Controlled release oral formulations of lipophilic drugs

Abstract

An oral drug delivery device for controlled delivery of a lipophilic drug, the device comprising a film-forming hydrophilic polymer, a release modulator, and a lipophilic drug emulsified in an emulsifier wherein the device is integrated into or formed into an orally administered dosage unit form, wherein upon ingestion of the dose unit form and contact with the gastric and / or intestinal medium, the release modulator forms a viscous gel that gradually erodes as it travels through the stomach and intestinal tract, thereby releasing the emulsified drug into the ambient environment at a controlled rate.

Description

Technical Field

[0001] The present invention discloses an oral administration delivery device and dosage form thereof for controlled delivery of drugs, and their use in medicine. Existing technology

[0002] The following is a list of references that are believed to be relevant to the background art of the presently disclosed subject matter:

[0003] 1. Zanchetta, Beatriz, Marco Vinícius Chaud, and Maria Helena Andrade Santana. "Self-emulsifying drug delivery systems (SEDDS) in pharmaceutical development." J Adv Chem Eng 5.3 (2015): 1-7.

[0004] 2. Thakare, Priya et al., "A review on self-emulsified drug delivery system." Journal of pharmaceutical and biological evaluations 3.2 (2016): 140-153.)

[0005] 3. Kalepu, Sandeep, Mohanvarma Manthina and VeerabhadhraswamyPadavala. “Orallipid-based drug delivery systems–an overview.” Acta Pharmaceutica Sinica B3.6 (2013): 361-372.

[0006] 4. Xiao, Lu, Tao Yi and Ying Liu. "A new self-microemulsifying mouthdissolving film to improve the oral bioavailability of poorly water-soluble drugs." Drug Development and Industrial Pharmacy 39.9 (2013): 1284-1290.

[0007] 5. Izgelov, Dvora, Michael Freidman, and Amnon Hoffman. “Investigation of cannabidiol gastro retentive tablets based on regional absorption of cannabinoids in rats.” European Journal of Pharmaceutics and Biopharmaceutics 152 (2020): 229 - 235.

[0008] 6. Punyamurthula, Nagendra S. et al., "Controlled release tablet formulation containing natural Δ9 - tetrahydrocannabinol." Drug development and industrial pharmacy 42.7 (2016): 1158 - 1164.

[0009] 7 US10004684B2

[0010] 8 US9265724B2

[0011] 9. WO2020014776A1

[0012] 10. WO2018011798A1

[0013] 11. WO2009117819A1

[0014] 12. US6399086B1

[0015] 13. US20070160677A1

[0016] 14. IN354423B

[0017] 15. CN112076177A

[0018] 16. US9358205B2 Background Art

[0019] Lipophilic drugs and lipid-based drug delivery (LBDD) systems

[0020] Poor drug absorption is often associated with active pharmaceutical ingredients (APIs) that have low water solubility and / or poor intestinal permeability. Among other approaches, drug solubilization has been improved in the dosage form itself and, importantly, in the gastrointestinal (GI) environment by employing lipid-based drug delivery (LBDD) systems. The absorption of drugs from lipid-based formulations depends on many factors, including particle size, degree of emulsification, dispersion of the drug upon dispersion, and precipitation rate [1].

[0021] Lipid digestion and absorption

[0022] Lipid digestion begins in the stomach by the continuously secreted gastric lipase. Gastric lipase activity is pH-dependent, being inactive under fasting conditions (gastric pH 1-2) and reaching maximum activity under fed (postprandial) conditions (gastric pH 4-5.5). The presence of lipids and fatty acids in the stomach triggers a series of rapid, hormone-promoted events leading to the secretion of bile and pancreatic substances (such as bile salts and phospholipids), which, together with pancreatic lipase in the duodenum and small intestine, create the commonly known fed state in the GI (gastrointestinal) tract, whereby dispersion, emulsification, micellization, and the formation of lamellar structures help maintain drug solubilization in the intestine [2, 3].

[0023] The process of lipid digestion and absorption is most efficient. When the pre-digested contents of the stomach empty into the duodenum, they mix with bile salts and surfactants, which are necessary for the hydrophobic lipid structure to disperse in the water-rich environment of the small intestine. Here, the digested lipid components are released in the outer layer of the mixed micelles. Lipase converts triglycerides and diglycerides into monoesters and free fatty acids. As emulsification continues, the subsequent reduction in fat droplet size increases the surface area of ​​the fat droplets, thereby facilitating additional lipolysis by intestinal lipase. The resulting micelles and lamellar structures trigger a further increase in solubilization capacity.

[0024] Lipid-based drug formulations should have the necessary composition (oil, surfactant, and cosurfactant or solvent) to self-emulsify in the intestinal tract in the presence of endogenous bile salts and pancreatic secretions. Some pharmaceutical excipients are self-emulsifying and can solubilize the API alone. Otherwise, the formulation needs to be customized to meet the requirements for API absorption and efficacy. Low HLB (hydrophile-lipophile balance) glycerides (oils) are rapidly lipolyzed in the stomach and then form their respective ester, diester, and free fatty acid components in the duodenum, which are required for drug emulsification and micellization in the GI environment [2,3].

[0025] Self-emulsifying lipid formulations (SELF)

[0026] Self-emulsification is a property of lipid systems that form emulsion particles upon contact with an aqueous medium without the need for mechanical or thermal energy. This can occur in the case of multicomponent excipients or formulations consisting of three different groups of molecules: an oil, a surfactant, and a cosurfactant or solvent in optimal proportions. The correct amounts of the components of each group are necessary for the spontaneous formation of emulsion particles upon contact with an aqueous medium [1].

[0027] Oral dosage forms containing self-emulsifying drug delivery systems (SEDDS)

[0028] Capsule filling is the simplest and most common technology used to encapsulate liquid or semisolid self-emulsifying (SE) formulations for oral delivery. In recent years, other solid SE dosage forms have emerged, such as incorporating liquid / semisolid SE ingredients into powders / nanoparticles through different solidification techniques (e.g., adsorption onto solid supports, spray drying, melt extrusion, nanoparticle technology). However, SEDDS are generally limited to liquid dosage forms because many excipients used in SEDDS are not solid at room temperature [1,7,8]. Another example of a solid SEEDS formulation is an orally dispersible or dissolving film from which the drug is absorbed via the oral mucosa [4,7,9,15].

[0029] Controlled-release (CR) formulations

[0030] Controlled-release (CR) dosage forms can be designed to release the drug along the gastrointestinal tract in a controlled or sustained profile. Compared to immediate-release (IR) formulations, the main benefits of these formulations are prolonged release, prolonged duration of effect, and a flatter and more stable PK profile—resulting in fewer side effects.

[0031] The primary technology used for CR formulations involves the use of a hydrophilic polymer matrix in which the API is dispersed or dissolved. Along the gastrointestinal tract, the matrix slowly erodes and dissolves, releasing the drug in a CR profile [11,12,16]. This approach can be applied to hydrophilic drugs. However, lipophilic drugs embedded in a hydrophilic polymer matrix are not released into the surrounding aqueous environment and do not release.

[0032] Another way to achieve CR of lipophilic drugs could be to use CR lipids, such as and [6] The disadvantage of this technology is that for effective absorption to occur, the action of gastric lipase and bile salts in the stomach and then in the duodenum is required. Lipophilic drugs that are released only and first in the small intestine cannot be emulsified and absorbed.

[0033] GR preparations

[0034] Another approach to achieving CR for lipophilic drugs is through the use of GR (gastric retentive) formulations—with which the entire drug content is released in the stomach and can be processed by gastric lipase and released bile salts.[5,10] However, GR formulations are most sensitive to the effects of gastric food content and gastric pH, and rapid gastric emptying significantly affects the drug release rate, which can lead to dose dumping. Furthermore, GR formulations are often limited by low drug loading.

[0035] Delayed preparations

[0036] The delayed immediate release of lipophilic drugs embedded in enteric matrices

[13] or gels

[14] to achieve acid protection has been described in various publications. These publications involve acid-sensitive APIs embedded in an insoluble gastric matrix that prevents drug-acid reactions. Once the matrix is ​​expelled from the stomach, it dissolves rapidly and the drug is released in an immediate profile. Summary of the Invention

[0037] Disclosed herein are oral drug delivery devices for the controlled delivery of lipophilic drugs, the devices comprising a pharmaceutically acceptable film-forming hydrophilic polymer, a pharmaceutically acceptable release-modifying agent, and the lipophilic drug emulsified in an emulsifier, wherein the device is incorporated into or formed into an orally administrable dosage unit form, and wherein upon ingestion of the dosage unit form and contact with gastric and / or intestinal media, the release-modifying agent forms a viscous gel that gradually erodes while passing through the stomach and intestines, thereby releasing the emulsified drug in micellar form at a controlled rate into the surrounding environment.

[0038] Disclosed herein is an oral drug delivery device for the controlled delivery of at least one lipophilic drug, the device comprising at least one pharmaceutically acceptable film-forming hydrophilic polymer, at least one pharmaceutically acceptable release-modifying agent, optionally at least one pharmaceutically acceptable plasticizer, and at least one lipophilic drug emulsified in at least one emulsifier, wherein the oral drug delivery device is configured for incorporation into or formation into an orally administrable dosage unit form, and wherein the oral drug delivery device is configured for enabling the at least one release-modifying agent to form a viscous gel upon ingestion of the dosage unit form and contact with gastric and / or intestinal media, the viscous gel being configured for gradual erosion while passing through the stomach and intestines and for controllably releasing the emulsified drug in micellar form into the surrounding environment.

[0039] In the disclosed oral drug delivery device, at least one pharmaceutically acceptable film-forming hydrophilic polymer, at least one pharmaceutically acceptable release modifier, and optionally at least one pharmaceutically acceptable plasticizer form a controlled release (CR) drug-containing polymer component of the delivery device, wherein at least one lipophilic drug emulsified in at least one emulsifier is embedded in the polymer component.

[0040] The present invention also discloses an oral drug delivery device for controlled delivery of at least one lipophilic drug, wherein the device comprises a polymer component containing a controlled-release (CR) drug, the polymer component comprising at least one pharmaceutically acceptable film-forming hydrophilic polymer component, at least one pharmaceutically acceptable release modifier, optionally at least one pharmaceutically acceptable plasticizer, and at least one lipophilic drug emulsified in at least one emulsifier embedded in the polymer component, wherein the oral drug delivery device is configured for integration into or formation into an orally administrable dosage unit form, wherein the oral drug delivery device is configured for effecting the at least one release modifier, wherein upon ingestion of the dosage unit form and contact with gastric and / or intestinal media, the device forms a viscous gel, the viscous gel being configured for gradual erosion while passing through the stomach and intestines, and for controllably releasing the emulsified drug in micellar form into the surrounding environment.

[0041] In a specific embodiment of the disclosed oral drug delivery device, the release modifier is a hydrophilic polymer that, when dissolved in water at 2% w / w, produces a solution having a viscosity of at least 150 mPa*sec.

[0042] In particular embodiments of the disclosed oral drug delivery devices, the release-modifying agent is included in an amount of at least about 30 mg per said dosage unit form.

[0043] In particular embodiments of the disclosed oral drug delivery devices, the total weight of the dosage unit form is from about 250 mg to about 2000 mg, preferably from about 300 mg to about 1200 mg.

[0044] In specific embodiments of the disclosed oral drug delivery device, the at least one lipophilic drug has a log P > 2. In the disclosed embodiments, the at least one emulsified drug is a pharmaceutically active cannabinoid or a mixture of at least two pharmaceutically active cannabinoids or a cannabis extract, ritonavir, fenofibrate, diclofenac, flurbiprofen diazepam, vitamin E, piroxicam, lopinavir, clofazimine, or a modified lipophilic drug such as a hydrophobic ion-paired peptide drug, a pharmaceutically acceptable derivative and a pharmaceutically active metabolite thereof, more specifically a pharmaceutically active cannabinoid or a mixture of at least two pharmaceutically active cannabinoids or a cannabis extract.

[0045] In specific embodiments, the disclosed oral drug delivery device comprises about 0.5 mg to about 500 mg, preferably about 1 mg to about 300 mg, more preferably about 5 mg to about 300 mg of the lipophilic drug per dosage unit form.

[0046] The dosage unit form may comprise the disclosed drug delivery device incorporated into an oral capsule, preferably a soft gel capsule.

[0047] In other embodiments, the disclosed dosage unit forms may comprise the CR drug-containing polymer component incorporated into an oral capsule, such as a hard capsule or soft gel capsule.

[0048] The dosage unit form according to the present disclosure may further comprise an immediate release IR (immediate release) drug-containing component comprising an emulsion of the at least one lipophilic drug in at least one emulsifier, the IR drug-containing component optionally further comprising a suitable carrier or diluent, wherein the IR drug-containing component may be in solid form, such as powder form or liquid form. The capsule may be coated with an immediate release (IR) drug-containing component comprising an emulsion of the at least one lipophilic drug in at least one emulsifier, and optionally further comprising a suitable carrier or diluent.

[0049] The oral drug delivery device of the present disclosure may comprise 1 to about 50 laminated layers containing a CR drug, each of the CR drug-containing layers comprising the at least one emulsified lipophilic drug embedded in the polymer component, each layer having a predetermined geometric shape, such as a substantially rectangular, square, or other polygonal shape or a non-polygonal shape, such as an elliptical shape, preferably wherein each of the layers has the same geometric shape. According to the present disclosure, the thickness of each of the drug-containing layers may be from about 20 μm to about 1000 μm, with each of the layers having the same or different thicknesses.

[0050] The laminated drug-containing layers of the oral drug delivery device disclosed herein can be rolled together into a substantially cylindrical body. The drug-containing member of the oral drug delivery device disclosed herein can be incorporated into an oral capsule (such as a soft gel capsule), and the capsule can also optionally contain or be coated with an immediate-release (IR) drug-containing component, the immediate-release (IR) drug-containing component comprising an emulsion of at least one lipophilic drug in at least one emulsifier, the IR drug-containing component optionally further comprising a suitable carrier or diluent, wherein the IR drug-containing component is in solid or liquid form.

[0051] In certain aspects and embodiments of the oral drug delivery devices of the present disclosure, the at least one is a pharmaceutically acceptable film-forming hydrophilic polymer, at least one pharmaceutically acceptable release modifier, optionally at least one pharmaceutically acceptable plasticizer, and at least one lipophilic drug emulsified in at least one emulsifier constitutes a substantially solid homogeneous CR mixture that is configured for incorporation into said orally administrable dosage unit form.

[0052] In some aspects and embodiments of the oral drug delivery disclosed herein, the at least one pharmaceutically acceptable film-forming hydrophilic polymer component, the at least one pharmaceutically acceptable release modifier, the at least one optional pharmaceutically acceptable plasticizer, and the at least one lipophilic drug emulsified in the at least one emulsifier embedded therein constitute a substantially homogeneous, substantially solid CR mixture configured for incorporation into the orally administrable dosage unit form. The CR mixture can be substantially shaped into a cylinder having a diameter of about 0.2 cm to about 1 cm.

[0053] The oral drug delivery device of the present disclosure can be incorporated into an oral capsule, preferably a soft gel capsule, wherein the capsule optionally further comprises and / or is coated with an immediate release (IR) drug-containing component comprising an emulsion of the at least one lipophilic drug in at least one emulsifier, the IR drug-containing component optionally further comprising a suitable carrier or diluent, wherein the IR drug-containing component is in solid form or liquid form.

[0054] Alternatively, the oral drug delivery device disclosed herein can be configured as a CR orally administrable tablet comprising at least one pharmaceutically acceptable film-forming hydrophilic polymer, at least one pharmaceutically acceptable release modifier, optionally the at least one pharmaceutically acceptable plasticizer, and the at least one lipophilic drug emulsified in at least one emulsifier embedded in the composition. In some such embodiments, the tablet comprises a first film-forming polymer and optionally a plasticizer, and at least one lipophilic drug emulsified in at least one emulsifier embedded in the polymer component, and the tablet further comprises a release modifier, optionally together with an additional film-forming polymer, which may be the same or different from the first film-forming polymer, wherein the tablet optionally further comprises at least one tableting excipient or additive, wherein the excipient or additive is any one of the following: a binder, a diluent, a filler, a lubricant, and a glidant, and any mixture of at least two thereof. The tablet may also optionally comprise an additional amount of at least one additional pharmaceutically acceptable release-modifying polymer in solid form, preferably in ground or powdered form, which additional release-modifying agent is the same as or different from the at least one additional pharmaceutically acceptable release-modifying agent, respectively.

[0055] The disclosed oral drug delivery device in tablet form may optionally be coated with an IR drug-containing component comprising an emulsion of the at least one lipophilic drug in at least one emulsifier, the IR drug-containing component optionally further comprising a suitable carrier or diluent, wherein the IR drug-containing component is in solid form or liquid form.

[0056] Furthermore, in all embodiments of the oral drug delivery device disclosed herein in tablet form, the tablet can be contained in an oral capsule (such as a soft gel capsule), which capsule optionally further comprises an immediate-release (IR) drug-containing component, which immediate-release (IR) drug-containing component comprises an emulsion of at least one lipophilic drug in at least one emulsifier, which IR drug-containing component optionally further comprises a suitable carrier or diluent, wherein the IR drug-containing component is in solid form or liquid form.

[0057] In some specific aspects and embodiments, the oral drug delivery device disclosed herein comprises at least one pharmaceutically acceptable film-forming hydrophilic polymer and optionally at least one pharmaceutically acceptable plasticizer, which form a drug-containing polymer component in which at least one lipophilic emulsified drug is embedded; and at least one pharmaceutically acceptable release modifier and optionally at least one pharmaceutically acceptable plasticizer form a CR polymer component, which may also optionally contain at least one pharmaceutically acceptable film-forming hydrophilic polymer; wherein the hydrophilic film-forming polymer and the optional plasticizer in the drug-containing polymer component and the CR polymer component may be the same or different.

[0058] In other specific aspects and embodiments, disclosed herein is an oral drug delivery device for controlled delivery of at least one lipophilic drug, the device comprising a drug-containing polymer component comprising at least one pharmaceutically acceptable film-forming hydrophilic polymer component, optionally at least one pharmaceutically acceptable plasticizer, in which an emulsified lipophilic drug is embedded; a controlled release (CR) polymer component comprising at least one pharmaceutically acceptable film-forming hydrophilic polymer, at least one pharmaceutically acceptable release modifier, and optionally At least one pharmaceutically acceptable plasticizer, wherein the hydrophilic film-forming polymer and the optional plasticizer in the drug-containing polymer component and the CR polymer component can be the same or different; the device is configured to be incorporated into an orally administrable dosage unit form, and the device is configured to enable the at least one release-modifying agent to form a viscous gel when the dosage unit form is ingested and comes into contact with gastric and / or intestinal media, the viscous gel being configured to gradually erode while passing through the stomach and intestines and to controllably release the emulsified drug in micellar form into the surrounding environment. The drug-containing polymer component of the device of these aspects and embodiments can include 1 to about 50 drug-containing layers, the drug-containing layers being laminated, each drug-containing layer having a predetermined geometric shape, such as a substantially rectangular, square, or other polygonal shape, or a non-polygonal shape, such as, for example, an elliptical shape, and more particularly, wherein the layers have the same geometric shape. The thickness of each drug-containing layer can be from about 15 μm to about 900 μm, with each layer having the same or different thicknesses. In these specific embodiments, the drug-containing polymer component and the CR polymer component may also be laminated together, and these laminated drug-containing layers and CR polymer components may be rolled together to form a substantially cylindrical body. The devices of these embodiments may be incorporated into an oral capsule (such as a soft gel capsule), which capsule optionally further comprises and / or is coated with an immediate-release (IR) drug-containing component comprising an emulsion of at least one lipophilic drug in at least one emulsifier, the drug being the same or different from the drug contained in the CR drug-containing layer, wherein the IR drug-containing component optionally further comprises a suitable carrier or diluent, and wherein the IR drug-containing component is in solid or liquid form.

[0059] Furthermore, disclosed herein is an oral drug delivery device for controlled delivery of at least one lipophilic drug, the device comprising at least one pharmaceutically acceptable film-forming hydrophilic polymer, at least one pharmaceutically acceptable release modifier, optionally at least one pharmaceutically acceptable plasticizer, and at least one lipophilic drug emulsified in at least one emulsifier, wherein the oral drug delivery device is configured for incorporation into or formed into an orally administrable dosage unit form, the oral drug delivery device being configured for enabling the at least one release modifier to form a viscous gel upon ingestion of the dosage unit form and contact with gastric and / or intestinal media, the viscous gel being configured to gradually erode while passing through the stomach and intestines, and for controllably releasing the emulsified drug in the form of micelles into the stomach and intestines. in an ambient environment, wherein the release-modifying agent is a hydrophilic polymer which, when dissolved in water at 2% w / w, produces a solution having a viscosity of at least 150 mPa*sec, wherein the release-modifying agent is contained in an amount of at least about 30 mg per said dosage unit form, and wherein said at least one emulsifier is a lipid excipient having an HLB (hydrophilic-lipophilic balance) greater than 6, optionally wherein said emulsifier is a mixture of lipid excipients of which at least 50% have an HLB greater than 6, and the remaining lipid excipients are any of the following: oils, fatty acids, glycerides, polyoxyglycerides, polyglycerol esters and polyol esters or water-insoluble surfactants, or any mixture of at least two thereof, wherein each of said remaining lipid excipients has an HLB less than, equal to or greater than 6.

[0060] Further, disclosed herein is an oral drug delivery device for controlled delivery of at least one lipophilic drug, the device comprising a polymer component containing a CR drug, the polymer component comprising at least one pharmaceutically acceptable film-forming hydrophilic polymer component, at least one pharmaceutically acceptable release modifier, optionally at least one pharmaceutically acceptable plasticizer, and at least one lipophilic drug emulsified in at least one emulsifier embedded in the polymer component, the device being configured to be incorporated into or formed into an orally administrable dosage unit form, and the device being configured to enable the at least one release modifier to form a viscous gel upon ingestion of the dosage unit form and contact with gastric and / or intestinal media, the viscous gel being configured to gradually erode while passing through the stomach and intestines, and for delivering the emulsified drug to the oral cavity. controllably released into the surrounding environment in the form of micelles, wherein the release modifier is a hydrophilic polymer which, when dissolved in water at 2% w / w, produces a solution having a viscosity of at least 150 mPa*sec, wherein the release modifier is contained in an amount of at least about 30 mg per said dosage unit form, and wherein said at least one emulsifier is a lipid excipient having an HLB (hydrophile-lipophile balance) greater than 6, optionally wherein said emulsifier is a mixture of lipid excipients wherein at least 50% of the HLB is greater than 6, and the remaining lipid excipients are any of the following: oils, fatty acids, glycerides, polyoxyglycerides, polyglycerol esters and polyol esters or water-insoluble surfactants, or any mixture of at least two thereof, wherein each of said remaining lipid excipients has an HLB less than, equal to or greater than 6.

[0061] Still further, disclosed herein is an oral drug delivery device for controlled delivery of at least one lipophilic drug, the device comprising a drug-containing polymer component comprising at least one pharmaceutically acceptable film-forming hydrophilic polymer component, optionally at least one pharmaceutically acceptable plasticizer, and at least one lipophilic drug emulsified in at least one emulsifier, wherein the emulsified drug is embedded in the polymer component; a controlled release (CR) polymer component comprising at least one pharmaceutically acceptable film-forming hydrophilic polymer, at least one pharmaceutically acceptable release modifier, and optionally at least one pharmaceutically acceptable plasticizer, wherein the hydrophilic film-forming polymer and the optional plasticizer in the drug-containing polymer component and the CR polymer component may be the same or different; and wherein the oral drug delivery device is configured for incorporation into an orally administrable dosage unit form, the drug delivery device being configured for administration upon ingestion of the dosage unit form and interaction with gastric and / or intestinal media. wherein the at least one emulsifier is a lipid excipient having an HLB (hydrophilic-lipophilic balance) greater than 6, optionally wherein the emulsifier is a mixture of lipid excipients wherein at least 50% of the HLB is greater than 6, and the remaining lipid excipients are any of the following: oils, fatty acids, glycerides, polyoxyglycerides, polyglycerol esters and polyol esters or water-insoluble surfactants, or any mixture of at least two thereof, wherein each of the remaining lipid excipients has an HLB less than, equal to or greater than 6.

[0062] Also in these specific embodiments of the disclosed oral drug delivery device, the total weight of the dosage unit form can be from about 250 mg to about 2000 mg, preferably from about 300 mg to about 1200 mg. The content of the at least one emulsified lipophilic drug can be from about 1 w / w% to about 65 w / w%, specifically from about 5 w / w% to about 65 w / w%, more specifically from about 10 w / w% to about 65 w / w%.

[0063] In all aspects and embodiments of the oral drug delivery devices disclosed herein, the pharmaceutically active cannabinoid can be any of the following: delta-9-tetrahydrocannabinol (Δ9-THC, THC), isotetrahydrocannabinol (iso-THC), cannabinol (CBN), cannabidiol (CBD), cannabigerol (CBG), cannachromene (CBC), cannabichromene (CBE), cannabichromene (CBL), dihydroxycannabinol (CBT), cannabinol (CBV), tetrahydrocannabinol (THCV), cannabigerol (CBDV), and many other pharmaceutically active cannabinoids such as tetrahydrocannabidiol (THCBD), tetrahydrocannabigerol (THCBG), tetrahydrocannachromene (THCBC), tetrahydrocannabidiol (THCBDV), cannabigerol (CBCV), cannabigerol (CBGV) and cannabigerol monomethyl ether (CBGM), as well as pharmaceutically acceptable derivatives and pharmaceutically active metabolites thereof.

[0064] In all aspects and embodiments of the oral drug delivery device disclosed herein, the pharmaceutically active drug can be ritonavir, fenofibrate, diclofenac, flurbiprofen diazepam, vitamin E, piroxicam, lopinavir, clofazimine or a modified lipophilic drug, such as a hydrophobic ion-pairing peptide drug, or a pharmaceutically acceptable derivative and pharmaceutically active metabolite thereof.

[0065] In all aspects and embodiments of the oral drug delivery device disclosed herein, the release modifier can be any of the following: methylcellulose (such as A4M), hydroxypropylmethylcellulose (such as K250, K750, K1500, K4M, E4M, E10M, K15M, K100M or K200M), hydroxypropylcellulose (such as Klucel GF, Klucel MF or Klucel HF), hydroxyethylcellulose (such as HEC G, HEC M, HEC HX, HEC HHX), polyethylene oxide, carboxymethylcellulose (such as CMC 7MF, CMC 7H3F or CMC 7HF), gelatin, gum and protein, and any mixture of at least two of them.

[0066] In all aspects and embodiments of the oral drug delivery device disclosed herein, the emulsifier may be a lipid excipient having an HLB (hydrophilic-lipophilic balance) greater than 6. Such lipid excipients can be any of the following: Gelucire 50 / 13 (stearoyl polyoxyl-32 glycerides), Gelucire 44 / 14 (lauroyl polyoxyl-32 glycerides), Gelucire 48 / 16 (polyoxyl-32 stearate (Type I) NF), Labrafil 2125 (linoleoyl polyoxyl-6 glycerides), Labrafil 1944 (oleoyl polyoxyl-6 glycerides), Labrasol (caprylocaproyl polyoxyl-8 glycerides), Kolliphor RH40 (polyoxyl-40 hydrogenated castor oil), Kolliphor EL (polyoxyl-35 castor oil), Kolliphor HS15 (polyethylene glycol-15-hydroxystearate), Kolliphor P407 / 124 / 188 (poloxamers 407 / 124 / 188), and Kolliphor RH40 (polyoxyl-40 hydrogenated castor oil). PS80 / 60 / 20 (polysorbate 80 / 60 / 20), and any mixture of at least two of them. The remaining lipid excipients can be any one of the following: oil, fatty acid, glyceride, polyoxyglycerol ester, polyglycerol ester and polyol ester or water-insoluble surfactant, or any mixture of at least two of them, wherein each of the remaining lipid excipients has an HLB lower than, equal to or higher than 6.

[0067] In all aspects and embodiments of the oral drug delivery device disclosed herein, the weight ratio of lipophilic drug:emulsifier may be from about 2:1 to about 1:100, preferably from about 1:1 to about 1:20.

[0068] In all aspects and embodiments of the oral drug delivery device disclosed herein, the hydrophilic film-forming polymer can be any one of the following: povidone, copovidone, polyvinyl alcohol, a hydrophilic polyacrylamide derivative, a protein, gelatin, hydroxypropyl cellulose, polyethylene oxide, amino-methacrylate copolymer NF, hydroxypropyl methylcellulose, hydroxyethyl cellulose, carboxymethyl cellulose, sodium carboxymethyl cellulose, methyl cellulose, or a polyvinyl alcohol-polyethylene glycol graft copolymer, and any combination of at least two thereof.

[0069] In all aspects and embodiments of the oral drug delivery devices disclosed herein, the film-forming polymer and the release-modifying agent may together comprise from about 25 w / w% to about 85 w / w% of the device, specifically from about 25 w / w% to 70 w / w%, more specifically from about 30 w / w% to about 70 w / w%.

[0070] In all aspects and embodiments of the present disclosure, the oral drug delivery device may optionally comprise up to 20 w / w%, specifically up to 15 w / w%, more specifically about 5 w / w% to about 10 w / w% plasticizer.

[0071] In other aspects and embodiments, an orally administrable drug dosage unit form comprising any of the above-mentioned drug delivery devices is disclosed, the drug delivery device being configured to be integrated into the drug dosage unit form, specifically integrated with or integrated into an oral capsule, specifically the capsule being a soft gel capsule. In other aspects and embodiments, the drug delivery device disclosed herein is formed as an orally administrable drug dosage unit, specifically formed as a tablet. Tablets according to the present disclosure may also be integrated with or integrated into an oral capsule, specifically the capsule being a soft gel capsule. In an orally administrable dosage unit form in the form of an oral capsule, the capsule may comprise a component containing an immediate-release IR drug, the IR component comprising an emulsion of the at least one lipophilic drug in at least one emulsifier, the drug in the IR component being the same or different from the drug contained in the drug delivery device, the component containing the IR drug optionally further comprising a suitable carrier or diluent, wherein the component containing the IR drug is in solid form, such as in powder form or liquid form. The drug can be distributed between the CR drug delivery device and the component containing the IR drug in a predetermined ratio. The tablets may be coated with an IR component comprising the same drug as in the CR component or another drug.In particular orally administrable pharmaceutical dosage unit forms, the active ingredient may be at least one pharmaceutically active cannabinoid or a mixture of at least two pharmaceutically active cannabinoids or a cannabis extract.

[0072] In yet another aspect of the present disclosure, the disclosed drug delivery devices and orally administrable drug dosage unit forms thereof, wherein the drug is a cannabinoid or a mixture of cannabinoids or a cannabis extract, may be used in a method of treating, alleviating, and preventing the exacerbation of a disease, disorder, or condition responsive to cannabinoid treatment in a subject in need thereof, the method comprising orally administering the drug delivery device or drug dosage unit form to the subject.

[0073] The disease, disorder or condition responsive to cannabinoid treatment may be any of the following: anorexia associated with weight loss in patients with AIDS, nausea and vomiting associated with cancer chemotherapy, pain, anxiety, depression, muscle spasms, arthritis and rheumatism, multiple sclerosis and other neuromuscular inflammatory conditions, inflammatory bowel disease such as Crohn's disease and colitis, post-traumatic stress disorder (PTSD) or seizures, Parkinson's disease, spinal cord injury, fibromyalgia, Alzheimer's disease and dementia, or any other condition responsive to cannabinoid treatment. Administration may be once or twice daily, or three times daily. Administration may be chronic.

[0074] In another aspect of the present disclosure, in the disclosed drug delivery device and orally administrable drug dosage unit form thereof, the pharmaceutically active drug can be ritonavir, fenofibrate, diclofenac, flurbiprofen diazepam, vitamin E, piroxicam, lopinavir, clofazimine or a modified lipophilic drug, such as a hydrophobic ion-pairing peptide drug, a pharmaceutically acceptable derivative and a pharmaceutically active metabolite thereof.

[0075] Also disclosed are methods for treating, alleviating, and preventing the exacerbation of a disease, disorder, or condition responsive to cannabinoid treatment in a subject in need thereof, the method comprising orally administering to the subject an oral drug delivery device or pharmaceutical dosage unit form thereof as disclosed herein, wherein the drug is a cannabinoid, a mixture of cannabinoids, or a cannabis extract. Disclosed are methods for treating, alleviating, and preventing the exacerbation of a disease, disorder, or condition responsive to ritonavir, fenofibrate, diclofenac, flurbiprofen diazepam, vitamin E, piroxicam, lopinavir, clofazimine, or a modified lipophilic drug, such as a hydrophobic ion-pairing peptide drug, a pharmaceutically acceptable derivative, and a pharmaceutically active metabolite thereof.

[0076] Also disclosed are methods for providing a subject in need thereof with stable, therapeutically effective plasma levels of at least one cannabinoid or a mixture of at least two cannabinoids and / or active metabolites thereof over an extended period of time, the method comprising orally administering to the subject an oral drug delivery device or drug dosage unit form as disclosed herein, wherein the drug is a cannabinoid or a mixture of cannabinoids or a cannabis extract.

[0077] In all of the methods of treatment disclosed herein, administration may be once or twice daily, or three times daily, or administration may be chronic. Administration may be performed under fed or fasting conditions. BRIEF DESCRIPTION OF THE DRAWINGS

[0078] In order to better understand the subject matter disclosed herein and to illustrate how it may be implemented in practice, embodiments will now be described, by way of non-limiting example only, with reference to the accompanying drawings, in which:

[0079] Figure 1 CBD release from Formulation 1 of Example 1 in SGF and SIF.

[0080] Figure 2 CBD release from Formulation 2 of Example 2 in SGF and SIF.

[0081] Figure 3 CBD release from Formulation 3 of Example 3 in SGF and SIF.

[0082] Figure 4 CBD release from Formulation 4 of Example 4 in SGF.

[0083] Figure 5 CBD release from Formulation 5 of Example 5 in SGF.

[0084] Figure 5A SEM image of the hot melt extrudate prepared in Example 5. DETAILED DESCRIPTION

[0085] General Description

[0086] The present disclosure relates to oral drug delivery devices and dosage forms thereof for the controlled delivery of lipophilic drugs and poorly water-soluble drugs, wherein the drug is contained in an emulsified form, particularly in the form of a drug emulsion in a suitable emulsifier, particularly various lipids, fats, and / or surfactants as described herein. The devices / dosage forms disclosed herein provide improved and prolonged controlled release of the emulsified drug in micellar form and provide improved absorption of the drug by the subject being treated.

[0087] In all aspects and embodiments, the oral drug delivery device for controlled release (CR) of at least one emulsified lipophilic drug comprises at least one pharmaceutically acceptable film-forming hydrophilic polymer, at least one pharmaceutically acceptable release modifier, optionally at least one pharmaceutically acceptable plasticizer, and at least one lipophilic drug emulsified in at least one emulsifier, wherein the oral drug delivery device is configured for integration into or formation into an orally administrable dosage unit form, and wherein the oral drug delivery device is configured for enabling the at least one release modifier to form a viscous gel upon ingestion of the dosage unit form and contact with gastric and / or intestinal media, the viscous gel being configured for gradual erosion while passing through the stomach and intestines and for controllably releasing the emulsified drug in micellar form into the surrounding environment.

[0088] After oral ingestion and when the delivery device comes into contact with the gastric environment, the delivery device becomes viscous, forming a gradually erodible viscous device or viscous body (which are used interchangeably herein) containing the emulsified drug, which provides controlled release of the emulsified drug contained therein in micellar form over an extended period of time, which begins in the stomach and continues after the viscous body / device is emptied from the stomach into the duodenum, and then continues its journey along the intestine until it is substantially completely eroded / biodegraded. Therefore, in all aspects and embodiments of the present disclosure, the drug delivery device and / or its dosage form provides release and absorption of the emulsified drug over a period of at least about 3 hours and up to about 24 hours, thereby providing stable, therapeutically effective and reliable plasma levels over an extended period of time. Treatment with the disclosed controlled release oral delivery device and its dosage form provides drug release shortly after administration and an extended residence time of the delivery device in the patient's gastrointestinal tract, improving the magnitude and duration of the drug's pharmacokinetic effect, thereby maximizing the therapeutic effect and minimizing any adverse side effects. The disclosed oral drug delivery devices and dosage forms enable administration of predetermined therapeutic doses of drugs and reduce the number of daily administrations, thereby leading to improved patient compliance.

[0089] Particular lipophilic drugs are cannabinoids, which, as described in more detail below, are useful in treating a variety of cannabinoid-responsive conditions.

[0090] In order to achieve the absorption of lipophilic drugs in vivo, as mentioned above, such drugs need to be processed and digested by gastric lipase in the stomach, resulting in the secretion of bile and pancreatic substances such as bile salts and phospholipids, which, together with the pancreatic lipase in the duodenum and small intestine, lead to the commonly known "fed state" in the gastrointestinal tract, whereby dispersion, emulsification, micellization and the formation of lamellar structures help to maintain the solubilization of drugs in the intestinal tract. When the pre-digested contents of the stomach are emptied into the duodenum, they are mixed with bile salts and surfactants, which are necessary for the dispersion of hydrophobic lipid structures in the water-rich environment of the small intestine. Here, the digested lipid components are released in the outer layer of the mixed micelles. Lipase converts triglycerides and diglycerides into monoesters and free fatty acids. As emulsification continues, the reduction in subsequent fat droplet size increases the surface area of ​​the fat droplets, thereby facilitating the additional lipolysis by intestinal lipase. The resulting micelles and lamellar structures trigger a further increase in solubilizing power, emulsions and micelles.

[0091] Due to the fact that the medicine in the delivery device disclosed in the present invention is an emulsified drug form, it is released into the surrounding medium in the form of drug micelles. Drug micelles can be easily absorbed along all gastrointestinal tracts, starting from the stomach and continuing to enter the duodenum, then along the intestine, without the need for digestion pre-treatment by gastric lipase, bile salts and phospholipids. According to this phenomenon, effective controlled release can be achieved, thereby causing the extension of lipophilic drugs and stable pharmacokinetic (PK) curve. Therefore, the oral drug delivery device of the present disclosure and all disclosed dosage unit forms thereof are not retained in the stomach, but they advance along the gastrointestinal tract until they are substantially completely eroded, thereby gradually releasing the active drug contained therein in a controlled manner. Therefore, in all aspects and embodiments of the present disclosure, drug delivery device and dosage form thereof are not gastric retention.

[0092] As shown in Example 11 below, in the absence of a suitable CR component as described herein and shown, for example, in Examples 1-5, the resulting delivery device (comprising the active ingredients THC and CBD) completely dissolved within 30 to 60 minutes.

[0093] In some aspects and embodiments of the present disclosure, oral drug delivery devices and dosage unit forms thereof, the active pharmaceutical ingredient (drug) is mixed with a lipid emulsifier at a drug:emulsifier ratio of 2:1 to 1:100.

[0094] The oral drug delivery device of the present disclosure and all disclosed dosage unit forms thereof include ingredients that provide controlled release of drug absorbed in the desired form, i.e., easily absorbed drug micelles when taken in, starting from the stomach and continuing when emptying into the duodenum and intestinal tract. Specifically, these ingredients are that the drug is included in emulsified form, and the delivery device / dosage form includes a release modifier that is a hydrophilic polymer that produces a solution having a viscosity of at least 150 mPa*sec when dissolved in water at 2 weight / weight%, preferably included in the dosage unit form in an amount of at least about 30 mg per the dosage unit form, wherein the gross weight of the dosage form is from about 250 mg to about 2000 mg, and an emulsifier that is a lipid excipient having an HLB (hydrophilic-lipophilic balance) greater than 6, or a mixture of lipid excipients having an HLB of at least 50% greater than 6. These oral drug delivery devices and dosage forms thereof provide extended release and effective absorption of active drugs.

[0095] In some specific aspects and embodiments of the delivery device of the present disclosure, the at least one pharmaceutically acceptable film-forming hydrophilic polymer, the at least one pharmaceutically acceptable release modifier, and the optional at least one pharmaceutically acceptable plasticizer are configured to form a controlled-release drug-containing polymer component of the delivery device, and at least one lipophilic drug emulsified in at least one emulsifier (also referred to herein as a drug emulsion) is embedded in the polymer component.

[0096] In some specific aspects and embodiments of the delivery device of the present disclosure, the dosage unit form comprises the drug delivery device integrated into an oral capsule (such as a soft gel capsule). In other specific aspects and embodiments of the present disclosure, the delivery device is formed into a dosage unit form, such as a tablet.

[0097] In one aspect, disclosed herein is an oral drug delivery device for controlled delivery of at least one lipophilic drug, the device comprising a CR drug-containing polymer component comprising at least one pharmaceutically acceptable film-forming hydrophilic polymer component, at least one pharmaceutically acceptable release-modifying agent, optionally at least one pharmaceutically acceptable plasticizer, and at least one lipophilic drug emulsified in at least one emulsifier embedded in the polymer component, wherein the oral drug delivery device is configured to be incorporated into or formed into an orally administrable dosage unit form, and wherein the oral drug delivery device is configured to enable the at least one release-modifying agent to form a viscous gel upon ingestion of the dosage unit form and contact with gastric and / or intestinal media, the viscous gel being configured to gradually erode while passing through the stomach and intestines and to controllably release the emulsified drug in micellar form into the surrounding environment.

[0098] In a specific embodiment of the aspects of the present disclosure, the drug delivery device comprises a single or multiple laminated CR drug-containing layers, for example, up to 6, 8, 10, 12, 15, 20 and up to 50 drug-containing layers. The polymer component of each CR drug-containing layer comprises a hydrophilic film-forming polymer, a release modifier and an optional plasticizer, and at least one lipophilic drug emulsified in at least one emulsifier. The CR drug-containing layer has a predetermined geometric shape, for example, but not limited to, a substantially rectangular, square or other polygonal shape or a non-polygonal shape, such as, for example, an elliptical shape, wherein each of the layers can have the same geometric shape, and can also have different geometric shapes. The CR drug-containing layers can each have the same or different thicknesses of about 20 μm to about 1000 μm. In some specific embodiments, the CR drug-containing layer or laminated CR drug-containing layers are wound together to form a substantially cylindrical body, or they can be formed together into different forms or shapes. The resulting drug delivery device can be integrated with an oral capsule (e.g., a soft gel capsule). Specifically, the resulting drug delivery device can be inserted into an oral capsule. Exemplary devices are described below in Examples 1-3.

[0099] In other specific embodiments of the aspects of the present disclosure, the drug delivery device is configured as a tablet, such as a pharmaceutical tablet, or a pill or a caplet, etc. An exemplary device is described in Example 12 below. Such tablets comprise at least one pharmaceutically acceptable film-forming hydrophilic polymer, at least one pharmaceutically acceptable release modifier, optionally at least one pharmaceutically acceptable plasticizer, and at least one lipophilic drug emulsified in at least one emulsifier, and optionally further comprise at least one tableting excipient or additive, which may be any of the following: a binder, a diluent, a filler, a lubricant, and a glidant, and any mixture of at least two of them. A specific tablet may comprise the drug, a first release modifier, and an optional plasticizer embedded in a hydrophilic film-forming polymer, and optionally at least one tableting excipient or additive. Such tablets may also comprise an amount of an additional (second) release modifier, which may be the same as or different from the first modifier.

[0100] In another embodiment, a tablet according to the present disclosure may comprise the emulsified lipophilic drug and an optional plasticizer embedded in a hydrophilic film-forming polymer, and further comprise a release modifier admixed therewith, and optionally at least one tableting excipient or additive. Generally, the various components or tablets are ground, mixed, and then compressed into tablets. An exemplary apparatus is described in Example 13 below.

[0101] Tablets according to the present disclosure may be inserted into oral capsules.

[0102] In the above aspects and embodiments of the present disclosure, wherein the drug delivery device is integrated with or incorporated into an oral capsule, the capsule may further optionally contain and / or be coated with an immediate-release (IR) drug-containing component comprising an emulsion of at least one lipophilic drug in at least one emulsifier, the IR drug-containing component optionally further comprising a suitable carrier or diluent, wherein the IR drug-containing component is in solid form, such as powder form or liquid form. Exemplary devices are described in Examples 1-3 below.

[0103] In embodiments of the disclosed delivery devices that are in tablet form, the tablets can optionally be coated with a similar IR drug-containing component comprising an emulsion of at least one lipophilic drug in at least one emulsifier, optionally further comprising a suitable carrier or diluent, wherein the IR drug-containing component is in solid form, such as powder form or liquid form.

[0104] In all aspects and embodiments of the present disclosure, the drug contained in the IR drug-containing component may be the same as or different from the drug contained in the CR drug-containing layer or component.

[0105] In other specific embodiments of the disclosed drug delivery device and dosage forms thereof, at least one lipophilic drug emulsified in at least one emulsifier is embedded in at least one pharmaceutically acceptable film-forming hydrophilic polymer component, at least one pharmaceutically acceptable release modifier and optionally at least one optional pharmaceutically acceptable plasticizer, the resulting drug-containing polymer mixture constitutes a substantially homogeneous, substantially solid CR mixture configured for incorporation into the orally administrable dosage unit form. The device can be produced using a hot melt extrusion process, as described in more detail below and exemplified in Example 5.

[0106] The CR mixture may be shaped into a suitable form, such as a substantially cylindrical body, for example, a substantially cylindrical body having a diameter of about 0.2 cm to about 1 cm.

[0107] In another embodiment, disclosed herein is an oral drug delivery device, wherein at least one pharmaceutically acceptable film-forming hydrophilic polymer and optionally at least one pharmaceutically acceptable plasticizer form a drug-containing polymer component, and at least one lipophilic drug emulsified in at least one emulsifier, the emulsified drug being embedded in the polymer component, and at least one pharmaceutically acceptable release modifier and optionally at least one pharmaceutically acceptable plasticizer form a CR polymer component, which CR component may also optionally contain at least one pharmaceutically acceptable film-forming hydrophilic polymer. In this embodiment, the hydrophilic film-forming polymer and the optional plasticizer in the drug-containing polymer component and the CR polymer component may be the same or different.

[0108] Also in this additional embodiment, a drug delivery device comprising essentially a CR polymer component and a drug-containing component can be incorporated into an oral capsule (such as a soft gel capsule), which capsule may further optionally comprise and / or be coated with an immediate release (IR) drug-containing component comprising an emulsion of at least one lipophilic drug in at least one emulsifier, the IR drug-containing component optionally further comprising a suitable carrier or diluent, wherein the IR drug-containing component is in solid form, e.g., powder form or liquid form.

[0109] In another aspect, the present disclosure relates to an oral drug delivery device for controlled delivery of at least one lipophilic drug, comprising essentially two different polymer components, a drug-containing component, and a CR component. An exemplary device is described in Example 4. Briefly, the device according to this embodiment comprises: (a) a drug-containing polymer component comprising at least one pharmaceutically acceptable film-forming hydrophilic polymer component, optionally at least one pharmaceutically acceptable plasticizer, and at least one lipophilic drug emulsified in at least one emulsifier, wherein the emulsified drug is embedded in the polymer component; and (b) a controlled release (CR) polymer component comprising at least one pharmaceutically acceptable film-forming hydrophilic polymer, at least one pharmaceutically acceptable release modifier, and optionally at least one pharmaceutically acceptable wherein the hydrophilic film-forming polymer and the optional plasticizer in the drug-containing polymer component and the CR polymer component may be the same or different; and wherein the oral drug delivery device is configured for incorporation into an orally administrable dosage unit form, and wherein the oral drug delivery device is configured for enabling the at least one release-modifying agent to form a viscous gel when the dosage unit form is ingested and comes into contact with gastric and / or intestinal media, the viscous gel being configured for gradual erosion while passing through the stomach and intestines and for controllably releasing the emulsified drug in micellar form into the surrounding environment.

[0110] In embodiments of this other aspect of the invention, the drug-containing polymer component may comprise 1 to about 50 drug-containing layers, such as 1, 2, 3, 4, 5, 6, up to 10, up to 12, up to 15, up to 20, 30, 40, and up to 50 layers, each layer comprising at least one emulsified lipophilic drug and optionally the plasticizer embedded in the hydrophilic polymer component, the drug-containing layers being laminated, each of the drug-containing layers having a predetermined geometric shape, preferably having a substantially rectangular, square, or other polygonal shape or non-polygonal shape, such as, for example, an elliptical shape, preferably wherein each of the layers has the same geometric shape. The thickness of each of the drug-containing layers is from about 15 μm to about 900 μm, and the thickness of each layer may be the same or different.

[0111] In a specific embodiment of this other aspect of the present disclosure, the drug-containing polymer component and the CR polymer component can be laminated together. The laminated drug-containing polymer component and the CR polymer component can be rolled together to form a substantially cylindrical body, or formed into a body of another configuration, such as an elongated block.

[0112] Also in this other aspect of the invention, the drug delivery device can be incorporated into an oral capsule, such as a soft gel capsule, which capsule optionally further comprises and / or is coated with an immediate release (IR) drug-containing component, the immediate release (IR) drug-containing component comprising an emulsion of the at least one lipophilic drug in at least one emulsifier, the IR drug-containing component optionally further comprising a suitable carrier or diluent, wherein the IR drug-containing component is in solid form or liquid form.

[0113] In all aspects and embodiments of the present disclosure, the release modifier is a hydrophilic polymer that produces a solution with a viscosity of at least 150 mPa*sec when dissolved in water at 2% w / w. Exemplary release modifiers are, but are not limited to, hydroxypropyl cellulose (such as Klucel GF (viscosity of 150-400 mPa*sec), Klucel MF (viscosity of 4000-6500 mPa*sec), or Klucel HF (viscosity of 3000-6000 mPa*sec)), hydroxypropyl methylcellulose (HPMC) (such as HPMC K250 (viscosity of 200-300 mPa*sec), K750 (viscosity of 600-900 mPa*sec), K1500 (viscosity of 1200-1800 mPa*sec), K4M (viscosity of 2700-5040 mPa*sec), E4M (viscosity of 2700-5040 mPa*sec), E10M (viscosity of 7500-14000 mPa*sec), K15M (viscosity of 13500-25200 mPa*sec), K100M (viscosity of 75000-140000 mPa*sec) or K200M (viscosity of 150000-280000 mPa*sec)), hydroxyethyl cellulose (such as HECG (viscosity of 250-400 mPa*sec), HEC M (viscosity of 4500-6500 mPa*sec), HEC HX (viscosity of 3000-5000 mPa*sec) or HEC HHX (viscosity of 7000-11000 mPa*sec)), carboxymethyl cellulose (such as 7MF (viscosity of 400-600 mPa*sec), 7H3F (viscosity of 2000-5600 mPa*sec), 7HF (viscosity of 3000-5000 mPa*sec) or 7H4 (viscosity of 5000-9000 mPa*sec)), methyl cellulose (such as A15C (viscosity of 1125-2100 mPa*sec) or A4M (viscosity of 3000-5600 mPa*sec)), polyethylene oxide, gelatin, gums and proteins, and any mixture of at least two of them.

[0114] In all aspects and embodiments of the present disclosure, the release modifier is included in an amount of at least about 30 mg per said dosage unit form, such as, for example, at least about 30 mg, about 35 mg, about 40 mg, about 45 mg, about 50 mg and up to about 150 mg, 200 mg, 250 mg or 300 mg, 350 mg, 400 mg, 450 mg or 500 mg per dosage unit form, for example, 50 mg to 150 mg, particularly wherein the total weight of the dosage unit form is from about 250 mg to about 2000 mg, such as, for example, from about 250 mg, 300 mg, 400 mg or 500 mg to about 1500 mg, more particularly from about 300 mg to about 1200 mg, and any range therebetween. In all of these specific aspects and embodiments, the release modifier is a hydrophilic polymer that produces a solution with a viscosity of at least 150 mPa*sec when dissolved in water at 2% w / w, and the drug emulsifier is a lipid excipient with an HLB greater than 6, or a mixture of lipid excipients of which at least 50% has an HLB greater than 6.

[0115] In all aspects and embodiments of the oral drug delivery device of the present disclosure, the lipophilic drug or the poorly water-soluble drug or the water-insoluble drug is a drug with log P>2. Examples of lipophilic drugs are cannabinoids and therapeutically active derivatives thereof, including but not limited to Δ-9-tetrahydrocannabinol (Δ9-THC, THC), isotetrahydrocannabinol (iso-THC), cannabinol (CBN) and cannabidiol (CBD) and pharmaceutically acceptable derivatives thereof, and pharmaceutically active metabolites thereof, and cannabis extracts. Other cannabinoids are also mentioned herein. The lipophilic drug according to the present disclosure can also be any one of ritonavir, fenofibrate, diclofenac, flurbiprofen diazepam, vitamin E, piroxicam, lopinavir, clofazimine, but is not limited thereto.

[0116] Additional examples of therapeutically active derivatives of cannabinoids are cannabigerol (CBG), cannabichromene (CBC), cannabebenone (CBE), cannabichromene (CBL), dihydroxycannabinol (CBT), cannabigerol (CBV), tetrahydrocannabinol (THCV), cannabidivarin (CBDV), tetrahydrocannabidiol (THCBD), tetrahydrocannabigerol (THCBG), tetrahydrocannabichromene (THCBC), tetrahydrocannabidivarin (THCBDV), cannabigerol (CBCV), cannabigerol (CBGV) and cannabigerol monomethyl ether (CBGM), as well as pharmaceutically acceptable derivatives thereof, and pharmaceutically active metabolites thereof.

[0117] In addition, the lipophilic or water-insoluble drug according to the present disclosure can be a non-lipophilic or water-soluble pharmaceutical active agent that has been rendered lipophilic by modification, specifically by chemical modification, such as hydrophobic ion pairing, wherein the modified active agent has a log P>2. Such modified pharmaceutical active agents may be referred to herein as "modified drugs" or the like. Non-limiting examples of pharmaceutically water-soluble active agents that have been modified to be lipophilic or water-insoluble with a log P>2 are peptide drugs modified by pairing with hydrophobic ions. Exemplary peptide drugs are leuprolide (LHRH agonist), insulin, desmopressin, and the like, such as, for example, therapeutic antibodies. Exemplary hydrophobic ions are anionic surfactants, such as sodium docusate or sodium lauryl sulfate, or fats or sodium oleate. Hydrophobic ion pairing of a water-soluble peptide drug with a hydrophobic ion results in an increase in the lipophilicity of the ion-paired peptide, and the ion-paired peptide product exhibits an increased Log P and is therefore capable of emulsification in an emulsifier as disclosed herein.

[0118] In all aspects and embodiments of the present disclosure, the drug delivery device or dosage form thereof may contain from about 0.5 mg to about 500 mg, e.g., from about 1 mg to about 300 mg, from about 5 mg to about 300 mg, from about 5 mg to about 300 mg, or 400 mg, and any range therebetween, of the lipophilic drug / device or unit dosage form.

[0119] In all aspects and embodiments of the present disclosure, the oral drug delivery device may comprise from about 1% to about 65% w / w, such as from about 10%, 15%, 20%, 25%, 30%, 35%, or 40% to about 50%, 55%, 60%, or 65% w / w, for example, but not limited to, from about 10% to about 65% w / w of the at least one emulsified lipophilic drug. The weight ratio of lipophilic drug to emulsifier may be from about 2:1 to about 1:100, such as, for example, from about 1:1 to about 1:20 or 1:30.

[0120] About emulsifier, the feature of lipid excipient is usually its dispersibility or solubilizing ability in aqueous medium.The hydrophilicity of lipid molecule (such as fatty acid ester) is partly affected by the type (glycerol, propylene glycol, polyethylene glycol, etc.) of the polar group esterified by fatty acid.The larger the polar group, the more hydrophilic the molecule becomes.The degree of esterification also affects the hydrophilicity of lipid.For example, monoester is more hydrophilic than diester.As mentioned, the empirical system called HLB is usually used to classify lipid excipient by the affinity degree to oil phase compared with the aqueous phase in the preparation.In more detail, HLB value is 1 and is applicable to triglyceride (oil solubilizing agent).The HLB value between 6 and 10 represents the ability of lipid / oil excipient to be dispersed in water.When higher than 10, HLB value shows that solubility in water increases.In short, the HLB of every kind of excipient changes according to the type and distribution of hydrophobic group and hydrophilic group, degree of esterification (such as monoester compared with diester or triester) and their amount in final excipient.

[0121] As used herein, lipid excipients can be oils, fatty acids, glycerides, polyoxyglycerides, polyglycerol esters and polyol esters, water-insoluble surfactants, water-soluble surfactants or cosolvents, such as, for example, coconut oil, cottonseed oil, soybean oil, castor oil, corn oil, olive oil, palm oil, peanut oil, peppermint oil, poppy seed oil, rapeseed oil, hydrogenated oils, fatty acid glycerides, glyceryl behenate, glyceryl distearate, glyceryl laurate, glyceryl monooleate, glyceryl palmitate, glyceryl palmitostearate, glyceryl glyceryl esters ... Oily esters, ricinoleic acid glyceryl, stearic acid glyceryl, oleic acid polyglyceryl, 10-tetralinoleic acid polyglyceryl, behenic acid, caprylic / capric glyceride, lauric acid, linoleic acid, linolenic acid, myristic acid, palmitic acid, palmitoleic acid, ricinoleic acid, stearic acid, soybean fatty acid, oleic acid, tocopherol, vitamin E, vitamin A, glycerides, short chain triglycerides, medium chain triglycerides, long chain triglycerides, polyethylene glycol fatty acids, phospholipids, dehydrated sorbitan derivatives, hydrogenated castor oil derivatives, glycerin, Polyglycolide glycerides, polyoxyethylene glycerides, polyethylene glycol fatty acid esters, polyethylene glycol glycerol fatty acid esters, transesterification products of oils and alcohols, polyglycerolized fatty acids, polyglycerol fatty acid esters, propylene glycol fatty acid esters, glycerol mono- and diglycerides, polyoxyethylene-polyoxypropylene block copolymers, oil PEG esters, hydrogenated oil PEG-esters, fatty acid glycerides, saturated polyglycolized glycerides, polyoxygenated castor oil, caprylic / capric diglyceride, medium chain (C8 / C10) mono- and diglycerides, propylene glycol caprylic ester / caprate, propylene glycol dicaprylate / dicaprate, propylene glycol monolaurate, propylene glycol ricinoleate, propylene glycol monooleate, poloxamers (108, 124, 182, 183, 188, 212, 217, 238, 288, 331, 338, 335, 407), sorbitan monooleate, dC-tocopheryl polyethylene glycol 1000 succinate, polysorbates (20, 60, 80), and any mixture of at least two thereof.

[0122] In all aspects and embodiments of the oral drug delivery device disclosed herein, the emulsifier may be a lipid excipient having an HLB (hydrophilic-lipophilic balance) greater than 6. Lipid excipients with an HLB value greater than 6 include, but are not limited to, Gelucire 50 / 13 (stearoyl polyoxyl-32 glycerides), Gelucire 44 / 14 (lauroyl polyoxyl-32 glycerides), Gelucire 48 / 16 (polyoxyl-32 stearate (Type I) NF), Labrafil 2125 (linoleoyl polyoxyl-6 glycerides), Labrafil 1944 (oleoyl polyoxyl-6 glycerides), Labrasol (caprylocaproyl polyoxyl-8 glycerides), Kolliphor RH40 (polyoxyl-40 hydrogenated castor oil), Kolliphor EL (polyoxyl-35 castor oil), Kolliphor HS15 (polyethylene glycol-15-hydroxystearate), Kolliphor P407 / 124 / 188 (poloxamers 407 / 124 / 188), and Kolliphor PS 80 / 60 / 20 (polysorbate 80 / 60 / 20), and any mixture of at least two thereof.

[0123] In some embodiments, the emulsifier is a mixture of lipid excipients (such as those listed above) of which at least 50% have an HLB greater than 6, and the remaining lipid excipients are any of the following: oils, fatty acids, glycerides, polyoxyglycerides, polyglycerol esters and polyol esters or water-insoluble surfactants, or any mixture of at least two of them, wherein each of the remaining lipid excipients has an HLB lower than, equal to or higher than 6.

[0124] In all aspects and embodiments of the oral drug delivery device and dosage forms thereof disclosed herein, the hydrophilic film-forming polymer may be any one of the following: povidone, copovidone, polyvinyl alcohol, a hydrophilic polyacrylamide derivative, a protein, gelatin, hydroxypropyl cellulose, polyethylene oxide, amino-methacrylate copolymer NF, hydroxypropyl methylcellulose, hydroxyethyl cellulose, carboxymethyl cellulose, sodium carboxymethyl cellulose, methyl cellulose, or a polyvinyl alcohol-polyethylene glycol graft copolymer, and any combination of at least two thereof.

[0125] In all aspects and embodiments of the oral drug delivery devices and dosage forms thereof disclosed herein, the film-forming polymer and release-modifying agent together comprise from about 25 w / w% to about 85 w / w% of the device, such as from about 25 w / w% to 70 w / w%, more specifically from about 30 w / w% to about 70 w / w%.

[0126] In all aspects and embodiments of the present disclosure, the drug delivery device optionally comprises up to 20 weight / weight %, preferably up to 15 weight / weight %, more preferably about 5 weight / weight % to about 10 weight / weight % of a plasticizer. Exemplary plasticizers (plasticizers) optionally used in the oral drug delivery devices of the present disclosure and dosage unit forms thereof are, but are not limited to, polyethylene glycols, citrate esters, phthalates, glycerides, short-chain triglycerides, medium-chain triglycerides, long-chain triglycerides, olive oil, hydrogenated castor oil, triacetin, glyceryl stearate, glyceryl behenate, dibutyl sebacate, fatty alcohols, fatty acids, polyethylene glycolated fatty alcohols and polyethylene glycolated fatty acids, phospholipids, sorbitan derivatives, polysorbates, poloxamers, hydrogenated castor oil derivatives, glycerol, propylene glycol, and any combination of at least two thereof.

[0127] In some aspects and embodiments of the oral drug delivery devices and dosage unit forms thereof disclosed herein, the devices / dosage unit forms are in the form of oral tablets. Such tablets may typically contain tableting excipients or additives, which may be, but are not limited to, binders, diluents / fillers, lubricants, and glidants.

[0128] Binders are materials that bind the tablet ingredients together, thereby giving the powdered materials used in tablet manufacturing shape and mechanical strength. Binders ensure that the tablet remains intact after compression and improve the free-flowing quality of the powdered materials without delaying disintegration or dissolution. Binders are used alone or in combination with each other. They are added as dry powders or in the form of solutions thereof in suitable and appropriate solvents. Materials commonly used as binders include gum arabic, hydroxypropyl methylcellulose, polyvinyl pyrrolidone (PVP), corn starch, microcrystalline cellulose, etc.

[0129] Diluents / fillers are added to increase the size of the tablet in order to obtain a significant tablet weight that can be handled or compressed. The filler should be chemically inert, non-hygroscopic, hydrophilic, and must exhibit good compression characteristics. Lactose is a commonly used filler in formulations. Other examples of extenders used in tablet manufacturing include mannitol, dicalcium phosphate, calcium sulfate, dry starch, cellulose, kaolin, sodium chloride, anhydrous lactose, sorbitol, sucrose, etc.

[0130] Lubricants reduce friction between the powder mixture and the die walls during compression and ejection. They also prevent the mixed powder / granules from sticking to the processing areas of the tablet press, especially the punches and dies. Materials commonly used as lubricants are polyoxyethylene stearates and lauryl sulfate. Other lubricants include magnesium stearate, glyceryl behenate, stearic acid, and glyceryl palmitostearate.

[0131] Glidants are fine powders that improve the flow of a blend during tablet manufacturing by reducing friction and adhesion between particles. They enhance the movement of powders or granules within the hopper and into the die cavity prior to compression. By increasing flow rate, the resulting tablets exhibit less weight variation, resulting in a more consistent dose of the drug substance. Examples of glidants used in tablet manufacturing include colloidal silicon dioxide, talc, corn starch, etc.

[0132] In all aspects and embodiments of the oral drug delivery devices and dosage unit forms thereof of the present disclosure, all ingredients, i.e., hydrophilic film-forming polymers, CR and IR release modifiers / regulators, lipid excipients (emulsifiers), and tableting excipients are pharmaceutically and physiologically acceptable.

[0133] Representative methods for producing oral drug CR delivery devices and dosage units thereof are shown in the following examples.

[0134] In some specific embodiments, emulsified drug, film-forming polymer, release regulating polymer and optional plasticizer are all included in the drug-containing laminated member of drug delivery device, and the laminated member comprises the same layer in which the drug is embedded. The preparation of exemplary such drug delivery device and dosage unit form thereof is shown in Example 1-3, which comprises CBD as exemplary lipophilic drug as defined herein. Generally speaking, the drug is emulsified by being dissolved in a suitable emulsifier (mixed with it). The solution is added to water or an optional plasticizer aqueous solution to form a self-emulsifying agent (micelle). Suitable film-forming polymer and release regulating agent are added to the drug emulsion and mixed until dissolved. The final emulsion is poured on a suitable carrier and dried. The product is a film, which can be cut into units; each unit is laminated, processed into a suitable configuration, and assembled into an oral capsule. The immediate release portion (in powder form in Example 1-3) is prepared respectively and introduced into a capsule. The dissolution profile of the test is similar in SGF and SIF. After the IR site of immediate drug release, dissolution continues for at least 12 hours, as Figures 1 to 3 shown.

[0135] In other embodiments, the drug-containing member of the drug delivery device according to the present disclosure is prepared by hot melt extrusion, as shown in Example 5. Generally speaking, the drug (e.g., CBD) is emulsified by dissolving in (mixing with) a suitable emulsifier. A suitable film-forming polymer, a release modifier, and an optional plasticizer are all added to the drug emulsion, and all the ingredients are blended. The blend is introduced into a hot melt extruder and processed. The final product is a uniform extrudate containing the emulsified drug. An extrudate with a suitable diameter (e.g., 7 mm to 8 mm diameter) can be prepared, cut into a suitable length, and inserted into an oral capsule. Figure 5As shown, the controlled release of the active drug (CBD) lasted for about 10 hours.The IR formulation in liquid or powder form can be introduced into a capsule containing a delivery device prepared by the exemplary hot melt technique, as in Examples 1 to 3.

[0136] In other embodiments, the drug delivery device according to the present disclosure includes a drug-containing component and a controlled release (CR) component. The preparation of this type of delivery device is shown in Example 4. The drug-containing component (layer) is usually prepared by dissolving the drug in a suitable emulsifier (mixing the drug with it). The solution is added to water or an optional plasticizer aqueous solution to form a self-emulsifying agent (micelle) of the drug. A suitable film-forming polymer is added to the drug emulsion and mixed until dissolved. The final emulsion is poured on a suitable carrier and dried. The product is a film. By dissolving or dispersing the release modifier in a suitable solvent, optionally together with an appropriate amount of film-forming polymer and / or plasticizer, a drug-free CR layer is prepared separately. The mixture is poured on a suitable carrier and dried. The dried product (which is a film) is laminated on a drug-containing film, and the laminated film is wound together to obtain a substantially cylindrical laminate, which comprises two different layers, a drug-containing layer and a CR layer. The cylindrical body can then be cut into cylindrical segments of suitable length. Optionally, before lamination, the drug-containing film and the CR film can be cut into similar or different units, and the units of drug-containing film and CR film can be laminated and rolled together to form a substantially cylindrical laminate comprising two different layers, a drug-containing layer and a CR layer. In the specific embodiment shown in Example 5, the CR layer is the innermost layer. If desired, the CR layer can be the outermost layer. The direction of rolling the laminated layers can be used for a specific drug release profile. The resulting cylindrical segment or cylindrical body is introduced into an oral capsule. If desired, the IR formulation in powder form or liquid form can be added to and / or coated onto the capsule. As in Examples 4 and Figure 4 As shown, the release profile in GSF exhibited a prolonged and controlled release profile up to 10 h.

[0137] In other embodiments, the drug delivery device according to the present disclosure can be formed into a drug controlled release tablet that can be orally administered. In Example 12, an exemplary preparation of a tablet according to the present disclosure is shown, wherein the active pharmaceutical ingredient is CBD, and a release modifier is added to a drug emulsion. Therefore, for example, a tablet formulation is prepared by dissolving the drug in an emulsifier. The mixture is added to an aqueous medium optionally comprising a plasticizer to form a self-emulsifier. Release modifiers and hydrophilic film-forming polymers are added until completely dissolved. The final solvent is poured onto a suitable carrier and dried. The dried product, such as a film, is ground and sieved using a suitable sieve (e.g., a 500 micron sieve). Tableting additives are added and blended, and the blend is pressed into tablets using a suitable tablet press.

[0138] An alternative method for preparing tablets is shown in Example 13, in which a release modifier is added to the tablet mixture in powder form. In this embodiment, THC is used as the active agent. THC is dissolved in an emulsifier. The mixture is added to an aqueous medium optionally containing a plasticizer to form a self-emulsifier. A hydrophilic film-forming polymer () is added and the ingredients are mixed until all dissolved. The final solvent is poured onto a suitable carrier and dried. The dried product, such as a film, is ground and sieved using a suitable sieve (e.g., a 500 micron sieve). Tableting additives are added together with the release modifier and all substances are blended. The blend is compressed into tablets using a suitable tablet press.

[0139] Alternatively, tablets can be prepared by hot melt extrusion, as shown in Example 14. CBD is used as the active agent. A hot melt extrudate is prepared as described above and in Example 5. The extrudate is ground and sieved using a suitable sieve (e.g., a 500 micron sieve). Tableting excipients and release modifiers are added. All ingredients are mixed. The blend is compressed into tablets using a suitable tablet press.

[0140] In all aspects and embodiments of the present disclosure, the disclosed oral drug delivery device or pharmaceutical dosage unit form thereof, wherein the pharmaceutical drug is at least one cannabinoid or cannabis extract, can be used in a method for treating, alleviating, and preventing the exacerbation of a disease, disorder, or condition responsive to cannabinoid treatment in a subject in need thereof, the method comprising orally administering the drug delivery device or pharmaceutical dosage unit form thereof to the subject. The disease, disorder, or condition responsive to cannabinoid treatment can be any of the following: anorexia associated with weight loss in patients with AIDS, nausea and vomiting associated with cancer chemotherapy, pain, anxiety, depression, muscle spasms, arthritis and rheumatism, multiple sclerosis and other neuromuscular inflammatory conditions, inflammatory bowel diseases such as Crohn's disease and colitis, post-traumatic stress disorder (PTSD) or epileptic seizures, Parkinson's disease, spinal cord injury, fibromyalgia, Alzheimer's disease and dementia, or any other condition responsive to cannabinoid treatment.

[0141] The present disclosure also relates to a method of increasing the absorption time of an active pharmaceutical ingredient (API) having a log P>2 in a subject in need thereof by administering to said subject a device or a pharmaceutical dosage unit form according to all described aspects and embodiments thereof.

[0142] In all aspects and embodiments of the subject matter disclosed herein, the methods of treatment and therapeutic uses of the drug delivery devices and drug dosage unit forms disclosed herein may include administering the dosage form once, twice, or three times a day or less frequently (such as, for example, once or twice a week). In addition, administration may be performed under fed as well as fasting conditions.

[0143] In all aspects and embodiments, the present disclosure also provides a specific oral delivery device for lipophilic or poorly water-soluble drugs (including but not limited to cannabinoids as defined herein) and their dosage forms, wherein the drug is in emulsified form or mixed with at least one emulsifier. The disclosed lipophilic drug formulation can provide a stable drug plasma level for a longer duration, prolonging drug availability, thereby leading to a potential improvement in the efficacy of the active ingredient. The proposed drug delivery device and its dosage unit form can continuously and effectively expose target organs and tissues to the drug, the formulation releases the drug in the stomach, and thereafter releases the drug in the duodenum and intestines for an extended period of time, such as, for example, from a few hours after administration to about 12 hours after administration, and at most 24 hours after administration, typically from about 3 hours, and at most 4 hours, 5 hours, 6 hours, 7 hours, 8 hours, 9 hours, 10 hours, 11 hours, any one of 12 hours, and at most 15 hours. The disclosed drug delivery device and its dosage unit form can improve therapeutic efficacy while reducing the number of daily doses. The proposed drug delivery device and its dosage unit form provide the use of a predetermined dose of active drug. Importantly, the drug delivery device according to all aspects of the present disclosure and embodiment can be general in terms of the rate of release of active ingredient. Mainly, although the release is controlled release, its rate can be controlled by the specific features of the delivery device disclosed herein. These features can be the load of the drug, the amount of the modified release agent, the drug emulsion or the features of the mixture with the emulsifier, such as the geometry and structure of a specific emulsion formulation, the ratio of API to emulsifier, micellar size, device or its layer (when present), as described in detail below and illustrated in the following examples. Controlled release can be carried out before the quick release of the component included in the disclosed dosage unit form of the disclosed drug delivery device or carried out simultaneously with it.

[0144] Also disclosed herein are pharmaceutical dosage forms, such as dosage unit forms of cannabinoids. Essentially, the pharmaceutical dosage forms as disclosed herein comprise a controlled release cannabinoid delivery device incorporated into an oral pharmaceutical capsule, which can be a hard gel or soft gel capsule.

[0145] The present disclosure also provides specific drug delivery devices and dosage unit forms thereof for cannabinoids, namely, CR and / or combined CR and IR delivery devices or dosage unit forms thereof for oral administration of cannabinoids as disclosed herein. The disclosed cannabinoid formulations can provide stable plasma levels of the cannabinoid drug for a longer duration, prolonging drug availability, thereby potentially improving the efficacy of the active ingredient. As mentioned, the proposed cannabinoid delivery devices and dosage unit forms thereof can provide continuous and effective exposure of target organs and tissues to the drug, can improve therapeutic efficacy while reducing the number of daily doses, can provide for the use of predetermined doses of the active cannabinoid ingredient, and can be versatile in terms of the release rate of the active ingredient.

[0146] definition

[0147] The terms "drug," "active substance," "API" (active pharmaceutical ingredient) or "active principal" or "active ingredient" or "active agent" used interchangeably herein refer to a pharmaceutically active substance that provides a therapeutic / physiological effect to a patient, and may also refer to a mixture of at least two of them.

[0148] As used herein, the terms "lipophilic drug" or "poorly water-soluble drug" or "lipophilic modified drug" or "poorly water-soluble modified drug" refer interchangeably to a drug that is insoluble or only slightly soluble in water or a drug that has been chemically modified to become insoluble or only slightly soluble in water, and specifically to a "drug having a LogP>2" or "modified drug having a LogP>2" or "drug modified, particularly chemically modified to have a LogP>2", which as used herein interchangeably refer to a drug or modified drug whose logarithm of the partition coefficient is greater than 2, which partition coefficient is defined as a specific ratio of the solute concentration between water and octanol.

[0149] As used interchangeably herein, the terms "cannabinoid," "cannabinoid derivative," or "cannabinoid metabolite" refer to any active ingredient of cannabis. As defined herein, a "cannabinoid" may also be a cannabinoid that is not derived from cannabis. As used interchangeably herein, the terms "cannabinoid," "cannabinoid derivative," or "cannabinoid metabolite" also refer to any mixture of at least two cannabinoids, as defined herein.

[0150] As used interchangeably herein, the terms "cannabis extract" or "cannabis concentrate" refer to an extract of the cannabis plant containing cannabinoids and optionally terpenes and / or other compounds.

[0151] As used herein, the term "drug release formulation" refers to any composition of matter that contains a drug and releases the drug after administration to a subject.

[0152] The terms "emulsified drug" or "drug emulsified in an emulsifier" or "drug emulsion" or "emulsion of drug in emulsifier" or "drug in emulsified form" and the like, which are used interchangeably herein, refer to a poorly water-soluble drug dissolved in or mixed with an emulsifier and which, upon dilution in an aqueous medium such as gastric fluid (GF), intestinal fluid (IF) or gastrointestinal fluid (GIF), can form a fine oil-in-water (o / w) emulsion or microemulsion. When referring to a defined amount / quantity of "emulsified drug" or "drug emulsion in an emulsifier" or "drug emulsion" or "emulsion of drug in emulsifier" or "drug in emulsified form" and the like, which are used interchangeably herein, the amount refers to the combined amount of both the drug and the emulsifier. Thus, both the terms "drug emulsion" and "mixture of drug and emulsifier" are used herein.

[0153] As used interchangeably herein, the terms "emulsifying agent" or "emulsifier" refer to a compound or substance that concentrates at the interface of two immiscible phases (usually oil and water). It reduces the interfacial free energy, reduces the interfacial tension between the phases, and forms a film or barrier around the droplets of the immiscible discontinuous phase as they form, thereby preventing the droplets from coalescing. The term "emulsifier" includes, but is not limited to, oils, glycerides, water-insoluble surfactants, water-soluble surfactants, or cosolvents, or any mixture of at least two of these, as described in detail herein.

[0154] As used interchangeably herein, "dosage unit," "dosage form," "oral dosage unit," "dosage unit form," "oral dosage unit form," and the like refer to solid dosage forms known in the art and are used interchangeably herein. The dosage form is intended for oral use, i.e., swallowing (ingestion) by a patient / subject in need thereof. The terms "oral capsule" and "peroral capsule" are used interchangeably herein.

[0155] As used herein, with respect to all aspects and embodiments of the disclosed drug delivery devices and dosage forms thereof, and with respect to various components thereof, such as drug-containing components (or layers or members), controlled release (CR) components (or layers or members), immediate release (IR) components (or layers or members or powders), or various mixtures of components (such as, but not limited to, mixtures of active drugs and emulsifiers), the term "solid" should be considered to mean a composition or article that is solid at room temperature and is malleable or pliable into a desired form. The terms "solid," "ductile solid," and "pliable solid" are used interchangeably herein.

[0156] The term "drug delivery device" or similar terms, as used interchangeably herein, refers to a component of the disclosed dosage unit that comprises at least one emulsified drug. A "drug delivery device" can be formed into a dosage unit form, as described herein.

[0157] As used herein, "controlled release" (CR) or "extended release" refers to a manner in which a dosage form, dosage unit form, drug delivery device, etc. releases a drug (such as but not limited to a cannabinoid) at a controlled rate in an amount required to achieve a desired serum level of the drug (such as but not limited to a cannabinoid) and produce a prolonged or sustained pharmacological effect over an extended, programmable time interval (specifically, a predetermined extended time interval).

[0158] As used interchangeably herein, the terms "release modifier" and "release regulating agent" are generally polymeric agents that cause a drug to be released from a drug delivery device or component thereof or dosage form in a manner different from that in their absence.

[0159] As used interchangeably herein in conjunction with controlled-release, the phrases "extended period of time," "extended time interval," and the like refer to a period of time during which at least 80% of the dose of drug contained in a dosage unit or drug delivery device is delivered, which lasts from a few hours after administration to about 12 hours after administration, and up to 24 hours, typically about 3 hours, and up to any of 4 hours, 5 hours, 6 hours, 7 hours, 8 hours, 9 hours, 10 hours, 11 hours, 12 hours, and up to 15 hours.

[0160] As used herein, the phrase "immediate release" (IR) refers to a dosage form or drug delivery device that releases the drug immediately upon exposure to or contact with the gastric medium. "Immediately after exposure to gastric fluid" is understood to mean release within a maximum of 2 hours from the exposure or contact. Specifically, the immediate release of the drug is within about 30 minutes to about 60 minutes from exposure to or contact with gastric fluid. As used herein, the term "immediate release (IR) component" is considered to mean a component from which the drug is released in the described manner. The IR component used herein can be in a coated form (e.g., on a capsule as described herein) or a powder form (e.g., in a capsule as described herein) or any other suitable form.

[0161] The term "stable" plasma or serum level of a drug, such as, but not limited to, a cannabinoid or its active derivative or metabolite as defined herein, is taken to mean a therapeutically effective plasma level of the active cannabinoid and / or its active metabolite over a suitable period of time. Specifically, a stable plasma level may, for example, refer to a continuous therapeutically effective level, a steady-state level, etc.

[0162] As known in the art and used herein, the term "AUC" refers to the area under the curve (mathematically known as the definite integral) in a plot of drug concentration in plasma versus time. In practice, drug concentrations are measured at certain discrete time points, and the trapezoidal rule is used to estimate AUC. AUC (from zero to infinity) represents the total drug exposure over time. Term C max It is the maximum (or peak) serum concentration of a drug achieved in a specified compartment or test area of ​​the body after administration of the drug. The relevant pharmacokinetic parameter t max It is observed that C max time.

[0163] As used herein, "simulated gastric fluid" ("SGF") and "simulated intestinal fluid" ("SIF") refer to "Simulated Gastric Fluid, TS" and "Simulated Intestinal Fluid, TS" solutions as defined in 30 USP, but without the corresponding enzymes.

[0164] As used interchangeably herein, "gastric medium," "gastric fluid," and "intestinal medium" refer to the biological media of the stomach and intestine, respectively, or artificial media used to simulate the environment of the stomach or intestine, such as, but not limited to, "simulated gastric fluid" ("SGF") and "simulated intestinal fluid" ("SIF").

[0165] As used herein, the term "aqueous medium" refers to a water-based liquid medium, specifically "gastric medium", "gastric juice", "intestinal medium" and distilled water as defined above.

[0166] As used herein, the terms "biodegradable" or "degradable" and "bioerodible" or "erodible" are intended to be capable of biochemical, chemical, and / or physical processing, reduction, or decomposition within a patient's body within a period ranging from seconds to days following ingestion of the dosage unit form or delivery device. The terms "complete degradation / biodegradation," "substantially complete degradation / biodegradation," or "complete erosion / bioerosion," or the terms used interchangeably herein, mean at least 70%, 80%, 90%, and up to 100% degradation / erosion and disappearance of the delivery device or dosage form.

[0167] As used interchangeably herein, the terms "inert" or "inactive" or "inactive ingredient" or "inert ingredient" or "inactive excipient" or "inert excipient" refer to components of a delivery device or dosage unit form that, when administered in reasonable amounts to a subject, does not immediately react with or adversely affect the properties of the drug or active ingredient, or cause any biological effect when administered to the subject. General examples of such components are described in "The Handbook of Pharmaceutical Excipients," 4th edition, Rowe, Sheskey, and Weller, Pharmaceutical press, 2003. An additional exemplary list is the U.S. Food and Drug Administration's Inactive Ingredients Guide.

[0168] The terms "film" and "layer," sometimes followed by the term "polymer," are used interchangeably herein in connection with some or all of the components of the drug delivery devices, laminated drug delivery devices, and dosage unit forms thereof, their preparation, and use as described herein, as the context dictates.

[0169] As used herein, the terms "drug-containing layer", "drug-containing component" or "drug-containing polymer component" are taken to mean a polymer film or polymer layer, respectively, comprising at least one polymer as defined herein and at least one drug (cannabinoid).

[0170] As used herein, the terms "emulsified drug-containing layer," "emulsified drug-containing component," or "emulsified drug-containing polymer component" are taken to mean a polymer film or polymer layer or polymer member or component, respectively, comprising at least one polymer and at least one drug (cannabinoid) in emulsified form. These terms may relate to a component or layer of a delivery device and also to an IR layer of a delivery device or dosage unit form.

[0171] As used herein, the term "polymer" refers to polymeric materials as known in the art and described in more detail below, but is also sometimes used in the context of more general aspects to encompass polymeric compositions of one or more polymers and optionally at least one plasticizer; that is, inert materials contained in polymeric layers, members, or components of the disclosed drug delivery devices and / or dosage unit forms thereof.

[0172] As used herein, the term "polymer component" or "drug-containing polymer component / member / film / layer" is taken to mean a portion of a drug delivery device in which the drug and optionally other pharmaceutically active agents are contained.

[0173] Unless the context clearly indicates otherwise, as used herein, the term "lamination" or the like means, with respect to two or more polymer components, components, films or layers, the step of layering, stacking, filling, piling up, superimposing at least one polymer component / component / film / layer on at least one additional polymer component / component / film / layer, bringing them into close contact, and applying a pressure sufficient to produce a uniform structure under suitable temperature and environmental conditions, wherein the boundaries of the individual layers are no longer easily distinguishable, or the individual layers are irreversibly bonded to adjacent layers. Lamination is typically between polymer sheets having similar to identical compositions and similar thicknesses, but films having significantly different thicknesses but similar or identical compositions may also be laminated. In addition, if at least two of such films are similar or identical in composition and / or thickness, and if the boundaries of the individual layers in the resulting structure are not easily distinguishable or the individual layers are irreversibly bonded to adjacent layers, lamination may also be performed on multiple films of different compositions. The term "easily distinguishable" should be understood to mean that within the capabilities of those skilled in the art, the individual layers can be distinguished without the need for microscopy or spectroscopy.

[0174] As referred to herein, a "patient" or "subject" is an animal, particularly a human, to whom the drug delivery devices and dosage units thereof disclosed herein can be administered.

[0175] As used herein, the term "treat" and forms thereof (such as "treatment" or "treated") are understood to mean preventing symptoms (e.g., pain or nausea), or preventing worsening, or arresting, or alleviating, or ameliorating or curing a patient's disease or disorder or the symptoms associated therewith.

[0176] As used herein, the term "ratio" refers to a weight ratio (also referred to as weight / weight), unless otherwise indicated.

[0177] As used herein, the term "suitable" is considered to mean having properties capable of providing the defined result.

[0178] As used herein, "about" generally refers to an approximate value. When referring to a drug dosage in milligrams, "about" should be understood to include a range of ±15% of that value. When referring to other values, the term should be understood to include a range of ±15% of that value, such as ±15%, ±12%, ±10%, ±8%, ±5%, ±2%, or ±1%.

[0179] As used in the specification and claims, the forms "a," "an," and "the" include singular as well as plural references unless the context clearly dictates otherwise.

[0180] Throughout the specification and claims that follow, unless the context requires otherwise, the word "comprise" and variations such as "comprises" and "comprising", will be understood to imply the inclusion of a stated integer or step or group of integers or steps but not the exclusion of any other integer or step or group of integers or steps.

[0181] Description of non-limiting embodiments

[0182] Example 1: CBD 5 mg IR and 20 mg CR Formulation 1

[0183] CR fraction:

[0184] The following shows an exemplary preparation of an emulsion containing CBD and the preparation of a CR (controlled release) unit dosage form containing CBD micelles. The composition of the individual units is summarized in Table 1.

[0185] Table 1:

[0186] CR Preparation 1 mg / unit % in the preparation CBD 20 3.2 Peceol 42 6.8 Kolliphor EL 98 15.8 Klucel EF 275 44.4 Klucel GF 135 21.8 PEG 400 50 8.1 total 620 100

[0187] CBD was dissolved in a mixture of Peceol and Kolliphor heated to 70 °C using a magnetic stirrer to obtain a clear solution.

[0188] In a 0.2 L planetary mixer, PEG 400 was dissolved in water. The clear CBD solution was added to form a self-emulsification. Klucel EF and Klucel GF were added and dissolved in the aqueous mixture for approximately 90 minutes.

[0189] The final emulsion was cast on PET (Mylar) using a benchtop caster with a blade spacing of 950 μm. TM ) screen. The cast emulsion was dried in an oven at 60° C. for about 60 minutes. The dried product was a film with a thickness of about 120 μm.

[0190] Six sheets of dry films were stacked one on top of the other and manually laminated to give a laminated film having a thickness of approximately 750 μm.

[0191] The laminated film was punched into 21 mm x 45 mm rectangular units, each unit having a weight of approximately 600 mg to 650 mg, and each unit contained 20 mg of CBD.

[0192] Each unit was rolled into a cylindrical shape, and each cylinder was inserted into a 00 hard gelatin capsule.

[0193] IR fraction

[0194] An exemplary preparation of a lipid-based powder containing CBD for IR (immediate release) is shown below. The materials used to prepare the powder formulation and the amounts present in a single capsule containing the powder unit are summarized in Table 2.

[0195] Table 2:

[0196] Powder preparation 1 mg / unit CBD 5 Peceol 6 Kolliphor EL 14 AVICEL 102 75

[0197] CBD was dissolved in a mixture of Peceol and Kolliphor heated to 70 °C using a magnetic stirrer to obtain a clear solution.

[0198] Avicel 102 was added to the solution and mixed for about 30 minutes to obtain a homogeneous powder.

[0199] 100 mg of powder containing 5 mg of CBD was inserted into capsules containing the CR fraction to obtain the final unit dosage form.

[0200] Each final unit contains 5mg IR CBD and 20mg CR CBD

[0201] The final unit was tested for dissolution profile.

[0202] Dissolution curve:

[0203] The dissolution of capsules containing IR and CR fractions was tested using the following method:

[0204] Dissolution parameters:

[0205] Culture medium:

[0206] Simulated gastric fluid (SGF), pH 1.2 or

[0207] Simulated intestinal fluid (SIF), pH 6.8

[0208] Temperature: 37±0.5℃

[0209] Equipment: 20 baskets, 100 RPM

[0210] Volume: 900ml

[0211] Sampling time points: 0.5; 1; 2; 3; 4; 5; 6; 8; 10; 12 hours

[0212] At each sampling point, 5 ml aliquots of the solution were sampled from the container. The samples were tested for CBD content using an HPLC method.

[0213] HPLC parameters:

[0214]

[0215]

[0216] The dissolution test results of Example 1 are Figure 1 As can be seen, the CBD release profiles were similar in both SGF and SIF. The release profiles were linear, exhibiting extended release and controlled release profiles up to 14 hours.

[0217] Example 2: CBD 5 mg IR and 20 mg CR Formulation 2

[0218] CR fraction:

[0219] The following shows an exemplary preparation of an emulsion containing CBD and a preparation of a CR dosage form containing CBD micelles. The composition of the individual units is summarized in Table 3.

[0220] Table 3:

[0221] CR Preparation 2 mg / unit % in the preparation CBD 20 3.2 Peceol 42 6.8 Kolliphor EL 98 15.8 Klucel EF 345 55.7 Klucel GF 65 10.5 PEG 400 50 8.1 total 620 100

[0222] CBD was dissolved in a mixture of Peceol and Kolliphor heated to 70 °C using a magnetic stirrer to obtain a clear solution.

[0223] In a 0.2 L planetary mixer, PEG 400 was dissolved in water.

[0224] The CBD clear solution was added to form a self-emulsification. Klucel EF and Klucel GF were added and dissolved in water for approximately 60 minutes.

[0225] The final emulsion was cast on PET (Mylar) using a benchtop caster with a blade spacing of 1000 μm. TM ) screen. The cast emulsion was dried in an oven at 60° C. for about 60 minutes. The dried product was a film with a thickness of about 150 μm.

[0226] Five sheets of dry film were stacked one on top of the other and laminated manually. The thickness of the laminated film was about 750 μm.

[0227] The laminated film was punched into 21 mm x 45 mm rectangular units, each unit having a weight of 600 mg to 650 mg, and each unit contained 20 mg of CBD.

[0228] The units were rolled into a cylindrical shape and each cylinder was inserted into a 00 hard gelatin capsule.

[0229] IR fraction

[0230] The IR score was the same as that of Example 1.

[0231] Each final unit contains 5mg IR CBD and 20mg CR CBD.

[0232] The final unit was tested using the same method and parameters as described in Example 1 to define the dissolution profile.

[0233] The dissolution test results of Example 2 are Figure 2 As shown in Figure 2 As can be seen in Figure 3, the CBD release profiles were similar in both SGF and SIF. The release profiles were linear, exhibiting extended release and controlled release profiles up to 12 hours.

[0234] Example 3: CBD 25 mg IR and 225 mg CR Formulation 3

[0235] CR fraction:

[0236] The following shows an exemplary preparation of an emulsion containing CBD and a preparation of a CR dosage form containing CBD micelles. The composition of the individual units is summarized in Table 4.

[0237] Table 4:

[0238] CR Preparation 3 mg / unit % in the preparation CBD 225 30.2 Lauroyl Polyoxyl-32 Glyceryl 225 30.2 CMC 7L2P 135 13.4 HPMC K1500 100 18.1 Poloxamer 407 60 8.1 total 745 100

[0239] CBD was dissolved in lauroyl polyoxyl-32 glyceride heated to 70°C using a magnetic stirrer to obtain a clear solution.

[0240] In a 0.2 L planetary mixer, Poloxamer 407 was dissolved in water.

[0241] The CBD clear solution was added to form a self-emulsification. CMC and HPMC were added and dissolved in water for about 60 minutes.

[0242] The final emulsion was cast on PET (Mylar) using a benchtop caster with a blade spacing of 1100 μm. TM ) screen. The cast emulsion was dried in an oven at 60° C. for about 60 minutes. The dried product was a film with a thickness of about 150 μm.

[0243] Five sheets of dry film were stacked one on top of the other and laminated manually. The thickness of the laminated film was about 750 μm.

[0244] The laminated film was punched into 21 mm x 45 mm rectangular units, each unit having a weight of 720 mg to 780 mg, and each unit contained 225 mg of CBD.

[0245] Each unit was rolled into a cylindrical shape, and each cylinder was inserted into a 00 hard gelatin capsule.

[0246] IR fraction

[0247] An exemplary preparation of a lipid-based powder containing CBD for IR is shown below. The materials used to prepare the powder and the amounts present in a single capsule containing a unit of the powder are summarized in Table 5.

[0248] Table 5:

[0249] Powder preparation 2 mg / unit CBD 25 Kolliphor EL 25 AVICEL 102 70

[0250] CBD was dissolved in Kolliphor EL heated to 70 °C using a magnetic stirrer to obtain a clear solution.

[0251] Avicel 102 was added to the solution and mixed for about 30 minutes to obtain a homogeneous powder.

[0252] 120 mg of powder containing 25 mg of CBD was inserted into the capsules containing the CR fraction.

[0253] Each final unit contains 25mg IR CBD and 225mg CR CBD

[0254] The final unit is tested to define the dissolution profile.

[0255] Dissolution curve:

[0256] The dissolution of capsules containing IR and CR fractions was tested using the same method and parameters as described in Example 1.

[0257] The dissolution test results of Example 3 are Figure 3 The CBD release profiles in SGF and SIF were similar. The release profiles were linear, exhibiting extended release and controlled release for up to 12 hours.

[0258] Example 4: CBD 10 mg CR Formulation 4 - Separate Layers

[0259] An exemplary preparation of an oral CR dosage form containing CBD micelles is shown below. Each unit contains 2 different layers that are laminated together to form the final unit: a drug layer and a CR layer

[0260] Drug layer:

[0261] The following shows an exemplary preparation of an emulsion containing CBD and a dry film containing CBD micelles. The composition of the individual units is summarized in Table 6.

[0262] Table 6:

[0263] Drug layer (without CR) formulation 1 mg / unit % in the preparation CBD 10 1.9 Peceol 42 7.9 Kolliphor EL 98 18.5 Klucel EF 350 66.0 PEG 400 30 5.7 total 530 100

[0264] CBD was dissolved in a mixture of Peceol and Kolliphor heated to 70 °C using a magnetic stirrer to obtain a clear solution.

[0265] In a 0.2 L planetary mixer, dissolve PEG 400 in water. Add the clear CBD solution to form a self-emulsification. Add Klucel EF and dissolve in water for approximately 20 minutes.

[0266] The final emulsion was cast on PET (Mylar) using a benchtop caster with a blade spacing of 1000 μm. TM ) screen. The cast emulsion was dried in an oven at 60° C. for about 60 minutes. The dried product was a film with a thickness of about 120 μm.

[0267] Four sheets of dry film were stacked one on top of the other and laminated manually. The thickness of the laminated film was about 500 μm.

[0268] CR layer:

[0269] An exemplary preparation of a dispersion containing a modified release agent and the preparation of a dry layer (without drug) for a CR is given below. The composition of the individual units is summarized in Table 7.

[0270] Table 7:

[0271] CR layer (without drug) formulation 1 mg / unit HPMC K100M 75 Klucel EF 75 PEG 400 30

[0272] In a 0.2 L planetary mixer, PEG 400 + Klucel EF was dissolved in ethanol.

[0273] HPMC K100M was added and dispersed in ethanol for approximately 30 minutes.

[0274] The final dispersion was cast on PET (Mylar) using a benchtop caster with a blade spacing of 1000 μm. TM ) on a mesh. The cast dispersion was dried in an oven at 50° C. for about 15 minutes. The dried product was a film with a thickness of about 200 μm.

[0275] laminated

[0276] The HPMC layer was manually laminated onto the drug layer. The laminated film was punched into 21 mm x 45 mm rectangular units, each unit having a weight of 700 mg, and each unit contained 10 mg of CBD.

[0277] Each unit was rolled into a cylindrical shape with the HPMC layer as the inner layer and the drug layer as the outer layer.

[0278] The final unit is inserted into 00 hard gelatin capsules.

[0279] The final unit is tested to define the dissolution profile.

[0280] Dissolution curve:

[0281] The dissolution of capsules containing the laminated drug+CR layer was tested using the same method and parameters as described in Example 1.

[0282] Example 4 Dissolution test results in SGF Figure 4 Shown in.

[0283] The release profile showed extended and controlled release up to 10 hours.

[0284] Example 5: CBD 20 mg CR Formulation 5 - Prepared by HME (Hot Melt Extrusion)

[0285] CR fraction:

[0286] An exemplary preparation of an oral CR dosage form containing CBD micelles is shown below. The composition of a single unit is summarized in Table 8 (same as Table 1).

[0287] Table 8:

[0288]

[0289]

[0290] CBD was dissolved in a mixture of Peceol and Kolliphor heated to 70 °C using a magnetic stirrer to obtain a clear solution.

[0291] The solution was manually mixed with other excipients before the hot-melt extrusion process.

[0292] The final blend was inserted into a MC 15HT microcompounder (Xplore) hot melt extruder and processed under the following conditions:

[0293] Temperature: 180℃.

[0294] Rotation: 50RPM.

[0295] Processing time: 5 minutes.

[0296] Screw Configuration: Counter-rotating.

[0297] The final product was a uniform extrudate with a diameter of 3 mm.

[0298] The extrudate was cut into units of approximately 7 cm in length, weighing approximately 650 mg, each unit containing 20 mg of CBD.

[0299] The unit is inserted into a 00 hard gelatin capsule.

[0300] The final unit is tested to define the dissolution profile.

[0301] Dissolution curve:

[0302] The dissolution rate of the capsules was tested using the same method and parameters as described in Example 1.

[0303] The dissolution test results of Example 5 in SGF are Figure 5 Shown in.

[0304] The release profile was linear, exhibiting extended release and controlled release up to 10 hours.

[0305] The final extrudates were examined in a scanning electron microscope according to the following procedure:

[0306] SEM images of the cross-section of the extrudate (coated with gold) were taken using a Zeiss Ultra-Plus system with an accelerating voltage of 4.0 kV. Images were taken using a secondary emission electron (SE) detector. Figure 5A The SEM images confirmed that the CBD was in the form of an emulsion in the final extrudate.

[0307] Example 6: THC 15mg CR

[0308] The following shows an exemplary preparation of an emulsion containing THC and the preparation of an oral CR dosage form containing THC micelles. The composition of the individual units is summarized in Table 9.

[0309] Table 9:

[0310] CR Preparation 4 mg / unit THC 15 sesame oil 15 Labrasol 135 Klucel EF 250 CMC 7MF 75 PEG 400 40

[0311] THC was dissolved in a mixture of Labrasol and sesame oil heated to 70 °C using a magnetic stirrer to obtain a clear solution.

[0312] In a 0.2 L planetary mixer, PEG 400 was dissolved in water. The clear THC solution was added to form a self-emulsification. Klucel EF and CMC were added and dissolved in water for about 60 minutes. The final emulsion was cast on PET (Mylar) using a benchtop casting machine with a blade spacing of 1000 μm. TM) screen. The cast emulsion was dried in an oven at 60° C. for about 60 minutes. The dried product was a film with a thickness of about 150 μm.

[0313] Five sheets of dry film were stacked one on top of the other and manually laminated. The laminated film had a thickness of approximately 750 μm. The laminated film was punched into 21 mm x 45 mm rectangular units, each weighing 600 mg to 650 mg, and containing 15 mg of THC.

[0314] These units were rolled into cylindrical shapes and individually inserted into 00 hard gelatin capsules.

[0315] Example 7: Plant Cannabis Extract 30mg CR

[0316] The following shows an exemplary preparation of an emulsion containing a plant cannabis extract and an oral CR dosage form containing micelles of a plant cannabis extract. The composition of the individual units is summarized in Table 10.

[0317] Table 10.

[0318]

[0319] The cannabis extract was dissolved in a mixture of Labrafac and Labrafil heated to 70 °C using a magnetic stirrer to obtain a clear solution.

[0320] In a 0.2 L planetary mixer, PEG 400 was dissolved in water and the clear cannabis extract solution was added to form a self-emulsification. HPMC E3 and K4M were added and dissolved in water for approximately 60 minutes.

[0321] The final emulsion was cast on PET (Mylar) using a benchtop caster with a blade spacing of 1000 μm. TM ) screen. The cast emulsion was dried in an oven at 60° C. for about 60 minutes. The dried product was a film with a thickness of about 150 μm.

[0322] Five sheets of dry film were stacked one on top of the other and manually laminated. The thickness of the laminated film was about 750 μm. The laminated film was punched into 21 mm × 45 mm rectangular units, each unit having a weight of 500 mg to 550 mg.

[0323] These units were rolled into cylindrical shapes and individually inserted into 00 hard gelatin capsules.

[0324] Example 8: Plant Cannabis Extract 300mg CR

[0325] The following shows an exemplary preparation of an emulsion containing a plant cannabis extract and an oral CR dosage form containing micelles of a plant cannabis extract. The composition of the individual units is summarized in Table 11.

[0326] Table 11:

[0327] CR Preparation 6 mg / unit Plant hemp extract 300 GELUCIRE 48 / 16 200 Klucel EF 180 Methylcellulose A4M 80 Propylene glycol 70

[0328] The plant cannabis extract was dissolved in Gelucire 48 / 16 heated to 70 °C using a magnetic stirrer to obtain a clear solution.

[0329] In a 0.2 L planetary mixer, dissolve propylene glycol in water. Add the clear cannabis solution to form a self-emulsifying solution. Add Klucel EF and methylcellulose A4M and dissolve in water for approximately 60 minutes.

[0330] The final emulsion was cast on PET (Mylar) using a benchtop caster with a blade spacing of 1100 μm. TM ) screen. The cast emulsion was dried in an oven at 60° C. for about 60 minutes. The dried product was a film with a thickness of about 150 μm.

[0331] Five sheets of dry film were stacked one on top of the other and manually laminated. The laminated film had a thickness of approximately 750 μm. The laminated film was punched into 21 mm x 45 mm rectangular units, each weighing 800 mg and containing 300 mg of plant cannabis extract.

[0332] These units were rolled into cylindrical shapes and individually inserted into 00 hard gelatin capsules.

[0333] Example 9 - Ritonavir 100 mg CR

[0334] The following shows an exemplary preparation of an emulsion containing ritonavir and the preparation of an oral CR dosage form containing ritonavir micelles. The composition of the individual units is summarized in Table 12.

[0335] Table 12:

[0336] CR Preparation 7 mg / internal unit Ritonavir 100 Labrasol 60 Kolliphor RH 40 60 PVP K30 180 Klucel GF 150 Poloxamer 407 35

[0337] Ritonavir was dissolved in the Labrasol and Kolliphor mixture using a magnetic stirrer to obtain a clear solution.

[0338] In a 0.2 L planetary mixer, Poloxamer 407 was dissolved in water.

[0339] Ritonavir clear solution was added to form a self-emulsion, PVP K30 and Klucel GF were added and dissolved for 90 minutes.

[0340] The final emulsion was cast onto silicon-coated PET (Mylar) using a benchtop caster with a blade spacing of 1200 μm. TM ) screen. The cast emulsion was dried in an oven at 60° C. for about 90 minutes. The dried product was a film having a solvent content (based on a drying loss test) of no more than 6% and a thickness of about 150 μm.

[0341] Five sheets of dry film were stacked one on top of the other and laminated manually. The thickness of the laminated film was about 750 μm.

[0342] The laminated film was punched into 21 mm x 45 mm rectangular units, each unit having a weight of 600 mg to 650 mg, and each unit contained 100 mg of ritonavir.

[0343] These units were rolled into cylindrical shapes and individually inserted into 00 hard gelatin capsules.

[0344] Example 10 - Fenofibrate 50 mg CR

[0345] The following shows an exemplary preparation of an emulsion containing fenofibrate and the preparation of an oral CR dosage form containing fenofibrate micelles. The composition of the individual units is summarized in Table 13.

[0346] Table 13:

[0347]

[0348] Dissolve fenofibrate in the Maisine and Tween mixture using a magnetic stirrer to obtain a clear solution.

[0349] In a 0.2 L planetary mixer, TEC was dissolved in water. The clear fenofibrate solution was added to form a self-emulsification, and CMC 7L2P and HPMC K15M were added and dissolved for 90 minutes. The final emulsion was cast on silicon-coated PET (Mylar) using a benchtop casting machine with a blade spacing of 1200 μm. TM ) screen. The cast emulsion was dried in an oven at 60° C. for about 90 minutes. The dried product was a film having a solvent content (based on a drying loss test) of no more than 6% and a thickness of about 150 μm.

[0350] Five sheets of dry film were stacked one on top of the other and manually laminated. The laminated film had a thickness of approximately 750 μm. The laminated film was punched into 21 mm × 45 mm rectangular units, each weighing 500 mg to 600 mg and containing 50 mg of fenofibrate. These units were rolled into a cylindrical shape and individually inserted into 00 hard gelatin capsules.

[0351] Comparative Example 11-(CBD+THC IR Film)

[0352] IR film:

[0353] The following shows an exemplary preparation of an emulsion containing THC and CBD and the preparation of an IR film containing THC and CBD micelles. The composition of the individual units is summarized in Table 14.

[0354] Table 14:

[0355]

[0356]

[0357] Dissolve THC and CBD in the Labrasol and Kolliphor mixture using a magnetic stirrer to obtain a clear solution.

[0358] TEC was dissolved in water in a 0.2 L planetary mixer.

[0359] The THC and CBD clear solutions were added to form a self-emulsification. HPMC E3 and Klucel GF were added and dissolved for 90 minutes. The final emulsion was cast on silicon-coated PET (Mylar) using a benchtop casting machine with a blade spacing of 1100 μm. TM ) screen. The cast emulsion was dried in an oven at 60° C. for about 120 minutes. The dried product was a film with a thickness of about 150 μm.

[0360] Three sheets of dry film were stacked one on top of the other and rolled. The thickness of the laminated film was approximately 450 μm. The laminated film was punched into 18 mm x 40 mm rectangular units, each weighing approximately 330 mg and containing 10 mg of THC and 10 mg of CBD.

[0361] The final unit was tested using the same method and parameters as described in Example 1 to define the dissolution rate.

[0362] The units completely dissolved within 30 to 60 minutes.

[0363] Example 12: CBD 15 mg CR Tablet (Modified Release Agent as Film)

[0364] The following shows an exemplary preparation of an emulsion containing CBD and the preparation of a CR tablet containing CBD micelles. The composition of a single tablet is summarized in Table 15.

[0365] Table 15:

[0366] Tablet preparation 1 mg / unit CBD 15 sesame oil 15 Labrasol 85 Klucel EF 250 CMC 7MF 75 PEG 400 30 MCC 40 anhydrous lactose 60 PVP K30 10 magnesium stearate 5

[0367] CBD was dissolved in a mixture of Labrasol and sesame oil heated to 70 °C using a magnetic stirrer to obtain a clear solution.

[0368] In a 0.2 L planetary mixer, dissolve PEG 400 in water. Add the clear CBD solution to form a self-emulsification. Add Klucel EF and CMC and dissolve in water for approximately 60 minutes.

[0369] The final emulsion was cast on PET (Mylar) using a benchtop caster with a blade spacing of 1000 μm. TM ) screen. The cast emulsion was dried in an oven at 60° C. for about 60 minutes. The dried product was a film with a thickness of about 150 μm.

[0370] The membrane was ground using a hammer mill and sieved using a 500 μm sieve.

[0371] MCC, PVP and lactose were added to the sifted powder and blended for about 15 minutes. Magnesium stearate was added and blended for about 2 minutes.

[0372] The final blend was compressed into 18 mm*6 mm tablets using a tablet press, each having a weight of approximately 600 mg, with each unit containing 15 mg of CBD.

[0373] Example 13: THC 20 mg CR tablets (modified release agent added in powder form)

[0374] The following shows an exemplary preparation of an emulsion containing THC and a preparation of a CR tablet containing THC micelles. The composition of a single tablet is summarized in Table 16.

[0375] Table 16:

[0376] Tablet formulation 2 mg / unit THC 10 Peceol 21 GELUCIRE 50 / 13 49 Klucel EF 250 Klucel GXF 80 PEG 400 30 Dicalcium phosphate dihydrate 75 Mannitol 30 magnesium stearate 5

[0377] THC was dissolved in the Peceol and GELUCIRE mixture heated to 70°C using a magnetic stirrer to obtain a clear solution.

[0378] In a 0.2 L planetary mixer, PEG 400 was dissolved in water. The clear CBD solution was added to form a self-emulsification. Klucel EF was added and dissolved in water for approximately 60 minutes.

[0379] The final emulsion was cast on PET (Mylar) using a benchtop caster with a blade spacing of 1000 μm. TM ) screen. The cast emulsion was dried in an oven at 60° C. for about 60 minutes. The dried product was a film with a thickness of about 150 μm.

[0380] The film was ground using a hammer mill. The ground film was sieved using a 500 micron sieve. Dicalcium phosphate dihydrate, mannitol, and Klucel GXF were added to the sieved powder and blended for approximately 15 minutes. Magnesium stearate was added and blended for approximately 2 minutes.

[0381] The final blend was compressed into 16 mm*5 mm tablets using a tablet press, each having a weight of approximately 600 mg, with each unit containing 15 mg of CBD.

[0382] Example 14: CBD 20 mg CR tablet (by hot melt extrusion)

[0383] The following shows an exemplary preparation of an emulsion containing CBD and the preparation of a CR tablet containing CBD micelles. The composition of the individual tablets is summarized in Table 17.

[0384] Table 17:

[0385] Tablet formulation 3 mg / unit CBD 20 Peceol 42 Kolliphor EL 98 Klucel EF 275 Klucel GF 135 PEG 400 50 MCC 40 anhydrous lactose 60 PVP K30 10 magnesium stearate 5

[0386] An extrudate containing CBD micelles was prepared as described in Example 5. The extrudate was ground using a hammer mill. The ground membrane was sieved using a 500 μm sieve. Dicalcium phosphate dihydrate, mannitol, and Klucel GXF were added to the sieved powder and blended for approximately 15 minutes. Magnesium stearate was added and blended for approximately 2 minutes.

[0387] The final blend was compressed into 20 mm*7 mm tablets using a tablet press, each having a weight of approximately 750 mg, with each unit containing 15 mg of CBD.

[0388] Example 15: Pharmacokinetic clinical study testing the CR formulations described in Examples 1, 2, and 3.

[0389]

[0390] Example 16: Leuprorelin-Docusate Complex 10 mg CR

[0391] The following shows an exemplary preparation of an emulsion containing a leuprolide-docusate complex and the preparation of an oral CR dosage form containing leuprolide-docusate micelles. The composition of the individual units is summarized in Table 18.

[0392] Table 18:

[0393] CR Preparation 9 mg / internal unit Leuprorelin 10 Docusate sodium 5 Kolliphor EL 120 HPMC E3 300 Klucel GF 150 Poloxamer 407 35

[0394] Hydrophobic Ion Pairing (HIP) Process:

[0395] The peptide solution was prepared by dissolving leuprolide in 0.1 N HCl at a concentration of 10 mg / ml (Griesser, G. et al., Int. J. Pharmaceutics, 520(1-2), 267-274 (2017)).

[0396] The surfactant solution was prepared by dissolving docusate sodium in water at a concentration of 5 mg / ml. The surfactant solution was added to the peptide solution under vigorous stirring (400 rpm). During the reaction, an immediate white precipitate indicated the formation of a hydrophobic peptide complex. The mixture was centrifuged at 4000 rpm for 10 minutes. The supernatant was separated from the precipitate, and the final precipitate containing the leuprorelin-docusate complex was dried in an oven at 40°C for 24 hours.

[0397] Final preparation :

[0398] Leuprorelin-docusate complex was dissolved in Kolliphor EL using a magnetic stirrer to obtain a clear solution.

[0399] In a 0.2 L planetary mixer, Poloxamer 407 was dissolved in water.

[0400] The clear solution of leuprolide-docusate complex was added to form a self-emulsification, HPMC E3 and Klucel GF were added and dissolved for 90 minutes.

[0401] The final emulsion was cast onto silicon-coated PET (Mylar) using a benchtop caster with a blade spacing of 1000 μm. TM ) screen. The cast emulsion was dried in an oven at 60° C. for about 90 minutes. The dried product was a film having a solvent content (based on loss on drying test) of no more than 6% and a thickness of about 150 μm.

[0402] Five sheets of dry film were stacked one on top of the other and laminated manually. The thickness of the laminated film was about 750 μm.

[0403] The laminated film was punched into 21 mm x 45 mm rectangular units, each unit having a weight of 600 mg to 650 mg, and each unit contained 15 mg of leuprolide-docusate complex (10 mg of leuprolide).

[0404] These units were rolled into cylindrical shapes and individually inserted into 00 hard gelatin capsules.

Claims

1. An oral drug delivery device for controlled delivery of at least one lipophilic drug, said device comprising at least one pharmaceutically acceptable film-forming hydrophilic polymer, at least one pharmaceutically acceptable release modifier, optionally at least one pharmaceutically acceptable plasticizer, and at least one lipophilic drug emulsified in at least one emulsifier, wherein the oral drug delivery device is configured for integration into or formed into an orally administrable dosage unit form, and wherein the oral drug delivery device is configured to enable the at least one release-modifying agent to form a viscous gel upon ingestion of the dosage unit form and contact with gastric and / or intestinal media, the viscous gel being configured to gradually erode while passing through the stomach and intestines and to controllably release the emulsified drug in micellar form into the surrounding environment.

2. The oral drug delivery device of claim 1 , wherein the at least one pharmaceutically acceptable film-forming hydrophilic polymer, the at least one pharmaceutically acceptable release modifier, the optional at least one pharmaceutically acceptable plasticizer form a controlled release (CR) drug-containing polymer component of the delivery device, and wherein the at least one lipophilic drug emulsified in at least one emulsifier is embedded in the polymer component.

3. An oral drug delivery device for controlled delivery of at least one lipophilic drug, the device comprising a CR drug-containing polymer component, the polymer component comprising at least one pharmaceutically acceptable film-forming hydrophilic polymer component, at least one pharmaceutically acceptable release modifier, optionally at least one pharmaceutically acceptable plasticizer, and the at least one lipophilic drug emulsified in at least one emulsifier embedded in the polymer component, wherein the oral drug delivery device is configured for integration into or formed into an orally administrable dosage unit form, and wherein the oral drug delivery device is configured to enable the at least one release-modifying agent to form a viscous gel upon ingestion of the dosage unit form and contact with gastric and / or intestinal media, the viscous gel being configured to gradually erode while passing through the stomach and intestines, the gel controllably releasing the emulsified drug in micellar form into the surrounding environment.

4. An oral drug delivery device according to any one of claims 1 to 3, wherein the release modifier is a hydrophilic polymer which, when dissolved in water at 2% w / w, produces a solution with a viscosity of at least 150 mPa*sec.

5. The oral drug delivery device according to any one of claims 1 to 4, wherein the release modifier is contained in an amount of at least about 30 mg per said dosage unit form.

6. The oral drug delivery device according to any one of claims 1 to 5, wherein the total weight of the dosage unit form is from about 250 mg to about 2000 mg, preferably from about 300 mg to about 1200 mg.

7. The oral drug delivery device according to any one of claims 1 to 6, wherein the at least one lipophilic drug has a log P > 2.

8. An oral drug delivery device according to any one of claims 1 to 7, wherein the at least one emulsified drug is a pharmaceutically active cannabinoid, or a mixture of at least two pharmaceutically active cannabinoids, or a cannabis extract, ritonavir, fenofibrate, diclofenac, flurbiprofen diazepam, vitamin E, piroxicam, lopinavir, clofazimine or a modified lipophilic drug such as a hydrophobic ion-paired peptide drug.

9. An oral drug delivery device according to any one of claims 1 to 8, wherein the at least one emulsified drug is a pharmaceutically active cannabinoid, or a mixture of at least two pharmaceutically active cannabinoids, or a cannabis extract.

10. The oral drug delivery device according to any one of claims 1 to 9, comprising from about 0.5 mg to about 500 mg, preferably from about 1 mg to about 300 mg, more preferably from about 5 mg to about 300 mg of the lipophilic drug per dosage unit form.

11. The oral drug delivery device according to any one of claims 1 to 10, wherein the dosage unit form comprises the drug delivery device integrated into an oral capsule, preferably a soft gel capsule.

12. The oral drug delivery device according to any one of claims 2 to 10, wherein the dosage unit form comprises the CR drug-containing polymer component incorporated into an oral capsule, preferably a soft gel capsule.

13. An oral drug delivery device according to claim 11 or 12, wherein the dosage unit form further comprises an immediate release IR (immediate release) drug-containing component, the IR component comprising an emulsion of the at least one lipophilic drug in at least one emulsifier, the IR drug-containing component optionally further comprising a suitable carrier or diluent, wherein the IR drug-containing component is in solid form, such as powder form or liquid form.

14. An oral drug delivery device according to any one of claims 11 to 13, wherein the capsule is coated with an immediate release (IR) drug-containing component comprising an emulsion of the at least one lipophilic drug in at least one emulsifier, and optionally further comprising a suitable carrier or diluent, wherein the IR drug-containing component is in solid form, such as in powder form or liquid form.

15. An oral drug delivery device according to any one of claims 2 to 10, wherein the delivery device comprises 1 to about 50 CR drug-containing layers, the CR drug-containing layers being laminated, each of the CR drug-containing layers comprising the at least one emulsified lipophilic drug embedded in the polymer component, each layer having a predetermined geometric shape, preferably having a substantially rectangular, square or other polygonal shape or non-polygonal shape, such as, for example, an elliptical shape, preferably wherein each of the layers has the same said geometric shape.

16. The oral drug delivery device of claim 15, wherein each of the drug-containing layers has a thickness of about 20 μm to about 1000 μm, wherein each of the layers has the same or different thickness.

17. An oral drug delivery device according to claim 15 or 16, wherein the laminated drug-containing layers are rolled together into a substantially cylindrical body.

18. The oral drug delivery device according to claim 17, wherein the drug-containing member is integrated into an oral capsule, preferably a soft gel capsule, wherein the capsule optionally further comprises or is coated with an immediate release (IR) drug-containing component, the immediate release (IR) drug-containing component comprising an emulsion of the at least one lipophilic drug in at least one emulsifier, the IR drug-containing component optionally further comprising a suitable carrier or diluent, wherein the IR drug-containing component is in solid form or liquid form.

19. The oral drug delivery device according to any one of claims 1 to 10, wherein the at least one pharmaceutically acceptable film-forming hydrophilic polymer, the at least one pharmaceutically acceptable release modifier, the optional at least one pharmaceutically acceptable plasticizer, and the at least one lipophilic drug emulsified in at least one emulsifier constitute a substantially solid homogeneous CR mixture configured for incorporation into the orally administrable dosage unit form.

20. The oral drug delivery device according to any one of claims 2 to 10, wherein the at least one pharmaceutically acceptable film-forming hydrophilic polymer component, the at least one pharmaceutically acceptable release modifier, the at least one optional pharmaceutically acceptable plasticizer, and the at least one lipophilic drug emulsified in the at least one emulsifier embedded in the polymer component constitute a substantially homogeneous, substantially solid CR mixture configured for incorporation into the orally administrable dosage unit form.

21. The oral drug delivery device according to claim 19 or 20, wherein the CR mixture is substantially shaped into a cylinder.

22. The oral drug delivery device of claim 21, wherein the cylinder has a diameter of about 0.2 cm to about 1 cm.

23. An oral drug delivery device according to any one of claims 19 to 22, wherein the drug delivery device is integrated into an oral capsule, preferably a soft gel capsule, wherein the capsule optionally further comprises and / or is coated with an immediate release (IR) drug-containing component, the immediate release (IR) drug-containing component comprising an emulsion of the at least one lipophilic drug in at least one emulsifier, the IR drug-containing component optionally further comprising a suitable carrier or diluent, wherein the IR drug-containing component is in solid form or liquid form.

24. The oral drug delivery device according to any one of claims 1 to 14, wherein the drug delivery device is configured as a CR orally administrable tablet comprising the at least one pharmaceutically acceptable film-forming hydrophilic polymer, the at least one pharmaceutically acceptable release modifier, the optional at least one pharmaceutically acceptable plasticizer, and the at least one lipophilic drug emulsified in at least one emulsifier embedded in the polymer component.

25. An oral drug delivery device according to any one of claims 1 to 14, wherein the drug delivery device is configured as a CR orally administrable tablet, said tablet comprising a first said film-forming polymer, said optional plasticizer and said at least one lipophilic drug emulsified in at least one emulsifier embedded in said polymer component, and a release modifier, optionally together with an additional film-forming polymer, said additional film-forming polymer being the same as or different from said first film-forming polymer, wherein said tablet optionally further comprises at least one tableting excipient or additive, wherein said excipient or additive is any one of the following: a binder, a diluent, a filler, a lubricant and a glidant, and any mixture of at least two thereof.

26. An oral drug delivery device according to claim 24 or claim 25, the tablet optionally further comprising an additional amount of at least one additional pharmaceutically acceptable release-modifying polymer in solid form, preferably in ground or powder form, wherein the additional release-modifying agent can be the same as or different from the at least one additional pharmaceutically acceptable release-modifying agent, respectively.

27. An oral drug delivery device according to any one of claims 24 to 26, wherein the tablet is optionally coated with an IR drug-containing component comprising an emulsion of the at least one lipophilic drug in at least one emulsifier, the IR drug-containing component optionally further comprising a suitable carrier or diluent, wherein the IR drug-containing component is in solid form or liquid form.

28. An oral drug delivery device according to any one of claims 24 to 26, wherein the tablet is contained in an oral capsule, preferably a soft gel capsule, wherein the capsule optionally further comprises an immediate release (IR) drug-containing component, the immediate release (IR) drug-containing component comprising an emulsion of the at least one lipophilic drug in at least one emulsifier, the IR drug-containing component optionally further comprising a suitable carrier or diluent, wherein the IR drug-containing component is in solid form or liquid form.

29. The oral drug delivery device according to any one of claims 1 to 28, wherein - the at least one pharmaceutically acceptable film-forming hydrophilic polymer and the optional at least one pharmaceutically acceptable plasticizer form a drug-containing polymer component, wherein the at least one lipophilic drug is emulsified in at least one emulsifier, the emulsified drug being embedded in the polymer component; and - wherein the at least one pharmaceutically acceptable release modifier and the optional at least one pharmaceutically acceptable plasticizer form a CR polymer component, the CR component optionally further comprising at least one pharmaceutically acceptable film-forming hydrophilic polymer; The hydrophilic film-forming polymer and the optional plasticizer in the drug-containing polymer component and the CR polymer component can be the same or different.

30. An oral drug delivery device for controlled delivery of at least one lipophilic drug, the device comprising: a drug-containing polymer component comprising at least one pharmaceutically acceptable film-forming hydrophilic polymer component, optionally at least one pharmaceutically acceptable plasticizer and at least one lipophilic drug emulsified in at least one emulsifier, wherein the emulsified drug is embedded in the drug-containing polymer component, a controlled-release (CR) polymer component comprising at least one pharmaceutically acceptable film-forming hydrophilic polymer, at least one pharmaceutically acceptable release modifier and optionally at least one pharmaceutically acceptable plasticizer, wherein the hydrophilic film-forming polymer and the optional plasticizer in the drug-containing polymer component and the CR polymer component can be the same or different; and wherein the oral drug delivery device is configured for incorporation into an orally administrable dosage unit form, and wherein the oral drug delivery device is configured to enable the at least one release-modifying agent to form a viscous gel upon ingestion of the dosage unit form and contact with gastric and / or intestinal media, the viscous gel being configured to gradually erode while passing through the stomach and intestines and to controllably release the emulsified drug in micellar form into the surrounding environment.

31. An oral drug delivery device according to claim 29 or 30, wherein the drug-containing polymer component comprises 1 to about 50 drug-containing layers, each of the layers comprising the at least one emulsified lipophilic drug and optionally the plasticizer embedded in the hydrophilic polymer component, the drug-containing layers being laminated, each of the drug-containing layers having a predetermined geometric shape, preferably having a substantially rectangular, square or other polygonal shape or non-polygonal shape, such as, for example, an elliptical shape, preferably wherein each of the layers has the same geometric shape.

32. The oral drug delivery device of claim 31, wherein each of the drug-containing layers has a thickness of about 15 μm to about 900 μm, wherein each of the layers has the same or different thickness.

33. The oral drug delivery device according to any one of claims 29 to 31, wherein the drug-containing polymer component and the CR polymer component are laminated together.

34. The oral drug delivery device of claim 33, wherein the laminated drug-containing polymer component and CR polymer component are rolled together to form a substantially cylindrical body.

35. An oral drug delivery device according to any one of claims 29 to 34, wherein the drug delivery device is integrated into an oral capsule, preferably a soft gel capsule, wherein the capsule optionally further comprises and / or is coated with an immediate release (IR) drug-containing component, the immediate release (IR) drug-containing component comprising an emulsion of the at least one lipophilic drug in at least one emulsifier, the IR drug-containing component optionally further comprising a suitable carrier or diluent, wherein the IR drug-containing component is in solid form or liquid form.

36. An oral drug delivery device for controlled delivery of at least one lipophilic drug, said device comprising at least one pharmaceutically acceptable film-forming hydrophilic polymer, at least one pharmaceutically acceptable release modifier, optionally at least one pharmaceutically acceptable plasticizer, and at least one lipophilic drug emulsified in at least one emulsifier, wherein the oral drug delivery device is configured for integration into or formed into an orally administrable dosage unit form, and wherein the oral drug delivery device is configured to enable the at least one release-modifying agent to form a viscous gel upon ingestion of the dosage unit form and contact with gastric and / or intestinal media, the viscous gel being configured to gradually erode while passing through the stomach and intestines and to controllably release the emulsified drug into the surrounding environment in the form of micelles, wherein the release-modifying agent is a hydrophilic polymer that, when dissolved in water at 2% w / w, produces a solution having a viscosity of at least 150 mPa*sec, wherein the release-modifying agent is present at a concentration of 1% per The dosage unit form comprises an amount of at least about 30 mg, and wherein the at least one emulsifier is a lipid excipient having an HLB (hydrophile-lipophile balance) greater than 6, optionally wherein the emulsifier is a mixture of lipid excipients of which at least 50% have an HLB greater than 6, and the remaining lipid excipients are any of the following: oils, fatty acids, glycerides, polyoxyglycerides, polyglycerol esters and polyol esters or water-insoluble surfactants, or any mixture of at least two thereof, wherein each of the remaining lipid excipients has an HLB less than, equal to or greater than 6.

37. An oral drug delivery device for controlled delivery of at least one lipophilic drug, said device comprising a CR drug-containing polymer component, said polymer component comprising at least one pharmaceutically acceptable film-forming hydrophilic polymer component, at least one pharmaceutically acceptable release modifier, optionally at least one pharmaceutically acceptable plasticizer, and said at least one lipophilic drug emulsified in at least one emulsifier embedded in said polymer component, wherein the oral drug delivery device is configured for integration into or formed into an orally administrable dosage unit form, and wherein the oral drug delivery device is configured to enable the at least one release-modifying agent to form a viscous gel upon ingestion of the dosage unit form and contact with gastric and / or intestinal media, the viscous gel being configured to gradually erode while passing through the stomach and intestines and to controllably release the emulsified drug in micellar form into the surrounding environment, wherein the release-modifying agent is a hydrophilic polymer that, when dissolved in water at 2% w / w, produces a solution having a viscosity of at least 150 mPa*sec, wherein the release modifier is contained in an amount of at least about 30 mg per said dosage unit form, and wherein said at least one emulsifier is a lipid excipient having an HLB (hydrophile-lipophile balance) greater than 6, optionally wherein said emulsifier is a mixture of lipid excipients of which at least 50% have an HLB greater than 6, and the remaining lipid excipients are any of the following: oils, fatty acids, glycerides, polyoxyglycerides, polyglycerol esters and polyol esters or water-insoluble surfactants, or any mixture of at least two thereof, wherein each of said remaining lipid excipients has an HLB less than, equal to or greater than 6.

38. An oral drug delivery device for controlled delivery of at least one lipophilic drug, the device comprising: a drug-containing polymer component comprising at least one pharmaceutically acceptable film-forming hydrophilic polymer component, optionally at least one pharmaceutically acceptable plasticizer and at least one lipophilic drug emulsified in at least one emulsifier, wherein the emulsified drug is embedded in the polymer component, a controlled-release (CR) polymer component comprising at least one pharmaceutically acceptable film-forming hydrophilic polymer, at least one pharmaceutically acceptable release modifier and optionally at least one pharmaceutically acceptable plasticizer, wherein the hydrophilic film-forming polymer and the optional plasticizer in the drug-containing polymer component and the CR polymer component can be the same or different; and wherein the oral drug delivery device is configured for incorporation into an orally administrable dosage unit form, and wherein the oral drug delivery device is configured to enable the at least one release-modifying agent to form a viscous gel upon ingestion of the dosage unit form and contact with gastric and / or intestinal media, the viscous gel being configured to gradually erode while passing through the stomach and intestines and to controllably release the emulsified drug in micellar form into the surrounding environment, wherein the release-modifying agent is a hydrophilic polymer that, when dissolved in water at 2% w / w, produces a solution having a viscosity of at least 150 mPa*sec, wherein the release modifier is contained in an amount of at least about 30 mg per said dosage unit form, and wherein said at least one emulsifier is a lipid excipient having an HLB (hydrophile-lipophile balance) greater than 6, optionally wherein said emulsifier is a mixture of lipid excipients of which at least 50% have an HLB greater than 6, and the remaining lipid excipients are any of the following: oils, fatty acids, glycerides, polyoxyglycerides, polyglycerol esters and polyol esters or water-insoluble surfactants, or any mixture of at least two thereof, wherein each of said remaining lipid excipients has an HLB less than, equal to or greater than 6.

39. The oral drug delivery device according to any one of claims 36 to 38, wherein the total weight of the dosage unit form is from about 250 mg to about 2000 mg, preferably from about 300 mg to about 1200 mg.

40. The oral drug delivery device according to any one of claims 1 to 39, comprising about 1 w / w% to about 65 w / w%, preferably about 5 w / w% to about 65 w / w%, more preferably about 10 w / w% to about 65 w / w% of the at least one emulsified lipophilic drug.

41. An oral drug delivery device according to any one of claims 8 to 40, wherein the pharmaceutically active cannabinoid is any one of the following: delta-9-tetrahydrocannabinol (Δ9-THC, THC), isotetrahydrocannabinol (iso-THC), cannabinol (CBN), cannabidiol (CBD), cannabigerol (CBG), cannachromene (CBC), cannabichromene (CBE), cannabichromene (CBL), dihydroxycannabinol (CBT), cannabinol (CBV), tetrahydrocannabinol (THCV), cannabichromene (CBDV), tetrahydrocannabidiol (THCBD), tetrahydrocannabigerol (THCBG), tetrahydrocannachromene (THCBC), tetrahydrocannabidiol (THCBDV), cannachromene (CBCV), cannabigerol (CBGV) and cannabigerol monomethyl ether (CBGM), and pharmaceutically acceptable derivatives and pharmaceutically active metabolites thereof.

42. The oral drug delivery device of any one of claims 8 to 40, wherein the at least one emulsified drug is ritonavir, fenofibrate, diclofenac, flurbiprofen diazepam, vitamin E, piroxicam, lopinavir, clofazimine, or a modified lipophilic drug such as a hydrophobic ion-paired peptide drug, a pharmaceutically acceptable derivative, and a pharmaceutically active metabolite thereof.

43. An oral drug delivery device according to any one of claims 1 to 41, wherein the at least one release modifier is any one of the following: methylcellulose, (such as A4M), hydroxypropyl methylcellulose (such as K250, K750, K1500, K4M E4M, E10M, K15M, K100M or K200M), hydroxypropyl cellulose (such as Klucel GF, Klucel MF or Klucel HF), hydroxyethyl cellulose (such as HEC, OG, HEC M, HEC HX, HEC HHX polyethylene oxide, carboxymethyl cellulose (such as CMC 7MF, CMC 7H3F or CMC 7HF), gelatin, gums and proteins, and any mixture of at least two of them.

44. The oral drug delivery device according to any one of claims 1 to 35 and 39 to 43, wherein the at least one emulsifier is a lipid excipient having an HLB (hydrophilic-lipophilic balance) greater than 6.

45. The oral drug delivery device according to any one of claims 36 to 44, wherein the lipid excipient having an HLB value greater than 6 is any one of the following: Gelucire 50 / 13 (stearoyl polyoxyl-32 glycerides), Gelucire 44 / 14 (lauroyl polyoxyl-32 glycerides), Gelucire 48 / 16 (polyoxyl-32 stearate (Type I) NF), Labrafil 2125 (linoleoyl polyoxyl-6 glycerides), Labrafil 1944 (oleoyl polyoxyl-6 glycerides), Labrasol (caprylocaproyl polyoxyl-8 glycerides), Kolliphor RH40 (polyoxyl-40 hydrogenated castor oil), Kolliphor EL (polyoxyl-35 castor oil), Kolliphor HS15 (polyethylene glycol-15-hydroxystearate), Kolliphor P 407 / 124 / 188 (Poloxamer 407 / 124 / 188) and Kolliphor PS 80 / 60 / 20 (Polysorbate 80 / 60 / 20), and any mixture of at least two thereof.

46. ​​An oral drug delivery device according to any one of claims 1 to 45, wherein the emulsifier is a mixture of lipid excipients of which at least 50% have an HLB greater than 6, such as Gelucire 50 / 13 (stearoyl polyoxyl-32 glycerides), Gelucire 44 / 14 (lauroyl polyoxyl-32 glycerides), Gelucire 48 / 16 (polyoxyl-32 stearate (Type I) NF), Labrafil 2125 (linoleoyl polyoxyl-6 glycerides), Labrafil 1944 (oleoyl polyoxyl-6 glycerides), Labrasol (caprylocaproyl polyoxyl-8 glycerides), Kolliphor RH40 (polyoxyl-40 hydrogenated castor oil), Kolliphor EL (polyoxyl-35 castor oil), Kolliphor HS15 (polyethylene glycol-15-hydroxystearate), Kolliphor P 407 / 124 / 188 (Poloxamer 407 / 124 / 188) and Kolliphor PS 80 / 60 / 20 (Polysorbate 80 / 60 / 20), and the remaining lipid excipients are any of the following: oils, fatty acids, glycerides, polyoxyglycerides, polyglycerol esters and polyol esters or water-insoluble surfactants, or any mixture of at least two of them, wherein each of the remaining lipid excipients has an HLB lower than, equal to or higher than 6.

47. The oral drug delivery device according to any one of claims 1 to 46, wherein the weight ratio of lipophilic drug:emulsifier is from about 2:1 to about 1:100, preferably from about 1:1 to about 1:

20.

48. The oral drug delivery device according to any one of claims 1 to 47, wherein the hydrophilic film-forming polymer is any one of the following: povidone, copovidone, polyvinyl alcohol, a hydrophilic polyacrylamide derivative, a protein, gelatin, hydroxypropyl cellulose, polyethylene oxide, amino-methacrylate copolymer NF, hydroxypropyl methylcellulose, hydroxyethyl cellulose, carboxymethyl cellulose, sodium carboxymethyl cellulose, methyl cellulose, or a polyvinyl alcohol-polyethylene glycol graft copolymer, and any combination of at least two thereof.

49. An oral drug delivery device according to any one of claims 1 to 48, wherein the film-forming polymer and the release-modifying agent together constitute about 25 w / w% to about 85 w / w% of the device, preferably about 25 w / w% to 70 w / w%, more preferably about 30 w / w% to about 70 w / w%.

50. The oral drug delivery device according to any one of claims 1 to 49, wherein the drug delivery device optionally comprises up to 20 w / w %, preferably up to 15 w / w %, more preferably about 5 w / w % to about 10 w / w % of the plasticizer.

51. An orally administrable pharmaceutical dosage unit form comprising a drug delivery device according to any one of claims 1 to 23 and 29 to 50 configured for integration into an oral capsule, preferably a soft gel capsule.

52. An orally administrable pharmaceutical dosage unit form comprising a drug delivery device according to any one of claims 24 to 28 formed as an orally administrable pharmaceutical tablet.

53. The orally administrable tablet according to claim 52, which is incorporated into an oral capsule, preferably a soft gel capsule.

54. An orally administrable pharmaceutical dosage unit form comprising a drug delivery device according to any one of claims 11 to 13, 18 or 28 and a capsule.

55. An orally administrable pharmaceutical dosage unit form according to any one of claims 51 to 54, wherein the capsule comprises an immediate-release IR drug-containing component, the IR component comprising an emulsion of the at least one lipophilic drug in at least one emulsifier, the drug in the IR component being the same as or different from the drug contained in the drug delivery device, the IR drug-containing component optionally further comprising a suitable carrier or diluent, wherein the IR drug-containing component is in solid form, such as in powder form or liquid form.

56. An orally administrable pharmaceutical dosage unit form according to any one of claims 51 to 55, wherein the delivery device comprises at least one pharmaceutically active cannabinoid or a mixture of at least two pharmaceutically active cannabinoids or a cannabis extract as the active ingredient.

57. An orally administrable pharmaceutical dosage unit form according to any one of claims 55 and 56, wherein the drug is distributed between the CR drug delivery device and the IR drug-containing component in a predetermined ratio.

58. A drug delivery device according to any one of claims 8 to 41 and 43 to 50 or an orally administrable pharmaceutical dosage unit form according to any one of claims 56 or 57, for use in a method for treating, alleviating and preventing the exacerbation of a disease, disorder or condition responsive to cannabinoid treatment in a subject in need thereof, the method comprising orally administering the drug delivery device or pharmaceutical dosage unit form to the subject.

59. A drug delivery device for use or a drug dosage unit for use according to claim 57, wherein the disease, disorder or condition responsive to cannabinoid treatment is any one of the following: anorexia associated with weight loss in patients with AIDS, nausea and vomiting associated with cancer chemotherapy, pain, anxiety, depression, muscle spasms, arthritis and rheumatism, multiple sclerosis and other neuromuscular inflammatory conditions, inflammatory bowel disease such as Crohn's disease and colitis, post-traumatic stress disorder (PTSD) or seizures, Parkinson's disease, spinal cord injury, fibromyalgia, Alzheimer's disease and dementia, or any other condition responsive to cannabinoid treatment.

60. A drug delivery device according to any one of claims 8 to 40 and 42 to 50 or an orally administrable pharmaceutical dosage unit form according to any one of claims 56 or 57 for use in a method for treating, alleviating and preventing the exacerbation of diseases, disorders and conditions responsive to any one of ritonavir, fenofibrate, diclofenac, flurbiprofen, diazepam, vitamin E, piroxicam, lopinavir, clofazimine or a modified lipophilic drug such as a hydrophobic ion-pairing peptide drug, pharmaceutically acceptable derivatives and pharmaceutically active metabolites thereof.

61. A drug delivery device for use or a pharmaceutical dosage unit form for use according to any one of claims 58 to 60, wherein the administration is once or twice daily, or three times daily.

62. A method for treating, alleviating and preventing the exacerbation of a disease, disorder or condition responsive to cannabinoid treatment in a subject in need thereof, the method comprising orally administering to the subject an oral drug delivery device according to any one of claims 7 to 41 and 43 to 50 or a pharmaceutical dosage unit form according to any one of claims 56 and 57, wherein the administration is carried out under fed or fasting conditions.

63. The method of claim 62, wherein the disease, disorder or condition responsive to cannabinoid treatment is any of the following: anorexia associated with weight loss in patients with AIDS, nausea and vomiting associated with cancer chemotherapy, pain, anxiety, depression, muscle spasms, arthritis and rheumatism, multiple sclerosis and other neuromuscular inflammatory conditions, inflammatory bowel disease such as Crohn's disease and colitis, post-traumatic stress disorder (PTSD) or seizures, Parkinson's disease, spinal cord injury, fibromyalgia, Alzheimer's disease and dementia, or any other condition responsive to cannabinoid treatment.

64. A method for providing a subject in need thereof with stable therapeutically effective plasma levels of at least one cannabinoid or a mixture of at least two cannabinoids and / or active metabolites thereof over an extended period of time, the method comprising orally administering to the subject an oral drug delivery device according to any one of claims 7 to 41 and 43 to 50 or a pharmaceutical dosage unit form according to any one of claims 56 and 57.

65. A method for treating, alleviating and preventing the exacerbation of a disease, disorder or condition responsive to ritonavir, fenofibrate, diclofenac, flurbiprofen, diazepam, vitamin E, piroxicam, lopinavir, clofazimine or a modified lipophilic drug such as a hydrophobic ion-pairing peptide drug, a pharmaceutically acceptable derivative and a pharmaceutically active metabolite thereof, the method comprising orally administering to the subject an oral drug delivery device according to any one of claims 8 to 40 and 42 to 50 or an orally administrable pharmaceutical dosage unit form according to any one of claims 56 or 57, wherein the administration is performed under fed or fasting conditions.

66. The method of any one of claims 62 to 64, wherein the administration is once or twice daily, or three times daily.

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