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Stable Multi-Dose Compositions Comprising an Antibody and a Preservative

a multi-dose composition and protein technology, applied in the field of stable multi-dose compositions containing proteins, can solve the problems of low bioactivity, serious challenges in the development of high-concentration formulations of mabs, and instability problems

Inactive Publication Date: 2013-05-30
NOVO NORDISK AS
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Benefits of technology

This patent describes a stable liquid medication that contains an antibody and other preservatives. It can be used for therapy. This helps to ensure the medication is safe and effective for multiple uses. The technical effect of this patent is to provide a reliable and consistent method for creating a multi-dose liquid medicine containing antibodies.

Problems solved by technology

However, the effect of the preservative on protein stability is a major concern.
Anti-microbial preservatives are known to interact with proteins and cause stability problems such as aggregation.
Thus, identifying formulation-compatible preservatives at concentrations that also provide the desired antimicrobial efficacy is a major challenge during drug product development.
There is a general consensus that development of high-concentration formulations of mAbs poses serious challenges with respect to the physical and chemical stability of the mAb, such as increased formation of soluble as well as insoluble aggregates which enhance the probability of an immunogenic response as well as give rise to low bioactivity.
Aggregate formation by a polypeptide during storage of a liquid pharmaceutical composition can adversely affect biological activity of that polypeptide, resulting in loss of therapeutic efficacy of the pharmaceutical composition.
Furthermore, aggregate formation may cause other problems such as blockage of tubing, membranes, or pumps when the polypeptide-containing pharmaceutical composition is administered using an infusion system.

Method used

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Examples

Experimental program
Comparison scheme
Effect test

example 1

4 Week Stability Analysis at 40° C. for Anti-IL-20

[0116]12 formulations were prepared (see Table 1 below). The formulations were prepared from a stock solution containing ca. 150 mg / ml of the Anti-IL-20 antibody and 10 mM histidine buffer, pH 6.5. This stock solution was prepared by conventional UF / DF / UF. Stock solution of the excipients were prepared and mixed in the correct proportion. The final formulations were filled in 3 ml Penfill® cartridges, type 1 glass. The formulations were stored at 40° C. for 4 weeks and then analysed chemically, pharmaceutically and biophysically. The increase in the formation of protein aggregates (% HMWP) was measured by SEC-HPLC (as described above).

TABLE 1Composition of tested formulationsAnti-IL-20100mg / mlHistidine33mMArginine25mMNaCl25mMPolysorbate 800.01mg / mlPreservative(s)ConcentrationvariedpH6.5

[0117]The results of the stability analysis are shown in Table 2 and demonstrates that all tested formulations resulted in a low content of aggregates...

example 2

3 Month Stability Analysis at 5° C. and 40° C. for Anti-IL-20

[0120]This study was conducted in an analogous manner to that described in Example 1 with the exception that the study was conducted for 3 months at 5° C. and 40° C. and the formulations contained sucrose as described in Table 4.

TABLE 4Composition of tested formulationsAnti-IL-20100mg / mlHistidine33mMArginine25mMNaCl25mMPolysorbate 800.01mg / mlSucroseTo tonicityPreservative(s)ConcentrationvariedpH6.5

[0121]The results of the stability analysis at 40° C. are shown in Table 5 and demonstrates that all tested formulations resulted in a low content of aggregates following 1 month storage at 40° C.

TABLE 5SEC-HPLC Analysis of increase of % HMWP for Anti-IL-20formed during 3 month study at 40° C. (Δ % HMWP)Months of storageΔ % HMWP0.513Reference0.00.52.4Phenol 5 mg / ml1.22.67.6m-cresol 3.5 mg / ml0.20.90.0Phenol / m-cresol 1.5 / 1.8 mg / ml2.9*4.6*8.9**The absolute value of % HMWP is given as time zero value was not available

[0122]In particu...

example 3

Results from Modified Preservative Efficacy Test for Anti-IL-20

[0127]To analyze the efficacy of different preservatives, a preservative efficacy screening test was performed. The efficacy of the preservative was measured using a modified USP / Ph Eur preservative efficacy test. In the modified test, formulations were tested against Staphylococcus aureus. After inoculation, samples were stored for 6 and 24 hours at room temperature and the total bacterial counts were measured using a colony counter. The log reduction values were calculated as log (initial count / final count).

In the unmodified USP / Ph Eur preservative efficacy tests several bacteria and fungi are tested. The USP and Ph Eur regulatory requirements are listed here below in Table 9. It should be noted that the Ph Eur requirements are more stringent than those of the USP, and that the Ph Eur requirements offer a minimal level that must be achieved (B criteria) and a suggested level that is recommended (A criteria). The preser...

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PUM

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Abstract

The invention relates to stable, multi-dose liquid compositions containing proteins, in particular, but not exclusively stable antibodies, and to the use of said compositions in therapy, in particular for the subcutaneous delivery of said stable protein.

Description

FIELD OF THE INVENTION[0001]The invention relates to stable, multi-dose liquid compositions containing proteins, in particular, but not exclusively stable antibodies, and to the use of said compositions in therapy, in particular for the subcutaneous delivery of said stable protein.BACKGROUND OF THE INVENTION[0002]Immunoglobulins, monoclonal antibodies (mAbs) and humanized antibodies have been in development as pharmaceutical products for a number of years. There is a clear incentive for developing multi-dose formulations of mAbs due to the potential for repeated dosage which results in higher convenience for the patient. However, multi-dose formulations must contain antimicrobial agents to protect them from microbial contamination during multiple dosage withdrawal. Multi-dose formulations containing preservatives offer several advantages over single dose containers. For example, product wastage is minimized because different sized doses may be obtained from the same container. Addit...

Claims

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Application Information

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Patent Type & Authority Applications(United States)
IPC IPC(8): A61K39/395
CPCA61K9/0019A61K9/08A61K47/10A61K47/14A61K39/39591A61K47/183A61K47/26C07K16/00A61K47/18A61P7/02A61P7/04A61P29/00A61P37/04A61K39/395
Inventor PARSHAD, HENRIKENGELUND, DORTHE KOT
Owner NOVO NORDISK AS
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