Chemistry: molecular biology and microbiology – Micro-organism – tissue cell culture or enzyme using process... – Enzymatic production of a protein or polypeptide
Reexamination Certificate
1999-10-25
2002-11-26
Tate, Christopher R. (Department: 1651)
Chemistry: molecular biology and microbiology
Micro-organism, tissue cell culture or enzyme using process...
Enzymatic production of a protein or polypeptide
C424S130100, C424S094660, C424S142100, C424S177100, C424S178100, C424S179100, C424S183100
Reexamination Certificate
active
06485932
ABSTRACT:
The present invention relates to a liquid composition for intravenous administration which comprises an aqueous solution of immunoglobulin. The immunoglobulin is generally immunoglobulin G (IgG) derived from human blood plasma.
Immunoglobulin for intravenous infusion has been in clinical use for several years. The product is available as a lyophilised dry formulation or in some cases, as an intravenously injectable liquid formulation. The dry formulation, presented as a vial containing for example 5 g of immunoglobulin, requires to be reconstituted into an injectable solution before use and doses of up to 1 g per Kg body weight per day are recommended for several clinical indications. Such large doses require a number of vials to be reconstituted into an injectable formulation, which is inconvenient and time consuming. There are therefore considerable advantages in providing a ready to use injectable formulation. However, such liquid formulations require to be stable on long term storage.
Conventionally, IgG is isolated from blood plasma using ethanol fractionation processes. These include the original Cohn-Oncley methods which are still in use principally in the USA and various other established modifications of that method which are used mainly in Europe (for a review of ethanol fractionation processes see Ethanol Precipitation by Kistler P. and Friedli H. in Methods of Plasma Protein Fractionation, J. M. Curling, ed., Academic Press, Inc., New York, 1980). A disadvantage of ethanol, namely its potential for denaturing proteins, is offset by using low processing temperatures and hence these methods are generally referred to as “cold ethanol fractionation”. Cold ethanol fractionation processes all depend on the manipulation of five variables, ie. ethanol concentration, pH, ionic strength, temperature and protein concentration to achieve the selective separation of proteins into different precipitates which, by convention, are known as Fractions. Fraction II is the principal immunoglobulin bearing precipitate in the cold ethanol fractionation of human blood plasma.
For some time preparations for the intramuscular administration of immunoglobulin have been formulated from Fraction II. However, the intravenous infusion of these preparations has been found to cause severe adverse reactions, resembling anaphylaxis (ie. cardiovascular collapse and bronchospasm), in recipients (see Immunoglobulins: Characteristics and uses of intravenous preparations, Alving B. M. and Finlayson J. S., eds, US Dept. of Health and Human Sciences Publication No. (FDA)-80-9005, 1979). These severe adverse reactions are now known to be caused principally by the presence of aggregates of IgG molecules and the contamination of Fraction II with trace quantities of vasoactive blood plasma enzymes such as pre-kallikrein activator (PKA) and kallikrein. Aggregated immunoglobulin can bind and activate the complement group of blood plasma proteins (so called “anti-complementary activity”) and the activation of the complement system results in the generation of the complement peptides C5a and C3a which are anaphylatoxins. It is also known that the administration of PKA and kallikrein in physiological significant quantities can cause severe hypertension and cardiovascular collapse.
Thus in the preparation of a formulation of immunoglobulin for intravenous infusion attention needs to be paid to the above issues. A number of approaches have been taken to solving this problem. These include, altering the processing of Fraction II in order to prevent aggregate formation; further purification of the immunoglobulin from Fraction II so as to remove aggregates and other contaminating plasma proteins and the treatment of immunoglobulin from Fraction II with very low levels of a proteolytic enzyme such as pepsin to dissociate any aggregates and residual PKA and kallikrein. (For a review of the production of Immunoglobulin for intravenous infusion see Methods for the Production of IVIG Preparations and Analysis of IVIG Preparations Available, by Lundblad J. L. and Schroeder D. D. in Clinical applications of intravenous immunoglobulin therapy, P. L. Yap, ed., Churchill Livingstone Inc., New York, 1992). The use of pepsin in this way has been found to be optimum at a relatively low pH, eg. 4.0. Additionally it is well understood in the art that such a low pH treatment is an effective virus inactivation procedure (see Reid, K. G. et al. Vox Sang. 55 p75-80 , 1988. Potential contribution of mild pepsin treatment at pH4 to the viral safety of human immunoglobulin products).
In fact, preparations of human immunoglobulin for intravenous infusion are required to meet certain standards, such as those recommended by the European Pharmacopoeia Commission which sets out guidelines for inter alia distribution of molecular size, anti-complementary activity, PKA and that the method of preparation includes a step or steps that have been shown to inactivate known agents or infection (see European Pharmacopoeia Third Edition published June 1996 to replace the second edition on Jan. 1, 1997, Monograph number 1997: 0918, Human Normal Immunoglobulin for Intravenous Administration).
The majority of human immunoglobulin products for intravenous infusion on the market currently are in the form of freeze dried preparations to provide stability on shipment and storage. These preparations must be reconstituted before use which can be inconvenient and time consuming as described earlier. In addition, liquid compositions of immunoglobulin for intravenous infusion are also available.
U.S. Pat. No. 4,499,073 (Cutter Laboratories Inc.) describes the production of an intravenous injectable solution of human immunoglobulin which is required to have a pH in the range 3.5 to 5.0. Furthermore, the ionic strength is required to be reduced to low levels, particularly below 0.001. The maintenance of the pH within this range and low ionic strength are said to be essential to the ability to store the liquid.
Formulation for extended periods, whilst satisfying criteria such as distribution of molecular size and anti-complementary activity.
Another proposal for the production of a stable liquid formulation of human immunoglobulin is contained in W095/22990 (The Green Cross Corporation) which requires a pH in the region 5.5 in conjunction with a low electrical conductivity of less than 1 mmho.
The proposals set out in U.S. Pat. No. 4,499,073 relate to the treatment of Fraction II or Fraction III filtrate (Supernatant III) produced using the methods described originally by E. J. Cohn et al (J. Am. Chem. Soc. 68 :459-475, 1946) and, L. J. Oncley et al (J. Am. Chem. Soc. 71: 541-550, 1949). However, these conditions do not appear to be suitable for the production of a stable IgG solution derived from other cold-ethanol fractionation schemes. The pH conditions and low ionic strength specified in this reference do not result in the formation of a stable product when applied to immunoglobulin prepared according to the cold ethanol fractionation scheme used by the present applicants. Since different modified cold ethanol fractionation methods are used widely, especially in Europe, there is therefore a need for a stable IgG solution derived from starting materials other than those taught as suitable in the prior art.
It has now been surprisingly discovered that stable intravenously injectable immunoglobulin solutions may be obtained by employing quite different conditions of pH and ionic strength to those taught in the prior art, with the additional inclusion of treating the immunoglobulin preparation with an enzyme such as pepsin.
Thus, the present invention provides a liquid composition for intravenous administration which comprises a solution of an immunoglobulin in a pharmaceutically acceptable aqueous carrier, the solution having a pH in the range 5.0 to 5.8 and an ionic strength On the range 0.02 to 0.25, the immunoglobulin having been subjected to treatment with pepsin.
The ionic strength may be in the range 0.04-0.25. Ionic strength (I) is defined as half the sum of th
McIntosh Ronald Vance
Welch Anne Gillian
Common Services Agency
Flood Michele
Myers Bigel Sibley & Sajovec P.A.
Tate Christopher R.
LandOfFree
Composition comprising immunoglobulin does not yet have a rating. At this time, there are no reviews or comments for this patent.
If you have personal experience with Composition comprising immunoglobulin, we encourage you to share that experience with our LandOfFree.com community. Your opinion is very important and Composition comprising immunoglobulin will most certainly appreciate the feedback.
Profile ID: LFUS-PAI-O-2983659