CN1305478C - Freeze drying preparation of amifostine, and preparation method - Google Patents
Freeze drying preparation of amifostine, and preparation method Download PDFInfo
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- CN1305478C CN1305478C CNB200410037763XA CN200410037763A CN1305478C CN 1305478 C CN1305478 C CN 1305478C CN B200410037763X A CNB200410037763X A CN B200410037763XA CN 200410037763 A CN200410037763 A CN 200410037763A CN 1305478 C CN1305478 C CN 1305478C
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- 238000002360 preparation method Methods 0.000 title claims abstract description 48
- 229960001097 amifostine Drugs 0.000 title claims abstract description 47
- JKOQGQFVAUAYPM-UHFFFAOYSA-N amifostine Chemical compound NCCCNCCSP(O)(O)=O JKOQGQFVAUAYPM-UHFFFAOYSA-N 0.000 title claims abstract 11
- 238000004108 freeze drying Methods 0.000 title claims description 19
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 claims abstract description 30
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims abstract description 26
- 238000001035 drying Methods 0.000 claims abstract description 25
- 238000000034 method Methods 0.000 claims abstract description 23
- 239000000546 pharmaceutical excipient Substances 0.000 claims abstract description 17
- 238000000859 sublimation Methods 0.000 claims abstract description 14
- 230000008022 sublimation Effects 0.000 claims abstract description 14
- 239000000243 solution Substances 0.000 claims description 44
- 239000000203 mixture Substances 0.000 claims description 19
- 238000009472 formulation Methods 0.000 claims description 17
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 claims description 11
- 239000003814 drug Substances 0.000 claims description 10
- 238000001914 filtration Methods 0.000 claims description 9
- FBPFZTCFMRRESA-KVTDHHQDSA-N D-Mannitol Chemical group OC[C@@H](O)[C@@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-KVTDHHQDSA-N 0.000 claims description 7
- 229930195725 Mannitol Natural products 0.000 claims description 7
- 238000002425 crystallisation Methods 0.000 claims description 7
- 230000008025 crystallization Effects 0.000 claims description 7
- 239000000594 mannitol Substances 0.000 claims description 7
- 235000010355 mannitol Nutrition 0.000 claims description 7
- DHMQDGOQFOQNFH-UHFFFAOYSA-N Glycine Chemical compound NCC(O)=O DHMQDGOQFOQNFH-UHFFFAOYSA-N 0.000 claims description 4
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 claims description 4
- 238000010438 heat treatment Methods 0.000 claims description 4
- 238000005057 refrigeration Methods 0.000 claims description 4
- 230000001954 sterilising effect Effects 0.000 claims description 4
- 238000004659 sterilization and disinfection Methods 0.000 claims description 4
- WQZGKKKJIJFFOK-GASJEMHNSA-N Glucose Natural products OC[C@H]1OC(O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-GASJEMHNSA-N 0.000 claims description 3
- GUBGYTABKSRVRQ-QKKXKWKRSA-N Lactose Natural products OC[C@H]1O[C@@H](O[C@H]2[C@H](O)[C@@H](O)C(O)O[C@@H]2CO)[C@H](O)[C@@H](O)[C@H]1O GUBGYTABKSRVRQ-QKKXKWKRSA-N 0.000 claims description 3
- 239000005924 Pirimiphos-methyl Substances 0.000 claims description 3
- 239000007864 aqueous solution Substances 0.000 claims description 3
- 239000008101 lactose Substances 0.000 claims description 3
- QHOQHJPRIBSPCY-UHFFFAOYSA-N pirimiphos-methyl Chemical group CCN(CC)C1=NC(C)=CC(OP(=S)(OC)OC)=N1 QHOQHJPRIBSPCY-UHFFFAOYSA-N 0.000 claims description 3
- 239000002510 pyrogen Substances 0.000 claims description 3
- GUBGYTABKSRVRQ-XLOQQCSPSA-N Alpha-Lactose Chemical compound O[C@@H]1[C@@H](O)[C@@H](O)[C@@H](CO)O[C@H]1O[C@@H]1[C@@H](CO)O[C@H](O)[C@H](O)[C@H]1O GUBGYTABKSRVRQ-XLOQQCSPSA-N 0.000 claims description 2
- 239000004471 Glycine Substances 0.000 claims description 2
- WQZGKKKJIJFFOK-VFUOTHLCSA-N beta-D-glucose Chemical compound OC[C@H]1O[C@@H](O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-VFUOTHLCSA-N 0.000 claims description 2
- 239000008103 glucose Substances 0.000 claims description 2
- 230000000630 rising effect Effects 0.000 claims description 2
- 239000011780 sodium chloride Substances 0.000 claims description 2
- 238000003860 storage Methods 0.000 abstract description 5
- 238000011031 large-scale manufacturing process Methods 0.000 abstract description 3
- 239000013078 crystal Substances 0.000 abstract 3
- TXQPXJKRNHJWAX-UHFFFAOYSA-N 2-(3-aminopropylamino)ethylsulfanylphosphonic acid;trihydrate Chemical compound O.O.O.NCCCNCCSP(O)(O)=O TXQPXJKRNHJWAX-UHFFFAOYSA-N 0.000 description 36
- 238000005352 clarification Methods 0.000 description 15
- 238000003756 stirring Methods 0.000 description 5
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 4
- 238000002347 injection Methods 0.000 description 4
- 229940090044 injection Drugs 0.000 description 4
- 239000007924 injection Substances 0.000 description 4
- 239000000843 powder Substances 0.000 description 4
- 239000008215 water for injection Substances 0.000 description 4
- 229910052799 carbon Inorganic materials 0.000 description 3
- 238000005262 decarbonization Methods 0.000 description 3
- 230000000694 effects Effects 0.000 description 3
- 239000000825 pharmaceutical preparation Substances 0.000 description 3
- 239000000047 product Substances 0.000 description 3
- 239000002904 solvent Substances 0.000 description 3
- 239000000126 substance Substances 0.000 description 3
- JGSARLDLIJGVTE-UHFFFAOYSA-N 3,3-dimethyl-7-oxo-6-[(2-phenylacetyl)amino]-4-thia-1-azabicyclo[3.2.0]heptane-2-carboxylic acid Chemical compound O=C1N2C(C(O)=O)C(C)(C)SC2C1NC(=O)CC1=CC=CC=C1 JGSARLDLIJGVTE-UHFFFAOYSA-N 0.000 description 2
- 239000002671 adjuvant Substances 0.000 description 2
- 229940035676 analgesics Drugs 0.000 description 2
- 239000000730 antalgic agent Substances 0.000 description 2
- 239000000872 buffer Substances 0.000 description 2
- 239000003795 chemical substances by application Substances 0.000 description 2
- 238000002512 chemotherapy Methods 0.000 description 2
- 231100000135 cytotoxicity Toxicity 0.000 description 2
- 230000003013 cytotoxicity Effects 0.000 description 2
- 238000002474 experimental method Methods 0.000 description 2
- 239000000706 filtrate Substances 0.000 description 2
- 238000007710 freezing Methods 0.000 description 2
- 230000008014 freezing Effects 0.000 description 2
- 229940041476 lactose 100 mg Drugs 0.000 description 2
- 238000004519 manufacturing process Methods 0.000 description 2
- 239000000463 material Substances 0.000 description 2
- 239000012982 microporous membrane Substances 0.000 description 2
- 238000001959 radiotherapy Methods 0.000 description 2
- 238000007789 sealing Methods 0.000 description 2
- 239000003381 stabilizer Substances 0.000 description 2
- 238000012360 testing method Methods 0.000 description 2
- 238000011282 treatment Methods 0.000 description 2
- 150000004684 trihydrates Chemical class 0.000 description 2
- XEEYBQQBJWHFJM-UHFFFAOYSA-N Iron Chemical compound [Fe] XEEYBQQBJWHFJM-UHFFFAOYSA-N 0.000 description 1
- 206010028980 Neoplasm Diseases 0.000 description 1
- 239000002253 acid Substances 0.000 description 1
- 230000001476 alcoholic effect Effects 0.000 description 1
- -1 alkylthio phosphate compounds Chemical class 0.000 description 1
- 229910021529 ammonia Inorganic materials 0.000 description 1
- 239000002246 antineoplastic agent Substances 0.000 description 1
- 229940041181 antineoplastic drug Drugs 0.000 description 1
- 210000004027 cell Anatomy 0.000 description 1
- 239000003610 charcoal Substances 0.000 description 1
- 239000002131 composite material Substances 0.000 description 1
- 238000007796 conventional method Methods 0.000 description 1
- 230000007812 deficiency Effects 0.000 description 1
- 238000005516 engineering process Methods 0.000 description 1
- 238000011049 filling Methods 0.000 description 1
- 239000012467 final product Substances 0.000 description 1
- 229940093181 glucose injection Drugs 0.000 description 1
- 229940086720 glycine 180 mg Drugs 0.000 description 1
- 210000002216 heart Anatomy 0.000 description 1
- 210000003958 hematopoietic stem cell Anatomy 0.000 description 1
- 230000008676 import Effects 0.000 description 1
- 239000012535 impurity Substances 0.000 description 1
- 210000003734 kidney Anatomy 0.000 description 1
- 210000004185 liver Anatomy 0.000 description 1
- 239000012528 membrane Substances 0.000 description 1
- 229910021645 metal ion Inorganic materials 0.000 description 1
- 230000001537 neural effect Effects 0.000 description 1
- 238000004806 packaging method and process Methods 0.000 description 1
- 239000002245 particle Substances 0.000 description 1
- 238000005498 polishing Methods 0.000 description 1
- 238000004321 preservation Methods 0.000 description 1
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 1
- 239000003223 protective agent Substances 0.000 description 1
- 230000001681 protective effect Effects 0.000 description 1
- 238000001953 recrystallisation Methods 0.000 description 1
- 238000011160 research Methods 0.000 description 1
- 238000005070 sampling Methods 0.000 description 1
- 239000008354 sodium chloride injection Substances 0.000 description 1
- 238000005728 strengthening Methods 0.000 description 1
- 238000011287 therapeutic dose Methods 0.000 description 1
- 230000001225 therapeutic effect Effects 0.000 description 1
- 238000002560 therapeutic procedure Methods 0.000 description 1
- 231100000331 toxic Toxicity 0.000 description 1
- 230000002588 toxic effect Effects 0.000 description 1
- 238000001291 vacuum drying Methods 0.000 description 1
Landscapes
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Medicinal Preparation (AREA)
Abstract
The present invention discloses an amifostine medical preparation and a preparing method thereof. The amifostine freeze-dried preparation of the present invention is made by solutions containing amifostine, acetone and acceptable excipient in pharmacy through a prefreezing step, a sublimation drying step, a drying step, etc. The preparation of the present invention contains crystal amifostine which comprises crystal water from 1 to 3 mol, preferably 3 mol of crystal water. The preparation of the present invention has the advantages of stable performance, easy transportation and storage, and simple and practical method, and is helpful for large-scale production.
Description
Technical field
The present invention belongs to field of pharmaceutical preparations, specifically, relates to a kind of amifostine lyophilized formulations and preparation method thereof.
Background technology
Amifostine is alkylthio phosphate compounds (D2EHDTPA dihydro S-2-(3-ammonia third an amino) second fat); it is a kind of broad-spectrum selecting cell protective agent; main effect is the protection hematopoietic stem cell; red white corpuscle, platelet are all had obvious protective effect, and can alleviate put, chemotherapy is to Liver and kidney, heart, neural toxic and side effects.Mainly be adapted to the auxiliary treatment of tumor radiotherapy or cytotoxicity chemotherapy, amifostine and radiotherapy or cytotoxicity antitumor drug share on the other hand, can strengthen the toleration of patient, help strengthening therapeutic dose and shorten the treatment dead time, thereby improve therapeutic effect antineoplaston.
The aqueous solution of amifostine or unstable under desiccation, the lyophilized formulations of traditional amorphous form that passes through lyophilization production is heat-labile, but not no matter freeze-dried formulation adopts crystallization still is polishing production, all be difficult to guarantee the particle size of amifostine, cause the exact dose packaging difficulties involved.Chinese patent 93117436.8 discloses the C that freezing and crystallizing contains amifostine
1～C
5The solution of alcohol and water, vacuum drying method prepare stable crystallized pirimiphos-methyl composite.Though the disclosed use of this method contains C
1～C
5The solution of alcohol and water is solvent, and freezing and exsiccant temperature range is very wide, but has only the embodiment of ethanol as solvent among the embodiment.Though aforementioned patent discloses a kind of method for preparing the stable crystalline amifostine, because the market amount of seeking of amifostine is very big, people still need to occur how better preparation method and prepare stable amifostine.
Summary of the invention
In order to overcome the deficiency of prior art, the object of the present invention is to provide a kind of pharmaceutical preparation of amifostine, its stable performance is easy to transportation and storage.
Another object of the present invention is to provide a kind of method for preparing the said medicine preparation, and method is simple for this, helps large-scale production.
The inventor is in order to seek the appropriate formulation of stable performance, convenient transportation storage, and the stability problem of solution preparation process Chinese medicine, having done a large amount of deep researchs explores, find by using recrystallisation solvent and excipient, measures such as employing freeze drying process prepare lyophilized formulations, can solve problems such as stability of formulation and transportation storage effectively.
The invention provides a kind of amifostine lyophilized formulations, it is made after lyophilization by the solution that contains amifostine, acetone and pharmaceutically acceptable excipient.
Described amifostine is amifostine or its hydrate conventional according to this area or that known method is made.
Described pharmaceutically acceptable excipient is to be generally used for preparing lyophilized formulations, get the filling bracket effect, make exsiccant medicine can keep the material of certain volume, for example: mannitol, glycine, lactose, sodium chloride, glucose or other pharmaceutically acceptable excipient or their mixture, preferred mannitol.
The amount that can contain amifostine in the described solution is that the described solution of every ml contains 50～300mg amifostine, preferred 125～250mg.The consumption of described excipient is to prepare the used conventional amount used of lyophilized formulations usually, also can be every milliliter of described solution with 5～300 milligrams, preferred 50～150 milligrams excipient.The consumption of described acetone can be that every milliliter of described solution contains 3～30% (percents by volume), preferred 8～15% (percents by volume).The consumption of described water can be that described solution contains 70～97% (percents by volume), preferred 85～92% (percents by volume).
The material that also can further comprise one or more in the acceptable adjuvant on the conventional pharmaceutical such as stabilizing agent, analgesics and buffer agent in the amifostine pharmaceutical preparation of the present invention.
A kind of amifostine lyophilized formulations provided by the invention can be made after lyophilization by the solution that contains (1) amifostine, (2) acetone and (3) mannitol; Every ml of formulation contains 50～300 milligrams of amifostines in the described solution, preferred 50～150 milligrams; Described acetone consumption is for being that every ml soln contains 3～30% (percents by volume), preferred 8～15% (percents by volume); The consumption of described mannitol be every milliliter of described solution with 5～300 milligrams, preferred 50～150 milligrams.
Contain crystallized pirimiphos-methyl in the amifostine lyophilized formulations of the present invention, it can contain 1 mole to 3 moles water of crystallization, preferably contains 3 moles of water of crystallization, i.e. the trihydrate of amifostine.
The invention provides a kind of method for preparing the amifostine medicament freeze-drying preparation, comprising: (1) preparation contains the solution of amifostine: preparation contains the acetone of amifostine and pharmaceutically acceptable excipient and the solution of water; (2) pre-freeze: (1) step gained solution is carried out pre-freeze under-35 ℃ of following temperature; (3) sublimation drying: with the sublimation drying that carries out of (2) step gains; And (4) are dry again: dry again (3) step gains under-20 ℃～15 ℃ temperature.
In described (1) step, acceptable adjuvant on the conventional pharmaceutical can be added, for example: stabilizing agent, analgesics and/or buffer agent etc. in gained solution.
Before the pre-freeze step in described (2) step, the described solution of (1) step gained can be removed impurity according to conventional method, removes pyrogen, decolouring, filtration sterilization.
Described (2) to (4) step can be conventional or known pre-freeze, sublimation drying, drying process step again.Can adopt this area routine or known equipment under aseptic condition, carry out.
The invention provides a kind of method for preparing the amifostine medicament freeze-drying preparation, can may further comprise the steps:
(1) preparation contains the acetone of amifostine and pharmaceutically acceptable excipient and the solution of water;
(2) (1) step gained solution activated carbon decolorizings are removed pyrogen, filtration sterilization;
(3) pre-freeze: (2) step gained solution is carried out pre-freeze, when the gained solution temperature is reduced to below-35 ℃, stop refrigeration, begin to heat up, when temperature reaches-5 ℃～5 ℃, stop to heat up, kept 2～10 hours, and then it was carried out freezingly, temperature is reduced to below-35 ℃;
(4) sublimation drying: vacuum in the freeze drying box of (3) step gains is risen to below the 20Pa, and slowly heating makes the medicine temperature from slowly rising to-20 ℃ below-35 ℃, carries out sublimation drying;
(5) dry again: with (4) step gains keep temperature be-20 ℃～15 ℃ to gained preparation drying.
In described (2) step, described activated carbon dosage can be 0.05%～5%, preferred 0.1%～2%.After adding active carbon, can stir filtering decarbonization 10～30 minutes down at 25 ℃～30 ℃.Described filtration sterilization can be with 0.22 μ m filtering with microporous membrane.
Described when (4) step, the sublimation drying step preferably reached-40 ℃ in temperature, vacuum in the freeze drying box is risen to below the 20Pa, slowly heating makes the medicine temperature slowly rise to-20 ℃ from-35 ℃, carries out sublimation drying 25～30 hours.
Described (5) step drying steps again in freeze drying box inner control flaggy temperature at-20 ℃～15 ℃, kept 10～15 hours.What obtain as hope is the product of three water of crystallization, preferably keeps 10～15 hours down at-5 ℃～5 ℃.
Should avoid the contact such as metal ions such as ferrum in the process of preparation preparation of the present invention, it might influence the color of preparation, and medicament contg is descended.
Freeze-dried powder preparation of the present invention can be dissolved in water for injection or other injection to lyophilized formulations before using.Described injection can be conventional injection, as is used for the isotonic water medium of venoclysis, for example 5% glucose injection or 0.9% sodium chloride injection.According to therapeutic process and patient's situation, use that the consumption of freeze-dried powder preparation of the present invention is general is advisable at about 250～750mg with use amount at every turn.
Lyophilized formulations stable performance of the present invention, dissolving is abundant, easy to use rapidly in use.Preparation of the present invention only needs airtight preservation to get final product, and this provides convenience for the transportation of preparation and storage.And preparation method of the present invention is simple and easy to do, helps large-scale production, and the crystallize situation of amifostine of using the same concentration of method of the present invention is than good in containing of prior art alcoholic acid aqueous solution.
The specific embodiment
Below will the invention will be further described by embodiment, these descriptions are not that content of the present invention is done further to limit.One skilled in the art will understand that to be equal to replacement to what technical characterictic of the present invention was done, or corresponding the improvement, still belong within protection scope of the present invention.
Embodiment 1
Get the commercially available amifostine of 250.0g (trihydrate), add 1150ml water for injection, stir and make dissolving fully.Stir the acetone that slowly in solution, drips 200.0ml down, this moment, solution was clear liquor, added the injection water and stirred the needle-use activated carbon of adding 0.1% down to 2000.0ml, and 25 ℃ kept 30 minutes, take off charcoal and filter, subsequent filtrate is extremely clear and bright by 0.22 μ m filtering with microporous membrane.Fill is in the cillin bottle of aseptic process, and every bottle of 2.0ml puts the interior method lyophilization according to embodiment 7 of freezer dryer, and sterile sealing promptly gets preparation A of the present invention.
Embodiment 2
Method according to embodiment 1 prepares preparation B of the present invention, has just also added 100.0g mannitol (the clean brilliant group in Shandong) in containing the solution of amifostine, according to the method lyophilization of embodiment 7.
Embodiment 3-5
Method according to embodiment 2 prepares formulation C of the present invention, D, E, be that every ml soln contains amifostine 60mg, 150mg, 280mg respectively, acetone 0.075ml, 0.1ml, 0.15ml, and do not contain excipient, contain lactose 100mg, contain glycine 180mg, and add active carbon according to the consumption of 0.06%, 0.5%, 2.5% (g/ml) respectively, stirred 30,20,10 minutes down at 20,25,30 ℃ respectively, decarbonization filtering is according to the method lyophilization of embodiment 7.
Embodiment 6
Get an amount of amifostine, add an amount of water for injection (total amount 65%), stirring is dissolved it fully, stirs down and slowly splashes into acetone, and solution is clear liquor, add lactose (import), obtain every milliliter of solution that contains amifostine 200mg, 0.1 milliliter in acetone and lactose 100mg.Add active carbon according to the consumption of 1% (g/ml), 30 ℃ were stirred 30 minutes down, decarbonization filtering, and gained filtrate is with 0.22 μ m microporous filter membrane fine straining degerming.Under aseptic condition gained solution is put in the aseptic cillin bottle, put the interior lyophilization of freezer dryer after about respectively 50 hours, sterile sealing promptly gets amifostine of the present invention and freezes thousand powder preparation F.
Embodiment 7
With embodiment 1 to 5 gained solution lyophilization in accordance with the following methods, prepare amifostine freeze-dried powder preparation of the present invention:
Pre-freeze: just embodiment 1 to 5 gained solution is put on the dividing plate of freeze drying box and is carried out pre-freeze, when treating that products temperature is reduced to below-35 ℃ by room temperature, stop refrigeration, begin to heat up, when its temperature reaches-5 ℃, stop to heat up, under this temperature, kept 8,7,3,5,10 hours, and then carry out freezingly, cool the temperature to below-35 ℃.
Sublimation drying: when the open cold condenser reaches-40 ℃, open vacuum pump (it is following that vacuum reaches 20Pa) and slowly heat, make temperature slowly rise to-20 ℃ from-35 ℃ by the heating system under the dividing plate.Carried out sublimation drying 26,28,30,30,25 hours.
Dry again: as the plate temperature to be controlled at-15 ℃ ,-10 ℃ ,-20 ℃, 0 ℃, 10 ℃ respectively, to keep 10,12,13,15,12 hours.
Embodiment 8
To the difference of the preparation of the present invention of embodiment 1 preparation drying condition again, experimentize, the result shows that different conditions can cause the preparation of the present invention of different water of crystallization.Experimental result sees the following form:
The different lyophilisation conditions of table 1 are to the influence of product
| Lyophilisation condition | Baking temperature＜-20 ℃ again | Baking temperature＞15 ℃ again | Baking temperature-5 ℃～5 ℃ again |
| The result | Water content＞30% | Water content＜10% | Water content 18～21% |
Experiment shows that for obtaining containing the hydrate of three water of crystallization, the temperature range of drying stage is-20 ℃～15 ℃ again, preferred-5～5 ℃ of the bests.
Embodiment 9
The solubility property of the preparation of the present invention that embodiment 1-6 is made is investigated.Preparation A of the present invention, B, C, D, E, F all can dissolve after adding water for injection well, and the clarity of gained solution is all qualified.
Embodiment 10 stability experiments
Preparation A of the present invention, B, C are placed under the condition of 25 ℃ of room temperatures, 60%RH, respectively at 3,6,9, the December sampling, investigate the variation equistability energy of outward appearance, pH value, loss on drying, clarity of solution and color, related substance and content, result of the test sees the following form.
Table 2: the test of preparation stability of the present invention
| Project | Preparation | Time | ||||
| 0 month | March | June | JIUYUE | December | ||
| Outward appearance | A B C | The block white blocks shape white of white is block | The block white blocks shape white of white is block | The block white blocks shape white of white is block | The block white blocks shape white of white is block | The block white blocks shape white of white is block |
| PH value | A B C | 7.24 7.26 7.22 | 7.23 7.26 7.23 | 7.23 7.25 7.23 | 7.22 7.26 7.21 | 7.22 7.26 7.22 |
| Clarity of solution and color | A B C | Clarification achromaticity and clarification achromaticity and clarification is colourless | Clarification achromaticity and clarification achromaticity and clarification is colourless | Clarification achromaticity and clarification achromaticity and clarification is colourless | Clarification achromaticity and clarification achromaticity and clarification is colourless | Clarification achromaticity and clarification achromaticity and clarification is colourless |
| Loss on drying (%) | A B C | 18.33 18.41 18.37 | 18.34 18.43 18.38 | 18.35 18.42 18.38 | 18.36 18.43 18.39 | 18.35 18.42 18.39 |
| Amifostine content (%) | A B C | 100.32 100.54 100.59 | 100.30 100.53 100.58 | 100.28 100.51 100.58 | 100.28 100.51 100.55 | 100.25 100.49 100.55 |
| Its related substances (%) | A B C | 0.385 0.387 0.381 | 0.384 0.392 0.387 | 0.385 0.396 0.393 | 0.388 0.402 0.397 | 0.389 0.404 0.398 |
Preparation of the present invention kept sample 12 months in room temperature, and its outward appearance, pH value, loss on drying, clarity of solution and color, related substance, Determination on content result all do not change.
Above-mentioned experimental result shows that preparation of the present invention is very stable.
Claims (6)
1. amifostine lyophilized formulations, it is characterized in that it being that method by may further comprise the steps makes: (1) preparation contains the acetone of amifostine and pharmaceutically acceptable excipient and the solution of water; (2) pre-freeze: when (1) step, the gained solution temperature was reduced to below-35 ℃, stop refrigeration, begin to heat up, when temperature reaches-5 ℃～5 ℃, stop to heat up, kept 2～10 hours, then it is carried out freezingly, temperature is reduced to below-35 ℃; (3) sublimation drying: (2) step gains are carried out sublimation drying; And (4) are dry again: dry again (3) step gains promptly get described preparation under-10 ℃～15 ℃ temperature.
2. preparation according to claim 1 is characterized in that described excipient is mannitol, glycine, lactose, sodium chloride, glucose or other pharmaceutically acceptable excipient or their mixture; Described solution is aqueous solution; Contain amifostine 50～300mg/ml in the described solution, described excipient 5～300mg/ml, every milliliter of described solution of the consumption of described acetone contains 3～30% (percents by volume), and the consumption of described water can be that described solution contains 70～97% (percents by volume); Crystallized pirimiphos-methyl described in the described preparation contains 1 mole to 3 moles water of crystallization.
3. preparation according to claim 2 is characterized in that containing in the described solution amifostine 125～250mg/ml, described excipient 50～150mg/ml, described acetone 8～15% (percent by volume), described water 85～92% (percent by volume).
4. according to any one described preparation in the claim 1 to 3, it is characterized in that described excipient is a mannitol.
5. method for preparing the amifostine medicament freeze-drying preparation may further comprise the steps:
(1) preparation contains the acetone of amifostine and pharmaceutically acceptable excipient and the solution of water;
(2) (1) step gained solution activated carbon decolorizings are removed pyrogen, filtration sterilization;
(3) pre-freeze: (2) step gained solution is carried out pre-freeze, when the gained solution temperature is reduced to below-35 ℃, stop refrigeration, begin to heat up, when temperature reaches-5 ℃～5 ℃, stop to heat up, kept 2～10 hours, and then it was carried out freezingly, temperature is reduced to below-35 ℃;
(4) sublimation drying: the vacuum around (3) the step gains is reduced to below the 20Pa, and slowly heating makes the medicine temperature from slowly rising to-20 ℃ below-35 ℃, carries out sublimation drying;
(5) dry again: with (4) step gains keep temperature be-10 ℃～15 ℃ to gained preparation drying.
6. method according to claim 5 is characterized in that described drying steps again kept 10～15 hours down at-5 ℃～5 ℃.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CNB200410037763XA CN1305478C (en) | 2004-05-12 | 2004-05-12 | Freeze drying preparation of amifostine, and preparation method |
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| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CNB200410037763XA CN1305478C (en) | 2004-05-12 | 2004-05-12 | Freeze drying preparation of amifostine, and preparation method |
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| Publication Number | Publication Date |
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| CN1695626A CN1695626A (en) | 2005-11-16 |
| CN1305478C true CN1305478C (en) | 2007-03-21 |
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| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CNB200410037763XA Expired - Lifetime CN1305478C (en) | 2004-05-12 | 2004-05-12 | Freeze drying preparation of amifostine, and preparation method |
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| Country | Link |
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| CN (1) | CN1305478C (en) |
Families Citing this family (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101347412B (en) * | 2008-09-02 | 2011-07-27 | 大连美罗药业股份有限公司 | Amifostine trihydrate crystal lyophilized preparation and method of preparing the same |
| BR112018000054A2 (en) * | 2015-07-02 | 2018-09-04 | Otsuka Pharmaceutical Co., Ltd. | lyophilized pharmaceutical compositions |
Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1070370C (en) * | 1992-07-31 | 2001-09-05 | 美国生物科学有限公司 | Crystalline amifostine compositions and mthods for the preparation and use of same |
-
2004
- 2004-05-12 CN CNB200410037763XA patent/CN1305478C/en not_active Expired - Lifetime
Patent Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1070370C (en) * | 1992-07-31 | 2001-09-05 | 美国生物科学有限公司 | Crystalline amifostine compositions and mthods for the preparation and use of same |
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| Publication number | Publication date |
|---|---|
| CN1695626A (en) | 2005-11-16 |
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