CN1300393C - Preparation method of ultrafine fiber medical agent type emulsion electro spinning fiber - Google Patents
Preparation method of ultrafine fiber medical agent type emulsion electro spinning fiber Download PDFInfo
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- CN1300393C CN1300393C CNB200510016928XA CN200510016928A CN1300393C CN 1300393 C CN1300393 C CN 1300393C CN B200510016928X A CNB200510016928X A CN B200510016928XA CN 200510016928 A CN200510016928 A CN 200510016928A CN 1300393 C CN1300393 C CN 1300393C
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Abstract
The present invention belongs to the technical field of ultrafine fiber medicine dosage form emulsion electric spinning preparation. The present invention comprises the following steps: under the existence of small quantities of surface active agents, first uniformly dispersing medicine solution in carrier macromolecule solution in the form of ultramicro emulsion drops in order to form emulsion; then, electrically spinning the emulsion to obtain ultrafine fiber non-woven cloth or fibrofelt carrying medicine. The method has the advantages of simple preparing processes and low equipment cost, and does not require medicine and carrier polymer to have common solvent, and therefore, compared with solution electric spinning, emulsion electric spinning has a wider application range. The present invention is especially suitable for carrying and slowly releasing water soluble medicine, and is especially suitable for carrying and releasing (through positioning control) medicine belonging to the class of proteins and genes. The medicine release action is stable, and the sudden release phenomenon at the initial stage of medicine release is obviously relieved.
Description
Technical field
The invention belongs to the technical field of the emulsion electro spinning preparation of superfine fiber medicine formulation.
Technical background
The electrospinning silk is to obtain the effective ways of nanometer to the micron diameter superfine fibre, is the spining technology of the invention thirties in 20th century.Because it is the method that obtains the long stapled rare or even unique simple possible of nanometer diameter, since the nineties, development along with nano science and nanometer technology, along with increase to the nano material demand, people more and more pay attention to electrospinning silk technology, aspects such as application at the technology of the mechanism of electrospinning silk, electrospinning silk and equipment, electrospinning silk have obtained a series of achievement in research and patented technology.
Up to the present, people successfully electricity consumption spining technology have spun the superfine fibre of tens of kinds of polymer, comprise synthetic polymer and natural polymer.The technology of electrospinning silk is mainly divided two kinds of solvent spinning and melt spinnings, is about to polymer dissolution in solvent, perhaps is heated into melt, carries out the electrospinning silk then.With regard to solution electrospinning silk, be that the water-soluble polymer water is cooked solvent basically, the oil-soluble polymers organic solvent, general all good solvents of selective polymer, because only in good solvent, polymer solution just has best viscosity and best spinning effect.
The application of electrospinning silk technology on materia medica divides three phases substantially.At first be that medicine absorption or coated (are seen United States Patent (USP) 4043331,4044404,4878908,5376116) to the electricity spinning fibre surface of having spun.Next is with medicine and polymer electrospinning silk together, form the composition of medicine and polymer, then this composition further is processed into known formulation, (world patent 0154667 is a Chinese patent 01804242.2: the pharmaceutical composition of electrospinning silk) as tablet, injection, capsule, mist agent etc.Further, with Chinese patent 03109880.0 (superfine fiber medicine formulation and technology of preparing thereof) is representative, the electricity spinning fibre that is loaded with medicine is used as independently formulation, promptly direct form administration with superfine fibre nonwoven cloth or felt, and select for use Biodegradable high molecular as pharmaceutical carrier, because the super large specific area and the high molecular biodegradation character of carrier of superfine fibre, this pharmaceutical dosage form can be realized the release dynamics of zero level, is specially adapted to the local chemotherapy behind the tumor operation.This novel superfine fiber medicine formulation also is embodied in Chinese patent 200310115823.0 (adriamycin superfine fibre formulation and preparation method thereof) and the Chinese patent 200310115824.5 (taxol superfine fibre formulation and preparation method thereof).
To in electricity spinning fibre, support medicine, at first medicine must be dissolved in the polymer solution of electrospinning silk.This is easily to many medicines, is dissolved in as hydrophilic medicine in the aqueous solution of water-soluble polymer, and lipophilic drugs is dissolved in the organic solution of oil-soluble polymers, all can the electrospinning silk.But this combination often can not be satisfied the needs of drug use.For example, water-soluble polymer absorbs water in a large number in human body, dissolves, and medicine wherein discharges rapidly, does not meet the requirement that control discharges.Hydrophilic medicament is dispersed in the lipophilic polymer, be convenient to realize that control discharges, but it can not be dissolved in the organic solvent again.In order to realize effective blending of hydrophilic medicament and lipophilic polymer, Chinese patent 200310115823.0 at first is converted into the oil-soluble adriamycin with water-soluble adriamycin, then with the biological degradation polyalcohol blending, but this conversion is impossible to most hydrophilic medicaments.Chinese patent 01804242.2 has adopted a large amount of surfactants, add ultrasonic concussion, but just suspension or the dispersion liquid of drug particles in polymer solution that is obtained, in the spun fiber, medicine still exists with the form of particulate, quite the drug particles of vast scale accumulates in fiber surface, and this discharges controlled delivery of pharmaceutical agents is very disadvantageous.Adopt the technology of melt electrospinning silk, certain possibility is arranged in theory, but seek the combination of a medicine and polymer support, they are stablized, dissolve each other under molten condition, in electrospinning silk process, do not produce and be separated, be very difficult, because most of water soluble drug heat endurance is not high, the protide medicine is will sex change more than 37 ℃.
So, press for the medicine that exists in the new above several technology of technology solution and support problem, realize the method for the effective electrospinning silk of hydrophilic medicament and oil-soluble polymers.
Summary of the invention
The present invention will solve the prominent problem of releasing of the medicine that water soluble drug/oil-soluble polymers composite ultrafine fiber Chinese traditional medicine particle aggregation causes at fiber surface of present electricity consumption spining technology spinning, realizes the method for the effective electrospinning silk of hydrophilic medicament and oil-soluble polymers.
One of purpose of the present invention provides a kind of method of emulsion electro spinning of superfine fiber medicine formulation, especially provides a kind of water soluble drug and oil-soluble polymers are prepared the superfine fiber medicine formulation by electrical spinning method.
The present invention is achieved by the following technical solution, and it comprises following step and condition:
(a) medicine is dissolved in the good solvent;
(b) solution of prepared polymer in good solvent, and in this solution, add pharmaceutically acceptable surfactant;
(c) said medicine solution and polymer organic solution are mixed, emulsification, obtain emulsion;
(d) emulsion is carried out the electrospinning silk, obtain the superfine fiber medicine formulation of medicine carrying.
The solvent that uses in the above operating procedure (a) can be single solvent, also can be mixed solvent, can also be the single or mixed solvent that has added solubilizer or pH regulator agent, and drug concentration is the 80-100% of the saturation solubility of medicine in this solvent.
The polymer that uses in the above operating procedure (b) can be single polymer, also can be mixture of polymers more than 2 kinds or 2 kinds; The polymer solvent that uses can be single solvent, also can be the mixture of solvent more than 2 kinds or 2 kinds; According to the kind and the composition of the kind of polymer and molecular weight, solvent, the concentration of selective polymer solution is generally at 1-20%; Used surfactant can be the surfactant of single variety, also can be 2 kinds or 2 kinds with the surfactant mixtures of raising variety, by the quality of used polymer, the consumption of surfactant is 0.1-5%.
Use high shearing mixing emulsor or sonic oscillation mulser to carry out emulsification in the above operating procedure (c), the former mixing speed is 4000-7000 rev/min, and time 3-40 minute, the latter's ultrasonic power was 50-200W, time 3-15 branch; The ratio of water and oil phase in the emulsion according to the decision of the concentration of drug solution, polymer solution, makes the drug loading of final fiber by mass at 1-50%.
According to the character of the medicine that will support, emulsion electro spinning method of the present invention comprises water-in-oil emulsion electrospinning silk and two kinds of preparation methods of O/w emulsion electrospinning silk.The former is applicable to and supports water soluble drug that the latter is applicable to and supports fat-soluble medicine.
The method, step and the condition that prepare superfine fiber medicine formulation water-in-oil emulsion electrospinning silk are as follows:
(a) water soluble drug is dissolved in water or the mixed solvent based on water, the drug concentration in the solution is near the 80-100% of the saturation solubility of medicine in this solvent;
(b) solution of prepared polymer in good solvent is according to kind and molecular weight, the kind of solvent and the concentration of composition selective polymer solution of polymer, generally at 1-20%, so that obtain the needed viscosity of electrospinning silk; And in this solution, add an amount of surfactant, by polymer quality, its consumption is generally 0.1-5%;
(c) said medicine aqueous solution and polymer organic solution are mixed, emulsification, obtain water-in-oil emulsion;
(d) water-in-oil emulsion is carried out the electrospinning silk, obtain to support the superfine fiber medicine formulation of water soluble drug.
Wherein, employed medicine is a kind of in the following medicine or several: carbohydrate medicine, protein drug and gene class medicine;
Employed drug solvent is the mixture of water, water and small molecular alcohol, ketone or cyanogen, or is added with the water of pH regulator agent or the mixture of water and small molecular alcohol, ketone or cyanogen;
Employed polymer is a biological degradation polyalcohol, and they are one or more the mixtures in the following polymers: PLA; Poly-epsilon-caprolactone; Binary between lactide, 6-caprolactone, the glycolide or ternary atactic copolymer or block copolymer;
The solvent of employed polymer is chloroform, acetone, carrene, oxolane, toluene or dimethylbenzene or their mixture;
Employed surfactant is a lauryl sodium sulfate; This dish; The two stearates of glycerine list; Glycerin monostearate; Propylene glycolmonostearate; Span-83; Ethylene glycol monostearate; Diglycol list dodecyl ester; C8-9 alkylphenol-polyethenoxy (4) ether; Secondary octyl phenol polyethenoxy (4) ether; Lecithin; The diglycerol dioleate; Glycerin mono-fatty acid ester; Or the mixture of above-mentioned substance.
The method, step and the condition that prepare superfine fiber medicine formulation O/w emulsion electrospinning silk are as follows:
(a) fat-soluble medicine is dissolved in the good solvent, the drug concentration in the solution is near the 80-100% of the saturation solubility of medicine in this solvent;
(b) aqueous solution in the prepared polymer is selected its concentration according to the molecular weight of polymer, generally at 1-20%, so that obtain the needed viscosity of electrospinning silk; And in this solution, add an amount of surfactant, by used polymer quality, its consumption is generally 0.1-5%;
(c) said medicine solution and aqueous polymer solution are mixed, emulsification, obtain O/w emulsion;
(d) O/w emulsion is carried out the electrospinning silk, obtain to support the superfine fiber medicine formulation of fat-soluble medicine.
Wherein, employed medicine belongs to oil-soluble medicine.For example: antituberculotic-rifampin; Anticancer class medicine-taxol, carmustinum etc.
Employed drug solvent is chloroform, acetone, carrene, oxolane, toluene or dimethylbenzene, or their mixture;
Employed polymer is a water-soluble polymer, preferred biodegradable polymers or Bioabsorbable polymeric in them, they are one or more the mixtures in the following polymers: PVP, polyethylene glycol or polyethylene glycol oxide, shitosan, modified cellulose, modified starch, sodium alginate, hyaluronic acid;
Employed polymer thing solvent is a water, the mixture of water and small molecular alcohol, ketone, cyanogen, or be added with the mixture of the water of pH regulator agent or water and small molecular alcohol, ketone, cyanogen;
Employed surfactant is tween, C8-10 alkylphenol-polyethenoxy (15) ether; The DBSA ammonium salt; PEG (20)-methyl glucoside sesqui-stearate; Lauryl sodium sulfate; Glycerin monostearate; Sucrose fatty ester; Polyethylene glycol; Polyoxyethylene lauryl ether; Polyoxyl 10 oleyl ether; Polyethylene glycol monolaurate; Polyoxyl 40 stearate; Polyethylene glycol monooleate; Or the mixture of above-mentioned substance.
The electric spinning device schematic diagram that the inventive method adopted as shown in Figure 1, it comprises:: 1. emulsion places the spinning solution container; 2. piston type delivery pump; 3. spinning nozzle; 4. high voltage source; 5. spinning solution jet; 6. receiving screen; 7. ground connection.
The preparation method of Water-In-Oil electrospinning silk that the present invention includes or oil-in-water electrospinning silk in the foreign minister of emulsion, can add another kind of medicine, is respectively fat-soluble medicine or water soluble drug.Like this, in the fiber that is spinned, promptly support fat-soluble medicine, supported water soluble drug again.
Different with the melt electrical spinning method with traditional solution electrospinning silk, spinning of the present invention is to liking emulsion.This method does not require that medicine and carrier can dissolve in a kind of solvent, this further widens the scope of application of electrospinning silk technology, is not only applicable to water-in-oil emulsion, also is applicable to O/w emulsion, the combination of medicine and carrier polymer kind and collocation no longer are subjected to the restriction of " cosolvent ".
The present invention uses electrospinning silk technology to prepare ultra-fine drug-loading fibre, its diameter in nanometer to micrometer range.Compare with conventional fibre or conventional pharmaceutical dosage forms, it has very high specific area, but unlike nano particle, Nano capsule and nano-micelle, specific area is too big, and drug is too fast.Its mechanical strength is higher, can be used as separate dosage forms and uses, and need not be processed into other regular dosage form.
The present invention uses the carrier of Biodegradable high molecular as medicine.They are degraded in human body, can compensate the drug releasing rate decay in time that descends and cause because of total dose, make the drug behavior more steady; And in drug release process, the bearer synchronization degraded finally is absorbed by the body or metabolism, does not remain in the human body, does not cause the harm to human body.
Emulsion electro spinning method of the present invention is the result with emulsifying technology and the ingenious combination of electrospinning silk technology.This combination has utilized the advantage of emulsifying technology, medicine is scattered in the polymer solution with the form of micro emulsion drop, rather than is suspended in the polymer solution with the form of solid particle, finally reaches the height of medicine in polymer support and evenly disperses.Utilized the advantage of electrospinning silk technology simultaneously, solution jet stretches at extremely short time inner height, and organic solvent and aqueous solvent be evaporation simultaneously in the extremely short time, obtains superfine fibre.Compare with emulsion method or two emulsion method of existing preparation nanometer and submicron particles, the technology of the present invention difficulty is little, can produce continuously, and the cycle is short, the efficient height, and cost is low, and drug-loading fibre can independently use, and need not further be processed into regular dosage form.
The technology of the present invention both had been applicable to O/w emulsion, also was applicable to water-in-oil emulsion, therefore, both had been applicable to hydrophilic medicament, also was applicable to lipophilic drugs.But consider from fiber pharmaceutical dosage form and its clinical practice, the present invention lays particular emphasis on water-in-oil emulsion, thereby be applicable to all kinds of water soluble drugs, especially more than room temperature, may decompose or the medicine of sex change, perhaps run into medicine, particularly albumen medicine and gene medicine that organic solvent can sex change, because the temperature of electrospinning silk is a room temperature, medicine was in the aqueous systems before drying substantially, was subjected to the influence of organic solvent little.Needs according to treatment can use the medicine more than 2 kinds or 2 kinds simultaneously.
Description of drawings:
Fig. 1 is the electric spinning device schematic diagram.
Fig. 2 is the ESEM photo of the superfine fibre medicine of embodiment 1 preparation.
Fig. 3 is the release profiles of the superfine fibre medicine of embodiment 1 preparation.(▲) is in containing the Tris-HCl cushioning liquid of 3mg/l Proteinase K; (●) is in blank Tris-HCl cushioning liquid.
Fig. 4 is the ESEM photo of the superfine fibre medicine of reference examples 1 preparation.
Fig. 5 is the release profiles of the superfine fibre medicine of reference examples 1 preparation.(▲) is in containing the Tris-HCl cushioning liquid of 5mg/l Proteinase K; (●) is in blank Tris-HCl cushioning liquid.
Fig. 6 is the ESEM photo of the superfine fibre medicine of embodiment 2 preparations.
Fig. 7 is the ESEM photo of the superfine fibre medicine of embodiment 3 preparations.
The specific embodiment
Further specify the present invention below by embodiment, but claim of the present invention is not limited in
The scope of embodiment.
Embodiment 1:
(a) 0.058g doxorubicin hydrochloride (polymer weight 2.46%) is dissolved in the 1.67ml distilled water;
(b) 2.3617g PLLA-PEG (number-average molecular weight of copolymer is 84800, and wherein PEG hop count average molecular weight is 750) is dissolved in the 25ml chloroform, obtains solution transparent, homogeneous.In this solution, add the 0.1181g lauryl sodium sulfate then as surfactant.Because of lauryl sodium sulfate is insoluble to chloroform,, it is evenly disperseed in the chloroformic solution of PLLA-PEG so can pass through sonic oscillation or churned mechanically method;
(c) solution that obtains in the step (b) is placed beaker, open the pre-emulsification of high shearing mixing emulsor 2 minutes, keep emulsive rate, the aqueous solution of doxorubicin hydrochloride is slowly splashed in this solution at 7000 rev/mins.After dropwising, continue emulsification 15 minutes, obtain stable w/o type emulsion.System is cooled off with ice-water bath in the whole emulsion process, to reduce solvent evaporates;
(d) the W/O emulsion that obtains in the step (c) is carried out the electrospinning silk, obtain to support the superfine fiber medicine formulation of water soluble drug.Referring to Fig. 1, the spinning solution container repacks into the 30ml syringe, and the piston 2 of syringe is a delivery pump, adopts the flat mouthful spinning nozzle of being made by No. 7 syringe needles 3 in right angle.Spinning nozzle 3 connects high pressure one end of high voltage source 4, and the earth terminal of high voltage source 4 is connected with the earth terminal 7 of fiber receiving screen 6.Emulsion is joined in the spinning solution container 1 of device for spinning, solution is about 3ml/h at the flow velocity at spinning nozzle 3 places, and the voltage that is applied is 45kV, and the distance of two interpolars is 18cm.
The average diameter of gained drug-loading fibre is about 500nm, sees Fig. 2.Fiber surface does not have drug particles, and the even dispersed encapsulated of medicine is at fibrous inside.Fiber is carried out simple elution can not isolate doxorubicin hydrochloride, and naked eyes can see that fiber has the redness of uniform adriamycin, illustrate that also the even dispersed encapsulated of medicine is at fibrous inside.
In 37 ℃ constant-temperature shaking culture case, carry out drug release test, drug-loading fibre in the Tris-HCl buffer solution and containing in the Tris-HCl buffer solution of Proteinase K the drug behavior as shown in Figure 3.As seen significantly do not dash forward and release phenomenon, in initial 50 minutes, only discharged 9%.
Below the electric spinning device of each example identical with present embodiment.
Reference examples 1:
0.5570g PLLA-PEG (number-average molecular weight of copolymer is 97600, and wherein PEG hop count average molecular weight is 5000) and 0.2785g benzyltriethylammoinium chloride (TEBAC) are dissolved in the 5ml chloroform, form the solution of homogeneous.0.0109g doxorubicin hydrochloride (polymer weight 1.96%) nano particle sonic oscillation is dispersed in the above-mentioned solution, forms suspension.This suspension is carried out electrospinning, adopt the flat mouthful spinning nozzle of being made by No. 8 syringe needles in right angle, the spinning flow velocity is 2.3ml/h, and institute's making alive is 50kV, and the distance of two interpolars is 18cm.
The gained drug-loading fibre is seen Fig. 4.Medicine is not wrapped in fibrous inside fully, but has quite a few drug particles to go to fiber surface or be clipped between the fiber.There is tangible drug particles on the surface that with the naked eye can find fibrofelt in the electrospinning process.
In 37 ℃ constant-temperature shaking culture case, carry out drug release test.Drug-loading fibre in the Tris-HCl buffer solution and containing in the Tris-HCl buffer solution of Proteinase K the drug behavior as shown in Figure 5, have the significantly prominent phenomenon of releasing.In the Tris-HCl buffer solution, in initial 50 minutes, discharged 67%.This is that the dissolving of drug particles in cushioning liquid by fiber surface causes.Estimate that thus the insecure medicine that supports accounts for 60-70%.In contrast, the superfine fibre medicine that embodiment 1 is prepared has only discharged 9% in same buffer solution with in the identical time.Explanation is in embodiment 1, and medicine is evenly to be wrapped in fibrous inside.
Embodiment 2
(a) 0.0401g doxorubicin hydrochloride (polymer weight 2.06%) is dissolved in the 1.67ml distilled water;
(b) 1.9474g PLLA-PEG (number-average molecular weight of copolymer is 97600, and wherein PEG hop count average molecular weight is 5000) is dissolved in the 25ml chloroform, obtains solution transparent, homogeneous.In this solution, add the 0.0974g lauryl sodium sulfate then as surfactant.Because of lauryl sodium sulfate is insoluble to chloroform,, it is evenly disperseed in the chloroformic solution of PLLA-PEG so can pass through sonic oscillation or churned mechanically method;
(c) with the step in the example 1 (c), just emulsive rate is 6500 rev/mins;
(d) the W/O emulsion that obtains in the step (c) is carried out the electrospinning silk, obtain to support the superfine fiber medicine formulation of water soluble drug.Parameter in the electrospinning process is: adopt the flat mouthful spinning nozzle of being made by No. 7 syringe needles in right angle, the spinning flow velocity is 4ml/h, and institute's making alive is 50kV, and the distance of two interpolars is 18cm.The average diameter 800nm of gained drug-loading fibre sees Fig. 6.
Embodiment 3
(a) 0.048g doxorubicin hydrochloride (polymer weight 3.33%) is dissolved in the 1.67ml distilled water;
(b) 1.1443g PLLA (viscosity average molecular weigh is 15.3 ten thousand) and 0.0572g glycerin monostearate are dissolved in the 25ml chloroform;
(c) with the step in the example 1 (c);
(d) the W/O emulsion that obtains in the step (c) is carried out the electrospinning silk, obtain to support the superfine fiber medicine formulation of water soluble drug.Parameter in the electrospinning process is: adopt the flat mouthful spinning nozzle of being made by No. 7 syringe needles in right angle, the spinning flow velocity is 3.5ml/h, and institute's making alive is 35kV, and the distance of two interpolars is 18cm.The average diameter 600nm of gained drug-loading fibre sees Fig. 7.
Embodiment 4
(a) with 0.088g plug for sending (tespamin, polymer weight 3.16%) to be dissolved in the 2.5ml distilled water;
(b) random copolymer PLGA of 2.7849g lactide and glycolide (wherein quality is formed lactide 80%, glycolide 20%, viscosity average molecular weigh is 5.5 ten thousand) and 0.1392g secondary octyl phenol polyethenoxy (4) ether are dissolved in the 25ml chloroform;
(c) with the step in the example 1 (c);
(d) the W/O emulsion that obtains in the step (c) is carried out the electrospinning silk, obtain to support the superfine fiber medicine formulation of water soluble drug.Parameter in the electrospinning process is: adopt the flat mouthful spinning nozzle of being made by No. 8 syringe needles in right angle, the spinning flow velocity is 2.0ml/h, and institute's making alive is 35kV, and the distance of two interpolars is 15cm.The average diameter 900nm of gained drug-loading fibre.
Embodiment 5
(a) 0.07g daunorubicin (polymer weight 2.51%) is dissolved in the 1.67ml distilled water;
(b) 2.7849g PLLA-PEG (number-average molecular weight of copolymer is 84800, and wherein PEG hop count average molecular weight is 750) and 0.1392g propylene glycolmonostearate are dissolved in the 25ml chloroform;
(c) with the step in the example 2 (c);
(d) the W/O emulsion that obtains in the step (c) is carried out the electrospinning silk, obtain to support the superfine fiber medicine formulation of water soluble drug.Parameter in the electrospinning process is 2.5ml/h except the spinning flow velocity, and other parameter is with embodiment 2.The average diameter 800nm of gained drug-loading fibre.
Embodiment 6
(a) 0.07g ifosfamide (polymer weight 6.77%) is dissolved in the 1.67ml distilled water;
(b) 1.0343g PCL (viscosity average molecular weigh is 22.6 ten thousand) and 0.0571g span 80 are dissolved in the 25ml chloroform;
(c) with the step among the embodiment 2 (c);
(d) the W/O emulsion that obtains in the step (c) is carried out the electrospinning silk, obtain to support the superfine fiber medicine formulation of water soluble drug.Parameter in the electrospinning process is: adopt the flat mouthful spinning nozzle of being made by No. 7 syringe needles in right angle, the spinning flow velocity is 2.0ml/h, and institute's making alive is 30kV, and the distance of two interpolars is 18cm.The average diameter 1 μ m of gained drug-loading fibre.
Embodiment 7:
(a) 0.213g taxol (polymer weight 6.54%) is dissolved in the 2ml chloroform;
(b) 3.2562g PVP (weight average molecular weight is 1,300,000 for PVP, K85-95) and 0.1598g polysorbate60 are dissolved in the mixed solution of 10ml water and 10ml ethanol;
(c) solution that obtains in the step (b) is placed beaker, open the pre-emulsification of high shearing mixing emulsor 2 minutes, keep emulsive rate at 6000 rev/mins, the drug solution that step (a) is obtained slowly splashes in this solution.After dropwising, continue emulsification 15 minutes, obtain stable emulsion oil-in-water.System is cooled off with ice-water bath in the whole emulsion process, to reduce solvent evaporates;
(d) O/w emulsion that obtains in the step (c) is carried out the electrospinning silk, obtain to support the superfine fiber medicine formulation of fat-soluble medicine.Parameter in the electrospinning process is: adopt the flat mouthful spinning nozzle of being made by No. 7 syringe needles in right angle, the spinning flow velocity is 1.0ml/h, and institute's making alive is 25kV, and the distance of two interpolars is 29cm.The average diameter 800nm of gained drug-loading fibre.
Embodiment 8
(a) 0.150g rifampin (polymer weight 12.0%) is dissolved in the 2ml chloroform;
(b) 1.2450g polyethylene glycol oxide (PEO, weight average molecular weight is 630,000) and 0.0623g C8-10 alkylphenol-polyethenoxy (15) ether are dissolved in the mixed solution of 10ml water and 10ml acetone;
(c) with the step among the embodiment 7 (c), just emulsive rate is 6300 rev/mins;
(d) O/w emulsion that obtains in the step (c) is carried out the electrospinning silk, obtain to support the superfine fiber medicine formulation of fat-soluble medicine.Parameter in the electrospinning process is: adopt the flat mouthful spinning nozzle of being made by No. 7 syringe needles in right angle, the spinning flow velocity is 1.1ml/h, and institute's making alive is 32kV, and the distance of two interpolars is 30cm.The average diameter 900nm of gained drug-loading fibre.
Embodiment 9
(a) 4.100g carmustinum (polymer weight 9.29%) is dissolved in the 5ml chloroform;
(b) 4.4118g polyacrylamide (PAM, weight average molecular weight 3,000,000, nonionic) and 0.1765g DBSA ammonium salt are dissolved in the 25ml water;
(c) polymer solution that obtains of the same step of drug solution (b) that obtains of step (a) mixes and is placed in the beaker, opens sonic oscillation mulser emulsification 15 minutes.The ultrasonic power of sonic oscillation mulser is 100W.System is cooled off with ice-water bath in the whole emulsion process, prevents the volatilization of solvent in the emulsion process;
(d) O/w emulsion that obtains in the step (c) is carried out the electrospinning silk, obtain to support the superfine fiber medicine formulation of fat-soluble medicine.Parameter in the electrospinning process is: adopt the flat mouthful spinning nozzle of being made by No. 6 syringe needles in right angle, the spinning flow velocity is 1.2ml/h, and institute's making alive is 32kV, and the distance of two interpolars is 30cm.The average diameter 500nm of gained drug-loading fibre.
Experimental procedure has just added the 0.0472g taxol in the chloroformic solution with the foreign minister PLLA-PEG described in the step (b) of embodiment 1 with embodiment 1, has obtained a kind of superfine fiber medicine formulation that supports oil-soluble medicine and water soluble drug simultaneously.
Embodiment 11
Experimental procedure has just added the 0.1181g carmustinum in the chloroformic solution with the foreign minister PLLA-PEG described in the step (b) of embodiment 1 with embodiment 1, has obtained a kind of superfine fiber medicine formulation that supports oil-soluble medicine and water soluble drug simultaneously.
Claims (4)
1. the emulsion electro spinning preparation method of a superfine fiber medicine formulation comprises following step and condition:
(a) medicine is dissolved in the good solvent
(b) solution of prepared polymer in good solvent, and in this solution, add pharmaceutically acceptable surfactant;
(c) said medicine solution and polymer solution are mixed, emulsification, obtain emulsion;
(d) emulsion is carried out the electrospinning silk, obtain the superfine fiber medicine formulation of medicine carrying;
It is characterized in that the good solvent that uses in the described step (a) can be single solvent, it also can be mixed solvent, can also be the single or mixed solvent that has added solubilizer or pH regulator agent, drug concentration be the 80-100% of the saturation solubility of medicine in this solvent;
The polymer that uses in the described step (b) can be single polymer, also can be mixture of polymers more than 2 kinds or 2 kinds; The polymer solvent that uses can be single solvent, also can be the mixture of solvent more than 2 kinds or 2 kinds; According to the kind and the composition of the kind of polymer and molecular weight, solvent, the concentration of selective polymer solution is generally at 1-20%; Used surfactant can be the surfactant of single variety, also can be 2 kinds or 2 kinds with the surfactant mixtures of raising variety, by the quality of used polymer, the consumption of surfactant is 0.1-5%;
Use high shearing mixing emulsor or sonic oscillation mulser to carry out emulsification in the described step (c), the former mixing speed is 4000-7000 rev/min, time 3-40 minute; The latter's ultrasonic power is 50-200W, time 3-15 branch; The ratio of water and oil phase in the emulsion according to the decision of the concentration of drug solution, polymer solution, makes the drug loading of final fiber by mass at 1-50%.
2, the emulsion electro spinning preparation method of superfine fiber medicine formulation according to claim 1 is characterized in that:
Employed medicine belongs to oil-soluble medicine in step (a), is anticancer class oil-soluble medicine;
The solvent of employed medicine is chloroform, acetone, carrene, oxolane, toluene or dimethylbenzene or their mixture in step (a);
Employed polymer is a water-soluble polymer in step (b), be biodegradable polymers or Bioabsorbable polymeric, they are one or more the mixtures in the following polymers: PVP, polyethylene glycol or polyethylene glycol oxide, shitosan, modified cellulose, modified starch, sodium alginate, hyaluronic acid;
Employed polymer solvent is a water in step (b), the mixture of water and small molecular alcohol, ketone, cyanogen, or be added with the mixture of the water of pH regulator agent or water and small molecular alcohol, ketone, cyanogen;
Employed surfactant is tween, C8-10 alkylphenol-polyethenoxy (15) ether in step (b); The DBSA ammonium salt; PEG (20)-methyl glucoside sesqui-stearate; Lauryl sodium sulfate; Glycerin monostearate; Sucrose fatty ester; Polyethylene glycol; Polyoxyethylene lauryl ether; Polyoxyl 10 oleyl ether; Polyethylene glycol monolaurate; Polyoxyl 40 stearate, polyethylene glycol monooleate; Or the mixture of above-mentioned substance.
3, the emulsion electro spinning preparation method of superfine fiber medicine formulation according to claim 1 is characterized in that:
Employed medicine is a water soluble drug in step (a), comprises a kind of in carbohydrate medicine, protein medicaments and the gene class medicine or several;
Employed drug solvent is a water in step (a), the mixture of water and small molecular alcohol, ketone, cyanogen, or be added with the mixture of the water of pH regulator agent or water and small molecular alcohol, ketone, cyanogen;
At the employed polymer of step (b) is biological degradation polyalcohol, and they are one or more the mixtures in the following polymers: PLA; Poly-epsilon-caprolactone; Binary between lactide, 6-caprolactone, the glycolide or ternary atactic copolymer or block copolymer;
Solvent at the employed polymer of step (b) is chloroform, acetone, carrene, oxolane, toluene or dimethylbenzene or their mixture;
At the employed surfactant of step (b) is lauryl sodium sulfate; This dish; The two stearates of glycerine list; Glycerin monostearate; Propylene glycolmonostearate; Span-83; Ethylene glycol monostearate; Diglycol list dodecyl ester; C8-9 alkylphenol-polyethenoxy (4) ether; Secondary octyl phenol polyethenoxy (4) ether; Lecithin; The diglycerol dioleate; Glycerin mono-fatty acid ester; Or the mixture of above-mentioned substance.
4,, it is characterized in that in the described step (b) in prepared polymer solution, having added a kind of or several oil-soluble medicines as the emulsion electro spinning preparation method of superfine fiber medicine formulation as described in claim 1 or 3.
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| JP2010501738A (en) * | 2006-08-21 | 2010-01-21 | ビーエーエスエフ ソシエタス・ヨーロピア | Method for producing nanofibers and mesofibers by electrospinning of colloidal dispersions |
| CN100562611C (en) * | 2007-06-27 | 2009-11-25 | 哈尔滨工业大学深圳研究生院 | The polymer nanofiber preparation facilities that large tracts of land aligns |
| CN101671665B (en) * | 2009-10-27 | 2010-12-15 | 北京师范大学 | Method for preparing immobilized laccase in electrospun fiber membrane |
| CN102251317B (en) * | 2011-05-18 | 2013-01-16 | 东华大学 | Preparation method of electrospun fibers with controllable drug release |
| CN102605466A (en) * | 2012-03-02 | 2012-07-25 | 北京化工大学 | Preparation method of natural polyelectrolyte-based core-shell structured nano-fiber |
| CN103205863B (en) * | 2013-04-17 | 2016-02-10 | 钟春燕 | A kind of preparation method of bacterial cellulose slow-release dressing |
| EP3204540A1 (en) * | 2014-10-10 | 2017-08-16 | The Procter and Gamble Company | Soluble fibrous structures and methods for making same |
| CN106567143A (en) * | 2016-10-27 | 2017-04-19 | 吉林农业大学 | Edible corn protein-based food packaging material and preparation method for same |
| CN107007889B (en) * | 2017-02-23 | 2020-07-07 | 中国科学院长春应用化学研究所 | Postoperative anti-adhesion polymer film and preparation method thereof |
| CN107829218A (en) * | 2017-11-03 | 2018-03-23 | 四川农业大学 | A kind of packaging for foodstuff level Cowhells tendon collagen film and its preparation method and application |
| CN108578393B (en) * | 2018-05-15 | 2021-05-28 | 上海市伤骨科研究所 | Drug permeation-promoted drug-loaded electro-spun fibrous membrane and preparation method thereof |
| CN108822309B (en) * | 2018-05-29 | 2021-11-09 | 南京林业大学 | Preparation method of nanofiber/microemulsion composite hydrogel with slow release performance |
| CN110623932A (en) * | 2019-10-29 | 2019-12-31 | 仁和堂药业有限公司 | Captopril tablets and application thereof |
Citations (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1396823A (en) * | 2000-01-28 | 2003-02-12 | 史密丝克莱恩比彻姆公司 | Electrospun pharmaceutical compositions |
| CN1442133A (en) * | 2003-04-17 | 2003-09-17 | 中国科学院长春应用化学研究所 | Ultrafine fiber medicine dosage form and its preparation method |
| WO2004014304A2 (en) * | 2002-08-07 | 2004-02-19 | Smithkline Beecham Corporation | Electrospun amorphous pharmaceutical compositions |
| US20040051201A1 (en) * | 2002-04-11 | 2004-03-18 | Greenhalgh Skott E. | Coated stent and method for coating by treating an electrospun covering with heat or chemicals |
| CN1543972A (en) * | 2003-11-27 | 2004-11-10 | 中国科学院长春应用化学研究所 | Adriamycin ultrafine fibre preparation and method for making the same |
-
2005
- 2005-07-01 CN CNB200510016928XA patent/CN1300393C/en not_active Expired - Fee Related
Patent Citations (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1396823A (en) * | 2000-01-28 | 2003-02-12 | 史密丝克莱恩比彻姆公司 | Electrospun pharmaceutical compositions |
| US20040051201A1 (en) * | 2002-04-11 | 2004-03-18 | Greenhalgh Skott E. | Coated stent and method for coating by treating an electrospun covering with heat or chemicals |
| WO2004014304A2 (en) * | 2002-08-07 | 2004-02-19 | Smithkline Beecham Corporation | Electrospun amorphous pharmaceutical compositions |
| CN1442133A (en) * | 2003-04-17 | 2003-09-17 | 中国科学院长春应用化学研究所 | Ultrafine fiber medicine dosage form and its preparation method |
| CN1543972A (en) * | 2003-11-27 | 2004-11-10 | 中国科学院长春应用化学研究所 | Adriamycin ultrafine fibre preparation and method for making the same |
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