EP1021209A1 - Inactivation of viruses by incubation with caprylate - Google Patents
Inactivation of viruses by incubation with caprylateInfo
- Publication number
- EP1021209A1 EP1021209A1 EP97945676A EP97945676A EP1021209A1 EP 1021209 A1 EP1021209 A1 EP 1021209A1 EP 97945676 A EP97945676 A EP 97945676A EP 97945676 A EP97945676 A EP 97945676A EP 1021209 A1 EP1021209 A1 EP 1021209A1
- Authority
- EP
- European Patent Office
- Prior art keywords
- caprylate
- albumin
- inactivation
- virus
- concentration
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Withdrawn
Links
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
- A61L2/00—Methods or apparatus for disinfecting or sterilising materials or objects other than foodstuffs or contact lenses; Accessories therefor
- A61L2/0005—Methods or apparatus for disinfecting or sterilising materials or objects other than foodstuffs or contact lenses; Accessories therefor for pharmaceuticals, biologicals or living parts
- A61L2/0082—Methods or apparatus for disinfecting or sterilising materials or objects other than foodstuffs or contact lenses; Accessories therefor for pharmaceuticals, biologicals or living parts using chemical substances
- A61L2/0088—Liquid substances
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
- A61L2/00—Methods or apparatus for disinfecting or sterilising materials or objects other than foodstuffs or contact lenses; Accessories therefor
- A61L2/16—Methods or apparatus for disinfecting or sterilising materials or objects other than foodstuffs or contact lenses; Accessories therefor using chemical substances
- A61L2/18—Liquid substances or solutions comprising solids or dissolved gases
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P31/12—Antivirals
Definitions
- the present invention relates to methods for the inactivation of enveloped virus in solutions of therapeutic proteins.
- the invention disclosed here describes the use of the fatty acid, caprylate, which is currently included in the albumin solution as part of the formulation and which has been shown in this invention to have virucidal potential at low pH and elevated temperatures.
- Pasteurisation of albumin was first introduced as early as 1948 to inactivate primarily hepatitis virus which was being transmitted through the intravenous administration of albumin.
- Hink and co-workers (1957) added the fatty acids sodium acetyl tryphophante and sodium caprylate as well as sodium chloride to confer stability on the albumin molecule.
- Boyer et al (1946) studied the turbidity of albumin at varying concentrations of several different fatty acid salts, including caprylate, at elevated temperatures. Caprylate had a pronounced effect on the stabilisation of albumin with the turbidity being most strongly influenced by the ratio of albumin to salt concentration. The concentration of caprylate used in these studies varied from as low as 8 mM and up to 150 mM.
- VSV vesicular stomatitis virus
- the present inventors have now found that concentrations of caprylic acid above the solubility level (where it exists as an emulsion) can be achieved with advantageous results in the inactivation of enveloped viruses within selected pH and temperature ranges.
- the present invention consists in a method of inactivating lipid-enveloped virus in a solution of therapeutic protein, the method comprising incubating the solution at temperature greater than 15°C at a pH in the range of about 4.0 to about 6.0 with caprylate at a concentration of at least about 6mM, the pH and caprylate concentration being selected such that the caprylic acid concentration is greater than 0.07% w/w.
- the incubation temperature is from 15°C to about 45°C and preferably from about 25°C to about 45°C.
- the concentration of caprylate is in the range of about 6mM to about lOOmM.
- the pH of the solution is in the range of about pH 4 to about pH 6.
- the method of the present invention can be used with any of a large range of therapeutic proteins and is particularly applicable to albumin.
- the method comprises incubating at 45°C solution comprising 10%(w/w) albumin, 16mM caprylate at a pH of 4.5. In another preferred embodiment of the present invention the method comprises incubating at 45°C solution comprising 20-25%(w/w) albumin, 30-40mM caprylate at a pH of about 5.2.
- the present invention consists in a solution of therapeutic protein prepared according to the method of the first aspect of the present invention.
- the present invention also consists in a composition including a therapeutic protein in which the therapeutic protein has been treated according to the method of the first aspect of the present invention.
- Figure 1 The effect of pH and caprylate on Sindbis Virus Inactivation in albumin.
- Figure 2 Inactivation of BVDV as a result of incubation with caprylate in albumin.
- Figure 4 Sindbis virus Inactivation in albumin treated with various caprylate concentrations. (• - 3mM caprylate: O - 8mM caprylate; T - 16mM caprylate; V - 26mM caprylate.)
- Figure 5 HAV inactivation in the presence of 12 mM caprylate.
- Figure 1 shows that Sindbis virus was not inactivated (i) without the addition of caprylate, even at pH 4.5 (ii) at 15°C in the presence of caprylate. Greater than 5 logs of virus were inactivated once caprylate is added and the temperature was elevated to 45°C. The kinetics of inactivation were enhanced (virus kill quickest) at the lower pH of 4.5 compared to pH 6.0 and at the highest caprylate concentration of 32 mM.
- Example 2 High titre bovine viral diarrhoea virus, BVDV, was spiked into approximately 10% w/v albumin concentrate. Incubation was performed at 30°C or 0°C with or without caprylate (16mM) and at pH 4.5. Figure 2 shows the importance of both the presence of caprylate at low pH and elevated temperature to inactivate this enveloped virus. Incubation at 0°C in the presence or absence of caprylate did not inactivate this virus.
- Albumin (10% w/v) containing approximately 14 mM caprylate was pH adjusted to pH 4.5 with 0.5M HC1.
- Bovine viral diarrhoea virus, BVDV, (NADL, strain, from ATCC) was spiked into the albumin and samples were then incubated at a range of temperatures from 25 to 45°C. A control sample was kept at 2-8°C. The turbidity of each of the albumin samples after incubation at each of the temperatures was measured to evaluate the stability of the albumin. Aggregate content was also measured by HPLC. The results of this study are illustrated in Figure 3 and Table 1.
- Example 5 Samples of albumin were pH adjusted to pH 4.5 and caprylate was added to achieve a final concentration of 12 mM.
- caprylate to inactivate the enveloped viruses was also found in these studies to be dependent on temperature, with no significant inactivation of Sindbis in an albumin solution seen at 15°C but at 45°C a 4 log reduction factor was achieved for the same concentration of caprylic acid and the same pH. A similar pattern of temperature dependency was seen with bovine viral diarrhoea virus (BVDV) spiked into albumin solutions.
- BVDV bovine viral diarrhoea virus
- Horowitz B Inactivation of viruses in labile protein containing compositions using fatty acids. US Patent No. 4,841,023, (1989).
Landscapes
- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Chemical & Material Sciences (AREA)
- General Health & Medical Sciences (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Veterinary Medicine (AREA)
- Public Health (AREA)
- Animal Behavior & Ethology (AREA)
- General Chemical & Material Sciences (AREA)
- Epidemiology (AREA)
- Medicinal Chemistry (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Biomedical Technology (AREA)
- Engineering & Computer Science (AREA)
- Virology (AREA)
- Communicable Diseases (AREA)
- Oncology (AREA)
- Molecular Biology (AREA)
- Organic Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Micro-Organisms Or Cultivation Processes Thereof (AREA)
- Medicines Containing Material From Animals Or Micro-Organisms (AREA)
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
- Peptides Or Proteins (AREA)
Abstract
Description
Claims
Applications Claiming Priority (3)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
AUPO4106A AUPO410696A0 (en) | 1996-12-06 | 1996-12-06 | Inactivation of viruses by incubation with caprylate |
AUPO410696 | 1996-12-06 | ||
PCT/AU1997/000824 WO1998024485A1 (en) | 1996-12-06 | 1997-12-05 | Inactivation of viruses by incubation with caprylate |
Publications (1)
Publication Number | Publication Date |
---|---|
EP1021209A1 true EP1021209A1 (en) | 2000-07-26 |
Family
ID=3798414
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
EP97945676A Withdrawn EP1021209A1 (en) | 1996-12-06 | 1997-12-05 | Inactivation of viruses by incubation with caprylate |
Country Status (8)
Country | Link |
---|---|
EP (1) | EP1021209A1 (en) |
JP (1) | JP2001505569A (en) |
KR (1) | KR20000057410A (en) |
AU (1) | AUPO410696A0 (en) |
CA (1) | CA2273924A1 (en) |
NZ (1) | NZ336099A (en) |
WO (1) | WO1998024485A1 (en) |
ZA (1) | ZA9710965B (en) |
Families Citing this family (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN101927011B (en) * | 2009-06-23 | 2014-03-19 | 武汉生物制品研究所有限责任公司 | Virus inactivation method for solution of globulin |
AU2013205138B2 (en) | 2012-08-09 | 2015-06-25 | Grifols, S.A. | Caprylate Viral Deactivation |
Family Cites Families (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US4997851A (en) * | 1987-12-31 | 1991-03-05 | Isaacs Charles E | Antiviral and antibacterial activity of fatty acids and monoglycerides |
US4939176A (en) * | 1988-12-20 | 1990-07-03 | Miles Inc. | Viral inactivation process |
FI912955A (en) * | 1990-06-25 | 1991-12-26 | Res Found Mental Hygiene | ANTIMIKROBA FETTSYRASAMMANSAETTNINGAR. |
-
1996
- 1996-12-06 AU AUPO4106A patent/AUPO410696A0/en not_active Abandoned
-
1997
- 1997-12-05 KR KR1019990704975A patent/KR20000057410A/en not_active Application Discontinuation
- 1997-12-05 NZ NZ336099A patent/NZ336099A/en not_active IP Right Cessation
- 1997-12-05 WO PCT/AU1997/000824 patent/WO1998024485A1/en not_active Application Discontinuation
- 1997-12-05 ZA ZA9710965A patent/ZA9710965B/en unknown
- 1997-12-05 EP EP97945676A patent/EP1021209A1/en not_active Withdrawn
- 1997-12-05 CA CA002273924A patent/CA2273924A1/en not_active Abandoned
- 1997-12-05 JP JP52493598A patent/JP2001505569A/en active Pending
Non-Patent Citations (1)
Title |
---|
See references of WO9824485A1 * |
Also Published As
Publication number | Publication date |
---|---|
ZA9710965B (en) | 1998-07-27 |
WO1998024485A1 (en) | 1998-06-11 |
AUPO410696A0 (en) | 1997-01-09 |
CA2273924A1 (en) | 1998-06-11 |
NZ336099A (en) | 1999-08-30 |
KR20000057410A (en) | 2000-09-15 |
JP2001505569A (en) | 2001-04-24 |
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