CN105535942B - A kind of preparation method of insulin lispro protamine sulfate preparation and its insulin lispro protamine sulfate preparation of preparation - Google Patents
A kind of preparation method of insulin lispro protamine sulfate preparation and its insulin lispro protamine sulfate preparation of preparation Download PDFInfo
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- CN105535942B CN105535942B CN201610059027.7A CN201610059027A CN105535942B CN 105535942 B CN105535942 B CN 105535942B CN 201610059027 A CN201610059027 A CN 201610059027A CN 105535942 B CN105535942 B CN 105535942B
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K38/00—Medicinal preparations containing peptides
- A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
- A61K38/17—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
- A61K38/22—Hormones
- A61K38/28—Insulins
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/02—Inorganic compounds
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
- A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
- A61K47/10—Alcohols; Phenols; Salts thereof, e.g. glycerol; Polyethylene glycols [PEG]; Poloxamers; PEG/POE alkyl ethers
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
- A61K47/42—Proteins; Polypeptides; Degradation products thereof; Derivatives thereof, e.g. albumin, gelatin or zein
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/10—Dispersions; Emulsions
Abstract
The present invention provides a kind of preparation method of insulin lispro protamine sulfate preparation, and the component and its concentration that the insulin lispro protamine sulfate preparation is included are：Insulin lispro 3.47mg/ml, 0.095~0.28mg/ml of protamine sulfate, 0.025~0.05mg/ml of zinc, 0.5~1.0mg/ml of phenol, 1.5~2.5mg/ml of metacresol, glycerine 16mg/ml, the 4mg/ml of disodium hydrogen phosphate 2；The preparation method includes being crystallized after insulin lispro acid solution is mixed with protamine sulfate alkaline solution solution, and metacresol glycerite is added and crystallized in complete crystal solution, is well mixed, produces.The preparation method takes short, to obtain product quality stabilization.
Description
Technical field
The invention belongs to biological medicine and galenic pharmacy field, and in particular to a kind of insulin lispro protamine sulfate preparation
Preparation method and its preparation insulin lispro protamine sulfate preparation.
Background technology
Diabetes (Diabetes Mellitus) be it is a kind of because of insulin definitely or relative deficiency or target cell are to insulin
Chronic comprehensive disease caused by reduced sensitivity based on carbohydrate metabolism disturbance, it has a strong impact on the Health and Living matter of patient
Amount.As economic level is improved and material conditions improvement, diabetes morbidity is in continue ascendant trend.According to international Tang Bing alliances
(International Diabetes Federation, IDF) is counted, and 1990s, whole world diabetic was about
1.00 hundred million people, numeral in 2007 has been increased rapidly to 2.46 hundred million people.It is expected that the whole world in 2015 there are about 4.15 hundred million patient of diabetes
Person, 6.42 hundred million will be risen to the year two thousand forty diabetic.Insulin and insulin analog formulations turn into the master for the treatment of diabetes
Want means.
The conventional insulin preparation for the treatment of diabetes divides from composition, including regular insulin, insulin isophane, pancreas
Island element zinc suspension liquid, protamine zinc insulin etc..According to action time length, insulin preparation can then be divided into Semilente Insulin,
Intermediate-acting insulins, protamine zine insulin and Ultrolente Insulin.The insulin preparation of snap action is usually insulin solutions, and is delayed
Slowly the insulin acted on can be suspension, and it contains by being individually added into zinc salt or adding the combination of both protamine or addition
Crystalline or indefiniteness form the insulin separated out.
Because diabetic's use of exogenous insulin needs even decades more than ten years, to insulin and insulin type seemingly
The safety and quality of thing preparation propose higher requirement.
Insulin lispro is to exchange actrapid monotard B28 and B29 amino acids and obtain.Insulin lispro belongs to quick-acting pancreases
Island element analog, being dissociated into monomer enters blood rapidly after hypodermic injection, works faster, up to peak earlier, makees than endogenous actrapid monotard
It is shorter with the time, the secretion of Human Physiology insulin is more nearly, is particularly suitable for the control of diabetic postprandial blood sugar.Rely dried meat
Insulin protamine sulfate preparation is the main suspension being made up of insulin lispro and zinc salt, protamine sulfate etc., its
Middle insulin lispro is to dissolve and exist in the form of crystalline deposit simultaneously.Therefore, after said preparation subcutaneous injection, insulin lispro
Dissociation release is slow compared with monomer solution preparation, with effect more lasting advantage.
Publication number CN101035557A Chinese invention patent application (publication date 2007 on September 12) discloses another
Protamine sulfate suspension of insulin analog --- insulin aspart and preparation method thereof.The suspension formulations are contained
Insulin aspart, protamine sulfate, zinc salt, metacresol, phenol, sodium chloride, glycerine, are prepared via a method which：1) will meter
The disodium hydrogen phosphate and sodium chloride solution of calculation amount add phenol, metacresol, glycerine and sodium hydroxide in water, adjust the pH of solution
About 9, constant volume obtains solution I；2) sodium chloride of amount of calculation, metacresol, phenol and glycerine are dissolved in water, then add amount of calculation
Protamine sulphate solution and insulin aspart, constant volume obtains solution II；3) solution I and solution II are mixed, pH is to about for regulation
7.2, constant volume.The component and preparation method of above-mentioned preparation are different from the present invention.
Publication number CN1266371A Chinese invention patent application (publication date 2000 on September 13) discloses a kind of bad dried meat
The compound method of insulin protamine sulfate suspension, the suspension contains insulin lispro, protamine sulfate, oxidation
Zinc, phenol, metacresol, disodium hydrogen phosphate and glycerine.The operation of the compound method is：1) first by the bad dried meat zinc pancreas islet of amount of calculation
Element crystallization is suspended in the aqueous solution containing phenol, metacresol, glycerine and zinc oxide, and adjusts pH to 2.8-3.0, and stirring makes pancreas islet
Element crystallization dissolving；Then the pH of the solution is adjusted to 7.4-7.7, adds pH=7.2 disodium phosphate soln, adjust the pH of solution
To 7.4, insulin lispro solution is obtained.2) protamine sulfate of amount of calculation is dissolved in containing phenol, metacresol and sweet
In the aqueous solution of oil, the solid phosphoric acid disodium hydrogen of amount of calculation is added, adjusts the pH of solution to 7.4, obtains nucleoprotamine solution.3) exist
At 15 DEG C, nucleoprotamine solution is added in insulin lispro solution, at 15 DEG C, lower incubation 24 hours is not upset, is relied
Dried meat insulin nucleoprotamine mixed liquor.4) Lispro Protamine mixed liquor and insulin lispro solution are pressed into certain ratio
Example is well mixed, obtains Lispro Protamine preparation.This method process for preparation is cumbersome, and crystallization time is long, configuration cycle
Also corresponding extension.In addition, this application is also disclosed, the stability of the insulin lispro suspension formulation by buffer of disodium hydrogen phosphate
Not as good as with suspension system that the TRIP salt of receiving (2- amino -2- hydroxymethyl -1,3- propane diols and its pharmacy attend class) is buffer
Agent.
The content of the invention
In view of the shortcomings of the prior art, the present invention provides a kind of system of the insulin lispro protamine sulfate preparation of stabilization
Preparation Method.This method is easy to operate, quick, so as to shorten preparation cycle, reduce industrial energy consumption.Prepared by this method
Insulin lispro protamine sulfate better stability of preparation, it is ensured that the drug safety of patient.
In order to realize foregoing invention purpose, present invention employs following technical scheme：
A kind of preparation method of insulin lispro protamine sulfate preparation, the insulin lispro protamine sulfate system
The component and its concentration that agent is included be：
Insulin lispro 3.47mg/ml, 0.095~0.28mg/ml of protamine sulfate, 0.025~0.05mg/ml of zinc,
0.5~1.0mg/ml of phenol, 1.5~2.5mg/ml of metacresol, glycerine 16mg/ml, 2~4mg/ml of disodium hydrogen phosphate；
The preparation method comprises the following steps：
1) prepare and prepare liquid：Weigh the zinc oxide, phenol and disodium hydrogen phosphate of amount of calculation；Zinc oxide is used as far as possible few
0.1mol/L dissolving with hydrochloric acid, obtains zinc and prepares liquid；Disodium hydrogen phosphate is dissolved with as far as possible few water, disodium hydrogen phosphate preparation is obtained
Liquid；Phenol is dissolved with as far as possible few water, phenol is obtained and prepares liquid；
2) insulin lispro acid solution is prepared：The insulin lispro of amount of calculation is weighed, adds water and suspension is made, is added
0.1mol/L hydrochloric acid clarifies solution, adds the zinc and prepares liquid, stirring adjusts pH=3~4, is settled to preparation cumulative volume
25%~37.5%, obtain insulin lispro acid solution；
3) protamine sulfate alkaline solution is prepared：The protamine sulfate of amount of calculation is weighed, adds water and is swelled, is added described
Disodium hydrogen phosphate prepares liquid and phenol prepares liquid, adjusts pH=8.0~9.0, is settled to the 25%~37.5% of preparation cumulative volume, obtains
To protamine sulfate alkaline solution；
4) the protamine sulfate alkaline solution is added in the insulin lispro acid solution, stirred, adjusted
PH ≈ 7.4, obtain crystal solution, are placed in 3~6h of stirred crystallization at 20 DEG C~30 DEG C；
5) metacresol glycerite is prepared：The metacresol and glycerine of amount of calculation are weighed, metacresol is added in glycerine, stirring
Dissolving, adds water, adjusts pH=7.4, and the volume summation of the volume and the crystal solution that are settled to solution is the insulin lispro
The cumulative volume of protamine sulfate preparation, obtains metacresol glycerite；
6) the metacresol glycerite is added in the crystal solution after the completion of crystallization, stirred, dispensed, sealing, i.e.,
.
It is preferred that, the insulin lispro acid solution and the protamine sulfate alkaline solution volume are equal.
It is preferred that, the step 3) in, protamine sulfate adds 30~40 DEG C it is water-swellable.
In the insulin lispro protamine sulfate preparation prepared by above-mentioned preparation method, preferably：
The concentration of protamine sulfate is 0.19~0.28mg/ml；
Zinc concentration is 0.025~0.0305mg/ml；
The concentration of phenol is 0.715~0.890mg/ml；
The concentration of metacresol is 1.76~2.20mg/ml；
The concentration of disodium hydrogen phosphate is 2mg/ml.
As a preferred embodiment, the present invention provides a kind of preparation of insulin lispro protamine sulfate preparation
Method, the component and its concentration that the insulin lispro protamine sulfate preparation is included be：
Insulin lispro 3.47mg/ml, 0.19~0.28mg/ml of protamine sulfate, 0.025~0.0305mg/ml of zinc,
0.715~0.890mg/ml of phenol, 1.76~2.20mg/ml of metacresol, glycerine 16mg/ml, disodium hydrogen phosphate 2mg/ml；
The preparation method comprises the following steps：
1) prepare and prepare liquid：Weigh zinc oxide, phenol, metacresol, glycerine and the disodium hydrogen phosphate of amount of calculation；By zinc oxide
With as far as possible few 0.1mol/L dissolving with hydrochloric acid, obtain zinc and prepare liquid；Dissolved by disodium hydrogen phosphate plus with as far as possible few water, obtain phosphorus
Sour disodium hydrogen prepares liquid；Phenol is dissolved with as far as possible few water, phenol is obtained and prepares liquid；
2) insulin lispro acid solution is prepared：The insulin lispro of amount of calculation is weighed, adds water and suspension is made, is added
0.1mol/L hydrochloric acid clarifies solution, adds the zinc and prepares liquid, stirring adjusts pH=3~4, is settled to preparation cumulative volume
37.5%, obtain insulin lispro acid solution；
3) protamine sulfate alkaline solution is prepared：Weigh the protamine sulfate of amount of calculation, plus 30~40 DEG C it is water-swellable,
Add the disodium hydrogen phosphate and prepare liquid and phenol preparation liquid, adjust pH to 8.0~9.0, be settled to the 37.5% of preparation cumulative volume,
Obtain protamine sulfate alkaline solution；
4) the protamine sulfate alkaline solution is added in the insulin lispro acid solution, stirred, adjusted
PH ≈ 7.4, obtain crystal solution, are placed in 3~6h of stirred crystallization at 20 DEG C~30 DEG C；
5) metacresol glycerite is prepared：The metacresol and glycerine of amount of calculation are weighed, metacresol is added in glycerine, stirring
Dissolving, adds water, adjusts pH=7.4, and the volume summation of the volume and the crystal solution that are settled to solution is the insulin lispro
The cumulative volume of protamine sulfate preparation, obtains metacresol glycerite；
6) the metacresol glycerite is added in the crystal solution after the completion of crystallization, stirred, dispensed, sealing, i.e.,
.
It is another object of the present invention to provide a kind of insulin lispro protamine sulfate preparation, the bad dried meat pancreas islet
The component and its concentration that plain protamine sulfate preparation is included be：Insulin lispro 3.47mg/ml, protamine sulfate 0.095
~0.28mg/ml, 0.025~0.05mg/ml of zinc, 0.5~1.0mg/ml of phenol, 1.5~2.5mg/ml of metacresol, glycerine
16mg/ml, 2~4mg/ml of disodium hydrogen phosphate；The insulin lispro protamine sulfate preparation passes through above-mentioned preparation method system
It is standby to obtain.
If without specified otherwise in present specification, " water " is to meet injection requirement by purification process
Water." ≈ " represents pH numerical value changes scope ± 0.1, i.e., " pH ≈ 7.4 " represent to adjust pH be all between 7.3~7.5 can be with
Receive.When preparing zinc oxide, phenol and disodium hydrogen phosphate and preparing liquid, add " as few as possible " solvent be refer to make it is above-mentioned
The minimum quantity of solvent of solute dissolving.
In the preparation method of insulin lispro protamine sulfate preparation of the present invention, pH regulations can use ability
The aqueous solution of the conventional acid in domain or alkali, such as hydrochloric acid, sodium hydroxide, potassium hydroxide or ammoniacal liquor.
The prior art that publication number CN1266371A Chinese invention patent application is recorded, with containing glycerine, phenol and
The aqueous solution of cresols is mixed to get crystal solution to prepare insulin lispro solution and nucleoprotamine solution respectively, then by both, knot
The brilliant time grows to 24 hours.Found by the numerous studies of inventor, glycerine can reduce the speed that crystallization is formed.Analyze reason,
It is probably because glycerine increases the solubility of insulin analog so that insulin lispro is difficult to saturation in the solution, separates out knot
It is brilliant more slow.But metacresol is insoluble in water, it is necessary to be dissolved by glycerine, so the feed postition of glycerine is and metacresol
It is added to together in the solution after the completion of crystallizing after mixing.So, it can not only adjust osmotic pressure but also not disturb the formation of crystal.Cause
This, the present invention compares prior art, and crystallization time was shortened to 3~6 hours by 24 hours.It is prepared by micro- Microscopic observation, the present invention
In obtained preparation, insulin lispro is in rhabdolith.In addition, in preparation method of the present invention, the preparation liquid of each component is matched somebody with somebody
Process processed is simple, easy to operate.
Also being disclosed in publication number CN1266371A patent application uses disodium hydrogen phosphate for buffer, is unfavorable for preparation
Stability.But the test example result of the present invention shows, the formation of the concentration of disodium hydrogen phosphate to crystallization is more crucial, low concentration
Disodium hydrogen phosphate is unfavorable for the formation of crystallization.
Brief description of the drawings
Hereinafter, embodiment of the present invention is described in detail with reference to accompanying drawing, wherein：
Fig. 1 shows the crystal solution of embodiment 1 400 times of enlarged photographs under the microscope.
Fig. 2 shows the crystal solution of embodiment 2 400 times of enlarged photographs under the microscope.
Fig. 3 shows the crystal solution of embodiment 3 400 times of enlarged photographs under the microscope.
Fig. 4 shows the crystal solution of embodiment 4 400 times of enlarged photographs under the microscope.
Fig. 5 shows the crystal solution of embodiment 5 400 times of enlarged photographs under the microscope.
Fig. 6 shows that the crystal solution crystallization of test example 1 starts rear different time 400 times of enlarged photograph under the microscope.
Wherein, crystal solution enlarged photograph when 6A is 3h, crystal solution enlarged photograph when 6B is 6h, crystal solution amplification when 6C is 12h
Photo, crystal solution enlarged photograph when 6D is 24h.
Embodiment
Illustrate the present invention referring to specific embodiment.It will be appreciated by those skilled in the art that these embodiments are only
For illustrating the present invention, it does not limit the scope of the present invention in any way.
Experimental method in following embodiments, is conventional method unless otherwise specified.Medicine used in following embodiments
Material raw material, reagent material etc., unless otherwise specified, are commercially available products.Wherein, portion of reagent and raw material buy situation such as
Under：
Insulin lispro：Self-control
Zinc oxide：Sichuan Kingsoft pharmaceutical Co. Ltd
Glycerine：Hu'nan Erkang Pharmaceutical Co., Ltd.
Metacresol：This hundred full chemistries (Shanghai) Co., Ltd.
Phenol：This hundred full chemistries (Shanghai) Co., Ltd.
Disodium hydrogen phosphate：The allusion quotation Pharmacy stock Co., Ltd of Hunan nine
Protamine sulfate：This hundred full chemistries (Shanghai) Co., Ltd.
Sodium hydroxide：Chengdu Hua Yi pharmaceutic adjuvants manufacture Co., Ltd
Hydrochloric acid：Chengdu Hua Yi pharmaceutic adjuvants manufacture Co., Ltd
Water：Make water for injection by oneself
Embodiment 1A kind of preparation method of insulin lispro protamine sulfate preparation (25R)
The common 1000ml of preparation, comprising：Insulin lispro：3.47mg/ml, protamine sulfate：0.28mg/ml, zinc：
0.025mg/ml, phenol：0.715mg/ml, metacresol：1.76mg/ml, glycerine：16mg/ml, disodium hydrogen phosphate：2.0mg/ml,
Remaining is water；It is prepared via a method which：
1) prepare and prepare liquid：Weigh the zinc oxide of 0.715g phenol, 2g disodium hydrogen phosphates and amount of calculation；Zinc oxide is used up
The few 0.1mol/L dissolving with hydrochloric acid of amount, obtains zinc and prepares liquid；Disodium hydrogen phosphate is dissolved with as far as possible few water, phosphoric acid hydrogen two is obtained
Sodium prepares liquid；Phenol is dissolved with as far as possible few water, phenol is obtained and prepares liquid；
2) insulin lispro acid solution is prepared：3.47g insulin lispro is weighed, adds water and suspension is made, is added
0.1mol/L hydrochloric acid clarifies solution, adds the zinc and prepares liquid, stirring adds water to about 300ml, adjusts pH=3~4, use water
375ml is settled to, insulin lispro acid solution is obtained；
3) protamine sulfate alkaline solution) is prepared：Claim 0.28g protamine sulfate, plus 30~40 DEG C it is water-swellable, plus
Enter the disodium hydrogen phosphate and prepare liquid and phenol preparation liquid, add water to about 300ml, adjust pH to 8.0~9.0, be settled to water
375ml, obtains protamine sulfate alkaline solution；
4) the protamine sulfate alkaline solution is added in the insulin lispro acid solution, stirred, adjusted
PH ≈ 7.4, obtain crystal solution, and crystal solution volume is 702ml, is placed in 20 DEG C of environment, stirred crystallization 3h；Its knot of microscope examination did
Brilliant situation, is shown in Fig. 1；
5) metacresol glycerite is prepared：1.76g metacresols and 16g glycerine are weighed, metacresol is added in glycerine, stirring
Dissolving, adds water to about 250ml, adjusts pH=7.4, is settled to 298ml with water, obtains metacresol glycerite；
6) the metacresol glycerite is added in the crystal solution for crystallizing and completing, stirred, dispensed, sealing is produced.
Embodiment 2A kind of preparation method of insulin lispro protamine sulfate preparation (50R)
The common 1000ml of preparation, comprising：Insulin lispro：3.47mg/ml, protamine sulfate：0.19mg/ml, zinc：
0.0305mg/ml, phenol：0.89mg/ml, metacresol：2.20mg/ml, glycerine：16mg/ml, disodium hydrogen phosphate：2.0mg/ml,
Remaining is water；It is prepared via a method which：
1) prepare and prepare liquid：Weigh the zinc oxide of 0.89g phenol, 2g disodium hydrogen phosphates and amount of calculation；Zinc oxide is used up
The few 0.1mol/L dissolving with hydrochloric acid of amount, obtains zinc and prepares liquid；Disodium hydrogen phosphate is dissolved with as far as possible few water, phosphoric acid hydrogen two is obtained
Sodium prepares liquid；Phenol is dissolved with as far as possible few water, phenol is obtained and prepares liquid；
2) insulin lispro acid solution is prepared：3.47g insulin lispro is weighed, adds water and suspension is made, is added
0.1mol/L hydrochloric acid clarifies solution, adds the zinc and prepares liquid, stirring adds water to about 200ml, adjusts pH=3~4, use water
250ml is settled to, insulin lispro acid solution is obtained；
3) protamine sulfate alkaline solution is prepared：Claim 0.19g protamine sulfate, plus 30~40 DEG C it is water-swellable, plus
Enter the disodium hydrogen phosphate and prepare liquid and phenol preparation liquid, add water to about 200ml, adjust pH to 8.0~9.0, be settled to water
250ml, obtains protamine sulfate alkaline solution；
4) the protamine sulfate alkaline solution is added in the insulin lispro acid solution, stirred, surveyed
Determine pH ≈ 7.4, obtain crystal solution, crystal solution volume is 500ml, is placed in 30 DEG C of environment, stirred crystallization 6h；Microscope examination did its
Crystallization situation, is shown in Fig. 2；
5) metacresol glycerite is prepared：2.20g metacresols and 16g glycerine are weighed, metacresol is added in glycerine, stirring
Dissolving, adds water to about 400ml, adjusts pH=7.5, is settled to 500ml with water, obtains metacresol glycerite；
6) the metacresol glycerite is added in the crystal solution for crystallizing and completing, stirred, dispensed, sealing is produced.
Embodiment 3A kind of preparation method of insulin lispro protamine sulfate preparation (75R)
The common 1000ml of preparation, comprising：Insulin lispro：3.47mg/ml, protamine sulfate：0.10mg/ml, zinc：
0.025mg/ml, phenol：0.5mg/ml, metacresol：2.5mg/ml, glycerine：16mg/ml, disodium hydrogen phosphate：2.5mg/ml, its
Yu Weishui；It is prepared via a method which：
1) prepare and prepare liquid：Weigh the zinc oxide of 0.5g phenol, 2.5g disodium hydrogen phosphates and amount of calculation；Zinc oxide is used up
The few 0.1mol/L dissolving with hydrochloric acid of amount, obtains zinc and prepares liquid；Disodium hydrogen phosphate is dissolved with as far as possible few water, phosphoric acid hydrogen two is obtained
Sodium prepares liquid；Phenol is dissolved with as far as possible few water, phenol is obtained and prepares liquid；
2) insulin lispro acid solution is prepared：3.47g insulin lispro is weighed, adds water and suspension is made, is added
0.1mol/L hydrochloric acid clarifies solution, adds the zinc and prepares liquid, stirring adds water to about 200ml, adjusts pH=3~4, use water
250ml is settled to, insulin lispro acid solution is obtained；
3) protamine sulfate alkaline solution is prepared：Claim 0.1g protamine sulfate, plus 30~40 DEG C of water-swellable, additions
The disodium hydrogen phosphate prepares liquid and phenol prepares liquid, adds water to about 200ml, adjusts pH to 8.0~9.0, is settled to water
250ml, obtains protamine sulfate alkaline solution；
4) the protamine sulfate alkaline solution is added in the insulin lispro acid solution, stirred, adjusted
PH ≈ 7.4, obtain crystal solution, the volume of crystal solution is 503ml, is placed in 25 DEG C of environment, stirred crystallization 4h；Microscope examination did its
Crystallization situation, is shown in Fig. 3；
5) metacresol glycerite is prepared：2.5g metacresols and 16g glycerine are weighed, metacresol is added in glycerine, stirring
Dissolving, adds water to about 400ml, adjusts pH=7.5, is settled to 497ml with water, obtains metacresol glycerite；
6) the metacresol glycerite is added in the crystal solution for crystallizing and completing, stirred, dispensed, sealing is produced.
Embodiment 4A kind of preparation method of insulin lispro protamine sulfate preparation
The common 1000ml of preparation, comprising：Insulin lispro：3.47mg/ml, protamine sulfate：0.20mg/ml, zinc：
0.0305mg/ml, phenol：0.9mg/ml, metacresol：2.20mg/ml, glycerine：16mg/ml, disodium hydrogen phosphate：3.78mg/ml,
Remaining is water；It is prepared via a method which：
1) prepare and prepare liquid：Weigh the zinc oxide of 0.9g phenol, 3.78g disodium hydrogen phosphates and amount of calculation；Zinc oxide is used
Few 0.1mol/L dissolving with hydrochloric acid, obtains zinc and prepares liquid as far as possible；Disodium hydrogen phosphate is dissolved with as far as possible few water, phosphoric acid hydrogen is obtained
Disodium prepares liquid；Phenol is dissolved with as far as possible few water, phenol is obtained and prepares liquid；
2) insulin lispro acid solution is prepared：3.47g insulin lispro is weighed, adds water and suspension is made, is added
0.1mol/L hydrochloric acid clarifies solution, adds the zinc and prepares liquid, stirring adds water to about 200ml, adjusts pH=3~4, constant volume
To 250ml, insulin lispro acid solution is obtained；
3) protamine sulfate alkaline solution is prepared：Claim 0.2g protamine sulfate, plus 30~40 DEG C of water-swellable, additions
The disodium hydrogen phosphate prepares liquid and phenol prepares liquid, adds water to about 250ml, adjusts pH to 8.0~9.0, is settled to water
300ml, obtains protamine sulfate alkaline solution；
4) the protamine sulfate alkaline solution is added in the insulin lispro acid solution, stirred, adjusted
PH ≈ 7.4, obtain crystal solution, the volume of crystal solution is 553ml, is placed in 20 DEG C of environment, stirred crystallization 3h；Microscope examination did its
Crystallization situation, is shown in Fig. 4；
5) metacresol glycerite is prepared：2.2g metacresols and 16g glycerine are weighed, metacresol is added in glycerine, stirring
Dissolving, adds water to about 350ml, adjusts pH=7.5, is settled to 447ml with water, obtains metacresol glycerite；
6) the metacresol glycerite is added in the crystal solution, stirred, dispensed, sealing is produced.
Embodiment 5A kind of preparation method of insulin lispro protamine sulfate preparation
The common 1000ml of preparation, comprising：Insulin lispro：3.47mg/ml, protamine sulfate：0.30mg/ml, zinc：
0.025mg/ml, phenol：0.7mg/ml, metacresol：1.8mg/ml, glycerine：16mg/ml, disodium hydrogen phosphate：3.78mg/ml, its
Yu Weishui；It is prepared via a method which：
1) prepare and prepare liquid：Weigh the zinc oxide of 0.7g phenol, 3.78g disodium hydrogen phosphates and amount of calculation；Zinc oxide is used
Few 0.1mol/L dissolving with hydrochloric acid, obtains zinc and prepares liquid as far as possible；Disodium hydrogen phosphate is dissolved with as far as possible few water, phosphoric acid hydrogen is obtained
Disodium prepares liquid；Phenol is dissolved with as far as possible few water, phenol is obtained and prepares liquid；
2) insulin lispro acid solution is prepared：3.47g insulin lispro is weighed, adds water and suspension is made, is added
0.1mol/L hydrochloric acid clarifies solution, adds the zinc and prepares liquid, stirring adds water to about 280ml, adjusts pH=3~4, use water
350ml is settled to, insulin lispro acid solution is obtained；
3) protamine sulfate alkaline solution is prepared：Claim 0.3g protamine sulfate, plus 30~40 DEG C of water-swellable, additions
The disodium hydrogen phosphate prepares liquid and phenol prepares liquid, adds water to about 280ml, adjusts pH to 8.0~9.0, is settled to water
350ml, obtains protamine sulfate alkaline solution；
4) the protamine sulfate alkaline solution is added in the insulin lispro acid solution, stirred, surveyed
PH ≈ 7.4 are obtained, crystal solution are obtained, the volume of crystal solution is 700ml, is placed in 30 DEG C of environment, stirred crystallization 3h；Microscope examination did
It crystallizes situation, sees Fig. 5；
5) metacresol glycerite is prepared：1.8g metacresols and 16g glycerine are weighed, metacresol is added in glycerine, stirring
Dissolving, adds water to about 240ml, adjusts pH=7.5, is settled to 300ml with water, obtains metacresol glycerite；
6) the metacresol glycerite is added in the crystal solution after the completion of the crystallization, stirred, dispensed, it is close
Envelope, is produced.
Comparative example 1A kind of preparation method of insulin lispro protamine sulfate preparation
The common 1000ml of preparation, comprising：Insulin lispro：3.47mg/ml, protamine sulfate：0.28mg/ml, zinc：
0.025mg/ml, phenol：0.715mg/ml, metacresol：1.76mg/ml, glycerine：16mg/ml, disodium hydrogen phosphate：2.0mg/ml,
Remaining is water；Prepared according to the method described in publication number CN1266371A Chinese invention patent application embodiment 6.
At 15 DEG C, stand still for crystals, 3h, 6h, 12h and 24h take the micro- Microscopic observation of crystal solution after crystallization starts respectively
Crystallization situation.It the results are shown in Table 1 and Fig. 6 A-6D.
The different crystallization time crystallization situations of 1 comparative example of table 1
Test exampleInsulin lispro protamine sulfate preparation stability prepared by embodiment 1 and comparative example 1 is investigated
According to 2015 pharmacopeia four 9001 " material medicine and preparation stability test direction principle ", to embodiment 1 and right
Insulin lispro protamine sulfate preparation prepared by ratio 1 carries out study on the stability.It is investigated in 40 DEG C and 4500 ± 500LX
Under the conditions of the steadiness of 30 days, mainly to content, A21, other are about material, soluble insulin lispro, macromolecule egg
Investigated in vain.
As a result：It is shown in Table 2.
Conclusion：
The as shown by data of table 2, the embodiment of the present invention 1 and the gained preparation stability of comparative example 1 are good, and poor without conspicuousness
It is different.
By test example 1 and test example 2, the side disclosed with publication number CN1266371A Chinese invention patent application
Method compares, and the preparation method operation of insulin lispro protamine sulfate preparation of the present invention is easier, takes significantly contracting
It is short；The preparation that two methods are prepared, stability is suitable.Therefore, compared with prior art, the preparation method that the present invention is provided
More efficient, cost is lower on the premise of product quality is ensured.
The study on the stability result of table 2
Specific description of embodiments of the present invention above is not intended to limit the present invention, and those skilled in the art can be according to this
Invention is variously modified or deformed, and without departing from the spirit of the present invention, all should belong to the model of appended claims of the present invention
Enclose.
Claims (7)
1. a kind of preparation method of insulin lispro protamine sulfate preparation, the insulin lispro protamine sulfate preparation
Comprising component and its concentration be：
Insulin lispro 3.47mg/ml, 0.095~0.28mg/ml of protamine sulfate, 0.025~0.05mg/ml of zinc, phenol
0.5~1.0mg/ml, 1.5~2.5mg/ml of metacresol, glycerine 16mg/ml, 2~4mg/ml of disodium hydrogen phosphate；
The step of preparation method is：
1) prepare and prepare liquid：Weigh the zinc oxide, phenol and disodium hydrogen phosphate of amount of calculation；Zinc oxide is used as far as possible few
0.1mol/L dissolving with hydrochloric acid, obtains zinc and prepares liquid；Disodium hydrogen phosphate is dissolved with as far as possible few water, disodium hydrogen phosphate preparation is obtained
Liquid；Phenol is dissolved with as far as possible few water, phenol is obtained and prepares liquid；
2) insulin lispro acid solution is prepared：The insulin lispro of amount of calculation is weighed, adds water and suspension is made, is added
0.1mol/L hydrochloric acid clarifies solution, adds the zinc and prepares liquid, stirring adjusts pH=3~4, is settled to preparation cumulative volume
25%~37.5%, obtain insulin lispro acid solution；
3) protamine sulfate alkaline solution is prepared：The protamine sulfate of amount of calculation is weighed, adds water and is swelled, the phosphoric acid is added
Disodium hydrogen prepares liquid and phenol prepares liquid, adjusts pH=8.0~9.0, is settled to the 25%~37.5% of preparation cumulative volume, obtains sulphur
Sour nucleoprotamine alkaline solution；
4) the protamine sulfate alkaline solution is added in the insulin lispro acid solution, stirred, adjust pH ≈
7.4, crystal solution is obtained, 3~6h of stirred crystallization at 20 DEG C~30 DEG C is placed in；The insulin lispro acid solution and the sulfuric acid
Nucleoprotamine alkaline solution volume is equal；
5) metacresol glycerite is prepared：The metacresol and glycerine of amount of calculation are weighed, metacresol is added in glycerine, is stirred molten
Solution, adds water, adjusts pH=7.4, and the volume summation of the volume and the crystal solution that are settled to solution is the insulin lispro sulphur
The cumulative volume of sour nucleoprotamine preparation, obtains metacresol glycerite；
6) the metacresol glycerite is added in the crystal solution after the completion of crystallization, stirred, dispensed, sealing is produced.
2. preparation method according to claim 1, it is characterised in that the step 3) in, protamine sulfate adds 30~
40 DEG C water-swellable.
3. preparation method according to claim 1, it is characterised in that the insulin lispro protamine sulfate preparation
In, the concentration of protamine sulfate is 0.19~0.28mg/ml.
4. preparation method according to claim 1, it is characterised in that the insulin lispro protamine sulfate preparation
In, zinc concentration is 0.025~0.0305mg/ml.
5. preparation method according to claim 1, it is characterised in that the insulin lispro protamine sulfate preparation
In, the concentration of phenol is 0.715~0.890mg/ml.
6. preparation method according to claim 1, it is characterised in that the insulin lispro protamine sulfate preparation
In, the concentration of metacresol is 1.76~2.20mg/ml.
7. preparation method according to claim 1, it is characterised in that the insulin lispro protamine sulfate preparation
In, the concentration of disodium hydrogen phosphate is 2mg/ml.
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Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1266371A (en) * | 1997-06-13 | 2000-09-13 | 伊莱利利公司 | Stable insulin formulations |
| CN101035557A (en) * | 2004-10-05 | 2007-09-12 | 诺和诺德公司 | A pharmaceutical formulation comprising crystalline insulin and dissolved insulin |
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2016
- 2016-01-28 CN CN201610059027.7A patent/CN105535942B/en active Active
Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1266371A (en) * | 1997-06-13 | 2000-09-13 | 伊莱利利公司 | Stable insulin formulations |
| CN101035557A (en) * | 2004-10-05 | 2007-09-12 | 诺和诺德公司 | A pharmaceutical formulation comprising crystalline insulin and dissolved insulin |
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