WO2017182584A1 - Nouvelles formulations de dérivés d'acide rétinoïque et leur utilisation pour le traitement du cancer - Google Patents

Nouvelles formulations de dérivés d'acide rétinoïque et leur utilisation pour le traitement du cancer Download PDF

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Publication number
WO2017182584A1
WO2017182584A1 PCT/EP2017/059424 EP2017059424W WO2017182584A1 WO 2017182584 A1 WO2017182584 A1 WO 2017182584A1 EP 2017059424 W EP2017059424 W EP 2017059424W WO 2017182584 A1 WO2017182584 A1 WO 2017182584A1
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Prior art keywords
nanoparticles
anyone
albumin
active ingredient
mixture
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PCT/EP2017/059424
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English (en)
Inventor
Helena BOUTZEN
Sophie Cazalbou
Hany IBRAHIM
Christian RECHER
Jean-Emmanuel SARRY
Original Assignee
Institut National De La Sante Et De La Recherche Medicale (Inserm)
Centre Hospitalier Universitaire De Toulouse
Universite Paul Sabatier Toulouse Iii
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Publication of WO2017182584A1 publication Critical patent/WO2017182584A1/fr

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    • 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
    • A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
    • A61K9/19—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles lyophilised, i.e. freeze-dried, solutions or dispersions
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
    • A61K31/19—Carboxylic acids, e.g. valproic acid
    • A61K31/20—Carboxylic acids, e.g. valproic acid having a carboxyl group bound to a chain of seven or more carbon atoms, e.g. stearic, palmitic, arachidic acids
    • A61K31/203—Retinoic acids ; Salts thereof
    • 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
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
    • A61K9/141—Intimate drug-carrier mixtures characterised by the carrier, e.g. ordered mixtures, adsorbates, solid solutions, eutectica, co-dried, co-solubilised, co-kneaded, co-milled, co-ground products, co-precipitates, co-evaporates, co-extrudates, co-melts; Drug nanoparticles with adsorbed surface modifiers
    • A61K9/146—Intimate drug-carrier mixtures characterised by the carrier, e.g. ordered mixtures, adsorbates, solid solutions, eutectica, co-dried, co-solubilised, co-kneaded, co-milled, co-ground products, co-precipitates, co-evaporates, co-extrudates, co-melts; Drug nanoparticles with adsorbed surface modifiers with organic macromolecular compounds
    • 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
    • A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
    • A61K9/16—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
    • A61K9/1605—Excipients; Inactive ingredients
    • A61K9/1629—Organic macromolecular compounds
    • A61K9/1658—Proteins, e.g. albumin, gelatin

Definitions

  • the invention relates to nanoparticles of all-trans retinoic acid (ATRA) or derivatives thereof, and protein, their preparation, the pharmaceutical compositions comprising them and their use for treating and/or preventing cancer and leukemia in particular.
  • ATRA all-trans retinoic acid
  • AML Acute myeloid leukemia
  • IDH isocitrate dehydrogenase
  • NPM1 NPM1 mutations found in 15% or 30% of AML patients, respectively.
  • AML therapy most patients relapse and die from the disease due to residual chemoresistant blasts. Thus, targeting this population is a mandatory requirement for effective AML therapy.
  • rexinoids/retinoids is mandatory in the treatment of acute promyelocytic leukaemia (APL, APML, PML-RARa, M3) and represents a promising therapeutic avenue for some other AML patient categories (such as IDH mutant and NPM1 mutant) in combination with chemotherapeutics.
  • ATRA All-trans retinoic acid
  • ATRA is a hydrophobic molecule with a very low aqueous solubility (4.53 ⁇ g/mL in water at 37 °C). This requires to improve the bioavailability and to avoid the use of extremely high doses responsible of side effects.
  • ATRA rapidly degrades when exposed to light, oxygen or heat. Its poor stability complicates handling and even limits its possible use in the clinic. Due to its hydrophobicity (0.2 ⁇ , pH 7.3), and short half-life in blood, ATRA parenteral administration is very difficult and to date no commercial parenteral formulation has been available. On the other hand, the oral formulations in clinical use suffer from uncertain drug bioavailability due to the variable gastro-intestinal tract absorption along with high first pass effect.
  • ATRA Despite its therapeutic effectiveness, ATRA thus presents a number of drawbacks that limit its use in therapy.
  • Nanosuspensions can be injected parenterally, especially intravenously, which, by definition, leads to 100% bioavailability. Nanoparticles have been used recently to improve drug dissolution rate, saturation solubility, bioavailability and hence efficacy. Moreover, drug nanoformulations can achieve sustained effects which eliminate fluctuations in drug plasma concentrations.
  • HSA human serum albumin
  • Human albumin quantitatively represents more than half of the total proteins of plasma. The most important physiological functions of albumin is its contribution to oncotic pressure of the blood and its transport role. Albumin stabilizes the circulating blood volume and ensures a role of hormone, enzymes, drugs and toxins carrier.
  • HSA has surface-active properties that can improve drug wettability and decrease particle aggregation.
  • Albumin has reactive functional groups (thiol, amino, and carboxyl) on its surface that can be used for ligand binding and other surface modifications. Drug release from albumin nanoparticles can be achieved naturally by protease digestion. Moreover, there are many glycoproteins (gp60, gp30, and gp18) acting as receptor for either native or modified albumin that were identified in various tissues and cell lines.
  • Albumin is known as a natural carrier of hydrophobic molecules that allows the transport of these molecules around the body and their release at the cell surface (Elzoghby et al., J. Control Releases 159, 168-182, 2012).
  • HSA can be conjugated with active targeting molecules such as aptamers, antibodies, and proteins to bind various over-expressed receptors (Elzoghby et al., 2012).
  • active targeting molecules such as aptamers, antibodies, and proteins
  • albumin-bound nanoparticles offer a 100% natural and organic solvent-free formulation.
  • FITC fluorescent dyes such as fluorescein derivatives including fluorescein isothiocyanate provides intense fluorescence and facilitates the follow up of the nanoparticles after injection.
  • the present invention concerns nanoparticles comprising:
  • albumin can act as a drug carrier and/or a stabilizer of ATRA or its derivatives.
  • Nanoparticles of albumin containing ATRA surprisingly leads to:
  • the active ingredient is all trans retinoic acid (ATRA).
  • Albumin refers to serum albumin and more particularly to human serum albumin (HSA), such as purified HSA.
  • HSA human serum albumin
  • Purified HSA corresponds to albumin essentially free of fatty acids, i.e. less than 0.005% fatty acids.
  • HSA is provided by Sigma-Aldrich under the tradename (Human serum albumin, essentially fatty acid free)
  • albumin is human serum albumin (HSA).
  • HSA human serum albumin
  • This protein has several advantages for an injectable formulation of nanoparticles to: (i) HSA has surfactant properties which enhance the wettability of the drug, (ii) HSA act as a cryoprotectant decreasing particle aggregation and preventing drug degradation during freeze-drying, (iii) the drug bioavailability is maximum (100%) for intravenous injection, (IV) the drug maintains its rapid activity, (v) the hepatic metabolism is avoided, (vi) therapeutic doses are reduced, which reduces the toxicity of the drug, (vii) HSA is biocompatible, biodegradable and non-immunogenic, (viii) HSA improves the hydrophilicity, provides dysopsonin-like activity by inhibiting the association of opsonins on the surface of nanoparticles leading to decrease their uptake by the mononuclear phagocytic system and hence increase their blood circulation time.
  • the nanoformulation has many advantages over conventional formulations.
  • the nanoparticles can improve the dissolution rate, the saturation solubility, bioavailability and therefore the effectiveness of active substances.
  • the nanoparticles may eliminate fluctuations in plasma concentrations of a drug so as to avoid sub-therapeutic concentrations at the origin of the development of resistance phenomena and to prolong the life of the active substances.
  • nanoparticles correspond to particles having a size of 10 to 1000 nm, especially 50 to 700 nm, particularly from 50 to 500 nm and more particularly 80 to 230 nm. Furthermore, the size of the nanoparticles mentioned above remains essentially unchanged before and after formulation of these nanoparticles in a pharmaceutical composition.
  • the nanoparticles are composed of albumin as a carrier and ATRA or derivatives thereof as an active ingredient.
  • the nanoparticles have a homogenous particle size distribution of less than 200 nm.
  • Size as used therein means the mean largest dimension of the particles: This can be the diameter in case of spherical nanoparticles or the largest dimension in case of non- spherical particles.
  • the nanoparticles are from a substantially homogenous mixture with polydispersity index of generally less than 0.25.
  • the invention relates to a nanoparticle as defined above, wherein the load of the active ingredient in the nanoparticle is comprised between 0.05 and 15 %, generally between 0.1 and 10% (in weight).
  • the invention thus has the advantage of making the ATRA soluble in an aqueous medium or a buffered aqueous medium. It thus leads to a new soluble formulation of ATRA, which is made more effective in that it has a longer half-life and can be used at lower doses and therefore involve less toxicity than ATRA when administered on its own.
  • the active ingredient and albumin are not bonded to each other by a chemical bond, including a covalent bond. Accordingly, the active ingredient and albumin are found in the composition in the form of two separate chemical entities, where the active ingredient is embedded within the albumin.
  • albumin acts both as a carrier/stabilizer of the active ingredient to solubilize it and as a targeting vector allowing release of the active ingredient to cancer cells.
  • carrier/stabilizer refers to an agent suitable to load the active ingredient and to improve the solubilization of the active ingredient. This term corresponds in particular to albumin used to solubilize ATRA and derivatives thereof.
  • targeted vector refers to an agent suitable to carry an active ingredient and to release it within the body. This term corresponds in particular to albumin used to carry ATRA and derivatives thereof.
  • the present invention also concerns a pharmaceutical composition comprising the nanoparticles of the invention.
  • said composition is suitable for injection.
  • said composition may be in the form of an injectable solution, such as for parenteral including intravenous (IV) administration, or a premix thereof, or in the form of a sterile lyophilized powder suitable for intravenous injection after reconstitution in a sterile and pyrogen-free isotonic aqueous solution (water for injection (WFI) as define in European Pharmacopeia).
  • injectable solution such as for parenteral including intravenous (IV) administration, or a premix thereof
  • WFI water for injection
  • the term "injectable” is used to indicate that a composition may be administered parenterally such as intravenously to deliver the drug to blood, in particular for early action and to avoid first pass metabolism (metabolism in the liver during enteral administration).
  • compositions may be soluble in water, in a phosphate buffer and/or in physiological fluids, in particularly blood.
  • the composition in the form of an injectable solution may be directly used or may be in the form of a premix, suitable for further dilution prior to injection.
  • the composition may be presented in unit-dose or a multi-dose container, for example sealed ampoules and vials with elastomeric stoppers, and may be stored in a freeze-drying (lyophilized) condition requiring only the addition of the sterile liquid carrier, for example water for injections, immediately prior to use.
  • Extemporaneous injection solutions and suspensions may be prepared from sterile lyophilized form or premix solution or suspension of the kind previously described.
  • the composition is suitable for administration once to three times a day according to drug plasma clearance.
  • the pharmaceutical composition may comprise one or more pharmaceutically acceptable excipients.
  • “Pharmaceutically acceptable excipients” as used herein refers in particular to excipients suitable for injection such as suspending agents, thickening agents, anti-oxidants, buffers, bacte ho stats, solutes which render the formulation isotonic and cryoprotectant (which facilitate the redispersion of the lyophilized particles, ex. sugars, polyols, mannitol, trehalose, ...)
  • Formulations suitable "for parenteral administration” mean formulations which are in a form suitable to be administered parenterally to a patient with a pH suitably adjusted to the blood of the intended recipient.
  • the formulations are typically sterile and include emulsions, suspensions, aqueous and non-aqueous injection solutions.
  • the invention relates to a pharmaceutical composition defined above wherein ATRA is present as a unit dose comprised between 10mg/m 2 /day and 45mg/m 2 /day.
  • the present invention concerns the nanoparticles or pharmaceutical compositions of the invention for use for the treatment and/or prevention of cancer, in particular leukemia, more particularly acute myeloid leukemia, including acute promyelocytic leukemia (APL).
  • the present invention also concerns the process of preparation of the nanoparticle of the invention.
  • nanoparticles according to the invention Two alternative manufacturing methods may be suitable to obtain nanoparticles according to the invention: desolvatation (coacervation) on the one hand and high-pressure homogenisation (emulsion- solvent evaporation processes) on the other hand.
  • the process of preparation of a nanoparticle according to the invention may include desolvatation (coacervation) or high-pressure homogenization (emulsification) of a mixture of albumin and ATRA or one of its derivatives, in water and one or more organic solvents.
  • the desolvatation (or coacervation) process is based on a physico-chemical principle which leads to the decrease of solubility of a polymer in a miscible solvent by the addition of large quantities of various alternative organic solvents such as ethanol, acetone.
  • the molecules of the polymer desolvate and then coalesce forming droplets, called coacervate droplets.
  • albumin may be dissolved in an aqueous solution at physiological pH and the active ingredient is dissolved in a suitable organic solvent.
  • the organic solution is added, generally drop-wise (typically between 0.1 ml/min and 10 ml/min, notably 0.8 to 1 .5 ml/min) to the aqueous solution containing albumin kept under continuous stirring (generally between 400 rpm and 600 rpm).
  • the addition of a certain amount (from one to four times the initial aqueous volume) of an organic solvent generally induces the desolvatation of the polymer and the formation of coacervate droplets.
  • the nanosuspension so obtained may be centrifuged and rinsed several times.
  • the process of the invention may thus comprise the following steps:
  • the mixing step comprises adding the organic solution to the aqueous solution.
  • the pH of the aqueous solution may be adjusted to a pH comprised between approximately 7 and 9, typically between 8-8.5. This can be done e.g. by adding aqueous NaOH solution to the mixture.
  • the high-pressure homogenisation (nanoemulsion-solvent evaporation) process is based on the preparation of a crude emulsion of albumin in an immiscible phase of the active ingredient.
  • the emulsion is then subjected to homogenization under high-pressure, followed by rapid evaporation under reduced pressure to remove organic solvent, so as to form a nanosuspension.
  • the process of the invention may comprise the following steps:
  • the high-pressure homogenisation may be typically conducted by 10 to 50 cycles, at a pressure comprised between 10 000 to 50 000 psi. Cycles can be performed in one or two stages.
  • the homogenization step can be carried out at 10 000 to 25 000 psi (69 000 to 172 400 kPa) for 15 cycles.
  • the homogenisation step is carried out at 10000 psi for 5 cycles followed by 10 cycles at 25 000 psi (69 000 to 172 400 kPa).
  • suitable organic solvents include acetone, dichloromethane, chloroform and ethanol.
  • the process of the invention may comprise the step of adding glutaraldehyde to the mixture before conducting the centrifugation in the coacervation method or after the high-pressure homogenization in the emulsification method.
  • Glutaraldehyde may be generally added in order to obtain sustained release nanoparticles. Indeed, the crosslinking of the polymer matrix which contains the drug slows down the drug release rate, thus prolonging the therapeutic effect.
  • the aqueous solutions may be adjusted to a physiological pH by addition of suitable acid, base or buffer.
  • the process of the invention may comprise the step of freeze-dying the obtained product.
  • Lyophilisation of the product devoid of organic solvent, obtained according to either variant may then be conducted to obtain a nanoparticles powder, in particular with a view to increase the physical stability.
  • the present invention also concerns the nanoparticles obtainable by the process of the invention.
  • the nanoparticles are typically spherical.
  • the nanoparticles are generally trapezoidal.
  • Figure 1 represents SEM photos of the lyophilized ATRA-HSA NPs (desolvation) and shows spherical nanoparticles with diameter comprise between 60 and 200 nm.
  • Figure 2 illustrates TEM photo of the lyophilized ATRA-BSA NPs (High pressure homogenisation) and shows that articles obtained by High pressure homogenisation present rhombus forms with length less than 230nm.
  • Figure 3 illustrates the X ray diffractograms of ATRA, bovine serum albumin (BSA), ATRA/BSA physical mixture (0,4:10,w/w), and ATRA/BSA nanoparticles NPs. All aqueous solutions were prepared using distilled high-purity water obtained through a Milli-Q water purification system ⁇ ®> (Millipore, Saint Quentin, France).
  • Example 1 ATRA-Albumin-qlutaraldehvde nanoparticles obtained by coacervation method
  • the albumin solution (2%, w/v) was prepared by dissolving BSA (440 mg) in NaCI aqueous solution (22 ml_, 5 mM), the pH was adjusted to 8.5 by addition of aqueous NaOH (1 M).
  • the drug solution was prepared by dissolving 20 mg ATRA in 3 ml_ acetone.
  • the drug solution was added drop-wise to the albumin solution and kept under continuous stirring (550 rpm) for 1 h to maximize the interaction with the native albumin [ ] before the precipitation step. Nanoparticles precipitation was achieved by the addition of acetone (44 ml_) at 1 mL/min under stirring (550 rpm).
  • glutaraldehyde 50%, w/w (82 ⁇ _) was added to the nanosuspension and kept under continuous stirring for 24 h then subjected to two cycles of centrifugation (6000 rpm/60 min) and washing with water MilliQ.
  • the nanoparticles were frozen at -195.3°C for 90 min using liquid nitrogen prior to lyophilisation (CT60e, Heto, Scandinavia).
  • X ray diagrams show the highly crystalline nature of ATRA (numerous distinct peaks at different diffraction angles) compared to amorphous state of BSA represented by two broad bands and show the "amorphization" of ATRA (transformation of crystalline state to amorphous state) when it is incorporated in albumin nanoparticles.
  • Example 2 ATRA-Albumin nanoparticles obtained by high-pressure emulsion-solvent evaporation method
  • ATRA 152 mg were dissolved in 5 ml_ dichloromethane/chloroform/ethanol (6:3:1 , v/v/v), the dissolution was enhanced in an ultra-sonic bath.
  • BSA 3.33 gm was dissolved in 166.5 ml_ Milli-Q water presaturated with dichloromethane and chloroform.
  • the ATRA solution was added to BSA solution.
  • This biphasic mixture was subjected to ultraturax ( ⁇ 25 digital, Germany) at 23 000 rpm during 3 min to obtain a crude emulsion.
  • the polydispersity index ( ⁇ 0.25) illustrates a very good homogeneity of the mixture.
  • the loading rates were 0.1 1 % and 4.2 % with an entrapment efficiency of 3% and 93% for the nanoparticles prepared by desolvatation and high pressure homogenization, respectively.
  • the desolvatation method offers slightly smaller (139 nm) and more stable nanoparticles (- 46 mV) compared to the high pressure homogenization method.
  • the high pressure homogenization method showed better loading capacity (4.2 %) with good entrapment efficiency (93%).

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Abstract

L'invention concerne des nanoparticules d'acide tout-trans rétinoïque (ATRA) ou de dérivés de celui-ci et d'albumine, leur préparation, des compositions pharmaceutiques les comprenant et leur utilisation pour traiter et/ou prévenir le cancer et la leucémie en particulier.
PCT/EP2017/059424 2016-04-20 2017-04-20 Nouvelles formulations de dérivés d'acide rétinoïque et leur utilisation pour le traitement du cancer WO2017182584A1 (fr)

Applications Claiming Priority (2)

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EP16305457.0 2016-04-20
EP16305457 2016-04-20

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WO2017182584A1 true WO2017182584A1 (fr) 2017-10-26

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Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2013188727A2 (fr) * 2012-06-15 2013-12-19 The Children's Hospital Of Philadelphia Nouveaux dérivés pro- et co-médicaments pour la délivrance par nanoparticules d'agents anticancer sélectionnés, formés en utilisant des ponts esters phénoliques rapidement clivables
EP2937080A1 (fr) * 2013-05-02 2015-10-28 Jinis Co., Ltd. Nanoparticules anticancéreuses présentant spécificité de cible amplifiée, et son procédé de préparation

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2013188727A2 (fr) * 2012-06-15 2013-12-19 The Children's Hospital Of Philadelphia Nouveaux dérivés pro- et co-médicaments pour la délivrance par nanoparticules d'agents anticancer sélectionnés, formés en utilisant des ponts esters phénoliques rapidement clivables
EP2937080A1 (fr) * 2013-05-02 2015-10-28 Jinis Co., Ltd. Nanoparticules anticancéreuses présentant spécificité de cible amplifiée, et son procédé de préparation

Non-Patent Citations (2)

* Cited by examiner, † Cited by third party
Title
ELZOGHBY ET AL., J. CONTROL RELEASES, vol. 159, 2012, pages 168 - 182
LI CHUNLEI ET AL: "Direct comparison of two albumin-based paclitaxel-loaded nanoparticle formulations: Is the crosslinked version more advantageous?", INTERNATIONAL JOURNAL OF PHARMACEUTICS, vol. 468, no. 1, 5 April 2014 (2014-04-05), pages 15 - 25, XP029029801, ISSN: 0378-5173, DOI: 10.1016/J.IJPHARM.2014.04.010 *

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