CN103957890A - Preparation method and application of injection for needleless injection - Google Patents
Preparation method and application of injection for needleless injection Download PDFInfo
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- CN103957890A CN103957890A CN201180074284.3A CN201180074284A CN103957890A CN 103957890 A CN103957890 A CN 103957890A CN 201180074284 A CN201180074284 A CN 201180074284A CN 103957890 A CN103957890 A CN 103957890A
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- 208000002672 hepatitis B Diseases 0.000 description 1
- 229940014041 hyaluronate Drugs 0.000 description 1
- 239000002955 immunomodulating agent Substances 0.000 description 1
- 230000002584 immunomodulator Effects 0.000 description 1
- 229940121354 immunomodulator Drugs 0.000 description 1
- 230000002779 inactivation Effects 0.000 description 1
- 230000005764 inhibitory process Effects 0.000 description 1
- 239000004026 insulin derivative Substances 0.000 description 1
- 238000010255 intramuscular injection Methods 0.000 description 1
- 239000007927 intramuscular injection Substances 0.000 description 1
- 238000010253 intravenous injection Methods 0.000 description 1
- 230000003902 lesion Effects 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- 210000004400 mucous membrane Anatomy 0.000 description 1
- 239000013642 negative control Substances 0.000 description 1
- 102000039446 nucleic acids Human genes 0.000 description 1
- 108020004707 nucleic acids Proteins 0.000 description 1
- 150000007523 nucleic acids Chemical class 0.000 description 1
- 229920001184 polypeptide Polymers 0.000 description 1
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- 210000003491 skin Anatomy 0.000 description 1
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- 239000000126 substance Substances 0.000 description 1
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- 231100000827 tissue damage Toxicity 0.000 description 1
- 239000003053 toxin Substances 0.000 description 1
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/0012—Galenical forms characterised by the site of application
- A61K9/0019—Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner
- A61K9/0021—Intradermal administration, e.g. through microneedle arrays, needleless injectors
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- A61K9/00—Medicinal preparations characterised by special physical form
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- A61K9/141—Intimate drug-carrier mixtures characterised by the carrier, e.g. ordered mixtures, adsorbates, solid solutions, eutectica, co-dried, co-solubilised, co-kneaded, co-milled, co-ground products, co-precipitates, co-evaporates, co-extrudates, co-melts; Drug nanoparticles with adsorbed surface modifiers
- A61K9/143—Intimate drug-carrier mixtures characterised by the carrier, e.g. ordered mixtures, adsorbates, solid solutions, eutectica, co-dried, co-solubilised, co-kneaded, co-milled, co-ground products, co-precipitates, co-evaporates, co-extrudates, co-melts; Drug nanoparticles with adsorbed surface modifiers with inorganic compounds
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- A61K9/141—Intimate drug-carrier mixtures characterised by the carrier, e.g. ordered mixtures, adsorbates, solid solutions, eutectica, co-dried, co-solubilised, co-kneaded, co-milled, co-ground products, co-precipitates, co-evaporates, co-extrudates, co-melts; Drug nanoparticles with adsorbed surface modifiers
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- A61P3/00—Drugs for disorders of the metabolism
- A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
- A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
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- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P31/04—Antibacterial agents
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- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P31/12—Antivirals
- A61P31/14—Antivirals for RNA viruses
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- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P31/12—Antivirals
- A61P31/20—Antivirals for DNA viruses
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Abstract
An injection for needleless injection, in the form of powder, comprises a biological product and an inorganic salt with water of crystallization removed, a mass ratio of the biological product to the inorganic salt being 1:20 to 1:80. The powder is solid particles formed of the biological product wrapped by an external surface of the inorganic salt with water of crystallization removed. The particle diameter of the powder is 20 to 200 micrometers, and preferably, 50 to 70 micrometers. The injection of the present invention may also comprise a tackifier or a Chinese medicinal adjuvant. The mass ratio of the biological product to the tackifier or Chinese medicinal adjuvant to the inorganic salt with water of crystallization removed is 1:0.2:20 to 1:10:80. Also disclosed are a preparation method of the injection for needleless injection, applications of the injection in preparing medicine for preventing or curing diseases, and a method for performing needleless injection by using the injection.
Description
A kind of preparation method and application of Needleless injection injection
Technical field
The present invention relates to a kind of preparation method and purposes of Needleless injection injection, and more particularly to a kind of biological products injection in powder type preparation method and purposes.
Background technology
Biological products are prepared by the biomaterials such as the tissue and liquid in microorganism, cell and various animals and the people source obtained using common biomaterial or by biotechnologys such as genetic engineering, cell engineering, protein engineering, Fermentation Engineerings, are prevented for human diseases, treatment and the medicine diagnosed.At present, Chinese people includes bacterium class vaccine with biological products（Containing toxoid）, virus type vaccine, antitoxin and immune serum, blood product, cell factor, in vivo and in-vitro diagnosis product and other active ingredients（Including toxin, antigen, allergen, monoclonal antibody, recombinant dna product, antigen-antibody complex, immunomodulator, microorganism formulation etc.）.The active component of most of biological products is the living matter of macromolecular（Such as protein, polypeptide, nucleic acid, polysaccharide）, its relative molecular mass is larger, is difficult penetrating gastrointestinal tract barrier and is absorbed by body, and is easily digested liquid and decomposes and inactivate, therefore is not suitable for oral administration, in most cases needs intravenous injection, intramuscular injection, hypodermic injection etc..But, there are many problems in normal injection administration, for example：1) bleeding can be caused, there is cross-infection risk；2) tissue damage is big, and some chronic diseases such as diabetic needs long term injections insulin, often results in the lesions such as injection site tissue hardening, caking；3) keenly feel strong, the compliance of patient is poor, be even more to be difficult in adapt to for children and the people for having probably pin sense, they can not stand for the pain of acupuncture；4) usually require professional to complete, be unsuitable for automedication.
The Needleless powder injection medicament administration technology of applicant earlier application（CN 201643226) it just compensate for these defects：Needleless powder injection technology is by percutaneous drug delivery, and Transdermal absorption can avoid first pass effect, and bioavilability is high, cross-infection, needleless, painless, operational efficiency height can be prevented effectively from, it self can operate, be particularly suitable for patient, children and the patient for having probably pin sense for needing long term administration to treat.Needleless powder injection technology has special requirement to the preparation method and powder properties of drug powder：1) density for carrying medicinal powder end is larger, and for full particle, with larger mechanical strength, beneficial to penetrating keratoderma；2) powder diameter is larger（Hundreds of microns are arrived as tens of）, so as to carry medicinal powder end by high velocity air
Larger kinetic energy is obtained during acceleration（Momentum）, beneficial to penetrating keratoderma；3) powder diameter narrow distribution, close kinetic energy is obtained to ensure to carry when medicinal powder end is accelerated by high velocity air（Momentum）, it is ensured that the reappearance and stability of medicine delivery.Current existing powder preparation method is not suitable for Needleless powder injection mostly, does not reach practical, commercialized require.Most of some published drug powders or particulate preparation method are directed to microballoon and micro- Nang designs, and carrier is mostly high-molecular compound, and density is low（Generally in lg/cm3 or so or lower）, and mostly hollow bead, mechanical strength is small, is difficult to penetrate keratoderma；Simultaneously, institute's acquisition microballoon or the most particle diameters of micro- Nang are smaller, such as a few micrometers to twenty or thirty micron, and particle diameter distribution is wider, it is difficult to meet the above-mentioned technical requirements to Needleless injection powder, thus it is relatively low by the inefficient of Needleless powder injection medicament administration, bioavilability；In addition, the biocompatibility issues of used carrier mass and in vivo degraded are also one of limiting factor.Before, inventor herein was once disclosed a kind of powder preparation method directly mixed, and the method still has larger defect：1) phosphate and insulin mixed solution, are dried under reduced pressure, so that insulin and phosphate cocrystallization（Or be only mixture that the two is crystallized respectively）, resulting powder diameter uniformity is poor；2) insulin effectively can not be attached on phosphate support, and operational efficiency is relatively low；3) being dried under reduced pressure makes the problems such as insulin inactivation is serious.The content of the invention
In view of above-mentioned factor, the invention provides a kind of efficient powder preparation method suitable for load biological products, the powder prepared in this way is full particle, density is big, mechanical strength is big, granularity is hooked, stability is strong, drugloading rate is high, keratoderma can effectively be penetrated, intracutaneous or subcutaneous location performance effect is reached, bioavilability is high.
The primary and foremost purpose of the present invention is to provide a kind of injection of Needleless injection.
It is a further object to provide a kind of preparation method of the injection of Needleless injection.
It is used for the purposes of medicine for preparing prevention or treatment disease it is a further object to provide a kind of injection of Needleless injection.
It is yet another object of the invention to provide the method that a kind of injection of use Needleless injection carries out Needleless injection.
In a first aspect, the invention provides a kind of injection of Needleless injection, injection of the invention is in powder type, and it is 1 that the injection, which includes mass ratio,:20-1 :80 biological products and the de- crystallization water without
Machine salt, the powder is that the biological products are wrapped in the full particle of the de- crystallization water inorganic salts outer surface, and the powder particle diameter between 20-200 microns.Preferably, the mass ratio is 1:20-1:60, most preferably 1:20-1:40;The particle diameter is between 50-70 microns.
In the embodiment of first aspect, the one or more that the biological products include but is not limited in following biological products：Insulin, interferon, vaccine, antitoxin and immune serum, blood product, cell factor, internal and in-vitro diagnosis product and other active ingredients.Preferably, one or more of the biological products in insulin, interferon and vaccine.It is highly preferred that the biological products are insulin.
Preferably, the insulin is selected from regular insulin, low protamine diction insulin, protamine diction insulin, Mixed insulin；The interferon is selected from：IFN-a 2b, IFN-a 2a, lymphoblastoid interferon or its combination；The vaccine be bacterium or viral vaccine, can be selected from the one or more in following vaccine：Hepatitis B 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 de- crystallization water inorganic salts are selected from the sour calcium of anhydrous sodium sulfate, anhydrous stone gram, the sour aluminium of anhydrous ^, the sour magnesium of anhydrous ^, anhydrous ^ acid diction, the sour aluminium potassium of anhydrous ^, anhydrous nitric acid potassium, the sour aluminium of anhydrous acid, ADKP or its combination.Preferably, the de- crystallization water inorganic salts are anhydrous thin sour sodium.
In the another embodiment of first aspect, in addition to above-mentioned biological products and de- crystallization water inorganic salts, injection of the invention also includes tackifier, wherein the mass ratio of the biological products, the tackifier and the de- crystallization water inorganic salts is： 1:0.2:20-1:10:80, preferably 1:0.5:20-1:2:60, more preferably 1:0.5:40-1:2:40.
The tackifier may be selected from Sodium Hyaluronate, human serum albumin or its combination.
In the another embodiment of first aspect, in addition to above-mentioned biological products and de- crystallization water inorganic salts, the injection of the present invention also includes pharmaceutically acceptable adjuvant, wherein the mass ratio of the biological products, the adjuvant and the de- crystallization water inorganic salts is 1:0.2:20-1:10:80, preferably 1:0.5:20-1:7:60, more preferably 1:0.8: 20-1:2:40.
The adjuvant is preferably traditional Chinese medicine adjuvant, the traditional Chinese medicine adjuvant may be selected from saponin(e, polysaccharide, flavones or its
Combination.
Preferably, saponin(e is selected from ginsenoside, notoginsenoside, gypenoside, root of Chinese clematis saponin(e, Dioscin or its combination etc.；Polysaccharide is selected from astragalus polyose, panaxan, grifola polysaccharide, Radix Phodiolae Polyose, date polysaccharide or its combination etc.；Flavones is selected from epimedium flavone, kumquat flavones, oldenlandia diffusa flavones, daizeol, Hippophate flavone or its combination etc..
In the another embodiment of first aspect, in addition to above-mentioned biological products and de- crystallization water inorganic salts, the injection of the present invention also includes pharmaceutically acceptable adjuvant and tackifier, wherein the biological products, the adjuvant, the mass ratio of the tackifier and the de- crystallization water inorganic salts are 1:0.2:0.2:20-1 :10:10:80,4 elect 1 as especially:0.5:0.5:20-1 :7:7:60, more preferably 1:0.8:0.8:20-1 :2:2:40.
The adjuvant is preferably traditional Chinese medicine adjuvant, and the traditional Chinese medicine adjuvant may be selected from saponin(e, polysaccharide, flavones or its combination.The tackifier may be selected from Sodium Hyaluronate, human serum albumin or its combination.
Preferably, saponin(e is selected from ginsenoside, notoginsenoside, gypenoside, root of Chinese clematis saponin(e, Dioscin or its combination etc.；Polysaccharide is selected from astragalus polyose, panaxan, grifola polysaccharide, Radix Phodiolae Polyose, date polysaccharide or its combination etc.；Flavones is selected from epimedium flavone, kumquat flavones, oldenlandia diffusa flavones, daizeol, Hippophate flavone or its combination etc..
In the embodiment above of the first aspect of the present invention, the injection is applied by Needleless injection.In the embodiment above of the first aspect of the present invention, the injection is prepared via a method which：By particle diameter at 20-200 microns in 0-4 °C of environment, it is preferred that in 50-70 micrometer ranges, the inorganic salt powder of the de- crystallization water of most preferably 50 microns be added in the aqueous solution of the biological products or the biological products with the aqueous solution of the tackifier and/or the mixture of the adjuvant to saturation；Continue the addition de- inorganic salt powder of the crystallization water and make it that the mass ratio of the biological products and total de- crystallization water inorganic salts is 1:20-1 :80, preferably 1:20-1 :60, most preferably 1:20-1 :40, obtain mixed crystallization solution；By mixed crystallization solution freeze-drying, collection cut size is at 20-200 microns, the powder preferably in 50-70 micrometer ranges, obtains the Needleless injection injection of the present invention.
In second aspect, the invention provides the preparation method of Needleless injection injection as described in relation to the first aspect, methods described comprises the following steps：By particle diameter at 20-200 microns in 0-4 °C of environment, preferably in 50-70 micrometer ranges, the inorganic salt powder of the de- crystallization water of most preferably 50 microns is added to the life
In the aqueous solution of Tetramune or the biological products and the tackifier and/or the adjuvant mixture the aqueous solution in saturation；Continue the addition de- inorganic salt powder of the crystallization water and make it that the mass ratio of the biological products and total de- crystallization water inorganic salts is 1:20-1:80, preferably 1:20-1:60, most preferably 1:20-1:40, obtain mixed crystallization solution；By mixed crystallization solution freeze-drying, collection cut size is at 20-200 microns, the powder preferably in 50-70 micrometer ranges, obtains the Needleless injection injection of the present invention.
In an embodiment of second aspect, the preparation method of injection of the invention comprises the steps：（1) crush and select particle diameter at 20-200 microns, preferably 50-70 microns, the inorganic salt powder of the de- crystallization water of most preferably 50 microns；（2) the de- inorganic salt powder of the crystallization water is added in the aqueous solution of biological products to saturation at 0-4 °C；(3) continue the addition de- inorganic salt powder of the crystallization water and make it that the mass ratio of the biological products and the de- inorganic salt powder of the crystallization water is 1:20-1:80, preferably 1:20-1:60, most preferably 1:20-1 :40, obtain mixed crystallization solution；（4) the mixed crystallization solution is freeze-dried, collection cut size is 20-200 microns, preferably 50-70 microns of powder obtains the injection of the present invention.
Preferably, Needleless injection of the invention includes insulin and anhydrous sodium sulfate with injection, and its preparation method comprises the steps：
(1) weigh insulin and use distilled water（4 °C) dissolving (a small amount of 0.01mol/l hydrochloric acid hydrotropy can be added）；
(2) anhydrous sodium sulfate particle is subjected to sieving processing, collects the particle of 50 microns, it is stand-by；
(3) by above-mentioned steps（1) insulin solutions prepared in are placed in water water-bath, add a certain amount of anhydrous sodium sulfate particle that sieved to saturation state；
(4) continue up to state and the anhydrous sodium sulfate particle that sieved is added in saturated solution, until insulin：The total mass ratio of anhydrous sodium sulfate is 1:20-1:80, preferably 1:20-1:60, most preferably 1:20-1:40, stirring is mixed to be hooked, untill a large amount of crystal are separated out；
(5) above-mentioned mixed crystallization solution is freeze-dried rapidly, afterwards about 20-200 microns of collection cut size, preferably the powder between 50-70 microns, obtains the injection of insulin agent of the present embodiment.
In another embodiment of second aspect, the preparation method of injection of the invention comprises the following steps：（1) crush and select particle diameter at 20-200 microns, preferably 50-70 microns, the inorganic salt powder of the de- crystallization water of most preferably 50 microns；（2) by the de- crystallization water inorganic salts in 0-4 °C of environment
It is 1 that powder, which is added to mass ratio,:0.2-1:10, preferably 1:0.2-1:2, most preferably 1:0.5-1:To saturation in 2 biological products and the aqueous solution of tackifier；（3) continue the addition de- inorganic salt powder of the crystallization water and make it that the mass ratio of the biological products, the tackifier and the de- inorganic salt powder of the crystallization water is 1:0.2:20-1:10:80,4 elect 1 as especially:0.5:20-1:2:60, most 4 elect 1 as especially:0.5:40-1:2:40, obtain h' elder brothers and close crystallization solution；（4) the mixed crystallization solution is freeze-dried, collection cut size is 20-200 microns, preferably 50-70 microns of powder obtains the injection of the present invention.
Preferably, Needleless injection of the invention is included with injection：Insulin, Sodium Hyaluronate and anhydrous sodium sulfate, its preparation method comprise the steps：
(1) weigh insulin and add distilled water（4 °C) to being completely dissolved（A small amount of 0.01mol/l hydrochloric acid hydrotropy can be added）；
(2) anhydrous sodium sulfate particle is subjected to sieving processing, collects the particle of 50 microns, it is stand-by；
(3) Sodium Hyaluronate is weighed to be added in insulin solutions（A small amount of concentrated ammonia liquor hydrotropy can be added) so that the mass ratio of insulin and Sodium Hyaluronate is 1:0.2-1:2;
(4) by above-mentioned steps（3) insulin-sodium hyaluronate solution obtained by is placed in water water-bath, adds a certain amount of sour sodium particle of the anhydrous stone gram that sieved to saturation state；
(5) continue to step（4) the anhydrous sodium sulfate particle sieved is added in the saturated solution obtained by, until insulin：Sodium Hyaluronate：The total mass ratio of anhydrous sodium sulfate is 1:0.5:20-1:2:40, stir and evenly mix, untill a large amount of crystal are separated out；
(6) above-mentioned mixed crystallization solution is freeze-dried rapidly, collection cut size is about at 20-200 microns afterwards, preferably the powder between 50-70 microns, obtains the injection of insulin agent of the present embodiment.
In another embodiment of second aspect, the preparation method of injection of the invention comprises the following steps：（1) crush and select particle diameter at 20-200 microns, preferably 50-70 microns, the inorganic salt powder of the de- crystallization water of most preferably 50 microns；（2) it is 1 the de- inorganic salt powder of the crystallization water to be added into mass ratio in 0-4 °C or so environment:0.2-1:10, preferably 1:0.5-1:7, most preferably 1:0.8-1:To saturation in 2 biological products and adjuvant, the preferably aqueous solution of traditional Chinese medicine adjuvant；（3) continue the addition de- inorganic salt powder of the crystallization water and make it that quality t an ancient type of spoons of the biological products, the adjuvant and the de- inorganic salt powder of the crystallization water are 1:0.2:20-1:10:80,4 select 1 especially:0.5:20-1:7:60, most 4 select 1 especially:0.8:20-1:2:40, obtain h' elder brothers and close crystallization solution；（4) the mixed crystallization solution is freeze-dried, collection cut size is 20-200 microns,
It is preferred that 50-70 microns of powder, obtains the injection of the present invention.
Preferably, Needleless injection of the invention includes interferon, traditional Chinese medicine adjuvant and de- crystallization water inorganic salts with injection, and the de- crystallization water inorganic salts are preferably anhydrous sodium sulfate, and its preparation method comprises the steps：
(1) measure interferon and add distilled water（4 °C) to being completely dissolved；
(2) anhydrous sodium sulfate particle is subjected to sieving processing, collects the particle of 50 microns, it is stand-by；
(3) weigh traditional Chinese medicine adjuvant and be added to step（1) in the interferon solution obtained by；
(4) by above-mentioned steps（3) interferon-traditional Chinese medicine adjuvant solution obtained by is placed in water water-bath, adds a certain amount of anhydrous sodium sulfate particle that sieved to saturation state；
(5) continue up and state step（4) the anhydrous sodium sulfate particle sieved is added in the saturated solution obtained by, until interferon：Traditional Chinese medicine adjuvant：The total mass ratio of anhydrous sodium sulfate is 1:0.2:20-1:2:60, preferably=1:1:25-1:2:25, stir and evenly mix, untill a large amount of crystal are separated out;
(6) it is rapid by above-mentioned steps（5) the mixed crystallization solution obtained by is freeze-dried, afterwards powder of the collection cut size about between 50-70 microns, obtains the injectable interferon of the present embodiment.
Preferably, Needleless injection of the invention includes vaccine, traditional Chinese medicine adjuvant and de- crystallization water inorganic salts with injection, and the de- crystallization water inorganic salts are preferably anhydrous sodium sulfate, and its preparation method comprises the steps：
(1) measure vaccinogen liquid and use distilled water（4 °C) it is diluted to lmg/ml;
(2) anhydrous sodium sulfate particle is subjected to sieving processing, collects the particle of 50 microns, it is stand-by；
(3) weigh traditional Chinese medicine adjuvant and be added to step（1) in the vaccine solution obtained by；
(4) by above-mentioned steps（3) vaccine-traditional Chinese medicine adjuvant solution obtained by is placed in water water-bath, adds a certain amount of anhydrous sodium sulfate particle that sieved to saturation state；
(5) continue up and state step（4) the anhydrous sodium sulfate particle sieved is added in the saturated solution obtained by, until vaccine：Traditional Chinese medicine adjuvant：The total mass ratio of the sour sodium of anhydrous stone gram is 1:0.5:20-1:10:60, preferably=1:0.5:20-1:5:20, stir and evenly mix, untill a large amount of crystal are separated out;
(6) above-mentioned mixed crystallization solution is freeze-dried rapidly, powder of the collection cut size about between 50-70 microns, obtains the vaccine injecta of the present embodiment afterwards.
In another embodiment of second aspect, the preparation method of injection of the invention comprises the following steps：（1) crush and select particle diameter at 20-200 microns, preferably 50-70 microns, most preferably 50 is micro-
The inorganic salt powder of the de- crystallization water of rice or so；（2) it is 1 the de- inorganic salt powder of the crystallization water to be added into mass ratio in 0-4 °C or so environment:0.2:0.2-1:10:10, preferably 1:0.5:0.5-1:7:7, most preferably 1:0.8:0.8-1:2:2 biological products, adjuvant (preferred traditional Chinese medicine adjuvant）With in the aqueous solution of the mixture of tackifier to saturation；(3) continue the addition de- inorganic salt powder of the crystallization water and cause the biological products, adjuvant（It is preferred that traditional Chinese medicine adjuvant）, tackifier and the de- inorganic salt powder of the crystallization water mass ratio be 1:0.2:0.2:20-1:10:10:80, remainder selects 1:0.5:0.5:20-1:7:7:60, most remainder selects 1:0.8:0.8:20-1:2:2:40;(4) it is freeze-dried, collection cut size is 20-200 microns, preferably 50-70 microns of powder obtains the injection of the present invention.
Preferably, Needleless injection of the invention includes interferon, traditional Chinese medicine adjuvant, tackifier and de- crystallization water inorganic salts with injection, and the de- crystallization water inorganic salts are preferably anhydrous sodium sulfate, and its preparation method comprises the steps：
(1) measure interferon and add distilled water（4 °C) to being completely dissolved；
(2) anhydrous sodium sulfate particle is subjected to sieving processing, collects the particle of 50 microns, it is stand-by；
(3) weigh traditional Chinese medicine adjuvant and tackifier are added to step（1) in the interferon solution obtained by；(4) by above-mentioned steps（3) interferon-tackifier-traditional Chinese medicine adjuvant solution obtained by is placed in water water-bath, adds a certain amount of sour sodium particle of the anhydrous stone gram that sieved to saturation state；
(5) continue up and state step（4) the anhydrous sodium sulfate particle sieved is added in the saturated solution obtained by, until interferon：Traditional Chinese medicine adjuvant：Tackifier：The gross mass of anhydrous sodium sulfate is=1:0.2:0.2:20-1:2:2:60, remainder elects 1 as:1:1:25-1:2:2:25, stir and evenly mix, untill a large amount of crystal are separated out；
(6) it is rapid by above-mentioned steps（5) the mixed crystallization solution obtained by is freeze-dried, afterwards powder of the collection cut size about between 50-70 microns, obtains the injectable interferon of the present embodiment.
Preferably, Needleless injection of the invention includes regular insulin, traditional Chinese medicine adjuvant, tackifier and de- crystallization water inorganic salts with injection, and the de- crystallization water inorganic salts are preferably anhydrous sodium sulfate, and its preparation method comprises the steps：
(1) measure insulin and with add distilled water（4 °C) (a small amount of 0.01mol/l hydrochloric acid hydrotropy can be added to being completely dissolved）；
(2) anhydrous sodium sulfate particle is subjected to sieving processing, collects the particle of 50 microns, it is stand-by；
(3) weigh traditional Chinese medicine adjuvant and tackifier are added to step（1) in the insulin solutions obtained by；
(4) by above-mentioned steps（3) insulin-tackifier-traditional Chinese medicine adjuvant solution obtained by is placed in water water-bath, adds a certain amount of sour sodium particle of the anhydrous stone gram that sieved to saturation state；
(5) continue up and state step（4) the anhydrous sodium sulfate particle sieved is added in the saturated solution obtained by, until insulin：Traditional Chinese medicine adjuvant：Tackifier：The total mass ratio of anhydrous sodium sulfate is
1 :0.5:0.5:20-1 :10:10:60, remainder elects 1 as:0.5:0.5:20-1 :5:5:20, stir and evenly mix, untill a large amount of crystal are separated out；
(6) above-mentioned mixed crystallization solution is freeze-dried rapidly, powder of the collection cut size about between 50-70 microns, obtains the injection of insulin agent of the present embodiment afterwards.
In the third aspect, the purposes for the medicine for being used to prepare prevention or treat disease with injection the invention provides Needleless injection as described in relation to the first aspect.
Wherein, the disease includes, but are not limited to：Diabetes, virus hepatitis, tumour, blood disease, Dermatology, viral keratitis, chronic cervicitis, lockjaw, mumps, diphtheria, measles, typhoid fever or influenza.
In fourth aspect, the invention provides the method that Needleless injection is carried out with injection using Needleless injection as described in relation to the first aspect.Methods described includes：The injection is fitted into the medicine casket of needleless injector, applied by the needleless injector.
Wherein, the automatic needleless powder delivery device that the needleless injector can be disclosed in No. 201643226 patent applications of CN（As shown in Figure 1）.When using, obtained injection is engaged with automatic needleless powder delivery device, prepared powdered injection is fitted into the medicine casket of needleless injector, caisson, the excitation apparatus having by needleless injector, emitter, the powdered injection loaded in medicine casket is transmitted into skin tissue cell by needleless injector, into intracutaneous, subcutaneous or mucosal tissue drug release.
The Needleless injection injection powder of the present invention has the advantages such as granular size is consistent, drugloading rate is high, Drug absorbability is firm, bioavilability is high, the stable safety of property.Suction-operated can be produced to biological products such as insulin, interferon, vaccines by having as the de- crystallization water inorganic salts of pharmaceutical carrier.
The preparation method of the powdered Needleless injection injection of the present invention and the preparation method of prior art are (for example, the crystalline powder preparation method disclosed in CN 1285753A and CN 1315854A patents）Principle and preparation process it is entirely different.The present invention uses recrystallization scattered adsorption method and prepares injection,
In the method for the invention, the inorganic salts of the de- crystallization water are used for carrier, by crush in advance and sieve have the inorganic salt powder of the de- crystallization water of regulation particle diameter and distribution, add in the saturation inorganic salt solution for having dissolved biological products in advance, the effect for absorbing the crystallization water using de- crystallization water inorganic salts absorbs the water in solution system, concentrate system, increase biological products are wrapped in the chance on inorganic salt powder surface, the tackifier such as Sodium Hyaluronate can be added in system in right amount, biological products are made to be more easy to absorption on inorganic salt particle surface, then mixed system is freeze-dried, in dehydration process, biological products are wrapped in inorganic salt particle surface securely.Due to the inorganic salt powder divided in advance is added into its saturated solution, therefore the initial particle of inorganic salt powder will not be changed substantially, so that the load medicine powder diameter finally obtained hooks and is full particle, the technical requirements of Needleless powder injection medicament administration can be met.The matrix of biological products is developed into based on suction-operated, its pharmacy advantage can be given full play to.The tackifier such as Sodium Hyaluronate, human serum albumin have certain thickening, ability to cure, can play auxiliary solidification, further enhancing the adsorption capacity of de- crystallization water inorganic salts.In addition, selected soluble inorganic salt dissolves quickly after being expelled in vivo, noresidue, nontoxic, good biocompatibility.The technology that the present invention prepares injection is properly termed as outer wrapping-last technology of preparing of full particle load medicinal powder.
The Needleless injection of the present invention provides a kind of novel form of biological products with injection, the formulation is particularly suitable for use in needleless injection techniques, so as to effectively prevent the first pass effect caused by oral drug preparation, the size of its particle diameter meets percutaneous dosing requirement, it is easy to by by stratum corneum barrier, the curative effect of medicine can be greatly improved, shortens onset time.Therefore, it is adaptable to which the injection of Needleless powder injection technology is particularly suitable for the medical prevention guarantee under the conditions of vital emergent event and outlying district, Large scale field operation etc., and has the patient of probably pin sense（Such as children）With need the patient of long-term automedication, and the formulation is more stablized, therefore application prospect is very wide.The present invention prepares Needleless injection injection using recrystallization scattered adsorption method, and technique is convenient, short flow, with low cost and prepared suitable for fairly large powder.
Summary of drawings
Fig. 1 shows the automatic needleless powder delivery device available for the present invention.
Fig. 2 shows the stereoscan photograph of the powder of the low protamine diction injection of insulin agent prepared by the embodiment of the present invention 5, and left figure is single powder stereoscan photograph, and right figure is surface details photo.
Fig. 3 A show the column diagram of the drugloading rate of the injection of insulin agent prepared by 1-4 of the embodiment of the present invention,
Abscissa is the mass ratio of insulin and anhydrous sodium sulfate, and ordinate is drugloading rate.
Fig. 3 B show the column diagram of the bioavilability of the injection of insulin agent prepared by 1-4 of the embodiment of the present invention, and abscissa is bioavilability, and ordinate is the mass ratio of insulin and anhydrous sodium sulfate.
Fig. 4 A show that the low protamine diction injection of insulin agent injection prepared by the embodiment of the present invention 5 is said after this White Rabbit, glucose in serum content time history plot, and abscissa is the time（H), ordinate is the content of glucose in serum（mmol/L ) .
Fig. 4 B show that Needleless injection prepared by prior art is taken leave injection of insulin agent injection with low protamine and said after this White Rabbit, glucose in serum content time history plot, and abscissa is the time（H), ordinate is the content of glucose in serum（mmol/L ) .
Fig. 5 A show that the low protamine prepared by 5-10 of the embodiment of the present invention takes leave the insulin content figure of injection of insulin agent, and abscissa represents the mass ratio of insulin, Sodium Hyaluronate and anhydrous sodium sulfate, and ordinate represents insulin content（mg/mg ) .
Fig. 5 B show the result figure of the bioavilability of the low protamine diction injection of insulin agent prepared by 5-10 of the embodiment of the present invention, and abscissa represents the mass ratio of insulin, Sodium Hyaluronate and anhydrous sodium sulfate, and ordinate represents bioavilability.
Fig. 6 shows the interferon titration result figure of the interference energy injection prepared by 12-16 of the embodiment of the present invention, and wherein abscissa represents interference energy, notoginsenoside, the mass ratio of anhydrous sodium sulfate, and ordinate represents interferon potency（ IU ) .
Fig. 7 shows the l of the hepatitis B vaccine injection agent prepared by 17-21 of the embodiment of the present inventiongG antibody titer measurement result figures, wherein abscissa represent the mass ratio of vaccine, ginsenoside, anhydrous sodium sulfate, and ordinate represents the concentration for the hepatitis B vaccine lgG antibody that hepatitis B vaccine is determined for 6 weeks after being injected to cavy（ U/L ).
Fig. 8 A show the immune effect figure of the tetanus vaccine injection prepared by the embodiment of the present invention 22, and abscissa represents the time（Week), ordinate represents the concentration of tetanus vaccine IgG antibody in serum（ U-L"1 )。
Fig. 8 B show the immune effect figure of Needleless injection tetanus vaccine injection prepared by prior art, and abscissa represents the time（Week）, ordinate represents the concentration (U-L- of tetanus vaccine IgG antibody in serum1 ) 。
Fig. 9 shows the interferon titration result figure of the injectable interferon prepared by 23-28 of the embodiment of the present invention, and wherein abscissa represents the matter of Recomvinated Interferon α-2a, astragalus polyose, Sodium Hyaluronate, anhydrous sodium sulfate
Amount ratio, ordinate represents interferon potency (IU)tThe better embodiment of the present invention
The present invention is further illustrated and explains by the following examples, but not as the limitation of the present invention.Embodiments contained herein is more fully understood from invention as described herein just for the sake of help.These embodiments do not limit as described herein or this paper scopes claimed in any way.Material used in following examples, except where noted, remaining is commercially available.
Embodiment 1:
The injection of insulin agent that the last technology of preparing of medicinal powder prepares Needleless injection is carried using outer wrapping-full particle of the present invention：
(1) regular insulin is weighed（Sigma) 40mg and 2mL distilled waters are added（4 °C) to being completely dissolved (the hydrochloric acid hydrotropy that a small amount of 0.01mol/l can be added)；
(2) anhydrous sodium sulfate particle is subjected to sieving processing, collects the particle of 50 microns, it is stand-by；(3) by above-mentioned steps（1) insulin solutions prepared in are placed in water water-bath, add a certain amount of anhydrous sodium sulfate particle that sieved to saturation state；
(4) continue up and state step（3) the basically identical anhydrous sodium sulfate particle of a large amount of particle sizes is put into the saturated solution obtained by, until insulin：The total mass ratio of anhydrous sodium sulfate is 1:40, stir and evenly mix, untill a large amount of crystal are separated out；
(5) it is rapid by above-mentioned steps（4) the mixed crystallization solution obtained by carries out frozen drying, afterwards powder of the collection cut size about between 50-70 microns, injection of insulin agent needed for obtaining.
Embodiment 2:
The injection of insulin agent of the Needleless injection of the present invention is prepared using method same as Example 1, the difference is that the total mass ratio of regular insulin and anhydrous sodium sulfate is 1 in the embodiment:80.
Embodiment 3:
The injection of insulin agent of the Needleless injection of the present invention is prepared using method same as Example 1, the difference is that the total mass ratio of regular insulin and anhydrous sodium sulfate is 1 in the embodiment:20.
Embodiment 4:
The injection of insulin agent of the Needleless injection of the present invention is prepared using present invention method same as Example 1, the difference is that the total mass ratio of regular insulin and anhydrous sodium sulfate is 1 in the embodiment:60.
Injection of insulin agent to the Needleless injection prepared by embodiment 1-4 carries out drugloading rate and Bioavailability Determination.
Drugloading rate, which is determined, uses Coomassie brilliant blue protein determination kit（Bioengineering Research Institute is built up in Nanjing）The drugloading rate for completing the injection of insulin agent obtained by embodiment 1-4 is determined, as a result referring to Fig. 3 A.Fig. 3 A show that the injection of insulin agent prepared by embodiment 1-4 is respectively provided with high drugloading rate, in more than 0.015/mg；
Hypoglycemic effect is determined:Saying this White Rabbit（Male, Beijing KeYu animal-breeding center）In the injection of insulin agent that is obtained to embodiment 1-4 carry out internal examination of glucose concentration.21 White Rabbits are randomly divided into 7 groups：Blank group, positive controls（It is injected intravenously 0.3mg insulin）, negative control group, 1 group of embodiment（The agent of Needleless powder injection 12mg injection of insulin), 2 groups of embodiment（The agent of Needleless powder injection 24mg injection of insulin), 3 groups of embodiment（The agent of Needleless powder injection 6mg injection of insulin), 4 groups of embodiment（Needleless powder injection 15mg injection of insulin agent）, each group experimental animal need to use alloxan in addition to blank group（Sigma) according to 120mg/kg modelings.After administration respectively at 0, the serum of White Rabbit is taken within 0.33,0.66,1,2,3,5,7,10 hours, then using Glucose estimation kit（Glucose oxidase-peroxidase method）（ShangHai RongSheng Biology Pharmacy Co., Ltd）The concentration of glucose in serum is determined according to explanation, glucose in serum content is drawn（The average value of every group of animal）Time history plot；
The curve map of gained calculates bioavilability with trapezoidal faces area method during bioavilability calculating is determined according to hypoglycemic effect, as a result referring to Fig. 3 B.Fig. 3 B show that the injection of insulin agent prepared by embodiment 1-4 is respectively provided with hypoglycemic effect, and bioavilability is more than 78%.
Embodiment 5:
The last technology of preparing of medicinal powder is carried using outer wrapping-full particle of the present invention, Sodium Hyaluronate thickening mode prepares Needleless injection and takes leave injection of insulin agent with low protamine：
(1) low protamine diction insulin is taken（Sigma) 20mg, adds (4 °C) dissolvings of distilled water 2mL, ultrasonically treated in ultrasonic cleaning machine, scattered 2 hours, dissolves it.If do not dissolve still, plus a small amount of concentrated hydrochloric acid；
(2) anhydrous sodium sulfate particle is subjected to sieving processing, collects the particle of 50 microns, it is stand-by；
(3) toward above-mentioned steps（1) 10m is added in the solution obtained bygSodium Hyaluronate (aladdin) and Slow is stirred slowly, until being completely dissolved, can add a small amount of concentrated ammonia liquor hydrotropy；
(4) by above-mentioned steps（3) insulin-sodium hyaluronate solution prepared is placed in water water-bath, adds a certain amount of anhydrous sodium sulfate particle that sieved to saturation state；
(5) continue up and state step（4) the basically identical anhydrous sodium sulfate particle of a large amount of particle sizes is put into the saturated solution obtained by, until insulin：Sodium Hyaluronate：The total mass ratio of anhydrous sodium sulfate is 1:0.5:40, stir and evenly mix, untill a large amount of crystal are separated out；
(6) it is rapid by above-mentioned steps（5) the mixed crystallization solution obtained by carries out frozen drying, afterwards powder of the collection cut size about between 50-70 microns, low protamine diction injection of insulin agent needed for obtaining.
Use following method by low protamine prepared in the embodiment take leave prepared by injection of insulin agent and the crystalline powder technology of preparing according to disclosed in CN 1315854A patents by mass ratio for 40:The Needleless injection of 1 aluminium hydroxide and low protamine diction insulin composition is compared with the diction injection of insulin agent of low protamine：
Morphological feature measurement uses S4800 cold field emission SEM（Beijing physico-chemical analysis test center）To observe the morphological feature of two kinds of injections；
Particle size uses laser particle size analyzer（American-European gram Science and Technology Ltd.）Conventionally determine the particle size of two kinds of injection powder；
Hardness ' use MC010-HV-5 type Smaller load Vickers（Shanghai Yanrun Ray Machine Technology Co., Ltd.）Conventionally determine the hardness of two kinds of injections；
Insulin content, which is determined, uses Coomassie brilliant blue protein determination kit（Bioengineering Research Institute is built up in Nanjing）Determine the insulin content in two kinds of injections；
Hypoglycemic effect is determined:Take different amounts of two kinds of injection samples, so that the amount of insulin contained in two kinds of injection samples is identical, the hypoglycemic effect of two kinds of injections is determined using hypoglycemic effect assay method as described above, glucose sugared content time history plot in serum is drawn, as a result referring to Fig. 4 A and Fig. 4 B;
Bioavilability:The curve map of gained in being determined according to hypoglycemic effect（Fig. 4 A and Fig. 4 B) bioavilabilities of two kinds of injections is tried to achieve using trapezoidal faces area method.
Two kinds of injection comparative results are referring to table 1 below.
The low protamine diction injection of insulin agent of the present invention of table 1 and the Needleless injection of prior art take leave the comparison of injection of insulin agent with low protamine
As shown in Table 1, the morphological feature of the low protamine diction injection of insulin agent prepared by the present invention is more suitable for Needleless injection, and insulin content and bioavilability with the low protamine diction injection of insulin agent prepared apparently higher than prior art.In addition, Fig. 4 A and Fig. 4 B show that there is the low protamine diction injection of insulin agent prepared by the present invention Needleless injection prepared than prior art to take leave the more preferable hypoglycemic effect of injection of insulin agent with low protamine.Embodiment 6:
The Needleless injection low protamine diction injection of insulin agent of the present invention is prepared using method same as Example 5, the difference is that Sodium Hyaluronate used in the embodiment is 4mg, and wherein insulin：Sodium Hyaluronate：The total mass ratio of the sour sodium of anhydrous stone gram is 1: 0.2: 20.
Embodiment 7:
The Needleless injection low protamine diction injection of insulin agent of the present invention is prepared using method same as Example 5, the difference is that Sodium Hyaluronate used in the embodiment is 200mg, and wherein insulin：Sodium Hyaluronate：The total mass ratio of the sour sodium of anhydrous stone gram is 1: 10: 80.
Embodiment 8:
The Needleless injection low protamine diction injection of insulin agent of the present invention is prepared using method same as Example 5, the difference is that insulin in the embodiment：Sodium Hyaluronate：The total mass ratio of anhydrous sodium sulfate is 1: 0.5 :20.
Embodiment 9:
The Needleless injection low protamine diction injection of insulin agent of the present invention is prepared using method same as Example 5, the difference is that Sodium Hyaluronate used in the embodiment is 40mg, and wherein insulin：Sodium Hyaluronate：The total mass ratio of the sour sodium of anhydrous stone gram is 1: 2: 60.
Embodiment 10:
The Needleless injection low protamine diction injection of insulin agent of the present invention is prepared using method same as Example 5, the difference is that Sodium Hyaluronate used in the embodiment is 40 mg, and wherein insulin：Sodium Hyaluronate：The total mass ratio of the sour sodium of anhydrous stone gram is 1: 2: 40.
The insulin content that the low protamine prepared by embodiment 5-10 takes leave injection of insulin agent is determined using method as discussed above, as a result referring to Fig. 5 A, Fig. 5 A show that the low protamine diction injection of insulin agent prepared by embodiment 5-10 is respectively provided with high insulin content（0.02 more than mg/mg）；The hypoglycemic effect of the low protamine diction injection of insulin agent prepared by embodiment 5-10 is determined using method as discussed above and glucose in serum content time history plot is drawn, then bioavilability is calculated using trapezoidal faces area method according to glucose in serum content time history plot, as a result referring to Fig. 5 B, Fig. 5 B show the hypoglycemic effect that the low protamine diction injection of insulin agent prepared by embodiment 5-10 has been respectively provided with, and bioavilability is more than 75%.
Embodiment 11:
The Mixed insulin for including human serum albumin of the Needleless injection of the present invention is prepared using method same as Example 5（30% short-acting insulin and 70% intermediate-acting insulins）Injection, the difference is that using Mixed insulin in the embodiment（Sigma) Sodium Hyaluronate is replaced instead of low protamine diction insulin, human serum albumin (Sigma).
Embodiment 12:
The interference energy comprising notoginsenoside that the last technology of preparing of medicinal powder prepares Needleless injection is carried using outer wrapping-full particle of the present invention（IFN- a2b) injection：
(1) interference energy is taken（Sigma) 40mg, adds distilled water 2mL (4 °C) to being completely dissolved, ultrasonically treated and filter off insoluble matter；
(2) anhydrous sodium sulfate particle is subjected to sieving processing, collects the particle of 50 microns, it is stand-by；
(3) toward above-mentioned steps（1) 40mg notoginsenosides are added in the solution obtained by and Slow is stirred slowly；
(4) by above-mentioned steps（3) interferon-notoginsenoside solution prepared is placed in water water-bath, adds a certain amount of anhydrous sodium sulfate particle that sieved to saturation state；
(5) immediately continue with to above-mentioned steps（4) the basically identical anhydrous sodium sulfate particle of a large amount of particle sizes is put into the saturated solution obtained by, until interferon：Notoginsenoside：The total mass ratio of anhydrous sodium sulfate is 1:1:25 ratio, is stirred and evenly mixed, untill a large amount of crystal are separated out；
(6) rapid that above-mentioned mixed crystallization solution is carried out into frozen drying, powder of the collection cut size about between 50-70 microns, disturbs energy injection afterwards needed for obtaining.
Embodiment 13:
Using the interference energy comprising notoginsenoside for the Needleless injection that the present invention is prepared with the identical method of embodiment 12（IFN- a2b) injection, the difference is that notoginsenoside used is 8mg, and wherein dry outstanding element：Notoginsenoside：The total mass ratio of the sour sodium of anhydrous ^ is 1: 0.2: 20.
Embodiment 14:
Using the interference energy comprising notoginsenoside for the Needleless injection that the present invention is prepared with the identical method of embodiment 12（IFN-a2b) injection, the difference is that notoginsenoside used is 400mg, and wherein interferon：Notoginsenoside：The total mass ratio of anhydrous thin sour sodium is 1: 10: 80.
Embodiment 15:
Using the interference energy comprising notoginsenoside for the Needleless injection that the present invention is prepared with the identical method of embodiment 12（IFN-a2b) injection, the difference is that notoginsenoside used is 32mg, and wherein interferon：Notoginsenoside：The total mass ratio of the sour sodium of anhydrous ^ is 1: 0.8: 20.
Embodiment 16:
Using the interference energy comprising notoginsenoside for the Needleless injection that the present invention is prepared with the identical method of embodiment 12（IFN-a2b) injection, the difference is that notoginsenoside used is 80mg, and wherein interferon：Notoginsenoside：The total mass ratio of anhydrous thin sour sodium is 1: 2: 40.
Interferon titration is carried out to the interference energy injection prepared by embodiment 12-16.
Interferon titration according to《Products in China code》Version " interferon titration " in 2000（Cytopathic-effect inhibition assay）Use human amniotic cell（WISH, purchased from the biological Co., Ltd in Beijing Sheng Xubai rivers), vesiculovirus stomatitis virus（Vsv, purchased from the biological Co., Ltd in Beijing Sheng Xubai rivers) determine, wherein using BH-2 inverted microscope (Olympus）Count determine the death rate and in this way provided in formula be translated into the potency of interferon, as a result referring to Fig. 6.Fig. 6 shows that the interference energy injection prepared by embodiment 12-16 is respectively provided with higher activity, and interferon potency is in 500 more than IU.
Embodiment 17:
The last technology of preparing of medicinal powder is carried using outer wrapping-full particle of the present invention, traditional Chinese medicine adjuvant liquid hybrid mode prepares the hepatitis B vaccine injection agent comprising ginsenoside of the Needleless injection of the present invention：
(1) hepatitis B vaccine is measured（Beijing Yang Zhou biotechnologies company in length and breadth) 40mL is diluted to, concentration is lmg/ml;
(2) 48mg ginsenoside distilled waters are weighed（4 °C) concentration is dissolved to for 0.5mg/ml;
(3) hepatitis B vaccine is pressed：The total mass ratio of ginsenoside is 1:1.2 ratio blend step（And step 1)（2) solution obtained by, it is ultrasonically treated in ultrasonic cleaning machine, scattered 2 hours, obtain suspension；
(4) by above-mentioned steps（3) hepatitis B vaccine-ginsenoside solution obtained by is placed in water water-bath, adds a certain amount of anhydrous sodium sulfate particle that sieved to saturation state；
(5) immediately continue with and the basically identical anhydrous sodium sulfate particle of a large amount of particle sizes is put into the saturated solution, until hepatitis B vaccine：Ginsenoside：The total mass ratio of anhydrous sodium sulfate is 1:1.2:40, it is separated out a large amount of crystal, mix；
(6) it is rapid by above-mentioned steps（5) the mixed crystallization solution obtained by is freeze-dried, powder of the collection cut size between 50-70 microns, Cord blood, hepatitis B vaccine injection agent needed for obtaining.
Embodiment 18:Hepatitis B vaccine vaccine injecta, unlike：In step（2) 40mg ginsenosides, step are weighed in（3) hepatitis B vaccine in：The mass ratio of ginsenoside is 1:1, and hepatitis B vaccine：Ginsenoside：The total mass ratio of the sour sodium of anhydrous ^ is 1: 1: 40.
Embodiment 19:Hepatitis B vaccine vaccine injecta, unlike：In step（2) 400mg ginsenosides, step are weighed in（3) hepatitis B vaccine in：The mass ratio of ginsenoside is 1:10, and hepatitis B vaccine：Ginsenoside：The total mass ratio of the sour sodium of anhydrous ^ is 1: 10: 80.
Embodiment 20:Hepatitis B vaccine vaccine injecta, unlike：In step（2) 32mg ginsenosides, step are weighed in（3) hepatitis B vaccine in：The mass ratio of ginsenoside is 1:0.8, and hepatitis B vaccine：Ginsenoside：The total mass ratio of the sour sodium of anhydrous ^ is 1: 0.8: 20.
Embodiment 21:Hepatitis B vaccine vaccine injecta, unlike：In step（2) 8mg ginsenosides, step are weighed in（3) hepatitis B vaccine in：Mass ratio=1 of ginsenoside:0.2, and hepatitis B vaccine：Ginsenoside：The total mass ratio of the sour sodium of anhydrous stone gram is 1: 0.2: 20.
Hepatitis B vaccine lgG antibody titers are carried out to the hepatitis B vaccine injection agent prepared by embodiment 17-21 to determine.
Hepatitis B vaccine lgG antibody titers are determined:In cavy（Male, Beijing KeYu animal-breeding center）In the vaccine injecta that is obtained to embodiment 17-21 carry out hepatitis B vaccine lgG antibody titers and determine.42 cavys are randomly divided into 7 groups：Blank group, control group（Be subcutaneously injected tetanus toxoid lmg), 17 groups of embodiment（Needleless powder injection vaccine injecta 40mg), 18 groups of embodiment（Needleless powder injection vaccine injecta 40mg), 19 groups of embodiment（Needleless powder injection vaccine injecta 80mg), 20 groups of embodiment（Needleless powder injection vaccine injecta 20mg), 21 groups of embodiment（Needleless powder injection vaccine injecta 20mg).After immune 6 weeks, guinea pig serum is taken, ELISA hepatitis B vaccine lgG antibody diagnosing reagent kits are used using ELISA ELISAs（Zhuhai Haitai Biology Pharmacy Co., Ltd) according to the concentration of hepatitis B vaccine IgG antibody in explanation measure serum（The average value of every group of animal）, as a result referring to Fig. 7.Fig. 7 shows the immune effect that the hepatitis B vaccine injection agent prepared by embodiment 17-21 has been respectively provided with.
Embodiment 22:
The tetanus vaccine injection comprising ginsenoside that the last technology of preparing of medicinal powder prepares Needleless injection is carried using outer wrapping-full particle of the present invention：
(1) 5.2 grams of ginsenoside is weighed, distilled water is used（4 °C) it is configured to the ginsenoside solution that concentration is 0.087 mg/ml, moist heat sterilization；
(2) step is taken（1) the ginsenoside solution 4ml prepared, by tetanus vaccine：The mass ratio of ginsenoside is about 1:7 ratio adds (^g (Beijing Yang Zhou biotechnologies companies in length and breadth of tetanus vaccine 5）, mix, suspension must be mixed by being stored at room temperature 15 minutes；
(3) by above-mentioned steps（2) tetanus vaccine-ginsenoside solution prepared is placed in water water-bath,
A certain amount of sour sodium particle of the anhydrous stone gram that sieved is added to saturation state；
(4) the basically identical anhydrous sodium sulfate particle of a large amount of particle sizes is put into the saturated solution, makes tetanus vaccine：Ginsenoside：The total mass ratio of anhydrous sodium sulfate is 1: 7:40, it is separated out a large amount of crystal, mix, stand；
(5) it is rapid by above-mentioned steps（4) the mixed crystallization solution freeze-drying obtained by, powder of the collection cut size about between 50-70 microns, tetanus vaccine injection needed for producing.
Use following method by cold vaccine injecta prepared in the embodiment and the crystalline powder technology of preparing according to disclosed in CN 1285753A patents prepare by mass ratio for 40:The tetanus vaccine injection of the Needleless injection of 1 aluminium hydroxide and tetanus vaccine composition is compared：
Morphological feature, particle size, hardness are measured using method as described in example 5 above；Tetanus vaccine assay uses Coomassie brilliant blue protein determination kit（Bioengineering Research Institute is built up in Nanjing）The tetanus vaccine content of two kinds of injections of phase homogenous quantities is determined according to explanation；
Immune effect：Using the IgG antibody concentration that two kinds of tetanus vaccine injections are determined with same procedure used in hepatitis B vaccine IgG antibody titer determination, the difference is that using ELISA lockjaw IgG antibody diagnosing reagent kits（Zhuhai Haitai Biology Pharmacy Co., Ltd）, as a result referring to Fig. 8 A and Fig. 8 B.
Two kinds of injection comparative results are referring to table 2 below.
The comparison of the tetanus vaccine injection of the present invention of table 2 and the Needleless injection tetanus vaccine injection of prior art
As shown in Table 2, the morphological feature of the tetanus vaccine injection prepared by the present invention is more suitable for Needleless injection, and with the tetanus vaccine content of the Needleless injection tetanus vaccine injection prepared apparently higher than prior art.In addition, Fig. 8 A and Fig. 8 B show that the tetanus vaccine injection prepared by the present invention has the Needleless injection more preferable immune effect of tetanus vaccine injection prepared than prior art.
Embodiment 23:
The last technology of preparing of medicinal powder is carried using outer wrapping-full particle of the present invention, Sodium Hyaluronate thickening mode and astragalus polyose liquid hybrid mode prepare Recomvinated Interferon α-2a (IFN-a2a) injection comprising astragalus polyose of Needleless injection：
(1) astragalus polyose 1.25g is weighed, distilled water is used（4 °C) it is configured to the astragalus polyose solution that concentration is 0.025 mg/ml, moist heat sterilization；
(2) in step（1) in solution, by Recomvinated Interferon α-2a：The mass ratio of astragalus polyose is 1:0.8 addition Recomvinated Interferon α-2a (Sigma) 1.5625g is simultaneously mixed, then with Recomvinated Interferon α-2a：The mass ratio of Sodium Hyaluronate is 1:0.8 adds 1.25g Sodium Hyaluronates into mixed solution and mixes, and suspension must be mixed by being stored at room temperature 15 minutes；
(3) by above-mentioned steps（2) Recomvinated Interferon α-2a-astragalus polyose-sodium hyaluronate solution prepared is placed in water water-bath, adds a certain amount of anhydrous sodium sulfate particle that sieved to saturation state；
(4) the basically identical anhydrous sodium sulfate particle of a large amount of particle sizes is put into the saturated solution, makes Recomvinated Interferon α-2a：Astragalus polyose：Sodium Hyaluronate：Anhydrous sodium sulfate total mass ratio is 1:0.8:0.8:20, it is separated out a large amount of crystal, mix, stand；
(5) the rapid mixed crystallization solution by obtained by above-mentioned steps (4) is freeze-dried, powder of the collection cut size about between 50-70 microns, Cord blood, Recomvinated Interferon α-2a injection needed for producing.Embodiment 24:
Using the Recomvinated Interferon α-2a injection comprising astragalus polyose for the Needleless injection that the present invention is prepared with the identical method of embodiment 23, the difference is that the Recomvinated Interferon α-2a added in step 2 is 0.625g, and Recomvinated Interferon α-2a：Astragalus polyose：Sodium Hyaluronate：The total mass ratio of the sour sodium of anhydrous stone gram is 1:2:2:40.
Embodiment 25:
Using the Recomvinated Interferon α-2a injection comprising astragalus polyose for the Needleless injection that the present invention is prepared with the identical method of embodiment 23, the difference is that the Recomvinated Interferon α-2a added in step 2 is 2.5g, and Recomvinated Interferon α-2a：Astragalus polyose：Sodium Hyaluronate：The total mass ratio of the sour sodium of anhydrous stone gram is 1:0.5:0.5:20.
Embodiment 26:
Using the Recomvinated Interferon α-2a injection comprising astragalus polyose for the Needleless injection that the present invention is prepared with the identical method of embodiment 23, the difference is that the Recomvinated Interferon α-2a added in step 2 is 0.18g, and Recomvinated Interferon α-2a：Astragalus polyose：Sodium Hyaluronate：The total mass ratio of the sour sodium of anhydrous stone gram is 1:7:7:60.Embodiment 27:
Using the Recomvinated Interferon α-2a injection comprising astragalus polyose for the Needleless injection that the present invention is prepared with the identical method of embodiment 23, the difference is that the Recomvinated Interferon α-2a added in step 2 is 6.25g, and Recomvinated Interferon α-2a：Astragalus polyose：Sodium Hyaluronate：The total mass ratio of the sour sodium of anhydrous stone gram is 1:0.2:0.2:20.Embodiment 28:
Using the Recomvinated Interferon α-2a for including astragalus polyose for the Needleless injection that the present invention is prepared with the identical method of embodiment 23（IFN-a2a) injection, the difference is that the Recomvinated Interferon α-2a added in step 2 is 0.125g, and Recomvinated Interferon α-2a：Astragalus polyose：Sodium Hyaluronate：The total mass ratio of anhydrous sodium sulfate is 1:10:10:80.
Interferon titration is carried out to the injectable interferon prepared by embodiment 23-28, interferon titration is using the identical method used in embodiment 12-16, as a result referring to Fig. 9.Fig. 9 shows that the injectable interferon prepared by embodiment 23-28 is respectively provided with high potency, so that with high activity.
Middle repetition.The term that is used and wording are with explaining and without restricted, and it is not intended to during using these terms and wording and excludes shown and described any equivalents of feature or part thereof, it should be recognized that a variety of changes may be within the scope of the invention.
Industrial applicibility
The Needleless injection injection powder of the present invention has the advantages such as granular size is consistent, drugloading rate is high, Drug absorbability is firm, bioavilability is high, the stable safety of property.Suction-operated can be produced to biological products such as insulin, interferon, vaccines by having as the de- crystallization water inorganic salts of pharmaceutical carrier.
The preparation method of the powdered Needleless injection injection of the present invention and the preparation method of prior art are (for example, the crystalline powder preparation method disclosed in CN 1285753A and CN 1315854A patents）
Principle and preparation process it is entirely different.The present invention uses recrystallization scattered adsorption method and prepares injection, in the method for the invention, the inorganic salts of the de- crystallization water are used for carrier, by crush in advance and sieve have the inorganic salt powder of the de- crystallization water of regulation particle diameter and distribution, add in the saturation inorganic salt solution for having dissolved biological products in advance, the effect for absorbing the crystallization water using de- crystallization water inorganic salts absorbs the water in solution system, concentrate system, increase biological products are wrapped in the chance on inorganic salt powder surface, the tackifier such as Sodium Hyaluronate can be added in system in right amount, biological products are made to be more easy to absorption on inorganic salt particle surface, then mixed system is freeze-dried, in dehydration process, biological products are wrapped in inorganic salt particle surface securely.Due to the inorganic salt powder divided in advance is added into its saturated solution, therefore the initial particle of inorganic salt powder will not be changed substantially, so that the load medicine powder diameter finally obtained hooks and is full particle, the technical requirements of Needleless powder injection medicament administration can be met.The matrix of biological products is developed into based on suction-operated, its pharmacy advantage can be given full play to.The tackifier such as Sodium Hyaluronate, human serum albumin have certain thickening, ability to cure, can play auxiliary solidification, further enhancing the adsorption capacity of de- crystallization water inorganic salts.In addition, selected soluble inorganic salt dissolves quickly after being expelled in vivo, noresidue, nontoxic, good biocompatibility.The technology that the present invention prepares injection is properly termed as outer wrapping-last technology of preparing of full particle load medicinal powder.
The Needleless injection of the present invention provides a kind of novel form of biological products with injection, the formulation is particularly suitable for use in needleless injection techniques, so as to effectively prevent the first pass effect caused by oral drug preparation, the size of its particle diameter meets percutaneous dosing requirement, it is easy to by by stratum corneum barrier, the curative effect of medicine can be greatly improved, shortens onset time.Therefore, it is adaptable to which the injection of Needleless powder injection technology is particularly suitable for the medical prevention guarantee under the conditions of vital emergent event and outlying district, Large scale field operation etc., and has the patient of probably pin sense（Such as children）With need the patient of long-term automedication, and the formulation is more stablized, therefore application prospect is very wide.
The present invention prepares Needleless injection injection using recrystallization scattered adsorption method, and technique is convenient, short flow, with low cost and prepared suitable for fairly large powder.
Claims (1)
- Claims1. a kind of Needleless injection injection, in powder type, it is 1 that the injection, which includes mass ratio,:20-1:80, preferably 1:20-1:60, most preferably 1:20-1:40 biological products and de- crystallization water inorganic salts, the powder are that the biological products are wrapped in the full particle of the de- crystallization water inorganic salts outer surface, and the powder particle diameter between 20-200 microns, preferably between 50-70 microns.2. injection as claimed in claim 1, wherein the biological products are selected from the one or more of following biological products：Insulin, interferon, vaccine, antitoxin and immune serum, blood product, cell factor, internal and in-vitro diagnosis product and other active ingredients, preferably, one or more of the biological products in insulin, interferon and vaccine, it is highly preferred that the biological products are insulin.3. injection as claimed in claim 2, wherein the insulin is selected from regular insulin, low protamine diction insulin, protamine diction insulin, Mixed insulin；The interferon is selected from IFN- a2b, IFN-a 2a, lymphoblastoid interferon or its combination；The vaccine is bacterium or viral vaccine, is preferably selected from the one or more in following vaccine：Hepatitis B 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, wherein the de- crystallization water inorganic salts are selected from the sour calcium of anhydrous sodium sulfate, anhydrous ^, the sour aluminium of anhydrous ^, the sour magnesium of anhydrous ^, anhydrous ^ acid diction, the sour aluminium potassium of anhydrous ^, anhydrous nitric acid potassium, the sour aluminium of anhydrous acid, the sour hydrogen dipotassium of anhydrous upright stone tablet or its combination；Preferably, the de- crystallization water inorganic salts are the sour sodium of anhydrous ^.5. the injection as any one of claim 1-4, the injection also includes tackifier, wherein the mass ratio of the biological products, the tackifier and the de- crystallization water inorganic salts is 1: 0.2: 20-1:10:80, preferably 1:0.5:20-1:2:60, more preferably 1:0.5:40-1:2:40;And the tackifier are selected from Sodium Hyaluronate, human serum albumin or its combination.6. the injection as any one of claim 1-4, the injection also includes pharmaceutically acceptable adjuvant, wherein the mass ratio of the biological products, the adjuvant and the de- crystallization water inorganic salts is 1:0.2:20-1:10:80, remainder elects 1 as:0.5:20-1:7:60, more preferably 1:0.8: 20-1:2:40;And the adjuvant is preferably traditional Chinese medicine adjuvant.7. the injection as any one of claim 1-4, the injection also includes pharmaceutically acceptable adjuvant and tackifier, wherein the biological products, the adjuvant, the mass ratio of the tackifier and the de- crystallization water inorganic salts are 1:0.2:0.2:20-1 :10:10:80, preferably 1:0.5:0.5:20-1 :7:7:60, more preferably 1:0.8:0.8:20-1 :2:2:40;And the adjuvant is preferably traditional Chinese medicine adjuvant.8. injection as claimed in claims 6 or 7, wherein the traditional Chinese medicine adjuvant is selected from saponin(e, polysaccharide, flavones or its combination, the saponin(e is selected from ginsenoside, notoginsenoside, gypenoside, root of Chinese clematis saponin(e, Dioscin or its combination；The polysaccharide is selected from astragalus polyose, panaxan, grifola polysaccharide, Radix Phodiolae Polyose, date polysaccharide or its combination；The flavones is selected from epimedium flavone, kumquat flavones, oldenlandia diffusa flavones, daizeol, Hippophate flavone or its combination.9. the injection as any one of claim 1-8, the injection is prepared via a method which：By particle diameter at 20-200 microns in 0-4 °C of environment, it is preferred that in 50-70 micrometer ranges, the inorganic salt powder of the de- crystallization water of most preferably 50 microns is added in the aqueous solution of the mixture of the aqueous solution of the biological products or the biological products and the tackifier and/or the adjuvant to saturation；Continue the addition de- inorganic salt powder of the crystallization water and make it that the mass ratio of the biological products and total de- crystallization water inorganic salts is 1:20-1 :80, preferably 1:20-1 :60, most preferably 1:20-1 :40;Freeze-drying, collection cut size is at 20-200 microns, the powder preferably in 50-70 micrometer ranges.10. a kind of method of the Needleless injection injection prepared any one of claim 1-9, comprises the following steps：By particle diameter at 20-200 microns in 0-4 °C of environment, it is preferred that in 50-70 micrometer ranges, the inorganic salt powder of the de- crystallization water of most preferably 50 microns be added in the aqueous solution of the biological products or the biological products with the aqueous solution of the tackifier and/or the mixture of the adjuvant to saturation；Continue the addition de- inorganic salt powder of the crystallization water and make it that the mass ratio of the biological products and total de- crystallization water inorganic salts is 1:20-1 :80, preferably 1:20-1 :60, most preferably 1:20-1 :40, obtain mixed crystallization solution；By mixed crystallization solution freeze-drying, collection cut size is at 20-200 microns, the powder preferably in 50-70 micrometer ranges.11. the Needleless injection any one of claim 1-9 is used for the purposes for the medicine for preparing prevention or treatment disease with injection. 12nd, purposes as claimed in claim 11, wherein the disease includes diabetes, virus hepatitis, tumour, blood disease, Dermatology, viral keratitis, chronic cervicitis, lockjaw, mumps, diphtheria, measles, typhoid fever or influenza.13. the method for Needleless injection is carried out using injection as claimed in any one of claims 1-9 wherein, including：The injection is fitted into the medicine casket of needleless injector, and applied by the needleless injector.
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| PCT/CN2011/081064 WO2013056453A1 (en) | 2011-10-20 | 2011-10-20 | Preparation method and application of injection for needleless injection |
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|---|---|---|---|---|
| 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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| 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 |
Non-Patent Citations (2)
| Title |
|---|
| MSSYNH-FUN 等: "Optimization of an ablum-adsorbed baccine powder formulation for epidermal powder innmunization", 《PHARMACEUTICAL RESEARCH》, vol. 20, no. 7, 31 July 2003 (2003-07-31), pages 969 - 977 * |
| 周旭: "无针粉末注射给药***的研制与应用", 《中国博士学位论文全文数据库》, no. 11, 30 November 2008 (2008-11-30), pages 079 - 28 * |
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