New protective compositions for recombinant factor viii

FIELD: medicine, pharmaceutics.

SUBSTANCE: present invention refers to medicine, namely to pharmacology and describes a histidine-free pharmaceutical composition containing high-purity factor VIII; arginine and saccharose, a surfactant for the prevention or at least the inhibition of a surface adsorption of factor VIII; 0.5 to 10 mM calcium chloride for the specific stabilisation of factor VIII, and sodium citrate or maleic acid as a pH buffer.

EFFECT: invention provides the protective function for preserve high-yield factor VIII over the whole cycle of pharmaceutical processing, long storage and end recovery and administration into the patient.

18 cl, 16 tbl, 8 ex

 

The present invention relates to liofilizirovannam compositions with the ability to protect recombinant factor VIII (r-factor VIII) of high purity. The invention also relates to liquid compositions of r-factor VIII before lyophilization and after recovery lyophilized solid composition of the injection fluid.

Factor VIII is an important blood plasma protein involved in blood coagulation. The lack of coagulation factor causes hemophilia a, life threatening disease that should be treated substitution therapy with factor VIII. Traditionally replacement therapy used purified concentrates of factor VIII from plasma (p-factor VIII). Recently became available recombinant factor VIII (r-factor VIII), which supplies independent from donating blood, reducing the risk of diseases transmitted by viruses.

Factor VIII is a complex molecule and highly sensitive protein associated with loss of activity over time. In the blood other blood proteins such as human serum albumin (HSA) and the factor a background of Villebranda (vWF), involved in keeping coagulants activity of factor VIII. However, it is desirable to avoid the presence of proteins obtained when cleaning blood plasma, in the pharmaceutical compositions of r-factor VIII because of the risk of re is achi virus. Therefore, it is necessary to provide compositions of other pharmaceutically acceptable auxiliary substances for the protection of the r-factor VIII from physical and chemical degradation and aggregation, which can cause loss of activity. The most commonly used method to prevent the loss of activity of protein during long-term storage is getting dry solid pharmaceutical compositions by lyophilization (freeze-drying). Pharmaceutical excipients should also protect factor VIII during pharmaceutical process during long-term storage after recovery of freeze-dried composition in a solution for injection.

The DNA sequence of the factor VIII is divided into six domains; And three-, two - and one In-domain and protein contains sites of interaction for other coagulation factors, vWF, phospholipids and metal ions. The smallest active form of the protein factor VIII is not In the domain and consists of a light chain of 80 kDa, associated with a heavy chain 90 kDa (Wang, W. et al, 2003). Both medicinal product r-factor VIII, and polnotsennoi (Kogenate®, Bayer and Helixate®, CSL Behring, Recombinate®, Baxter and Advate®, Baxter) and without In-domain (ReFacto®, Wyeth and Xyntha®, Wyeth) are currently on the market.

In the pharmaceutical compositions of factor VIII all components must be carefully selected. Each auxiliary substance about which has a protective function to maintain a high yield of factor VIII throughout the pharmaceutical process, long-term storage and ultimate recovery and the introduction of the patient. It also describes the clinical safety of all auxiliaries.

The purpose of lyophilization (Manning, M.C. et al., 1989, X. Tang et al, 2004, Schwegman, J.J. et al, 2005) is the removal of water from the composition, as in the aqueous phase, are often undesirable physical and chemical reactions.

Cryo/lisamarie substances are required to protect the protein during the process of freeze-drying and during storage through the formation of an amorphous matrix surrounding the protein.

The filler include as a tool for sediment to create a mechanical support during freeze-drying and to increase the dry weight of the medicinal product. The filler, thus, participates in ensuring uniform quality and appearance of dried product.

A buffering agent may be added to maintain the pH at a level suitable for protein for therapeutic use of the product.

Due to the high efficiency of factor VIII concentration of factor VIII in the treatment solution is low. In addition, factor VIII is easily adsorbed on the surface, making the surface adsorption main source of loss of activity during production and after recovery of the product. For currently available products on the market factor VIII usually savla is t, which surfactant is used above its critical micellization concentration (CMC), which represents the concentration at which the surfactant forms a micellar aggregates. The values of CMC polyoxyethylene-containing nonionic detergents are dependent on temperature so that the CMC values are higher at lower temperatures (Alexandridis, P. et al., 1994, Nilsson, M, et al. 2007). KCM poloxamer 188 is at least 20-30 mg/ml at 37°C (Kabanov, A.V. et al, 1995, Alexandridis, P. et al, 1994, Moghimi, S.M. et al, 2004) and increased to 100 mg/ml at 20°C (Nakashima, K. et al, 1994). Therefore, in accordance with such messages ECR poloxamer 188 is in the range of 20-100 mg/ml at 25°C.

It was shown that metal ions are involved in the Association of light and heavy chains of factor VIII (W. Wang et al, 2003) and, therefore, calcium ions (Ca2+) are usually present in the compositions of factor VIII to maintain the Association complex of 80 and 90 kDa chains.

Considerable efforts have been applied for the detection of suitable compositions of factor VIII, for example:

In the publication Osterberg et al (1997) describe a composition including sodium chloride as filler, in combination with surface-active agent, calcium chloride and sucrose as a stabilizer and histidine as a buffer.

In US-B-7247707 (Bestman et l) describe the composition without albumin, include 300-500 nm sodium chloride, 1-4% of a stabilizer selected from the group consisting of sucrose, trehalose, raffinose, and arginine, 1-5 mm CaCl2and buffer substances, preferably histidine. Surfactant is also included in the composition at a concentration of up to 0.1%.

In US-A-5874408 (Nayar) describe the composition of recombinant factor VIII, which includes glycine, histidine, sucrose, CaCl2and small amounts of sodium chloride. Nayar found that histidine, which today include as buffer substances in commercially available preparations of r-factor VIII has a destabilizing effect in lyophilised compositions of factor VIII. This effect, however, overcome by the addition of salts, glycine and sucrose.

In US-A-4877608 (Lee et al) describe the use of high purity composition of the protein of factor VIII in an aqueous solution composed mainly of therapeutically active factor VIII activity, at least 130 IU/mg; 0.4 to 1.2 M sodium chloride, potassium chloride or mixtures thereof; 1.5 to 40 mm of calcium chloride and 1-50 mm histidine, and optionally up to 10% of sugar, selected from the group consisting of mannitol, sucrose and maltose.

In US-A-2005/0256038 (White et al) describes the composition of lyophilized factor VIII, which includes surface-active agent, calcium chloride, sucrose, sodium chloride, trisodium citrate and puff the R without amino acids.

In WO-A-99/10011 (Kanellos et al) describes teploobrazovanija composition of plasma factor VIII high purity. The composition includes a stabilizing effective amount of sucrose, trehalose, and at least one amino acid. The preferred amino acid is lysine, but others that may be used are isoleucine, leucine, lysine, methionine, phenylalanine, threonine, tryptophan, valine, alanine, arginine, histidine, Proline, serine and glycine.

In EP-A-1016673 (Osterberg et al.) describes the use of compositions comprising non-ionic surfactant as a stabilizer and factor VIII has a specific activity of more than 5000 IU/mg. Additionally indicated that the concentration of surfactant must be above the critical concentration of micelle formation in the amount of at least 0.01 mg/ml

In US-B-6887852 (Paik et al) describes a freeze-dried composition of factor VIII, comprising a mixture of L-arginine, L-isoleucine and L-glutamic acid as a stabilizer. The basic composition comprises low amounts of sodium chloride, calcium chloride and histidine. The songs do not add surfactants, as a composition, as described, shows a better stability compared to compositions comprising surface-active substance.

In US-A-5565427 (Freudenberg described the use of stable solution of factor VIII, includes detergent and amino acid or one of its salts. The specific activity of the protein is at least 2000 IU/mg.

In US-A-5328694 (Schwinn) described a stable injectable solution comprising factor VIII purified from plasma, and a combination of disaccharides and one or more amino acids. Preferably, the amino acid is lysine or glycine.

The present invention relates to compositions of recombinant factor VIII (r-factor VIII) of high purity. Compositions do not contain histidine. To implement the maximum protective effects of the composition of the present invention is based on the purposeful choice of auxiliary substances, such as cryo/lisamine substance, a filler and a surfactant. Each added excipient may not exert its protective effects on all stages, i.e. during the pharmaceutical process, long-term storage and during recovery and injection.

Lyophilized compositions of the present invention is not limited, as filled with the same amount and recoverable amount. For professionals in the field of technology it is obvious that receptively product can also be recovered in a more diluted form.

The present invention relates to compositions according to claim 1, having the ability to protect recombin ntny factor VIII.

Composition of r-factor VIII without histidine of the present invention typically include cryo/lisamine substance, such as arginine or sucrose, or a combination of arginine and sucrose; filler, which is sodium chloride or arginine; a surfactant; and optionally a buffering agent for pH. The term "without histidine"when it appears in the present context, does not mean the song "completely devoid of histidine", because a small amount can follow the party medicinal substance from the previous stages of production, but rather the histidine is not added during pharmaceutical processing. Histidine is often used as a buffering agent in the compositions of factor VIII and while some sources report a stabilizing effect on factor VIII (EP-A-1016673, Osterberg et al), other sources report destabilizers effect in the compositions of factor VIII (US-A-5874408, Nayar). The present invention, in accordance covers sodium citrate, maleic acid or Tris (Tris(hydroxymethyl)aminomethan) as pH buffering agents. A buffering agent is, for example, sodium citrate, present in amount to maintain the pH range of 6.5 to 7.5. A suitable form of sodium citrate is digitalnow salt. Typically, the compositions according to the invention can be in iofilizirovanny form but it also presents solutions, such as the solution for lyophilization and the solution recovered from the freeze-dried composition.

The composition may additionally include calcium chloride in an amount of from about 0.5 to 10 mm to improve specific stabilization of factor VIII molecule. The compositions may additionally include other compounds as antioxidants, such as glutathione or methionine.

Filler called auxiliary substance that is present in the composition to provide mechanical support to the dried pellet and to increase dry matter. The filler may be either in the crystalline state, as sodium chloride, or in an amorphous state as arginine.

The buffer substance pH call connection with a buffer capacity in the pH range between about pH 5 and 9. The buffer capacity refers to the value of the pKa of the buffer substance in the specified range of pH.

Supplier of ionic strength is called the ionic compound, which is present in the composition to increase the ionic strength.

Cryo - and lisamine substance (cryo/neoprotestant) is a compound present in the composition to reduce or even prevent the loss of protein activity during stages of freezing and drying lyophilization process and during subsequent storage of lyophilized product.

Surface-active agent refers to the connection, which is adsorbed on the surface and boundaries and thereby counteracts the loss of the activity of factor VIII due to adsorption. This type of loss of activity may occur throughout the pharmaceutical processing, and the processing of recovered product before or during administration to the patient. Some surface-active products form in solution micellar aggregates. The critical concentration of micelle formation of surfactants represents the concentration above which micelles are formed.

The protective composition of factor VIII refers to a composition consisting of selected excipients, each of the excipients provides a protective function to maintain a high yield of factor VIII during pharmaceutical processing, long-term storage and ultimate recovery and the introduction of the patient. Pharmaceutical treatment applies in particular to the last stages of the production process, starting with the delivery of medicinal substance with production until the end of lyophilization receptivo medicinal product. You must understand that the stages of the pharmaceutical treatment is usually well-known specialist in the field of engineering receptionarea protein and include stage as receptionarea, sterile filtered, filled in the e vials and lyophilization.

Loss of active factor VIII has a wide meaning, including, but not limited to, loss due to surface adsorption, aggregation, physical and/or chemical changes in the protein structure or loss due to rejection of liofilizatow unsatisfactory kind.

r-factor-VIII in particular, is a deletion derivative, fully or partially without In-domain, thus providing a specific activity, which may significantly exceed 5000 IU/mg before receptionism. Examples of such deletion derivatives, partially or completely no-domains described and received in EP-A-1136553 (Hauser et al) and EP-A-1739179 (Schroder et al) from human cell lines. Understand that the composition of the present invention, as described in the next section, is particularly well adapted for the protection of these deletion derivatives of factor VIII.

In accordance with the present invention cryo/lisamine ingredient is arginine or sucrose, or a combination of arginine and sucrose. Arginine can usually be salt or a derivative of arginine, such as arginine hydrochloride.

The filler of the present invention also has the additional function provider ionic strength, which minimizes the number of components necessary for adequate clinical product. Fillers really izobreteniya to be sodium chloride or arginine. Arginine may be in salt form, in particular in the form of hydrochloride.

In accordance with one embodiment of the present invention cryo/lisamine substance is a combination of arginine and sucrose. Filler and supplier of ionic strength, in particular, is sodium chloride. If the sodium chloride acts as a filler, the composition according to the invention in particular includes as cryo/lionising matter about 3-15 mg/ml of sucrose, and about 3-15 mg/ml arginine, provided that at least 6 mg/ml cryo/lionising substance is present as a filler, from about 10 mg/ml to about 40 mg/ml sodium chloride. The composition may in particular include from about 3 mg/ml to about 10 mg/ml, in particular from about 4.5 mg/ml to about 9 mg/ml sucrose, from about 3 mg/ml to about 8 mg/ml, in particular from about 4.5 mg/ml to about 6.8 mg/ml arginine and in particular, from about 15 mg/ml to about 23 mg/ml sodium chloride. Other suitable ranges of concentrations include, in particular, from about 4.5 to about 6.8 mg/ml sucrose, from about 4.5 mg/ml to about 6.8 mg/ml arginine and from about 15 mg/ml to about 23 mg/ml sodium chloride. Preferably, arginine and sucrose are present in equal amounts. The composition includes from then till about 9 mg/ml arginine and up to about 9 mg/ml sucrose. Moreover, the composition may include calcium chloride, the surface is surface-active substance and optionally sodium citrate as pH buffering agents. In another embodiment of the invention the composition according to the invention include sucrose in an amount of from about 10 mg/ml to about 25 mg/ml and sodium chloride in an amount of from 10 mg/ml to 40 mg/ml

In accordance with another embodiment of the invention the composition is alternatively essentially free from sodium chloride, cryo/lisamine substance is sucrose and the filler and supplier of ionic strength is arginine. In particular, the composition includes from about 5 to about 25 mg/ml sucrose and from about 20 to about 70 mg/ml arginine. Additionally, the composition may include calcium chloride, surfactant and, optionally, sodium citrate as a buffer substance. The term "essentially free from sodium chloride" when in the present context should not mean that the composition is completely devoid of sodium chloride", but rather contain traces of NaCl, for example, <1%as the minimum amount of sodium chloride can follow from batches of drug substance from the earlier stages of production, but rather that sodium chloride was not added during the production process.

Typically, the composition provides in dried form. In yet another embodiment, the invention composition provides in the form of a solution for lyophilization, or in the form of restoring the aqueous solution, obtained from the dried composition and diluent.

In the following embodiment of the invention in the compositions according to the invention the surface-active substance is a protein, in particular, the recombinant protein. Protein is particularly recombinante received albumin, for example, in amounts of from about 0.5 mg/ml to about 5 mg/ml This number is substantially smaller than, and different from the amount normally used in traditional compositions of plasma factor VIII, where albumin is effective only as cryo/lisamine substance. Suddenly albumin, in particular, recombinant albumin, very suitable for use as surfactants in the compositions of recombinant factor VIII for storage at room temperature.

In another embodiment of the invention surface-active agent is a nonionic surfactant, for example, a copolymer of polyoxyethylene-polyoxypropylene. In accordance with the invention, the surfactant is present at a concentration below the critical concentration of micelle formation, for example, a copolymer of polyoxyethylene-polyoxypropylene less than about 5 mg/ml

In one embodiment of the invention the composition comprises r-factor VIII having specifices the th activity of ≥5000 IU/mg protein.

In accordance with another embodiment of the invention the composition contains cryo/lisamine agent and filler, such as arginine, which also acts as a supplier of ionic strength. In particular, the arginine is present in an amount of from about 20 mg/ml to about 70 mg/ml Optionally, the composition may include calcium chloride, surfactant and, optionally, sodium citrate as a buffer substance.

Various compositions described include all surface-active agent, which in one aspect is a non-ionic detergent, in particular, polymeric non-ionic surfactant type block copolymer such as a copolymer of polyoxyethylene-polyoxypropylene, for example, Poloxamer 188 or non-ionic surfactant of the type of ester polyoxyethylene sorbitol and fatty acids, for example, Polysorbate 20 or Polysorbate 80. Suitable non-ionic surface-active agent is poloxamer 188, which can be used at a concentration below its critical micellization concentration (CMC), preferably in particular, at concentrations below about 5 mg/ml Reported that poloxamer 188 has a CMC in the range of 20-100 mg/ml at 25°C (Kabanov, A.V. et al, 1995, Alexandridis, P. et al, 1994, Moghimi, S.M. et al, 2004, Nakashima, K. et al, 1994).

In another aspect, the surface-the active substance is a recombinant protein, other than the protein of factor VIII, in particular, recombinant human albumin, in particular such compositions include recombinant albumin in an amount of from about 0.5 mg/ml to about 5 mg/ml

Various embodiments of the invention will be described in more detail in the following examples, which illustrate the invention, but should not be construed as narrowing or limiting the scope of the invention.

Examples

Factor VIII used in the experiments is a protein of recombinant human factor VIII with a deletion In the domain obtained in human cell lines HEK293F in accordance with the method described in EP 1739179 (Schroder et al). Cleaning method consists of five stages chromatography and gives high-purity preparation of a protein factor VIII (Winge et al, European patent application 08158893.1) with a variant type of human glycosylation (Sandberg et al, European patent application 08162765.5).

The activity of the protein was measured using a chromogenic analysis or by using a single-stage analysis.

Chromogenic analysis is a two-step photometric method, which measures the biological activity of factor VIII, as a cofactor. Factor VIII activates factor X to factor XA, which in turn, enzymatically cleaved in the product, which can be measured spectrophotometrically.

odnostadiinyi analysis is based on the ability of the sample, contains factor VIII, to correct the coagulation time of plasma deficient in factor VIII, in the presence of phospholipid, contact activator and calcium ions. The time of appearance of fibrin clot is measured at one stage.

EXAMPLE 1

Recombinant factor VIII was obtained in accordance with the description in the experimental section above. In the present experiment compared the composition containing cryo/lisamine substance that is a combination of arginine and sucrose, with compositions containing either sucrose or arginine as cryo/lionising substances. Sodium chloride acts as a filler and supplier of ionic strength.

Compositions studied in relation to the recovery of factor VIII in lyophilised compositions in the initial concentration of 150 IU/ml of the Investigated compositions indicated in table I.

TABLE I
Track
1A1B1C
Sucrose, mg/ml9-9
Arginine HCl, mg/ml9 9-
Sodium chloride, mg/ml303030
The dihydrate of calcium chloride, mg/ml0,50,50,5
Poloxamer 188, mg/ml222
The dihydrate sodium citrate, mg/ml222

1.5 ml aliquots liofilizirovanny in the freeze dryer in laboratory scale. Lyophilized samples were stored up to 12 months at +5°C, +25°C and +40°C to evaluate the activity of the protein over time. The samples were recovered in 1.5 ml of water for injection and analyzed using chromogenic analysis described in the experimental section above. The results are summarized in table II.

TABLE II
Results
The activity of factor VIII c time (months) (% of original value)
00,51236912
1A5°C100n.a.107n.a.951169290
25°C10097999589967670
40°C1009310276n.a.n.a.n.a.n.a.
1B5°C100n.a.106n.a.81111 9792
25°C10098999684816245
40°C100857959n.a.n.a.n.a.n.a.
1C5°C100n.a.101n.a.861028882
25°C10085868083827163
40°C100706656 n.a.n.a.n.a.n.a.
n.a. - not analyzed

The results of example 1 show that, unexpectedly, there is an additive synergistic cryo/lisamary effect between sucrose and arginine, whereas the composition 1A shows better recovery activity over time compared with compositions 1B and 1C.

EXAMPLE 2

Recombinant factor VIII was obtained in accordance with the description in the experimental section above. In the present experiment investigated the composition containing sucrose as cryo/lionising substances and arginine as filler and supplier of ionic strength. Compositions investigated in relation to the recovery of factor VIII in lyophilised compositions in the initial concentration of 150 IU/ml Investigated compositions shown in table III.

tr>
TABLE III
Track
2A2B2C
Sucrose, mg/ml101010
Arginine HCl, mg/ml503570
The dihydrate of calcium chloride, mg/ml0,50,50,5
Poloxamer 188, mg/ml222
The dihydrate sodium citrate, mg/ml222

1.5 ml aliquots of the solutions liofilizirovanny in the freeze dryer in laboratory scale. Lyophilized samples were stored up to 12 months at +5°C, +25°C and +40°C to evaluate the activity of the protein over time. The samples were recovered in 1.5 ml of water for injection and analyzed using chromogenic analysis, as described in the experimental section above. The results are summarized in table IV, as a percentage of the original value.

TABLE IV
Results
The activity of factor VIII c time (months) (% Ref is underwater values)
0136912
2A5°C10094809289101
25°C1009484867484
40°C1009081n.a.n.a.n.a.
2B5°C10099899085105
25°C1009993868086
40°C1009782n.a.n.a.n.a.
2C5°C1009788938897
25°C1009378877680
40°C10090n.a.n.a.n.a.n.a.
n.a. - not analyzed

The results of example 2 show that arginine works satisfactorily as a filler and supplier of ionic strength in combination with sucrose as cryo/lionising substances.

EXAMPLE 3

Recombinant factor VIII was obtained in accordance with the experimental section above. In the present experiment compared the song with or poloxamer 188 or Polysorbate 80 as a surface the surface-active substance with a composition without the surfactant. Cryo/lisamine substance is a combination of arginine and sucrose and sodium chloride is used as a filler and supplier of ionic strength. The compositions listed in table V, were investigated in relation to the recovery of factor VIII during the stage of freeze-drying with the initial concentration of factor VIII 150 IU/ml

TABLE V
Track
3A3B3C
Sucrose, mg/ml999
Arginine HCl, mg/ml999
Sodium chloride, mg/ml303030
The dihydrate of calcium chloride, mg/ml0,50,50,5
Poloxamer 188, mg/ml2--
-0,2-
The dihydrate sodium citrate, mg/ml222

1.5 ml aliquots of the solutions liofilizirovanny in the freeze dryer in laboratory scale. Samples were obtained before lyophilization and freeze. Lyophilized samples were recovered in 1.5 ml of water for injection prior to analysis. The activity of factor VIII was analyzed using chromogenic analysis described in the experimental section above. The results of the recovery of activity in frozen-thawed samples, and during the stage of freeze-drying are shown in table VI.

TABLE VI
Results recovery of activity during lyophilization
The activity of factor VIII (% of added amount)
Added numberFrozen-ottaviaRecovered after lyophilization
3A 10010493
3B10010197
3C100180

The results of example 3 show that the surface-active substance is necessary in the compositions to counteract the loss of protein, probably caused by surface adsorption and during the stage of freezing-thawing and during the process of lyophilization. This example additionally shows that the non-ionic polymer surfactant, poloxamer 188, when used in concentrations below the critical micellization concentration (CMC), effectively protects factor VIII during lyophilization. The protective effect is as high as that of non-ionic surfactant Polysorbate 80 used above its CMC values.

EXAMPLE 4

In example 3, it is shown that the surface-active substance is necessary in the composition to avoid loss of activity of factor VIII, caused by surface adsorption, and in this example, we investigate whether for this purpose to be used recombinant albumin.

Recombinant factor VIII was obtained according the description in the experimental section above. The compositions listed in table VII, were investigated in relation to the recovery of factor VIII in solution at the initial concentration of factor VIII 140 IU/ml of the Composition of the protein was stored at +25°C and analyzed at 0, 3, 7 and 10 day using chromogenic analysis described in the experimental section above. The results are shown in table VIII, as a percentage of the original value.

TABLE VII
Track
4A4B4C4D
Sucrose, mg/ml9999
Arginine HCl, mg/ml9999
Sodium chloride, mg/ml30303030
Calcium chloride, mg/ml0,50,50,5 0,5
Poloxamer 188, mg/ml2---
Recombinant albumin, mg/ml-124
Sodium citrate, mg/ml2222

TABLE VIII
Results
The activity of factor VIII over time (days) (% initial value)
03710
4A100938783
4B1001039996
4C 100110104100
4D100969585

The results of example 4 show that recombinant albumin can protect r-factor VIII against loss of activity, probably caused by surface adsorption.

EXAMPLE 5

In example 3, it is shown that the surface-active substance is necessary in the composition to avoid loss of activity of factor VIII, probably caused by surface adsorption and in example 4, it was shown that recombinant albumin may be used to prevent loss of activity of the protein in solution. In this example, we examine whether the recombinant albumin to protect against loss of protein activity is likely due to the surface adsorption is also at the stage of lyophilization.

Recombinant factor VIII was obtained in accordance with the description in the experimental section above. The composition did not contain a non-ionic detergent, but contained the recombinant albumin is added to prevent loss of activity. Cryo/lisamine substance is a combination of arginine and sucrose and sodium chloride is used as filler and supplier of ionic strength. Composition, Azania in table VII, investigated in relation to the recovery of factor VIII in lyophilised compositions when the initial concentration of factor VIII 150 IU/ml

1.5 ml aliquots of the solutions liofilizirovanny in the freeze dryer in laboratory scale. Lyophilized samples were stored for up to 12 months at +5°C, +25°C and +40°C to evaluate the activity of the protein over time. The samples were recovered in 1.5 ml of water for injection and analyzed using chromogenic analysis described in the experimental section above. The results are summarized in table IX.

TABLE IX
Results
The activity of factor VIII c time (months) (% of original values)
0136912
4A5°C10011011793112100
25°C 10010495757459
40°C1008447n.a.n.a.n.a.
4B5°C10099100949795
25°C10010098929592
40°C1008174n.a.n.a.n.a.
4C5°C100101114103106112
25°C 100106105102102102
40°C100108101n.a.n.a.n.a.
4D5°C1001001039996101
25°C100991121039999
40°C10010193n.a.n.a.n.a.
n.a. - not analyzed

The results of example 5 show that recombinant albumin can replace non-ionic detergent in the compositions of r-factor VIII (compositions 4B-4D) to avoid loss of activity, probably caused by the surface the adsorption at the stage of lyophilization. It also shows that the recombinant albumin is very suitable for use as surfactants in the compositions of recombinant factor VIII for storage at room temperature.

EXAMPLE 6

Recombinant factor VIII was obtained in accordance with the description in the experimental section above. The composition did not contain a non-ionic detergent, but was added recombinant albumin to prevent the loss of activity is likely due to surface adsorption. Cryo/lisamine the substance is sucrose and sodium chloride is used as a filler and supplier of ionic strength. The compositions listed in table X, investigated in relation to the recovery of factor VIII in lyophilised compositions, when the initial concentration of factor VIII 160 IU/ml

TABLE X
Track
6A6B
Sucrose, mg/ml2424
Sodium chloride, mg/ml3030
Calcium chloride, mg/ml 0,50,5
Recombinant albumin, mg/ml24
Sodium citrate, mg/ml22

1.5 ml aliquots of the solutions liofilizirovanny in the freeze dryer in laboratory scale. Lyophilized samples were stored for up to 6 months at +5°C, +25°C and +40°C to evaluate the activity of the protein over time. The samples were recovered in 1.5 ml of water for injection and analyzed using chromogenic analysis described in the experimental section above. The results are shown in table XI.

TABLE XI
Results
The activity of factor VIII (months) (% of original values)
01236
6A5°C100n.a.n.a. 93101
25°C10096n.a.106101
40°C100998989n.a.
6B5°C100n.a.n.a.95107
25°C100102n.a.79104
40°C10010199102n.a.
n.a. - not analyzed

The results of example 6 show that recombinant albumin can replace non-ionic detergent in the compositions of r-factor VIII to prevent loss of activity, which may be caused by surface adsorption at the stage of lyophilization. They also show, Thu the recombinant albumin is very suitable for use as surfactants in the compositions of recombinant factor VIII for storage at room temperature.

EXAMPLE 7

In the example studied the recovery of factor VIII in the solution containing histidine as a pH buffer substances, in comparison with a solution that does not contain pH buffering agents.

Recombinant factor VIII was obtained in accordance with the description in the experimental section above. The solutions listed in table XII, was investigated in relation to the recovery of factor VIII in the solution with the initial concentration of factor VIII 100 IU/ml

TABLE XII
Track
7A7B
Sucrose, mg/ml1818
The dihydrate of calcium chloride, mg/ml0,50,5
Polysorbate 80 mg/ml0,20,2
Histidine (mg/ml3-

The composition of the protein was stored at +25°C and analyzed at day 0 and after 3 and 7 days using chromogenic analysis described in the experimental section the above. The results are shown in table XIV, as a percentage of the original value.

TABLE XIV
Results
The activity of factor VIII over time (days) (% of original values)
037
7A25°C1008172
7B25°C1009590

The results of example 7 show that the composition without histidine protects factor VIII is better than the composition containing histidine.

EXAMPLE 8

Recombinant factor VIII was obtained in accordance with the description in the experimental section above. In the present experiment studied composition containing arginine as and cryo-/lionising substance, filler and supplier of ionic strength. Compositions investigated in relation to the recovery of factor VIII in lyophil the inpatient compositions in the initial concentration of 160 IU/ml The analyzed compositions shown in table XV.

TABLE XV
Track
8A
Arginine, mg/ml70
The dihydrate of calcium chloride, mg/ml0,5
Poloxamer 188, mg/ml2
The dihydrate sodium citrate, mg/ml2

1.5 ml aliquots of the solutions liofilizirovanny in the freeze dryer in laboratory scale. Lyophilized samples were stored for up to 9 months at +5°C, +25°C and +40°C to evaluate the activity of the protein over time. The samples were recovered in 1.5 ml of water for injection and analyzed using chromogenic analysis, as described in the experimental section above. The results are summarized in table XVI, as a percentage of the original value.

TABLE XVI
Results
The activity of factor VIII is Uchenie time (months) (% of original values)
012369
8A5°C10088n.a.988592
25°C10083n.a.978180
40°C100857985n.a.n.a.
n.a. - not analyzed

The results of example 8 show that arginine may be multifunctional auxiliary substance, as it operates satisfactorily as a filler and as a provider of ionic strength, as well as cryo/lisamine substance.

List of links

Wang, W., Wang, Y. W. and Kelner, D. N., Coagulation factor VIII: structure and stability (Review), Int. J. Pharm., 259, (2003), 1-15

Schwegman, J. J., Hardwick, L. M. and Akes, M. J., Practical Formulation and process Development of Freeze-Dried Products, Pharm. Dev. and Techn., 10, (2005), 151-173

Tang, X. and Pikal, M. J., Design of Freeze-Drying Processes for Pharmaceuticals: Practical Advice, Pharm. Res., 21 (2), (2004), 191-200

Manning, M. C, Patel, K. and Borchardt, R. T., Stability of Protein Pharmaceuticals, Pharm. Res., 6 (11), (1989), 903-918

Osterberg, T., Fatouros, A. and Mikaelsson, M., Development of a Freeze-Dried Albumin-Free Formulation of Recombinant Factor VIII SQ, Pharm. Res., 14, (1997), 892-898

Alexandridis, P. et al, Micellization of Poly(ethylene oxide)-Poly(propylene oxide)-Poly(ethylene oxide) Triblock Copolymers in Aqueous Solutions: Thermodynamics of Copolymer Association, Macromolecules, 27, (1994), 2414-2425

Kabanov, A. V. et al, Micelle Formation and Solubilization of Fluorescent Probes in Poly(oxyethylene-b-oxypropylene-b-oxyethylene) Solutions, Macromolecules, 28, (1995), 2303-2314

Moghimi, S. M. et al, Biochimica et Biophysica Acta, 2004, 1689, 103-113

Nakashima, K. et al, Fluorescence Studies on the Properties of a Pluronic F68

Micelle, Langmuir, 10, (1994), 658-661

Nilsson, M. et al, Influence of Polydispersity on the Micellization of Triblock Copolymers Investigated by Pulsed Field Gradient Nuclear Magnetic Resonance, Macromolecules, 40, (2007), 8250-8258

1. The pharmaceutical composition without histidine, including factor VIII or r-factor VIII high purity;
arginine and sucrose;
surfactant for preventing or at least inhibiting surface adsorption of factor VIII;
from 0.5 to 10 mm of calcium chloride for specific stabilization of factor VIII and sodium citrate or maleic acid as a pH buffering agent.

2. Composition without histidine according to claim 1, in which the sodium chloride is present as a filler, if arginine and/or sucrose are as cu is about-/lisamine substance, but not as a filler.

3. Composition without histidine according to claim 1, in which essentially no sodium chloride, in particular, if arginine is used as a cryo-/lionising substance and filler.

4. The composition according to claim 1, in which the r-factor VIII is a deletion derivative of the natural factor VIII, partially or completely lacking In the natural domain of factor VIII.

5. The composition according to claim 1 in lyophilized form.

6. The composition according to claim 1 in the form of a solution for lyophilization, or in the form of recovered solution obtained from the freeze-dried composition and diluent.

7. Composition according to any one of claim 2, 4-6, including as cryo/lionising matter about 3-15 mg/ml of sucrose, and about 3-15 mg/ml arginine, provided that there is at least 6 mg/ml cryo/lionising substances and as a filler from about 10 mg/ml to about 40 mg/ml sodium chloride.

8. The composition according to claim 7, in which cryo/lisamine substance includes arginine and sucrose, in particular, from about 3 mg/ml to about 10 mg/ml, especially from about 4.5 mg/ml to about 9 mg/ml sucrose, from about 3 mg/ml to about 8 mg/ml, especially from about 4.5 mg/ml to about 6.8 mg/ml arginine and from about 10 to about 40 mg/ml NaCl in particular, from about 15 mg/ml to about 23 mg/ml sodium chloride.

9. The composition according to claim 1, in which the sucrose is present in amount from about the olo 10 mg/ml to about 25 mg/ml and sodium chloride is present in an amount of from about 10 mg/ml to about 40 mg/ml

10. Composition according to any one of p-6, including cryo/lisamine substance, which is sucrose, and the filler, which is arginine, in particular, from about 5 mg/ml to about 25 mg/ml sucrose and from about 20 mg/ml to about 70 mg/ml arginine.

11. Composition according to any one of p-6, in which the arginine acts as a filler and as cryo/lisamine substance.

12. The composition according to claim 11, in which the arginine is present in an amount of from about 20 mg/ml to about 70 mg/ml

13. The composition according to claim 1, in which the surface-active substance is a protein, in particular, the recombinant protein.

14. The composition according to item 13, in which the protein is recombinant albumin, in particular, in amounts of from about 0.5 mg/ml to about 5 mg/ml

15. The composition according to claim 1, in which the surface-active agent is a nonionic surface-active substance.

16. The composition according to item 15, in which the surfactant is present at a concentration below the critical concentration of micelle formation.

17. The composition according to item 15 or 16, in which the nonionic surface-active agent is a copolymer of polyoxyethylene-polyoxypropylene.

18. The composition according to claim 1, in which the specific activity of the r-factor VIII is ≥5000 IU/mg protein.



 

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