CN101204377A - Novel cryoprotectants prescription for treatment of botulinum toxin a freeze-dried powder and injection preparation - Google Patents
Novel cryoprotectants prescription for treatment of botulinum toxin a freeze-dried powder and injection preparation Download PDFInfo
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- CN101204377A CN101204377A CNA2006101677698A CN200610167769A CN101204377A CN 101204377 A CN101204377 A CN 101204377A CN A2006101677698 A CNA2006101677698 A CN A2006101677698A CN 200610167769 A CN200610167769 A CN 200610167769A CN 101204377 A CN101204377 A CN 101204377A
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- human albumin
- sucrose
- lactose
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Abstract
The invention relates to a medicine preparation of botulinus toxin A, which can be stored for 12 months under room temperature, and for 36 months under 4 DEG. C in the solid form of lyophiled powder injection when a preferable lyopilization protecting agent is added. The lyopilization protecting agent is prepared by mixing human serum albumin, sucrose or human serum albumin, lactose, with water in a certain ratio. The medicine preparation of botulinus toxin A is applied to diseases such as heterotropia, blepharospasm, mimic convulsion and spastic strabismus. Compared with former formulation, the botulinus toxin A of the invention has good quality and high stability.
Description
Technical field
The present invention relates to the pharmaceutical preparation of botulinum toxin type A, at room temperature can stablize storage at least 12 months with the solid form of lyophilized injectable powder adding preferred a kind of freeze drying protectant, but 4 ℃ of storage-stable 36 months.
Background technology:
(botulinum neurotoxin BoNT), also claims botulinum toxin (botulinumtoxin) to botulinum neurotoxin, is the under anaerobic excretory polypeptide neurotoxins of bacillus botulinus.Neurotoxin is by the release of the neurotransmitter acetylcholine of inhibition neuromuscular junction, and the transmission of the impulsion that affects the nerves causes property paralysis of flaccid muscles.
A type BoNT is one of at present known extremely toxic substance, but in recent years, has been applied to diseases such as stravismus, blepharospasm, facial spasm and spastic strabismus are treated, and has obtained satisfactory effect.A type BoNT in 1989 is used for more than 12 years old diseases (http://www.garlandscience.com/cbl/pdflibrary/botox_timeline.pdf) such as the stravismus that is caused by the muscle tone obstacle, blepharospasm more than 12 years old by U.S. food and drug administration (FDA) approval.This is the 1st microbial toxin that is approved for medicine in the world.
A type BoNT exists with a species complex form usually under naturalness or on the synthetic medium, i.e. neurotoxin and hemagglutinin or the proteic complex of non-hemagglutination activity.As many biological activity proteins, the biological activity of BoNT is relevant with its spatial shape structure, and (Sugiyama 1980 keeping BoNT three dimensional structure and stability to play an important role for hemagglutinin; Schantz ﹠amp; Johnson 1992).BoNT is easy to be destroyed by the high temperature more than 80 ℃, particularly under alkali condition; The bubble that air/liquid interface forms can cause that the stretching, extension of neurotoxin and form change, and then make BoNT solution lose toxicity, in the environment that nitrogen and carbon dioxide are arranged, also can make the BoNT degeneration, be diluted to low concentration (ng/ml) stability of BoNT is reduced, lose the part activity.Because BoNT is the macromolecular substances of about 150 kDa, deactivated BoNT promptly becomes nontoxic toxoid albumen, such toxin protein is a kind of good immunogenicity material, makes the injector produce antibody, and then influences the further therapeutic effect of BoNT preparation.How in diluting low concentration BoNT preparation process, to guarantee its stability, just become a crucial measure.Experimental study shows, by strengthening its stability (Goodnough ﹠amp with buffer (pH＜6.8) the dilution BoNT stock solution that contains other albumen such as gelatin, cattle or human serum albumin; Johnson 1992).
In China existing injection A type BoNT lyophilized formulations, all adopted gelatin as the active substance protective agent in the preparation (Yang Zhong 1997); but gelatin is mainly derived from cattle belongs to xenobiotic concerning the people, and danger (for example bovine spongiform encephalopathy) Japan and some American-European countries of also existing viral pollution have simultaneously forbidden this series products import.The present invention be directed to the deficiency that exists as the protective agent in the injection A type BoNT lyophilized formulations with gelatin designed a kind of novel prescription be used as A type BoNT frozen-dried protective liquid, make Product Safety higher, have more the market competitiveness.The human albumin is the albumen that is rich in people's the blood plasma, about 69 kDa of human serum albumin's molecular weight, and (Kurono 1982 often to be used as the protein drug protective agent; Tarelli1998), albumin mainly is to reduce by: the adhesion (2) that (1) reduces protein active composition and surface that generable active component degeneration comes the stabilize proteins active component in the low dilution factor formulations prepared from solutions process of active component, except stablizing the protein active composition in the drug regimen, compare with gelatin and Sanguis Bovis seu Bubali albumin, the human albumin also has injection when giving the patient, can ignore usually that it is immunogenic and use advantages such as safer.
Summary of the invention
The present invention is by in the pharmaceutical preparation of A type BoNT; add the preferred freeze drying protectant of a kind of process; reach the purpose of stablizing A type BoNT; different with the A type BoNT pharmaceutical preparation of having gone on the market; goods of the present invention are made up of pharmaceutically acceptable freeze drying protectant and A type BoNT crystalline composites; it is characterized in that freeze drying protectant is wherein formed by a certain percentage by human human albumin and lactose or by human human albumin and sucrose.
The prescription of the preferential freeze drying protectant of the present invention is as follows:
Human human albumin 0.5%～10%
Lactose or sucrose 0.5%～10%
All the other are water for injection
The prescription of freeze drying protectant of the present invention is more preferably following prescription:
Human human albumin 1%～5%
Lactose or sucrose 1%～5%
All the other are water for injection
The prescription of freeze drying protectant of the present invention, most preferred is following prescription
Human human albumin 2.5%
Lactose or sucrose 2.5%
All the other are water for injection
Human human albumin in the prescription selects the human human albumin that can circulate through State Food and Drug Administration's approval on market, lactose and sucrose are selected pharmaceutical lactose or the sucrose through State Food and Drug Administration's approval.
Related BoNT can be selected from A, B, C, D, E, F, G serotype among the present invention, can prepare by the way that document is reported, specifically can prepare by following a kind of method:
I, toxin producing medium composition:
Enzyme hydrolysis casein 1%～10%
Yeast soaks powder 1%～10%
Sodium thioglycolate 0.01%～0.05%
Cysteine hydrochloride 0.01%～0.1%
Glucose 1%～2%
II, toxin producing medium form:
(1) casein hydrolysate, yeast are soaked powder, sulfo-sodium thioglycollate, cysteine hydrochloride and be dissolved in distilled water, regulate pH to 7.1-7.5,121 ℃ of sterilizations 30 minutes are standby.
(2) join 112 ℃ of sterilizations of 20% glucose solution 30 minutes in addition.Add in proportion before the inoculation.
III, product poison are cultivated:
A type bacillus botulinus through adapting to after cultivating is seeded in the toxin producing medium, cultivated 4 days for 37 ℃, cultivate the end back and survey virulence with white mice, its virulence is not less than 1 * 10
5LD
50/ ml.
The purification of IV, toxin:
(1) Acid precipitation: will produce malicious culture fluid and transfer about pH to 3.4 with 3N sulphuric acid.2～8 ℃ are spent the night.
(2) toxin is purified: abandon supernatant, precipitation is washed twice with distillation.Add an amount of pH 6.0,0.2 M phosphate buffer, dissolve at twice, extract.After centrifugal supernatant is merged.
(3) enzyme is handled and is concentrated: added 34 ℃ of incubations of ribonuclease 3 hours.It is saturated to add ammonium sulfate to 60%, and 2～8 ℃ are spent the night, centrifugal, after precipitation is dissolved with an amount of pH 5.5,0.05M citrate buffer solution, and dialysis.
(4) chromatography: OD is collected, merged to dialysis solution through the DEAE-A50 ion-exchange chromatography
260/ OD
280Be 0.5～0.6 cross post liquid.
(5) crystallization: amalgamation liquid man ammonium sulfate to 60% is saturated, and 2～8 ℃ are spent the night, centrifugal, precipitation is dialysed in the above-mentioned buffer that contains 0.9 M ammonium sulfate with an amount of pH 6.8, the dissolving of 0.05M phosphate buffer again, forms crystallization naturally, also can repeat said process, to form crystallization for the second time;
The dilution of V, toxin, lyophilizing:
(1) dilution
A) with phosphate buffer dissolving and percrystallization toxin, measure virulence after the aseptic filtration;
B) with phosphate buffer the toxin soiutions of known virulence is diluted to suitable solubility (10
5～10
6LD
50/ ml);
C) an amount of dilution toxin solution is joined in the quantitative frozen-dried protective liquid, make content of toxins in every milliliter of frozen-dried protective liquid at the scope (100-800LD that tires and require
50/ ml);
(2) packing, lyophilizing
Every bottle of above-mentioned toxin dilution 0.5ml that contains frozen-dried protective liquid of quantitative packing carries out lyophilizing with the freeze-drying curve of protein articles to it, and the lyophilizing finished product should be aseptic, moisture is no more than 3%.
A type BoNT preparation with the preparation of the method for example of the present invention is diluted to 240LD
50/ ml, and pack in the 2ml cillin bottle by 0.5 ml aliquots amount according to proteinic freeze-drying curve lyophilizing, reaches and comprises 36 months in 4 ℃ of storages.From 0,6,12,18,24,30,36 month of beginning to preserve, randomization, and make mice LD
50Analysis is renderd a service and aseptic, moisture with test.
Table 1, table 2 are listed the measurement result of the sample of different time points taking-up.These results show that A type BoNT preparation prepared in accordance with the present invention is stable.Table 1 explanation, when A type BoNT preparation prepared in accordance with the present invention, in the time of at least 36 months, A type BoNT preparation is tired also in storage time is the scope of tiring that was write down at 0 o'clock 4 ℃ of storages.(before packing, press the 240U/ml dilution, should be 120U/0.5ml in theory being one bottle is 120U, and the actual value of measuring after the lyophilizing is the 110U/ bottle, and this is because the loss that is caused in the freeze-drying process, tire owing to measuring in addition, so its measured value changes within the specific limits) with animal.
A type BoNT stability of formulation (1U=1LD during 4 ℃ in table 1
50)
Table 2 explanation, when A type BoNT preparation prepared in accordance with the present invention, in the time of at least 12 months, A type BoNT preparation is tired also in storage time is the scope of tiring that was write down at 0 o'clock 25 ℃ of storages.(before packing, press the 240U/ml dilution, should be 120U/0.5ml in theory being one bottle is 120U, and the actual value of measuring after the lyophilizing is the 110U/ bottle, and this is because the loss that is caused in the freeze-drying process, tire owing to measuring, so its measured value changes within the specific limits) with animal.
A type BoNT stability of formulation during 25 ℃ in table 2
Freeze drying protectant of the present invention makes the A type BoNT preparation loss rate of tiring when lyophilizing be (120-110)/120=8.3% loss rate of 40% in the bibliographical information in the time of the pH6.8 buffering range being provided and making preservable injectable powder by the liquid solution lyophilizing.Pharmaceutical preparation of the present invention can be with solid form 4 ℃ of storages in the time of at least 36 months, at least 12 months A types of 25 ℃ of storages BoNT preparation tire also in storage time is the scope of being measured of tiring at 0 o'clock (110U ± 20%, i.e. 88U-132U).
Preparation of the present invention, compared with prior art, it is stronger to have stability, and side effect is still less prepared simply, and raw material is easy to get, and is easy to use, and safety is higher, and curative effect is better.
The specific embodiment:
Following example is supplied with the common skilled person in this area so that implement the present invention with particularly preferred method in the scope of the invention, is not the invention scope of having a mind to limit the inventor.
Embodiment 1
A type BoNT of the present invention specifically can prepare by the following method:
I, toxin producing medium composition
Enzyme hydrolysis casein 1%～10%
Yeast soaks powder 1%～10%
Sodium thioglycolate 0.01%～0.05%
Cysteine hydrochloride 0.01%～0.1%
Glucose 1%～2%
All the other are water
II, toxin producing medium form
(1) casein hydrolysate, yeast are soaked powder, sulfo-sodium thioglycollate, cysteine hydrochloride and be dissolved in distilled water, regulate pH to 7.2-7.3.121 ℃ the sterilization 30 minutes standby.
(2) join 112 ℃ of sterilizations of 20% glucose solution 30 minutes in addition, add in proportion before the inoculation.
III, product poison are cultivated
A type bacillus botulinus through adapting to after cultivating is seeded in the toxin producing medium, cultivated 4 days for 37 ℃.
The exquisiteness of IV, toxin is purified
(1) Acid precipitation: toxin solution is transferred about pH to 3.4 with 3N sulphuric acid.2～8 ℃ are spent the night.
(2) toxin is purified: abandon supernatant, precipitation is washed twice with distillation.Add an amount of pH 6.0,0.2 M phosphate buffer, dissolve at twice, extract.After centrifugal supernatant is merged.
(3) enzyme is handled and is concentrated: added 30 ℃～34 ℃ incubations of ribonuclease 3 hours.It is saturated to add ammonium sulfate to 60%, and 2～8 ℃ are spent the night, centrifugal, after precipitation is dissolved with an amount of pH5.2-5.8,0.05M citrate buffer solution, and dialysis.
(4) chromatography: OD is collected, merged to dialysis solution through the DEAE-A50 ion-exchange chromatography
260/ OD
280Be 0.5～0.6 cross post liquid.
(5) crystallization: it is saturated that amalgamation liquid adds ammonium sulfate to 60%, and 2～8 ℃ are spent the night, centrifugal, precipitation is dialysed in containing the above-mentioned buffer of 0.9M ammonium sulfate with an amount of pH 6.8,0.05 M phosphate buffer dissolving again, forms crystallization naturally, also can repeat said process, to form crystallization for the second time;
The dilution of V, toxin, lyophilizing
(1) dilution
A) with phosphate buffer dissolving and percrystallization toxin, measure virulence after the aseptic filtration;
B) with phosphate buffer the toxin soiutions of known virulence is diluted to debita spissitudo (10
5～10
6LD
50/ ml);
C) an amount of dilution toxin is joined in the quantitative frozen-dried protective liquid, make content of toxins in every milliliter of frozen-dried protective liquid at the scope (240LD that tires and require
50/ ml);
Embodiment 2
(1) frozen-dried protective liquid composition:
20% human human albumin 125ml
Sucrose 25g
Water for injection adds water to 875ml
(2) collocation method:
A) measure the human albumin by amount of preparation;
B) take by weighing sucrose by amount of preparation, after the dissolving of adding water for injection, transferring pH is 6.8,121 ℃, 20 minutes autoclavings.
A) with behind a and the b solution mixing, add a certain amount of A type BoNT diluent then, use 0.22 filtering with microporous membrane, prop up according to 0.5ml/ and be sub-packed in the cillin bottle.
B) freeze-drying curve with protein articles carries out lyophilizing to it, and the lyophilizing finished product is aseptic qualified, and moisture is no more than 3%.
Embodiment 3
(1) frozen-dried protective liquid composition:
20% human human albumin 125ml
Lactose 25g
Water for injection adds to 875ml
(2) collocation method
A) measure the human albumin by amount of preparation;
B) take by weighing lactose by amount of preparation, add injection water dissolving after, transferring pH is 6.8,121 ℃, 20 minutes autoclavings;
C) with behind a and the b solution mixing, add a certain amount of A type BoNT diluent then, use 0.22 filtering with microporous membrane, prop up according to 0.5ml/ and be sub-packed in the cillin bottle;
D) freeze-drying curve with protein articles carries out lyophilizing to it, and the lyophilizing finished product is aseptic, and moisture is no more than 3%.
The main reference document
Goodnough?MC?and?Johnson?EA.Stabilization?of?botulinum?toxin?type?A?duringIyophilization.Appl?Environ?Microbiol，1992，58：3426-3428.
Kurono?Y，Ohta?N，Ikeda?K.Utilization?of?human?serum?albumin?as?drug?additives?I.Stabilizer?of?prostacyclin.Chem?Pharm?Bull(Tokyo).1982，30：2635-2638.
Schantz?EJ?and?Johnson?EA.Properties?and?use?of?botulinum?toxin?and?other?microbialneurotoxins?in?medicine.Microbiol.Rev.1992，56：80-92.
Sugiyama?H.Clostridium?botulinum?neurotoxin.Microbiol.Rev.1980，44：419-448.
Tarelli?E，Mire-Sluis?A，Tivnann?HA，et?al.Recombinant?human?albumin?as?a?stabilizer?forbiological?materials?and?for?the?preparation?of?international?reference?reagents.
Biologicals.1998，26：331-346.
Yang Zhong, Xue Feng, Xiao Zaiying etc. the treatment preparation and the quality control thereof of botulinum toxin type A. microbiology immunology progress .1997,27 (3): 41-44.
Claims (8)
1.A the pharmaceutical preparation of BOTULINUM TOXIN TYPE A A (BoNT); form by pharmaceutically acceptable freeze drying protectant and botulinum toxin; it is characterized in that freeze drying protectant is wherein made with water by a certain percentage by human human albumin, sucrose or human human albumin, lactose.
2. the preparation of claim 1, freeze drying protectant wherein is by the human albumin, and sucrose or human albumin, lactose and water are made, and the weight proportion between each component is as follows:
The human albumin 0.5%～10%
Sucrose or lactose 0.5%～10%
All the other are water for injection
3. the weight proportion between each component of the preparation of claim 1 freeze drying protectant wherein is as follows:
The human albumin 1%～5%
Sucrose or lactose 1%～5%
All the other are water for injection
4. the weight proportion between each component of the preparation of claim 1 freeze drying protectant wherein is as follows:
The human albumin 2.5%
Sucrose or lactose 2.5%
All the other are water for injection
5. the formulation characteristics of claim 1 is, pH 6.8 buffering ranges that freeze drying protectant wherein provides and make when making preservable injectable powder by the solution lyophilizing BoNT loss of tiring be lower than 20%.
6. the preparation of claim 1 is a lyophilized injectable powder, and wherein said preparation can 4 ℃ of stable storages 36 months, can be stablized storage 12 months at 25 ℃ with solid form.The preparation of claim 1-6, wherein said BoNT are selected from A, B, C, D, E, F and G serotype.
7. the preparation of claim 1, wherein said BoNT is with 100-400 LD
50The A type BoNT that/ml scope concentration exists.
8. the preparation method of the preparation of claim 1 is characterized in that, the process following steps:
A) measure the human albumin by amount of preparation;
B) take by weighing lactose or sucrose by amount of preparation, after the dissolving of adding water for injection, transferring pH is 6.8,121 ℃, 20 minutes autoclavings;
C) with in a and the b mixing, add a certain amount of A type BoNT diluent then, behind 0.22 filtering with microporous membrane,
Be sub-packed in the cillin bottle according to 0.5/;
D) freeze-drying curve with protein articles carries out lyophilizing to it, and the lyophilizing finished product is aseptic, pyrogen is qualified, and moisture is no more than 3%.
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|---|---|---|---|
| CN200610167769A CN100577149C (en) | 2006-12-21 | 2006-12-21 | Novel lyophilization protecting agent prescription of A type botulinum toxin freeze-dried powder injection preparation for treatment |
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| CN200610167769A CN100577149C (en) | 2006-12-21 | 2006-12-21 | Novel lyophilization protecting agent prescription of A type botulinum toxin freeze-dried powder injection preparation for treatment |
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| CN101204377A true CN101204377A (en) | 2008-06-25 |
| CN100577149C CN100577149C (en) | 2010-01-06 |
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Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102937653A (en) * | 2008-03-14 | 2013-02-20 | 阿勒根公司 | Immuno-based botulinum toxin serotype A activity assays |
| CN109803980A (en) * | 2016-07-08 | 2019-05-24 | 儿童医学中心公司 | New botulinum neurotoxin and its derivative |
| WO2023186016A1 (en) * | 2022-04-01 | 2023-10-05 | 重庆誉颜制药有限公司 | Botulinum toxin protein composition, method for preparing same, and use thereof |
Family Cites Families (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO1994000481A1 (en) * | 1992-06-23 | 1994-01-06 | Associated Synapse Biologics | Pharmaceutical composition containing botulinum b complex |
| CN1205996C (en) * | 2002-12-16 | 2005-06-15 | 长春力尔凡药业有限公司 | Mannan peptide freeze dried powder ampoule for injection |
| CN1562352A (en) * | 2004-04-16 | 2005-01-12 | 北京凯文伟业医药科技有限公司 | Technique for producing injection of freeze drying powder of A type botulinus toxin in use for treatment, and formula of protectant of freeze drying powder |
-
2006
- 2006-12-21 CN CN200610167769A patent/CN100577149C/en active Active
Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102937653A (en) * | 2008-03-14 | 2013-02-20 | 阿勒根公司 | Immuno-based botulinum toxin serotype A activity assays |
| CN109803980A (en) * | 2016-07-08 | 2019-05-24 | 儿童医学中心公司 | New botulinum neurotoxin and its derivative |
| CN109803980B (en) * | 2016-07-08 | 2023-07-25 | 儿童医学中心公司 | Novel botulinum neurotoxin and derivatives thereof |
| WO2023186016A1 (en) * | 2022-04-01 | 2023-10-05 | 重庆誉颜制药有限公司 | Botulinum toxin protein composition, method for preparing same, and use thereof |
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Address after: 102600 Beijing City, Daxing District Daxing biomedical industry base of Zhongguancun science and Technology Park Si Miao Road No. 1 Co-patentee after: Institute of Microbiology and Epidemiology, Academy of Military Medical Sciences, PR China Patentee after: Beijing Min Hai Bio-Scientific Inc. Address before: 100071 No. 15 West Fengtai Road, Beijing, Fengtai District Co-patentee before: Institute of Microbiology and Epidemiology, Academy of Military Medical Sciences, PR China Patentee before: Beijing Min Hai Bio-Scientific Inc. |
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Address after: 102600 Beijing City, Daxing District Daxing biomedical industry base of Zhongguancun science and Technology Park Si Miao Road No. 35 Patentee after: Beijing Min Hai Bio-Scientific Inc. Patentee after: Institute of Microbiology and Epidemiology, Academy of Military Medical Sciences, PR China Address before: 102600 Beijing City, Daxing District Daxing biomedical industry base of Zhongguancun science and Technology Park Si Miao Road No. 1 Patentee before: Beijing Min Hai Bio-Scientific Inc. Patentee before: Institute of Microbiology and Epidemiology, Academy of Military Medical Sciences, PR China |