WO2018109690A1 - Production de nanoparticules lipidiques par synthèse par micro-ondes - Google Patents

Production de nanoparticules lipidiques par synthèse par micro-ondes Download PDF

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WO2018109690A1
WO2018109690A1 PCT/IB2017/057900 IB2017057900W WO2018109690A1 WO 2018109690 A1 WO2018109690 A1 WO 2018109690A1 IB 2017057900 W IB2017057900 W IB 2017057900W WO 2018109690 A1 WO2018109690 A1 WO 2018109690A1
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lipid
microwave
nanoparticles
process according
microwave tube
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PCT/IB2017/057900
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English (en)
Portuguese (pt)
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José Lamartine SOARES SOBRINHO
Suellen MELO TIBÚRCIO CAVALCANTI DUARTE COELHO
Maria De La Salette DE FREITAS FERNANDES HIPÓLITO REIS DIAS RODRIGUES
Cláudia Daniela OLIVEIRA DE LACERDA NUNES PINHO
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Universidade Do Porto
Universidade Federal De Pernambuco - Ufpe
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Publication of WO2018109690A1 publication Critical patent/WO2018109690A1/fr

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    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01J—CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
    • B01J13/00—Colloid chemistry, e.g. the production of colloidal materials or their solutions, not otherwise provided for; Making microcapsules or microballoons
    • 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

Definitions

  • the present invention is in the field of nanotechnology, specifically in the technology of producing lipid nanoparticles, for medicinal (therapeutic and / or diagnostic), cosmetic and food purposes. It concerns a simple, fast and economical process of obtaining lipid nanoparticles by a new microwave preparation method.
  • LNPs Lipid nanoparticles
  • Solid lipid nanoparticles appeared in the early 1990s (H. Muller et al.,
  • LNPs are generally composed of a physiological or physiologically related lipid matrix and characterized by their versatility, biocompatibility and biodegradability (Das and Chaudhury, 2011, Battaglia and Gallarate, 2012, Pardeike et al., 2009). Lipids are materials that can be degraded by natural processes such as enzymatic activity.
  • the excipients that make up the LNPS matrix are generally recognized as safe (GRAS) (Severino et al., 2012, Pardeike et al., 2009).
  • the lipids used may be triglycerides (example: tristrearin), partial glycerides (example: Imwitor), fatty acids (examples: stearic acid and palmitic acid), steroids (example: cholesterol) and waxes (example: cetyl palmitate) (Mukherjee et al., 2009).
  • Various emulsifying agents and combinations thereof have been used to stabilize lipid dispersions.
  • LNPS have other circulating advantages compared to other colloidal drug delivery systems, including improved kinetic stability, controlled drug release, low toxicity, high drug payload, and the ability to encapsulate lipophilic and hydrophilic drugs (Das and Chaudhury,
  • LNPs have been investigated for various pharmaceutical applications and include various types of administration, such as parenteral (Bondi et al., 2007, Brioschi et al., 2007, Wissing et al., 2004) (Blasi et al. 2007). , perorai (Muller et al., 2006, Martins et al., 2007, Sarmento et al., 2007, Yuan et al., 2007), dermally (Muller et al., 2002) (Priano et al.
  • lipid nanoparticles have become very attractive to the cosmetic industry (Pardeike et al., 2009).
  • Hot and cold high pressure homogenization In high pressure homogenization a particle dispersion is driven at high pressure (100-2000 bar) through a narrow cavity (few micrometers) and accelerated over a short distance at high speed ( about 100 km / h) to meet a barrier. The collision with the barrier enables the formation of small diameter nanoparticles (Mehnert and Mder, 2001). Disadvantages - hot homogenization: Induction of drug degradation by temperature; partitioning effect; complexity of crystallization. Disadvantages - Cold Homogenization: Large particle sizes and wider size distribution; It does not prevent thermal exposure, but minimizes.
  • High Shear Homogenization This method includes fusion of lipids and formation of an emulsion using ultra-turrax and / or sonication.
  • Several parameters influence the particle size obtained such as emulsification time, stirring and cooling rate.
  • Disadvantages Potential metal contamination; wider particle size distribution; physical instability as well as particle growth under storage.
  • Microemulsion technique Preparation by stirring an optically clear mixture at 65 - 70 ° C, comprising: a low melting fatty acid, emulsifier, co-emulsifier and water. This hot microemulsion is immediately dispersed in cold water (2-4 ° C) under stirring. Disadvantages: Need to remove excess water (by ultracentrifugation, lyophilization or dialysis); use of high concentrations of surfactants and co-surfactants.
  • Microwave-assisted microemulsion technique Similar to conventional microemulsion technique. The difference is that the heating step is performed in a microwave and already with all the constituents of the formulation. The microemulsion formed is immediately dispersed in cold water (2-4 ° C) under agitation to form the nanoparticles. Disadvantages: Need to remove excess water (by ultracentrifugation, lyophilization or dialysis); use of high concentrations of surfactants and co-surfactants.
  • Solvent evaporation Lipids are dissolved in an immiscible organic solvent (eg chloroform) and the solution will be emulsified in an aqueous phase with co-solvent. After evaporation of the organic solvent, the lipid will precipitate forming the nanoparticles.
  • an immiscible organic solvent eg chloroform
  • Residual Organic Solvent very dilute dispersions; produces microparticles and not nanoparticles.
  • Solvent Diffusion Lipids are dissolved in a miscible organic solvent (eg acetone) and the solution will be mixed in an aqueous phase with surfactant. Then the organic solvent will be evaporated.
  • a miscible organic solvent eg acetone
  • Disadvantages Residual Organic Solvent; difficulty in producing the particles on a large scale.
  • Double Emulsion An aqueous solution is emulsified in a previously melted lipid or lipid mixture to produce a primary w / o emulsion and is stabilized by surfactants added to the aqueous phase. Thereafter the primary emulsion will be dispersed in a second surfactant solution under constant stirring, forming a double w / o / w emulsion. Disadvantages: Low lipid content; difficult stability; long and multistep process.
  • Solvent Injection (Displacement): The lipid or lipid mixture is solubilized in a semi-polar, water-soluble solvent. The organic phase is rapidly injected under constant agitation into the aqueous phase containing the surfactant. Thus lipid nanopathules precipitate due to the distribution of the solvent to the aqueous phase. Disadvantages: Difficult solvent removal; need for lyophilization or evaporation processes under reduced pressure; low lipid content.
  • a lipid / oil phase is diffused through the pores of a membrane into a tangentially flowing aqueous phase, forming droplets. Oil droplets crystallize to form lipid particles. Disadvantages: Saturation of the pores of the membrane, which lead to its obstruction; Frequent cleaning and membrane replacement procedure.
  • Coacervation technique Lipid nanoparticles are formed from a micellar solution of alkaline salts in the presence of a stabilizing polymeric agent. Acidification by a coacervent solution leads to a drop in pH, causing proton exchange and consequent lipid precipitation. Disadvantages: Method not suitable for encapsulation of pH sensitive drugs.
  • Phase inversion temperature technique Spontaneous inversion of an o / w emulsion to a w / o type emulsion caused by heat treatment (through heating / cooling cycles). Crystallization of lipids results from the breakdown of the emulsion due to the irreversible shock caused by rapid cooling. Disadvantages: Particle aggregation; emulsion instability; Different excipients influence the phase inversion behavior.
  • Spray Drier Lipid and drug are dissolved in an organic solvent (eg chloroform). The solution is then sprayed into an apparatus in which the continuous flow of hot air rapidly evaporates the solvent from the sprayed droplets to dry particles.
  • organic solvent eg chloroform
  • lecithin is used together with lipid.
  • sray-congealing technique Disadvantages: Applied to obtain microparticles and not nanoparticles.
  • US20060024374A1 (Gasco et al., 2006a, Gasco et al., 2006b) describes solid lipid nanoparticle formulations for the treatment of ophthalmic diseases suitable for topical ocular and systemic administration, with a mean diameter of 50 and 400 nm. These nanoparticles being obtained by the microemulsion technique.
  • EP2413918A1 (Padois et al., 2012) relates to the suspension of solid lipid nanoparticles in an aqueous phase with the encapsulated minoxidil drug prepared by high pressure homogenization technique.
  • US20110171308A1 reports a pH-sensitive solid compound used for oral preparations and a method of preparation thereof. It is pH sensitive and can increase the absorption of drugs in the gastrointestinal tract or improve other performances.
  • the method of preparation is reported as novel and uses solvent to dissolve the pH sensitive polymer and drug with subsequent solvent removal.
  • CN102151250A describes a new method for preparing
  • Lipid nanoparticles characterized by 5 steps: (1) dissolution of lipid components, drug and the surfactant may be included in water-miscible organic solvent, corresponding to the oil phase; (2) hydrophilic compounds dissolved in water to form an aqueous phase; (3) then the appropriate oil volume is injected into the stirring aqueous phase in an appropriate volume ratio to obtain a solid dispersion of nanoparticles; (4) the dispersion is lyophilized to remove solvent and deliver a dry product; (5) Finally, it is hydrated to obtain the lipid nanoparticles.
  • Lipid nanostructures characterized by 6 steps: (1) vegetable oil and a suitable proportion fatty acid are mixed to form the oil phase; (2) Span emulsifier in appropriate proportion is added to the oil phase; (3) this mixture is heated to 60-80 ° C, a fat-soluble drug is added, and the water at the same temperature with subsequent use of the high shear homogenizer; (4) the polysorbate emulsifier dissolved in water and heated is added under stirring; (5) the preparation is subjected to ultrasound; (6) Finally, freeze-drying.
  • thermolabile nanoparticles consisting of biocompatible materials such as lipids and biopolymers.
  • a prototype aerosol system is described for single step production of these nanoparticles.
  • - BR1020140173161A2 (Rigon; et al., 2016) describes a process of obtaining solid lipid nanoparticles with trans-resveratrol (RES) by sonication using pegylated lipid, as well as the nanoparticles obtained and their use in antitumor therapy of melanoma.
  • RES trans-resveratrol
  • CN101890170A et al., 2010 refers to the formulation technology of
  • the method presented herein makes it possible to obtain SLN and NLC type lipid particles using the microwave reactor only, and it is possible to produce lipid particles in a very short time (preferably 5-20 minutes).
  • the method is robust, reproducible and allows to control particle characteristics such as particle size by adjusting some factors such as process time, temperature and applied power.
  • the present invention consists in the process of obtaining lipid nanoparticles, especially of the NLC type (nanostructured lipid carriers), by one-pot technique performed solely by microwave equipment.
  • lipid or lipid mixture the constituents are added: the lipid or lipid mixture, surfactant (s), if applicable, co-sufactor (s), aqueous solution and the active compound (s) for therapeutic and / or preventive and / or nutritional and / or cosmetic and / or diagnostic, and subjected to heating at or above the melting temperature of the lipid constituents for a given time (1 to 60 minutes) and agitation (low, medium or high).
  • lipid constituents, surfactant (s) and, if applicable, co-surfactant (s) and active compound (s) are added to the microwave tube; This microwave tube is subjected to heating at or above the melting temperature of the lipid constituents for a specified time (1 to 60 minutes) and stirring (low, medium or high). Afterwards the aqueous phase is added to the same tube which is then re-heated at or above the melting temperature of the lipid constituents for a given time (1 to 60 minutes) and stirring (low, medium or high).
  • the nanoemulsions are already obtained by letting them cool - with or without stirring, with or without thermal shock - until reaching room temperature for the solidification of the lipid matrix, with the consequent formation of the lipid nanoparticles themselves.
  • the invention features a closed system, which means less human manipulation - handling of hazardous substances is minimized, less error passivity and thus greater reproducibility.
  • batch processes have inherent risks of batch-to-batch variation, thus requiring careful and complex procedures and controls, continuous processes are typically preferred in the pharmaceutical and chemical industry over batch processes. Continuous processes can lower the cost of production by requiring less space, labor and resources, as well as providing high efficiency and better quality of the desired product compared to a batch process. As such, it would be desirable to provide a continuous process for nanoparticle formulation (ICH, 2000, ICH, 2009a, ICH, 2009b).
  • the present invention circumvents yet other drawbacks such as degradation of sonication energy sensitive active compounds and titanium detachment from the sonication tip inherent in the High Shear Homogenization technique. Additionally, it makes it possible to avoid the isolated step of conventional heating of the aforementioned technique and High Pressure Hot Homogenization, as well as circumvent problems such as high sample stress, low yield, relatively low sample volumes. high requirements and the need for special know-how.
  • microwave microwave
  • the lipid nanoparticles produced by the process of the present invention are within gauge scale, have moderate zeta potentials, and acceptable range polydispersion.
  • the magnitude of the zeta potential in all cases is high enough to provide good physical stability of the nonionic surfactant stabilized systems as used in this invention.
  • FIGURE 1 Process of production of lipid nanoparticles in a single step may or may not have thermal shock and agitation.
  • FIGURE IA Scheme of the invention in single step.
  • FIGURE 1B Flowchart of the invention in single step.
  • FIGURE 2 Two-step lipid nanoparticle production process with or without thermal shock and agitation.
  • FIGURE 2A Scheme of the invention in two steps.
  • FIGURE 2B Flowchart of the invention in two steps.
  • FIGURE 3 Ishikawa diagram for selection of the most critical factors considered development of the new microwave lipid nanoparticle process - bolding the most relevant factors.
  • FIGURE 4 Pareto plots of standard effects for (4A) loading capacity, (4B) polydispersion "PI” and (4C) mean particle size responses. Optimized development of zidovudine formulation.
  • FIGURE 5 Response Surfaces for each of three responses considered in the zidovudine formulation development study.
  • Response load capacity (5A) polydispersity (5B) and average particle size (SC).
  • FIGURE 6 Pareto plots for the polydispersion response "PI” (6A) and average particle size “Size” (6B).
  • FIGURE 7 TEM images of the selected formulation of zidovudine and nevirapine - Figure 7A with zidovudine drug and Figure 7B with nevirapine drug.
  • FIGURE 8 Graph of the in vitro release study of zidovudine optimized formulations.
  • FIGURE 9 Formulation stability study graph. Bars represent mean particle size in nm and circular markers represent zeta potential in mv. In this study the formulations were stored as aqueous suspensions at 4 ° C and protected from light.
  • FIGURE 9A Stability study of "Example 14" zidovudine drug.
  • FIGURE 9B Stability study of "Example 15", nevirapine drug. DETAILED DESCRIPTION OF THE INVENTION
  • the present invention relates to a one-pot microwave synthesis process of solid lipid nanoparticles with an average diameter of 30 to 900 nm, more preferably 60 to 300 nm characterized in that the synthesis of the nanoparticles is performed by heating with micro under 90 ° C with continuous simultaneous stirring followed by cooling.
  • the process is characterized in that the synthesis of lipid nanoparticles comprises:
  • the process is characterized in that the heating is carried out at or above the melting temperature of the lipid constituents for 1 to 60 minutes.
  • the process has a single heating step and is characterized in that the heating is carried out at a temperature of 5 to 20 ° C above the melting temperature of the lipid constituents for 5 to 20 minutes.
  • the process has two heating steps and characterized in that heating is carried out at a temperature of 5 to 15 ° C above the melting temperature of the lipid constituents for 5 to 15 minutes.
  • the process is characterized in that the cooling is performed without constant agitation; with constant stirring to room temperature; or by constant stirring with thermal shock, for partial cooling or to room temperature, by cooling programmed by the microwave itself, by ice bath or a combination thereof.
  • the process is characterized in that agitation is of moderate to vigorous intensity, preferably 900 rpm.
  • stirring is effected by adding a magnetic bar to the microwave tube, which is as large as possible to allow greater homogeneity and more vigorous stirring.
  • the process is characterized in that the final volume of the constituents inserted in the microwave tube is preferably 1/7 to 1/2 the volume of the tube to ensure complete and controlled homogenization during the process. stirring.
  • the process is characterized in that the lipid constituent consists of one or more components selected from the group of fatty acids, steroids, waxes, monoglycerides, diglycerides, triglycerides and optionally phospholipids.
  • the process is characterized in that the surfactant or surfactant assembly is of the nonionic type.
  • the process is characterized in that the co-surfactant consists of one or more components selected from the group butanol, hexanediol, propylene glycol, hexanol, butyric and hexanoic acid, phosphoric acid esters, benzyl alcohol.
  • the process is characterized in that the aqueous solution has an appropriate pH, preferably between 5 and 7, adjustable with buffer solutions, and optionally contains salts, preservatives, antioxidants, stabilizers and markers.
  • the process is characterized in that the lipid or lipid group is comprised in a ratio of 1 to 20%, preferably 1.5 to 8%, of the total weight; 70 to 96% aqueous solution, preferably 80 to 95.5%, of the total weight; surfactants from 1 to 20%, preferably from 2 to 15%, of the total weight; co-surfactants between 0 and 15%, preferably 0 to 10%, of the total weight; and, the active compounds are from 0 to 50% of the lipid constituents, preferably from 1 to 15%.
  • the process is characterized by incorporating binders or markers, specific to each formulation, on the surface of lipid nanoparticles.
  • the process is characterized in that solid lipid nanoparticles having an average diameter of 30 to 900nm, preferably 60 to 300nm, with polydispersion of 0.05 to 0.5, preferably 0, are obtained. , 1 to 0.3, and zeta potential of 10 to 70 mv, preferably 20 to 40 mv.
  • the invention further relates to lipid nanoparticles obtained by the process described above, preferably lipid nanoparticles having an average diameter of 30 to 900 nm, preferably 60 to 300 nm, with polydispersion of 0.05 to 0.5, preferably of 0, 1 to 0.3, and zeta potential of 10 to 70 mV, preferably 20 to 40 mV.
  • the process of the invention has proven to be a surprisingly simple technique for producing lipid nanoparticles which contain active compound (s) which have at least one effective physiological and / or diagnostic effect.
  • the technology of the present invention allows one-pot manufacture of said particles in one or two steps - but in the same reaction tube and same equipment - and, if desired, with active compound (s) charged by these nanostructures.
  • This technique allows the manufacture of small as well as large quantities, ie it is scalable. Contrary to the state of the art nanotechnology, the technique can be carried out in a very simple and fast way, enabling the manufacture by people without know-how in the area, as well as the problem of handling hazardous substances is solved. Unstable substances (eg substances sensitive to sonication energy or organic solvents) as well as substances with distinct physicochemical properties may be inserted into lipid-based nanoparticles.
  • the magnetic bar added to the microwave tube, in which the constituents of the preparation are contained, should preferably be as large as possible with respect to the diameter of the microwave tube, so as to allow greater homogeneity and more vigorous agitation leading to better values. polydispersion and smaller particle sizes of nanoemulsions and hence nanoparticles.
  • the final volume of the constituents inserted into the microwave tube must be controlled and sufficient, preferably from ⁇ to 1 ⁇ 2, to ensure complete and controlled homogenization during the stirring process. Very large or very small volumes compromise the homogenization and consequently the quality parameters of lipid nanoparticles.
  • the nanoparticles obtained by this invention have average sizes between 30 and 900 nm, preferably between 60 and 300 nm; a polydispersion of from 0.05 to 0.5, preferably from 0.1 to 0.3; and the zeta potential has a modular value between 10 and 70 mv, preferably between 20 and 40 mv.
  • the encapsulation efficiency and load capacity, image microscopy analysis, in vitro release study and stability were very similar to the traditional technique "Hot Homogenization by Ultrasonication", by making a comparative.
  • the process of this invention has delivered profiles superior to those of the traditional technique. These aspects depend heavily on formulation for formulation - preselected excipients, compound to be encapsulated, and adjustments to the critical process factors presented here for optimization for each formulation.
  • the method described in the present invention has multiple advantages.
  • the present method enables the production of nanoparticles in a larger size range, between 30 and 900 nm, which is much more interesting for drug delivery systems.
  • the method described by Dunn et al. 2017 first requires the formation of a lipid film on the tube walls, with subsequent addition of water, needs to use organic solvents, chloroform, something our method does not use. Additionally it presupposes the use of very high temperatures, over 200 oc, which in an aqueous environment is only possible with low pressure, so that the water does not boil, therefore the energy consumption is much higher. Additionally, the present methodology also permits the obtainment of NLC.
  • the preparation of the nanoparticles mentioned in the invention may not occur in a single step, preferably, or in two steps, in some cases, for example, of very lipophilic active compounds.
  • One-step preparation In a suitable microwave tube, the lipid or lipid mixture, surfactant (s) and optionally co-sufactant (s), aqueous solution (with appropriate pH and or other required constituent) are added, and may contain the active compound (s) for therapeutic and / or preventative and / or nutritional and / or cosmetic and / or diagnostic purposes which may have lipophilic or hydrophilic characteristics.
  • a magnetic bar is inserted and then sealed with the specific microwave tube cap.
  • This tube with the preparation is then placed in the microwave reactor (CEM Discover SP ® ) and subjected to a temperature equal to or greater than the melting temperature of the lipid constituents, preferably 5 to 20 higher than the melting temperature of the lipid constituents. and at low, medium or high, preferably high (approximately 900 rmp) magnetic stirring, and at a time of 1 to 60 minutes, preferably 5 to 20 minutes.
  • 2-Step Preparation In a suitable microwave tube the lipid or lipid mixture, surfactant (s) and optionally co-sufactant (s) are placed, and may further contain the active compound (s). A magnetic bar is inserted and then sealed with the specific microwave tube cap. This tube with the preparation is then placed in the microwave reactor (CEM Discover SP ® ) and subjected to a temperature equal to or greater than the melting temperature of the lipid constituents, preferably 5 to 15 ° C above the melting temperature of the lipid constituents, and at low, medium or high, preferably high (approximately 900 rmp) magnetic stirring, and at a time of 1 to 60 minutes, preferably 5 to 15 minutes.
  • CEM Discover SP ® the microwave reactor
  • an aqueous solution (with appropriate pH and or other required constituent) is added to the same microwave tube and subjected to a melting temperature of the lipid constituents or above, preferably 5 to 15 ° C above the melting temperature. of the lipid constituents, and at low, medium or high, preferably high (approximately 900 rmp) magnetic stirring, and at a time of 1 to 60 minutes, preferably 5 to 15 minutes.
  • the nanoemulsions formed may or may not be subjected to immediate thermal shock and may or may not be subjected to stirring to ambient temperature with the consequent formation of the nanoparticles themselves.
  • some cooling options among them:
  • Thermal shock which may be partial or even room temperature.
  • Thermal shock can be caused by a cooling mechanism programmed by the microwave itself or by an ice bath or a combination of these. Stirring should be constant until it reaches room temperature;
  • the lipid components used in the process of the present invention may be from the group of fatty acids, steroids, waxes, monoglycerides, diglycerides and triglycerides. Phospholipids may also be added.
  • Surfactants may be selected from the group of nonionics.
  • Co-surfactants are selected but not limited to the group comprising: low molecular weight alcohols or glycols, such as, for example, butanol, hexanol, hexanediol, propylene glycol; low molecular weight fatty acids such as butyric acid, hexanoic acid, phosphoric acid esters and benzyl alcohol, among others.
  • composition of the formulation may be: lipid components, between 1 and 20%, preferably 1.5 and 8% (by total mass); aqueous solution, between 70 and 96%, preferably 80 and 95.5% (by total mass); surfactants, 1 and 20%, preferably 2 and 15% (by total mass); 0 and 15% co-surfactants, preferably 0 and 10% (by total mass).
  • lipid components between 1 and 20%, preferably 1.5 and 8% (by total mass); aqueous solution, between 70 and 96%, preferably 80 and 95.5% (by total mass); surfactants, 1 and 20%, preferably 2 and 15% (by total mass); 0 and 15% co-surfactants, preferably 0 and 10% (by total mass).
  • the process of the present invention has numerous advantages over the state of the art, including, for example: better process control, considerably simplified, fast, scalable, sustainable operation, safe and economical operation, all-in-one process, pot, and necessarily using only one device.
  • the process of the non-invention does not require the use of any organic solvent,
  • Lipid nanoparticles according to the present invention have an average diameter of between 30 and 900 nm, preferably between 60 and 300 nm; a polydispersion of from 0.05 to 0.5, preferably from 0.1 to 0.3; and the zeta potential has a modular value between 10 and 70 mv, preferably between 20 and 40 mv. These parameters are adjustable according to each objective. Thus, they may be successfully employed as carriers for active compounds that have at least one effective physiological and / or diagnostic effect.
  • Table 1 General table with all formulations used as examples of the Invention (1-a) and test results (1-b).
  • * 17 partial heat shock cooling (up to 70 to 60 ° C) and constant stirring and then complete cooling at room temperature;
  • Compritol ® ATO 888 solid lipid
  • Ratio lipid phase / aqueous phase 1/10
  • Lipid phase / surfactant ratio 1 / 1.5
  • the microwave tube was properly closed with appropriate airtight cap and inserted into the microwave equipment for 15 minutes at 90 ° C.
  • the obtained nanoemulsion microwave tube was allowed to cool to room temperature without magnetic stirring for at least 10 minutes.
  • the obtained lipid nanoformulations had - through n.6 - average size of 853nm and polydispersion of 0.376.
  • Ratio lipid phase / aqueous phase 1/20
  • Lipid phase / surfactant ratio 1 / 1.5
  • the microwave tube was properly closed with appropriate airtight cap and inserted into the microwave equipment for 15 minutes at 90 ° C.
  • the microwave tube with nanoemulsions obtained was placed in an ice bath (thermal shock) with constant magnetic stirring for 10 minutes. Time required for formulation to reach room temperature.
  • the obtained lipid nanoformulations had - through n.6 - average size of 703 nm and polydispersion of 0.356.
  • Ratio lipid phase / aqueous phase 1/20
  • Lipid phase / surfactant ratio 1 / 1.5
  • the microwave tube was properly closed with appropriate airtight cap and inserted into the microwave equipment for 15 minutes at 90 ° C.
  • the obtained nanoemulsion microwave tube was allowed to cool to room temperature with magnetic stirring for at least 10 minutes.
  • the obtained lipid nanoformulations had - through n.6 - average size of 716 nm and polydispersion of 0.361.
  • Compritol ® ATO 888 solid lipid
  • Mygliol 812 liquid lipid
  • 250.5 mg Tween 80 5 mL aqueous solution pH 7.4 (Hepes buffer plus adjustment with NaCI IM) and the largest possible magnetic bar that fits into the microwave tube.
  • Ratio lipid phase / aqueous phase 1/30
  • Lipid phase / surfactant ratio 1 / 1.5
  • the microwave tube was properly closed with appropriate airtight cap and inserted into the microwave equipment for 15 minutes at 90 ° C.
  • the microwave tube with nanoemulsions obtained was placed in an ice bath (thermal shock) with constant magnetic stirring for 10 minutes. Time required for formulation to reach room temperature.
  • the lipid nanoformulations obtained had - through n.6 - average size of 233 nm and polydispersion of 0.278.
  • Ratio lipid phase / aqueous phase 1/30
  • Lipid phase / surfactant ratio 1 / 1.5 Solid lipid / liquid lipid ratio: 3/1
  • the microwave tube was properly closed with appropriate airtight cap and inserted into the microwave equipment for 15 minutes at 90 ° C.
  • the obtained nanoemulsion microwave tube was allowed to cool to room temperature with magnetic stirring for at least 10 minutes.
  • the lipid nanoformulations obtained had - through n.6 - average size of 183 nm and polydispersion of 0.298.
  • Ratio lipid phase / aqueous phase 1/40
  • Lipid phase / surfactant ratio 1 / 1.5
  • the microwave tube was properly closed with appropriate airtight cap and inserted into the microwave equipment for 15 minutes at 90 ° C.
  • the microwave tube with nanoemulsions obtained was placed in an ice bath (thermal shock) with constant magnetic stirring for 10 minutes. Time required for formulation to reach room temperature.
  • the lipid nanoformulations obtained had - through n.6 - average size of 93 nm and polydispersion of 0.218.
  • Ratio lipid phase / aqueous phase 1/40
  • Lipid phase / surfactant ratio 1 / 1.5
  • the microwave tube was properly closed with appropriate airtight cap and inserted into the microwave equipment for 15 minutes at 90 ° C.
  • the obtained nanoemulsion microwave tube was allowed to cool to room temperature with magnetic stirring for at least 10 minutes.
  • the lipid nanoformulations obtained had - through n.6 - average size of 95 nm and polydispersion of 0.205.
  • Lipid phase / surfactant ratio 1 / 1.5
  • the microwave tube was properly closed with appropriate airtight cap and inserted into the microwave equipment for 15 minutes at 90 ° C.
  • the obtained nanoemulsion microwave tube was allowed to cool to room temperature with magnetic stirring for at least 10 minutes.
  • the obtained lipid nanoformulations had - through n.6 - average size of 759.5 nm and polydispersion of 0.398.
  • Ratio lipid phase / aqueous phase 1/40
  • Lipid phase / surfactant ratio 1 / 1.5
  • the microwave tube was properly closed with appropriate airtight cap and inserted into the microwave equipment for 15 minutes at 90 ° C.
  • the obtained nanoemulsion microwave tube was allowed to cool to room temperature with magnetic stirring for at least 10 minutes.
  • the obtained lipid nanoformulations had - through n.6 - average size of 121 nm and polydispersion of 0.309.
  • Ratio lipid phase / aqueous phase 1/50
  • Lipid phase / surfactant ratio 1 / 1.5 Solid lipid / liquid lipid ratio: 4/1
  • the microwave tube was properly closed with appropriate airtight cap and inserted into the microwave equipment for 15 minutes at 90 ° C.
  • the obtained nanoemulsion microwave tube was allowed to cool to room temperature with magnetic stirring for at least 10 minutes.
  • the lipid nanoformulations obtained had - through n.6 - average size of 162 nm and polydispersion of 0.231.
  • Ratio lipid phase / aqueous phase 1/50
  • the microwave tube was properly closed with appropriate airtight cap and inserted into the microwave equipment for 20 minutes at 90 ° C.
  • the obtained nanoemulsion microwave tube was allowed to cool to room temperature with magnetic stirring for at least 10 minutes.
  • the lipid nanoformulations obtained had - through n.6 - average size of 219 nm and polydispersion of 0.390.
  • Ratio lipid phase / aqueous phase 1/50
  • Lipid phase / surfactant ratio 1/1
  • the microwave tube was properly closed with appropriate airtight cap and inserted into the microwave equipment for 20 minutes at 90 ° C.
  • the obtained nanoemulsion microwave tube was allowed to cool to room temperature with magnetic stirring for at least 10 minutes.
  • the lipid nanoformulations obtained had - through n.6 - average size of 902 nm and polydispersion of 0.395.
  • Ratio lipid phase / aqueous phase 1/50
  • Lipid phase / surfactant ratio 2/1
  • the microwave tube was properly closed with appropriate airtight cap and inserted into the microwave equipment for 10 minutes at 90 ° C.
  • the obtained nanoemulsion microwave tube was allowed to cool to room temperature with magnetic stirring for at least 10 minutes.
  • the obtained lipid nanoformulations had - through n.6 - average size of 288 nm and polydispersion of 0.374.
  • Mygliol 812 liquid lipid
  • 150 mg Tween 80 15 mg zidovudine (drug)
  • 5 mL of aqueous solution (MiliQ ultrapure water) and a largest possible magnetic bar that fits into the microwave tube.
  • Ratio lipid phase / aqueous phase 1/50
  • Lipid phase / surfactant ratio 1 / 1.58
  • the microwave tube was properly closed with appropriate airtight cap and inserted into the microwave equipment for 10 minutes at 90 ° C.
  • the nanoemulsion microwave tube immediately went into the microwave cooling program going to 70 ° C. After this program the formulation microwave tube was removed from the equipment and allowed to cool naturally until it reached room temperature with the consequent formation of NLC.
  • the lipid nanoformulations obtained had - through n.6 - average size of 113 nm, polydispersion of 0.216, zeta potential of -21 mv, TEM analysis confirmed the size of these nanoparticles and showed that they have spherical shape (Figure 7A). 23% encapsulation efficiency, 1.4% load capacity. Drug release assay showed in gastric medium more than 50% of the drug remains in the nanoparticle without being released and at least 24 hours are required to release 100% of the drug in physiological medium from this nanoformulation ( Figures 8 - 8A and 8B).
  • LC - loading capacity
  • PI polydispersion
  • average particle size Some parameters were previously set as a result of the pre-formulation study. Only two quantitative variables were selected for continuation of this study: LL: LS ratio (liquid lipid and solid lipid) in a range of 36.7 mg LL to 63.3 mg SL and 13.3 mg LL to 86.7 mg SL, and amount of Tween surfactant 80, in a range of 79.3 to 220.7 mg.
  • Table 2 presents the matrix of experimental conditions with the combinations of lower (-1) and upper (+1) levels, axial points and central point replication, resulting in a total of 13 experiments for the purpose of analyzing the influence of these variables. study.
  • Table 2 Experimental design performed for optimized development of the zidovudine formulation by the methodology of the invention.
  • B The Pareto diagram shown in figure 4 (4A, 4B, 4C) illustrates the effects of individual factors and their interactions. The length of each bar is proportional to the absolute value of the associated regression coefficient or estimated effect. The effects of all parameters and interactions were standardized (each effect was divided by its standard error). The order in which bars are displayed corresponds to the order of effect size. The chart includes a vertical line indicating the 95% statistical significance limit. An effect was therefore significant if the corresponding bar crossed this vertical line.
  • X and Y are Tween 80 amount and LL: SL ratio, respectively.
  • the critical values found were 158 mg T-80 and 27 mg LL: 73 mg SL for LC response.
  • the critical values were 150 mg T-80 and 25 mg LL: 75 mg SL.
  • the amount of T-80 was fixed at 158 mg and the ratio of LL: SL was fixed at 25mg LL: 75mg SL for the developed formulation.
  • Step 1 In a microwave tube was added 75 mg Compritol ® ATO 888 (solid lipid), 25 mg Mygliol 812 (liquid lipid), 150 mg Tween 80, 2 mg nevirapine (drug) and a sized magnetic bar. as large as possible that fits in the microwave tube.
  • the microwave tube was properly closed with appropriate airtight cap and inserted into the microwave equipment for 10 minutes at 90 ° C.
  • Step 2 To the microwave tube was added 5mL of aqueous solution at pH 8.7 (Hepes buffer plus adjustment with 1M NaCl). The microwave tube was properly closed with appropriate airtight cap and inserted into the microwave equipment for 10 minutes at 90 ° C.
  • Ratio lipid phase / aqueous phase 1/50
  • Lipid phase / surfactant ratio 1 / 1.5
  • the nanoemulsion microwave tube immediately went into the microwave cooling program going to 70 ° C. After this program the formulation tube was removed from the equipment and allowed to cool naturally until it reached room temperature with the consequent formation of NLC.
  • the lipid nanoformulations obtained had - through n.6 - average size of 69 nm, polydispersion of 0.263, zeta potential of -22 mv, TEM analysis confirmed the size of these nanoparticles and showed that they have a spherical shape (Figure 7B). 42% encapsulation efficiency, 0.2% load capacity. Physical stability of this formulation was observed for 30 days for all parameters evaluated. This was the time when the stability study was conducted ( Figure 9B).
  • the pH chosen was 8.7, as it corresponds to the isoelectric point of nevirapine drug, aiming to contribute to the greater preference and retention of nevirapine molecular form by the lipid matrix in the formulation.
  • the aqueous phase is composed of Hepes buffer adjusted with 1M NaCl.
  • the solid lipid Stearic Acid was eliminated from the study because it is incompatible with alkaline medium.
  • the solid lipids chosen to remain in this study were: Compritol ® ATO 888, Precitol ® ATO 5.
  • the amount of NVP was set at 2mg because it is an average value that already shows saturation in the lipid phase. And the NVP addition medium was in the lipid phase due to the high lipophilicity of this drug.
  • the surfactant was fixed on Tween 80 for its characteristics of being a steric surfactant and non-toxic. This being added to the lipid phase of the preparation.
  • the ratio of lipid mass to aqueous solution was set at 1 : 50 (w / w). While the solid lipid: liquid lipid ratio was set at 3: 1 (75mg: 25mg) and the total lipid mass: surfactant ratio was set at 1: 1.5 (100mg: 150mg).
  • Cooling was fixed, with partial cooling under stirring for formulation rapidly reaching 70 ° C (programmed in the microwave reactor itself) and completion of cooling at room temperature without stirring.
  • Table 4 Factorial Planning performed for the development of nevirapine formulation by the methodology of the invention
  • Ratio lipid phase / aqueous phase 1/50
  • Lipid phase / surfactant ratio 1 / 1.5
  • the microwave tube was properly closed with an appropriate airtight cap and inserted into the microwave equipment for 20 minutes at 120oC.
  • the nanoemulsion microwave tube immediately went into the microwave cooling program going to 70 ° C. After this program the formulation microwave tube was removed from the equipment and allowed to cool naturally until it reached room temperature with the consequent formation of NLC.
  • the lipid nanoformulations obtained had - through n.6 - average size of 73 nm, polydispersion of 0.261, zeta potential of -21 mv. Encapsulation efficiency 2.75%, load capacity 0.02%.
  • Step 1 In a microwave tube was added 75 mg Compritol ® ATO 888 (solid lipid), 25 mg oleic acid (liquid lipid), 150 mg Tween 80, 2 mg nevirapine (drug) and a sized magnetic bar. as large as possible that fits in the microwave tube.
  • the microwave tube was properly closed with appropriate airtight cap and inserted into the microwave equipment for 10 minutes at 90 ° C.
  • Step 2 To the microwave tube was added 5mL of aqueous solution at pH 8.7 (Hepes buffer plus adjustment with 1M NaCl). The tube was properly closed with appropriate airtight cap and inserted into the microwave equipment for 10 minutes at 90 ° C.
  • Ratio lipid phase / aqueous phase 1/50
  • Lipid phase / surfactant ratio 1 / 1.5
  • the nanoemulsion microwave tube immediately went into the microwave cooling program going to 70 ° C. After this program the formulation tube was removed from the equipment and allowed to cool naturally until it reached room temperature with the consequent formation of NLC.
  • the obtained lipid nanoformulations had - through n.6 - average size of 459 nm and polydispersion of 0.371.
  • Ratio lipid phase / aqueous phase 1/50
  • Lipid phase / surfactant ratio 1 / 1.5
  • the microwave tube was properly closed with an appropriate airtight cap and inserted into the microwave equipment for 20 minutes at 120oC.
  • the nanoemulsion microwave tube immediately went into the microwave cooling program going to 70 ° C. After this program the formulation tube was removed from the equipment and allowed to complete the cooling naturally to room temperature with the consequent formation of NLC.
  • the obtained lipid nanoformulations had - through n.6 - average size of 579 nm and polydispersion of 0.381.
  • Step 1 In a microwave tube was added 75 mg of Compritol ® ATO 888 (solid lipid), 150 mg of Tween 80 and a largest possible magnetic bar that fits into the microwave tube. The microwave tube was properly closed with appropriate airtight cap and inserted into the microwave equipment for 10 minutes at 90 ° C.
  • Step 2 To the microwave tube was added 5mL of aqueous solution at pH 8.7 (Hepes buffer plus adjustment with 1M NaCl). The microwave tube was properly closed with appropriate airtight cap and inserted into the microwave equipment for 10 minutes at 90 ° C.
  • Ratio lipid phase / aqueous phase 1/50
  • Lipid phase / surfactant ratio 1 / 1.5
  • the nanoemulsion microwave tube immediately went into the microwave cooling program going to 70 ° C. After this program the formulation tube was removed from the equipment and allowed to cool naturally until it reached room temperature with the consequent formation of SLN.
  • the lipid nanoformulations obtained had - through n.6 - average size of 67 nm, polydispersion of 0.198 and zeta potential of -19mv.
  • Ratio lipid phase / aqueous phase 1/50
  • Lipid phase / surfactant ratio 1 / 1.58
  • the microwave tube was properly closed with appropriate airtight cap and inserted into the microwave equipment for 10 minutes at 90 ° C.
  • the nanoemulsion microwave tube immediately went into the microwave cooling program going to 70 ° C. After this program the formulation microwave tube was removed from the equipment and allowed to cool naturally until it reached room temperature with the consequent formation of SLN.
  • the lipid nanoformulations obtained had - through n.6 - average size of 118 nm, polydispersion of 0.234 and zeta potential of -15mv.
  • Lipid nanoparticles have increasingly attracted much interest from the food industry, particularly pharmaceuticals (Kuchler et al., 2009, Wissing et al., 2004), cosmetics (Wissing and Muller, 2003, Wissing et al., 2004) ( Jee et al., 2006, Weiss et al., 2008) and textile.
  • the present invention is in the field of nanotechnology, specifically the technology of production of lipid nanoparticles, for the purpose of obtaining medicinal (therapeutic and / or diagnostic), cosmetic and food products. Being possible the encapsulation of one or more fat soluble but also water soluble active compound.
  • Lipid nanoparticles may or may not be entrapped and / or have specific markers, and have the potential for their own advantages of lipid nanoparticles, such as: increased bioavailability and stability of very unstable assets, increased solubility of lipophilic active compounds, controlled release of active compound, reduced absorption variability, reduced toxicity, increased efficacy and improved organoleptic characteristics (Llner and Yener, 2007, Severino et al., 2012, Muchow et al., 2008).
  • they may be used for intravenous, intramuscular, oral, rectal, ocular or dermal administration as already mentioned above.
  • Lipid nanoparticles are also considered promising carriers of cosmetic active ingredients as they allow: protection of unstable compounds against chemical degradation, eg retinoids (Volkhard Jenning, 2001); release of the active ingredient in a controlled manner; function as occlusion complexes; be used as UV blockers, capable of acting on their own as sunscreens or in combination with other substances (Wissing and Muller, 2003).
  • Lipid nanoparticles state of the art, new preparation methods and challenges in drug delivery. Expert Opinion on Drug Delivery, 9, 497-508.
  • Nanostructured Lipid Carriers - Containing Anticancer Compounds Preparation , Characterization, and Cytotoxicity Studies. Drug Delivery, 14, 61-67.
  • BRIOSCHI A., ZENGA, F., ZARA, G. P., GASCO, M. R., DUCATI, A. & MAURO, A.
  • Solid lipid nanoparticles could they help to improve the efficacy of pharmacologic treatments for brain tumors? Neurological Research, 29, 324-330.
  • Solid Lipid Nanoparticles with a matrix (SLN ®, NLC ®, ® CDP) for Oral Drug Delivery. Drug Development and Industrial Pharmacy, 34, 1394-1405.
  • thermolabile nanoparticles with controlled properties and nanoparticles matrices made thereby.

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Abstract

La présente invention concerne un procédé de production simple, rapide, économique et durable pour l'obtention de nanoparticules lipidiques au moyen d'un réacteur à micro-ondes. La technologie selon la présente invention permet la fabrication monotopes desdites particules, en une ou deux systèmes, avec système fermé. Elle ne fait pas intervenir de solvants organiques, ni de volumes d'eau importants. Elle permet l'obtention de nanoparticules lipidiques à des fins médicales (thérapeutique et/ou diagnostique), cosmétiques et alimentaires. Grâce à des ajustements des principaux facteurs critiques du procédé, tels que le temps, la température et le rendement d'agitation (selon les dimensions de la barre magnétique, la vitesse d'agitation et le volume totale de la formulation), il est possible d'obtenir des nanoparticules lipidiques présentant les caractéristiques souhaitées, telles que : taille moyenne comprise entre 30 et 900 nm, de préférence entre 60 et 300 nm; polydispersion comprise entre 0,05 et 0,5, de préférence entre 0,1 et 0,3; et potentiel zêta d'une valeur modulaire comprise entre 10 et 50 mV, de préférence entre 20 et 40 mV.
PCT/IB2017/057900 2016-12-13 2017-12-13 Production de nanoparticules lipidiques par synthèse par micro-ondes WO2018109690A1 (fr)

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Publication number Priority date Publication date Assignee Title
IT201900009258A1 (it) * 2019-06-17 2020-12-17 R Bio Transfer S R L Metodo per la preparazione di nanoparticelle lipidiche

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KALAYCIOGLU GOKCE DICLE ET AL: "Preparation and investigation of solid lipid nanoparticles for drug delivery", COLLOIDS AND SURFACES A: PHYSIOCHEMICAL AND ENGINEERING ASPECTS, ELSEVIER, AMSTERDAM, NL, vol. 510, 21 June 2016 (2016-06-21), pages 77 - 86, XP029780652, ISSN: 0927-7757, DOI: 10.1016/J.COLSURFA.2016.06.034 *
ROHAN M. SHAH ET AL: "Encapsulation of clotrimazole into solid lipid nanoparticles by microwave-assisted microemulsion technique", APPLIED MATERIALS TODAY, vol. 5, 13 October 2016 (2016-10-13), pages 118 - 127, XP055466144, ISSN: 2352-9407, DOI: 10.1016/j.apmt.2016.09.010 *
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Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
IT201900009258A1 (it) * 2019-06-17 2020-12-17 R Bio Transfer S R L Metodo per la preparazione di nanoparticelle lipidiche
WO2020254934A1 (fr) * 2019-06-17 2020-12-24 R Bio Transfer S.R.L. Procédé de préparation de nanoparticules lipidiques

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