another is after administration 1,1.5,2,3,4,6 hours eye sockets blood sampling 0.3ml, with blood at 4 ℃, under 3000 rpms of conditions centrifugal 10 minutes, collect upper serum ,-20 ℃ of refrigerators are preserved, and are to be measured.
To detecting the content of Exenatide in the test serum sample, the results are shown in Table 1 with the ELA method
Table 1 time-blood Chinese medicine concentration tabulation
| Time (minute) | A organizes (ng/ml) | B organizes (ng/ml) | C organizes (ng/ml) | A.B.C organizes mean concentration (ng/ml) | D organizes (ng/ml) |
| 5? | 2.243? | 2.151? | 2.201? | 2.198? | 1.082? |
| 10? | 4.673? | 4.973? | 4.169? | 4.605? | 2.301? |
| 20? | 5.866? | 4.397? | 5.863? | 5.375? | 0.315? |
| 30? | 0.317? | 0.136? | 0.271? | 0.241? | 0.142? |
| 60? | 0.256? | 0.163? | 0.348? | 0.256? | 0.056? |
| 90? | 0.367? | 0.269? | 0.338? | 0.325? | 0.006? |
| 120? | 0.252? | 0.264? | 0.310? | 0.275? | 0.000? |
| 180? | 1.673? | 1.827? | 1.184? | 1.561? | 0.000? |
| 240? | 1.543? | 0.652? | 0.988? | 1.061? | 0.000? |
| 360? | 0.531? | 0.341? | 0.788? | 0.553? | 0.000? |
As seen, not with the bonded Exenatide of nano-particle in blood drug level and the holdup time far below with the Exenatide of calcium phosphate nano particle.
Embodiment 4
The effect experiment of collunarium medicine
Laboratory animal:
The ICR mice, 18～22g, male, 30
The experiment medicine:
Test group: with the nose drops medicinal powder dilute with water that embodiment 1 obtains, dilution back active drug Exenatide concentration 0.5mg/ml; Glucose.
Negative control group: glucose.
Positive controls: subcutaneous injection Exenatide aqueous solution (0.5mg/ml); Glucose.
Experimental technique:
Experiment ICR mice precuring 3 days.The ICR mice is divided into 3 groups: test group (n=10), positive controls (n=10) negative control group (n=10); Mouse test fasting the previous day 12h can't help water and use electronics blood glucose monitoring system (the complete superior type Germany Luo Shi diagnosis company limited of Luo Kang) measuring blood concentration before test.The nose drops medicinal powder that test group obtains for embodiment 1 is irritated stomach glucose (glucose dosage is 2.5g/kg, and concentration is 10%, down together) later on; Negative control group is only irritated the stomach glucose; The stomach glucose is irritated in positive controls subcutaneous injection Exenatide aqueous solution (0.5mg/ml) back; Use electronics blood glucose monitoring system (the complete superior type Germany Luo Shi diagnosis company limited of Luo Kang) to detect after the administration 0 hour, 0.5 hour, 1 hour, 2 hours, 3 hours blood sugar concentrations, and meansigma methods that each group detects data listed in table 2.
Table 2 test group/negative control group/positive controls detects the data contrast
| Time (min) | Nasal mucosa administration (mmol/L) | Positive control (mmol/L) | Negative control (mmol/L) |
| 0? | 4.1? | 7.69? | 6.88? |
| 30? | 5.7? | 7.29? | 15.96? |
| 60? | 4.2? | 5.75? | 9.62? |
| 120? | 3.6? | 5.09? | 6.48? |
| 180? | 3.9? | 5.02? | 5.82? |
By table 2 as seen, test group is compared with negative control group, and the present invention is that effectively test group is compared with positive controls to the treatment diabetes, and its therapeutic effect obviously is better than using the positive controls of subcutaneous injection Exenatide aqueous solution.
More than each embodiment be not to concrete restriction of the present invention; any those of ordinary skill in the art; do not breaking away under the technical solution of the present invention scope situation; utilize the method content of above-mentioned announcement that technical solution of the present invention is made many possible changes and modification, all belong to the scope of claims protection.
Claims (6)
1. nasal cavity drop for the treatment of diabetes, comprise solvent and adjuvant, it is characterized in that: the complex that contains calcium phosphate nano particle and Exenatide in the solvent, calcium phosphate nano particle and the Exenatide weight ratio in complex is 1～10: 0.1～10, and the content of Exenatide is 0.01～0.5mg/ml in the solvent.
2. the nasal cavity drop of treatment diabetes according to claim 1 is characterized in that: the calcium phosphate nano particle by concentration be the calcium salt soln, phosphate solution, citrate solution of 0.001-1mol/L according to 1～20: 1～20: 1～10 volume ratio is mixed the back and is obtained.
3. the nasal cavity drop of treatment diabetes according to claim 2, it is characterized in that: described calcium salt is calcium sulfate or calcium chloride, described phosphate is sodium phosphate, or sodium dihydrogen phosphate, or sodium hydrogen phosphate, or Ammonium biphosphate, described citrate is a potassium citrate, or citrate of magnesia, or sodium citrate, described solution is aqueous solution, the pH=6 of solvent～7.
4. according to the nasal cavity drop of claim 2 or 3 described treatment diabetes, it is characterized in that: described solvent is a water for injection, adds aqua medicine adjuvant commonly used in the solvent.
5. preparation method as nasal cavity drop as described in the claim 4 is characterized in that:
A) with described calcium salt soln, phosphate solution, citric acid salt solution mix, obtain the calcium phosphate nano particle after the supersound process, be that the aqueous solution of 0.01～50mg/mL mixes with Exenatide concentration again;
B) at room temperature stir 1～3 day, supersound process, centrifugal, supernatant discarded, the complex of acquisition calcium phosphate nano particle and Exenatide, calcium phosphate nano particle and the Exenatide weight ratio in complex is 1～10: 0.1～10;
C) complex that the b step is obtained forms drug solvent with the water for injection dilution, and the content of the Exenatide in the drug solvent after the dilution is 0.01～0.5mg/ml;
D) in the drug solvent that the c step obtains, add water preparation adjuvant commonly used, detect pH behind the mix homogeneously, when pH ≠ 6～7, after adjusting by the pH regulator agent, obtain the nasal cavity drop of treatment diabetes medicament.
6. preparation method as nasal cavity drop as described in the claim 4 is characterized in that:
A) with concentration be calcium salt soln, phosphate solution, citrate solution and the concentration of 0.001-1mol/L be the Exenatide aqueous solution of 0.01-50mg/mL according to volume ratio 1～10: mix stir at 1～10: 1～5: 0.01～1;
B) at room temperature stir 1～3 day, supersound process, centrifugal, supernatant discarded, the complex of acquisition calcium phosphate nano particle and Exenatide, the weight ratio of calcium phosphate nano particle and Exenatide is 1～10: 0.1～10 in the complex;
C) complex that the b step is obtained forms drug solvent with the water for injection dilution, and the content of the Exenatide in the drug solvent after the dilution is 0.01～0.5mg/ml;
D) in the drug solvent that the c step obtains, add water preparation adjuvant commonly used, detect pH behind the mix homogeneously, when pH ≠ 6～7, after adjusting by the pH regulator agent, obtain the nasal cavity drop of treatment diabetes medicament.
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| US9694053B2 (en) | 2013-12-13 | 2017-07-04 | Sanofi | Dual GLP-1/glucagon receptor agonists |
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| US9750788B2 (en) | 2013-12-13 | 2017-09-05 | Sanofi | Non-acylated exendin-4 peptide analogues |
| US9758561B2 (en) | 2014-04-07 | 2017-09-12 | Sanofi | Dual GLP-1/glucagon receptor agonists derived from exendin-4 |
| US9771406B2 (en) | 2014-04-07 | 2017-09-26 | Sanofi | Peptidic dual GLP-1/glucagon receptor agonists derived from exendin-4 |
| US9775904B2 (en) | 2014-04-07 | 2017-10-03 | Sanofi | Exendin-4 derivatives as peptidic dual GLP-1/glucagon receptor agonists |
| US9789165B2 (en) | 2013-12-13 | 2017-10-17 | Sanofi | Exendin-4 peptide analogues as dual GLP-1/GIP receptor agonists |
| US9932381B2 (en) | 2014-06-18 | 2018-04-03 | Sanofi | Exendin-4 derivatives as selective glucagon receptor agonists |
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| US9670261B2 (en) | 2012-12-21 | 2017-06-06 | Sanofi | Functionalized exendin-4 derivatives |
| US9745360B2 (en) | 2012-12-21 | 2017-08-29 | Sanofi | Dual GLP1/GIP or trigonal GLP1/GIP/glucagon agonists |
| US10253079B2 (en) | 2012-12-21 | 2019-04-09 | Sanofi | Functionalized Exendin-4 derivatives |
| US9694053B2 (en) | 2013-12-13 | 2017-07-04 | Sanofi | Dual GLP-1/glucagon receptor agonists |
| US9751926B2 (en) | 2013-12-13 | 2017-09-05 | Sanofi | Dual GLP-1/GIP receptor agonists |
| US9750788B2 (en) | 2013-12-13 | 2017-09-05 | Sanofi | Non-acylated exendin-4 peptide analogues |
| US9789165B2 (en) | 2013-12-13 | 2017-10-17 | Sanofi | Exendin-4 peptide analogues as dual GLP-1/GIP receptor agonists |
| US9758561B2 (en) | 2014-04-07 | 2017-09-12 | Sanofi | Dual GLP-1/glucagon receptor agonists derived from exendin-4 |
| US9771406B2 (en) | 2014-04-07 | 2017-09-26 | Sanofi | Peptidic dual GLP-1/glucagon receptor agonists derived from exendin-4 |
| US9775904B2 (en) | 2014-04-07 | 2017-10-03 | Sanofi | Exendin-4 derivatives as peptidic dual GLP-1/glucagon receptor agonists |
| US9932381B2 (en) | 2014-06-18 | 2018-04-03 | Sanofi | Exendin-4 derivatives as selective glucagon receptor agonists |
| US9982029B2 (en) | 2015-07-10 | 2018-05-29 | Sanofi | Exendin-4 derivatives as selective peptidic dual GLP-1/glucagon receptor agonists |
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