CN101664391A - Nelarabine freeze-drying powder needle preparation and preparation method thereof - Google Patents
Nelarabine freeze-drying powder needle preparation and preparation method thereof Download PDFInfo
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- CN101664391A CN101664391A CN200910102210A CN200910102210A CN101664391A CN 101664391 A CN101664391 A CN 101664391A CN 200910102210 A CN200910102210 A CN 200910102210A CN 200910102210 A CN200910102210 A CN 200910102210A CN 101664391 A CN101664391 A CN 101664391A
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Abstract
The invention discloses a nelarabine freeze-drying powder needle preparation for treating T cell acute lymphocytic leukemia and T cell lymphomata and a preparation method thereof. The nelarabine freeze-drying powder needle preparation is prepared from a main medicine and a solution of an excipient which is acceptable in pharmacy by freeze-drying. By the optimization of the preparation and the improvement of the preparation method, the invention overcomes the problems of instability, high requirements for storage, light shielding and the like and inconvenience of the original water needle.
Description
Technical field
The present invention relates to the medicine nelarabine 506u (nelarabine) of a kind of T of treatment cell acute lymphoblastic leukemia and t cell lymphoma, specifically is nelarabine freeze-drying powder needle preparation and preparation method thereof.
Background technology
Nelarabine 506u (nelarabine) is a T cell selective nucleoside analog, is the water-soluble prodrug of 9-β-D-arabinofuranosyl adenin sugar guanine (ara-G).The nelarabine 506u hydro-acupuncture preparation is gone on the market in approval in 2005 by U.S. FDA.We find the hydro-acupuncture preparation and the instability of this kind in the process of research, and all comparatively strict for the requirement of storage, lucifuge.Therefore, all need especially to note in research, clinical use, preservation and when transporting this hydro-acupuncture preparation.
Summary of the invention
The purpose of this invention is to provide the T cell selective nucleoside analog pharmaceutical preparation of a kind of use, convenient transportation and stable performance, it has solved existing T cell selective nucleoside analog medicine and has had the problems such as inconvenience of using, preserving and transport, and stable performance.
Another object of the present invention provides a kind of method for preparing the said medicine preparation, and method is simple for this, and the cycle is short, helps large-scale production.
The inventor stores this suitable pharmaceutical preparation in order to seek stable performance, convenient use and transportation, having done a large amount of deep researchs explores, find by using excipient, the pH value of regulator solution, measures such as employing freeze drying process prepare lyophilized formulations, can solve stability of formulation and problem such as transportation storage etc. effectively, and preparation stabilization, good drug efficacy.
Nelarabine freeze-drying powder needle preparation of the present invention is made after lyophilization by the solution of principal agent nelarabine 506u and pharmaceutically acceptable excipient.Described solution pH value is controlled at 4.0～10.0, and preferred 5.0～7.0.
Described pharmaceutically acceptable excipient is used for the filling bracket effect, makes exsiccant medicine can keep certain volume.We found through experiments, and the material of one or more in mannitol, lactose, sodium chloride, glucose, the glycine is proper as the excipient of nelarabine 506u medicine, and preferred excipient is a mannitol.
Described solution can be to be the solution of solvent with water, can be to be the solution of solvent with the organic solvent, also can be to be the solution of solvent with water and organic solvent.Described organic solvent can be pharmaceutically acceptable organic solvent.
Described solution can comprise pharmaceutically acceptable pH regulator agent, to regulate the pH value of described solution.Described pH regulator agent can be at least a pharmaceutically acceptable material that is used to regulate pH value, it can be one or more the material in alkali compounds, buffer system and the acid, as: sodium hydroxide, hydrochloric acid, acetic acid, phosphoric acid, phosphate buffer, gluconic acid sodium salt, preferred hydrochloric acid and sodium hydroxide.
Nelarabine freeze-drying powder needle preparation of the present invention contains principal agent nelarabine 506u 150mg～250mg, excipient 50～1500mg in every component of unit dose; Preferably contain principal agent nelarabine 506u 200mg, mannitol 100～500mg; More preferably contain principal agent nelarabine 506u 200mg, mannitol 200mg.
The invention provides a kind of method for preparing nelarabine freeze-drying powder needle preparation, comprising:
1) configuration contains the solution of nelarabine 506u and pharmaceutically acceptable excipient, and described solution control pH value is 4.0～10.0, and preferred 5.0～7.0; And
2) lyophilization the 1st) step gained solution.
The invention provides a kind of method for preparing nelarabine freeze-drying powder needle preparation, also can comprise:
1) configuration contains the solution of nelarabine 506u and mannitol, and described solution control pH value is 4.0～10.0, and preferred 5.0～7.0; And
2) lyophilization the 1st) step gained solution.
The described the 1st) in the step, described nelarabine 506u and excipient can be dissolved in water for injection or other solvents separately or together, or described nelarabine 506u adding is contained in the solution of described excipient, or the adding of described excipient contains in the solution of described nelarabine 506u.Described solution can be to be the solution of solvent with water and/or organic solvent.Described organic solvent can be pharmaceutically acceptable organic solvent.
The described the 1st) in the step, can or add before or after adding nelarabine 506u before the excipient, among or afterwards, add aforementioned pharmaceutically acceptable pH regulator agent.
The described the 2nd) before the lyophilization step in step, the described solution that contains nelarabine 506u and excipient can be removed impurity according to conventional method, removes pyrogen, decolouring, filtration sterilization.
The described the 2nd) Bu lyophilization step can be conventional or known freeze drying process step.Described freeze drying process carries out under aseptic condition, can adjust lyophilization cycle according to conventional or known method according to the demand of clinical preparation and concrete production equipment.
Lyophilized formulations of the present invention is soluble in water, and good light durability is arranged, and therefore, dissolving is rapidly fully used easily in use.Preparation of the present invention only needs airtight preservation to get final product, and does not need the airtight preservation of lucifuge, and this provides convenience for the transportation of preparation and storage.Compare with existing like product nelarabine 506u hydro-acupuncture preparation, be easy to store and transportation, long-time placement is more stable, uses more convenient.And preparation method of the present invention is simple and easy to do, helps large-scale production, and is with short production cycle.
The specific embodiment
Embodiment 1～4
Get an amount of nelarabine 506u, mannitol, water for injection, it is dissolved fully.Transfer solution pH value to 5.0, about 5.5,6.0,6.5 with hydrochloric acid, an amount of NaOH, phosphoric acid-sodium dihydrogen phosphate buffer, sodium gluconate solution respectively, obtain every milliliter of solution that contains nelarabine 506u 5mg and mannitol 5mg.Add proper amount of active carbon (according to 0.02,0.5,1,3%g/ml consumption) respectively, stirred 30,25,20,10 minutes down at 25,30,35,55 ℃ respectively, decarbonization filtering, gained filtrate is with the degerming of 0.22 micron microporous filter membrane fine straining.Under aseptic condition gained solution is put in the aseptic cillin bottle, put in the freezer dryer according to the method lyophilization of embodiment 10 after about respectively 22,25,28,30 hours, sterile sealing promptly gets nelarabine freeze-drying powder needle preparation A of the present invention, B, C, D.
Embodiment 5
Get an amount of nelarabine 506u, glucose and lactose, add an amount of water for injection, stirring is dissolved it fully, adds sodium hydroxide solution and transfers solution pH value to 7.0, obtains every milliliter of solution that contains nelarabine 506u 8mg, glucose 6mg, lactose 10mg.Add active carbon according to the consumption of 1%g/ml, stirred 30 minutes down at 30 ℃, decarbonization filtering, gained filtrate is with the degerming of 0.22 micron microporous filter membrane fine straining.Under aseptic condition gained solution is put in the aseptic cillin bottle, put the interior lyophilization of freezer dryer after about 25 hours, sterile sealing promptly gets nelarabine freeze-drying powder needle preparation E of the present invention.
Embodiment 6
Get an amount of nelarabine 506u and mannitol, add an amount of water for injection, stirring is dissolved it fully, adds an amount of sodium hydroxide solution and transfers solution pH value to 7.5, obtains every milliliter of solution that contains nelarabine 506u 10mg and mannitol 12mg.Add active carbon according to the consumption of 2%g/ml, stirred 25 minutes down at 25 ℃, decarbonization filtering, gained filtrate is with the degerming of 0.22 micron microporous filter membrane fine straining.Under aseptic condition gained solution is put in the aseptic cillin bottle, put the interior lyophilization of freezer dryer after about 28 hours, sterile sealing promptly gets nelarabine freeze-drying powder needle preparation F of the present invention.
Embodiment 7
Get an amount of nelarabine 506u, lactose, add an amount of water for injection, stirring is dissolved it fully, adds sodium hydroxide solution and transfers solution pH value to 8.0, obtains every milliliter of solution that contains nelarabine 506u 8mg and lactose 12mg.Add active carbon according to the consumption of 1%g/ml, stirred 30 minutes down at 25 ℃, decarbonization filtering, gained filtrate is with the degerming of 0.22 micron microporous filter membrane fine straining.Under aseptic condition gained solution is put in the aseptic cillin bottle, put the interior lyophilization of freezer dryer after about 30 hours, sterile sealing promptly gets nelarabine freeze-drying powder needle preparation G of the present invention.
Embodiment 8
Get an amount of nelarabine 506u and glycine, add an amount of water for injection, stirring is dissolved it fully, adds appropriate hydrochloric acid solution and transfers solution pH value to 5.5, obtains every milliliter of solution that contains nelarabine 506u 8mg, glycine 15mg.Add active carbon according to the consumption of 1.2%g/ml, stirred 20 minutes down at 25 ℃, decarbonization filtering, gained filtrate is with the degerming of 0.22 micron microporous filter membrane fine straining.Under aseptic condition gained solution is put in the aseptic cillin bottle, put the interior lyophilization of freezer dryer after about 30 hours, sterile sealing promptly gets nelarabine freeze-drying powder needle preparation H of the present invention.
Embodiment 9
Get an amount of nelarabine 506u and sodium chloride, add an amount of water for injection, stirring is dissolved it fully, adds about NaH2PO4 solution regulator solution pH value to 6.5, obtains every milliliter of solution that contains nelarabine 506u 10mg and sodium chloride 20mg.Add active carbon according to the consumption of 3%g/ml, stirred 30 minutes down at 25 ℃, decarbonization filtering, gained filtrate is with the degerming of 0.22 micron microporous filter membrane fine straining.Under aseptic condition gained solution is put in the aseptic cillin bottle, put the interior lyophilization of freezer dryer after about 28 hours, sterile sealing promptly gets nelarabine freeze-drying powder needle preparation I of the present invention.
Embodiment 10
With embodiment 1 to 4 gained solution lyophilization in accordance with the following methods, prepare nelarabine freeze-drying powder needle preparation of the present invention:
Pre-freeze: respectively the temperature in the freeze drying box is reduced in advance about-20 ℃ ,-25 ℃ ,-30 ℃ ,-40 ℃, lyophilizing solution is put into carries out pre-freeze on the freeze drying box internal partition treating of installing of branch.
Sublimation drying: vacuum in the freeze drying box is risen to below the 13.33Pa (0.1mmHg), close fridge.Slowly heat by the heating system under the dividing plate, dividing plate suitably is heated to about 10 ℃, to supply with distillation institute calorific requirement, condenser temperature drops to below-30 ℃, carries out sublimation drying 15,11,13,12 hours.
Dry again: baking temperature is controlled at 15 ℃, 20 ℃, 30 ℃, 10 ℃ respectively, and the plate temperature control overlaps with the plate temperature until products temperature below 30 ℃, promptly reaches exsiccant emphasis.Condenser temperature drops to-33 ℃, dry 11,10,13,15 hours again.
Embodiment 11
The solubility property of the preparation of the present invention that embodiment 1-9 is made is investigated.Preparation A of the present invention, B, C, D, E, F, G, H, I all can dissolve after adding water for injection well, and the clarity of gained solution is qualified.
Embodiment 12
Can investigate the stability of formulation of the present invention that embodiment 1 makes.
(1) stability experiment
Preparation A of the present invention is placed 4000 lux illumination, and 92.5%RH under 60 ℃ the condition, respectively at sampling in 5,10 days, investigates outward appearance, pH value, the variation of loss on drying, clarity of solution and color, related substance and content, and result of the test sees the following form.
By table as seen, preparation of the present invention is stable under these conditions.
(2) damp and hot accelerated tests
Preparation A of the present invention is placed in the exsiccator that contains saturated sodium-chloride water solution, exsiccator places 40 ± 1 ℃ calorstat, respectively at sampling in 0,1,2,3,6 month, observe outward appearance, pH value, loss on drying, clarity of solution and color, measure related substance and content, the results are shown in Table 2.
Table 2: damp and hot accelerated test
The result indicates, preparation of the present invention under 40 ℃, the condition of relative humidity 75%, through 6 months, before the outward appearance of preparation, pH value, loss on drying, related substance and assay result and the experiment with the analysis result basically identical of batch sample.Preparation stabilization of the present invention is described.
Claims (7)
1. nelarabine freeze-drying powder needle preparation, solution by nelarabine 506u and pharmaceutically acceptable excipient makes after lyophilization, it is characterized in that described pharmaceutically acceptable excipient is one or more the material that is selected from mannitol, lactose, sodium chloride, glucose, the glycine; The pH value of described solution is 4.0～10.0.
2. nelarabine freeze-drying powder needle preparation as claimed in claim 1, the pH value that it is characterized in that described solution is 5.0～7.0.
3. nelarabine freeze-drying powder needle preparation as claimed in claim 1 or 2 is characterized in that containing in every component of described nelarabine freeze-drying powder needle preparation principal agent nelarabine 506u 150mg～250mg, excipient 50～1500mg.
4. nelarabine freeze-drying powder needle preparation as claimed in claim 3 is characterized in that containing in every component of described nelarabine freeze-drying powder needle preparation principal agent nelarabine 506u 200mg, mannitol 50～1500mg.
5. nelarabine freeze-drying powder needle preparation as claimed in claim 4 is characterized in that containing in every component of described nelarabine freeze-drying powder needle preparation principal agent nelarabine 506u 200mg, mannitol 200mg.
6. method for preparing nelarabine freeze-drying powder needle preparation comprises:
1) presses preparation prescription batching, get the nelarabine 506u of recipe quantity, the solution of pharmaceutically acceptable excipient, remove impurity, remove thermal source, decolouring, filtration sterilization; And
2) lyophilization the 1st) step gained solution.
7. the method for preparing nelarabine freeze-drying powder needle preparation as claimed in claim 6 is characterized in that: the pH value of described solution is 5.0～7.0; Contain principal agent nelarabine 506u 200mg in every component of described nelarabine freeze-drying powder needle preparation, mannitol 50～1500mg; The described pyrogen of removing is by the 1st) add 0.05%～5% active carbon in the step gains, under 25 ℃～60 ℃, stirred 10～30 minutes, filter decarburization and finish.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN200910102210A CN101664391A (en) | 2009-09-08 | 2009-09-08 | Nelarabine freeze-drying powder needle preparation and preparation method thereof |
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| Application Number | Priority Date | Filing Date | Title |
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| CN200910102210A CN101664391A (en) | 2009-09-08 | 2009-09-08 | Nelarabine freeze-drying powder needle preparation and preparation method thereof |
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| CN101664391A true CN101664391A (en) | 2010-03-10 |
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| CN200910102210A Pending CN101664391A (en) | 2009-09-08 | 2009-09-08 | Nelarabine freeze-drying powder needle preparation and preparation method thereof |
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2009
- 2009-09-08 CN CN200910102210A patent/CN101664391A/en active Pending
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Application publication date: 20100310 |