CN100463693C - Interferon oculentum - Google Patents
Interferon oculentum Download PDFInfo
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- CN100463693C CN100463693C CNB2004100515536A CN200410051553A CN100463693C CN 100463693 C CN100463693 C CN 100463693C CN B2004100515536 A CNB2004100515536 A CN B2004100515536A CN 200410051553 A CN200410051553 A CN 200410051553A CN 100463693 C CN100463693 C CN 100463693C
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- interferon
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- ointment
- pasting substrate
- eye ointment
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Abstract
The present invention provides interferon oculentum and its preparation process. The interferon oculentum contains interferon solution as the medicinal active component and matrix to form stable water-in-oil structure. Each gram of matrix contains interferon in 1E3-5E6 IU. The interferon solution contains interferon in 1E5-3E8/ml, stabilizer in 0.1-2 %, disodium phosphate 0.5-1.2 %, sodium dihydrogen phosphate 0.2-0.8 % and sodium chloride 0.1-0.8 %; and the matrix contains yellow vaseline 60-80 %, liquid paraffin 5-20 %, lanoline 5-20 % and emulsifier 0-20 %. The interferon oculentum is used in treatment of eye's viral infection and has the features of direct treatment, comprehensive and central treatment and lasting.
Description
Affiliated field the present invention relates to a kind of interferon eye ointment and preparation method thereof, and it is a kind of eye antiviral drugs, is the exterior-applied formulation of interferon.
The background technology interferon came out till now from nineteen fifty-seven, had developed many dosage forms, lyophilized injectable powder, liquid infusion agent, ointment, gel, gynecological suppository, eye drop or the like is just arranged at home, but as Eye ointments, also do not appear in the newspapers up to now.Kind of disease surplus interferon has been used for the treatment of 20 as broad-spectrum antiviral, antiproliferative and immunoregulation medicament is as chronic viral hepatitis B, hepatitis C, hepatitis D, hairy cell leukemia, chronic granulocytic leukemia, multiple myeloma, lymphoma, melanoma, ovarian cancer, hepatocarcinoma, renal cell carcinoma, the relevant syndrome of AIDS, influenza and other Respirovirus disease, condyloma acuminatum, viral pneumonia, herpes zoster, chickenpox, epidemic encephalitis type B, epidemic hemorrhagic fever, viral keratitis.Local application is also very wide, and especially at skin and mucosa medication, as the interferon eye ointment, it mainly treats ophthalmics such as blepharal herpes simplex, simple acute conjunctivitis, simple property iritis, cyclitis.And the effect of the eye part disease that the interferon eye drop of liquid treatment virus causes has been affirmed that as the serious epidemic keratitis that adenovirus causes, infectiousness is strong, the kinsfolk who has the source of infection is put with 3 times every day, there is 90% preventive effect in about 5000 units, (matched group 75% infects).Morbidity is early stage to be used, and can shorten the course of disease, reduces the cornea sequela, prevents visual deterioration.Herpes ophthalmicus disease, IDU intractable herpes keratitis that herpes simplex virus is caused are also effective.The treatment herpes simplex keratitis, cure rate can reach 84-92.4%.But eye drop is a liquid preparation, has following some deficiency:
1. stability is bad, and effect duration is short, and interferon activity reduces very fast before the deadline.
2. drug utilization degree low (1-10%), this is because the human eye conjunctival sac temporarily holds 30ul solution only, splashes into the part medicinal liquid and can be rapidly overflows or run off from tear from membrane vesicle.
3. the medication part can produce and organize (cornea, conjunctiva, sclera, aqueous humor, corpus ciliare) medicine than (crystalline lens, vitreous body, retina) concentration height in the tissue of eye rear portion at the moment, is difficult to reach the effect of treatment eye rear portion tissue.
In the past few years, though that clinician and patient are reflected eye drop is easy to use daytime, but need repeatedly drop, and night can not SM.And use eye to use unguentum, not only reduce the medication number of times, and can the medication at night, improved therapeutic effect thereby prolonged administration time.The inventor has solved the problems referred to above through a large amount of experiments and clinical research.So the interferon eye ointment overcomes these deficiencies that the interferon eye drop exists, have easy to usely, act on characteristics such as direct, concentrated, comprehensive, lasting.
Summary of the invention the purpose of this invention is to provide a kind of interferon eye ointment, and it not only has good stability, drug utilization degree height, lasting medicine, good effect, and has easy to usely, acts on characteristics such as direct, concentrated, comprehensive, lasting.
Another object of the present invention provides a kind of preparation method of interferon eye ointment.It has stable preparation process, and the goods homogeneity is good, and biological activity is stable, advantages such as lasting medicine.
Technical scheme of the present invention is, a kind of interferon eye ointment contains the interferon solution and the eye pasting substrate of medicinal active ingredient interferon; Contain interferon, sodium dihydrogen phosphate, sodium dihydrogen phosphate, sodium chloride, stabilizing agent in the described interferon solution, stabilizing agent is selected from one or more the combination in human albumin, mannitol, glycerol, the glycine; Contain Yellow Vaselin in the described eye pasting substrate, liquid paraffin, lanoline, emulsifying agent; Emulsifying agent is selected from one or more the combination in Tween-60, Tween-80, the Arlacel-80.Excipient such as interferon and eye pasting substrate and emulsifying agent Tween-80 form the stable Eye ointments of water-in-oil type jointly.Interferon shows stable biological activity in excipient, during ophthalmic administration, and interferon utilization rate height, lasting medicine has demonstrated fully the superiority of interferon broad-spectrum antiviral.
In the component of aforesaid interferon eye ointment: described interferon solution, interferon is 1.0 * 10 by biological activity volume ratio in its component
5IU/ml～3.0 * 10
8IU/ml, other is by volume: sodium hydrogen phosphate 0.5%～1.2%, sodium dihydrogen phosphate 0.2%～0.8%, sodium chloride 0.1%～0.8%, 0.1%～2.0% stabilizing agent, stabilizing agent is selected from one or more the combination in blood albumin, mannitol, glycerol, the glycine, and the human albumin is as preferred.Described eye pasting substrate, by weight, its component: Yellow Vaselin 60%～90%, liquid paraffin 5%～20%, lanoline 5%～20%, 0～2.0% emulsifying agent, emulsifying agent are selected from one or more the combination in Tween-60, Tween-80, the Arlacel-80, wherein with Tween-80 as preferred.Interferon: eye pasting substrate=1.0 * 10
3IU～5.0 * 10
6The IU:1 gram.
The preparation method of aforesaid interferon eye ointment, mainly be divided into three steps: the first prepares eye pasting substrate, promptly takes by weighing each excipient by the eye pasting substrate component ratio, and heating mixes then, 150 ℃ of dry heat sterilizations 1 hour, the cooling back is standby; It two is to get interferon stock solution, stabilizing agent, buffer solution by the eye ointment component ratio, and preparation interferon solution liquid is standby after the degerming of 0.22um filter membrane under aseptic condition; It three is preparation interferon Eye ointments, promptly earlier the oil phase eye pasting substrate is preheated to 40 ℃ to 56 ℃, to the water interferon solution slowly be added in the oil phase eye pasting substrate by component ratio, the limit edged stirs again, and stirs to utilize after 10 minutes to 30 minutes and divides assembling system to be distributed into finished product.
The interferon of aforesaid interferon eye ointment is natural, or the human interferon of gene recombinaton, can be arbitrary type of three kinds of α β γ.Three kinds of interferon have very big homology, and just three kinds of interferon are slightly different on gene order, and its efficacy of drugs is close substantially.
The interferon of aforesaid interferon eye ointment is preferably α 2b hypotype.Because interferon alpha 2 b has the specific activity height, antivirus action is strong, the advantage that the neutralizing antibody generation rate is low.Use recombined human to disturb plain α 2b eye ointment and can treat the ophthalmic diseases that causes by viral infection, as blepharal herpes simplex, simple acute conjunctivitis, keratitis, simple property iritis, cyclitis or the like.Simultaneously, interferon eye ointment of the present invention has and is easy to be coated on uniformly in the eyelid, and cohesiveness is good, and nonirritant, easilier absorbed by the eye mucosa, and advantage easy to use.
Interferon eye ointment product of the present invention, advantage such as it has stable preparation process, and the goods homogeneity is good, and biological activity is stable.What prescription adopted is the water-in-oil type Eye ointments that interferon and eye ointment excipient substrate, stabilizing agent and emulsifying agent etc. are formed.During ophthalmic administration, lasting medicine is compared with the interferon eye drop, has significantly improved therapeutic effect.Adopt polyoxyethylene sorbitan monoleate as preferred emulsifier in the substrate, have the stability that improves interferon, strengthen the biological curative effect of interferon.
The invention will be further described below in conjunction with embodiment for the specific embodiment
Embodiment 1 interferon eye ointment and preparation method thereof
1. component:
Eye pasting substrate: Yellow Vaselin: 900.0g liquid paraffin: 50.0g
Lanoline: 50.0g
Interferon solution: IFN α 2b:2.0 * 10
7IU human albumin: 5.0g
Na
2HPO
4：4.2g NaH
2PO
4：2.3g
NaCl:0.6g H
2O: to 500ml
Interferon content: eye pasting substrate=2.0 * 10
5IU:1g
2. preparation method
A. take by weighing each component of eye pasting substrate, and heat mixing, mixed substrate is carried out 150 ℃ do roasting sterilization 1 hour, the cooling back is standby;
B. get interferon stock solution, stabilizing agent, buffer solution by the eye ointment component ratio, preparation interferon solution liquid is standby after the degerming of 0.22um filter membrane under aseptic condition;
C. interferon solution is joined in the eye pasting substrate, promptly earlier the oil phase eye pasting substrate is preheated to 40 ℃ to 56 ℃, to the water interferon solution slowly be added in the oil phase substrate by component ratio, the limit edged stirs again, and stirs to utilize after 10 minutes to 30 minutes and divides assembling system to carry out packing.
Embodiment 2 interferon eye ointment and preparation method thereof
1. component:
Eye pasting substrate: Yellow Vaselin: 800.0g liquid paraffin: 98.0g
Lanoline: 100.0g Tween-60: 2.0g
Interferon solution: IFN α 2b:5.0 * 10
7IU mannitol: 5.0g
Na
2HPO
4：5.6g NaH
2PO
4：1.1g
NaCl:0.5g H
2O: to 500ml
Interferon content: eye pasting substrate=1.0 * 10
5IU:1g
2. preparation method is with specific embodiment 1.
Embodiment 3 interferon eye ointment and preparation method thereof
1. component:
Eye pasting substrate: Yellow Vaselin: 800.0g liquid paraffin: 97.5g
Lanoline: 100.0g Tween-80: 2.5g
Interferon solution: IFN α 2b:2.0 * 10
7IU human albumin: 2.5g
Na
2HPO
4：4.2g NaH
2PO
4：2.3g
NaCl:0.6g H
2O: to 500ml
Interferon content: eye pasting substrate=2.0 * 10
5IU:1g
2. preparation method is with specific embodiment 1.
Embodiment 4 interferon eye ointment and preparation method thereof
1. component:
Eye pasting substrate: Yellow Vaselin: 800.0g liquid paraffin: 97.5g
Lanoline: 100.0g Arlacel-80: 2.5g
Interferon solution: IFN α 2b:2.0 * 10
7IU human albumin: 2.5g
Na
2HPO
4：4.2g NaH
2PO
4：2.3g
NaCl:0.6g H
2O: to 500ml
Interferon content: eye pasting substrate=2.0 * 10
5IU:1g
2. preparation method is with specific embodiment 1.
Embodiment 5 interferon eye ointment and preparation method thereof
1. component:
Eye pasting substrate: Yellow Vaselin: 600.0g liquid paraffin: 195.0g
Lanoline: 200.0g Tween-80: 5.0g
Interferon solution: IFN α 2b:2.0 * 10
7IU glycerol: 2.5g
Na
2HPO
4：4.2g NaH
2PO
4：2.3g
NaCl:0.6g H
2O: to 500ml
Interferon content: eye pasting substrate=2.0 * 10
5IU:1g
2. preparation method is with specific embodiment 1.
The test of experimental example 1 pharmaceutical research
1. test material: adopt the acycloguanosine group, drip peaceful (the recombinant human interferon alpha 1 b eye drop of producing available from Changsheng Gene Medicine Co., Ltd.,Changchun) positive contrast medicine, the negative contrast medicine of the blank substrate of eye ointment, the interferon eye ointment that uses is the recombinant human interferon alpha 2 b eye ointment according to preparation among the most preferred embodiment three, and be divided into basic, normal, high three kinds of dosage, utilizing body weight is that the large ear rabbit (Univ. of Farming and Stockbreeding, PLA's Experimental Animal Center provides) of 2～3Kg is an animal model.
2. test method:
(1) model preparation: some of White Rabbits is fixing respectively, splash into 1 tetracaine solution of ophthalmic respectively, expand the eyelid of widening the view with reamer, on cornea, bore an annular marking with the 6mm trepan, with knife blade corneal epithelium is scraped off 3 * 3mm
2Wound surface, then 50 μ l herpes simplex virus are splashed on the cornea of damage, rubbed for 30 seconds with have gentle hands, right and left eyes is all done above-mentioned operation.
(2) grouping and administration: above-mentioned rabbit is divided equally 6 groups: model group, negative control group, positive controls, interferon eye ointment group.In the positive group, acycloguanosine is 2 droplets/time, drip rather is 7500IU/ time, the recombinant human interferon alpha 2 b eye ointment, be by basic, normal, high dosage group 3750IU/ time, 7500IU/ time, 15000IU/ time, 3 times/day, continuous 7 days, wherein middle dosage group is clinical group, and the right and left eyes that large ear rabbit has been infected herpes simplex virus is coated with (or dripping) medicament for the eyes simultaneously.
(3) and standards of grading: respectively at after 24h, the administration behind the modeling type 3,5,7, day, with the filter paper dyeing of being stained with 1% fluorescein sodium, observe cornea lesion degree, photograph down in slit lamp, after observation in the 7th day after the administration, taking a picture, cornea is got in anesthesia, 10% neutral formalin is fixed, and does pathological examination.
The scoring of keratopathy degree: marking ring is obvious, fills the air point-like, lamellar and dendroid and is colored as 5 fens; Marking ring is obvious, is dispersed in point-like, lamellar and dendroid and is colored as 4 fens; Marking ring is not obvious, is dispersed in point-like, slice colouring is 3 minutes; Marking ring is not obvious, is dispersed in minority point-like, lamellar and shallow branch and is colored as 2 fens; Marking ring is not obvious, is dispersed in the minority point-like and is colored as 1 fen; Smooth surface has the only a few point-like to be colored as 0 fen.
3. result of the test: with each keratopathy degree of each large ear rabbit by above-mentioned standards of grading marking after, add up by statistics, then the P value is all less than 0.001.After observed result shows the application acycloguanosine and rather drips, the disease of cornea is decreased and is shoaled, diminishes, use the recombinant human interferon alpha 2 b eye ointment, the disease of cornea is decreased and is also shoaled, diminishes, wherein the curative effect with middle and high dosage group is good, so recombinant human interferon alpha 2 b has the effect that suppresses herpes simplex virus keratitis significantly.
The acute toxicity test of experimental example 2 large ear rabbits
1. test material: the interferon eye ointment of use is the recombinant human interferon alpha 2 b eye ointment according to preparation among the most preferred embodiment 3, and utilizing body weight is that the large ear rabbit (Univ. of Farming and Stockbreeding, PLA's Experimental Animal Center provides) of 2～3Kg is an animal model.
2. test method: utilize recombinant human interferon alpha 2 b eye ointment maximum dosage-feeding 4.8 ten thousand IU/Kg as experimental drug, each rabbit eyes all applies interferon alpha 2 b eye ointment 3cm * 2, be 120mg, be equivalent to 120,000 IU/2.5Kg (4.8IU/Kg), behind the coating eye ointment, observe every day, and continuous 7 days, observed result.
3. result of the test: observe and find after the administration that the weight of animals within 7 days, hair, appetite, extremity activity, the mental status are all no abnormal, none is only dead.And the clinical consumption of recombinant human interferon alpha 2 b eye ointment is the 1.5cm of 400,000 IU/g, calculates if body weight for humans is pressed 60Kg, is equivalent to 0.04 ten thousand IU/Kg; And the anxious malicious evidence of recombinant human interferon alpha 2 b eye ointment rabbit, toxic reaction does not appear in its maximum dosage-feeding 4.8IU/Kg, and this dosage is equivalent to 120 times of clinical dosage, so clinical application is as safe as a house.
The eye irritant test of experimental example 3 large ear rabbits
1. test material: the negative contrast medicine of blank substrate that adopts eye ointment, the interferon eye ointment that uses is to be the test unguentum according to recombinant human interferon alpha 2 b eye ointment clinical application specification 200,000 IU/g that prepare among the most preferred embodiment, and utilizing body weight is that the large ear rabbit (Univ. of Farming and Stockbreeding, PLA's Experimental Animal Center provides) of 2～3Kg is an animal model.
2. test method: get the recombinant human interferon alpha 2 b eye ointment, its 100mg is coated in the eye conjunctival sac of large ear rabbit right side, the blank substrate of opposite side coating equivalent compares, and makes eyes after the administration passive closed 5～10 seconds, administration every day 3 times, successive administration 7 days.The local response situation (slit lamp is observed down, taken a picture) of 6h, 24h, 48h, 72h after the record first administration, 5 days, 7 days eyes.
3. result of the test: carry out standards of grading according to " new drug (Western medicine) preclinical study guideline compilation ", irritant reaction score value addition with the cornea of every animal, iris, conjunctiva, it promptly is the total mark of 1 animal eye irritant reaction, stimulate evaluation criterion to judge by " new drug (Western medicine) preclinical study guideline compilation " eye again, see the following form.
The last score value appraisal result of IFN α 2b eye ointment irritation test table
According to pressing " new drug (Western medicine) preclinical study guideline compilation " eye irritation standards of grading, the recombinant human interferon alpha 2 b eye ointment of interior three lot numbers is to the equal nonirritant reaction of eye during the administration.So this interferon eye ointment 100mg/ time, 3 times/day, administration in continuous 7 days is to the equal nonirritant reaction of lagophthalmos.
Claims (4)
1. interferon eye ointment that is used for the treatment of the eye part disease due to the viral infection, contain the interferon solution and the eye pasting substrate of medicinal active ingredient interferon, contain alpha-interferon, human albumin, sodium hydrogen phosphate, sodium dihydrogen phosphate and sodium chloride in the wherein said interferon solution; Contain Yellow Vaselin in the described eye pasting substrate, liquid paraffin, lanoline and emulsifying agent; Each composition proportion is:
Interferon solution: interferon is 1.0 * 10 by biological activity volume ratio in its component
5IU/ml～3.0 * 10
8IU/ml, other by weight volume ratio be: human albumin 0.1%～2.0%, sodium hydrogen phosphate 0.5%～1.2%, sodium dihydrogen phosphate 0.2%～0.8%, sodium chloride 0.1%～0.8%;
Eye pasting substrate: by weight, it consists of: Yellow Vaselin 60%～90%, liquid paraffin 5%～20%, lanoline 5%～20%, emulsifying agent polyoxyethylene sorbitan monoleate 0.02%～2.0%; And
In the described interferon eye ointment, interferon: eye pasting substrate=1.0 * 10
5IU～5.0 * 10
8IU:100g.
2. interferon eye ointment as claimed in claim 1 is characterized in that the component content of interferon eye ointment is: interferon: eye pasting substrate=2.0 * 10
5IU:1g.
3. interferon eye ointment as claimed in claim 1 is characterized in that the interferon in the described interferon eye ointment is a α 2b interferon.
4. the preparation method of the described interferon eye ointment of claim 1 comprises following process steps:
A. take by weighing each component of eye pasting substrate, and heat mixing, mixed substrate is carried out the roasting sterilization of 150 ℃ do 1 hour, the cooling back is standby;
B. under aseptic condition, prepare interferon solution by the eye ointment component ratio, standby after the degerming of 0.22um filter membrane;
C. with 40 ℃ to 56 ℃ of eye pasting substrate preheatings, the interferon solution for preparing is slowly added in the eye pasting substrate, the limit edged stirs again, and stirs to utilize after 10 minutes to 30 minutes and divides assembling system to carry out packing.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CNB2004100515536A CN100463693C (en) | 2004-09-17 | 2004-09-17 | Interferon oculentum |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CNB2004100515536A CN100463693C (en) | 2004-09-17 | 2004-09-17 | Interferon oculentum |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN1616088A CN1616088A (en) | 2005-05-18 |
| CN100463693C true CN100463693C (en) | 2009-02-25 |
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| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CNB2004100515536A Expired - Fee Related CN100463693C (en) | 2004-09-17 | 2004-09-17 | Interferon oculentum |
Country Status (1)
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|---|---|
| CN (1) | CN100463693C (en) |
Families Citing this family (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN108904633A (en) * | 2018-10-19 | 2018-11-30 | 长沙浩然医疗科技有限公司 | A kind of eye ointment and preparation method thereof improving eyesight |
| CN111617031A (en) * | 2020-06-25 | 2020-09-04 | 长春生物制品研究所有限责任公司 | Stable recombinant human interferon alpha 1b eye drops and production method thereof |
Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1020252C (en) * | 1987-12-26 | 1993-04-14 | 沈阳市红旗制药厂 | Prepn. of rifampin eye ointment |
| US5585354A (en) * | 1994-04-18 | 1996-12-17 | Suntory Limited | Suppressant of corneal subepithelial clouding |
| CN1100565C (en) * | 1997-07-21 | 2003-02-05 | 合肥兆峰科大药业有限公司 | Interferon ointment and its preparation |
-
2004
- 2004-09-17 CN CNB2004100515536A patent/CN100463693C/en not_active Expired - Fee Related
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1020252C (en) * | 1987-12-26 | 1993-04-14 | 沈阳市红旗制药厂 | Prepn. of rifampin eye ointment |
| US5585354A (en) * | 1994-04-18 | 1996-12-17 | Suntory Limited | Suppressant of corneal subepithelial clouding |
| CN1100565C (en) * | 1997-07-21 | 2003-02-05 | 合肥兆峰科大药业有限公司 | Interferon ointment and its preparation |
Non-Patent Citations (2)
| Title |
|---|
| 酶联免疫分析法测定人a1型基因工程干扰素成品中的干扰素蛋白含量. 庄晨杰等.病毒学报，第11卷第2期. 1995 |
| 酶联免疫分析法测定人a1型基因工程干扰素成品中的干扰素蛋白含量. 庄晨杰等.病毒学报，第11卷第2期. 1995 * |
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| CN1616088A (en) | 2005-05-18 |
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