CN101584857A - Ophthalmic preparation and preparation method thereof - Google Patents
Ophthalmic preparation and preparation method thereof Download PDFInfo
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- CN101584857A CN101584857A CNA2008100444401A CN200810044440A CN101584857A CN 101584857 A CN101584857 A CN 101584857A CN A2008100444401 A CNA2008100444401 A CN A2008100444401A CN 200810044440 A CN200810044440 A CN 200810044440A CN 101584857 A CN101584857 A CN 101584857A
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- preparation
- receptor antagonist
- ophthalmic
- mannitol
- interleukin
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Abstract
The invention provides an ophthalmic preparation of interleukin-1 receptor antagonist anakinra and a preparation method thereof. The pharmaceutical preparation has the advantages of good effect, fast effecting, high biological utilization, stable property, controllable quality and the like in treating ophthalmic diseases such as corneal injury, inflammation as well as cataract, keratitis, and the like.
Description
Technical field:
The present invention relates to a kind of pharmaceutical preparation and preparation method thereof, particularly ophthalmic preparation belongs to field of pharmaceutical preparations.
Background technology:
(interleukin-1 IL-1) is a kind of important cytokine to interleukin-1, is mainly produced by mononuclear phagocyte, has biologic activity widely, is considered to one of key factor in the cytokine network.It not only has important regulatory role to the panimmunity competent cell, and participates in various physiological processes such as hemopoietic, neuroendocrine and antitumor, and closely related with heating, inflammation, shock and leukemic pathological change.Interleukin-1 receptor antagonist (interleukin-1 receptor antagonist, IL-1Ra) be a kind of protein of from the post-stimulatory person monocytic cell's culture supernatant of IgG, finding, can be specifically and the IL-1 receptors bind, do not activate target cell, the biologic activity of blocking-up IL-1.
Verified now: the generation of the biologic activity of IL-1 and corneal injury inflammation and the generation of new vessels are closely related.Existing both at home and abroad correlational study data is pointed out: IL-1 plays critical effect in the process that the inflammation and the new vessels of eyeball and cornea tissue produces.
Studies show that this kind has following pharmacological property:
(1) formation of inhibition cornea rebirth blood vessel;
(2) alleviate inflammatory reactions such as the back hyperemia of cornea burn, edema, suppress inflammatory cell infiltration, help the regeneration of corneal epithelial cell, the treatment of the keratitis that can be used for because various wounds etc. causes;
(3) IL-1ra helps damaging the recovery of cornea light transmittance, helps the recovery of patient's corneal transparence and cornea the dwindling of muddy speckle of burning;
(4) reduce vision that cornea inflammation and cornea burn and wound etc. cause and weaken incidence rate with blinding;
(5) suppress to have a liking for the generation that acid is granulocyte, mastocyte and chemokine, the inflammatory infiltration of the eye conjunctival tissue that reasons such as allergy are caused has clear and definite inhibitory action, can be used for the keratitis that factor such as anaphylaxis causes and the treatment of conjunctivitis;
(6) effect specificity height to not influence of intraocular pressure, can not cause the medicine glaucoma, can be used for suffering from glaucomatous patient;
(7) no drug dependence, genetoxic can not cause the cornea atrophy after the drug withdrawal, can be used for old man and child.
Clinical test results shows that this kind not only has the keratitis that the multiple reason of treatment causes, corneal injury, and ophthalmic diseasess such as cataract, effect is better than adrenal cortex hormones drug, and side effect is little, safe.
Simultaneously, according to incompletely statistics, China's annual ophthalmology outpatient service prescription on individual diagnosis number is about 4,380 ten thousand people, wherein eye surface damage patient accounts for ophthalmology outpatient's's every day 1/3, because of diseases of eye surface blinding numbers such as corneal injury reach more than 2,000,000 people, cause the number of visual deterioration to reach more than 3,000,000 people, therefore, develop a kind of bioavailability height, low price, safety, the little ophthalmic preparation of side effect is extremely urgent, interleukin-1 receptor antagonist is for the user of recessive glasse simultaneously, and alleviating the cornea inflammation and the various discomforts of releiving also has unique effect, has very big market popularization value.
Summary of the invention:
The objective of the invention is to:, provide a kind of pharmaceutical preparation and preparation method thereof at prior art; The preparation that provides is for corneal injury, inflammation, and cataract, ophthalmic diseasess such as keratitis and visual disturbance have unique curative effect; And drug effect is obvious, and toxicity is very low, drug safety, cheap; Its preparation formulation is easy to carry, be easy to use; The preparation method that is provided can effectively prepare needs preparation, guarantee that the preparation effect obtain is remarkable; Production technology is scientific and reasonable, and is simple to operate; Quality controllable, safety, the characteristics that side effect is little.
The present invention constitutes like this:
Medicine of the present invention is the ophthalmic preparation that is prepared from by leukocyte-1 receptor antagonist (IL-1ra) crude drug and adjuvant.
More specifically be by interleukin-1 receptor antagonist, protective agent, osmotic pressure regulator, the ophthalmic preparation that buffer is formulated.
The said interleukin-1 receptor antagonist of the present invention is to adopt the method for gene recombinaton to prepare, and is meant people's recombinant interleukin-1 receptor antagonist (rhIL-1ra) especially;
The said osmotic pressure regulator buffer of the present invention is a phosphate buffer, by KH
2PO
4, Na
2HPO
4, KCl, NaCl be formulated, its sodium chloride concentration is 0.5%～0.8%, preferred 0.7%;
The said protective agent of the present invention is preferably mannitol and human serum albumin, and the concentration of its mannitol is 0.3%～1%, and human serum albumin's concentration is 0.005%～0.01%, and preferred mannitol is 0.6%, and the human serum albumin is 0.01%
The said ophthalmic preparation of the present invention is the eye liquid preparation, preferred eye drop;
The said liquid preparation preparation method of the present invention is: measures interleukin-1 receptor antagonist stock solution, adds an amount of buffer, add an amount of protective agent agent then, and osmotic pressure regulator, filtration sterilization then, packing are promptly.
Concrete embodiment:
Illustrate: following embodiment is only for illustrating the present invention more fully, but do not limit the present invention's content required for protection.
Embodiment 1:
1. the foundation selected of preparation prescription
Biological product will keep its biological activity as much as possible, and dosage form must be stablized, and is easy and simple to handle, is easy to repetition, and the management that can strictly regulate.My company develops recombination human interleukins-11 receptor antagonist eye drop, is used for the treatment of corneal injury and inflammation and anaphylaxis conjunctivitis that the various non-infectious causes of disease cause, symptoms such as cataract and visual disturbance thereof.Look into the sale that does not have like product on the present domestic and international market of new demonstration, have only the recombination human interleukins-11 receptor antagonist remover liquid injection of U.S. Amgen company exploitation to be used for the treatment of rheumatoid arthritis, commodity are called Kiniret
TM
2. the selection of adjuvant:
(1) selection of protective agent and buffer thereof
In the biological product manufacture process, adding mannitol has good protective effect to the stability of albumen or polypeptide usually, thereby is often used as protective agent.Consider that the eye drop bottle may have a small amount of absorption to rhIL-1ra, we add a spot of human serum albumin and reduce the absorption of eye drop bottle to rhIL-1ra.We select mannitol and human serum albumin as protective agent on the basis of experiment, and the buffer of preparation different formulations carries out the stability of sample investigation under different temperatures.The investigation time is 6 months.The result is following (all to contain 0.024%KH in all samples
2PO
4, 0.144%Na
2HPO
4, 0.02%KCl, 0.8%NaCl, 50 μ g/ml rhIL-1ra.Difference is in No. 1 and contains 0.01% human albumin, 0.6% mannitol; Contain 0.05% human albumin, 0.6% mannitol for No. 2; Contain 0.01% human albumin, 1% mannitol for No. 3; Contain 0.005% human albumin, 0.3% mannitol for No. 4; Do not contain human albumin and mannitol No. 5.Every kind of prescription is done three multiple holes):
| Sample number | Investigate activity value for 4-8 ℃ | Room temperature is investigated activity value | Investigate activity value for 37 ℃ |
| 1 | 930.9mU/mg | 907.2mU/mg | 207.9mU/mg |
| 2 | 994.4mU/mg | 918.9mU/mg | 198.9mU/mg |
| 3 | 952.2mU/mg | 928.6mU/mg | 205.8mU/mg |
| 4 | 821.7mU/mg | 725.5mU/mg | 205.8mU/mg |
| 5 | 797.4mU/mg | 630.6mU/mg | 197.1mU/mg |
Experimental result shows, adds human albumin and mannitol and can effectively improve the stability of goods and reduce plastic bottle to proteic absorption in goods.Select for use the effect of 0.01% human albumin and 0.6% mannitol better, increase human albumin and mannitol concentration DeGrain, reducing human albumin and mannitol concentration has certain influence to the result, and does not add the human albumin and mannitol has considerable influence to activity.Take all factors into consideration, we select 0.01% human albumin and 0.6% mannitol as the final protective agent of goods, and this prescription is workable, the resulting product good stability.
(2) selection of osmotic pressure regulator
In the manufacturing process, contain NaCl in the IL-1ra solution that obtains, consider that eye drop is a dosing eyes, need keep the osmotic pressure of certain intensity, so need to contain NaCl in the goods.We measure the osmotic pressure of the buffer that contains variable concentrations NaCl, and the result is following, and (sample contains 0.024%KH No. 1
2PO
4, 0.144%Na
2HPO
4, 0.02%KCl, 0.8%NaCl, 0.01% human albumin, 0.6% mannitol; Contain 0.024%KH No. 2
2PO
4, 0.144%Na
2HPO
4, 0.02%KCl, 0.8%NaCl; Contain 0.024%KH No. 3
2PO
4, 0.144%Na
2HPO
4, 0.02%KCl, 0.7%NaCl; Contain 0.024%KH No. 4
2PO
4, 0.144%Na
2HPO
4, 0.02%KCl, 0.6%NaCl; Contain 0.024%KH No. 5
2PO
4, 0.144%Na
2HPO
4, 0.02%KCl, 0.5%NaCl)
According to last table result, in conjunction with " the osmotic pressure molar density scope of 2000 editions regulation eye drops of Chinese pharmacopoeia is 220-320mOsmol, and we select 0.024%KH
2PO
4, 0.144%Na
2HPO
4, 0.02%KCl, 0.7%NaCl be as sample buffer, add 0.01% human albumin, 0.6% mannitol and sample and promptly get recombination human interleukins-11 receptor antagonist eye drop finished product, at this moment the osmotic pressure molar density value of measuring finished product meets the " relevant regulations that Chinese pharmacopoeia is 2000 editions about 290mOsmol.
Embodiment 2:
Preparation method:
The rhIL-1ra stock solution that obtains through purification add the semi-finished product that certain adjuvant makes contain (/ml):
rhIL-1ra 50mU(0.05mg)
Na
2HPO
4 1.44mg
KH
2PO
4 0.24mg
KCl 0.2mg
NaCl 7mg
Human serum albumin 0.1mg
Mannitol 6mg
Prop up the packing rear seal-cover by 3ml/.Be to contain 150mU (0.15mg) rhIL-1ra, 21mgNaCl, 4.32mg Na in every finished product
2HPO
4, 0.72mgKH
2PO
4, 0.6mgKCl, 0.3mg human serum albumin, 18mg mannitol.
Claims (7)
1, a kind of ophthalmic preparation and preparation method thereof is characterized in that described pharmaceutical preparation comprises leukocyte-1 receptor antagonist (IL-1ra), and the ophthalmic preparation that is prepared from of this leukocyte-1 receptor antagonist (IL-1ra) crude drug and adjuvant.
2, a kind of ophthalmic preparation and preparation method thereof is characterized in that described pharmaceutical preparation is by raw material interleukin-1 receptor antagonist and adjuvant protective agent, osmotic pressure regulator, the ophthalmic preparation that buffer is formulated.
3, according to claim 1,2 described interleukin-1 receptor antagonists are to adopt the method for gene recombinaton to prepare, and are meant people's recombinant interleukin-1 receptor antagonist (rhIL-1ra) especially.
4, according to claim 1,2 described adjuvant osmotic pressure regulator buffer are phosphate buffer, by KH
2PO
4, Na
2HPO
4, KCl, NaCl be formulated, its sodium chloride concentration is 0.5%～0.8%, preferred 0.7%.
5, according to claim 1; 2 described adjuvant protective agents are preferably mannitol and human serum albumin, and the concentration of its mannitol is 0.3%～1%, and human serum albumin's concentration is 0.005%～0.01%; preferred mannitol is 0.6%, and the human serum albumin is 0.01%.
6, according to claim 1,2 described ophthalmic preparations are the eye liquid preparation, preferred eye drop.
7, according to claim 1,2,6 described ophthalmic preparation preparation methoies are: measure interleukin-1 receptor antagonist stock solution, add an amount of buffer, add an amount of protective agent agent then, and osmotic pressure regulator, filtration sterilization then, packing are promptly.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CNA2008100444401A CN101584857A (en) | 2008-05-23 | 2008-05-23 | Ophthalmic preparation and preparation method thereof |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CNA2008100444401A CN101584857A (en) | 2008-05-23 | 2008-05-23 | Ophthalmic preparation and preparation method thereof |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CN101584857A true CN101584857A (en) | 2009-11-25 |
Family
ID=41369426
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CNA2008100444401A Pending CN101584857A (en) | 2008-05-23 | 2008-05-23 | Ophthalmic preparation and preparation method thereof |
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Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101912355A (en) * | 2010-04-29 | 2010-12-15 | 佟丽 | Recombinant human interleukin-1 receptor antagonist in-situ gel |
| WO2012108828A1 (en) * | 2011-02-11 | 2012-08-16 | Swedish Orphan Biovitrum Ab (Publ) | Citrate free pharmaceutical compositions comprising anakinra |
| CN105214092A (en) * | 2015-09-30 | 2016-01-06 | 无锡大周生物工程有限公司 | RHuIL-1Ra and compositions thereof and medicinal usage |
-
2008
- 2008-05-23 CN CNA2008100444401A patent/CN101584857A/en active Pending
Cited By (7)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101912355A (en) * | 2010-04-29 | 2010-12-15 | 佟丽 | Recombinant human interleukin-1 receptor antagonist in-situ gel |
| CN101912355B (en) * | 2010-04-29 | 2012-07-25 | 佟丽 | Recombinant human interleukin-1 receptor antagonist in-situ gel |
| WO2012108828A1 (en) * | 2011-02-11 | 2012-08-16 | Swedish Orphan Biovitrum Ab (Publ) | Citrate free pharmaceutical compositions comprising anakinra |
| US9198954B2 (en) | 2011-02-11 | 2015-12-01 | Swedish Orphan Biovitrum Ab (Publ) | Citrate free pharmaceutical compositions comprising anakinra |
| US10179162B2 (en) | 2011-02-11 | 2019-01-15 | Swedish Orphan Biovitrum Ab (Publ) | Citrate free pharmaceutical compositions comprising anakinra |
| CN105214092A (en) * | 2015-09-30 | 2016-01-06 | 无锡大周生物工程有限公司 | RHuIL-1Ra and compositions thereof and medicinal usage |
| CN105214092B (en) * | 2015-09-30 | 2018-12-21 | 无锡大周生物工程有限公司 | RHuIL-1Ra and combinations thereof and medicinal usage |
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Open date: 20091125 |