WO2014128079A1

WO2014128079A1 - Glatiramer acetate multidose formulation

Info

Publication number: WO2014128079A1
Application number: PCT/EP2014/053019
Authority: WO
Inventors: Lisa BAKKER-HOLMDAHL; Frans Henri Nicolaas HAAN DE
Original assignee: Synthon BV
Current assignee: Synthon BV
Priority date: 2013-02-19
Filing date: 2014-02-17
Publication date: 2014-08-28
Anticipated expiration: 2015-08-19

Abstract

The present invention relates to a formulation comprising multiple doses of glatiramer acetate and one or more preservatives selected from the group consisting of benzyl alcohol, m-cresol, phenol, methylparaben, and propylparaben. Preferably, the preservative is benzyl alcohol or m-cresol, most preferably benzyl alcohol.

Description

GLATIRAMER ACETATE MULTIDOSE FORMULATION

The present invention relates to a formulation comprising multiple doses of glatiramer acetate and one or more preservatives selected from the group consisting of benzyl alcohol, m-cresol, phenol, methylparaben, and propylparaben.

BACKGROUND OF THE INVENTION

Glatiramer acetate is the Active Pharmaceutical Ingredient (API) in the drug product COPAXONE® (20 mg/ml, subcutaneous (sc) injection), which is authorized by a number of regulatory authorities, e.g. since 2002 by the FDA for marketing and sale in the US, for the treatment of various forms of multiple sclerosis (MS), including relapsing-remitting MS. The product is currently available as a pre-filled syringe for daily administration. Each syringe is discarded after single use. Besides the currently marketed product, a three-times weekly dosing regimen of a 40 mg/ml formulation for subcutaneous injection is in clinical development. Presently, no multidose formulation of glatiramer acetate exists or has been disclosed in publicly available documents.

In view of the fact that currently only a pre-filled syringe is (or will become) available for either daily (or three-times weekly) sc injection, there is a need for a multidose formulation, which offers a number of advantages in terms of logistics, waste of packaging material, and notably convenience to patients.

SUMMARY OF THE INVENTION

The present invention relates to a formulation comprising multiple doses of glatiramer acetate and one or more preservatives selected from the group consisting of benzyl alcohol, m-cresol, phenol, methylparaben, and propylparaben. DETAILED DESCRIPTION OF THE PRESENT INVENTION

Glatiramer acetate is a well-known active pharmaceutical ingredient and the drug substance may either be obtained from a commercial source or it may be prepared in accordance with prior art publications using methods and equipment described therein. See e.g. WO 95/31990.

The formulation of the present invention comprises one or more preservatives selected from the group consisting of benzyl alcohol, m-cresol, phenol, methylparaben, and propylparaben. Preferably, the preservative is benzyl alcohol or m-cresol. Most preferably, benzyl alcohol is used.

The formulation according to the present invention further comprises one or more pharmaceutically acceptable excipients, such as mannitol which is present in the commercial product. In accordance with the present invention, the one or more pharmaceutically acceptable excipients are selected from mannitol, sorbitol, trehalose, histidine, and polyoxyethylene sorbitan fatty acid esters (e.g. polysorbates), preferably selected from mannitol and a polysorbate. These excipients act as tonicity agents and/or stabilizers.

Typically, the formulation according to the present invention comprises from 0.005 wt to 3 wt of the preservative. Preferably, the formulation comprises from 0.01 wt to 2 wt of a preservative, more preferably from 0.1 wt to 2 wt , most preferably from 0.1 wt% to 0.5 wt%.

The formulation according to the present invention typically comprises from 40 mg to 560 mg of glatiramer acetate. Preferably, the formulation comprises from 120 mg to 560 mg, more preferably from 120 mg to 240 mg of glatiramer acetate.

The present invention also relates to a multiple dose device (or multiple dose medication dispensing device) comprising a formulation according to any one of the embodiments described hereinabove. Examples of suitable devices are well-known to the person skilled in this art.

Typically, the device according to the present invention is in the form of a multiple dose injection pen.

EXAMPLES

Example 1

Five different formulations (see Table 1 below), having twice the glatiramer acetate strength of COPAXONE® (20 mg/ml) and an equal amount of mannitol (40 mg/ml) as in COPAXONE®, were made by dissolving the indicated amount(s) of excipient(s) in 1 ml of water followed by adding glatiramer acetate. After homogenizing, the solutions were filtered over a 0.2 micron filter before they were filled into 10 ml transparent glass vials (i.e.

headspace GC vials) equipped with a rubber stopper, and then were put on stability testing over time.

Table 1. Formulations containing 40 mg/ml of glatiramer acetate (GA)

No. Formulation

1 40 mg GA, 40 mg mannitol, 2.5 mg benzyl alcohol (0.5%),

0.3 mg polysorbate 20

2 40 mg GA, 40 mg mannitol, 2.5 mg benzyl alcohol (0.5%)

3 40 mg GA, 40 mg mannitol, 2.5 mg m-cresol (0.25%)

4 40 mg GA, 40 mg mannitol, 2.5 mg phenol (0.5%)

5 40 mg GA, 40 mg mannitol, 2 mg methylparaben (0.2%),

0.2 mg propylparaben (0.02%) The samples were analyzed for essential quality attributes at t=0, 1, 3, and 6 months of storage under different conditions, i.e. 4°C, 25°C/60 RH, and 40°C/75 RH.

For testing of the structure and functionality of glatiramer acetate, different bioanalytical methods were used, including Circular Dichroism (CD) spectroscopy, Coomassie Brilliant Blue staining, Fluorescence spectroscopy, and Enzyme-Linked Immuno-Sorbant Assay

(ELISA). All five formulations tested with the aforementioned methods gave similar results, which were additionally similar as obtained for reference products without preservatives at t=0.

For testing the amount of particles originating in solution, which is an undesired property, Micro flow Imaging (MFI) was used. The results after 3 months at 4°C,

25°C/60 RH, and 40°C/75 RH showed that the increase in the amount of particles was the largest with parabens, and the lowest with benzyl alcohol as the preservative.

For other essential quality parameters, i.e. colour of solution, clarity of solution, molecular weight of glatiramer acetate, pH, and content of glatiramer acetate, no differences were seen for the different formulations after storage at 4°C, 25°C/60 RH, and

40°C/75 RH. However, levels of impurities arising during storage were higher when phenol and parabens were used as the preservative.

In conclusion, the best results were obtained when benzyl alcohol was included as the preservative. Acceptable results were obtained when m-cresol was incorporated.

Claims

1. A formulation comprising multiple doses of glatiramer acetate and one or more

preservatives selected from the group consisting of benzyl alcohol, m-cresol, phenol, methylparaben, and propylparaben.

2. A formulation according to claim 1, wherein the preservative is benzyl alcohol or m- cresol.

3. A formulation according to claim 1 or 2, wherein the preservative is benzyl alcohol.

4. A formulation according to any one of claims 1-3, further comprising one or more

pharmaceutically acceptable excipients.

5. A formulation according to any one of claims 1-4, wherein the one or more

pharmaceutically acceptable excipients are selected from mannitol and a polysorbate.

6. A formulation according to any one of claims 1-5, comprising from 0.005 wt to 3 wt of the preservative.

7. A formulation according to any one of claims 1-6, comprising from 40 mg to 560 mg of glatiramer acetate.

8. A multiple dose device comprising a formulation according to any one of claims 1-7.

9. A device according to claim 8 in the form of a multiple dose injection pen.