Compositions and methods for treating hypertension

Abstract

Disclosed herein are compositions and methods for delivering cannabidiol to a subject in need of treatment for hypertension. The disclosed compositions are delivered orally. Additionally, kits are disclosed that include the disclosed compositions as part of a method for delivering a cannabidiol-containing composition.

Description

[Technical Field]

[0001] Disclosed herein are compositions and methods for delivering cannabidiol to a subject in need of treatment for hypertension. The disclosed compositions are delivered orally. Additionally, disclosed are kits containing the disclosed compositions as part of a method for delivering cannabidiol-containing compositions. [Brief explanation of the drawings]

[0002] [Figure 1] FIG. 1 is a plot of the individual plasma concentrations of CBD in animals 1-10 following oral administration of 25 mg / kg of the composition disclosed in Table 1. [Figure 2] FIG. 2 is a plot of the mean plasma concentrations of CBD in animals 1-10 following oral administration of 25 mg / kg of a composition disclosed in Table 1. [Figure 3] FIG. 3 is a plot of the individual plasma concentrations of CBD in animals 11-20 following oral administration of 25 mg / kg of a composition disclosed in Table 2. [Figure 4] FIG. 4 is a plot of the mean plasma concentrations of CBD in animals 11-20 following oral administration of 25 mg / kg of a composition disclosed in Table 2. [Figure 5] FIG. 5 is a plot of the individual plasma concentrations of CBD in animals 21-30 following oral administration of 25 mg / kg of a composition disclosed in Table 3. [Figure 6] FIG. 6 is a plot of the mean plasma concentrations of CBD in animals 21-30 following oral administration of 25 mg / kg of a composition disclosed in Table 3. [Figure 7] FIG. 7 is a plot of the individual plasma concentrations of CBD in animals 31-40 following oral administration of 25 mg / kg of the composition disclosed in Table 4. [Figure 8] FIG. 8 is a plot of the mean plasma concentrations of CBD in animals 31-40 following oral administration of 25 mg / kg of a composition disclosed in Table 4. [Figure 9]FIG. 9 is a plot of the individual plasma concentrations of CBD in animals 41-50 following oral administration of 25 mg / kg of the composition disclosed in Table 5. [Figure 10] FIG. 10 is a plot of the mean plasma concentrations of CBD in animals 41-50 following oral administration of 25 mg / kg of a composition disclosed in Table 5. [Figure 11] FIG. 11 is a 24-hour plot of systolic blood pressure for subjects receiving a composition disclosed in Table 6 (●) versus placebo (◯). [Figure 12] FIG. 12 is a 24-hour plot of mean arterial pressure for subjects receiving a composition disclosed in Table 6 (●) versus placebo (◯). [Figure 13] FIG. 13 is a 24-hour plot of diastolic blood pressure for subjects receiving a composition disclosed in Table 6 (●) versus placebo (◯). DETAILED DESCRIPTION OF THE INVENTION

[0003] The materials, compounds, compositions, articles, and methods described herein may be more readily understood by reference to the following detailed description of specific embodiments of the disclosed subject matter and the examples included therein.

[0004] Also, various publications are referenced throughout this specification. The disclosures of these publications in their entireties are hereby incorporated by reference into this application in order to more fully describe the state of the art to which the disclosed subject matter pertains. The references disclosed are also individually and specifically incorporated by reference into this application for the material contained in them that is discussed in the sentence in which the reference is relied upon.

[0005] General definition In this specification and in the claims that follow, reference will be made to a number of terms, which shall be defined to have the following meanings.

[0006] All percentages, ratios, and proportions herein are by weight unless otherwise specified. All temperatures are in degrees Celsius (°C) unless otherwise specified.

[0007] Unless this disclosure expressly requires otherwise, the terms "a" and "an" are defined as one or more.

[0008] Ranges may be expressed herein as from "about" one particular value and / or to "about" another particular value. When such a range is expressed, another embodiment includes from the one particular value and / or to the other particular value. Similarly, when values ​​are expressed as approximations, by use of "about," the particular value will be understood to form another embodiment. Further, it will be understood that each endpoint of a range is significant both in relation to the other endpoint, and independently of the other endpoint.

[0009] The terms "comprise" (and any form of "comprise," e.g., "comprises" and "comprising"), "have" (and any form of "have," e.g., "has" and "having"), "include" (and any form of "include," e.g., "includes" and "including"), and "contain" (and any form of "contain," e.g., "contains" and "containing") are open linking verbs. Consequently, an apparatus that "comprises," "has," "includes," or "contains" one or more elements includes, but is not limited to, including only, those one or more elements. Similarly, a method that "comprises," "has," "includes," or "contains" one or more steps includes, but is not limited to, including only those one or more steps.

[0010] Any embodiment of any of the methods or compositions of the present disclosure may consist of or consist essentially of any of the recited steps, elements, and / or features. Thus, in any of the claims, the terms "consisting of" or "consisting essentially of" may be used in place of any of the open linking verbs set forth above to modify the scope of a given claim from what it would otherwise be with the open linking verb.

[0011] The term "composition" is defined herein as a composition that does not require approval by a regulatory agency and that may be offered for sale by any retailer, such as a pharmacy, grocery store, convenience store, department store, and the like.

[0012] Unless expressly prohibited by the nature of the disclosure or the embodiments, feature(s) of one embodiment may be applied to other embodiments without being described or illustrated.

[0013] Any embodiment of any of the compounds or methods of the present disclosure may consist of or consist essentially of any of the recited steps, elements, and / or features, rather than comprising / comprising / containing / having. Thus, in any of the claims, the terms "consisting of" or "consisting essentially of" may be used in place of any of the open linking verbs set forth above to modify the scope of a given claim from what it would otherwise be with the open linking verb.

[0014] composition In one embodiment, the disclosed composition comprises: A) a base composition; and B) one or more delivery agents.

[0015] Main composition According to the present disclosure, the base composition may include CBD oil. As used herein, the term "CBD oil" refers to a cannabidiol-containing extract from the cannabis plant Cannabis sativa. CBD oil useful for preparing the disclosed compositions may be a crude extract containing less than about 80% cannabidiol by weight. CBD oils used herein containing less than about 80% cannabidiol by weight are referred to as "crude CBD oils." When using lower percentage extracts, formulators will necessarily adjust the amount of CBD oil present in the disclosed compositions to ensure sufficient delivery of the desired amount of cannabidiol.

[0016] In one embodiment, the composition comprises a "cannabis distillate" containing about 80% to about 92% cannabidiol by weight. In yet a further embodiment, isolated pure cannabidiol may be used in the composition. When a cannabis distillate containing 80% to about 92% cannabidiol by weight is used, the term "CBD oil" applies. In some descriptions of "CBD oil," this component may be referred to as "CBD resin."

[0017] Another aspect of the present disclosure relates to a base composition comprising: a) about 0.5% to about 20% CBD oil by weight; b) from about 0.5% to about 60% by weight of one or more edible oils; and c) The remainder is the carrier.

[0018] In another embodiment of this aspect, the base composition comprises: a) about 0.5% to about 20% CBD oil by weight; b) from about 0.5% to about 60% by weight of one or more edible oils; and c) the balance being from about 20% to about 99% by weight of a carrier selected from gum arabic, inulin, microcrystalline cellulose, D-lactose monohydrate, quillaja, xanthan gum, pectin, guar, and psyllium.

[0019] In one embodiment of this aspect, the composition comprises: a) about 2% to about 5% CBD oil by weight; b) about 4% to about 15% by weight sunflower oil; and c) A carrier selected from gum arabic, inulin, microcrystalline cellulose, D-lactose monohydrate, quillaja, xanthan gum, pectin, guar, and psyllium.

[0020] In a non-limiting example of this iteration, the base composition includes: a) about 2% to about 5% CBD oil by weight; b) about 6% to about 15% sunflower oil by weight; c) about 5% to about 20% bile salts; and d) A carrier selected from gum arabic, inulin, microcrystalline cellulose, D-lactose monohydrate, and quillaja.

[0021] In a further example, the carrier is gum arabic. In another example, the carrier is inulin. In yet another example, the carrier is microcrystalline cellulose. In a still further example, the carrier is D-lactose monohydrate. In yet another example, the carrier is quillaja.

[0022] In a further embodiment of this aspect, the base composition comprises: a) about 0.5% to about 8% CBD oil by weight; b) about 0.5% to about 15% by weight of coconut oil; and c) A carrier selected from gum arabic, inulin, microcrystalline cellulose, D-lactose monohydrate, quillaja, xanthan gum, pectin, guar, and psyllium.

[0023] In a further iteration of this embodiment, the base composition includes: a) about 2% to about 5% CBD oil by weight; b) about 4% to about 15% by weight coconut oil; and c) A carrier selected from gum arabic, inulin, microcrystalline cellulose, D-lactose monohydrate, quillaja, xanthan gum, pectin, guar, and psyllium.

[0024] In a non-limiting example of this iteration, the base composition includes: a) about 2% to about 5% CBD oil by weight; b) about 0.5% to about 15% by weight coconut oil; c) about 5% to about 15% bile salts; and d) A carrier selected from gum arabic, inulin, microcrystalline cellulose, D-lactose monohydrate, and quillaja.

[0025] In one embodiment of this aspect, the base composition comprises: a) about 0.5% to about 8% CBD oil by weight; b) about 0.5% to about 15% by weight of coconut oil; and c) A carrier selected from gum arabic, inulin, microcrystalline cellulose, D-lactose monohydrate, quillaja, xanthan gum, pectin, guar, and psyllium.

[0026] In a further embodiment of this aspect, the base composition comprises: a) about 0.5% to about 8% CBD oil by weight; b) about 0.5% to about 15% by weight of coconut oil; and c) A carrier selected from gum arabic, inulin, microcrystalline cellulose, D-lactose monohydrate, quillaja, xanthan gum, pectin, guar, and psyllium.

[0027] In a further iteration of this embodiment, the base composition includes: a) about 2% to about 5% CBD oil by weight; b) about 4% to about 15% by weight coconut oil; and c) A carrier selected from gum arabic, inulin, microcrystalline cellulose, D-lactose monohydrate, quillaja, xanthan gum, pectin, guar, and psyllium.

[0028] In a non-limiting example of this iteration, the base composition includes: a) about 2% to about 5% CBD oil by weight; b) about 0.5% to about 15% by weight coconut oil; c) about 5% to about 15% bile salts; and d) A carrier selected from gum arabic, inulin, microcrystalline cellulose, D-lactose monohydrate, and quillaja.

[0029] The disclosed compositions comprise about 0.5% to about 20% CBD oil by weight. In one embodiment, the disclosed base composition may comprise about 0.5% to about 8% CBD oil by weight. In one embodiment, the base composition may comprise about 1% to about 5% CBD oil by weight. In another embodiment, the base composition may comprise about 2% to about 6% CBD oil by weight. In a further embodiment, the base composition may comprise about 2% to about 5% CBD oil by weight. In yet a further embodiment, the base composition may comprise about 3% to about 5% CBD oil by weight. For example, the amount of CBD oil can be 0.5%, 0.6%, 0.7%, 0.8%, 0.9%, 1%, 2%, 3%, 4%, 5%, 6%, 7%, or 8% by weight, or any fractional amount, such as 1.5%, 3.25%, and 5.75%.

[0030] The addition of a carboxylic acid, in some embodiments, aids in the formulation of a flowable powder for encapsulation or packaging as described below in this application, particularly when the carboxylic acid serves to form a salt with one or more of the carriers or delivery agents.

[0031] Disclosed antihypertensive compositions include: a) about 5 mg to about 15 mg by weight of CBD oil; and b) about 5 mg to about 45 mg by weight of one or more edible oils.

[0032] In one embodiment, the disclosed composition comprises: a) about 5 mg to about 15 mg of CBD oil by weight; b) about 5 mg to about 45 mg by weight of one or more edible oils; and c) The remainder is one or more carriers.

[0033] In one embodiment of this aspect, the disclosed composition comprises: a) about 5 mg to about 15 mg of CBD oil by weight; b) about 5 mg to about 45 mg by weight of one or more edible oils; and c) about 150 mg to about 500 mg by weight of one or more carriers.

[0034] In one iteration of this embodiment, the disclosed composition includes: a) about 5 mg to about 12 mg of CBD oil by weight; b) about 5 mg to about 30 mg by weight of one or more edible oils; and c) about 200 mg to about 350 mg by weight of one or more carriers.

[0035] In another iteration of this embodiment, the disclosed composition includes: a) about 7 mg to about 12 mg of CBD oil by weight; b) about 7 mg to about 24 mg by weight of one or more edible oils; and c) about 250 mg to about 350 mg by weight of one or more carriers.

[0036] In one non-limiting example, the disclosed compositions include: a) about 5 mg to about 15 mg of CBD oil by weight; b) about 5 mg to about 45 mg by weight of one or more edible oils; and c) about 200 mg to about 350 mg by weight of one or more carriers selected from gum arabic, inulin, or mixtures thereof.

[0037] In one non-limiting example, the disclosed compositions include: a) about 5 mg to about 15 mg of CBD oil by weight; b) about 5 mg to about 45 mg by weight of one or more edible oils; c) about 25 mg to about 45 mg by weight of one or more bile salts; and d) about 200 mg to about 350 mg by weight of one or more carriers selected from gum arabic, inulin, or mixtures thereof.

[0038] In a further non-limiting example, the disclosed compositions include: a) Approximately 10 mg of CBD oil by weight; b) approximately 20 mg of sunflower oil by weight; c) approximately 34 mg by weight of ox bile; and c) Approximately 278 mg of gum arabic by weight.

[0039] In a further non-limiting example, the disclosed compositions include: a) Approximately 10 mg of CBD oil by weight; b) about 20 mg by weight of coconut oil; and c) Approximately 240 mg of inulin by weight.

[0040] In further aspects of the disclosed antihypertensive compositions, the compositions contain about 5 mg to about 15 mg of CBD oil by weight. In one embodiment, the base composition may contain about 5 mg to about 12 mg of CBD oil by weight. In another embodiment, the base composition may contain about 7 mg to about 15 mg of CBD oil by weight. In a further embodiment, the base composition may contain about 7 mg to about 12 mg of CBD oil by weight. The base composition may contain 5 mg, 6 mg, 7 mg, 8 mg, 9 mg, 10 mg, 11 mg, 12 mg, 13 mg, 14 mg, or 15 mg of CBD oil by weight.

[0041] cooking oil The disclosed compositions include one or more edible oils, including oils that are primarily triglyceride-containing oils, including, but not limited to, sunflower oil, coconut oil, canola oil, palm oil, soybean oil, corn oil, safflower oil, and peanut oil.

[0042] In another non-limiting example, the edible oil is sunflower oil. In a further non-limiting example, the edible oil is coconut oil. In a still further non-limiting example, the edible oil is canola oil. In a still further non-limiting example, the edible oil is palm oil. In a still further non-limiting example, the edible oil is soybean oil. In another non-limiting example, the edible oil is corn oil. In a still further non-limiting example, the edible oil is safflower oil. In yet another non-limiting example, the edible oil is peanut oil.

[0043] The disclosed base composition may comprise from about 0.5% to about 60% edible oil by weight. In one embodiment, the base composition may comprise from about 3% to about 15% edible oil by weight. In another embodiment, the base composition may comprise from about 5% to about 17% edible oil by weight. In a further embodiment, the base composition may comprise from about 7.5% to about 15% edible oil by weight. In a still further embodiment, the base composition may comprise from about 5% to about 10% edible oil by weight. In a still further embodiment, the composition may comprise from about 20% to about 40% edible oil by weight. In a still yet further embodiment, the composition may comprise from about 15% to about 30% edible oil by weight.

[0044] The disclosed compositions can include from about 0.5% to about 60% by weight of one or more edible oils. For example, the amount of edible oil can be 0.5%, 0.6%, 0.7%, 0.8%, 0.9%, 1%, 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, 11%, 12%, 13%, 14%, 15%, 16%, 17%, 18%, 19%, 20%, 21%, 22%, 23%, 24%, 25%, 26%, 27%, 28%, 29%, 30%, 31%, 32%, 33%, 34%, 35%, 36%, 37%, 38%, 39%, 40%, 41%, 42%, 43%, 44%, 45%, 46%, 47%, 48%, 49%, 50%, 51%, 52%, 53%, 54%, 55%, 56%, 57%, 58%, 59%, 60%, 61%, 62%, 63%, 64%, 65%, 66%, 67%, 68%, 69%, 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, 100%, 101%, 102%, 103%, 104%, 105%, 106%, 107%, 108%, 109%, 110%, 1 The amount of one or more edible oils may be 31%, 32%, 33%, 34%, 35%, 36%, 37%, 38%, 39%, 40%, 41%, 42%, 43%, 44%, 45%, 46%, 47%, 48%, 49%, 50%, 51%, 52%, 53%, 54%, 55%, 56%, 57%, 58%, 59%, or 60%, or any fraction thereof.

[0045] In accordance with this embodiment, the ratio of CBD oil to edible oil is from about 1:1 to about 1:4. For example, the ratio of CBD oil to edible oil can be 1:1, 1:1.1, 1:1.2, 1:1.3, 1:1.4, 1:1.5, 1:1.6, 1:1.7, 1:1.8, 1:1.9, 1:2, 1:2.1, 1:2.2, 1:2.3, 1:2.4, 1:2.5, 1:2.6, 1:2.7, 1:2.8, 1:2.9, or 1:3.

[0046] The disclosed base composition of this aspect comprises about 5 mg to about 45 mg of edible oil by weight. In one embodiment, the base composition may comprise about 5 mg to about 30 mg of one or more edible oils by weight. In another embodiment, the base composition may comprise about 5 mg to about 20 mg of one or more edible oils by weight. In a further embodiment, the base composition may comprise about 5 mg to about 15 mg of one or more edible oils by weight. In a still further embodiment, the base composition may comprise about 5 mg to about 12 mg of one or more edible oils by weight. In a still further embodiment, the base composition may comprise about 10 mg to about 30 mg of one or more edible oils by weight. In yet another embodiment, the base composition may comprise about 15 mg to about 25 mg of one or more edible oils by weight. The composition may comprise 5 mg, 6 mg, 7 mg, 8 mg, 9 mg, 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, or 45 mg by weight of one or more edible oils.

[0047] The edible oils disclosed include oils that are primarily triglyceride-containing oils, non-limiting examples of which are selected from sunflower oil, coconut oil, canola oil, palm oil, soybean oil, corn oil, safflower oil, and peanut oil.

[0048] In another non-limiting example, the edible oil is sunflower oil. In a further non-limiting example, the edible oil is coconut oil. In a still further non-limiting example, the edible oil is canola oil. In a still further non-limiting example, the edible oil is palm oil. In a still further non-limiting example, the edible oil is soybean oil. In another non-limiting example, the edible oil is corn oil. In a still further non-limiting example, the edible oil is safflower oil. In yet another non-limiting example, the edible oil is peanut oil.

[0049] In another embodiment, highly unsaturated carboxylic acids derived from vegetable triglycerides can be mixed with one or more edible oils. In this embodiment, for example, a formulator with a base composition containing 10% by weight of edible oil can substitute 5% of the disclosed carboxylic acids for 5% of the edible oil.

[0050] Carrier In one embodiment, the disclosed carrier is a polysaccharide. Non-limiting examples of polysaccharide carriers include inulin, galactogen, cellulose, chitin, pectin, psyllium, guar, hemicellulose, potato starch, and partially hydrolyzed polysaccharides. In another embodiment, the carrier is a sugar alcohol, such as sorbitol, erythritol, xylitol, lactitol, maltitol, mannitol, hydrogenated starch hydrolysates, isomaltose, or any combination thereof. In further aspects, the carrier component is based on natural or modified agar, alginate, carrageenan gum, cellulose, chitosan, chitin, cyclodextrin, dextran, gellan gum, glycogen, glycosaminoglycans, karaya gum, inulin, pectin, polydextrose, xanthan gum, or any other starch, gum, or other polysaccharide, including functionalized derivatives, dextrinized, hydrolyzed, oxidized, alkylated, hydroxyalkylated, acetylated, classified, and physically modified starches, and mixtures thereof. In some embodiments, glycerin and / or propylene glycol may be added as a carrier.

[0051] In another embodiment, the carrier is selected from gum arabic, inulin, mannitol, silicon dioxide, colloidal silicon dioxide, microcrystalline cellulose, D-lactose monohydrate, tapioca starch, tapioca flour, quillaja, or a mixture thereof. In a further example, the carrier is gum arabic. In another example, the carrier is inulin. In yet another example, the carrier is microcrystalline cellulose. In a still further example, the carrier is D-lactose monohydrate. In yet another example, the carrier is quillaja. The carrier can be a combination of gum arabic, inulin, microcrystalline cellulose, D-lactose monohydrate, or quillaja.

[0052] In one non-limiting example, the carrier is mannitol. A non-limiting example is Partek™ Mannitol available from Partek. In a further non-limiting example, the carrier is microcrystalline cellulose. In a still further example, the carrier is colloidal silicon dioxide.

[0053] The disclosed base compositions may comprise from about 50% to about 99% by weight of one or more carriers. In one embodiment, the disclosed compositions may comprise from about 60% to about 95% by weight of one or more carriers. In another embodiment, the disclosed compositions may comprise from about 60% to about 80% by weight of one or more carriers. In yet another embodiment, the disclosed compositions may comprise from about 75% to about 95% by weight of one or more carriers. In a further embodiment, the disclosed compositions may comprise from about 65% to about 90% by weight of one or more carriers. As such, the disclosed base compositions can comprise 50%, 51%, 52%, 53%, 54%, 55%, 56%, 57%, 58%, 59%, 60%, 61%, 62%, 63%, 64%, 65%, 66%, 67%, 68%, 69%, 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% of one or more carriers.

[0054] The disclosed base composition may contain from about 100 mg to about 500 mg by weight of one or more carriers. In one embodiment, the base composition contains from about 250 mg to about 350 mg by weight of one or more carriers. In another embodiment, the base composition contains from about 150 mg to about 300 mg by weight of one or more carriers. In a further embodiment, the base composition contains from about 200 mg to about 300 mg by weight of one or more carriers. In yet a further embodiment, the base composition contains from about 300 mg to about 400 mg by weight of one or more carriers. In one embodiment, the base composition contains from about 200 mg to about 450 mg by weight of one or more carriers. The disclosed base compositions may have a weight percentage of 100 mg, 101 mg, 102 mg, 103 mg, 104 mg, 105 mg, 106 mg, 107 mg, 108 mg, 109 mg, 110 mg, 111 mg, 112 mg, 113 mg, 114 mg, 115 mg, 116 mg, 117 mg, 118 mg, 119 mg, 120 mg, 121 mg, 122 mg, 123 mg, 124 mg, 125 mg, 126 mg, 127 mg, 128 mg, 129 mg, 130 mg 31mg, 132mg, 133mg, 134mg, 135mg, 136mg, 137mg, 138mg, 139mg, 140mg, 141mg, 142mg, 143mg, 144mg, 145mg, 146mg, 147mg, 148mg, 149mg, 150mg, 151mg, 152mg , 153mg, 154mg, 155mg, 156mg, 157mg, 158mg, 159mg, 160mg, 161mg, 162mg, 163mg, 164mg, 165mg, 166mg, 167mg, 168mg, 169mg, 170mg, 171mg, 172mg, 173mg, 174 mg, 175mg, 167mg, 177mg, 178mg, 179mg, 180mg, 181mg, 182mg, 183mg, 184mg, 185mg, 186mg, 187mg, 188mg, 189mg, 190mg, 191mg, 192mg, 193mg, 194mg, 195mg, 1 96mg, 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 g、239mg、240mg、241mg、242mg、243mg、244mg、245mg、246mg、247mg、248mg、 249mg、250mg、251mg、252mg、253mg、254mg、255mg、256mg、257mg、258mg、259 mg、260mg、261mg、262mg、263mg、264mg、265mg、266mg、267mg、268mg、269mg 、270mg、271mg、272mg、273mg、274mg、275mg、276mg、277mg、278mg、279mg、2 80mg、281mg、282mg、283mg、284mg、285mg、286mg、287mg、288mg、289mg、290 mg、290mg、291mg、292mg、293mg、294mg、295mg、296mg、297mg、298mg、299mg、 300mg、301mg、302mg、303mg、304mg、305mg、306mg、307mg、308mg、309mg、31 0mg、311mg、312mg、313mg、314mg、315mg、316mg、317mg、318mg、319mg、320m g, 321mg, 322mg, 323mg, 324mg, 325mg, 326mg, 327mg, 328mg, 329mg, 330mg, 331mg, 332mg, 333mg, 334mg, 335mg, 336mg, 337mg, 338mg, 339mg, 340mg, 341mg mg、342mg、343mg、344mg、345mg、346mg、347mg、348mg、349mg、350mg、351mg 、352mg、353mg、354mg、355mg、356mg、357mg、358mg、359mg、360mg、361mg、3 62mg, 363mg, 364mg, 365mg, 366mg, 367mg, 368mg, 369mg, 370mg, 371mg, 372mg, 373mg, 374mg, 375mg, 376mg, 377mg, 378mg, 379mg, 380mg, 381mg, 382mg383mg, 384mg, 385mg, 386mg, 387mg, 388mg, 389mg, 390mg, 390mg, 391mg, 392mg, 393mg, 394mg, 395mg, 396mg, 3 97mg, 398mg, 399mg, 400mg, 401mg, 402mg, 403mg, 404mg, 405mg, 406mg, 407mg, 408mg, 409mg, 410mg, 411mg, 412 mg, 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, 4 43mg, 444mg, 445mg, 446mg, 447mg, 448mg, 449mg, 450mg, 451mg, 452mg, 453mg, 454mg, 455mg, 456mg, 457mg, 458 mg, 459mg, 460mg, 461mg, 462mg, 463mg, 464mg, 465mg, 466mg, 467mg, 468mg, 469mg, 470mg, 471mg, 472mg, 473mg , 474 mg, 475 mg, 476 mg, 477 mg, 478 mg, 479 mg, 480 mg, 481 mg, 482 mg, 483 mg, 484 mg, 485 mg, 486 mg, 487 mg, 488 mg, 489 mg, 490 mg, 490 mg, 491 mg, 492 mg, 493 mg, 494 mg, 495 mg, 496 mg, 497 mg, 498 mg, 499 mg, or 500 mg of one or more carriers.

[0055] Bile salts The disclosed base compositions may further comprise 5% to about 20% by weight of bile salts. Bile salts enhance the ability of the disclosed compositions to target the duodenum. Non-limiting examples of bile salts and / or bile acids include steroid acids (and / or their carboxylate anions) and salts thereof found in animal (e.g., human) bile, including cholic acid, cholate, deoxycholic acid, deoxycholate, hyodeoxycholic acid, hyodeoxycholate, glycocholic acid, glycocholate, taurocholic acid, taurocholate, chenodeoxycholic acid, chenodeoxycholate, lithocholic acid, lithocholate, and the like. Taurocholic acid and / or taurocholate are referred to herein as TCAs.

[0056] Bile salts are typically conjugated with glycine or taurine. For example, the term "bile acid" as used herein includes cholic acid conjugated with either glycine or taurine: glycocholic acid and taurocholic acid (and salts thereof), respectively. Reference to either bile salts or bile acids as used herein includes reference to the same compounds, whether naturally or synthetically prepared. In one non-limiting example, the bile salt is ox bile.

[0057] The disclosed compositions may contain about 5% to about 20% by weight of one or more bile salts. In one embodiment, the composition contains about 7.5% to about 20% by weight of one or more bile salts. In one embodiment, the composition contains about 7.5% to about 12.5% ​​by weight of one or more bile salts. In one embodiment, the composition contains about 15% to about 20% by weight of one or more bile salts. In one embodiment, the composition contains about 5% to about 15% by weight of one or more bile salts. In one embodiment, the composition contains about 12% to about 15% by weight of one or more bile salts. The composition may contain, for example, 5%, 6%, 7%, 8%, 9%, 10%, 11%, 12%, 13%, 14%, 15%, 16%, 17%, 18%, 19%, or 20% by weight of one or more bile salts.

[0058] The disclosed compositions comprise from about 25 mg to about 50 mg by weight of one or more bile salts. In one embodiment, the composition comprises from about 30 mg to about 50 mg by weight of one or more bile salts. In another embodiment, the composition comprises from about 30 mg to about 40 mg by weight of one or more bile salts. In a further embodiment, the composition comprises from about 25 mg to about 40 mg by weight of one or more bile salts. In yet another embodiment, the composition comprises from about 25 mg to about 35 mg by weight of one or more bile salts. The disclosed base compositions can contain, for example, 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, or 50 mg by weight of one or more bile salts.

[0059] In further embodiments of the disclosed antihypertensive compositions, the compositions include: a) about 10 mg to about 100 mg of CBD oil by weight; b) about 10 mg to about 300 mg by weight of sunflower oil; and c) The remainder is one or more carriers.

[0060] In one embodiment of this aspect, the base composition comprises: a) about 10 mg to about 100 mg of CBD oil by weight; b) about 10 mg to about 300 mg by weight of sunflower oil; and c) about 200 mg to about 800 mg by weight of one or more carriers.

[0061] In one non-limiting example of this embodiment, the base composition comprises: a) about 10 mg to about 100 mg of CBD oil by weight; b) about 10 mg to about 300 mg by weight of sunflower oil; c) about 50 mg to about 8 mg by weight of one or more bile salts; and d) about 200 mg to about 800 mg by weight of one or more carriers.

[0062] In another non-limiting example of this embodiment, the base composition comprises: a) about 10 mg to about 100 mg of CBD oil by weight; b) about 10 mg to about 300 mg by weight of sunflower oil; c) about 50 mg to about 80 mg by weight of one or more bile salts; and d) about 200 mg to about 800 mg by weight of one or more carriers, the carriers being selected from tapioca starch, tapioca flour, silicon dioxide, and mixtures thereof.

[0063] In another non-limiting example of this embodiment, the base composition comprises: a) about 25 mg to about 40 mg of CBD oil by weight; b) about 50 mg to about 80 mg by weight of sunflower oil; c) about 60 mg to about 70 mg by weight of one or more bile salts; and d) about 500 mg to about 600 mg by weight of one or more carriers, the carriers being selected from tapioca starch, tapioca flour, silicon dioxide, and mixtures thereof.

[0064] In a further non-limiting example of this embodiment, the base composition comprises: a) about 75 mg to about 90 mg of CBD oil by weight; b) about 55 mg to about 70 mg by weight of sunflower oil; c) about 60 mg to about 70 mg by weight of one or more bile salts; and d) about 500 mg to about 600 mg by weight of one or more carriers, the carriers being selected from tapioca starch, tapioca flour, silicon dioxide, and mixtures thereof.

[0065] In a still further non-limiting example of this embodiment, the base composition comprises: a) Approximately 81 mg of CBD oil by weight; b) approximately 62 mg of sunflower oil by weight; c) about 65 mg by weight of one or more bile salts; and d) about 575 mg by weight of one or more carriers, the carrier being selected from tapioca starch, tapioca flour, silicon dioxide, and mixtures thereof.

[0066] In another embodiment of this aspect, the base composition comprises: a) about 20 mg to about 40 mg of CBD oil by weight; b) about 40 mg to about 80 mg by weight of sunflower oil; and c) about 500 mg to about 600 mg by weight of one or more carriers.

[0067] In one iteration of this embodiment, the base composition includes: a) about 70 mg to about 100 mg of CBD oil by weight; b) about 70 mg to about 200 mg by weight of sunflower oil; and c) about 300 mg to about 450 mg by weight of one or more carriers.

[0068] In one non-limiting example of this iteration, the base composition includes: a) about 70 mg to about 100 mg of CBD oil by weight; b) about 70 mg to about 200 mg by weight of sunflower oil; and c) about 300 mg to about 450 mg by weight of one or more carriers, the carriers being selected from mannitol, silicon dioxide, colloidal silicon dioxide, microcrystalline cellulose, and mixtures thereof.

[0069] In another non-limiting example of this iteration, the base composition includes: a) about 80 mg to about 95 mg of CBD oil by weight; b) about 160 mg to about 190 mg by weight of sunflower oil; and c) about 300 mg to about 400 mg by weight of one or more carriers, the carriers being selected from mannitol, silicon dioxide, colloidal silicon dioxide, microcrystalline cellulose, and mixtures thereof.

[0070] In a further iteration, the base composition includes: a) about 80 mg to about 95 mg of CBD oil by weight; b) about 160 mg to about 190 mg of sunflower oil by weight; c) about 60 mg to about 70 mg by weight of one or more bile salts, and d) about 300 mg to about 400 mg by weight of one or more carriers, the carriers being selected from mannitol, silicon dioxide, colloidal silicon dioxide, microcrystalline cellulose, and mixtures thereof.

[0071] In a still further non-limiting example of this iteration, the base composition includes: a) Approximately 87mg of CBD oil by weight; b) approximately 174 mg of sunflower oil by weight; c) about 65 mg by weight of one or more bile salts; and d) about 375 mg by weight of one or more carriers, the carrier being selected from mannitol, silicon dioxide, colloidal silicon dioxide, and microcrystalline cellulose.

[0072] In a still further embodiment of this aspect, the base composition comprises: a) about 65 mg to about 85 mg of CBD oil by weight; b) about 135 mg to about 170 mg by weight of sunflower oil; and c) about 300 mg to about 400 mg by weight of one or more carriers.

[0073] In one iteration of this embodiment, the base composition includes: a) about 65 mg to about 85 mg of CBD oil by weight; b) about 135 mg to about 170 mg by weight of sunflower oil; and c) about 300 mg to about 400 mg by weight of one or more carriers, the carriers being selected from mannitol, silicon dioxide, colloidal silicon dioxide, microcrystalline cellulose, and mixtures thereof.

[0074] In one non-limiting example of this iteration, the base composition includes: a) approximately 70 mg to approximately 80 mg of CBD oil by weight; b) about 145 mg to about 160 mg by weight of sunflower oil; and c) about 300 mg to about 350 mg by weight of one or more carriers, the carriers being selected from mannitol, silicon dioxide, colloidal silicon dioxide, microcrystalline cellulose, and mixtures thereof.

[0075] In another non-limiting example of this iteration, the base composition includes: a) approximately 70 mg to approximately 80 mg of CBD oil by weight; b) about 145 mg to about 160 mg of sunflower oil by weight; c) about 5 mg to about 8 mg by weight of one or more bile salts; and d) about 300 mg to about 350 mg by weight of one or more carriers, the carriers being selected from mannitol, silicon dioxide, colloidal silicon dioxide, microcrystalline cellulose, and mixtures thereof.

[0076] In a further non-limiting example of this iteration, the base composition includes: a) Approximately 76 mg of CBD oil by weight; b) approximately 152 mg of sunflower oil by weight; c) about 7 mg by weight of one or more bile salts; and d) about 335 mg by weight of one or more carriers, the carrier being selected from mannitol, silicon dioxide, colloidal silicon dioxide, microcrystalline cellulose, and mixtures thereof.

[0077] In another example, the base composition includes: a) about 5 mg to about 15 mg of CBD oil by weight; b) about 5 mg to about 60 mg by weight of an admixture of carboxylic acids derived from plant-based triglycerides and one or more edible oils, wherein the ratio of carboxylic acids to edible oils is about 1:9 to about 9:1; and c) about 100 mg to about 300 mg by weight of one or more carriers.

[0078] The disclosed compositions are free-flowing solids. The disclosed compositions have less than about 0.01% moisture by weight. Any residual moisture can be removed by standard dehydration processes. As free-flowing solids, the compositions can be easily encapsulated and made into tablets or pellets. If the formulator desires to form a liquid composition, the compositions can be dissolved or suspended in a carrier.

[0079] The following are suitable forms for delivery of the disclosed compositions: sublingual tablets, buccal tablets, orally disintegrating tablets, chewable tablets, troches, oral powders, oral granules, oral pellets, chewable gels, granules of pellets intended for reconstitution with a liquid medium for immediate administration, hard candy, gelatin-based chewy candy, gummy candy, jelly candy, sprinkle formulations, swallowable immediate-release capsules, pills, or tablets, sustained-release capsules, pills, or tablets, or delayed-release capsules, pills, or tablets.

[0080] method Disclosed herein is a method for treating hypertension in a subject in need thereof, comprising administering to the subject in need thereof an effective amount of a composition as defined herein above.

[0081] In one embodiment of the disclosed method, the total dose of the disclosed composition is from about 90 mg to about 450 mg over the course of a 24 hour period, depending on the severity of the hypertension. For an average hum weighing 60 kg, this equates to about 1.5 mg / kg to about 75 mg / kg per 24 hour period.

[0082] In one embodiment, the daily dose is from about 90 mg to about 150 mg. In a further embodiment, the daily dose is from about 140 mg to about 250 mg. In another embodiment, the daily dose is from about 200 mg to about 400 mg. In a still further embodiment, the daily dose is from about 300 mg to about 450 mg. In a still further embodiment, the daily dose is from about 250 mg to about 350 mg.

[0083] Dosages of one or more of the disclosed compositions may range from about 90 mg to about 450 mg per 24 hours, e.g., 90 mg, 91 mg, 92 mg, 93 mg, 94 mg, 95 mg, 96 mg, 97 mg, 98 mg, 99 mg, 100 mg, 101 mg, 102 mg, 103 mg, 104 mg, 105 mg, 106 mg, 107 mg, 108 mg, 109 mg, 110 mg, 111 mg, 112 mg, 113 mg, 114 mg, 115 mg, 116 mg, 117 mg, 118 mg, 119 mg, 120 mg, 121 mg, 122 mg, 123 mg, 124 mg, 125 mg, 126 mg, 127 mg, 128 mg, 129 mg, 130 mg, 131 mg, 132 mg, 133 mg, 134 mg, 135 mg, 136 mg, 137 mg, 138 mg, 139 mg, 140 mg, 141 mg, 142 mg, 143 mg, 144 mg, 145 mg, 146 mg, 147 mg, 148 mg, 149 mg, 150 mg, 151 mg, 152 mg, 153 mg, 154 mg, 155 mg, 156 mg, 157 mg, 158 mg, 159 mg, 160 mg, 161 mg, 162 mg, 163 mg, 164 mg, 165 mg, 166 mg, 167 mg, 168 mg, 169 mg, 17 4mg, 125mg, 126mg, 127mg, 128mg, 129mg, 130mg, 31mg, 132mg, 133mg, 134mg, 135mg, 136mg, 137mg, 138mg, 139mg, 140mg, 141mg, 142mg, 143mg, 144mg, 1 45mg, 146mg, 147mg, 148mg, 149mg, 150mg, 151mg, 152mg, 153mg, 154mg, 155mg, 156mg, 157mg, 158mg, 159mg, 160mg, 161mg, 162mg, 163mg, 164mg, 165mg, 166mg, 167mg, 168mg, 169mg, 170mg, 171mg, 172mg, 173mg, 174mg, 175mg, 167mg, 177mg, 178mg, 179mg, 180mg, 181mg, 182mg, 183mg, 184mg, 185mg, 186m g, 187mg, 188mg, 189mg, 190mg, 191mg, 192mg, 193mg, 194mg, 195mg, 196mg, 197mg, 198mg, 199mg, 200mg, 201mg, 202mg, 203mg, 204mg, 205mg, 206mg, 207 mg, 208mg, 209mg, 210mg, 211mg, 212mg, 213mg, 214mg, 215mg, 216mg, 217mg, 218mg, 219mg, 220mg, 221mg, 222mg, 223mg, 224mg, 225mg, 226mg, 227mg, 2 28mg, 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、25 9mg、260mg、261mg、262mg、263mg、264mg、265mg、266mg、267mg、268mg、269m g、270mg、271mg、272mg、273mg、274mg、275mg、276mg、277mg、278mg、279mg、 280mg、281mg、282mg、283mg、284mg、285mg、286mg、287mg、288mg、289mg、290 mg、290mg、291mg、292mg、293mg、294mg、295mg、296mg、297mg、298mg、299mg 、300mg、301mg、302mg、303mg、304mg、305mg、306mg、307mg、308mg、309mg、3 10mg、311mg、312mg、313mg、314mg、315mg、316mg、317mg、318mg、319mg、320 mg、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 g, 352mg, 353mg, 354mg, 355mg, 356mg, 357mg, 358mg, 359mg, 360mg, 361mg, 362mg, 363mg, 364mg, 365mg, 366mg, 367mg, 368mg, 369mg, 370mg, 371mg, 372 mg、373mg、374mg、375mg、376mg、377mg、378mg、379mg、380mg、381mg、382mg 、383mg、384mg、385mg、386mg、387mg、388mg、389mg、390mg、390mg、391mg、3 92mg、393mg、394mg、395mg、396mg、397mg、398mg、399mg、400mg、401mg、402 mg、403mg、404mg、405mg、406mg、407mg、408mg、409mg、410mg、411mg、412mg、It can be 413 mg, 414 mg, 415 mg, 416 mg, 417 mg, 418 mg, 419 mg, 420 mg, 421 mg, 422 mg, 423 mg, 424 mg, 425 mg, 426 mg, 427 mg, 428 mg, 429 mg, 430 mg, 431 mg, 432 mg, 433 mg, 434 mg, 435 mg, 436 mg, 437 mg, 438 mg, 439 mg, 440 mg, 441 mg, 442 mg, 443 mg, 444 mg, 445 mg, 446 mg, 447 mg, 448 mg, 449 mg, or 450 mg. [Example]

[0084] Preparation Example 1 The following additions were made using a stainless steel reaction vessel, paddles, and scraper to aid in the formation of the blend: High oleic olive oil (90 g) was charged to the reaction vessel and stirred while heated to approximately 75°C. Cannabidiol (44.97 g of a 99.378% sample) was combined with the high oleic olive oil, and the blend was stirred uniformly at approximately 75°C. The cannabidiol / high oleic olive oil blend was added slowly to the reaction vessel containing Aeroperl® 300 (80.62 g) with uniform, continuous, and efficient stirring. Parteck-M® 100 mannitol (80.62 g) was added to the reaction mixture with continuous stirring at 75°C. The contents of the vessel were spread evenly onto a dehydrator tray, and the tray was then placed in a convection air dehydrator at approximately 65°C for 90 minutes. The tray was then allowed to cool to room temperature. The dehydrated blend was transferred to a stainless steel vessel, and deoxycholic acid (3.86 g) was added with continuous stirring until the blend was uniform. The yield was approximately 309 g of total product. The compositions for testing were formed into capsules having the quantities disclosed in Table 1.

[0085] The next addition was made using a stainless steel reaction vessel, paddle, and scraper to aid in the formation of a blend. Sunflower oil (25.52 g) was charged to the reaction vessel and heated to approximately 75°C while stirring. CBD oil (12.76 g of a 78.33% sample) was melted at approximately 75°C, then combined with the sunflower oil and stirred for 2 hours, then stirred at 80°C for 30 minutes with efficient stirring to form a uniform blend. Gum arabic (231.73 g) was charged to a second stainless steel vessel. The CBD oil / sunflower oil blend was added to the gum arabic with efficient mixing (note that the resulting blend will be clumped and must be processed to a uniform state). The contents of the vessel were spread evenly onto a dehydrator tray, and the tray was then placed in a convection air dehydrator at approximately 65°C for 90 minutes. After cooling, the blend was sifted to break up any clumps. A clean stainless steel vessel was charged with bovine bile salts (30g). The sifted blend was added to the bovine bile salts and the blend was efficiently mixed for 20 minutes. The final blend weighed 284g. The test compositions were formed into capsules having the quantities disclosed in Table 5.

[0086] animal research

[0087] [Table 1]

[0088] [Table 2]

[0089] [Table 3]

[0090] Nanoemulsion CBD oil (10g) and sunflower oil (10g) were combined with 100g of D-lactose monohydrate to form a uniform blend. The blend was then weighed into 212.5g of Quillaja in 467.5mL of water to form a pre-emulsion. The pre-emulsion was then passed through a high-pressure microfluidizer homogenizer to obtain a liquid nanoemulsion.

[0091] [Table 4]

[0092] [Table 5]

[0093] Individual and mean plasma concentrations (ng / mL) and pharmacokinetic parameters of CBD following oral administration of the compositions in Table 1 at 25 mg / kg CBD in male Sprague-Dawley rats (Group 1)

[0094] [Table 6]

[0095] [Table 7]

[0096] Table III provides the means and standard deviations of the results for animals 1-10.

[0097] [Table 8]

[0098] Individual and mean plasma concentrations (ng / mL) and pharmacokinetic parameters of CBD after oral administration of the compositions in Table 2 at 25 mg / kg CBD in male Sprague-Dawley rats (Group 2)

[0099] [Table 9]

[0100] [Table 10]

[0101] Table VI provides the means and standard deviations of the results for animals 11-20.

[0102] [Table 11]

[0103] Individual and mean plasma concentrations (ng / mL) and pharmacokinetic parameters of CBD following oral administration of the compositions in Table 3 at 25 mg / kg CBD in male Sprague-Dawley rats (Group 3)

[0104] [Table 12]

[0105] [Table 13]

[0106] Table XIX provides the means and standard deviations of the results for animals 21-30.

[0107] [Table 14]

[0108] Individual and mean plasma concentrations (ng / mL) and pharmacokinetic parameters of CBD following oral administration of the compositions in Table 4 at 25 mg / kg CBD in male Sprague-Dawley rats (Group 4)

[0109] [Table 15]

[0110] [Table 16]

[0111] Table XII provides the means and standard deviations of the results for animals 31-40.

[0112] [Table 17]

[0113] Individual and mean plasma concentrations (ng / mL) and pharmacokinetic parameters of CBD following oral administration of the compositions in Table 5 at 25 mg / kg CBD in male Sprague-Dawley rats (Group 5)

[0114] [Table 18]

[0115] [Table 19]

[0116] Table XV provides the means and standard deviations of the results for animals 41-50.

[0117] [Table 20]

[0118] Summary of mean plasma exposure to CBD following oral administration of the compositions disclosed in Tables 1 through 8 at 25 mg / kg CBD in male Sprague-Dawley rats

[0119] [Table 21]

[0120] Summary of mean plasma exposure to CBD following oral administration of the compositions disclosed in Tables 1 through 5 at 25 mg / kg CBD in male Sprague-Dawley rats

[0121] [Table 22]

[0122] CBD concentrations in brain tissue after oral administration of the compositions in Table 1 at 25 mg / kg CBD in male Sprague-Dawley rats (Group 1)

[0123] [Table 23]

[0124] CBD concentrations in brain tissue after oral administration of the compositions in Table 2 at 25 mg / kg CBD in male Sprague-Dawley rats (Group 2)

[0125] [Table 24]

[0126] CBD concentrations in brain tissue after oral administration of the compositions in Table 3 at 25 mg / kg CBD in male Sprague-Dawley rats (Group 3)

[0127] [Table 25]

[0128] CBD concentrations in brain tissue after oral administration of the compositions in Table 4 at 25 mg / kg CBD in male Sprague-Dawley rats (Group 5)

[0129] [Table 26]

[0130] CBD concentrations in brain tissue after oral administration of the compositions in Table 5 at 25 mg / kg CBD in male Sprague-Dawley rats (Group 5)

[0131] [Table 27]

[0132] Human studies The following compositions were used in human controlled trials to measure differences in systolic blood pressure (SBP), mean arterial pressure (MSP), and diastolic blood pressure (DBP) between volunteers taking a composition disclosed in Table 6 or Table 7 versus a placebo over a 24-hour period.

[0133] [Table 28]

[0134] [Table 29]

[0135] The compositions disclosed in Table 8 are used in human clinical trials.

[0136] [Table 30]

[0137] The compositions disclosed in Table 6 were administered to human volunteers with mild to moderate hypertension according to the following protocol: During the 24-hour study, 16 volunteers in each group were administered a composition from Table 6 or a placebo at selected times: t=0, t=13 hours, and t=22 hours. The results are illustrated in FIG. 11. Results for subjects receiving a composition containing a composition from Table 6 are represented by a dotted line with filled circles (●), while results for subjects receiving placebo are represented by a solid line and open circles (○). As illustrated in FIG. 11, the approximately 7% difference in systolic blood pressure (SBP) persisted after the ambulatory period, i.e., during the sleep period.

[0138] Figure 12 shows the mean arterial pressure (MAP) of the two groups. During the ambulatory period, volunteers had a significant 5.3% reduction in MAP compared to the placebo group. Figure 13 shows a 3.5% reduction in diastolic pressure compared to the placebo group.

[0139] Analysis of physical activity levels in volunteers with mild to moderate hypertension showed no significant differences in activity between volunteers treated with placebo and the compositions from Table 6 during the 24-hour monitoring period, indicating that the observed differences in BP were not due to different physical exertion or demands.

[0140] Arterial stiffness is a strong predictor of human disease. The impact of increased arterial stiffness is not limited to coronary heart disease, e.g., hypertension, but also includes other disease states, e.g., diabetes, kidney disease, etc. It may also be a prognostic marker for cardiovascular events and total mortality, even in asymptomatic individuals without overt cardiovascular disease.

[0141] The effectiveness of blood pressure treatment and differences in effectiveness between different types of antihypertensive agents are strongly correlated with arterial stiffness measurements. Thus, the significant blood pressure lowering effects illustrated in Figures 11 through 13 appear to be due, at least in part, to these improvements in arterial stiffness. The arterial stiffness results from this study are summarized in Table XXIII below. All comparisons between subjects receiving the composition and placebo were statistically significant (p<0.01).

[0142] [Table 31]

[0143] In this study, 60 volunteers between the ages of 45 and 70 will receive 150 mg of the composition disclosed in Table 7 three times daily for six weeks. The study is a double-blind, randomized, crossover design and utilizes a placebo control. Some volunteers are already taking major standard-of-care hypertension medications, such as ACE inhibitors, with or without diuretics to aid in the evaluation of the composition disclosed in Table 7 to determine the effectiveness of this composition with or without other hypertension treatments. The purpose of this study is to evaluate potential longer-term health benefits.

[0144] This study is more comprehensive than the studies conducted above and will include many types of analyses, including 24-hour ambulatory blood pressure (which is the primary outcome); arterial stiffness and autonomic balance; brain structure and function by brain magnetic resonance imaging ("MRI"); blood biomarkers (including lipids, e.g., cholesterol); kidney, liver, sleep quality / daytime sleepiness / sleep disturbances; actigraphy, Geriatric Depression Scale, perceived stress, and the Beck Anxiety Questionnaire.

[0145] Other advantages, both obvious and inherent in the present disclosure, will be apparent to those skilled in the art. It will be understood that certain features and subcombinations are advantageous and may be employed without regard to other features and subcombinations. This is contemplated by and within the scope of the claims. Because many possible embodiments may be made with respect to this disclosure without departing from its scope, it should be understood that all matters presented in this application or shown in the accompanying drawings are to be interpreted as illustrative and not in a limiting sense.

Claims

1. 1. A composition for treating hypertension, comprising: a) 5 mg to 15 mg of CBD oil containing 80% to 92% cannabidiol by weight; b) 5 mg to 45 mg sunflower oil; c) 200 mg to 350 mg of inulin; and d) 25 mg to 45 mg of one or more bile salts; The ratio of CBD oil to sunflower oil is 1:1 to 1:

4. composition.

2. 10. The composition of claim 1, comprising 5 mg to 12 mg of CBD oil by weight.

3. 10. The composition of claim 1, comprising between 7 mg and 12 mg of CBD oil by weight.

4. A composition for treating hypertension, comprising: a) 10 mg to 100 mg of CBD oil containing 80% to 92% cannabidiol by weight; b) 10 mg to 300 mg by weight of sunflower oil; c) 60 to 70 mg by weight of one or more bile salts; and d) 200 mg to 800 mg by weight of one or more carriers.

5. 5. The composition of claim 4, comprising: a) 25 mg to 40 mg of CBD oil containing 80% to 92% cannabidiol by weight; b) 50 mg to 80 mg by weight of sunflower oil; c) 60 mg to 70 mg by weight of one or more bile salts; and d) 500 mg to 600 mg by weight of one or more carriers, said carriers being selected from tapioca starch, tapioca flour, silicon dioxide, and mixtures thereof.

6. 5. The composition of claim 4, comprising: a) 75 mg to 90 mg of CBD oil containing 80% to 92% cannabidiol by weight; b) 55 mg to 70 mg by weight of sunflower oil; c) 60 mg to 70 mg by weight of one or more bile salts; and d) 500 mg to 600 mg by weight of one or more carriers, said carriers being selected from tapioca starch, tapioca flour, silicon dioxide, and mixtures thereof.

7. 5. The composition of claim 4, comprising: a) 80 mg to 95 mg of CBD oil containing 80% to 92% cannabidiol by weight; b) 160 mg to 190 mg by weight of sunflower oil; c) 60 mg to 70 mg by weight of one or more bile salts, and d) 300 mg to 400 mg by weight of one or more carriers, said carriers being selected from mannitol, silicon dioxide, colloidal silicon dioxide, microcrystalline cellulose, and mixtures thereof.

8. 5. The composition of claim 4, comprising: a) 81 mg of CBD oil, the CBD oil containing 80% to 92% cannabidiol by weight; b) 62 mg sunflower oil by weight; c) 65 mg by weight of one or more bile salts; and d) 575 mg by weight of one or more carriers, said carriers being selected from tapioca starch, tapioca flour, silicon dioxide, and mixtures thereof.

9. 5. The composition of claim 4, comprising: a) 80 mg to 95 mg of CBD oil containing 80% to 92% cannabidiol by weight; b) 160 mg to 190 mg by weight of sunflower oil; c) 60 to 70 mg by weight of one or more bile salts; and d) 300 mg to 400 mg by weight of one or more carriers, said carriers being selected from mannitol, silicon dioxide, colloidal silicon dioxide, microcrystalline cellulose, and mixtures thereof.

10. 5. The composition of claim 4, comprising: a) 87 mg of CBD oil, the CBD oil containing 80% to 92% cannabidiol by weight; b) 174 mg sunflower oil by weight; c) 65 mg by weight of one or more bile salts; and d) 375 mg by weight of one or more carriers, said carriers being selected from mannitol, silicon dioxide, colloidal silicon dioxide, microcrystalline cellulose.

11. 5. The composition of claim 4, comprising: a) 70 mg to 80 mg of CBD oil containing 80% to 92% cannabidiol by weight; b) 145 mg to 160 mg by weight of sunflower oil; c) 60 to 70 mg by weight of one or more bile salts; and d) 300 mg to 350 mg by weight of one or more carriers, said carriers being selected from mannitol, silicon dioxide, colloidal silicon dioxide, microcrystalline cellulose, and mixtures thereof.

12. 5. The composition of claim 4, comprising: a) 76 mg of CBD oil, the CBD oil containing 80% to 92% cannabidiol by weight; b) 152 mg sunflower oil by weight; c) 60 to 70 mg by weight of one or more bile salts; and d) 335 mg by weight of one or more carriers, said carriers being selected from mannitol, silicon dioxide, colloidal silicon dioxide, microcrystalline cellulose, and mixtures thereof.

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