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WO2017005853A1 - Liposomes enrobés d'albumine - Google Patents

Liposomes enrobés d'albumine Download PDF

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Publication number
WO2017005853A1
WO2017005853A1 PCT/EP2016/066121 EP2016066121W WO2017005853A1 WO 2017005853 A1 WO2017005853 A1 WO 2017005853A1 EP 2016066121 W EP2016066121 W EP 2016066121W WO 2017005853 A1 WO2017005853 A1 WO 2017005853A1
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WO
WIPO (PCT)
Prior art keywords
particle
albumin
liposomes
active ingredient
vancomycin
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/EP2016/066121
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English (en)
Inventor
María José DE JESÚS VALLE
Amparo SÁNCHEZ NAVARRO
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Universidad de Salamanca
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Universidad de Salamanca
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Filing date
Publication date
Application filed by Universidad de Salamanca filed Critical Universidad de Salamanca
Publication of WO2017005853A1 publication Critical patent/WO2017005853A1/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
    • A61K9/10—Dispersions; Emulsions
    • A61K9/127—Synthetic bilayered vehicles, e.g. liposomes or liposomes with cholesterol as the only non-phosphatidyl surfactant
    • A61K9/1271—Non-conventional liposomes, e.g. PEGylated liposomes or liposomes coated or grafted with polymers
    • 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
    • A61K9/10—Dispersions; Emulsions
    • A61K9/127—Synthetic bilayered vehicles, e.g. liposomes or liposomes with cholesterol as the only non-phosphatidyl surfactant
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • A61K38/04—Peptides having up to 20 amino acids in a fully defined sequence; Derivatives thereof
    • A61K38/14—Peptides containing saccharide radicals; Derivatives thereof, e.g. bleomycin, phleomycin, muramylpeptides or vancomycin
    • 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
    • A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
    • A61K47/42—Proteins; Polypeptides; Degradation products thereof; Derivatives thereof, e.g. albumin, gelatin or zein

Definitions

  • the present invention relates to spherical particles consisting of albumin- coated liposomes and their preparation process based on flocculation induced by electrostatic attraction.
  • the resulting particles can encapsulate a wide range of active ingredients or molecules, making them useful as a versatile, biocompatible and biodegradable carrier for the controlled release of drugs and/or diagnostic agents.
  • liposomes are currently one of the most promising systems in this field and numerous strategies based on the selection of the components of the lipid bilayer are being tested in order to achieve a controlled release restricted to the biophase (Qian et al. Journal of Controlled Release, 2015, 207(10), 86- 92; Movahedi et al. Nanomedicine, 2015, 77(6), 1575-1584), and for the formulation of vaccines.
  • Albumin which is a hydrophilic molecule with an isoelectric point of about 5, is the most abundant plasma protein in mammals, with significant physiological functions in terms of regulation of colloid osmotic pressure and transport of numerous solutes (fatty acids, hormones, bile acids, amino acids, metals, etc.) from the bloodstream to the tissues. Furthermore, it appears that albumin facilitates endothelial transcytosis of certain plasma components due to their binding to a membrane receptor (albondin) with consequent formation of vesicles called caveolae. On the other hand, it appears that albumin is involved in selective tissue distribution of certain drugs which it protects against oxidation phenomena, while it influences the kinetic profile thereof (Feng et al ., Int. J. Mol. Sci. 2014, 15(3), 3580-3595; Mita et al., Invest New Drugs, 2015, 33, 341- 348).
  • albumin a good candidate to be included in formulations seeking a selective release in the tissue affected by the above-mentioned processes, especially if they have low water solubility (Krazt et ai, J. Control. Release, 2008, 132(3), 171-183).
  • bovine albumin nanoparticles have proven effective in the incorporation of certain dyes, drugs and vectorising agents.
  • albumin is an excellent formulation component since it is a product with a molecular weight that is suitable to benefit from the EPRE effect (enhanced permeability and retention effect) reported in tumour tissues.
  • the first drug marketed in oncology based on nanoparticle albumin was Abraxane® with indication for the treatment of breast cancer; it consists of 130 nm nanoparticles formed by human albumin and paclitaxel. This technology patented as nab- technology promises broad application for other drugs similar to paclitaxel.
  • albumin and liposomes for drug formulation and none of them use native, unmodified albumin; published studies relate to the use of denatured albumin to coat pegylated or non-pegylated liposomes containing doxorubicin or antisense oligonucleotide G3139 and both consistently affirm the benefits of incorporating albumin into the formulation.
  • Spherical particles have been designed, formulated and characterised comprising at least one liposome of different composition and/or zeta potential, coated with albumin, which may contain different active ingredients, or other molecules or products. Their characteristics vary depending on the experimental conditions applied during the production process, which is carried out in the absence of organic solvents and without needing extreme temperature and/or pressure conditions, although this process is not limiting and could also be applied to liposomes obtained by any other method.
  • Products were prepared without active ingredient and charged with different active ingredients, such as vancomycin and ciprofloxacin.
  • active ingredients such as vancomycin and ciprofloxacin.
  • the first a glycopeptide of complex structure with bactericidal effect, was selected as a model of water soluble drug with moderate affinity for albumin and the kinetic release profile in vitro of vancomyn was studied by means of dialysis tests.
  • the proposed particles are biocompatible, biodegradable and innocuous carriers of great versatility in terms of size, zeta potential and content in active principles, which gives them a high potential for the formulation of therapeutic agents, diagnostic agents and vaccines.
  • a first aspect of the present invention relates to a spherical particle formed by a core coated with albumin by electrostatic interaction, wherein the core comprises at least one liposome which can be anionic or cationic with zeta potential comprised between + 90mV and - 90mV.
  • liposome means a spherical vesicle wherein an aqueous core and at least one membrane consisting of a double layer of amphiphilic lipids, also referred to as lipid bilayer, which includes hydrophilic and lipophilic parts, are distinguished.
  • Liposomes can be uni-, oligo - or multilamellar, i.e. that may include one or several double layers of lipids. Although for those of the invention, the most appropriate and preferred for their topical application are the unilamellar ones.
  • albumin means, generally, a recombinant or native albumin of mammalian origin. More preferably, albumin is of human, bovine (BSA), murine, or rabbit origin; other albumins of possible use are ovalbumin and lactalbumin. Even more preferably, the albumin used is recombinant human serum albumin, or fresh or lyophilised bovine serum albumin.
  • the particle has a micron size with a particle diameter comprised between 0.1 m and ⁇ ⁇ , preferably between 0.2 ⁇ and 1 ⁇ . In a preferred embodiment, the particle has a nanomicron size with a particle diameter comprised between 0.1 nm and 100 nm.
  • albumin is unmodified albumin of human origin.
  • the lipids that constitute the lipid bilayer of the liposome include: a) phospholipids, both of natural and synthetic origin, such as phosphatidylcholine, or cholesterol and b) another lipid with ionic charge, i.e. charged positively or negatively; or any mixture thereof.
  • lipids with ionic charge are, for example, dimethyl dioctadecyl ammonium, linoleic acid and phosphatidylglycerol, among others.
  • the spherical particle comprises a molecule or an encapsulated active ingredient in the liposome, or trapped in the albumin coating, or encapsulated in the liposome and trapped in the albumin coating.
  • active ingredient means any component that potentially provides pharmacological activity or other different effect in the diagnosis, cure, mitigation, treatment, or prevention of a disease, or affect the structure or function of the human body or body of other animals.
  • the term includes those components that promote a chemical change in the development of the drug and are present in the same in a planned modified form that provides the specific activity or effect.
  • the preferred active ingredients are selected from the non-limiting list of the following: antifungals (amphotericin, fluorocytosine, itraconazole, posaconazole, caspofungin, anidulafungin, micafungin, isavuconazole, aminocandin, among others), antibiotics (ciprofloxacin, vancomycin, erythromycin, azithromycin, clarithromycin, penicillins and cephalosporins, rifampin, isoniazid and streptomycin, quinolones, among others), progestogens (ethinyl estradiol, norelgestromin, levonorgestrel, drospirenone, norgestimate, among others), antineoplastics (doxorubicin, epirrubcin, dactinomycin, paclitaxel, docetaxel, lapatinib, capecitabine, tegafur, methotrexate, among others), antiretrovirals
  • NSAIDs for example eletriptan or almotriptan
  • triptans for example eletriptan or almotriptan
  • cydooxygenase 2 inhibitors for example celecoxib
  • oxicam derivatives e.g. piroxicam
  • pyrazole derivatives e.g. phenylbutazone
  • diagnostic agents paramagnetic material, etc.
  • compounds were prepared loaded with vancomycin and ciprofloxacin.
  • compositions comprising the spherical particle of the invention, this composition being preferably pharmaceutical or cosmetic.
  • the pharmaceutical or cosmetic composition further comprises pharmaceutically or cosmetically acceptable excipients.
  • excipient means a substance that helps the administration of any component of the product of the invention, stabilises said components or assists in the preparation of the pharmaceutical or cosmetic composition in the sense of giving consistency and thus stabilising the suspension.
  • the excipients may have the function of maintaining the binding of the components as for example starches, sugars or cellulose, the function of odourising or deodourising, the function of colouring, the function of protection of the drug, the function of freeze-drying of the drug or cosmetic, among others.
  • excipient is defined as that which, included in the dosage forms, is added to the active ingredients or its associations to assist in its administration, penetration into the skin, hair and nails, enable its preparation or formulation and stabilise it, modify its organoleptic properties or determine the physical- chemical properties of the pharmaceutical composition and its bio-availability.
  • the "cosmetic or pharmaceutically acceptable” excipient should allow the compounds' activity of the composition, i.e., that it is compatible with these components. Examples of excipients are isotonizants, pH controllers, binders, fillers, disintegrators, lubricants, flavourings or aromas and colourings.
  • Non- limiting more specific examples of pharmaceutical or cosmetically acceptable excipients are starches, sugars and hyaluronic acid, xanthans, glycerol, sorbitol, xylitol, or glycerin among others.
  • composition can comprise different antioxidants, such as vitamin E, vitamin A and vitamin C, which would mainly provide a chemical stabiliser effect to the composition.
  • Another aspect of the invention relates to the use of the particles of the invention as carrier, preferably for the controlled release of drugs and in particular non water-soluble active ingredients.
  • Another aspect of the invention relates to the use of the particles of the invention for the manufacture of a medicament, theranostic products or vaccines, preferably for the prevention and/or treatment of cancer, HIV and Hepatitis C.
  • aqueous core of liposomes preferably for the prevention and/or treatment of cancer, HIV and Hepatitis C.
  • bilayer lipid of liposomes and protein with binding and carrier capacity each of them capable of hosting active ingredients of different solubility and affinity, which is interesting for the manufacture of a medicament for treatment in combination therapies.
  • the carrier described in the present invention could be applied to the formulation of medicaments that may be applied according to the non- limiting following list:
  • Parenteral routes size requirements are achieved by controlling the process conditions in particular the zeta potential of the vesicle and the amount of albumin incorporated into the compound.
  • parenteral routes stand out: intravenous, especially for antineoplastic and antibiotics for the ability to accumulate albumin in tumours and infected tissues; intramuscular, intradermal and subcutaneous (vaccines and others).
  • Another aspect of the invention relates to a method for obtaining the particles of the invention comprising contacting a suspension of liposomes with a solution of albumin by flocculation at any pH, preferably between 3 and 8, according to the net load of the liposome.
  • an equal volume of albumin solution is added, with or without organic solvents, preferably without organic solvents, and even more preferably in water or buffer solution.
  • the albumin solution concentration ranges between 0.05 and 30% w/v. In a more preferred embodiment the albumin solution concentration is 1 % w/v.
  • the flocculation step is induced at a pH up to 5 when starting from negative zeta potential liposomes, preferably between 3 and 5; and induced at a pH above 5, preferably between 5 and 8, when starting from liposomes with positive zeta potential.
  • the buffer solution comprises preferably phosphate or citrate salts.
  • the carriers obtained by the method described were coated with bovine albumin of human origin by a flocculation phenomenon in aqueous medium, atmospheric pressure (about 1 atmosphere) and temperature between 2 and 10 °C.
  • the flocculation temperature is 4 °C.
  • FIG. 1 Morphology of liposomes coated with albumin obtained by scanning electron microscopy (SEM) of different size.
  • FIG. 5 Vancomycin in vitro release kinetics. Results of studies with the compounds prepared from cationic liposomes. The quantities released (milligrams) are illustrated at various times for a period of 48 h.
  • FIG. 6 Curve analysis of remaining amounts in compounds. It shows that the kinetic drug (vancomycin) release process is polyexponential by nature in all cases, regardless of the amount of albumin and active ingredient incorporated.
  • Example 1 The invention will be illustrated below by assays performed by the inventors, which show the effectiveness of the product of the invention.
  • Example 1
  • the constituent lipids of the lipid bilayer of the liposome are mixed with Milli-Q water preheated to 60 °C, by stirring the mixture until dispersion of the lipids, and then placed in an ultrasonic bath (50Hz) for 20 min at 60 ⁇ 2 °C.
  • Liposomes whose composition includes egg phosphatidylcholine, cholesterol and an ionically charged lipid (dimethyl dioctadecyl ammonium, linoleic acid or phosphatidylglycerol), were prepared in all cases from the same concentration of lipids in water (1 .73% w/v).
  • the zeta potential was found to be +61 .9 ⁇ 2.08 mV and -47.95 ⁇ 4.71 mV, respectively.
  • liposomes loaded with vancomycin a solution of the active ingredient (vancomycin) of 5 mg/mL concentration was used.
  • the sonicated samples were kept at rest for 1 h, at room temperature for 60 min, so that the assembly process of the lipids and vesicles formation was complete; then they were filtered through a 0.22 ⁇ membrane.
  • An aliquot of the liposome suspension for characterisation (morphology, size, zeta potential and active ingredient content) was taken, and the rest were sent for coating with albumin for the formation of the carriers.
  • the efficiency of uptake of active ingredient in the liposomes was 15% in the cationics and slightly lower in the anionics in the case of vancomycin.
  • Lipid vesicles of different composition and zeta potential obtained by the method described were coated with bovine albumin.
  • an equal volume of albumin solutions of different concentrations 0.1 -3% w/v was added drop-wise.
  • the resulting samples were kept under mechanical stirring at room temperature for 15 min and then in an incubation bath at 4 °C and gentle stirring for 20 h.
  • the samples were centrifuged at 10,000 rpm and 4 °C and the supernatant was separated from the pellet. The volume of supernatant was measured, the albumin and vancomycin levels were quantified and the presence of liposomes was investigated. An aliquot of the pellet was separated to characterise the formed particles (morphology, size, zeta potential, and drug content) and the rest was used for in vitro assay of vancomycin release.
  • the liposome suspensions and pellet obtained were observed under a microscope using light microscopy equipment connected to a camera and image capture software (Canon remote capture) and also with a scanning electron microscopy (SEM) instrument, for which samples were previously subjected to a fixing process using poly-L lysine and osmium as fixing agents.
  • SEM scanning electron microscopy
  • the hydrodynamic diameter (dh) and polydispersity index (PDI) of the particles before (liposomes) and after coating with albumin (encapsulated liposome) was determined using two types of instruments, Mastersizer 2000, which analyses particles of a size greater than 0.5 ⁇ , and Zetasizer nano ZN, which detects and analyses those of smaller size. The determinations were performed at 25 °C, with a correlation function for an angle of 173° in the Zetasizer nano and 90° in the Mastersizer, applying the Stokes-Einstein relation to determine the dh. The samples were diluted with Milli-Q water to obtain the optimum degree of obscuration for the determinations.
  • the zeta potential of the resulting carriers takes different values depending on the initial load of the liposomes and the amount of albumin incorporated therein.
  • V volume of the liposome suspension in a dialysis bag (12-14k Da cut-off) that is suspended in 25 mL of Milli-Q water preheated at 37 °C is placed in closed tube under stirring. Samples from the external environment are taken every 15 min, replacing the volume removed with an equal amount of fresh medium until reaching dialysis equilibrium. Parallel assays were performed in identical conditions but including the same volume (V) of a solution of vancomycin of known concentration (5 mg/mL) in the dialysis bag, as a reference. The amount of vancomycin in liposomes (Qlip) was determined from the equilibrium concentrations of active ingredient in the dialysate from the reference and the liposomes (Cer and Celip respectively).
  • f is the fraction of active ingredient available for dialysis exchange
  • C and V are the drug concentration and the volume inside the dialysis bag, respectively
  • Vlip is the volume entrapped in the liposomes.
  • the encapsulation efficiency of the active ingredient in liposomes (EElip) was expressed as 100 x (Qlip/Qi), where Qi is the initial amount of vancomycin used for the preparation of liposomes.
  • composition of micro-nano-spheres with encapsulated liposomes Composition of micro-nano-spheres with encapsulated liposomes
  • composition of the particles formed by the interaction between liposomes and albumin induced by the applied experimental conditions was determined indirectly from the composition of the supernatant separated by centrifugation from the flocculated samples. Since centrifugation can perfectly separate the pellet from the supernatant, it is assumed that all components of the mixture (liposomes, albumin and vancomycin) not found in the supernatant are the pellet (encapsulated liposome). Accordingly, the amount of albumin and vancomycin trapped in encapsulated liposomes (Qalb and Qvan, respectively) was calculated as follows:
  • the release of vancomycin from the encapsulated liposomes was characterised in vitro by a dialysis assay, similar to that used for determining the active ingredient content of the liposomes.
  • the pellet separated by centrifugation was dispersed in 1 .5 ml_ of Milli-Q water and included in a dialysis bag (12-14k Da cut-off) which, in turn, was suspended in 25 ml_ of Milli-Q water preheated at 37 °C in sealed tube and subjected to stirring throughout the test.
  • samples were taken from the external medium, being replaced with equal volume of fresh medium at the same temperature. The concentrations in the samples were measured and the amounts of active ingredient released at the different times (Q)tn were calculated as follows:
  • Ctn is the concentration of active ingredient in the dialysate at time tn
  • ⁇ (Ctn-1 x 2) is the amount of drug extracted in the above samples
  • f is the fraction of active ingredient that is exchanged through the dialysis membrane .
  • This type of sample contains only water and vancomycin, allowing its quantification from the absorbance measured by UV spectroscopy at a wavelength of 220 nm.
  • Standards of the active ingredient in Milli-Q water were prepared in a concentration range of 0.01 mg/ml to 0.1 mg/ml and 0.1 mg/ml to 0.25 mg/mL.
  • the albumin standards were prepared in Milli-Q water at a concentration range of 0.05 to 0.20 mg/ml. In this case, the presence of vancomycin does not affect the absorbance of the protein, therefore, a pretreatment of the sample is not required.

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  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • General Health & Medical Sciences (AREA)
  • Veterinary Medicine (AREA)
  • Epidemiology (AREA)
  • Medicinal Chemistry (AREA)
  • Animal Behavior & Ethology (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Public Health (AREA)
  • Dispersion Chemistry (AREA)
  • Proteomics, Peptides & Aminoacids (AREA)
  • Medicinal Preparation (AREA)
  • Gastroenterology & Hepatology (AREA)
  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Immunology (AREA)
  • Inorganic Chemistry (AREA)
  • Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)

Abstract

La présente invention concerne la préparation de particules par micro-encapsulation, avec de l'albumine, de liposomes ayant une composition et un potentiel zêta différents préparés par des procédés utilisant des solvants organiques mais également en leur absence, et sans conditions extrêmes de température et/ou de pression, utiles en tant que véhicules de principes actifs présentant un intérêt potentiel dans le domaine de la médecine.
PCT/EP2016/066121 2015-07-07 2016-07-07 Liposomes enrobés d'albumine Ceased WO2017005853A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
ES201530974A ES2596558B1 (es) 2015-07-07 2015-07-07 Liposomas recubiertos con albúmina
ES201530974 2015-07-07

Publications (1)

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WO2017005853A1 true WO2017005853A1 (fr) 2017-01-12

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Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2019126766A1 (fr) * 2017-12-21 2019-06-27 Taiwan Liposome Co., Ltd. Compositions de triptan à libération prolongée et procédé d'utilisation de celles-ci par voie sous-dermale ou similaire
CN116747196A (zh) * 2023-07-31 2023-09-15 西南医科大学 脂质体包人血清白蛋白载药纳米粒及其制备方法和用途

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Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2019126766A1 (fr) * 2017-12-21 2019-06-27 Taiwan Liposome Co., Ltd. Compositions de triptan à libération prolongée et procédé d'utilisation de celles-ci par voie sous-dermale ou similaire
US11406628B2 (en) 2017-12-21 2022-08-09 Taiwan Liposome Co., Ltd Sustained-release triptan compositions and method of use the same through subdermal route or the like
CN116747196A (zh) * 2023-07-31 2023-09-15 西南医科大学 脂质体包人血清白蛋白载药纳米粒及其制备方法和用途

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ES2596558B1 (es) 2018-01-26

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