CN106137979A - A kind of lyophilized injectable powder and preparation method thereof - Google Patents
A kind of lyophilized injectable powder and preparation method thereof Download PDFInfo
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- CN106137979A CN106137979A CN201510147399.0A CN201510147399A CN106137979A CN 106137979 A CN106137979 A CN 106137979A CN 201510147399 A CN201510147399 A CN 201510147399A CN 106137979 A CN106137979 A CN 106137979A
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- velcalcetide
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- dried
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- injectable powder
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Abstract
The present invention relates to field of pharmaceutical preparations, particularly to a kind of lyophilized injectable powder and preparation method thereof.The velcalcetide lyophilized injectable powder quality that the present invention provides is good, improve the stability of velcalcetide, makes this pharmaceutical preparation to place for a long time.Can dissolve rapidly in water for injection, 0.9% sodium chloride injection or 5% glucose injection, after dissolving, solution achromaticity and clarification, free from admixture precipitation, histocompatibility well, are more beneficial for popularization and the use of velcalcetide.Additionally, the lyophilizing technique of the present invention can effectively solve the problem that the broken bottle phenomenon in freeze-drying process, without broken bottle after lyophilizing.The lyophilized injectable powder that the present invention provides does not has finished laminar and atrophy phenomenon, improves product yield.
Description
Technical field
The present invention relates to field of pharmaceutical preparations, particularly to a kind of lyophilized injectable powder and preparation method thereof.
Background technology
Chronic renal failure (CRF) refers to that a variety of causes causes chronic progressive external Renal lesion, causes kidney
Substantially atrophy, it is impossible to maintaining basic function, clinical occur with metabolite retention, water, electrolyte, acid
Soda balance is lacked of proper care, and each system involvement of whole body is the clinical syndrome of main performance.Etiological has constitutional
Glomerulonephritis, chronic pyelonephritis, hypertensive renal arteriolar sclerosis, diabetic nephropathy, Secondary cases kidney
Bead nephritis, interstitial disease of renal tubule, hereditary Kidney Diseases and long-term taking antipyretic-antalgic agent and connect
Touch heavy metal etc..Total several hundred million patients, only China just have people more than 100,000,000 in the whole world.But this disease not by
Extensively diagnosis, its harm also can not show a candle to diabetes, what's frequently heard can be repeated in detail by masses for hyperlipidemia.But its final result
It it is end-stage renal failure.After obstacle occurs in renal function, internal parathyroid gland of secreting is to maintain blood calcium and serium inorganic phosphorus
Concentration, but once dialysis start that parathyroid gland is too high may adventurous consequence.Parathyroid gland increases blood
Calcium but reduce serium inorganic phosphorus, patients with renal failure due to blood calcium reduce, serium inorganic phosphorus rose, so pth secretion generation
Repaying property increases.
Velcalcetide is for accepting the secondary hyperparathyroidism of the Patients with Chronic Renal Disease of dialysis.
Velcalcetide structure is as shown in formula I:
Owing to Velcalcetide belongs to peptide medicament, extremely unstable, it is typically only capable at 2-8 DEG C preserve,
It is unfavorable for popularization and the use of velcalcetide.And the lyophilizing process program of routine can not be fully solved
Bottle layering and atrophy phenomenon are broken in velcalcetide freeze-dried powder lyophilizing.
Summary of the invention
In view of this, the present invention provides a kind of velcalcetide lyophilized injectable powder and preparation method thereof.Should
Velcalcetide lyophilized injectable powder significantly improves the stability of velcalcetide injection, and should
Velcalcetide lyophilized injectable powder need not preserve at 2-8 DEG C, can place for a long time, more have
It is beneficial to popularization and the use of velcalcetide.Additionally, the lyophilizing technique of the present invention can effectively solve the problem that and freezing
Broken bottle phenomenon during Gan, velcalcetide lyophilized injectable powder prepared by the lyophilizing technique of the present invention is without broken
Bottle.There is not layering and atrophy phenomenon in the lyophilized injectable powder outward appearance that the present invention provides, improves product yield.
In order to realize foregoing invention purpose, the present invention provides techniques below scheme:
The invention provides a kind of lyophilized injectable powder, by effective ingredient and pharmaceutically acceptable adjuvant
Lyophilization is made；
Described lyophilization includes pre-freeze, evacuation, dry step；
Described pre-freeze includes:
First pre-freeze, the temperature of described first pre-freeze is-36 DEG C～-29 DEG C, the insulation of described first step pre-freeze
Time is 1h～3h；
Second pre-freeze, the temperature of described second pre-freeze is-55 DEG C～-42 DEG C, the insulation of described second step pre-freeze
Time is 1h～2h；
3rd pre-freeze, described 3rd pre-freeze is to be warming up to-10 DEG C～-7 DEG C in 1h-2h, is incubated 1h～2h；
4th pre-freeze, described 4th pre-freeze is that 1h-2h is cooled to-36 DEG C～-29 DEG C, is incubated 1h～3h；
5th pre-freeze, the temperature of described 5th pre-freeze is-55 DEG C～-42 DEG C, the insulation of described 5th step pre-freeze
Time is 1h～3h.
In some specific embodiments of the present invention, the vacuum of described evacuation gained be 5Pa～
30Pa。
In some specific embodiments of the present invention, described being dried includes:
The first step is dried, and the temperature that the described first step is dried is-35 DEG C～-25 DEG C, and the described first step is dried
Time is 15h～30h；
Second step is dried, and the temperature that described second step is dried is-20 DEG C～-10 DEG C, and described second step is dried
Time is 10h～20h；
3rd step is dried, and the temperature that described 3rd step is dried is-5 DEG C～5 DEG C, described 3rd step be dried time
Between be 5h～10h；
4th step is dried, and the temperature that described 4th step is dried is for 25 DEG C～40 DEG C, and described 4th step is dried
Time be 5h～10h.
In some specific embodiments of the present invention, described effective ingredient is velcalcetide.
In some specific embodiments of the present invention, described pharmaceutically acceptable adjuvant include excipient,
A kind of or both mixture above in stabilizer, pH adjusting agent or water for injection.
As preferably, the pH value of pH value regulator regulation is 3.0～5.0.
In some specific embodiments of the present invention, described lyophilized injectable powder by take velcalcetide,
Excipient, stabilizer mix with the water for injection of recipe quantity mass percent 52.9%～99.0%, add pH
After value regulator regulation pH value is 3.0～5.0, add the water for injection of surplus, after mixing, obtain velcalcetide
Aqueous solution, freeze-dried, to obtain final product.
As preferably, in the lyophilized injectable powder that the present invention provides, excipient is mannitol, lactose, Fructus Vitis viniferae
One in sugar, sucrose or sorbitol or both thing mixed above, preferably mannitol, lactose, sucrose.
It is further preferable that the excipient in the lyophilized injectable powder of present invention offer is mannitol, lactose.
Preferably, the present invention provide lyophilized injectable powder in stabilizer be sodium sulfite, sodium pyrosulfite,
Ascorbic acid, sodium thiosulfate, METHIONINE, L-glycine, tyrosine, glycine, serine,
L-Leu, cysteine, agedoite, glutamine, lysine, arginine, histidine, sky
One in winter propylhomoserin, Pidolidone or both things mixed above.
Preferably, in the lyophilized injectable powder that the present invention provides, pH value regulator is acetic acid, sodium acetate, salt
Acid, sulphuric acid, lactic acid, malic acid, citric acid, phosphoric acid, sodium hydroxide, sodium carbonate, sodium bicarbonate,
One in disodium hydrogen phosphate or sodium citrate or both things mixed above.
In some specific embodiments of the present invention, in the lyophilized injectable powder that the present invention provides
The mass ratio of velcalcetide, excipient, stabilizer and water for injection is (0.1～2): (10～107):
(0.03～0.2): (892.25～989.3).
Present invention also offers the preparation method of a kind of lyophilized injectable powder, take effective ingredient with pharmaceutically
Acceptable adjuvant is freeze-dried, prepares described lyophilized injectable powder；
Described lyophilization includes pre-freeze, evacuation, dry step；
Described pre-freeze includes:
The first step, the temperature of the described first step is-36 DEG C～-29 DEG C, and the temperature retention time of the described first step is
1h～3h；
Second step, the temperature of described second step is-55 DEG C～-42 DEG C, and the temperature retention time of described second step is
1h～2h；
3rd step, described 3rd step is to be warming up to-10 DEG C～-7 DEG C in 1h-2h, is incubated 1h～2h；
4th step, described 4th step is that 1h-2h is cooled to-36 DEG C～-29 DEG C, is incubated 1h～3h；
5th step, the temperature of described 5th step is-55 DEG C～-42 DEG C, and the temperature retention time of described 5th step is
1h～3h.
In some specific embodiments of the present invention, take out described in the preparation method of described lyophilized injectable powder
The vacuum of vacuum gained is 5Pa～30Pa.
In some specific embodiments of the present invention, dry described in the preparation method of described lyophilized injectable powder
Dry include:
The first step is dried, and the temperature that the described first step is dried is-35 DEG C～-25 DEG C, and the described first step is dried
Time is 15h～30h；
Second step is dried, and the temperature that described second step is dried is-20 DEG C～-10 DEG C, and described second step is dried
Time is 10h～20h；
3rd step is dried, and the temperature that described 3rd step is dried is-5 DEG C～5 DEG C, described 3rd step be dried time
Between be 5h～10h；
4th step is dried, and the temperature that described 4th step is dried is for 25 DEG C～40 DEG C, and described 4th step is dried
Time be 5h～10h.
In some specific embodiments of the present invention, medicine described in the preparation method of described lyophilized injectable powder
Thing effective ingredient is velcalcetide.
In some specific embodiments of the present invention, medicine described in the preparation method of described lyophilized injectable powder
One during acceptable adjuvant includes excipient, stabilizer, pH adjusting agent or water for injection on or two
Mixture more than person.
As preferably, the pH value of pH value regulator regulation is 3.0～5.0.
In some specific embodiments of the present invention, the preparation method of described lyophilized injectable powder is for taking
Velcalcetide, excipient, stabilizer and the water for injection of recipe quantity mass percent 52.9%～99.0%
Mixing, after addition pH value regulator regulation pH value is 3.0～5.0, adds the water for injection of surplus, mixed
Velcalcetide aqueous solution is obtained after conjunction, freeze-dried, to obtain final product.
As preferably, in the preparation method of the lyophilized injectable powder that the present invention provides, excipient be mannitol,
One in lactose, glucose, sucrose or sorbitol or both thing mixed above, preferably mannitol, breast
Sugar.
It is further preferable that the excipient in the preparation method of the lyophilized injectable powder of present invention offer is mannitol,
Lactose.
Preferably, the present invention provide lyophilized injectable powder preparation method in stabilizer be sodium sulfite,
Sodium pyrosulfite, ascorbic acid, sodium thiosulfate, METHIONINE, L-glycine, tyrosine, sweet ammonia
Acid, serine, L-Leu, cysteine, agedoite, glutamine, lysine, arginine,
One in histidine, aspartic acid, Pidolidone or both things mixed above.
Preferably, the present invention provide lyophilized injectable powder preparation method in, pH value regulator be acetic acid,
Sodium acetate, hydrochloric acid, sulphuric acid, lactic acid, malic acid, citric acid, phosphoric acid, sodium hydroxide, sodium carbonate,
One in sodium bicarbonate, disodium hydrogen phosphate or sodium citrate or both things mixed above.
In some specific embodiments of the present invention, the preparation method of the lyophilized injectable powder that the present invention provides
The mass ratio of middle velcalcetide, excipient, stabilizer, pH adjusting agent or water for injection is (0.1～2):
(10～107): (0.03～0.2): (892.25～989.3).
The invention provides a kind of velcalcetide lyophilized injectable powder and preparation method thereof.This velcalcetide
Lyophilized injectable powder is by velcalcetide, excipient, stabilizer, pH value regulator and water for injection lyophilizing system
Become.The preparation method that the present invention provides uses multistep processes when velcalcetide preparation pre-freeze, is dropped by flaggy
Temperature, to-36 DEG C～-29 DEG C, is incubated 1h～3h；It is cooled to-55 DEG C～-42 DEG C again, is incubated 1h～2h, then uses
1h～2h is warming up to-10 DEG C～-7 DEG C, is incubated 1h～2h, then is cooled to-36 DEG C～-29 DEG C with 1h～2h,
Insulation 1h～3h, then it is cooled to-55 DEG C～-42 DEG C, it is incubated 1～3h.Research finds, the ginseng of lyophilizing technique
Number is broken bottle yield and the outward appearance of goods after affecting lyophilizing.
This velcalcetide lyophilized injectable powder significantly improves the stability of velcalcetide injection, and should
Velcalcetide lyophilized injectable powder need not preserve at 2-8 DEG C, can place for a long time, more have
It is beneficial to popularization and the use of velcalcetide.
The velcalcetide lyophilized injectable powder that the present invention provides significantly improves the multiple capacitive of velcalcetide,
The velcalcetide lyophilized injectable powder quality that the present invention provides is good, improve the stability of velcalcetide,
Make this pharmaceutical preparation and this velcalcetide lyophilized injectable powder need not at 2-8 DEG C to preserve, can be in room temperature
Lower long-term placement.Experimental result confirms, this velcalcetide lyophilized injectable powder quality is good, can be in room temperature
Lower long-term placement；Can be the most molten in water for injection, 0.9% sodium chloride injection or 5% glucose injection
Solving, after dissolving, solution achromaticity and clarification, free from admixture precipitation, histocompatibility well, are more beneficial for velcalcetide
Popularization and use.Additionally, the lyophilizing technique of the present invention can effectively solve the problem that the broken bottle in freeze-drying process
Phenomenon, without broken bottle after lyophilizing, and the solution of routine is to improve yield, it is impossible to is fully solved and freezes
Dry broken bottle phenomenon, still has a small amount of broken bottle.There is not layering in the lyophilized injectable powder outward appearance that the present invention provides
With atrophy phenomenon, improve product yield.Summary result of the test, prescription addition stabilizer can improve and change
Its sensitivity to temperature kind, it is not necessary to preserve under the conditions of 2-8 DEG C, can preserve at 25 DEG C..Freeze
Dry technique improves product yield, solves broken bottle, layering, the phenomenon of atrophy, improves and redissolve, mainly solve
Common lyophilizing technique produced problem.
Detailed description of the invention
The invention discloses a kind of lyophilized injectable powder and preparation method thereof, those skilled in the art can use for reference
Present disclosure, is suitably modified technological parameter and realizes.Special needs to be pointed out is, all similar replacements and
Changing apparent to those skilled in the art, they are considered as being included in the present invention.This
Method and the application of invention are described by preferred embodiment, and related personnel substantially can not take off
In present invention, spirit and scope, method described herein and application it is modified or suitably changes
With combination, realize and apply the technology of the present invention.
In lyophilized injectable powder and preparation method thereof that the present invention provides, raw materials used and reagent all can be purchased by market
?.
Below in conjunction with embodiment, the present invention it is expanded on further:
The preparation of embodiment 1 velcalcetide lyophilized injectable powder
Prescription:
Weigh velcalcetide, sorbitol, ascorbic acid by recipe quantity, dissolve with the water for injection of 100g
The water for injection of velcalcetide, 300g dissolves sorbitol, the water for injection of 100g dissolves ascorbic acid,
By gained velcalcetide solution, sorbitol solution, ascorbic acid solution mix homogeneously, regulate with acetic acid
PH value, to after pH3.0, continues to add remaining water for injection, obtains 1000g velcalcetide aqueous solution,
0.2 μm filter filtration sterilization, props up with 5.0mL/ and is sub-packed in cillin bottle.
Putting in vacuum freeze drier by gained equipped with the cillin bottle of velcalcetide aqueous solution, pre-freeze is opened
Begin, flaggy is cooled to-29 DEG C, and is incubated 3h；It is cooled to-50 DEG C again, is incubated 1h, then heats up with 1h
To-7 DEG C, it is incubated 2h, then is cooled to-29 DEG C with 1h, and be incubated 3h, then be cooled to-50 DEG C, be incubated 1h,
The most i.e. complete pre-freeze.After pre-freeze is terminated, evacuation (vacuum: 5pa), startup heat up, and do
Dry ,-35 DEG C of dry 30h, it is warming up to-20 DEG C, is dried 10h；It is warming up to-5 DEG C, is dried 10h；It is warming up to
25 DEG C, it is dried 10h.
Tamponade, outlet, Zha Gai, obtain velcalcetide lyophilized injectable powder.
The preparation of embodiment 2 velcalcetide lyophilized injectable powder
Prescription:
Velcalcetide, mannitol, METHIONINE is weighed by recipe quantity, water-soluble by the injection of 100g
The water for injection solving velcalcetide, 400g dissolves mannitol, the water for injection of 100g dissolves L-first sulfur ammonia
Acid, by gained velcalcetide solution, mannitol solution, METHIONINE solution mix homogeneously, uses salt
Acid for adjusting pH value, to after pH4.0, continues to add remaining water for injection, obtains 1000g velcalcetide
Aqueous solution, 0.2 μm filter filtration sterilization, prop up with 5.0mL/ and be sub-packed in cillin bottle.
Putting in vacuum freeze drier by gained equipped with the cillin bottle of velcalcetide aqueous solution, pre-freeze is opened
Begin, flaggy is cooled to-31 DEG C, be incubated 2h；It is cooled to-55 DEG C again, is incubated 1h, then is warming up to 2h
-8 DEG C, it is incubated 2h, then is cooled to-31 DEG C with 2h, be incubated 1h, then be cooled to-55 DEG C, be incubated 1h.
After pre-freeze is terminated, evacuation (vacuum: 10pa), startup heat up, and are dried, and-30 DEG C are dried
20h, is warming up to-15 DEG C, is dried 15h；It is warming up to 0 DEG C, is dried 10h；It is warming up to 28 DEG C, is dried 10h.
Tamponade, outlet, Zha Gai, obtain velcalcetide lyophilized injectable powder.
The preparation of embodiment 3 velcalcetide lyophilized injectable powder
Prescription:
Weigh velcalcetide, lactose, L-Leu by recipe quantity, dissolve with the water for injection of 100g
The water for injection solubilized lactose of velcalcetide, 500g, 50g water for injection dissolve L-Leu, general
Gained velcalcetide solution, lactose solution, L-Leu solution, mix homogeneously, use salt acid for adjusting pH
It is worth after pH3.5, continues to add remaining water for injection, obtain 1000g velcalcetide aqueous solution,
0.2 μm filter filtration sterilization, props up with 5.0mL/ and is sub-packed in cillin bottle.
Putting in vacuum freeze drier by gained equipped with the cillin bottle of velcalcetide aqueous solution, pre-freeze is opened
Begin, flaggy is cooled to-32 DEG C, be incubated 1h；It is cooled to-48 DEG C again, is incubated 2h, then is warming up to 2h
-9 DEG C, it is incubated 2h, then is cooled to-32 DEG C with 2h, be incubated 1h, then be cooled to-48 DEG C, be incubated 2h.
After pre-freeze is terminated, evacuation (vacuum: 12pa), startup heat up, and are dried, and-25 DEG C are dried
20h, is warming up to-10 DEG C, is dried 15h；It is warming up to 5 DEG C, is dried 5h；It is warming up to 30 DEG C, is dried 8h.
Tamponade, outlet, Zha Gai, obtain velcalcetide lyophilized injectable powder.
The preparation of embodiment 4 velcalcetide lyophilized injectable powder
Prescription:
Weigh velcalcetide, mannitol, arginine by recipe quantity, dissolve with the water for injection of 100g
The water for injection of velcalcetide, 700g dissolves mannitol, the water for injection of 100g dissolves arginine, will
Gained velcalcetide solution, mannitol solution, arginine solution mix homogeneously, use vinegar acid for adjusting pH
It is worth after pH3.0, continues to add remaining water for injection, obtain 1000g velcalcetide aqueous solution,
0.2 μm filter filtration sterilization, props up with 5.0mL/ and is sub-packed in cillin bottle.
Putting in vacuum freeze drier by gained equipped with the cillin bottle of velcalcetide aqueous solution, pre-freeze is opened
Begin, flaggy is cooled to-33 DEG C, be incubated 1h；It is cooled to-45 DEG C again, is incubated 1h, then is warming up to 2h
-10 DEG C, it is incubated 1h, then is cooled to-33 DEG C with 1h, be incubated 1h, then be cooled to-45 DEG C, be incubated 3h.
After pre-freeze is terminated, evacuation (vacuum: 22pa), startup heat up, and are dried, and-27 DEG C are dried
15h, is warming up to-18 DEG C, is dried 15h；It is warming up to 0 DEG C, is dried 8h；It is warming up to 35 DEG C, is dried 6h.
Tamponade, outlet, Zha Gai, obtain velcalcetide lyophilized injectable powder.
The preparation of embodiment 5 velcalcetide lyophilized injectable powder
Prescription:
Weigh velcalcetide, mannitol, Pidolidone by recipe quantity, dissolve with the water for injection of 100g
The water for injection of velcalcetide, 500g dissolves mannitol, the water for injection of 100g dissolves Pidolidone,
By gained velcalcetide solution, mannitol solution, Pidolidone solution mix homogeneously, regulate with acetic acid
PH value, to after pH3.3, continues to add remaining water for injection, obtains 1000g velcalcetide aqueous solution,
0.2 μm filter filtration sterilization, props up with 5.0mL/ and is sub-packed in cillin bottle.
Putting in vacuum freeze drier by gained equipped with the cillin bottle of velcalcetide aqueous solution, pre-freeze is opened
Begin, flaggy is cooled to-34 DEG C, be incubated 1h；It is cooled to-48 DEG C again, is incubated 2h, then is warming up to 1h
-10 DEG C, it is incubated 1h, then is cooled to-34 DEG C with 2h, be incubated 1h, then be cooled to-48 DEG C, be incubated 3h.
After pre-freeze is terminated, evacuation (vacuum: 25pa), startup heat up, and are dried-25 DEG C and are dried
30h, is warming up to-20 DEG C of dry 18h；It is warming up to 0 DEG C, is dried 5h；It is warming up to 40 DEG C, is dried 5h.
Tamponade, outlet, Zha Gai, obtain velcalcetide lyophilized injectable powder.
The preparation of embodiment 6 velcalcetide lyophilized injectable powder
Prescription:
Weigh velcalcetide, lactose, L-glycine by recipe quantity, dissolve with the water for injection of 100g
The water for injection solubilized lactose of velcalcetide, 400g, the water for injection of 100g dissolve L-glycine, will
Gained velcalcetide solution, mannitol solution, L-glycine solution mix homogeneously, with acetic acid, hydrogen-oxygen
Change sodium regulation pH value to after pH3.5, continue to add remaining water for injection, obtain 1000g velcalcetide
Aqueous solution, 0.2 μm filter filtration sterilization, prop up with 5.0mL/ and be sub-packed in cillin bottle.
Gained is put in vacuum freeze drier equipped with the cillin bottle of velcalcetide aqueous solution and lowers the temperature, in advance
Freeze beginning, flaggy is cooled to-35 DEG C, and is incubated 1h；Again by the temperature of goods to-43 DEG C, it is incubated 1h；
It is warming up to-10 DEG C with 1h again, is incubated 1h, then is cooled to-35 DEG C with 2h, be incubated 1h, then be cooled to-43 DEG C,
Insulation 3h.
After pre-freeze is terminated, evacuation (vacuum: 20pa), startup heat up, and are dried-25 DEG C and are dried
15h, is warming up to-20 DEG C of dry 17h；It is warming up to 0 DEG C, is dried 7h；It is warming up to 40 DEG C, is dried 6h.
Tamponade, outlet, Zha Gai, obtain velcalcetide lyophilized injectable powder.
The preparation of embodiment 7 velcalcetide lyophilized injectable powder
Prescription:
Velcalcetide, mannitol, METHIONINE is weighed by recipe quantity, water-soluble by the injection of 100g
The water for injection solving velcalcetide, 400g dissolves mannitol, the water for injection of 100g dissolves L-first sulfur ammonia
Acid, by gained velcalcetide solution, mannitol solution, METHIONINE solution mix homogeneously, uses phosphorus
Acid dihydride sodium regulation pH value, to after pH4.0, continues to add residue water for injection, obtains 1000g
Velcalcetide aqueous solution, 0.2 μm filter filtration sterilization, prop up with 5.0mL/ and be sub-packed in cillin bottle.
Putting in vacuum freeze drier by gained equipped with the cillin bottle of velcalcetide aqueous solution, pre-freeze is opened
Begin, flaggy is cooled to-36 DEG C, and is incubated 2h；It is cooled to-42 DEG C again, is incubated 1h, then uses 1.5h liter
Temperature, to-9 DEG C, is incubated 2h, then is cooled to-36 DEG C with 1.5h, is incubated 3h, then is cooled to-42 DEG C, insulation
1h。
After pre-freeze is terminated, evacuation (vacuum: 30pa), startup heat up, and are first warming up to-28 DEG C, are dried
20h；It is warming up to-18 DEG C again, is dried 20h；It is warming up to 3 DEG C again, is dried 5h；It is warming up to 38 DEG C again, dry
Dry 5h.Tamponade, outlet, Zha Gai, obtain velcalcetide lyophilized injectable powder.
The preparation of embodiment 8 velcalcetide preparations. Control group
The velcalcetide preparation prepared with matched group 1 to matched group 3 is for comparison.Matched group 1 is
Velcalcetid injection, matched group 2 and matched group 3 are to use conventional freeze drying process to prepare
Velcalcetide preparation, the preparation method of the velcalcetide preparation of each matched group is as follows:
Matched group 1:
Prescription:
Weigh velcalcetide, mannitol by recipe quantity, dissolve velcalcetide with water for injection respectively,
Mannitol, and mix.Continuing to add and inject water to gross weight, 0.2 μm filters, and props up subpackage with 5.0mL/
In cillin bottle.
Matched group 2:
Prescription:
Weigh velcalcetide, mannitol by recipe quantity, dissolve velcalcetide with water for injection respectively,
Mannitol, and mix, adjust pH value pH7.2 with disodium hydrogen phosphate.Continue to add and inject water to gross weight,
0.2 μm filters, and props up with 5.0mL/ and is sub-packed in cillin bottle.
Putting in vacuum freeze drier by gained equipped with the cillin bottle of velcalcetide aqueous solution, pre-freeze is opened
Begin, through 1h, flaggy is cooled to-42 DEG C, be incubated 3h.Pre-freeze is terminated, and starts evacuation, when vacuum reaches
During to 24Pa, start to warm up, be first warming up to-35 DEG C, be dried 2h；It is warming up to-20 DEG C again, is dried 2h；
It is warming up to-5 DEG C again, is dried 2h；It is warming up to 10 DEG C again, is dried 12 hours, tamponade, outlet, Zha Gai,
Obtain.
Matched group 3:
Prescription:
Weigh velcalcetide, mannitol by recipe quantity, dissolve velcalcetide with water for injection respectively,
Mannitol, and mix, adjust pH value pH2.5 with hydrochloric acid.Continue to add and inject water to gross weight, 0.2 μm
Filter, prop up with 5.0mL/ and be sub-packed in cillin bottle.
Putting in vacuum freeze drier by gained equipped with the cillin bottle of velcalcetide aqueous solution, pre-freeze is opened
Begin, through 1h, flaggy is cooled to-45 DEG C, be incubated 3h.Pre-freeze is terminated, and starts evacuation, when vacuum reaches
During to 20Pa, first it is warming up to-28 DEG C, is dried 14h；It is warming up to-18 DEG C again, is dried 8h；It is warming up to again
3 DEG C, it is dried 4h；It is warming up to 38 DEG C again, is dried 5h, tamponade, outlet, Zha Gai, obtains velcalcetide
Lyophilized injectable powder.
Bottle destroying rate after embodiment 9 lyophilizing and product yield
Bottle destroying rate and product yield after lyophilizing are shown in Table 1.
Bottle destroying rate and product yield result after table 1 lyophilizing
Use multistep processes pre-freeze, completely solve the problem that velcalcetide lyophilized formulations breaks bottle.After lyophilizing
Without broken bottle, and the solution of routine is can not to be fully solved lyophilizing to break bottle phenomenon, still has a small amount of broken bottle；
And the lyophilizing technique finished appearance of the employing present invention is good, without atrophy and lamination, hence it is evident that improve finished product and receive
Rate.
Embodiment 10 stability test
Stability test: the velcalcetide lyophilized powder that Example 1 to embodiment 7 prepares respectively
Injection, each matched group provide velcalcetide preparation, in temperature 25 ± 2 DEG C, relative humidity 60 ± 10%,
In the proof box of intensity of illumination: 200 ± 10LX, place 6 months, respectively the 0th, 1,2,3,6
The sampling at the end of month of individual month carries out stability key project investigation, the results are shown in Table 2.
Table 2 stability test testing result
From table 2, result of the test understands, matched group 1 (velcalcetide injection) prolongation over time,
Impurity content is significantly increased, clarity is defective, and redissolution gained solution turned yellow, particulate matter exceeds standard；
The velcalcetide lyophilized injectable powder that matched group 2 and matched group 3 prepare when within 0 month, redissolving just
Occur redissolving difficulty, be layered, the phenomenon such as precipitation, clarity is defective；So, matched group 1, matched group
2 and the velcalcetide quality of the pharmaceutical preparations for preparing of matched group 3 poor, defective.
The velcalcetide lyophilized injectable powder quality that the embodiment of the present invention 1 to embodiment 7 prepares is more steady
Fixed, after placing June, solubility is good, and after gained redissolves, clarity is good, and velcalcetide injection
Liquor turns yellow, has particulate matter to produce.The velcalcetide that embodiment 1 to embodiment 7 prepares
Lyophilized injectable powder is after placing 6 months, and the weight/mass percentage composition of total impurities is less than 1.5%, and maximum list is miscellaneous
Less than 0.5%, and the total impurities of the velcalcetide preparation of matched group 1. matched group 2. matched group 3 preparation
All having exceeded 3%, single impurity has all exceeded 2%, and significant difference (P ＜ 0.05) illustrates embodiment 1
The velcalcetide lyophilized injectable powder stability prepared to embodiment 7 is higher than velcalcetide injection,
The lyophilized formulations prepared also superior to conventional method.
In sum, the velcalcetide freeze-dried powder that the embodiment of the present invention 1 to embodiment 7 prepares
The solubility of agent is good, can place for a long time.
Embodiment 11 velcalcetide lyophilized injectable powder animal safety is tested
(1) vascular stimulation tests
Study subject: choose the undamaged healthy rabbits of ears and (derive from Third Military Medical University's laboratory animal
Center) 42, it is randomly divided into 7 groups, often group 6, is labeled as test group 1 to test group 7.
Test medicine: the velcalcetide lyophilized injectable powder that embodiment 1 to embodiment 7 prepares.
Test method: Example 1 to embodiment 7 prepares velcalcetide lyophilized injectable powder, often
Individual cillin bottle is separately added into 1mL 5% glucose redissolve, obtain velcalcetide injection standby
With.The left side auricular vein injection velcalcetide injection 1mL, auris dextra injection 1mL of all study subjects
5% glucose injection, every day 1 time, continuously injection 7 days, wherein the study subject note of test group 1
Penetrate velcalcetide injection, examination that the velcalcetide lyophilized injectable powder that embodiment 1 prepares is made
Test what the study subject injection velcalcetide lyophilized injectable powder for preparing of embodiment 2 of group 2 was made
The velcalcetide that velcalcetide injection, the study subject injection embodiment 3 of test group 3 prepare
Velcalcetide injection, the study subject injection embodiment 4 of test group 4 that lyophilized injectable powder is made are made
Velcalcetide injection that the standby velcalcetide lyophilized injectable powder obtained is made, test group 5 tested
The velcalcetide injection that the velcalcetide lyophilized injectable powder that target injection embodiment 5 prepares is made
The velcalcetide lyophilized injectable powder system that liquid, the study subject injection embodiment 6 of test group 6 prepare
The velcalcetide injection, the study subject injection embodiment 7 of test group 7 that become prepare
The velcalcetide injection that velcalcetide lyophilized injectable powder is made.
Detection method and result of the test: during injection, every day, the irritative response of auricular vein was observed in timing.
Within 8th day, put to death rabbit, take bilateral auricular vein and surrounding tissue, fix with formaldehyde, away from injection site
The proximal part being respectively 110cm, 215cm, 315cm makees conventional organization section, and light Microscopic observation has anosis
Reason change.The observation index of blood vessel irritation, standards of grading and criterion are shown in Table 3, and each group is tested
The left ear blood vessel irritation testing result table 4 of object, the auris dextra blood vessel irritation inspection of each group study subject
Survey the results are shown in Table 4.
Table 3 blood vessel irritation observation index, standards of grading and criterion
The blood vessel irritation testing result of each group study subject of table 4
Knowable to table 4 testing result, the evaluation result of the left and right ear of all groups is similar to, and naked eyes are seen
Examine, be showed no the inflammatory reactions such as the congestion of blood vessel, peripheral tissue edema；Tissue slice checks, also has no blood
Tubular construction is abnormal, endothelial injury, thrombosis and other pathological changes.I.e. embodiment 1 to embodiment 7
The zest of the injection that the velcalcetide lyophilized injectable powder prepared is configured to is compared with solvent, poor
Different not notable (P ＞ 0.05), does not the most produce zest, the embodiment of the present invention 1 to embodiment 7 is described
The velcalcetide lyophilized injectable powder prepared is to blood vessel nonirritant.
(2) muscle irritation test
Study subject: take healthy rabbits (deriving from Third Military Medical University's Experimental Animal Center) 42, with
Machine is divided into 7 groups, and often group 6, is labeled as test group 1 to test group 7.
Test medicine: the velcalcetide lyophilized injectable powder that embodiment 1 to embodiment 7 prepares；
Test method: Example 1 to embodiment 7 prepares velcalcetide lyophilized injectable powder, often
The normal saline being separately added into 1mL in individual cillin bottle redissolves, and obtains velcalcetide injection standby.
The left side quadriceps femoris injection velcalcetide injection 1mL of all study subjects, right lateral thigh four-head intramuscular injection
Penetrating the normal saline of 1mL, wherein the study subject injection embodiment 1 of test group 1 prepares
Velcalcetide injection, the study subject of test group 2 that velcalcetide lyophilized injectable powder is made are injected
Velcalcetide injection that the velcalcetide lyophilized injectable powder that embodiment 2 prepares is made, test
The velcalcetide lyophilized injectable powder that the study subject injection embodiment 3 of group 3 prepares is made
The velcalcetide that velcalcetide injection, the study subject injection embodiment 4 of test group 4 prepare
Velcalcetide injection, the study subject injection embodiment 5 of test group 5 that lyophilized injectable powder is made are made
Velcalcetide injection that the standby velcalcetide lyophilized injectable powder obtained is made, test group 6 tested
The velcalcetide injection that the velcalcetide lyophilized injectable powder that target injection embodiment 6 prepares is made
The velcalcetide lyophilized injectable powder system that liquid, the study subject injection embodiment 7 of test group 7 prepare
The velcalcetide injection become.
Detection method and result of the test: after injection, observe injection site muscle with or without hyperemia, and edema etc. is anti-
Should, (the 3rd day) sacrificed by exsanguination after half animal 48h, longitudinally slit skin, perusal both sides are noted
Penetrate position with or without hyperemia, the reaction such as edema, and take its tissue and do pathologic finding.Remaining animal continues to observe
14 days, after the 18th day sacrificed by exsanguination, repeat aforesaid operations.Velcalcetide injection is to muscle irritation
Reaction evaluating standard is shown in Table 5, and within the 3rd day, testing result is shown in Table 6, and the testing result of the 18th day is shown in Table 7.
Table 5 muscle irritation reaction evaluating standard
| Rank | Irritant reaction phenomenon |
| 0 grade | Medicine-feeding part is without significant reaction. |
| 1 grade | Medicine-feeding part mild hyperaemia, diameter is less than 0.15cm. |
| 2 grades | Medicine-feeding part moderate is congested, diameter 0.15～1.0cm. |
| 3 grades | Medicine-feeding part severe is congested, and red and swollen, muscle has degeneration. |
| 4 grades | Muscle brown degeneration occurs, downright bad. |
| 5 grades | Muscle serious degenerative, occurs that large area is downright bad. |
The 3rd day each group study subject muscle irritation reaction detection result of table 6
The 18th day each group study subject muscle irritation reaction detection result of table 7
From table 6, table 7, testing result understands, the injection embodiment of the present invention 1 in quadriceps femoris on the left of rabbit
To the injection that the 7 velcalcetide lyophilized injectable powders prepared are made, perusal injection site
Muscle is without reactions such as hyperemia, edema, and pathologic diagnosis also has no that the explicitly such as tissue degeneratiaon or necrosis stings
Swash reaction, there was no significant difference (P ＞ 0.05) compared with normal saline.Illustrate the embodiment of the present invention 1 to
The velcalcetide lyophilized injectable powder that embodiment 7 prepares does not has zest to muscle, uses safety.
(3) sensitization test (STT) to Cavia porcellus
Study subject: choose healthy guinea pig (deriving from Guangdong Province's Experimental Animal Center) 54, divide at random
Being 9 groups, often group 6, is respectively labeled as negative control group, positive controls, test group 1 to test
Group 7.
Test medicine: test group is the velcalcetide lyophilized powder that embodiment 1 to embodiment 7 prepares
Injection；Negative control group is solvent；Positive controls gives bovine serum albumin (known sensitization positive thing
Matter).
Test method and detection method: Example 1 to embodiment 7 prepares velcalcetide lyophilizing
Injectable powder, each cillin bottle is separately added into 1mL 5% glucose injection redissolve,
Velcalcetide injection is standby.Each group study subject at lumbar injection test medicine, the next day injection 1
Secondary, injection 3 times, are then randomly divided into 2 groups altogether, are administered latter 14 days at the 1st time the most again, and vein is noted
Penetrate test medicine, the allergic symptoms such as observation Cavia porcellus, with or without perpendicular hair, sneeze, is retched, cough, dyspnea,
As two or more symptom occurs, or there is tic, collapse, the one of the phenomena of mortality, it is judged to the positive.
Testing result is shown in Table 8.Wherein the study subject injection embodiment 1 of test group 1 prepares
Velcalcetide injection, the study subject of test group 2 that velcalcetide lyophilized injectable powder is made are injected
Velcalcetide injection that the velcalcetide lyophilized injectable powder that embodiment 2 prepares is made, test
The velcalcetide lyophilized injectable powder that the study subject injection embodiment 3 of group 3 prepares is made
The velcalcetide that velcalcetide injection, the study subject injection embodiment 4 of test group 4 prepare
Velcalcetide injection, the study subject injection embodiment 5 of test group 5 that lyophilized injectable powder is made are made
Velcalcetide injection that the standby velcalcetide lyophilized injectable powder obtained is made, test group 6 tested
The velcalcetide injection that the velcalcetide lyophilized injectable powder that target injection embodiment 6 prepares is made
The velcalcetide lyophilized injectable powder system that liquid, the study subject injection embodiment 7 of test group 7 prepare
The glucose injection of the velcalcetide injection of one-tenth, negative control group injection 5%, positive controls note
Penetrate bovine serum albumin.
Table 8 sensitization test (STT) testing result
| Group | Testing result |
| Test group 1 | Study subject is feminine gender |
| Test group 2 | Study subject is feminine gender |
| Test group 3 | Study subject is feminine gender |
| Test group 4 | Study subject is feminine gender |
| Test group 5 | Study subject is feminine gender |
| Test group 6 | Study subject is feminine gender |
| Test group 7 | Study subject is feminine gender |
| Negative control group | Study subject is feminine gender |
| Positive controls | Study subject is the positive |
Result shows, positive test group Cavia porcellus all creates anaphylaxis and negative control group and test group 1
All movable normal to test group 7 study subject, have no the reactions such as adnormal respiration, i.e. do not have anaphylaxis.
Illustrate that the embodiment of the present invention 1 to embodiment 7 prepares velcalcetide lyophilized injectable powder and do not has Cavia porcellus
Sensitivity response, uses safety.
(4) hemolysis in vitro experiment
Subject material: take rabbit blood, prepares the red blood cell suspension that packed cell volume percentage ratio is 2%:
Preparation method is: take fresh Sanguis Leporis seu oryctolagi 15mL, puts in the conical flask filling bead and shakes 10 minutes,
Remove celloglobulin, make into defibrinated blood.Add normal saline 100mL, shake up, 1500r/min from
The heart 15 minutes, removes supernatant, and the erythrocyte of precipitation washs with normal saline 3 times more as stated above,
Not showing redness to supernatant.Gained erythrocyte normal saline is made into the suspension (erythrocyte of 2%
2mL, adds normal saline to 100mL), it is for experiment.
Test medicine: the velcalcetide lyophilized injectable powder that embodiment 1 to embodiment 7 prepares, often
0.9% sodium chloride injection being separately added into 1mL in individual cillin bottle redissolves, and obtains velcalcetide note
Penetrate liquid.
Test method: test is divided into 7 groups, test group 1 to test group 7 carries out each group respectively
The hemolytic experiment of velcalcetide injection, wherein test group 1 uses embodiment 1 to prepare
Velcalcetide injection, test group 2 that velcalcetide lyophilized injectable powder is made use embodiment 2 to make
Velcalcetide injection, test group 3 that the standby velcalcetide lyophilized injectable powder obtained is made use reality
Execute velcalcetide injection, test group that the velcalcetide lyophilized injectable powder that example 3 prepares is made
4 use velcalcetide injection that the velcalcetide lyophilized injectable powders that prepare of embodiments 4 make,
The velcalcetide that the velcalcetide lyophilized injectable powder that test group 5 uses embodiment 5 to prepare is made
The velcalcetide lyophilized injectable powder that injection, test group 6 use embodiment 6 to prepare is made
Velcalcetide injection, test group 7 use the velcalcetide freeze-dried powder that embodiment 7 prepares
The velcalcetide injection that agent is made.Test operation particularly as follows: each group takes 7, test tube respectively,
It is numbered, then adds various liquid by table 9, each test tube is shaken up gently, put 37 DEG C of waters bath with thermostatic control
In hatch, observe the result of 0.5,1,2,3 hours, record the testing result of each time point.Red carefully
Born of the same parents' agglutination in vitro is shown in Table 10 with the criterion of haemolysis, and the testing result of each group is shown in Table 11.
Table 9 injecting fluid outer hemolytic test sample-adding table
Table 10 erythrocyte agglutination in vitro and the criterion of haemolysis
The testing result of each group of table 11
Note: "--" represents this testing sample and do not occur haemolysis within 3h
Experimental result from table 11 understands, and all group distilled water control tube, i.e. No. 7 test tubes, 0.5
Hour complete hemolysis and there occurs that cell agglutination reacts；And other test tubes did not the most occur molten in 3 hours
Blood phenomenon, the most cell agglutination is not occurred to react.Illustrate that the embodiment of the present invention 1 to embodiment 7 preparation obtains
The velcalcetide lyophilized injectable powder obtained does not produces haemolysis, uses safety.
(5) acute systemic toxicity
Study subject: take healthy mice (deriving from Guangdong Province's Experimental Animal Center) 40, by mice with
Machine is divided into 8 groups, and often group 5, is labeled as matched group, test group 1 to test group 7, is respectively put into fixing
In device.
Test medicine: the velcalcetide lyophilized injectable powder that embodiment 1 to embodiment 7 prepares.
Test method: Example 1 embodiment 7 prepares velcalcetide lyophilized injectable powder, each
The water for injection being separately added into 1mL in cillin bottle redissolves, and obtains velcalcetide injection standby.
Test group 1 to test group 7 is injected into the velcalcetide of the embodiment of the present invention 1 to embodiment 7 preparation respectively
The velcalcetide injection that lyophilized injectable powder is made, matched group injects water for injection, and injection speed is
0.1mL/s, injection dosage is 50mL/kg.Wherein prepared by the study subject injection embodiment 1 of test group 1
Obtain velcalcetide lyophilized injectable powder make velcalcetide injection, test group 2 tested right
The velcalcetide injection made as the injection velcalcetide lyophilized injectable powder for preparing of embodiment 2,
The velcalcetide lyophilized injectable powder that the study subject injection embodiment 3 of test group 3 prepares is made
The velcalcetide that velcalcetide injection, the study subject injection embodiment 4 of test group 4 prepare
Velcalcetide injection, the study subject injection embodiment 5 of test group 5 that lyophilized injectable powder is made are made
Velcalcetide injection that the standby velcalcetide lyophilized injectable powder obtained is made, test group 6 tested
The velcalcetide injection that the velcalcetide lyophilized injectable powder that target injection embodiment 6 prepares is made
The velcalcetide lyophilized injectable powder system that liquid, the study subject injection embodiment 7 of test group 7 prepare
The velcalcetide injection become.
Detection method and result of the test: after injection, observe mice immediate reaction, and in 4h, 24h,
During 48h and 72h, observe respectively and record test group 1 to test group 7, the general state of control animals,
Toxicity performance and dead animal number, finally add up the toxic reaction situation of the study subject of each group.Sentence
Whether disconnected animal occurs the observation index of toxic reaction to be shown in Table 12.The tested 72h of study subject of each group
Testing result afterwards is shown in Table 13.
Table 12 judges the observation index of animal toxic reaction after injecting test medicine
The acute systemic toxicity testing result of the study subject of each group of table 13
From table 13 data understand, within 72 hour observation period, compared with matched group, test group 1 to
The most there is not toxic reaction in the animal subject of experimental group 7, without animal dead, weight is without significant change.
In illustrating that mice is not produced by the velcalcetide lyophilized injectable powder that embodiment 1 embodiment 7 prepares
Poison reaction, uses safety.
In sum, the velcalcetide lyophilizing that the injection embodiment of the present invention 1 to embodiment 7 prepares
The velcalcetide injection that injectable powder is made has good histocompatibility, shows prepared by the present invention
Velcalcetide lyophilized injectable powder steady quality, histocompatibility are good, safety is good, are available for clinical injection
Use.
The above is only the preferred embodiment of the present invention, it is noted that general for the art
For logical technical staff, under the premise without departing from the principles of the invention, it is also possible to make some improvement and profit
Decorations, these improvements and modifications also should be regarded as protection scope of the present invention.
Claims (10)
1. a lyophilized injectable powder, it is characterised in that auxiliary with pharmaceutically acceptable by effective ingredient
Material lyophilization is made；
Described lyophilization includes pre-freeze, evacuation, dry step；
Described pre-freeze includes:
First pre-freeze, the temperature of described first pre-freeze is-36 DEG C～-29 DEG C, during the insulation of described first pre-freeze
Between be 1h～3h；
Second pre-freeze, the temperature of described second pre-freeze is-55 DEG C～-42 DEG C, during the insulation of described second pre-freeze
Between be 1h～2h；
3rd pre-freeze, described 3rd pre-freeze is to be warming up to-10 DEG C～-7 DEG C in 1h-2h, is incubated 1h～2h；
4th pre-freeze, described 4th pre-freeze is that 1h-2h is cooled to-36 DEG C～-29 DEG C, is incubated 1h～3h；
5th pre-freeze, the temperature of described 5th pre-freeze is-55 DEG C～-42 DEG C, during the insulation of described 5th pre-freeze
Between be 1h～3h；
Lyophilized injectable powder the most according to claim 1, it is characterised in that described evacuation gained
Vacuum is 5Pa～30Pa.
Lyophilized injectable powder the most according to claim 1 and 2, it is characterised in that described being dried includes:
First is dried, and the described first temperature being dried be-35 DEG C～-25 DEG C, and the described first dry time was
15h～30h；
Second is dried, and the described second temperature being dried be-20 DEG C～-10 DEG C, and the described second dry time was
10h～20h；
3rd is dried, and the described 3rd temperature being dried be-5 DEG C～5 DEG C, and the described 3rd dry time was
5h～10h；
4th is dried, and the described 4th temperature being dried is to 25 DEG C～40 DEG C, the described 4th time being dried
For 5h～10h.
4. according to the lyophilized injectable powder described in any one of claims 1 to 3, it is characterised in that described medicine
Thing effective ingredient is velcalcetide.
5. according to the lyophilized injectable powder described in any one of Claims 1-4, it is characterised in that described medicine
One during acceptable adjuvant includes excipient, stabilizer, pH adjusting agent or water for injection on or two
Mixture more than person.
6. the preparation method of a lyophilized injectable powder, it is characterised in that take effective ingredient with pharmaceutically
Acceptable adjuvant is freeze-dried, prepares described lyophilized injectable powder；
Described lyophilization includes pre-freeze, evacuation, dry step；
Described pre-freeze includes:
First pre-freeze, the temperature of described first pre-freeze is-36 DEG C～-29 DEG C, during the insulation of described first pre-freeze
Between be 1h～3h；
Second pre-freeze, the temperature of described second pre-freeze is-55 DEG C～-42 DEG C, during the insulation of described second pre-freeze
Between be 1h～2h；
3rd pre-freeze, described 3rd pre-freeze is to be warming up to-10 DEG C～-7 DEG C in 1h-2h, is incubated 1h～2h；
4th pre-freeze, described 4th pre-freeze is that 1h-2h is cooled to-36 DEG C～-29 DEG C, is incubated 1h～3h；
5th pre-freeze, the temperature of described 5th pre-freeze is-55 DEG C～-42 DEG C, during the insulation of described 5th pre-freeze
Between be 1h～3h.
Preparation method the most according to claim 6, it is characterised in that described evacuation gained true
Reciprocal of duty cycle is 5Pa～30Pa.
8. according to the preparation method described in claim 6 or 7, it is characterised in that described being dried includes:
First is dried, and the described first temperature being dried be-35 DEG C～-25 DEG C, and the described first dry time was
15h～30h；
Second is dried, and the described second temperature being dried be-20 DEG C～-10 DEG C, and the described second dry time was
10h～20h；
3rd is dried, and the described 3rd temperature being dried be-5 DEG C～5 DEG C, and the described 3rd dry time was
5h～10h；
4th is dried, and the described 4th temperature being dried is to 25 DEG C～40 DEG C, the described 4th time being dried
For 5h～10h.
9. according to the preparation method described in any one of claim 6 to 8, it is characterised in that described medicine
Effective ingredient is velcalcetide.
10. according to the preparation method described in any one of claim 6 to 9, it is characterised in that described medicine
One during acceptable adjuvant includes excipient, stabilizer, pH adjusting agent or water for injection on or two
Mixture more than person.
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| CN115969034A (en) * | 2022-11-01 | 2023-04-18 | 重庆深山生物科技有限公司 | Oral freeze-dried powder food for diabetic patients and preparation method thereof |
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Application publication date: 20161123 |