CN102327186A - Method adopting supercritical CO2 fluid technology to produce water-soluble medicine controlled-release particles - Google Patents
Method adopting supercritical CO2 fluid technology to produce water-soluble medicine controlled-release particles Download PDFInfo
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- CN102327186A CN102327186A CN201110293184A CN201110293184A CN102327186A CN 102327186 A CN102327186 A CN 102327186A CN 201110293184 A CN201110293184 A CN 201110293184A CN 201110293184 A CN201110293184 A CN 201110293184A CN 102327186 A CN102327186 A CN 102327186A
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Abstract
The invention relates to a method adopting a supercritical CO2 fluid technology to produce water-soluble medicine controlled-release particles, which belongs to the technical field of the novel preparation method and application of pharmaceutical dosage form variation. The traditional microsphere preparation method cannot keep the bioactivity of medicine, the supercritical anti-solvent technique is mild and safe, but is limited because the supercritical CO2 is difficult to be mixed with the polar solvent. In the invention, a mixer which is specially designed is adopted to mix the supercritical CO2 and ethanol, so the water blending performance is increased; and a triple-channel coaxial nozzle is adopted, the medicine aqueous solution, macromolecule carrier organic solution and ethanol are mixed with the supercritical CO2 to be simultaneously sprayed into a reactor through the inner layer of channel, the intermediate layer of channel and the outer layer of channel of the nozzle, extraction and separation are completed in one step, so medicine controlled-release particles are prepared. The method has mild conditions, the retentivity degree of the medicine activity is high, the residual amount of the organic solvent is low, and the operation is simple. The produced microspheres are smooth and spherical, have the particle size of 1-5mum, and the particle size distribution is narrow. The invention has application prospect in preparing water-soluble controlled-release microspheres.
Description
Technical field
The invention belongs to novel preparation method and applied technical field that pharmaceutical dosage form changes, particularly traditional supercritical fluid technology is improved, the new method of employing new technology changes the form of administration of existing medicine.
Background technology
Because the high development of biotechnology, water soluble drug such as albumen, polypeptide etc., because characteristics such as biologically active is strong, and relative cost is low, and action target spot is single-minded, successful application becomes new research focus to the inapparent field of chemicals curative effect.But protein and peptide drugs has shortcomings such as short, certain immunogenicity, toxic and side effects of half-life is big more.Controlled drug delivery system can reduce poisonous side effect of medicine in effective range through keeping blood drug level, improves bioavailability of medicament.Therefore, medicine is carried out embedding, be prepared into the carried medicine sustained-release microgranule, become the novel form that protein and peptide drugs is used through Biodegradable Polymers.Method for preparing microsphere commonly used comprises spray drying method, freeze-drying, emulsifying partition method etc.These methods perhaps have the process of high-temperature process, perhaps medicine are directly contacted with organic solvent, all can impact pharmaceutically active, and prepared microsphere pattern are irregular, and particle size distribution is wide, can not reach the clinical criteria of intravenously administrable preferably.
Different characteristic, near liquid, solvability and liquid flux are close like its density; Viscosity is near gas, and mass transfer velocity is compared the common liq solvent and is greatly increased.Using more supercritical fluid at present is supercritical CO
2, supercritical carbon dioxide fluid has following outstanding advantage: it is low to have a critical temperature, is merely 31.1 ℃, is applicable to temperature sensitive property material; Purify easily and separate the no solvent residue problem; Inertia, safety, green.Based on supercritical CO
2Fluid technique and the supercritical CO that produces
2Fluid is forced dispersion method (Solution enhanced dispersion by supercritical fluids; SEDS) have operating condition gentleness, advantage such as Determination of Residual Organic Solvents is low and microsphere physics pattern is controlled; Successfully apply to the medicament slow-release microsphere preparation field, for the preparation water-soluble drug sustained-release microsphere provides probability.
The ultimate principle of traditional SEDS method is to adopt supercritical CO
2As anti-solvent, the solvent in the extraction solution makes solute in the solution reach supersaturation and separates out.This just requires solvent at supercritical CO
2In higher dissolubility is arranged and solute is insoluble or be insoluble in supercritical CO
2For water soluble drug and biologically active drug (polypeptide, albumen), because aqueous solvent is a polar solvent, and supercritical CO
2In be difficult to blend, limited the application aspect preparation water soluble drug medicine carrying microgranule of SEDS technology.
The objective of the invention is: overcome the defective that supercritical carbon dioxide and aqueous solvent can not blend, provide a kind of new thinking to prepare water-soluble drug sustained-release microsphere.
Basic design of the present invention is: on the basis of traditional SEDS method, introduce and a kind ofly can be dissolved in supercritical CO
2Again can with the organic solvent (ethanol) of water blend as modifier, utilize the effect between aqueous solvent and the modifier to make supercritical CO
2Extract this two kinds of solvents simultaneously, to reach and the isolating purpose of solute.Adopted blender with ethanol and supercritical CO
2Mix, adopt the triple channel coaxial nozzle and the supercritical CO after the ethanol modification
2, medicine aqueous solution and polymer organic solution feed agitated reactor from separate passage respectively, one step of extract and separate accomplishes, the drug-carrying polymer particulate deposits is separated out.SEDS method after the improvement has avoided biologically active drug directly to contact for a long time with organic solvent, can make pharmaceutically active exempt from destruction, has prepared carried medicine sustained-release microsphere again, has bigger application potential.
Summary of the invention
The object of the present invention is to provide a kind of method for preparing of new pharmaceutical preparation, solve the shortcoming that traditional supercritical fluid technology can not prepare the water-soluble drug sustained-release microgranule.
The object of the invention is mainly realized through following technology path: the CO in the steel cylinder
2Liquefy through refrigeration system; By the high-pressure plunger pump pressurization, after water bath with thermostatic control heats up, pump into autoclave through blender with constant speed; After treating that the autoclave internal pressure reaches setting value; Regulate the venting that the valve of autoclave base keeps given pace, make the still internal pressure stable, the temperature and pressure through temperature and pressure pick off control autoclave reaches and is stable at setting value simultaneously.After this ethanol pumps into blender by efficient liquid-phase chromatographic pump, ethanol and supercritical CO
2In mixer mixing; Mixed fluid continues to feed autoclave with constant speed; Reach stable after, pharmaceutical aqueous solution, the organic solution of polymer pumps into autoclave from different pipelines through efficient liquid-phase chromatographic pump respectively simultaneously; And from the different passages ejection of triple channel coaxial nozzle, in the course of reaction in the control autoclave temperature and pressure remain setting value.After finishing pump appearance, holding temperature and pressure are constant, the supercritical CO after the modification of lasting feeding ethanol
2Remove dissolvent residual in 30 minutes, continue to feed supercritical CO again
2It is residual to remove ethanol in 60 minutes, and drying sample, and sample is collected in slowly pressure release.
Purposes of the present invention: the present invention is mainly used in preparation water-soluble drug sustained-release medicine carrying microgranule, keeps the medicine biological activity, improves drug bioavailability, reduces toxic and side effects, improves therapeutic effect.
Advantage of the present invention: this method prepares the process gentleness, avoids medicine and organic solution Long contact time, and is high to the pharmaceutically active conservation degree; Adopt CO
2Environmental protection, easily separated, the product no solvent residue, toxicity is little; Simple to operate, be prone to promote.
Description of drawings
The improved supercritical fluid of Fig. 1 is forced dispersion soln subtraction unit figure
The sem photograph of Fig. 2 morphine polylactic acid microgranule
The sem photograph of Fig. 3 bovine serum albumin polylactic acid microgranule.
The specific embodiment
Instantiation below in conjunction with the inventor provides further is discussed in more detail the technology of being invented.Need to prove that the present invention is not limited to these embodiment,, in the category that the present invention provides, carry out the interpolation and the replacement of technical characterictic, all belong to protection scope of the present invention for those skilled in the art.
Instance one preparation morphine polylactic acid medicine carrying microballoons
(1) gets morphine hydrochloride injection 10mg/ml 4ml, to 24ml, place brown bottle subsequent use with distilled water diluting.Taking by weighing molecular weight is the PLLA 300mg of 100 KDa, in reaction bulb, adds organic solvent 60ml, stirring and dissolving under the room temperature.Prepare analytical pure ethanol.
(2) assembling autoclave is opened supercritical fine particle device, and refrigeration system is started working, and it is 33 ℃ that reaction temperature is set, and pressure is 12MPa, CO
2The flow velocity that pumps into be 300ml/min.Open high-pressure plunger pump, constant water bath box and air dry oven are to the agitated reactor intensification of boosting.It is setting value that adjusting venting valve and temperature detect switch (TDS) make temperature, the constant pressure of agitated reactor.
(3) open the ethanol pump, it is 1.5ml/min that flow velocity is set, and ethanol is through blender and supercritical CO
2Mix after the coaxial nozzle outer layer channel pumps into agitated reactor; Open water-soluble liquid pump of medicine and polymer organic solution pump simultaneously, flow velocity is set is respectively 0.2ml/min, and 0.5ml/min, aqueous morphine solution and polylactic acid dichloromethane solution pump into agitated reactor through the internal layer and the intermediate layer passage of coaxial nozzle.
(4) keep three kinds liquid continuously to pump into agitated reactor to set flow velocity, the temperature and pressure that keeps agitated reactor simultaneously is a setting value, to the aqueous morphine solution of configuration and polylactic acid dichloromethane solution simultaneously pump finish, close internal layer and intermediate layer passage.
(5) keep reaction temperature and pressure, continue to feed the blended supercritical CO of ethanol
2Close the ethanol pump behind the 30min, continue to feed CO again
2Close the gas passage behind the 60min, close high-pressure plunger pump.
(6) open the venting valve, slowly pressure release treats that pressure gets back to normal pressure, opens autoclave, collects the bottom powder body.
The morphine polylactic acid carried medicine sustained-release microsphere of above process preparation is smooth, spherical, and mean diameter is 2.5 μ m, and the drug loading of microsphere is 4.73%.
Instance two preparation bovine serum albumin polylactic acid medicine carrying microballoonss
(1) takes by weighing bovine serum albumin (BSA) 20mg, be dissolved in the 12ml distilled water.Take by weighing the PLLA that molecular weight is 10KDa (PLLA) 300mg, in reaction bulb, add organic solvent 60ml, stirring and dissolving under the room temperature.Prepare analytical pure ethanol.
(2) assembling autoclave is opened supercritical fine particle device, and refrigeration system is started working, and it is 33 ℃ that reaction temperature is set, and pressure is 12MPa, CO
2The flow velocity that pumps into be 300ml/min.Open high-pressure plunger pump, constant water bath box and air dry oven are to the agitated reactor intensification of boosting.It is setting value that adjusting venting valve and temperature detect switch (TDS) make temperature, the constant pressure of agitated reactor.
(3) open the ethanol pump, it is 1ml/min that flow velocity is set, and ethanol is through blender and supercritical CO
2Mix after the coaxial nozzle outer layer channel pumps into agitated reactor; Open water-soluble liquid pump of medicine and polymer organic solution pump simultaneously, flow velocity is set is respectively 0.25ml/min, and 1ml/min, BSA aqueous solution and polylactic acid dichloromethane solution pump into agitated reactor through the internal layer and the intermediate layer passage of coaxial nozzle.
(4) keep three kinds liquid continuously to pump into agitated reactor to set flow velocity, the temperature and pressure that keeps agitated reactor simultaneously is a setting value, to the aqueous morphine solution of configuration and polylactic acid dichloromethane solution simultaneously pump finish, close internal layer and intermediate layer passage.
(5) keep reaction temperature and pressure, continue to feed the blended supercritical CO of ethanol
2Close the ethanol pump behind the 30min, continue to feed CO again
2Close the gas passage behind the 60min, close high-pressure plunger pump.
(6) open the venting valve, slowly pressure release treats that pressure gets back to normal pressure, opens autoclave, collects the bottom powder body.
The BSA-PLLA sustained-release micro-spheres of above process preparation is elliposoidal, and particle size distribution is at 1 ~ 3 μ m, and microsphere has the good slow release effect.
Claims (5)
1. one kind is adopted supercritical CO
2Fluid technique prepares the method for water-soluble drug sustained-release microgranule, it is characterized in that, at first dehydrated alcohol is mixed with supercritical carbon dioxide; Pass through efficient liquid-phase chromatographic pump again with pharmaceutical aqueous solution; Supercritical carbon dioxide after polymer organic solution and the ethanol modification pumps into autoclave respectively simultaneously through the triple channel coaxial nozzle, directly from aqueous solution, extracts biologically active drug, and makes it to separate out simultaneously with macromolecule carrier; Keep pharmaceutically active, extract and separate a step and accomplish.
2. according to the employing supercritical CO described in the right 1
2Fluid technique prepares the method for water-soluble drug sustained-release microgranule, it is characterized in that drug concentrations at 5% ~ 20% wt, and the concentration of polymer organic solution is at 0.5 ~ 1.5 wt/v, and the flow velocity of efficient liquid-phase chromatographic pump is 0.2 ~ 1.5ml/min; Velocity ratio between aqueous solution, ethanol and the organic solution three is 1:2.5:2.5 ~ 1:7.5:7.5.
3. according to the employing supercritical CO described in the right 1
2Fluid technique prepares the method for water-soluble drug sustained-release microgranule, it is characterized in that CO
2Pump into speed at 300 ~ 380 ml/min, temperature is at 32 ~ 35 ℃, and pressure is at 10 ~ 14 MPa.
4. according to the employing supercritical CO described in the right 1
2Fluid technique prepares the method for water-soluble drug sustained-release microgranule, it is characterized in that pharmaceutical carrier is biodegradable PLLA (PLLA), and molecular weight is between 50 ~ 200KDa.
5. according to the employing supercritical CO described in the right 1
2Fluid technique prepares the method for water-soluble drug sustained-release microgranule, it is characterized in that microsphere type of being is spherical, smooth surface, and particle size distribution is between 1 ~ 5 μ m.
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Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102727448A (en) * | 2012-07-19 | 2012-10-17 | 四川大学 | Method for preparing sustained-release morphine microspheres by using supercritical CO2 fluid technology |
| CN102847494A (en) * | 2012-08-10 | 2013-01-02 | 浙江医药高等专科学校 | Device and method for preparing pulsatile release microspheres |
| CN103424305A (en) * | 2013-08-08 | 2013-12-04 | 江南大学 | Device used for monitoring biological sample treatment and/or biochemical reaction under ultrahigh pressure on line and in situ |
Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP1133284B1 (en) * | 1998-11-23 | 2004-10-06 | AstraZeneca AB | A process for the preparation of crystalline particles |
| CN1720902A (en) * | 2005-06-23 | 2006-01-18 | 同济大学 | The supercritical anti-dissolving agent process prepares the method for biological degradable polymer drug-carried fine particle |
| CN101444709A (en) * | 2008-12-05 | 2009-06-03 | 厦门大学 | Method for obtaining solid particles from water solution by utilizing supercritical carbon dioxide |
| CN101502477A (en) * | 2009-02-27 | 2009-08-12 | 四川大学 | Novel SEDS method for preparing protein polypeptide drug-loaded microspheres |
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Patent Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP1133284B1 (en) * | 1998-11-23 | 2004-10-06 | AstraZeneca AB | A process for the preparation of crystalline particles |
| CN1720902A (en) * | 2005-06-23 | 2006-01-18 | 同济大学 | The supercritical anti-dissolving agent process prepares the method for biological degradable polymer drug-carried fine particle |
| CN101444709A (en) * | 2008-12-05 | 2009-06-03 | 厦门大学 | Method for obtaining solid particles from water solution by utilizing supercritical carbon dioxide |
| CN101502477A (en) * | 2009-02-27 | 2009-08-12 | 四川大学 | Novel SEDS method for preparing protein polypeptide drug-loaded microspheres |
Non-Patent Citations (1)
| Title |
|---|
| SRINIVAS PALAKODATY,ET A: "Supercritical Fluid Processing of Materials from Aqueous Solutions:The Application of SEDS to Lactose as a Model Substance", 《PHARMACEUTICAL RESEARCH》, vol. 15, no. 12, 31 December 1998 (1998-12-31), XP002386662, DOI: doi:10.1023/A:1011949805156 * |
Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102727448A (en) * | 2012-07-19 | 2012-10-17 | 四川大学 | Method for preparing sustained-release morphine microspheres by using supercritical CO2 fluid technology |
| CN102847494A (en) * | 2012-08-10 | 2013-01-02 | 浙江医药高等专科学校 | Device and method for preparing pulsatile release microspheres |
| CN102847494B (en) * | 2012-08-10 | 2014-11-05 | 浙江医药高等专科学校 | Device and method for preparing pulsatile release microspheres |
| CN103424305A (en) * | 2013-08-08 | 2013-12-04 | 江南大学 | Device used for monitoring biological sample treatment and/or biochemical reaction under ultrahigh pressure on line and in situ |
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