CN107260690A - Lyophilized formulations of Decitabine and preparation method thereof - Google Patents
Lyophilized formulations of Decitabine and preparation method thereof Download PDFInfo
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
- A61K9/19—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles lyophilised, i.e. freeze-dried, solutions or dispersions
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/70—Carbohydrates; Sugars; Derivatives thereof
- A61K31/7042—Compounds having saccharide radicals and heterocyclic rings
- A61K31/7052—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides
- A61K31/706—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/02—Inorganic compounds
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
- A61K47/26—Carbohydrates, e.g. sugar alcohols, amino sugars, nucleic acids, mono-, di- or oligo-saccharides; Derivatives thereof, e.g. polysorbates, sorbitan fatty acid esters or glycyrrhizin
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/0012—Galenical forms characterised by the site of application
- A61K9/0019—Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner
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Abstract
The present invention relates to a kind of lyophilized formulations of Decitabine and preparation method thereof.Lyophilized formulations of the present invention include Decitabine, meglumine, potassium dihydrogen phosphate and sodium hydroxide, substantially increase the stability of Decitabine, and present invention process is simple and easy to apply, are adapted to industrialized production.
Description
Technical field
The invention belongs to field of medicine preparations, and in particular to a kind of containing the pharmaceutical composition of Decitabine and its preparation side
Method.
Background technology
Decitabine is a kind of analogue of cytosine, is belonged to after dnmt rna inhibitor, phosphorylation directly and DNA
With reference to dnmt rna is suppressed, cause DNA hypomethylations and cell differentiation apoptosis.
Because Decitabine is extremely unstable in aqueous, the hydrone in aqueous environment is to the miscellaneous nitrogen cytosine rings of its 5-
Carry out nucleophillic attack so that 5- is miscellaneous, and nitrogen cytosine ring is broken, and is degraded to its inactive isomer of α types.Therefore, by normal
Rule, which are made solvent of water and can not prepared, stablizes qualified lyophilized formulations.
In order to improve stability of solution, existing known technology proposes the technical scheme of a variety of solution problems, use more
First Decitabine is dissolved using organic solvent, then the preparation technology with the miscible formation preparation aqueous solution of water, utilize this preparation work
Skill, which prepares decitabine freeze-dried preparation, can bring many problems and potential safety hazard.The introducing of organic solvent first can be caused into
Contain more organic solvent residual in product preparation, and organic solvent is very big to human toxicity, can cause a series of body poison
Property；Secondly, contain organic solvent in lyophilized preceding formulation soln, larger infringement can be caused to freeze-drier, and in freeze-drying process
In main ingredient can be caused to be taken out of with organic solvent, influence pharmaceutical preparation mouldability.
The patents such as Chinese patent CN101361718, CN102106831, CN10231922 are frozen there is provided a variety of Decitabines
Technique prepared by dry preparation, but has used organic solvent, and consumption is from 0.3~4.0% to 5~80%, organic solvent
Use bring great side effect and body to poison to human body, be unsuitable for clinical safety and use.Chinese patent
CN101623267 provides a kind of Decitabine and the aseptic powdery of other auxiliary material direct packagings, but is due to Decitabine in water
Middle dissolving is difficult, can not be dissolved in time during Clinical practice, causes using difficulty.
Chinese patent CN101637458 is adjusted to suitable pH by pH adjusting agent there is provided a kind of, and controls suitably
Freeze temperature, improves preparation technology of the Decitabine in preparation stability.Chinese patent CN102688199 passes through in extremely low temperature
Under the conditions of the relevant material of control Decitabine increase.Temperature control proposes higher requirement to production operation and personnel, increase
The risk of technique.In addition, solubility of the Decitabine in water is smaller, too low temperature is less useful for the dissolving of Decitabine.
The content of the invention
To solve the above problems, the present invention is intended to provide a kind of decitabine freeze-dried preparation of unused organic solvent, and
And process for preparation, without temperature control, technique is simple, it is easy to operate.
The present invention provides a kind of decitabine freeze-dried preparation of stabilization, including Decitabine, meglumine, potassium dihydrogen phosphate and
Sodium hydroxide.
According to the decitabine freeze-dried preparation of the present invention, the mass ratio of Decitabine and meglumine is 1:1~1.5.
According to the decitabine freeze-dried preparation of the present invention, the mass ratio of Decitabine and potassium dihydrogen phosphate is 1:1.2~
1.5。
According to the decitabine freeze-dried preparation of the present invention, the mass ratio of Decitabine and sodium hydroxide is 1:0.2~0.5.
According to the decitabine freeze-dried preparation of the present invention, the percentage by weight of each component is as follows：
According to the decitabine freeze-dried preparation of the present invention, the unit dose of Decitabine is 10mg and 50mg.
According to the decitabine freeze-dried preparation of the present invention, the weight of each component is as follows：
The decitabine freeze-dried preparation of the present invention, is not required to control the temperature of solution in preparation process, prepares at room temperature
, reduce technology difficulty.In addition, decitabine freeze-dried preparation prepared by the present invention has good stability, through redissolving
Sample afterwards is placed 8 hours at ambient temperature, or is placed 16 hours under the conditions of 2~8 DEG C, still meets medication requirement, without
I.e. with i.e. use.
In addition, the invention provides the preparation method of decitabine freeze-dried preparation, comprising the following steps：
(1) measure 80% water for injection, add potassium dihydrogen phosphate, sodium hydroxide, stirring dissolve it；
(2) activated carbon is added, charcoal is taken off, obtains buffer salt solution, filtrate is standby；
(3) measure 20% water for injection, sequentially add meglumine, Decitabine, stir evenly, ultrasound, obtain suspension.
(4) buffer salt solution of preparation is added in suspension, it is stirring while adding, to complete drug dissolution, filling, jelly
It is dry, obtain decitabine freeze-dried preparation.
Present invention also offers decitabine freeze-dried technique：
The pre-freeze stage：- 45 DEG C are incubated 6~8 hours；
Once distil：- 35 DEG C are kept for 24 hours, and -30 DEG C are kept for 10~15 hours, and 0 DEG C is kept for 3~6 hours；
Redrying：30 DEG C are kept for 10~16 hours；
Holding stage：30 DEG C are kept for 5 hours.
Embodiment
Following examples further describe technical scheme.The embodiment of the present invention is done to illustrate the present invention
Go out, rather than limitation of the present invention, thus technical scheme is modified under the premise of the method for the present invention or
Equivalent substitution belongs to protection scope of the present invention.
Embodiment 1
Preparation method：
Under room temperature condition, 68.0g potassium dihydrogen phosphates, 11.6g sodium hydroxides are dissolved in 4000mL waters for injection, and stirring makes it
Dissolving, injection is matched somebody with somebody in bag equipped with activated carbon 25g, is stirred 15 minutes, is taken off charcoal, is obtained buffer salt solution.1000mL waters for injection are taken,
50.0g meglumines are added, then stirring adds 50.0g Decitabines to dissolving, and ultrasound prepares suspension.By buffer salt solution
Add in Decitabine suspension, stirring obtains intermediate decoction to dissolving；Intermediate decoction filters 0.2 μm of press filtration through nitrogen pressure
Filter membrane, and 5ml is dispensed into injection bottle, it is freeze-dried, lid is rolled in tamponade, packs, obtain freeze drying powder injection.Wherein freeze dry
Dry process is as follows：The pre-freeze stage：- 45 DEG C are incubated 7 hours, and -35 DEG C are incubated 24 hours；Once distil：- 30 DEG C keep 11 hours, 0
DEG C keep 5 hours；Redrying：30 DEG C are kept for 15 hours；Holding stage：30 DEG C are kept for 5 hours.
Embodiment 2
Preparation method：
Under room temperature condition, 68.0g potassium dihydrogen phosphates, 11.6g sodium hydroxides are dissolved in 4000mL waters for injection, and stirring makes it
Dissolving, injection is matched somebody with somebody in bag equipped with activated carbon 25g, is stirred 15 minutes, is taken off charcoal, is obtained buffer salt solution.1000mL waters for injection are taken,
65.0g meglumines are added, then stirring adds 50.0g Decitabines to dissolving, and ultrasound prepares suspension.By buffer salt solution
Add in Decitabine suspension, stirring obtains intermediate decoction to dissolving；Intermediate decoction filters 0.2 μm of press filtration through nitrogen pressure
Filter membrane, and 5ml is dispensed into injection bottle, it is freeze-dried, lid is rolled in tamponade, packs, obtain freeze drying powder injection, lyophilized technique is such as
Prepare embodiment 1.
Embodiment 3
Preparation method：
Under room temperature condition, 68.0g potassium dihydrogen phosphates, 11.6g sodium hydroxides are dissolved in 4000mL waters for injection, and stirring makes it
Dissolving, injection is matched somebody with somebody in bag equipped with activated carbon 25g, is stirred 15 minutes, is taken off charcoal, is obtained buffer salt solution.1000mL waters for injection are taken,
30.0g meglumines are added, then stirring adds 50.0g Decitabines to dissolving, and ultrasound prepares suspension.By buffer salt solution
Add in Decitabine suspension, stirring obtains intermediate decoction to dissolving；Intermediate decoction filters 0.2 μm of press filtration through nitrogen pressure
Filter membrane, and 5ml is dispensed into injection bottle, it is freeze-dried, lid is rolled in tamponade, packs, obtain freeze drying powder injection, lyophilized technique is such as
Prepare embodiment 1.
Embodiment 4
Preparation method：
Under room temperature condition, 68.0 potassium dihydrogen phosphates, 11.6g sodium hydroxides are dissolved in 4000mL waters for injection, and stirring makes it
Dissolving, injection is matched somebody with somebody in bag equipped with activated carbon 25g, is stirred 15 minutes, is taken off charcoal, is obtained buffer salt solution.Take 1000mL waters for injection
50.0g Decitabines are added, ultrasound prepares suspension.Buffer salt solution is added in Decitabine suspension, stirred to molten
Solution, obtains intermediate decoction；Intermediate decoction filters 0.2 μm of press filtration filter membrane through nitrogen pressure, and dispenses 5ml into injection bottle, cold
Dry, tamponade is freezed, lid is rolled, packed, freeze drying powder injection is obtained, lyophilized technique is as prepared embodiment 1.
Embodiment 5
Preparation method：
Under room temperature condition, 60.0g potassium dihydrogen phosphates, 10.0g sodium hydroxides are dissolved in 4000mL waters for injection, and stirring makes it
Dissolving, injection is matched somebody with somebody in bag equipped with activated carbon 25g, is stirred 15 minutes, is taken off charcoal, is obtained buffer salt solution.1000mL waters for injection are taken,
50.0g meglumines are added, then stirring adds 50.0g Decitabines to dissolving, and ultrasound prepares suspension.By buffer salt solution
Add in Decitabine suspension, stirring obtains intermediate decoction to dissolving；Intermediate decoction filters 0.2 μm of press filtration through nitrogen pressure
Filter membrane, and 5ml is dispensed into injection bottle, it is freeze-dried, lid is rolled in tamponade, packs, obtain freeze drying powder injection, lyophilized technique is such as
Prepare embodiment 1.
Embodiment 6
Preparation method：
Under room temperature condition, 70.0g potassium dihydrogen phosphates, 15.0g sodium hydroxides are dissolved in 4000mL waters for injection, and stirring makes it
Dissolving, injection is matched somebody with somebody in bag equipped with activated carbon 25g, is stirred 15 minutes, is taken off charcoal, is obtained buffer salt solution.1000mL waters for injection are taken,
50.0g meglumines are added, then stirring adds 50.0g Decitabines to dissolving, and ultrasound prepares suspension.By buffer salt solution
Add in Decitabine suspension, stirring obtains intermediate decoction to dissolving；Intermediate decoction filters 0.2 μm of press filtration through nitrogen pressure
Filter membrane, and 5ml is dispensed into injection bottle, it is freeze-dried, lid is rolled in tamponade, packs, obtain freeze drying powder injection, lyophilized technique is such as
Prepare embodiment 1.
Comparative example
Preparation method：
Under room temperature condition, 68.0g potassium dihydrogen phosphates, 11.6g sodium hydroxides are dissolved in 4000mL waters for injection, and stirring makes it
Dissolving, injection is matched somebody with somebody in bag equipped with activated carbon 25g, is stirred 15 minutes, is taken off charcoal, is obtained buffer salt solution.1000mL absolute ethyl alcohols are taken,
50.0g Decitabines are added, ultrasound prepares organic suspension.Buffer salt solution is added in Decitabine suspension, stirring is extremely
Dissolving, obtains intermediate decoction, control solution temperature is to about -10 DEG C；Intermediate decoction filters 0.2 μm of press filtration filter membrane through nitrogen pressure,
And quickly packing 5ml is into injection bottle, lid is rolled in freeze-drying, tamponade, packs, and obtains freeze drying powder injection, lyophilized technique is as made
Standby embodiment 1.
Claims (10)
1. decitabine freeze-dried preparation, the lyophilized formulations include Decitabine, meglumine, potassium dihydrogen phosphate and sodium hydroxide.
2. decitabine freeze-dried preparation according to claim 1, it is characterised in that the mass ratio of Decitabine and meglumine
For 1:1~1.5.
3. decitabine freeze-dried preparation according to claim 1, it is characterised in that the matter of Decitabine and potassium dihydrogen phosphate
Amount is than being 1:1.2~1.5.
4. decitabine freeze-dried preparation according to claim 1, it is characterised in that the quality of Decitabine and sodium hydroxide
Than for 1:0.2~0.5.
5. the decitabine freeze-dried preparation according to any one of Claims 1 to 4, it is characterised in that the weight hundred of each component
Divide ratio as follows：
6. decitabine freeze-dried preparation according to claim 5, it is characterised in that the percentage by weight of each component is as follows：
7. decitabine freeze-dried preparation according to claim 5, it is characterised in that the unit dose of Decitabine is 10mg
And 50mg.
8. decitabine freeze-dried preparation according to claim 7, it is characterised in that the weight of each component is as follows：
9. the preparation method of decitabine freeze-dried preparation, comprises the following steps：
1) measure 80% water for injection, add potassium dihydrogen phosphate and sodium hydroxide, stirring dissolves it；
2) activated carbon is added, charcoal is taken off, obtains buffer salt solution, filtrate is standby；
3) measure 20% water for injection, sequentially add meglumine and Decitabine, ultrasound, obtain suspension；
4) buffer salt solution of preparation is added in suspension, it is stirring while adding, it is filling, lyophilized to complete drug dissolution, obtain
Decitabine freeze-dried preparation.
10. preparation method according to claim 9, it is characterised in that including following lyophilized technique：
The pre-freeze stage：- 45 DEG C are incubated 6~8 hours；
Once distil：- 35 DEG C are kept for 24 hours, and -30 DEG C are kept for 10~15 hours, and 0 DEG C is kept for 3~6 hours；
Redrying：30 DEG C are kept for 10~16 hours；
Holding stage：30 DEG C are kept for 5 hours.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201710479468.7A CN107260690A (en) | 2017-06-22 | 2017-06-22 | Lyophilized formulations of Decitabine and preparation method thereof |
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| Application Number | Priority Date | Filing Date | Title |
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| CN201710479468.7A CN107260690A (en) | 2017-06-22 | 2017-06-22 | Lyophilized formulations of Decitabine and preparation method thereof |
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Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102475687A (en) * | 2010-11-27 | 2012-05-30 | 山东新时代药业有限公司 | Decitabine freeze-dry powder injection solution |
| CN102743343A (en) * | 2012-05-21 | 2012-10-24 | 江苏奥赛康药业股份有限公司 | Decitabine composition, preparation method thereof, application thereof in medicinal lyophilized preparation, medicinal lyophilized preparation product, and preparation method of medicinal lyophilized preparation product |
| CN106265536A (en) * | 2016-08-24 | 2017-01-04 | 江苏豪森药业集团有限公司 | Bortezomib pharmaceutical composition and preparation method thereof |
-
2017
- 2017-06-22 CN CN201710479468.7A patent/CN107260690A/en active Pending
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102475687A (en) * | 2010-11-27 | 2012-05-30 | 山东新时代药业有限公司 | Decitabine freeze-dry powder injection solution |
| CN102743343A (en) * | 2012-05-21 | 2012-10-24 | 江苏奥赛康药业股份有限公司 | Decitabine composition, preparation method thereof, application thereof in medicinal lyophilized preparation, medicinal lyophilized preparation product, and preparation method of medicinal lyophilized preparation product |
| CN106265536A (en) * | 2016-08-24 | 2017-01-04 | 江苏豪森药业集团有限公司 | Bortezomib pharmaceutical composition and preparation method thereof |
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Application publication date: 20171020 |
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