CN102258488B - Clindamycin phosphate composition for injection and preparation method thereof - Google Patents
Clindamycin phosphate composition for injection and preparation method thereof Download PDFInfo
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- CN102258488B CN102258488B CN 201110202527 CN201110202527A CN102258488B CN 102258488 B CN102258488 B CN 102258488B CN 201110202527 CN201110202527 CN 201110202527 CN 201110202527 A CN201110202527 A CN 201110202527A CN 102258488 B CN102258488 B CN 102258488B
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Abstract
The invention relates to a clindamycin phosphate composition for injection. The composition is freeze-dried powder which consists of clindamycin phosphate and sodium hydroxide, wherein the weight ratio of the clindamycin phosphate to the sodium hydroxide is (24-26):1; the average grain diameter of the freeze-dried powder is 70-130nm; and the porosity is 92-98 percent. A preparation method of the composition comprises the following steps of: (1) preparing: weighing the clindamycin phosphate and the sodium hydroxide, filling in a preparation tank, adding water for injection, stirring to fully dissolve the clindamycin phosphate and the sodium hydroxide and uniformly mixing; (2) decarbonizing and performing sterile filtration; (3) performing sterile subpackaging; and (4) freeze-drying under vacuum. The composition has the advantages of simple formula, advanced process, uniform quality and superior stability and meanwhile has better redissolving performance and clinical medication safety.
Description
Technical field
What the present invention relates to is a kind of clindamycin phosphate for injection composition and method of making the same, can be used for the treatment of gram positive bacteria and the microbial various infectious disease of anaerobism through the clindamycin phosphate for injection compositions of this method preparation.
Background technology
The clindamycin phosphate chemical name is 6-(1-methyl-anti--4-propyl group-L-2-pyrrolidine formyl is amino)-1-sulfidomethyl-7 (S)-chloro-6,7, the hot pyranoside of 8-three deoxidations-L-Su Shi-α-D-gala-2-dihydrogen phosphoric acid ester.
Its structural formula is:
Molecular formula: C
18H
34ClN
2O
8PS
Molecular weight: 504.97.
Clindamycin phosphate is that third generation woods can type antibiotic, and for lincomycin contains chlorine derivative, the hydroxyl that replaces in the lincomycin molecule the 7th with chloride ion is synthesized into.Clindamycin phosphate has bacteriostasis to the anaerobe of gram positive bacteria and wide scope, is mainly used in the microbial various infectious disease of gram positive bacteria and anaerobism.
Clindamycin phosphate is compared with lincomycin; Antibacterial action strengthens 4～8 times, and the drug level in blood, bone and bone marrow is higher, and the incidence rate of the pseudomembranous colitis due to the generation clostridium difficile is obviously lower; Injection is easy to use; Need not skin test, but but also intravenous drip of intramuscular injection, practical value is bigger in the infection due to treatment Gram-positive aerobe and the various anaerobe.But clindamycin phosphate injection is when pressure sterilizing; Less stable influences end product quality, and domestic some producer adopts sterile working's method to prepare injection; But its effect duration is shorter; And strict to working condition, there is the aseptic safeguard level of carelessness promptly significantly to descend slightly, bring great clinical application hidden danger.The clindamycin phosphate for injection composite freeze-dried powder can overcome this shortcoming, increases the stability of finished product and is convenient to transportation etc.
But in the process of preparation clindamycin phosphate for injection compositions, the clindamycin phosphate preparating liquid takes off charcoal and filters very difficulty, has prolonged the production cycle greatly, is unfavorable for the quality control of product.In addition, because clindamycin phosphate preparating liquid solid content is higher, the cryodesiccated cycle is also longer; And along with the rising of flaggy temperature, skeleton must occur and the lyophilizing micro structure is subsided, these have all limited the raising of clindamycin phosphate for injection composition product quality and production efficiency; The most key is; Because skeleton and lyophilizing micro structure are subsided, also directly had influence on clindamycin phosphate for injection compositions redissolution performance, cause particulate matter and clarity variation; Even do not meet the pharmacopeia regulation, cause scrapping of medicine by the gross.Even if solubility clindamycin phosphate for injection compositions preferably when dispatching from the factory; Because the existence that skeleton and lyophilizing micro structure are subsided; Micro structure is subsided and is continued to extend in put procedure, causes whole lyophilizing pore structure further to destroy, the feasible performance variation gradually of redissolving.Press for and a kind ofly both can significantly promote lyophilizing efficient, can effectively avoid clindamycin phosphate for injection compositions skeleton and lyophilizing micro structure to subside again, ensure that it redissolves the technical scheme of performance.
CN200610090703.3 discloses a kind of liposome composite medicine and preparation method thereof.The liposome composite medicine that provides is any one or a few the liposome of arbitrary proportion mixture that is enclosed with in clindamycin and fleroxacin, left oxygen fleroxacin, the ciprofloxacin, does not solve above-mentioned technological deficiency.
CN200810127044.5 discloses a kind of clindamycin phosphate freeze-dried powder needle; Get by lyophilizing behind the adding NaOH in the clindamycin phosphate topical solution; Wherein the weight ratio of clindamycin phosphate: NaOH is 12～18: 1, preferred 16.5: 1, does not solve above-mentioned technological deficiency.
CN200810138179.1 discloses the method for the injectable sterile powder (injectable powder) that adopts superfine communication technique to prepare chemicals and the medicine injectable powder of preparation; The preferred Nulomoline of its chemicals, clindamycin phosphate, cefpiramide sodium, cefepime hydrochloride, Latamoxef Sodium or Cefmetazon (Sankyo) do not solve above-mentioned technological deficiency.
CN200810080151.7 discloses a kind of method for preparing of clindamycin phosphate powder injection raw medicine, may further comprise the steps: (a) the clindamycin phosphate bullion is carried out purification; (b) above-mentioned filtrating is put into crystallizer and carry out crystallization, growing the grain; (c) crystal solution centrifugalize, washing; (d) with the clindamycin phosphate wet finished product drying that is rapidly heated, do not solve above-mentioned technological deficiency.
CN200910019999.3 discloses a kind of clindamycin phosphate lipidosome freeze-dried preparation and preparation method thereof; Each component and weight portion are: clindamycin phosphate 15-25 part; Two myristic acid lecithin 10-40 parts, cholesterol 1-10 part, antioxidant 1-5 part; Frozen-dried supporting agent 5-25 part does not solve above-mentioned technological deficiency.
CN200910016134.1 discloses a kind of method for preparing of clindamycin phosphate for injection, and a kind of freeze-dried powder pre-freeze solution and compound method thereof mainly are provided, and has solved the unsettled deficiency of clindamycin phosphate preheating, does not solve above-mentioned technological deficiency.
CN200810162432.7 discloses a kind of lyophilized clindamycin phosphate powder needle reagent and method for preparing; The surface activity solubilising reagent that contains lower concentration; Can significantly reduce and haemolysis in use occurs and anaphylactoid risk takes place, not influence this medicine simultaneously and get serviceability.In its concrete embodiment, comprise 1.2～2.0% Tween 80 and regulate the sodium hydroxide that pH value is used, let the pH value be pH 6.0～6.5.In addition, in the method for this medicine of preparation, before filtration, solution is handled, do not solved above-mentioned technological deficiency with 0.1%～0.3% active carbon.
CN201010165860.2 discloses a kind of method for preparing of clindamycin phosphate powder for injection, and step is: get clindamycin phosphate, add the alkaline solution stirring at normal temperatures and make dissolving, process the sterile solution of high concentration; Under gnotobasis, add mineral acid or organic acid regulator solution to certain pH value, add inert organic solvents and under gnotobasis, carry out crystallization, filtration under diminished pressure, drying obtains the clindamycin phosphate aseptic powder; Under aseptic condition, be sub-packed in the sterilization cillin bottle, add a cover butyl rubber plug, roll aluminium lid, process sterile powder injection, well do not solve above-mentioned technological deficiency.
CN201010139935.X discloses a kind of composition of medicine of clindamycin phosphate, is processed by the active ingredient of following parts by weight: clindamycin phosphate 0.2-0.45, polyene phosphatidylcholine 0.1-0.2, reduced glutathion 0.02-0.04; And method for preparing is provided, do not solve above-mentioned technological deficiency.
CN200410057318.X discloses a kind of method for preparing of clindamycin phosphoric acid cosmetics injection, comprising: get clindamycin phosphoric acid fat and add alcoholic solution to dissolving; After adding activated carbon decolorizing, carry out coarse filtration, fine straining, place crystallize, cross and filter to remove supernatant, get clindamycin phosphoric acid fat crystalline solid; Carry out again change dissolving the second time, recrystallization once, filter the clindamycin phosphoric acid fat crystalline solid that obtains recrystallization; Oven dry is pulverized, and lid is rolled in packing under gnotobasis, and packing promptly gets, and does not solve above-mentioned technological deficiency.
CN201010567417.8 discloses a kind of method that keeps clindamycin phosphate injection quality stability; Concrete steps are following: (1) adds 0.05%～4% antioxidant that adds the injection gross mass in the clindamycin phosphate injection in the clindamycin phosphate injection of having prepared, fully stirs and makes its dissolving; (2) injection is sealed after in above-mentioned solution, feeding nitrogen 10～20min that flow velocity is 2ml/min.Wherein antioxidant is a sodium sulfite, does not solve above-mentioned technological deficiency.
Existing known technology is all less than the suggestion that above defective is proposed improve.
Summary of the invention
The objective of the invention is provides the clindamycin phosphate for injection composition and method of making the same to above weak point, and to this poor stability of clindamycin phosphate, the pressure sterilizing process conditions are strict; Poor controllability (has the aseptic safeguard level of carelessness promptly significantly to descend slightly; Bring great clinical application hidden danger), take off the charcoal difficulty, need lyophilizing but the medicine that exists skeleton and lyophilizing micro structure to subside at freeze-drying process; The present invention can significantly promote lyophilizing efficient; And effectively avoided clindamycin phosphate for injection compositions skeleton and lyophilizing micro structure to subside, thus fundamentally ensureing its redissolution performance, clinical application safety is more guaranteed.In addition, the present invention has also solved the clindamycin phosphate preparating liquid and takes off charcoal and filter the very problem of difficulty.
Inventor of the present invention finds through research experiment; Part by weight through clindamycin phosphate and sodium hydroxide in the control clindamycin phosphate for injection compositions; Can effectively reduce clindamycin phosphate with the temperature degraded of aggravation gradually that raises,, both can guarantee that clindamycin phosphate dissolves also mix homogeneously fully when the part by weight of clindamycin phosphate and sodium hydroxide is 24～26: 1; Can guarantee the degraded amplitude minimum that it raises and increase gradually with temperature again; On this basis, reduce sodium hydroxide concentration, clindamycin phosphate dissolving difficulty; Increase sodium hydroxide concentration, clindamycin phosphate raises with temperature, and change is big rapidly for the degraded amplitude that increases gradually.Preferred, the part by weight of clindamycin phosphate and sodium hydroxide is 25: 1 o'clock, and this preparation stability effect is best.
The clindamycin phosphate preparating liquid is similar to colloid solution; This solution resistance when passing through the small duct of various filters is bigger, and therefore in the process of preparation clindamycin phosphate for injection compositions, the clindamycin phosphate preparating liquid takes off charcoal and filters the ten minutes difficulty; When more the or active carbon addition of particularly whole preparating liquid is bigger; Tend to extend manufacture cycle significantly, or frequent change and cleaning and filtering utensil, be unfavorable for the quality control of product.More prior art adopts and reduces the amount of activated or the way of ultrafiltration; For reducing amount of activated, maybe be not enough because of adsorbance, bring halfway quality of pyrogen and impurity absorption and potential safety hazard; And the way of employing ultrafiltration; Not only increased production equipment and consumables cost input greatly, the prolongation producing on the time spent also at double is unfavorable for controllable quality.
On the basis of preferred and accurate control clindamycin phosphate and sodium hydroxide part by weight, the medicinal liquid of being prepared has had better stability of solution, at this moment; Then might eliminate all drawbacks that the approximate colloid solution of preparating liquid is brought through the temperature that improves obtain solution; Lot of test shows, suitably improves the temperature of preparating liquid, can effectively eliminate approximate colloidal structure in the medicinal liquid; The drawback of getting rid of its filtration difficulty; Medicinal liquid is heated to 35 ℃ and be incubated 20 minutes,, takes off charcoal and carry out aseptic filtration simultaneously the microfilter series connection of titanium rod filter and 0.22 μ m; Through investigating filter each section pressure decline situation and using front and back bubble experimental tests; Show that being prone to strainability significantly improves, even if increase substantially the addition of production lot and active carbon, the phenomenon of filtration difficulty under the prior art processes do not occur yet.
Because clindamycin phosphate preparating liquid solid content is higher, be difficult to form complete vapor channel, be unfavorable for the distillation of steam in the goods; Therefore the cryodesiccated cycle also longer, this product is along with the rising of flaggy temperature simultaneously, skeleton must occur when carrying out lyophilizing by prior art and the lyophilizing micro structure is subsided; With regard to these defectives; The lyophilization cycle length also only be the raising that has limited clindamycin phosphate for injection composition production efficient, skeleton that occurs when carrying out lyophilizing by prior art and lyophilizing micro structure are subsided and then are directly connected to the quality of final products, this be because of; Skeleton and lyophilizing micro structure are subsided and have directly been had influence on clindamycin phosphate for injection compositions redissolution performance; Must cause particulate matter and clarity variation, even not meet the pharmacopeia regulation, cause scrapping of medicine by the gross.Even if solubility clindamycin phosphate for injection compositions preferably when dispatching from the factory; Because the existence that skeleton and lyophilizing micro structure are subsided; Micro structure is subsided and is continued to extend in put procedure, causes whole lyophilizing pore structure further to destroy, the feasible performance variation gradually of redissolving.Find through great deal of experimental; Adopt unique advanced vacuum freeze-drying technique; Both can significantly promote lyophilizing efficient; Can effectively avoid clindamycin phosphate for injection compositions skeleton and lyophilizing micro structure to subside again; Prepare a kind of mean diameter and porosity and the remarkable different clindamycin phosphate for injection compositions of the product of prior art for preparing, this clindamycin phosphate for injection compositions has lyophilizing structure, mean diameter and the porosity of remarkable excellence, can effectively improve the redissolution performance of clindamycin phosphate for injection compositions and ensure that this performance is in the stable and concordance of its preparation in effect duration.
This vacuum freeze-drying technique is at first put the clindamycin phosphate medicinal liquid that branch installs in the freeze dryer; Reduce products temperature rapidly; When products temperature is lower than-45 ℃; Continue the clindamycin phosphate medicinal liquid to be freezed fully in freezing 60 minutes, this pre-freeze process can guarantee to obtain to be easy to relatively the crystalline state that distils on the one hand, abandons known technology pre-freeze insulating process on the other hand fully; Continued freezing 60 minutes; This process is except making the clindamycin phosphate medicinal liquid freezes fully, also can be so that temperature of articles is low as much as possible before the final distillation that heats up, be follow-up surmount routine techniques rapidly greatly amplitude heat up and create the bigger products temperature safety rising space.
Secondly,, utilize compressor, make the rear cabinet condenser temperature be lower than-70 ℃, carry out the cold deposit for the follow-up rapidly very big amplitude that surmounts routine techniques heats up to rear cabinet cold-trap refrigeration in the rear cabinet refrigeration stage.
Once more,, guarantee preceding case vacuum is evacuated to below the 10Pa, carry out the vacuum preparation for the follow-up rapidly very big amplitude that surmounts routine techniques heats up in vacuumizing phase.
Next, at the high speed drying stage, disposablely rapidly the conduction oil temperature is risen to 50 ℃ in the short time at the utmost point; High and the product that subside with skeleton and lyophilizing micro structure for this type of clindamycin phosphate for injection compositions solid content; This is inconceivable at existing known technology, yet, owing to carried out the preparation of aspects such as the said products temperature safety rising space, cold deposit and vacuum; This sublimation drying process that heats up at a high speed can be able to smooth security implementation; Its direct preparation effect is exactly, and a large amount of heat supplies make that moisture is fallen by a large amount of distillations in extremely short time (being generally 4～6 hours) lining in the goods, and products temperature also can rise rapidly therebetween; But because the time is short; Initial products temperature is low, does not reach the temperature that skeleton and lyophilizing micro structure are subsided as yet, therefore can possess splendid lyophilizing skeleton and micro structure.
At last, after high-speed dry dryness accumulated in the stomach and intestine bundle, promptly when products temperature reaches-16 ℃, rapidly the conduction oil temperature is reduced to 20 ℃; Get at the uniform velocity drying stage, and keep this temperature sublimation drying that at the uniform velocity heats up, when products temperature reaches 15 ℃; And close after the case vacuum does not have significant change before the valve tamponade, outlet; With plastic-aluminum composite cover tying, packing promptly gets the clindamycin phosphate for injection compositions after quality inspection is qualified.Find through a large amount of development tests; When products temperature reaches-16 ℃; Rapidly the conduction oil temperature is reduced to 20 ℃; Can prevent effectively that products temperature from further rapidly raising, and then avoid goods before bone dry, to level off to the temperature that skeleton and lyophilizing micro structure subside, guarantee also the situation that lyophilizing skeleton and micro structure are subsided can not occur at drying stage at the uniform velocity.Because high speed drying stage moisture drying amount is bigger, even if adopted the existing lower baking temperature of known technology, also can thoroughly remove residual moisture at drying stage at the uniform velocity, make the requirement of final products moisture conformance with standard.Because it is the existing known technology of final baking temperature is low, also littler in the dry run simultaneously to lyophilizing skeleton and the destructive probability of micro structure.
Find that through detecting the product of the existing known technology preparation of the clindamycin phosphate for injection compositions of the inventive method preparation has lyophilizing structure, mean diameter and the porosity of remarkable excellence.
Experimental study further through a large amount of is found; The mean diameter of the clindamycin phosphate for injection compositions of the inventive method preparation is 70～130nm; Porosity is 92%～98% o'clock, can effectively improve the redissolution performance of clindamycin phosphate for injection compositions and ensure that this performance is in the stable and concordance of its preparation in effect duration.
Clindamycin phosphate for injection compositions provided by the invention, specific as follows:
A kind of clindamycin phosphate for injection compositions; By the lyophilized powder that clindamycin phosphate and sodium hydroxide are formed, wherein, the part by weight of clindamycin phosphate and sodium hydroxide is 24～26: 1; The mean diameter of said lyophilized powder is 70～130nm, and porosity is 92%～98%.
In above-mentioned a kind of clindamycin phosphate for injection compositions, the preferred part by weight of clindamycin phosphate and sodium hydroxide is 25: 1.
Above-mentioned clindamycin phosphate for injection compositions, its preferred mean diameter is 90～110nm, porosity is 96%～98%.
A kind of clindamycin phosphate for injection compositions prepares according to following method:
1) preparation: by weight 24～26: 1 takes by weighing clindamycin phosphate and sodium hydroxide, puts in the preparing tank, adds water for injection, stirs to make it to dissolve fully and mix homogeneously;
2) take off charcoal, aseptic filtration: add the needle-use activated carbon of medicinal liquid weight 0.3%, continue to stir, and medicinal liquid is heated to 35 ℃ of insulations 20 minutes,, take off charcoal and carry out aseptic filtration simultaneously with the microfilter series connection of titanium rod filter and 0.22 μ m;
3) aseptic subpackaged: that the step is gathered 2) be filtered to the clindamycin phosphate medicinal liquid in the sterilizing room, be sub-packed in the cillin bottle false add plug;
4) vacuum lyophilization:
A, pre-freeze: the step is gathered 3) divide the clindamycin phosphate medicinal liquid that installs to put in the freeze dryer, reduce products temperature rapidly, when products temperature is lower than-45 ℃, continue the clindamycin phosphate medicinal liquid to be freezed fully in freezing 60 minutes;
B, rear cabinet refrigeration: utilize compressor to rear cabinet cold-trap refrigeration, make the rear cabinet condenser temperature be lower than-70 ℃;
C, evacuation: the open vacuum pump is evacuated to preceding case vacuum below the 10Pa;
D, dry at a high speed: rapidly the conduction oil temperature is risen to 50 ℃, begin to heat up at a high speed sublimation drying;
E, at the uniform velocity dry: when products temperature reaches-16 ℃, rapidly the conduction oil temperature is reduced to 20 ℃, and keep this temperature sublimation drying that at the uniform velocity heats up; When products temperature reaches 15 ℃, and in closing after the case vacuum does not have significant change before the valve, tamponade; Outlet; With plastic-aluminum composite cover tying, packing promptly gets after quality inspection is qualified.
A kind of clindamycin phosphate for injection preparation of compositions method comprises following process:
1) preparation: by weight 24～26: 1 takes by weighing clindamycin phosphate and sodium hydroxide, puts in the preparing tank, adds water for injection, stirs to make it to dissolve fully and mix homogeneously;
2) take off charcoal, aseptic filtration: add the needle-use activated carbon of medicinal liquid weight 0.3%, continue to stir, and medicinal liquid is heated to 35 ℃ of insulations 20 minutes,, take off charcoal and carry out aseptic filtration simultaneously with the microfilter series connection of titanium rod filter and 0.22 μ m;
3) aseptic subpackaged: that the step is gathered 2) be filtered to the clindamycin phosphate medicinal liquid in the sterilizing room, be sub-packed in the cillin bottle false add plug;
4) vacuum lyophilization:
A, pre-freeze: the step is gathered 3) divide the clindamycin phosphate medicinal liquid that installs to put in the freeze dryer, reduce products temperature rapidly, when products temperature is lower than-45 ℃, continue the clindamycin phosphate medicinal liquid to be freezed fully in freezing 60 minutes;
B, rear cabinet refrigeration: utilize compressor to rear cabinet cold-trap refrigeration, make the rear cabinet condenser temperature be lower than-70 ℃;
C, evacuation: the open vacuum pump is evacuated to preceding case vacuum below the 10Pa;
D, dry at a high speed: rapidly the conduction oil temperature is risen to 50 ℃, begin to heat up at a high speed sublimation drying;
E, at the uniform velocity dry: when products temperature reaches-16 ℃, rapidly the conduction oil temperature is reduced to 20 ℃, and keep this temperature sublimation drying that at the uniform velocity heats up; When products temperature reaches 15 ℃, and in closing after the case vacuum does not have significant change before the valve, tamponade; Outlet; With plastic-aluminum composite cover tying, packing promptly gets after quality inspection is qualified.
In the above-mentioned clindamycin phosphate for injection preparation of compositions method, wherein the part by weight of clindamycin phosphate and sodium hydroxide is preferably 24～26: 1.
A kind of clindamycin phosphate for injection preparation of compositions method, wherein the preferred part by weight of clindamycin phosphate and sodium hydroxide is 25: 1.
In freeze dried product, only contain clindamycin phosphate and sodium hydroxide, in the finished product in component and the raw material ratio do not have substantial variation.
Clindamycin phosphate for injection composition and method of making the same of the present invention; Problem such as solved that such medicine stability is poor, filtering decarbonization difficulty, lyophilization cycle are long, skeleton and lyophilizing micro structure are subsided; Adopted rational prescription proportioning and unique advanced preparation technology, significantly promoted lyophilizing efficient, and effectively avoided clindamycin phosphate for injection compositions skeleton and lyophilizing micro structure to subside; Prepare a kind of mean diameter and porosity and the remarkable different clindamycin phosphate for injection compositions of the product of prior art for preparing; This clindamycin phosphate for injection compositions has lyophilizing structure, mean diameter and the porosity of remarkable excellence, can effectively improve the redissolution performance of clindamycin phosphate for injection compositions and ensure that this performance is in the stable and concordance of its preparation in effect duration, its quality stable homogeneous; Content is evenly accurate; Moisture drying is thorough, and the stability in transportation and storage process is better, and clinical use has better safety.Preparation technology of the present invention is simple, and is convenient feasible, good reproducibility, and production cost is lower, is easy to realize industrialized great production, thereby can produce considerable economic and social benefit.
The specific embodiment
Further specify the present invention through embodiment below.Should correct understanding be: embodiments of the invention are only used for the present invention is described and provide, rather than limitation of the present invention, so, under method prerequisite of the present invention, simple modifications of the present invention is all belonged to the present invention and requires the scope protected.
Be guarantee test result's concordance, reference examples of the present invention, embodiment and Test Example have been used identical raw material, adjuvant, cillin bottle and plug.
Reference examples 1:
Prescription:
Clindamycin phosphate 3660g
Water for injection adds to 20Kg
Preparation: get water for injection 12Kg and put in the preparing tank and be cooled to below 20 ℃; Taking by weighing clindamycin phosphate by recipe quantity joins wherein; Open and stir, slowly add the sodium hydroxide solution 2500ml of 2mol/L, continue stirring it is dissolved fully; The pH of regulator solution is 6.2, continues to mix.
Take off charcoal, aseptic filtration: the needle-use activated carbon that adds medicinal liquid weight 0.03%; Continued stirring and adsorbing 30 minutes; Use 0.45 μ m filtering with microporous membrane to take off charcoal; Filtrating adds the injection water to 20Kg, continues to stir to make the solution mix homogeneously in 20 minutes, and the solution for preparing carries out aseptic filtration through the microfilter of 0.22 μ m;
Aseptic subpackaged: will be filtered to the clindamycin phosphate medicinal liquid in the sterilizing room, the loading amount of propping up by 2ml/ is sub-packed in the cillin bottle, the false add plug;
Vacuum lyophilization:
Pre-freeze: temperature is-45 ℃, and the time is 4 hours; After medicine freezes, the temperature of condenser is controlled at below-45 ℃, to the whole system evacuation, temperature slowly is warming up to 0 ℃, is incubated 20 hours; Control temperature and vacuum rise to 25 ℃ with temperature, are incubated 8 hours, tamponade; Outlet, with plastic-aluminum composite cover tying, packing promptly gets after quality inspection is qualified.Prepared clindamycin phosphate for injection compositions is put in the F-Sorb 3400-porosimeter, adopts nitrogen absorption continuous flow method to measure and calculates its mean diameter and porosity.
This method is taken off relatively difficulty of charcoal, wants the frequent change filter membrane if need to continue to strengthen the needle-use activated carbon used in amounts.Whole freeze-drying time reaches 32 hours.
Reference examples 2:
Prescription:
Clindamycin phosphate 3660g
Tetrasodium pyrophosphate 20g
Water for injection adds to 20Kg
Preparation: get water for injection 8Kg and put in the preparing tank, take by weighing clindamycin phosphate by recipe quantity and join wherein, open stirring and make it to be scattered in the water; Get suspension; Regulate suspension pH value to 6.5 with sodium hydroxide, and suspension is heated to 80 ℃, continue stirring and make it to dissolve fully; Gained solution is cooled to 20 ℃, continues to mix.
Take off charcoal, aseptic filtration: the needle-use activated carbon that adds medicinal liquid weight 0.03%; Continue to stir 30 minutes; Add the injection water to 20Kg after using titanium rod filter filtering decarbonization, continue stirring and made the solution mix homogeneously in 10 minutes, the solution for preparing carries out aseptic filtration through the microfilter of 0.22 μ m;
Aseptic subpackaged: will be filtered to the clindamycin phosphate medicinal liquid in the sterilizing room, the loading amount of propping up by 2ml/ is sub-packed in the cillin bottle, the false add plug;
Vacuum lyophilization:
Open the condenser electromagnetic valve, condenser temperature reaches subzero below 40 ℃, at a distance from valve, opens oil pump in closing, and compresses plug, opens chamber door, the product outlet.
A, pre-freeze: the clindamycin phosphate medicinal liquid that branch installs is put in the freeze dryer, opened fridge, when treating that products temperature reaches-35 ℃, continue insulation and the clindamycin phosphate medicinal liquid was freezed fully in 4 hours;
B, rear cabinet refrigeration: utilize compressor to rear cabinet cold-trap refrigeration, make the rear cabinet condenser temperature be lower than-40 ℃;
C, intensification sublimation drying: the open vacuum pump, carry out sublimation drying to goods, in whole sublimation process; Should keep a close eye on vacuum and condenser temperature and change, vacuum should be controlled in the 30Pa, and condenser temperature is not higher than-40 ℃; Distillation through 18 hours; Vacuum Pa value diminishes gradually, the continuous step-down of condenser temperature, and goods sesquialter water sample is drained.When products temperature reaches 28 ℃, vacuum representes that promptly the sublimation drying stage finishes in 10Pa; Keep products temperature at 28 ℃, under vacuum state, continue drying after 4 hours, and after the case vacuum does not have significant change before the separated valve in closing; Tamponade, outlet is with plastic-aluminum composite cover tying; Packing promptly gets after quality inspection is qualified.Prepared clindamycin phosphate for injection compositions is put in the F-Sorb 3400-porosimeter, adopts nitrogen absorption continuous flow method to measure and calculates its mean diameter and porosity.
This method is taken off relatively difficulty of charcoal, wants the frequent change filter membrane if need to continue to strengthen the needle-use activated carbon used in amounts.Whole freeze-drying time reaches 34 hours.
Embodiment 1:
Prescription:
Clindamycin phosphate 3660g
Sodium hydroxide 146.4g
Water for injection adds to 20Kg
Preparation: take by weighing clindamycin phosphate and sodium hydroxide, put in the preparing tank, add water for injection, stir and make it to dissolve fully also mix homogeneously;
Take off charcoal, aseptic filtration: add the needle-use activated carbon of medicinal liquid weight 0.3%, continue to stir, and medicinal liquid is heated to 35 ℃ of insulations 20 minutes,, take off charcoal and carry out aseptic filtration simultaneously with the microfilter series connection of titanium rod filter and 0.22 μ m;
Aseptic subpackaged: will be filtered to the clindamycin phosphate medicinal liquid in the sterilizing room, the loading amount of propping up by 2ml/ is sub-packed in the cillin bottle, the false add plug;
Vacuum lyophilization:
A, pre-freeze: the clindamycin phosphate medicinal liquid that branch installs is put in the freeze dryer, reduced products temperature rapidly, when products temperature is lower than-45 ℃, continue the clindamycin phosphate medicinal liquid to be freezed fully in freezing 60 minutes;
B, rear cabinet refrigeration: utilize compressor to rear cabinet cold-trap refrigeration, make the rear cabinet condenser temperature be lower than-70 ℃;
C, evacuation: the open vacuum pump is evacuated to preceding case vacuum below the 10Pa;
D, dry at a high speed: rapidly the conduction oil temperature is risen to 50 ℃, begin to heat up at a high speed sublimation drying;
E, at the uniform velocity dry: when products temperature reaches-16 ℃, rapidly the conduction oil temperature is reduced to 20 ℃, and keep this temperature sublimation drying that at the uniform velocity heats up; When products temperature reaches 15 ℃, and in closing after the case vacuum does not have significant change before the valve, tamponade; Outlet; With plastic-aluminum composite cover tying, packing promptly gets after quality inspection is qualified.Prepared clindamycin phosphate for injection compositions is put in the F-Sorb 3400-porosimeter, adopts nitrogen absorption continuous flow method to measure and calculates its mean diameter and porosity.
It is easy that this method is taken off charcoal, also need not to change filter even if continue to strengthen the needle-use activated carbon consumption.Whole freeze-drying time is 15 hours.
Embodiment 2:
Prescription:
Clindamycin phosphate 3660g
Sodium hydroxide 140.8g
Water for injection adds to 20Kg
Preparation: take by weighing clindamycin phosphate and sodium hydroxide, put in the preparing tank, add water for injection, stir and make it to dissolve fully also mix homogeneously;
Take off charcoal, aseptic filtration: add the needle-use activated carbon of medicinal liquid weight 0.3%, continue to stir, and medicinal liquid is heated to 35 ℃ of insulations 20 minutes,, take off charcoal and carry out aseptic filtration simultaneously with the microfilter series connection of titanium rod filter and 0.22 μ m;
Aseptic subpackaged: will be filtered to the clindamycin phosphate medicinal liquid in the sterilizing room, the loading amount of propping up by 2ml/ is sub-packed in the cillin bottle, the false add plug;
Vacuum lyophilization:
A, pre-freeze: the clindamycin phosphate medicinal liquid that branch installs is put in the freeze dryer, reduced products temperature rapidly, when products temperature is lower than-45 ℃, continue the clindamycin phosphate medicinal liquid to be freezed fully in freezing 60 minutes;
B, rear cabinet refrigeration: utilize compressor to rear cabinet cold-trap refrigeration, make the rear cabinet condenser temperature be lower than-70 ℃;
C, evacuation: the open vacuum pump is evacuated to preceding case vacuum below the 10Pa;
D, dry at a high speed: rapidly the conduction oil temperature is risen to 50 ℃, begin to heat up at a high speed sublimation drying;
E, at the uniform velocity dry: when products temperature reaches-16 ℃, rapidly the conduction oil temperature is reduced to 20 ℃, and keep this temperature sublimation drying that at the uniform velocity heats up; When products temperature reaches 15 ℃, and in closing after the case vacuum does not have significant change before the valve, tamponade; Outlet; With plastic-aluminum composite cover tying, packing promptly gets after quality inspection is qualified.Prepared clindamycin phosphate for injection compositions is put in the F-Sorb 3400-porosimeter, adopts nitrogen absorption continuous flow method to measure and calculates its mean diameter and porosity.
It is easy that this method is taken off charcoal, also need not to change filter even if continue to strengthen the needle-use activated carbon consumption.Whole freeze-drying time is 16 hours.
Embodiment 3:
Prescription:
Clindamycin phosphate 3660g
Sodium hydroxide 152.5g
Water for injection adds to 20Kg
Preparation: take by weighing clindamycin phosphate and sodium hydroxide, put in the preparing tank, add water for injection, stir and make it to dissolve fully also mix homogeneously;
Take off charcoal, aseptic filtration: add the needle-use activated carbon of medicinal liquid weight 0.3%, continue to stir, and medicinal liquid is heated to 35 ℃ of insulations 20 minutes,, take off charcoal and carry out aseptic filtration simultaneously with the microfilter series connection of titanium rod filter and 0.22 μ m;
Aseptic subpackaged: will be filtered to the clindamycin phosphate medicinal liquid in the sterilizing room, the loading amount of propping up by 2ml/ is sub-packed in the cillin bottle, the false add plug;
Vacuum lyophilization:
A, pre-freeze: the clindamycin phosphate medicinal liquid that branch installs is put in the freeze dryer, reduced products temperature rapidly, when products temperature is lower than-45 ℃, continue the clindamycin phosphate medicinal liquid to be freezed fully in freezing 60 minutes;
B, rear cabinet refrigeration: utilize compressor to rear cabinet cold-trap refrigeration, make the rear cabinet condenser temperature be lower than-70 ℃;
C, evacuation: the open vacuum pump is evacuated to preceding case vacuum below the 10Pa;
D, dry at a high speed: rapidly the conduction oil temperature is risen to 50 ℃, begin to heat up at a high speed sublimation drying;
E, at the uniform velocity dry: when products temperature reaches-16 ℃, rapidly the conduction oil temperature is reduced to 20 ℃, and keep this temperature sublimation drying that at the uniform velocity heats up; When products temperature reaches 15 ℃, and in closing after the case vacuum does not have significant change before the valve, tamponade; Outlet; With plastic-aluminum composite cover tying, packing promptly gets after quality inspection is qualified.Prepared clindamycin phosphate for injection compositions is put in the F-Sorb 3400-porosimeter, adopts nitrogen absorption continuous flow method to measure and calculates its mean diameter and porosity.
It is easy that this method is taken off charcoal, also need not to change filter even if continue to strengthen the needle-use activated carbon consumption.Whole freeze-drying time is 16 hours.
The present invention also further provides following Test Example, so that effect of the present invention is further described:
Test Example 1:
Clindamycin phosphate 3660g is got in this test respectively, finally is mixed with the 20Kg medicinal liquid, investigates the influence to preparating liquid stability of part by weight and the fluid temperature of different clindamycin phosphates and sodium hydroxide, simultaneously
Investigated the time of different activities charcoal addition decarbonization filtering under the corresponding temperature, its result sees table 1.
Table 1 clindamycin phosphate for injection compositions preparating liquid stability and decarbonization filtering are investigated
Annotate: " part by weight " described in the table 1 refers to " part by weight of clindamycin phosphate and sodium hydroxide ".
Can find out that from table 1 part by weight of clindamycin phosphate and sodium hydroxide is at 24～26: 1 o'clock, adopt 35 ℃ take off charcoal and filtration temperature, its related substances is low and the decarbonization filtering time is shorter.
Test Example 2:
This test by embodiment 1 preparating liquid, take off charcoal, filter and packing, put in the freeze dryer, investigate of the influence of different vacuum freeze-drying techniques to final freeze-drying prods, its result sees table 2.
Table 2 clindamycin phosphate for injection compositions vacuum freeze-drying technique is investigated
Annotate: the concrete technology of numbering representative described in the table 2 is following:
A1---pre-freeze: slowly reduce products temperature, when products temperature was lower than-45 ℃, products temperature-45 ℃ maintenance 3 hours was freezed the clindamycin phosphate medicinal liquid fully;
A2---pre-freeze: reduce products temperature rapidly, when products temperature was lower than-45 ℃, products temperature-45 ℃ maintenance 3 hours was freezed the clindamycin phosphate medicinal liquid fully;
A3---pre-freeze: slowly reduce products temperature, when products temperature is lower than-45 ℃, continue the clindamycin phosphate medicinal liquid to be freezed fully in freezing 60 minutes;
A4---pre-freeze: reduce products temperature rapidly, when products temperature is lower than-45 ℃, continue the clindamycin phosphate medicinal liquid to be freezed fully in freezing 60 minutes;
B1---rear cabinet refrigeration: utilize compressor to rear cabinet cold-trap refrigeration, make the rear cabinet condenser temperature be lower than-45 ℃;
B2---rear cabinet refrigeration: utilize compressor to rear cabinet cold-trap refrigeration, make the rear cabinet condenser temperature be lower than-50 ℃;
B3---rear cabinet refrigeration: utilize compressor to rear cabinet cold-trap refrigeration, make the rear cabinet condenser temperature be lower than-60 ℃;
B4---rear cabinet refrigeration: utilize compressor to rear cabinet cold-trap refrigeration, make the rear cabinet condenser temperature be lower than-70 ℃;
C1---evacuation: the open vacuum pump is evacuated to preceding case vacuum below the 50Pa;
C2---evacuation: the open vacuum pump is evacuated to preceding case vacuum below the 20Pa;
C3---evacuation: the open vacuum pump is evacuated to preceding case vacuum below the 10Pa;
D1---common drying: in first hour conduction oil is risen to-15 ℃, later conduction oil heats up with 5 ℃/hour speed, when the temperature of conduction oil rises to 38 ℃; Keep the temperature-resistant of conduction oil, when treating that products temperature reaches 28 ℃～32 ℃, be incubated 4 hours; Tamponade, outlet;
D2---common drying: in first hour conduction oil is risen to-15 ℃, later conduction oil heats up with 3 ℃/hour speed, when the temperature of conduction oil rises to 38 ℃; Keep the temperature-resistant of conduction oil, when treating that products temperature reaches 28 ℃～32 ℃, be incubated 4 hours; Tamponade, outlet;
D3---common drying: temperature slowly rises to 0 ℃, is incubated 20 hours, and control temperature and vacuum rise to 25 ℃ with temperature, are incubated 8 hours, tamponade, outlet;
D4---fully at a high speed dry: rapidly the conduction oil temperature is risen to 50 ℃, the beginning sublimation drying that heats up at a high speed, when products temperature reaches 15 ℃, and in closing after the case vacuum does not have significant change before the valve, tamponade, outlet;
D5---dry at a high speed, at the uniform velocity dry: as rapidly the conduction oil temperature to be risen to 50 ℃, begin to heat up at a high speed sublimation drying, when products temperature reaches-16 ℃; Rapidly the conduction oil temperature is reduced to 20 ℃; And keep this temperature sublimation drying that at the uniform velocity heats up, when products temperature reaches 15 ℃, and in closing after the case vacuum does not have significant change before the valve; Tamponade, outlet.
Can find out that from table 2 adopt A4, B4, C3, D5 group technology, freeze dried preparation effect is best, freeze-drying time also can significantly shorten.
Test Example 3:
Respectively prepare the clindamycin phosphate for injection compositions respectively by reference examples 1～2 and embodiment 1～3, check mean diameter, porosity, solubility, visible foreign matters, clarity, related substance and particulate matter more respectively, its result sees table 3.
Table 3 clindamycin phosphate for injection compositions check result
Can find out from table 3; Technical scheme of the present invention (embodiment 1～3) compares with prior art (reference examples 1～2); Have better mean diameter and porosity; Significantly improved the redissolution performance of clindamycin phosphate compositions, simultaneously on the quality control level of particulate matter, had clear superiority, the drug risks such as capillary embolism that cause because of particulate matter in the time of can significantly reducing clinical use.
Test Example 4:
Respectively prepare the clindamycin phosphate for injection compositions respectively by reference examples 1～2 and embodiment 1～3; Put under the room temperature lucifuge condition and carry out study on the stability; Mean diameter, porosity, clarity and particulate matter are checked in inspection respectively again, and its result sees table 4, table 5, table 6.
Table 4 clindamycin phosphate for injection compositions mean diameter, porosity study on the stability result
Table 5 clindamycin phosphate for injection compositions clarity study on the stability result
Table 6 clindamycin phosphate for injection compositions particulate matter study on the stability result
Technical scheme of the present invention (embodiment 1～3) compares with prior art (reference examples 1～2), has better stability at aspects such as mean diameter, porosity, clarity and particulate matters, and quality-advantage is obvious.
In addition; Respectively according to the clindamycin phosphate for injection compositions of each embodiment preparation of Chinese patent CN200810127044.5, CN200910016134.1, CN200810162432.7 and CN201010165860.2 etc., measure through F-Sorb 3400-porosimeter nitrogen absorption continuous flow method and to calculate its mean diameter and porosity, carry out solubility and long-term shelf-stability simultaneously and investigate; The product that the result shows the preparation of above-mentioned known technology is with the skeleton of varying degree and the lyophilizing structure is little subsides; Its mean diameter product also of the present invention head and shoulders above, porosity is low than product of the present invention, the redissolution poor-performing; Study on the stability shows; Along with the prolongation of standing time, above-mentioned defective is more obvious, is further improved.
The present invention has also carried out similar test to other embodiment and Test Example, has obtained result, conclusion and the trend similar with above embodiment and Test Example, because length is limit, the inventor enumerates no longer one by one.
Claims (6)
1. clindamycin phosphate for injection compositions; It is characterized in that the lyophilized powder that said compositions is made up of clindamycin phosphate and sodium hydroxide; Wherein, The part by weight of clindamycin phosphate and sodium hydroxide is 24～26:1, and the mean diameter of said lyophilized powder is 70～130nm, and porosity is 92%～98%; Described clindamycin phosphate for injection compositions prepares according to following method:
1) preparation: take by weighing clindamycin phosphate and sodium hydroxide by weight 24～26:1, put in the preparing tank, add water for injection, stir and make it to dissolve fully also mix homogeneously;
2) take off charcoal, aseptic filtration: add the needle-use activated carbon of medicinal liquid weight 0.3%, continue to stir, and medicinal liquid is heated to 35 ℃ of insulations 20 minutes,, take off charcoal and carry out aseptic filtration simultaneously with the microfilter series connection of titanium rod filter and 0.22 μ m;
3) aseptic subpackaged: that the step is gathered 2) be filtered to the clindamycin phosphate medicinal liquid in the sterilizing room, be sub-packed in the cillin bottle false add plug;
4) vacuum lyophilization:
A, pre-freeze: the step is gathered 3) divide the clindamycin phosphate medicinal liquid install to put in the freeze dryer, reduce products temperature rapidly, when products temperature hangs down in 45 ℃ of –, continue the clindamycin phosphate medicinal liquid to be freezed fully in freezing 60 minutes;
B, rear cabinet refrigeration: utilize compressor to rear cabinet cold-trap refrigeration, make 70 ℃ of rear cabinet condenser temperature Di Yu –;
C, evacuation: the open vacuum pump is evacuated to preceding case vacuum below the 10Pa;
D, dry at a high speed: rapidly the conduction oil temperature is risen to 50 ℃, begin to heat up at a high speed sublimation drying;
E, at the uniform velocity dry: as products temperature Da during, rapidly the conduction oil temperature is reduced to 20 ℃, and keep this temperature sublimation drying that at the uniform velocity heats up Dao 16 ℃ of –; When products temperature reaches 15 ℃, and in closing after the case vacuum does not have significant change before the valve, tamponade; Outlet; With plastic-aluminum composite cover tying, packing promptly gets product after quality inspection is qualified.
2. clindamycin phosphate for injection compositions according to claim 1, the part by weight that it is characterized in that described clindamycin phosphate and sodium hydroxide is 25:1.
3. clindamycin phosphate for injection compositions according to claim 1 is characterized in that described clindamycin phosphate for injection compositions mean diameter is 90～110nm, and porosity is 96%～98%.
4. the described clindamycin phosphate for injection preparation of compositions of claim 1 method is characterized in that method for preparing is:
1) preparation: take by weighing clindamycin phosphate and sodium hydroxide by weight 24～26:1, put in the preparing tank, add water for injection, stir and make it to dissolve fully also mix homogeneously;
2) take off charcoal, aseptic filtration: add the needle-use activated carbon of medicinal liquid weight 0.3%, continue to stir, and medicinal liquid is heated to 35 ℃ of insulations 20 minutes,, take off charcoal and carry out aseptic filtration simultaneously with the microfilter series connection of titanium rod filter and 0.22 μ m;
3) aseptic subpackaged: that the step is gathered 2) be filtered to the clindamycin phosphate medicinal liquid in the sterilizing room, be sub-packed in the cillin bottle false add plug;
4) vacuum lyophilization:
A, pre-freeze: the step is gathered 3) divide the clindamycin phosphate medicinal liquid install to put in the freeze dryer, reduce products temperature rapidly, when products temperature hangs down in 45 ℃ of –, continue the clindamycin phosphate medicinal liquid to be freezed fully in freezing 60 minutes;
B, rear cabinet refrigeration: utilize compressor to rear cabinet cold-trap refrigeration, make 70 ℃ of rear cabinet condenser temperature Di Yu –;
C, evacuation: the open vacuum pump is evacuated to preceding case vacuum below the 10Pa;
D, dry at a high speed: rapidly the conduction oil temperature is risen to 50 ℃, begin to heat up at a high speed sublimation drying;
E, at the uniform velocity dry: as products temperature Da during, rapidly the conduction oil temperature is reduced to 20 ℃, and keep this temperature sublimation drying that at the uniform velocity heats up Dao 16 ℃ of –; When products temperature reaches 15 ℃, and in closing after the case vacuum does not have significant change before the valve, tamponade; Outlet; With plastic-aluminum composite cover tying, packing promptly gets product after quality inspection is qualified.
5. clindamycin phosphate for injection preparation of compositions method according to claim 4 is characterized in that wherein the part by weight of clindamycin phosphate and sodium hydroxide is 24～26:1.
6. clindamycin phosphate for injection preparation of compositions method according to claim 5 is characterized in that wherein the part by weight of clindamycin phosphate and sodium hydroxide is 25:1.
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| CN104666253B (en) * | 2015-03-23 | 2018-04-20 | 山东北大高科华泰制药有限公司 | Clindamycin phosphate powder for injection pharmaceutical composition and preparation method |
| US20220133754A1 (en) * | 2018-08-03 | 2022-05-05 | Sinotherapeutics Inc. | Method for hydrating lyophilized cyclophosphamide composition and product thereof |
| CN110327361A (en) * | 2019-08-11 | 2019-10-15 | 天津乾丰瑞科技有限公司 | A kind of pharmaceutical composition of clindamycin phosphate and preparation method thereof |
| CN111000803A (en) * | 2019-12-03 | 2020-04-14 | 珠海亿邦制药有限责任公司 | Preparation process of clindamycin phosphate pharmaceutical composition for injection |
| CN113081975B (en) * | 2021-04-13 | 2022-11-29 | 海南锦瑞制药有限公司 | Preparation method of clindamycin phosphate freeze-dried powder injection for injection |
| CN115581675B (en) * | 2022-11-02 | 2024-04-16 | 海南锦瑞制药有限公司 | Preparation method of clindamycin phosphate for injection |
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