WO2018021927A1 - Stabilisateur pour suspensions liposomales - Google Patents

Stabilisateur pour suspensions liposomales Download PDF

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Publication number
WO2018021927A1
WO2018021927A1 PCT/RU2016/000491 RU2016000491W WO2018021927A1 WO 2018021927 A1 WO2018021927 A1 WO 2018021927A1 RU 2016000491 W RU2016000491 W RU 2016000491W WO 2018021927 A1 WO2018021927 A1 WO 2018021927A1
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WO
WIPO (PCT)
Prior art keywords
chitosan
liposomes
solution
peg
folic acid
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PCT/RU2016/000491
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English (en)
Russian (ru)
Inventor
Ирина Михайловна ДЕЙГЕН
Елена Вадимовна КУДРЯШОВА
Original Assignee
Федеральное государственное бюджетное образовательное учреждение высшего образования "Московский государственный университет имени М.В. Ломоносова"
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Application filed by Федеральное государственное бюджетное образовательное учреждение высшего образования "Московский государственный университет имени М.В. Ломоносова" filed Critical Федеральное государственное бюджетное образовательное учреждение высшего образования "Московский государственный университет имени М.В. Ломоносова"
Priority to PCT/RU2016/000491 priority Critical patent/WO2018021927A1/fr
Publication of WO2018021927A1 publication Critical patent/WO2018021927A1/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
    • A61K9/10—Dispersions; Emulsions
    • A61K9/127—Liposomes
    • 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
    • A61K31/70—Carbohydrates; Sugars; Derivatives thereof
    • A61K31/715—Polysaccharides, i.e. having more than five saccharide radicals attached to each other by glycosidic linkages; Derivatives thereof, e.g. ethers, esters
    • A61K31/716—Glucans
    • A61K31/722—Chitin, chitosan

Definitions

  • the invention relates to biotechnology, in particular to stabilizers of liposomal suspensions.
  • the stabilizer is a chitosan of molecular weight 15-120 kDa, modified by chains of polyethylene glycol or folic acid residues.
  • the invention can be used in pharmaceutical systems, as a stabilizer of liposomes loaded with various drugs. Liposome complexes with this stabilizer can be used as drug delivery systems.
  • Liposomes are particles that are formed by one or more concentric closed lipid bilayers, the internal volume of which is isolated from the external environment.
  • the following liposomes are distinguished depending on the particle size and the number of lipid layers forming them: 1) small monolamellar, formed by a single lipid bilayer (diameter 20-50 nm); 2) large monolamellar (macrovesicular), also formed by a single bilayer (diameter 50-200 nm and above); 3) multilayer (multilamellar), counting up to several tens and even hundreds of lipid bilayers (diameter up to 5000-10000 nm).
  • Liposomes appear to be promising drug delivery systems. Liposomes have a number of significant advantages, such as biocompatibility, low immunogenicity [Yasuda, T., Dancey, GF, Kinsky, S. C. Immunogenicity of liposomal model membranes in mice: Dependence on phospholipid composition. // Proc. Natl. Acad. Sci USA: Immunology 1977, V. 74, p. 1234 - 1236].
  • the size of liposomes allows them to penetrate into the tumor more efficiently. Moreover, the tumor does not have its own lymphatic system, which leads to the accumulation of the drug.
  • the similarity in chemical composition of liposomes to cell membranes ensures efficient intracellular delivery.
  • liposomes can serve as delivery systems for both hydrophobic substances and hydrophilic drugs in view of the amphiphilic nature of lipids.
  • the use of liposomes in medicine is still limited due to the low thermodynamic stability of liposomes, a tendency to aggregation and oxidation. It was found that the inclusion of drugs in liposomes can accelerate the process of membrane destruction [Fonseca M, van Winden E., Crommelin D. Doxorubicin induces aggregation of small negatively charged liposomes. // Eur. J. Pharm and Biopharm. 1997, V. 43, p. 9-17].
  • liposomes as colloidal systems are unstable and are influenced by kinetic control [Ulrich A. Biophysical aspects of using liposomes as delivery vehicles. // Bioscience reports 2002, V. 22, p. 129-150.].
  • liposomal systems are stable upon dilution, in contrast to micellar systems or microemulsions [Chung N., Kim TW, Kwon M., Kwon IC, Jeong SY Oil components modulate physical characteristics and function of the natural oil emulsions as drug or gene delivery system. // J. Control. Release 2001, V. 71, p. 339 - 350].
  • lipids can undergo oxidation during storage. Liposomes can be stored frozen in the form of lyophilized powder; however, cryoprotectants such as urea must be used to prevent phase transitions and damage to the membrane. Even with the use of cryoprotectants, each new batch of liposomes obtained from such a powder, must be studied to determine the size and morphology, which makes this storage method convenient only with rare use of liposomes.
  • liposome stability should be considered. While in silica and in vitro the main factors affecting liposome stability are lipid composition and temperature, many factors are found in in vivo systems that can also influence liposome stability. So, it was shown that in blood lipids from liposomes are able to pass to plasma lipoproteins. This effect was especially noticeable for lipids with a single hydrocarbon chain or containing short chains and liposomes in the liquid crystalline phase.
  • chitosan forms gels in neutral and alkaline media [Varlamov VP, Nemtsev SV., Tikhonov V.E. Chitin and chitosan: nature, preparation and use. M .: Russian Khitinovskoe Society, 2010.]. Therefore, chitosan derivatives have been used in the past decade, for example [Khameneh B., Momennejad M., Tafaghodi M. In vivo evaluation of mucoadhesive properties of nanoliposomal formulations upon coating with trimethylchitosan polymer. // Nanomed. J. 2014, V. 1, p. 147-154]. In [Prabaharan M.
  • a method for preparing a liposome suspension stabilized by chitosan and PEG [CN 102772802 "Chitosan and polyethylene glycol-modified oleanolic acid joint nanoliposomes"].
  • a simple mixture of polymers does not allow achieving uniformity of the system, which is important for biomedical applications.
  • the key difference of the claimed invention from this analogue is the presence of covalent crosslinking of PEG with chitosan, and not the use of a simple mixture. Covalent crosslinking allows for greater system uniformity, which is important for biomedical applications.
  • CN 103520720 A "Preparation method of folic acid coupled carboxymethyl chitosan nanoparticle serving as photo-release NO carrier" uses not chitosan itself, but its carboxymethylchitosan derivative. This fact complicates the use of the invention in industry. Moreover, the preliminary activation of folic acid is not used in the synthesis, which reduces the yield of the reaction.
  • EP 2706988 A2 "Liposomes composed polymer-conjugated lipids and related uses", proposes a covalent modification of a lipid with chitosan and folic acid. Such an approach can lead to disruption of the liposome structure, up to destruction.
  • the proposed stabilizer includes a modified chitosan, which is obtained by modifying the particles of chitosan in the emulsion of an organic solvent - water with a pH of 6.0-6.5, by first exposure to a mixture consisting of a carboxylic acid in an organic solvent and a condensing agent, and then an organic base, with either palmitic or stearic, or dodecanoic acid, as a condensing agent, a mixture of hydroxysuccinimide and aliphatic carbodiimide or formaldehyde and aliphatic isocyanide, and triethylamine as an organic base.
  • fatty acid residues are used instead of PEG.
  • Such a stabilizer does not give the system an active targeting effect, it is able to change the structural properties of the bilayer due to the interaction of the stabilizer fatty residues and lipids. Due to changes in the hydrophobic-hydrophilic balance, the solubility of chitosan may decrease, which leads to the formation of an uneven suspension and aggregates. The synthesis takes a long time and is complicated by additional purification.
  • the objective of the invention is the creation of a stabilizer for liposome suspensions based on chitosan with improved properties.
  • the technical result to which the claimed invention is directed is to increase the stability of liposome suspensions due to effective binding to liposomes.
  • the structure and size of the complex of liposomes with a stabilizer remains unchanged for at least 30 days, due to improved electrostatic interaction of the stabilizer with the surface of the liposomes.
  • the resulting stabilizer is readily soluble in neutral and alkaline environments, including physiological solutions, which ensures the uniformity of the resulting systems.
  • the resulting delivery vehicles — liposomes coated with chitosan – PEG conjugate are not detected by the reticulo-endethelial system, and liposomes coated with chitosan – folic acid conjugate exhibit an active targeting effect.
  • the inventive stabilizer is obtained from chitosan through a minimum number of stages, and the pH of the reaction mixture is in the range from 4 to 9, the reaction time varies from 1 to 4 hours. Purification is carried out by dialysis against distilled water, a buffer solution, or chromatographically. The stabilizer obtained non-covalently binds to liposomes, forming a complex that is stable for at least 30 days.
  • the stabilizer for liposomal suspensions is a modified chitosan (chitosan conjugate) of the formula (C 6 0 4 H 9 NH 2 ) m (C 6 0 4 H9NHX) n , where, as an amino substituent, X PEG or folic acid acts.
  • PEG chitosan conjugate
  • the inventive stabilizer for liposomal suspensions can be obtained by mixing a solution that modifies the amino group of the chitosan agent with an acidic solution of chitosan and adjusting the resulting mixture to a pH of 7.5-8.0.
  • a solution of an agent modifying the amino group of chitosan (or a modifying agent) a solution of N-hydroxysuccinimide ester of PEG5000 hemisuccinate in dimethylformamide or dimethyl sulfoxide, or a solution of folic acid pre-activated with a solution of carbodiimide can be used.
  • the inventive stabilizer can also be used to obtain means for the delivery of the active substance, including the base, which is used as liposomes that carry the active substance, non-covalently linked to the complex chitosan conjugate according to claim 1.
  • the basic ratio of phosphate lipids on the surface of liposomes to unmodified amino groups is from 1: 0.25 to 1: 20.
  • PEG chitosan in FIG. 2 shows a synthesis scheme of a conjugate of chitosan with folic acid
  • FIG. 3 and in FIG. 4 presents graphs of the stability of liposomal suspensions.
  • the positions in figure 3 indicate: a - shift of the absorption bands of vCH 2 as during storage of free liposomes, b - liposomes in combination with chitosan, c - in combination with REO-chitosan-25.
  • the position of the corresponding absorption bands for free liposomes in the aggregated state (g).
  • the positions in figure 4 indicate: a - Shift of the vCO absorption bands during storage of free liposomes, b - liposomes in combination with chitosan, c - in complex with REO-chitosan-25. Position corresponding absorption bands for free liposomes in the aggregated state (g).
  • chitosan derivatives which may be a chitosan conjugate of the formula (C 6 04H9NH 2 ) m (C604H9NHX) ⁇ , where PEG or folic acid acts as a substituent on amino group X, where m and p is the number of units in the molecule.
  • branched copolymers based on chitosan modified with polyethylene glycol PEG-chitosan
  • Chitosan copolymers are synthesized with an activated PEG derivative, monomethoxy-PEG-N-hydroxysuccinimidyl succinate (mPEG-suc-NHS, M 5 kDa), which is highly reactive and under mild conditions acylates the amino groups of biomolecules in high yield.
  • Chitosan-folic acid conjugate was synthesized with preliminary activation of the carboxyl group using N- (3-Dimethylaminopropyl) -> ethylcarbodiimide. It should be noted the rapidity of this technique and a high yield of the reaction.
  • Complexation occurs by simple mixing of anionic liposomes and modified chitosan in a basic ratio of 1: 0.25 to 1: 20, calculated on the phosphate groups of the anionic lipid on the surface of the liposomes and unmodified amino groups of chitosan. Moreover, saturation is detected at the initial base-grinding ratio of 1: 7. After mixing, the complexes are incubated for half an hour at a temperature of 37 ° C, then the unbound polymer is separated chromatographically or by centrifugation. This approach compares favorably with simple and efficient. The structure of the resulting complexes is determined using the method of infrared spectroscopy Fourier and the method of dynamic light scattering.
  • the solution was purified by dialysis against distilled water for a day, against a PBS solution for 2 days. The final concentration was 3 mg / ml.
  • a solution of the required liposomes in a borate buffer, pH 9.0 (5 mg / ml) was added dropwise with stirring a polymer solution in 5 mM sodium phosphate buffer, pH 7.0-7.5 in a liposome-polymer ratio of 1: 0.25 to 1: 20 groundwater.
  • the complexes are incubated for one hour at a temperature of 37C, then the unbound polymer is separated by chromatography or by centrifugation.
  • branched copolymers based on chitosan modified with polyethylene glycol (PEG chitosan).
  • PEG chitosan modified with polyethylene glycol
  • the method allows you to determine the content of characteristic functional groups in the structure of the studied molecules and, accordingly, the degree of modification of biopolymers. From an analysis of the IR spectrum of PEG chitosan, it follows that as a result of the modification of chitosan with an activated PEG derivative (mPEG-suc-NHS), a high-intensity absorption band appears at 1089 cm "1 , which corresponds to the stretching vibrations of the ⁇ - ⁇ - ⁇ -bond and is the main characteristic absorption band of the PEG molecule It should be noted that the absorption band of chitosan in the region of 1200–950 cm ⁇ 1 is significantly less intense than the absorption band of the ⁇ – ⁇ – ⁇ bond in PEG and makes only a small contribution to the total absorption intensity at 1089 cm "1 in PEG chitosan. The observed increase in the intensity of this band in the spectrum of PEG chitosan compared to the initial chitosan confirms the past modification.
  • the degrees of REOylation of the copolymers synthesized in the work were determined as 5, 15, and 25% with respect to the initial number of deacylated amino groups in chitosan (respectively, REO-chitosan-5, -15, -25), which corresponds to 25 ( ⁇ 2), 40 ( ⁇ 5) and 60 ( ⁇ 5) residues of the PEG-5000 molecule for each chitosan M molecule of 90-100 kDa.
  • the degree of modification was determined spectrophotometrically by the absorption of A 2 p. A number of pronounced peaks stand out on the spectrum: 360 nm, 280 nm, 253 nm and 217 nm. For analytical purposes, an absorption band of 217 nm was chosen as the most intense and narrowest.
  • the main potential binding site of anionic liposomes (DPPC / CL) with aminopolysaccharides (chitosan and its derivatives) by the electrostatic mechanism are phosphate groups of cardiolipin. Indeed, we have found that the most significant shifts of the absorption bands during the formation of complexes are observed for phosphate groups of liposomes.
  • the absorption band of the phosphate group in free liposomes is located at 1225 cm '1 , which corresponds to a high degree of hydration.
  • the phosphate groups of cardiolipin act as the main binding sites both in the case of chitosan and in the case of its conjugates.
  • the most significant shift of the absorption band is observed in the case of a complex with chitosan conjugates. This indicates that in the case of complexation with chitosan conjugates, a more effective electrostatic interaction between the phosphate groups of liposomes and the polymer is realized in comparison with unmodified chitosan.
  • Another potential binding site for chitosan derivatives with liposomes is the carbonyl group, which carries a partially negative charge on oxygen. It was found that complexation with both unmodified chitosan and conjugates leads to significant changes in the absorption region of the carbonyl groups. In the liposomes studied, the absorption band of the carbonyl group is located at 1739 cm "1. It is known that the absorption band of the carbonyl group groups in liposomes is sensitive to the degree of hydration at the lipid-water interface. Thus, from an independent experiment, it was found that with maximum hydration of liposomes, the absorption band of the carbonyl group is observed at 1725 cm "1. In the most dehydrated liposomes (in the dried film), the absorption band of the carbonyl group is shifted toward large wave numbers and amounts to 1745 cm " 1 .
  • the interaction with chitosan leads to a low-frequency shift of the absorption band from 1740 to 1735 cm-1, which corresponds to raising the degree of hydration of lipid carbonyl groups.
  • the considered band in the case of complexes of liposomes with chitosan, as well as free liposomes includes several components corresponding to different states of carboxyl groups.
  • ⁇ modified chitosan differs from the structure of the complex with chitosan conjugates.
  • liposomes with chitosan and its derivatives affects the state of hydration of electrostatic binding sites in liposomes - phosphate and carbonyl groups - due to interaction with deacylated amino groups of chitosan. It is important that the binding of the lipid membrane to chitosan conjugates is more effective than with unmodified chitosan.
  • the DLS method allows one to estimate the thickness of the layer formed by the polymer on the surface of liposomes based on the obtained radii of free liposomes and liposomes in combination with the polymer. It was found that the radius of liposomes not connected into a complex at low ionic strength is 60 ⁇ 2 nm. Complexation with PEG-chitosan and conjugate of chitosan with folic acid leads to an increase in particle size to 85 ⁇ 4 and 120 ⁇ 6 nm.
  • chitosan conjugates are able to interact with liposomes at both low and high ionic strength due to non-specific adsorption, since the particle size significantly exceeds that determined for free liposomes under the same conditions.
  • the inclusion of PEG-chitosan in the system ionic strength of 0.2 M leads to an increase in the radius of liposomes from 64 ⁇ 2 nm to 72 ⁇ 2 nm.
  • the increase in the size of liposomes at high ionic strength is 8 ⁇ 2 nm, which, although significantly lower than the increase observed at low ionic strength, is significant, since it significantly exceeds the measurement error.
  • nonspecific adsorption contributes to the formation and stabilization of the complex of liposomes with chitosan conjugates.
  • liposomes are not stable enough during storage, are prone to the formation of defects in the bilayer, to aggregation and oxidation, which limits their use in medicine as a carrier for drug delivery.
  • liposomes form strong complexes with aminopolysaccharides in a wide range of ionic strengths.
  • PEG-chitosan can significantly increase the stability of liposomes during storage and prevent their aggregation due to electrostatic repulsion of the polymer chains of the polyelectrolyte associated with liposomes.
  • the A549 cell line of non-small cell lung carcinoma of a person is characterized by a normal level of foltany receptors and seems to be a convenient system for evaluating antitumor activity.
  • the Saso-2 cell line of human colorectal adenocarcinoma is characterized by an excess of folate receptors on the surface and allows us to evaluate the effect of active targeting for systems with a folate address tag.
  • the MTT test is a convenient way to assess the toxicity of a drug.
  • the concentration of doxorubicin was equal to 1 micromol / liter.

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Abstract

L'invention concerne la biotechnologie et notamment des stabilisateurs pour suspensions liposomales et peut être utilisée dans des systèmes à usage pharmaceutique, y.c. ceux destinés à l'administration de médicaments. Le stabilisateur pour suspensions liposomales se présente comme une chitosane modifiée (un conjugué de chitosane) ayant la formule (C6O4H9NH2)m(C6O4H9NHX)n dans laquelle le substitutif du groupe aminé X est un polyéthylène glycol ou l'acide folique. Le meilleur résultat est obtenu lors de l'utilisation de chitosane avec un poids moléculaire de 15 à 120 kilodalton et un rapport m/n de 6 à 19. Le stabilisateur pour suspensions liposomales peut s'obtenir en mélangeant une solution modifiant le groupe aminé de chitosane de l'agent à une solution acide de chitosane et en portant le mélange obtenu à un pH de 7,5-8,0 puis en assurant le filtrage par dialyse face à une solution tampon. La solution d'agent modifiant le groupe aminé de chitosane (ou de l'agent modifiant) peut être représentée par une solution d'éther N-hydroxysuccinimidique de hémisuccinate de polyéthylène glycol dans du diméthylformamide ou diméthylsulfoxyde, ou une solution d'acide folique préalablement activé par une solution de carbodiimide.
PCT/RU2016/000491 2016-07-27 2016-07-27 Stabilisateur pour suspensions liposomales WO2018021927A1 (fr)

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Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN112544630A (zh) * 2020-11-27 2021-03-26 上海弗艾柏生物科技有限公司 次氯酸溶液稳定剂及应用

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1999001498A1 (fr) * 1997-07-03 1999-01-14 West Pharmaceutical Services Drug Delivery & Clinical Research Centre Limited Conjugue de polyethyleneglycol et de chitosane
CN102488658A (zh) * 2011-12-23 2012-06-13 华东理工大学 一种叶酸-羧甲基壳聚糖修饰的pH敏感紫杉醇纳米脂质体
RU2529179C1 (ru) * 2013-04-23 2014-09-27 Общество с ограниченной ответственностью "Уральский центр биофармацевтических технологий" Стабилизатор липосомальных суспензий и способ его получения

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1999001498A1 (fr) * 1997-07-03 1999-01-14 West Pharmaceutical Services Drug Delivery & Clinical Research Centre Limited Conjugue de polyethyleneglycol et de chitosane
CN102488658A (zh) * 2011-12-23 2012-06-13 华东理工大学 一种叶酸-羧甲基壳聚糖修饰的pH敏感紫杉醇纳米脂质体
RU2529179C1 (ru) * 2013-04-23 2014-09-27 Общество с ограниченной ответственностью "Уральский центр биофармацевтических технологий" Стабилизатор липосомальных суспензий и способ его получения

Non-Patent Citations (1)

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SOLODUKHINA N.M.: "Analiz opiatov, barbituratov i kannabinoidov metodom lateksnoi aggliutinatsii s ispolzovaniem funktsionalnykh polimernykh mikrosfer", DISSERTATSIYA NA SOISKANIE UCHENOI STEPENI KANDIDATA KHIMICHESKIKH NAUK, M., vol. 80, 2012, pages 34 *

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN112544630A (zh) * 2020-11-27 2021-03-26 上海弗艾柏生物科技有限公司 次氯酸溶液稳定剂及应用

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