CN101143131A - Method for preparing human insulin inhaled dry powder using with supercritical fluid technology - Google Patents
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Abstract
A method of preparing an absorptive dry powder of human insulin by the supercritical liquid technology is a concrete method that the raw material of the human insulin is diluted into liquid medicine by acidic solution; the liquid medicine, counter solvent and supercritical carbon dioxide are synchronously pumped into a nozzle of a particle forming kettle for being mixed and atomized to form particles with the granularity of one to ten microns, and the particles are applied as the dry powder preparation for the pulmonary absorption. The absorptive dry powder of human insulin which is prepared by the invention can be used for preparing amorphous superfine powder, the drug loading quantity of which is more than 90 percent, according to different prescription designs, and the residual solvent is very little; the water content is less than 10 percent; the amorphous superfine powder can be stably stored at the room temperature; the biological activity is hardly lost.
Description
(1) technical field:
The present invention relates to the preparation method of human insulin inhaled dry powder, particularly a kind of method of utilizing supercritical fluid technology to prepare human insulin inhaled dry powder.
(2) background technology:
Diabetes have now become global commonly encountered diseases and frequently-occurring disease, are listed in the third-largest disease after cardiovascular disease and tumor in developed country.China has nearly 3,000 ten thousand diabeticss at present, and diabetes prevalence strides into 3%～10% medium level rapidly from＜3%.The investigation and analysis data that IDF announces shows, will reach 4,600 ten thousand to 20 years old-79 years old diabetics of China in 2025.
Diabetes mainly are divided into type i diabetes and type ii diabetes.The type i diabetes accounting is about 10%, owing to lack insulin in the patient body, just need make insulinize from the morbidity beginning, and lifelong use.The type ii diabetes accounting is about 90%, because the insulin that produces in the patient body lacks relatively, generally needs oral drugs to stimulate secretion of insulin in the body, just must carry out insulinize as I type patient but many patients develop into late period.The human insulin secretion has 2 kinds: basal insulin, and glycogen constantly disengages in the body to deal with in continual release every day; Can Time insulin, meal Hou is risen synchronously with blood glucose, normal person β Fine born of the same parents after the meal discharged a Ge crest of insulin at 3 to 10 minutes, go out and stimulate the secondary peak Buddhism of insulin to put to suppress glycogen Lose, secondary peak arrived at ripple peak Knot bundle back Approximately in 15 seconds; hold continuous Approximately 1～2 little Time, to reduce post-prandial glycemia, ended until the normal As of the extensive Complex of blood glucose.
Usually insulin can only pass through subcutaneous or intravenous administration, needs early, middle and late 30 minutes before the meal injection short-acting insulins, and regulating and control after the meal change of blood sugar in the body, protamine zine insulin in the injection once again before sleeping is kept the interior basal insulin level of body.In fact current preparation also has weak point, and for example, Enough is not fast for fugitive preparation speed of action, and feed back blood glucose is often higher; Middle durative action preparation: steady like that not as normal basal insulin secretion, insulin concentration still has spike to occur in the blood, and needing to take food prevent that hypoglycemia from taking place.In addition, diabetics needs lifelong medication, and long term injections is not only brought pain and inconvenience, and can make the injection site side effect such as inflammation, scleroma, allergy occur.Therefore, the physiological adjustment type insulin preparation of non-injection just becomes patient's the dream and the pursuit of pharmacy research and development.
In the various effort of innovation insulin administration mode, comprise approach such as oral, oral mucosa, nasal cavity, ophthalmic, pulmonary's suction, rectum, transdermal, the common difficult point that runs into is to absorb slowly, peak concentration of drug is low, is not suitable for diabetes patient's clinical treatment.But pulmonary's inhalation is hopeful most, because pulmonary's trachea arborizations structure has abundant blood capillary and alveolar, not only medicine is very slow from the process of base of lung elimination, avoids being similar to the gastrointestinal destruction, has reduced the first pass effect of medicine, improve bioavailability of medicament, and insulin is very fast through the speed that alveolar absorbs, and can form higher pulse concentration, meets the physiology release characteristic of insulin in the body, thereby can in diet, use, medication is convenient.
Pulmonary's inhalation has aerosol, spray and three kinds of dosage forms of powder spray.Because the chemical stability of insulin in water is relatively poor, does not dissolve in ethanol and fluorine-containing propellant, difficulty is made liquid type aerosol or spray.The drug loading of powder spray is big, needs adjuvant little with good water solubility, zest, good biocompatibility.Recent two decades comes, because drug particle design and powder technology progress, powder spray becomes the focus of insulin new preparation developing, and each big Pharmaceutical of the world drops into exploitation one after another.As Pfizer, gift comes, and Novo Nordisk etc. all release one after another and enter the new product of clinical trial.This person of winning who takes turns competition is a Pfizer, and the said firm utilizes the human insulin inhaled dry powder Exubera of Nektar technological development to go on the market by U.S. FDA and European Union's approval in January, 2006.
The key of insulin dry powder inhalant is to design the powder body of prepared sizes distribution 1-5 micron, makes its physics and chemistry and biological nature reach the basic demand of pulmonary administration.This is a huge challenge to conventional art, studies show that lyophilizing or spray drying are not ideal methods, present disclosed patent adopts spray drying method more, as described in Chinese patent CN1129904A, CN1152867, CN1372973 and CN 1507362A, insulin must be dissolved in the buffer, its biological activity is less stable under solution state, adheres to easily on the molten wall; Solution becomes drop through nozzle ejection, needs experience TRANSIENT HIGH TEMPERATURE drying, causes the insulin degraded easily, reduces its biological activity; Drying process with atomizing is simple relatively, and preparation time is very short, but needs more adjuvant, causes drug loading limited, uncontrollable crystal formation, and productive rate is lower, and residual solvent content is higher.In the patent of Exubera, employing is dissolved in insulin in the acceptable aqueous buffer solution of physiology, and for example pH is the citrate of about 2 to 9 scopes, mannitol and buffered with amino acid liquid, dissolved concentration of insulin is 0.01% weight ratio to 1% weight ratio, is generally 0.1 to 0.2%.With this solution spray drying in the spray drying device of routine, obtain being essentially unbodied particulate product at last then.
The Exubera clinical experiment was gone through more than ten years from 1993, comprised 30 multinomial single dose clinical pharmacology research and 20 multinomial II/III clinical trial phases.The pharmacokinetic result shows the Exubera peak reaching time of blood concentration faster than regular insulin, and onset and Semilente Insulin are close, and the insulin of blood sugar control effect and snap action is close.Yet Exubera is not an optimum formula, because wherein adjuvant accounts for gross mass 40%, and drug loading 60%, the biological activity work in-process is lost, and bioavailability only is 10%-20%, and powder body is at bubble-cap residual too much (25%-45%), powder fluidity, viscosity and surface electrostatic still have room for improvement.
(3) summary of the invention:
The object of the present invention is to provide a kind of method of utilizing supercritical fluid technology to prepare human insulin inhaled dry powder, it can overcome the deficiency that prior art exists, and obtains a kind of new-type human insulin pulmonary and sucks dry powder.
A kind of method of utilizing supercritical fluid technology to prepare human insulin inhaled dry powder is characterized in that it may further comprise the steps:
(1) with acid solution the insulin human raw material is diluted to medicinal liquid;
(2) adopt supercritical fluid as main preparation medium;
(3) prepare the supercritical process condition;
(4) adopt counter solvent and utilization to be suitable for the equipment of reverse extraction technology;
(5) insulin human raw material diluent and counter solvent and supercritical fluid being prepared medium mixes by the nozzle of reverse extraction technology equipment simultaneously, atomizing, under the supercritical process condition, enter particle molding still, counter solvent flow 0.5-5ml/min wherein, medicinal liquid flow 0.01-0.5ml/min, supercritical fluid prepare rate-of flow 10-200ml/min;
(6) form the dry powder body of 1～10 micron of particle diameter, drug loading reaches more than 90%;
(7) the residual gas liquid after the preparation process is handled.
The used acid solution of insulin human raw material dilute liquid medicine in the above-mentioned said step (1), be with organic acid, mineral acid preparation, typically as citric acid, acetic acid, the hydrochloric acid solution of 10-100mM, insulin human is prepared into concentration 10-80mg/ml medicinal liquid after dissolving under acid condition.
It is carbon dioxide that supercritical fluid in the above-mentioned said step (2) prepares medium.
Super critical condition pressure power 8-35MPa in the above-mentioned said step (3), temperature 35-55 ℃; Optimized process conditions is pressure 11MPa, 37 ℃ of temperature.
Counter solvent in the above-mentioned said step (4) is got ethanol, isopropyl alcohol or acetone.
Reverse extraction technology equipment in the above-mentioned said step (5) comprises carbon dioxide steel cylinder 1, booster pump 2, spray pump 3, solvent pump 4, nozzle 5, microgranule molding still 6, back pressure controller 7, remaining gas-liquid separating still 8, residual gas floss hole 9 and residual liquid catcher 10, with the upper-part order of connection be: the outfan of carbon dioxide steel cylinder 1 connects booster pump 2, the outfan of booster pump 2 connects nozzle 5, spray pump 3 is connected nozzle 5 with solvent pump 4, nozzle 5 feeds microgranule molding still 6, microgranule molding still 6 connects remaining gas-liquid separating still 8 through back pressure controller 7, remaining gas-liquid separating still 8 has residual gas floss hole 9 respectively and feeds the residual liquid discharge mouth of residual liquid catcher 10, and wherein all have can be according to the function of process conditions regulating and controlling temperature for microgranule molding still and remaining gas-liquid separating still.
The productive rate of the dry powder in the above-mentioned said step (6) is 70%-80%.
Remaining gas-liquid after the preparation process in the above-mentioned said step (7) is handled, comprise that residual liquid enters remaining gas-liquid separating still 8 by back pressure controller 7 in the particle molding still, remaining gas-liquid separating still 8 is discharged residual gas respectively by residual gas floss hole 9, residual liquid is collected by residual liquid catcher 10.
A kind of human insulin inhaled dry powder that utilizes above-mentioned supercritical fluid technology preparation, it is characterized in that prepared human insulin inhaled dry powder is the unformed powder body of particle diameter at 1～10 micron more than 90%, insulin content is more than or equal to 90%, and residual solvent content is far below the Chinese Pharmacopoeia required standard; Tire 〉=27.5U/mg hmw protein content≤0.5%, A21 deamination insulin content≤0.5%, zinc content≤0.7%, loss on drying≤10% in the biochemical indicator of prepared human insulin inhaled dry powder.
Prepared dry powder stability is: 1 year room temperature is deposited stable, it is tired, hmw protein content, A21 deamination insulin content, zinc content, loss on drying all with preparation at the beginning of relatively, obviously do not change, still do not reach China and American-European standards of pharmacopoeia.
Operation principle of the present invention is: during preparation insulin human dry powder, earlier the carbon dioxide supercharging is warmed up to required process conditions, setting required flow enters microgranule molding still through nozzle and sets up supercriticality, then insulin human solution and counter solvent are passed through nozzle by required flow, form the atomizing turbulent flow of high velocity jet, fine droplet moment becomes particulate deposits at the bottom of the still on the filter membrane, residual solution by still at the bottom of filter membrane enter separating still, finish gas-liquid separation.Regulate parameters such as pressure, temperature, flow, concentration, can controlling particle size distribute micrograined texture.With traditional method of granulating relatively, epigranular, smooth surface, noresidue solvent almost, production process does not have the three wastes, is energy-efficient, green environmental protection technique.
Superiority of the present invention is: 1, by utilizing supercritical fluid technology to prepare the insulin human Foradil Aerolizer formoterol fumarate that high bioactivity and availability are stablized, had to the room temperature long-term storage, comprise the powder body of particle size distribution at the 1-10 micron; 2, for fear of the destruction of temperature to insulin active, select for use carbon dioxide as supercritical fluid, because of 31.4 ℃ of its critical temperatures, pressure is 7.38MPa, can prepare the insulin human micropowder near the human body temperature scope; 3, select different organic counter solvent, can prepared sizes be distributed in powder body between the 1-10 micron, drug loading is up to more than 90%, and residual solvent is very low, and moisture less than 10%, room temperature is deposited stable, and biological activity is not loss almost; 4, the biochemical indicator of prepared human insulin inhaled dry powder is as tiring, hmw protein content, and A21 deamination insulin content, zinc content, loss on drying all reaches China and American-European standards of pharmacopoeia;
(4) description of drawings:
Accompanying drawing 1 is related a kind of structure and the process flow diagram that utilizes supercritical fluid technology to prepare used producing equipment in human insulin inhaled dry powder and preparation method thereof of the present invention.
Wherein: 1 is carbon dioxide steel cylinder, 2 is booster pump, 3 is spray pump, and 4 is solvent pump, and 5 is nozzle, 6 is microgranule molding still, 7 is the back pressure controller, and 8 is remaining gas-liquid separating still, and 9 is the residual gas floss hole, 10 is the residual liquid catcher, and wherein all have can be according to the function of process conditions regulating and controlling temperature for microgranule molding still 6 and remaining gas-liquid separating still 8.
(5) specific embodiment:
Embodiment 1: adopt ethanol as counter solvent.Be dissolved in an amount of insulin human raw material medicine that to make concentration in the hydrochloric acid solution that concentration is 10-100mM be that the medicinal liquid of 10-80mg/ml is standby.Selecting preparation condition for use is pressure 8-20MPa, 35～50 ℃ of temperature, carbon dioxide flow 10-50ml/min, ethanol flow 0.5-5ml/min, medicinal liquid flow 0.01-0.5ml/min, the technology of optimizing is pressure 11MPa, 37 ℃ of temperature, carbon dioxide flow 25ml/min, ethanol flow 1.5ml/min, concentration is 50mg/ml medicinal liquid flow 0.05ml/min, powder body that can prepared sizes 1-5 micron, and productive rate is more than 80%.
Embodiment 2: adopt isopropyl alcohol as counter solvent.Be dissolved in an amount of insulin human raw material medicine that to make concentration in the hydrochloric acid solution that concentration is 10-100mM be that the medicinal liquid of 10-80mg/ml is standby.Selecting preparation condition for use is pressure 8-20MPa, 35～50 ℃ of temperature, carbon dioxide flow 10-50ml/min, isopropyl alcohol flow 0.5-5ml/min, medicinal liquid flow 0.01-0.5ml/min, the technology of optimizing is pressure 11MPa, 37 ℃ of temperature, carbon dioxide flow 35ml/min, isopropyl alcohol flow 1.0ml/min, concentration is 50mg/ml medicinal liquid flow 0.05ml/min, powder body that can prepared sizes 1-10 micron, productive rate about 70%.
Embodiment 3: adopt acetone as counter solvent.Be dissolved in an amount of insulin human raw material medicine that to make concentration in the hydrochloric acid solution that concentration is 10-100mM be that the medicinal liquid of 10-80mg/ml is standby.Selecting preparation condition for use is pressure 8-20MPa, 35～50 ℃ of temperature, carbon dioxide flow 10-50ml/min, acetone flow 0.5-5ml/min, medicinal liquid flow 0.01-0.5ml/min, the technology of optimizing is pressure 11MPa, 37 ℃ of temperature, carbon dioxide flow 30ml/min, acetone flow 1.5ml/min, concentration is 50mg/ml medicinal liquid flow 0.05ml/min, powder body that can prepared sizes 1-10 micron, productive rate about 70%.
Technique effect experimental test data of the present invention sees Table 1-7:
Embodiment 4: particulate form and particle size distribution observation.With optical microscope (DMRXEHC) and scanning electron microscope (1530VP) powder body is observed respectively, powder body is spherical or subsphaeroidal microgranule, no adhesion, no agglomerate, good dispersion.Adopt the laser granulometry of Britain Malvem company that the different batches powder body has been carried out particle size distribution, the result show all samples granularity less than 10 microns parts all greater than 90%, concrete data are as shown in table 1.
Table 1 insulin human powder size measure of spread result
| Batch | Counter solvent | Particle mean size (micron) | Percentage ratio is at the granularity below 10% (micron) | Percentage ratio is at the granularity below 90% (micron) |
| 1 | Ethanol | 3.57 | 0.66 | 4.13 |
| 2 | Acetone | 5.09 | 0.86 | 10.03 |
| 3 | Isopropyl alcohol | 4.47 | 1.03 | 9.78 |
Embodiment 5: tires, and hmw protein content, A21 deamination insulin content and loss on drying detect.According to Chinese Pharmacopoeia and American-European pharmacopeia regulation to the insulin human biochemical property, more than every detection up to standard require as shown in table 2.
The relevant regulation that table 2 pharmacopeia detects insulin human
| Detect target | Standards of pharmacopoeia |
| Tire | >27.5U/mg |
| A21 deamination insulin | Maximum 1-2％ |
| Hmw protein | ≤1.0％ * |
| Loss on drying | ≤10％ |
| Zinc content | <1.0％ |
Prepare the destruction degraded whether process causes insulin human in order to assess supercritical fluid, measure with the insulin human dry powder of HPLC method after to insulin human raw material and supercritical fluid preparation.Method is according to the Chinese Pharmacopoeia regulated procedure, calculates insulin by peak area method and tires hmw protein content and A21 deamination insulin content.The loss on drying of insulin human detects and adopts thermogravimetric analysis (TGA/SDTA851e of Mettler Toledo company) to finish, zinc content adopts XRF power spectrum (S4 Pioneer) to detect, every testing result is as shown in table 3. and visible supercritical fluid prepares tiring of descendant's insulin and does not significantly change, hmw protein content and A21 deamination insulin content significantly do not increase, zinc content is constant, and loss on drying is up to standard.The insulin human biological activity keeps than spray drying and lyophilizing preparation very big lifting being arranged, and loss is less than 5%.
Table 3 insulin human is tired, hmw protein, and A21 content, zinc content and loss on drying detect
| Sample | (U/mg) tires | Hmw protein percentage ratio (%) | A21 percentage ratio (%) | Zinc content (%) | Loss on drying (%) |
| The insulin human raw material | 28.5 | 0.10 | 0.16 | 0.62 | 4.6 |
| With ethanol preparation | 26.9 | 0.13 | 0.26 | 0.62 | 5.5 |
| Prepare with isopropyl alcohol | 26.1 | 0.12 | 0.33 | 0.62 | 6.6 |
| Prepare with acetone | 26.2 | 0.1 5 | 0.36 | 0.62 | 5.6 |
Embodiment 6: residual solvent detects.Residual solvent can influence the stability and the physicochemical property of medicine, even produces toxic and side effects, and its content must be controlled in the pharmacopeia prescribed limit.Adopt headspace gas chromatography that the powder body with the acetone preparation has been carried out the residual solvent detection, the result is as shown in table 4, and data show adopts content and the international standard of the dry powder residual solvent content of supercritical fluid technology preparation well below crude drug.
Table 4 insulin human dry powder residual solvent testing result
| Sample | Ethanol | Acetone | Total amount | |||
| ％w/w | ppm | ％w/w | ppm | ％w/w | ppm | |
| The insulin human raw material | 5.439 | 54397 | 0.009 | 86 | 5.451 | 54505 |
| Prepare with acetone | 0.045 | 450 | 0.063 | 630 | 0.11 3 | 1 130 |
Embodiment 7: Detection of Stability.In 1 year study on the stability cycle of dry powder, preservation condition is 20-25 ℃.Reach per subsequently 4 months according to embodiment 5 described detection methods from preparing initially, to tiring, hmw protein content and A21 deamination insulin content detect, and the result is shown in table 5-7, and it is quite stable under room temperature preservation that data show adopts the dry powder of supercritical fluid technology preparation.Keep insulin human bioactive stable aspect the suction dry powder of supercritical fluid technology preparation, the loss that one term room temperature is deposited is less than 5%, other indexs of correlation such as hmw protein content and A21 deamination insulin content almost do not change, and have shown superiority of the present invention.
The table 5 insulin human Detection of Stability result that tires
| Sample | Beginning (%) | 4 months (%) | 8 months (%) | 12 months (%) |
| The insulin human raw material | 28.5 | 28.4 | 28.6 | 28.4 |
| With ethanol preparation | 27.6 | 27.3 | 27.8 | 27.7 |
| Prepare with isopropyl alcohol | 27.4 | 27.7 | 27.6 | 27.5 |
| Prepare with acetone | 27.0 | 27.2 | 27.1 | 27.1 |
Table 6 insulin human hmw protein stable content testing result
| Sample | Beginning (%) | 4 months (%) | 8 months (%) | 12 months (%) |
| The insulin human raw material | 0.45 | 0.51 | 0.47 | 0.60 |
| With ethanol preparation | 0.27 | 0.38 | 0.45 | 0.59 |
| Prepare with isopropyl alcohol | 0.48 | 0.51 | 0.60 | 0.89 |
| Prepare with acetone | 0.32 | 0.41 | 0.61 | 0.76 |
Table 7 insulin human A21 deamination insulin content Detection of Stability result
| Sample | Beginning (%) | 4 months (%) | 8 months (%) | 12 months (%) |
| The insulin human raw material | 0.55 | 0.54 | 0.52 | 0.56 |
| With ethanol preparation | 0.07 | 0.08 | 0.06 | 0.09 |
| Prepare with isopropyl alcohol | 0.15 | 0.19 | 0.1 7 | 0.16 |
| Prepare with acetone | 0.73 | 0.74 | 0.70 | 0.75 |
Claims (10)
1. method of utilizing supercritical fluid technology to prepare human insulin inhaled dry powder is characterized in that it may further comprise the steps:
(1) with acid solution the insulin human raw material is diluted to medicinal liquid;
(2) with the supercritical fluid that is suitable for as mainly preparing medium;
(3) prepare the supercritical process condition;
(4) adopt counter solvent and reverse extraction technology equipment;
(5) insulin human raw material diluent is mixed by the nozzle of reverse extraction technology equipment simultaneously with the preparation medium of counter solvent and suitable supercritical fluid, through nozzle atomization, under the supercritical process condition, enter particle molding still, counter solvent flow 0.5-5ml/min wherein, medicinal liquid flow 0.01-0.5ml/min, preparation rate-of flow 10-200ml/min;
(6) form drug loading and reach more than 90%, particle diameter is 1～10 micron a powder body, promptly is suitable for the dry powder that pulmonary sucks;
(7) residual liquid after the preparation process is handled.
2. according to the said a kind of method of utilizing supercritical fluid technology to prepare human insulin inhaled dry powder of claim 1, it is characterized in that the used acid solution of insulin human raw material dilute liquid medicine in the said step (1), be with organic acid, mineral acid preparation, typical citric acid, acetic acid, hydrochloric acid solution as 10-100mM, after insulin human dissolved under acid condition, being prepared into concentration was the 10-80mg/ml medicinal liquid.
3. according to the said a kind of method of utilizing supercritical fluid technology to prepare human insulin inhaled dry powder of claim 1, the preparation medium that it is characterized in that suitable supercritical fluid in the said step (2) (3) is got carbon dioxide, super critical condition pressure power 8-35MPa, temperature 35-55 ℃, carbon dioxide flow 10-50ml/min.
4. according to the said a kind of method of utilizing supercritical fluid technology to prepare human insulin inhaled dry powder of claim 1, it is characterized in that the counter solvent in the said step (4) is got ethanol, isopropyl alcohol or acetone.
5. according to the said a kind of method of utilizing supercritical fluid technology to prepare human insulin inhaled dry powder of claim 1, it is characterized in that the reverse extraction technology equipment in the said step (5) comprises carbon dioxide steel cylinder 1, booster pump 2, spray pump 3, solvent pump 4, nozzle 5, microgranule molding still 6, back pressure controller 7, remaining gas-liquid separating still 8, residual gas floss hole 9 and residual liquid catcher 10, with the upper-part order of connection be: the outfan of carbon dioxide steel cylinder 1 connects booster pump 2, the outfan of booster pump 2 connects nozzle 5, spray pump 3 is connected nozzle 5 with solvent pump 4, nozzle 5 feeds microgranule molding still 6, microgranule molding still 6 connects remaining gas-liquid separating still 8 through back pressure controller 7, remaining gas-liquid separating still 8 has residual gas floss hole 9 respectively and feeds the residual liquid discharge mouth of residual liquid catcher 10, and wherein all have can be according to the function of process conditions regulating and controlling temperature for microgranule molding still and remaining gas-liquid separating still.
6. according to the said a kind of method of utilizing supercritical fluid technology to prepare human insulin inhaled dry powder of claim 1, it is characterized in that the productive rate of the dry powder that is suitable for pulmonary's suction in the said step (6) is 70%-80%.
7. according to the said a kind of method of utilizing supercritical fluid technology to prepare human insulin inhaled dry powder of claim 1-6, it is characterized in that: adopt ethanol as counter solvent; Ethanol flow 0.5-5ml/min, medicinal liquid flow 0.01-0.5ml/min; The technology of optimizing is pressure 11MPa, 37 ℃ of temperature, and carbon dioxide flow 25ml/min, ethanol flow 1.5ml/min, concentration is 50mg/ml medicinal liquid flow 0.05ml/min, powder body that can prepared sizes 1-5 micron, productive rate is more than 80%.
8. according to the said a kind of method of utilizing supercritical fluid technology to prepare human insulin inhaled dry powder of claim 1-6, it is characterized in that: adopt isopropyl alcohol as counter solvent; Isopropyl alcohol flow 0.5-5ml/min, medicinal liquid flow 0.01-0.5ml/min; The technology of optimizing is pressure 11MPa, 37 ℃ of temperature, and carbon dioxide flow 35ml/min, isopropyl alcohol flow 1.0ml/min, concentration is 50mg/ml medicinal liquid flow 0.05ml/min, powder body that can prepared sizes 1-10 micron, productive rate about 70%.
9. according to the said a kind of method of utilizing supercritical fluid technology to prepare human insulin inhaled dry powder of claim 1-6, it is characterized in that: adopt acetone as counter solvent; Acetone flow 0.5-5ml/min, medicinal liquid flow 0.01-0.5ml/min; The technology of optimizing is pressure 11MPa, 37 ℃ of temperature, and carbon dioxide flow 30ml/min, acetone flow 1.5ml/min, concentration is 50mg/ml medicinal liquid flow 0.05ml/min, powder body that can prepared sizes 1-10 micron, productive rate about 70%.
10. human insulin inhaled dry powder that utilizes the preparation of above-mentioned supercritical fluid technology, it is characterized in that prepared human insulin inhaled in powder more than 90% for particle diameter at 1～10 micron unformed powder body, insulin human content is more than or equal to 90%, residual solvent representative value ethanol 450ppm, acetone 630ppm is far below the Chinese Pharmacopoeia required standard; Tiring 〉=27.5U/mg of prepared human insulin inhaled dry powder, hmw protein content≤0.5%, A21 deamination insulin content≤0.5%, zinc content≤0.7%, loss on drying≤10%, one a year room temperature is deposited stable, it is tired, hmw protein content, A21 deamination insulin content, zinc content, loss on drying all with preparation at the beginning of relatively, obviously do not change, still reach China and American-European standards of pharmacopoeia.
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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102058539A (en) * | 2010-12-24 | 2011-05-18 | 国家纳米技术与工程研究院 | Process for preparing composite fine insulin particles by applying supercritical fluid crystallization technology |
| CN109620962A (en) * | 2017-10-09 | 2019-04-16 | 中牧实业股份有限公司 | A kind of thinner for vaccine and the preparation method and application thereof |
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| Publication number | Priority date | Publication date | Assignee | Title |
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| FR2797398B1 (en) * | 1999-08-11 | 2002-10-18 | Mainelab | MICROPARTICLES FOR PULMONARY ADMINISTRATION |
| US20030091513A1 (en) * | 2001-10-03 | 2003-05-15 | Mohsen Nahed M. | Method to generate water soluble or nonwater soluble in nanoparticulates directly in suspension or dispersion media |
| CN1226371C (en) * | 2004-05-13 | 2005-11-09 | 四川大学 | Collagen purification method using CO2 supercritical fluidization method |
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Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102058539A (en) * | 2010-12-24 | 2011-05-18 | 国家纳米技术与工程研究院 | Process for preparing composite fine insulin particles by applying supercritical fluid crystallization technology |
| CN109620962A (en) * | 2017-10-09 | 2019-04-16 | 中牧实业股份有限公司 | A kind of thinner for vaccine and the preparation method and application thereof |
| CN109620962B (en) * | 2017-10-09 | 2021-11-26 | 中牧实业股份有限公司 | Vaccine diluent and preparation method and application thereof |
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