EP4380552A1

EP4380552A1 - Process for preparing particles comprising an encapsulated lipid

Info

Publication number: EP4380552A1
Application number: EP22744319.9A
Authority: EP
Inventors: Robin DE BRUIJN
Original assignee: Stabican BV
Current assignee: Stabican BV
Priority date: 2021-07-13
Filing date: 2022-07-12
Publication date: 2024-06-12
Also published as: NL2028709B1; WO2023287283A1

Abstract

The invention relates to a process for preparing particles comprising an encapsulated lipid, wherein first a solution is provided wherein the solvent has a water solubility in the range of 2–100 g/L at 25 °C and wherein the solution comprises 1) a lipid component comprising one or more lipids; and 2) a shell- forming component comprising one or more compounds selected from the group of C10–C30 fatty alcohols, C10–C30 fatty acids and esters of C10–C30 fatty alcohols and C10–C30 fatty acids. Then, droplets of the solution are generated in an aqueous medium and the solvent is allowed to migrate from the droplets to the aqueous medium to thereby form solid particles wherein a shell of shell- forming component encapsulates the lipid component.

Description

Process for preparing particles comprising an encapsulated lipid

FIELD OF THE INVENTION

The present invention relates to a process for preparing particles comprising an encapsulated lipid, to a particle obtainable by such method and to a particle comprising an encapsulated lipid.

BACKGROUND

Many pharmaceuticals, food supplements and other chemical compounds need to be provided in a form wherein they do not degrade until their consumption, and in a form that makes their, handling, dosing and administration convenient to e.g. a producer, a supplier and a consumer.

One method of doing so is to mix the substance with a filler material, to thereby provide a dosage composition with a particular amount of substance in it. In some cases, the substance is merely diluted in such filler so that there is substantial but no complete shielding from the atmosphere. In other cases, the substance is truly encapsulated by a protective shell. Present dosage compositions however still have some shortcomings.

For example, it is difficult to prepare dosage compositons in a reproducible way, in particular to include the same amounts of substance in each dosage composition. Especially for medical purposes, this is very important.

Another shortcoming is that many conventional dosage compositions as such are difficult to handle, for example because they cannot be obtained as a dry and easy to dose powder whilst also meeting the requirement of providing sufficient protection to the enclosed substance.

Yet another shortcoming is that the stability of conventional dosage forms is often insufficient. This is in particular encountered when it is desired to use the composition as a medicine, since this requires long shelf lives.

A difficulty that is often observed with terpenes is that they are volatile and therefore easily evaporate during processing and storage. For example, compositions comprising such volatile terpenes may release the terpenes over time. This results in a decreased terpene content of such compositions, which is undesired.

It can generally be stated that at present, dosage compositions of many substances are not available in a satisfactory form, e.g. a form that is convenient to handle and/or has a long shelf-life. In particular, there is a need for a standardized formulation comprising the substance, preferably in a powder form, as a way to enable consumers and patients to accurately and repeatably take the same dose of a pharmaceutical or food supplement to address their (medical) needs. At the same time, it is desired that the manufacturing of such formulation can be performed in a way that is easy, reliable and/or reproducible.

SUMMARY OF THE INVENTION

It is therefore an object of the present invention to provide a formulation comprising a lipid that does not suffer from one or more of the abovementioned shortcomings.

It has now been found that a particular encapsulation method may overcome these shortcomings.

Accordingly, the invention relates to a process for preparing particles comprising an encapsulated lipid, the process comprising - providing a solution wherein the following components are dissolved in a solvent that has a water solubility in the range of 2-100 g/L at 25 °C: o a shell-forming component comprising one or more compounds selected from the group of C10-C30 fatty alcohols, C10-C30 fatty acids and esters of C10-C30 fatty alcohols and C10-C30 fatty acids; o a lipid component comprising one or more lipids that have the property that they do not form a single phase with the one or more compounds of the shell-forming component when they are mixed with the one or more compounds of the shell-forming component in a mass ratio of 50:50 at the temperature at which the process is carried out; - generating droplets of the solution in an aqueous medium and allowing the solvent to migrate from the droplets to the aqueous medium to thereby form solid particles wherein a shell of shell-forming component encapsulates the lipid component.

The invention also relates to a particle comprising an encapsulated lipid obtainable by such process.

The invention also relates to a particle comprising an encapsulated lipid wherein

- one or more lipids are encapsulated by a shell of one or more compounds selected from the group of C10-C30 fatty alcohols, C10-C30 fatty acids and esters of C10-C30 fatty alcohols and C10-C30 fatty acids;

- the one or more lipids has the property that it does not form a single phase with the one or more compounds of the shell when it is mixed with the one or more compounds of the shell in a mass ratio of 1 :1 ;

- the content of the one or more lipids in the particle is in the range of 25-95 wt.%

The invention also relates to a pharmaceutical composition comprising such a particle and a pharmaceutically acceptable excipient.

BRIEF DESCRIPTION OF THE DRAWINGS

Figure 1 displays a micrograph of particles containing cannabidiol, nicotine and alpha-tocopherol, produced with a method of the invention.

Figure 2 displays a micrograph of particles containing cannabidiol and terpene extract, produced with a method of the invention.

DETAILED DESCRIPTION OF THE INVENTION

The invention relates to a process for preparing particles comprising an encapsulated lipid, the process comprising

- providing a solution wherein the following components are dissolved in a solvent that has a water solubility in the range of 2-100 g/L at 25 °C: o a shell-forming component comprising one or more compounds selected from the group of C10-C30 fatty alcohols, C10-C30 fatty acids and esters of C10-C30 fatty alcohols and C10-C30 fatty acids; o a lipid component comprising one or more lipids;

- generating droplets of the solution in an aqueous medium and allowing the solvent to migrate from the droplets to the aqueous medium to thereby form solid particles wherein a shell of shell-forming component encapsulates the lipid component.

Usually, the one or more lipids has the property that it does not form a single phase with the one or more compounds of the shell-forming component when it is mixed with the one or more compounds of the shell forming component in a mass ratio of 50:50 at the temperature at which the process is carried out.

The solvent has a solubility in water that is in the range of 2-100 g/L at 25 °C. This range on the one hand ensures that the solution of the lipid component and the shell-forming component in the solvent is capable of existing as droplets in a water phase; and on the other hand that the solvent migrates from the droplet to the water phase. For example, a solvent with a solubility higher than 100 g/L (including infinite solubility), will not form droplets, or only droplets with insufficient stability, so that the two water- insoluble components do not phase separate and solid particles are not formed. Also, a solvent with a solubility lower than 2 g/L (including complete insolubility) will nevertheless form droplets, but its migration from the droplets to the water phase, if any, cannot be accomplished under satisfying conditions.

The solubility of the solvent in water may also be in the range of 6-90 g/L at 25 °C, in the range of 8-80 g/L at 25 °C, in the range of 10-70 g/L at 25 °C, in the range of 12-60 g/L at 25 °C, or in the range of 15-50 g/L at 25 °C.

It may also be in the range of 5-75 g/L at 25 °C, in the range of 8-50 g/L at 25 °C or in the range of 10-40 g/L at 25 °C.

The solvent may be selected from the group of benzyl alcohol,

1 -butanol, n-butyl acetate, gamma-butyrolacton, chloroform, 1,2- dichloroethane, diethylene glycol, diethyl ether, diethoxyethane, di- isopropylether, ethyl acetate, methyl f-butyl ether, methylene chloride, A/-methyl-2-pyrrolidinone, nitromethane, 1-pentanol, 2-pentanol, 3-pentanol, 3-pentanone, benzaldehyde, prenol, o-cresol, m-cresol, and p-cresol. The solvent may also be a terpenoid with a water solubility in the range of 2-100 g/L at 25 °C. In particular, the solvent is benzyl alcohol or methylene chloride.

The solvent usually has a molar mass of less than 200 g/mol. It is in particular less than 150 g/mol. It may also be less than 140 g/mol, less than 125 g/mol or less than 100 g/mol.

Usually, the log Poct/wat of the solvent is lower than the Poct/wat of each of the one or more lipids in the lipid component. Herein, P is the partition coefficient, which is defined as a particular ratio of the concentrations of a solute between 1-octanol and water (a biphase of two liquid phases). A higher value of P indicates a higher lipophilicity than a lower value of Pdoes. In case of the present invention, the solute is the solvent that is used to provide the solution wherein the shell-forming component and the lipid component are dissolved. When the log Poct/wat of the solvent is lower than the Poct/wat of a lipid, then the solvent is more prone to migration from the droplet to the water than the lipid is.

The solution in a process of the invention comprises a mixture of the two components that in the end make up the particles that comprise an encapsulated lipid. This means that both components are dissolved in the solvent. The migration of the solvent from the droplet to the aqueous medium has the effect that both components come separately out of solution and gain their natural appearance, i.e. the appearance they normally have as a neat substance; the C10-C30 fatty acids, alcohols and ester are solid (or at least waxy), while the lipid is typically a solid or a liquid (such as an oil).

Importantly, the solvent migration also results in the separation of both components, wherein the lipid component constitutes the inner part of the particles and the shell-forming component constitutes a shell that completely surrounds the lipid component.

Usually, the solution consists of these two components and the solvent, i.e. no other dissolved or undissolved substances are present in the solution. It is however possible that certain additives are contained in the solution (preferably dissolved therein), which either end up in the produced particle or migrate together with the solvent. For example, an additional active pharmaceutical ingredient may be present. It is also possible that a co-solvent is present in the solution, which migrates together with the solvent (i.e. the primary solvent) out of the droplet (or particle) into the aqueous medium. For example, such co-solvent is a solvent selected from the group of the (primary) solvents mentioned above.

In the solution, the weight ratio of lipid component to shell-forming component is usually in the range of 0.05 : 0.95 to 0.95 : 0.05. The ratio may also be in the range of 0.25 : 0.75 to 0.95 : 0.05, in particular in the range of 0.50 : 0.50 to 0.90 : 0.10. It may also be in the range of 0.40 : 0.60 to 0.80 : 0.20, or in the range of 0.60 : 0.40 to 0.95 : 0.05.

With the method of the invention, it is possible to prepare particles in suspension (in particular a suspension in water) that are dry and not tacky. This is an important advantage of the method of the invention, since the dry form of the product makes the handling of the product convenient.

Another advantage is that the lipids that are contained in the particles are surprisingly stable (see Examples’ section 8).

Yet another advantage of the process of the invention is that lipid levels in the particles of over 70 wt.% can be achieved (see Examples’ section 7).

It is a further advantage of the process of the invention that the produced particles contain virtually no residues of the solvent that is used for the extracton (see Examples’ section 9). Thus, the solvent essentially completely migrates out of the droplets during the process. The solvent levels that were detected in the particles are well below the levels that are commonly imposed to commercial products, in particular to pharmaceutical products.

The lipid component comprises one or more lipids. It in particular consists of one or more lipids. The one or more lipids is preferably selected from the group of alkaloids, fat-soluble vitamins and terpenes.

In case the one or more lipids comprises an alkaloid, then the alkaloid is typically an alkaloid having a molecular structure comprising an N- heterocycle, i.e. a molecular structure wherein a nitrogen atom forms part of a heterocycle. By an /V-heterocycle is meant a ring or ring structure that has one or more nitrogen atoms as members of the ring or ring structure. An alkaloid in a process of the invention for example comprises one or more /V-heterocycles selected from the group of a pyrrolidine-based heterocycle, a tropane-based heterocycle, a pyrrolizidine-based heterocycle, a piperidine- based heterocycle, a quinolizidine-based heterocycle, an indolizidine-based heterocycle, a prydine-based heterocycle, an isoquinoline-based heterocycle, an oxazole-based heterocycle, an isoxazole-based heterocycle, a thiazole- based heterocycle, a quinazoline-based heterocycle, an acridine-based heterocycle, a quinoline-based heterocycle, an indole-based heterocycle, an imidazole-based heterocycle and a purine-based heterocycle.

The one or more lipids is in particular selected from the group of atropine, nicotine, morphine, psilocybine, psilocine, A/,A/-dialkyltryptamines such as A/,A/-dimethyltryptamine, bufotenin, baeocystin, aeruginascin, ergolines such as lysergic acid diethylamide (LSD) and lysergic acid amide (LSA), phenethylamines such as alpha-methyl-phenethylamines (amphetamines), and benzoxazines such as efavirenz.

In case the one or more lipids comprises a fat-soluble vitamin, then the fat-soluble vitamin is typically selected from the group of vitamin A, vitamin D, vitamin E and vitamin K.

Vitamin A is known as a group of unsaturated nutritional organic compounds that includes retinol, retinal and several provitamin A carotenoids such as alpha-carotene, beta-carotene and beta-cryptoxanthin.

Vitamin D includes vitamin D2 (ergocalciferol) and vitamin D3 (cholecalciferol),

Vitamin E is known as a group of eight nutritional organic compounds that include four tocopherols (alpha-tocopherol, beta-tocopherol, gamma- tocopherol and delta-tocopherol) and four tocotrienols (alpha-tocotrienol, beta-tocotrienol, gamma-tocotrienol and delta-tocotrienol). Also derivatives of vitamin E may be applied in the present invention, for example acetates of vitamin E (alpha-tocoferylacetate, beta-tocoferylacetate, gamma-tocoferylacetate and delta-tocoferylacetate). Vitamin K is the collective term for compounds that share a 2-methyl- 1 ,4-naphthoquinone ring, but differ in the side-chain at the 3-position. The main classes of vitamin K concern vitamin Ki (phylloquinone) and vitamin K2 (menaquinone). Vitamin K2 comprises a number of related chemical subtypes, such as menaquinone-4 (MK-4) and menaquinone-7 (MK-7). Another main vitamin K class concerns vitamin K3 (menadione), a synthetic form of vitamin K.

In case the one or more lipids comprises a terpene, then the terpene is typically selected from the group of alpha-bulnessene, beta-bulnessene, caryophyllene, farnesene, alpha-humulene, geraniol, alpha-guaiene, beta- guaiene, delta-guaiene, guaiol, limonene, linalool, lavandulol, grandisol, dendrolasin, santolina alcohol, 1 ,8-cineole, abietic acid, lanosterol, beta- vetivone, iridomyrmecin, santonin, squalene, carvone, chrysanthemic acid, nepetalactone, camphor, myrcene, terpinolene, patchoulol, norpatchoulenol, alpha-patchoulene, beta-patchoulene, gamma-patchoulene, delta- patchoulene, alpha-pinene, beta-pinene, pogostol, seychellene, cycloseychellene, santalene, santalol and valencene.

A process according to the invention may be a process as claimed in claim 1 , with the proviso that the one or more lipids does not comprise a cannabinoid. In this respect, a cannabinoid is understood to be a compound that naturally occurs in Cannabis plants such as Cannabis sativa, Cannabis indica or Cannabis ruderalis. Examples of a cannabinoid are delta-9- tetrahydrocannabinol, cannabidiol, cannabinol cannabigerol, tetrahydrocannabivarin, cannabidivarin, cannabichromene, delta-9- tetrahydrocannabinolic acid and cannabidiolic acid.

In a process of the invention, the one or more lipids to be encapsulated in principle has the property that, at the temperature at which the process of the invention is carried out, it does not form a single phase when it is mixed with the one or more compounds of the shell-forming component (i.e. with the one or more compounds selected from the group of C10-C30 fatty alcohols, C10-C30 fatty acids and esters of C10-C30 fatty alcohols and C10-C30 fatty acids) in a mass ratio of 50:50, e.g. when equal masses of both are mixed. In particular, the one or more lipids to be encapsulated has the property that it does not form a single phase with the one or more compounds when it is mixed with the one or more compounds in a mass ratio in the range of 60:40 to 40:60, in a mass ratio in the range of 70:30 to 30:70, in a mass ratio in the range of 80:20 to 20:80, in a mass ratio in the range of 90:10 to 10:90 or in a mass ratio in the range of 95:5 to 5:95.

The term ‘not forming a single phase’ includes the formation of two phases on the basis of non-miscibility (one phase does not dissolve in the other) as well as the formation of two phases on the basis of a different state of matter ( e.g . a solid phase and a liquid phase).

Further, the defintition that a particular first substance ‘does not form a single phase with a particular second substance at a particular temperature’ is to be viewed as a property of matter of the particular first substance as the neat substance {e.g. in pure form and not dissolved in any solvent), which property may be known from handbooks or which can be determined unambiguously by a person skilled in the art performing conventional procedures.

The shell-forming component contains the material from which the shell is formed. The shell-forming component is mostly formed by the one or more compounds selected from the group of C10-C30 fatty alcohols, C10- C30 fatty acids and esters of C10-C30 fatty alcohols and C10-C30 fatty acids. Usually, the one or more compounds makes 100% of the weight of the shell-forming component, i.e. the shell-forming component consists of the one or more compounds. Optionally, the shell-forming component comprises one or more other compounds that also end up in the shell. For example, any such other compound(s) makes up 10 wt.% of the shell-forming component or less than that. It may also make up 7 wt.% or less, 5 wt.% or less, 3 wt.% or less, 2 wt.% or less, 1 wt.% or less or 0.5 wt.% or less. So, the one or more compounds of the shell-forming component makes up at least 90 wt.%, at least 93 wt.%, at least 95 wt.%, at least 97 wt.%, at least 98 wt.%, at least 99 wt.% or at least 99.5 wt.% of the shell-forming component.

The C10-C30 fatty alcohol may be an alcohol selected from the group of capric alcohol, lauryl alcohol, myristyl alcohol, cetyl alcohol, palmitoleyl alcohol, stearyl alcohol, isostearyl alcohol, oleyl alcohol, elaidyl alcohol, petroselinyl alcohol, elaeostearyl alcohol, arachyl alcohol, gadoleyl alcohol, behenyl alcohol, erucyl alcohol and brassidyl alcohol.

The C10-C30 fatty acid may be an acid selected from the group of capric acid, lauric acid, palmitic acid, palmitoleic acid, stearic acid, isostearic acid, oleic acid, elaidic acid, petroselic acid, elaeostearic acid, arachic acid, gadoleic acid, behenic acid and erucic acid.

It may also be any of the abovementioned fatty acids with a branched chain, as long as the total number of carbons does not exceed 30.

The esters of C10-C30 fatty alcohols and C10-C30 fatty acids may also be composed of branched C10-C30 fatty alcohols and/or branched C10-C30 fatty acids.

In particular, the shell-forming component in the solvent comprises cetyl alcohol and/or cetyl palmitate.

In the process of the invention, droplets of the solution are generated in an aqueous medium. During the solvent migration, the droplets become the solid particles as the product of the process. The droplets are usually prepared by conventional methods, in particular by stirring. Vigorous stirring is typically applied to attain droplets that in the form particles with dimensions in the micrometer domain, in particular in the range of 2-500 pm. A person skilled in the art can reach the appropriate conditions for this by routine experimentation and without exerting any inventive effort.

The temperature at which the process is performed (i.e. the operating temperature) may in principle be any temperature above the freezing point of water and below the boiling point of the solvent. For example, the temperature may be in the range 0-60 °C, in the range of 5-50 °C or in the range of 10-35 °C. Usually, however, the temperature is in the range of 15- 30 °C. In particular, it is in the range of 20-25 °C.

The invention further relates to a particle comprising an encapsulated lipid obtainable by the process described above.

A particle comprising an encapsulated lipid that is obtained by a process of the invention has a core of one or more lipids and a shell encapsulating this core. The shell compartimentalizes the one or more lipids and so protects them against influences from the outer environment such as micro-organisms or reactive compounds such as oxygen.

Accordingly, the invention further relates to a particle comprising an encapsulated lipid, wherein

- the content of the one or more lipids in the particle is in the range of 5-95 wt.%, in particular in the range of 25-85 wt.%.

For the particle of the invention, the same considerations apply as those mentioned hereabove for the process of the invention, when the following is concerned: 1) the presence of the types of C10-C30 fatty alcohols; 2) the presence of the types of C10-C30 fatty acids; 3) the presence of the types of esters of C10-C30 fatty alcohols and C10-C30 fatty acids; 4) the presence of the types of terpenes.

Usually, the one or more lipids has the property that it does not form a single phase with the one or more compounds of the shell when it is mixed with the one or more compounds of the shell in a mass ratio of 1 :1 at 25 °C, in particular a temperature in the range of 15-30 °C, more in particular a temperature in the range of 0-50 °C.

In particular, the one or more lipids has the property that it does not form a single phase with the one or more compounds when it is mixed with the one or more compounds in a mass ratio in the range of 60:40 to 40:60, in a mass ratio in the range of 70:30 to 30:70, in a mass ratio in the range of 80:20 to 20:80, in a mass ratio in the range of 90:10 to 10:90 or in a mass ratio in the range of 95:5 to 5:95.

Usually, the content of lipid in a particle of the invention is in the range of 20-80 wt.%, preferably it is in the range of 25-75 wt.%, more preferably it is in the range of 30-70 wt.% (the weight percentages are based on the total weight of the particle). Assuming no other constituents are present (in particular not encapsulated), it then follows that the shell constitutes 5-95 wt.% of the particle, in particular 15-75 wt.%. Usually, it is 20-80 wt.%, preferably 25-75 wt.%, more preferably 30-70 wt.%. In similar disclosures of particles that comprise an encapsulated lipid, a wax is present as a filler material that forms an interpenetrating network between the lipd(s). In particles with such composition, a plurality of lipid domains is present. The wax then remains tacky due to such morphology. In contrast, a particle of the invention in principle comprises one domain, namely the core of the particle.

It has been demonstrated that the lipid in a particle of the invention is stable during extended periods of time. Preliminary experiments have established a period of at least 13 months, whereas in the Examples, a period of at least 6 months is reported (section 8). Such a high stability is (beside the non-tackyness) also an effect of the excellent shielding that is provided by the process of the invention. Moreover, particles of the invention have even proved to survive underwater storage for at least one month (see also section 8).

In a particle of the invention, the one or more lipids in particular comprises an alkaloid. In an embodiment, the one or more lipids is selected from the group of atropine, nicotine, morphine, psilocybine, psilocine, N,N- dialkyltryptamines such as A/,A/-dimethyltryptamine, bufotenin, baeocystin, aeruginascin, ergolines such as lysergic acid diethylamide (LSD) and lysergic acid amide (LSA), phenethylamines such as alpha-methyl-phenethylamines (amphetamines), and benzoxazines such as efavirenz.

In a particle of the invention, the one or more lipids may also or alternatively comprise a terpene, for example a terpene is typically selected from the group of alpha-bulnessene, beta-bulnessene, caryophyllene, farnesene, alpha-humulene, geraniol, alpha-guaiene, beta-guaiene, delta- guaiene, guaiol, limonene, linalool, lavandulol, grandisol, dendrolasin, santolina alcohol, 1 ,8-cineole, abietic acid, lanosterol, beta-vetivone, iridomyrmecin, santonin, squalene, carvone, chrysanthemic acid, nepetalactone, camphor, myrcene, terpinolene, patchoulol, norpatchoulenol, alpha-patchoulene, beta-patchoulene, gamma-patchoulene, delta- patchoulene, alpha-pinene, beta-pinene, pogostol, seychellene, cycloseychellene, santalene, santalol and valencene. In a particle of the invention, the one or more lipids may also or alternatively comprise a fat-soluble vitamin, for example a fat-soluble vitamin typically selected from the group of vitamin A, vitamin D, vitamin E and vitamin K.

In a particle of the invention, the weight ratio of lipid to shell is typically in the range of 0.25 : 0.75 to 0.95 : 0.05. It may also be 0.50 : 0.50 to 0.90 : 0.10, in the range of 0.40 : 0.60 to 0.80 : 0.20, or in the range of 0.60 : 0.40 to 0.95 : 0.05. This ratio is reflected by the ratio of lipid component to shell-forming component in the solution that is used for preparing the particle.

Lipid-containing particles of the invention are displayed in the micrographs of Figure 1 and Figure 2, recorded with an optical microscope. In the particles of Figure 1 , three different lipids are encapsulated, viz. cannabidiol, nicotine and alpha-tocopherol (equal weight ratios). In the particles of Figure 2, the encapsulated lipds comprise cannabidiol and terpene extract (a mixture of at least four terpenes). The particles in the micrographs are more or less spherical with a diameter of 10-20 pm. Their outer surface appears not completely smooth, as it appears to be wrinkled a little bit. The displayed particles are in an ambient atmosphere and do not stick to one another.

A particle of the invention is usually globular. This shape is governed by the shape of the initial droplet in the process of the invention, which is usually globular.

The diameter of a particle of the invention is usually in the range of 100 nm-500 pm, in particular in the range of 250 nm-400 pm, more in particular in the range of 1-250 pm, even more in particular in the range of 3- 100 pm or yet even more in particular in the range of 5-50 pm. For example, it is 200 nm or more, 300 nm or more, 400 nm or more, 500 nm or more, 750 nm or more, 1 pm or more, 2 pm or more, 3 pm or more, 4 pm or more, 5 pm or more, 6 pm or more, 7 pm or more, 8 pm or more, 9 pm or more, 10 pm or more, 12 pm or more, 14 pm or more, 20 pm or more, 30 pm or more, 40 pm or more, 50 pm or more, 75 pm or more, 100 pm or more, 200 pm or more, 300 pm or more, or 400 pm or more. It may also be 500 pm or less, 400 pm or less, 300 pm or less, 200 pm or less, 100 pm or less, 75 pm or less, 70 pm or less, 25 mih or less, 20 mih or less, 15 mih or less, 10 mih or less, 8 mih or less, 7 mih or less, 6 mih or less, 5 mih or less, 4 mih or less, 3 mih or less, 2 mih or less, 1 mih or less, 800 nm or less, 600 nm or less, 400 nm or less or 200 nm or less.

The shell of a particle of the invention is mostly composed of the one or more compounds selected from the group of C10-C30 fatty alcohols, C10- C30 fatty acids and esters of C10-C30 fatty alcohols and C10-C30 fatty acids. In a preferred embodiment, the one or more compounds makes up 100% of the weight of the shell, i.e. the shell then consists of the one or more compounds. Optionally, the shell comprises one or more other compounds. For example, any such other compound(s) makes up 10 wt.% of the shell or less than that. It may also make up 7 wt.% or less, 5 wt.% or less, 3 wt.% or less, 2 wt.% or less, 1 wt.% or less or 0.5 wt.% or less. So, the one or more compounds of the shell makes up at least 90 wt.%, at least 93 wt.%, at least 95 wt.%, at least 97 wt.%, at least 98 wt.%, at least 99 wt.% or at least 99.5 wt.% of the shell.

The invention further relates to a pharmaceutical composition comprising a particle comprising an encapsulated lipid as described above and an excipient.

The term excipient as used herein refers to any substance, generally pharmaceutically inert, used to formulate active pharmaceutical ingredients (API) into pharmaceutical formulations. For example, an excipient is selected from the group of diluents, binders, glidants, lubricants, colouring agents and disintegrants. The excipient material itself may be composed of one or more materials selected from the group of sugar alcohols, polyols ( e.g . sorbitol, mannitol, xylitol), crystalline sugars, monosaccharides {e.g. glucose, arabinose), disaccharides {e.g. maltose, saccharose, dextrose, lactose), oligosaccharides {e.g. dextrins, cyclodextrins), polysaccharides {e.g. cellulose starch and derivatives thereof), inorganic salts {e.g. sodium chloride, calcium carbonate, magnesium carbonate, talc), and organic salts {e.g. sodium lactate, magnesium stearate). The invention further relates to a particle comprising an encapsulated lipid as described above or a pharmaceutical composition as described above for use as a medicament.

The invention further relates to a particle comprising an encapsulated lipid as described above or a pharmaceutical composition as described above, wherein the one or more lipids comprises an alkaloid, in particular an alkaloid selected from the group of atropine, nicotine, morphine, psilocybine, psilocine, A/,A/-dialkyltryptamines such as A/,A/-dimethyltryptamine, bufotenin, baeocystin, aeruginascin, ergolines such as lysergic acid diethylamide (LSD) and lysergic acid amide (LSA), and benzoxazines such as efavirenz, for use in the treatment of a neurological disorder.

Such neurological disorder is in particular a neurological disorder selected from the group of acute spinal cord injury, Alzheimer's disease, amyotrophic lateral sclerosis (ALS), ataxia, bell's palsy, brain tumors, cerebral aneurysm, epilepsy and, seizures, Guillain-Barre syndrome, headache, head injury, hydrocephalus, lumbar disk disease (herniated disk), meningitis, multiple sclerosis, muscular dystrophy, neurocutaneous syndromes, Parkinson's disease, stroke (brain attack), cluster headaches, tension headaches, migraine headaches, encephalitis, septicemia, types of muscular dystrophy and neuromuscular diseases, and myasthenia gravis.

For a particular medical use or treatment, such as any of the treatments mentioned above, the particle is a delayed release composition for the release of one or more lipids in for example the small intestine or the large intestine. In the context of the present invention, delayed release means that the composition releases the one or more encapsulated lipids after passing through the stomach. In particular, a delayed release composition of the invention releases the one or more encapsulated lipids in the distal small intestine. Preferably, no dissolution of the composition occurs in the stomach

The invention further relates to a method for treating a medical condition of a human or an animal, comprising administering to the human or animal an effective amount of a particle comprising an encapsulated lipid or of a pharmaceutical composition as described above. As used herein, the term "effective amount" means that amount of a drug or pharmaceutical agent that will elicit the biological or medical response of an animal or human that is being sought, for instance, by a researcher or clinician.

The invention further relates to the use of a particle comprising an encapsulated lipid or a pharmaceutical composition as described above for treating a human or an animal.

The invention further relates to the use of a particle comprising an encapsulated lipid or a pharmaceutical composition as described above for the manufacture of a medicament for the treatment of a medical condition.

The term medical condition as used herein is a broad term that includes all diseases, lesions, disorders, or nonpathologic condition that normally receives medical treatment, such as pregnancy or childbirth.

EXAMPLES

1. Materials

The chemicals and solvents were purchased from commercial sources and used without further purification. Terpenes were extracted from hops. If necessary, residual water was removed prior to use. When water was used, it was demineralized prior to use.

The following 40 mg/ml encapsulation solutions were prepared, using dichloromethane as a solvent (mentioned ratios refer to weight percentages):

1. cannabidiol, nicotine, alpha-tocopherol and cetyl alcohol 23.3 : 23.3 :

23.3 : 30

2. cannabidiol, terpene extract and cetyl alcohol 50 : 20 : 30

3. alpha-tocopherol and cetyl alcohol 70 : 30

The homogenizer that was used in the preparation of particles was an IKA T25 Digital Ultra Turrax® 0.05-2 liter.

All GC analyses were performed on an 8890 gas chromatograph (Agilent Technologies, Waldbronn, Germany) equipped with a flame ionization detector (FID) and an apolar column. Micrographs of the isolated products were made using a Visiscope 500 microscope with 400x magnification factor.

2. Preparation of terpene extract

Dried flowers from Humulus (hops) were extracted using a Soxhlet set-up with dichloromethane as solvent. The extraction liquor was decolorized by five filtration steps over activated carbon. Dichloromethane was removed by rotational film evaporation to yield a light orange oil. The terpenes that are most abundantly present herein are humulene, caryophyllene, pinene and myrcene.

3. General procedure for the preparation of particles

A 1.000 ml_ beaker charged with 792 ml_ of water was subjected to stirring at 3.000 rpm using the homogenizer. During the stirring, 8 ml_ of the encapsulation solution were added to the beaker. After the addition, stirring was continued for 1 minute. The resulting mixture was then subjected to an immersed air flow for 30 minutes to remove the dichloromethane from the water. The resulting suspension was filtered on a nylon filter membrane and washed with water to yield a solid. Any residual moist on the solid was removed by allowing the solid to dry to the air, yielding a dry, white powder.

4. General procedure for the GC-analvsis of the particles

The quantitative analysis of the particles was performed with gas chromatography (apparatus identified above in section 1). Helium was used as the carrier gas. The GC instrument conditions were as follows: start temperature 45 °C; gradual increase to 300 °C; total run time of 22 minutes.

Samples for the GC-analysis were prepared by dissolving a known mass of product (i.e. the produced particles) in a known volume of a suitable solvent. An amount of 1 mI of the sample solution was injected in the GC. The quantitative amounts of the components in the sample solutions were determined against standard solutions each containing a known amount of the component(s). The sample content is interpolated between two concentration levels in the standard solution. 5. Preparation of the particles

The general procedure for the preparation of particles (see section 3 above) was performed for encapsulation solutions 1-3, yielding four different products as dry, white solids.

6. Micrograph analysis of the different products 1-3

Micrographs of all obtained products were recorded. All micrographs display separate particles, which all have a similar appearance (i.e. they do not differ much from one micrograph to another micrograph). Figure 1 displays the micrograph of the isolated product resulting from encapsulation solution 1 (cannabidiol, nicotine, alpha-tocopherol and cetyl alcohol). Figure 2 displays the micrograph of the isolated product resulting from encapsulation solution 2 (cannabidiol, terpene extract and cetyl alcohol). The product obtained with encapsulation solution 3 looks similar to those shown in Figures 1 and 2. In the micrographs, the isolated product is visible as particles of a spherical form with some apparent relief on their surface. Their diameter is in the range of 10-20 pm. This forms direct evidence for the presence of the product of the invention in the form of particles.

7. GC-analvsis results of the different products 1-3

The isolated products were analyzed by GC-analysis according to the general procedure described above (section 4). A quantitative analysis based on the obtained GC-data is shown in Table 1.

The initial weight percentages (referring to the starting compounds) and the measured weight percentages (referring to the compounds that make up the particle) represent the weight percentages relative to the other compounds that are present. It was however also checked whether the measured weight percentages reflect the absolute weight percentages in the particles (which in theory may deviate due to degradation or contamination). It was found that the absolute weight percentages of the compounds in the particles corresponded nicely to the (relative) weight percentages that are presented in the table. The table shows that the initial ratio of lipid to shell-forming component in the sample solutions is largely maintained in the different products that were formed.

Table 1. Quantitative analysis of the products

As regards the encapsulation of terpenes extracted from hop, it is noted that this extract concerns a mixture of terpenes wherein humulene, caryophyllene, pinene and myrcene are most abundant. There are however also other terpenes present in the extract, as well as some non-terpenes that were co-extracted form the hop. This likely explains why the measured wt.% exhibits a significant deviation from the initial wt.%.

The overall yield of encapsulated lipid in the process, based on the initial amount added in the encapsulant solution, was at least 65% for the three different products.

Analysis of the water phase of the particle preparation, aqueous filtration liquids, aqueous washing liquids and eventual other aqueous supernatants generated in the preparation process and sample preparation did not show the presence of any of the lipids and/or shell materials. It is contemplated that any product loss mainly occurs during filtration and washing procedures as described in section 3, for example because part of the product cannot be removed from a filter (dissolution of residual product on a filter would destroy the particles). Moreover, when filter residue is analysed, it exhibits the same ratio of lipid component to shell-forming component. Therefore, the overall conversion to the encapsulated cannabinoid of the process may well be nearly 100%.

8. Lipid stability experiments

The stability of the lipid(s) contained in the particles was investgated by storing the different samples of particles. To this end, the samples were stored in an ICH standard climate cabinet with controlled temperature and moisture (-20 °C, 5 °C, 25 °C, RH = 65%). At certain time intervals, a product sample was taken and analyzed according to the procedures as described hereabove. Analysis of the particles demonstrated 100% retention of all lipids after 6 months.

Also, particles were suspended in standard deionized water for up to one month. Afterwards, the particles showed 100% retention of all lipids while no lipids could be detected in the water phase. This indicates that particle degradation and lipid leaking to the water does not occur during underwater storage of particles of the invention.

9. Determination of residual dichloromethane

It was determined whether the particles as prepared above comprise any residual dichloromethane. The quantitative analysis method used for this is the ‘method of standard addition’.

A sample solution was prepared by dissolving an accurately weighted amount of product sample in an appropriate solvent. Four different analyte solutions were prepared by dissolving different amounts dichloromethane in the appropriate solvent. The dichloromethane concentrations of the four analyte solutions were 0 pg/g, 300 pg/g, 600 pg/g and 900 pg/g. Four volumetric flasks were filled with equal and exactly determined volumes of the sample solution, which were then diluted to the same volume by adding one of the dichloromethane analyte solutions. The solutions were measured on the GC (column at 30°C for 3 minutes followed by a gradual increase to 300°C; total runtime of approx. 13 minutes) and the results were plotted; amounts of analyte added (x) against the signal (y). Extrapolation to the point on the x-axis at which y = 0 corresponded to the amount of dichloromethane in the product sample.

All obtained values were well below 600 pg/g, which value defines a common maximum level for the amount of dichloromethane that is acceptable in commercial (pharmaceutical) products.

This proves that the dichloromethane that is used in the method for preparing the particles is virtually absent in the particles, and in any case is well below the levels that are commonly imposed to commercial products, in particular to pharmaceutical products.

Claims

1. Process for preparing particles comprising an encapsulated lipid, comprising

- providing a solution wherein the following components are dissolved in a solvent that has a water solubility in the range of 2-100 g/L at 25 °C: o a shell-forming component comprising one or more compounds selected from the group of C10-C30 fatty alcohols, C10-C30 fatty acids and esters of C10-C30 fatty alcohols and C10-C30 fatty acids; o a lipid component comprising one or more lipids that have the property that they do not form a single phase with the one or more compounds of the shell-forming component when they are mixed with the one or more compounds of the shell-forming component in a mass ratio of 1 :1 at the temperature at which the process is carried out;

2. Process according to claim 1 , wherein the one or more lipids is selected from the group of alkaloids, fat-soluble vitamins and terpenes.

3. Process according to claim 2, wherein the one or more lipids comprises an alkaloid having a molecular structure comprising an /V-heterocycle.

4. Process according to claim 1 , wherein the one or more lipids is selected from the group of atropine, nicotine, morphine, psilocybine, psilocine, N,N- dialkyltryptamines such as A/,A/-dimethyltryptamine, bufotenin, baeocystin, aeruginascin, ergolines such as lysergic acid diethylamide (LSD) and lysergic acid amide (LSA), phenethylamines such as alpha-methyl-phenethylamines (amphetamines), and benzoxazines such as efavirenz.

5. Process according to claim 2, wherein the one or more lipids comprises a fat- soluble vitamin selected from the group of vitamin A, vitamin D, vitamin E and vitamin K.

6. Process according to claim 2, wherein the one or more lipids comprises a terpene selected from the group of alpha-bulnessene, beta-bulnessene, caryophyllene, farnesene, alpha-humulene, geraniol, alpha-guaiene, beta- guaiene, delta-guaiene, guaiol, limonene, linalool, lavandulol, grandisol, dendrolasin, santolina alcohol, 1 ,8-cineole, abietic acid, lanosterol, beta- vetivone, iridomyrmecin, santonin, squalene, carvone, chrysanthemic acid, nepetalactone, camphor, myrcene, terpinolene, patchoulol, norpatchoulenol, alpha-patchoulene, beta-patchoulene, gamma-patchoulene, delta- patchoulene, alpha-pinene, beta-pinene, pogostol, seychellene, cycloseychellene, santalene, santalol and valencene.

7. Process according to any one of claims 1-6, with the proviso that at least one of the one or more lipids does not comprise a cannabinoid.

8. Process according to any one of claims 1-7, wherein the solvent is selected from the group of 1 -butanol, n-butyl acetate, gamma-butyrolacton, chloroform, 1 ,2-dichloroethane, diethylene glycol, diethyl ether, diethoxyethane, di-isopropylether, dimethyl sulfoxide, ethyl acetate, methyl f-butyl ether, A/-methyl-2-pyrrolidinone, nitromethane, 1-pentanol, 2-pentanol, 3-pentanol, 3-pentanone, benzaldehyde, prenol, o-cresol, m-cresol, and p-cresol.

9. Process according to any one of claims 1-8, wherein the solvent is benzyl alcohol or methylene chloride.

10. Process according to any one of claims 1-9, wherein the solvent has a solubility in water that is in the range of 8-80 g/L at 25 °C, in particular in the range of 10^fO g/L at 25 °C.

11. Process according to any one of claims 1 -10, wherein the shell-forming component comprises cetyl alcohol and/or cetyl palmitate.

12. Process according to any one of claims 1-11, wherein the weight ratio of lipid component to shell-forming component in the solution is in the range of 0.25 : 0.75 to 0.95 : 0.05, in particular in the range of 0.55 : 0.45 to 0.75 : 0.25.

13. Particle comprising an encapsulated lipid obtainable by a process of any one of claims 1-12.

14. Particle comprising an encapsulated lipid, wherein

- the content of the one or more lipids in the particle is in the range of 25-95 wt.%.

15. Particle comprising an encapsulated lipid according to claim 13 or 14, wherein the shell is substantially free of the one or more lipids, in particular free of alkaloids, fat-soluble vitamins and terpenes.

16. Particle comprising an encapsulated lipid according to any one of claims 13-

15, wherein the weight ratio of the one or more lipids to shell is in the range of 0.50 : 0.50 to 0.90 : 0.10 or in the range of 0.60 : 0.40 to 0.95 : 0.05.

17. Particle comprising an encapsulated lipid according to any one of claims 13-

16, wherein the particle has a diameter in the range of 100 nm-500 pm, in particular in the range of 1-50 pm.

18. Particle comprising an encapsulated lipid according to any one of claims 13-

17, with the proviso that the one or more lipids does not comprise a cannabinoid.

19. Pharmaceutical composition comprising a particle comprising an encapsulated lipid according to any one of claims 13-18 and an excipient.

20. Particle comprising an encapsulated lipid according to any one of claims 13- 18 or a pharmaceutical composition according to claim 19 for use as a medicament.

21. Particle according to any one of claims 13-18 or pharmaceutical composition according to claim 19, wherein the one or more lipids is selected from the group of atropine, nicotine, morphine, psilocybine, psilocine, N,N- dialkyltryptamines such as A/,A/-dimethyltryptamine, bufotenin, baeocystin, aeruginascin, ergolines such as lysergic acid diethylamide (LSD) and lysergic acid amide (LSA), phenethylamines such as alpha-methyl-phenethylamines (amphetamines), and benzoxazines such as efavirenz, for use in the treatment of neurological disorders.

22. Particle or pharmaceutical composition for use according to claim 21 , wherein the neurological disorder is a neurological disorder selected from the group of acute spinal cord injury, Alzheimer's disease, amyotrophic lateral sclerosis (ALS), ataxia, bell's palsy, brain tumors, cerebral aneurysm, epilepsy and seizures, Guillain-Barre syndrome, headache, head injury, hydrocephalus, lumbar disk disease (herniated disk), meningitis, multiple sclerosis, muscular dystrophy, neurocutaneous syndromes, Parkinson's disease, stroke (brain attack), cluster headaches, tension headaches, migraine headaches, encephalitis, septicemia, types of muscular dystrophy and neuromuscular diseases, and myasthenia gravis.

23. Particle or pharmaceutical composition for use according to claim 22, wherein the particle or composition, respectively, is a delayed release composition for the release of one or more lipids in the small intestine and/or the large intestine.

24. Method for treating a medical condition of a human or an animal, comprising administering to the human or animal an effective amount of a particle comprising an encapsulated lipid according to any one of claims 13-18 or a pharmaceutical composition according to claim 19.