CN105749290A - Protein medicinal preparation containing beta-glucan as auxiliary material - Google Patents
Protein medicinal preparation containing beta-glucan as auxiliary material Download PDFInfo
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- CN105749290A CN105749290A CN201610219609.7A CN201610219609A CN105749290A CN 105749290 A CN105749290 A CN 105749290A CN 201610219609 A CN201610219609 A CN 201610219609A CN 105749290 A CN105749290 A CN 105749290A
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- protein
- beta glucan
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- drug formulation
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
- A61K47/36—Polysaccharides; Derivatives thereof, e.g. gums, starch, alginate, dextrin, hyaluronic acid, chitosan, inulin, agar or pectin
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K38/00—Medicinal preparations containing peptides
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K38/00—Medicinal preparations containing peptides
- A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
- A61K38/43—Enzymes; Proenzymes; Derivatives thereof
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K38/00—Medicinal preparations containing peptides
- A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
- A61K38/43—Enzymes; Proenzymes; Derivatives thereof
- A61K38/46—Hydrolases (3)
- A61K38/47—Hydrolases (3) acting on glycosyl compounds (3.2), e.g. cellulases, lactases
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K39/00—Medicinal preparations containing antigens or antibodies
- A61K39/395—Antibodies; Immunoglobulins; Immune serum, e.g. antilymphocytic serum
-
- 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
- A61K9/08—Solutions
-
- 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
- A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
- A61K9/19—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles lyophilised, i.e. freeze-dried, solutions or dispersions
Abstract
The invention discloses a protein medicinal preparation containing beta-glucan as an auxiliary material. The preparation is prepared from at least one protein medicinal material having a concentration of 10-300mg/ml, a buffer agent having a salt concentration of 1-120mM and pH value of 6.5+/-1.5, a stabilizing agent which is beta-glucan and has a concentration of 0.1-10 percent, and a nonionic surfactant having a concentration of 0.01-0.1 percent. The beta-glucan is a high-molecular polymer formed by connecting monomer beta-D-glucopyranose through beta-(1-3) and beta-(1-6). Soluble beta-glucan has a water-absorbing swelling capability, has an excellent water binding capacity in water, can form a high-viscosity solution after being dissolved in water, can be used for effectively preventing protein aggregation and enhancing the protein stability, and can be used as a protecting agent of protein medicines.
Description
Technical field
The invention belongs to biological technical field, be specifically related to one and can stablize egg in various liquid or lyophilized formulations
White matter medicine, the invention still further relates to include the beta glucan as stabilizer and the most at least containing a kind of pharmaceutical grade protein, its
Its buffer agent, the preparaton of surfactant.
Background technology
Along with the development of modern biotechnology, increasing protein is applied to medicine, including polypeptide, enzyme
Class, monoclonal antibody etc..But compared with traditional organic or inorganic molecule, protein molecule is the most more complicated.Some albumen
Matter, if polypeptide is in addition to having three dimensional structure, the most multiple functional groups.Therefore the preparaton of this type of pharmaceutical grade protein is proposed
Higher requirement, preparaton at least must can keep the integrity that protein core aminoacid sequence conformation is overall, and can protect
The functional group protecting protein is not degraded；And this degraded may be caused by chemically or physically unstability.Chemical instability
Typically come from the processes such as hydrolysis, oxidation, raceme, deacylated tRNA amine or disulfide exchange, relate to being become by key-like or cutting repairing
Adorn protein thus produce the process of new chemical entities.Physical instability comes from into degeneration, assembles, adsorbs or precipitation waited
Journey, thus causes the change of protein higher structure.Thereby it is ensured that the chemistry of this type of reactive compound and physical stability are to closing
Important.
Beta glucan is glucose polymer, and it derives from multiple-microorganism and plant origin, including antibacterial, yeast, sea
Algae, mushroom, Herba bromi japonici and Fructus Hordei Vulgaris etc..Structurally, yeast beta-dextran is made up of glucose monomer, and structure is by β-(1,3)-connection
Main chain backbone, the branch of same β-(1,3)-connection is become to be connected by β-(1,6) glycosidic bond with main chain backbone.Solubility β-Portugal gathers
Sugar is complicated because of its purifying process, due to dissolubility and impurity content reason, limits its applied research.
United States Patent (USP) US2015125451 discloses one " COMPOSITIONS AND METHODS FOR BETA-
GLUCAN IMMUNOTHERAPY ", wherein point out yeast beta-dextran medicinal characteristic applied research in terms of immunization therapy.
Chinese patent application 201410503958.2 discloses the one " medicine of the high enrichment comprising anti-CD 20 antibodies
Preparaton ", which disclosing conventional stabilizer is saccharide, the most such as α, α-trehalose dihydrate compound or sucrose；Or with
Methionine is as stabilizer.
The protective effect of saccharide chemical constitution with itself has substantial connection.They are generally of the hydroxyl of more than 5,
Hydrogen bond can be formed to replace water, it is ensured that the stability of protein with protein；They easy bound water molecules in the solution, send out
Raw hydration, decreases the content of free water and adds the viscosity of solution, thus slowing down the growth course of nucleus, making formation
Ice crystal relatively fine, with reach protection purpose.
The aldehyde radical of restitutive protection's sugar can react with the primary amino radical generation non-enzymatic brown of protein, thus affects protein
Function.The reproducibility of sugar is the most weak, the strongest to the bin stability of lyophilizing biomolecule.Machine about sugar biological protective action
Reason, still in research and inquiring into, but its mechanism has two kinds of hypothesis: " water replacement hypothesis " and " glassy state hypothesis ".
One common feature of sucrose, trehalose and beta glucan has substantial amounts of free hydroxyl exactly, and is all non-
Reproducibility, they all can show " water replacement hypothesis ".
But sucrose is at high temperature hardly formed glassy state, does not has protective effect.Trehalose has higher vitrification point,
Relatively it is easily formed glassy state, protein molecule is supported and wraps up, being allowed to the most variable.
Summary of the invention
The defect existed in view of above-mentioned prior art, the purpose of the present invention is to propose to a kind of containing with beta glucan as adjuvant
Protein drug formulation, beta glucan is as the stabilizer of pharmaceutical preparation, at the liquid preparation of various pharmaceutical grade proteins or freeze
The activity of stable protein in dry preparation.
The purpose of the present invention, will be achieved by the following technical programs:
A kind of containing the protein drug formulation with beta glucan as adjuvant, comprise: 1-120mM buffer agent, its pH is 6.5 ±
1.5；The stabilizer of 0.1% ~ 10%；0.01 ~ 0.1% nonionic surfactant；Described stabilizer is beta glucan.
Preferably, described buffer agent is histidine buffer, citrate buffer agent, acetate buffer, succinate
Buffer agent or disodium hydrogen phosphate buffer agent, concentration is 1 ~ 50mM.
Preferably, described beta glucan is soluble ss-glucans.
Preferably, described soluble ss-glucans derives from microorganism and plant.
Preferably, described soluble ss-glucans derives from saccharomyces cerevisiae (Saccharomyces cerevisiae).By
Protecting in preparation as stabilizer for pharmaceutical protein in beta glucan, the production of beta glucan uses fermentable to be prepared into
Arriving, saccharomyces cerevisiae (Saccharomyces cerevisiae) uses the international public GRAS certification microorganism known, safety non-toxic, nothing
Anaphylaxis；
Preferably, described soluble ss-glucans comprise β (1,6)-[poly-(1,3)-D-glucopyranosyl]-poly-β (1,3)-
D-Glucopyranose..
Preferably, described soluble ss-glucans molecular weight is 20kDa to 360kDa.The present invention use technological means by β-
Glucosan is hydrolyzed into the beta glucan of different molecular weight, so that its space being more easy to enter protein molecule, finally at albumen
Matter intramolecule and outside all form glassy state so that it is protection and stabilizing effect to protein are greatly improved.
Preferably, described nonionic surfactant is Polysorbate.
Preferably, described nonionic surfactant is that polysorbate 20, polyoxyethylene sorbitan monoleate or polyethylene-polypropylene are total to
Polymers, the mass concentration of described surfactant is 0.02% ~ 0.1%.
Preferably, described pharmaceutical grade protein form includes but not limited to liquid form, lyophilized form.
Described lyophilizing comprises the following steps:
Freezing described medicine under (a)-40 DEG C or lower temperature；
B () described pharmaceutical grade protein is cooled to 5 DEG C in advance；
C the temperature of described pharmaceutical grade protein is reduced to-40 DEG C or lower by ()；
D () is dried described pharmaceutical grade protein at-20 DEG C under decompression in the first drying steps；
E () is dried described pharmaceutical grade protein at 25 DEG C under decompression in the second drying steps.
Described pharmaceutical grade protein route of administration form includes but not limited to subcutaneous injection, intravenous injection.
The principle of the present invention is: protein (such as antibody or enzyme) is active biomacromolecule, prepares at preparation
During, as during pre-cooling, primary drying, redrying and storage, the protein in medicine all there may be certain journey
The degeneration of degree.
During chilled storage, due to the interaction of ice crystal Yu the hydrate water of protein, make ice crystal close to protein
Hydration layer, form grid system, the hydrone of hydration layer moves to the direction of ice crystal, produces de-hydration phenomena, makes protein
Hydration structure destroyed, thus make the higher structure of protein change, the physiological function of protein is affected.
It is because it has higher vitrification point that beta glucan has protective effect, can be at the protein molecular such as enzyme or antibody
Around form glassy state, thus protective enzyme molecule is from the damage caused by high temperature.In general, beta glucan and protein are equal
For macromole, beta glucan molecule is not easily accessed in the space of protein molecule, and dried beta glucan only divides at protein
Son around forms the protection shell of glassy state.The protein molecule being in shell can make the change of the space structure of certain limit
Change, cause part to inactivate.And at high temperature, immixture increases between beta glucan and protein molecule, part β-Portugal is had to gather
Glycan molecule is internally formed glassy state at protein molecule, thus more effectively limit protein matter spatial configuration of molecules changes.
The present invention highlights effect: owing to the composition monomer of beta glucan (β-Glucan) is β-D-Glucopyranose., logical
Cross β-(1-3) and β-(1-6) glycosidic bond to couple together, form a kind of high molecular polymer.Solvable beta glucan has water suction
Swelling Capacity, has good retentiveness in water, can form full-bodied solution, and can effectively prevent albumen after being dissolved in water
Assemble, strengthen the stability of protein, for the protective agent of pharmaceutical grade protein.
Hereinafter the most in conjunction with the embodiments, the detailed description of the invention of the present invention is described in further detail, so that the technology of the present invention
Scheme is more readily understood, grasps.
Detailed description of the invention
The present invention relates to a kind of can be used in various liquid preparation and lyophilized formulations can the stabilizer of stable protein, use
In polypeptide, antibody, the protection in production process of the protein active ingredients such as enzyme；And the non-active ingredient nontoxic to experimenter
Protection, include but not limited to stabilizer, buffer agent and surfactant.
By further illustrating the technological means and effect, being preferable to carry out below in conjunction with the present invention that the present invention taked
Example further illustrates technical scheme, but the present invention is not limited in scope of embodiments.
Unreceipted concrete technology or condition person in embodiment, according to the technology described by the document in this area or condition,
Or carry out according to product description.Agents useful for same or instrument unreceipted production firm person, be and can be purchased by regular channel
The conventional products obtained.
Embodiment 1: the preparation of soluble ss-glucans
Use saccharomyces cerevisiae (Saccharomyces cerevisiae, ATCC 7752) fermentation culture, it is thus achieved that yeast thalline.
Specifically, saccharomyces cerevisiae is used progressively to expand the fermenting and producing of 1000L scale to through shake-flask culture.Yeast is at carbon
Source, nitrogen source, vitamin, inorganic salt and trace element grow, it is possible to add defoamer and control foam, such as defoamer
Antifoam204。
Combine, with deep ventilation, the training method production that feed supplement stream adds, select carbon source glucose or glycerol as the restricted end
Thing controls stream and adds.During producing fermentation, timing sampling, to measure optical density OD of fermentation liquid600nm, work as OD600nmReach stable
After value or certain value, terminate fermenting and producing.After culture propagation is cultivated, use filter press or continuous flow centrifuge to separate and obtain
Yeast thalline.Can use any of chemistry, enzyme or mechanical means, or their any combination, division or Breaking Yeast are thin
Born of the same parents.
Alkali clears up process: use 0.05M-6.5M NaOH aqueous slkali.The surfactant being suitable for includes, such as Triton
X-100, sodium lauryl sulfate (SDS), polysorbas20 etc..Yeast thalline can be extracted one or many.Extract generally between about
Carry out at a temperature of 60 DEG C-about 100 DEG C.According to temperature, agents useful for same and concentration thereof, the persistent period every time extracted is between about 30
Minute between-about 3 hours.
Acid treatment: centrifugal collect insoluble matter, by regulation pH between about between 5 and 9, and between about 70 DEG C-100 DEG C
At a temperature of, make material mixing about 30 minutes-about 12 hours in about 0.05M-about 1.0M acetic acid, it is achieved one or more acid carry
Take.Wash insoluble material, at room temperature, make material mixing in pure water a minimum of about 20 minutes.It is washed twice with water, centrifugal
Collect purified beta glucan product.
High pressure-temperature processes: make the pressure in container maintain about to 0.05 ~ 0.25Mpa, heating suspension to about 110 ~ 135 DEG C
3.5-6.0 hour.
Chromatography purification processes: use chromatography to be further purified.Hydrophobic interaction chromatography (HIC) or gel permeation chromatography
(GPC), collect eluent by stream part, analyze the various combinations from each sample flowing part, to determine the group with best distribution
Close.The mean molecule quantity of soluble ss-glucans is between about 20kDa-about 360kDa.
Embodiment 2: as follows according to the present invention is used for liquid and the freeze-dried drug product formulation of parenteral administration；
1, the preparation of liquid adjustments
By ultrafiltration/diafiltration method by Herceptin (Trastuzumab) solution exchange to corresponding Formulation Buffer (as
20mM L-Histidine, pH6.0 or 20mM L-Histidine, 0.02% w/v polysorbate 20, pH6.0), and it is concentrated into certain
Protein concentration, such as 70mg/ml.Then it is diluted to required protein concentration with corresponding Formulation Buffer.Stabilizer is solvable
Property beta glucan can add with dissolved form, and surfactant can add in the form of a solution.Finally by the toltrazuril of same volume
Monoclonal antibody formulation soln mix homogeneously.
By all preparatons by 0.22 μm Filter Sterile filtration sterilization, and aseptically subpackage to sterile glass
Bottle blend compounds plug and aluminium lid seal, and by these formulation storage in different temperature and different time, take at corresponding time point
Go out to carry out quality analysis.
, the preparation of lyophilized formulations
Above to preparing Herceptin formulation soln as described in liquid preparation, by complete soln by 0.22 μm Filter Sterile
Filter, then press the loading amount aseptically subpackage of 10ml/ bottle to cillin bottle, partly jump a queue, be then transferred to doing of freeze dryer
In dry room.Any freeze drying process as known in the art is included within the scope of the present invention.Such as, first that product is cold from room temperature
But to about 5 DEG C (precooling), then it is cooled to-40 DEG C with the flaggy cooldown rate of about 1 DEG C/min and carries out freezing step, then
It is incubated about 2 hours in-40 DEG C.Negative pressure in the flaggy temperature of about-20 DEG C and about 100 μ bar is implemented first drying steps and is reached
About 48 hours, subsequently, start second drying steps, then in 25 from-25 DEG C to 25 DEG C with the temperature intensification of 0.2 DEG C/min
DEG C holding step with the negative pressure persistently at least 5 hours of about 100 μ bar, concrete steps are as shown in table 1.
Table 1: the preparation freeze-drying process of antibody compositions
.The antibody composition preparation using the freeze-drying process described to be dried has the quick reconfiguration time of about 2 ~ 3 minutes, according to
Karl fischer method (Karl-Fischer method), the residual amount of involved lyophilized cake is about 0.1 ~ 2.0%.
Embodiment 3: Herceptin (Trastuzumab) and handkerchief trastuzumab (Pertuzumab) Antibody Combination liquid system
Agent
Formula: 25mg/ml Herceptin, 25mg/ml handkerchief trastuzumab, 20mM L-Histidine, 2% soluble ss-glucans,
0.02%Tween 20, pH6.5；Concrete steps are as shown in table 2,
Table 2: Herceptin and the stability data of handkerchief trastuzumab Antibody Combination liquid preparation
.Embodiment 4: hyaluronidase lyophilized formulations
Formula: 180IU/ml hyaluronidase, disodium hydrogen phosphate buffer agent (8.5mg/ml sodium chloride, 1.4mg/ml phosphoric acid hydrogen two
Sodium, 0.9mg/ml EDTA, 0.3mg/ml calcium chloride), 5.5% soluble ss-glucans, 0.02%Tween 20, pH7.0；Specifically
Step is as shown in table 3,
Table 3: the stability data of hyaluronidase lyophilized formulations
.Embodiment 5: Cetuximab (Cetuximab) liquid preparation
Formula: 2mg/ml Cetuximab, phosphate buffer (0.41mg/ml sodium dihydrogen phosphate (water), 1.00 mg/ml phosphorus
Acid disodium hydrogen, 8.48mg/ml sodium chloride), 5.0% soluble ss-glucans, 0.01%Tween 80, pH6.4 ~ 7.0；Concrete step
It is rapid as shown in table 4,
Table 4: the stability data of Cetuximab liquid preparation
In the present invention, term " monoclonal antibody " refers to the antibody that the antibody population from substantially homogeneity obtains, i.e. except permissible
The possible variant (this type of variant typically exists with a small amount of) generated during the generation of monoclonal antibody outward, constitutes the anti-of colony
Body is individual identical and/or combines identical epi-position.
" antibody fragment " comprises a part for full length antibody, general including at least its antigen-binding portion thereof or variable region.Anti-
The example of body fragment includes Fab, Fab ', F (ab ') 2 and Fv fragments；Double antibody, single-chain antibody molecules, immunotoxin and from anti-
The multi-specificity antibody that body fragment is formed.
" biologic activity " of monoclonal antibody refers to antibodies bind antigen, and produces and can measure in vitro or in vivo
The ability of the biological answer-reply measured.
Term " pharmaceutical formulation " refers to be in the effective form of the biologic activity so that allowing active component, and without right
In accepting the preparation that the experimenter that preparaton uses has other component of unacceptable toxicity.This type of preparaton is aseptic
's." aseptic " preparaton is microorganism and the spore thereof of aseptic or the most all work.
" stable " preparaton is that all proteins therein is intended storage temperature, such as base after 2-8 DEG C storage
Its physical stability and/or chemical stability and/or the preparaton of biologic activity is retained in basis.Preferably, preparaton is in storage
Its physics and chemical stability, and biologic activity is substantially retained after depositing.
It is available in the art for measuring the various analytical technologies of protein stability, assembles the bodily form including assessment
Become (such as using size exclusion chromatography, by measuring turbidity, and/or carried out by visual inspection)；Use cation exchange layer
Analysis or capillary zone electrophoresis, assessment electric charge is heterogeneous；SDS-PAGE analyzes to compare that reduce and complete antibody；Assessment is anti-
The biologic activity of body or antigen combined function etc..Unstability can involve following any one or more: assembles, deacylated tRNA amine
Change (such as Asn desamidization), oxidation (such as Met oxidation), isomerization (such as Asp isomerization), cut out (clipping)/water
Solution/fragmentation (such as hinge region fragmentation), butanimide formation, azygous cysteine etc..
" buffer " means pharmaceutically acceptable buffer.As used herein, term " provides pH's 6.5 ± 1.5
Buffer agent " refer to be provided the reagent of the solution opposing pH change comprising it by the effect of its acid/base conjugation component.According to the present invention
Suitable pharmaceutically acceptable buffer agent include but not limited to that histidine buffering liquid, citrate buffer, gluconate buffer
Liquid, Succinate Buffer, acetate buffer, glycylglycine and other organic acid buffer liquid and phosphate buffer.
Preferably buffer comprises the mixture of L-Histidine or L-Histidine and hydrochloric acid L-Histidine, and it has isotonic agent and uses ability
Known acid or the potential pH regulator of alkali in territory.Most preferably L-Histidine.
" histidine buffering liquid " is the buffer comprising amino acid histidine.The example of histidine buffering liquid includes hydrochloric acid group
Propylhomoserin, acetic acid histidine, phosphohistidine, sulphuric acid histidine.Find the preferred histidine buffer identified in example herein
Liquid is histidine monohydrochloride.In a preferred embodiment, by with dilution HCI L-Histidine (free alkali, Gu
Body) or made by the amount to limit and ratio solvent L-Histidine and hydrochloric acid L-Histidine (such as with monohydrate form)
Standby histidine monohydrochloride buffer.
The present invention still has numerous embodiments, all employing equivalents or equivalent transformation and all technical sides of being formed
Case, within all falling within protection scope of the present invention.
Claims (9)
1. the protein drug formulation contained with beta glucan as adjuvant, it is characterised in that: described preparation includes following group
Point
A. the preparation of at least one protein component, described protein concentration is 10-300mg/ml；
B. buffer agent, its salinity is 1 ~ 120mM, and its pH is 6.5 ± 1.5；
C. stabilizer, its concentration is 0.1% ~ 10%(W/V%), described stabilizer is beta glucan；
D. nonionic surfactant, its concentration is 0.01 ~ 0.1%(W/V%).
It is the most according to claim 1 a kind of containing the protein drug formulation with beta glucan as adjuvant, it is characterised in that:
Described buffer agent is histidine buffer, citrate buffer agent, acetate buffer, succinate buffers or phosphoric acid hydrogen two
Sodium buffer agent, concentration is 1 ~ 50mM.
It is the most according to claim 1 a kind of containing the protein drug formulation with beta glucan as adjuvant, it is characterised in that:
Described beta glucan is soluble ss-glucans, and described soluble ss-glucans molecular weight is 20kDa to 360kDa.
It is the most according to claim 3 a kind of containing the protein drug formulation with beta glucan as adjuvant, it is characterised in that:
Described soluble ss-glucans derives from microorganism and plant.
It is the most according to claim 3 a kind of containing the protein drug formulation with beta glucan as adjuvant, it is characterised in that:
Described soluble ss-glucans derives from saccharomyces cerevisiae.
It is the most according to claim 3 a kind of containing the protein drug formulation with beta glucan as adjuvant, it is characterised in that:
Described soluble ss-glucans can be or derived from β (1,6)-[poly-(1,3)-D-glucopyranosyl]-poly-β (1,3)-D-
Glucopyranose..
It is the most according to claim 6 a kind of containing the protein drug formulation with beta glucan as adjuvant, it is characterised in that:
Described soluble ss-glucans be with β (1,3) key be connected glucose polymer main chain backbone at least contain three glucoses
At least contain on monomer or the glucose polymer being connected with β (1,3) key and the branched skeleton being connected with main chain by β (1,6) key
There is a glucose monomer.
It is the most according to claim 1 a kind of containing the protein drug formulation with beta glucan as adjuvant, it is characterised in that:
Described nonionic surfactant is polysorbate 20, polyoxyethylene sorbitan monoleate or polyethylene-polypropylene copolymer, lives in described surface
The mass concentration of property agent is 0.02% ~ 0.1%.
It is the most according to claim 1 a kind of containing the protein drug formulation with beta glucan as adjuvant, it is characterised in that:
Described pharmaceutical grade protein form is liquid form or lyophilized form.
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| WO2020200337A1 (en) * | 2019-04-04 | 2020-10-08 | Vysoka Skola Chemicko-Technologicka V Praze | Method of production of a composite of yeast-derived beta glucan particle with incorporated poorly-water-soluble low-molecular-weight compound, pharmaceutical preparation and use thereof |
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