Controlled release oral formulations of lipophilic drugs

Abstract

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

Description

[Technical Field]

[0001] Oral administration delivery devices and dosage forms thereof for the controlled delivery of drugs and their use in medicine are disclosed. [Background technology]

[0002] prior art References considered to be relevant as background to the presently disclosed subject matter are listed below. 1. Zanchetta, Beatriz, Marco Vinicius Chaud, and Maria Helena Andrade Santana. “Self-emulsifying drug delivery systems (SEDDS) in pharmaceutical development.” J Adv Chem Eng 5.3(2015):1-7. 2. Thakare, Priya, et al. “A review on self-emulsified drug delivery system.” Journal of pharmaceutical and biological evaluations 3.2(2016):140-153.) 3. Kalepu, Sandeep, Mohanvarma Manthina, and Veerabhadhraswamy Padavala. “Oral lipid-based drug delivery systems-an overview.” Acta Pharmaceutica Sinica B 3.6(2013):361-372. 4. Xiao, Lu, Tao Yi, and Ying Liu. “A new self-microemulsifying mouth dissolving film to improve the oral bioavailability of poorly water-soluble drugs.” Drug Development and Industrial Pharmacy 39.9(2013):1284-1290. 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. 6. Punyamurthula, Nagendra S., et al. “Controlled release tablet formulation containing natural Δ9-tetrahydrocannabinol.” Drug development and industrial pharmacy 42.7(2016):1158-1164. 7. U.S. Patent No. 10004684(B2) 8. U.S. Patent No. 9265724 (B2) 9. International Publication No. 2020014776(A1) 10. International Publication No. 2018011798(A1) 11. International Publication No. 2009117819(A1) 12. U.S. Patent No. 6,399,086(B1) 13. U.S. Patent Application No. 20070160677(A1) 14. Indian Patent No. 354423(B) 15. Chinese Patent No. 112076177(A) 16. U.S. Patent No. 9358205 (B2)

[0003] Background technology Lipophilic drugs and lipid-based drug delivery (LBDD) systems Poor drug absorption is commonly associated with active pharmaceutical ingredients (APIs) that have low aqueous solubility and / or poor intestinal permeability. Among other approaches, drug solubilization is improved in the dosage form itself and, importantly, in the gastrointestinal (GI) environment by using lipid-based drug delivery (LBDD) systems. Drug absorption from lipid-based formulations depends on a number of factors, including particle size, degree of emulsification, rate of dispersion, and drug precipitation upon dispersion [1].

[0004] Lipid digestion and absorption Lipid digestion begins in the stomach by continuously secreting gastric lipase. Gastric lipase activity is pH-dependent, being inactive under fasted conditions (gastric pH 1-2) and reaching maximal activity under fed (postprandial) conditions (gastric pH 4-5.5). The presence of lipids and fatty acids in the stomach triggers a rapid series of hormonally stimulated events that result in the secretion of bile and pancreatic substances, such as bile salts and phospholipids, along with pancreatic lipase in the duodenum and small intestine, creating what is commonly known as the fed state in the GI tract, whereby dispersion, emulsification, micellization, and the formation of lamellar structures help maintain drug solubilization in the intestine [2, 3].

[0005] The process of lipid digestion and absorption is most efficient here. When the predigested contents of the stomach are emptied into the duodenum, they mix with bile salts and surfactants, essential for dispersing the hydrophobic lipid structures within the aqueous environment of the small intestine. Here, the digested lipid components are released in the outer layer of mixed micelles. Lipase converts triglycerides and diglycerides into monoesters and free fatty acids. As emulsification continues, the subsequent reduction in lipid droplet size increases the surface area of ​​the lipid droplets, facilitating further lipolysis by intestinal lipase. The resulting micellar and lamellar structures induce a further increase in solubilization capacity.

[0006] Lipid pharmaceutical formulations should have the necessary components (oil, surfactant, and cosurfactant or solvent) to self-emulsify in the intestine in the presence of endogenous bile salts and pancreatic secretions. Some pharmaceutical excipients are self-emulsifying and can solubilize the API by themselves. Otherwise, the formulation must be customized to meet the requirements for the API to be absorbable and effective. Low HLB (Hydrophilic-Lipophilic Balance) glycerides (oils) are rapidly lipolyzed in the stomach and then in the duodenum into their respective esters, diesters, and free fatty acid components, which are required for drug emulsification and micellization in the GI environment [2, 3].

[0007] Self-Emulsifying Lipid Formulation (SELF) Self-emulsification is the property of lipid systems to form emulsion particles when they come into contact with an aqueous medium without the need for mechanical or thermal energy. This can occur in multi-component excipients or formulations consisting of three different molecular groups: oils, surfactants, and co-surfactants or solvents, in optimal ratios. The appropriate amount of components from each group is required for the spontaneous formation of emulsion particles when they come into contact with an aqueous medium [1].

[0008] Oral dosage forms containing a self-emulsifying drug delivery system (SEDDS) Capsule filling is the simplest and most common technique for encapsulating 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 components into powders / nanoparticles via different solidification techniques (e.g., adsorption onto solid carriers, spray drying, melt extrusion, and nanoparticle technology). However, because many excipients used in SEDDS are not solid at room temperature, SEDDS are usually limited to liquid dosage forms [1, 7, 8]. Another example of a SEDS solid formulation is an orodispersible or dissolving thin film, which allows drug absorption through the oral mucosa [4, 7, 9, 15].

[0009] Controlled Release (CR) formulations Controlled-release (CR) dosage forms can be designed to release drugs along the GI tract in a controlled or sustained profile. The main advantages of these formulations compared to immediate-release (IR) formulations are extended release, longer duration of effect, and a flatter and more stable PK profile, leading to fewer side effects.

[0010] The primary technique for CR formulation involves the use of a hydrophilic polymer matrix, in which the API is dispersed or dissolved. Along the GI tract, the matrix slowly erodes and dissolves, releasing the drug in a CR profile [11, 12, 16]. This method may be suitable for hydrophilic drugs. However, lipophilic drugs embedded in a hydrophilic polymer matrix are not released into the surrounding aqueous environment, and release does not occur.

[0011] Another way to achieve CR of lipophilic drugs can be the use of CR lipids such as Precirol® and Compritrol®. [6] The drawback of this technique is that the action of gastric lipase and bile salts in the stomach and subsequently in the duodenum is required to achieve efficient absorption. Lipophilic drugs that are released only and only in the small intestine cannot be emulsified and absorbed.

[0012] GR preparation Another approach to achieving CR of lipophilic drugs is through the use of gastro-retentive (GR) formulations, which allow the entire drug content to be released in the stomach, where it can be processed by gastric lipase and release 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 result in dose dumping. In addition, GR formulations are generally limited to low drug loads.

[0013] Delayed formulation 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 refer to acid-sensitive APIs embedded in insoluble gastric matrices that prevent the drug-acid reaction. Once the matrix is ​​emptied from the stomach, it dissolves rapidly and the drug is released with an immediate profile. Summary of the Invention

[0014] Disclosed herein is an oral drug delivery device for the controlled delivery of a lipophilic drug, the device comprising a lipophilic drug emulsified in a pharmaceutically acceptable film-forming hydrophilic polymer, a pharmaceutically acceptable release modifier, and an emulsifier, the device being incorporated into or formed as an orally administrable dosage unit form, and wherein upon ingestion of the dosage unit and contact with the gastric and / or intestinal media, the release modifier forms a viscous gel that gradually erodes upon passage through the stomach and intestinal tract, thus releasing the emulsified drug into the surrounding environment in the form of micelles at a controlled rate.

[0015] Disclosed herein is an oral drug delivery device for the controlled delivery of at least one lipophilic drug, the device comprising at least one lipophilic drug emulsified in 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 emulsifier, the oral drug delivery device configured to be incorporated into or formed as an orally administrable unit dosage form, the oral drug delivery device configured to enable the at least one release modifier, upon ingestion of the unit dosage form and contact with gastric and / or intestinal media, to form a viscous gel configured to gradually erode upon passage through the stomach and intestinal tract, and to controllably release the emulsified drug into the surrounding environment in the form of micelles.

[0016] 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.

[0017] Also disclosed is an oral drug delivery device for controlled delivery of at least one lipophilic drug, the device comprising a controlled-release (CR) drug-containing polymer component, the controlled-release drug-containing polymer component comprising at least one lipophilic drug emulsified in 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 emulsifier embedded in the polymer component, the oral drug delivery device being configured to be incorporated into or formed as an orally administrable unit dosage form, the oral drug delivery device being configured to allow the at least one release modifier to evolve, upon ingestion of the unit dosage form and contact with gastric and / or intestinal media, the device forming a viscous gel configured to gradually erode upon passage through the stomach and intestinal tract and controllably release the emulsified drug into the surrounding environment in the form of micelles.

[0018] In certain embodiments of the disclosed oral drug delivery device, the release modifier has a viscosity of at least 150 mPa when dissolved in water at 2% w / w. * It is a hydrophilic polymer that gives a solution with a viscosity of 1000 s.

[0019] In certain embodiments of the disclosed oral drug delivery devices, the release modifier is included in an amount of at least about 30 mg per dosage unit.

[0020] In certain embodiments of the disclosed oral drug delivery device, the unit dosage form is of a total weight of about 250 to about 2000 mg, preferably about 300 to about 1200 mg.

[0021] In certain embodiments of the disclosed oral drug delivery devices, the at least one lipophilic drug has a logP > 2. In 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-pair peptide drug, their pharmaceutically acceptable derivatives and pharmaceutically active metabolites, more particularly a pharmaceutically active cannabinoid, or a mixture of at least two pharmaceutically active cannabinoids, or a cannabis extract.

[0022] In certain embodiments, the disclosed oral drug delivery devices contain about 0.5 to about 500 mg, preferably about 1 to about 300 mg, and more preferably about 5 to about 300 mg of the lipophilic drug per unit dosage form.

[0023] The unit dosage form can include the disclosed drug delivery device incorporated into an oral capsule, preferably a softgel capsule.

[0024] In other embodiments, the disclosed unit dosage forms can include the CR drug-containing polymer component incorporated into an oral capsule, such as a hard or soft gel capsule.

[0025] The unit dosage form according to the present disclosure can further comprise an immediate release (IR) drug-containing component, which comprises an emulsion of at least one lipophilic drug in the at least one emulsifier, optionally further comprising a suitable carrier or diluent, and which can be in solid or liquid form, such as a powder. The capsule can be coated with an immediate release (IR) drug-containing component, which comprises an emulsion of at least one lipophilic drug in the at least one emulsifier, optionally further comprising a suitable carrier or diluent.

[0026] The oral drug delivery device of the present disclosure can include 1 to about 50 CR drug-containing laminates, each of which contains at least one emulsified lipophilic drug embedded in the polymer component, and each of which is of a predetermined geometric shape, such as an essentially rectangular, square, or other polygonal shape, or a non-polygonal shape, e.g., an elliptical shape, and preferably each of which is of the same geometric shape. According to the present disclosure, the thickness of each of the drug-containing layers can be about 20 μm to about 1000 μm, and each of the layers can have the same or different thicknesses.

[0027] The laminated drug-containing layers of the oral drug delivery device of the present disclosure can be rolled together into an essentially cylindrical body. The drug-containing member of the oral drug delivery device of the present disclosure can be incorporated into an oral capsule, such as a softgel capsule, which can optionally further comprise 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, and the IR drug-containing component is in solid or liquid form.

[0028] In certain aspects and embodiments of the oral drug delivery device of the present disclosure, at least one lipophilic drug emulsified in 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 emulsifier constitutes an essentially solid homogeneous CR mixture configured to be incorporated into the orally administrable unit dosage form.

[0029] In some aspects and particular embodiments of the oral drug delivery system of the present disclosure, the at least one pharmaceutically acceptable film-forming hydrophilic polymer component, the at least one pharmaceutically acceptable release-modifying agent, the optional at least one pharmaceutically acceptable plasticizer, and the at least one lipophilic drug emulsified in the at least one emulsifier embedded therein comprise an essentially homogeneous, essentially solid CR mixture configured to be incorporated into the orally administrable dosage unit. The CR mixture can be shaped essentially as a cylinder, which can have a diameter of about 0.2 cm to about 1 cm.

[0030] The oral drug delivery device of the present disclosure can be incorporated into an oral capsule, preferably a softgel capsule, which 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 the at least one emulsifier, which IR drug-containing component optionally further comprises a suitable carrier or diluent, and which IR drug-containing component is in solid or liquid form.

[0031] Alternatively, the oral drug delivery device of the present disclosure can be configured as a CR orally administrable tablet, the tablet comprising at least one lipophilic drug emulsified in 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 at least one emulsifier embedded therein. In some such specific 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 therein, and optionally a release modifier together with an additional film-forming polymer that may be the same as or different from the first film-forming polymer, the tablet optionally further comprising at least one tableting excipient or additive, the excipient or additive being any one of a binder, a diluent, a filler, a lubricant, and a glidant, and any mixture of at least two thereof. The tablet may optionally further comprise an additional amount of at least one additional pharmaceutically acceptable release-modifying polymer in solid form, preferably crushed or powdered form, which additional release modification is the same as or different from the at least one respective additional pharmaceutically acceptable release-modifying agent.

[0032] The disclosed tablet form oral drug delivery devices can optionally be coated with an IR drug-containing component, which comprises an emulsion of at least one lipophilic drug in the at least one emulsifier, which optionally further comprises a suitable carrier or diluent, and which is in solid or liquid form.

[0033] Furthermore, in all embodiments of the tablet form oral drug delivery device disclosed herein, the tablet can be contained in an oral capsule, such as a softgel capsule, which optionally further comprises an immediate release (IR) drug-containing component comprising 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, and which IR drug-containing component is in solid or liquid form.

[0034] 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 forming a drug-containing polymer component in which at least one emulsified lipophilic drug is embedded, and at least one pharmaceutically acceptable release modifier and optionally at least one pharmaceutically acceptable plasticizer forming a CR polymer component which may optionally further comprise at least one pharmaceutically acceptable film-forming hydrophilic polymer, wherein the hydrophilic film-forming polymer and optional plasticizer in the drug-containing polymer component and the CR polymer component can be the same or different.

[0035] In further particular aspects and embodiments, there is provided an oral drug delivery device for the 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, wherein an emulsified lipophilic drug is embedded in the drug-containing polymer component; a controlled release (CR) polymer component comprising a drug-containing polymer component, at least one pharmaceutically acceptable film-forming hydrophilic polymer, at least one pharmaceutically acceptable release modifier, and optionally at least one pharmaceutically acceptable plasticizer; Disclosed herein is an oral drug delivery device in which the hydrophilic film-forming polymer and the optional plasticizer in the drug-containing polymer component and the CR polymer component comprise a controlled-release polymer component, which may be the same or different, and the device is configured to be incorporated into an orally administrable unit dosage form, and the at least one release modifier is configured to enable the unit dosage form to form a viscous gel configured to gradually erode upon ingestion and contact with gastric and / or intestinal media, and to controllably release the emulsified drug in the form of micelles into the surrounding environment upon ingestion of the unit dosage form and contact with gastric and / or intestinal media. The drug-containing polymer component in the device of these aspects and embodiments can include 1 to about 50 drug-containing layers, which are stacked, and each drug-containing layer has a predetermined geometric shape, such as an essentially rectangular, square, or other polygonal shape, or a non-polygonal shape, such as an elliptical shape. More specifically, the layers have the same geometric shape. The thickness of each drug-containing layer can be from about 15 μm to about 900 μm and can be the same or different in each layer. In these particular embodiments, the drug-containing polymer component and the CR polymer component can also be laminated together, and these laminated drug-containing layers and CR polymer component can be rolled together to form an essentially cylindrical body.The devices of these embodiments can be incorporated into oral capsules, such as softgel capsules, which optionally further comprise and / or are coated with an immediate-release (IR) drug-containing component comprising an emulsion of at least one lipophilic drug in at least one emulsifier, where the drug is the same as or different from the drug contained in the CR drug-containing layer, and the IR drug-containing component optionally further comprises a suitable carrier or diluent, where the IR drug-containing component is in solid or liquid form.

[0036] and at least one lipophilic drug emulsified in 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 emulsifier, wherein the oral drug delivery device is configured to be incorporated into or formed as an orally administrable unit dosage form, and wherein the oral drug delivery device is configured to enable the at least one release modifier, upon ingestion of the unit dosage form and contact with gastric and / or intestinal media, to form a viscous gel configured to gradually erode upon passage through the stomach and intestinal tract and to controllably release the emulsified drug into the surrounding environment in the form of micelles, wherein the release modifier has a viscosity of at least 150 mPa when dissolved in water at 2% w / w. *and wherein the release modifier is a hydrophilic polymer that provides a solution having a viscosity of 0.1 s, the release modifier is present in an amount of at least about 30 mg per unit dosage form, the at least one emulsifier is a lipid excipient having an HLB (Hydrophilic Lipophilic Balance) of greater than 6, and optionally the emulsifier is a mixture of lipid excipients, at least 50% of which have an HLB of greater than 6, and the remaining lipid excipients are any one of oils, fatty acids, glycerides, polyoxyglycerides, polyglyceryl and polyalcohol esters, or water-insoluble surfactants, or any mixture of at least two thereof, and each of the remaining lipid excipients has an HLB of less than, equal to, or greater than 6.

[0037] and (c) a viscous gel containing at least one lipophilic drug emulsified in 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 emulsifier embedded in the polymer component; the device is configured to be incorporated into or formed as an orally administrable unit dosage form; the device is configured to enable the at least one release modifier, upon ingestion of the unit dosage form and contact with gastric and / or intestinal media, to form a viscous gel configured to gradually erode upon passage through the stomach and intestinal tract and to controllably release the emulsified drug into the surrounding environment in the form of micelles; the release modifier has a viscosity of at least 150 mPa s when dissolved in water at 2% w / w. *and wherein the release modifier is a hydrophilic polymer that provides a solution having a viscosity of 0.1 s, the release modifier is present in an amount of at least about 30 mg per unit dosage form, the at least one emulsifier is a lipid excipient having an HLB (hydrophilic lipophilic balance) greater than 6, and optionally the emulsifier is a mixture of lipid excipients, at least 50% of which have an HLB greater than 6, and the remaining lipid excipients are any one of oils, fatty acids, glycerides, polyoxyglycerides, polyglyceryl and polyalcohol esters, or water-insoluble surfactants, or any mixture of at least two thereof, and each of the remaining lipid excipients has an HLB less than, equal to, or greater than 6.

[0038] Further, an oral drug delivery device for the 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 drug-containing polymer component The oral drug delivery device comprises a controlled release polymer component, wherein the hydrophilic film-forming polymer and optional plasticizer in the polymer component and the CR polymer component can be the same or different, and the oral drug delivery device is configured to be incorporated into an orally administrable unit dosage form, wherein the drug delivery device is configured to enable the at least one release modifier, upon ingestion of the unit dosage form and contact with gastric and / or intestinal media, to form a viscous gel configured to gradually erode upon passage through the stomach and intestinal tract, and to controllably release the emulsified drug into the surrounding environment in the form of micelles, wherein the release modifier has a viscosity of at least 150 mPa s when dissolved in water at 2% w / w. *and wherein the release modifier is a hydrophilic polymer that provides a solution having a viscosity of 0.1 s, the release modifier is present in an amount of at least about 30 mg per unit dosage form, the at least one emulsifier is a lipid excipient having an HLB (hydrophilic lipophilic balance) greater than 6, and optionally the emulsifier is a mixture of lipid excipients, at least 50% of which have an HLB greater than 6, and the remaining lipid excipients are any one of oils, fatty acids, glycerides, polyoxyglycerides, polyglyceryl and polyalcohol esters, or water-insoluble surfactants, or any mixture of at least two thereof, and each of the remaining lipid excipients has an HLB less than, equal to, or greater than 6.

[0039] Also, in these specific embodiments of the disclosed oral drug delivery device, the unit dosage form may be of a total weight of about 250 to about 2000 mg, preferably about 300 to about 1200 mg, and the at least one emulsified lipophilic drug may be present in an amount of about 1 to about 65% w / w, specifically about 5 to about 65% w / w, and more specifically about 10 to about 65% w / w.

[0040] In all aspects and embodiments of the oral drug delivery device of the present disclosure, the pharmaceutically active cannabinoid is selected from the group consisting of Δ-9-tetrahydrocannabinol (Δ9-tetrahydrocannabinol, Δ9-THC, tetrahydrocannabinol, THC), iso-tetrahydrocannabimol (iso-THC), cannabinol (CBN), cannabidiol (CBD), cannabigerol (CBG), cannabichromene (CBC), cannabielsoin (CBE), cannabicyclol (CBL), cannabicitran (CBT), cannabivarin (cannab cannabidivarin (CBV), tetrahydrocannabivarin (THCV), cannabidivarin (CBDV), and any one of many others such as tetrahydrocannabidiol (THCBD), tetrahydrocannabigerol (THCBG), tetrahydrocannabichromene (THCBC), tetrahydrocannabidivarol (THCBDV), cannabichromevarin (CBCV), cannabigerovarin (CBGV), and cannabigerol conomethyl ether (CBGM), as well as pharmaceutically acceptable derivatives and pharmaceutically active metabolites thereof.

[0041] In all aspects and embodiments of the oral drug delivery device of the present disclosure, the pharmaceutically active drug may be a modified lipophilic drug such as ritonavir, fenofibrate, diclofenac, flurbiprofen diazepam, vitamin E, piroxicam, lopinavir, clofazimine, or a hydrophobic ion-pair peptide drug, their pharmaceutically acceptable derivatives and pharmaceutically active metabolites.

[0042] In all aspects and embodiments of the oral drug delivery device of the present disclosure, the release modifier can be any one of 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 G, 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 thereof.

[0043] In all aspects and embodiments of the oral drug delivery device of the present disclosure, the emulsifier may be a lipid excipient having an HLB (hydrophilic lipophilic balance) of greater than 6. Such lipid excipients include Gelucire 50 / 13 (stearoyl polyoxyl-32 glyceride), Gelucire 44 / 14 (lauroyl polyoxyl-32 glyceride), Gelucire 48 / 16 (polyoxyl-32 stearate (type I) NF), Labrafil 2125 (linoleoyl polyoxyl-6 glyceride), Labrafil 1944 (oleoyl polyoxyl-6 glyceride), Labrasol (caprylocaproyl polyoxyl-8 glyceride), Kolliphor RH40 (polyoxyl-40 hydrogenated castor oil), Kolliphor EL (polyoxyl-35 castor oil), Kolliphor HS15 (macrogol-15-hydroxystearate), Kolliphor HS20 (macrogol-15-hydroxystearate), Kolliphor HS30 (macrogol-15-hydroxystearate), Kolliphor HS40 (macrogol-15-hydroxystearate), Kolliphor HS50 (macrogol-15-hydroxystearate), Kolliphor HS60 (macrogol-15-hydroxystearate), Kolliphor HS60 (macrogol-15-hydroxystearate), Kolliphor HS70 (macrogol-15-hydroxystearate), Kolliphor HS80 (macrogol-15-hydroxystearate), Kolliphor HS90 (macrogol-15-hydroxystearate), Kolliphor HS10 (macrogol-15-hydroxystearate), Kolliphor HS11 (macrogol-15-hydroxystearate), Kolliphor HS12 (macrogol-15-hydroxystearate), Kolliphor HS13 (macrogol-15-hydroxystearate), Kolliphor HS14 (macrogol-15-hydroxystearate), Kolliphor HS15 (macrog The remaining lipid excipients may be any one of P407 / 124 / 188 (poloxamer 407 / 124 / 188) and Kolliphor PS80 / 60 / 20 (polysorbate 80 / 60 / 20), and any mixture of at least two of them. The remaining lipid excipients may be any one of oils, fatty acids, glycerides, polyoxyglycerides, polyglyceryl and polyalcohol esters, or water-insoluble surfactants, or any mixture of at least two of them, each having an HLB of less than, equal to, or greater than 6.

[0044] In all aspects and embodiments of the oral drug delivery device of the present disclosure, the weight ratio of lipophilic drug to emulsifier can be from about 2:1 to about 1:100, preferably from about 1:1 to about 1:20.

[0045] In all aspects and embodiments of the oral drug delivery device of the present disclosure, the hydrophilic film-forming polymer can be any one of povidone, copovidone, polyvinyl alcohol, hydrophilic polyacrylamide derivatives, proteins, gelatin, hydroxypropyl cellulose, polyethylene oxide, amino-methacrylate copolymer NF, hydroxypropyl methylcellulose, hydroxyethyl cellulose, carboxymethyl cellulose, sodium carboxymethyl cellulose, methyl cellulose, or polyvinyl alcohol-polyethylene glycol graft copolymer, and any combination of at least two thereof.

[0046] In all aspects and embodiments of the oral drug delivery devices of the present disclosure, the film-forming polymer and release-modifying agent together may comprise from about 25 to about 85% w / w of the device, specifically from about 25 to about 70% w / w, and more specifically from about 30 to about 70% w / w.

[0047] In all aspects and embodiments of the present disclosure, the oral drug delivery device may optionally include a plasticizer at up to 20% w / w, specifically up to 15% w / w, and more specifically about 5% to about 10% w / w.

[0048] In further aspects and embodiments, orally administrable pharmaceutical unit dosage forms are disclosed, including any of the above drug delivery devices configured to be incorporated into a pharmaceutical unit dosage form, particularly an oral capsule, particularly a softgel capsule, integrated with or incorporated therein. In further aspects and embodiments, the drug delivery devices disclosed herein are formed as orally administrable pharmaceutical dosage units, particularly tablets. Also, tablets according to the present disclosure can be integrated with or incorporated into oral capsules, particularly softgel capsules. In orally administrable unit dosage forms in the form of oral capsules, the capsule can contain an immediate-release IR drug-containing component, which comprises an emulsion of at least one lipophilic drug in the at least one emulsifier, and the drug in the IR component can be the same or different from the drug contained in the drug delivery device, and the IR drug-containing component optionally further comprises a suitable carrier or diluent, and the IR drug-containing component can be in solid or liquid form, such as a powder. The drug can be distributed in a predetermined ratio between the CR drug delivery device and the IR drug-containing component. The tablet can be coated with an IR component that is the same as the CR component or contains another drug. In certain orally administrable pharmaceutical unit dosage forms, the active ingredient can be at least one pharmaceutically active cannabinoid, or a mixture of at least two pharmaceutically active cannabinoids, or a cannabis extract.

[0049] In a further aspect of the present disclosure, the disclosed drug delivery devices and orally administrable pharmaceutical unit dosage forms thereof, wherein the drug is a cannabinoid or a mixture of cannabinoids or a cannabis extract, can be used in a method for any one of treating, alleviating, and preventing the worsening of a disease, disorder, or condition responsive to cannabinoid therapy in a subject in need thereof, the method comprising orally administering the drug delivery device or pharmaceutical unit dosage form to the subject.

[0050] The disease, disorder, or condition that responds to cannabinoid therapy may be any one of anorexia associated with weight loss in AIDS patients, nausea and vomiting associated with cancer chemotherapy, pain, anxiety, depression, muscle spasms, arthritis and rheumatism, multiple sclerosis and other neuromuscular inflammatory disorders, 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 that responds to cannabinoid therapy. Administration may be once or twice daily or three times daily. Administration may be chronic.

[0051] In a further aspect of the present disclosure, in the disclosed drug delivery devices and orally administrable pharmaceutical unit dosage forms thereof, the pharmaceutically active drug can be ritonavir, fenofibrate, diclofenac, flurbiprofen diazepam, vitamin E, piroxicam, lopinavir, clofazimine, or modified lipophilic drugs such as hydrophobic ion-pair peptide drugs, their pharmaceutically acceptable derivatives and pharmaceutically active metabolites thereof.

[0052] Also disclosed are methods for the treatment, alleviation, and prevention of worsening of diseases, disorders, or conditions responsive to cannabinoid therapy in a subject in need thereof, comprising orally administering to the subject an oral drug delivery device or pharmaceutical unit formulation thereof as disclosed herein, wherein the drug is a cannabinoid, a mixture of cannabinoids, or a cannabis extract. Also disclosed are methods for the treatment, alleviation, and prevention of worsening of diseases, disorders, or conditions responsive to modified lipophilic drugs, such as ritonavir, fenofibrate, diclofenac, flurbiprofen diazepam, vitamin E, piroxicam, lopinavir, clofazimine, or hydrophobic ion-pair peptide drugs, their pharmaceutically acceptable derivatives, and pharmaceutically active metabolites.

[0053] Also disclosed is 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 their active metabolites over an extended period of time, the method comprising orally administering to the subject an oral drug delivery device or pharmaceutical unit dosage as disclosed herein, wherein the drug is a cannabinoid or a mixture of cannabinoids or a cannabis extract.

[0054] In all methods of treatment disclosed herein, administration can be once or twice daily or three times daily, or administration can be chronic. Administration can be under fed or fasted conditions.

[0055] In order to better understand the subject matter disclosed herein, and to illustrate how it may be carried out in practice, embodiments will now be described, by way of non-limiting example only, with reference to the accompanying drawings, in which: [Brief explanation of the drawings]

[0056] [Figure 1] CBD release from Formulation 1 of Example 1 in SGF and SIF. [Figure 2] CBD release from Formulation 2 of Example 2 in SGF and SIF. [Figure 3] CBD release from Formulation 3 of Example 3 in SGF and SIF. [Figure 4] CBD release from Formulation 4 of Example 4 in SGF. [Figure 5] CBD release from Formulation 5 of Example 5 in SGF. [Figure 5A] SEM image of the hot melt extrudate prepared in Example 5. DETAILED DESCRIPTION OF THE INVENTION

[0057] overview The present disclosure relates to oral drug delivery devices and dosage forms thereof for the controlled delivery of lipophilic and poorly water-soluble drugs, in which the drug is contained in a pre-emulsified form, specifically as a drug emulsion in a suitable emulsifier, specifically various lipids, fats, and / or surfactants as described herein. The devices / dosage forms of the present disclosure provide improved, prolonged, controlled release of the emulsified drug in the form of micelles, and provide improved absorption of the drug by the treated subject.

[0058] In all aspects and embodiments, disclosed herein is an orally administered drug delivery device for controlled release (CR) of at least one emulsified lipophilic drug, comprising at least one lipophilic drug emulsified in 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 emulsifier, wherein the oral drug delivery device is configured to be incorporated into or formed as an orally administrable unit dosage form, wherein the oral drug delivery device is configured to enable the at least one release modifier, upon ingestion of the unit dosage form and contact with gastric and / or intestinal media, to form a viscous gel configured to gradually erode upon passage through the stomach and intestinal tract, and to controllably release the emulsified drug into the surrounding environment in the form of micelles.

[0059] After oral ingestion and upon contact of the delivery device with the gastric environment, the delivery device becomes viscous and forms a slowly eroding viscous device or viscous body (which may be used interchangeably herein) containing the emulsified drug, which provides controlled release of the emulsified drug contained therein in the form of micelles over an extended period of time, beginning in the stomach and continuing after the viscous body / device empties from the stomach into the duodenum, and then continues its journey along the intestine until essentially completely eroded / biodegraded. Thus, in all aspects and embodiments of the present disclosure, the drug delivery device and / or dosage forms thereof provide release and absorption of the emulsified drug over a period of at least about 3 hours and up to about 24 hours, providing stable, therapeutically effective, and reliable plasma levels over an extended period of time. Treatment with the disclosed controlled-release oral delivery devices and their dosage forms provides release of the drug immediately after administration and over an extended residence time of the delivery device in the patient's GI tract, improving both the magnitude and duration of the drug's pharmacodynamic effect, maximizing therapeutic efficacy, and minimizing any negative side effects. The disclosed oral drug delivery devices and dosage forms allow for the administration of a predetermined therapeutic dose of a drug and reduced frequency of daily administration, resulting in improved patient compliance.

[0060] Certain lipophilic drugs are cannabinoids, which are useful in the treatment of various cannabinoid-responsive conditions, as described in more detail below.

[0061] As mentioned above, to achieve absorption of lipophilic drugs in the body, such drugs must be processed and digested in the stomach by gastric lipase. This results in the secretion of bile and pancreatic substances, such as bile salts and phospholipids, and together with pancreatic lipase in the duodenum and small intestine, creates what is commonly known as the "fed state" in the GI tract, whereby dispersion, emulsification, micellization, and the formation of lamellar structures help maintain drug solubilization in the intestine. When the pre-digested contents of the stomach are emptied into the duodenum, they mix with bile salts and surfactants, which are essential for dispersing hydrophobic lipid structures in the aqueous 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 lipid droplet size increases the surface area of ​​the lipid droplets, facilitating further lipolysis by intestinal lipase. The resulting micellar and lamellar structures induce a further increase in the solubilizing capacity of emulsions and micelles.

[0062] Due to the fact that the drug in the delivery device of the present disclosure is in the form of an emulsified drug, the drug is released into the surrounding medium as drug micelles. The drug micelles can be easily absorbed along the entire GI tract, starting in the stomach, continuing to the duodenum, and then along the intestine, without the need for pre-digestive processing by gastric lipase, bile salts, and phospholipids. This phenomenon allows for efficient controlled release, resulting in a long-term and stable pharmacokinetic (PK) profile of lipophilic drugs. Therefore, the oral drug delivery devices of the present disclosure, and all of their disclosed unit dosage forms, are not retained in the stomach. Rather, they travel along the GI tract until essentially completely eroded, gradually releasing the active drug contained therein in a controlled manner. Therefore, in all aspects and embodiments of the present disclosure, the drug delivery devices and their dosage forms are not gastroretentive.

[0063] As shown in Example 11 below, in the absence of suitable CR components as described herein and presented, for example, in Examples 1-5, the resulting delivery device (containing the active ingredients THC and CBD) completely dissolved within 30-60 minutes.

[0064] In some aspects and embodiments of the present disclosure, oral drug delivery devices and their unit dosage forms, the active pharmaceutical ingredient (drug) is mixed with a lipid emulsifier in a drug:emulsifier ratio of 2:1 to 1:100.

[0065] The oral drug delivery devices of the present disclosure, and all disclosed unit dosage forms thereof, contain components that provide for the absorption of the drug in the desired form described, i.e., the controlled release of readily absorbable drug micelles upon ingestion, beginning in the stomach and continuing upon emptying into the duodenum and intestine. Specifically, these components ensure that the drug is contained in an emulsified form and that the delivery device / dosage form has a viscosity of at least 150 mPa when dissolved in water at 2% w / w. * The dosage form preferably contains a release-modifying agent, which is a hydrophilic polymer that provides a solution with a viscosity of 1000 s, preferably in an amount of at least about 30 mg per dosage unit, the dosage form has a total weight of about 250 to about 2000 mg, and the emulsifier is a lipid excipient having an HLB (hydrophilic lipophilic balance) greater than 6 or a mixture of lipid excipients, at least 50% of which has an HLB greater than 6. These oral drug delivery devices and dosage forms thereof provide extended release and efficient absorption of the active drug.

[0066] In some particular aspects and embodiments of the delivery devices of the present disclosure, the at least one pharmaceutically acceptable film-forming hydrophilic polymer, the at least one pharmaceutically acceptable release-modifying agent, and optionally the 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.

[0067] In some particular aspects and embodiments of the delivery device of the present disclosure, the unit dosage form comprises the drug delivery device incorporated into an oral capsule, such as a softgel capsule. In other particular aspects and embodiments of the present disclosure, the delivery device is formed as a unit dosage form, for example, a tablet.

[0068] In one aspect, disclosed herein is an oral drug delivery device for the 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 modifier, and 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 oral drug delivery device being configured to be incorporated into or formed as an orally administrable unit dosage form, the oral drug delivery device being configured to enable the at least one release modifier, upon ingestion of the unit dosage form and contact with gastric and / or intestinal media, to form a viscous gel configured to gradually erode upon passage through the stomach and intestinal tract, and to controllably release the emulsified drug into the surrounding environment in the form of micelles.

[0069] In specific embodiments of this aspect of the present disclosure, the drug delivery device comprises a single or multiple stacked CR drug-containing layers, e.g., up to 6, 8, 10, 12, 15, 20, and up to 50 drug-containing layers. Each CR drug-containing layer polymer component comprises a hydrophilic film-forming polymer, a release-modifying agent, and optionally a plasticizer. At least one lipophilic drug emulsified in at least one emulsifier. The CR drug-containing layers are of a predetermined geometric shape, for example, but not limited to, an essentially rectangular, square, or other polygonal shape, or a non-polygonal shape, e.g., an elliptical shape, and the layers can each be of the same or different geometric shapes. The CR drug-containing layers can each be of the same or different thicknesses, from about 20 μm to about 1000 μm. In some specific embodiments, the CR drug-containing layer or stacked CR drug-containing layers can be rolled together to form an essentially cylindrical body, or they can be molded together into different forms or shapes. The resulting drug delivery device can be integrated into an oral capsule, such as a softgel capsule. Specifically, the resulting drug delivery device can be inserted into an oral capsule. Exemplary devices are described in Examples 1-3 below.

[0070] In other specific embodiments of this aspect of the present disclosure, the drug delivery device is configured as a tablet, such as a pharmaceutical tablet, or as a pill or caplet. An exemplary device is described in Example 12 below. Such a tablet comprises at least one lipophilic drug emulsified in 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 emulsifier, and optionally further comprises at least one tableting excipient or additive, which may be any one of a binder, a diluent, a filler, a lubricant, and a glidant, and any mixture of at least two thereof. Certain tablets may comprise the drug embedded in a hydrophilic film-forming polymer, a first release modifier, and an optional plasticizer, and optionally at least one tableting excipient or additive. Such tablets may further comprise an amount of an additional (second) release modifier, which may be the same as or different from the first modifier.

[0071] In another specific embodiment, a tablet according to the present disclosure may comprise the emulsified lipophilic drug embedded in a hydrophilic film-forming polymer and an optional plasticizer, mixed therewith, a release-modifying agent, and optionally at least one tableting excipient or additive. Generally, the various ingredients or tablets are crushed, mixed, and then pressed into a tablet. An exemplary device is described in Example 13 below.

[0072] A tablet according to the present disclosure may be inserted into an oral capsule.

[0073] In the above aspects and embodiments of the present disclosure in which a drug delivery device is integrated with or incorporated within an oral capsule, the capsule may optionally further 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, the IR drug-containing component being in solid, e.g., powder, or liquid form. Exemplary devices are described in Examples 1-3 below.

[0074] In embodiments of the delivery device of the present disclosure in tablet form, the tablet may optionally be coated with a similar 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, the IR drug-containing component being in solid, e.g., powder, or liquid form.

[0075] In all aspects and embodiments of the present disclosure, the drug contained in the IR drug-containing component can be the same as or different from the drug contained in the CR drug-containing layer or component.

[0076] 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-modifying agent, and optionally at least one optional pharmaceutically acceptable plasticizer, and the resulting drug-containing polymer mixture constitutes an essentially homogeneous, essentially solid CR mixture configured to be incorporated into the orally administrable dosage unit. This device can be produced using a hot-melt extrusion process, as described in more detail below and exemplified in Example 5.

[0077] The CR mixture can be formed into a suitable shape, for example, an essentially cylindrical body, for example, about 0.2 cm to about 1 cm in diameter.

[0078] In a further embodiment, disclosed herein is an oral drug delivery device in which at least one pharmaceutically acceptable film-forming hydrophilic polymer and optionally at least one pharmaceutically acceptable plasticizer form a drug-containing polymer component, at least one lipophilic drug emulsified in the at least one emulsifier is embedded in the polymer component, and at least one pharmaceutically acceptable release-modifying agent and optionally at least one pharmaceutically acceptable plasticizer form a CR polymer component, which may optionally further comprise at least one pharmaceutically acceptable film-forming hydrophilic polymer. In this embodiment, the hydrophilic film-forming polymer and optional plasticizer in the drug-containing polymer component and the CR polymer component may be the same or different.

[0079] Also in this further embodiment, a drug delivery device essentially comprising a CR polymer component and a drug-containing component may be incorporated into an oral capsule, such as a softgel capsule, which may optionally further 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, the IR drug-containing component being in solid, e.g., powder, or liquid form.

[0080] In another aspect, the present disclosure relates to an oral drug delivery device for the controlled delivery of at least one lipophilic drug, essentially comprising two separate 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 lipophilic drug emulsified in at least one pharmaceutically acceptable film-forming hydrophilic polymer component, optionally at least one pharmaceutically acceptable plasticizer, and at least one emulsifier, wherein the emulsified drug is embedded in the polymer component; (b) a controlled-release (CR) 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; ) polymer component, wherein the hydrophilic film-forming polymer and optional plasticizer in the drug-containing polymer component and the CR polymer component can be the same or different, and the oral drug delivery device is configured to be incorporated into an orally administrable unit dosage form, and the oral drug delivery device is configured to enable at least one release-modifying agent, upon ingestion of the unit dosage form and contact with gastric and / or intestinal media, to form a viscous gel configured to gradually erode upon passage through the stomach and intestinal tract, and to controllably release the emulsified drug into the surrounding environment in the form of micelles.

[0081] In another embodiment of the present invention, the drug-containing polymer component may comprise from 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 embedded in a hydrophilic polymer component and, optionally, the plasticizer, and the drug-containing layers are stacked one on top of the other, each of the drug-containing layers being of a predetermined geometric shape, preferably essentially rectangular, square, or other polygonal shape, or a non-polygonal shape such as an ellipse, and preferably each of the layers being of the same geometric shape. The thickness of each of the drug-containing layers is from about 15 μm to about 900 μm and may be the same or different for each layer.

[0082] In certain embodiments of this other aspect of the present disclosure, the drug-containing polymer component and the CR polymer component may be laminated together. The laminated drug-containing polymer component and the CR polymer component may be wound together to form an essentially cylindrically shaped body, or may be formed into a body of another configuration, for example, as an elongated block.

[0083] Also, in this other aspect of the invention, the drug delivery device may be incorporated into an oral capsule, e.g., a softgel capsule, which 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 the at least one emulsifier, which IR drug-containing component optionally further comprises a suitable carrier or diluent, and which IR drug-containing component is in solid or liquid form.

[0084] In all aspects and embodiments of the present disclosure, the release modifier has a viscosity of at least 150 mPa when dissolved in water at 2% w / w. * An exemplary release-modifying agent is hydroxypropyl cellulose (Klucel GF, viscosity 150-400 mPa.s). * seconds), Klucel MF (viscosity 4000~6500mPa *seconds), or Klucel HF (viscosity 3000-6000 mPa * sec), hydroxypropyl methylcellulose (HPMC) (HPMC K250 (viscosity 200-300 mPa) * seconds), K750 (viscosity 600~900mPa * seconds), K1500 (viscosity 1200~1800mPa * seconds), K4M (viscosity 2700~5040mPa * seconds), E4M (viscosity 2700~5040mPa * seconds), E10M (viscosity 7500~14000mPa * seconds), K15M (viscosity 13500~25200mPa * seconds), K100M (viscosity 75000~140000mPa * seconds), or K200M (viscosity 150,000 to 280,000 mPa * sec), hydroxyethyl cellulose (HEC G (viscosity 250-400mPa) * seconds), HEC M (viscosity 4500~6500mPa * seconds), HEC HX (viscosity 3000~5000mPa * seconds), or HEC HHX (viscosity 7000-11000mPa * sec), carboxymethyl cellulose (7MF (viscosity 400-600mPa) * seconds), 7H3F (viscosity 2000~5600), 7HF (viscosity 3000~5000mPa * seconds), or 7H4 (viscosity 5000-9000mPa * sec), methylcellulose (A15C (viscosity 1125-2100 mPa) * seconds) or A4M (viscosity 3000~5600mPa * s), polyethylene oxide, gelatin, gums, proteins, and any mixture of at least two of these.

[0085] In all aspects and embodiments of the present disclosure, the release modifier is present in an amount of at least about 30 mg per unit dosage form, e.g., 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 unit dosage form, e.g., 50 to 150 mg per unit dosage form, and specifically, the unit dosage form has a total weight of about 250 mg to about 2000 mg, e.g., about 250 mg, 300 mg, 400 mg, or 500 mg to about 1500 mg, more specifically, about 300 mg to about 1200 mg, and any range therebetween. In all these particular aspects and embodiments, the release modifier has a viscosity of at least 150 mPa s when dissolved in water at 2% w / w. * The drug emulsifier is a hydrophilic polymer that provides a solution with a viscosity of 1000 s, and the drug emulsifier is a lipid excipient with an HLB greater than 6, or a mixture of lipid excipients, at least 50% of which has an HLB greater than 6.

[0086] In all aspects and embodiments of the oral drug delivery device of the present disclosure, lipophilic or poorly water-soluble drugs, or water-insoluble drugs, are drugs with a logP > 2. Examples of lipophilic drugs are cannabinoids and their therapeutically active derivatives, including, but not limited to, Δ-9-tetrahydrocannabinol (Δ9-THC, THC), iso-tetrahydrocannabinol (iso-THC), cannabinol (CBN), and cannabidiol (CBD), as well as their pharmaceutically acceptable derivatives and their pharmaceutically active metabolites, and cannabis extracts. Other cannabinoids are also mentioned herein. Lipophilic drugs according to the present disclosure may also be, but are not limited to, any one of ritonavir, fenofibrate, diclofenac, flurbiprofen diazepam, vitamin E, piroxicam, lopinavir, and clofazimine.

[0087] Further examples of therapeutically active derivatives of cannabinoids are cannabigerol (CBG), cannabichromene (CBC), cannabielsoin (CBE), cannabicyclol (CBL), cannabicitran (CBT), cannabivarin (CBV), tetrahydrocannabidivarin (THCV), cannabidivarin (CBDV), and tetrahydrocannabidiol (THCBD), tetrahydrocannabigerol (THCBG), tetrahydrocannabichromene (THCBC), tetrahydrocannabidivarin (THCBDV), cannabichromevarin (CBCV), cannabigerovarin (CBGV), and cannabigerol methyl ether (CBGM), as well as many others such as pharmaceutically acceptable derivatives thereof and pharmaceutically active metabolites thereof.

[0088] Additionally, lipophilic or water-insoluble drugs according to the present disclosure can be non-lipophilic or water-soluble pharmaceutically active agents that have been rendered lipophilic by modification, specifically chemical modification, e.g., hydrophobic ion pairing, such that the modified active agent has a logP > 2. Such modified pharmaceutically active agents may be referred to herein as "modified drugs," etc. Non-limiting examples of pharmaceutically water-soluble active agents with a logP > 2 that have been modified to be lipophilic or water-insoluble are peptide drugs modified by pairing with hydrophobic ions. Exemplary peptide drugs include leuprorelin (an LHRH agonist), insulin, desmopressin, and others, such as therapeutic antibodies. Exemplary hydrophobic ions are anionic surfactants, such as docusate sodium or sodium dodecyl sulfate, or fatty acids 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 LogP and is therefore capable of being emulsified in an emulsifier as disclosed herein.

[0089] In all aspects and embodiments of the present disclosure, the drug delivery device or dosage form thereof may contain from about 0.5 to about 500 mg of the lipophilic drug per device or unit dosage form, e.g., from about 1 mg to about 300 mg, from about 5 to about 300 mg, from about 5 mg to about 300 or 400 mg, and any range therebetween.

[0090] In all aspects and embodiments of the present disclosure, the oral drug delivery device may comprise the at least one emulsified lipophilic drug at about 10, 15, 20, 25, 30, 35, or 40% to about 50%, 55%, 60%, or 65% w / w, for example, but not limited to, about 1 to about 65% w / w, such as about 1 to about 65% w / w. The weight ratio of lipophilic drug:emulsifier may be, for example, about 2:1 to about 1:100, such as about 1:1 to about 1:20 or 1:30.

[0091] As with emulsifiers, lipid excipients are generally characterized by the degree of dispersibility or solubilization ability in aqueous media. The hydrophilicity of lipid molecules, such as fatty acid esters, is partially influenced by the type of polar group (glycerol, propylene glycol, polyethylene glycol, etc.) to which the fatty acid is esterified. The larger the polar group, the more hydrophilic the molecule. The degree of esterification also affects the hydrophilicity of the lipid. For example, monoesters are more hydrophilic than diesters. As mentioned above, an empirical system known as the HLB (Heavy Load Balance) scale is commonly used to classify lipid excipients by their degree of affinity for the oil phase relative to the aqueous phase in a formulation. More specifically, an HLB value of 1 applies to triglycerides (oil-based solubilizers). An HLB value of 6 to 10 indicates the lipid / oil excipient's ability to disperse in water. An HLB value greater than 10 indicates increased solubility in water. Briefly, the HLB of each excipient varies depending on the type and distribution of hydrophobic and hydrophilic groups, the degree of esterification, such as monoesters compared to diesters or triesters, and their amounts in the final excipient.

[0092] Fatty excipients as used herein include oils, fatty acids, glycerides, polyoxylglycerides, polyglyceryl and polyalcohol esters, water-insoluble surfactants, water-soluble surfactants, or cosolvents, such as coconut oil, cottonseed oil, soybean oil, castor oil, corn oil, olive oil, coconut oil, peanut oil, peppermint oil, poppy seed oil, canola oil, hydrogenated oils, glyceryl esters of fatty acids, glyceryl behenate, glyceryl distearate, glyceryl laurate, glyceryl monooleate, glyceryl palmitate, glyceryl palmitostearate, Glyceryl ricinoleate, glyceryl stearate, polyglyceryl oleate, polyglyceryl 10 tetralaurate, behenic acid, caprylic / capric glyceride, lauric acid, linoleic acid, linolenic acid, myristic acid, palmitic acid, palmitoleic acid, ricinoleic acid, stearic acid, soybean fatty acids, oleic acid, tocopherol, vitamin E, vitamin A, glyceryl esters, short-chain triglycerides, medium-chain triglycerides, long-chain triglycerides, PEGylated fatty acids, phospholipids, sorbitan derivatives, hydrogenated castor oil derivatives, glycerin, poly Glycolide glycerides, polyoxyethylene glycerides, polyethylene glycol-fatty acid esters, polyethylene glycol glycerol fatty acid esters, transesterification products of oils and alcohols, polyglycerinated fatty acids, polyglycerol fatty acid esters, propylene glycol fatty acid esters, mono- and diglycerides, polyoxyethylene-polyoxypropylene block copolymers, oil PEG esters, hydrogenated oil PEG-esters, glycerol esters of fatty acids, saturated polyglycolized glycerides, polyoxyl castor oil, caprylic acid Capric acid medium chain (C8 / C10) mono- and diglycerides, propylene glycol caprylate / caprate, propylene glycol dicaprylate / dicaprate, propylene glycol monolaurate, propylene glycol ricinoleate, propylene glycol monooleate, poloxamer (108, 124, 182, 183, 188, 212, 217, 238, 288, 331, 338, 335, 407), sorbitan monooleate, dC-tocopheryl polyethylene glycol 1000 succinate, polysorbate (20, 60, 80),and any mixture of at least two of them.

[0093] In all aspects and embodiments of the oral drug delivery device of the present disclosure, the emulsifier may be a lipid excipient having an HLB (hydrophilic lipophilic balance) of greater than 6. Excipients with an HLB value greater than 6 include, but are not limited to, Gelucire 50 / 13 (stearoyl polyoxyl-32 glyceride), Gelucire 44 / 14 (lauroyl polyoxyl-32 glyceride), Gelucire 48 / 16 (polyoxyl-32 stearate (type I) NF), Labrafil 2125 (linoleoyl polyoxyl-6 glyceride), Labrafil 1944 (oleoyl polyoxyl-6 glyceride), Labrasol (caprylocaproyl polyoxyl-8 glyceride), Kolliphor RH40 (polyoxyl-40 hydrogenated castor oil), Kolliphor EL (polyoxyl-35 castor oil), Kolliphor HS15 (macrogol-15-hydroxystearate), Kolliphor P407 / 124 / 188 (poloxamer 407 / 124 / 188), and Kolliphor PS80 / 60 / 20 (polysorbate 80 / 60 / 20), and any mixture of at least two of them.

[0094] In some embodiments, the emulsifier is a mixture of lipid excipients, at least 50% of which have an HLB greater than 6, such as those listed above, and the remaining lipid excipients are any one of oils, fatty acids, glycerides, polyoxy-glycerides, polyglyceryl and polyalcohol esters, or water-insoluble surfactants, or any mixture of at least two thereof, each of which has an HLB less than, equal to, or greater than 6.

[0095] In all aspects and embodiments of the oral drug delivery device and dosage forms thereof of the present disclosure, the hydrophilic film-forming polymer can be any one of povidone, copovidone, polyvinyl alcohol, hydrophilic polyacrylamide derivatives, proteins, gelatin, hydroxypropyl cellulose, polyethylene oxide, amino-methacrylate copolymer NF, hydroxypropyl methylcellulose, hydroxyethyl cellulose, carboxymethyl cellulose, sodium carboxymethyl cellulose, methyl cellulose, or polyvinyl alcohol-polyethylene glycol graft copolymer, and any combination of at least two thereof.

[0096] In all aspects and embodiments of the oral drug delivery devices and dosage forms thereof of the present disclosure, the film-forming polymer and release-modifying agent together comprise about 25 to 70% w / w of the device, more specifically about 25 to about 85% w / w, such as about 30 to about 70% w / w.

[0097] In all aspects and embodiments of the present disclosure, the drug delivery device optionally comprises a plasticizer in an amount of up to 20% w / w, preferably up to 15% w / w, and more preferably about 5% to about 10% w / w. Exemplary plasticizing agents (plasticizers) optionally used in the oral drug delivery devices and unit dosage forms thereof of the present disclosure include, but are not limited to, polyethylene glycol, citrate esters, phthalate esters, glyceryl esters, 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, PEGylated fatty alcohols and fatty acids, phospholipids, sorbitan derivatives, polysorbates, poloxamers, hydrogenated castor oil derivatives, glycerin, propylene glycol, and any combination of at least two thereof.

[0098] In some aspects and embodiments of the oral drug delivery device and unit dosage forms thereof of the present disclosure, the device / unit dosage form is in the form of an oral pharmaceutical tablet. Such tablets generally may include tableting excipients or additives, which may be, but are not limited to, binders, diluents / fillers, lubricants, and glidants.

[0099] Binders are materials that bind tablet components together and provide shape and mechanical strength to the powdered materials used in tablet production. Binders ensure that the tablet remains intact after compression and improve the free flow of the powdered materials without delaying disintegration or dissolution. Binders can be used alone or in combination with each other. They can be added as a dry powder or in the form of a solution in a suitable and appropriate solvent. Materials commonly used as binders include gum acacia, hydroxypropyl methylcellulose, polyvinyl pyrrolidone (PVP), corn starch, microcrystalline cellulose, etc.

[0100] Diluents / fillers are added to increase the size of tablets to obtain a significant tablet weight that can be handled or compressed. Fillers should be chemically inert, non-hygroscopic, hydrophilic, and exhibit good compression properties. Lactose is a common filler used in pharmaceutical formulations. Other examples of fillers used in tablet production include mannitol, dicalcium phosphate, calcium sulfate, dry starch, cellulose, kaolin, sodium chloride, anhydrous lactose, sorbitol, sucrose, etc.

[0101] Lubricants reduce friction between the powder mixture and the die wall during compression and ejection. They also prevent the mixed powder / granules from sticking to the processing zones of the tablet press, especially the punches and dies. Materials commonly used as lubricants include polyoxyethylene stearate and lauryl sulfate. Magnesium stearate, glyceryl behenate, stearic acid, glyceryl palmitostearate, etc.

[0102] Glidants are fine powders that improve the flow of the blend during tablet production by reducing interparticle friction and adhesion. They facilitate the movement of powder or granules into the hopper and die cavity before compression. Increasing the flow rate reduces the weight variation of the tablets produced, resulting in more consistent dosing of the drug substance. Examples of glidants used in tablet production include colloidal silicon dioxide, talc, cornstarch, etc.

[0103] In all aspects and embodiments of the oral drug delivery device and unit dosage forms thereof of the present disclosure, all components, i.e., hydrophilic film-forming polymers, CR and IR release modifying / regulating agents, lipid excipients (emulsifiers), and tableting excipients, are pharmaceutically and physiologically acceptable.

[0104] Representative methods for producing oral drug CR delivery devices and dosage units thereof are provided in the Examples below.

[0105] In some specific embodiments, the emulsified drug, film-forming polymer, release-modifying polymer, and optional plasticizer are all contained in the drug-containing laminate member of the drug delivery device, including the same layer in which the drug is embedded. The preparation of an exemplary such drug delivery device and its unit dosage form, including CBD as an exemplary lipophilic drug as defined herein, is presented in Examples 1-3. Generally, the drug is emulsified by dissolving in (and mixing with) a suitable emulsifier. The solution is added to water or an optional aqueous solution of plasticizer, thereby forming a self-emulsion (micelle) of the drug. A suitable film-forming polymer and release-modifying agent are added to the drug emulsion and mixed until dissolved. The final emulsion is cast onto a suitable support and dried. The product is a film that can be cut into units. The units are laminated, processed into a suitable shape, and adapted for oral capsules. An immediate-release fraction is prepared separately (in powder form in Examples 1-3) and incorporated into the capsule. The dissolution profiles tested were similar for SGF and SIF. After immediate release of the drug at the IR location, dissolution continued for at least 12 hours, as shown in Figures 1 to 3 .

[0106] In another embodiment, the drug-containing member of a drug delivery device according to the present disclosure is prepared by hot-melt extrusion, as shown in Example 5. Generally, the drug (e.g., CBD) is emulsified by dissolving it in (and mixing with) a suitable emulsifier. A suitable film-forming polymer, release modifier, and optional plasticizer are all added to the drug emulsion, and all components are blended. The blend is introduced into a hot-melt extruder and processed. The final product is a uniform extrudate containing the emulsified drug. The extrudate is produced with a suitable diameter, e.g., 7-8 mm, and can be cut to a suitable length and inserted into oral capsules. As shown in Figure 5, the controlled release of the active drug (CBD) lasted for approximately 10 hours. An IR formulation in liquid or powder form can be introduced into the capsule-containing delivery device produced by the exemplified hot-melt technique, as in Examples 1-3.

[0107] In another embodiment, a drug delivery device according to the present disclosure comprises a drug-containing member and a controlled-release (CR) member. Preparation of this type of delivery device is presented in Example 4. The drug-containing member (layer) is generally prepared by dissolving the drug in a suitable emulsifier (mixing the drug with a suitable emulsifier). The solution is added to water or an aqueous solution of an optional plasticizer, thereby forming a self-emulsion (micelle) of the drug. A suitable film-forming polymer is added to the drug emulsion and mixed until dissolved. The final emulsion is cast onto a suitable support and dried. The product is a film. The drug-free CR layer is separately prepared by dissolving or dispersing the release modifier, optionally together with a suitable amount of film-forming polymer and / or plasticizer, in a suitable solvent. The mixture is cast onto a suitable support and dried. The dried product, a film, is laminated onto the drug-containing film, and the laminated films are rolled together to obtain an essentially cylindrical laminate comprising two distinct layers: the drug-containing layer and the CR layer. The cylindrical body can then be cut into cylindrical segments of suitable length. Optionally, the drug-containing film and CR film can be cut into similar or different units before lamination, and the drug-containing film unit and the CR film unit are laminated and rolled together to form an essentially cylindrical laminated body comprising two distinct layers: a drug-containing layer and a CR layer. In a specific embodiment presented 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 to achieve a specific drug release profile. The resulting cylindrical segments or cylindrical bodies are then incorporated into oral capsules. If desired, an IR formulation in powder or liquid form can be added to and / or coated onto the capsule. As shown in Example 4 and Figure 4, the release profile in GSF demonstrated a prolonged and controlled release profile of up to 10 hours.

[0108] In other embodiments, the drug delivery device according to the present disclosure may be formed as an orally administrable pharmaceutical controlled-release tablet. An exemplary preparation of a tablet according to the present disclosure, in which the active pharmaceutical ingredient is CBD and a release modifier is added to the drug emulsion, is presented in Example 12. Thus, for example, a tablet formulation is prepared by dissolving the drug in an emulsifier. The mixture is added to an aqueous medium, optionally containing a plasticizer, to form a self-emulsion. The release modifier and hydrophilic film-forming polymer are added until all are dissolved. The final emulsion is cast onto a suitable support and dried. The dried product, e.g., a film, is pulverized and sieved using a suitable sieve (e.g., a 500-micron sieve). Tableting additives are added, blended, and the blend is pressed into a tablet using a suitable press.

[0109] An alternative method for preparing tablets is presented in Example 13, in which the release modifier is added as a powder to the tablet mixture. In this example, THC was used as the active pharmaceutical agent. THC is dissolved in an emulsifier. The mixture is added to an aqueous medium, optionally containing a plasticizer, to form a self-emulsion. A hydrophilic film-forming polymer is added () and the ingredients are mixed until everything is dissolved. The final emulsion is cast onto a suitable support and dried. The dried product, e.g., a film, is crushed and sieved using a suitable sieve (e.g., a 500 micron sieve). Tableting additives are added together with the release modifier, and everything is blended. The blend is pressed into tablets using a suitable press.

[0110] 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 blended. The blend is pressed into tablets using a suitable press.

[0111] In all aspects and embodiments of the present disclosure, the disclosed oral drug delivery devices or pharmaceutical unit formulations thereof, wherein the drug is at least one cannabinoid or cannabis extract, can be used in a method for any one of treating, alleviating, and preventing the worsening of a disease, disorder, or condition responsive to cannabinoid therapy in a subject in need thereof, the method comprising orally administering to the subject the drug delivery device or pharmaceutical unit formulation thereof. The disease, disorder, or condition responsive to cannabinoid therapy can be any one of anorexia associated with weight loss in AIDS patients, nausea and vomiting associated with cancer chemotherapy, pain, anxiety, depression, muscle spasticity, arthritis and rheumatism, multiple sclerosis and other neuromuscular inflammatory disorders, inflammatory bowel disease 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 therapy.

[0112] The present disclosure also relates to a method of increasing the absorption time of an active pharmaceutical ingredient (API) having a logP>2 in a subject in need thereof by administering to the subject a device or pharmaceutical unit dosage form according to all described aspects and embodiments thereof.

[0113] In all aspects and certain embodiments of the presently disclosed subject matter, methods of treatment and therapeutic uses of the presently disclosed oral drug delivery devices and pharmaceutical unit dosage forms thereof can include administration of the dosage forms once, twice, or three times daily, or less frequently, such as once or twice weekly. Furthermore, administration can be under fed and fasted conditions.

[0114] In all aspects and embodiments, the present disclosure further provides specific oral delivery devices for lipophilic or poorly water-soluble drugs, including but not limited to cannabinoids as defined herein, and dosage forms thereof, where the drug is in an emulsified form or mixed with at least one emulsifier. The disclosed lipophilic drug formulations can provide stable plasma levels of the drug over a longer period of time, extending drug availability and potentially improving the efficacy of the active ingredient. The proposed drug delivery devices and their unit dosage forms can result in continuous and effective exposure of target organs and tissues to the drug, with the formulations releasing the drug in the stomach and subsequently in the duodenum and intestine over an extended period of time, for example, from several hours after administration to about 12 hours and up to 24 hours, typically from about 3 hours to any one of 4, 5, 6, 7, 8, 9, 10, 11, 12, and up to 15 hours. The disclosed drug delivery devices and their unit dosage forms can improve the efficacy of treatment while reducing the number of daily administrations. The proposed drug delivery devices and their unit dosage forms provide for the use of a predetermined dose of an active drug. Importantly, the drug delivery devices according to all aspects and embodiments of the present disclosure can be versatile in terms of the release rate of the active ingredient. Primarily, the release is controlled, but the rate can be controlled by specific features of the delivery devices disclosed herein. Such features can be the drug loading, the amount of modified-release agent, the characteristics of the drug emulsion or mixture with an emulsifier, for example, the specific emulsion formulation, the API-to-emulsifier ratio, the micelle size, the geometry and structure of the device, or its layers, if present, as detailed below and illustrated in the examples. The controlled release can be preceded by or accompanied by an immediate release of the ingredients contained in the disclosed unit dosage forms of the disclosed drug delivery devices.

[0115] Also disclosed herein are pharmaceutical dosage forms, such as unit dosage forms of cannabinoids. Essentially, the pharmaceutical dosage forms disclosed herein comprise a controlled release cannabinoid delivery device incorporated into an oral pharmaceutical capsule, which may be a hard or soft gel capsule.

[0116] The present disclosure further provides specific drug delivery devices for cannabinoids and their unit formulations, i.e., orally administered CR and / or CR and IR combination delivery devices of the cannabinoids disclosed herein, or unit formulations thereof. The disclosed cannabinoid formulations can provide stable plasma levels of the cannabinoid drug over a longer period of time, extending drug availability and potentially improving the efficacy of the active ingredient. As described above, the proposed cannabinoid delivery devices and their unit formulations can result in continuous and effective exposure of target organs and tissues to the drug, improve therapeutic efficacy while reducing the number of daily administrations, provide for the use of a predetermined dose of the active cannabinoid ingredient, and be versatile in terms of the release rate of the active ingredient.

[0117] definition The terms "drug", "active substance", "API" (active pharmaceutical ingredient) or "active ingredient" or "active ingredient" or "active agent", as used interchangeably herein, refer to a pharmaceutically active substance that provides a therapeutic / physiological effect to a patient, and can also refer to a mixture of at least two of them.

[0118] The terms "lipophilic drug" or "poorly water-soluble drug" or "lipophilically modified drug" or "poorly water-soluble modified drug", as used interchangeably herein, refer to a drug that is insoluble or only slightly soluble in water, or a drug that has been chemically modified to be insoluble or only slightly soluble in water, specifically "a drug having a LogP>2" or "a modified drug having a LogP>2" or "a drug specifically 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, defined as a specific ratio of the concentrations of a solute between water and octanol, is greater than 2.

[0119] The terms "cannabinoid," "cannabinoid derivative," or "cannabinoid metabolite," as used interchangeably herein, refer to any active ingredient of cannabis. A "cannabinoid," as defined herein, may be a cannabinoid-like substance that is not derived from cannabis. The terms "cannabinoid," "cannabinoid derivative," or "cannabinoid metabolite," as used interchangeably herein, also refer to any mixture of at least two cannabinoids, as defined herein.

[0120] The terms "cannabis extract" or "cannabis concentrate", as used interchangeably herein, refer to an extract of the cannabis plant containing cannabinoids and optionally terpenes and / or other compounds.

[0121] As used herein, the term "drug-releasing formulation" refers to any composition that contains a drug and releases the drug after administration to a subject.

[0122] Terms such as "emulsified drug" or "drug emulsified in an emulsifier" or "drug emulsion" or "emulsion of drug in emulsifier" or "drug in emulsified form," which are used interchangeably herein, refer to a poorly water-soluble drug that is dissolved in or mixed with an emulsifier and can form a fine oil-in-water (o / w) emulsion or microemulsion when diluted in an aqueous medium such as gastric fluid (GF), intestinal fluid (IF), or gastrointestinal fluid (GIF). When referring to a defined amount / quantity such as "emulsified drug" or "drug emulsified in an emulsifier" or "drug emulsion" or "emulsion of drug in emulsifier" or "drug in emulsified form," which are used interchangeably herein, the amount indicates the combined amount of both drug and emulsifier. Therefore, the terms "drug emulsion" and "mixture of drug and emulsifier" are both used herein.

[0123] The terms "emulsifying agent" or "emulsifier," used interchangeably herein, refer to a compound or substance that concentrates at the interface of two immiscible phases, usually oil and water. It lowers the interfacial free energy, reduces the interfacial tension between the phases, and forms a film or barrier around droplets of the immiscible discontinuous phase as they form, 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 them, as described in detail herein.

[0124] As used interchangeably herein, the terms "dosage unit," "dosage form," "oral dosage unit," "unit formulation," "oral unit formulation," and the like refer to solid dosage forms known in the art and may be used interchangeably herein. The dosage forms are intended for oral use, i.e., to be swallowed (ingested) by a patient / subject in need thereof. The terms "oral capsule" and "peroral capsule" are used interchangeably herein.

[0125] The term "solid" as used herein with respect to all aspects and embodiments of the disclosed drug delivery devices and dosage forms thereof, and with respect to their various components, such as the drug-containing component (or layer or component), the controlled-release (CR) component (or layer or component), the immediate-release (IR) component (or layer or component or powder), or various mixtures of components (such as, but not limited to, a mixture of an active drug and an emulsifier), should be taken to mean a composition or article of manufacture that is solid at room temperature and malleable or pliable to a desired form. The terms "solid," "malleable solid," and "pliable solid" are used interchangeably herein.

[0126] The term "drug delivery device" or similar terms, which may be used interchangeably herein, refers to a component of the disclosed dosage units that includes at least one emulsified drug. The "drug delivery device" can be formed as a unit dosage form, as described herein.

[0127] As used herein, "controlled release" (CR) or "extended release" refers to a manner in which a dosage form, unit dosage form, drug delivery device, etc., releases a drug, such as but not limited to, a cannabinoid, at a controlled rate over an extended, designable time interval, specifically a predetermined extended time interval, in an amount necessary to achieve a desired serum level of the drug, such as but not limited to, a cannabinoid, to produce a prolonged or sustained pharmacological effect.

[0128] The terms "release modifier" and "release modifying agent," as used interchangeably herein, are generally polymeric agents that cause the release of a drug from a drug delivery device or a component thereof or a dosage form thereof in a manner that is different from the release in their absence.

[0129] The phrases "extended period," "extended time interval," and the like, as used interchangeably herein in reference to controlled release, refer to a period of delivery of at least 80% of the drug dose contained in a dosage unit or drug delivery device that lasts from a few hours after administration to about 12 hours and up to 24 hours after administration, typically from about 3 hours to any one of up to 4, 5, 6, 7, 8, 9, 10, 11, 12, and up to 15 hours.

[0130] As used herein, the phrase "immediate release" (IR) refers to a dosage form or drug delivery device that releases drug immediately upon exposure to or contact with gastric media. "Immediately upon exposure to gastric fluid" should be understood to mean release within a maximum of two hours of such exposure or contact. Specifically, immediate release of drug occurs within about 30 to about 60 minutes of exposure to or contact with gastric fluid. The term "immediate release (IR) component" as used herein should be interpreted to mean a component that releases drug therefrom in this described manner. The IR component as used herein can be in the form of a coating (e.g., on a capsule as described herein) or a powder (e.g., within a capsule as described herein), or any other suitable form.

[0131] The term "stable" plasma or serum level of a drug, such as, but not limited to, a cannabinoid or an active derivative or metabolite thereof as defined herein, should be taken to mean a therapeutically effective plasma level of an active cannabinoid and / or an active metabolite thereof over a suitable period of time. Specifically, a stable plasma level can refer, for example, to a continuous therapeutically effective level, a steady-state level, etc.

[0132] The term "AUC" as known in the art and used herein refers to the Area Under the Curve (known mathematically as a definite integral) in a plot of plasma drug concentration versus time. In practice, drug concentrations are measured at specific discrete time points, and the trapezoidal rule is used to estimate AUC. AUC (0 to infinity) represents total drug exposure over time. C max The term t is the maximum (or peak) serum concentration achieved by a drug in a specified compartment or test region of the body after the drug is administered. The related pharmacokinetic parameter t max is C max is the time at which the observation is made.

[0133] 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 by the United States Pharmacopeia 30 National Formulary, but without the corresponding enzymes.

[0134] "Gastric medium," "gastric fluid," and "intestinal medium," as used interchangeably herein, refer to the biological media of the stomach and intestine, respectively, or artificial media used to mimic the stomach or intestinal environment, exemplified, but not limited to, "simulated gastric fluid" ("SGF") and "simulated intestinal fluid" ("SIF").

[0135] As used herein, the term "aqueous medium" refers to a water-based liquid medium, specifically the "gastric medium," "gastric juice," "intestinal medium" as defined above, and distilled water.

[0136] As used herein, the terms "biodegradable" or "degradable" and "bioerodible" or "erodible" are intended to mean capable of being biochemically, chemically, and / or physically processed, reduced, or broken down within a patient's body within a period of between seconds and days after ingestion of a dosage unit or delivery device. As used interchangeably herein, "completely degraded / biodegraded," "essentially completely degraded / biodegraded," or "completely eroded / bioeroded" refers to at least 70%, 80%, 90%, and up to 100% degradation / erosion and disappearance of the delivery device or dosage form.

[0137] The terms "inert" or "inactive" or "inactive ingredient" or "inert ingredient" or "inactive excipient" or "inert excipient," as used interchangeably herein, refer to a component of a delivery device or dosage unit that does not immediately react with or adversely affect the properties of a drug or active ingredient, or that, when administered to a subject in reasonable amounts, does not cause any biological effect upon administration to the subject. Common examples of these components are listed in "The Handbook of Pharmaceutical Excipients," 4 th Edition, by Rowe, Sheskey and Weller, Pharmaceutical press, 2003. A further exemplary list is the Inactive Ingredients Guide of the Food and Drug Administration, USA.

[0138] The terms "film" and "layer," which may be preceded by the term "polymer," are used interchangeably herein, as the context indicates, in reference to some or all components of the drug delivery devices, layered drug delivery devices, and unit dosage forms thereof, their preparation and use, as described herein.

[0139] As used herein, the terms "drug-containing layer," "drug-containing component," or "drug-containing polymer component" shall be taken to mean a polymer film or polymer layer that comprises at least one polymer and at least one drug, respectively, a cannabinoid, as defined herein.

[0140] As used herein, the terms "emulsified drug-containing layer," "emulsified drug-containing component," or "emulsified drug-containing polymer component" should be interpreted as meaning a polymer film or layer or polymer member or component that contains at least one polymer and at least one drug, respectively, a cannabinoid, in emulsified form. These terms relate to a component or layer of a delivery device, and may also relate to an IR layer of a delivery device or unit dosage form.

[0141] The term "polymer," as used herein, refers to polymeric materials known in the art and described in more detail below, but may also be used in the context of more general aspects to encompass polymeric compositions of one or more polymers and, optionally, at least one plasticizer, i.e., inert materials of polymeric layers, members, or components included in the disclosed drug delivery devices and / or unit dosage forms thereof.

[0142] The term "polymeric component" or "drug-containing polymeric component / member / film / layer" as used herein should be taken to mean the portion of the drug delivery device that contains the drug, and optionally other pharmaceutically active agents.

[0143] As used herein, unless the context clearly indicates otherwise, terms such as "lamination" refer to the act of layering, stacking, packing, piling, superimposing, or placing at least one polymer component / component / film / layer on at least one additional polymer component / component / film / layer, bringing them into intimate contact, and applying sufficient pressure to produce, under suitable conditions of temperature and atmosphere, a uniform structure in which the boundaries of the individual layers are no longer readily distinguishable or in which the individual layers are irreversibly bonded to adjacent layers. Lamination is typically performed between polymer sheets of similar or identical composition and thickness, although films of similar or identical composition but significantly different thicknesses can also be laminated. Additionally, lamination can also be performed on multiple films of different compositions, provided that at least two of such films are similar or identical in composition and / or thickness, and provided that in the resulting structure the boundaries of the individual layers are no longer readily distinguishable or in which the individual layers are irreversibly bonded to adjacent layers. The term "easily distinguishable" should be understood to be within the ability of a person skilled in the art to distinguish between individual layers without applying microscopy or spectroscopy.

[0144] A "patient" or "subject" as referred to herein is an animal, particularly a human, to which the drug delivery devices and dosage units thereof disclosed herein can be administered.

[0145] As used herein, the term "treat" and forms thereof, such as "treatment" or "treated," should be interpreted to mean preventing or preventing the worsening of, or arresting or alleviating, a symptom (e.g., pain or nausea), or improving or curing a patient's disease or condition or symptoms associated therewith.

[0146] As used herein, the term "ratio" is a weight ratio (also designated w / w) unless otherwise indicated.

[0147] The term "suitable" as used herein should be taken to mean having properties that make it possible to provide a defined result.

[0148] As used herein, "about" generally refers to an approximate value. When referring to a dose of a drug in milligrams, "about" should be understood to include a range of the value ±15%. When referring to other values, the term should be understood to include a range of the value ±15%, for example, ±15%, ±12%, ±10%, ±8%, ±5%, ±2%, or ±1%.

[0149] As used in the description and claims, the forms "a," "an," and "the" include both the singular and the plural unless the context clearly dictates otherwise.

[0150] Throughout the following specification and examples and claims, 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. [Example]

[0151] Description of Non-Limiting Examples Example 1: CBD 5 mg IR and 20 mg CR Formulation 1 CR fraction: Exemplary preparations of emulsions containing CBD and CR (controlled release) unit dosage forms containing CBD micelles are presented below. The composition of a single unit is summarized in Table 1.

[0152] [Table 1]

[0153] CBD was dissolved in a mixture of Peceol and Kolliphor heated to 70°C using a magnetic stirrer to obtain a clear solution. In a 0.2 liter planetary mixer, PEG400 was dissolved in water. The CBD clear solution was added to form a self-emulsion. Klucel EF and Klucel GF were added and allowed to dissolve in the aqueous mixture for approximately 90 minutes. The final emulsion was cast onto a PET (Mylar™) web using a tabletop casting machine with a knife space of 950 μm. The cast emulsion was dried in an oven at 60° C. for approximately 60 minutes. The dried product was a film with a thickness of approximately 120 μm. Six dry films were stacked one on top of the other and manually laminated to obtain a laminated film having a thickness of approximately 750 μm. The laminated film was die-cut into rectangular units of 21 x 45 mm, each weighing approximately 600-650 mg and each containing 20 mg of CBD. Each unit was rolled into a cylinder and each cylinder was inserted into a 00 hard gelatin capsule.

[0154] IR fraction An exemplary preparation of a lipid-based powder containing CBD for IR (immediate release) is presented 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.

[0155] [Table 2]

[0156] CBD was dissolved in a mixture of Peceol and Kolliphor heated to 70°C using a magnetic stirrer to obtain a clear solution. Avicel 102 was added to the solution and mixed for approximately 30 minutes to obtain a uniform powder. 100 mg of powder containing 5 mg of CBD was inserted into a capsule containing the CR fraction to obtain the final unit dosage form. Each final unit contains 5mg of IR CBD and 20mg of CR CBD The dissolution profile of the final unit was tested.

[0157] Dissolution Profile: The dissolution of capsules containing the IR and CR fractions was tested using the following method.

[0158] Solubility parameters: Medium: Simulated gastric fluid (SGF), pH 1.2 or Simulated intestinal fluid (SIF), pH6.8 Temperature: 37±0.5℃ Equipment: 20 mesh basket at 100 RPM Capacity: 900ml Sampling time points: 0.5; 1; 2; 3; 4; 5; 6; 8; 10; 12 hours At each sampling point, a 5 ml aliquot of the solution was sampled from the container. The samples were tested using an HPLC method to analyze the CBD content.

[0159] HPLC parameters: [Table A]

[0160] The results of the dissolution test of Example 1 are presented in Figure 1. As can be seen, the CBD release profile is similar in both SGF and SIF. The release profile is linear, demonstrating a prolonged, controlled release profile of up to 14 hours.

[0161] Example 2: CBD 5 mg IR and 20 mg CR Formulation 2 CR fraction: Exemplary preparations of emulsions containing CBD and oral CR dosage forms containing CBD micelles are provided below. The compositions of the single units are summarized in Table 3.

[0162] [Table 3]

[0163] CBD was dissolved in a mixture of Peceol and Kolliphor heated to 70°C using a magnetic stirrer to obtain a clear solution. PEG400 was dissolved in water in a 0.2 liter planetary mixer. The CBD clear solution was added to form a self-emulsion. Klucel EF and Klucel GF were added and dissolved in water for approximately 60 minutes. The final emulsion was cast onto a PET (Mylar™) web using a tabletop casting machine with a knife space of 1000 μm. The cast emulsion was dried in an oven at 60° C. for approximately 60 minutes. The dried product is a film with a thickness of approximately 150 μm. Five dry films were stacked one on top of the other and manually laminated together to a thickness of approximately 750 μm. The laminated film was die-cut into rectangular units of 21 x 45 mm, each weighing 600-650 mg, and each unit containing 20 mg of CBD. The units were rolled into a cylindrical shape and each cylinder was inserted into a 00 hard gelatin capsule.

[0164] IR fraction The IR fraction was the same as in Example 1. Each final unit contains 5 mg of IR CBD and 20 mg of CR CBD. The final units were tested to define the dissolution profile using the same methods and parameters as described in Example 1.

[0165] The results of the dissolution test of Example 2 are presented in Figure 2. As can be seen in Figure 2, the CBD release profile is similar in both SGF and SIF. The release profile is linear, demonstrating a prolonged, controlled release profile for up to 12 hours.

[0166] Example 3: CBD 25 mg IR and 225 mg CR Formulation 3 CR fraction: Exemplary preparations of emulsions containing CBD and oral CR dosage forms containing CBD micelles are provided below. The compositions of the single units are summarized in Table 4.

[0167] [Table 4]

[0168] CBD was dissolved in lauroyl polyoxyl-32 glyceride heated to 70°C using a magnetic stirrer to obtain a clear solution. Poloxamer 407 was dissolved in water in a 0.2 liter planetary mixer. The CBD clear solution was added to form a self-emulsion. CMC and HPMC were added and dissolved in water for approximately 60 minutes. The final emulsion was cast onto a PET (Mylar™) web using a tabletop casting machine with a knife space of 1100 μm. The cast emulsion was dried in an oven at 60° C. for approximately 60 minutes. The dried product was a film with a thickness of approximately 150 μm. Five dry films were stacked one on top of the other and manually laminated together to a thickness of approximately 750 μm. The laminated film was die-cut into rectangular units of 21 x 45 mm, each weighing 720-780 mg, with each unit containing 225 mg of CBD. Each unit was rolled into a cylinder and each cylinder was inserted into a 00 hard gelatin capsule.

[0169] IR fraction An exemplary preparation of a lipid-based powder containing CBD for IR is provided below. The materials used to prepare the powder and the amounts present in a single capsule containing the powder unit are summarized in Table 5.

[0170] [Table 5]

[0171] CBD was dissolved in Kolliphor EL heated to 70°C using a magnetic stirrer to obtain a clear solution. Avicel 102 was added to the solution and mixed for approximately 30 minutes to obtain a uniform powder. 120 mg of powder containing 25 mg of CBD was inserted into a capsule containing the CR fraction. Each final unit contains 25mg of IR CBD and 225mg of CR CBD The final units were tested to define the dissolution profile.

[0172] Dissolution Profile: The dissolution of capsules containing the IR and CR fractions was tested using the same method and parameters as described in Example 1.

[0173] The results of the dissolution test of Example 3 are presented in Figure 3. The CBD release profile is similar in both SGF and SIF. The release profile is linear, demonstrating a prolonged, controlled release profile of up to 12 hours.

[0174] Example 4: CBD 10 mg CR formulation 4-layer separation An exemplary preparation of an oral CR dosage form containing CBD micelles is provided below. Each unit contains two distinct layers: a drug layer and a CR layer, which are laminated together to form the final unit.

[0175] Drug layer: Exemplary preparations of emulsions containing CBD and dry films containing CBD micelles are provided below. The compositions of the single units are summarized in Table 6.

[0176] [Table 6]

[0177] CBD was dissolved in a mixture of Peceol and Kolliphor heated to 70°C using a magnetic stirrer to obtain a clear solution. In a 0.2 liter planetary mixer, PEG400 was dissolved in water. The CBD clear solution was added and allowed to self-emulsify. Klucel EF was added and allowed to dissolve in the water for approximately 20 minutes. The final emulsion was cast onto a PET (Mylar™) web using a tabletop casting machine with a knife space of 1000 μm. The cast emulsion was dried in an oven at 60° C. for approximately 60 minutes. The dried product was a film with a thickness of approximately 120 μm. Four dry films were stacked one on top of the other and manually laminated to a thickness of approximately 500 μm.

[0178] CR layer: An exemplary preparation of a dispersion containing a modified release agent and a dry layer preparation for CR (drug-free) is provided below. The composition of a single unit is summarized in Table 7.

[0179] [Table 7]

[0180] In a 0.2 liter planetary mixer, PEG400+Klucel EF was dissolved in ethanol. HPMC K100M was added and dispersed in ethanol for about 30 minutes. The final dispersion was cast onto a PET (Mylar™) web using a benchtop casting machine with a knife space of 1000 μm. 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.

[0181] Lamination The HPMC layer was manually laminated onto the drug layer. The laminated film was die-cut into 21 x 45 mm rectangular units, each weighing 700 mg, and each unit contained 10 mg of CBD. Each unit was rolled into a cylindrical shape with the HPMC layer as the inner layer and the drug layer as the outer layer. The final unit was inserted into a 00 hard gelatin capsule. The final units were tested to define the dissolution profile.

[0182] Dissolution Profile: The dissolution of capsules containing layered drug+CR layers was tested using the same method and parameters as described in Example 1. The results of the dissolution test of Example 4 in SGF are presented in FIG.

[0183] The release profile demonstrates a prolonged, controlled release profile of up to 10 hours.

[0184] Example 5: CBD 20 mg CR formulation prepared by 5-HME (hot melt extrusion) CR fraction: An exemplary preparation of an oral CR dosage form containing CBD micelles is provided below. The composition of a single unit is summarized in Table 8 (same as Table 1).

[0185] [Table 8]

[0186] CBD was dissolved in a mixture of Peceol and Kolliphor heated to 70°C using a magnetic stirrer to obtain a clear solution. The solution was manually mixed with other excipients prior to the hot melt extrusion process. The final blend was fed into a MC15HT Microcompounder (Xplore) hot melt extruder and processed under the following conditions: Temperature: 180℃. Rotation: 50 RPM. Processing time: 5 minutes. Screw configuration: counter-rotating. The final product is a uniform extrudate with a diameter of 3 mm. The extrudate was cut into units approximately 7 cm long weighing approximately 650 mg, each containing 20 mg of CBD. The units were inserted into 00 hard gelatin capsules. The final units were tested to define the dissolution profile.

[0187] Dissolution Profile: The dissolution rate of the capsules was tested using the same method and parameters as described in Example 1. The results of the dissolution test of Example 5 in SGF are presented in FIG. The release profile is linear demonstrating a prolonged controlled release profile of up to 10 hours.

[0188] The final extrudate was examined by scanning electron microscopy according to the following procedure. SEM images were taken of cross sections of the extrudates (gold coated) using a Zeiss Ultra-Plus system with an accelerating voltage of 4.0 kV. Images were taken using a secondary emitted electron (SE) detector. An SEM image of the extrudates is presented in Figure 5A. The SEM image confirms that the CBD was in emulsion form in the final extrudates.

[0189] Example 6: THC 15 mg CR Exemplary preparations of emulsions containing THC and oral CR dosage forms containing THC micelles are provided below. The compositions of the single units are summarized in Table 9.

[0190] [Table 9]

[0191] THC is dissolved in a Labrasol and sesame oil mixture heated to 70° C. using a magnetic stirrer to obtain a clear solution. In a 0.2 liter planetary mixer, PEG400 is dissolved in water. The THC clear solution is added to form a self-emulsion. Klucel EF and CMC are added and dissolved in water for about 60 minutes. The final emulsion is cast onto a PET (Mylar™) web using a tabletop casting machine with a knife space of 1000 μm. The cast emulsion is dried in an oven at 60° C. for about 60 minutes. The dried product is a film with a thickness of about 150 μm. 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 die-cut into rectangular units measuring 21 × 45 mm, each weighing 600–650 mg, each unit containing 15 mg of THC. The units are rolled into a cylindrical shape and each is inserted into a 00 hard gelatin capsule.

[0192] Example 7: Botanical cannabis extract 30mg CR Exemplary preparations of emulsions containing botanical cannabis extract and oral CR dosage forms containing botanical cannabis extract micelles are provided below. The compositions of the single units are summarized in Table 10.

[0193] [Table 10]

[0194] The cannabis extract is dissolved in the Labrafac and Labrafil mixture heated to 70°C using a magnetic stirrer to obtain a clear solution. In a 0.2 liter planetary mixer, dissolve PEG400 in water. Add the clear solution of cannabis extract to form a self-emulsion. Add HPMC E3 and K4M and dissolve in water for approximately 60 minutes. The final emulsion is cast onto a PET (Mylar™) web using a tabletop casting machine with a knife space of 1000 μm. The cast emulsion is dried in an oven at 60° C. for about 60 minutes. The dried product is a film with a thickness of about 150 μm. Five sheets of dry film are stacked one on top of the other and manually laminated. The laminated film has a thickness of approximately 750 μm. The laminated film is punched into rectangular units of 21×45 mm, each weighing 500-550 mg. The units are rolled into a cylindrical shape and each is inserted into a 00 hard gelatin capsule.

[0195] Example 8: Botanical cannabis extract 300mg CR Exemplary preparations of emulsions containing botanical cannabis extract and oral CR dosage forms containing botanical cannabis extract micelles are provided below. The compositions of the single units are summarized in Table 11.

[0196] [Table 11]

[0197] The botanical cannabis extract is dissolved in Gelucire 48 / 16 heated to 70°C using a magnetic stirrer to obtain a clear solution. In a 0.2 liter planetary mixer, dissolve propylene glycol in water. Add the cannabis clear solution to form a self-emulsion. Add Klucel EF and methylcellulose A4M and dissolve in water for approximately 60 minutes. The final emulsion is cast onto a PET (Mylar™) web using a tabletop casting machine with a knife space of 1100 μm. The cast emulsion is dried in an oven at 60° C. for approximately 60 minutes. The dried product is a film with a thickness of approximately 150 μm. Five sheets of dry film are stacked one on top of the other and manually laminated. The laminated film has a thickness of approximately 750 μm. The laminated film is die-cut into rectangular units of 21×45 mm, each weighing 800 mg, and each unit containing 300 mg of botanical cannabis extract. The units are rolled into a cylindrical shape and each is inserted into a 00 hard gelatin capsule.

[0198] Example 9 - Ritonavir 100mg CR Exemplary preparations of emulsions containing ritonavir and oral CR dosage forms containing ritonavir micelles are provided below. The compositions of the single units are summarized in Table 12.

[0199] [Table 12]

[0200] Ritonavir is dissolved in the Labrasol and Kolliphor mixture using a magnetic stirrer to obtain a clear solution. In a 0.2 liter planetary mixer, dissolve the poloxamer 407 in the water. The ritonavir clear solution is added to form a self-emulsion, and PVP K30 and Klucel GF are added and allowed to dissolve for 90 minutes. The final emulsion is cast onto a silicone-coated PET (Mylar™) web using a tabletop casting machine with a knife space of 1200 μm. The cast emulsion is dried in an oven at 60° C. for approximately 90 minutes. The dried product is a film with a solvent content (based on loss on drying test) value of 6% or less and a thickness of approximately 150 μm. Five dry films are stacked one on top of the other and manually laminated together to a thickness of approximately 750 μm. The laminated film is die cut into rectangular units of 21 x 45 mm, each weighing 600-650 mg, with each unit containing 100 mg of ritonavir. The units are rolled into a cylindrical shape and each is inserted into a 00 hard gelatin capsule.

[0201] Example 10 - Fenofibrate 50 mg CR Exemplary preparations of emulsions containing fenofibrate and oral CR dosage forms containing fenofibrate micelles are presented below. The compositions of the single units are summarized in Table 13.

[0202] [Table 13]

[0203] The fenofibrate is dissolved in the Maisine and Tween mixture using a magnetic stirrer to obtain a clear solution. In a 0.2 liter planetary mixer, dissolve TEC in water. Add fenofibrate clear solution to form a self-emulsion, then add CMC7L2P and HPMC K15M and dissolve for 90 minutes. The final emulsion is cast onto a silicone-coated PET (Mylar™) web using a tabletop casting machine with a knife space of 1200 μm. The cast emulsion is dried in an oven at 60°C for about 90 minutes. The dried product is a film with a solvent content of 6% or less (based on loss on drying test) and a thickness of about 150 μm. Five sheets of dry film are stacked one on top of the other and manually laminated. The resulting laminated film has a thickness of approximately 750 μm. The laminated film is punched into rectangular units measuring 21 × 45 mm, each weighing 500–600 mg and containing 50 mg of fenofibrate. The units are rolled into a cylindrical shape and each is inserted into a 00 hard gelatin capsule.

[0204] Comparative Example 11-(CBD+THC IR Film) IR Film: Exemplary preparations of emulsions containing THC and CBD, as well as IR films containing THC and CBD micelles, are presented below. The compositions of the single units are summarized in Table 14.

[0205] [Table 14]

[0206] The THC and CBD were dissolved in the Labrasol and Kolliphor mixture using a magnetic stirrer to obtain a clear solution. TEC was dissolved in water in a 0.2 liter planetary mixer. A clear solution of THC and CBD was added to form a self-emulsion. HPMC E3 and Klucel GF were added and dissolved for 90 minutes. The final emulsion was cast onto a silicone-coated PET (Mylar™) web using a tabletop casting machine with a knife space of 1100 μm. The cast emulsion was dried in an oven at 60° C. for approximately 120 minutes. The dried product was a film with a thickness of approximately 150 μm. Three dry films were stacked one on top of the other and laminated using a roller. The laminated film had a thickness of approximately 450 μm. The laminated film was punched into rectangular units of 18×40 mm, each weighing approximately 330 mg and containing 10 mg of THC and 10 mg of CBD.

[0207] The final units were tested to define the dissolution rate using the same method and parameters as described in Example 1. The units dissolved completely within 30-60 minutes.

[0208] Example 12: CBD 15 mg CR Tablets (Modified Release in Film) Exemplary preparations of emulsions containing CBD and CR tablets containing CBD micelles are provided below. The composition of a single tablet is summarized in Table 15.

[0209] [Table 15]

[0210] CBD is dissolved in a mixture of Labrasol and sesame oil heated to 70°C using a magnetic stirrer to obtain a clear solution. In a 0.2 liter planetary mixer, dissolve PEG400 in water. Add CBD clear solution to form a self-emulsion. Add Klucel EF and CMC and dissolve in water for approximately 60 minutes. The final emulsion is cast onto a PET (Mylar™) web using a tabletop casting machine with a knife space of 1000 μm. The cast emulsion is dried in an oven at 60° C. for approximately 60 minutes. The dried product is a film approximately 150 μm thick. The film is ground using a hammer mill and the ground film is sieved through a 500 micron sieve. Add MCC, PVP, and lactose to the sieved powder and blend for approximately 15 minutes. Add magnesium stearate and blend for approximately 2 minutes. The final blend was then mixed in a tablet press for 18 minutes. * Pressed into 6mm tablets, each weighing approximately 600mg, each unit contains 15mg of CBD.

[0211] Example 13: THC 20 mg CR Tablets (Modified-Release Agent Added as a Powder) Exemplary preparations of emulsions containing THC and CR tablets containing THC micelles are provided below. The composition of a single tablet is summarized in Table 16.

[0212] [Table 16]

[0213] THC is dissolved in a mixture of Peceol and GELUCIRE heated to 70° C. using a magnetic stirrer to obtain a clear solution. In a 0.2 liter planetary mixer, dissolve PEG400 in water. Add CBD clear solution to form a self-emulsion. Add Klucel EF and dissolve in water for approximately 60 minutes. The final emulsion is cast onto a PET (Mylar™) web using a tabletop casting machine with a knife space of 1000 μm. The cast emulsion is dried in an oven at 60° C. for approximately 60 minutes. The dried product is a film approximately 150 μm thick. The film is ground using a hammer mill. The ground film is sieved through a 500 micron sieve. Dicalcium phosphate dihydrate, mannitol, and Klucel GXF are added to the sieved powder and blended for approximately 15 minutes. Magnesium stearate is added and blended for approximately 2 minutes. The final blend was then mixed in a tablet press for 16 minutes. * Pressed into 5mm tablets, each weighing approximately 600mg, each unit contains 15mg of CBD.

[0214] Example 14: CBD 20 mg CR Tablets (Hot Melt Extrusion) Exemplary preparations of emulsions containing CBD and CR tablets containing CBD micelles are provided below. The composition of a single tablet is summarized in Table 17.

[0215] [Table 17]

[0216] An extrudate containing CBD micelles is prepared as described in Example 5. The extrudate is pulverized using a hammer mill. The pulverized film is sieved through a 500 micron sieve. Dicalcium phosphate dihydrate, mannitol, and Klucel GXF are added to the sieved powder and blended for approximately 15 minutes. Magnesium stearate is added and blended for approximately 2 minutes. The final blend was then mixed in a tablet press for 20 minutes. * Pressed into 7mm tablets, each weighing approximately 750mg, each unit contains 15mg of CBD.

[0217] Example 15: Pharmacokinetic clinical study testing the CR formulations described in Examples 1, 2, and 3. [Table B]

[0218] Example 16: Leuprorelin-docusate complex 10 mg CR Exemplary preparations of emulsions containing leuprorelin-docusate complexes and oral CR dosage forms containing leuprorelin-docusate micelles are presented below. The compositions of the single units are summarized in Table 18.

[0219] [Table 18]

[0220] Hydrophobic ion pairing (HIP) process: The peptide solution is prepared by dissolving leuprorelin 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)).

[0221] A surfactant solution is prepared by dissolving docusate sodium in water at a concentration of 5 mg / ml. The surfactant solution is added to the peptide solution under vigorous stirring (400 rpm). During the reaction, an immediate white precipitate indicates the formation of a hydrophobic peptide complex. The mixture is centrifuged at 4000 rpm for 10 minutes using a high-speed centrifuge. The supernatant is separated from the precipitate, and the final precipitate containing the leuprorelin-docusate complex is dried in an oven at 40°C for 24 hours.

[0222] Final preparation: The leuprorelin-docusate complex is dissolved in Kolliphor EL using a magnetic stirrer to obtain a clear solution. In a 0.2 liter planetary mixer, dissolve the poloxamer 407 in the water. The clear solution of leuprorelin-docusate complex is added to form a self-emulsion, and HPMC E3 and Klucel GF are added and allowed to dissolve for 90 minutes. The final emulsion is cast onto a silicone-coated PET (Mylar™) web using a tabletop casting machine with a knife space of 1000 μm. The cast emulsion is dried in an oven at 60° C. for approximately 90 minutes. The dried product is a film with a solvent content (based on loss on drying test) value of 6% or less and a thickness of approximately 150 μm. Five dry films are stacked one on top of the other and manually laminated together to a thickness of approximately 750 μm. The laminated film is punched into rectangular units of 21 x 45 mm, each weighing 600-650 mg, with each unit containing 15 mg of leuprorelin-docusate complex (10 mg of leuprorelin). The units are rolled into a cylindrical shape and each is inserted into a 00 hard gelatin capsule.

Claims

1. 1. An oral drug delivery device for the 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-modifying agent, and optionally at least one pharmaceutically acceptable plasticizer, and at least one lipophilic drug emulsified in at least one emulsifier; the oral drug delivery device is configured to be incorporated into or formed as an orally administrable unit dosage form; The oral drug delivery device is configured to enable the at least one release modifier to form a viscous gel configured to gradually erode upon ingestion of the unit dosage form and contact with gastric and / or intestinal media, and to controllably release the emulsified drug into the surrounding environment in the form of micelles.

2. 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, and optionally the at least one pharmaceutically acceptable plasticizer form a controlled-release (CR) drug-containing polymer component of the delivery device, and at least one lipophilic drug emulsified in the at least one emulsifier is embedded in the polymer component.

3. 1. An oral drug delivery device for the controlled delivery of at least one lipophilic drug, said 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, and optionally at least one pharmaceutically acceptable plasticizer, and at least one lipophilic drug emulsified in at least one emulsifier embedded in said polymer component; the oral drug delivery device is configured to be incorporated into or formed as an orally administrable unit dosage form; The oral drug delivery device, wherein the at least one release modifier is configured to form a viscous gel that is configured to gradually erode upon ingestion of the unit dosage form and contact with gastric and / or intestinal media, and that gradually erodes as it passes through the stomach and intestinal tract, and the gel controllably releases the emulsified drug in the form of micelles into the surrounding environment.

4. The release modifier has a viscosity of at least 150 mPa when dissolved in water at 2% w / w. ＊ 4. The oral drug delivery device of claim 1, wherein the polymer is a hydrophilic polymer that results in a solution having a viscosity of 1000 s.

5. 5. The oral drug delivery device of claim 1, wherein the release modifier is included in an amount of at least about 30 mg per dosage unit.

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

7. 7. The oral drug delivery device of claim 1, wherein the at least one lipophilic drug has a log P > 2.

8. 8. The oral drug delivery device of 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 modified lipophilic drug such as cannabis extract, ritonavir, fenofibrate, diclofenac, flurbiprofen diazepam, vitamin E, piroxicam, lopinavir, clofazimine, or a hydrophobic ion-pair peptide drug.

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

11. An oral drug delivery device according to any one of claims 1 to 10, wherein said unit dosage form comprises said drug delivery device incorporated into an oral capsule, preferably a softgel capsule.

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

13. 13. The oral drug delivery device of claim 11 or 12, wherein the unit dosage 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, and the IR drug-containing component is in solid or liquid form, such as a powder.

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

15. 11. The oral drug delivery device of claim 2, wherein the delivery device comprises 1 to about 50 CR drug-containing layers, the CR drug-containing layers being stacked, each CR drug-containing layer comprising the at least one emulsified lipophilic drug embedded in the polymer component, and each layer being of a predetermined geometric shape, preferably essentially rectangular, square, or other polygonal shape, or a non-polygonal shape such as, for example, an oval shape, and preferably each of the layers being of the same geometric shape.

16. 16. The oral drug delivery device of claim 15, wherein the thickness of each of the drug-containing layers is from about 20 μm to about 1000 μm, and the layers each have the same or different thicknesses.

17. 17. An oral drug delivery device according to claim 15 or 16, wherein a plurality of the drug-containing layers stacked together are rolled to form an essentially cylindrical body.

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

19. 11. 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-modifying agent, the optional at least one pharmaceutically acceptable plasticizer, and the at least one lipophilic drug emulsified in the at least one emulsifier constitute an essentially solid, homogeneous CR mixture adapted to be incorporated into the orally administrable unit dosage form.

20. 11. The oral drug delivery device of 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-modifying agent, the optional at least one pharmaceutically acceptable plasticizer, and the at least one lipophilic drug emulsified in the at least one emulsifier embedded therein constitute an essentially homogeneous, essentially solid CR mixture configured to be incorporated into the orally administrable unit dosage form.

21. 21. The oral drug delivery device of claim 19 or 20, wherein the CR mixture is shaped essentially as a cylinder.

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

23. 23. The oral drug delivery device of any one of claims 19 to 22, wherein the drug delivery device is incorporated into an oral capsule, preferably a softgel capsule, and the 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 the at least one emulsifier, and the IR drug-containing component optionally further comprises a suitable carrier or diluent, and the IR drug-containing component is in solid or liquid form.

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

25. 15. The oral drug delivery device of claim 1, wherein the drug delivery device is configured as a CR orally administrable tablet, the tablet comprising at least one lipophilic drug emulsified in a first of the film-forming polymers, and optionally the plasticizer, and the at least one emulsifier embedded therein, and a release modifier, optionally together with a further film-forming polymer, which may be the same as or different from the first of the film-forming polymers, and the tablet optionally further comprising at least one tableting excipient or additive, the excipient or additive being any one of a binder, a diluent, a filler, a lubricant, and a glidant, and any mixture of at least two thereof.

26. 26. The oral drug delivery device of claim 24 or 25, wherein the tablet optionally further comprises an additional amount of at least one additional pharmaceutically acceptable release-modifying polymer in solid form, preferably in crushed or powder form, wherein the additional release-modifying agent may be the same as or different from the at least one each additional pharmaceutically acceptable release-modifying agent.

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

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

29. - 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, and the at least one lipophilic drug emulsified in the at least one emulsifier is embedded in the polymer component; and - said at least one pharmaceutically acceptable release modifier and said optional at least one pharmaceutically acceptable plasticizer form a CR polymer component, said CR component optionally further comprising at least one pharmaceutically acceptable film-forming hydrophilic polymer; 29. An oral drug delivery device according to any one of claims 1 to 28, comprising: An oral drug delivery device, 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.

30. 1. An oral drug delivery device for the controlled delivery of at least one lipophilic drug, said 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 said emulsified drug is embedded in said drug-containing polymer component; and - 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; Including, 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 oral drug delivery device is configured to be incorporated into an orally administrable unit dosage form; The oral drug delivery device is configured to enable the at least one release modifier to form a viscous gel configured to gradually erode upon ingestion of the unit dosage form and contact with gastric and / or intestinal media, and to controllably release the emulsified drug into the surrounding environment in the form of micelles.

31. 31. The oral drug delivery device of claim 29 or 30, wherein the drug-containing polymer component comprises 1 to about 50 drug-containing layers, each layer comprising the at least one emulsified lipophilic drug embedded in the hydrophilic polymer component and optionally the plasticizer, the drug-containing layers being stacked one on top of the other, and each drug-containing layer being of a predetermined geometric shape, preferably essentially rectangular, square, or other polygonal shape, or a non-polygonal shape such as, for example, an oval, and preferably each of the layers being of the same geometric shape.

32. 32. The oral drug delivery device of claim 31, wherein the thickness of each of the drug-containing layers is from about 15 μm to about 900 μm, and the layers each have the same or different thicknesses.

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

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

35. 35. The oral drug delivery device of any one of claims 29 to 34, wherein the drug delivery device is incorporated into an oral capsule, preferably a softgel capsule, and 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, and the IR drug-containing component optionally further comprises a suitable carrier or diluent, and the IR drug-containing component is in solid or liquid form.

36. 1. An oral drug delivery device for the 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-modifying agent, and optionally at least one pharmaceutically acceptable plasticizer, and at least one lipophilic drug emulsified in at least one emulsifier; the oral drug delivery device is configured to be incorporated into or formed as an orally administrable unit dosage form; In the oral drug delivery device, the at least one release modifier is configured, upon ingestion of the dosage unit and contact with gastric and / or intestinal media, to form a viscous gel configured to gradually erode upon passage through the stomach and intestinal tract and controllably release the emulsified drug in the form of micelles to the surrounding environment, and the release modifier has a viscosity of at least 150 mPa when dissolved in water at 2% w / w. ＊ 10. An oral drug delivery device comprising: a hydrophilic polymer that provides a solution having a viscosity of 1000 s, the release modifier being present in an amount of at least about 30 mg per unit dosage; the at least one emulsifier being a lipid excipient having an HLB (hydrophilic lipophilic balance) of greater than 6, optionally at least 50% of the emulsifier being a mixture of lipid excipients having an HLB of greater than 6; and the remaining lipid excipients being any one of oils, fatty acids, glycerides, polyoxyglycerides, polyglyceryl and polyalcohol esters, or water-insoluble surfactants, or any mixture of at least two thereof, each of the remaining lipid excipients having an HLB of less than, equal to, or greater than 6.

37. 1. An oral drug delivery device for the controlled delivery of at least one lipophilic drug, said 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, and optionally at least one pharmaceutically acceptable plasticizer; and at least one lipophilic drug emulsified in at least one emulsifier embedded in said polymer component; the oral drug delivery device is configured to be incorporated into or formed as an orally administrable unit dosage form; The oral drug delivery device is configured to enable the at least one release modifier to form a viscous gel upon ingestion of the dosage unit and contact with gastric and / or intestinal media, the viscous gel being configured to gradually erode upon passage through the stomach and intestinal tract, and to controllably release the emulsified drug into the surrounding environment in the form of micelles, the release modifier having a viscosity of at least 150 mPa when dissolved in water at 2% w / w. ＊ is a hydrophilic polymer that gives a solution with a viscosity of 0.05 s, An oral drug delivery device, wherein the release-modifying agent is included in an amount of at least about 30 mg per unit dosage form, and the at least one emulsifier is a lipid excipient having an HLB (hydrophilic lipophilic balance) of greater than 6, and optionally the emulsifier is a mixture of lipid excipients, at least 50% of which have an HLB of greater than 6, and the remaining lipid excipients are any one of oils, fatty acids, glycerides, polyoxyglycerides, polyglyceryl and polyalcohol esters, or water-insoluble surfactants, or any mixture of at least two thereof, and each of the remaining lipid excipients has an HLB of less than, equal to, or greater than 6.

38. 1. An oral drug delivery device for the controlled delivery of at least one lipophilic drug, said 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 said emulsified drug is embedded in said 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; the hydrophilic film-forming polymer and optional plasticizer in the drug-containing polymer component and the CR polymer component can be the same or different; the oral drug delivery device is configured to be incorporated into an orally administrable unit dosage form; The oral drug delivery device is configured to enable the at least one release modifier to form a viscous gel upon ingestion of the dosage unit and contact with gastric and / or intestinal media, the viscous gel being configured to gradually erode upon passage through the stomach and intestinal tract, and to controllably release the emulsified drug into the surrounding environment in the form of micelles, the release modifier having a viscosity of at least 150 mPa when dissolved in water at 2% w / w. ＊ is a hydrophilic polymer that gives a solution with a viscosity of 0.05 s, An oral drug delivery device, wherein the release-modifying agent is included in an amount of at least about 30 mg per unit dosage form, and the at least one emulsifier is a lipid excipient having an HLB (hydrophilic lipophilic balance) of greater than 6, and optionally the emulsifier is a mixture of lipid excipients, at least 50% of which have an HLB of greater than 6, and the remaining lipid excipients are any one of oils, fatty acids, glycerides, polyoxyglycerides, polyglyceryl and polyalcohol esters, or water-insoluble surfactants, or any mixture of at least two thereof, and each of the remaining lipid excipients has an HLB of less than, equal to, or greater than 6.

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

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

41. The pharmaceutically active cannabinoid is selected from the group consisting of delta-9-tetrahydrocannabinol (Δ9-THC, THC), iso-tetrahydrocannabimol (iso-THC), cannabinol (CBN), cannabidiol (CBD), cannabigerol (CBG), cannabichromene (CBC), cannabielsoin (CBE), cannabicyclol (CBL), cannabicitran (CBT), cannabivarin (CBV), tetrahydrocannabivarin (THCV), cannabidivarin (CBDV), tetrahydrocannabivarin (THCV), cannabidivarin (CBDV), tetrahydrocannabicyclol (CBL), cannabicitran (CBT), cannabivarin (CBV), tetrahydrocannabivarin (THCV), cannabidivarin (CBDV), tetrahydrocannabicyclol (CBL), can ...

41. The oral drug delivery device of any one of claims 8 to 40, wherein the active ingredient is any one of tetrahydrocannabidiol (THCBD), tetrahydrocannabigerol (THCBG), tetrahydrocannabichromene (THCBC), tetrahydrocannabidivalol (THCBDV), cannabichromevaline (CBCV), cannabigerovaline (CBGV), and cannabigerol methyl ether (CBGM), and pharmaceutically acceptable derivatives and pharmaceutically active metabolites thereof.

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

43. 42. The oral drug delivery device of any one of claims 1 to 41, wherein the at least one release modifier is any one of 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 G, HEC M, HEC HX, HEC HHX), polyethylene oxide, carboxymethyl cellulose such as (CMC 7MF, CMC 7H3F, or CMC 7HF), gelatin, gum, and protein, and any mixture of at least two thereof.

44. 44. An 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 lipid excipient having an HLB value of more than 6 is selected from the group consisting of Gelucire 50 / 13 (stearoyl polyoxyl-32 glyceride), Gelucire 44 / 14 (lauroyl polyoxyl-32 glyceride), Gelucire 48 / 16 (polyoxyl-32 stearate (type I) NF), Labrafil 2125 (linoleoyl polyoxyl-6 glyceride), Labrafil 1944 (oleoyl polyoxyl-6 glyceride), Labrasol (caprylocaproyl polyoxyl-8 glyceride), Kolliphor RH40 (polyoxyl 40 hydrogenated castor oil), Kolliphor EL (polyoxyl-35 ...

45. The oral drug delivery device of any one of claims 36 to 44, wherein the active ingredient is any one of HS15 (macrogol-15-hydroxystearate), Kolliphor P407 / 124 / 188 (poloxamer 407 / 124 / 188), and Kolliphor PS80 / 60 / 20 (polysorbate 80 / 60 / 20), and any mixture of at least two thereof.

46. The emulsifier is selected from the group consisting of Gelucire 50 / 13 (stearoyl polyoxyl-32 glyceride), Gelucire 44 / 14 (lauroyl polyoxyl-32 glyceride), Gelucire 48 / 16 (polyoxyl-32 stearate (type I) NF), Labrafil 2125 (linoleoyl polyoxyl-6 glyceride), Labrafil 1944 (oleoyl polyoxyl-6 glyceride), Labrasol (caprylocaproyl polyoxyl-8 glyceride), Kolliphor RH40 (polyoxyl 40 hydrogenated castor oil), Kolliphor EL (polyoxyl-35 castor oil), Kolliphor HS15 (macrogol-15-hydroxystearate), Kolliphor 46. ​​The oral drug delivery device of any one of claims 1 to 45, wherein the device is a mixture of lipid excipients, at least 50% of which have an HLB greater than 6, such as P407 / 124 / 188 (poloxamer 407 / 124 / 188), and Kolliphor PS80 / 60 / 20 (polysorbate 80 / 60 / 20), and the remaining lipid excipients are any one of oils, fatty acids, glycerides, polyoxyglycerides, polyglyceryl and polyalcohol esters, or water-insoluble surfactants, or any mixture of at least two thereof, each said remaining lipid excipient having an HLB less than, equal to, or greater than 6.

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

20.

48. 48. The oral drug delivery device of any one of claims 1 to 47, wherein the hydrophilic film-forming polymer is any one of povidone, copovidone, polyvinyl alcohol, hydrophilic polyacrylamide derivatives, proteins, gelatin, hydroxypropyl cellulose, polyethylene oxide, amino-methacrylate copolymer NF, hydroxypropylmethylcellulose, hydroxyethylcellulose, carboxymethylcellulose, sodium carboxymethylcellulose, methylcellulose, or polyvinyl alcohol-polyethylene glycol graft copolymer, and any combination of at least two thereof.

49. 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 from about 25 to about 85% w / w of the device, preferably from about 25 to 70% w / w, more preferably from about 30 to about 70% w / w.

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

51. 51. An orally administrable pharmaceutical unit dosage comprising a drug delivery device according to any one of claims 1 to 23 and 29 to 50 adapted to be incorporated into an oral capsule, preferably a softgel capsule.

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

53. 53. An orally administrable tablet according to claim 52, which is incorporated into an oral capsule, preferably a softgel capsule.

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

55. 55. The orally administrable pharmaceutical unit dosage form of 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 at least one lipophilic drug in the 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, and the IR drug-containing component being in solid or liquid form, such as a powder.

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

57. 57. The orally administrable pharmaceutical unit dosage form of claim 55 or 56, wherein the drug is distributed in a predetermined ratio between the CR drug delivery device and the IR drug-containing component.

58. 58. A drug delivery device according to any one of claims 8 to 41 and 43 to 50 or an orally administrable pharmaceutical unit formulation according to claim 56 or 57 for use in a method for any one of the treatment, alleviation and prevention of worsening of a disease, disorder or condition responsive to cannabinoid therapy in a subject in need thereof, said method comprising orally administering said drug delivery device or pharmaceutical unit formulation to said subject.

59. 58. A drug delivery device for use or a pharmaceutical dosage unit for use as described in claim 57, wherein the disease, disorder, or condition responsive to cannabinoid therapy is any one of anorexia associated with weight loss in AIDS patients, nausea and vomiting associated with cancer chemotherapy, pain, anxiety, depression, muscle spasticity, arthritis and rheumatism, multiple sclerosis and other neuromuscular inflammatory disorders, inflammatory bowel disease 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 therapy.

60. 58. A drug delivery device according to any one of claims 8 to 40 and 42 to 50 or an orally administrable pharmaceutical unit dosage form according to claim 56 or 57 for use in a method for any one of the treatment, alleviation, and prevention of worsening of a disease, disorder, or condition responsive to any one of modified lipophilic drugs such as ritonavir, fenofibrate, diclofenac, flurbiprofen diazepam, vitamin E, piroxicam, lopinavir, clofazimine, or hydrophobic ion-pair peptide drugs, their pharmaceutically acceptable derivatives, and pharmaceutically active metabolites.

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

62. 58. A method for any one of the treatment, alleviation, and prevention of worsening of a disease, disorder, or condition responsive to cannabinoid therapy in a subject in need thereof, 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 unit dosage form according to claim 56 or 57, wherein the administration is under fed or fasted conditions.

63. 63. The method of claim 62, wherein the disease, disorder, or condition responsive to cannabinoid therapy is any one of anorexia associated with weight loss in AIDS patients, nausea and vomiting associated with cancer chemotherapy, pain, anxiety, depression, muscle spasticity, arthritis and rheumatism, multiple sclerosis and other neuromuscular inflammatory disorders, inflammatory bowel disease 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 therapy.

64. 58. 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 their active metabolites 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 unit dosage form according to claim 56 or 57.

65. 58. A method for any one of the treatment, alleviation, and prevention of worsening of a disease, disorder, or condition responsive to any one of modified lipophilic drugs such as ritonavir, fenofibrate, diclofenac, flurbiprofen diazepam, vitamin E, piroxicam, lopinavir, clofazimine, or hydrophobic ion-pair peptide drugs, their pharmaceutically acceptable derivatives, and pharmaceutically active metabolites, comprising orally administering to the subject an oral drug delivery device described in any one of claims 8 to 40 and 42 to 50 or an orally administrable pharmaceutical unit dosage form described in claim 56 or 57, wherein the administration is under fed or fasted conditions.

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

Images