Controlled release formulations of highly lipophilic physiologically active substances

Abstract

To provide a solid formulation, in particular an oral solid formulation, for highly lipophilic physiologically active substances such as cannabinoids, which releases a physiologically active substance and can be prepared by a simple method.SOLUTION: The invention relates to a solid formulation that comprises a matrix with one or more highly lipophilic physiologically active substances, one or more water-soluble binders and, relative to the weight of all components, not more than 20 wt% of other auxiliary substances.SELECTED DRAWING: None

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 solid formulation comprising a matrix having one or more highly lipophilic bioactive substances, one or more water-soluble binders, and up to 20% by weight of additional excipients based on the weight of all components, wherein a bioactive substance is highly lipophilic if it has a logP of 4 or greater.

[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, whose release can be controlled by the amount of water-soluble binder relative to the amount of the highly lipophilic substance(s). The use of one or more water-soluble binders not only enables the formation of a matrix containing the bioactive substance(s), but also helps to control the release. In particular, the water-soluble binder promotes the release of highly lipophilic substances that are only very slightly soluble in water. Only with the binder 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 substance and low viscosity hydroxypropyl methylcellulose is shown. DETAILED DESCRIPTION OF THE INVENTION

[0024] The formulations 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 pellets according to the invention are particularly suitable for biologically active substances with a logP of 5 or more, especially for biologically active 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 derived 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, e.g., one or more pharmaceutically active ingredients, such as cannabinoids, are contained in a matrix, which preferably does not contain any other bioactive substances.

[0051] The matrix includes one or more water-soluble binders, which are polymeric film-forming substances.

[0052] Examples of suitable water-soluble film-forming agents are methylcellulose (MC), hydroxypropylmethylcellulose (HPMC), hydroxypropylcellulose (HPC), hydroxyethylcellulose (HEC), sodium carboxymethylcellulose (Na-CMC) and polyvinylpyrrolidone (PVP).

[0053] 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.

[0054] 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.

[0055] The matrix containing one or more highly lipophilic bioactive substances and one or more water-soluble binders may contain other commonly used excipients, such as one or more fillers or carriers. 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.

[0056] In a particularly preferred embodiment, the matrix consists of highly lipophilic bioactive substance(s) and binder(s), for example, cannabinoid(s) and binder(s).

[0057] The matrix contains one or more water-soluble binders 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 substances.

[0058] If the amount of binder 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.

[0059] The solid oral formulation according to the present invention comprises a matrix with one or more highly lipophilic bioactive substances and can be provided and used in any form, for example, the formulation can be provided in the form of granules, matrix pellets or matrix tablets, or can comprise any of these forms.

[0060] The preparation can be carried out in a manner known per se.

[0061] In a preferred embodiment, the formulation comprises matrix pellets.

[0062] The matrix pellets typically have a size ranging from 30 μm to 1800 μm, which size can be determined by sieve analysis.

[0063] The matrix pellets may be provided, for example, in a sachet, or they may be further processed.

[0064] For example, the matrix pellets may be provided with one or more additional coatings, which allow for additional control of release.

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

[0066] Matrix pellets can be used to obtain multiparticulate dosage forms, which can be filled into capsules or incorporated into tablets.

[0067] Matrix pellets with different release profiles can be combined in one dosage form (capsule / tablet / sachet).

[0068] The oral formulations according to the present 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 formulations 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 particularly 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.

[0069] 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]

[0070] The following examples demonstrate that water-soluble film-forming materials can be used to control the release of highly lipophilic bioactive agents.

[0071] Example 1: Pellets production Pellets were made using the ingredients in the amounts shown in Table 1 below.

[0072] 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.

[0073] A separate solution was prepared by dissolving HPMC (Pharmacoat® 603) in water.

[0074] The HPMC solution was then slowly added to the cannabidiol solution.

[0075] Amorphous silicon dioxide (Syloid® 244 FP) was then added.

[0076] The mixture was stirred with a propeller stirrer.

[0077] The resulting spray solution was sprayed onto starter cores made of microcrystalline cellulose (Cellets® 500).

[0078] 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.

[0079] [Table 1]

[0080] [Table 2]

[0081] 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.

[0082] [Embodiment 1] A solid formulation comprising a matrix having one or more highly lipophilic bioactive substances, one or more water-soluble binders, and 20% by weight or less of other excipients based on the weight of all components, wherein the bioactive substances are highly lipophilic if they have a logP of 4 or greater.

[0083] [Embodiment 2] 2. The formulation of embodiment 1, wherein the highly lipophilic bioactive agent comprises one or more highly lipophilic pharmaceutically active ingredients.

[0084] [Embodiment 3] 3. The formulation of embodiment 2, wherein the highly lipophilic active ingredient comprises one or more cannabinoids.

[0085] [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 derived from cannabis (hemp) extracts, such as nabiximols; and Synthetic cannabinoids such as nabilone or 1-naphthyl-(1-pentylindol-3-yl)methanone; 4. The formulation of embodiment 3, comprising one or more cannabinoids selected from:

[0086] [Embodiment 5] 5. The formulation 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.

[0087] [Embodiment 6] 6. The formulation of any one of embodiments 1 to 5, wherein hydroxypropyl methylcellulose (HPMC) is used as the water-soluble binder.

[0088] [Embodiment 7] 7. The formulation of embodiment 6, wherein the HPMC has a viscosity as a 2% aqueous solution at 20° C. of 6 mPa s or less.

[0089] [Embodiment 8] 8. The formulation according to any one of embodiments 1 to 7, wherein the binder 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 physiologically active substances.

[0090] [Embodiment 9] 9. The formulation according to any of the preceding embodiments, provided in the form of granules, matrix pellets or matrix tablets, or comprising any of these forms.

[0091] [Embodiment 10] 10. The formulation of embodiment 9, comprising matrix pellets.

[0092] [Embodiment 11] 10. The formulation of embodiment 9, wherein the matrix pellets have a size, as determined by sieve analysis, in the range of 30 μm to 1800 μm.

[0093] [Embodiment 12] 12. The formulation according to any one of embodiments 1 to 11, wherein more than 30% and less than 80% by weight of the biologically active substance contained therein is released within 2 hours.

[0094] [Embodiment 13] 13. The formulation of embodiment 12, wherein more than 40% and less than 90% by weight of the bioactive agent is released within 3 hours.

[0095] [Embodiment 14] 14. The formulation of embodiment 13, wherein more than 50% and less than 95% by weight of the bioactive agent is released within 4 hours.

Claims

1. A solid preparation comprising a matrix containing one or more highly lipophilic physiologically active substances and one or more water-soluble binders, wherein the highly lipophilic physiologically active substances have 5 or more logP values. The one or more water-soluble binders are selected from methylcellulose (MC), hydroxypropyl methylcellulose (HPMC), hydroxypropylcellulose (HPC), hydroxyethylcellulose (HEC), sodium carboxymethylcellulose (Na-CMC), and polyvinylpyrrolidone (PVP). The water-soluble binder is included in a total ratio of 0.1 to 10% by weight relative to the total amount of the highly lipophilic physiologically active substance. The matrix is ​​a solid dosage form that does not contain any other physiologically active substances.

2. The formulation according to claim 1, wherein the highly lipophilic physiologically active substance has 6 or more logP.

3. The formulation according to claim 1 or 2, wherein the one or more highly lipophilic active ingredients are one or more cannabinoids.

4. The formulation according to claim 3, wherein the one or more cannabinoids are 2-[1R-3-methyl-6R-(1-methylethenyl)-2-cyclohexen-1-yl]-5-pentyl-1,3-benzenediol (cannabidiol) and / or (6aR,10aR)-6,6,9-trimethyl-3-pentyl-6a,7,8,10a-tetrahydro-6H-benzo[c]chromen-1-ol (Δ9-THC).

5. The formulation according to claim 3, wherein the one or more cannabinoids is 2-[1R-3-methyl-6R-(1-methylethenyl)-2-cyclohexen-1-yl]-5-pentyl-1,3-benzenediol (cannabidiol).

6. The formulation according to claim 3, wherein the one or more cannabinoids is (6aR,10aR)-6,6,9-trimethyl-3-pentyl-6a,7,8,10a-tetrahydro-6H-benzo[c]chromen-1-ol (Δ9-THC).

7. The formulation according to claim 3, wherein the one or more cannabinoids are one or more phytocannabinoids and / or one or more synthetic cannabinoids.

8. The formulation according to claim 7, wherein the one or more phytocannabinoids are selected from cannabinoids or cannabinoid mixtures derived from cannabis (hemp) extract.

9. The formulation according to claim 7 or 8, wherein the one or more synthetic cannabinoids is nabilone and / or 1-naphthyl-(1-pentylindole-3-yl)methanone.

10. The formulation according to any one of claims 1 to 9, wherein hydroxypropyl methylcellulose (HPMC) and / or polyvinylpyrrolidone (PVP) are used as the water-soluble binder.

11. The formulation according to any one of claims 1 to 10, wherein the water-soluble binder is contained in a total ratio of 0.3 to 10% by weight relative to the total amount of the highly lipophilic physiologically active substance.

12. The formulation according to any one of claims 1 to 11, provided in the form of granules, matrix pellets, or matrix tablets, or comprising any of these forms.

13. The formulation according to claim 12, comprising a matrix pellet.

14. The formulation according to claim 13, wherein the matrix pellet is coated with one or more coatings.

15. The formulation according to claim 14, wherein the one or more coatings provide additional release control.

16. The formulation according to claim 13, wherein the matrix pellet is not coated to control release.

17. The formulation according to any one of claims 1 to 16, wherein more than 30% by weight and less than 80% by weight of the high lipophilic physiologically active substance contained herein is released within 2 hours.

18. The formulation according to claim 17, wherein more than 40% by weight and less than 90% by weight of the high lipophilic physiologically active substance contained herein is released within 3 hours.

19. The formulation according to claim 18, wherein more than 50% by weight and less than 95% by weight of the high lipophilic physiologically active substance contained herein is released within 4 hours.

20. The formulation according to any one of claims 17 to 19, wherein the release is determined at 37°C in 1000 ml of pH 6.8 phosphate buffer with 0.4% Tween® 80 added, using a blade stirrer device.

21. The formulation according to any one of claims 1 to 20, which is an oral formulation.

22. The formulation according to any one of claims 13 to 21, which is a multi-particle formulation comprising the matrix pellet.

23. The formulation according to claim 22, wherein matrix pellets having different release profiles are combined in a single multi-particle formulation.

24. The formulation according to claim 22 or 23, wherein the matrix pellet is filled into a capsule or sachet, or the matrix pellet is incorporated into a tablet.

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