CN103054805A - Preparation method and application of injection for needle-free injection - Google Patents
Preparation method and application of injection for needle-free injection Download PDFInfo
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- CN103054805A CN103054805A CN201110322321XA CN201110322321A CN103054805A CN 103054805 A CN103054805 A CN 103054805A CN 201110322321X A CN201110322321X A CN 201110322321XA CN 201110322321 A CN201110322321 A CN 201110322321A CN 103054805 A CN103054805 A CN 103054805A
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- injection
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Images
Classifications
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- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02A—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE
- Y02A50/00—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE in human health protection, e.g. against extreme weather
- Y02A50/30—Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change
Abstract
The invention relates to an injection for needle-free injection, wherein the injection is in a powder form and comprises a biological product and a crystal water removed organic salt according to the mass ratio of (1:20) to (1:80); the powder consists of solid particles in which the biological product is coated at the outer surface of the crystal water removed organic salt. The injection provided by the invention may also comprise a thickener or traditional Chinese medicine adjuvant, wherein the mass ratio of the biological product to the thickener or traditional Chinese medicine adjuvant to the crystal water removed organic salt is (1:0.2:20) to (1:10:80). The particle size of the powder of the injection provided by the invention is between 20microns and 200microns, preferably is between 50microns and 70micorns. The invention also relates to a preparation method of the injection for needle-free injection, an application of the injection for needle-free injection in preparation of drugs for preventing or treating diseases and a method for using the injection for needle-free injection to perform needle-free injection.
Description
Technical field
The present invention relates to a kind of Needleless injection preparation method and the purposes of injection, and relate in particular to a kind of preparation method and purposes that is the injection of powder type.
Background technology
Biological product are to use common biomaterial or the biomaterial preparations such as the tissue in the microorganism, cell and the various animal and humans source that obtain by biotechnology such as genetic engineering, cell engineering, protein engineering, fermentation engineerings and liquid, are used for the medicine of human diseases prevention, treatment and diagnosis.At present, Chinese people comprises in antibacterial class vaccine (containing toxoid), virus type vaccine, antitoxin and immune serum, blood products, cytokine, the body and in-vitro diagnosis goods and other active ingredients (comprising toxin, antigen, allergen, monoclonal antibody, recombinant dna product, antigen-antibody complex, immunomodulator, microorganism formulation etc.) with biological product.The active component of most of biological product is macromolecular living matter (such as protein, polypeptide, nucleic acid, polysaccharide etc.), its relative molecular mass is larger, being difficult for penetrating gastrointestinal tract barrier is absorbed by body, and easy digested liquid decomposes and inactivation, so be not suitable for oral administration, in most cases need intravenous injection, intramuscular injection, subcutaneous injection etc.But there are a lot of problems in the normal injection administration, for example: 1) can cause hemorrhagely, have the cross infection risk; 2) tissue injury is large, and some chronic diseases such as diabetics need the long term injections insulin, often cause the pathological changes such as injection site tissue sclerosis, caking; 3) pain is strong, and patient's compliance is relatively poor, is difficult to especially adapt to for child and the people that probably pin sense is arranged, and they can't be stood for the pain of acupuncture; 4) usually need the professional to finish, be unsuitable for automedication.
Applicant has just remedied these defectives in the Needleless powder injection medicament administration technology (CN 201643226) of first to file: the Needleless powder injection technology is passed through percutaneous drug delivery, Transdermal absorption can be avoided first pass effect, bioavailability is high, can effectively avoid cross infection, needleless, painless, operational efficiency is high, can the oneself operate, and needing to be particularly suitable for patient, the child of long term administration treatment and the probably patient of pin sense is arranged.
The Needleless powder injection technology has special requirement to preparation method and the powder properties of drug powder: 1) density of medicine carrying powder is larger, and is full particle, has larger mechanical strength, is beneficial to the transdermal horny layer; 2) powder diameter large (as tens of to hundreds of microns) is so that medicine carrying powder larger kinetic energy (momentum) of acquisition when being accelerated by high velocity air is beneficial to the transdermal horny layer; 3) powder diameter narrow distribution obtains akin kinetic energy (momentum) to guarantee the medicine carrying powder when being accelerated by high velocity air, guarantee repeatability and the stability of drug delivery.Present existing powder preparation method scarcely is adapted to Needleless powder injection, does not reach practical, business-like requirement.More published drug powders or microgranule preparation method great majority are aimed at microsphere and microcapsule design, and carrier mostly is greatly macromolecular compound, and density is low (usually at 1g/cm
3About or lower), and mostly be hollow bead, mechanical strength is little, is difficult for the transdermal horny layer; Simultaneously, institute's acquisition microsphere or the most particle diameter of microcapsule are less, and micron is to the twenty or thirty micron in full, and particle size distribution is wider, is difficult to satisfy above-mentioned specification requirement to the Needleless injection powder, thus not high by the efficient of Needleless powder injection medicament administration, bioavailability is lower; In addition, the biocompatibility issues of the carrier mass that adopts and vivo degradation also are one of limiting factors.Before, the inventor herein once disclosed a kind of powder preparation method of direct mixing, still there is larger defective in the method: 1) phosphate and insulin mixed solution, drying under reduced pressure, so that insulin and phosphate cocrystallization (or only being the two respectively mixture of crystallization), resulting powder diameter uniformity is relatively poor; 2) insulin can not effectively be attached on the phosphate carrier, and operational efficiency is lower; 3) drying under reduced pressure makes the problems such as the insulin inactivation is serious.
Summary of the invention
In view of above-mentioned factor, the invention provides a kind of efficient powder preparation method that is suitable for the load biological product, the powder of preparing take this method as full particle, density is large, mechanical strength is large, epigranular, stability is strong, drug loading is high, effectively transdermal horny layer, arrival Intradermal or subcutaneous location performance are renderd a service, and bioavailability is high.
The injection that provides a kind of Needleless injection to use is provided primary and foremost purpose of the present invention.
Another object of the present invention provides the preparation method of the injection that a kind of Needleless injection uses.
Another object of the present invention provides injection that a kind of Needleless injection uses for the preparation of the purposes of the medicine of prevention or treatment disease.
Another purpose of the present invention provides the method that a kind of injection that uses Needleless injection to use carries out Needleless injection.
In first aspect, the invention provides the injection that a kind of Needleless injection is used, injection of the present invention is powder type, and described injection comprises that mass ratio is 1: 20-1: 80 biological product and take off the water of crystallization inorganic salt, described powder is that described biological product are wrapped in the described full particle that takes off water of crystallization inorganic salt outer surface, and the particle diameter of described powder is between the 20-200 micron.Preferably, described mass ratio is 1: 20-1: 60, most preferably be 1: 20-1: 40; Described particle diameter is between the 50-70 micron.
In the embodiment of first aspect, described biological product include but not limited to one or more in the following biological product: reach in-vitro diagnosis goods and other active ingredients in insulin, interferon, vaccine, antitoxin and immune serum, blood products, cytokine, the body.Preferably, described biological product are selected from one or more in insulin, interferon and the vaccine.More preferably, described biological product are insulin.
Preferably, described insulin is selected from regular insulin, isophane insulin, insulin zinc protamine, premix insulin; Described interferon is selected from: IFN-α 2b, IFN-α 2a, lymphoblastoid interferon or its combination; Described vaccine is antibacterial or viral vaccine, can be selected from the following vaccine one or more: Hepatitis B virus vaccine, tetanus toxoid vaccine, Mumps Vaccine, Measles Vaccine, antityphoid vaccine, influenza vaccines, diphtheria vaccine, Anthrax vaccine, Brucella vaccine, leptospira vaccine and Teck-borne Encephalitis Vaccine.
In the embodiment of first aspect, the described water of crystallization inorganic salt that takes off is selected from anhydrous sodium sulfate, dead plaster, anhydrous slufuric acid aluminum, anhydrous magnesium sulfate, anhydro-zinc sulfate, anhydrous potassium aluminium sulfate, anhydrous nitric acid potassium, anhydrous acid acid aluminum, ADKP or its combination.Preferably, the described water of crystallization inorganic salt that takes off is anhydrous sodium sulfate.
In another embodiment of first aspect, except above-mentioned biological product and taking off the water of crystallization inorganic salt, injection of the present invention also comprises viscosifier, wherein said biological product, described viscosifier and the described mass ratio that takes off the water of crystallization inorganic salt are: 1: 0.2: 20-1: 10: 80, be preferably 1: 0.5: 20-1: 2: 60, more preferably 1: 0.5: 40-1: 2: 40.
The optional self-induced transparency matter acid of described viscosifier sodium, human albumin or its combination.
In another embodiment of first aspect, except above-mentioned biological product and taking off the water of crystallization inorganic salt, injection of the present invention also comprises pharmaceutically acceptable adjuvant, wherein said biological product, described adjuvant and the described mass ratio that takes off the water of crystallization inorganic salt are 1: 0.2: 20-1: 10: 80, be preferably 1: 0.5: 20-1: 7: 60, more preferably 1: 0.8: 20-1: 2: 40.
Described adjuvant is preferably the Chinese medicine adjuvant, and described Chinese medicine adjuvant can be selected from saponin, polysaccharide, flavone or its combination.
Preferably, saponin is selected from ginsenoside, arasaponin, gypenoside, Radix Clematidis saponin, dioscin or its combination etc.; Polysaccharide is selected from astragalus polysaccharides, ginseng polysaccharide, polyporusum bellatus, Radix Rhodiolae polysaccharide, jujube polysaccharide or its combination etc.; Flavone is selected from epimedium flavone, Fructus Fortunellae Margaritae flavone, Herba Hedyotidis Diffusae flavone, daidzein, Fructus Hippophae flavone or its combination etc.
In another embodiment of first aspect, except above-mentioned biological product and taking off the water of crystallization inorganic salt, injection of the present invention also comprises pharmaceutically acceptable adjuvant and viscosifier, wherein said biological product, described adjuvant, described viscosifier and the described mass ratio that takes off the water of crystallization inorganic salt are 1: 0.2: 0.2: 20-1: 10: 10: 80, be preferably 1: 0.5: 0.5: 20-1: 7: 7: 60, more preferably 1: 0.8: 0.8: 20-1: 2: 2: 40.
Described adjuvant is preferably the Chinese medicine adjuvant, and described Chinese medicine adjuvant can be selected from saponin, polysaccharide, flavone or its combination.The optional self-induced transparency matter acid of described viscosifier sodium, human albumin or its combination.
Preferably, saponin is selected from ginsenoside, arasaponin, gypenoside, Radix Clematidis saponin, dioscin or its combination etc.; Polysaccharide is selected from astragalus polysaccharides, ginseng polysaccharide, polyporusum bellatus, Radix Rhodiolae polysaccharide, jujube polysaccharide or its combination etc.; Flavone is selected from epimedium flavone, Fructus Fortunellae Margaritae flavone, Herba Hedyotidis Diffusae flavone, daidzein, Fructus Hippophae flavone or its combination etc.
In the above-mentioned embodiment of a first aspect of the present invention, described injection is used by Needleless injection.
In the above-mentioned embodiment of a first aspect of the present invention, described injection prepares by the following method: in 0-4 ℃ of environment with particle diameter at the 20-200 micron, in the preferred 50-70 micrometer range, most preferably about 50 microns take off in the aqueous solution that water of crystallization inorganic salt powder adds described biological product to or extremely saturated in the aqueous solution of the mixture of described biological product and described viscosifier and/or described adjuvant; Continue to add and describedly to take off water of crystallization inorganic salt powder so that described biological product and the total mass ratio that takes off the water of crystallization inorganic salt are 1: 20-1: 80, preferred 1: 20-1: 60, most preferably 1: 20-1: 40, obtain mixed crystallization solution; With the lyophilization of described mixed crystallization solution, collection cut size is at the 20-200 micron, and the powder in the preferred 50-70 micrometer range obtains Needleless injection injection of the present invention.
In second aspect, the invention provides such as the preparation method of the described Needleless injection of first aspect with injection, described method comprises the following steps: in 0-4 ℃ of environment particle diameter at the 20-200 micron, in the preferred 50-70 micrometer range, most preferably about 50 microns take off in the aqueous solution that water of crystallization inorganic salt powder adds described biological product to or extremely saturated in the aqueous solution of the mixture of described biological product and described viscosifier and/or described adjuvant; Continue to add and describedly to take off water of crystallization inorganic salt powder so that described biological product and the total mass ratio that takes off the water of crystallization inorganic salt are 1: 20-1: 80, preferred 1: 20-1: 60, most preferably 1: 20-1: 40, obtain mixed crystallization solution; With the lyophilization of described mixed crystallization solution, collection cut size is at the 20-200 micron, and the powder in the preferred 50-70 micrometer range obtains Needleless injection injection of the present invention.
In an embodiment of second aspect, the preparation method of injection of the present invention comprise the steps: (1) pulverize and the screening particle diameter at the 20-200 micron, preferred 50-70 micron most preferably takes off water of crystallization inorganic salt powder about 50 microns; (2) take off in the aqueous solution that water of crystallization inorganic salt powder adds biological product to saturated described at 0-4 ℃; (3) continue to add and describedly to take off water of crystallization inorganic salt powder so that described biological product and the described mass ratio that takes off water of crystallization inorganic salt powder are 1: 20-1: 80, preferred 1: 20-1: 60, most preferably 1: 20-1: 40, obtain mixed crystallization solution; (4) with the lyophilization of described mixed crystallization solution, collection cut size is the 20-200 micron, and the powder of preferred 50-70 micron obtains injection of the present invention.
Preferably, Needleless injection of the present invention comprises insulin and anhydrous sodium sulfate with injection, and its preparation method comprises the steps:
(1) takes by weighing insulin also with distilled water (4 ℃) dissolving (the hydrochloric acid hydrotropy that can add a small amount of 0.01mol/l);
(2) about 50 microns granule is collected in the anhydrous sodium sulfate granule is sieved processing, and is stand-by;
(3) insulin solutions with preparation in the above-mentioned steps (1) places ice-water bath, adds a certain amount of anhydrous sodium sulfate granule that sieved to saturation;
(4) continue in above-mentioned saturated solution, to add the anhydrous sodium sulfate granule that sieved, until insulin: the total mass ratio of anhydrous sodium sulfate is 1: 20-1: 80, preferred 1: 20-1: 60, most preferably be 1: 20-1: 40, stirring and evenly mixing is till separating out a large amount of crystal;
(5) rapidly above-mentioned mixed crystallization solution is carried out lyophilization, the about 20-200 micron of collection cut size afterwards, preferably the powder between the 50-70 micron obtains the injection of insulin agent of the present embodiment.
In another embodiment of second aspect, the preparation method of injection of the present invention comprise the following steps: (1) pulverize and the screening particle diameter at the 20-200 micron, preferred 50-70 micron most preferably takes off water of crystallization inorganic salt powder about 50 microns; (2) in 0-4 ℃ of environment, take off water of crystallization inorganic salt powder to be added into mass ratio be 1: 0.2-1: 10, preferred 1: 0.2-1 described: 2, most preferably 1: 0.5-1: in 2 biological product and the aqueous solution of viscosifier to saturated; (3) the continuation interpolation is described takes off water of crystallization inorganic salt powder so that described biological product, described viscosifier and the described mass ratio that takes off water of crystallization inorganic salt powder are 1: 0.2: 20-1: 10: 80, be preferably 1: 0.5: 20-1: 2: 60, most preferably be 1: 0.5: 40-1: 2: 40, obtain mixed crystallization solution; (4) with the lyophilization of described mixed crystallization solution, collection cut size is the 20-200 micron, and the powder of preferred 50-70 micron obtains injection of the present invention.
Preferably, Needleless injection of the present invention comprises with injection: insulin, hyaluronate sodium and anhydrous sodium sulfate, its preparation method comprises the steps:
(1) take by weighing insulin and add distilled water (4 ℃) to fully the dissolving (the hydrochloric acid hydrotropy that can add a small amount of 0.01mol/l);
(2) about 50 microns granule is collected in the anhydrous sodium sulfate granule is sieved processing, and is stand-by;
(3) taking by weighing hyaluronate sodium joins in the insulin solutions and (can add a small amount of strong aqua ammonia hydrotropy) so that the mass ratio of insulin and hyaluronate sodium is 1: 0.2-1: 2;
(4) insulin-sodium hyaluronate solution with above-mentioned steps (3) gained places ice-water bath, adds a certain amount of anhydrous sodium sulfate granule that sieved to saturation;
(5) continue in the saturated solution of step (4) gained, to add the anhydrous sodium sulfate granule that has sieved, until insulin: hyaluronate sodium: the total mass ratio of anhydrous sodium sulfate is 1: 0.5: 20-1: 2: 40, stirring and evenly mixing is till separating out a large amount of crystal;
(6) rapidly above-mentioned mixed crystallization solution is carried out lyophilization, collection cut size is about the 20-200 micron afterwards, and preferably the powder between the 50-70 micron obtains the injection of insulin agent of the present embodiment.
In another embodiment of second aspect, the preparation method of injection of the present invention comprise the following steps: (1) pulverize and the screening particle diameter at the 20-200 micron, preferred 50-70 micron most preferably takes off water of crystallization inorganic salt powder about 50 microns; (2) in 0-4 ℃ of left and right sides environment, take off water of crystallization inorganic salt powder to be added into mass ratio be 1: 0.2-1: 10, preferred 1: 0.5-1 described: 7, most preferably 1: 0.8-1: 2 biological product and adjuvant, in the aqueous solution of preferred Chinese medicine adjuvant to saturated; (3) the continuation interpolation is described takes off water of crystallization inorganic salt powder so that described biological product, described adjuvant and the described mass ratio that takes off water of crystallization inorganic salt powder are 1: 0.2: 20-1: 10: 80, preferred 1: 0.5: 20-1: 7: 60, most preferably 1: 0.8: 20-1: 2: 40, obtain mixed crystallization solution; (4) with the lyophilization of described mixed crystallization solution, collection cut size is the 20-200 micron, and the powder of preferred 50-70 micron obtains injection of the present invention.
Preferably, Needleless injection of the present invention comprises interferon, Chinese medicine adjuvant and takes off the water of crystallization inorganic salt that the described water of crystallization inorganic salt that takes off is preferably anhydrous sodium sulfate with injection, and its preparation method comprises the steps:
(1) measure interferon and add distilled water (4 ℃) to fully the dissolving;
(2) about 50 microns granule is collected in the anhydrous sodium sulfate granule is sieved processing, and is stand-by;
(3) take by weighing in the interferon solution that the Chinese medicine adjuvant joins step (1) gained;
(4) interferon of above-mentioned steps (3) gained-Chinese medicine assist agent solution is placed ice-water bath, adds a certain amount of anhydrous sodium sulfate granule that sieved to saturation;
(5) continue in the saturated solution of above-mentioned steps (4) gained, to add the anhydrous sodium sulfate granule that has sieved, until interferon: Chinese medicine adjuvant: the total mass ratio of anhydrous sodium sulfate is 1: 0.2: 20-1: 2: 60, preferably=and 1: 1: 25-1: 2: 25, stirring and evenly mixing is till separating out a large amount of crystal;
(6) rapidly the mixed crystallization solution of above-mentioned steps (5) gained is carried out lyophilization, the powder of collection cut size between the 50-70 micron afterwards obtains the injectable interferon of the present embodiment.
Preferably, Needleless injection of the present invention comprises vaccine, Chinese medicine adjuvant and takes off the water of crystallization inorganic salt that the described water of crystallization inorganic salt that takes off is preferably anhydrous sodium sulfate with injection, and its preparation method comprises the steps:
(1) measures vaccinogen liquid and also be diluted to 1mg/ml with distilled water (4 ℃);
(2) about 50 microns granule is collected in the anhydrous sodium sulfate granule is sieved processing, and is stand-by;
(3) take by weighing in the vaccine solution that the Chinese medicine adjuvant joins step (1) gained;
(4) vaccine of above-mentioned steps (3) gained-Chinese medicine assist agent solution is placed ice-water bath, adds a certain amount of anhydrous sodium sulfate granule that sieved to saturation;
(5) continue in the saturated solution of above-mentioned steps (4) gained, to add the anhydrous sodium sulfate granule that has sieved, until vaccine: Chinese medicine adjuvant: the total mass ratio of anhydrous sodium sulfate is 1: 0.5: 20-1: 10: 60, preferably=and 1: 0.5: 20-1: 5: 20, stirring and evenly mixing is till separating out a large amount of crystal;
(6) rapidly above-mentioned mixed crystallization solution is carried out lyophilization, the powder of collection cut size between the 50-70 micron afterwards obtains the vaccine injecta of the present embodiment.
In another embodiment of second aspect, the preparation method of injection of the present invention comprise the following steps: (1) pulverize and the screening particle diameter at the 20-200 micron, preferred 50-70 micron most preferably takes off water of crystallization inorganic salt powder about 50 microns; (2) in 0-4 ℃ of left and right sides environment, take off water of crystallization inorganic salt powder to be added into mass ratio be 1: 0.2: 0.2-1: 10: 10 described, preferred 1: 0.5: 0.5-1: 7: 7, most preferably 1: 0.8: 0.8-1: extremely saturated in the aqueous solution of the mixture of 2: 2 biological product, adjuvant (preferred Chinese medicine adjuvant) and viscosifier; (3) the continuation interpolation is described takes off water of crystallization inorganic salt powder so that described biological product, adjuvant (preferred Chinese medicine adjuvant), viscosifier and the described mass ratio that takes off water of crystallization inorganic salt powder are 1: 0.2: 0.2: 20-1: 10: 10: 80, preferred 1: 0.5: 0.5: 20-1: 7: 7: 60, most preferably 1: 0.8: 0.8: 20-1: 2: 2: 40; (4) lyophilization, collection cut size are the 20-200 micron, and the powder of preferred 50-70 micron obtains injection of the present invention.
Preferably, Needleless injection of the present invention comprises interferon, Chinese medicine adjuvant, viscosifier and takes off the water of crystallization inorganic salt that the described water of crystallization inorganic salt that takes off is preferably anhydrous sodium sulfate with injection, and its preparation method comprises the steps:
(1) measure interferon and add distilled water (4 ℃) to fully the dissolving;
(2) about 50 microns granule is collected in the anhydrous sodium sulfate granule is sieved processing, and is stand-by;
(3) take by weighing in the interferon solution that Chinese medicine adjuvant and viscosifier join step (1) gained;
(4) interferon-viscosifier of above-mentioned steps (3) gained-Chinese medicine assist agent solution is placed ice-water bath, adds a certain amount of anhydrous sodium sulfate granule that sieved to saturation;
(5) continue in the saturated solution of above-mentioned steps (4) gained, to add the anhydrous sodium sulfate granule that has sieved, until interferon: Chinese medicine adjuvant: viscosifier: the gross mass of anhydrous sodium sulfate is=1: 0.2: 0.2: 20-1: 2: 2: 60, be preferably 1: 1: 1: 25-1: 2: 2: 25, stirring and evenly mixing is till separating out a large amount of crystal;
(6) rapidly the mixed crystallization solution of above-mentioned steps (5) gained is carried out lyophilization, the powder of collection cut size between the 50-70 micron afterwards obtains the injectable interferon of the present embodiment.
Preferably, Needleless injection of the present invention comprises regular insulin, Chinese medicine adjuvant, viscosifier and takes off the water of crystallization inorganic salt that the described water of crystallization inorganic salt that takes off is preferably anhydrous sodium sulfate with injection, and its preparation method comprises the steps:
(1) measures insulin also with adding distilled water (4 ℃) to fully dissolving (the hydrochloric acid hydrotropy that can add a small amount of 0.01mol/l);
(2) about 50 microns granule is collected in the anhydrous sodium sulfate granule is sieved processing, and is stand-by;
(3) take by weighing in the insulin solutions that Chinese medicine adjuvant and viscosifier join step (1) gained;
(4) insulin-viscosifier of above-mentioned steps (3) gained-Chinese medicine assist agent solution is placed ice-water bath, adds a certain amount of anhydrous sodium sulfate granule that sieved to saturation;
(5) continue in the saturated solution of above-mentioned steps (4) gained, to add the anhydrous sodium sulfate granule that has sieved, until insulin: Chinese medicine adjuvant: viscosifier: the total mass ratio of anhydrous sodium sulfate is 1: 0.5: 0.5: 20-1: 10: 10: 60, be preferably 1: 0.5: 0.5: 20-1: 5: 5: 20, stirring and evenly mixing is till separating out a large amount of crystal;
(6) rapidly above-mentioned mixed crystallization solution is carried out lyophilization, the powder of collection cut size between the 50-70 micron obtains the injection of insulin agent of the present embodiment afterwards.
In the third aspect, the invention provides such as the described Needleless injection of first aspect and use injection for the preparation of the purposes of the medicine of prevention or treatment disease.
Wherein, described disease includes, but are not limited to: diabetes, viral hepatitis, tumor, hematopathy, Dermatology, viral keratitis, chronic cervicitis, tetanus, mumps, diphtheria, measles, typhoid fever or influenza.
In fourth aspect, the invention provides the method for carrying out Needleless injection such as the described Needleless injection of first aspect with injection of using.Described method comprises: described injection is packed in the medicine casket of needleless injector, use by described needleless injector.
Wherein, described needleless injector can be disclosed automatic Needleless powder injection device (as shown in Figure 1) in No. 201643226 patent applications of CN.During use, prepared injection is matched with automatic Needleless powder injection device, prepared Powdered injection is packed in the medicine casket of needleless injector, the caisson, the excitation apparatus that have by needleless injector, discharger, the Powdered injection that loads in the medicine casket is passed through needleless injector transmission skin tissue cell, enter Intradermal, subcutaneous or mucosal tissue release.
Needleless injection of the present invention has with the injection powder that granular size is consistent, drug loading is high, Drug absorbability is firm, bioavailability is high, stable in properties waits safely advantage.The water of crystallization inorganic salt that takes off as pharmaceutical carrier has and can produce adsorption to biological product such as insulin, interferon, vaccines.
Powdered Needleless injection of the present invention is fully different with principle and the preparation process of the preparation method of injection and the preparation method of prior art (for example, disclosed crystalline powder preparation method in CN 1285753A and the CN 1315854A patent).What the present invention adopted is the standby injection of recrystallization scattered adsorption legal system, in the method for the invention, the inorganic salt that water of crystallization is taken off in employing is carrier, with pulverize in advance and sieve have regulation particle diameter and a distribution take off water of crystallization inorganic salt powder, add and dissolved in advance in the saturated inorganic salt solution of biological product, the effect that water of crystallization inorganic salt absorption water of crystallization is taken off in utilization absorbs the water in the solution system, make system concentrated, increase the chance that biological product are wrapped in the inorganic salt powder surface, can add in right amount the viscosifier such as hyaluronate sodium in the system, make the easier inorganic salt particle surface that is adsorbed on of biological product, then with the mixed system lyophilization, in dehydration process, biological product are wrapped in the inorganic salt particle surface securely.Since will be the inorganic salt powder of prescreening add its saturated solution, therefore substantially can not change the initial particle of inorganic salt powder, so that the final medicine carrying powder diameter that obtains evenly and be full particle, can satisfy the specification requirement of Needleless powder injection medicament administration.Be developed to the substrate of biological product based on adsorption, can give full play to its pharmaceutics advantage.The viscosifier such as hyaluronate sodium, human albumin have certain tackify, ability to cure, can play the Curing effect, have further strengthened the absorbability that takes off the water of crystallization inorganic salt.In addition, very fast dissolving after selected soluble inorganic salt is expelled in the body, noresidue, nontoxic, good biocompatibility.The technology that the present invention prepares injection can be called outer wrapping-full particle medicine carrying powder preparation technology.
Needleless injection of the present invention provides a kind of novel form of biological product with injection, this dosage form is particularly useful for the Needleless injection technology, thereby effectively avoided the first pass effect that causes because of oral drug preparation, the size of its particle diameter meets the percutaneous dosing requirement, be easy to by by stratum corneum barrier, can significantly improve the curative effect of medicine, shorten onset time.Therefore, the injection that is applicable to the Needleless powder injection technology is particularly suitable for the medical prevention guarantee under the conditions such as vital emergent event and outlying district, extensive field work, and the patient (such as the child) of probably pin sense and the patient of the long-term automedication of need arranged, and this dosage form is more stable, so application prospect is very wide.
The present invention adopts the standby Needleless injection injection of recrystallization scattered adsorption legal system, and technique is convenient, and flow process is brief, and is with low cost and be applicable to fairly large powder preparation.
Description of drawings
Fig. 1 demonstration can be used for automatic Needleless powder injection device of the present invention.
Fig. 2 shows the stereoscan photograph of the powder of the isophane insulin injection that the embodiment of the invention 5 is prepared, and left figure is single powder stereoscan photograph, and right figure is the surface details photo.
Fig. 3 A shows the bar diagram of the drug loading of the injection of insulin agent that embodiment of the invention 1-4 is prepared, and abscissa is the mass ratio of insulin and anhydrous sodium sulfate, and vertical coordinate is drug loading.
Fig. 3 B shows the bar diagram of the bioavailability of the injection of insulin agent that embodiment of the invention 1-4 is prepared, and abscissa is bioavailability, and vertical coordinate is the mass ratio of insulin and anhydrous sodium sulfate.
After Fig. 4 A shows that the embodiment of the invention 5 prepared isophane insulin injections are injected Japan large rabbit, glucose in serum content time history plot, abscissa is time (h), and vertical coordinate is the content (mmol/L) of glucose in serum.
After Fig. 4 B shows that the Needleless injection of prior art preparation is injected Japan large rabbit with the isophane insulin injection, glucose in serum content time history plot, abscissa is time (h), and vertical coordinate is the content (mmol/L) of glucose in serum.
Fig. 5 A shows the insulin content figure of the isophane insulin injection that embodiment of the invention 5-10 is prepared, and abscissa represents the mass ratio of insulin, hyaluronate sodium and anhydrous sodium sulfate, and vertical coordinate represents insulin content (mg/mg).
Fig. 5 B shows the as a result figure of the bioavailability of the isophane insulin injection that embodiment of the invention 5-10 is prepared, and abscissa represents the mass ratio of insulin, hyaluronate sodium and anhydrous sodium sulfate, and vertical coordinate represents bioavailability.
The interferon titration that Fig. 6 shows the Recombinant Interferon α-2b injection that embodiment of the invention 12-16 is prepared is figure as a result, and wherein abscissa represents the mass ratio of Recombinant Interferon α-2b, arasaponin, anhydrous sodium sulfate, and vertical coordinate represents interferon tire (IU).
Fig. 7 shows the lgG antibody titer measurement result figure of the hepatitis B vaccine injection agent that embodiment of the invention 17-21 is prepared, wherein abscissa represents the mass ratio of vaccine, ginsenoside, anhydrous sodium sulfate, and vertical coordinate represents that Hepatitis B virus vaccine is to the concentration (U/L) of the rear Hepatitis B virus vaccine lgG antibody of measuring in 6 weeks of Cavia porcellus injection.
Fig. 8 A shows the immune effect figure of the tetanus vaccine injection that the embodiment of the invention 22 is prepared, and abscissa express time (week), vertical coordinate represent the concentration (UL of tetanus vaccine IgG antibody in the serum
-1).
Fig. 8 B shows the Needleless injection of the prior art preparation immune effect figure of tetanus vaccine injection, and abscissa express time (week), vertical coordinate represent the concentration (UL of tetanus vaccine IgG antibody in the serum
-1).
The interferon titration that Fig. 9 shows the injectable interferon that embodiment of the invention 23-28 is prepared is figure as a result, wherein abscissa represents the mass ratio of Recomvinated Interferon α-2a, astragalus polysaccharides, hyaluronate sodium, anhydrous sodium sulfate, and vertical coordinate represents interferon tire (IU).
The specific embodiment
Further specify by the following examples and explain the present invention, but not as restriction of the present invention.The included embodiment of this paper more completely understands invention as herein described in order to help.These embodiment limit as herein described or this paper scope required for protection never in any form.Used material in following examples, except indicating, all the other are commercially available.
Embodiment 1:
Adopt outer wrapping of the present invention-full particle medicine carrying powder preparation technology to prepare the injection of insulin agent that Needleless injection is used:
(1) take by weighing regular insulin (Sigma) 40mg and add 2mL distilled water (4 ℃) to fully the dissolving (the hydrochloric acid hydrotropy that can add a small amount of 0.01mol/l);
(2) about 50 microns granule is collected in the anhydrous sodium sulfate granule is sieved processing, and is stand-by;
(3) insulin solutions with preparation in the above-mentioned steps (1) places ice-water bath, adds a certain amount of anhydrous sodium sulfate granule that sieved to saturation;
(4) continue to drop into the basically identical anhydrous sodium sulfate granule of a large amount of size in the saturated solution of above-mentioned steps (3) gained, until insulin: the total mass ratio of anhydrous sodium sulfate is 1: 40, and stirring and evenly mixing is till separating out a large amount of crystal;
(5) rapidly the mixed crystallization solution of above-mentioned steps (4) gained is carried out frozen drying, the powder of collection cut size between the 50-70 micron obtains required injection of insulin agent afterwards.
Embodiment 2:
Adopt the method identical with embodiment 1 to prepare the injection of insulin agent that Needleless injection of the present invention is used, the total mass ratio of different is among this embodiment regular insulin and anhydrous sodium sulfate is 1: 80.
Embodiment 3:
Adopt the method identical with embodiment 1 to prepare the injection of insulin agent that Needleless injection of the present invention is used, the total mass ratio of different is among this embodiment regular insulin and anhydrous sodium sulfate is 1: 20.
Embodiment 4:
Adopt the present invention and embodiment 1 identical method to prepare the injection of insulin agent that Needleless injection of the present invention is used, the total mass ratio of different is among this embodiment regular insulin and anhydrous sodium sulfate is 1: 60.
Drug loading and Bioavailability Determination are carried out in the injection of insulin agent that the prepared Needleless injection of embodiment 1-4 is used.
Drug loading is measured: the drug loading that adopts Coomassie brilliant blue protein determination kit (bio-engineering research institute is built up in Nanjing) to finish the injection of insulin agent of embodiment 1-4 gained is measured, and the result is referring to Fig. 3 A.Fig. 3 A shows that the prepared injection of insulin agent of embodiment 1-4 all has high drug loading, more than 0.015/mg;
Hypoglycemic effect is measured: examination of glucose concentration in the body is carried out in the injection of insulin agent that in Japan large rabbit (male, Beijing section space animal cultivation center) embodiment 1-4 is obtained.21 White Rabbits are divided into 7 groups at random: blank group, positive controls (intravenous injection 0.3mg insulin), negative control group, embodiment 1 group of (agent of Needleless powder injection 12mg injection of insulin), embodiment 2 groups of (agent of Needleless powder injection 24mg injection of insulin), embodiment 3 groups of (agent of Needleless powder injection 6mg injection of insulin), 4 groups of embodiment (agent of Needleless powder injection 15mg injection of insulin), respectively organize laboratory animal and need use alloxan (Sigma) according to the 120mg/kg modeling except the blank group.After the administration respectively at the serum of getting White Rabbit in 0,0.33,0.66,1,2,3,5,7,10 hour, then adopt glucose assays test kit (glucose oxidase-peroxidase method) (ShangHai RongSheng Biology Pharmacy Co., Ltd) according to the concentration of explanation mensuration glucose in serum, draw glucose in serum content (meansigma methods of every treated animal) time history plot;
Bioavailability is calculated: the curve chart of gained uses the trapezoidal area method to calculate bioavailability in measuring according to hypoglycemic effect, and the result is referring to Fig. 3 B.Fig. 3 B shows that the prepared injection of insulin agent of embodiment 1-4 all has hypoglycemic effect, and bioavailability is all more than 78%.
Embodiment 5:
Adopt outer wrapping of the present invention-full particle medicine carrying powder preparation technology, hyaluronate sodium tackify mode prepares Needleless injection isophane insulin injection:
(1) get isophane insulin (Sigma) 20mg, add distilled water 2mL (4 ℃) dissolving, supersound process, dispersion are 2 hours in ultrasonic cleaner, make its dissolving.If still do not dissolve, then add a small amount of concentrated hydrochloric acid and get final product;
(2) about 50 microns granule is collected in the anhydrous sodium sulfate granule is sieved processing, and is stand-by;
(3) fully dissolving in the solution of above-mentioned step (1) gained, adds 10mg hyaluronate sodium (aladdin) and slowly stirring, until can add a small amount of strong aqua ammonia hydrotropy;
(4) insulin-sodium hyaluronate solution with above-mentioned steps (3) preparation places ice-water bath, adds a certain amount of anhydrous sodium sulfate granule that sieved to saturation;
(5) continue in the saturated solution of above-mentioned steps (4) gained, to drop into the basically identical anhydrous sodium sulfate granule of a large amount of size, until insulin: hyaluronate sodium: the total mass ratio of anhydrous sodium sulfate is 1: 0.5: 40, stirring and evenly mixing is till separating out a large amount of crystal;
(6) rapidly the mixed crystallization solution of above-mentioned steps (5) gained is carried out frozen drying, the powder of collection cut size between the 50-70 micron obtains required isophane insulin injection afterwards.
Adopt following method with isophane insulin injection prepared among this embodiment be that the Needleless injection that 40: 1 aluminium hydroxide and isophane insulin form compares with the isophane insulin injection according to disclosed crystalline powder technology of preparing preparation in the CN 1315854A patent by mass ratio:
Morphological feature is measured: adopt S4800 awkward silence at a meeting emission scan ultramicroscope (Beijing physico-chemical analysis test center) to observe the morphological feature of two kinds of injections;
Size: adopt laser particle size analyzer (the American-European Science and Technology Ltd. that restrains) to measure the size of two kinds of injection powder according to conventional method;
Hardness: adopt the MC010-HV-5 little load Vickers of type (Shanghai Yanrun Ray Machine Technology Co., Ltd.) to measure the hardness of two kinds of injections according to conventional method;
Insulin content is measured: adopt the insulin content in two kinds of injections of Coomassie brilliant blue protein determination kit (bio-engineering research institute is built up in Nanjing) mensuration;
Hypoglycemic effect is measured: get two kinds of not commensurability injection samples, so that the amount of contained insulin is identical in two kinds of injection samples, adopt hypoglycemic effect assay method as described above to measure the hypoglycemic effect of two kinds of injections, draw glucose sugar content time history plot in the serum, the result is referring to Fig. 4 A and Fig. 4 B;
Bioavailability: the curve chart (Fig. 4 A and Fig. 4 B) according to gained in the hypoglycemic effect mensuration adopts the trapezoidal area method to try to achieve the bioavailability of two kinds of injections.
Two kinds of injection comparative results see table 1.
The comparison of isophane insulin injection of the Needleless injection of table 1 isophane insulin injection of the present invention and prior art
As shown in Table 1, the morphological characteristic of the isophane insulin injection that the present invention is prepared more is applicable to Needleless injection, and has apparently higher than insulin content and the bioavailability of the isophane insulin injection of prior art preparation.In addition, Fig. 4 A and Fig. 4 B show that the prepared isophane insulin injection of the present invention has the Needleless injection better hypoglycemic effect of isophane insulin injection than the prior art preparation.
Embodiment 6:
Adopt the method identical with embodiment 5 to prepare Needleless injection of the present invention isophane insulin injection, different is that hyaluronate sodium used among this embodiment is 4mg, and insulin wherein: hyaluronate sodium: the total mass ratio of anhydrous sodium sulfate is 1: 0.2: 20.
Embodiment 7:
Adopt the method identical with embodiment 5 to prepare Needleless injection of the present invention isophane insulin injection, different is that hyaluronate sodium used among this embodiment is 200mg, and insulin wherein: hyaluronate sodium: the total mass ratio of anhydrous sodium sulfate is 1: 10: 80.
Embodiment 8:
Adopt the method identical with embodiment 5 to prepare Needleless injection of the present invention isophane insulin injection, different is insulin among this embodiment: hyaluronate sodium: the total mass ratio of anhydrous sodium sulfate is 1: 0.5: 20.
Embodiment 9:
Adopt the method identical with embodiment 5 to prepare Needleless injection of the present invention isophane insulin injection, different is that hyaluronate sodium used among this embodiment is 40mg, and insulin wherein: hyaluronate sodium: the total mass ratio of anhydrous sodium sulfate is 1: 2: 60.
Embodiment 10:
Adopt the method identical with embodiment 5 to prepare Needleless injection of the present invention isophane insulin injection, different is that hyaluronate sodium used among this embodiment is 40mg, and insulin wherein: hyaluronate sodium: the total mass ratio of anhydrous sodium sulfate is 1: 2: 40.
Adopt method mentioned above to measure the insulin content of the prepared isophane insulin injection of embodiment 5-10, the result is referring to Fig. 5 A, and Fig. 5 A shows that the prepared isophane insulin injection of embodiment 5-10 all has high insulin content (more than the 0.02mg/mg); Adopt the hypoglycemic effect of the prepared isophane insulin injection of method mensuration embodiment 5-10 mentioned above and draw glucose in serum content time history plot, then adopt the trapezoidal area method to calculate bioavailability according to glucose in serum content time history plot, the result is referring to Fig. 5 B, Fig. 5 B shows that the prepared isophane insulin injection of embodiment 5-10 all has good hypoglycemic effect, and bioavailability is all more than 75%.
Embodiment 11:
Adopt the method identical with embodiment 5 to prepare the premix insulin that comprises the human albumin (30% short-acting insulin and 70% the intermediate-acting insulins) injection that Needleless injection of the present invention is used, different is to use premix insulin (Sigma) replacement isophane insulin, human albumin (Sigma) to replace hyaluronate sodium among this embodiment.
Embodiment 12:
Adopt outer wrapping of the present invention-full particle medicine carrying powder preparation technology to prepare the Recombinant Interferon α-2b that comprises arasaponin (the IFN-α 2b) injection that Needleless injection is used:
(1) gets Recombinant Interferon α-2b (Sigma) 40mg, add distilled water 2mL (4 ℃) to fully dissolving, supersound process and elimination insoluble matter;
(2) about 50 microns granule is collected in the anhydrous sodium sulfate granule is sieved processing, and is stand-by;
(3) in the solution of above-mentioned step (1) gained, add 40mg arasaponin and slowly stirring;
(4) interferon of above-mentioned steps (3) being prepared-arasaponin solution places ice-water bath, adds a certain amount of anhydrous sodium sulfate granule that sieved to saturation;
(5) continue immediately in the saturated solution of above-mentioned steps (4) gained, to drop into the basically identical anhydrous sodium sulfate granule of a large amount of size, until interferon: arasaponin: the total mass ratio of anhydrous sodium sulfate is 1: 1: 25 ratio, stirring and evenly mixing is till separating out a large amount of crystal;
(6) rapidly above-mentioned mixed crystallization solution is carried out frozen drying, the powder of collection cut size between the 50-70 micron obtains required Recombinant Interferon α-2b injection afterwards.
Embodiment 13:
Adopt the method identical with embodiment 12 to prepare the Recombinant Interferon α-2b that comprises arasaponin (the IFN-α 2b) injection that Needleless injection of the present invention is used, different is that used arasaponin is 8mg, and interferon wherein: arasaponin: the total mass ratio of anhydrous sodium sulfate is 1: 0.2: 20.
Embodiment 14:
Adopt the method identical with embodiment 12 to prepare the Recombinant Interferon α-2b that comprises arasaponin (the IFN-α 2b) injection that Needleless injection of the present invention is used, different is that used arasaponin is 400mg, and interferon wherein: arasaponin: the total mass ratio of anhydrous sodium sulfate is 1: 10: 80.
Embodiment 15:
Adopt the method identical with embodiment 12 to prepare the Recombinant Interferon α-2b that comprises arasaponin (the IFN-α 2b) injection that Needleless injection of the present invention is used, different is that used arasaponin is 32mg, and interferon wherein: arasaponin: the total mass ratio of anhydrous sodium sulfate is 1: 0.8: 20.
Embodiment 16:
Adopt the method identical with embodiment 12 to prepare the Recombinant Interferon α-2b that comprises arasaponin (the IFN-α 2b) injection that Needleless injection of the present invention is used, different is that used arasaponin is 80mg, and interferon wherein: arasaponin: the total mass ratio of anhydrous sodium sulfate is 1: 2: 40.
The Recombinant Interferon α-2b injection prepared to embodiment 12-16 carries out the interferon titration.
Interferon titration: according to " Products in China rules " version " interferon titration " (cytopathic-effect inhibition assay) in 2000 end user amnion cell (WISH, contain the biological company limited in the rising sun hundred rivers available from Beijing), blister stomatitis virus (vsv, contain the biological company limited in the rising sun hundred rivers available from Beijing) measure, wherein use BH-2 inverted microscope (Olympus) counting to measure mortality rate and be translated into tiring of interferon by the formula that provides in the method, the result is referring to Fig. 6.Fig. 6 shows that the prepared Recombinant Interferon α-2b injection of embodiment 12-16 all has higher activity, and interferon is tired all more than 500IU.
Embodiment 17:
Adopt outer wrapping of the present invention-full particle medicine carrying powder preparation technology, the liquid hybrid mode of Chinese medicine adjuvant prepares the hepatitis B vaccine injection agent that comprises the ginsenoside that Needleless injection of the present invention is used:
(1) measure Hepatitis B virus vaccine (Beijing in length and breadth foreign continent biotechnology company) and be diluted to 40mL, concentration is 1mg/ml;
(2) taking by weighing the 48mg ginsenoside, to be dissolved to concentration with distilled water (4 ℃) be 0.5mg/ml;
(3) in Hepatitis B virus vaccine: ginsenoside's total mass ratio is 1: 1.2 ratio blend step (1) and the solution of step (2) gained, and supersound process, dispersion are 2 hours in ultrasonic cleaner, obtain suspension;
(4) Hepatitis B virus vaccine of above-mentioned steps (3) gained-ginsenoside's solution is placed ice-water bath, adds a certain amount of anhydrous sodium sulfate granule that sieved to saturation;
(5) continue immediately to drop into the basically identical anhydrous sodium sulfate granule of a large amount of size in this saturated solution, until Hepatitis B virus vaccine: the ginsenoside: the total mass ratio of anhydrous sodium sulfate is 1: 1.2: 40, makes it separate out a large amount of crystal, mixing;
(6) rapidly the mixed crystallization solution of above-mentioned steps (5) gained is carried out lyophilization, the powder of collection cut size between the 50-70 micron, cryopreservation obtains required hepatitis B vaccine injection agent.
Embodiment 18:
Adopt the method identical with embodiment 17 to prepare the Hepatitis B virus vaccine vaccine injecta that comprises the ginsenoside that Needleless injection of the present invention is used, different is: take by weighing the 40mg ginsenoside in step (2), Hepatitis B virus vaccine in the step (3): ginsenoside's mass ratio is 1: 1, and Hepatitis B virus vaccine: the ginsenoside: the total mass ratio of anhydrous sodium sulfate is 1: 1: 40.
Embodiment 19:
Adopt the method identical with embodiment 17 to prepare the Hepatitis B virus vaccine vaccine injecta that comprises the ginsenoside that Needleless injection of the present invention is used, different is: take by weighing the 400mg ginsenoside in step (2), Hepatitis B virus vaccine in the step (3): ginsenoside's mass ratio is 1: 10, and Hepatitis B virus vaccine: the ginsenoside: the total mass ratio of anhydrous sodium sulfate is 1: 10: 80.
Embodiment 20:
Adopt the method identical with embodiment 17 to prepare the Hepatitis B virus vaccine vaccine injecta that comprises the ginsenoside that Needleless injection of the present invention is used, different is: take by weighing the 32mg ginsenoside in step (2), Hepatitis B virus vaccine in the step (3): ginsenoside's mass ratio is 1: 0.8, and Hepatitis B virus vaccine: the ginsenoside: the total mass ratio of anhydrous sodium sulfate is 1: 0.8: 20.
Embodiment 21:
Adopt the method identical with embodiment 17 to prepare the Hepatitis B virus vaccine vaccine injecta that comprises the ginsenoside that Needleless injection of the present invention is used, different is: take by weighing the 8mg ginsenoside in step (2), Hepatitis B virus vaccine in the step (3): ginsenoside's mass ratio=1: 0.2, and Hepatitis B virus vaccine: ginsenoside: the total mass ratio of anhydrous sodium sulfate is 1: 0.2: 20.
Hepatitis B virus vaccine lgG antibody titer mensuration is carried out in prepared hepatitis B vaccine injection agent to embodiment 17-21.
Hepatitis B virus vaccine lgG antibody titer is measured: the vaccine injecta that in Cavia porcellus (male, Beijing section space animal cultivation center) embodiment 17-21 is obtained carries out Hepatitis B virus vaccine lgG antibody titer and measures.42 Cavia porcelluss are divided into 7 groups at random: blank group, matched group (subcutaneous injection tetanus toxoid 1mg), embodiment 17 groups of (Needleless powder injection vaccine injecta 40mg), embodiment 18 groups of (Needleless powder injection vaccine injecta 40mg), embodiment 19 groups of (Needleless powder injection vaccine injecta 80mg), embodiment 20 groups of (Needleless powder injection vaccine injecta 20mg), 21 groups of embodiment (Needleless powder injection vaccine injecta 20mg).After immune 6 weeks, get guinea pig serum, utilize the ELISA euzymelinked immunosorbent assay (ELISA) to adopt ELISA Hepatitis B virus vaccine lgG antibody diagnosing reagent kit (Zhuhai Hai Tai Biology Pharmacy Co., Ltd) according to the concentration (meansigma methods of every treated animal) of Hepatitis B virus vaccine IgG antibody in the explanation mensuration serum, the result is referring to Fig. 7.Fig. 7 shows that the prepared hepatitis B vaccine injection agent of embodiment 17-21 all has good immune effect.
Embodiment 22:
Adopt outer wrapping of the present invention-full particle medicine carrying powder preparation technology to prepare the tetanus vaccine injection that comprises the ginsenoside that Needleless injection is used:
(1) takes by weighing ginsenoside's 5.2 grams, be mixed with ginsenoside's solution that concentration is 0.087mg/ml, moist heat sterilization with distilled water (4 ℃);
(2) get ginsenoside's solution 4ml that step (1) is prepared, in tetanus vaccine: ginsenoside's mass ratio is about 1: 7 ratio and adds tetanus vaccine 50 μ g (Beijing in length and breadth foreign continent biotechnology company), mixing, room temperature leave standstill and must mix suspension in 15 minutes;
(3) tetanus vaccine of above-mentioned steps (2) being prepared-ginsenoside's solution places ice-water bath, adds a certain amount of anhydrous sodium sulfate granule that sieved to saturation;
(4) drop into the basically identical anhydrous sodium sulfate granule of a large amount of size in this saturated solution, make tetanus vaccine: the ginsenoside: the total mass ratio of anhydrous sodium sulfate is 1: 7: 40, makes it separate out a large amount of crystal, and mixing leaves standstill;
(5) rapidly with the mixed crystallization solution lyophilization of above-mentioned steps (4) gained, the powder of collection cut size between the 50-70 micron namely gets required tetanus vaccine injection.
Adopt following method with cold vaccine injecta prepared among this embodiment be that the tetanus vaccine injection that Needleless injection that 40: 1 aluminium hydroxide and tetanus vaccine form is used compares according to disclosed crystalline powder technology of preparing preparation in the CN1285753A patent by mass ratio:
Morphological feature, size, hardness all adopt method as described in example 5 above to measure;
Tetanus vaccine assay: adopt Coomassie brilliant blue protein determination kit (bio-engineering research institute is built up in Nanjing) to measure the tetanus vaccine content of two kinds of injections of equal in quality according to explanation;
Immune effect: used same procedure was measured the lgG antibody concentration of two kinds of tetanus vaccine injections during employing was measured with Hepatitis B virus vaccine lgG antibody titer, different is, and what to use is ELISA tetanus IgG antibody diagnosing reagent kit (Zhuhai Hai Tai Biology Pharmacy Co., Ltd), and the result is referring to Fig. 8 A and Fig. 8 B.
Two kinds of injection comparative results see table 2.
The comparison of tetanus vaccine injection of the Needleless injection of table 2 tetanus vaccine injection of the present invention and prior art
As shown in Table 2, the morphological characteristic of the tetanus vaccine injection that the present invention is prepared more is applicable to Needleless injection, and has the tetanus vaccine content of using the tetanus vaccine injection apparently higher than the Needleless injection of prior art preparation.In addition, Fig. 8 A and Fig. 8 B show that the prepared tetanus vaccine injection of the present invention has the Needleless injection better immune effect of tetanus vaccine injection than the prior art preparation.
Embodiment 23:
Adopt outer wrapping of the present invention-full particle medicine carrying powder preparation technology, the liquid hybrid mode of hyaluronate sodium tackify mode and astragalus polysaccharides prepares the Recomvinated Interferon α-2a that comprises astragalus polysaccharides (the IFN-α 2a) injection that Needleless injection is used:
(1) takes by weighing astragalus polysaccharides 1.25g, be mixed with the astragalus polyose solution that concentration is 0.025mg/ml, moist heat sterilization with distilled water (4 ℃);
(2) in the solution of step (1), by Recomvinated Interferon α-2a: the mass ratio of astragalus polysaccharides is to add Recomvinated Interferon α-2a (Sigma) 1.5625g and mixing at 1: 0.8, again take Recomvinated Interferon α-2a: the mass ratio of hyaluronate sodium added 1.25g hyaluronate sodium and mixing as 1: 0.8 in mixed solution, room temperature leaves standstill must mix suspension in 15 minutes;
(3) Recomvinated Interferon α-2a-astragalus polysaccharides of above-mentioned steps (2) being prepared-sodium hyaluronate solution places ice-water bath, adds a certain amount of anhydrous sodium sulfate granule that sieved to saturation;
(4) drop into the basically identical anhydrous sodium sulfate granule of a large amount of size in this saturated solution, make Recomvinated Interferon α-2a: astragalus polysaccharides: hyaluronate sodium: the anhydrous sodium sulfate total mass ratio is 1: 0.8: 0.8: 20, and make it separate out a large amount of crystal, mixing leaves standstill;
(5) rapidly with the mixed crystallization solution lyophilization of above-mentioned steps (4) gained, the powder of collection cut size between the 50-70 micron, cryopreservation namely gets required Recomvinated Interferon α-2a injection.
Embodiment 24:
Adopt the method identical with embodiment 23 to prepare the Recomvinated Interferon α-2a injection that comprises astragalus polysaccharides that Needleless injection of the present invention is used, different is that the Recomvinated Interferon α-2a that adds in the step 2 is 0.625g, and Recomvinated Interferon α-2a: astragalus polysaccharides: hyaluronate sodium: the total mass ratio of anhydrous sodium sulfate is 1: 2: 2: 40.
Embodiment 25:
Adopt the method identical with embodiment 23 to prepare the Recomvinated Interferon α-2a injection that comprises astragalus polysaccharides that Needleless injection of the present invention is used, different is that the Recomvinated Interferon α-2a that adds in the step 2 is 2.5g, and Recomvinated Interferon α-2a: astragalus polysaccharides: hyaluronate sodium: the total mass ratio of anhydrous sodium sulfate is 1: 0.5: 0.5: 20.
Embodiment 26:
Adopt the method identical with embodiment 23 to prepare the Recomvinated Interferon α-2a injection that comprises astragalus polysaccharides that Needleless injection of the present invention is used, different is that the Recomvinated Interferon α-2a that adds in the step 2 is 0.18g, and Recomvinated Interferon α-2a: astragalus polysaccharides: hyaluronate sodium: the total mass ratio of anhydrous sodium sulfate is 1: 7: 7: 60.
Embodiment 27:
Adopt the method identical with embodiment 23 to prepare the Recomvinated Interferon α-2a injection that comprises astragalus polysaccharides that Needleless injection of the present invention is used, different is that the Recomvinated Interferon α-2a that adds in the step 2 is 6.25g, and Recomvinated Interferon α-2a: astragalus polysaccharides: hyaluronate sodium: the total mass ratio of anhydrous sodium sulfate is 1: 0.2: 0.2: 20.
Embodiment 28:
Adopt the method identical with embodiment 23 to prepare the Recomvinated Interferon α-2a that comprises astragalus polysaccharides (the IFN-α 2a) injection that Needleless injection of the present invention is used, different is that the Recomvinated Interferon α-2a that adds in the step 2 is 0.125g, and Recomvinated Interferon α-2a: astragalus polysaccharides: hyaluronate sodium: the total mass ratio of anhydrous sodium sulfate is 1: 10: 10: 80.
The injectable interferon prepared to embodiment 23-28 carries out the interferon titration, and the used identical method of embodiment 12-16 is adopted in the interferon titration, and the result is referring to Fig. 9.Fig. 9 shows that the prepared injectable interferon of embodiment 23-28 all has high tiring, thereby has high activity.
Other aspects of the present invention will be clearly and not to need to repeat in this article for those skilled in the art.The term that adopts and wording are with explaining and not having restricted, and be not intended to get rid of any equivalents or its part of shown feature with describing when using these terms and wording, will be appreciated that multiple change may be within the scope of the invention.
Claims (13)
1. Needleless injection injection, be powder type, it is characterized in that: described injection comprises that mass ratio is 1: 20-1: 80, be preferably 1: 20-1: 60, most preferably be 1: 20-1: 40 biological product and take off the water of crystallization inorganic salt, described powder is that described biological product are wrapped in the described full particle that takes off water of crystallization inorganic salt outer surface, and the particle diameter of described powder is between the 20-200 micron, preferably between the 50-70 micron.
2. injection as claimed in claim 1, wherein said biological product are selected from one or more of following biological product: reach in-vitro diagnosis goods and other active ingredients in insulin, interferon, vaccine, antitoxin and immune serum, blood products, cytokine, the body, preferably, described biological product are selected from one or more in insulin, interferon and the vaccine, more preferably, described biological product are insulin.
3. injection as claimed in claim 2, wherein said insulin is selected from regular insulin, isophane insulin, insulin zinc protamine, premix insulin; Described interferon is selected from IFN-α 2b, IFN-α 2a, lymphoblastoid interferon or its combination; Described vaccine is antibacterial or viral vaccine, is preferably selected from the following vaccine one or more: Hepatitis B virus vaccine, tetanus toxoid vaccine, Mumps Vaccine, Measles Vaccine, antityphoid vaccine, influenza vaccines, diphtheria vaccine, Anthrax vaccine, Brucella vaccine, leptospira vaccine and Teck-borne Encephalitis Vaccine.
4. injection as claimed in claim 1, the wherein said water of crystallization inorganic salt that takes off is selected from anhydrous sodium sulfate, dead plaster, anhydrous slufuric acid aluminum, anhydrous magnesium sulfate, anhydro-zinc sulfate, anhydrous potassium aluminium sulfate, anhydrous nitric acid potassium, anhydrous acid acid aluminum, ADKP or its combination; Preferably, the described water of crystallization inorganic salt that takes off is anhydrous sodium sulfate.
5. such as each described injection among the claim 1-4, described injection also comprises viscosifier, wherein said biological product, described viscosifier and the described mass ratio that takes off the water of crystallization inorganic salt are 1: 0.2: 20-1: 10: 80, be preferably 1: 0.5: 20-1: 2: 60, more preferably 1: 0.5: 40-1: 2: 40; And described viscosifier are selected from hyaluronate sodium, human albumin or its combination.
6. such as each described injection among the claim 1-4, described injection also comprises pharmaceutically acceptable adjuvant, wherein said biological product, described adjuvant and the described mass ratio that takes off the water of crystallization inorganic salt are 1: 0.2: 20-1: 10: 80, be preferably 1: 0.5: 20-1: 7: 60, more preferably 1: 0.8: 20-1: 2: 40; And described adjuvant is preferably the Chinese medicine adjuvant.
7. such as each described injection among the claim 1-4, described injection also comprises pharmaceutically acceptable adjuvant and viscosifier, wherein said biological product, described adjuvant, described viscosifier and the described mass ratio that takes off the water of crystallization inorganic salt are 1: 0.2: 0.2: 20-1: 10: 10: 80, be preferably 1: 0.5: 0.5: 20-1: 7: 7: 60, more preferably 1: 0.8: 0.8: 20-1: 2: 2: 40; And described adjuvant is preferably the Chinese medicine adjuvant.
8. such as claim 6 or 7 described injections, wherein said Chinese medicine adjuvant is selected from saponin, polysaccharide, flavone or its combination, and described saponin is selected from ginsenoside, arasaponin, gypenoside, Radix Clematidis saponin, dioscin or its combination; Described polysaccharide is selected from astragalus polysaccharides, ginseng polysaccharide, polyporusum bellatus, Radix Rhodiolae polysaccharide, jujube polysaccharide or its combination; Described flavone is selected from epimedium flavone, Fructus Fortunellae Margaritae flavone, Herba Hedyotidis Diffusae flavone, daidzein, Fructus Hippophae flavone or its combination.
9. such as each described injection among the claim 1-8, described injection prepares by the following method: in 0-4 ℃ of environment with particle diameter at the 20-200 micron, in the preferred 50-70 micrometer range, most preferably about 50 microns take off in the aqueous solution of mixture that water of crystallization inorganic salt powder adds the aqueous solution of described biological product or described biological product and described viscosifier and/or described adjuvant to extremely saturated; Continue to add and describedly to take off water of crystallization inorganic salt powder so that described biological product and the total mass ratio that takes off the water of crystallization inorganic salt are 1: 20-1: 80, preferred 1: 20-1: 60, most preferably 1: 20-1: 40; Lyophilization, collection cut size be at the 20-200 micron, the powder in the preferred 50-70 micrometer range.
10. a method for preparing each described Needleless injection usefulness injection among the claim 1-9 comprises the following steps:
In 0-4 ℃ of environment with particle diameter at the 20-200 micron, in the preferred 50-70 micrometer range, most preferably about 50 microns take off in the aqueous solution that water of crystallization inorganic salt powder adds described biological product to or extremely saturated in the aqueous solution of the mixture of described biological product and described viscosifier and/or described adjuvant;
Continue to add and describedly to take off water of crystallization inorganic salt powder so that described biological product and the total mass ratio that takes off the water of crystallization inorganic salt are 1: 20-1: 80, preferred 1: 20-1: 60, most preferably 1: 20-1: 40, obtain mixed crystallization solution;
With the lyophilization of described mixed crystallization solution, collection cut size is at the 20-200 micron, the powder in the preferred 50-70 micrometer range.
11. each described Needleless injection uses injection for the preparation of the purposes of the medicine of prevention or treatment disease among the claim 1-9.
12. purposes as claimed in claim 11, wherein said disease comprises diabetes, viral hepatitis, tumor, hematopathy, Dermatology, viral keratitis, chronic cervicitis, tetanus, mumps, diphtheria, measles, typhoid fever or influenza.
13. use the method for carrying out Needleless injection such as each described injection among the claim 1-9, comprising: described injection is packed in the medicine casket of needleless injector, and use by described needleless injector.
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| Application Number | Priority Date | Filing Date | Title |
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| CN201110322321XA CN103054805A (en) | 2011-10-20 | 2011-10-20 | Preparation method and application of injection for needle-free injection |
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| Application Number | Priority Date | Filing Date | Title |
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| CN201110322321XA CN103054805A (en) | 2011-10-20 | 2011-10-20 | Preparation method and application of injection for needle-free injection |
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| CN103054805A true CN103054805A (en) | 2013-04-24 |
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| CN201110322321XA Withdrawn CN103054805A (en) | 2011-10-20 | 2011-10-20 | Preparation method and application of injection for needle-free injection |
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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN105999257A (en) * | 2016-05-11 | 2016-10-12 | 长春海基亚生物技术股份有限公司 | Influenza vaccine needle-free injection system and application |
| CN105999259A (en) * | 2016-05-11 | 2016-10-12 | 长春海基亚生物技术股份有限公司 | Rabies vaccine needle-free injection system and application |
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|---|---|---|---|---|
| CN1562355A (en) * | 2004-04-14 | 2005-01-12 | 中国人民解放军第三○二医院 | Method for preparing injection without needle of interferon |
| CN102133396A (en) * | 2011-03-16 | 2011-07-27 | 中国人民解放军第三〇二医院 | Vaccine injection and preparation method thereof |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1562355A (en) * | 2004-04-14 | 2005-01-12 | 中国人民解放军第三○二医院 | Method for preparing injection without needle of interferon |
| CN102133396A (en) * | 2011-03-16 | 2011-07-27 | 中国人民解放军第三〇二医院 | Vaccine injection and preparation method thereof |
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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN105999257A (en) * | 2016-05-11 | 2016-10-12 | 长春海基亚生物技术股份有限公司 | Influenza vaccine needle-free injection system and application |
| CN105999259A (en) * | 2016-05-11 | 2016-10-12 | 长春海基亚生物技术股份有限公司 | Rabies vaccine needle-free injection system and application |
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Application publication date: 20130424 |