Compositions containing cannabidiol and hydroxychloroquine in fixed dose combination capsules

Abstract

The present disclosure generally relates to a composition comprising a synergistic combination of cannabidiol (CBD) or a pharma- ceutically acceptable salt or derivative thereof and hydroxychloroquine or a pharma-ceutically acceptable salt thereof, which advantageously allows for the simultaneous administration of two active pharmaceutical ingredients (APIs) in a single dosage form. In one embodiment, the present disclosure also relates to the use of the method and composition for the treatment of inflammatory conditions.

Description

[Technical field]

[0001] (Related Applications) This application claims priority from Australian Provisional Patent Application No. 2021902170, filed on July 15, 2021, the entire contents of which are incorporated herein by reference.

[0002] The present disclosure generally relates to a composition comprising a synergistic combination of cannabidiol (CBD) or a pharma- ceutically acceptable salt or derivative thereof and hydroxychloroquine or a pharma-ceutically acceptable salt thereof, which advantageously allows for the co-administration of two active pharmaceutical ingredients (APIs) in a single dosage form. In one embodiment, the present disclosure also relates to a method and use of the composition for treating inflammatory conditions. [Prior art documents] [Patent documents]

[0003] [Patent Document 1] Australian Provisional Patent Application No. 2021902170 [Patent Document 2] International Publication No. 2021 / 062481 [Patent Document 3] U.S. Patent No. 9,433,584 [Patent Document 4] U.S. Patent No. 10,383,826 [Patent Document 5] International Publication No. 2012 / 017325 [Patent Document 6] U.S. Patent No. 10,189,762 [Patent Document 7] International Publication No. 2004 / 016277 [Patent Document 8] U.S. Patent No. 10,059,682 [Patent Document 9] U.S. Patent No. 2,546,658 [Patent Document 10] U.S. Patent No. 5,314,894

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Non-licensed literature

[0004] [Non-licensed document 1] Lopez-Valero,2018,Biochemical Pharmacology,157:266-274 [Non-licensed document 2] Wassmann,2020,Scientific Reports,10,Article No.4112 [Non-licensed document 3] Remington's Pharmaceutical Handbook (Mack Publishing Co., NY, USA)

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[0005] Fixed dose combination (FDC) drug products containing multiple active pharmaceutical ingredients (APIs) are often difficult to formulate when the active ingredients are incompatible, i.e., the APIs react adversely with each other when combined at the desired concentration levels. FDCs also require significant formulation and manufacturing optimization of the product to address stability, dose differentials, and physical and chemical compatibility.

[0006] For FDCs containing cannabidiol (CBD), these limitations may be even more burdensome due to bioavailability issues, variable pharmacokinetic profiles, potential for polymorphism, and a higher risk of drug-drug interactions (DDIs) associated with CBD. However, recent studies have shown that CBD may synergize with other APIs for the treatment of a variety of different conditions, including traumatic brain injury (e.g., WO 2021 / 062481), glioblastoma multiforme (GBM; Lopez-Valero, 2018, Biochemical Pharmacology, 157:266-274), and gram-positive bacterial infections (Wassmann, 2020, Scientific Reports, 10, Article No. 4112).

[0007] In most cases, synergy between CBD and one or more additional APIs occurs when two or more APIs are delivered to a subject simultaneously. Using standard methods in the art, the formulation and development of such a single dosage form or FDC is expected to require extensive consideration of the physical properties of the API, the delivery mode, the flow properties of the composition, the compatibility of excipients, the uniformity of manufacture and the release profile to ensure that the pharmacokinetic properties of the API are maintained (or improved) and / or the composition is stabilized to have an acceptable shelf life.

[0008] Therefore, there remains an urgent need to develop pharmaceutical compositions that allow the simultaneous delivery of CBD and one or more additional APIs in a single dosage form (e.g., FDC), regardless of physical-chemical compatibility and / or stability issues.

[0009] (overview) In one aspect of the present disclosure, a. cannabidiol (CBD) or a pharma- ceutically acceptable salt or derivative thereof; and b. A solid dosage form of hydroxychloroquine or a pharma- ceutically acceptable salt thereof; A composition comprising: A composition is provided, wherein CBD or a pharma- ceutically acceptable salt or derivative thereof is encapsulated in a first capsule, and a solid dosage form of hydroxychloroquine or a pharma- ceutically acceptable salt thereof is encapsulated in a second capsule, wherein the second capsule is at least partially encapsulated in the first capsule.

[0010] Various examples and embodiments of the present invention are herein described, by way of non-limiting example only, with reference to the following figures: [Brief description of the drawings]

[0011] [Figure 1] 1 is a schematic diagram of a composition comprising a first capsule and a second capsule, the second capsule comprising a tablet solid dosage form of hydroxychloroquine enclosed within the first capsule.

[0012] [Diagram 2] Schematic diagram of a composition comprising a first capsule and a second capsule, the second capsule comprising a particulate solid dosage form (e.g., powder, microgranules, nanoparticles) of hydroxychloroquine.

[0013] [Diagram 3] Figure 1 shows that CBD and hydroxychloroquine are effective in treating mice with pneumonia. (A) Photograph of normal lung tissue from a sham-treated control mouse; (B) Photograph of lung tissue from a vehicle control mouse; (C) Photograph of lung tissue from a mouse treated with CBD (1 mg / kg); (D) Photograph of lung tissue from a mouse treated with hydroxychloroquine (2.5 mg / kg); (E) Photograph of lung tissue from a mouse treated with CBD (1 mg / kg) and hydroxychloroquine (2.5 mg / kg); (F) Photograph of lung tissue from a mouse treated with CBD (10 mg / kg); (G) Photograph of lung tissue from a mouse treated with hydroxychloroquine (25 mg / kg); and (H) Photograph of lung tissue from a mouse treated with CBD (10 mg / kg) and hydroxychloroquine (25 mg / kg). All images are shown at 100x magnification and stained with hematoxylin and eosin (H&E). Arrows indicate infiltration of inflammatory cells.

[0014] [Figure 4]Figure 1 shows that CBD and hydroxychloroquine are effective in treating TNBS-induced colitis mice. (A) Photograph of normal colon tissue from a sham-treated control mouse; (B) Photograph of colon tissue from a vehicle control mouse ("*" indicates areas of inflammatory cell infiltration in submucosal edema); (C) Photograph of colon tissue from a mouse treated with CBD (1 mg / kg) ("*" indicates areas of inflammatory cell infiltration in submucosal edema); (D) Photograph of colon tissue from a mouse treated with hydroxychloroquine (2.5 mg / kg) ("*" indicates areas of mild abnormalities, cystic dilation, and aberrant crypts); (E) Photograph of colon tissue from a mouse treated with CBD (1 mg / kg) and hydroxychloroquine (2.5 mg / kg) ("*" indicates areas of minimal cellular infiltration). All images are shown at 100x magnification and stained with hematoxylin and eosin (H&E).

[0015] [Diagram 5] CBD and hydroxychloroquine are effective in treating rats with collagen-induced arthritis. (A) Photograph of normal hind ankle tissue from a sham-treated control rat; (B) Photograph of hind ankle tissue from a vehicle control rat; (C) Photograph of hind ankle tissue from a rat treated with CBD (1 mg / kg); (D) Photograph of hind ankle tissue from a rat treated with hydroxychloroquine (2.5 mg / kg); (E) Photograph of hind ankle tissue from a rat treated with CBD (1 mg / kg) and hydroxychloroquine (2.5 mg / kg). All images are shown at 50x magnification and stained with hematoxylin and eosin (H&E).

[0016] [Figure 6] Figure 1 shows the dissolution profiles of hydroxychloroquine sulfate tablets 200 mg and hydroxychloroquine sulfate tablets 100 mg. Graphical representation of dissolution (%; y-axis) versus sampling time (min; x-axis). The line with diamond data points represents hydroxychloroquine sulfate tablets 200 mg. The line with square data points represents hydroxychloroquine sulfate tablets 100 mg. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0017] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this disclosure belongs. All materials and methods described herein, and all materials and methods similar or equivalent, can also be used to practice the present invention.

[0018] Throughout this specification, unless the context requires otherwise, the word "comprise", or variations such as "comprises" or "comprising", will be understood to indicate the inclusion of a stated element or integer or group of elements or integers, but not the exclusion of any other element or integer or group of elements or integers.

[0019] The phrase "consisting of" means inclusive and limited to whatever follows the phrase "consisting of." Thus, the phrase "consisting of" indicates that the recited elements are required or essential, and that no other elements may be present. The phrase "consisting essentially of" means limited to the elements recited after this phrase, and that other elements do not interfere with or contribute to the activity or action specified in this disclosure for the recited elements. Thus, the phrase "consisting essentially of" indicates that the recited elements are required or essential, but that other elements are optional and may or may not be present depending on whether they affect the activity or action of the recited elements.

[0020] As used herein, the singular forms "a," "an," and "the" include plural embodiments unless the context clearly dictates otherwise. Thus, for example, reference to "a compound" includes a single compound, as well as two or more compounds, reference to "an agent" includes one agent, as well as two or more agents, etc.

[0021] The term "about" is understood by those of ordinary skill in the art and will vary to some extent depending on the context in which it is used. If there are uses of a term which are not clear to persons of ordinary skill in the art, "about" will mean up to plus or minus 10% of the particular term, given the context in which it is used.

[0022] The present disclosure relates, at least in part, to a method for treating a patient with cannabidiol (CBD) or a pharma- ceutically acceptable salt or derivative thereof, comprising administering to the patient a dose of at least one hydroxychloroquine or a pharma- ceutically acceptable salt ... CBD or a pharma- ceutically acceptable salt or derivative thereof is encapsulated in a first capsule; By incorporating hydroxychloroquine or a pharma- ceutically acceptable salt thereof into a second capsule, Based on the inventors' surprising discovery that a synergistic combination of CBD and hydroxychloroquine can be formulated where a second capsule is at least partially encapsulated in a first capsule, thereby enabling simultaneous administration of the synergistic combination of CBD and hydroxychloroquine.

[0023] Thus, in the embodiments disclosed herein, a. CBD or a pharma- ceutically acceptable salt or derivative thereof; and b. A solid dosage form of hydroxychloroquine or a pharma- ceutically acceptable salt thereof; wherein CBD or a pharma- ceutically acceptable salt or derivative thereof is encapsulated in a first capsule, a solid dosage form of hydroxychloroquine or a pharma- ceutically acceptable salt thereof is encapsulated in a second capsule, and the second capsule is at least partially encapsulated by the first capsule.

[0024] composition In accordance with the present disclosure, the compositions allow for the delivery of two synergistic active pharmaceutical ingredients (APIs) that have not previously been combined in a single dosage form. The compositions described herein advantageously avoid issues related to API incompatibility that can limit the ability to formulate combinations into a single dosage form or fixed dose combination (FDC).

[0025] As used herein, the phrase "fixed dose combination" or "FDC" refers to a combination of two or more APIs contained in a single dosage form, such as a capsule or tablet. Thus, the compositions described herein may also be referred to as FDCs.

[0026] The composition described herein, i.e., a solid dosage form of CBD or a pharma- ceutically acceptable salt or derivative thereof encapsulated in a first capsule and hydroxychloroquine or a pharma- ceutically acceptable salt thereof encapsulated in a second capsule, wherein the second capsule is at least partially encapsulated in the first capsule, provides a physical barrier between the two APIs.As described elsewhere herein, by physically separating the two APIs, problems related to incompatibility between CBD and hydroxychloroquine that may limit the ability to provide synergistic FDC are avoided.

[0027] Encapsulation can be achieved using any film-forming material known in the art, including gelatin, starch, carrageenan, gums, or synthetic materials such as hydroxypropylmethylcellulose (HPMC), other hydroxyalkylated celluloses, etc. The film-forming material is usually aqueous based and ingestible. As used herein, the term "ingestible" refers to a film-forming material that dissolves under conditions that simulate the human digestive tract or water.

[0028] In one embodiment, the first capsule can comprise, consist of, or consist essentially of animal or non-animal based materials.Non-animal materials suitable for capsules are known to those skilled in the art, and illustrative examples thereof include starch, carrageenan, gum, or synthetic materials such as hydroxyalkylated cellulose (e.g., hydroxypropylmethylcellulose) and polymers (e.g., synthetic polymers).Animal materials suitable for capsules are known to those skilled in the art, and illustrative examples thereof include hard gelatin capsules and soft gelatin capsules.

[0029] In one embodiment, the first capsule is a soft gelatin capsule.

[0030] Soft gelatin capsules or "soft gels" generally include a shell composed primarily of gelatin, plasticizers, and water. Soft gelatin capsules are widely used in the pharmaceutical industry for oral administration or as rectal or vaginal suppositories. Other applications include topical and ophthalmic medications, for example, in the cosmetics industry, soft gelatin capsules are used as specialized packaging for various types of perfumes, oils, shampoos, skin creams, etc. Soft gelatin capsules are available in various sizes and shapes, for example, tubes, ovals, ellipses, tubes, and other special types of shapes such as stars. The finished soft gelatin capsules can be in various colors, and opacifiers may be added to the soft gelatin capsules.

[0031] Processes for the manufacture of soft gelatin capsules and for the encapsulation of APIs within soft gelatin capsules are known to those skilled in the art, illustrative examples of which include the methods described in U.S. Pat. No. 9,433,584, U.S. Pat. No. 10,383,826, and WO 2012 / 017325.

[0032] In one embodiment, the soft gelatin capsule comprises a gelatin selected from the group consisting of beef gelatin, pork gelatin, fish gelatin, and blends thereof.

[0033] It is also contemplated herein that the soft gelatin capsule may contain one or more of starch, carrageenan, gums, or synthetic materials, such as hydroxyalkylated cellulose.

[0034] In one embodiment, CBD or a pharma- ceutically acceptable salt or derivative thereof is solubilized in a liquid solvent. Suitable liquid solvents are known to those skilled in the art, and examples thereof include oils, alcohols (e.g., ethanol), propylene glycol, and glycerol.

[0035] In one embodiment, the liquid vehicle is an oil selected from the group consisting of hemp seed oil, olive oil, caprylic / capric triglyceride (MCT) oil, sunflower oil, and sesame oil.

[0036] In one preferred embodiment, the oil is sesame oil.

[0037] In one embodiment, the liquid vehicle further comprises one or more agents selected from the group consisting of sweeteners, flavoring agents, coloring agents, and preservatives.Suitable sweeteners include sucrose, lactose, glucose, aspartame, or saccharin.Suitable flavorings include peppermint oil, wintergreen oil, cherry flavor, orange flavor, or raspberry flavor.Suitable preservatives include sodium benzoate, vitamin E, alpha tocopherol, ascorbic acid, methylparaben, propylparaben, sodium bisulfite, or butylated hydroxytoluene (BHT).

[0038] In one embodiment, the liquid solvent further comprises BHT.

[0039] As described elsewhere herein, the composition advantageously separates one API (i.e., CBD) from the other API (i.e., hydroxychloroquine) by a second capsule that encapsulates the second API. In one embodiment, without being bound to a particular theory, the separation of the first API from the second API is achieved based on the encapsulation of the second API with a material that is not solubilized by the liquid solvent in which CBD or a pharma- ceutically acceptable salt or derivative thereof is solubilized. For example, CBD or a pharma- ceutically acceptable salt or derivative thereof can be formulated in a pH range such that the second capsule is not solubilized.

[0040] Thus, in one embodiment, the second capsule is a capsule that is not solubilized by the liquid solvent.

[0041] The second capsule may comprise, consist of, or consist essentially of animal or non-animal based materials, as described elsewhere herein.

[0042] In one embodiment, the second capsule is selected from the group consisting of a polymeric capsule, a soft gelatin capsule, and a cellulose capsule.

[0043] In one embodiment, the second capsule is a soft gelatin capsule.

[0044] In another embodiment, the second capsule is a polymeric capsule.

[0045] Suitable polymer capsules are known to those skilled in the art, and illustrative examples include capsules comprising polyvinyl alcohol, hydroxypropyl methylcellulose, hydroxypropyl methylcellulose phthalate, hydroxypropyl methylcellulose acetate succinate, cellulose polymers, polyvinyl acetate, cellulose acetate phthalate, cellulose acetate trimellitate, and polyvinyl acetate phthalate. In one embodiment, the polymer capsule comprises polyvinyl alcohol (e.g., Opadry® 200).

[0046] In some embodiments, the material of the first capsule and the second capsule are the same, e.g., both are soft gelatin capsules. In other embodiments, the material of the first capsule and the second capsule are different, e.g., a soft gelatin first capsule and a polymeric second capsule.

[0047] In another embodiment, the second capsule is an enteric coated capsule.

[0048] The term "enteric" as used herein means a coating material to provide sustained, modified or controlled release of a solid dosage form of hydroxychloroquine or a pharma- ceutically acceptable salt thereof. Enteric coated capsules may also be used to prevent dissolution of the solid dosage form of hydroxychloroquine or a pharma-ceutically acceptable salt thereof in the gastric environment.

[0049] In one embodiment, the second capsule further comprises a coating agent. Suitable coating agents are known to those skilled in the art, and illustrative examples thereof include sealants, glazes, polishes, and shellac. The coating agent contemplated herein provides an additional functional barrier against moisture and far. In one embodiment, the coating agent is a clear coating agent comprising sodium carboxymethylcellulose, maltodextrin, dextrose monohydrate, and refined stearic acid (i.e., Opaglos®2).

[0050] As used herein, the phrase "solid dosage form" refers to any solid form of hydroxychloroquine or a pharma- ceutically acceptable salt thereof, such as tablets, caplets, granules, nanoparticles, pellets, etc. Thus, in one embodiment, the solid dosage form is selected from the group consisting of tablets, powders, microgranules, nanoparticles, and pellets.

[0051] In one preferred embodiment, the solid dosage form is a tablet.

[0052] The phrase "at least partially encapsulated" refers to the first capsule fully or partially encapsulating the solid dosage form of hydroxychloroquine or a pharma- ceutically acceptable salt thereof. The appropriate configuration of the first and second capsules will be determined by one skilled in the art, for example, by reference to the manufacturing process, encapsulation materials, and formulation of the solid dosage form of CBD and hydroxychloroquine.

[0053] In one embodiment, the second capsule is fully integrated within the first capsule. For example, the second capsule may be fully integrated according to the schematic diagram of the composition shown in FIG.

[0054] In one preferred embodiment, the composition is formulated for oral administration.

[0055] The composition for oral administration may contain one or more agents selected from the group of sweeteners, flavoring agents, coloring agents and preservatives to produce pharma- ceutical elegant and palatable preparations. Suitable sweeteners include sucrose, lactose, glucose, aspartame or saccharin. Suitable disintegrants include corn starch, methylcellulose, polyvinylpyrrolidone, xanthan gum, bentonite, alginic acid or agar. Suitable flavorings include peppermint oil, wintergreen oil, cherry flavor, orange flavor or raspberry flavor. Suitable preservatives include sodium benzoate, vitamin E, alpha tocopherol, ascorbic acid, methylparaben, propylparaben or sodium bisulfite. Suitable lubricants include magnesium stearate, stearic acid, sodium oleate, sodium chloride or talc. Suitable time delay agents include glyceryl monostearate or glyceryl distearate.

[0056] In one embodiment, the composition further comprises one or more pharma- ceutically acceptable carriers, diluents or excipients.

[0057] Suitable pharma- ceutically acceptable carriers, diluents or excipients are known to those skilled in the art, and illustrative examples include inert diluents (e.g., calcium carbonate, lactose, calcium phosphate or sodium phosphate), granulating and disintegrating agents (e.g., corn starch or alginic acid), binding agents (e.g., starch, gelatin or acacia), lubricants (e.g., magnesium stearate, stearic acid or talc), and materials that delay disintegration and absorption in the gastrointestinal tract, thereby providing a sustained action over a longer period (e.g., glyceryl monostearate or glyceryl distearate).

[0058] The compositions disclosed herein may be prepared according to conventional methods well known in the pharmaceutical and dietary supplement industries, such as those described in Remington's Pharmaceutical Handbook (Mack Publishing Co., NY, USA).

[0059] Oral administration of CBD has been demonstrated to be an effective route of administration (reviewed by Millar et al., 2018, Frontiers in Pharmacology, 9:1365). Similarly, oral administration of hydroxychloroquine has been demonstrated to be efficiently absorbed and to have high bioavailability (Tett et al., 1989, British Journal of Clinical Pharmacology, 27:771-779).

[0060] Cannabidiol "Cannabidiol" or "CBD" is a cannabinoid produced by plants of the Cannabis genus. CBD has antagonist activity to CB1 and CB2 receptor agonists and acts as an inverse agonist of CB1 and CB2 receptors.

[0061] CBD is synthesized in the cannabis plant as cannabidiolic acid (CBDA), which is decarboxylated to CBD (Table 1). Although some decarboxylation may occur within the plant, decarboxylation usually occurs post-harvest and is increased by exposing the plant material to heat (Sanchez and Verpoote, 2008, Plant Cell Physiology, 49(12):1767-82). Decarboxylation is usually achieved by drying and / or heating the plant material. Those skilled in the art are familiar with methods by which decarboxylation of CBDA can be promoted, illustrative examples of which include air drying, burning, vaporization, curing, heating and calcination. Decarboxylated CBD usually binds to and / or stimulates cannabinoid receptors, including CB1 and / or CB2, directly or indirectly.

[0062] CBD can be extracted from any suitable plant part, including leaves, flowers, or stems, and can be produced by any suitable means known to those skilled in the art.For example, CBD extracts can be produced by extraction with supercritical or subcritical CO2, or by volatilization of plant material with heated gas.Illustrative examples of methods used to extract CBD and other cannabinoids from plant material include those described in US Patent No. 10189762 and WO 2004 / 016277.

[0063] In one embodiment, the CBD described herein is a synthetic compound.

[0064] Synthetic CBD is particularly useful for pharmaceutical development and contains few contaminants. Many methods for the synthesis of CBD are known in the art, illustrative examples of which include the method for the synthesis of CBD described in U.S. Patent No. 10,059,682.

[0065] In one embodiment, the synthetic CBD comprises, consists of, or consists essentially of the (-)-CBD enantiomer.

[0066] The present disclosure further contemplates the use of pharma- ceutically acceptable salts or derivatives of CBD.Suitable pharma-ceutically acceptable salts or derivatives of CBD are known to those skilled in the art, and illustrative examples include the dihydro- and tetrahydro-cannabidiol derivatives H2-CBD and H4-CBD, (-)-dihydro-7-hydroxy-CBD enantiomers and (+)-dihydro-7-hydroxy-CBD enantiomers, and 1',1'-dimethylheptyl-CBD derivatives.

[0067] In one embodiment, the composition comprises at least about 25 mg (e.g., 25 mg, 26 mg, 27 mg, 28 mg, 29 mg, 30 mg, 31 mg, 32 mg, 33 mg, 34 mg, 35 mg, 36 mg, 37 mg, 38 mg, 39 mg, 40 mg, 41 mg, 42 mg, 43 mg, 44 mg, 45 mg, 46 mg, 47 mg, 48 mg, 49 mg, 50 mg, 51 mg, 52 mg, 53 mg, 54 mg, 55 mg, 56 mg, 57 mg, 58 mg, 59 mg, 60 mg, 61 mg, 62 mg, 63 mg, 64 mg, 65 mg, 66 mg, 67 mg, 68 mg , 69mg, 70mg, 71mg, 72mg, 73mg, 74mg, 75mg, 76mg, 77mg, 78mg, 79mg, 80mg, 81mg, 82mg, 83mg, 84mg, 85mg, 86mg, 87mg, 88mg, 89mg, 90mg, 91mg, 92mg, 93mg , 94mg, 95mg, 96mg, 97mg, 98mg, 99mg, 100mg, 101mg, 102mg, 103mg, 104mg, 105mg, 106mg, 107mg, 108mg, 109mg, 110mg, 111mg, 112mg, 113mg, 114mg, 115m g, 116mg, 117mg, 118mg, 119mg, 120mg, 121mg, 122mg, 123mg, 124mg, 125mg, 126mg, 127mg, 128mg, 129mg, 130mg, 131mg, 132mg, 131mg, 134mg, 135mg, 136 mg, 137mg, 138mg, 139mg, 140mg, 141mg, 142mg, 143mg, 144mg, 145mg, 146mg, 147mg, 148mg, 149mg, 150mg, 151mg, 152mg, 153mg, 154mg, 155mg, 156mg, 15 7mg, 158mg, 159mg, 160mg, 161mg, 162mg, 163mg, 164mg, 165mg, 166mg, 167mg, 168mg, 169mg, 170mg, 171mg, 172mg, 173mg, 174mg, 175mg, 176mg, 177mg, 1 78mg, 179mg, 180mg, 181mg, 182mg, 183mg, 184mg, 185mg, 186mg, 187mg, 188mg, 189mg, 190mg, 191mg, 192mg, 193mg, 194mg, 195mg, 196mg, 197mg, 198mg,<h2 style=";text-align:left;direction:ltr">199mg、200mg、201mg、202mg、203mg、204mg、205mg、206mg、207mg、208mg、20 9mg、210mg、211mg、212mg、213mg、214mg、215mg、216mg、217mg、218mg、219m g、220mg、221mg、222mg、223mg、224mg、225mg、226mg、227mg、228mg、229mg、 230mg、231mg、232mg、233mg、234mg、235mg、236mg、237mg、238mg、239mg、240 mg、241mg、242mg、243mg、244mg、245mg、246mg、247mg、248mg、249mg、250mg 、251mg、252mg、253mg、254mg、255mg、256mg、257mg、258mg、259mg、260mg、2 61mg、262mg、263mg、264mg、265mg、266mg、267mg、268mg、269mg、270mg、271 mg、272mg、273mg、274mg、275mg、276mg、277mg、278mg、279mg、280mg、281mg、 282mg、283mg、284mg、285mg、286mg、287mg、288mg、289mg、290mg、291mg、29 2mg、293mg、294mg、295mg、296mg、297mg、298mg、299mg、300mg、301mg、302m g、303mg、304mg、305mg、306mg、307mg、308mg、309mg、310mg、311mg、312mg、 313mg、314mg、315mg、316mg、317mg、318mg、319mg、320mg、321mg、322mg、323 mg, 324mg, 325mg, 326mg, 327mg, 328mg, 329mg, 330mg, 331mg, 332mg, 333mg, 334mg, 335mg, 336mg, 337mg, 338mg, 339mg, 340mg, 341mg, 342mg, 343mg, 3 44mg, 345mg, 346mg, 347mg, 348mg, 349mg, 350mg, 351mg, 352mg, 353mg, 354mg, 355mg, 356mg, 357mg, 358mg, 359mg, 360mg, 361mg, 362mg, 363mg, 364mg365mg、366mg、367mg、368mg、369mg、370mg、371mg、372mg、373mg、374mg、375mg、376mg、377mg、378mg、379mg、380mg、381mg、382mg、383mg、384mg、385mg、386mg、387mg、388mg、389mg、390mg、391mg、392mg、393mg、394mg、395mg、396mg、397mg、398mg、399mg、400mg、401mg、402mg、403mg、404mg、405mg、406mg、407mg、408mg、409mg、410mg、411mg、412mg、413mg、414mg、415mg、416mg、417mg、418mg、419mg、420mg、421mg、422mg、423mg、424mg、425mg、426mg、427mg、428mg、429mg、430mg、431mg、432mg、433mg、434mg、435mg、436mg、437mg、438mg、439mg、440mg、441mg、442mg、443mg、444mg、445mg、446mg、447mg、448mg、449mg、450mg、451mg、452mg、453mg、454mg、455mg、456mg、457mg、458mg、459mg、460mg、461mg、462mg、463mg、464mg、465mg、466mg、467mg、468mg、469mg、470mg、471mg、472mg、473mg、474mg、475mg、476mg、477mg、478mg、479mg、480mg、481mg、482mg、483mg、484mg、485mg、486mg、487mg、488mg、489mg、490mg、491mg、492mg、493mg、494mg、495mg、496mg、497mg、498mg、499mg、500mg、501mg、502mg、503mg、504mg、505mg、506mg、507mg、508mg、509mg、510mg、511mg、512mg、513mg、514mg、515mg、516mg、517mg、518mg、519mg、520mg、521mg、522mg、523mg、524mg、525mg、526mg、527mg、528mg、529mg、530mg、531mg、532mg、533mg、534mg、535mg、536mg、537mg、538mg、539mg、540mg、541mg、542mg、543mg、544mg、545mg、546mg、547mg、548mg、549mg、550mg、551mg、552mg、553mg、554mg、555mg、556mg、557mg、558mg、559mg、560mg、561mg、562mg、563mg、564mg、565mg、566mg、567mg、568mg、569mg、570mg、571mg、572mg、573mg、574mg、575mg、576mg、577mg、578mg、579mg、580mg、581mg、582mg、583mg、584mg、585mg、586mg、587mg、588mg、589mg、590mg、591mg、592mg、593mg、594mg、595mg、596mg、597mg、598mg、599mg、600mg、601mg、602mg、603mg、604mg、605mg、606mg、607mg、608mg、609mg、610mg、611mg、612mg、613mg、614mg、615mg、616mg、617mg、618mg、619mg、620mg、621mg、622mg、623mg、624mg、625mg、626mg、627mg、628mg、629mg、630mg、631mg、632mg、633mg、634mg、635mg、636mg、637mg、638mg、639mg、640mg、641mg、642mg、643mg、644mg、645mg、646mg、647mg、648mg、649mg、650mg、651mg、652mg、653mg、654mg、655mg、656mg、657mg、658mg、659mg、660mg、661mg、662mg、663mg、664mg、665mg、666mg、667mg、668mg、669mg、670mg、671mg、672mg、673mg、674mg、675mg、676mg、677mg、678mg、679mg、680mg、681mg、682mg、683mg、684mg、685mg、686mg、687mg、688mg、689mg、690mg、691mg、692mg、693mg、694mg、695mg、696mg、697mg、698mg、699mg、700mg、701mg、702mg、703mg、704mg、705mg、706mg、707mg、708mg、709mg、710mg、711mg、712mg、713mg、714mg、715mg、716mg、717mg、718mg、719mg、720mg、721mg、722mg、723mg、724mg、725mg、726mg、727mg、728mg、729mg、730mg、731mg、732mg、733mg、734mg、735mg、736mg、737mg、738mg、739mg、740mg、741mg、742mg、743mg、744mg、745mg、746mg、747mg、748mg、749mg、750mg、751mg、752mg、753mg、754mg、755mg、756mg、757mg、758mg、759mg、760mg、761mg、762mg、763mg、764mg、765mg、766mg、767mg、768mg、769mg、770mg、771mg、772mg、773mg、774mg、775mg、776mg、777mg、778mg、779mg、780mg、781mg、782mg、783mg、784mg、785mg、786mg、787mg、788mg、789mg、790mg、791mg、792mg、793mg、794mg、795mg、796mg、797mg、798mg、799mg、800mg、801mg、802mg、803mg、804mg、805mg、806mg、807mg、808mg、809mg、810mg、811mg、812mg、813mg、814mg、815mg、816mg、817mg、818mg、819mg、820mg、821mg、822mg、823mg、824mg、825mg、826mg、827mg、828mg、829mg、830mg、831mg、832mg、833mg、834mg、835mg、836mg、837mg、838mg、839mg、840mg、841mg、842mg、843mg、844mg、845mg、846mg、847mg、848mg、849mg、850mg、851mg、852mg、853mg、854mg、855mg、856mg、857mg、858mg、859mg、860mg、861mg、862mg、863mg、864mg、865mg、866mg、867mg、868mg、869mg、870mg、871mg、872mg、873mg、874mg、875mg、876mg、877mg、878mg、879mg、880mg、881mg、882mg、883mg、884mg、

[0068] 885mg、886mg、887mg、888mg、889mg、890mg、891mg、892mg、893mg、894mg、895mg、896mg、897mg、898mg、899mg、900mg、901mg、902mg、903mg、904mg、905mg、906mg、907mg、908mg、909mg、910mg、911mg、912mg、913mg、914mg、915mg、916mg、917mg、918mg、919mg、920mg、921mg、922mg、923mg、924mg、925mg、926mg、927mg、928mg、929mg、930mg、931mg、932mg、933mg、934mg、935mg、936mg、937mg、938mg、939mg、940mg、941mg、942mg、943mg、944mg、945mg、946mg、947mg、948mg、949mg、950mg、951mg、952mg、953mg、954mg、955mg、956mg、957mg、958mg、959mg、960mg、961mg、962mg、963mg、964mg、965mg、966mg、967mg、968mg、969mg、970mg、971mg、972mg、973mg、974mg、975mg、976mg、977mg、978mg、979mg、980mg、981mg、982mg、983mg、984mg、985mg、986mg、987mg、988mg、989mg、990mg、991mg、992mg、993mg、994mg、995mg、996mg、997mg、998mg、999mg、1000mg、1100mg、1101mg、1102mg、1103mg、1104mg、1105mg、1106mg、1107mg、1108mg、1109mg、1110mg、1111mg、1112mg、1113mg、1114mg、1115mg、1116mg、1117mg、1118mg、1119mg、1120mg、1121mg、1122mg、1123mg、1124mg、1125mg、1126mg、1127mg、1128mg、1129mg、1130mg、1131mg、1132mg、1133mg、1134mg、1135mg、1136mg、1137mg、1138mg、1139mg、1140mg、1141mg、1142mg、1143mg、1144mg、1145mg、1146mg、1147mg、1148mg、1149mg、1150mg、1151mg、1152mg、1153mg、1154mg、1155mg、1156mg、1157mg、1158mg、1159mg、1160mg、1161mg、1162mg、1163mg、1164mg、1165mg、1166mg、1167mg、1168mg、1169mg、1170mg、1171mg、1172mg、1173mg、1174mg、1175mg、1176mg、1177mg、1178mg、1179mg、1180mg、1181mg、1182mg、1183mg、1184mg、1185mg、1186mg、1187mg、1188mg、1189mg、1190mg、1191mg、1192mg、1193mg、1194mg、1195mg、1196mg、1197mg、1198mg、1199mg、1200mg、1201mg、1202mg、1203mg、1204mg、1205mg、1206mg、1207mg、1208mg、1209mg、1210mg、1211mg、1212mg、1213mg、1214mg、1215mg、1216mg、1217mg、1218mg、1219mg、1220mg、1221mg、1222mg、1223mg、1224mg、1225mg、1226mg、1227mg、1228mg、1229mg、1230mg、1231mg、1232mg、1233mg、1234mg、1235mg、1236mg、1237mg、1238mg、1239mg、1240mg、1241mg、1242mg、1243mg、1244mg、1245mg、1246mg、1247mg、1248mg、1249mg、1250mg、1251mg、1252mg、1253mg、1254mg、1255mg、1256mg、1257mg、1258mg、1259mg、1260mg、1261mg、1262mg、1263mg、1264mg、1265mg、1266mg、1267mg、1268mg、1269mg、1270mg、1271mg、1272mg、1273mg、1274mg、1275mg、1276mg、1277mg、1278mg、1279mg、1280mg、1281mg、1282mg、1283mg、1284mg、1285mg、1286mg、1287mg、1288mg、1289mg、1290mg、1291mg、1292mg、1293mg、1294mg、1295mg、1296mg、1297mg、1298mg、1299mg、1300mg、1301mg、1302mg、303mg、1304mg、1305mg、1306mg、1307mg、1308mg、1309mg、1310mg、1311mg、1312mg、1313mg、1314mg、1315mg、1316mg、1317mg、1318mg、1319mg、1320mg、1321mg、1322mg、1323mg、1324mg、1325mg、1326mg、1327mg、1328mg、1329mg、1330mg、1331mg、1332mg、1333mg、1334mg、1335mg、1336mg、1337mg、1338mg、1339mg、1340mg、1341mg、1342mg、1343mg、1344mg、1345mg、1346mg、1347mg、1348mg、1349mg、1350mg、1351mg、1352mg、1353mg、1354mg、1355mg、1356mg、1357mg、1358mg、1359mg、1360mg、1361mg、1362mg、1363mg、1364mg、1365mg、1366mg、1367mg、1368mg、1369mg、1370mg、1371mg、1372mg、1373mg、1374mg、1375mg、1376mg、1377mg、1378mg、1379mg、1380mg、1381mg、1382mg、1383mg、1384mg、1385mg、1386mg、1387mg、1388mg、1389mg、1390mg、1391mg、1392mg、1393mg、1394mg、1395mg、1396mg、1397mg、1398mg、1399mg、1400mg、1401mg、1402mg、1403mg、1404mg、1405mg、1406mg、1407mg、1408mg、1409mg、1410mg、1411mg、1412mg、1413mg、1414mg、1415mg、1416mg、1417mg、1418mg、1419mg、1420mg、1421mg、1422mg、1423mg、1424mg、1425mg、1426mg、1427mg、1428mg、1429mg, 1430mg, 1431mg, 1432mg, 1433mg, 1434mg, 1435mg, 1436mg, 1437mg, 1438mg, 1439mg, 1440mg, 1441mg, 1442mg, 1443mg, 1444mg, 1445mg, 1446mg, 1447mg, 1 448mg, 1449mg, 1450mg, 1451mg, 1452mg, 1453mg, 1454mg, 1455mg, 1456mg, 1457m g, 1458mg, 1459mg, 1460mg, 1461mg, 1462mg, 1463mg, 1464mg, 1465mg, 1466mg, 146 7mg, 1468mg, 1469mg, 1470mg, 1471mg, 1472mg, 1473mg, 1474mg, 1475mg, 1476mg, 1477mg, 1478mg, 1479mg, 1480mg, 1481mg, 1482mg, 1483mg, 1484mg, 1485mg, 1486mg, 1487mg, 1488mg, 1489mg, 1490mg, 1491mg, 1492mg, 1493mg, 1494mg, 1495mg, 1496mg, 1497mg, 1498mg, 1499mg, or 1500mg of CBD or a pharma- ceutically acceptable salt or derivative thereof.

[0069] In one embodiment, the composition comprises about 25 mg to about 100 mg, preferably about 25 mg, preferably about 26 mg, preferably about 27 mg, preferably about 28 mg, preferably about 29 mg, preferably about 30 mg, preferably about 31 mg, preferably about 32 mg, preferably about 33 mg, preferably about 34 mg, preferably about 35 mg, preferably about 36 mg, preferably about 37 mg, preferably about 38 mg, preferably about 39 mg, preferably about 40 mg, preferably about 41 mg, preferably about 42 mg. g, preferably about 43 mg, preferably about 44 mg, preferably about 45 mg, preferably about 46 mg, preferably about 47 mg, preferably about 48 mg, preferably about 49 mg, preferably about 50 mg, preferably about 51 mg, preferably about 52 mg, preferably about 53 mg, preferably about 54 mg, preferably about 55 mg, preferably about 56 mg, preferably about 57 mg, preferably about 58 mg, preferably about 59 mg, preferably about 60 mg, preferably about 61 mg, preferably about 62 mg, is about 63 mg, preferably about 64 mg, preferably about 65 mg, preferably about 66 mg, preferably about 67 mg, preferably about 68 mg, preferably about 69 mg, preferably about 70 mg, preferably about 71 mg, preferably about 72 mg, preferably about 73 mg, preferably about 74 mg, preferably about 75 mg, preferably about 76 mg, preferably about 77 mg, preferably about 78 mg, preferably about 79 mg, preferably about 80 mg, preferably about 81 mg, preferably about 82 mg, preferably about 83 mg , preferably about 84 mg, preferably about 85 mg, preferably about 86 mg, preferably about 87 mg, preferably about 88 mg, preferably about 89 mg, preferably about 90 mg, preferably about 91 mg, preferably about 92 mg, preferably about 93 mg, preferably about 94 mg, preferably about 95 mg, preferably about 96 mg, preferably about 97 mg, preferably about 98 mg, preferably about 99 mg, or more preferably about 100 mg of CBD or a pharma- ceutically acceptable salt or derivative thereof.

[0070] In one preferred embodiment, the composition contains about 75 mg of CBD or a pharma- ceutically acceptable salt or derivative thereof.

[0071] Hydroxychloroquine "Hydroxychloroquine" is a chemical derivative of chloroquine that has a hydroxyethyl group instead of an ethyl group. Hydroxychloroquine, commonly referred to by the trade name "Plaquenil®", is known to be effective in treating malaria and has also shown efficacy in treating systemic lupus erythematosus, rheumatoid arthritis, and Sjogren's syndrome. Functionally, hydroxychloroquine has been demonstrated to increase the lysosomal pH of antigen-presenting cells and inhibit or block activation of Toll-like receptors on plasmacytoid dendritic cells.

[0072] As used herein, the term "hydroxychloroquine" includes either racemic hydroxychloroquine, which is 2-[[4-[(7-chloro-4-quinolinyl)amino]pentyl]-ethylamino]ethanol, as disclosed in U.S. Pat. No. 2,546,658, or the single enantiomers "(S)-(+)hydroxychloroquine" or "(R)-(-)hydroxychloroquine," as disclosed in U.S. Pat. No. 5,314,894. The term may refer to either the free form of hydroxychloroquine, or a pharma- ceutically acceptable salt of hydroxychloroquine, such as hydroxychloroquine sulfate.

[0073] The present disclosure further contemplates the use of pharma- ceutically acceptable salts of hydroxychloroquine. Suitable pharma- ceutically acceptable salts are known to those skilled in the art, and illustrative examples include salts or esters prepared from pharma- ceutically acceptable non-toxic bases or acids, including inorganic bases or acids and organic bases or acids.

[0074] In one embodiment, the pharma- ceutically acceptable salt is hydroxychloroquine sulfate.

[0075] In one embodiment, the composition comprises at least about 10 mg (e.g., 10 mg, 11 mg, 12 mg, 13 mg, 14 mg, 15 mg, 16 mg, 17 mg, 18 mg, 19 mg, 20 mg, 21 mg, 22 mg, 23 mg, 24 mg, 25 mg, 26 mg, 27 mg, 28 mg, 29 mg, 30 mg, 31 mg, 32 mg, 33 mg, 34 mg, 35 mg, 36 mg, 37 mg, 38 mg, 39 mg, 40 mg, 41 mg, 42 mg, 43 mg, 44 mg, 45 mg, 46 mg, 47 mg, 48 mg, 49 mg, 50 mg, 51 mg, 52 mg, 53 mg , 54mg, 55mg, 56mg, 57mg, 58mg, 59mg, 60mg, 61mg, 62mg, 63mg, 64mg, 65mg, 66mg, 67mg, 68mg, 69mg, 70mg, 71mg, 72mg, 73mg, 74mg, 75mg, 76mg, 77mg, 78m g. 103mg, 104mg, 105mg, 106mg, 107mg, 108mg, 109mg, 110mg, 111mg, 112mg, 113mg, 114mg, 115mg, 116mg, 117mg, 118mg, 119mg, 120mg, 121mg, 122mg, 123m g, 124mg, 125mg, 126mg, 127mg, 128mg, 129mg, 130mg, 131mg, 132mg, 131mg, 134mg, 135mg, 136mg, 137mg, 138mg, 139mg, 140mg, 141mg, 142mg, 143mg, 144 mg, 145mg, 146mg, 147mg, 148mg, 149mg, 150mg, 151mg, 152mg, 153mg, 154mg, 155mg, 156mg, 157mg, 158mg, 159mg, 160mg, 161mg, 162mg, 163mg, 164mg, 1 65mg, 166mg, 167mg, 168mg, 169mg, 170mg, 171mg, 172mg, 173mg, 174mg, 175mg, 176mg, 177mg, 178mg, 179mg, 180mg, 181mg, 182mg, 183mg, 184mg, 185mg,186mg、187mg、188mg、189mg、190mg、191mg、192mg、193mg、194mg、195mg、196mg、197mg、198mg、199mg、200mg、201mg、202mg、203mg、204mg、205mg、206mg、207mg、208mg、209mg、210mg、211mg、212mg、213mg、214mg、215mg、216mg、217mg、218mg、219mg、220mg、221mg、222mg、223mg、224mg、225mg、226mg、227mg、228mg、229mg、230mg、231mg、232mg、233mg、234mg、235mg、236mg、237mg、238mg、239mg、240mg、241mg、242mg、243mg、244mg、245mg、246mg、247mg、248mg、249mg、250mg、251mg、252mg、253mg、254mg、255mg、256mg、257mg、258mg、259mg、260mg、261mg、262mg、263mg、264mg、265mg、266mg、267mg、268mg、269mg、270mg、271mg、272mg、273mg、274mg、275mg、276mg、277mg、278mg、279mg、280mg、281mg、282mg、283mg、284mg、285mg、286mg、287mg、288mg、289mg、290mg、291mg、292mg、293mg、294mg、295mg、296mg、297mg、298mg、299mg、300mg、301mg、302mg、303mg、304mg、305mg、306mg、307mg、308mg、309mg、310mg、311mg、312mg、313mg、314mg、315mg、316mg、317mg、318mg、319mg、320mg、321mg、322mg、323mg、324mg、325mg、326mg、327mg、328mg、329mg、330mg、331mg、332mg、333mg、334mg、335mg、336mg、337mg、338mg、339mg、340mg、341mg、342mg、343mg、344mg、345mg、346mg、347mg、348mg、349mg、350mg、351mg、352mg、353mg、354mg、355mg、356mg、357mg、358mg、359mg、360mg、361mg、362mg、363mg、364mg、365mg、366mg、367mg、368mg、369mg、370mg、371mg、372mg、373mg、374mg、375mg、376mg、377mg、378mg、379mg、380mg、381mg、382mg、383mg、384mg、385mg、386mg、387mg、388mg、389mg、390mg、391mg、392mg、393mg、394mg、395mg、396mg、397mg、398mg、399mg、400mg、401mg、402mg、403mg、404mg、405mg、406mg、407mg、408mg、409mg、410mg、411mg、412mg、413mg、414mg、415mg、416mg、417mg、418mg、419mg、420mg、421mg、422mg、423mg、424mg、425mg、426mg、427mg、428mg、429mg、430mg、431mg、432mg、433mg、434mg、435mg、436mg、437mg、438mg、439mg、440mg、441mg、442mg、443mg、444mg、445mg、446mg、447mg、448mg、449mg、450mg、451mg、452mg、453mg、454mg、455mg、456mg、457mg、458mg、459mg、460mg、461mg、462mg、463mg、464mg、465mg、466mg、467mg、468mg、469mg、470mg、471mg、472mg、473mg、474mg、475mg、476mg、477mg、478mg、479mg、480mg、481mg、482mg、483mg、484mg、485mg、486mg、487mg、488mg、489mg、490mg、491mg、492mg、493mg、494mg、495mg、496mg、497mg、498mg、499mg、500mg、501mg、502mg、503mg、504mg、505mg、506mg、507mg、508mg、509mg、510mg、511mg、512mg、513mg、514mg、515mg、516mg、517mg、518mg、519mg、520mg、521mg、522mg、523mg、524mg、525mg、526mg、527mg、528mg、529mg、530mg、531mg、532mg、533mg、534mg、535mg、536mg、537mg、538mg、539mg、540mg、541mg、542mg、543mg、544mg、545mg、546mg、547mg、548mg、549mg、550mg、551mg、552mg、553mg、554mg、555mg、556mg、557mg、558mg、559mg、560mg、561mg、562mg、563mg、564mg、565mg、566mg、567mg、568mg、569mg、570mg、571mg、572mg、573mg、574mg、575mg、576mg、577mg、578mg、579mg、580mg、581mg、582mg、583mg、584mg、585mg、586mg、587mg、588mg、589mg、590mg、591mg、592mg、593mg、594mg、595mg、596mg、597mg、598mg、599mg、600mg、601mg、602mg、603mg、604mg、605mg、606mg、607mg、608mg、609mg、610mg、611mg、612mg、613mg、614mg、615mg、616mg、617mg、618mg、619mg、620mg、621mg、622mg、623mg、624mg、625mg、626mg、627mg、628mg、629mg、630mg、631mg、632mg、633mg、634mg、635mg、636mg、637mg、638mg、639mg、640mg、641mg、642mg、643mg、644mg、645mg、646mg、647mg、648mg、649mg、650mg、651mg、652mg、653mg、654mg、655mg、656mg、657mg、658mg、659mg、660mg、661mg、662mg、663mg、664mg、665mg、666mg、667mg、668mg、669mg、670mg、671mg、672mg、673mg、674mg、675mg、676mg、677mg、678mg、679mg、680mg、681mg、682mg、683mg、684mg、685mg、686mg、687mg、688mg、689mg、690mg、691mg、692mg、693mg、694mg、695mg、696mg、697mg、698mg、699mg、700mg、701mg、702mg、703mg、704mg、705mg、706mg、707mg、708mg、709mg、710mg、711mg、712mg、713mg、714mg、715mg、716mg、717mg、718mg、719mg、720mg、721mg、722mg、723mg、724mg、725mg、726mg、727mg、728mg、729mg、730mg、731mg、732mg、733mg、734mg、735mg、736mg、737mg、738mg、739mg、740mg、741mg、742mg、743mg、744mg、745mg、746mg、747mg、748mg、749mg、750mg、751mg、752mg、753mg、754mg、755mg、756mg、757mg、758mg、759mg、760mg、761mg、762mg、763mg、764mg、765mg、766mg、767mg、768mg、769mg、770mg、771mg、772mg、773mg、774mg、775mg、776mg、777mg、778mg、779mg、780mg、781mg、782mg、783mg、784mg、785mg、786mg、787mg、788mg、789mg、790mg、791mg、792mg、793mg、794mg、795mg、796mg、797mg、798mg、799mg、800mg、801mg、802mg、803mg、804mg、805mg、806mg、807mg、808mg、809mg、810mg、811mg、812mg、813mg、814mg、815mg、816mg、817mg、818mg、819mg、820mg、821mg、822mg、823mg、824mg、825mg、826mg、827mg、828mg、829mg、830mg、831mg、832mg、833mg、834mg、835mg、836mg、837mg、838mg、839mg、840mg、841mg、842mg、843mg、844mg、845mg、846mg、847mg、848mg、849mg、850mg, 851mg, 852mg, 853mg, 854mg, 855mg, 856mg, 857mg, 858mg, 859mg, 860mg, 861mg, 862mg, 863mg, 864mg, 865mg, 866mg, 867mg, 868mg, 869mg, 870mg, 871mg, 872mg,

[0076] 873mg, 874mg, 875mg, 876mg, 877mg, 878mg, 879mg, 880mg, 881mg, 882mg, 883mg, 884mg, 885mg, 886mg, 887mg, 888mg, 889m g, 890mg, 891mg, 892mg, 893mg, 894mg, 895mg, 896mg, 897mg, 898mg, 899mg, 900mg, 901mg, 902mg, 903mg, 904mg, 905mg, 906 mg, 907mg, 908mg, 909mg, 910mg, 911mg, 912mg, 913mg, 914mg, 915mg, 916mg, 917mg, 918mg, 919mg, 920mg, 921mg, 922mg, 9 23mg, 924mg, 925mg, 926mg, 927mg, 928mg, 929mg, 930mg, 931mg, 932mg, 933mg, 934mg, 935mg, 936mg, 937mg, 938mg, 939mg, 940mg, 941mg, 942mg, 943mg, 944mg, 945mg, 946mg, 947mg, 948mg, 949mg, 950mg, 951mg, 952mg, 953mg, 954mg, 955mg, 956m g, 957mg, 958mg, 959mg, 960mg, 961mg, 962mg, 963mg, 964mg, 965mg, 966mg, 967mg, 968mg, 969mg, 970mg, 971mg, 972mg, 973 mg, 974 mg, 975 mg, 976 mg, 977 mg, 978 mg, 979 mg, 980 mg, 981 mg, 982 mg, 983 mg, 984 mg, 985 mg, 986 mg, 987 mg, 988 mg, 989 mg, 990 mg, 991 mg, 992 mg, 993 mg, 994 mg, 995 mg, 996 mg, 997 mg, 998 mg, 999 mg, or 1000 mg of hydroxychloroquine or a pharma- ceutically acceptable salt thereof.

[0077] In one embodiment, the composition comprises about 10 mg to about 200 mg, preferably about 10 mg, preferably about 11 mg, preferably about 12 mg, preferably about 13 mg, preferably about 14 mg, preferably 15 mg, preferably about 16 mg, preferably about 17 mg, preferably about 18 mg, preferably about 19 mg, preferably about 20 mg, preferably about 21 mg, preferably about 22 mg, preferably about 23 mg, preferably about 24 mg, preferably 25 mg, preferably about 26 mg, preferably about 27 mg, preferably about 28 mg, preferably about 29 mg, or about 30 mg, preferably about 31 mg, preferably about 32 mg, preferably about 33 mg, preferably about 34 mg, preferably about 35 mg, preferably about 36 mg, preferably about 37 mg, preferably about 38 mg, preferably about 39 mg, preferably about 40 mg, preferably about 41 mg, preferably about 42 mg, preferably about 43 mg, preferably about 44 mg, preferably about 45 mg, preferably about 46 mg, preferably about 47 mg, preferably about 48 mg, preferably about 49 mg, preferably about 50 mg, preferably about 51 mg, preferably about 52 mg g, preferably about 53 mg, preferably about 54 mg, preferably about 55 mg, preferably about 56 mg, preferably about 57 mg, preferably about 58 mg, preferably about 59 mg, preferably about 60 mg, preferably about 61 mg, preferably about 62 mg, preferably about 63 mg, preferably about 64 mg, preferably about 65 mg, preferably about 66 mg, preferably about 67 mg, preferably about 68 mg, preferably about 69 mg, preferably about 70 mg, preferably about 71 mg, preferably about 72 mg, preferably about 73 mg, preferably about 74 mg, is about 75 mg, preferably about 76 mg, preferably about 77 mg, preferably about 78 mg, preferably about 79 mg, preferably about 80 mg, preferably about 81 mg, preferably about 82 mg, preferably about 83 mg, preferably about 84 mg, preferably about 85 mg, preferably about 86 mg, preferably about 87 mg, preferably about 88 mg, preferably about 89 mg, preferably about 90 mg, preferably about 91 mg, preferably about 92 mg, preferably about 93 mg, preferably about 94 mg, preferably about 95 mg, preferably about 96 mg, preferably about 97 mg,Preferably about 98 mg, preferably about 99 mg, preferably about 100 mg, preferably about 101 mg, preferably about 102 mg, preferably about 103 mg, preferably about 104 mg, preferably about 105 mg, preferably about 106 mg, preferably about 107 mg, preferably about 108 mg, preferably about 109 mg, preferably about 110 mg, preferably about 111 mg, preferably about 112 mg, preferably about 113 mg, preferably about 114 mg, preferably about 115 mg, preferably about 116 mg, preferably about 117 mg, preferably about 118 mg g, preferably about 119 mg, preferably about 120 mg, preferably about 121 mg, preferably about 122 mg, preferably about 123 mg, preferably about 124 mg, preferably about 125 mg, preferably about 126 mg, preferably about 127 mg, preferably about 128 mg, preferably about 129 mg, preferably about 130 mg, preferably about 131 mg, preferably about 132 mg, preferably about 133 mg, preferably about 134 mg, preferably about 135 mg, preferably about 136 mg, preferably about 137 mg, preferably about 138 mg, 39 mg, preferably about 140 mg, preferably about 141 mg, preferably about 142 mg, preferably about 143 mg, preferably about 144 mg, preferably about 145 mg, preferably about 146 mg, preferably about 147 mg, preferably about 148 mg, preferably about 149 mg, preferably about 150 mg, preferably about 151 mg, preferably about 152 mg, preferably about 153 mg, preferably about 154 mg, preferably about 155 mg, preferably about 156 mg, preferably about 157 mg, preferably about 158 ​​mg, preferably about 159 mg, or about 160 mg, preferably about 161 mg, preferably about 162 mg, preferably about 163 mg, preferably about 164 mg, preferably about 165 mg, preferably about 166 mg, preferably about 167 mg, preferably about 168 mg, preferably about 169 mg, preferably about 170 mg, preferably about 171 mg, preferably about 172 mg, preferably about 173 mg, preferably about 174 mg, preferably about 175 mg, preferably about 176 mg, preferably about 177 mg, preferably about 178 mg, preferably about 179 mg, preferably about 180 mg,Preferably, the composition contains about 181 mg, preferably about 182 mg, preferably about 183 mg, preferably about 184 mg, preferably about 185 mg, preferably about 186 mg, preferably about 187 mg, preferably about 188 mg, preferably about 189 mg, preferably about 190 mg, preferably about 191 mg, preferably about 192 mg, preferably about 193 mg, preferably about 194 mg, preferably about 195 mg, preferably about 196 mg, preferably about 197 mg, preferably about 198 mg, preferably about 199 mg, or more preferably about 200 mg of hydroxychloroquine or a pharma- ceutically acceptable salt thereof.

[0078] In one preferred embodiment, the composition contains about 20 mg of hydroxychloroquine or a pharma- ceutically acceptable salt thereof.

[0079] In another preferred embodiment, the composition contains about 100 mg of hydroxychloroquine or a pharma- ceutically acceptable salt thereof.

[0080] In one embodiment, the compositions defined herein are for use in the treatment of an inflammatory condition.

[0081] Inflammatory conditions The term "inflammatory condition" as used herein generally refers to a condition characterized by inflammation or a complex biological response to a harmful stimulus, such as injury, autoimmunity, infection by a microbial pathogen and / or a virus. The clinical characteristics of an inflammatory condition will vary depending on the noxious stimulus (or stimuli), but are usually characterized by heat, pain, redness, and swelling of the affected organ or tissue. An inflammatory condition may be acute or chronic.

[0082] In one embodiment, the inflammatory condition is selected from the group consisting of inflammatory respiratory conditions, inflammatory bowel disease and arthritis.

[0083] In one embodiment, the inflammatory condition is an inflammatory respiratory condition.

[0084] Inflammatory respiratory conditions are known to those of skill in the art, illustrative examples of which include ARDS, chronic obstructive pulmonary disease (COPD), asthma, bronchitis, bronchiectasis, sarcoidosis, and cystic fibrosis (CF).

[0085] In one embodiment, the inflammatory respiratory condition is selected from the group consisting of chronic obstructive pulmonary disease (COPD), asthma, bronchitis, cystic fibrosis (CF) and acute respiratory distress syndrome (ARDS).

[0086] In one embodiment, the inflammatory respiratory condition is ARDS. In another embodiment, the inflammatory respiratory condition is sepsis-associated ARDS.

[0087] In one embodiment, the inflammatory condition is inflammatory bowel disease.

[0088] The term "inflammatory bowel disease" refers to diseases or disorders involving chronic inflammation of the digestive tract. Such diseases or disorders are known to those skilled in the art, and illustrative examples include ulcerative colitis and Crohn's disease.

[0089] In one embodiment, the inflammatory condition is arthritis.

[0090] The term "arthritis" generally refers to diseases characterized by inflammation of the joints, which may also include loss of cartilage. Such diseases are known to those skilled in the art, and illustrative examples include rheumatoid arthritis, osteoarthritis, psoriatic arthritis, and ankylosing spondylitis.

[0091] In one embodiment, the arthritis is rheumatoid arthritis.

[0092] In one embodiment, the inflammatory condition is associated with increased or upregulated levels of a pro-inflammatory cytokine selected from the group consisting of IL-1β, IL-6, TNF-α, IL-1α, IL-12(p70), IFN-γ, CXCL-1, MCP-1 and MIP-1α, or a combination thereof.

[0093] In one embodiment, the inflammatory condition is associated with increased or upregulated levels of a pro-inflammatory cytokine selected from the group consisting of IL-1β, IL-6 and TNF-α, or a combination thereof.

[0094] Inflammatory conditions associated with increased levels or upregulation of IL-1β, IL-6, TNF-α, IL-1α, IL-12(p70), IFN-γ, CXCL-1, MCP-1 and / or MIP-1α are known to those of skill in the art, and illustrative examples thereof include arthritis (e.g., as described by Feldman et al., 1996, Annual Review of Immunology, 14:397-440; McInnes et al., 2007, Nature Reviews Immunology, 7:429-442; Tanaka et al., 2014, Cold Spring Harbor Perspectives in Biology, 6:a016292-a016295; Woo, 2002, Current Rheumatology Reports, 4:452-457; Kapoor et al., 2011, Nature Reviews Immunology, 7:429-442). Rheumatology, 7:33-42), inflammatory bowel disease (described, for example, by Neurath, 2014, Nature Reviews Immunology, 14: 329-342; Papadakis and Targan, 2000, The Annual Review of Medicine, 51:289-298), pain (described, for example, by Zhang, 2007, International Anesthesiology Clinics, 45:27-37), gout (described, for example, by Busso, 2010, Arthritis Research & Therapy, 12:206), fibromyalgia (described, for example, by Rodriguez-Pinto et al., 2014, Immunology Letters, 161:200-203), endometriosis (described, for example, by Wu and Ho, 2003, American Journal of Reproductive Immunology, 49:285-296), chronic obstructive pulmonary disease (e.g., Chung, 2001, European Respiratory Journal, 18:50s-59s), asthma (e.g., Rincon and Irvin, 2012, International Journal of Biological Sciences, 8:1281-1290;Thomas, 2001, Immunology & Cell Biology, 79: 132-140), alcoholic liver disease (e.g., McClain et al., 1999, in Seminars in Liver Diseases, 205-220; Kawaratani et al., 2013, Mediators of Inflammation, 2013:495-156), psoriasis / dermatitis (e.g., as described by Jensen, 2010, Current Opinions in Investigative Drug Discovery, 11:1211-1220; Baliwag et al., 2015, Cytokine, 31:781-789; Toshitani et al., 1993, Journal of Investigative Dermatology, 100:299-304), and lupus (e.g., as described by Davis et al., 2011, Journal of Interferon & Cytokine Research, 31:781-789).

[0095] Acute respiratory distress syndrome (ARDS) The terms "acute respiratory distress syndrome," "adult respiratory distress syndrome," or "ARDS" are used interchangeably herein and may refer to an inflammatory condition typically characterized by disruption of the alveolar-capillary barrier, flooding of the alveolar space with protein-rich edema fluid, and cellular recruitment through stimulation of the immune system. ARDS may develop after direct lung injury, such as pneumonia, aspiration, inhalation injury, near drowning, pulmonary contusion, reperfusion pulmonary edema, and fat embolism. ARDS may also occur during the course of indirect lung injury, for example, sepsis, severe trauma, acute pancreatitis, cardiopulmonary bypass, massive transfusion, and drug overdose.

[0096] "Sepsis-associated acute respiratory distress syndrome" or "sepsis-associated ARDS" refers to ARDS that is typically induced after a pulmonary infection or infection at an extrapulmonary site. The abnormal host response to infection causes disruption of the alveolar-capillary barrier, resulting in lung injury characterized by hypoxemia, inflammation, and noncardiogenic pulmonary edema.

[0097] In one embodiment, the ARDS is sepsis-associated ARDS.

[0098] The types of pathogens that can cause sepsis-associated ARDS are known to those of skill in the art, and illustrative examples include bacteria, such as Streptococcus pneumoniae, Staphylococcus aureus, Pseudomonas aeruginosa, Acinetobacter baumannii; fungi, such as Pneumocystis jirovecii, Candida albicans, Candida tropicalis, Candida glabrata; and viruses, such as cytomegalovirus, influenza, herpes simplex virus type 1, respiratory syncytial virus, parainfluenza, human metapneumovirus, enterovirus, and coronavirus.

[0099] In one embodiment, the sepsis-associated ARDS is caused by a bacterial, fungal or viral infection. In one embodiment, the bacterial infection is selected from the group consisting of a Streptococcus pneumoniae infection, a Staphylococcus aureus infection, a Pseudomonas aeruginosa infection, and an Acinetobacter baumannii infection. In one embodiment, the viral infection is selected from the group consisting of a cytomegalovirus infection, an influenza infection, a herpes simplex virus type 1 infection, a respiratory syncytial virus infection, a parainfluenza infection, a human metapneumovirus infection, an enterovirus infection, and a coronavirus infection. In one embodiment, the fungal infection is selected from the group consisting of a Pneumocystis jirovecii infection, a Candida albicans infection, a Candida tropicalis infection, and a Candida glabrata infection.

[0100] ARDS can be classified, for example, using the Berlin criteria described in The ARDS Definition Task Force (2012, American Medical Association, 307(23): 2526-2234). The criteria are based on the ratio of arterial blood oxygen partial pressure to inspired oxygen concentration measured at a minimum level of positive end-expiratory pressure (PEEP) of 5 cmH2O. According to the Berlin criteria, the severity of ARDS is classified as mild, moderate, or severe (Table 2).

[0101] Classification of ARDS based on the Berlin criteria can also be done by considering the risk factors and the duration of exposure to the risk factors (i.e., the maximum duration between exposure to the risk factors and the onset of ARDS is 7 days).Risk factors for ARDS include direct risk factors, i.e., pneumonia, aspiration of gastric contents, inhalation injury, pulmonary contusion, pulmonary vasculitis and drowning, and indirect risk factors, i.e., non-pulmonary sepsis, multiple trauma, pancreatitis, non-cardiogenic shock, drug overdose and transfusion-related acute lung injury (TRALI).

[0102] Imaging of lung pathology in patients with ARDS, measurement of inflammatory or other biomarkers for ARDS may also be used to classify ARDS.

[0103] Suitable imaging methods are known to those skilled in the art, illustrative examples of which include, for example, computed tomography (CT) as described by Puybasset et al. (1998, American Journal of Respiratory and Critical Care Medicine, 158(5).1644-1655). Similarly, suitable inflammatory markers and other biomarkers for ARDS are known to those skilled in the art, illustrative examples of which include, for example, the biomarkers reviewed by Blondennet et al. (2016, DiseaseMarkers, 2016:35101373).

[0104] The inventors have surprisingly found that CBD and hydroxychloroquine act synergistically to inhibit the production of inflammatory cytokines in response to harmful stimuli. The inventors have also surprisingly found that administration of CBD and hydroxychloroquine can treat conditions associated with pulmonary inflammation, including COPD, asthma, CF and ARDS (e.g., by reducing or alleviating the symptoms or severity of ARDS, in particular by reducing acute pulmonary inflammatory responses, reversing edema, and limiting lung damage).

[0105] Methods for treating or preventing inflammatory conditions According to aspects disclosed herein, there is provided a method for the treatment of an inflammatory condition, comprising administering to a subject in need thereof a composition described herein.

[0106] In another aspect of the present disclosure, there is also provided the use of a composition disclosed herein in the manufacture of a medicament for the treatment of an inflammatory condition.

[0107] As used herein, the terms "treat", "treating", "treatment" and the like are used interchangeably herein to mean to alleviate, reduce, alleviate, improve, or suppress the severity of one or more symptoms of an inflammatory condition in a subject. It should be understood that the terms "treat", "treating", "treatment" and the like as used herein do not mean to treat a subject until the inflammatory condition disappears or is no longer evident. Treatment can also reduce the severity of one or more symptoms of an inflammatory condition.

[0108] As used herein, the terms "prevent," "preventing," "prevention," and the like are used interchangeably herein and mean to hinder the establishment of a disease state, or in any case to prevent, hinder, slow, neutralize, or reverse the onset or progression of a condition or disease or other undesirable symptom.

[0109] The term "subject" as used herein refers to any mammal, including livestock and other farm animals (such as cows, goats, sheep, horses, pigs and chickens), performance animals (such as race horses), pet animals (such as cats and dogs), laboratory test animals and humans. In one embodiment, the subject is a human.

[0110] A change in the symptoms or severity of the inflammatory condition as measured by any quantitative method or clinical device known in the art (e.g., a reduction in inflammatory mediators, a reduction in white blood cell count and / or neutrophil infiltration, a reduction in acute pulmonary inflammatory response, resolution of edema, and limitation of damage to the lungs). Beneficial or desired therapeutic outcomes can be quantified by measuring clinical parameters, illustrative examples of which include measurement of the oxygenation index (OI [FIO2 × mean airway pressure × 100) / PaO2]) or oxygenation saturation index (OSI [FIO2 × mean airway pressure × 100) / oxygen saturation by pulse oximetry (SpO2)) (DesPrez et al. (2017, Chest, 152(6):1151-1158), measurement of the ratio of arterial oxygen pressure to inspired oxygen concentration (PaO2:FiO2) as described by The ARDS Definition Task Force (2012, supra), detection of bilateral pulmonary opacities by chest radiography, detection of altered levels of immunological biomarkers as described by Blondennet et al. (2016, supra), endoscopic and histological evaluation of the colonic mucosa, and stool analysis (including fecal occult blood score and stool consistency).Subjective measurements of beneficial or desired treatment outcomes can also be made using clinical instruments known in the art, illustrative examples of which include the Lung Injury Score (LIS) (Murray et al., 1988, American Review of Respiratory Disease, 138(3):720), the American-European Consensus Conference (AECC) definition (Bernard et al., 1994, American Journal of Respiratory and Critical Care Medicine, 149:818-824), Disease Severity Scores (e.g., Acute Physiology and Chronic Health Evaluation II (APACHE II) and Simplified Index Score II), the Berlin criteria (The ARDS Definition Task Force, 2012, supra), Crohn's Disease Activity Index (CDAI; Best et al., 1976, Gastroenterology, 70: 439-444), the MayoScore for Ulcerative Colitis (UC; Lewis et al., 2008, Inflammatory Bowel Score (UC; Disease, 14:1660-1666).

[0111] In one embodiment, the methods disclosed herein reduce the symptoms or severity of an inflammatory condition by at least 10%, preferably at least 20%, preferably at least 30%, preferably at least 40%, preferably at least 50%, preferably at least 60%, preferably at least 70%, preferably at least 80%, preferably at least 90%, or more preferably at least 100%, as compared to a subject with the same inflammatory condition who is not administered the composition.

[0112] In one embodiment, the composition is for use in the treatment or prevention of an inflammatory condition.

[0113] In one embodiment, the composition is for use in the treatment or prevention of an inflammatory respiratory condition.

[0114] In one embodiment, the composition is for use in the treatment or prevention of an inflammatory respiratory condition selected from the group consisting of ARDS, COPD, asthma, bronchitis, and CF.

[0115] In one embodiment, the composition is for use in the treatment or prevention of ARDS.

[0116] In one embodiment, the composition is for use in the treatment or prevention of sepsis associated ARDS.

[0117] In one embodiment, the composition is for use in the treatment or prevention of sepsis-associated ARDS caused by bacterial, fungal, or viral infection, as described elsewhere herein.

[0118] In one embodiment, the composition is for use in the treatment or prevention of inflammatory bowel disease.

[0119] In one embodiment, the composition is for use in the treatment or prevention of arthritis. In another embodiment, the composition is for use in the treatment or prevention of rheumatoid arthritis.

[0120] In one embodiment disclosed herein, there is provided a use of a composition described herein in the manufacture of a medicament for the treatment or prevention of an inflammatory condition.

[0121] In one embodiment, the inflammatory condition is an inflammatory respiratory condition.

[0122] In one embodiment, the inflammatory respiratory condition is selected from the group consisting of ARDS, COPD, asthma, bronchitis and CF.

[0123] In one embodiment, the inflammatory condition is ARDS. In another embodiment, the ARDS is sepsis-associated ARDS.

[0124] In another embodiment, the inflammatory condition is inflammatory bowel disease.

[0125] In another embodiment, the inflammatory condition is arthritis, hi another embodiment, the arthritis is rheumatoid arthritis.

[0126] In some embodiments, periodic re-administration of the composition may be required to obtain desired therapeutic effect.The exact dosage and administration rate of the composition varies depending on many factors, such as the subject's age, weight, general health condition, sex, and dietary requirements, as well as the drugs or medications used in combination with or simultaneously with the administration of the composition (examples of which are described elsewhere herein).When multiple administrations are required, they can be administered hourly, daily, weekly, monthly, or at other suitable time intervals, or the dosage can be proportionally reduced according to the exigencies of the situation.

[0127] In one embodiment, the composition is administered twice daily.

[0128] In one embodiment, the composition is administered for a period of at least one week.

[0129] In one embodiment, the composition is administered to the subject for a period of 1 to 10 weeks (e.g., 1 week, 2 weeks, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 7 weeks, 8 weeks, 9 weeks, or 10 weeks).

[0130] Thus, in one embodiment, the composition is administered to the subject for a period of 1 to 10 weeks, preferably about 1 week, preferably about 2 weeks, preferably about 3 weeks, preferably about 4 weeks, preferably about 5 weeks, preferably about 6 weeks, preferably about 7 weeks, preferably about 8 weeks, preferably about 9 weeks, or more preferably about 10 weeks.

[0131] In one embodiment, the composition is administered to the subject for a period of three to four weeks.

[0132] Methods for modulating immune responses In another aspect disclosed herein, there is provided a method of modulating an immune response comprising administering to a subject in need thereof a composition described herein.

[0133] One of ordinary skill in the art will appreciate that modulation of an immune response according to the methods disclosed herein can be determined by a variety of methods known in the art, illustrative examples of which include measuring changes in cytokine production (e.g., levels, concentrations, ratios) in a subject, such as before and after treatment or during the course of treatment. The term "modulation" as used herein should be understood to mean a decrease or increase in the immune response, as determined by a decrease or increase in the levels, concentrations and / or ratios of inflammatory mediators, such as cytokines.

[0134] As used herein, the terms "level" and "amount" are used interchangeably herein and refer to quantitative amounts (e.g., moles or numbers), semi-quantitative amounts, relative amounts (e.g., weight percent or mole percent within a class, or ratios), concentrations, etc. Thus, these terms encompass absolute or relative amounts or concentrations, including inflammatory mediators, in a sample.

[0135] Inflammatory mediators such as cytokines can be quantified or detected using any suitable technique, including but not limited to nucleic acid and protein-based assays.In an exemplary nucleic acid-based assay, nucleic acid is isolated from cells contained in biological samples according to standard methodology (Sambrook et al., 1989, Molecular Cloning: A Laboratory Manual; and Ausubel et al., 1994, Current Protocols in Molecular Biology).

[0136] In other exemplary embodiments, the protein levels of inflammatory mediators can be measured using protein-based assays known in the art. For example, antibody-based techniques can be employed to measure the levels of autoantibodies in a sample, illustrative examples of which include immunoassays such as enzyme-linked immunosorbent assay (ELISA), immunohistochemistry (IHC), and radioimmunoassay (RIA).

[0137] In one embodiment, protein expression is measured using a multiplexed protein expression analysis method. In another embodiment, the multiplexed protein expression analysis method is a protein microarray or a Luminex® bead array.

[0138] Protein capture arrays may also be employed that allow for simultaneous detection and / or quantification of multiple proteins. For example, low-density protein arrays on filter membranes, such as the Universal Protein Array System, allow imaging of arrayed antigens using standard ELISA techniques and scanning charge-coupled device (CCD) detectors. Exemplary protein capture arrays include protein function arrays with spatially positioned protein binding molecules (i.e., antigens), which can facilitate extensive parallel analysis of autoantibodies with specificity for the antigens that make up the protein function array. Central to this type of analysis is the retention of confirmation of correctly folded proteins of the arrayed antigens. Protein function arrays have been shown to have the required properties of specificity and acceptable background, and are commercially available (e.g., from Sengenics). Various methods for preparing protein function arrays have been reported (see, e.g., Gnjatic et al., 2009, Journal of Immunological Methods, 341(50):1-2; PCT / GB01 / 00395, PCT / GB02 / 05499, PCT / GB03 / 00362). The individual spatially distinct functional proteins are typically attached to a planar or contoured support surface. Common physical supports include glass slides, silicon, microwells, nitrocellulose or PVDF membranes, as well as magnetic and other microbeads.

[0139] Particles in suspension can also be used as the basis for arrays if they are coded for identification. Systems include color coding of microbeads (e.g., available from Luminex, Bio-Rad, NanomicsBiosystems) and semiconductor nanocrystals (e.g., QDots™ available from Quantum Dots), as well as bar coding of beads (UltraPlex™ available from Smartbeads) and multimetal microrods (Nanobarcodes™ particles available from Surromed). Beads can also be assembled into planar arrays on semiconductor chips (e.g., available from LEAPStechnology and BioArray Solutions). When particles are used, individual protein capture agents (e.g., antibodies against inflammatory mediators or inflammatory mediator-binding fragments thereof) are usually attached to individual particles to provide spatial definition or separation of the array. The particles can then be assayed separately but in parallel, for example in a compartmentalized format, such as the wells of a microtiter plate or separate test tubes.

[0140] In an illustrative example, a patient sample or a control sample is delivered to a protein functional array under conditions suitable for protein or peptide binding, and the array is washed to remove unbound or non-specifically bound sample components from the array. The array is then incubated with a fluorescently labeled antibody to detect interactions between the array antigens and inflammatory mediators present in the sample. The presence or amount of protein or peptide bound to each feature of the array is detected using a suitable fluorescence detection system. The amount of protein bound to a feature of the array is proportional to the fluorescence intensity. In certain embodiments, local background fluorescence obtained from control features of the array is automatically subtracted, and the relative fluorescence units (rfu) of each feature of the array are recorded.

[0141] In some embodiments, the protein function array is a Luminex-based multiplex assay, which is a bead-based multiplex assay, where the beads are internally stained with fluorescent dyes to generate specific spectral addresses. Biomolecules (such as oligos or antibodies) can be attached to the bead surface to capture the analytes of interest, i.e., inflammation markers, such as cytokines. Flow cytometry or other suitable imaging techniques known to those skilled in the art can then be used to characterize the beads and detect the presence of the analytes. Luminex technology allows the detection of a large number of proteins, genes or other gene expression products (e.g., 100 or more, 200 or more, 300 or more, 400 or more) with very small sample volumes (e.g., 96 or 384 well plates).

[0142] In some embodiments, the levels of inflammatory mediators can be normalized to a housekeeping biomarker. The term "housekeeping biomarker" refers to a biomarker or group of biomarkers (e.g., polynucleotides and / or polypeptides) that are typically found at consistent levels in the cell type or tissue being analyzed and across the conditions being evaluated.

[0143] In other embodiments, the levels of inflammatory mediators measured using protein arrays can be normalized by both intra-array and inter-array data normalization. For example, intra-array normalization is achieved by calculating the overall median of the median relative fluorescence units (rfu) of each protein in the protein function array (excluding the data of control proteins) and dividing the median of quadruplicate spots of each protein on the array by the overall median of all proteins on the array in each sample. Inter-array normalization can be achieved using bioinformatics software packages known in the art. For example, inter-array normalization can be achieved using the normalize.quantiles package in R (Bolstad et al., 2003, Bioinformatics, 19(2):185-193).

[0144] As described elsewhere herein, those skilled in the art will understand that the method of analyzing the level of inflammatory mediator in a sample can be quantitative, semi-quantitative, or qualitative in nature. For example, quantitative analysis usually provides the concentration or number of inflammatory mediator nucleic acid molecules or proteins in a sample within a suitable error range (e.g., mean + / - standard deviation). In contrast, semi-quantitative or qualitative analysis usually provides an indication of the relative amount of inflammatory mediator in a sample. This may include comparing the amount of inflammatory mediator in a first sample with the amount of inflammatory mediator in a second sample to determine the relative amount of inflammatory mediator between the first sample and the second sample.

[0145] It will be understood by those skilled in the art that if a comparison is made to a reference value, the method by which the sample is assessed for the level of one or more inflammatory mediators should be substantially the same as the method by which the reference value is derived, to ensure that an appropriate comparison can be made for purposes of determining whether the immune response has been modulated in the subject following administration of CBD and hydroxychloroquine.

[0146] In one embodiment, the method of modulating an immune response comprises reducing the level of an inflammatory mediator relative to a baseline level.

[0147] In one embodiment, the inflammatory mediator is a cytokine.

[0148] The term "cytokine" as used herein refers to factors that have a variety of effects on cells, e.g., factors that induce growth or proliferation, illustrative examples of which include IL-1β, IL-2, IL-10, IL-12(p70), IFN-γ, TNF-α, IL-1α, IL-3, IL-4, IL-5, IL-6, IL-9, IL-12(p40), IL-13, IL-17A, eotaxin, G-CSF, GM-CSF, IFN-γ, KC, MCP-1 (MCAF), MIP-1α, MIP-1β, RANTES, and CXCL-1.

[0149] In one embodiment, the method of modulating an immune response comprises reducing the level of a proinflammatory cytokine selected from the group consisting of IL-1β, IL-6, TNF-α, IL-1α, IL-12(p70), IFN-γ, CXCL-1, MCP-1 and MIP-1α relative to a baseline level.

[0150] In one embodiment, the method of modulating an immune response comprises reducing the level of a pro-inflammatory cytokine selected from the group consisting of IL-1β, IL-6 and TNF-α relative to a baseline level.

[0151] Those skilled in the art will understand that the invention described herein may be subject to variations and modifications other than those specifically described. It is to be understood that the present invention includes all such variations and modifications within its spirit and scope. The present invention also includes all steps, features, compositions and compounds, and any and all combinations of any two or more of the steps or features, individually or collectively referred to or shown in this specification.

[0152] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs.

[0153] All patents, patent applications and publications mentioned herein are hereby incorporated by reference in their entirety.

[0154] The various embodiments enabled herein are further illustrated by the following non-limiting examples. EXAMPLES

[0155] material Activator Cannabidiol (CBD) and hydroxychloroquine (HCQ) were purchased from commercial suppliers and provided to Pharmacology Discovery Services Taiwan, Ltd. The formulations are summarized in Table 3.

[0156] chemicals 0.9% NaCl (Sintong Chemical Industry Co., Ltd, Taiwan), Bio-PIex mouse cytokine Thl-7plex panel (Bio-Rad, USA), Bio-PIex mouse cytokine group I 23-plex panel (Bio-Rad, USA), Lipopolysaccharide (Escherichia coli O55:B5, Sigma L-2880, USA), Mouse D-Dimer (D2D) ELISA kit (MyBioSource, USA), phosphate buffered saline (Sigma, USA) and water for injection (WFI) (Tai-Yu, Taiwan).

[0157] Lipopolysaccharide (LPS)-induced sepsis Male C57BL / 6 mice weighing 10–20 g were used. Vehicle and active agents (i.e., CBD and hydroxychloroquine), alone or in combination, were administered intraperitoneally (IP) or orally 1 h prior to intravenous (IV) injection of LPS (100 μg / 100 μL / mouse). Two hours after LPS injection, blood was collected by cardiac puncture from all mice and serum was processed and assayed for biomarkers using either Thl7-plex for IL-1β, IL-2, IL-10, IL-12(p70), IFN-γ, and TNF-α by Luminex, plus IL-6 and D-dimer by ELISA, or 23-plex for IL-1α, IL-1β, IL-2, IL-3, IL-4, IL-5, IL-6, IL-9, IL-10, IL-12(p40), IL-12(p70), IL-13, IL-17A, eotaxin, G-CSF, GM-CSF, IFN-γ, KC, MCP-1 (MCAF), MIP-1α, MIP-1β, RANTES, and TNF-α by Luminex, plus IL-6 by ELISA. Comparisons between vehicle and treatment groups were performed using ANOVA followed by Dunnett's test. p<0.05 was considered significant.

[0158] For synergy analysis, data were baseline subtracted using cytokine levels in sham-treated mice (i.e., no LPS injection) before normalizing the values ​​for each cytokine to the maximum value across the group. Normalized values ​​were used to calculate relative inhibition, where a value of 1 represents complete inhibition and a value of 0 represents no inhibition. Synergy was calculated using statistical methods described elsewhere herein.

[0159] LPS-induced pulmonary inflammation Male C57BL / B6 mice weighing 10–20 g were used. Vehicle and active agents (i.e., CBD and hydroxychloroquine), alone or in combination, were administered intraperitoneally (IP) 1 h before intratracheal administration of LPS (approximately 80 mg / kg). 24 h after LPS injection, mice were anesthetized with pentobarbital and approximately 0.6 mL of bronchoalveolar lavage fluid (BALF) was obtained after two doses of 0.5 mL of PBS through the tracheal cannula. BALF was assayed for IL-1β, TNF-α, MCP-l (MCAF) and CXCL-1 by Luminex. ANOVA followed by Dunnett's test was applied for comparisons between vehicle and treatment groups. p<0.05 was considered significant.

[0160] In a separate test group of animals in which pneumonia was induced as described above, lungs were removed (five lobes per lung) at termination and fixed in 10% neutral buffered formalin for histopathological examination. Samples were sectioned at 4-6 μm and stained with hematoxylin and eosin (H&E) to examine for inflammatory lesions as described by Shackleford et al. (2002, Toxicologic Pathology, 30(1):93-96). Briefly, a score of 0 means no lesions and a score of 5 indicates that lesions are severe / numerous. Scores were averaged across lobes for each animal and then across animals in each treatment group.

[0161] For synergy analysis, data were baseline subtracted using cytokine levels in sham-treated mice (i.e., no LPS injection) before normalizing the values ​​for each cytokine to the maximum value across the group. Normalized values ​​were used to calculate relative inhibition, where a value of 1 represents complete inhibition and a value of 0 represents no inhibition. Synergy was calculated using statistical methods described elsewhere herein.

[0162] 2,4,6-trinitrobenzenesulfonic acid (TNBS)-induced colitis We used male BALB / c mice as an in vivo model of colitis induced by intracolonic administration of 2,4,6-trinitrobenzenesulfonic acid (TNBS) in 50% ethanol as previously described by Antoniou et al. (2016, Annals of Medicine and Surgery, 11:9-15). Briefly, ethanol disrupts the intestinal barrier, allowing TNBS to interact with proteins in the colon. The interaction of TNBS with high molecular weight proteins renders TNBS immunogenic, triggering Thl-mediated inflammation and resulting in symptoms such as heterogeneous stool formation and bloody stool.

[0163] Vehicle and active agents (i.e., CBD and hydroxychloroquine), alone or in combination, were administered intraperitoneally (IP) once daily for a total of 4 consecutive days from day 1 (i.e., 24 hours prior to TNBS) through day 4 (days 1-4). On the day of TNBS challenge (i.e., day 2), test articles and vehicle were administered 2 hours prior to TNBS.

[0164] Colonic tissue was collected from all animals at the time of sacrifice. Colonic samples were taken from 0.5, 2, and 3.5 cm from the anus, fixed in formalin, and embedded in paraffin blocks. Four-micrometer tissue sections were cut and stained with H&E for histological analysis according to the method of Dieleman et al. (1998, Clinical Experimental Immunology, 114:385-391). Histological criteria included abnormalities in mucosal architecture, degree of inflammation, erosion or ulceration, epithelial regeneration, and percentage of disease process involvement. Scoring was based on the observer's findings, with three sections examined from each colon per animal. A total colitis index was added, resulting in a combined histological score ranging from 0 to 60.

[0165] Other endpoint measurements included stool consistency score (i.e., 0-normal stool, 1-loose but still formed stool, 2-very loose stool, 3-diarrhea), stool occult blood score (i.e., 0-negative stool, 1-positive stool, 2-visible traces of blood in stool, 3-rectal bleeding), colon weight, colon macroscopic damage score (a composite of adhesions, strictures, ulcers / inflammation, and wall thickness), and myeloperoxidase levels in colonic tissue. Data from each of these endpoints were subtracted from baseline using the equivalent measurements from sham-treated mice (i.e., no TNBS), and reductions in any measurements were calculated as relative reductions. Synergy was calculated using statistical methods described elsewhere herein.

[0166] Collagen-induced arthritis Arthritis was induced in female Lewis rats by subcutaneous injection of porcine type II collagen supplemented with Freund's adjuvant (0.2 mg / 0.2 mL / rat) at the base of the tail on day 1. A booster injection (0.1 mg / 0.1 mL / rat) was administered on day 7. On day 16, rats were assigned to six groups based on hind paw volume, with animals assigned to groups such that hind paw volumes were similarly distributed.

[0167] Vehicle and active agents (i.e., CBD and hydroxychloroquine), alone or in combination, were administered intraperitoneally (IP) once daily from days 17 to 30, for a total of 14 consecutive days.

[0168] On days 1, 7, 10, 14, 16, 18, 20, 22, 24, 26, 28 and 30, disease was assessed by measuring hind paw volume using a plethysmometer and using the qualitative severity scoring system shown in Table 16.

[0169] After sacrifice on day 30, blood was collected from all rats and analyzed for the levels of inflammatory cytokines IL-1β, IL-6, and TNF-α by ELISA. Both hind limbs were harvested, weighed, and formalin-fixed for histopathology. Tissues were evaluated to assess cartilage and bone destruction due to pannus formation and mononuclear cell infiltration in synovial tissue according to the scoring matrix shown in Tables 17 and 18. A total histological score was also calculated, which was the sum of the pannus formation score and the mononuclear cell infiltration score.

[0170] For synergy analysis, data were baseline subtracted using sham-treated mice (i.e., no collagen injection) before normalizing values ​​to vehicle controls. Synergy was calculated using statistical methods described elsewhere herein.

[0171] In vitro analysis of the anti-inflammatory activity of CBD in combination with hydroxychloroquine The anti-inflammatory activity of the combination of CBD and hydroxychloroquine was evaluated by measuring cytokine release from human peripheral blood mononuclear cells (PBMCs) stimulated with bacterial lipopolysaccharide (LPS) using a Luminex-based assay. A 96-well microtiter plate-based checkerboard assay in which CBD and hydroxychloroquine were co-evaluated at seven concentrations (including a no-drug control) was used to measure drug-drug interactions. Briefly, frozen PBMCs from two independent donors were thawed, diluted in culture medium, seeded into 96-well microtiter plates, and incubated at 37 °C and 5% CO2 for 1 h before adding test compounds. After addition of test compounds, cells were returned to the incubator for 1 h, after which LPS was added to the wells. Plates were incubated at 37 °C and 5% CO2 for 24 h. After 24 h, cell culture supernatants were removed and cytokine levels were analyzed using the Luminex method according to the manufacturer's instructions. All values ​​were vehicle background subtracted before further analysis. Three plates were set up in parallel using PBMCs from the same donor. Inhibition of cytokine release was measured relative to untreated controls (i.e., stimulated with LPS) and averaged over three replicates. Cytotoxicity assays using AlamarBlue were also performed in parallel in the same plate set up.

[0172] statistical analysis Drug synergy was measured using the Bliss Independence method, where the predicted effect of a drug combination is calculated using the following formula: E predA+B =(E A +E B )-(E A E B )

[0173] The synergy value for each drug concentration combination was calculated using the Excess Over Bliss method (difference between observed and predicted inhibition), e.g., as described in Liu et al. (2018, Statistics in Biopharmaceutical Research, 10:112-122), where values ​​greater than 0 indicate synergy, and larger values ​​indicate stronger synergy.

[0174] Example 1: The combination of CBD and hydroxychloroquine acts synergistically to modulate inflammatory responses in vitro CBD and hydroxychloroquine act synergistically at multiple drug concentrations to inhibit LPS-induced production of the inflammatory cytokines IL-1β, IL-6, TNF-α, IL-1α, and MIP-1α. PBMCs from donor 1 were treated with 5 μg / mL CBD in combination with 0.63, 1.25, 2.5, 5, and 10 μg / mL hydroxychloroquine, with the results shown in Table 19. PBMCs from donor 2 were treated with 5 μg / mL CBD in combination with 0.63, 1.25, 2.5, 5, 10, and / or 20 μg / mL hydroxychloroquine, with the results shown in Table 4.

[0175] Values ​​presented herein are expressed as inhibition relative to untreated controls, i.e., a value of 0 indicates no inhibition and a value of 1 indicates complete inhibition of the release of the relevant cytokine. Cell viability was greater than 84% for all treatments shown in Tables 3 and 4.

[0176] Example 2: The combination of CBD and hydroxychloroquine synergizes to modulate inflammatory responses in vivo CBD and hydroxychloroquine act synergistically at multiple drug concentrations to inhibit LPS-induced production of the proinflammatory cytokines IL-1β, IL-6, IL-12(p70), IFN-γ, and / or TNF-α (Tables 5-8).

[0177] Example 3: The combination of CBD and hydroxychloroquine synergizes to modulate immune responses in an in vivo model of pulmonary inflammation Mice were challenged with LPS intratracheally to induce pulmonary inflammation in a manner that recapitulates clinical aspects of pulmonary inflammation observed in inflammatory respiratory conditions such as COPD (see, e.g., Hakannsson et al., 2012, Pulmonary Pharmacology & Therapeutics, 25:399-406).

[0178] CBD and hydroxychloroquine act synergistically to inhibit the production of the proinflammatory cytokines IL-1β, IL-6, TNF-α, CXCL-1 and MCP-1 at multiple concentrations as measured in BALF from mice with LPS-induced pneumonia (Tables 9 and 10).

[0179] BALF collected from mice was also analyzed for white blood cell (WBC) counts using an automated hematology analyzer. Cell counts were normalized using sham-treated mice and analyzed relative to the highest value across the group (Table 11). These data indicate that the combination of CBD and hydroxychloroquine reduced total white blood cell counts and neutrophil levels to a greater extent than CBD or hydroxychloroquine alone.

[0180] The combination of CBD and hydroxychloroquine was superior to CBD or hydroxychloroquine alone at equivalent doses in reducing inflammatory lesions in the lungs of mice with LPS-induced pneumonia (Tables 14 and 15, Figure 3).

[0181] Example 4: The combination of CBD and hydroxychloroquine synergizes to treat inflammatory bowel disease in vivo CBD and hydroxychloroquine acted synergistically to reduce myeloperoxidase (MPO) levels in colonic tissue, stool consistency scores, and macroscopic damage scores (Table 11).

[0182] As assessed by histological analysis of changes to colitis in the distal colon of TNBS-induced colitis mice, the combination of CBD and hydroxychloroquine was shown to be superior to each drug alone in reducing the Total Colitis Index (Table 12). Representative stained sections are shown in Figure 4. The combination of CBD and hydroxychloroquine also improved colon to body weight ratio compared to either drug administered alone (Table 12).

[0183] Example 5: The combination of CBD and hydroxychloroquine synergizes to treat arthritis in vivo CBD and hydroxychloroquine at doses of 1 mg / kg and 2.5 mg / kg, respectively, act synergistically to reduce clinical score and paw pad volume at day 24, as well as pannus formation and total histological score at the endpoint (i.e., day 30). The Bliss excess scores for clinical score, paw pad volume, pannus formation and total histological score were 0.05, 0.26, 0.30 and 0.03, respectively (Table 19).

[0184] The combination of CBD 1 mg / kg and hydroxychloroquine 2.5 mg / kg was shown to be superior to each drug alone in reducing serum levels of the pro-inflammatory cytokines IL-1β and IL-6 (Table 20; Figure 5).

[0185] Hydroxychloroquine is used to treat rheumatoid arthritis in the form of hydroxychloroquine sulfate. However, long-term use of hydroxychloroquine is associated with ocular toxicity and cardiac effects (e.g., cardiomyopathy and QT prolongation). Clinically, the most important predictor of ocular toxicity and cardiac effects in rheumatoid arthritis patients is the cumulative dose of hydroxychloroquine. To understand the ability of CBD to allow for a reduction in hydroxychloroquine dose while maintaining therapeutic efficacy, the results obtained with the combination of 1 mg / kg CBD and 2.5 mg / kg hydroxychloroquine (i.e., low-dose HCQ) were compared with 25 mg / kg hydroxychloroquine alone (i.e., high-dose HCQ). The combination of 1 mg / kg CBD and low-dose HCQ was more or equally effective in reducing arthritis across all endpoints, except for mononuclear cell infiltration (Table 21). These data indicate that the combination of CBD and hydroxychloroquine allows for a ten-fold reduction in the dose of hydroxychloroquine without sacrificing therapeutic efficacy.

[0186] Example 6: Exemplary Compositions Containing CBD and Hydroxychloroquine Exemplary compositions according to the present disclosure include the components in Table 22 and Table 23.

[0187] The first and second capsules in this example are both soft gelatin capsules, however, other exemplary embodiments described herein include a first capsule that is a soft gelatin capsule and a second capsule that is a polymer capsule.

[0188] The solid dosage form of hydroxychloroquine according to this embodiment may be: Calcium phosphate, dibasic, anhydrous (UNII: L11K75P92J); Hypromellose 2910 (6MPA.S) (UNII:0WZ8WG20P6); Magnesium stearate (UNII:70097M6I30); Polyethylene glycol 400 (UNII: B697894SGQ); Polysorbate 80 (UNII:60ZP39ZG8H); Corn starch (UNII:08232NY3SJ); Titanium dioxide (UNII:15FIX9V2JP); Carnauba wax (UNII:R12CBM0EIZ), and Iron oxide (UNII:XM0M87F357), It is a solid tablet that contains a number of inactive ingredients (i.e., excipients), including

[0189] As described elsewhere herein, the compositions may be produced according to the methods disclosed in U.S. Patent No. 9,433,584, U.S. Patent No. 10,383,826, and International Publication No. WO 2012 / 017325. Because the exemplary compositions described herein include tablet solid dosage forms of hydroxychloroquine in which the capsule is of the same material (see, e.g., FIG. 1), such exemplary compositions may be produced according to the methods described in U.S. Patent No. 9,433,584 and U.S. Patent No. 10,383,826 for "double" softgel capsules (see, e.g., U.S. Patent No. 9,433,584, column 6, lines 25-50).

[0190] Example 7: Preparation of a fixed dose combination product An exemplary fixed-dose combination product (i.e., composition) comprising a film-coated hydroxychloroquine tablet contained within a softgel capsule containing CBD was manufactured under Good Manufacturing Practice (GMP) certified conditions by ProCaps, Inc. (Barranquilla, Colombia). The manufacturing process consists of three steps: (i) manufacturing a solid dosage form (e.g., tablet) of hydroxychloroquine; (ii) manufacturing a CBD oil solution; and (iii) combining the solid dosage form of hydroxychloroquine and the CBD oil solution in a softgel capsule.

[0191] Hydroxychloroquine sulfate tablets Each hydroxychloroquine tablet contained 100 mg of active pharmaceutical ingredients (API) and the inactive ingredients listed in Table 24. Hydroxychloroquine, calcium phosphate, pregelatinized starch, and 50% croscarmellose sodium were first blended as dry powders. Water was then added to 10-15% to act as a binder while mixing continued. The mixture was then heated to 40°C to dry, followed by the addition of the remaining 50% croscarmellose sodium and further mixing. Magnesium stearate was then added and a final blending step was performed. The blended powders were then compressed to produce tablets having the properties listed in Table 25.

[0192] The dissolution of hydroxychloroquine tablets in water was then evaluated and compared with the Reference Listed Drug (RLD) Plaquenil® (i.e., hydroxychloroquine sulfate 200 mg) using a USP No. 2 apparatus with a paddle 50 rpm and sampling times of 5, 10, 15, 20, 30, 45, and 60 minutes, and infinity (Figure 6). The f2 between the produced hydroxychloroquine tablets (i.e., hydroxychloroquine sulfate 100 mg) and the RLD was 58, indicating that the dissolution of the two tablets was comparable and that the produced tablets met the USP monograph specification of Q≧70% at 60 minutes.

[0193] Cannabidiol (CBD) Sesame Oil Solution The CBD sesame oil solution contained 12.5% ​​w / w CBD and 0.02% w / v butylated hydroxytoluene (BHT). Sesame oil with BHT and sesame oil without BHT were mixed in a ratio of 57:43. CBD was then dissolved evenly into the oil in two portions. The solution was mixed until no visible particles remained and the density was recorded.

[0194] The inactive ingredients of the fixed dose combination products are listed in Table 24. Samples of the fixed dose combination formulations were stored at 5±3°C, 25±2°C / 60±5% relative humidity (RH) and 40°C / 75%RH and stability was evaluated at 0, 1, 2, 3 and 6 months using the United States Pharmacopeia (USP) monograph method for Hydroxychloroquine Tablets and high performance liquid chromatography (HPLC) analysis for CBD, hydroxychloroquine and related substances. Samples stored at 5±3°C, 25±2°C / 60±5%RH are evaluated every 6 months for 24 months. Dissolution of CBD and hydroxychloroquine from the fixed dose combination products was also evaluated in vitro.

[0195] Fixed dose combination products The fixed dose combination product is manufactured according to the method described by Salazar Altamaer et al. (US Pat. No. 9,433,584). Briefly, a softgel capsule containing a solid dose formulation encapsulated in a polymer capsule is manufactured in a liquid-filled softgel capsule. In the fixed dose combination product described herein, a hydroxychloroquine tablet is contained within a softgel capsule of CBD in sesame oil. The resulting softgel capsules are size 20 rectangular softgel capsules (i.e., 0.986-1.232 cc). Each softgel capsule contains 100 mg of hydroxychloroquine sulfate and 75 mg of CBD. The softgel capsules were manufactured and stored at ambient temperature prior to release analysis. Release of hydroxychloroquine tablet ingredients was performed using the method in the USP monograph for hydroxychloroquine sulfate tablets, with impurities assessed using HPLC. CBD impurities were assessed using an HPLC method developed by SCIPharmtech based on that described in the USP monograph for dronabinol, a synthetic form of THC.

[0196] Analytical data for the fixed-dose combination products are shown in Tables 26 to 28.

[0197] Example 8: Stability of Softgel Capsule Fixed Dose Combination Product The softgel capsule fixed dose combination product described in Example 7 was packaged in a blister pack. Formal stability studies are being conducted at 5±3°C and 25±2°C / 60±5%RH for time points up to 24 months. Stability studies are being conducted at 40°C / 75%RH for time points up to 6 months. At least six dose units were tested in each assay. The one-month data from this stability study are shown in Table 29. All study results met the acceptance criteria at one month in all three conditions.

[0198] summary Taken together, these data demonstrate that the combination of CBD and hydroxychloroquine acts synergistically to significantly modulate inflammatory responses in vitro and in vivo. The simultaneous administration of these two APIs was made possible by encapsulating CBD in a first capsule and a solid dosage form of hydroxychloroquine in a second capsule, which is incorporated into the first capsule. Thus, the present disclosure provides a composition that allows for the simultaneous delivery of a synergistic combination of CBD and hydroxychloroquine, regardless of physico-chemical compatibility and / or stability issues of the two APIs.

[0199] Table 1: Cannabidiol and related cannabinoids [Table 1]

[0200] Table 2: Classification of ARDS according to the ratio of arterial blood oxygen pressure to inspired oxygen concentration (PaO2:FiO2) [Table 2] 1 measurements at ventilator settings including positive end-expiratory pressure (PEEP) or continuous positive airway pressure (CPAP) ≥ 5 cmH2O; 2 Measured at ventilator settings including PEEP ≥ 5cmH2O.

[0201] Table 3: Synergistic inhibition of IL-1β, IL-6, TNF-α, IL-1α, and MIP-1α release by CBD and HCQ in human PBMCs (donor 1). [Table 3] FIE: Fractional Inhibitory Effect, EOB: Excess Bliss

[0202] Table 4: Synergistic inhibition of IL-1β, IL-6, TNF-α, IL-1α, MIP-1α release by CBD and HCQ in human PBMCs (donor 2). [Table 4] FIE: Fractional Inhibitory Effect, EOB: Excess Bliss

[0203] Table 5: Synergistic inhibition of inflammatory cytokine release in vivo following administration of CBD 10 mg / kg and HCQ 25 mg / kg. [Table 5] EOB:Bliss exceeded

[0204] Table 6: Synergistic inhibition of inflammatory cytokine release in vivo following administration of CBD 10 mg / kg and HCQ 100 mg / kg. [Table 6] EOB:Bliss exceeded

[0205] Table 7: Synergistic inhibition of inflammatory cytokine release in vivo following administration of CBD 25 mg / kg and HCQ 25 mg / kg. [Table 7] EOB:Bliss exceeded

[0206] Table 8: Synergistic inhibition of inflammatory cytokine release in vivo following administration of CBD 25 mg / kg and HCQ 100 mg / kg. [Table 8] EOB:Bliss exceeded

[0207] Table 9: Synergistic inhibition of inflammatory cytokine release in an in vivo pulmonary inflammation model following administration of CBD 1 mg / kg and HCQ 25 mg / kg. [Table 9] EOB:Bliss exceeded

[0208] Table 10: Synergistic inhibition of inflammatory cytokine release in an in vivo pulmonary inflammation model following administration of CBD 10 mg / kg and HCQ 25 mg / kg. [Table 10] EOB:Bliss exceeded

[0209] Table 11: Relative reduction in white blood cell counts in an in vivo lung inflammation model [Table 11]

[0210] Table 12: Synergistic effect of CBD 1 mg / kg and HCQ 2.5 mg / kg in an in vivo colitis model [Table 12] EOB:Bliss exceeded

[0211] Table 13: Relative reduction in total colitis index and colon to body weight ratio for CBD 1 mg / kg and HCQ 2.5 mg / kg in an in vivo colitis model [Table 13]

[0212] Table 14: Relative reduction in lung lesion scores for CBD 1 mg / kg and HCQ 2.5 mg / kg in an in vivo lung inflammation model [Table 14]

[0213] Table 15: Relative reduction in lung lesion scores for CBD 10 mg / kg and HCQ 25 mg / kg in an in vivo lung inflammation model [Table 15]

[0214] Table 16: Severity score matrix for in vivo models of arthritis [Table 16]

[0215] Table 17: Cartilage and bone destruction by pannus formation scoring matrix in an in vivo model of arthritis. [Table 17]

[0216] Table 18: Mononuclear cell infiltration scoring matrix in in vivo models of arthritis [Table 18]

[0217] Table 19: Synergistic activity of CBD 1 mg / kg and HCQ 2.5 mg / kg in an in vivo model of arthritis [Table 19] EOB:Bliss exceeded

[0218] Table 20: Relative reduction in serum cytokine levels with CBD 1 mg / kg and HCQ 2.5 mg / kg in an in vivo model of arthritis [Table 20]

[0219] Table 21: Comparison of high dose HCQ and low dose HCQ combined with CBD 1 mg / kg in reducing disease severity in an in vivo model of arthritis. [Table 21]

[0220] Table 22: Exemplary compositions containing CBD and HCQ [Table 22]

[0221] Table 23: Exemplary compositions containing CBD and HCQ [Table 23]

[0222] Table 24: List of inactive ingredients in an exemplary softgel capsule fixed dose combination product [Table 24]

[0223] Table 25: Characteristics of HCQ tablets in an exemplary softgel capsule fixed dose combination product [Table 25]

[0224] Table 26: Analysis of an exemplary softgel capsule fixed dose combination product [Table 26] ND=Not Detected; NMT=Below

[0225] Table 27: Dissolution of HCQ from an exemplary softgel capsule fixed dose combination product using USP monograph UV spectrophotometry [Table 27] IRPM = Infinite RPM Mode; SD = Standard Deviation

[0226] Table 28: Dissolution of CBD from an exemplary softgel capsule fixed dose combination product using USP No. 2 (paddle apparatus) [Table 28] IRPM = Infinite RPM Mode; Q = amount of dissolved active ingredient (i.e. CBD); SD = Standard Deviation

[0227] Table 29: Stability of an exemplary softgel capsule fixed dose combination after 1 month storage [Table 29] ND = Not Detectable; NMT = Less Than or Equal; Q = Amount of Active Ingredients Dissolved (i.e., CBD, HCQ)

Claims

1. a. Cannabidiol (CBD) or a pharmaceutically acceptable salt or derivative thereof; and b. A solid dosage form of hydroxychloroquine or a pharmaceutically acceptable salt thereof, A composition comprising, wherein the CBD or a pharmaceutically acceptable salt or derivative thereof is encapsulated in a first capsule, and the solid dosage form of hydroxychloroquine or a pharmaceutically acceptable salt thereof is encapsulated in a second capsule, where the second capsule is at least partially encapsulated in the first capsule.

2. The composition according to claim 1, wherein the CBD or a pharmaceutically acceptable salt or derivative thereof is solubilized in a liquid solvent selected from the group consisting of oils, alcohols, propylene glycol, and glycerol.

3. The composition according to claim 2, wherein the liquid solvent is an oil selected from the group consisting of hemp seed oil, olive oil, caprylic / capric triglyceride (MCT) oil, sunflower oil, and sesame oil.

4. The composition according to claim 1, wherein the first capsule is a soft gelatin capsule.

5. The composition according to claim 2, wherein the second capsule is a capsule that is not solubilized by a liquid solvent.

6. The composition according to claim 5, wherein the second capsule is selected from the group consisting of polymer capsules, soft gelatin capsules, and cellulose capsules.

7. The composition according to claim 6, wherein the second capsule is a polymer capsule.

8. The composition according to claim 1, wherein the solid dosage form is selected from the group consisting of tablets, powders, microparticles, nanoparticles, and pellets.

9. The composition according to claim 8, wherein the solid dosage form is a tablet.

10. The composition according to claim 1, wherein the second capsule is incorporated within the first capsule.

11. The composition according to claim 1, wherein the CBD or a pharmaceutically acceptable salt or derivative thereof is a synthetic compound.

12. The composition according to claim 1, containing at least about 25 mg of CBD or a pharmaceutically acceptable salt or derivative thereof.

13. The composition according to claim 12, containing about 25 mg to about 100 mg of CBD or a pharmaceutically acceptable salt or derivative thereof.

14. The composition according to claim 13, containing about 75 mg of CBD or a pharmaceutically acceptable salt or derivative thereof.

15. The composition according to claim 1, containing at least about 10 mg of said hydroxychloroquine or a pharmaceutically acceptable salt thereof.

16. The composition according to claim 15, containing from about 10 mg to about 200 mg of said hydroxychloroquine or a pharmaceutically acceptable salt thereof.

17. The composition according to claim 16, containing about 20 mg of said hydroxychloroquine or a pharmaceutically acceptable salt thereof.

18. The composition according to claim 16, containing about 100 mg of said hydroxychloroquine or a pharmaceutically acceptable salt thereof.

19. The composition according to claim 1, for use in the treatment of an inflammatory condition.

20. Use of the composition according to claim 1 in the manufacture of a medicament for the treatment of an inflammatory condition.

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