CN101623265B - Production process for dexamethasone sodium phosphate bulk medicament - Google Patents
Production process for dexamethasone sodium phosphate bulk medicament Download PDFInfo
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- CN101623265B CN101623265B CN200810053768XA CN200810053768A CN101623265B CN 101623265 B CN101623265 B CN 101623265B CN 200810053768X A CN200810053768X A CN 200810053768XA CN 200810053768 A CN200810053768 A CN 200810053768A CN 101623265 B CN101623265 B CN 101623265B
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- sodium phosphate
- hot air
- dexamethasone sodium
- injection
- medicinal liquid
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- 229960002344 dexamethasone sodium phosphate Drugs 0.000 title claims abstract description 72
- PLCQGRYPOISRTQ-FCJDYXGNSA-L dexamethasone sodium phosphate Chemical compound [Na+].[Na+].C1CC2=CC(=O)C=C[C@]2(C)[C@]2(F)[C@@H]1[C@@H]1C[C@@H](C)[C@@](C(=O)COP([O-])([O-])=O)(O)[C@@]1(C)C[C@@H]2O PLCQGRYPOISRTQ-FCJDYXGNSA-L 0.000 title claims abstract description 72
- 239000003814 drug Substances 0.000 title claims abstract description 49
- 238000004519 manufacturing process Methods 0.000 title claims abstract description 24
- 239000007924 injection Substances 0.000 claims abstract description 50
- 238000002347 injection Methods 0.000 claims abstract description 50
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Chemical compound O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims abstract description 27
- 238000001694 spray drying Methods 0.000 claims abstract description 20
- 239000008215 water for injection Substances 0.000 claims abstract description 20
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims abstract description 4
- 239000003889 eye drop Substances 0.000 claims abstract description 4
- 201000010099 disease Diseases 0.000 claims abstract description 3
- DNIAPMSPPWPWGF-UHFFFAOYSA-N Propylene glycol Chemical compound CC(O)CO DNIAPMSPPWPWGF-UHFFFAOYSA-N 0.000 claims description 127
- 229940079593 drug Drugs 0.000 claims description 35
- 239000007788 liquid Substances 0.000 claims description 28
- 238000005516 engineering process Methods 0.000 claims description 23
- 230000001954 sterilising effect Effects 0.000 claims description 16
- 238000004659 sterilization and disinfection Methods 0.000 claims description 16
- 241000124008 Mammalia Species 0.000 abstract 1
- 238000002360 preparation method Methods 0.000 description 15
- 239000008363 phosphate buffer Substances 0.000 description 13
- 238000012856 packing Methods 0.000 description 12
- 238000001914 filtration Methods 0.000 description 11
- 238000000034 method Methods 0.000 description 11
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 description 8
- 229910052708 sodium Inorganic materials 0.000 description 8
- 239000011734 sodium Substances 0.000 description 8
- WVDDGKGOMKODPV-UHFFFAOYSA-N Benzyl alcohol Chemical compound OCC1=CC=CC=C1 WVDDGKGOMKODPV-UHFFFAOYSA-N 0.000 description 6
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 6
- 239000000843 powder Substances 0.000 description 6
- UREBDLICKHMUKA-CXSFZGCWSA-N dexamethasone Chemical compound C1CC2=CC(=O)C=C[C@]2(C)[C@]2(F)[C@@H]1[C@@H]1C[C@@H](C)[C@@](C(=O)CO)(O)[C@@]1(C)C[C@@H]2O UREBDLICKHMUKA-CXSFZGCWSA-N 0.000 description 5
- 238000003756 stirring Methods 0.000 description 5
- 239000002671 adjuvant Substances 0.000 description 4
- 238000006243 chemical reaction Methods 0.000 description 4
- 239000002994 raw material Substances 0.000 description 4
- 210000003491 skin Anatomy 0.000 description 4
- GEHJYWRUCIMESM-UHFFFAOYSA-L sodium sulfite Chemical compound [Na+].[Na+].[O-]S([O-])=O GEHJYWRUCIMESM-UHFFFAOYSA-L 0.000 description 4
- LYCAIKOWRPUZTN-UHFFFAOYSA-N Ethylene glycol Chemical compound OCCO LYCAIKOWRPUZTN-UHFFFAOYSA-N 0.000 description 3
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 3
- 229960003957 dexamethasone Drugs 0.000 description 3
- 230000000694 effects Effects 0.000 description 3
- 235000013305 food Nutrition 0.000 description 3
- 239000011521 glass Substances 0.000 description 3
- 208000006443 lactic acidosis Diseases 0.000 description 3
- 239000000203 mixture Substances 0.000 description 3
- 206010002198 Anaphylactic reaction Diseases 0.000 description 2
- 201000004624 Dermatitis Diseases 0.000 description 2
- 206010012434 Dermatitis allergic Diseases 0.000 description 2
- 206010018910 Haemolysis Diseases 0.000 description 2
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 2
- 230000036783 anaphylactic response Effects 0.000 description 2
- 208000003455 anaphylaxis Diseases 0.000 description 2
- 235000019445 benzyl alcohol Nutrition 0.000 description 2
- 230000003115 biocidal effect Effects 0.000 description 2
- 239000006184 cosolvent Substances 0.000 description 2
- 230000002950 deficient Effects 0.000 description 2
- BNIILDVGGAEEIG-UHFFFAOYSA-L disodium hydrogen phosphate Chemical compound [Na+].[Na+].OP([O-])([O-])=O BNIILDVGGAEEIG-UHFFFAOYSA-L 0.000 description 2
- 229910000397 disodium phosphate Inorganic materials 0.000 description 2
- 235000019800 disodium phosphate Nutrition 0.000 description 2
- 230000008588 hemolysis Effects 0.000 description 2
- 238000010255 intramuscular injection Methods 0.000 description 2
- 239000007927 intramuscular injection Substances 0.000 description 2
- 238000001990 intravenous administration Methods 0.000 description 2
- 229910000403 monosodium phosphate Inorganic materials 0.000 description 2
- 235000019799 monosodium phosphate Nutrition 0.000 description 2
- WVDDGKGOMKODPV-ZQBYOMGUSA-N phenyl(114C)methanol Chemical compound O[14CH2]C1=CC=CC=C1 WVDDGKGOMKODPV-ZQBYOMGUSA-N 0.000 description 2
- 238000011160 research Methods 0.000 description 2
- 230000029058 respiratory gaseous exchange Effects 0.000 description 2
- AJPJDKMHJJGVTQ-UHFFFAOYSA-M sodium dihydrogen phosphate Chemical compound [Na+].OP(O)([O-])=O AJPJDKMHJJGVTQ-UHFFFAOYSA-M 0.000 description 2
- 235000010265 sodium sulphite Nutrition 0.000 description 2
- 239000000243 solution Substances 0.000 description 2
- 239000002904 solvent Substances 0.000 description 2
- 238000012360 testing method Methods 0.000 description 2
- 206010000830 Acute leukaemia Diseases 0.000 description 1
- 206010006784 Burning sensation Diseases 0.000 description 1
- 206010048610 Cardiotoxicity Diseases 0.000 description 1
- 206010009900 Colitis ulcerative Diseases 0.000 description 1
- MFYSYFVPBJMHGN-ZPOLXVRWSA-N Cortisone Chemical compound O=C1CC[C@]2(C)[C@H]3C(=O)C[C@](C)([C@@](CC4)(O)C(=O)CO)[C@@H]4[C@@H]3CCC2=C1 MFYSYFVPBJMHGN-ZPOLXVRWSA-N 0.000 description 1
- OVBJJZOQPCKUOR-UHFFFAOYSA-L EDTA disodium salt dihydrate Chemical compound O.O.[Na+].[Na+].[O-]C(=O)C[NH+](CC([O-])=O)CC[NH+](CC([O-])=O)CC([O-])=O OVBJJZOQPCKUOR-UHFFFAOYSA-L 0.000 description 1
- 206010015150 Erythema Diseases 0.000 description 1
- 208000005654 Hip Contracture Diseases 0.000 description 1
- 206010020751 Hypersensitivity Diseases 0.000 description 1
- 206010061218 Inflammation Diseases 0.000 description 1
- 206010025323 Lymphomas Diseases 0.000 description 1
- SNIOPGDIGTZGOP-UHFFFAOYSA-N Nitroglycerin Chemical compound [O-][N+](=O)OCC(O[N+]([O-])=O)CO[N+]([O-])=O SNIOPGDIGTZGOP-UHFFFAOYSA-N 0.000 description 1
- 239000000006 Nitroglycerin Substances 0.000 description 1
- 208000005374 Poisoning Diseases 0.000 description 1
- 201000006704 Ulcerative Colitis Diseases 0.000 description 1
- 238000010521 absorption reaction Methods 0.000 description 1
- 230000002411 adverse Effects 0.000 description 1
- 208000030961 allergic reaction Diseases 0.000 description 1
- 235000001014 amino acid Nutrition 0.000 description 1
- 150000001413 amino acids Chemical class 0.000 description 1
- 239000003708 ampul Substances 0.000 description 1
- 230000003266 anti-allergic effect Effects 0.000 description 1
- 230000003110 anti-inflammatory effect Effects 0.000 description 1
- 208000006673 asthma Diseases 0.000 description 1
- 201000008937 atopic dermatitis Diseases 0.000 description 1
- 208000010668 atopic eczema Diseases 0.000 description 1
- 238000012550 audit Methods 0.000 description 1
- 230000001363 autoimmune Effects 0.000 description 1
- 230000033228 biological regulation Effects 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- 239000008280 blood Substances 0.000 description 1
- 210000004369 blood Anatomy 0.000 description 1
- 231100000259 cardiotoxicity Toxicity 0.000 description 1
- 230000007681 cardiovascular toxicity Effects 0.000 description 1
- 210000003169 central nervous system Anatomy 0.000 description 1
- 230000000052 comparative effect Effects 0.000 description 1
- 208000018631 connective tissue disease Diseases 0.000 description 1
- 239000002537 cosmetic Substances 0.000 description 1
- 239000013078 crystal Substances 0.000 description 1
- 238000002425 crystallisation Methods 0.000 description 1
- 230000008025 crystallization Effects 0.000 description 1
- 230000006378 damage Effects 0.000 description 1
- 238000011082 depyrogenation Methods 0.000 description 1
- 150000004683 dihydrates Chemical class 0.000 description 1
- 239000002552 dosage form Substances 0.000 description 1
- 230000004064 dysfunction Effects 0.000 description 1
- 238000005538 encapsulation Methods 0.000 description 1
- 210000002615 epidermis Anatomy 0.000 description 1
- 231100000321 erythema Toxicity 0.000 description 1
- 229960001617 ethyl hydroxybenzoate Drugs 0.000 description 1
- NUVBSKCKDOMJSU-UHFFFAOYSA-N ethylparaben Chemical compound CCOC(=O)C1=CC=C(O)C=C1 NUVBSKCKDOMJSU-UHFFFAOYSA-N 0.000 description 1
- 238000002474 experimental method Methods 0.000 description 1
- 238000009472 formulation Methods 0.000 description 1
- 231100000734 genotoxic potential Toxicity 0.000 description 1
- 229960003711 glyceryl trinitrate Drugs 0.000 description 1
- PCHJSUWPFVWCPO-UHFFFAOYSA-N gold Chemical compound [Au] PCHJSUWPFVWCPO-UHFFFAOYSA-N 0.000 description 1
- 229910052737 gold Inorganic materials 0.000 description 1
- 239000010931 gold Substances 0.000 description 1
- 230000010247 heart contraction Effects 0.000 description 1
- 230000001506 immunosuppresive effect Effects 0.000 description 1
- 208000015181 infectious disease Diseases 0.000 description 1
- 230000004054 inflammatory process Effects 0.000 description 1
- 208000030603 inherited susceptibility to asthma Diseases 0.000 description 1
- 230000005764 inhibitory process Effects 0.000 description 1
- 208000001875 irritant dermatitis Diseases 0.000 description 1
- 239000008297 liquid dosage form Substances 0.000 description 1
- 206010025135 lupus erythematosus Diseases 0.000 description 1
- 238000007726 management method Methods 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- 231100000647 material safety data sheet Toxicity 0.000 description 1
- 230000004060 metabolic process Effects 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 210000004877 mucosa Anatomy 0.000 description 1
- QJGQUHMNIGDVPM-UHFFFAOYSA-N nitrogen group Chemical group [N] QJGQUHMNIGDVPM-UHFFFAOYSA-N 0.000 description 1
- GYCKQBWUSACYIF-UHFFFAOYSA-N o-hydroxybenzoic acid ethyl ester Natural products CCOC(=O)C1=CC=CC=C1O GYCKQBWUSACYIF-UHFFFAOYSA-N 0.000 description 1
- 230000003647 oxidation Effects 0.000 description 1
- 238000007254 oxidation reaction Methods 0.000 description 1
- 208000001297 phlebitis Diseases 0.000 description 1
- 230000000704 physical effect Effects 0.000 description 1
- 231100000572 poisoning Toxicity 0.000 description 1
- 230000000607 poisoning effect Effects 0.000 description 1
- HMHOKYMBSWDQKS-UHFFFAOYSA-N propane-1,2-diol silver Chemical compound C(C(C)O)O.[Ag] HMHOKYMBSWDQKS-UHFFFAOYSA-N 0.000 description 1
- 239000002510 pyrogen Substances 0.000 description 1
- 206010039073 rheumatoid arthritis Diseases 0.000 description 1
- 238000005070 sampling Methods 0.000 description 1
- 238000007789 sealing Methods 0.000 description 1
- 210000002374 sebum Anatomy 0.000 description 1
- 230000035807 sensation Effects 0.000 description 1
- 210000002966 serum Anatomy 0.000 description 1
- 239000011780 sodium chloride Substances 0.000 description 1
- 239000001509 sodium citrate Substances 0.000 description 1
- NLJMYIDDQXHKNR-UHFFFAOYSA-K sodium citrate Chemical compound O.O.[Na+].[Na+].[Na+].[O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O NLJMYIDDQXHKNR-UHFFFAOYSA-K 0.000 description 1
- 239000001488 sodium phosphate Substances 0.000 description 1
- 239000012064 sodium phosphate buffer Substances 0.000 description 1
- GOLXNESZZPUPJE-UHFFFAOYSA-N spiromesifen Chemical compound CC1=CC(C)=CC(C)=C1C(C(O1)=O)=C(OC(=O)CC(C)(C)C)C11CCCC1 GOLXNESZZPUPJE-UHFFFAOYSA-N 0.000 description 1
- 239000007921 spray Substances 0.000 description 1
- 230000006641 stabilisation Effects 0.000 description 1
- 238000011105 stabilization Methods 0.000 description 1
- 239000003381 stabilizer Substances 0.000 description 1
- 230000000638 stimulation Effects 0.000 description 1
- 238000005728 strengthening Methods 0.000 description 1
- SEEPANYCNGTZFQ-UHFFFAOYSA-N sulfadiazine Chemical compound C1=CC(N)=CC=C1S(=O)(=O)NC1=NC=CC=N1 SEEPANYCNGTZFQ-UHFFFAOYSA-N 0.000 description 1
- 229960004306 sulfadiazine Drugs 0.000 description 1
- 230000000699 topical effect Effects 0.000 description 1
- 231100000419 toxicity Toxicity 0.000 description 1
- 230000001988 toxicity Effects 0.000 description 1
- 239000003643 water by type Substances 0.000 description 1
Landscapes
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The invention provides a production process for a dexamethasone sodium phosphate bulk medicament, which dissolves certain amount of dexamethasone sodium phosphate into proper amount of water for injection and performs spray drying to obtain the dexamethasone sodium phosphate bulk medicament. The dexamethasone sodium phosphate bulk medicament can be used for preparing medicaments for treating human or mammal diseases, and is preferably prepared into injection or eye drop.
Description
Technical field:
The present invention relates to a kind of production technology of 17-hydroxy-11-dehydrocorticosterone production of raw medicine technology, particularly dexamethasone sodium phosphate.
Background technology:
Dexamethasone sodium phosphate (DEXAMETHASONE SODIUM PHOSPHATE is called for short " sodium ") is a kind of Aeroseb-Dex.Have antiinflammatory, antiallergic, rheumatism, immunosuppressive action, be widely used in treatment anaphylaxis and autoimmune inflammation disease.As connective tissue disease, activeness rheumatism, rheumatoid arthritis, lupus erythematosus, serious bronchial asthma, serious dermatitis, ulcerative colitis, acute leukemia etc., also be used for the Comprehensive Treatment of some severe infections and poisoning, malignant lymphoma.Common dosage form is the ground sodium injection.Because the ground process for producing sodium is different, the adjuvant of using in the prescription of the ground sodium injection of home and overseas is also different, for example used adjuvant is that every ml injection contains the 13.5mg Sodium Citrate, usp, Dihydrate Powder in the ground sodium injection of external 10mg/ml specification, the 10mg benzyl alcohol, and can be with the citric acid or the sodium hydroxide (http://www.appdrugs.com/PIs/Dexamethasone_45955A.pdf) of pH regulator to 7.0～8.5.
Yet, the injection that contains benzyl alcohol is easy to generate serious adverse effects such as hip contracture when intramuscular injection is especially used to the child, " about strengthening the notice of benzyl alcohol injection management " of State Food and Drug Administration's issue (state's food medicine prison is annotated [2005] No. 263) also requires every injection that contains benzyl alcohol, should forbid the intramuscular injection in the child.
(process modification of dexamethasone sodium phosphate injection, medical Leader the 24th the 7th phase of volume of July in 2005 such as Xu Xuemei; 621) point out: the ground sodium injection that adopts domestic raw material, because the difference of ground sodium raw materials production technology, when adopting prescription identical and explained hereafter with external injection, cause injection to separate out white point, white piece easily, make that the yield rate of preparation is very low, for overcoming the problems referred to above, adopted dexamethasone sodium phosphate 5g, sodium sulfite 2g, disodium edetate 0.3g, sodium dihydrogen phosphate 0.39g, sodium hydrogen phosphate 11g, the prescription that propylene glycol 300mL, water for injection add to 1000mL can make the yield rate of preparation reach 96.2%.
(craft discussion of dexamethasone sodium phosphate injection, the practical combination of Chinese and Western medicine the 6th the 5th phase of volume of clinical 2006 October such as Huang Xiang; 83) also point out: because refinement, the crystallization processes and variant abroad of homemade goods, meeting generation white point, white piece behind the dexamethasone sodium phosphate injection sterilization back of employing domestic raw material preparation, yield rate is very low, improve process using dexamethasone sodium phosphate 5g for this reason, propylene glycol 400mL, 10% sodium hydroxide is an amount of, and the new recipe that water for injection adds to 1000mL can prevent medicinal liquid white point, the generation of piece in vain, makes the yield rate of dexamethasone sodium phosphate injection be greatly improved.
And described propylene glycol is medicinal propylene glycol, is 1, and the 2-propylene glycol claims Propylene Glycol again, and molecular formula is C
3H
8O
2, in the ground sodium injection, play the effect of hydrotropy and stabilization formulations.Though FDA (Food and Drug Adminstration) (FDA) and U.S. cosmetic composition audit committee, assert all that haply the propylene glycol safety is higher, and Chinese Pharmacopoeia version in 2005 has been recorded propylene glycol for the 896th page, but on the material safety data sheet (Material Safty Date Sheets) of propylene glycol, then speak of propylene glycol skin has been had the constitutional stimulation, might cause subjective burning sensation, sensation of pricking and gargalesthesia; In addition, because propylene glycol has the characteristic of fat-soluble solvent, the propylene glycol of life-time service high concentration can be influential to epidermis sebum structure; In addition, especially higher because propylene glycol might cause irritant dermatitis to the zest of skin and mucosa in concentration, under the situation that sealing is used, easier skin rubefaction, an erythema, the scratchy and coarse situation of decortication of causing; There is 1～5% people can when touching propylene glycol, produce local skin allergic eczema reaction allergic dermatitis approximately, and, taking or using the food or the medicine that contain the propylene glycol composition can cause the general skin allergy for the people of anaphylaxis system.
In fact abroad, as far back as last century the '30s begin just to set about deep research has been carried out in the propylene glycol safety, accumulated great mass of data, security related and the clinical research document delivered at present have more than 160 piece.The seventies in last century, G.Martin writes articles at the department of pediatrics magazine and points out, the propylene glycol tool genotoxic potential problem in the liquid dosage form.K.Arulananthan in 1978 have reported the maincenter toxicity of propylene glycol.After this in the period of 1985～1988, Demey and partner thereof report that the nitroglycerin preparation that intravenous drip contains propylene glycol can cause that height oozes untoward reaction, haemolysis, lactic acidosis and nervus centralis dysfunction.The topical application of having reported Fligner contains the propylene glycol silver sulfadiazin in the burn patient, because the Transdermal absorption of propylene glycol, the propylene glycol peak concentration is up to 1059 μ g/ml in the blood, and except that being oozed by height the untoward reaction that causes, breathing still can appear in the patient, heart beating stops.After this Keiner report, when 5 patients accept to contain the treatment of propylene glycol intravenous pharmacy, propylene glycol concentration is respectively 6～711 μ g/ml and 11～599 μ g/ml in 35 parts of serum samples and the 8 parts of CSF sample, because the metabolism of propylene glycol, lactic acidosis has appearred in the patient.This shows that as adjuvant and solvent, propylene glycol has potential danger, can produce hyperosmosis, lactic acidosis, central nervous system's inhibition, haemolysis, local phlebitis and breathing, cardiac toxicity reaction, its safety makes people worried.
This shows,, but still exist certain risk though the used propylene glycol consumption of every dexamethasone sodium phosphate injection is little, especially when using for a long time or in a large number, bigger to the potential harm of human body.
Summary of the invention
For overcoming the defective of homemade dexamethasone sodium phosphate raw material of the prior art, we provide a kind of new dexamethasone sodium phosphate production technology.Under study for action, the discovery that we are surprised, the injection that adopts this technology to make the preparation of dexamethasone sodium phosphate crude drug can significantly reduce even avoid the use of propylene glycol.
Production technology provided by the invention is characterised in that:
(1) a certain amount of dexamethasone sodium phosphate is dissolved in a certain amount of water for injection, is stirred to the complete molten medicinal liquid (1) that obtains.
(2) medicinal liquid (1) is carried out spray drying, the spray drying condition is as follows:
Hot air flowrate: 0.5～0.75m
3/ min
Hot air inlet temperature: 110～130 ℃
Hot air outlet temperature: 85～95 ℃
Heat air pressure: 100～150kpa (gauge pressure)
Medicinal liquid flow velocity: 5～10ml/min
Described production technology preferably is dissolved in 10～15 times of (weight ratio) waters for injection,
The preferably spray drying condition is as follows
Hot air flowrate: 0.7～0.75m
3/ min
Hot air inlet temperature: 120～130 ℃
Hot air outlet temperature: 85～95 ℃
Heat air pressure: 120～150kpa (gauge pressure)
Medicinal liquid flow velocity: 5～10ml/min
Described production technology is preferably carried out sterilization treatment with medicinal liquid (1), and adopt aseptic manipulation in whole technical process, to make aseptic dexamethasone sodium phosphate bulk medicament powder.Described Biocidal treatment method and aseptic manipulation can be according to " pharmaceutics " (Cui Fude, November in 2003 the 5th edition) disclosed method in, can adopt moist hear heat test, dry heat sterilization or sterilization by filtration, the preferred sterilization by filtration that adopts as mechanical sterilization as Biocidal treatment method, as adopt the G6 sintered glass filter of 0.22 μ m, carry out filtration sterilization.
The invention also discloses the application of dexamethasone sodium phosphate crude drug in the medicine of preparation treatment people or mammalian diseases, be particularly preferred for preparing injection, eye drop according to described prepared.
The discovery that we are surprised, the dexamethasone sodium phosphate crude drug that technology of the present invention makes in use, especially at the preparation preparation, especially during dexamethasone sodium phosphate injection, produced beyond thought effect, not only simplified the production craft step of injection, and overcome adopt original feedstock production injection need up to 30% in addition more propylene glycol as the shortcoming of cosolvent.Use dexamethasone sodium phosphate crude drug that technology of the present invention makes when the preparation injection, the consumption of propylene glycol can reduce to 0～15%, preferred especially propylene glycol consumption reduces to 0～2%, and injection still can keep stable and meet the regulation of 2005 editions second one of Chinese Pharmacopoeia.Thereby overcome original dexamethasone sodium phosphate crude drug when the preparation injection, needed to add a large amount of propylene glycol, high zest and potential risk that causes allergic reaction easily and defective when causing injection to use as cosolvent and stabilizing agent.We think, pass through spray drying method, physical propertys such as the crystal formation of dexamethasone sodium phosphate and water content have been changed, thereby its stability in solution is improved, and is to cause the injection of the dexamethasone sodium phosphate preparation of adopting prepared of the present invention compared with prior art obviously to reduce the reason of propylene glycol.
The specific embodiment:
Embodiment in the specific embodiment only for illustrating further the technical scheme of invention, can not be interpreted as the restriction to embodiment of the present invention.
In the production of dexamethasone crude drug, preferably adopt aseptic manipulation to produce.
Phosphate buffer described in the specific embodiment is the sodium phosphate buffer of the 0.2mol/L of pH=8.0, and soon the disodium phosphate soln of the sodium dihydrogen phosphate of 0.2mol/L and 0.2mol/L is mixed promptly by 53: 947 volume ratio.Above-mentioned solution is all prepared with water for injection.
Used dexamethasone sodium phosphate is Tianjin Tianyao Pharmaceutical Co., Ltd.'s production in following examples, meets 2005 editions standards of Chinese Pharmacopoeia.
The preferred employing filled the situation generation that nitrogen form is avoided oxidation in the dexamethasone sodium phosphate crude drug injection preparation encapsulation process of using embodiment to make.
The used equipment of spray drying is the SD1000 type spray dryer that Japanese EYELA produces among the embodiment of the present invention.
Embodiment 1
Dexamethasone sodium phosphate 10g
Water for injection 100g
(1) dexamethasone sodium phosphate with recipe quantity is dissolved in the water for injection of recipe quantity, is stirred to the complete molten medicinal liquid (1) that obtains.
(2) medicinal liquid (1) is carried out spray drying, obtain the dexamethasone sodium phosphate crude drug.The spray drying condition is as follows:
Hot air flowrate: 0.55m
3/ min
Hot air inlet temperature: 110 ℃
Outlet temperature: 85 ℃
Heat air pressure (gauge pressure): 120kpa
Medicinal liquid flow velocity: 5ml/min
(3) the dexamethasone sodium phosphate crude drug through testing sequence (2) gained obtains dexamethasone sodium phosphate crude drug branch packing with step (2).
Embodiment 2
Dexamethasone sodium phosphate 10g
Water for injection 150g
(1) dexamethasone sodium phosphate with recipe quantity is dissolved in the water for injection of recipe quantity, is stirred to the complete molten medicinal liquid (1) that obtains.
(2) medicinal liquid (1) is carried out spray drying, obtain the dexamethasone sodium phosphate crude drug.The spray drying condition is as follows:
Hot air flowrate: 0.65m
3/ min
Hot air inlet temperature: 115 ℃
Outlet temperature: 90 ℃
Medicinal liquid flow velocity: 5ml/min
Heat air pressure (gauge pressure): 130kpa
(3) step (2) is obtained the dexamethasone sodium phosphate crude drug and divide packing.
Embodiment 3
Dexamethasone sodium phosphate 10g
Water for injection 150g
(1) dexamethasone sodium phosphate with recipe quantity is dissolved in the water for injection of recipe quantity, is stirred to the complete molten medicinal liquid (1) that obtains.
(2) medicinal liquid (1) is carried out filtration sterilization with G6 glass sintered filter funnel, depyrogenation is handled.
(3) medicinal liquid (1) is carried out spray drying, obtain dexamethasone sodium phosphate crude drug powder.The spray drying condition is as follows:
Hot air flowrate: 0.75m
3/ min
Hot air inlet temperature: 120 ℃
Outlet temperature: 90 ℃
Medicinal liquid flow velocity: 10min/L
Heat air pressure (gauge pressure): 140kpa
(4) the dexamethasone crude drug powder that step (3) is obtained carries out aseptic branch packing.
Embodiment 4
Dexamethasone sodium phosphate 10g
Water for injection 150g
(1) dexamethasone sodium phosphate with recipe quantity is dissolved in the water for injection of recipe quantity, is stirred to the complete molten medicinal liquid (1) that obtains.
(2) medicinal liquid (1) is carried out filtration sterilization with G6 glass sintered filter funnel, pyrogen is handled.
(3) medicinal liquid (1) is carried out spray drying, obtain dexamethasone sodium phosphate crude drug powder.The spray drying condition is as follows:
Hot air flowrate: 0.75m
3/ min
Hot air inlet temperature: 130 ℃
Outlet temperature: 95 ℃
Medicinal liquid flow velocity: 10ml/L
Heat air pressure (gauge pressure): 140kpa
(4) the dexamethasone crude drug powder that step (3) is obtained carries out aseptic branch packing.
Embodiment 5 preparation injection
The present embodiment various injection of preparation is down made the ampoule bottle packaged form, but can not be interpreted as the restriction to injection packing form.
Embodiment 5-1
Embodiment 1 makes dexamethasone sodium phosphate crude drug 5g
The phosphate buffer 1 00ml of pH=8.0
Recipe quantity dexamethasone sodium phosphate crude drug is dissolved in the proper amount of water for injection, adds the phosphate buffer of recipe quantity, stir, add the injection water to 1000ml, filtration, packing, sterilization obtain the every ml of injection and contain dexamethasone sodium phosphate 5mg.
Embodiment 5-2
Embodiment 2 makes dexamethasone sodium phosphate crude drug 2g
The phosphate buffer 50ml of pH=8.0
Medicinal propylene glycol 2ml
The dexamethasone sodium phosphate crude drug of recipe quantity is dissolved in phosphate buffer, the medicinal propylene glycol that proper amount of water for injection adds recipe quantity to stir, add the injection water to 1000ml, filtration, packing, sterilization obtain the every ml of injection and contain dexamethasone sodium phosphate 2mg.
Embodiment 5-3
Embodiment 3 makes dexamethasone sodium phosphate crude drug 5g
The phosphate buffer 20ml of pH=8.0
Medicinal propylene glycol 5ml
The dexamethasone sodium phosphate crude drug of recipe quantity is dissolved in phosphate buffer, the medicinal propylene glycol that proper amount of water for injection adds recipe quantity to stir, add the injection water to 1000ml, filtration, packing, sterilization obtain the every ml of injection and contain dexamethasone sodium phosphate 5mg.
Embodiment 5-4
Embodiment 4 makes dexamethasone sodium phosphate crude drug 2g
The phosphate buffer 1 5ml of pH=8.0
Medicinal propylene glycol 10ml
The dexamethasone sodium phosphate crude drug of recipe quantity is dissolved in phosphate buffer, the medicinal propylene glycol that proper amount of water for injection adds recipe quantity to stir, add the injection water to 1000ml, filtration, packing, sterilization obtain the every ml of injection and contain dexamethasone sodium phosphate 2mg.
Embodiment 5-5
Embodiment 4 makes dexamethasone sodium phosphate crude drug 5g
The phosphate buffer 1 0ml of pH=8.0
Medicinal propylene glycol 15ml
The dexamethasone sodium phosphate crude drug of recipe quantity is dissolved in phosphate buffer, the medicinal propylene glycol that proper amount of water for injection adds recipe quantity to stir, add the injection water to 1000ml, filtration, packing, sterilization obtain the every ml of injection and contain dexamethasone sodium phosphate 5mg.
Embodiment 6, eye drop (in 1000ml)
Embodiment 4 makes the phosphate buffer 1 0ml of dexamethasone sodium phosphate crude drug 0.25g pH=8.0
Sodium chloride is adjusted to etc. and oozes ethyl hydroxybenzoate 0.1g, sodium sulfite 0.2g
The dexamethasone sodium phosphate crude drug of recipe quantity is dissolved in the phosphate buffer that proper amount of water for injection adds recipe quantity, the adjuvant that adds other recipe quantity, add the injection water to 1000ml, filtration, packing, sterilization obtain the every ml of injection and contain dexamethasone sodium phosphate 0.25mg.
The stability comparative example
Requirement according to stability experiment in the Chinese Pharmacopoeia 2005 editions, get embodiment 5-1 to embodiment 5-5 respectively and make each three batches of dexamethasone sodium phosphate injections, get 5 for every batch, get commercially available dexamethasone sodium phosphate injection (1ml: 5mg, Tianjin gold credit aminoacid company limited is produced, and recording this product content of propylene glycol is 30%) three batches, get 5 all samples lucifuges packings for every batch, putting (60 ± 2) ℃, kept in Dark Place 3 months in the thermostatic container of (75 ± 5) % humidity.Respectively at 0,1,2,3 months sampling and measuring are checked pH value, clarity, content etc.The results are shown in following table.
(X±s，n＝15)
The dexamethasone sodium phosphate crude drug that adopts method of the present invention to make as can be seen from aforementioned stable embodiment, when the modal injection of preparation, compared with prior art, beyond thoughtly only need 0～15%, in addition be low to moderate 0～2% medicinal ethylene glycol can reach with now commercially available content of propylene glycol up to the identical stability of 30% Decameth.
Claims (10)
1. a dexamethasone sodium phosphate production of raw medicine technology is characterized in that
(1) a certain amount of dexamethasone sodium phosphate is dissolved in the water for injection, is stirred to the complete molten medicinal liquid (1) that obtains;
(2) medicinal liquid (1) is carried out spray drying, the spray drying condition is as follows:
Hot air flowrate: 0.5～0.75m
3/ min
Hot air inlet temperature: 110～130 ℃
Hot air outlet temperature: 85～95 ℃
Heat air pressure gauge pressure: 100～150kpa
Medicinal liquid flow velocity: 5～10ml/min.
2. production technology as claimed in claim 1 is characterized in that, the spray drying condition is as follows:
Hot air flowrate: 0.7～0.75m3/min hot air outlet temperature: 85～95 ℃
Heat air pressure gauge pressure: 120～150kpa medicinal liquid flow velocity: 5～10ml/min
Hot air inlet temperature: 120～130 ℃.
3. production technology as claimed in claim 1 is characterized in that the spray drying condition is as follows:
Hot air flowrate: 0.55m
3/ min hot air inlet temperature: 110 ℃
Hot air outlet temperature: 85 ℃ of heat air pressure gauge pressure: 120kpa
Medicinal liquid flow velocity: 5ml/min.
4. production technology as claimed in claim 1 is characterized in that the spray drying condition is as follows:
Hot air flowrate: 0.65m
3/ min hot air inlet temperature: 115 ℃
Hot air outlet temperature: 90 ℃ of medicinal liquid flow velocity: 5ml/min
Heat air pressure gauge pressure: 130kpa.
5. production technology as claimed in claim 1 or 2 is characterized in that the spray drying condition is as follows:
Hot air flowrate: 0.75m
3/ min hot air inlet temperature: 120 ℃
Hot air outlet temperature: 90 ℃ of medicinal liquid flow velocity: 10ml/min
Heat air pressure gauge pressure: 140kpa.
6. production technology as claimed in claim 1 or 2 is characterized in that preferably medicinal liquid being carried out sterilization treatment, and adopt aseptic manipulation in whole technology.
7. the dexamethasone sodium phosphate crude drug that production technology as claimed in claim 1 or 2 makes is used to prepare the medicine for the treatment of people or mammalian diseases.
8. the dexamethasone sodium phosphate crude drug that production technology as claimed in claim 1 or 2 makes is used to prepare injection.
9. the prepared injection of dexamethasone sodium phosphate crude drug that makes as claim 1 or 3 described production technologies is characterized in that containing in the described injection propylene glycol of 0～15% percentage by weight.
10. the dexamethasone sodium phosphate crude drug that production technology as claimed in claim 1 or 2 makes is used to prepare eye drop.
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Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1559413A (en) * | 2004-02-26 | 2005-01-05 | 胡秀爱 | Freezing-drying powder-injection contg. dexamethasone sodium phosphate, and its prepn. method |
| CN101120915A (en) * | 2006-08-10 | 2008-02-13 | 天津药业集团新郑股份有限公司 | Dexamethasone sodium phosphate injection |
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2008
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Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1559413A (en) * | 2004-02-26 | 2005-01-05 | 胡秀爱 | Freezing-drying powder-injection contg. dexamethasone sodium phosphate, and its prepn. method |
| CN101120915A (en) * | 2006-08-10 | 2008-02-13 | 天津药业集团新郑股份有限公司 | Dexamethasone sodium phosphate injection |
Non-Patent Citations (1)
| Title |
|---|
| 黄湘等.地塞米松磷酸钠注射液的工艺探讨.《实用中西医结合临床》.2006,第6卷(第5期),第83页. * |
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