CN115400076B - Recombinant human growth hormone-Fc fusion protein injection formulation - Google Patents
Recombinant human growth hormone-Fc fusion protein injection formulation Download PDFInfo
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- 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
- A61K38/17—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
- A61K38/22—Hormones
- A61K38/27—Growth hormone [GH] (Somatotropin)
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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
- A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
- A61K47/16—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing nitrogen, e.g. nitro-, nitroso-, azo-compounds, nitriles, cyanates
- A61K47/18—Amines; Amides; Ureas; Quaternary ammonium compounds; Amino acids; Oligopeptides having up to five amino acids
- A61K47/183—Amino acids, e.g. glycine, EDTA or aspartame
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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
- A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
- A61K47/22—Heterocyclic compounds, e.g. ascorbic acid, tocopherol or pyrrolidones
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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
- A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
- A61K47/26—Carbohydrates, e.g. sugar alcohols, amino sugars, nucleic acids, mono-, di- or oligo-saccharides; Derivatives thereof, e.g. polysorbates, sorbitan fatty acid esters or glycyrrhizin
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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
- A61K47/50—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 the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
- A61K47/51—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 the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent
- A61K47/68—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 the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an antibody, an immunoglobulin or a fragment thereof, e.g. an Fc-fragment
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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
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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
- A61K9/08—Solutions
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P5/00—Drugs for disorders of the endocrine system
- A61P5/06—Drugs for disorders of the endocrine system of the anterior pituitary hormones, e.g. TSH, ACTH, FSH, LH, PRL, GH
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- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02A—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE
- Y02A50/00—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE in human health protection, e.g. against extreme weather
- Y02A50/30—Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change
Abstract
The invention discloses a recombinant human growth hormone-Fc fusion protein injection formulation, which belongs to the technical field of biological medicine, and comprises 25-35mg/mL of recombinant human growth hormone-Fc fusion protein, 1.24-1.86mg/mL of L-histidine, 30-60mg/mL of sucrose, 1880.5-3.0mg/mL of poloxamer, 5.0-30.0mg/mL of glycine and the balance of water for injection; the preparation process does not need a complicated freeze-drying process, and the recombinant human growth hormone-Fc fusion protein has high stability in an injection preparation and is convenient for transportation and storage; the content and the concentration of the recombinant human growth hormone-Fc fusion protein in the injection preparation are determined, so that concentration errors caused by re-dissolution are avoided, accurate administration is facilitated, and compared with the traditional freeze-drying preparation, the recombinant human growth hormone-Fc fusion protein is more convenient to use and higher in safety, and has important clinical significance.
Description
Technical Field
The invention belongs to the technical field of biological medicine, and particularly relates to a formula of a recombinant human growth hormone-Fc fusion protein injection preparation.
Background
Human growth hormone (hGH) is a peptide hormone which is a protein hormone synthesized, stored and secreted by growth hormone cells in the pituitary. The growth hormone molecule is composed of 191 amino acid residues, has a relative molecular mass of 22124 daltons, is combined with a receptor (hGH R) thereof on the surface of target cells, activates biological reaction, and promotes the development of animals and humans and the proliferation of cells. Has the functions of regulating metabolism, stimulating protein synthesis, accelerating fat metabolism, promoting growth and development of skeleton and muscle tissue, etc., and is a specific medicine for treating short stature of children. The problem of the height of children is more and more concerned, and the demand for improving the height is also more and more great. The etiology of short stature in children is up to 10 more, with Growth Hormone Deficiency (GHD) and idiopathic short stature being the most common. Recombinant human growth hormone (rhGH) is mainly used for treating or relieving short stature of children, tissue repair, burn and scald, adult Growth Hormone Deficiency (GHD) and the like caused by insufficient or deficient Growth Hormone (GH) secretion. Recombinant human growth hormone-Fc fusion protein (rhGH-Fc) is produced by combining human growth hormone and antibody Fc domains together through a connecting peptide to form a homodimer through a gene recombination technology and utilizing Chinese hamster ovary Cells (CHO). The amino acid content and the sequence of the recombinant human growth hormone-Fc fusion protein (rhGH-Fc) N-terminal growth hormone are completely the same as those of the human growth hormone, and the recombinant human growth hormone-Fc fusion protein has the same effect as that of the human endogenous growth hormone; the C end of the mutant is a human IgG subtype antibody Fc domain mutant, the half life of the medicine can be prolonged through a neonatal Fc receptor (FcRn) mediated recycling mechanism, and the mutant is only required to be injected once every week or every two weeks, has the same curative effect as recombinant human growth hormone (rhGH) and lower injection frequency, and can obviously improve the medication compliance and the overall treatment effect of patients. The rhGH-Fc does not need additional chemical modification, has lower potential safety hazard, high expression quantity, stable and reliable product preparation process and easy quality control.
Recombinant human growth hormone is an unstable macromolecular protein, and is easy to generate changes such as oxidation, deamidation, polymerization and the like in aqueous solution. At present, recombinant human growth hormone on the market is mostly prepared into powder injection by adopting a freeze drying technology, and the powder injection is required to be self-reconstituted by a patient, so that the patient has complicated use and potential safety hazard of pollution. Therefore, a recombinant human growth hormone-Fc fusion protein injection formulation is provided.
Disclosure of Invention
The invention aims to provide a formula of a recombinant human growth hormone-Fc fusion protein injection preparation, so as to solve the problems in the background technology.
The aim of the invention can be achieved by the following technical scheme:
the recombinant human growth hormone-Fc fusion protein injection formulation comprises the following components:
25-35mg/mL of recombinant human growth hormone-Fc fusion protein, 1.24-1.86mg/mL of L-histidine, 30-60mg/mL of sucrose, 1880.5-3.0mg/mL of poloxamer, 5.0-30.0mg/mL of glycine and the balance of water for injection.
Further, the pH value of the recombinant human growth hormone-Fc fusion protein injection preparation is 6.0-8.0.
Furthermore, the L-histidine and water for injection form an L-histidine buffer solution, and the L-histidine buffer solution is used as a basic buffer system of recombinant human growth hormone-Fc fusion protein injection, so that the recombinant human growth hormone-Fc fusion protein is more stable.
Furthermore, the glycine can improve the stability of the recombinant human growth hormone-Fc fusion protein injection under the illumination condition, and the preparation is more stable under the illumination condition within a certain range, wherein the lower the concentration of the recombinant human growth hormone-Fc fusion protein is, the higher the pH of the L-histidine buffer solution is, and the higher the concentration of sucrose is.
Further, the recombinant human growth hormone-Fc fusion protein is 27-33mg/mL, L-histidine is 1.30-1.55mg/mL, sucrose is 40-50mg/mL, poloxamer 1880.8-1.2mg/mL, glycine is 9.6-14.4mg/mL, and the balance is water for injection.
Further, the pH value of the recombinant human growth hormone-Fc fusion protein injection preparation is 6.3-7.3.
The invention has the beneficial effects that:
the preparation formula of the recombinant human growth hormone-Fc fusion protein injection adopts an L-histidine buffer solution as a basic buffer solution, wherein the L-histidine is a pH regulator; sucrose acts as a protein stabilizer and an isotonicity modifier; poloxamer 188 acts as a solubilizing agent and surfactant; glycine acts as an antioxidant and a pH regulator; the preparation process does not need a complicated freeze-drying process, and the recombinant human growth hormone-Fc fusion protein has high stability in an injection preparation and is convenient for transportation and storage; the content and the concentration of the recombinant human growth hormone-Fc fusion protein in the injection preparation are determined, so that concentration errors caused by re-dissolution are avoided, accurate administration is facilitated, and compared with the traditional freeze-drying preparation, the recombinant human growth hormone-Fc fusion protein is more convenient to use and higher in safety, and has important clinical significance.
Drawings
The invention is further described below with reference to the accompanying drawings.
FIG. 1 is a line diagram of SEC-HPLC purity (40-2W) and the like of key influencing factors of DOE screening recombinant human growth hormone-Fc fusion protein injection formulation;
FIG. 2 is a main effect chart of SEC-HPLC purity (40-2W) of key influencing factors of DOE screening recombinant human growth hormone-Fc fusion protein injection formulation of the present invention;
FIG. 3 is a line graph of SEC-HPLC purity (40-6W) and the like of key influencing factors of DOE screening recombinant human growth hormone-Fc fusion protein injection formulation;
FIG. 4 is a main effect chart of SEC-HPLC purity (40-6W) of key influencing factors of DOE screening recombinant human growth hormone-Fc fusion protein injection formulation of the present invention;
FIG. 5 is a line graph of SEC-HPLC purity (25-1M) and the like of key influencing factors of DOE screening recombinant human growth hormone-Fc fusion protein injection formulation of the invention;
FIG. 6 is a main effect chart of SEC-HPLC purity (25-1M) of key influencing factors of DOE screening recombinant human growth hormone-Fc fusion protein injection formulation of the present invention;
FIG. 7 is a line graph of SEC-HPLC purity (25-2M) and the like of key influencing factors of DOE screening recombinant human growth hormone-Fc fusion protein injection formulation;
FIG. 8 is a main effect chart of SEC-HPLC purity (25-2M) of key influencing factors of DOE screening recombinant human growth hormone-Fc fusion protein injection formulation of the present invention;
FIG. 9 is a Pareto chart showing the SEC-HPLC purity (illumination-5D) normalization effect of key influencing factors of DOE screening recombinant human growth hormone-Fc fusion protein injection formulations of the present invention;
FIG. 10 is a chart showing the principal effect of SEC-HPLC purity (light-5D) of key influencing factors in the formulation of DOE-screened recombinant human growth hormone-Fc fusion protein injection according to the present invention.
Detailed Description
The technical solutions of the embodiments of the present invention will be clearly and completely described below in conjunction with the embodiments of the present invention, and it is apparent that the described embodiments are only some embodiments of the present invention, not all embodiments. All other embodiments, which can be made by those skilled in the art based on the embodiments of the invention without making any inventive effort, are intended to be within the scope of the invention.
Example 1
Screening a basic buffer solution of recombinant human growth hormone-Fc fusion protein injection, which comprises the following steps:
step 1: 8 common basic buffers for protein injection (refer to table 1) are selected, 8 experimental groups are defined, 69.5mL (188.35 mg) of recombinant human growth hormone-Fc fusion protein which is qualified in verification is measured and placed in an ultrafiltration concentration tube for concentration, and 8 experimental group samples are obtained;
TABLE 1
Step 2: adding different basic buffer solutions into each experimental group sample in the step 1 for liquid exchange, wherein the liquid exchange volume is 9+/-1 times of the volume; then preparing the sample concentration of each experimental group to 30+/-5 mg/mL by using a corresponding buffer solution, filtering by a microporous filter membrane with the thickness of 0.22 mu m in a sterile environment, and subpackaging to obtain a subpackaged sample;
step 3: and (3) respectively inspecting the stability of the split charging sample in the step (2) under the conditions that the temperature is 40+/-2 ℃, the humidity is 60+/-5% RH and the freezing and thawing (-30+/-10 ℃,12h; 25+/-2 ℃ and 12h; and 5 times of circulation) are repeated. The SEC-HPLC purity results and RP-HPLC purity results of recombinant human growth hormone-Fc fusion protein injection base buffer screening were recorded as shown in tables 2 and 3 (units:%):
TABLE 2
TABLE 3 Table 3
As can be seen from table 2, the stability of the recombinant human growth hormone-Fc fusion protein in the histidine buffer system is significantly higher than that in the phosphate buffer system; as can be seen from Table 3, the recombinant human growth hormone-Fc fusion protein was most stable in experimental group 6 (10 mM L-histidine buffer (pH 6.5)) at 40.+ -.2 ℃ (60.+ -.5% RH).
Example 2
The method for screening the key influencing factors of the recombinant human growth hormone-Fc fusion protein injection by a DOE experimental design comprises the following steps:
step 1: taking an L-histidine buffer solution as a basic buffer solution of recombinant human growth hormone-Fc fusion protein injection, selecting 5 factors (protein concentration, buffer system pH, mannitol concentration, sucrose concentration and Tween 80 concentration) to carry out experimental design of five-factor and two-level DOE parts (resolution is V), and carrying out 19 groups of experiments; buffer stock solutions required for the experiments were prepared as shown in table 4;
TABLE 4 Table 4
Step 2: using the buffer mother liquor in step 1 and formulating the base buffer required for the experiment according to table 5;
TABLE 5
Step 3: preparing auxiliary material concentrated solution (4 times concentration) required by experiments according to table 6 by using the buffer mother solution in the step 1;
TABLE 6
Step 4: performing concentration and liquid change (TFF) operation on recombinant human growth hormone-Fc fusion protein qualified by test according to the experimental requirement of table 7 by using the buffer solution in the step 2;
TABLE 7
Step 5: preparing recombinant human growth hormone-Fc fusion protein injection preparations according to the material proportions in table 8 by using the buffer solution in the step 2, the auxiliary material concentrated solution in the step 3 and the concentrated solution liquid-changing samples (TFF 1, TFF2, TFF3, TFF4 and TFF 5) in the step 4, filtering and split charging each experimental group sample with a 0.22 mu m filter membrane under a sterile environment after the preparation is completed; the formulation components corresponding to each experimental group are shown in table 9;
TABLE 8
TABLE 9
Step 6: the preparation of each experimental component in the step 5 is respectively placed under the conditions of 40+/-2 ℃ (60+/-5 RH), 25+/-2 ℃ (60+/-5% RH) and illumination (the illumination intensity is 4500+/-500 lx, 5+/-3 ℃ and the ultraviolet intensity is 200 hw), and the analysis is carried out on the experimental results by taking the SEC-HPLC purity as a response.
Referring to fig. 1-10, under the condition of accelerating experiment, the protein concentration, buffer pH and sucrose concentration of the recombinant human growth hormone-Fc fusion protein injection have a significant effect on the aggregation/degradation degree of protein, and within a certain range, the lower the protein concentration, the higher the buffer pH and the higher the sucrose concentration, the more stable the sample. The recombinant human growth hormone-Fc fusion protein injection with low protein concentration is more stable under the illumination condition.
Example 3
The single variable experimental method optimizes the formula of recombinant human growth hormone-Fc fusion protein injection, and comprises the following steps:
step 1: according to the experimental results of example 1 and example 2, in the experiment 8 groups of experiments, L-histidine buffer solution is used as a basic buffer solution, the concentration of recombinant human growth hormone-Fc fusion protein is 30mg/mL, the concentration of sucrose is 50mg/mL, and on the basis, the influence of Tween 80, poloxamer 188 and glycine on the stability of recombinant human growth hormone-Fc fusion protein injection is studied by changing the concentration of Tween 80, poloxamer 188 and glycine.
Solutions required for univariate experiments were formulated as per table 10:
table 10
Step 2: preparing auxiliary material concentrated solution required by univariate experiments by using the solution in the step 1 according to the material proportion of the table 11;
TABLE 11
Step 3: using the solution in the step 1 and the auxiliary material concentrated solution in the step 2, respectively weighing 156mg of qualified recombinant human growth hormone-Fc fusion protein stock solution in each experimental group, preparing recombinant human growth hormone-Fc fusion protein injection preparation according to the material proportion in the table 12, and respectively filtering and split charging each experimental group sample with a 0.22 mu m filter membrane in a sterile environment after the preparation is completed; the corresponding formulation components for each experimental group are shown in table 13;
table 12
TABLE 13
Step 4: the preparation of each experimental component in the step 3 is respectively placed at 40+/-2 ℃ (60+/-5% RH), 25+/-2 ℃ (60+/-5% RH) and 5+/-3 ℃, repeatedly frozen and thawed (-30+/-10 ℃ for 12 hours, placed at 25+/-2 ℃ after being taken out for 12 hours, circulated for 5 times), irradiated (the irradiation intensity is 4500+/-500 lx, 5+/-3 ℃ and the ultraviolet intensity is 200 hw), oscillated (180 rpm, 5+/-3 ℃) and the like, and the SEC-HPLC purity and the RP-HPLC purity of the preparation are detected, and the experimental results are shown in tables 14 and 15.
TABLE 14
As can be seen from Table 14, in example 3, there was no significant decay in SEC-HPLC purity under the conditions of 25+ -2deg.C (60+ -5% RH) -3M, 5+ -3-6M, repeated freeze thawing-5T (5 times), and shaking-5D (180 rpm, 5+ -3deg.C); the SEC-HPLC purity result under the condition of illumination-10D (illumination intensity 4500+/-500 lx, 5+/-3 ℃ and ultraviolet intensity 200 hw) shows that the glycine can improve the stability of the sample under the illumination condition, and the stability of the glycine content 12mg/mL and 25mg/mL in the preparation under the illumination condition of recombinant human growth hormone-Fc fusion protein is not obviously different.
TABLE 15
As can be seen from Table 15, there was no significant decrease in RP-HPLC purity under conditions of 5+ -3-6M, repeated freeze thawing-5T, and shaking-5D (180 rpm, 5+ -3deg.C) for all experimental groups in example 3.
The formula of the recombinant human growth hormone-Fc fusion protein injection preparation is determined according to the experimental result, and is shown as follows:
25-35mg/mL of recombinant human growth hormone-Fc fusion protein, 1.24-1.86mg/mL of L-histidine, 30-60mg/mL of sucrose, 1880.5-3.0mg/mL of poloxamer, 5.0-30.0mg/mL of glycine and the balance of water for injection.
It should be noted that in this document, terms such as "comprises," "comprising," or any other variation thereof, are intended to cover a non-exclusive inclusion, such that a process, method, article, or apparatus that comprises a list of elements does not include only those elements but may include other elements not expressly listed or inherent to such process, method, article, or apparatus.
Although embodiments of the present invention have been shown and described, it will be understood by those skilled in the art that various changes, modifications, substitutions and alterations can be made therein without departing from the principles and spirit of the invention, the scope of which is defined in the appended claims and their equivalents.
Claims (3)
1. The recombinant human growth hormone-Fc fusion protein injection preparation is characterized by comprising the following components:
25-35mg/mL of recombinant human growth hormone-Fc fusion protein, 1.24-1.86mg/mL of L-histidine, 30-60mg/mL of sucrose, 0.5-3.0mg/mL of poloxamer 188, 5.0-30.0mg/mL of glycine and the balance of water for injection;
the pH value of the recombinant human growth hormone-Fc fusion protein injection preparation is 6.0-8.0.
2. The recombinant human growth hormone-Fc fusion protein injection formulation of claim 1, consisting of:
27-33mg/mL of recombinant human growth hormone-Fc fusion protein, 1.30-1.55mg/mL of L-histidine, 40-50mg/mL of sucrose, 0.8-1.2mg/mL of poloxamer 188, 9.6-14.4mg/mL of glycine and the balance of water for injection.
3. The recombinant human growth hormone-Fc fusion protein injection formulation of claim 2, wherein the pH of the recombinant human growth hormone-Fc fusion protein injection formulation is between 6.3 and 7.3.
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