WO2019016692A1 - Stabilisation de taille de particule de particules liées à une protéine et procédés associés - Google Patents

Stabilisation de taille de particule de particules liées à une protéine et procédés associés Download PDF

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Publication number
WO2019016692A1
WO2019016692A1 PCT/IB2018/055279 IB2018055279W WO2019016692A1 WO 2019016692 A1 WO2019016692 A1 WO 2019016692A1 IB 2018055279 W IB2018055279 W IB 2018055279W WO 2019016692 A1 WO2019016692 A1 WO 2019016692A1
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WO
WIPO (PCT)
Prior art keywords
nanosuspension
paclitaxel
mixtures
albumin
carbon atoms
Prior art date
Application number
PCT/IB2018/055279
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English (en)
Inventor
Pramanick Sougata
Aasiya BURHAN ASLAM
Priti NAVALE VIKRAM
Venkata Sai Dheeraj MUNJULURY
Mukund Keshav Gurjar
Original Assignee
Emcure Pharmaceuticals Limited
Priority date (The priority date 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 date listed.)
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Publication date
Application filed by Emcure Pharmaceuticals Limited filed Critical Emcure Pharmaceuticals Limited
Publication of WO2019016692A1 publication Critical patent/WO2019016692A1/fr

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Classifications

    • 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
    • A61K31/33—Heterocyclic compounds
    • A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
    • A61K31/337—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having four-membered rings, e.g. taxol
    • 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
    • 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

Definitions

  • the present invention relates to stable paclitaxel and albumin nanosuspension suitable for intravenous administration and a method of preparation thereof.
  • Cancer is one of the leading causes of deaths worldwide with an estimated 7.6 million individuals lost each year and accounting for 13% of all deaths. Cancer is a single disease which affects a multitude of organs with each organ or system developing a distinct set of symptoms and methods for treating it. Many instances of cancer could be avoided, with some estimates indicating that about 30% of cancer deaths are associated with smoking or other lifestyle factors or dietary practices that could potentially be avoided by changes in human behavior. Nonetheless, majority of cancers cannot be avoided by simple behavioral changes and require technological innovation to improve outcomes. The success in limiting cancer could be further enhanced by more widespread development and implementation of these advanced technologies.
  • Nanotechnology and nanoscience methods are increasingly being evaluated as a potential solution for treatment of cancer.
  • Nanotechnology is a multidisciplinary area of inquiry and application.
  • Nanosuspensions are colloidal dispersions of nanosized drug particles stabilized by surfactants. They can also be defined as a biphasic system or carrier-free colloidal drug delivery system consisting of pure drug particles and stabilizers dispersed in an aqueous or non-aqueous vehicle in which the diameter of the suspended particle is less than 1 ⁇ in size.
  • the reduced particle size in the nanosuspension technology obviates the possibility of blood capillaries blockade by intravenous administration rendering it a safe method for administration of poorly soluble drugs.
  • Paclitaxel a poorly soluble drug, was first isolated in 1971 from the Pacific yew and approved for medical use in 1993. It is listed on the World Health Organization's list of Essential Medicines, as the most effective and safe medicine needed in a health system. Worldwide, it is approved for treatment of ovarian, breast, lung, bladder, prostate, melanoma, esophageal, and other types of solid tumor cancers as well as Kaposi's sarcoma.
  • paclitaxel Due to its aqueous insolubility, paclitaxel was first formulated by using a mixture of Cremophor (50%) and absolute alcohol (50%) for the use of parenteral administration. Cremophor EL, as a formulation vehicle, is not inert biologically and pharmacologically. It is involved with toxic side effects such as hypersensitivity reaction, anaphylactic shock, neuropathy, 'pseudo'- nonlinear pharmacokinetic behavior of paclitaxel and death. With this formulation, premedication with steroids, antihistamines and/or H 2 receptor blockers was required prior to dosing in order to prevent hypersensitivity reactions. Additionally, specialized IV tubings were required to prevent leaching of plasticizers.
  • Albumin bound paclitaxel is an improved alternative formulation where paclitaxel is bound to albumin in the form of nanosuspension and is marketed worldwide under the brand name of ABRAXANE®.
  • U.S. Patent No. 7,820,788 discloses that the pharmaceutical composition is in form of nanosuspension for intravenous administration comprising paclitaxel and albumin and the particle size of the formulation is not more than 200 nm.
  • Albumin bound nanoparticles are biocompatible, non-immunogenic and biodegradable. Albumin is useful for targeting cancer cells as it is taken up by growing tumor cells as a source of amino acids and energy due to increasing cellular stress.
  • HSA human serum albumin
  • gp60 glycoprotein 60
  • EPR enhanced permeability and retention
  • the weight ratio of albumin to paclitaxel is about 9: 1.
  • the available literature suggests that the albumin/paclitaxel ratio of about 9: 1 is associated with higher therapeutic efficacy and substantially reduced toxicity when compared with the formulation that differs in the ratio of albumin to paclitaxel.
  • the formulation having albumin to paclitaxel ratio 9: 1 has increased cellular binding, therefore slight variation from this ratio is likely to affect the safety and efficacy profile of the formulation. It is needless to mention that the slight variation in the manufacturing process may change the ratio of albumin to paclitaxel available in the final product.
  • the inventors of the ABRAXANE® formulation have reported that during the manufacturing of the formulation, the starting ratio of albumin to drug always increased in the final resultant composition, i.e. the final ratio was 13.3: 1, when the starting ratio was 9: 1. Not only with the manufacturing process, but inventors have also reported that even during scaling up, the ratio increases.
  • nanoparticle formulation The principal parameters of nanoparticle formulation are their shape, size, and the morphological sub-structure of the substance. Their small size and large surface area can lead to particle-particle agglomeration, making physical handling of nanoparticles difficult in liquid and dry forms. In addition, small particles size and large surface area result in limited drug loading and burst release.
  • the objective of the present invention is to maintain the desired particle size of paclitaxel-albumin nanoparticle, during the course of manufacturing process.
  • Another objective is to increase physical and chemical stability, by reducing the level of physiologically harmful organic solvents. It is desirable that such pharmaceutical compositions should remain stable under conventional storage conditions and remain physically and/or chemically stable after rehydration or reconstitution.
  • the present invention is directed towards a stable paclitaxel and albumin nanosuspension for intravenous administration.
  • the present invention is directed towards a process for preparation of a stable paclitaxel and albumin nanosuspension comprising: a) preparing aqueous phase by dissolving human albumin in water
  • the process of the present invention has no impact on the particle size of paclitaxel- albumin nanoparticle.
  • the present invention is directed towards a stable paclitaxel and albumin nanosuspension for intravenous administration.
  • the process for preparation of a stable paclitaxel and albumin nanosuspension according to the present invention typically involves the following steps: a) preparing aqueous phase by dissolving human albumin in water
  • the present inventors have found that the immediate dilution of bulk solution with water, after size reduction step (d) helps in reducing the effective concentration of organic solvent and, in turn, avoids destabilization of paclitaxel- albumin nanoparticle.
  • nanoparticle or “nanoparticulate” as used herein refers to the solid particles of active ingredient having a particle size in nanometer (nm), such that 90% of the particles (D90) have a size not more than lOOOnm. It may be noted that the solid particles may include excipients adsorbed onto its surface, such as for example wetting agents, surfactants or surface stabilizers, which are adsorbed onto the surface of the active ingredient and there is no composite particle formed thereof.
  • nanosuspension refers to a suspension obtained after size reduction, comprising the solid particles of paclitaxel and albumin having particle size in nm, such that 90% of the particles (D90) have a size not more than lOOOnm.
  • the pharmaceutically stable composition of the present invention remains physically and/or chemically stable without any precipitation or sedimentation for at least about 8 hours, or up to about 24 hours following reconstitution or rehydration when stored in refrigerator (2 to 8°C) and/or at room temperature (20 to 25°C).
  • the stable nanosuspension of the present invention obviates the formation of floccules and maintains the particle size in an acceptable range of not more than lOOOnm, preferably not more than 500nm, more preferably not more than 230nm (Table 3).
  • the organic solvent is used to suspend or dissolve paclitaxel.
  • the organic solvent may include aliphatic, cycloaliphatic, or aromatic hydrocarbons having 4-30 carbon atoms such as n-dodecane, n-decane, n-hexane, cyclohexane, toluene, benzene, and mixtures thereof, aliphatic or aromatic alcohols having 2-30 carbon atoms such as ethanol, octanol and mixtures thereof, alkyl, aryl, or cyclic ethers having 2-30 carbon atoms such as diethyl ether, tetrahydrofuran, and mixtures thereof, alkyl or aryl halides having 1 -30 carbon atoms selected from the group of CHCb, CH2CI-CH2CI, and mixtures thereof, aliphatic or aromatic esters having 2-30 carbon atoms such as ethyl acetate, methyl acetate, ethyl caprylate
  • the preferred organic solvent(s) is chloroform, ethanol, or mixtures thereof.
  • the crude emulsion is prepared using homogenization or mixing or sonication method while the nanosuspension is prepared by high pressure homogenizer or ultrasonication or extrusion or high energy wet milling techniques.
  • the nanosuspension obtained after step (d) is diluted with water in an amount that is 2 to 10 times the quantity of nanosuspension bulk of step (d), preferably 2 to 8 times the quantity of nanosuspension bulk of step (d), preferably 2 to 6 times the quantity of nanosuspension bulk of step (d), preferably 2 to 4 times the quantity of nanosuspension bulk of step (d).
  • the diluted nanosuspension is passed through tangential flow filtration or wiped film evaporator or thin film evaporator or combinations thereof for removal of organic solvents and excess water. After final concentration, small amounts of nanosuspension are transferred to rotary evaporator for removal of residual organic solvents under reduced pressure.
  • paclitaxel-albumin nanoparticle prevents the paclitaxel-albumin nanoparticle from agglomerate formation, thus maintains the particles in acceptable size range of not more than 230nm. Hence immediate removal of organic solvent/s results in desired particle size.
  • Paclitaxel and albumin nanosuspension were made by using composition as summarized in below Table 1.
  • Table 1 Composition of paclitaxel and albumin nanosuspension
  • compositions of paclitaxel and albumin nanosuspension were prepared in accordance with the present invention in the following manner:
  • Table 2 discloses the effect of dilution with water (step-e) on particle size of paclitaxel- albumin nanoparticles. The particle size was measured using Zetasizer apparatus. Table 2: Effect of dilution on particle size of paclitaxel-albumin nanoparticles
  • Table 3 Stability data of reconstituted paclitaxel and albumin nanosuspension

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  • Health & Medical Sciences (AREA)
  • Epidemiology (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Engineering & Computer Science (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Medicinal Preparation (AREA)

Abstract

La présente invention concerne une nanosuspension stable de paclitaxel et d'albumine appropriée pour une administration intraveineuse et son procédé de préparation.
PCT/IB2018/055279 2017-07-21 2018-07-17 Stabilisation de taille de particule de particules liées à une protéine et procédés associés WO2019016692A1 (fr)

Applications Claiming Priority (2)

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ININ201721025975 2017-07-21
IN201721025975 2017-07-21

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WO2019016692A1 true WO2019016692A1 (fr) 2019-01-24

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Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5916596A (en) * 1993-02-22 1999-06-29 Vivorx Pharmaceuticals, Inc. Protein stabilized pharmacologically active agents, methods for the preparation thereof and methods for the use thereof
CN101843582A (zh) * 2010-05-18 2010-09-29 南京工业大学 紫杉醇纳米混悬剂及其制备方法

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5916596A (en) * 1993-02-22 1999-06-29 Vivorx Pharmaceuticals, Inc. Protein stabilized pharmacologically active agents, methods for the preparation thereof and methods for the use thereof
CN101843582A (zh) * 2010-05-18 2010-09-29 南京工业大学 紫杉醇纳米混悬剂及其制备方法

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