CN103340830B - Nano ganciclovir freeze-drying preparation for injection and preparation method thereof - Google Patents
Nano ganciclovir freeze-drying preparation for injection and preparation method thereof Download PDFInfo
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Abstract
The invention discloses a nano ganciclovir freeze-drying preparation for injection and a preparation method thereof. The nano ganciclovir freeze-drying preparation for injection comprises the following components in parts by weight: 100-400 parts of ganciclovir, 10-50 parts of dextran 40, 5-50 parts of solubilizer, 10-100 parts of nano carrier material and 10-80 parts of freeze-drying skeleton agent. The preparation method comprises the following steps of: sequentially adding dextran 40, solubilizer, ganciclovir, nano carrier material and freeze-drying skeleton agent into water for injection to be dissolved, filtering a solution step by step, and carrying out freeze-drying, thus a freeze-drying preparation is obtained. According to the preparation method, no activated carbon is introduced, thus a risk that damage is done to a human body when activated carbon particles are introduced into the preparation as the activated carbon is used is avoided; besides, pH of the nano ganciclovir freeze-drying preparation for injection is 6-8 and close to that of plasma, and local irritation produced to the human body owning to overhigh alkalinity is avoided.
Description
Technical field
The present invention relates to a kind of ganciclovir for injection nanocapsule lyophilized formulations and preparation method thereof.
Background technology
Ganciclovir (GCV), chemical name is 9-(1,3-dihydroxy-2-propoxyl group)-guanine, it is guanosint glycoside derivates, it is a kind of wide spectrum anti-herpesvirus medicament, especially strong especially to the activity of human cytomegalic inclusion disease virus, become the choice drug that control giant cell infects at present.Its principle is turned to monophosphate GCV by the protein kinase of encoding viral (thymidine kinase, TK) phosphoric acid rapidly after GCV enters cell, and the effect then through cell kinase generates diphosphonic acid and triphosphoric acid GCV.Triphosphoric acid GCV suppresses virus replication by competitive inhibition viral DNA polymerase with these two kinds of modes of prolongation of mixing blocking virus DNA in viral DNA chain and plays its antivirus action.Ganciclovir is water insoluble, dissolves in sodium hydroxide solution, existing injection pH value about 12, belongs to strong basicity, comparatively large to the zest of vascular tissue, therefore prepares ganciclovir for injection nanocapsule lyophilized formulations and has important clinical meaning.
Summary of the invention
The object of this invention is to provide a kind of ganciclovir for injection nanocapsule lyophilized formulations that simultaneously can improve dissolubility and stability in water.
Ganciclovir for injection nanocapsule lyophilized formulations provided by the present invention, it comprises the following component with parts by weight: ganciclovir 100 ~ 400 parts, dextran 4010 ~ 50 parts, solubilizing agent 5 ~ 50 parts, nano carrier material 10 ~ 100 parts and lyophilizing skeleton agent 10 ~ 80 parts.
Described ganciclovir for injection nanocapsule lyophilized formulations, can comprise the following component with parts by weight further: ganciclovir 250 parts, dextran 4010 ~ 40 parts, solubilizing agent 30 ~ 40 parts, nano carrier material 60 ~ 80 parts and lyophilizing skeleton agent 30 ~ 80 parts.
In order to increase the stability of preparation, in described ganciclovir for injection nanocapsule lyophilized formulations, also antioxidant can be comprised.The weight portion of described antioxidant can be 1-5 part.
Certain described ganciclovir for injection nanocapsule lyophilized formulations, also can only be made up of the following component with parts by weight: ganciclovir 250 parts, dextran 4010 ~ 40 parts, solubilizing agent 30 ~ 40 parts, nano carrier material 60 ~ 80 parts, lyophilizing skeleton agent 30 ~ 80 parts, antioxidant 1-5 part.
In the present invention, described solubilizing agent is selected from least one in PVP K30,30 POVIDONE K 30 BP/USP 15, cyclodextrin, cyclodextrin derivative (as HP-β-CD), poly yamanashi esters (as tween 80), spans (as Arlacel-80), poloxamer class (as PLURONICS F87), preferred HP-β-CD.
In the present invention, described nano carrier material is selected from copolymer, poly butyric ester, at least one of gathering in hydroxyl valerate, Merlon, polyethylene glycol-polylactic acid block copolymer, poly glycol monomethyl ether-polylactide di-block copolymer of polylactic acid, PGA, Acetic acid, hydroxy-, bimol. cyclic ester and lactide, preferred polyethylene glycol-polylactic acid block copolymer.The number-average molecular weight of above-mentioned polymer can be 600 ~ 2000.
In the present invention, the agent of described lyophilizing skeleton is selected from least one in mannitol, lactose, glucose, sorbitol, sodium chloride, glycine, preferred mannitol.
In the present invention, described antioxidant is selected from least one in sodium sulfite, sodium pyrosulfite, sodium thiosulfate, sodium sulfite, preferred sodium sulfite.
Present invention also offers the method preparing above-mentioned ganciclovir for injection nanocapsule lyophilized formulations.
The method preparing ganciclovir for injection nanocapsule lyophilized formulations provided by the present invention, comprises the following steps:
In Agitation Tank, add appropriate water for injection (temperature 50 ~ 60 DEG C), take the Dextran 40 of recipe quantity, solubilizing agent, antioxidant add in Agitation Tank, be stirred to dissolving; The ganciclovir taking recipe quantity adds in above-mentioned medicinal liquid, is stirred to dissolving; Under agitation add the nano carrier material of recipe quantity, continue stirring 3 ~ 5 little of evenly; Add the lyophilizing skeleton agent of recipe quantity again, stir and make it dissolve, obtain solution I, then filtered by solution I, add water for injection, the concentration making ganciclovir in solution I is 0.040 ~ 0.085g/ml, obtains the nanocapsule solution II of ganciclovir; Institute join solution II content qualified after, be divided in 10ml cillin bottle, partly jump a queue, obtain lyophilized formulations through lyophilization.
In said process, before described filtration, the temperature of described solution I can be comprised to be down to be more than or equal to the step that 40 DEG C are less than or equal to 45 DEG C.Usually the injection water yield added for the first time is 80% of total injection water yield.
In said process, the method for described filtration can comprise the steps: described solution I to carry out 0.22 μm of bore filter, obtains filtrate a; Filtrate a being carried out molecular cut off is again 10000 daltonian ultrafiltration, obtains filtrate b; Filtrate b is carried out 0.22 μm of bore filter, obtain filtrate c, mend and inject water to prescription full dose, obtain the nanocapsule solution II of ganciclovir.
In said process, described lyophilization comprises following steps; 1. pre-freeze: point medicinal liquid installed is placed in-40 DEG C of pre-freezes 5 ~ 8 hours; 2. temperature is down to-45 DEG C, is evacuated to below 15Pa; 3. distil: intensification heating 15 ~ 20 is little of-20 DEG C, is incubated 10 ~ 18 hours, to substantially dry; Be warming up to-10 DEG C, be incubated 2 ~ 3 hours; Be warming up to 0 DEG C of insulation 2 ~ 3 hours; Be warming up to 10 DEG C, be incubated 2 ~ 3 hours; Be warming up to 20 DEG C, be incubated 1 ~ 2 hour; Be warming up to 25 DEG C, be incubated 1 ~ 2 hour; Be warming up to 40 DEG C, be incubated 7 hours; 3. continue evacuation 2 ~ 4 hours, tamponade, obtains lyophilized formulations.
Compared with prior art, advantage of the present invention is:
1. the pH value of this preparation is 6 ~ 8, similar to blood plasma pH value, avoid the local excitation side effect that blood vessel irritation after the input human body that existing ganciclovir injection causes because of strong basicity is larger, improve human tolerance, increase therapeutical effect, and can be used for intramuscular injection.Its process for preparation does not need adjust ph, facilitates production control.
2. the present invention selects HP-β-CD as solubilizing agent.In common ganciclovir preparation technology, general solubilizing agent cannot make ganciclovir completely soluble in water, is according to regulating pH to reach the object of dissolving ganciclovir substantially, but in redissolution process, does not often reach the requirement of injection clarity.The present invention selects the medicine of HP-β-CD enclose just to solve the drawback of this respect, and not only dissolution velocity is fast, and can increase the absorption of organism to medicine, is conducive to improving bioavailability, eliminates blood vessel irritation.In addition, HP-β-CD is not substantially decomposed metabolism in human body, does not accumulate yet, and oral hydroxyl propyl-beta-cyclodextrin is the overwhelming majority excretes with feces, parenterai administration all excretes with urine substantially, can reduce the toxic and side effects of medicine to human body.
3. select polyethylene glycol-polylactic acid block as biodegradable nano carrier material.Polyethylene glycol-polylactic acid block copolymer is as biodegradable nano carrier material, in the process forming emulsion and polymerizing curable nanocapsule, namely medicine is wrapped in nanocapsule or is adsorbed in nanocapsule surface, substantially increase ganciclovir dissolubility in aqueous and stability, ensure that output and quality.Compare the ordinary preparation not adding nano carrier material, in like product under equal conditions, stability is better, and effectiveness is higher.In addition, by the carrier of biodegradable polyethylene glycol-polylactic acid block copolymer as nanocapsule, can be degraded faster in human body, relative to nondegradable nano carrier material, ganciclovir rate of releasing drug in vivo and effective rate of utilization are enhanced.Simultaneously, biodegradable nano carrier material is relative to the polylactic acid of monomer and Polyethylene Glycol, the hydrophilicity of polyethylene glycol-polylactic acid block copolymer improves greatly, ensure that the qualified of the long-term clarity of preparation, and the Release Performance of nanocapsule medicine is improved greatly.
4. by HP-β-CD and polyethylene glycol-polylactic acid block copolymer (PELA) with the use of time, substantially increase dissolubility and the stability of ganciclovir ejection preparation, especially the stability of solution state is more excellent, make ganciclovir can keep clarity eligible state for a long time, HP-β-CD is as solubilizing agent, the effect making nanocapsule maintenance compared with small particle diameter can be played, the long circulating that simultaneously can be used for nano-particle is modified, improve the drug loading of granule, and extra raising ganciclovir rate of releasing drug in vivo.
5. in technique, adopt cooling remove impurity fine straining method, first the temperature of solution is regulated below 45 DEG C, some macromolecular substances in ganciclovir or impurity are separated out by the reduction of temperature, use 0.22 μm of filter circulating filtration, remove the antibacterial and granule and insoluble impurities that exist in the macromolecular substances of precipitation, medicinal liquid, the remaining quantity of the antibacterial in medicinal liquid is reduced greatly, improves the stability of preparation.
6. in technique, adopt the ultrafilter membrane ultrafiltration of 10000 Dalton molecular weights, eliminate the macromolecular substances that may exist in endotoxin and raw material, improve the clarity of solution, reduce further the microbial contamination level of medicinal liquid before aseptic filtration, improve the sterility assurance level of preparation, thus reduce the incidence rate of the untoward reaction of ganciclovir lyophilized formulations, improve the safety of product.
7. preparation method of the present invention only need adopt conventional process equipment, just can scale, high efficiency production, constant product quality is a kind of method of preparation of industrialization ganciclovir preparation of uniqueness, low cost.
Detailed description of the invention
Below by specific embodiment, the present invention will be described, but the present invention is not limited thereto.
Experimental technique described in following embodiment, if no special instructions, is conventional method; Described reagent and material, if no special instructions, all can obtain from commercial channels.
The ganciclovir used in following embodiment is purchased from Hubei Ge Dianren good fortune pharmaceutcal corporation, Ltd, and its batch number is 100107201001.
Accelerated test in following embodiment: be carry out under acceleration conditions, its objective is the chemistry by accelerating medicine or physical change, inquires into the stability of medicine, for formulation design, packaging, transport, storage provide necessary data.Test sample has three batches, places 6 months under the condition of temperature 40 DEG C ± 2 DEG C, relative humidity 75% ± 5%, detects respectively at sampling in 1,2,3,6 month.
Long term test in following embodiment: be carry out under close to the actual storage requirement of medicine, its objective is that the effect duration for formulating medicine provides foundation.Test sample has three batches, places 24 months under the condition of temperature 25 ± 2 DEG C, relative humidity 60% ± 10%, detects respectively at sampling in 0,3,6,9,12,18,24 month.
Embodiment 1:
One, the preparation (3000ml amount) of ganciclovir for injection nanocapsule lyophilized formulations
Prescription: ganciclovir 250g, Dextran 40 10g, HP-β-CD 30g, polyethylene glycol-polylactic acid block copolymer (number-average molecular weight 1000) 60g, mannitol 30g, sodium sulfite 1g, water for injection is settled to 3000ml.
Preparation method:
(1) prepare: after processing dosing container tool used, pipeline, clean with water for injection; Cillin bottle, plug clean according to a conventional method, sterilizing, dry for standby.
(2) dosing: the water for injection (2400ml) (temperature 50 ~ 60 DEG C) adding recipe quantity 80% in Agitation Tank, first takes the Dextran 40 of recipe quantity, solubilizing agent, sodium sulfite adds in Agitation Tank, be stirred to dissolving; Take the ganciclovir of recipe quantity, add in above-mentioned medicinal liquid, be stirred to dissolving; Under agitation add the polyethylene glycol-polylactic acid block copolymer (number-average molecular weight 600) of recipe quantity, continue stirring 4 little of evenly; Add the mannitol of recipe quantity again, stir and make it dissolve, obtain solution I.
(3) the temperature of solution I is down to 40 DEG C, then solution I 0.22 μm of aperture filter is filtered, obtain filtrate a.Be 10000 daltonian ultrafilter membrane ultrafiltration by filtrate a molecular cut off, obtain filtrate b.With water for injection, filtrate b is complemented to 3000ml, then filter with 0.22 μm of aperture filter, obtain filtrate c.
(4) following index test is carried out to filtrate c: ganciclovir content, medicinal liquid pH value, clarity and visible foreign matters.Be up to the standards, be sub-packed in by filtrate c in cillin bottle (10ml), every bottled amount is 3ml, partly jumps a queue.
(5) lyophilization: 1. pre-freeze: point medicinal liquid installed is placed in-40 DEG C of pre-freezes 5 hours; 2. temperature is down to-45 DEG C, is evacuated to below 15Pa; 3. distil: intensification heating 15 is little of-20 DEG C, is incubated about 12 hours, to substantially dry; Be warming up to-10 DEG C, be incubated 2 hours; Be warming up to 0 DEG C of insulation 2 hours; Be warming up to 10 DEG C, be incubated 2 hours; Be warming up to 20 DEG C, be incubated 1 hour; Be warming up to 25 DEG C, be incubated 1 hour; Be warming up to 40 DEG C, be incubated 7 hours; 3. continue evacuation 2 hours, tamponade, obtains lyophilized formulations.
(6) roll lid, packaging, inspection, warehouse-in.
Two, the detection of ganciclovir for injection nanocapsule lyophilized formulations
Get prepare according to method described in step one, different batches, preserve the ganciclovir for injection nanocapsule lyophilized formulations of different time and detect as follows.
1, the content of ganciclovir is detected
Detect in Acceleration study and long-term experiment, the ganciclovir content in the lyophilized formulations of different time points, carries out all as follows.
According to standard-required, in ganciclovir for injection nanocapsule lyophilized formulations, the content of ganciclovir should be 90.0% ~ 110.0%.
Get lyophilized formulations 5, respectively to wherein add mobile phase (mobile phase is methanol-water (volume ratio is 5:95)) dissolve and full dose be transferred in same measuring bottle, mixing, precision measures in right amount, the solution made about containing ganciclovir 40 μ g in every 1ml is quantitatively diluted, as need testing solution with mobile phase; Separately get ganciclovir reference substance to be about 25mg(and to be purchased from Nat'l Pharmaceutical & Biological Products Control Institute, lot number: 100380-201002), accurately weighed, put in 25ml measuring bottle, add 0.4% sodium hydroxide solution 1ml and make dissolving, add mobile phase and be diluted to scale, shake up, precision measures in right amount, adds mobile phase and makes the solution containing ganciclovir 40 μ g in every 1ml, solution in contrast.
Detect in the steps below:
Be filler with octadecylsilane chemically bonded silica; With methanol-water (5:95, v/v) for mobile phase; Determined wavelength is 252nm, and number of theoretical plate calculates by ganciclovir peak and is not less than 3000.Sample size 20 μ l, flow velocity 1.0ml/min, the retention time at main constituent peak is 9 ~ 11min.
Get above-mentioned test liquid and each 20 μ l of contrast liquid respectively, injection liquid chromatography, record chromatogram; By external standard method with calculated by peak area ganciclovir content, computing formula is as follows:
Labelled amount is 12.5mg/ml.
Experiment establishes 2 repetitions, results averaged, and as shown in Table 1 and Table 2, result shows testing result:
Concentration in the preparation of ganciclovir different time points in Acceleration study with long-term experiment is almost identical, and content, all more than 98%, meets the requirements; Show ganciclovir stable content in preparation of the present invention, not degraded.
2, the content of " related substance " in ganciclovir preparation is detected
The definition of " related substance ": other material in medicament except the adjuvant in ganciclovir and prescription.
Detection method: get ganciclovir for injection nanocapsule lyophilized formulations 1, adds mobile phase (mobile phase is methanol-water (5:95, v/v)) and dissolves and dilute the solution made containing 0.3mg in every 1ml, as need testing solution; Precision measures above-mentioned solution 1ml, puts in 100ml measuring bottle, adds as above-mentioned mobile phase is diluted to scale, shakes up, in contrast product solution.
Carry out chromatograph detection, liquid phase chromatogram condition is: be filler with octadecylsilane chemically bonded silica, and with methanol-water (5:95) for mobile phase, determined wavelength is 252nm; Sample size 20 μ l, flow velocity 1.0ml/min; Number of theoretical plate calculates by ganciclovir peak and is not less than 3000.
Get above-mentioned contrast solution 20 μ l, injection liquid chromatography, regulate detection sensitivity, make the peak height of main constituent chromatographic peak be 15% of full scale.Precision measures need testing solution and each 20 μ l of contrast solution, respectively injection liquid chromatography, and record chromatogram is to 2 times of main constituent peak retention time.If any impurity peaks in the chromatogram of need testing solution, each impurity peak area and the main peak area (1.0%) of contrast solution must not be greater than.
The computational methods of " related substance ":
2 repetitions are established in experiment, and result is taken the mean.Testing result as shown in Table 1 and Table 2.Result shows, " its related substances " in the ganciclovir preparation that the present invention obtains all is less than 0.2%, meets the requirement lower than 1.0%.
3, the content of " particulate matter " of ganciclovir preparation in the present invention is detected
" particulate matter " refers to the particulate contamination in injection.
Detection method: adopt light blockage method to measure.Get this product 5, with water, container outer wall is cleaned, dry, add 5ml microparticles water respectively, make contents melting, the careful solution (making cumulative volume be no less than 20ml) merged in container, test liquid is placed in sampling cup, sampling cup is placed on sampler, opens stirring and make dissolution homogeneity (avoiding bubble to produce), then detect.
4 repetitions are established in experiment, and data are disregarded for the first time, get the meansigma methods of subsequent measurements result, calculate the particle number contained by each sampling cup; Testing result as shown in Table 1 and Table 2.Result shows, the content conformance with standard requirement of " particulate matter " in the ganciclovir preparation that the present invention obtains.Standard-required is: the granule containing more than 10 μm and 10 μm in each test sample container must not cross 6000, must not cross 600 containing the microgranules of more than 25 μm and 25 μm.
4, " visible foreign matters " content of ganciclovir preparation in the present invention is detected
" visible foreign matters " refers to that in injection, visual that can observe, particle diameter or length are greater than the insoluble substance of 50 μm usually.
Detection method: get this product 5, clean container outer wall, add 3ml solvent respectively, after medicated powder is all dissolved, rotate gently and turnover bottle, the visible foreign matters existed in the medicinal liquid in bottle is suspended (noting not making medicinal liquid produce bubble), under bottle being placed in lamp inspection instrument black background, overturn gently under 1000 ~ 1500lx intensity of illumination, visual inspection is looked.
3 repetitions are established in experiment, and testing result as shown in Table 1 and Table 2.Result shows, does not detect visible foreign matters in the ganciclovir preparation that the present invention obtains.
To sum up analyze each index to show, in the ganciclovir preparation that the present invention obtains, the content of material such as the macromole of untoward reaction can be caused very low.
5, the pH value of ganciclovir preparation in the present invention is detected
PH value: refer to the numerical value representing solution acidic or degree of alkalinity.
Detection method: get this product 1, adds 3ml water for injection and dissolves, measure pH value with acidometer, should 6.0 ~ 8.0.
Testing result as shown in Table 1 and Table 2.Result shows, the pH value of the ganciclovir preparation that the present invention obtains is all between 6.0 ~ 8.0.
Embodiment 2:
One, the preparation (3000ml amount) of ganciclovir for injection nanocapsule lyophilized formulations
Prescription: ganciclovir 250g, Dextran 40 15g, HP-β-CD 40g, polyethylene glycol-polylactic acid block copolymer (number-average molecular weight 1000) 70g, mannitol 60g, sodium sulfite 3g, water for injection is settled to 3000ml.
Preparation method:
(1) prepare: after processing dosing container tool used, pipeline, clean with water for injection; Cillin bottle, plug clean according to a conventional method, sterilizing, dry for standby.
(2) dosing: the water for injection (2400ml) (temperature 50 ~ 60 DEG C) adding recipe quantity 80% in Agitation Tank, first takes the Dextran 40 of recipe quantity, solubilizing agent, sodium sulfite adds in Agitation Tank, be stirred to dissolving; Take the ganciclovir of recipe quantity, add in above-mentioned medicinal liquid, be stirred to dissolving; Under agitation add the polyethylene glycol-polylactic acid block copolymer of recipe quantity, continue stirring 4 little of evenly; Add the mannitol of recipe quantity again, stir and make it dissolve, obtain solution I.
(3) the temperature of solution I is down to 40 DEG C, then solution I 0.22 μm of aperture filter is filtered, obtain filtrate a.Be 10000 daltonian ultrafilter membrane ultrafiltration by filtrate a molecular cut off, obtain filtrate b.With water for injection, filtrate b is complemented to 3000ml, then filter with 0.22 μm of aperture filter, obtain filtrate c.
(4) following index test is carried out to filtrate c: ganciclovir content, medicinal liquid pH value, clarity and visible foreign matters.Be up to the standards, be sub-packed in by filtrate c in cillin bottle (10ml), every bottled amount is 3ml, partly jumps a queue.
(5) lyophilization: 1. pre-freeze: point medicinal liquid installed is placed in-40 DEG C of pre-freezes 8 hours; 2. temperature is down to-45 DEG C, is evacuated to below 15Pa; 3. distil: intensification heating 20 is little of-20 DEG C, is incubated about 12 hours, to substantially dry; Be warming up to-10 DEG C, be incubated 3 hours; Be warming up to 0 DEG C of insulation 3 hours; Be warming up to 10 DEG C, be incubated 3 hours; Be warming up to 20 DEG C, be incubated 2 hours; Be warming up to 25 DEG C, be incubated 2 hours; Be warming up to 40 DEG C, be incubated 7 hours; 3. continue evacuation 4 hours, tamponade, obtains lyophilized formulations.
(6) roll lid, packaging, inspection, warehouse-in.
Two, the detection of ganciclovir for injection nanocapsule lyophilized formulations
Get prepare according to method described in step one, different batches, preserve the ganciclovir for injection nanocapsule lyophilized formulations of different time and detect as follows.
1, the content of ganciclovir is detected
Detect in Acceleration study and long-term experiment, in the ganciclovir for injection nanocapsule lyophilized formulations of different time points, the content of ganciclovir, all carries out according to method described in embodiment 1.Labelled amount is 12.5mg/ml.
2 repetitions are established in experiment, and experiment establishes 2 repetitions, results averaged, and as shown in Table 1 and Table 2, result shows testing result:
Concentration in the preparation of ganciclovir different time points in Acceleration study with long-term experiment is almost identical, and content, all more than 98%, meets the requirements; Show ganciclovir stable content in preparation of the present invention, not degraded.
2, the content of " related substance " in ganciclovir preparation is detected
Detect in Acceleration study and long-term experiment, its related substances in the ganciclovir for injection nanocapsule lyophilized formulations of different time points, all carries out according to method described in embodiment 1.
2 repetitions are established in experiment, and result is taken the mean.Testing result as shown in Table 1 and Table 2.Result shows, " related substance " content in the ganciclovir preparation that the present invention obtains all is less than 0.2%, meets the requirement lower than 1.0%.
3, the content of " particulate matter " of ganciclovir preparation in the present invention is detected.
Detect in Acceleration study and long-term experiment, the content of the particulate matter in the ganciclovir for injection nanocapsule lyophilized formulations of different time points, all carries out according to method described in embodiment 1.
4 repetitions are established in experiment, and data are disregarded for the first time, get the meansigma methods of subsequent measurements result, calculate the particle number contained by each sampling cup; Testing result as shown in Table 1 and Table 2.Result shows, the content conformance with standard requirement of " particulate matter " in the ganciclovir preparation that the present invention obtains.
4, " visible foreign matters " content of ganciclovir preparation in the present invention is detected
Detect in Acceleration study and long-term experiment, the content of " visible foreign matters " in the ganciclovir for injection nanocapsule lyophilized formulations of different time points, all carries out according to method described in embodiment 1.
3 repetitions are established in experiment, and testing result as shown in Table 1 and Table 2.Result shows, does not detect visible foreign matters in the ganciclovir preparation that the present invention obtains.
5, the pH value of ganciclovir preparation in the present invention is detected
Detect in Acceleration study and long-term experiment, the pH value of the ganciclovir for injection nanocapsule lyophilized formulations of different time points, all carries out according to method described in embodiment 1.
Testing result as shown in Table 1 and Table 2.Result shows, the pH value of the ganciclovir preparation that the present invention obtains is all between 6.0 ~ 8.0.
To sum up analyze each index to show, in the ganciclovir preparation that the present invention obtains, the content of material such as the macromole of untoward reaction can be caused very low.
Embodiment 3:
One, the preparation (3000ml amount) of ganciclovir for injection nanocapsule lyophilized formulations
Prescription: ganciclovir 125g, Dextran 40 20g, HP-β-CD 20g, polyethylene glycol-polylactic acid block copolymer (number-average molecular weight 2000) 40g, mannitol 40g, sodium sulfite 2g, water for injection is settled to 3000ml.
Preparation method:
(1) prepare: after processing dosing container tool used, pipeline, clean with water for injection; Cillin bottle, plug clean according to a conventional method, sterilizing, dry for standby.
(2) dosing: the water for injection (2400ml) (temperature 50 ~ 60 DEG C) adding recipe quantity 80% in Agitation Tank, first takes the Dextran 40 of recipe quantity, solubilizing agent, sodium sulfite adds in Agitation Tank, be stirred to dissolving; Take the ganciclovir of recipe quantity, add in above-mentioned medicinal liquid, be stirred to dissolving; Under agitation add the polyethylene glycol-polylactic acid block copolymer of recipe quantity, continue stirring 4 little of evenly; Add the mannitol of recipe quantity again, stir and make it dissolve, obtain solution I.
(3) the temperature of solution I is down to 40 DEG C, then solution I 0.22 μm of aperture filter is filtered, obtain filtrate a.Be 10000 daltonian ultrafilter membrane ultrafiltration by filtrate a molecular cut off, obtain filtrate b.With water for injection, filtrate b is complemented to 3000ml, then filter with 0.22 μm of aperture filter, obtain filtrate c.
(4) following index test is carried out to filtrate c: ganciclovir content, medicinal liquid pH value, clarity and visible foreign matters.Be up to the standards, filtrate c be sub-packed in cillin bottle, partly jump a queue.
(5) lyophilization: 1. pre-freeze: point medicinal liquid installed is placed in-40 DEG C of pre-freezes 7 hours; 2. temperature is down to-45 DEG C, is evacuated to below 15Pa; 3. distil: intensification heating 15 ~ 20 is little of-20 DEG C, is incubated 12 hours, to substantially dry; Be warming up to-10 DEG C, be incubated 2 hours; Be warming up to 0 DEG C of insulation 2 hours; Be warming up to 10 DEG C, be incubated 2 hours; Be warming up to 20 DEG C, be incubated 2 hours; Be warming up to 25 DEG C, be incubated 2 hours; Be warming up to 40 DEG C, be incubated 7 hours; 3. continue evacuation 2 hours, tamponade, obtains lyophilized formulations.
(6) roll lid, packaging, inspection, warehouse-in.
Two, the detection of ganciclovir for injection nanocapsule lyophilized formulations
Get prepare according to method described in step one, different batches, preserve the ganciclovir for injection nanocapsule lyophilized formulations of different time and detect as follows.
1, the content of ganciclovir is detected
Detect in Acceleration study and long-term experiment, in the ganciclovir for injection nanocapsule lyophilized formulations of different time points, the content of ganciclovir, all carries out according to method described in embodiment 1.Labelled amount is 12.5mg/ml.
2 repetitions are established in experiment, and experiment establishes 2 repetitions, results averaged, and as shown in Table 1 and Table 2, result shows testing result:
Concentration in the preparation of ganciclovir different time points in Acceleration study with long-term experiment is almost identical, and content, all more than 98%, meets the requirements; Show ganciclovir stable content in preparation of the present invention, not degraded.
2, the content of " related substance " in ganciclovir preparation is detected
Detect in Acceleration study and long-term experiment, its related substances in the ganciclovir for injection nanocapsule lyophilized formulations of different time points, all carries out according to method described in embodiment 1.
2 repetitions are established in experiment, and result is taken the mean.Testing result as shown in Table 1 and Table 2.Result shows, " related substance " content in the ganciclovir preparation that the present invention obtains all is less than 0.2%, meets the requirement lower than 1.0%.
3, the content of " particulate matter " of ganciclovir preparation in the present invention is detected.
Detect in Acceleration study and long-term experiment, the content of the particulate matter in the ganciclovir for injection nanocapsule lyophilized formulations of different time points, all carries out according to method described in embodiment 1.
4 repetitions are established in experiment, and data are disregarded for the first time, get the meansigma methods of subsequent measurements result, calculate the particle number contained by each sampling cup; Testing result as shown in Table 1 and Table 2.Result shows, the content conformance with standard requirement of " particulate matter " in the ganciclovir preparation that the present invention obtains.
4, " visible foreign matters " content of ganciclovir preparation in the present invention is detected
Detect in Acceleration study and long-term experiment, the content of " visible foreign matters " in the ganciclovir for injection nanocapsule lyophilized formulations of different time points, all carries out according to method described in embodiment 1.
3 repetitions are established in experiment, and testing result as shown in Table 1 and Table 2.Result shows, does not detect visible foreign matters in the ganciclovir preparation that the present invention obtains.
5, the pH value of ganciclovir preparation in the present invention is detected
Detect in Acceleration study and long-term experiment, the pH value of the ganciclovir for injection nanocapsule lyophilized formulations of different time points, all carries out according to method described in embodiment 1.
Testing result as shown in Table 1 and Table 2.Result shows, the pH value of the ganciclovir preparation that the present invention obtains is all between 6.0 ~ 8.0.
To sum up analyze each index to show, in the ganciclovir preparation that the present invention obtains, the content of material such as the macromole of untoward reaction can be caused very low.
Table 1 ganciclovir for injection nanocapsule lyophilized formulations accelerated test result
Table 2 ganciclovir for injection nanocapsule lyophilized formulations long-term test results
Claims (9)
1. a ganciclovir for injection nanocapsule lyophilized formulations, it comprises the following component with parts by weight: ganciclovir 250 parts, dextran 4010 ~ 40 parts, solubilizing agent 30 ~ 40 parts, nano carrier material 60 ~ 80 parts and lyophilizing skeleton agent 30 ~ 80 parts;
Described solubilizing agent is HP-β-CD;
Described nano carrier material is polyethylene glycol-polylactic acid block copolymer; The number-average molecular weight 600 ~ 2000 of described nano carrier material.
2. ganciclovir for injection nanocapsule lyophilized formulations according to claim 1, is characterized in that: also comprise antioxidant in described ganciclovir for injection nanocapsule lyophilized formulations, and the weight portion of described antioxidant is 1-5 part.
3. ganciclovir for injection nanocapsule lyophilized formulations according to claim 1, is characterized in that: described ganciclovir for injection nanocapsule lyophilized formulations is made up of the following component with parts by weight: ganciclovir 250 parts, dextran 4010 ~ 40 parts, solubilizing agent 30 ~ 40 parts, nano carrier material 60 ~ 80 parts, lyophilizing skeleton agent 30 ~ 80 parts, antioxidant 1-5 part.
4. the ganciclovir for injection nanocapsule lyophilized formulations according to any one of claim 1-3, is characterized in that: the agent of described lyophilizing skeleton is selected from least one in mannitol, lactose, glucose, sorbitol, sodium chloride, glycine.
5. the ganciclovir for injection nanocapsule lyophilized formulations according to Claims 2 or 3, is characterized in that described antioxidant is selected from least one in sodium sulfite, sodium pyrosulfite, sodium thiosulfate, sodium sulfite.
6. prepare the method for ganciclovir for injection nanocapsule lyophilized formulations according to any one of claim 2-5, comprise the steps: to add water for injection in Agitation Tank and be heated to 50 ~ 60 DEG C, take the Dextran 40 of weight portion according to any one of claim 2-5, solubilizing agent, antioxidant add in Agitation Tank, be stirred to dissolving; Take the ganciclovir of weight portion according to any one of claim 2-5 to add in above-mentioned medicinal liquid, be stirred to dissolving; Under agitation add the nano carrier material of weight portion according to any one of claim 2-5, continue to be stirred to evenly; Add the lyophilizing skeleton agent of weight portion according to any one of claim 2-5 again, stir and make it dissolve, obtain solution I, then solution I is filtered, add water for injection, the concentration making ganciclovir in solution I is 0.040 ~ 0.085g/ml, obtains the nanocapsule solution II of ganciclovir; The nanocapsule solution II of described ganciclovir is divided in cillin bottle, partly jumps a queue, obtain lyophilized formulations through lyophilization.
7. method according to claim 6, is characterized in that: before described filtration, also comprises the temperature of described solution I to be down to be more than or equal to the step that 40 DEG C are less than or equal to 45 DEG C.
8. the method according to claim 6 or 7, is characterized in that: the method for described filtration comprises the steps: described solution I to carry out 0.22 μm of bore filter, obtains filtrate a; Filtrate a being carried out molecular cut off is again 10000 daltonian ultrafiltration, obtains filtrate b; Filtrate b is carried out 0.22 μm of bore filter, obtain filtrate c, mending the concentration injecting water to ganciclovir in solution I is 0.040 ~ 0.085g/ml, obtains the nanocapsule solution II of ganciclovir.
9. method according to claim 6, is characterized in that: described lyophilization comprises following steps; 1. pre-freeze: point medicinal liquid installed is placed in-40 DEG C of pre-freezes 5 ~ 8 hours; 2. temperature is down to-45 DEG C, is evacuated to below 15Pa; 3. distil: intensification heating 15 ~ 20 is little of-20 DEG C, is incubated 10 ~ 18 hours, to substantially dry; Be warming up to-10 DEG C, be incubated 2 ~ 3 hours; Be warming up to 0 DEG C of insulation 2 ~ 3 hours; Be warming up to 10 DEG C, be incubated 2 ~ 3 hours; Be warming up to 20 DEG C, be incubated 1 ~ 2 hour; Be warming up to 25 DEG C, be incubated 1 ~ 2 hour; Be warming up to 40 DEG C, be incubated 7 hours; 3. continue evacuation 2 ~ 4 hours, tamponade, obtains lyophilized formulations.
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