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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- 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
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/13—Amines
- A61K31/133—Amines having hydroxy groups, e.g. sphingosine
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/70—Carbohydrates; Sugars; Derivatives thereof
- A61K31/7028—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
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Abstract
The invention belongs to the field of medicine technology, and concretely relates to a medicinal preparation suitable for Duchenne muscular dystrophy. The preparation comprises the following components: an active component Eteplirsen, sodium chloride, disodium glycyrrhizate, meglumine, a pH conditioning agent, and injection water. The quality is stable, long-term acceleration tests and investigations show that appearance and properties, pH value, visible foreign matters, insoluble particles and titer are not obviously changed; at the same time, after the preparation and 0.9% sodium chloride are compatible, the preparation is placed at a room temperature for a long time, insoluble particles and titer are not obviously changed, the preparation is greatly convenient for clinic usage, and usage safety of patients is improved.
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)
1. a kind of pharmaceutical preparation suitable for duchenne muscular dystrophy：It is characterized in that by active component Eteplirsen, chlorine
Change sodium, disodium glycyrrhizinate, meglumine, pH adjusting agent and water for injection composition；
The concentration of described active component Eteplirsen is 25.0～100.0mg/ml；
Described sodium chloride is isotonic regulator, and its concentration is 7.0～9.0mg/ml；
Described disodium glycyrrhizinate concentration is 0.1～0.8mg/ml；
The concentration of described meglumine is 0.5～1.5mg/ml；
Described pH adjusting agent is the one kind or several in hydrochloric acid, acetic acid, phosphoric acid or citric acid；
The pH value of the pharmaceutical preparation is 6.2～7.2.
2. a kind of pharmaceutical preparation suitable for duchenne muscular dystrophy according to claim 1, it is characterised in that described
Active component Eteplirsen concentration be 50.0mg/ml；
The concentration of the disodium glycyrrhizinate is 0.3mg/ml；
The concentration of the meglumine is 0.8mg/ml；
The concentration of the sodium chloride is 8.4mg/ml；
Described pH adjusting agent is phosphoric acid；
The pH value of the pharmaceutical preparation is 6.7.
3. a kind of pharmaceutical preparation suitable for duchenne muscular dystrophy according to claim 1, it is characterised in that its system
Preparation Method is comprised the following steps：
A, ampoule process：By ampoule by ultrasonic bottle washing machine washes clean, Jing tunnel types sterilizing drying machine is in 290 DEG C of sterilizing dries
After dry, 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% injection
With in water, stirring mixes 10～20 minutes；
(2). mend to (1) Chinese medicine liquid and inject water to the 80～90% of cumulative volume, be uniformly mixed, add the Portugal of formula ratio
Methylamine, stirring liquid to colorless clear liquid adjusts pH value to 6.2～7.2 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, is produced 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 neutral borosilicate according to 2ml/
In injection bottles made of glass tubes；
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.
4. a kind of pharmaceutical preparation suitable for duchenne muscular dystrophy according to claim 3, it is characterised in that its preparation
Method is comprised the following steps：
A, ampoule process：By ampoule by ultrasonic bottle washing machine washes clean, Jing tunnel types sterilizing drying machine is in 290 DEG C of sterilizing dries
After dry, 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% 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 to 6.7 with pH adjusting agent；
(3). total amount is settled to water for injection, pH value is adjusted 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 neutral borosilicate according to 2ml/
Glass control is noted in injection bottle processed；
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.
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| Application Number | Priority Date | Filing Date | Title |
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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 |
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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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| Title |
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| PETER SAZANI ET AL: "Repeat-Dose Toxicology Evaluation in Cynomolgus Monkeys of AVI-4658,a Phosphorodiamidate Morpholino Oligomer (PMO) Drug for the Treatment of Duchenne Muscular Dystrophy", 《INTERNATIONAL JOURNAL OF TOXICOLOGY》 * |
| PETER SAZANI ET AL: "Safety Pharmacology and Genotoxicity Evaluation of AVI-4658", 《INTERNATIONAL JOURNAL OF TOXICOLOGY》 * |
| 刘颖: "Duchenne型肌营养不良症治疗药物Eteplirsen", 《热点药物追踪》 * |
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Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| 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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