CN1051224C - Lyophilized bougie and producing process thereof - Google Patents
Lyophilized bougie and producing process thereof Download PDFInfo
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- CN1051224C CN1051224C CN94107669A CN94107669A CN1051224C CN 1051224 C CN1051224 C CN 1051224C CN 94107669 A CN94107669 A CN 94107669A CN 94107669 A CN94107669 A CN 94107669A CN 1051224 C CN1051224 C CN 1051224C
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- bougie
- lyophilized
- substrate
- bolt
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Abstract
The present invention relates to a lyophilized bougie and a producing process thereof, particularly to a biological product bougie such as natural alpha, beta and gamma interferon bougies and alpha, beta and gamma interferon bougies produced by genetic engineering. The present invention has solid inner bougies which are uniformly distributed in a substrate, and an outer film. The lyophilized bougie is characterized in that the substrate is mannitol; the outer film is a liposoluble substance. The producing process comprises substrate preparation, medical solution addition, uniform mixture, molding, dryness, film suspension and package. The producing process is characterized in that the substrate is the mannitol; the substrate content of water solution is from 20 to 50%; a molding method comprises film reverse, freezing and film opening; freezing temperature is below-10 DEG C; after the substrate is molded, vacuum dryness at low temperature is carried out so that the bougie is sufficiently dewatered.
Description
The present invention relates to medical bolt and method for making thereof, be specially adapted to the bolt of biological product, as natural α, β, the interferon gamma bolt of producing with genetic engineering.
The suppository in market is a solid now, is made up of medicine, substrate.By the difference of substrate, existing suppository is divided into two classes: a class is water solublity (or hydrophilic) substrate bolt, and another kind of is oil-soluble substrate bolt, though two class suppository profiles can have many differences, key all is solid, and medicine is evenly distributed in the substrate.For the water-soluble base bolt, its substrate is the mixture of gelatin and glycerol, also can be the mixture of alginate jelly or Polyethylene Glycol and glycerol.In order to make bolt (1 hour) dissolving rapidly in human body, the water content of bolt will be more than 50%, and glycerol plays preserves moisture, to prevent that the dry hardening of bolt can not be by the rapid dissolved effect of body fluid.The content of drug of existing suppository is all bigger, does not also find biological product and the suppository that the antibiotic equal size is small and water content is very little, does not also find the bibliographical information of this respect.
Interferon is a kind of broad-spectrum antiviral, antineoplastic biological product, and it has excellent curative for multiple viral disease.The sickness rate of chronic cervicitis, cervical erosion accounts for married woman's 50%, application of interference extract for treating chronic cervicitis starts from 1972, so far existing two more than ten years history, case has reached thousands of examples, and the local topical interferon can make medicine directly act on the affected part target cell, and effect directly, dosage is little, determined curative effect, cure rate height (60-70%), and also treatment back relapse rate is far below laser, Therapeutic Method such as freezing.But for interferon is a kind of water-soluble biological goods, these goods are unstable under liquid condition, effect duration is short, after how clinical practice makes dried frozen aquatic products earlier, face with the preceding water dissolution of using, so mostly be the injectable powder type, and as medicine for external use local application, the dissolved mode of this powder is difficult to adopt for the patient oneself, and other agent shapes also are difficult to large-scale production and the formal medicine commercialization of conduct because of its stability problem on producing.
We had once submitted the application for a patent for invention of a " hard porous foam embolus and manufacturing process thereof " by name to Patent Office of the People's Republic of China on January 27th, 94, moisture back instability and the small medicine of consumption (such as biological product, antibiotic such as penicillins) are made the difficult problem of suppository with solution.
The object of the present invention is to provide another lyophilized bougie and manufacturing process thereof, moisture back instability and the small medicine of consumption (such as biological product, antibiotic such as penicillins) are made the difficult problem of suppository with solution.
Lyophilized bougie of the present invention, particularly biological product bolt, as natural α, β, the interferon gamma bolt of producing with genetic engineering, it has medicine bolt and adventitia in the equally distributed solid in substrate, it is characterized in that substrate is mannitol, and adventitia is a liposoluble substance.
Also be evenly distributed with stabilizing agent in the bolt in above-mentioned, the part by weight of mannitol and stabilizing agent is 1: 1--0.01.Stabilizing agent is the human albumin, sorbitol, trehalose, glucosan, dextran, degraded gelatin, lactose, calcium gluconate a kind of or two kinds.
The liposoluble substance of adventitia can be with semi-synthetic fatty acid ester, oleum theobromatis, Sapium sebiferum (L.) Roxb. fat, wherein can add an amount of antiseptic, antibiotic, surfactant, the painted additive that waits, have lubricated and isolate extraneous effect, with guarantee the convenient and interior bolt of medication in the drug storage process not because of the stability decreases of suction messenger drug.
Lyophilized bougie manufacturing process of the present invention, be specially adapted to the bolt of biological product, as natural α, β, the interferon gamma bolt of producing with genetic engineering, it comprises preparation substrate, add medicinal liquid, mix homogeneously, shaping, drying, biofilm, packing is characterized in that used substrate is mannitol, and the matrix content of its aqueous solution is 20-50%, manufacturing process is pour mask, freeze, skinning, the temperature of freezing is carried out low-temperature vacuum drying below-10 ℃ after the shaping, bolt is fully dewatered.
Above-mentioned lyophilized bougie manufacturing process is characterized in that the temperature freezed is-40--30 ℃.
Above-mentioned lyophilized bougie manufacturing process, when it is characterized in that low-temperature vacuum drying under the evacuation state from-70--30 ℃, be warming up to 30 ℃ through 30-60 hour.
Above-mentioned lyophilized bougie manufacturing process is characterized in that adding stabilizing agent before the mix homogeneously, and the part by weight of mannitol and stabilizing agent is 1: 1--0.01, the content of both aqueous solutions are 20-50%.
Above-mentioned lyophilized bougie manufacturing process, the content that it is characterized in that mannitol in the Osmitrol is 30-35%.
Above-mentioned lyophilized bougie manufacturing process is characterized in that the adding temperature of medicinal liquid should be at 10-40 ℃.
Above-mentioned lyophilized bougie manufacturing process is characterized in that continuing after the molding that cold preservation made it to freeze fully more than 30 hours under solidification point, so that during lyophilizing, moisture content is to distil from level to level in the bolt, and can not cause key to shrink because of moisture content inside and outside the bolt distils simultaneously.
Below to be example to lyophilized bougie and manufacturing process thereof do further describes with the refining human leukocyte interferon of medicine.
Refining human leukocyte interferon bolt is used for treating female chronic cervicitis, cervical erosion, and it is a principal agent with refining human leukocyte interferon, and mannitol is substrate, and the human albumin is the protective agent (stabilizing agent) of interferon, and adventitia is with semi-synthetic fatty acid mixed fat.Write out a prescription for example down:
Mannitol 795g
Refining human leukocyte interferon 6 * 10
7IU
Human albumin 32g
Semi-synthetic fatty acid ester (36 type) 500g
Water adds to 2650g
Manufacturing process:
1, preparation substrate: take by weighing 795g mannitol, be dissolved in water.Put after the sterilization and be chilled to 30 ℃.
2, add medicinal liquid: will make with extra care human leukocyte interferon 6 * 10
7IU and human albumin 32g add in the substrate, mend and add water to 2650g (mannitol content is 30%).
3, reverse mould: after will handling clean and scribbling the bolt mould pre-cooling of lubricant, mix homogeneously pastille substrate example is gone in the mould, puts-30 ℃ and locates to freeze.
4, molding: after freezing, cut with cutter and to overflow part, open mould, bolt is taken out.
5, cold storage: the bolt after the molding can be put into-30 ℃ again and locate to deposit 48 hours.
6, lyophilizing: the bolt after the cold preservation is put into drying cupboard,, make it dry by the operation of lyophilizing rules.
7, biofilm: incite somebody to action plug-in first Acrawax adventitia of lyophilizing pearl bolt.
8, packing: the bolt package encapsulation that will finish biofilm.
Make 1000 on refining human leukocyte interferon bolt by above prescription and technology, every bolt contains interferon 6 * 10
4IU, its recall rate of tiring is about 40%, the water content of bolt＜10%, there have suitable hardness can guarantee in producing, transport and using to be not damaged, can dissolve fully in 1 hour in vagina.Preliminary test shows under the 4-8 ℃ of condition that each physicochemical property and biological activity do not have significant change in 1 year, and temperature low more effect duration is long more.
Recipe specifies:
Refining human leukocyte interferon: be the principal agent in the side, mainly get its antivirus action.The topical mode can make it directly act on target cell, plays antivirus action, finally reaches the effect of treatment female chronic cervicitis, cervical erosion.Dose can increase and reduce as required.
Mannitol: interferon and kanamycin are water soluble drugs, and it is to skin and mucosa nonirritant, and patient uses the no sense of discomfort in back, and can fully dewater in freezing dry process, and suitable hardness is arranged behind the patent medicine, can dissolve rapidly again in body fluid.
Semi-synthetic fatty acid ester: semi-synthetic fatty acid ester is a kind of the most frequently used fat-soluble substrate, also be commonly used to prepare multiple suppository, we are that it is wrapped in mannitol is the outside of the key (interior bolt) made of substrate with this substrate, make key form the fat-soluble adventitia of one deck outward, can make the key smooth outer surface, the patient is easy to use, bolt drying in can keeping again, can be because of the moisture absorption does not make the medicine stability decreases, the effect phase shortens.Same substance also has oleum theobromatis, Sapium sebiferum (L.) Roxb. fat etc.
Human albumin: as the protective agent (stabilizing agent) of interferon; can under higher temperature, prolong the effect duration of interferon widely; when having stabilizing agent, need could not preserve below-10 ℃ more than 1 year the lyophilizing interferon suppository; can under 4-8 ℃ of condition, preserve more than 1 year after adding stabilizing agent, if can preserve 921 days at 0 ℃.Play same function and also have trehalose, sorbitol, glucosan, dextran, degraded gelatin, calcium gluconate, lactose etc.
Water: the effect of water in prescription is to make the mannitol dissolving earlier, plays the effect of solvent; Another effect is the allotment ratio.The content of Osmitrol directly influences the recall rate of tiring in the hardness of finished product bolt and the bolt, test shows, content should be in the 20-50% scope, the recall rate of tiring reduces to 30% from 60% along with its hardness rising of increase of mannitic acid content, content is frangible less than 20% finished product bolt matter pine, can descend significantly though content is higher than the fine recall rate of tiring of 50% hardness.Preferably content is controlled at 30%-35%, hardness at this moment suitably, tire recall rate about 40%.
Description of the process:
1, preparation substrate:
(1) mannitol dissolving: commercially available mannitol is generally white powder, when being used for preparing suppository, at first substrate must be made aqueous solution.
(2) sterilization: owing to diversified reason, have a large amount of antibacterials in the commercial mannitol, pathogenic microorganisms such as mycete reach requirement for making the final hygiology index of product, must carry out autoclaving, guarantee that the hygiology index is qualified.Sterilising conditions is 105 ℃, 30 minutes.
(3) put after the substrate sterilization that to be chilled to below 40 ℃ be in order to make when adding medicinal liquid, Yin Wendu is too high and the activity of refining human leukocyte interferon is descended and influence product quality.
2, add medicinal liquid: added medicine can be various biological product or antibiotic, and their modes with aqueous solution are added, and also can the powder mode add.Adding water after medicine adds makes the content of substrate reach 20-50%.The way that water is added in employing can be eliminated every batch of medicine and tire and do not wait influence to matrix content, makes the content of mannitol accurately reach some values among the 20-50%.
There is data to show, the fluid temperature of biological product (or production temperature) is the upper limit with 60 ℃, too high temperature can make it inactivation and have a strong impact on the property of medicine, therefore reduce to below 60 ℃ for about 100 ℃ when the temperature of the system bolt process mesostroma aqueous solution of this technology should be from dissolving and just can pour medicinal liquid into, we are chosen as 10-40 ℃ for the sake of assurance, the low more activity that helps preserving medicine more of temperature can be solidified and is unfavorable for the medicinal liquid mix homogeneously but be lower than 10 ℃ of mannitol solutions.The effect of each side can be taken into account preferably when being taken as 30 ℃ of left and right sides.
3, be shaped: put rapidly behind the reverse mould to-30 ℃ and make the bolt quick freezing, guarantee interferon activity.General technology is placed in room temperature or cold place (0-5 ℃), but substrate is solidified just molding of back, but during preparation biological product bolt, even solidified but key owing to contain a large amount of water, can not be shaped after the molding, so must be placed on quick freezing below-10 ℃, guarantee the activity of biological product on the one hand, make not cracky of key skinning on the other hand.Solidification point is low more, and the time that key freezes is just short more, and test shows-10 ℃ of freeze-off times 3 hours,-20 ℃ of freeze-off times 1.5 hours ,-30 ℃ of freeze-off times 40 minutes are considered and are shortened production cycle and cost, solidification point is taken as-40--30 ℃ better, freeze good bolt skinning.
4, lyophilizing: freeze-dry process is one of peculiar technology of the present invention, and its purpose is to remove the moisture content in the key, makes its final moisture being controlled in 10%, like this, biological product activity stabilized, product can long preservation.Freeze dried initial temperature is-70--30 ℃, and the time that the low more key of temperature freezes is just short more, and product quality is good more, but it is proper to be taken as-50 ℃ of left and right sides.Freeze dried programming rate rises to 30 ℃ with 30-60 ℃ and is as the criterion.
Can also make it to freeze fully with key frozen more than 30 hours below-30 ℃ before the lyophilizing so that during lyophilizing in the bolt moisture content be to distil from level to level, and can not cause key to shrink because of moisture content inside and outside the bolt distils simultaneously.
Claims (12)
1. lyophilized bougie, it has medicine bolt and adventitia in the equally distributed solid in substrate, it is characterized in that substrate is mannitol, and adventitia is a liposoluble substance.
2. lyophilized bougie as claimed in claim 1 is characterized in that described bolt is the biological product bolts, as natural α, β, the interferon gamma bolt of producing with genetic engineering.
3. lyophilized bougie as claimed in claim 2 also is evenly distributed with stabilizing agent in the bolt in it is characterized in that, the part by weight of mannitol and stabilizing agent is 1: 1-0.01.
4. lyophilized bougie as claimed in claim 3 is characterized in that stabilizing agent is the human albumin, sorbitol, trehalose, glucosan, dextran, degraded gelatin, lactose, calcium gluconate a kind of or two kinds.
5. as claim 1,2,3,4 described lyophilized bougies, it is characterized in that liposoluble substance is semi-synthetic fatty acid ester, oleum theobromatis, Sapium sebiferum (L.) Roxb. fat.
6. as claim 1,2 described lyophilized bougie manufacturing process, it comprises preparation substrate, add medicinal liquid, mix homogeneously, shaping, drying, biofilm, packing is characterized in that used substrate is mannitol, and the matrix content of its aqueous solution is 20-50%, manufacturing process is pour mask, freeze, skinning, the temperature of freezing is carried out low-temperature vacuum drying below-10 ℃ after the shaping, bolt is fully dewatered.
7. lyophilized bougie manufacturing process as claimed in claim 6 is characterized in that the temperature freezed is-40-30 ℃.
8. lyophilized bougie manufacturing process as claimed in claim 6, when it is characterized in that low-temperature vacuum drying under the evacuation state from-70--30 ℃, be warming up to 30 ℃ through 30-60 hour.
9. lyophilized bougie manufacturing process as claimed in claim 8 is characterized in that adding stabilizing agent before the mix homogeneously, and the part by weight of mannitol and stabilizing agent is 1: 1-0.01.
10. as claim 7,8,9 described lyophilized bougie manufacturing process, the content that it is characterized in that mannitol in the Osmitrol is 30-35%.
11. lyophilized bougie manufacturing process as claimed in claim 10 is characterized in that the adding temperature of medicinal liquid should be at 10-40 ℃.
12. lyophilized bougie manufacturing process as claimed in claim 11 is characterized in that continuing after the molding under solidification point cold preservation and carries out lyophilization again after making it to freeze fully more than 30 hours.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN94107669A CN1051224C (en) | 1994-07-02 | 1994-07-02 | Lyophilized bougie and producing process thereof |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN94107669A CN1051224C (en) | 1994-07-02 | 1994-07-02 | Lyophilized bougie and producing process thereof |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN1124617A CN1124617A (en) | 1996-06-19 |
| CN1051224C true CN1051224C (en) | 2000-04-12 |
Family
ID=5033165
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN94107669A Expired - Lifetime CN1051224C (en) | 1994-07-02 | 1994-07-02 | Lyophilized bougie and producing process thereof |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN1051224C (en) |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2004002451A1 (en) * | 2002-06-28 | 2004-01-08 | Fang Chen | Controllable released suppository used in milk-secreting channel |
Families Citing this family (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN114667999A (en) * | 2022-05-27 | 2022-06-28 | 广东先康达生物科技有限公司 | Immune cell cryopreservation stabilizer, cryopreservation liquid and cryopreservation method |
Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4675184A (en) * | 1981-11-28 | 1987-06-23 | 501 Sunstar Kabushiki Kaisha | Pharmaceutical composition containing interferon in stable state |
| JPH02124832A (en) * | 1988-07-08 | 1990-05-14 | Toray Ind Inc | Interferon-beta composition |
-
1994
- 1994-07-02 CN CN94107669A patent/CN1051224C/en not_active Expired - Lifetime
Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4675184A (en) * | 1981-11-28 | 1987-06-23 | 501 Sunstar Kabushiki Kaisha | Pharmaceutical composition containing interferon in stable state |
| JPH02124832A (en) * | 1988-07-08 | 1990-05-14 | Toray Ind Inc | Interferon-beta composition |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2004002451A1 (en) * | 2002-06-28 | 2004-01-08 | Fang Chen | Controllable released suppository used in milk-secreting channel |
Also Published As
| Publication number | Publication date |
|---|---|
| CN1124617A (en) | 1996-06-19 |
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| C14 | Grant of patent or utility model | ||
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| C53 | Correction of patent for invention or patent application | ||
| COR | Change of bibliographic data |
Free format text: CORRECT: PATENTEE; FROM: ZHONGKE KANGYI BIOLOGICAL PHARMACEUTICAL FACTORY, WUHAN TO: WUHAN TIAN AO PHARMACEUTICAL CO., LTD. |
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| CP03 | Change of name, title or address |
Address after: 430060 Peng Liu, Yang Lu, 232, Wuchang, Hubei, Wuhan Patentee after: Wuhan Tian Ao Pharmaceutical Co., Ltd. Address before: 430071 No. 44, Middle District, little Wuchang, Wuhan, Hubei, Hongshan Patentee before: Zhongke Kangyi Biological Pharmaceutical Factory, Wuhan |
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| C56 | Change in the name or address of the patentee |
Owner name: WUHAN WEIAO PHARMACEUTICAL CO., LTD. Free format text: FORMER NAME OR ADDRESS: WUHAN TIAN AO PHARMACEUTICAL CO., LTD. |
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| CP01 | Change in the name or title of a patent holder |
Patentee after: Wuhan Vital Pharmaceutical Co., Ltd. Patentee before: Wuhan Tian Ao Pharmaceutical Co., Ltd. |
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| C17 | Cessation of patent right | ||
| CX01 | Expiry of patent term |
Expiration termination date: 20140702 Granted publication date: 20000412 |