CN113559261A - Boron carrier injection - Google Patents

Boron carrier injection Download PDF

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CN113559261A
CN113559261A CN202110452982.8A CN202110452982A CN113559261A CN 113559261 A CN113559261 A CN 113559261A CN 202110452982 A CN202110452982 A CN 202110452982A CN 113559261 A CN113559261 A CN 113559261A
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injection
bpa
sterilization
impurity
antioxidant
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李小莲
赵步文
游劲松
黄芳芳
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Dongguan Dongyangguang Boron Drug R & D Co ltd
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Dongguan Dongyangguang Boron Drug R & D Co ltd
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K41/00—Medicinal preparations obtained by treating materials with wave energy or particle radiation ; Therapies using these preparations
    • A61K41/009—Neutron capture therapy, e.g. using uranium or non-boron material
    • A61K41/0095—Boron neutron capture therapy, i.e. BNCT, e.g. using boronated porphyrins
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/69—Boron compounds
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K41/00—Medicinal preparations obtained by treating materials with wave energy or particle radiation ; Therapies using these preparations
    • A61K41/10—Inactivation or decontamination of a medicinal preparation prior to administration to an animal or a person
    • 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
    • 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
    • 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
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents

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Abstract

The invention relates to a boron carrier injection, belonging to the technical field of pharmacy. The injection comprises a boron carrying agent and a cosolvent, does not need to be redissolved, can be directly used and has good stability. Meanwhile, the invention also provides a sterilization method of the boron carrier injection and a method for reducing the osmotic pressure of the boron carrier injection, and the method is simple and easy to implement, has good controllability and is suitable for industrial production.

Description

Boron carrier injection
Technical Field
The invention relates to a boron carrier injection, in particular to a boron carrier ready-to-use liquid injection, a sterilization method and a method for reducing osmotic pressure thereof, belonging to the technical field of pharmacy.
Background
The chemical name of L-BPA is 4-dihydroxy boron-L-phenylalanine, and the structural formula is as follows:
Figure BDA0003039544870000011
in nature10B and11the distribution ratio of B is 1:4, in common L-BPA10With a B abundance of about 20%, of boron carriers for use in boron neutron capture therapy10The abundance of B is high and can reach 99.999%, and the structural formula is as follows:
Figure BDA0003039544870000012
boron Neutron Capture Therapy (BNCT) is a non-invasive precise cancer radiotherapy technology, and is suitable for treating local tumors which are difficult to operate, such as brain glioma, head and neck cancer and the like. The treatment process of BNCT mainly comprises two steps: first, injecting boron into a patient10B compound: boron10The compound B is designed to have strong affinity with tumor cells, can be rapidly gathered in the tumor cells after entering a human body, and is rarely distributed in other normal tissues. In addition to this, the present invention is,10b is a stable isotope of boron, non-radioactive, and boron10The B compound is metabolized in human body quickly, and the compound itself has no toxic action on tissue cells. Second, irradiating the tumor site of the patient with a neutron beam, which is focused in the tumor cells10B capture of neutrons, forming isotopes11B, and then rapidly split into high-energy particles4He and7li, tumor cell is finally covered4He and7radiation killing by Li release. Helium4He and lithium7The radiation radius of Li is only 5-9 μm (about equal to the radius of human body cells), so BNCT ensures that the tumor cells are killed without damaging the surrounding normal cells, and the safety is highHigher. BNCT has three basic requirements for boron drugs: 1. the toxicity is low, the absorption in normal tissues is low, the ratio of the enrichment degree in tumor to the enrichment degree in normal tissues (T/NT) and the ratio of the enrichment degree in tumor tissues to the enrichment degree in blood (T/B) are more than 3; 2.10the concentration of B in tumor is more than 20ppm, i.e. at least 10 per tumor cell9An10B atom or 10-30 μ g per g tumor tissue10A B atom; 3. boron in blood and normal tissues is metabolized relatively rapidly during neutron irradiation, and the residence time in the tumor is sufficiently long.
There are two BNCT drugs that have been clinically approved for use today, 4-dihydroxyboryl-L-phenylalanine (L-BPA) and mercaptododecaborane disodium salt (BSH). L-BPA is an analogue of phenylalanine, can be taken up by cells, has no physiological activity to a human body when being used alone, has the ratio of tumor tissues to normal tissues of 1.1-2.9 after entering the human body, has the ratio of tumor tissues to blood of 1.1-3.6, and has certain targeting property. Due to BNCT technical requirements in tumor tissues10The concentration of B is high, and the dosage is 100-500 mg/kg in the process of clinically using the L-BPA, and the administration is carried out in an infusion mode. In the process of developing the preparation, large infusion is preferred for convenient administration and reduction of aseptic risk.
However, L-BPA is poorly water soluble and it is difficult to meet the drug solubility requirements of large infusion solutions.
Patent US 5492900 describes a composition of L-BPA-fructose, which was subjected to animal experiments using a method of filter sterilization.
JP 5150084 describes a composition of L-BPA-meglumine, which is finally made into freeze-dried powder by a method of filtration sterilization.
JP 5345771 describes a composition of L-BPA-sorbitol by filter sterilization.
The physical introduction of the antibiotic-based interaction on l-p-borophenylalkane solubility for boron neutron capture therapy (Journal of Pharmaceutical Sciences,2012,101(1):223-232.2012,101(1):223-232.) describes various cosolvents, and does not describe the feasibility of large infusion solutions.
A cancer research UK pharmaceutical study of BPA-mannitol in tissues with high grade glucose to optimal upper parameters for clinical trials of BNCT (Applied radiations and Isotopes,2009,67(7-8):0-0.) was performed using the L-BPA-mannitol prescription.
Due to the poor stability of the L-BPA prescription, in the prior literature reports, hospital preparations are mostly adopted in the clinical test of the L-BPA, prepared in a sterile environment, sterilized by filtration and administered within 72 hours. Under the condition, the mass production of the L-BPA preparation is limited, the use is inconvenient, the small water injection needs to be diluted in the use process, the freeze-dried powder needs to be re-dissolved and then diluted, and the medication safety risk is higher.
Disclosure of Invention
Summary of The Invention
The invention aims to provide an injection which can be directly used without redissolution and has good stability. After L-BPA is solubilized, terminal sterilization is carried out, and the stable and convenient infusion solution is prepared, so that a new drug choice is provided for patients with fruit sugar intolerance. The large infusion preparation can be directly used in clinic, avoiding misoperation and introduction of aseptic risk during reconstitution and dilution.
The invention provides an injection containing L-BPA, which comprises a cosolvent, wherein the content of impurity phenylalanine in the injection is less than 10.0%. Meanwhile, the L-BPA ready-to-use liquid injection is provided, and the injection is safe and effective and has good storage stability.
The second aspect of the present invention provides a method for sterilizing the injection of the first aspect, which is simple and easy to implement, has good stability and high safety, and is suitable for industrial production.
The third aspect of the invention provides a method for reducing osmotic pressure of the injection, which has simple operation and good controllability and is suitable for industrial production.
Definition of terms
The term "comprising" or "comprises" is open-ended, i.e. comprising what is specified in the present invention, but not excluding other aspects.
In the context of the present invention, all numbers disclosed herein are approximate values, regardless of whether the word "about" or "approximately" is used. There may be differences below 10% in the value of each number or reasonably considered by those skilled in the art, such as differences of 1%, 2%, 3%, 4% or 5%.
In the present invention, mg/mL represents mg/mL, μ M represents μ M, mmol/L represents mmol/L, min represents min, h represents h, mg represents mg, g represents g, mL represents mL, mg/kg represents mg/kg, μ L represents μ L, M represents mol/L, mL/min represents mL/min, nm represents nm, DEG C represents centigrade, and mosm/kg represents milliosmol/kg.
The term "API" refers to an active ingredient, the active ingredient of the present invention being L-BPA, wherein10The abundance ratio of B is between 20 and 99.999 percent.
In the present invention, the concentration of L-BPA as an active ingredient is the ratio of the weight (mg) of the active ingredient to the total volume (mL) of the injection, i.e., W/V, mg/mL, for example, 30mg/mL of L-BPA means that 30mg of L-BPA is contained per 1mL of the injection.
The term "moist heat sterilization" refers to a method of sterilizing microorganisms by denaturing proteins and nucleic acids in microbial cells by means of high-pressure saturated steam, superheated water spray, or the like.
Detailed Description
Based on the defects of the prior art, the invention is subjected to intensive investigation and research, L-BPA is solubilized and then is subjected to terminal sterilization to prepare the ready-to-use liquid injection, and the obtained solution is thoroughly sterilized and has good stability and can meet the solubility requirement of preparing the injection.
In a first aspect of the invention, an injection is provided, which contains an active ingredient L-BPA and a cosolvent. The injection may have a phenylalanine content of less than 10.0%, alternatively less than 9.0%, alternatively less than 8.0%, alternatively less than 7.0%, alternatively less than 6.0%, alternatively less than 5.0%, alternatively less than 1.0%, alternatively less than 0.5%, alternatively less than 0.1%, which may be considered as an impurity.
In some embodiments, the injection is a ready-to-use liquid injection. In some embodiments, the injection is a bolus infusion.
In some embodiments, the injectable formulation, prior to sterilization, contains less than 10.0%, alternatively less than 9.0%, alternatively less than 8.0%, alternatively less than 7.0%, alternatively less than 6.0%, alternatively less than 5.0%, alternatively less than 1.0%, alternatively less than 0.5%, alternatively less than 0.1% of phenylalanine as an impurity. In some embodiments, the injectable formulation, after sterilization, has an impurity phenylalanine content of less than 10.0%, alternatively less than 9.0%, alternatively less than 8.0%, alternatively less than 7.0%, alternatively less than 6.0%, alternatively less than 5.0%, alternatively less than 1.0%, alternatively less than 0.5%, alternatively less than 0.1%. In some embodiments, the impurity phenylalanine content of the injection before sterilization is less than 0.1%. In some embodiments, the impurity phenylalanine content of the injection after sterilization is less than 5.0%. In some embodiments, the injection has an impurity phenylalanine content of less than 0.1% before sterilization and an impurity phenylalanine content of less than 5.0% after sterilization.
The injection can adopt any method capable of achieving the sterilization effect. In some embodiments, the injection is sterilized by moist heat sterilization, and the desired effects of the present invention can be well achieved.
In some embodiments, the injection is sterilized by moist heat sterilization, wherein the content of the impurity phenylalanine is less than 0.1% before sterilization, and the content of the impurity phenylalanine is less than 5.0% after sterilization. In some embodiments, the impurity phenylalanine content before sterilization is 0.05%, and the impurity phenylalanine content after sterilization is 2.49%. In some embodiments, the impurity phenylalanine content before sterilization is 0.06%, and the impurity phenylalanine content after sterilization is 3.75%. In some embodiments, the impurity phenylalanine content before sterilization is 0.05%, and the impurity phenylalanine content after sterilization is 3.97%. In some embodiments, the impurity phenylalanine content before sterilization is 0.05%, and the impurity phenylalanine content after sterilization is 4.10%.
In the injection, the content of impurity tyrosine is less than 1.0%. In some embodiments, the impurity tyrosine is present in the injection in an amount of less than 0.8%. In some embodiments, the injection contains less than 0.7% tyrosine as an impurity. In some embodiments, the injection contains less than 0.6% tyrosine as an impurity. In some embodiments, the injection contains less than 0.5% tyrosine as an impurity. In some embodiments, the injection contains less than 0.1% tyrosine as an impurity.
In some embodiments, the concentration of L-BPA ranges from 10.0mg/mL to 150.0mg/mL (W/V) as a ratio of the weight of L-BPA to the total volume of the injection. In some embodiments, the concentration of L-BPA ranges from 30.0mg/mL to 150.0mg/mL (W/V). In some embodiments, the concentration of L-BPA ranges from 10.0mg/mL to 30.0 mg/mL; in some embodiments, the concentration of L-BPA ranges from 10.0mg/mL to 80.0 mg/mL; in some embodiments, the concentration of L-BPA ranges from 10.0mg/mL to 120.0 mg/mL; in some embodiments, the concentration of L-BPA ranges from 30.0mg/mL to 50.0 mg/mL; in some embodiments, the concentration of L-BPA ranges from 30.0mg/mL to 80.0 mg/mL; in some embodiments, the concentration of L-BPA ranges from 30.0mg/mL to 120.0 mg/mL; in some embodiments, the concentration of L-BPA ranges from 50.0mg/mL to 80.0 mg/mL; in some embodiments, the concentration of L-BPA ranges from 50.0mg/mL to 120.0 mg/mL; in some embodiments, the concentration of L-BPA ranges from 50.0mg/mL to 150.0 mg/mL; in some embodiments, the concentration of L-BPA ranges from 80.0mg/mL to 120.0 mg/mL; in some embodiments, the concentration of L-BPA ranges from 80.0mg/mL to 150.0 mg/mL; in some embodiments, the concentration of L-BPA ranges from 120.0mg/mL to 150.0 mg/mL. In some embodiments, the concentration of L-BPA is 30.0mg/mL, 50.0mg/mL, 80.0mg/mL, 120.0mg/mL, or 150.0 mg/mL. The L-BPA with a certain concentration range can be prepared into large infusion with proper administration volume and has better stability.
The cosolvent may include at least one selected from sorbitol and mannitol. In some embodiments, the co-solvent comprises sorbitol; in some embodiments, the co-solvent comprises mannitol. L-BPA has poor water solubility, and a clear and transparent solution with good stability can be obtained by adding a certain kind of cosolvent.
The amount of the cosolvent used can be 0.8-1.6 times the amount of L-BPA used in terms of weight ratio. In some embodiments, the co-solvent is present in an amount from 1.0 to 1.3 times the amount of L-BPA. In some embodiments, the co-solvent is present in an amount from 0.8 to 1.0 times the amount of L-BPA; in some embodiments, the co-solvent is present in an amount from 0.8 to 1.1 times the amount of L-BPA; in some embodiments, the co-solvent is present in an amount from 0.8 to 1.3 times the amount of L-BPA; in some embodiments, the co-solvent is present in an amount from 1.0 to 1.1 times the amount of L-BPA; in some embodiments, the co-solvent is present in an amount from 1.0 to 1.6 times the amount of L-BPA; in some embodiments, the co-solvent is present in an amount from 1.1 to 1.3 times the amount of L-BPA; in some embodiments, the co-solvent is present in an amount from 1.1 to 1.6 times the amount of L-BPA; in some embodiments, the co-solvent is present in an amount from 1.3 times to 1.6 times the amount of L-BPA. In some embodiments, the co-solvent is used in an amount that is 0.79 times, 0.96 times, 1.13 times, 1.31 times, or 1.57 times the amount of L-BPA. And a certain amount of cosolvent is added to increase the solubility of the L-BPA.
In some embodiments, the injection contains the active ingredients of L-BPA and sorbitol, and the content of the impurity phenylalanine is less than 10.0%. In some embodiments, the injection contains the active ingredients of L-BPA and mannitol, and the content of the impurity phenylalanine is less than 10.0%. In some embodiments, the injection contains active ingredients of L-BPA and sorbitol, the dosage of the sorbitol is 0.8-1.6 times of that of the L-BPA, and the content of the impurity phenylalanine is less than 10.0%. In some embodiments, the injection contains active ingredients of L-BPA and mannitol, the dosage of the mannitol is 0.8-1.6 times of that of the L-BPA, and the content of impurity phenylalanine is less than 10.0%.
The injection may further contain an antioxidant. The injection may contain no antioxidant.
The antioxidant may include at least one selected from the group consisting of sodium bisulfite, sodium sulfite, and sodium thiosulfate. The antioxidant can be used in an amount ranging from 0.025% to 0.5% by weight (g) of the antioxidant to the total volume (mL) of the injection. In some embodiments, the antioxidant comprises sodium bisulfite. In some embodiments, the antioxidant is present in an amount ranging from 0.025% to 0.05%; in some embodiments, the antioxidant is present in an amount ranging from 0.025% to 0.1%; in some embodiments, the antioxidant is present in an amount ranging from 0.025% to 0.2%; in some embodiments, the antioxidant is present in an amount ranging from 0.05% to 0.1%; in some embodiments, the antioxidant is present in an amount ranging from 0.05% to 0.2%; in some embodiments, the antioxidant is present in an amount ranging from 0.05% to 0.5%; in some embodiments, the antioxidant is present in an amount ranging from 0.1% to 0.2%; in some embodiments, the antioxidant is present in an amount ranging from 0.1% to 0.5%; in some embodiments, the antioxidant is present in an amount ranging from 0.2% to 0.5%; in some embodiments, the antioxidant is used in an amount of 0.025%, 0.05%, 0.1%, 0.2%, or 0.5%. And a certain amount of antioxidant is added, so that the growth of the oxidized impurities can be effectively controlled.
The injection may have a pH of 6.8-9.0. In some embodiments, the injection has a pH of 7.8 to 9.0. In some embodiments, the pH of the injection is 6.8 to 7.2; in some embodiments, the pH of the injection is 6.8 to 7.4; in some embodiments, the pH of the injection is 6.8 to 7.8; in some embodiments, the pH of the injection is 6.8 to 8.5; in some embodiments, the pH of the injection is 7.2 to 7.4; in some embodiments, the pH of the injection is 7.2 to 7.8; in some embodiments, the pH of the injection is 7.2 to 8.5; in some embodiments, the pH of the injection is 7.2 to 9.0; in some embodiments, the pH of the injection is 7.4 to 7.8; in some embodiments, the pH of the injection is 7.4 to 8.5; in some embodiments, the pH of the injection is 7.4 to 9.0; in some embodiments, the pH of the injection is 7.8 to 8.5; in some embodiments, the injection has a pH of 8.5 to 9.0. In some embodiments, the pH of the injection is 6.8, 7.0, 7.2, 7.4, or 7.8. The L-BPA solution has good physical stability in a certain pH range.
In some embodiments, the aforementioned injectable formulation comprises: L-BPA and a cosolvent, wherein the pH of the injection is 6.8-9.0.
In some embodiments, the injectable formulation comprises: L-BPA, a cosolvent and/or an antioxidant, wherein the pH of the injection is 6.8-9.0.
In some embodiments, the injectable formulation comprises:
(1) the concentration range of the L-BPA is 30.0mg/mL-150.0mg/mL according to the ratio of the weight of the L-BPA to the total volume of the injection;
(2) the cosolvent is 1.0-1.3 times of the L-BPA in weight ratio;
(3) and/or an antioxidant, wherein the dosage range of the antioxidant is 0.025-0.5% according to the proportion of the weight (g) of the antioxidant to the total volume (mL) of the injection;
the pH of the injection is 7.8-9.0.
In some embodiments, the injectable formulation comprises:
(1) the concentration of the L-BPA is 100.0mg/mL according to the ratio of the weight of the L-BPA to the total volume of the injection;
(2) sorbitol, the dosage of which is 1.0 time of that of L-BPA calculated according to the weight ratio;
(3) and/or sodium bisulfite, the dosage of which is 0.05 percent;
the pH of the injection is 7.8.
In another aspect of the present invention, there is provided a method for sterilizing the injection, which comprises a moist heat sterilization method. In some embodiments, the sterilization process is a moist heat sterilization process.
In some embodiments, the sterilization method comprises: sterilizing at 121 deg.C for 8-15 min. In some embodiments, the sterilization method comprises: sterilizing at 121 deg.C for 8-10 min; in some embodiments, the sterilization method comprises: sterilizing at 121 deg.C for 8-12 min; in some embodiments, the sterilization method comprises: sterilizing at 121 deg.C for 10min-12 min; in some embodiments, the sterilization method comprises: sterilizing at 121 deg.C for 10min-15 min; in some embodiments, the sterilization method comprises: sterilizing at 121 deg.C for 12-15 min. In some embodiments, the sterilization method comprises: sterilizing at 121 deg.C for 8 min; in some embodiments, the sterilization method comprises: sterilizing at 121 deg.C for 10 min; in some embodiments, the sterilization method comprises: sterilizing at 121 deg.C for 12 min; in some embodiments, the sterilization method comprises: sterilizing at 121 deg.C for 15 min.
In some embodiments, the sterilization method comprises: sterilizing at 115 deg.C for 30-40 min. In some embodiments, the sterilization method comprises: sterilizing at 115 deg.C for 30 min; in some embodiments, the sterilization method comprises: sterilizing at 115 deg.C for 40 min.
Different injection component compositions can lead to different product stability and different impurity content. Different sterilization methods may also result in different levels of impurities. The injection can meet the requirement of impurity content of the product. The wet heat sterilization method can meet the sterilization requirement, is simple, convenient, controllable and feasible, can stabilize the product, and controls the content of impurities within the range of quality requirement.
The injection disclosed by the invention is good in stability, and can be subjected to terminal sterilization by adopting the method.
The wet heat sterilization method adopted by the invention is simple and easy to implement, has good stability and high safety, and is suitable for industrial production.
In a third aspect of the present invention, there is provided a method for reducing the osmotic pressure of an injection according to the present invention, the method comprising: and nano-filtration technology is adopted. In some embodiments, L-BPA injections with osmotic pressures of 280-330 mosm/kg can be obtained using nanofiltration techniques.
The nanofiltration technology adopted by the invention has simple operation and good controllability, and is suitable for industrial production.
Detailed Description
In order to make the technical solutions of the present invention better understood by those skilled in the art, the following further discloses some non-limiting examples to further explain the present invention in detail.
The reagents used in the present invention are either commercially available or can be prepared by the methods described herein.
N/A in the example table indicates nothing.
L-BPA content and related substance detection methods (general examples):
chromatographic conditions are as follows: high performance liquid chromatography (Agilent HPLC-DAD); a chromatographic column: welch Ultimate AQ-C18(D),4.6 × 250mm,5 um; a detector: DAD detector, 210 nm; flow rate: 1.0 ml/min; mobile phase A: 10mmol/LpH2.8 KH2PO4Buffer; mobile phase B: methanol; diluting liquid: 0.1M HCl; column temperature: 35 ℃ is carried out.
The related substances were determined as gradient elution, the elution conditions are shown in Table A, the running time is 55min, and the sample volume is 10. mu.L.
TABLE A gradient elution conditions
Figure BDA0003039544870000071
The content determination is isocratic elution, and the elution conditions are as follows: mobile phase A: mobile phase B95: 5, run time 20min, sample size 10 μ L.
EXAMPLE 1 Sterilization stability test of high concentration L-BPA solutions of different formulations (moist Heat Sterilization, overkill, 121 ℃, 15min)
TABLE 1-1 prescription Table
Figure BDA0003039544870000081
The preparation process of the formula 1-3 comprises the following steps:
(1) weighing API in the prescription amount, and adding water for injection for dispersion;
(2) adding a proper amount of sodium hydroxide, and stirring until the API is completely dissolved;
(3) adding sugar alcohol (one of fructose, sorbitol and mannitol) in a prescribed amount, and stirring to completely dissolve;
(4) adjusting pH of the solution back to 7.8 with hydrochloric acid, diluting to constant volume, filtering with 0.45 μm PES filter membrane, filling 4ml each, plugging, and capping;
(5) sterilizing at 121 deg.C for 15min (overkill condition is commonly used).
Prescription 4 preparation process:
(1) weighing API in the prescription amount, and adding water for injection for dispersion;
(2) adding the meglumine with the prescription amount, and stirring until the API and the meglumine are completely dissolved;
(3) adjusting pH of the solution back to 7.8 with hydrochloric acid, diluting to constant volume, filtering with 0.45 μm PES filter membrane, filling 4ml each, plugging, and capping;
(4) sterilizing at 121 deg.C for 15min (overkill condition is commonly used).
The results are shown in the following table:
TABLE 1-2121 ℃ sterilization results in 15min
Figure BDA0003039544870000082
Figure BDA0003039544870000091
From the above table, the material growth results for formula 2 and formula 3 can be seen: the main growth impurity is phenylalanine, the impurity is essential amino acid for human body, the safety is good, and the product has poor thermal stability, so the product is considered to be acceptable under the condition that the impurity growth is not more than 10% and the content is not more than 10%. After the solution is excessively killed at the temperature of 121 ℃ for 15min, the solution in the formula 1 is obviously changed from light yellow to black brown, so that the stability conditions of the content and related substances are not investigated; formula 2 has a color change slightly better than formula 1, but related substances increase obviously, and the total impurity increase exceeds 13%; formula 3 has no obvious color change, but the related substances increase by more than 12%; the method for over-killing has larger influence on the content and related substances and higher risk under the concentration condition, and the method is not satisfactory.
EXAMPLE 2 Sterilization stability of L-BPA formulation solutions at Low concentrations
TABLE 2-1 prescription Table
Figure BDA0003039544870000092
The preparation process of the formula 1-3 comprises the following steps:
(1) weighing API in the prescription amount, and adding water for injection for dispersion;
(2) adding a proper amount of sodium hydroxide, and stirring until the API is completely dissolved;
(3) adding sugar alcohol (one of fructose, sorbitol and mannitol) in a prescribed amount, and stirring to completely dissolve;
(4) adjusting the pH value of the solution back to 7.8 by using hydrochloric acid, fixing the volume, filtering by using a 0.45 mu mPES filter membrane, diluting the solution of each prescription to the concentration of 30mg/ml of L-BPA according to a proportion, filling 4ml of each solution, plugging and capping;
(5) sterilizing at 121 deg.C for 15 min.
Prescription 4 preparation process:
(1) weighing API in the prescription amount, and adding water for injection for dispersion;
(2) adding the meglumine with the prescription amount, and stirring until the API and the meglumine are completely dissolved;
(3) adjusting pH of the solution back to 7.8 with hydrochloric acid, fixing volume, filtering with 0.45 μm PES filter membrane, diluting the solution in the formula to a concentration of 30mg/ml L-BPA, filling 4ml per bottle, plugging, and capping;
(4) sterilizing at 121 deg.C for 15min (overkill condition is commonly used).
The results are shown in the following table:
TABLE 2-2121 ℃ C., 15min sterilization results
Figure BDA0003039544870000101
According to the table above, the overkill was performed at a concentration of 30mg/ml, and the cases of formula 2 and formula 3 were better than those of formula 1 and formula 4, where formula 3 was optimal, the color did not change significantly, the content was reduced less, the total impurity increased by about 6%, the main impurity increased was phenylalanine, and the impurity increase was lower compared to sterilization performed at a concentration of 200mg/ml in example 1. According to the actual situation, the prescription 2 and the prescription 3 are acceptable, namely the cosolvent is sorbitol or mannitol prescription which can meet the requirement.
EXAMPLE 3 stability of high concentration L-BPA solutions at 121 ℃ for 8min
TABLE 3-1 prescription Table
Figure BDA0003039544870000111
The preparation process comprises the following steps:
(1) weighing API in the prescription amount, and adding water for injection for dispersion;
(2) adding a proper amount of sodium hydroxide, and stirring until the API is completely dissolved;
(3) adding sugar alcohol (one of fructose, sorbitol and mannitol) in a prescribed amount, and stirring to completely dissolve;
(4) adjusting pH of the solution back to 7.8 with hydrochloric acid, diluting to constant volume, filtering with 0.45 μm PES filter membrane, filling 4ml each, plugging, and capping;
(5) sterilizing at 121 deg.C for 8 min.
The results are given in the following table:
TABLE 3-2121 ℃ C., 8min sterilization results
Figure BDA0003039544870000112
According to the table, the solutions of each formula of the high-concentration L-BPA are sterilized at the temperature of 121 ℃ for 8min, the impurities in the formula 2 can be accepted after sterilization, the total impurities in the formula 3 exceed 10 percent after sterilization, and the risk is high.
Example 4: stability of low-concentration L-BPA solution at 121 ℃ for 8min under sterilization
TABLE 4-1 prescription Table
Figure BDA0003039544870000121
The preparation process comprises the following steps:
(1) weighing API in the prescription amount, and adding water for injection for dispersion;
(2) adding a proper amount of sodium hydroxide, and stirring until the API is completely dissolved;
(3) adding sugar alcohol (one of fructose, sorbitol and mannitol) in a prescribed amount, and stirring to completely dissolve;
(4) adjusting pH of the solution back to 7.8 with hydrochloric acid, diluting to constant volume, filtering with 0.45 μm PES filter membrane, diluting each prescription to 30mg/ml in proportion, filling 4ml each, plugging, and capping;
(5) the cells were sterilized at 121 ℃ for 8min (survival probability method).
The results are given in the following table:
TABLE 4-2121 ℃ C., 8min sterilization results
Figure BDA0003039544870000122
Figure BDA0003039544870000131
According to the table, the solution of each prescription of 30mg/ml L-BPA is sterilized at the temperature of 121 ℃ for 8min, wherein the sterilization stability of the prescription 2 and the prescription 3 is better than that of the prescription 1, the related substances are increased by about 4 percent, the main increased impurities are phenylalanine, the phenylalanine is essential amino acid for human bodies, and the safety is high; tyrosine is non-essential amino acid of human body, and has no safety risk; the increase of RRT2.69 impurity is about 0.2%. The effect of the sterilization conditions of 121 ℃, 8min on the product was less compared to the sterilization conditions of 121 ℃, 15min in example 2. At this concentration, both recipe 2 and recipe 3 are acceptable.
Example 5: stability of high concentration L-BPA solution at 115 deg.C for 30min
TABLE 5-1 prescription Table
Figure BDA0003039544870000132
The preparation process comprises the following steps:
(1) weighing API in the prescription amount, and adding water for injection for dispersion;
(2) adding a proper amount of sodium hydroxide, and stirring until the API is completely dissolved;
(3) adding sugar alcohol (one of fructose, sorbitol and mannitol) in a prescribed amount, and stirring to completely dissolve;
(4) adjusting pH of the solution back to 7.8 with hydrochloric acid, diluting to constant volume, filtering with 0.45 μm PES filter membrane, filling 4ml each, plugging, and capping;
(5) the sterilization was carried out at 115 ℃ for 30min (survival probability method).
The results are given in the following table:
TABLE 5-2115 ℃ C., 30min sterilization results
Figure BDA0003039544870000133
Figure BDA0003039544870000141
According to the table, the solution of each formula of high-concentration L-BPA is sterilized at 115 ℃ for 30min, wherein the sterilization stability of the formula 2 and the formula 3 is better than that of the formula 1, but the related substances increase by about 9%, the formula 2 is acceptable, the total impurity of the formula 3 exceeds 10%, and the risk is high.
Example 6: stability of low-concentration L-BPA solution at 115 ℃ for 30min under sterilization
TABLE 6-1 prescription Table
Figure BDA0003039544870000142
The preparation process comprises the following steps:
(1) weighing API in the prescription amount, and adding water for injection for dispersion;
(2) adding a proper amount of sodium hydroxide, and stirring until the API is completely dissolved;
(3) adding sugar alcohol (fructose, sorbitol, mannitol, meglumine) in a prescribed amount, and stirring to dissolve completely;
(4) adjusting pH of the solution to 7.8 with hydrochloric acid, diluting to constant volume, filtering with 0.45 μm PES filter membrane, filling the solutions into infusion bags (200 ml/bag), and sealing.
(5) The sterilization was carried out at 115 ℃ for 30min (survival probability method).
The results are given in the following table:
TABLE 6-2115 ℃ C., 30min sterilization results
Figure BDA0003039544870000151
According to the table, the solution of each prescription of 30mg/ml L-BPA is sterilized at 115 ℃ for 30min, wherein the sterilization stability of prescription 2 and prescription 3 is better than that of prescription 1, the main growth impurity is phenylalanine, no new unknown impurity is added, the tyrosine and phenylalanine have no safety risk, and the impurity growth of RRT2.69 is below 0.1%, and is relatively controllable. At this concentration, both recipe 2 and recipe 3 are acceptable.
Example 7 investigation of different Co-solvent amounts
TABLE 7-1 prescription Table
Figure BDA0003039544870000152
Figure BDA0003039544870000161
The preparation process comprises the following steps:
(1) weighing API in the prescription amount, and adding water for injection for dispersion;
(2) adding a proper amount of sodium hydroxide, and stirring until the API is completely dissolved;
(3) adding sugar alcohol (sorbitol, mannitol) in a prescribed amount, and stirring to dissolve completely;
(4) adjusting pH of the solution back to 7.8 with hydrochloric acid, diluting to constant volume, filtering with 0.45 μm PES filter membrane, filling into 30ml borosilicate tube glass injection bottle, plugging, capping, and observing physical stability after standing.
The results are given in the following table:
TABLE 7-2 prescription physical stability for different amounts of co-solvent
Figure BDA0003039544870000162
Figure BDA0003039544870000171
From the above table, it can be stated that: the larger the amount of the cosolvent, the better the physical stability of the solution, but for large infusion, the higher the osmotic pressure of the product needs to be considered, the higher the amount of the cosolvent, the higher the osmotic pressure, the increased viscosity of the solution, and the higher the administration risk, so the amount of the cosolvent in the prescription should not be too large. According to the above data, the amount of the cosolvent used may be 0.8 to 1.6 times, preferably 1.0 to 1.3 times the amount of the API used.
Example 8 different prescription pH stability Studies
TABLE 8-1 prescription Table
Figure BDA0003039544870000172
The preparation process comprises the following steps:
(1) weighing API in the prescription amount, and adding water for injection for dispersion;
(2) adding a proper amount of sodium hydroxide, and stirring until the API is completely dissolved;
(3) adding sugar alcohol (sorbitol, mannitol) in a prescribed amount, and stirring to dissolve completely;
(4) dilute hydrochloric acid was added and the pH was adjusted as in the formula: adjusting the prescriptions 1 and 8 until API is separated out, recording pH value, adjusting the other prescriptions to corresponding pH values, diluting to constant volume, filtering, filling into 30ml borosilicate glass injection bottles, and observing physical stability.
The results are given in the following table:
TABLE 8-2 physical stability at different pH recipes
Figure BDA0003039544870000181
From the above table, it can be stated that: the higher the pH, the better the physical stability of the solution, but for large infusion the product should be as close as possible to physiological pH7.4, at least in the range of 3-9. According to the above data, the pH can be selected from the range of 6.8 to 9.0, preferably 7.8 to 9.0.
Example 9 Sterilization stability Studies (121 ℃, 8min) for different concentration recipes
TABLE 9-1 prescription Table
Figure BDA0003039544870000182
Figure BDA0003039544870000191
The preparation process comprises the following steps:
(1) weighing API in the prescription amount, and adding water for injection for dispersion;
(2) adding a proper amount of sodium hydroxide, and stirring until the API is completely dissolved;
(3) adding sugar alcohol (sorbitol, mannitol) in a prescribed amount, and stirring to dissolve completely;
(4) adjusting pH of the solution back to 7.8 with hydrochloric acid, diluting to constant volume, filtering with 0.45 μm PES filter membrane, filling 4ml each, plugging, and capping;
(5) sterilizing at 121 deg.C for 8 min.
The results are given in the following table:
TABLE 9-2 Sterilization results for different concentration recipes
Figure BDA0003039544870000192
Figure BDA0003039544870000201
From the above table, it can be stated that: the higher the concentration is, the larger the impurity growth after sterilization is, the main grown impurity is phenylalanine, but phenylalanine belongs to essential amino acid for human body, and the safety is good, so that the impurity is considered to be acceptable under the condition that the total impurity is not more than 10% and the content is not more than 10% after sterilization. With the combination of the above embodiments, the sterilization result of the prescription containing sorbitol at 121 ℃ for 8min is acceptable under the condition that the API concentration is 10-200 mg/ml, and the sterilization result of the prescription containing mannitol at 121 ℃ for 8min is acceptable under the condition that the API concentration is 10-150 mg/ml; the concentration of the product is preferably 30-150 mg/ml because the administration volume of the product is large and the product can bring burden to human body at the concentration of 10 mg/ml.
Example 10 different Sterilization Process investigation
TABLE 10-1 prescription Table
Figure BDA0003039544870000202
The preparation process comprises the following steps:
(1) weighing API in the prescription amount, and adding water for injection for dispersion;
(2) adding a proper amount of sodium hydroxide, and stirring until the API is completely dissolved;
(3) adding sugar alcohol (sorbitol, mannitol) in a prescribed amount, and stirring to dissolve completely;
(4) adjusting pH of the solution back to 7.8 with hydrochloric acid, diluting to constant volume, filtering with 0.45 μm PES filter membrane, filling 4ml each, plugging, and capping;
(5) the 2 prescriptions are sterilized by different sterilization processes respectively: at 121 ℃, 8min/10min/12min/15 min; 115 ℃ and 30min/40 min.
The results are given in the following table:
TABLE 10-2 Sterilization results for different sterilization procedures
Figure BDA0003039544870000211
From the above table, it can be stated that: the longer the sterilization time, the larger the impurity growth, but the main growing impurity is phenylalanine which belongs to essential amino acid for human body, and the safety is good, so it is considered that the product is acceptable under the condition that the total impurity is not more than 10% and the content is not more than 10% after sterilization, namely the product is acceptable under the sterilization condition. The longer the sterilization time, the faster the impurities grow, and when the F0 values are all equal to or greater than 8, the higher the temperature is preferable, so 121 ℃, 8-15 min is preferable.
Example 11 formulation with addition of antioxidant
TABLE 11-1 prescription Table
Figure BDA0003039544870000221
The preparation process comprises the following steps:
(1) weighing API in the prescription amount, and adding water for injection for dispersion;
(2) adding a proper amount of sodium hydroxide, and stirring until the API is completely dissolved;
(3) adding sorbitol and sodium bisulfite according to the prescription amount, and stirring until the sorbitol and the sodium bisulfite are completely dissolved;
(4) adjusting pH of the solution back to 7.8 with hydrochloric acid, diluting to constant volume, filtering with 0.45 μm PES filter membrane, filling 4ml each, plugging, and capping;
(5) sterilizing at 121 deg.C for 8 min.
The experimental results are as follows:
Figure BDA0003039544870000222
Figure BDA0003039544870000231
according to the table, it can be shown that the increase of impurities is still controllable after adding sodium bisulfite, and the dosage of sodium bisulfite is acceptable between 0.025 percent and 0.5 percent.
To summarize: according to the experimental result, the color of all fructose-containing formulas becomes black brown after sterilization, the properties of the meglumine formula at high concentration can be changed after sterilization, and the sterilization conditions of the formulas containing sorbitol and mannitol are controlled under a certain concentration, so that the obtained product meets the requirements: the content is reduced a little, the color has no obvious change, and no new unknown impurity is added; phenylalanine is increased rapidly, but is essential amino acid for human body, so that the safety is high; tyrosine is a non-essential amino acid for human body, and has good safety. When the dosage of L-BPA is 500mg/kg, the dosage of phenylalanine impurity is calculated by 10 percent at most, the dosage concentration of phenylalanine is 50mg/kg, the dosage of a single person (60 kg) is 3g, and the safety problem does not exist (the dosage of phenylalanine in Huarui pharmaceutical compound amino acid injection 18 AA-I can be up to 11 g/day); the tyrosine impurity is calculated as 2 percent at most, the tyrosine administration concentration is 10mg/kg, the single (60 kg) administration amount is 0.6g, and the safety problem does not exist (the tyrosine administration amount in the Huarui pharmaceutical compound amino acid injection 18 AA-I reaches 1.0 g/day).
While the methods of the present invention have been described in terms of preferred embodiments, it will be apparent to those of ordinary skill in the art that variations and modifications of the methods and applications described herein, as well as other suitable variations and combinations, may be made to implement and use the techniques of the present invention within the context, spirit and scope of the invention. Those skilled in the art can modify the process parameters appropriately to achieve the desired results with reference to the disclosure herein. It is expressly intended that all such similar substitutes and modifications which would be obvious to those skilled in the art are deemed to be included within the invention.
In the description herein, references to the description of the term "one embodiment," "some embodiments," "some implementations," "some embodiments," "examples," "specific examples," or "some examples" or the like, mean that a particular feature, structure, material, or characteristic described in connection with the embodiment or example is included in at least one embodiment or example of the invention. In this specification, the schematic representations of the terms used above are not necessarily intended to refer to the same embodiment or example. Furthermore, the particular features, structures, materials, or characteristics described may be combined in any suitable manner in any one or more embodiments or examples. Furthermore, various embodiments or examples and features of different embodiments or examples described in this specification can be combined and combined by one skilled in the art without contradiction.
Although embodiments of the present invention have been shown and described above, it is understood that the above embodiments are exemplary and should not be construed as limiting the present invention, and that variations, modifications, substitutions and alterations can be made to the above embodiments by those of ordinary skill in the art within the scope of the present invention.

Claims (13)

1. An injection contains an active ingredient L-BPA and a cosolvent, and the content of impurity phenylalanine in the injection is less than 10.0%.
2. The injection of claim 1, which is a ready-to-use liquid injection.
3. The injection according to claim 1 or 2, wherein the content of impurity phenylalanine in the injection is less than 5.0%; or the content of impurity phenylalanine in the injection is less than 0.1%.
4. The injection according to claim 1 or 2, wherein the injection is sterilized by a moist heat sterilization method, the content of the impurity phenylalanine is less than 0.1% before sterilization, and/or the content of the impurity phenylalanine is less than 5.0% after sterilization.
5. An injection according to any one of claims 1 to 4, wherein the impurity tyrosine is present in the injection in an amount of less than 1.0%.
6. The injection according to any one of claims 1 to 5, wherein the concentration of L-BPA is in the range of 10.0mg/mL to 150.0mg/mL in terms of the ratio of the weight of L-BPA to the total volume of the injection.
7. The injection according to any one of claims 1 to 6, wherein the cosolvent comprises at least one selected from sorbitol, mannitol; and/or the dosage of the cosolvent is 0.8-1.6 times of that of the L-BPA calculated according to the weight ratio.
8. The injection according to any one of claims 1 to 6, further comprising an antioxidant; the antioxidant comprises at least one selected from sodium bisulfite, sodium sulfite and sodium thiosulfate; according to the proportion of the weight of the antioxidant to the total volume of the injection, the dosage range of the antioxidant is 0.025 percent to 0.5 percent.
9. An injection according to any one of claims 1 to 8, which has a pH of from 6.8 to 9.0.
10. An injection according to any one of claims 1 to 6, comprising: L-BPA, cosolvent and/or antioxidant, wherein the pH value of the injection is 6.8-9.0.
11. An injection according to any one of claims 1 to 6, comprising:
(1) the concentration range of the L-BPA is 30.0mg/mL-150.0mg/mL according to the ratio of the weight of the L-BPA to the total volume of the injection;
(2) the cosolvent is 1.0-1.3 times of the L-BPA in weight ratio;
(3) and/or antioxidant, the dosage range of the antioxidant is 0.025 percent to 0.5 percent according to the proportion of the weight of the antioxidant to the total volume of the composition; the pH of the injection is 7.8-9.0.
12. A method of sterilizing an injection according to any one of claims 1 to 11, comprising moist heat sterilization; the moist heat sterilization method comprises the following steps: sterilizing at 121 deg.C for 8-15 min; or comprises the following steps: sterilizing at 115 deg.C for 30-40 min.
13. A method of reducing the osmotic pressure of an injectable according to any of claims 1-11, comprising: and nano-filtration technology is adopted.
CN202110452982.8A 2020-04-29 2021-04-26 Boron carrier injection Pending CN113559261A (en)

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