| Stabilised compositions of factor vii -> Monitor Keywords |
|
|
  Stabilised compositions of factor viiUSPTO Application #: 20070021338Title: Stabilised compositions of factor vii Abstract: The invention relates to chemically as well as physically stable kits and compositions comprising polypeptides, in particular Factor VII or Factor VII-related polypeptides, such that these compositions can be stored, handled and used at room temperature. (end of abstract) Agent: Novo Nordisk, Inc. Patent Department - Princeton, NJ, US Inventors: Birthe Lykkegaard Hansen, Michael Bech Jensen, Troels Kornfelt USPTO Applicaton #: 20070021338 - Class: 514012000 (USPTO) Related Patent Categories: Drug, Bio-affecting And Body Treating Compositions, Designated Organic Active Ingredient Containing (doai), Peptide Containing (e.g., Protein, Peptones, Fibrinogen, Etc.) Doai, Cyclopeptides, 25 Or More Peptide Repeating Units In Known Peptide Chain Structure The Patent Description & Claims data below is from USPTO Patent Application 20070021338. Brief Patent Description - Full Patent Description - Patent Application Claims
FIELD OF INVENTION [0001] The present invention relates to kits comprising chemically as well as physically stable compositions comprising Factor VII or a Factor VII-related polypeptide such that these compositions can be stored, handled and used at room temperature. BACKGROUND OF THE INVENTION [0002] Medicaments containing polypeptides are complex compositions. When developing such a medicament several parameters need to be considered. By example, the medicament needs to be effective, safe and lead to good patient compliance. Moreover, the medicament may be formulated for parenteral administration using pharmaceutically acceptable excipients, which will have to meet with the approval of various world-wide medical regulatory agencies. For the purpose of parenteral administration, it is highly desirable that the formulation is approximately isotonic and that the pH of the formulation is in a physiologically suitable range upon injection/infusion, otherwise it may result in pain and discomfort for the patient. For a general review of polypeptide formulations, see, for example, Cleland et al.: The development of stable protein formulations: A closer look at protein aggregation, deamidation and oxidation, Critical Reviews in Therapeutic Drug Carrier Systems 1993, 10(4): 307-377; and Wang et al., Parenteral formulations of polypeptides and peptides: Stability and stabilizers, Journal of Parenteral Science and Technology 1988 (Supplement), 42 (2S). [0003] However, for medicaments comprising polypeptides the safety may directly be related to the physical and chemical stability of the polypeptide. Polypeptides are susceptible to physical degradation, including denaturation and aggregation such as the formation of soluble or insoluble aggregates in the form of dimers, oligomers and polymers, or to chemical degradation, including for example, hydrolysis, deamidation and oxidation. Consequently, the said physical and chemical instability may lead to loss of activity of the polypeptide, formation of toxic and immunogenic degradation products, in case of coagulation factor polypeptides there is serious risk of introducing thrombosis upon injection of the degraded polypeptides, clogging of needles used for injections and risk of non-homogeneity, to name just a few. [0004] Thus, compositions comprising polypeptides need to be stabilised so as allowing storage and handling at ambient temperatures. One approach of stabilising a polypeptide relates to removal of water from the polypeptide, e.g. such as providing the polypeptide in the form of a lyophilised cake, the final matter obtained in a freeze-drying process. However, the freeze-drying process itself is also harmful to polypeptides; during freeze-drying, the polypeptide solution is first cooled until adequately frozen and bulk water in the polypeptide solution will form ice at this stage. The polypeptide is hereby prone to freeze-induced stress resulting in deformation and precipitation. In the next step, the so-called primary drying stage, the ice sublimes and in the secondary drying stage, adsorbed or bound water is removed under elevated temperatures. During this water removal, the polypeptides may loose their proper conformation that is provided mainly through hydrogen bonding. [0005] Therefore, to preserve polypeptide conformation, activity and stability during freeze-drying, the polypeptide solution needs to be supplemented with sufficient amounts of proper excipients with cryoprotectant and/or lyoprotectant properties so as to protect the polypeptide from freeze-induced stress and/or stress during removal of water, respectively. [0006] U.S. 20010031721 A1 (American Home Products) concerns highly concentrated, lyophilised, and liquid Factor IX formulations. [0007] WO 97/26909 (Genetics Institute) concerns lyophilised preparations of Factor IX suitable for storage and administration. The preparations may comprise sucrose or mannitol as a cryoprotectant. [0008] WO 95/28954 (Genetics Institute) concerns preparations of Factor IX suitable for storage and administration. The preparations may comprise sucrose as a cryoprotectant. [0009] Additionally, when providing a lyophilised product, an essential feature relates to the properties of the lyophilised cake. It needs to have good properties as to its form and structure, i.e. it should not collapse in that such collapsed cakes can be hard or even impossible to dissolve (reconstitute) before use. Conversely, the physical structure of the lyophilised cake may not be too loosen and soft. Therefore, one or more so-called bulking agents are added to the polypeptide solution before freeze-drying. [0010] Apart from choosing the right bulking agents it is also essential to avoid excipients which destabilises the physical properties of the cake. The concentration of these substances should be as low as possible. Furthermore, it is important that the reconstituted solution is not too hypotonic or hypertonic as this will cause injection inconvenience or even pain for the patient when administered. Therefore, it is normally necessary to add tonicity to the composition. Another excipient could be a buffer substance in order to keep the pH of the reconstituted solution stable during storage. [0011] Vitamin K-dependent polypeptides are a group of polypeptides involved in the blood clotting process; the group include factor VII, factor IX, factor X, factor II, Protein C, Protein S, gas6, and bone matrix Gla polypeptide or can be a protease selected from the group consisting of factor VIIa, factor IXa, factor Xa, factor IIa, and activated protein C. Factors VIIa, IXa, and Xa are particularly useful proteases. Factor VIII is a polypeptides involved in the blood clotting process. It can be made by recombinant techniques or prepared from plasma and is widely used in treatment of bleeding episodes in haemophilia patients. [0012] Factor VII is a polypeptide involved in the blood clotting process. Today, Factor VIIa can be made by recombinant techniques (rFVIIa) and is widely used as a pro-haemostatic agent. Factor VII (human wild-type) has been described in U.S. Pat. No. 4,784,950. rFVIIa offers today a rapid and highly effective pro-haemostatic response in haemophilic individuals experiencing bleeding. Advantageously, rFVIIa can be used for treating haemophilic individuals that cannot be treated with other coagulation factor products due to antibody formation. Also individuals suffering from Factor VII deficiency or individuals having a normal coagulation system but still experiencing excessive bleeding can be treated successfully with rFVIIa. [0013] Today, recombinantly-made FVII polypeptide is provided as freeze-dried product that is meant to be stored at temperatures between about 2 and about 8.degree. C. The requirement of cooled conditions causes a burden to and is inconvenient for the manufacturer or provider as well as the end user (the patient). [0014] The actual recombinantly-made FVII product is NovoSeven.RTM. (Novo Nordisk A/S, Denmark) that consists of 1.2 mg recombinant human Factor VIIa, 5.84 mg NaCl, 2.94 mg CaCl2, 2H2O, 2.64 mg Glycylglycine, 0.14 mg polysorbate 80 and 60.0 mg mannitol. When reconstituted by 2.0 ml of water for injection (WFI), the pH is 5.5 and the thus prepared FVII-containing solution is sufficiently stable for 24 hours at room temperature. [0015] The present investigators have found that upon storage of the lyophilised NovoSeven.RTM. product for 6 months at 25.degree. C. about 6 to 7% w/w of the initial content of the rFVIIa is present in the form of aggregates. [0016] Thus, compositions comprising Factor VII polypeptides need to be stabilised so as allowing storage and handling at ambient temperatures. [0017] It is an objective of the present invention to provide improved compositions, kits, and methods for producing these, wherein the dry compositions comprising the polypeptides are stabilized against chemical and physical degradation (such as, e.g., forming less dimer/oligomer degradation forms); with good properties of the lyophilised cake as to its form and structure, i.e. it should not collapse; with good and stable physical structure of the lyophilised cake; where the dry composition is devoid of excipients which destabilises the physical properties of the cake, e.g., by decreasing the eutectic melting point and thus increasing the risk of collapse of the cake; wherein the reconstituted composition prepared by dissolving the dry polypeptide-containing composition in the administration vehicle is isotonic, or closely isotonic, and has a well-defined pH (pH-stable). Particularly, it is an object to provide improved compositions comprising Factor VII polypeptides, substantially without the presence of degradation products and without decreased activity of the Factor VII polypeptides, preferable after prolonged storage at ambient conditions, e.g. for at least 6 months. Furthermore, it is an objective that the stable compositions are suitable for parenteral administration so as not to cause any inconvenience for the patient. SUMMARY OF THE INVENTION [0018] It has been found by the present investigators that polypeptide-containing medicaments can be provided as a kit of parts comprising a first unit form consisting of a dry (e.g., a freeze-dried) composition comprising a polypeptide and at least one stabilizing agent wherein the composition has a moisture content of not more than about 3%, and container means for containing said first unit form; and, in container means for containing such a unit, a second unit form consisting of an administration vehicle comprising a solvent for solution (reconstitution) of said composition and at least one of the components selected from the list of: (i) an agent suitable for keeping the pH of said composition in the range of 3 to 9 when dissolved in aqueous solvent in an amount of from about 0.1 mM to 100 mM; and (ii) a tonicity modifying agent in an amount sufficient to make essentially isotonic the reconstituted solution resulting from dissolving the composition of the first unit form in the administration vehicle of the second unit form. [0019] Substances which usually are present in the formulation like buffer substances and tonicity modifiers will very often decrease the eutectic melting point and will increase the risk of collapse of the cake. If these substances are present during freeze drying the temperature of the ice during the primary drying must be lowered to avoid collapse and consequently the time for freeze drying is prolonged. The concentration of these substances in the freeze-dried cake should be as low as possible or they should be completely avoided. Instead they may beneficially be added to the reconstitution liquid. [0020] By lowering the concentration of these excipients or completely removing them, the reconstituted solution will in some instances become hypotonic and it is necessary the add tonicity modifiers to the solvent so as to obtain a solution with the needed tonicity, such as isotonicity, or closely so ("essentially isotonic"). Another necessary excipient in the solvent could be a buffer substance in order to keep the pH of the reconstituted solution stable during storage. [0021] The kit of parts is sufficiently stable so as to allow for storage at room temperature for about at least 8 months. Continue reading... Full patent description for Stabilised compositions of factor vii Brief Patent Description - Full Patent Description - Patent Application Claims Click on the above for other options relating to this Stabilised compositions of factor vii patent application. ###  How KEYWORD MONITOR works... a FREE service from FreshPatents1. Sign up (takes 30 seconds). 2. Fill in the keywords to be monitored. 3. Each week you receive an email with patent applications related to your keywords. Start now! - Receive info on patent apps like Stabilised compositions of factor vii or other areas of interest. ### Previous Patent Application: Pharmaceutical compositions based on anticholinergics and soluble tnf receptor fusion proteins Next Patent Application: Stabilized teriparatide solutions Industry Class: Drug, bio-affecting and body treating compositions ### FreshPatents.com Support Thank you for viewing the Stabilised compositions of factor vii patent info. IP-related news and info Results in 2.343 seconds Other interesting Feshpatents.com categories: Canon USA , Celera Genomics , Cephalon, Inc. , Cingular Wireless , Clorox , Colgate-Palmolive , Corning , Cymer , |
||
