CN101130064A - Freeze dried injection for treating type 2 diabetes and method of preparing the same - Google Patents
Freeze dried injection for treating type 2 diabetes and method of preparing the same Download PDFInfo
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- CN101130064A CN101130064A CNA2007100661606A CN200710066160A CN101130064A CN 101130064 A CN101130064 A CN 101130064A CN A2007100661606 A CNA2007100661606 A CN A2007100661606A CN 200710066160 A CN200710066160 A CN 200710066160A CN 101130064 A CN101130064 A CN 101130064A
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- gla protein
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Abstract
The invention relates to a Chinese medicinal freeze dried powder injection for treating type II diabetes and process for preparation, wherein the freeze dried powder injection comprises osteocalcin or its medicinal complex compounds and freeze-drying support agent. Compared with the existing pharmaceuticals for treating type II diabetes, the freeze dried powder injection has the advantages of high biological availability, quick medicament adsorption speed, rapid allocation and persistent effect.
Description
Technical field
The present invention relates to medical technical field, specifically a kind of (Bone Gla protein) lyophilized injectable powder for the treatment of type ii diabetes and preparation method thereof.
Background technology:
Bone Gla protein (Osteocalcin) also is called bone r-carboxyglutamic acid albumen (Bone-car-boxyglumaticAcid-Containing Protein, BGP), being to be become with special of odontoblast and the former albumen in excretory a kind of non-chamber by osteoblast, is one of composition that constitutes bone matrix.Studies have shown that BGP can keep the normal mineralization rate of bone, suppress the unusual crystalline formation of hydroxyapatite (HA), is sensitivity, reliable index that reaction body bone metabolism changes.Begin to there are some researches show gradually from the beginning of the eighties, measure the serum BGP changes of contents understanding bone physiology, the bone metabolism instantaneous variation, it is significant to observe osteoblastic functional status.
1975-1976 Hauschka and Price be respectively from chicken, in calf and the people's bone first separation and Extraction r-hydroxygultamic acid albumen, identified this proteic structure, and named and be Bone Gla protein.1986, Celeste utilized recombinant DNA technology, was probe with synthetic oligonucleotide, had obtained people's BGP genomic dna cloning and the cDNA clone of mice.
Scientist exists between conjecture skeletal system and the hormonal endocrine organ of release always and gets in touch.U.S.'s scientist's current research shows, the excretory Bone Gla protein of skeleton (osteocalcin) can be regulated the absorption of sugar and fat. on " cell " magazine on August 10th, 2007, the geneticist Gerard Karsenty of Columbia Univ USA finds that adipose cell can influence the quantity of osteoblast by releasing hormone leptin (leptin).Consider the effect of human body feedback system, therefore infer that skeleton also can discharge the hormone of oneself and regulate and control fatty metabolism.
In order to understand fully this problem, Karsenty and research group have launched experiment at two groups of mices, and wherein one group of applying gene technology makes it produce a large amount of Bone Gla proteins.When raising with normal food, the genetic modification mice can show the blood sugar level that is lower than normal level and the insulin level that is higher than normal level, and, the sensitivity of insulin has also been increased.In addition, when raising with high-fat food, the fat of the mice body inner accumulated of genetic modification lacks than normal mouse, and when the applying gene technology made that mice no longer produces Bone Gla protein, even raise with normal diet, this kind mice also can produce type ii diabetes.This experiment has proved absolutely that the Bone Gla protein by skeleton produces has played effect in other organ, meet the definition of hormone, so formally skeleton is called a kind of endocrine organ.
This discovery of Karsenty has great importance for treatment of diabetes.Bone Gla protein has triple function, and it can improve the level of insulin, promotes the absorption of insulin, and can stop the accumulation of fat.This will be expected to bring hope for the patient of type ii diabetes.
Summary of the invention
The purpose of this invention is to provide a kind of Bone Gla protein lyophilized injectable powder that is used for the treatment of type ii diabetes, its bioavailability height, drug absorption is good, distribution is fast, effect is lasting; The present invention also provides its preparation method.
Bone Gla protein lyophilized injectable powder of the present invention is by the active component Bone Gla protein or it can make medicinal metal ion complex and frozen-dried supporting agent is formed.
Above-mentioned active component Bone Gla protein can be cattle Bone Gla protein, pig Bone Gla protein, sheep Bone Gla protein, rat OC, rabbit Bone Gla protein, chicken Bone Gla protein or through people's Bone Gla protein of gene engineering expression preparation.
It can be Bone Gla protein calcium complex, Bone Gla protein iron complex or Bone Gla protein zinc complex that Bone Gla protein can be made medicinal metal ion complex.
Frozen-dried supporting agent can be one or more in mannitol, sorbitol, cyclodextrin, sodium chloride, xylitol, dextran and the gelatin hydrolysate.
The preparation method of Bone Gla protein lyophilized injectable powder of the present invention is:
(1) the pharmaceutical grade Bone Gla protein that takes by weighing recipe quantity maybe can be made medicinal Bone Gla protein metal ion complex, add the injection water and make its dissolving, it is an amount of to add needle-use activated carbon, stir, filter, regulate pH 5.5-7.5, add the injection water to capacity with 0.1mol/L HCI and 0.1mol/L NaOH, by the aseptic manipulation aseptic filtration, packing;
(2) sample that branch is installed was-40 ℃ of pre-freezes 2 hours, and being evacuated to vacuum is 10KPa, and heat drying is warming up to 30 ℃ after 28 hours, kept vacuum 2 hours, automatically jumped a queue in freeze drying box then and sealed, and added aluminium lid, promptly made the Bone Gla protein lyophilized injectable powder.
After the Bone Gla protein lyophilized injectable powder injection of the present invention, have the promotion insulin secretion, improve the sensitivity of body, improve the triple roles such as tolerance of body, thereby effectively treat diabetes, alleviate complication blood glucose to insulin.
By following experiment safety of the present invention and curative effect can be described.
One, the long-time stability of Bone Gla protein lyophilized injectable powder
The effects condition and project: medicine is pressed the method preparation of embodiment 1, places under 25 ℃ of conditions of temperature, observes 0 month, 3 months, 6 months, 9 months, 12 months outward appearance, pH value, clarity, flora, thermal source, content.Outward appearance, pH value, clarity, flora, thermal source detect by 2000 editions requirements of Chinese Pharmacopoeia.Content detects with the HPLC method.
| Lot number | Time (moon) | Outward appearance | pH | Clarification | Flora | Thermal source | Content (%) |
| 060601 | 0 | Colourless liquid | 6.52 | Up to specification | Up to specification | Up to specification | 99.3 |
| 3 | Colourless liquid | 6.54 | Up to specification | Up to specification | Up to specification | 99.1 | |
| 6 | Colourless liquid | 6.49 | Up to specification | Up to specification | Up to specification | 99.8 | |
| 9 | Colourless liquid | 6.51 | Up to specification | Up to specification | Up to specification | 99.0 | |
| 12 | Colourless liquid | 6.52 | Up to specification | Up to specification | Up to specification | 99.2 | |
| 060602 | 0 | Colourless liquid | 6.51 | Up to specification | Up to specification | Up to specification | 99.4 |
| 3 | Colourless liquid | 6.56 | Up to specification | Up to specification | Up to specification | 98.9 | |
| 6 | Colourless liquid | 6.55 | Up to specification | Up to specification | Up to specification | 99.2 | |
| 9 | Colourless liquid | 6.54 | Up to specification | Up to specification | Up to specification | 99.5 | |
| 12 | Colourless liquid | 6.57 | Up to specification | Up to specification | Up to specification | 99.1 | |
| 060603 | 0 | Colourless liquid | 6.53 | Up to specification | Up to specification | Up to specification | 99.6 |
| 3 | Colourless liquid | 6.58 | Up to specification | Up to specification | Up to specification | 99.4 | |
| 6 | Colourless liquid | 6.50 | Up to specification | Up to specification | Up to specification | 99.7 | |
| 9 | Colourless liquid | 6.55 | Up to specification | Up to specification | Up to specification | 99.3 | |
| 12 | Colourless liquid | 6.53 | Up to specification | Up to specification | Up to specification | 99.4 |
Conclusion: Bone Gla protein lyophilized injectable powder good stability.Can the room temperature long preservation.
Two, the safety testing of Bone Gla protein lyophilized injectable powder
1, test objective
Observe the zest of Bone Gla protein lyophilized injectable powder multiple dosing to rabbit, the anaphylaxis of Cavia porcellus, and, be the clinical safety foundation that provides to the hemolytic response situation of tame Sanguis Leporis seu oryctolagi.
2, reagent and instrument
Normal saline, 5% glucose, ovalbumin, 10% formaldehyde;
The tissue slice instrument, constant incubator, syringe, centrifuge.
3, animal subject
Large ear rabbit, 4, body weight 2.0-2.5kg.
Cavia porcellus, male, body weight 250-300g.
The raising condition: keep 23 ± 2 ℃ of room temperatures, relative humidity 60%～65%, natural lighting is freely intake.
4, test method
(1) blood vessel irritation test
Get 4 of large ear rabbits, body weight 2.0-2.5kg does not use any medicine for first, makes blank parallel control and observes.3 are adopted self consubstantiality dystopy controlled trial in addition.Is 0.01% (0.1mg/ml) with medicine with the dilution of 5% glucose injection, to the rabbit vein dropleting medicine-feeding, with 2ml/kg (by the conversion of people 50ml/60kg body surface area), injection speed is 0.5ml/ minute to Bone Gla protein lyophilized injectable powder usefulness primary sterilization infusion set after the administration group will be made into through left auricular vein; Matched group is through equivalent 5% glucose injection of right side auricular vein instillation 2ml/kg.Once a day, continuous five days, observed the intravascular injection position and whole outer auricular concha has or not variation every day during the administration, and compare with matched group.After the last administration, put to death animal in 24 hours, draw medicine place blood vessel and surrounding tissue, fix, through dehydration, transparent, paraffin embedding, HE dyeing with 10% formalin.The section position is entad end distance inserting needle position 1-5cm of inserting needle position, and 0-1cm and 4-5cm draw materials for two sections.
(2) hemolytic test
The Bone Gla protein lyophilized injectable powder is 0.01% (0.1mg/ml) with the dilution of 5% glucose injection.Get 1 of rabbit, heart extracting blood 20ml places graduated cylinder, stirs with glass rod, removes and defibrinates, and leaves standstill, and takes out blood, adds the equivalent normal saline, and centrifugal, it is standby to prepare 2% red blood cell suspension.Get 7 in test tube again, press table 1 and add various injection, wherein the 6th, 7 pipes are respectively normal saline solution control tube and hemolytic positive control pipe.Each pipe is shaken up, and incubation is 3 hours in 37 ℃ of water-baths, carries out external hemolytic test and observes.
The external hemolytic test application of sample of table 1 table
| Test solution | 1 | 2 | 3 | 4 | 5 | 6 | 7 |
| The Bone Gla protein lyophilized injectable powder | 0.1 | 0.2 | 0.3 | 0.4 | 0.5 | 0 | 0 |
| 5% glucose injection | 2.4 | 2.3 | 2.2 | 2.1 | 2.0 | 2.5 | 0 |
| Distilled water | 0 | 0 | 0 | 0 | 0 | 0 | 2.5 |
| 2% red blood cell suspension | 2.5 | 2.5 | 2.5 | 2.5 | 2.5 | 2.5 | 2.5 |
(3) sensitivity test
The Bone Gla protein lyophilized injectable powder is 0.01% (0.1mg/ml) with the dilution of 5% glucose injection, gets healthy nothing and hinders 18 of Cavia porcelluss, and body weight 250-300g is divided into 3 groups at random.By the sterile working, administration group, normal saline solution group, positive sensitization group respectively the next day lumbar injection Bone Gla protein lyophilized injectable powder, normal saline solution, each 0.5ml/ of 5% ovalbumin only, totally 3 times.After the injection the 14th day got 3 Cavia porcelluss respectively for every group first, only attacked by forelimb intravenous injection Bone Gla protein lyophilized injectable powder, normal saline solution, each 1ml/ of 5% ovalbumin respectively.After injection first the 21st day of every group of remaining 3 animal carried out second time by above method and attacked the observation anaphylaxis.
5, date processing
(1) blood vessel irritation test: pathology section examination normal saline injection site and Bone Gla protein lyophilized injectable powder injection site blood vessel structure, whether the vascular tissue of comparative drug injection site has pathological change.
(2) hemolytic test: judge according to the haemolysis criterion whether each pipe haemolysis or coacervation occurred in 0.5-3 hour.
(3) sensitivity test: judge by the anaphylaxis classification whether animal has anaphylaxis.
6, result of the test
(1) blood vessel irritation test: perusal is the result show, the administration group is not seen the congestion of blood vessel, hemorrhage, tissue edema, necrosis.Normal saline solution matched group blood vessel is not seen the congestion of blood vessel, hemorrhage yet, unusual pathological change such as tissue edema, necrosis.The pathological tissue check result shows: administration group, normal saline solution control animals auricular vein blood vessel structure are normal, the vascular endothelial cell not damaged, and surrounding tissue is abnormal change such as the swollen or necrosis of water breakthrough not.Show that the Bone Gla protein lyophilized injectable powder does not have the obvious stimulation effect to the rabbit vein blood vessel.
(2) hemolytic test: result of the test shows that each concentration of Bone Gla protein lyophilized injectable powder did not all have haemolysis or agglutination to tame rabbit erythrocyte in 0.5-3 hour.
(3) sensitivity test: reuse the Bone Gla protein lyophilized injectable powder, do not cause that obvious anaphylaxis appears in animal subject.It is dead all to twitch in 15 minutes after the 5% ovalbumin group animal subject administration.
7, conclusion
The Bone Gla protein lyophilized injectable powder does not have blood vessel zest, hemolytic, anaphylactic reaction, and is safe and reliable, can be used for intravenous injection.
Three, the clinical trial of Bone Gla protein lyophilized injectable powder treatment type ii diabetes
Carry out the clinical trial that the Bone Gla protein lyophilized injectable powder is treated type ii diabetes by the test of pesticide effectiveness that state-promulgated pharmacopoeia is worked out.After treating in Chinese medicine matched group 60 examples, produce effects 12 examples (20%), effective 27 examples (45%), invalid 21 examples (35%), total effective rate is 65%.Produce effects 33 examples (55%) in Bone Gla protein lyophilized injectable powder group 60 examples, effective 24 examples (40%), invalid 3 examples (5%), total effective rate is 95%, and effect is lasting, it is effectively above that injection once can continue a week.Bone Gla protein lyophilized injectable powder group obviously is better than the Chinese medicine matched group, and two groups relatively, and utmost point significant difference (P＜0.01) is arranged.
The specific embodiment
Embodiment 1:
The agent of injection Os Bovis seu Bubali calcium freezing-dried powder
1, prepare raw material by following prescription:
Get commercially available pharmaceutical grade cattle Bone Gla protein 200g, mannitol 50g, water for injection 2000ml
2, preparation technology:
Get Bone Gla protein 200g, the liquor-saturated 50g of manna, add injection water 1600ml and make dissolving, add an amount of needle-use activated carbon, stir, filter, make it slough impurity, regulate pH value pH 5.5-5.7 with 0.1mol/L HCI and 0.1mol/L NaOH, add the injection water to 2000ml, by the aseptic manipulation degerming, with 0.22 μ filtering with microporous membrane, the filtrate sample presentation carries out the inspection of semi-finished product content with this medicinal liquid, then by 1000 of equivalent packing, the sample that branch is installed was-40 ℃ of pre-freezes 2 hours, and being evacuated to vacuum is 10Kpa, heat drying, be warming up to 30 ℃ in 28 hours, kept vacuum 2 hours, and then, automatically jumped a queue in the freeze drying box and seal, add aluminium lid, promptly get 1000 of dried frozen aquatic productses of the present invention.
The recommendation usage of this Bone Gla protein lyophilized injectable powder is for once a week, each one.
Embodiment 2:
The agent of injection Os Sus domestica calcium freezing-dried powder
Get commercially available pharmaceutical grade pig Bone Gla protein 250g, sorbitol 50g, water for injection 2000ml, make 1000 of dried frozen aquatic productses altogether.
Preparation technology: preparation method is except that the main ingredient difference that adds, and other are with embodiment 1.
Embodiment 3:
Injection Bone Gla protein calcium complex lyophilized injectable powder
Get commercially available medicinal Bone Gla protein calcium complex 210g, sodium chloride 50g, water for injection 2000ml, make 1000 of dried frozen aquatic productses altogether.
System is put forth energy technology: preparation method is removed the main ingredient difference that adds, and pH regulator is outside 7.1-7.3, and other are with embodiment 1.
Embodiment 4:
The agent of injection Os Caprae seu Ovis calcium freezing-dried powder
Get commercially available pharmaceutical grade sheep Bone Gla protein 150g, dextran 50g, water for injection 2000ml, make 1000 of dried frozen aquatic productses altogether.
Preparation technology: preparation method is removed the main ingredient difference that adds, and pH transfers to outside the 6.6-6.8, and other are with embodiment 1.
Embodiment 5:
Injection Bone Gla protein ferrum lyophilized injectable powder
Get commercially available pharmaceutical grade Bone Gla protein ferrum 300g, cyclodextrin 50g, water for injection 2000ml, make 1000 of dried frozen aquatic productses altogether.
Preparation technology: preparation method is removed the raw material difference that adds, and pH regulator is outside 5.6-5.8, and other are with embodiment 1.
Embodiment 6:
Injection rat OC lyophilized injectable powder
Get commercially available medicinal rat OC 180g, sorbitol 25g, mannitol 25g, water for injection 2000ml, make 1000 of dried frozen aquatic productses altogether.
Preparation technology: preparation method is removed the main ingredient difference that adds, and pH transfers to outside the 5.9-6.1, and other are with embodiment 1.
Embodiment 7:
The agent of injection Os Leporis seu Oryctolagi calcium freezing-dried powder
Get commercially available pharmaceutical grade rabbit Bone Gla protein 280g, mannitol 40g, sodium chloride 10g, water for injection 2000ml, make 1000 of dried frozen aquatic productses altogether.
Preparation technology: preparation method is removed the main ingredient difference that adds, and pH transfers to outside the 6.5-6.7, and other are with embodiment 1.
Embodiment 8:
The agent of injection Os Gallus domesticus calcium freezing-dried powder
Get commercially available pharmaceutical grade chicken Bone Gla protein 220g, xylitol 50g, water for injection 2000ml, make 1000 of dried frozen aquatic productses altogether.
Preparation technology: preparation method is removed the main ingredient difference that adds, and pH transfers to outside the 7.3-7.5, and other are with embodiment 1.
Embodiment 9:
Injection Bone Gla protein zinc complex lyophilized injectable powder
Get commercially available pharmaceutical grade Bone Gla protein zinc complex 240g, gelatin hydrolysate 50g, water for injection 2000ml, make 1000 of dried frozen aquatic productses altogether.
Preparation technology: preparation method is removed the main ingredient difference that adds, and pH transfers to outside the 5.8-6.0, and other are with embodiment 1.
Embodiment 10:
Injection personnel selection Bone Gla protein lyophilized injectable powder
Get people's Bone Gla protein 165g, sorbitol 50g, the water for injection 2000ml of commercially available genetic engineering preparation, make 1000 of dried frozen aquatic productses altogether.
Preparation technology: preparation method is removed the main ingredient difference that adds, and pH transfers to outside the 6.9-7.1, and other are with embodiment 1.
Claims (5)
1. a lyophilized injectable powder for the treatment of type ii diabetes is characterized in that forming by maybe making medicinal Bone Gla protein metal ion complex and frozen-dried supporting agent by the Bone Gla protein of pharmaceutical dosage.
2. the lyophilized injectable powder of treatment type ii diabetes according to claim 1, it is characterized in that described Bone Gla protein is cattle Bone Gla protein, pig Bone Gla protein, sheep Bone Gla protein, rat OC, rabbit Bone Gla protein, chicken Bone Gla protein or a kind of in people's Bone Gla protein of gene engineering expression preparation.
3. the lyophilized injectable powder of treatment type ii diabetes according to claim 1 is characterized in that, described to make medicinal Bone Gla protein metal ion complex be a kind of in Bone Gla protein calcium complex, Bone Gla protein iron complex or the Bone Gla protein zinc complex.
4. the lyophilized injectable powder of treatment type ii diabetes according to claim 1, it is characterized in that described frozen-dried supporting agent is one or more in the following listed material: mannitol, sorbitol, cyclodextrin, sodium chloride, xylitol, dextran and gelatin hydrolysate.
5. the preparation method of the lyophilized injectable powder of the described treatment type ii diabetes of claim 1 is characterized in that may further comprise the steps:
(1) the pharmaceutical grade Bone Gla protein that takes by weighing recipe quantity maybe can be made medicinal Bone Gla protein metal ion complex and frozen-dried supporting agent, add the injection water and make its dissolving, it is an amount of to add needle-use activated carbon, stir, filter, regulate pH5.5-7.5, add the injection water to capacity with 0.1mol/L HCI and 0.1mol/LNaOH, by the aseptic manipulation aseptic filtration, packing;
(2) sample that branch is installed was-40 ℃ of pre-freezes 2 hours, and being evacuated to vacuum is 10KPa, and heat drying is warming up to 30 ℃ after 28 hours, kept vacuum 2 hours, automatically jumped a queue in freeze drying box then and sealed, and added aluminium lid, promptly made the Bone Gla protein lyophilized injectable powder.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CNA2007100661606A CN101130064A (en) | 2007-09-03 | 2007-09-03 | Freeze dried injection for treating type 2 diabetes and method of preparing the same |
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| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CNA2007100661606A CN101130064A (en) | 2007-09-03 | 2007-09-03 | Freeze dried injection for treating type 2 diabetes and method of preparing the same |
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| CN101130064A true CN101130064A (en) | 2008-02-27 |
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Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102178655A (en) * | 2011-04-29 | 2011-09-14 | 济南环肽医药科技有限公司 | Osteocalcin (OC) freeze-dried powder preparation for injection |
| CN102258479A (en) * | 2011-05-04 | 2011-11-30 | 吉林医药学院 | Osteocalcin slow-release microsphere preparation for injection |
| CN102319216A (en) * | 2011-09-23 | 2012-01-18 | 范圣刚 | Insulin liposome lyophilized powder, oral insulin compound preparation and preparation methods and applications thereof |
| CN107320714A (en) * | 2016-12-30 | 2017-11-07 | 山西医科大学 | Uncarboxylated BGP promotes the new opplication of insulin secretion |
-
2007
- 2007-09-03 CN CNA2007100661606A patent/CN101130064A/en active Pending
Cited By (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102178655A (en) * | 2011-04-29 | 2011-09-14 | 济南环肽医药科技有限公司 | Osteocalcin (OC) freeze-dried powder preparation for injection |
| CN102178655B (en) * | 2011-04-29 | 2012-08-15 | 济南环肽医药科技有限公司 | Preparation method of osteocalcin (OC) freeze-dried powder preparation for injection |
| CN102258479A (en) * | 2011-05-04 | 2011-11-30 | 吉林医药学院 | Osteocalcin slow-release microsphere preparation for injection |
| CN102258479B (en) * | 2011-05-04 | 2012-11-14 | 吉林医药学院 | Osteocalcin slow-release microsphere preparation for injection |
| CN102319216A (en) * | 2011-09-23 | 2012-01-18 | 范圣刚 | Insulin liposome lyophilized powder, oral insulin compound preparation and preparation methods and applications thereof |
| CN107320714A (en) * | 2016-12-30 | 2017-11-07 | 山西医科大学 | Uncarboxylated BGP promotes the new opplication of insulin secretion |
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