IT202100023570A1 - METHOD FOR THE PREPARATION OF LIPID NANOPARTICLES - Google Patents
METHOD FOR THE PREPARATION OF LIPID NANOPARTICLES Download PDFInfo
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- IT202100023570A1 IT202100023570A1 IT102021000023570A IT202100023570A IT202100023570A1 IT 202100023570 A1 IT202100023570 A1 IT 202100023570A1 IT 102021000023570 A IT102021000023570 A IT 102021000023570A IT 202100023570 A IT202100023570 A IT 202100023570A IT 202100023570 A1 IT202100023570 A1 IT 202100023570A1
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- lipid nanoparticles
- nanoparticles
- trimyristin
- surfactant
- lipid
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- 239000002105 nanoparticle Substances 0.000 title claims description 52
- 238000000034 method Methods 0.000 title claims description 47
- 150000002632 lipids Chemical class 0.000 title claims description 40
- 238000002360 preparation method Methods 0.000 title claims description 13
- 239000000203 mixture Substances 0.000 claims description 22
- 239000004094 surface-active agent Substances 0.000 claims description 19
- 239000002047 solid lipid nanoparticle Substances 0.000 claims description 13
- 238000005119 centrifugation Methods 0.000 claims description 12
- 238000000746 purification Methods 0.000 claims description 11
- 239000007864 aqueous solution Substances 0.000 claims description 10
- 238000002523 gelfiltration Methods 0.000 claims description 10
- 239000011159 matrix material Substances 0.000 claims description 10
- 238000000926 separation method Methods 0.000 claims description 10
- 238000009472 formulation Methods 0.000 claims description 8
- 229920002307 Dextran Polymers 0.000 claims description 7
- 239000004064 cosurfactant Substances 0.000 claims description 7
- 229940079593 drug Drugs 0.000 claims description 7
- 239000003814 drug Substances 0.000 claims description 7
- 239000000839 emulsion Substances 0.000 claims description 7
- 239000007787 solid Substances 0.000 claims description 7
- 238000010438 heat treatment Methods 0.000 claims description 5
- 229920000136 polysorbate Polymers 0.000 claims description 5
- 238000001816 cooling Methods 0.000 claims description 4
- 239000002246 antineoplastic agent Substances 0.000 claims description 3
- 229940041181 antineoplastic drug Drugs 0.000 claims description 3
- 239000002736 nonionic surfactant Substances 0.000 claims description 3
- -1 sorbitan ester Chemical class 0.000 claims description 3
- JNYAEWCLZODPBN-JGWLITMVSA-N (2r,3r,4s)-2-[(1r)-1,2-dihydroxyethyl]oxolane-3,4-diol Chemical class OC[C@@H](O)[C@H]1OC[C@H](O)[C@H]1O JNYAEWCLZODPBN-JGWLITMVSA-N 0.000 claims description 2
- 229930195733 hydrocarbon Natural products 0.000 claims description 2
- 150000002430 hydrocarbons Chemical class 0.000 claims description 2
- 238000002156 mixing Methods 0.000 claims description 2
- 229950008882 polysorbate Drugs 0.000 claims description 2
- 229940121896 radiopharmaceutical Drugs 0.000 claims description 2
- 239000012217 radiopharmaceutical Substances 0.000 claims description 2
- 230000002799 radiopharmaceutical effect Effects 0.000 claims description 2
- 238000002270 exclusion chromatography Methods 0.000 claims 1
- DUXYWXYOBMKGIN-UHFFFAOYSA-N trimyristin Chemical compound CCCCCCCCCCCCCC(=O)OCC(OC(=O)CCCCCCCCCCCCC)COC(=O)CCCCCCCCCCCCC DUXYWXYOBMKGIN-UHFFFAOYSA-N 0.000 description 76
- 229940113164 trimyristin Drugs 0.000 description 38
- 239000004530 micro-emulsion Substances 0.000 description 12
- 238000002296 dynamic light scattering Methods 0.000 description 10
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 9
- 231100000135 cytotoxicity Toxicity 0.000 description 8
- 230000003013 cytotoxicity Effects 0.000 description 8
- 239000000975 dye Substances 0.000 description 8
- 239000012071 phase Substances 0.000 description 7
- 229920001213 Polysorbate 20 Polymers 0.000 description 6
- 230000007717 exclusion Effects 0.000 description 6
- 238000001825 field-flow fractionation Methods 0.000 description 6
- 239000000256 polyoxyethylene sorbitan monolaurate Substances 0.000 description 6
- 235000010486 polyoxyethylene sorbitan monolaurate Nutrition 0.000 description 6
- 238000004062 sedimentation Methods 0.000 description 6
- 238000010348 incorporation Methods 0.000 description 5
- BBJQPKLGPMQWBU-UHFFFAOYSA-N Palmitinsaeurecholesterylester Natural products C12CCC3(C)C(C(C)CCCC(C)C)CCC3C2CC=C2C1(C)CCC(OC(=O)CCCCCCCCCCCCCCC)C2 BBJQPKLGPMQWBU-UHFFFAOYSA-N 0.000 description 4
- BBJQPKLGPMQWBU-JADYGXMDSA-N cholesteryl palmitate Chemical compound C([C@@H]12)C[C@]3(C)[C@@H]([C@H](C)CCCC(C)C)CC[C@H]3[C@@H]1CC=C1[C@]2(C)CC[C@H](OC(=O)CCCCCCCCCCCCCCC)C1 BBJQPKLGPMQWBU-JADYGXMDSA-N 0.000 description 4
- 238000010790 dilution Methods 0.000 description 4
- 239000012895 dilution Substances 0.000 description 4
- 238000011068 loading method Methods 0.000 description 4
- 238000002844 melting Methods 0.000 description 4
- 230000008018 melting Effects 0.000 description 4
- 239000000693 micelle Substances 0.000 description 4
- 239000000243 solution Substances 0.000 description 4
- 239000000725 suspension Substances 0.000 description 4
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 3
- 229960000956 coumarin Drugs 0.000 description 3
- 238000004141 dimensional analysis Methods 0.000 description 3
- 238000000265 homogenisation Methods 0.000 description 3
- 239000002245 particle Substances 0.000 description 3
- 238000002076 thermal analysis method Methods 0.000 description 3
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 2
- 241000700157 Rattus norvegicus Species 0.000 description 2
- NWGKJDSIEKMTRX-AAZCQSIUSA-N Sorbitan monooleate Chemical compound CCCCCCCC\C=C/CCCCCCCC(=O)OC[C@@H](O)[C@H]1OC[C@H](O)[C@H]1O NWGKJDSIEKMTRX-AAZCQSIUSA-N 0.000 description 2
- 229930182558 Sterol Natural products 0.000 description 2
- 238000004458 analytical method Methods 0.000 description 2
- 230000015572 biosynthetic process Effects 0.000 description 2
- 239000012455 biphasic mixture Substances 0.000 description 2
- 230000000052 comparative effect Effects 0.000 description 2
- 238000001514 detection method Methods 0.000 description 2
- 230000000694 effects Effects 0.000 description 2
- 238000001990 intravenous administration Methods 0.000 description 2
- 239000007788 liquid Substances 0.000 description 2
- 238000004519 manufacturing process Methods 0.000 description 2
- VOFUROIFQGPCGE-UHFFFAOYSA-N nile red Chemical compound C1=CC=C2C3=NC4=CC=C(N(CC)CC)C=C4OC3=CC(=O)C2=C1 VOFUROIFQGPCGE-UHFFFAOYSA-N 0.000 description 2
- 239000003921 oil Substances 0.000 description 2
- 239000002243 precursor Substances 0.000 description 2
- 235000003702 sterols Nutrition 0.000 description 2
- 230000007704 transition Effects 0.000 description 2
- 150000003626 triacylglycerols Chemical class 0.000 description 2
- PVNIQBQSYATKKL-UHFFFAOYSA-N tripalmitin Chemical compound CCCCCCCCCCCCCCCC(=O)OCC(OC(=O)CCCCCCCCCCCCCCC)COC(=O)CCCCCCCCCCCCCCC PVNIQBQSYATKKL-UHFFFAOYSA-N 0.000 description 2
- 238000000825 ultraviolet detection Methods 0.000 description 2
- 231100000002 MTT assay Toxicity 0.000 description 1
- 238000000134 MTT assay Methods 0.000 description 1
- RJECHNNFRHZQKU-UHFFFAOYSA-N Oelsaeurecholesterylester Natural products C12CCC3(C)C(C(C)CCCC(C)C)CCC3C2CC=C2C1(C)CCC(OC(=O)CCCCCCCC=CCCCCCCCC)C2 RJECHNNFRHZQKU-UHFFFAOYSA-N 0.000 description 1
- 229920001214 Polysorbate 60 Polymers 0.000 description 1
- IYFATESGLOUGBX-YVNJGZBMSA-N Sorbitan monopalmitate Chemical compound CCCCCCCCCCCCCCCC(=O)OC[C@@H](O)[C@H]1OC[C@H](O)[C@H]1O IYFATESGLOUGBX-YVNJGZBMSA-N 0.000 description 1
- HVUMOYIDDBPOLL-XWVZOOPGSA-N Sorbitan monostearate Chemical compound CCCCCCCCCCCCCCCCCC(=O)OC[C@@H](O)[C@H]1OC[C@H](O)[C@H]1O HVUMOYIDDBPOLL-XWVZOOPGSA-N 0.000 description 1
- 238000010521 absorption reaction Methods 0.000 description 1
- 238000009825 accumulation Methods 0.000 description 1
- 239000004480 active ingredient Substances 0.000 description 1
- 239000008186 active pharmaceutical agent Substances 0.000 description 1
- 125000001931 aliphatic group Chemical group 0.000 description 1
- 230000004075 alteration Effects 0.000 description 1
- 239000008346 aqueous phase Substances 0.000 description 1
- 239000008280 blood Substances 0.000 description 1
- 210000004369 blood Anatomy 0.000 description 1
- 238000009835 boiling Methods 0.000 description 1
- 210000004556 brain Anatomy 0.000 description 1
- 210000004027 cell Anatomy 0.000 description 1
- RJECHNNFRHZQKU-RMUVNZEASA-N cholesteryl oleate Chemical compound C([C@@H]12)C[C@]3(C)[C@@H]([C@H](C)CCCC(C)C)CC[C@H]3[C@@H]1CC=C1[C@]2(C)CC[C@H](OC(=O)CCCCCCC\C=C/CCCCCCCC)C1 RJECHNNFRHZQKU-RMUVNZEASA-N 0.000 description 1
- 238000010835 comparative analysis Methods 0.000 description 1
- 235000014113 dietary fatty acids Nutrition 0.000 description 1
- 238000000113 differential scanning calorimetry Methods 0.000 description 1
- 238000007865 diluting Methods 0.000 description 1
- 238000005538 encapsulation Methods 0.000 description 1
- 239000000194 fatty acid Substances 0.000 description 1
- 229930195729 fatty acid Natural products 0.000 description 1
- 150000004665 fatty acids Chemical class 0.000 description 1
- 150000002191 fatty alcohols Chemical class 0.000 description 1
- 239000007850 fluorescent dye Substances 0.000 description 1
- 230000004927 fusion Effects 0.000 description 1
- 239000001963 growth medium Substances 0.000 description 1
- IPCSVZSSVZVIGE-UHFFFAOYSA-M hexadecanoate Chemical compound CCCCCCCCCCCCCCCC([O-])=O IPCSVZSSVZVIGE-UHFFFAOYSA-M 0.000 description 1
- 238000004128 high performance liquid chromatography Methods 0.000 description 1
- 238000011534 incubation Methods 0.000 description 1
- 230000003993 interaction Effects 0.000 description 1
- 239000000178 monomer Substances 0.000 description 1
- 210000000056 organ Anatomy 0.000 description 1
- 239000003960 organic solvent Substances 0.000 description 1
- 238000007911 parenteral administration Methods 0.000 description 1
- 239000000546 pharmaceutical excipient Substances 0.000 description 1
- 235000010482 polyoxyethylene sorbitan monooleate Nutrition 0.000 description 1
- 229920000053 polysorbate 80 Polymers 0.000 description 1
- 239000002244 precipitate Substances 0.000 description 1
- 238000001556 precipitation Methods 0.000 description 1
- 230000008569 process Effects 0.000 description 1
- 238000001542 size-exclusion chromatography Methods 0.000 description 1
- 230000002269 spontaneous effect Effects 0.000 description 1
- 150000003432 sterols Chemical class 0.000 description 1
- 238000003756 stirring Methods 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 239000006228 supernatant Substances 0.000 description 1
- 229960001947 tripalmitin Drugs 0.000 description 1
- 210000004881 tumor cell Anatomy 0.000 description 1
- 239000001993 wax Substances 0.000 description 1
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
- A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
- A61K9/50—Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals
- A61K9/51—Nanocapsules; Nanoparticles
- A61K9/5192—Processes
-
- 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
-
- 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
- A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
- A61K9/50—Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals
- A61K9/51—Nanocapsules; Nanoparticles
- A61K9/5107—Excipients; Inactive ingredients
- A61K9/5123—Organic compounds, e.g. fats, sugars
Description
Descrizione di Brevetto per Invenzione Industriale avente per titolo: Description of Patent for Industrial Invention having the title:
?METODO PER LA PREPARAZIONE DI NANOPARTICELLE LIPIDICHE?. ?METHOD FOR THE PREPARATION OF LIPID NANOPARTICLES?.
DESCRIZIONE DESCRIPTION
La presente invenzione si riferisce ad un metodo per la preparazione di nanoparticelle lipidiche. The present invention relates to a method for preparing lipid nanoparticles.
? noto e ampiamente diffuso l?impiego di nanoparticelle lipidiche in campo farmaceutico per la veicolazione di principi attivi farmaceutici. ? The use of lipid nanoparticles in the pharmaceutical field for the delivery of active pharmaceutical ingredients is known and widespread.
Con particolare riferimento al campo farmaceutico sono noti numerosi metodi per la preparazione di nanoparticelle lipidiche. With particular reference to the pharmaceutical field, numerous methods for the preparation of lipid nanoparticles are known.
Una delle tecniche pi? utilizzate per la produzione di nanoparticelle lipidiche ? quella dell?omogeneizzazione ad alta pressione, che pu? essere effettuata a caldo o a freddo. In entrambi i casi il farmaco viene dissolto o solubilizzato nella matrice lipidica fusa (5-10?C sopra la temperatura di fusione). Nella tecnica di omogeneizzazione a caldo la miscela ottenuta viene dispersa sotto agitazione in una soluzione acquosa di tensioattivo, precedentemente portata alla stessa temperatura dei lipidi. Si ottiene cos? una pre-emulsione che viene omogeneizzata tramite omogeneizzatori ad alta pressione e successivamente raffreddata per fare cristallizzare i lipidi ed ottenere nanoparticelle lipidiche solide. One of the techniques used for the production of lipid nanoparticles ? that of? homogenization at high pressure, which can? be done hot or cold. In both cases the drug is dissolved or solubilized in the molten lipid matrix (5-10°C above the melting temperature). In the hot homogenization technique, the mixture obtained is dispersed under stirring in an aqueous solution of surfactant, previously brought to the same temperature as the lipids. Is it obtained like this? a pre-emulsion which is homogenized using high pressure homogenizers and subsequently cooled to crystallize the lipids and obtain solid lipid nanoparticles.
La tecnica a caldo non pu? essere per? utilizzata per incorporare nelle nanoparticelle farmaci termolabili, che verrebbero degradati per effetto delle alte temperature, o idrofili, che potrebbero ripartirsi nella fase acquosa durante l?omogeneizzazione. The hot technique can not? be for? used to incorporate thermolabile drugs into nanoparticles, which would be degraded by the effect of high temperatures, or hydrophilic drugs, which could be repartitioned in the aqueous phase during homogenization.
Tale metodica ? stata descritta nel documento brevettuale EP0605497 e presenta numerosi inconvenienti, tra i quali qua annoverato il fatto che richiede l?utilizzo di strumenti complessi e costosi, oltre che l?uso di temperature elevate. This method? It has been described in the patent document EP0605497 and has numerous drawbacks, among which is the fact that it requires the use of complex and expensive tools, as well as the use of high temperatures.
A ci? si aggiunge che le elevate forze di cavitazione generate determinano l?alterazione del principio attivo veicolato. To there? it is added that the high cavitation forces generated determine the alteration of the active principle conveyed.
Un alternativo metodo di preparazione ? basato sulla formazione di microemulsioni a caldo come precursori delle nanoparticelle lipidiche. An alternative method of preparation? based on the formation of hot microemulsions as precursors of lipid nanoparticles.
Le microemulsioni sono miscele bifasiche stabili e trasparenti costituite da due liquidi immiscibili, acqua e olio, stabilizzate da un tensioattivo e da un cotensioattivo. In particolare, la dimensione della fase interna le rende idonee come precursori di sistemi nanoparticellari. Microemulsions are stable and transparent biphasic mixtures consisting of two immiscible liquids, water and oil, stabilized by a surfactant and a cosurfactant. In particular, the size of the internal phase makes them suitable as precursors of nanoparticle systems.
Tale metodo, descritto nel documento brevettuale US1993/5250236, consiste nella diluizione della microemulsione in acqua fredda al fine di romperla e causare la precipitazione delle particelle costituite dai lipidi solidificati. Tuttavia, anche tale metodo non ? privo di inconvenienti. This method, described in the patent document US1993/5250236, consists in diluting the microemulsion in cold water in order to break it and cause the particles formed by the solidified lipids to precipitate. However, even this method is not? free from drawbacks.
Infatti, uno degli svantaggi presentati dal suddetto metodo ? correlato alla diluizione della microemulsione iniziale che porta ad ottenere una sospensione diluita di nanoparticelle, a cui si aggiunge il fatto che tale metodo ? laborioso da eseguire su larga scala. In fact, one of the disadvantages presented by the aforementioned method ? related to the dilution of the initial microemulsion which leads to obtain a diluted suspension of nanoparticles, to which is added the fact that this method ? laborious to perform on a large scale.
Per ovviare almeno in parte a tali inconvenienti ? stato messo a punto un metodo di preparazione di nanoparticelle lipidiche, descritto nel documento brevettuale US2006/0292183, che consente di ottenere nanoparticelle lipidiche per semplice raffreddamento di una microemulsione olio in acqua. Tuttavia, questo metodo permette di ottenere una concentrazione di lipide impiegabile per la realizzazione di una microemulsione stabile a caldo e una sospensione di nanoparticelle a freddo, estremamente bassa pari a 0,2% p/v, riducendo notevolmente la possibilit? di caricamento del principio attivo. To overcome at least in part these drawbacks? A method for the preparation of lipid nanoparticles has been developed, described in the patent document US2006/0292183, which allows to obtain lipid nanoparticles by simply cooling an oil-in-water microemulsion. However, this method allows to obtain an extremely low lipid concentration of 0.2% w/v, which can be used for the production of a hot-stable microemulsion and a cold-stable suspension of nanoparticles, considerably reducing the possibility of loading of the active ingredient.
Un ulteriore metodo di preparazione di nanoparticelle lipidiche, descritto nel documento brevettuale WO 01/64328, consiste nel riscaldamento e nel raffreddamento di una miscela. Tale metodo ? basato sul principio dell?inversione di fase che richiede l?uso di tensioattivi non approvati dalla Food and Drug Administration (FDA) e che ne impediscono la somministrazione parenterale. A further method of preparing lipid nanoparticles, described in the patent document WO 01/64328, consists in heating and cooling a mixture. This method? based on the phase inversion principle which requires the use of surfactants not approved by the Food and Drug Administration (FDA) and which prevent parenteral administration.
Il compito principale della presente invenzione ? quello di escogitare un metodo per la preparazione di nanoparticelle lipidiche che consenta di preparare nanoparticelle solide in soluzione acquosa concentrata e stabilizzate da tensioattivi e cotensioattivi biocompatibili. The main task of the present invention ? that of devising a method for the preparation of lipid nanoparticles which allows the preparation of solid nanoparticles in concentrated aqueous solution and stabilized by biocompatible surfactants and co-surfactants.
Ulteriore scopo del presente trovato ? quello di escogitare un metodo per la preparazione di nanoparticelle lipidiche che consenta di semplificare notevolmente le operazioni di preparazione rispetto ai metodi di tipo noto. Altro scopo del presente trovato ? quello di escogitare un metodo per la preparazione di nanoparticelle lipidiche che consenta di superare i menzionati inconvenienti della tecnica nota nell?ambito di una soluzione semplice, razionale, di facile ed efficace impiego e dal costo contenuto. Altre caratteristiche e vantaggi della presente invenzione risulteranno maggiormente evidenti dalla descrizione di una forma di esecuzione preferita, ma non esclusiva, di un metodo per la preparazione di nanoparticelle lipidiche, illustrata a titolo indicativo, ma non limitativo, nelle unite tavole di disegni in cui: Another purpose of the present invention ? that of devising a method for the preparation of lipid nanoparticles which allows the preparation operations to be considerably simplified with respect to methods of the known type. Another object of the present invention ? that of devising a method for the preparation of lipid nanoparticles which allows the aforementioned drawbacks of the prior art to be overcome within the scope of a simple, rational, easy and effective to use and low-cost solution. Other characteristics and advantages of the present invention will become more evident from the description of a preferred, but not exclusive, embodiment of a method for the preparation of lipid nanoparticles, illustrated by way of example, but not in limitation, in the attached tables of drawings in which:
la figura 1 ? un grafico elaborato in funzione dell?analisi termica di nanoparticelle di trimiristina prodotto con il metodo in accordo con il presente trovato; figure 1 ? a graph elaborated as a function of the thermal analysis of trimyristin nanoparticles produced with the method according to the present invention;
la figura 2 mostra il grafico di confronto tra i frattogrammi con rivelazione UV di trimiristina 1, trimiristina 2 e trimiristina 3 prodotte con il metodo secondo il trovato; figure 2 shows the comparison graph between the fractograms with UV detection of trimyristin 1, trimyristin 2 and trimyristin 3 produced with the method according to the invention;
le figure 3-5 sono grafici rappresentativi rispettivamente del frattogramma FFF DLS delle nanoparticelle di trimiristina 1, trimiristina 2 e trimiristina 3; Figures 3-5 are representative graphs respectively of the FFF DLS fractogram of the nanoparticles of trimyristin 1, trimyristin 2 and trimyristin 3;
le figure 6 e 7 sono grafici a colonna rappresentativi dell?analisi comparativa realizzata relativamente all?efficacia di inglobamento e caricamento del colorante rispettivamente di Trimiristina 1, Trimiristina 2 e Trimiristina 3 a seguito di separazione per gel filtrazione e separazione per centrifugazione in destrano; figures 6 and 7 are column graphs representative of the comparative analysis carried out in relation to the efficacy of incorporation and loading of the dye respectively of Trimyristin 1, Trimyristin 2 and Trimyristin 3 following separation by gel filtration and separation by centrifugation in dextran;
la figura 8 ? un grafico a colonna relativo alla citotossicit? delle nanoparticelle lipidiche di trimiristina 2; the figure 8 ? a bar graph related to cytotoxicity? of the lipid nanoparticles of trimyristin 2;
la figura 9-12 sono grafici a colonna relativi allo studio comparativo inerente alla biodistribuzione delle nanoparticelle lipidiche marcate con 6-cumarina nei ratti Wistar dopo somministrazione endovenosa. Figure 9-12 are bar graphs of the comparative study regarding the biodistribution of 6-coumarin-labelled lipid nanoparticles in Wistar rats after intravenous administration.
Il presente trovato riguarda un metodo per la preparazione di nanoparticelle lipidiche solide. The present invention relates to a method for preparing solid lipid nanoparticles.
Si specifica che nell?ambito della presente trattazione con il termine ?nanoparticelle? si intendono particelle di dimensioni comprese tra 1 nm e 100 nm. It is specified that in the context of this discussion the term ?nanoparticles? refers to particles with dimensions between 1 nm and 100 nm.
Secondo il trovato, il metodo comprende la fase di miscelare in un unico contenitore una miscela comprendente una soluzione acquosa con una matrice lipidica solida e con almeno un tensioattivo non-ionico biocompatibile. According to the invention, the method comprises the step of mixing in a single container a mixture comprising an aqueous solution with a solid lipidic matrix and with at least one biocompatible non-ionic surfactant.
Nel seguito, con l?espressione ?matrice lipidica? si fa riferimento ad una matrice di natura lipofila, insolubile in acqua e solubile nei solventi organici, bassofondente e avente diversa natura chimica: paraffine, trigliceridi, cere, steroli, acidi grassi, alcooli grassi. In the following, with the expression ?lipidic matrix? reference is made to a lipophilic matrix, insoluble in water and soluble in organic solvents, low melting point and having a different chemical nature: paraffins, triglycerides, waxes, sterols, fatty acids, fatty alcohols.
La miscela lipidica solida comprende almeno uno tra trigliceridi, una miscela di esteri alifatici o sterolici. The solid lipid mixture comprises at least one of triglycerides, a mixture of aliphatic or sterol esters.
Preferibilmente, la suddetta miscela comprende idrocarburi. Preferably, the above mixture comprises hydrocarbons.
Vantaggiosamente, il tensioattivo ? un polisorbato. Advantageously, the surfactant ? a polysorbate.
Nel dettaglio, il tensioattivo ? scelto dall?elenco comprendente: Tween 20, Tween 40, Tween 60, Tween 80. In detail, the surfactant ? chosen from the list including: Tween 20, Tween 40, Tween 60, Tween 80.
In alternativa, il tensioattivo ? un derivato del sorbitano etossilato. Alternatively, the surfactant ? an ethoxylated sorbitan derivative.
Inoltre, la miscela comprende un cotensioattivo comprendente un estere del sorbitano. Additionally, the blend comprises a cosurfactant comprising a sorbitan ester.
Il cotensioattivo ? scelto dall?elenco comprendente: Span 40, Span 60, Span 80. The cosurfactant? chosen from the list including: Span 40, Span 60, Span 80.
Il metodo comprende: The method includes:
- la fase di riscaldare il contenitore a una temperatura di lavoro inferiore a 100?C ad ottenere un?emulsione; - the step of heating the container to a working temperature lower than 100°C to obtain an emulsion;
- la fase di raffreddare l?emulsione fino ad una temperatura inferiore a 30?C a ottenere nanoparticelle lipidiche solide di dimensione inferiore a 500 nm; - the step of cooling the emulsion down to a temperature lower than 30°C to obtain solid lipid nanoparticles having a size lower than 500 nm;
- la fase di separazione delle nanoparticelle lipidiche solide dall?emulsione. - the phase of separation of the solid lipidic nanoparticles from the emulsion.
La matrice lipidica ? presente in una concentrazione in peso/volume, valutata rispetto al peso complessivo della soluzione acquosa, compresa tra 0,3% e 5% e preferibilmente tra 0,5% e 4%. The lipid matrix? present in a weight/volume concentration, evaluated with respect to the total weight of the aqueous solution, comprised between 0.3% and 5% and preferably between 0.5% and 4%.
Vantaggiosamente, il tensioattivo ? presente in una concentrazione peso/volume, valutata rispetto al peso complessivo della soluzione acquosa, compresa tra 1% e 20% e preferibilmente tra 2% e 16%. Advantageously, the surfactant ? present in a weight/volume concentration, evaluated with respect to the total weight of the aqueous solution, comprised between 1% and 20% and preferably between 2% and 16%.
Preferibilmente, il cotensioattivo ? presente in una concentrazione in peso/volume, valutata rispetto al peso complessivo della soluzione acquosa, compreso tra 0,5% e 10%, preferibilmente tra 1% e 8%. Preferably, the cosurfactant ? present in a weight/volume concentration, evaluated with respect to the total weight of the aqueous solution, comprised between 0.5% and 10%, preferably between 1% and 8%.
? bene puntualizzare che durante la fase di riscaldare, la miscela viene riscaldata fino ad una temperatura superiore al punto di fusione del lipide e al cloud point del tensioattivo, cio? del Tween, ma inferiore al punto di ebollizione dell?acqua. ? good to point out that during the heating phase, the mixture is heated up to a temperature higher than the melting point of the lipid and the cloud point of the surfactant, the cio? of Tween, but lower than the boiling point of water.
In queste condizioni il Tween diventa insolubile in acqua, si separa dalla soluzione della medesima e interagisce intimamente con il cotensioattivo, cio? lo Span, e con un lipide fuso. Tale interazione avviene all?interno di un sistema dall?aspetto torbido in cui i componenti non acquosi della miscela si miscelano tra loro. Under these conditions, the Tween becomes insoluble in water, separates from the solution of the same and interacts intimately with the cosurfactant, ie? the Span, and with a molten lipid. This interaction takes place within a turbid-looking system in which the non-aqueous components of the mixture mix together.
A seguire, il metodo comprende una fase di purificazione delle nanoparticelle lipidiche solide. Subsequently, the method comprises a purification step of the solid lipid nanoparticles.
La fase di purificazione ? scelta dal gruppo comprendente: cromatografia a esclusione molecolare, sedimentazione e risospensione. The purification stage? selected from the group comprising: size exclusion chromatography, sedimentation and resuspension.
Vantaggiosamente, le nanoparticelle lipidiche solide presentano una dimensione compresa tra 40 nm e 500 nm. Advantageously, the solid lipid nanoparticles have a size of between 40 nm and 500 nm.
A seguire, la fase di separazione ? eseguita mediante gel filtrazione. Next, the separation phase? performed by gel filtration.
Preferibilmente, la separazione ? mediante separazione per centrifugazione in destrano. Preferably, the separation ? by centrifugation separation in dextran.
Il presente trovato riguarda, inoltre, l?uso di nanoparticelle lipidiche solide in formulazioni di farmaci a radiofrequenza, di farmaci antitumorali, di radiofarmaci, e in sensori. The present invention also relates to the use of solid lipid nanoparticles in formulations of radiofrequency drugs, anticancer drugs, radiopharmaceuticals, and in sensors.
In particolare, tali farmaci antitumorali sono farmaci per organi con massa. Si elencano qui di seguito esempi di formulazioni di nanoparticelle lipidiche solide. In particular, such anticancer drugs are organ drugs with mass. Examples of solid lipid nanoparticle formulations are listed below.
ESEMPIO 1 EXAMPLE 1
Formulazione di nanoparticelle lipidiche solide di trimiristina e colesteriloleato. Solid lipid nanoparticle formulation of trimyristin and cholesteryl oleate.
Si elencano nella seguente tabella (Tabella 1) diverse formulazioni di nanoparticelle lipidiche solide ottenute con il procedimento in accordo con il presente trovato e comprendenti un lipide scelto tra trimiristina, colesteril palmitato o tripalmitina. The following table (Table 1) lists various formulations of solid lipid nanoparticles obtained with the process according to the present invention and comprising a lipid selected from trimyristin, cholesteryl palmitate or tripalmithine.
Tabella 1 Table 1
Il lipide scelto tra Trimiristina e Colesteril palmitato ? stato miscelato con la soluzione acquosa, Tween 20 e Span 80. Tale soluzione ? stata riscaldata a 80?C, cio? una temperatura superiore al cloud point del Tween 20. The lipid chosen between Trimyristin and Cholesteryl palmitate? been mixed with the aqueous solution, Tween 20 and Span 80. This solution? been heated to 80?C, that is? a temperature above the Tween 20 cloud point.
Successivamente tale soluzione ? stata raffreddata a 60?C, il raggiungimento di tale temperatura consente la formazione di una microemulsione. Subsequently this solution? been cooled to 60°C, the achievement of this temperature allows the formation of a microemulsion.
Si specifica che nell?ambito della presente trattazione, con il termine ?microemulsione? si fa riferimento ad una miscela bifasica stabile e di colore trasparente, consistente in due liquidi immiscibili (acqua e olio) stabilizzati da un tensioattivo e in genere da un cotensioattivo. It is specified that in the context of this discussion, with the term ?microemulsion? we refer to a stable biphasic mixture of transparent colour, consisting of two immiscible liquids (water and oil) stabilized by a surfactant and generally by a cosurfactant.
Nel dettaglio, la microemulsione ? limpida e le nanoparticelle lipidiche sono sospese in essa. In detail, the microemulsion ? limpida and the lipid nanoparticles are suspended in it.
A seguire, la microemulsione viene raffreddata fino a temperatura ambiente, determinando la precipitazione di nanoparticelle. Subsequently, the microemulsion is cooled down to room temperature, resulting in the precipitation of nanoparticles.
ESEMPIO 2 EXAMPLE 2
Analisi termica delle nanoparticelle di trimiristina 2 Thermal analysis of trimyristin nanoparticles 2
L?analisi termica ? stata condotta mediante calorimetrica a scansione differenziale (DSC) sulle nanoparticelle in sospensione sia precedentemente che successivamente alla fase di purificazione. Nel dettaglio, la fase di purificazione ? stata eseguita per esclusione molecolare (tecnica di gel filtrazione con limite di esclusione di 100000 Da). The thermal analysis? was carried out by differential scanning calorimetry (DSC) on the nanoparticles in suspension both before and after the purification step. In detail, the purification phase? was performed by molecular exclusion (gel filtration technique with an exclusion limit of 100,000 Da).
In particolare, la gel filtrazione rimuove il Tween 20 in eccesso, libero e in micelle. In particular, gel filtration removes excess Tween 20, both free and in micelles.
Come osservabile in figura 1, la microemulsione prima della purificazione non mostra transizioni di fase alla luce del fatto che la temperatura di fusione del lipide ricade nell?intervallo di temperatura di esistenza e stabilit? della microemulsione. Invece, il campione purificato dalle micelle mostra una transizione di fusione tipica della trimiristina. As can be seen in figure 1, the microemulsion before purification does not show phase transitions in the light of the fact that the melting temperature of the lipid falls within the temperature range of existence and stability? of the microemulsion. Instead, the sample purified from the micelles shows a fusion transition typical of trimyristin.
ESEMPIO 3 EXAMPLE 3
Analisi dimensionale delle nanoparticelle di trimiristina L?analisi dimensionale delle nanoparticelle di trimiristina (Trimiristina 1, Trimiristina 2, Trimiristina 3) ? stata condotta con il Dynamic Light Scattering (DLS). Dimensional analysis of trimyristin nanoparticles The dimensional analysis of trimyristin nanoparticles (Trimyristin 1, Trimyristin 2, Trimyristin 3) ? was conducted with Dynamic Light Scattering (DLS).
Nella tabella sottostante (Tabella 2) si riportano i risultati ottenuti: The table below (Table 2) shows the results obtained:
Tabella 2 Table 2
L?analisi dimensionale ? stata ulteriormente approfondita con la Field Flow Fractionation (FFF) con rivelazione UV e DLS. The dimensional analysis? was further investigated with Field Flow Fractionation (FFF) with UV and DLS detection.
La figura 2 mostra il grafico di confronto tra i frattogrammi con rivelazione UV di trimiristina 1, trimiristina 2 e trimiristina 3. Figure 2 shows the comparison graph between the UV detection fractograms of trimyristin 1, trimyristin 2 and trimyristin 3.
I picchi corrispondenti alla Trimiristina 1, Trimiristina 2 e Trimiristina 3 sono stati ulteriormente analizzati con rivelazione DLS. The peaks corresponding to Trimyristin 1, Trimyristin 2 and Trimyristin 3 were further analyzed with DLS detection.
Le figure 3, 4 e 5 sono raffigurano il grafico comparativo dei frattogrammi ottenuti con FFF UV. Figures 3, 4 and 5 show the comparative graph of the fractograms obtained with FFF UV.
In particolare, in figura 3 ? osservabile il frattogramma FFF DLS delle nanoparticelle di trimiristina 1 caratterizzato da: In particular, in figure 3 ? observable the FFF DLS fractogram of the nanoparticles of trimyristin 1 characterized by:
- picco 1: 38 nm; - peak 1: 38 nm;
- picco 2: 70 nm; - peak 2: 70 nm;
- picco 3: 136 nm. - peak 3: 136 nm.
Parallelamente, in figura 4 ? osservabile il frattogramma FFF DLS delle nanoparticelle di trimiristina 2 caratterizzato da: In parallel, in figure 4 ? observable the FFF DLS fractogram of the nanoparticles of trimyristin 2 characterized by:
- picco 1: 59 nm; - peak 1: 59 nm;
- picco 2: 202 nm. - peak 2: 202 nm.
Ancora, in figura 5 ? osservabile il frattogramma FFF DLS delle nanoparticelle di trimiristina 3 caratterizzato da: Again, in figure 5 ? observable the FFF DLS fractogram of the nanoparticles of trimyristin 3 characterized by:
- picco 1: 72 nm; - peak 1: 72 nm;
- picco 2: 407 nm. - peak 2: 407 nm.
Dall?analisi di tali grafici di evince che le nanoparticelle di trimiristina 1, che presentano una polidispersione pi? alta rispetto alla lettura in batch del DLS, risultano composte da una miscela di tra popolazioni. Quelle di trimiristina 2 e 3 invece risultano costituite da una popolazione maggioritaria, con una limitata quantit? di nanoparticelle pi? piccole. From the analysis of these graphs it can be seen that the nanoparticles of trimyristin 1, which have a more polydispersion? higher than the batch reading of the DLS, are composed of a mixture of between populations. Those of trimiristina 2 and 3, on the other hand, are made up of a majority population, with a limited quantity? of nanoparticles pi? small.
La dimensione media delle nanoparticelle di trimiristina 1 ? stata ulteriormente analizzata mediante DLS, dopo essere state purificate con tecniche di esclusione molecolare (gel filtrazione e gel centrifugazione) e, successivamente, sedimentazione (centrifugazione dopo diluzione 1:1 con destrano 30%, seguita da risospensione in acqua del precipitato). La gel centrifugazione ha un limite di esclusione di 100000 Da; ci? significa che tale tipologia di tecnica esclude il Tween 20 in forma monomera e in micelle. The mean size of the nanoparticles of trimyristin 1 ? was further analyzed by DLS, after being purified with molecular exclusion techniques (gel filtration and gel centrifugation) and, subsequently, sedimentation (centrifugation after 1:1 dilution with 30% dextran, followed by resuspension of the precipitate in water). Gel centrifugation has an exclusion limit of 100,000 Da; There? it means that this type of technique excludes Tween 20 in monomer and micelle form.
Inoltre, la sedimentazione per centrifugazione separa le nanoparticelle da tutti i componenti idrosolubili. Furthermore, sedimentation by centrifugation separates the nanoparticles from all water-soluble components.
Tabella 3 Table 3
ESEMPIO 4 EXAMPLE 4
Caricamento e inglobamento di coloranti nelle nanoparticelle di trimiristina, tripalmitina e colesteril palmitato. Loading and encapsulation of dyes in nanoparticles of trimyristin, tripalmitin and cholesteryl palmitate.
Le nanoparticelle lipidiche sono state caricate con due coloranti fluorescenti lipofili: il rosso Nilo e la 6-cumarina. Lipid nanoparticles were loaded with two lipophilic fluorescent dyes: Nile red and 6-coumarin.
Tali coloranti sono stati aggiunti al contenitore precedentemente alla fase di riscaldare. These dyes were added to the container prior to the heating step.
Il colorante in eccesso ? stato successivamente rimosso in seguito a sedimentazione spontanea. The excess dye? subsequently removed following spontaneous sedimentation.
L?analisi dell?inglobamento ha tenuto conto di due parametri: The incorporation analysis took into account two parameters:
- capacit? di carico (cio? il rapporto tra il colorante veicolato e il lipide); - efficienza di inglobamento (cio? il rapporto tra il colorante inglobato nella matrice lipidica e quello totale presente nella formulazione). - capacity? loading (ie the ratio between the dye conveyed and the lipid); - incorporation efficiency (ie the ratio between the dye incorporated in the lipidic matrix and the total one present in the formulation).
Nel dettaglio, le tecniche di misurazione dell?efficienza di inglobamento del colorante nelle nanoparticelle sono: tecniche di esclusione molecolare (gel filtrazione, gel centrifugazione) e sedimentazione. In detail, the techniques for measuring the efficiency of incorporation of the dye in the nanoparticles are: molecular exclusion techniques (gel filtration, gel centrifugation) and sedimentation.
Allo scopo di valutare l?efficienza di inglobamento sono state analizzate le formulazioni di trimiristina 1, trimiristina 2 e trimiristina 3 caricate con 6-cumarina e rosso Nilo. In order to evaluate the absorption efficiency, the formulations of trimyristin 1, trimyristin 2 and trimyristin 3 loaded with 6-coumarin and Nile red were analysed.
Come osservabile in figura 6, la separazione mediante gel centrifugazione ha portato ad un?efficienza di inglobamento superiore a 90%. As can be seen in figure 6, the separation by gel centrifugation has led to an incorporation efficiency higher than 90%.
I risultati ottenuti mediante gel filtrazione e sedimentazione sono riportati nelle figure 6 e 7. In particolare, la capacit? di carico ? stata calcolata a seguito di centrifugazione in destrano 30% e risospensione delle nanoparticelle di trimiristina e colesteril palmitato caricate con 6-cumarina. Successivamente, sono stati prelevati 100 microlitri delle nanoparticelle lipidiche sospese e, successivamente, sono state diluite in 900 microlitri di etanolo al fine di estrarre il colorante. Qui di seguito (Tabella 4) si riportano i risultati ottenuti. The results obtained by gel filtration and sedimentation are shown in figures 6 and 7. In particular, the capacity? of load ? was calculated following centrifugation in 30% dextran and resuspension of nanoparticles of trimyristin and cholesteryl palmitate loaded with 6-coumarin. Subsequently, 100 microliters of the suspended lipid nanoparticles were collected and subsequently diluted in 900 microliters of ethanol in order to extract the dye. The results obtained are reported below (Table 4).
Tabella 4 Table 4
Dai suddetti dati, ? evidente come il Colesteril palmitato mostra una capacit? di carico sorprendentemente maggiore rispetto alla trimiristina. From the aforementioned data, ? evident as the Colesteril palmitate shows a capacity? surprisingly higher load than trimiristin.
ESEMPIO 5 EXAMPLE 5
Citotossicit? delle nanoparticelle di trimiristina 2. Cytotoxicity? of trimyristin nanoparticles 2.
La citotossicit? ? stata studiata su linee cellulari tumorali con il saggio MTT dopo 72 ore di incubazione (figura 8). Cytotoxicity? ? was studied on tumor cell lines with the MTT assay after 72 hours of incubation (figure 8).
Infatti, sebbene gli eccipienti utilizzati per la preparazione delle nanoparticelle siano sicuri e biocompatibili, i tensioattivi, a seguito di lunga esposizione sulle cellule possono causare citotossicit?. Pertanto, ? stato considerato l?effetto del metodo di purificazione dal tensioattivo (Tween 20) sulla citotossicit? dopo 72 ore di esposizione. La purificazione ? avvenuta tramite le metodiche descritte nell?esempio 3. In fact, although the excipients used for the preparation of the nanoparticles are safe and biocompatible, the surfactants can cause cytotoxicity following long exposure on the cells. Therefore, ? the effect of the surfactant purification method (Tween 20) on the cytotoxicity? after 72 hours of exposure. The purification ? occurred through the methods described in example 3.
Come si pu? notare in figura 8, la tecnica di purificazione influisce notevolmente sulla citotossicit? delle nanoparticelle lipidiche. How can you? note in figure 8, the purification technique greatly affects the cytotoxicity? of lipid nanoparticles.
La gel filtrazione ?, infatti, in grado di assicurare la minore citotossicit?. La purificazione per centrifugazione con destrano 30% e risospensione consente di minimizzare la citotossicit? soltanto dopo diluizione 1:200 del campione in terreno di coltura. Gel filtration is, in fact, capable of ensuring the least cytotoxicity. Does purification by centrifugation with 30% dextran and resuspension minimize cytotoxicity? only after 1:200 dilution of the sample in culture medium.
Ci? fa supporre che la metodica della gel filtrazione sia il pi? efficace nel rimuovere il tensioattivo. Al contrario, la gel centrifugazione sembra non funzionare a causa del range di esclusione molecolare utilizzato (6000 Da), che non consente di separare le micelle di tensioattivo dalle nanoparticelle. There? suggests that the method of gel filtration is the pi? effective in removing surfactant. On the contrary, gel centrifugation does not seem to work due to the molecular exclusion range used (6000 Da), which does not allow to separate the surfactant micelles from the nanoparticles.
ESEMPIO 6 EXAMPLE 6
Biodistribuzione delle nanoparticelle lipidiche marcate con 6-cumarina nei ratti Wistar (250g) dopo somministrazione endovenosa. Biodistribution of 6-coumarin-labelled lipid nanoparticles in Wistar rats (250g) after intravenous administration.
Sono state utilizzate le seguenti formulazioni (Figure 9-12): The following formulations were used (Figures 9-12):
Tabella 5 Table 5
I tessuti sono stati omogenati 1:4 con acqua e il sangue centrifugato a 4000 rpm. Plasma e omogenati sono stati diluiti 1:4 con metanolo e centrifugati. Il surnatante ? stato successivamente iniettato in HPLC. The tissues were homogenized 1:4 with water and the blood was centrifuged at 4000 rpm. Plasma and homogenates were diluted 1:4 with methanol and centrifuged. The supernatant? was subsequently injected into HPLC.
Non sembrano esserci differenze nella biodistribuzione di nanoparticelle formulate con lipidi o tensioattivi diversi. Sembra esserci influenza del metodo di purificazione delle nanoparticelle sulla loro biodistribuzione: le particelle purificate con destrano 30% presentano un significativo aumento dell?accumulo a livello cerebrale; ci? ? riconducibile alla maggiore concentrazione di tensioattivo residuo presente in sospensione. There appear to be no differences in the biodistribution of nanoparticles formulated with different lipids or surfactants. There seems to be an influence of the nanoparticle purification method on their biodistribution: the particles purified with 30% dextran show a significant increase in accumulation in the brain; There? ? attributable to the higher concentration of residual surfactant present in the suspension.
Si ? in pratica constatato come l?invenzione descritta raggiunga gli scopi proposti. Yes ? in practice it has been observed that the described invention achieves the proposed aim and objects.
In particolare, si sottolinea che il particolare accorgimento di prevedere una miscela comprendente una soluzione acquosa con una matrice lipidica solida e con almeno un tensioattivo non-ionico biocompatibile inserita all?interno di un solo contenitore, consente di ottenere nanoparticelle lipidiche solide concentrate, evitando diluizioni. In particular, it is emphasized that the particular trick of providing a mixture comprising an aqueous solution with a solid lipid matrix and with at least one biocompatible non-ionic surfactant inserted inside a single container, allows to obtain concentrated solid lipid nanoparticles, avoiding dilutions .
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