CN101297961A - Preparation of dog interferon novel dosage form - Google Patents
Preparation of dog interferon novel dosage form Download PDFInfo
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- CN101297961A CN101297961A CNA2008100533640A CN200810053364A CN101297961A CN 101297961 A CN101297961 A CN 101297961A CN A2008100533640 A CNA2008100533640 A CN A2008100533640A CN 200810053364 A CN200810053364 A CN 200810053364A CN 101297961 A CN101297961 A CN 101297961A
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Abstract
The invention relates to a preparation method of a new formulation canine interferon, which has the steps as follows: (1) the canine interferon is dissolved in an aqueous phase buffer solution to form a solution (A), the pH value of which ranges from 2.5 to 7.0 and the content of the canine interferon is 0.5-5.0 mg/ml; (2) the acid solution (A) containing the canine interferon 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 preparation method of the invention has simple preparation, simple and convenient application and easy absorption, and can better realize the effect of treating canine viral diseases.
Description
Technical field
The invention belongs to the preparing technical field of bio-pharmaceutical, particularly a kind of preparation method of dog interferon novel dosage form.
Background technology
At present, dog interferon all is with the administration of injecting better therapeutic effect to be arranged, and many persons need inject 1-2 time every day, and provisions dog person's use brings a lot of inconvenience, and therefore being made into oral formulations just becomes the target that people pursue.If have breakthrough in this regard, will produce huge social and economic benefit.But directly that these bio-pharmaceuticals are 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 dog interferon novel dosage form, effectively prevent and prevent and treat various canine viral 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, the obvious results dog interferon novel dosage form.
A kind of preparation method of dog interferon novel dosage form is characterized in that comprising the steps:
(1) a certain amount of dog interferon is dissolved in the water buffer solution, the pH value of this solution (A) is 2.5-7.0, and the content of dog interferon is the 0.5-5.0 mg/ml;
(2) the above-mentioned acid solution (A) that contains dog interferon 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.
Described mixing speed is 100-1800 rev/min, and mixing time is 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 5-30 ℃, and mixing speed is 100-1800 rev/min, and mixing time is 0.4-4.0 hour.
Described stabilizing agent is selected from one or more of trehalose, bovine serum albumin, porcine hemoglobin and Polyethylene Glycol.
The addition of described stabilizing agent is the 0.1%-10% of final solution.
Described dog interferon is reorganization dog genetic engineering interferon IFN-α, IFN-β and the natural LeIF of dog.
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 dog interferon in oil phase, finally become a kind of transparent dog interferon 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 dog interferon still is wrapped in basically in the oil and does not enter water.Therefore when oral, the Degradation of the reasonable opposing gastrointestinal enzyme of energy, and absorption are easily better brought into play the antiviral drug effect.
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 dog interferon novel dosage form is characterized in that concrete implementation step is as follows:
(1) is to add 32.0mg dog genetic engineering interferon IFN-α 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 porcine hemoglobin at C solution; And mix homogeneously, deposit in refrigerator and cooled and hide.
Embodiment 2
A kind of preparation method of dog interferon novel dosage form is characterized in that concrete implementation step is as follows:
(1) in the solution of 10ml pH=3.5, adds the natural LeIF 16.0mg of dog, 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.
Embodiment 3
A kind of preparation method of dog interferon novel dosage form is characterized in that concrete implementation step is as follows:
(1) add 50.0mg dog genetic engineering interferon IFN-β in the solution of 10ml pH=4,200mg Polyethylene Glycol 5000 makes its dissolving (A solution);
(2) taking polyethylene glycol-8-glycerol sad/decanoin 80ml; A solution is added, be mixed into 90ml; Mixing speed: 1500 rev/mins; Time: 2 hours; Temperature: 25 ℃ (B solution);
(3) get polyglycereol 3 oleate 55ml and Polyethylene Glycol-6-glycerol list olein 55ml, be mixed into 110ml solution, then B solution is mixed mixing speed with this mixed liquor under following condition: 1500 rev/mins; Time: 2 hours; Temperature: 25 ℃ (C solution), deposit in refrigerator and cooled and hide, preserve down at 4-10 ℃.
Application example 1
Dog interferon novel dosage form is to the clinical efficacy test of canine distemper
One, materials and methods
(1) test material
Dog interferon novel dosage form is to adopt the preparation of embodiment 2 methods; Usage and dosage is oral, 1ml/ bar dog.The strong malicious separated strain of strain canine distemper (CDV).
40 of the soil species dogs of 3 monthly age of laboratory animal outward appearance health.
(2) test method
1. the separation of canine distemper (CDV) virulent strain: after clinical diagnosis, tissue are forgiven health check-up and looked into, but filter out the hypochondriasis dog, getting brain, liver, lung tissue extracting RNA then carries out RT-PCR and detects, after will confirming as the male sick dog tissue homogenate of canine distemper, handle through mycillin, as the counteracting toxic substances strain.
2. laboratory animal is carried out the CDV diagnosis: every dog blood sampling separation of serum, whether the CDV antibody ELISA test kit detection with the Anheal Laboratories Co., Ltd is canine distemper antibody, if it is positive, then eliminate, the restock laboratory animal, again detect, until obtaining 60 canine distemper negative antibody dogs.
3. grouping: 40 of dogs of test are divided into four groups of A, B, C, D at random, 10 every group, treat with dog interferon novel dosage form behind the A group counteracting toxic substances, with the virazole treatment, the C group is the counteracting toxic substances matched group behind the B group counteracting toxic substances, an infective virus but do not treat, the D group is normal healthy controls group, not infective virus.
4. three groups of counteracting toxic substances: A, B, C inoculate canine distemper virus in conjunction with eye dripping, collunarium and three kinds of modes of lumbar injection, and the D group compares with normal saline, also carries out according to eye dripping, collunarium and three kinds of modes of lumbar injection.Wherein eye dripping is each 0.5 milliliter, each 1 milliliter of collunarium, each 3 milliliters of lumbar injection.
5. treatment: 10 dogs of A group were treated by the oral dog interferon novel dosage form of 1ml/ bar dog behind the inoculation canine distemper virus in 24 hours, 48 hours; 10 dogs of B group were treated by 2 milligrams/kg body weight injecting virus azoles respectively behind the inoculation canine distemper virus in 24 hours, 48 hours; C group, D group are not carried out any treatment.
6. record: observe also record clinical symptoms, the statistics death toll.
(3) result of the test and analysis
Dog interferon novel dosage form sees table 1 for details to the clinical therapeutic efficacy of canine distemper.
By table 1 as seen, the oral dog interferon novel dosage form of dog will be far superior to virazole to the therapeutic effect of canine distemper.
A organizes 24 hours and double oral dog interferon novel dosage form treatment in 48 hours behind counteracting toxic substances, the result is 6 symptoms that loss of appetite and lassitude occur only, but state is better than B group counteracting toxic substances dog, and cough and symptoms of emesis do not occur, death toll is 1, and mortality rate is 10.0%.
B organizes 24 hours and double intramuscular injection virazole treatment in 48 hours behind counteracting toxic substances, and the result has 8 symptoms that loss of appetite and lassitude occur, cough and symptoms of emesis occur, and dead 5, mortality rate is 50.0%.
C organizes behind counteracting toxic substances the 3rd day and anorexia occurs, and purulence or serosity secretions appear in the canthus, and with symptoms such as cough, vomitings, 9 sick dog death, mortality rate being arranged in 10～15 days behind counteracting toxic substances is 90.0%.
Any clinical symptoms does not appear in the D group, and dead bar number is 0.
The oral dog interferon novel dosage form of table 1 dog is to the clinical trial result of canine distemper
| Numbering | Group | Mortality rate % | Effective percentage % |
| A | The oral dog interferon of dog | 10.0 | 80.0 |
| B | Virazole treatment group | 50.0 | 40.0 |
| C | The counteracting toxic substances matched group | 90.0 | 10.0 |
| D | The normal healthy controls group | 0 | 100.0 |
Experimental result is as follows: this result of the test shows, dog interferon novel dosage form treatment canine distemper effective percentage of the present invention is 88.6%, analyze by statistics, the A group is organized difference highly significant (P＜0.01) with B group, C group, D, illustrates that the oral dog interferon novel dosage form of dog of the present invention has significant therapeutical effect to canine distemper disease.
Application example 2
Dog interferon novel dosage form is to the therapeutical effect of infectious canine hepatitis
Typical infectious canine hepatitis morbidity dog is selected in the clinical treatment test, and 30 dogs are divided into 3 groups at random, and the A group gives dog interferon novel dosage form 1.0ml/ bar with the spice oral way, and dog interferon novel dosage form is to adopt the preparation of embodiment 2 methods; B group injection dog hyper-immune serum.C organizes oral normal saline.
Experimental result
The sick result of the test of table 2 dog oral " dog interferon novel dosage form " treatment infectious canine hepatitis
| Group | Quantity | The morbidity number | Invalid number | Inefficiency % | Significant figure | Effective percentage % |
| The A group | 10 | 10 | 3 | 30.0 | 7 | 70.0 |
| The B group | 10 | 10 | 2 | 20.0 | 8 | 80.0 |
| The C group | 10 | 10 | 8 | 80.0 | 2 | 20.0 |
By table 2 as seen, " dog interferon novel dosage form " test group effective percentage is 70.0%, and the effective percentage of oral normal saline group is 10.0%.As seen, give dog interferon novel dosage form with the spice oral way infectious canine hepatitis is had good therapeutic effect.Experiment showed, the explanation spice orally give dog interferon novel dosage form may command infectious canine hepatitis state of an illness.
Dog interferon novel dosage form mainly has significant advantage to the prevention and the treatment of treatment canine viral disease.Studies confirm that: dog interferon novel dosage form also has remarkable therapeutical effect to the canine model and the infectious canine hepatitis morbidity dog of artificial challenge's canine distemper virus.As seen, give the active drug that dog interferon novel dosage form is the treatment canine viral disease with oral way.
Above-mentioned detailed description of the preparation method of this dog interferon 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 dog interferon novel dosage form is characterized in that comprising the steps:
(1) a certain amount of dog interferon is dissolved in the water buffer solution, the pH value of this solution (A) is 2.5-7.0, and the content of dog interferon is the 0.5-5.0 mg/ml;
(2) the above-mentioned acid solution (A) that contains dog interferon 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 dog interferon 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 dog interferon 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 dog interferon 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, porcine hemoglobin and Polyethylene Glycol.
5, the preparation method of dog interferon 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 dog interferon novel dosage form according to claim 1 is characterized in that described dog interferon is reorganization dog genetic engineering interferon IFN-α, IFN-β and the natural LeIF of dog.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CNA2008100533640A CN101297961A (en) | 2008-05-30 | 2008-05-30 | Preparation of dog interferon novel dosage form |
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| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CNA2008100533640A CN101297961A (en) | 2008-05-30 | 2008-05-30 | Preparation of dog interferon novel dosage form |
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| Publication Number | Publication Date |
|---|---|
| CN101297961A true CN101297961A (en) | 2008-11-05 |
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| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CNA2008100533640A Pending CN101297961A (en) | 2008-05-30 | 2008-05-30 | Preparation of dog interferon novel dosage form |
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| CN (1) | CN101297961A (en) |
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- 2008-05-30 CN CNA2008100533640A patent/CN101297961A/en active Pending
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Open date: 20081105 |