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WO2023281367A1 - Formulations liquides stables d'aflibercept - Google Patents

Formulations liquides stables d'aflibercept Download PDF

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Publication number
WO2023281367A1
WO2023281367A1 PCT/IB2022/056138 IB2022056138W WO2023281367A1 WO 2023281367 A1 WO2023281367 A1 WO 2023281367A1 IB 2022056138 W IB2022056138 W IB 2022056138W WO 2023281367 A1 WO2023281367 A1 WO 2023281367A1
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WO
WIPO (PCT)
Prior art keywords
formulation
aflibercept
buffer
present
bile acid
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Ceased
Application number
PCT/IB2022/056138
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English (en)
Inventor
Vaibhav D. DEOKAR
Sanjay G. TIWARI
Prashant D. GIRI
Kiran R. KUMBHARE
Anup A. PURANPOLE
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Lupin Ltd
Original Assignee
Lupin Ltd
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Filing date
Publication date
Application filed by Lupin Ltd filed Critical Lupin Ltd
Publication of WO2023281367A1 publication Critical patent/WO2023281367A1/fr
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

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Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0019—Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • A61K38/17—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
    • A61K38/177—Receptors; Cell surface antigens; Cell surface determinants
    • A61K38/179—Receptors; Cell surface antigens; Cell surface determinants for growth factors; for growth regulators
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/02—Inorganic compounds

Definitions

  • the present invention relates to pharmaceutical formulations suitable for intravitreal administration comprising a vascular endothelial growth factor (VEGF) specific fusion protein antagonist and method for making and using such formulations for the treatment of methods of manufacture of the formulations, method of their administration, and kits containing the same. More specifically, the invention relates to stable aqueous pharmaceutical formulation for intravitreal administration comprising a therapeutically effective amount of aflibercept, buffer, bile acid salt, anti-aggregating agent, optionally tonicity modifier and one or more pharmaceutically acceptable excipients suitable for ophthalmic administration.
  • VEGF vascular endothelial growth factor
  • VEGF vascular endothelial growth factor
  • a recombinant fusion protein consisting of portions of human VEGF receptors 1 and 2 extracellular domains fused to the Fc portion of human IgGl.
  • Eylea® (aflibercept) is approved in the form of intravitreal injection and it is indicated for the treatment of Neovascular (Wet) Age-Related Macular Degeneration (AMD), Macular Edema Following Retinal Vein Occlusion (RVO), Diabetic Macular Edema (DME) and Diabetic Retinopathy (DR).
  • Neovascular Wet
  • AMD Age-Related Macular Degeneration
  • RVO Macular Edema Following Retinal Vein Occlusion
  • DME Diabetic Macular Edema
  • DR Diabetic Retinopathy
  • Aflibercept acts as a soluble decoy receptor that binds VEGF-A and placental growth factor (P1GF) with higher affinity than their natural receptors, and thereby can inhibit the binding and activation of these cognate VEGF receptors.
  • Aflibercept’ s high affinity for VEGF prevents the subsequent binding and activation of native VEGF receptors. Reduced VEGF activity leads to decreased angiogenesis and vascular permeability.
  • U.S. Patent No. 8,092,803 and US 10,464,992 discloses liquid ophthalmic formulation of aflibercept, sodium phosphate buffer, polysorbate, sucrose, sodium chloride with pH about 6.2-6.3.
  • U.S. Patent Application No. 20190030123 discloses liquid pharmaceutical composition comprising a) a histidine containing buffer, b) a non-ionic surfactant, c) a VEGF antagonist, d) an inorganic salt, and e) a carbohydrate.
  • U.S. Patent Application No. 20190160145 discloses ophthalmic pharmaceutical composition
  • ophthalmic pharmaceutical composition comprising a) aflibercept; b) an acetate salt buffering agent; c) a sugar or a sugar alcohol; and d) a surfactant in an aqueous medium, wherein the ophthalmic pharmaceutical composition is free of an ionic tonicity agent.
  • U.S. Patent Application No. 20190276528 discloses aqueous formulation comprising: a) aflibercept; b) a stabilizer; and c) an organic co-solvent, wherein the formulation is free of buffer.
  • Aflibercept ophthalmic formulations were disclosed in the art. There is still exists a need to develop an alternative, stable, ready to use pharmaceutical formulation of aflibercept.
  • the inventors of the present invention have surprisingly found that a stable pharmaceutical formulation of aflibercept suitable for intravitreal administration can be developed using bile acid salt and anti-aggregating agent.
  • the invention is directed to a stable aqueous pharmaceutical formulation comprising a therapeutically effective amount of aflibercept, buffer, bile acid salt, anti-aggregating agent and optionally, tonicity modifier.
  • the object of present invention is to reduce aggregates or impurities or flocculation formation during formulation and storage.
  • the inventors of the present invention found that the addition of bile acid salt and anti-aggregating agent in formulation makes the stable formulation by inhibiting aggregation and formation of degradant species.
  • the invention provides a stable aqueous pharmaceutical formulation suitable for intravitreal administration comprising a therapeutically effective amount of aflibercept, buffer, bile acid salt, anti- aggregating agent and optionally, tonicity modifier wherein the pharmaceutical formulation has a pH from about 5.0 to 7.0.
  • a stable aqueous pharmaceutical formulation suitable for intravitreal administration comprising:
  • a stable aqueous pharmaceutical formulation suitable for intravitreal administration comprising:
  • a stable aqueous pharmaceutical formulation suitable for intravitreal administration comprising:
  • sucrose and optionally sodium chloride sucrose and optionally sodium chloride.
  • the pH of the formulation may be between 5.5 to 7.5, preferably between 6.0 to 7.0. Also, preferably, the pH is 6.2 or 6.8.
  • aflibercept formulation comprising combination of bile acid salt with anti-aggregating agent shows comparable stability over the formulation containing polysorbate.
  • Eylea ® aflibercept
  • contains inactive ingredient such as sodium phosphate, sodium chloride, polysorbate 20, and sucrose, with a pH of 6.2.
  • the formulation comprising combination of bile acid salt with anti aggregating agent reduces the low and high molecular weight impurities.
  • the invention further features ophthalmic formulations provided in a pre-filled syringe or vial or any device, particularly suitable for intravitreal administration.
  • VEGF antagonist refers to a molecule, which specifically interacts with VEGF and inhibits one or more of its biological activities, e.g. its mitogenic, angiogenic and/or vascular permeability activity. It is intended to include both anti- VEGF antibodies and antigen-binding fragments thereof and non-antibody VEGF antagonists.
  • Aflibercept is a recombinant fusion protein consisting of Vascular Endothelial Growth Factor (VEGF) -binding portions from the extracellular domains of human VEGF Receptors 1 and 2 fused to the Fc portion of the human IgGl.
  • VEGF Vascular Endothelial Growth Factor
  • Aflibercept is a dimeric glycoprotein with a protein molecular weight of 97 kilodaltons (kDa) and contains glycosylation, constituting an additional 15% of the total molecular mass, resulting in a total molecular weight of 115 kDa.
  • Amino acid and nucleic acid sequences of aflibercept are known in the art.
  • compositions refers to a mixture of a protein, such as a fusion protein, e.g., aflibercept, together with one or more additional components.
  • the additional components may include, e.g., one or more excipients, such as a buffer, anti aggregating agent, tonicity modifier, bile acid salts, water and the like, e.g., a pharmaceutically acceptable carrier or excipient that is conventional in the art and which is suitable for administration to a subject for therapeutic, diagnostic, or prophylactic purposes.
  • the additional component is suitable for ophthalmic administration.
  • pharmaceutical compositions/formulations according to the present invention may be aqueous formulation suitable for intravitreal administration.
  • buffer refers to a buffered solution that resists changes in pH by the action of its acid-base conjugate components.
  • a buffer consists of a weak acid and a conjugate salt or a weak base and a conjugate salt (e.g. sodium phosphate mono-basic and di-basic, Histidine-Histidine HC1).
  • Buffers suitable for use in connection with this invention may have a pH in the range from about 4.0 to about 9.0; from about pH 4.0 to about 7.0; or from about pH 4.5 to about 6.5. A pH of any point in between the above ranges is also contemplated.
  • stable is understand to mean that aflibercept contained in the formulation or pharmaceutical compositions does not lose more than 20%, or more preferably 15%, or even more preferably 10%, and most preferably 5% of its activity relative to activity of the formulation or composition at the beginning of storage.
  • stable mean that the aflibercept formulations or compositions are at least comparable to, or better than commercially available aflibercept formulation, in terms of their stability and/or ability to resist formation of particulates during storage.
  • the term means that the aflibercept formulations or compositions are stable when agitated, mixed, or handled.
  • vitreous humor also called vitreous body or simply vitreous
  • clear gel fills the space between the lens and the retina of the eyeball of humans and other vertebrates.
  • excipient used here in refers to additional component may include, e.g., one or more excipients, such as water, buffer, bile acid salt, anti-aggregating agent, tonicity modifier etc. and the like, e.g., a pharmaceutically acceptable carrier or excipient that is conventional in the art and which is suitable for administration to a subject for therapeutic, diagnostic, or prophylactic purposes.
  • the additional component is suitable for ophthalmic administration.
  • pharmaceutical formulations according to the present invention may be aqueous formulation suitable for intravitreal administration.
  • high molecular weight species refers to higher order oligomeric species like dimers, trimers, tetramers, etc., formed by addition of monomers that can be either covalently or non-covalently linked, which consist of misfolded monomers in which surfaces of the monomer are exposed that typically would not be in the folded monomeric form.
  • low molecular weight species refers to clipped species of intact antibodies composed of heavy and light chains.
  • the aflibercept used as an active ingredient in the pharmaceutical formulation of the present invention may be included in a therapeutically effective amount.
  • aflibercept may be present in a concentration ranging from 10 to 100 mg/ml, preferably in a concentration ranging from 20 to 50 mg/ml, more preferably in a concentration of about 40 mg/ml, but not limited thereto.
  • the buffer is selected from the group consisting of acetate, histidine, phosphate, citrate, succinate, tartrate, maleate and combination thereof.
  • the buffer is a phosphate buffer, for example, sodium phosphate.
  • the buffer is present at a concentration in the range of about 1 mM to 150 mM. In a preferred embodiment, the buffer is in a concentration in the range of 1 mM to 40 mM, preferably of 2 mM to 35 mM, more preferably of 3 mM to 30 mM, even more preferably of 5 mM to 20 mM and more preferably of 8 mM to 15 mM. Most preferably, the buffer is present at a concentration of about 10 mM. In one embodiment, sodium phosphate buffer is present at a concentration in the range of about 5-40 mM of. In a particular preferred embodiment, the buffer is in a concentration of 10 mM.
  • Bile acid salts are naturally occurring cholesterol derivatives with a steroidal skeleton and specific self-assembly and interface behaviors.
  • Cholic acid is a primary bile acid and salts of cholic acid are called cholates.
  • Deoxycholic acid is one of the secondary bile acids.
  • bile acid salt is selected from the group consisting of sodium deoxycholate and sodium cholate. In another embodiment, bile acid salt is sodium deoxycholate.
  • the bile acid salt is present in a concentration ranging from 0.01 to 0.001% w/v. In a particular preferred embodiment, the bile acid salt is present in a concentration ranging from 0.01 to 0.05 w/v %, preferably from 0.01 to 0.03 w/v%.
  • the anti-aggregating agent is selected from the group consisting of amino acids, sugars, polyols, polymers, and combinations.
  • the anti-aggregating agent is a sugar. In another embodiment, the anti-aggregating agent is sucrose, sorbitol, trehalose, glycerol, or mannitol. In another preferred embodiment, the anti-aggregating agent is sucrose.
  • the sugar may be present in a concentration ranging from 5% w/v to 12% w/v, preferably from 6% w/v to 10% w/v, more preferably about >8% w/v, most preferably about 9% w/v.
  • a tonicity modifier is an ingredient that contributes to the osmolality of a solution.
  • tonicity modifier is selected from the group consisting of sugars, amino acids or inorganic salt, which have osmoregulatory properties.
  • Preferred inorganic salts for use in the pharmaceutical formulation of the present invention are potassium chloride, calcium chloride, sodium chloride, sodium phosphate, potassium phosphate and sodium bicarbonate.
  • the inorganic salt is a sodium salt; more preferably, it is sodium chloride (NaCl).
  • the concentration of the inorganic salt or sodium chloride in the pharmaceutical formulation used in the present invention is preferably in the range of 0 to 150 mM, more preferably in the range of 0 to 80 mM, even more preferably the inorganic salt has a concentration in the range of 0 to 60 mM or 0 to 45 mM, and most preferably the concentration is 0 mM to 40 mM.
  • the inorganic salt is sodium chloride with a concentration of 0 to 40 mM.
  • compositions containing proteins has multiple stability challenges in view of the unique chemical and physical properties of protein.
  • Physical instability involves aggregates/ impurities/ flocculation.
  • Inventors of this present invention found that by using bile acid salt with buffer, anti-aggregating agent and optionally, tonicity modifier in aflibercept formulation prevents aggregates/ impurities/ flocculation resulting in stable formulation.
  • Most common protein based impurities includes aggregates such as high molecular weight (HMW) and low molecular weight (LMW) species, charged variants such as acidic variants and basic variants, and host-cell proteins.
  • HMW high molecular weight
  • LMW low molecular weight
  • charged variants such as acidic variants and basic variants
  • host-cell proteins host-cell proteins.
  • High molecular weight and low molecular weight species have the potential to affect the safety and efficacy of biopharmaceuticals.
  • the levels of these protein impurities in biologic drug substances and drug products must be controlled and are typically considered as critical quality attributes.
  • the properties of the different contaminants vary significantly.
  • a stable aqueous formulation is a formulation having less than about 10%, or less than about 5% of the protein being present as aggregate in the formulation.
  • VEGF antagonist aqueous formulation comprising a bile acid salt such as sodium cholate, sodium deoxycholate or combination thereof; surprisingly shows lower protein based impurities such as high molecular weight (HMW) and low molecular weight (LMW) species formation over longer duration.
  • HMW high molecular weight
  • LMW low molecular weight
  • aqueous aflibercept formulation comprising sodium deoxycholate in concentration 0.01% w/v to 0.05% w/v, shows lower percentage of HMW and LMW formation than control formulation.
  • the control formulation is Eylea® (aflibercept) by Regeneron Pharmaceuticals, Inc.
  • a protein in an aqueous formulation can be stable at frozen storage temperatures (- 20°C or -80°C), liquid storage temperatures such as refrigeration (e.g. 2-8°C) and room temperature (about 25 °C), and under accelerated liquid stability testing temperatures (e.g. 40 °C.).
  • SEC Size exclusion chromatography
  • osmolality of a pharmaceutical formulation is adjusted to minimize discomfort to the patient upon administration. Additionally, osmolality of a formulation may affect the active ingredient's stability and can be adjusted to improve the stability. It is generally preferred that a pharmaceutical formulation for intravitreal administration to a patient be isotonic with vitreous, i.e., have the same or similar osmolality, which is achieved by addition of a tonicity modifier. However, hypertonic formulations which would then be diluted in an isotonic vehicle are also within the scope of this invention.
  • the osmolality of the present formulations is from about 180 to about lOOOmOsM. In another embodiment, the osmolality of the present formulations is from about 300 mOsM.
  • the present invention preferably has a pH in the range from about 6.0 to about 7.0, preferably from about 6.1 to about 6.8, more preferably from about 6.0 to 6.5, even more preferably from about 6.2 to 6.5 and most preferably has a pH of about 6.2 or 6.8.
  • the stable pharmaceutical formulation of the present invention is a liquid or aqueous formulation.
  • the liquid ophthalmic formulation of the present invention may be administered by various routes to the eye; such as topical, local ocular (subconjunctival, intravitreal, retrobulbar, intracameral), and systemic, depending on purposes.
  • the present ophthalmic formulation is preferably administered through intravitreal injection for the treatment of ophthalmic diseases.
  • the invention further features ophthalmic formulations provided in a pre-filled syringe or vial, particularly suitable for intravitreal administration.
  • the suitable amount of administration of the liquid formulation of the present invention may vary depending on factors such as formulation methods, administration modes, age, weight, sex, and disease state of patients, foods, administration time, administration routes, excretion rates, and reaction sensitivity. Physicians with ordinary skills may easily determine and prescribe the amount of administration effective for desired therapy or prevention.
  • the liquid protein formulation is prepared by buffer exchange techniques like dialysis or diafiltration, wherein the excipient such as bile acid salt; can be added during the buffer exchange process to avoid any aggregation due to shear involved in processing.
  • the bulk processed aflibercept material was formulated using procedures mentioned below.
  • the aflibercept material was buffered exchanged following the dialysis procedure using tangential flow filtration. After dialysis the osmotic pressure and the pH was checked, if the pH of the sample was not within range pH units, the formulation buffer was made more acidic or basic, by repeat dialysis or by addition of HC1 or NaOH, until the pH target was reached. Following pH adjustment if needed, the sample was concentrated above the target formulation concentration. The pH, osmotic pressure and the protein concentration was then measured once more. The sample was then diluted with the formulation buffer to reach the target formulation protein concentration within 10%. The protein concentration was then measured once more to ensure the diluted sample was within 10% of the target concentration. The last step was the addition of the bile acid salt (diluted in water) to the sample based on weight, if required.
  • the stable liquid ophthalmic formulation for intravitreal administration comprises about 40-100 mg/ml aflibercept, about 5-40 mM sodium phosphate or Histidine - Histidine HC1 buffer pH of about 5.8 to about 7.0, 0.001% w/v to 0.1% w/v Sodium deoxycholate, about 5% w/v - 12% w/v sucrose, and optionally about 40-150 mM sodium chloride, pH of formulation about 6.0-7.0.
  • Example 5 An ophthalmic liquid formulation containing 40 mg/ml Aflibercept, 10 mM, Histidine buffer system 0.001% to 0.1% Sodium deoxycholate, 8-10% sucrose, and pH 6.2 ⁇ 0.3 pH, was stored at 5 °C in 3 ml container and samples tested as per ICH guideline. Stability was determined by SE-HPLC.
  • Example 6 An ophthalmic liquid formulation containing 40 mg/ml Aflibercept, 10 mM, Histidine buffer system 0.001% to 0.1% Sodium deoxycholate, 8-10% sucrose, and pH 6.2 ⁇ 0.3 pH, was stored at 5 °C in 3 ml container and samples tested as per ICH guideline. Stability was determined by SE-HPLC.
  • Example 6 An ophthalmic liquid formulation containing 40 mg/ml Aflibercept, 10 mM, Histidine buffer system 0.001% to 0.1% Sodium deoxycholate, 8-10% sucrose, and pH 6.2 ⁇ 0.3 pH, was stored at 5

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Abstract

L'invention concerne une formulation pharmaceutique aqueuse stable appropriée pour une administration intravitréenne comprenant un antagoniste de protéine de fusion spécifique du facteur de croissance vasculaire endothéliale (VEGF). Plus particulièrement, l'invention concerne une composition aqueuse stable comprenant une quantité thérapeutiquement efficace d'aflibercept, de tampon, de sel d'acide biliaire et d'agent anti-agrégation et éventuellement de modificateur de tonicité, le pH de ladite formulation étant compris entre environ pH 6,0 et pH 7,0. L'invention concerne également un procédé pour la fabrication de ladite formulation et son utilisation.
PCT/IB2022/056138 2021-07-03 2022-07-01 Formulations liquides stables d'aflibercept Ceased WO2023281367A1 (fr)

Applications Claiming Priority (2)

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IN202121029915 2021-07-03
IN202121029915 2021-07-03

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WO2023281367A1 true WO2023281367A1 (fr) 2023-01-12

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Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20200246423A1 (en) * 2018-03-08 2020-08-06 Coherus Biosciences Inc. Stable aqueous formulations of aflibercept
WO2021033898A1 (fr) * 2019-08-20 2021-02-25 아영창 Composition aqueuse contenant du désoxycholate de sodium, stable contre la précipitation

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20200246423A1 (en) * 2018-03-08 2020-08-06 Coherus Biosciences Inc. Stable aqueous formulations of aflibercept
WO2021033898A1 (fr) * 2019-08-20 2021-02-25 아영창 Composition aqueuse contenant du désoxycholate de sodium, stable contre la précipitation

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