WO2018109690A1

WO2018109690A1 - Production of lipid nanoparticles by microwave synthesis

Info

Publication number: WO2018109690A1
Application number: PCT/IB2017/057900
Authority: WO
Inventors: 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
Original assignee: Universidade Do Porto; Universidade Federal De Pernambuco - Ufpe
Priority date: 2016-12-13
Filing date: 2017-12-13
Publication date: 2018-06-21

Abstract

The present invention describes a simple, quick, economical and sustainable production process for producing lipid nanoparticles using a microwave reactor. The technology of the present invention allows one-pot production of said particles, in one or two steps and in a closed system. Said technology does not use organic solvents or large volumes of water. Said technology allows lipid nanoparticles to be produced for medicinal (therapeutic and/or diagnostic), cosmetic and nutritional purposes. By adjusting the main critical factors of the process, such as time, temperature and stirring efficiency (which are dependent on the dimensions of the magnetic bar, stirring speed and total volume of the formulation), it is possible to produce lipid nanoparticles with the intended features, such as: average size comprised between 30 and 900 nm, preferably between 60 and 300 nm; polydispersion between 0.05 and 0.5, preferably between 0.1 and 0.3; and modular zeta potential value between 10 and 50 mV, preferably between 20 and 40 mV.

Description

DESCRIPTION

PRODUCTION OF LIPID NANO PARTICULES BY MICROWAVE SYNTHESIS

Field of the invention

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.

Background of the invention

Over the past decades, many colloidal systems have been developed and studied to improve drug delivery to increase delivery to target tissues and decrease side effects. These vehicles include micelles, nanoemulsions, nanosuspensions, polymeric nanoparticles and liposomes. For most of these carriers, a low cost large scale production method does not exist. Lipid nanoparticles (LNPs) have emerged with the potential to overcome this limitation, with other advantages.

Solid lipid nanoparticles (SLN) appeared in the early 1990s (H. Muller et al.,

2011). Since then, several groups have devoted themselves to their study and modifications in order to improve their properties from the original concept, thus creating more complex systems such as nanostructured lipid carriers (NLC) and lipid-drug conjugates (Kriti Soni). , 2015). They all rely on the use of lipid materials to form a carrier vehicle, which is very advantageous over other types of materials. All 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. Due to these processes, complex lipids are easily and completely degraded in the human body. Therefore, 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,

2011).

Currently, more than 40 research groups around the world work systematically with LNPs, and more than 2000 peer-reviewed articles have been published since 1995. This proves the growing interest in the field of lipid nanoparticles. 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. 2007) , ocular (Attama and Muller-Goymann, 2008, Ugazio et al., 2002) and pulmonary (Xiang et al. 2007; Liu et al. 2008). Additionally, and since they have been extensively studied for dermal application, lipid nanoparticles have become very attractive to the cosmetic industry (Pardeike et al., 2009).

There are several reported techniques for the production of lipid nanoparticles, each with its advantages and disadvantages and therefore appropriate to different realities (Llner and Yener, 2007, Marcato, 2009). The following briefly describe the existing preparation methods:

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. Disadvantages: 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. 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.

Contact Membrane: 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.

Extraction of emulsions by supercritical fluids: Simultaneous process of extraction by supercritical fluids (diffusion) of organic emulsion solvents and lipid dissolution. The expansion of the organic phase leads to lipid crystallization. Disadvantages: Use of large quantities of organic solvents. Need sophisticated equipment.

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. To avoid particle aggregation and to increase flow properties, for example, lecithin is used together with lipid. There is a variation of the sray-congealing technique. Disadvantages: Applied to obtain microparticles and not nanoparticles.

Regarding intellectual property related to nanoparticle production technology:

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 (Zhang et al., 2011b, Zhang et al., 2011a) 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.

- Document CN1490055A 2004) reports a method for the preparation of a

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.

- Document UA81093 (U) (Yevheniivna; et al., 2013) describes a method for producing solid nanoparticles comprised of reaction between fatty acids and the active ingredient in appropriate proportion in the solvent (chloroform) medium under heating. The solvent is finally evaporated, and the lipid film is obtained.

- US20130035279A1 (Venkataraman and Pawar, 2013) reports a method and system for producing 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.

CN101890170A et al., 2010) refers to the formulation technology of

lectin lipid nanoparticles, their application and preparation method by high pressure homogenization in hot.

In addition to these, various other documents, such as: CN1278682C, US8715736B2, CN102846552B (and 2014), RO128703A2 (Lacatusu loana et al., 2013), US8709487B1 (Kinnan and

Schreuder-Gibson, 2014) and US6551619B1 (Penkler et al., 2003) describe formulations and methods for obtaining nanoparticles, but not related to the technique proposed in this invention.

The extensive research in the field of obtaining lipid particles, as well as the various methods developed so far for their production, attest to their enormous potential and commercial interest. However, the vast majority of methods developed so far have difficulty being transferred to industrial scale, which is a major impediment for this type of particle to effectively succeed as either drug carriers, cosmetic or diagnostic applications. The new method for obtaining lipid nanoparticles presented in this document by microwave is distinct from all the hitherto implemented. In fact, and as described above, there is already a method in which uses the microwave, but only for the purpose of heating the formulation constituents in order to replace the traditional technique with "thermal bath". As specified by the authors themselves. That is, the method itself is microemulsion, which uses the microwave only to preheat the formulation components in place of the "thermal bath".

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.

SUMMARY OF THE INVENTION AND ADVANTAGES

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.

The technique is briefly characterized by:

In a microwave tube all 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). Or, at first, 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).

At the end of the process, 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.

TECHNICAL PROBLEMS SOLVED

As it is a one-pot process, it is associated with time and resource saving, as well as greater performance, practicality and reproducibility when compared to other techniques that require several distinct steps, transfers and controls. differentiated in each step of the process (ICH, 2005, ICH, 2009a, Broadwater et al., 2005).

In addition, the invention features a closed system, which means less human manipulation - handling of hazardous substances is minimized, less error passivity and thus greater reproducibility. Because 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).

It is a fast (usually 5 to 20 minutes) process, economical (only microwave equipment and its own utensils required for production), more controllable and measurable, with less human handling, greater uniformity of heat distribution, control of the fusion of the constituents of the formulation and control of the applied energy required to form the nanoparticles Moreover, it is an ecological technique (no need for organic solvents) and scalable for industrial production. 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.

The use of organic solvents is not environmentally friendly, as they are potentially toxic and must go through the formulation removal step (Wissing et al., 2004), even though there is a risk of residual amounts in preparations made by techniques such as: "Solvent Evaporation" and "Solvent Diffusion".

It also avoids additional steps (dilutions, aqueous solvent removal by techniques such as diafiltration) and additional apparatus which makes the process more complex, more expensive and subject to higher quality controls as in the "microemulsion technique" and "microemulsion assisted technique" processes. 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. BRIEF DESCRIPTION OF DRAWINGS

For a complete view of the object of this invention, reference figures are given as follows:

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 8A: In vitro release profile of Zidovudine from formulation "Example 14" simulating gastric environment and body temperature (pH 1.2 at 37 ° C). Data correspond to mean and standard deviation for n = 2.

FIGURE 8B: In vitro release profile of Zidovudine to formulation "example 14" simulating physiological medium and body temperature (pH 7.4 at 37 ° C). Data correspond to mean and standard deviation for n = 2.

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.

In a preferred embodiment of the invention, the process is characterized in that the synthesis of lipid nanoparticles comprises:

(i) placing the lipid or mixture of lipids, surfactants and optionally co-suffactants, aqueous solution and active compounds in a microwave tube;

ii) heating the mixture with microwave energy with simultaneous stirring;

iii) cooling to room temperature.

In a further preferred embodiment of the invention the process according to claim 1 wherein the synthesis of lipid nanoparticles comprises:

i) placing the lipid or mixture of lipids, surfactants and, optionally, co-sufactants and active compounds in a microwave tube;

ii) heating the mixture with microwave energy with simultaneous stirring;

iii) adding aqueous solution;

iv) heating the mixture with microwave energy with simultaneous stirring;

v) cooling to room temperature.

In an even more preferred embodiment of the invention, 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.

In a still more preferred embodiment of the invention, 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.

In another even more preferred embodiment of the invention, 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. In another even more preferred embodiment of the invention, 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.

In a still more preferred embodiment of the invention, the process is characterized in that agitation is of moderate to vigorous intensity, preferably 900 rpm. In an even more preferred embodiment, 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.

In a still more preferred embodiment of the invention, 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.

In a still more preferred embodiment of the invention, 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.

In a still more preferred embodiment of the invention, the process is characterized in that the surfactant or surfactant assembly is of the nonionic type.

In a still more preferred embodiment of the invention, 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.

In a still more preferred embodiment of the invention, 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.

In a still more preferred embodiment of the invention, 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%.

In a still more preferred embodiment of the invention, the process is characterized by incorporating binders or markers, specific to each formulation, on the surface of lipid nanoparticles.

In a still more preferred embodiment of the invention, 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.

In particular, 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.

By adjusting key process critical factors - such as time, temperature and stirring efficiency (magnetic bar characteristics, stirring speed, total formulation volume) - it is possible to obtain lipid nanoparticles with the desired characteristics.

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 ½, 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.

It is observed that, in general, 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. In some respects 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.

With respect to microwave heating methods in the literature, the method described in the present invention has multiple advantages.

For example, compared to the method described by Dunn et al. 2017, 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. In addition 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.

In turn, in relation to the method of Shah et al. 2016, the main difference from our methodology is that when the microwave process is over, the nanoparticles are ready; no need to disperse in water. This step is time consuming and greatly dilutes the suspension. Increasing the amount of water decreases the number of particles per mL, which for an industrial process is not recommended as it may increase the number of steps to eliminate the largest amounts of water. 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. After this step 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.

Optionally, which varies with the optimization of each case, 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. For this there are some cooling options, among them:

- immediately subject to 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;

- subject to constant stirring only until the ambient temperature

- neither subject to thermal shock nor agitation and progressively the ambient temperature is reached.

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, where applicable, 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.

As for the composition of the formulation, it 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). 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, sonication energy, heavy metal contamination, or aggressive technique and presents minimal risk of cross contamination.

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.

To illustrate the invention the following examples are summarized in Table 1 and detailed below:

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; * 18: AZT: zidovidine. It has lopP at about 0.05; * 19: NVP: nevirapine. It has logP at about 2.5; * 20: time in minutes.

EXAMPLE 1

(placebo)

400 mg Compritol ^® ATO 888 (solid lipid) was added to a microwave tube,

100 mg Mygliol 812 (liquid lipid), 750 mg Tween 80, 5mL aqueous solution at pH 7.4 (Hepes buffer plus fit with 1M NaCl) and a largest possible magnetic bar that fits into the microwave tube.

Ratio lipid phase / aqueous phase: 1/10

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.

At the end of the programmed time, 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.

EXAMPLE 2

(placebo)

To a microwave tube was added 187.5 mg of Compritol ^® ATO 888 (solid lipid), 62.5 mg of Mygliol 812 (liquid lipid), 312.5 mg of Tween 80, 5 mL of aqueous solution at pH 7.4 (Hepes buffer plus NaCI adjustment 1M) and the largest possible magnetic bar that fits into the microwave tube.

Ratio lipid phase / aqueous phase: 1/20

Lipid phase / surfactant ratio: 1 / 1.5

Solid lipid / liquid lipid ratio: 3/1

At the end of the programmed time, 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. EXAMPLE 3

(placebo)

To a microwave tube was added 187.5 mg Compritol ^® ATO 888 (solid lipid), 65.5 mg Mygliol (liquid lipid), 312.5 mg Tween 80.5 mL aqueous solution pH 7.4 (Hepes buffer plus NaCI IM adjustment). ) and the largest possible magnetic bar that fits into the microwave tube.

Ratio lipid phase / aqueous phase: 1/20

Lipid phase / surfactant ratio: 1 / 1.5

Solid lipid / liquid lipid ratio: 3/1

At the end of the programmed time 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.

EXAMPLE 4

(placebo)

To a microwave tube was added 125.25 mg Compritol ^® ATO 888 (solid lipid), 41.75 mg 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

Solid lipid / liquid lipid ratio: 3/1

The lipid nanoformulations obtained had - through n.6 - average size of 233 nm and polydispersion of 0.278.

EXAMPLE 5

(placebo)

To a microwave tube was added 125.25 mg Compritol ^® ATO 888 (solid lipid), 41.75 mg Mygliol 812 (liquid lipid), 250.5 mg Tween 80.5 mL aqueous solution pH 7.4 (Hepes buffer plus NaCI adjustment 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 Solid lipid / liquid lipid ratio: 3/1

At the end of the programmed time 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.

EXAMPLE 6

(placebo)

In a microwave tube was added 93.75 mg of Compritol ^® ATO 888 (solid lipid),

31.25 mg of Mygliol 812 (liquid lipid), 18.75 mg of Tween 80, 5 mL of aqueous solution at pH 7.4 (Hepes buffer plus fit with 1M NaCl) and a largest possible magnetic bar that fits into the microwave tube.

Ratio lipid phase / aqueous phase: 1/40

Lipid phase / surfactant ratio: 1 / 1.5

Solid lipid / liquid lipid ratio: 3/1

The lipid nanoformulations obtained had - through n.6 - average size of 93 nm and polydispersion of 0.218.

EXAMPLE 7

(placebo)

In a microwave tube was added 93.75 mg Compritol ^® ATO 888 (solid lipid), 31.25 mg Mygliol 812 (liquid lipid), 18.75 mg Tween 80.5 mL aqueous solution at pH 7.4 (Hepes buffer plus NaCI adjustment 1M) and the largest possible magnetic bar that fits into the microwave tube.

Ratio lipid phase / aqueous phase: 1/40

Lipid phase / surfactant ratio: 1 / 1.5

Solid lipid / liquid lipid ratio: 3/1

At the end of the programmed time 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. EXAMPLE 8

(placebo)

To a microwave tube was added 104 mg Precirol ^® ATO 5 (solid lipid), 20.8 mg Mygliol 812 (liquid lipid), 187.5 mg Tween 80.5 ml aqueous solution (MiliQ ultrapure water) and a larger size magnetic bar may fit in the microwave tube. Ratio lipid phase / aqueous phase: 1/40

Lipid phase / surfactant ratio: 1 / 1.5

Solid lipid / liquid lipid ratio: 5/1

At the end of the programmed time 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.

EXAMPLE 9

(placebo)

To a microwave tube was added 93.75 mg Precirol ^® ATO 5 (solid lipid), 31.25 mg Mygliol 812 (liquid lipid), 187.5 mg Tween 80, 5 mL of aqueous solution (MiliQ ultrapure water) and a larger size magnetic bar may fit in the microwave tube.

Ratio lipid phase / aqueous phase: 1/40

Lipid phase / surfactant ratio: 1 / 1.5

Solid lipid / liquid lipid ratio: 3/1

At the end of the programmed time 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.

EXAMPLE 10

(placebo)

To a microwave tube was added 96 mg Precirol ^® ATO 5 (solid lipid), 24 mg Mygliol 812 (liquid lipid), 180 mg Tween 80, 6mL aqueous solution (MiliQ ultrapure water) and a larger size magnetic bar may fit in the microwave tube.

Ratio lipid phase / aqueous phase: 1/50

Lipid phase / surfactant ratio: 1 / 1.5 Solid lipid / liquid lipid ratio: 4/1

At the end of the programmed time 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.

EXAMPLE 11

(placebo)

To a microwave tube was added 66.6 mg Precirol ^® ATO 5 (solid lipid), 33.3 mg Mygliol 812 (liquid lipid), 200 mg Tween 80.5 ml aqueous solution (MiliQ ultrapure water) and a larger size magnetic bar may fit in the microwave tube.

Ratio lipid phase / aqueous phase: 1/50

Lipid phase / surfactant ratio: 1/2

Solid lipid / liquid lipid ratio: 2/1

The microwave tube was properly closed with appropriate airtight cap and inserted into the microwave equipment for 20 minutes at 90 ° C.

At the end of the programmed time 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.

EXAMPLE 12

(placebo)

Ratio lipid phase / aqueous phase: 1/50

Lipid phase / surfactant ratio: 1/1

Solid lipid / liquid lipid ratio: 2/1

At the end of the programmed time 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.

EXAMPLE 13

(placebo)

To a microwave tube was added 83.3 mg Precirol ^® ATO 5 (solid lipid), 16.7 mg Mygliol 812 (liquid lipid), 200 mg Tween 80.5mL. of aqueous solution (MiliQ ultrapure water) and the largest possible magnetic bar that fits into the microwave tube.

Ratio lipid phase / aqueous phase: 1/50

Lipid phase / surfactant ratio: 2/1

Solid lipid / liquid lipid ratio: 5/1

The microwave tube was properly closed with appropriate airtight cap and inserted into the microwave equipment for 10 minutes at 90 ° C.

At the end of the programmed time 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.

EXAMPLE 14

(with the drug Zidovudine)

To a microwave tube was added 75 mg Precirol ^® ATO 5 (solid lipid), 25 mg

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

Solid lipid / liquid lipid ratio: 3/1

At the end of the programmed time 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).

Regarding the physical stability of the formulation, it was observed that it remained stable for the total evaluated time of 45 days, however, with only 22 days already showed high decay (greater than 50%) for the load capacity response (Figure 9A).

The approach of developing this formulation with zidovudine drug is detailed below. - Previously a pre-formulation study was carried out which consisted of the following steps: a. Zidovudine microwave degradation drug degradation test under the conditions: 20 mg zidovudine was placed in the microwave tube, solubilized with 5 mL of ultrapure water and subjected to 90 ° C for 10 minutes in microwave. Subsequently, zidovudine was quantified by spectrophotometer and the assay value was equivalent to the heavy amount, ie, it did not show degradation.

B. The methodology was optimized and the thermal shock of the formulation when leaving the microwave was not necessary. For the improvement in particle size and / or polydispersion was negligible, while there was loss of charge capacity of the evaluated nanoparticles suggesting that heat shock was contributing to partial release of the drug from the lipid matrix.

ç. Based on preliminary studies of NLC-like lipid nanoparticle development by traditional ultrasonic hot homogenization technique, with comparative purpose, we have determined the qualitative choice of solid lipid, liquid, surfactant and pH of aqueous solution.

d. Through preliminary testing we made an assessment of the ratio of lipids: aqueous solution to 1:10, 1:20, 1:30, 1:40 and 1:50. We observed that for the lipid and surfactant composition used in this study the best lipid: aqueous solution ratio was 1:50. That factor then being fixed.

- Response Surface construction and optimized formulation selection.

The. A central composite design and response surface design were made to identify the optimal experimental condition that simultaneously satisfies three important responses.

- loading capacity (LC), polydispersion (PI) and 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.

ç. Two-dimensional Response Surface plots (contour curves) were plotted to fit the experimental data for each response (Figure 5: 5A, 5B, SC) to identify optimal conditions for analysis.

d. A statistically significant quadratic model, corresponding to 95%, 93% and 68% of the variance for L.C., PI and mean particle size responses, respectively, was fitted to the data, describing the relationship between maximum responses and optimal experimental conditions. The quadratic regression model obtained are as follows:

Loading capacity (L.C.) = - 45,91882 + 0.08973x - 0.00024x2 + 1.11304y - 0.00741y2 -

0.00020x0079

Polydispersion (PI) = 6.02791 - 0.00751x + 0.00003x2 - 0.14017y + 0.00095y2 - O.OOOOlxy Average Particle Size = 12861.01158 - 27.19887x + 0.13332x2 - 282.37724y + 2.21025y2 - 0.26229xy

Where X and Y are Tween 80 amount and LL: SL ratio, respectively. Das surfaces obtained, the critical values found were 158 mg T-80 and 27 mg LL: 73 mg SL for LC response. For the PI response the critical values were 150 mg T-80 and 25 mg LL: 75 mg SL. And 175mg T-80 and 26mg LL: 74mg SL for the average particle size response. and. From the analysis of the response surface methodology, it was possible to determine the process conditions to simultaneously optimize all the responses of interest in the present study, since the critical values for each response were similar. Thus, 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.

EXAMPLE 15

(with the drug Nevirapine)

2 step process.

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

Solid lipid / liquid lipid ratio: 3/1

At the end of the programmed time 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 approach of developing this formulation with nevirapine is detailed below. - Previously a pre-formulation study was carried out which consisted of the following steps: a. Degradation test of nevirapine submitted to microwave reactor under the conditions: 2 mg nevirapine was placed in the microwave tube, solubilized with 5 mL of ultrapure water and subjected to 100 ° C for 10 minutes in microwave. Subsequently nevirapine was quantified by spectrophotometer and the assay value was equivalent to the amount weighed.

B. A nevirapine solubility study was performed against various solid and liquid lipids - as shown in Table 3. Of these, the solid lipids were pre-selected to remain in the study: Compritol ^® ATO 888, Precitol ^® ATO 5, Stearic Acid and Superpolystrate and liquid lipids: Miglyol 812 and Oleic acid.

Table 3: Nevirapine drug solubility test against various lipids.

ç. 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. Thus, the aqueous phase is composed of Hepes buffer adjusted with 1M NaCl. At this stage 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.

d. 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.

and. Some qualitative factors have been fixed. 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.

f. Quantitative factors were also fixed based on various tests and prior knowledge to satisfy this variety of lipids of this investigation, shown in some examples in this invention - Figure 4. Therefore, 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).

g. A test was performed using the parameters of temperature 90ºC for 10 minutes under high stirring in the microwave reactor. However, nevirapine was almost all precipitated, partly flocculated and with several coarse lipid particles in the final preparation. Nevirapine is a very hydrophobic drug. Thus, optimizations and variations of the methodology of the invention were made by adjusting critical process factors, such as time and temperature in the application of the methodology in one step and in two steps, which will allow us to evaluate which one would be the most suitable for the development of this method. formulation.

H. 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.

- Factorial planning employed in formulation development after pre-formulation studies:

The. A complete 2 ³ factorial design of this study (Table 4) was made to optimize the responses: loading capacity (LC), particle size (SIZE) and polydispersion (PI). The three critical factors selected for this optimization were the qualitative factors solid lipid, liquid lipid and production process - however, in the production process factor, which will indicate whether the process should be single or 2 steps, 2 quantitative factors are contained. which is time and temperature. The other factors were fixed at the pre-formulation stage.

Table 4: Factorial Planning performed for the development of nevirapine formulation by the methodology of the invention

B. For the "PI" response the liquid lipid and solid lipid factor were statistically significant (see Pareto Chart of Figure 6A), indicating that for lower polydispersion responses the liquid lipid to be selected is Miglyol 812, and the solid lipid to be selected. is Compritol ^® ATO 888. For the "SIZE" answer only the liquid lipid factor was statistically significant (p = 0.05), indicating the level (-) of the liquid lipid factor, ie the formulations with Miglyol 812 as the formulations that delivered particle size values smaller than 400 nm (see Pareto Chart of Figure 6B). For the "LC" response, only formulations that delivered values close to the acceptable values for the "SIZE" and "PI" responses were evaluated. From these results it became evident that the one-step production process should be eliminated from the development of this formulation under the investigated conditions.

ç. Thus, the qualitative factors of the conducted factorial design were fixed and the optimized nevirapine formulation was selected.

Example 16

(with the drug Nevirapine)

To a microwave tube was added 75 mg Compritol ^® ATO 888 (solid lipid), 25 mg Mygliol 812 (liquid lipid), 150 mg Tween 80, nevirapine 15 mg (drug), 5 mL aqueous solution at pH 8, 7 (Hepes buffer plus fit with 1M NaCI) and one largest possible magnetic bar that fits into the microwave tube.

Ratio lipid phase / aqueous phase: 1/50

Lipid phase / surfactant ratio: 1 / 1.5

Solid lipid / liquid lipid ratio: 3/1

The microwave tube was properly closed with an appropriate airtight cap and inserted into the microwave equipment for 20 minutes at 120ºC.

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%.

Example 17

(with the drug Nevirapine)

2 step process.

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

Solid lipid / liquid lipid ratio: 3/1

The obtained lipid nanoformulations had - through n.6 - average size of 459 nm and polydispersion of 0.371.

EXAMPLE 18

(with the drug Nevirapine)

To a microwave tube was added 75 mg Compritol ^® ATO 888 (solid lipid), 25 mg oleic acid (liquid lipid), 150 mg Tween 80, nevirapine 15 mg (drug), 5 mL aqueous solution at pH 8, 7 (Hepes buffer plus fit with 1M NaCI) and one largest possible magnetic bar that fits into the microwave tube.

Ratio lipid phase / aqueous phase: 1/50

Lipid phase / surfactant ratio: 1 / 1.5

Solid lipid / liquid lipid ratio: 3/1

At the end of the programmed time 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.

Example 19

(placebo)

2 step process.

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.

Ratio lipid phase / aqueous phase: 1/50

Lipid phase / surfactant ratio: 1 / 1.5

At the end of the programmed time 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.

EXAMPLE 20

(placebo)

To a microwave tube was added 75 mg Precirol ^® ATO 5 (solid lipid), 150 mg Tween 80 and 5mL aqueous solution (MiliQ ultrapure water) and the largest possible magnetic bar to fit in the microwave tube.

Ratio lipid phase / aqueous phase: 1/50

Lipid phase / surfactant ratio: 1 / 1.58

At the end of the programmed time 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.

INDUSTRIAL APPLICATION

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). In addition 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).

Emerging new diets related to improving health to prevent / combat circulatory system diseases, obesity, hypertension or cancer have led to the incorporation of bioactive compounds into the food industry. In fact, clinical trials have already confirmed the health benefits of including bioactive components in the daily diet (Alissa and Ferns, 2012, Ellwood et al., 2014). However, many of these beneficial components are highly lipophilic, have low absorption, limited bioavailability in the human organism and are very unstable. This occurs in various classes of bioactive components, such as carotenoids, which are practically insoluble in water. In this sense, the inclusion of this type of compound in food products presents a challenge that can be overcome by incorporating these compounds in lipid particles (Weiss et al., 2008). In recent years there has been a tendency to incorporate bioactive compounds into tissues as well, and many have even been marketed, such as compounds and anti-cellulites in jeans. Also in this area incorporation of such compounds into lipid nanoparticles can prevent their degradation and increase permeability through the skin. Indeed, very recent research has demonstrated the potential of lipid particles to be used as patches for selective targeting and death of cancer cells (Sempkowski et al., 2016), with potential future application being their incorporation into textiles.

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Claims

1. One-pot microwave synthesis process of 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 microwaves to a temperature below 90 ° C with continuous simultaneous stirring followed by cooling.

Process according to claim 1, characterized in that the synthesis of lipid nanoparticles comprises:

ii) heating the mixture with microwave energy with simultaneous stirring;

iii) cooling to room temperature.

ii) heating the mixture with microwave energy with simultaneous stirring;

iii) adding aqueous solution;

iv) heating the mixture with microwave energy with simultaneous stirring;

v) cooling to room temperature.

Process according to any one of the preceding claims, characterized in that the heating is carried out at or above the melting temperature of the lipid constituents for 1 to 60 minutes.

Process according to Claim 2, 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.

Process according to Claim 3, characterized in that the 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.

Process according to any one of the preceding claims, characterized in that the cooling is carried out without agitation; with constant stirring to room temperature; or with constant stirring and thermal shock, for partial cooling or to room temperature, by cooling programmed by the microwave apparatus itself, by ice bath or a combination thereof.

Process according to any one of the preceding claims, characterized in that the agitation is of moderate to vigorous intensity, preferably of 900rpm.

Method according to the preceding claim, characterized in that the stirring is carried out by the addition of a magnetic rod to the microwave tube, which is as large as possible to allow greater homogeneity and more vigorous stirring.

Process according to any one of the preceding claims, characterized in that the final volume of the constituents inserted in the microwave tube is preferably 1/7 to 1/2 of the volume of the tube to ensure complete and controlled homogenization during the stirring process.

Process according to any one of the preceding claims, 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.

Process according to any one of the preceding claims, characterized in that the surfactant or set of surfactants is of the nonionic type.

Process according to any one of the preceding claims, 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.

Process according to any one of the preceding claims, 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.

Process according to any one of the preceding claims, characterized in that the lipid or lipid group comprises from 1 to 20%, preferably from 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 from 0 to 15%, preferably from 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%.

Process according to any one of the preceding claims, characterized in that incorporation of formulation-specific binders or markers on the surface of lipid nanoparticles.

Process according to any one of the preceding claims, characterized in that lipid nanoparticles with an average diameter of 30 to 900 nm, preferably 60 to 300 nm, with a polydispersion of 0.05 to 0.5, preferably 0.1, are obtained. at 0.3, and zeta potential from 10 to 70 mV, preferably from 20 to 40 mV.

Solid lipid nanoparticles (SLN) or nanostructured lipid carriers (NLC) obtained by the process described in claims 1 to 17.

Solid lipid nanoparticles (SLN) or nanostructured lipid carriers (NLC) according to the preceding claim, characterized in that they have an average diameter of 30 to 900 nm, preferably 60 to 300 nm, with polydispersion of 0.05 to 0.5. preferably from 0.1 to 0.3, and zeta potential from 10 to 70 mV, preferably from 20 to