CN101297959A - Preparation of chicken interleukin-2 microsphere novel dosage form - Google Patents
Preparation of chicken interleukin-2 microsphere novel dosage form Download PDFInfo
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- CN101297959A CN101297959A CNA2008100533636A CN200810053363A CN101297959A CN 101297959 A CN101297959 A CN 101297959A CN A2008100533636 A CNA2008100533636 A CN A2008100533636A CN 200810053363 A CN200810053363 A CN 200810053363A CN 101297959 A CN101297959 A CN 101297959A
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Abstract
The invention relates to a preparation method of a new microsphere formulation chicken interleukin-2, which has the steps as follows: (1) the chicken interleukin-2 is dissolved in an aqueous phase buffer solution, the pH value of the solution (A) is 2.5 to 7.0 and the content of the chicken interleukin-2 is 1.0 to 10.0 mg/ml; (2) the acid solution (A) containing the chicken interleukin-2 is added into a liquid nonionic type surfactant solution, the hydrophile-lyophile balance value of which is HLB being more than or equal to 9 and less than or equal to 15, or into amphipathic grease, or into the intermixture of the nonionic type surfactant solution and the amphipathic grease to be mixed as a solution (B); (3) the solution (B) is added into liquid oil phase with the hydrophile-lyophile balance value of HLB being more than or equal to 0 and less than or equal to 9, or into a lipophilic emulsifier, or into the intermixture of the oil phase and the lipophilic emulsifier. The ratio of the solution (B) and the intermixture ranges from 1:1 to 1:9 and the two solutions are stirred and mixed at the temperature of 5 DEG C to 30 DEG C to form an oil phase formulation (C); (4) a stabilizing agent is added. The embedment ratio of the interleukin-2 is improved to 60 to 92 percent by adopting the preparation method of the invention.
Description
Technical field
The invention belongs to the preparing technical field of bio-pharmaceutical, particularly a kind of preparation method of chicken interleukin-2 microsphere novel dosage form.
Background technology
At present, chicken interleukin-2 has been widely used in clinical as a kind of immunomodulator.Chicken interleukin-2 is a kind of natural immunity reinforcing agent.It has activated T cell, promotes and keep the T cell long-period to survive; Promote the B cell differentiation and produce functions such as antibody, inducing interferon generation.The reorganization chicken interleukin-2 is used for chicken, and vaccine is had good immunoenhancement result.It can overcome big, the difficult shortcoming that absorbs of the caused toxicity of other conventional adjuvant, but also can overcome the immunosuppressive condition that some disease causes, reduces in the aviculture because the heavy economic losses that immunosuppressant caused that causes behind the pathogen infection.
In recent years, one of popular main threat that has become livestock and poultry breeding industry of immunosuppressive disease large tracts of land.Therefore, immunoregulatory factor such as chicken interleukin-2 has been subjected to the extensive concern of Chinese scholars.In veterinary clinic test, chicken interleukin-2 has also been obtained satisfied effect at animal epidemic aspect preventing and treating.
Chicken interleukin-2 all is with the administration of injecting better therapeutic effect to be arranged, many persons need inject 1-2 time every day, logotype 2-5 days, bring a lot of inconvenience for the use of culturing the owner, therefore being made into drinking-water, oral formulations just becomes the target that people pursue.If have breakthrough in this regard, will produce huge social and economic benefit.But directly with these bio-pharmaceutical drinking-water, oral, because the degraded digestion of gastrointestinal tract endoenzyme and the absorption barrier of intestinal make its availability very low, therapeutic effect is relatively poor.
Therefore, providing a kind of preparation method of chicken interleukin-2 microsphere novel dosage form, effectively prevent and treat various fowl disease pathogenic diseases, is one of this technical field scientific research personnel new problem of being badly in need of developing.
Summary of the invention
The objective of the invention is for overcoming the weak point of prior art, provide a kind of and prepare simply, use preparation method convenient, obvious results chicken interleukin-2 microsphere novel dosage form,
A kind of preparation method of chicken interleukin-2 microsphere novel dosage form is characterized in that comprising the steps:
(1) a certain amount of chicken genetic engineering interleukin II is dissolved in the water buffer solution, the pH value of this solution (A) is 2.5-7.0, and the content of chicken genetic engineering interleukin II is the 1.0-10.0 mg/ml;
(2) the above-mentioned acid solution (A) that contains chicken interleukin-2 is joined in the nonionic surfactant solution of liquid state that hydrophile-lipophile balance value (HLB) is 9≤HLB≤15, or in the amphiphilic grease, or in their mixed liquor; Described solution (A) and these surfactants, or amphiphilic grease, or the ratio of their mixed liquor is 1: 4 to 1: 40; These two kinds of solution stir under temperature 5-30 ℃, and it is mixed uniformly, become a kind of transparent solution (B);
(3) solution (B) is added in the oil phase of liquid state that hydrophile-lipophile balance value is 0≤HLB≤9, or in the lipophilic emulsifier, or in the mixed liquor of oil phase and lipophilic emulsifier, solution (B) is 1: 1 to 1: 9 with its ratio, these two kinds of solution are mixed under temperature 5-30 ℃, finally become a kind of transparent oil phase formulation (C), preserve down at 4-10 ℃;
(4) in order to keep the stable of solution, add certain amount of stabilizer; Stabilizing agent directly joins in described preparation process (1) solution, in the solution in the perhaps described step (3).
Surfactant in the described step (2), or amphiphilic grease, or their mixed liquor adopts following one or more mixing: ten Monooctamoins, Polyethylene Glycol-8-glycerol are sad/decanoin, Tween 80.
Whipping temp in the described step (2) is that 5-30 ℃, mixing speed are that 100-1800 rev/min, mixing time are 0.4-4 hour.
Lipophile solution or emulsifying agent in the described step (3) are: glyceryl oleate, polyglycereol-3-oleate, Polyethylene Glycol-6-glycerin mono-fatty acid ester.
Whipping temp in the described step (3) is that 5-30 ℃, mixing speed are that 100-1800 rev/min, mixing time are 0.4-4.0 hour.
Described stabilizing agent is selected from one or more of trehalose, bovine serum albumin, egg white powder and Polyethylene Glycol.
The addition of described stabilizing agent is the 0.1%-10% of final solution.
Described chicken interleukin-2 is reorganization chicken genetic engineering interleukin II and chicken natural interleukin-2.
The beneficial effect of the inventive method is: it is simple to have preparation technology, realize easily, it is convenient to use, characteristics such as required cost is low, this method adopts toxicity little, materials such as oral safe dispersant and oil phase make the uniform dispersing and dissolving of chicken interleukin-2 in oil phase, finally become a kind of transparent chicken interleukin-2 oil phase formulation.The oil phase formulation experiment in vitro that adopts this method to make shows that it in different pH (2-11) solution emulsification can both take place, and chicken interleukin-2 still is wrapped in basically in the oil and does not enter water.Therefore at drinking-water, when oral, Degradation that can reasonable opposing gastrointestinal enzyme, and absorbing is easily better brought into play the antiviral drug effect.The chicken interleukin-2 microsphere that adopts the inventive method to make, can make the embedding rate of interleukin II bring up to 60-92%, in simulated gastric fluid, discharge medicine less than 10%, in simulated intestinal fluid, discharge medicine more than 80%, can realize directed release of intestinal of interleukin II.
The specific embodiment
Below in conjunction with embodiment, to details are as follows according to the specific embodiment provided by the invention:
Embodiment 1
A kind of preparation method of chicken interleukin-2 microsphere novel dosage form is characterized in that concrete implementation step is as follows:
(1) is to add 50.0mg chicken genetic engineering interleukin II in 4.5 the solution at 8ml pH, makes its dissolving (A solution);
(2) taking polyethylene glycol-8-glycerol sad/decanoin 40.0ml, A solution added mix into 48ml.Mixing speed: 500 rev/mins; Time: 3.0 hours; Temperature: 20 ℃ (B solution);
(3) get polyglycereol-3-oleate 152ml, the adding of B solution is mixed into 200ml, mixing speed: 500 rev/mins, the time: 3.0 hours, temperature: 20 ℃ (C solution);
(4) add 500mg trehalose and 500mg egg white powder at C solution; And mix homogeneously, deposit in refrigerator and cooled and hide.
Adopt this this method to make the chicken interleukin-2 microsphere, can make the embedding rate of interleukin II bring up to 82.6%, discharging medicine in the 2h in simulated gastric fluid is 37.5%, discharges medicine 81.9% in simulated intestinal fluid, can realize directed release of intestinal of interleukin II.
Embodiment 2
A kind of preparation method of chicken interleukin-2 microsphere novel dosage form is characterized in that concrete implementation step is as follows:
(1) in the solution of 10ml pH=3.5, adds chicken natural interleukin-220.0mg, make its dissolving (solution A);
(2) get Tween 80 14ml, ten Monooctamoin 26ml, mix homogeneously adds solution A then and mixes, and stirs; Mixing speed: 1000 rev/mins; Time: 2.5 hours; Temperature: 18 ℃ (solution B);
(3) get glyceryl oleate 150ml, above-mentioned B solution adding is mixed into 200ml; Mixing speed: 1000 rev/mins; Time: 2.5 hours; Temperature: 18 ℃ (C solution);
(4) add 100mg trehalose and 200mg bovine serum albumin in C solution, mix homogeneously is deposited in refrigerator and cooled and is hidden.
Adopt this this method to make the chicken interleukin-2 microsphere, can make the embedding rate of interleukin II bring up to 91.0%, discharging medicine in the 2h in simulated gastric fluid is 36.2%, discharges medicine 86.4% in simulated intestinal fluid, can realize directed release of intestinal of interleukin II.
Above-mentioned detailed description of the preparation method of this chicken interleukin-2 microsphere novel dosage form being carried out with reference to embodiment; be illustrative rather than determinate; can list several embodiment according to institute's limited range; therefore in the variation and the modification that do not break away under the general plotting of the present invention, should belong within protection scope of the present invention.
Claims (6)
1, a kind of preparation method of chicken interleukin-2 microsphere novel dosage form is characterized in that comprising the steps:
(1) a certain amount of chicken interleukin-2 is dissolved in the water buffer solution, the pH value of this solution (A) is 2.5-7.0, and the content of chicken interleukin-2 is the 1.0-10.0 mg/ml;
(2) the above-mentioned acid solution (A) that contains chicken interleukin-2 is joined in the nonionic surfactant solution of liquid state that hydrophile-lipophile balance value (HLB) is 9≤HLB≤15, or in the amphiphilic grease, or in their mixed liquor; Described solution (A) and these surfactants, or amphiphilic grease, or the ratio of their mixed liquor is 1: 4 to 1: 40; These two kinds of solution stir under temperature 5-30 ℃, and it is mixed uniformly, become a kind of transparent solution (B);
(3) solution (B) is added in the oil phase of liquid state that hydrophile-lipophile balance value is 0≤HLB≤9, or in the lipophilic emulsifier, or in the mixed liquor of oil phase and lipophilic emulsifier, solution (B) is 1: 1 to 1: 9 with its ratio, these two kinds of solution are mixed under temperature 5-30 ℃, finally become a kind of transparent oil phase formulation (C), preserve down at 4-10 ℃;
(4) in order to keep the stable of solution, add certain amount of stabilizer; Stabilizing agent directly joins in described preparation process (1) solution, in the solution in the perhaps described step (3).
2, the preparation method of chicken interleukin-2 microsphere novel dosage form according to claim 1, it is characterized in that the surfactant in the described step (2), or amphiphilic grease, or their mixed liquor adopts following one or more mixing: Polyethylene Glycol-8-glycerol is sad/and decanoin, Tween 80, ten Monooctamoins.
3, the preparation method of chicken interleukin-2 microsphere novel dosage form according to claim 1 is characterized in that lipophile solution or the emulsifying agent in the described step (3) is: glyceryl oleate, polyglycereol-3-oleate, Polyethylene Glycol-6-glycerin mono-fatty acid ester.
4, the preparation method of chicken interleukin-2 microsphere novel dosage form according to claim 1 is characterized in that described stabilizing agent is selected from one or more of trehalose, bovine serum albumin, egg white powder and Polyethylene Glycol.
5, the preparation method of chicken interleukin-2 microsphere novel dosage form according to claim 1, the addition that it is characterized in that described stabilizing agent is the 0.1%-10% of final solution.
6, the preparation method of chicken interleukin-2 microsphere novel dosage form according to claim 1 is characterized in that described chicken interleukin-2 is reorganization chicken genetic engineering interleukin II and chicken natural interleukin-2.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CNA2008100533636A CN101297959A (en) | 2008-05-30 | 2008-05-30 | Preparation of chicken interleukin-2 microsphere novel dosage form |
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| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CNA2008100533636A CN101297959A (en) | 2008-05-30 | 2008-05-30 | Preparation of chicken interleukin-2 microsphere novel dosage form |
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| Publication Number | Publication Date |
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| CN101297959A true CN101297959A (en) | 2008-11-05 |
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| CNA2008100533636A Pending CN101297959A (en) | 2008-05-30 | 2008-05-30 | Preparation of chicken interleukin-2 microsphere novel dosage form |
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- 2008-05-30 CN CNA2008100533636A patent/CN101297959A/en active Pending
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Application publication date: 20081105 |