WO1996022107A1 - Dried blood factor composition comprising trehalose - Google Patents

Dried blood factor composition comprising trehalose Download PDF

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Publication number
WO1996022107A1
WO1996022107A1 PCT/GB1996/000119 GB9600119W WO9622107A1 WO 1996022107 A1 WO1996022107 A1 WO 1996022107A1 GB 9600119 W GB9600119 W GB 9600119W WO 9622107 A1 WO9622107 A1 WO 9622107A1
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WO
WIPO (PCT)
Prior art keywords
trehalose
dried
blood factor
composition according
factor
Prior art date
Application number
PCT/GB1996/000119
Other languages
French (fr)
Inventor
Bruce Joseph Roser
Original Assignee
Quadrant Holdings Cambridge Limited
Priority date (The priority date 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 date listed.)
Filing date
Publication date
Priority to DE69629209T priority Critical patent/DE69629209T2/en
Priority to US08/875,796 priority patent/US6649386B2/en
Priority to EP96900633A priority patent/EP0871476B1/en
Application filed by Quadrant Holdings Cambridge Limited filed Critical Quadrant Holdings Cambridge Limited
Priority to DK96900633T priority patent/DK0871476T3/en
Priority to DK03002147T priority patent/DK1308170T3/en
Priority to AU44540/96A priority patent/AU704317B2/en
Priority to CA002210872A priority patent/CA2210872C/en
Priority to JP52213396A priority patent/JP3898221B2/en
Priority to AT96900633T priority patent/ATE245442T1/en
Publication of WO1996022107A1 publication Critical patent/WO1996022107A1/en
Priority to US09/888,734 priority patent/US7253262B2/en
Priority to US10/658,219 priority patent/US7244825B2/en
Priority to US10/679,723 priority patent/US7220836B2/en
Priority to US10/681,948 priority patent/US7244824B2/en
Priority to US11/690,778 priority patent/US7381796B2/en
Priority to US11/841,801 priority patent/US7501493B2/en
Priority to US12/371,459 priority patent/US7803911B2/en

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Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0019—Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K35/00—Medicinal preparations containing materials or reaction products thereof with undetermined constitution
    • A61K35/12—Materials from mammals; Compositions comprising non-specified tissues or cells; Compositions comprising non-embryonic stem cells; Genetically modified cells
    • A61K35/14—Blood; Artificial blood
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • A61K38/17—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
    • A61K38/36—Blood coagulation or fibrinolysis factors
    • A61K38/37—Factors VIII
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • A61K38/43—Enzymes; Proenzymes; Derivatives thereof
    • A61K38/46—Hydrolases (3)
    • A61K38/48—Hydrolases (3) acting on peptide bonds (3.4)
    • A61K38/482—Serine endopeptidases (3.4.21)
    • A61K38/4846—Factor VII (3.4.21.21); Factor IX (3.4.21.22); Factor Xa (3.4.21.6); Factor XI (3.4.21.27); Factor XII (3.4.21.38)
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
    • A61K47/10—Alcohols; Phenols; Salts thereof, e.g. glycerol; Polyethylene glycols [PEG]; Poloxamers; PEG/POE alkyl ethers
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/16—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing nitrogen, e.g. nitro-, nitroso-, azo-compounds, nitriles, cyanates
    • A61K47/18—Amines; Amides; Ureas; Quaternary ammonium compounds; Amino acids; Oligopeptides having up to five amino acids
    • A61K47/183—Amino acids, e.g. glycine, EDTA or aspartame
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/26—Carbohydrates, e.g. sugar alcohols, amino sugars, nucleic acids, mono-, di- or oligo-saccharides; Derivatives thereof, e.g. polysorbates, sorbitan fatty acid esters or glycyrrhizin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
    • A61K9/19—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles lyophilised, i.e. freeze-dried, solutions or dispersions
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P7/00—Drugs for disorders of the blood or the extracellular fluid
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P7/00—Drugs for disorders of the blood or the extracellular fluid
    • A61P7/04—Antihaemorrhagics; Procoagulants; Haemostatic agents; Antifibrinolytic agents

Definitions

  • This invention relates to dried compositions of blood factors for reconstitution with water or aqueous solutions.
  • Blood factors are now the standard treatment for diseases caused by a lack of the appropriate factor, in particular haemophilia.
  • the blood factor has generally been derived from human blood by various extraction techniques, for example as disclosed in EP-A-0083483. or by expression in genetically modified micro ⁇ organisms, for example as disclosed in EP-A-0160457 and EP-A-0182448.
  • Blood factor products such as factor VIII are highly delicate, unstable proteins. They are usually supplied in the form of frozen solutions in an appropriate buffer or, more generally, as freeze-dried powders. Even the freeze-dried powders must be kept cold during storage.
  • a stabilising protein in particular human serum albumin (HSA). It has not been thought possible to prepare a dry blood factor composition which is stable at ambient temperatures and at pasteurisation temperatures (e.g. 60°C) in the absence of HSA.
  • HSA human serum albumin
  • Trehalose is known to be a highly effective stabilising agent for delicate proteins, as disclosed in US-A-4891319. enabling proteins to be dried at temperatures above freezing.
  • trehalose is used to stabilise a blood factor product, not only can the product be dried with or without freezing, but also the product is stable even when retained at a temperature of 60°C for an extended period, in the complete absence of HSA. According to the present invention therefore we provide a stable dried blood factor composition containing a stabilising amount of trehalose in the absence of albumin.
  • any stabilising amount of trehalose may be used and an excess in general causes no problems. Indeed, the presence of trehalose aids the rehydration process and is physiologically acceptable for injection, being rapidly metabolised to glucose.
  • the composition is particularly suited to formulations of factor VIII. which may also contain appropriate buffering and ion-reinforcing salts, in particular a source of calcium. In general, a ratio of about 1.0 to 1.5 mg of calcium ions per unit of factor VIII is appropriate.
  • buffering and modifying agents may also be present in the dried material for reconstitution to the injection solution, for example histidine.
  • level of salts, particularly sodium chloride present can affect the preservation on drying. It is thought desirable for the commercial product for injection to have an isotonic salt concentration.
  • commercial freeze-dried formulations generally have a high salt content and are reconstituted for injection with the appropriate amount of sterile water to obtain an isotonic solution.
  • a considerably reduced salt content is preferred for the dried material of the invention and. in general a solution of about 500 units of Factor VIII per ml to be dried should preferably contain less than 200 mM e.g. 75 to 150 mM, NaCl, especially about 100 mM. , or even lower, e.g. 20 to 50 mM, especially about 22 to 30 mM. Low salt preparations possess a higher dry stability.
  • the dried product can be reconstituted to the desired salt level with a saline solution instead of the conventional water.
  • the molar ratio of trehalose to salt should be above 1 :1, especially above 2.5:1 e.g. above 10: 1, preferably above 12.5:1.
  • the dried composition may be obtained by drying an appropriate solution of the blood factor containing the correct proportions of trehalose and other desired components.
  • the solution that is dried should simply contain all the components required in the reconstituted injection solution, although the solution for drying may not necessarily be at the same dilution.
  • the solution for drying will contain from 1 to 1000 units of factor VIII per ml.
  • the methods of drying may include freeze drying, vacuum drying and spray-drying.
  • a particularly preferred method according to the invention comprises vacuum drying at a temperature no greater than 25°C, preferably no greater than 10°C, to form a foam, thus maximising the exposed surface and the drying effect.
  • Recombinant factor VIII was received as a deep frozen solution containing approximately 2000 to 2500 units/ml in the manufacturer's high salt buffer.
  • the thawed solution was dialysed against a buffer solution containing 500 mM NaCl, 15 mM CaCl 2 and 10 mM histidine at pH 6.8.
  • the dialysed protein was diluted in the same buffer, but with added trehalose, to give a final concentration of 500 units per ml and 10% by weight trehalose at pH 6.8.
  • This solution was vacuum dried in 1 ml aliquots. Vacuum was reduced step-wise from atmospheric to 4 Pa (30 mTorr) to avoid freezing the sample. The temperature of the sample was not allowed to rise above 12°C until the formation of a foam, after which the temperature was kept below 30°C. Total drying times were 24 to 28 hours.
  • Example 2 Samples were dried as described in Example 1 but using a buffer formulation comprising 100 mM NaCl, 15 mM CaCl : 15mM histidine and 1.27 molar trehalose (48%) and stored at 60°C before reconstitution.
  • the results are given in the following table, in which the activity is measured on an ACL 100 automated coagulometer (Instrumentation Laboratory SpA, Milan, Italy).
  • the test sample, with a low salt content showed no significant loss of activity on storage, even after four weeks at 60°C.
  • Freeze-drying was performed in a Laconco (Lyph-lock 12 stoppering) freeze drier. Initially, the samples were cooled to -40°C and then placed under vacuum, before being warmed to -35°C. After 80 hours, the samples were warmed at a rate of 2.5°C/h until the shelf temperature reached 25°C. The samples were then kept at 25°C for two hours before being sealed under vacuum and removed from the drier.

Abstract

A stable blood factor composition contains a stabilising amount of trehalose in the absence of human serum albumin to provide a product stable at up to 60 °C.

Description

DRIED BLOOD FACTOR COMPOSITION COMPRISING TREHALOSE
This invention relates to dried compositions of blood factors for reconstitution with water or aqueous solutions.
Blood factors, particularly factor VIII and factor IX, are now the standard treatment for diseases caused by a lack of the appropriate factor, in particular haemophilia. The blood factor has generally been derived from human blood by various extraction techniques, for example as disclosed in EP-A-0083483. or by expression in genetically modified micro¬ organisms, for example as disclosed in EP-A-0160457 and EP-A-0182448.
Blood factor products such as factor VIII are highly delicate, unstable proteins. They are usually supplied in the form of frozen solutions in an appropriate buffer or, more generally, as freeze-dried powders. Even the freeze-dried powders must be kept cold during storage. In order to stabilise the freeze-dried material, commercial products contain a stabilising protein, in particular human serum albumin (HSA). It has not been thought possible to prepare a dry blood factor composition which is stable at ambient temperatures and at pasteurisation temperatures (e.g. 60°C) in the absence of HSA. However, the presence of HSA introduces considerable problems of purification since it is essential that the protein is free of viral contamination. The use of recombinant HSA to overcome these problems is expensive.
Trehalose is known to be a highly effective stabilising agent for delicate proteins, as disclosed in US-A-4891319. enabling proteins to be dried at temperatures above freezing. We have now found that if trehalose is used to stabilise a blood factor product, not only can the product be dried with or without freezing, but also the product is stable even when retained at a temperature of 60°C for an extended period, in the complete absence of HSA. According to the present invention therefore we provide a stable dried blood factor composition containing a stabilising amount of trehalose in the absence of albumin.
In general, any stabilising amount of trehalose may be used and an excess in general causes no problems. Indeed, the presence of trehalose aids the rehydration process and is physiologically acceptable for injection, being rapidly metabolised to glucose. The composition is particularly suited to formulations of factor VIII. which may also contain appropriate buffering and ion-reinforcing salts, in particular a source of calcium. In general, a ratio of about 1.0 to 1.5 mg of calcium ions per unit of factor VIII is appropriate.
Other buffering and modifying agents may also be present in the dried material for reconstitution to the injection solution, for example histidine. However, we have found that the level of salts, particularly sodium chloride, present can affect the preservation on drying. It is thought desirable for the commercial product for injection to have an isotonic salt concentration. However, the processing formulations which are freeze-dried are desirably hypertonic, typically containing about 500 mM NaCl (isotonic NaCl = 150 mM), as this is considered to help stabilise the blood factor. As a result, commercial freeze-dried formulations generally have a high salt content and are reconstituted for injection with the appropriate amount of sterile water to obtain an isotonic solution.
A considerably reduced salt content is preferred for the dried material of the invention and. in general a solution of about 500 units of Factor VIII per ml to be dried should preferably contain less than 200 mM e.g. 75 to 150 mM, NaCl, especially about 100 mM. , or even lower, e.g. 20 to 50 mM, especially about 22 to 30 mM. Low salt preparations possess a higher dry stability. The dried product can be reconstituted to the desired salt level with a saline solution instead of the conventional water. In general, the molar ratio of trehalose to salt should be above 1 :1, especially above 2.5:1 e.g. above 10: 1, preferably above 12.5:1.
The dried composition may be obtained by drying an appropriate solution of the blood factor containing the correct proportions of trehalose and other desired components. In general, the solution that is dried should simply contain all the components required in the reconstituted injection solution, although the solution for drying may not necessarily be at the same dilution. Typically, the solution for drying will contain from 1 to 1000 units of factor VIII per ml. The methods of drying may include freeze drying, vacuum drying and spray-drying. A particularly preferred method according to the invention comprises vacuum drying at a temperature no greater than 25°C, preferably no greater than 10°C, to form a foam, thus maximising the exposed surface and the drying effect.
The following examples illustrate the invention further.
Example 1
Recombinant factor VIII was received as a deep frozen solution containing approximately 2000 to 2500 units/ml in the manufacturer's high salt buffer. The thawed solution was dialysed against a buffer solution containing 500 mM NaCl, 15 mM CaCl2 and 10 mM histidine at pH 6.8. The dialysed protein was diluted in the same buffer, but with added trehalose, to give a final concentration of 500 units per ml and 10% by weight trehalose at pH 6.8. This solution was vacuum dried in 1 ml aliquots. Vacuum was reduced step-wise from atmospheric to 4 Pa (30 mTorr) to avoid freezing the sample. The temperature of the sample was not allowed to rise above 12°C until the formation of a foam, after which the temperature was kept below 30°C. Total drying times were 24 to 28 hours.
The samples were stored for 0, 1.5, 3 and 6 months at 40°C and then reconstituted in 5 ml aliquots of sterile distilled water before being tested for activity. The results are shown in the following table in comparison with a commercial freeze-dried product containing HSA. Both the test and commercial samples have a high salt content. The post-drying results show that with trehalose it is possible to dry factor VIII successfully in the absence of HSA, but that a high salt content is unsatisfactory for long term storage, even in the presence of HSA. Percentage of initial activity
Time (months) Sample Commercial Product
0 100.0 100.0
1.5 86.8 95.3
3 75.1 71.2
6 76.6 63.6
Example 2
Samples were dried as described in Example 1 but using a buffer formulation comprising 100 mM NaCl, 15 mM CaCl: 15mM histidine and 1.27 molar trehalose (48%) and stored at 60°C before reconstitution. The results are given in the following table, in which the activity is measured on an ACL 100 automated coagulometer (Instrumentation Laboratory SpA, Milan, Italy). The test sample, with a low salt content showed no significant loss of activity on storage, even after four weeks at 60°C.
Percentage of initial activity recovered
Wet control 100.0
Post-drying 95.5 Two weeks 96.0 Four weeks 96.8
Example 3
Two formulations were prepared containing different salt concentrations as shown:
Formulation A Formulation B
NaCl 0.13% NaCl 1.03%
CaCl . 0.01 1% CaCl . 0.01 1%
L-histidine 0.12% L-histidine 0.12%
Tris 0.002% Tris 0.002%
Tween 80 0.002% Tween 80 0.002%
PEG 3350 0.004% PEG 3350 0.004%
Trehalose 7.5% Trehalose 7.5%
Factor VIII 50 U/ml Factor VIII 50 U rn
Water to 100% Water to 100% 10ml portions of the formulations were dispensed into separate 30ml vials so as to give a concentration of factor VIII of 500 units/vial.
Freeze-drying was performed in a Laconco (Lyph-lock 12 stoppering) freeze drier. Initially, the samples were cooled to -40°C and then placed under vacuum, before being warmed to -35°C. After 80 hours, the samples were warmed at a rate of 2.5°C/h until the shelf temperature reached 25°C. The samples were then kept at 25°C for two hours before being sealed under vacuum and removed from the drier.
After drying, the samples were rehydrated with 10ml of water and the concentration of factor VIII was measured twice (Assays 1 and 2). The results are given in the following table and are expressed as a percentage of the concentration of Factor VIII with respect to the prefill control (which had been frozen at -70CC). From the results shown, it can be concluded that Factor VIII can be successfully freeze dried in a trehalose based formulation in the absence of HSA.
Sample Assay 1 Assay 2
Formulation A 77% 85%o Formulation B 91% 94%

Claims

1. A stable dried blood factor composition containing a stabilising amount of trehalose in the absence of albumin.
2. A composition according to claim 1 containing 0.15 to 2.5 mg trehalose per unit of blood factor.
3. A composition according to claim 1 or claim 2 containing factor VIII.
4. A composition according to claim 3 containing 1.0 to 1.5 mg calcium ion per unit of factor VIII.
5. A composition according to any of claims 1 to 4 containing more than 2.5 moles trehalose per mole of salt.
6. A composition according to claim 5 containing more than 10 moles trehalose per mole of salt.
7. A method of preparing a composition according to any of claims 1 to 6. in which an aqueous solution of the blood factor containing trehalose is dried at a temperature no greater than 25°C.
8. A method according to claim 7. in which the solution is dried at a temperature no greater than 10°C.
PCT/GB1996/000119 1995-01-19 1996-01-19 Dried blood factor composition comprising trehalose WO1996022107A1 (en)

Priority Applications (16)

Application Number Priority Date Filing Date Title
AT96900633T ATE245442T1 (en) 1995-01-19 1996-01-19 DRIED PREPARATION OF BLOOD FACTORS CONTAINING TREHALOSE
US08/875,796 US6649386B2 (en) 1995-01-19 1996-01-19 Dried blood factor composition comprising trehalose
JP52213396A JP3898221B2 (en) 1995-01-19 1996-01-19 Dry blood factor composition containing trehalose
DK96900633T DK0871476T3 (en) 1995-01-19 1996-01-19 Dried blood factor preparation containing trehalose
DK03002147T DK1308170T3 (en) 1995-01-19 1996-01-19 Dried blood factor preparation containing trehalose
AU44540/96A AU704317B2 (en) 1995-01-19 1996-01-19 Dried blood factor composition comprising trehalose
CA002210872A CA2210872C (en) 1995-01-19 1996-01-19 Dried composition
DE69629209T DE69629209T2 (en) 1995-01-19 1996-01-19 DRIED PREPARATION OF BLOOD FACTORS, CONTAINING TREHALOSE
EP96900633A EP0871476B1 (en) 1995-01-19 1996-01-19 Dried blood factor composition comprising trehalose
US09/888,734 US7253262B2 (en) 1995-01-19 2001-06-25 Dried blood factor composition comprising trehalose
US10/658,219 US7244825B2 (en) 1995-01-19 2003-09-08 Dried blood factor composition trehalose
US10/679,723 US7220836B2 (en) 1995-01-19 2003-10-06 Dried blood factor composition comprising trehalose
US10/681,948 US7244824B2 (en) 1995-01-19 2003-10-08 Dried blood factor composition comprising trehalose
US11/690,778 US7381796B2 (en) 1995-01-19 2007-03-23 Dried blood factor composition comprising trehalose
US11/841,801 US7501493B2 (en) 1995-01-19 2007-08-20 Dried blood factor composition comprising trehalose
US12/371,459 US7803911B2 (en) 1995-01-19 2009-02-13 Dried blood factor composition comprising trehalose

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
GBGB9501040.1A GB9501040D0 (en) 1995-01-19 1995-01-19 Dried composition
GB9501040.1 1995-01-19

Related Child Applications (3)

Application Number Title Priority Date Filing Date
US08/875,796 A-371-Of-International US6649386B2 (en) 1995-01-19 1996-01-19 Dried blood factor composition comprising trehalose
US08875796 A-371-Of-International 1996-01-19
US09/888,734 Continuation US7253262B2 (en) 1995-01-19 2001-06-25 Dried blood factor composition comprising trehalose

Publications (1)

Publication Number Publication Date
WO1996022107A1 true WO1996022107A1 (en) 1996-07-25

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PCT/GB1996/000119 WO1996022107A1 (en) 1995-01-19 1996-01-19 Dried blood factor composition comprising trehalose

Country Status (15)

Country Link
US (2) US6649386B2 (en)
EP (4) EP1308170B1 (en)
JP (1) JP3898221B2 (en)
KR (1) KR100417593B1 (en)
CN (1) CN1152713C (en)
AT (2) ATE245442T1 (en)
AU (1) AU704317B2 (en)
CA (2) CA2210872C (en)
DE (2) DE69629209T2 (en)
DK (2) DK1308170T3 (en)
ES (2) ES2316658T3 (en)
GB (1) GB9501040D0 (en)
PT (2) PT1308170E (en)
SI (1) SI1308170T1 (en)
WO (1) WO1996022107A1 (en)

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WO1998005305A1 (en) * 1996-08-06 1998-02-12 Quadrant Holdings Cambridge Ltd. Tablet dosage form of clavulanic acid and amoxycillin comprising a trehalose excipient
WO1999010011A1 (en) * 1997-08-25 1999-03-04 Csl Limited Dried biologically or therapeutically active preparations
US6887852B1 (en) 2004-06-25 2005-05-03 Korea Green Cross Corporation Pharmaceutical preparation of recombinant factor VIII lyophilized without albumin as a stabilizer
US6964771B1 (en) 1995-06-07 2005-11-15 Elan Drug Delivery Limited Method for stably incorporating substances within dry, foamed glass matrices
EP1154796B1 (en) * 1999-02-22 2007-06-20 University of Connecticut Novel albumin-free factor viii formulations
EP2289547A1 (en) 2003-09-12 2011-03-02 Antigenics Inc. Vaccine for treatment and prevention of herpes simplex virus infection
WO2016183486A1 (en) 2015-05-13 2016-11-17 Agenus Inc. Vaccines for treatment and prevention of cancer
US10232022B2 (en) 2008-10-21 2019-03-19 Baxalta Incorporated Lyophilized recombinant VWF formulations
US10238718B2 (en) 2014-08-04 2019-03-26 Csl Limited Factor VIII formulation
WO2019210055A2 (en) 2018-04-26 2019-10-31 Agenus Inc. Heat shock protein-binding peptide compositions and methods of use thereof
US10512674B2 (en) 2008-11-07 2019-12-24 Baxalta Incorporated Factor VIII formulations
WO2021001522A1 (en) 2019-07-04 2021-01-07 CSL Behring Lengnau AG A truncated von willebrand factor (vwf) for increasing the in vitro stability of coagulation factor viii
US11191837B2 (en) 2007-12-28 2021-12-07 Takeda Pharmaceutical Company Limited Recombinant VWF formulations
US11197916B2 (en) 2007-12-28 2021-12-14 Takeda Pharmaceutical Company Limited Lyophilized recombinant VWF formulations
WO2022099223A2 (en) 2020-11-09 2022-05-12 Takeda Pharmaceutical Company Limited Purification of fviii from plasma using silicon oxide adsorption
WO2022261716A1 (en) * 2021-06-16 2022-12-22 Exopharm Limited Aqueous formulations for preservation of extracellular vesicles

Families Citing this family (18)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
GB9501040D0 (en) * 1995-01-19 1995-03-08 Quadrant Holdings Cambridge Dried composition
US7253262B2 (en) * 1995-01-19 2007-08-07 Quandrant Drug Delivery Limited Dried blood factor composition comprising trehalose
US7244824B2 (en) * 1995-01-19 2007-07-17 Quadrant Drug Delivery Limited Dried blood factor composition comprising trehalose
US6632648B1 (en) * 1996-05-14 2003-10-14 Elan Drug Delivery Limited Methods of terminal sterilization of fibrinogen
CN100436466C (en) * 2001-08-10 2008-11-26 株式会社林原生物化学研究所 Association compound of trehalose or maltitol with metal ion compound
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