Use of nanocarriers for active agent delivery

Abstract

Disclosed is the use of a composition for preparing a medicament for a subject or guest in need of treatment, the composition comprising nanoelements comprising: a) at least one water-insoluble thermoplastic compound (WITC) capable of forming a core; and b) at least one active agent capable of being disposed in the core or a shell surrounding the core. Nanoelements having an average diameter in the submicron range are composed of a material having a low vapor pressure and can be dispersed in a polar carrier. Methods of making these nanoelements and administering them to treat conditions corresponding to the active agents contained therein are also provided.

Description

Cross - reference to related applications

[0001] This application claims Paris Convention priority from UK Patent Application No. 2217477.5, filed on November 22, 2022, and International Patent Application No. PCT / IB2023 / 057187, filed on July 13, 2023. The contents of these applications are incorporated herein by reference in their entirety as if fully set forth herein. Technical Field

[0002] The present disclosure relates to compositions comprising nanoparticles suitable for delivering an active agent and their use. Methods for preparing these compositions are also provided. Background Art

[0003] Drugs are used for the diagnosis, prevention, or treatment of diseases. They have various pharmaceutical dosage forms and can be administered to animal or human subjects by various routes. Generally, the active ingredient of such a composition (which enables the composition to be used for the diagnosis or treatment of a disease) is administered in admixture with a suitable pharmaceutically acceptable excipient, which is selected according to the intended dosage form and route of administration. Such drugs can enter the body through several routes (e.g., local or systemic administration, including enteral and parenteral routes), and each route has its own advantages and disadvantages for a particular purpose and / or disease.

[0004] Nanotechnology has proven to be advantageous in drug development, particularly in drug formulation and delivery. Nanoparticles produced by this technology typically have a particle size in the range of 10 nanometers (nm) to 1000 nanometers, and due to the ability of nanoparticles of this size to, for example, cross the blood-brain barrier (BBB), enter the pulmonary system, or be absorbed through the tight junctions of vascular endothelial cells if small enough (e.g., with a particle size up to 200 nm or even 100 nm), drugs can achieve site-specific and targeted delivery. It is thought that if the drug itself is a small enough molecule, with a molecular weight not exceeding about 1000 g / mol and preferably less than 500 g / mol according to Lipinski's "rule of five", it may even be able to achieve intracellular delivery. These nanoparticles of nanoscale size can be in the form of nanospheres, nanocapsules, nanocrystals, nanoemulsions, nanofibers, nanotubes, polymeric micelles, polymeric vesicles, dendrimers, liposomes, etc.

[0005] A variety of compounds, such as polymers (biodegradable or non - biodegradable), are used as nanocarriers for therapeutic agents in nanomedicine, allowing the transfer of such therapeutic agents to the target site while protecting the drug from premature degradation and / or reducing the premature interaction of the drug with the biological environment. Such nanocarriers can also enable controlled or sustained release of the drug at the target site. Polymers, whether homopolymers, blend polymers or copolymers, can be used either to form the envelope of hollow vesicles with the drug located in the core of such polymer vesicles and / or inserted into the surrounding membrane, or to embed the drug into the polymer matrix that constitutes the entire nanocarrier.

[0006] A variety of conventional methods for preparing these nanocarriers (e.g., polymer nanocarriers) have been described in the literature, but most of them rely on the use of solvents that typically remain in the conventionally prepared particles. When the solvent used is a volatile organic compound (VOC), there are many drawbacks because, despite their relative volatility, such solvents cannot be completely removed to below negligible residual levels. First, nanocarriers for use in the pharmaceutical industry must comply with the guidelines issued by the International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use (ICH), and thus the content of such residual VOCs should be correspondingly restricted due to their toxicity. Second, since VOCs may gradually evaporate over time until their residual levels are reached, during which the structure or properties of the nanoparticles may change, thereby affecting the efficacy of the carried drug, such as the drug release profile. Although elaborate methods have been developed to attempt to solve the problem of unwanted solvent residual entrapment, the methods reported to date cannot provide nanoparticles or even microparticles with a narrow particle size distribution, and / or lack commercial feasibility due to their complexity, inability to form stable dispersions or low encapsulation efficiency when active ingredients need to be added.

[0007] Despite in - depth research in the field of drug delivery via nanocarriers aimed at improving the stability, drug - loading capacity or selective targeting and controlled release of the carried drug at relevant sites, there is still a need for such nanocarriers. Advantageously, such carriers can exhibit low concentrations of volatile organic solvents and allow the delivery of water - insoluble drug molecules with a relatively high average molecular weight. Summary of the Invention

[0008] Multiple aspects of the present invention relate to the use of a composition for the preparation of a medicament suitable for administration to a living subject or a living being, said composition comprising a water-insoluble thermoplastic compound (WITC), such as a water-insoluble thermoplastic polymer (WITP), which is capable of being dispersed in a polar liquid carrier in the form of nanoparticles or nanodroplets (collectively referred to as "nano-elements"). These nanoparticles or nanodroplets can be used to deliver at least one active agent and, accordingly, they can also be referred to as nanocarriers.

[0009] The nano-elements can be in the form of core nano-elements, where the core containing the WITC and the active agent is not further encapsulated by a shell. Alternatively, the nano-elements can be in the form of core-shell or core-multishell nano-elements, where the active agent can be within the core containing the WITC and / or form a shell directly or indirectly around the core, as will be explained below. It is noted that the nanoparticles or nanodroplets thus prepared contain less than 2 wt.% of volatile organic compounds. Further, in view of the method of their preparation, the core of the nano-elements is considered to form a continuous phase, resulting in a non-porous core. In certain cases, the WITC can be biodegradable and / or can be modified to enhance any desired property thereof (e.g., with respect to the release of the active agent).

[0010] As used herein, the term "nanoelement" refers to a structure that particularly includes WITC (plasticized or unplasticized) and an active agent (regardless of the location of these active agents relative to the core), and refers to particles that are generally spherical in shape, which can be relatively solid nanoparticles or relatively liquid nanodroplets at room temperature, with an average diameter of 1000 or less, 750 nm or less, 500 nm or less, or 250 nm or less, particularly 200 nm or less, 150 nm or less, 100 nm or less, 75 nm or less, or 50 nm or less. Such structures can be dispersed (e.g., due to nanosizing) in a homogeneous medium and are capable of forming a nano-suspension therein. Such nanoelements generally have an average diameter of 2 nm or greater, 5 nm or greater, 10 nm or greater, 15 nm or greater, or 20 nm or greater. In some embodiments, the average diameter of the nanoelements for use in preparing a pharmaceutical composition according to the present teachings is between 2 nm and 1000 nm, between 2 nm and 750 nm, between 2 nm and 500 nm, or between 2 nm and 250 nm. In other embodiments, the average diameter of the nanoelements is between 2 nm and 200 nm, between 5 nm and 150 nm, between 10 nm and 100 nm, between 15 nm and 75 nm, or between 20 nm and 50 nm. The average diameter of the nanoelements can be determined by any suitable method and can refer to the hydrodynamic diameter determined for 50% of the nanoelements measured by dynamic light scattering (DLS) and counted by number (D N 50) or by volume (D V 50). In a particular embodiment, the average diameter of the nanoelements is determined by number.

[0011] Although one of the characteristics of nanoelements is their dispersibility in a polar liquid carrier, e.g., the nanoelements are hydrophobic and the liquid is aqueous, the composition to be administered to a subject or living object in need thereof is not necessarily in liquid form. The nanoelements can be separated from the polar liquid carrier in which they may be dispersed for use in preparing the desired drug in dry form. Thus, although the nanoelements contained in the present drug (when the composition is liquid) are generally referred to as "dispersed", the term encompasses nanoelements that are "dispersible" if in a suitable liquid environment.

[0012] When the dispersible nanoelements are dispersed in a polar liquid carrier, they are typically characterized by discrete individual nanoelements, separated from each other, with minimal aggregation or agglomeration, so as to stably maintain their particle size distribution (PSD) as described herein for a long period of time (e.g., the fluctuations in the PSD of the dispersion are not significant and are stable for at least 1 day). The dispersibility can be confirmed by microscopic means and the particle size distribution of the nanoelements can be analyzed by standard methods such as DLS.

[0013] These compositions can be used for the benefit of living animals (such as mammals or non-mammals, humans or non-humans) or living organisms (such as seasonal or perennial plants and their parts or products). Therefore, the drugs prepared therefrom can be referred to by various names depending on the target group, the intended use of the active agent contained in the nano-elements (in their core and / or shell), and / or the route of administration. Regarding the latter, the present invention particularly relates to administration via a route other than the visible skin of a living animal or the external / exposed surface of an object. For simplicity, all routes of administration other than the above-excluded routes can be referred to as "non-exposed-surface administration (NESA)" or "internal administration", even when referring to an object, and when the subject is a living animal, it can particularly be referred to as "non-dermal administration (NDA)", the surface excluded by this route of administration being its exposed skin. The route of administration of this drug can also be abbreviated as NESA (or NDA) or NES (or ND) administration, as well as similar grammatical variants. When referring to the use of drugs and / or the present compositions that can be administered via the NES or ND route, the acronyms NES or ND can be used similarly to other terms.

[0014] These compositions or the drugs made therefrom are generally referred to as pharmaceuticals when intended for administration to a living subject, and when the living subject is a non-human animal, the term includes veterinary products. Pharmaceuticals can be used to deliver active agents via various routes, including local routes (the effects of which are essentially limited to the site of administration, such as oral, ocular, otic, rectal, nasal, vaginal, and via similar non-exposed cavities of the subject's body) and systemic routes (for systemic effects, i.e., enteral or parenteral routes, such as injection, sublingual, inhalation, nebulization, intrathecal, epidural, etc.). As shown by the exemplary routes of administration to a living subject, some organs that may be treated by this drug or that may serve as entry points for the active agents it carries have exposed parts including the skin, such as the eyelids, but the envisioned delivery is considered non-dermal (through the eye surface, through mucous membranes, through the internal parts of the organ, etc.).

[0015] When used to prepare agrochemical products, the compositions can deliver specific active agents by injection into the plant or its related parts (such as the trunk or branches). Irrigating the soil around the plant with an agrochemical product can also achieve systemic delivery of the active agent through root absorption.

[0016] As used herein, the term "active agent" refers to any substance that is capable of diagnosing, preventing, ameliorating, alleviating, delaying, or arresting the progression of and / or curing a condition being treated by NES (e.g., ND) administration of a medicament, or a substance having any similar effect commonly associated with active agents known to those of skill in the art. By way of example, such substances include those commonly referred to as medicaments, as well as food supplements (e.g., electrolytes, vitamins, minerals, metals, and any similar nutrients) and alternative substances traditionally known to improve an individual's health or wellness. Thus, similarly, a "medicament" refers to a composition containing such an active agent that can provide a similar diagnostic, prophylactic, or therapeutic effect (to whatever degree) for a target condition, and the medicament is typically formulated according to the NES route by which it is to be administered. Any and all of these effects that an active agent or a medicament containing an active agent can achieve are considered to be a "treatment" of the subject or object to which the medicament is to be administered, and the term encompasses the detection of disease.

[0017] The medicament can be administered by NES (e.g., ND) to provide any such desired treatment alone, or can be used to increase the efficacy of a co-administered treatment for the same condition, regardless of the mode of administration and / or the composition of the co-treatment. The degree of treatment or co-treatment (as meant by the foregoing examples) and the efficacy of the medicament prepared and administered according to this teaching can be evaluated by the alleviation of symptoms associated with the condition being treated or the increase in activity associated with the property desired to be enhanced.

[0018] In a first aspect of the present disclosure, there is provided the use of a composition for the preparation of a medicament for treating a subject or object by administration to a non-exposed surface of a living subject or object (e.g., by the ND route), the composition comprising nano-elements dispersible in a polar carrier, the nano-elements comprising:

[0019] a) at least one water-insoluble thermoplastic compound (WITC) that forms the core of each nano-element; and

[0020] b) at least one active agent miscible with the WITC and insoluble in the polar carrier and thus located within the core;

[0021] wherein each component of the nano-elements has a vapor pressure of 40 Pascals (Pa) or less as measured at a temperature of about 20 °C; and wherein the nano-elements have an average diameter of 1000 nm or less (e.g., D N 50).

[0022] An active agent that is miscible with WITC (and thus is referred to as a "WITC - miscible" active agent) and insoluble in a polar carrier (and thus is referred to as a "polar - carrier - insoluble active agent" or "carrier - insoluble active agent") can be referred to as "WITC - miscible / polar - carrier - insoluble". As used herein, a component is considered "insoluble" in a polar liquid carrier (such as water) when its solubility in the polar liquid carrier at a temperature of 20 °C is less than 5 wt.%, more typically less than 4 wt.%, less than 3 wt.%, less than 2 wt.%, less than 1 wt.% or less than 0.5 wt.%, based on the weight of the polar carrier. Additionally, a component is considered "miscible" in WITC if it can form a homogeneous mixture with WITC without causing phase separation or any other similar change in the mixture due to the formation of continuous nuclei. The solubility of such WITC - miscible materials in WITC is typically 5 wt.% or higher (more typically 6 wt.% or higher, 7 wt.% or higher, 8 wt.% or higher, 9 wt.% or higher or 10 wt.% or higher), based on the weight of the WITC with which it is mixed.

[0023] In some embodiments, the nano - elements (separated from the liquid medium) have a dynamic viscosity measured at at least one temperature between 20 °C and 80 °C and a shear rate of 10 -1 millipascal - seconds (mPa·s) or lower, 10 7 mPa·s or lower, 10 6 mPa·s or lower, 10 5 mPa·s or lower, 10 4 mPa·s or lower or 10 3 mPa·s or lower. In some embodiments, under the same measurement conditions, the dynamic viscosity of the nano - elements is at least 1 mPa·s, at least 10 mPa·s or at least 100 mPa·s. This viscosity of the nano - elements can be generated by the inherent viscosity of WITC or each WITC, or when there is more than one WITC, by their mixture, or can be generated by the active agent (or any other compound to be discussed later) present in WITC. In other cases, a non - volatile liquid can be present in the core to plasticize WITC so as to reduce the viscosity of the nano - elements of the present drug to the above - mentioned range.

[0024] The viscosity of the bulk WITC used to prepare the nano - elements can be referred to as the first (or natural) viscosity of WITC or its mixture, while the viscosity of the nano - elements containing at least WITC and the active agent can be referred to as the second viscosity. More generally, the property characterizing the bulk WITC contained in the core can be referred to as the "first" property, while the similar property measured on the nano - elements can be referred to as the "second" property, which can have the same or different values compared to the natural WITC.

[0025] In some embodiments, at least one WITC (and / or a nanoelement comprising it, optionally a WITC plasticized by a non-volatile liquid) has at least one, at least two, or at least three of the following structural properties:

[0026] i. The WITC and / or the nanoelement is insoluble in a polar carrier;

[0027] ii. The WITC and / or the nanoelement is biodegradable and / or biocompatible;

[0028] iii. At least one of the melting temperature (Tm), softening temperature (Ts), or glass transition temperature (Tg) of the WITC and / or the nanoelement is at most 300 °C, at most 250 °C, at most 200 °C, at most 180 °C, at most 150 °C, or at most 120 °C, where the temperature is the first (i.e., natural) Tm, Ts, or Tg of the WITC, or the second Tm, Ts, or Tg of the nanoelement, or both;

[0029] iv. The WITC and / or the nanoelement each have a first and / or second Tm of at least 0 °C, at least 10 °C, at least 20 °C, at least 30 °C, at least 40 °C, at least 50 °C, or at least 60 °C;

[0030] v. The WITC and / or the nanoelement each have a first and / or second Tm between 0 °C and 300 °C, between 10 °C and 300 °C, between 20 °C and 300 °C, between 20 °C and 250 °C, between 20 °C and 200 °C, between 30 °C and 180 °C, between 40 °C and 150 °C, or between 50 °C and 120 °C;

[0031] vi. The WITC and / or the nanoelement have a first and / or second Tg or Ts of -75 °C or higher, -50 °C or higher, -25 °C or higher, 0 °C or higher, 10 °C or higher, 20 °C or higher, 25 °C or higher, 30 °C or higher, 40 °C or higher, 50 °C or higher, or 60 °C or higher;

[0032] vii. The WITC and / or the nanoelement have a first and / or second Ts or Tg between -75 °C and 300 °C, between -50 °C and 250 °C, between -25 °C and 200 °C, between 0 °C and 180 °C, between 20 °C and 300 °C, between 20 °C and 250 °C, between 20 °C and 200 °C, between 20 °C and 180 °C, between 30 °C and 180 °C, between 40 °C and 180 °C, between 30 °C and 150 °C, between 50 °C and 150 °C, or between 50 °C and 120 °C;

[0033] viii. Each of the WITC and / or the nano-elements has at least one temperature between 20 °C and 80 °C and a first and / or second viscosity measured at a shear rate of 10 sec -1 and a shear rate of 10 sec 7 mPa·s or less, 5 x 10 6 mPa·s or less, 10 6 mPa·s or less, 5 x 10 5 mPa·s or less, 10 5 mPa·s or less, 5 x 10 4 mPa·s or less, 10 4 mPa·s or less, 5 x 10 3 mPa·s or less or 10 3 mPa·s or less;

[0034] ix. The WITC has a molecular weight of 0.5 kDa or higher, 0.7 kDa or higher, 0.8 kDa or higher, 0.9 kDa or higher, 1 kDa or higher, 1.5 kDa or higher, 2 kDa or higher, 2.5 kDa or higher, 3 kDa or higher, 3.5 kDa or higher, 4 kDa or higher, 4.5 kDa or higher, 5 kDa or higher, 5.5 kDa or higher, 6 kDa or higher, 6.5 kDa or higher, or 7 kDa or higher;

[0035] x. The WITC has a molecular weight of 500 kDa or lower, 300 kDa or lower, 200 kDa or lower, 100 kDa or lower, 80 kDa or lower, 50 kDa or lower, 25 kDa or lower, or 15 kDa or lower; and

[0036] xi. The WITC has a molecular weight between 0.5 kDa and 500 kDa, between 0.6 kDa and 500 kDa, between 0.7 kDa and 300 kDa, between 0.8 kDa and 200 kDa, between 1 kDa and 100 kDa, between 2 kDa and 80 kDa, between 1.5 kDa and 500 kDa, between 2.5 kDa and 300 kDa, between 3 kDa and 200 kDa, between 3.5 kDa and 500 kDa, between 4 kDa and 500 kDa, between 5 kDa and 300 kDa, between 5.5 kDa and 300 kDa, between 6 kDa and 200 kDa, between 6.5 kDa and 200 kDa, or between 7 kDa and 200 kDa.

[0037] In some embodiments, at least one structural property satisfied by at least one WITC and the nano-elements (optionally including plasticized WITC) is: property i) listed above, property ii) listed above, property iii) listed above, property iv) listed above, property v) listed above, property vi) listed above, property vii) listed above, property viii) listed above, property ix) listed above, property x) listed above, or property xi) listed above.

[0038] In some embodiments, at least two structural properties satisfied by at least one WITC and the nano-elements (optionally including plasticized WITC) are: property i) and ii), property i) and v), property i) and vii), property i) and viii), property i) and xi), property ii) and v), property ii) and vii), property ii) and viii), property ii) and xi), property v) and xi), property vii) and xi), or property viii) and xi).

[0039] In some embodiments, at least three structural properties satisfied by at least one WITC and the nano-elements (optionally including plasticized WITC) are: property i), ii) and iii), property i), ii) and v), property i), ii) and vii), property i), ii) and viii), property i), ii) and xi), property i), v) and vii), property i), v) and viii), property i), vii) and viii), property i), v) and xi), property i), vii) and xi), or property i), viii) and xi).

[0040] In certain embodiments, the water-insoluble thermoplastic compound (WITC) is a water-insoluble thermoplastic polymer (WITP) composed of repeating structural units, where these monomers can be the same (forming a homopolymer) or different (forming a random or block copolymer). While the molecular weight of non-polymeric compounds is typically up to 2 kDa and generally does not exceed 1 kDa, the WITP can be a larger molecule of at least several thousand Daltons.

[0041] Taking into account their intended use and / or method of preparation, WITCs suitable for the medicaments of the present invention are advantageously but not necessarily relatively solid within the range from room temperature (about 25 °C) to body temperature (e.g., about 37 °C for a human subject). This preference also applies to the nano-elements containing them, further taking into account the presence of any materials that affect the thermal behavior of the product, such as active agents and / or non-volatile liquids and their respective relative contents. Those skilled in the art will understand that since WITCs can be thermoplastic polymers, the "relatively solid state" or "relative solidity" of such materials at any given temperature refers to the fact that they are not necessarily in a solid state but exhibit viscoelastic behavior. Without wishing to be bound by any particular theory, this property of WITCs should ensure to the necessary extent that the nano-elements made therefrom are relatively non-sticky, facilitating their uniform distribution in the compositions or medicaments according to the present teachings.

[0042] The composition can be incorporated into the medicament of the present invention in the form of a nano-suspension. Depending on the Tm or Ts of the WITC forming the core of the nano-elements, the composition can be in the form of a nano-dispersion at room temperature (i.e., if the Tm or Ts is higher than 25 °C, for example, between 25 °C and 80 °C), with the nano-elements being relatively solid nano-particles, or can be in the form of a nano-emulsion (i.e., if the Tm or Ts is lower than 25 °C), with the nano-elements being relatively liquid nano-droplets. Alternatively, although the nano-elements can be dispersed in a polar liquid and are capable of forming a nano-dispersion or nano-emulsion therewith, they are used in a form separated from such a medium during the preparation of the medicament. For example, the present composition can be added in liquid form to a solid excipient of a dry dosage form and dried and compacted therewith, or added to the excipient after lyophilization.

[0043] WITCs (such as WITP) can be natural compounds, even synthetic ones, or synthetic compounds that do not have a natural occurrence form. Some compounds suitable for the present teachings may assemble to form larger molecules regarded as polymers under certain circumstances. Such compounds should be referred to as polymerizable before the formation of these linkages.

[0044] In some embodiments, the polymerizable WITCs are natural compounds selected from resins, gums, gum resins, and combinations thereof. In a particular embodiment, the polymerizable WITC is shellac or rosin.

[0045] In some embodiments, the WITC is non-polymerizable, such as quinones, in particular ubiquinone, also known as 1,4-benzoquinone or coenzyme Q10 (CoQ10).

[0046] In other embodiments, the WITC is a WITP, which can also be of synthetic or natural origin. In some embodiments, the thermoplastic polymer is a biodegradable polymer selected from the polymer families including: aliphatic polyesters, polyhydroxyalkanoates, poly(olefin dicarboxylates), polycarbonates, aliphatic-aromatic copolyesters, their isomers, their copolymers, and combinations thereof. Although some of the above polymers have natural counterparts, these exceptions are generally only commercially available in almost exclusively artificially prepared forms, so the entire group is generally regarded as representative of synthetic polymers.

[0047] Alternatively, the thermoplastic polymer can be a non-biodegradable synthetic polymer such as polyamide (PA), polyethylene (PE), poly(ethylene-co-acrylic acid) (PEAA), poly(ethylene-co-methacrylic acid) (PEMAA), poly(ethylene-co-n-butyl acrylate) (PEBA), poly(ethylene-co-vinyl acetate) (PEVA), polymethyl methacrylate (PMMA), polypropylene (PP), polysiloxane, polystyrene (PS), polytetrafluoroethylene (PTFE), polyurethane (PU), or polyvinyl chloride (PVC).

[0048] In other embodiments, the WITP is a natural biodegradable polymer selected from polysaccharides, lignin, and combinations thereof.

[0049] In certain embodiments, the WITC is a biodegradable material such as CoQ10, shellac, rosin, or a WITP that is an aliphatic polyester. In further specific embodiments, the aliphatic polyester is selected from polycaprolactone, polylactic acid, poly(lactic-co-glycolic acid), poly(butylene succinate-adipate), their isomers, their copolymers, and combinations thereof.

[0050] In some embodiments, the non-volatile liquid that can be added to the WITC to reduce at least one of its first (natural) viscosity, Tm, Tg, and Ts is selected from the group including: monofunctional and polyfunctional aliphatic esters, aromatic esters, fatty esters, cyclic organic esters, terpenes, aromatic alcohols, aromatic ethers, aldehydes, and combinations thereof. In some embodiments, the non-volatile liquid is an aliphatic or aromatic fatty ester. In certain embodiments, the non-volatile liquid is selected from: dibutyl adipate, dibutyl sebacate, benzyl benzoate, triethyl O-acetylcitrate, C 12 -C 15 alkyl benzoates, and dioctyl carbonate.

[0051] In other embodiments, when the polymer is a non-biodegradable synthetic polymer, the non-volatile liquid can also be selected from the group including: mineral oils, natural oils, vegetable oils, essential oils, synthetic oils, and combinations thereof, provided that they meet this requirement. Non-limiting examples of synthetic oils include synthetic isoparaffins (such as Isopar TMM and Isopar TM V), C 12 -C 15 alkyl ethylhexanoate, C 12 -C 15 alkyl benzoate, or isononyl isononanoate, to name just a few. Non-limiting examples of suitable vegetable oils include castor oil, corn oil, pomegranate seed oil, or avocado oil, to name just a few. Non-limiting examples of essential oils include clove leaf oil, lavender oil, or oregano oil, to name just a few.

[0052] In some embodiments, the polar carriers in which the nano-elements comprising WITC and the carrier-insoluble surfactant can be dispersed (e.g., if the composition is in dry form) or dissolved (e.g., if the composition is in liquid form) therein include water, diols (e.g., propylene glycol, 1,3-butanediol, 1,4-butanediol, 2-ethyl-1,3-hexanediol, and 2-methyl-2-propyl-1,3-propanediol), formamide, acetonitrile, glycerol, its precursors and derivatives, collectively referred to herein as “glycerols” (e.g., acrolein, dihydroxyacetone, glyceric acid, tartronic acid, epichlorohydrin, glycerol tert-butyl ether, polyglycerol, glycerol esters, and glycerol carbonate), and combinations thereof. In certain embodiments, the polar carrier comprises water, consists of water, or is water.

[0053] In some embodiments, the composition further comprises at least one surfactant selected from emulsifiers and cosolvents. The surfactant can be present in the nano-elements comprising WITC (e.g., if it is a polar carrier-insoluble surfactant), in the liquid phase comprising the polar carrier (e.g., if it is a polar carrier-soluble surfactant), or in both (e.g., if it is an intermediate emulsifier).

[0054] In some embodiments, the composition for preparing the present medicament further comprises more than one active agent in addition to the active agent embedded in the WITC nano-elements. The additional active agents can be in the same or different phases. For example, a first additional active agent, which is WITC-miscible / polar carrier-insoluble, can be included within the nano-elements, while a second additional active agent, which is carrier-soluble, can be included in the polar carrier phase.

[0055] If the solubility of an active agent in the carrier in which it is immersed is 5 wt.% or higher (more typically 6 wt.% or higher, 7 wt.% or higher, 8 wt.% or higher, 9 wt.% or higher, or 10 wt.% or higher) by weight of the polar carrier at a temperature of 20 °C, the active agent is considered soluble in the liquid carrier and is, for example, a "polar carrier-soluble active agent" (or "carrier-soluble active agent"). Those skilled in the art will understand that some materials with the desired activity may be insoluble in the polar carrier in one chemical form and soluble in the polar carrier in another chemical form, and salts of the material generally increase its solubility.

[0056] Advantageously, compared with conventional compositions containing such components, the composition for preparing the present drug can have: a) a relatively high concentration (e.g., 1 wt.% or higher) of WITC (e.g., WITP) and / or a WITC miscible / carrier-insoluble active agent embedded therein; and / or b) the WITC and / or the active agent therein can have a relatively high molecular weight. Therefore, the present nanocarrier can be used to prepare pharmaceutical and / or agrochemical products capable of delivering an active agent with a relatively high molecular weight and / or a relatively high concentration. Without wishing to be bound by theory, the relatively high loading of WITC and / or the active agent, and the relatively high potency of the nanoelement (when the efficacy also depends on the molecular weight of the active agent that may be delivered), are each expected to improve the efficacy of the product (whether a pharmaceutical or an agricultural product).

[0057] In a second aspect of the present disclosure, there is provided the use of a composition for preparing a drug for treating a subject or an object by administering the drug through a non-exposed surface of the living subject or object (e.g., through the ND route), the composition comprising nanoelements dispersible in a polar carrier, the nanoelements being core-shell nanoelements and consisting of:

[0058] I. A core containing at least one WITC;

[0059] II. A shell surrounding the core, the shell containing at least one polar carrier-insoluble shell-forming agent (SFA) or a part thereof; and

[0060] III. A polar carrier-insoluble active agent located at least in one of the core and the shell of the nanoelement;

[0061] wherein the vapor pressure of each component of the core-shell nanoelement is 40 pascals (Pa) or lower as measured at a temperature of about 20 °C; and wherein the nanoelement has an average diameter of 1000 nm or smaller (e.g., D N 50).

[0062] As for materials, the WITC and polar carriers of the core-shell nano-elements, as well as the carrier-insoluble active agents, non-volatile liquids, surfactants, and carrier-soluble active agents in the presence in the composition, are substantially as described above and detailed herein. Since the methods for preparing the core and core-shell nano-elements have common steps, in any case, the core is considered to be continuous / non-porous.

[0063] All materials forming the core or core-shell nano-elements according to the first or second aspect disclosed herein are set to be relatively non-volatile, with their respective or combined vapor pressures not exceeding 40 Pa. In some embodiments, the vapor pressures of the nano-elements and each of their components are measured to be 20 Pa or lower, 5 Pa or lower, or 1 Pa or lower at a temperature of about 20 °C.

[0064] In some embodiments, the SFA does not form a covalent bond with the WITC.

[0065] When the shell former is mixed with the WITC during the preparation of the nano-elements, a shell-like structure surrounding the core is generated. They are generally amphiphilic molecules, consisting of a relatively large hydrophobic part forming a hydrophobic "tail" and a hydrophilic "head", where the hydrophobic tail is encompassed (trapped) within the core containing the WITC, and the hydrophilic head migrates to the core surface under suitable conditions (such as the viscosity of the core, the polarity of the surrounding liquid) to form a shell.

[0066] It is mainly found that the hydrophobic tail of the SFA in the core of the core-shell nano-elements is usually the fatty part of an aliphatic compound, and this tail is usually a straight-chain, branched-chain, or cyclic, saturated or unsaturated, aliphatic or aromatic, alkyl or aryl hydrocarbon chain. In some embodiments, the water-insoluble / WITC-miscible SFA forming the shell is selected from the group including: fatty amines, fatty acids, and metal salts of alkylaryl sulfonates or petroleum sulfonates. When the SFA is a fatty amine, the hydrocarbon chain usually contains 8 to 22 carbon atoms. When the SFA is a fatty acid, the chain usually contains 5 to 40 carbon atoms. When the SFA is a metal salt of a sulfonate, the metal counterion can be, for example, barium, calcium, magnesium, or sodium, and the alkylaryl or petroleum hydrocarbon chain usually contains 20 to 30 carbon atoms.

[0067] Unlike other molecules that may be added to the WITC and may migrate inherently during the preparation of the nano-elements, the hydrophilic head of the SFA, which is mainly found in the shell of the core-shell nano-elements, is usually a chemically group that can be charged in a polar carrier (in which the core-shell nano-elements can be dispersed). Depending on the chargeable chemical group and the polar carrier (such as composition and pH), the shell can be positively charged or negatively charged. The total charge of the core-shell nano-elements in the same polar carrier also depends on the relative ratio of SFA to WITC, as well as the chemical properties of WITC, which usually provides a negative charge. Therefore, depending on the chemical properties and respective amounts of the material constituting the core and the material constituting the shell (if present), and the medium in which such core or core-shell nano-elements are dispersed, they can be adjusted to have a positive or negative charge with an absolute value of 5 mV or higher, 10 mV or higher, 20 mV or higher, 30 mV or higher, or 40 mV or higher, and the absolute value of the charge generally does not exceed 100 mV. For example, the negative charge can be in the range of -100 mV to -5 mV, and the positive charge can be in the range of +5 mV to +100 mV. In the presence or absence of a shell, this charge or chargeability of the nano-elements is generally evaluated in the presence of water and measured at room temperature.

[0068] The relative charge of the nano-elements can promote their dispersibility in a liquid medium and / or the attachment of additional molecules (e.g., and / or attachment to a desired target tissue). Nano-elements with sufficient charge (positive charge (e.g., +30 mV or higher) or negative charge (e.g., at least -30 mV)) can be stably dispersed by the electrostatic repulsion force between the charged nano-elements, thus eliminating the need for a dedicated dispersant. A composition containing such nano-elements that are self-sufficient in terms of dispersibility can be referred to as "self-emulsifying", "capable of self-emulsifying", and similar grammatical variants. If the drug is in liquid form, nano-elements with a charge between -30 mV and +30 mV may require special attention to maintain stable dispersion, and appropriate modification of the liquid medium may be required (e.g., by adding a dispersant or any other reagent that promotes nanoparticle repulsion through a mechanism other than electrostatics). However, the chargeability of the nano-elements is not essential, and the core or core-shell nano-elements can have a near-neutral charge between -5 mV and +5 mV.

[0069] In certain embodiments, the water-insoluble / WITC-miscible SFA is selected from the group consisting of oleylamine, octylamine, oleyl bis(2-hydroxyethyl)amine, N,N-dimethyldodecylamine (DMDA), cetyltrimethylammonium chloride (CTAC), octanoic acid, and combinations thereof.

[0070] In some embodiments of the second aspect of the present invention, the composition used in the present invention further comprises a water-soluble active agent in a polar carrier, and this material forms a second shell on the surface of the core-shell nanoelement. In some embodiments, the second shell consists of at least one layer of carrier-soluble active agent. The nanoelement comprising a) a WITC core including at least a WITC miscible / polar carrier-insoluble active agent (and optionally non-volatile liquids, surfactants, and similar WITC miscible / polar carrier-insoluble materials that may be required in the core), b) a first shell including at least the polar part of SFA, and c) a second shell that is at least one layer of carrier-soluble active agent may be referred to as a core-shell or core-multishell nanoelement. As used herein, the term core-shell encompasses core-shell nanoelements having only a first shell containing SFA directly surrounding the core, as well as core-shell nanoelements further having a second shell surrounding the first shell and indirectly surrounding the core.

[0071] Advantageously, the first shell of the core-multishell nanoelement is charged in the aqueous polar carrier of the composition, which facilitates the non-covalent formation of the second shell. For example, a positively charged first shell can electrostatically attract negatively charged carrier-soluble active agent molecules in the polar carrier. In this case, a nanoelement that was originally positively charged and had only one layer of SFA shell in the medium under consideration may become less positively charged, electrostatically neutral, or negatively charged. Additionally, or alternatively, the first shell can form a covalent bond with the second shell of the carrier-soluble active agent, promoting their indirect attachment to the core.

[0072] Preferably, the covalent or non-covalent wrapping manner of the second shell around the first shell should be such that the size of the nanoelement does not exceed the size range disclosed herein.

[0073] Since the active agents applicable to the preparation of this drug can be non-polar and completely soluble in WITC, polar and completely soluble in the polar carrier, or amphiphilic, similar to SFA, their hydrophobic parts can be in the core and their hydrophilic parts form a shell around the core. Accordingly, the active agents can be considered to be (completely) contained in the core, (externally) anchored to the core (e.g., covalently or electrostatically through the first shell), or (partially) encompassed in the core (i.e., through the hydrophobic tail). If more than one active agent is included in the present nanoelement, they can also be distributed in different regions of the core-shell.

[0074] Regarding the uses of the compositions for preparing drugs disclosed herein, and the treatments of living subjects or objects that they may achieve after administering the drugs through non-exposed surfaces (e.g., through the ND route), which depend on the active agents contained within, entrapped within, and / or anchored to the core of the nano-elements. If the subjects who benefit from such drugs or treatments are humans or non-human animals, such uses can be for preparing drugs as pharmaceuticals (including veterinary products), and such drugs are configured for treating (including any medically relevant steps from diagnosis to cure, by means of prevention, delay, or alleviation, etc.) any disease according to the active agents present in the nano-elements (regardless of which part of the nano-elements they are located in).

[0075] If the non-exposed surface is not of the subject to be treated, but of an object related to human or veterinary medicine, the use of the nano-elements can still be regarded as a pharmaceutical use. For example, the present drug can be used to coat a prosthetic implant intended to artificially replace a part of the body. Alternatively, the nano-elements can be used to prepare agrochemical products, with the object being a plant or its part.

[0076] Other objects, features, and advantages of the present disclosure will be set forth in the following detailed description, and some will be apparent from the description, or will be recognized by practicing the disclosure described in the specification and claims, as well as the accompanying drawings. Sub-combinations of various features and embodiments of the present disclosure can be used without reference to other features and sub-combinations.

[0077] For example, other objects include corresponding treatment methods for treatable conditions by the active agents deliverable by the present nano-elements, administering the active agents in an effective amount to a subject or object in need of such treatment, and the drugs deliverable in such methods. Description of the Drawings

[0078] Some embodiments of the present disclosure will now be further described by way of example, with reference to the accompanying drawings, in which the same reference numerals or characters represent corresponding or similar components. The description in conjunction with the drawings enables those of ordinary skill in the art to clearly understand how some embodiments of the present disclosure can be implemented. The drawings are for illustrative discussion and do not attempt to show the structural details of the embodiments in more detail than is necessary for understanding the basic content of the present disclosure. For clarity and ease of presentation, some of the objects depicted in the drawings are not necessarily shown to scale.

[0079] In the drawings:

[0080] Figure 1 A simplified schematic diagram of a method for preparing nano-elements suitable for a composition according to an embodiment of the present teachings is depicted;

[0081] Figure 2AShows the particle size distribution of core nano-elements containing WITC miscible active agents prepared according to the present teachings, measured by dynamic light scattering and presented as a number;

[0082] Figure 2B Shows the particle size distribution of core-shell nano-elements containing WITC miscible active agents and SFA prepared according to the present teachings, measured by dynamic light scattering and presented as a number;

[0083] Figure 3 Schematically illustrates a core-shell nano-element in which the polar part of the SFA forming the first shell is uncharged (e.g., in a non-aqueous polar carrier);

[0084] Figure 4 Schematically illustrates a positively charged core-shell nano-element surrounded by a second shell formed by surfactant molecules;

[0085] Figure 5 Is a cryo-transmission electron microscopy (CryoTEM) image of a core nano-element prepared according to the present teachings, which contains a WITC miscible / polar carrier-insoluble active ingredient and is safe outside;

[0086] Figure 6A Is a CryoTEM image of a core-shell nanoparticle prepared according to the present teachings and surrounded by a second shell of a carrier-soluble surfactant;

[0087] Figure 6B Is related to Figure 6A A CryoTEM image of a core-shell nanoparticle surrounded by a second shell that has undergone partial coalescence, similar to that shown in;

[0088] Figure 7A Is a picture of cortical neuron cells after applying the nano-elements according to an embodiment of the present teachings, and the nucleus includes a fluorescent label for demonstrating cell penetration;

[0089] Figure 7B Is Figure 7A A schematic depiction of the cell penetration image of; and

[0090] Figure 8 Is a pharmacokinetic graph showing the change in tadalafil concentration over time in rat plasma after oral administration of nano-elements according to the present teachings containing tadalafil in their core, compared to commercial And tadalafil API provided as a suspension at a similar dose. Detailed Description

[0091] The present invention relates in particular to the use of a composition for the preparation of pharmaceutical products (for the treatment of human and non-human subjects) and agrochemical products (for the treatment of objects), said composition being administered via a non-exposed surface of the subject or object, said composition comprising nano-elements, such as nanoparticles or nano-droplets, which comprise a water-insoluble thermoplastic compound (WITC) capable of forming a core (in particular a water-insoluble thermoplastic polymer (WITP)), said nano-elements further comprising an active agent and being capable of being dispersed or dispersed as a nano-suspension in a polar carrier. The nano-elements can be in the form of nuclei or core-shell nano-elements as described above and detailed herein. Advantageously, if desired, the WITC can be plasticized by a non-volatile liquid, which can also be referred to as a plasticizer. Since the nano-elements can be prepared from components having low volatility, they can be characterized by a low content of volatile organic compounds (VOC), the content of such volatile compounds being less than 1 wt.% of VOC or a mixture thereof by weight of the nano-elements. The nano-elements comprising optionally plasticized WITC and an active agent can also include any other desired compounds, such as any material miscible with the core or (for core-shell nano-elements) any shell, to achieve or increase the dispersibility of the nano-elements in the composition, to adjust their charge or any other property suitable for increasing the stability of the nano-elements over time, to further enhance or modify the activity of the composition (e.g., release of the active agent from the nano-elements) and / or to increase the compatibility of the nano-elements with their intended formulation as a drug. A method for preparing such nano-elements is also disclosed.

[0092] Before explaining at least one embodiment in detail, it is to be understood that the present disclosure is not necessarily limited to the structural details and arrangements of components and / or methods set forth herein. The present disclosure is capable of other embodiments or of being practiced or carried out in various ways. The language and terminology used herein are for descriptive purposes and should not be regarded as limiting.

[0093] It is to be understood that the foregoing general description and the following detailed description (including materials, methods, and examples) are merely exemplary of the present disclosure, and are intended to provide an overview or framework for understanding the nature and characteristics of the claimed invention, and are not necessarily intended to be limiting.

[0094] Biodegradability

[0095] The WITC used in the present invention can be biodegradable and can thus be decomposed by any suitable biodegradation mechanism appropriate to its structure and chemical properties. After the nano-elements are administered to a living subject or object, the WITC can be degraded by biological mechanisms such that the active agent carried thereby can be released at the site and time of biodegradation and during degradation. Suitable WITCs are generally biocompatible with the physiological environment in which they may be biodegradable, such as the environment found after delivery in the form of nano-elements. Suitable WITCs can also be referred to in the general literature as bioabsorbable or biouptakeable, depending on their fate in the body and the expected elimination from the body, but for simplicity, all such compounds will generally be collectively referred to herein as "biodegradable". A WITC is said to be biodegradable if it decomposes relatively rapidly (e.g., by bacterial decomposition processes in the environment or by enzymatic or metabolic processes in the body) after achieving its purpose, producing natural by-products. Biodegradable WITCs are known and new WITCs are being developed. Their relative biodegradability in various environments can be evaluated by a number of methods, which can be based on standards such as ASTM F1635 or protocols modified therefrom, depending on the conditions of interest.

[0096] Although the biodegradable WITC suitable for the present invention tends to decompose naturally under suitable physiological conditions, it should be stable and durable enough for its intended use during storage and administration until the nano-elements reach the site targeted by the active agent, which can be particularly challenging if such use involves conditions that enhance biodegradability. For example, a composition containing a WITC and formulated for oral administration as a tablet is expected to withstand the processes of the digestive system, and such a drug should avoid degradation of the WITC before reaching the target. Therefore, these factors should be considered when selecting a suitable WITC for pharmaceutical and agrochemical compositions of the present invention.

[0097] The WITC used in the composition can also be biocompatible, not causing undesirable local or systemic effects when administered to a subject or object. Standard methods for evaluating biocompatibility are known, such as those specified in ASTM F748 and ISO 10993.

[0098] Insoluble

[0099] In addition to possible biodegradability and biocompatibility, the WITC is preferably substantially insoluble in the liquid phase of a composition containing a polar carrier (such as water) in which they are dispersed as nano-elements during the preparation process. For similar reasons, they should be substantially insoluble in the liquid carrier of a liquid formulation (whether the same as or different from the polar carrier used during the preparation process).

[0100] As used herein, the solubility of a material (such as WITC, a non-volatile liquid, or an active agent) refers to the amount of such a component that can be introduced into a liquid (such as a polar) carrier while maintaining the liquid medium clear. The solubility of a particular component in any particular liquid in a composition is typically evaluated in the absence of any other possible components of the composition and in the presence of only the polar carrier, but can also be determined relative to the final composition of the liquid phase including the carrier or relative to the final composition of the liquid carrier of the liquid formulation.

[0101] If the solubility of WITC (or any other material of interest in the present invention) in a polar carrier, a liquid phase containing the polar carrier, or the liquid carrier of a dosage form is 5 wt.% or less, 4 wt.% or less, 3 wt.% or less, 2 wt.% or less, 1 wt.% or less, 0.5 wt.% or less, or 0.1 wt.% or less, by weight of the fluid being considered, it is considered insoluble. For example, in 100 g of a polar carrier, no more than 5 g of the material insoluble in the polar carrier will dissolve. This substantial insolubility, although typically measured at room temperature, preferably should apply at any temperature at which these components are combined and processed, i.e., even at relatively high temperatures, the solubility of these compounds in the polar carrier should remain within the desired range. When the liquid environment being considered is a polar carrier, a material meeting these conditions can be referred to as a "polar carrier-insoluble" material.

[0102] The insolubility of such a material is expected to prevent or reduce the exudation of one or more of WITC and any other WITC miscible components in the nanoelement (such as a carrier-insoluble active agent, a non-volatile liquid, or an SFA) into the surrounding medium. If the material is soluble in the polar carrier, such exudation may affect the relative proportions of the nanoelement components, their size, or any other parameter that may ultimately have an adverse effect on drug efficacy. For example, considering an active agent initially embedded in a WITC nanoelement, if such an active agent leaks in an uncontrolled manner due to inappropriate solubility, such an active agent may be discharged from the nano-carrier inappropriately and / or may be discharged at a location inappropriate relative to the desired target site.

[0103] Regardless of the composition of the polar liquid phase of the polar carrier in which the nanoelement can be dispersed, a polar carrier-insoluble WITC, active agent, or SFA (and any similar WITC miscible material) can first be characterized as water-insoluble (i.e., typically having a solubility in water at room temperature of less than 5 wt.%).

[0104] Molecular weight

[0105] Advantageously, the present invention allows for the delivery of nano-elements comprising a WITC having a relatively high molecular weight as compared to compounds that are typically able to sufficiently penetrate biological barriers such as the vascular wall or cell membrane to exhibit any efficacy. The molecular weight (MW) of the WITC suitable for the present compositions, methods and uses can be 0.6 kDa or higher, 0.7 kDa or higher, 0.8 kDa or higher, 0.9 kDa or higher, 1 kDa or higher, 1.5 kDa or higher, and the molecular weight of the WITP can also be 2 kDa or higher, 2.5 kDa or higher, 3 kDa or higher, 3.5 kDa or higher, 4 kDa or higher, 4.5 kDa or higher, 5 kDa or higher, 5.5 kDa or higher, 6 kDa or higher, 6.5 kDa or higher, 7 kDa or higher or 10 kDa or higher. Generally, if the compound is not a polymer, its molecular weight does not exceed 2 kDa, the molecular weight of the WITP can be up to 500 kDa, and is generally 300 kDa or lower, 200 kDa or lower, 100 kDa or lower, 80 kDa or lower, 50 kDa or lower, 25 kDa or lower or 15 kDa or lower. In another embodiment, the molecular weight of the WITC is between 0.6 kDa and 500 kDa, between 0.7 kDa and 300 kDa, between 0.8 kDa and 200 kDa, between 1 kDa and 100 kDa, between 2 kDa and 80 kDa, between 1.5 kDa and 500 kDa, between 2.5 kDa and 300 kDa, between 3 kDa and 200 kDa, between 3.5 kDa and 500 kDa, between 4 kDa and 500 kDa, between 5 kDa and 300 kDa, between 5.5 kDa and 300 kDa, between 6 kDa and 200 kDa, between 6.5 kDa and 200 kDa or between 7 kDa and 200 kDa.

[0106] As used herein, the term "molecular weight" (or "MW") refers to the actual molecular weight that can be calculated for a non-polymeric WITC or any other compound with a known molecular structure, which can also be expressed in grams per mole, or refers to the weight-average molecular weight of a polymeric WITC or WITP, which may be a mixture of polymers each containing slightly different numbers of repeating units, and the weight-average molecular weight of the polymer is typically expressed in daltons.

[0107] The molecular weight of the WITC can be provided by its supplier and can be independently determined by standard methods, such as including gel permeation chromatography, high performance liquid chromatography (HPLC), size exclusion chromatography, light scattering or matrix-assisted laser desorption / ionization time-of-flight mass spectrometry (MALDI-TOFMS), some of which are described in ASTM D4001 or ISO 16014-3.

[0108] The general rules regarding the molecular weight of WITC examples can be applied to any other component of the composition, whether polymeric or not, and in some embodiments, the active agents added to the core and / or shell of the nanoelement can also be relatively large molecules with a molecular weight of 0.6 kDa or higher, as well as any other values specifically listed for WITC. While most active agents are relatively small molecules (most less than 1 kDa, many with a molecular weight less than 0.6 kDa), many important active agents are relatively large. This is the case, for example, with biologics or biopharmaceuticals, which are typically derivatives of naturally occurring compounds (such as proteins, polysaccharides, nucleic acids, etc.). Examples of relatively large active agents include the hormone insulin (about 6 kDa), the polysaccharide hyaluronic acid, vaccines, blood factors, enzymes, antibodies or parts thereof, and adalimumab with a molecular weight of about 144 kDa

[0109] Characteristic temperature

[0110] While the vast majority of non-polymeric compounds can be characterized by their melting point (Tm), at which they transition from the solid phase to the liquid phase, polymeric compounds, if amorphous, can alternatively or additionally be defined by their glass transition temperature (Tg), and pure amorphous polymers do not have a Tm. Pure crystalline polymers can be characterized by their Tm, and semi-crystalline polymers typically exhibit two characteristic temperatures (e.g., Tg and Tm), reflecting the respective proportions of the amorphous and crystalline portions in the molecule. Such polymers can also be defined by their softening temperature (Ts), which is the midpoint of the logarithmic step during the melting process. Since the glass transition temperature describes the transition from the glassy state to the rubbery state and the softening temperature is the midpoint inflection in the thermal analysis of materials, they typically refer to a temperature range or the temperature at which the process is first observed.

[0111] Therefore, depending on the chemical properties of WITC, the temperature that may characterize its thermal behavior can be at least one of Tm, Ts, and Tg. Thus, when WITC (or a nanoelement containing WITC) is defined as suitably having at least one of a first (or second) Tm, Ts, and Tg within a specific range, the temperature considered is relevant to the material. Some compounds may be identified by two such characteristic temperatures, in which case performing a method step at a temperature higher than either of the two temperatures may be higher than the lower of the two temperatures (which would prolong the step) or higher than the higher one (which would accelerate the step). Conversely, performing a method step at a temperature lower than either of the two temperatures may be lower than the higher or lower of the two temperatures. Taking a semi-crystalline polymer that can be characterized by all three temperatures (Tm, Ts, and Tg, arranged in descending order of value) as an example, heating to above Tg (i.e., above at least one temperature) may not be sufficient to reach Ts or Tm, while heating to above Ts (i.e., above at least two temperatures) may not be sufficient to reach Tm. Only heating to above Tm can ensure that the heating temperature is higher than all three temperatures that can characterize such an exemplary polymer.

[0112] In some embodiments, WITC suitable for use in the present composition is characterized in that at least one of its first (natural) melting point (Tm), softening temperature (Ts), or glass transition temperature (Tg) is at most 300 °C, at most 250 °C, at most 200 °C, at most 190 °C, at most 180 °C, at most 150 °C, or at most 120 °C.

[0113] In some embodiments, the first Tm of WITC is at least 0 °C, at least 10 °C, at least 20 °C, at least 30 °C, at least 40 °C, at least 50 °C, or at least 60 °C. In other embodiments, the first Tm of WITC is between 0 °C and 300 °C, between 10 °C and 300 °C, between 20 °C and 300 °C, between 20 °C and 250 °C, between 20 °C and 200 °C, between 30 °C and 180 °C, between 40 °C and 150 °C, or between 50 °C and 120 °C.

[0114] In some embodiments, WITC is characterized in that at least one of its first Ts and first Tg is -75 °C or higher, -50 °C or higher, -25 °C or higher, 0 °C or higher, 10 °C or higher, 20 °C or higher, 25 °C or higher, 30 °C or higher, 40 °C or higher, 50 °C or higher, or 60 °C or higher. In some embodiments, at least one of the first Ts and Tg of WITC is between -75 °C and 300 °C, between -50 °C and 250 °C, between -25 °C and 200 °C, between 0 °C and 180 °C, between 20 °C and 300 °C, between 20 °C and 250 °C, between 20 °C and 200 °C, between 20 °C and 180 °C, between 30 °C and 180 °C, between 40 °C and 180 °C, between 30 °C and 150 °C, between 50 °C and 150 °C, or between 50 °C and 120 °C;

[0115] When referring to the native / unmodified compound, the characteristic temperature (Tm, Ts or Tg) of WITC can be referred to as the "first" Tm, Ts or Tg, and when referring to the WITC modified to form the core of this nanoelement, it can be referred to as the "second" Tm, Ts or Tg. In some embodiments, the second Tm, Ts or Tg measured on the mixture obtained after mixing WITC with other components (such as WITC miscibility activators, shell-forming agents (SFA), non-volatile liquids or any other desired components), or more precisely, the second Tm, Ts or Tg measured on the nanoelement containing these components, is similar to the corresponding first Tm, Ts or Tg of WITC. Alternatively, the second Tm, Ts or Tg can be lower than the corresponding first characteristic temperature of WITC, in which case WITC is considered to be plasticized or swollen.

[0116] The general rules regarding the suitable thermal behavior of WITC examples can be applied to any other component of the nanoelement that may exhibit or affect the characteristic temperatures described herein. Thus, in some embodiments, a component of the nanoelement (other than WITC), whether alone or in combination with WITC and all other materials forming the nanoelement (such as activators, SFA, etc.), can satisfy the above ranges. In other words, the above thermal properties of the host, native WITC (e.g., the first Tm, the first Ts or the first Tg and the values they should preferably satisfy) can be similarly applied to the nanoelement and its respective second Tm, second Ts or second Tg.

[0117] The thermal properties of WITC or any other component can be provided by its manufacturer or, particularly for nano-elements, determined independently by standard methods. Thermal analysis methods, such as differential scanning calorimetry (DSC), are described in, for example, ASTM3418, ISO3146, ASTM D1525, ISO11357-3, or ASTM E1356. Such measurements can be carried out on the raw material (e.g., the main body WITC), or on intermediate products containing WITC (e.g., mixtures), or on the final product (e.g., nano-elements). For this purpose, the nano-elements containing WITC can be separated from the polar carrier and other reagents present therein. The separation of the nano-elements from the liquid medium can be carried out according to standard methods, such as by drying (e.g., in a vacuum oven) or freeze-drying to evaporate the carrier, or by destabilizing the composition (e.g., by changing the pH) to precipitate the nano-elements. The nano-elements separated from the sample by any suitable method can be additionally rinsed (e.g., with water) to remove residues that may affect the intended measurement, and then the nano-elements are separated from the rinsing liquid. For example, the nano-elements precipitated from the initial medium can be separated by centrifugation, the precipitate can be rinsed and centrifuged again, repeating the cycle until separated and ideally rinsed nano-elements are obtained.

[0118] Polymeric and non-polymeric WITC

[0119] In some embodiments, the water-insoluble thermoplastic compound (WITC) used according to the present teachings is a water-insoluble thermoplastic polymer (WITP), and such polymers also include their fragmented / shorter versions, i.e., oligomers. Since WITP is expected to be biodegradable in the physiological environment of a living subject or object to which it is delivered, such polymers typically contain hydrolysable functional groups or enzymatically cleavable sites. However, the presence of hydrolysable or other cleavable sites is not necessary, and polymers that are considered non-biodegradable may lack these sites.

[0120] In some embodiments, WITC (or WITP) may be non-reactive and unable to establish more complex interactions, being only capable of biodegradation, such as polycaprolactone. In other embodiments, WITC (or WITP) may be biodegradable and have reactive groups capable of interacting with other different molecules, such as polylactic acid, or with other identical molecules, such as a polymerizable natural resin having aldehyde groups. In addition, WITC (or WITP) can be modified, for example, by chemically bonding functional groups to provide, enhance, or regulate its properties.

[0121] Similarly, when WITC is a non-biodegradable compound, such materials can also be reactive or non-reactive. Non-reactive non-biodegradable synthetic thermoplastic polymers can be, for example, polyethylene or polypropylene polymers, while polymers containing reactive groups can be, for example, ethylene-acrylic acid or ethylene-methacrylic acid copolymers.

[0122] As a suitable WITP, it can be of natural or synthetic origin, is essentially thermoplastic, and its shape can be reversibly changed upon appropriate heating and cooling. A suitable WITP can also be plasticized with a suitable non-volatile liquid, and such treatment of the WITP helps to nanosize it, to a certain extent accelerating the delivery of the nano-components and the active agent contained or carried therein.

[0123] Synthetic WITP can be biodegradable and is selected from aliphatic polyesters, polyhydroxyalkanoates, poly(olefin dicarboxylates), polycarbonates, aliphatic-aromatic copolyesters, their enantiomers, their copolymers, and combinations thereof.

[0124] In cases where the monomers forming the WITP have chiral centers, all enantiomers and stereoisomers are encompassed. For example, lactic acid (2-hydroxypropanoic acid, LA) has two enantiomers, L-lactic acid and D-lactic acid, and thus PLA has stereoisomers such as poly(L-lactide) (PLLA), poly(D-lactide) (PDLA), and poly(D,L-lactide) (PDLLA). Thus, the WITP can be a mixture of isomers of the same molecule or a specific stereoisomer (or stereocopolymer).

[0125] In some embodiments, the WITP is biodegradable and is selected from the group consisting of: aliphatic polyesters such as polycaprolactone (PCL), polylactic acid (PLA), poly(L-lactic acid) (PLLA), poly(D-lactic acid) (PDLA), poly(D,L-lactic acid) (PDLLA), polyglycolic acid (PGA), poly(lactic acid-co-glycolic acid) (PLGA), and poly(p-dioxanone) (PPDO); polyhydroxyalkanoates (PHA) including polyhydroxybutyrate (PHB) (such as poly-3-hydroxybutyrate (P3HB), poly-4-hydroxybutyrate (P4HB), poly(3-hydroxybutyrate-co-3-hydroxyvalerate) (PHBV), polyhydroxyvalerate (PHV), polyhydroxyhexanoate (PHH), and polyhydroxyoctanoate (PHO)); poly(olefin dicarboxylates) such as poly(butylene succinate) (PBS), poly(butylene succinate-adipate) (PBSA), and poly(vinyl succinate) (PES); polycarbonates such as poly(trimethylene carbonate) (PTMC), poly(propylene carbonate) (PPC), and poly[oligo(tetramethylene succinate)-co-(trimethylene carbonate)]; aliphatic-aromatic copolyesters such as poly(ethylene terephthalate) (PET) and poly(butylene adipate-co-butylene terephthalate) (PBAT); their isomers, copolymers, and combinations thereof.

[0126] In certain embodiments, the biodegradable WITP is or comprises an aliphatic polyester, its isomers, copolymers, and combinations thereof. In further specific embodiments, the WITP is PCL. In another further specific embodiment, the WITP is PLA. In further specific embodiments, the WITP is PLGA. In another further specific embodiment, the WITP is PBSA.

[0127] The naturally biodegradable WITP can be selected from polysaccharides (e.g., cellulose, starch, chitin, and chitosan), lignin, and combinations thereof.

[0128] In some embodiments, the WITP is non - biodegradable and is selected from polyamide (PA), polyethylene (PE), poly(ethylene - co - acrylic acid) (PEAA), poly(ethylene - co - methacrylic acid) (PEMAA), poly(ethylene - co - n - butyl acrylate) (PEBA), poly(ethylene - co - vinyl acetate) (PEVA), polymethyl methacrylate (PMMA), polypropylene (PP), polysiloxane, polystyrene (PS), polytetrafluoroethylene (PTFE), polyurethane (PU), or polyvinyl chloride (PVC). In specific embodiments, the non - biodegradable WITP is selected from PA, PE, PEAA, PEMAA, PEBA, PEVA, their substituted or modified versions, their ionomers, and combinations thereof.

[0129] The above - mentioned polymers can be identified according to standard methods known to those skilled in the art, such as by Fourier transform infrared (FTIR) spectroscopy, based on their respective characteristic functional groups.

[0130] The non - polymeric WITC applicable to the compositions, methods, and uses of the present invention can also be natural or synthetic. Under suitable conditions, some natural WITC may react in a polymerization reaction to form WITP.

[0131] The natural WITC that may undergo polymerization can be selected from: natural resins (e.g., shellac, rosin, dammar resin, copal resin, sandarac, amber, frankincense, and manila resin); natural gums (either derived from gum - producing trees such as babul, khair, kullu, dhawra, palas, semal, lendia, and neem, or from plant seeds such as guar, tamarind, and cassia); natural gum resins (such as asafoetida, myrrh, Indian frankincense, and galbanum); and combinations thereof. In specific embodiments, the natural polymerizable WITC is shellac or rosin.

[0132] Non-polymerizable WITCs include quinones. In certain embodiments, the non-polymerizable WITC is coenzyme Q10 (CoQ10).

[0133] In addition, the WITC can be a mixture of different compounds, whether polymeric or polymerizable, where the properties of the mixture (such as characteristic temperature, viscosity, etc.) meet the ranges suitable for the individual compounds. For example, a WITC or WITP having a Tm, Ts, or Tg outside of the previously considered suitable range (e.g., below 20 °C or above 300 °C) can be combined with a WITC or WITP having a Tm, Ts, or Tg suitable for "correcting" the characteristic temperature of the resulting mixture to meet the purposes of the present invention. For example, the WITC can be a mixture of polymers or a copolymer comprising at least one of the above WITPs, such copolymers can contribute to the biocompatibility, biodegradability, and mechanical and optical properties of the nano-elements.

[0134] The compositions used in the present invention can comprise nano-elements prepared using various types of WITCs respectively. For example, the composition can include a combination of nano-elements prepared using one type of WITC and nano-elements prepared using a different type of WITC. Alternatively, or additionally, the present composition can comprise nano-elements that differ in type (core or core-shell), function (e.g., each type of nano-element contains a different active agent, thereby producing a combined activity), and / or viscosity (e.g., each type of nano-element is capable of releasing the same or different active agents at different starting times and / or at different rates, thereby producing activity over an extended period of time).

[0135] Viscosity

[0136] Without wishing to be bound by any particular theory, it is believed that the viscosity of the nano-component can contribute to controlling the release profile of the active agent entrapped within or otherwise attached to the core. Put simply, it is expected that nano-components with a relatively low viscosity will release the active agent more readily and more quickly than nano-components with a relatively high viscosity. Since the release of the active agent can be adjusted accordingly to be relatively fast or relatively slow (the release rate need not be constant during the release), in cases where an extended release duration is desired, it may be advantageous to include nano-components spanning a wide viscosity range in the drug, with each part of the viscosity range providing release of the active agent within a corresponding part of the release window. Alternatively, if for a particular treatment the onset time and duration of release are to be more specific, the viscosity of the nano-components can be adjusted and selected accordingly for these narrower purposes. The viscosity suitable for a particular onset time, rate, peak, and / or release duration will particularly depend on the composition of the nano-component (e.g., the type of WITC and / or the content of the plasticizing material) and the environment to which the drug is targeted and its effect on the degradation of the nano-component. These parameters can be evaluated experimentally, for example by monitoring the release of the active agent of interest from the expected nano-components with a series of predetermined viscosities, where the nano-components are incubated in a medium that most closely mimics the conditions in which the drug is expected to act and the release is monitored at a certain temperature.

[0137] Thus, the viscosity of the WITC can be selected according to the desired release profile of the active agent from the nano-component. WITCs suitable for this use and methods of preparing nano-components generally have a viscosity, measured at at least one temperature between 20 °C and 80 °C and a shear rate of 10 sec -1 not exceeding 10 11 millipascal seconds (mPa·s, equivalent to centipoise), and are typically 5 x 10 10 mPa·s or lower, 10 10 mPa·s or lower, 5 x 10 9 mPa·s or lower, 10 9 mPa·s or lower, 5 x 10 8 mPa·s or lower, 10 8 mPa·s or lower, 5 x 10 7 mPa·s or lower, 10 7 mPa·s or lower, or 5 x 10 6 mPa·s or lower.

[0138] It should be noted that the temperature at which the viscosity of the WITC (or the nanoelement containing the same WITC) is measured for assessing applicability may depend on the natural characteristic temperature of the WITC (i.e., the first Tm, Ts, or Tg) or the second Tm, Ts, or Tg that characterizes the nanoelement. For example, the first Tm of polycaprolactone is about 60 °C and can be plasticized to produce a second Tm of 50 °C or lower, and thus the viscosity of the plasticized PCL can be measured at about 50 °C. WITCs or nanoelements with relatively high first or second Tms may require viscosity measurements at temperatures above 50 °C. Conversely, if the WITC or nanoelement has a relatively low first or second Tm, its viscosity can be measured at temperatures below 50 °C. Although the characteristic temperature range of the present WITC (or the nanoelement prepared therefrom) is wide, it is believed that at least one temperature within a range of 30 °C, 20 °C, or 10 °C from 50 °C (i.e., between 20 °C and 80 °C, 30 °C and 70 °C, or 40 °C and 60 °C), the WITC or nanoelement may exhibit the disclosed dynamic viscosity.

[0139] When the viscosity pertains to the natural property of the isolated unmodified WITC or WITC mixture, it can be referred to as the "first viscosity". When the viscosity pertains to the WITC modified by mixing with a miscible material, it can be referred to as the "second viscosity" of the mixture (or nanoelement) containing the WITC. For example, the second viscosity can be the viscosity of the WITP plasticized with a suitable plasticizer (such as a non-volatile liquid) and may also be affected by the presence of an active agent or SFA. The viscosity of a material (whether modified by the presence of other materials or not) at any temperature of interest (or within its range) can be determined by conventional thermorheological analysis, such as the methods described in ASTM D3835 or ASTM D440.

[0140] Although non-volatile liquids can be added regardless of the natural viscosity of the WITC or WITP, such materials are typically used in the present compositions or methods for preparing nanoelements when the WITC has a relatively high first viscosity (e.g., as measured above 10 7 mPa·s). The non-volatile liquid (which can also be referred to as a plasticizing liquid) is included in the core of the nanoelement and is typically adsorbed or otherwise retained by the WITC.

[0141] This "plasticization" generally results in an increase in weight and / or volume relative to the mass or volume of the WITC itself. This plasticization of the WITC renders the plasticized WITC softer and more processable, manifested as a second viscosity less than the first viscosity, facilitating the incorporation of any desired WITC miscible materials (such as carrier-insoluble active agents and / or SFAs) into the core, followed by its nanosizing to form nano-elements, and / or enabling the migration of materials capable of forming a shell (if desired) around the core of the element. Compared to nano-elements without non-volatile liquids, the resulting nano-elements can accelerate the release of the active agent contained or encapsulated in the core and anchored thereon.

[0142] Advantageously, the reduced viscosity in the first stage should be adapted to the shear process (such as shear equipment, shear temperature, etc.) selected for nanosizing the plasticized WITC (such as plasticized WITP) to prepare the present nano-elements, and ultimately be able to provide the desired release profile of the active agent in the nano-elements (for example, as the nano-elements degrade at their targeted sites, the WITC miscible / polar carrier-insoluble active agent is released from the core of the nano-elements, or as the nano-elements degrade, their interaction with the core weakens, and the polar carrier-soluble active agent is released from its anchoring to the core). For example, the non-volatile liquid and its ratio relative to the WITC can be selected such that the viscosity of the WITC is reduced by at least half a logarithm, or at least one logarithm, and so on, adjusted as needed. For example, if the first viscosity of the WITC is 10 8 mPa·s, a plasticizer and its dosage that can make the plasticized WITC have a second viscosity of 5x10 -1 mPa·s measured at at least one temperature between 20 °C and 80 °C and a shear rate of 10 sec 7 can achieve a reduction of half a logarithm; or if the dosage of the plasticizer is increased or a more effective plasticizer is selected, making the plasticized WITC have a second viscosity of 10 7 mPa·s under the same measurement conditions, a reduction of one logarithm can be achieved.

[0143] In some embodiments, the first viscosity of the WITC or the second viscosity of the WITC plasticized with a non-volatile liquid (and / or the nano-elements containing it), measured at at least one temperature between 20 °C and 80 °C and a shear rate of 10 sec -1 is between 10 2 mPa·s and 10 7 mPa·s, between 5×10 2 mPa·s and 10 6 mPa`s, between 5×10 2 mPa·s and 10 5 mPa·s, between 10 3 mPa·s and 5×104 between mPa·s, or 10 3 mPa·s to 10 4 between mPa·s. Any suitable rheometer equipped with a spindle suitable for the desired viscosity range can be used to measure the viscosity at an appropriate shear rate.

[0144] Plasticizing effect of WITC

[0145] Although the effect of non-volatile liquids on the viscosity of WITC has been mentioned above (if viscosity reduction is required), non-volatile liquids used in combination with WITC in nano-components may also have other functions. The plasticizing effect on WITP can be visually observed because the polymer swells at temperatures below its melting point. At higher temperatures, the effect of non-volatile liquids (or any other plasticizing reagent) can be detected by its plasticizing activity, which includes the ability to lower at least one characteristic temperature of native WITC.

[0146] Lowering the characteristic temperature of WITC can correspondingly reduce the processing temperature for preparing the nano-components of the composition. For example, in the absence of a suitable non-volatile liquid, the first (native) Tm, Ts or Tg of WITC may be 200 °C or lower, and adding such a plasticizer may result in a second (modified) Tm, Ts or Tg of the plasticized WITC that is lower than the first temperature, e.g., the second temperature is 95 °C or lower. Obviously, the temperature drop caused by non-volatile liquids is not necessarily so significant, which depends on the value of the first Tm, Ts or Tg of native WITC, and the desired second Tm, Ts or Tg for facilitating the preparation and / or subsequent delivery of the nano-components, and preferably also depends on the boiling point (Tb) of the liquid still present in the composition (but not necessarily if the steps are short enough and / or the liquid is in excess to prevent partial boiling and evaporation of the liquid), and / or depends on the concentration of the plasticizer relative to the plasticized compound.

[0147] The characteristic temperature of WITC may be satisfactorily reduced only by the presence of a WITC miscibility activator or SFA (which has an inherent plasticizing effect in addition to its main intended function when added to WITC). Alternatively, a non-volatile liquid can be used in combination with WITC to reduce (or further reduce) at least one of its characteristic temperatures.

[0148] Generally, the second Tm, Ts or Tg of the plasticized WITC (along with any other components miscible with it) is at least 5 °C, at least 10 °C, at least 15 °C, at least 20 °C, at least 25 °C, at least 30 °C, at least 35 °C, at least 40 °C, at least 45 °C, or at least 50 °C lower than the respective first Tm, Ts or Tg of the bulk WITC.

[0149] If the WITC, in combination with any carrier-insoluble active agent, SFA, and non-volatile liquid that may be included, further contains or has the potential to contain components (such as rheology modifiers, surfactants, preservatives, or any similar plasticizing materials) that affect the softening characteristics of the combination that ultimately forms the nuclei of the nano-elements, then additionally, the thermal properties applicable to the present invention will also apply to the entire mixture.

[0150] Thus, in some embodiments, at least one of the second Tm, Ts, or Tg of the nano-elements (whether nuclei or core-shell nano-elements) is at most 290 °C, at most 250 °C, at most 200 °C, at most 190 °C, at most 180 °C, at most 170 °C, at most 150 °C, or at most 120 °C.

[0151] In some embodiments, the nano-elements have a second Tm of 0 °C or higher, 10 °C or higher, 20 °C or higher, 30 °C or higher, 40 °C or higher, 50 °C or higher, or 60 °C or higher. In some embodiments, the second Tm of the nano-elements is in the range of 0 °C to 290 °C, 10 °C to 290 °C, 20 °C to 290 °C, 10 °C to 250 °C, 20 °C to 250 °C, 20 °C to 200 °C, 30 °C to 190 °C, 50 °C to 170 °C, 50 °C to 150 °C, 30 °C to 180 °C, 40 °C to 180 °C, 40 °C to 150 °C, 50 °C to 170 °C, 50 °C to 150 °C, or 50 °C to 120 °C.

[0152] In some embodiments, at least one of the second Ts and the second Tg of the nano-elements (nuclei or core-shell) is -75 °C or higher, -50 °C or higher, -25 °C or higher, -20 °C or higher, -10 °C or higher, 0 °C or higher, 10 °C or higher, 20 °C or higher, 25 °C or higher, 30 °C or higher, 40 °C or higher, 50 °C or higher, or 60 °C or higher. In other embodiments, at least one of the second Ts and Tg measured on the nano-elements is in the range of -75 °C to 290 °C, -50 °C to 290 °C, -25 °C to 290 °C, -20 °C to 290 °C, -10 °C to 290 °C, 0 °C to 290 °C, 10 °C to 250 °C, 20 °C to 200 °C, 30 °C to 190 °C, 30 °C to 180 °C, 40 °C to 180 °C, 50 °C to 170 °C, 50 °C to 150 °C, or 50 °C to 120 °C.

[0153] This thermal behavior and characteristic temperature can be evaluated during the preparation of the plasticized WITC or the mixture containing it, or after the completion of the composition preparation method, i.e., on the nano-elements isolated therefrom.

[0154] Non-volatile plasticizing liquid

[0155] As described above, controlling the release profile of an active agent contained or encapsulated in or anchored to the core of a nanoelement can be facilitated by the viscosity of the nanoelement, which can be adjusted in particular by the presence of a non-volatile liquid in the core of the nanoelement. Since such a non-volatile liquid may also affect the characteristic temperature of the nanoelement and thus the temperature at which drug release is promoted, it may be advantageous to select a non-volatile liquid that both reduces the viscosity of the WITC and reduces at least one of its Tm, Ts and Tg, as previously discussed separately.

[0156] When selecting such materials, it is also possible to consider improving the processability of the WITC in order to facilitate the preparation and dispersion of the nanoelements in a polar carrier phase from which the nanoelements may subsequently be separated (e.g., transferring them to a different liquid carrier suitable for a particular liquid formulation or preparing a dry formulation). Advantageously, a suitable non-volatile liquid improves the processability of the WITC under conditions suitable for shearing the WITC into nanoparticles, the shearing temperature initially causing the formation of nano-droplets. First, by its very nature, a reagent suitable for plasticizing the WITC according to this teaching is liquid at the temperature at which the WITC is processed, i.e., liquid at at least one temperature at which it is mixed and sheared with the WITC. Such liquid reagents may also be liquid at room temperature.

[0157] To ensure its lasting effect, the plasticizing liquid is preferably non-volatile. As used herein, the term "non-volatile" with respect to a liquid that may plasticize the WITC refers to a liquid with a low vapor pressure, e.g., less than 40 Pascals (Pa, also known as Newtons per square meter) at a temperature of about 20 °C. In some embodiments, the vapor pressure of the non-volatile liquid (or any other preferably low-volatility component) measured at about 20 °C may be 20 Pa or less, 5 Pa or less, 1 Pa or less, 0.1 Pa or less, or 0.01 Pa or less. These vapor pressure values are typically provided by the liquid manufacturer but may also be determined independently by standard methods, e.g., according to methods described in ASTM D2879, E1194 or E1782 for vapor pressure ranges. The low or substantially zero volatility of the non-volatile liquid used to plasticize the WITC should preferably be maintained at the highest temperature at which the plasticized WITC is processed. The use of such non-volatile liquids keeps the WITC in a plasticized state without the risk of liquid evaporation or elimination even at the elevated temperatures used to prepare the nanoelements of pharmaceutical and agrochemical compositions according to the methods described herein.

[0158] Suitable non-volatile liquids also have a boiling point (Tb l)Characteristics of being higher than room temperature, higher than body temperature, and higher than the elevated temperature required for preparing the composition, because preferably, the liquid used to plasticize WITC in the present invention will basically not evaporate during and after the composition preparation process. That being said, a certain degree of boiling loss can be tolerated if the mixing step of plasticizing WITC is short enough to ensure the expected residual amount, and / or if a sufficient excess of non-volatile liquid is added to compensate for any partial boiling evaporation that may occur.

[0159] For similar reasons of remaining bound to the plasticized WITC and being retained in the nano-elements containing it, the non-polar liquid should preferably not migrate into the polar carrier phase. Therefore, a suitable non-volatile liquid is substantially insoluble in such polar carriers (such as water), and its solubility in the pure polar carrier or the liquid phase containing it is the same as that detailed for WITC before, that is, 5 wt.% or less, 4 wt.% or less, 3 wt.% or less, 2 wt.% or less, 1 wt.% or less, 0.5 wt.% or less, or 0.1 wt.% or less based on the weight of the carrier or the phase containing it.

[0160] Such non-volatile liquids need to be compatible with the WITC in the composition (i.e., capable of plasticizing it: for example, reducing its Tm, Ts, or Tg, and / or reducing its viscosity). The non-volatile liquid suitable for a specific WITC can be correspondingly selected through routine experiments. For example, for a specific WITC, various non-volatile liquids can be mixed with it at one or more relative concentrations, and optionally at an elevated temperature to facilitate plasticization, and their effects on the plasticized WITC can be monitored by thermorheology (monitoring its ability to reduce viscosity as a function of temperature) and thermal analysis (such as by DSC, monitoring its ability to reduce the Tm, Ts, or Tg of the native WITC). Accordingly, the non-volatile liquid most effective for a specific WITC can be selected.

[0161] Fundamentally, if a material or chemical composition does not prevent the activity of another material or reduce its activity to a degree that significantly affects the intended purpose, then they are compatible with each other. This compatibility may be from a chemical perspective, for example, sharing similar functional chemical groups, or each material having respective parts that may interact ideally with each other. This compatibility can be demonstrated by forming a homogeneous mixture of the combined materials rather than separating into different phases. If a material causes another material to degrade, then the material is incompatible with the other material. For example, if the polar liquid phase dissolves the nano-elements, makes them unstable, makes the charges they carry incompatible with their intended use, etc., then the polar liquid phase is incompatible with the nano-elements.

[0162] The material should also be compatible with the method of preparing the composition, not be adversely affected by any of the steps the material undergoes during preparation, and not volatilize (or otherwise be eliminated) at the temperature at which it is incorporated into the composition. It will be appreciated that these materials also need to be compatible with their intended use, which in this case may include, for example, biocompatibility, non-irritancy, non-immunogenicity, and having any such properties to ensure regulatory approval at concentrations suitable for effective pharmaceutical and / or agrochemical compositions, as used herein.

[0163] Although compatibility between the WITC and the non-volatile liquid is required, it is not desired for the WITC to dissolve in the non-volatile liquid. Thus, the non-volatile liquid is not a solvent for the WITC but rather a plasticizer intended to remain bound to the WITC.

[0164] It is believed that solvents are generally composed of relatively small molecules that can enter between WITC molecules and separate them from each other such that the WITC can readily dissolve in the solvent at room temperature to form a homogeneous solution. As used herein, the term "solvent" refers to a liquid that can dissolve more than about 5 wt.% of WITC at room temperature.

[0165] In contrast, non-volatile (e.g., plasticizing) liquids are generally larger than solvent molecules and do not readily separate WITC molecules to form a solution at room temperature, at most only causing a preliminary swelling of the WITC at room temperature. An elevated temperature is required to sufficiently separate the WITC molecules from each other to allow sufficient non-volatile liquid to enter the resulting gaps. Even under such favorable conditions, mixing may be required to uniformly form the plasticized WITC. Such elevated temperature can be equal to or higher than at least one of the first Tm, Ts, and Tg of the WITC.

[0166] Non-volatile liquids suitable for use in the present invention may be selected from: monofunctional or polyfunctional aliphatic esters (such as dimethyl glutarate, dimethyl maleate, dimethyl methylglutarate, dipropylene glycol dibenzoate, and isopentyl lactate); fatty esters (such as 2-ethylhexyl lactate, benzyl benzoate, butyl butyryllactate, C 12 -C 15A mixture of alkyl benzoates, caprylic / capric triglyceride, and octyl octanoate, decyl oleate, dibutyl adipate, dicaprylyl carbonate, dibutyl maleate, dibutyl sebacate, diethyl succinate, ethyl oleate, glycerol monooleate, glycerol monocaprylate, glyceryl trioctanoate, glyceryl trioctanoate, isopropyl myristate, isopropyl palmitate, L-menthyl lactate, lauryl lactate, n-amyl benzoate, PEG-6 caprylic / capric glycerides, propylene glycol monolaurate, propylene glycol monocaprylate, triacetin, triethyl citrate, O-acetyltriethyl citrate, O-acetyltri(2-ethylhexyl) citrate, O-acetyltributyl citrate, and tributyl citrate); cyclic organic esters (such as decanolide, γ-decalactone, mentholactone, and undecanolide); aromatic esters (such as diethyl phthalate); terpenes (such as citronellol, eugenol, farnesol, hinokitiol, linalool, menthol, menthone, nerolidol, terpineol, and thymol); aromatic alcohols (such as benzyl alcohol); aromatic ethers (such as phenoxyethanol); aldehydes (such as cinnamaldehyde); and combinations thereof.

[0167] In some embodiments, the non-volatile liquid that can be used to plasticize WITC as disclosed herein is a polyfunctional aliphatic ester (PFAE), which is a diester derivative of common dicarboxylic acids (i.e., adipic acid (C6), azelaic acid (C9), and sebacic acid (C 10 )) and the alcohol portion of the diester typically has a carbon number in the range of C3-C 20 and includes straight-chain and branched-chain alcohols with even and odd carbon numbers. In certain embodiments, the non-volatile liquid as the PFAE is selected from dibutyl adipate (e.g., trade name B), dibutyl sebacate, O-acetyltriethyl citrate (e.g., trade name AII), C 12 -C 15 alkyl benzoate (e.g., trade name 256) and dicaprylyl carbonate (e.g., trade name CC). In another specific embodiment, the non-volatile liquid is the aromatic ester benzyl benzoate.

[0168] When WITC is not biodegradable, additional non-volatile liquids can be used. Such additional liquids can be mineral oil, natural oil, vegetable oil, essential oil, synthetic oil, and combinations thereof, provided that they preferably meet this requirement.

[0169] Polar medium

[0170] The liquid medium in which the nano-elements forming the continuous phase and comprising WITC and a carrier-insoluble active agent are dispersible is polar. In some embodiments, the liquid phase consists essentially of a polar carrier, while in other cases, other components may be present within the polar carrier. Such additional components may be, for example, surfactants, carrier-soluble active agents, or any other additives commonly present in pharmaceutical and / or agrochemical compositions. Polar carriers suitable for the present invention may be selected from the group consisting of water, diols (such as propylene glycol, dipropylene glycol, 1,2-butanediol, 1,3-butanediol, 1,4-butanediol, 2-ethyl-1,3-hexanediol, and 2-methyl-2-propyl-1,3-propanediol), glycerols including glycerol, its precursors and derivatives (such as acrolein, dihydroxyacetone, glyceric acid, tartronic acid, epichlorohydrin, glycerol tert-butyl ether, polyglycerol, glycerol esters, and glycerol carbonate), formamide, acetonitrile, and combinations thereof.

[0171] The polar medium may be formed from one or more suitable polar carriers, and when water is the main polar carrier, the resulting liquid is commonly referred to as an aqueous solution (or aqueous phase). In certain cases, a liquid that is considered to be insufficiently polar per se (such as a fatty alcohol) may be present in the liquid phase together with the polar carrier, provided that such a liquid: a) is soluble in the main polar carrier (e.g., has a water solubility of 5 wt.% or higher) so as to form a single liquid phase therewith; and b) maintains the overall polarity of the liquid phase. The polarity index of the resulting liquid phase may be 3 or higher, 4 or higher, or 5 or higher, with the reference polarity index of water being 9-10.

[0172] Since the polarity index of a solvent refers to its relative ability to dissolve a test solute, liquids can also be classified as polar or non-polar alternatively or additionally based on their dielectric constant (εr). Liquids with a dielectric constant less than 15 are generally considered non-polar, while liquids with a higher dielectric constant are considered polar, and the relative polarity of a liquid increases with the value of the dielectric constant. Preferably, the polar carrier suitable for the present composition has a dielectric constant of 20 or higher, 30 or higher, 40 or higher, 50 or higher, or 60 or higher at room temperature. For example, the dielectric constant of propylene glycol is 32, that of glycerol is 46, and that of water is 80. For simplicity, although this guidance is provided for pure polar carriers, in practice this should preferably apply to the entire polar liquid phase prepared therefrom (e.g., including other polar soluble materials and / or consisting of a mixture of liquid carriers). It is noted that the polar liquid phase can be formed by mixing a formally polar solvent (e.g., having εr≥15) with a formally non-polar solvent (e.g., having εr<15), as long as their respective volumes render the entire liquid phase polar (e.g., having εr≥15). The dielectric constant of a liquid is usually provided by the manufacturer, but can also be independently determined by any suitable method, such as the method described in ASTM-D924.

[0173] As mentioned above, the composition of the polar liquid phase should ensure that the nano-elements containing WITC (and optionally carrier-insoluble active agents and / or SFA) are substantially insoluble and stably dispersed therein, and in the event of undesired circumstances, the content of the nano-elements does not significantly leach into the surrounding medium. When the nano-elements are core-shell nano-elements, the polar liquid phase should also be able to render them appropriately charged, for example, to achieve the desired delivery profile and efficacy across barriers.

[0174] Since the polar medium may contain other liquids and / or materials dissolved therein, the polar carrier may account for at least 50 wt.%, at least 60 wt.%, at least 70 wt.%, at least 80 wt.%, or at least 90 wt.% by weight of the liquid phase.

[0175] In a particular embodiment, the polar carrier comprises water (e.g., 45 wt.% water, 45 wt.% propylene glycol, and 10 wt.% fatty alcohol), consists of water (e.g., containing 51 wt.% to 80 wt.% of water), consists essentially of water (e.g., containing 81 wt.% to 99 wt.% of water), or is water.

[0176] As mentioned above, the detailed principles regarding the polar carrier used in the preparation of nano-elements also apply to any other liquid carrier to which the nano-elements may be transferred in order to prepare a liquid formulation of a pharmaceutical and / or agrochemical composition suitable for its selected route of administration.

[0177] Surfactant

[0178] Some nano-elements can remain in a nano-dispersed state in a liquid medium due to their inherent chemical properties. For example, the nano-elements (core or shell, if present) carry sufficient charges to ensure that the particles repel each other, thus ensuring their stable dispersion.

[0179] In this case, regardless of their underlying principles, these nano-elements can be considered self-emulsifying (e.g., remaining as discrete individual nano-elements in a liquid medium without surfactants specifically for this purpose). When the particles reach the desired size (and / or particle size distribution), the nano-elements are considered dispersed, and when the particles can maintain the desired size (or PSD) over time, they are considered "stably dispersed". The original size and PSD can be determined when the nanoparticle preparation is completed or at any other desired time point. Since the size may vary in repeated measurements at the same time point, if the size or PSD at a subsequent time point differs from the previously determined value by no more than 10% or 5%, the size or PSD is considered substantially similar to the previous value. Thus, if the measured values of the particle size and / or size distribution vary by no more than 10% or 5% over at least 1 day, at least 2 days, or at least 3 days, the particles are considered stably dispersed. This stability can be evaluated under any desired storage conditions, whether at room temperature, at a lower temperature (e.g., 4 - 8 °C), or conversely at a higher temperature (e.g., 30 - 40 °C) when accelerated stability testing is required.

[0180] Although the compositions used in the present invention may remain stable due to the composition of the core-shell nano-elements and / or their environmental conditions (e.g., the pH value of the liquid medium), in some embodiments, the compositions may further comprise at least one (specialized) surfactant to keep the nano-elements stably dispersed (and thus also within their intended size range).

[0181] According to its chemical formulation, the surfactant can be miscible with WITC (and any other components contained in the core) or soluble / dispersible in the polar carrier forming the nano-suspension.

[0182] Surfactants can be anionic, cationic, amphoteric or nonionic surfactants. If the surfactants are nonionic or amphoteric and have an overall charge close to neutral, and moreover are insoluble in polar carriers but miscible with WITC, they can be included in the core of the nanoelement, and their migration to the outer surface of the core will not significantly affect the charge or charging ability of the nanoelement (contrary to SFA used for this purpose). For simplicity, such surfactants can be called "charge-neutral surfactants", and they can promote the interaction with substances in the liquid phase through dipole-dipole forces or other mechanisms that do not require the surfactant to be charged. For example, the carrier-insoluble nonionic surfactants present in the nanoelement can form dipole-dipole interactions with the carrier-soluble anionic surfactants present in the polar liquid phase through their outer ends.

[0183] If the surfactant is relatively soluble in the polar carrier, or for ease of preparation, regardless of its solubility, it can be added to the liquid phase without considering the charge it may or may not form therein.

[0184] Anionic surfactants that can be added to or present in the polar carrier can be selected from the group including: alkyl sulfates (e.g., sodium dodecyl sulfate, ammonium dodecyl sulfate, and ammonium laureth sulfate); sulfosuccinates (e.g., sodium dodecyl sulfosuccinate, sodium laureth sulfosuccinate, sodium dioctyl sulfosuccinate, and their mixtures with sulfonic acid and lauramidopropyl betaine); alkylbenzene sulfonates (e.g., salts of toluene sulfonic acid, xylene sulfonic acid, cumene sulfonic acid (e.g., sodium, potassium, calcium, ammonium salts)); acylmethyl taurates (e.g., sodium methyl lauroyl taurate and sodium methyl cocoyl taurate); acyl sarcosinates (e.g., sodium lauroyl sarcosinate, sodium cocoyl sarcosinate, and sodium myristoyl sarcosinate); hydroxyethanesulfonates (e.g., sodium butyl hydroxyethanesulfonate, sodium octanoyl hydroxyethanesulfonate, and sodium lauroyl hydroxyethanesulfonate); propyl peptide condensates; monoglyceride sulfates; ether sulfonates and fatty acid salts (e.g., sodium stearoyl lactate). Alkylbenzene sulfonates usually have larger hydrocarbon residues (20 to 30 carbon atoms) and are thus carrier-insoluble and can also be used as SFA when mixed with WITC.

[0185] Cationic surfactants that can be added to or present in the polar carrier can be selected from the group including: quaternary ammonium compounds, most of which are highly soluble in water (e.g., benzalkonium chloride and trimethylammonium methyl sulfate). Relatively water-insoluble fatty amine quaternary ammonium compounds (e.g., stearyl trimethyl ammonium chloride and cetyl trimethyl ammonium chloride) can also be used as SFA when mixed with WITC.

[0186] The amphoteric surfactants that can be added to or present in the polar carrier, or present in the nanoelement if miscible with WITC, can be selected from the group including the following: betaines (e.g., cocamidopropyl betaine); alkyl amphopropionates (e.g., cocoamphopropionate); alkyliminopropionates (e.g., sodium lauroiminopropionate); and alkyl amphoacetates (e.g., cocoamphodiacetate).

[0187] The nonionic surfactants that can be added to or present in the polar carrier, or present in the nanoelement if miscible with WITC, can be selected from the group including the following: fatty alcohols (e.g., cetearyl alcohol); ethoxylated fatty alcohols (e.g., C8-C18 alcohol polyethylene glycol, polyethylene oxide 6 stearate, and polyethylene oxide 32 stearate); poly(ethylene glycol) block copolymers (e.g., poloxamer); ethylene oxide (EO) / propylene oxide (PO) copolymers; alkylphenol ethoxylates (e.g., octylphenol polyethylene glycol ether and nonylphenol polyethylene glycol ether); alkyl glycosides and polyglucosides (e.g., lauryl glucoside); fatty alkanolamides (e.g., lauramide diethanolamine and cocoamide diethanolamine); ethoxylated alkanolamides; ethoxylated fatty acids; sorbitol derivatives (e.g., polysorbate, sorbitol laurate, sorbitol, 1,4-sorbitol, isosorbitol, and 1,4-sorbitol triester, PEG-80); alkyl carbohydrate esters (e.g., sucrose fatty acid monoester); amine oxides; cetearyl polyether; oleyl polyether; alkylamines (except fatty amines); fatty acid esters (e.g., ascorbyl palmitate, ethylene glycol stearate, polyglycerol-6 esters, polyglycerol-6 pentaoleate, polyglycerol-10 pentaoleate, and polyglycerol-10 pentaisostearate); polyoxyglycerol esters (e.g., oleoyl polyoxyethylene-6 glycerol ester); natural oil derivatives; ester carboxylates (e.g., D-α-tocopheryl polyethylene glycol succinate (vitamin E TPGS)); and urea.

[0188] These surfactants can be classified into emulsifiers and cosolvents according to their mechanism of action. Emulsifiers generally contain a relatively large hydrophobic or hydrophilic moiety and readily form micelles (thus having a critical micelle concentration (CMC) value). Generally speaking, emulsifiers usually refer to surfactants that ensure the dispersion of one liquid into another liquid, where the two liquids have opposite polarities, while dispersants refer to surfactants that ensure the dispersion of solids into liquids. Since this method can prepare nanoemulsions and nanodispersions, the surfactant that is called an emulsifier in the step where the nano-suspension is an emulsion (e.g., at an elevated temperature) may actually become a dispersant because the initial nanoemulsion may become a nanodispersion at a lower temperature. Therefore, as used herein, the term "emulsifier" also includes other surfactants that are called dispersants.

[0189] Emulsifiers that are lipophilic in nature, i.e., those containing a relatively large hydrophobic moiety, are in principle more suitable for binding with WITC (and any other material insoluble in the polar carrier, such as non-volatile liquids, active agents, or SFA), although they can also be added to the liquid phase. Their incorporation into each phase actually depends on their ability or lack of ability to become charged, as previously mentioned. They can be referred to as polar carrier-insoluble emulsifiers (or surfactants in general). These relatively hydrophobic emulsifiers typically have an HLB value on the Griffin scale of 9 or lower, 8 or lower, 7 or lower, or 6 or lower.

[0190] Emulsifiers that are more hydrophilic in nature have a relatively large hydrophilic moiety and are only compatible with the polar phase of the composition. They can be referred to as polar carrier-soluble emulsifiers (or surfactants in general). Such relatively hydrophilic emulsifiers typically have an HLB value of 11 or higher, 13 or higher, 15 or higher, 17 or higher, or 20 or higher.

[0191] Emulsifiers with an HLB value in the range of 9 to 11 are considered "intermediate" types, and the hydrophobic and hydrophilic moieties of such emulsifiers are quite balanced. Such intermediate emulsifiers can be added to WITC in this method (provided they do not significantly charge the core) or added to the polar carrier, and thus can be found in the nano-elements or their media.

[0192] The emulsifier can be selected from the group consisting of: alkyl sulfates, sulfosuccinates, C7-C 10 alkylbenzene sulfonates, acylmethyl taurates, acylsarcosinates, isethionates, propyl peptide condensates, monoglyceride sulfates, ether sulfonates, ester carboxylates, betaines, alkyl amphopropionates, alkyliminopropionates, alkyl amphoacetates, fatty alcohols, ethoxylated fatty alcohols, poly(ethylene glycol) block copolymers; ethylene oxide (EO) / propylene oxide (PO) copolymers, alkylphenol ethoxylates, alkyl glycosides and polyglucosides, fatty alkanolamides, ethoxylated alkanolamides, ethoxylated fatty acids, sorbitol derivatives, alkyl carbohydrate esters, amine oxides, cetostearyl ethers, oleyl ethers, alkylamines, fatty acid esters, polyoxyglycerol esters, natural oil derivatives, and ester carboxylates.

[0193] In a specific embodiment, the emulsifier is selected from: vitamin E TPGS, poly(ethylene glycol) block copolymers, a mixture of polyoxyethylene 6 stearate type I, ethylene glycol stearate, and polyoxyethylene 32 stearate type I (e.g., obtained under the trade name 63 from Gattefossé France), a mixture containing olive oil-derived extracts (e.g., obtained under the trade name (purchased), ascorbyl palmitate, polyglyceryl-10 pentaoleate, polyglyceryl-10 pentaisostearate, oleoyl polyoxyethylene-6 glyceride (e.g., purchased from Gattefossé, France under the trade name M1944CS), disodium laureth sulfosuccinate, disodium dodecyl sulfosuccinate, disodium dodecyl sulfosuccinate, a mixture of sodium C14-C16 olefin sulfonate and lauramidopropyl betaine (e.g., purchased from Colonial Chemical, USA under the trade name DetEQ-154), and a mixture of olive oil and glutamate (e.g., purchased from Kalichem, Italy under the trade name glutamate).

[0194] While the surfactants used as emulsifiers are generally sufficient to stabilize the nano-elements in the present composition that are not self-emulsifying, the inventors have found that when WITC is present at a relatively high concentration as permitted by the present teachings, the addition of another type of surfactant, namely a co-solvent, helps to achieve satisfactory stability.

[0195] In contrast to emulsifiers, co-solvents contain relatively short lipophilic chains. Since the lipophilic portion of the co-solvent is generally too short to form micelles, the co-solvent alternatively dissolves hydrophobic compounds in a polar carrier and co-emulsifies with the emulsifier. Generally, co-solvents are mainly miscible in the polar carrier phase (e.g., the aqueous phase) of the nano-suspension and are characterized by an HLB value of 10 or higher, 12 or higher, 15 or higher, or 18 or higher.

[0196] Suitable co-solvents can be selected from the group including: sodium dioctyl sulfosuccinate, urea, adenosine triphosphate, and salts of toluenesulfonic acid, xylenesulfonic acid, and cumenesulfonic acid (e.g., sodium, potassium, calcium, ammonium salts).

[0197] In a particular embodiment, the co-solvent is selected from: sodium dioctyl sulfosuccinate, urea, and salts of xylenesulfonic acid, such as ammonium xylenesulfonate.

[0198] Active agents

[0199] The nano-elements having a core made of WITC further contain one or more active agents, and these nano-elements act as nano-carriers to deliver such active agents as drugs.

[0200] The active agent can be a polar carrier-insoluble active agent, which is usually miscible with WITC and any components contained in the core matrix of the nanoelement, for example, miscible with non-volatile liquids and the hydrophobic tails of SFA encapsulated in the core (when these materials are present). When the components of the nanoelement form a single phase, they are miscible with each other, and this property in turn produces a core composed of a continuous matrix. The carrier-insoluble (and WITC-miscible) active agent can be completely contained within the core (if it is substantially non-polar) or partially encapsulated within the core (if it is amphiphilic).

[0201] Similar to the above-mentioned WITC, SFA, and non-volatile liquids, the solubility of the WITC-miscible active agent in the polar carrier or the liquid phase including the polar carrier should be less than 5 wt.%, 4 wt.%, 3 wt.%, 2 wt.%, 1 wt.%, 0.5 wt.%, or 0.1 wt.% by weight to be considered polar carrier-insoluble.

[0202] Alternatively, or additionally, the active agent can also be a polar carrier-soluble active agent. In this case, they are usually located in the shell surrounding the core. In one embodiment, the shell is a second shell formed by amphiphilic molecules (such as other active agents or SFA), indirectly surrounding the core and anchored thereto through the first shell. The second shell can be composed of more than one layer of carrier-soluble active agents. An excess of polar carrier-soluble active agent can also be dissolved in the polar carrier.

[0203] In some embodiments, regardless of where the active agent is located in the nanoelement, its molecular weight does not exceed 1000 g / mol, or does not exceed 500 g / mol, especially if passive cell penetration is desired at the delivery site. However, since the active agent can also be effective for the diagnosis or treatment of diseases without the need to penetrate specific target cells, the active agents that can be incorporated into the core or shell of the nanoelement are not necessarily limited to such molecular weights.

[0204] Therefore, it is advantageous that the active agent, whether non-polar, amphiphilic, or polar, can also have a molecular weight greater than 1000 g / mol, for example, at least 1200 g / mol, at least 1400 g / mol, at least 1600 g / mol, or at least 1800 g / mol. Generally, the molecular weight of the active agent that can be incorporated into this nanoelement (for example, with an average diameter of 1000 nm or less, even 200 nm or less) does not exceed 500 kDa. In some embodiments, the molecular weight of the active agent is 400 kDa or lower, 300 kDa or lower, 200 kDa or lower, or 100 kDa or lower. In a specific embodiment, the molecular weight of the active agent does not exceed 50 kDa, does not exceed 40 kDa, does not exceed 30 kDa, does not exceed 20 kDa, does not exceed 10 kDa, or does not exceed 5 kDa.

[0205] Although the active agents are selected based on the diagnostic, prophylactic, or therapeutic activity they provide for the current drug, they may have secondary functions. For example, a WITC miscible / polar carrier-insoluble active agent can optionally act as a plasticizer when it is capable of reducing the viscosity of the WITC within the core of the nanoelement; a polar carrier-soluble active agent can optionally act as a surfactant when it is capable of stabilizing the core-shell nanoelement in the liquid phase (in which the active agent is dispersed).

[0206] Although the present invention is mainly concerned with the ability of the nanoelement having a core made of WITC to deliver an active agent contained or encapsulated therein and / or anchored thereto, thereby providing an effective pharmaceutical and / or agrochemical agent, such an agent is not necessarily the only drug present in the final dosage form. Other active agents can be included in the compositions used in accordance with this teaching. Other drugs can, for example, be dissolved in a liquid formulation containing the present nanoelement or can be added to a suitable dosage form in a drug carrier different from the present nanoelement, with the additional active agent being external to the nanoelement. For example, the composition can be formulated as a liquid formulation for administration, in which case the additional active agent can be dispersed or dissolved in the liquid carrier in which the nanoelement is dispersed.

[0207] Active agents suitable for incorporation into pharmaceutical compositions for use in the preparation of human or non-human (i.e., veterinary) drugs that can be administered to a subject in need thereof by a non-transdermal route can be found, for example, in the Drugs@FDA database of the U.S. Food and Drug Administration (FDA), the European Public Assessment Reports (EPARs) database of the European Medicines Agency (EMA), or in any similar authoritative list published by relevant professionals in the pharmaceutical industry.

[0208] Active agents suitable for incorporation into agrochemical compositions for use in the preparation of drugs that can be applied to an object in need thereof through a non-exposed surface of the object can be found, for example, in the Pesticide Product Information System (PPIS) maintained by the U.S. Environmental Protection Agency (EPA), the EU Pesticide Database maintained by the Directorate-General for Health and Food Safety (DGSANTE) of the European Commission, or in any similar authoritative list published by relevant professionals in the agrochemical industry.

[0209] Volatile organic compounds

[0210] Methods for preparing nanomaterials have been extensively described in the literature. The main method applicable to the hydrophobic compounds used in the present invention involves emulsification. Conventional emulsification methods applicable for this purpose include oil-in-water (O / W) emulsification or W / O / W emulsification, which are typically achieved by solvent evaporation or solvent displacement (e.g., by solvent diffusion or salting out). These methods are cumbersome and time-consuming and are to some extent not commercially viable. More importantly, they usually result in non-negligible amounts of solvents remaining in the nanoparticles prepared by these methods, which can be particularly critical when the solvents used are volatile organic compounds (VOCs) with high vapor pressures and low boiling points at room temperature.

[0211] As used herein, the term "volatile organic compound" ("VOC") refers to an organic compound having a vapor pressure of 0.1 kPa or higher measured at a temperature of 20 °C.

[0212] Typically, when it is reported that nanoparticles are obtained after a polymer is dissolved in a volatile solvent and then evaporated, the authors usually remain silent about their actual VOC content in view of the difficulty of complete removal. When relatively low contents of VOCs are actually measured and reported, the particles obtained are at least microparticles (e.g., with a particle size of 2 - 100 micrometers (μm)), rather than nanoparticles in the submicron range.

[0213] Different from the methods commonly used for preparing microparticles or nanoparticles, the preparation of the compositions used in the present invention does not involve emulsification techniques that require adding a solvent (such as VOC) and dissolving WITC (especially WITP) therein, followed by removing the solvent. When the volatile solvent is removed from the particles prepared by conventional methods (presumably by long and cumbersome methods), some phenomena may be observed. The removal of the solvent usually produces porous and fragile particles. In addition, since the removal of the solvent may simultaneously require removing the medium in which the particles may be dispersed, this process essentially causes the dispersion to collapse and the particles to dry, and then these particles may become aggregates or agglomerates. Once dried, in order to remove the solvents used for preparing them, the conventionally prepared particles are believed to generally have poor dispersibility as individual particles and, if any, poor spreadability, and their consistency is essentially solid (i.e., having an extremely high "viscosity"). It is believed that the disadvantages of such porous particles prepared according to the prior art methods can be overcome by the non-porous nano-elements of the present invention.

[0214] Accordingly, the nano-components of the present invention are substantially free of conventionally used VOCs such as acetone, acetonitrile, aniline, benzene, carbon tetrachloride, chloroform, cyclohexanone, dichloromethane, dioxane, dimethyl sulfoxide, ethyl acetate, hexafluoroisopropanol, dichloromethane, N,N-dimethylformamide, 2-nitropropane, 1,1,2,2-tetrachloroethane, tetrahydrofuran, 1,1,2-trichloroethane, and toluene, whether as a single solvent or as a mixture of two or more VOCs.

[0215] In some embodiments, the nano-components of WITC contain less than 2 wt.%, less than 1.5 wt.%, or preferably less than 1 wt.%, less than 0.5 wt.%, less than 0.4 wt.%, less than 0.3 wt.%, less than 0.2 wt.%, or less than 0.1 wt.% of VOCs or a mixture thereof, based on the weight of the nano-components. In certain embodiments, the nano-components contain less than 0.09 wt.%, less than 0.08 wt.%, less than 0.07 wt.%, less than 0.06 wt.%, less than 0.05 wt.%, less than 0.04 wt.%, less than 0.03 wt.%, or less than 0.02 wt.% of VOCs or a mixture thereof, based on the weight of the nano-components. In some embodiments, the nano-components are free of any VOCs, but may contain up to 0.001 wt.% (equivalent to ten parts per million - ppm), up to 0.002 wt.% (20 ppm), up to 0.003 wt.% (30 ppm), up to 0.004 wt.% (40 ppm), up to 0.005 wt.% (50 ppm), up to 0.006 wt.% (60 ppm), up to 0.007 wt.% (70 ppm), up to 0.008 wt.% (80 ppm), up to 0.009 wt.% (90 ppm), or up to 0.01 wt.% (100 ppm) of VOCs or a mixture thereof. The above contents are the cumulative amounts in the case where multiple VOCs are present in the nano-components.

[0216] In certain embodiments, the nano-components contain from 0 wt.% to 1 wt.%, from 0.0001 wt.% to 0.5 wt.%, from 0.0005 wt.% to 0.5 wt.%, from 0.001 wt.% to 0.5 wt.%, from 0.002 wt.% to 0.4 wt.%, from 0.003 wt.% to 0.3 wt.%, from 0.004 wt.% to 0.2 wt.%, from 0.005 wt.% to 0.2 wt.%, from 0.005 wt.% to 0.1 wt.%, from 0.001 wt.% to 0.09 wt.%, from 0.002 wt.% to 0.08 wt.%, from 0.003 wt.% to 0.07 wt.%, from 0.004 wt.% to 0.06 wt.%, or from 0.005 wt.% to 0.05 wt.% of VOCs or a mixture thereof, based on the weight of the nano-components.

[0217] It should be emphasized that the low content of VOCs in the above-mentioned nanocomponents is relative to the nanocomponents, because the liquid phase in which they are dispersed may tolerate higher contents of such materials, depending on the dissolution resistance of the nanocomponents and / or the amounts permitted by the relevant regulatory authorities for the use of the compositions for the purposes applicable to the present invention.

[0218] The nature and content of the VOCs hypothetically present in the nanocomponents can be determined by conventional analysis, for example by removing the polar carrier and analyzing the nanocomponents isolated therefrom by, for example, gas chromatography (GC) coupled with mass spectrometry (MS) for quantitative determination. Exemplary standard methods for determining the presence of VOCs are described in ASTM D4526 or VDA 277, and the analysis is carried out at a temperature of 90 °C, and the absolute amount is measured by MS. Alternatively, once the presence of VOCs is estimated by GC, the weight loss of the sample can be tested at 90 °C.

[0219] Since the method for preparing the present nanocarriers does not involve dissolving WITC in a solvent (such as VOC) and subsequently removing the solvent, resulting in the formation of porous particles, the core phase of the present nanocomponents is substantially non-porous.

[0220] Core-shell nanocomponents

[0221] When it is desired for the nanocomponents within the compositions used in the present invention to have different charges, a shell-forming agent (SFA) can be combined with WITC and a WITC miscibility reagent, thereby producing positively or negatively charged core-shell nanocomponents when placed in a polar carrier, and the charge of the core-shell nanocomponents is different from that of the nanocomponents having only a similar core.

[0222] The added SFA is not intended to remain entirely within the core of the nanocomponents. On the contrary, under the conditions selected for preparing the nanocomponents, they are considered to migrate towards the outer surface of the core, exposing their hydrophilic heads to the polar carrier surrounding the nanocomponents, while their hydrophobic tails tend to remain in the water-insoluble environment of the core. This phenomenon results in the formation of a chargeable shell in the presence of water, which can be confirmed by the change in the charge of the nanocomponents with or without SFA.

[0223] As previously mentioned, WITC is usually negatively charged. Therefore, the core containing WITC (and other WITC miscible components) is expected to exhibit a negative charge in aqueous polar liquids (such as water). However, when SFA is further included in the composition, a shell of the hydrophilic head of SFA is formed. When positively charged in an aqueous environment, such a shell will mask the core, reducing its negative charge, and depending on the respective charge densities, the amounts of the core and shell materials, and the liquid environment (such as pH) that may regulate these charges, it may even provide a positive charge for the core-shell nanoelement. Negatively charged SFA may provide a more negative charge for the core-shell nanoelement.

[0224] It is noteworthy that the SFA forming the shell of the nanoelement is not covalently bonded to the WITC of the core. This is considered to advantageously maintain the original activity of each molecule in the core and shell, and no part of them participates in covalent bonding through electron sharing, which may reduce or alter their respective contributions to the efficacy of the composition. In addition, the fact that SFA is not covalently bonded to WITC allows them to migrate to the outer surface of the nanoelement to form a shell thereon under suitable conditions.

[0225] Figure 3 The core-shell nanoparticle 300 in a non-aqueous polar carrier is schematically depicted. The nanoelement comprises a core 310, which consists of WITC (shown as a gray background), WITC miscible active agents (shown as small black dots), and any other optional components that are WITC miscible and insoluble in the polar carrier (such as non-volatile liquids). The core encompasses at least a part of the hydrophobic tail 314 of SFA. The polar head 322 of SFA (shown as an example of a fatty amine in the figure, represented by a circled "N") is away from the core surface 312, forming the shell 320 of the nanoelement. Due to the absence of water, the hydrophilic head of SFA is not charged.

[0226] The electrostatic charging of the nanoelement, especially as a core-shell nanoelement (but not limited to), is beneficial for its further coating with a shell of a carrier-soluble active agent having an opposite charge. The resulting core-multiple shell forms a moderately charged or even uncharged nanoelement. Moderately charged core-multiple shells can generally maintain their original charge (i.e., positive or negative charge), but have less charge than the core-shell without the second shell of the active agent respectively. Alternatively, the core-multiple shell can be oppositely charged. For example, a positively charged core-shell nanoelement can become a negatively charged core-multiple shell nanoelement, provided that the collapse of the composition can be avoided (such as by the aggregation of the nanoelement at its isoelectric point).

[0227] Figure 4 A core-multiple shell nanoparticle 400 coated with a carrier-soluble active agent in an aqueous environment is schematically depicted.

[0228] With Figure 3Similar to the previously described nanoparticles 300, the nanoparticles 400 consist of a core 410 that encompasses at least a portion of the hydrophobic tails 414 of the SFA. Different from the nanoparticles 300 dispersed in a non-aqueous polar carrier, the aqueous environment in which the nanoparticles 400 are dispersed allows the polar heads 424 of the SFA (a positively charged fatty amine in the figure, for illustrative purposes) to become charged, forming a now positively charged first shell 420 of the nanoparticles around the core surface 412. This charging of the first shell enables the carrier soluble surfactant molecules 432 to anchor to the surface of the first shell 422 of the nanoparticles, thereby forming a second shell 430 containing the surfactant, and there is a zeta potential difference (Δζ) between the surface zeta potential of the core-shell nanoelement and the surface zeta potential of the carrier soluble surfactant. The carrier polar soluble surfactant molecules may be negatively charged, resulting in a relatively large Δζ between the positively charged first shell 420 of the nanoparticles and the surfactant molecules 432. Alternatively, the surfactant molecules may be positively charged in the polar carrier, resulting in a relatively small Δζ and a weaker attraction compared to negatively charged molecules. However, as long as Δζ is 5 mV or greater, these conditions are sufficient to form the second shell 430.

[0229] Although Figure 4 Depicted is an exemplary first shell around the core that enables it to be positively charged so that the carrier soluble surfactant for forming a second shell thereon can be negatively charged, but the core-shell nanoelement can also be negatively charged, thereby allowing a second shell to be formed by a positively charged carrier soluble surfactant. A negatively charged inner core-shell can be obtained by adjusting the environment of the nanoelement or by using a fatty compound (such as a fatty acid) with a negatively chargeable hydrophilic head to form the first shell.

[0230] In a particular embodiment, the core-shell nanoelement is positively charged, and in a liquid environment used to anchor such a surfactant to the nanoelement core through a first shell containing the hydrophilic head of the SFA, the carrier soluble surfactant molecules are negatively charged.

[0231] Without wishing to be bound by theory, it is believed that the charge of the nanoelement initially having only a single shell is mainly contributed by the hydrophilic heads of the SFA, which become charged according to the pH in the polar carrier and the nature of the SFA when exposed to an aqueous environment.

[0232] For example, when the SFA is a fatty amine, the amino groups in the first shell are protonated at a suitable acidic pH, and the protons come from water. Thus, when the polar carrier is an aqueous polar carrier (such as water or an aqueous mixture), the nanoelement can be positively charged. Alternatively, when the SFA is a fatty acid, the acidic groups in the first shell may be deprotonated and negatively charged at a basic pH, forming carboxylates.

[0233] However, when a non-aqueous polar carrier is used in the preparation of the nanoelement, it is believed that coordination bonds are formed with the SFA hydrophilic head of the first shell, and a polar carrier that cannot protonate the first shell molecules "masks" any positive charges that may potentially arise on the surface of the core-shell nanoelement in the presence of a protonating liquid. In this case, or when the charge detected in the liquid carrier is considered insufficient, the charge can be "un-masked" or increased by replacing at least part of the polar carrier with water (e.g., by mixing the nano-suspension with water), thereby creating an aqueous environment in which the charge can be generated or become available.

[0234] As is known to those skilled in the art, when measuring the charge and ζ potential of a composition, it should be emphasized that in this particular case, the aqueous polar carrier only needs to contain a sufficient amount of water (e.g., ≥5 wt.%) to facilitate the formation of positive or negative charges of SFA within the shell (e.g., protonation of fatty amines or deprotonation of fatty acids). These values can be measured with any suitable device and can be determined in the composition "as is" or in its diluted sample.

[0235] Although water itself can create an environment that promotes the charging of nanoelements, pH regulators can be added to further facilitate charge formation. For example, when SFA is a fatty amine, acidic reagents are thought to react with the polar carrier molecules (presumably through hydrogen bonds), moving them away from the shell surface of the nanoparticle and exposing the amine head to a proton-rich acidic environment, thus allowing positive charges to form on the shell surface. Alternatively, a base can be added to the polar carrier, which helps in the formation of positive charges of the amine, although with a slightly weaker effect than acidic reagents. If added to the composition, the basic pH regulator can also selectively further promote the formation of negative charges of the carrier-soluble surfactant. Adding an acid or a base to the nano-suspension can be referred to as "acid doping" or "base doping", respectively.

[0236] It is expected that the charge of the material for forming the second shell, whether enhanced by doping or not, will promote their attraction to the charged core-shell nanoelement, facilitating the formation of core-multiple shell nanoelements through non-covalent electrostatic attraction of opposite charges. Alternatively, or additionally, the surfactant of the second shell can be selected to covalently bind to the material of the first shell (e.g., SFA, surfactant, etc.).

[0237] The amount of the pH regulator added to the composition should be controlled so as to create an environment that maintains a balance between the sufficient charging of SFA and the sufficient charging of the carrier-soluble surfactant, and their respective opposite charges attract each other appropriately. For example, the amount of the acidic reagent should be high enough to allow the amine head to achieve optimal positive charge, but low enough to keep the carrier-soluble surfactant sufficiently negatively charged.

[0238] In some embodiments, the amount of pH regulator added is such that the pH of the composition is between 1 and 11, between 1 and 10, between 1 and 9, between 1 and 8, between 2 and 7, or between 2 and 5. In certain embodiments, when it is desired to make the core-shell nanoelement positively charged, the amount of pH regulator added should be such that the pH is 7 or lower, 6 or lower, 5 or lower, or 4 or lower. In other embodiments, when it is desired to make the core-shell nanoelement negatively charged, the pH regulator is added to make the pH greater than 7, greater than 8, greater than 9, or greater than 10.

[0239] Although pH regulators are typically added to the liquid carrier in which the nanoelements are dispersed, they can alternatively or additionally be added to the nanoelements, for example incorporated into their core, regardless of the number of shells that may surround them. Suitable pH regulators for incorporation into the core, which are desired to exude from the core at the appropriate time, should be miscible and compatible with the core and also with the polar carrier.

[0240] In some embodiments, the core-shell nanoelement has a positive charge of +5 mV or higher, +10 mV or higher, +20 mV or higher, +30 mV or higher, or +40 mV or higher when placed in an aqueous environment at room temperature, and the positive charge generally does not exceed +100 mV.

[0241] In other embodiments, the core-shell nanoelement has a negative charge between -100 mV and -5 mV, between -80 mV and -5 mV, between -60 mV and -5 mV, between -50 mV and -10 mV, between -40 mV and -20 mV, between -50 mV and -30 mV, or between -60 mV and -30 mV when placed in an aqueous environment at room temperature.

[0242] In a further embodiment, the core-shell nanoelement has a near-neutral charge between -5 mV and +5 mV when placed in an aqueous environment at room temperature, for example in the presence of a non-ionic surfactant.

[0243] As the particle size decreases, its specific surface area increases, and thus the amount of material that may be present on its outer surface also increases. Since one of the characteristics of the nanoelements used in the present invention is that D N 50 is 1000 nm or less, particularly 200 nm or less, in some embodiments the nanoelements can be small enough to achieve a high enough specific surface area to allow for a sufficient number of hydrophilic heads in the shell to contribute the desired positive charge to the nano-dispersion. In such cases, the use of a pH regulator (which can be used to further enhance the charge) may be redundant (as shown in Example 4-II below).

[0244] The amount of the carrier soluble surfactant added to the core-shell nanoelement may in particular depend on the particle size of the nanoelement and thus on the surface area available for attachment to anchor the external surfactant to the core of the nanoelement. In addition, the zeta potential of the core-shell nanoelement and of the carrier soluble surfactant, respectively, may also indicate in what proportions they can be present in the composition to optimize the formation of the core-multishell nanoelement and, if desired, to avoid an excess of the surfactant in the polar carrier. While allowing such an excess, especially as long as it promotes the stabilization of the second shell, too much unbound surfactant may be redundant if the molecular weight of the carrier soluble surfactant molecules is high and prevents their cellular delivery, if desired.

[0245] The attachment of the carrier soluble surfactant to the core-shell nanoelement is achieved or facilitated by a difference between the zeta potential (ζ1) of the original core-shell nanoelement induced by the fatty compound of the first shell and the zeta potential (ζ2) of the surfactant that will form the second shell. In some embodiments, the absolute value of the zeta potential difference defined as Δζ = |ζ2 - ζ1| measured in the presence of water or an aqueous polar carrier is at least 5 mV, at least 10 mV, at least 15 mV, at least 20 mV, at least 25 mV, or at least 30 mV. The method for determining these values is the same as the method for determining the charge of the core-shell nanoelement, and the conditions selected for the measurement (such as the equipment, temperature, and pH) are the same for the nanoelement acting as the anchor and the carrier soluble surfactant intended to form the further shell.

[0246] Although in the previous paragraphs the chargeability of the nanoelement has been regarded as a means to form different shells around the core in a selected and adapted liquid environment to promote the corresponding charging of the components and the formation of the core-shell or core-multishell, this may not be the only reason for wanting to control the charge of the nanoelement. Other factors to be considered may be the chargeability of the nanoelement (whether or not there is a shell around the core) in the physiological environment where the drug will be administered. Taking animals (such as humans) as an example, these organisms are mainly composed of water, and aqueous body fluids generally make up the majority of body weight.

[0247] Under normal physiological conditions, the outer surface or wall of internal cells, tissues or organs (such as the blood-brain barrier, blood vessel wall, cell membrane, etc.) is usually negatively charged. Therefore, the total charge of the nano-elements in physiological fluids (partially contributed by the WITC of the core, the active agent, and the SFA when present) can regulate the electrostatic interaction of the nano-elements with the charged surface and their retention on these surfaces, thereby promoting the delivery of the active agent at these sites, and / or the penetration of the nano-elements through these barriers. It is believed that nano-elements with a more positive charge (regardless of the number of shells) are expected to be better retained and adhered to the surface of such barriers with the opposite charge, but their penetration rate will be slower compared to nano-elements with a less positive charge or even a negative charge. Negatively charged nano-elements may be slightly repelled when passing through the barrier, but this phenomenon may prompt them to further "penetrate" the barrier.

[0248] Based on this theory, it is believed that the relative penetration rate of nano-elements across organ barriers can be controlled to a certain extent not only by their size and / or extensibility (such as viscosity), but also according to their charge (such as the value of their positive or negative charge). Therefore, compositions containing nano-elements can be designed for site-specific drug delivery according to the charge of the nano-elements and the charge of the target tissue under relevant physiological or pathological conditions.

[0249] For example, consider a pharmaceutical product for treating endothelial cell dysfunction in the inner wall of blood vessels. Positively charged nano-elements containing a suitable active agent (in the core and / or any shell of the nano-elements) are expected to migrate electrostatically to the damaged endothelial cells (usually negatively charged) and accumulate on their surface area, releasing the active agent they carry. Similarly, when needed, negatively charged nano-elements may be more likely to penetrate the negatively charged blood vessel wall, thereby delivering the active agent outside the vascular system.

[0250] Shell-forming agent (SFA)

[0251] SFA molecules are miscible with the WITC forming the core and thus contain a hydrophobic part (also called a fatty "tail"), which can be a straight-chain, branched-chain or cyclic, saturated or unsaturated, aliphatic or aromatic, alkyl or aryl chain. SFA also includes a hydrophilic part that can be charged (such as an amine, acid or sulfonate "head") and is capable of forming a shell around the core.

[0252] Generally, SFA is in a liquid state at the temperature of the subject or object to which the nano-elements are to be administered. They can also be in a liquid state at room temperature, that is, the melting point is at most 25 °C, at most 20 °C, at most 15 °C, or at most 10 °C. However, this is not necessary, and the melting point of SFA may be higher than 25 °C (such as quaternary ammonium fatty amines).

[0253] The hydrophobic tail typically contains from 5 to 40 carbon atoms, which renders the SFA insoluble in polar carriers. For example, the SFA is water-insoluble, i.e., its solubility in a liquid is 5 wt.% or lower, 4 wt.% or lower, 3 wt.% or lower, 2 wt.% or lower, 1 wt.% or lower, 0.5 wt.% or lower, or 0.1 wt.% or lower based on the weight of the liquid.

[0254] Suitable SFAs include: metal salts of fatty amines, fatty acids, and sulfonates. Combinations of these SFAs can also be used.

[0255] Suitable fatty amines for use as SFAs include straight-chain, branched-chain, or cyclic, saturated or unsaturated, aliphatic C8-C 22 primary, secondary, tertiary, or quaternary amines. Comprehensive lists of fatty amines can be found in chemical databases, and the following compounds are provided only as examples of each class. Stearylamine (C 18 H 39 N) is an example of a straight-chain, saturated, aliphatic primary alkylamine (general formula R-NH2), isostearylamine is its branched-chain counterpart, and oleylamine (C 18 H 37 N) differs in having an unsaturated bond in an alkyl chain of the same length. Dinonylamine is a secondary amine (general formula R1-NH-R2), and trioctylamine is a tertiary amine (N-R1,R2,R3). Quaternary ammonium fatty amines can be quaternary ammonium salts or cationic fatty imidazolines, the latter being an example of a fatty amine containing a heterocyclic ring. In some embodiments, they are C8-C 22 primary, secondary, tertiary, or quaternary amines. In some embodiments, the fatty amine has a C8-C 20 or C8-C 18 alkyl chain.

[0256] Compared to secondary and tertiary amines included at similar concentrations, primary amines have an advantage in contributing charge to the shell. Suitable primary amines include: oleylamine, octylamine, cocamidopropyl dimethylamine, undecylamine, dodecylamine, stearylamine, and isostearylamine). Secondary and tertiary amines can be selected from: ethoxylated oleylamine (such as oleyl bis(2-hydroxyethyl)amine, trade name O020Special), N,N-dimethyldodecylamine, alkyl (C 12 -C 16 ) dimethylamine, avocadamide propyl dimethylamine, laurylamine dipropylenediamine, stearyl dimethylamine, stearamide propyl dimethylamine, dinonylamine, and trioctylamine. Quaternary ammonium amines can be quaternary ammonium salts, such as cetyltrimethylammonium chloride. In certain embodiments, the fatty amine is selected from the group consisting of: oleyl bis(2-hydroxyethyl)amine, N,N-dimethyldodecylamine, oleylamine, octylamine, and cetyltrimethylammonium chloride.

[0257] Fatty acids suitable as SFA include mono- or di-C5-C 40 、C6-C 30 、C8-C 22 、C8-C 20 or C8-C 18 acids, such as valeric acid, caproic acid, caprylic acid, lauric acid, linoleic acid, linolenic acid, myristic acid, oleic acid, palmitic acid, stearic acid, and isostearic acid. In certain embodiments, the fatty acid is caprylic acid.

[0258] Metal salts of sulfonates can also be used as SFA, where the metal counterion can be selected from: barium, calcium, magnesium, or sodium, and the sulfonate bears an aliphatic residue, such as an alkylaryl or petroleum hydrocarbon chain containing 20 to 30 carbon atoms. Suitable metal salts of sulfonates include: barium alkylaryl sulfonate, calcium alkylaryl sulfonate, magnesium alkylaryl sulfonate, sodium alkylaryl sulfonate, barium petroleum sulfonate, calcium petroleum sulfonate, magnesium petroleum sulfonate, and sodium petroleum sulfonate.

[0259] The temperature used in preparing the core-shell nano-elements of the present invention should preferably be lower than the degradation point of the SFA or any other component involved in the preparation of the nano-elements. For example, at high temperatures, fatty amines may be prone to degradation, resulting in amine loss (due to oxidative amidation of the amine). This degradation can be analyzed by placing the fatty amine at the test temperature for a sufficient length of time (e.g., 24 hours) and then measuring the amine value by conventional analysis using standard methods (such as those described in ASTM D2074-07). As a non-limiting example, the amine value can be evaluated by titrating the fatty amine (which has been treated at the test temperature) with hydrochloric acid, and the amine value corresponds to the number of milliliters of 0.1 N HCl required to neutralize 10 g of the product. The results obtained are then compared with the amine value of the same fatty amine in its native unheated form, which is provided by the manufacturer or can be independently measured as described above. Any decrease in the amine value of the heated fatty amine may indicate degradation of the amine at the test temperature (this temperature is referred to as the "degradation point" of the fatty amine). Similarly, fatty acids used as SFA may undergo decarboxylation at high temperatures, resulting in the elimination of their chargeable acidic groups. A method similar to that described above for fatty amines can be employed to analyze the decarboxylation reaction of fatty acids, with adjustments applicable to fatty acids. This analysis can include placing the fatty acid at the test temperature for a sufficient length of time and then measuring the acid value by standard methods (such as titrating with a base to neutralization and calculating the acid value, as described in ASTM D1980-87). The measured acid value can then be compared with the value reported by the fatty acid manufacturer to confirm or negate whether decarboxylation has occurred. More generally, considering that the function of interest regarding SFA is its chargeability, the degradation point of SFA refers to the temperature at which the chargeability of SFA is significantly impaired in the presence of water.

[0260] In order to form a shell, the SFA must be mixed with the WITC. Their miscibility with the WITC, insolubility in polar carriers (e.g., SFA is water-insoluble), and the conditions selected when forming the nano-elements enable their tails and heads to be correctly oriented and to be respectively distributed between the core and the shell of the nano-elements, while the SFA does not exude into the liquid medium. If a material seemingly similar to the SFA of the present invention is added after the formation of the nanoparticles, a shell will not be formed thereby. Such materials can at most exist as dispersants in the liquid medium and will not be partially incorporated into the particles. To be used as a dispersant, such non-shell-forming materials generally have a certain degree of solubility in polar carriers, which is in contrast to the SFA.

[0261] Like other components of the nano-elements of the present invention, in addition to forming an electrically chargeable shell, the SFA can also have other uses.

[0262] Some SFAs (such as oleylamine) can act as plasticizers, capable of reducing the intrinsic viscosity of the WITC in the core, facilitating its processing and being incorporated into the composition of the present invention as nano-elements. When doing so, or alternatively, the SFA can act as a "solubilizer", capable of increasing the miscibility of other materials (such as carrier-insoluble active agents) in the WITC.

[0263] Alternatively, or additionally, the SFA (such as oil-based bis(2-hydroxyethyl)amine) can also act as a surfactant, suitable for stabilizing the core-shell nano-elements in a polar carrier. In some embodiments, the portion of the SFA exposed in the shell can render the core-shell nano-elements charged, such that these elements can be stably dispersed in the composition without the externally provided dedicated surfactant in the liquid phase (as shown in Examples 1-II and 2-II). In this case, the core-shell nano-elements can be regarded as "self-emulsifying" or "self-emulsified".

[0264] Alternatively, or additionally, the SFA can also act as a carrier-insoluble active agent, not only forming the shell of the core-shell nano-elements but also exerting its own activity (such as acting as a bactericide or bacteriostatic agent).

[0265] Composition

[0266] After reviewing the various components available for the compositions of the present invention, suitable concentrations or respective proportions will be provided below. It should be noted that, for simplicity, the compounds are classified according to their main role in the present nano-elements, but these functions are not mutually exclusive, and some components according to the present teachings can play multiple roles. The predominance of one role over another may depend on the intrinsic efficacy of the material in the respective field of activity considered, and also on the relative content of the material in the composition. For example, if a material is considered a carrier when it accounts for a large enough proportion in the liquid phase (e.g., more than 20 wt.%), then it may be considered to have a different function if its content is relatively low, and this lower content is more suitable for its secondary role. Thus, when referring to the concentration of a certain component in a nano-element or a composition containing a nano-element, this information only refers to the dedicated compound intentionally added to play this role and does not include compounds with different main roles.

[0267] In some embodiments, the concentration of WITC (or a combination of WITCs) in the nano-element is in the range of 0.1 wt.% to 99.9 wt.% based on the total weight of the nano-element. In some embodiments, the concentration of WITC is in the range of 1 wt.% to 99 wt.%, 1 wt.% to 90 wt.%, 5 wt.% to 80 wt.%, 10 wt.% to 50 wt.%, or 15 wt.% to 40 wt.% based on the total weight of the nano-element.

[0268] In some embodiments, the concentration of WITC in the composition or in the drug prepared therefrom is at least 0.1 wt.%, at least 0.5 wt.%, at least 1 wt.%, at least 2 wt.%, at least 3 wt.%, or at least 4 wt.% based on the total weight of the composition. In other embodiments, the concentration of WITC is at most 30 wt.%, at most 25 wt.%, at most 20 wt.%, at most 15 wt.%, at most 13 wt.%, at most 10 wt.% or at most 8 wt.% based on the total weight of the composition. In other embodiments, the concentration of WITC is in the range of 0.1 wt.% to 30 wt.% based on the total weight of the composition, preferably in the range of 0.5 wt.% to 25 wt.%, 1 wt.% to 20 wt.%, or 1.5 wt.% to 15 wt.%, 0.5 wt.% to 13 wt.%, 1 wt.% to 10 wt.%, 2 wt.% to 10 wt.%, 3 wt.% to 10 wt.%, 4 wt.% to 10 wt.%, or 4 wt.% to 8 wt.% based on the total weight of the composition.

[0269] The active agent is usually present in the medicament of the present invention in an amount effective to treat the desired disorder by administering the medicament to a subject or object in need one or more times. Taking the medicament administered to a living subject as an example, the amount or concentration of the active agent is usually referred to as the therapeutically effective amount, which depends in particular on the nature of the active agent, the concentration required to achieve a therapeutic response at the target site without significant adverse effects, the route of administration, the duration of treatment, the dosing regimen, the absorption and excretion rates of the active agent, and similar factors known to those of ordinary skill in the pharmacological arts. It is understood that even for a specific active agent, some of the above factors may vary depending on the circumstances. It is noted that the dose value may vary depending on the severity of the disorder to be alleviated. Generally, the dosing regimen should be adjusted over time according to individual needs and the judgment of the professional administering or supervising the administration. The medicament can be administered as a single dose or divided into multiple smaller doses and administered at different time intervals. Thus, when the medicament prepared according to this teaching is a pharmaceutical product, an appropriate amount of the active agent (e.g., an amount capable of providing the desired therapeutic effect without producing adverse effects) can be within the known values for each active agent, which are known to those of ordinary skill in the pharmacological arts, or can be optimized by conducting relevant tests (such as bioequivalence studies).

[0270] In some embodiments, if the carrier-insoluble active agent is present in the nanoelement, the concentration of the carrier-insoluble active agent is in the range of 0.1 wt.% to 99.9 wt.%, in the range of 0.5 wt.% to 85 wt.%, in the range of 1 wt.% to 85 wt.%, in the range of 2 wt.% to 70 wt.%, in the range of 3 wt.% to 55 wt.%, in the range of 5 wt.% to 45 wt.%, in the range of 5 wt.% to 35 wt.%, in the range of 10 wt.% to 30 wt.%, in the range of 15 wt.% to 25 wt.%, in the range of 0.1 wt.% to 25 wt.%, in the range of 0.5 wt.% to 25 wt.%, or in the range of 1 wt.% to 25 wt.% based on the total weight of the nanoelement.

[0271] In some embodiments, if the carrier-insoluble active agent is present in the composition, its concentration is in the range of 0.01 wt.% to 30 wt.%, preferably in the range of 0.05 wt.% to 25 wt.%, 0.1 wt.% to 20 wt.%, 0.5 wt.% to 15 wt.%, 1 wt.% to 12.5 wt.%, 2 wt.% to 10 wt.%, 3 wt.% to 10 wt.%, or 5 wt.% to 10 wt.% based on the total weight of the composition.

[0272] In some embodiments, if a carrier soluble surfactant is present, it is added to the nano-suspension at a concentration of up to 200 wt.% by weight of WITC, preferably in the range of 0.1 wt.% to 170 wt.%, in the range of 1 wt.% to 150 wt.%, in the range of 5 wt.% to 100 wt.%, in the range of 5 wt.% to 50 wt.%, in the range of 5 wt.% to 40 wt.%, or in the range of 10 wt.% to 20 wt.%.

[0273] The non-volatile liquid(s) used for plasticization can be added at a weight ratio of at least 1:200, at least 1:20, at least 1:10, at least 1:5, or at least 1:3, at least 1:1, at least 2:1, or at least 3:1 relative to the weight of the WITC to be plasticized. In some embodiments, the weight ratio of the non-volatile liquid to WITC is at most 100:1, at most 50:1, at most 20:1, at most 10:1, or at most 5:1.

[0274] In some embodiments, the concentration of the non-volatile liquid is at least 1 wt.%, at least 5 wt.%, at least 10 wt.%, or at least 20 wt.% by weight of the nano-components. In some embodiments, the concentration of the non-volatile liquid is at most 99 wt.%, at most 90 wt.%, at most 80 wt.%, at most 70 wt.%, or at most 60 wt.% by weight of the total nano-components. In other embodiments, the concentration of the non-volatile liquid is in the range of 1 wt.% to 99 wt.% by weight of the total nano-components, preferably in the range of 5 wt.% to 90 wt.%, 10 wt.% to 80 wt.%, 20 wt.% to 70 wt.%, or 20 wt.% to 60 wt.%.

[0275] In some embodiments, if a non-volatile liquid is present in the composition, its concentration is at least 0.1 wt.%, at least 0.5 wt.%, at least 1 wt.%, or at least 5 wt.% by weight of the composition. In other embodiments, the concentration of the non-volatile liquid is at most 50 wt.%, at most 45 wt.%, at most 40 wt.%, at most 35 wt.%, at most 30 wt.%, at most 25 wt.%, at most 22.5 wt.%, or at most 20 wt.% by weight of the composition. In other embodiments, the concentration of the non-volatile liquid is in the range of 0.1 wt.% to 50 wt.% by weight of the total composition, preferably in the range of 0.1 wt.% to 45 wt.%, 0.1 wt.% to 40 wt.%, 0.5 wt.% to 35 wt.%, 0.5 wt.% to 30 wt.%, 0.5 wt.% to 25 wt.%, 1 wt.% to 22.5 wt.%, or 5 wt.% to 20 wt.%.

[0276] In some embodiments, the concentration of SFA (or a combination of SFAs) in the nanoelement is in the range of 1 wt.% to 99 wt.%, 1 wt.% to 90 wt.%, 5 wt.% to 80 wt.%, 10 wt.% to 50 wt.%, or 15 wt.% to 40 wt.%, based on the total weight of the nanoelement.

[0277] In some embodiments, the concentration of SFA in the composition is at least 0.1 wt.%, at least 0.5 wt.%, at least 1 wt.%, or at least 1.5 wt.%, based on the total weight of the composition. In other embodiments, the concentration of SFA is at most 30 wt.%, at most 25 wt.%, at most 20 wt.%, or at most 15 wt.%, based on the total weight of the composition. In other embodiments, the concentration of SFA is in the range of 0.1 wt.% to 30 wt.%, preferably in the range of 0.5 wt.% to 25 wt.%, 1 wt.% to 20 wt.%, or 1.5 wt.% to 15 wt.%, based on the total weight of the composition.

[0278] In some embodiments, the content of the polar carrier (such as water) in the composition or drug as a liquid preparation is in the range of 30 wt.% to 90 wt.%, 30 wt.% to 80 wt.%, 40 wt.% to 70 wt.%, or 30 wt.% to 60 wt.%, based on the total weight of the composition or drug. As mentioned above, the nanoelements can also be isolated to prepare dry-form drugs and thus are substantially free of any liquid carrier, whether polar or not.

[0279] In some embodiments, if a nonionic or zwitterionic "charge-neutral" surfactant is present in the nanoelement, its concentration is in the range of 0.1 wt.% to 50 wt.%, 1 wt.% to 50 wt.%, 5 wt.% to 50 wt.%, 10 wt.% to 50 wt.%, 15 wt.% to 45 wt.%, or 20 wt.% to 40 wt.%, based on the total weight of the nanoelement. These concentrations refer to surfactants intentionally added for this purpose and do not include any other materials that can also act as surfactants, such as certain SFAs.

[0280] In some embodiments, if a surfactant (including, for example, an emulsifier and / or a co-solvent present only in the liquid phase) is present in the composition, its total concentration is at least 0.1 wt.%, at least 0.5 wt.%, at least 1 wt.%, at least 5 wt.%, at least 6 wt.%, at least 7 wt.%, or at least 8 wt.% based on the total weight of the composition. In other embodiments, the total concentration of the surfactant is at most 60 wt.%, at most 40 wt.%, at most 35 wt.%, at most 30 wt.%, at most 25 wt.%, at most 20 wt.%, or at most 15 wt.% based on the total weight of the composition. In other embodiments, the total concentration of the surfactant is in the range of 0.1 wt.% to 60 wt.%, 0.5 wt.% to 60 wt.%, 1 wt.% to 60 wt.%, 5 wt.% to 40 wt.%, 6 wt.% to 30 wt.%, 7 wt.% to 25 wt.%, 8 wt.% to 20 wt.%, or 5 wt.% to 15 wt.% based on the total weight of the composition. Alternatively, the composition is substantially free of a dedicated surfactant, and the concentration of one or more surfactants is less than 0.1 wt.% based on the total weight of the composition.

[0281] In some embodiments, if an emulsifier is present in the composition, its concentration is at least 0.01 wt.%, at least 0.1 wt.%, at least 0.5 wt.%, at least 1 wt.%, at least 3 wt.%, or at least 5 wt.% based on the total weight of the composition. In other embodiments, the concentration of the emulsifier in the composition is at most 60 wt.%, at most 50 wt.%, at most 40 wt.%, at most 30 wt.%, at most 25 wt.%, or at most 20 wt.% based on the total weight of the composition. In other embodiments, the concentration of the emulsifier in the composition is in the range of 0.01 wt.% to 60 wt.%, 0.1 wt.% to 50 wt.%, 0.5 wt.% to 40 wt.%, 1 wt.% to 30 wt.%, 3 wt.% to 25 wt.%, or 5 wt.% to 20 wt.% based on the total weight of the composition.

[0282] In some embodiments, if a co-solvent is present in the composition, its concentration is at least 0.01 wt.%, at least 0.05 wt.%, at least 0.1 wt.%, at least 0.5 wt.%, or at least 1 wt.% based on the total weight of the composition. In other embodiments, the concentration of the co-solvent in the composition is at most 60 wt.%, at most 50 wt.%, at most 40 wt.%, at most 30 wt.%, at most 25 wt.%, at most 20 wt.%, at most 15 wt.%, or at most 10 wt.% based on the total weight of the composition. In some embodiments, the concentration of the co-solvent in the composition is in the range of 0.01 wt.% to 60 wt.%, 0.05 wt.% to 50 wt.%, 0.1 wt.% to 40 wt.%, 0.1 wt.% to 30 wt.%, 0.5 wt.% to 25 wt.%, 1 wt.% to 20 wt.%, or 1 wt.% to 10 wt.% based on the total weight of the composition.

[0283] Although the concentration of each intended component of the nanoelement may be within a relatively wide range of values, it is clear that the respective concentrations of each component present in the nanoelement, the composition containing the nanoelement, or the medicament should be such that the sum of all components is 100 wt.%.

[0284] Preferably, the above ingredients are approved for diagnosing or treating diseases in a living subject or other harmful conditions affecting an object at the intended concentrations. For example, they do not cause allergic reactions or any other acute or chronic adverse effects, whether administered to an animal subject or an edible plant that may be consumed by an animal. In addition, all ingredients need to be compatible with each other, and such compatibility is as described above. It can be easily understood that this principle of compatibility may be affected not only by the chemical properties of the materials but also by their relative proportions determined according to the intended use, and it should preferably guide the selection of all materials required for the compositions disclosed herein.

[0285] Preparation method

[0286] A nanoelement having a core made of a water-insoluble thermoplastic compound (WITC), especially a water-insoluble thermoplastic polymer (WITP), which can be dispersed as a nano-suspension in a polar liquid and further containing an active agent in the core or shell of the nanoelement can be prepared as follows. The nature and characteristics of the materials used in this method are as described above for each material applicable to this medicament. It is noteworthy that the nanoelement containing WITC and the active agent is substantially free of VOC compounds and contains less than 2 wt.% and even less than 0.2 wt.% of VOC or a mixture thereof by weight of the nanoelement.

[0287] The steps of this method are in Figure 1Briefly shown herein and further described in detail below, steps with dashed outlines are optional.

[0288] In the first step (S01) of the method, at least one WITC (e.g., at least one WITP) is provided.

[0289] In the second step (S02) of the method, the WITC can be mixed with other materials that are usually miscible with the WITC, such as at least one of the following: i) a non-volatile liquid; ii) SFA (when a core-shell nanoelement with an electrically chargeable shell is desired); and iii) a WITC-miscible / polarity-carrier-insoluble active agent (when an active agent is desired to be present in the core of the nanoelement).

[0290] When the viscosity of the WITC provided in S01 is low enough for further processing (e.g., measured at 10 -1 mPa·s or lower at at least one temperature between 20 °C and 80 °C and a shear rate of 10 sec 7 ), the addition of the non-volatile liquid is optional. Alternatively, any other desired component of the core (such as an active agent or SFA), when suitable for this purpose, can also act as a reagent to sufficiently plasticize the WITC, making the addition of the non-volatile liquid an optional step.

[0291] If intentional plasticization of the WITC is desired, its mixing with the non-volatile liquid (and any other possible plasticizing reagent) can be carried out at any mixing temperature and / or mixing pressure suitable for such mixing.

[0292] The temperature at which the mixing (which may include plasticization of the WITC) is carried out is generally selected according to the characteristic temperatures of the substances involved in the process, e.g., considering the first Ts, Tm, and / or Tg characterizing the WITC, and optionally the Tb of the SFA (referred to as Tb SFA ) and / or the Tb of the non-volatile liquid (referred to as Tb l ) and / or the degradation point of the SFA (if applicable, e.g., when the polar head of the SFA loses its chargeability when heated above a specific point). As mentioned above, the mixing temperature should be appropriately higher than at least one characteristic temperature of the WITC (e.g., at least 5 °C higher, at least 10 °C higher, at least 15 °C higher, or at least 20 °C higher), and preferably lower than the lowest boiling point of the non-volatile liquid and / or SFA and the degradation point of the SFA at the pressure at which the mixing step is carried out (e.g., at least 5 °C lower, at least 10 °C lower, at least 15 °C lower, or at least 20 °C lower). However, as long as the selected mixing temperature does not cause any material mixed with the WITC to form the core of the nanoelement to boil off significantly or degrade, this recommended upper limit of the mixing temperature is not necessary. Thus, in some cases, the mixing temperature can even reach Tb l 、TbSFA or the SFA degradation point (if applicable) or higher, if the step is short enough and / or the non-volatile liquid is in sufficient excess, and / or the mixing is carried out in a sufficiently sealed chamber to limit the evaporation of the liquid components / facilitate their condensation back into the mixture.

[0293] It can be readily understood that if the pressure ensuring the mixing process for WITC plasticization is correspondingly reduced or increased in a sealed chamber, the change in the properties of the substance reflected by these temperatures dropping from the first value to the second value can occur at a lower or higher mixing temperature. Thus, while in describing the method applicable to preparing the composition used according to the present teachings, it is assumed that the process is carried out at standard atmospheric pressure and specific temperatures and time durations can be referred to, such guidance should not be considered restrictive, and all temperatures and durations that achieve similar results in terms of the behavior of plasticizing WITC and / or considering the activity of SFA and the possible electrification of the core-shell nano-elements are included.

[0294] It should be noted in this case that when WITC is WITP, although the Tm and / or Tg of the polymer may set relatively definite temperatures below and above which the polymer may exhibit different behaviors, this generally does not apply to Ts. Due to its viscoelasticity, the polymer or the plasticized polymer may remain "sufficiently solid" even at a temperature slightly above its official softening point.

[0295] The mixing or plasticization of WITC and the materials miscible with it can be carried out under various conditions, such as elevated temperatures (i.e., 30 °C or higher, for example at 40 °C or higher, 50 °C or higher, 60 °C or higher, 75 °C or higher, or 90 °C or higher) and / or elevated pressures (i.e., 100 kPa or higher, for example at 125 kPa or higher, 150 kPa or higher, 175 kPa or higher, 200 kPa or higher, 250 kPa or higher, or 300 kPa or higher). Since the mixing step generally achieves at least some plasticization of WITC, it can also be called a plasticization step, and the above temperatures and / or pressures will generally accelerate the plasticization process (i.e., shorten the duration of the plasticization period), or cause the boiling point Tb l or Tb SFA to undergo the required change, at which boiling point they may evaporate. Since mixing under elevated pressure increases Tb l and / or Tb SFA, so that the temperature range in which plasticization can be carried out can be widened accordingly. On the contrary, if WITC is plasticized under conditions more adverse than those arbitrarily set for evaluating the ability of WITC to be plasticized by a specific reagent (for example, at a temperature below 50 °C and / or under a reduced pressure below 100 kPa), the plasticization process may be prolonged (if necessary). The ability of WITC to be plasticized by a specific plasticizer can be evaluated under any of the above temperature or pressure conditions.

[0296] The plasticization / mixing period can also be shortened by mixing WITC with a reagent that promotes its plasticization and / or modifies the core content by stirring the mixture. This stirring also ensures that all parts of WITC are plasticized, and / or all parts of the expected core are mixed in a relatively uniform manner. The plasticized WITC behaves quite uniformly in the subsequent steps of the method and in terms of the expected results. If an excessive amount of non-volatile liquid is used during the plasticization process, it can be optionally removed before proceeding with the subsequent steps. When the material to be plasticized has a relatively high viscosity, the mixing step can also be referred to as compounding, and the mixing equipment can be selected accordingly.

[0297] The duration of plasticization depends in particular on the WITC to be plasticized, the non-volatile liquid used, the plasticization conditions (such as temperature, pressure, and / or stirring), and the desired degree of plasticization. The plasticization period can be at least 1 minute and at most 4 days. The plasticization conditions and their duration also need to be suitable for the active agent and optionally the SFA to be incorporated into the WITC being plasticized.

[0298] Mixing can be carried out by any method known to those skilled in the art, such as: sonication, using a double-jacketed planetary mixer or a high-shear mixer, etc. When the materials to be mixed have a relatively high viscosity, the mixing step can be carried out using equipment of types such as a two-roll mill, a three-roll mill, an extruder, etc. In a specific embodiment, mixing is carried out by sonication.

[0299] If desired, other WITC-compatible components can be added, such as: polar carrier-insoluble charge-neutral nonionic or amphoteric surfactants, pH regulators, and any other desired additives.

[0300] When a WITC-compatible / polar carrier-insoluble active agent is also included, it can be combined with WITC before heating WITC and / or mixing it with an optional non-volatile liquid, SFA, charge-neutral surfactant, and / or any other desired components with which it is miscible, or after any such heating and / or mixing, once WITC is at least partially softened or plasticized by the heating and / or the components with which it is mixed.

[0301] In the third step (S03) of the method, the WITC from step S01 or the mixture containing it obtained in the optional step S02 is combined with at least one polar carrier. If desired, at least one surfactant, which is a relatively polar emulsifier or co-solvent, can be added to the polar carrier in this step. Other materials soluble in the polar carrier (e.g., an active agent that may form a shell around the core formed in a previous step) can also be added in this step, but can also be introduced after the subsequent nano-sizing step.

[0302] In the fourth step (S04), the liquid mixture obtained in step S03 is nano-sized to form a nano-suspension, whereby the WITC nano-elements containing any desired WITC miscible and polar carrier-insoluble materials are dispersed in a polar liquid containing the polar carrier (optionally combined with other polar materials).

[0303] Since nano-sizing is typically carried out at a relatively high temperature by applying a shear force, the nano-elements are typically nano-droplets in this step, and the resulting nano-suspension is a nano-emulsion. The mixture of the desired materials can be nano-sized to obtain a nano-emulsion by any method capable of shearing WITC (whether plasticized or not, or whether containing other compounds), and the shearing method is selected from the group including: sonication, grinding, milling, high-pressure homogenization, high-shear mixing, and high-shear microfluidization. In a particular embodiment, the nano-sizing is carried out by sonication.

[0304] The nano-sizing is carried out at a shear temperature that is at least equal to at least one of the first Ts, Tm, and Tg of WITC, at least equal to at least one of the second Ts, Tm, and Tg of WITC after plasticization and / or mixing, and in some embodiments, can be at least 5 °C, at least 10 °C, or at least 15 °C higher than the highest characteristic temperature of the WITC mixture being sheared. However, this is not necessary if the shearing step is short enough and / or the polar liquid is in sufficient excess, but the shear temperature should preferably prevent significant boiling and evaporation of the bulk liquid phase (and avoid significant degradation of the SFA, if present). In some embodiments, the shear temperature at which the nano-sizing is carried out does not exceed the boiling point of the liquid phase being sheared (or any other liquid for which evaporation should be prevented) and the degradation point of the SFA (or any other material for which thermal degradation, such as inactivation, destruction, etc., should be prevented). Thus, the shear temperature is typically lower than the Tb of the polar carrier at the pressure at which the nano-sizing step is carried out (referred to as Tb c) and the lowest value among the degradation points of the materials mixed with WITC. For example, when the polar carrier is water and assuming that the nano-sizing is carried out at atmospheric pressure, the shear temperature can be selected to be below 95 °C, below 90 °C, below 85 °C, or below 80 °C. However, if the nano-sizing is carried out at elevated pressure, the Tb of the polar carrier c will increase, and the shear temperature can be increased accordingly. Still taking water as an example, although its boiling point is 100 °C at about 100 kPa, this boiling point increases to 120 °C at about 200 kPa. In this case, the nano-sizing temperature that does not exceed can be as high as 115 °C. As mentioned above, these upper limits, although preferred, are not essential because even at higher temperatures, if the steps are short enough, and / or the polar carrier is in sufficient excess, and / or the nano-sizing is carried out in a sufficiently sealed chamber to limit its evaporation / facilitate its condensation back into the nano-suspension, partial boiling evaporation or degradation of, for example, the polar carrier, active agent, surfactant, or SFA can be prevented.

[0305] At a shear temperature above the Ts, Tm, or Tg of WITC and optionally below the Tb of the liquid carrier c or within the degradation temperature of any existing material, WITC, especially WITP, can be completely melted, and the nano-sizing process can be regarded as "molten nano-emulsification".

[0306] In some embodiments, at least 50% of the total number (D N 50) or the total volume (D V 50) of the nano-elements (including core and core-shell nano-elements, whether nano-droplets or nano-particles) formed in this nano-sizing step have a hydrodynamic diameter of at most 1000 or less, 750 nm or less, 500 nm or less, or 250 nm or less. In a specific embodiment, the D N 50 or D V 50 of the nano-elements is at most 200 nm, at most 150 nm, at most 100 nm, at most 90 nm, at most 80 nm, or at most 70 nm. In some embodiments, the median diameter of the nano-elements is at least 5 nm, at least 10 nm, at least 15 nm, or at least 20 nm. Advantageously, these values also apply when determined by the number of nano-elements.

[0307] As can be easily understood, depending on the characteristic temperature of the nano-element material and / or the temperature at the time of measurement, the nano-elements can be relatively liquid nano-droplets or relatively solid nano-particles when the temperature decreases. The size of the nano-particles at room temperature is commensurate with or slightly tighter than that of the nano-droplets at higher temperatures, and its average diameter does not exceed 1000 nm, preferably not exceeding 200 nm.

[0308] In some embodiments, the size of the nanoparticles or nanodroplets is determined by microscopy techniques known in the art (e.g., by cryogenic transmission electron microscopy (CryoTEM)). In some embodiments, the size of the nano-elements is determined by dynamic light scattering (DLS). In the DLS technique, the particles are approximated as behaviorally equivalent spheres, and the size can be represented by the hydrodynamic diameter. DLS can also more easily evaluate the size distribution of the nano-element population.

[0309] The distribution results can be represented by the hydrodynamic diameter for a given cumulative particle size distribution percentage, either by particle number or by volume, and typically provide the cumulative particle size distributions of 10%, 50%, and 90%. For example, D50 refers to the maximum hydrodynamic diameter below which 50% of the sample volume or particle number (as appropriate) lies, and can be interchangeably referred to as the volume median diameter (D V 50) or the number median diameter (D N 50), and is usually more simply referred to as the average diameter.

[0310] In some embodiments, the cumulative particle size distribution D90 of the nano-elements of the present disclosure is 500 nm or less, or D95 is 500 nm or less, or D97.5 is 500 nm or less, or D99 is 500 nm or less, that is, the hydrodynamic diameters of 90%, 95%, 97.5%, or 99% of the sample volume or particle number are not greater than 500 nm, respectively.

[0311] Thereafter, any hydrodynamic diameter with a cumulative particle size distribution of 90%, 95%, 97.5%, or 99% (either by particle number or by sample volume) of the particle population can be referred to as the "maximum diameter", that is, the maximum hydrodynamic diameter of the particles present in the respective cumulative size distribution of the population. It should be understood that the term "maximum diameter" is not intended to limit the scope of the present teachings to nanoparticles with a perfect spherical shape.

[0312] In some embodiments, the nanoparticles or nanodroplets can have a uniform shape, and / or be symmetrically distributed relative to the population median, and / or have a relatively narrow size distribution.

[0313] If at least one of the following conditions is met, the particle size distribution is said to be relatively narrow:

[0314] A) The difference between the hydrodynamic diameters of 90% of the nano-elements and 10% of the nano-elements is equal to or less than 250 nm, equal to or less than 200 nm, equal to or less than 150 nm, or equal to or less than 100 nm, or equal to or less than 50 nm, which can be mathematically expressed as: (D90–D10) ≤ 250 nm, etc.;

[0315] B) The ratio between a) the difference in the hydrodynamic diameter of 90% of the nano-elements and the hydrodynamic diameter of 10% of the nano-elements, and b) the hydrodynamic diameter of 50% of the nano-elements does not exceed 2.5, does not exceed 2.0, or does not exceed 1.5, or even does not exceed 1.0, which can be mathematically expressed as: (D90–D10) / D50 ≤ 2.5, etc.; and

[0316] C) The polydispersity index (PDI) of the nano-elements is equal to or less than 0.5, equal to or less than 0.4, or equal to or less than 0.3, or equal to or less than 0.2, which can be mathematically expressed as: PDI = σ 2 / d 2 ≤ 0.5, etc., where σ is the standard deviation of the particle distribution and d is the average size of the particles. Optionally, the PDI is equal to 0.01 or greater, 0.05 or greater, or 0.1 or greater.

[0317] PDI information can generally be easily obtained from the instrument used to measure the hydrodynamic diameter of the nanoparticles.

[0318] In the fifth step (S05) of the method, if required in the preparation, the nanoemulsion obtained in step S04 can be optionally actively cooled to a temperature below the first Tm, Ts, or Tg of the WITC (or the second Tm, Ts, or Tg of the nano-elements, if lower) to accelerate the relative solidification of the nano-elements. This cooling can be actively achieved by refrigerating the nano-suspension (e.g., placing it in a coolant with the required low temperature), continuously stirring the nano-suspension to accelerate heat dissipation (and incidentally maintaining its proper dispersion when the nano-droplets are cooled), or by combining these two methods. This cooling step is optional because the nanoemulsion can be passively cooled without stirring after the termination of nano-sizing. When the nanoemulsion is mixed with water (pH-adjusted water) and / or a polar carrier-soluble surfactant in subsequent optional steps, it can also be passively cooled if their temperatures are low enough. Despite the cooling during the preparation, the WITC (or the plasticized WITC) may still remain in a liquid state in the form of nano-droplets, or may easily transform back into nano-droplets once administered to a subject with a body temperature higher than 30 °C (the body temperature of mammals is usually higher than 32 °C and 35 °C, respectively).

[0319] When the polar carrier added in step S03 for nano-sizing is non-aqueous, the method can optionally include a sixth step (S06) of at least partially replacing the polar carrier with water or pH-adjusted water. As mentioned before, when the polar carrier is water or a mixture of water and a non-aqueous polar carrier, this replacement step may not be necessary.

[0320] Alternatively, an aqueous pH-adjusting solution of a polar carrier can be used in the fourth step (S04) of the method to create an environment that promotes the charging of the nano-elements, thereby at least partially avoiding the possible masking effect of the polar carrier.

[0321] Assuming that the expected active agents are all WITC-miscible and have been incorporated into the above nano-elements and the compositions containing them in previous steps, the nano-elements and the compositions containing them can be formulated into a drug (pharmaceutical or agrochemical) suitable for administration to a subject or object to be treated according to the NES pathway (e.g., the ND pathway) through which they are to pass, so that the active agent can exert its expected effect.

[0322] Alternatively, in another optional seventh step (S07) of the method, a polar-carrier-soluble active agent can be added and dissolved in the polar carrier by stirring. When the polar-carrier-soluble active agent is added to the core-shell nano-elements (which may optionally contain other active agents in their core), the soluble active agent can coat the outer surface of the nano-elements, forming a second shell as described above. The second shell can be covalently and / or non-covalently linked to the first shell composed of the amphiphilic SFA and / or the chargeable polar part of the active agent, and the first shell is not covalently linked to the core.

[0323] When the charge of the core-shell nano-elements in the polar carrier is insufficient to attract a compound with an opposite charge, S07 can also include adding a carrier-soluble pH regulator in an amount suitable for increasing the charge of the core-shell nano-elements (e.g., increasing the positive charge), while maintaining the opposite (e.g., negative) charge of the carrier-soluble active agent, and vice versa. Depending on the chargeable groups present on the SFA molecules of the first shell, the pH regulator can be an acid or a base.

[0324] Although shown in the figure as a separate step after the cooling of the nano-suspension (either actively (S05) or passively), the optional at least partial replacement of the polar carrier (S06) can also be carried out before or during cooling.

[0325] The addition of the polar-carrier-soluble active agent (S07) can also be carried out at different steps in the preparation of the composition, depending on the tolerance of the active agent to temperature, mixing, or shear conditions. Active agents with relatively high tolerance can be added in the following steps: i) when combining WITC (and optionally other WITC-miscible components) with the polar carrier; or ii) when nano-sizing the composition components to obtain core or core-multi-shell nano-elements. Alternatively, the carrier-soluble active agent, especially if it is shear-sensitive, can be added to the obtained nano-suspension, and active agents that are relatively sensitive to heat are preferably combined with the nano-emulsion or nano-dispersion after cooling.

[0326] In a further optional eighth step (S08) of the method, the nano-elements can be separated from the polar carrier. This step allows the separated nano-elements to be later combined with a suitable excipient, depending on the type of dosage form into which they are to be incorporated. For example, if the dosage form is in dry form, the separated nano-elements can be mixed with a suitable excipient to form a dry dosage form (such as a tablet or a capsule). If the dosage form is in liquid form (such as for intravenous administration), such a step can be used to transfer the separated nano-elements from the polar carrier to a different liquid carrier suitable for the desired liquid formulation.

[0327] Although in the above detailed method, some components are described as being introduced (or optionally introduced) into the composition at specific steps, this should not be construed as restrictive. Some components can be introduced in multiple steps and can in fact be introduced gradually in two separate steps during the preparation process, and / or added incrementally as the step proceeds, adding materials as the step progresses. For example, one or more polar carrier-soluble surfactants can be added during the shearing step, optionally adding different surfactants at the start and end of the step. Thus, the above steps can be modified, omitted (such as S02, S05, S06, S07 or S08), and additional steps can be included. For example, the composition can contain any additives commonly used in drugs or drug preparation compositions, such as diluents, extenders, binders, lubricants, disintegrants, colorants, flavorants, humectants, emollients, wetting agents, ultraviolet protectants, thickeners, preservatives, antioxidants, bactericides, fungicides, chelating agents, vitamins, and fragrances, to name just a few. The nature and concentration of these conventional compounds (also known as pharmaceutical excipients when considering pharmaceutical compositions) are known to those skilled in the art for each such drug and route of administration and need not be further elaborated here. The additives can be added in the method steps already described or by new steps. Additionally, the composition can be further processed (such as sterilized, filtered, irradiated, etc.) according to health or agricultural regulations to make it suitable for its intended use.

[0328] Advantageously, the method, regardless of the steps involved and the composition prepared, does not seek to chemically modify its components, such as might be required to link them together. The absence of such modification in the present composition is expected to prevent the formation of large particles, which may be difficult to reach the target site due to their size, and / or assuming they are successfully delivered to the target site, is considered to prevent an undesired reduction in the biological activity that these components may provide in their native (unmodified) form.

[0329] Although, for the sake of brevity, the compositions are mainly described as being suitable for the diagnosis and treatment of animal subjects (related to veterinary or human use), they can also be used for delivering relevant medicaments to the plant field, such as factors capable of promoting plant growth (e.g., phytohormones or other fertilizers) or medicaments capable of reducing adverse conditions that have an adverse effect on plant growth (e.g., pesticides, fungicides, insecticides, etc.).

[0330] The compositions used in the present invention can be delivered by any route suitable for their intended use, depending on the object, subject, and / or the condition to be treated. These modes of administration are known and have been exemplified previously.

[0331] According to the ND route of administration, the medicament can be formulated into dosage forms selected from the following group: solid dosage forms, such as cachets, capsules (hard or soft shell), tablets (including lozenges, sublingual tablets, chewable tablets, dispersible tablets, disintegrating tablets, coated tablets, and effervescent tablets, to name just a few), granules, powders, which dosage forms can optionally be coated to achieve modification or extended release of the active agent, or to provide enhanced resistance to certain physiological environments (e.g., having gastric acid resistance), and some of the above solid dosage forms are used to prepare liquid formulations at the time of intended administration (e.g., when effervescing or for reconstituting solutions or dispersions when necessary, and can be administered in liquid form or as a vapor). The solid dosage forms can also be in the form of a film, such as an oral film, suppository or stick, or a device impregnated with the drug, such as an impregnated pad, intrauterine device or implant. The dosage form can also be semi-solid (e.g., cream, foam, paste or gel) or liquid (e.g., syrup, solution, dispersion or emulsion), either as the final dosage form for immediate use or as an intermediate concentrate for preparing the final drug at the time of administration. For example, the concentrated dosage form can be used to prepare mouthwashes, hemodialysis solutions, rectal solutions (e.g., enemas), injection solutions (e.g., by intravenous injection, intraperitoneal injection, intramuscular injection, subcutaneous injection, etc.), infusions, irrigation fluids or drip solutions. The drug to be prepared into the final form at the time of administration can be provided as part of a kit that includes materials related to such preparation. The solid or liquid drug can be intended for administration by inhalation (e.g., orally or nasally) and be in the form of an aerosol or spray, and include a gas for propelling the drug when needed. The dosage form can also be selected according to the organ to be treated. Taking the eye as an example, it can be an eye cream, eye drops, eye gel, eye wash, eye spray, eye lotion, etc., or a powder and / or liquid for reconstituting the above liquid drug by resuspension and / or dilution, and the final drug is mixed before administration. Some of the dosage forms described above for ocular administration also exist in oral, gingival, dental, gastrointestinal, vaginal, rectal, tracheal, urethral or pulmonary administration.

[0332] The therapeutic use of the present drug or the therapeutic method using the present drug is achieved by the delivery of an effective amount of an active agent carried by a nanoelement. These active agents, whether they are WITC miscible / polar carrier insoluble so as to be included or encapsulated in the core of the nanoelement, or carrier soluble so as to form the shell of a core-shell nanoelement, can be analgesics, anesthetics, anti-addiction agents, antibacterial agents, anticonvulsants, anti-dementia agents, antidepressants, antiemetics, antifungal agents, antigout agents, anti-inflammatory agents, anti-migraine agents, anti-myasthenia agents, anti-mycobacterial agents, anti-tumor agents, anti-obesity agents, anti-parasitic agents, anti-Parkinson's agents, antipsychotics, anti-spasmodics, antiviral agents, anti-anxiety agents, bipolar disorder therapeutic agents, blood glucose regulators, cardiovascular drugs, central nervous system drugs, contraceptives, dental and oral agents, gastrointestinal agents, genetic / enzyme / protein disease therapeutic agents, urogenital agents, hormone agents (including: adrenal hormones, pituitary hormones, prostaglandins, sex hormones and thyroid hormones), hormone inhibitors (including: adrenal hormones, pituitary hormones and thyroid hormones), immune agents, infertility therapeutic agents, inflammatory bowel disease therapeutic agents, metabolic bone disease therapeutic agents, ophthalmic agents, otologic agents, respiratory agents, sexual dysfunction therapeutic agents, skeletal muscle relaxants, sleep disorder therapeutic agents and dietary supplements (such as: vitamins, electrolytes, minerals and metals). Drugs prepared using nanoelements containing such active agents generally have similar names (and vice versa), and the therapeutic methods using these drugs have corresponding names, which are easily understood and are not listed here. For example, if the active agent is an analgesic, then the drug can be considered an analgesic and can be used to treat pain.

[0333] The present nanoelement can also be used to deliver diagnostic agents and to prepare a composition that can be used for diagnostic purposes after administration to a subject or object to be diagnosed.

[0334] The present composition can also be an agrochemical composition for treating an object in need by NSE. Such drugs are usually in the form of a solution or an emulsion, or in the form of powders, granules or pellets for preparing them, and are applied to a suitable object, such as a plant, by injection into the plant (such as injection into the tree trunk) or by irrigating the soil with the agrochemical composition.

[0335] The active agents that can be used in the nanoelement to prepare such agrochemical products can be acaricides, algicides, anthelmintics, anti-moth agents, avicides, bactericides, chemical sterilants, fertilizers, fungicides, herbicides, insecticides (including ovicides), insect repellents, insect pheromones, molluscicides, nematicides, nitrification inhibitors, pesticides, pest repellents, plant growth promoters, rodenticides, termiticides, virucides and plant wound protectants.

[0336] The preparation of the above-mentioned pharmaceutical dosage forms suitable for their mode of administration and intended therapeutic activity (in the broad sense given to this term herein) can be carried out routinely. Similarly, the treatment by administration of such drugs can also be implemented in a traditional therapeutic manner, and no detailed description is required here.

[0337] As mentioned above, the nature of the nano-elements can allow control of the release profile of the active agent from the nano-elements. Thus, in some embodiments, the drugs used in the present invention allow the active agent to be released over an extended period of at least twelve hours, and thus, with respect to the active agent, the drug can be considered a sustained-release drug.

[0338] Examples

[0339] Materials

[0340] The materials used in the following examples are listed in Table 1 below. The listed properties were obtained from the product data sheets provided by the respective suppliers or estimated by standard methods. Unless otherwise stated, all materials were purchased at the highest available purity level. "N / A" indicates that specific information is not available.

[0341] Table 1

[0342] Equipment

[0343] Conductivity meter: EutechCON700 from Thermo Fisher Scientific, USA

[0344] Cryogenic transmission electron microscope (Cryo-TEM): Thermo Fisher Scientific, USA TM Talos200C transmission electron microscope equipped with Lacey grids

[0345] Differential scanning calorimeter (DSC): DSCQ2000 from TA Instruments, USA

[0346] Oven: DFO-240 from MRC, Israel

[0347] Particle size analyzer (dynamic light scattering): Malvern, UK Zen3600Zetasizer and Zetasizer Nano ZS

[0348] Ultrasonic generator: VCX750 from Sonics & Materials, USA

[0349] Thermorheometer: Haake Mars III from Thermo Scientific, Germany, equipped with a C20 / 1° spindle, a gap of 0.052 mm, and a shear rate of 10 sec -1 。

[0350] I. Preparation of Nuclear Nanocomponents

[0351] Example 1 - I: Screening of Non - volatile Liquids Suitable for Plasticizing WITC

[0352] In this study, the plasticization applicability of various non-volatile liquids (also known as plasticizers or swelling agents) to water-insoluble thermoplastic compounds (WITC), especially water-insoluble thermoplastic polymers (WITP), was tested.

[0353] Each different liquid was incubated with polycaprolactone (PCL-14) with a molecular weight of 14 kDa at a weight ratio of 1:1 at 80 °C for 1 hour, that is, 2 g of non-volatile liquid was added to 2 g of PCL-14 in a glass vial. After sealing the vial, it was placed in an oven preheated to the plasticization temperature. After incubation, the contents of the vial were manually mixed for about 30 seconds until a clear solution was obtained. The plasticized polymer samples were left to cure at room temperature overnight (i.e., at least 12 hours). None of the tested liquids showed exudation from the plasticized PCL-14, indicating that they may be applicable even at higher weight ratios.

[0354] Then the solid samples were transferred to a rheometer, and the change in viscosity with temperature was measured in the temperature range of 20 °C to 80 °C at a heating rate of 10 °C / min. A reference sample of unplasticized PCL-14 was included in the study, and this control sample showed a gradual decrease in viscosity with increasing temperature, from about 2 x 10 5 mPa·s (measured at 50 °C) to about 2 x 10 4 mPa·s (measured at 80 °C). For comparison, higher molecular weight unplasticized PCLs, namely PCL-37, PCL-45, and PCL-80, which will be described in detail later, had viscosities as high as about 6.2 x 10 6 mPa·s at 50 °C in the heating temperature range.

[0355] In additional viscosity measurements in this temperature range on samples prepared similarly at a 1:1 weight ratio, the following non-volatile liquids were found to reduce viscosity. For PCL-14, compared with the first viscosity of this WITC, 2 x 10 5 mPa·s, all of these liquids had a second viscosity below 104 mPa·s, so the viscosity is reduced by at least 1.5 logarithmic orders. These non-volatile liquids include octanoic acid, dioctyl carbonate, C 12 -C 15 alkyl benzoate, triethyl citrate, citronellol, cyclohexanecarboxylic acid, dibutyl adipate, hinokitiol, linalool, menthol, propylene carbonate, terpineol, tert-butyl acetate and thymol, which can be obtained from Sigma-Aldrich, or Phoenix Chemical for example.

[0356] Based on the above screening results, the first pair of WITP and non-volatile liquid was selected, namely PCL (PCL-14) with a molecular weight of about 14 kDa and dibutyl adipate. Combinations of other WITC and non-volatile liquids were similarly tested and found to be suitable for preparing nano-elements that can be combined with active agents and are suitable for preparing pharmaceutical or agrochemical compositions of this drug.

[0357] Example 2 - I: Nanoparticle Suspension of Nanocomponents in Aqueous Polar Phase

[0358] An aqueous solution containing a surfactant mixture (including an emulsifier and a co-solvent) was prepared as follows: 6.6 g of distilled water, 0.3 g of ammonium xylene sulfonate, 0.1 g of adenosine triphosphate and 1 g of vitamin E TPGS were placed in a 20 ml glass vial and sonicated for 10 minutes (power 40%, running in 7-second pulses followed by a 1-second pause) until a clear aqueous liquid serving as the liquid polar phase of the WITC nano-elements was obtained.

[0359] A WITC premix was prepared as follows: In another 20 ml glass vial, 3 g of PCL-14 with a natural melting point of about 62 °C (determined by DSC) was mixed with 7 g of B, and the vial was placed in an oven at 70 °C - 80 °C for 1 hour until the PCL-14 was completely melted. Then the contents of the vial were manually mixed for about 30 seconds until a clear and homogeneous solution of 30 wt.% molten PCL plasticized with 70 wt.% B was obtained. Then the melting point of the plasticized polymer was determined by DSC and found to be about 50 °C. Plasticization with B effectively reduced the Tm of the polymer by more than 10 °C.

[0360] 2 g of the WITC premix containing the molten plasticized polymer solution was added to a vial containing 8 g of the aqueous solution containing the surfactant and sonicated at a shear temperature of about 70 °C for 20 minutes to obtain a nanoemulsion containing liquid polymer nanodroplets in the aqueous solution.

[0361] This composition is listed as Composition 2.1 in Table 2-I(A). Other compositions were prepared following a similar procedure, each containing different components and amounts, and prepared under different conditions as specified in Tables 2-I(A) - 2-I(F). Sonication was carried out as described above. The values listed in the table correspond to the weight percentages (wt.%) of each component based on the total weight of the composition, except for the values in the WITC premix part which correspond to the weight percentages of each component in that specific premix. The nanoemulsions thus prepared were passively cooled at room temperature for 1 hour to relatively solidify the nanodroplets and, where applicable, form a nanodispersion. Alternatively, the nanodroplets remained liquid in the nanoemulsion at room temperature. The size of the core nanoparticles thus prepared was measured by dynamic light scattering (DLS) on a sample of the composition, with the sample diluted 1:100 in water, and the measured volume median diameter (D V 50) and number median diameter (D N 50) as well as the polydispersity index (PDI) are also listed in the table below.

[0362] Table 2-I(A)

[0363] Table 2-I(B)

[0364] Table 2-I(C)

[0365] Other compositions were also prepared in which PCL-14 was replaced by various WITCs to form the core of the nanoelement. Compositions prepared using higher molecular weight polycaprolactones, specifically 25 kDa, 37 kDa, 45 kDa, and 80 kDa, are described in Table 2-I(D). Compositions prepared using natural WITC shellac and rosin as core components, as well as compositions prepared using the following WITPs: poly(butylene succinate - adipate) (PBSA) and poly(lactic - co - glycolic acid) (PLGA) and non - polymeric WITC coenzyme Q10, are listed in Table 2-I(E), with the latter two compositions prepared without using any dedicated plasticizing non - volatile liquid. It is noteworthy that the polar carrier - insoluble active agent DL-α - tocopherol (a vitamin E derivative) added to the WITC premixes of Compositions 2.31 and 2.32 can also act as a plasticizer.

[0366] Table 2-I(D)

[0367] Table 2-I(E)

[0368] Other non-volatile liquids were also used as substitutes More compositions were prepared using B, namely 256, CC and dibutyl sebacate. These compositions are as described in Table 2-I(F).

[0369] Table 2-I(F)

[0370] Compositions were also prepared using non-biodegradable polymers to form the cores of the nano-elements. These compositions are as described in Table 2-I(G).

[0371] Table 2-I(G)

[0372] As can be seen from Tables 2-I(A) - 2-I(G), the present method is suitable for preparing nano-suspensions of core nano-elements containing WITC in the core, where the D V 50 and D N 50 do not exceed 200 nm, and for some of the above compositions, these values are even less than 100 nm. The PDI of the core nano-particle population is at most about 0.4.

[0373] Viscosity tests were also carried out on the samples corresponding to the above premixes at the end of the mixing step, at which time WITC had been at least uniformly mixed with the polar carrier-insoluble material and, in most cases, had been plasticized by the non-volatile liquid if present. As previously mentioned, the viscosity was measured in the temperature range of 20 °C to 80 °C and at a shear rate of 10 sec -1 For all the test samples, the viscosity measured at 50 °C was generally less than 10 6 mPa·s, generally between 10 3 mPa·s and 10 5 mPa·s, usually not exceeding 5x10 4 mPa·s, and the viscosity of many samples was even less than 10 4 mPa·s.

[0374] Example 3 - I: Nanoparticle Suspension of Nanocomponents Containing a Polar Carrier - insoluble Active Agent in WITC

[0375] In this example, an active agent was added to the WITC. Water-insoluble active agents were used: retinyl palmitate (MW ~525 g / mol), tadalafil (MW ~389 g / mol), Funapide (MW ~429 g / mol), neem oil (MW ~720 g / mol), and castor oil (MW ~927 g / mol) to illustrate the incorporation of polar carrier-insoluble and WITC-miscible active agents into the core of the nanoelement containing WITC. Retinyl palmitate can be regarded as an exemplary vitamin suitable for the preparation of dietary supplements or nutraceuticals; tadalafil can be regarded as an exemplary active agent for the treatment of erectile dysfunction, pulmonary arterial hypertension, and benign prostatic hyperplasia; Funapide can be regarded as an exemplary analgesic for the treatment of various chronic pain conditions. Although neem oil and castor oil can be used in living subjects (e.g., for reducing blood sugar levels or as a laxative, respectively), they can also be used as exemplary pesticides suitable for systemic treatment of plants.

[0376] A WITC / active agent premix was prepared in a 20 ml glass vial by mixing 2 g of PCL-14, 1 g of retinyl palmitate, 1 g of 12C and 6 g of B as a plasticizing non-volatile liquid. The vial was sonicated at about 80 °C for 2 minutes (as described above) to obtain a clear homogeneous solution of the plasticized WITC. The WITC / active agent premix was kept in an oven at 80 °C until mixed with the aqueous phase.

[0377] In another 20 ml glass vial, 7.5 g of distilled water and 0.5 g of sodium dioctyl sulfosuccinate as an additional surfactant (cosolvent) were placed and sonicated at about 60 °C for 1 minute until a clear aqueous solution for use as the liquid polar phase was obtained.

[0378] Then, 2 g of the hot WITC / active agent premix was added to the vial containing 8 g of the aqueous solution and sonicated at a shear temperature of about 70 - 80 °C for 1 minute to obtain a nanoemulsion in which liquid PCL nanodroplets containing retinyl palmitate were dispersed in the aqueous polar phase.

[0379] This composition was listed as composition 3.1 in Table 3-I. Other compositions were prepared according to a similar procedure, each composition containing different components and amounts as specified in the table. Tadalafil and Funapide were each first mixed with the non-volatile liquid and sonicated at 80 °C for 2 minutes to obtain a clear solution containing the active agent, and then mixed with WITC and other components as described above.

[0380] The values listed in the table correspond to the weight percentages (wt.%) of each component based on the total weight of the composition, except for the WITC / active agent premix part where the values correspond to the weight percentages of each component in that specific premix. The nanoemulsion thus prepared was passively cooled at room temperature for 1 hour to relatively solidify the nanodroplets. The degree of solidification can be evaluated by sampling the premix of the mixed materials to determine whether the nanodroplets are solid enough at room temperature to form a nanodispersion or liquid enough to form a nanoemulsion. The separated samples were also cooled without shearing into the liquid phase. The size and PDI values of the core nanoparticles thus prepared, measured by DLS as described above, are also listed in Table 3-I.

[0381] Table 3-I

[0382] As can be seen from Table 3-I, the present method is applicable to the preparation of nanosuspensions of nano-elements, the cores of which contain water-insoluble thermoplastic compounds (WITC) and carrier-insoluble active agents, and the D V 50 and D N 50 do not exceed 200 nm, and for some of the above compositions, these values are even lower than 100 nm. The PDI of the core nanoparticle population is at most about 0.3.

[0383] Figure 2A Representative results of the particle size distribution in the sample of Composition 3.6 are shown, indicating the volume percentage of core nanoparticles with hydrodynamic diameters in the range of 10 - 1000 nm.

[0384] Example 4 - I: Nanoparticle Suspension of WITC in a Liquid Polar Phase Containing a Polar Carrier - soluble Active Agent

[0385] An aqueous solution containing a surfactant mixture (including an emulsifier and a cosolvent) was prepared as follows: 4.4 g of distilled water, 0.6 g of ammonium xylene sulfonate, and 1 g of vitamin E TPGS were placed in a 20 ml glass vial and sonicated for 10 minutes (as described above) until a clear aqueous solution containing the surfactant, which was used as the liquid polar phase, was obtained.

[0386] In another 20 ml glass vial, a WITC premix was prepared as follows: 3 g of PCL-14 and 7 g B were mixed, and the vial was placed in an oven at 80 °C for 1 hour until the PCL was plasticized and completely melted. Then the contents of the vial were hand-mixed for about 30 seconds until a clear homogeneous solution of 30 wt.% molten PCL plasticized with 70 wt.% B was obtained.

[0387] A molten solution of 2 g of a plasticized polymer was added to a vial containing 6 g of an aqueous surfactant solution and sonicated for 20 minutes at a shear temperature of about 70 °C (as described above), thereby obtaining a nanoemulsion containing liquid polymer nanodroplets in an aqueous polar phase.

[0388] The nanoemulsion was allowed to cool passively to room temperature over 1 hour, at which point 1 g of propylene glycol was added and the contents of the vial were mixed by hand for 10 seconds. Subsequently, 1 g of low molecular weight hyaluronic acid (LMW hyaluronic acid) was added as a polar carrier-soluble surfactant and the contents of the vial were again mixed by hand for about 10 seconds until the HA was completely dissolved in the liquid polar phase.

[0389] This composition was listed as Composition 4.1 in Table 4-I. Other compositions were prepared in a similar manner, containing different amounts of different components. The values listed in the table correspond to the weight percentages (wt.%) of each component in the total weight of the composition, but the values for the WITC premix portion correspond to the weight percentages of each component in that particular premix. As described above, the size and PDI values of the prepared nanoparticles were measured by dynamic light scattering (DLS) and are also listed in Table 4-I.

[0390] Table 4-I

[0391] As can be seen from Table 4-I, the present method is suitable for preparing nano-suspensions of nano-elements containing WITC and carrier-soluble surfactants, where the D V 50 and D N 50 do not exceed 200 nm and the PDI of the nanoparticle population is at most about 0.2.

[0392] The size of the core nanoparticles of Composition 4.1 was confirmed by transmission electron microscopy (TEM) microscopy of cryosection images of the nano-dispersion. The size of the cryo-nanoparticles observed in the images was consistent with the DLS measurements. Figure 5 An example image is shown where the nanoparticles appear as dark grey spheres in the background, showing the core.

[0393] It is believed that when the nano-dispersion is to contain WITC nano-elements and the dispersion contains two types of surfactants (a carrier-insoluble surfactant within the WITC matrix of the nano-elements and a carrier-soluble surfactant in the surrounding polar carrier), the methods of Examples 3-I and 4-I can be used in combination.

[0394] II. Preparation of Core - shell Nanocomponents

[0395] Example 1 - II: Reduction of the Viscosity of WITC

[0396] In the previous study of Example 1-I, the ability of various non-volatile liquids to plasticize WITC (especially PCL-14) has been screened. In this study, the viscosities of PCL-14 (abbreviated as PCL in this example) and its mixtures with shell formers and non-volatile liquids used as plasticizers were further measured at different weight ratios of PCL to plasticizer.

[0397] In the first series of experiments, viscosity measurements were made on mixtures that form homogeneous substances suitable for nanosizing by this method. PCL was mixed with non-volatile liquids or fatty amines as shell formers (SFA) in different weight ratios in glass vials. After sealing the vials, they were placed in an oven preheated to 80 °C. The ratios of PCL to non-volatile liquids tested were 1:1 and 1:2.33, and the ratios of PCL to fatty amines were 1:0.1, 1:0.33, 1:0.5, and 1:1. After heating and incubating for 1 hour, the contents of the vials were mixed by hand for about 30 seconds until a clear solution was obtained. The samples were cooled overnight (i.e., at least 12 hours) at room temperature to solidify. None of the plasticizers tested exuded from the solidified polymer, indicating that their ratios to PCL could even be higher.

[0398] Then the solid samples were transferred to a rheometer, and the variation of their viscosities with temperature was measured at a heating rate of 10 °C / min in the temperature range from room temperature to 70 °C. The viscosities (or second viscosities) of the samples measured at 50 °C and 70 °C are summarized in Table 2-II(A), and the first row lists the first viscosity of the unplasticized pure PCL reference sample under the same conditions.

[0399] Table 2-II(A)

[0400] As can be seen from the above table, at 50 °C and 70 °C, all the plasticizers tested (whether dedicated non-volatile liquids or fatty amines with plasticizing effects) can reduce the viscosity of PCL to less than 10 4 mPa·s at the tested weight ratios. Different weight ratios, such as relatively low contents of plasticizers or fatty amines to WITC (e.g., oleylamine 1:0.1), may have less effect, but suitable ratios and reagents capable of plasticizing the material can be easily determined by routine experiments, as shown herein.

[0401] Based on the above results or similar experiments, a PCL:plasticizer ratio with a dynamic viscosity of 1 × 10 4 mPa·s or lower (although higher viscosities are allowed) measured at least at 50 °C was selected for the preparation of core-shell nanoparticles for pharmaceutical or agrochemical compositions, as described in the following examples.

[0402] In a second series of experiments, the viscosity was measured at another stage of the preparation process, namely on core-shell nano-elements isolated from the compositions prepared in detail in the following examples. Nanoparticles containing only PCL-14 were used as a reference, compared with nanoparticles containing 1 wt.% or 5 wt.% O 020Special (hereinafter abbreviated as GenA2 in the following table) as a fatty amine and mixed with PCL, and nanoparticles containing 30 wt.% PCL-14, 30 wt.% GenA2 and additionally containing 40 wt.% non-volatile liquid ( B or dibutyl sebacate (DBS)). The variation of viscosity with temperature (°C) was measured as described above, but the maximum temperature was 85 °C, and the results are listed in Table 2-II(B) in descending order of temperature in units of mPa·s.

[0403] Table 2-II(B)

[0404] As can be seen from the above table, in the temperature range of 30 °C to 85 °C, even a trace amount of fatty amine (e.g., 1 wt.% GenA2) can be detected through its plasticizing effect on WITC, while at lower temperatures, a higher proportion of plasticized fatty amine is required to detect the plasticizing effect. Interestingly, even a small amount of plasticizing fatty amine (e.g., 5 wt.% GenA2) can make the viscosity of the core-shell nano-elements less than 1×10 7 mPa·s at a temperature close to body temperature (35 °C).

[0405] Example 2 - II: Preparation of Core - shell Nanodispersions

[0406] 2 g of PCL-14, 2 g of SFA (N,N-dimethyldodecylamine, DMDA, a fatty amine) and 6 g of non-volatile liquid B (used as a special plasticizer) were placed in a 20 ml glass vial. The contents of the vial were sonicated at about 70 °C for 2 minutes until a clear WITC / SFA premix containing the non-volatile liquid was obtained.

[0407] In another 20 ml glass vial, 8 g of glycerol was heated to about 70 °C with an ultrasonic device, and then 2 g of the hot premix prepared above was added. The composition was sonicated for 5 minutes while maintaining 70 °C to obtain a nanoemulsion. Then the nanoemulsion was allowed to cool to room temperature until a nano-dispersion containing core-shell nanoparticles was obtained.

[0408] The nano-dispersion (ND1) is listed in Table 3-II, which also lists other nano-dispersions prepared according to similar procedural steps. Each nano-dispersion contains different amounts of different components and is prepared under different conditions as described in the table. Unless otherwise stated, the values reported in this table and subsequent tables describing the compositions and their preparation correspond to the weight percentages (wt.%) of each component in the total weight of the nano-dispersion, except for the values in the WITC / SFA premix portion, which correspond to the weight percentages of each component in that specific premix, which may also contain any other WITC miscible components such as non-volatile liquids. Water refers to double-distilled water.

[0409] The size of the nanoparticles prepared according to this example or similar examples below was measured by dynamic light scattering (DLS) on a composition sample diluted 1:100 in water. The measured number-average median diameter (D N 50) and polydispersity index (PDI) are also listed in the relevant tables below. When measuring, the maximum hydrodynamic diameters at which 10% and 90% of the particles are present in the sample (D N 10 and D N 90) are also listed in the relevant tables.

[0410] Table 3-II

[0411] As can be seen from Table 3-II, the method is suitable for preparing nano-suspensions of core-shell nano-elements, the cores of which contain WITC and SFA. The D N 50 of the nano-elements does not exceed 200 nm, and for some of the above nano-suspensions, this value is even lower than 100 nm. The PDI of the core-shell nano-element population is at most about 0.5.

[0412] Example 3 - II: Preparation of Positively Charged Core - shell Nanoparticles by Acid Doping

[0413] 8 g of double-distilled water was placed in a 20 ml glass vial. 2 g of the nano-dispersion ND1 obtained in Example 2-II was added, and the contents of the vial were shaken by hand for about 10 seconds until a homogeneous mixture (referred to as charged ND1 or cND1) was obtained. The ζ potential of the mixture was measured using a Malvern zeta potential analyzer Nano ZS and found to be -14.7 mV. Unless otherwise stated, all measurements performed using this instrument (e.g., ζ potential and particle size distribution) were carried out on samples diluted 1:100 in double-distilled water. All pH measurements reported in this example and subsequent examples were performed at least using pH test strips suitable for the relevant pH range and, in some cases, confirmed using a suitable pH meter.

[0414] Then, 1 drop of acetic acid was added to the mixture to bring the pH to 5.5, and the vial was shaken by hand for about 10 seconds until a nano-dispersion containing positively charged core-shell PCL / DMDA nanoparticles, designated as cND1’, was obtained. The ζ-potential of the nanoparticles in the acid-doped nano-dispersion was measured and confirmed to be positive, with a charge of +52.4 mV.

[0415] The hydrodynamic diameter of the nanoparticles in the acid-doped cND1’ was determined by DLS, and it was found that the D N 50 of the sample was similar to the D N 50 of the nanoparticles of ND1 in Table 3-II.

[0416] Example 4 - II: Preparation of Positively Charged Core - shell Nanoparticles under Acid - free Conditions

[0417] 9.9 g of double-distilled water was placed in a 20-ml glass vial. 0.1 g of the nano-dispersion ND3 obtained in Example 2-II was added, and the contents of the vial were shaken by hand for 10 seconds until a homogeneous mixture, designated as cND3, was obtained. The ζ-potential of the mixture was measured and found to be +43 mV. The particle size distribution of the resulting nanoparticles was determined by DLS, and it was found that the D N 50 of the sample was similar to the D N 50 of the nanoparticles of ND3 in Table 3-II.

[0418] Example 5 - II: Preparation of Positively Charged Core - shell Nanoparticles by Acid Doping of Diluted Samples

[0419] 9 g of double-distilled water was placed in a 20-ml glass vial. 1 g of the nano-dispersion cND3 obtained in Example 4-II was added, and the contents of the vial were shaken by hand for 10 seconds until a homogeneous mixture, designated as cND3’, was obtained. The ζ-potential of the mixture was measured and found to be -9.9 mV. This mixture was different from the mixture described in Example 4-II in that the content of ND3 was 10 times less in the same total weight of the aqueous carrier. The currently prepared 10-fold diluted nano-dispersion showed a relatively low charge of -9.9 mV, whereas in the previous case the charge was +43 mV.

[0420] Then, 1 drop of acetic acid was added to the relatively diluted mixture to bring the pH to 5.5, and the vial was shaken by hand for about 10 seconds until an acid-doped nano-dispersion containing positively charged core-shell PCL / DMDA nanoparticles, designated as cND3”, was obtained. The ζ-potential of the acid-doped nano-dispersion cND3” was measured and confirmed to be positive, with a charge of +7.8 mV. The hydrodynamic diameter of the resulting nanoparticles was determined, and it was found that the D N 50 of the sample was similar to the D N 50 of the nanoparticles of ND3 in Table 3-II.

[0421] Example 6 - II: Preparation of Core - shell Nanoparticles in a pH - adjusted Polar Carrier

[0422] Place 2 g of PCL-14, 2 g of DMDA, and 6 g of B into a 20 ml glass vial. Sonicate the vial contents at approximately 70 °C for 2 minutes until a clear WITC / SFA premix is obtained.

[0423] In another 20 ml glass vial, mix 8 g of glycerol and 1 g of 3 wt.% HCl solution (as a pH regulator) to obtain a solution with a pH of 3. Add 1 g of the above-prepared hot WITC / SFA premix to the acidic liquid carrier and sonicate the vial contents for 30 seconds to obtain a nanoemulsion. Allow the nanoemulsion to cool to room temperature until a nanodispersion is obtained.

[0424] Measure the ζ potential of the nanodispersion and find it to be +72.8 mV. This charge is generated by diluting the sample in water. Therefore, positively charged nanoparticles can be easily obtained after sonication in an acidic polar carrier without using the two-step method as described previously.

[0425] The nanodispersion (ND7) thus obtained is listed in Table 4-II(A). Other nanodispersions were prepared according to a similar procedure. All these nanodispersions can be charged in the presence of water. Each nanodispersion contains different contents of different components and is prepared under different conditions, as described in Tables 4-II(A)-(C). Samples of some nanodispersions were measured after dilution to 1:100 in double-distilled water, and the measured parameter values are also listed in the following table. The pH values of nanodispersions ND15 and ND16 were obtained by adding approximately 1 drop of acetic acid to their respective aqueous phases.

[0426] Table 4-II(A)

[0427] In addition to measuring the ζ potential of the nanodispersion, the effect of the pH regulator in the polar liquid carrier was monitored by measuring the pH change during the preparation of the nanodispersion. Taking ND7 as an example, when an acidic glycerol solution with a pH of 3 is mixed with the WITC / SFA mixture (SFA is the fatty amine DMDA), the pH increases to 6, indicating that the hydrogen ions in the liquid carrier are consumed, and it is believed that these hydrogen ions react with the amine groups of the fatty amine shell. The pH remains at 6 after cooling and increases to 6.5 after dilution with water, indicating that the amine groups remain protonated, which is also confirmed by the positive ζ potential.

[0428] Other nanodispersions prepared using WITC from various synthetic and natural sources are summarized in Table 4-II (B)-(C). The aqueous phases of the nanodispersions listed in the table were pH-adjusted (for ND17-ND23 and ND26, approximately 1 drop of acetic acid was added to make the pH acidic; for ND27, 1-2 drops of 25% ammonium hydroxide solution were added to make the pH basic. The amounts of pH regulators added to adjust the pH values of ND24 and ND25 are noted in the table).

[0429] Table 4-II (B)

[0430] Table 4-II (C)

[0431] The core-shell nano-elements of ND24 and ND25 were separated and subjected to thermorheological analysis, and the results are shown in Table 2-II (B).

[0432] ND26 and ND27 contain fatty acids as SFAs, which promoted the generation of negative charges, as indicated by the ζ potential. At higher pH values, the negative charge of ND27 increased.

[0433] Nanodispersions prepared using non-biodegradable thermoplastic polymers are summarized in Table 4-II (C). The pH values of the nanodispersions in the table were obtained by adding approximately one drop of acetic acid to their aqueous phases.

[0434] Table 4-II (C)

[0435] Example 7 - II: Preparation of Core - shell Nanoparticles with Acid - containing Cores

[0436] In the following examples, the pH of the nanodispersion was adjusted from the interior of the core of the core-shell, which is different from the previous method (e.g., in Example 6-II) of forming a nanoemulsion by mixing the core-shell with an acidified polar carrier.

[0437] 2 g of PCL-14, 2 g of O 020Special and 6 g of B were placed in a 20 ml glass vial. 0.01 g of anhydrous acetic acid was added, and the contents of the vial were sonicated at approximately 70 °C for 2 minutes until a clear WITC / SFA / acid premix was obtained.

[0438] In another 20 ml glass vial, 9 g of water was added, and then 1 g of the above-prepared hot WITC / SFA / acid premix was added. The vial contents were sonicated at about 80 °C for 1 minute to obtain a nanoemulsion. The nanoemulsion was allowed to cool to room temperature until a nanodispersion was obtained.

[0439] Its pH value was measured and found to be 5. The ζ potential was measured in a nanodispersion sample (diluted 1:100 in double-distilled water) and found to be +54.1 mV, indicating that the nanoparticles were positively charged, presumably due to the leakage of acetic acid from the core of the nanoparticles into the polar carrier, thereby protonating the amine heads in the nanoparticle shell. The D N 50 and PDI were also measured and were 35.3 nm and 0.198, respectively.

[0440] Example 8 - II: Preparation of Core - shell Nanoparticles with a Core Containing a WITC - miscible Active Agent

[0441] 2 g of PCL-14 and 0.1 g of benzoyl peroxide as a WITC miscibility activator were placed in a 20 ml glass vial. 2 g of O 020Special and 5.9 g of B were added, and the vial contents were sonicated at about 70 °C for 2 minutes until a clear WITC / SFA / activator premix was obtained.

[0442] In another 20 ml glass vial, 9 g of water was added and acidified to pH 4 by adding a drop of acetic acid. 1 g of the above-prepared hot WITC / SFA / activator premix was added to the acidic liquid carrier, and the vial contents were sonicated at about 80 °C for 1 minute to obtain a nanoemulsion. The nanoemulsion was allowed to cool to room temperature until a nanodispersion was obtained.

[0443] The nanodispersion (ND31) thus obtained is listed in Table 5-II. Other nanodispersions were prepared according to a similar procedure. All these nanodispersions were chargeable in the presence of water, and each nanodispersion contained a different activator miscible with WITC and insoluble in water (which could be a pharmaceutical activator or an agricultural activator), as described in the table.

[0444] The ζ potential, D N 50 and PDI were measured for samples of some of the nanodispersions (charged by diluting 1:100 in double-distilled water), and the measured values are listed in Table 5-II.

[0445] Table 5-II

[0446] Figure 2BShows representative results of the particle size distribution in the ND32 sample, showing the percentage of the number of core-shell nanoparticles with hydrodynamic diameters in the range of 10 - 1000 nm.

[0447] It can be seen that ND37 and ND38 do not contain a dedicated non-volatile liquid. It is believed that neem oil and castor oil, which are WITC miscible surfactants included in ND37 and ND38 respectively in relatively high contents three times the weight of WITC, also act as plasticizers for the premix containing WITC.

[0448] Example 9 - II: Preparation of Core - shell Nanoparticles Coated with a Water - soluble Active Agent Externally

[0449] 1 g of collagen peptide powder and 2.1 g of water were placed in a 20 ml glass vial and mixed at room temperature until completely dissolved.

[0450] In another 20 ml vial, 6.9 g of the core-shell nano-dispersion ND11 obtained in Example 6-II was added, and then a collagen solution providing water-soluble surfactant molecules to form a second shell was added. The contents of the vial were shaken by hand for 10 seconds until a homogeneous mixture was obtained. The composition of the collagen-coated nano-elements thus obtained (collagen-ND11) is listed in Table 6-II, which also lists the composition of the low molecular weight hyaluronic acid-coated nano-elements (LMWHA-ND11) prepared in the same way. A reference composition containing uncoated nano-elements (uncoated-cND11) was also prepared, which contained 3.1 g of water without any carrier-soluble surfactant.

[0451] Based on ND6 and ND14, three other nano-dispersions (designated LMW HA-ND6 and LMW HA-ND14 respectively) were prepared, and low molecular weight hyaluronic acid was added to reach the concentrations reported in Table 6-II. Samples of LMWHA-ND6 and LMWHA-ND14 were prepared, in which the low molecular weight hyaluronic acid solution was mixed with the ND6 or ND14 composition by ultrasound. For comparison, another LMW HA-ND6 sample with the same composition concentration was also prepared by manually mixing the low molecular weight hyaluronic acid solution and the ND6 composition.

[0452] These compositions are also listed in Table 6-II, which details the different components and contents. The values listed in the table correspond to the weight percentages (wt.%) of each component in the total weight of the nano-dispersion. The D N 50 and ζ potential values are also listed in Table 6-II.

[0453] Table 6-II

[0454] From the change in the ζ potential, it can be seen that adding an active agent to the previously prepared core-shell nanoparticles reduces the charge perceived on the outer surface of the newly formed nanoparticles, which supports that a change has occurred at this interface with the liquid carrier, indicating the formation of a second shell composed of the active agent. For example, while the ζ potential of the nano-dispersion ND14 without coated nano-elements was +56.0 mV (according to Table 4-II(A) of Example 6-II), it can be seen that after coating these nano-elements with low molecular weight hyaluronic acid (LMWHA), the ζ potential decreased to +34.9 mV.

[0455] As a reference, 0.1 g of collagen peptide was dispersed in 9.9 g of distilled water, and its ζ potential was measured to be -7.7 mV, which indicates that there is a satisfactory Δζ between the ζ potential of the collagen intended to coat the nanoparticles and the ζ potential of the nanoparticles to be coated, enabling the collagen to attach to the surface of the nanoparticles that previously contained only the first shell. The ζ potential of a similarly prepared aqueous solution of LMW HA was measured and found to be -17 mV, and this Δζ is even higher compared to the Δζ observed when preparing the collagen-coated nanoparticle composition.

[0456] It is believed that the rate at which the carrier-soluble active agent forming the second shell is mixed with the "uncoated" core-shell having only a positively charged amine in the first shell affects the morphology of the core-multilayer-shell nanoparticles that can be obtained.

[0457] Figure 6A The results of cryogenic transmission electron microscopy (CryoTEM) analysis of the first sample of the LMWHA-ND6 composition obtained by high-shear mixing (i.e., ultrasonic) of LMW HA with the core-shell nano-elements of ND6 are shown. In the figure, the core 610 containing PCL (presented as black small spheres) is surrounded by a second shell 630 composed of LMW HA. As Figure 6A shown, the second shell can be composed of multiple layers of HA, stacked one on top of the other.

[0458] Figure 6B is another image of the second sample of the LMWHA-ND6 composition taken by CryoTEM, where LMW HA was manually mixed with the core-shell nano-elements of ND6. In the image, two black PCL cores 610 can be seen surrounded by a common shell 630', and the shell 630' is also composed of LMW HA layers, forming a larger nano-element. It is believed that manual mixing may be too slow / low in energy, and the active agent shell formed on the core will converge and merge into such larger particles. Therefore, it is recommended that high-energy mixing (such as high-shear) is more beneficial for forming the second shell around a single core than low-energy mixing methods, and the particle size distribution of such core-multilayer-shell nano-elements is commensurate with the size of a single core-shell and is more likely to remain within the size range suitable for transdermal delivery.

[0459] Similarly, the ND12 nanoparticles prepared in Example 6-II were coated with various water-soluble surfactants, and an uncoated ND12 composition was prepared as a reference. The ND12-based compositions, including their respective components and their concentrations, are summarized in Table 7-II, and the concentration of each component is expressed as wt.% of the total weight of the nanodispersion. The D N 50 and ζ-potential values of each composition are also listed in Table 7-II.

[0460] Table 7-II

[0461] Nanoparticles with a shell composed of vitamins can be used to prepare dietary supplements, while a shell containing collagen, elastin, or HA (which are known adhesion proteins or polysaccharides) can be used to promote the retention of the nanoparticles (and other active agents contained therein) at the desired delivery site.

[0462] Example 10 - II: Conductivity Measurement

[0463] To further demonstrate the adsorption of water-soluble surfactants onto the surface of the core-shell nanoparticles, the conductivity of various ND12-based composition samples was measured using a conductivity meter, and the results are listed in Table 8-II in units of microsiemens (μS).

[0464] The basic principle of this study is that if two substances that each have conductivity as electrolytes in a specific medium are mixed, the conductivity of the mixture is the sum of the relative contributions of the two substances only when the two substances remain separated. In other words, if the conductivity of the mixture is not the sum of the conductivities of its components, it can be assumed that the two substances interact.

[0465] In this study, it was assumed that water-soluble surfactant molecules could attach to the core-shell nanoparticles. Therefore, when core-shell nanoparticles with a given concentration and conductivity A in a medium were mixed with a surfactant with a given concentration and conductivity B in a substantially the same medium, the conductivity of the mixture should be lower than the sum of A + B.

[0466] Samples of various water-soluble surfactants were prepared in a carrier substantially similar to the liquid mixture used to prepare the ND12 nanoparticles and their coated versions. The conductivity of the individual surfactant, the core-shell nanoparticles before being coated with a second shell of the surfactant, and the nanoparticles coated with the surfactant were measured, and all the results are listed in Table 8-II.

[0467] Table 8-II

[0468] As can be seen from the above table, the conductivities of uncoated nanoparticles containing only the first shell formed by the hydrophilic part of SFA (fatty amine in this study) are basically similar, which is consistent with the expectation of core-shell nanoparticle samples in similar carriers (without any specific externally applied active agent).

[0469] In contrast, the conductivity of each individual active agent or the core-shell nanoparticles coated therewith depends on the active agent under consideration (such as LMWHA, vitamin C, collagen, and elastin). It is noteworthy that the conductivities of all active agent-coated nanoparticle samples are lower than the sum of the conductivity of the core-shell nanoparticles in the carrier (A) and the conductivity of the active agent in the substantially same carrier (B). These results support that this method can prepare core-shell nanoparticles having a core composed of WITC material, a first shell composed of SFA, and a second shell composed of water-soluble active agent that interacts with the first shell.

[0470] III. Cellular Penetration of Nanocomponents

[0471] The cell penetration ability of the nano-elements in this composition was tested in vitro by culturing a nano-element composition containing a fluorescent dye in cell cultures and monitoring using a fluorescence microscope. The penetration of the nano-elements was evaluated in cortical neuron cells isolated from neonatal rodents.

[0472] Materials

[0473] The materials used in the following studies are listed in Table 9.

[0474] Research system

[0475] All solutions and equipment used in cell culture studies were sterile, and all operations were carried out in a laminar flow cabinet. All culturing was carried out in a tissue culture incubator with the temperature maintained at 37 °C, the CO2 concentration at 5%, and the relative humidity at 95%. The following solutions were used during the study: Brain Neuron Culture (BNC) medium, containing Neurobasal TM medium, containing 5 vol.% of FBS, 2 vol.% of B-27 TM supplement, 1 vol.% of GlutaMAX TM and 30 ppm of gentamicin sulfate; Supplemented NB (SNB) medium, the same as BNC medium but without FBS; Dissociation solution, HBSS solution containing 2 vol.% of HEPES.

[0476] The 24-well tissue culture plates were pretreated as follows to receive the cells to be cultured therein. A round glass microscope coverslip was placed at the bottom of each well. 0.3 ml of a poly-L-lysine (PLL) solution with a concentration of 0.1 mg / mL was added to each well, and the culture plates were incubated at 37 °C for 3 hours while gently shaking to ensure that the coverslips were completely covered with the solution. Then the PLL was aspirated, and the wells were rinsed with NB medium to remove the residual PLL. 0.5 ml of BNC medium was added to each rinsed well, and the culture plates containing the pretreated coverslips (to promote cell adhesion) were kept in the incubator until use.

[0477] Cell culture preparation

[0478] Cells were prepared according to the following steps:

[0479] 1. Tissue collection: Two newborn C57 black mice were sacrificed by cervical dislocation, and their brains were rapidly dissected using sterilized standard scissors. The brain slices were collected in a 35 mm culture dish containing 5 ml of dissociation solution and placed on ice.

[0480] 2. Dissociation: Then the contents of the culture dish were transferred to a 15 ml centrifuge tube to precipitate the brain slices, and subsequently the supernatant was removed and discarded. Dissociation solution was added to the separated brain slices to make the total volume reach 4 ml, and 1 ml of TrypLE TM Express Enzyme was added to induce the separation of neuronal cells from other tissues. The centrifuge tube and its contents were incubated in an incubator at 37 °C for 20 minutes while gently shaking. Then the supernatant was carefully removed and replaced with 1.2 ml of NB medium.

[0481] 3. Grinding: Subsequently, the tissue was ground into single cells by pipetting up and down through a series of glass Pasteur pipettes with decreasing tip sizes to obtain a homogeneous solution containing single cells. The obtained cell suspension was centrifuged at 500 revolutions per minute for 5 minutes, the supernatant was discarded, and the pellet was resuspended in 2 ml of BNC medium. The cell pellet for the rinse cycle was resuspended again by centrifugation (500 revolutions per minute, 5 minutes).

[0482] 4. Resuspension: The supernatant was carefully removed, and the rinsed cells were resuspended in 1.5 ml of BNC medium, and the cell concentration was determined using a counting chamber and a stereomicroscope (Stemi200-C from Olympus) with an appropriate magnification.

[0483] 5. Cultivation: Add the suspended cells into the wells of a pre-treated 24-well plate with a poly-L-lysine-coated coverslip at the bottom of the well. The added volume should ensure that approximately 80,000 cells are seeded in each well. Incubate the culture plate containing 0.5 ml of BNC medium and 80,000 neuronal cells per well in an incubator for 3 days. One day before adding the test composition, aspirate the medium and replace it with 1 ml of SNB medium per well.

[0484] Test composition

[0485] The composition used in this experiment was prepared as described in Example 2-I, and 2 mg of the fluorescent marker Nile Red was added during the preparation of the WITC premix. The final composition contains: 4 wt.% of PCL-14, 1.3 wt.% of M1944CS, 2.7 wt.% of 63, 12 wt.% of B, 0.004 wt.% of Nile Red, 1.3 wt.% of dioctyl sulfosuccinate, 18.7 wt.% of glutamate and 60 wt.% of water.

[0486] Then, sterilize the nano-dispersion through a syringe equipped with a 100 nm filter and store it in a sealed container at room temperature until use.

[0487] In vitro study

[0488] After culturing neuronal cells in BNC medium for 3 days and in SNB medium for 1 day, add the test composition to the wells containing the pre-treated coverslips. The cells adhere to the coverslips during the cultivation. Add the sample to the wells in two steps, adding 1 μl to reach a concentration of 0.1 vol.%, and adding 10 μl to reach a concentration of 1 vol.%. Then incubate the culture plate at 37 °C for 20 minutes to allow the nano-elements to penetrate the neuronal cells.

[0489] At the end of the incubation with the test composition, remove the coverslips from their respective wells, rinse them with DPBS, and place them in a 35 mm culture dish containing 2 ml of DPBS for studying the still-viable cells under a microscope (e.g., within one hour after transferring to DPBS). Determine the presence of intracellular dye by fluorescence microscopy (using a BX43 Olympus microscope equipped with fluorescence filters and measuring at a wavelength of 594 nm using cellSens software).

[0490] Results

[0491] Figure 7AIt shows cortical neuron cells 70, and nano-elements 72 containing the dye can be seen inside the neuron cells, thus confirming that the present nano-elements have the ability to penetrate cells. Nano-elements 74 can also be seen outside the cells, which is expected considering that the composition containing them is externally applied to the cell culture. Figure 7B schematically depicts Figure 7A the cells in, in order to better illustrate the cells, their outer membranes, and the positions of the nano-elements relative to these biological barriers.

[0492] IV. Use of the Composition as a Pharmaceutical Nanocarrier

[0493] The following pharmacokinetic (PK) study was conducted to determine the efficacy of the composition according to the present invention after oral administration to rats.

[0494] Study system

[0495] Nine healthy young adult rats (Sprague Dawley) with an initial average body weight of approximately 243.1 ± 1.8 g were used in this study. They were individually marked by their tails and housed in a limited-access cage rodent facility. The rats were randomly divided into 3 groups of 3 each, and they were housed in their respective groups in the cages throughout the study. The environmental temperature was controlled at 17 - 23 °C, the relative humidity (RH) was 30 - 70%, the light and dark cycle was 12:12 hours, and the air in the study room was exchanged 15 times per hour. During the 5-day acclimation period and throughout the study, the rats had free access to commercial rodent feed and fresh drinking water.

[0496] Test composition and its administration

[0497] The nano-dispersion ND39 listed in Table 5-II was used as the test composition. ND39 contains tadalafil as a polar carrier-insoluble active agent in the nano-element core, and its concentration in the rat blood was monitored.

[0498] Under anesthesia, a 1-ml composition with a concentration of 4 mg / ml was administered to the fed animals once using a 2-ml syringe and a gavage needle, and the dose was approximately 16 mg / kg. Blood samples were collected at 0.25 hours, 0.5 hours, 1 hour, 2 hours, 4 hours, 8 hours, 12 hours, 24 hours, and 48 hours after the administration of the nano-elements.

[0499] Blood collection

[0500] At each time point, blood was collected from 3 rats through the retro-orbital sinus, the blood was collected in EDTA Eppendorf tubes, and immediately centrifuged at 3000 revolutions per minute for 5 minutes. The plasma was collected into vials using a filtered pipette tip and immediately stored at a temperature of -80 °C.

[0501] Experiment termination

[0502] At the end of the study, animals were euthanized with sodium pentobarbital.

[0503] PK analysis

[0504] Plasma samples were mixed with acetone to dissolve the nano-components, making tadalafil available for measurement, and then centrifuged to precipitate plasma proteins. The obtained supernatant was taken and analyzed by LC-MS / MS in comparison with a pre-prepared tadalafil calibration curve (range from 1 ng / ml to 10 μg / ml).

[0505] Figure 8 The solid black line in... shows the change in tadalafil concentration (ng / ml) over time (hours) after administration of the ND39 composition. The figure also shows similar pharmacokinetic data obtained in another study where a reference composition was administered to 3 rats per group. "Ref.C" refers to a commercially available (containing tadalafil) tablet, which was crushed and suspended in water to prepare a 2 mg / ml solution and administered at a dose of approximately 18.7 mg / kg (represented by the dashed line). "Ref.T" refers to an aqueous suspension of 2 mg / ml tadalafil API administered at a dose of approximately 18.1 mg / kg (represented by the dotted line).

[0506] From Figure 8 it can be seen that the level of tadalafil delivered by the reference composition decreased relatively rapidly, and tadalafil could not be detected in the blood 24 hours after administration. In contrast, the nano-components of ND39 remained in the blood for a longer time, and tadalafil extracted from them could no longer be significantly detected until 48 hours after administration. This indicates that, compared with traditional treatment methods, the active agent carried by this nano-component can make the drug have a longer therapeutic activity after being released from the nano-component.

[0507] The area under the curve (AUC 0-∞ , in units of ng·hr / ml) from zero to infinity in the figure, and normalized according to the dose of tadalafil in each group (AUC 0-∞ / D, in units of h·mg / mL), which also indicates that this nano-component may have an advantage in delivering the active agent. The AUC 0-∞ / D value of the reference composition, Ref.C is approximately 930 h·mg / ml, and Ref.T is approximately 1249 h·mg / ml. In contrast, the calculated AUC 0-∞The / D value is almost twice as high, approximately 1897 h·mg / ml. This significant difference is attributed to the fact that in the present composition (such as ND39 tested here), the active agent (tadalafil here) is protected by the WITC of the core and released from the core, while tadalafil in Ref.C and Ref.T lacks such a protective nanocarrier.

[0508] Interestingly, the results obtained for the test composition ND39 showed less variability (represented by calculating the coefficient of variation (%CV) between the standard deviation and the mean for all animals at each time point), with an average coefficient of variation of only 17.7% for all time points. In contrast, the %CV values for Ref.C and Ref.T were 57.5% and 31.1% on average for all time points, indicating that the nanoelements of this composition can provide more reproducible effects.

[0509] It should be understood that certain features of the present disclosure described in the context of different embodiments for clarity can also be provided in combination in a single embodiment. Conversely, various features of the present disclosure described in the context of a single embodiment for brevity can also be provided separately, or in any suitable sub - combination, or in any other described embodiment of the present disclosure in a suitable manner. Certain features described in the context of various embodiments should not be considered essential features of those embodiments unless the embodiment cannot operate without those elements.

[0510] Although the present disclosure is described for illustrative purposes with respect to various specific embodiments, these specifically disclosed embodiments should not be considered limiting. Based on the applicant's disclosure herein, many other alternatives, modifications, and variations will occur to those skilled in the art. Accordingly, the present disclosure is intended to cover all such alternatives, modifications, and variations and is limited only by the spirit and scope of the present disclosure and any changes falling within its meaning and equivalents.

[0511] In the description and claims of the present disclosure, the verbs "comprise", "include", and "have" and their conjugates are used to indicate that the object of the verb is not necessarily a complete list of the features, members, steps, components, elements, or parts of the subject. However, it is contemplated that the compositions of the present invention also consist essentially of, or consist of, the recited components, and the methods of the present invention also consist essentially of, or consist of, the recited process steps.

[0512] As used herein, the singular forms "a", "an", and "the" include plural references and mean "at least one" or "one or more", unless the context clearly indicates otherwise. At least one of A and B is intended to mean A or B, and in some embodiments, may mean A and B. A "material" that can exist alone in a composition or in combination with other materials of the same type may be referred to as "(a) material"; (a) WITC, (a) WITP, (a) polar carrier, (a) non-volatile liquid, (a) surfactant, (a) active agent, etc. respectively mean that at least one WITC, at least one WITP, at least one polar carrier, at least one non-volatile liquid, at least one surfactant, at least one active agent, etc. can be used in the method, or these components can be included in the composition, or meet the listed parameters or a suitable range thereof.

[0513] Unless otherwise indicated, the use of "and / or" between the last two members of an alternative list means that one or more options in the list of alternatives are suitable and can be selected.

[0514] Unless otherwise indicated, when the upper and lower limits of the range of a certain feature of an embodiment of the present technology are indicated in this disclosure, it should be understood that in this embodiment, the possible values of this feature may include the indicated upper and lower limits and the values between the upper and lower limits.

[0515] As used herein, unless otherwise indicated, adjectives modifying the conditional or relational characteristics of the features of embodiments of the present technology, such as "substantially", "about", and "approximately", should be understood to mean that the condition or characteristic is defined within an acceptable tolerance range for the intended application of the embodiment, or within the expected variation range for measurement and / or the use of measuring instruments. When the terms "about" and "approximately" are before a numerical value, they are intended to mean ±15%, or ±10%, or even only ±5%, and in some cases represent the exact value. In addition, unless otherwise indicated, the terms (such as numbers) used in this disclosure, even without these adjectives, should be interpreted as having tolerances that may deviate from the exact meaning of the relevant terms, but will enable the invention or its relevant parts to operate and function as understood by those skilled in the art.

[0516] Although this disclosure is described with respect to certain embodiments and generally related methods, changes and permutations of the embodiments and methods will be apparent to those skilled in the art. It should be understood that this disclosure is not limited to the specific embodiments described herein.

[0517] Certain trademarks cited herein may be common law trademarks or registered trademarks of third parties. The use of these trademarks is for illustrative purposes only and should not be construed as descriptive, nor should the scope of this disclosure be limited to materials related only to these trademarks.

Claims

1. Use of a composition for the preparation of a medicament for treating a living subject or object, the medicament being configured to be administered through a non-exposed surface of the subject or object, the composition comprising nano-elements, the nano-elements comprising: a) a core comprising at least one water-insoluble thermoplastic compound (WITC) and a non-volatile liquid miscible therewith; and b) at least one active agent, the active agent being at least partially located in the core or, when a shell directly or indirectly surrounding the core is present, in the shell surrounding the core; Among them, Each component of the nanoelement has a vapor pressure of 40 Pascals (Pa) or less as measured at a temperature of about 20 °C; and wherein the nanoelement, whether or not a shell is present, i) is dispersible in a polar carrier; ii) has an average diameter D of 1000 nm or less N 50.

2. The use according to claim 1, wherein The nano-elements further comprise at least one amphiphilic shell-forming agent (SFA), the SFA or each SFA being WITC-miscible and polar carrier-insoluble, the hydrophilic portion of the SFA forming a first shell directly surrounding each core, and the shell being chargeable.

3. The use according to claim 2, wherein, The SFA or each individual SFA is selected from the group consisting of metal salts of fatty amines, fatty acids, arylalkylsulfonates or petroleum sulfonates and combinations thereof.

4. Use according to any one of claims 1 to 3, wherein, At least one of the one or more active agents is WITC-miscible and polar carrier-insoluble, the active agent being included in the core of the nano-element when non-polar, the active agent being at least partially encompassed in the core of the nano-element when amphiphilic, and the hydrophilic portion of the amphiphilic active agent forming a first shell around each core in the absence or presence of SFA.

5. Use according to any one of claims 2 to 4, wherein At least one of the one or more active agents is polar carrier-soluble, the active agent forming a second shell anchored to the core of the nano-element via the first shell.

6. The use according to any one of claims 1 to 5, wherein, The WITC or blend of WITCs, and / or the nano-elements having cores made therefrom, have at least one, at least two or at least three of the following properties: i. The WITC or blend thereof, and / or the nano-elements are polar carrier-insoluble; ii. The WITC or blend thereof, and / or the nano-elements are biodegradable and / or biocompatible; iii. The WITC or blend thereof, and / or the nano-elements each separately have at least one of a first melting point (Tm) and a second melting point (Tm) between 0 °C and 300 °C, 20 °C and 250 °C or 30 °C and 180 °C, the second Tm being lower than the first Tm; iv. The WITC or blend thereof, and / or the nano-elements each separately have at least one of a first glass transition temperature (Tg), a first softening temperature (Ts), a second glass transition temperature (Tg) and a second softening temperature (Ts) between -75 °C and 300 °C, -25 °C and 200 °C or 0 °C and 180 °C, the second Tg or Ts being lower than the corresponding first Tg or Ts; v. The molecular weight of the WITC or each individual WITC is between 0.6 kDa and 500 kDa, 2 kDa and 300 kDa or 5 kDa and 200 kDa.

7. Use according to any one of claims 1 to 6, wherein The WITC or each individual WITC is selected from: (I) Polymers selected from the group consisting of the following polymer families: aliphatic polyesters, polyhydroxyalkanoates, poly(olefin dicarboxylates), polycarbonates, aliphatic-aromatic copolyesters, polysaccharides, lignin, their isomers, their copolymers, and combinations thereof; and (II) Naturally polymerizable WITCs selected from resins, gums, and gum resins.

8. Use according to any one of claims 1 to 7, wherein, The active agent or each individual active agent has a molecular weight of up to 500 kDa, up to 100 kDa, or up to 10 kDa.

9. Use according to any one of claims 1 to 8, wherein, The medicament is for treating a living subject, and the treatment includes diagnosing, preventing, ameliorating, alleviating, delaying, or arresting disease progression and / or curing the disease of a subject in need thereof. The active agent is selected from the group consisting of: analgesics, anesthetics, anti-addiction agents, antibacterial agents, anticonvulsants, anti-dementia agents, antidepressants, antiemetics, antifungal agents, antigout agents, anti-inflammatory agents, antimigraine agents, anti-myasthenia agents, anti-mycobacterial agents, anti-tumor agents, anti-obesity agents, anti-parasitic agents, anti-Parkinson agents, antipsychotics, antispasmodics, antiviral agents, anti-anxiety agents, bipolar disorder therapeutics, blood glucose regulators, cardiovascular agents, central nervous system agents, contraceptive agents, dental and oral agents, gastrointestinal agents, genetic / enzyme / protein disorder therapeutics, urogenital agents, hormonal agents, hormone inhibitors, immune agents, infertility therapeutics, inflammatory bowel disease therapeutics, metabolic bone disease therapeutics, ophthalmic agents, otological agents, respiratory agents, sexual dysfunction therapeutics, skeletal muscle relaxants, sleep disorder therapeutics, and nutritional supplements.

10. The use according to claim 9, wherein The medicament contains an effective amount of an active agent, and the medicament is a pharmaceutical dosage form selected from the group consisting of solid dosage forms, semi-solid dosage forms, and liquid dosage forms, and the dosage form is an immediate-use type or a dosage form for preparing a final dosage form upon administration.

11. Use according to any one of claims 1 to 8, wherein, The medicament is for treating an object in need thereof, and the active agent is selected from the group consisting of: acaricides, algaecides, insect repellents, anti-moth agents, avicides, bactericides, chemical sterilants, fertilizers, fungicides, herbicides, insecticides, insect repellents, insect pheromones, molluscicides, nematicides, nitrification inhibitors, ovicides, pesticides, pest repellents, plant growth promoters, rodenticides, termiticides, virucides, and plant wound protectants.

12. The use according to claim 11, wherein, The medicament contains an effective amount of an active agent, and the medicament is an agrochemical dosage form selected from the group consisting of solutions, dispersions, emulsions, or granules, pellets, or powders for preparing them.

13. Use according to any one of claims 1 to 12, wherein, The non-volatile liquid contained in the core of the nanoelement is selected from the group consisting of: mono-functional or multi-functional aliphatic esters, fatty esters, cyclic organic esters, terpenes, aromatic alcohols, aromatic esters, aromatic ethers, aldehydes, and combinations thereof.

14. The use according to any one of claims 1 to 13, wherein The dynamic viscosity of the nanoelement is selected to release the active agent from the nanoelement at a predetermined starting time and / or a desired time period after administration of the medicament.

15. The use according to claim 14, wherein, The dynamic viscosity of the nano-component is 10 7 mPa·s or less, 5×10 6 mPa·s or less, 10 6 mPa·s or less, 5×10 5 mPa·s or less, 10 5 mPa·s or less, 5×10 4 mPa·s or less, 10 4 mPa·s or less, 5×10 3 mPa·s or less or 10 3 mPa·s or less, and the nano-component optionally has a dynamic viscosity of 1 mPa·s or higher measured at at least one temperature between 20 °C and 80 °C and a shear rate of 10 s-1.

16. The use according to any one of claims 1 to 15, wherein, Each component of the nanoelement has a vapor pressure of 20 Pa or lower, 5 Pa or lower, or 1 Pa or lower measured at a temperature of about 20 °C, and the core of the nanoelement is non-porous.

17. The use according to any one of claims 1 to 16, wherein When measured in the presence of water and at room temperature, the nanoelement has a positive or negative charge and has an absolute value of 5 mV or higher, 20 mV or higher, or 40 mV or higher; the absolute value of the charge of the nanoelement is optionally 100 mV or lower.

18. The use according to any one of claims 1 to 17, wherein, The polar carrier in which the nanoelement can be dispersed contains at least one polar liquid selected from the group consisting of water, diols, glycerol, formamide, acetonitrile, and combinations thereof.

19. Use according to any one of claims 1 to 18, wherein The composition further contains a polar carrier in liquid form in addition to the nanoelement, and the liquid contains at least one of the following: i) a surfactant as an emulsifier or co-solvent; and ii) a pH regulator.

20. The use according to any one of claims 1 to 19, wherein The average diameter D of the nano-elements N is 200 nm or less, 100 nm or less, or 50 nm or less; the nano-elements optionally have a D of at least 5 nm N 50.

21. The use according to any one of claims 1 to 20, wherein, The WITC or each WITC has a molecular weight between 0.6 kDa and 500 kDa, 2 kDa and 300 kDa, or 5 kDa and 200 kDa.

22. The use according to any one of claims 1 to 21, wherein, The active agent or each active agent, at least one active agent, is an active agent that is insoluble in the polar carrier and miscible with WITC, and is at least partially located in the core of the nanoelement.

23. The use according to any one of claims 1 to 22, wherein, The nanoelement is substantially free of volatile organic compounds (VOCs), and the nanoelement optionally contains less than 0.2 wt.%, less than 0.1 wt.%, less than 0.05 wt.%, or less than 0.02 wt.% of VOCs or their blends by weight of the nanoelement.

24. The use according to any one of claims 1 to 23, wherein, At least one of the one or more active agents is released from the nanoelement over an extended period of at least twelve hours, whereby the drug is a sustained-release drug with respect to the active agent.

25. The use according to any one of claims 1 to 24, wherein The nanoelement is prepared by a method comprising the following steps: a) Providing at least one WITC, wherein: i. The WITC or its blend has at least one of a first melting point (Tm), a first softening temperature (Ts), and a first glass transition temperature (Tg) of 300 °C or lower; and ii. The WITC or its blend optionally has a first viscosity higher than 10 7 mPa·s, which is measured at at least one temperature between 20°C and 80°C and a shear rate of 10 s-1; b) Mix at least one WITC with a non-volatile liquid and, optionally, SFA when present, said mixing being carried out at a mixing temperature equal to or higher than at least one of the first Tm, Ts and Tg of the WITC, thereby forming a homogeneous mixture of a plasticized WITC optionally including SFA miscible therewith, said plasticized mixture having a second Tm, Ts or Tg lower than the corresponding first Tm, Ts or Tg, and a second viscosity lower than the first viscosity, at least one of said first and second viscosities being measured at 10 -1 mPa·s or less at at least one temperature between 20 °C and 80 °C and a shear rate of 10 7 s; c) Combining the polar carrier with the plasticized mixture containing at least WITC in step b); and d) Nanoscale-sizing the combination in step c) by applying a shear force at a shear temperature equal to or higher than at least one of the second Tm, Ts, and Tg of the plasticized WITC to obtain a nano-suspension, whereby nanoelements containing at least one core comprising plasticized WITC and optionally a first shell comprising at least the hydrophilic portion of SFA surrounding the core are dispersed in the polar carrier; wherein each active agent that is miscible in the WITC and insoluble in the polar carrier is combined with the WITC in step b); and / or wherein each active agent soluble in the polar carrier is added in step c) or step d), provided that the SFA and / or the amphiphilic active agent is present in step b) to form a first shell, and the polar carrier-soluble active agent indirectly surrounds the core of the nanoelement and anchors thereon through the first shell to form a second shell.

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