CN101785856A - Stably isoosmotic desmoteplase alpha1 or mutant preparation thereof - Google Patents
Stably isoosmotic desmoteplase alpha1 or mutant preparation thereof Download PDFInfo
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- CN101785856A CN101785856A CN200910013968A CN200910013968A CN101785856A CN 101785856 A CN101785856 A CN 101785856A CN 200910013968 A CN200910013968 A CN 200910013968A CN 200910013968 A CN200910013968 A CN 200910013968A CN 101785856 A CN101785856 A CN 101785856A
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Abstract
The invention discloses a stably isoosmotic freeze-drying preparation, which takes a recombinant desmoteplase alpha1vampire bat plasminogen activator or mutant thereof as an active ingredient. The stably isoosmotic freeze-drying preparation comprises the desmoteplase alpha1 or the mutant thereof and a freeze-drying protective agent. The freeze-drying preparation of the invention can be re-prepared into a solution preparation by using a proper diluent so as to be used in clinic.
Description
Technical field
The present invention relates to a kind of is the lyophilized formulations of active component with reorganization vampire plasminogen activator Desmoteplase alpha 1 or its mutant, belongs to the biological medicine technology field.
Background technology
Desmoteplase (DSPA) is an isolating plasminogen activator in a kind of vampire saliva in South America, mainly comprises four kinds of protein: DSPA α 1, DSPA α 2, DSPA β and DSPA γ.Test finds that wherein Desmoteplase alpha 1 has best biochemistry and pharmacological property, so further studied.Studies show that: under fibrin stimulated, Desmoteplase alpha 1 is active to increase by 10500 times, and tissue plasminogen activator (tPA) only is 550 times; Under the condition of fibrin and Fibrinogen existence, the active ratio of Desmoteplase alpha 1 is 12900 times, and tPA only is 72 times, and Desmoteplase alpha 1 has higher fibrin selectivity.Pharmaceutical research shows, in the model of pulmonary infarction, compares with tPA, and Desmoteplase alpha 1 has better fibrin clot specificity; In the artificial model of Mus, Desmoteplase alpha 1 also showed than better fibrin specificity of tPA and longer half-life; In the crown thrombotic model of Canis familiaris L. acute myocardial infarction, Desmoteplase alpha 1 has faster perfusion and lower occlusion rate more again; In Mus mesenteric vein model, to compare and tPA, Desmoteplase alpha 1 shows lower hemorrhage rate; In Mus and macaque pharmacological experiment, Desmoteplase alpha 1 also shows the clearance rate lower than tPA in addition.In experimentation, do not find the direct toxic action of Desmoteplase alpha 1, only when heavy dose, show side effect.
DSPA α 1 has finished II phase clinical experiment: DIAS test and DEDAS test at present, wherein the DIAS result of the test shows: two groups of blood flows of placebo and administration filling rate again reach 46.7% and 71.4% respectively, patient's brain thromboembolism blood flow obtains remarkable improvement, has effectively stoped brain injury.In the time of 90 days, two groups have 46.7% and 60% patient to reach main clinical endpoint respectively, and the intracranial hemorrhage incidence rate is 3.3% (tPA is in large-scale experiment, and hemorrhage incidence rate is about 6%) for two groups; The DEDAS test is a multicenter, the II clinical trial phase research of dosage escalation, purpose is in the evaluation acute cerebral ischemia paresthesia epilepsy 3～9 hours, DSPA α 1 is with the curative effect and the safety of dosage escalation (concrete test dose does not appear in the newspapers), the result shows: have 38 routine patients and accepted placebo treatment at the apoplexy paresthesia epilepsy in 3～9 hours, DSPA α 1 treatment of the Desmoteplase alpha 1 treatment of 90mcg/kg or 125mcg/kg, experimenter's inclusion criteria is that MRI confirms that disperse perfusion disappearance area reaches more than 20% and cortical tissue low perfusion zone surpasses 2cm, in the time of the 90th day, placebo group has 25% patients clinical result to make moderate progress, 90mcg/kg group has 28.6% patient outcomes to make moderate progress, and the ratio of 125mcg/kg group is 60%.Importantly, in the patient who receives treatment, nobody cerebral hemorrhage occurs.
For the wild type Desmoteplase alpha 1, the Desmoteplase alpha 1 mutant specific activity improves, expression improves, the half-life prolongs, thrombolysis activity improves, therefore, the Desmoteplase alpha 1 mutant (number of patent application: CN200810237709.8) have more the potential using value that is developed to the novel and effective thrombolytic drug that relates to of applicant's patent of applying for before this.
Along with development of biology, polypeptide as medicine application clinically more and more widely, corresponding preparation research also comes into one's own day by day.Yet, to compare with traditional micromolecule organic drug, there is the problem of poor stability in polypeptide.Causing that the unsettled reason of polypeptide is discovered comprises the following aspects:
(1) deacylated tRNA amine is reflected in the de-acyl reaction, and agedoite/glutamine residue hydrolysis forms aspartic acid/glutamic acid.The carrying out of the deacylated tRNA amine reaction of non-enzymatic catalysis, the amide group in agedoite-glycine-structure is facile hydrolysis more, and the amide group that is positioned at molecular surface is also than intramolecular amide group facile hydrolysis.
(2) main cause of the easy oxidation of oxidation polypeptide solution has two kinds, and the one, the pollution of peroxide is arranged in the solution, the 2nd, the spontaneous oxidation of polypeptide.In all amino acid residues, the easiest oxidations such as methionine, cysteine and histidine, tryptophan, tyrosine.Partial pressure of oxygen, temperature and buffering solution are also all influential to oxidation.
(3) fracture of the peptide bond facile hydrolysis in the hydrolyzed peptide.Participate in the peptide bond form by aspartic acid than other peptide bond more easy fracture, especially aspartic acid-proline and aspartic acid-glycine peptide bond.
Between the disulfide bond disulfide bond of (4) formation mistake or between disulfide bond and the sulfydryl exchange taking place and can form wrong disulfide bond, causes tertiary structure change and loss of activity.
(5) racemization is except that glycine, and the alpha-carbon atom of all amino acid residues all is a chirality, easily under base catalysis racemization takes place.The easiest generation racemization of asparagicacid residue wherein.
(6) β-elimination β-elimination is meant the elimination of group on the β carbon atom in the amino acid residue.Residues such as cysteine, serine, threonine, phenylalanine, tyrosine all can pass through β-elimination degraded.β-elimination easily takes place under alkaline pH, and temperature and metal ion are also influential to it.
(7) degeneration, absorption, gathering or precipitation degeneration are general all relevant with the destruction of tertiary structure and secondary structure.At denatured state, the often easier generation chemical reaction of polypeptide, activity is difficult to recover.In the polypeptide degenerative process, at first form intermediate.Usually the dissolubility of intermediate is low, is easy to assemble, and forms aggregation, and then forms macroscopic precipitation.
The approach that improves polypeptide stability comprises the following aspects:
(1) rite-directed mutagenesis is replaced by genetic engineering means and is caused the unsettled residue of polypeptide or introduce the residue that can increase polypeptide stability, can improve the stability of polypeptide.
(2) chemical modification method of chemical modification polypeptide is a lot, and studying maximum is that PEG (Polyethylene Glycol) modifies.PEG is a kind of water-soluble high-molecular compound, and degradable is nontoxic in vivo.PEG with can improve heat stability after polypeptide combines, the degraded of opposing protease reduces antigenicity, the half-life in the extension body.Select suitable method of modifying and control degree of modification can improve the protozoa activity.
(3) additive as saccharide, polyhydric alcohol, gelatin, aminoacid and some salt, can improve the stability of polypeptide by adding additive.Sugar and polyhydric alcohol force more hydrone to be centered around around the protein under low concentration, thereby have improved the stability of polypeptide.In freeze-drying process, above-mentioned substance can also replace water and stablize the native conformation of polypeptide with polypeptide formation hydrogen bond, but also can improve the vitrification point of freeze-dried products.This external surfactants such as SDS (sodium lauryl sulphate), Tween (tween), Pluronic (general stream Buddhist nun gram) can prevent polypeptide surface adsorption, gathering and precipitation.
(4) series of chemical of lyophilizing polypeptide generation such as deacylated tRNA amine, β-elimination, hydrolysis etc. all need water to participate in, and water can also be as the mobile phase of other reactant.In addition, water content reduces the denaturation temperature rising that can make polypeptide.Therefore, lyophilizing can improve the stability of polypeptide.
Summary of the invention
The purpose of this invention is to provide a kind of store and transportation in stable Desmoteplase alpha 1 (DSPA α 1) or the lyophilized formulations of its mutant, and in conjunction with the clinical practice of this product, product after the reconstruction is kept etc. is oozed.
Of the present invention is the stable isotonic lyophilized formulations of active component with reorganization vampire plasminogen activator Desmoteplase alpha 1 or its mutant, comprises Desmoteplase alpha 1 or its mutant and freeze drying protectant; It is characterized in that, described Desmoteplase alpha 1 mutant is meant the peptide chain that 195 phenylalanine in the wild type Desmoteplase alpha 1 peptide chain is replaced to valine, called after DSMa, or continuation changes its aminoacid of 210～213 on the DSMa basis, 210～213 four aminoacid glutamic acid, aspartic acid, arginine, arginine (QNRR) in the described peptide chain replaced to the peptide chain of four alanine (AAAA), called after DSMb; Described freeze drying protectant comprises that aminoacid, sugar/polyhydric alcohol, isoosmotic adjusting agent and pH value are 5.5～7.0 buffer system, wherein aminoacid is glycine, L-arginine or L-histidine, sugar/polyhydric alcohol is sucrose, lactose, glucose, mannitol or sorbitol, isoosmotic adjusting agent is a sodium chloride, and buffer system is phosphate buffer, citrate buffer or acetate buffer; In the described lyophilized formulations, the unit dose scope of Desmoteplase alpha 1 or its mutant is 3～10mg, and the adaptive freeze drying protectant glycine consumption of every milligram of Desmoteplase alpha 1 or its mutant is that 0.01～10mg or the arginic consumption of L-are that the consumption of 0.1～100mg or L-histidine is 0.1～50mg, and the consumption of sucrose is that the consumption of 0.1～100mg or lactose is that the consumption of 0.1～100mg or glucose is that the consumption of 1～200mg or mannitol is that the consumption of 1～200mg or sorbitol is 1～200mg; Buffer system is phosphate buffer or 0.05M～0.5M citrate buffer or the 0.01M～0.2M acetate buffer of 0.01M～0.2M.
Also can add surfactant polysorbas20 or Tween 80 in the above-mentioned freeze drying protectant, wherein the consumption of every milligram of Desmoteplase alpha 1 or the adaptive polysorbas20 of its mutant is that the consumption of 0.001～1mg or adaptive Tween 80 is 0.01～5mg.Preferred mode is: the consumption of described every milligram of Desmoteplase alpha 1 or the adaptive polysorbas20 of its mutant is that the consumption of 0.01～0.5mg or adaptive Tween 80 is 0.01～1mg.Preferred mode is: the consumption of described every milligram of Desmoteplase alpha 1 or the adaptive polysorbas20 of its mutant is that the consumption of 0.05～0.3mg or adaptive Tween 80 is 0.05～0.5mg.
Preferred 1～the 20mg of consumption of the preferred 0.05～5mg of consumption of every milligram of Desmoteplase alpha 1 or the adaptive glycine of its mutant or preferred 1～50mg of the arginic consumption of adaptive L-or adaptive L-histidine in the above-mentioned lyophilized formulations, the preferred 5～100mg of consumption of the preferred 1～50mg of consumption of preferred 1～50mg of the consumption of sucrose or lactose or the preferred 5～100mg of consumption of glucose or mannitol or the preferred 5～100mg of consumption of sorbitol.Further preferred mode is: the consumption of every milligram of Desmoteplase alpha 1 or the adaptive glycine of its mutant is that 0.1～1mg or the arginic consumption of L-are that the consumption of 5～30mg or L-histidine is 2～10mg, and the consumption of sucrose is that the consumption of 5～30mg or lactose is that the consumption of 5～30mg or glucose is that the consumption of 10～50mg or mannitol is that the consumption of 10～50mg or sorbitol is 10～50mg.
Above-mentioned lyophilized formulations is the preparation of stable isotonic.
In the above-mentioned Desmoteplase alpha 1 or the lyophilized formulations of its mutant, freeze drying protectant is that aminoacid, sugar/polyhydric alcohol, isoosmotic adjusting agent and pH value are the preferred following several modes of assembled scheme of 5.5～7.0 buffer system:
Scheme 1: aminoacid (glycine or L-arginine or L-histidine)+sugar (sucrose or lactose or glucose)+isoosmotic adjusting agent+buffer system (phosphate buffer or citrate buffer or acetate buffer).
Scheme 2: aminoacid (glycine or L-arginine or L-histidine)+sugar (sucrose or lactose or glucose)+isoosmotic adjusting agent+buffer system (phosphate buffer or citrate buffer or acetate buffer)+surfactant (polysorbas20 or Tween 80).
Scheme 3: aminoacid (glycine or L-arginine or L-histidine)+polyhydric alcohol (mannitol or sorbitol)+isoosmotic adjusting agent+buffer system (phosphate buffer or citrate buffer or acetate buffer).
Scheme 4: aminoacid (glycine or L-arginine or L-histidine)+polyhydric alcohol (mannitol or sorbitol)+isoosmotic adjusting agent+buffer system (phosphate buffer or citrate buffer or acetate buffer)+surfactant (polysorbas20 or Tween 80).
The preparation method of lyophilized formulations of the present invention is:
(1) prepares needed buffer system by the testing program of setting with recipe quantity,, obtain to be suitable for Desmoteplase alpha 1 or its mutant stock solution of formulation preparation with this buffer system displacement Desmoteplase alpha 1 or its mutant stock solution buffer;
(2) accurately take by weighing each adjuvant (freeze drying protectant) of recipe quantity, with the buffer dissolving of described buffer system, and to regulate pH value be 5.5～7.0, must contain the buffer solution of freeze drying protectant;
(3) Desmoteplase alpha 1 or the adding of its mutant stock solution are contained in the buffer solution of freeze drying protectant standardize solution; Aseptic filtration, packing, lyophilizing; Get the lyophilized formulations of Desmoteplase alpha 1 (DSPA α 1) or its mutant.
(4) will divide that packaging container is jumped a queue, gland, get product.
Adding an amount of water for injection during lyophilized formulations clinical practice of the present invention rebuilds and can use.
The present invention has following remarkable advantage: (1) has significantly improved the stability of product by the choose reasonable and the use of freeze drying protectant, is convenient to store, transports and uses; (2) used adjuvant was easy to get during prescription was formed, and price is suitable, can obviously not increase product cost, was easy to accept; (3) preparation technology is simple, and is workable, is suitable for suitability for industrialized production.
The specific embodiment
Following examples will further specify the present invention, but not limit the present invention.
Embodiment 1: the 10mM phosphate buffer with pH5.8 is DSPA α 1 lyophilized formulations that buffer system prepares stable isotonic
Prescription is fine into
Preparation method:
The 10mM phosphate buffer of pH5.8 of preparation recipe quantity accurately takes by weighing each adjuvant of recipe quantity, adds an amount of phosphate buffer dissolving, and the adjusting pH value is 5.5～6.5, and being settled to volume is the difference of dosing cumulative volume and DSPA α 1 stock solution.DSPA α 1 stock solution of recipe quantity is added wherein, and the jog mixing is the microporous filter membrane aseptic filtration of 0.22 μ m with the aperture, packing, lyophilizing, jump a queue, gland, promptly.
Embodiment 2: the 20mM phosphate buffer with pH6.0 is the DSPA alpha 1 mutant DSMa lyophilized formulations that buffer system prepares stable isotonic
Prescription is formed
Preparation method:
The 20mM phosphate buffer of pH6.0 of preparation recipe quantity accurately takes by weighing each adjuvant of recipe quantity, adds an amount of phosphate buffer dissolving, and the adjusting pH value is 5.5～6.5, is settled to the difference that volume is dosing cumulative volume and DSMa stock solution.The DSMa stock solution of recipe quantity is added wherein, and the jog mixing is the microporous filter membrane aseptic filtration of 0.22 μ m with the aperture, packing, lyophilizing, jump a queue, gland, promptly.
Embodiment 3: the 0.1M citrate buffer with pH6.2 is the DSPA alpha 1 mutant DSMb lyophilized formulations that buffer system prepares stable isotonic
Prescription is formed
Preparation method:
The 0.1M citrate buffer of pH6.2 of preparation recipe quantity accurately takes by weighing each adjuvant of recipe quantity, adds an amount of phosphate buffer dissolving, and the adjusting pH value is 5.5～6.5, is settled to the difference that volume is dosing cumulative volume and DSMb stock solution.The DSMb stock solution of recipe quantity is added wherein, and the jog mixing is the microporous filter membrane aseptic filtration of 0.22 μ m with the aperture, packing, lyophilizing, jump a queue, gland, promptly.
Embodiment 4: the 0.2M acetate buffer with pH6.0 is DSPA α 1 lyophilized formulations that buffer system prepares stable isotonic
Prescription is formed
Preparation method:
The 0.2M acetate buffer of pH6.0 of preparation recipe quantity accurately takes by weighing each adjuvant of recipe quantity, adds an amount of citrate buffer dissolving, and the adjusting pH value is 5.5～6.5, and being settled to volume is the difference of dosing cumulative volume and DSPA α 1 stock solution.DSPA α 1 stock solution of recipe quantity is added wherein, and the jog mixing is the microporous filter membrane aseptic filtration of 0.22 μ m with the aperture, packing, lyophilizing, jump a queue, gland, promptly.
Embodiment 5: the 50mM phosphate buffer with pH6.5 is the DSPA alpha 1 mutant DSMa lyophilized formulations that buffer system prepares stable isotonic
Prescription is formed
Preparation method:
The 50mM phosphate buffer of pH6.5 of preparation recipe quantity accurately takes by weighing each adjuvant of recipe quantity, adds an amount of phosphate buffer dissolving, and the adjusting pH value is 6.0～7.0, is settled to the difference that volume is dosing cumulative volume and DSMa stock solution.The DSMa stock solution of recipe quantity is added wherein, and the jog mixing is the microporous filter membrane aseptic filtration of 0.22 μ m with the aperture, packing, lyophilizing, jump a queue, gland, promptly.
Embodiment 6: the 50mM acetate buffer with pH6.0 is the DSPA alpha 1 mutant DSMb lyophilized formulations that buffer system prepares stable isotonic
Prescription is formed
Preparation method:
The 50mM acetate buffer of pH6.0 of preparation recipe quantity accurately takes by weighing each adjuvant of recipe quantity, adds an amount of phosphate buffer dissolving, and the adjusting pH value is 5.5～6.5, is settled to the difference that volume is dosing cumulative volume and DSMb stock solution.The DSMb stock solution of recipe quantity is added wherein, and the jog mixing is the microporous filter membrane aseptic filtration of 0.22 μ m with the aperture, packing, lyophilizing, jump a queue, gland, promptly.
Embodiment 7: the 10mM phosphate buffer with pH6.0 is DSPA α 1 lyophilized formulations that buffer system prepares stable isotonic
Prescription is formed
Preparation method:
The 10mM phosphate buffer of pH6.0 of preparation recipe quantity accurately takes by weighing each adjuvant of recipe quantity, adds an amount of acetate buffer dissolving, and the adjusting pH value is 5.5～6.5, and being settled to volume is the difference of dosing cumulative volume and DSPA α 1 stock solution.DSPA α 1 stock solution of recipe quantity is added wherein, and the jog mixing is the microporous filter membrane aseptic filtration of 0.22 μ m with the aperture, packing, lyophilizing, jump a queue, gland, promptly.
Embodiment 8: the 0.1M acetate buffer with pH6.2 is the DSPA alpha 1 mutant DSMa lyophilized formulations that buffer system prepares stable isotonic
Prescription is formed
Preparation method:
The 0.1M acetate buffer of pH6.2 of preparation recipe quantity accurately takes by weighing each adjuvant of recipe quantity, adds an amount of citrate buffer dissolving, and the adjusting pH value is 5.5～6.5, is settled to the difference that volume is dosing cumulative volume and DSMa stock solution.The DSMa stock solution of recipe quantity is added wherein, and the jog mixing is the microporous filter membrane aseptic filtration of 0.22 μ m with the aperture, packing, lyophilizing, jump a queue, gland, promptly.
Embodiment 9: the 0.1M citrate buffer with pH6.2 is the DSPA alpha 1 mutant DSMb lyophilized formulations that buffer system prepares stable isotonic
Prescription is formed
Preparation method:
The 0.1M citrate buffer of pH6.2 of preparation recipe quantity accurately takes by weighing each adjuvant of recipe quantity, adds an amount of acetate buffer dissolving, and the adjusting pH value is 5.5～6.5, is settled to the difference that volume is dosing cumulative volume and DSMb stock solution.The DSMb stock solution of recipe quantity is added wherein, and the jog mixing is the microporous filter membrane aseptic filtration of 0.22 μ m with the aperture, packing, lyophilizing, jump a queue, gland, promptly.
Claims (6)
1. one kind is the stable isotonic lyophilized formulations of active component with reorganization vampire plasminogen activator Desmoteplase alpha 1 or its mutant, comprises Desmoteplase alpha 1 or its mutant and freeze drying protectant; It is characterized in that, described Desmoteplase alpha 1 mutant is meant the peptide chain that 195 phenylalanine in the wild type Desmoteplase alpha 1 peptide chain is replaced to valine, called after DSMa, or continuation changes its aminoacid of 210～213 on the DSMa basis, 210～213 four aminoacid glutamic acid, aspartic acid, arginine, arginine in the described peptide chain are replaced to the peptide chain of four alanine, called after DSMb; Described freeze drying protectant comprises that aminoacid, sugar/polyhydric alcohol, isoosmotic adjusting agent and pH value are 5.5～7.0 buffer system, wherein aminoacid is glycine, L-arginine or L-histidine, sugar/polyhydric alcohol is sucrose, lactose, glucose, mannitol or sorbitol, isoosmotic adjusting agent is a sodium chloride, and buffer system is phosphate buffer, citrate buffer or acetate buffer; In the described lyophilized formulations, the unit dose scope of Desmoteplase alpha 1 or its mutant is 3～10mg, and the adaptive freeze drying protectant glycine consumption of every milligram of Desmoteplase alpha 1 or its mutant is that 0.01～10mg or the arginic consumption of L-are that the consumption of 0.1～100mg or L-histidine is 0.1～50mg, and the consumption of sucrose is that the consumption of 0.1～100mg or lactose is that the consumption of 0.1～100mg or glucose is that the consumption of 1～200mg or mannitol is that the consumption of 1～200mg or sorbitol is 1～200mg; Buffer system is phosphate buffer or 0.05M～0.5M citrate buffer or the 0.01M～0.2M acetate buffer of 0.01M～0.2M.
2. lyophilized formulations according to claim 1; it is characterized in that; also add surfactant polysorbas20 or Tween 80 in the described freeze drying protectant, wherein the consumption of every milligram of Desmoteplase alpha 1 or the adaptive polysorbas20 of its mutant is that the consumption of 0.001～1mg or adaptive Tween 80 is 0.01～5mg.
3. lyophilized formulations according to claim 2 is characterized in that, the consumption of described every milligram of Desmoteplase alpha 1 or the adaptive polysorbas20 of its mutant is that the consumption of 0.01～0.5mg or adaptive Tween 80 is 0.01～1mg.
4. lyophilized formulations according to claim 3 is characterized in that, the consumption of described every milligram of Desmoteplase alpha 1 or the adaptive polysorbas20 of its mutant is that the consumption of 0.05～0.3mg or adaptive Tween 80 is 0.05～0.5mg.
5. lyophilized formulations according to claim 1, it is characterized in that, the consumption of described every milligram of Desmoteplase alpha 1 or the adaptive glycine of its mutant is that 0.05～5mg or the arginic consumption of adaptive L-are that the consumption of 1～50mg or adaptive L-histidine is 1～20mg, and the consumption of sucrose is that the consumption of 1～50mg or lactose is that the consumption of 1～50mg or glucose is that the consumption of 5～100mg or mannitol is that the consumption of 5～100mg or sorbitol is 5～100mg.
6. lyophilized formulations according to claim 5, it is characterized in that, the consumption of described every milligram of Desmoteplase alpha 1 or the adaptive glycine of its mutant is that 0.1～1mg or the arginic consumption of L-are that the consumption of 5～30mg or L-histidine is 2～10mg, and the consumption of sucrose is that the consumption of 5～30mg or lactose is that the consumption of 5～30mg or glucose is that the consumption of 10～50mg or mannitol is that the consumption of 10～50mg or sorbitol is 10～50mg.
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| CN106714823A (en) * | 2014-09-10 | 2017-05-24 | 克霖固鲁制药股份有限公司 | Hgf preparation suitable for treatment of nervous diseases |
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| CN1267152C (en) * | 2003-06-02 | 2006-08-02 | 长春生物制品研究所 | Polythylene glycol-interferon alpha foreeze dried preparation |
| US20060286171A1 (en) * | 2005-06-17 | 2006-12-21 | Tianhong Zhou | Bone morphogenetic protein formulations |
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| Publication number | Priority date | Publication date | Assignee | Title |
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| CN106714823A (en) * | 2014-09-10 | 2017-05-24 | 克霖固鲁制药股份有限公司 | Hgf preparation suitable for treatment of nervous diseases |
| US10213485B2 (en) | 2014-09-10 | 2019-02-26 | Kringle Pharma Inc. | HGF preparation suitable for treatment of neurological disorders |
| US10702582B2 (en) | 2014-09-10 | 2020-07-07 | Kringle Pharma Inc. | HGF preparation suitable for treatment of neurological disorders |
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