CN104587455A - Insulin preparation - Google Patents
Insulin preparation Download PDFInfo
- Publication number
- CN104587455A CN104587455A CN201310527159.4A CN201310527159A CN104587455A CN 104587455 A CN104587455 A CN 104587455A CN 201310527159 A CN201310527159 A CN 201310527159A CN 104587455 A CN104587455 A CN 104587455A
- Authority
- CN
- China
- Prior art keywords
- insulin
- solution
- preparation
- lispro
- add
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Pending
Links
Landscapes
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
Abstract
The invention relates to the field of biological agents and especially relates to an insulin preparation. Multitime injection of different insulin injections each day brings inconvenience for diabetics. The insulin preparation solves the above problem, is a quick-acting and long-acting insulin mixture and is needed once every day thereby preventing multitime injection puzzle. The disclosed insulin preparation is obtained by mixing an insulin glargine solution and an insulin lispro solution. The insulin preparation is prepared from insulin glargine and insulin lispro as raw materials, is a clinical insulin preparation which can be stabilized only by pH condition and an phenol stabilizing agent without overmuch additives, simplifies a production technology, saves a production cost and further improves clinical use safety.
Description
Technical field
The present invention relates to field of biological, particularly relate to a kind of insulin preparation.
Background technology
In recent years, along with factors such as the change of growth in the living standard, dietary structure, the rhythm of life be becoming tight day, aged tendency of population and few dynamic life style of sitting more, whole world onset diabetes rate rapid development, and age of onset rejuvenation increasingly, diabetes have become the chronic disease of the third-largest serious threat human health after tumor, cardiovascular pathological changes.According to IDF (International Diabetes Federation) data, expecting the year two thousand thirty whole world has diabetics number to press on towards 500,000,000.
Although along with the development of science and technology and the progress of medical skill, Remedies for diabetes also continues to bring out, insulin and analog thereof the function and position in treating diabetes can not be substituted.At present, the treatment suggestion of diabetes (I type and type Ⅱdiabetes mellitus) adopts so-called strengthening insulin treatment, namely adopts multiple analgesic composition.According to this scheme, diabetics need be treated with the regular iletin that multiple injection is different every day, comprise once a day or double injection protamine zine insulin to meet the demand of basal insulin, supplement in addition and inject Semilente Insulin to meet the demand of Related Insulin after the meal.And diabetics wants insulinize many decades usually, in order to safety and quality of life, be starved of improvement analgesic composition, although also have analgesic composition to occur at present, be mostly PI or protamine zinc insulin.This is because think that protamine right and wrong are immunogenic in the early time, but find now that PI crystallization may have immunogenicity in human body, for antibody can be caused during medical object to be formed, some patients must avoid using the protamine zine insulin compositions containing protamine.Therefore we study fast and the combination of protamine zine insulin at this, while avoiding using protamine, improve the quality of life of diabetics.
Summary of the invention
The present invention live the inconvenience brought to diabetics in view of the different regular iletin of multiple injection every day, provides a kind of quick-acting and protamine zine insulin mixture, only needs injection every day once, avoid the puzzlement of multiple injection.
Technical scheme provided by the present invention is as follows:
Insulin preparation disclosed by the invention is mixed by insulin Glargine solution and insulin lispro solution.
Further, we also disclosed described insulin Glargine solution to be made up of a or several parts of insulin Glargine premix zoariums, a copy of it insulin Glargine premix zoarium is made up of at acidic injectable water, 300 μ g zinc ioies, metacresol 27mg, the glycerol 170mg of 3.5 ~ 4.5 37.04mg insulin Glargine raw material, 10ml pH.
Simultaneously, we also disclosed described insulin lispro solution to be made up of a or several parts of insulin lispro premix zoariums, a copy of it insulin lispro premix zoarium is made up of at acidic injectable water, 300 μ g zinc ioies, phenol 5mg, metacresol 27mg, the glycerol 170mg of 6.5 ~ 7.5 35.71mg insulin lispro raw material, 10ml pH.
Further, in the composition of insulin lispro solution, we also disclosed described pH 6.5 ~ 7.5 acidic injectable water be by sodium hydrogen phosphate-potassium dihydrogen phosphate buffer system, and dilute hydrochloric acid and sodium hydroxide solution regulate formation jointly.
Further, we also disclosed described insulin preparation and mixed by the insulin Glargine solution of 70 parts and the insulin lispro solution of 30 parts, the whole pH of described insulin preparation is 3.5 ~ 4.5.
Meanwhile, we also disclosed a kind of preparation method of insulin preparation disclosed in this invention, specifically comprise the following steps:
Steps A: take insulin Glargine raw material 1000IU by the content precision of insulin Glargine, i.e. 37.04mg, add injection water 4ml to stir, drip 0.1mol/L hydrochloric acid to dissolve completely to insulin Glargine, add in zinc oxide to every 100IU insulin glargine injecta containing zinc 30 μ g, then glycerol 170mg is added, metacresol 27mg, be stirred to benefit after all dissolving and add water to 9ml, then use 1mol/L hydrochloric acid solution or 1mol/L sodium hydroxide solution adjust ph to 3.5-4.5, moisturizing to final volume is 10ml, carries out filtration sterilization with 0.22 micrometer Millipore filter membrane;
Step B: take insulin lispro raw material 1000IU by the content precision of insulin lispro, i.e. 35.71mg, add injection water 4ml to stir, drip 0.1mol/L hydrochloric acid to dissolve completely to insulin lispro, add in zinc oxide to every 100IU Insulin Lispro Injection and contain zinc 30 μ g, then add glycerol 170mg, phenol 5mg, metacresol 27mg, be stirred to after all dissolving and add buffer, described buffer is containing 1.5mg/mlNa2HPO4,1.25mg/mlKH
2pO
4, to overall solution volume 9ml, then use 1mol/L hydrochloric acid solution or 1mol/L sodium hydroxide solution adjust ph to 6.5-7.5, moisturizing to final volume is 10ml, carries out filtration sterilization with 0.22 micrometer Millipore filter membrane;
According to steps A product: the ratio that step B product calculates 70:30 with volume ratio mixes, regulate pH to 3.5-4.5, obtain insulin preparation.
Insulin preparation disclosed in this invention with insulin lispro and insulin Glargine for raw material, when without the need to adding too much additive, only just can obtain stably insulin clinical practice system with pH condition and phenol stabilizer, thus not only simplify production technology, saved production cost, also further increase clinical use safety degree simultaneously.
Accompanying drawing explanation
Fig. 1 is the blood sugar concentration-time graph after the formulation samples of Beagle dog subcutaneous injection embodiment 1 preparation;
Fig. 2 is the blood sugar concentration-time graph after the formulation samples of Beagle dog subcutaneous injection embodiment 2 preparation.
Detailed description of the invention
Embodiment 1
First product A in the middle of preparation: take insulin Glargine raw material 1000IU(37.04mg by the content precision of insulin Glargine), add injection water 4ml to stir, drip 0.1mol/L hydrochloric acid to dissolve completely to insulin Glargine, add in zinc oxide to every 100IU insulin glargine injecta containing zinc 30 μ g, then glycerol 170mg is added, metacresol 27mg, is stirred to benefit after all dissolving and adds water to 10ml, carry out filtration sterilization with 0.22 micrometer Millipore filter membrane.
Then product B in the middle of preparation: take insulin lispro raw material 1000IU(35.71mg by the content precision of insulin lispro), add injection water 4ml to stir, drip 0.1mol/L hydrochloric acid to dissolve completely to insulin lispro, add in zinc oxide to every 100IU Insulin Lispro Injection containing zinc 30 μ g, then glycerol 170mg is added, phenol 5mg, metacresol 27mg, be stirred to after all dissolving and add buffer (containing 1.5mg/mlNa2HPO4,1.25mg/mlKH2PO4) to 10ml, carry out filtration sterilization with 0.22 micrometer Millipore filter membrane.
Finally, as required by middle product A: middle product B mixes with the ratio of volume ratio 70:30, and regulates pH to 3.5-4.5.
Embodiment 2
First product A in the middle of preparation: take insulin Glargine raw material 1000IU(37.04mg by the content precision of insulin Glargine), add injection water 4ml to stir, drip 0.1mol/L hydrochloric acid to dissolve completely to insulin Glargine, add in zinc oxide to every 100IU insulin glargine injecta containing zinc 30 μ g, then glycerol 170mg is added, metacresol 27mg, be stirred to benefit after all dissolving and add water to 9ml, then use 1mol/L hydrochloric acid solution or 1mol/L sodium hydroxide solution adjust ph to 3.5-4.5, moisturizing to final volume is 10ml, filtration sterilization is carried out with 0.22 micrometer Millipore filter membrane.
Then product B in the middle of preparation: take insulin lispro raw material 1000IU(35.71mg by the content precision of insulin lispro), add injection water 4ml to stir, drip 0.1mol/L hydrochloric acid to dissolve completely to insulin lispro, add in zinc oxide to every 100IU Insulin Lispro Injection containing zinc 30 μ g, then glycerol 170mg is added, phenol 5mg, metacresol 27mg, be stirred to after all dissolving and add buffer (containing 1.5mg/mlNa2HPO4, 1.25mg/mlKH2PO4) to 9ml, then use 1mol/L hydrochloric acid solution or 1mol/L sodium hydroxide solution adjust ph to 3.5-4.5, moisturizing to final volume is 10ml, filtration sterilization is carried out with 0.22 micrometer Millipore filter membrane.
Finally, as required by middle product A: middle product B mixes with the ratio of volume ratio 70:30.
Comparative example
Insulin Glargine raw material 700IU(25.93mg is taken respectively) according to the content precision of insulin Glargine and insulin lispro, insulin lispro 300IU(10.71mg) add injection water 4ml and stir, drip 0.1mol/L hydrochloric acid to dissolve completely to insulin lispro and insulin Glargine, add in zinc oxide to every 100IU regular iletin containing zinc 30 μ g, then glycerol 170mg is added, phenol 5mg, metacresol 27mg, be stirred to after all dissolving and add buffer (containing 1.5mg/mlNa
2hPO
4, 1.25mg/mlKH
2pO
4) to 9ml, then use 1mol/L hydrochloric acid solution or 1mol/L sodium hydroxide solution adjust ph to 3.5-4.5, moisturizing to final volume is 10ml, carries out filtration sterilization with 0.22 micrometer Millipore filter membrane.
Embodiment 3 study on the stability
Embodiment 3-1 gets each 10 samples of injection prepared by above often kind of method, observe its Apparent character after the centrifugal certain hour of 12000rpm: namely centrifugal rear taking-up sample observation bottom it with or without precipitation, record quantity, the sample of preparation method of the same race occur precipitation or floccule quantity fewer, illustrate that formulation samples prepared by the method is more stable.
Table 1 centrefuge experiment
| Sample | There is precipitation number in centrifugal 30min | There is precipitation number in centrifugal 60min |
| Embodiment 1 | 0 | 0 |
| Embodiment 2 | 0 | 0 |
| Comparative example 1 | 0 | 2 |
Embodiment 3-2
Get each 10 samples of injection prepared by above often kind of method after 4 DEG C of storage set times, after opening, room temperature observes its character after placing certain hour: occur that insoluble matter, floccule quantity are fewer, illustrate that preparation prepared by this preparation method is more stable.
The apparent study on the stability of table 2
| Sample | Place 10 days existing insoluble matter sample numbers | Place 20 days existing insoluble matter sample numbers | Place 30 days existing insoluble matter sample numbers |
| Embodiment 1 | 0 | 0 | 0 |
| Embodiment 2 | 0 | 0 | 0 |
| Comparative example | 1 | 5 | 7 |
Above result is known, the formulation samples storage set time prepared by example 1 and example 2, and after opening, room temperature places the Apparent character of certain hour without significant change, and stability is better.
Embodiment 4 shelf-stability is investigated
The storage of samples of the acquisition in Example 1 and embodiment 2, at 4 DEG C of certain hours, after unlatching, continues 4 DEG C of placements, detects its character, pH, macromolecule protein, related substance and content as following table respectively at sampling in 0,3,6,9 day:
Table 34 DEG C of shelf-stability tests
Formulation samples prepared by embodiment 1 and embodiment 2 is opened latter 4 DEG C and is placed 0,3,6,9 day, and its character, pH value, macromolecule protein, related substance and content, all without significant change, have good stability.
Embodiment 5 animal allergic test
Formulation samples prepared by Example 1 and embodiment 2 carries out the research of animal sensitization type respectively: namely get 18 Beagle dogs, when administration starts, body weight is 7.0-11.2kg, be divided into 3 groups at random according to sex, body weight, often organize each 3 heros 3 female, be respectively matched group, embodiment 1 group and embodiment 2 groups.The normal saline of matched group injection equivalent, other are the group corresponding sample injected corresponding embodiment and obtain respectively respectively, every treated animal gives 1.5IU/kg through neck dorsal sc injection respectively simultaneously, successive administration 7 days, once a day, after observation per injection, whether the reaction of each dog, namely occur that there are erythema, edematous condition in injection site, observe anaphylaxiss such as whether having edema, sialorrhea, nausea,vomiting,diarrhea simultaneously.
Result of study finds, during the administration of all Beagle dogs, does not all find that there are erythema, edema, the obviously abnormal conditions such as hemorrhage in injection site, does not also occur the anaphylaxiss such as edema, sialorrhea, nausea,vomiting,diarrhea after injection.Therefore, illustrate that the product clinical safety that the present invention obtains is good, there is higher clinical value.
Embodiment 6 pharmacodynamic experiment
Get adult healthy Beagle dog 6 respectively, male and female half and half, female without pregnant, at the 7-9 monthly age, body weight 9.6-12.5kg, forms embodiment 1 experimental group and embodiment 2 experimental group.The sample for preparing of subcutaneous injection embodiment 1, embodiment 2 respectively, before administration, different time gets blood from Beagle dog foreleg vein, get before blood time point is respectively 0h(administration), 1h, 2h, 3h, 4h, 5h, 6h, 8h, 10h, 12h, 16h, 24h, get blood 2mL at every turn, 4 DEG C, separated plasma after the centrifugal 10min of 3500rpm, carry out glucose concentration determination, draw different time blood sugar concentration variation diagram, result respectively as depicted in figs. 1 and 2.
Can find out that insulin preparation disclosed by the invention has long-acting, efficient hypoglycemic activity.
Claims (6)
1. an insulin preparation, is characterized in that: described insulin preparation is mixed by insulin Glargine solution and insulin lispro solution.
2. insulin preparation according to claim 1, it is characterized in that: described insulin Glargine solution is made up of a or several parts of insulin Glargine premix zoariums, a copy of it insulin Glargine premix zoarium is made up of at acidic injectable water, 300 μ g zinc ioies, metacresol 27mg, the glycerol 170mg of 3.5 ~ 4.5 37.04mg insulin Glargine raw material, 10ml pH.
3. insulin preparation according to claim 1, it is characterized in that: described insulin lispro solution is made up of a or several parts of insulin lispro premix zoariums, a copy of it insulin lispro premix zoarium is made up of at acidic injectable water, 300 μ g zinc ioies, phenol 5mg, metacresol 27mg, the glycerol 170mg of 6.5 ~ 7.5 35.71mg insulin lispro raw material, 10ml pH.
4. insulin preparation according to claim 3, is characterized in that: described pH is by sodium hydrogen phosphate-potassium dihydrogen phosphate buffer system at the acidic injectable water of 6.5 ~ 7.5, and dilute hydrochloric acid and sodium hydroxide solution regulate formation jointly.
5. insulin preparation according to claim 1, is characterized in that: described insulin preparation is mixed by the insulin Glargine solution of 70 parts and the insulin lispro solution of 30 parts, and the whole pH of described insulin preparation is 3.5 ~ 4.5.
6. a preparation method for the insulin preparation in claim 1 to 5 described in any one, is characterized in that, comprises the following steps:
Steps A: take insulin Glargine raw material 1000IU by the content precision of insulin Glargine, i.e. 37.04mg, add injection water 4ml to stir, drip 0.1mol/L hydrochloric acid to dissolve completely to insulin Glargine, add in zinc oxide to every 100IU insulin glargine injecta containing zinc 30 μ g, then glycerol 170mg is added, metacresol 27mg, be stirred to benefit after all dissolving and add water to 9ml, then use 1mol/L hydrochloric acid solution or 1mol/L sodium hydroxide solution adjust ph to 3.5-4.5, moisturizing to final volume is 10ml, carries out filtration sterilization with 0.22 micrometer Millipore filter membrane;
Step B: take insulin lispro raw material 1000IU by the content precision of insulin lispro, i.e. 35.71mg, add injection water 4ml to stir, drip 0.1mol/L hydrochloric acid to dissolve completely to insulin lispro, add in zinc oxide to every 100IU Insulin Lispro Injection and contain zinc 30 μ g, then add glycerol 170mg, phenol 5mg, metacresol 27mg, be stirred to after all dissolving and add buffer, described buffer is containing 1.5mg/mlNa
2hPO
4, 1.25mg/mlKH
2pO4, to overall solution volume 9ml, then use 1mol/L hydrochloric acid solution or 1mol/L sodium hydroxide solution adjust ph to 6.5-7.5, moisturizing to final volume is 10ml, carries out filtration sterilization with 0.22 micrometer Millipore filter membrane;
According to steps A product: the ratio that step B product calculates 70:30 with volume ratio mixes, regulate pH to 3.5-4.5, obtain insulin preparation.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201310527159.4A CN104587455A (en) | 2013-10-31 | 2013-10-31 | Insulin preparation |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201310527159.4A CN104587455A (en) | 2013-10-31 | 2013-10-31 | Insulin preparation |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CN104587455A true CN104587455A (en) | 2015-05-06 |
Family
ID=53113726
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN201310527159.4A Pending CN104587455A (en) | 2013-10-31 | 2013-10-31 | Insulin preparation |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN104587455A (en) |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN110087674A (en) * | 2016-12-16 | 2019-08-02 | 诺和诺德股份有限公司 | The pharmaceutical composition of insulin-containing |
Citations (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101454019A (en) * | 2006-04-12 | 2009-06-10 | 百达尔公司 | Rapid acting and long acting insulin combination formulations |
| CN101951957A (en) * | 2008-01-04 | 2011-01-19 | 百达尔公司 | Insulin discharges the insulin preparation as the function of the glucose level of tissue |
| CN102199206A (en) * | 2011-03-17 | 2011-09-28 | 甘李药业有限公司 | Insulin analogue having quick response and stability under acidic condition and preparation thereof |
| CN102319422A (en) * | 2010-05-19 | 2012-01-18 | 赛诺菲-安万特 | Insulin Glargin |
| US20130178415A1 (en) * | 2012-01-09 | 2013-07-11 | Adocia | Injectable solution at pH 7 comprising at least one basal insulin the PI of which is between 5.8 and 8.5 and a substituted co-polyamino acid |
-
2013
- 2013-10-31 CN CN201310527159.4A patent/CN104587455A/en active Pending
Patent Citations (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101454019A (en) * | 2006-04-12 | 2009-06-10 | 百达尔公司 | Rapid acting and long acting insulin combination formulations |
| CN101951957A (en) * | 2008-01-04 | 2011-01-19 | 百达尔公司 | Insulin discharges the insulin preparation as the function of the glucose level of tissue |
| CN102319422A (en) * | 2010-05-19 | 2012-01-18 | 赛诺菲-安万特 | Insulin Glargin |
| CN102199206A (en) * | 2011-03-17 | 2011-09-28 | 甘李药业有限公司 | Insulin analogue having quick response and stability under acidic condition and preparation thereof |
| US20130178415A1 (en) * | 2012-01-09 | 2013-07-11 | Adocia | Injectable solution at pH 7 comprising at least one basal insulin the PI of which is between 5.8 and 8.5 and a substituted co-polyamino acid |
Non-Patent Citations (3)
| Title |
|---|
| LUCCHESI MBB ET AL.: "A 12-wk follow-up study to evaluate the effects of mixing insulin lispro and insulin glargine in young individuals with type 1 diabetes", 《PEDIATRIC DIABETES》 * |
| 张石革 陈瑞红: "胰岛素类似物的进展与优势", 《中国医药导刊》 * |
| 郭立新: "预混胰岛素的应用", 《药品评价》 * |
Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN110087674A (en) * | 2016-12-16 | 2019-08-02 | 诺和诺德股份有限公司 | The pharmaceutical composition of insulin-containing |
| CN115154591A (en) * | 2016-12-16 | 2022-10-11 | 诺和诺德股份有限公司 | Pharmaceutical composition containing insulin |
| CN115154591B (en) * | 2016-12-16 | 2023-04-14 | 诺和诺德股份有限公司 | Pharmaceutical composition containing insulin |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| Cochrane et al. | Familial hypoglycemia precipitated by amino acids | |
| Anderson et al. | Suppression of insulin secretion by the growth hormone of the anterior pituitary as determined with the isolated rat pancreas in a perfusion apparatus | |
| CN102199206B (en) | Insulin analogue having quick response and stability under acidic condition and preparation thereof | |
| Tarail et al. | Hypoglycemic activity of tris buffer in man and dog | |
| CAMPBELL et al. | Metahypophyseal diabetes produced by growth hormone | |
| CN104587455A (en) | Insulin preparation | |
| Salvesen | Studies on the physiology of the parathyroids | |
| CN102247373A (en) | Composition of methionine vitamin B1 compound | |
| CN105147598B (en) | A kind of veterinary ciprofloxacin lactate injection and preparation method thereof | |
| CN101380329A (en) | Preparation method of arginine aspirin and powder and injection preparation thereof | |
| Colowick et al. | Aminoethyl Phosphoric Ester in the Small Intestine of Rabbits and Pigs | |
| CN102188367B (en) | Insulin glargine injecta and preparation method thereof | |
| CN109010362A (en) | A kind of children's compound electrolyte glucose injection and preparation method thereof | |
| CN111297808B (en) | Darlinomycin hydrochloride soluble powder capable of being directly dissolved in oil seedlings and preparation method thereof | |
| CN107158026A (en) | Application of the low-ester pectin in preventing and treating or auxiliary treatment diabetes | |
| CN100409835C (en) | Composition and great volume injection containing bromhexine salt and the injection preparing process | |
| CN105535942A (en) | Insulin lispro-protamine sulfate preparation and preparation method thereof | |
| Best | Recent work on insulin | |
| CN102441160B (en) | Thymosin alpha1 medicinal composition and preparation method thereof | |
| CN105597087B (en) | A kind of insulin glargine injecta and preparation method thereof | |
| CN106729639B (en) | A kind of insulin glargine injecta and preparation method thereof | |
| BR112021005267A2 (en) | complex compound | |
| CN105111328A (en) | Preparation method of sCVPs (selenic acid esterified catathelasma ventricosum polysaccharides) | |
| CN101607080A (en) | Oral drugs of treatment diabetes and preparation method thereof | |
| CN101978944B (en) | Water-soluble preparation of anesthetic eugenol for fish and preparation method thereof |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| C06 | Publication | ||
| PB01 | Publication | ||
| C10 | Entry into substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| RJ01 | Rejection of invention patent application after publication | ||
| RJ01 | Rejection of invention patent application after publication |
Application publication date: 20150506 |