Controlled release formulation of highly lipophilic bioactive substances

Abstract

The present invention relates to a product for the release of highly lipophilic bioactive substances, comprising a core and a coating on the core, wherein the coating comprises one or more highly lipophilic bioactive substances, one or more water-soluble film-forming agents, and up to 20% by weight of other excipients based on the weight of all ingredients.

Description

[Technical Field]

[0001] The present invention relates to formulations of highly lipophilic physiologically active substances, particularly controlled-release formulations, and the manufacture of the same. Highly lipophilic physiologically active substances are, for example, pharmaceutical active ingredients. An example of a highly lipophilic pharmaceutical active ingredient is cannabinoids. [Background technology]

[0002] Many physiologically active substances have high lipophilicity, meaning they have a relatively high logP, for example, logP of 4 or more, where logP is the common logarithm of the n-octanol / water partition coefficient.

[0003] Providing formulations containing such physiologically active substances, particularly oral formulations, presents special challenges, especially when it is necessary to achieve controlled release (or controlled release) of the physiologically active substance.

[0004] Cannabinoids are examples of physiologically active substances that possess high lipophilicity.

[0005] Cannabinoids are a heterogeneous group of pharmacologically active substances that have affinity for so-called cannabinoid receptors. Examples of cannabinoids include tetrahydrocannabinol (THC) and non-psychoactive cannabidiol (CBD).

[0006] Cannabinoids are attracting significant interest as a drug. There is evidence that cannabinoids may be beneficial in treating a number of clinical conditions, including pain, inflammation, epilepsy, sleep disorders, symptoms of multiple sclerosis, loss of appetite, and schizophrenia (Non-Patent Literature 1).

[0007] However, because cannabinoids are highly lipophilic molecules (logP6-7) with very low water solubility (2-10 μg / ml), providing them in an appropriate dosage form is difficult.

[0008] Therefore, due to the low oral bioavailability of cannabinoids, transdermal, intranasal, and transmucosal administration methods have been proposed.

[0009] In addition, due to the high lipophilicity of cannabinoids, emulsification (including salt formation (i.e., pH adjustment), cosolvation (e.g., ethanol, propylene glycol, PEG400), micelle formation (e.g., polysorbate 80, cremophor-ELP), microemulsion formation and nanoemulsion formation), complex formation (e.g., cyclodextrin), and encapsulation in lipid-based formulations (e.g., liposomes) have been explored in conventional formulation strategies. Nanoparticle systems have also been proposed (Non-Patent Literature 1).

[0010] Various oral solid dosage forms have been proposed in patent documents such as Patent Documents 1 and 2. Since these documents do not include data on release behavior, the actual suitability of the proposed forms for cannabinoid administration remains unclear.

[0011] Non-patent document 3 describes compressed tablets containing lactose and sucrose fatty acid monoester in addition to cannabidiol.

[0012] Dronabinol (Δ9-THC) is commercially available in capsule form (Marinol®) and as an oral solution (Syndros®). Marinol® capsules are soft gelatin capsules containing the active ingredient in sesame oil.

[0013] Sativex®, a final pharmaceutical product containing nabiximols, is an oral spray that is applied to the inside of the cheek.

[0014] Epidiolex, a recently approved formulation for treating a specific form of epilepsy, is provided in the form of an oral solution that contains, in addition to the active ingredient cannabidiol, the excipients ethanol anhydrous, sesame oil, strawberry flavor, and sucralose.

[0015] However, despite all these proposals, there remains a need for improved dosage forms for highly lipophilic bioactive substances, such as cannabinoids, as pharmaceutical active ingredients, particularly for oral solid dosage forms.

Prior Art Documents

Patent Documents

[0016]

Patent Document 1

Patent Document 2

Patent Document 3

Non-Patent Documents

[0017]

Non-Patent Document 1

Summary of the Invention

Problems to be Solved by the Invention

[0018] An object of the present invention is to provide a solid dosage form, particularly an oral solid dosage form, for highly lipophilic bioactive substances such as cannabinoids, which releases the bioactive substance(s) and can be prepared by a simple method.

Means for Solving the Problems

[0019] This objective is achieved by providing a product for the release of highly lipophilic bioactive substances, comprising a core and a coating on the core, wherein the coating comprises one or more highly lipophilic bioactive substances, one or more water-soluble film-forming agents (film formers), and other excipients in an amount of 20% by weight or less based on the total weight of the components.

[0020] Remarkably, it has been found that a solid formulation of a highly lipophilic bioactive substance, particularly an oral solid formulation, can be provided in which the release can be controlled by the amount of film-forming agent relative to the amount of highly lipophilic bioactive substance (single) / highly lipophilic bioactive substance (multiple). The use of one or more film-forming agents not only enables the formation of a coating containing the bioactive substance (single or multiple), but also helps in controlling its release. In particular, film-forming agents promote the release of highly lipophilic substances that are only slightly soluble in water. Only with the help of film-forming agents are they released in sufficient quantities and at a sufficient rate.

[0021] Further objectives and solutions will become apparent from the detailed description of the present invention below.

[0022] The present invention will be described in more detail below with reference to the drawings. [Brief explanation of the drawing]

[0023] [Figure 1] This document demonstrates the in vitro release from three pellet products containing 2-[1R-3-methyl-6R-(1-methylethenyl)-2-cyclohexen-1-yl]-5-pentyl-1,3-benzenediol as the active substance and low-viscosity hydroxypropyl methylcellulose as a film-forming agent. [Modes for carrying out the invention]

[0024] The product provided by the present invention comprises one or more highly lipophilic physiologically active substances.

[0025] A substance is highly lipophilic if its logP value is 4 or greater. logP is the common logarithm of the n-octanol / water partition coefficient. The partition coefficient can be determined experimentally. The value typically refers to the value at room temperature (25°C). The partition coefficient can also be roughly calculated from the molecular structure.

[0026] The product according to the present invention is particularly suitable for physiologically active substances having a logP of 5 or more, and especially suitable for physiologically active substances having a logP of 6 or more.

[0027] The term "bioactive substance" refers to a substance that, when administered to a human or animal, exerts an effect within the human or animal's body. A bioactive substance may, for example, be a pharmaceutically active substance in a pharmaceutical or nutritional supplement for human or animal use.

[0028] An example of a highly lipophilic pharmacoactive substance that can be used in accordance with the present invention is cannabinoids.

[0029] Cannabinoids may be both phytocannabinoids and synthetic cannabinoids.

[0030] Phytocannabinoids are a group of approximately 70 terpene phenol compounds (VR Preedy (ed.), Handbook of Cannabis and Related Pathologies (1997)). These compounds typically contain a monoterpene group bonded to a phenol ring and have a C3-C5 alkyl chain at the meta position relative to the phenolic hydroxyl group.

[0031] The preferred group of cannabinoids is tetrahydrocannabinol, represented by the following general formula (1): [ka] In the formula, R is C1~C 20 Alkyl, C2~C 20 Alkenyl, or C2-C 20Selected from alkynyl and optionally having one or more substituents.

[0032] In a further preferred group of the compounds of general formula (1) above, R is C1-C 10 alkyl, or C2-C 10 alkenyl, selected from and optionally having one or more substituents.

[0033] In particular, in formula (1), R is an alkyl group of the formula C5H 11 .

[0034] The compounds of general formula (1) may exist in the form of stereoisomers. Preferably, centers 6a and 10a each have the R configuration.

[0035] Tetrahydrocannabinol is in particular Δ9-THC having the chemical name (6aR,10aR) 6,6,9-trimethyl-3-pentyl-6a,7,8,10a-tetrahydro-6H-benzo[c]chromen-1-ol. Its structure is represented by the following formula (2):

Chemical formula

[0036] Another preferred group of cannabinoids is cannabidiol of the following general formula (3):

Chemical formula

[0037] In a further preferred group of the compounds of general formula (the above 3), R is C1-C 10 alkyl, or C2-C 10 alkenyl, selected from and optionally having one or more substituents.

[0038] In particular, in equation (3), R is given by equation C5H 11 It is an alkyl group.

[0039] Cannabidiol is, in particular, 2-[1R-3-methyl-6R-(1-methylethenyl)-2-cyclohexen-1-yl]-5-pentyl-1,3-benzenediol.

[0040] According to the present invention, a combination of Δ9-THC((6aR,10aR)-6,6,9-trimethyl-3-pentyl-6a,7,8,10a-tetrahydro-6H-benzo[c]chromen-1-ol) and CBD(2-[1R-3-methyl-6R-(1-methylethenyl)-2-cyclohexen-1-yl]-5-pentyl-1,3-benzenediol) can also be used as the active ingredient.

[0041] A more preferred group of cannabinoids is cannabinol, represented by the following general formula (4): [ka] In the formula, R is C1~C 20 Alkyl, C2~C 20 Alkenyl, or C2-C 20 Selected from alkynyls, and optionally having one or more substituents.

[0042] In the further preferred group of compounds of the general formula (4) described above, R is C1-C 10 Alkyl, or C2-C 10 Selected from alkenyls, and optionally having one or more substituents.

[0043] In particular, in equation (4), R is given by equation C5H 11 It is an alkyl group.

[0044] Cannabinol is, in particular, 6,6,9-trimethyl-3-pentyl-6H-dibenzo[b,c]pyran-1-ol.

[0045] According to the present invention, cannabinoids or cannabinoid mixtures derived from cannabis (hemp) extracts can also be used.

[0046] For example, nabiximols is a mixture of plant extracts used as a medicine from the leaves and flowers of the cannabis plant (Cannabis sativa L.), containing standardized amounts of tetrahydrocannabinol (THC) and cannabidiol (CBD).

[0047] Synthetic cannabinoids can also be used.

[0048] These include 3-(1,1-dimethylheptyl)-6,6a,7,8,10,10a-hexahydro-1-hydroxy-6,6-dimethyl-9H-dibenzo[b,d]pyran-9-one. This compound contains two chiral centers. The drug nabilone is a 1:1 mixture (racemate) of the (6aR,10aR) form and the (6aS,10aS) form. Nabilone is a preferred cannabinoid according to the present invention.

[0049] Another example of a synthetic cannabinoid is JWH-018 (1-naphthyl-(1-pentylindole-3-yl)methanone).

[0050] According to the present invention, one or more highly lipophilic bioactive substances, such as cannabinoids, are included in the coating on the core. For this purpose, the core is coated with a coating comprising one or more highly lipophilic bioactive substances in addition to one or more water-soluble film-forming agents. Preferably, the coating does not contain any other bioactive substances in addition to the highly lipophilic bioactive substances.

[0051] Suitable examples of water-soluble film-forming agents include methylcellulose (MC), hydroxypropyl methylcellulose (HPMC), hydroxypropylcellulose (HPC), hydroxyethylcellulose (HEC), sodium carboxymethylcellulose (Na-CMC), and polyvinylpyrrolidone (PVP).

[0052] Hydroxypropyl methylcellulose (HPMC), and especially low-viscosity HPMC such as HPMC in which the viscosity of a 2% (w / w) aqueous solution at 20°C is 6 mPa·s or less, is preferred.

[0053] HPMC, such as the commercially available product Pharmacoat® 603, which has a viscosity of 3 mPa·s in a 2% (w / w) aqueous solution at 20°C, is particularly preferred.

[0054] A coating comprising one or more highly lipophilic bioactive substances and one or more water-soluble film-forming agents may contain other commonly used excipients. According to the present invention, the amount of further excipients is limited to 20% by weight or less based on the total weight of the components. Preferably, the coating contains 10% by mass or less of further excipients based on the total weight of the components.

[0055] In a particularly preferred embodiment, the coating comprises one or more highly lipophilic physiologically active substances and one or more film-forming agents, for example, one or more cannabinoids and one or more film-forming agents.

[0056] The pellets according to the present invention have a coating containing one or more water-soluble film-forming agents in a total ratio of 0.1 to 10% by weight, preferably 0.5 to 8% by weight, and particularly 1 to 6% by weight, relative to the total amount of highly lipophilic physiologically active substances.

[0057] If the amount of film-forming agent is too small, the release is likely to be very slow and incomplete. The release of the bioactive substance can be regulated by selecting a ratio within a specified range. For example, the release from an oral formulation can be regulated so that the bioactive substance is released over the normal time of gastrointestinal transit.

[0058] A coating is applied to the core. The core can have any structure and may be composed of any physiologically acceptable material. As the core, for example, tablets, minitablets, pellets, granules, or crystals can be used. The core may contain or consist of, for example, sugar, tartaric acid, or microcrystalline cellulose. An inert starter core, such as pellets made of microcrystalline cellulose, is preferred. Such pellets are commercially available under the name Cellets®.

[0059] The core size is not limited. Suitable sizes are in the range of 10 μm to 2000 μm, for example, 50 μm to 1500 μm, preferably 100 μm to 1000 μm, and the size can be determined by sieve analysis. In particular, pellets consisting of sieve classifiers of 500 to 710 μm may be used.

[0060] The product of the present invention can be manufactured by first preparing a spray solution containing one or more highly lipophilic physiologically active substances and one or more water-soluble film-forming agents.

[0061] Because highly lipophilic substances have very low water solubility, organic solvents or mixtures of organic solvents and water are typically used.

[0062] Next, the spray solution is applied to the core. The liquid components are evaporated, thereby forming a coating on the core that contains little to no solvent and water. This can be done, for example, in a fluidized bed system, a jet bed system, a spray dryer, or a coater.

[0063] The coated core can then be used as an oral formulation. The coated pellets can be supplied, for example, in a sachet, or may be further processed.

[0064] The core coated according to the present invention may be provided with one or more additional coatings. This allows for additional control over emission.

[0065] In one preferred embodiment, no further coating is provided to control emission.

[0066] Coated pellets can be used to obtain multiparticulate dosage forms. For example, they can be filled into capsules or incorporated into tablets. According to one embodiment, they can be processed into orally dispersible tablets.

[0067] Coated pellets with different release profiles can be combined in a single dosage form (capsule / tablet / sachet). The products according to the present invention release the highly lipophilic bioactive substances contained therein, or all of the highly lipophilic bioactive substances if two or more are contained therein, in the gastrointestinal tract after ingestion. The products are used particularly for release control. Specifically, they release more than 30% by weight and less than 80% by weight of the contained bioactive substances within 2 hours. Furthermore, they release more than 40% by weight and less than 90% by weight of the contained bioactive substances within 3 hours. Furthermore, they release more than 50% by weight and less than 95% by weight of the contained bioactive substances within 4 hours. If two or more bioactive substances are contained, the information pertains to all of the contained substances.

[0068] In each case, the release is determined using a blade stirrer device in 1000 ml of phosphate buffer (pH 6.8) with 0.4% Tween® 80 added at 37°C. [Examples]

[0069] The present invention will be described based on specific application examples, but will not be limited thereto.

[0070] Example 1: Pellet production Pellets were prepared using the quantities of components shown in Table 1 below.

[0071] For this purpose, 2-[1R-3-methyl-6R-(1-methylethenyl)-2-cyclohexen-1-yl]-5-pentyl-1,3-benzenediol (Canapure PH) was dissolved in 96% ethanol. This active ingredient has a logP of approximately 6.1.

[0072] HPMC (Pharmacoat® 603) was dissolved in water to prepare another solution.

[0073] Next, the HPMC solution was gradually added to the cannabidiol solution.

[0074] Next, amorphous silicon dioxide (Syloid® 244 FP) was added.

[0075] The mixture was stirred with a propeller stirrer.

[0076] The resulting spray solution was sprayed onto a starter core made of microcrystalline cellulose (Cellets® 500).

[0077] This was performed in a Mini-Glat fluidized bed system with a Wurster insert. The air inlet air temperature was 40°C. The average spray velocity was 0.5 g / min.

[0078] [Table 1]

[0079] [Table 2]

[0080] Example 2: Release The release from the pellet product obtained in Example 1 was examined, in particular, at 37°C in 1000 ml of phosphate buffer (pH 6.8) with 0.4% Tween® 80 added, using a blade stirrer. Finally, preferred embodiments of the present invention are described in separate sections. [Embodiment 1] A product for the release of a highly lipophilic bioactive substance, comprising a core and a coating on the core, wherein the coating comprises one or more highly lipophilic bioactive substances, one or more water-soluble film-forming agents, and other excipients in an amount of 20% by weight or less based on the total weight of the components, and the bioactive substance is highly lipophilic when it has a logP of 4 or more. [Embodiment 2] The product according to Embodiment 1, wherein the aforementioned highly lipophilic physiologically active substance includes one or more highly lipophilic pharmacoactive ingredients. [Embodiment 3] The product according to Embodiment 2, wherein the highly lipophilic active ingredient comprises one or more cannabinoids. [Embodiment 4] Compounds of the following general formulas (1), (3), or (4): [ka] [In the formula, R is C 1 ~C 20 Alkyl, C 2 ~C 20 Alkenyl, or C 2 ~C 20 Selected from alkynyls, and optionally having one or more substituents; Cannabinoids or cannabinoid mixtures from cannabis (hemp) extracts such as nabiximols; and Synthetic cannabinoids such as nabilone or 1-naphthyl-(1-pentylindole-3-yl)methanone; The product according to Embodiment 3, comprising one or more cannabinoids selected from the following. [Embodiment 5] The product according to Embodiment 4, wherein the cannabinoid is 2-[1R-3-methyl-6R-(1-methylethenyl)-2-cyclohexen-1-yl]-5-pentyl-1,3-benzenediol; (6aR,10aR)-6,6,9-trimethyl-3-pentyl-6a,7,8,10a-tetrahydro-6H-benzo[c]chromen-1-ol, or a mixture thereof. [Embodiment 6] The product according to any one of Embodiments 1 to 5, wherein hydroxypropyl methylcellulose (HPMC) is used as the water-soluble film-forming agent. [Embodiment 7] The product according to Embodiment 6, wherein the HPMC has a viscosity of 6 mPa·s or less in a 2% aqueous solution at 20°C. [Embodiment 8] The product according to any one of Embodiments 1 to 7, wherein the film-forming agent is contained in a total ratio of 0.3 to 10% by weight, preferably 0.5 to 8% by weight, and particularly 1 to 6% by weight, relative to the total amount of the highly lipophilic active substance. [Embodiment 9] The product according to any one of embodiments 1 to 8, wherein the coating is applied to an inert starter core. [Embodiment 10] The product according to Embodiment 9, wherein the starter core has a size in the range of 10 μm to 2000 μm, for example, in the range of 50 μm to 1500 μm, preferably in the range of 100 μm to 1000 μm, and the size is determined by sieve analysis. [Embodiment 11] The product according to embodiment 9 or 10, wherein a neutral pellet made of microcrystalline cellulose is used as the starter core. [Embodiment 12] The product according to any one of Embodiments 1 to 11, wherein more than 30% by weight and less than 80% by weight of the contained bioactive substance are released within 2 hours. [Embodiment 13] The product according to Embodiment 12, wherein more than 40% by weight and less than 90% by weight of the contained bioactive substances are released within 3 hours. [Embodiment 14] The product according to Embodiment 13, wherein more than 50% by weight and less than 95% by weight of the contained bioactive substances are released within 4 hours. [Embodiment 15] A multi-particle formulation based on the product described in any of Embodiments 1 to 14.

Claims

1. A product for the release of a highly lipophilic bioactive substance, comprising a core and a coating on the core, wherein the coating comprises one or more cannabinoids as the highly lipophilic bioactive substance, one or more water-soluble film-forming agents, and other excipients in an amount of 20% by weight or less based on the total weight of the components, the highly lipophilic bioactive substance having 4 or more logP, the water-soluble film-forming agents are present in a total ratio of 0.3 to 10% by weight relative to the total amount of the highly lipophilic bioactive substance, the one or more water-soluble film-forming agents are selected from methylcellulose (MC), hydroxypropyl methylcellulose (HPMC), hydroxypropylcellulose (HPC), hydroxyethylcellulose (HEC), sodium carboxymethylcellulose (Na-CMC), and polyvinylpyrrolidone (PVP), and the core is not provided with any further coating to control the release.

2. The one or more cannabinoids described above Compounds of the following general formulas (1), (3), or (4): 【Chemistry 1】 [wherein R is optionally C having one or more substituents] １ ~C ２０ Alkyl, C ２ ~C ２０ Alkenyl, or C ２ ~C ２０ [Selected from Alkinil]; Cannabinoids or cannabinoid mixtures derived from cannabis (hemp) extract; and Synthetic cannabinoids; A product according to claim 1, selected from the following.

3. The cannabinoid or cannabinoid mixture derived from the cannabis (hemp) extract is a nabiximol, and / or The product according to claim 2, wherein the synthetic cannabinoid is nabilone or 1-naphthyl-(1-pentylindole-3-yl)methanone.

4. The product according to claim 2, wherein the cannabinoid is 2-[1R-3-methyl-6R-(1-methylethenyl)-2-cyclohexen-1-yl]-5-pentyl-1,3-benzenediol, (6aR,10aR)-6,6,9-trimethyl-3-pentyl-6a,7,8,10a-tetrahydro-6H-benzo[c]chromen-1-ol, or a mixture thereof.

5. The product according to any one of claims 1 to 4, wherein hydroxypropyl methylcellulose (HPMC) is used as the water-soluble film-forming agent.

6. The product according to claim 5, wherein the HPMC has a viscosity of 6 mPa·s or less in a 2% aqueous solution at 20°C.

7. The product according to any one of claims 1 to 6, wherein the coating is applied to an inert starter core.

8. The product according to claim 7, wherein the starter core has a size in the range of 10 μm to 2000 μm, and the size is determined by sieve analysis.

9. The product according to claim 7 or 8, wherein a neutral pellet made of microcrystalline cellulose is used as the starter core.

10. The product according to any one of claims 1 to 9, wherein more than 30% by weight and less than 80% by weight of the contained highly lipophilic physiologically active substance is released within 2 hours.

11. The product according to claim 10, wherein more than 40% by weight and less than 90% by weight of the contained highly lipophilic physiologically active substance are released within 3 hours.

12. The product according to claim 11, wherein more than 50% by weight and less than 95% by weight of the contained highly lipophilic physiologically active substance are released within 4 hours.

13. A multi-particle formulation comprising the product according to any one of claims 1 to 12.

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