PHARMACEUTICAL COMPOSITIONS AND METHODS FOR TREATING HYPERTENSION

FIELD

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

BRIEF DESCRIPTION OF THE FIGURES

FIG. 1 is a plot of the individual plasma concentration of CBD in Animals 1-10 after oral administration of 25 mg/kg of the composition disclosed in Table 1.

FIG. 2 is the plot of the average plasma concentrations of CBD in Animals 1-10 after oral administration of 25 mg/kg of the composition disclosed in Table 1.

FIG. 3 is a plot of the individual plasma concentration of CBD in Animals 11-20 after oral administration of 25 mg/kg of the composition disclosed in Table 2.

FIG. 4 is the plot of the average plasma concentrations of CBD in Animals 11-20 after oral administration of 25 mg/kg of the composition disclosed in Table 2.

FIG. 5 is a plot of the individual plasma concentration of CBD in Animals 21-30 after oral administration of 25 mg/kg of the composition disclosed in Table 3.

FIG. 6 is the plot of the average plasma concentrations of CBD in Animals 21-30 after oral administration of 25 mg/kg of the composition disclosed in Table 3.

FIG. 7 is a plot of the individual plasma concentration of CBD in Animals 31-40 after oral administration of 25 mg/kg of the composition disclosed in Table 4.

FIG. 8 is the plot of the average plasma concentrations of CBD in Animals 31-40 after oral administration of 25 mg/kg of the composition disclosed in Table 4.

FIG. 9 is a plot of the individual plasma concentration of CBD in Animals 41-50 after oral administration of 25 mg/kg of the composition disclosed in Table 5.

FIG. 10 is the plot of the average plasma concentrations of CBD in Animals 41-50 after oral administration of 25 mg/kg of the composition disclosed in Table 5.

FIG. 11 is the 24-hour plot of the systolic blood pressure of subjects given the composition disclosed in Table 6 (●) versus placebo (◯).

FIG. 12 is the 24-hour plot of the mean arterial pressure of subjects given the composition disclosed in Table 6 (●) versus placebo (◯).

FIG. 13 is the 24-hour plot of the diastolic blood pressure of subjects given the composition disclosed in Table 6 (●) versus placebo (◯).

DETAILED DESCRIPTION OF THE DISCLOSURE

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

Also, throughout this specification, various publications are referenced. 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 matter pertains. The references disclosed are also individually and specifically incorporated by reference herein for the material contained in them that is discussed in the sentence in which the reference is relied upon.

General Definitions

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:

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

The terms “a” and “an” are defined as one or more unless this disclosure explicitly requires otherwise.

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 aspect includes from the one particular value and/or to the other particular value. Similarly, when values are expressed as approximations, by use of the antecedent “about,” it will be understood that the particular value forms another aspect. It will be further understood that the endpoints of each of the ranges are significant both in relation to the other endpoint, and independently of the other endpoint.

The terms “comprise” (and any form of comprise, such as “comprises” and “comprising”), “have” (and any form of have, such as “has” and “having”), “include” (and any form of include, such as “includes” and “including”) and “contain” (and any form of contain, such as “contains” and “containing”) are open-ended linking verbs. As a result, an apparatus that “comprises,” “has,” “includes” or “contains” one or more elements possesses those one or more elements, but is not limited to possessing only those elements. Likewise, a method that “comprises,” “has,” “includes” or “contains” one or more steps possesses those one or more steps, but is not limited to possessing only those one or more steps.

Any embodiment of any of the disclosed methods or compositions can consist of or consist essentially of—rather than comprise/include/contain/have—any of the described steps, elements, and/or features. Thus, in any of the claims, the term “consisting of” or “consisting essentially of” can be substituted for any of the open-ended linking verbs recited above, in order to change the scope of a given claim from what it would otherwise be using the open-ended linking verb.

The term “pharmaceutical composition” is defined herein as a composition which is approved by a regulatory body, for example, the Federal Drug Administration (FDA), European Medicines Agency (EMA), Japanese Pharmaceutical and Food Safety Bureau (PFSB), and the like.

The feature or features of one embodiment may be applied to other embodiments, even though not described or illustrated, unless expressly prohibited by this disclosure or the nature of the embodiments.

Any embodiment of any of the disclosed compounds or methods can consist of or consist essentially of—rather than comprise/include/contain/have—any of the described steps, elements, and/or features. Thus, in any of the claims, the term “consisting of” or “consisting essentially of” can be substituted for any of the open-ended linking verbs recited above, in order to change the scope of a given claim from what it would otherwise be using the open-ended linking verb.

COMPOSITIONS

In one aspect disclosed compositions comprise:

- A) a base pharmaceutical composition; and
- B) one or more delivery agents.

Base Compositions

According to the present disclosure base compositions comprise CBD oil. What is meant herein by the term “CBD oil” is the cannabidiol-containing extract from the hemp plant Cannabis sativa. The CBD oil useful for preparing the disclosed compositions can be extracts which are crude extracts containing less than about 80% by weight of cannabidiol. As used herein CBD oil comprising less than about 80% by weight of cannabidiol is referred to a “crude CBD oil.” When using lower percentage extracts the formulator will necessarily adjust the amount of CBD oil present in the disclosed compositions to ensure adequate delivery of the desired amount of cannabidiol.

In one embodiment, the compositions comprise a “hemp distillate” comprising from about 80% to about 92% by weight of cannabidiol. In a still further embodiment isolated, pure cannabidiol can be used in the present compositions. When pure cannabidiol is used in the disclosed compositions, the term “cannabidiol” is substituted for “CBD oil.” When the hemp distillate comprising from 80% to about 92% by weight cannabidiol is used, the term “CBD oil” applies. In some descriptions of the “CBD oil” this ingredient can be referred to as a “CBD resin.” Cannabidiol has the chemical name 2-[(1R,6R)-6-Isopropenyl-3-methylcyclohex-2-en-1-yl]-5-pentylbenzene-1,3-diol.

The disclosed pharmaceutical compositions comprise a base composition comprising:

- a) cannabidiol; and
- b) high oleic acid olive oil.

In one aspect of the present disclosure, the base pharmaceutical compositions, comprise:

- a) from about 0.5% to about 8% by weight of cannabidiol;
- b) from about 0.5% to about 24% by weight of olive oil; and
- c) the balance a carrier.

In one embodiment of this aspect the base pharmaceutical compositions, comprise:

- a) from about 0.5% to about 8% by weight of cannabidiol;
- b) from about 0.5% to about 24% by weight of olive oil; and
- c) a carrier chosen from gum Arabic, inulin, microcrystalline cellulose, D-lactose monohydrate, quillaia, xanthan gum, pectin, guar, and psyllium.

In one iteration of this embodiment the base pharmaceutical compositions, comprise:

- a) from about 0.5% to about 8% by weight of cannabidiol;
- b) from about 0.5% to about 24% by weight of high oleic acid olive oil; and
- c) a carrier chosen from gum Arabic, inulin, microcrystalline cellulose, D-lactose monohydrate, quillaia, xanthan gum, pectin, guar, and psyllium.

In a further iteration of this embodiment the base pharmaceutical compositions, comprise:

- a) from about 2% to about 5% by weight of cannabidiol;
- b) from about 4% to about 15% by weight of high oleic acid olive oil; and
- c) a carrier chosen from gum Arabic, inulin, microcrystalline cellulose, D-lactose monohydrate, quillaia, xanthan gum, pectin, guar, and psyllium.

In a non-limiting example of this iteration the base pharmaceutical compositions, comprise:

- a) from about 2% to about 5% by weight of cannabidiol;
- b) from about 0.5% to about 15% by weight of high oleic acid olive oil;
- c) from about 5% to about 15% of a bile salt; and
- d) a carrier chosen from gum Arabic, inulin, microcrystalline cellulose, D-lactose monohydrate, and quillaia.

The disclosed pharmaceutical base compositions can comprise from about 0.5% to about 8% by weight of cannabidiol. In one embodiment, the base composition can comprise from about 1% to about 5% by weight of cannabidiol. In another embodiment, the base composition can comprise from about 2% to about 6% by weight of cannabidiol. In a further embodiment, the base composition can comprise from about 2% to about 5% by weight of cannabidiol. In a yet further embodiment, the base composition can comprise from about 3% to about 5% by weight of cannabidiol. For example, the amount of cannabidiol 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 amounts, for example, 1.5%, 3.25%, and 5.75%.

The disclosed base compositions can comprise from about 0.5% to about 25% by weight of olive oil. In one embodiment the base compositions can comprise from about 3% to about 15% by weight of olive oil. In another embodiment the base compositions can comprise from about 5% to about 17% by weight of olive oil. In a further embodiment the base compositions can comprise from about 7.5% to about 15% by weight of olive oil. In a still further embodiment the base compositions can comprise from about 5% to about 10% by weight of olive oil. For example, the amount of olive 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%, or 25% by weight of olive oil or any fractional amounts, for example, 10.5%, 13.6%, and 17.5%.

According to this aspect the ratio of cannabidiol to olive oil is from about 1:1 to about 1:4. For example, the ratio of cannabidiol to olive 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.

In another aspect of the present disclosure, the base over-the-counter compositions, comprise:

- a) from about 0.5% to about 8% by weight of CBD oil;
- b) from about 0.5% to about 24% by weight of one or more edible oils; and
- c) the balance a carrier.

In another iteration of this embodiment the base compositions, comprise:

- a) from about 0.5% to about 8% by weight of CBD oil;
- b) from about 0.5% to about 24% by weight of sunflower oil; and
- c) a carrier chosen from gum Arabic, inulin, microcrystalline cellulose, D-lactose monohydrate, quillaia, xanthan gum, pectin, guar, and psyllium.

In a further iteration of this embodiment the base compositions, comprise:

- a) from about 2% to about 5% by weight of CBD oil;
- b) from about 4% to about 15% by weight of sunflower oil; and
- c) a carrier chosen from gum Arabic, inulin, microcrystalline cellulose, D-lactose monohydrate, quillaia, xanthan gum, pectin, guar, and psyllium.

In a non-limiting example of this iteration the base compositions, comprise:

- a) from about 2% to about 5% by weight of CBD oil;
- b) from about 0.5% to about 15% by weight of sunflower oil;
- c) from about 5% to about 15% of a bile salt; and
- d) a carrier chosen from gum Arabic, inulin, microcrystalline cellulose, D-lactose monohydrate, and quillaia.

In a further example the carrier is gum Arabic. In another example the carrier is inulin. In a yet another example the carrier is microcrystalline cellulose. In a still further example the carrier is D-lactose monohydrate. In a still another example the carrier is quillaia.

In a further embodiment of this aspect the base compositions, comprise:

- a) from about 0.5% to about 8% by weight of CBD oil;
- b) from about 0.5% to about 15% by weight of coconut oil; and
- c) a carrier chosen from gum Arabic, inulin, microcrystalline cellulose, D-lactose monohydrate, quillaia, xanthan gum, pectin, guar, and psyllium.

In a further iteration of this embodiment the base compositions, comprise:

- a) from about 2% to about 5% by weight of CBD oil;
- b) from about 4% to about 15% by weight of coconut oil; and
- c) a carrier chosen from gum Arabic, inulin, microcrystalline cellulose, D-lactose monohydrate, quillaia, xanthan gum, pectin, guar, and psyllium.

In a non-limiting example of this iteration the base compositions, comprise:

- a) from about 2% to about 5% by weight of CBD oil;
- b) from about 0.5% to about 15% by weight of coconut oil;
- c) from about 5% to about 15% of a bile salt; and
- d) a carrier chosen from gum Arabic, inulin, microcrystalline cellulose, D-lactose monohydrate, and quillaia.

In one embodiment of this aspect, the base composition comprises:

- a) from about 0.5% to about 8% by weight of CBD oil;
- b) from about 0.5% to about 15% by weight of coconut oil; and
- c) a carrier chosen from gum Arabic, inulin, microcrystalline cellulose, D-lactose monohydrate, quillaia, xanthan gum, pectin, guar, and psyllium.

In a further embodiment of this aspect the base compositions, comprise:

- a) from about 0.5% to about 8% by weight of CBD oil;
- b) from about 0.5% to about 15% by weight of coconut oil; and
- c) a carrier chosen from gum Arabic, inulin, microcrystalline cellulose, D-lactose monohydrate, quillaia, xanthan gum, pectin, guar, and psyllium.

In a further iteration of this embodiment the base compositions, comprise:

- a) from about 2% to about 5% by weight of CBD oil;
- b) from about 4% to about 15% by weight of coconut oil; and
- c) a carrier chosen from gum Arabic, inulin, microcrystalline cellulose, D-lactose monohydrate, quillaia, xanthan gum, pectin, guar, and psyllium.

In a non-limiting example of this iteration the base compositions, comprise:

- a) from about 2% to about 5% by weight of CBD oil;
- b) from about 0.5% to about 15% by weight of coconut oil;
- c) from about 5% to about 15% of a bile salt; and
- d) a carrier chosen from gum Arabic, inulin, microcrystalline cellulose, D-lactose monohydrate, and quillaia.

The disclosed base compositions can comprise from about 0.5% to about 8% by weight of CBD oil. In one embodiment, the base composition can comprise from about 1% to about 5% by weight of CBD oil. In another embodiment, the base composition can comprise from about 2% to about 6% by weight of CBD oil. In a further embodiment, the base composition can comprise from about 2% to about 5% by weight of CBD oil. In a yet further embodiment, the base composition can comprise from about 3% to about 5% by weight of CBD oil. 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 amounts, for example, 1.5%, 3.25%, and 5.75%.

The disclosed base compositions can comprise from about 0.5% to about 25% by weight of edible oil. In one embodiment the base compositions can comprise from about 3% to about 15% by weight of edible oil. In another embodiment the base compositions can comprise from about 5% to about 17% by weight of edible oil. In a further embodiment the base compositions can comprise from about 7.5% to about 15% by weight of edible oil. In a still further embodiment the base compositions can comprise from about 5% to about 10% by weight of edible oil. 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%, or 25% by weight of edible oil or any fractional amounts, for example, 10.5%, 13.6%, and 17.5%.

According to this aspect 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.

Edible Oils

The disclosed edible oils include oils that are primarily triglyceride-containing oils. Ono-limiting examples of these oils are chosen from sunflower oil, coconut oil, canola oil, palm oil, soybean oil, corn oil, safflower oil, and peanut oil.

In one non-limiting example, the pharmaceutical compositions comprise olive oil. In this example, high oleic acid olive oil can be used.

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 yet further non-limiting example the edible oil is palm oil. In a still yet non-limiting example the edible oil is soybean oil. In another non-limiting example the edible oil is corn oil. In a still another non-limiting example the edible oil is safflower oil. In a yet another non-limiting example the edible oil is peanut oil.

In another aspect highly unsaturated carboxylic acids derived from plant-based triglycerides can be admixed with one or more edible oils. In this aspect, for example, a formulator having a base composition comprising 10% by weight of an edible oil, can substitute 5% of that edible oil with 5% of a disclosed carboxylic acid.

In another example, the base pharmaceutical compositions, comprise:

- a) from about 5 mg to about 15 mg by weight of cannabidiol;
- b) from about 5 mg to about 60 mg by weight of an admixture of a carboxylic acids derived from a plant-based triglyceride and olive oil, wherein the ratio of the carboxylic acid and olive oil is from about 1:9 to about 9:1; and
- c) from about 100 mg to about 300 mg by weight of one or more carriers

In another example, an over-the-counter base composition comprises:

- a) from about 5 mg to about 15 mg by weight of CBD oil;
- b) from about 5 mg to about 60 mg by weight of an admixture of a carboxylic acids derived from a plant-based triglyceride and one or more edible oils, wherein the ratio of the carboxylic acid and the edible oils is from about 1:9 to about 9:1; and
- c) from about 100 mg to about 300 mg by weight of one or more carriers.

The addition of a carboxylic acid in some embodiments aid in the formulation a flowable powder for encapsulation or packaging as described herein below, especially when the carboxylic acid serves to form a salt with one or more of the carriers or delivery agents.

Carriers

In one aspect the disclosed carriers are polysaccharides. Non-limiting examples of poly saccharide carriers include inulin, galactogen, cellulose, chitin, pectin, psyllium, guar, hemicellulose, potato starch, and partially hydrolyzed polysaccharides. In another aspect the carriers are sugar alcohols, for example, sorbitol, erythritol, xylitol, lactitol, maltitol, mannitol, hydrogenated starch hydrolysates, isomaltose, or any combination thereof. In a further aspect carrier component is based on a native or chemically modified agar, alginates, carrageenan gum, cellulose, chitosan, chitin, cyclodextrin, dextran, gellan gum, glycogen, glycosaminoglycan, gum karaya, inulin, pectin, polydextrose, xanthan gum, or any other starches, gums or other polysaccharide, including functionalized derivatives, dextrinized, hydrolyzed, oxidized, alkylated, hydroxyalkylated, acetylated, fractionated, and physically modified starches and mixtures thereof. In some embodiments glycerin and/or propylene glycol can be added as a carrier.

In another aspect the carrier is chosen from gum Arabic, inulin, microcrystalline cellulose, D-lactose monohydrate, and quillaia. In a further example the carrier is gum Arabic. In another example the carrier is inulin. In a yet another example the carrier is microcrystalline cellulose. In a still further example the carrier is D-lactose monohydrate. In a still another example the carrier is quillaia. The carrier can be a combination of gum Arabic, inulin, microcrystalline cellulose, D-lactose monohydrate, or quillaia.

The disclosed base compositions can comprise from about 75% to about 99% by weight of one or more carriers. In one embodiment disclosed compositions can comprise from about 80% to about 95% by weight of one or more carriers. In another embodiment the disclosed compositions can comprise from about 80% to about 90% by weight of one or more carriers. In a yet another embodiment the disclosed compositions can comprise from about 85% to about 95% by weight of one or more carriers. In a further embodiment the disclosed compositions can comprise from about 85% to about 90% by weight of one or more carriers. As such, the disclosed base compositions can comprise 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%0, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% of one or more carriers.

In another aspect the base compositions can comprise:

- a) from about 5 mg to about 15 mg by weight of CBD oil;
- b) from about 5 mg to about 60 mg by weight of one or more edible oils; and
- c) from about 100 mg to about 300 mg by weight of one or more carriers.

The disclosed base compositions can comprise from about 5 mg to about 15 mg by weight of CBD oil. In one embodiment the base compositions can comprise from about 5 mg to about 12 mg by weight of CBD oil. In another embodiment the base compositions can comprise from about 7 mg to about 15 mg by weight of CBD oil. In further embodiment the base compositions can comprise from about 7 mg to about 12 mg by weight of CBD oil. The base compositions can comprise 5 mg, 6 mg, 7 mg, 8 mg, 9 mg, 10 mg, 11 mg, 12 mg, 13 mg, 14 mg, or 15 mg by weight of CBD oil.

The disclosed base compositions can comprise from about 5 mg to about 60 mg by weight of an edible oil. In one embodiment the base compositions can comprise from about 15 mg to about 50 mg by weight of one or more edible oils. In another embodiment the base compositions can comprise from about 5 mg to about 20 mg by weight of one or more edible oils. In a further embodiment the base compositions can comprise from about 5 mg to about 15 mg by weight of one or more edible oils. In a yet further embodiment the base compositions can comprise from about 5 mg to about 12 mg by weight of one or more edible oils. In a still further embodiment the base compositions can comprise from about 10 mg to about 30 mg by weight of one or more edible oils. In a yet another embodiment the base compositions can comprise from about 15 mg to about 25 mg by weight of one or more edible oils. The compositions can 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, 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, or 60 mg by weight of one or more edible oils.

The disclosed base compositions can comprise from about 100 mg to about 300 mg by weight of one or more carriers. In one embodiment the base compositions comprise from about 150 mg to about 300 mg by weight of one or more carriers. In another embodiment the base compositions comprise from about 150 mg to about 300 mg by weight of one or more carriers. In a further embodiment the base compositions comprise from about 200 mg to about 300 mg by weight of one or more carriers. In a yet further embodiment the base compositions comprise from about 250 mg to about 300 mg by weight of one or more carriers. In one embodiment the base compositions comprise from about 200 mg to about 250 mg by weight of one or more carriers. The disclosed base compositions can comprise 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 31 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, 170 mg, 171 mg, 172 mg, 173 mg, 174 mg, 175 mg, 167 mg, 177 mg, 178 mg, 179 mg, 180 mg, 181 mg, 182 mg, 183 mg, 184 mg, 185 mg, 186 mg, 187 mg, 188 mg, 189 mg, 190 mg, 191 mg, 192 mg, 193 mg, 194 mg, 195 mg, 196 mg, 197 mg, 198 mg, 199 mg, 200 mg, 201 mg, 202 mg, 203 mg, 204 mg, 205 mg, 206 mg, 207 mg, 208 mg, 209 mg, 210 mg, 211 mg, 212 mg, 213 mg, 214 mg, 215 mg, 216 mg, 217 mg, 218 mg, 219 mg, 220 mg, 221 mg, 222 mg, 223 mg, 224 mg, 225 mg, 226 mg, 227 mg, 228 mg, 229 mg, 230 mg, 231 mg, 232 mg, 233 mg, 234 mg, 235 mg, 236 mg, 237 mg, 238 mg, 239 mg, 240 mg, 241 mg, 242 mg, 243 mg, 244 mg, 245 mg, 246 mg, 247 mg, 248 mg, 249 mg, 250 mg, 251 mg, 252 mg, 253 mg, 254 mg, 255 mg, 256 mg, 257 mg, 258 mg, 259 mg, 260 mg, 261 mg, 2.62 mg, 263 mg, 264 mg, 265 mg, 266 mg, 267 mg, 268 mg, 269 mg, 270 mg, 271 mg, 272 mg, 273 mg, 274 mg, 275 mg, 276 mg, 277 mg, 278 mg, 279 mg, 280 mg, 281 mg, 282 mg, 283 mg, 284 mg, 285 mg, 286 mg, 287 mg, 288 mg, 289 mg, 290 mg, 290 mg, 291 mg, 292 mg, 293 mg, 294 mg, 295 mg, 296 mg, 297 mg, 298 mg, 299 mg, or 300 mg by weight of one or more carriers.

Bile Salts

The disclosed base compositions can further comprise from 5% to about 20% by weight of a bile salt. Bile salts enhance the ability of the disclosed compositions to target the duodenum. Non-limiting examples of bile salts and/or bile acids includes steroid acids (and/or the carboxylate anion thereof) and salts thereof, found in the bile of an animal (e.g., a human), including cholic acid, cholate, deoxycholic acid, deoxycholate, hyodeoxycholic acid, hyodeoxycholate, glycocholic acid, glycocholate, taurocholic acid, taurocholate, chenodeoxycholic acid, chenodeoxycholate, lithocholic acid, lithocolate, and the like. Taurocholic acid and/or taurocholate are referred to herein as TCA.

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: glycocholate and taurocholate, respectively (and salts thereof). Any reference to a bile salt or bile acid used herein includes reference to an identical compound naturally or synthetically prepared. In one non-limiting example the bile salt is ox bile.

The disclosed compositions can comprise from about 5% to about 20% by weight of one or more bile salts. In one embodiment the compositions comprise from about 7.5% to about 20% by weight of one or more bile salts. In one embodiment the compositions comprise from about 7.5% to about 12.5% by weight of one or more bile salts. In one embodiment the compositions comprise from about 15% to about 20% by weight of one or more bile salts. In one embodiment the compositions comprise from about 5% to about 15% by weight of one or more bile salts. In one embodiment the compositions comprise from about 12% to about 15% by weight of one or more bile salts. The compositions can comprise, 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.

The disclosed compositions comprise from about 25 mg to about 50 mg by weight of one or more bile salts. In one embodiment, the compositions comprise from about 30 mg to about 50 mg by weight of one or more bile salts. In another embodiment, the compositions comprise from about 30 mg to about 40 mg by weight of one or more bile salts. In further embodiment, the compositions comprise from about 25 mg to about 40 mg by weight of one or more bile salts. In yet another embodiment, the compositions comprise from about 25 mg to about 35 mg by weight of one or more bile salts. The disclosed base compositions can comprise, 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 one or more bile salts.

Methods

Disclosed herein are methods for treating hypertension in a subject in need of treatment, comprising administering to the subject in need an effective amount of a composition defined herein above.

In one aspect of the disclosed method a total dosage of the disclosed composition is from about 90 mg to about 450 mg over the course of 24 hours depending upon the severity of the hypertension. For an average hum weighing 60 kg, this equates to from about 1.5 mg/kg to about 75 mg/kg per 24 hours.

In one embodiment the dosage per day is from about 90 mg to about 150 mg. In a further embodiment the dosage per day is from about 140 mg to about 250 mg. In another embodiment the dosage per day is from about 200 mg to about 400 mg. In a still further embodiment the dosage per day is from about 300 mg to about 450 mg. In a yet further embodiment the dosage per day is from about 250 mg to about 350 mg.

The dosage of one or more disclosed compositions can be from about 90 mg to about 450 mg per 24 hours, for example, 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 31 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, 170 mg, 171 mg, 172 mg, 173 mg, 174 mg, 175 mg, 167 mg, 177 mg, 178 mg, 179 mg, 180 mg, 181 mg, 182 mg, 183 mg, 184 mg, 185 mg, 186 mg, 187 mg, 188 mg, 189 mg, 190 mg, 191 mg, 192 mg, 193 mg, 194 mg, 195 mg, 196 mg, 197 mg, 198 mg, 199 mg, 200 mg, 201 mg, 202 mg, 203 mg, 204 mg, 205 mg, 206 mg, 207 mg, 208 mg, 209 mg, 210 mg, 211 mg, 212 mg, 213 mg, 214 mg, 215 mg, 216 mg, 217 mg, 218 mg, 219 mg, 220 mg, 221 mg, 222 mg, 223 mg, 224 mg, 225 mg, 226 mg, 227 mg, 228 mg, 229 mg, 230 mg, 231 mg, 232 mg, 233 mg, 234 mg, 235 mg, 236 mg, 237 mg, 238 mg, 239 mg, 240 mg, 241 mg, 242 mg, 243 mg, 244 mg, 245 mg, 246 mg, 247 mg, 248 mg, 249 mg, 250 mg, 251 mg, 252 mg, 253 mg, 254 mg, 255 mg, 256 mg, 257 mg, 258 mg, 259 mg, 260 mg, 261 mg, 262 mg, 263 mg, 264 mg, 265 mg, 266 mg, 267 mg, 268 mg, 269 mg, 270 mg, 271 mg, 272 mg, 273 mg, 274 mg, 275 mg, 276 mg, 277 mg, 278 mg, 279 mg, 280 mg, 281 mg, 282 mg, 283 mg, 284 mg, 285 mg, 286 mg, 287 mg, 288 mg, 289 mg, 290 mg, 290 mg, 291 mg, 292 mg, 293 mg, 294 mg, 295 mg, 296 mg, 297 mg, 298 mg, 299 mg, 300 mg, 301 mg, 302 mg, 303 mg, 304 mg, 305 mg, 306 mg, 307 mg, 308 mg, 309 mg, 310 mg, 311 mg, 312 mg, 313 mg, 314 mg, 315 mg, 316 mg, 317 mg, 318 mg, 319 mg, 320 mg, 321 mg, 322 mg, 323 mg, 324 mg, 325 mg, 326 mg, 327 mg, 328 mg, 329 mg, 330 mg, 331 mg, 332 mg, 333 mg, 334 mg, 335 mg, 336 mg, 337 mg, 338 mg, 339 mg, 340 mg, 341 mg, 342 mg, 343 mg, 344 mg, 345 mg, 346 mg, 347 mg, 348 mg, 349 mg, 350 mg, 351 mg, 352 mg, 353 mg, 354 mg, 355 mg, 356 mg, 357 mg, 358 mg, 359 mg, 360 mg, 361 mg, 362 mg, 363 mg, 364 mg, 365 mg, 366 mg, 367 mg, 368 mg, 369 mg, 370 mg, 371 mg, 372 mg, 373 mg, 374 mg, 375 mg, 376 mg, 377 mg, 378 mg, 379 mg, 380 mg, 381 mg, 382 mg, 383 mg, 384 mg, 385 mg, 386 mg, 387 mg, 388 mg, 389 mg, 390 mg, 390 mg, 391 mg, 392 mg, 393 mg, 394 mg, 395 mg, 396 mg, 397 mg, 398 mg, 399 mg, 400 mg, 401 mg, 402 mg, 403 mg, 404 mg, 405 mg, 406 mg, 407 mg, 408 mg, 409 mg, 410 mg, 411 mg, 412 mg, 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 per 24 hours.

In one aspect the disclosed methods comprise administering to a subject a composition comprising:

- A) a base pharmaceutical composition; and
- B) one or more delivery agents.

In another aspect the disclosed methods comprise administering to a subject a composition comprising:

- A) a base over-the-counter composition; and
- B) one or more delivery agents.

According to the disclosed methods the compositions comprise CBD oil. What is meant herein by the term “CBD oil” is the cannabidiol-containing extract from the hemp plant Cannabis sativa. The CBD oil useful for preparing the disclosed compositions can be extracts which are crude extracts containing less than about 80% by weight of cannabidiol. As used herein CBD oil comprising less than about 80% by weight of cannabidiol is referred to a “crude CBD oil.” When using lower percentage extracts, the formulator will necessarily adjust the amount of CBD oil present in the disclosed compositions to ensure adequate delivery of the desired amount of cannabidiol.

In one embodiment of the disclosed methods, the compositions comprise a “hemp distillate” comprising from about 80% to about 92% by weight of cannabidiol. In a still further embodiment isolated, pure cannabidiol can be used in the present compositions. When pure cannabidiol is used in the disclosed compositions, the term “cannabidiol” is substituted for “CBD oil.” When the hemp distillate comprising from 80% to about 92% by weight cannabidiol is used, the term “CBD oil” applies. In some descriptions of the “CBD oil” this ingredient can be referred to as a “CBD resin.” Cannabidiol has the chemical name 2-[(1R,6R)-6-Isopropenyl-3-methylcyclohex-2-en-1-yl]-5-pentylbenzene-1,3-diol.

In one aspect of the disclosed methods, the base pharmaceutical compositions, comprise:

- a) cannabidiol; and
- b) high oleic acid olive oil.

In a further aspect the disclosed methods, the pharmaceutical compositions, comprise:

- a) from about 0.5% to about 8% by weight of cannabidiol;
- b) from about 0.5% to about 24% by weight of olive oil; and
- c) the balance a carrier.

In one embodiment of this aspect, the pharmaceutical compositions, comprise:

- a) from about 0.5% to about 8% by weight of cannabidiol;
- b) from about 0.5% to about 24% by weight of olive oil; and
- c) a carrier chosen from gum Arabic, inulin, microcrystalline cellulose, D-lactose monohydrate, quillaia, xanthan gum, pectin, guar, and psyllium.

In one iteration of this embodiment, the pharmaceutical compositions, comprise:

- a) from about 0.5% to about 8% by weight of cannabidiol;
- b) from about 0.5% to about 24% by weight of high oleic acid olive oil; and
- c) a carrier chosen from gum Arabic, inulin, microcrystalline cellulose, D-lactose monohydrate, quillaia, xanthan gum, pectin, guar, and psyllium.

In a further iteration of this embodiment, the pharmaceutical compositions, comprise:

- a) from about 2% to about 5% by weight of cannabidiol;
- b) from about 4% to about 15% by weight of high oleic acid olive oil; and
- c) a carrier chosen from gum Arabic, inulin, microcrystalline cellulose, D-lactose monohydrate, quillaia, xanthan gum, pectin, guar, and psyllium.

A non-limiting example of the disclosed methods comprise administering to a subject in need a pharmaceutical composition, comprising:

- a) from about 2% to about 5% by weight of cannabidiol;
- b) from about 0.5% to about 15% by weight of high oleic acid olive oil;
- c) from about 5% to about 15% of a bile salt; and
- d) a carrier chosen from gum Arabic, inulin, microcrystalline cellulose, D-lactose monohydrate, and quillaia.

For example, administering to a subject in need a base composition comprising:

- a) from about 5 mg to about 15 mg by weight of cannabidiol;
- b) from about 5 mg to about 60 mg by weight of an admixture of a carboxylic acid derived from a plant-based triglyceride and olive oil, wherein the ratio of the carboxylic acid and the edible oils is from about 1:9 to about 9:1; and
- c) from about 100 mg to about 300 mg by weight of one or more carriers.

In another aspect of the disclosed methods for treating hypertension the base compositions administered to a subject in need comprise:

- a) from about 5 mg to about 15 mg by weight of cannabidiol;
- b) from about 5 mg to about 60 mg by weight of olive oil; and
- c) from about 100 mg to about 300 mg by weight of one or more carriers.

In a further aspect of the disclosed methods, the base over-the-counter compositions, comprise:

- a) from about 0.5% to about 8% by weight of CBD oil;
- b) from about 0.5% to about 25% by weight of one or more edible oils; and
- c) the balance a carrier.

In one embodiment of this aspect of the disclosed methods the base compositions, comprise:

- a) from about 0.5% to about 8% by weight of CBD oil;
- b) from about 0.5% to about 25% by weight of one or more edible oils; and
- c) a carrier chosen from gum Arabic, inulin, microcrystalline cellulose, D-lactose monohydrate, quillaia, xanthan gum, pectin, guar, and psyllium.

In one iteration of this embodiment of the disclosed methods the base compositions, comprise:

- a) from about 0.5% to about 8% by weight of CBD oil;
- b) from about 0.5% to about 24% by weight of sunflower oil; and
- c) a carrier chosen from gum Arabic, inulin, microcrystalline cellulose, D-lactose monohydrate, quillaia, xanthan gum, pectin, guar, and psyllium.

In a further iteration of this embodiment of the disclosed methods the base compositions, comprise:

- a) from about 2% to about 5% by weight of CBD oil;
- b) from about 4% to about 15% by weight of sunflower oil; and
- c) a carrier chosen from gum Arabic, inulin, microcrystalline cellulose, D-lactose monohydrate, quillaia, xanthan gum, pectin, guar, and psyllium.

In a non-limiting example of this iteration of the disclosed methods the base compositions, comprise:

- a) from about 2% to about 5% by weight of CBD oil;
- b) from about 0.5% to about 15% by weight of sunflower oil;
- c) from about 5% to about 15% of a bile salt; and
- d) a carrier chosen from gum Arabic, inulin, microcrystalline cellulose, D-lactose monohydrate, and quillaia.

In a further example of the disclosed methods the compositions comprise the carrier gum Arabic. In another example the carrier is inulin. In a yet another example the carrier is microcrystalline cellulose. In a still further example the carrier is D-lactose monohydrate.

In a still another example the carrier is quillaia.

In a further embodiment of this aspect of the methods from controlling hypertension the base compositions, comprise:

- a) from about 0.5% to about 8% by weight of CBD oil;
- b) from about 0.5% to about 15% by weight of coconut oil; and
- c) a carrier chosen from gum Arabic, inulin, microcrystalline cellulose, D-lactose monohydrate, quillaia, xanthan gum, pectin, guar, and psyllium.

In a further iteration of this embodiment of the disclosed methods the base compositions, comprise:

- a) from about 2% to about 5% by weight of CBD oil;
- b) from about 4% to about 15% by weight of coconut oil; and
- c) a carrier chosen from gum Arabic, inulin, microcrystalline cellulose, D-lactose monohydrate, quillaia, xanthan gum, pectin, guar, and psyllium.

In a non-limiting example of this iteration of the disclosed methods for treating a subject having hypertension the base compositions, comprise:

- a) from about 2% to about 5% by weight of CBD oil;
- b) from about 0.5% to about 15% by weight of coconut oil;
- c) from about 5% to about 15% of a bile salt; and
- d) a carrier chosen from gum Arabic, inulin, microcrystalline cellulose, D-lactose monohydrate, and quillaia.

For example, administering to a subject in need a base composition comprising:

- a) from about 5 mg to about 15 mg by weight of CBD oil;
- b) from about 5 mg to about 60 mg by weight of an admixture of a carboxylic acid derived from a plant-based triglyceride and one or more edible oils, wherein the ratio of the carboxylic acid and the edible oils is from about 1:9 to about 9:1; and
- c) from about 100 mg to about 300 mg by weight of one or more carriers.

In another aspect of the disclosed methods for treating hypertension the base compositions administered to a subject in need comprise:

- a) from about 5 mg to about 15 mg by weight of CBD oil;
- b) from about 5 mg to about 60 mg by weight of one or more edible oils; and
- c) from about 100 mg to about 300 mg by weight of one or more carriers.

Human Studies

The composition disclosed in Table 1 is used for a human clinical trial

TABLE 1

Ingredients
Mass (mg)
Percent %

Cannabidiol oil¹
75.76
13.29

High oleic acid olive oil
151.52
26.58

Partek-M mannitol
142.95
25.08

Aeroperl ® 300
142.95
25.08

Deoxycholic acid
6.8
1.2

Microcrystalline cellulose
50.00
8.77

Total
570.00
100

¹contains 99% cannabidiol for an effective amount of 75 mg.

The following compositions were used in controlled human clinical trials measuring the difference in systolic blood pressure (SBP), mean arterial pressure (MSP), and diastolic blood pressure (DBP) between volunteers taking a composition disclosed in Table 2 or Table 3 versus placebo over a 24-hour period.

TABLE 2

Ingredients
Mass (mg)
Percent %

Cannabidiol oil¹
30.83
4.21

High oleic acid sunflower oil
61.67
8.41

Tapioca starch
492.50
67.1

Ox bile extract²
65.00
8.87

Silicon dioxide
18.00
2.69

Tapioca flour
65.00
8.87

Total
733.00
100

¹contains 85.34% cannabidiol for an effective amount of 25 mg.

²contains 45-55% deoxycholic acid, taurocholate and glycocholic acid

TABLE 3

Ingredients
Mass (mg)
Percent %

Cannabidiol oil¹
87.1
12.44

High oleic acid sunflower oil
174.20
24.89

Tapioca starch
164.84
23.55

Aeroperl ® 300
158.86
22.69

Ox bile extract²
65.00
9.29

Microcrystalline cellulose
50.00
7.14

Total
700.00
100

¹contains 90.64% cannabidiol for an effective amount of 75 mg.

²contains 45-55% deoxycholic acid, taurocholate and glycocholic acid

TABLE 4

Ingredients
Mass (mg)
Percent %

Cannabidiol oil¹
75.76
13.29

High oleic acid olive oil
151.52
26.58

Partek-M mannitol
142.95
25.08

Aeroperl ® 300
142.95
25.08

Deoxycholic acid
6.8
1.2

Microcrystalline cellulose
50.00
8.77

Total
570.00
100

¹contains 99% cannabidiol for an effective amount of 75 mg.

The composition disclosed in Table 2 was administered to human volunteers with mild to moderate hypertension under the following protocol. During a 24-hour study, 16 volunteers in each group were administered the composition of Table 2 or a placebo at selected times, t=0, t=13 hours, and t=22 hours. The results are depicted in FIG. 11. The results of subjects given the composition containing the composition in Table 2 are reflected in the dashed line with solid circles (●) and the subjects given the placebo are reflected in the solid line and open circles (◯). As depicted in FIG. 11 the approximately 7% difference in systolic blood pressure (SBP) continued after the ambulatory period, i.e., during the sleep period.

FIG. 12 reflects the mean arterial pressures (MAP) of the two groups. During the ambulatory period, volunteers averaged a significant reduction of 5.3% in MAP versus the group given a placebo. FIG. 13 reflects the reduction of 3.5% in diastolic pressure versus placebo.

An analysis of the physical activity levels of the volunteers with mild to moderate hypertension during the 24-hour monitored period showed no significant differences in activity between the placebo and the composition from Table 2 treated volunteers, indicating that the observed differences in BP were not due to disparate physical movement or demands.

Arterial stiffness is a strong predictor of disease in humans. The impacts of increased arterial stiffness are not limited only to coronary heart disease such as hypertension, but also include other disease states such as diabetes mellitus, renal disease and more. It can also be a prognostic marker for cardiovascular events and all-cause mortality, even in asymptomatic individuals without overt cardiovascular disease.

The efficacy of blood pressure treatment and differences in efficacy between different types of antihypertensive agents is strongly correlated with measuring arterial stiffness, whereby the significant blood pressure reduction effects depicted in FIGS. 11 to 13 appear to have been at least partially due to these improvements in arterial stiffness. Arterial stiffness results from this study are summarized in Table I below. All comparisons between the subject given the composition and placebo statistically significant (p<0.01).

TABLE I

Composition

Measurement
Table 2
Placebo

Pulse Wave
8.1 ± 0.3 m/s
8..31 ± 0.3 m/s

Velocity

Augmentation
28.4 ± 1.4%
32.3 ± 1.3%

Index

Augmentation
27.8 ± 1.3%
30.4 ± 1.3%

Index corrected

to heart rate of 75 BPM

Augmentation pressure
12.0 ± 1.0 mmHg
14.6 ± 1.0 mmHg

In this study 60 volunteers between the ages of 45-70 administering three 150 mg doses of the composition disclosed in Table 7, every day for 6-weeks. This study is a double blinded, randomized cross-over design, and utilizes a placebo control. Some volunteers are already using leading standard of care hypertension drugs such as ACE inhibitors with or without diuretics to assist in the evaluation of the composition disclosed in Table 7 to determine the efficacy of this composition with and without other hypertension treatments. The purpose of this study is to evaluate the potential for longer term health benefits.

Animal Studies

TABLE 5

Ingredients
%
mg

CBD oil¹
3.2
10

Sunflower oil
6.4
20

Gum Arabic
90.4
278

Total
100
308

¹Contains 78.33% cannabidiol

TABLE 6

Ingredients
%
mg

CBD oil¹
2.9
10

Sunflower oil
5.8
20

Ox bile
10
34.2

Gum Arabic
81.3
278

Total
100
342.2

¹Contains 78.33% cannabidiol

TABLE 7

Ingredients
%
mg

CBD oil²
3.7
10

Coconut oil
7.4
20

Inulin
88.9
239.14

Total
100
269.14

²Contains 89.73% cannabidiol

Nanoemulsions

CBD oil (10 g) and sunflower oil (10 g) is combined with 100 g of D-lactose monohydrate to form a homogeneous admixture. The admixture is then metered into 212.5 gm of quillaja in 467.5 mL of water to form a pre-emulsion. The pre-emulsion is then passed through a high pressure microfluidizer homogenizer to afford the liquid nanoemulsion.

TABLE 8

Ingredients
%
mg

Cannabidiol³
6.5
10

Sunflower oil
6.6
10

D-lactose monohydrate
6.6
10

quillaia
25.8
37.5

water
54.4
83.5

Total
100
151

³Contains 99.65% cannabidiol

TABLE 9

Ingredients
%
mg

Cannabidiol³
6.5
10

Sunflower oil
6.6
10

D-lactose monohydrate
6.6
10

quillaia
25.8
37.5

water
54.4
83.5

Total
100
151

³Contains 89.73% cannabidiol

Individual and Average Plasma Concentrations (Ng/mL) and Pharmacokinetic Parameters for CBD after Oral Administration of the Composition of Table 5 at 25 mg/kg of CBD in Male Sprague-Dawley Rats (Group 1)

TABLE II

Animal number

Sample time (hr)
1
2
3
4
5

0.033
BLOQ
BLOQ
BLOQ
BLOQ
BLOQ

0.067
1.71
BLOQ
0.549
2.70
1.22

0.1
3.01
2.84
1.84
6.40
4.07

0.13
539
3.69
3.85
12.0
7.52

2.0
21.7
8.39
10.2
20.2
17.7

0.25
37.4
13.0
22.3
31.5
37.0

0.5
116
62.6
39.6
59.4
62.8

0.75
191
95.0
73.7
55.2
79.4

1.0
174
84.2
75.9
53.4
80.4

Dose (mg/kg)
0.296
0.288
0.288
0.286
0.286

Vol. dosed (mL)
1.48
1.44
1.44
1.42
1.43

C_max(ng/mL)
191
95.0
75.9
59.4
80.4

t_max(hr)
0.75
0.75
1.0
0.5
1.0

t_1/2
ND²
ND²
ND³
ND²
ND³

MRT_last(hr)
0.697
0.699
0.696
0.616
0.653

AUC_last(hr · ng/mL)
106
52.7
42.0
42.2
52.8

AUC_∞(hr · ng/mL)
ND³
ND²
ND³
ND²
ND³

AUC_last/D
4.23
2.11
1.68
1.69
2.11

(hr · kg · ng/mL/mg)

AUC_∞/D
ND²
ND²
ND³
ND²
ND³

(hr · kg · ng/mL/mg)

1. Dose-normalized by dividing the parameter by the nominal dose in mg/kg.

²Not determined due to a lack of quantifiable data points trailing the Cmax.

³Not determined because the terminal elimination phase was not observed.

BLOQ = below the limit of quantitation (1 ng/mL)

TABLE III

Animal number

Sample time (hr)
6
7
8
9
10

0.033
BLOQ
BLOQ
BLOQ
0.570
2.31

0.067
0.692
BLOQ
1.66
3.12
9.67

0.1
1.70
1.10
5.28
5.32
14.0

0.13
4.78
1.92
6.82
9.80
23.3

2.0
11.0
5.67
17.1
16.8
25.5

0.25
26.2
10.1
21.9
29.2
38.4

0.5
83.6
53.1
114
92.1
102

0.75
114
77.6
128
80.0
174

1.0
133
78.9
89.2
57.9
188

Dose (mg/kg)
0.300
0.289
0.286
0281
0.287

Vol. dosed (mL)
1.50
1.45
1.43
1.41
1.44

C_max(ng/mL)
133
78.9
128
92.1
188

t_max(hr)
1.0
1.0
0.75
0.50
1.0

t_1/2
ND³
ND³
ND²
ND²
ND³

MRT_last(hr)
0.699
0.708
0.660
0.623
0.696

AUC_last(hr · ng/mL)
70.9
44.5
76.5
56.4
102

AUC_∞(hr · ng/mL)
ND³
ND³
ND²
ND²
ND³

AUC_last/D
2.84
1.78
3.06
2.26
4.07

(hr · kg · ng/mL/mg)

AUC_∞/D
ND³
ND³
ND²
ND²
ND³

(hr · kg · ng/mL/mg)

1. Dose-normalized by dividing the parameter by the nominal dose in mg/kg.

²Not determined due to a lack of quantifiable data points trailing the Cmax.

³Not determined because the terminal elimination phase was not observed.

BLOQ = below the limit of quantitation (1 ng/mL)

TABLE IV provides the mean and standard deviation for the results of Animals 1-10.

TABLE IV

Sample time (hr)
mean
SD

0.033
1.44
ND

0.067
2.67
2.97

0.10
4.56
3.75

0.13
7.91
6.19

0.20
15.4
6.37

0.25
26.7
9.96

0.50
78.5
26.8

0.75
107
45.1

1.0
101
47.1

Dose (mg/kg)
0.289
0.005

Vol. dosed (mL)
1.45
0.03

C_max(ng/mL)
112
46.6

t_max(hr)
0.83
0.21

t_1/2
ND
ND

MRT_last(hr)
0.675
0.0341

AUC_last(hr · ng/mL)
64.6
23.6

AUC_∞(hr · ng/mL)
ND
ND

AUC_last/D
2.58
0.946

(hr · kg · ng/mL/mg)

AUC_∞/D
ND
ND

(hr · kg · ng/mL/mg)

Individual and Average Plasma Concentrations (Ng/mL) and Pharmacokinetic Parameters for CBD after Oral Administration of the Composition of Table 6 at 25 mg/kg of CBD in Male Sprague-Dawley Rats (Group 2)

TABLE V

Animal number

Sample time (hr)
11
12
13
14
15

0.033
BLOQ
BLOQ
BLOQ
BLOQ
BLOQ

0.067
2.91
1.29
1.77
2.76
BLOQ

0.1
6.24
5.39
7.75
8.67
3.23

0.13
15.2
9.32
17.7
18.4
5.57

2.0
22.0
19.7
29.3
22.3
15.9

0.25
45.0
40.6
84.1
40.9
24.4

0.5
188
144
310
168
84.5

0.75
243
307
389
200
125

1.0
223
325
372
171
112

Dose (mg/kg)
0.297
0.287
0.282
0.287
0.293

Vol. dosed (mL)
149
1.44
141
1.44
1.47

C_max(ng/mL)
243
325
389
200
125

t_max(hr)
0.75
1.0
2.75
0.75
0.75

t_1/2
ND²
ND³
ND²
ND²
ND²

MRT_last(hr)
0.684
0.732
0.683
0.670
0.689

AUC_last(hr · ng/mL)
145
161
237
122
71.4

AUC_∞(hr · ng/mL)
ND²
ND³
ND²
ND²
ND²

AUC_last/D
5.79
6.45
9.47
4.89
2.85

(hr · kg · ng/mL/mg)

AUC_∞/D
ND²
ND³
ND²
ND²
ND²

(hr · kg · ng/mL/mg)

1. Dose-normalized by dividing the parameter by the nominal dose in mg/kg.

²Not determined due to a lack of quantifiable data points trailing the Cmax.

³Not determined because the terminal elimination phase was not observed.

BLOQ = below the limit of quantitation (1 ng/mL)

TABLE VI

Animal number

Sample time (hr)
16
17
18
18
20

0.033
BLOQ
BLOQ
BLOQ
BLOQ
BLOQ

0.067
5.89
5.94
2.05
2.64
4.42

0.1
17.0
15.1
6.86
6.53
6.01

0.13
23.6
24.8
10.4
12.6
14.0

2.0
38.7
47.1
20.7
27.3
23.1

0.25
71.4
79.4
49.2
45.7
45.2

0.5
156
339
105
93.2
99.8

0.75
120
434
155
128
191

1.0
92.0
316
133
123
106

Dose (mg/kg)
0.293
0.284
0.297
0.293
0.287

Vol. dosed (mL)
1.47
1.42
1.49
1.47
1.44

C_max(ng/mL)
156
434
155
128
191

t_max(hr)
0.50
0.75
0.75
0.75
0.75

t_1/2
ND²
ND²
ND²
ND³
ND²

MRT_last(hr)
0.596
0.670
0.670
0.664
0.669

AUC_last(hr · ng/mL)
95.4
249
91.1
80.1
95.2

AUC_∞(hr · ng/mL)
ND²
ND²
ND²
ND³
ND²

AUC_last/D
3.82
9.98
3.64
3.20
3.81

(hr · kg · ng/mL/mg)

AUC_∞/D
ND²
ND²
ND²
ND³
ND²

(hr · kg · ng/mL/mg)

1. Dose-normalized by dividing the parameter by the nominal dose in mg/kg.

²Not determined due to a lack of quantifiable data points trailing the Cmax.

³Not determined because the terminal elimination phase was not observed.

BLOQ = below the limit of quantitation (1 ng/mL)

TABLE VII provides the mean and standard deviation for the results of Animals 11-20.

TABLE VII

Sample time (hr)
mean
SD

0.033
ND
ND

0.067
3.30
1.72

0.10
8.28
4.36

0.13
15.
6.13

0.20
26.6
9.56

0.25
52.6
19.2

0.50
169
89.3

0.75
229
113

1.0
197
105

Dose (mg/kg)
0.290
0.005

Vol. dosed (mL)
1.45
0.03

C_max(ng/mL)
235
111

t_max(hr)
0.75
0.12

t_1/2
ND
ND

MRT_last(hr)
0.673
0.0333

AUC_last(hr · ng/mL)
135
63.7

AUC_∞(hr · ng/mL)
ND
ND

AUC_last/D
5.39
2.55

(hr · kg · ng/mL/mg)

AUC_∞/D
ND
ND

(hr · kg · ng/mL/mg)

Individual and Average Plasma Concentrations (Ng/mL) and Pharmacokinetic Parameters for CBD after Oral Administration of the Composition of Table 7 at 25 mg/kg of CBD in Male Sprague-Dawley Rats (Group 3)

TABLE VIII

Animal number

Sample time (hr)
21
22
23
24
25

0.033
BOLQ
BOLQ
BOLQ
BOLQ
BOLQ

0.067
BOLQ
BOLQ
NS
BOLQ
BOLQ

0.1
0.72
BOLQ
BOLQ
BOLQ
BOLQ

0.13
1.15
BOLQ
0.597
BOLQ
BOLQ

2.0
2.55
0.516
1.61
0.918
1.66

0.25
3.25
0.884
2.60
1.71
3.56

0.5
5.44
2.15
9.37
13.8
20.5

0.75
12.2
6.08
11.8
24.3
28.9

1.0
16.1
7.19
15.2
31.3
32.6

Dose (mg/kg)
0.304
0.303
0.325
0.314
0.336

Vol. dosed (mL)
1.52
1.52
1.63
1.57
1.68

C_max(ng/mL)
16.1
7.19
15.2
31.3
32.6

t_max(hr)
1.0
1.0
1.0
1.0
1.0

t_1/2
ND²
ND²
ND²
ND²
ND²

MRT_last(hr)
0.719
0.752
0.701
0.747
0.716

AUC_last(hr · ng/mL)
7.16
3.12
7.71
13.7
17.1

AUC_∞(hr · ng/mL)
ND²
ND²
ND²
ND²
ND²

AUC_last/D
0.286
0.125
0.308
0.550
0.682

(hr · kg · ng/mL/mg)

AUC_∞/D
ND²
ND²
ND²
ND²
ND²

(hr · kg · ng/mL/mg)

1. Dose-normalized by dividing the parameter by the nominal dose in mg/kg.

²Not determined due to a lack of quantifiable data points trailing the Cmax.

³Not determined because the terminal elimination phase was not observed.

BLOQ = below the limit of quantitation (1 ng/mL)

TABLE IX

Animal number

Sample time (hr)
26
27
28
29
30

0.033
BOLQ
BOLQ
BOLQ
BOLQ
BOLQ

0.067
BOLQ
BOLQ
2.97
BOLQ
BOLQ

0.1
BOLQ
BOLQ
6.67
0.743
BOLQ

0.13
0.722
BOLQ
7.08
1.85
1.48

2.0
1.91
1.26
11.2
4.24
4346

0.25
2.99
2.48
14.4
6.97
7.60

0.5
7.86
13.3
18.0
16.4
33.7

0.75
16.5
28.9
42.9
16.5
38.4

1.0
15.3
35.8
26.6
21.8
39.1

Dose (mg/kg)
0.292
0.296
0.309
0.286
0287

Vol. dosed (mL)
1.46
1.48
1.55
1.43
1.44

C_max(ng/mL)
16.5
35.8
42.9
21.8
39.1

t_max(hr)
0.75
1.0
0.75
1.0
1.0

t_1/2
ND²
ND²
ND³
ND²
ND²

MRT_last(hr)
0.712
0754
0.652
0.663
0.682

AUC_last(hr · ng/mL)
8.60
15.5
22.0
12.4
24.4

AUC_∞(hr · ng/mL)
ND²
ND²
ND³
ND²
ND²

AUC_last/D
0.344
0.619
0.495
0.495
0.976

(hr · kg · ng/

mL/mg)

AUC_∞/D
ND²
ND²
ND³
ND²
ND²

(hr · kg · ng/

mL/mg)

1. Dose-normalized by dividing the parameter by the nominal dose in mg/kg.

²Not determined due to a lack of quantifiable data points trailing the Cmax.

³Not determined because the terminal elimination phase was not observed.

BLOQ = below the limit of quantitation (1 ng/mL)

TABLE X provides the mean and standard deviation for the results of Animals 21-30.

TABLE X

Sample time (hr)
mean
SD

0.033
ND
ND

0.067
ND
ND

0.10
2.72
3.42

0.13
2.20
2.44

0.20
3.03
3.15

0.25
4.64
4.04

0.50
14.1
8.98

0.75
22.6
12.1

1.0
24.1
10.6

Dose (mg/kg)
0.305
0.016

Vol. dosed (mL)
1.53
0.08

C_max(ng/mL)
25.8
12.0

t_max(hr)
0.95
0.11

t_1/2
ND
ND

MRT_last(hr)
0.710
0.0260

AUC_last(hr · ng/mL)
13.2
6.78

AUC_∞(hr · ng/mL)
ND
ND

AUC_last/D
0.527
0.271

(hr · kg · ng/mL/mg)

AUC_∞/D
ND
ND

(hr · kg · ng/mL/mg)

Individual and Average Plasma Concentrations (Ng/mL) and Pharmacokinetic Parameters for CBD after Oral Administration of the Composition of Table 8 at 25 mg/kg of CBD in Male Sprague-Dawley Rats (Group 4)

TABLE XI

Animal number

Sample time (hr)
31
32
33
34
35

0.033
BOLQ
BOLQ
BOLQ
BOLQ
1.19

0.067
4.23
2.41
3.98
2.98
8.71

0.1
8.33
4.62
3.67
6.36
18.2

0.13
15.0
5.90
8.09
13.7
27.2

2.0
23.1
9.06
11.9
26.7
32.2

0.25
38.0
12.6
20.7
36.4
32.2

0.5
16.1
31.0
34.0
63.0
90.5

0.75
15.1
46.5
56.9
113
151

1.0
47.6
50.8
46.5
154
155

Dose (mg/kg)
0.281
0.291
0.284
0.292
0.283

Vol. dosed (mL)
1.41
1.46
1.42
1.46
1.42

C_max(ng/mL)
47.6
50.8
56.9
154
155

t_max(hr)
1.0
1.0
0.75
1.0
1.0

t_1/2
ND²
ND²
ND³
ND²
ND²

MRT_last(hr)
0.595
0.683
0.658
0.703
0.685

AUC_last(hr · ng/mL)
37.0
28.7
33.0
71.3
88.8

AUC_∞(hr · ng/mL)
ND²
ND²
ND³
ND²
ND²

AUC_last/D
1.48
1.15
1.32
2.85
3.55

(hr · kg · ng/mL/mg)

AUC_∞/D
ND²
ND²
ND³
ND²
ND²

(hr · kg · ng/mL/mg)

1. Dose-normalized by dividing the parameter by the nominal dose in mg/kg.

²Not determined due to a lack of quantifiable data points trailing the Cmax.

³Not determined because the terminal elimination phase was not observed.

BLOQ = below the limit of quantitation (1 ng/mL)

TABLE XII

Animal number

Sample time (hr)
36
37
38
39
40

0.033
6.27
BOLQ
6.01
0.614
BOLQ

0.067
5.56
9.90
25.6
1.91
2.63

0.1
11.8
6.17
27.4
3.49
4.53

0.13
18.7
18.7
43.6
7.30
7.64

2.0
31.8
18.4
50.1
7.13
9.07

0.25
36.9
22.3
46.5
16.8
9.46

0.5
44.8
31.6
84.3
34.8
30.7

0.75
59.7
40.2
91.5
34.1
59.3

1.0
44.7
33.8
82.8
46.7
76.8

Dose (mg/kg)
0.279
0.267
0.287
0.284
0.279

Vol. dosed (mL)
1.40
1.34
1.44
1.42
1.40

C_max(ng/mL)
59.7
40.2
91.5
46.7
76.8

t_max(hr)
0.75
0.75
0.75
1.0
1.0

t_1/2
ND³
ND³
ND³
ND²
ND²

MRT_last(hr)
0.598
0.603
0.597
0.653
0.724

AUC_last(hr · ng/mL)
10.7
28.1
68.4
26.6
34.7

AUC_∞(hr · ng/mL)
ND³
ND³
ND³
ND²
ND²

AUC_last/D
1.63
1.12
2.74
1.06
1.39

(hr · kg · ng/mL/mg)

AUC_∞/D
ND³
ND³
ND³
ND²
ND²

(hr · kg · ng/mL/mg)

1. Dose-normalized by dividing the parameter by the nominal dose in mg/kg.

²Not determined due to a lack of quantifiable data points trailing the Cmax.

³Not determined because the terminal elimination phase was not observed.

BLOQ = below the limit of quantitation (1 ng/mL)

TABLE XIII provides the mean and standard deviation for the results of Animals 31-40.

TABLE XIII

Sample time (hr)
mean
SD

0.033
2.11
2.61

0.067
6.79
7.13

0.10
9.46
7.76

0.13
16.6
11.6

0.20
21.9
13.7

0.25
27.2
12.5

0.50
49.1
22.6

0.75
69.7
37.4

1.0
73.9
45.0

Dose (mg/kg)
0.283
0.007

Vol. dosed (mL)
1.42
0.03

C_max(ng/mL)
77.9
43.1

t_max(hr)
0.90
0.13

t_1/2
ND
ND

MRT_last(hr)
0.650
0.0488

AUC_last(hr · ng/mL)
45.7
22.0

AUC_∞(hr · ng/mL)
ND
ND

AUC_last/D
1.83
0.882

(hr · kg · ng/mL/mg)

AUC_∞/D
ND
ND

(hr · kg · ng/mL/mg)

Individual and Average Plasma Concentrations (Ng/mL) and Pharmacokinetic Parameters for CBD after Oral Administration of the Composition of Table 9 at 25 mg/kg of CBD in Male Sprague-Dawley Rats (Group 5)

TABLE XIV

Animal number

Sample time (hr)
41
42
43
44
45

0.033
BOLQ
0.521
1.59
BOLQ
BOLQ

0.067
4.50
5.30
8.02
3.11
5.35

0.1
16.5
14.1
17.5
3.14
9.37

0.13
20.7
19.3
26.4
5.72
20.1

2.0
521.0
39.5
56.5
9.71
37.5

0.25
31.7
55.0
61.0
14.5
45.6

0.5
72.9
92.3
81.4
63.8
101

0.75
84.1
116
93.2
42.2
102

1.0
77.8
114
93.1
68.3
127

Dose (mg/kg)
0.297
0.289
0.285
0.283
0.270

Vol. dosed (mL)
1.49
1.45
1.45
1.42
1.35

C_max(ng/mL)
84.1
116
93.2
68.3
127

t_max(hr)
0.75
0.75
0.75
1.0
1.0

t_1/2
ND²
ND³
ND³
ND³
ND³

MRT_last(hr)
0.639
0.640
0.607
0.657
0.647

AUC_last(hr · ng/mL)
56.7
78.5
70.0
38.3
77.2

AUC_∞(hr · ng/mL)
ND²
ND³
ND³
ND³
ND³

AUC_last/D
2.27
3.14
2.80
1.53
3.09

(hr · kg · ng/mL/mg

AUC_∞/D
ND²
ND³
ND³
ND³
ND³

(hr · kg · ng/mL/mg)

1. Dose-normalized by dividing the parameter by the nominal dose in mg/kg.

²Not determined due to a lack of quantifiable data points trailing the Cmax.

³Not determined because the terminal elimination phase was not observed.

BLOQ = below the limit of quantitation (1 ng/mL)

TABLE XV

Animal number

Sample time (hr)
46
47
48
49
50

0.033
2.34
BLOQ
BLOQ
0.950
3.04

0.067
8.58
3.37
1.26
4.25
17.1

0.1
14.2
5.85
3.18/
6.41
37.6

0.13
19.6
9.35
6.38
13.1
41.7

2.0
27.6
13.8
11.1
13.6
47.9

0.25
58.9
16.4
19.3
28.1
55.2

0.5
124
49.5
31.7
52.5
105

0.75
188
73.5
48.0
117
143

1.0
188
87.5
59.2
136
174

Dose (mg/kg)
0.274
0.288
0.283
0.278
0.277

Vol. dosed (mL)
1.37
1.44
1.42
1.39
1.39

C_max(ng/mL)
188
87.5
59.2
136
174

t_max(hr)
0.75
1.0
1.0
1.0
1.0

t_1/2
ND²
ND³
ND³
ND³
ND³

MRT_last(hr)
0.677
0.695
0.678
0.716
0.655

AUC_last(hr · ng/mL)
114
45.7
31.4
65.4
98.9

AUC_∞(hr · ng/mL)
ND²
ND³
ND³
ND³
ND³

AUC_last/D
4.55
1.53
1.25
2.62
3.95

(hr · kg · ng/mL/mg)

AUC_∞/D
ND²
ND³
ND³
ND³
ND³

(hr · kg · ng/mL/mg)

1. Dose-normalized by dividing the parameter by the nominal dose in mg/kg.

²Not determined due to a lack of quantifiable data points trailing the Cmax.

³Not determined because the terminal elimination phase was not observed.

BLOQ = below the limit of quantitation (1 ng/mL)

TABLE XVI provides the mean and standard deviation for the results of Animals 41-50.

TABLE XVI

Sample time (hr)
mean
SD

0.033
1.69
1.02

0.067
6.08
4.45

0.10
12.8
10.2

0.13
18.2
10.7

0.20
27.8
16.7

0.25
38.6
18.6

0.50
77.4
28.7

0.75
101
43.7

1.0
112
43.8

Dose (mg/kg)
0.282
0.008

Vol. dosed (mL)
1.42
0.04

C_max(ng/mL)
116
43.3

t_max(hr)
0.90
0.13

t_1/2
ND
ND

MRT_last(hr)
0.661
0.0312

AUC_last(hr · ng/mL)
67.6
269.0

AUC_∞(hr · ng/mL)
ND
ND

AUC_last/D
2.70
1.04

(hr · kg · ng/mL/mg)

AUC_∞/D
ND
ND

(hr · kg · ng/mL/mg)

A Summary of the Average Plasma Exposures for CBD after Oral Administration of the Compositions Disclosed in Tables 5 to 9 at 25 mg/kg of CBD in Male Sprague-Dawley Rats

TABLE XVII

Dose-normalized

AUC_last

Test
Cmax
t_max
AUC_last
(hr · kg · ng/

Group
Composition
(ng/mL)
(hr)
(hr · ng/mL)
mL/mg)

1
Table 5
112
0.83
64.6
2.58

2
Table 6
235
0.75
135
5.39

3
Table 7
25.8
0.95
13.2
0.527

4
Table 8
77.9
0.90
15.7
1.83

5
Table 9
113
0.90
67.6
2.70

A Summary of the Average Plasma Exposures for CBD after Oral Administration of the Composition Disclosed in Tables 5 to 9 at 25 mg/kg of CBD in Male Sprague-Dawley Rats

TABLE XVIII

Dose-normalized

AUC_last

Test
Cmax
t_max
AUC_last
(hr · kg · ng/

Group
Composition
(ng/mL)
(hr)
(hr · ng/mL)
mL/mg)

1
Table 5
112
0.83
64.6
2.58

2
Table 6
235
0.75
135
5.39

3
Table 7
25.8
0.95
13.2
0.527

4
Table 8
77.9
0.90
15.7
1.83

5
Table 9
113
0.90
67.6
2.70

Concentrations of CBD in Brain Tissue after Oral Administration of a Composition from Table 5 at 25 mg/kg of CBD in Male Sprague-Dawley Rats (Group 1)

TABLE XIX

Brain
Brain

homo-
homo-
Brain

Brain
genate
genate
tissue

Time
Anim
mass
volume
conc.
conc.
Mean
SD

(hr)
No.
(g)
(mL)
(ng/ml)
(ng/g)
(ng/g)
(ng/g)

8.0
1
1.85
5.55
14.1
42.3
46.8
12.3

2
1.92
5.76
17.2
51.6

3
1.86
5.58
22.0
66.0

4
1.89
5.67
12.0
36.0

5
1.66
4.98
12.7
38.1

24
6
1.94
5.82
0.946
2.84
2.49
0.804

7
1.87
5.61
0.625
1.88

8
1.88
5.64
0.781
2.34

9
1.82
5.46
0.566
1.70

10
1.82
5.46
1.23
3.69

Concentrations of CBD in Brain Tissue after Oral Administration of the Composition of Table 6 at 25 mg/kg of CBD in Male Sprague-Dawley Rats (Group 2)

TABLE XX

Brain
Brain

homo-
homo-
Brain

Brain
genate
genate
tissue

Time
Anim
mass
volume
conc.
conc.
Mean
SD

(hr)
No.
(g)
(mL)
(ng/ml)
(ng/g)
(ng/g)
(ng/g)

8.0
21
1.88
5.64
48.8
146
275
155

22
1.82
5.46
130
390

23
1.77
5.31
38.1
114

24
1.88
5.64
93.6
251

25
1.78
5.34
158
474

24
26
1.92
5.76
2.78
8.34
6.21
2.00

27
1.69
5.07
2.21
6.63

28
1.92
5.76
2.48
7.44

29
1.86
5.58
1.82
5.46

30
1.84
5.52
1.06
3.18

Concentrations of CBD in Brain Tissue after Oral Administration of the Composition of Table 7 at 25 mg/kg of CBD in Male Sprague-Dawley Rats (Group 3)

TABLE XXI

Brain
Brain

homo-
homo-
Brain

Brain
genate
genate
tissue

Time
Anim
mass
volume
conc.
conc.
Mean
SD

(hr)
No.
(g)
(mL)
(ng/ml)
(ng/g)
(ng/g)
(ng/g)

8.0
41
1.94
5.82
3.36
10.1
13.5
9.11

42
1.92
5.76
3.32
10.0

43
2.04
6.12
1.77
5.31

44
1.86
5.58
4.46
13.4

45
2.12
6.36
9.67
29.0

24
46
1.74
5.22
BLOQ
ND
ND
ND

47
1.94
5.82
BLOQ
ND

48
1.92
5.76
BLOQ
ND

49
1.84
5.52
BLOQ
ND

50
1.99
5.97
BLOQ
ND

Concentrations of CBD in Brain Tissue after Oral Administration the Composition from Table 8 at 25 mg/kg of CBD in Male Sprague-Dawley Rats (Group 5)

TABLE XXII

Brain
Brain

homo-
homo-
Brain

Brain
genate
genate
tissue

Time
Anim
mass
volume
conc.
conc.
Mean
SD

(hr)
No.
(g)
(mL)
(ng/ml)
(ng/g)
(ng/g)
(ng/g)

8.0
61
1.87
5.61
31.9
95.7
167
115

62
1.95
5.85
77.7
233

63
1.90
5.70
113
339

64
1.88
5.64
22.6
67.8

65
1.84
5.52
33.7
101

24
66
1.78
5.34
1.17
3.51
2.78
1.00

67
1.87
5.61
1.76
5.28

68
1.73
5.19
1.21
3.63

69
1.81
5.43
1.33
3.99

70
1.74
5.22
0.834
2.50

Concentrations of CBD in Brain Tissue after Oral Administration of the Composition of Table 59 at 25 mg/kg of CBD in Male Sprague-Dawley Rats (Group 5)

TABLE XXIII

Brain
Brain

homo-
homo-
Brain

Brain
genate
genate
tissue

Time
Anim
mass
volume
conc.
conc.
Mean
SD

(hr)
No.
(g)
(mL)
(ng/ml)
(ng/g)
(ng/g)
(ng/g)

8.0
71
1.79
5.37
38.9
117
142
38.3

72
4.91
5.73
42.9
129

73
1.94
5.82
70.1
210

74
1.74
5.22
42.2
127

75
1.79
5.37
43.2
130

24
76
1.86
5.58
1.94
5.82
5.33
0.703

77
2.04
6.12
1.62
4.86

78
1.94
5.82
1.78
5.34

79
1.94
5.82
1.48
4.44

80
1.92
5.76
2.06
6.18

This study is more comprehensive than the study conducted above and many types of analysis are performed including 24-hour ambulatory blood pressure (which is the primary outcome); arterial stiffness and autonomic balance; brain structure and function through brain magnetic resonance imaging (“MRI”); blood biomarkers (including lipids such as cholesterol and more); renal, hepatic, sleep quality/daytime sleepiness/sleep disorders; actigraphy, geriatric depression scale, perceived stress, and Beck anxiety inventory.

Preparation of Compositions

The disclosed oral solid compositions can be prepared by conventional methods of blending, filling or tableting. The blending operation can be repeated to distribute the active principle throughout compositions containing large quantities of adjunct ingredients. Such operations are conventional.

The disclosed base compositions can be prepared by the following general procedure. CBD oil is combined with sunflower oil in a vessel with adequate stirring. The amount of each ingredient varies depending upon the formulator's choice of the ratio of the CBD-oil and sunflower oil, i.e., the ratio of nicotine-containing ingredient to sunflower oil is from about 1:1 to about 1:3. The choice of ratio will also dictate the relative amounts of adjunct ingredients that are added. With stirring, CBD oil/sunflower oil admixture is then slowly heated to from about 50° C. to about 75° C., again predicated on the ratio of ingredients and the choice of excipients. The final raw ingredient admixture is then rendered homogeneous then dehydrated. The dehydration process used can be determined by the formulator.

APPENDIX

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PHARMACEUTICAL COMPOSITIONS AND METHODS FOR TREATING HYPERTENSION

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