CN1961961B - A pharmaceutical formulation and preparation process thereof - Google Patents
A pharmaceutical formulation and preparation process thereof Download PDFInfo
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- CN1961961B CN1961961B CN200510124441A CN200510124441A CN1961961B CN 1961961 B CN1961961 B CN 1961961B CN 200510124441 A CN200510124441 A CN 200510124441A CN 200510124441 A CN200510124441 A CN 200510124441A CN 1961961 B CN1961961 B CN 1961961B
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Abstract
The invention relates to a drug formed by 106-1013vp/ml virus particles and findings, wherein the findings comprise microcosmic salt buffer system, 10-200mM NaCl, 1-2mM MgCl2 or CaCl2, 10-500 muM EDTA, 0.15-1% absolute ethyl alcohol, 0.01-0.09% Tween 80, 0-21mMhistidine, and glycerin, while it can also contain L-aminothiopropionic acid. The invention can be stored more than 3 years under 8Deg. C.
Description
Technical field
The invention belongs to pharmaceutical preparation and preparation field, especially relate to a kind of recombinant virus preparation and preparation method thereof.
Background technology
Along with the listing of first gene therapy product Gendicine in the world in 2004, gene therapy more and more obtained people's approval.Gene therapy has three elements: genes of interest, carry the carrier that gene enters cell inner expression, target cell.Wherein, the gene transfer vector of shortage specificity, targeting and high efficiency is a difficult problem of gene therapy always.At present, the carrier that is used for gene therapy research mainly is divided into viral vector and non-virus carrier two big classes.Non-virus carrier mainly refers to liposome and naked DNA, its gene transfer system since can reprint gene unrestricted, safe, can be handling characteristics such as by force, its exploitation comes into one's own in recent years, but, limited non-virus carrier in the field of gene broader applications because gene imports the low and poor specificity of efficient.
Virus has some unique character such as most virus can infect special cell, is difficult for degraded etc. in cell, so viral vector is good gene delivery body, and the utilization in gene therapy more and more widely.It is pathogenic that but most of wild-type virus all have body, just can be used for human body after therefore need transforming it.In principle, various types of viruses can both be transformed into viral vector.But because the multiformity of virus reaches and the dependence of body complexity, people so far to the biocycle of many viruses, molecular biology, take place with disease and the understanding of the relation of development etc. also very not comprehensive, develop into carrier thereby limited many viruses with practicality.Over nearly 20 years, retrovirus retrovirus, adenovirus, adeno-associated virus, herpesvirus (comprising herpes simplex virus, vaccinia virus and Epstein-Barr virus), Alphavirus etc. are transformed, and success be used for gene transfer vector.
Along with the extensive use of viral vector, the viral vector stability of formulation also more and more is subjected to related personnel's attention, because the pharmaceutical preparation stability study is the important means of ensuring drug quality.The stability of pharmaceutical preparation relates to the transportation and the condition of storage of pharmaceutical preparation, has influence on the cost of medicine, and the safety that also has influence on medication is with effective.The factor that influences the recombinant adenovirus preparation stability is a lot, and principal element comprises prescription factor and extraneous factor.Extraneous factor mainly refers to light, humidity, temperature, number of freezing and thawing or the like; The prescription factor mainly refers to the prescription composition, except that principal agent, has also added various adjuvants, and prescription is formed the stability of formulation influence bigger.
Gu Jing, the patent of Tong Yong etc. (200410016000.7) has been introduced the preparation of lyophilizing recombinant adenovirus: adopt freezing dry process, can good stability be arranged in 4-8 ℃ of preservation 30 months after making it to become lyophilized formulations.
The patent of U.S. merck company has also been protected the preparation of recombinant adenovirus, and wherein the preparation of patent 20050186225 protections comprises virus, at least one antioxidant and at least a sugar, and concentration is the salt of 100mM.Said preparation can store 2 years at 2-8 ℃.
The preparation of patent 20020041884 protections comprises purified virus, Tris, sucrose, salt, MgCl
2And nonionic detergent.
WO99/41416 has protected virus formulation, comprises glycerol, sodium phosphate buffer, Tris, sucrose, MgCl
2With Tween 80.Said preparation stores 1 year its virus titer, 0.52 log that descends at 4 ℃.
United States Patent (USP) 6,451,256 have protected the preparation of 0.75-1.5M sucrose concentration.
Nyberg-Hoffman etc. disclose the adenovirus lyophilized formulations, and its composition comprises Tris, sucrose and MgCl
2
Croyle etc. disclose adenovirus lyophilized formulations and liquid preparation, comprise Tris, sodium phosphate buffer, sucrose, trehalose or sorbose/gel.Stability based on the adjuvant energy enhance liquid adenovirus preparation of cyclodextrin is also disclosed simultaneously.
Have only the listing of gene therapy product at present in the world, i.e. Gendicine, its storage temperature is-20 ℃, the storage time is 3 years.
Summary of the invention
The object of the present invention is to provide a kind of pharmaceutical preparation of good stability.This medicine has characteristics such as safety, efficient, good stability.
For achieving the above object, the invention provides a kind of preparation composition that comprises virion and adjuvant.This virion number is 10
6-10
13Vp/ml.Adjunct ingredient comprises buffer system, the NaCl of 10-200mM, and activator, antioxidant, non-ionic surface active agent, one-tenth such as heat stabilizer are grouped into.
Recombinant virus of the present invention is the virus through transforming of any kind, comprises adenovirus, adeno-associated virus, retrovirus, herpesvirus, Alphavirus etc.Be preferably adenovirus through transforming.Including, but not limited to Ad5, Ad2, Ad6, Ad24, the mixed type of Ad35 hypotype or each hypotype.
Buffer system of the present invention is a phosphate buffer, can be HPO
4 2-And H
2PO
4 -Sodium salt and potassium salt, as K
2HPO
4, KH
2PO
4Buffer system and Na
2HPO
4, KH
2PO
4Buffer system.Be preferably 20-50mM K
2HPO
4With 2-5mM KH
2PO
4In the liquid preparation prescription, often need to add a large amount of buffer agents and keep the required pH value of preparation, make it maintain the scope that can tolerate on the physiology, be preferably 7.0-8.0.Simultaneously, add NaCl, the grade of regulating preparation is oozed a little, to satisfy the biocompatibility requirement.
Activator of the present invention can be a divalent salts, as MgCl
2, CaCl
2Deng.The main activation virus activity that plays a part.
Antioxidant of the present invention can be ethylenediaminetetraacetic acid (EDTA), histidine, and ethanol, L-cysteine etc., the basic antioxidant among the present invention is EDTA and ethanol, can also add a kind of in histidine, the L-cysteine or two kinds.Thereby EDTA avoids virally inactivated by preventing the metal ion catalysis free-radical oxidation in preparation; Thereby histidine and ethanol are by preventing free-radical oxidation protection virus.
Non-ionic surface active agent of the present invention can be Tween-80,40 etc., be preferably Tween-80.In recombinant virus preparation, add non-ionic surface active agent and can prevent that thereby virus is adsorbed on vessel surface and avoids the virus loss active.
Heat stabilizer of the present invention is a glycerol.
Pharmaceutical preparation of the present invention can be used for the treatment of and prevent the disease of animal, particularly the disease of the mankind, mammal and birds.
Pharmaceutical preparation of the present invention can be by following approach: intramuscular, and subcutaneous in the trachea, intranasal, intradermal, rectum, per os, and parenteral.
Virus formulation of the present invention can be a gene therapy product, can be vaccine also, comprises preventative and therapeutic vaccine.
Description of drawings
Accompanying drawing 1 different prescriptions change through the titre behind the different number of freezing and thawing
Different prescriptions are changing through the titre behind the different time under 28 ℃ of conditions of accompanying drawing
Different prescriptions are changing through the titre behind the different time under 3 37 ℃ of conditions of accompanying drawing
The titre of accompanying drawing 4 preparation accelerated tests changes
The titre of accompanying drawing 5 long-time stability experiment changes
The specific embodiment
Mode below by embodiment further specifies the present invention, does not therefore limit the present invention among the described scope of embodiments.
Embodiment 1: pharmaceutical formulation is selected experiment
Recombined human hepatitis B virus core antigen adenovirus preparation prescription:
Prescription 1:KH
2PO
40.41g; K
2HPO
45.59g; NaCl 4.38g;
MgCl
26H
2O 0.20g; Glycerol 100ml; Tween80 0.2ml;
EDTA 0.03g; Ethanol 5ml; PH 7.5
Prescription 2:KH
2PO
40.41g; K
2HPO
45.59g; NaCl 9.00g;
Histidine 1.55g; Glycerol: 100ml; PH 7.5
Prescription 3:KH
2PO
40.41g; K
2HPO
45.59g; NaCl 4.38g;
MgCl
2·6H
2O：0.20g；pH?7.5
Prescription 4:KH2PO4 0.41g; K2HPO4 5.59g; NaCl 9.00g;
Glycerol 100ml; Tween80:0.2ml; L-cysteine 1.20g; PH 7.5 preparations:
By each component of prescription weighing, add distilled water to about 500ml, stir evenly, treat CL, be 5 * 10 with the concentration behind the purification again
11The recombined human hepatitis B virus core antigen 10ml of adenovirus preparation of vp/ml joins in the good adjuvant of above-mentioned dissolving, transfers pH, and distilled water is supplied 1000ml, mix homogeneously, 0.22 μ m film aseptic filtration, at last by 1ml/ prop up carry out aseptic subpackaged.
For the adenovirus goods, generally require refrigerated storage below freezing, in transportation and use, take place, so design multigelation and test and investigate the recombinant adenovirus stability of formulation because variations in temperature just has the situation of freeze thawing.The once circulation of freezing-thawing test is: freeze more than 15 minutes at-80 ℃ of refrigerators, thawed about 15 minutes 37 ℃ of water-baths then.Each prescription is respectively got 4 (1ml/ props up), and freeze thawing is 0 time respectively, and 5 times, 10 times, 20 times.Carry out the mensuration of TCID50 afterwards.Measurement result is seen accompanying drawing 1.Experimental result shows: adopt prescription 1 through behind the different number of freezing and thawing, preservation recombinant adenovirus stability of formulation is best, and the virus titer loss is minimum.Taking second place of prescription 2 and 4.
Because adenovirus preparation is relatively more responsive to temperature, so design at 8 ℃, 37 ℃ of two temperature are carried out the virus titer mensuration of four prescription different times, come four kinds of prescriptions of comparison with this in addition.Measurement result is seen Fig. 2,3 respectively.Virus titer detection at 8 ℃ of different times that carry out shows the place: adopt prescription 1 to carry out 8 ℃ of preservations, in 8 weeks of preservation that can be complete, virus titer is variation not; And preserve at 37 ℃, virus titer loses, but comparatively speaking, the loss minimum of prescription 1, the loss of prescription 2 and 4 is taken second place
The test method of medicine stability comprises accelerated test and long term test.
Embodiment 2: preparation accelerated test (temperature-time test)
By quickening the chemistry or the physical change of medicine, the prediction stability of drug.
Table 1: preparation accelerated tests condition of different temperatures detects frequency
Testing result is seen Fig. 4.As seen from the figure, deposited for 24 weeks at-80 ℃ ,-20 ℃ and 8 ℃, the quality of preparation is all very stable, and testing result fluctuates in the measured deviation scope, and 37 ℃ of its quality remarkable decline is arranged.So adenovirus preparation can carry out short-term in these three temperature and deposit, and does not influence the infection titer of preparation.Whether can carry out long-term storage and need further checking.
Embodiment 3: long-term stable experiment
Long term test is to carry out under the actual storage requirement near medicine, its objective is that the effect duration for working out medicine provides foundation.
3 result designs this experiment: select 8 ℃ and carry out the long-time stability experiment in conjunction with the embodiments.Three batches prescriptions, 1 preparation is deposited at 8 ℃, and on the same day of depositing (0 month), sampling detects, and the TCID50 detection is carried out in sampling when depositing 1,3,6,9,12,18,24,36 months later on.Testing result sees Table 2:
Show the 2:8 ℃ of long-term stable experiment result who deposits: (unit: IU/ml)
According to the laboratory test results mapping, see Fig. 5.The result shows: by the present invention's 1 adenovirus liquid preparation of making of writing out a prescription, have good stable, deposit 36 months (promptly 3 years) under 8 ℃ of conditions, preparation infection titer 0.2 logTCID50IU/ml that on average descended.Be specially batch 1 the preparation infection titer 0.22logTCID50IU/ml that descended, batches 2 the preparation infection titer 0.12logTCID50IU/ml that descended, batch the preparation infection titer 0.26logTCID50IU/ml that descended.According to the measurement result of this experiment, show and select for use prescription 1 preparation of the present invention to reach 3 years deposit that the result is little to the infection titer influence of preparation at 8 ℃.
Embodiment 4: pharmaceutical formulation and preparation
Prescription: KH
2PO
40.27g; K
2HPO
48.70g; NaCl 0.58g; MgCl
26H
2O 0.40g; Glycerol 10ml; Tween 80 0.20ml; EDTA 0.03g; Ethanol 5ml; Histidine 0.75g; PH 7.5
Preparation: by above-mentioned each component of prescription weighing, adding distilled water to about 500ml, stir evenly, treat CL, is 5 * 10 with the concentration behind the purification again
13The recombined human hepatitis B virus core antigen 200ml of adenovirus preparation of vp/ml joins in the good adjuvant of above-mentioned dissolving, transfers pH, and distilled water is supplied 1000ml, mix homogeneously, 0.22 μ m film aseptic filtration, at last by 1ml/ prop up carry out aseptic subpackaged.
Embodiment 5: pharmaceutical formulation and preparation
Prescription: KH
2PO
40.27g; K
2HPO
43.48g; NaCl 11.60g; MgCl
26H
2O 0.20g; Glycerol 150ml; Tween 80 0.90ml; EDTA1.00g; Ethanol 1.50ml; PH 7.5
Preparation: by above-mentioned each component of prescription weighing, adding distilled water to about 500ml, stir evenly, treat CL, is 1 * 10 with the concentration behind the purification again
9The recombined human hepatitis B virus core antigen 1ml of adenovirus preparation of vp/ml joins in the good adjuvant of above-mentioned dissolving, transfers pH, and distilled water is supplied 1000ml, mix homogeneously, 0.22 μ m film aseptic filtration, at last by 1ml/ prop up carry out aseptic subpackaged.
Embodiment 6: pharmaceutical formulation and preparation
Prescription: KH
2PO
40.27g; K
2HPO
48.70g; NaCl 0.58g; CaCl
20.23g; Glycerol 10ml; Tween800.10ml; EDTA 0.15g; Ethanol 5ml; Histidine 1.55g; PH 7.0
Preparation: by above-mentioned each component of prescription weighing, adding distilled water to about 500ml, stir evenly, treat CL, is 1 * 10 with the concentration behind the purification again
10The recombined human hepatitis B virus core antigen 10ml of adenovirus preparation of vp/ml joins in the good adjuvant of above-mentioned dissolving, transfers pH, and distilled water is supplied 1000ml, mix homogeneously, 0.22 μ m film aseptic filtration, at last by 1ml/ prop up carry out aseptic subpackaged.
Embodiment 7: pharmaceutical formulation and preparation
Prescription: KH
2PO
40.68g; K
2HPO
45.59g; NaCl 4.38gCaCl
20.11g; Glycerol 50ml; Tween 80 0.90ml; EDTA 0.09g; Ethanol 10ml; Histidine 1.55g; L-cysteine 1.20g; PH 8.0
Preparation: by above-mentioned each component of prescription weighing, adding distilled water to about 500ml, stir evenly, treat CL, is 5 * 10 with the concentration behind the purification again
11The recombined human hepatitis B virus core antigen 10ml of adenovirus preparation of vp/ml joins in the good adjuvant of above-mentioned dissolving, transfers pH, and distilled water is supplied 1000ml, mix homogeneously, 0.22 μ m film aseptic filtration, at last by 1ml/ prop up carry out aseptic subpackaged.
Embodiment 8: pharmaceutical formulation and preparation
Prescription: KH
2PO
40.68g; Na
2HPO
45.59g; NaCl 4.38g; MgCl
26H2O 0.40g; Glycerol 50ml; Tween 80 0.90ml; EDTA 0.03g; Ethanol 10ml; Histidine 1.55g; L-cysteine 1.20g; PH 8.0
Preparation: by above-mentioned each component of prescription weighing, adding distilled water to about 500ml, stir evenly, treat CL, is 1 * 10 with the concentration behind the purification again
9The recombined human hepatitis B virus core antigen 10ml of adenovirus preparation of vp/ml joins in the good adjuvant of above-mentioned dissolving, transfers pH, and distilled water is supplied 1000ml, mix homogeneously, 0.22 μ m film aseptic filtration, at last by 1ml/ prop up carry out aseptic subpackaged.
Embodiment 9: pharmaceutical formulation and preparation
Prescription: KH
2PO
40.68g; Na
2HPO
45.59g; NaCl 9.68g; MgCl
26H
2O 0.20g; Glycerol 100ml; Tween 80 0.90ml; EDTA0.03g; Ethanol 10ml; Histidine 0.75g; L-cysteine 0.80g; PH 8.0
Preparation: by above-mentioned each component of prescription weighing, adding distilled water to about 500ml, stir evenly, treat CL, is 1 * 10 with the concentration behind the purification again
13The recombined human hepatitis B virus core antigen 100ml of adenovirus preparation of vp/ml joins in the good adjuvant of above-mentioned dissolving, transfers pH, and distilled water is supplied 1000ml, mix homogeneously, 0.22 μ m film aseptic filtration, at last by 1ml/ prop up carry out aseptic subpackaged.
Claims (6)
1. pharmaceutical preparation, it is by 10
6-10
13Vp/ml purification of recombinant human hepatitis B virus core antigen adenovirus particles and adjuvant are formed, and its pH is 7.0-8.0, and adjuvant comprises: buffer system, the NaCl of 10-200mM, the MgCl of 1-2mM
2Perhaps CaCl
2, 10-500 μ M EDTA, the dehydrated alcohol of 0.15-1%, the Tween 80 of 0.01-0.09%, the 0-21mM histidine is characterized in that: buffer system is 20-50mM K
2HPO
4/ Na
2HPO
4With 2-5mM KH
2PO
4Phosphate buffer, adjuvant also comprises the glycerol of 1-15%.
2. the pharmaceutical preparation in the claim 1, glycerol consumption wherein is 5-15%.
3. the pharmaceutical preparation in the claim 1, glycerol consumption wherein is 10%.
4. the pharmaceutical preparation in the claim 1, histidine consumption wherein is 0-10mM.
5. the pharmaceutical preparation in the claim 1, adjuvant wherein can also comprise the L-cysteine.
6. the pharmaceutical preparation in the claim 5, L-cysteine consumption wherein is 0.001-10mM.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN200510124441A CN1961961B (en) | 2005-11-11 | 2005-11-11 | A pharmaceutical formulation and preparation process thereof |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN200510124441A CN1961961B (en) | 2005-11-11 | 2005-11-11 | A pharmaceutical formulation and preparation process thereof |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN1961961A CN1961961A (en) | 2007-05-16 |
| CN1961961B true CN1961961B (en) | 2010-05-26 |
Family
ID=38081300
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN200510124441A Active CN1961961B (en) | 2005-11-11 | 2005-11-11 | A pharmaceutical formulation and preparation process thereof |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN1961961B (en) |
Families Citing this family (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| SG11201602887QA (en) | 2013-10-25 | 2016-05-30 | Psioxus Therapeutics Ltd | Oncolytic adenoviruses armed with heterologous genes |
| SG11201805137XA (en) | 2015-12-17 | 2018-07-30 | Psioxus Therapeutics Ltd | Virus encoding an anti-tcr-complex antibody or fragment |
| GB201801614D0 (en) * | 2018-01-31 | 2018-03-14 | Psioxus Therapeutics Ltd | Formulation |
| CN115141813A (en) * | 2022-07-29 | 2022-10-04 | 深圳源兴基因技术有限公司 | Adenovirus purification method for efficiently removing residual proteins of host cells |
Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1297478A (en) * | 1998-02-17 | 2001-05-30 | 先灵公司 | Compositions comprising viruses and methods for concentrating virus preparations |
| CN1347450A (en) * | 1999-04-09 | 2002-05-01 | 阿文蒂斯药物股份有限公司 | Composition for preservation of infections recombinant adenoviruses |
| US6451256B1 (en) * | 1996-07-16 | 2002-09-17 | Transgene S.A. | Method for preserving infectious recombinant viruses, aqueous viral suspension and use as medicine |
-
2005
- 2005-11-11 CN CN200510124441A patent/CN1961961B/en active Active
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US6451256B1 (en) * | 1996-07-16 | 2002-09-17 | Transgene S.A. | Method for preserving infectious recombinant viruses, aqueous viral suspension and use as medicine |
| CN1297478A (en) * | 1998-02-17 | 2001-05-30 | 先灵公司 | Compositions comprising viruses and methods for concentrating virus preparations |
| CN1347450A (en) * | 1999-04-09 | 2002-05-01 | 阿文蒂斯药物股份有限公司 | Composition for preservation of infections recombinant adenoviruses |
Non-Patent Citations (2)
| Title |
|---|
| 施明等.腺病毒载体的研究进展.世界华人消化杂志第8卷 第11期.2000,第8卷(第11期),1282-1286. |
| 施明等.腺病毒载体的研究进展.世界华人消化杂志第8卷 第11期.2000,第8卷(第11期),1282-1286. * |
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| Publication number | Publication date |
|---|---|
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Application publication date: 20070516 Assignee: Shenzhen Source Technology Co., Ltd. Assignor: Shenzhen Yuanxing Bio-Pharm Co., Ltd. Contract record no.: 2014440020355 Denomination of invention: Medicinal preparation and its making method Granted publication date: 20100526 License type: Exclusive License Record date: 20141105 |
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Effective date of registration: 20200529 Address after: 518000 Guangdong city of Shenzhen province Nanshan District Xili Street Song Ping Road No. 1 South Building Room 1509 Lite Technology Patentee after: SHENZHEN YUANXING GENE TECHNOLOGY Co.,Ltd. Address before: 518057 Lang Shan Road, North District, Shenzhen hi tech Zone, Guangdong Patentee before: BIO-PHARM SCIENCE & TECHNOLOGY Co.,Ltd. |
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