CN105663127B - Injection is freeze-dried famotidine composition - Google Patents
Injection is freeze-dried famotidine composition Download PDFInfo
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- CN105663127B CN105663127B CN201610180285.0A CN201610180285A CN105663127B CN 105663127 B CN105663127 B CN 105663127B CN 201610180285 A CN201610180285 A CN 201610180285A CN 105663127 B CN105663127 B CN 105663127B
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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
- A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
- A61K31/425—Thiazoles
- A61K31/426—1,3-Thiazoles
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- 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
- A61K47/16—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing nitrogen, e.g. nitro-, nitroso-, azo-compounds, nitriles, cyanates
- A61K47/18—Amines; Amides; Ureas; Quaternary ammonium compounds; Amino acids; Oligopeptides having up to five amino acids
- A61K47/183—Amino acids, e.g. glycine, EDTA or aspartame
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- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/0012—Galenical forms characterised by the site of application
- A61K9/0019—Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner
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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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Abstract
The present invention relates to injections to be freeze-dried famotidine composition, wherein comprising famotidine, mannitol and L-aminobutanedioic acid, the pH value of the composition moisture solution when it is dissolved into the solution of the concentration of 1mg/ml containing famotidine with water for injection less than 5% is in the range of 4.5~6.0.The composition preparation process is as follows：The famotidine, mannitol, L-aminobutanedioic acid of recipe quantity are weighed, appropriate water for injection is added in, is stirred to dissolve；Add in activated carbon stir process, filtering decarbonization；Benefit injects water to prescription full dose, stirs evenly, measure/adjusting solution ph to pH4.5~6.0；Liquid aseptic filtration, it is filling in cillin bottle；Freeze-drying remove moisture, tamponade to get.Injection freeze-drying famotidine composition of the present invention has excellent pharmaceutical properties.
Description
Technical field
The invention belongs to pharmaceutical technology fields, and in particular to a kind of drug for treating stomach trouble has more particularly to one kind
The famotidine for injection freeze-drying powder-injection pharmaceutical composition of excellent properties.The invention further relates to the famotidine for injection
The preparation method of freeze-drying powder-injection pharmaceutical composition.The famotidine for injection freeze-drying powder-injection pharmaceutical composition can
For be used for gastric and duodenal ulcer, reflux esophagitis, upper gastrointestinal bleeding (peptic ulcer, acute stress ulcer,
Caused by hemorrhagic gastritis), the treatment of Zhuo Ai syndromes etc. disease.The famotidine for injection powder needle that the present invention is prepared
Agent has excellent physicochemical property.
Background technology
Famotidine (Famotidine), famotidine chemical name are：[1- amino -3- [[[2- [(diamino methylenes
Base) amino] -4- thiazolyls] methyl] sulfenyl] propylidene] sulphamide, molecular formula：C8H15N7O2S3, molecular weight：337.45.
Peptic ulcer includes gastric duodenal ulcer, is a kind of common disease, and the incidence average out to 8 in crowd~
10%.Treatment for peptic ulcer should not excessively be emphasized to eliminate the attack function of hydrochloric acid in gastric juice and pepsin, and should focus on
Adjustment causes ulcer factor and antiulcer factor balance between the two, payes attention to the resistant function of mucous membrane, but gastric acid secretion inhibiting and
It is still the major measure for treating canker to neutralize hydrochloric acid in gastric juice.Famotidine is the H2 receptor antagonists that the third generation has specificity,
Suitable for gastric and duodenal ulcer, reflux esophagitis, (peptic ulcer, goes out acute stress ulcer upper gastrointestinal bleeding
Caused by courageous and upright gastritis), Zhuo Ai syndromes etc., have it is curative for effect, adverse reaction is small, cheap, and social required quantity is higher
The features such as.
Famotidine is bisfentidine, is a kind of derivative for narrowing thiazole, and chemical constitution is different from imidazole ring-containing
Cimetidine and ranitidine containing furan nucleus, Acidinhibitor there are the various H2 receptor antagonists acid suppressions of dosage correlation to make
With intensity difference, compared with Cimetidine, famotidine is its 20~37 times.Famotidine is as H2 receptor antagonists, except use
In outside treatment peptic ulcer, ulcer caused by applying also for prevention and treatment non-steroidal anti-inflammatory drugs prevents critical patient from sending out
Raw stress ulcer and bleeding, treatment Zhuo-Emhorn syndrome, gastroesophageal reflux disease etc. and acid-related disease.Generally speaking
Each medicine rate of side effects is low, and about 5% or lower, serious side reaction is rare, and can be reversed after being discontinued.Collective effect mechanism is
H2 receptors on blocking histamine and parietal cell combine, so as to gastric acid secretion inhibiting.H2 receptor antagonists have great inhibition
Gastric acid secretion acts on, and can inhibit basal gastric acid secretion and be stimulated by food, pentagastrin, histamine, insulin, caffeine
Gastric acid secretion, but the latter's effect is incomplete, therefore, it is considered that its treat ulcer effect with the former act as it is important.Existing market method
There are not tablet, capsule, injection etc. for the main dosage form of fourth.
Famotidine stability is poor, and the dosage form of freeze-dried powder is used during Clinical practice more.For example, the 2015 of latest edition
The famotidine and its preparation that version Chinese Pharmacopoeia two records, wherein when carrying out Related substances separation, are related to two kinds of typical cases
Impurity, i.e. the impurity I and impurity I of 1- amino groups form continue the impurity II of desulfurization amide group, and these impurity
It generally is intended to what is especially monitored.Three's chemical structural formula is as follows：
Famotidine
Impurity I[N'-[3-[[[2-
(diamino methylene) amino] -4- thiazolyls] methyl] sulfenyl] propiono] sulphamide；
Impurity II3- [[[2- [(diamino
Methylene) amino] -4- thiazolyls] methyl] sulfenyl] propionamide.
The prior art uses L-aminobutanedioic acid as medicinal auxiliary more when preparing the various preparation such as powder-injection of famotidine
Expect the stability to improve drug.
For example, CN200910172752.5 discloses a kind of preparation method of famotidine injection, in the note of 1000ml
It penetrates in liquid, the medical charcoal of the L-aminobutanedioic acid of famotidine, 3.5g, the natrium adetate of 0.2g, 0.5g containing 20.0g, surplus
For water for injection.
For example, CN 201310245628.3 discloses a kind of preparation method of famotidine injection of famotidine, it is special
Sign is, includes the following steps：Step 1, the water for injection of addition amount of preparation 50% in dense preparing tank, addition L-aminobutanedioic acid,
Disodium ethylene diamine tetraacetate, stirring and dissolving；Step 2 adds in famotidine in the above-mentioned solution of step 1, adds injection
With water, stirring and dissolving；Step 3 adds in water for injection to full dose, stirs 15 minutes, make it uniformly；Step 4, with Suzhou sand
Stick, 0.45 μm of collapsible filter of polyether sulfone return filter；Visible foreign matters inspection is done in step 5, sampling, while samples the survey of inspection measured center
Intermediates content and pH value, it is every it is qualified after, liquid is filtered into receiver, is passed through nitrogen；Step 6, the liquid in receiver
Through the collapsible filter filtering of 0.22 μm of polyether sulfone, after visible foreign matters passed examination is done in sampling, input seat bottle supplies embedding；Step 7,
Logical nitrogen embedding；Step 8 sterilizes under conditions of temperature is 100 DEG C, the time is 30 minutes.
However, in terms of medicament excellent properties such as its stability is maintained, necessity that the prior art is still improved.Cause
This, those skilled in the art still expect the preparation side for having the famotidine freeze-drying powder-injection for having excellent pharmaceutical property
Method.
Invention content
The purpose of the present invention is to provide a kind of famotidine freeze-drying powder-injections for preparing and having excellent pharmaceutical property
Method, and expect this powder-injection have excellent pharmaceutical properties such as having excellent stability.The present inventor goes out
Finding to people's will material, the powder-injection being prepared by the method for the present invention can realize the above-mentioned purpose of at least one aspect, and
And obtained freeze-drying powder needle set has excellent physicochemical property.It finds and is accomplished the present invention is based on this.
For this purpose, first aspect present invention provides a kind of composition of famotidine freeze-drying powder-injection, wherein including
Famotidine, mannitol and L-aminobutanedioic acid.
The composition of any embodiment according to a first aspect of the present invention, wherein including 20 parts by weight of famotidine, sweet dew
5~15 parts by weight of 15~45 parts by weight of alcohol and L-aminobutanedioic acid.
The composition of any embodiment according to a first aspect of the present invention, wherein including 20 parts by weight of famotidine, sweet dew
6~12 parts by weight of 20~40 parts by weight of alcohol and L-aminobutanedioic acid.
The composition of any embodiment according to a first aspect of the present invention, wherein including 20 parts by weight of famotidine, sweet dew
7~10 parts by weight of 25~35 parts by weight of alcohol and L-aminobutanedioic acid.
The composition of any embodiment according to a first aspect of the present invention, wherein including 20 parts by weight of famotidine, sweet dew
8 parts by weight of 30 parts by weight of alcohol and L-aminobutanedioic acid.
The composition of any embodiment according to a first aspect of the present invention, is packed by cillin bottle.
The composition of any embodiment according to a first aspect of the present invention, wherein moisture are less than 10%, preferably shorter than
8%, preferably shorter than 7%, more preferably less than 5%.
The composition of any embodiment according to a first aspect of the present invention, wherein further including acid-base modifier.In a reality
It applies in scheme, the acid-base modifier is selected from sodium hydroxide, potassium hydroxide, sodium dihydrogen phosphate, disodium hydrogen phosphate, biphosphate
Potassium, dipotassium hydrogen phosphate, hydrochloric acid, phosphoric acid, nitric acid, sulfuric acid, or combination.In one embodiment, the acid-base modifier
It is hydrochloric acid solution either sodium hydroxide solution such as 1M hydrochloric acid solutions or 1M sodium hydroxide solutions.
It is well known that freeze-drying powder-injection (the often referred to simply as freeze-dried powder obtained through cryogenic freezing-vacuum drying
Agent or freeze-dried powder), it is that each material is dissolved into (being typically with water dissolution) with solvent first, is configured to a solution, so
After the solution is made to carry out cryogenic freezing, then substantially anhydrous (the typically water of one kind for being vacuumized, distilling, being dried and obtained
Content is less than 8%, is especially generally lower than 7%, is especially generally lower than powdered object or block 5%).Therefore, this is solid
The acid-base value of body lyophilized products usually adjusts the pH value of solution to control by process for preparation；Or can by prescription adjust so that
The solid lyophilized products of acquisition control the pH value of the dissolving/dilution (referred to herein as to be controlled to control under defined dissolving/dilute strength
The acid-base value of solid lyophilized products processed)；Latter means generally more generally use, such as many freeze drying powder injections contained in pharmacopeia
The acid-base value of product is controlled by this method, and this mode controls the acid-base value of product usually can not concrete regulation soda acid tune
The recipe quantity of agent is saved, and only provides the acid-base value of finished product.The present invention is equally applicable to, according to first party of the present invention
Freeze drying powder injection described in any embodiment of face, wherein the amount of the optional acid-base modifier is to make the freeze-dried powder
The pH value of the solution is in the range of 4.5~6.0 when agent is dissolved into the solution of the concentration of 1mg/ml containing famotidine with water for injection
Amount, such as amount of the pH value in the range of 5.0~5.5 of the solution.
The composition of any embodiment according to a first aspect of the present invention is substantially pressed and includes steps preparation
's：
(a) famotidine, mannitol, L-aminobutanedioic acid of recipe quantity are weighed, appropriate water for injection is added in, is stirred to dissolve；
(b) activated carbon is added in rapid gained liquid one step up, stirs 5~15 hours at a temperature of 0~5 DEG C, then exist
It is stirred 0.5~1.5 hour at a temperature of 35~45 DEG C, filtering decarbonization；
(c) it mends and injects water to prescription full dose, stir evenly, measure solution ph and optional measure active constituent contains
Amount, when necessary (or optionally) adjusted with acid-base modifier to pH4.5~6.0, preferably pH5.0~5.5；
(d) it is filling in cillin bottle by liquid aseptic filtration；
(e) freeze-drying remove moisture, tamponade to get.
The composition of any embodiment according to a first aspect of the present invention, wherein appropriate water for injection described in step (a)
It is the water for injection of 20~40% amounts (such as 25~35% amounts) of prescription full dose.
The addition of the composition of any embodiment according to a first aspect of the present invention, wherein activated carbon described in step (b)
Amount is the amount that concentration of activated carbon reaches 0.05~0.15% in liquid.Oneself is passed through surprisingly it has been found that will add in this step
The liquid for entering activated carbon first handles a long period at low temperature, then handles to the short period, obtains at relatively high temperatures
Powder-injection has unexpected superior stability.
It is stirred at a temperature of 0~5 DEG C in the composition of any embodiment according to a first aspect of the present invention, wherein step (b)
It mixes 8~12 hours.
In the composition of any embodiment according to a first aspect of the present invention, wherein step (b) at a temperature of 35~45 DEG C
Stirring 1 hour.
The side of the composition of any embodiment according to a first aspect of the present invention, wherein filtering decarbonization described in step (b)
Formula is：With aperture be 1um stud decarburization filtering after, then with the polyether sulfone filter core of 0.45um by liquid coarse filtration.
The composition of any embodiment according to a first aspect of the present invention, wherein adds water for injection described in step (c)
Refer to add water for injection the amount until activity component concentration is 15~25mg/ml (such as 20mg/ml) to prescription full dose.
The composition of any embodiment according to a first aspect of the present invention, wherein aseptic filtration described in step (d) are to make
Aseptic filtration is carried out with the polyether sulfone filter core of 0.22um.
Further, second aspect of the present invention, which provides, prepares the freeze-drying powder-injection of the famotidine such as present invention the
The method of freeze-drying powder-injection described in one side any embodiment, consists essentially of following steps：
(a) famotidine, mannitol, L-aminobutanedioic acid of recipe quantity are weighed, appropriate water for injection is added in, is stirred to dissolve；
(b) activated carbon is added in rapid gained liquid one step up, stirs 5~15 hours at a temperature of 0~5 DEG C, then exist
It is stirred 0.5~1.5 hour at a temperature of 35~45 DEG C, filtering decarbonization；
(c) it mends and injects water to prescription full dose, stir evenly, measure solution ph and optional measure active constituent contains
Amount, when necessary (or optionally) adjusted with acid-base modifier to pH4.5~6.0, preferably pH5.0~5.5；
(d) it is filling in cillin bottle by liquid aseptic filtration；
(e) freeze-drying remove moisture, tamponade to get.
The method of any embodiment according to a second aspect of the present invention, wherein the famotidine freeze-drying powder-injection
Composition includes famotidine, mannitol and L-aminobutanedioic acid.
The method of any embodiment according to a second aspect of the present invention, wherein the famotidine freeze-drying powder-injection
Composition includes 5~15 parts by weight of 20 parts by weight of famotidine, 15~45 parts by weight of mannitol and L-aminobutanedioic acid.
The method of any embodiment according to a second aspect of the present invention, wherein the famotidine freeze-drying powder-injection
Composition includes 6~12 parts by weight of 20 parts by weight of famotidine, 20~40 parts by weight of mannitol and L-aminobutanedioic acid.
The method of any embodiment according to a second aspect of the present invention, wherein the famotidine freeze-drying powder-injection
Composition includes 7~10 parts by weight of 20 parts by weight of famotidine, 25~35 parts by weight of mannitol and L-aminobutanedioic acid.
The method of any embodiment according to a second aspect of the present invention, wherein the famotidine freeze-drying powder-injection
Composition includes 8 parts by weight of 20 parts by weight of famotidine, 30 parts by weight of mannitol and L-aminobutanedioic acid.
The method of any embodiment according to a second aspect of the present invention, wherein further including acid in gained freeze-drying powder-injection
Alkali conditioning agent.In one embodiment, the acid-base modifier is selected from sodium hydroxide, potassium hydroxide, sodium dihydrogen phosphate, phosphorus
Sour disodium hydrogen, potassium dihydrogen phosphate, dipotassium hydrogen phosphate, hydrochloric acid, phosphoric acid, nitric acid, sulfuric acid, or combination.In one embodiment,
The acid-base modifier is hydrochloric acid solution either sodium hydroxide solution such as 1M hydrochloric acid solution or 1M sodium hydroxide solutions.
The method of any embodiment according to a second aspect of the present invention, wherein appropriate water for injection described in step (a) are
The water for injection of 20~40% amounts (such as 25~35% amounts) of prescription full dose.
The additive amount of the method for any embodiment according to a second aspect of the present invention, wherein activated carbon described in step (b)
It is the amount that concentration of activated carbon reaches 0.05~0.15% in liquid.Oneself is passed through surprisingly it has been found that will add in this step
The liquid of activated carbon first handles a long period at low temperature, then handles to the short period at relatively high temperatures, obtained powder
Injection has unexpected superior stability.
In the method for any embodiment according to a second aspect of the present invention, wherein step (b) 8 are stirred at a temperature of 0~5 DEG C
~12 hours.
It is stirred at a temperature of 35~45 DEG C in the method for any embodiment according to a second aspect of the present invention, wherein step (b)
It mixes 1 hour.
The mode of the method for any embodiment according to a second aspect of the present invention, wherein filtering decarbonization described in step (b)
It is：With aperture be 1um stud decarburization filtering after, then with the polyether sulfone filter core of 0.45um by liquid coarse filtration.
The method of any embodiment according to a second aspect of the present invention is wherein mended described in step (c) and is injected water to
Prescription full dose refers to add water for injection the amount until activity component concentration is 15~25mg/ml (such as 20mg/ml).
The method of any embodiment according to a second aspect of the present invention, wherein aseptic filtration described in step (d) are to use
The polyether sulfone filter core of 0.22um carries out aseptic filtration.
It is removed obtained by after moisture in method described in any embodiment according to a second aspect of the present invention, wherein step (e)
It is freeze-dried moisture in material and is less than 10%, preferably shorter than 8%, preferably shorter than 7%, more preferably less than 5%.
In the step of above-mentioned preparation method of the invention, although the specific steps of its description are in certain details or language
Step different from description and described in the preparation example of following detailed description part, however, people in the art
Member can summarize approach described above step completely according to the detailed disclosure of full text of the present invention.
Any embodiment of the either side of the present invention, can be combined with other embodiments, as long as they are not
It will appear contradiction.In addition, in any embodiment of either side of the present invention, any technical characteristic can be adapted for other realities
The technical characteristic in scheme is applied, as long as they are not in contradiction.
The invention will be further described below.
All documents recited in the present invention, their full content are incorporated herein by reference, and if these are literary
When offering expressed meaning and the inconsistent present invention, it is subject to the statement of the present invention.In addition, the various terms that use of the present invention and
Phrase has well known to a person skilled in the art general sense, nonetheless, the present invention remain desirable at this to these terms and
Phrase is described in more detail and explains, the term and phrase referred to is if any inconsistent with common art-recognized meanings, with institute's table of the present invention
Subject to the meaning stated.
It has been found that the famotidine for injection freeze-drying powder-injection that the method for the present invention is prepared is with unexpected
The advantages of.Such as in terms of being embodied in following stability test：
Stability test：Whole powder-injection that Examples below 1 to embodiment 11 is prepared are placed at 42 DEG C and place 5
Month to carry out high-temperature treatment experiment；For each powder-injection, use【HPLC methods】The powder-injection is measured at 0 month and in May
When related substance (relative to principal component) content, particularly track and calculate the content of impurity I；Impurity I is calculated as follows
Content increase percentage (% may be simply referred to as " impurity I increments ")：
Above-mentioned whole powder-injection is used to be prepared with a collection of famotidine raw material medicine, and whole powder-injection are miscellaneous at 0 month
Matter I contents are substantially suitable, in the range of 0.27~0.33%.But after above-mentioned high-temperature treatment, different samples present bright
Aobvious different impurity I situations of change；Specifically, the impurity I increments (%) of the whole powder-injection of 9~11 gained of embodiment exist
In the range of 186~233%, the impurity I increments (%) of whole powder-injection are in the range of 33~57% obtained by embodiment 1-8.This
Show using same materials through famotidine powder needle made from distinct methods, in the initial state substantially without difference, but not
But there are significant differences in terms of the stability characterized with method products obtained therefrom in stability particularly impurity I.
The test specimen for disposing May for above-mentioned 42 DEG C measures their famotidine contents at 0 month and May respectively,
For every a sample, relative amount when calculating its May relative to 0 month, this relative amount is powder needle through high-temperature treatment 5
The residual content of active constituent after month.The results show that the residual content of the whole powder-injection of the gained of embodiment 9~11 92~
In the range of 95%, the residual content of whole powder-injection is in the range of 97~99% obtained by embodiment 1-8, although this shows
9~11 powder needle of embodiment substantially meets requirement after high-temperature treatment still above 90%, but its stability is significantly too late
Embodiment 1-8 powder-injection.
In the present invention, it is preferred to freeze drying powder injection of the present invention in the solution that the 1mg containing active constituent in every 1ml is made of water
Afterwards, the acid of the freeze-dried powder is measured further according to method, that is, pH value measuring method under Chinese Pharmacopoeia annex VI H of version two in 2010
Basicity.
The preparation process of freeze-drying powder-injection is well known to those skilled in the art pharmaceutical technology, such as following freeze-drying song
Two kinds of schematical freeze-drying curves shown in line A and freeze-drying curve B：
It prepares below in the specific example in freeze-drying powder-injection, if not otherwise specified, freeze-drying used is bent
Line is freeze-drying curve A.
Water content in freeze-drying powder-injection is hereinafter, preferably shorter than 7%, more preferably less than 5% generally 8%.Water
Sub-control system can be controlled by suitably adjusting freeze-drying program.Moisture in the freeze-drying powder-injection can be according to many
Known method measures, such as dry weight-loss method.
In the present invention, for the pH value of regulating liquid medicine if necessary, appropriate pH can be added in into composition and is adjusted
Agent.Although the present inventor, which only uses, does not have the strong acid of buffer capacity or strong base solution such as sodium hydrate aqueous solution and aqueous hydrochloric acid solution
It is adjusted, if however, it will be appreciated by those skilled in the art that body can be met with this pH adjusting agent processing for not having buffer capacity
The pH requirements of system, then the pH adjusting agent with buffer capacity will be better able to realization the object of the invention, therefore these buffers are not
But pH value can be adjusted, and pH value can be stablized.Therefore any pH adjusting agent or combination listed by the present invention is included in this hair
In bright spirit and scope.
When preparing freeze drying powder injection of the present invention, in prepared liquid, solid content be for 1~20% (w/v), it is excellent
2~15% (w/v) are selected, even more preferably 3~10%, even more preferably 4~8%.Since freeze drying powder injection is typically in tubulose XiLin
It is freeze-dried to obtain in bottle, those skilled in the art understand that this product is obtaining finished product or even using it for doctor
Before, a round pie is typically each presented, (slightly contracts although lecture is fewer than the volume of original aqueous solution in the volume theory of the cake
It is small), however usually this diminution will not usually narrow down to raw water liquor capacity 50%, it will usually in the 80- of raw water liquor capacity
Between 120%, it is more typically between the 90-100% of raw water liquor capacity, and it is molten that raw water can be observed out of finished product cillin bottle
(main body pie remains in the liquid level trace in bottle wall to liquid liquid level trace after being reduced because of freeze-drying, even if the dried frozen aquatic products in cillin bottle
In powdered due to a variety of causes reason such as colliding, still can usually retain original liquid level trace), trace is also accordingly
The aqueous solution volume of the freeze-dried composition before freeze-drying can be estimated.Therefore, although the present invention is to provide one
The substantially anhydrous freeze-drying powder-injection of kind, however it still can be substantially estimated according to the powder-injection when preparing, at least
Medicine liquid volume before freeze-drying starts, the weight of the drying final product in the volume estimated and cillin bottle
Amount, can also calculate when preparing freeze drying powder injection of the present invention, the content of the solid content in prepared liquid.Therefore, according to
The freeze drying powder injection of first aspect present invention, the solid content of the liquid when preparing for 1~20% (w/v), preferably 2~
15% (w/v), even more preferably 3~10%, even more preferably 4~8%.
In the present invention, symbol %, according to its used linguistic context, can have skilled addressee readily understands that
Meaning.Such as when referring to solid content, the percentage (w/v, such as g/100ml) of the symbolic indication weight/volume；Example again
Such as in " water content " in referring to freeze-drying powder-injection, for example, water content 8% hereinafter, at this time symbol % represent weight
The percentage (w/w, g/100g) of amount/weight.In general, when solid disperses in a liquid, % represents weight/volume percentage
Number；When solid disperses in solids or liquid disperses (such as water content of powder needle) in solids, % represents w/w
Percentage.In other cases, unless otherwise noted, symbol % represents w/w percentage.
It is well known to those skilled in the art in the liquid for preparing the present invention, for example, about miillpore filter of 0.45um can be used
Coarse filtration filtering is carried out, before liquid is filled in cillin bottle, the miillpore filter of for example, about 0.22um can be used to carry out essence
Filtration filter is with degerming, it may be necessary to which filtering is multiple.
Freeze drying powder injection according to the present invention is freeze-drying powder-injection.In one embodiment, the freeze-drying
Powder-injection is single-dose preparations (such as XiLin bottled powder-injection), and the amount of reactive compound can be such as in per unit dosage
But it is not limited to about 10mg, about 20mg, about about 40mg, 50mg.
Freeze drying powder injection according to the present invention, is redissolved with water for injection, typically redissolves the time in 30 seconds, preferably
In 20 seconds, more preferably in 15 seconds.
With water the solution of the 1mg containing reactive compound in every 1ml is made and in freeze drying powder injection according to the present invention
Method under state's pharmacopeia annex VI H of version two in 2010 measures, and the pH value of the solution is 4.5~6.0.In an embodiment party
In case, pH value is 5.0~5.5.
Freeze drying powder injection provided by the invention can preserve at least 24 months below 25 DEG C at drying, can meet one
As freeze-drying powder-injection Storage Requirement.
Obtained freeze-drying powder-injection of the present invention particularly freeze-drying powder-injection is usually white or the freeze-drying bulk of off-white color
Object or its fragment or its powder, odorless, bitter are soluble easily in water.
Famotidine is bisfentidine, is a kind of derivative for narrowing thiazole, and chemical constitution is different from imidazole ring-containing
Cimetidine and ranitidine containing furan nucleus, Acidinhibitor have dosage correlation.Various H2 receptor antagonists acid suppressions are made
With intensity difference, compared with Cimetidine, famotidine is its 20~37 times.Famotidine is as H2 receptor antagonists, except use
In outside treatment peptic ulcer, ulcer caused by applying also for prevention and treatment non-steroidal anti-inflammatory drugs prevents critical patient from sending out
Raw stress ulcer and bleeding, treatment Zhuo-Emhorn syndrome, gastroesophageal reflux disease etc. and acid-related disease.Generally speaking
Each medicine rate of side effects is low, and about 5% or lower, serious side reaction is rare, and can be reversed after being discontinued.Collective effect mechanism is
H2 receptors on blocking histamine and parietal cell combine, so as to gastric acid secretion inhibiting.H2 receptor antagonists have great inhibition
Gastric acid secretion acts on, and can inhibit basal gastric acid secretion and be stimulated by food, pentagastrin, histamine, insulin, caffeine
Gastric acid secretion, but the latter's effect is incomplete, therefore, it is considered that its treat ulcer effect with the former act as it is important.
Specific embodiment
The present invention can be further described by the following examples, however, the scope of the present invention and unlimited
In following embodiments.One of skill in the art, can be with it is understood that under the premise of without departing substantially from the spirit and scope of the present invention
Various change and modification are carried out to the present invention.The present invention carries out the material and test method that are arrived used in experiment general
And/or specific description.Although to realize the present invention many materials used in purpose and operating method be it is known in the art that
But the present invention is still described in detail as far as possible herein.Following embodiment further illustrates the present invention rather than limits this hair
It is bright.The made only formal but not substantive equivalent transformation of any design according to the present invention is regarded as the present invention
Technical solution scope.
It is if not otherwise indicated, when preparing powder-injection use with a batch of famotidine raw material in following example
Medicine (it meets the quality standard of Chinese Pharmacopoeia two famotidines recorded of version in 2015).
In following example, the pH adjusting agent (in the present invention that is, acid-base modifier) that uses, unless otherwise noted,
1M sodium hydroxide solutions or 1M hydrochloric acid solutions, dosage be when making to prepare powder-injection make it is prepared molten before freeze-drying
The pH value of liquid is adjusted to a certain regulation value or range, which is that freeze-drying gained dry powder is diluted with water for injection
The value or range of pH value measured into the solution of the 1mg/ml containing active constituent.Hereafter preparation process is for the purpose of citing, and
Comparability based on each citing and make some specific description, those skilled in the art completely can be therefrom according to existing knowledge
Summarize the method that the present invention prepares freeze drying powder injection that obtains.It is prepared in various compositions with liquid below, if not otherwise indicated, often
Batch be always 10000ml with liquid measure, but when listing formula, illustrated by every bottle of amount containing 20mg in terms of famotidine.
Assay method：
What the assay of various samples (including powder-injection of the present invention) was recorded using Chinese Pharmacopoeia version two in 2015
In " famotidine for injection " kind【Assay】Recorded method carries out；Various samples (including powder-injection of the present invention)
" famotidine for injection " kind for being recorded using Chinese Pharmacopoeia version two in 2015 of related substance in " related substance "
Recorded method carries out.
Embodiment 1：Prepare famotidine freeze-drying powder-injection
Formula：
Famotidine 20mg,
Mannitol 30mg,
L-aminobutanedioic acid 8mg,
Acid-base modifier：In right amount, the specified value in pH to following preparation method is adjusted,
Water for injection：Add to 1ml
Preparation method：
(a) famotidine, mannitol, L-aminobutanedioic acid of recipe quantity are weighed, adds in 30% water for injection of recipe quantity, stirring makes
Dissolving；
(b) activated carbon (in terms of medicine liquid volume 0.1%) is added in rapid gained liquid one step up, is stirred at a temperature of 0~5 DEG C
It mixes 10 hours, is then stirred 1 hour at a temperature of 40 DEG C, filtering decarbonization (after the stud decarburization for being 1um with aperture is filtered, then is used
The polyether sulfone filter core of 0.45um is by liquid coarse filtration)；
(c) it mends and injects water to prescription full dose, stir evenly, measure solution ph and optional measure active constituent contains
Amount, when necessary (or optionally) adjusted with acid-base modifier to pH5.2；
(d) it is filling in cillin bottle by liquid aseptic filtration (carrying out aseptic filtration with the polyether sulfone filter core of 0.22um)；
(e) freeze-drying removes moisture (moisture be less than 5%), tamponade to get.
Embodiment 2：Prepare famotidine freeze-drying powder-injection
Formula：
Famotidine 20mg,
Mannitol 25mg,
L-aminobutanedioic acid 10mg,
Acid-base modifier：In right amount, the specified value in pH to following preparation method is adjusted,
Water for injection：Add to 0.8ml
Preparation method：
(a) famotidine, mannitol, L-aminobutanedioic acid of recipe quantity are weighed, adds in 35% water for injection of recipe quantity, stirring makes
Dissolving；
(b) activated carbon (in terms of medicine liquid volume 0.15%) is added in rapid gained liquid one step up, at a temperature of 0~5 DEG C
Stirring 5 hours, is then stirred 1.5 hours at a temperature of 45 DEG C, filtering decarbonization (after the stud decarburization for being 1um with aperture is filtered, then
With the polyether sulfone filter core of 0.45um by liquid coarse filtration)；
(c) it mends and injects water to prescription full dose, stir evenly, measure solution ph and optional measure active constituent contains
Amount, when necessary (or optionally) adjusted with acid-base modifier to pH5.3；
(d) it is filling in cillin bottle by liquid aseptic filtration (carrying out aseptic filtration with the polyether sulfone filter core of 0.22um)；
(e) freeze-drying removes moisture (moisture be less than 5%), tamponade to get.
This example is freeze-dried using freeze-drying curve B.
Embodiment 3：Prepare famotidine freeze-drying powder-injection
Formula：
Famotidine 20mg,
Mannitol 35mg,
L-aminobutanedioic acid 7mg,
Acid-base modifier：In right amount, the specified value in pH to following preparation method is adjusted,
Water for injection：Add to 1.33ml
Preparation method：
(a) famotidine, mannitol, L-aminobutanedioic acid of recipe quantity are weighed, adds in 25% water for injection of recipe quantity, stirring makes
Dissolving；
(b) activated carbon (in terms of medicine liquid volume 0.05%) is added in rapid gained liquid one step up, at a temperature of 0~5 DEG C
Stirring 15 hours, is then stirred 0.5 hour at a temperature of 35 DEG C, filtering decarbonization (after the stud decarburization for being 1um with aperture is filtered,
Again with the polyether sulfone filter core of 0.45um by liquid coarse filtration)；
(c) it mends and injects water to prescription full dose, stir evenly, measure solution ph and optional measure active constituent contains
Amount, when necessary (or optionally) adjusted with acid-base modifier to pH4.5；
(d) it is filling in cillin bottle by liquid aseptic filtration (carrying out aseptic filtration with the polyether sulfone filter core of 0.22um)；
(e) freeze-drying removes moisture (moisture be less than 5%), tamponade to get.
Embodiment 4：Prepare famotidine freeze-drying powder-injection
Formula：
Famotidine 20mg,
Mannitol 40mg,
L-aminobutanedioic acid 6mg,
Acid-base modifier：In right amount, the specified value in pH to following preparation method is adjusted,
Water for injection：Add to 1ml
Preparation method：
(a) famotidine, mannitol, L-aminobutanedioic acid of recipe quantity are weighed, adds in 40% water for injection of recipe quantity, stirring makes
Dissolving；
(b) activated carbon (in terms of medicine liquid volume 0.1%) is added in rapid gained liquid one step up, is stirred at a temperature of 0~5 DEG C
It mixes 10 hours, is then stirred 1 hour at a temperature of 38 DEG C, filtering decarbonization (after the stud decarburization for being 1um with aperture is filtered, then is used
The polyether sulfone filter core of 0.45um is by liquid coarse filtration)；
(c) it mends and injects water to prescription full dose, stir evenly, measure solution ph and optional measure active constituent contains
Amount, when necessary (or optionally) adjusted with acid-base modifier to pH5.5；
(d) it is filling in cillin bottle by liquid aseptic filtration (carrying out aseptic filtration with the polyether sulfone filter core of 0.22um)；
(e) freeze-drying removes moisture (moisture be less than 5%), tamponade to get.
Embodiment 5：Prepare famotidine freeze-drying powder-injection
Formula：
Famotidine 20mg,
Mannitol 20mg,
L-aminobutanedioic acid 12mg,
Acid-base modifier：In right amount, the specified value in pH to following preparation method is adjusted,
Water for injection：Add to 1ml
Preparation method：
(a) famotidine, mannitol, L-aminobutanedioic acid of recipe quantity are weighed, adds in 20% water for injection of recipe quantity, stirring makes
Dissolving；
(b) activated carbon (in terms of medicine liquid volume 0.1%) is added in rapid gained liquid one step up, is stirred at a temperature of 0~5 DEG C
It mixes 8 hours, is then stirred 0.8 hour at a temperature of 42 DEG C, filtering decarbonization (after the stud decarburization for being 1um with aperture is filtered, then is used
The polyether sulfone filter core of 0.45um is by liquid coarse filtration)；
(c) it mends and injects water to prescription full dose, stir evenly, measure solution ph and optional measure active constituent contains
Amount, when necessary (or optionally) adjusted with acid-base modifier to pH5.0；
(d) it is filling in cillin bottle by liquid aseptic filtration (carrying out aseptic filtration with the polyether sulfone filter core of 0.22um)；
(e) freeze-drying removes moisture (moisture be less than 5%), tamponade to get.
Embodiment 6：Prepare famotidine freeze-drying powder-injection
Formula：
Famotidine 20mg,
Mannitol 30mg,
L-aminobutanedioic acid 10mg,
Acid-base modifier：In right amount, the specified value in pH to following preparation method is adjusted,
Water for injection：Add to 1ml
Preparation method：
(a) famotidine, mannitol, L-aminobutanedioic acid of recipe quantity are weighed, adds in 35% water for injection of recipe quantity, stirring makes
Dissolving；
(b) activated carbon (in terms of medicine liquid volume 0.12%) is added in rapid gained liquid one step up, at a temperature of 0~5 DEG C
Stirring 12 hours, is then stirred 1 hour at a temperature of 40 DEG C, filtering decarbonization (after the stud decarburization for being 1um with aperture is filtered, then
With the polyether sulfone filter core of 0.45um by liquid coarse filtration)；
(c) it mends and injects water to prescription full dose, stir evenly, measure solution ph and optional measure active constituent contains
Amount, when necessary (or optionally) adjusted with acid-base modifier to pH5.2；
(d) it is filling in cillin bottle by liquid aseptic filtration (carrying out aseptic filtration with the polyether sulfone filter core of 0.22um)；
(e) freeze-drying removes moisture (moisture be less than 5%), tamponade to get.
Embodiment 7：Prepare famotidine freeze-drying powder-injection
Formula：
Famotidine 20mg,
Mannitol 20mg,
L-aminobutanedioic acid 5mg,
Acid-base modifier：In right amount, the specified value in pH to following preparation method is adjusted,
Water for injection：Add to 1ml
Preparation method：
(a) famotidine, mannitol, L-aminobutanedioic acid of recipe quantity are weighed, adds in 25% water for injection of recipe quantity, stirring makes
Dissolving；
(b) activated carbon (in terms of medicine liquid volume 0.1%) is added in rapid gained liquid one step up, is stirred at a temperature of 0~5 DEG C
It mixes 10 hours, is then stirred 1 hour at a temperature of 45 DEG C, filtering decarbonization (after the stud decarburization for being 1um with aperture is filtered, then is used
The polyether sulfone filter core of 0.45um is by liquid coarse filtration)；
(c) it mends and injects water to prescription full dose, stir evenly, measure solution ph and optional measure active constituent contains
Amount, when necessary (or optionally) adjusted with acid-base modifier to pH5.5；
(d) it is filling in cillin bottle by liquid aseptic filtration (carrying out aseptic filtration with the polyether sulfone filter core of 0.22um)；
(e) freeze-drying removes moisture (moisture be less than 5%), tamponade to get.
Embodiment 8：Prepare famotidine freeze-drying powder-injection
Formula：
Famotidine 20mg,
Mannitol 25mg,
L-aminobutanedioic acid 5mg,
Acid-base modifier：In right amount, the specified value in pH to following preparation method is adjusted,
Water for injection：Add to 1ml
Preparation method：
(a) famotidine, mannitol, L-aminobutanedioic acid of recipe quantity are weighed, adds in 35% water for injection of recipe quantity, stirring makes
Dissolving；
(b) activated carbon (in terms of medicine liquid volume 0.1%) is added in rapid gained liquid one step up, is stirred at a temperature of 0~5 DEG C
It mixes 10 hours, is then stirred 1 hour at a temperature of 40 DEG C, filtering decarbonization (after the stud decarburization for being 1um with aperture is filtered, then is used
The polyether sulfone filter core of 0.45um is by liquid coarse filtration)；
(c) it mends and injects water to prescription full dose, stir evenly, measure solution ph and optional measure active constituent contains
Amount, when necessary (or optionally) adjusted with acid-base modifier to pH5.3；
(d) it is filling in cillin bottle by liquid aseptic filtration (carrying out aseptic filtration with the polyether sulfone filter core of 0.22um)；
(e) freeze-drying removes moisture (moisture be less than 5%), tamponade to get.
Embodiment 9：Prepare famotidine freeze-drying powder-injection
Embodiment 1-8 is respectively referred to, different is only the mistake without " at a temperature of 0~5 DEG C stir " in step (b)
Journey, but the process of the stir process at a temperature of 35~45 DEG C is directly carried out, 8 batches of powder needles are made.
Embodiment 10：Prepare famotidine freeze-drying powder-injection
Embodiment 1-8 is respectively referred to, different is only to be changed to step (b)：It adds in and lives in rapid gained liquid one step up
Property charcoal, be stirred at room temperature 2 hours, filtering decarbonization, be made 8 batches of powder needles.
Embodiment 11：Prepare famotidine freeze-drying powder-injection
Prescription and preparation method with reference to China Patent No. 201010500571.3 (CN 101972248B) embodiment 3 into
Row, obtains powder-injection.
Industrial applicability
The present invention provides a kind of famotidine for injection freeze-drying powder-injection with excellent properties and the injections
With the preparation method of famotidine freeze-drying powder-injection.Famotidine for injection freeze-drying powder-injection of the present invention can be used for stomach
Portion's relevant disease.The famotidine for injection freeze-drying powder-injection that the present invention is prepared has excellent physicochemical property.
Claims (17)
1. a kind of composition of famotidine freeze-drying powder-injection, wherein including 20 parts by weight of famotidine, mannitol 20 ~ 40
Parts by weight, 6 ~ 12 parts by weight of L-aminobutanedioic acid, optional acid-base modifier；The amount of the acid-base modifier is to make the freeze-dried powder
The pH value of the solution is in the range of 4.5 ~ 6.0 when injection is dissolved into the solution of the concentration of 1mg/ml containing famotidine with water for injection
Amount；The composition is prepared by the method included the following steps：
(a) famotidine, mannitol, L-aminobutanedioic acid of recipe quantity are weighed, appropriate water for injection is added in, is stirred to dissolve；It is described
Appropriate water for injection is the water for injection of 20 ~ 40% amounts of prescription full dose；
(b) activated carbon is added in rapid gained liquid one step up, is stirred 5 ~ 15 hours at a temperature of 0 ~ 5 °C, then at 35 ~ 45 °C
At a temperature of stir 0.5 ~ 1.5 hour, filtering decarbonization；The additive amount of the activated carbon is that concentration of activated carbon reaches 0.05 in liquid
~ 0.15% amount；
(c) it mends and injects water to prescription full dose, stir evenly, measure solution ph and optional measure active component content,
Optionally adjusted with acid-base modifier to pH4.5 ~ 6.0；The benefit injects water to prescription full dose and refers to add water for injection
Until activity component concentration is the amount of 15 ~ 25mg/ml；
(d) it is filling in cillin bottle by liquid aseptic filtration；
(e) freeze-drying remove moisture, tamponade to get.
2. composition according to claim 1, wherein including 20 parts by weight of famotidine, 25 ~ 35 parts by weight of mannitol and Men Dong
7 ~ 10 parts by weight of propylhomoserin.
3. composition according to claim 1, wherein including 20 parts by weight of famotidine, 30 parts by weight of mannitol and L-aminobutanedioic acid
8 parts by weight.
4. composition according to claim 1, is packed by cillin bottle.
5. composition according to claim 1, wherein moisture are less than 5%.
6. composition according to claim 1, the acid-base modifier be selected from sodium hydroxide, potassium hydroxide, sodium dihydrogen phosphate,
Disodium hydrogen phosphate, potassium dihydrogen phosphate, dipotassium hydrogen phosphate, hydrochloric acid, phosphoric acid, nitric acid, sulfuric acid, or combination.
7. composition according to claim 1, the acid-base modifier is hydrochloric acid solution or sodium hydroxide solution.
8. composition according to claim 1, the acid-base modifier is 1M hydrochloric acid solutions or 1M sodium hydroxide solutions.
9. composition according to claim 1, wherein the amount of the optional acid-base modifier is to use the freeze drying powder injection
Amount of the pH value of the solution in the range of 5.0 ~ 5.5 when water for injection is dissolved into the solution of the concentration of 1mg/ml containing famotidine.
10. composition according to claim 1, optionally adjusted in step (c) with acid-base modifier to pH5.0 ~ 5.5.
11. composition according to claim 1, appropriate water for injection described in step (a) is 25 ~ 35% amounts of prescription full dose
Water for injection.
12. it is stirred 8 ~ 12 hours at a temperature of 0 ~ 5 °C in composition according to claim 1, wherein step (b).
13. composition according to claim 1, stirred 1 hour at a temperature of 35 ~ 45 °C in step (b).
14. composition according to claim 1, the mode of filtering decarbonization described in step (b) are：The stud for being 1um with aperture
After decarburization filtering, then with the polyether sulfone filter core of 0.45um by liquid coarse filtration.
15. composition according to claim 1, benefit described in step (c) injects water to prescription full dose and refers to add injection
With water until the amount that activity component concentration is 20mg/ml.
16. composition according to claim 1, aseptic filtration described in step (d) be using 0.22um polyether sulfone filter core into
Row aseptic filtration.
17. preparing the method for claim 1-16 any one of them compositions, include the following steps：
(a) famotidine, mannitol, L-aminobutanedioic acid of recipe quantity are weighed, appropriate water for injection is added in, is stirred to dissolve；It is described
Appropriate water for injection is the water for injection of 20 ~ 40% amounts of prescription full dose；
(b) activated carbon is added in rapid gained liquid one step up, is stirred 5 ~ 15 hours at a temperature of 0 ~ 5 °C, then at 35 ~ 45 °C
At a temperature of stir 0.5 ~ 1.5 hour, filtering decarbonization；The additive amount of the activated carbon is that concentration of activated carbon reaches 0.05 in liquid
~ 0.15% amount；
(c) it mends and injects water to prescription full dose, stir evenly, measure solution ph and optional measure active component content,
Optionally adjusted with acid-base modifier to pH4.5 ~ 6.0；The benefit injects water to prescription full dose and refers to add water for injection
Until activity component concentration is the amount of 15 ~ 25mg/ml；
(d) it is filling in cillin bottle by liquid aseptic filtration；
(e) freeze-drying remove moisture, tamponade to get.
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| CN111904936B (en) * | 2020-08-28 | 2022-07-19 | 开封康诺药业有限公司 | Famotidine freeze-dried powder injection |
| CN113197869A (en) * | 2021-04-13 | 2021-08-03 | 河北智同生物制药股份有限公司 | Famotidine freeze-dried powder injection for injection and preparation method thereof |
| CN114681409A (en) * | 2021-10-20 | 2022-07-01 | 海南倍特药业有限公司 | Famotidine for injection and preparation method thereof |
| WO2024062287A1 (en) * | 2022-09-21 | 2024-03-28 | Maiva Pharma Private Limited | A premixed room temperature stable composition of famotidine for intravenous bolus injection and method thereof |
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| CN101972248A (en) * | 2010-10-09 | 2011-02-16 | 江苏奥赛康药业有限公司 | Famotidine composition for injection and preparation method thereof |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101972248A (en) * | 2010-10-09 | 2011-02-16 | 江苏奥赛康药业有限公司 | Famotidine composition for injection and preparation method thereof |
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