CN107510837A - A kind of freeze drying powder injection of injection octreotide acetate and preparation method thereof - Google Patents
A kind of freeze drying powder injection of injection octreotide acetate and preparation method thereof Download PDFInfo
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- CN107510837A CN107510837A CN201710818239.3A CN201710818239A CN107510837A CN 107510837 A CN107510837 A CN 107510837A CN 201710818239 A CN201710818239 A CN 201710818239A CN 107510837 A CN107510837 A CN 107510837A
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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
- A61K38/04—Peptides having up to 20 amino acids in a fully defined sequence; Derivatives thereof
- A61K38/08—Peptides having 5 to 11 amino acids
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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
- A61K47/06—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
- A61K47/18—Amines; Amides; Ureas; Quaternary ammonium compounds; Amino acids; Oligopeptides having up to five amino acids
- A61K47/183—Amino acids, e.g. glycine, EDTA or aspartame
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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
- A61K47/26—Carbohydrates, e.g. sugar alcohols, amino sugars, nucleic acids, mono-, di- or oligo-saccharides; Derivatives thereof, e.g. polysorbates, sorbitan fatty acid esters or glycyrrhizin
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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
- A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
- 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
Abstract
The invention discloses a kind of Octreotide acetate freeze-dried powder injection for injection, including octreotide acetate, mannitol, trehalose, L cysteines, lactic acid and sodium acid carbonate；The octreotide acetate, mannitol, trehalose, the mass ratio of L cysteines are 1:200‑250:50‑100:5‑10.Octreotide acetate freeze-dried powder injection for injection provided by the invention combines freeze drying protectant by adding a certain proportion of mannitol, trehalose and L cysteines, substantially increases the stability of octreotide acetate, extends its storage time.
Description
Technical field
The present invention relates to field of pharmaceutical preparations, and in particular to the freeze drying powder injection of injection octreotide acetate and its preparation side
Method.
Background technology
Octreotide acetate is artificial synthesized octapeptide compounds, is tetradecapeptide people's SMS 201-995.Octreotide removes
6 amino acid in ST, Isosorbide-5-Nitrae position is D type amino acid, 8 are amino L alcohol, are not easy to be hydrolyzed rapidly by protease, extend body
Interior half-life period, compared with natural growth hormone release inhibiting hormone tetradecapeptide, there is plasma half-life is long, effect is more powerful, action time is lasting etc.
Feature.
Octreotide acetate has extensive pharmacological action.Octreotide suppresses anteriorpituitary growth hormone and thyroid swashs
The secretion of element, while the pathological discharge that can also suppress GEP hormone is excessive.Other Octreotide can substantially suppress pancreas
The exocrine function of gland acinar cells, accumulation of the zymogen granule in cytoplasm is prevented, prevents acute pancreatitis from further deteriorating,
Therefore can be used for treating Severe Acute Pancreatitis SAP.Octreotide has inhibitory action to local inflammation；Can suppress gastrointestinal hormone and
Gastric acid secretion, smooth muscle spasm is released, effect is better than ranitidine, atropine, and can strong inhibition exocrine pancreas；Meanwhile
Octreotide may play the role of directly protection and inhibition of phospholipase A 2 activity to pancreatic parenchmal cells, activate PGI2, reduce toxin
Synthesis, improve pancreas microcirculation；Octreotide can also effectively prevent the release of various digestive ferments in pancreas lyase body, organize pancreas thin
The dissolved destruction of born of the same parents.Clinical research shows：To patients with severe acute pancreatitis early stage plus with Octreotide to improving acute pancreatitis
Symptom has to be acted on certainly, and relative to traditional remedies, Octreotide is evident in efficacy to be higher than the former.Octreotide can also be used to treat pancreatic injury
Or postoperative pancreas fistula, and available for prevention pancreatic surgery infectious-related complication.
For carcinoid tumor patient, Octreotide can improve its flush and symptom of diarrhea, while serotonin level also shows
Write and decline.Because Octreotide can control hypergastrinemia and enterochromaffin cell's like cell to grow, Octreotide may be to II type
Carcinoid of stomach is effective.Substantial amounts of research shows that Octreotide can not only suppress most increasings with neuroendocrine function tumour
Grow, inhibitory action, such as stomach cancer, colon cancer, breast cancer, cancer of pancreas to common solid tumor also be present.
The Octreotide trade name Novartis Co., Ltd of clinical practice is kind peaceful at present, and it is the acetic acid saline injection of Octreotide,
Lactic acid, mannitol are added in injection as excipient, but can only be preserved two weeks under the parenteral solution normal temperature, stability compared with
Difference, it is unfavorable for storing and transports.Because condition of storage is harsh, Storage period is short, and transport is inconvenient, and this all considerably increases acetic acid Austria
The application cost of bent peptide.
In order to strengthen the stability of octreotide acetate, it is readily transported, extends storage time, prior art has done many works
Make.CN102526700A discloses a kind of Octreotide acetate freeze-dried combination for injection, including octreotide acetate, mannitol and suitable
The buffer substance of amount, the octreotide acetate, the mass ratio of mannitol are 1:450-500.Described buffer substance be lactic acid and
Sodium acid carbonate, or tartaric acid and sodium tartrate.Product needs stored refrigerated.CN102416001B discloses a kind of injection
Octreotide acetate freeze drying powder injection, octreotide acetate are active component, and mannitol is freeze-dried excipient, and citric acid is conditioning agent,
The pH value of freeze drying powder injection is 5.5~5.7.It address only product and redissolve problem, do not refer to the situation of product stability.
The content of the invention
In order to overcome drawbacks described above, it is an object of the invention to provide a kind of Octreotide acetate freeze-dried powder injection for injection and its
Preparation method, strengthen the redissolution ability of octreotide acetate freeze drying powder injection, improve the stability of octreotide acetate, extend its storage
Time.
It is an object of the present invention to provide a kind of Octreotide acetate freeze-dried powder injection for injection, including following components：Vinegar
Sour Octreotide, mannitol, trehalose, Cys, lactic acid and sodium acid carbonate.
Further the octreotide acetate, mannitol, trehalose, the mass ratio of Cys are 1:200-250:
50-100:5-10。
Further the buffer substance of the octreotide acetate freeze drying powder injection is lactic acid and sodium acid carbonate.
Further the pH value of the octreotide acetate freeze drying powder injection is 4.2-4.7.
Further the octreotide acetate, mannitol, trehalose, the mass ratio of Cys are 1:230:70:7.
Preparation method it is a further object to provide said injector with octreotide acetate freeze drying powder injection, including
Following steps：
(1) mannitol of recipe quantity is weighed, adds 40% water for injection, after quick stirring and dissolving, adds the sea of recipe quantity
Algae sugar, adds 20% water for injection, quick stirring and dissolving, is eventually adding the Cys and lactic acid of recipe quantity, adds 20% injection
With water, after quick stirring and dissolving, the activated carbon of mass volume ratio 0.05% is added, 30min is stirred, by solution decarbonization filtering；
(2) octreotide acetate for weighing recipe quantity is added in the solution obtained by step (1), and stirring is completely dissolved it,
Manganese hydrogen sodium regulating solution pH value is added between 4.2-4.7, adds remaining water for injection；
(3) step (2) resulting solution is pumped in desinfection chamber through wriggling, be sterile filtered through 0.22 μm of miillpore filter
Afterwards, it is filled into cillin bottle, filling amount is 1ml/ bottles, sabot, freeze-drying, is freeze-dried and terminates rear inflated with nitrogen, tamponade, envelope
Mouthful.
Further in preparation process the temperature control of solution at 15-25 DEG C.
Further before step (3) freeze-drying, deoxidation treatment is carried out to the solution for being filled into cillin bottle.
Further the freezing dry process comprises the following steps：
(1) sabot for being placed with cillin bottle is put into freeze drying box, adjusts freeze drying box temperature, decline its temperature in 80min
To -45 DEG C, pre-freeze 2 hours at -45 DEG C；
(2) after pre-freeze is terminated, vavuum pump is opened, vacuum slow heating, is made freeze drying box 1 in 5-10Pa
- 10 DEG C are warming up in hour, continues to be slowly heated after being kept for 5 hours, 5 hours, is heated to 30 DEG C within 3 hours, 6 are kept at 30 DEG C
Outlet after hour.
In order to improve the stability of octreotide acetate freeze drying powder injection, the present inventor passes through substantial amounts of experimental exploring, to freezing
Dry production technology and auxiliary material include pH buffer, the condition such as selection of freeze drying protectant is studied, and find freeze drying protectant
Selection to improve octreotide acetate stability it is particularly important.
A kind of excellent freeze drying protectant can not only protect the medicine in freeze-drying process, and can suppress finished stock storage
The denaturation of medicine in phase.In order to strengthen protective effect, it is often necessary to the protective agent added more than two types in freeze-drying process.
Due to having multiple free hydroxyls in molecule, these free hydroxyls can be formed with protein for mannitol and trehalose
Hydrogen bond ensure that the stability of protein to substitute water；Their easy bound water molecules in the solution, aquation occurs, reduce
The content of free water simultaneously adds the viscosity of solution, so as to slow down the growth course of nucleus, makes the nucleus to be formed relatively fine, from
And play a part of protection.Cys not only have protective effect during medicament freeze-drying, and due to the Guang ammonia of L- half
Acid contains sulfydryl, also with oxidation resistant effect.The present inventor passes through substantial amounts of experimental exploring, finds mannitol, trehalose
Combined in certain proportion with Cys, form a kind of combination freeze drying protectant, the stability to improving octreotide acetate
Play more excellent effect.
In freezing dry process, during due to vacuumizing, the oxygen in solution can escape, and can so make with being lyophilized into quality
It is uneven, show bubble.Solution is carried out deoxidation treatment by the present inventor before freeze-drying, so as to get it is with being lyophilized into quality equal
It is even, the redissolution performance of dried frozen aquatic products is also enhanced to a certain extent.
Compared with prior art, Octreotide acetate freeze-dried powder injection for injection of the present invention is by adding certain proportion
Mannitol, trehalose and Cys combination freeze drying protectant, substantially increase the stability of octreotide acetate, extend
Its storage time, also enhance the solubility of octreotide acetate freeze drying powder injection to a certain extent by specific preparation method
Energy.
Embodiment
Embodiment 1
Octreotide acetate freeze-dried powder injection for injection is prepared, in terms of 1000 bottles, by octreotide acetate 0.1g, mannitol 20g,
Trehalose 5g, Cys 0.5g, lactic acid 3.8g compositions, manganese hydrogen sodium regulating solution PH to 4.2, solution temperature are controlled 15
DEG C, before freeze-drying, deoxidation treatment is carried out to the solution for being filled into cillin bottle.
Specific preparation method is as follows:
(1) mannitol of recipe quantity is weighed, adds 40% water for injection (400ml), after quick stirring and dissolving, adds prescription
The trehalose of amount, adds 20% water for injection (200ml), quick stirring and dissolving, is eventually adding the Cys and breast of recipe quantity
Acid, adds 20% water for injection (200ml), after quick stirring and dissolving, adds the activated carbon of mass volume ratio 0.05%, stirring
30min, by solution decarbonization filtering；
(2) octreotide acetate for weighing recipe quantity is added in the solution obtained by step (1), and stirring is completely dissolved it,
Manganese hydrogen sodium regulating solution pH value is added to 4.2, adds remaining water for injection (200ml)；
(3) step (2) resulting solution is pumped in desinfection chamber through wriggling, be sterile filtered through 0.22 μm of miillpore filter
Afterwards, it is filled into cillin bottle, filling amount is 1ml/ bottles, sabot, freeze-drying, is freeze-dried and terminates rear inflated with nitrogen, tamponade, envelope
Mouthful.
Freezing dry process comprises the following steps：
(1) sabot for being placed with cillin bottle is put into freeze drying box, adjusts freeze drying box temperature, decline its temperature in 80min
To -45 DEG C, pre-freeze 2 hours at -45 DEG C；
(2) after pre-freeze is terminated, vavuum pump is opened, vacuum slow heating, is made freeze drying box 1 in 5-10Pa
- 10 DEG C are warming up in hour, continues to be slowly heated after being kept for 5 hours, 5 hours, is heated to 30 DEG C within 3 hours, 6 are kept at 30 DEG C
Outlet after hour.
Embodiment 2
Octreotide acetate freeze-dried powder injection for injection is prepared, in terms of 1000 bottles, by octreotide acetate 0.1g, mannitol 23g,
Trehalose 7g, Cys 0.7g, lactic acid 3.8g compositions, manganese hydrogen sodium regulating solution PH to 4.5, solution temperature are controlled 20
DEG C, before freeze-drying, deoxidation treatment is carried out to the solution for being filled into cillin bottle.
Specific preparation method is as follows:
(1) mannitol of recipe quantity is weighed, adds 40% water for injection (400ml), after quick stirring and dissolving, adds prescription
The trehalose of amount, adds 20% water for injection (200ml), quick stirring and dissolving, is eventually adding the Cys and breast of recipe quantity
Acid, adds 20% water for injection (200ml), after quick stirring and dissolving, adds the activated carbon of mass volume ratio 0.05%, stirring
30min, by solution decarbonization filtering；
(2) octreotide acetate for weighing recipe quantity is added in the solution obtained by step (1), and stirring is completely dissolved it,
Manganese hydrogen sodium regulating solution pH value is added to 4.5, adds remaining water for injection (200ml)；
(3) step (2) resulting solution is pumped in desinfection chamber through wriggling, be sterile filtered through 0.22 μm of miillpore filter
Afterwards, it is filled into cillin bottle, filling amount is 1ml/ bottles, sabot, freeze-drying, is freeze-dried and terminates rear inflated with nitrogen, tamponade, envelope
Mouthful.
Freezing dry process comprises the following steps：
(1) sabot for being placed with cillin bottle is put into freeze drying box, adjusts freeze drying box temperature, decline its temperature in 80min
To -45 DEG C, pre-freeze 2 hours at -45 DEG C；
(2) after pre-freeze is terminated, vavuum pump is opened, vacuum slow heating, is made freeze drying box 1 in 5-10Pa
- 10 DEG C are warming up in hour, continues to be slowly heated after being kept for 5 hours, 5 hours, is heated to 30 DEG C within 3 hours, 6 are kept at 30 DEG C
Outlet after hour.
Embodiment 3
Octreotide acetate freeze-dried powder injection for injection is prepared, in terms of 1000 bottles, by octreotide acetate 0.1g, mannitol 25g,
Trehalose 10g, Cys 1.0g, lactic acid 3.8g compositions, manganese hydrogen sodium regulating solution PH to 4.7, solution temperature control exist
25 DEG C, before freeze-drying, deoxidation treatment is carried out to the solution for being filled into cillin bottle.
Specific preparation method is as follows:
(1) mannitol of recipe quantity is weighed, adds 40% water for injection (400ml), after quick stirring and dissolving, adds prescription
The trehalose of amount, adds 20% water for injection (200ml), quick stirring and dissolving, is eventually adding the Cys and breast of recipe quantity
Acid, adds 20% water for injection (200ml), after quick stirring and dissolving, adds the activated carbon of mass volume ratio 0.05%, stirring
30min, by solution decarbonization filtering；
(2) octreotide acetate for weighing recipe quantity is added in the solution obtained by step (1), and stirring is completely dissolved it,
Manganese hydrogen sodium regulating solution pH value is added to 4.7, adds remaining water for injection (200ml)；
(3) step (2) resulting solution is pumped in desinfection chamber through wriggling, be sterile filtered through 0.22 μm of miillpore filter
Afterwards, it is filled into cillin bottle, filling amount is 1ml/ bottles, sabot, freeze-drying, is freeze-dried and terminates rear inflated with nitrogen, tamponade, envelope
Mouthful.
Freezing dry process comprises the following steps：
(1) sabot for being placed with cillin bottle is put into freeze drying box, adjusts freeze drying box temperature, decline its temperature in 80min
To -45 DEG C, pre-freeze 2 hours at -45 DEG C；
(2) after pre-freeze is terminated, vavuum pump is opened, vacuum slow heating, is made freeze drying box 1 in 5-10Pa
- 10 DEG C are warming up in hour, continues to be slowly heated after being kept for 5 hours, 5 hours, is heated to 30 DEG C within 3 hours, 6 are kept at 30 DEG C
Outlet after hour.
Embodiment 4
Octreotide acetate freeze-dried powder injection for injection is prepared, in terms of 1000 bottles, by octreotide acetate 0.1g, mannitol 23g,
Trehalose 7g, Cys 0.7g, lactic acid 3.8g compositions, manganese hydrogen sodium regulating solution PH to 4.4, solution temperature are controlled 20
DEG C, before freeze-drying, deoxidation treatment is carried out to the solution for being filled into cillin bottle.
Specific preparation method is as follows:
(1) mannitol of recipe quantity is weighed, adds 40% water for injection (400ml), after quick stirring and dissolving, adds prescription
The trehalose of amount, adds 20% water for injection (200ml), quick stirring and dissolving, is eventually adding the Cys and breast of recipe quantity
Acid, adds 20% water for injection (200ml), after quick stirring and dissolving, adds the activated carbon of mass volume ratio 0.05%, stirring
30min, by solution decarbonization filtering；
(2) octreotide acetate for weighing recipe quantity is added in the solution obtained by step (1), and stirring is completely dissolved it,
Manganese hydrogen sodium regulating solution pH value is added to 4.4, adds remaining water for injection (200ml)；
(3) step (2) resulting solution is pumped in desinfection chamber through wriggling, be sterile filtered through 0.22 μm of miillpore filter
Afterwards, it is filled into cillin bottle, filling amount is 1ml/ bottles, sabot, freeze-drying, is freeze-dried and terminates rear inflated with nitrogen, tamponade, envelope
Mouthful.
Freezing dry process comprises the following steps：
(1) sabot for being placed with cillin bottle is put into freeze drying box, adjusts freeze drying box temperature, decline its temperature in 80min
To -45 DEG C, pre-freeze 2 hours at -45 DEG C；
(2) after pre-freeze is terminated, vavuum pump is opened, vacuum slow heating, is made freeze drying box 1 in 5-10Pa
- 10 DEG C are warming up in hour, continues to be slowly heated after being kept for 5 hours, 5 hours, is heated to 30 DEG C within 3 hours, 6 are kept at 30 DEG C
Outlet after hour.
Embodiment 5
Octreotide acetate freeze-dried powder injection for injection is prepared, in terms of 1000 bottles, by octreotide acetate 0.1g, mannitol 23g,
Trehalose 7g, Cys 0.7g, lactic acid 3.8g compositions, manganese hydrogen sodium regulating solution PH to 4.6, solution temperature are controlled 20
DEG C, before freeze-drying, deoxidation treatment is carried out to the solution for being filled into cillin bottle.
Specific preparation method is as follows:
(1) mannitol of recipe quantity is weighed, adds 40% water for injection (400ml), after quick stirring and dissolving, adds prescription
The trehalose of amount, adds 20% water for injection (200ml), quick stirring and dissolving, is eventually adding the Cys and breast of recipe quantity
Acid, adds 20% water for injection (200ml), after quick stirring and dissolving, adds the activated carbon of mass volume ratio 0.05%, stirring
30min, by solution decarbonization filtering；
(2) octreotide acetate for weighing recipe quantity is added in the solution obtained by step (1), and stirring is completely dissolved it,
Manganese hydrogen sodium regulating solution pH value is added to 4.6, adds remaining water for injection (200ml)；
(3) step (2) resulting solution is pumped in desinfection chamber through wriggling, be sterile filtered through 0.22 μm of miillpore filter
Afterwards, it is filled into cillin bottle, filling amount is 1ml/ bottles, sabot, freeze-drying, is freeze-dried and terminates rear inflated with nitrogen, tamponade, envelope
Mouthful.
Freezing dry process comprises the following steps：
(1) sabot for being placed with cillin bottle is put into freeze drying box, adjusts freeze drying box temperature, decline its temperature in 80min
To -45 DEG C, pre-freeze 2 hours at -45 DEG C；
(2) after pre-freeze is terminated, vavuum pump is opened, vacuum slow heating, is made freeze drying box 1 in 5-10Pa
- 10 DEG C are warming up in hour, continues to be slowly heated after being kept for 5 hours, 5 hours, is heated to 30 DEG C within 3 hours, 6 are kept at 30 DEG C
Outlet after hour.
Comparative example 1
Octreotide acetate freeze-dried powder injection for injection is prepared, in terms of 1000 bottles, by octreotide acetate 0.1g, mannitol
30.7g, lactic acid 3.8g are formed, manganese hydrogen sodium regulating solution PH to 4.5, and solution temperature is controlled at 20 DEG C, before freeze-drying, to filling
The solution for loading cillin bottle carries out deoxidation treatment.
Specific preparation method is as follows:
(1) mannitol of recipe quantity is weighed, adds 40% water for injection (400ml), after quick stirring and dissolving, adds prescription
Lactic acid is measured, adds 20% water for injection (200ml), after quick stirring and dissolving, adds the activated carbon of mass volume ratio 0.05%, stirring
30min, by solution decarbonization filtering；
(2) octreotide acetate for weighing recipe quantity is added in the solution obtained by step (1), and stirring is completely dissolved it,
Manganese hydrogen sodium regulating solution pH value is added to 4.5, adds remaining water for injection (400ml)；
(3) step (2) resulting solution is pumped in desinfection chamber through wriggling, be sterile filtered through 0.22 μm of miillpore filter
Afterwards, it is filled into cillin bottle, filling amount is 1ml/ bottles, sabot, freeze-drying, is freeze-dried and terminates rear inflated with nitrogen, tamponade, envelope
Mouthful.
Freezing dry process comprises the following steps：
(1) sabot for being placed with cillin bottle is put into freeze drying box, adjusts freeze drying box temperature, decline its temperature in 80min
To -45 DEG C, pre-freeze 2 hours at -45 DEG C；
(2) after pre-freeze is terminated, vavuum pump is opened, vacuum slow heating, is made freeze drying box 1 in 5-10Pa
- 10 DEG C are warming up in hour, continues to be slowly heated after being kept for 5 hours, 5 hours, is heated to 30 DEG C within 3 hours, 6 are kept at 30 DEG C
Outlet after hour.
Comparative example 2
Octreotide acetate freeze-dried powder injection for injection is prepared, in terms of 1000 bottles, by octreotide acetate 0.1g, trehalose
30.7g, lactic acid 3.8g are formed, manganese hydrogen sodium regulating solution PH to 4.5, and solution temperature is controlled at 20 DEG C, before freeze-drying, to filling
The solution for loading cillin bottle carries out deoxidation treatment.
Specific preparation method is as follows:
(1) trehalose of recipe quantity is weighed, adds 40% water for injection (400ml), after quick stirring and dissolving, adds prescription
Lactic acid is measured, adds 20% water for injection (200ml), after quick stirring and dissolving, adds the activated carbon of mass volume ratio 0.05%, stirring
30min, by solution decarbonization filtering；
(2) octreotide acetate for weighing recipe quantity is added in the solution obtained by step (1), and stirring is completely dissolved it,
Manganese hydrogen sodium regulating solution pH value is added to 4.5, adds remaining water for injection (400ml)；
(3) step (2) resulting solution is pumped in desinfection chamber through wriggling, be sterile filtered through 0.22 μm of miillpore filter
Afterwards, it is filled into cillin bottle, filling amount is 1ml/ bottles, sabot, freeze-drying, is freeze-dried and terminates rear inflated with nitrogen, tamponade, envelope
Mouthful.
Freezing dry process comprises the following steps：
(1) sabot for being placed with cillin bottle is put into freeze drying box, adjusts freeze drying box temperature, decline its temperature in 80min
To -45 DEG C, pre-freeze 2 hours at -45 DEG C；
(2) after pre-freeze is terminated, vavuum pump is opened, vacuum slow heating, is made freeze drying box 1 in 5-10Pa
- 10 DEG C are warming up in hour, continues to be slowly heated after being kept for 5 hours, 5 hours, is heated to 30 DEG C within 3 hours, 6 are kept at 30 DEG C
Outlet after hour.
Comparative example 3
Octreotide acetate freeze-dried powder injection for injection is prepared, in terms of 1000 bottles, by octreotide acetate 0.1g, Cys
30.7g, lactic acid 3.8g are formed, manganese hydrogen sodium regulating solution PH to 4.5, and solution temperature is controlled at 20 DEG C, before freeze-drying, to filling
The solution for loading cillin bottle carries out deoxidation treatment.
Specific preparation method is as follows:
(1) Cys of recipe quantity are weighed, add 40% water for injection (400ml), after quick stirring and dissolving, are added
Recipe quantity lactic acid, adds 20% water for injection (200ml), after quick stirring and dissolving, adds the activated carbon of mass volume ratio 0.05%,
30min is stirred, by solution decarbonization filtering；
(2) octreotide acetate for weighing recipe quantity is added in the solution obtained by step (1), and stirring is completely dissolved it,
Manganese hydrogen sodium regulating solution pH value is added to 4.5, adds remaining water for injection (400ml)；
(3) step (2) resulting solution is pumped in desinfection chamber through wriggling, be sterile filtered through 0.22 μm of miillpore filter
Afterwards, it is filled into cillin bottle, filling amount is 1ml/ bottles, sabot, freeze-drying, is freeze-dried and terminates rear inflated with nitrogen, tamponade, envelope
Mouthful.
Freezing dry process comprises the following steps：
(1) sabot for being placed with cillin bottle is put into freeze drying box, adjusts freeze drying box temperature, decline its temperature in 80min
To -45 DEG C, pre-freeze 2 hours at -45 DEG C；
(2) after pre-freeze is terminated, vavuum pump is opened, vacuum slow heating, is made freeze drying box 1 in 5-10Pa
- 10 DEG C are warming up in hour, continues to be slowly heated after being kept for 5 hours, 5 hours, is heated to 30 DEG C within 3 hours, 6 are kept at 30 DEG C
Outlet after hour.
Comparative example 4
Octreotide acetate freeze-dried powder injection for injection is prepared, in terms of 1000 bottles, by octreotide acetate 0.1g, mannitol 23g,
Trehalose 7g, Cys 0.7g, lactic acid 3.8g compositions, manganese hydrogen sodium regulating solution PH to 4.5, solution temperature are controlled 20
DEG C, before freeze-drying, deoxidation treatment is not carried out to the solution for being filled into cillin bottle.
Specific preparation method is as follows:
(1) mannitol of recipe quantity is weighed, adds 40% water for injection (400ml), after quick stirring and dissolving, adds prescription
The trehalose of amount, adds 20% water for injection (200ml), quick stirring and dissolving, is eventually adding the Cys and breast of recipe quantity
Acid, adds 20% water for injection (200ml), after quick stirring and dissolving, adds the activated carbon of mass volume ratio 0.05%, stirring
30min, by solution decarbonization filtering；
(2) octreotide acetate for weighing recipe quantity is added in the solution obtained by step (1), and stirring is completely dissolved it,
Manganese hydrogen sodium regulating solution pH value is added to 4.5, adds remaining water for injection (200ml)；
(3) step (2) resulting solution is pumped in desinfection chamber through wriggling, be sterile filtered through 0.22 μm of miillpore filter
Afterwards, it is filled into cillin bottle, filling amount is 1ml/ bottles, sabot, freeze-drying, is freeze-dried and terminates rear inflated with nitrogen, tamponade, envelope
Mouthful.
Freezing dry process comprises the following steps：
(1) sabot for being placed with cillin bottle is put into freeze drying box, adjusts freeze drying box temperature, decline its temperature in 80min
To -45 DEG C, pre-freeze 2 hours at -45 DEG C；
(2) after pre-freeze is terminated, vavuum pump is opened, vacuum slow heating, is made freeze drying box 1 in 5-10Pa
- 10 DEG C are warming up in hour, continues to be slowly heated after being kept for 5 hours, 5 hours, is heated to 30 DEG C within 3 hours, 6 are kept at 30 DEG C
Outlet after hour.
Comparative example 5
Octreotide acetate freeze-dried powder injection for injection is prepared, in terms of 1000 bottles, by octreotide acetate 0.1g, mannitol 23g,
Trehalose 7g, lactic acid 3.8g are formed, manganese hydrogen sodium regulating solution PH to 4.5, and solution temperature is controlled at 20 DEG C, before freeze-drying,
Deoxidation treatment is not carried out to the solution for being filled into cillin bottle.
Specific preparation method is as follows:
(1) mannitol of recipe quantity is weighed, adds 40% water for injection (400ml), after quick stirring and dissolving, adds prescription
The trehalose of amount, add 20% water for injection (200ml), quick stirring and dissolving, be eventually adding the lactic acid of recipe quantity, add 20% injection
With water (200ml), after quick stirring and dissolving, the activated carbon of mass volume ratio 0.05% is added, 30min is stirred, solution is taken off into charcoal
Filtering；
(2) octreotide acetate for weighing recipe quantity is added in the solution obtained by step (1), and stirring is completely dissolved it,
Manganese hydrogen sodium regulating solution pH value is added to 4.5, adds remaining water for injection (200ml)；
(3) step (2) resulting solution is pumped in desinfection chamber through wriggling, be sterile filtered through 0.22 μm of miillpore filter
Afterwards, it is filled into cillin bottle, filling amount is 1ml/ bottles, sabot, freeze-drying, is freeze-dried and terminates rear inflated with nitrogen, tamponade, envelope
Mouthful.
Freezing dry process comprises the following steps：
(1) sabot for being placed with cillin bottle is put into freeze drying box, adjusts freeze drying box temperature, decline its temperature in 80min
To -45 DEG C, pre-freeze 2 hours at -45 DEG C；
(2) after pre-freeze is terminated, vavuum pump is opened, vacuum slow heating, is made freeze drying box 1 in 5-10Pa
- 10 DEG C are warming up in hour, continues to be slowly heated after being kept for 5 hours, 5 hours, is heated to 30 DEG C within 3 hours, 6 are kept at 30 DEG C
Outlet after hour.
The measure of content of octreotide
Chromatographic condition and system suitability test
It is filler with octadecylsilane chemically bonded silica；With 10% tetramethyl ammonium hydroxide solution-water-acetonitrile (2:88:
10) it is mobile phase A (to adjust pH value to 5.4 with 10% phosphoric acid solution), with 10% tetramethyl ammonium hydroxide solution-water-acetonitrile (2:
38:60) it is Mobile phase B (to adjust pH value to 5.4 with 10% phosphoric acid solution), carries out gradient elution；Detection wavelength is 210nm；Take de-
Soviet Union's ammonia alcohol Octreotide and octreotide acetate reference substance are each appropriate, are dissolved in water and are made in every 1ml containing about de- Soviet Union's ammonia alcohol Octreotide
10 μ g and octreotide acetate 0.1mg mixed solution, take 20 μ L to inject liquid chromatograph, record chromatogram.Number of theoretical plate presses vinegar
Sour Octreotide peak, which calculates, should be not less than 3000；The separating degree of de- Soviet Union ammonia alcohol Octreotide and Octreotide peak should meet the requirements.Gradient is washed
De- program is as follows:
| Time (minute) | Mobile phase A (%) | Mobile phase B (%) |
| 0 | 73 | 27 |
| 30 | 55 | 45 |
| 31 | 73 | 27 |
| 37 | 73 | 27 |
Method of testing：Take this product appropriate, be dissolved in water and be quantitatively diluted to solution of every 1ml containing 0.1mg as need testing solution,
Separately take octreotide acetate reference substance appropriate, be measured in the same method, by external standard method with calculated by peak area, produce.
Related substances separation
Take this product appropriate, be dissolved in water and be quantitatively diluted to solution of every 1ml containing 0.1mg as need testing solution, precise volume
1ml is taken, is added in clean 50ml measuring bottles, is added water to graduation mark, shake up, as contrast solution.According under assay item
Chromatographic condition, precision measures need testing solution and each 100 μ L of contrast solution, is injected separately into liquid chromatograph, records chromatogram.
If any impurity peaks in test sample chromatogram, remove outside chromatographic peak of the relative retention time less than 0.5, single impurity peak area must not
More than contrast solution main peak area (1.0%), each impurity peak area sum cannot be greater than 2 times of contrast solution main peak area
(2.0%).
Experiment 1
According to test stone, the product of embodiment 1~5, comparative example 1~3 is tested, content of octreotide etc. in sample
Related check the results are shown in Table 1：
| Sequence number | PH value | Content (%) | Clarity | Solubility | Visible foreign matters | Particulate matter | Sterility test |
| Embodiment 1 | 4.2 | 98.7 | Clarification | Redissolution is exceedingly fast | Meet regulation | Meet regulation | Meet regulation |
| Embodiment 2 | 4.5 | 99.9 | Clarification | Redissolution is exceedingly fast | Meet regulation | Meet regulation | Meet regulation |
| Embodiment 3 | 4.7 | 99.1 | Clarification | Redissolution is exceedingly fast | Meet regulation | Meet regulation | Meet regulation |
| Embodiment 4 | 4.4 | 99.4 | Clarification | Redissolution is exceedingly fast | Meet regulation | Meet regulation | Meet regulation |
| Embodiment 5 | 4.6 | 99.3 | Clarification | Redissolution is exceedingly fast | Meet regulation | Meet regulation | Meet regulation |
| Comparative example 1 | 4.5 | 98.3 | Clarification | Redissolve very fast | Meet regulation | Meet regulation | Meet regulation |
| Comparative example 2 | 4.5 | 96.4 | Clarification | Redissolve very fast | Meet regulation | Meet regulation | Meet regulation |
| Comparative example 3 | 4.5 | 95.7 | Clarification | Redissolve very fast | Meet regulation | Meet regulation | Meet regulation |
Experiment 2
According to test stone, the product of embodiment 1~5, comparative example 4~5 is tested, content of octreotide etc. in sample
Related check the results are shown in Table 2：
By adding a certain proportion of mannitol, trehalose and the Guang ammonia of L- half it can be seen from the data in Tables 1 and 2
Acid combination freeze drying protectant will be good than individually adding a kind of any of the above described protectant effect.This shows the combination frozen-dried protective
Agent substantially increases the stability of octreotide acetate.Freezed it can be seen from the data in comparative example 4 and comparative example 5 in table 2
Do not carry out deoxidation treatment before drying to solution, the content of octreotide acetate has more obvious reduction, the content about material
There is more obvious rising, the redissolution ability of freeze drying powder injection is also affected.The addition of Cys is to vinegar simultaneously
Sour Octreotide and content about material have active influence.
Experiment 3
Study on the stability is carried out to octreotide acetate freeze drying powder injection obtained in embodiment 2, Octreotide contains in sample
The correlation test results (25 DEG C, RH60%) such as amount are shown in Table 3：
Experiment 4
Carry out long-term stable experiment (2-8 DEG C, lucifuge) to the product of embodiment 2, the correlation such as content of octreotide in sample
It the results are shown in Table 4：
It can be seen that by the test data in table 3 and preserved 7 months under product normal temperature, Octreotide contains in freeze drying powder injection
Amount, relevant material and all other inspections are showed no significant change.Product is in 2-8 it can be seen from the test data in table 4
DEG C, the holding time is up to 4 years under the conditions of lucifuge, and content of octreotide, relevant material and all other inspections are showed no obvious change
Change.This shows that octreotide acetate freeze drying powder injection provided by the invention either preserves under normal temperature or low temperature, all with ten
The stability divided.
The foregoing is merely illustrative of the preferred embodiments of the present invention, is not intended to limit the invention, all essences in the present invention
God any modification, equivalent substitution and improvements made etc., should be included in the scope of the protection with principle.
Claims (8)
1. a kind of Octreotide acetate freeze-dried powder injection for injection, including following components：Octreotide acetate, mannitol, trehalose, L-
Cysteine, lactic acid and sodium acid carbonate, the octreotide acetate, mannitol, trehalose, the mass ratio of Cys are 1:
200-250:50-100:5-10。
2. Octreotide acetate freeze-dried powder injection for injection according to claim 1, it is characterised in that the octreotide acetate
The buffer substance of freeze drying powder injection is lactic acid and sodium acid carbonate.
3. Octreotide acetate freeze-dried powder injection for injection according to claim 1, it is characterised in that the octreotide acetate
The pH value of freeze drying powder injection is 4.2-4.7.
4. Octreotide acetate freeze-dried powder injection for injection according to claim 1, it is characterised in that the acetic acid is difficult to understand bent
Peptide, mannitol, trehalose, the mass ratio of Cys are 1:230:70:7.
5. a kind of preparation method of any described Octreotide acetate freeze-dried powder injection for injection of Claims 1 to 4, its feature exist
In comprising the following steps：
(1) mannitol of recipe quantity is weighed, adds 40% water for injection, after quick stirring and dissolving, adds the trehalose of recipe quantity,
Add 20% water for injection, quick stirring and dissolving, be eventually adding the Cys and lactic acid of recipe quantity, add 20% water for injection,
After quick stirring and dissolving, the activated carbon of mass volume ratio 0.05% is added, 30min is stirred, by solution decarbonization filtering；
(2) octreotide acetate for weighing recipe quantity is added in the solution obtained by step (1), and stirring is completely dissolved it, is added
Manganese hydrogen sodium regulating solution pH value adds remaining water for injection between 4.2-4.7；
(3) step (2) resulting solution is pumped in desinfection chamber through wriggling, after 0.22 μm of miillpore filter is sterile filtered, filled
It is fitted into cillin bottle, filling amount is 1ml/ bottles, sabot, freeze-drying, is freeze-dried and terminates rear inflated with nitrogen, tamponade, sealing.
6. the preparation method of Octreotide acetate freeze-dried powder injection for injection according to claim 5, it is characterised in that prepare
During solution temperature control at 15-25 DEG C.
7. the preparation method of Octreotide acetate freeze-dried powder injection for injection according to claim 5, it is characterised in that in step
Suddenly before (3) freeze-drying, deoxidation treatment is carried out to the solution for being filled into cillin bottle.
8. according to the preparation method of any described Octreotide acetate freeze-dried powder injection for injection of claim 5~8, its feature exists
In the freezing dry process comprises the following steps：
(1) sabot for being placed with cillin bottle is put into freeze drying box, adjusts freeze drying box temperature, its temperature in 80min is dropped to -45
DEG C, pre-freeze 2 hours at -45 DEG C；
(2) after pre-freeze is terminated, vavuum pump is opened, vacuum slow heating, is made freeze drying box 1 hour in 5-10Pa
- 10 DEG C are inside warming up to, continues to be slowly heated after being kept for 5 hours, 5 hours, is heated to 30 DEG C within 3 hours, is kept for 6 hours at 30 DEG C
Outlet afterwards.
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| CN109187804A (en) * | 2018-10-18 | 2019-01-11 | 成都天台山制药有限公司 | The method for preparing octreotide acetate |
| CN109876136A (en) * | 2019-02-21 | 2019-06-14 | 国药集团成都信立邦生物制药有限公司 | A kind of octreotide acetate freeze drying powder injection and preparation method thereof |
| CN111346214A (en) * | 2020-05-13 | 2020-06-30 | 吉林吉力生物技术研究有限公司 | Octreotide acetate freeze-dried powder injection for animal injection and preparation method and application thereof |
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