Controlled release formulations of highly lipophilic bioactive substances

Abstract

To provide a solid preparation for a highly lipophilic physiologically active substance such as cannabinoid which releases the physiologically active substance and can be prepared by a simple method.SOLUTION: The present invention relates to 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 up to 20% by weight, based on the weight of all components, of other excipients.SELECTED DRAWING: Figure 1

Description

[Technical Field]

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

[0002] Many biologically active substances have highly lipophilic properties, ie, a relatively high log P, for example, a log P of 4 or greater, where log P is the base 10 logarithm of the n-octanol / water partition coefficient.

[0003] Providing formulations, particularly oral formulations, containing such bioactive agents presents particular challenges, particularly where controlled release (or controlled release) of the bioactive agent is to be achieved.

[0004] Bioactive substances with highly lipophilic properties include cannabinoids.

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

[0006] Cannabinoids have attracted significant interest as drugs, and evidence indicates that they may be beneficial in treating many clinical conditions, including pain, inflammation, epilepsy, sleep disorders, symptoms of multiple sclerosis, anorexia, and schizophrenia (Non-Patent Document 1).

[0007] However, cannabinoids are highly lipophilic molecules (logP 6-7) with very low water solubility (2-10 μg / ml), making it difficult to provide suitable dosage forms.

[0008] Therefore, the low oral bioavailability of cannabinoids has led to proposals for transdermal, intranasal and transmucosal administration.

[0009] Additionally, due to the high lipophilicity of cannabinoids, salt formation (i.e., pH adjustment), cosolvation (e.g., ethanol, propylene glycol, PEG 400), micelle formation (e.g., polysorbate 80, Cremophor-ELP), emulsification, including microemulsion and nanoemulsion formation, complexation (e.g., cyclodextrins), and encapsulation in lipid-based formulations (e.g., liposomes) have been considered among the formulation strategies in the prior art. Nanoparticle systems have also been proposed (Non-Patent Document 1).

[0010] Various oral solid formulations have been proposed in patent documents, such as U.S. Patent Nos. 5,999,949 and 5,999,962. These documents do not contain data on the release behavior, so the actual suitability of the proposed forms for the administration of cannabinoids remains unclear.

[0011] Non-Patent Document 3 describes compressed tablets containing lactose and sucrose fatty acid monoesters 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] The final medication containing nabiximols, Sativex®, is an oral spray that is sprayed into the inside of the cheek.

[0014] Epidiolex, a recently approved drug for treating certain forms of epilepsy, comes in the form of an oral solution containing the active ingredient cannabidiol, as well as the excipients absolute ethanol, sesame oil, strawberry flavoring, and sucralose.

[0015] However, despite all of these proposals, there remains a need for improved dosage forms of pharmaceutical active ingredients such as highly lipophilic bioactive substances, e.g. cannabinoids, particularly for oral solid formulations. [Prior art documents] [Patent documents]

[0016] [Patent Document 1] International Publication No. 2008 / 024490 [Patent Document 2] International Publication No. 2018 / 035030 [Patent Document 3] International Publication No. 2015 / 065179 [Non-patent literature]

[0017] [Non-Patent Document 1] N. Bruni et al., Cannabinoid Delivery Systems for Pain and Inflammation Treatment. Molecules 2018, 23, 2478 Summary of the Invention [Problem to be solved by the invention]

[0018] It is an object of the present invention to provide a solid dosage form, in particular an oral solid dosage form, for highly lipophilic bioactive substances such as cannabinoids, which releases the bioactive substance(s) and which can be prepared in a simple manner. [Means for solving the problem]

[0019] This object 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 formers, and up to 20% by weight of other excipients based on the weight of all ingredients.

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

[0021] Further objects and means for solving the same will become apparent from the following detailed description of the invention.

[0022] In the following, the invention will be explained in more detail with reference to the drawings. [Brief explanation of the drawings]

[0023] [Figure 1] 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 agent and low viscosity hydroxypropyl methylcellulose as the film-forming agent is shown. DETAILED DESCRIPTION OF THE INVENTION

[0024] The products provided by the present invention include one or more highly lipophilic bioactive agents.

[0025] A substance is highly lipophilic if its logP 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 products according to the invention are particularly suitable for bioactive substances with a logP of 5 or more, especially for bioactive substances with a logP of 6 or more.

[0027] The term "bioactive agent" refers to a substance that is administered to a human or animal and exerts an effect in the human or animal body. The bioactive agent may be, for example, a pharmaceutical active agent of a human or veterinary medicine or dietary supplement.

[0028] An example of a highly lipophilic pharmaceutical active substance that can be used according to the present invention is a cannabinoid.

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

[0030] Phytocannabinoids are a group of approximately 70 terpene-phenolic compounds (V.R. Preedy (ed.), Handbook of Cannabis and Related Pathologies (1997)). These compounds typically contain a monoterpene group attached to a phenolic ring with a C3-C5 alkyl chain meta to the phenolic hydroxyl group.

[0031] A preferred group of cannabinoids are the tetrahydrocannabinols of the following general formula (1): [ka] In the formula, R is C1 to C 20 Alkyl, C2-C 20 Alkenyl, or C2-C 20alkynyl, optionally bearing one or more substituents.

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

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

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

[0035] Tetrahydrocannabinol is specifically Δ9-THC, which has the chemical name (6aR,10aR)6,6,9-trimethyl-3-pentyl-6a,7,8,10a-tetrahydro-6H-benzo[c]chromen-1-ol, and its structure is represented by the following formula (2): [ka]

[0036] Another preferred group of cannabinoids are the cannabidiols of the following general formula (3): [ka] In the formula, R is C1 to C 20 Alkyl, C2-C 20 Alkenyl, or C2-C 20 alkynyl, optionally bearing one or more substituents.

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

[0038] In particular, in formula (3), R is a group of formula CH 11 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 ingredients.

[0041] A further preferred group of cannabinoids are the cannabinols of the following general formula (4): [ka] In the formula, R is C1 to C 20 Alkyl, C2-C 20 Alkenyl, or C2-C 20 alkynyl, optionally bearing one or more substituents.

[0042] In a further preferred group of compounds of the above general formula (4), R is C1-C 10 Alkyl, or C2-C 10 alkenyl, optionally bearing one or more substituents.

[0043] In particular, in formula (4), R is a group of formula CH 11 is an alkyl group.

[0044] The 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 from cannabis (hemp) extracts may also be used.

[0046] For example, nabiximols is a plant extract mixture used as a drug 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) and (6aS,10aS) forms. Nabilone is the preferred cannabinoid according to the present invention.

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

[0050] According to the present invention, one or more highly lipophilic bioactive substances, such as one or more medicament active ingredients, such as cannabinoids, are contained in the coating on the core.For this purpose, the core is provided with a coating that comprises one or more highly lipophilic bioactive substances and one or more water-soluble film-forming agents.Preferably, the coating does not comprise any other bioactive substances in addition to the highly lipophilic bioactive substances.

[0051] Examples of suitable water-soluble film-forming agents are methylcellulose (MC), hydroxypropylmethylcellulose (HPMC), hydroxypropylcellulose (HPC), hydroxyethylcellulose (HEC), sodium carboxymethylcellulose (Na-CMC) and polyvinylpyrrolidone (PVP).

[0052] Hydroxypropylmethylcellulose (HPMC), particularly low viscosity HPMC such as HPMC having a viscosity of 6 mPa·s or less in a 2% (w / w) aqueous solution at 20° C., is preferred.

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

[0054] The coating containing 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 additional excipients is limited to 20% by weight or less based on the weight of the total components. Preferably, the amount of additional excipients is 10% by weight or less based on the weight of the total components.

[0055] In a particularly preferred embodiment, the coating consists of highly lipophilic bioactive agent(s) and film-forming agent(s), for example consisting of cannabinoid(s) and film-forming agent(s).

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

[0057] If the amount of film-forming agent is too small, the release will be very slow and incomplete. By selecting a ratio within the specified range, the release of the bioactive substance can be adjusted. For example, the release from an oral formulation can be adjusted 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 can be made of any physiologically acceptable material. For example, tablets, minitablets, pellets, granules, or crystals can be used as the core. The core can comprise or consist of, for example, sugar, tartaric acid, or microcrystalline cellulose. Inactive starter cores, such as pellets made of microcrystalline cellulose, are preferred. Such pellets are commercially available under the name Cellets®.

[0059] The size of the core is not limited. Suitable sizes are 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 can be determined by sieve analysis. In particular, pellets consisting of a sieve fraction of 500 to 710 μm can be used.

[0060] The products of the present invention can be manufactured by first creating a spray solution that includes one or more highly lipophilic bioactive agents and one or more water-soluble film-forming agents.

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

[0062] The spray liquid is then applied to the core. The liquid component is evaporated, thereby forming a coating on the core that is substantially free of solvent and water. This can be done, for example, in a fluidized bed system, a spouted bed system, a spray dryer, or a coater.

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

[0064] The cores coated according to the present invention may be provided with one or more further coatings, which allow for additional control of release.

[0065] In a preferred embodiment, no additional release-controlling coating is provided.

[0066] The 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 are processed into orally dispersible tablets.

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

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

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

[0070] Example 1: Pellets production Pellets were made using the ingredients in the amounts 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 log P of approximately 6.1.

[0072] A separate solution was prepared by dissolving HPMC (Pharmacoat® 603) in water.

[0073] The HPMC solution was then slowly added to the cannabidiol solution.

[0074] Amorphous silicon dioxide (Syloid® 244 FP) was then added.

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

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

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

[0078] [Table 1]

[0079] [Table 2]

[0080] Example 2: Release The release from the pellet product obtained from Example 1 is investigated in particular at 37° C. in 1000 ml of phosphate buffer (pH 6.8) supplemented with 0.4% Tween® 80 using a blade stirrer device. Finally, preferred embodiments of the present invention are described in sections.

[0081] [Embodiment 1] 1. A product for the release of highly lipophilic bioactive substances, comprising a core and a coating on the core, said coating comprising one or more highly lipophilic bioactive substances, one or more water-soluble film-forming agents, and 20% by weight or less of other excipients based on the weight of all components, wherein a bioactive substance is highly lipophilic if it has a logP of 4 or greater.

[0082] [Embodiment 2] 2. The product of embodiment 1, wherein the highly lipophilic bioactive agent comprises one or more highly lipophilic pharmaceutically active ingredients.

[0083] [Embodiment 3] 3. The product of embodiment 2, wherein the highly lipophilic active ingredient comprises one or more cannabinoids.

[0084] [Embodiment 4] A compound of the following general formula (1), (3) or (4): [ka] [Wherein R is C1 to C 20 Alkyl, C2-C 20 Alkenyl, or C2-C 20 alkynyl, optionally bearing 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-pentylindol-3-yl)methanone; 4. The product of embodiment 3, comprising one or more cannabinoids selected from:

[0085] [Embodiment 5] 5. The product of 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.

[0086] [Embodiment 6] 6. The product of any one of claims 1 to 5, wherein the water-soluble film-forming agent is hydroxypropyl methylcellulose (HPMC).

[0087] [Embodiment 7] 7. The product of claim 6, wherein the HPMC has a viscosity as a 2% aqueous solution at 20° C. of 6 mPa·s or less.

[0088] [Embodiment 8] 8. Product according to any one of the preceding claims, wherein the film-forming agent is present in a total proportion of 0.3 to 10% by weight, preferably in a total proportion of 0.5 to 8% by weight, in particular in a total proportion of 1 to 6% by weight, relative to the total amount of highly lipophilic active substance.

[0089] [Embodiment 9] 9. The product of any one of claims 1 to 8, wherein the coating is applied to an inert starter core.

[0090] [Embodiment 10] 10. The product of embodiment 9, wherein the starter cores have a size in the range of 10 μm to 2000 μm, such as in the range of 50 μm to 1500 μm, preferably in the range of 100 μm to 1000 μm, the size being determined by sieve analysis.

[0091] [Embodiment 11] 11. The product of embodiment 9 or 10, wherein neutral pellets made of microcrystalline cellulose are used as the starter core.

[0092] [Embodiment 12] 12. The product of any one of embodiments 1 to 11, wherein more than 30% and less than 80% by weight of the bioactive substance contained therein is released within 2 hours.

[0093] [Embodiment 13] 13. The product of embodiment 12, wherein more than 40% and less than 90% by weight of the bioactive agent is released within 3 hours.

[0094] [Embodiment 14] 14. The product of embodiment 13, wherein more than 50% and less than 95% by weight of the bioactive agent is released within 4 hours.

[0095] [Embodiment 15] 15. A multiparticulate formulation based on a product according to any one of embodiments 1 to 14.

Claims

[Claim 1] 1. A product for the release of highly lipophilic bioactive substances, comprising a core and a coating on the core, said coating comprising 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 components, wherein the bioactive substance is highly lipophilic if it has a log P of 4 or greater.

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