CN115177719A - Canine alpha interferon water injection formulation, preparation method and application thereof - Google Patents

Canine alpha interferon water injection formulation, preparation method and application thereof Download PDF

Info

Publication number
CN115177719A
CN115177719A CN202210906425.3A CN202210906425A CN115177719A CN 115177719 A CN115177719 A CN 115177719A CN 202210906425 A CN202210906425 A CN 202210906425A CN 115177719 A CN115177719 A CN 115177719A
Authority
CN
China
Prior art keywords
canine
interferon
alpha
water injection
alpha interferon
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Pending
Application number
CN202210906425.3A
Other languages
Chinese (zh)
Inventor
刘昕
赖强
王弋
罗维方
韩麒麟
郑飞
吴先戈
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Dongguan Bosheng Biological Technology Co ltd
Guangzhou Yuanbo Pharmaceutical Technology Co ltd
Original Assignee
Dongguan Bosheng Biological Technology Co ltd
Guangzhou Yuanbo Pharmaceutical Technology Co ltd
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Dongguan Bosheng Biological Technology Co ltd, Guangzhou Yuanbo Pharmaceutical Technology Co ltd filed Critical Dongguan Bosheng Biological Technology Co ltd
Priority to CN202210906425.3A priority Critical patent/CN115177719A/en
Publication of CN115177719A publication Critical patent/CN115177719A/en
Pending legal-status Critical Current

Links

Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • A61K38/17—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
    • A61K38/19—Cytokines; Lymphokines; Interferons
    • A61K38/21—Interferons [IFN]
    • A61K38/212—IFN-alpha
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
    • A61K47/36—Polysaccharides; Derivatives thereof, e.g. gums, starch, alginate, dextrin, hyaluronic acid, chitosan, inulin, agar or pectin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • 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
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/12—Antivirals
    • 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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • A61P37/02—Immunomodulators

Abstract

The invention belongs to the technical field of canine alpha interferon protective preparations, and particularly relates to a canine alpha interferon water injection preparation, and a preparation method and application thereof. The dog alpha interferon water injection comprises recombinant dog alpha interferon protein, an isotonic agent, a preservative, a stabilizer A, a stabilizer B and water for injection; the isotonic agent comprises more than one of PBS, citrate buffer solution, acetate buffer solution and L-histidine buffer solution; the stabilizer A comprises more than one of Tween 80, tween 20, arginine, dog serum albumin, mannitol, sorbitol and EDTA-disodium; the stabilizer B comprises more than one of dextran, beta-glucan, inulin and chitosan, can stabilize the spatial conformation of the canine alpha interferon molecule, stabilize the activity of the canine alpha interferon molecule and has an antioxidant effect; the dog alpha interferon water injection has the characteristics of stability, safety, convenience, effectiveness and the like, and has better application and popularization prospects.

Description

Canine alpha interferon water injection formulation, preparation method and application thereof
Technical Field
The invention belongs to the technical field of canine alpha interferon protective preparations, and particularly relates to a canine alpha interferon water injection preparation, and a preparation method and application thereof.
Background
The Interferon is a glycoprotein generated by virus or Interferon inducer (Interferon inducer) entering an organism to induce host cells, and has the biological properties of species specificity, broad action spectrum, harmlessness (no obvious toxicity or obvious antigenicity) and the like. Interferon is a broad-spectrum antiviral agent, and has inhibitory effect on both RNA virus and DNA virus. The interferon has the effects of resisting tumor, regulating immunity, resisting parasite and resisting fibrosis. The method for expressing and producing the interferon by genetic engineering means and related molecular biological technology is an economic and efficient method. At present, human recombinant alpha interferon has various formulations and various administration routes, such as freeze-dried powder injection, water injection, suppository, eye drop, buccal preparation, external gel preparation and the like, but the recombinant alpha interferon is widely used in clinic as freeze-dried powder formulation and water injection formulation, the two formulations play an important role in treating various diseases, and the freeze-dried powder formulation and the water injection formulation have wide application and good use effect in clinic.
The canine alpha interferon has the biological activities of broad-spectrum antivirus, immunoregulation, anti-tumor and the like. The antiviral activity is the main biological activity of canine alpha interferon, and is widely used for preventing and treating canine viral diseases, and comprises the following components: canine distemper, canine parvovirus enteritis, canine adenovirus, canine parainfluenza, canine coronavirus infection, canine herpesvirus infection, canine viral keratitis and other viral diseases. The animal source interferon and the human source interferon have certain difference in amino acid sequence, at present, the commonly used human source interferon IFN alpha 2b is composed of 166 amino acids, the isoelectric point is 5.5-6.8, the natural canine alpha interferon amino acid sequences in the literature reports are completely the same and are all proteins composed of 164 amino acids, and the isoelectric point is 6.0-6.4.
The interferon preparation for human use at present mainly comprises a freeze-dried powder type and a water injection type, and the freeze-dried powder type needs to be re-dissolved before use. The freeze-dried powder has good stability, but the process is complex, the production cost is high, the use is tedious, and the problem of whether insoluble particles exist during redissolution is particularly required to be noticed during use. The injection has the characteristics of rapidness and convenience in clinical use, and single-resistant medicine injection in protein injection for human and interferon injection for human and the like have good clinical use effects. Canine interferon-alpha is a protein, is easily influenced by various factors such as temperature, illumination, shaking, pH, dissolved oxygen, heavy metal ions, enzymes and microorganisms in an aqueous solution, and is easily oxidized, degraded and polymerized to denaturalize and inactivate. Because the amino acid sequences of the animal-derived interferon and the human-derived interferon have certain difference and the dog alpha interferon water injection does not have a corresponding product, the preparation formula of the dog alpha interferon water injection needs further research to ensure that the corresponding water injection achieves good use effect in clinical use.
Disclosure of Invention
In view of the above problems, the present invention aims to provide a canine alpha interferon water injection formulation, a preparation method and applications thereof.
The technical content of the invention is as follows:
the invention provides a dog alpha interferon water injection preparation, which comprises recombinant dog alpha interferon protein, an isotonic agent, a preservative, a stabilizer A, a stabilizer B and water for injection; the recombinant canine alpha interferon protein is a recombinant canine alpha interferon expressed by expression systems such as pronucleus, yeast or rod-shaped systems, or a mutant or fusion protein thereof;
the isotonic agent comprises more than one of PBS, citrate buffer solution, acetate buffer solution and L-histidine buffer solution, and is adjusted to a corresponding pH value to maintain the ionic strength of the canine alpha interferon in a solution system;
the dosage of the PBS is 0.01 to 0.08mM, preferably 0.02mM;
the dosage of the citrate buffer solution is 0.01 to 0.1mM, preferably 0.02mM;
the dosage of the acetate buffer solution is 0.01-0.1 mM, preferably 0.01mM;
the dosage of the L-histidine salt buffer solution is 0.01-0.1 mM, preferably 0.01mM;
the pH value of the solution system of the dog alpha interferon water injection dosage form is 6.0-7.5;
the preservative comprises one or two of benzyl alcohol and m-cresol, is low in content or even free, and has no obvious stimulation when being injected;
the dosage of the benzyl alcohol is 0-50 mg/mL, preferably 10mg;
the dosage of the m-cresol is 0-10 mg/mL, preferably 2mg;
the stabilizer A comprises more than one of Tween 80, tween 20, arginine, dog serum albumin, mannitol, sorbitol and EDTA-disodium;
the dosage of the Tween 80 is 0.01-2 mg/mL, preferably 0.1mg;
the dosage of the arginine is 0.1-20 mg/mL, preferably 2mg;
the dosage of the EDTA-disodium is 0.001-0.1 mg/mL, preferably 0.01mg;
the stabilizer B comprises more than one of dextran, beta-glucan, inulin and chitosan, can stabilize the spatial conformation of the canine alpha interferon molecule, stabilize the activity of the canine alpha interferon molecule and has an antioxidant effect;
the dosage of the dextran is 0.1-10 mg/mL, preferably 1mg;
the dosage of the beta-glucan is 0.1-10 mg/mL, and preferably 2mg.
The invention also provides a preparation method of the dog alpha interferon water injection preparation, which comprises the following steps: mixing the components of the dog alpha interferon water injection preparation, mixing the components of the dog alpha interferon water injection preparation to ensure that the final concentration of the recombinant dog alpha interferon protein is 200-2000 ten thousand IU/mL, then sterilizing and filtering by using a filter membrane with the aperture of 0.22 mu m, and storing at the temperature of 2-8 ℃.
The invention also provides application of the canine alpha interferon water injection preparation in the aspect of preserving the canine alpha interferon, wherein the canine alpha interferon water injection preparation is used for preserving the canine alpha interferon for more than 24 months, and the activity is stable during 24-month preservation.
The invention has the following beneficial effects:
the dog alpha interferon water injection preparation has high stability, can be stored at 2-8 ℃ after being placed, can maintain the stability for more than two years, and has stable activity without obvious reduction; the formed injection does not need freeze-drying, thereby simplifying the production procedure and saving the production cost; the use is convenient, re-dissolution is not needed before the administration, and the injection is directly carried out, so that the chance of secondary pollution is reduced; the injection contains a small amount of preservative, even no preservative, the physico-chemical properties of the liquid medicine are close to the physiological internal environment of normal body fluid of animals, and the irritation of the injection part is small; the water injection does not contain any protein composition (such as common animal albumin) extracted from animal sources except interferon, so that potential infection risk of external viruses is avoided; the formed water injection can be directly used in the valid period, and can be used for a plurality of times in a certain time after the bottle is opened.
Detailed Description
The present invention is further described in detail in the following detailed description with reference to specific embodiments, it is to be understood that these embodiments are merely illustrative of the present invention and are not intended to limit the scope of the invention, which is defined in the appended claims.
All the raw materials and reagents of the invention are conventional market raw materials and reagents unless otherwise specified.
Example 1
Dog alpha interferon water injection formulation
TABLE 1 Canine alpha interferon water injection formulation
Figure BDA0003772623230000051
The preparation of the recombinant canine alpha interferon can be prepared by a specific implementation scheme of a high-activity canine alpha interferon recombinant protein of a patent CN112079912B of the applicant, a preparation method and application thereof, wherein the recombinant canine alpha interferon or a mutant or fusion protein thereof is expressed by a prokaryotic expression system, a yeast expression system, a rod-shaped expression system or the like, and the adopted recombinant canine alpha interferon is prepared by the following steps.
Example 2
Dog alpha interferon water injection formulation
TABLE 2 Canine alpha interferon water injection formulation
Figure BDA0003772623230000052
Figure BDA0003772623230000061
Example 3
Dog alpha interferon water injection formulation
TABLE 3 Canine alpha interferon water injection formulation
Figure BDA0003772623230000062
Example 4
Dog alpha interferon water injection formulation
TABLE 4 Canine alpha interferon water injection formulation
Figure BDA0003772623230000063
Figure BDA0003772623230000071
Example 5
Dog alpha interferon water injection formulation
TABLE 5 Canine alpha interferon water injection formulation
Figure BDA0003772623230000072
Example 6
Dog alpha interferon water injection formulation
TABLE 6 Canine alpha interferon water injection formulation
Figure BDA0003772623230000073
Figure BDA0003772623230000081
The prepared dog alpha interferon water injection preparation is subjected to related performance detection, and the result is as follows:
1. appearance and clarity monitoring
In the monitoring period, the dog alpha interferon water injections of examples 1 to 6 are clear and transparent in appearance at 28 months, no turbidity is found, the dog alpha interferon water injections are qualified, and the appearance and clarity data are shown in table 7 in detail.
TABLE 7 appearance and clarity monitoring
Figure BDA0003772623230000082
Stability monitoring of pH
In the monitoring period, the dog alpha interferon water injections of examples 1 to 6 were all within 0.1 of the pH change range at 28 months, within a smaller reasonable deviation range, and were qualified, and the pH stability data are detailed in table 8.
TABLE 8 stability monitoring of 8 pH
Figure BDA0003772623230000091
3. Sterility testing
The sterility test of the canine interferon alpha water injections of examples 1 to 6 within 28 months during the monitoring period showed that the samples were all sterile and acceptable, and the sterility test data are detailed in table 9.
TABLE 9 sterility testing
Figure BDA0003772623230000092
Figure BDA0003772623230000101
4. Monitoring of Activity
The canine interferon alpha water injections according to examples 2 to 6 showed good stability at 24 months of activity during the monitoring period, except for example 1. In the case of the example group containing beta-glucan, the interferon activity was decreased to a lower degree than that in the case of the group containing no beta-glucan, and the case of 2mg of beta-glucan was better than that in the case of 1mg of beta-glucan. As shown in the dog alpha interferon water injections of examples 2 to 6, the modified buffer system, preservative, arginine, EDTA-disodium, etc. were effective in protecting the interferon activity from a significant decrease even at 28 months, with the beta-glucan component.
The activity change data are detailed in Table 10.
TABLE 10 monitoring of Activity (Unit: 10) 6 IU/mL)
Figure BDA0003772623230000102
Figure BDA0003772623230000111
5. Body temperature and stress observation of beagle dogs
6 healthy beagle dogs with the age of 8-10 weeks are selected, the safety test of subcutaneous injection beagle dogs is carried out on the dog alpha interferon preparation at the beginning 0 week, the body temperature change of the dogs before and 2 days after injection is measured, and the irritation and general state observation of the dogs after injection are observed at the same fixed time. At 24 months of sample monitoring, the same number of 8-10 week old healthy beagle dogs were selected and 24 months of canine interferon-alpha formulations were tested for safety of injection beagle dogs, as described above. No significant increase in body temperature, nor stress response, was observed in beagle dogs injected with the canine interferon-alpha formulations at week 0 and month 24, as detailed in Table 11.
TABLE 11 temperature and stress observations of beagle dogs injected
Figure BDA0003772623230000112
Figure BDA0003772623230000121
6. Antiviral effect
Healthy beagle dogs of 8-10 weeks of age were randomly divided into 8 groups of 5 dogs each. The interferon treatment components are shown in examples 1-6, and an offensive toxin control group and a blank control group are set, wherein offensive toxin of the offensive toxin control group is not treated, and offensive toxin and treatment of the blank control group are not carried out. A canine parvovirus infection model is established by using a canine parvovirus challenge method, each challenge group adopts a canine anus swab, a canine parvovirus colloidal gold detection test strip is used for detecting the detoxification condition, and the successful establishment of the model is judged when a typical canine parvovirus infection symptom appears. In the treatment group, interferon placed at 8 ℃ for 24 months is injected subcutaneously into neck at 40 ten thousand IU/kg body weight for 7 days, and the same amount of sterile PBS (0.02 mM) solution is injected into the toxicity-counteracting control group and the blank control group; after the injection is finished, the clinical symptom degree of each group of dogs is observed for 7 days, and the survival rate of each group of dogs is counted.
After the experiment is finished, except that the survival rate of example 1 without glucan is 40%, the survival rates of other components are all over 80%, and the canine parvovirus infection symptoms of the dogs surviving in the interferon treatment group are changed from the typical ones to slight ones; the control group of the virus attacking dogs seriously develop from the typical state and die completely, and the survival rate is 0; the blank control group dogs had no clinical symptoms and the survival rate of the dogs was 100%, as detailed in table 12. Experimental results show that the glucan-containing canine alpha interferon water injection preparation of each example group placed at 8 ℃ for 24 months has better antiviral effect in canine parvovirus infection models.
TABLE 12 clinical symptom degree and survival rate of each group of surviving dogs
Figure BDA0003772623230000122
Figure BDA0003772623230000131
Therefore, the dog alpha interferon water injection has the characteristics of high stability, small injection stimulation, effectiveness and the like, solves the technical problems that the dog alpha interferon is difficult to stabilize in an aqueous solution for a long time and the like, and has good application prospect due to the preparation of the dosage form.

Claims (9)

1. The dog interferon alpha water injection preparation is characterized by comprising recombinant dog interferon alpha protein, an isotonic agent, a preservative, a stabilizer A, a stabilizer B and water for injection;
the recombinant canine alpha interferon protein is a recombinant canine alpha interferon expressed by a prokaryotic, yeast or rod-shaped expression system or a mutant or fusion protein thereof;
the isotonic agent comprises more than one of PBS, citrate buffer solution, acetate buffer solution and L-histidine buffer solution.
2. The aqueous injectable canine interferon-alpha dosage form of claim 1, wherein the amount of PBS is 0.01 to 0.08mM;
the dosage of the citrate buffer solution is 0.01-0.1 mM;
the dosage of the acetate buffer solution is 0.01-0.1 mM;
the dosage of the L-histidine salt buffer solution is 0.01-0.1 mM.
3. The canine interferon alpha water injection formulation according to claim 1, wherein the solution system of the canine interferon alpha water injection has a pH of 6.0 to 7.5.
4. The aqueous injectable canine interferon-alpha dosage form of claim 1, wherein the stabilizer a comprises one or more of tween 80, tween 20, arginine, canine serum albumin, mannitol, sorbitol, and EDTA-disodium.
5. The aqueous injectable canine interferon-alpha dosage form of claim 4, wherein the amount of tween 80 is 0.01 to 2mg/mL;
the dosage of the arginine is 0.1-20 mg/mL;
the dosage of the EDTA-disodium is 0.001-0.1 mg/mL.
6. The canine interferon alpha hydro-acupuncture dosage form of claim 1, wherein the stabilizer B comprises one or more of dextran, beta-glucan, inulin, and chitosan.
7. The canine interferon-alpha hydro-acupuncture dosage form of claim 6, wherein the dextran is used in an amount of 0.1 to 10mg/mL;
the dosage of the beta-glucan is 0.1-10 mg/mL.
8. A method of preparing the aqueous injectable form of canine interferon-alpha according to any one of claims 1 to 7, comprising the steps of: mixing the components of the dog alpha interferon water injection preparation formulation to ensure that the final concentration of the recombinant dog alpha interferon protein is 200-2000 ten thousand IU/mL, then sterilizing and filtering by using a filter membrane with the aperture of 0.22 mu m, and storing at 2-8 ℃.
9. Use of the canine interferon alpha water injection type according to any one of claims 1 to 7 for the preservation of canine interferon alpha, wherein the canine interferon alpha water injection type is used for the preservation of canine interferon alpha for more than 24 months.
CN202210906425.3A 2022-07-29 2022-07-29 Canine alpha interferon water injection formulation, preparation method and application thereof Pending CN115177719A (en)

Priority Applications (1)

Application Number Priority Date Filing Date Title
CN202210906425.3A CN115177719A (en) 2022-07-29 2022-07-29 Canine alpha interferon water injection formulation, preparation method and application thereof

Applications Claiming Priority (1)

Application Number Priority Date Filing Date Title
CN202210906425.3A CN115177719A (en) 2022-07-29 2022-07-29 Canine alpha interferon water injection formulation, preparation method and application thereof

Publications (1)

Publication Number Publication Date
CN115177719A true CN115177719A (en) 2022-10-14

Family

ID=83522209

Family Applications (1)

Application Number Title Priority Date Filing Date
CN202210906425.3A Pending CN115177719A (en) 2022-07-29 2022-07-29 Canine alpha interferon water injection formulation, preparation method and application thereof

Country Status (1)

Country Link
CN (1) CN115177719A (en)

Similar Documents

Publication Publication Date Title
US4847079A (en) Biologically stable interferon compositions comprising thimerosal
DE69636953T2 (en) LYOPHILIZED HGF PREPARATIONS
EA011652B1 (en) Therapeutic composition whit a botulinum neurotoxin
SE451850B (en) SET TO MAKE A GLYCOPROTEIN WITH KNOWN ABILITY TO STIMULATE EDUCATION AND DIFFERENTIZATION OF HUMAN GRANULOCYTES
CA2026149A1 (en) Stabilized aqueous formulations of small peptides
CN106632682A (en) Fusion protein IFN-ELP and application thereof
MX2014004792A (en) Method of treating or reducing efp.
CN1311035A (en) Recombination high efficiency composite interferon used as hepatitis B surface antigen and e antigen inhibitor
CN113274486A (en) Stable acidic fibroblast growth factor preparation and preparation method and application thereof
CN111494611A (en) Interferon injection liquid packaged by cartridge bottle multi-dose pen type injection combination
CN110151592B (en) Composition and preparation method and application thereof
KR100399156B1 (en) Liquid Formulation of α-Interferon
CN107429228B (en) Stem cell material and preparation method thereof
DE3600083C2 (en) Use of alpha interferon to treat the respiratory disease complex in cattle
CN113081957A (en) Umbilical cord mesenchymal stem cell exosome preparation and preparation method thereof
CN102000324A (en) Long-efficiency and stable animal interferon solution preparation and preparation method thereof
CN115177719A (en) Canine alpha interferon water injection formulation, preparation method and application thereof
EP2389924B1 (en) An eyedrops of the deproteinized calf blood extract
CN104888196A (en) Stable interferon alpha multi-dose pen injection
US20030124110A1 (en) Use of modified lysozyme c to prepare medicinal compositions for the treatment of some serious diseases
CN103432569B (en) Recombinant human serum albumin-interferon alpha fusion protein water solution and preparation method thereof
CN103613668A (en) Long-acting fusion interferon for dogs and cats, as well as preparation method and application thereof
DE1617659C3 (en) Interferon-forming drug and its use
CN115531315B (en) Recombinant human interferon lambda 1 nasal spray and application thereof
KR20190053461A (en) Pharmaceutical composition comprising epidermal growth factor having thermal stability for wound therapy

Legal Events

Date Code Title Description
PB01 Publication
PB01 Publication
SE01 Entry into force of request for substantive examination
SE01 Entry into force of request for substantive examination