CN100560062C - A kind of clindamycin phosphate freeze-dried powder needle and preparation method thereof - Google Patents
A kind of clindamycin phosphate freeze-dried powder needle and preparation method thereof Download PDFInfo
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Abstract
The object of the present invention is to provide a kind of clindamycin phosphate freeze-dried powder needle, got 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.Its prescription is simple, and adjuvant has seldom overcome because of adjuvant adds the side effect that too much brings, and the patient uses safer.
Description
Technical field
The present invention relates to clindamycin phosphate for injection and preparation method thereof, belong to field of pharmaceutical preparations.
Background technology
Clindamycin phosphate, English Clindamycin phosphate by name, chemical formula is 6-(1-methyl-4-propyl group-2-pyrrolidine phosphinylidyne amide groups)-1-1 sulfo--methyl-7-chloro-6,7,8-three deoxidations-L-Su Shi-α-D-galactose pyranoside-2-dihydrogen phosphoric acid ester, structural formula is:
Clindamycin phosphate is chemical semisynthetic clindamycin derivant, it is in external no antibiotic activity, entering body is hydrolyzed to clindamycin rapidly and shows its pharmacologically active, so antimicrobial spectrum, antibacterial activity and therapeutic effect are identical with clindamycin, but its ester dissolubility and permeability are better than crin mycin, but can oral also intramuscular injection and intravenous drip administration.Compare its antibacterial action with lincomycin strong 4～8 times, good absorbing, and bone concentration height, and anaerobic infection had good curative effect.Mainly gram-positive cocci and anaerobe there is very strong antibacterial activity, comprise: gram-positive cocci: staphylococcus aureus, staphylococcus epidermidis, streptococcus (except the phosphorus streptococcus), streptococcus pneumoniae, Micrococcus etc., anaerobe, Clostridium, Bacteroides, bacillus fusiformis genus, propionibacterium, Eubacterium, anaerobic cocci etc.
Clindamycin phosphate is to heat-labile medicine, shows that after deliberation this product can produce degraded for 60 ℃, 80 ℃ following 30 minutes related substance (impurity) can reach 5%-6%, 100 ℃ can reach 8%-10% in 30 minutes.Tradition clindamycin phosphate injection production technology adopts 115 ℃, 30 minutes final sterilizations, and related substance (impurity) can surpass 10%, has increased the probability of untoward reaction greatly.
In order to address this problem, there has been research this to be done many work.Application number is the Chinese patent of CN200610134458, a kind of preparation process of clindamycin phosphate injection is provided, it is characterized in that: at air purity is under the hundred grades of conditions in full chamber, earlier a certain amount of clindamycin phosphate raw material is dissolved in water for injection, clindamycin phosphate and proper amount of sodium hydroxide alternately drop into, keep pH value between 6.0～6.4, stir, be settled to the concentration of liquid medicine injection with water for injection, the needle-use activated carbon that adds 0.05% in the medicinal liquid was adsorbed 10～20 minutes, then with 0.45 μ m microporous filter membrane or the filter cartridge coarse filtration of 0.45 μ m filter element is housed, with 0.22 μ m microporous filter membrane or filter cartridge fine straining degerming that 0.22 μ m filter element is housed, filling and sealing promptly gets this finished product injection under hundred grades of conditions again.But this technology is hydro-acupuncture preparation, and its related substances is 2.7-3.0%, and it according to the freeze-dried powder that conventional freeze-dry process is made, poor, the shortcoming such as become turbid of solubility occurred.
Application number is the Chinese patent of CN01133218, a kind of clindamycin phosphate powder and preparation method thereof is provided, this injectable powder contains clindamycin phosphate 77-97.3%, it is characterized in that it also contains the surfactant that can make the rapidly-soluble effective dose of clindamycin phosphate, surfactant is poloxamer 188 or Tween 80, but there is side effect in surfactant to human body, the ubiquity haemolysis, and the toxicity that is used for intravenously administrable is bigger.As the Tweens nonionic surfactant cardiovascular system there is tangible influence.Zoopery shows: tween 80 energy decreased heart rate, bring high blood pressure down, and concentration can make coronary flow increase by 3 times when 0.1g/ml, and is also stronger than persantin (Coronary Vasodilators) and sorbide nitrate (sorbitrate) with dosage.Its interaction property is similar with papaverine, promptly directly acts on vascular smooth muscle.In addition, the tween 80 of variable concentrations has certain influence to erythrocyte membrane stability.When concentration 0.012% the time, can make the erythrocyte dissolving of all breaking.Also the report that brings out anaphylaxis, promotes growth of cancer cells and diffusion is arranged relevant for Tweens.
Application number is the Chinese patent of CN200410057318, a kind of preparation method of clindamycin phosphate powder is provided, it is characterized in that this method may further comprise the steps: (1) gets the clindamycin phosphate of recipe quantity, add 5-8 and doubly measure the alcoholic solution that concentration is 70-90%, be stirred to dissolving; (2) amount of pressing the 0.01-0.08%g/v of clindamycin phosphate alcoholic solution adds activated carbon decolorizing, after 20-50 minute, with diatomaceous earth filter or titanium filter coarse filtration, coarse filtration liquid; (3) with above-mentioned coarse filtration liquid under gnotobasis, with the filter membrane fine straining of 0.15-0.45 μ m, fine straining liquid; (4) above-mentioned fine straining liquid is placed crystallize, cross with filter cloth and filter to remove supernatant, get the clindamycin phosphate crystalline solid; (5) again by (1) method to (4) step, that the clindamycin phosphate crystalline solid that (4) step is obtained carries out changeing the second time again is molten, recrystallization once, cross with filter cloth and to filter to remove the clindamycin phosphate crystalline solid that supernatant gets recrystallization; (6) the clindamycin phosphate crystalline solid is dried under 60-80 ℃ of condition for the second time, pulverizes, and in gnotobasis (local 100 grades) packing down, becomes 148.5-1426mg/ to prop up, and rolls lid, and packing promptly.But this technology is actually sterilization solvent crystallization powder pin, step is very loaded down with trivial details, and need dry under 60-80 ℃ of condition in the step (6), and the front mentioned 60 ℃ of clindamycin phosphates and can produce degraded, must cause related substance (impurity) to increase like this.
Therefore, be necessary to provide a kind of simple, few side effects of filling a prescription, solubility is good, stability is high clindamycin phosphate freeze-dried powder needle.
Summary of the invention
The object of the present invention is to provide a kind of clindamycin phosphate freeze-dried powder needle, its prescription is simple, and adjuvant has seldom overcome because of adjuvant adds the side effect that too much brings, and the patient uses safer.
Another object of the present invention is to provide the preparation method of above-mentioned clindamycin phosphate freeze-dried powder needle, the preparation outward appearance that makes is full, and solubility is good, has better stability.
Briefly, a kind of clindamycin phosphate freeze-dried powder needle provided by the invention, for being got by lyophilizing after adding NaOH in the clindamycin phosphate topical solution, wherein the weight ratio of clindamycin phosphate: NaOH is 12～18: 1, preferred 16.5: 1.
Wherein, the consumption of described clindamycin phosphate is 150～200mg/mL water for injection, preferred 185mg/mL water for injection.
Described NaOH consumption is 10～15mg/mL water for injection, preferred 11.2mg/mL water for injection.
The concentration of preferred described NaOH is 2mol/L.
The specification of preferred described clindamycin phosphate freeze-dried powder needle is 300mg/ bottle or 600mg/ bottle, in clindamycin.
The present invention also provides the preparation method of above-mentioned clindamycin phosphate freeze-dried powder needle, comprise: at air purity is 100000 grades, under local 100 grades the condition, the water for injection that clindamycin phosphate is added 60% dosing amount, water for injection must be cooled to below 20 ℃ in advance, slowly add recipe quantity 2mol/l sodium hydroxide solution while stirring, it is dissolved fully, the pH that makes solution is between 6.10～6.30, the medicinal carbon that adds 0.03%g/mL, stirring and adsorbing 30 minutes, through 0.45 μ m filtering with microporous membrane carbon removal, filtrate adds to the full amount of water for injection, fully stir and made the solution mix homogeneously in 20 minutes, the solution for preparing carries out the end-filtration degerming through the microporous filter membrane of 0.22 μ m, gets filtrate; Filtrate is encased in the injection bottle, and frozen drying obtains freeze-dried powder;
Wherein said frozen drying process is:
(1) freezing period
The injection bottle that filtrate is housed is put into material disc in time put on the dividing plate of freeze drying box pre-freeze: temperature is-45 ℃, and the time is 4 hours;
(2) the distillation phase
After medicine freezes, the temperature of condenser is controlled at below-45 ℃, to the whole system evacuation, vacuum is lower than 15pa, and temperature slowly was warming up to-2～5 ℃ in 8～12 hours, be incubated 8 hours;
(3) dry period
Control temperature and vacuum rise to 25 ℃ with temperature, are incubated 7 hours, promptly get clindamycin phosphate freeze-dried powder needle.
Wherein, preferred described freezing period process be-10 ℃ for medicinal liquid is cooled to eutectic point earlier from room temperature, stop temperature-fall period, make temperature autobalance in the medicinal liquid, eliminate the thermograde in it; Then medicinal liquid is put into the freeze drying box that is cooled to-45 ℃, freezing 4 hours.
Also preferably suitably mix gas, vacuum values is fluctuateed in 10-20Pa in the distillation phase.
It below is detailed description of the present invention.
At first from the screening of prescription, in the selection of adjuvant, the inventor follows and can prepare on the basis of stable and controllable for quality, the product that meets clinical needs the few more good more principle of the kind of adjuvant, consumption; This is because supplementary product kind is few more, can simplify batching step greatly when meaning production technology; The side effect that is difficult to expect that simultaneously can avoid various adjuvants to bring.Therefore, final decision of the present invention is except transferring pH with the dissolubility that increases clindamycin phosphate with NaOH, need not any adjuvant, and to reduce side effect as much as possible.
In order to obtain the freeze-dried powder of excellent quality, need before the lyophilizing clindamycin phosphate is dissolved in the water for injection with suitable concentration, the consumption of clindamycin phosphate is 150～200mg/mL water for injection, preferred 185mg/mL water for injection.And then transfer pH with NaOH, and the NaOH consumption is 10～15mg/mL water for injection, preferred 11.2mg/mL water for injection, and the concentration of NaOH is preferably 2mol/L.The weight ratio of clindamycin phosphate and NaOH is 12～18: 1 like this, preferred 16.5: 1.The specification of the clindamycin phosphate freeze-dried powder needle that obtains is preferably 300mg/ bottle or 600mg/ bottle, in clindamycin.
Because the used adjuvant of this product is simple; Must carry out all improvement from the lyophilizing of preparing burden to technology, just can produce qualified products.To this, the inventor has paid all effort, obtains following technology finally:
Be under 100000 grades, local 100 grades the condition at air purity, the water for injection that clindamycin phosphate is added 60% dosing amount, water for injection must be cooled to below 20 ℃ in advance, slowly add recipe quantity 2mol/l sodium hydroxide solution while stirring, it is dissolved fully, and the pH that makes solution is between 6.10～6.30, and this is because in this pH scope, the related substances of final products (being impurity) content is minimum, and the result can be referring to experimental example 1.
The medicinal carbon that adds 0.03%g/mL then, stirring and adsorbing 30 minutes, at this, the selection of activated carbon concentration is most important, and the effect of activated carbon is to adsorb pyrogen in the supplementary material, impurity etc., improve the purity and the yield rate of product, but consumption is excessive, can adsorb principal agent drug content is reduced, and consumption is very few, impurity content is too high in the final products, and the clarity of final products is defective.The screening experiment of activated carbon is seen experimental example 2, and finally selecting concentration is 0.03% activated carbon.
Through 0.45 μ m filtering with microporous membrane carbon removal, filtrate adds to the full amount of water for injection, and fully stirs and makes the solution mix homogeneously in 20 minutes, and the solution for preparing carries out the end-filtration degerming through the microporous filter membrane of 0.22 μ m, gets filtrate with the pyrogen of thoroughly removing in the powder pin; Filtrate is fed through in the basin standby through pipeline, quality inspection personnel extracts solution, carries out clarity, content, pH value, bacterial endotoxin mensuration, inserts detecting qualified solution, adjust loading amount and false add plug quality by detecting intermediate amounts, fill is in low Pyrex control injection bottle respectively.Frozen drying obtains finished product then.Lyophilization is the freeze-dried powder key of success, has directly influenced the various performances of product; The present invention has done significant improvement to Freeze Drying Technique just, just makes the so simple clindamycin phosphate freeze-dried powder needle agent of adjuvant be able to success.
In brief, freezing dry process of the present invention also is divided into three processes: pre-freeze, distillation and drying are the detailed process process below:
(1), pre-freeze is freezing period
The injection bottle that filtrate is housed is put into material disc in time put on the dividing plate of freeze drying box pre-freeze: temperature is-45 ℃, and the time is 4 hours;
The purpose of pre-freeze is for fixed product, so that distil under vacuum.If do not freeze reality, then product can emit bottle outlet external during evacuation, causes the spray bottle, does not have certain shape; If temperature is low excessively, then wasted the energy and time, in addition, the pre-freeze process has also determined the quality of the speed and the freeze-drying prods of dry run to a great extent.
Because the design cryogenic temperature of this product is-45 ℃, and why freeze drying box will be cooled in advance-45 ℃, is in order to strengthen the temperature difference of medicine and freeze dryer median septum.In practical operation, the medicine of bottling is mainly finished exchange heat with the freeze dryer median septum.Baffle temperature is low, and the temperature difference of medicine and freeze dryer median septum is big, and rate of temperature fall is fast more, and the degree of supercooling of solution and degree of supersaturation are bigger, and critical crystalline granularity is then little, and nucleation rate is fast more, can form the less thin ice crystal of the more size of granule easily.After these thin ice crystal distillations, the pore-size that forms in the material is less, though dry rate afterwards is low, it is good to do the back solubility.Otherwise, not cooling in advance, rate of temperature fall is slow, forms oarse-grained ice crystal, and the aqueous vapor discharge channel size that ice crystal distillation back forms is bigger, though help improving dry rate, it is poor to do the back solubility.
In the selection of time, because the pre-freeze temperature is lower, so the pre-freeze time is shorter, is 4 hours, and the screening of cooling time can be referring to experimental example 3 table 3-1.
The freeze drying box resulting product solubility of lowering the temperature in advance is good, and product appearance is also qualified substantially, but the slightly atrophy of product of minority bottle is arranged, and this is because the present invention is a freeze drying process that adopts bottle to freeze, and is heated and can not accomplishes fully evenly.In when cooling, the medicinal liquid in the bottle up and down two parts can to produce thermograde poor, in the propulsive from bottom to top process in ice interface, upwards migration of solute causes the solute of upper epidermis often more in the solution, density is higher, and bottom density is less down, short texture.Though because the design cryogenic temperature is lower, shortened crystallization time to a great extent, shortened the solute migration time equally, improved the atrophy situation that causes owing to density variation greatly, but in order to reach better effect, the present invention preferably adopts three-step approach pre-freeze, being about to medicinal liquid is cooled to eutectic point earlier from room temperature and is about-10 ℃, stop temperature-fall period, make temperature autobalance in the medicinal liquid, eliminate the thermograde in it; Then medicinal liquid is put into the freeze drying box that is cooled to-45 ℃, freezing 4 hours, can reduce like this in the bottle medicinal liquid up and down two parts can to produce thermograde poor, and it is supercool to make that easily medicinal liquid forms, when energy accumulation is enough, whole crystallizations of moment, prepared product solubility is splendid, and outward appearance is full, color even, hole densification, and is better than the outward appearance that adopts direct pre-freeze method product, clarity and stability.Can be referring to experimental example 3 table 3-2.
(2) the distillation phase
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,
The distillation phase can be removed the moisture about 90%.
The choice relation of sublimation temperature is to the speed of distillation, why select 0 ℃, rather than higher temperature, be because when distillation, the upper materials drying that will take the lead in, if it is too fast that its temperature rises, might reach the temperature of caving in (or being referred to as the disintegrate temperature), porous skeleton rigidity reduces, and coming off appears in the granule in the drying layer, can seal the micro channel of drying nest, stop the carrying out of distillation, rate of sublimation is slowed down, even make underclad portion atrophy slightly, influence the content of goods residual moisture, cause solubility, stability and clarity variation simultaneously.
In addition, temperature retention time is unsuitable long, this is because the small crystals that medicinal liquid quick freezing of the present invention produces has very high surface energy, when heating recrystallize might take place; mutually combining between the little ice crystal forms big ice crystal; make its surface to volume ratio reach minimum, and big ice crystal makes the dried frozen aquatic products outward appearance bad, solubility is poor.
Therefore, excessive temperature or after distillation for a long time or insulation all has adverse effect to the present invention, through a large amount of experiment screenings, can be referring to experimental example 4, and being elevated temperature is 0 ℃, temperature retention time is 20 hours.
Pressure during the distillation is preferably 10Pa, rather than lower, though this is because the low distillation that helps ice in the product of pressure, because pressure is unfavorable to conducting heat when too low, product is difficult for the acquisition heat, and rate of sublimation reduces on the contrary.But when pressure was too high, the rate of sublimation of ice slowed down in the product, and minimizing falls in the product caloric receptivity.So the temperature of product self rises, when being higher than temperature of eutectic point, product will melt, and cause the lyophilizing failure.Therefore, pressure is set at 10Pa, not only has been beneficial to the transmission of heat but also has been beneficial to the carrying out of distillation.
In addition, can also suitably mix gas, vacuum values is fluctuateed in 10-20Pa at sublimation stage, can shorten distillation phase time 2-3h, this is because it no longer is leading by conduction of heat that this way makes thermaltransmission mode, has also strengthened the mode of thermal convection current, has accelerated the speed that moisture is resolved.
(3) dry period
In case the ice distillation finishes in the product, can enter drying stage.Do not freeze ice though in this stage product, do not exist, also have the moisture content about 10% in the product, reach qualified remaining water content in order to make product, must be further dry to product.
Control temperature and vacuum rise to 25 ℃ with temperature, are incubated 8 hours, promptly get clindamycin phosphate freeze-dried powder needle.
Clindamycin freeze-dried powder of the present invention, prescription is simple, few side effects, and has taked advanced freeze drying process, and the product appearance that makes is full, and solubility is good, and is best in quality.
The specific embodiment
Embodiment 1
At air purity is 100000 grades, under local 100 grades the condition, the water for injection that 370.25 clindamycin phosphates (being equivalent to the 300g clindamycin) is added 1200ml, water for injection must be cooled to below 20 ℃ in advance, slowly add 2mol/l sodium hydroxide solution 280ml while stirring, it is dissolved fully, the pH that makes solution is between 6.10～6.30, the medicinal carbon that adds 0.03%g/mL, stirring and adsorbing 30 minutes, through 0.45 μ m filtering with microporous membrane carbon removal, filtrate adds the injection water to 2000mL, fully stirs and makes the solution mix homogeneously in 20 minutes, the solution for preparing carries out the end-filtration degerming through the microporous filter membrane of 0.22 μ m, gets filtrate; Filtrate is encased in 1000 bottles of injection bottles, and the injection bottle that filtrate is housed is put into material disc in time put on the dividing plate of freeze drying box 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, and control temperature and vacuum rise to 25 ℃ with temperature, are incubated 8 hours, promptly get clindamycin phosphate freeze-dried powder needle.
Embodiment 2
At air purity is 100000 grades, under local 100 grades the condition, the water for injection that 740.5 clindamycin phosphates (being equivalent to the 600g clindamycin) is added 2400ml, water for injection must be cooled to below 20 ℃ in advance, slowly add 2mol/l sodium hydroxide solution 560ml while stirring, it is dissolved fully, the pH that makes solution is between 6.10～6.30, the medicinal carbon that adds 0.03%g/mL, stirring and adsorbing 30 minutes, through 0.45 μ m filtering with microporous membrane carbon removal, filtrate adds the injection water to 4000mL, fully stirs and makes the solution mix homogeneously in 20 minutes, the solution for preparing carries out the end-filtration degerming through the microporous filter membrane of 0.22 μ m, gets filtrate; Filtrate is encased in the injection bottle, and the injection bottle that filtrate is housed is put into material disc in time put on the dividing plate of freeze drying box 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, and control temperature and vacuum rise to 25 ℃ with temperature, are incubated 8 hours, promptly get clindamycin phosphate freeze-dried powder needle.
Embodiment 3
At air purity is 100000 grades, under local 100 grades the condition, the water for injection that 300 clindamycin phosphates is added 1200ml, water for injection must be cooled to below 20 ℃ in advance, slowly add 2mol/l sodium hydroxide solution 250ml while stirring, it is dissolved fully, the pH that makes solution is between 6.10～6.30, the medicinal carbon that adds 0.03%g/mL, stirring and adsorbing 30 minutes, through 0.45 μ m filtering with microporous membrane carbon removal, filtrate adds the injection water to 2000mL, fully stirs and makes the solution mix homogeneously in 20 minutes, the solution for preparing carries out the end-filtration degerming through the microporous filter membrane of 0.22 μ m, gets filtrate; Filtrate is encased in 1000 bottles of injection bottles, and the injection bottle that filtrate is housed is put into material disc in time put on the dividing plate of freeze drying box 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, and control temperature and vacuum rise to 25 ℃ with temperature, are incubated 8 hours, promptly get clindamycin phosphate freeze-dried powder needle.
Embodiment 4
At air purity is 100000 grades, under local 100 grades the condition, the water for injection that 400 clindamycin phosphates is added 1200ml, water for injection must be cooled to below 20 ℃ in advance, slowly add 2mol/l sodium hydroxide solution 375ml while stirring, it is dissolved fully, the pH that makes solution is between 6.10～6.30, the medicinal carbon that adds 0.03%g/mL, stirring and adsorbing 30 minutes, through 0.45 μ m filtering with microporous membrane carbon removal, filtrate adds the injection water to 2000mL, fully stirs and makes the solution mix homogeneously in 20 minutes, the solution for preparing carries out the end-filtration degerming through the microporous filter membrane of 0.22 μ m, gets filtrate; Filtrate is encased in 1000 bottles of injection bottles, and the injection bottle that filtrate is housed is put into material disc in time put on the dividing plate of freeze drying box 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, and control temperature and vacuum rise to 25 ℃ with temperature, are incubated 8 hours, promptly get clindamycin phosphate freeze-dried powder needle.
Embodiment 5
Other process is with embodiment 1.
Freezing period,, process was about-3 ℃ for medicinal liquid is cooled to eutectic point earlier from room temperature, stopped temperature-fall period, made temperature autobalance in the medicinal liquid, eliminated the thermograde in it; Then medicinal liquid is put into oneself and be cooled to-45 ℃ freeze drying box, freezing 4 hours.
Embodiment 6
Other process is with embodiment 2.
Freezing period,, process was about-3 ℃ for medicinal liquid is cooled to eutectic point earlier from room temperature, stopped temperature-fall period, made temperature autobalance in the medicinal liquid, eliminated the thermograde in it; Then medicinal liquid is put into the freeze drying box that is cooled to-45 ℃, freezing 4 hours.
The distillation phase is suitably mixed gas, and vacuum values is fluctuateed in 10-20Pa, can shorten 3h drying time.
Experimental example 1
This experimental example is the screening experiment example of pH in the freeze-dried powder preparation process, other component technological parameter is all with embodiment 1, regulate pH with NaOH solution and divide and be clipped to 9.0,9.5,10,11,11.5 in preparation process, the assay method of pH is seen two ones of Chinese Pharmacopoeia versions in 2000.
The test of table 1pH value scope
As seen, pH its related substances when 6.1-6.3 is minimum.
Experimental example 2
This experimental example is the screening experiment of activated carbon concentration.Other component technological parameter selects for use the injection active carbon of variable concentrations to adsorb respectively all with embodiment 1, serves as to investigate index with clindamycin phosphate content, clarity, the consumption of screening active carbon.Two clarity inspection techniques of Chinese Pharmacopoeia version in 2000 are adopted in the inspection of clarity, the results are shown in Table 3:
Table 2 activated carbon dosage screening test
By drawing in the table, 0.03% active carbon can make the clarity of lyophilizing liquid qualified, and is less to principal agent absorption, and pollutes minimumly, is that the active carbon of 0.03% (g/ml) adsorbs so select concentration for use.
Experimental example 3
This experimental example is the screening experiment of pre-freeze time and pre-freeze mode.
Other parameter is with embodiment 2.
Table 3-1
Table 3-2
Experimental example 4
This experimental example is the screening experiment of sublimation temperature and time.
Other parameter is with embodiment 4
Table 4
Experimental example 6:
This experimental example is the stability test of product of the present invention.
At 40 ℃ ± 2 ℃, placed 12 months by relative humidity 75% ± 5% through temperature for the clindamycin freeze-dried powder of embodiment 1-6, and accelerated test shows that significant change does not all take place for its character, basicity, clarity, related substance and content; Clindamycin phosphate freeze-dried powder needle is through 25 ℃ ± 2 ℃, relative humidity 60% ± 10% is placed test in 12 months and is investigated, the result shows that significant change does not all take place for its character, basicity, clarity, related substance and content, and clindamycin phosphate sodium freeze-drying powder stable in properties is described.
And the clindamycin phosphate freeze-dried powder needle that makes according to each embodiment of Chinese patent application CN01133218 and CN200410057318 respectively, according to above-mentioned processing after 6 months, though its outward appearance is still full, but the clarity experiment becomes muddy, the survey its related substances rises, and illustrates that its stability also need improve.
Claims (11)
1, a kind of clindamycin phosphate freeze-dried powder needle, it is characterized in that, 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, the preparation method of described clindamycin phosphoric acid freeze-dried powder comprises: at air purity is 100000 grades, under local 100 grades the condition, the water for injection that clindamycin phosphate is added 60% dosing amount, water for injection must be cooled to below 20 ℃ in advance, slowly add recipe quantity 2mol/l sodium hydroxide solution while stirring, it is dissolved fully, the pH that makes solution is between 6.10～6.30, the medicinal carbon that adds 0.03%g/mL, stirring and adsorbing 30 minutes, through 0.45 μ m filtering with microporous membrane carbon removal, filtrate adds to the full amount of water for injection, and fully stirs and makes the solution mix homogeneously in 20 minutes, the solution for preparing carries out the end-filtration degerming through the microporous filter membrane of 0.22 μ m, gets filtrate; Filtrate is encased in the injection bottle, and frozen drying obtains freeze-dried powder;
Wherein said frozen drying process is:
(1) freezing period
The injection bottle that filtrate is housed is put into material disc in time put on the dividing plate of freeze drying box pre-freeze: temperature is-45 ℃, and the time is 4 hours;
(2) the distillation phase
After medicine freezes, the temperature of condenser is controlled at below-45 ℃, to the whole system evacuation, vacuum is lower than 15pa, and temperature slowly was warming up to-2～5 ℃ in 8～12 hours, be incubated 8 hours;
(3) dry period
Control temperature and vacuum rise to 25 ℃ with temperature, are incubated 7 hours, promptly get clindamycin phosphate freeze-dried powder needle.
2, clindamycin phosphate freeze-dried powder needle according to claim 1 is characterized in that, wherein clindamycin phosphate: the weight ratio of NaOH is 16.5: 1.
3, clindamycin phosphate freeze-dried powder needle according to claim 1 is characterized in that, the consumption of described clindamycin phosphate is 150～200mg/mL water for injection.
4, clindamycin phosphate freeze-dried powder needle according to claim 3 is characterized in that, the consumption of described clindamycin phosphate is a 185mg/mL water for injection.
5, clindamycin phosphate freeze-dried powder needle according to claim 1 is characterized in that, described NaOH consumption is 10～15mg/mL water for injection.
6, clindamycin phosphate freeze-dried powder needle according to claim 5 is characterized in that, described NaOH consumption is a 11.2mg/mL water for injection.
7, clindamycin phosphate freeze-dried powder needle according to claim 1 is characterized in that, the concentration of described NaOH is 2mol/L.
8, according to any described clindamycin phosphate freeze-dried powder needle among the claim 1-7, it is characterized in that the specification of described clindamycin phosphate freeze-dried powder needle is 300mg/ bottle or 600mg/ bottle, in clindamycin.
9, the preparation method of any described clindamycin phosphate freeze-dried powder needle among the claim 1-9, it is characterized in that, comprise: at air purity is 100000 grades, under local 100 grades the condition, the water for injection that clindamycin phosphate is added 60% dosing amount, water for injection must be cooled to below 20 ℃ in advance, slowly add recipe quantity 2mol/l sodium hydroxide solution while stirring, it is dissolved fully, the pH that makes solution is between 6.10～6.30, the medicinal carbon that adds 0.03%g/mL, stirring and adsorbing 30 minutes, through 0.45 μ m filtering with microporous membrane carbon removal, filtrate adds to the full amount of water for injection, and fully stirs and makes the solution mix homogeneously in 20 minutes, the solution for preparing carries out the end-filtration degerming through the microporous filter membrane of 0.22 μ m, gets filtrate; Filtrate is encased in the injection bottle, and frozen drying obtains freeze-dried powder;
Wherein said frozen drying process is:
(1) freezing period
The injection bottle that filtrate is housed is put into material disc in time put on the dividing plate of freeze drying box pre-freeze: temperature is-45 ℃, and the time is 4 hours;
(2) the distillation phase
After medicine freezes, the temperature of condenser is controlled at below-45 ℃, to the whole system evacuation, vacuum is lower than 15pa, and temperature slowly was warming up to-2～5 ℃ in 8～12 hours, be incubated 8 hours;
(3) dry period
Control temperature and vacuum rise to 25 ℃ with temperature, are incubated 7 hours, promptly get clindamycin phosphate freeze-dried powder needle.
10, preparation method according to claim 9 is characterized in that, described freezing period process be-10 ℃ for medicinal liquid is cooled to eutectic point earlier from room temperature, stop temperature-fall period, make temperature autobalance in the medicinal liquid, eliminate the thermograde in it; Then medicinal liquid is put into the freeze drying box that is cooled to-45 ℃, freezing 4 hours.
11, according to claim 9 or 10 described preparation methoies, it is characterized in that, suitably mix gas, vacuum values is fluctuateed in 10-20Pa in the distillation phase.
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Families Citing this family (11)
| Publication number | Priority date | Publication date | Assignee | Title |
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| CN101569589B (en) * | 2009-06-05 | 2013-06-12 | 辰欣药业股份有限公司 | Clindamycin phosphate for injection and preparation method thereof |
| CN101829060B (en) * | 2010-04-30 | 2011-12-28 | 湖北荷普药业有限公司 | Preparation method of clindamycin phosphate powder for injection |
| CN102000036A (en) * | 2010-11-17 | 2011-04-06 | 商丘市康森动物药品研究所 | Lincomycin hydrochloride freeze-dried powder injection for livestock injection and preparation method thereof |
| CN102258488B (en) * | 2011-07-19 | 2012-10-31 | 江苏奥赛康药业股份有限公司 | Clindamycin phosphate composition for injection and preparation method thereof |
| CN102379853B (en) * | 2011-11-16 | 2013-01-16 | 海南锦瑞制药股份有限公司 | Vidarabine monophosphate freeze-dried powder injection and preparation method thereof |
| CN103142507B (en) * | 2011-12-07 | 2017-07-21 | 重庆药友制药有限责任公司 | A kind of clindamycin phosphate for injection preparation and preparation method thereof |
| CN102552180B (en) * | 2012-01-17 | 2013-08-14 | 山东罗欣药业股份有限公司 | Clindamycin phosphate composition liensinine freeze-dried powder and preparation method thereof |
| CN105213326A (en) * | 2014-05-30 | 2016-01-06 | 海南通用康力制药有限公司 | A kind of preparation method of clindamycin phosphate for injection lyophilized powder |
| CN106511283B (en) * | 2016-12-02 | 2019-09-24 | 苏州天马医药集团天吉生物制药有限公司 | A kind of lyophilized technique of clindamycin phosphate for injection |
| CN112206212B (en) * | 2020-10-16 | 2023-04-28 | 海南锦瑞制药有限公司 | Preparation method of clindamycin phosphate 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 |
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