CN111494611A - Interferon injection liquid packaged by cartridge bottle multi-dose pen type injection combination - Google Patents
Interferon injection liquid packaged by cartridge bottle multi-dose pen type injection combination Download PDFInfo
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- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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- 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
- A61K38/19—Cytokines; Lymphokines; Interferons
- A61K38/21—Interferons [IFN]
- A61K38/212—IFN-alpha
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- 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
- A61K47/02—Inorganic compounds
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- 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
- A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
- A61K47/10—Alcohols; Phenols; Salts thereof, e.g. glycerol; Polyethylene glycols [PEG]; Poloxamers; PEG/POE alkyl ethers
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- 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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- 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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- 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
- A61K47/42—Proteins; Polypeptides; Degradation products thereof; Derivatives thereof, e.g. albumin, gelatin or zein
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- 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
- A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
- A61P1/16—Drugs for disorders of the alimentary tract or the digestive system for liver or gallbladder disorders, e.g. hepatoprotective agents, cholagogues, litholytics
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P17/00—Drugs for dermatological disorders
- A61P17/12—Keratolytics, e.g. wart or anti-corn preparations
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P31/12—Antivirals
- A61P31/14—Antivirals for RNA viruses
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P31/12—Antivirals
- A61P31/20—Antivirals for DNA viruses
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P31/12—Antivirals
- A61P31/20—Antivirals for DNA viruses
- A61P31/22—Antivirals for DNA viruses for herpes viruses
Abstract
The invention discloses a cassette bottle multi-dose pen type injection combined packaged interferon injection, which is any type of gene recombined human interferon α, β and gamma, and has the characteristics of reliable quality, convenient use, accurate medication, safety, environmental protection, good patient compliance and the like.
Description
Technical Field
The invention relates to the technical field of pharmaceutical preparations, in particular to an interferon injection packed by a card bottle multi-dose pen type injection combination.
Background
The interferon is a kind of induced protein with high activity and multiple functions, has been widely proved to have broad-spectrum antiviral, antitumor and immunoregulation effects, mainly takes respiratory virus resistance, hepatitis virus resistance, herpes virus resistance and human papilloma virus resistance as antiviral effects, mainly takes melanoma, leukemia and liver cancer as tumor treatment effects, can be used for preparing HIV vaccine, inhibiting transplant rejection and treating autoimmune diseases as immunoregulation effects, can be divided into types such as α, β and gamma according to different generation positions and action mechanisms, has the functions of resisting virus infection, inhibiting tumor growth and the like as α interferon, is an interferon which is the most widely researched and applied at present, and is mainly divided into three types of interferon α 2a, interferon α 2b and interferon α 1b, and has various dosage forms and administration routes as freeze-dried preparations, ointments, injection liquid, suppositories, powder injection, eye drops, external preparations, long-acting gels, nasal cavity administration preparations, sustained-release preparations and the like as α interferon.
Interferon α 2b belongs to α series of type I interferon, recombinant human interferon α 2b is engineering bacteria obtained by transforming BMH71-18 escherichia coli with PBV889 plasmid with human interferon α 2b gene, the engineering bacteria are crushed after fermentation, interferon protein is separated from the bacteria by advanced bioengineering means and purified to obtain high-purity recombinant human interferon α 2b, recombinant human interferon α 2b injection is mostly in the forms of injection and freeze-dried powder injection in clinic and market, compared with the traditional freeze-dried powder injection, the injection has the advantages that freeze-drying is not needed in the production process, the production procedure is simplified, the production cost is saved, the use is convenient, re-dissolution is not needed before medication, direct injection is needed, the chance of secondary pollution is reduced, the currently used preparation is mainly injection, the main indications include chronic viral hepatitis, hairy cell leukemia, acute wet tumor and the like, the treatment period of patients is longer, generally half a year to a year, even longer treatment period is needed by nurses, the patients can be treated by the doctors, the patients can be treated by the injection frequently, and the hospital can not be treated by the traditional medicine administration method, and the patients can not be taken frequently.
The traditional injection adopts the packaging material in the ampoule bottle for decades, and the cassette bottle multi-dose pen injection combination mode is a new injection mode which is developed in recent years and can be used by patients independently and repeatedly, and the cassette bottle multi-dose pen injection mode is widely applied to insulin injection products, and compared with the ampoule bottle injection products, the cassette bottle multi-dose pen injection products have the following advantages: (1) the medicine bottle is not required to be subjected to irregular destructive opening treatment when in use, so that part of broken glass fragments can be prevented from entering the medicine liquid and causing damage to a human body along with the medicine liquid, (2) the medicine bottle can be prevented from being used by a disposable syringe when intravenous injection and intramuscular injection are carried out, the adverse effects on a patient caused by particles in the disposable syringe and the medicine liquid pollution caused by possible incomplete sterilization are eliminated, and medical wastes caused by the consumption of disposable syringe products can be greatly reduced, so that the environment is protected, and (3) the medicine liquid is prevented from being exposed in the air without cleanliness requirement when injection is carried out, and the particles and microorganisms in the air have the possibility of polluting the medicine liquid and causing potential harm to the patient; however, the opened multi-dose pen injection product is used for a plurality of times compared with other disposable medicine injection products, so that the times and time of exposing the medicine to the surrounding environment in the using process are increased, the production process, the formula, the safety and the stability of the multi-dose pen interferon injection product are required to be optimized, and the quality of the product can be guaranteed to be improved.
Therefore, aiming at the market demand, the invention further develops the interferon injection in the cartridge multi-dose pen type injection combined package.
Disclosure of Invention
The invention aims to provide an interferon injection packed by a card bottle multi-dose pen type injection combination, which has the advantages of optimizing a formula process and improving the quality of an interferon injection product, and solves the problem of insufficient administration mode of the existing interferon injection.
In order to achieve the aim, the invention provides the following technical scheme that the interferon injection solution packaged by the cassette bottle multi-dose pen type injection combination is any type of gene recombinant human interferons α, β and gamma.
Preferably, the interferon type is any one of recombinant human interferon α 1b, recombinant human interferon α 2b and recombinant human interferon α 2 a.
Preferably, the interferon type is recombinant human interferon α 2b type.
Preferably, the recombinant human interferon α 2b injection is prepared by taking a recombinant human interferon α 2b stock solution as a main active ingredient, adding a protective agent, a pH regulator, a stabilizer, a surfactant, a bacteriostatic agent and an osmotic pressure regulator according to a certain formula proportion, mixing, diluting, sterilizing and packaging.
Preferably, the concentration of the recombinant human interferon α 2b stock solution is 5 × 106IU/ml～3.0×107IU/ml, the protective agent is selected from one or a combination of more of albumin substances, the pH regulator is selected from one or a combination of more of phosphate buffer solution system, citrate buffer solution system and ascorbate buffer solution system, the stabilizer is selected from one or a combination of more of amino acids, saccharides and polyols, the surfactant is selected from one or a combination of more of polysorbate and poloxamer nonionic surfactants, the bacteriostatic agent is selected from one or a combination of more of benzyl alcohol, benzoic acid, phenol and m-cresol, the osmotic pressure regulator is selected from one or a combination of more of sodium chloride and glucose, the pH of the finished product of the interferon injection after subpackaging is 6.5-7.5, and the specification of the finished product of the interferon injection after subpackaging is 3000 ten thousand IU/3 ml/bottle, the minimum scale of the injection pen is 50 ten thousand IU per lattice, the maximum administration of one time is 12 lattices, namely 600 ten thousand IU, the adjustment of a doctor on the dosage in the treatment process is easily met, a patient can also select to gradually increase the administration amount from the minimum dosage, and the serious adverse reaction caused by overlarge first dosage of the traditional injection administration mode is avoided.
Preferably, the interferon injection is a liquid injection formulation packaged in a cartridge bottle.
Preferably, the interferon injection is administrated by subcutaneous or intramuscular injection by adopting a multi-dose pen type injector, and the dosage is controlled more accurately.
Preferably, the interferon injection can be used for treating various diseases such as viral hepatitis, upper respiratory tract virus infection, herpes zoster, condyloma acuminatum and the like caused by virus infection.
Preferably, each card type bottle interferon injection is stored at 2-8 ℃ for 3-5 weeks at most after being opened, and can be stored for at least 24 months at 2-8 ℃ in a dark place if not opened.
Preferably, the patient uses a multi-dose pen-type injector to realize self-accurate injection and administration under the guidance of a doctor, so that the interference of running and traveling inconvenience to treatment in a hospital is avoided, the influence on the normal life of the patient is eliminated, the accurate administration dose is realized, and the compliance of the patient and the treatment effect are greatly improved.
Compared with the prior art, the invention has the characteristics of reliable quality, convenient use, accurate medication, safety, environmental protection, good patient compliance and the like, and is specifically embodied as follows:
1. the invention relates to a cassette bottle package which is a novel packaging material of a medicine, is similar to an injector without a push rod and is equivalent to a bottle without a bottom, the front part of the bottle is provided with a syringe needle protected by rubber seal, the bottle mouth is sealed by a rubber plug aluminum cover, the tail part of the bottle is sealed by a rubber piston, the injection liquid of the cassette bottle package can be injected only by putting the cassette bottle and the syringe needle into a matched and reusable multi-dose pen type injector, glass scraps can not be generated in the whole injection process, the liquid medicine can not be transferred, can not be exposed in the air and can not be contacted with any part of the injector, thereby reducing the chance of secondary pollution, avoiding unsafe injection factors, being more convenient for using the injection agent packaged by the cassette bottle, obviously reducing the operation procedures for medical personnel to carry out injection and obviously reducing the labor intensity because the liquid medicine does not need to be transferred, thereby improving the labor efficiency and saving the human resources; the injection packed by the cassette bottle does not use a disposable injector when injection is carried out, thus saving raw materials and energy of the disposable injector, reducing medical waste, being beneficial to environmental protection and avoiding the problem of unsafe injection caused by repeated use of the disposable injector.
2. The invention can realize that the patient uses the multi-dose pen-type injector to realize self-injection administration under the guidance of the doctor's advice, avoids the interference of the running and the travel inconvenience of the hospital to the treatment, eliminates the influence on the normal life of the patient, realizes accurate administration dose, and greatly improves the compliance of the patient and the curative effect of the treatment.
3 the injection method of the invention has simple and easy operation and low manufacturing cost, and is suitable for large-scale industrial production and application.
Drawings
FIG. 1 is a trend chart of biological activity of component screening of recombinant human interferon α 2b injection preparation;
FIG. 2 is a trend chart of biological activities of component optimal concentration screening of recombinant human interferon α 2b injection preparation;
FIG. 3 is an appearance diagram of a cassette bottle of recombinant human interferon α 2b injection;
FIG. 4 is a pH variation trend curve of a recombinant human interferon α 2b injection finished product long-term (2-8 ℃) stability test;
FIG. 5 is a curve of the change trend of biological activity of a recombinant human interferon α 2b injection finished product in long-term (2-8 ℃) stability test;
FIG. 6 is a block diagram of the components of a multiple dose injection of rIFN α 2b injectate;
figure 7 recombinant human interferon α 2b injection solution multiple dose injection administration steps.
Detailed Description
The technical solutions in the embodiments of the present invention will be clearly and completely described below with reference to the drawings in the embodiments of the present invention, and it is obvious that the described embodiments are only a part of the embodiments of the present invention, and not all of the embodiments. All other embodiments, which can be derived by a person skilled in the art from the embodiments given herein without making any creative effort, shall fall within the protection scope of the present invention.
Referring to fig. 1-7, a card-type bottle multi-dose pen-type injection combination packaged interferon injection, wherein the interferon is any one of the types of genetically recombinant human interferons α, β and gamma;
the interferon type is any one of recombinant human interferon α 1b, recombinant human interferon α 2b and recombinant human interferon α 2 a;
the interferon type is recombinant human interferon α 2b type;
the recombinant human interferon α 2b injection is prepared by taking a recombinant human interferon α 2b stock solution as a main active ingredient, adding a protective agent, a pH regulator, a stabilizer, a surfactant, a bacteriostatic agent and an osmotic pressure regulator according to a certain formula proportion, mixing, diluting, sterilizing and packaging;
the concentration of the recombinant human interferon α 2b stock solution is 5 × 106IU/ml～3.0×107IU/ml, the protective agent is selected from one or a combination of a plurality of albumin substances, the pH regulator is selected from one or a combination of a plurality of phosphate buffer solution systems, citrate buffer solution systems and ascorbate buffer solution systems, the stabilizer is selected from one or a combination of a plurality of amino acids, saccharides and polyols, the surfactant is selected from one or a combination of a plurality of polysorbate and poloxamer nonionic surfactants, the bacteriostatic agent is selected from one or a combination of a plurality of benzyl alcohol, benzoic acid, phenol and m-cresol, the osmotic pressure regulator is selected from one or a combination of a plurality of sodium chloride and glucose, the pH of the finished interferon injection after subpackaging is 6.5-7.5, the specification of the finished interferon injection after subpackaging is 3000 ten thousand IU/3 ml/bottle, the minimum scale of the injection pen is 50 IU per lattice, the maximum dose of one dose is 12 cells, namely 600 ten thousand IU, so that the adjustment of a doctor on the dose in the treatment process is more easily met, a patient can also select to gradually increase the dose from the minimum dose, and the serious adverse reaction caused by overlarge first dose in the traditional injection administration mode is avoided; albumin, also called albumin, is the highest in human or animal plasmaThe serum albumin is applied to a pharmaceutical preparation, particularly a biotechnological drug injection preparation, and mainly has the functions of helping to maintain the biological activity of a biotechnological drug, reducing the adsorption of the container wall to the biotechnological drug and regulating the osmotic pressure of the biotechnological drug, the albumin can be selected from animal serum albumin such as bovine serum albumin or human serum albumin, the human serum albumin is generally considered to be a substance which is substantially nontoxic and nonirritating, the albumin is generally used for a protein prescription at a low concentration of 0.003 percent, the albumin is used as a protein stabilizer for injecting drugs at a concentration of 1 to 5 percent, except for nausea, vomiting, increased salivary secretion, cold and fever reactions, adverse reactions are uncommon, eruptions and skin rash are reported, allergic reactions also include anaphylactic tremor, the human serum albumin is used for intestinal tract for replacing the volume of plasma and treating serious loss, the albumin is considered to be refrigerated and fever reaction, the human serum albumin is selected from a polyvalent phosphate buffer solution of 0.7 to 365, the human serum albumin is preferably selected from a polyvalent phosphate buffer solution of 0.7 to 365, the human serum albumin is selected from a polyvalent phosphate buffer solution of a polyvalent alcohol buffer for reducing the serum albumin, the serum albumin buffer solution of the serum albumin is selected from a polyvalent alcohol buffer solution of the trehalose buffer solution of the invention, the inventionThe composition is characterized in that the composition is prepared from amino acid and histidine, more preferably, the stabilizing agents are sucrose and methionine, in the formula of a recombinant human interferon α b injection solution preparation, the concentration of sucrose is preferably 5.0-20.0 g/L, the concentration of methionine is preferably 2.0-5.0 g/L, the surfactant can reduce the surface tension of a protein solution, inhibit aggregation, precipitation and adsorption of proteins on a hydrophobic surface, or inhibit chemical degradation of proteins, the composition is preferably poloxamer 188 and polysorbate 80, more preferably, the composition is poloxamer 188, in the formula of a recombinant human interferon α b injection solution preparation, the composition is preferably 2.0-5.0 g/L, the benzyl alcohol has stronger bacteriostatic activity on gram-positive bacteria, has extremely weak bacteriostatic activity on gram-negative bacteria and fungi, has a narrow bacteriostatic spectrum, the benzyl alcohol is required to have stronger bacteriostatic efficacy in an acidic environment with pH being less than pH 5, in an alkaline environment with pH being more than pH 8, the composition is not required to be used as a bacteriostatic agent, the composition is suitable for reducing the toxicity of a bacteriostatic agent, and is suitable for a bacteriostatic human formaldehyde injection, when the composition is used as a bacteriostatic, the composition is prepared from cresol, the composition is prepared from formaldehyde, the cresolThe concentration of m-cresol is 0.15-0.3% and can be used as bacteriostatic preservative for intramuscular, subcutaneous and intradermal injection formulations according to the handbook of pharmaceutic adjuvants (sixth edition), the concentration in the prescription of the recombinant human interferon α 2b injection preparation is preferably 1.8-3.0 g/L, the concentration of sodium chloride is used as a solvent for regulating osmotic pressure, and the concentration in the prescription of the recombinant human interferon α 2b injection preparation is preferably 0.5-1.5 g/L;
the interferon injection is a liquid injection formulation packaged by a cassette bottle;
the interferon injection adopts a multi-dose pen type injector to carry out subcutaneous or intramuscular injection administration, and the dose control is more accurate; different dosages can be used according to patients with different body weights, and doctors can adjust the dosage and treatment scheme at any time according to the progress of the disease course, so that the doctor can write medical advice more easily and the patients can use the medicine more clearly;
the interferon injection can be used for treating viral hepatitis, upper respiratory tract virus infection, herpes zoster, condyloma acuminatum, etc. caused by virus infection;
after being opened, each card-type bottle of interferon injection is stored at 2-8 ℃ for 3-5 weeks at most, and if not opened, the card-type bottle of interferon injection can be stored for at least 24 months under the condition of being stored at 2-8 ℃ in a dark place, so that the card-type bottle of interferon injection has good stability;
under the guidance of a doctor, a patient uses a multi-dose pen-type injector to realize self-accurate injection and administration, so that the interference of running and traveling inconvenience to treatment in a hospital is avoided, the influence on the normal life of the patient is eliminated, the administration dosage is accurate, and the compliance of the patient and the treatment effect are greatly improved;
the invention relates to a cassette bottle package which is a novel packaging material of a medicine, is similar to an injector without a push rod and is equivalent to a bottle without a bottom, the front part of the bottle is provided with a syringe needle protected by rubber seal, the bottle mouth is sealed by a rubber plug aluminum cover, the tail part of the bottle is sealed by a rubber piston, the injection liquid of the cassette bottle package can be injected only by putting the cassette bottle and the syringe needle into a matched and reusable multi-dose pen type injector, glass scraps can not be generated in the whole injection process, the liquid medicine can not be transferred, can not be exposed in the air and can not be contacted with any part of the injector, thereby reducing the chance of secondary pollution, avoiding unsafe injection factors, being more convenient for using the injection agent packaged by the cassette bottle, obviously reducing the operation procedures for medical personnel to carry out injection and obviously reducing the labor intensity because the liquid medicine does not need to be transferred, thereby improving the labor efficiency and saving the human resources; the injection packed by the cassette bottle does not use a disposable injector when injection is carried out, so that the raw materials and energy sources of the disposable injector are saved, medical waste is reduced, the environment is protected, and the problem of unsafe injection caused by repeated use of the disposable injector can be avoided;
the invention can realize that the patient uses the multi-dose pen-type injector to realize self-injection administration under the guidance of the doctor's advice, avoids the interference of the running and the inconvenience of going to and from the hospital to the treatment, eliminates the influence on the normal life of the patient, realizes accurate administration dosage, and greatly improves the compliance of the patient and the curative effect of the treatment;
the injection method of the invention has simple and easy operation and low manufacturing cost, and is suitable for large-scale industrial production and application;
the first embodiment is as follows:
prescription screening of recombinant human interferon α 2b injection preparation
The interferon α 2b protein component is in a liquid environment, and has relatively poor stability, so that liquid preparation prescription screening is required, protein denaturation, degradation and inactivation are delayed to the maximum extent, the stability, safety and effectiveness of the preparation in the storage process are ensured, and the effective period of the preparation is prolonged as far as possible.
Protective agents, stabilizing agents, surfactants, pH regulators, osmotic pressure regulators and bacteriostats are usually added into the protein stabilizing preparations, and for the recombinant human interferon α 2b injection, the selection of the components of the prescription of the preparation has two starting points, namely (1) the pH and the osmotic pressure of the liquid environment of the preparation are maintained within a reasonable range, and (2) the protein component of the recombinant human interferon α 2b in the preparation is kept stable and the reduction of the biological activity of the protein component is delayed.
(ii) Components of protective Agents and optimum concentration Range screening
The protective agent is selected from one or a combination of several kinds of albumins, the albumins can be selected from animal serum albumins, such as bovine serum albumin or human serum albumin, the human serum albumin is generally considered as a substance which is basically nontoxic and nonirritating, the albumins are generally used for protein prescription at a low concentration of 0.003%, a concentration of 1% -5% is used as a protein stabilizer of an injection medicament, besides nausea, vomiting, increased salivary secretion, cold and fever reactions, adverse reactions are not common, rubella and rash are reported, allergic reactions are possible, allergic tremor is also included, the human serum albumin is used for intestinal tract to replace plasma volume and treat the deletion of severe acute albumin, so the invention preferably selects the human serum albumin as the protective agent in order to reduce immunogenicity, the content of the human serum albumin in a recombinant human interferon α 2b stock solution is 1% -5%, and the optimal concentration range is preferably selected between 10 g/L-20 g/L.
(II) component and optimum concentration range screening of pH regulator
The pH regulator is selected from one or a combination of a plurality of phosphate buffer solution systems, citrate buffer solution systems and ascorbate buffer solution systems, and the buffer system of the stock solution of the recombinant human interferon α 2b is 0.05-0.1M phosphate buffer solution with pH of 6.5-7.5, so as to avoid increasing the complexity of the production process and ensure the consistency of the stock solution buffer system and a preparation prescription system, the phosphate buffer system is preferentially selected as the pH regulator in the invention for dissolving and diluting products and adjusting the pH value of the products, and the phosphate buffer solution with pH of 6.5-7.5 is preferentially selected in the optimal concentration range of the prescription of the recombinant human interferon α 2b injection preparation.
(III) component and optimum concentration range screening of stabilizer, surfactant
Performing two-step screening to determine components and optimal concentration ranges of the stabilizer and the surfactant, and performing the first-step component screening; and the second step of component optimal concentration combination screening.
(1) Component screening
The stabilizer is selected from one or more of amino acids, saccharides and polyols, the saccharides and the polyols belong to nonspecific protein stabilizers or protective agents and are used for stabilizing or protecting active ingredients of biological products and preventing the active ingredients from being degraded or inactivated, and because reducing sugar and the amino acids have interaction, the saccharides preferentially select sucrose and trehalose as screening objects of components of a preparation formula; the polyalcohol preferentially selects glycerol and mannitol as screening objects of the components of the preparation prescription; the amino acids are preferably methionine and histidine as the screening objects of the prescription components of the preparation.
The surfactant is selected from one or more of polysorbate and poloxamer nonionic surfactant, and can reduce the surface tension of protein solution, inhibit aggregation, precipitation and adsorption of protein on hydrophobic surface, or prevent chemical degradation of protein, so poloxamer 188 and polysorbate 80 are preferably selected as screening objects of formulation components of the preparation.
Sucrose, trehalose, glycerol and mannitol of polyols, methionine and histidine of amino acids and poloxamer 188 and polysorbate 80 of surfactants are selected as screening objects of preparation components to carry out a single-component accelerated screening experiment, namely, 0.05-0.1M PB buffer solution with pH 6.5-7.5 is used for diluting interferon stock solution to the concentration of 1000 ten thousand IU/ml to obtain base solution, the base solution is used for respectively preparing the single-component preparation, the concentration of the component in each single component is 2g/l, each prepared preparation solution is subjected to filtration sterilization and then is respectively filled into Ep tubes, the Ep tubes are placed in an incubator at 37 ℃ in a dark place, sampling is carried out on time for biological activity detection, stabilizer components having a stabilizing effect on interferon α 2b protein are preliminarily selected by comparing the change trend of the biological activity of the interferon α 2b protein component after each stabilizer component is added, the design of the components is shown in Table 1, and the screening results of the components are shown in Table 2.
TABLE 1 design of component Screen
TABLE 2 results of component screening
The analysis of the screening results of the components shows that 6 components, namely sucrose, trehalose, methionine, histidine, poloxamer 188 and polysorbate 80, can play a relatively obvious stabilizing role in the recombinant human interferon α 2b protein component by adding one component, namely the 6 components, sucrose, trehalose, methionine, histidine, poloxamer 188 and polysorbate 80, and the reduction trend of the biological activity of the interferon in a preparation solution containing the 6 protective agent components is lower than that of an interferon protein solution without adding the stabilizer component in a visual effect on the detection data and the activity change trend curve, the addition of glycerol and mannitol does not play a very obvious stabilizing effect on the biological activity of the interferon, the activity curve of the interferon solution without adding the stabilizer component is similar to that of the similar components, the stabilizing effect of the interferon protein is not difficult to see, the protecting effects of sucrose and trehalose are similar to that of methionine and histidine are good, and the poloxamer 188 is good than that of polysorbate 80, so that the stabilizing effect of the components and the difference of the stabilizing effect of the methionine and the final concentration of the amino acid in the preparation of the same components are comprehensively considered, and the final concentration of the poloxamer 188 is selected as the poloxamer 188.
(2) Screening of optimum concentration ranges of Components
According to the screening results of the components of the stabilizer and the surfactant, the components of the stabilizer and the surfactant which have the stabilizing effect on the protein component of the interferon α 2b are determined, and the concentration range of the single component is screened, namely, different amounts of the single stabilizer and the surfactant are respectively added into base liquid to prepare various preparations with different concentrations of the single component, the prepared preparation solutions are respectively filled into Ep tubes after filtration and sterilization, the Ep tubes are placed in an incubator at 37 ℃ in a dark place, the samples are sampled at regular time for biological activity detection, and the influence of the components of the stabilizer and the surfactant on the change trend of the biological activity of the protein component of the interferon α 2b is compared by combining with the partial detection results in the first-step screening, the optimal concentration ranges of the components of the single stabilizer and the surfactant are screened, the screening design of the optimal concentration ranges of the components is shown in table 3, and the screening results of the optimal concentration ranges of the components are shown in table 4.
TABLE 3 design of optimum concentration screening of Components
TABLE 4 screening results for optimum concentration of Components
The result analysis of the component optimum concentration screening combines the partial results of the first round of component screening, and the analysis of the biological activity change trend chart of the component optimum concentration screening shown in the table 4 and the component optimum concentration screening shown in the figure 2 shows that the protective effect is better when the sucrose is in the range of 5.0-20.0 g/L, the protective effect is better when the methionine is in the range of 2.0-5.0 g/L, and the protective effect is better when the poloxamer 188 is in the range of 2.0-5.0 g/L;
in conclusion, in the formula of the recombinant human interferon α 2b injection preparation, the preferred stabilizers are sucrose and methionine, the preferred concentration range of sucrose is 5.0-20.0 g/L, the preferred concentration range of methionine is 2.0-5.0 g/L, the preferred surfactant is poloxamer 188, and the preferred concentration range is 2.0-5.0 g/L.
(IV) component and optimum concentration range screening of bacteriostatic agent
The recombinant human interferon α 2b injection is a multi-dose liquid preparation, and a single medicine can meet the requirement of multiple times of administration, so in order to ensure that the preparation is not polluted by microorganisms in the use process after being opened, a certain concentration of bacteriostatic agent needs to be added into the liquid preparation to ensure the sterile state of the preparation in the use process.
The selection of the ideal bacteriostatic agent follows the following principle: (1) the physical and chemical properties of the bacteriostatic agent are stable; (2) the solubility of the bacteriostatic agent should be sufficiently high that at least the dissolved part of the bacteriostatic agent should be able to achieve an effective bacteriostatic concentration; (3) the antibacterial spectrum is wide, and the antibacterial power is strong; (4) no harm to human body in the effective bacteriostatic concentration range; (5) the bacteriostatic agent has no interaction with the medicinal components and auxiliary materials in the preparation.
The bacteriostatic agent is selected from one or a combination of more of benzyl alcohol, benzoic acid, phenol and m-cresol.
The benzyl alcohol has strong antibacterial activity to gram-positive bacteria and gram-negative bacteria and fungi.
The activity is very weak, the antibacterial spectrum is narrow, the antibacterial effect of the benzyl alcohol is strongest in an acidic environment with the pH value less than 5, the antibacterial activity is almost not generated in an alkaline environment with the pH value more than 8, in addition, the benzyl alcohol is unstable and is easy to be oxidized into benzaldehyde and anisole, the preparation is a liquid injection, the pH value of a buffer system is 6.5-7.5, and the pH value is neutral and alkaline, so the benzyl alcohol is not suitable to be selected as the antibacterial agent of the recombinant human interferon α 2b injection in consideration of the self characteristics of the benzyl alcohol and the combination of the self attributes of the preparation.
The solubility of the benzoic acid in water is less than 0.29%, undissociated molecules of the benzoic acid have strong bacteriostatic action, so that the bacteriostatic effect in an acidic solution is better, the most suitable pH value for bacteriostasis is 4, the dissociation degree is increased when the pH value of the solution is increased, and the bacteriostatic effect is reduced, therefore, the benzoic acid is not suitable to be used as a bacteriostatic agent of the recombinant human interferon α 2b injection.
Phenol has strong bacteriostatic effect but also has strong corrosivity and toxicity, and phenol is suitable for acidic liquid medicine, and alkaline solution greatly reduces the bacteriostatic effect, so phenol is not suitable to be used as the bacteriostatic agent of the recombinant human interferon α 2b injection.
The metacresol has wide bacteriostatic spectrum, strong bacteriostatic activity, is similar to phenol, and has weaker corrosivity and toxicity than phenol, so that the metacresol is preferentially selected as the bacteriostatic agent of the recombinant human interferon α 2b injection by combining the characteristics of the preparation and comparing the performances of various bacteriostatic agents.
Any bacteriostatic agent has certain toxicity, so the bacteriostatic agent amount in the preparation is the minimum effective amount, and meanwhile, in order to ensure the medication safety, the effective concentration of the bacteriostatic agent in the finished preparation is lower than the concentration harmful to human bodies.
According to the handbook of pharmaceutical excipients (sixth edition), when the concentration of m-cresol is 0.15-0.3%, the metacresol can be used as an antibacterial preservative for intramuscular, subcutaneous and intradermal injection formulations, and the effective antibacterial concentration of m-cresol is screened according to the guideline of the efficacy inspection method of the X VII A antibacterial agent (preservative) in the appendix X VII A pharmacopoeia of the three parts (2015 year edition) of the pharmacopoeia of the people's republic of China.
(1) Preparation of bacterial liquid
Inoculating fresh cultures of Escherichia coli, staphylococcus aureus and pseudomonas aeruginosa into a trypticase soy agar culture medium, and culturing for 24 hours at 30-35 ℃; inoculating a fresh culture of Candida albicans into a glucose agar culture medium, culturing for 48 hours at 20-25 ℃, adding a proper amount of 0.9% sterile sodium chloride solution to elute the culture on the surface of the agar, sucking out the bacterial suspension to a sterile test tube, adding a proper amount of 0.9% sterile sodium chloride solution, and preparing the bacterial content of about 10 per 1ml by a turbidimetric method8Bacterial suspension of CFU.
Inoculating a fresh culture of Aspergillus niger to a Sasa dextrose agar culture medium, culturing at 23-28 ℃ for 5 days, adding 3-5 ml of 0.9% sterile sodium chloride solution containing 0.05% (ml/ml) polysorbate 80, eluting spores, sucking the spore suspension out of a sterile test tube, adding a proper amount of 0.9% sterile sodium chloride solution containing 0.05% (ml/ml) polysorbate 80, and preparing the spore suspension with the spore content of about 10 per 1ml by a turbidimetric method8CFU spore suspension.
(2) Inoculation of test article
According to the screening result of a preparation prescription, 5 preparations with the m-cresol concentration of 1.5g/l, 1.8g/l, 2.0g/l, 2.5g/l and 3.0g/l are respectively prepared to serve as a test sample, the prepared 1 preparation is divided into 5 parts, staphylococcus aureus, pseudomonas aeruginosa, escherichia coli, candida albicans and aspergillus niger suspension are respectively inoculated, the inoculation amount of each ml of the test sample is 105-106 CFU, the volume of the inoculated bacterial liquid is not more than 0.5-1% of the volume of the test sample, the test bacteria in the test sample are fully mixed to be uniformly distributed, then the test sample is placed at 20-25 ℃ and stored in the dark, and the other 4 preparations are operated by the same method.
(3) Viable bacteria count assay
Sampling at the time interval specified in the table immediately after inoculation (0) and the following table, sampling 1ml (25 parts in total) of each sample, respectively carrying out 10-fold serial dilution by using sterile sodium chloride-peptone buffer solution with pH7.0 for later use, respectively adding 1ml of each sample with the concentration of not more than 100CFU after dilution into a sterile plate, respectively injecting 15-20 ml of tryptone soy peptone agar medium or Sabouraud's dextrose agar medium melted at the temperature of not more than 45 ℃, preparing 2 inoculated plates in parallel, uniformly mixing, solidifying, placing for 3 days (tryptone soy peptone agar medium) or 5 days (Sabouraud's dextrose agar medium) for culture at the temperature of 30-35 ℃ or 5 days (Sabouraud ' dextrose agar medium) for counting, replacing the sample solution with the diluent for carrying out a negative control test, wherein the negative control test needs to grow aseptically.
The number of bacteria added to each test bacteria in 1ml of the test sample and the number of bacteria in each interval time were calculated from the results of the measurement of the number of bacteria, and converted into lg.
The injection belongs to 1 type of test products according to the product classification principle in the "appendix X VII A bacteriostatic agent (preservative) efficacy inspection method guiding principle" of the three parts (2010 edition) of pharmacopoeia of the people's republic of China.
TABLE 5 bacteriostatic efficacy judgment standard table for bacteriostatic agent
Note: in the table, "no increase" means that the test bacteria were increased by a value of not more than 0.5lg for the previous measurement time.
The test results are as follows
TABLE 61.5 g/l M-cresol bacteriostatic effect test results (in lg value)
TABLE 71.8 g/l M-cresol bacteriostatic effect test results (in lg value)
TABLE 82.0 g/l M-cresol bacteriostatic efficacy test results (in lg value)
TABLE 92.5 g/l M-cresol bacteriostatic efficacy test results (in lg value)
TABLE 103.0 g/l M-cresol bacteriostatic efficacy test results (in lg value)
And (5) judging a result: according to the corresponding requirements of the instruction principle of the ' appendix X VII A bacteriostatic agent (preservative) efficacy inspection method ' of the three parts (2010 edition) of the pharmacopoeia of the people's republic of China, the efficacy of the bacteriostatic agent is evaluated according to the reduction degree of the bacterial count lg value of each interval time relative to the initial value (the bacterial count lg value at 0), the test result is subjected to division according to the reduction rule of effective numbers, 1 effective number after the decimal point is reserved, and the result meets the requirement of a ' bacteriostatic agent bacteriostatic efficacy judgment standard table ' so that the bacteriostatic efficacy of the product can be judged to meet the requirements.
As shown in the test results in tables 6 to 10, the results of the above criteria indicate that the bacteriostatic efficacy is satisfied with the specification when the concentration of m-cresol is 1.8g/l, 2.0g/l, 2.5g/l, or 3.0g/l, and therefore, the optimal concentration range of m-cresol in the formulation of the recombinant human interferon α 2b injection preparation is preferably 1.8-3.0 g/L.
(V) component and optimum concentration range screening of osmotic pressure regulator
The osmotic pressure regulator is selected from one or more of sodium chloride and glucose, and the sodium chloride is preferably selected as a solvent for regulating the osmotic pressure in the invention in consideration of the requirement of the osmotic pressure of the preparation.
Calculated according to the formula, the theoretical osmolality of 0.05-0.1 MPB is about 100-200 mOsmol/kg, the theoretical osmolality of sucrose is about 15-58 mOsmol/kg for 5.0-20.0 g/L, the theoretical osmolality of methionine is about 12.5-31.25 mOsmol/kg for 2.0-5.0 g/L, poloxamer 188 is a block polymer (polyether) of ethylene oxide and propylene oxide, is a novel high molecular nonionic surfactant, has a molecular weight of more than 1000-7000, and is huge and unfixed, so that the generated osmolality can be basically ignored, and the osmolality of normal human blood is 280-310 mOsmol/kg.
In order to screen the optimal concentration range of sodium chloride for regulating osmotic pressure, 5 parts of recombinant human interferon α 2b injection preparation are respectively prepared, wherein the amounts of protective agents human serum albumin, stabilizing agent methionine and sucrose, surfactant poloxamer 188, pH regulator phosphate buffer solution and bacteriostatic agent m-cresol are fixed, the concentrations of sodium chloride are respectively 0.1g/l, 0.5g/l, 1.0g/l, 1.5g/l and 2.0g/l, the osmotic pressure molar concentrations of the 5 parts of recombinant human interferon α 2b injection preparation are respectively detected, and the detection results are shown in Table 11.
TABLE 11 screening of optimum concentration of sodium chloride
As can be seen from the results in Table 11, the osmolality range is maintained between 280-310 mOsmol/kg when the concentration of NaCl ranges between 0.5-1.5 g/L, so that the optimal concentration range of NaCl in the formulation of the rIFN α 2b injection is preferably between 0.5-1.5 g/L to ensure that the osmolality of the formulation reaches the range of human blood osmolality.
(V) screening results of prescription components of the recombinant human interferon α 2b injection preparation and optimal concentration ranges of the components.
In summary, the screening results of the components of the prescription of the recombinant human interferon α 2b injection preparation include human serum albumin as a protective agent, methionine and sucrose as stabilizers, poloxamer 188 as a surfactant, a phosphate buffer solution as a pH regulator, and m-cresol as a bacteriostatic agent, and the screening results of the optimal concentration ranges of the components are shown in Table 12.
TABLE 12 screening results of prescription components of the formulations and optimum concentration ranges of the components
Example two:
preparation of recombinant human interferon α 2b injection
The recombinant human interferon α 2b stock solution is prepared by the company, and all the auxiliary materials are commercially available.
(1) Determination of relative Density
Firstly, weighing the volumetric flask, then weighing the total weight of 100ml preparation and volumetric flask, wherein the difference between the former and the latter is the weight of 100ml preparation, cleaning and drying the volumetric flask, adding 100ml cooled water for injection in constant volume, weighing the total weight of 100ml water for injection and the volumetric flask, subtracting the weight of the volumetric flask to obtain the weight of 100ml water for injection, and obtaining the ratio of the weight of 100ml preparation to the weight of 100ml water for injection as the relative density (rho, kg/L) of the preparation.
(2) Preparation of semi-finished product
Adding water for injection to dissolve, then fixing the volume to the volume of the actual pre-prepared semi-finished product (V, L), and stirring to mix evenly.
Taking 3 sterilized 10L bottles, respectively adding 10% of injection water to the volume of a pre-prepared semi-finished product, calculating the amount of the raw material of the recombinant human interferon α 2b and the using amount of each component according to a certain preparation ratio according to the screening results of components and the optimal concentration range of each component in a formula of the recombinant human interferon α b injection liquid preparation, weighing, adding weighed poloxamer 188 into a first 10L bottle containing the injection water, shaking gently for 15 minutes to fully dissolve the components, accurately weighing m-cresol by using a measuring cylinder as a container and adding the m-cresol into a second 10L bottle containing the injection water, repeatedly flushing the measuring cylinder for 3 times by using the solution in the 10L bottle, pouring the flushing liquid into the 10L bottle each time to ensure that no m-cresol remains in the measuring cylinder, shaking gently for 15 minutes to fully dissolve the m-cresol, weighing other weighed phosphate buffer solutions (disodium hydrogen phosphate, sodium dihydrogen phosphate), sucrose, methionine and sodium chloride, adding the three bottles containing the L and shaking to ensure that the three bottles contain the injection water together.
Adding cooled injection water with the volume of about 50% of that of a pre-prepared semi-finished product into a liquid preparation tank under a liquid preparation interlayer flow hood, sequentially adding the three solutions in 10L bottles, starting the stirring function of the liquid preparation tank, stirring for 10 minutes, accurately measuring the amounts of the recombinant human interferon α 2b raw liquid and the human serum albumin by using a measuring cylinder, adding the recombinant human interferon 352 b raw liquid and the human serum albumin into the liquid preparation tank, accurately adding the injection water to the actually prepared semi-finished product by using a weighing module of the liquid preparation tank to fix the weight (m is V × 110% × rho), and stirring for 15 minutes.
(3) Sterilizing filtration
1) The liquid inlet silicone tube on the filter is connected with a liquid supply pipeline of the liquid distribution tank, a filtrate pipeline is sent into a buffer cabin of the aseptic operation isolator through a pipeline hole of the aseptic operation isolator, the pipeline hole is sealed, the liquid inlet pipeline connected to the semi-finished tank is sent into the buffer cabin of the aseptic operation isolator through the pipeline hole of the aseptic operation isolator, the pipeline hole is sealed, articles such as sample bottles and bottle plugs are put into the buffer cabin of the aseptic operation isolator through a buffer cabin door, the aseptic operation isolator VHP is opened, and the sterilization is carried out for 30-40 minutes.
2) The filter liquor pipeline connected to the filter and the pipeline hole connected between the main cabin and the buffer cabin are sent into the main cabin of the aseptic operation isolator after the semi-finished product tank liquid inlet pipeline is subjected to external packing, the pipeline hole is sealed, and articles such as sample bottles and bottle plugs are placed into the main cabin of the aseptic operation isolator through a door between the two cabins, the innermost layer package is removed, and the two pipeline buckles are connected.
3) Placing the semi-finished product tank on a weighbridge for zero clearing, opening a tank bottom valve of the liquid preparation tank, supplying a liquid valve, starting to perform sterilization filtration, observing upper and lower filter plates of a filter and an exhaust valve, wherein no liquid overflows to perform next operation, filtering the liquid in the liquid preparation tank into the sterilized semi-finished product tank to a pre-prepared semi-finished product volume, wherein the weight is (m is V × rho), closing a peristaltic pump, clamping a filter filtrate silicone tube by hemostatic forceps, and obtaining the barrel filtrate which is a recombinant human interferon α 2b injection semi-finished product, then performing semi-finished product verification, and performing next-step sub-packaging on qualified rear.
(3) Subpackaging finished products
Installing a filling system, fixing a rubber plug vibrating disc and an aluminum cover vibrating disc on an oscillator, evacuating air in a filling pipeline, starting filling equipment, debugging the filling quantity by using an electronic balance, filling a finished product into a cassette bottle after the finished product is qualified, wherein the filling speed is less than or equal to 30 counts/minute, weighing the filling quantity of the product every hour after the filling is started, weighing and calculating the filling quantity of each bottle according to the density (1.016g/ml) of a semi-finished product to be between 3.10ml and 3.30ml, the receiving quantity of each batch of the product to be between 5000 bottles and 6000 bottles, the final receiving quantity of the finished product after labeling and packaging to be between 4500 counts and 6000 counts, and the finished product is prepared into 3000 IU/3 ml/bottle, wherein an appearance diagram of the finished product (cassette bottle recombinant interferon α 2b injection) is shown in figure 3.
Example three:
stability study of recombinant human interferon α 2b injection finished product
Stability study of influence factors of (I) recombinant human interferon α 2b injection finished product
(1) Illumination stability study of recombinant human interferon α 2b injection influencing factor
The finished product of the recombinant human interferon α 2b injection is respectively stored for 5 days and 10 days under the illumination of 4500L x +/-500L x (25 +/-2 ℃), then all main quality indexes are detected, and the detection result is shown in table 13.
TABLE 13 stability examination results of factors affecting illumination of recombinant human interferon α 2b injection
Influencing factor-light stability survey summary: as can be seen from table 13, the detection results of the main quality indicators all meet the quality standard requirements, and are unchanged from the initial detection results, so that the quality indicators of the product are not significantly adversely affected by the strong light irradiation, but the product is still prevented from being exposed to the strong light irradiation environment for a long time in order to avoid the product from being affected by the chemical modification reactions such as oxidation and amidation which may occur when the product is exposed to the strong light.
(2) High temperature (40 +/-2 ℃) stability test of recombinant human interferon α 2b injection influencing factor
The recombinant human interferon α 2b injection finished product is placed at 40 +/-2 ℃ for 5 days and 10 days, and then the detection of the key investigation items is respectively carried out, and the detection results are shown in a table 14.
TABLE 14 stability test results of the factor of influence of the recombinant human interferon α 2b injection product at high temperature (40 + -2 deg.C)
The influence factor, namely the high temperature (40 +/-2 ℃) stability test summary, can be seen from table 14, the detection results of the appearance, the visible foreign matters, the pH and the biological activity all meet the requirements of quality standards, and have no difference with the initial detection result, the detection results of the appearance and the visible foreign matters are unqualified after the recombined human interferon α 2b injection is stored for 1 month under the condition of 40 +/-2 ℃, white precipitate substances which are visible to the naked eyes and can not be dispersed by shaking appear in the preparation, but the pH value of the preparation is not changed, the detection result of the biological activity (1.11 × 107IU/ml) still meets the requirements of the quality standards (0.80 × 107-1.50 × 107IU/ml), and has no great change compared with the initial detection result (1.18 × 107IU/ml), therefore, the influence of the ultra-high temperature on the stability of the protein in the preparation is large, and the protein polymerization and precipitation are easily caused, therefore, the long-term exposure of the product to the high temperature environment in the storage and the use process is avoided.
(3) The stability of the factor influencing high temperature (37 +/-2 ℃) of the recombinant human interferon α 2b injection is examined.
The finished product of the recombinant human interferon α 2b injection is placed at 37 +/-2 ℃ for 5 days, 10 days, 1 month and 2 months, then sampling and detection of key investigation items are carried out, and the detection results are shown in table 15.
TABLE 15 stability test results of high temperature (37 + -2 deg.C) for influencing factor of recombinant human interferon α 2b injection
Influence factors-high temperature (37 + -2 ℃) stability survey summary, as can be seen from Table 15, the detection results of appearance, visible foreign matters, pH and biological activity all accord with the quality standard requirements, and the detection results of all detection results have no difference with the initial detection results when 1 month is up, the sampling detection results after 2 months show that the biological activity is 0.89 × IU/ml, the detection results have larger reduction compared with the initial detection results (1.18 × IU/ml), other detection results have no difference with the initial detection results, the recombinant human interferon α b injection is sampled and detected after 3 months under the condition of 37 + -2 ℃, the detection results of appearance, visible foreign matters and biological activity are unqualified, white sediment substances which can be seen by naked eyes and can not be scattered appear in the preparation, the biological activity is 0.71 × IU/ml, the quality standard (0.3680 × -1.50 IU/ml) can not be met, but the pH value of the preparation is not changed, the influence on the high temperature stability is large, and the high temperature polymerization protein can be prevented from being used in the preparation, and even the high temperature inactivation is caused by the comprehensive storage process.
(II) accelerated (25 +/-2 ℃) stability test of recombinant human interferon α 2b injection finished product
The recombinant human interferon α 2b injection is placed at 25 +/-2 ℃, samples are taken periodically to detect key research items, and the detection results are shown in table 16.
TABLE 16 stability test results of the recombinant human interferon α 2b injection product accelerated (25 + -2 deg.C)
The summary of stability investigation at 25 +/-2 ℃ is shown in Table 16, that is, after the recombinant human interferon α 2b injection is placed at 25 +/-2 ℃ for 6 months, the detection results of the appearance, visible foreign matters, pH, osmotic pressure, biological activity, bacterial endotoxin, m-cresol content and poloxamer 188 content (main monitoring indexes) of three batches of products (S20190401, S20190502 and S20190503) are not changed compared with the initial detection results, which shows that the product has good stability, and can be stably stored for 6 months at 25 +/-2 ℃, but considering that the product is a recombinant protein biological product, long-term exposure to unconventional storage and transportation temperature conditions is avoided, so that the biological activity of protein components and the product effectiveness are better maintained.
(III) long-term (2-8 ℃) stability test of a recombinant human interferon α 2b injection finished product
The recombinant human interferon α 2b injection is placed at the temperature of 2-8 ℃, samples are taken periodically to detect key investigation items, and the detection results are shown in table 17.
Table 17, the long-term (2-8 ℃) stability test results of the recombinant human interferon α 2b injection finished product
The summary of long-term (2-8 ℃) stability examination is shown in Table 17, the recombinant human interferon α 2b injection is stored at 2-8 ℃, the periodic sampling is performed to detect the key examination items, the stability examination of 24 months has been completed, the appearance, visible foreign matters and pH detection results of three batches of products (S20150401, S20150402 and S20150403) are unchanged from the initial detection results, and the biological activity detection results are 0.92 × 107IU/ml、0.92×107IU/ml、0.88×107IU/ml, and initial test result of biological activity of three batches of products 1.17 × 107IU/ml、1.12×107IU/ml、1.23×107IU/ml is changed slightly, but the change range is not large, and the IU/ml is in the qualified range specified by the quality standard (0.80 × 10)7IU/ml～1.50×107IU/ml), the change trend curve of the pH and the biological activity detection result is shown in figure 4 and figure 5, and the result shows that the product has good stability at the temperature of 2-8 ℃ and can be stored for at least 24 months in a dark place for a long time.
(IV) observing the unsealing (2-8 ℃) stability of the finished product of the recombinant human interferon α 2b injection
After the recombinant human interferon α 2b injection is started, the injection is placed at the temperature of 2-8 ℃, samples are taken periodically to detect key research items, and the detection results are shown in table 18.
TABLE 18 stability test results of unsealing (2-8 ℃) of the recombinant human interferon α 2b injection
The stability of unsealing (2-8 ℃) is summarized, as can be seen from Table 18, after the recombinant human interferon α 2b injection is opened, the test sample is placed under the condition of 2-8 ℃ until each test result of the 35 th day meets the quality standard requirement, and after the batch preparations of S20190401, S20190502 and S20190503 are placed for 35 days, the biological activity test results are respectively 1.32 × 107IU/ml、1.22×107IU/ml、1.26×107IU/ml, and initial assay results (1.18 × 10)7IU/ml、1.23×107IU/ml、1.02×107IU/ml) has no obvious change, and in conclusion, the preparation can be stably stored for at least 35 days at the temperature of 2-8 ℃ in the using process, so that the medicine can be stored at the temperature of 2-8 ℃ in a dark place after being opened, and the safety and the effectiveness of the medicine can be ensured within the service life of 3-5 weeks.
Example four:
multi-dose injection administration step of recombinant human interferon α 2b injection
Both the cartridge and the multi-dose injection pen are commercially available.
Figure 6 shows the recombinant human interferon α 2b injection solution multiple dose injection administration of each components structure diagram
Figure 7 shows the steps of multi-dose injection administration of recombinant human interferon α 2b injection:
(1) taking out the recombinant human interferon α 2b injection from a refrigerator at 2-8 ℃, and balancing to room temperature.
(2) The pen cap of the multi-dose injection pen is pulled out, the drug bin is taken down in a rotating mode, the recombinant human interferon α 2b injection is placed in the drug bin, and the drug bin portion filled with the drug and the tail portion of the injection pen are screwed up through the middle connecting thread.
(2) The outer package of the injection needle and the protective cap at the front of the needle are pulled off, and the tap button at the tail of the multi-dose injection pen is rotated to align the scale value with 100.
(3) The injection pen is inverted, the needle point is upward, and the cock button at the tail part of the injection pen is pushed to remove air bubbles in the liquid medicine.
(4) Before injection, the skin of the injection site is locally sterilized by dipping 75% alcohol on a cotton swab, and a cock button at the tail of the injection pen is rotated to a scale value of the required injection amount (taking 100 ten thousand IU for injection). Considerations in injection site selection: subcutaneous injection suggests that the abdomen is selected and covered with a fist (no injection is performed within a range of 4 to 5cm around the umbilicus), and injection is performed at a distance of about one palm width on both sides of the umbilicus, and in other abdominal injections, the needle is easy to stick to the muscle, and the subcutaneous layer becomes thinner toward both sides of the body. The injection point is changed every time of injection, and multiple injections at the same point are avoided, so that local skin induration, lipoatrophy or influence on medicine absorption are avoided.
(5) After the alcohol is volatilized, the skin is pinched up by a thumb and a forefinger, the needle is inserted vertically and rapidly, after the needle is inserted, the liquid medicine is slowly injected at a constant speed by pressing a cock button at the tail part of the injection pen by the thumb, after the injection is finished, the injection key is still pressed by the thumb, and the needle head is rapidly pulled out along the needle inserting direction after being kept subcutaneously for 10-15 seconds. The needle hole can be pressed by a dry cotton swab for 30-40 seconds to prevent subcutaneous extravasated blood, and kneading or squeezing an injection point is avoided to prevent the influence on the absorption of the liquid medicine.
Although embodiments of the present invention have been shown and described, it will be appreciated by those skilled in the art that changes, modifications, substitutions and alterations can be made in these embodiments without departing from the principles and spirit of the invention, the scope of which is defined in the appended claims and their equivalents.
Claims (10)
1. An interferon injection packed by a cassette bottle multi-dose pen type injection combination is characterized in that the interferon is any type of gene recombinant human interferons α, β and gamma.
2. The interferon injection solution of claim 1, wherein the interferon type is any one of recombinant human interferon α 1b, recombinant human interferon α 2b and recombinant human interferon α 2 a.
3. The interferon injection solution in a cartridge bottle multi-dose pen type injection combination package according to claim 2, wherein the interferon type is recombinant human interferon α 2b type.
4. The interferon injection in the cartridge bottle multi-dose pen type injection combined package as claimed in claim 3, wherein the recombinant human interferon α 2b injection is prepared by taking a recombinant human interferon α 2b stock solution as a main active ingredient, adding a protective agent, a pH regulator, a stabilizer, a surfactant, a bacteriostatic agent and an osmotic pressure regulator according to a certain formula proportion, mixing, diluting, sterilizing and packaging.
5. The interferon injection solution of claim 4, wherein the concentration of the original solution of recombinant human interferon α 2b is 5 × 106IU/ml～3.0×107IU/ml, the protective agent is selected from one or a combination of more of albumin substances, the pH regulator is selected from one or a combination of more of a phosphate buffer solution system, a citrate buffer solution system and an ascorbate buffer solution system, the stabilizer is selected from one or a combination of more of amino acids, saccharides and polyols, the surfactant is selected from one or a combination of more of polysorbate and poloxamer nonionic surfactants, the bacteriostatic agent is selected from one or a combination of more of benzyl alcohol, benzoic acid, phenol and m-cresol, the osmotic pressure regulator is selected from one or a combination of more of sodium chloride and glucose, and the interferon injection after being subpackaged is preparedThe pH of the finished product of the interferon injection is 6.5-7.5, the specification of the finished product of the interferon injection after subpackage is 3000 ten thousand IU/3 ml/bottle, the minimum scale of an injection pen is 50 ten thousand IU per lattice, the maximum dosage of one time administration is 12 lattices, namely 600 ten thousand IU, the dosage adjustment of a doctor in the treatment process is easily met, a patient can also select to gradually increase the dosage from the minimum dosage, and the serious adverse reaction caused by overlarge first dosage of the traditional injection administration mode is avoided.
6. The cartridge multi-dose pen injection combination packaged interferon injection solution according to claims 1 to 5, wherein: the interferon injection is a liquid injection formulation packaged by a cassette bottle.
7. The cartridge multi-dose pen injection combination packaged interferon injection solution according to claims 1 to 6, wherein: the interferon injection adopts a multi-dose pen type injector to carry out subcutaneous or intramuscular injection administration, and the dose control is more accurate.
8. The cartridge multi-dose pen injection combination packaged interferon injection solution according to claims 1 to 7, wherein: the interferon injection can be used for treating various diseases such as viral hepatitis, upper respiratory tract virus infection, herpes zoster, condyloma acuminatum and the like caused by virus infection.
9. The cartridge multi-dose pen injection combination packaged interferon injection solution according to claims 1 to 8, wherein: after being opened, each card-type bottle of interferon injection is stored at 2-8 ℃ for 3-5 weeks at most, and if not opened, the card-type bottle of interferon injection can be stored for at least 24 months under the condition of being kept away from light at 2-8 ℃.
10. The cartridge multi-dose pen injection combination packaged interferon injection solution according to claims 1 to 9, wherein: under the guidance of a doctor, a patient uses a multi-dose pen-type injector to realize self-accurate injection and administration, so that the interference of running and traveling inconvenience to treatment in a hospital is avoided, the influence on the normal life of the patient is eliminated, the administration dosage is accurate, and the compliance of the patient and the treatment effect are greatly improved.
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