Regulatable structured nanocarrier compositions, methods of making and uses thereof

Abstract

The application relates to the technical field of pharmaceutical compositions, in particular to a nano-carrier composition with adjustable structure, a preparation method and application thereof. The nano-carrier composition is prepared by adding a regulating agent into lecithin. By adding different kinds of regulating agents, the nano-carrier composition can be converted between a microvesicle structure and a micelle structure at will. When applied to medical purposes, under the same preparation process of the nano-carrier composition, only by changing the kind of the added regulating agent, the structure of the nano-carrier composition can be changed, and then the drug release time, drug penetration and bioavailability can be controlled, so that the nano-carrier composition can be converted into a suitable structure according to the requirements of different dosage forms to facilitate drug delivery.

Description

Technical Field

[0001] This application belongs to the field of pharmaceutical composition technology, and particularly relates to a nanocarrier composition with a tunable structure, its preparation method and its use. Background Technology

[0002] Lecithin is a natural phospholipid, mainly derived from soybeans or egg yolks. It plays a key role in the preparation of liposomes because its phospholipid bilayer structure allows it to self-assemble into lipid vesicles.

[0003] Liposomes are spherical vesicles surrounded by a phospholipid bilayer. They are typically composed of phospholipid molecules that spontaneously form a closed bilayer structure in aqueous solution. The formation mechanism is that when phospholipid molecules are dispersed in aqueous solution, due to their amphiphilic characteristics (hydrophilic head and hydrophobic tail), they spontaneously organize into a phospholipid bilayer structure. They can be used as carriers to encapsulate water-soluble and lipid-soluble molecules, and therefore have potential applications in drug delivery.

[0004] On the other hand, a microcell is a smaller, spherical structure formed by surfactant molecules. It typically consists of a monolayer of molecules with the hydrophobic tail facing inwards and the hydrophilic head facing outwards. The formation mechanism involves the spontaneous aggregation of molecules into a microcell structure when the surfactant concentration exceeds the critical microcell concentration (CMC). This allows the hydrophobic portion to contact the oil, while the hydrophilic portion interacts with water. Therefore, the core of a microcell is usually hydrophobic, while the outer layer is hydrophilic. This structure allows microcells to encapsulate hydrophobic molecules, making them commonly used as carriers for encapsulating lipid-soluble drugs.

[0005] Generally, microcells are relatively easy to prepare, but their structure is less stable. When stored for a long time or under certain environmental conditions (such as high temperature or low pH), microcells may decompose or aggregate. Conversely, liposomes generally have good stability. Due to the good protection provided by the structure of phospholipid molecules, they can preserve drugs or active ingredients for a long time, which makes liposomes more advantageous in terms of preparation and long-term storage.

[0006] In drug delivery systems, the applications of liposomes and microcells have been extensively studied, and the two have their own characteristics and differences in structure, properties, and applications. Microcells are commonly used in cosmetics, drug delivery systems, and biochemical research, suitable for applications requiring rapid release of drugs or active ingredients; while liposomes are widely used in drug delivery, biomedical research, and other fields, especially those requiring long-term stable delivery. Therefore, liposomes are suitable for controlled drug release, increasing drug bioavailability, and improving drug stability.

[0007] Therefore, microcells and liposomes are different nanoscale carrier systems, each with its own characteristics in terms of structure, drug delivery, stability and application areas. The choice of which system to use depends on the specific application requirements and the required performance.

[0008] In summary, liposomes and microcells differ in drug loading capacity, release behavior, and tissue distribution. Therefore, there is a need for a microstructure of the carrier that can be easily modified by a regulator, so as to allow for differentiated design for different drug loading requirements and achieve better drug delivery efficiency. Summary of the Invention

[0009] The purpose of this application is to provide a nanocarrier composition with a tunable structure, a preparation method thereof, and its uses, in order to solve the problem that in the prior art, nanocarrier compositions cannot be converted between the configurations of liposomes and microcells, and cannot change their nanostructure properties to adapt to the encapsulation requirements of different substances.

[0010] To achieve the above-mentioned objectives, the technical solution adopted in this application is as follows:

[0011] In a first aspect, this application provides a nanocarrier composition with a tunable structure, comprising:

[0012] Lecithin;

[0013] Regulator;

[0014] Surfactants; and

[0015] Water, of which,

[0016] The regulator is a terpene compound, and the terpene compound is selected from at least one of monocyclic terpene compounds, bicyclic terpene compounds, and chain terpene compounds;

[0017] The surfactant is at least one of anionic surfactants, cationic surfactants, zwitterionic surfactants, nonionic surfactants, and ionic surfactants.

[0018] In some embodiments, the monocyclic terpene compound is selected from at least one of D-limonene, phellandrene, menthone, sapinene, terpinene, DL-menthol, terpineol, humulene, and (-)-α-bisabolol.

[0019] In some embodiments, the bicyclic terpene compound is selected from at least one of camphene, pinene, senna, (-)-borneol, camphor, senna alcohol, trans-caryophyllene, cinnamon terpene, caryophyllene oxide, guaiacol, cedrene, and (+)-cedrol.

[0020] In some embodiments, the chain terpene compound is selected from at least one of linalool, geraniol, β-myrcene, ocimene, nerolidol, and farnesene.

[0021] In some embodiments, the surfactant is selected from any one or a combination of polysorbate, polyethylene glycol, polymethyl methacrylate, polyglycolic acid, polylactide, polycaprolactone, polylactide-polyethylene glycol, polycaprolactone-polyethylene glycol, vitamin E polyethylene glycol succinate, poloxamer, or polyoxyethylene hydrogenated castor oil.

[0022] In some embodiments, when the nanocarrier composition forms a liposome structure, the terpene compound is a monocyclic terpene compound or a bicyclic terpene compound.

[0023] In some embodiments, when the nanocarrier composition forms a microcellular structure, the terpene compound is a chain-like terpene compound.

[0024] Secondly, this application provides a method for preparing a nanocarrier composition with a tunable structure, comprising the following steps:

[0025] Step S1: Dissolve lecithin, regulator and surfactant in an organic solvent to form a mixed solution;

[0026] Step S2: Evaporate and remove the organic solvent in the mixed solution to form a film containing lecithin, regulator and surfactant;

[0027] Step S3: Add water to re-dissolve the film, and perform a hydration reaction by applying energy to obtain a nanocarrier composition containing a regulator, wherein,

[0028] The regulator is a terpene compound, and the terpene compound is selected from at least one of monocyclic terpene compounds, bicyclic terpene compounds, and chain terpene compounds;

[0029] The organic solvent is selected from any one or a combination of methanol, n-hexane, ethanol, isopropanol, acetone, formic acid, acetic acid, acetonitrile, dichloromethane, dimethylformamide or tetrahydrofuran;

[0030] The surfactant is any one or a combination of anionic surfactants, cationic surfactants, zwitterionic surfactants, nonionic surfactants, or ionic surfactants; and

[0031] Energy can be applied through stirring, vortex oscillation, or ultrasonic oscillation in a water bath.

[0032] Thirdly, this application provides the use of a nanocarrier composition with a tunable structure for loading a drug, wherein the drug is selected from any one of the group consisting of cannabinoids, flavonoids, carotenoids, triterpenoids, polyphenols, alkaloids, fatty acids, fat-soluble vitamins, polysaccharides, volatile oils, and amino acid compounds; and,

[0033] The tunable nanocarrier composition includes lecithin, a regulator, a surfactant, and water, wherein...

[0034] The regulator is a terpene compound, and the terpene compound is selected from monocyclic terpene compounds, bicyclic terpene compounds, or chain terpene compounds;

[0035] The surfactant is any one or a combination of anionic surfactants, cationic surfactants, zwitterionic surfactants, nonionic surfactants, or ionic surfactants.

[0036] The first aspect of this application provides a nanocarrier composition with a tunable structure. By adding a regulator, the microstructure of the nanocarrier can be controlled. Terpenes, due to their hydrophobic properties and ability to interact with other molecules, can be used to adjust the assembly behavior and physicochemical properties of liposomes such as lecithin. For example, terpenes can embed into the bilayer membrane formed by lecithin, altering its encapsulation properties and release kinetics to enhance the membrane permeability of liposomes, making it easier for drugs to be released through the liposome membrane, or improving the drug loading efficiency of liposomes. Furthermore, terpenes with specific structures can induce the collapse of the liposome structure, transforming compounds with a liposome structure, such as lecithin, into a microcellular structure. Also, due to the hydrophobic properties of terpenes, they can interact with the hydrophobic tail of lecithin, thereby affecting the size, shape, and surface properties of the microcells. Therefore, precise control of drug release rate, penetration, and bioavailability can be achieved, which is of great significance for improving therapeutic efficacy and reducing side effects.

[0037] The second aspect of this application provides a method for preparing a nanocarrier composition with a controllable structure. The method involves simply combining the components to form a mixed solution, then milling the mixture, adding water to re-dissolve the film, and finally applying energy to initiate a hydration reaction to obtain the nanocarrier composition containing the control agent. This preparation method is simple and convenient, and is beneficial for widespread industrial application.

[0038] The use of the tunable structure nanocarrier composition provided in the third aspect of this application is that, due to the types of terpenoid compounds contained therein, the nanocarrier composition can be tunable to form liposomes or microcells, and the encapsulated drugs can be administered orally or transdermally according to the characteristics of the liposomes or microcells, thereby improving drug delivery efficiency and thus increasing its bioavailability. Attached Figure Description

[0039] To more clearly illustrate the technical solutions in the embodiments of this application, the drawings used in the description of the embodiments or the prior art will be briefly introduced below. Obviously, the drawings described below are only some embodiments of this application. For those skilled in the art, other drawings can be obtained based on these drawings without creative effort.

[0040] Figure 1 This is a schematic diagram of the structure of the nanocarrier composition containing monocyclic terpenoids, chain terpenoids, and bicyclic terpenoids provided in the embodiments of this application, and lecithin liposomes without added terpenoids, observed under a transmission electron microscope without the addition of dyes for negative staining; wherein, Figure 1 (a) is a nanocarrier composition containing (-)-α-bisabolol. Figure 1 (b) is a nanocarrier composition containing farnesene. Figure 1 (c) is a nanocarrier composition containing (-)-borneol. Figure 1 (d) represents lecithin liposomes without the addition of terpenoids.

[0041] Figure 2 This is a schematic diagram of the structure observed under an electron microscope of the nanocarrier composition containing cyclic terpenoids and chain terpenoids, and lecithin liposomes without added terpenoids, provided in the embodiments of this application, after negative staining with added dye; wherein, Figure 2 (a) represents lecithin liposomes without added terpenoids. Figure 2 (b) is a nanocarrier composition containing D-limonene. Figure 2 (c) is a nanocarrier composition containing linalool.

[0042] Figure 3 This is a schematic diagram illustrating the particle size and polymer dispersion index analysis of the nanocarrier composition containing cyclic terpenoids and chain terpenoids provided in this application over three months; wherein, Figure 3 (a) is a graph showing the particle size variation. Figure 3 (b) is a graph showing the change in polymer dispersion index. Detailed Implementation

[0043] To make the technical problems, technical solutions, and beneficial effects of this application clearer, the following detailed description is provided in conjunction with embodiments. It should be understood that the specific embodiments described herein are merely illustrative and not intended to limit the scope of this application.

[0044] In this application, the term "and / or" describes the relationship between related objects, indicating that three relationships can exist. For example, A and / or B can represent: A existing alone, A and B existing simultaneously, or B existing alone. A and B can be singular or plural. The character " / " generally indicates that the preceding and following related objects have an "or" relationship.

[0045] In this application, "at least one" means one or more, and "more than one" means two or more. "At least one of the following" or similar expressions refer to any combination of these items, including any combination of single or multiple items. For example, "at least one of a, b, or c", or "at least one of a, b, and c", can both mean: a, b, c, ab (i.e., a and b), ac, bc, or abc, where a, b, and c can be single or multiple.

[0046] It should be understood that in the various embodiments of this application, the order of the above processes does not imply the order of execution. Some or all steps may be executed in parallel or sequentially. The execution order of each process should be determined by its function and internal logic, and should not constitute any limitation on the implementation process of the embodiments of this application.

[0047] The terminology used in the embodiments of this application is for the purpose of describing particular embodiments only and is not intended to be limiting of this application. The singular forms "a" and "the" as used in the embodiments of this application and the appended claims are also intended to include the plural forms, unless the context clearly indicates otherwise.

[0048] The weights of the relevant components mentioned in the embodiments of this application can refer not only to the specific content of each component, but also to the proportional relationship between the weights of the components. Therefore, any scaling up or down of the content of the relevant components according to the embodiments of this application is within the scope disclosed in the embodiments of this application. Specifically, the mass in the embodiments of this application can be a well-known unit of mass in the chemical industry, such as μg, mg, g, or kg.

[0049] The terms "first" and "second" are used for descriptive purposes only, to distinguish objects, such as substances, from one another, and should not be construed as indicating or implying relative importance or implicitly specifying the number of technical features indicated. For example, without departing from the scope of the embodiments of this application, "first XX" may also be referred to as "second XX," and similarly, "second XX" may also be referred to as "first XX." Thus, features defined with "first" and "second" may explicitly or implicitly include one or more of that feature.

[0050] In view of the above-mentioned deficiencies of the prior art, the present application provides a nanocarrier composition with a tunable structure, which is formed by adding a regulator to lecithin. By controlling the type and proportion of the regulator, the nanocarrier composition can be converted between the configurations of liposomes and microcells to change its nanostructure properties and adapt to the encapsulation requirements of different substances. When used as a nanocarrier for drugs, it is beneficial to have better drug delivery efficiency in both oral and transdermal drug delivery.

[0051] The first aspect of this application provides a nanocarrier composition with a tunable structure, comprising:

[0052] Lecithin;

[0053] Regulator;

[0054] Surfactants; and

[0055] Water, of which,

[0056] The regulator is a terpene compound, and the terpene compound is selected from at least one of monocyclic terpene compounds, bicyclic terpene compounds, and chain terpene compounds;

[0057] The surfactant is at least one of anionic surfactants, cationic surfactants, zwitterionic surfactants, nonionic surfactants, and ionic surfactants.

[0058] The tunable nanocarrier composition provided in the first aspect of this application regulates the microstructure of the nanocarrier by adding a regulator. Terpenes, due to their hydrophobic properties and ability to interact with other molecules, can be used to adjust the assembly behavior and physicochemical properties of liposomes such as lecithin. For example, terpenes can embed into the bilayer membrane formed by lecithin, altering its encapsulation performance and release kinetics to enhance the membrane permeability of liposomes, making it easier for drugs to be released through the liposome membrane, or improving the drug loading efficiency of liposomes. Furthermore, terpenes with specific structures can induce the collapse of the liposome structure, transforming compounds with a liposome structure, such as lecithin, into a microcellular structure. Also, due to the hydrophobic properties of terpenes, they can interact with the hydrophobic tails of lecithin, thereby affecting the size, shape, and surface properties of the microcells. Therefore, precise control of drug release rate, penetration, and bioavailability can be achieved, which is of great significance for improving therapeutic efficacy and reducing side effects.

[0059] This application's embodiments utilize the addition of modulators to regulate the microstructure of nanocarriers, enabling precise control over drug release rate, penetration, and bioavailability. This is significant for improving therapeutic efficacy and reducing side effects. For example, liposomes, when used as drug carriers, possess sustained-release properties and reduced toxicity, making them suitable for systemic drug delivery systems for antifungal drugs (such as amphotericin B) and anticancer drugs (such as daunorubicin or doxorubicin). Microcells, on the other hand, provide faster drug release and enhance drug permeability in the intestinal wall. Therefore, microcells are commonly used in oral drug delivery systems for drugs such as BCS Class II drugs (such as metoprolol) and BCS Class IV drugs (such as hydrochlorothiazide).

[0060] In this application, the regulator used in the embodiments is a terpene. Terpenes are a class of hydrocarbons widely found in nature. Terpenoid compounds are those hydrocarbons that can be divided into several isoprene structural units, and their molecular formula has a simple multiple relationship with isoprene, and the general formula can be written as (C5H8)n. Initially, it was thought that terpenes were derived from isoprene (C5H8), mainly produced by plants, and responsible for giving plants such as pine trees, flowers, and spices their unique aromas. Terpenes can be divided into several categories according to their different structures, including monoterpenes, sesquiterpenes, and diterpenes. These compounds have wide applications in the perfume, food additive, pharmaceutical, and aromatherapy industries.

[0061] Terpenes, due to their hydrophobic properties and ability to interact with other molecules, can be used to modulate the assembly behavior and physicochemical properties of liposomes such as lecithin. For example, terpenes can be embedded in the bilayer membrane formed by lecithin to change its encapsulation performance and release kinetics, thereby enhancing the permeability of liposomes, making it easier for drugs to be released through the liposome membrane, or improving the loading efficiency of drugs in liposomes.

[0062] Furthermore, terpenoids with specific structures can induce the collapse of liposome structures, transforming compounds with liposome structures, such as lecithin, into microcellular structures. Also, due to the hydrophobic properties of terpenoids, they can interact with the hydrophobic tails of lecithin, thereby affecting the size, shape, and surface properties of microcells.

[0063] On the other hand, because liposomes have sustained-release properties and the ability to reduce toxicity when used as drug carriers, they are more suitable for use as carriers of oral drugs. While loading the drug, they form a physical barrier to protect the drug from destruction by gastric acid and digestive enzymes, so that the drug's efficacy is not affected by the gastrointestinal environment. They can also promote the absorption of the drug through intestinal epithelial cells, increase the effective concentration of the drug in the body, and improve the bioavailability of the drug.

[0064] Furthermore, since microcells can interact with lipids in the stratum corneum of the skin, temporarily disturbing the structure of the stratum corneum to reduce the skin barrier function, thereby enhancing the ability of drugs to penetrate the skin, they are more suitable as carriers for topical drugs and can provide faster drug release. In addition, the hydrophobic core of microcells can encapsulate lipid-soluble drugs, which can increase the solubility of lipid-soluble drugs in the formulation, thereby improving the transdermal absorption rate.

[0065] In some embodiments, a nanocarrier composition with a tunable structure is provided, the nanocarrier composition comprising lecithin, a regulator, a surfactant, and the balance water; wherein, based on the total weight of the nanocarrier composition, the content of lecithin is 1-5 wt%, the content of the regulator is 0.5-5 wt%, the content of the surfactant is 1-5 wt%, and the water content is 85-97.5 wt%.

[0066] Preferably, based on the total weight of the nanocarrier composition, the content of lecithin is 1-3 wt%, the content of regulator is 1 wt%, the content of surfactant is 1-3 wt%, and the water content is 93-97 wt%.

[0067] The regulator is a terpene compound, and the terpene compound is selected from monocyclic terpene compounds, bicyclic terpene compounds, or chain terpene compounds. Among them, the monocyclic terpenoid compounds are selected from D-limonene, phellandrene, pulegone, sabinene, terpinene, DL-menthol, terpineol, humulene, and (-)-α-bisabolol, but are not limited to these; the bicyclic terpenoid compounds are selected from camphene, pinene, fenchone, (-)-borneol, camphor, fenchol, trans-caryophyllene, Valencene, and caryophyllene oxide. Oxide, guaiacol, cedrene, (+)-cedrol, but not limited thereto; and chain terpenoid compounds selected from linalool, geraniol, β-myrcene, ocimene, nerolidol, farnesene, but not limited thereto.

[0068] Preferably, the monocyclic terpene compounds are selected from (-)-α-bisabolol, DL-menthol, and D-limonene; the bicyclic terpene compounds are selected from (+)-cedrol, trans-caryophyllene, and (-)-borneol; and the chain terpene compounds are selected from β-myrcene, farnesene, ocimene, and linalool.

[0069] Preferably, when the nanocarrier composition is intended to form a liposome structure, the terpene compound is a monocyclic terpene compound or a bicyclic terpene compound; more preferably, the terpene compound is D-limonene.

[0070] Preferably, when the nanocarrier composition is intended to form a microcellular structure, the terpene compound is a chain-like terpene compound; more preferably, the terpene compound is linalool.

[0071] The surfactant is any one or a combination of anionic surfactants, cationic surfactants, zwitterionic surfactants, nonionic surfactants, or ionic surfactants; preferably, the surfactant is selected from any one or a combination of polysorbate, polyethylene glycol, polymethyl methacrylate, polyglycolic acid, polylactide, polycaprolactone, polylactide-polyethylene glycol, polycaprolactone-polyethylene glycol, vitamin E polyethylene glycol succinate, poloxamer, or polyoxyethylene hydrogenated castor oil; more preferably, the surfactant is polysorbate, such as polysorbate 20 (Tween 20) or polysorbate 80 (Tween 80); even more preferably, the surfactant is polysorbate 80.

[0072] The effective average particle size of the nanocarrier composition is less than about 1,000 nanometers; preferably, the effective average particle size is about 30 to 700 nanometers; more preferably, the effective average particle size is about 50 to 450 nanometers; and even more preferably, the effective average particle size is about 50 to 400 nanometers.

[0073] The effective polymer dispersion index (PDI) of the nanocarrier composition is about 0 to 1; preferably, the effective polymer dispersion index is about 0 to 0.6; more preferably, the effective polymer dispersion index is about 0.05 to 0.5.

[0074] The effective zeta potential range of the nanocarrier composition is approximately 0 to -100 mV; preferably, the effective zeta potential range is approximately 0 to -50 mV; more preferably, the effective zeta potential range is approximately -10 to -50 mV. Within the aforementioned specific zeta potential range, the nanocarrier composition maintains a stable structural morphology and can remain unchanged for several months. Preferably, it can remain unchanged for approximately three months.

[0075] The effective coating percentage (EE) of the nanocarrier composition ranges from about 30% to 100%; preferably, the effective coating percentage ranges from about 50% to 100%; more preferably, the effective coating percentage ranges from about 70% to 100%.

[0076] The effective drug loading (DL) of the nanocarrier composition ranges from about 0.1% to 50%; preferably, the effective drug loading ranges from about 5% to 40%; more preferably, the effective drug loading ranges from about 20% to 30%.

[0077] The second aspect of this application provides a method for preparing a nanocarrier composition with a tunable structure, comprising the following steps:

[0078] Step S1: Dissolve lecithin, regulator and surfactant in an organic solvent to form a mixed solution;

[0079] Step S2: Evaporate and remove the organic solvent in the mixed solution to form a film containing lecithin, regulator and surfactant;

[0080] Step S3: Add water to re-dissolve the film, and perform a hydration reaction by applying energy to obtain a nanocarrier composition containing a regulator, wherein,

[0081] The regulator is a terpene compound, and the terpene compound is selected from at least one of monocyclic terpene compounds, bicyclic terpene compounds, and chain terpene compounds;

[0082] The organic solvent is selected from any one or a combination of methanol, n-hexane, ethanol, isopropanol, acetone, formic acid, acetic acid, acetonitrile, dichloromethane, dimethylformamide or tetrahydrofuran;

[0083] The surfactant is any one or a combination of anionic surfactants, cationic surfactants, zwitterionic surfactants, nonionic surfactants, or ionic surfactants; and

[0084] Energy can be applied through stirring, vortex oscillation, or ultrasonic oscillation in a water bath.

[0085] The second aspect of this application provides a method for preparing a nanocarrier composition with a controllable structure. The method only requires combining the components to form a mixed solution, then milling the mixture, adding water to re-dissolve the film, and finally applying energy to initiate a hydration reaction to obtain the nanocarrier composition containing the control agent. This preparation method is simple and convenient, and is beneficial for widespread industrial application.

[0086] A third aspect of this application provides the use of a nanocarrier composition with a tunable structure for loading a drug, wherein the drug is selected from any one of the group consisting of cannabinoids, flavonoids, carotenoids, triterpenoids, polyphenols, alkaloids, fatty acids, fat-soluble vitamins, polysaccharides, volatile oils, and amino acid compounds; and,

[0087] The tunable nanocarrier composition includes lecithin, a regulator, a surfactant, and water, wherein...

[0088] The regulator is a terpene compound, and the terpene compound is selected from monocyclic terpene compounds, bicyclic terpene compounds, or chain terpene compounds;

[0089] The surfactant is any one or a combination of anionic surfactants, cationic surfactants, zwitterionic surfactants, nonionic surfactants, or ionic surfactants.

[0090] The use of the tunable structure nanocarrier composition provided in the third aspect of this application is that, due to the type of terpene compounds contained in the provided tunable structure nanocarrier composition, the nanocarrier composition can be tunable to form liposomes or microcells, and the encapsulated drug can be administered orally or transdermally according to the characteristics of the liposomes or microcells, so as to improve the drug delivery efficiency and thus improve its bioavailability.

[0091] Specifically, when the loaded drug is intended to be administered orally, the terpenoids contained in the nanocarrier composition are monocyclic or bicyclic terpenoids, and the nanocarrier composition exhibits a liposome structure; while when the loaded drug is intended to be administered transdermally, the terpenoids contained in the nanocarrier composition are chain-like terpenoids, and the nanocarrier composition exhibits a microcellular structure.

[0092] The embodiments of this application have shown that by adding terpenoid compounds, the outer ring structure of liposomes can be significantly enhanced. This enhancement effect not only improves the thickness and stability of the outer ring of the liposome, but also effectively improves the drug encapsulation efficiency and the long-term stability of the carrier.

[0093] In summary, the tunable nanocarrier composition provided in this application embodiment can regulate the formation of liposomes or microcells by the types of terpenoid compounds it contains. Based on the characteristics of the liposomes or microcells, the encapsulated drug can be administered orally or transdermally to improve drug delivery efficiency and thus enhance its bioavailability.

[0094] The following detailed description, in conjunction with the accompanying drawings, will make it easier to understand the purpose, technical content, features, and effects achieved by the embodiments of this application.

[0095] The following description is based on specific embodiments.

[0096] Preparation Example 1

[0097] A nanocarrier composition with a tunable structure, prepared by the following steps:

[0098] Step S1: Dissolve lecithin, regulator and surfactant in an organic solvent to form a mixed solution.

[0099] In step S1, the weight ratio of lecithin, regulator and surfactant is 1-3:1:1-3, and there is no limit to the amount of organic solvent used, as long as it can completely dissolve lecithin, regulator and surfactant.

[0100] The regulator is a terpene compound, and the terpene compound is selected from monocyclic terpene compounds, bicyclic terpene compounds, or chain terpene compounds; among them, the monocyclic terpene compounds are selected from (-)-α-bisabolol, DL-menthol, and D-limonene, the bicyclic terpene compounds are selected from (+)-cedrol, trans-caryophyllene, and (-)-borneol, and the chain terpene compounds are selected from β-myrcene, farnesene, ocimene, and linalool; the monocyclic, bicyclic, or chain terpene compounds are not limited to the specific terpene compounds mentioned above, and all kinds of monocyclic, bicyclic, or chain terpene compounds can be used.

[0101] Preferably, when the nanocarrier composition is intended to form a liposome structure, the terpene compound is a monocyclic terpene compound or a bicyclic terpene compound; more preferably, the terpene compound is D-limonene.

[0102] Preferably, when the nanocarrier composition is intended to form a microcellular structure, the terpene compound is a chain-like terpene compound; more preferably, the terpene compound is linalool.

[0103] The organic solvent is selected from any one or a combination of methanol, n-hexane, ethanol, isopropanol, acetone, formic acid, acetic acid, acetonitrile, dichloromethane, dimethylformamide or tetrahydrofuran; preferably, the organic solvent is methanol.

[0104] The surfactant is any one or a combination of anionic surfactants, cationic surfactants, zwitterionic surfactants, nonionic surfactants, or ionic surfactants; preferably, the surfactant is selected from any one or a combination of polysorbate, polyethylene glycol, polymethyl methacrylate, polyglycolic acid, polylactide, polycaprolactone, polylactide-polyethylene glycol, polycaprolactone-polyethylene glycol, vitamin E polyethylene glycol succinate, poloxamer, or polyoxyethylene hydrogenated castor oil; more preferably, the surfactant is polysorbate, such as polysorbate 20 (Tween 20) or polysorbate 80 (Tween 80); even more preferably, the surfactant is polysorbate 80.

[0105] Step S2: Evaporate and remove the organic solvent in the mixed solution to form a film containing lecithin, regulator and surfactant.

[0106] In step S2, the temperature at which the organic solvent is evaporated and removed is 40–70°C; preferably, the temperature at which the organic solvent is evaporated and removed is 55°C.

[0107] Step S3: Add water to re-dissolve the film, and perform a hydration reaction by applying energy to obtain a nanocarrier composition containing a regulator.

[0108] In step S3, the total weight ratio of the added water to lecithin, regulator and surfactant is 93:7 to 97:3, and the time for applying energy to carry out the hydration reaction is 5 to 15 minutes.

[0109] The energy can be applied by stirring, vortex oscillation or water bath ultrasonic oscillation; preferably, the energy is applied by water bath ultrasonic oscillation.

[0110] In addition, similar to the preparation steps described above, lecithin liposomes were prepared using only lecithin and surfactants without the addition of regulators (i.e., terpenoids) as a control group for subsequent nanocarrier compositions containing regulators.

[0111] Example 1

[0112] The specific types of regulators (i.e., terpenoid compounds) used in the nanocarrier compositions containing regulators obtained by the method of Example 1, as well as the ratio of lecithin, regulators, and surfactants, are shown in Table 1. Furthermore, the particle size and polymer dispersion index (PDI) of these nanocarrier compositions containing regulators were measured using dynamic light scattering (DLS), and the results are also shown in Table 1.

[0113] Table 1

[0114]

[0115]

[0116] The results in Table 1 show that different terpenoid compounds, different proportions of lecithin and surfactants all have a significant impact on the size and uniformity of the nanocarriers. The smaller the PDI value, the more uniform the molecular weight distribution of the polymer in the nanocarrier.

[0117] Next, representative groups were selected for transmission electron microscopy (TEM) observation to gain a deeper understanding of the microscopic morphology and structural characteristics of the nanocarriers.

[0118] Please see Figure 1 , Figure 1 This diagram illustrates the structures of the nanocarrier compositions containing monocyclic terpenoids, chain terpenoids, and bicyclic terpenoids of the present invention, as well as lecithin liposomes without added terpenoids, observed under a transmission electron microscope without the addition of dyes for negative staining; wherein... Figure 1 (a) is a nanocarrier composition containing (-)-α-bisabolol. Figure 1 (b) is a nanocarrier composition containing farnesene. Figure 1 (c) is a nanocarrier composition containing (-)-borneol. Figure 1 (d) represents lecithin liposomes without the addition of terpenoids.

[0119] Depend on Figure 1 As can be seen, the nanocarrier composition exhibits different microstructures when containing terpene compounds with different structures; since the structure of liposomes is mainly composed of spherical vesicles surrounded by a phospholipid bilayer with high electron density, a membrane structure is clearly visible on their periphery (e.g., Figure 1 of (a), Figure 1 (c) and Figure 1 (d)), and the structure of a microcell is mainly an aggregated spherical structure, without an outer membrane structure, so it looks like a dark gray sphere (e.g. Figure 1 (b)

[0120] Therefore, the above results show that the nanocarrier compositions containing monocyclic or bicyclic terpenoids exhibit a liposome structure similar to lecithin liposomes without added terpenoids, while the nanocarrier compositions containing chain terpenoids exhibit a cellular structure. This confirms that the structure of terpenoids has a significant impact on nanocarriers. By adding cyclic or chain terpenoids to lecithin, the microstructure of the nanocarrier composition can be controlled, thereby enabling carrier design for different drug delivery needs.

[0121] Example 2

[0122] Based on the experimental results obtained in Example 1, terpenoid compounds with similar chemical structures were further selected for comparison. The terpenoid compounds used for comparison here are D-limonene with a cyclic structure and linalool with a chain structure. Both of them were further loaded with the active ingredient cannabidiol (CBD), and their encapsulation efficiency (EE) and drug loading (DL) were compared.

[0123] Please refer to Table 2. Table 2 shows the experimental results of particle size, polymer dispersion index (PDI), and zeta potential of each component when D-limonene with a cyclic structure is added to lecithin to form a nanocarrier composition with a micro-liposome structure at different usage ratios.

[0124] Table 2

[0125]

[0126] From Table 2, when using cyclic D-limonene, considering the combined results of particle size, polymer dispersion index and zeta potential, groups 1-8 of the nanocarrier compositions were selected for subsequent experiments.

[0127] Please refer to Table 3. Table 3 shows the experimental results of particle size, polymer dispersion index (PDI), and zeta potential of each component when linalool with a chain structure is added to lecithin to form a nanocarrier composition with a liposome structure at different usage ratios.

[0128] Table 3

[0129]

[0130] From Table 3, when using linalool with a chain structure, considering the combined results of particle size, polymer dispersion index and zeta potential, groups 2-8 of the nanocarrier compositions were selected for subsequent experiments.

[0131] Next, groups 1-8 and 2-8 were loaded with different proportions of cannabidiol, and the particle size, polymer dispersion index (PDI), zeta potential, encapsulation efficiency (EE), and drug loading (DL) of the nanocarrier compositions were compared. In addition, cannabidiol-loaded lecithin liposomes prepared using only lecithin and surfactants were used as a control group for comparison. The experimental results are shown in Tables 4 and 5.

[0132] Table 4

[0133]

[0134] Table 5

[0135]

[0136] The results in Tables 4 and 5 show that the presence of different types and proportions of terpenoids in the nanocarrier composition not only affects the microstructure of the nanocarrier composition, but also further affects the encapsulation efficiency (EE) and drug loading (DL) of the nanocarrier. Table 5 also shows that the lecithin liposomes prepared using only lecithin and surfactants (control group) had significantly lower encapsulation efficiency and drug loading compared to the nanocarrier compositions containing terpenoids (1-9 to 1-11, 2-9 to 2-11), indicating that the addition of terpenoids can effectively improve the encapsulation efficiency and drug loading.

[0137] Furthermore, in the nanocarrier compositions 1-9 to 1-11 with added D-limonene containing cyclic structures, it was found that even with increasing the amount of cannabidiol, the coating efficiency could not be improved, and precipitation even occurred (in groups 1-10 and 1-11). The particle size and polymer dispersion index (PDI) of the nanocarrier compositions also increased. Considering the comprehensive factors of high coating efficiency, small particle size, and PDI value at appropriate dosage, group 1-9 was selected as the best group.

[0138] Furthermore, among the nanocarrier compositions of linalool with added chain structure, groups 2-9 to 2-11 were found to have larger particle size and PDI value, but their encapsulation rate was still over 80%, and the drug loading was also higher than that of groups 2-9 and 2-10, and no precipitation occurred. Therefore, after comprehensive consideration, group 2-11 was selected as the best group.

[0139] Please see Figure 2 , Figure 2 This is a schematic diagram of the structures observed under an electron microscope of the nanocarrier compositions containing cyclic terpenoids and chain terpenoids, and lecithin liposomes without added terpenoids, as described in this invention, under negative staining with added dyes; wherein... Figure 2 (a) represents lecithin liposomes without added terpenoids. Figure 2 (b) is a nanocarrier composition containing D-limonene. Figure 2 (c) is a nanocarrier composition containing linalool.

[0140] Figure 2 of (a), Figure 2 (b) and Figure 2 (c) shows the results of negative staining of the nanocarriers from the control group, groups 1-9, and groups 2-11 with phosphotungstic acid (PTA). After negative staining, the hydrophilic regions are more likely to appear as black patches, while the oleophilic regions will appear as lighter blackish-gray areas, thus clearly showing the difference. Figure 2 of (a), Figure 2 The structure of (b) is a liposome structure. Because the hydrophobic end of the microcell faces inward and the hydrophilic end faces outward, the interior is less likely to be negatively stained by the dye, and thus exhibits a structure like... Figure 2 In (c), the light gray area is contrasted with the outer hydrophilic end, which is negatively stained and appears as a darker gray. Therefore, it can be further derived from... Figure 2 It can be seen that, when loaded with cannabidiol, the structure of each nanocarrier still maintains the complete morphology of liposomes or microcells.

[0141] In addition, by Figure 2 It can also be seen that the addition of terpenoid compounds to liposomes ( Figure 2 (b) compared to the control group without added terpenes ( Figure 2 (a) shows that the outer ring thickness is significantly increased and the morphology is more regular. This result indicates that terpenes can enhance the structural stability of liposomes by altering the arrangement of the lipid bilayer.

[0142] Please refer to the following as well. Figure 3 , Figure 3 This is a schematic diagram illustrating the particle size and polymer dispersion index analysis of the nanocarrier composition containing cyclic and chain terpenoid compounds of the present invention over three months; wherein, Figure 3 (a) is a graph showing the particle size variation. Figure 3 (b) is a graph showing the change in polymer dispersion index.

[0143] Figure 3 As shown in (a), neither groups 1-9 containing D-limonene nor groups 2-11 containing linalool exhibited significant changes in particle size after three months. Furthermore, from... Figure 3 As can be seen in (b), the PDI values ​​of groups 1-9 of the nanocarrier compositions containing D-limonene remained almost unchanged within three months, indicating that the polymer in the nanocarrier was in a stable state, and its molecular weight distribution remained basically unchanged; while the PDI values ​​of groups 2-11 of the nanocarrier compositions containing linalool continued to decrease within three months, indicating that the molecular weight distribution of the polymer in the nanocarrier gradually became more uniform over time, and was in a stable state without significant change after two months.

[0144] Therefore, by Figure 3 The results show that nanocarrier compositions containing terpenoids, whether in the form of liposomes or microcells, can maintain a stable state over a long period of time, which is more conducive to the long-term preservation of drugs and the maintenance of drug activity when loading them.

[0145] Example 3

[0146] As shown in the experimental results of Example 2, the nanocarrier composition containing specific types and proportions of terpenoid compounds not only has good encapsulation rate and drug loading, but also maintains the particle size and PDI value of the nanocarrier itself within an acceptable range. Next, in order to confirm whether the nanocarrier composition containing terpenoid compounds has similar encapsulation ability for other types of drugs in addition to cannabidiol, loading tests were conducted on 32 compounds of 11 different properties, including cannabinoids, flavonoids, carotenoids, triterpenoids, polyphenols, alkaloids, fatty acids, fat-soluble vitamins, polysaccharides, volatile oils, and amino acid compounds. Each group of tests was repeated three times and the average value was taken to confirm that the nanocarrier composition containing terpenoid compounds has excellent encapsulation ability for various compounds. The results are shown in Table 6.

[0147] Table 6

[0148]

[0149]

[0150] The results in Table 6 show that the nanocarrier composition containing terpenoids as regulators has excellent encapsulation ability for 32 compounds of 11 different properties, including cannabinoids, flavonoids, carotenoids, triterpenoids, polyphenols, alkaloids, fatty acids, fat-soluble vitamins, polysaccharides, volatile oils, and amino acids. After encapsulating the above compounds, the nanocarrier composition containing terpenoids as regulators exhibits ideal particle size and PDI value, indicating that the nanocarrier composition containing terpenoids as regulators has wide applicability.

[0151] In summary, the tunable nanocarrier composition disclosed in this invention, as a nanocarrier system, does indeed possess significant innovative design and broad applicability, providing a completely new solution for the field of drug delivery, and has important practical value and broad application prospects.

[0152] The above description is merely a preferred embodiment of this application and is not intended to limit this application. Any modifications, equivalent substitutions, and improvements made within the spirit and principles of this application should be included within the protection scope of this application.

Claims

1. A regulatable structured nanocarrier composition, characterized in that, include: Lecithin; Regulator; Surfactants; as well as Water, of which, The regulator is a terpene compound, and the terpene compound is selected from at least one of monocyclic terpene compounds, bicyclic terpene compounds, and chain terpene compounds; The surfactant is at least one of anionic surfactants, cationic surfactants, zwitterionic surfactants, nonionic surfactants, and ionic surfactants.

2. The nanocarrier composition with tunable structure according to claim 1, characterized in that, The monocyclic terpene compound is selected from at least one of D-limonene, phellandrene, menthone, sapinene, terpinene, DL-menthol, terpineol, humulene, and (-)-α-bisabolol; The bicyclic terpene compound is selected from at least one of camphene, pinene, senna, (-)-borneol, camphor, senna alcohol, trans-caryophyllene, cinnamon terpene, caryophyllene oxide, guaiacol, cedrene, and (+)-cedrol. The chain terpene compound is selected from at least one of linalool, geraniol, β-myrcene, ocimene, nerolidol, and farnesene.

3. The regulatable structured nanocarrier composition according to claim 1, wherein, The surfactant is selected from any one or a combination of polysorbate, polyethylene glycol, polymethyl methacrylate, polyglycolic acid, polylactide, polycaprolactone, polylactide-polyethylene glycol, polycaprolactone-polyethylene glycol, vitamin E polyethylene glycol succinate, poloxamer, or polyoxyethylene hydrogenated castor oil.

4. The regulatable structured nanocarrier composition according to claim 1, wherein, When the nanocarrier composition forms a liposome structure, the terpene compound is a monocyclic terpene compound or a bicyclic terpene compound.

5. The nanocarrier composition with tunable structure according to claim 1, characterized in that, When the nanocarrier composition forms a microcellular structure, the terpene compound is a chain-like terpene compound.

6. A method for preparing a nanocarrier composition with a tunable structure, characterized in that, Includes the following steps: Step S1: Dissolve lecithin, regulator and surfactant in an organic solvent to form a mixed solution; Step S2: Evaporate and remove the organic solvent in the mixed solution to form a film containing lecithin, regulator and surfactant; Step S3: Add water to re-dissolve the film, and perform a hydration reaction by applying energy to obtain a nanocarrier composition containing a regulator, wherein, The regulator is a terpene compound, and the terpene compound is selected from at least one of monocyclic terpene compounds, bicyclic terpene compounds, and chain terpene compounds; The organic solvent is selected from any one or a combination of methanol, n-hexane, ethanol, isopropanol, acetone, formic acid, acetic acid, acetonitrile, dichloromethane, dimethylformamide, or tetrahydrofuran. The surfactant is any one or a combination of anionic surfactants, cationic surfactants, zwitterionic surfactants, nonionic surfactants, or ionic surfactants. as well as The methods of applying energy include stirring, vortex oscillation, or water bath ultrasonic oscillation.

7. The use of a nanocarrier composition with a tunable structure, characterized in that, The tunable nanocarrier composition is used to load a drug, wherein the drug is selected from any one of the group consisting of cannabinoids, flavonoids, carotenoids, triterpenoids, polyphenols, alkaloids, fatty acids, fat-soluble vitamins, polysaccharides, volatile oils, and amino acid compounds. as well as, The tunable nanocarrier composition comprises lecithin, a regulator, a surfactant, and water, wherein... The regulator is a terpene compound, and the terpene compound is selected from monocyclic terpene compounds, bicyclic terpene compounds, or chain terpene compounds; The surfactant is any one or a combination of anionic surfactants, cationic surfactants, zwitterionic surfactants, nonionic surfactants, or ionic surfactants.

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