# US 11,298,405 B2 · Pre-filled pharmaceutical package comprising a liquid formulation of a VEGF-antagonist

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- Number: US 11,298,405 B2
- Document ID: US11298405B2
- Status: Granted
- Kind: B2
- Application number: 17/154,702
- Filed: 2021-01-21
- Published: 2021-07-22
- Granted: 2022-04-12
- Earliest claimed: 2015-11-18
- Assignees: Formycon AG; Sio2 Medical Products, Inc.; Klinge Biopharma GmbH
- Applicants: Formycon AG; Sio2 Medical Products, Inc.; Klinge Biopharma GmbH
- Inventors: Carsten Brockmeyer; Christopher Weikart; Murray Stephen Bennett; Jean-Pierre Giraud; Thomas Strungmann
- Web page: https://patentgrep.com/patent/US11298405B2

## CPC

- A61K 38/179: {for growth factors; for growth regulators}
- A61K 9/0019: {Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner (non-active ingredients are additionally classified in A61K47/00)}
- A61K 9/0048: {Eye, e.g. artificial tears}
- A61K 39/39591: {Stabilisation, fragmentation}
- A61M 5/3129: {Syringe barrels (A61M5/3205, A61M5/50 take precedence)}
- A61P 27/02: Ophthalmic agents
- C07K 16/22: against growth factors {; against growth regulators}
- A61K 9/08: Solutions {(composition of solutions A61K47/00)}
- A61K 45/06: Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
- A61K 2300/00: Mixtures or combinations of active ingredients, wherein at least one active ingredient is fully defined in groups A61K31/00 - A61K41/00
- A61M 2005/3131: {specially adapted for improving sealing or sliding}
- C07K 2317/24: containing regions, domains or residues from different species, e.g. chimeric, humanized or veneered
- C07K 2317/55: Fab or Fab'
- C07K 2317/76: Antagonist effect on antigen, e.g. neutralization or inhibition of binding
- C07K 2319/30: Non-immunoglobulin-derived peptide or protein having an immunoglobulin constant or Fc region, or a fragment thereof, attached thereto
- A61K: PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES (devices or methods specially adapted for bringing pharmaceutical products into particular physical or administering forms A61J3/00; chemical aspects of, or use of materials for deodorisation of air, for disinfection or sterilisation, or for bandages, dressings, absorbent pads or surgical articles A61L; soap compositions C11D)
- A61M: DEVICES FOR INTRODUCING MEDIA INTO, OR ONTO, THE BODY (introducing media into or onto the bodies of animals A61D7/00; means for inserting tampons A61F13/26; devices for administering food or medicines orally A61J; containers for collecting, storing or administering blood or medical fluids A61J1/05); DEVICES FOR TRANSDUCING BODY MEDIA OR FOR TAKING MEDIA FROM THE BODY (surgery A61B; chemical aspects of surgical articles A61L); DEVICES FOR PRODUCING OR ENDING SLEEP OR STUPOR {(Electrotherapy, e.g. producing anaesthesia by the use of alternating or intermittent currents A61N1/36021)}
- A61P: SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- C07K: PEPTIDES (peptides in foodstuffs A23; obtaining protein compositions for foodstuffs, working-up proteins for foodstuffs A23J; preparations for medicinal purposes A61K; peptides containing beta-lactam rings C07D; cyclic dipeptides not having in their molecule any other peptide link than those which form their ring, e.g. piperazine-2,5-diones, C07D; ergot alkaloids of the cyclic peptide type C07D519/02; macromolecular compounds having statistically distributed amino acid units in their molecules, i.e. when the preparation does not provide for a specific; but for a random sequence of the amino acid units, homopolyamides and block copolyamides derived from amino acids C08G69/00; macromolecular products derived from proteins C08H1/00; preparation of glue or gelatine C09H; single cell proteins, enzymes C12N; genetic engineering processes for obtaining peptides C12N15/00; compositions for measuring or testing processes involving enzymes C12Q; investigation or analysis of biological material G01N33/00)

## Abstract

A pre-filled pharmaceutical package comprising a liquid formulation of a VEGF-antagonist, for example Ranibizumab, in a pre-filled pharmaceutical package, for example a syringe, cartridge, or vial, made in part or in whole of a thermoplastic polymer, coated on the interior with a tie coating or layer, a barrier coating or layer, a pH protective coating or layer, and optionally a lubricity coating or layer. Stability performance of the VEGF-antagonist packaged in the coated COP vessel comparable to or better than glass was obtained.

## Claims

### Claim 1

A pre-filled pharmaceutical package comprising a liquid formulation of a VEGF-antagonist, wherein the pre-filled pharmaceutical package comprises:
a wall comprising a cyclic olefin polymer, having an interior surface enclosing at least a portion of a lumen;
a tie coating or layer on the wall interior surface comprising SiOxCyHz, in which x is from about 0.5 to about 2.4 as measured by X-ray photoelectron spectroscopy (XPS), y is from about 0.6 to about 3 as measured by XPS, and z is from about 2 to about 9 as measured by at least one of Rutherford backscattering spectrometry (RBS) or hydrogen forward scattering (HFS);
a barrier coating or layer of SiOx, in which x is from about 1.5 to about 2.9 as measured by XPS, the barrier coating or layer positioned between the tie coating or layer and the lumen;
a pH protective coating or layer of SiOxCyHz, in which x is from about 0.5 to about 2.4 as measured by XPS, y is from about 0.6 to about 3 as measured by XPS, and z is from about 2 to about 9 as measured by at least one of RBS or HFS, positioned between the barrier coating or layer and the lumen;
a lubricity coating or layer positioned between the pH protective coating or layer and the lumen, wherein the lubricity coating or layer has the atomic proportions SiOxCyHz, in which x is from about 0.5 to about 2.4 as measured by XPS, y is from about 0.6 to about 3 as measured by XPS, and z is from about 2 to about 9 as measured by at least one of RBS or HFS;
a liquid formulation of a VEGF-antagonist in the lumen; and
a closure closing the lumen;
wherein the VEGF antagonist is Ranibizumab.

### Claim 2 (depends on 1)

The prefilled pharmaceutical package according to claim 1, in which the liquid formulation of Ranibizumab in the lumen comprises Ranibizumab at a concentration of 6 or 10 mg/ml.

### Claim 3 (depends on 1)

The pre-filled pharmaceutical package according to claim 1, having a nominal maximum fill volume of 0.5 or 1 mL.

### Claim 4 (depends on 1)

The pre-filled pharmaceutical package according to claim 1, in which the liquid formulation of Ranibizumab contains no more than 50 particles ≥10 μm diameter per mL, no more than 5 particles ≥25 μm diameter per mL, and/or no more than 2 particles ≥50 μm diameter per mL, during shelf life, measured by microscopic inspection.

### Claim 5 (depends on 1)

The pre-filled pharmaceutical package according to claim 1, which is free of baked-on silicone.

### Claim 6 (depends on 1)

The pre-filled pharmaceutical package according to claim 1, which is terminally sterilized.

### Claim 7 (depends on 1)

The pre-filled pharmaceutical package according to claim 1, in which the liquid formulation of Ranibizumab in the lumen forms an equal or smaller area % of basic decomposition species, after storage of the pharmaceutical package at 5° C. for three months, than a glass pharmaceutical package of the same volumetric capacity, internally coated with baked-on silicone.

### Claim 8 (depends on 1)

The pre-filled pharmaceutical package according to claim 1, in which the liquid formulation of Ranibizumab in the lumen forms an equal or smaller area % of acidic decomposition species, after storage of the pharmaceutical package at 5° C. for three months, than a glass pharmaceutical package of the same volumetric capacity, internally coated with baked-on silicone.

### Claim 9 (depends on 1)

The pre-filled pharmaceutical package according to claim 1, in which the Ranibizumab retains its biological activity when stored at a temperature of 2 to 8° C. for at least six months.

### Claim 10 (depends on 1)

The pre-filled pharmaceutical package according to claim 1, being a syringe.

### Claim 11 (depends on 10)

The pre-filled pharmaceutical package according to claim 10, comprising a plunger which comprises a side surface slidable along the wall, wherein at least a portion of the side surface comprises a fluoropolymer lubricity coating or layer abutting the wall.

### Claim 12 (depends on 10)

The pre-filled pharmaceutical package according to claim 10, having a breakout force less than or equal to 15N for initiating travel of the stopper in the lumen.

### Claim 13 (depends on 10)

The pre-filled pharmaceutical package according to claim 10, having a plunger sliding force less than or equal to 15N for advancing the stopper in the lumen.

### Claim 14 (depends on 1)

The pre-filled pharmaceutical package of claim 1 for use in administering a liquid formulation of a VEGF-antagonist to a patient having an ocular disease.

### Claim 15 (depends on 14)

The pre-filled pharmaceutical package for the use according to claim 14, wherein the ocular disease is selected from the group consisting of age-related macular degeneration (AMD), visual impairment due to diabetic macular edema (DME), visual impairment due to macular edema secondary to retinal vein occlusion (branch RVO or central RVO), or visual impairment due to choroidal neovascularization (CNV) secondary to pathologic myopia.

### Claim 16 (depends on 14)

The pre-filled pharmaceutical package for the use according to claim 14, wherein the VEGF antagonist is Ranibizumab which is administered in a volume of 0.05 mL.

### Claim 17 (depends on 1)

A liquid formulation of a VEGF-antagonist in a pre-filled pharmaceutical package according to claim 1, in which the liquid formulation of Ranibizumab has been adjusted to pH 5.5 with HCl.

### Claim 18 (depends on 1)

A liquid formulation of a VEGF-antagonist in a pre-filled pharmaceutical package according to claim 1, in which the liquid formulation of Ranibizumab in the lumen comprises, per mL of formulation:
6 or 10 mg. Ranibizumab;
100 mg. α,α-trehalose dihydrate;
0.32 mg. L-histidine
1.66 mg. L-histidine hydrochloride monohydrate;
0.1 mg Polysorbate 20; and
water for injection qs to 1 mL.

### Claim 19 (depends on 1)

Kit comprising one or more pre-filled pharmaceutical packages according to claim 1.