CN105982892A - Antioxidant-containing temozolomide medicinal composition and preparation method thereof - Google Patents
Antioxidant-containing temozolomide medicinal composition and preparation method thereof Download PDFInfo
- Publication number
- CN105982892A CN105982892A CN201510079367.1A CN201510079367A CN105982892A CN 105982892 A CN105982892 A CN 105982892A CN 201510079367 A CN201510079367 A CN 201510079367A CN 105982892 A CN105982892 A CN 105982892A
- Authority
- CN
- China
- Prior art keywords
- temozolomide
- agent
- pharmaceutical composition
- antioxidant
- dissolving
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Pending
Links
Landscapes
- Medicinal Preparation (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The invention belongs to the field of medicinal preparations, and concretely relates to a stable temozolomide medicinal composition. The composition comprises an active component temozolomide or a pharmaceutically acceptable salt thereof, and at least one antioxidant. The antioxidant is added to reduce the temozolomide degradation rate in order to make a temozolomide preparation be stable, so the medicinal composition being able to guarantee the stability of temozolomide is obtained, and the production, the storage and the clinic use of the temozolomide are facilitated. The invention also provides a preparation method of the medicinal composition.
Description
Technical field
The invention belongs to field of pharmaceutical preparations, be specifically related to a kind of stable pharmaceutical composition of temozolomide, it comprises activity one-tenth
Divide temozolomide or its officinal salt and at least one antioxidant.
Background technology
Temozolomide (temozolomide) chemical name: 3,4-dihydro-3-methyl-4-oxomidazos also [5, l-d]-l, 2,3,
5-tetrazine-8-amide, has the protective embankment agent of anti-tumor activity for imidazo tetrazine class, and chemical structural formula is as follows:
This product is treatment cerebral glioma and the medicine of malignant melanoma of first Ling-Bao Ya (Schering-Plough) company production
Thing.It is hard capsule that domestic temozolomide lists preparation, and oral formulations is easy to use, can be completely absorbed after being administered orally, biological profit
Expenditure is up to 98%, and main side effect is Nausea and vomiting, weak, constipation and slight bone marrow depression, wherein severe
The side reactions such as Nausea and vomiting are common.This often results in the fluctuation of drug absorption, thus affects bioavailability.Some patients
Nausea and vomiting reaction is excessively serious and is difficult to be administered orally, and has a lot of patient's dysphagia clinically, it is impossible to
Being administered orally, urgent clinical needs can temozolomide's preparation of intravenously administrable.But temozolomide is stable at pH < 7 time,
Easily decomposing during pH > 7, temozolomide is as prodrug, the most degradable for activated product, and preparation becomes conventional
Intravenous fluid it cannot be guaranteed that long-time stability, therefore consider to be solidified by lyophilization and prepare and become aseptic freeze-dried
Powder, uses the aqueous diluent of front injection to rebuild, obtains temozolomide's injection, it will be the one of temozolomide's preparation
Individual good breakthrough.
Chinese patent CN 1923197 discloses a kind of freeze-dried temzolomide powder, and it is by adding in water for injection
Lyophilizing proppant, temozolomide, then regulate pH to 1.2-7.0 by pH adjusting agent, filters lyophilizing and obtains.In product only
Containing lyophilizing proppant and pH adjusting agent, products obtained therefrom stability is bad.
Chinese patent CN 101172104 discloses a kind of temozolomide freeze-dried powder pin, containing lyophilizing proppant, profit in prescription
Humectant, pH adjusting agent, solubilizing agent.Except regulation product pH value, control, outside preparation moisture, prescription not to strengthen product
The adjuvant of product stability, product stability is not the best enough.
To sum up, a kind of more stable freeze-dried temzolomide powder it is badly in need of clinically.
Summary of the invention
For the problem that freeze-dried temzolomide powder stability present in prior art is relatively poor, the present inventor is by big
The prescription screening of amount and Study on Preparation, it is provided that a kind of stable pharmaceutical composition of temozolomide and preparation method thereof.Invention
By research, people finds that adding antioxidant in the formulation can improve the stability of temozolomide.
The present invention provides a kind of pharmaceutical composition, comprises active component temozolomide or its pharmaceutically acceptable salt, Yi Jizhi
Few a kind of antioxidant, wherein said antioxidant is selected from Inorganic antioxidant, organic oxidation-resistant agent or a combination thereof.Described
Inorganic antioxidant is selected from: sodium sulfite, Potassium acid sulfite, sodium pyrosulfite, potassium metabisulfite, sodium sulfite, sulfur
Sodium thiosulfate or its combination in any, described organic oxidation-resistant agent is selected from: vitamin E, coenzyme Q10, the tert-butyl group are to hydroxyl fennel
Fragrant ether, thioglycerol, dibenzylatiooluene, propylgallate or its combination in any.
The pharmaceutical composition of the present invention, wherein said temozolomide or its pharmaceutically acceptable salt are in terms of temozolomide, described
Antioxidant and weight ratio≤1 of temozolomide；Preferred anti-oxidant and weight ratio≤0.5 of temozolomide.
The pharmaceutical composition of the present invention, also comprises at least one aqueous diluent, described aqueous diluent selected from water for injection,
Normal saline, one of the dextrose solution of 5% or its mixture, preferably water for injection.
The pharmaceutical composition of the present invention, for injectable parenteral medicinal, described pharmaceutical preparation preferred lyophilized powder form.
The pharmaceutical composition of the present invention, it is also possible to comprise the one in excipient, wetting agent, pH adjusting agent or buffer agent or
Multiple.
The pharmaceutical composition of the present invention, wherein said excipient selected from sodium chloride, glucose, lactose, mannitol, trehalose,
One of xylitol, sucrose, sorbitol, dextrose, albumin, hetastarch, cyclodextrin, glycine or its any group
Close；Wherein said wetting agent selected from polysorbate, polyoxyethylene castor oil, polyoxyethylene hydrogenated Oleum Ricini, bile salts,
One of lecithin, Polyethylene Glycol or its combination in any, be preferably selected from polysorbate-20, polysorbate-40, poly-Pyrusussuriensis
One of alcohol ester-60, Polyoxyethylene Sorbitan Monooleate or its combination in any；Wherein said buffer agent is selected from citrate, lactate, vinegar
One of hydrochlorate, tartrate, succinate, phosphate or its combination in any, be preferably selected from citrate, acetate, phosphorus
One of hydrochlorate or its combination in any；Wherein said pH adjusting agent selected from hydrochloric acid, sodium hydroxide, citric acid, phosphoric acid, lactic acid,
One of tartaric acid, succinic acid or its combination in any.
For excipient, wetting agent, buffer agent, pH adjusting agent, those skilled in the art prepare requirement according to lyophilized formulations
May be made that selection and adjust.
Preferably, the pharmaceutical composition of the present invention, wherein said excipient is selected from mannitol, and described wetting agent is selected from poly-Pyrusussuriensis
Alcohol ester-80, described buffer agent is selected from sodium citrate, and described pH adjusting agent is selected from hydrochloric acid.
The present invention, by adding antioxidant, reduces the degradation rate of temozolomide, it is ensured that gained temozolomide's preparation
Stability, thus obtained ensure that the pharmaceutical composition that temozolomide is stable, is conducive to it to prepare, stores and clinic makes
With.It was discovered by researchers that for the pharmaceutical composition of temozolomide with lyophilized powder as representative, the addition of antioxidant is further
Improve the stability of temozolomide, this stability shows that the related substance amplification that has that ensure that injection temozolomide becomes
Slowly.
The present invention also provides for a kind of method preparing aforementioned pharmaceutical compositions, including by temozolomide or its officinal salt with at least
A kind of mixed uniformly step of antioxidant.
The preparation method of the present invention, specifically includes following steps:
1) by one or more and at least one the antioxidant stirring and dissolving in excipient, wetting agent, buffer agent in aqueous
In diluent, solution temperature 0-60 DEG C；
2) use pH adjusting agent that pH value of solution is adjusted to 2.0-6.0, preferably 2.5-5.5, more preferably 3.0-5.0；
3) by temozolomide or its officinal salt, stirring and dissolving is in above-mentioned solution；
4) addition aqueous diluent is to final volume, stirs.
The preparation method of the present invention, also includes step 4) mixed solution that obtains carries out filtering, lyophilization, to obtain
A kind of lyophilized powder.
In this preparation method, the process for preparation of medicinal liquid suitably controls temperature, it is therefore an objective to reduce the degraded of temozolomide.
Detailed description of the invention
In order to preferably illustrate the present invention, compare explanation using the dosage form of lyophilized powder as embodiment below, but do not limit
In this.The pharmaceutical composition of the present invention is generally prepared by below step:
Weighing excipient, wetting agent, buffer agent, antioxidant stirring and dissolving in water for injection, water is dispensing cumulative volume
About 90%.
Add pH adjusting agent to regulate the pH value of above-mentioned solution to 3.0-5.0.
Weighing temozolomide, stirring and dissolving, in above-mentioned solution, measures the pH value of solution after being completely dissolved, as required,
Regulation solution ph is to 3.0-5.0 again.
Solution, to final volume, is continued stirring to mix homogeneously by addition water for injection.
Above-mentioned solution is filtered, lyophilization.
Embodiment 1
Weigh 15.00g mannitol, 0.075g sodium sulfite, 3.0g polyoxyethylene sorbitan monoleate, 5.88g sodium citrate dihydrate,
Adding 900mL and be cooled to the water for injection of room temperature, stirring and dissolving, using hydrochloric acid conditioning solution pH is 3.8, adds 2.50g
Temozolomide's stirring and dissolving, adds water to 1000mL after dissolving, feed liquid stir after by 0.22 μm microporous filter membrane mistake
Filter, lyophilization obtains temozolomide freeze-dried powder.
Embodiment 2
Weigh 15.00g mannitol, 2.5g Potassium acid sulfite, 3.0g polyoxyethylene sorbitan monoleate, 5.88g sodium citrate dihydrate,
Adding 900mL and be cooled to the water for injection of room temperature, stirring and dissolving, using hydrochloric acid conditioning solution pH is 3.0, adds 2.50g
Temozolomide's stirring and dissolving, adds water to 1000mL after dissolving, feed liquid stir after by 0.22 μm microporous filter membrane mistake
Filter, lyophilization obtains temozolomide freeze-dried powder.
Embodiment 3
Weigh 15.00g mannitol, 1.25g sodium pyrosulfite, 3.0g polyoxyethylene sorbitan monoleate, 5.88g sodium citrate dihydrate,
Adding 900mL and be cooled to the water for injection of room temperature, stirring and dissolving, using hydrochloric acid conditioning solution pH is 5.0, adds 2.50g
Temozolomide's stirring and dissolving, adds water to 1000mL after dissolving, feed liquid stir after by 0.22 μm microporous filter membrane mistake
Filter, lyophilization obtains temozolomide freeze-dried powder.
Embodiment 4
Weigh 15.00g mannitol, 0.075g potassium metabisulfite, 3.0g polyoxyethylene sorbitan monoleate, 5.88g sodium citrate dihydrate,
Adding 900mL and be cooled to the water for injection of room temperature, stirring and dissolving, using hydrochloric acid conditioning solution pH is 3.0, adds 2.50g
Temozolomide's stirring and dissolving, adds water to 1000mL after dissolving, feed liquid stir after by 0.22 μm microporous filter membrane mistake
Filter, lyophilization obtains temozolomide freeze-dried powder.
Embodiment 5
Weigh 15.00g mannitol, 0.25g sodium sulfite, 3.0g polyoxyethylene sorbitan monoleate, 5.88g sodium citrate dihydrate,
Adding 900mL and be cooled to the water for injection of room temperature, stirring and dissolving, using hydrochloric acid conditioning solution pH is 5.0, adds 2.50g
Temozolomide, stirring and dissolving, add water to 1000mL after dissolving, feed liquid stir after with 0.22 μm microporous filter membrane
Filtering, lyophilization obtains temozolomide freeze-dried powder.
Embodiment 6
Weigh 15.00g mannitol, 0.75g sodium thiosulfate, 3.0g polyoxyethylene sorbitan monoleate, 5.88g sodium citrate dihydrate,
Adding 900mL and be cooled to the water for injection of room temperature, stirring and dissolving, using hydrochloric acid conditioning solution pH is 3.8, adds 2.50g
Temozolomide, stirring and dissolving, add water to 1000mL after dissolving, feed liquid stir after with 0.22 μm microporous filter membrane
Filtering, lyophilization obtains temozolomide freeze-dried powder.
Embodiment 7
Weigh 15.00g mannitol, 5.88g sodium citrate dihydrate, add 900mL and be cooled to the water for injection of room temperature,
Stirring and dissolving, weighs 1.0g vitamin E, after mixing with 3.0g polyoxyethylene sorbitan monoleate, adds stirring and dissolving in above-mentioned solution,
Using hydrochloric acid conditioning solution pH is 3.8, adds 2.50g temozolomide's stirring and dissolving, adds water to 1000mL after dissolving,
Feed liquid obtains temozolomide freeze-dried powder with 0.22 μm filtering with microporous membrane, lyophilization after stirring.
Embodiment 8
Weigh 15.00g mannitol, 5.88g sodium citrate dihydrate, add 900mL and be cooled to the water for injection of room temperature,
Stirring and dissolving, weighs 0.20g coenzyme Q10, after mixing with 3.0g polyoxyethylene sorbitan monoleate, adds stirring and dissolving in above-mentioned solution,
Using hydrochloric acid conditioning solution pH is 4.0, adds 2.50g temozolomide, stirring and dissolving, adds water to 1000mL after dissolving,
Feed liquid obtains temozolomide freeze-dried powder with 0.22 μm filtering with microporous membrane, lyophilization after stirring.
Embodiment 9
Weigh 15.00g mannitol, 5.88g sodium citrate dihydrate, add 900mL and be cooled to the water for injection of room temperature,
Stirring and dissolving, weighs 0.25g butylated hydroxyarisol, after the stirring mixing of 3.0g polyoxyethylene sorbitan monoleate, adds above-mentioned molten
Stirring and dissolving in liquid, using hydrochloric acid conditioning solution pH is 4.5, adds 2.50g temozolomide, stirring and dissolving, dissolves complete
After add water to 1000mL, feed liquid obtains temozolomide freeze with 0.22 μm filtering with microporous membrane, lyophilization after stirring
Dry powder.
Embodiment 10
Weigh 15.00g mannitol, 5.88g sodium citrate dihydrate, add 900mL and be cooled to the water for injection of room temperature,
Stirring and dissolving, weigh 0.45g thioglycerol and 3.0g polyoxyethylene sorbitan monoleate stirring mixing after, add above-mentioned solution stirs molten
Solving, using hydrochloric acid conditioning solution pH is 3.5, adds 2.50g temozolomide's stirring and dissolving, adds water to after dissolving
1000mL, feed liquid obtains temozolomide freeze-dried powder with 0.22 μm filtering with microporous membrane, lyophilization after stirring.
Embodiment 11
Weigh 15.00g mannitol, 5.88g sodium citrate dihydrate, add 900mL and be cooled to the water for injection of room temperature,
Stirring and dissolving, weigh 0.8g dibenzylatiooluene and 3.0g polyoxyethylene sorbitan monoleate mixing after, add above-mentioned solution stirs molten
Solving, using hydrochloric acid conditioning solution pH is 3.8, adds 2.50g temozolomide's stirring and dissolving, adds water to after dissolving
1000mL, feed liquid obtains temozolomide freeze-dried powder with 0.22 μm filtering with microporous membrane, lyophilization after stirring.
Embodiment 12
Weigh 15.00g mannitol, 5.88g sodium citrate dihydrate, add 900mL and be cooled to the water for injection of room temperature,
Stirring and dissolving, weighs 0.6g propylgallate, after mixing with 3.0g polyoxyethylene sorbitan monoleate, add above-mentioned solution stirs molten
Solving, using hydrochloric acid conditioning solution pH is 5.0, adds 2.50g temozolomide, stirring and dissolving, adds water to after dissolving
1000mL, feed liquid obtains temozolomide freeze-dried powder with 0.22 μm filtering with microporous membrane, lyophilization after stirring.
Embodiment 13
Weigh 15.00g mannitol, 0.25g sodium sulfite, 5.88g sodium citrate dihydrate, add 900mL the coldest
To the water for injection of room temperature, stirring and dissolving, after weighing 0.2g vitamin E and the mixing of 3.0g polyoxyethylene sorbitan monoleate, in addition
Stating stirring and dissolving in solution, using hydrochloric acid conditioning solution pH is 3.7, adds 2.50g temozolomide's stirring and dissolving, has dissolved
Add water to 1000mL after Biing, feed liquid stir after with 0.22 μm filtering with microporous membrane, lyophilization obtains temozolomide
Lyophilized powder.
Reference examples 1 (with reference to Chinese patent CN 1923197)
Weighing 20g sodium chloride, add in water for injection, under room temperature, stirring makes to be completely dissolved, addition 1g temozolomide, and 40
DEG C stirring in water bath makes temozolomide be completely dissolved and mix homogeneously, adds water for injection to 400ml, uses salt acid for adjusting pH value
To 3.0, with 0.22 μm microporous filter membrane aseptic filtration, fill 40ml/ bottle in 100ml lyophilizing bottle, lyophilization.
Reference examples 2 (Chinese patent CN 101172104 embodiment 2)
Weigh 4.00gL-threonine, 3.00g Tween-80,15.00g mannitol, 5.88g sodium citrate dihydrate,
1.48g hydrochloric acid is sequentially added in 800mL water for injection, stirring and dissolving, adds 2.5g temozolomide, and stirring and dissolving is complete
Quan Hou, adds water to 1000mL, with 0.22 μm filtering with microporous membrane, lyophilization, obtains temozolomide freeze-dried powder.
Stability comparative experiments
Preparing corresponding temozolomide's solution according to embodiment 1-13 prescription and reference examples 1,2 prescription, lyophilization is prepared into
To lyophilized powder.The lyophilized powder of preparation is kept sample under the conditions of 60 DEG C investigate 10 days have related substance situation, have related substance to make
Measure by high performance liquid chromatography (HPLC), the method being referred to 2010 editions second annex V D of Chinese Pharmacopoeia, knot
Fruit is shown in Table 1.
Table 1 embodiment contrasts with reference examples product stability
Note: " ND " expression is not detected by
Result shows, in the present invention embodiment 1-13 group lyophilized powder place at 60 DEG C 10 days stability be superior to matched group 1,
2, illustrate that the addition of antioxidant can significantly improve preparation stability.
Claims (10)
1. a pharmaceutical composition, it is characterised in that comprise active component temozolomide or its pharmaceutically acceptable salt,
And at least one antioxidant, described antioxidant is selected from sodium sulfite, Potassium acid sulfite, sodium pyrosulfite, Jiao Ya
Potassium sulfate, sodium sulfite, sodium thiosulfate, vitamin E, coenzyme Q10, butylated hydroxyarisol, thioglycerol,
One of dibenzylatiooluene, propylgallate or its combination in any.
Pharmaceutical composition the most according to claim 1, it is characterised in that wherein said temozolomide or its pharmaceutically
Acceptable salt in terms of temozolomide, weight ratio≤1 of described antioxidant and temozolomide；Preferred anti-oxidant with for not
Weight ratio≤0.5 of azoles amine.
Pharmaceutical composition the most according to claim 1, also comprises at least one aqueous diluent, and described aqueous dilutes
Agent is selected from water for injection, normal saline, one of the dextrose solution of 5% or its mixture, preferably water for injection.
Pharmaceutical composition the most according to claim 1, for injectable parenteral medicinal, described medicine system
Agent preferred lyophilized powder form.
5., according to the pharmaceutical composition according to any one of claim 1-4, also comprise excipient, wetting agent, pH regulator
One or more in agent or buffer agent.
Pharmaceutical composition the most according to claim 5, wherein said excipient selected from sodium chloride, glucose, lactose,
Mannitol, trehalose, xylitol, sucrose, sorbitol, dextrose, albumin, hetastarch, cyclodextrin, sweet ammonia
One of acid or its combination in any；Wherein said wetting agent is selected from polysorbate, polyoxyethylene castor oil, polyethylene glycol hydrogenated
One of Oleum Ricini, bile salts, lecithin, Polyethylene Glycol or its combination in any, be preferably selected from polysorbate-20, poly-mountain
One of pears alcohol ester-40, polysorbate-60, Polyoxyethylene Sorbitan Monooleate or its combination in any；Wherein said buffer agent is selected from Chinese holly
One of same regimen acid salt, lactate, acetate, tartrate, succinate, phosphate or its combination in any, be preferably selected from Chinese holly
One of same regimen acid salt, acetate, phosphate or its combination in any；Wherein said pH adjusting agent selected from hydrochloric acid, sodium hydroxide,
One of citric acid, phosphoric acid, lactic acid, tartaric acid, succinic acid or its combination in any.
Pharmaceutical composition the most according to claim 6, wherein said excipient is selected from mannitol, and described wetting agent selects
From Polyoxyethylene Sorbitan Monooleate, described buffer agent is selected from sodium citrate, and described pH adjusting agent is selected from hydrochloric acid.
8. the method preparing pharmaceutical composition as claimed in claim 6, including by temozolomide or its officinal salt
Step mixed uniformly with at least one antioxidant.
Method the most according to claim 8, comprises the following steps:
1) by one or more and at least one the antioxidant stirring and dissolving in excipient, wetting agent, buffer agent in aqueous
In diluent, solution temperature 0-60 DEG C；
2) use pH adjusting agent that pH value of solution is adjusted to 2.0-6.0, preferably 2.5-5.5, more preferably 3.0-5.0；
3) by temozolomide or its officinal salt, stirring and dissolving is in above-mentioned solution；
4) addition aqueous diluent is to final volume, stirs.
Method the most according to claim 9, also includes step 4) mixed solution that obtains carries out filtering, freezing
It is dried, to obtain a kind of lyophilized powder.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201510079367.1A CN105982892A (en) | 2015-02-14 | 2015-02-14 | Antioxidant-containing temozolomide medicinal composition and preparation method thereof |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201510079367.1A CN105982892A (en) | 2015-02-14 | 2015-02-14 | Antioxidant-containing temozolomide medicinal composition and preparation method thereof |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CN105982892A true CN105982892A (en) | 2016-10-05 |
Family
ID=57041364
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN201510079367.1A Pending CN105982892A (en) | 2015-02-14 | 2015-02-14 | Antioxidant-containing temozolomide medicinal composition and preparation method thereof |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN105982892A (en) |
Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US20140275195A1 (en) * | 2013-03-14 | 2014-09-18 | Mahmoud S. AlSwisi | Stabilized pharmaceutical formulations comprising antineoplastic compounds |
-
2015
- 2015-02-14 CN CN201510079367.1A patent/CN105982892A/en active Pending
Patent Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US20140275195A1 (en) * | 2013-03-14 | 2014-09-18 | Mahmoud S. AlSwisi | Stabilized pharmaceutical formulations comprising antineoplastic compounds |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| EP1658848B1 (en) | Formulations comprising ecteinascidin and a disaccharide | |
| CA3002113C (en) | Aqueous composition comprising dantrolene | |
| US20080145431A1 (en) | Medicinal Composition and Process for Producing the Same | |
| CN104721155B (en) | A kind of temozolomide freeze-dried powder preparation and preparation method thereof | |
| EP4393480A1 (en) | Lyophilized formulation solution and lyophilized formulation, and method and use thereof | |
| CN106137985A (en) | A kind of stable Palmic acid 9-hydroxy-risperidone durative action preparation | |
| CN102481288B (en) | Pharmaceutical composition of temozolomide comprising amino acid stabilizer and preparation method thereof | |
| CN102614492B (en) | Liquid pharmaceutical composition containing echinocandin antifungal agent micafungin | |
| CN103405385A (en) | Temozolomide intravenous injection fat emulsion and preparation method thereof | |
| CN102860980A (en) | Method for preparing rocuronium bromide injection | |
| CN102552134B (en) | Fat emulsion containing vitamin K1 | |
| EP3287138A1 (en) | Improved daptomycin injectable formulation | |
| CN103172576B (en) | The malate acid addition salt of Gefitinib and Synthesis and applications thereof | |
| KR102095536B1 (en) | Oral formulation for improved dissolution rate and disintegrability of herbal extract | |
| CN110433131A (en) | A kind of pharmaceutical composition | |
| CN104940135A (en) | Fluconazole injection and preparation method thereof | |
| CN104274412A (en) | Pharmaceutical preparation containing temozolomide, pharmaceutically acceptable salts or other derivatives thereof | |
| CN104800172A (en) | Carbazochrome sodium sulfonate powder injection for injection and preparation method thereof | |
| CN105982892A (en) | Antioxidant-containing temozolomide medicinal composition and preparation method thereof | |
| EP3679925B1 (en) | Pharmaceutical composition of docetaxel conjugate and preparation method | |
| CN113559261A (en) | Boron carrier injection | |
| CN102757471B (en) | Novel active cytidine disodium triphosphate compound and pharmaceutical composition thereof | |
| CN106176626B (en) | L-alanine- (14-oridonin) ester parenteral pharmaceutical composition | |
| WO2017198224A1 (en) | Pharmaceutical composition of remimazolam | |
| WO2024179467A1 (en) | Solution, freeze-dried formulation, freeze-dried formulation unit package, injection, and injection preparation method |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| C06 | Publication | ||
| PB01 | Publication | ||
| SE01 | Entry into force of request for substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| RJ01 | Rejection of invention patent application after publication | ||
| RJ01 | Rejection of invention patent application after publication |
Application publication date: 20161005 |