CN1301747C - Protein medicine microcapsule and inhalational aerosol thereof - Google Patents
Protein medicine microcapsule and inhalational aerosol thereof Download PDFInfo
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- CN1301747C CN1301747C CNB200410096165XA CN200410096165A CN1301747C CN 1301747 C CN1301747 C CN 1301747C CN B200410096165X A CNB200410096165X A CN B200410096165XA CN 200410096165 A CN200410096165 A CN 200410096165A CN 1301747 C CN1301747 C CN 1301747C
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Abstract
The present invention relates to a protein medicine microcapsule which is suitable for preparing aerosol. A protein medicine is wrapped on a microcapsule, and the particle diameter of each of most of the microcapsules is less than 10 micrometers; the present invention has the action of slow release and controlled release and can maintain the bioactivity of the medicine. The present invention also relates to a compound which comprises a microcapsule and a carrier, the microcapsule comprises the protein medicine of the present invention, and the carrier can be accepted by pharmacy. The present invention also relates to imbedibility aerosol of the protein medicine, which comprises a microcapsule and a propellant, wherein the microcapsule comprises the protein medicine of the present invention; the imbedibility aerosol can be prepared into the preparation of an aerosol by which administration can be absorbed. Administration can be realized in the mode of inhalation, the protein medicine is transported to a respiratory system so the purpose of therapy is achieved. The present invention provides an ideal novel dosage form used for conveying the protein medicine.
Description
Technical field
The present invention relates to a kind of protein medicine microcapsule that contains protein drug.
The invention still further relates to a kind of novel drugs dosage form of protein drug, specifically contain the inhalational aerosol of protein medicine microcapsule.
Background technology
Existing protein drug mainly is by the injecting pathway medication, simultaneously many new dosage forms is arranged also, develops as eye drop, suppository, ointment, gel, tablet, capsule, ointment etc.
For treatment of diseases, can carry out inhalation.Inhalation is meant and utilizes the granule of atomising device with tens microns to several microns of medicinal atomized one-tenth, make medicine arrive the administering mode of pulmonary by respiratory tract, this administering mode comprises three kinds of dosage forms, (1) spray, it is by a small-sized machine device under external force, and drug solution pressurization back is formed spraying.(2) powder spray, medicine powdered form sucks powder by the air-breathing energetically of patient.(3) aerosol, its feature are to add the material that a class is called propellant in the container of medicine is housed, and propellant is compressed into liquid state in container, but expand into gaseous state immediately when disengaging by valve, and the medicine that will together take out of is dispersed into tiny microgranule.It comprises solution-type and suspension aerosol.
Aerosol is divided into inhalational aerosol and non-inhalational aerosol.Undoubtedly, the imbedibility aerosol is with the mode administration that sucks.By the inhalation of aerosol, can make medicine reach the alveolar position rapidly, and because alveolar is a simple epithelium cell composition, medicine can be absorbed preferably at this position enter blood, thereby reaches the purpose of treatment systemic disease.The surface that is unlikely to be deposited on respiratory tract chambeies such as trachea, bronchus in order to make medicine effectively arrive alveolar is necessary the granule that atomizing produces is controlled at below 10 microns, and major part is controlled at below 5 microns.
The propellant that uses in the aerosol comprises dichlorodifluoromethan hydro carbons material, is commonly called as fluorine Lyons, alkane hydrofluoride hydrocarbons and alkanes substance.Dichlorodifluoromethan hydro carbons material is considered to that atmospheric ozone layer is had destruction and disabled gradually (will forbid fully to 2010), the new propellant that is hopeful most to replace them is the alkane hydrofluoride hydro carbons, 1.1.1.2-tetrafluoroethane (HFC134a) for example, 1.1.1.2.3.3.3.-heptafluoro-propane (HFA227ea), 1.1-Difluoroethane (HFA152a), iso-butane.They not only can be accepted on environmental problem, and since they hypotoxicity and be adapted to the air pressure of aerosol, thereby make them become a kind of ideal medicine propellant.Because adjuvants such as the surfactant that uses in the fluorochloroparaffins aerosol and cosolvent can not be adapted in the propellant of a new generation, thereby must study new pharmaceutical formulation and could adapt to the hydrofluoroalkane propellant.
U.S. Patent number 5,284,656 disclose a kind of granulocytosis colony stimulative factor preparation, it comprises and is suspended in the pulverizing powder that contains granulocytosis colony stimulative factor in the propellant, and surfactant such as sorbitan trioleate are arranged, and soybean lecithin or oleic acid etc. are as adjuvant, U.S. Patent number 5,364,838 disclose a kind of insulin preparation, and wherein insulin dry powder is suspended in and contains in the oleic low boiling propellant of excipient.
Chinese patent publication number 1171046A (WO 96/19197) discloses peptide and protein drug mixes with the surfactant with promotion Absorption, and dry system post-treatment makes fine grained, and these particle suspendings are in propellant HFCl34a.PCT/JP91/00486 (WO91/16038) discloses protein drug and ground to form fine powder after the saccharide lyophilization, joins with surfactant to prepare aerosol in the propellant again.
WO01/60420 (PCT/US01/00117) is disclosed to be the particulate aerosol of macromolecular drug, and it does not use cosolvent, surfactant, and what it used is the deflocculant with protective effect.U.S. Patent number 5,230,884 disclose the aqueous solution that forms reversed phase micelle encirclement albumen or polypeptide drugs with surfactant, avoid these bioactive molecules to contact with the direct of propellant, thereby protect their bioactive methods.
Because the HFA that uses in the aerosol has the characteristic of organic solvent, protein drug with it directly contact can cause degeneration and loss of activity, must adopt with prior art in different guard method just can obtain ideal aerosol.Thereby design that a kind of to protect protein drug active structures such as interferon in HFA be significant.The purpose of this structure is to prevent direct contact the between HFA and the protein molecular.
Microcapsule be utilize natural or synthesized polymer material as cyst membrane wall shell, by some processing step, drug molecule parcel is made Drug Storage type microencapsulation, i.e. microcapsule.Microcapsule can make in the capsule drug molecule and outside liquid molecule effectively isolate, and safeguards the especially stability of protein molecular of drug molecule, and has characteristics such as sustained-release and controlled release.At present, the microcapsule common method of preparation comprises single coacervation, complex coacervation, thin-film ultrasonic emulsion process, emulsified solvent evaporation, the even method of high pressure breast, microemulsion cooling method, spray drying method, second emulsifying method etc.
(Guangdong pharmacy such as Zhang Lijun, the 11st the 5th phase of volume of calendar year 2001,11-19) development of Bao Dao thrombin aerosol is to adopt calcium alginate that enzyme is made microcapsule structure, again this microcapsule is suspended in the propellant and forms, this thrombin aerosol is for the external of medicine design, belong to non-inhalational aerosol, it is not a purpose with the inhalation of medicine.And calcium alginate is to be difficult to biodegradable macromolecular material, and it falls to respiratory mucosa meeting long-term existence, thereby causes the infringement to the respiratory system 26S Proteasome Structure and Function, so this microcapsule structure also is unsuitable for vivo medicine-feeding.
Summary of the invention
One object of the present invention is to provide a kind of protein medicine microcapsule that is suitable for preparing aerosol, and it wraps up protein drug with microcapsule, and the particle diameter of most of microcapsule has the biological activity that the sustained-release and controlled release effect also can be kept protein drug below 10 microns.
Another object of the present invention is to provide a kind of compositions, and it contains protein medicine microcapsule of the present invention and pharmaceutically acceptable carrier.
A further object of the present invention is to provide a kind of inhalational aerosol of protein drug, and it contains protein medicine microcapsule of the present invention and propellant, but is prepared into the aerosol dosage forms of inhalation.Can pass through the suction administration, protein drug is delivered to respiratory system, reach the purpose of treatment.
According to an aspect of the present invention, protein medicine microcapsule is that various protein drugs and excipient are mixed with the microencapsulated material with biological degradability, prepares protein medicine microcapsule of the present invention.
In the present invention, term " protein drug " or " albumen " or " protein " be meant comprise the preparation of natural existence or recombinant technique, its molecular structure be by several amino acids by the material of molecular weight more than 1000 dalton that peptide bond is formed by connecting, comprise normal " protein " and " polypeptide " that claims of people.Include but not limited to interferon, interleukin, nerve growth factor, granulocyte macrophage colony stimulating factor, granulocyte colony-stimulating factor, erythropoietin, short TP, enzyme, polypeptide vaccine, insulin, glucagon, the C peptide of insulin, vasopressin, Desmopressin, thyroliberin, corticotropin releasing hormone, gonadotropin releasing hormone, gonadotropin releasing hormone agonist and antagonist, the gonadotropin lutropin, calcitonin, parathyroid hormone, thyroxine, growth hormone, growth hormone releasing hormone, somatostatin, oxytocin, atrial natriuretic peptide, prolactin antagonist, follitropin, endorphins, glycoprotein, lipoprotein.
Term " protein medicine microcapsule " be meant utilize natural or synthesized polymer material as cyst membrane wall shell, by some processing step, protein drug molecule parcel is made Drug Storage type microencapsulation, i.e. microcapsule.It can safeguard the stability of protein drug molecule, and has characteristics such as sustained-release and controlled release.But the microencapsulated material of preparation inhalation should have biodegradable, and suitable material includes but not limited to gelatin, arabic gum, tragakanta, albumin, polylactic acid (PLA), polylactic acid-glycolic (PLGA), Polyethylene Glycol.
Be wrapped in the effective dose of the protein drug in the microcapsule, those skilled in the art can determine easily according to the treatment effective dose and the physiology effective dose of the protein drug of concrete use, here term " treatment effective dose " be meant be present in the compositions, patient with after the amount of the required protein drug of physiological reaction can appear.The white amount of drug of every hatching egg is decided as the case may be, and it depends on the biological activity of every hatching egg BAIYAO thing.Term " physiology effective dose " be meant dose a patient with, can produce the expection mitigation or the amount of curative effect, this amount all is specific to every hatching egg BAIYAO thing.
In protein medicine microcapsule of the present invention, also can in protein drug, further add pharmaceutically acceptable excipient keeping the stability of protein drug, preferred excipient is the albumin and/or the carbohydrate of mannitol for example.
The method for preparing protein medicine microcapsule for example can adopt, and is ultrasonic-the low-temperature extraction method, and this method is that---several steps such as separation are processed into microcapsule with protein drug to ultrasonic atomizatio---extraction---by disperseing under cryogenic conditions.Prepare in the method for microcapsule at this, protein drug is made powder type earlier.Can be by protein drug and excipient to be made mixed solution, excipient is an albumin, or carbohydrate, or the combination of their the two arbitrary proportions, mixed liquor is pulverized in jet mill after by lyophilization, can make powder.Also this mixed solution can be made powder by spray drying.The excipient here is in order to safeguard the stability of protein drug, and their shared percentage by weights in mixture are 50%～99%, and promptly the weight ratio of excipient and protein drug is 50: 50～99: 1.The mixture of protein drug and excipient and the weight ratio between the microencapsulated material are 1: 0.1～1: 100, preferred 1: 1～1: 10.The above-mentioned powder that contains protein drug is added to microencapsulated material; for example in the PLGA-dichloromethane solution; behind the ultra-sonic dispersion; be sprayed onto under the nitrogen protection in the ethanol that is chilled to-40 ℃～-80 ℃ through ultrasonic atomizatio; protein drug is very stable in the environment of supercool, and the dichloromethane in the microemulsion is very fast to be extracted by ethanol, and protein medicine microcapsule is separated out; through vacuum drying, microcapsule gets product.The Cryogenic-process device that U.S. Sono-Tek company produces can be used for producing this microcapsule.The particle diameter of microcapsule more than 65% below 10 microns, more than 50% below 5 microns.
Also protein drug and excipient can be prepared into the solution form, then this solution is joined oil medium, for example in the Oleum Arachidis hypogaeae semen, obtain water/fat liquor after the grinding, again this emulsion is ground the double emulsion that obtains water/oil/water in microencapsulated material solution, precipitation is separated out and is made the microcapsule that contains protein drug.
According to a further aspect in the invention, the compositions that contains protein medicine microcapsule can comprise protein medicine microcapsule of the present invention and pharmaceutically acceptable carrier, protein medicine microcapsule and carrier fully are mixed and made into mixture, the ratio of microcapsule in mixture should be determined according to different pharmaceutical, in general carrier shared percentage by weight in mixture is 30%～90%, preferred proportion is 40%～85%, preferred ratio is 50%～80%, the weight ratio that is protein medicine microcapsule and carrier is 70: 30～10: 90, be preferably 60: 40～15: 85, more preferably 50: 50～20: 80.
Term " pharmaceutically acceptable carrier " is meant and can be used to the carrier that pulmonary there is no serious bad toxic action.The amount of acceptable carrier is in order to keep the stable of aerosol and to guarantee the uniform administration in patient's pulmonary.Type as carrier comprises stabilizing agent, pH regulator agent or buffer agent, salt, antioxidant, surfactant, lubricant.
The suitable example of stabilizing agent has human blood from albumen (HSA), also can select carbohydrate, aminoacid, polypeptide etc. for use, as lactose, glucose, fructose, galactose, trehalose, sucrose, maltose, Raffinose, melezitose, threitol, lactose, sorbitol, cyclodextrin, mannitol (or mannitol), xylitol, alanine, glycine, betanin.Trehalose preferably.
PH regulator or buffer agent such as acid phosphate, subphosphate, sodium citrate, sodium ascorbate etc.Sodium citrate preferably.
The suitable example of salt has sodium chloride, sodium alginate etc.
The suitable example of antioxidant has vitamin C, vitamin E etc.
Surfactant can play a part to promote to absorb and lubricate in compositions, also can play emulsifying agent in the microcapsule preparation process, and suitable example has fatty acid and salt thereof, preferred C
8～C
20Fatty acid and salt thereof; as oleic acid, sodium caprylate, sodium laurate; suitable example also has bile acid and salt thereof; as cholic acid, chenodeoxy cholic acid, glycocholic acid, cholyltaurine, glycochenodeoxycholate, Calculus Bovis chenodeoxy cholic acid, deoxycholic acid, glycodesoxycholic acid, Calculus Bovis deoxycholic acid, and salt.Suitable surfactant example also has phospholipid, and as lecithin, cuorin, cephalin, suitable surfactant also comprises Tweens, as Tween 80, and polysorbate85, spans, as sorbester p17, as sorbester p37, and Polyethylene Glycol etc.
In accordance with a further aspect of the present invention, the protein drug inhalational aerosol comprises protein medicine microcapsule of the present invention and propellant, also can comprise compositions and the propellant that contains protein medicine microcapsule of the present invention.Propellant can be selected from 1,1,1,2-tetrafluoroethane (HFC134a), 1,1,1,2,3,3,3-heptafluoro-propane (HFA227ea) 1,1-Difluoroethane (HFA152a), fluorine Lyons F
11, fluorine Lyons F
12, fluorine Lyons F
22With one or more of iso-butane, preferred can be to be selected from 1,1,1,2-tetrafluoroethane (HFC134a), 1,1,1,2,3,3,3-heptafluoro-propane (HFA227ea), 1, one or more of 1-Difluoroethane (HFA152a) and iso-butane.Protein medicine microcapsule or contain its compositions and the weight ratio of propellant can be between 1: 99～30: 70.
In the preparation aerosol, protein medicine microcapsule of the present invention or the compositions that contains it are metered in the pressure vessel, load onto the metering valve that is applicable to aerosol, add propellant, promptly can be made into aerosol.Also can at low temperatures said composition be added in the pressure vessel, pour into propellant again, load onto the metering valve that is applicable to aerosol then, promptly can be made into aerosol.When using button extruding metering valve, because pressure disengages a certain amount of volume with propellant and medicament microcapsule from vessel port to the pressure in jar more than the atmospheric pressure greater than one, propellant is gasification expansion rapidly container outside, form aerosol, and the medicament microcapsule of taking out of is disperseed to deliver to patient's alveolar.
The present invention can further include the medicine box of protein medicine microcapsule inhalation, and this medicine box comprises a unit container that contains protein medicine microcapsule of the present invention or contain its compositions, and this container can provide a predetermined dosage at every turn quantitatively.Protein medicine microcapsule of the present invention or the compositions and the propellant that contain it are packed in this container, and this dosage can provide enough protein drugs for the treatment of patient's unit dose.Can adopt the container that comprises that tank body, metering valve, button three parts constitute.For example, wherein tank body can adopt the C128P type jar that Britain Presspart company produces, the model that metering valve can adopt French Valois company to produce is DF10 or DF30 metering valve, and the model that button can adopt French Valois company to produce is the Inhale actuator of KN1/IN3.
Protein medicine microcapsule of the present invention, the diameter major part is suitable for preparing inhalational aerosol below 10 μ m.In the aerosol of the present invention, microcapsule structure plays a very good protection to protein drug, and the stability of protein drug is improved greatly.The cooperation of propellant in less microcapsule diameter and the aerosol can be delivered to protein drug positions such as alveolar, and medicine can be absorbed preferably, and have the function of sustained-release and controlled release medicine, be a kind of ideal novel form of protein drug.
Below, by description, describe in detail but do not limit the present invention better embodiment of the present invention.
The specific embodiment of invention
The preparation of [embodiment 1] interferon microcapsule and aerosol thereof
Material source: recombinant human interferon alpha 2 b solution, according to " Chinese biological goods rules " (2000 editions) it " recombinant human interferon alpha 2 b manufacturing vertification regulation ", preparation, promptly.
Other all ingredients are the commercially available prod.
Recombinant human interferon alpha 2 b solution 500ml (protein concentration is 0.2mg/ml) adds albumin 1g, mannitol 8.9g, and spray drying obtains the interferon powder.Buchi Laboratory spray dryer can be used for producing this powder.
Above-mentioned powder 5g is added among the dichloromethane solution 50ml that contains 10% (w/v) PLGA, behind the ultra-sonic dispersion, be sprayed onto under the nitrogen protection in the ethanol that is chilled to-40 ℃～-80 ℃, form microemulsion through ultrasonic atomizatio.0.5 after～5 hours, the interferon microcapsule is separated out, through vacuum drying, the interferon microcapsule gets product.The Cryogenic-process device that U.S. Sono-Tek company produces can be used for producing this microcapsule, and it is the coherent device that comprises dispersion, atomizing, extraction, dry each step.
Get 70 parts of interferon microcapsules (weight portion, down together), 0 part of phosphatidase 11,5 parts of oleic acid, 10 parts of trehaloses, sorbester p17 are 5 parts, mix, and get the interferon microcapsule composition.
1 part of interferon microcapsule composition (weight portion, down together) is joined in the container, load onto metering valve, the WQH type sealing machine that metering valve can adopt Shanghai China to win the production of aerosol machinery company limited is loaded onto.Pour into 99 parts of propellant HFC134a under the room temperature, the WQG type aeration machine of the mechanical company limited production of available Shanghai China's victory aerosol is pressed into propellant in the container.
Acutely rocked 30 seconds, in ultrasonic bath, handled 5～20 minutes, can make interferon microcapsule aerosol.
The preparation of [embodiment 2] interleukin II microcapsule aerosol
Material source: it is plain according to " Chinese biological goods rules " (2000 editions) it " the recombinant human interferon alpha 2 interleukin-2 is made vertification regulation " to be situated between certainly, preparation, promptly.
Other all ingredients is the commercially available prod.
Interleukin solution 250ml (protein concentration is 4mg/ml) adds mannitol 30g, and spray drying obtains the interleukin powder.The U.S. produces Buchi Laboratory spray dryer and can be used for producing this powder.
Above-mentioned powder 1g is added among the dichloromethane solution 1000ml that contains 10% (w/v) Polyethylene Glycol, behind the ultra-sonic dispersion, be sprayed onto under the nitrogen protection in the ethanol that is chilled to-40 ℃～-80 ℃, form microemulsion through ultrasonic atomizatio.0.5 after～5 hours, the interleukin microcapsule is separated out, through vacuum drying, the interleukin microcapsule gets product.
Get 10 parts of interleukin-2 microcapsules (weight portion, down together), 0 part of phosphatidase 14,10 parts of oleic acid, 30 parts of trehaloses, sorbester p17 are 10 parts, mix, and get the interleukin microcapsule composition.
30 parts of interferon microcapsule compositions (weight portion, down together) are joined in the container, load onto metering valve, pour into 70 parts of propellant fluorine Lyons F under the room temperature
12In container.
[embodiment 3] low temperature process prepares interferon microcapsule aerosol
In embodiment 1, the interferon microcapsule composition that makes is joined in the container under low temperature-30 ℃～-50 ℃ of conditions, under this cryogenic conditions, add propellant HFA152a, load onto metering valve, in 10 seconds of jolting, obtain interferon microcapsule aerosol.
[embodiment 4] freeze-drying prepares the interferon microcapsule
Recombinant human interferon alpha 2 b solution 1000ml (1mg/ml) adds albumin 40g, and lyophilization is sprayed and pulverized.
Press embodiment 1 described preparation interferon microcapsule and interferon microcapsule composition, make aerosol again.
The preparation of [embodiment 5] W/O/W type interferon microcapsule
Interferon alpha 2 b solution 10ml (1mg/ml) adds albumin 0.2g.This solution is joined in the 30ml Oleum Arachidis hypogaeae semen, ground 0.5～3 hour, obtain the emulsion of W/O.With this emulsion join 3% (w/v) gelatin solution 100ml in, fully grind, obtain the emulsion solution of W/O/W.Add saturated ammonium sulfate solution under 40 ℃～60 ℃ condition, the microcapsule precipitation is separated out, with dilute ammonium sulfate solution washing microcapsule, add 10%～30% formalin under 2 ℃～10 ℃ conditions, curing microcapsules is with distilled water or normal saline washing microcapsule, lyophilization gets finished product interferon microcapsule.
Above-mentioned powder 1g is added among the dichloromethane solution 100ml that contains 10% (w/v) PLGA, behind the ultra-sonic dispersion, be sprayed onto under the nitrogen protection in the ethanol that is chilled to-40 ℃～-80 ℃, form microemulsion through ultrasonic atomizatio.0.5 after～5 hours, the interferon microcapsule is separated out, through vacuum drying, the interferon microcapsule gets product.
Get 40 parts of interferon microcapsules (weight portion, down together), 0 part of phosphatidase 12,5 parts of oleic acid, 30 parts of trehaloses, sorbester p17 are 5 parts, mix, and get the interferon microcapsule composition.
15 parts of interferon microcapsule compositions (weight portion, down together) are joined in the container, load onto metering valve, pour into 85 parts of propellant iso-butanes under the room temperature.
Acutely rocked 30 seconds, in ultrasonic bath, handled 5～20 minutes, can make interferon microcapsule aerosol.
The preparation of [embodiment 6] insulin microcapsule aerosol
Material source: insulin, commercially available, the Xuzhou biochemical-pharmaceutical factory produces, and is mixed with 10mg/ml.
Insulin solutions 1000ml (10mg/ml) with mannitol 10g dissolving, makes mixed solution, and other joins 2% (w/v) gelatin solution 100ml as microencapsulated material.The nitro-atomizerospray drying twin-jet nozzle spray dryer that uses Denmark to produce, the insulin mixed solution of one of them nozzle ejection is in exsiccator rapidly after the drying, another nozzle ejection gelatin solution covers insulin granule outer surface, and, promptly get the insulin microcapsule by dry rapidly.
Get 60 parts of insulin microcapsules, 5 parts of sodium caprylate, 5 parts of oleic acid, 25 parts of trehaloses, sorbester p17 are 5 parts, mix, and get the insulin microcapsule composition.Compositions is joined in the container for 30 parts, load onto metering valve, pour into 70 parts of propellant HFA227ea under the room temperature, promptly get insulin microcapsule aerosol.
The aerosol stability that [embodiment 7] interferon microcapsule aerosol and interferon directly prepare relatively
Recombinant human interferon alpha 2 b solution 500ml (protein concentration is 0.2mg/ml) adds albumin 1g, mannitol 8.9g, and spray drying obtains the interferon powder.
Get 70 parts in interferon powder (weight portion, down together), 0 part of phosphatidase 11,5 parts of oleic acid, 10 parts of trehaloses, sorbester p17 are 5 parts, mix.
1 part of said mixture (weight portion, down together) is joined in the container, load onto metering valve, pour into 99 parts of propellant HFC134a under the room temperature.
Get the aerosol of above preparation and the interferon microcapsule aerosol among the embodiment 1, put under the room temperature condition, measure the percent that interferon activity keeps after 1 month, 6 months respectively according to " Chinese biological goods rules " (2000 editions) it " recombinant human interferon alpha 2 b manufacturing vertification regulation ".The result is as follows:
| The percent of retentive activity after one month | The percent of retentive activity after 6 months | |
| The interferon aerosol | 0％ | 0％ |
| Interferon microcapsule aerosol | 90％ | 88％ |
By above result as can be seen, interferon microcapsule aerosol good stability, microcapsule structure is the biological activity of protected protein molecule effectively.
The particle size determination of [embodiment 8] protein medicine microcapsule
Get slide, be coated with mixture (2: 1) with liquid paraffin and vaseline, add the heat extraction bubble and make cushion, get the protein microcapsule aerosol of embodiment 1～embodiment 6 (being numbered 1～6 in the following table), its nozzle is being sprayed apart from above-mentioned cushion 25～30cm place, cushion is put microscopically observe, measure the particle diameter of collecting granules, calculate 10 microns and 5 micron particle and account for whole particulate percents.
| The percent of 10 micron particle | The percent of 5 micron particle | |
| 1 | 68.3％ | 53.6％ |
| 2 | 71.2％ | 54.7％ |
| 3 | 66.8％ | 58.3％ |
| 4 | 74.5％ | 59.8％ |
| 5 | 70.2％ | 60.4％ |
| 6 | 64.5％ | 51.6％ |
By above result as seen, the grain diameter of protein medicine microcapsule more than 60% that the present invention makes is below the 10 μ m, below 5 microns, is very suitable for preparing aerosol more than 50%, can disperse effectively and absorb in vivo.
Above detailed description of the present invention does not limit the present invention, and those skilled in the art can make various changes and distortion according to the present invention, only otherwise break away from spirit of the present invention, all should belong to the defined scope of claim of the present invention.
Claims (6)
1, a kind of protein drug inhalational aerosol comprises
Protein medicine microcapsule, described protein medicine microcapsule contains
The protein drug of effective dose;
Microencapsulated material, described microencapsulated material is selected from one or more of gelatin, arabic gum, tragakanta, albumin, Polyethylene Glycol, polylactic acid and polylactic acid-glycollic acid;
The grain diameter of wherein said protein medicine microcapsule at least 60% is less than 10 microns, and at least 50% grain diameter is less than 5 microns; And
Propellant, the weight ratio of described protein medicine microcapsule and described propellant are 1: 99～30: 70;
Wherein said protein medicine microcapsule is the interferon microcapsule.
2, the described protein drug inhalational aerosol of claim 1 is characterized in that described propellant is selected from 1,1,1,2-tetrafluoroethane, 1,1,1,2,3,3,3-heptafluoro-propane, 1,1-Difluoroethane, iso-butane, fluorine Lyons F
11, fluorine Lyons F
12With fluorine Lyons F
22One or more.
3, the described protein drug inhalational aerosol of claim 2 is characterized in that described propellant is selected from 1,1,1,2-tetrafluoroethane, 1,1,1,2,3,3,3-heptafluoro-propane, 1, one or more of 1-Difluoroethane and iso-butane.
4, the described protein drug inhalational aerosol of claim 1 is characterized in that it further contains pharmaceutically acceptable carrier.
5, the described protein drug inhalational aerosol of claim 4, the weight ratio that it is characterized in that described protein medicine microcapsule and described carrier is 70: 30～10: 90.
6, a kind of protein drug inhalation medicine box comprises
The described protein drug inhalational aerosol of claim 1; And
One unit container is used to take in described protein drug inhalational aerosol, and described container is through push the protein drug that can provide a predetermined close quantitatively at every turn.
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| GB201114725D0 (en) * | 2011-08-25 | 2011-10-12 | Altacor Ltd | Ophthalmic formulations |
| CN102416008A (en) * | 2011-11-22 | 2012-04-18 | 华侨大学 | Sustained-release anti-tumor aptamer medicine microcapsules and preparation technology thereof |
| CN102552215B (en) * | 2012-02-02 | 2014-08-13 | 浙江海正药业股份有限公司 | Microcapsule lyophilized powder and preparation method thereof |
| CN104414974A (en) * | 2013-08-29 | 2015-03-18 | 宋金春 | Neferine sublingual spraying agent and preparation method thereof |
| CN104549085B (en) * | 2015-01-12 | 2016-06-08 | 中国科学院化学研究所 | A kind of antioxidase Nano capsule and its preparation method and application |
| CN105664137B (en) * | 2016-02-29 | 2019-10-18 | 泉州台商投资区大千机械科技有限公司 | Powder spray of insulin-containing and preparation method thereof |
| US20230347080A1 (en) * | 2020-01-28 | 2023-11-02 | Chiesi Farmaceutici S.P.A | Pressured metered dose inhalers comprising a buffered pharmaceutical formulation |
Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1171046A (en) * | 1994-12-22 | 1998-01-21 | 阿斯特拉公司 | Aerosol formulations of peptides and proteins |
| US5747001A (en) * | 1995-02-24 | 1998-05-05 | Nanosystems, L.L.C. | Aerosols containing beclomethazone nanoparticle dispersions |
| US6264922B1 (en) * | 1995-02-24 | 2001-07-24 | Elan Pharma International Ltd. | Nebulized aerosols containing nanoparticle dispersions |
-
2004
- 2004-11-30 CN CNB200410096165XA patent/CN1301747C/en not_active Expired - Fee Related
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1171046A (en) * | 1994-12-22 | 1998-01-21 | 阿斯特拉公司 | Aerosol formulations of peptides and proteins |
| US5747001A (en) * | 1995-02-24 | 1998-05-05 | Nanosystems, L.L.C. | Aerosols containing beclomethazone nanoparticle dispersions |
| US6264922B1 (en) * | 1995-02-24 | 2001-07-24 | Elan Pharma International Ltd. | Nebulized aerosols containing nanoparticle dispersions |
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