CN106581043A - Medicinal preparation suitable for Duchenne muscular dystrophy and preparation method thereof - Google Patents
Medicinal preparation suitable for Duchenne muscular dystrophy and preparation method thereof Download PDFInfo
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- CN106581043A CN106581043A CN201610924386.4A CN201610924386A CN106581043A CN 106581043 A CN106581043 A CN 106581043A CN 201610924386 A CN201610924386 A CN 201610924386A CN 106581043 A CN106581043 A CN 106581043A
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- 206010013801 Duchenne Muscular Dystrophy Diseases 0.000 title claims abstract description 27
- 238000002360 preparation method Methods 0.000 title claims description 37
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 claims abstract description 34
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Chemical compound O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims abstract description 30
- 229950005470 eteplirsen Drugs 0.000 claims abstract description 26
- 239000008215 water for injection Substances 0.000 claims abstract description 22
- 239000000825 pharmaceutical preparation Substances 0.000 claims abstract description 21
- KPQJOKRSYYJJEL-VLQRKCJKSA-K [Na+].[Na+].CC1(C)[C@H](CC[C@@]2(C)[C@H]1CC[C@]1(C)[C@@H]2C(=O)C=C2[C@@H]3C[C@](C)(CC[C@]3(C)CC[C@@]12C)C([O-])=O)O[C@H]1O[C@@H]([C@@H](O)[C@H](O)[C@H]1O[C@@H]1O[C@@H]([C@@H](O)[C@H](O)[C@H]1O)C([O-])=O)C([O-])=O Chemical compound [Na+].[Na+].CC1(C)[C@H](CC[C@@]2(C)[C@H]1CC[C@]1(C)[C@@H]2C(=O)C=C2[C@@H]3C[C@](C)(CC[C@]3(C)CC[C@@]12C)C([O-])=O)O[C@H]1O[C@@H]([C@@H](O)[C@H](O)[C@H]1O[C@@H]1O[C@@H]([C@@H](O)[C@H](O)[C@H]1O)C([O-])=O)C([O-])=O KPQJOKRSYYJJEL-VLQRKCJKSA-K 0.000 claims abstract description 17
- 239000011780 sodium chloride Substances 0.000 claims abstract description 17
- MBBZMMPHUWSWHV-BDVNFPICSA-N N-methylglucamine Chemical compound CNC[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO MBBZMMPHUWSWHV-BDVNFPICSA-N 0.000 claims abstract description 10
- 229960003194 meglumine Drugs 0.000 claims abstract description 10
- 238000012360 testing method Methods 0.000 claims abstract description 8
- 239000004480 active ingredient Substances 0.000 claims abstract 4
- 239000000047 product Substances 0.000 claims description 45
- 238000007689 inspection Methods 0.000 claims description 22
- 239000007788 liquid Substances 0.000 claims description 22
- 239000000243 solution Substances 0.000 claims description 21
- 239000003708 ampul Substances 0.000 claims description 20
- 238000003756 stirring Methods 0.000 claims description 19
- 238000011049 filling Methods 0.000 claims description 13
- 238000002347 injection Methods 0.000 claims description 12
- 239000007924 injection Substances 0.000 claims description 12
- 238000004806 packaging method and process Methods 0.000 claims description 10
- 230000001954 sterilising effect Effects 0.000 claims description 10
- 238000005406 washing Methods 0.000 claims description 10
- 239000013067 intermediate product Substances 0.000 claims description 9
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 claims description 8
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 claims description 6
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 claims description 6
- 239000000203 mixture Substances 0.000 claims description 6
- 229910000147 aluminium phosphate Inorganic materials 0.000 claims description 4
- 238000004382 potting Methods 0.000 claims 3
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims 2
- 239000002033 PVDF binder Substances 0.000 claims 2
- 239000005388 borosilicate glass Substances 0.000 claims 2
- 230000007935 neutral effect Effects 0.000 claims 2
- 229920002981 polyvinylidene fluoride Polymers 0.000 claims 2
- 239000003814 drug Substances 0.000 abstract description 11
- 238000011835 investigation Methods 0.000 abstract description 3
- 230000007774 longterm Effects 0.000 abstract description 3
- 239000002245 particle Substances 0.000 abstract 2
- 239000003002 pH adjusting agent Substances 0.000 description 17
- 238000005516 engineering process Methods 0.000 description 14
- 235000002639 sodium chloride Nutrition 0.000 description 13
- 238000000034 method Methods 0.000 description 12
- 230000000052 comparative effect Effects 0.000 description 10
- 230000008569 process Effects 0.000 description 10
- 239000013618 particulate matter Substances 0.000 description 9
- 238000005070 sampling Methods 0.000 description 9
- RZVAJINKPMORJF-UHFFFAOYSA-N Acetaminophen Chemical compound CC(=O)NC1=CC=C(O)C=C1 RZVAJINKPMORJF-UHFFFAOYSA-N 0.000 description 8
- 241000894006 Bacteria Species 0.000 description 8
- 238000003556 assay Methods 0.000 description 8
- 238000001514 detection method Methods 0.000 description 8
- 238000001035 drying Methods 0.000 description 8
- 239000005297 pyrex Substances 0.000 description 8
- WCUXLLCKKVVCTQ-UHFFFAOYSA-M Potassium chloride Chemical compound [Cl-].[K+] WCUXLLCKKVVCTQ-UHFFFAOYSA-M 0.000 description 6
- 230000008859 change Effects 0.000 description 6
- 238000002156 mixing Methods 0.000 description 6
- 239000003182 parenteral nutrition solution Substances 0.000 description 6
- 230000001186 cumulative effect Effects 0.000 description 5
- 238000002474 experimental method Methods 0.000 description 5
- 150000001412 amines Chemical class 0.000 description 4
- 201000010099 disease Diseases 0.000 description 4
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 4
- 241001635911 Sarepta Species 0.000 description 3
- BNIILDVGGAEEIG-UHFFFAOYSA-L disodium hydrogen phosphate Chemical compound [Na+].[Na+].OP([O-])([O-])=O BNIILDVGGAEEIG-UHFFFAOYSA-L 0.000 description 3
- HUGILZFVSVLCAO-XVKRXUDYSA-N drisapersen Chemical compound CO[C@@H]1[C@H](O)[C@@H](COP(=O)(S)O[C@@H]2[C@@H](COP(=O)(S)O[C@@H]3[C@@H](COP(=O)(S)O[C@@H]4[C@@H](COP(=O)(S)O[C@@H]5[C@@H](COP(=O)(S)O[C@@H]6[C@@H](COP(=O)(S)O[C@@H]7[C@@H](COP(=O)(S)O[C@@H]8[C@@H](COP(=O)(S)O[C@@H]9[C@@H](COP(=O)(S)O[C@@H]%10[C@@H](COP(=O)(S)O[C@@H]%11[C@@H](COP(=O)(S)O[C@@H]%12[C@@H](COP(=O)(S)O[C@@H]%13[C@@H](COP(=O)(S)O[C@@H]%14[C@@H](COP(=O)(S)O[C@@H]%15[C@@H](COP(=O)(S)O[C@@H]%16[C@@H](COP(=O)(S)O[C@@H]%17[C@@H](COP(=O)(S)O[C@@H]%18[C@@H](COP(=O)(S)O[C@@H]%19[C@@H](COP(=O)(S)O[C@@H]%20[C@@H](CO)O[C@H]([C@@H]%20OC)N%21C=CC(=O)NC%21=O)O[C@H]([C@@H]%19OC)N%22C=CC(=NC%22=O)N)O[C@H]([C@@H]%18OC)n%23cnc%24c(N)ncnc%23%24)O[C@H]([C@@H]%17OC)n%25cnc%26c(N)ncnc%25%26)O[C@H]([C@@H]%16OC)n%27cnc%28C(=O)NC(=Nc%27%28)N)O[C@H]([C@@H]%15OC)n%29cnc%30C(=O)NC(=Nc%29%30)N)O[C@H]([C@@H]%14OC)n%31cnc%32c(N)ncnc%31%32)O[C@H]([C@@H]%13OC)n%33cnc%34c(N)ncnc%33%34)O[C@H]([C@@H]%12OC)n%35cnc%36C(=O)NC(=Nc%35%36)N)O[C@H]([C@@H]%11OC)n%37cnc%38c(N)ncnc%37%38)O[C@H]([C@@H]%10OC)N%39C=CC(=O)NC%39=O)O[C@H]([C@@H]9OC)n%40cnc%41C(=O)NC(=Nc%40%41)N)O[C@H]([C@@H]8OC)n%42cnc%43C(=O)NC(=Nc%42%43)N)O[C@H]([C@@H]7OC)N%44C=CC(=NC%44=O)N)O[C@H]([C@@H]6OC)n%45cnc%46c(N)ncnc%45%46)O[C@H]([C@@H]5OC)N%47C=CC(=O)NC%47=O)O[C@H]([C@@H]4OC)N%48C=CC(=O)NC%48=O)O[C@H]([C@@H]3OC)N%49C=CC(=O)NC%49=O)O[C@H]([C@@H]2OC)N%50C=CC(=NC%50=O)N)O[C@H]1N%51C=CC(=O)NC%51=O HUGILZFVSVLCAO-XVKRXUDYSA-N 0.000 description 3
- 230000000694 effects Effects 0.000 description 3
- 229910000402 monopotassium phosphate Inorganic materials 0.000 description 3
- 235000019796 monopotassium phosphate Nutrition 0.000 description 3
- 201000006938 muscular dystrophy Diseases 0.000 description 3
- 239000002547 new drug Substances 0.000 description 3
- PJNZPQUBCPKICU-UHFFFAOYSA-N phosphoric acid;potassium Chemical compound [K].OP(O)(O)=O PJNZPQUBCPKICU-UHFFFAOYSA-N 0.000 description 3
- 239000001103 potassium chloride Substances 0.000 description 3
- 235000011164 potassium chloride Nutrition 0.000 description 3
- 238000012797 qualification Methods 0.000 description 3
- OOUGLTULBSNHNF-UHFFFAOYSA-N 3-[5-(2-fluorophenyl)-1,2,4-oxadiazol-3-yl]benzoic acid Chemical compound OC(=O)C1=CC=CC(C=2N=C(ON=2)C=2C(=CC=CC=2)F)=C1 OOUGLTULBSNHNF-UHFFFAOYSA-N 0.000 description 2
- 206010028372 Muscular weakness Diseases 0.000 description 2
- SMWDFEZZVXVKRB-UHFFFAOYSA-N Quinoline Chemical compound N1=CC=CC2=CC=CC=C21 SMWDFEZZVXVKRB-UHFFFAOYSA-N 0.000 description 2
- 230000000692 anti-sense effect Effects 0.000 description 2
- 229960003995 ataluren Drugs 0.000 description 2
- 229960000378 drisapersen Drugs 0.000 description 2
- 230000007246 mechanism Effects 0.000 description 2
- 230000008439 repair process Effects 0.000 description 2
- 150000003431 steroids Chemical class 0.000 description 2
- 108010069091 Dystrophin Proteins 0.000 description 1
- 108700024394 Exon Proteins 0.000 description 1
- 206010064571 Gene mutation Diseases 0.000 description 1
- 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 1
- 208000026350 Inborn Genetic disease Diseases 0.000 description 1
- VTAJIXDZFCRWBR-UHFFFAOYSA-N Licoricesaponin B2 Natural products C1C(C2C(C3(CCC4(C)CCC(C)(CC4C3=CC2)C(O)=O)C)(C)CC2)(C)C2C(C)(C)CC1OC1OC(C(O)=O)C(O)C(O)C1OC1OC(C(O)=O)C(O)C(O)C1O VTAJIXDZFCRWBR-UHFFFAOYSA-N 0.000 description 1
- 208000010428 Muscle Weakness Diseases 0.000 description 1
- 206010028289 Muscle atrophy Diseases 0.000 description 1
- 210000001766 X chromosome Anatomy 0.000 description 1
- 230000001133 acceleration Effects 0.000 description 1
- 239000002253 acid Substances 0.000 description 1
- 230000037444 atrophy Effects 0.000 description 1
- 239000003795 chemical substances by application Substances 0.000 description 1
- 150000004985 diamines Chemical class 0.000 description 1
- ANCLJVISBRWUTR-UHFFFAOYSA-N diaminophosphinic acid Chemical compound NP(N)(O)=O ANCLJVISBRWUTR-UHFFFAOYSA-N 0.000 description 1
- 238000010790 dilution Methods 0.000 description 1
- 239000012895 dilution Substances 0.000 description 1
- 238000004090 dissolution Methods 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 208000016361 genetic disease Diseases 0.000 description 1
- 239000003862 glucocorticoid Substances 0.000 description 1
- LPLVUJXQOOQHMX-UHFFFAOYSA-N glycyrrhetinic acid glycoside Natural products C1CC(C2C(C3(CCC4(C)CCC(C)(CC4C3=CC2=O)C(O)=O)C)(C)CC2)(C)C2C(C)(C)C1OC1OC(C(O)=O)C(O)C(O)C1OC1OC(C(O)=O)C(O)C(O)C1O LPLVUJXQOOQHMX-UHFFFAOYSA-N 0.000 description 1
- 229960004949 glycyrrhizic acid Drugs 0.000 description 1
- UYRUBYNTXSDKQT-UHFFFAOYSA-N glycyrrhizic acid Natural products CC1(C)C(CCC2(C)C1CCC3(C)C2C(=O)C=C4C5CC(C)(CCC5(C)CCC34C)C(=O)O)OC6OC(C(O)C(O)C6OC7OC(O)C(O)C(O)C7C(=O)O)C(=O)O UYRUBYNTXSDKQT-UHFFFAOYSA-N 0.000 description 1
- 239000001685 glycyrrhizic acid Substances 0.000 description 1
- 235000019410 glycyrrhizin Nutrition 0.000 description 1
- LPLVUJXQOOQHMX-QWBHMCJMSA-N glycyrrhizinic acid Chemical compound O([C@@H]1[C@@H](O)[C@H](O)[C@H](O[C@@H]1O[C@@H]1C([C@H]2[C@]([C@@H]3[C@@]([C@@]4(CC[C@@]5(C)CC[C@@](C)(C[C@H]5C4=CC3=O)C(O)=O)C)(C)CC2)(C)CC1)(C)C)C(O)=O)[C@@H]1O[C@H](C(O)=O)[C@@H](O)[C@H](O)[C@H]1O LPLVUJXQOOQHMX-QWBHMCJMSA-N 0.000 description 1
- JGPMMRGNQUBGND-UHFFFAOYSA-N idebenone Chemical compound COC1=C(OC)C(=O)C(CCCCCCCCCCO)=C(C)C1=O JGPMMRGNQUBGND-UHFFFAOYSA-N 0.000 description 1
- 229960004135 idebenone Drugs 0.000 description 1
- 230000006872 improvement Effects 0.000 description 1
- 230000001939 inductive effect Effects 0.000 description 1
- 230000006742 locomotor activity Effects 0.000 description 1
- 210000004072 lung Anatomy 0.000 description 1
- 239000002075 main ingredient Substances 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- 201000000585 muscular atrophy Diseases 0.000 description 1
- 230000035772 mutation Effects 0.000 description 1
- 230000036473 myasthenia Effects 0.000 description 1
- 210000004165 myocardium Anatomy 0.000 description 1
- 230000010494 opalescence Effects 0.000 description 1
- 239000002859 orphan drug Substances 0.000 description 1
- 229940000673 orphan drug Drugs 0.000 description 1
- LFGREXWGYUGZLY-UHFFFAOYSA-N phosphoryl Chemical group [P]=O LFGREXWGYUGZLY-UHFFFAOYSA-N 0.000 description 1
- 239000000902 placebo Substances 0.000 description 1
- 229940068196 placebo Drugs 0.000 description 1
- 230000001681 protective effect Effects 0.000 description 1
- 108090000623 proteins and genes Proteins 0.000 description 1
- 230000009467 reduction Effects 0.000 description 1
- 238000011160 research Methods 0.000 description 1
- 150000003839 salts Chemical group 0.000 description 1
- 210000002027 skeletal muscle Anatomy 0.000 description 1
- 229910052708 sodium Inorganic materials 0.000 description 1
- 239000011734 sodium Substances 0.000 description 1
- 239000013589 supplement Substances 0.000 description 1
- 238000002560 therapeutic procedure Methods 0.000 description 1
- 238000005303 weighing Methods 0.000 description 1
Classifications
-
- 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
- A61K31/74—Synthetic polymeric materials
- A61K31/785—Polymers containing nitrogen
- A61K31/787—Polymers containing nitrogen containing heterocyclic rings having nitrogen as a ring hetero atom
-
- 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
- A61K31/13—Amines
- A61K31/133—Amines having hydroxy groups, e.g. sphingosine
-
- 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
- A61K31/7028—Compounds having saccharide radicals attached to non-saccharide compounds by glycosidic linkages
- A61K31/7034—Compounds having saccharide radicals attached to non-saccharide compounds by glycosidic linkages attached to a carbocyclic compound, e.g. phloridzin
- A61K31/704—Compounds having saccharide radicals attached to non-saccharide compounds by glycosidic linkages attached to a carbocyclic compound, e.g. phloridzin attached to a condensed carbocyclic ring system, e.g. sennosides, thiocolchicosides, escin, daunorubicin
Landscapes
- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- Pharmacology & Pharmacy (AREA)
- Epidemiology (AREA)
- Medicinal Chemistry (AREA)
- Chemical & Material Sciences (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Molecular Biology (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Medicinal Preparation (AREA)
Abstract
本发明属于医药技术领域，具体涉及一种适用于杜氏肌营养不良症的药物制剂：由活性成分Eteplirsen、氯化钠、甘草酸二钠、葡甲胺、pH调节剂和注射用水组成。本发明质量稳定，经长期加速试验考察发现，其外观性状、pH值、可见异物、不溶性微粒和效价均未发生明显变化；同时本发明与0.9％氯化钠配伍后，室温下长时间放置，不溶性微粒和效价也均未发生明显变化，极大的方便了临床的使用，提高了患者使用的安全性。The invention belongs to the technical field of medicine, and specifically relates to a pharmaceutical preparation suitable for Duchenne muscular dystrophy: it consists of active ingredients Eteplirsen, sodium chloride, disodium glycyrrhizinate, meglumine, a pH regulator and water for injection. The quality of the present invention is stable, and it is found through long-term accelerated test investigation that its appearance, pH value, visible foreign matter, insoluble particles and potency have not changed significantly; at the same time, after the present invention is compatible with 0.9% sodium chloride, it can be placed at room temperature for a long time , the insoluble particles and potency have not changed significantly, which greatly facilitates clinical use and improves the safety of patients.
Description
Technical field
The invention belongs to pharmaceutical technology field, and in particular to a kind of pharmaceutical preparation suitable for duchenne muscular dystrophy and
Its preparation method.
Background technology
Duchenne muscular dystrophy (DMD) is a kind of X chromosome recessive genetic disorder, takes place mostly in boy.According to statistics,
The whole world just has a people to suffer from this disease averagely per 3500 in newborn boy baby.Patient constantly will degenerate preschool because of skeletal muscle
Existing muscle weakness or atrophy, cause inconvenient walking.Probably at 7 years old to 12 years old, locomotor activity can be thoroughly lost, generally to more than 20
Year will be dead because of myocardium, lung myasthenia.For the disease, medical circle there is no effective therapy.
At present, clinically the only effective treatment means are glucocorticoid steroids medicines, and steroids has seriously
Side effect, it is impossible to long-term taking.Due to the harsh supervision standards of FDA, there are 4 DMD new drugs to suffer in succession within half a year before this
The refusal of FDA, the hope of DMD infants and family members is hit again and again.Mid-January, FDA have rejected BioMarin companies DMD
The application for quotation of new drug Kyndrisa (drisapersen), reason is drisapersen validity lacks of evidence；23 days 2 months,
FDA refusals accept the application for quotation of PTC Therapeutics company ataluren, it is believed that the application materials of PTC are imperfect, nothing
Method is entered and subsequently evaluates flow process.Ataluren is the oral albumen repair medicine of first in class, for treating nonsense
Saltant type duchenne muscular dystrophy (nmDMD), once obtains European Union and has ready conditions approval in August, 2014；April 25, FDA consultings
The committee is with 7:6 voting results (3 people abstention) have vetoed the application for quotation of Sarepta companies eteplirsen, and reason is
Although eteplirsen safe enoughs but curative effect are not enough, need to do for supplement that one random, double blinding, placebo controlled clinical research；July
14, FDA refusals accepted the acceleration approval application of Raxone, it is believed that its lack of evidence.
FDA have approved the Exondys 51 of SAREPTA THERAPEUTICS INC on the 19th in September in 2016
(eteplirsen) parenteral solution, Exondys 51 (eteplirsen) is the new drug of first treatment duchenne muscular dystrophy, is used
In the DMD patient for confirming to carry the exon jump mutation of myotrophy GFP the 51st.Although before eteplirsen also by
The ballot of FDA Advisory Boards was vetoed, but was obtained Orphan drug qualification, express passway qualification, preferentially evaluated qualification
Eteplirsen, this time still obtains FDA and accelerates to criticize by the surrogate end point that can make myotrophy protein content increase by 0.28%
It is accurate.
Eteplirsen is for oligomer (phosphorodiamidate using Sarepta novel phosphoryl diamine quinoline
Morpholinooligomer, PMO) based on chemistry and proprietary exon skipping technology, skip 51 extras of Dys genes
Aobvious son, so as to repair specific gene mutation.By 51 exons that jump, eteplirsen can Restore gene ability, produce
Life is a kind of shorter but still has functional Dys albumen, so as to process that is stable or significantly slowing disease, extends and improve DMD trouble
The quality of life of person.The molecular formula of Eteplirsen is C364H569N177O122P30, and its molecular weight is 10305.7 dalton,
Its molecular structure is：
At present, Eteplirsen is mainly injection, and Chinese Patent Application No. 201480026195.5 discloses one kind and changes
The composition for treating muscular dystrophy for entering, patent describes treating muscular dystrophy by applying antisense molecule
Improved composition and method, the antisense molecule can with reference to people's dystrophin gene in selected target position with inducing exon
Jump.
Inventor has found that in an experiment the storage temperature of the parenteral solutions of Exondys 51 is 2-8 DEG C, but either in 2-8
DEG C storage is still deposited at room temperature, and different degrees of increase can all occur in its particulate matter and potency；Furthermore, Exondys
During 51 parenteral solution Clinical practices, drip-feed after the sodium chloride solution dilution with 0.9% is needed, but with standing time
Prolongation its particulate matter become big, its potency is reduced, and using current technology, can not solve these problems.
The content of the invention
Not enough for more than, inventor passes through substantial amounts of experiment investigation, there is provided one kind is applied to Du Shi muscular dystrophy
Pharmaceutical preparation of disease and preparation method thereof, a kind of pharmaceutical preparation suitable for duchenne muscular dystrophy：By active component
Eteplirsen, sodium chloride, disodium glycyrrhizinate, meglumine, pH adjusting agent and water for injection composition.
A kind of pharmaceutical preparation suitable for duchenne muscular dystrophy that the present invention is provided：Described active component
The concentration of Eteplirsen is 25.0～100.0mg/ml, more preferably 50.0mg/ml.
A kind of pharmaceutical preparation suitable for duchenne muscular dystrophy that the present invention is provided：Described sodium chloride is isotonic tune
Section agent, its concentration is 7.0～9.0mg/ml, more preferably 8.4mg/ml..
A kind of pharmaceutical preparation suitable for duchenne muscular dystrophy that the present invention is provided：Described disodium glycyrrhizinate concentration
For 0.1～0.8mg/ml, more preferably 0.3mg/ml.
A kind of pharmaceutical preparation suitable for duchenne muscular dystrophy that the present invention is provided：The concentration of the meglumine is
0.5～1.5mg/ml, more preferably 0.8mg/ml.
A kind of pharmaceutical preparation suitable for duchenne muscular dystrophy that the present invention is provided：The pH value of the pharmaceutical preparation is
6.2～7.2, more preferably 6.7.
A kind of pharmaceutical preparation suitable for duchenne muscular dystrophy that the present invention is provided：Described pH adjusting agent is salt
One kind in acid, acetic acid, phosphoric acid or citric acid or several, more preferably phosphoric acid.
The present invention provide a kind of pharmaceutical preparation suitable for duchenne muscular dystrophy preparation method, mainly include with
Lower step：
A, ampoule process：By ampoule by ultrasonic bottle washing machine washes clean, Jing tunnel types sterilizing drying machine is killed at 290 DEG C
After bacterium is dried, bottling department is reached standby.
B, preparation：1. the Eteplirsen and disodium glycyrrhizinate that weigh formula ratio are dissolved in of the total volume 20～40% note
Penetrate with water, stirring mixes 10～20 minutes；
2. mend to 1 Chinese medicine liquid and inject water to the 80～90% of cumulative volume, stirring and dissolving is well mixed, add formula ratio
Meglumine, stirring liquid adjusts pH value to 6.2～7.2 to colorless clear liquid with pH adjusting agent；
3. total amount is settled to water for injection, pH value is adjusted to 6.2～7.2 with pH adjusting agent again, in the middle of sampling detection
Product solution, qualified rear preparation embedding.
C, embedding：Solution is filtered to bottling department and filtered, and filter core is Kynoar filter core, filling in neutrality according to 2ml/
In Pyrex control note office preparation bottle.
D, lamp inspection, packaging：Lamp inspection is carried out to product, substandard product is rejected, qualified products pack to obtain finished product.
E, put in storage after the assay was approved.
Invention further provides a kind of preparation method of the pharmaceutical preparation suitable for duchenne muscular dystrophy, mainly
Comprise the following steps：
A, ampoule process：By ampoule by ultrasonic bottle washing machine washes clean, Jing tunnel types sterilizing drying machine is killed at 290 DEG C
After bacterium is dried, bottling department is reached standby.
B, preparation：1. the Eteplirsen and disodium glycyrrhizinate that weigh formula ratio are dissolved in of the total volume 30% injection
In water, stirring mixing 15 minutes；
2. mend to 1 Chinese medicine liquid and inject water to the 85% of cumulative volume, be uniformly mixed, add Portugal's first of formula ratio
Amine, stirring liquid to colorless clear liquid adjusts pH value to 6.7 with pH adjusting agent；
3. total amount is settled to water for injection, adjusts pH value to 6.7 with pH adjusting agent again, sampling detection intermediate products are molten
Liquid, qualified rear preparation embedding.
C, embedding：Solution is filtered to bottling department and filtered, and filter core is Kynoar filter core, filling in neutrality according to 2ml/
In Pyrex control injection bottle.
D, lamp inspection, packaging：Lamp inspection is carried out to product, substandard product is rejected, qualified products pack to obtain finished product.
E, put in storage after the assay was approved.
A kind of pharmaceutical preparation suitable for duchenne muscular dystrophy that the present invention is provided and preparation method thereof and existing skill
Art is compared with advantages below：Steady quality of the present invention, the long-term accelerated tests of Jing are investigated and found, its appearance character, pH value, visible
There is no significant change in foreign matter, particulate matter and potency；It is long under room temperature simultaneously after of the invention and 0.9% sodium chloride compatibility
Time places, and particulate matter and potency do not occur significant change yet, greatly facilitates the use of clinic, improves patient
The security for using.
Specific embodiment
Embodiment 1：
Prescription
Preparation technology
A, ampoule process：By ampoule by ultrasonic bottle washing machine washes clean, Jing tunnel types sterilizing drying machine is killed at 290 DEG C
After bacterium is dried, bottling department is reached standby；
B, preparation：1. the Eteplirsen and disodium glycyrrhizinate that weigh formula ratio are dissolved in of the total volume 30% injection
In water, stirring mixing 15 minutes；
2. mend to 1 Chinese medicine liquid and inject water to the 85% of cumulative volume, be uniformly mixed, add Portugal's first of formula ratio
Amine, stirring liquid to colorless clear liquid adjusts pH value with pH adjusting agent；
3. total amount is settled to water for injection, adjusts pH value with pH adjusting agent again, sampling detection intermediate products solution is closed
Prepare embedding after lattice.
C, embedding：Solution is filtered to bottling department and filtered, and filter core is Kynoar filter core, filling in neutrality according to 2ml/
In Pyrex control injection bottle.
D, lamp inspection, packaging：Lamp inspection is carried out to product, substandard product is rejected, qualified products pack to obtain finished product.
E, put in storage after the assay was approved.
Embodiment 2：
Prescription
Preparation technology:With embodiment 1
Embodiment 3：
Prescription
Preparation technology:With embodiment 1
Embodiment 4：
Prescription
Preparation technology:With embodiment 1
Embodiment 5：
Prescription
Preparation technology:With embodiment 1
Comparative example 1：
Prescription
Preparation technology
A, ampoule process：By ampoule by ultrasonic bottle washing machine washes clean, Jing tunnel types sterilizing drying machine is killed at 290 DEG C
After bacterium is dried, bottling department is reached standby.
B, preparation：1. sodium chloride, potassium chloride, potassium dihydrogen phosphate, disodium hydrogen phosphate and the Eteplirsen of formula ratio are weighed
In being dissolved in of the total volume 80% water for injection, stirring mixed dissolution is uniform, and with pH adjusting agent pH value is adjusted；
2. total amount is settled to water for injection, adjusts pH value with pH adjusting agent again, sampling detection intermediate products solution is closed
Prepare embedding after lattice.
C, embedding：Solution is filtered to bottling department and filtered, and filter core is Kynoar filter core, filling in neutrality according to 2ml/
In Pyrex control injection medicament.
D, lamp inspection, packaging：Lamp inspection is carried out to product, substandard product is rejected, qualified products pack to obtain finished product.
E, put in storage after the assay was approved.
Comparative example 2：
Prescription
Preparation technology
A, ampoule process：By ampoule by ultrasonic bottle washing machine washes clean, Jing tunnel types sterilizing drying machine is killed at 290 DEG C
After bacterium is dried, bottling department is reached standby.
B, preparation：1. weigh the sodium chloride of formula ratio, disodium glycyrrhizinate, potassium chloride, potassium dihydrogen phosphate, disodium hydrogen phosphate and
Eteplirsen is dissolved in of the total volume 30% water for injection, stirring mixing 15 minutes, and with pH adjusting agent pH value is adjusted；
2. total amount is settled to water for injection, adjusts pH value with pH adjusting agent again, sampling detection intermediate products solution is closed
Prepare embedding after lattice.
C, embedding：Solution is filtered to bottling department and filtered, and filter core is Kynoar filter core, filling in neutrality according to 2ml/
In Pyrex control injection bottle.
D, lamp inspection, packaging：Lamp inspection is carried out to product, substandard product is rejected, qualified products pack to obtain finished product.
E, put in storage after the assay was approved.
Comparative example 3：
Prescription
Preparation technology
A, ampoule process：By ampoule by ultrasonic bottle washing machine washes clean, Jing tunnel types sterilizing drying machine is killed at 290 DEG C
After bacterium is dried, bottling department is reached standby；
B, preparation：1. sodium chloride, disodium glycyrrhizinate and the Eteplirsen for weighing formula ratio is dissolved in of the total volume 30%
Water for injection in, stirring mixing 15 minutes；
2. be settled to total amount with water for injection, with pH adjusting agent adjust pH value, sampling detection intermediate products solution, it is qualified after
Prepare embedding；
C, embedding：Solution is filtered to bottling department and filtered, and filter core is Kynoar filter core, filling in neutrality according to 2ml/
In Pyrex control injection bottle；
D, lamp inspection, packaging：Lamp inspection is carried out to product, substandard product is rejected, qualified products pack to obtain finished product；
E, put in storage after the assay was approved.
Comparative example 4：
Prescription
Preparation technology
A, ampoule process：By ampoule by ultrasonic bottle washing machine washes clean, Jing tunnel types sterilizing drying machine is killed at 290 DEG C
After bacterium is dried, bottling department is reached standby.
B, preparation：1. weigh the sodium chloride of formula ratio, glycyrrhizic acid two and be dissolved in of the total volume 30% with sodium Eteplirsen
Water for injection in, stirring mixing 15 minutes；
2. mend to 1 Chinese medicine liquid and inject water to the 85% of cumulative volume, be uniformly mixed, add Portugal's first of formula ratio
Amine, stirring liquid to colorless clear liquid adjusts pH value with pH adjusting agent；
3. total amount is settled to water for injection, adjusts pH value with pH adjusting agent again, sampling detection intermediate products solution is closed
Prepare embedding after lattice.
C, embedding：Solution is filtered to bottling department and filtered, and filter core is Kynoar filter core, filling in neutrality according to 2ml/
In Pyrex control injection bottle.
D, lamp inspection, packaging：Lamp inspection is carried out to product, substandard product is rejected, qualified products pack to obtain finished product.
E, put in storage after the assay was approved.
Comparative example 5：
Prescription
Preparation technology
A, ampoule process：By ampoule by ultrasonic bottle washing machine washes clean, Jing tunnel types sterilizing drying machine is killed at 290 DEG C
After bacterium is dried, bottling department is reached standby.
B, preparation：1. weigh the sodium chloride of formula ratio, disodium glycyrrhizinate, potassium chloride, potassium dihydrogen phosphate, disodium hydrogen phosphate and
Eteplirsen is dissolved in the water for injection for accounting for of the total volume 30%, stirring mixing 15 minutes；
2. mend to 1 Chinese medicine liquid and inject water to the 85% of cumulative volume, be uniformly mixed, add Portugal's first of formula ratio
Amine, stirring liquid to colorless clear liquid adjusts pH value with pH adjusting agent；
3. total amount is settled to water for injection, adjusts pH value with pH adjusting agent again, sampling detection intermediate products solution is closed
Prepare embedding after lattice.
C, embedding：Solution is filtered to bottling department and filtered, and filter core is Kynoar filter core, filling in neutrality according to 2ml/
In Pyrex control injection bottle.
D, lamp inspection, packaging：Lamp inspection is carried out to product, substandard product is rejected, qualified products pack to obtain finished product.
E, put in storage after the assay was approved.
Checking embodiment
1st, accelerated test is investigated
The embodiment of the present invention 1～5 and the gained finished product preparation of comparative example 1～5 are placed in 25 DEG C of climatic chambers, point
The change of appearance character, pH value, particulate matter and potency is not investigated in the 0th, 3, sampling in 6 months, result of the test is shown in Table 1
The embodiment 1～5 of table 1 investigates result with the gained finished product preparation accelerated test of comparative example 1～3
From experiment investigation result：The appearance character of the embodiment of the present invention 1～5, pH value, visible foreign matters, particulate matter
There is no significant change with the indices such as potency, and the addition of disodium glycyrrhizinate is to particulate matter in comparative example
Reduction is significantly improved, and can effectively eliminate the appearance of opalescence in parenteral solution；Simultaneously disodium glycyrrhizinate is in parenteral solution
Main ingredient also has certain protective effect so as to slow down its degraded in aqueous at normal temperatures, inventor is by substantial amounts of
What experiment found meglumine is individually added into the potency that can not affect parenteral solution, but its with disodium glycyrrhizinate synergy but
Improvement to potency has large effect.
2nd, compatibility mechanism is investigated
The embodiment of the present invention 1 and the gained finished product preparation of comparative example 1 are diluted respectively with 0.9% sodium chloride of 150ml
In being placed in 25 DEG C of climatic chambers, the change of its particulate matter and potency was investigated respectively at 0,3,6,9 hours, result of the test is shown in
Table 2
The embodiment 1 of table 2 and the gained finished product preparation of comparative example 1 and 0.9% sodium chloride solution compatibility mechanism
Result is investigated in the experiment from more than：After the sodium chloride compatibility of the embodiment of the present invention 1 and 0.9% its particulate matter and
There is no significant change in potency, further illustrate the feasibility of the present invention.
Claims (4)
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| CN201610924386.4A CN106581043A (en) | 2016-10-24 | 2016-10-24 | Medicinal preparation suitable for Duchenne muscular dystrophy and preparation method thereof |
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Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
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| CN112424352A (en) * | 2018-05-11 | 2021-02-26 | 阿尔法阿诺麦里克公司 | Oligonucleotide conjugates comprising 7 '-5' -alpha-anomeric bicyclic sugar nucleosides |
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| CN105307723A (en) * | 2013-03-15 | 2016-02-03 | 萨勒普塔医疗公司 | Improved compositions for treating muscular dystrophy |
| CN105796485A (en) * | 2016-03-14 | 2016-07-27 | 张光泉 | Medicinal composition for treating thrombus and preparation method thereof |
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2016
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| CN105307723A (en) * | 2013-03-15 | 2016-02-03 | 萨勒普塔医疗公司 | Improved compositions for treating muscular dystrophy |
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| CN112424352A (en) * | 2018-05-11 | 2021-02-26 | 阿尔法阿诺麦里克公司 | Oligonucleotide conjugates comprising 7 '-5' -alpha-anomeric bicyclic sugar nucleosides |
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