CN104721155B - A kind of temozolomide freeze-dried powder preparation and preparation method thereof - Google Patents
A kind of temozolomide freeze-dried powder preparation and preparation method thereof Download PDFInfo
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Abstract
The invention belongs to technical field of medicine, specifically related to a kind of temozolomide freeze-dried powder preparation, wherein active component is Temozolomide or its pharmaceutically acceptable salt, also contain excipient, wetting agent, buffer, osmotic pressure regulator, pH adjusting agent, water for injection and organic solvent before lyophilized in solution, wherein described organic solvent is selected from one of ethanol, acetone, isopropanol, normal propyl alcohol, butanone, sec-butyl alcohol, methanol or any combination, preferred alcohol.The temozolomide freeze-dried powder preparation steady quality of the present invention, redissolves speed soon, organic solvent residual is low.The present invention also provides a kind of method for preparing above-mentioned preparation, and technique preparation process of the invention is easy, and production link is easily controllable, and organic solvent accounts for that feed liquid cumulative volume is less, reduces pollution of the organic solvent to production equipment and environment, is adapted to large-scale production.
Description
Technical field
The invention belongs to technical field of medicine.Specifically related to a kind of steady quality, the fireballing Temozolomide of redissolution
It is freeze-dried powder injection formulation and preparation method thereof.
Background technology
Temozolomide (temozolomide) chemical name：3,4- dihydro-3-methyl-4-oxomidazos simultaneously [5, l-d]-l, 2,
3,5- tetrazine -8- acid amides, are the protective embankment agent that imidazo tetrazine class has antitumor activity, and chemical structural formula is as follows：
This product is the treatment glioma and malignant mela noma of first Ling-Bao Ya (Schering-Plough) company production
Medicine.Domestic Temozolomide listing preparation is hard shell capsules, and oral formulations are easy to use, it is oral after can be completely absorbed, it is biological
Availability is up to 98%, and main side effect is Nausea and vomiting, weak, constipation and slight bone marrow suppression, and wherein severe is disliked
The side reactions such as the heart, vomiting are common.This often results in the fluctuation of drug absorption, so as to influence bioavilability.Some patients nausea,
Vomiting reaction is excessively serious and is difficult to be administered orally, and clinically has many patient's dysphagias, it is impossible to pass through mouth
The Temozolomide preparation of intravenously administrable is capable of in clothes administration, urgent clinical needs.But Temozolomide is in pH<7 times stable, pH>Easily divide when 7
Solution, Temozolomide is as pro-drug, and degradable in aqueous is activated product, is prepared as conventional intravenous fluid not
Long-time stability are can guarantee that, therefore considers to solidify it by freeze-drying and prepares as aseptic freeze-dried powder, using preceding with note
The aqueous diluent penetrated is rebuild, and obtains Temozolomide injection, is a breakthrough of Temozolomide preparation.
Disclose a kind of with micronized in the parenteral administration of Temozolomide, United States Patent (USP) US6251886 to realize
The Temozolomide preparation of suspension administration, still, suspension formulation is unsatisfactory, and it can cause blood vessel blockage.In view of for not
Azoles amine unstable characteristic in aqueous, therefore it is solidified and preparing turns into aseptic freeze-dried powder by being freeze-dried, face use
Preceding rebuild it using the aqueous diluent of injection obtains being capable of the Temozolomide injection of parenteral administration, be one very
Good strategy.
Due to Temozolomide, solubility is poor in water, about 3.1mg/ml, and dissolution velocity is slower, when causing dispensing
Between it is long, the relevant material of product is higher.It is slow using ordinary recipe and technique dispensing speed, it is unfavorable for ensureing product quality, finally
The freeze-dried powder solubility of preparation is poor, is made troubles to Clinical practice and risk, while making doctor and patient produce product quality
It is raw to suspect, it is unfavorable for clinical practice.
Disclose a kind of freeze-dried temzolomide powder in Chinese patent CN100588399, said preparation by adjust pH and
Heating ultrasound dissolves Temozolomide, and the dispensing time is longer, and heating produces a large amount of hydrolysates, is unfavorable for solution-stabilized.In addition,
Its preparation solubility is poor, needs the long period to redissolve completely before Clinical practice.Longer redissolution time-bands carry out three aspect wind
Danger：On the one hand such as fruit product, venoclysis will produce serious clinical application risk on the basis of without all dissolvings, another
Aspect, the long period, which does not redissolve, may make doctor and patient throw doubt upon product quality, be unfavorable for clinical practice；Third party
Face, longer redissolution disadvantage in time is stable in feed liquid, influences product quality.
A kind of freeze-dried temzolomide powder is disclosed in Chinese patent CN 102949350, it uses niacinamide, contracting two
Urea or mixture are as solubilizer to improve redissolution speed.But both solubilizer are injected after human body with preparation to be had necessarily
Pharmacological action, it cannot be guaranteed that preparation clinical safety when dosage is larger.
A kind of freeze-dried temzolomide powder is disclosed in Chinese patent CN 101172104, solubilizer is which used,
Including urea, L-threonine, L-Histidine, L-Aspartic acid, Serine, Glu or its mixture.Its dispensing speed
Slowly, stirring at least 2 hours raw materials can dissolve, and longer dispensing disadvantage in time is in production assurance.
A kind of preparation method of temozolomide freeze-dried preparation is disclosed in Chinese patent CN 102949351, wherein employing
The mixed solvent system of butanol/water, its technique dispensing speed is slow, is unfavorable for amplification production, the organic solvent used is uncle
Butanol is not belonging to《Chinese Pharmacopoeia》Lower toxicity organic solvent as defined in versions in 2010, its consumption in prescription is generally larger, unfavorable
In safety and environmental protection.Tert-butyl alcohol freezing point is higher, is difficult to remove in freezing dry process, causes it to remain in the formulation dense
Degree is higher, is unfavorable for drug safety.
Temozolomide powder-injection common problem in preparation process is at present：1st, the dispensing time is long, produces hydrolysis
Impurity, is unfavorable for the guarantee of product quality；2nd, product solubility is poor, is unfavorable for clinical preparation and uses, there is Clinical practice risk.
3rd, in order to improve product solubility, extra material is with the addition of as solubilizer, and these solubilizer have Pharmacological,
It is unfavorable for the security of clinical application.4th, the consumption of organic solvent used is big, is unfavorable for security and environmental protection, You Jirong
Agent remains higher in the formulation, is unfavorable for drug safety.
The content of the invention
The technical problems to be solved by the invention are to overcome the deficiencies in the prior art being capable of quickly dispensing, matter there is provided one kind
Amount is stable, redissolve speed soon, facilitate Clinical practice, the temozolomide freeze-dried powder injection formulation for reducing clinical application risk and its preparation
Method.
A kind of temozolomide freeze-dried powder preparation of the present invention, active component is Temozolomide or its is pharmaceutically acceptable
Also contain excipient, wetting agent, buffer, osmotic pressure regulator, pH adjusting agent, water for injection in salt, lyophilized preceding solution and have
Machine solvent, wherein the organic solvent is selected from one of ethanol, acetone, isopropanol, normal propyl alcohol, butanone, sec-butyl alcohol, methanol or any
Combination.
In a preferred embodiment of the invention, the organic solvent is ethanol.
In a preferred embodiment of the invention, the organic solvent accounts for the 0.01%~10% of lyophilized preceding overall solution volume,
It is preferred that 0.05%~5%, most preferably 0.1%~4.5%.
In a preferred embodiment of the invention, mass percent of the Temozolomide in lyophilized preceding solution is 0.1~2%.
In a preferred embodiment of the invention, in the temozolomide freeze-dried powder preparation, the quality percentage of Temozolomide
It is 1%~50% than content.
In the temozolomide freeze-dried powder preparation of the present invention, mass percent of the excipient in temozolomide freeze-dried powder preparation
For 30%~90%, the excipient is selected from glucose, albumin, sodium chloride, lactose, mannitol, sorbierite, xylitol, the right side
One of the sugared acid anhydride of rotation, sodium alginate or any combination；
Mass percent of the wetting agent in temozolomide freeze-dried powder preparation is 0%~50%, and the wetting agent is selected from poly-
Sorb ester -20, Tween-80, Emulsifier EL-60, Crodaret, bile salt, lecithin, poly- second two
One of alcohol or any combination；
Mass percent of the buffer in temozolomide freeze-dried powder preparation is 1%~50%, and the buffer is selected from lemon
One of lemon hydrochlorate, lactate, acetate, tartrate, succinate, phosphate or any combination, preferably citric acid salt；
The pH adjusting agent is selected from one of hydrochloric acid, citric acid, phosphoric acid, lactic acid, tartaric acid, butanedioic acid or any combination；
Mass percent of the osmotic pressure regulator in temozolomide freeze-dried powder preparation is 1%~50%, the osmotic pressure
Conditioning agent is selected from one of glycerine, sodium chloride, potassium chloride, mannitol, glucose, sorbierite or any combination
In a preferred embodiment of the invention, excipient is mannitol, and wetting agent is polyoxyethylene sorbitan monoleate, and buffer is
Sodium citrate, pH adjusting agent is hydrochloric acid, and osmotic pressure regulator is sodium chloride.
In a preferred embodiment of the invention, the pH scopes of solution are 2~7 before freezing.
The temozolomide freeze-dried powder preparation of the present invention, steady quality redissolves speed soon, Clinical practice is convenient, safety.
The present invention also provides a kind of preparation method of above-mentioned temozolomide freeze-dried powder preparation, comprises the following steps：
1) excipient of recipe quantity, wetting agent, buffer, osmotic pressure regulator stirring and dissolving are weighed in water for injection；
2) using pH adjusting agent by step 1) in the pH value of gained feed liquid adjust to 2-7；
3) Temozolomide or its officinal salt of recipe quantity are weighed, is dispersed in organic solvent, dispersion liquid is added
Step 2) gained feed liquid in, stirring and dissolving；
4) vial is dispensed into after feed liquid being settled into cumulative volume, filtration sterilization；
5) it is freeze-dried, produces the temozolomide freeze-dried powder preparation of final products.
It is preferred that, in above-mentioned preparation method, step 3) the scattered method in organic solvent is uses high shear
The scattered mode of dispersion emulsifying machine.Rate of dispersion is fast by the way of high-shearing dispersion emulsifying machine disperse, and is stirred than common
Mix dispersing mode and save the time, and dispersion effect is good.
Found in the present inventor's process of the test, raw material is unstable in aqueous, and batch temperature is higher, raw material is contacted with water
Time is longer, and impurity increases more notable.And Temozolomide raw material belongs to insoluble drug, speed is dissolved when temperature is relatively low in aqueous
Degree is slow, so as to cause the dispensing time longer, a large amount of impurity is produced in blending process, rise temperature can contract to a certain extent
The short dissolution of raw material time, but raw material equally produces a large amount of impurity in the high temperature aqueous solution in the short time, be unfavorable for product quality
Ensure.Therefore on the premise of batch temperature is not raised, the shortening dispensing time could fundamentally ensure product quality.
The inventors discovered that, under the premise of batch temperature is not raised, introducing organic solvent can reach contracting in proportioning process
The purpose of short dispensing time, innovation of the present invention is that selected organic solvent is the poor solvent of Temozolomide, for not
Azoles amine is almost insoluble in these organic solvents.This poor solvent is introduced in solution can reduce the dissolution velocity of raw material, still
Inventor has found that, if raw material disperseed first in organic solvent, then adding stirring in aqueous solution can significantly add
Fast drug dissolution rates.It is this to introduce adverse drug solvent in preparation technology and reach that the effect for speeding drug dissolution rates is
It is unexpected.
The inventors discovered that, the present invention selected by organic solvent freezing point it is relatively low, but due in prescription consumption it is less,
Therefore product is not influenceed to be freeze-dried.Organic solvent is introduced in preparation prescription on the premise of no solubilizer, organic solvent is most
It is removed eventually by freeze-drying, the preparation finally prepared redissolves speed and dramatically speeded up, and the organic solvent of introducing can change cold
It is lyophilized it is dry during medicine crystallization behavior, generation redissolves fireballing drug crystal forms, answered so as to fundamentally accelerate preparation
Molten speed, it is this to change the crystallization behavior in pharmaceutical freeze drying process by introducing lower boiling raw material poor solvent, so that
It is unexpected to accelerate preparation redissolution speed.
The selected organic solvent of the present invention is《Chinese Pharmacopoeia》Equations of The Second Kind or the 3rd class have specified in versions in 2010
Machine solvent, this two classes organic solvent toxicity is relatively low, while organic solvent proportion in prescription is smaller, therefore to the dirt of environment
The infringement of dye and equipment is smaller, and final residue in the formulation meets《Chinese Pharmacopoeia》Version requirement in 2010, therefore energy
Enough ensure Product Safety.
To sum up, organic solvent is introduced in the pleasantly surprised discovery of inventor, this product preparation technology, has both sides good to preparation
Place, can solve the problem that the subject matter that temozolomide freeze-dried preparation presently, there are：
First：Under the premise of batch temperature is not raised, it can significantly shorten the dissolution of raw material time, fundamentally ensure product
Quality.
Second：1. solubilizer is not added in prescription additionally, but obtained preparation redissolution speed is equally satisfactory, reduction
During Clinical practice due to redissolving not exclusively caused by drug risk, reduce the adverse reaction that solubilizer is brought；2. institute
The organic solvent of use is that organic residue is relatively low in low-toxic organic solvent, preparation, is met《Chinese Pharmacopoeia》Version will within 2010
Ask, consumption of organic solvent is less, toxicity is relatively low, environmental pollution is small, product quality is stable, be adapted to large-scale production.
Preparation technology of the present invention is simple, facilitates feasible, reproducible, it is easy to industry amplification, it is ensured that product can industry put
Big requirement；The dispensing time is shortened, cost has been saved, product impurity is reduced, it is ensured that Product Safety and validity；System
Standby preparation solubility is good, reduces clinical application risk, facilitates Clinical practice, it is ensured that the security of clinical application.
Embodiment
Following specific embodiment further illustrates the present invention.Method is only intended to illustrate this hair in embodiments of the invention
It is bright, the scope of protection of present invention is not limited in any way.
Embodiment 1
| Temozolomide | 10g |
| Mannitol | 60g |
| Polyoxyethylene sorbitan monoleate | 12g |
| Sodium citrate | 23.5g |
| Sodium chloride | 4g |
| Hydrochloric acid | In right amount |
| Ethanol | 40ml |
| Water for injection | Add to 4000ml |
Preparation method：60g mannitol, 12g polyoxyethylene sorbitan monoleates, 23.5g sodium citrates, 4g sodium chloride are sequentially added into injection
With in water, stirring and dissolving is complete, using salt acid for adjusting pH to 3.7.Temozolomide is distributed to using high-shearing dispersion emulsifying machine
Dispersion liquid is obtained in 40ml ethanol, dispersion liquid is added in the above-mentioned aqueous solution, after stirring and dissolving is complete, constant volume to 4000ml, material
Liquid is dispensed into 100ml cillin bottles through 0.22 μm of miillpore filter aseptic filtration, every bottle of 40ml, and Temozolomide is made in freeze-drying
Freeze-dried powder.
Embodiment 2
| Temozolomide | 10g |
| Mannitol | 60g |
| Polyoxyethylene sorbitan monoleate | 12g |
| Sodium citrate | 23.5g |
| Sodium chloride | 5g |
| Hydrochloric acid | In right amount |
| Ethanol | 180ml |
| Water for injection | Add to 4000ml |
Preparation method：60g mannitol, 12g polyoxyethylene sorbitan monoleates, 23.5g sodium citrates, 5g sodium chloride are sequentially added into injection
With in water, stirring and dissolving is complete, using salt acid for adjusting pH to 3.0.Temozolomide is distributed to using high-shearing dispersion emulsifying machine
Dispersion liquid is obtained in 180ml ethanol, dispersion liquid is added in the above-mentioned aqueous solution, completely, constant volume to 4000ml is passed through stirring and dissolving
0.22 μm of miillpore filter aseptic filtration, is dispensed into 100ml cillin bottles, every bottle of 40ml, and freeze-drying is made temozolomide freeze-dried
Powder injection formulation.
Embodiment 3
| Temozolomide | 10g |
| Mannitol | 60g |
| Polyoxyethylene sorbitan monoleate | 15g |
| Sodium citrate | 23.5g |
| Sodium chloride | 5g |
| Hydrochloric acid | In right amount |
| Ethanol | 10ml |
| Water for injection | Add to 4000ml |
Preparation method：60g mannitol, 15g polyoxyethylene sorbitan monoleates, 23.5g sodium citrates, 5g sodium chloride are sequentially added into injection
With in water, stirring and dissolving is complete, using salt acid for adjusting pH to 4.5.Temozolomide is distributed to using high-shearing dispersion emulsifying machine
Dispersion liquid is obtained in 10ml ethanol, dispersion liquid is added in the above-mentioned aqueous solution, completely, constant volume to 4000ml is passed through stirring and dissolving
0.22 μm of miillpore filter aseptic filtration, is dispensed into 100ml cillin bottles, every bottle of 40ml, and freeze-drying is made temozolomide freeze-dried
Powder injection formulation.
Embodiment 4
| Temozolomide | 10g |
| Mannitol | 80g |
| Polyoxyethylene sorbitan monoleate | 12g |
| Sodium citrate | 23.5g |
| Sodium chloride | 5g |
| Hydrochloric acid | In right amount |
| Acetone | 15ml |
| Water for injection | Add to 4000ml |
Preparation method：80g mannitol, 12g polyoxyethylene sorbitan monoleates, 23.5g citric acids, 5g sodium chloride are sequentially added into injection
In water, stirring and dissolving is complete, using salt acid for adjusting pH to 2.0.Temozolomide is distributed to using high-shearing dispersion emulsifying machine
Dispersion liquid is obtained in 15ml acetone, dispersion liquid is added in the above-mentioned aqueous solution, completely, constant volume to 4000ml is passed through stirring and dissolving
0.22 μm of miillpore filter aseptic filtration, is dispensed into 100ml cillin bottles, every bottle of 40ml, and freeze-drying is made temozolomide freeze-dried
Powder injection formulation.
Embodiment 5
| Temozolomide | 10g |
| Mannitol | 50g |
| Polyoxyethylene sorbitan monoleate | 12g |
| Sodium citrate | 25g |
| Sodium chloride | 5g |
| Hydrochloric acid | In right amount |
| Isopropanol | 40ml |
| Water for injection | Add to 4000ml |
Preparation method：50g mannitol, 12g polyoxyethylene sorbitan monoleates, 25g sodium citrates, 5g sodium chloride are sequentially added into injection
In water, stirring and dissolving is complete, using salt acid for adjusting pH to 6.0.Temozolomide is distributed to using high-shearing dispersion emulsifying machine
Dispersion liquid is obtained in 40ml isopropanols, dispersion liquid is added in the above-mentioned aqueous solution, completely, constant volume to 4000ml is passed through stirring and dissolving
0.22 μm of miillpore filter aseptic filtration, is dispensed into 100ml cillin bottles, every bottle of 40ml, and freeze-drying is made temozolomide freeze-dried
Powder injection formulation.
Embodiment 6
| Temozolomide | 10g |
| Mannitol | 60g |
| Polyoxyethylene sorbitan monoleate | 12g |
| Sodium citrate | 23.5g |
| Sodium chloride | 5g |
| Hydrochloric acid | In right amount |
| Normal propyl alcohol | 40ml |
| Water for injection | Add to 4000ml |
Preparation method：60g mannitol, 12g polyoxyethylene sorbitan monoleates, 23.5g sodium citrates, 5g sodium chloride are sequentially added into injection
With in water, stirring and dissolving is complete, using salt acid for adjusting pH to 7.0.Temozolomide is distributed to using high-shearing dispersion emulsifying machine
Dispersion liquid is obtained in 40ml normal propyl alcohols, dispersion liquid is added in the above-mentioned aqueous solution, completely, constant volume to 4000ml is passed through stirring and dissolving
0.22 μm of miillpore filter aseptic filtration, is dispensed into 100ml cillin bottles, every bottle of 40ml, and freeze-drying is made temozolomide freeze-dried
Powder injection formulation.
Embodiment 7
| Temozolomide | 10g |
| Mannitol | 60g |
| Polyoxyethylene sorbitan monoleate | 10g |
| Sodium citrate | 23.5g |
| Hydrochloric acid | In right amount |
| Sodium chloride | 5g |
| Butanone | 40ml |
| Water for injection | Add to 4000ml |
Preparation method：60g mannitol, 10g polyoxyethylene sorbitan monoleates, 23.5g sodium citrates, 5g sodium chloride are sequentially added into injection
With in water, stirring and dissolving is complete, using salt acid for adjusting pH to 3.7.Temozolomide is distributed to using high-shearing dispersion emulsifying machine
Dispersion liquid is obtained in 40ml butanone, dispersion liquid is added in the above-mentioned aqueous solution, completely, constant volume to 4000ml is passed through stirring and dissolving
0.22 μm of miillpore filter aseptic filtration, is dispensed into 100ml cillin bottles, every bottle of 40ml, and freeze-drying is made temozolomide freeze-dried
Powder injection formulation.
Embodiment 8
| Temozolomide | 10g |
| Mannitol | 60g |
| Polyoxyethylene sorbitan monoleate | 12g |
| Sodium citrate | 23.5g |
| Sodium chloride | 5g |
| Hydrochloric acid | In right amount |
| Sec-butyl alcohol | 40ml |
| Water for injection | Add to 4000ml |
Preparation method：60g mannitol, 12g polyoxyethylene sorbitan monoleates, 23.5g sodium citrates, 5g sodium chloride are sequentially added into injection
With in water, stirring and dissolving is complete, using salt acid for adjusting pH to 3.7.Temozolomide is distributed to using high-shearing dispersion emulsifying machine
Dispersion liquid is obtained in 40ml sec-butyl alcohols, dispersion liquid is added in the above-mentioned aqueous solution, completely, constant volume to 4000ml is passed through stirring and dissolving
0.22 μm of miillpore filter aseptic filtration, is dispensed into 100ml cillin bottles, every bottle of 40ml, and freeze-drying is made temozolomide freeze-dried
Powder injection formulation.
Embodiment 9
| Temozolomide | 10g |
| Mannitol | 60g |
| Polyoxyethylene sorbitan monoleate | 12g |
| Sodium citrate | 23.5g |
| Sodium chloride | 5g |
| Hydrochloric acid | In right amount |
| Methanol | 40ml |
| Water for injection | Add to 4000ml |
Preparation method：60g mannitol, 12g polyoxyethylene sorbitan monoleates, 23.5g sodium citrates, 5g sodium chloride are sequentially added into injection
With in water, stirring and dissolving is complete, using salt acid for adjusting pH to 3.7.Temozolomide is distributed to using high-shearing dispersion emulsifying machine
Dispersion liquid is obtained in 40ml methanol, dispersion liquid is added in the above-mentioned aqueous solution, completely, constant volume to 4000ml is passed through stirring and dissolving
0.22 μm of miillpore filter aseptic filtration, is dispensed into 100ml cillin bottles, every bottle of 40ml, and freeze-drying is made temozolomide freeze-dried
Powder injection formulation.
Embodiment 10
| Temozolomide | 10g |
| Mannitol | 60g |
| Polyoxyethylene sorbitan monoleate | 12g |
| Sodium citrate | 23.5g |
| Sodium chloride | 5g |
| Hydrochloric acid | In right amount |
| Ethanol | 20ml |
| Acetone | 20ml |
| Water for injection | Add to 4000ml |
Preparation method：60g mannitol, 12g polyoxyethylene sorbitan monoleates, 23.5g sodium citrates, 5g sodium chloride are sequentially added into injection
With in water, stirring and dissolving is complete, using salt acid for adjusting pH to 3.7.Temozolomide is distributed to using high-shearing dispersion emulsifying machine
Dispersion liquid is obtained in the mixed solution of 20ml ethanol and 20ml acetone composition, dispersion liquid is added in the above-mentioned aqueous solution, is stirred molten
Solution is complete, and constant volume to 4000ml, through 0.22 μm of miillpore filter aseptic filtration, is dispensed into 100ml cillin bottles, and every bottle of 40ml is cold
Lyophilized dry obtained temozolomide freeze-dried powder injection formulation.
Embodiment 11
| Temozolomide | 10g |
| Mannitol | 60g |
| Polyoxyethylene sorbitan monoleate | 12g |
| Sodium citrate | 23.5g |
| Sodium chloride | 5g |
| Hydrochloric acid | In right amount |
| Methanol | 10ml |
| Ethanol | 10ml |
| Acetone | 10ml |
| Isopropanol | 10ml |
| Water for injection | Add to 4000ml |
Preparation method：60g mannitol, 12g polyoxyethylene sorbitan monoleates, 23.5g sodium citrates, 5g sodium chloride are sequentially added into injection
With in water, stirring and dissolving is complete, using salt acid for adjusting pH to 3.7.Temozolomide is distributed to using high-shearing dispersion emulsifying machine
The in the mixed solvent of each 10ml compositions of methanol, ethanol, acetone, isopropanol obtains dispersion liquid, and dispersion liquid is added into the above-mentioned aqueous solution
In, completely, constant volume to 4000ml, through 0.22 μm of miillpore filter aseptic filtration, is dispensed into 100ml cillin bottles, often stirring and dissolving
Temozolomide freeze-dried powder injection formulation is made in bottle 40ml, freeze-drying.
Embodiment 12
| Temozolomide | 10g |
| Mannitol | 60g |
| Polyoxyethylene sorbitan monoleate | 12g |
| Sodium citrate | 23.5g |
| Glycerine | 16g |
| Hydrochloric acid | In right amount |
| Ethanol | 40ml |
| Water for injection | Add to 4000ml |
Preparation method：60g mannitol, 12g polyoxyethylene sorbitan monoleates, 23.5g sodium citrates, 16g glycerine are sequentially added into injection
With in water, stirring and dissolving is complete, using salt acid for adjusting pH to 3.7.Temozolomide is distributed to using high-shearing dispersion emulsifying machine
Dispersion liquid is obtained in 40ml ethanol, dispersion liquid is added in the above-mentioned aqueous solution, after stirring and dissolving is complete, constant volume to 4000ml, material
Liquid is dispensed into 100ml cillin bottles through 0.22 μm of miillpore filter aseptic filtration, every bottle of 40ml, and Temozolomide is made in freeze-drying
Freeze-dried powder.
Embodiment 13
| Temozolomide | 10g |
| Mannitol | 60g |
| Polyoxyethylene sorbitan monoleate | 12g |
| Sodium citrate | 23.5g |
| Glucose | 26g |
| Hydrochloric acid | In right amount |
| Ethanol | 40ml |
| Water for injection | Add to 4000ml |
Preparation method：60g mannitol, 12g polyoxyethylene sorbitan monoleates, 23.5g sodium citrates, 26g glucose are sequentially added into note
Penetrate with water, stirring and dissolving is complete, using salt acid for adjusting pH to 3.7.Temozolomide is disperseed using high-shearing dispersion emulsifying machine
Obtain dispersion liquid into 40ml ethanol, dispersion liquid added in the above-mentioned aqueous solution, after stirring and dissolving is complete, constant volume to 4000ml,
Feed liquid is dispensed into 100ml cillin bottles through 0.22 μm of miillpore filter aseptic filtration, every bottle of 40ml, and freeze-drying is made for not azoles
Amine freeze-dried powder.
Embodiment 14
| Temozolomide | 10g |
| Mannitol | 60g |
| Polyoxyethylene sorbitan monoleate | 12g |
| Sodium citrate | 23.5g |
| Sorbierite | 26g |
| Hydrochloric acid | In right amount |
| Ethanol | 40ml |
| Water for injection | Add to 4000ml |
Preparation method：60g mannitol, 12g polyoxyethylene sorbitan monoleates, 23.5g sodium citrates, 26g sorbierites are sequentially added into note
Penetrate with water, stirring and dissolving is complete, using salt acid for adjusting pH to 3.7.Temozolomide is disperseed using high-shearing dispersion emulsifying machine
Obtain dispersion liquid into 40ml ethanol, dispersion liquid added in the above-mentioned aqueous solution, after stirring and dissolving is complete, constant volume to 4000ml,
Feed liquid is dispensed into 100ml cillin bottles through 0.22 μm of miillpore filter aseptic filtration, every bottle of 40ml, and freeze-drying is made for not azoles
Amine freeze-dried powder.
Embodiment 15
| Temozolomide | 10g |
| Mannitol | 60g |
| Polyoxyethylene sorbitan monoleate | 12g |
| Sodium citrate | 23.5g |
| Potassium chloride | 4g |
| Hydrochloric acid | In right amount |
| Ethanol | 40ml |
| Water for injection | Add to 4000ml |
Preparation method：60g mannitol, 12g polyoxyethylene sorbitan monoleates, 23.5g sodium citrates, 4g potassium chloride are sequentially added into injection
With in water, stirring and dissolving is complete, using salt acid for adjusting pH to 3.7.Temozolomide is distributed to using high-shearing dispersion emulsifying machine
Dispersion liquid is obtained in 40ml ethanol, dispersion liquid is added in the above-mentioned aqueous solution, after stirring and dissolving is complete, constant volume to 4000ml, material
Liquid is dispensed into 100ml cillin bottles through 0.22 μm of miillpore filter aseptic filtration, every bottle of 40ml, and Temozolomide is made in freeze-drying
Freeze-dried powder.
Reference examples 1 (the freeze-drying prescription for not adding organic solvent)
| Temozolomide | 10g |
| Mannitol | 60g |
| Polyoxyethylene sorbitan monoleate | 12g |
| Sodium citrate | 23.5g |
| Sodium chloride | 4g |
| Hydrochloric acid | In right amount |
| Water for injection | Add to 4000ml |
Preparation method：60g mannitol, 12g polyoxyethylene sorbitan monoleates, 23.5g sodium citrates, 4g sodium chloride are sequentially added into injection
With in water, stirring and dissolving is complete, using salt acid for adjusting pH to 3.7.Temozolomide is added in the above-mentioned aqueous solution, stirring and dissolving is complete
Quan Hou, constant volume to 4000ml, feed liquid is dispensed into 100ml cillin bottles through 0.22 μm of miillpore filter aseptic filtration, every bottle of 40ml,
Temozolomide freeze-dried powder injection formulation is made in freeze-drying.
Reference examples 2 (with reference to Chinese patent CN100588399)
20g sodium chloride is weighed, is added in water for injection, stirring at room temperature makes to be completely dissolved, 1g Temozolomides, stirring is added
Temozolomide is completely dissolved and is well mixed, water for injection is added to 400ml, with salt acid for adjusting pH value to 3.0, with 0.22 μm
Miillpore filter aseptic filtration, filling 40ml/ bottles freezes in bottle in 100ml, freeze-drying.
Reference examples 3 (embodiments 2 of Chinese patent CN 101172104)
15.00g mannitol is weighed, 3.00g Tween-80s, 4.00gL- threonines, 5.88g sodium citrates two are hydrated
Thing, 1.48g hydrochloric acid adds the water for injection that 800mL has been cooled to room temperature, and stirring and dissolving adds 2.5g Temozolomides, stirring and dissolving
After completely, 1000mL is added water to, with 0.22 micrometer Millipore membrane filtration, is dispensed into 100ml cillin bottles, every bottle of 40ml, freezed
Dry and temozolomide freeze-dried powder injection formulation is made.
Reference examples 4 (embodiments 5 of Chinese patent CN 102949351)
Weigh the 1000ml tert-butyl alcohols to be placed in container, add water for injection 3200ml, add 60g mannitol, the poly- sorbs of 12g
Ester -80,24g sodium citrates, 16g hydrochloric acid, stir and are well mixed, and add 10g Temozolomides, and stirring and dissolving completely, adds note
Penetrate and 4000ml supplied with water, solution is dispensed into 100ml cillin bottles through 0.22 μm of miillpore filter aseptic filtration, every bottle of 40ml,
Temozolomide freeze-dried powder injection formulation is made in freeze-drying.
Dissolution of raw material time in blending process of embodiment 1-15 and comparative example 1-4, final preparation organic residue are entered
Row is determined, as a result as follows：
The dissolution of raw material time contrast of the embodiment of table 1 and reference examples, dissolvent residual testing result
| Classification | The dissolution of raw material time (min) | Dissolvent residual (%) |
| Embodiment 1 | 20 | 0.08 |
| Embodiment 2 | 14 | 0.06 |
| Embodiment 3 | 18 | 0.08 |
| Embodiment 4 | 20 | 0.09 |
| Embodiment 5 | 24 | 0.05 |
| Embodiment 6 | 26 | 0.06 |
| Embodiment 7 | 18 | 0.07 |
| Embodiment 8 | 20 | 0.06 |
| Embodiment 9 | 22 | 0.07 |
| Embodiment 10 | 25 | 0.04 |
| Embodiment 11 | 22 | 0.05 |
| Embodiment 12 | 20 | 0.06 |
| Embodiment 13 | 20 | 0.05 |
| Embodiment 14 | 21 | 0.05 |
| Embodiment 15 | 20 | 0.04 |
| Control 1 | 180 | \ |
| Control 2 | 180 | \ |
| Control 3 | 120 | \ |
| Control 4 | 200 | 0.26 |
As a result show, when can significantly reduce dissolution of raw material using the distribution being redissolved after organic solvent dispersion raw material
Between, and the organic solvent used can be removed in freeze-drying, the organic residue of final preparation is relatively low, meets《In
State's pharmacopeia》Residual bound requirements of the version in 2010 to solvent.And the dissolution of raw material time of reference examples 4 is longer, and organic residue is obvious
It is higher.
The dried frozen aquatic products prepared to embodiment and comparative example, 1 month study on the stability, inspection target bag under the conditions of carrying out 25 DEG C
Include redissolution speed (observation redissolution situation under 40ml sterilizeds water for injection, slight wobble, lamp inspection instrument is added in every bottle), relevant thing
Matter is as a result as follows：
The embodiment of table 2 redissolves time, stability contrast with reference examples
As a result show, freeze-dried powder is substantially better than control group 1 and 2 in terms of speed is redissolved in embodiment 1-15 in the present invention,
Illustrate that the sample prepared according to this patent can significantly improve product and redissolve speed, reduction caused by redissolving not exclusively due to facing
Bed drug risk, facilitates Clinical practice, simultaneously because dispensing speed is fast, the relevant material of freeze-dried powder prepared by this patent is less than control
Group 1,2,3 and 4, and have good stability, it ensure that the security, stability and validity of product.
Claims (9)
1. a kind of temozolomide freeze-dried powder preparation, active component is Temozolomide or its pharmaceutically acceptable salt, its feature exists
In, it is lyophilized before also containing excipient, wetting agent, buffer, osmotic pressure regulator, pH adjusting agent, water for injection and have in solution
Machine solvent, wherein the organic solvent is selected from one of ethanol, acetone, isopropanol, normal propyl alcohol, butanone, sec-butyl alcohol, methanol or any
Combination；The organic solvent accounts for the 0.1%~4.5% of lyophilized preceding overall solution volume.
2. temozolomide freeze-dried powder preparation according to claim 1, it is characterised in that the organic solvent is ethanol.
3. temozolomide freeze-dried powder preparation according to claim 1, it is characterised in that Temozolomide is in lyophilized preceding solution
Mass percent be 0.1~2%.
4. temozolomide freeze-dried powder preparation according to claim 1, it is characterised in that in the temozolomide freeze-dried powder system
In agent, the mass percent of Temozolomide is 1%~50%.
5. temozolomide freeze-dried powder preparation according to claim 1, it is characterised in that excipient is in temozolomide freeze-dried powder
Mass percent in preparation is 30%~90%, and the excipient is selected from glucose, albumin, sodium chloride, lactose, sweet dew
One of alcohol, sorbierite, xylitol, dextran, sodium alginate or any combination；
Mass percent of the wetting agent in temozolomide freeze-dried powder preparation is 0%~50%, and the wetting agent is selected from poly- sorb
Ester -20, Tween-80, Emulsifier EL-60, Crodaret, bile salt, lecithin, polyethylene glycol it
One or any combination；
Mass percent of the buffer in temozolomide freeze-dried powder preparation is 1%~50%, and the buffer is selected from citric acid
One of salt, lactate, acetate, tartrate, succinate, phosphate or any combination；
The pH adjusting agent is selected from one of hydrochloric acid, citric acid, phosphoric acid, lactic acid, tartaric acid, butanedioic acid or any combination；
Mass percent of the osmotic pressure regulator in temozolomide freeze-dried powder preparation is 1%~50%, the osmotic pressure regulation
Agent is selected from one of glycerine, sodium chloride, potassium chloride, mannitol, glucose, sorbierite or any combination.
6. temozolomide freeze-dried powder preparation according to claim 1, it is characterised in that excipient is mannitol, wetting agent
For polyoxyethylene sorbitan monoleate, buffer is sodium citrate, and pH adjusting agent is hydrochloric acid, and osmotic pressure regulator is sodium chloride.
7. temozolomide freeze-dried powder preparation according to claim 1, it is characterised in that the pH scopes of the lyophilized preceding solution
For 2~7.
8. the preparation method of temozolomide freeze-dried powder preparation, comprises the following steps any one of claim 1-7：
1) excipient of recipe quantity, wetting agent, buffer, osmotic pressure regulator stirring and dissolving are weighed in water for injection；
2) using pH adjusting agent by step 1) pH value of gained feed liquid adjusted to 2-7；
3) Temozolomide or its officinal salt of recipe quantity are weighed, is dispersed in organic solvent, dispersion liquid is added into step
2) in gained feed liquid, stirring and dissolving；
4) vial is dispensed into after feed liquid being settled into cumulative volume, filtration sterilization；
5) it is freeze-dried, produces the temozolomide freeze-dried powder preparation of final products.
9. preparation method according to claim 8, it is characterised in that step 3) stock dispersion is in organic solvent
Method is by the way of high-shearing dispersion emulsifying machine.
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| US10806732B2 (en) * | 2016-05-02 | 2020-10-20 | Double Bond Pharmaceutical AB | Stable anti-neoplastic pharmaceutical composition comprising temozolomide and method of preparing the composition |
| CN105902504B (en) * | 2016-05-09 | 2021-04-16 | 石雷 | Tetrazine diformamide nano preparation and preparation method thereof |
| CN116440087A (en) * | 2017-11-08 | 2023-07-18 | 上海汇伦医药股份有限公司 | Preparation method of temozolomide freeze-dried preparation |
| CN109925283B (en) * | 2017-12-15 | 2021-07-20 | 江苏奥赛康药业有限公司 | Temozolomide pharmaceutical composition and preparation method thereof |
| CN110327284B (en) * | 2019-07-18 | 2022-11-22 | 石药集团中诺药业（石家庄）有限公司 | Cefodizime sodium for injection and preparation method thereof |
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| WO2011077458A1 (en) * | 2009-12-23 | 2011-06-30 | Sahaj Life Sciences Pvt. Ltd. | Formulations of temozolomide for parenteral administration |
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| CN100588399C (en) * | 2005-09-01 | 2010-02-10 | 天津帝士力投资控股集团有限公司 | Freeze-dried temzolomide powder for injection and its preparing process |
| CN101467967B (en) * | 2007-12-29 | 2012-05-23 | 北京京卫燕康药物研究所有限公司 | Double-element solution type preparation for intravenous injection and intracerebral injection |
| CN101559037B (en) * | 2008-04-16 | 2013-01-30 | 北京京卫燕康药物研究所有限公司 | Binary solution type preparation for intravenous injection and intracerebral injection |
| CN101869551B (en) * | 2010-06-28 | 2012-04-18 | 江苏奥赛康药业股份有限公司 | Temozolomide freeze-dried preparation |
| CN101984968A (en) * | 2010-10-29 | 2011-03-16 | 北京润德康医药技术有限公司 | Preparation method of pharmaceutical preparation of antitumor agent temozolomide |
| CN102949350A (en) * | 2011-08-16 | 2013-03-06 | 上海汇伦生命科技有限公司 | Lyophilized preparation of temozolomide and its preparation method |
| CN102949351B (en) * | 2011-08-16 | 2015-05-13 | 上海汇伦生命科技有限公司 | Preparation method of temozolomide lyophilized preparation |
| CN102688202B (en) * | 2012-06-07 | 2013-08-14 | 北京莱瑞森医药科技有限公司 | Temozolomide freeze-dried preparation |
| CN103845294A (en) * | 2012-12-03 | 2014-06-11 | 杭州容立医药科技有限公司 | Injectable temozolomide powder injection preparation and preparation method thereof |
| CN103432085A (en) * | 2013-08-19 | 2013-12-11 | 南京海纳医药科技有限公司 | Temozolomide freeze-drying preparation containing amino acid solubilizer, and preparation method thereof |
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