CN112107678B - Freeze-dried composition containing thymalfasin and preparation method thereof - Google Patents
Freeze-dried composition containing thymalfasin and preparation method thereof Download PDFInfo
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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
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- A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
- A61K47/16—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing nitrogen, e.g. nitro-, nitroso-, azo-compounds, nitriles, cyanates
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- A61K9/19—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles lyophilised, i.e. freeze-dried, solutions or dispersions
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- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P31/12—Antivirals
- A61P31/14—Antivirals for RNA viruses
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- A61P37/02—Immunomodulators
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- F—MECHANICAL ENGINEERING; LIGHTING; HEATING; WEAPONS; BLASTING
- F26—DRYING
- F26B—DRYING SOLID MATERIALS OR OBJECTS BY REMOVING LIQUID THEREFROM
- F26B5/00—Drying solid materials or objects by processes not involving the application of heat
- F26B5/04—Drying solid materials or objects by processes not involving the application of heat by evaporation or sublimation of moisture under reduced pressure, e.g. in a vacuum
- F26B5/06—Drying solid materials or objects by processes not involving the application of heat by evaporation or sublimation of moisture under reduced pressure, e.g. in a vacuum the process involving freezing
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Abstract
The invention discloses a freeze-dried composition containing thymalfasin and a preparation method thereof. The composition consists of an active ingredient of thymalfasin and a pH regulator. The invention has single auxiliary material, only one auxiliary material, simple prescription and convenient operation, adopts a specific freeze drying procedure, has good product appearance, no powder scattering phenomenon, stable quality and short redissolution time in use, and the visible foreign matters and insoluble particles of the redissolved product are superior to the existing products in the market.
Description
Technical Field
The invention belongs to the technical field of medicine preparation, and particularly relates to a thymalfasin-containing freeze-dried composition and a preparation method thereof.
Background
The thymosin is a protein and polypeptide hormone produced by animal thymus, and has been clinically applied for more than 20 years in China. Thymalfasin (also known as Thymosin alpha 1, english name Thymosin alpha 1) is a high-end product in Thymosin, is a main bioactive component of Thymosin, and is an important immunoregulation substance in human body, said medicine is a small molecular bioactive polypeptide separated and purified from Thymosin component 5 (TF 5), its content is about 0.6% of TF5, its bioactivity is 10-1000 times higher than TF5, and possesses higher immunopotentiation activity, at the same time it also has the functions of stimulating vascular endothelial cell migration, promoting angiogenesis and wound healing, etc., and can be used for clinical treatment and research of hepatitis B, hepatitis C, malignant tumor and immunodeficiency disease, etc.. Thymalfasin as a broad-spectrum immunomodulator has a definite structure, a clear action mechanism and no need of skin test, and the curative effect of thymalfasin is known by doctors and patients.
Thymalfasin has an amino acid sequence as follows:
N-Acetyl-Ser-Asp-Ala-Ala-Val-Asp-Thr-Ser-Ser-Glu-Ile
-Thr-Thr-Lys-Asp-Leu-Lys-Glu-Lys-Lys-Glu-Val-Val-Glu-Glu. -Ala-Glu-Asn-OH; the molecular formula is: c 129 H 215 N 33 O 35 (ii) a The molecular weight is: 3108.280; the molecular structure is as follows:
the inventor finds in experiments that because the content of thymalfasin in the lyophilized composition containing thymalfasin is low, a large amount of auxiliary material proppants (such as mannitol, sorbitol, glucose, sodium chloride and the like) are required to be added so as to enable the lyophilized composition to have good formability and ensure that the powder scattering phenomenon does not occur in the freeze-drying process of the preparation; however, for the medicine, the introduction of excessive auxiliary materials invisibly increases the safety of clinical use, especially injection.
Disclosure of Invention
In view of the defects of the prior art, the invention provides a lyophilized composition containing thymalfasin and a preparation method thereof.
The lyophilized composition containing thymalfasin comprises an active ingredient of thymalfasin and a pH value regulator.
The pH value regulator is one or more of sodium phosphate, sodium acetate, sodium citrate and meglumine, preferably meglumine.
The preparation method of the lyophilized composition containing thymalfasin comprises the following steps: weighing thymalfasin in a prescription amount, adding the thymalfasin into water for injection, adjusting the pH value to 7.5-7.7, preferably 7.6 by using a pH value regulator, fixing the volume to the full amount by using water for injection, stirring, dissolving, uniformly mixing, filtering to obtain a thymalfasin solution, filling, freeze-drying and carrying out visual inspection to obtain the finished product.
The concentration of the thymalfasin solution is 1.8-2.6mg/ml, and preferably 2.2mg/ml.
The pH of the solution of the lyophilized composition prior to lyophilization was 7.6.
The specific operation steps of the freeze drying are as follows:
1. a pre-freezing stage:
(1) Filling the solution, and then placing the solution on a partition plate in a freeze-drying machine box to cool the solution to 0-4 ℃, preferably-2 ℃, and keeping the temperature for 60-120 min, preferably 90min;
(2) After the heat preservation is finished, the temperature is reduced to minus 40 to minus 50 ℃ for the second time, preferably minus 45 ℃, and the temperature reduction time is 120 to 180min, preferably 150min; keeping the temperature at-40 to-50 ℃ for 60 to 120min, preferably 90min;
(3) After the heat preservation is finished, the temperature is raised to-6 to-8 ℃, preferably-7 ℃, and the temperature raising time is 60 to 120min, preferably 90min; keeping the temperature at minus 6 to minus 8 ℃ for 30 to 60min, preferably 45min;
(4) After the heat preservation is finished, rapidly cooling to-40 to-50 ℃ for the third time, and preferably selecting to-45 ℃; keeping the temperature at minus 40 to minus 50 ℃ for 120 to 180min, preferably 150min;
2. a sublimation drying stage: when the vacuum degree in the drying box is 80-120mTorr, preferably 100mTorr, the drying temperature is increased to-16.0 to-20.0 ℃, preferably-18 ℃, the temperature rise time is 60-120 min, preferably 90min, and the heat preservation time is 300-420 min, preferably 360min;
3. and a re-drying stage: and raising the re-drying temperature to 15-25 ℃, preferably 20 ℃, for 90-150 min, preferably 120min, continuously vacuumizing the drying oven, and keeping the temperature for 210-270 min, preferably 240min to obtain the freeze-dried composition containing the thymalfasin.
The invention has the following beneficial effects:
1) The invention has single auxiliary material, only one auxiliary material is provided, and the auxiliary material is only used as a pH value regulator, and the dosage of the auxiliary material is less;
2) The invention has simple prescription, convenient operation, good product appearance, no powder scattering phenomenon and stable quality;
3) The invention has short redissolution time due to less auxiliary material types and dosage, and the product after redissolution has visible foreign matters and insoluble particles superior to the existing products in the market.
Detailed Description
Example 1:
prescription
Thymalfasin 2.2g
Adjusting pH value of 0.1mol/L meglumine solution to 7.6
Adding water for injection to 1000ml
Preparation process
Weighing thymalfasin according to the prescription amount, adding the thymalfasin into water for injection, adjusting the pH value by using a pH value regulator, fixing the volume to the full volume by using the water for injection after the pH value is adjusted, stirring, dissolving, uniformly mixing, filtering, filling, freeze-drying and carrying out visual inspection to obtain the finished product.
Freeze drying curve
1. Prefreezing stage
(1) Placing the semi-finished product filled and half-plugged on a partition plate in a freeze-drying machine case, cooling to-2 ℃, and preserving heat for 90min;
(2) After the heat preservation is finished, the temperature is reduced to minus 45 ℃ for the second time, the temperature reduction time is 150min, and the heat preservation time at minus 45 ℃ is 90min;
(3) After the heat preservation is finished, the temperature is raised to minus 7 ℃, the temperature raising time is 90min, and the heat preservation time at minus 7 ℃ is 45min;
(4) After the heat preservation is finished, the temperature is reduced to minus 45 ℃ for the third time, the temperature reduction time is as short as possible, and the heat preservation time at minus 45 ℃ is 150min;
2. sublimation drying stage
The vacuum degree in the drying oven reaches 100mTorr, the main drying temperature is raised to-18 ℃, the time is 90min, and the heat preservation time is 360min;
3. and a re-drying stage: raising the redrying temperature to 20 ℃; the application time is 120min; and (3) pumping the vacuum degree in the drying box to the limit vacuum, and keeping the temperature for 240min to obtain the thymalfasin-containing freeze-dried composition.
Example 2:
prescription
Thymalfasin 1.8g
Adjusting pH value of 0.1mol/L meglumine solution to 7.6
Adding water for injection to 1000ml
The preparation process comprises the following steps: same as example 1
Example 3:
prescription
Thymalfasin 2.2g
Adjusting the pH value of 0.1mol/L sodium phosphate solution to 7.6
Adding water for injection to 1000ml
The preparation process comprises the following steps: same as example 1
Example 4:
prescription
Thymalfasin 2.6g
Adjusting pH value to 7.6 with 0.1mol/L sodium citrate solution
Adding water for injection to 1000ml
The preparation process comprises the following steps: same as example 1
Example 5:
prescription
Thymalfasin 2.2g
Adjusting pH value of 0.1mol/L meglumine solution to 7.6
Adding water for injection to 1000ml
Preparation process
Weighing thymalfasin in a prescription amount, adding the thymalfasin into water for injection, adjusting the pH value by using a pH value regulator, fixing the volume to the full amount by using the water for injection after the pH value is adjusted, stirring, dissolving, uniformly mixing, filtering, filling, freeze-drying and visually inspecting to obtain a finished product.
Freeze drying curve
1. Prefreezing stage
(1) Placing the semi-finished product filled and half-plugged on a partition plate in a freeze-drying machine case, cooling to 0 ℃, and keeping the temperature for 60min;
(2) After the heat preservation is finished, the temperature is reduced to minus 40 ℃ for 120min for the second time, and the heat preservation time at minus 40 ℃ is 60min;
(3) After the heat preservation is finished, the temperature is raised to minus 6 ℃, the temperature raising time is 60min, and the heat preservation time at minus 6 ℃ is 30min;
(4) After the heat preservation is finished, the temperature is reduced to-40 ℃ for the third time, the temperature reduction time is as short as possible, and the heat preservation time at-40 ℃ is 120min;
2. sublimation drying stage
The vacuum degree in the drying box reaches 80mTorr; raising the main drying temperature to-16.0 ℃; the application time is 60min; the heat preservation time is 300min;
3. and a re-drying stage: raising the redrying temperature to 15 ℃; the application time is 90min; and (3) pumping the vacuum degree in the drying box to the limit vacuum, and keeping the temperature for 210min to obtain the freeze-dried composition containing the thymalfasin.
Example 6:
prescription
Thymalfasin 2.2g
Adjusting pH value of 0.1mol/L meglumine solution to 7.6
Adding water for injection to 1000ml
Preparation process
Weighing thymalfasin in a prescription amount, adding the thymalfasin into water for injection, adjusting the pH value by using a pH value regulator, fixing the volume to the full amount by using the water for injection after the pH value is adjusted, stirring, dissolving, uniformly mixing, filtering, filling, freeze-drying and visually inspecting to obtain a finished product.
Freeze drying curve
1. Prefreezing stage
(1) Placing the semi-finished product filled and half-plugged on a partition plate in a freeze-drying machine case, cooling to-4 ℃, and preserving heat for 120min;
(2) After the heat preservation is finished, the temperature is reduced to minus 50 ℃ for 180min for the second time, and the heat preservation time at minus 50 ℃ is 120min;
(3) After the heat preservation is finished, the temperature is raised to-8 ℃, the temperature raising time is 120min, and the heat preservation time at-8 ℃ is 60min;
(4) After the heat preservation is finished, the temperature is reduced to minus 50 ℃ for the third time, the temperature reduction time is as short as possible, and the heat preservation time at minus 50 ℃ is 180min;
2. sublimation drying stage
When the vacuum degree in the drying box reaches 120mTorr, the main drying temperature is raised to-20.0 ℃, the time is 120min, and the heat preservation time is 420min;
3. and a re-drying stage: and raising the re-drying temperature to 25 ℃, taking the time for 150min, pumping the vacuum degree in the drying oven to the limit vacuum, and keeping the temperature for 270min to obtain the freeze-dried composition containing the thymalfasin.
Comparative example 1:
prescription
Thymalfasin 2.2g
Adjusting pH value of 0.1mol/L meglumine solution to 7.6
Adding water for injection to 1000ml
The preparation process comprises the following steps:
weighing thymalfasin in a prescription amount, adding the thymalfasin into water for injection, adjusting the pH value by using a pH value regulator, fixing the volume to the full amount by using the water for injection after the pH value is adjusted, stirring, dissolving, uniformly mixing, filtering, filling, freeze-drying and visually inspecting to obtain a finished product.
Freeze drying curve
1. Prefreezing stage
Placing the semi-finished product filled and half-plugged on a partition plate in a freeze-drying machine case, cooling to-45 ℃, and preserving heat for 150min;
2. sublimation drying stage
The vacuum degree in the drying oven reaches 100mTorr, the main drying temperature is raised to-18 ℃, the time is 90min, and the heat preservation time is 360min;
3. and a re-drying stage: raising the redrying temperature to 20 ℃; the application time is 120min; and (3) pumping the vacuum degree in the drying box to the limit vacuum, and keeping the temperature for 240min to obtain the thymalfasin freeze-dried composition.
Comparative example 2:
prescription
Thymalfasin 2.2g
Adjusting pH value of 0.1mol/L meglumine solution to 6.8
Adding water for injection to 1000ml
The preparation process comprises the following steps: same as example 1
Comparative example 3:
prescription
Thymalfasin 1.6g
Adjusting the pH value of 0.1mol/L sodium phosphate solution to 6.8
Adding water for injection to 1000ml
The preparation process comprises the following steps: same as example 1
And (3) verification experiment:
accelerated test investigation
The finished preparations obtained in the examples 1-6, the original research and the comparative examples 1-3 of the invention are placed in a constant temperature and humidity box at 25 ℃, the samples are respectively taken in the 0 th, the 3 rd and the 6 th months to investigate the changes of appearance, redissolution time, insoluble particles and content, and the test results are shown in the table.
Accelerated test (high temperature 25 ℃ C.) examination result
* And (3) dissolving immediately: the dissolution is completed when 1ml of water for injection is added.
In conclusion, compared with the original preparation, the embodiment of the invention has the advantages that the redissolution time and the number of insoluble particles are superior to those of the original preparation due to the reduction of the types and the dosage of the auxiliary materials; it was also surprisingly found in the experiments that the lyophilized composition of thymalfasin was free of powder scattering in the absence of proppant, by adjusting the formulation and the lyophilization process.
Claims (1)
1. A preparation method of a lyophilized composition containing thymalfasin is characterized in that the preparation method comprises the following specific operation steps: weighing thymalfasin in a prescription amount, adding the thymalfasin into water for injection, adjusting the pH value to 7.5-7.7 by using a pH value regulator, fixing the volume to the full amount by using the water for injection, stirring, dissolving, uniformly mixing, filtering to obtain a thymalfasin solution, filling, freeze-drying, and performing visual inspection to obtain a finished product;
the pH value regulator is sodium phosphate, sodium citrate or meglumine;
the concentration of the thymalfasin solution is 1.8-2.6mg/ml;
the pH value of the solution of the freeze-dried composition before freeze-drying is 7.6;
the freeze drying comprises the following specific operation steps:
1. a pre-freezing stage:
(1) Filling the solution, and then placing the solution on a partition plate in a freeze-drying machine box to cool to 0 to-4 ℃, wherein the heat preservation time is 60 to 120min;
(2) After the heat preservation is finished, the temperature is reduced to minus 40 to minus 50 ℃ for the second time, and the temperature reduction time is 120 to 180min; keeping the temperature at minus 40 to minus 50 ℃ for 60 to 120min;
(3) After the heat preservation is finished, heating to minus 6 to minus 8 ℃, wherein the heating time is 60 to 120min; keeping the temperature at 6 ℃ below zero to 8 ℃ below zero for 30 to 60min;
(4) Rapidly cooling to-40-50 ℃ for the third time after the heat preservation is finished; keeping the temperature at minus 40 to minus 50 ℃ for 120 to 180min;
2. a sublimation drying stage: when the vacuum degree in the drying box is 80-120mTorr, the drying temperature is increased to-16.0 to-20.0 ℃, the temperature rise time is 60 to 120min, and the heat preservation time is 300 to 420min;
3. and a re-drying stage: and raising the drying temperature to 15-25 ℃, raising the temperature for 90-150min, continuously vacuumizing the drying box, and keeping the temperature for 210-270 min to obtain the thymalfasin-containing freeze-dried composition.
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