CN108272755B - A kind of hydrochloride for injection mycophenolate mofetil lyophilized preparation and preparation method thereof - Google Patents
A kind of hydrochloride for injection mycophenolate mofetil lyophilized preparation and preparation method thereof Download PDFInfo
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- CN108272755B CN108272755B CN201810273774.XA CN201810273774A CN108272755B CN 108272755 B CN108272755 B CN 108272755B CN 201810273774 A CN201810273774 A CN 201810273774A CN 108272755 B CN108272755 B CN 108272755B
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- mycophenolate mofetil
- injection
- sodium hydroxide
- hydrochloric acid
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- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 title claims abstract description 81
- RTGDFNSFWBGLEC-SYZQJQIISA-N mycophenolate mofetil Chemical compound COC1=C(C)C=2COC(=O)C=2C(O)=C1C\C=C(/C)CCC(=O)OCCN1CCOCC1 RTGDFNSFWBGLEC-SYZQJQIISA-N 0.000 title claims abstract description 48
- 229960004866 mycophenolate mofetil Drugs 0.000 title claims abstract description 48
- 238000002360 preparation method Methods 0.000 title claims abstract description 38
- 238000002347 injection Methods 0.000 title claims abstract description 26
- 239000007924 injection Substances 0.000 title claims abstract description 26
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims abstract description 82
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 claims abstract description 40
- 229920001214 Polysorbate 60 Polymers 0.000 claims abstract description 31
- 229960000443 hydrochloric acid Drugs 0.000 claims abstract description 26
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims abstract description 21
- 229960004543 anhydrous citric acid Drugs 0.000 claims abstract description 18
- 150000001298 alcohols Chemical class 0.000 claims abstract description 14
- 229960000935 dehydrated alcohol Drugs 0.000 claims abstract description 12
- 229940083608 sodium hydroxide Drugs 0.000 claims abstract description 11
- 239000002994 raw material Substances 0.000 claims abstract description 6
- 235000019441 ethanol Nutrition 0.000 claims description 19
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Chemical compound O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 18
- 239000008215 water for injection Substances 0.000 claims description 18
- 239000000243 solution Substances 0.000 claims description 17
- 239000012530 fluid Substances 0.000 claims description 15
- 238000004108 freeze drying Methods 0.000 claims description 11
- 238000013019 agitation Methods 0.000 claims description 10
- 150000002148 esters Chemical class 0.000 claims description 10
- 238000001914 filtration Methods 0.000 claims description 9
- 241000209140 Triticum Species 0.000 claims description 7
- 235000021307 Triticum Nutrition 0.000 claims description 7
- 239000000203 mixture Substances 0.000 claims description 7
- 238000009472 formulation Methods 0.000 claims description 6
- -1 Phenolic ester Chemical class 0.000 claims description 5
- 229960004756 ethanol Drugs 0.000 claims description 5
- 238000011049 filling Methods 0.000 claims description 5
- 230000010494 opalescence Effects 0.000 claims description 5
- 238000003756 stirring Methods 0.000 claims description 5
- 230000001954 sterilising effect Effects 0.000 claims description 2
- 238000000034 method Methods 0.000 abstract description 12
- 239000012535 impurity Substances 0.000 abstract description 7
- 238000005516 engineering process Methods 0.000 abstract description 5
- 239000002904 solvent Substances 0.000 abstract description 5
- 238000003860 storage Methods 0.000 abstract description 2
- 239000000047 product Substances 0.000 description 32
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 14
- 239000003814 drug Substances 0.000 description 11
- 229910052757 nitrogen Inorganic materials 0.000 description 7
- 230000015572 biosynthetic process Effects 0.000 description 6
- 235000002710 Ilex cornuta Nutrition 0.000 description 5
- 241001310146 Ilex cornuta Species 0.000 description 5
- 235000010326 Osmanthus heterophyllus Nutrition 0.000 description 5
- 239000002253 acid Substances 0.000 description 5
- 229940079593 drug Drugs 0.000 description 5
- RQFCJASXJCIDSX-UUOKFMHZSA-N guanosine 5'-monophosphate Chemical compound C1=2NC(N)=NC(=O)C=2N=CN1[C@@H]1O[C@H](COP(O)(O)=O)[C@@H](O)[C@H]1O RQFCJASXJCIDSX-UUOKFMHZSA-N 0.000 description 5
- 235000013928 guanylic acid Nutrition 0.000 description 5
- HPNSFSBZBAHARI-RUDMXATFSA-N mycophenolic acid Chemical class OC1=C(C\C=C(/C)CCC(O)=O)C(OC)=C(C)C2=C1C(=O)OC2 HPNSFSBZBAHARI-RUDMXATFSA-N 0.000 description 5
- 229940124597 therapeutic agent Drugs 0.000 description 5
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 4
- ISWSIDIOOBJBQZ-UHFFFAOYSA-N Phenol Chemical compound OC1=CC=CC=C1 ISWSIDIOOBJBQZ-UHFFFAOYSA-N 0.000 description 4
- 235000015165 citric acid Nutrition 0.000 description 4
- 238000001514 detection method Methods 0.000 description 4
- 239000006185 dispersion Substances 0.000 description 4
- HPNSFSBZBAHARI-UHFFFAOYSA-N micophenolic acid Natural products OC1=C(CC=C(C)CCC(O)=O)C(OC)=C(C)C2=C1C(=O)OC2 HPNSFSBZBAHARI-UHFFFAOYSA-N 0.000 description 4
- 239000011859 microparticle Substances 0.000 description 4
- 239000003960 organic solvent Substances 0.000 description 4
- 230000008569 process Effects 0.000 description 4
- 238000003786 synthesis reaction Methods 0.000 description 4
- DKGAVHZHDRPRBM-UHFFFAOYSA-N Tert-Butanol Chemical compound CC(C)(C)O DKGAVHZHDRPRBM-UHFFFAOYSA-N 0.000 description 3
- 239000003795 chemical substances by application Substances 0.000 description 3
- 230000000694 effects Effects 0.000 description 3
- 239000004226 guanylic acid Substances 0.000 description 3
- 239000008176 lyophilized powder Substances 0.000 description 3
- 238000004519 manufacturing process Methods 0.000 description 3
- 229940014456 mycophenolate Drugs 0.000 description 3
- 241000894006 Bacteria Species 0.000 description 2
- YASYEJJMZJALEJ-UHFFFAOYSA-N Citric acid monohydrate Chemical compound O.OC(=O)CC(O)(C(O)=O)CC(O)=O YASYEJJMZJALEJ-UHFFFAOYSA-N 0.000 description 2
- LRHPLDYGYMQRHN-UHFFFAOYSA-N N-Butanol Chemical compound CCCCO LRHPLDYGYMQRHN-UHFFFAOYSA-N 0.000 description 2
- 239000012752 auxiliary agent Substances 0.000 description 2
- 229960002303 citric acid monohydrate Drugs 0.000 description 2
- 239000000470 constituent Substances 0.000 description 2
- 239000002552 dosage form Substances 0.000 description 2
- 239000007788 liquid Substances 0.000 description 2
- 239000011159 matrix material Substances 0.000 description 2
- 239000003002 pH adjusting agent Substances 0.000 description 2
- 239000000546 pharmaceutical excipient Substances 0.000 description 2
- BDERNNFJNOPAEC-UHFFFAOYSA-N propan-1-ol Chemical compound CCCO BDERNNFJNOPAEC-UHFFFAOYSA-N 0.000 description 2
- 229940114072 12-hydroxystearic acid Drugs 0.000 description 1
- 206010067484 Adverse reaction Diseases 0.000 description 1
- VEXZGXHMUGYJMC-UHFFFAOYSA-M Chloride anion Chemical compound [Cl-] VEXZGXHMUGYJMC-UHFFFAOYSA-M 0.000 description 1
- 206010012735 Diarrhoea Diseases 0.000 description 1
- 102000004190 Enzymes Human genes 0.000 description 1
- 108090000790 Enzymes Proteins 0.000 description 1
- 101710200424 Inosine-5'-monophosphate dehydrogenase Proteins 0.000 description 1
- 206010028813 Nausea Diseases 0.000 description 1
- 239000002202 Polyethylene glycol Substances 0.000 description 1
- 210000001744 T-lymphocyte Anatomy 0.000 description 1
- 206010047700 Vomiting Diseases 0.000 description 1
- 230000001133 acceleration Effects 0.000 description 1
- 239000008186 active pharmaceutical agent Substances 0.000 description 1
- 230000006838 adverse reaction Effects 0.000 description 1
- 150000001450 anions Chemical class 0.000 description 1
- 210000003719 b-lymphocyte Anatomy 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 230000000903 blocking effect Effects 0.000 description 1
- 210000001185 bone marrow Anatomy 0.000 description 1
- 239000006227 byproduct Substances 0.000 description 1
- 239000002775 capsule Substances 0.000 description 1
- 239000008395 clarifying agent Substances 0.000 description 1
- 150000001875 compounds Chemical class 0.000 description 1
- 239000006184 cosolvent Substances 0.000 description 1
- 239000013078 crystal Substances 0.000 description 1
- 238000000354 decomposition reaction Methods 0.000 description 1
- 230000007423 decrease Effects 0.000 description 1
- 238000005238 degreasing Methods 0.000 description 1
- 238000004090 dissolution Methods 0.000 description 1
- OPCRGEVPIBLWAY-QNRZBPGKSA-N ethyl (2E,4Z)-deca-2,4-dienoate Chemical compound CCCCC\C=C/C=C/C(=O)OCC OPCRGEVPIBLWAY-QNRZBPGKSA-N 0.000 description 1
- 125000005909 ethyl alcohol group Chemical group 0.000 description 1
- 231100000025 genetic toxicology Toxicity 0.000 description 1
- 230000001738 genotoxic effect Effects 0.000 description 1
- 238000000227 grinding Methods 0.000 description 1
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 1
- 238000005286 illumination Methods 0.000 description 1
- 230000001506 immunosuppresive effect Effects 0.000 description 1
- 229960003444 immunosuppressant agent Drugs 0.000 description 1
- 230000001861 immunosuppressant effect Effects 0.000 description 1
- 239000003018 immunosuppressive agent Substances 0.000 description 1
- 230000003993 interaction Effects 0.000 description 1
- 150000002500 ions Chemical class 0.000 description 1
- 230000007774 longterm Effects 0.000 description 1
- 210000004698 lymphocyte Anatomy 0.000 description 1
- 230000010534 mechanism of action Effects 0.000 description 1
- 239000002207 metabolite Substances 0.000 description 1
- 239000000693 micelle Substances 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 229960000951 mycophenolic acid Drugs 0.000 description 1
- 230000008693 nausea Effects 0.000 description 1
- 238000005457 optimization Methods 0.000 description 1
- 210000000056 organ Anatomy 0.000 description 1
- 229920001223 polyethylene glycol Polymers 0.000 description 1
- 230000002980 postoperative effect Effects 0.000 description 1
- 239000000843 powder Substances 0.000 description 1
- 238000004321 preservation Methods 0.000 description 1
- 230000035755 proliferation Effects 0.000 description 1
- 239000002213 purine nucleotide Substances 0.000 description 1
- 150000003212 purines Chemical class 0.000 description 1
- 150000003839 salts Chemical class 0.000 description 1
- 239000007787 solid Substances 0.000 description 1
- 238000001228 spectrum Methods 0.000 description 1
- 239000003381 stabilizer Substances 0.000 description 1
- 239000004094 surface-active agent Substances 0.000 description 1
- 239000000725 suspension Substances 0.000 description 1
- 238000002560 therapeutic procedure Methods 0.000 description 1
- 230000008673 vomiting Effects 0.000 description 1
Classifications
-
- 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
- A61K9/16—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
- A61K9/1605—Excipients; Inactive ingredients
- A61K9/1629—Organic macromolecular compounds
- A61K9/1641—Organic macromolecular compounds obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyethylene glycol, poloxamers
-
- 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
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
- A61K31/5375—1,4-Oxazines, e.g. morpholine
- A61K31/5377—1,4-Oxazines, e.g. morpholine not condensed and containing further heterocyclic rings, e.g. timolol
-
- 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
-
- 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
- A61K9/16—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
- A61K9/1605—Excipients; Inactive ingredients
- A61K9/1611—Inorganic compounds
-
- 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
- A61K9/16—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
- A61K9/1605—Excipients; Inactive ingredients
- A61K9/1617—Organic compounds, e.g. phospholipids, fats
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- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Engineering & Computer Science (AREA)
- Epidemiology (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Pharmacology & Pharmacy (AREA)
- Medicinal Chemistry (AREA)
- Inorganic Chemistry (AREA)
- Biophysics (AREA)
- Molecular Biology (AREA)
- Dermatology (AREA)
- Medicinal Preparation (AREA)
Abstract
The invention discloses a kind of hydrochloride for injection mycophenolate mofetil lyophilized preparation, raw material includes mycophenolate mofetil, polyoxyethylene sorbitan monoleate, anhydrous citric acid, hydrochloric acid, dehydrated alcohol and sodium hydroxide, and parts by weight recipe ratio is：5~200 parts of mycophenolate mofetil, 1~10 part of polyoxyethylene sorbitan monoleate, 0.1~2 part of anhydrous citric acid, 1~10 part of hydrochloric acid, 5~200 parts of dehydrated alcohols and 0.1~1 part of sodium hydroxide.The present invention also provides the preparation methods of above-mentioned hydrochloride for injection mycophenolate mofetil lyophilized preparation.The present invention is by changing the key problem in technology points such as product charging sequence, dosing temperature, solvent formula, lyophilized technique, the impurity level of product can be effectively controlled, and raising is to the tolerance degree of the influence factors such as light, heat, to extend the validity period of product, the storage condition requirement for expanding product, improves the economy and validity of product.
Description
Technical field
The present invention relates to pharmaceutical technology fields, and in particular to a kind of hydrochloride for injection mycophenolate mofetil lyophilized preparation and its
Preparation method.
Background technique
Neotype immunosuppressant --- mycophenolate mofetil is a kind of 2- ethyl ester derivative of mycophenolic acid, after degreasing
Being formed has the mould powder of the metabolite of immunosuppressive activity sour (MPA).MPA reversibly inhibits guanylic acid (GMP) to pass through
Rate-limiting enzyme in allusion quotation route of synthesis --- carnine acidohydrogenase (IMPDH), to block the warp of guanylic acid
Allusion quotation route of synthesis, exhausts guanylic acid, and then the synthesis of blocking dna and RNA.Therefore, MMF is by exhausting GMP selection
Property block the classical synthesis of T and the galloping purine nucleotide of bone-marrow-derived lymphocyte bird, to inhibit T lymph and B lymphocyte proliferation.It replaces
Mycophenolate has the characteristics that mechanism of action is unique, anti-repulsive interaction is strong, pharmacokinetics are superior, safety is good, cost performance is high
Deng, it has also become the important component in the postoperative new triple therapy of organ transplant.
Currently, mycophenolate mofetil listing dosage form has capsule, tablet, oral administration mixed suspension etc., but these oral preparations are often drawn
Play the adverse reactions such as nausea,vomiting,diarrhea.In addition, constitution decline can not be administered orally after patient carries out transfer operation, because
This, injection type becomes the preferred dosage form of clinical application.Mycophenolate mofetil is prepared into sterile lyophilized powder, facilitate preservation,
Transport and clinical application.
Publication number CN101953807A, entitled " a kind of Mycophenolate mofetil lyophilized powder injection for injection and its preparation side
The patent of invention of method " provides a kind of Mycophenolate mofetil lyophilized powder injection for injection, and active constituent is used to examine phenol for wheat
Ester is made with solubilizer polyethylene glycol -12- hydroxy stearic acid ester, and weight ratio is 250~1250: 100~500.In the patent
The stability data of announcement is worse than the former data for grinding drug, and impurity content is higher than original and grinds drug, according to the non-bad of Conformance Assessment
The requirement that effect property compares, the product will not pass through Conformance Assessment.
Publication number CN106913531A, the hair of entitled " a kind of mycophenolate mofetil freeze-dried composition and preparation method thereof "
Bright patent is mainly made of active constituent mycophenolate mofetil, stabilizer, cosolvent, pH adjusting agent and water for injection.The patent
Long-time stability data difference, the safety of product and validity leaves a question open,
Summary of the invention
To solve problems of the prior art, the present invention provides a kind of freeze-dryings of hydrochloride for injection mycophenolate mofetil
Preparation and preparation method thereof.The effectively impurity level of control product produces the lyophilized preparation that stability grinds product better than state's exogenesis
Product.
In order to achieve the object of the present invention, the technical solution adopted by the present invention is that：
A kind of hydrochloride for injection mycophenolate mofetil lyophilized preparation, raw material include mycophenolate mofetil, polyoxyethylene sorbitan monoleate, nothing
Citric acid monohydrate, hydrochloric acid, dehydrated alcohol and sodium hydroxide, parts by weight recipe ratio are：5~200 parts of mycophenolate mofetil, 1~10
Part polyoxyethylene sorbitan monoleate, 0.1~2 part of anhydrous citric acid, 1~10 part of hydrochloric acid, 5~200 parts of organic solvents and 0.1~1 part of hydroxide
Sodium.
Preferably, a kind of hydrochloride for injection mycophenolate mofetil lyophilized preparation, raw material include mycophenolate mofetil, poly- sorb
Ester 80, anhydrous citric acid, hydrochloric acid, dehydrated alcohol, sodium hydroxide, water for injection and nitrogen, parts by weight recipe ratio are：80~
120 parts of mycophenolate mofetil, 3~7 parts of polyoxyethylene sorbitan monoleates, 0.5~1.5 part of anhydrous citric acid, 5~10 parts of hydrochloric acid, 10~120 parts
Organic solvent and 0.3~0.5 part of sodium hydroxide.
Polyoxyethylene sorbitan monoleate reduces the turbidity of solution as the clarifying agent of solution, and as excipient to form specific nothing
Crystalline structure provides stable base structure, to prevent or slow down the decomposition of therapeutic agent.Anhydrous citric acid as buffer,
As addition H+And OH-The compound of pH variation is resisted when ion, it is ensured that pH value of solution is in particular range, when improving its production and using
Stability.Hydrochloric acid is compounded to form the villaumite of relative medicine with therapeutic agent as salt forming agent, anion chloride ion value.Sodium hydroxide
As pH adjusting agent, for solution to be adjusted to specific pH value.
Organic solvent of the present invention is one of ethyl alcohol, normal propyl alcohol, isopropanol, the tert-butyl alcohol and hydroxyl alcohol.
The present invention increases product stability by changing product solvent formula, passes through ethyl alcohol, normal propyl alcohol, isopropanol, uncle
The alcohols of butanol or other hydroxyls forms specific stabilized matrix knot as the auxiliary agent for forming specific anhydrous crystalline structure, auxiliary
Structure.
Preferably, the organic solvent is ethyl alcohol.Ethyl alcohol is formed as the auxiliary agent for forming specific anhydrous crystalline structure, auxiliary
Specific stabilized matrix structure.
The present invention also provides the methods for preparing above-mentioned hydrochloride for injection mycophenolate mofetil lyophilized preparation, including walk as follows
Suddenly：
(1) water for injection of 60% demand is added in Agitation Tank；
(2) sequentially add 0.1~2 part of anhydrous citric acid, 1~10 part of hydrochloric acid, 5~200 parts of dehydrated alcohols, 1~10 part it is poly-
Sorb ester 80 and 5~200 part mycophenolate mofetil, stirring is to forming uniform opalescence solution；
(3) medical fluid pH is adjusted to 3.0~4.0 using sodium hydroxide solution；
(4) the water for injection constant volume of remaining 40% demand is added, and fluid temperature is reduced to 20~25 DEG C；
(5) aseptic filtration, it is filling, after freeze-drying, obtain formulation products.
Preferably, the temperature of Agitation Tank is 40 DEG C~45 DEG C in step (1)~(3).
Technique is controlled by temperature, so that polyoxyethylene sorbitan monoleate is formed the micella of specific dimensions at a certain temperature to wrap up treatment
Agent, and the base structure for intersecting firm microparticle dispersion system is formed in freeze-drying process.
Preferably, the step (5) carries out aseptic filtration to medical fluid by two concatenated sterilizing filters.
The beneficial effects of the invention are as follows：
1, the present invention, which passes through, changes the key problem in technology points such as product charging sequence, dosing temperature, solvent formula, lyophilized technique,
The impurity level that product can be effectively controlled produces the lyophilized preparation product that stability grinds product better than state's exogenesis.
2, the product stability that the technique is produced significantly increases, can be by product more than the stability that state's exogenesis grinds product
The effect phase was promoted to 5 years from 3 years.Hydrochloric acid mycophenolate mofetil can be replaced in ester linkage breaking formation under light, thermocatalytic in the product
Mycophenolic Acid, if active pharmaceutical ingredient and polyoxyethylene sorbitan monoleate pass through the charging sequence of technology controlling and process such as production process, match liquid temperature
The formation such as degree, solvent formula intersect the solid structure of firm smaller size of microparticle dispersion system, can effectively prevent product
Ester linkage breaking reduces impurity to enhance the stability of product.
3, polyoxyethylene sorbitan monoleate is used as in freeze-drying finished product and generates as surfactant and association agent in this product solution
The excipient of the anhydrous crystal object of specific structure.The concentration of polyoxyethylene sorbitan monoleate is more than its critical micelle concentration in inventive formulation,
It is to exist in the form of micella wraps up therapeutic agent, therefore make poly- mountain by controlling specific charging sequence in medical fluid and redissolution liquid
Pear ester 80 wraps up therapeutic agent with the micella of uniform-dimension, and the base of uniformly firm microparticle dispersion system is formed in freeze-drying process
Body structure, the freeze-drying prods of institute's output can effectively prevent the ester linkage breaking of product to enhance the stability of product.It sequentially adds
Anhydrous citric acid, hydrochloric acid, dehydrated alcohol, polyoxyethylene sorbitan monoleate, and so that polyoxyethylene sorbitan monoleate is formed uniform-dimension by technological parameter
Therapeutic agent is added in micella, is allowed to dissolution and is scattered in micella, and is formed in freeze-drying process and intersect firm microparticle dispersion system
Base structure.
Specific embodiment
In order to it is clearer, explain purpose of the present invention technical solution in detail, below by related embodiment to this hair
It is bright to be described further.Following embodiment is only to illustrate implementation method of the invention, does not limit protection of the invention
Range.
Embodiment 1
A kind of hydrochloride for injection mycophenolate mofetil lyophilized preparation, raw material include mycophenolate mofetil, polyoxyethylene sorbitan monoleate, nothing
Citric acid monohydrate, hydrochloric acid, dehydrated alcohol, sodium hydroxide, water for injection and nitrogen, parts by weight recipe ratio are：100 parts are examined for wheat
Phenolic ester, 5 parts of polyoxyethylene sorbitan monoleates, 1 part of anhydrous citric acid, 8.42 parts of hydrochloric acid, 100 parts of dehydrated alcohols and 0.4 part of sodium hydroxide.
Embodiment 2
A kind of hydrochloride for injection mycophenolate mofetil lyophilized preparation, including mycophenolate mofetil, polyoxyethylene sorbitan monoleate, anhydrous Chinese holly
Rafter acid, hydrochloric acid, dehydrated alcohol, sodium hydroxide, water for injection and nitrogen, parts by weight recipe ratio are：50 parts of mycophenolate mofetil,
1 part of polyoxyethylene sorbitan monoleate, 0.1 part of anhydrous citric acid, 1 part of hydrochloric acid, 50 parts of dehydrated alcohols and 0.1 part of sodium hydroxide.
Embodiment 3
A kind of hydrochloride for injection mycophenolate mofetil lyophilized preparation, including mycophenolate mofetil, polyoxyethylene sorbitan monoleate, anhydrous Chinese holly
Rafter acid, hydrochloric acid, dehydrated alcohol, sodium hydroxide, water for injection and nitrogen, parts by weight recipe ratio are：200 parts are examined phenol for wheat
Ester, 10 parts of polyoxyethylene sorbitan monoleates, 2 parts of anhydrous citric acids, 15 parts of hydrochloric acid, 200 parts of dehydrated alcohols and 1 part of sodium hydroxide.
Embodiment 4
A kind of hydrochloride for injection mycophenolate mofetil lyophilized preparation, including mycophenolate mofetil, polyoxyethylene sorbitan monoleate, anhydrous Chinese holly
Rafter acid, hydrochloric acid, dehydrated alcohol, sodium hydroxide, water for injection and nitrogen, parts by weight recipe ratio are：80 parts of mycophenolate mofetil,
3 parts of polyoxyethylene sorbitan monoleates, 0.5 part of anhydrous citric acid, 5 parts of hydrochloric acid, 80 parts of dehydrated alcohols and 0.3 part of sodium hydroxide.
Embodiment 5
A kind of hydrochloride for injection mycophenolate mofetil lyophilized preparation, including mycophenolate mofetil, polyoxyethylene sorbitan monoleate, anhydrous Chinese holly
Rafter acid, hydrochloric acid, dehydrated alcohol, sodium hydroxide, water for injection and nitrogen, parts by weight recipe ratio are：120 parts are examined phenol for wheat
Ester, 7 parts of polyoxyethylene sorbitan monoleates, 1.5 parts of anhydrous citric acids, 9 parts of hydrochloric acid, 120 parts of dehydrated alcohols and 0.5 part of sodium hydroxide.
Embodiment 6
A kind of hydrochloride for injection mycophenolate mofetil lyophilized preparation, including mycophenolate mofetil, polyoxyethylene sorbitan monoleate, anhydrous Chinese holly
Rafter acid, hydrochloric acid, dehydrated alcohol, sodium hydroxide, water for injection and nitrogen, parts by weight recipe ratio are：110 parts are examined phenol for wheat
Ester, 6 parts of polyoxyethylene sorbitan monoleates, 1.1 parts of anhydrous citric acids, 10 parts of hydrochloric acid, 110 parts of dehydrated alcohols and 0.4 part of sodium hydroxide.
Embodiment 7
The present embodiment on the basis of embodiment 1, provides a kind of hydrochloride for injection mycophenolate mofetil lyophilized preparation
Preparation method includes the following steps：
(1) water for injection of 60% demand is added in Agitation Tank；
(2) be added 1 part of anhydrous citric acid, 8.42 parts of hydrochloric acid, 100 parts of dehydrated alcohols, 5 parts of polyoxyethylene sorbitan monoleates, 100 parts replace
Mycophenolate, stirring is to forming uniform opalescence solution；
(3) medical fluid pH is adjusted to 3.6 using sodium hydroxide solution；
(4) the water for injection constant volume of remaining 40% demand is added, and fluid temperature is reduced to 22 DEG C；
(5) aseptic filtration, it is filling, after freeze-drying, obtain formulation products.
Wherein, the temperature of Agitation Tank is 42 DEG C in step (1)~(3).
Embodiment 8
The present embodiment provides a kind of hydrochloride for injection mycophenolate mofetil lyophilized preparation on the basis of embodiment 2
Preparation method includes the following steps：
(1) water for injection of 60% demand is added in Agitation Tank；
(2) be added 0.1 part of anhydrous citric acid, 1 part of hydrochloric acid, 50 parts of dehydrated alcohols, 1 part of polyoxyethylene sorbitan monoleate, 50 parts replace wheat
Examine phenolic ester, stirring is to forming uniform opalescence solution；
(3) medical fluid pH is adjusted to 3.5 using sodium hydroxide solution；
(4) the water for injection constant volume of remaining 40% demand is added, and fluid temperature is reduced to 20 DEG C；
(5) aseptic filtration, it is filling, after freeze-drying, obtain formulation products.
Wherein, the temperature of Agitation Tank is 40 DEG C in step (1)~(3), and the step (5) concatenated is removed by two
Bacterium filter carries out aseptic filtration to medical fluid.
Embodiment 9
The present embodiment provides a kind of hydrochloride for injection mycophenolate mofetil lyophilized preparation on the basis of embodiment 3
Preparation method includes the following steps：
(1) water for injection of 60% demand is added in Agitation Tank；
(2) be added 2 parts of anhydrous citric acids, 15 parts of hydrochloric acid, 200 parts of dehydrated alcohols, 10 parts of polyoxyethylene sorbitan monoleates, 200 parts replace
Mycophenolate, stirring is to forming uniform opalescence solution；
(3) medical fluid pH is adjusted to 3.8 using sodium hydroxide solution；
(4) the water for injection constant volume of remaining 40% demand is added, and fluid temperature is reduced to 25 DEG C；
(5) aseptic filtration, it is filling, after freeze-drying, obtain formulation products.
Wherein, the temperature of Agitation Tank is 45 DEG C in step (1)~(3), and the step (5) concatenated is removed by two
Bacterium filter carries out aseptic filtration to medical fluid.
The Detection of Stability of product under 1 illumination condition of table
The Detection of Stability of product under 2 hot conditions of table
The Detection of Stability of product under 3 acceleration environment of table
The Detection of Stability of product under 4 long-term conditions of table
By table 1- table 4 as it can be seen that lyophilized preparation and original that the present invention by the optimization to production technology, produces grind drug matter
Amount is consistent with curative effect, meets the fundamental requirement of national drug Conformance Assessment, and stability grinds the drug of product better than original, reduces
The genotoxicity hidden danger of related impurities in impurity spectrum.And it improves to the tolerance degrees of the influence factors such as light, heat, to extend product
Validity period, expand the storage condition requirement of product, improve the economy and validity of product.
A specific embodiment of the invention above described embodiment only expresses, the description thereof is more specific and detailed, but simultaneously
Limitations on the scope of the patent of the present invention therefore cannot be interpreted as.It should be pointed out that for those of ordinary skill in the art
For, without departing from the inventive concept of the premise, various modifications and improvements can be made, these belong to guarantor of the invention
Protect range.
Claims (3)
1. a kind of preparation method of hydrochloride for injection mycophenolate mofetil lyophilized preparation, which is characterized in that raw material includes replacing wheat
Phenolic ester, polyoxyethylene sorbitan monoleate, anhydrous citric acid, hydrochloric acid, dehydrated alcohol and sodium hydroxide are examined, parts by weight recipe ratio is：5~200
Part mycophenolate mofetil, 1~10 part of polyoxyethylene sorbitan monoleate, 0.1~2 part of anhydrous citric acid, 1~10 part of hydrochloric acid, 5~200 parts it is anhydrous
Ethyl alcohol and 0.1~1 part of sodium hydroxide；
Include the following steps：
(1) water for injection of 60% demand is added in Agitation Tank；
(2) 0.1~2 part of anhydrous citric acid, 1~10 part of hydrochloric acid, 5~200 parts of dehydrated alcohols, 1~10 portion of poly- sorb are sequentially added
Ester 80 and 5~200 part mycophenolate mofetil, stirring is to forming uniform opalescence solution；
(3) medical fluid pH is adjusted to 3.0~4.0 using sodium hydroxide solution；
(4) the water for injection constant volume of remaining 40% demand is added, and fluid temperature is reduced to 20~25 DEG C；
(5) aseptic filtration, it is filling, after freeze-drying, obtain formulation products；
The temperature of Agitation Tank is 40 DEG C~45 DEG C in step (1)~(3).
2. a kind of preparation method of hydrochloride for injection mycophenolate mofetil lyophilized preparation according to claim 1, feature
It is, raw material includes mycophenolate mofetil, polyoxyethylene sorbitan monoleate, anhydrous citric acid, hydrochloric acid, dehydrated alcohol and sodium hydroxide, heavy
Measuring part recipe ratio is：80~120 parts of mycophenolate mofetil, 3~7 parts of polyoxyethylene sorbitan monoleates, 0.5~1.5 part of anhydrous citric acid, 5~
10 parts of hydrochloric acid, 10~100 parts of dehydrated alcohols and 0.3~0.5 part of sodium hydroxide.
3. a kind of preparation method of hydrochloride for injection mycophenolate mofetil lyophilized preparation according to claim 1, feature
It is, the step (5) carries out aseptic filtration to medical fluid by two concatenated sterilizing filters.
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| CN106913531B (en) * | 2015-12-25 | 2020-05-01 | 山东新时代药业有限公司 | Mycophenolate mofetil freeze-dried composition and preparation method thereof |
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