CN114470167A - Interferon eye drops and preparation method thereof - Google Patents
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Abstract
The invention discloses an interferon eye drop and a preparation method thereof, and the composition of the interferon eye drop comprises an interferon active component, polyvinyl alcohol, a non-ionic surfactant, a metal ion chelating agent, an ionic strength regulator, a bacteriostatic agent and a pH buffer salt system. The eye drops have good biological activity and stability, cost advantage and safety advantage, and the addition of the polyvinyl alcohol can improve the compliance of patients and is used for treating viral ophthalmopathy.
Description
Technical Field
The invention belongs to the field of biological pharmaceutical preparations, and particularly relates to interferon eye drops and a preparation method thereof.
Background
Interferons are a family of cytokines with antiviral, antiproliferative, and immunomodulatory activities that induce the production of antiviral proteins by allogeneic cells, establish an antiviral state, and limit further replication and spread of the virus. Recombinant human interferon alpha (abbreviated as IFN-alpha) has the advantages of high yield, high efficiency, low side effect and the like compared with natural interferon, is widely used for treating virus infectious diseases and has definite clinical curative effect.
Acute hemorrhagic conjunctivitis (Acute hemorrhagic conjuctivitis), commonly known as pinkeye, is an Acute and infectious ophthalmic disease and was first reported in 1969. It is characterized by severe painful conjunctivitis and rapid subconjunctival hemorrhage. It is mainly caused by enterovirus E70 type and coxsackievirus a 24.
The recombinant human interferon alpha 2a has wide and effective antiviral, antiproliferative and immunoregulatory activity. In the field of clinical ophthalmology, recombinant human interferon alpha 2a can be used for treating viral eye diseases, such as conjunctival and corneal intraepithelial neoplasia, herpes simplex keratitis, acute adenovirus conjunctivitis, acute hemorrhagic conjunctivitis and the like.
The recombinant human interferon alpha 2a can keep the bioactivity in the excessive human serum albumin. However, human serum albumin and recombinant human interferon α 2a may form a high molecular weight complex, which may lead to the formation of neutralizing antibodies against the active ingredient. Furthermore, human serum albumin from blood sources is expensive and may risk contamination by viruses or other pathogens.
The safety, stability and effectiveness are key problems in biological pharmaceutical preparations, how to ensure the stability of the preparation and simultaneously can not reduce the safety of the medicine, the addition of the bacteriostatic agent becomes key, and the microbial contamination prevention is necessary in the processes of production, storage, transportation and use. In order to achieve the purpose of bacteriostasis, a bacteriostat is usually added into the eye drop preparation, but the unreasonable application of the bacteriostat can not only affect the quality of the eye drop, but also can generate toxic and side effects and damage eye tissues.
Therefore, there is a need to develop a new safe and stable interferon eye drop formulation.
Disclosure of Invention
The invention aims to provide the interferon eye drops, which do not contain human serum substances, have good stability of interferon activity and good prevention and treatment effects on viral eye diseases.
In order to achieve the purpose, the invention adopts the following technical scheme.
The invention provides an interferon eye drop, which contains an interferon active ingredient, polyvinyl alcohol, a nonionic surfactant, a metal ion chelating agent, an ionic strength regulator, a bacteriostatic agent, a pH buffer salt system and water for injection.
Preferably, the interferon active component is recombinant human interferon alpha 2 a. The recombinant human interferon alpha 2a has wide and effective antiviral, antiproliferative and immunoregulatory activity. In the field of clinical ophthalmology, recombinant human interferon alpha 2a can be used for treating viral eye diseases, such as conjunctival and corneal intraepithelial neoplasia, herpes simplex keratitis, acute adenovirus conjunctivitis, acute hemorrhagic conjunctivitis and the like.
As the preferred scheme, the medical grade polyvinyl alcohol is selected, is a safe high molecular polymer, has good biocompatibility and can be applied to eye drop products; has hydrophilic and film-forming properties, and can also give consideration to the stability and biological activity of interferon active ingredients.
Preferably, the nonionic surfactant is one or more selected from polysorbate 20 and polysorbate 80.
Preferably, the metal ion chelating agent is edetate disodium.
Preferably, the ionic strength regulator is one or more selected from sodium chloride, potassium chloride and potassium nitrate.
Preferably, the bacteriostatic agent is p-hydroxybenzoate ester, and is selected from one or more of methyl p-hydroxybenzoate, ethyl p-hydroxybenzoate and propyl p-hydroxybenzoate. The bacteriostatic agent is a combination of methyl p-hydroxybenzoate (with a concentration of 0.01-0.05%) and propyl p-hydroxybenzoate (with a concentration of 0.005-0.01%) at a certain concentration ratio.
Preferably, the pH buffer salt system is one or more selected from a phosphate buffer system and a citrate buffer system. The pH of the buffer salt system is 6-7.
Preferably, the interferon eye drops comprise 10L of components as follows:
10mg-250mg of interferon active component,
10g to 140g of polyvinyl alcohol,
1g to 5g of nonionic surfactant,
1g to 10g of metal ion chelating agent,
10g to 80g of ionic strength regulator,
1g to 6g of bacteriostatic agent,
pH buffer salt system 5-80mmol/L
And water for injection.
Preferably, the interferon eye drops comprise 10L, and the components specifically comprise:
10mg-250mg of recombinant human interferon alpha 2a,
10g to 140g of polyvinyl alcohol,
the polysorbate 801 g-5g of the compound,
1g to 10g of edetate disodium,
10g-80g of sodium chloride,
1g to 6g of p-hydroxybenzoate ester,
pH buffer salt system 5-80mmol/L
And water for injection.
The invention also provides a preparation method of the interferon eye drops, which comprises the following steps:
(1) uniformly placing polyvinyl alcohol in a proper amount of water for injection, sterilizing at 121 ℃, and cooling to room temperature to obtain a polyvinyl alcohol stock solution;
(2) sequentially dissolving an ionic strength regulator, a metal ion chelating agent, a bacteriostatic agent, a pH buffer salt system, a nonionic surfactant and an interferon active ingredient into water for injection to obtain an interferon stock solution;
(3) uniformly mixing the polyvinyl alcohol stock solution and the interferon stock solution under the aseptic condition, adding water for injection to a constant volume, sterilizing and filtering to obtain the interferon eye drops.
And (3) aseptically filling the interferon eye drops to obtain finished product eye drops.
The invention also provides the application of the interferon eye drops in preparing the medicine for treating the viral eye diseases, wherein the viral eye diseases are selected from conjunctival and corneal intraepithelial neoplasia, herpes simplex keratitis, acute adenovirus conjunctivitis and acute hemorrhagic conjunctivitis.
The positive progress effects of the invention are as follows: the invention ensures that the interferon eye drops have good biological activity and stability, and has cost advantage and safety advantage compared with a prescription containing human serum albumin. The invention adds polyvinyl alcohol to prepare the interferon eye drops, so that the interferon eye drops have better hydrophilicity and film forming property and improve the compliance of patients. And the reasonable range application of the bacteriostatic agent ensures the quality of the eye drops.
Detailed Description
The following examples are further illustrative of the present invention and should not be construed as limiting thereof. Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art. In addition, any methods and materials similar or equivalent to those described herein can be used in the methods of the present invention. The preferred embodiments and materials described herein are intended to be exemplary only.
The recombinant human interferon alpha 2a sequence used in the following examples is a recombinant human interferon alpha 2a sequence published in Chinese pharmacopoeia 2020 edition, and is prepared by a method disclosed in Chinese patent CN 200510046590.2; other raw and auxiliary materials in the examples can be obtained commercially. In the following examples, the stability test and the related biological test were carried out according to the specifications of the Chinese pharmacopoeia.
Example 1: interferon eye drops I
The interferon eye drops I comprise the following components:
TABLE 1
| Composition (I) | Content (in 10L) |
| Recombinant human interferon alpha 2a | 50mg |
| Polyvinyl alcohol | 10g |
| Polysorbate 80 | 5g |
| Edetate disodium | 10g |
| Sodium chloride | 50g |
| P-hydroxybenzoic acid methyl ester | 5g |
| Propyl p-hydroxybenzoate | 1g |
| Phosphate buffer system | 20mmol/L，pH＝6.7 |
| Water for injection | Constant volume is 10L |
The interferon eye drops are prepared according to the following method (the components and the dosage are shown in the table 1):
1. uniformly placing 10g of polyvinyl alcohol into a proper amount of water for injection, sterilizing at 121 ℃, and cooling to room temperature to obtain a polyvinyl alcohol stock solution;
2. sequentially dissolving sodium chloride, disodium edetate, p-hydroxybenzoate, a phosphate buffer system, polysorbate 80 and recombinant human interferon alpha 2a stock solution in water for injection to obtain a recombinant human interferon alpha 2a stock solution;
3. uniformly mixing a polyvinyl alcohol stock solution and a recombinant human interferon alpha 2a stock solution under an aseptic condition, metering the volume to 10L by using water for injection, and performing sterilization and filtration to obtain the recombinant human interferon alpha 2a eye drops;
4. and (3) aseptically filling the recombinant human interferon alpha 2a eye drops to obtain finished product eye drops.
Wherein the phosphate buffer system consists of disodium hydrogen phosphate and sodium dihydrogen phosphate monohydrate, and the pH value is 6.7.
Example 2: interferon eye drops II
The interferon eye drops II comprise the following components:
TABLE 2
| Composition (A) | Content (in 10L) |
| Recombinant human stemInterferon alpha 2a | 250mg |
| Polyvinyl alcohol | 20g |
| Polysorbate 80 | 1g |
| Edetate disodium | 10g |
| Sodium chloride | 80g |
| P-hydroxybenzoic acid methyl ester | 5g |
| Propyl p-hydroxybenzoate | 0.5g |
| Phosphate buffer system | 10mmol/L，pH＝6.2 |
| Water for injection | Constant volume is 10L |
The interferon eye drops were prepared according to the ingredients and contents in table 2 by the preparation method referred to in example 1.
Example 3: interferon eye drops III
The interferon eye drops III comprise the following components:
TABLE 3
| Composition (I) | Content (in 10L) |
| Recombinant human interferon alpha 2a | 10mg |
| Polyvinyl alcohol | 100g |
| Polysorbate 80 | 3g |
| Edetate disodium salt | 1g |
| Sodium chloride | 10g |
| P-hydroxybenzoic acid methyl ester | 3g |
| Propyl p-hydroxybenzoate | 1g |
| Phosphate buffer system | 80mmol/L，pH＝6.7 |
| Water for injection | Constant volume is 10L |
The interferon eye drops were prepared according to the ingredients and contents in table 3, and the preparation method was referenced to example 1.
Example 4: interferon eye drops IV
The interferon eye drops IV comprise the following components:
TABLE 4
The interferon eye drops were prepared according to the ingredients and contents in table 4, by the preparation method in reference to example 1.
Example 5: interferon eye drops V
The interferon eye drops V comprise the following components:
TABLE 5
| Composition (I) | Content (in 10L) |
| Recombinant human interferon alpha 2a | 150mg |
| Polyvinyl alcohol | 120g |
| Polysorbate 80 | 5g |
| Edetate disodium | 5g |
| Sodium chloride | 40g |
| P-hydroxybenzoic acid methyl ester | 4g |
| Propyl p-hydroxybenzoate | 1g |
| Phosphate buffer system | 40mmol/L，pH＝6.9 |
| Water for injection | Constant volume is 10L |
The interferon eye drops were prepared according to the ingredients and contents in table 5, and the preparation method was referenced to example 1.
Example 6: interferon eye drops VI
The interferon eye drops VI comprise the following components:
TABLE 6
The interferon eye drops were prepared according to the ingredients and contents in table 6, by the preparation method referred to example 1.
Example 7: interferon eye drops VII
The interferon eye drops VII comprises the following components:
TABLE 7
| Composition (I) | Content (in 10L) |
| Recombinant human interferon alpha 2a | 10mg |
| Polyvinyl alcohol | 100g |
| Human serum albumin | 50g |
| Sodium chloride | 10g |
| P-hydroxybenzoic acid methyl ester | 3g |
| Propyl p-hydroxybenzoate | 1g |
| Phosphate buffer system | 80mmol/L，pH＝6.7 |
| Water for injection | Constant volume is 10L |
The interferon eye drops were prepared according to the ingredients and contents in table 7 by the preparation method referred to in example 1.
Example 8: interferon eye drops VIII
The interferon eye drops VIII comprise the following components:
TABLE 8
| Composition (I) | Content (in 10L) |
| Recombinant human interferon alpha 2a | 100mg |
| Polysorbate 80 | 1g |
| Edetate disodium | 5g |
| Sodium chloride | 60g |
| P-hydroxybenzoic acid methyl ester | 7g |
| Phosphate buffer system | 30mmol/L，pH＝6.4 |
| Water for injection | Constant volume is 10L |
The interferon eye drops were prepared according to the ingredients and contents shown in Table 8, by the methods described in reference to Steps 2 to 4 of example 1.
Example 9: stability study test
The determination method comprises the following steps: the interferon eye drops prepared in examples 1 to 8 were filled in 5mL eye drops bottles and subjected to accelerated examination at 37. + -. 2 ℃ for appearance, pH, protein content and biological activity examination at 0 day, 14 days and 28 days, respectively. The test results are shown in table 9.
TABLE 9 stability study test results
As can be seen from the results in Table 9, compared with the interferon eye drops VII formulated with human serum albumin, the other interferon eye drops without human serum albumin as the formulation component have relatively good stability; compared with the interferon eye drops VIII which do not adopt polyvinyl alcohol and use a single kind of bacteriostatic agent, the other interferon eye drops have better stability.
Example 10: bacteriostatic efficacy research test
The interferon eye drops prepared in examples 1 to 8 were subjected to bacteriostatic efficacy measurement according to the requirement of bacteriostatic efficacy measurement in the chinese pharmacopoeia of 2020 edition. The results are shown in Table 10.
TABLE 10 results of the bacteriostatic efficacy studies
| Name (R) | Escherichia coli | Staphylococcus aureus | Candida albicans | Aspergillus niger | Pseudomonas aeruginosa |
| I | Conform to | Conform to | Conform to | Meet with | Conform to |
| II | Conform to | Conform to | Conform to | Conform to | Conform to |
| III | Conform to | Conform to | Conform to | Conform to | Conform to |
| IV | Conform to | Conform to | Conform to | Conform to | Conform to |
| V | Conform to | Conform to | Conform to | Conform to | Conform to |
| VI | Conform to | Conform to | Conform to | Conform to | Conform to |
| VII | Conform to | Conform to | Conform to | Conform to | Conform to |
| VIII | Conform to | Conform to | Is not in compliance with | Is not in compliance with | Non-conforming to |
As can be seen from the above Table 10, the interferon eye drops I-VI of the present invention have good bacteriostatic effect and can effectively inhibit Escherichia coli, Staphylococcus aureus, Candida albicans, Aspergillus niger and Pseudomonas aeruginosa.
Claims (11)
1. An interferon eye drop is characterized by comprising an interferon active ingredient, polyvinyl alcohol, a nonionic surfactant, a metal ion chelating agent, an ionic strength regulator, a bacteriostatic agent, a pH buffer salt system and water for injection.
2. The interferon eye drops according to claim 1, wherein the interferon active ingredient is recombinant human interferon alpha 2 a.
3. The interferon eye drops according to claim 1, wherein the non-ionic surfactant is one or more selected from polysorbate 20 and polysorbate 80.
4. The interferon eye drops of claim 1, wherein the metal ion chelating agent is edetate disodium.
5. The interferon eye drops according to claim 1, wherein the ionic strength modifier is one or more selected from sodium chloride, potassium chloride and potassium nitrate.
6. The interferon eye drops according to claim 1, wherein the bacteriostatic agent is p-hydroxybenzoate ester selected from one or more of methyl p-hydroxybenzoate, ethyl p-hydroxybenzoate and propyl p-hydroxybenzoate.
7. The interferon eye drops according to claim 1, wherein the pH buffer salt system is selected from one or more of phosphate buffer system and citrate buffer system, and the pH of the buffer salt system is 6-7.
8. The interferon eye drops according to any one of claims 1 to 7, wherein the composition of the interferon eye drops comprises 10mg to 250mg of interferon active ingredient, 10g to 140g of polyvinyl alcohol, 1g to 5g of nonionic surfactant, 1g to 10g of metal ion chelating agent, 10g to 80g of ionic strength regulator, 1g to 6g of bacteriostatic agent, 5 to 80mmol/L of pH buffer salt system and water for injection, wherein the amount of the interferon active ingredient is 10L.
9. The interferon eye drops according to claim 8, wherein the composition of the interferon eye drops comprises 10mg to 250mg of recombinant human interferon alpha 2a, 10g to 140g of polyvinyl alcohol, 801 g to 5g of polysorbate, 1g to 10g of edetate disodium, 10g to 80g of sodium chloride, 1g to 6g of p-hydroxybenzoate, 5 to 80mmol/L of pH buffer salt system and water for injection, wherein the amount of the interferon eye drops is 10L.
10. A method for preparing an interferon eye drop according to claims 1 to 9, comprising the steps of:
(1) uniformly placing polyvinyl alcohol in a proper amount of water for injection, sterilizing at 121 ℃, and cooling to room temperature to obtain a polyvinyl alcohol stock solution;
(2) sequentially dissolving an ionic strength regulator, a metal ion chelating agent, a bacteriostatic agent, a pH buffer salt system, a nonionic surfactant and an interferon active ingredient into water for injection to obtain an interferon stock solution;
(3) uniformly mixing the polyvinyl alcohol stock solution and the interferon stock solution under the aseptic condition, adding water for injection to a constant volume, sterilizing and filtering to obtain the interferon eye drops.
11. Use of an interferon eyedrop according to claims 1-9 for the preparation of a medicament for the treatment of a viral ocular disease selected from the group consisting of conjunctival and corneal intraepithelial neoplasia, herpes simplex keratitis, acute adenoviral conjunctivitis, and acute hemorrhagic conjunctivitis.
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Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN113797318A (en) * | 2021-10-26 | 2021-12-17 | 深圳科兴药业有限公司 | Interferon composition, and preparation method and application thereof |
| CN113797317A (en) * | 2021-10-26 | 2021-12-17 | 科兴生物制药股份有限公司 | Composition and preparation method and application thereof |
| CN117959251A (en) * | 2024-03-29 | 2024-05-03 | 长春生物制品研究所有限责任公司 | Recombinant human interferon alpha 1b eye drops and preparation method thereof |
-
2020
- 2020-11-13 CN CN202011267445.8A patent/CN114470167A/en active Pending
Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN113797318A (en) * | 2021-10-26 | 2021-12-17 | 深圳科兴药业有限公司 | Interferon composition, and preparation method and application thereof |
| CN113797317A (en) * | 2021-10-26 | 2021-12-17 | 科兴生物制药股份有限公司 | Composition and preparation method and application thereof |
| CN113797317B (en) * | 2021-10-26 | 2024-01-09 | 科兴生物制药股份有限公司 | Composition, and preparation method and application thereof |
| CN117959251A (en) * | 2024-03-29 | 2024-05-03 | 长春生物制品研究所有限责任公司 | Recombinant human interferon alpha 1b eye drops and preparation method thereof |
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