CN105560195A - Freeze-dried ropivacaine hydrochloride composition for injection - Google Patents
Freeze-dried ropivacaine hydrochloride composition for injection Download PDFInfo
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- CN105560195A CN105560195A CN201610174107.7A CN201610174107A CN105560195A CN 105560195 A CN105560195 A CN 105560195A CN 201610174107 A CN201610174107 A CN 201610174107A CN 105560195 A CN105560195 A CN 105560195A
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
- A61K9/19—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles lyophilised, i.e. freeze-dried, solutions or dispersions
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
- A61K31/445—Non condensed piperidines, e.g. piperocaine
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
- A61K47/26—Carbohydrates, e.g. sugar alcohols, amino sugars, nucleic acids, mono-, di- or oligo-saccharides; Derivatives thereof, e.g. polysorbates, sorbitan fatty acid esters or glycyrrhizin
Abstract
The invention relates to a freeze-dried ropivacaine hydrochloride composition for injection. The freeze-dried ropivacaine hydrochloride composition comprises ropivacaine hydrochloride and lactose, for example, 75 parts by weight of ropivacaine hydrochloride and 20-60 parts by weight of lactose. The composition is basically prepared by a method comprising the following steps: weighing a formulated amount of ropivacaine hydrochloride and lactose, adding an appropriate amount of injection water, and stirring for dissolution; adding active carbon into a medicinal solution obtained in the previous step, stirring, and filtering to remove carbon; refilling the injection water to a full formulated amount, stirring uniformly, measuring the pH value of the solution and optionally measuring the content of active ingredients, and adjusting the pH value to 4.0-6.0 by using a pH value regulator if necessary; carrying out sterilization and filtration on the medicinal solution, and filling the solution into a penicillin bottle; and carrying out freeze-drying to remove water, and carrying out tamponment. The freeze-dried ropivacaine hydrochloride composition for injection, provided by the invention, has excellent pharmaceutical properties as described in the specification.
Description
Technical field
The invention belongs to medical art, be specifically related to a kind of local anaesthetics compositions, particularly relate to a kind of ropivacaine hydrochloride in use for injection lyophilized powder injection drug compositions with excellent properties.The invention still further relates to the preparation method of this ropivacaine hydrochloride in use for injection lyophilized powder injection drug compositions.This ropivacaine hydrochloride in use for injection lyophilized powder injection drug compositions can be used for surgical operation anesthesia; Epidural anesthesia, comprises cesarean; Acute pain controls; Continual epidural infusion or intermittent single medication, as postoperative or labor pains; Field block.The ropivacaine hydrochloride in use for injection injectable powder that the present invention prepares has excellent physicochemical property.
Background technology
Ropivacaine (Ropivacaine) is a kind of long-acting amide-type local anesthetic, and its pharmacological characteristics is that cardiac toxicity is low, and sensation retardance is separated more obvious with motion retardance, has vasoconstrictor effects.Ropivacaine has Anesthesia and anagelsia dual function, be applicable to regional areas anesthesia in 72 hours of surgical operation anesthesia, epidural anesthesia, Postoperative Analgesia After and birth process, can effectively block sensory nerve transmission and produce analgesic activity, it be less on nervus motorius impact.First this product developed city Ropivacaine HCL injection by Aktiebolaget Astra of Sweden in 1994, and nineteen ninety-five gets the Green Light goes on the market in the U.S..The problem of Ropivacaine HCL preparation sold in the market mainly Ropivacaine HCL aqueous injection and Ropivacaine HCL injectable powder existence and stability difference, affect Clinical practice, be thus necessary to develop the Ropivacaine HCL preparation that a kind of dissolubility is good, stability is strong.
The molecular formula C of Ropivacaine HCL
17h
26n
2o (n) H
2o (n=0 or 1), molecular weight: 310.88, chemical name: S-(-)-N-(2,6-3,5-dimethylphenyl)-1-propyl group-2-piperidine formyl amine hydrochlorate (or monohydrate), chemical structural formula is:
Ropivacaine HCL crude drug is that a kind of white is to off-white color crystallization or crystalline powder.
The shortcomings such as Ropivacaine HCL preparation existence and stability is poor, light fugitive is hot, easily freeze, storage and transport are all inconvenient.In the following documents, refer to preparation method and the improvement of Ropivacaine HCL preparation.
A kind of ropivacaine hydrochloride in use for injection and preparation technology thereof is disclosed in CN1660094A.Added the support substance of pharmacology permission by Ropivacaine HCL, make stay-in-grade injection powder pin or freeze-dried powder, its support substance is lactose, lactose, glucose, dextran.Preparation method, except adopting conventional freeze-drying preparation, also can adopt up-to-date sterile cryogenic vacuum spray drying method preparation method.
The preparation technology of a kind of ropivacaine and officinal salt lyophilized injectable powder thereof is disclosed, particularly product freeze-drying preparation technology in CN100998567A.This invention ropivacaine and pharmaceutical salts freeze-dried powder preparation technology lyophilization stage thereof comprise: (1) pre-freeze stage; (the 2 pre-freeze constant temperature stages; (3) the drying bu sublimation stage; (4) gradient increased temperature drying stage again.
Disclose a kind of ropivacaine lyophilized injectable powder and preparation method in CN1626081A, it is characterized in that being made up of the ropivacaine pharmaceutical salts for the treatment of effective dose and cryodesiccated additives.Wherein, ropivacaine pharmaceutical salts is selected from s-ropivacaine mesylate and Ropivacaine HCL, can comprise diluent, isoosmotic adjusting agent, pH adjusting agent etc. by cryodesiccated additives, diluent is selected from lactose, lactose, sodium chloride, dextran, glucose, glycine, gelatin hydrolysate, polyvidone.
Disclose a kind of formula components and preparation process thereof of Ropivacaine HCL injection in CN102697708A, preparation process comprises: (1) takes supplementary material by formula; (2) supplementary material mixing leaves standstill and filters; (3) measure and regulate solution ph; (4) medicinal liquid is through 0.45 μm and 0.22 μm of filtering with microporous membrane; (5) medicinal liquid embedding, leads to nitrogen during embedding; (6) sterilizing is carried out.
A kind of high-safety ropivacaine hydrochloride injection and preparation method thereof is disclosed in CN102552126A.Its formula consists of: Ropivacaine HCL 20-200g, sodium chloride 70-100g, and sodium hydroxide or hydrochloric acid are appropriate, and water for injection adds to 10000ml; Described formula is made into 1000 injection, and the pH value of injection is 4.0-6.0.
Disclose a kind of Ropivacaine hydrochloride sodium chloride injection and preparation method thereof in CN102670489A, comprise the processing steps such as batching, carbon adsorption, coarse filtration, fine straining, fill, sterilizing, lamp inspection and packaging.
The feature of Ropivacaine HCL preparation existence and stability difference, its reason is that Ropivacaine HCL has enantiomer, easily there is the phenomenon of enantiomer transition in aqueous, cause Ropivacaine HCL preparation instability (for example, see Chinese Patent Application No. 2007100130274 and Chinese Patent Application No. 2014104487577).In the prescription announced in several the patents about Ropivacaine HCL preparation above and preparation method, adjuvant only mentions sodium chloride and sodium hydroxide or hydrochloric acid, there is not the material suppressing enantiomer transition, so and the shortcoming such as its poor stability unresolved, light fugitive are hot, easily freeze.
But, in maintenance medicament excellent properties such as its stability, necessity that prior art is still improved.Therefore, those skilled in the art still expect to have the preparation method of the Ropivacaine HCL lyophilization injectable powder possessing excellent pharmaceutical property.
Summary of the invention
The object of the present invention is to provide a kind of method preparing the Ropivacaine HCL lyophilization injectable powder possessing excellent pharmaceutical property, and expect that this injectable powder has excellent pharmaceutical properties and such as possesses excellent stability etc.The present inventor have been surprisingly found that, the injectable powder prepared by the inventive method can realize the above-mentioned purpose of at least one aspect, and obtained freeze-drying powder needle set has excellent physicochemical property.The present invention is based on this find and be accomplished.
For this reason, first aspect present invention provides a kind of compositions of Ropivacaine HCL lyophilization injectable powder, wherein comprises Ropivacaine HCL and lactose.
The compositions of arbitrary embodiment according to a first aspect of the present invention, wherein comprises Ropivacaine HCL 75 weight portion, lactose 20 ~ 60 weight portion.
The compositions of arbitrary embodiment according to a first aspect of the present invention, wherein comprises Ropivacaine HCL 75 weight portion, lactose 30 ~ 50 weight portion.
The compositions of arbitrary embodiment according to a first aspect of the present invention, wherein comprises Ropivacaine HCL 75 weight portion, lactose 35 ~ 45 weight portion.
The compositions of arbitrary embodiment according to a first aspect of the present invention, wherein comprises Ropivacaine HCL 75 weight portion, lactose 40 weight portion.
The compositions of arbitrary embodiment according to a first aspect of the present invention, it is packed by cillin bottle.
The compositions of arbitrary embodiment according to a first aspect of the present invention, wherein moisture is lower than 10%, preferably lower than 8%, preferably lower than 7%, more preferably less than 5%.
The compositions of arbitrary embodiment, wherein also comprises acid-base modifier according to a first aspect of the present invention.In one embodiment, 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.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.
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 again, substantially anhydrous (typically water content is lower than 8% for drying and the one that obtains, particularly be usually less than 7%, be particularly usually less than 5%) Powdered thing or block.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, the amount of pH value in 4.0 ~ 6.0 scopes of this solution when making described lyophilized injectable powder water for injection be dissolved into the solution of hydrochloric ropivacaine 1mg/ml concentration, the amount of pH value in 4.5 ~ 5.5 scopes of such as this solution.
The compositions of arbitrary embodiment according to a first aspect of the present invention, it is prepare by comprising following step substantially:
A () takes Ropivacaine HCL, the lactose of recipe quantity, add appropriate water for injection, be stirred to dissolve;
B () adds active carbon in previous step gained medicinal liquid, regulate the pH value 3.0 ~ 3.5 of solution with acid-base modifier, stir 1.5 ~ 2.5 hours at 15 ~ 35 DEG C of temperature, filtering decarbonization, pH4.0 ~ 6.0 of solution are regulated, preferred pH4.5 ~ 5.5 with acid-base modifier;
C () is mended and is injected water to prescription full dose, stir, and measures solution ph and optional mensuration active component content, if desired (or optionally) be adjusted to pH4.0 ~ 6.0 with acid-base modifier, preferred pH4.5 ~ 5.5;
D (), by medicinal liquid aseptic filtration, fill is in cillin bottle;
E () lyophilization removing moisture, tamponade, to obtain final product.
The compositions of arbitrary embodiment according to a first aspect of the present invention, wherein appropriate water for injection described in step (a) is the water for injection of 50 ~ 70% amounts (such as 55 ~ 65% amounts) of prescription full dose.
The compositions of arbitrary embodiment according to a first aspect of the present invention, wherein the addition of active carbon described in step (b) is that concentration of activated carbon reaches the amount of 0.05 ~ 0.15% in medicinal liquid.Oneself is through have been surprisingly found that, in this step, carry out charcoal treatment when the pH value of medicinal liquid being adjusted to lower value, the injectable powder obtained has beat all more excellent stability.
The compositions of arbitrary embodiment according to a first aspect of the present invention, wherein stirs 1.5 ~ 2.5 hours in step (b) at 20 ~ 30 DEG C of temperature.
The compositions of arbitrary embodiment according to a first aspect of the present invention, wherein stirs 2 hours in step (b) at 25 DEG C of temperature.
The compositions of arbitrary embodiment according to a first aspect of the present invention, wherein the mode of filtering decarbonization described in step (b) is: after filtering with the titanium rod decarburization that aperture is 1um, then use the polyether sulfone filter element of 0.45um by medicinal liquid coarse filtration.
The compositions of arbitrary embodiment according to a first aspect of the present invention, wherein mends described in step (c) and injects water to prescription full dose and refer to and add water for injection until activity component concentration is the amount of 20 ~ 30mg/ml (such as 25mg/ml).
The compositions of arbitrary embodiment according to a first aspect of the present invention, wherein aseptic filtration described in step (d) uses the polyether sulfone filter element of 0.22um to carry out aseptic filtration.
Further, second aspect present invention provides the method for the lyophilization injectable powder described in the arbitrary embodiment of lyophilization injectable powder such as first aspect present invention preparing Ropivacaine HCL, and it consists essentially of following steps:
B () adds active carbon in previous step gained medicinal liquid, regulate the pH value 3.0 ~ 3.5 of solution with acid-base modifier, stir 1.5 ~ 2.5 hours at 15 ~ 35 DEG C of temperature, filtering decarbonization, pH4.0 ~ 6.0 of solution are regulated, preferred pH4.5 ~ 5.5 with acid-base modifier;
C () is mended and is injected water to prescription full dose, stir, and measures solution ph and optional mensuration active component content, if desired (or optionally) be adjusted to pH4.0 ~ 6.0 with acid-base modifier, preferred pH4.5 ~ 5.5;
D (), by medicinal liquid aseptic filtration, fill is in cillin bottle;
E () lyophilization removing moisture, tamponade, to obtain final product.
The method of arbitrary embodiment according to a second aspect of the present invention, the compositions of wherein said Ropivacaine HCL lyophilization injectable powder comprises Ropivacaine HCL, lactose.
The method of arbitrary embodiment according to a second aspect of the present invention, the compositions of wherein said Ropivacaine HCL lyophilization injectable powder comprises Ropivacaine HCL 75 weight portion, lactose 20 ~ 60 weight portion.
The method of arbitrary embodiment according to a second aspect of the present invention, the compositions of wherein said Ropivacaine HCL lyophilization injectable powder comprises Ropivacaine HCL 75 weight portion, lactose 30 ~ 50 weight portion.
The method of arbitrary embodiment according to a second aspect of the present invention, the compositions of wherein said Ropivacaine HCL lyophilization injectable powder comprises Ropivacaine HCL 75 weight portion, lactose 35 ~ 45 weight portion.
The method of arbitrary embodiment according to a second aspect of the present invention, the compositions of wherein said Ropivacaine HCL lyophilization injectable powder comprises Ropivacaine HCL 75 weight portion, lactose 40 weight portion.
The method of arbitrary embodiment according to a second aspect of the present invention, wherein also comprises acid-base modifier in gained lyophilization injectable powder.In one embodiment, 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.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.
The method of arbitrary embodiment according to a second aspect of the present invention, wherein appropriate water for injection described in step (a) is the water for injection of 50 ~ 70% amounts (such as 55 ~ 65% amounts) of prescription full dose.
The method of arbitrary embodiment according to a second aspect of the present invention, wherein the addition of active carbon described in step (b) is that concentration of activated carbon reaches the amount of 0.05 ~ 0.15% in medicinal liquid.Oneself is through have been surprisingly found that, in this step, carry out charcoal treatment when the pH value of medicinal liquid being adjusted to lower value, the injectable powder obtained has beat all more excellent stability.
The method of arbitrary embodiment according to a second aspect of the present invention, wherein stirs 1.5 ~ 2.5 hours in step (b) at 20 ~ 30 DEG C of temperature.
The method of arbitrary embodiment according to a second aspect of the present invention, wherein stirs 2 hours in step (b) at 25 DEG C of temperature.
The method of arbitrary embodiment according to a second aspect of the present invention, wherein the mode of filtering decarbonization described in step (b) is: after filtering with the titanium rod decarburization that aperture is 1um, then use the polyether sulfone filter element of 0.45um by medicinal liquid coarse filtration.
The method of arbitrary embodiment according to a second aspect of the present invention, wherein mends described in step (c) and injects water to prescription full dose and refer to and add water for injection until activity component concentration is the amount of 20 ~ 30mg/ml (such as 25mg/ml).
The method of arbitrary embodiment according to a second aspect of the present invention, wherein aseptic filtration described in step (d) uses the polyether sulfone filter element of 0.22um to carry out aseptic filtration.
Method according to a second aspect of the present invention described in arbitrary embodiment, wherein in step (e) after removing moisture in gained lyophilization material moisture lower than 10%, preferably lower than 8%, preferably lower than 7%, more preferably less than 5%.
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.
Have been found that the ropivacaine hydrochloride in use for injection lyophilization injectable powder that the inventive method prepares has beat all advantage.Such as be embodied in following stability test aspect:
Stability test: whole injectable powder that Examples below 1 to embodiment 13 prepares, is placed in 42 DEG C of places and places May to carry out high-temperature treatment test; For each injectable powder, the assay method of dextroisomer described in user's rule 1, dextroisomer when measuring this injectable powder 0 month time and in May (relative to main constituent) content, particularly follows the tracks of and calculates the content of dextroisomer; The content being calculated as follows dextroisomer increases percent (%, can referred to as " dextroisomer increment "):
Above-mentioned whole injectable powder uses and prepares with a collection of Ropivacaine HCL crude drug, and the dextroisomer content of whole injectable powder 0 month time is substantially suitable, all in 0.11 ~ 0.17% scope.But after above-mentioned high-temperature treatment, different sample presents visibly different dextroisomer situation of change; Specifically, the dextroisomer increment (%) of the whole injectable powder of embodiment 9 ~ 13 gained is all in 132 ~ 186% scopes, and the dextroisomer increment (%) of the whole injectable powder of embodiment 1-8 gained is all in 27 ~ 46% scopes.This shows, the Ropivacaine HCL powder pin using same materials to obtain through distinct methods, does not have difference in an initial condition substantially, but distinct methods products obtained therefrom but exists significant difference in the stability stability that particularly dextroisomer characterizes.
For above-mentioned 42 DEG C of test specimens disposing May, measure respectively they 0 month and May time Ropivacaine HCL content, for each sample, relative amount time when calculating its May relative to 0 month, this relative amount is the residual content of powder pin at active component after high-temperature treatment May.Result shows, the residual content of the whole injectable powder of embodiment 9 ~ 13 gained is all in 94 ~ 96% scopes, the whole injectable powder of embodiment 1-8 gained residual content all in 97 ~ 99% scopes, this shows, although embodiment 9 ~ 13 powder pin is still greater than 90% and substantially meets the demands after high-temperature treatment, its stability is significantly not as good as embodiment 1-8 injectable powder.
In the present invention, preferred lyophilized injectable powder of the present invention after make the solution containing active component 7.5mg in every 1ml with water, then measures the acid-base value of this freeze-dried powder according to the method under Chinese Pharmacopoeia version in 2010 two annex VIH items and pH value algoscopy.
The preparation process of lyophilization injectable powder well known to a person skilled in the art pharmaceutical technology, such as following kind of the schematic freeze-drying curve of two shown in freeze-drying curve A and freeze-drying curve B:
Hereafter preparing in the instantiation in lyophilization injectable powder, if not otherwise specified, freeze-drying curve used is freeze-drying curve A.
Water content in lyophilization injectable powder is general below 8%, preferably lower than 7%, more preferably less than 5%.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 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 1 ~ 20% (w/v), preferably 1 ~ 15% (w/v), more more preferably 1 ~ 10%, more more preferably 1 ~ 5%.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 1 ~ 20% (w/v), preferably 1 ~ 15% (w/v), more more preferably 1 ~ 10%, more more preferably 1 ~ 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), and in per unit dosage, the amount of reactive compound can such as but not limited to about 25mg, about 50mg, about 75mg, about 100mg, about 150mg.
According to lyophilized injectable powder of the present invention, it redissolves with water for injection, and typically the redissolution time is in 30 seconds, preferably in 20 seconds, more preferably in 15 seconds.
According to lyophilized injectable powder of the present invention, its with water make in every 1ml containing reactive compound 7.5mg solution and according under Chinese Pharmacopoeia version in 2010 two annex VIH items method measure, the pH value of this solution is 4.0 ~ 6.0.In one embodiment, pH value is 4.5 ~ 5.5.
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.
After discovery long effective local anesthetic can bring out that heart is poly-and stops, people are seeking fat-soluble lower, safer alternative medicine always.Ropivacaine is exactly so a kind of New-type long-acting local anesthetics of amide derivatives, and its acting duration is long, and has anesthesia and analgesic effect.Its pharmacological characteristic is that cardiac toxicity is humble, and sensation retardance is separated comparatively obvious with motion retardance, have peripheral blood vessel contraction.Therefore this medicine is particularly useful for Postoperative Analgesia After and obstetrical analgesia.Ropivacaine, compared with traditional local anaesthetics, has following advantages: 1, curative effect effect---and ropivacaine is obviously longer than other long effective local anesthetic action time, and subcutaneous infiltration anesthesia comparatively grows 2 to 3 times with the bupivacaine of concentration action time.Sensation-motion retardance the separating degree of 2, special effect---ropivacaine is much larger than bupivacaine, and clearance rate is higher, makes it be more suitable for analgesia.3, controllability is strong---and the anaesthetic effect of ropivacaine is dose dependent, and sensation and the motion retarding degree of that is ropivacaine generation are measurable controllable.4, toxic and side effects is humble---and ropivacaine does not have the shortcoming that the cardiac toxicity of general long effective local anesthetic is larger, and these product seldom cardiac toxicity occur, and fetus is to the well tolerable property of this product tool.
Ropivacaine indication is:----epidural anesthesia, comprises cesarean---control of-acute pain----Continual epidural infusion or intermittent single medication, as postoperative or labor pains----field block in surgical operation anesthesia.
The dosage of ropivacaine and usage: ropivacaine is only provided with the clinician of regional anesthesia's experience or uses under it instructs.The reference dose of conventional anesthesia is determined according to the rules.When determining dosage, the experience of clinician and the health of patient are very important.Generally speaking, surgical anesthesia needs higher concentration and dosage.For analgesia medication, we advise using lower concentration and dosage.Before the injection and injection during, should carefully resorption to prevent intravenous injection.When needs large bolus injection, as epidural anesthesia, that advises use 3-5ml test dose contains adrenergic lignocaine.Of short duration increased heart rate can be caused as caused intravenous injection because of carelessness, or cause subarachnoid injection because of carelessness and can occur spinal anesthesia.Before injection standard dose and inject and need repeatedly resorption and blunting of attention injection or increment injection gradually, simultaneously close observation patient vital signs and keep talking with patient.When anesthesia need be extended, the lasting danger injected or repeat single injection and all should consider to reach poisoning plasma concentration or bring out local nerve damage.If there is poisoning symptom, injection should be stopped immediately.
To the treatment of postoperative pain, suggestion adopts following technology: place epidural catheter if preoperative, can give ropivacaine injection 7.5mg/ml implement epidural anesthesia through this pipe.Postoperative 2mg/ml ropivacaine maintains analgesia.To most of medium postoperative pain to severe, clinical research shows the transfusion speed of 6-10ml per hour, can provide effective analgesia, only with slight but not progressive nervus motorius retardance.After adopting this technology, the demand of opiates is obviously declined.Clinical research also shows, for the patient that need use higher dosage, the transfusion speed of 12-14ml per hour also can tolerate preferably.The concentration of more than 7.5mg/ml had not had for cesarean record.It is feasible that clinical experience shows that ropivacaine injection epidural input reaches 24 hours.Before not obtaining further result of the test, ropivacaine injection shall not be applied to the child of less than 12 years old.
Use points for attention during ropivacaine, the enforcement of regional anesthesia must be carried out on personnel and well-appointed basis.Should be easily available with the Drug and Paraphernalia of emergency resuscitation for monitoring.First venous channel should be set up to patient before the larger anesthesia of enforcement.Pertinent clinical medical worker should carry out suitable training and can be familiar with the Diagnosis and Treat of side effect, general toxicity and other complication.Some local anesthesia is as the injection of incidence, and the incidence rate of serious adverse reaction is higher, and has nothing to do with local anaesthetics used.For old or the patient of regional anesthesia need be used with other serious condition, should be specifically noted that.For reducing the potential danger of serious adverse reaction, before administration of anaesthetic, should improve the situation of patient as possible, drug dose also should adjust thereupon.Because ropivacaine is at liver metabolism, so Patients with Severe Liver Diseases should be cautious use of, because excretion of drug postpones, during repeated drug taking, dosage need be reduced.Renal insufficiency patient adjusts dosage as do not needed with single dose or short term therapy under normal circumstances.Chronic renal insufficiency patient is with acidosis and hypoproteinemia, and the probability that systemic toxicity occurs increases.Epidural anesthesia can produce hypotension and bradycardia, and as dilatation or the use vascular supercharging medicine of infusing in advance, can reduce the generation of this side effect, hypotension, if desired can repeated drug taking once occur to use 5-10mg ephedrine intravenous medical treatment.
The pharmacological characteristics of ropivacaine: ropivacaine is first long-acting local anesthetics of amide derivatives of pure enantiomorph, there is Anesthesia and anagelsia double effect, high dose can produce surgical anesthesia, and during low dosage, then sensigenous retardance is only blocked with the non-Progressive symmetric erythrokeratodermia nervus motorius of limitation.Add the retardance intensity and the persistent period that do not change ropivacaine with epinephrine.
The pharmacodynamic profiles of ropivacaine: ropivacaine as other local anaesthetics, enters in neural fibrocyte film and produces reversible retardance by blocking sodium ion stream to the conduction of impulse along nerve fiber.Local anaesthetics also may produce same effect to excitable cell membrane such as such as brain cell and myocardial cell etc., if overdose of medicine thing enters body circulation rapidly, central nervous system cardiovascular system of unifying will produce poisoning symptom and sign.The generation of central nervous system toxicity will early than cardiovascular system, because it occurs when lower plasma concentration.The effect of the cardiovascular system that living animal records unanimously shows to ropivacaine tolerance better.Local anaesthetics directly acts on heart, shows delayed conduction, negative inotropic action and finally causes cardiac arrhythmia and heart failure, and intravenous injection high dose ropivacaine can cause similar Heart surgical procedures.Extremely successful to the recovery of the Canis familiaris L. giving over much dosage ropivacaine, isolated myocardium can obtain the result similar with above-mentioned effect.Heavy ewe is compared with not conceived ewe, does not show and has stronger sensitivity to ropivacaine.Well-tolerated after healthy volunteer's intravenous injection ropivacaine, this medicine clinical experience points out a good safety range.According to adjoint sympatholytic degree, epidural uses this medicine can occur indirectly cardiovascular effect.
The pharmacokinetics of ropivacaine: the pKa of ropivacaine is 8.1, and distributive law is 141.The plasma concentration of ropivacaine depends on the vascularity of dosage, route of administration and injection site.Ropivacaine meets linear pharmacokinetics, maximal plasma concentration and dose proportional.Ropivacaine is complete with two-phase from peridural absorption, and its half-life order is respectively 14 minutes and 4 hours.Slow absorption is the rate-limiting factor removing ropivacaine, and it is longer than the intravenous administration removing half-life that what Epidural Administration this can be interpreted as.The total plasma clearance 440ml/min of ropivacaine.Free plasma clearance is 8L/min.Kidney clearance rate is 1ml/min, and the distribution volume of steady statue is 47L, and t1/2 is 1.8h.Ropivacaine is 0.4 through liver intermediate supersession rate.Ropivacaine is main and 1-acid Glycoprotein binding in blood plasma, and non-protein combination rate is 6%.When continuous epidural injection, the increase that can be observed the total plasma concentration of ropivacaine is relevant with the increase of Post operation 1-acid glycoprotein concentration, and the change of unconjugated concentration is less than the change of total plasma concentration.Ropivacaine is easy to through Placenta Hominis, and relatively non-binding concentration reaches balance very soon.Compared with parent in fetus body ropivacaine and plasma protein binding rate degree low, thus make total plasma concentration of fetus also lower than parent.Ropivacaine mainly by aromatic hydroxy group turn into and fully metabolism, after intravenous injection, 86% of accumulated dose is excreted by urine, wherein only 1% relevant with the medicine of non-metabolism.Major metabolite is 3-hydroxyl ropivacaine, wherein about 37% excretes from urine with conjugate form, the 4-hydroxyl ropivacaine excreted in urine, and N-goes alkyl metabolite and 4-hydroxyl to go alkyl metabolite to be about 1-3%.In conjunction with in blood plasma, only show the concentration that can predict with uncombined 3-hydroxyl ropivacaine.3-hydroxyl ropivacaine and 4-hydroxyl ropivacaine have local anesthetic action, but anesthetic action is more weak than ropivacaine.
Ropivacaine preparation prepared by the present invention has excellent pharmaceutical property.
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.Any conceive according to the present invention done be only pro forma but not substantial equivalent transformation and all should be considered as technical scheme category of the present invention.
In example below, if not otherwise indicated, be the Ropivacaine HCL crude drug (it meets the quality standard of Chinese Pharmacopoeia version in 2015 two Ropivacaine HCLs recorded) of same batch of use when preparing injectable powder.
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 scopes that lyophilization gained dry powder water for injection is diluted to the pH value that the solution containing active component 7.5mg/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.Dosing is prepared in various compositions below, and if not otherwise indicated, the total dosing amount often criticized is 10000ml, but when listing formula, all illustrates in the amount of every bottle of hydrochloric ropivacaine 75mg.
method example 1: assay method
The method described in [assay] in " ropivacaine hydrochloride in use for injection " kind that the assay of various sample (comprising injectable powder of the present invention) adopts Chinese Pharmacopoeia version two in 2015 to record is carried out; The method described in " dextroisomer " in " ropivacaine hydrochloride in use for injection " kind that the dextroisomer of various sample (comprising injectable powder of the present invention) adopts Chinese Pharmacopoeia version two in 2015 to record is carried out.
embodiment 1: prepare Ropivacaine HCL lyophilization injectable powder
formula:
Ropivacaine HCL 75mg,
Lactose 40mg,
Acid-base modifier: appropriate, regulates the setting in pH to following method for making,
Water for injection: add to 3ml.
method for making:
A () takes Ropivacaine HCL, the lactose of recipe quantity, add recipe quantity 60% water for injection, be stirred to dissolve;
B () adds active carbon (in medicine liquid volume 0.1%) in previous step gained medicinal liquid, the pH value 3.2 of solution is regulated with acid-base modifier, stir 2.0 hours at 25 DEG C of temperature, filtering decarbonization, regulate the pH5.0 of solution with acid-base modifier;
C () is mended and is injected water to prescription full dose, stir, and measures solution ph and optional mensuration active component content, if desired (or optionally) be adjusted to the final medicinal liquid pH value of previous step with acid-base modifier;
D (), by medicinal liquid aseptic filtration (carrying out aseptic filtration with the polyether sulfone filter element of 0.22um), fill is in cillin bottle;
E () lyophilization removing moisture (moisture is lower than 5%), tamponade, to obtain final product.
embodiment 2: prepare Ropivacaine HCL lyophilization injectable powder
formula:
Ropivacaine HCL 75mg,
Lactose 45mg,
Acid-base modifier: appropriate, regulates the setting in pH to following method for making,
Water for injection: add to 3.75ml.
method for making:
A () takes Ropivacaine HCL, the lactose of recipe quantity, add recipe quantity 65% water for injection, be stirred to dissolve;
B () adds active carbon (in medicine liquid volume 0.05%) in previous step gained medicinal liquid, the pH value 3.0 of solution is regulated with acid-base modifier, stir 2.0 hours at 20 DEG C of temperature, filtering decarbonization, regulate the pH5.5 of solution with acid-base modifier;
C () is mended and is injected water to prescription full dose, stir, and measures solution ph and optional mensuration active component content, if desired (or optionally) be adjusted to the final medicinal liquid pH value of previous step with acid-base modifier;
D (), by medicinal liquid aseptic filtration (carrying out aseptic filtration with the polyether sulfone filter element of 0.22um), fill is in cillin bottle;
E () lyophilization removing moisture (moisture is lower than 5%), tamponade, to obtain final product.
embodiment 3: prepare Ropivacaine HCL lyophilization injectable powder
formula:
Ropivacaine HCL 75mg,
Lactose 35mg,
Acid-base modifier: appropriate, regulates the setting in pH to following method for making,
Water for injection: add to 2.5ml.
method for making:
A () takes Ropivacaine HCL, the lactose of recipe quantity, add recipe quantity 55% water for injection, be stirred to dissolve;
B () adds active carbon (in medicine liquid volume 0.15%) in previous step gained medicinal liquid, the pH value 3.5 of solution is regulated with acid-base modifier, stir 2.3 hours at 30 DEG C of temperature, filtering decarbonization, regulate the pH4.5 of solution with acid-base modifier;
C () is mended and is injected water to prescription full dose, stir, and measures solution ph and optional mensuration active component content, if desired (or optionally) be adjusted to the final medicinal liquid pH value of previous step with acid-base modifier;
D (), by medicinal liquid aseptic filtration (carrying out aseptic filtration with the polyether sulfone filter element of 0.22um), fill is in cillin bottle;
E () lyophilization removing moisture (moisture is lower than 5%), tamponade, to obtain final product.
embodiment 4: prepare Ropivacaine HCL lyophilization injectable powder
formula:
Ropivacaine HCL 75mg,
Lactose 30mg,
Acid-base modifier: appropriate, regulates the setting in pH to following method for making,
Water for injection: add to 3ml.
method for making:
A () takes Ropivacaine HCL, the lactose of recipe quantity, add recipe quantity 50% water for injection, be stirred to dissolve;
B () adds active carbon (in medicine liquid volume 0.1%) in previous step gained medicinal liquid, the pH value 3.3 of solution is regulated with acid-base modifier, stir 1.8 hours at 25 DEG C of temperature, filtering decarbonization, regulate the pH4.0 of solution with acid-base modifier;
C () is mended and is injected water to prescription full dose, stir, and measures solution ph and optional mensuration active component content, if desired (or optionally) be adjusted to the final medicinal liquid pH value of previous step with acid-base modifier;
D (), by medicinal liquid aseptic filtration (carrying out aseptic filtration with the polyether sulfone filter element of 0.22um), fill is in cillin bottle;
E () lyophilization removing moisture (moisture is lower than 5%), tamponade, to obtain final product.
embodiment 5: prepare Ropivacaine HCL lyophilization injectable powder
formula:
Ropivacaine HCL 75mg,
Lactose 50mg,
Acid-base modifier: appropriate, regulates the setting in pH to following method for making,
Water for injection: add to 3ml.
method for making:
A () takes Ropivacaine HCL, the lactose of recipe quantity, add recipe quantity 70% water for injection, be stirred to dissolve;
B () adds active carbon (in medicine liquid volume 0.1%) in previous step gained medicinal liquid, the pH value 3.4 of solution is regulated with acid-base modifier, stir 2.0 hours at 23 DEG C of temperature, filtering decarbonization, regulate the pH6.0 of solution with acid-base modifier;
C () is mended and is injected water to prescription full dose, stir, and measures solution ph and optional mensuration active component content, if desired (or optionally) be adjusted to the final medicinal liquid pH value of previous step with acid-base modifier;
D (), by medicinal liquid aseptic filtration (carrying out aseptic filtration with the polyether sulfone filter element of 0.22um), fill is in cillin bottle;
E () lyophilization removing moisture (moisture is lower than 5%), tamponade, to obtain final product.
embodiment 6: prepare Ropivacaine HCL lyophilization injectable powder
formula:
Ropivacaine HCL 75mg,
Lactose 20mg,
Acid-base modifier: appropriate, regulates the setting in pH to following method for making,
Water for injection: add to 3ml.
method for making:
A () takes Ropivacaine HCL, the lactose of recipe quantity, add recipe quantity 60% water for injection, be stirred to dissolve;
B () adds active carbon (in medicine liquid volume 0.1%) in previous step gained medicinal liquid, the pH value 3.1 of solution is regulated with acid-base modifier, stir 2.5 hours at 25 DEG C of temperature, filtering decarbonization, regulate the pH5.0 of solution with acid-base modifier;
C () is mended and is injected water to prescription full dose, stir, and measures solution ph and optional mensuration active component content, if desired (or optionally) be adjusted to the final medicinal liquid pH value of previous step with acid-base modifier;
D (), by medicinal liquid aseptic filtration (carrying out aseptic filtration with the polyether sulfone filter element of 0.22um), fill is in cillin bottle;
E () lyophilization removing moisture (moisture is lower than 5%), tamponade, to obtain final product.
embodiment 7: prepare Ropivacaine HCL lyophilization injectable powder
formula:
Ropivacaine HCL 75mg,
Lactose 60mg,
Acid-base modifier: appropriate, regulates the setting in pH to following method for making,
Water for injection: add to 3ml.
method for making:
A () takes Ropivacaine HCL, the lactose of recipe quantity, add recipe quantity 58% water for injection, be stirred to dissolve;
B () adds active carbon (in medicine liquid volume 0.1%) in previous step gained medicinal liquid, the pH value 3.4 of solution is regulated with acid-base modifier, stir 1.5 hours at 27 DEG C of temperature, filtering decarbonization, regulate the pH5.0 of solution with acid-base modifier;
C () is mended and is injected water to prescription full dose, stir, and measures solution ph and optional mensuration active component content, if desired (or optionally) be adjusted to the final medicinal liquid pH value of previous step with acid-base modifier;
D (), by medicinal liquid aseptic filtration (carrying out aseptic filtration with the polyether sulfone filter element of 0.22um), fill is in cillin bottle;
E () lyophilization removing moisture (moisture is lower than 5%), tamponade, to obtain final product.
This example freeze-drying curve used is freeze-drying curve B.
embodiment 8: prepare Ropivacaine HCL lyophilization injectable powder
formula:
Ropivacaine HCL 75mg,
Lactose 50mg,
Acid-base modifier: appropriate, regulates the setting in pH to following method for making,
Water for injection: add to 3ml.
method for making:
A () takes Ropivacaine HCL, the lactose of recipe quantity, add recipe quantity 65% water for injection, be stirred to dissolve;
B () adds active carbon (in medicine liquid volume 0.15%) in previous step gained medicinal liquid, the pH value 3.2 of solution is regulated with acid-base modifier, stir 1.5 hours at 25 DEG C of temperature, filtering decarbonization, regulate the pH5.0 of solution with acid-base modifier;
C () is mended and is injected water to prescription full dose, stir, and measures solution ph and optional mensuration active component content, if desired (or optionally) be adjusted to the final medicinal liquid pH value of previous step with acid-base modifier;
D (), by medicinal liquid aseptic filtration (carrying out aseptic filtration with the polyether sulfone filter element of 0.22um), fill is in cillin bottle;
E () lyophilization removing moisture (moisture is lower than 5%), tamponade, to obtain final product.
embodiment 9: prepare Ropivacaine HCL lyophilization injectable powder
Respectively with reference to embodiment 1-8, different is only in step (b), after adding active carbon, directly stirs at the corresponding temperature, and does not regulate the operation of pH value to 3.0-3.5 scope of solution in advance with acid-base modifier, obtained 8 batches of powder pins.
embodiment 10: prepare Ropivacaine HCL lyophilization injectable powder
Prescription and compound method are with reference to Chinese Patent Application No. 201410448757.7 (CN104208020A) embodiment 1, but step c) gained medicinal liquid performs the step (d) of the embodiment of the present invention 1 and the operation of (e), obtains injectable powder.
embodiment 11: prepare Ropivacaine HCL lyophilization injectable powder
Prescription and compound method are with reference to China Patent No. 201010604883.9 (CN102038651B) embodiment 1, but active component uses Ropivacaine HCL instead, obtains injectable powder.
embodiment 12: prepare Ropivacaine HCL lyophilization injectable powder
Prescription and compound method are with reference to Chinese Patent Application No. 200710013027.4 (CN100998567A) embodiment 1, but active component uses Ropivacaine HCL instead, obtains injectable powder.
embodiment 13: prepare Ropivacaine HCL lyophilization injectable powder
(CN1626081A embodiment 6, obtains injectable powder with reference to Chinese Patent Application No. 200310117329.8 for prescription and compound method.
industrial applicability
The invention provides a kind of ropivacaine hydrochloride in use for injection lyophilization injectable powder with excellent properties, and the preparation method of this ropivacaine hydrochloride in use for injection lyophilization injectable powder.Ropivacaine hydrochloride in use for injection lyophilization injectable powder of the present invention can be used for clinical anesthesia medication.The ropivacaine hydrochloride in use for injection lyophilization injectable powder that the present invention prepares has excellent physicochemical property.
Claims (10)
1. a compositions for Ropivacaine HCL lyophilization injectable powder, wherein comprises Ropivacaine HCL, lactose.
2. compositions according to claim 1, is characterized in that:
Wherein comprise Ropivacaine HCL 75 weight portion, lactose 20 ~ 60 weight portion;
Wherein comprise Ropivacaine HCL 75 weight portion, lactose 30 ~ 50 weight portion;
Wherein comprise Ropivacaine HCL 75 weight portion, lactose 35 ~ 45 weight portion; And/or
Wherein comprise Ropivacaine HCL 75 weight portion, lactose 40 weight portion.
3., according to the compositions of claim 1-2, it is characterized in that:
It is packed by cillin bottle;
Wherein moisture is lower than 10%, preferably lower than 8%, preferably lower than 7%, more preferably less than 5%;
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 amount of wherein said optional acid-base modifier is, the amount of pH value in 4.0 ~ 6.0 scopes of this solution when making described lyophilized injectable powder water for injection be dissolved into the solution of hydrochloric ropivacaine 1mg/ml concentration, the amount of pH value in 4.5 ~ 5.5 scopes of such as this solution.
4., according to the compositions of claim 1-3, it is prepare by comprising following step substantially:
A () takes Ropivacaine HCL, the lactose of recipe quantity, add appropriate water for injection, be stirred to dissolve;
B () adds active carbon in previous step gained medicinal liquid, regulate the pH value 3.0 ~ 3.5 of solution with acid-base modifier, stir 1.5 ~ 2.5 hours at 15 ~ 35 DEG C of temperature, filtering decarbonization, pH4.0 ~ 6.0 of solution are regulated, preferred pH4.5 ~ 5.5 with acid-base modifier;
C () is mended and is injected water to prescription full dose, stir, and measures solution ph and optional mensuration active component content, if desired (or optionally) be adjusted to pH4.0 ~ 6.0 with acid-base modifier, preferred pH4.5 ~ 5.5;
D (), by medicinal liquid aseptic filtration, fill is in cillin bottle;
E () lyophilization removing moisture, tamponade, to obtain final product.
5., according to the compositions of claim 1-4, it is characterized in that:
Wherein appropriate water for injection described in step (a) is the water for injection of 50 ~ 70% amounts (such as 55 ~ 65% amounts) of prescription full dose;
Wherein the addition of active carbon described in step (b) is that concentration of activated carbon reaches the amount of 0.05 ~ 0.15% in medicinal liquid;
Wherein stir 1.5 ~ 2.5 hours at 20 ~ 30 DEG C of temperature in step (b);
Wherein stir 2 hours at 25 DEG C of temperature in step (b); And/or
Wherein the mode of filtering decarbonization described in step (b) is: after filtering with the titanium rod decarburization that aperture is 1um, then use the polyether sulfone filter element of 0.45um by medicinal liquid coarse filtration.
6., according to the compositions of claim 1-5, it is characterized in that:
Wherein mend described in step (c) and inject water to prescription full dose and refer to and add water for injection until activity component concentration is the amount of 20 ~ 30mg/ml (such as 25mg/ml); And/or
Wherein aseptic filtration described in step (d) uses the polyether sulfone filter element of 0.22um to carry out aseptic filtration.
7. prepare the method for the lyophilization injectable powder such as compositions of any one of claim 1-6 of Ropivacaine HCL, it consists essentially of following steps:
B () adds active carbon in previous step gained medicinal liquid, regulate the pH value 3.0 ~ 3.5 of solution with acid-base modifier, stir 1.5 ~ 2.5 hours at 15 ~ 35 DEG C of temperature, filtering decarbonization, pH4.0 ~ 6.0 of solution are regulated, preferred pH4.5 ~ 5.5 with acid-base modifier;
C () is mended and is injected water to prescription full dose, stir, and measures solution ph and optional mensuration active component content, if desired (or optionally) be adjusted to pH4.0 ~ 6.0 with acid-base modifier, preferred pH4.5 ~ 5.5;
D (), by medicinal liquid aseptic filtration, fill is in cillin bottle;
E () lyophilization removing moisture, tamponade, to obtain final product.
8. method according to claim 7, is characterized in that:
The compositions of wherein said Ropivacaine HCL lyophilization injectable powder comprises Ropivacaine HCL, lactose;
The compositions of wherein said Ropivacaine HCL lyophilization injectable powder comprises Ropivacaine HCL 75 weight portion, lactose 20 ~ 60 weight portion;
The compositions of wherein said Ropivacaine HCL lyophilization injectable powder comprises Ropivacaine HCL 75 weight portion, lactose 30 ~ 50 weight portion;
The compositions of wherein said Ropivacaine HCL lyophilization injectable powder comprises Ropivacaine HCL 75 weight portion, lactose 35 ~ 45 weight portion; And/or
The compositions of wherein said Ropivacaine HCL lyophilization injectable powder comprises Ropivacaine HCL 75 weight portion, lactose 40 weight portion.
9., according to the method for claim 7-8, it is characterized in that:
Wherein also comprise acid-base modifier in gained lyophilization injectable powder;
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; And/or
Described acid-base modifier is hydrochloric acid solution or sodium hydroxide solution, such as 1M hydrochloric acid solution or 1M sodium hydroxide solution.
10., according to the method for claim 7-9, it is characterized in that:
Appropriate water for injection described in step (a) is the water for injection of 50 ~ 70% amounts (such as 55 ~ 65% amounts) of prescription full dose;
The addition of active carbon described in step (b) is that concentration of activated carbon reaches the amount of 0.05 ~ 0.15% in medicinal liquid;
Stir 1.5 ~ 2.5 hours at 20 ~ 30 DEG C of temperature in step (b);
Stir 2 hours at 25 DEG C of temperature in step (b);
The mode of filtering decarbonization described in step (b) is: after filtering with the titanium rod decarburization that aperture is 1um, then use the polyether sulfone filter element of 0.45um by medicinal liquid coarse filtration;
Mend described in step (c) and inject water to prescription full dose and refer to and add water for injection until activity component concentration is the amount of 20 ~ 30mg/ml (such as 25mg/ml);
Wherein aseptic filtration described in step (d) uses the polyether sulfone filter element of 0.22um to carry out aseptic filtration; And/or
In step (e) after removing moisture in gained lyophilization material moisture lower than 10%, preferably lower than 8%, preferably lower than 7%, more preferably less than 5%.
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