Pharmaceutical Formulations and Methods of Making the Same

Inactive Publication Date: 2018-04-26
AMGEN INC
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Benefits of technology

[0006]Provided herein are new and improved formulations of etanercept. In particular, the invention provides pharmaceutical compositions containing etanercept that are stable and can be conveniently stored as a liquid at controlled room temperature (CRT) for extended periods of time, even in the absence of an additional b

Problems solved by technology

Formulation of a protein drug can present many challenges for the pharmaceutical scientist.
Especially for engineered proteins that differ in subst

Method used

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  • Pharmaceutical Formulations and Methods of Making the Same
  • Pharmaceutical Formulations and Methods of Making the Same
  • Pharmaceutical Formulations and Methods of Making the Same

Examples

Experimental program
Comparison scheme
Effect test

Example

Example 1: Stability Testing of Various Formulations

[0048]This example demonstrates the effects of pH and buffer on etanercept at 50 mg / mL, and assesses the stability of a high concentration (100 mg / mL) solution without added phosphate buffer. The following formulations were tested.

TABLE 1Formulations for pH ScreenProteinPolysorbateFinalConcFormulation NameBufferExcipientsAddedpH(mg / mL)A45SuT10 mM9% sucrose0.004%4.550sodiumPS20acetateA52SuT10 mM9% sucrose0.004%5.250sodiumPS20acetateA58SuT10 mM9% sucrose0.004%5.850sodiumPS20acetate50_SAST_100NaClNone25 mM L-0.004%6.350arginine, 100 mMPS20NaCl, 1% sucrose100_SAST_100NaClNone25 mM L-0.004%6.3100arginine, 100 mMPS20NaCl, 1% sucrosePASST + BeOH25 mM25 mM L-0.004%6.350phosphatearginine, 100 mMPS20NaCl, 1% sucrose,0.9% benzyl alcoholPASST (control)25 mM25 mM L-0.004%6.350phosphatearginine, 100 mMPS20NaCl, 1% sucrose

[0049]Materials:

[0050]Enbrel drug substance in PASS (25 mM phosphate buffer, 25 mM L-arginine, 100 mM NaCl, 1% sucrose) at 50 ...

Example

Example 2: Pain Study

[0057]This study was a single-center, randomized, single-blind, crossover design in which 48 healthy men and women received single SC injections of 6 solutions.

[0058]Test formulations (detailed below in Table 9) were administered by a trained healthcare professional in 6 unique sequences with 8 subjects randomized to each sequence. Injections were administered in each quadrant of the anterior abdominal wall and administered approximately 1 hour apart. Within 30 seconds after each injection, subjects assessed their level of injection pain using a 100 mm Visual Analog Scale (VAS). Adverse events were collected from the beginning of the first injection through 30 days after the first injection. Safety follow-up phone calls were conducted on day 2 (24 hours after the sixth injection) and day 31 (+2 days).

TABLE 9Tested FormulationsSolutionDescriptionVolumeCompositionA.Negative pain1.010 mM sodium acetate, 9% (w / v)controlsucrose, 0.004% (w / v) polysorbate20, pH 5.2B.Co...

Example

Example 3: Long Term Stability Testing of Formulation Candidates

[0065]A long-term study was performed to monitor etanercept stability in several new formulation candidates at 50 mg / mL. The stability was assessed on 1 mL fills in 1 mL staked glass needle syringes using SE-HPLC, HIC HPLC, dSEC HPLC, and particulate matter (HIAC) after storage at 4° C., 25° C. and 40° C. Osmolality and protein concentration were tested at time zero only, and pH was tested at time zero and after 12 weeks of storage to confirm that there was no pH drift. The results of the study showed that the formulations tested remained similar to the current commercial formulation after 12 weeks at the accelerated temperature of 40° C., as well as 24 weeks at the recommended storage of 2-8° C. and at the accelerated temperature of 25° C.

TABLE 11Formulation conditions at 50 mg / mL etanerceptFormulationOtherNameBufferExcipientspHPASST25 mM25 mM L-arginine, 100 mM NaCl,6.3(control)phosphate1% sucrose, 0.010% polysorbate ...

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Abstract

The invention relates to the formulation of pharmaceutical compositions of etanercept. The invention also relates to methods of removing buffer and of formulating pharmaceutical compositions of etanercept.

Description

CROSS-REFERENCE TO RELATED APPLICATION[0001]This application claims the benefit of U.S. Provisional Application No. 62 / 411,458 filed Oct. 21, 2016, which is incorporated in its entirety by reference herein.FIELD OF THE INVENTION[0002]The invention relates to the formulation of pharmaceutical compositions of etanercept. The invention also relates to methods of removing buffer and of formulating pharmaceutical compositions of etanercept.BACKGROUND OF THE INVENTION[0003]Formulation of a protein drug can present many challenges for the pharmaceutical scientist. A formulation must be found that stabilizes the protein drug and makes it resistant to degradation by proteolysis, aggregation, misfolding, etc. Especially for engineered proteins that differ in substantial respects to known proteins, finding appropriate stability conditions can be challenging. It is also desirable to have the protein drug be in a format that is convenient for the patient. Desired properties include stability at ...

Claims

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Application Information

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IPC IPC(8): A61K39/395A61K47/02A61K47/18A61K47/26A61K9/08A61K38/17
CPCA61K39/39591A61K47/02A61K47/183A61K47/26A61K9/08A61K38/1793A61K9/0019A61P17/06A61P19/00A61P19/02A61P29/00C07K14/7151C07K19/00C07K2319/30C07K2319/32
Inventor GOSS, MONICABALL, NICOLE
Owner AMGEN INC
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