CN104825431A - Compound diisopropylamine dichloroacetate freeze-dried powder injection medicinal composition for injection - Google Patents
Compound diisopropylamine dichloroacetate freeze-dried powder injection medicinal composition for injection Download PDFInfo
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Abstract
The invention relates to a compound diisopropylamine dichloroacetate freeze-dried powder injection medicinal composition for injection. The freeze-dried powder injection medicinal composition includes diisopropylamine dichloroacetate, sodium gluconate, and an optionally selected acidifying or alkalizing agent. A weight ratio of diisopropylamine dichloroacetate to sodium gluconate is 40:30-50. The invention relates to a preparation method of the compound diisopropylamine dichloroacetate freeze-dried powder injection medicinal composition for injection. The method comprises the steps of liquid preparation and freeze drying. The compound diisopropylamine dichloroacetate freeze-dried powder injection medicinal composition for injection can be used for treating fatty liver, intrahepatic cholestasis, acute and chronic hepatitis, hepatomegaly and early hepatic cirrhosis. The freeze-dried powder injection medicinal composition has expected good properties.
Description
Technical field
The invention belongs to medical art, relate to a kind of lyophilized injectable powder pharmaceutical composition for hepatoprotective, this lyophilized injectable powder pharmaceutical composition can be used for fatty liver, intrahepatic cholestasis.This product is used for acute hepatitis, chronic hepatitis, hepatomegaly, early stage liver cirrhosis.Especially, the present invention relates to a kind of injection use compound diisopropylamine dichloroacetate lyophilized powder injection drug compositions, the active component of said composition comprises: diisopropylamine dichloroacetate and gluconic acid sodium salt.Lyophilized injectable powder pharmaceutical composition of the present invention has the good nature of expectation.
Background technology
The dichloroacetate (1:1) that diisopropylamine dichloroacetate (Diisopropylamine Dichloroacetate) is diisopropylamine, its molecular formula is C8H17O2NCl2, and molecular weight is 230.14, CAS registration number is 660-27-5.The chemical structural formula of diisopropylamine dichloroacetate is:
The different name of diisopropylamine dichloroacetate has dichloroacetic acid diisopropylammonium salt, diisopropylammonium dichloroacetate, diisopropylamine dichloroethanoate, DADA, DIPA-DCA, DIEDI etc.Commercially available prod trade name common abroad has Disotat (Isis), Kalodil (Fidia), Oxypangam (Sanorania) etc.The synthesis of diisopropylamine dichloroacetate is see GB 862248 (1961, Italseber).The pharmacology of diisopropylamine dichloroacetate is see V.A.E.Kraushaar etal., Arzneim.-Forsch.13,109 (1963).The Ames mutagenicity test of diisopropylamine dichloroacetate is see M.D.Gelernt, V.Herbert, Nutr.Cancer 3,129 (1982).The pharmacokinetics of diisopropylamine dichloroacetate is see J.-M.Yang et al., Gen.Pharmacol.19,683 (1988).The Pharmacological Reviews of diisopropylamine dichloroacetate is see P.W.Stacpoole, J.Clin.Pharmacol.J.New Drugs 9,282-291 (1969).Diisopropylamine dichloroacetate is white crystalline powder, mildly bitter flavor.Diisopropylamine dichloroacetate is easily molten, slightly molten in ether in water, ethanol or chloroform, almost insoluble in petroleum ether.The fusing point (annex VI C) of diisopropylamine dichloroacetate is 119 ~ 122 DEG C.The Mouse oral LD50:1700mg/kg (Kraushaar) of diisopropylamine dichloroacetate.
Gluconic acid sodium salt (Sodium gluconate) also known as sodium pentahydyoxycaproate, D-Gluconate sodium salt etc., molecular formula: C6H11NaO7, molecular weight: 218.14, CAS registration number: 527-07-1.Gluconic acid sodium salt is white or light yellow crystalline powder, fusing point (DEG C): 206, the acute toxicity of gluconic acid sodium salt: rabbit is through vein LD50:7630mg/kg.The dissolubility of gluconic acid sodium salt in water (25 °): 59g/100ml, is slightly soluble in ethanol, is insoluble to ether.
The compound medicine formed with both diisopropylamine dichloroacetate and gluconic acid sodium salt has gone on the market for many years.Typical preparation has lyophilization injectable powder and little aqueous injection, and tablet adopts both diisopropylamine dichloroacetate and calcium gluconate to combine.
The lyophilization injectable powder compound medicine that both typical diisopropylamine dichloroacetate and gluconic acid sodium salt form is produced by Shandong PKU Hi-tech Huatai Pharmaceutical Co., Ltd., you are auspicious for trade name, authentication code is the accurate word H20052437 of traditional Chinese medicines, formal adopted name: injection use compound diisopropylamine dichloroacetate, English name: Compound Diisopropylamine Dichloroacetate for Injection.The common preparation specification of this product is every bottle and contains diisopropylamine dichloroacetate 40mg and gluconic acid sodium salt 38mg.Also every bottle of injection use compound diisopropylamine dichloroacetate containing diisopropylamine dichloroacetate 80mg and gluconic acid sodium salt 76mg specification is had to go on the market.
Commercially available injection use compound diisopropylamine dichloroacetate lyophilization injectable powder to loosen block or powder for white or off-white color.Its indication is hepatinica; For fatty liver, intrahepatic cholestasis.This product is used for acute hepatitis, chronic hepatitis, hepatomegaly, early stage liver cirrhosis.
The usage and dosage of commercially available injection use compound diisopropylamine dichloroacetate lyophilization injectable powder is: intramuscular injection: dissolve with appropriate water for injection, a 40mg (in diisopropylamine dichloroacetate), 1 ~ 2 times/day; 2. intravenous injection: dissolve with appropriate water for injection, a 40mg (in diisopropylamine dichloroacetate), 1 ~ 2 times/day; 3. intravenous drip: a 40 ~ 80mg (in diisopropylamine dichloroacetate), 1 ~ 2 times/day, after dissolving with appropriate water for injection, then use 5% or 10% glucose solution, or 0.9% sodium chloride solution be diluted to (50 ~ 100ml) in right amount, the course for the treatment of please follow the doctor's advice.Need slow down when instiling and drip speed, and make bedridden patient, hypotensive is cautious use of.During injection, single cases finds that there is temporary discomfort, as dizzy and E Xin ﹑ vomit, can take slow down injection speed and make the measures such as bedridden patient rest.
The pharmacological toxicology of injection use compound diisopropylamine dichloroacetate lyophilization injectable powder: 1. on the impact of fatty liver: (1) consumes liver fat: be decomposed into diisopropylamine and dichloroacetic acid in this product body, the former generates methionine under ATP activation, the latter's metabolism is glycine, N5N10-CH2-FH4 (methyl tetrahydrofolate) is generated under glycine cleavage enzyme effect, energy supply simultaneously, the two all can provide methyl, promote choline synthesis, choline and liver fat act on, generate lecithin, promote liver steatolysis; (2) operate liver fat: lecithin, liver fat, cholesterol are combined with apolipoprotein and generate lipoprotein.Lipoprotein is soluble in blood plasma, thus by fat by being transported to outside liver in liver, reducing intrahepatic fat and assembling; (3) this product can reduce the concentration of glycerol in arterial blood and free fatty, reduces liver to sweet pick up the oil, stimulates triglyceride to enter blood with very low density lipoprotein (VLDL) (VLDL) simultaneously, thus effectively suppresses the synthesis of liver tg.2. on lipometabolic impact: (1) this product, by the activity of inhibitory hormone sensitive lipase, suppresses lipid mobilization; (2) by suppressing the activity of synthetic cholesterol rate-limiting enzyme (HMGCoA reductase), the synthesis of cholesterol is suppressed.(3) synthesis by suppressing the activity of the citrate synthetase in citric acid-Pyruvate recycling and acetyl-CoA carboxylase to suppress fatty acid.3. Hepatocyte protection: (1) improves hepatocellular energy metabolism.By promoting that the sequential of membrane phospholipid methylates, the mobility of enhance hepatocyte film.(2) improve as the activity of bile secretion with the Na+-K+-ATP enzyme of the major impetus of flowing; Promote that the function reparation of wounded hepatocytes improves histiocyte respiratory function and coefficient of oxygen utilization.(3) improve the metabolic activity of fatty acid, accelerate the oxidation of fatty acid, for liver function recovers to create conditions.
Lyophilized formulations generally adopts Freeze Drying Technique to prepare, and being about to needs dry drug solution to be frozen into solid in advance, then under low-temp low-pressure condition, makes water from solid state removing that directly distils without liquid state.But for ensureing the quality of preparation and the feasibility of technique, in the prescription of medicine, usually add adjuvant (also can be called carrier or proppant), as added appropriate mannitol, lactose, dextran, glucose, sodium chloride, phosphate etc.Add adjuvant in lyophilized formulations, although be conducive to the molding of preparation and the feasibility of technique, adjuvant add obvious Shortcomings: (1) adds the production cost of preparation; (2) increase of prescription complexity improves the difficulty of Drug's control; (3) during patient's intravenous injection medication, a large amount of exogenous materials is introduced in body, the probability that patient body works the mischief is increased.
Therefore, those skilled in the art are still expected for the clinical lyophilization injectable powder compound medicinal formulation providing both the diisopropylamine dichloroacetate and gluconic acid sodium salt with Good Pharmacy performance to form.
Summary of the invention
The object of the invention be to provide a kind of have some/lyophilized injectable powder comprising both diisopropylamine dichloroacetate and gluconic acid sodium salt of certain good nature, expect that it has one or more good pharmaceutical properties.The present inventor surprisingly, has the bag diisopropylamine dichloroacetate of special formulation and the lyophilized injectable powder both gluconic acid sodium salt and has the desirable features making us expecting.Therefore the present invention is accomplished.
In addition, the object of the present invention is to provide a kind of can the lyophilized formulations of injection and preparation technology containing the compound diisopropylamine dichloroacetate of any adjuvant: adding of adjuvant can be avoided completely by the present invention, make the quality of the pharmaceutical preparations more easy to control, reduce production cost, patient's drug safety is more guaranteed.
Character due to diisopropylamine dichloroacetate and gluconic acid sodium salt itself determines and adopts common Freeze Drying Technique can not be prepared into not containing the lyophilized formulations of adjuvant.The technology of the present invention key adopts special repeatedly pre-freeze sublimed method freeze drying technology technique to realize the object of inventing, this key problem in technology can improve lyophilizing sample crystallization behavior state and aeration significantly, steam is overflowed smoothly, sublimation process is carried out smoothly.
Therefore, first aspect present invention provides a kind of lyophilized injectable powder, wherein comprises diisopropylamine dichloroacetate and gluconic acid sodium salt.
Lyophilized injectable powder according to a first aspect of the present invention described in arbitrary embodiment, wherein the weight ratio of diisopropylamine dichloroacetate and gluconic acid sodium salt is 40:30 ~ 50.
Lyophilized injectable powder according to a first aspect of the present invention described in arbitrary embodiment, wherein the weight ratio of diisopropylamine dichloroacetate and gluconic acid sodium salt is 40:35 ~ 45.
Lyophilized injectable powder according to a first aspect of the present invention described in arbitrary embodiment, wherein the weight ratio of diisopropylamine dichloroacetate and gluconic acid sodium salt is 40:38.
Lyophilized injectable powder according to a first aspect of the present invention described in arbitrary embodiment, does not wherein comprise freeze-dried excipient.Such as wherein do not comprise sucrose, glucose, mannitol, lactose, sorbitol, glycine etc.
Lyophilized injectable powder according to a first aspect of the present invention described in arbitrary embodiment, wherein also comprises acid-base modifier.
Lyophilized injectable powder according to a first aspect of the present invention described in arbitrary embodiment, wherein said acid-base modifier is selected from sodium hydroxide, potassium hydroxide, sodium dihydrogen phosphate, sodium hydrogen phosphate, potassium dihydrogen phosphate, dipotassium hydrogen phosphate, hydrochloric acid, phosphoric acid, nitric acid, sulphuric acid or its combination.In one embodiment, described acid-base modifier is hydrochloric acid solution or sodium hydroxide solution, such as 1M hydrochloric acid solution or 1M sodium hydroxide solution.
Lyophilized injectable powder according to a first aspect of the present invention described in arbitrary embodiment, the consumption of wherein said acid-base modifier is, when to make this lyophilized injectable powder water for injection be dissolved into containing diisopropylamine dichloroacetate concentration be the solution of 20mg/ml, the amount of pH value in 5.0 ~ 6.5 scopes of this solution, the amount of pH value in 5.5 ~ 6.0 scopes of such as this solution.
As everyone knows, the lyophilization injectable powder (usually referred to as lyophilized injectable powder or freeze-dried powder) obtained through freezing-vacuum drying, it is first by each material dissolution with solvents (being typically with water dissolution), be mixed with a solution, then this solution is made to carry out freezing, carry out evacuation, distillation, drying and the Powdered thing of one substantially anhydrous (typically water content is lower than 5%, is particularly usually less than 3%) that obtains or block again.Therefore, the acid-base value of this solid lyophilized products regulates the pH value of solution to control by process for preparation usually; Or the pH value that the solid lyophilized products of acquisition can be made under the dissolve/dilute degree of regulation to control this dissolve/dilute liquid by prescription adjustment controls (this is called the acid-base value controlling solid lyophilized products); A rear mode more generally uses usually, such as, in pharmacopeia contained many lyophilized injectable powders control the acid-base value of goods all in this way, and the acid-base value that this mode controls product usually can not the recipe quantity of concrete regulation acid-base modifier, and only specify the acid-base value of finished product.Be equally applicable to of the present inventionly be, lyophilized injectable powder according to a first aspect of the present invention described in arbitrary embodiment, the amount of wherein said optional acid-base modifier is, when to make obtained lyophilized injectable powder water for injection be dissolved into containing diisopropylamine dichloroacetate concentration be the solution of 20mg/ml, the amount of pH value in 5.0 ~ 6.5 scopes of this solution, the amount of pH value in 5.5 ~ 6.0 scopes of such as this solution.
Lyophilized injectable powder according to a first aspect of the present invention described in arbitrary embodiment, it is prepare by comprising following step substantially:
A () takes the gluconic acid sodium salt of recipe quantity, add appropriate water for injection (being such as the 30-40% of dosing prescription volume), make dissolving, then add active carbon, stir, filtering decarbonization; Take the diisopropylamine dichloroacetate of recipe quantity in addition, add appropriate water for injection (being such as the 15-20% of dosing prescription volume) and make dissolving, adding dehydrated alcohol to liquor ethanol concentration reaches 20-30%, then adds active carbon, stirs, filtering decarbonization; Make two kinds of medicinal liquid mixing;
B () is mended and is injected water to its recipe quantity, stir, and measure solution ph and optional mensuration active component content, the situation that the departs from acid-base modifier according to medicinal liquid pH value is adjusted to pH5.0 ~ 6.5, preferred pH5.5 ~ 6.0;
C (), by medicinal liquid aseptic filtration, fill is in cillin bottle;
D () lyophilization removing moisture, tamponade, to obtain final product.
Lyophilized injectable powder according to a first aspect of the present invention described in arbitrary embodiment, its freeze-dry process process is:
(i). be cooled to-30 ~-50 DEG C, per minute l ~ 2 DEG C fall, be incubated 2 ~ 4 hours, make sample be warming up to-15 ~-30 DEG C again, intensification per hour 2 ~ 5 DEG C (such as 2 DEG C), keep l hours at this temperature, and then be cooled to-30 ~-50 DEG C, per minutely fall l ~ 2 DEG C, be incubated 2 ~ 5 hours, so repeat pre-freeze 0 ~ 3 time;
(ii). evacuation makes vacuum be 0.01 ~ 200Pa (such as 10Pa) again, sample is made to be warming up to-15 ~-30 DEG C, intensification per hour 2 ~ 5 DEG C (such as 2 DEG C), and carry out primary drying at this temperature 2 ~ 50 hours (such as 15 ~ 30 hours);
(iii). and then make sample be warming up to 10 ~ 30 DEG C, and be retained at this temperature vacuum change little time, be incubated and terminate whole freeze-drying process in l hour.
Lyophilized injectable powder according to a first aspect of the present invention described in arbitrary embodiment, wherein activated carbon dosage described in step (a) two kinds of drug solution preparing is 0.02% ~ 0.5% (w/v) of solution weight, preferably 0.02% ~ 0.2%.The consumption of this active carbon is conventional consumption.
Lyophilized injectable powder according to a first aspect of the present invention described in arbitrary embodiment, the water for injection of described " recipe quantity " wherein in step (b) in " benefit injects water to its recipe quantity " is 10-50 times of diisopropylamine dichloroacetate weight, such as 15-30 doubly, and such as about 18-25 doubly.The amount of this water for injection easily controls by solid content described in step (c).
Lyophilized injectable powder according to a first aspect of the present invention described in arbitrary embodiment, wherein acid-base modifier described in step (b) is the aqueous solution being selected from following acid-base modifier: sodium hydroxide, potassium hydroxide, sodium dihydrogen phosphate, sodium hydrogen phosphate, potassium dihydrogen phosphate, dipotassium hydrogen phosphate, hydrochloric acid, phosphoric acid, nitric acid, sulphuric acid or its combination.The concentration of these aqueous solutions well known to a person skilled in the art, such as 1 ~ 10%, such as 2% ~ 5%.In one embodiment, described acid-base modifier is hydrochloric acid solution or sodium hydroxide solution, such as 1M hydrochloric acid solution or 1M sodium hydroxide solution.
Lyophilized injectable powder according to a first aspect of the present invention described in arbitrary embodiment, the wherein filtered filtrate of step (c) gained, wherein solid content is 2 ~ 20% (w/v), preferably 2 ~ 15% (w/v), more more preferably 2 ~ 10%.
Lyophilized injectable powder according to a first aspect of the present invention described in arbitrary embodiment, wherein in step (d) after removing moisture in gained lyophilization material moisture lower than 10%, preferably lower than 8%, preferably lower than 5%, more preferably less than 3%.
Further, second aspect present invention provides a kind of method preparing lyophilized injectable powder described in the arbitrary embodiment of first aspect present invention, and it consists essentially of following steps:
A () takes the gluconic acid sodium salt of recipe quantity, add appropriate water for injection (being such as the 30-40% of dosing prescription volume), make dissolving, then add active carbon, stir, filtering decarbonization; Take the diisopropylamine dichloroacetate of recipe quantity in addition, add appropriate water for injection (being such as the 15-20% of dosing prescription volume) and make dissolving, adding dehydrated alcohol to liquor ethanol concentration reaches 20-30%, then adds active carbon, stirs, filtering decarbonization; Make two kinds of medicinal liquid mixing;
B () is mended and is injected water to its recipe quantity, stir, and measure solution ph and optional mensuration active component content, the situation that the departs from acid-base modifier according to medicinal liquid pH value is adjusted to pH5.0 ~ 6.5, preferred pH5.5 ~ 6.0;
C (), by medicinal liquid aseptic filtration, fill is in cillin bottle;
D () lyophilization removing moisture, tamponade, to obtain final product.
Method according to a second aspect of the present invention described in arbitrary embodiment, its freeze-dry process process is:
(i). be cooled to-30 ~-50 DEG C, per minute l ~ 2 DEG C fall, be incubated 2 ~ 4 hours, make sample be warming up to-15 ~-30 DEG C again, intensification per hour 2 ~ 5 DEG C (such as 2 DEG C), keep l hours at this temperature, and then be cooled to-30 ~-50 DEG C, per minutely fall l ~ 2 DEG C, be incubated 2 ~ 5 hours, so repeat pre-freeze 0 ~ 3 time;
(ii). evacuation makes vacuum be 0.01 ~ 200Pa (such as 10Pa) again, sample is made to be warming up to-15 ~-30 DEG C, intensification per hour 2 ~ 5 DEG C (such as 2 DEG C), and carry out primary drying at this temperature 2 ~ 50 hours (such as 15 ~ 30 hours);
(iii). and then make sample be warming up to 10 ~ 30 DEG C, and be retained at this temperature vacuum change little time, be incubated and terminate whole freeze-drying process in l hour.
Method according to a second aspect of the present invention described in arbitrary embodiment, wherein activated carbon dosage described in step (a) two kinds of drug solution preparing is 0.02% ~ 0.5% (w/v) of solution weight, preferably 0.02% ~ 0.2%.The consumption of this active carbon is conventional consumption.
Method according to a second aspect of the present invention described in arbitrary embodiment, the water for injection of described " recipe quantity " wherein in step (b) in " benefit injects water to its recipe quantity " is 10-50 times of diisopropylamine dichloroacetate weight, such as 15-30 doubly, and such as about 18-25 doubly.The amount of this water for injection easily controls by solid content described in step (c).
Method according to a second aspect of the present invention described in arbitrary embodiment, wherein acid-base modifier described in step (b) is the aqueous solution being selected from following acid-base modifier: sodium hydroxide, potassium hydroxide, sodium dihydrogen phosphate, sodium hydrogen phosphate, potassium dihydrogen phosphate, dipotassium hydrogen phosphate, hydrochloric acid, phosphoric acid, nitric acid, sulphuric acid or its combination.The concentration of these aqueous solutions well known to a person skilled in the art, such as 1 ~ 10%, such as 2% ~ 5%.In one embodiment, described acid-base modifier is hydrochloric acid solution or sodium hydroxide solution, such as 1M hydrochloric acid solution or 1M sodium hydroxide solution.
Method according to a second aspect of the present invention described in arbitrary embodiment, the wherein filtered filtrate of step (c) gained, wherein solid content is 2 ~ 20% (w/v), preferably 2 ~ 15% (w/v), more more preferably 2 ~ 10%.
Method according to a second aspect of the present invention described in arbitrary embodiment, wherein in step (d) after removing moisture in gained lyophilization material moisture lower than 10%, preferably lower than 8%, preferably lower than 5%, more preferably less than 3%.
Method according to a second aspect of the present invention described in arbitrary embodiment, wherein the weight ratio of diisopropylamine dichloroacetate and gluconic acid sodium salt is 40:30 ~ 50.
Method according to a second aspect of the present invention described in arbitrary embodiment, wherein the weight ratio of diisopropylamine dichloroacetate and gluconic acid sodium salt is 40:35 ~ 45.
Method according to a second aspect of the present invention described in arbitrary embodiment, wherein the weight ratio of diisopropylamine dichloroacetate and gluconic acid sodium salt is 40:38.
Method according to a second aspect of the present invention described in arbitrary embodiment, does not wherein comprise freeze-dried excipient.Such as wherein do not comprise sucrose, glucose, mannitol, lactose, sorbitol, glycine etc.
Method according to a second aspect of the present invention described in arbitrary embodiment, the consumption of wherein said acid-base modifier is, when to make this lyophilized injectable powder water for injection be dissolved into containing diisopropylamine dichloroacetate concentration be the solution of 20mg/ml, the amount of pH value in 5.0 ~ 6.5 scopes of this solution, the amount of pH value in 5.5 ~ 6.0 scopes of such as this solution.
State on the invention in the step of preparation method, although its concrete steps described in some details or the language step described in preparation example that describes up and down literary composition detailed description of the invention part distinguish to some extent, but those skilled in the art can summarize the above method step completely according to the open in detail of the present invention's full text.
Arbitrary embodiment of either side of the present invention, can combine with other embodiment, as long as they there will not be contradiction.In addition, in arbitrary embodiment of either side of the present invention, arbitrary technical characteristic goes for this technical characteristic in other embodiment, as long as they there will not be contradiction.
The invention will be further described below.
All documents that the present invention quotes from, their full content is incorporated to herein by reference, and if the implication expressed by these documents and the present invention inconsistent time, be as the criterion with statement of the present invention.In addition, the various term that the present invention uses and phrase have and well known to a person skilled in the art general sense, nonetheless, the present invention still wishes to be described in more detail at this these terms and phrase and to explain, the term mentioned and phrase, if any inconsistent with common art-recognized meanings, are as the criterion with the implication that the present invention states.
According to the present invention, term " excipient " also can be described as adjuvant, filler etc.
" the acceptable excipient of pharmacy " used herein refers to the excipient that can be used for compounding pharmaceutical, it there is no harmful effect to organism, and normally organism can tolerate.
In the present invention, preferred lyophilized injectable powder of the present invention make with water in every 1ml containing active component in the solution of diisopropylamine dichloroacetate 20mg after, then to measure according to the method under Chinese Pharmacopoeia version in 2010 two annex VI H items and pH value algoscopy.
Water content in lyophilization injectable powder is general below 8%, preferably lower than 5%, more preferably less than 3%.Moisture Control is by suitably adjusting lyophilization program to control.Moisture in this lyophilization injectable powder can measure according to many known methods, such as dry weight-loss method.
In the present invention, in order to regulate the pH value of medicinal liquid where necessary, suitable pH adjusting agent (being also called acid-base modifier in the present invention) can be added in compositions.Although the present inventor only regulates with not having the strong acid of buffer capacity or strong base solution such as a sodium hydrate aqueous solution and aqueous hydrochloric acid solution, but, those skilled in the art understand, if the pH requirement of system can be met with this pH adjusting agent process of not having buffer capacity, the pH adjusting agent then with buffer capacity will can realize the object of the invention more, therefore these buffer agents not only can adjust ph, and can stablize pH value.Therefore arbitrary pH adjusting agent listed by the present invention or its combination include in spirit and scope of the invention.
When preparing lyophilized injectable powder of the present invention, in the medicinal liquid prepared, solid content is 5 ~ 25% (w/v), preferably 5 ~ 20% (w/v), more more preferably 5 ~ 15%.Obtain because lyophilized injectable powder normally carries out lyophilization in tubulose cillin bottle, those skilled in the art understand this product at acquisition finished product even before for doctor, usually a round pie is all presented, although in the volume theory of this cake, lecture is fewer than the volume of original aqueous solution (slightly reducing), but this reducing can not narrow down to former aqueous solution volume 50% usually usually, usual meeting is between the 80-120% of former aqueous solution volume, between the 90-100% being more typically in former aqueous solution volume, and can be observed in finished product cillin bottle former aqueous solution liquid level vestige (main body cake because of lyophilizing reduce after remain in liquid level vestige bottle wall, even if the dried frozen aquatic products in cillin bottle is Powdered because of reasons such as a variety of causes such as collide, usually original liquid level vestige can still be retained), vestige also can estimate the aqueous solution volume of this freeze-dried composition before lyophilization accordingly.Therefore, although the present invention is to provide a kind of substantially anhydrous lyophilization injectable powder, but still roughly can estimate it when preparing according to this injectable powder, medicine liquid volume at least before lyophilization starts, the weight of the dry end-product in the volume estimated according to this and cillin bottle, also can calculate when preparing lyophilized injectable powder of the present invention, the content of the solid content in the medicinal liquid prepared.Therefore, lyophilized injectable powder according to a first aspect of the present invention, its solid content of medicinal liquid when preparing is 5 ~ 25% (w/v), preferably 5 ~ 20% (w/v), more more preferably 5 ~ 15%.
Term " solid content " refers to solid matter (such as reactive compound of the present invention and whole excipient used, weight/gram) join in solvent (such as water for injection), a solution is obtained after dissolving, the weight of described solid matter such as, divided by the percent (weight/volume percent, g/100ml) of whole liquor capacity.Such as in the present invention, if material medicine and all solids adjuvant amount to 5g add appropriate aqueous solution for injection, be mixed with the solution that final volume is 100ml, then the solid content of this medicinal liquid is 5%.
In the present invention, symbol %, according to the linguistic context that it uses, can have the implication of those skilled in the art's easy understand.Such as when mentioning solid content, this symbol represents the percent (w/v, such as g/100ml) of weight/volume; Again such as when mentioning " water content " in lyophilization injectable powder, such as water content is below 8%, and now this symbol % represents the percent (w/w, g/100g) of w/w.Generally speaking, solid dispersal in a liquid time, % represents weight/volume percent; Solid dispersal in solids or liquid dispersion in solids (such as the water content of powder pin) time, % represents w/w percent.In other cases, unless otherwise noted, symbol % represents w/w percent.
When preparing medicinal liquid of the present invention, as well known to those skilled in the art, the microporous filter membrane of example 0.45um according to appointment can carry out coarse filtration filtration, by before in liquid medicine filling to cillin bottle, the microporous filter membrane of example 0.22um according to appointment can carry out fine straining and filter with degerming, can filter repeatedly if desired.
According to lyophilized injectable powder of the present invention, it is lyophilization injectable powder.In one embodiment, this lyophilization injectable powder is single-dose preparations (injectable powder that such as XiLin is bottled), in per unit dosage, the amount (its in the present invention if not otherwise indicated, all in diisopropylamine dichloroacetate) of reactive compound can such as but not limited to about 20mg, about 40mg, about 60mg, about 80mg, about 100mg.
According to lyophilized injectable powder of the present invention, it redissolves with water for injection, and typically the redissolution time is in 60 seconds, preferably in 50 seconds, more preferably in 40 seconds.
According to lyophilized injectable powder of the present invention, it is after making the solution containing active component diisopropylamine dichloroacetate 20mg in every 1ml with water, the pH value of this solution is 5.0 ~ 6.5.In one embodiment, pH value is 5.5 ~ 6.0.
Lyophilized injectable powder provided by the invention can be preserved at least 24 months at place dry below 25 DEG C, can meet the Storage Requirement of general lyophilization injectable powder.
Obtained freeze-drying injectable powder of the present invention particularly lyophilization injectable powder is generally white or the lyophilizing block of off-white color or its fragment or its powder, odorless, bitter in the mouth, soluble in water.
Diisopropylamine dichloroacetate (DIPA), another name diisopropylamine dichloroacetate, sharp liver energy, the main pharmacological of DADA, DIPA regulates disorders of lipid metabolism, for choline and membrane phospholipid provide methyl; DIPA mainly by suppressing citrate lyase activity on the impact of fat, suppresses the synthesis of fatty acid and cholesterol biosynthesis raw material-S-acetyl-coenzyme-A (acetyl-CoA) in cytosol, reduces fatty acid and cholesterol biosynthesis; DIPA also can suppress the key enzyme-hydroxymethyl glutaryl CoA reductase activity of the synthesis of cholesterol, thus suppresses the synthesis of cholesterol; DIPA also suppresses hormonesensitive triglyceride lipase in fatty tissue active, reduces lipid mobilization, reduces the level of blood free fatty and glycerol; DIPA, by activating pyruvic dehydrogenase (PDH) complex activity, increases glucose oxidase, promotes tricarboxylic acid cycle thus be hepatocyte energy supply; DIPA is promote that the sequential of membrane phospholipid methylates to hepatocellular effect, the mobility of enhance hepatocyte film, the major impetus improving bile secretion and flowing is-Na+--K+--ATP enzymatic activity, promote the recovery of wounded hepatocytes physiological function, promote that lecithin generates, repair liver plasma membrane, promote liver regeneration.Therefore, DIPA has a better role to steatohepatitis patients's symptom and Signs; And effectively can improve glucose-lipid metabolism disorder, there is fast, significantly reduce the effect of serum triglycerides, cholesterol.
In addition, DIPA can be used as the donor of methyl needed for body synthesis choline, has removing toxic substances, improves liver function, reduces the effects such as Liver fatty deposition; And energy vasodilator, increase cerebral blood supply amount.Be mainly used in the auxiliary treatment of acute, chronic hepatitis, early stage liver cirrhosis, fatty liver and blood supply in brain deficiency.Domestic: DIPA is used for the treatment of fatty liver, intrahepatic cholestasis, general hepatic dysfunction; For acute, chronic hepatitis, hepatomegaly, early stage liver cirrhosis.External: DIPA is also for apoplexy sequela, cerebral hemorrhage, cerebral malacia, arteriosclerosis is levied, hypertension, angina pectoris, myocardial infarction, myocarditis and Cardiac Insufficiency cause various obstacles.
Advantage of the present invention is: provide a kind of can the lyophilized formulations of injection and preparation technology containing the compound diisopropylamine dichloroacetate of any adjuvant; Can avoid adding of adjuvant completely by the present invention, make the quality of the pharmaceutical preparations more easy to control, reduce production cost, patient's drug safety is more guaranteed.
Detailed description of the invention
Can be conducted further description the present invention by the following examples, but scope of the present invention is not limited to following embodiment.One of skill in the art can understand, and under the prerequisite not deviating from the spirit and scope of the present invention, can carry out various change and modification to the present invention.The present invention carries out generality and/or concrete description to the material used in test and test method.Although for realizing many materials that the object of the invention uses and operational approach is well known in the art, the present invention still describes in detail as far as possible at this.Following examples further illustrate the present invention, instead of restriction the present invention.In example below, the pH adjusting agent (in the present invention that is acid-base modifier) used, unless otherwise noted, 1M sodium hydroxide solution or 1M hydrochloric acid solution, its consumption is when making to prepare injectable powder, make the pH value of the solution prepared before lyophilization be adjusted to a certain setting or scope, this setting or scope are value or the scope of the pH value that solution that to make obtained lyophilized injectable powder water for injection be dissolved into containing diisopropylamine dichloroacetate concentration be 20mg/ml measures.The hereafter object of preparation process in order to illustrate, and based on each citing comparability and make some specific description, those skilled in the art therefrom can summarize the method obtaining the present invention and prepare lyophilized injectable powder completely according to existing knowledge.
Following example, uses with a collection of marketable material medicine to prepare preparation.This batch of crude drug and obtained preparation detect related substance according to #909 method, and wherein the content (relative to diisopropylamine dichloroacetate) of RRT1.19 impurity is 0.136%.Above-mentioned #909 method refers to the method for CN102297909B embodiment 1, specific as follows:
Adopt high performance liquid chromatography main constituent self dilution counter point;
Chromatographic condition: BDS-C18 chromatographic column: be filler with octadecylsilane chemically bonded silica, particle diameter is 5 μm, and specification is 250mm × 4.6mm (Hypersil); Column temperature 25 DEG C, with perchloric acid solution-acetonitrile (perchloric acid solution and acetonitrile volume ratio are for 100: 1) for mobile phase, flow velocity is 1mL/min; Determined wavelength is 225nm;
The compound method of perchloric acid solution is: 0.8ml perchloric acid is added water to 1000ml, then adds triethylamine 2ml, by phosphoric acid adjust ph to 4.2, and obtained perchloric acid solution;
Need testing solution is prepared: get test sample injection use compound diisopropylamine dichloroacetate and (comprise diisopropylamine dichloroacetate and gluconic acid sodium salt; Have been found that containing or all can not affect measurement result containing excipient) appropriate, add mobile phase and dissolve and dilute the solution made containing diisopropylamine dichloroacetate 5mg in every 1ml, as need testing solution;
Contrast solution is prepared: precision measures need testing solution 1mL, puts in 100ml measuring bottle, adds mobile phase and dissolves and be diluted to scale, shake up, in contrast solution;
Blank solution is prepared: separately get gluconic acid sodium salt and right amount of auxiliary materials optional accordingly in test sample prescription ratio, add mobile phase dissolve and dilute the solution made and be equivalent to diisopropylamine dichloroacetate 5mg and adjuvant optional accordingly in every 1ml containing gluconic acid sodium salt, as blank solution;
Algoscopy: precision measures contrast solution 20 μ l and injects high performance liquid chromatograph, regulate detection sensitivity, the peak height making main constituent chromatographic peak (chromatographic peak of diisopropylamine dichloroacetate) is 20% of full scale, precision measures each 20 μ l of need testing solution, contrast solution and adjuvant blank solution again, inject high performance liquid chromatograph respectively, record chromatogram is to 2.5 times of main constituent peak (chromatographic peak of diisopropylamine dichloroacetate) retention time; Outside the chromatographic peak of the corresponding retention time occurred in deduction blank solution chromatogram, the percent of other each impurity peak area and contrast solution main peak (chromatographic peak of diisopropylamine dichloroacetate) area ratio is the content of this impurity (related substance), and the percent of each impurity peak area sum and contrast solution main peak (chromatographic peak of diisopropylamine dichloroacetate) area ratio is the amount of total related substance.As described in #909 method, the impurity phase that in table 1, retention time is about 7.750min place is about 1.19 for the relative retention time of main peak (chromatographic peak of diisopropylamine dichloroacetate), and therefore this impurity in the present invention can referred to as RRT1.19 impurity.
Have been surprisingly found that, when using the inventive method carry out dosing and carry out lyophilization, not only effectively can reduce the RRT1.19 impurity content in gained preparation, and this RRT1.19 impurity content increase in Long-term Storage process of this preparation of gained is very limited.In addition, have been found that and state dosing on the invention and carry out in cryodesiccated preparation of injection, if add the excipient of this area routine, the injectable powder obtained effectively can not control this RRT1.19 impurity content and increase in Long-term Storage process.
one, injectable powder prepares embodiment part
embodiment 1
Prescription: (1000 bottles, dosage is for containing diisopropylamine dichloroacetate 20mg and gluconic acid sodium salt 19mg)
Diisopropylamine dichloroacetate 20g
Gluconic acid sodium salt 19g
Water for injection, adds to 1000ml in right amount
Preparation technology:
1., under cleaning condition, get freshly prepd water for injection (about prescription 80% amount), cool the temperature to less than 40 DEG C, add diisopropylamine dichloroacetate and the gluconic acid sodium salt of recipe quantity, be stirred to dissolve;
2. add the needle-use activated carbon of 0.1% by amount of preparation, stirring and adsorbing 15 minutes, filtering decarbonization;
3. the water for injection adding less than 40 DEG C, to recipe quantity, stirs evenly, degerming with 0.22 μm of filtering with microporous membrane;
4. press 1ml/ every bottle fill in cillin bottle, be placed in freeze dryer, carry out lyophilization by following freeze-dry process:
A. be cooled to-40 DEG C with l per minute DEG C, be incubated 2 hours, then make sample be warming up to-20 DEG C with intensification per hour 2 DEG C, keep 1 hours at this temperature, and then be cooled to-40 DEG C with 1 DEG C per minute, be incubated 2 hours; Repetition pre-freeze like this 1 time;
B. evacuation makes vacuum be 10Pa again, and intensification per hour 2 DEG C makes sample be warming up to-20 DEG C, and carries out primary drying at this temperature 20 hours;
And then make sample be warming up to 10 DEG C c., and be retained at this temperature vacuum change little time, be incubated and terminate whole freeze-drying process in 1 hour.
embodiment 2
Prescription: (1000 bottles, dosage is for containing diisopropylamine dichloroacetate 40mg and gluconic acid sodium salt 38mg)
Diisopropylamine dichloroacetate 40g
Gluconic acid sodium salt 38g
Water for injection, adds to 2000ml in right amount
Preparation technology:
1., under cleaning condition, get freshly prepd water for injection (about prescription 80% amount), cool the temperature to less than 40 DEG C, add diisopropylamine dichloroacetate and the gluconic acid sodium salt of recipe quantity, be stirred to dissolve;
2. add the needle-use activated carbon of 0.1% by amount of preparation, stirring and adsorbing 15 minutes, filtering decarbonization:
3. the water for injection adding less than 40 DEG C, to recipe quantity, stirs evenly, degerming with 0.22 μm of filtering with microporous membrane;
4. press 2ml/ every bottle fill in cillin bottle, be placed in freeze dryer, carry out lyophilization by following freeze-dry process:
A. be cooled to-50 DEG C with 2 DEG C per minute, be incubated 3 hours, then make sample be warming up to-20 DEG C with intensification per hour 2 DEG C, keep l hours at this temperature, and then be cooled to-50 DEG C with 2 DEG C per minute, be incubated 3 hours; Repetition pre-freeze like this 2 times;
B. evacuation makes vacuum power 10Pa again, and intensification per hour 2 DEG C makes sample be warming up to-20 DEG C, and carries out primary drying at this temperature 30 hours;
And then make sample be warming up to 20 DEG C c., and be retained at this temperature vacuum change little time, be incubated and terminate whole freeze-drying process in 1 hour.
embodiment 3
Prescription: (1000 bottles, dosage is for containing diisopropylamine dichloroacetate 10mg and gluconic acid sodium salt 9.5mg)
Dichloroacetic acid diisopropyl 10g
Gluconic acid sodium salt 9.5g
Water for injection, adds to 1000ml in right amount
Preparation technology:
1., under cleaning condition, get freshly prepd water for injection (about prescription 80% amount), cool the temperature to less than 40 DEG C, add diisopropylamine dichloroacetate and the gluconic acid sodium salt of recipe quantity, be stirred to dissolve;
2. add the needle-use activated carbon of 0.05% by amount of preparation, stirring and adsorbing 30 minutes, filtering decarbonization;
3. the water for injection adding less than 40 DEG C, to recipe quantity, stirs evenly, degerming with 0.22 μm of filtering with microporous membrane;
4. press 1ml/ every bottle fill in cillin bottle, be placed in freeze dryer, carry out lyophilization by following freeze-dry process:
A. be cooled to-30 DEG C with l per minute DEG C, be incubated 3 hours, then make sample be warming up to-15 DEG C with intensification per hour 2 DEG C, keep 1 hours at this temperature, and then be cooled to-30 DEG C with 1 DEG C per minute, be incubated 3 hours;
B. evacuation makes vacuum be 10Pa again, and intensification per hour 2 DEG C makes sample be warming up to-15 DEG C, and carries out primary drying at this temperature 15 hours:
And then make sample be warming up to 30 DEG C c., and be retained at this temperature vacuum change little time, be incubated and terminate whole freeze-drying process in 1 hour.
embodiment 4
Prescription: (1000 bottles, dosage is for containing diisopropylamine dichloroacetate 80mg and gluconic acid sodium salt 76mg)
Diisopropylamine dichloroacetate 80g
Gluconic acid sodium salt 76g
Water for injection, adds to 1000ml in right amount
Preparation technology:
1., under cleaning condition, get freshly prepd water for injection (about prescription 80% amount), cooling the temperature to less than 40 DEG C, as entered diisopropylamine dichloroacetate and the gluconic acid sodium salt of recipe quantity, being stirred to dissolve;
2. add the needle-use activated carbon of 0.2% by amount of preparation, stirring and adsorbing 45 minutes, filtering decarbonization;
3. the water for injection adding less than 40 DEG C, to recipe quantity, stirs evenly, degerming with 0.22 μm of filtering with microporous membrane:
4. press 1ml/ every bottle fill in cillin bottle, be placed in freeze dryer, carry out lyophilization by following freeze-dry process:
A. be cooled to-50 DEG C with l per minute DEG C, be incubated 4 hours, then make sample be warming up to-30 DEG C with intensification per hour 2 DEG C, keep 1 hours at this temperature, and then be cooled to-50 DEG C with 1 DEG C per minute, be incubated 4 hours; Repetition pre-freeze like this 3 times;
B. evacuation makes vacuum be 10Pa again, and intensification per hour 2 DEG C makes sample be warming up to-30 DEG C, and carries out primary drying at this temperature 30 hours;
And then make sample be warming up to 25 DEG C c., and be retained at this temperature vacuum change little time, be incubated and terminate whole freeze-drying process in 1 hour.
Above embodiment 1-4 gained injectable powder is when to be dissolved into containing diisopropylamine dichloroacetate concentration with water for injection be the solution of 20mg/ml, and the pH value of this solution is all in 5.5 ~ 6.0 scopes.
embodiment 11
Prescription: (1000 bottles, dosage is for containing diisopropylamine dichloroacetate 20mg and gluconic acid sodium salt 19mg)
Diisopropylamine dichloroacetate 20g
Fructus Vitis viniferae a kind of farm tools acid sodium 19g
Water for injection, adds to 1000ml in right amount
Preparation technology:
A () takes the gluconic acid sodium salt of recipe quantity, add appropriate water for injection (being about 35% of dosing prescription volume), make dissolving, then add 0.05% active carbon, stirs, filtering decarbonization; Take the diisopropylamine dichloroacetate of recipe quantity in addition, add appropriate water for injection (being about 20% of dosing prescription volume) and make dissolving, add dehydrated alcohol and reach 25% to liquor ethanol concentration, then add 0.05% active carbon, stir, filtering decarbonization; Make two kinds of medicinal liquid mixing;
B () is mended and is injected water to its recipe quantity, stir, measure solution ph and optional mensuration active component content, pH5.5 ~ 6.0 (thus make gained injectable powder when to be dissolved into containing diisopropylamine dichloroacetate concentration with water for injection be the solution of 20mg/ml, the pH value of this solution is all in 5.5 ~ 6.0 scopes) are adjusted to according to the situation that the departs from acid-base modifier of medicinal liquid pH value;
C (), by medicinal liquid aseptic filtration, fill is in cillin bottle;
D () lyophilization removing moisture, tamponade, to obtain final product.
Its freeze-dry process process is:
I. be cooled to-40 DEG C with l per minute DEG C, be incubated 2 hours, then make sample be warming up to-20 DEG C with intensification per hour 2 DEG C, keep 1 hours at this temperature, and then be cooled to-40 DEG C with 1 DEG C per minute, be incubated 2 hours; Repetition pre-freeze like this 1 time;
Ii. evacuation makes vacuum be 10Pa again, and intensification per hour 2 DEG C makes sample be warming up to-20 DEG C, and carries out primary drying at this temperature 20 hours;
And then make sample be warming up to 10 DEG C iii., and be retained at this temperature vacuum change little time, be incubated and terminate whole freeze-drying process in 1 hour.
embodiment 12
Prescription: (1000 bottles, dosage is for containing diisopropylamine dichloroacetate 40mg and gluconic acid sodium salt 38mg)
Diisopropylamine dichloroacetate 40g
Gluconic acid sodium salt 38g
Water for injection, adds to 2000ml in right amount
Preparation technology:
A () takes the gluconic acid sodium salt of recipe quantity, add appropriate water for injection (being about 30% of dosing prescription volume), make dissolving, then add 0.1% active carbon, stirs, filtering decarbonization; Take the diisopropylamine dichloroacetate of recipe quantity in addition, add appropriate water for injection (being about 15% of dosing prescription volume) and make dissolving, add dehydrated alcohol and reach 20% to liquor ethanol concentration, then add 0.1% active carbon, stir, filtering decarbonization; Make two kinds of medicinal liquid mixing;
B () is mended and is injected water to its recipe quantity, stir, measure solution ph and optional mensuration active component content, pH5.5 ~ 6.0 (thus make gained injectable powder when to be dissolved into containing diisopropylamine dichloroacetate concentration with water for injection be the solution of 20mg/ml, the pH value of this solution is all in 5.5 ~ 6.0 scopes) are adjusted to according to the situation that the departs from acid-base modifier of medicinal liquid pH value;
C (), by medicinal liquid aseptic filtration, fill is in cillin bottle;
D () lyophilization removing moisture, tamponade, to obtain final product.
Its freeze-dry process process is:
I. be cooled to-50 DEG C with 2 DEG C per minute, be incubated 3 hours, then make sample be warming up to-20 DEG C with intensification per hour 2 DEG C, keep l hours at this temperature, and then be cooled to-50 DEG C with 2 DEG C per minute, be incubated 3 hours; Repetition pre-freeze like this 2 times;
Ii. evacuation makes vacuum power 10Pa again, and intensification per hour 2 DEG C makes sample be warming up to-20 DEG C, and carries out primary drying at this temperature 30 hours;
And then make sample be warming up to 20 DEG C iii., and be retained at this temperature vacuum change little time, be incubated and terminate whole freeze-drying process in 1 hour.
embodiment 13
Prescription: (1000 bottles, dosage is for containing diisopropylamine dichloroacetate 10mg and gluconic acid sodium salt 9.5mg)
Dichloroacetic acid diisopropyl 10g
Gluconic acid sodium salt 9.5g
Water for injection, adds to 1000ml in right amount
Preparation technology:
A () takes the gluconic acid sodium salt of recipe quantity, add appropriate water for injection (being about 40% of dosing prescription volume), make dissolving, then add 0.02% active carbon, stirs, filtering decarbonization; Take the diisopropylamine dichloroacetate of recipe quantity in addition, add appropriate water for injection (being about 15% of dosing prescription volume) and make dissolving, add dehydrated alcohol and reach 30% to liquor ethanol concentration, then add 0.02% active carbon, stir, filtering decarbonization; Make two kinds of medicinal liquid mixing;
B () is mended and is injected water to its recipe quantity, stir, measure solution ph and optional mensuration active component content, pH5.5 ~ 6.0 (thus make gained injectable powder when to be dissolved into containing diisopropylamine dichloroacetate concentration with water for injection be the solution of 20mg/ml, the pH value of this solution is all in 5.5 ~ 6.0 scopes) are adjusted to according to the situation that the departs from acid-base modifier of medicinal liquid pH value;
C (), by medicinal liquid aseptic filtration, fill is in cillin bottle;
D () lyophilization removing moisture, tamponade, to obtain final product.
Its freeze-dry process process is:
I. be cooled to-30 DEG C with l per minute DEG C, be incubated 3 hours, then make sample be warming up to-15 DEG C with intensification per hour 2 DEG C, keep 1 hours at this temperature, and then be cooled to-30 DEG C with 1 DEG C per minute, be incubated 3 hours;
Ii. evacuation makes vacuum be 10Pa again, and intensification per hour 2 DEG C makes sample be warming up to-15 DEG C, and carries out primary drying at this temperature 15 hours:
And then make sample be warming up to 30 DEG C iii., and be retained at this temperature vacuum change little time, be incubated and terminate whole freeze-drying process in 1 hour.
embodiment 14
Prescription: (1000 bottles, dosage is for containing diisopropylamine dichloroacetate 80mg and gluconic acid sodium salt 76mg)
Diisopropylamine dichloroacetate 80g
Gluconic acid sodium salt 76g
Water for injection, adds to 1000ml in right amount
Preparation technology:
A () takes the gluconic acid sodium salt of recipe quantity, add appropriate water for injection (being about 35% of dosing prescription volume), make dissolving, then add 0.2% active carbon, stirs, filtering decarbonization; Take the diisopropylamine dichloroacetate of recipe quantity in addition, add appropriate water for injection (being about 20% of dosing prescription volume) and make dissolving, add dehydrated alcohol and reach 25% to liquor ethanol concentration, then add 0.2% active carbon, stir, filtering decarbonization; Make two kinds of medicinal liquid mixing;
B () is mended and is injected water to its recipe quantity, stir, measure solution ph and optional mensuration active component content, pH5.5 ~ 6.0 (thus make gained injectable powder when to be dissolved into containing diisopropylamine dichloroacetate concentration with water for injection be the solution of 20mg/ml, the pH value of this solution is all in 5.5 ~ 6.0 scopes) are adjusted to according to the situation that the departs from acid-base modifier of medicinal liquid pH value;
C (), by medicinal liquid aseptic filtration, fill is in cillin bottle;
D () lyophilization removing moisture, tamponade, to obtain final product.
Its freeze-dry process process is:
I. be cooled to-50 DEG C with l per minute DEG C, be incubated 4 hours, then make sample be warming up to-30 DEG C with intensification per hour 2 DEG C, keep 1 hours at this temperature, and then be cooled to-50 DEG C with 1 DEG C per minute, be incubated 4 hours; Repetition pre-freeze like this 3 times;
Ii. evacuation makes vacuum be 10Pa again, and intensification per hour 2 DEG C makes sample be warming up to-30 DEG C, and carries out primary drying at this temperature 30 hours;
And then make sample be warming up to 25 DEG C iii., and be retained at this temperature vacuum change little time, be incubated and terminate whole freeze-drying process in 1 hour.
embodiment 15
Prescription: (1000 bottles, dosage is for containing diisopropylamine dichloroacetate 20mg and gluconic acid sodium salt 19mg)
Diisopropylamine dichloroacetate 20g
Fructus Vitis viniferae a kind of farm tools acid sodium 19g
Water for injection, adds to 2000ml in right amount
Preparation technology:
A () takes the gluconic acid sodium salt of recipe quantity, add appropriate water for injection (being about 35% of dosing prescription volume), make dissolving, then add 0.05% active carbon, stirs, filtering decarbonization; Take the diisopropylamine dichloroacetate of recipe quantity in addition, add appropriate water for injection (being about 20% of dosing prescription volume) and make dissolving, add dehydrated alcohol and reach 25% to liquor ethanol concentration, then add 0.05% active carbon, stir, filtering decarbonization; Make two kinds of medicinal liquid mixing;
B () is mended and is injected water to its recipe quantity, stir, measure solution ph and optional mensuration active component content, pH5.5 ~ 6.0 (thus make gained injectable powder when to be dissolved into containing diisopropylamine dichloroacetate concentration with water for injection be the solution of 20mg/ml, the pH value of this solution is all in 5.5 ~ 6.0 scopes) are adjusted to according to the situation that the departs from acid-base modifier of medicinal liquid pH value;
C (), by medicinal liquid aseptic filtration, fill is in cillin bottle;
D () lyophilization removing moisture, tamponade, to obtain final product.
Its freeze-dry process process is:
I. be cooled to-40 DEG C with l per minute DEG C, be incubated 2 hours, then make sample be warming up to-20 DEG C with intensification per hour 2 DEG C, keep 1 hours at this temperature, and then be cooled to-40 DEG C with 1 DEG C per minute, be incubated 2 hours; Repetition pre-freeze like this 1 time;
Ii. evacuation makes vacuum be 10Pa again, and intensification per hour 2 DEG C makes sample be warming up to-20 DEG C, and carries out primary drying at this temperature 20 hours;
And then make sample be warming up to 10 DEG C iii., and be retained at this temperature vacuum change little time, be incubated and terminate whole freeze-drying process in 1 hour.
embodiment 16
Prescription: (1000 bottles, dosage is for containing diisopropylamine dichloroacetate 40mg and gluconic acid sodium salt 38mg)
Diisopropylamine dichloroacetate 40g
Gluconic acid sodium salt 38g
Water for injection, adds to 1000ml in right amount
Preparation technology:
A () takes the gluconic acid sodium salt of recipe quantity, add appropriate water for injection (being about 30% of dosing prescription volume), make dissolving, then add 0.1% active carbon, stirs, filtering decarbonization; Take the diisopropylamine dichloroacetate of recipe quantity in addition, add appropriate water for injection (being about 15% of dosing prescription volume) and make dissolving, add dehydrated alcohol and reach 20% to liquor ethanol concentration, then add 0.1% active carbon, stir, filtering decarbonization; Make two kinds of medicinal liquid mixing;
B () is mended and is injected water to its recipe quantity, stir, measure solution ph and optional mensuration active component content, pH5.5 ~ 6.0 (thus make gained injectable powder when to be dissolved into containing diisopropylamine dichloroacetate concentration with water for injection be the solution of 20mg/ml, the pH value of this solution is all in 5.5 ~ 6.0 scopes) are adjusted to according to the situation that the departs from acid-base modifier of medicinal liquid pH value;
C (), by medicinal liquid aseptic filtration, fill is in cillin bottle;
D () lyophilization removing moisture, tamponade, to obtain final product.
Its freeze-dry process process is:
I. be cooled to-50 DEG C with 2 DEG C per minute, be incubated 3 hours, then make sample be warming up to-20 DEG C with intensification per hour 2 DEG C, keep l hours at this temperature, and then be cooled to-50 DEG C with 2 DEG C per minute, be incubated 3 hours; Repetition pre-freeze like this 2 times;
Ii. evacuation makes vacuum power 10Pa again, and intensification per hour 2 DEG C makes sample be warming up to-20 DEG C, and carries out primary drying at this temperature 30 hours;
And then make sample be warming up to 20 DEG C iii., and be retained at this temperature vacuum change little time, be incubated and terminate whole freeze-drying process in 1 hour.
embodiment 17
Prescription: (1000 bottles, dosage is for containing diisopropylamine dichloroacetate 10mg and gluconic acid sodium salt 9.5mg)
Dichloroacetic acid diisopropyl 10g
Gluconic acid sodium salt 9.5g
Water for injection, adds to 1500ml in right amount
Preparation technology:
A () takes the gluconic acid sodium salt of recipe quantity, add appropriate water for injection (being about 40% of dosing prescription volume), make dissolving, then add 0.02% active carbon, stirs, filtering decarbonization; Take the diisopropylamine dichloroacetate of recipe quantity in addition, add appropriate water for injection (being about 15% of dosing prescription volume) and make dissolving, add dehydrated alcohol and reach 30% to liquor ethanol concentration, then add 0.02% active carbon, stir, filtering decarbonization; Make two kinds of medicinal liquid mixing;
B () is mended and is injected water to its recipe quantity, stir, measure solution ph and optional mensuration active component content, pH5.5 ~ 6.0 (thus make gained injectable powder when to be dissolved into containing diisopropylamine dichloroacetate concentration with water for injection be the solution of 20mg/ml, the pH value of this solution is all in 5.5 ~ 6.0 scopes) are adjusted to according to the situation that the departs from acid-base modifier of medicinal liquid pH value;
C (), by medicinal liquid aseptic filtration, fill is in cillin bottle;
D () lyophilization removing moisture, tamponade, to obtain final product.
Its freeze-dry process process is:
I. be cooled to-30 DEG C with l per minute DEG C, be incubated 3 hours, then make sample be warming up to-15 DEG C with intensification per hour 2 DEG C, keep 1 hours at this temperature, and then be cooled to-30 DEG C with 1 DEG C per minute, be incubated 3 hours;
Ii. evacuation makes vacuum be 10Pa again, and intensification per hour 2 DEG C makes sample be warming up to-15 DEG C, and carries out primary drying at this temperature 15 hours:
And then make sample be warming up to 30 DEG C iii., and be retained at this temperature vacuum change little time, be incubated and terminate whole freeze-drying process in 1 hour.
embodiment 18
Prescription: (1000 bottles, dosage is for containing diisopropylamine dichloroacetate 80mg and gluconic acid sodium salt 76mg)
Diisopropylamine dichloroacetate 80g
Gluconic acid sodium salt 76g
Water for injection, adds to 1500ml in right amount
Preparation technology:
A () takes the gluconic acid sodium salt of recipe quantity, add appropriate water for injection (being about 35% of dosing prescription volume), make dissolving, then add 0.2% active carbon, stirs, filtering decarbonization; Take the diisopropylamine dichloroacetate of recipe quantity in addition, add appropriate water for injection (being about 20% of dosing prescription volume) and make dissolving, add dehydrated alcohol and reach 25% to liquor ethanol concentration, then add 0.2% active carbon, stir, filtering decarbonization; Make two kinds of medicinal liquid mixing;
B () is mended and is injected water to its recipe quantity, stir, measure solution ph and optional mensuration active component content, pH5.5 ~ 6.0 (thus make gained injectable powder when to be dissolved into containing diisopropylamine dichloroacetate concentration with water for injection be the solution of 20mg/ml, the pH value of this solution is all in 5.5 ~ 6.0 scopes) are adjusted to according to the situation that the departs from acid-base modifier of medicinal liquid pH value;
C (), by medicinal liquid aseptic filtration, fill is in cillin bottle;
D () lyophilization removing moisture, tamponade, to obtain final product.
Its freeze-dry process process is:
I. be cooled to-50 DEG C with l per minute DEG C, be incubated 4 hours, then make sample be warming up to-30 DEG C with intensification per hour 2 DEG C, keep 1 hours at this temperature, and then be cooled to-50 DEG C with 1 DEG C per minute, be incubated 4 hours; Repetition pre-freeze like this 3 times;
Ii. evacuation makes vacuum be 10Pa again, and intensification per hour 2 DEG C makes sample be warming up to-30 DEG C, and carries out primary drying at this temperature 30 hours;
And then make sample be warming up to 25 DEG C iii., and be retained at this temperature vacuum change little time, be incubated and terminate whole freeze-drying process in 1 hour.
Embodiment 21: formula and method for making are respectively with reference to embodiment 1-4, embodiment 11-18, and add mannitol unlike together with diisopropylamine dichloroacetate, the amount of mannitol is identical with diisopropylamine dichloroacetate, obtains 12 powder pin samples.
Embodiment 22: formula and method for making are respectively with reference to embodiment 1-4, embodiment 11-14, and add mannitol unlike together with diisopropylamine dichloroacetate, the amount of mannitol is 4 times of diisopropylamine dichloroacetate, obtains 8 powder pin samples.
Embodiment 23: formula and method for making are respectively with reference to embodiment 2, following freeze-dried excipient is added respectively: lactose, sorbitol, sucrose, dextran, sodium chloride or glucose unlike together with diisopropylamine dichloroacetate, the addition of this freeze-dried excipient is identical with the amount of diisopropylamine dichloroacetate in formula, obtains 6 powder pin samples.
Embodiment 24: formula and method for making are respectively with reference to embodiment 12, following freeze-dried excipient is added respectively: lactose, sorbitol, sucrose, dextran, sodium chloride or glucose unlike together with diisopropylamine dichloroacetate, the addition of this freeze-dried excipient is identical with the amount of diisopropylamine dichloroacetate in formula, obtains 6 powder pin samples.
Embodiment 25: formula and method for making are respectively with reference to embodiment 11-18, directly inject unlike not adding ethanol when preparing the medicinal liquid containing diisopropylamine dichloroacetate and make dissolving with water (being about 40% of dosing prescription volume), obtain 8 powder pin samples.
Embodiment 26: formula and method for making with reference to embodiment 1-4, unlike not adding gluconic acid sodium salt, obtain 4 powder pin samples respectively; Formula and method for making with reference to embodiment 11-14, unlike not adding gluconic acid sodium salt, obtain 4 powder pin samples respectively.
Embodiment 27: according to formula and the method for making of CN1628650A (200310111617.2, Liu Li) embodiment 1, prepare injectable powder.
Embodiment 28: according to CN 103304424 B (201310274191.6, Merrill Lynch) method of embodiment 1 prepares diisopropylamine dichloroacetate crude drug, then uses this crude drug to prepare injectable powder according to the formula of CN 103304424 B embodiment 3 and method for making.
two, test example part is investigated
1, injectable powder detects
Prepare in the process of injectable powder at above-described embodiment 1-4, embodiment 11-18, embodiment 21-28, #909 method is used to detect, active component diisopropylamine dichloroacetate content in discovery end-product injectable powder and theoretical inventory fit like a glove, and show that in the inventive method, active component diisopropylamine dichloroacetate can not have loss.
Prepare in the process of injectable powder at above-described embodiment 1-4, embodiment 11-18, embodiment 21-28, use #909 method to detect, by measuring the content of RRT1.19 impurity (relative to diisopropylamine dichloroacetate) in crude drug, final gained injectable powder.For often criticizing injectable powder, compare the situation of change of this injectable powder diisopropylamine dichloroacetate crude drug used with it RRT1.19 impurity under #909 method detects.Result shows, the injectable powder that different formulations/technique is obtained, and this RRT1.19 impurity situation of change presents significant difference.Particularly, in the injectable powder that embodiment of the present invention 11-18 is obtained, the content of RRT1.19 impurity is all well below the content of RRT1.19 impurity (relative to diisopropylamine dichloroacetate) in crude drug, and step (a) gained medicinal liquid is substantially identical with the content of RRT1.19 impurity (relative to diisopropylamine dichloroacetate) in final both gained injectable powder, this shows, through step (a) process, the RRT1.19 impurity mixed in crude drug effectively can be reduced.The amount that this RRT1.19 impurity reduces, can characterize with RRT1.19 impurity residual volume in the present invention, the available following formula of this RRT1.19 impurity residual volume (%) calculates:
RRT1.19 impurity residual volume=[injectable powder RRT1.19 impurity content ÷ crude drug RRT1.19 impurity content] × 100%
Close to 100%, above-mentioned RRT1.19 impurity residual volume (%) more represents that in experience step (a) raw materials treated medicine, RRT1.19 impurity removes fewer, when lower than 100% and from 100% more away from time, show that RRT1.19 impurity removes more.
Result: embodiment 1-4 gained injectable powder, embodiment 21 is respectively according to embodiment 1-4 gained injectable powder, embodiment 22 is respectively according to embodiment 1-4 gained injectable powder, embodiment 23 gained injectable powder, embodiment 25 gained injectable powder, embodiment 26 is respectively according to embodiment 1-4 gained injectable powder, embodiment 27 gained injectable powder, embodiment 28 gained injectable powder, these do not use Ethanol Treatment diisopropylamine dichloroacetate in dosing technique, the RRT1.19 impurity residual volume of gained injectable powder is all greater than 93%, all in 93.4 ~ 102.1% scopes, show the content that can not reduce wherein RRT1.19 impurity after these do not use Ethanol Treatment diisopropylamine dichloroacetate in gained injectable powder, embodiment 11-18 gained injectable powder, embodiment 21 is respectively according to embodiment 11-18 gained injectable powder, embodiment 22 is respectively according to embodiment 11-14 gained injectable powder, embodiment 24 gained injectable powder, embodiment 26 is respectively according to embodiment 11-14 gained injectable powder, these use Ethanol Treatment diisopropylamine dichloroacetate in dosing technique, the RRT1.19 impurity residual volume of gained injectable powder is all less than 17%, all in 6.3% ~ 16.5% scope, the content of wherein RRT1.19 impurity can be reduced in gained injectable powder significantly after showing these use Ethanol Treatment diisopropylamine dichloroacetate.
2, injectable powder detects
For injectable powder prepared by above-described embodiment 1-4, embodiment 11-18, embodiment 21-28, June is placed, the rate of increase of RRT1.19 impurity content (relative to diisopropylamine dichloroacetate) when measuring and calculate these injectable powder 0 month time and in June under they being placed in the room temperature condition of 40 ± 2 DEG C.For a certain injectable powder, its RRT1.19 impurity content rate of increase (%) calculating formula is as follows:
RRT1.19 impurity content rate of increase (%)=
[(RRT1.19 impurity content in June-0 month RRT1.19 impurity content) ÷ 0 month RRT1.19 impurity content] × 100%
Close to 0%, above-mentioned RRT1.19 impurity content rate of increase (%) more represents that injectable powder RRT1.19 impurity increasing degree in the process that keeps sample for a long time of simulation is less.
Result: embodiment 21 gained injectable powder, embodiment 22 gained injectable powder, embodiment 23 gained injectable powder, embodiment 24 gained injectable powder, embodiment 27 gained injectable powder, embodiment 28 gained injectable powder, these with the addition of conventional excipients in formula, the RRT1.19 impurity content rate of increase (%) of gained injectable powder is all greater than 138%, all in 138.7% ~ 196.2% scope, show that these add excipient even the injectable powder of conventional excipients, it is quite obvious in the RRT1.19 impurity increase in process that keeps sample for a long time; Embodiment 1-4 gained injectable powder, embodiment 11-18 gained injectable powder, embodiment 25 gained injectable powder, embodiment 26 gained injectable powder, these do not add conventional excipients in formula, the RRT1.19 impurity content rate of increase (%) of gained injectable powder is all less than 25%, all in 8.7% ~ 24.1% scope, show that these do not add excipient even the injectable powder of conventional excipients, it is quite little in the RRT1.19 impurity increase in process that keeps sample for a long time.
3, injectable powder quality testing example:
For foregoing embodiments 11-18 gained 8 batches of injectable powder and commercially available product injection use compound diisopropylamine dichloroacetate (H20052438, high-tech China of Beijing University is safe to produce, every bottle containing diisopropylamine dichloroacetate 40mg and gluconic acid sodium salt 38mg), according to the quality/character index such as the clarity of their solution of following methods detection and color, acidity, related substance, loss on drying, aseptic, visible foreign matters, particulate matter, content:
The clarity of solution and color: get test sample, add water the solution made containing diisopropylamine dichloroacetate 20mg in every 1ml, and this area requires that solution answers clear, colorless usually; As aobvious muddiness, compare with No. 1 turbidity standard (Chinese Pharmacopoeia version in 2010 two annex Ⅸ B), the usual requirement in this area must not be denseer; As colour developing, compare with yellow No. 1 standard color solution (Chinese Pharmacopoeia version in 2010 two annex Ⅸ A), the usual requirement in this area must not be darker.
Acidity: get test sample, add water and make the solution of every 1ml containing diisopropylamine dichloroacetate 20mg, measure (Chinese Pharmacopoeia version in 2010 two annex VI H), this area requires that pH value should be 5.0 ~ 6.5 usually in accordance with the law.
Related substance: get test sample, adds mobile phase and dissolves and dilute the solution made about containing diisopropylamine dichloroacetate 5mg in every 1ml, as need testing solution; It is appropriate that precision measures need testing solution, adds mobile phase and be diluted to the solution about containing diisopropylamine dichloroacetate 50 μ g in every 1ml, solution in contrast.According to the chromatographic condition test under assay item, get contrast solution 20 μ l injection liquid chromatography, regulate detection sensitivity, make the peak height at main constituent peak be about 10 ~ 20% of full scale; Get each 20 μ l of above-mentioned two kinds of solution injection liquid chromatography respectively again, record chromatogram is to 3 times of main constituent peak retention time, as aobvious impurity peaks in test solution chromatogram, this area requires that impurity peak area summation must not be greater than the main peak area sum (1.0%) of contrast solution usually.
Loss on drying: get test sample, is dried to constant weight at 80 DEG C, and this area requires that less loss weight must not cross 2.5% (Chinese Pharmacopoeia version in 2010 two annex VIII L) usually.
Aseptic: to get test sample, check (Chinese Pharmacopoeia version in 2010 two annex Ⅺ H), the usual requirement in this area should conform with the regulations in accordance with the law.
Visible foreign matters: get test sample, check (Chinese Pharmacopoeia version in 2010 two annex Ⅸ H), the usual requirement in this area should conform with the regulations in accordance with the law.
Particulate matter: get test sample, check (Chinese Pharmacopoeia version in 2010 two annex Ⅸ C), the usual requirement in this area should conform with the regulations in accordance with the law.
Assay: measure according to high performance liquid chromatography (Chinese Pharmacopoeia version in 2010 two annex V D);
Chromatographic condition and system suitability: be filler with octadecylsilane chemically bonded silica; Be mobile phase with high chloro acid solution's (0.82ml → 1000ml, adds triethylamine 2ml, with H3PO4 adjust pH to 3.0)-acetonitrile (98:2), regulate flow velocity to make gluconic acid sodium salt peak retention time be 4 ~ 5 minutes, determined wavelength is 215nm.Number of theoretical plate calculates should be not less than 2000 by diisopropylamine dichloroacetate peak;
Algoscopy precision takes test sample appropriate (being equivalent to diisopropylamine dichloroacetate 10mg), puts in 10ml measuring bottle, adds mobile phase and be diluted to scale, shake up, as need testing solution; Separately get diisopropylamine dichloroacetate reference substance and gluconic acid sodium salt reference substance appropriate, add mobile phase and make containing diisopropylamine dichloroacetate 1mg and the solution containing gluconic acid sodium salt 1mg in every 1ml, product solution in contrast; Draw each 20 μ l of above-mentioned two kinds of solution, injection liquid chromatography, by external standard method with calculated by peak area, to obtain final product respectively; This area requires to calculate by average loading amount usually, all should be 93.0% ~ 107.0% of labelled amount (theoretical inventory) containing diisopropylamine dichloroacetate (C8H17O2NCl2) and gluconic acid sodium salt (C6H11NaO7).
Each batch of injectable powder to be measured detects according to said method, and indices is all in the scope that above-mentioned each index specifies usually.
4, long-term stable experiment example:
For preparation example 11 to preparation example 18 gained 8 batches of injectable powder and commercially available product injection use compound diisopropylamine dichloroacetate (H20052438 above, high-tech China of Beijing University is safe to produce, every bottle containing diisopropylamine dichloroacetate 40mg and gluconic acid sodium salt 38mg), these samples are made to place June under the room temperature condition of 40 ± 2 DEG C, with reference to the method for " 3, injectable powder quality testing example " above, each index when investigating these injectable powder 0 month time and in June.The whole each injectable powder to be measured of result display is after placing June through 40 DEG C, and every Testing index is still in the scope that above-mentioned each index specifies usually.Show that injectable powder of the present invention has excellent stability.
5, safety testing example:
This test example carries out safety testing investigation to present composition powder pin
Gained sample embodiments 11 powder pin of the present invention, embodiment 12 powder pin, embodiment 13 powder pin, embodiment 14 powder pin, and commercially available product injection use compound diisopropylamine dichloroacetate (H20052438, high-tech China of Beijing University is safe to produce, every bottle containing diisopropylamine dichloroacetate 40mg and gluconic acid sodium salt 38mg), according to existing drug registration laws and regulations requirement (" Chemical induced irritation, anaphylaxis and hemolytic investigative technique guideline problem " seminar; Chemical induced irritation, anaphylaxis and hemolytic investigative technique guideline, drug research technological guidance principle, Beijing: China Medical Science Press, 2006:124), carry out vascular stimulation test, hemolytic experiment, anaphylaxis experiment, result shows the regulation that these samples all meet vascular stimulation test, hemolytic experiment, anaphylaxis experiment.The display present composition has good safety.Such as, in zest, the injectable powder Sample Injection area skin all detected, vein all present similar change, have no the abnormal phenomenas such as hyperemia, edema, scleroma and necrosis.
Claims (10)
1. a lyophilized injectable powder, wherein comprises diisopropylamine dichloroacetate and gluconic acid sodium salt.
2. lyophilized injectable powder according to claim 1, is characterized in that:
Wherein the weight ratio of diisopropylamine dichloroacetate and gluconic acid sodium salt is 40:30 ~ 50;
Wherein the weight ratio of diisopropylamine dichloroacetate and gluconic acid sodium salt is 40:35 ~ 45; And/or
Wherein the weight ratio of diisopropylamine dichloroacetate and gluconic acid sodium salt is 40:38.
3. lyophilized injectable powder according to claim 1, is characterized in that:
Wherein do not comprise freeze-dried excipient; And/or
Wherein do not comprise sucrose, glucose, mannitol, lactose, sorbitol, glycine etc.
4. lyophilized injectable powder according to claim 1, is characterized in that:
Wherein also comprise acid-base modifier;
Described acid-base modifier is selected from sodium hydroxide, potassium hydroxide, sodium dihydrogen phosphate, sodium hydrogen phosphate, potassium dihydrogen phosphate, dipotassium hydrogen phosphate, hydrochloric acid, phosphoric acid, nitric acid, sulphuric acid or its combination;
Described acid-base modifier is hydrochloric acid solution or sodium hydroxide solution, such as 1M hydrochloric acid solution or 1M sodium hydroxide solution; And/or
The consumption of described acid-base modifier is, when to make this lyophilized injectable powder water for injection be dissolved into containing diisopropylamine dichloroacetate concentration be the solution of 20mg/ml, the amount of pH value in 5.0 ~ 6.5 scopes of this solution, the amount of pH value in 5.5 ~ 6.0 scopes of such as this solution.
5. lyophilized injectable powder according to claim 1, it is prepare by comprising following step substantially:
A () takes the gluconic acid sodium salt of recipe quantity, add appropriate water for injection (being such as the 30-40% of dosing prescription volume), make dissolving, then add active carbon, stir, filtering decarbonization; Take the diisopropylamine dichloroacetate of recipe quantity in addition, add appropriate water for injection (being such as the 15-20% of dosing prescription volume) and make dissolving, adding dehydrated alcohol to liquor ethanol concentration reaches 20-30%, then adds active carbon, stirs, filtering decarbonization; Make two kinds of medicinal liquid mixing;
B () is mended and is injected water to its recipe quantity, stir, and measure solution ph and optional mensuration active component content, the situation that the departs from acid-base modifier according to medicinal liquid pH value is adjusted to pH5.0 ~ 6.5, preferred pH5.5 ~ 6.0;
C (), by medicinal liquid aseptic filtration, fill is in cillin bottle;
D () lyophilization removing moisture, tamponade, to obtain final product.
6. lyophilized injectable powder according to claim 5, its freeze-dry process process is:
(i). be cooled to-30 ~-50 DEG C, per minute l ~ 2 DEG C fall, be incubated 2 ~ 4 hours, make sample be warming up to-15 ~-30 DEG C again, intensification per hour 2 ~ 5 DEG C (such as 2 DEG C), keep l hours at this temperature, and then be cooled to-30 ~-50 DEG C, per minutely fall l ~ 2 DEG C, be incubated 2 ~ 5 hours, so repeat pre-freeze 0 ~ 3 time;
(ii). evacuation makes vacuum be 0.01 ~ 200Pa (such as 10Pa) again, sample is made to be warming up to-15 ~-30 DEG C, intensification per hour 2 ~ 5 DEG C (such as 2 DEG C), and carry out primary drying at this temperature 2 ~ 50 hours (such as 15 ~ 30 hours);
(iii). and then make sample be warming up to 10 ~ 30 DEG C, and be retained at this temperature vacuum change little time, be incubated and terminate whole freeze-drying process in l hour.
7. lyophilized injectable powder according to claim 5, is characterized in that:
Activated carbon dosage described in step (a) two kinds of drug solution preparing is 0.02% ~ 0.5% (w/v) of solution weight, preferably 0.02% ~ 0.2%.The consumption of this active carbon is conventional consumption;
The water for injection of described " recipe quantity " in step (b) in " benefit injects water to its recipe quantity " is 10-50 times of diisopropylamine dichloroacetate weight, and such as 15-30 doubly, and such as about 18-25 doubly.The amount of this water for injection easily controls by solid content described in step (c);
Acid-base modifier described in step (b) is the aqueous solution being selected from following acid-base modifier: sodium hydroxide, potassium hydroxide, sodium dihydrogen phosphate, sodium hydrogen phosphate, potassium dihydrogen phosphate, dipotassium hydrogen phosphate, hydrochloric acid, phosphoric acid, nitric acid, sulphuric acid or its combination;
The filtered filtrate of step (c) gained, wherein solid content is 2 ~ 20% (w/v), preferably 2 ~ 15% (w/v), more more preferably 2 ~ 10%;
In step (d) after removing moisture in gained lyophilization material moisture lower than 10%, preferably lower than 8%, preferably lower than 5%, more preferably less than 3%.
8. prepare the method for the lyophilized injectable powder of any one of claim 1-7, it consists essentially of following steps:
A () takes the gluconic acid sodium salt of recipe quantity, add appropriate water for injection (being such as the 30-40% of dosing prescription volume), make dissolving, then add active carbon, stir, filtering decarbonization; Take the diisopropylamine dichloroacetate of recipe quantity in addition, add appropriate water for injection (being such as the 15-20% of dosing prescription volume) and make dissolving, adding dehydrated alcohol to liquor ethanol concentration reaches 20-30%, then adds active carbon, stirs, filtering decarbonization; Make two kinds of medicinal liquid mixing;
B () is mended and is injected water to its recipe quantity, stir, and measure solution ph and optional mensuration active component content, the situation that the departs from acid-base modifier according to medicinal liquid pH value is adjusted to pH5.0 ~ 6.5, preferred pH5.5 ~ 6.0;
C (), by medicinal liquid aseptic filtration, fill is in cillin bottle;
D () lyophilization removing moisture, tamponade, to obtain final product.
9. method according to claim 8, its freeze-dry process process is:
(i). be cooled to-30 ~-50 DEG C, per minute l ~ 2 DEG C fall, be incubated 2 ~ 4 hours, make sample be warming up to-15 ~-30 DEG C again, intensification per hour 2 ~ 5 DEG C (such as 2 DEG C), keep l hours at this temperature, and then be cooled to-30 ~-50 DEG C, per minutely fall l ~ 2 DEG C, be incubated 2 ~ 5 hours, so repeat pre-freeze 0 ~ 3 time;
(ii). evacuation makes vacuum be 0.01 ~ 200Pa (such as 10Pa) again, sample is made to be warming up to-15 ~-30 DEG C, intensification per hour 2 ~ 5 DEG C (such as 2 DEG C), and carry out primary drying at this temperature 2 ~ 50 hours (such as 15 ~ 30 hours);
(iii). and then make sample be warming up to 10 ~ 30 DEG C, and be retained at this temperature vacuum change little time, be incubated and terminate whole freeze-drying process in l hour.
10. lyophilized injectable powder according to claim 8, is characterized in that:
Activated carbon dosage described in step (a) two kinds of drug solution preparing is 0.02% ~ 0.5% (w/v) of solution weight, preferably 0.02% ~ 0.2%.The consumption of this active carbon is conventional consumption;
The water for injection of described " recipe quantity " in step (b) in " benefit injects water to its recipe quantity " is 10-50 times of diisopropylamine dichloroacetate weight, and such as 15-30 doubly, and such as about 18-25 doubly.The amount of this water for injection easily controls by solid content described in step (c);
Acid-base modifier described in step (b) is the aqueous solution being selected from following acid-base modifier: sodium hydroxide, potassium hydroxide, sodium dihydrogen phosphate, sodium hydrogen phosphate, potassium dihydrogen phosphate, dipotassium hydrogen phosphate, hydrochloric acid, phosphoric acid, nitric acid, sulphuric acid or its combination;
The filtered filtrate of step (c) gained, wherein solid content is 2 ~ 20% (w/v), preferably 2 ~ 15% (w/v), more more preferably 2 ~ 10%;
In step (d) after removing moisture in gained lyophilization material moisture lower than 10%, preferably lower than 8%, preferably lower than 5%, more preferably less than 3%;
Wherein the weight ratio of diisopropylamine dichloroacetate and gluconic acid sodium salt is 40:30 ~ 50;
Wherein the weight ratio of diisopropylamine dichloroacetate and gluconic acid sodium salt is 40:35 ~ 45;
Wherein the weight ratio of diisopropylamine dichloroacetate and gluconic acid sodium salt is 40:38;
Wherein do not comprise freeze-dried excipient;
Wherein do not comprise sucrose, glucose, mannitol, lactose, sorbitol, glycine etc.;
The consumption of described acid-base modifier is, when to make this lyophilized injectable powder water for injection be dissolved into containing diisopropylamine dichloroacetate concentration be the solution of 20mg/ml, the amount of pH value in 5.0 ~ 6.5 scopes of this solution, the amount of pH value in 5.5 ~ 6.0 scopes of such as this solution.
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Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN115784901A (en) * | 2022-12-01 | 2023-03-14 | 山东北大高科华泰制药有限公司 | Diisopropylamine dichloroacetate and application thereof |
Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1557289A (en) * | 2004-02-04 | 2004-12-29 | 天津市资福医药科技开发有限公司 | Tensicor freeze-drying formulation and its making method |
| CN101422438A (en) * | 2007-11-02 | 2009-05-06 | 大道隆达（北京）医药科技发展有限公司 | Composite diisopropyiarmini dichloroacetas freeze-dry preparation without adjuvant and preparation technique thereof |
| CN103304424A (en) * | 2013-07-02 | 2013-09-18 | 湖北美林药业有限公司 | Diisopropylamine dichloroacetate compound and compound medicine composition injection thereof |
| CN105311010A (en) * | 2014-06-30 | 2016-02-10 | 南京瑞尔医药有限公司 | Compound diisopropylamine dichloroacetate freeze-dried powder injection and preparation method of same |
-
2015
- 2015-03-31 CN CN201510149866.3A patent/CN104825431A/en active Pending
Patent Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1557289A (en) * | 2004-02-04 | 2004-12-29 | 天津市资福医药科技开发有限公司 | Tensicor freeze-drying formulation and its making method |
| CN101422438A (en) * | 2007-11-02 | 2009-05-06 | 大道隆达（北京）医药科技发展有限公司 | Composite diisopropyiarmini dichloroacetas freeze-dry preparation without adjuvant and preparation technique thereof |
| CN103304424A (en) * | 2013-07-02 | 2013-09-18 | 湖北美林药业有限公司 | Diisopropylamine dichloroacetate compound and compound medicine composition injection thereof |
| CN105311010A (en) * | 2014-06-30 | 2016-02-10 | 南京瑞尔医药有限公司 | Compound diisopropylamine dichloroacetate freeze-dried powder injection and preparation method of same |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN115784901A (en) * | 2022-12-01 | 2023-03-14 | 山东北大高科华泰制药有限公司 | Diisopropylamine dichloroacetate and application thereof |
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