CN117062606A - Compositions and methods comprising cannabis extracts for treating animals in need thereof - Google Patents

Compositions and methods comprising cannabis extracts for treating animals in need thereof Download PDF

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Publication number
CN117062606A
CN117062606A CN202280024699.8A CN202280024699A CN117062606A CN 117062606 A CN117062606 A CN 117062606A CN 202280024699 A CN202280024699 A CN 202280024699A CN 117062606 A CN117062606 A CN 117062606A
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China
Prior art keywords
cannabis extract
dosage form
cannabis
cannabidiol
cbd
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CN202280024699.8A
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Chinese (zh)
Inventor
J·瓦克什拉格
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Portland Technology Holding Co ltd
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Portland Technology Holding Co ltd
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Priority claimed from PCT/US2022/070630 external-priority patent/WO2022174255A1/en
Publication of CN117062606A publication Critical patent/CN117062606A/en
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Abstract

The present disclosure relates to non-naturally occurring or engineered compositions and methods comprising one or more cannabis extracts for use in treating a disease, disorder, syndrome, and/or condition in an animal in need thereof.

Description

Compositions and methods comprising cannabis extracts for treating animals in need thereof
Technical Field
The present disclosure relates to non-naturally occurring or engineered compositions and methods comprising one or more cannabis extracts for use in treating a disease, disorder, syndrome, and/or condition in an animal in need thereof.
Background
Industrial cannabis products containing 0.3% or less Tetrahydrocannabinol (THC) are legal according to the industrial cannabis act. These products are reported to have health benefits, including analgesics, anxiolytics, anti-inflammatory agents, anxiolytics and antiepileptics, alone or in combination with other Cannabinoids (CBD). There are many companies selling cannabis products containing CBD oil that claim to be safe and effective for a variety of medical conditions in humans and animals. Other potentially effective agents, such as CBD, are often sought without optimal treatment with traditional agents for patients in need thereof. However, there is little published data to support the safety and effectiveness claims of using these products in human and veterinary patients.
Thus, there is a need for safer and more targeted cannabis products.
Disclosure of Invention
In one aspect, the presently disclosed technology relates to a method for treating a recurrent diarrhea disease in a veterinary subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of cannabis extract. In some embodiments, the veterinary subject is a primate. In some embodiments, the primate is a non-human primate. In some embodiments, the non-human primate is a cynomolgus monkey. In some embodiments, the recurrent diarrhea disease is a idiopathic diarrhea disease. In some embodiments, the cannabis extract is administered orally. In some embodiments, the cannabis extract is applied in the form of a chew, marshmallow, fudge, or by syringe. In some embodiments, the cannabis extract is administered at a dose of about 2mg/kg, about 4mg/kg, or about 8 mg/kg. In some embodiments, the cannabis extract is administered until the fecal score of the veterinary subject is less than or equal to 2 for 3 days or for 21 days. In some embodiments, the cannabis extract is administered once a day, twice a day, three times a day, or four times a day.
In another aspect, the presently disclosed technology relates to a method for treating inflammation in a veterinary subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of cannabis extract. In some embodiments, the animal is a dog. In some embodiments, the cannabis extract comprises CBD, CBDA, or a combination thereof. In some embodiments, the cannabis extract modulates neutrophil function, production of reactive oxygen species, phagocytosis, eicosanoid concentration, chemotaxis, cytokine production, and/or fibroblast response. In some embodiments, these modulations are measured using an in vitro assay using a sample from the veterinary subject. In some embodiments, these modulations occur in vivo, and optionally are measured in vivo.
In another aspect, the presently disclosed technology relates to a method for treating noise aversion to a veterinary subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of cannabis extract. In some embodiments, the veterinary subject is a dog. In some embodiments, the noise aversion is a phobia. In some embodiments, the phobia is a storm phobia or a noise phobia. In some embodiments, the noise aversion is to fireworks or thunderstorms. In some embodiments, the cannabis extract is administered at a dose of 2mg/kg to 10 mg/kg. In some embodiments, the cannabis extract is administered at a dose of 4mg/kg to 10 mg/kg.
In another aspect, the presently disclosed technology relates to a method for treating dehairing of a veterinary subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of cannabis extract. In some embodiments, the veterinary subject is a bird. In some embodiments, the cannabis extract comprises CBD, CBDA, or a combination thereof. In some embodiments, the cannabis extract comprises 70mg/mL total cannabinoids. In some embodiments, the cannabis extract comprises 60mg/mL CBD and CBDA. In some embodiments, the cannabis extract is administered twice daily at a dose of 15mg/kg for three months. In some embodiments, the cannabis extract is administered at a dose of 30mg/kg to 120mg/kg twice daily for three months. In some embodiments, the cannabis extract is administered at a dose of 40mg/kg to 80mg/kg twice daily for three months. In some embodiments, the cannabis extract is administered twice daily at a dose of 30mg/kg for three months. In some embodiments, the cannabis extract is administered twice daily at a dose of 60mg/kg for three months. In some embodiments, the cannabis extract is administered twice daily at a dose of 120mg/kg for three months.
In another aspect, the presently disclosed technology relates to a method for treating arthritis in a veterinary subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of cannabis extract. In some embodiments, the veterinary subject is a rabbit. In some embodiments, the cannabis extract comprises CBD, CBDA, or a combination thereof. In some embodiments, the cannabis extract is administered at a dose of 10mg/kg to 25 mg/kg. In some embodiments, the cannabis extract is administered at a dose of about 15 mg/kg. In some embodiments, the cannabis extract is administered at a dose of about 20 mg/kg. In some embodiments, the cannabis extract is administered twice daily.
In another aspect, the presently disclosed technology relates to a method for treating lameness in a veterinary subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of cannabis extract. In some embodiments, the veterinary subject is a horse. In some embodiments, the cannabis extract comprises CBD, CBDA, or a combination thereof. In some embodiments, the cannabis extract is administered every 12 hours at a dose of 1 mg/kg. In some embodiments, the cannabis extract is administered at an acute dose of 2mg/kg to 8 mg/kg.
In another aspect, the presently disclosed technology relates to a method for promoting wound healing in a veterinary subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of cannabis extract. In some embodiments, the cannabis extract is topically applied. In some embodiments, the veterinary subject is a dog. In some embodiments, the cannabis extract comprises CBG and CBGA. In some embodiments, 20mg CBG and CBGA are applied to the wound. In some embodiments, the CBG and CBGA are applied to the wound every 12 hours.
In another aspect, the presently disclosed technology relates to a method for treating cancer in a veterinary subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of cannabis extract. In some embodiments, the veterinary subject is a dog. In some embodiments, the cannabis extract comprises CBD, CBDA, or a combination thereof. In some embodiments, the cannabis extract is administered at a dose of 5 mg/kg.
In another aspect, the presently disclosed technology relates to a method for treating sepsis in a veterinary subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of cannabis extract. In some embodiments, the cannabis extract is topically applied. In some embodiments, the veterinary subject is a dog. In some embodiments, the cannabis extract comprises CBD and CBG. In some embodiments, 30mg CBD and CBG are applied to the site of sepsis. In some embodiments, 35mg CBD and CBG are applied to the site of sepsis. In some embodiments, 40mg CBD and CBG are applied to the site of sepsis. In some embodiments, 45mg CBD and CBG are applied to the site of sepsis. In some embodiments, 50mg CBD and CBG are applied to the site of sepsis. In some embodiments, 30mg to 50mg CBD and CBG are applied to the site of the pyoderma. In some embodiments, the CBD and CBG are applied every 12 hours to the site of the pyoderma.
In another aspect, the presently disclosed technology relates to a method for treating atopy in a veterinary subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of cannabis extract. In some embodiments, the veterinary subject is a dog. In some embodiments, the cannabis extract comprises CBD and CBDA. In some embodiments, the cannabis extract is administered orally. In some embodiments, the cannabis extract is administered by capsule. In some embodiments, the cannabis extract comprises CBD and CBDA, and the cannabis extract is administered such that a dose of about 2mg/kg of CBD and CBDA is administered. In some embodiments, the cannabis extract is administered once every 12 hours.
In another aspect, the presently disclosed technology relates to a method for treating itch in a veterinary subject in need thereof, said method comprising administering to said subject a therapeutically effective amount of cannabis extract. In some embodiments, the veterinary subject is a dog. In some embodiments, the cannabis extract comprises CBD and CBDA. In some embodiments, the cannabis extract is administered orally. In some embodiments, the cannabis extract is administered by capsule. In some embodiments, the cannabis extract comprises CBD and CBDA, and the cannabis extract is administered such that a dose of about 2mg/kg of CBD and CBDA is administered. In some embodiments, the cannabis extract is administered once every 12 hours.
In another aspect, the presently disclosed technology relates to a method for treating a neurological condition in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of cannabis extract. In some embodiments, the subject is a human. In some embodiments, the subject is a veterinary subject. In some embodiments, the neurological condition includes traumatic nerve injury or degenerative nerve disease (e.g., proteopathy), such as ALS, parkinson's disease, dementia, or Alzheimer's disease. In some embodiments, the cannabis extract comprises tetrahydrocannabinolic acid (THCA).
In some embodiments, the cannabis extract comprises cannabidiol and cannabidiol, wherein the ratio of cannabidiol to cannabidiol is about 0.6:1 to about 1:0.6. In some embodiments, the cannabis extract further comprises cannabigerol acid, Δ9-tetrahydrocannabinol, and cannabidene. In some embodiments, the cannabis extract further comprises THCA.
In some embodiments, the cannabis extract comprises:
cannabidiol;
cannabidiol;
Cannabigerol acid;
Δ9-tetrahydrocannabinol; and
cannabichromene;
wherein the ratio of cannabidiol to cannabidiol is from about 0.6:1 to about 1:0.6.
In some embodiments, the cannabis extract further comprises:
alpha-pinene;
beta-myrcene;
beta-pinene;
delta-limonene;
linalool;
beta-caryophyllene;
alpha-lupulin;
nerolidol 2;
guaifenesin;
a caryophyllene oxide; and
alpha-bisabolol.
In some embodiments, the concentration of Δ9-tetrahydrocannabinol is insufficient to produce a psychotropic effect. In some embodiments, the ratio of Δ9-tetrahydrocannabinol to other cannabinoids is about 1:25. In some embodiments, the concentration of Δ9-tetrahydrocannabinol is less than about 1mg/mL. In some embodiments, the concentration of Δ9-tetrahydrocannabinol is less than about 0.5mg/mL. In some embodiments, the concentration of Δ9-tetrahydrocannabinol is less than about 0.3mg/mL. In some embodiments, the concentration of Δ9-tetrahydrocannabinol is less than about 0.2mg/mL. In some embodiments, the concentration of Δ9-tetrahydrocannabinol is less than about 0.1mg/mL. In some embodiments, the concentration of Δ9-tetrahydrocannabinol is about 0mg/mL. In some embodiments, the cannabis extract further comprises THCA.
In some embodiments, the cannabis extract comprises:
about 1-10mg/mL cannabidiol;
about 1-10mg/mL cannabidiol;
about 0.05-0.2mg/mL cannabigerol acid;
about 0.1-0.3mg/mL of Δ9-tetrahydrocannabinol; and
about 0.1-0.4mg/mL cannabigerol.
In some embodiments, the cannabis extract comprises:
about 5mg/mL cannabidiol;
about 5mg/mL cannabidiol;
about 0.11mg/mL cannabigerol acid;
about 0.25mg/mL of Δ9-tetrahydrocannabinol; and
about 0.27mg/mL cannabigerol.
In some embodiments, the cannabis extract comprises:
about 0.09% to about 0.13% α -pinene;
about 0.23% to about 0.44% of beta-myrcene;
about 0.04-0.09% beta-pinene;
about 0.05-0.09% delta-limonene;
about 0.03% to about 0.06% linalool;
about 0.04-0.07% beta-caryophyllene;
about 0.02-0.04% of alpha-lupulin;
about.04% to about 0.07% nerolidol 2;
about 0.04% to about 0.08% caryophyllene oxide; and
about 0.01-0.04% alpha-bisabolol.
In some embodiments, the cannabis extract further comprises:
camphene;
beta-ocimene;
eucalyptol;
isopulegol; and/or
Nerolidol 1.
In some embodiments, the cannabis extract further comprises THCA.
In some embodiments, the cannabis extract comprises:
about 0.02% camphene;
about 0.02% to about 0.03% of beta-ocimene;
from about 0.02% to about 0.05% eucalyptol;
about 0.02% isopulegol; and/or
About 0.02-0.04% nerolidol 1.
In some embodiments, the cannabis extract further comprises THCA.
In some embodiments, the cannabis extract is formulated in a carrier. In some embodiments, the carrier is selected from the group consisting of: hemp seed oil, linseed oil, olive oil, fish oil, salmon oil, coconut oil, catmint oil, sesame oil, MCT oil and grape seed oil. In some embodiments, the carrier is grape seed oil. In some embodiments, the carrier is catmint oil. In some embodiments, the carrier is sesame oil. In some embodiments, the cannabis extract comprises lecithin. In some embodiments, the lecithin is sunflower lecithin. In some embodiments, the sunflower lecithin comprises up to 40%. In some embodiments, the cannabis extract further comprises NF-971P. In some embodiments, the weight/volume ratio of NF-971P is at most 2%. In some embodiments, the cannabis extract comprises nepetalactone. In some embodiments, the cannabis extract comprises taurine.
In some embodiments, the cannabis extract comprises:
cannabidiol;
cannabidiol;
cannabigerol acid;
Δ9-tetrahydrocannabinol; and
cannabichromene;
wherein the carrier is grape seed oil.
In some embodiments, the cannabis extract comprises:
cannabidiol;
cannabidiol;
cannabigerol acid;
cannabigerol;
Δ9-tetrahydrocannabinol; and
cannabichromene;
wherein the carrier is grape seed oil.
In some embodiments, the ratio of cannabidiol to cannabidiol is selected from the group consisting of: about 1:100, about 1:50, about 1:10, and about 1:1. In some embodiments, the ratio of cannabidiol to cannabidiol is about 1:1. In some embodiments, the concentration of Δ9-tetrahydrocannabinol is insufficient to produce a psychotropic effect. In some embodiments, the ratio of Δ9-tetrahydrocannabinol to other cannabinoids is about 1:25. In some embodiments, the concentration of Δ9-tetrahydrocannabinol is less than about 1mg/mL. In some embodiments, the concentration of Δ9-tetrahydrocannabinol is less than about 0.5mg/mL. In some embodiments, the concentration of Δ9-tetrahydrocannabinol is less than about 0.3mg/mL. In some embodiments, the cannabis extract further comprises THCA.
In some embodiments, the cannabis extract comprises:
about 1-10mg/mL cannabidiol;
about 1-10mg/mL cannabidiol;
about 0.05-0.2mg/mL cannabigerol acid;
about 0.1-0.3mg/mL of Δ9-tetrahydrocannabinol; and
about 0.1-0.4mg/mL cannabigerol.
In some embodiments, the cannabis extract comprises:
about 5mg/mL cannabidiol;
about 5mg/mL cannabidiol;
about 0.11mg/mL cannabigerol acid;
about 0.25mg/mL of Δ9-tetrahydrocannabinol; and
about 0.27mg/mL cannabigerol.
In some embodiments, the cannabis extract comprises:
about 1-10mg/mL cannabidiol;
about 1-10mg/mL cannabidiol;
about 0.05-0.2mg/mL cannabigerol acid;
cannabigerol;
about 0.1-0.3mg/mL of Δ9-tetrahydrocannabinol; and
about 0.1-0.4mg/mL cannabigerol.
In some embodiments, the cannabis extract comprises:
about 5mg/mL cannabidiol;
about 5mg/mL cannabidiol;
cannabigerol;
about 0.11mg/mL cannabigerol acid;
about 0.25mg/mL of Δ9-tetrahydrocannabinol; and
about 0.27mg/mL cannabigerol.
In some embodiments, the cannabis extract comprises:
alpha-pinene;
Beta-myrcene;
beta-pinene;
delta-limonene;
linalool;
beta-caryophyllene;
alpha-lupulin;
nerolidol 2;
guaifenesin;
a caryophyllene oxide; and
alpha-bisabolol.
In some embodiments, the cannabis extract comprises:
about 0.09% to about 0.13% α -pinene;
about 0.23% to about 0.44% of beta-myrcene;
about 0.04-0.09% beta-pinene;
about 0.05-0.09% delta-limonene;
about 0.03% to about 0.06% linalool;
about 0.04-0.07% beta-caryophyllene;
about 0.02-0.04% of alpha-lupulin;
about 0.04-0.07% nerolidol 2;
about 0.02% to about 0.04% guaifenesin;
about 0.04% to about 0.08% caryophyllene oxide; and
about 0.01-0.04% alpha-bisabolol.
In some embodiments, the cannabis extract further comprises:
camphene;
beta-ocimene;
eucalyptol;
isopulegol; and/or
Nerolidol 1
In some embodiments, the cannabis extract comprises:
about 0.02% camphene;
about 0.02% to about 0.03% of beta-ocimene;
from about 0.02% to about 0.05% eucalyptol;
about 0.02% isopulegol; and/or
About 0.02-0.04% nerolidol 1.
In some embodiments, the cannabis extract is administered in a dosage form comprising: one or more pharmaceutically acceptable additives, flavoring agents, surfactants and adjuvants. In some embodiments, the flavoring agent is selected from the group consisting of: peppermint oil, mango extract, beef, poultry and seafood. In some embodiments, the flavoring agent is selected from the group consisting of: peanut butter, catmint oil, chicken liver powder, poultry meat extract, maltodextrin, butter and bacon. In some embodiments, the flavoring agent is chicken liver powder. In some embodiments, the flavoring agent is catmint oil. In some embodiments, the flavoring agent is molasses or dry molasses. In some embodiments, the flavoring agent is peanut butter. In some embodiments, the dosage form comprises nepetalactone. In some embodiments, the dosage form comprises taurine. In some embodiments, the dosage form is formulated as a sublingual spray. In some embodiments, the dosage form is formulated as a water, polyethylene glycol, glycerol, or alcohol soluble solution or cream for topical or transdermal application. In some embodiments, the dosage form is formulated as a gel for buccal or mucosal administration. In some embodiments, the dosage form is formulated as a paste for buccal or mucosal administration. In some embodiments, the dosage form is formulated as a powder. In some embodiments, the dosage form is formulated as a solution for subcutaneous injection. In some embodiments, the dosage form is formulated as a tablet. In some embodiments, the dosage form is formulated as a capsule. In some embodiments, the dosage form is formulated as a hard chewable. In some embodiments, the dosage form is formulated as a soft chewable. In some embodiments, the dosage form is formulated for administration using a nebulizer. In some embodiments, the dosage form is formulated for inhalation. In some embodiments, the dosage form is formulated for administration using a pet collar. In some embodiments, the composition is formulated as an edible product for oral administration. In some embodiments, the edible product comprises a pet food.
In some embodiments, the dosage form is formulated as a chew for oral administration. In some embodiments, the chew is produced using cold extrusion. In some embodiments, the chew weighs between about 0.5 and 10g. In some embodiments, the chew weighs about 4g, about 6g, about 9g, or about 10g. In some embodiments, the chew weighs about 4g.
In some embodiments, the chew comprises:
about 7mg cannabidiol;
about 6mg cannabidiol;
about 0.12mg cannabigerol acid;
about 0.32mg Δ9-tetrahydrocannabinol; and
about 0.36mg cannabigerol.
In some embodiments, the chew further comprises THCA.
In some embodiments, the dosage form is formulated in a carrier for oral administration. In some embodiments, the carrier is selected from the group consisting of: hemp seed oil, linseed oil, olive oil, fish oil, salmon oil, coconut oil, catmint oil, sesame oil, MCT oil and grape seed oil. In some embodiments, the carrier is grape seed oil. In some embodiments, the carrier is catmint oil. In some embodiments, the carrier is sesame oil.
In some embodiments, the dosage form comprises:
HCl glucosamine;
chondroitin sulfate (76%);
beer yeast;
acacia gum;
guar gum;
a flavoring agent;
Verdilox；
Previon；
cannabis sativa extract;
glycerol;
sunflower lecithin; and
and (3) water.
In some embodiments, the dosage form comprises:
about 12-17% HCl glucosamine;
about 1-4% chondroitin sulfate (76%);
about 29-33% brewer's yeast;
about 3-6% acacia;
about 0.5-2% guar gum;
about 12-16% flavoring agent;
about 0.01% to about 0.1% Verdilox;
about 0.5-1.5% Previon;
about 3-6% cannabis extract;
about 13-17% glycerol;
about 3-7% sunflower lecithin; and
about 3-7% water.
In some embodiments, the dosage form comprises:
about 15.6% HCl glucosamine;
about 2.6% chondroitin sulfate (76%);
about 30% brewer's yeast;
about 4.7% acacia;
about 0.9% guar gum;
about 14.2% flavoring agent;
about 0.05% Verdilox;
about 0.9% Previon;
about 4.7% cannabis extract;
about 15.1% glycerol;
about 5.7% sunflower lecithin; and
about 5.7% water.
In some embodiments, the dosage form comprises:
HCl glucosamine;
Hyaluronic acid;
beer yeast;
acacia gum;
guar gum;
a flavoring agent;
Verdilox；
Previon；
cannabis sativa extract;
glycerol;
sunflower lecithin; and
and (3) water.
In some embodiments, the dosage form comprises:
about 12-17% HCl glucosamine;
about 0.01-1% hyaluronic acid;
about 29-33% brewer's yeast;
about 3-6% acacia;
about 0.5-2% guar gum;
about 12-16% flavoring agent;
about 0.01% to about 0.1% Verdilox;
about 0.5-1.5% Previon;
about 3-6% cannabis extract;
about 13-17% glycerol;
about 3-7% sunflower lecithin; and about 3-7% water.
In some embodiments, the dosage form comprises:
about 16% HCl glucosamine;
about 0.1% hyaluronic acid;
about 30.6% brewer's yeast;
about 4.8% acacia;
about 0.97% guar gum;
about 14.5% flavoring agent;
about 0.05% Verdilox;
about 0.97% Previon;
about 4.8% cannabis extract;
about 15.5% glycerol;
about 5.8% sunflower lecithin; and about 5.8% water.
In some embodiments, the dosage form comprises:
cannabis sativa extract;
peanut butter;
rice bran;
HCl glucosamine;
sweet potato;
Dry molasses;
sorbic acid;
beer yeast;
sugar;
water;
glycerol;
potato starch;
dehydrated peanut butter;
rice starch; and
guar gum.
In some embodiments, the dosage form comprises:
about 3.0-10.0% cannabis extract;
about 10.0-20.0% peanut butter;
about 10.0% to about 15.0% rice bran;
about 5.0% to about 15.0% HCl glucosamine; about 4.0-10.0% sweet potato;
about 6.0% to about 13.0% dry molasses;
about 0.5-5.0% sorbic acid;
about 2.0-8.0% brewer's yeast;
about 3.0-8.0% sugar;
about 5.0% to about 15.0% water;
about 8.0% to about 18.0% glycerol;
about 1.0% to about 8.0% potato starch;
about 0.5% to about 5.0% dehydrated peanut butter;
about 1.0% to about 5.0% rice starch; and about 1.0-5.0% guar gum.
In some embodiments, the dosage form comprises:
about 5.0% cannabis extract;
about 15.0% peanut butter;
about 12.5% rice bran;
about 12.75% HCl glucosamine;
about 5.5% sweet potato;
about 8.0% dry molasses;
about 1% sorbic acid;
about 5.0% brewer's yeast;
about 6.0% sugar;
about 9.25% water;
about 13.0% glycerol;
about 2.0% potato starch;
about 1.0% dehydrated peanut butter;
about 2.0% rice starch; and
About 2.0% guar gum.
In some embodiments, the dosage form comprises: about 5.0% cannabis extract;
about 15.0% peanut butter;
about 13.0% rice bran;
about 8.5% HCl glucosamine;
about 6.0% sweet potato;
about 9.0% dry molasses;
about 1% sorbic acid;
about 5.0% brewer's yeast;
about 6.0% sugar;
about 9.5% water;
about 13.0% glycerol;
about 4.0% potato starch;
about 1.0% dehydrated peanut butter;
about 2.0% rice starch; and
about 2.0% guar gum.
In some embodiments, the dosage form comprises:
cannabis sativa extract;
peanut butter;
rice bran;
HCl glucosamine;
sweet potato;
dry molasses;
sorbic acid;
beer yeast;
sugar;
water;
glycerol;
potato starch;
dehydrated peanut butter;
DigestaWell PET；
rice starch; and
guar gum.
In some embodiments, the dosage form comprises:
about 3.0-10.0% cannabis extract;
about 5.0% to about 20.0% peanut butter;
about 10.0% to about 15.0% rice bran;
about 5.0% to about 15.0% HCl glucosamine; about 4.0-10.0% sweet potato;
about 6.0% to about 13.0% dry molasses;
about 0.5-5.0% sorbic acid;
about 2.0-8.0% brewer's yeast;
about 3.0-8.0% sugar;
About 5.0% to about 15.0% water;
about 8.0% to about 18.0% glycerol;
about 1.0% to about 8.0% potato starch;
about 0.5% to about 5.0% dehydrated peanut butter;
about 0.1-3.0% DigestaWell PET; about 1.0% to about 8.0% rice starch; and about 1.0-5.0% guar gum.
In some embodiments, the dosage form comprises:
about 5.0% cannabis extract;
about 10.0% peanut butter;
about 12.0% rice bran;
about 12.75% HCl glucosamine;
about 5.5% sweet potato;
about 8.0% dry molasses;
about 1% sorbic acid;
about 5.0% brewer's yeast;
about 6.0% sugar;
about 7.25% water;
about 10.0% glycerol;
about 5.0% potato starch;
about 4.0% dehydrated peanut butter;
about 0.5% DigestaWell PET;
about 6.0% rice starch; and
about 2.0% guar gum.
In some embodiments, the dosage form comprises: about 5.0% cannabis extract;
about 10.0% peanut butter;
about 12.5% rice bran;
about 8.5% HCl glucosamine;
about 8.0% sweet potato;
about 9.0% dry molasses;
about 1% sorbic acid;
about 5.0% brewer's yeast;
about 6.0% sugar;
about 6.0% water;
about 10.0% glycerol;
about 6.0% potato starch;
About 4.0% dehydrated peanut butter;
about 0.5% DigestaWell PET;
about 6.5% rice starch; and
about 2.0% guar gum.
In some embodiments, the dosage form comprises:
cannabis sativa extract;
peanut butter;
rice bran;
HCl glucosamine;
sweet potato;
dry molasses;
sorbic acid;
beer yeast;
sugar;
water;
glycerol;
potato starch;
dehydrated peanut butter;
chondroitin;
DigestaWell PET；
rice starch; and
guar gum.
In some embodiments, the dosage form comprises:
about 3.0-10.0% cannabis extract;
about 5.0% to about 20.0% peanut butter;
about 10.0% to about 15.0% rice bran;
about 5.0% to about 15.0% HCl glucosamine; about 4.0-10.0% sweet potato;
about 6.0% to about 13.0% dry molasses;
about 0.5-5.0% sorbic acid;
about 2.0-8.0% brewer's yeast;
about 3.0-8.0% sugar;
about 5.0% to about 15.0% water;
about 8.0% to about 18.0% glycerol;
about 1.0% to about 8.0% potato starch;
about 0.5% to about 5.0% dehydrated peanut butter;
about 0.5-5.0% chondroitin;
about 0.1-3.0% DigestaWell PET; about 1.0% to about 8.0% rice starch; and about 1.0-5.0% guar gum.
In some embodiments, the dosage form comprises:
about 5.0% cannabis extract;
About 10.0% peanut butter;
about 12.0% rice bran;
about 12.75% HCl glucosamine;
about 5.5% sweet potato;
about 8.0% dry molasses;
about 1% sorbic acid;
about 5.0% brewer's yeast;
about 6.0% sugar;
about 7.25% water;
about 10.0% glycerol;
about 4.0% potato starch;
about 4.0% dehydrated peanut butter;
about 2.5% chondroitin;
about 0.5% DigestaWell PET;
about 4.5% rice starch; and
about 2.0% guar gum.
In some embodiments, the dosage form comprises:
about 5.0% cannabis extract;
about 10.0% peanut butter;
about 12.5% rice bran;
about 8.5% HCl glucosamine;
about 8.0% sweet potato;
about 9.0% dry molasses;
about 1% sorbic acid;
about 5.0% brewer's yeast;
about 6.0% sugar;
about 6.0% water;
about 10.0% glycerol;
about 5.0% potato starch;
about 4.0% dehydrated peanut butter;
about 2.5% chondroitin;
about 0.5% DigestaWell PET;
about 5.0% rice starch; and
about 2.0% guar gum.
In some embodiments, the cannabis extract, dosage form, or pharmaceutical composition is packaged to provide one or more doses of cannabis extract per package. In some embodiments, the package is resealable. In some embodiments, one dose of cannabis extract is a therapeutically effective amount.
Drawings
Aspects, features, benefits and advantages of the embodiments described herein will become apparent with regard to the following description, appended claims and accompanying drawings, in which:
FIG. 1A is a graph showing a 48-hour MTT proliferation assay for cannabinoid treatment performed with Cannabidiol (CBD) in accordance with an embodiment of the present teachings;
FIG. 1B shows a graph of a 48-hour MTT proliferation assay for cannabinoid treatment performed with Cannabidiol (CBDA) in accordance with an embodiment of the present teachings;
FIG. 1C shows a graph of a 48-hour MTT proliferation assay of cannabinoid treatment performed with a whole plant cannabis extract enriched in CBD in accordance with embodiments of the present teachings;
FIG. 2 is a bar graph showing the percent trypan blue positivity of fibroblasts, 17-71, D17 and CMT12 at 48 hours after treatment with 15, 7.5, 3.75ug/mL CBD and with methanol Vehicle Control (VC) according to an embodiment of the present teachings;
FIG. 3A is an image of an immunoblot of cleaved caspase 3 (17 Kda) after CBD treatment for 8 and 16 hours compared to methanol vehicle control according to an embodiment of the present teachings;
FIG. 3B is a bar graph showing apoptosis of tumor cell lines 17-71 after treatment with 15 μg/mL CBD in accordance with an embodiment of the present teachings;
FIG. 3C is a bar graph showing apoptosis of tumor cell line D17 after treatment with 15 μg/mL CBD according to an embodiment of the present teachings;
FIG. 3D is a bar graph showing apoptosis of tumor cell line CMT12 after treatment with 15 μg/mL CBD according to an embodiment of the present teachings;
FIG. 4A is an image of a time course immunoblot of phosphorylated MAP kinases associated with baseline protein expression or 10 μg/mL CBD for ERK and phosphorylated ERK expression treated with vehicle control at time 2, 4 and 8 hours according to an embodiment of the present teachings;
FIG. 4B is an image of a time course immunoblot of phosphorylated MAP kinases associated with baseline protein expression or 10 μg/mL CBD for JNK and phosphorylated JNK expression treated with vehicle control at time 2, 4 and 8 hours according to an embodiment of the present teachings;
FIG. 5A is an image of an immunoblot of LC 3I/II in 17-71, CMT12 and D17 cell lines treated with vehicle control or 10 μg/mL CBD for 2, 4 or 8 hours according to an embodiment of the present teachings; and is also provided with
FIG. 5B is an immunofluorescence image of LC3A/B with CMT12 (600-fold) and D17 (400-fold) cells depicted in a column according to an embodiment of the present teachings.
Fig. 6A is a box and whisker plot showing the VAS scores of dogs in CBD treated and control groups at weeks zero, 2 and 4. Significant differences are marked with asterisks at zero and 4 weeks.
Fig. 6B is a box and whisker plot showing the cadsi scores of dogs in CBD treated and control groups at weeks zero, 2 and 4. Significant differences are marked with asterisks at zero and 4 weeks.
Fig. 7A is a graph showing alkaline aminotransferase levels in dogs treated with CBD treatment or placebo. Values of both zero and 4 weeks are shown.
Fig. 7B is a graph showing alkaline phosphatase levels in dogs treated with CBD treatment or placebo. Values of both zero and 4 weeks are shown.
FIG. 8 is a bar graph showing alkaline phosphatase levels in dogs as shown when CBD treatment is combined with various other drugs, or when CBD treatment is administered without other drugs (rightmost column).
FIG. 9A is a graph showing serum levels of monocyte chemotactic protein-1 (MCP-1) in dogs receiving CBD treatment or placebo at weeks zero and 4.
Fig. 9B is a graph showing serum levels of IL-6 for dogs receiving CBD treatment or placebo at weeks zero and 4.
Figure 10A is a graph showing serum levels of IL-31 in dogs receiving CBD treatment or placebo at weeks zero and 4.
FIG. 10B is a graph showing serum levels of IL-34 in dogs receiving CBD treatment or placebo at weeks zero and 4.
Figure 11 shows serum levels of CBDA, CBD, THCA and THC at the indicated time points in macaques receiving oral cannabis extract doses.
Figure 12A shows CYP3a12 activity after treatment with vehicle or various potential inhibitors. Data for each potential inhibitor without preincubation (left column, no outline) and with 20 minutes preincubation (right column, outlined) are shown.
Figure 12B shows CYP2D15 activity after treatment with vehicle or various potential inhibitors. Data for each potential inhibitor without preincubation (left column, no outline) and with 20 minutes preincubation (right column, outlined) are shown.
Figure 12C shows CYP2B11 activity after treatment with vehicle or various potential inhibitors. Data for each potential inhibitor without preincubation (left column, no outline) and with 20 minutes preincubation (right column, outlined) are shown.
Figure 13A shows CYP3A12 activity after treatment with vehicle or various potential inhibitors. Data for each potential inhibitor at different concentrations is shown. No pre-incubation was used.
Figure 13B shows CYP3a12 activity after treatment with vehicle or various potential inhibitors. Data for each potential inhibitor at different concentrations is shown. Preincubation was performed for 20 minutes.
Figure 14A shows CYP2B11 activity after treatment with vehicle or various potential inhibitors. Data for each potential inhibitor at different concentrations is shown. No pre-incubation was used.
Figure 14B shows CYP2B11 activity after treatment with vehicle or various potential inhibitors. Data for each potential inhibitor at different concentrations is shown. Preincubation was performed for 20 minutes.
Figure 15A shows CYP2D15 activity after treatment with vehicle or various potential inhibitors. Data for each potential inhibitor at different concentrations is shown. No pre-incubation was used.
Figure 15B shows CYP2D15 activity after treatment with vehicle or various potential inhibitors. Data for each potential inhibitor at different concentrations is shown. Preincubation was performed for 20 minutes.
Detailed Description
It should be appreciated that for clarity, the following disclosure will describe various aspects of the embodiments. It should be noted that the specific embodiments are not intended as an exhaustive description or as a limitation on the broader aspects discussed herein. An aspect described in connection with a particular embodiment is not necessarily limited to the embodiment and may be practiced with any other embodiment. Reference throughout this specification to "one embodiment," "an example embodiment," means that a particular feature, structure, or characteristic described in connection with the embodiment is included in at least one embodiment of the present invention. Thus, appearances of the phrases "in one embodiment," "in an embodiment," or "example embodiment" in various places throughout this specification are not necessarily all referring to the same embodiment, but may. Furthermore, the particular features, structures, or characteristics may be combined in any suitable manner in one or more embodiments as would be apparent to one of ordinary skill in the art in view of this disclosure. Moreover, while some embodiments described herein include some but not other features included in other embodiments, combinations of features of different embodiments are intended to be within the scope of the invention. For example, in the appended claims, any of the claimed embodiments may be used in any combination.
Definition of the definition
The definitions of the various terms used herein are set forth below. These definitions apply to the terms used throughout this specification and claims unless otherwise limited in specific examples alone or as part of a larger group.
Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs. Generally, the nomenclature used herein and the laboratory procedures in cell culture, molecular genetics, organic chemistry, and peptide chemistry are those well known and commonly employed in the art.
As used herein, the articles "a" and "an" refer to one or more than one (i.e., to at least one) of the grammatical object of an article. For example, "an element" means one element or more than one element. Furthermore, the use of the term "include" and other forms, such as "include", "include" and "include", are not limiting.
As used herein, the term "about" will be understood by one of ordinary skill in the art and will to some extent change the context in which it is used. As used herein, when referring to measurable values such as amount, time duration, etc., the term "about" is intended to encompass variations of ±5% from the specified value, as such variations are suitable for performing the disclosed methods.
As used in the specification and in the claims, the term "comprising" may include embodiments that "consist of …" and "consist essentially of …. As used herein, the terms "comprising," "including," "having," "possibly," "containing," and variations thereof are intended to be open-ended transitional phrases, terms, or words that require the presence of the specified elements/steps and allow the presence of other elements/steps. However, such description should be understood to also describe compositions or methods as "consisting of" and "consisting essentially of" the enumerated compounds, which allows for the presence of only the specified compound, as well as any pharmaceutically acceptable carrier, and excludes other compounds.
All ranges disclosed herein are inclusive of the endpoints and independently combinable (e.g., ranges of "50mg to 500mg" are inclusive of the endpoints 50mg and 500mg, and all intermediate values). The endpoints of the ranges and any values disclosed herein are not limited to the precise range or value; which is very imprecise to include values approximating these ranges and/or values.
As used herein, the term "treatment" or "treatment" is defined as the application or administration of a therapeutic agent, i.e., a compound provided herein (alone or in combination with another agent), to a patient or subject, or to an isolated tissue or cell line from a patient (e.g., for diagnostic or ex vivo application) for the purpose of healing, alleviating, altering, remedying, ameliorating or affecting the symptoms of a disease, disorder, syndrome, or condition. Such treatments may be specifically tailored or modified based on knowledge gained from the pharmacological arts.
In certain embodiments, the compositions described herein treat and/or reduce the severity of a disease, disorder, syndrome, or condition in a subject. For example, the compositions described herein treat and/or ameliorate one or more of the following: inflammation, dysuria, anxiety, depression, insomnia, pain (e.g., chronic pain, non-chronic pain, neuropathic pain, neurological dysfunction pain, nociceptive pain, postoperative pain), skin disorders, cancer, psychotic disorders, convulsions, epilepsy, osteoarthritis, lymphoma, atopy, allergy, diarrhea (e.g., idiopathic diarrhea), noise aversion, feather withdrawal, hair withdrawal, skin wounds, sepsis, gastrointestinal tract conditions, behavioral problems, compulsive behavior, migraine, headache, insect bites, diabetes, inflammatory bowel disease, skin disorders (e.g., pruritus, pyoderma), urine disorders, anxiety, or depression.
As used herein, the term "prevent" or "prevention" means that a disorder or disease does not develop if it does not occur, or does not develop further if it has already occurred. Also contemplated is a person's ability to prevent some or all of the symptoms associated with the disorder, disease, and/or condition.
As used herein, the term "use" encompasses any one or more of the following embodiments of the invention, respectively: use in the treatment of a disease, disorder, syndrome and/or condition for the preparation of a pharmaceutical composition for the treatment of such a disease, disorder, syndrome and/or condition, e.g., for the preparation and/or manufacture of a medicament; the compounds of the invention are useful in methods of treating such diseases, disorders, syndromes and/or conditions; pharmaceutical formulations having a compound of the invention for use in the treatment of such diseases, disorders, syndromes and/or conditions; and compounds of the invention for use in the treatment of such diseases, disorders, syndromes and/or conditions; if appropriate and expedient, if not otherwise stated.
As used herein, the terms "patient," "individual," or "subject" are intended to include an organism capable of suffering from or afflicted with a disease, disorder, syndrome, and/or condition. Examples of subjects include animals. Examples of subjects include mammals. Examples of subjects include dogs, cats, horses, cows, pigs, sheep, goats, mice, rabbits, rats, birds, fish, non-human primates, amphibians, reptiles, and transgenic non-human animals.
When used in connection with methods of treatment/prevention, and use of the compounds described herein, as well as pharmaceutical compositions thereof, an "in need" individual may be an individual who has been diagnosed with or previously treated for a condition to be treated. With respect to prophylaxis, an individual in need thereof may also be an individual at risk of having a condition (e.g., family history of a disease, disorder, syndrome, and/or condition, lifestyle factors indicative of the risk of a disease, disorder, syndrome, and/or condition, etc.). Generally, when the step of administering a compound of the invention is disclosed herein, the invention further contemplates the step of identifying an individual or subject in need of administration of a particular treatment or having a particular condition to be treated.
In some embodiments, the individual is a mammal, including but not limited to, a cow, horse, cat, rabbit, dog, rodent, or primate. In some embodiments, the mammal is a primate. In some embodiments, the individual is a human or other animal, and is an elderly person, an adult, a young adult, a child, an adolescent, a neonate, a pre-weaning, an infant, or a premature infant. In some embodiments, the subject is non-mammalian. In some embodiments, the primate is a non-human primate, such as chimpanzees and other apes and monkey species. The term "individual" does not denote a particular age or sex. In some embodiments, the individual is a female. In some embodiments, the individual is male.
As used herein, the term "pharmaceutically acceptable" refers to materials, such as carriers or diluents, that do not abrogate the biological activity or properties of the compound and are relatively non-toxic, i.e., the material may be administered to an individual without causing an undesirable biological effect or interacting in a deleterious manner with any of the components of the composition in which it is contained.
As used herein, the term "pharmaceutically acceptable salt" refers to a derivative of the disclosed compounds wherein the parent compound is modified by converting an existing acid or base moiety to its salt form. Examples of pharmaceutically acceptable salts include, but are not limited to: mineral salts or organic acid salts of basic residues such as amines; basic salts or organic salts of acidic residues such as carboxylic acids; etc. Pharmaceutically acceptable salts of the invention include, for example, conventional non-toxic salts of the parent compound formed from non-toxic inorganic or organic acids. Pharmaceutically acceptable salts of the invention can be synthesized from the parent compound containing a basic or acidic moiety by conventional chemical methods. Typically, such salts can be prepared by reacting the free acid or base forms of these compounds with an amount (e.g., stoichiometric) of the appropriate base or acid in water or in an organic solvent or in a mixture of both; in general, nonaqueous media such as ether, ethyl acetate, ethanol, isopropanol or acetonitrile are preferred. A list of suitable salts can be found in Remington pharmaceutical science (Remington's Pharmaceutical Sciences), 17 th edition, mark publication Inc. (Mack Publishing Company, easton, pa.), 1985, page 1418 and journal of pharmaceutical science (Journal of Pharmaceutical Science), 66,2 (1977), each of which is incorporated herein by reference in its entirety.
As used herein, the term "composition" or "pharmaceutical composition" refers to a mixture of at least one compound useful in the present invention and a pharmaceutically acceptable carrier. The pharmaceutical composition facilitates administration of the compound to a patient or subject. Various techniques for administering compounds present in the art include, but are not limited to, intravenous, oral, aerosol, parenteral, ocular, pulmonary, and topical administration.
As used herein, the term "pharmaceutically acceptable carrier" or "carrier" means a pharmaceutically acceptable material, composition or carrier (such as a liquid or solid (e.g., solid filler)), stabilizer, dispersant, suspending agent, diluent, excipient, thickener, solvent or encapsulating material involved in transporting or transporting a compound useful within the present invention within or to a patient or subject such that it can perform its intended function. Typically, such constructs are carried or transported from one organ or body part to another organ or body part. Each carrier must be "acceptable" in the sense of being compatible with the other ingredients of the formulation, including the compounds useful in the present invention, and not injurious to the patient or subject. Some examples of materials that may be pharmaceutically acceptable carriers include: sugars such as lactose, glucose, sucrose, and the like; starches such as corn starch, potato starch, etc.; cellulose and its derivatives such as sodium carboxymethyl cellulose, ethyl cellulose, cellulose acetate, etc.; powder gum tragacanth; malt; gelatin; talc; excipients such as cocoa butter, coconut oil, suppository waxes, and the like; oils such as peanut oil, cottonseed oil, safflower oil, sesame oil, olive oil, corn oil, soybean oil, and the like; ethylene glycol such as propylene glycol and the like; polyols such as glycerol, sorbitol, mannitol, polyethylene glycol and the like; esters such as ethyl oleate, ethyl laurate, and the like; agar; buffering agents such as magnesium hydroxide, aluminum hydroxide, etc.; a surfactant; alginic acid; water such as tap water, purified water, distilled water, milligram water, pyrogen-free water, etc.; isotonic saline; ringer's solution; ethanol; phosphate buffer; as well as other non-toxic compatible substances employed in pharmaceutical formulations. As used herein, a "pharmaceutically acceptable carrier" also includes any and all coatings, antibacterial agents, antifungal agents, antioxidants, absorption retarders, preservatives, stabilizers, and the like that are compatible with the activity of the compounds useful within the invention and physiologically acceptable to the patient or subject. One or more additional active and/or inactive compounds may also be incorporated into the composition. A "pharmaceutically acceptable carrier" or "carrier" may further comprise one or more pharmaceutically acceptable salts of one or more compounds useful in the present invention. Other additional ingredients that may be included in the pharmaceutical compositions used to practice the present invention are known in the art and are described, for example, in the "Ramington pharmaceutical science" (Genaro, inc., mok publishing Co., iston, pa., 1985), which is incorporated herein by reference.
As used herein, the term "stabilizer" refers to a polymer that is capable of chemically inhibiting or preventing degradation. Stabilizers are added to the formulation of the compounds to improve the chemical and physical stability of the compounds.
As used herein, the term "adjuvant" may include, for example, preservatives, wetting agents, suspending agents, sweeteners, flavoring agents, fragrances, emulsifiers, and dispersants. Prevention of the action of microorganisms is generally provided by various antibacterial and antifungal agents, such as parabens, chlorobutanol, phenol, sorbic acid, and the like. Isotonic agents, such as sugars, sodium chloride, and the like may also be included. Prolonged absorption of the injectable pharmaceutical form can be brought about by the use of agents which delay absorption, for example, aluminum monostearate and gelatin. Adjuvants may also include wetting agents, emulsifying agents, pH buffering agents, and antioxidants, such as citric acid, sorbitan monolaurate, triethanolamine oleate, butylated hydroxytoluene, and the like.
As used herein, the terms "effective amount," "pharmaceutically effective amount," and "therapeutically effective amount" refer to a nontoxic but sufficient amount of an agent to provide a desired biological result. The result may be a reduction or alleviation of the signs, symptoms, and/or causes of a disease, or any other desired alteration of a biological system. In any individual case, the appropriate therapeutic amount can be determined by one of ordinary skill in the art using routine experimentation.
As used herein, the term "weight percent" means that the amount of a compound and/or component in a composition by weight is referred to as the percentage of the amount of the constituent component in the composition by weight of the total composition. The weight percent may also be calculated by multiplying the mass fraction by 100. The "mass fraction" is the ratio of one substance of mass m1 to the mass of the total composition mT, such that the weight percentage= (m 1/mT) x 100.
By "aqueous buffer" is meant an aqueous solution that prevents the concentration of hydronium and hydroxide ions (and subsequent pH) from changing after the addition of a small amount of acid or base or after dilution. Buffers are composed of weak acids and their conjugate bases (more common) and/or weak bases and their conjugate acids (less common). Buffers can be prepared by methods well known in the art with appropriate buffers to obtain the desired pH. Examples of suitable buffers include hydrochloric acid, lactic acid, acetic acid, citric acid, malic acid, maleic acid, pyruvic acid, succinic acid, tris, sodium hydroxide, sodium bicarbonate, phosphoric acid, sodium phosphate, and other biologically acceptable buffers. Aqueous buffers are readily commercially available and can be used to prepare the compositions of the present invention without further processing.
As used herein, the term "cannabis extract" refers to a combination of cannabinoids and terpenes isolated from cannabis plants. The terms "cannabis extract", "CBD oil" and "cannabis oil" have the same meaning and are used interchangeably herein. The cannabis extract may be obtained by any method known in the art. For example, cannabis extracts may be obtained by supercritical (or subcritical) CO 2 Extraction results, which uses carbon dioxide at high pressure and low temperature to separate, preserve and maintain the purity of the cannabis extract. In an embodiment, the cannabis extract is derived from supercritical CO 2 Extracting to obtain the final product. For example, supercritical CO 2 Extraction may be performed as described in U.S. patent No. 8,895,078, which is incorporated herein by reference in its entirety. Alternatively, solvents such as petroleum ether, ethanol, methanol, butanol, acetone, dry ice or olive oil may be heated to a temperature above room temperature by passive extraction under stirring at room temperature (ambient temperature) or used under reflux, as known in the art, to provide a cannabis extract. In another embodiment, cannabis extract from butanol extraction is used as a starting material for the methods readily disclosed herein.
As used herein, the term "quality of life" or "QoL" is generally considered a multidimensional concept that involves subjective assessment of factors contributing to overall well-being, where recent publications indicate the presence of discomfort, anxiety and digestive function. The Likett scale system (Likert scaling system) appears to be a reasonable assessment of QoL, and is used in some embodiments herein (see Giuffrida et al (2018), journal of veterinary society (J Amer Vet Med Assoc), 252:1073-1083, incorporated herein by reference in its entirety). The pruritus visual analog scale (pVAS) appears to be a reasonable assessment of QoL and is used in some embodiments herein.
Cannabinoids are compounds isolated from cannabis plants. The class of cannabinoids includes, for example, but is not limited to, cannabigerol, cannabidiol, cannabinoid, cannabigerol, cannabinol, cannabinodiol (cannabinodiol), dihydroxycannabinol, delta-8-tetrahydrocannabinol, and delta-9-tetrahydrocannabinol. Cannabinoid compounds include, for example, but are not limited to: cannabichromene (CBC), cannabichromene acid (CBCA), hypocrehromene (CBCV), hypocresylic acid (CBCVA), cannabinol (CBL), cannabicyclic acid (CBLA), hypocreosol (CBLV), cannabidiol (CBD), cannabidiol monomethyl ether (CBDM), cannabidiol (CBDA), cannabidiol (CBD-C1), hypocreosol (CBDV), hypocresylic acid (CBDVA), cannabichromene acid B (CBEA-B), cannabinoid (CBE), cannabichromene a (CBEA-a), cannabigerol (CBG), cannabigerol monomethyl ether (CBGM), cannabigerol acid (CBGA) cannabigerol monomethyl ether (CBGAM), hypocrefolan (CBGV), hypocrefolan (CBGVA), cannabidiol (CBND), hypocrefolan (CBVD), cannabinol (CBN), cannabinol methyl ether (CBNM), cannabinol-C2 (CBN-C2), cannabinol-C4 (CBN-C4), cannabinol acid (CBNA), cannabinol (CBN-C1), hypocrefolan (CBV), 10-ethoxy-9-hydroxy-delta-6 a-tetrahydrocannabinol, 8, 9-dihydroxy-delta-6 a-tetrahydrocannabinol, dihydroxycannabinol (CBT), hypocrebinol (CBTV), and the like, Δ8-tetrahydrocannabinol (Δ8-THC), Δ8-tetrahydrocannabinol (Δ8-THCA), Δ9-Tetrahydrocannabinol (THC), Δ9-tetrahydrocannabinol-C4 (THC-C4), Δ9-tetrahydrocannabinol a (THCA-a), Δ9-tetrahydrocannabinol B (THCA-B), Δ9-tetrahydrocannabinol-C4 (THCA-C4), Δ9-tetrahydrocannabinol (THC-C1), Δ9-tetrahydrocannabinol (THCA-C1), Δ9-Tetrahydrocannabinol (THCV), Δ9-Tetrahydrocannabinol (THCVA), 10-oxo- Δ6 a-tetrahydrocannabinol (OTHC), cannabinone (CBCF), cannabinol (CBF), cannabinol (CBR), cannabinoid (CBT), dehydrocannabis (dcf), Δ9-tetrahydrocannabinol (THC-cis) and Δ9-tetrahydrocannabinol (THC-THC).
Suitable methods for measuring the cannabinoid and terpene content in cannabis extracts are known in the art. In an embodiment, the cannabinoid content is determined using liquid chromatography with mass spectrometry detection (LC-MS). In another embodiment, the terpene content is determined using gas chromatography with a headspace flame ionization detection (GC-FID) analysis.
As used herein, the term "flavoring agent" refers to an ingredient added to a composition to impart a particular flavor, odor, or other organoleptic property. Flavoring agents may be natural or artificial.
As used herein, the term "oil" refers to a non-polar viscous liquid having both hydrophobicity and lipophilicity. The oil may be isolated from animals, vegetables or petrochemicals.
As used herein, the term "chew" refers to a product or portion thereof having rheological and other texture and sensory properties that tend to promote the chewing of an article by a target subject. Generally, the chewable matrix will exhibit sufficient malleability when chewed by a target subject, such that it is at least slightly plastic, and is sufficiently palatable that the target subject is not unable to chew multiple times due to its taste. In contrast, "chewable" does not merely mean that the article may be chewed by the subject (i.e., it does not merely mean that some portion of the article will sufficiently fit the subject's mouth to allow the subject's teeth to engage with that portion).
As used herein, the "maximum serum concentration level" of a substance refers to the maximum level of the substance found in a plasma sample after a single administration.
As used herein, the term "cold extrusion" refers to a process for producing an edible food product that includes several unit operations, including adding, mixing, kneading, pressing, shearing, shaping, and forming, all at or near ambient temperature.
As used herein, the term "mental effect" refers to a change in brain function that results in a change in cognition, emotion, consciousness, and/or behavior.
SUMMARY
Embodiments disclosed herein provide non-naturally occurring or engineered compositions and methods comprising one or more cannabis extracts for use in treating a disease, disorder, syndrome, and/or condition in an animal in need thereof. The diseases, disorders, syndromes and/or conditions include, for example, but are not limited to: inflammation, dysuria, anxiety, depression, insomnia, pain (e.g., chronic pain, non-chronic pain, neuropathic pain, neurological dysfunction pain, nociceptive pain, postoperative pain), skin disorders, cancer, psychotic disorders, convulsions, epilepsy, osteoarthritis, lymphoma, atopy, allergy, diarrhea (e.g., idiopathic diarrhea), noise aversion, feather withdrawal, hair withdrawal, skin wounds, sepsis, gastrointestinal tract conditions, behavioral problems, compulsive behavior, migraine, headache, insect bites, diabetes, inflammatory bowel disease, skin disorders (e.g., pruritus, pyoderma), urine disorders, anxiety, or depression. Clinical trial and pharmacokinetic data relating to administration and dosing in therapy are disclosed herein.
Regarding the treatment of inflammation, the endogenous cannabinoid receptor system is known to play a role in pain modulation and inflammation attenuation. Cannabinoid receptors (CB 1 and CB 2) are widely distributed throughout the central and peripheral nervous systems, and are also present in synovium. However, the mental effects of certain cannabinoids have prevented extensive research into their use as single agents for pain relief. Cannabinoids are a group of up to 60 different compounds that may or may not act on CB receptors. One class of cannabinoids, namely Cannabidiol (CBD), may actually be antagonists of the CB receptor. CBD can also have immunomodulatory, anti-hyperalgesic, analgesic, anxiolytic and anti-inflammatory effects in lower vertebrates, making it an attractive therapeutic option in animals.
Regarding the treatment of improper urination (problem of soil formation in the urine compartment), such conditions in cats can be classified into those related to toilet behavior and those related to marking. Chronic pain and anxiety/depression may be indicated in both of those conditions. Markers are generally considered to be responsive to threats posed by critical resources within the cat core field, and toilet-related problems are generally caused by cat exposure to appropriate toilets (Barcelos et al, (2018) veterinary frontier (front. Vet. Sci.) 5:108). Both of these can be considered limitations on the autonomy of the cat and thus can lead to depression. This may be combined with anxiety, as the animal perceives a physical threat (in the case of a marker) from other individuals, or may be annoying due to lack of contact with the desired toilet. In addition, anxiety may occur in the prospect of discomfort during elimination if the cat has some painful condition of the urinary system. Recent reviews indicate that cats with improper urination may be about 4 times more likely than cats with a history of urinary tract disease. (Barcelos et al, 2018). Recently it has been reported that cats may change posture from squat to jet if the soil in the room becomes uncomfortable and vice versa (Ramos et al (2018) cat internal and surgical (J Feline Med Surg) doi:10.1177/1098612X 18801034). It is also notable that about 40% of superficial healthy subjects with improper urination may have detectable medical problems at the initial clinical examination, with the number rising to 66.7% for the injected cats and 56.5% for the towed cats following a more intimate medical assessment (Ramos et al 2018).
With respect to the treatment of migraine, this condition is a common neurovascular disorder, manifested as a headache episode, to the extent that severe pain can be reached in many patients, resulting in substantial functional impairment. The global disease burden study (GBD 2010) recently conducted by the world health organization estimated that the incidence of global migraine was 14.7%, third among the most common diseases, seventh among the specific etiologies of disability, and top rank among neurological disorders as the etiology of the total years of disabled life. Migraine thus affects millions of people. The pathophysiology of migraine is not fully understood so far.
With respect to the treatment of neurological disorders, the use of cannabinoid derivatives in the treatment of a variety of neurological disorders in humans, in particular in the treatment of chronic pain and epilepsy, has recently been explored. Full spectrum cannabinoid rich industrial cannabis-based nutrients (HBN) below 0.3% THC have been shown to have no psychotropic and modest activity through the non-cannabinoid receptor pathway affecting serotonergic, glycinergic and GABA neurotransmission pathways that may be able to reduce pain and inflammation. Recent studies using full spectrum cannabinoid-rich HBN have shown that these products have efficacy in dogs with chronic pain, such as Gamble L-J, boesch JM, frye CW, schwark WS, mann S, wolfe L, brown H, berthelsen ES and Wakshlag JJ (2018), pharmacokinetics, safety and clinical efficacy of cannabidiol treatment in osteoarthritis dogs (Pharmacokinetics, safety, and Clinical Efficacy of Cannabidiol Treatment in Osteoarthritic Dogs), veterinary frontage 5:165,DOI 10.3389/fvets.00165, which is incorporated herein by reference in its entirety. In addition, seizures and for humans Is available from greenwich bioscience corporation (Greenwich Biosciences, carlsbad, california) of Carlsbad, california as a viable treatment showing the cheating of cannabidiol in the treatment of epilepsy. />
Regarding the treatment of Cancer, the efficacy of cannabinoids alone and in combination with ondansetron for the delay of chemotherapy-induced nausea and vomiting (Efficacy of dronabinol alone and in combination with ondansetron versus ondansetron alone for delayed chemotherapy-induced nausea and vomiting), 2007, current medical research and understanding (Current Medical Research and Opinion), 23:3,533-543, DOI: 10.1185/0300799167525; gonzalez-Rosales F and D, the relief of intractable nausea and vomiting due to gastrointestinal metastasis (Intractable nausea and vomiting due to gastrointestinal mucosal metastases relieved by tetrahydrocannabinol (abanol)) by tetrahydrocannabinol (dronabinol), dronabinol (J Pain Symptom Manage), 1997, 11:14, pages 7-29:29, etc.) has been studied and utilized for the alleviation of Cancer symptoms or treatment of side effects associated with standard Cancer therapies (e.g., eyal Meiri, haresh Jhangiani, james J. Vridenburgh, luigi M. Barbato, frederick J. Carter, hwa-Ming Yang and Vickie Baranowski), relative to ondansetron alone; and May MB and Glode AE, dronabinol for chemotherapy-induced nausea and vomiting (Dronabinol for chemotherapy-induced nausea and vomiting unresponsive to antiemetics) unresponsive to antiemetics, (Cancer manager Manag. Res.), (5 months in 2016, 12 (8), pages 49-55, doi:10.2147/CMAR. S81425, which is incorporated herein by reference in its entirety). However, more recent studies have been exploring CBD and its direct antitumor properties alone or in combination with standard Cancer therapies (such as chemotherapy or ionizing radiation) (e.g., S nchez C, de Ceballos ML, gomez del Pulgar T, rueda D, corbacho C, velasto G, galve-Roperh I, huffman JW, ram N y Cajal S and Guzm N M, inhibition of glioma growth in vivo by selective activation of CB (2) cannabinoid receptors (Inhibition of glioma growth in vivo by selective activation of the CB (2) cannabinoid receptor), cancer research (Cancer Res), 1 st day 2001, 61 (15), 5784-9;Scott KA,Dalgleish AG and Liu WM, cannabidiol and Δ9-tetrahydrocannabinol in combination, molecular Cancer therapy (mol. Cancer therapy) (2014 months, 13 (12), 2-D, stei 2955/p 5, and 5-8238 th, and 2) in vitro, quantitative analysis of the activity of glial cell proliferation in vitro and human tumor models (52.35.35.48) and the pharmacological responses between these two-p, in vitro and the study of the human tumor cell culture (52.35.35,166, month 1, 2017, 360 (1), pages 215-224, doi: 10.1124/jpeg.116.236968; and Luciano De Petrocellis, alessia Ligresti, aniello Schiano Moriello, mariagrazia Iappelli, roberta Verde, colin G Stott, luigia Cristino, pierangelo Orlando and Vincenzo Di Marzo, non-THC cannabinoids counteract prostate cancer growth in vitro and in vivo: pro-apoptotic effects and underlying mechanisms (Non-THC cannabinoids counteract prostate carcinoma growth in vitro and in vivo: pro-apoptotic effects and underlying mechanisms), "journal of British pharmacology (Br. J. Pharmacol.)," 2012,168, pages 79-102, which is incorporated herein by reference in its entirety. Also CBD' S ability to activate GPCR18 and GPCR55, whose role Is not well elucidated in cancer cell biology (e.g. Brown AJ and Robin Hiley C, GPR55 Is a cannabinoid receptor (Is GPR55 an anandamide receptor), month 8, 171 (16) 2014, pages 3908-17, doi:10.1111/bph.12746, incorporated herein by reference in its entirety.
Still with respect to cancer treatment glioblastoma multiforme has been the primary focus of cannabinoid-based research in human tumor models. These studies showed that reduced cell viability of glioma cell lines treated with CBD, and synergistic reduction of cell viability in combination with both ionizing radiation and/or DNA damaging agents (e.g., scott KA, dalgleish AG and Liu WM, combination of cannabidiol and Δ9-tetrahydrocannabinol enhanced anticancer effects of radiation in an in situ murine neurokeratoma model, molecular cancer treatment, 2014,13 (12), pages 2955-2967; quantitative analysis of proliferation and viability of glioblastoma and neural precursor cells in culture by synergistic reactions between Deng L, ng L, ozawa T and stilla N, cannabidiol and DNA damaging agents journal of pharmacological and experimental therapeutics, 2017,360 (1), pages 215-224, and Marcu JP, christian RT, lau D, zieinski AJ, horowitz MP, lee J, pakdel A, allison J, limpad C, moore DH, yount GL, desprez PY and McAllist SD, cannabidiol enhancing the inhibition of Δ9-tetrahydrocannabinol on proliferation and survival of human glioblastoma cells (Cannabidiol enhances the inhibitory effects of delta9-tetrahydrocannabinol on human glioblastoma cell proliferation and survival), molecular cancer treatment, month 1531, 9 (1), pages 180-9, doi: 10.1158/5-7163, the entire contents of which are incorporated herein by reference. Induction of apoptosis was observed in many cell culture models and appears to have been affected by many cell signaling pathways leading to apoptosis and/or autophagy, i.e., the mammalian target of rapamycin (mTOR), phosphatidylinositol-3 kinase (PI 3K) and Mitogen Activated Protein (MAP) kinases (e.g., sultan AS, marie MA and Shewita SA, new mechanisms of cannabidiol-induced apoptosis in Breast cancer cell lines (Novel mechanism of cannabidiol-induced apoptosis in Breast cancer cell lines), "mammary gland (Breast)," 2018,41, pages 34-41; ropeh I, sanchez C and Cortes M, antitumor effects of cannabinoids: sustained ceramide accumulation and participation in extracellular signal-related kinase activation (Anti-tumoral action of cannabinoids: involvement of sustained ceramide accumulation and extracellular signal-related kinase activation), "Nature Med", 2000,6, pages 313-9; powles T, te Powlee R, shamah J, chaplin T, propper D, jover T and Liver T, and Blood vessel (35: 35-95:35), toxicity of the Blood-35:35, 6:35:35, and the Blood-35:35:95:35 (35:35, 35:35:35, 35:35, 35:35:35, 95:35, and the Blood-35:35:35, 35:35, 1-35:35, and the Blood-35:35:35, 35:35, 1, 35:35, and the Blood-1, 35:35, 35, 1, 35:3,95,35,95,95,35,96,v respectively, kaminsha B and Konarska l. cannabinoids down regulate PI3K/Akt and Erk signaling pathways and activate pro-apoptotic functions of bad proteins (Cannabinoids downregulate PI K/Akt and Erk signaling pathways and activate proapoptotic function of bad protein), "Cell signal.)," 2005,17, pages 25-37; and the Sarker KP, biswas KK, yamakuchi M, lee KY, hahiguchi T, kracht M, kitajima I and Maruyama I, ASK1-p38 MAPK/JNK signaling cascades mediate cannabinoid-induced PC12 cell death (ASK 1-p38 MAPK/JNK signaling cascade mediates anandamide-reduced PC12 cell death), "journal of neurochemistry (J Neurochem)," month 4, 85 (1), pages 50-61, doi:10.1046/j.1471-4159.2003.01663.X, which is incorporated herein by reference in its entirety). To date, there has been little examination of the effects of CBD on canine cell culture models or the effects of standard CBD enriched cannabis extracts.
Still regarding the treatment of cancer, considering that cannabis extracts with relatively similar CBD concentrations appear to have different effects on cell culture systems, the use of cannabis extracts in controlling cell growth is complex, thereby suggesting a "satellite effect" in which terpenes and other cannabinoids might act synergistically with CBD to affect cell proliferation (e.g. Russo EB and Taming THC, potential cannabis synergy and phytocannabinoid-terpenoid satellite effect (Potential cannabis synergy and phytocannabinoid-terpenoid entourage effects), brit pharmacological journal (Brit J Phacol), 2011,163 (7), pages 1344-1364, blasco-bento S, seijo-Vila M, caro-villato M, tundor I, andrads C, garce-tapad E, wade J, smith S, guzm ' n M, P-G-mez E, go-G and gorboom M ' S, gorge ' S, and the pharmacological effect of the drugs in the eye (p.p.157. 5, p.157. 5, p.5, M) is assessed against the tumor by the clinical model of the drugs of the type II, B, G.m.p.b.b., the following effect: inactive endogenous fatty acid glycerides enhance 2-arachidonic acid acylglycerol cannabinoid activity (An entourage effect: inactive endogenous fatty acid glycerol esters enhance 2-arachidoonyl-glycerol cannabinoid activity), "J.European pharmacology (European journal of pharmacology), 7 months 17, 1998, 353 (1), pages 23-31, incorporated herein by reference in its entirety). The cell death response may be combined with chemotherapeutic agents commonly used in veterinary therapy, as many owners wish to enrich the cannabis product with CBD during chemotherapy to affect the cancer itself, or to alleviate some of the adverse effects of chemotherapy (nausea and somnolence) to maintain or improve the quality of life of their pets (e.g., kogan LR, hellyer PW and Robinson NG, consumer opinion of cannabis product for animals (Consumers' perceptions of hemp products for animals), journal of general veterinary medicine association (J Am Holist Vet Med assoc.), 2016,42, pages 40-48, which is incorporated herein by reference in its entirety).
With respect to the treatment of lymphomas, the disease is one of the most frequently diagnosed cancers of the hematopoietic system in dogs. The most common chemotherapy regimen for this disease is the doxorubicin-based multi-drug regimen (L-asparaginase, cyclophosphamide, doxorubicin, vincristine, and prednisone). The remission rate of such protocols ranges from 80-90%. Median survival time in dogs diagnosed with lymphoma treated with doxorubicin-based chemotherapy regimen was 6 to 12 months. About 20% up to 50% of dogs receiving CHOP or L-CHOP chemotherapy may experience varying degrees of GI toxicity (Tomiyasu et al (2010), "journal of veterinary science (J Vet Med sci.)" 72 (11): 1391-7; mason et al (2014), "journal of Small animal practice.))" 55 (8): 391-8, which is incorporated herein by reference in its entirety). The availability of dense treatment modalities and greater willingness of customers to seek treatment have led to improved survival times for veterinary cancer patients. However, as therapies become denser, the risk of related morbidity increases and balancing quality of life with number of lives has become an important role for veterinary oncologists. Owners of pets suffering from absolute symptoms tend to appreciate quality of life (QoL) rather than longevity and are willing to sacrifice time-to-live to maintain QoL (Iliopoulou et al (2013) & journal of the American veterinary medical Association (J Am Vet Med assoc.) 242 (12): 1679-87; giufrida et al (2018) & journal of the American veterinary medical Association (J Amer Vet Med assoc.) & 252:1073-1083, which is incorporated herein by reference in its entirety).
Pharmaceutical composition
In one aspect, provided herein is a pharmaceutical composition comprising a cannabis extract and a carrier, wherein the cannabis extract comprises:
cannabidiol; and
cannabidiol.
In another embodiment, the cannabis extract comprises:
cannabidiol;
cannabidiol;
cannabigerol acid;
Δ9-tetrahydrocannabinol; and
cannabichromene.
In another embodiment, the cannabis extract comprises:
cannabidiol;
cannabidiol;
cannabigerol acid;
cannabigerol;
Δ9-tetrahydrocannabinol; and
cannabichromene.
In another embodiment, the ratio of Δ9-tetrahydrocannabinol to other cannabinoids is from about 1:50 to about 1:20. In embodiments, the ratio of cannabidiol to cannabidiol is from about 0.1:1 to about 1:0.1. In another embodiment, the ratio of cannabidiol to cannabidiol is about 0.1:1, about 0.2:1, about 0.3:1, about 0.4:1, about 0.5:1, about 0.6:1, about 0.7:1, about 0.8:1, about 0.9:1, about 1:1, about 1:0.9, about 1:0.8, about 1:0.7, about 1:0.6, about 1:0.5, about 1:0.4, about 1:0.3, about 1:0.2, or about 1:0.1. In yet another embodiment, the ratio of cannabidiol to cannabidiol is from about 0.6:1 to about 1:0.6. In yet another embodiment, the ratio of cannabidiol to cannabidiol is about 1:1.
In the examples, the concentration of Δ9-tetrahydrocannabinol is insufficient to produce a psychotropic effect. In another embodiment, the ratio of Δ9-tetrahydrocannabinol to other cannabinoids is from about 1:50 to about 1:20. In yet another embodiment, the ratio of Δ9-tetrahydrocannabinol to other cannabinoids is about 1:50. In yet another embodiment, the ratio of Δ9-tetrahydrocannabinol to other cannabinoids is about 1:45. In an embodiment, the ratio of Δ9-tetrahydrocannabinol to other cannabinoids is about 1:40. In another embodiment, the ratio of Δ9-tetrahydrocannabinol to other cannabinoids is about 1:35. In yet another embodiment, the ratio of Δ9-tetrahydrocannabinol to other cannabinoids is about 1:30. In yet another embodiment, the ratio of Δ9-tetrahydrocannabinol to other cannabinoids is about 1:25. In an embodiment, the ratio of Δ9-tetrahydrocannabinol to other cannabinoids is about 1:20.
In embodiments, the concentration of Δ9-tetrahydrocannabinol is less than about 2mg/mL. In another embodiment, the concentration of Δ9-tetrahydrocannabinol is less than about 1.5mg/mL. In yet another embodiment, the concentration of Δ9-tetrahydrocannabinol is less than about 1mg/mL. In yet another embodiment, the concentration of Δ9-tetrahydrocannabinol is less than about 0.9mg/mL. In yet another embodiment, the concentration of Δ9-tetrahydrocannabinol is less than about 0.8mg/mL. In embodiments, the concentration of Δ9-tetrahydrocannabinol is less than about 0.7mg/mL. In another embodiment, the concentration of Δ9-tetrahydrocannabinol is less than about 0.6mg/mL. In yet another embodiment, the concentration of Δ9-tetrahydrocannabinol is less than about 0.5mg/mL. In yet another embodiment, the concentration of Δ9-tetrahydrocannabinol is less than about 0.4mg/mL. In embodiments, the concentration of Δ9-tetrahydrocannabinol is less than about 0.3mg/mL. In another embodiment, the concentration of Δ9-tetrahydrocannabinol is less than about 0.2mg/mL. In yet another embodiment, the concentration of Δ9-tetrahydrocannabinol is less than about 0.1mg/mL. In another embodiment, the concentration of Δ9-tetrahydrocannabinol is less than about 0.05mg/mL. In another embodiment, the concentration of Δ9-tetrahydrocannabinol is about 0mg/mL.
In an embodiment, the cannabis extract comprises:
about 0.1-20mg/mL cannabidiol;
about 0.1-20mg/mL cannabidiol;
about 0.01-0.5mg/mL cannabigerol acid;
about 0.01-0.5mg/mL of Δ9-tetrahydrocannabinol; and/or
About 0.01-0.5mg/mL cannabigerol.
In another embodiment, the cannabis extract comprises:
about 1-10mg/mL cannabidiol;
about 1-10mg/mL cannabidiol;
about 0.05-0.2mg/mL cannabigerol acid;
about 0.1-0.3mg/mL of Δ9-tetrahydrocannabinol; and/or
About 0.1-0.4mg/mL cannabigerol.
In yet another embodiment, the cannabis extract comprises:
about 5mg/mL cannabidiol;
about 5mg/mL cannabidiol;
about 0.11mg/mL cannabigerol acid;
about 0.25mg/mL of Δ9-tetrahydrocannabinol; and/or
About 0.27mg/mL cannabigerol.
In an embodiment, the cannabis extract comprises:
about 0.1-20mg/mL cannabidiol;
about 0.1-20mg/mL cannabidiol;
about 0.01-0.5mg/mL cannabigerol acid;
cannabigerol;
about 0.01-0.5mg/mL of Δ9-tetrahydrocannabinol; and/or
About 0.01-0.5mg/mL cannabigerol.
In another embodiment, the cannabis extract comprises:
About 1-10mg/mL cannabidiol;
about 1-10mg/mL cannabidiol;
about 0.05-0.2mg/mL cannabigerol acid;
cannabigerol;
about 0.1-0.3mg/mL of Δ9-tetrahydrocannabinol; and/or
About 0.1-0.4mg/mL cannabigerol.
In yet another embodiment, the cannabis extract comprises:
about 5mg/mL cannabidiol;
about 5mg/mL cannabidiol;
about 0.11mg/mL cannabigerol acid;
cannabigerol;
about 0.25mg/mL of Δ9-tetrahydrocannabinol; and/or
About 0.27mg/mL cannabigerol.
In some embodiments, the cannabis extract comprises tetrahydrocannabinolic acid (THCA).
In embodiments, the cannabis extract comprises about 0.01mg/mL of cannabinoid. In embodiments, the cannabis extract comprises about 0.05mg/mL of cannabinoid. In embodiments, the cannabis extract comprises about 0.1mg/mL of cannabinoid. In embodiments, the cannabis extract comprises about 0.5mg/mL cannabinoid. In embodiments, the cannabis extract comprises about 1mg/mL of cannabinoid. In embodiments, the cannabis extract comprises about 2mg/mL cannabinoid. In embodiments, the cannabis extract comprises about 3mg/mL of cannabinoid. In embodiments, the cannabis extract comprises about 4mg/mL cannabinoid. In embodiments, the cannabis extract comprises about 5mg/mL cannabinoid. In embodiments, the cannabis extract comprises about 10mg/mL cannabinoid. In embodiments, the cannabis extract comprises about 20mg/mL cannabinoid. In embodiments, the cannabis extract comprises about 30mg/mL of cannabinoid. In embodiments, the cannabis extract comprises about 40mg/mL of cannabinoid. In embodiments, the cannabis extract comprises about 50mg/mL cannabinoid. In embodiments, the cannabis extract comprises about 60mg/mL of cannabinoid. In embodiments, the cannabis extract comprises about 70mg/mL cannabinoid. In embodiments, the cannabis extract comprises about 80mg/mL cannabinoid. In embodiments, the cannabis extract comprises about 90mg/mL cannabinoid. In embodiments, the cannabis extract comprises about 100mg/mL cannabinoid. In embodiments, the cannabinoids are cannabidiol and cannabidiol. According to some embodiments, about 0.05-0.5mL of the extract is topically applied.
In an embodiment, provided herein is a pharmaceutical composition comprising a cannabis extract and a carrier, wherein the cannabis extract comprises:
alpha-pinene;
beta-myrcene;
beta-pinene;
delta-limonene;
linalool;
beta-caryophyllene;
alpha-lupulin;
nerolidol 2;
guaifenesin;
a caryophyllene oxide; and/or
Alpha-bisabolol.
In another embodiment, the cannabis extract comprises:
about 0.09% to about 0.13% α -pinene;
about 0.23% to about 0.44% of beta-myrcene;
about 0.04-0.09% beta-pinene;
about 0.05-0.09% delta-limonene;
about 0.03% to about 0.06% linalool;
about 0.04-0.07% beta-caryophyllene;
about 0.02-0.04% of alpha-lupulin;
0.04-0.07% of nerolidol 2;
about 0.02% to about 0.04% guaifenesin;
about 0.04% to about 0.08% caryophyllene oxide; and/or about 0.01-0.04% alpha-bisabolol.
In another embodiment, the cannabis extract comprises:
about 0.07-0.30% α -pinene;
about 0.10% to about 0.60% of beta-myrcene;
about 0.02-0.20% β -pinene;
about 0.03-0.20% delta-limonene;
about 0.01% to about 0.08% linalool;
about 0.03-0.09% beta-caryophyllene;
about 0.01-0.06% of alpha-lupulin;
About 0.02-0.09% nerolidol 2; and/or
About 0.01-0.06% guaifenesin;
in another embodiment, the cannabis extract comprises:
about 0.01-0.50% of alpha-pinene;
about 0.01-0.90% beta-myrcene;
about 0.01-0.50% β -pinene;
about 0.01-0.50% delta-limonene;
about 0.01% to about 0.50% linalool;
about 0.01-0.50% beta-caryophyllene;
about 0.01-0.50% of alpha-lupulin;
about 0.01-0.50% nerolidol 2;
about 0.01-0.50% guaifenesin;
about 0.01% to about 0.50% caryophyllene oxide; and/or
About 0.01-0.50% alpha-bisabolol.
In another embodiment, the cannabis extract further comprises:
camphene;
beta-ocimene;
eucalyptol;
isopulegol; and/or
Nerolidol 1.
In another embodiment, the cannabis extract comprises:
about 0.02% camphene;
about 0.02% to about 0.03% of beta-ocimene;
from about 0.02% to about 0.05% eucalyptol;
about 0.02% isopulegol; and/or
About 0.02-0.04% nerolidol 1.
In another embodiment, the cannabis extract comprises:
about 0.01-0.04% camphene;
about 0.01-0.05% of beta-ocimene;
from about 0.01% to about 0.07% eucalyptol;
From about 0.01% to about 0.04% isopulegol; and/or
About 0.01-0.05% nerolidol 1.
In another embodiment, the cannabis extract comprises:
about 0.01% to about 0.50% camphene;
about 0.01-0.50% of beta-ocimene;
from about 0.01% to about 0.50% eucalyptol;
from about 0.01% to about 0.50% isopulegol; and/or
About 0.01-0.50% nerolidol 1.
In embodiments, the cannabis extract does not include terpenes.
In embodiments, the cannabis extract comprises 1 or more of the following: alpha-pinene, beta-myrcene, beta-pinene, delta-limonene, linalool, beta-caryophyllene, alpha-lupulin, nerolidol 2, guaifenesin, caryophyllene oxide, alpha-bisabolol, camphene, beta-ocimene, eucalyptol, isopulegol, and nerolidol 1.
In embodiments, the cannabis extract comprises 2 or more of the following: alpha-pinene, beta-myrcene, beta-pinene, delta-limonene, linalool, beta-caryophyllene, alpha-lupulin, nerolidol 2, guaifenesin, caryophyllene oxide, alpha-bisabolol, camphene, beta-ocimene, eucalyptol, isopulegol, and nerolidol 1.
In embodiments, the cannabis extract comprises 3 or more of the following: alpha-pinene, beta-myrcene, beta-pinene, delta-limonene, linalool, beta-caryophyllene, alpha-lupulin, nerolidol 2, guaifenesin, caryophyllene oxide, alpha-bisabolol, camphene, beta-ocimene, eucalyptol, isopulegol, and nerolidol 1.
In embodiments, the cannabis extract comprises 4 or more of the following: alpha-pinene, beta-myrcene, beta-pinene, delta-limonene, linalool, beta-caryophyllene, alpha-lupulin, nerolidol 2, guaifenesin, caryophyllene oxide, alpha-bisabolol, camphene, beta-ocimene, eucalyptol, isopulegol, and nerolidol 1.
In embodiments, the cannabis extract comprises 5 or more of the following: alpha-pinene, beta-myrcene, beta-pinene, delta-limonene, linalool, beta-caryophyllene, alpha-lupulin, nerolidol 2, guaifenesin, caryophyllene oxide, alpha-bisabolol, camphene, beta-ocimene, eucalyptol, isopulegol, and nerolidol 1.
In embodiments, the cannabis extract comprises 6 or more of the following: alpha-pinene, beta-myrcene, beta-pinene, delta-limonene, linalool, beta-caryophyllene, alpha-lupulin, nerolidol 2, guaifenesin, caryophyllene oxide, alpha-bisabolol, camphene, beta-ocimene, eucalyptol, isopulegol, and nerolidol 1.
In embodiments, the cannabis extract comprises 7 or more of the following: alpha-pinene, beta-myrcene, beta-pinene, delta-limonene, linalool, beta-caryophyllene, alpha-lupulin, nerolidol 2, guaifenesin, caryophyllene oxide, alpha-bisabolol, camphene, beta-ocimene, eucalyptol, isopulegol, and nerolidol 1.
In embodiments, the cannabis extract comprises 8 or more of the following: alpha-pinene, beta-myrcene, beta-pinene, delta-limonene, linalool, beta-caryophyllene, alpha-lupulin, nerolidol 2, guaifenesin, caryophyllene oxide, alpha-bisabolol, camphene, beta-ocimene, eucalyptol, isopulegol, and nerolidol 1.
In embodiments, the cannabis extract comprises 9 or more of the following: alpha-pinene, beta-myrcene, beta-pinene, delta-limonene, linalool, beta-caryophyllene, alpha-lupulin, nerolidol 2, guaifenesin, caryophyllene oxide, alpha-bisabolol, camphene, beta-ocimene, eucalyptol, isopulegol, and nerolidol 1.
In embodiments, the cannabis extract comprises 10 or more of the following: alpha-pinene, beta-myrcene, beta-pinene, delta-limonene, linalool, beta-caryophyllene, alpha-lupulin, nerolidol 2, guaifenesin, caryophyllene oxide, alpha-bisabolol, camphene, beta-ocimene, eucalyptol, isopulegol, and nerolidol 1.
In embodiments, the cannabis extract comprises 11 or more of the following: alpha-pinene, beta-myrcene, beta-pinene, delta-limonene, linalool, beta-caryophyllene, alpha-lupulin, nerolidol 2, guaifenesin, caryophyllene oxide, alpha-bisabolol, camphene, beta-ocimene, eucalyptol, isopulegol, and nerolidol 1.
In embodiments, the cannabis extract comprises 12 or more of the following: alpha-pinene, beta-myrcene, beta-pinene, delta-limonene, linalool, beta-caryophyllene, alpha-lupulin, nerolidol 2, guaifenesin, caryophyllene oxide, alpha-bisabolol, camphene, beta-ocimene, eucalyptol, isopulegol, and nerolidol 1.
In embodiments, the cannabis extract comprises 13 or more of the following: alpha-pinene, beta-myrcene, beta-pinene, delta-limonene, linalool, beta-caryophyllene, alpha-lupulin, nerolidol 2, guaifenesin, caryophyllene oxide, alpha-bisabolol, camphene, beta-ocimene, eucalyptol, isopulegol, and nerolidol 1.
In embodiments, the cannabis extract comprises 14 or more of the following: alpha-pinene, beta-myrcene, beta-pinene, delta-limonene, linalool, beta-caryophyllene, alpha-lupulin, nerolidol 2, guaifenesin, caryophyllene oxide, alpha-bisabolol, camphene, beta-ocimene, eucalyptol, isopulegol, and nerolidol 1.
In embodiments, the cannabis extract comprises 15 or more of the following: alpha-pinene, beta-myrcene, beta-pinene, delta-limonene, linalool, beta-caryophyllene, alpha-lupulin, nerolidol 2, guaifenesin, caryophyllene oxide, alpha-bisabolol, camphene, beta-ocimene, eucalyptol, isopulegol, and nerolidol 1.
In embodiments, the cannabis extract comprises the following: alpha-pinene, beta-myrcene, beta-pinene, delta-limonene, linalool, beta-caryophyllene, alpha-lupulin, nerolidol 2, guaifenesin, caryophyllene oxide, alpha-bisabolol, camphene, beta-ocimene, eucalyptol, isopulegol, and nerolidol 1.
In embodiments, the composition is formulated as an oil. In another embodiment, the carrier is selected from the group consisting of: hemp seed oil, linseed oil, olive oil, fish oil, salmon oil, coconut oil, catmint oil, sesame oil, MCT oil and grape seed oil. In yet another embodiment, the carrier is grape seed oil. In embodiments, the carrier is sesame oil.
In embodiments, the dosage form comprises nepetalactone.
In embodiments, the dosage form comprises taurine.
In an embodiment, the pharmaceutical composition comprises lecithin. In another embodiment, the lecithin is sunflower lecithin. In another embodiment, the sunflower is about 5%, about 10%, about 15%, about 20%, about 25%, about 30%, about 35%, about 40%, about 45%, or about 50%.
In an embodiment, the pharmaceutical composition comprises NF-971P. In embodiments, the NF-971P weight/volume ratio is about 0.5%, about 1.0%, about 1.5%, about 2.0%, about 2.5%, or about 3.0%.
In embodiments, the pharmaceutical composition is formulated as a sublingual spray. In yet another embodiment, the pharmaceutical composition is formulated as a water or alcohol soluble solution, gel or cream for topical or transdermal application. In an embodiment, the pharmaceutical composition is applied to the back of the neck. In embodiments, the pharmaceutical composition is applied by transdermal auditory application. In another embodiment, the pharmaceutical composition is administered at a dose of 4 mg/kg. In another embodiment, the pharmaceutical composition is administered twice daily for four weeks. In embodiments, the pharmaceutical composition is formulated as a gel for buccal or mucosal administration. In embodiments, the pharmaceutical composition is formulated as a paste for buccal or mucosal administration. In embodiments, the pharmaceutical composition is formulated as a powder. In another embodiment, the pharmaceutical composition is formulated as a solution for subcutaneous injection. In yet another embodiment, the pharmaceutical composition is formulated as a tablet. In yet another embodiment, the pharmaceutical composition is formulated as a capsule. In embodiments, the pharmaceutical composition is formulated as a hard chewable. In embodiments, the pharmaceutical composition is formulated as a soft chewable.
In embodiments, the composition is formulated as a chew for oral administration. In another embodiment, the chew is produced using cold extrusion. In another embodiment, the chew weighs between about 0.5 and 10g. In yet another embodiment, the chew weighs about 4g, about 6g, about 9g, or about 10g. In yet another embodiment, the chew weighs about 0.5g. In an embodiment, the chew weighs about 1g. In another embodiment, the chew weighs about 1.5g. In yet another embodiment, the chew weighs about 2g. In yet another embodiment, the chew weighs about 3g. In an embodiment, the chew weighs about 4g. In another embodiment, the chew weighs about 5g. In yet another embodiment, the chew weighs about 6g. In yet another embodiment, the chew weighs about 7g. In an embodiment, the chew weighs about 8g. In another embodiment, the chew weighs about 9g. In yet another embodiment, the chew weighs about 10g.
In an embodiment, the 4g chew comprises:
about 7mg cannabidiol;
about 6mg cannabidiol;
about 0.12mg cannabigerol acid;
about 0.32mg Δ9-tetrahydrocannabinol; and
about 0.36mg cannabigerol.
The pharmaceutical compositions of the present disclosure may be prepared by methods well known in the art, for example, by means of conventional mixing, dissolving, granulating, levigating, pulverizing, dragee-making, levigating, emulsifying, encapsulating, entrapping or lyophilizing processes.
Thus, compositions for use in accordance with the present disclosure may be formulated in conventional manner using one or more pharmaceutically acceptable carriers comprising excipients and adjuvants, which facilitate processing of the active compounds into pharmaceutically usable formulations. The appropriate formulation depends on the route of administration selected.
Dosage form
In one aspect, provided herein is a dosage form comprising:
cannabidiol;
cannabidiol; and/or
One or more pharmaceutically acceptable additives, flavoring agents, surfactants and adjuvants.
In another embodiment, the dosage form comprises:
cannabidiol;
cannabidiol;
cannabigerol acid;
Δ9-tetrahydrocannabinol;
cannabichromene; and/or
One or more pharmaceutically acceptable additives, flavoring agents, surfactants and adjuvants.
In another embodiment, the dosage form comprises:
cannabidiol;
cannabidiol;
cannabigerol acid;
cannabigerol;
Δ9-tetrahydrocannabinol;
cannabichromene; and/or
One or more pharmaceutically acceptable additives, flavoring agents, surfactants and adjuvants.
In some embodiments, the source of cannabinoid in the dosage form is cannabis extract or pharmaceutical composition as disclosed herein.
In embodiments, the ratio of cannabidiol to cannabidiol is selected from the group consisting of: about 1:100, about 1:50, about 1:10, and about 1:1. In embodiments, the ratio of cannabidiol to cannabidiol is from about 0.1:1 to about 1:0.1. In another embodiment, the ratio of cannabidiol to cannabidiol is about 0.1:1, about 0.2:1, about 0.3:1, about 0.4:1, about 0.5:1, about 0.6:1, about 0.7:1, about 0.8:1, about 0.9:1, about 1:1, about 1:0.9, about 1:0.8, about 1:0.7, about 1:0.6, about 1:0.5, about 1:0.4, about 1:0.3, about 1:0.2, or about 1:0.1. In yet another embodiment, the ratio of cannabidiol to cannabidiol is from about 0.6:1 to about 1:0.6. In yet another embodiment, the ratio of cannabidiol to cannabidiol is about 1:1.
In the examples, the concentration of Δ9-tetrahydrocannabinol is insufficient to produce a psychotropic effect. In another embodiment, the ratio of Δ9-tetrahydrocannabinol to other cannabinoids is from about 1:50 to about 1:20. In yet another embodiment, the ratio of Δ9-tetrahydrocannabinol to other cannabinoids is about 1:50. In yet another embodiment, the ratio of Δ9-tetrahydrocannabinol to other cannabinoids is about 1:45. In an embodiment, the ratio of Δ9-tetrahydrocannabinol to other cannabinoids is about 1:40. In another embodiment, the ratio of Δ9-tetrahydrocannabinol to other cannabinoids is about 1:35. In yet another embodiment, the ratio of Δ9-tetrahydrocannabinol to other cannabinoids is about 1:30. In yet another embodiment, the ratio of Δ9-tetrahydrocannabinol to other cannabinoids is about 1:25. In an embodiment, the ratio of Δ9-tetrahydrocannabinol to other cannabinoids is about 1:20.
In embodiments, the concentration of Δ9-tetrahydrocannabinol is less than about 2mg/mL. In another embodiment, the concentration of Δ9-tetrahydrocannabinol is less than about 1.5mg/mL. In yet another embodiment, the concentration of Δ9-tetrahydrocannabinol is less than about 1mg/mL. In yet another embodiment, the concentration of Δ9-tetrahydrocannabinol is less than about 0.9mg/mL. In yet another embodiment, the concentration of Δ9-tetrahydrocannabinol is less than about 0.8mg/mL. In embodiments, the concentration of Δ9-tetrahydrocannabinol is less than about 0.7mg/mL. In another embodiment, the concentration of Δ9-tetrahydrocannabinol is less than about 0.6mg/mL. In yet another embodiment, the concentration of Δ9-tetrahydrocannabinol is less than about 0.5mg/mL. In yet another embodiment, the concentration of Δ9-tetrahydrocannabinol is less than about 0.4mg/mL. In embodiments, the concentration of Δ9-tetrahydrocannabinol is less than about 0.3mg/mL. In another embodiment, the concentration of Δ9-tetrahydrocannabinol is less than about 0.2mg/mL. In yet another embodiment, the concentration of Δ9-tetrahydrocannabinol is less than about 0.1mg/mL. In another embodiment, the concentration of Δ9-tetrahydrocannabinol is less than about 0.05mg/mL. In another embodiment, the concentration of Δ9-tetrahydrocannabinol is about 0mg/mL.
In an embodiment, the dosage form comprises:
about 0.1-20mg/mL cannabidiol;
about 0.1-20mg/mL cannabidiol;
about 0.01-0.5mg/mL cannabigerol acid;
about 0.01-0.5mg/mL of Δ9-tetrahydrocannabinol; and/or about 0.01-0.5mg/mL cannabidiol.
In another embodiment, the dosage form comprises:
about 1-10mg/mL cannabidiol;
about 1-10mg/mL cannabidiol;
about 0.05-0.2mg/mL cannabigerol acid;
about 0.1-0.3mg/mL of Δ9-tetrahydrocannabinol; and/or about 0.1-0.4mg/mL cannabidene.
In yet another embodiment, the dosage form comprises:
about 5mg/mL cannabidiol;
about 5mg/mL cannabidiol;
about 0.11mg/mL cannabigerol acid;
about 0.25mg/mL of Δ9-tetrahydrocannabinol; and/or
About 0.27mg/mL cannabigerol.
In some embodiments, the cannabis extract comprises THCA. In some embodiments, the dosage form comprises: alpha-pinene;
beta-myrcene;
beta-pinene;
delta-limonene;
linalool;
beta-caryophyllene;
alpha-lupulin;
nerolidol 2;
guaifenesin;
a caryophyllene oxide; and/or
Alpha-bisabolol.
In another embodiment, the dosage form comprises:
about 0.09% to about 0.13% α -pinene;
About 0.23% to about 0.44% of beta-myrcene;
about 0.04-0.09% beta-pinene;
about 0.05-0.09% delta-limonene;
about 0.03% to about 0.06% linalool;
about 0.04-0.07% beta-caryophyllene;
about 0.02-0.04% of alpha-lupulin;
about 0.04-0.07% nerolidol 2;
about 0.02% to about 0.04% guaifenesin;
about 0.04% to about 0.08% caryophyllene oxide; and/or
About 0.01-0.04% alpha-bisabolol.
In another embodiment, the dosage form comprises:
about 0.07-0.30% α -pinene;
about 0.10% to about 0.60% of beta-myrcene;
about 0.02-0.20% β -pinene;
about 0.03-0.20% delta-limonene;
about 0.01% to about 0.08% linalool;
about 0.03-0.09% beta-caryophyllene;
about 0.01-0.06% of alpha-lupulin;
about 0.02-0.09% nerolidol 2; and/or
About 0.01-0.06% guaifenesin.
In another embodiment, the dosage form comprises:
about 0.01-0.50% of alpha-pinene;
about 0.01-0.90% beta-myrcene;
about 0.01-0.50% β -pinene;
about 0.01-0.50% delta-limonene;
about 0.01% to about 0.50% linalool;
about 0.01-0.50% beta-caryophyllene;
about 0.01-0.50% of alpha-lupulin;
about 0.01-0.50% nerolidol 2;
about 0.01-0.50% guaifenesin;
About 0.01% to about 0.50% caryophyllene oxide; and/or
About 0.01-0.50% alpha-bisabolol.
In another embodiment, the dosage form further comprises:
camphene;
beta-ocimene;
eucalyptol;
isopulegol; and/or
Nerolidol 1.
In another embodiment, the dosage form comprises:
about 0.02% camphene;
about 0.02% to about 0.03% of beta-ocimene;
from about 0.02% to about 0.05% eucalyptol;
about 0.02% isopulegol; and/or
About 0.02-0.04% nerolidol 1.
In another embodiment, the dosage form comprises:
about 0.01-0.04% camphene;
about 0.01-0.05% of beta-ocimene;
from about 0.01% to about 0.07% eucalyptol;
from about 0.01% to about 0.04% isopulegol; and/or
About 0.01-0.05% nerolidol 1.
In another embodiment, the dosage form comprises:
about 0.01% to about 0.50% camphene;
about 0.01-0.50% of beta-ocimene;
from about 0.01% to about 0.50% eucalyptol;
from about 0.01% to about 0.50% isopulegol; and/or
About 0.01-0.50% nerolidol 1.
In embodiments, the cannabis extract does not include terpenes.
In embodiments, the cannabis extract comprises 1 or more of the following: alpha-pinene, beta-myrcene, beta-pinene, delta-limonene, linalool, beta-caryophyllene, alpha-lupulin, nerolidol 2, guaifenesin, caryophyllene oxide, alpha-bisabolol, camphene, beta-ocimene, eucalyptol, isopulegol, and nerolidol 1.
In embodiments, the cannabis extract comprises 2 or more of the following: alpha-pinene, beta-myrcene, beta-pinene, delta-limonene, linalool, beta-caryophyllene, alpha-lupulin, nerolidol 2, guaifenesin, caryophyllene oxide, alpha-bisabolol, camphene, beta-ocimene, eucalyptol, isopulegol, and nerolidol 1.
In embodiments, the cannabis extract comprises 3 or more of the following: alpha-pinene, beta-myrcene, beta-pinene, delta-limonene, linalool, beta-caryophyllene, alpha-lupulin, nerolidol 2, guaifenesin, caryophyllene oxide, alpha-bisabolol, camphene, beta-ocimene, eucalyptol, isopulegol, and nerolidol 1.
In embodiments, the cannabis extract comprises 4 or more of the following: alpha-pinene, beta-myrcene, beta-pinene, delta-limonene, linalool, beta-caryophyllene, alpha-lupulin, nerolidol 2, guaifenesin, caryophyllene oxide, alpha-bisabolol, camphene, beta-ocimene, eucalyptol, isopulegol, and nerolidol 1.
In embodiments, the dosage form comprises 5 or more of the following: alpha-pinene, beta-myrcene, beta-pinene, delta-limonene, linalool, beta-caryophyllene, alpha-lupulin, nerolidol 2, guaifenesin, caryophyllene oxide, alpha-bisabolol, camphene, beta-ocimene, eucalyptol, isopulegol, and nerolidol 1.
In embodiments, the dosage form comprises 6 or more of the following: alpha-pinene, beta-myrcene, beta-pinene, delta-limonene, linalool, beta-caryophyllene, alpha-lupulin, nerolidol 2, guaifenesin, caryophyllene oxide, alpha-bisabolol, camphene, beta-ocimene, eucalyptol, isopulegol, and nerolidol 1.
In embodiments, the dosage form comprises 7 or more of the following: alpha-pinene, beta-myrcene, beta-pinene, delta-limonene, linalool, beta-caryophyllene, alpha-lupulin, nerolidol 2, guaifenesin, caryophyllene oxide, alpha-bisabolol, camphene, beta-ocimene, eucalyptol, isopulegol, and nerolidol 1.
In embodiments, the dosage form comprises 8 or more of the following: alpha-pinene, beta-myrcene, beta-pinene, delta-limonene, linalool, beta-caryophyllene, alpha-lupulin, nerolidol 2, guaifenesin, caryophyllene oxide, alpha-bisabolol, camphene, beta-ocimene, eucalyptol, isopulegol, and nerolidol 1.
In embodiments, the dosage form comprises 9 or more of the following: alpha-pinene, beta-myrcene, beta-pinene, delta-limonene, linalool, beta-caryophyllene, alpha-lupulin, nerolidol 2, guaifenesin, caryophyllene oxide, alpha-bisabolol, camphene, beta-ocimene, eucalyptol, isopulegol, and nerolidol 1.
In embodiments, the dosage form comprises 10 or more of the following: alpha-pinene, beta-myrcene, beta-pinene, delta-limonene, linalool, beta-caryophyllene, alpha-lupulin, nerolidol 2, guaifenesin, caryophyllene oxide, alpha-bisabolol, camphene, beta-ocimene, eucalyptol, isopulegol, and nerolidol 1.
In embodiments, the dosage form comprises 11 or more of the following: alpha-pinene, beta-myrcene, beta-pinene, delta-limonene, linalool, beta-caryophyllene, alpha-lupulin, nerolidol 2, guaifenesin, caryophyllene oxide, alpha-bisabolol, camphene, beta-ocimene, eucalyptol, isopulegol, and nerolidol 1.
In embodiments, the dosage form comprises 12 or more of the following: alpha-pinene, beta-myrcene, beta-pinene, delta-limonene, linalool, beta-caryophyllene, alpha-lupulin, nerolidol 2, guaifenesin, caryophyllene oxide, alpha-bisabolol, camphene, beta-ocimene, eucalyptol, isopulegol, and nerolidol 1.
In embodiments, the dosage form comprises 13 or more of the following: alpha-pinene, beta-myrcene, beta-pinene, delta-limonene, linalool, beta-caryophyllene, alpha-lupulin, nerolidol 2, guaifenesin, caryophyllene oxide, alpha-bisabolol, camphene, beta-ocimene, eucalyptol, isopulegol, and nerolidol 1.
In embodiments, the dosage form comprises 14 or more of the following: alpha-pinene, beta-myrcene, beta-pinene, delta-limonene, linalool, beta-caryophyllene, alpha-lupulin, nerolidol 2, guaifenesin, caryophyllene oxide, alpha-bisabolol, camphene, beta-ocimene, eucalyptol, isopulegol, and nerolidol 1.
In embodiments, the dosage form comprises 15 or more of the following: alpha-pinene, beta-myrcene, beta-pinene, delta-limonene, linalool, beta-caryophyllene, alpha-lupulin, nerolidol 2, guaifenesin, caryophyllene oxide, alpha-bisabolol, camphene, beta-ocimene, eucalyptol, isopulegol, and nerolidol 1.
In embodiments, the dosage form comprises the following: alpha-pinene, beta-myrcene, beta-pinene, delta-limonene, linalool, beta-caryophyllene, alpha-lupulin, nerolidol 2, guaifenesin, caryophyllene oxide, alpha-bisabolol, camphene, beta-ocimene, eucalyptol, isopulegol, and nerolidol 1.
In an embodiment, the flavoring agent is selected from the group consisting of: peanut butter, catmint oil, peppermint oil, mango extract, beef, poultry meat and seafood. In another embodiment, the flavoring agent is peanut butter.
In embodiments, the dosage form is formulated as a sublingual spray. In yet another embodiment, the dosage form is formulated as a water or alcohol soluble solution, gel or cream for topical or transdermal application. In an embodiment, the dosage form is applied to the back of the neck. In embodiments, the dosage form is applied by transdermal auditory application. In another embodiment, the dosage form is administered at a dose of 4 mg/kg. In another embodiment, the dosage form is administered twice daily for four weeks. In embodiments, the dosage form is formulated as a gel for buccal or mucosal administration. In some embodiments, the dosage form is formulated as a paste for buccal or mucosal administration. In embodiments, the dosage form is formulated as a powder. In another embodiment, the dosage form is formulated as a solution for subcutaneous injection. In yet another embodiment, the dosage form is formulated as a tablet. In yet another embodiment, the dosage form is formulated as a capsule. In embodiments, the dosage form is formulated as a soft chewable.
In some embodiments, the invention comprises injecting an edible product having cannabis extract. In another embodiment, the edible product is a puffed food, a baked food, a nut butter, a spread, a pellet feed, or a processed food. In another embodiment, the edible product is a pet food. In another embodiment, the edible product is in a dry, shelf stable form, such as dried fish, dried dairy products, fish meal, edible fish meal, cereal, flour, carbohydrates, dried fruit, and the like. In another embodiment, the edible product is wet or semi-wet. In another embodiment, the edible product contains additives or supplements, such as vitamins, minerals, pharmaceutical agents, etc., e.g., chemicals, enzymes, etc., that are capable of removing plaque or tartar, etc., from the teeth of an animal. In embodiments, the cannabis extract is administered with catmint oil. In another embodiment, any of the dosage forms described may further comprise catmint oil.
In another embodiment, the cannabis extract is administered using an atomizer. In another embodiment, the nebulizer delivery apparatus and system are capable of effectively and efficiently administering one or more spray medications to an animal. In another embodiment, the atomizer system may be easily used with animals without removing it from its natural environment. In another embodiment, the nebulizer delivery apparatus and system can facilitate treatment of animals on a daily or multiple daily basis without undue stress or need for extensive resources. In another embodiment, the nebulizer delivery apparatus and system can be used with animals having different levels of training.
In one embodiment, the cannabis extract is applied using a diffuser. The diffuser may be any means for diffusing the cannabis extract into the air. The cannabis extract may be spread by any method, including by natural convection, by forced convection, by heating the wick or pad, for example, by holding the cannabis extract, by using a pump or by using a fan.
In one embodiment, the cannabis extract is administered through a pet collar. The pet collar may include a strap with a buckle on one side and a free end on the other side and an accessory device, such as a hole longitudinally disposed in a central portion of the strap, or a quick release buckle mechanism for securing the collar in a closed loop configuration. The pet collar may be made from a variety of materials, including nylon, polyester leather, or other suitable materials. The belt material may be treated with a water repellent compound. Nylon or polyester straps may be interwoven with the reflective fibers to enhance the visibility of the pet collar during the night. In one embodiment, the collar is impregnated with cannabis extract.
Chewing article
In embodiments, the dosage form is formulated as a chew for oral administration. In another embodiment, the chew is produced using cold extrusion. In another embodiment, the chew weighs between about 0.5 and 10g. In yet another embodiment, the chew weighs about 4g, about 6g, about 9g, or about 10g. In yet another embodiment, the chew weighs about 0.5g. In an embodiment, the chew weighs about 1g. In another embodiment, the chew weighs about 1.5g. In yet another embodiment, the chew weighs about 2g. In yet another embodiment, the chew weighs about 3g. In an embodiment, the chew weighs about 4g. In another embodiment, the chew weighs about 5g. In yet another embodiment, the chew weighs about 6g. In yet another embodiment, the chew weighs about 7g. In an embodiment, the chew weighs about 8g. In another embodiment, the chew weighs about 9g. In yet another embodiment, the chew weighs about 10g.
In one embodiment, the dosage form comprises:
beer yeast;
acacia gum;
guar gum;
a flavoring agent;
Verdilox；
Previon；
cannabis sativa extract;
glycerol;
sunflower lecithin; and/or
And (3) water.
In another embodiment, the dosage form comprises: about 25-35% brewer's yeast;
about 1-10% acacia;
about 0.1-4% guar gum;
about 10-20% flavoring agent;
about 0.01-1% Verdilox;
about 0.1-2% Previon;
about 1-10% cannabis extract;
about 10-20% glycerol;
about 1-10% sunflower lecithin; and/or about 1-10% water.
In another embodiment, the dosage form comprises:
about 29-33% brewer's yeast;
about 3-6% acacia;
about 0.5-2% guar gum;
about 12-16% flavoring agent;
about 0.01% to about 0.1% Verdilox;
about 0.5-1.5% Previon;
about 3-6% cannabis extract;
about 13-17% glycerol;
about 3-7% sunflower lecithin; and/or about 3-7% water.
In yet another embodiment, the dosage form comprises:
about 30% brewer's yeast;
about 4.7% acacia;
about 0.9% guar gum;
about 14.2% flavoring agent;
about 0.05% Verdilox;
about 0.9% Previon;
About 4.7% cannabis extract;
about 15.1% glycerol;
about 5.7% sunflower lecithin; and/or
About 5.7% water.
In one embodiment, the dosage form comprises:
HCl glucosamine;
beer yeast;
acacia gum;
guar gum;
a flavoring agent;
Verdilox；
Previon；
cannabis sativa extract;
glycerol;
sunflower lecithin; and/or
And (3) water.
In another embodiment, the dosage form comprises:
about 10-20% HCl glucosamine;
about 25-35% brewer's yeast;
about 1-10% acacia;
about 0.1-4% guar gum;
about 10-20% flavoring agent;
about 0.01-1% Verdilox;
about 0.1-2% Previon;
about 1-10% cannabis extract;
about 10-20% glycerol;
about 1-10% sunflower lecithin; and/or
About 1-10% water.
In another embodiment, the dosage form comprises:
about 12-17% HCl glucosamine;
about 29-33% brewer's yeast;
about 3-6% acacia;
about 0.5-2% guar gum;
about 12-16% flavoring agent;
about 0.01% to about 0.1% Verdilox;
about 0.5-1.5% Previon;
about 3-6% cannabis extract;
about 13-17% glycerol;
about 3-7% sunflower lecithin; and/or
About 3-7% water.
In yet another embodiment, the dosage form comprises:
about 15.6% HCl glucosamine;
about 30% brewer's yeast;
about 4.7% acacia;
about 0.9% guar gum;
about 14.2% flavoring agent;
about 0.05% Verdilox;
about 0.9% Previon;
about 4.7% cannabis extract;
about 15.1% glycerol;
about 5.7% sunflower lecithin; and/or
About 5.7% water.
In one embodiment, the dosage form comprises:
HCl glucosamine;
chondroitin sulfate (76%);
beer yeast;
acacia gum;
guar gum;
a flavoring agent;
Verdilox；
Previon；
cannabis sativa extract;
glycerol;
sunflower lecithin; and/or
And (3) water.
In another embodiment, the dosage form comprises:
about 10-20% HCl glucosamine;
about 0.1-7% chondroitin sulfate (76%);
about 25-35% brewer's yeast;
about 1-10% acacia;
about 0.1-4% guar gum;
about 10-20% flavoring agent;
about 0.01-1% Verdilox;
about 0.1-2% Previon;
about 1-10% cannabis extract;
about 10-20% glycerol;
about 1-10% sunflower lecithin; and/or about 1-10% water.
In another embodiment, the dosage form comprises:
About 12-17% HCl glucosamine;
about 1-4% chondroitin sulfate (76%);
about 29-33% brewer's yeast;
about 3-6% acacia;
about 0.5-2% guar gum;
about 12-16% flavoring agent;
about 0.01% to about 0.1% Verdilox;
about 0.5-1.5% Previon;
about 3-6% cannabis extract;
about 13-17% glycerol;
about 3-7% sunflower lecithin; and/or about 3-7% water.
In yet another embodiment, the dosage form comprises:
about 15.6% HCl glucosamine;
about 2.6% chondroitin sulfate (76%);
about 30% brewer's yeast;
about 4.7% acacia;
about 0.9% guar gum;
about 14.2% flavoring agent;
about 0.05% Verdilox;
about 0.9% Previon;
about 4.7% cannabis extract;
about 15.1% glycerol;
about 5.7% sunflower lecithin; and/or
About 5.7% water.
In another embodiment, the dosage form comprises:
hyaluronic acid;
beer yeast;
acacia gum;
guar gum;
a flavoring agent;
Verdilox；
Previon；
cannabis sativa extract;
glycerol;
sunflower lecithin; and/or
And (3) water.
In another embodiment, the dosage form comprises:
about 0.01-3% hyaluronic acid;
about 25-35% brewer's yeast;
About 1-10% acacia;
about 0.1-5% guar gum;
about 10-20% flavoring agent;
about 0.01-1% Verdilox;
about 0.1-3% Previon;
about 1-10% cannabis extract;
about 10-20% glycerol;
about 1-10% sunflower lecithin; and/or
About 1-10% water.
In another embodiment, the dosage form comprises:
about 0.01-1% hyaluronic acid;
about 29-33% brewer's yeast;
about 3-6% acacia;
about 0.5-2% guar gum;
about 12-16% flavoring agent;
about 0.01% to about 0.1% Verdilox;
about 0.5-1.5% Previon;
about 3-6% cannabis extract;
about 13-17% glycerol;
about 3-7% sunflower lecithin; and/or
About 3-7% water.
In yet another embodiment, the dosage form comprises:
about 0.1% hyaluronic acid;
about 30.6% brewer's yeast;
about 4.8% acacia;
about 0.97% guar gum;
about 14.5% flavoring agent;
about 0.05% Verdilox;
about 0.97% Previon;
about 4.8% cannabis extract;
about 15.5% glycerol;
about 5.8% sunflower lecithin; and/or
About 5.8% water.
In another embodiment, the dosage form comprises:
HCl glucosamine;
Hyaluronic acid;
beer yeast;
acacia gum;
guar gum;
a flavoring agent;
Verdilox；
Previon；
cannabis sativa extract;
glycerol;
sunflower lecithin; and/or
And (3) water.
In another embodiment, the dosage form comprises:
about 10-20% HCl glucosamine;
about 0.01-3% hyaluronic acid;
about 25-35% brewer's yeast;
about 1-10% acacia;
about 0.1-5% guar gum;
about 10-20% flavoring agent;
about 0.01-1% Verdilox;
about 0.1-3% Previon;
about 1-10% cannabis extract;
about 10-20% glycerol;
about 1-10% sunflower lecithin; and/or
About 1-10% water.
In another embodiment, the dosage form comprises:
about 12-17% HCl glucosamine;
about 0.01-1% hyaluronic acid;
about 29-33% brewer's yeast;
about 3-6% acacia;
about 0.5-2% guar gum;
about 12-16% flavoring agent;
about 0.01% to about 0.1% Verdilox;
about 0.5-1.5% Previon;
about 3-6% cannabis extract;
about 13-17% glycerol;
about 3-7% sunflower lecithin; and/or about 3-7% water.
In yet another embodiment, the dosage form comprises:
about 16% HCl glucosamine;
about 0.1% hyaluronic acid;
About 30.6% brewer's yeast;
about 4.8% acacia;
about 0.97% guar gum;
about 14.5% flavoring agent;
about 0.05% Verdilox;
about 0.97% Previon;
about 4.8% cannabis extract;
about 15.5% glycerol;
about 5.8% sunflower lecithin; and/or about 5.8% water.
In yet another embodiment, the dosage form comprises:
cannabis sativa extract;
peanut butter;
rice bran;
sweet potato;
dry molasses;
sorbic acid;
beer yeast;
sugar;
water;
glycerol;
potato starch;
dehydrated peanut butter;
rice starch; and/or
Guar gum.
In another embodiment, the dosage form comprises:
about 3.0-10.0% cannabis extract;
about 10.0-20.0% peanut butter;
about 10.0% to about 15.0% rice bran;
about 4.0-10.0% sweet potato;
about 6.0% to about 13.0% dry molasses;
about 0.5-5.0% sorbic acid;
about 2.0-8.0% brewer's yeast;
about 3.0-8.0% sugar;
about 5.0% to about 15.0% water;
about 8.0% to about 18.0% glycerol;
about 1.0% to about 8.0% potato starch;
about 0.5% to about 5.0% dehydrated peanut butter;
about 1.0% to about 5.0% rice starch; and/or about 1.0-5.0% guar gum.
In another embodiment, the dosage form comprises:
About 5.0% cannabis extract;
about 15.0% peanut butter;
about 12.5% rice bran;
about 5.5% sweet potato;
about 8.0% dry molasses;
about 1% sorbic acid;
about 5.0% brewer's yeast;
about 6.0% sugar;
about 9.25% water;
about 13.0% glycerol;
about 2.0% potato starch;
about 1.0% dehydrated peanut butter;
about 2.0% rice starch; and/or
About 2.0% guar gum.
In yet another embodiment, the dosage form comprises:
about 5.0% cannabis extract;
about 15.0% peanut butter;
about 13.0% rice bran;
about 6.0% sweet potato;
about 9.0% dry molasses;
about 1% sorbic acid;
about 5.0% brewer's yeast;
about 6.0% sugar;
about 9.5% water;
about 13.0% glycerol;
about 4.0% potato starch;
about 1.0% dehydrated peanut butter;
about 2.0% rice starch; and/or
About 2.0% guar gum.
In an embodiment, the dosage form comprises:
cannabis sativa extract;
peanut butter;
rice bran;
HCl glucosamine;
sweet potato;
dry molasses;
sorbic acid;
beer yeast;
sugar;
water;
glycerol;
potato starch;
dehydrated peanut butter;
rice starch; and/or
Guar gum.
In another embodiment, the dosage form comprises:
About 5.0% cannabis extract;
about 15.0% peanut butter;
about 12.5% rice bran;
about 12.75% HCl glucosamine;
about 5.5% sweet potato;
about 8.0% dry molasses;
about 1% sorbic acid;
about 5.0% brewer's yeast;
about 6.0% sugar;
about 9.25% water;
about 13.0% glycerol;
about 2.0% potato starch;
about 1.0% dehydrated peanut butter;
about 2.0% rice starch; and/or
About 2.0% guar gum.
In yet another embodiment, the dosage form comprises:
about 5.0% cannabis extract;
about 15.0% peanut butter;
about 13.0% rice bran;
about 8.5% HCl glucosamine;
about 6.0% sweet potato;
about 9.0% dry molasses;
about 1% sorbic acid;
about 5.0% brewer's yeast;
about 6.0% sugar;
about 9.5% water;
about 13.0% glycerol;
about 4.0% potato starch;
about 1.0% dehydrated peanut butter;
about 2.0% rice starch; and/or
About 2.0% guar gum.
In yet another embodiment, the dosage form comprises: about 3.0-10.0% cannabis extract;
about 10.0-20.0% peanut butter;
about 10.0% to about 15.0% rice bran;
about 5.0% to about 15.0% HCl glucosamine;
about 4.0-10.0% sweet potato;
About 6.0% to about 13.0% dry molasses;
about 0.5-5.0% sorbic acid;
about 2.0-8.0% brewer's yeast;
about 3.0-8.0% sugar;
about 5.0% to about 15.0% water;
about 8.0% to about 18.0% glycerol;
about 1.0% to about 8.0% potato starch;
about 0.5% to about 5.0% dehydrated peanut butter;
about 1.0% to about 5.0% rice starch; and/or
About 1.0-5.0% guar gum.
In another embodiment, the dosage form further comprises chondroitin sulfate. In an embodiment, the dosage form comprises:
cannabis sativa extract;
peanut butter;
rice bran;
HCl glucosamine;
sweet potato;
dry molasses;
sorbic acid;
beer yeast;
sugar;
water;
glycerol;
potato starch;
dehydrated peanut butter;
DigestaWell PET；
rice starch; and/or
Guar gum.
In another embodiment, the dosage form comprises:
about 3.0-10.0% cannabis extract;
about 5.0% to about 20.0% peanut butter;
about 10.0% to about 15.0% rice bran;
about 5.0% to about 15.0% HCl glucosamine;
about 4.0-10.0% sweet potato;
about 6.0% to about 13.0% dry molasses;
about 0.5-5.0% sorbic acid;
about 2.0-8.0% brewer's yeast;
about 3.0-8.0% sugar;
about 5.0% to about 15.0% water;
about 8.0% to about 18.0% glycerol;
about 1.0% to about 8.0% potato starch;
About 0.5% to about 5.0% dehydrated peanut butter;
about 0.1-3.0% DigestaWell PET; about 1.0% to about 8.0% rice starch; and/or about 1.0-5.0% guar gum.
In another embodiment, the dosage form comprises:
about 5.0% cannabis extract;
about 10.0% peanut butter;
about 12.0% rice bran;
about 12.75% HCl glucosamine;
about 5.5% sweet potato;
about 8.0% dry molasses;
about 1% sorbic acid;
about 5.0% brewer's yeast;
about 6.0% sugar;
about 7.25% water;
about 10.0% glycerol;
about 5.0% potato starch;
about 4.0% dehydrated peanut butter;
about 0.5% DigestaWell PET;
about 6.0% rice starch; and/or
About 2.0% guar gum.
In yet another embodiment, the dosage form comprises: about 5.0% cannabis extract;
about 10.0% peanut butter;
about 12.5% rice bran;
about 8.5% HCl glucosamine;
about 8.0% sweet potato;
about 9.0% dry molasses;
about 1% sorbic acid;
about 5.0% brewer's yeast;
about 6.0% sugar;
about 6.0% water;
about 10.0% glycerol;
about 6.0% potato starch;
about 4.0% dehydrated peanut butter;
about 0.5% DigestaWell PET;
about 6.5% rice starch; and/or
About 2.0% guar gum.
In an embodiment, the dosage form comprises:
cannabis sativa extract;
peanut butter;
rice bran;
HCl glucosamine;
sweet potato;
dry molasses;
sorbic acid;
beer yeast;
sugar;
water;
glycerol;
potato starch;
dehydrated peanut butter;
chondroitin;
DigestaWell PET；
rice starch; and/or
Guar gum.
In another embodiment, the dosage form comprises:
about 3.0-10.0% cannabis extract;
about 5.0% to about 20.0% peanut butter;
about 10.0% to about 15.0% rice bran;
about 5.0% to about 15.0% HCl glucosamine;
about 4.0-10.0% sweet potato;
about 6.0% to about 13.0% dry molasses;
about 0.5-5.0% sorbic acid;
about 2.0-8.0% brewer's yeast;
about 3.0-8.0% sugar;
about 5.0% to about 15.0% water;
about 8.0% to about 18.0% glycerol;
about 1.0% to about 8.0% potato starch;
about 0.5% to about 5.0% dehydrated peanut butter;
about 0.5-5.0% chondroitin;
about 0.1-3.0% DigestaWell PET; about 1.0% to about 8.0% rice starch; and/or about 1.0-5.0% guar gum.
In another embodiment, the dosage form comprises:
about 5.0% cannabis extract;
about 10.0% peanut butter;
about 12.0% rice bran;
about 12.75% HCl glucosamine;
About 5.5% sweet potato;
about 8.0% dry molasses;
about 1% sorbic acid;
about 5.0% brewer's yeast;
about 6.0% sugar;
about 7.25% water;
about 10.0% glycerol;
about 4.0% potato starch;
about 4.0% dehydrated peanut butter;
about 2.5% chondroitin;
about 0.5% DigestaWell PET;
about 4.5% rice starch; and/or
About 2.0% guar gum.
In yet another embodiment, the dosage form comprises:
about 5.0% cannabis extract;
about 10.0% peanut butter;
about 12.5% rice bran;
about 8.5% HCl glucosamine;
about 8.0% sweet potato;
about 9.0% dry molasses;
about 1% sorbic acid;
about 5.0% brewer's yeast;
about 6.0% sugar;
about 6.0% water;
about 10.0% glycerol;
about 5.0% potato starch;
about 4.0% dehydrated peanut butter;
about 2.5% chondroitin;
about 0.5% DigestaWell PET;
about 5.0% rice starch; and/or
About 2.0% guar gum.
In embodiments, the dosage form further comprises dried brewer's yeast, fructo-oligosaccharides, fumaric acid, lactic acid, citric acid, malic acid, thyme oil, anethole, cinnamic aldehyde, vegetable oil, dehydrated alfalfa meal, mineral oil, and/or sodium aluminosilicate.
In another embodiment, the dosage form comprises 2.0% cannabis extract. In another embodiment, the dosage form comprises 3.0% cannabis extract. In another embodiment, the dosage form comprises 4.0% cannabis extract. In another embodiment, the dosage form comprises 5.0% cannabis extract. In another embodiment, the dosage form comprises 6.0% cannabis extract. In another embodiment, the dosage form comprises 7.0% cannabis extract. In another embodiment, the dosage form comprises 8.0% cannabis extract. In another embodiment, the dosage form comprises 9.0% cannabis extract. In another embodiment, the dosage form comprises 10.0% cannabis extract.
In an embodiment, the cannabis extract comprises:
cannabidiol;
cannabidiol;
cannabigerol acid;
Δ9-tetrahydrocannabinol; and/or
Cannabichromene.
In embodiments, the ratio of cannabidiol to cannabidiol is selected from the group consisting of: about 1:100, about 1:50, about 1:10, and about 1:1. In embodiments, the ratio of cannabidiol to cannabidiol is from about 0.1:1 to about 1:0.1. In another embodiment, the ratio of cannabidiol to cannabidiol is about 0.1:1, about 0.2:1, about 0.3:1, about 0.4:1, about 0.5:1, about 0.6:1, about 0.7:1, about 0.8:1, about 0.9:1, about 1:1, about 1:0.9, about 1:0.8, about 1:0.7, about 1:0.6, about 1:0.5, about 1:0.4, about 1:0.3, about 1:0.2, or about 1:0.1. In yet another embodiment, the ratio of cannabidiol to cannabidiol is from about 0.6:1 to about 1:0.6. In yet another embodiment, the ratio of cannabidiol to cannabidiol is about 1:1.
In the examples, the concentration of Δ9-tetrahydrocannabinol is insufficient to produce a psychotropic effect. In another embodiment, the ratio of Δ9-tetrahydrocannabinol to other cannabinoids is from about 1:50 to about 1:20. In yet another embodiment, the ratio of Δ9-tetrahydrocannabinol to other cannabinoids is about 1:50. In yet another embodiment, the ratio of Δ9-tetrahydrocannabinol to other cannabinoids is about 1:45. In an embodiment, the ratio of Δ9-tetrahydrocannabinol to other cannabinoids is about 1:40. In another embodiment, the ratio of Δ9-tetrahydrocannabinol to other cannabinoids is about 1:35. In yet another embodiment, the ratio of Δ9-tetrahydrocannabinol to other cannabinoids is about 1:30. In yet another embodiment, the ratio of Δ9-tetrahydrocannabinol to other cannabinoids is about 1:25. In an embodiment, the ratio of Δ9-tetrahydrocannabinol to other cannabinoids is about 1:20.
In embodiments, the concentration of Δ9-tetrahydrocannabinol is less than about 2mg/mL. In another embodiment, the concentration of Δ9-tetrahydrocannabinol is less than about 1.5mg/mL. In yet another embodiment, the concentration of Δ9-tetrahydrocannabinol is less than about 1mg/mL. In yet another embodiment, the concentration of Δ9-tetrahydrocannabinol is less than about 0.9mg/mL. In yet another embodiment, the concentration of Δ9-tetrahydrocannabinol is less than about 0.8mg/mL. In embodiments, the concentration of Δ9-tetrahydrocannabinol is less than about 0.7mg/mL. In another embodiment, the concentration of Δ9-tetrahydrocannabinol is less than about 0.6mg/mL. In yet another embodiment, the concentration of Δ9-tetrahydrocannabinol is less than about 0.5mg/mL. In yet another embodiment, the concentration of Δ9-tetrahydrocannabinol is less than about 0.4mg/mL. In embodiments, the concentration of Δ9-tetrahydrocannabinol is less than about 0.3mg/mL. In another embodiment, the concentration of Δ9-tetrahydrocannabinol is less than about 0.2mg/mL. In yet another embodiment, the concentration of Δ9-tetrahydrocannabinol is less than about 0.1mg/mL. In another embodiment, the concentration of Δ9-tetrahydrocannabinol is less than about 0.05mg/mL. In yet another embodiment, the concentration of Δ9-tetrahydrocannabinol is about 0mg/mL.
In an embodiment, the cannabis extract comprises:
about 0.1-20mg/mL cannabidiol;
about 0.1-20mg/mL cannabidiol;
about 0.01-0.5mg/mL cannabigerol acid;
about 0.01-0.5mg/mL of Δ9-tetrahydrocannabinol; and/or
About 0.01-0.5mg/mL cannabigerol.
In another embodiment, the cannabis extract comprises:
about 1-10mg/mL cannabidiol;
about 1-10mg/mL cannabidiol;
about 0.05-0.2mg/mL cannabigerol acid;
about 0.1-0.3mg/mL of Δ9-tetrahydrocannabinol; and/or
About 0.1-0.4mg/mL cannabigerol.
In yet another embodiment, the cannabis extract comprises:
about 5mg/mL cannabidiol;
about 5mg/mL cannabidiol;
about 0.11mg/mL cannabigerol acid;
about 0.25mg/mL of Δ9-tetrahydrocannabinol; and/or
About 0.27mg/mL cannabigerol.
In some embodiments, the cannabis extract comprises THCA. In an embodiment, the cannabis extract comprises: alpha-pinene;
beta-myrcene;
beta-pinene;
delta-limonene;
linalool;
beta-caryophyllene;
alpha-lupulin;
nerolidol 2;
guaifenesin;
a caryophyllene oxide; and/or
Alpha-bisabolol.
In another embodiment, the cannabis extract comprises: about 0.09% to about 0.13% α -pinene;
About 0.23% to about 0.44% of beta-myrcene;
about 0.04-0.09% beta-pinene;
about 0.05-0.09% delta-limonene;
about 0.03% to about 0.06% linalool;
about 0.04-0.07% beta-caryophyllene;
about 0.02-0.04% of alpha-lupulin;
about 0.04-0.07% nerolidol 2;
about 0.02% to about 0.04% guaifenesin;
about 0.04% to about 0.08% caryophyllene oxide; and/or
About 0.01-0.04% alpha-bisabolol.
In another embodiment, the cannabis extract comprises: about 0.07-0.30% α -pinene;
about 0.10% to about 0.60% of beta-myrcene;
about 0.02-0.20% β -pinene;
about 0.03-0.20% delta-limonene;
about 0.01% to about 0.08% linalool;
about 0.03-0.09% beta-caryophyllene;
about 0.01-0.06% of alpha-lupulin;
about 0.02-0.09% nerolidol 2; and/or
About 0.01-0.06% guaifenesin;
in another embodiment, the cannabis extract comprises:
about 0.01-0.50% of alpha-pinene;
about 0.01-0.90% beta-myrcene;
about 0.01-0.50% β -pinene;
about 0.01-0.50% delta-limonene;
about 0.01% to about 0.50% linalool;
about 0.01-0.50% beta-caryophyllene;
about 0.01-0.50% of alpha-lupulin;
about 0.01-0.50% nerolidol 2;
About 0.01-0.50% guaifenesin;
about 0.01% to about 0.50% caryophyllene oxide; and/or
About 0.01-0.50% alpha-bisabolol.
In another embodiment, the cannabis extract further comprises: camphene;
beta-ocimene;
eucalyptol;
isopulegol; and/or
Nerolidol 1.
In another embodiment, the cannabis extract comprises:
about 0.02% camphene;
about 0.02% to about 0.03% of beta-ocimene;
from about 0.02% to about 0.05% eucalyptol;
about 0.02% isopulegol; and/or
About 0.02-0.04% nerolidol 1.
In another embodiment, the cannabis extract comprises:
about 0.01-0.04% camphene;
about 0.01-0.05% of beta-ocimene;
from about 0.01% to about 0.07% eucalyptol;
from about 0.01% to about 0.04% isopulegol; and/or
About 0.01-0.05% nerolidol 1.
In another embodiment, the cannabis extract comprises:
about 0.01% to about 0.50% camphene;
about 0.01-0.50% of beta-ocimene;
from about 0.01% to about 0.50% eucalyptol;
from about 0.01% to about 0.50% isopulegol; and/or
About 0.01-0.50% nerolidol 1.
In embodiments, the composition is formulated as an oil. In another embodiment, the carrier is selected from the group consisting of: hemp seed oil, linseed oil, olive oil, fish oil, salmon oil, coconut oil, catmint oil, sesame oil, MCT oil and grape seed oil. In yet another embodiment, the carrier is grape seed oil. In embodiments, the carrier is sesame oil.
In an embodiment, the flavoring agent is selected from the group consisting of: peanut butter, catmint oil, chicken liver powder, poultry meat extract, maltodextrin, butter and bacon. In another embodiment, the flavoring agent is chicken liver powder. In another embodiment, the flavoring agent is peanut butter.
In embodiments, the composition is formulated as a chew for oral administration. In another embodiment, the chew is produced using cold extrusion. In another embodiment, the chew weighs between about 0.5 and 10g. In yet another embodiment, the chew weighs about 4g, about 6g, about 9g, or about 10g. In yet another embodiment, the chew weighs about 0.5g. In an embodiment, the chew weighs about 1g. In another embodiment, the chew weighs about 1.5g. In yet another embodiment, the chew weighs about 2g. In yet another embodiment, the chew weighs about 3g. In an embodiment, the chew weighs about 4g. In another embodiment, the chew weighs about 5g. In yet another embodiment, the chew weighs about 6g. In yet another embodiment, the chew weighs about 7g. In an embodiment, the chew weighs about 8g. In another embodiment, the chew weighs about 9g. In yet another embodiment, the chew weighs about 10g.
In an embodiment, the 4g chew comprises:
about 7mg cannabidiol;
about 6mg cannabidiol;
about 0.12mg cannabigerol acid;
about 0.32mg Δ9-tetrahydrocannabinol; and/or
About 0.36mg cannabigerol.
Therapeutic method
In one aspect, provided herein is a method for treating a disease, disorder, syndrome, and/or condition in a veterinary subject in need thereof, the method comprising administering to the veterinary subject a therapeutically effective amount of any of the above compositions or dosage forms. In embodiments, the veterinary subject suffers from inflammation, dysuria, anxiety, depression, insomnia, pain (e.g., chronic pain, non-chronic pain, neuropathic pain, nerve dysfunction pain, nociceptive pain, post-operative pain), skin disease, cancer, psychotic disorder, convulsions, epilepsy, osteoarthritis, lymphoma, atopy, allergy, diarrhea (e.g., idiopathic diarrhea), noise aversion, feather withdrawal, hair withdrawal, skin wounds, sepsis, gastrointestinal tract conditions, behavioral problems, compulsive behavior, migraine, headache, insect bite, diabetes, inflammatory bowel disease, skin disease (e.g., pruritus, sepsis), urine disease, anxiety, or depression.
In embodiments, the veterinary subject is a cat. In embodiments, cats are >6 months and <12 years old. In an embodiment, the cat is <6 months. In embodiments, the cat is about 6-12 months. In embodiments, the cat is about 1-3 years old. In embodiments, the cat is about 3-6 years old. In embodiments, the cat is about 6-9 years old. In embodiments, the cat is about 9-12 years old. In embodiments, the cat is about 12-15 years old. In embodiments, the cat is about >15 years old.
In embodiments, the pharmaceutical composition, dosage form or cannabis extract is administered at a dose of about 0.1-50.0 mg/kg. In embodiments, the pharmaceutical composition, dosage form or cannabis extract is administered at a dose of about 1-50.0 mg/kg. In embodiments, the pharmaceutical composition, dosage form or cannabis extract is administered at a dose of about 10-50.0 mg/kg. In embodiments, the pharmaceutical composition, dosage form or cannabis extract is administered at a dose of about 10-25 mg/kg. In embodiments, the pharmaceutical composition, dosage form or cannabis extract is administered at a dose of about 15-50.0 mg/kg. In embodiments, the pharmaceutical composition, dosage form or cannabis extract is administered at a dose of about 15-25 mg/kg. In embodiments, the pharmaceutical composition, dosage form or cannabis extract is administered at a dose of about 20-50.0 mg/kg. In embodiments, the pharmaceutical composition, dosage form or cannabis extract is administered at a dose of about 25-50.0 mg/kg. In embodiments, the pharmaceutical composition, dosage form or cannabis extract is administered at a dose of about 30-50.0 mg/kg. In embodiments, the pharmaceutical composition, dosage form or cannabis extract is administered at a dose of about 20-35 mg/kg. In embodiments, the pharmaceutical composition, dosage form or cannabis extract is administered at a dose of about 25-35 mg/kg. In embodiments, the pharmaceutical composition, dosage form or cannabis extract is administered at a dose of about 35-50.0 mg/kg. In embodiments, the pharmaceutical composition, dosage form or cannabis extract is administered at a dose of about 0.1-15.0 mg/kg. In another embodiment, the pharmaceutical composition, dosage form or cannabis extract is administered at a dosage of about 0.1-10.0 mg/kg. In embodiments, the dose is administered orally. In embodiments, the dose is administered locally.
In yet another embodiment, the pharmaceutical composition, dosage form or cannabis extract is administered at a dose of about 0.1 mg/kg. In yet another embodiment, the pharmaceutical composition, dosage form or cannabis extract is administered at a dose of about 0.2 mg/kg. In yet another embodiment, the pharmaceutical composition, dosage form or cannabis extract is administered at a dose of about 0.3 mg/kg. In embodiments, the pharmaceutical composition, dosage form, or cannabis extract is administered at a dose of about 0.4 mg/kg. In another embodiment, the pharmaceutical composition, dosage form or cannabis extract is administered at a dose of about 0.5 mg/kg. In yet another embodiment, the pharmaceutical composition, dosage form or cannabis extract is administered at a dose of about 0.6 mg/kg. In yet another embodiment, the pharmaceutical composition, dosage form or cannabis extract is administered at a dose of about 0.7 mg/kg. In yet another embodiment, the pharmaceutical composition, dosage form or cannabis extract is administered at a dose of about 0.8 mg/kg. In embodiments, the pharmaceutical composition, dosage form, or cannabis extract is administered at a dose of about 0.9 mg/kg. In another embodiment, the pharmaceutical composition, dosage form or cannabis extract is administered at a dose of about 1 mg/kg. In yet another embodiment, the pharmaceutical composition, dosage form or cannabis extract is administered at a dose of about 1.5 mg/kg. In yet another embodiment, the pharmaceutical composition, dosage form or cannabis extract is administered at a dose of about 2 mg/kg. In embodiments, the pharmaceutical composition, dosage form, or cannabis extract is administered at a dose of about 3 mg/kg. In another embodiment, the pharmaceutical composition, dosage form or cannabis extract is administered at a dose of about 4 mg/kg. In yet another embodiment, the pharmaceutical composition, dosage form or cannabis extract is administered at a dose of about 5 mg/kg. In yet another embodiment, the pharmaceutical composition, dosage form or cannabis extract is administered at a dose of about 6 mg/kg. In embodiments, the pharmaceutical composition, dosage form, or cannabis extract is administered at a dose of about 7 mg/kg. In another embodiment, the pharmaceutical composition, dosage form or cannabis extract is administered at a dose of about 8 mg/kg. In yet another embodiment, the pharmaceutical composition, dosage form or cannabis extract is administered at a dose of about 9 mg/kg. In yet another embodiment, the pharmaceutical composition, dosage form or cannabis extract is administered at a dose of about 10 mg/kg. In embodiments, the pharmaceutical composition, dosage form, or cannabis extract is administered at a dose of about 11 mg/kg. In another embodiment, the pharmaceutical composition, dosage form or cannabis extract is administered at a dose of about 12 mg/kg. In yet another embodiment, the pharmaceutical composition, dosage form or cannabis extract is administered at a dose of about 13 mg/kg. In yet another embodiment, the pharmaceutical composition, dosage form or cannabis extract is administered at a dose of about 14 mg/kg. In embodiments, the pharmaceutical composition, dosage form, or cannabis extract is administered at a dose of about 15 mg/kg. In embodiments, the pharmaceutical composition, dosage form, or cannabis extract is administered at a dose of about 20 mg/kg. In embodiments, the pharmaceutical composition, dosage form, or cannabis extract is administered at a dose of about 25 mg/kg. In embodiments, the pharmaceutical composition, dosage form, or cannabis extract is administered at a dose of about 30 mg/kg. In embodiments, the pharmaceutical composition, dosage form, or cannabis extract is administered at a dose of about 35 mg/kg. In embodiments, the pharmaceutical composition, dosage form, or cannabis extract is administered at a dose of about 40 mg/kg. In embodiments, the pharmaceutical composition, dosage form, or cannabis extract is administered at a dose of about 45 mg/kg. In embodiments, the pharmaceutical composition, dosage form, or cannabis extract is administered at a dose of about 50 mg/kg. In embodiments, the dose is administered orally. In embodiments, the dose is administered locally.
In another embodiment, the pharmaceutical composition, dosage form or cannabis extract is administered at twice the therapeutically effective dose for one week and then subsequently at the therapeutically effective dose. In yet another embodiment, the therapeutically effective dose is about 0.1-0.5mg/kg. In yet another embodiment, the therapeutically effective dose is about 2mg/kg. In an embodiment, the therapeutically effective dose is about 8mg/kg.
In embodiments, the pharmaceutical composition, dosage form or cannabis extract is administered at a dose of about 1mg/kg for one week and then subsequently at a dose of about 0.1-0.5mg/kg. In another embodiment, the pharmaceutical composition, dosage form or cannabis extract is administered at a dose of about 4mg/kg for one week and then subsequently at a dose of about 2mg/kg.
In an embodiment, the pharmaceutical composition, dosage form or cannabis extract is administered once daily at a dose of about 1.0 mg/kg. In an embodiment, the pharmaceutical composition, dosage form or cannabis extract is administered twice daily at a dose of about 1.0 mg/kg. In an embodiment, the pharmaceutical composition, dosage form or cannabis extract is administered three times daily at a dose of about 1.0 mg/kg. In an embodiment, the pharmaceutical composition, dosage form or cannabis extract is administered four times per day at a dose of about 1.0 mg/kg.
In an embodiment, the pharmaceutical composition, dosage form or cannabis extract is administered once daily at a dose of about 2.0 mg/kg. In an embodiment, the pharmaceutical composition, dosage form or cannabis extract is administered twice daily at a dose of about 2.0 mg/kg. In an embodiment, the pharmaceutical composition, dosage form or cannabis extract is administered three times daily at a dose of about 2.0 mg/kg. In an embodiment, the pharmaceutical composition, dosage form or cannabis extract is administered four times per day at a dose of about 2.0 mg/kg.
In an embodiment, the pharmaceutical composition, dosage form or cannabis extract is administered once daily at a dose of about 3.0 mg/kg. In an embodiment, the pharmaceutical composition, dosage form or cannabis extract is administered twice daily at a dose of about 3.0 mg/kg. In an embodiment, the pharmaceutical composition, dosage form or cannabis extract is administered three times daily at a dose of about 3.0 mg/kg. In an embodiment, the pharmaceutical composition, dosage form or cannabis extract is administered four times per day at a dose of about 3.0 mg/kg.
In an embodiment, the pharmaceutical composition, dosage form or cannabis extract is administered once daily at a dose of about 4.0 mg/kg. In an embodiment, the pharmaceutical composition, dosage form or cannabis extract is administered twice daily at a dose of about 4.0 mg/kg. In an embodiment, the pharmaceutical composition, dosage form or cannabis extract is administered three times daily at a dose of about 4.0 mg/kg. In an embodiment, the pharmaceutical composition, dosage form or cannabis extract is administered four times per day at a dose of about 4.0 mg/kg. In an embodiment, the pharmaceutical composition, dosage form or cannabis extract is administered once daily at a dose of about 5.0 mg/kg. In an embodiment, the pharmaceutical composition, dosage form or cannabis extract is administered twice daily at a dose of about 5.0 mg/kg. In an embodiment, the pharmaceutical composition, dosage form or cannabis extract is administered three times daily at a dose of about 5.0 mg/kg. In an embodiment, the pharmaceutical composition, dosage form or cannabis extract is administered four times per day at a dose of about 5.0 mg/kg.
In an embodiment, the pharmaceutical composition, dosage form or cannabis extract is administered once daily at a dose of about 6.0 mg/kg. In an embodiment, the pharmaceutical composition, dosage form or cannabis extract is administered twice daily at a dose of about 6.0 mg/kg. In an embodiment, the pharmaceutical composition, dosage form or cannabis extract is administered three times daily at a dose of about 6.0 mg/kg. In an embodiment, the pharmaceutical composition, dosage form or cannabis extract is administered four times per day at a dose of about 6.0 mg/kg.
In an embodiment, the pharmaceutical composition, dosage form or cannabis extract is administered once daily at a dose of about 7.0 mg/kg. In an embodiment, the pharmaceutical composition, dosage form or cannabis extract is administered twice daily at a dose of about 7.0 mg/kg. In an embodiment, the pharmaceutical composition, dosage form or cannabis extract is administered three times daily at a dose of about 7.0 mg/kg. In an embodiment, the pharmaceutical composition, dosage form or cannabis extract is administered four times per day at a dose of about 7.0 mg/kg.
In an embodiment, the pharmaceutical composition, dosage form or cannabis extract is administered once daily at a dose of about 8.0 mg/kg. In an embodiment, the pharmaceutical composition, dosage form or cannabis extract is administered twice daily at a dose of about 8.0 mg/kg. In an embodiment, the pharmaceutical composition, dosage form or cannabis extract is administered three times daily at a dose of about 8.0 mg/kg. In an embodiment, the pharmaceutical composition, dosage form or cannabis extract is administered four times per day at a dose of about 8.0 mg/kg.
In an embodiment, the pharmaceutical composition, dosage form or cannabis extract is administered once daily at a dose of about 9.0 mg/kg. In an embodiment, the pharmaceutical composition, dosage form or cannabis extract is administered twice daily at a dose of about 9.0 mg/kg. In an embodiment, the pharmaceutical composition, dosage form or cannabis extract is administered three times daily at a dose of about 9.0 mg/kg. In an embodiment, the pharmaceutical composition, dosage form or cannabis extract is administered four times per day at a dose of about 9.0 mg/kg.
In an embodiment, the pharmaceutical composition, dosage form or cannabis extract is administered once daily at a dose of about 10.0 mg/kg. In an embodiment, the pharmaceutical composition, dosage form or cannabis extract is administered twice daily at a dose of about 10.0 mg/kg. In an embodiment, the pharmaceutical composition, dosage form or cannabis extract is administered three times daily at a dose of about 10.0 mg/kg. In an embodiment, the pharmaceutical composition, dosage form or cannabis extract is administered four times per day at a dose of about 10.0 mg/kg.
In an embodiment, the pharmaceutical composition, dosage form or cannabis extract is administered twice daily at a dose of about 2 mg/kg.
In embodiments, a pharmaceutical composition, dosage form, or drop of cannabis extract is administered to a subject. In another embodiment, 0.5mL of the pharmaceutical composition, dosage form, or cannabis extract is administered to a subject. In another embodiment, 1mL of the pharmaceutical composition, dosage form, or cannabis extract is administered to a subject. In another embodiment, 2mL of the pharmaceutical composition, dosage form, or cannabis extract is administered to a subject. In another embodiment, 3mL of the pharmaceutical composition, dosage form, or cannabis extract is administered to a subject. In another embodiment, 4mL of the pharmaceutical composition, dosage form, or cannabis extract is administered to the subject. In another embodiment, 5mL of the pharmaceutical composition, dosage form, or cannabis extract is administered to the subject. In another embodiment, 6mL of the pharmaceutical composition, dosage form, or cannabis extract is administered to the subject. In another embodiment, 7mL of the pharmaceutical composition, dosage form, or cannabis extract is administered to a subject. In another embodiment, 8mL of the pharmaceutical composition, dosage form, or cannabis extract is administered to the subject. In another embodiment, 9mL of the pharmaceutical composition, dosage form, or cannabis extract is administered to the subject. In another embodiment, 10mL of the pharmaceutical composition, dosage form, or cannabis extract is administered to a subject.
In embodiments, the methods result in a therapeutically effective median maximum serum concentration of Cannabidiol (CBD). In another embodiment, the median maximum serum concentration of CBD is about 30-90ng/mL. In another embodiment, the median maximum serum concentration of CBD is about 30ng/mL. In another embodiment, the median maximum serum concentration of CBD is about 50ng/mL. In another embodiment, the median maximum serum concentration of CBD is about 70ng/mL. In another embodiment, the median maximum serum concentration of CBD is about 90ng/mL. In another embodiment, the median maximum serum concentration of CBD is about 90-310ng/mL. In yet another embodiment, the median maximum serum concentration of CBD is about 90ng/mL. In yet another embodiment, the median maximum serum concentration of CBD is about 100ng/mL. In yet another embodiment, the median maximum serum concentration of CBD is about 102ng/mL. In an embodiment, the median maximum serum concentration of CBD is about 200ng/mL. In another embodiment, the median maximum serum concentration of CBD is about 300ng/mL. In yet another embodiment, the median maximum serum concentration of CBD is about 400ng/mL. In yet another embodiment, the median maximum serum concentration of CBD is about 500ng/mL. In an embodiment, the median maximum serum concentration of CBD is about 590ng/mL. In another embodiment, the median maximum serum concentration of CBD is about 600ng/mL.
In embodiments, the methods result in a therapeutically effective median maximum serum concentration of Cannabidiol (CBDA). In another embodiment, the median maximum serum concentration of CBDA is about 30-90ng/mL. In another embodiment, the median maximum serum concentration of CBDA is about 30ng/mL. In another embodiment, the median maximum serum concentration of CBDA is about 50ng/mL. In another embodiment, the median maximum serum concentration of CBDA is about 70ng/mL. In another embodiment, the median maximum serum concentration of CBDA is about 90ng/mL. In another embodiment, the median maximum serum concentration of CBDA is from about 90-310ng/mL. In yet another embodiment, the median maximum serum concentration of CBDA is about 90ng/mL. In yet another embodiment, the median maximum serum concentration of CBDA is about 100ng/mL. In yet another embodiment, the median maximum serum concentration of CBDA is about 102ng/mL. In an embodiment, the median maximum serum concentration of CBDA is about 200ng/mL. In another embodiment, the median maximum serum concentration of CBDA is about 300ng/mL. In yet another embodiment, the median maximum serum concentration of CBDA is about 400ng/mL. In yet another embodiment, the median maximum serum concentration of CBDA is about 500ng/mL. In an example, the median maximum serum concentration of CBDA is about 590ng/mL. In another embodiment, the median maximum serum concentration of CBDA is about 600ng/mL.
In embodiments, the methods result in a therapeutically effective median maximum serum concentration of CBD and CBDA. In another embodiment, the median maximum serum concentration of CBD and CBDA is about 30-90ng/mL. In another embodiment, the median maximum serum concentration of CBD and CBDA is about 30ng/mL. In another embodiment, the median maximum serum concentration of CBD and CBDA is about 50ng/mL. In another embodiment, the median maximum serum concentration of CBD and CBDA is about 70ng/mL. In another embodiment, the median maximum serum concentration of CBD and CBDA is about 90ng/mL. In another embodiment, the median maximum serum concentration of CBD and CBDA is from about 90-310ng/mL. In yet another embodiment, the median maximum serum concentration of CBD and CBDA is about 90ng/mL. In yet another embodiment, the median maximum serum concentration of CBD and CBDA is about 100ng/mL. In yet another embodiment, the median maximum serum concentration of CBD and CBDA is about 102ng/mL. In an embodiment, the median maximum serum concentration of CBD and CBDA is about 200ng/mL. In another embodiment, the median maximum serum concentration of CBD and CBDA is about 300ng/mL. In yet another embodiment, the median maximum serum concentration of CBD and CBDA is about 400ng/mL. In yet another embodiment, the median maximum serum concentration of CBD and CBDA is about 500ng/mL. In an embodiment, the median maximum serum concentration of CBD and CBDA is about 590ng/mL. In another embodiment, the median maximum serum concentration of CBD and CBDA is about 600ng/mL.
In embodiments, the veterinary subject is a canine, feline, bovine, porcine, or equine. In another embodiment, the veterinary subject is a canine. In yet another embodiment, the veterinary subject is a cat. In yet another embodiment, the veterinary subject is a horse.
In embodiments, the cannabis extract is administered at a dose of about 0.1-15.0 mg/kg. In another embodiment, the cannabis extract is administered at a dose of about 0.1-10.0 mg/kg. In yet another embodiment, the cannabis extract is administered at a dose of about 0.1 mg/kg. In yet another embodiment, the cannabis extract is administered at a dose of about 0.2 mg/kg. In yet another embodiment, the cannabis extract is administered at a dose of about 0.3 mg/kg. In an embodiment, the cannabis extract is administered at a dose of about 0.4 mg/kg. In another embodiment, the cannabis extract is administered at a dose of about 0.5 mg/kg. In yet another embodiment, the cannabis extract is administered at a dose of about 0.6 mg/kg. In yet another embodiment, the cannabis extract is administered at a dose of about 0.7 mg/kg. In yet another embodiment, the cannabis extract is administered at a dose of about 0.8 mg/kg. In an embodiment, the cannabis extract is administered at a dose of about 0.9 mg/kg. In another embodiment, the cannabis extract is administered at a dose of about 1 mg/kg. In yet another embodiment, the cannabis extract is administered at a dose of about 1.5 mg/kg. In yet another embodiment, the cannabis extract is administered at a dose of about 2 mg/kg. In an embodiment, the cannabis extract is administered at a dose of about 3 mg/kg. In another embodiment, the cannabis extract is administered at a dose of about 4 mg/kg. In yet another embodiment, the cannabis extract is administered at a dose of about 5 mg/kg. In yet another embodiment, the cannabis extract is administered at a dose of about 6 mg/kg. In an embodiment, the cannabis extract is administered at a dose of about 7 mg/kg. In another embodiment, the cannabis extract is administered at a dose of about 8 mg/kg. In yet another embodiment, the cannabis extract is administered at a dose of about 9 mg/kg. In yet another embodiment, the cannabis extract is administered at a dose of about 10 mg/kg. In an embodiment, the cannabis extract is administered at a dose of about 11 mg/kg. In another embodiment, the cannabis extract is administered at a dose of about 12 mg/kg. In yet another embodiment, the cannabis extract is administered at a dose of about 13 mg/kg. In yet another embodiment, the cannabis extract is administered at a dose of about 14 mg/kg. In an embodiment, the cannabis extract is administered at a dose of about 15 mg/kg.
In another embodiment, the cannabis extract is administered at twice the therapeutically effective dose for one week and then subsequently at the therapeutically effective dose. In yet another embodiment, the therapeutically effective dose is about 0.1-0.5mg/kg. In yet another embodiment, the therapeutically effective dose is about 2mg/kg. In an embodiment, the therapeutically effective dose is about 8mg/kg.
In an embodiment, the cannabis extract is administered at a dose of about 1mg/kg for one week and then subsequently at a dose of about 0.1-0.5mg/kg. In another embodiment, the cannabis extract is administered at a dose of about 4mg/kg for one week and then subsequently at a dose of about 2mg/kg.
In embodiments, the methods result in a therapeutically effective median maximum serum concentration of cannabidiol. In another embodiment, the median maximum serum concentration of cannabidiol is about 90-310ng/mL. In yet another embodiment, the median maximum serum concentration of cannabidiol is about 90ng/mL. In yet another embodiment, the median maximum serum concentration of cannabidiol is about 100ng/mL. In yet another embodiment, the median maximum serum concentration of cannabidiol is about 102ng/mL. In an embodiment, the median maximum serum concentration of cannabidiol is about 200ng/mL. In another embodiment, the median maximum serum concentration of cannabidiol is about 300ng/mL. In yet another embodiment, the median maximum serum concentration of cannabidiol is about 400ng/mL. In yet another embodiment, the median maximum serum concentration of cannabidiol is about 500ng/mL. In an example, the median maximum serum concentration of cannabidiol is about 590ng/mL. In another embodiment, the median maximum serum concentration of cannabidiol is about 600ng/mL.
The pharmaceutical compositions and dosage forms of the present disclosure may be administered by any convenient route, such as by infusion or bolus injection, by absorption through epithelial or mucosal lining (e.g., oral mucosa, rectal and intestinal mucosa, etc.), and may be administered with any other therapeutic agent. Administration may be systemic or local. In embodiments, the administration is topical. In another embodiment, topical administration is used to treat local pain. In another embodiment, the localized pain is joint pain. In embodiments, the veterinary subject is an animal (e.g., a horse, cow, or pig) of >100 kg.
The therapeutic compositions of the present invention will be administered with suitable carriers, excipients, and other agents incorporated into the formulation to provide improved transfer, delivery, tolerability, etc. Many suitable formulations can be found in the prescription set known to all pharmaceutical chemists: lemington's pharmaceutical sciences, mark publishing company of Iston, pa. These formulations comprise, for example, powders, pastes, ointments, gels, waxes, oils, lipids, vesicle-containing lipids (cationic or anionic) (e.g., LIPOFECTIN) TM ) DNA conjugates, anhydrous absorption pastes, oil-in-water and water-in-oil emulsions, carbowax emulsions (polyethylene glycols of various molecular weights), semi-solid gels, and semi-solid mixtures containing carbowax. See also Powell et al, "Assembly of excipients for parenteral formulations (Compendium of excipients for parenteral formulations)". PDA (1998) journal of pharmaceutical science and technology (J Pharm Sci Technol) 52:238-311.
The compositions and dosages may vary depending on the age, weight and sex of the subject to be administered, the disease, disorder, syndrome, condition, route of administration, and the like of interest. Various delivery systems are known and may be used to administer the pharmaceutical compositions of the present invention, for example encapsulated in liposomes, microparticles, microcapsules, receptor-mediated endocytosis (see, e.g., wu et al (1987) journal of biochemistry (j. Biol. Chem.) 262:4429-4432). Methods of introduction include, but are not limited to, intradermal, intramuscular, intraperitoneal, intravenous, topical, transdermal, buccal, sublingual, subcutaneous, intranasal, epidural, and oral routes. The compositions may be administered by any convenient route, for example by infusion or bolus injection, by absorption through epithelial or skin mucosal linings (e.g., oral mucosa, rectal and intestinal mucosa, etc.), and may be administered with other bioactive agents. Administration may be systemic or local.
Pharmaceutical formulations for oral use may be prepared by: the resulting mixture is optionally ground using solid excipients and, if desired, the mixture of granules is processed after adding suitable adjuvants to obtain tablets or dragee cores. Suitable excipients are in particular fillers, such as sugars, including lactose, sucrose, mannitol, or sorbitol; cellulose preparations, such as corn starch, wheat starch, rice starch, potato starch, gelatin, methylcellulose, hydroxypropyl methylcellulose, sodium carboxymethylcellulose and/or physiologically acceptable polymers, such as polyvinylpyrrolidone (PVP). If desired, disintegrating agents may be added, such as crosslinked polyvinylpyrrolidone, agar, or alginic acid or a salt thereof, such as sodium alginate.
Providing dragee cores with suitable coatings. For this purpose, concentrated sugar solutions may be used, which may optionally contain gum arabic, talc, polyvinyl pyrrolidone, carbomer gel, polyethylene glycol, titanium dioxide, lacquer solutions, and suitable organic solvents or solvent mixtures.
Injectable formulations may contain dosage forms for intravenous, subcutaneous, intradermal and intramuscular injection, topical injection, drip infusion and the like. These injectable formulations can be prepared by publicly known methods. For example, injectable formulations may be prepared, for example, by dissolving, suspending or emulsifying the pharmaceutical composition, dosage form or cannabis extract in a sterile aqueous or oily medium conventionally used for injection. As the aqueous medium for injection, there are, for example, physiological saline, isotonic solution containing glucose and other auxiliary agents, etc., which may be used in combination with an appropriate solubilizing agent such as alcohol (e.g., ethanol), polyol (e.g., propylene glycol, polyethylene glycol), nonionic surfactant [ e.g., polysorbate 80, HCO-50 (polyoxyethylene (50 mol) adduct of hydrogenated castor oil) ] and the like. As the oily medium, for example, sesame oil, soybean oil, etc., are used, and they may be used in combination with a solubilizing agent such as benzyl benzoate, benzyl alcohol, etc. The injection thus prepared may be filled into an appropriate ampoule.
Pharmaceutical compositions that can be used orally include push-fit capsules made of gelatin and soft, sealed capsules made of gelatin and a plasticizer, such as glycerol or sorbitol. Push-fit capsules may contain the active ingredient in admixture with fillers such as lactose, binders such as starches, lubricants such as talc or magnesium stearate and, optionally, stabilizers. In soft capsules, the active ingredient may be dissolved or suspended in a suitable liquid, such as a fatty oil, liquid paraffin or liquid polyethylene glycol.
Alternatively, the composition may be in powder form for constitution prior to use with a suitable vehicle, e.g., sterile pyrogen-free water. The exact formulation, route of administration, and dosage may be selected by a physician familiar with the patient's pathology. (see, e.g., fingl et al, 1975, "pharmacological basis for therapeutics (The Pharmacological Basis of Therapeutics)", chapter I, page 1). Depending on the severity and responsiveness of the condition being treated, administration may also be a single administration of a slow-release composition, wherein the course of treatment lasts from several days to several weeks, or until a cure is achieved or a reduction in the disease state is achieved.
Advantageously, the pharmaceutical compositions described above for oral or parenteral use are prepared in dosage forms in unit doses suitable for compounding with a dose of the active ingredient. Such dosage forms in unit doses include, for example, tablets, pills, capsules, injections (ampoules), suppositories, chews and the like. In certain embodiments, for the doses provided above, they are administered in a portion of cannabis extract provided in an edible product, e.g., a single product, of 1 mg/kg.
The cannabis extracts, dosage forms, and pharmaceutical compositions described herein may be packaged to provide one or more doses of cannabis extract per package. Any suitable type of packaging may be used, including encapsulators, pockets, boxes, drums, jars, blister packs and bags. Such packages are convenient and readily available to consumers, enhance consumer ease, reduce the presence of pathogens, increase shelf life, and reduce spoilage. In embodiments, the cannabis extract, dosage form, or pharmaceutical composition is packaged to provide one or more doses of cannabis extract per package. In an embodiment, the package is resealable. In some embodiments, the dosage form is edible. In some embodiments, the edible dosage forms are formed in a flat shape that can be more easily separated. In some embodiments, this flat shape is a disk or cookie shape. In some embodiments, the edible dosage form includes indentations to indicate where the edible dosage form should be divided to provide a particular dose. In some embodiments, the edible dosage form is presented in multiple pieces. In some embodiments, each of the plurality of pieces provides a dose. In some embodiments, the package comprises 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 25, 30, 35, 40, 45, 50, or more fragments. In some embodiments, the package is resealable. In embodiments, one dose of cannabis extract is a therapeutically effective amount. According to the methods disclosed herein, the pharmaceutical formulation may be administered to a patient or subject using any acceptable device or mechanism. For example, the administration may be accomplished using a syringe and needle or with a reusable pen and/or an auto-injector delivery device. The methods of the present invention comprise administering a pharmaceutical formulation using a number of reusable pen and/or auto-injector delivery devices.
In embodiments for non-human animal administration, the term "drug" as used herein may be replaced with a "veterinary".
In some embodiments, the patient is a subject before, during, and/or after treatment with CHOP chemotherapy. CHOP chemotherapies include, for example, but are not limited to, cyclophosphamide, doxorubicin, vincristine, and steroids (e.g., prednisolone).
Examples
While several experimental examples are contemplated, these examples are intended to be non-limiting.
Example 1:
single dose pharmacokinetics for healthy dogs and cats
The single dose oral pharmacokinetic of CBD during 12 weeks of administration using cannabis-based products in healthy dogs and cats was determined in this study as well as the assessment of safety and adverse effects. Eight of each species provided a total CBD/CBDA (1 mg/kg CBD and 1mg/kg CBDA) concentration of 2mg/kg orally twice daily for 12 weeks, and six of each species were screened for single dose pharmacokinetics. For dogs and cats, the pharmacokinetics showed average maximum CBD concentrations (Cmax) of 301ng/mL and 43ng/mL, areas under the curve (AUC) of 1297ng-h/mL and 164ng-h/mL, and times to maximum concentrations (Tmax) of 1.4 hours and 2 hours, respectively. Serum chemistry and CBC results showed no clinically significant changes, however, one cat showed a sustained elevation of alanine Aminotransferase (ALT) beyond the reference range for the duration of the trial. In healthy dogs and cats, oral CBD-enriched cannabis supplements administered every 12 hours are not detrimental based on CBC or biochemical values. Cats appear to absorb or eliminate CBD differently than dogs, exhibiting lower serum concentrations and the adverse effects of excessive licking and head shaking during oil administration. Further details regarding this study can be found in "Deabold, k.a.; schwark, w.s.; wolf, l.; wakshlag, J.J., single dose pharmacokinetic and preliminary safety assessment of CBD enrichment of cannabis nutrients in healthy dogs and cats (Single-Dose Pharmacokinetics and Preliminary Safety Assessment with Use of CBD-Rich Hemp Nutraceutical in Healthy Dogs and Cats), animal (Animals) 2019,9,832,DOI 10.3390/ani9100832", which is incorporated herein by reference in its entirety.
Example 2:
pharmacokinetics of oral and transdermal administration of cannabis oil in dogs
The pharmacokinetics of Cannabidiol (CBD), cannabidiol (CBDA), Δ9-Tetrahydrocannabinol (THC) and Tetrahydrocannabinol (THCA) on CBD enriched cannabis extracts containing nearly equal amounts of CBD and CBDA and small amounts (< 0.3 wt%) of THC and THCA in three oral forms in dogs were studied. The psychoactive components of the metabolism of THC, 11-hydroxy- Δ9-tetrahydrocannabinol (11-OH-THC) and the CBD metabolites 7-hydroxycannabidiol (7-OH-CBD) and 7-nor-7-carboxycannabidiol (7-COOH-CBD) were also evaluated to better understand the pharmacokinetic differences between the three formulations with respect to THC and CBD and their metabolism. Six intentionally incubated female beagle dogs were used for research purposes, each with a 2mg/kg body weight dose of CBD/CBDA (about 1mg/kg CBD and about 1mg/kg CBDA) for an initial 7-point 24-hour pharmacokinetic study. The dogs were then dosed every 12 hours for 2 weeks after the morning dose for 6 hours, and additional serum analysis was performed at weeks 1 and 2 to assess serum cannabinoids. Serum from each cannabinoid or cannabinoid metabolite was analyzed using liquid chromatography and tandem mass spectrometry (LC-MS/MS). Regardless of the form provided (1, 2, or 3), the 24 hour pharmacokinetics of CBD, CBDA and THCA are similar, and only form 2 generates enough data beyond the lower limit of quantitation to evaluate the pharmacokinetics of THC. CBDA and THCA concentrations were 2 to 3 times higher than CBD and THC concentrations, respectively. There was no significant difference in steady state concentrations between the two oil or soft chew forms for 1 week and 2 weeks. Form 2 CBDA concentrations were statistically higher than the other forms, showing better absorption/retention of CBDA. Furthermore, at weeks 1 and 2, form 1 showed less THCA retention than soft chew form 3 or form 2. Almost all samples had THC below the quantitative limit of the assay. Overall, these findings indicate that the absorption or elimination of CBDA and THCA is different from CBD or THC, respectively, and that part of the lecithin base provides better absorption and/or retention of CBDA and THCA. Further details regarding this study can be found in "Wakshlag JJ, schwark WS, deabold KA, talsma BN, cital S, lyubimo A, iqbal A and Zakharov A, the pharmacokinetics of cannabidiol, Δ9-Tetrahydrocannabinol, tetrahydrocannabinol and related metabolites in canine serum following administration of three oral forms of cannabis extract (Pharmacokinetics of Cannabidiol, cannabidiolic Acid, Δ9-Tetrahydrocannabinol, tetrahydrocannabinolic Acid and Related Metabolites in Canine Serum After Dosing With Three Oral Forms of Hemp Extract), 2020, veterinary frontier 7:505.DOI 10.3389/fvets.2020.00505", which is incorporated herein by reference in its entirety. The pharmacokinetics of transdermal administration of CBD-containing bases in beagle dogs was also studied, wherein the transdermal formulations were prepared with a commercially available carrier (pekream). The base was applied topically to the auricle at 70mg (CBD/CBDA) twice daily.
Example 3:
cynomolgus monkey study
This study evaluates the pharmacokinetics and utility of proprietary hemp oil, including a mixture of cannabinoids (and about 90% of the mixture being CBD and CBDA), in managing idiopathic diarrhea in cynomolgus monkeys.
In one experiment, the pharmacokinetic profile of a population of 4 macaques was evaluated. A single oral dose of 2mg/kg of hemp oil was administered to each macaque via viscous treatment. Fig. 11 shows serum levels of CBDA (upper/blue dotted line), CBD (upper/blue solid line), THCA (lower/green dotted line) and THC (lower/green solid line) at specified time points. Notably, the acidic form of cannabinoid appears to be better absorbed. In addition, CBDA and CBD are present in hemp oil in approximately equal proportions.
In another experiment, 9 macaques diagnosed with idiopathic diarrhea received proprietary hemp oil at a dose of 2mg/kg stored in cotton candy every 12 hours. This treatment is outside of the typical treatments provided for macaques in the group diagnosed with idiopathic diarrhea. Macaques receiving both cannabis oil treatment and typical treatment showed a 33% reduction in hospitalization time (p=0.1) compared to the historical data of macaques receiving only typical treatment.
In another experiment, 15 macaques (7 females, 8 males) were given a single dose of 2, 4 or 8mg of cannabis extract. Macaques were bled at zero, 0.5, 1, 2, 4, 8, 12, 24, 168 (7 days) and 336 hours (14 days) post-dose. Data for various cannabinoids and cannabinoid metabolites in cynomolgus serum were collected and analyzed via targeted mass spectrometry, and the results are shown in table 1 below. Animals 1, 2, 5, 7, 8, 9, 12 and 14 received cannabis extract in oil form. Animals 3, 4, 6, 10, 11, 13 and 15 received cannabis extract in a viscous dosage form.
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Example 4:
treatment of noise aversion to dogs
The present study evaluates the efficacy of treating noise aversion to dogs with proprietary hemp oil.
Method
In this study, a population of 15 dogs was evaluated. The patient received a sesame oil-based chew formulation at a dose of 4mg/kg for 2 hours once for a duration of 1 day prior to the event. Proprietary hemp oils include mixtures of cannabinoids, and about 90% of the mixture is CBD and CBDA. The study had a crossover design, contained an elution period of 3 days, and was double blind.
Inclusion criteria inclusion dogs were manageable and matched with the study procedure. The dog must also have at least 3 signs of fear of responding to recordings of fireworks, storms or mines (day 1) and score at least 30 on the lincoln sound sensitivity scale. The host must be able to connect to for video conferencing. A diagnosis of noise aversion (storm phobia, noise phobia) must be established. The approved drugs include heartworm prophylaxis (topical and oral), antiparasitic therapy, vaccination, ocular drugs (including corticosteroids), antibiotics or antimicrobials and non-steroidal anti-inflammatory agents. The owner must be able to collect saliva and the dog cannot have a history of attacking the owner.
Exclusion criteria included potential diagnosis of clinical signs that facilitated noise aversion, such as, but not limited to: a. current or previous urinary tract disorders over the past 30 days; b. current or previous urine Dan Zhengshi over the past 30 days; diagnosing patients with or suspected of having renal failure, diabetes, hypothyroidism and neurological disorders. The excluded drugs contained general anesthesia or sedation within 5 days of day 0, or CBD products, corticosteroids, diuretics (diurics), pheromones (pheomones), tramadol (tramadol), trazodone (trazodone), benzodiazepines (benzodiazepines), gabapentin (gabapentin), opioids (opioids), hormones or antihistamines within 7 days of study visit on day 0 or at any time during the study. The excluded drugs include buspirone (buspirone), monoamine oxidase inhibitors, serotonin reuptake inhibitors, other serotonin-derived drugs not listed herein, tricyclic antidepressants, serotonin norepinephrine reuptake inhibitors, and serotonin reuptake inhibitors/antagonists within 30 days of day 0. The excluded supplements and diets include those containing psychoactive ingredients such as, but not limited to, l-theanine, yulan, phellodendron, alpha-cassietin (alpha-casapine) and Shen Calmer, within 7 days of day 0.
The daily protocol is as follows. Day 1: dogs and pet owners underwent a three minute habituation period with study coordinators in a clinical setting. The only allowed treatment is a typical stroking. Saliva was collected for cortisol measurement within 3 hours after waking up, without stress events. Day 4: the special sesame oil or placebo is administered orally. Two hours later, there was a three minute habituation period in which the dogs and pet owners were in the clinical setting with the study coordinator. The only allowed treatment is a typical stroking. The dogs were exposed to thunderstorm audio for 3 minutes. Saliva was collected for cortisol measurement. Day 7: the special sesame oil or placebo is administered orally. Two hours later, there was a three minute habituation period in which the dogs and pet owners were in the clinical setting with the study coordinator. The only allowed treatment is a typical stroking. The dogs were exposed to thunderstorm audio for 3 minutes. Saliva was collected for cortisol measurement.
Example 5:
safety and efficacy of applying hemp oil in pet birds
The present study assessed the safety and efficacy of managing refractory hairiness in parrot pet birds.
Method
In this study, a population of 24 birds was evaluated. The patient received a proprietary sesame oil at a dose of 15mg/kg every 12 hours for a period of 3 months. Proprietary hemp oils include mixtures of cannabinoids, and about 90% of the mixture is CBD and CBDA.
Included in this study were birds with dehairing behavior with unidentified underlying medical causes removed by radiographs, fecal directness and blood tests; birds with identified and medically managed diseases, in which there is no clinical improvement; and a regular blood sample may be collected monthly to assess birds of hematology serum chemistry.
Excluded from this study are birds less than 175 grams, birds exhibiting any identified medical condition associated with untreated feathering or birds not following veterinary advice by the customer, and birds exposed to stress and unhealthy environmental conditions typically associated with feathering.
Eligible birds were blood sampled for hematology and chemistry and aliquoted (200 μl) for HPLC-MS method development.
Example 6:
treatment of high grade lymphomas with CBD/CBDA in dogs
This study assessed the quality of life of dogs with intermediate to high grade lymphomas treated with a standardized cbd+cbda regimen.
Method
In this study, a population of 30 dogs was evaluated. The study was blind and patients with cytologically diagnosed multicenter large cell lymphomas were randomized into two treatment groups, namely (a) prednisone alone and (B) prednisone plus CBD oil (5 mg/kg CBD/CBDA mixture as soft gel). The dosages were as follows: (A) Prednisone alone (2 mg/kg, PO,24 hours for one week, then 1mg/kg, PO,48 hours for one week) and prednisone (2 mg/kg, PO,24 hours for one week, then 1mg/kg, PO,48 hours for one time) plus CBD oil (5 mg/kg). The clinician evaluates the patient on day 0, day 21 and day 42. During each visit, a physical examination was performed and the following measurements were made: lymph node, CBC, chemical profile, and UA. Half of the mL of serum was saved after each visit and stored at about-20℃for future CBD/CBA analysis. The owners also evaluated patients on day 0, day 21, and day 42 to evaluate quality of life using quality of life (QOL) questionnaires.
The following diagnosis was made at admission: physical examination, whole blood count, chemical profile, urinalysis, lymph node measurement, and immunophenotyping.
The following inclusion and exclusion criteria apply: 1. a dog comprising a cytological or histopathological diagnosis with medium to high grade (medium to large cell) peripheral lymphomas; 2. a dog comprising a life expectancy estimated to be ≡3 days without any intervention; 3. excluding dogs known or suspected of gastrointestinal tract involvement; 4. excluding dogs with known or suspected skin involvement; 5. dogs known or suspected to have only medical disease (liver/spleen) (peripheral lymph nodes not involved) were excluded; 6. dogs with clinically relevant complications and small cell lymphomas were excluded; dogs receiving chemotherapy, L-asparaginase and/or corticosteroid prior to inclusion in the group. Corticosteroid therapy (oral and/or topical) was not allowed for the first 2 months of the group.
The following four responses were evaluated in patients: (1) Complete Remission (CR), defined as the complete disappearance of evidence of all diseases; (2) Partial Remission (PR), defined as a reduction of the average total LD (one dimension) of a target lesion by at least 30%; (3) Progressive Disease (PD), defined as an increase in average total LD of at least 20% in a target lesion; and (4) Stable Disease (SD), defined as neither lowering enough to meet PR nor increasing enough to meet PD. Patients experiencing CR, PR or SD continue to receive treatment until PD develops. If CR is achieved, the Disease Free Interval (DFI) and/or Median Survival Time (MST) are compared using a Kaplan Meier survival curve. The study applied the following two exit criteria: (1) PD for more than 10 days; and (2) the development of cancer-related clinical signs or unacceptable toxicity as determined by the owner/guardian or veterinarian.
All cases were reviewed by the same clinical pathologist. For patients with cytology, histopathology and/or immunophenotyping, 3-6 lymph node aspirates per case were collected on positively charged slides. Slides from a single junction are preferably obtained. Slides from the group of cases were labeled with patient name, lymph node site and date of collection. Slides were then placed into slide containers and stored for delivery to a laboratory (EVP) once every two months.
Quality of life (QOL) questionnaires are used by owners to assess pathology in patients. A "canine cancer treatment survey" file (pdf) was provided to the dog owner. The baseline form (day 0) was filled in by the dog owner at the time of group entry and submitted to state of iowa. The subsequent QOL questionnaire was filled out by the state of the aihua staff on day 7, day 14 and then monthly with the dog owners by telephone. Conclusion QOL questionnaires are filled out by the state of aihua personnel after the dog dies or is euthanized. Dog owners expect the state of love personnel to update and complete QOL surveys based on the summarized schedule.
Example 7:
treatment of skin wounds in dogs with CBG/CBGA
The present study evaluates the effect of topical CBG/CBGA in wound healing and topical CBD/CBG pyoderma models in dogs.
Method
In this study, a population of 6 dogs was evaluated. Patients received 20mg CBG/CBGA or vehicle control to the area every 12 hours, (one side treatment, one side vehicle control) and foci were photographed every 2 days until regressing or necessary closing at week 2. The study was blind and contained an elution period of 2 weeks. The second phase is to apply 30mg of CBD/CBG to the area of the induced pyoderma. Dogs were screened for any skin abnormalities and were checked for physical examination.
During stage 1, lesions were photographed every 2 days until resolved or necessarily closed at 2 weeks. Visual assessment of lesions was performed daily by a clinician blinded to the treatment. The images were evaluated for pelletization and re-epithelialization. At the end of the study, skin biopsies were collected for histopathology and aerobic and anaerobic culture, and whole blood count (CBC), blood chemistry and urinalysis were performed to assess any systemic effects of treatment. Blood cannabinoid levels were also assessed.
During stage 2, the dogs had an area directly above the bilaterally shaved shoulders. The outer skin layer of this area was mechanically disrupted and a staphylococcal inoculum was applied for three days to induce superficial pyoderma. Once sepsis has been induced (confirmed by visual inspection and impression cytology; surface aerobic bacterial cultures were also collected), the areas were then treated with vehicle control or 40mg CBD/CBG. Pyoderma was assessed by blind clinicians every 2 days by daily clinical lesion scores and skin impression cytology until regressions. Photographs of lesions were also taken. At the end of the study, skin biopsies for histopathology and superficial swabs for aerobic skin culture were collected at break down or at the end of 2 weeks later. Dogs underwent CBC, blood chemistry and urinalysis to assess any systemic effects of treatment. Blood cannabinoid levels were also assessed.
Example 8:
pharmacokinetics of hemp oil treatment in horses
The study assessed the pharmacokinetics of proprietary hemp oil in horses. Proprietary hemp oils include mixtures of cannabinoids and about 90% of the mixture is CBD or CBDA. In this study, a population of 8 horses was evaluated at a dose of 2 mg/kg. The patient received a 12mg/kg dose of proprietary hemp oil (70 mg/mL) once every 12 hours for a period of time. The study contained a 2 week washout period between randomized CBD or CBDA treatments. Serum sample collection times were as follows: day 1: 0. 1, 2, 4, 12 and 24 hours; day 7: 0. 1 and 2 hours; day 14: 0. 1 and 2 hours.
Example 9:
pharmacokinetic and safety studies of cannabidiol-based oil treatment in horses
The study assessed the pharmacokinetics and safety of proprietary hemp oil in horses.
Method
In this study, a population of 7 horses was evaluated. Patients received CBD or CBDA separation oil at a dose of 1mg/kg CBD or CBDA for 6 weeks every 12 hours. The study had a crossover design and contained an elution period of 2 weeks. Horse selection is based on previously diagnosed chronic musculoskeletal pathology.
Specific clinical and laboratory evaluations were performed on each horse to meet the following 3 goals: (1) pharmacokinetics: blood samples were obtained from each horse at time points (0, 15 min, 30 min, 1 hour, 2 hours, 4 hours, 8 hours, 12 hours, 24 hours and 1 week, 2 weeks, 4 weeks, 6 weeks per oil administration period). Serum was stored at-80 ℃ for subsequent cannabinoid concentration assessment. (2) security: the safety of the cannabinoid oils was evaluated based on the following: 2a, clinical examination: an administration period lasting 12 weeks was performed daily to rule out psychotic effects and evaluate the development of signs suggesting complications. Diagnostic test to assess changes in body system function, inflammatory and metabolic states: blood work includes Complete Blood Count (CBC), serum chemistry, metabolome (baseline cortisol, ACTH, insulin, leptin) and cytokine sets. Blood was collected at time points (0, 2, 6, 10 and 14 weeks after group entry) The solution was then analyzed. 2c. Liver ultrasound and histopathological evaluation: percutaneous ultrasound evaluations were performed at the beginning and end of the study to assess the final changes in liver structure and echogenicity and identify the location of liver biopsies. Liver biopsies are obtained percutaneously under ultrasound guidance using a puncture gun device. Liver biopsy samples taken at the beginning (week 0) and at the end (week 14) of the study period. (3) efficacy: using a standardized objective pain scoring system and lameness assessment, a commercially available inertial sensor system (Equisis Q TM With claudicationBiomechanical platform [ Columbia (Columbia, missouri, USA)]) To evaluate the clinical response of the administration of CBD and in particular its effect on chronic pain, which provides an objective measure of sound. After recording baseline data at time 0, the pain scoring system was applied daily for 14 cycles, while lameness was graded and recorded weekly by the lameness locator system, prior to CBD administration.
Example 10:
pharmacokinetics of hemp oil treatment in horses
The present study evaluates the intestinal pharmacokinetics and gastrointestinal motility of the equine cannabidiol-based oil treatment.
Method
In this study, a population of 8 horses was evaluated. The patient received a single dose of 2 or 8mg/kg of proprietary hemp oil (70 mg/mL) once. Proprietary hemp oils include mixtures of cannabinoids, and about 90% of the mixture is CBD and CBDA. The study contained 2 weeks of washout period and 9 healthy adult horses with physical status scores of 3-7. A dose (2 mg/kg or 8 mg/kg) was administered prior to the elution period. After the elution period, a second dose is administered that includes a dose that has not been administered to the horse. The following parameters were calculated: plasma concentrations of cannabidiol (and other cannabinoids) at 0, 0.5, 1, 1.5, 2, 3, 4, 8, 12, 24 and 48 hours after oral administration of cannabis oil at 2mg/kg CBD and CBDA; plasma concentrations of cannabidiol at 0, 0.5, 1, 1.5, 2, 3, 4, 8, 12, 24 and 48 hours after oral administration of 8mg/kg CBD and CBDA; physical examination results, including all identified clinical abnormalities; neurological examination findings and video recordings; the weight of feces produced every 6 hours; and the amount of barium spheres discharged from the feces every 6 hours. From the collected data, the following parameters were calculated: tmax: the time to reach the highest measured plasma concentration; cmax is as follows: maximum measured plasma concentration; t0.5: measuring the time for which the plasma concentration decreases by half; AUC: area under plasma concentration curve; k: a first order cancellation rate constant; kilogram of feces produced per hour; and the amount of barium spheres produced per kilogram of stool.
Tables 2 and 3 below show pharmacokinetic data for 8 different horses given 2mg/kg and 8mg/kg doses of hemp oil. Blood samples were collected from each horse at the indicated time points and subjected to targeted mass spectrometry to determine the serum concentrations of the indicated cannabinoid compounds and metabolites.
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Example 11:
pharmacokinetic study of cannabis extract paste in cats
The study evaluates the pharmacokinetics of the hemp oil paste in cats.
Method
In this study, a population of 10 cats was evaluated. The patient received a paste of proprietary hemp oil at a dose of 2mg/kg for about 15 days every 12 hours. Proprietary hemp oils include mixtures of cannabinoids, and about 90% of the mixture is CBD and CBDA. The patient was a healthy domestic short-haired cat, 1-8 years old, and had a weight of 4 to 5.5kg.
The test uses 10 cats for 15 days. At day 0, the test article was applied in the morning and food was provided shortly thereafter. Continuous blood collection was obtained from each cat over 24 hours for pharmacokinetic analysis. Starting on day 1, after 24 hours of blood collection, the test article was administered twice daily for 14 days. Six hour blood collection was performed for pharmacokinetic analysis following the morning dose at day 7 and day 14. All cats were fed only the control diet during the study. Daily observations, food consumption and weekly body weights were assessed throughout the course of the study. Physical examination was performed before the study began and at the completion of the study. Blood analysis (CBC and chemical screening) was performed before the study start and at the study end.
Example 12:
anti-inflammatory effects of CBD/CBDA in dogs
The study evaluates the pharmacokinetics of hemp oil chews in dogs.
Method
In this study, a population of 8 dogs was evaluated. Blood was collected from dogs and subjected to lymphocyte and neutrophil separation. PMA-induced neutrophil chemokines, reactive oxygen species production and phagocytic function were assessed 24-48 hours later using an in vitro assay. Incubations were performed with 50 and 500ng CBD, CBDA and whole plant extracts. In addition, conA and PHA stimulated T cell function assays were performed with similar incubations, thereby examining T cell refinement of pro-inflammatory cytokines (IL-17, IL2, IL-4, and IFNγ) and anti-inflammatory cytokines IL-10 using the ELISPOT assay within 72 hours. Additional prostaglandin ELISA was performed on neutrophil supernatants and in a-72 fibroblast assay following 48 hours and subsequent 24 hours of LPS stimulation of CBD, CBDA and whole plant extracts. In addition, cytokine arrays of treated A-72 fibroblast supernatants were performed by Eve Technologies. Based on the results, a second group of studies was evaluated to examine the in vivo effects on cells before and after treatment of dogs with chronic inflammatory conditions to further understand the effects of cannabis oil on immune cell function.
Example 13:
pharmacokinetic study of CBG/CBGA hemp oil in dogs
The study evaluated the pharmacokinetics of cannabis oil including Cannabigerol (CBG) and cannabigerol acid in dogs.
Method
In this study, a population of 6 dogs was evaluated. Patients received proprietary sesame oil in sesame oil base comprising cannabigerol/cannabigerolic acid at 2mg/kg oral dose (about 1mg CBG and 1mg CBGA), assessed 24 hours pharmacokinetics and then every 12 hours on days 2-14 and serum assessments were made 2, 6 hours after morning dose on week 1 and on days 7 and 14 of administration. During this trial phase, dogs fasted during this phase and fed 2 hours after dosing. The dogs then had an elution period of 2 weeks and the same protocol was followed during the next two weeks of CBG/CBGA oil administration, followed by a 1/4 tank of wet food feed. Dogs were evaluated for multiple physical examinations and heart rates on the first day of administration and then every 3-4 days during the trial week.
The daily protocol is as follows. Day 1: blood was drawn at 0.5, 1, 2, 4, 8, 12 and 24 hours for physical examination and heart rate measurement. Day 2: blood drawing, physical examination, and heart rate measurement were performed. Day 3: blood heart rate measurements and physical examinations were performed. Day 7: physical examination, heart rate measurement and blood drawing were performed. Day 10: physical examination and heart rate measurement were performed. Day 14: physical examination, heart rate measurement and blood drawing were performed. Day 27: blood drawing, physical examination, and heart rate measurement were performed. Day 28: blood was drawn for 1, 2, 4, 8 and 12 hours and physical examination and heart rate measurements were performed. Day 29: blood drawing, physical examination, and heart rate measurement were performed. Day 30: physical examination and heart rate measurement were performed. Day 35: physical examination, heart rate measurement and blood drawing were performed. Day 38: physical examination and heart rate measurement were performed. Day 42: physical examination, heart rate measurement and blood drawing were performed.
Example 14:
characterization of CBD, CBDA and P450 and P-gp of cannabis extracts in dogs
These two studies aim to identify the major canine P450 and P-gp proteins responsible for metabolism of CBD and CBDA in the liver and to determine the likelihood that CBD, CBDA and CBD-and CBDA-enriched cannabis extracts inhibit canine P450 drug metabolism.
Method (P450 characterization)
In this first study, an in vitro substrate depletion assay was performed to measure CBD and the metabolic rate of CBDA in dog livers. The pooled dog liver microsomal fractions and P450 cofactors were used for incubation. The substrate remaining in the incubation was measured by HPLC-MS and compared to a negative control reaction using inactivated microsomes. Complementary studies were also performed using the same approach (using UGT cofactor instead of P450 cofactor) to evaluate direct conjugation through UDP-glucosyltransferase (UGT) as an alternative (non-P450) metabolic pathway.
The metabolic rates of CBD and CBDA were determined by all available dog recombinant P450 enzymes (8 commercialized and 3 generated in PI laboratories). The assay was the same as above except that recombinant P450 enzymes were used instead of liver microsomes. Since the differences in each P450 enzyme in the liver are large, the results of extrapolation to canine livers using the tissue specific P450 concentrations previously determined for each isoform are used.
Inhibition efficacy (i.e., IC 50) was determined by measuring the metabolic decrease in P450-specific marker activity in pooled dog liver microsomes with increasing concentrations of CBD, CBDA and cannabis extract. The P450 specific markers include bupropion (bupropion) 6-hydroxylation (CYP 2B 11), dextromethorphan (dextromethorphan) O-demethylation (CYP 2D 15) and omeprazole (omeprazole) sulphonation oxidation (CYP 3A 12). IC50 values were determined with and without pre-incubation of liver microsomes with potential inhibitors to assess whether mechanism-based time-dependent inhibition was present.
The following parameters were evaluated: (1) CBD and CBDA metabolic rates by dog liver microsomes and by 11 recombinant dog P450 enzymes; (2) Each P450 contributes to a predicted percentage of total CBD and CBDA metabolism in dog livers; and (3) IC50 values inhibiting CYP2B11, CYP2D15 and CYP3a12 metabolism in dog livers with and without pre-incubation with inhibitors.
Partial results
Fig. 12-15 depict the initial results.
CBD and CBDA extracts produced the same results as the corresponding pure compounds. See FIGS. 12A-12C, and compare "10. Mu.M CBD" to "10. Mu.M CBD extract" and "10. Mu.M CBDA" to "10. Mu.M CBDA extract".
CBD and CBD extracts showed time-dependent inhibition (TDI) for all P450 activities; CBDA and CBDA extracts did not show TDI (compare "no preincubation" bars (left bar, no outline) with "20 min preincubation" (right bar, outlined).
Figures 13-15 show activity assays for CYP3A12 (figures 13A and 13B), CYP2B11 (figures 14A and 14B), and CYP2D15 (figures 15A and 15B). Assays were performed without pre-incubation (fig. 13A, 14A and 15A) or pre-incubation for 20 minutes (fig. 13B, 14B and 15B). Only CBD and CBD extracts showed potent inhibition (e.g., IC50 less than 1 μm). This occurs when CBD or CBD extract is pre-incubated with microsomes and NADPH, and when CYP2B11 activity (tramadol N-demethylation, fig. 14B) or CYP3a12 activity (midazolam) hydroxylation, fig. 13B) is measured.
CYP2D15 activity (tramadol O-demethylation, FIGS. 15A and 15B) was significantly lower (IC 50>3 uM) by the effective inhibition of all compounds, whether or not pre-incubation was performed.
5. Overall, these results indicate that CBD and CBD extracts may have clinically significant interactions with CYP2B11 and CYP3a12 substrates in the body. However, these results are preliminary.
Method (P-gp characterization)
In this second study, a competitive P-gp substrate assay incorporating canine P-gp expressing cell lines was used to assess the ability of each test compound to compete with the P-gp substrate rhodamine (rhodomine) 123. Each concentration was tested on 3 separate daily replicates of samples. Positive and negative controls were included in each run.
The results of each concentration of test compound evaluated are reported as non-P-gp substrate, weak P-gp substrate, medium P-gp substrate, or strong P-gp substrate. The concentrations of CBD and CBDA were as follows: 10ng/mL, 100ng/mL, and 1,000ng/mL.
Results
Competitive P-gp substrate assays using canine P-gp expressing cell lines were used to evaluate CBDA and/or CBD as substrates for canine P-glycoprotein.
The suggested concentrations of CBD and CBDA are as follows: 10ng/mL, 100ng/mL and 1,000ng/mL
The data for CBDs at 1,000ng/mL are shown in Table 4. The highest concentration of CBD tested did not compete with rhodamine for PGP effluent and the MFI ratio was essentially the same as the negative control, meaning that CBD was not a substrate for canine PGP in this assay. The results for lower CBD concentrations look similar but no final data has been collected.
Table 4: competitive transport assay for P-glycoprotein
Example 15:
effects of cannabidiol on dog tumor cell proliferation and mitogen-activated protein kinase activation during autophagy and apoptosis
The present study was directed to assessing anti-proliferative and cell death responses associated with the in vitro treatment of canine cancer cell lines with CBD alone and in combination with co-chemotherapy and proliferation pathways potentially involved in response to CBD treatment (e.g., p38, JNK, AKT and mTOR).
Materials and methods
1. Cannabinoids and chemotherapy
CBD and its acid derivative CBDA were purchased as a formulation of 10mg/mL and 1mg/mL in methanol, respectively (Cayman Chemical Corporation, ann Arbor, michigan). Receiving the whole cannabis-based extract directly from the manufacturer, third party analysis (praise Mo De laboratory, proverde Laboratory, milford, massachusetts)) reveals a product having approximately 30mg/mL CBD, 31mg/mL CBDA, 1.4mg/mL THC and 1.3mg/mL tetrahydrocannabinolic acid (THCA), less than 1mg/mL cannabigerol, cannabigene and cannabinol, and 5.2mg/mL complex terpenes (elevet Sciences, portland, main) in ethanol base. The extract was diluted to 20mg/mL in a 50%/50% mixture of ethanol and DMSO. The final stock extract contained 20mg/mL cannabidiol as CBD (10 mg) and CBDA (10 mg), 0.4mg/mL THC, 0.4mg THCA, 0.1mg or less of cannabidiol (CBC) and an equal mixture of Cannabigerol (CBG) and 1.8mg of complex terpenes. The chemotherapeutic agent doxorubicin hydrochloride (doxorubicin hydrochloride) (Sigma Aldrich, st.louis, missouri) was freshly diluted in water to a 2mM stock solution, while vincristine sulfate (vincristine sulfate) (Sigma Aldrich, st.louis, missouri) was prepared in sterile water to a 10 μm stock solution prior to use in cell culture experiments.
2. Cell lines and culture conditions
Five established canine tumor cell lines were obtained and used for all experiments; cell line of epithelial breast cancer cell line-CMT 12; b cell lymphoma lineage-17-71, three mesenchymal osteosarcoma cell lines HMPOS, D17 (#CCL-183; ATCC Inc. of Marassas, va., manassas, virginia) and Abrams (Abrams). The ibutum cell line was validated from its original source, while the D17 cell line was a validated cell line from the american culture collection. CMT12, 17-71 and HMPOS cell lines have not been genetically validated but show cell markers and characteristics of epithelial, round and osteosarcoma cell lines, respectively. All cell lines were considered to be mycoplasma free by polymerase chain reaction from the university of kanneler animal health and diagnostics laboratory (the Animal Health and Diagnostic Laboratory at Cornell University).
All cells were maintained in tissue culture-treated plates (laboratory product sales (LPS) company (Laboratory Product Sales [ LPS) of Rochester, N.Y. ] with Rockwell park (Invitrogen, carlsbad, calif.) and 1% antibiotic and antifungal solutions (Enjer. Of Calif.) medium 1640 (Enjer. Of Calif.) at Rockwell park (Roswell Park Memorial Institute, RPMI) ]Rochester, new York). All experimental and cell passaged cell lines were at 37 ℃ and 5% CO unless otherwise indicated 2 And (5) growing downwards. Application Biomaterials (ABM) company (Applied Biological Materials [ ABM]Richmond, BC, canada)) was propagated and maintained on PriCoat T25 flasks in Prigrow II medium (ABM) containing 10HI-FBS and 1% penicillin/streptomycin (invitrogen of carlsbad, california). Dermal fibroblasts were used to determine the effect of the extract on normal cells.
3. Cannabidiol and CBD enriched cannabis 48 hour MTT proliferation
All previously described cell lines, namely CMT12, HMPOS, D17, aibloms and 17-71 were subjected to 3- (4, 5-dimethylthiazol-2-yl) -2, 5-diphenyltetrazolium bromide (MTT) assay. Cells were plated in 96-well tissue culture-treated plates (laboratory product of rochester, new york)Product marketing company) were plated at a density of 2500 cells per well. Cells were treated with vehicle (methanol or ethanol/DMSO mixture) or CBD, CBDA or CBD enriched cannabis extract at various concentrations ranging from 0.42 to 20 μg/mL under serial dilutions for 48 hours. After 48 hours of treatment, the sample was prepared by adding 20. Mu.L of MTT dye (phosphate buffered saline [ PBS ] ]5mg/mL of 0.7. Mu.M filtered) was added to each well and at 5% CO 2 The MTT assay was performed by 2 hours of incubation at 37 ℃. The medium was then aspirated, washed once with 200 μl of PBS, and then dissolved in 200 μl of ethanol. An immediate analysis of the optical density of each well (e.g., vega-Avila E and Pugsley MK, overview of colorimetry for assessing survival or proliferation of mammalian cells (An overview of colorimetric assay methods used to assess survival or proliferation of mammalian cells) was performed using a spectrophotometric plate reader (Epoch; bertoni instruments, winoski, vermont.) of Winuski, buddha, inc.), pages 2011,54, pages 10-14, incorporated herein by reference in its entirety) as described previously. The percentage of proliferating cells for each concentration of control was averaged and reported as the mean +/-SD of triplicate wells from three experiments.
4. Doxorubicin cytotoxicity/proliferation assay
CMT12, 17-71 and D17 cells were plated in 96-well tissue culture treated plates (laboratory product sales company, rochester, new york) at a density of 2500 cells per well. All cell lines were treated with the same concentration of pure CBD (0.34, 0.67, 1.25, 2.5, 5, 10, 20 g/mL) and different concentrations of doxorubicin or vincristine. The concentration of doxorubicin varies between cell lines in order to achieve proliferation inhibition of between 20% and 80%. The cell line was treated with serial dilutions of doxorubicin as follows; CMT12 and D17 (0.067-2. Mu.M) and 17-71 (0.0167-0.5. Mu.M). Methanol was used as vehicle control for all CBD treatments, and sterile water was used to treat wells with doxorubicin and vincristine at the highest dose used to represent vehicle control. The cells were then incubated for 48 hours prior to performing the MTT assay, as previously described. Wells treated with vehicle control were considered to represent 100% proliferating triplicate cells in three experiments. The percentage of viable cells for each particular combination was averaged and reported as the average percentage proliferation +/-SD for further CI assessment.
5. Trypan blue dye exclusion assay for cell viability
Since these normal canine cells proliferate at a slow rate and have low metabolic activity, trypan blue exclusion assay was performed on canine primary dermal fibroblasts (CDFs), thereby excluding productive MTT assay. For comparison purposes, the effect of CBD treatment was compared with the results obtained on the 17-71, CMT12 and D17 cell lines. For CDF cells, the applied extracellular matrix (ABM) was applied overnight to a 24-well tissue culture-treated plate (applied biosubstance (ABM) company, risman, british, canada). For all cell lines, cells were plated at 5X 10 per well 3 The density of individual cells was plated and incubated until 60% confluence before 48 hours of treatment of cells with methanol vehicle control, 3.75, 7.5 and 15 μg/mL CBD. Cells were then trypsinized, collected and centrifuged at 1900g for 10 min. In addition to the 17-71 cell line, cells were isolated with Accumax (England, calif., inc.). The cell pellet was resuspended in PBS containing 0.1% trypan blue (Sigma Aldrich, st. Louis, mitsui), loaded onto a cell Countess disposable cell count slide, and all positive stained cells were automatically counted in a Countess II cell counter (Inje; carlsbad, calif.) using the same parameters for each cell line at the same settings for each cell line. All treatments were performed in triplicate and the percentage of viable cells was averaged.
Mtt and trypan blue data management and calculation
Raw data from MTT proliferation assay and trypan blue exclusion assay (individual optical density per well) were normalized to vehicle control treatment for each cell line, considered to represent 100% proliferating cells (single or combined treatment). The percentage of proliferating cells was determined by comparing the individual optical density readings or viable counts of the treated wells at each concentration to vehicle control wells for each cell line.
CBD, CBDA and cannabis extract concentrations required to obtain 50% inhibition of cell proliferation (IC 50) were then calculated in experiments by inhibition analysis using XLFit5 software (IDBS, guildford, united Kingdom) to report the results of each cell line.
The interactions of chemotherapy and CBD-treated compounds in CI studies were calculated by multiplex drug action analysis using the Compusyn software (2 nd edition; compusyn Inc. Paramus, new Jersey) which employed the median equation principle according to the methods described by Chou and Talay to determine CI values by formula I (Chou TC, drug combination study and its synergistic quantification using the Chou-Talay method (Drug combination studies and their synergy quantification using the Chou-Talay method), "cancer research", 2010,70 (2), pages 440-446, which is incorporated herein by reference in its entirety):
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Wherein (D) 1 And (D) 2 Is the dose of the two compounds combined, and (D x ) 1 Sum (D) x ) 2 Is the individual dose of each compound at% inhibition by x. CI less than or equal to 0.9 indicates synergy, CI>0.9 and<1.1 indicates additive effect and CI value of 1.1 or more indicates antagonism.
7. Annexin V-FITC apoptosis assay
Apoptosis after 4 and 8 hours of treatment was measured using annexin V staining (invitrogen annexin V-FITC staining kit of carlsbad, california). Briefly, cells were isolated with Accumax (Innovative cell technology Co., san Diego, calif. (Innovative Cell Technologies, san Diego, calif.) and collected and centrifuged at 1000g for 10 min at 4 ℃. Will be precipitated at about 1X 10 6 Individual cell/mL density resuspended in annexin binding bufferABB;10mM HEPES,140mM NaCl,2.5mM CaCl 2 pH 7.4) was washed once with PBS before. Annexin V-FITC conjugate was added to the cell suspension and incubated for 15 minutes at room temperature according to the manufacturer's recommendations. After incubation, ABB was added to the cell suspension and kept on ice until fluorescence was measured with BD FACScalibur flow cytometer using an argon laser (BD Biosciences, ashland, oregon). Ten thousand events were collected per sample. Analysis was performed by first gating on forward and side scatter characteristics based on each cell line using FlowJo software (10.7.1. Becton, dickinson, ashland, oregon) followed by annexin V-FITC positive cells. The negative fluorescent control was unstained cells. Three independent replicates of each treatment were examined.
8. Western blot assessment of signaling pathways and autophagy
Cells were plated on 100mm tissue culture treated plates and incubated overnight in complete medium until 60% confluence was achieved. Cells were treated with methanol vehicle control or 10 μg/mL CBD for 2 hours, 4 hours or 8 hours. Cells were harvested and lysed at each time point using mammalian lysis buffer (25 mM Tris, 100mM NaCl, 1mM EDTA, 1% Triton X-100, pH 7.4) and then centrifuged at 12000g for 5 min at 4 ℃. Supernatants were collected and protein concentrations were determined using Bradford assay (coomassie dye; sammer feichi pierce, waltham, ma). The samples were equilibrated to a common volume (. Mu.g/. Mu.L) in lysis buffer and 5-fold laemmi loading buffer (300 mM Tris-HCl pH 6.8, 10% sodium dodecyl sulfate, 50% glycerol, 12.5% beta-mercaptoethanol, 0.025% bromophenol blue). For each protein of interest, 30 μg of total protein was subjected to sodium dodecyl sulfate polyacrylamide gel electrophoresis (SDS-PAGE) on a gel ranging from 6% to 15% based on the molecular weight of the protein of interest. The protein was then transferred to a 0.45 μm pore size polyvinylidene fluoride membrane (Immobilon-P membrane, EMD Miibo corporation of Billerica, massachusetts for 1 hour and then blocked in 5% milk in triple buffered saline/0.05% Tween 20 solution (TBST). Membranes were incubated overnight in TBST at 1:1000 dilution in primary antibody solution on a shake platform at 4 ℃. Primary antibodies confirmed to have cross-reactivity with canine cells or tissues comprise mouse Extracellular Regulated Kinase (ERK) (R of boston, ma&D bioscience Co Ltd (R&D Biosciences, boston, massachusetts)); rabbit anti-protein kinase B (AKT), ser473 phosphorylated AKT, stress-activated protein kinase/jun amino-terminal kinase (SAPK/JNK), thr183/Tyr185 phosphorylated SAPK/JNK, mammalian rapamycin target protein (mTOR), ser2448 phosphorylated mTOR, anti-Thr 202/Tyr204 phosphorylated p44/42MAPK (ERK 1/2), anti-p 38, anti-phosphorylated p38, anti-p 62, and anti-LC 3A/B (cell signaling technologies Inc. (Cell Signalling Technology, danvers, massachusetts) of Danfos, massachusetts) (e.g.,P,Anwar T,Jokinen T,K,/>KH,Cozzi F,Rohdin C,Hahn K,Wohlsein P,/>w, henke D, oevermann A, sukura A, leeb T, lohi H and Eskelien EL, whether basal autophagy was altered in Lago Roman pavilion Norway dogs with ATG4D mutations (Basal Autophagy Is Altered in Lagotto Romagnolo Dogs with an ATG D Mutation), veterinary pathology (Vet Pathol), 2017, 11 months, 54 (6), pages 953-963, doi:10.1177/0300985817712793; gordon IK, ye F and Kent M, the effect of mammalian rapamycin target protein pathway and rapamycin on targeted expression and cell proliferation in osteosarcoma cells of dogs was evaluated (Evaluation of the mammalian target of rapamycin pathway and the effect of rapamycin on target expression and cellular proliferation in osteosarcoma cells from dogs), journal of veterinary research (Amer J Vet Res), 2008,69, pages 1079-1084; ikari A, atom K, kinjo Y and Sugatani J, magnesium deprivation inhibits MEK-ERK cascade and cell proliferation in epithelial Madin-Darby canine kidney cells (Magnesium deprivation inhibits a MEK-ERK cascade and cell proliferation in epithelial Madin-Darby canine kidney cells), life sciences (Life Sci), 2010,86, pages 766-773; and Levine CB, bayle J, biourge V and Wakshlag JJ, effects and synergy of feed ingredients on canine tumor cell proliferation (Effects and synergy of feed ingredients on canine neoplastic cell proliferation), "BMC veterinary research (BMC Vet Res)," 2016,12 (1), 159, which is incorporated herein by reference in its entirety). Membranes were washed three times with TBST and incubated for 1 hour at room temperature in the corresponding secondary anti-rabbit IgG or anti-mouse IgG horseradish peroxidase conjugated antibodies (cell signaling technologies, denfos, ma) at a dilution of 1:2000. The membranes were washed three times with TBST and visualized with chemiluminescent reagents (Clarity Western ECL substrate; bere Inc. of Heracles, calif., bio-Rad, hercules, california). Digital images were captured using an imaging system (biospace 410; UVP, uland, california, UVP, or FluorChem E; cell Biosciences, san Jose, california). Each blot was run twice from two different experiments to confirm findings.
D17 and CMT12 immunofluorescence
CMT12 and D17 adherent cell lines were divided into Nunc chamber slides (sammer feichi technologies, rochester, new York), and 70% confluent cells were treated with methanol control or 10 μg/mL CBD for 6 hours. Cells were fixed with 4% paraformaldehyde for 1 hour and then permeabilized with PBS containing 0.1% Triton X-100 for 30 minutes. The cells were then washed with PBS and incubated with bovine serum albumin (sigma aldrich of st.Louis, missouri) for 30 minutes, and then with goat antisera (carrier of buring gram, california)The body Labs (Vector Labs, burlingame, california)) was incubated for 1 hour and then washed twice with PBS for 10 minutes while shaking at room temperature. Equal concentrations of rabbit polyclonal non-specific antibodies (carrier laboratories, bolingmu, calif.) or polyclonal rabbit anti-LC 3A/B antibodies (cell signaling technologies, danfos, massachusetts) at the same concentrations as described by Syrja and colleagues were requiredP,Anwar T,Jokinen T,KH,Cozzi F,Rohdin C,Hahn K,Wohlsein P,/>W, henke D, oevermann A, sukura A, leeb T, lohi H and Eskelien EL, whether basal autophagy of the Lagotor Roman pavilion dog with ATG4D mutation was altered, veterinary pathology, 2017, 11, 54 (6), pages 953-963, doi:10.1177/0300985817712793, which is incorporated herein by reference in its entirety). Cells were incubated overnight at 4 ℃ and then washed twice with PBS. Cells were then incubated with oregon green 488 conjugated secondary goat anti-rabbit antibody (invitrogen of carlsbad, california) at 1:400 dilution for 2 hours at room temperature. Coverslips were mounted using Vectrashield DAPI mounting medium (carrier laboratories, burlinger, california) and images were captured at 400 or 600 magnification at the same fluorescence intensity per image and processed using an Olympus fluorescence microscope and DP controller software (Olympus corp., center Valley, pennsylvania).
10. Statistical analysis
All statistical analyses were performed on the percentage of proliferating cells as measured by MTT assay and annexin-FITC assay using JMP Pro (version 11.2.1; SAS Institute inc., cary, north Carolina) in Cary. The residual of the statistical model was evaluated for normalization and abnormal distribution was found in most analyses. Thus, the nonparametric Kruskal-Wallis test was used to compare the differences in the percentage of proliferating cells for each therapeutic dose used within each cell line in the experiment. Comparisons between each treatment group and vehicle control group were made using the Steel method (Steel method) to adjust alpha risk (alpha risk) for multiple comparisons.
Results of percent viability determined by trypan blue exclusion assay residual of statistical model were found to be normally distributed and thus analyzed using analysis of variance using the Dunnett method to control multiple comparisons compared to vehicle controls. For all statistical tests, the difference in P <.05 was considered statistically significant.
Results
1.48 hour MTT assay for CBD, CBDA and whole hemp extract
When the probability analysis of CBD was examined on 5 cell lines, 17-71 cells were found to have an IC50 of 2.5. Mu.g/mL and a concentration that caused a significant reduction in proliferation of 2.5. Mu.g/mL and above. The CMT12 cell line showed a similar curve with a significant reduction in proliferation at 2.5 μg/mL and above, with a slightly higher probability IC50 of 3.5 μg/mL. Ibutilus, D17 and HMPOS showed similar probability analysis concentrations of 4.1, 4.1 and 3.6 μg/mL, respectively, significantly slowed cell proliferation when compared to vehicle control treated cells, 5 μg/mL and above (fig. 1A).
The use of lower concentrations of CBD in 20 μg/mL extract combined with other cannabinoids and terpenes of whole cannabis extract showed that lower CBD concentrations were required in all cell lines. Cannabis extract showed a probability IC50 of about 0.8 μg/mL for the 17-71 cell line, with the first significantly different concentration that slowed proliferation being 0.67 μg/mL and higher. CMT12, aibrahm, D17 and HMPOS cell probabilities showed IC 50's of 1.5, 1.3, 1.6 and 1.7 μg/mL, respectively, compared to vehicle control treated cells; and these cell lines showed a significant reduction in proliferation at 1.25 μg/mL and higher (fig. 1B).
Considering that the cannabis extract used had a considerable proportion of CBDA, a 48 hour MTT assay was performed with CBDA. CBDA treatment of 17-71 cells showed an IC50 of 15.1 μg/mL, with concentrations of 5 μg/mL and higher showing significant slowing of cell proliferation. The CMT12 cell line showed a significant slowing of proliferation starting at 10 μg/mL or higher and IC50 could not be determined since a 50% inhibition of growth was not achieved in the assay. The three osteosarcoma cell lines ibutum, D17 and HMPOS showed significant growth inhibition at 20 μg/mL, whereas IC50 calculations could not be calculated due to lack of growth inhibition (fig. 1C).
The graphs in fig. 1A-1C depict the results of the assays at 3 different time points performed in duplicate. * Initial concentrations of 17-71, including any higher concentrations (P <.05), are depicted, as are initial points of CMT12, including any higher concentrations (P <.05), that are significantly different from the baseline of the vehicle control treatment. # depicts the initial points of D17, HMPOS and ibutilus that were significantly different from the baseline of vehicle control treatment, including any higher concentrations (P <.05).
Trypan blue dye exclusion assay for cbd
The percentage of trypan blue positive dermal fibroblasts for methanol vehicle control cells was 16±3% of the cell population. This was significantly higher when treated with CBD at 15, 7.5 and 3.75 μg/mL at 77±12%, 58±7% and 32±5%, respectively, for 48 hours (fig. 2). 17-71 cells showed 3+ -1% trypan blue positive cell population when treated with methanol as vehicle control. Trypan blue positive cells were significantly increased at both 15 μg/mL and 7.5 μg/mL at 55% ± 6% and 27 ± 8%, respectively. 17-71 cells treated with 3.75 μg/mL at 7+ -4% positive cells were not different from vehicle control treated cells. D17 cells showed 5±1% trypan blue positive cell populations when treated with methanol as vehicle control. Trypan blue positive cells at 15 μg/mL increased significantly at 35±4%. D17 cells treated with 7.5 and 3.75 μg/mL at 5±2% and 4±2% positive cells, respectively, were not different from vehicle control treated cells. When treated with methanol as vehicle control, CMT12 cells showed 3±1% trypan blue positive cell population. Trypan blue positive cells were significantly increased at 87% ± 8% at 15 μg/mL and 7.5 μg/mL with 9 ± 3%. CMT12 cells treated with 3.75 μg/mL at 4+ -2% were not different from vehicle control treated cells (FIG. 2). Trypan positive cell death in three experiments was evaluated for each cell line from figure 2, indicating a significant increase in trypan positive cells compared to VC cells (P <.05).
3. Combination index MTT dual therapy assay with CBD and chemotherapy (doxorubicin/vincristine)
When all three cell lines were treated with doxorubicin, the 17-71 lymphoma cell line was most sensitive and the inhibitory concentration of IC20-IC80 was between 0.033 and 0.125. Mu.M, whereas the CMT12 and D17 cell lines required higher concentrations to block cell proliferation (0.5-2. Mu.M). Regardless of the cell line treated with doxorubicin, it was apparent that there was a synergistic or additive effect of higher concentrations of CBD (10 and 5 μm) with CI values less than 1.1 when combined with IC20-IC80 concentrations of CBD (table 5). The only general antagonism observed in the cell lines (CI values above 1.1) was with lower concentrations of CBD (2.5 and 1.25. Mu.g/mL) and lower concentrations of doxorubicin.
Table 5: CI values for 17-71, D17 and CMT12 cell lines at various concentrations between the IC80-IC20 concentrations of each drug combination under dual treatment with CBD and doxorubicin (Dox) or CBD and vincristine (Vin).
Note that: CI values less than 0.9 indicate synergistic interaction, 0.9-1.1 indicate additive interaction, and bq 1.1 values indicate antagonism between drug combinations. All bolded numbers represent additive or synergistic interactions, while italic numbers are antagonistic interactions.
When all three cell lines were treated with vincristine, the 17-71 lymphoma cell line again showed the most sensitivity to treatment with IC20-IC80 values between 0.25 and 1nM, whereas the CMT12 and D17 cell lines treated with vincristine required higher concentrations to block cell proliferation (1.7-6.8 nM). Almost universally, treatment with vincristine and CBD showed synergistic or additive effects, regardless of the examined cell line, and almost all CI values were 1.1 or less, suggesting that vincristine and CBD might enhance each other's effects in the examined canine tumor cell line (table 5).
4. Annexin V apoptosis assay
Annexin V apoptosis assays were performed using flow cytometry at 4 and 8 hours after treatment with 15 μg CBD or vehicle control (methanol) for 8 hours. Annexin V staining showed an average percentage and SD in 17-71 cell lines at time 4 and 8 hours was 31.0±10.8% and 79.0±6.1% positively stained cells, respectively, showing a significant increase in positive cells (10.1±0.4% and 9.9±1.2%) at both 4 and 8 hours when compared to VC cells and untreated cells, respectively. D17 cells treated with CBD showed a significant increase in annexin V positive cells (24.0±3.6%) at the time point of only 8 hours when compared to VC cells (6.5±0.6%) and untreated cells (3.3±1.0%). D17 cells treated with 15 μg CBD (9.4±1.8%) for 4 hours were higher than VC or untreated cells, but this increase was not significant. Similarly, CMT12 cell line showed a significant increase in positive cells at the 8 hour time point of staining for cells with annexin V21.5±2.5%. In the CMT12 cell line, there was also an increase in annexin V stained cells (15.7±2.2%) at 4 hours when using non-parametric conservation statistical tests, but no significant increase with VC treated cells (10.9±2.0%) or untreated (13.9+0.6%) (fig. 3B, 3C and 3D). FIGS. 3B, 3C and 3D are bar graphs showing apoptosis of tumor cell lines 17-71, D17 and CMT12 after treatment with 15 μg/mL CBD. In these figures, the annexin V apoptosis assay represents the relative percentage of annexin V positive cells identified by flow cytometry. In these figures, results from baseline vehicle control treated cells (VC), untreated cells, and treated cells (CBD treatment of 15 μg/mL for 4 and 8 hours) are compared, and "×" indicates the percentage of significant increase from VC treatment (P <.05).
5. Time course western blot analysis for pathway indication
Multiple immunoblots were performed after 2, 4 and 8 hours of treatment of cells with methanol vehicle control or 10 μg/mL CBD. Immunoblots performed with AKT and phosphorylated AKT or mTOR and phosphorylated mTOR showed that the signal was not inhibited or increased in intensity over time, regardless of treatment, in two different time course analysis experiments. Lack of change indicates that there is no change in the PI3Kinase-AKT-mTOR pathway, as this involves induction of autophagy or apoptosis. Evaluation of the MAP kinase pathway showed that ERK and JNK phosphorylation was repeatedly increased in all three cell lines in the presence of 10 μg/mL CBD compared to the equivalent methanol vehicle control treatment over the 8 hour period (fig. 4A and 4B). Comparison of ERK and phosphorylated ERK expression at time 2, 4 and 8 hours with methanol vehicle control treated cells indicated that 17-71, D17 and CMT12 cell lines were heavily phosphorylated at 2, 4 and 8 hours. The presence of baseline ERK and JNK phosphorylation was not evident in 17-71 cells, and both showed adequate phosphorylation peaks at 4 hours of treatment with CBD. ERK baseline phosphorylation was more pronounced in D17 and CMT12 cells, and peaks were rapidly induced in these cell lines at 2-4 hours (fig. 4A). After CBD treatment, JNK phosphorylation status was robust in CMT12 cell lines, while D17 cells showed milder induction of phosphorylated JNK. Overall, baseline JNK and ERK protein expression in the cell lines did not significantly change regardless of treatment or time. The presented blots represent the repeated time course immunoblotting experiments performed.
Simultaneously with these time course analyses, the LC3 protein was assessed as part of the autophagy response in the cells within 8 hours. Generally, LC3II proportion of LC3 protein was increased in all three cell lines, which represents ethanolamine conjugated forms of the proteins found in autophagic vesicles or autophagosomes. This increase in LC3II began to be significant at 2 hours of treatment and persisted during the course of 8 hours of treatment, which was not observed in vehicle control treated cells. (FIG. 5A). In combination with LC3II responses, a significant decrease in western blot of autophagy carrier protein p62 was also observed, another autophagy marker often discussed in the literature (Yoshi SR and Mizushima N, monitoring and measuring autophagy (Monitoring and measuring autophagy), "journal of international molecular science (Int J Mol Sci)," 2017,18,1865), which is incorporated herein by reference in its entirety. These observations were also accompanied by activation of caspase 3, which can also be seen in 17-71 cells at 2 hours, but was not evident in CMT12 and D17 CBD treated cells until 8 hours, showing that autophagy appears to precede apoptotic response in these cells (fig. 5A).
Immunofluorescence of LC3I/II
Cellular fluorescence imaging of D17 and CMT12 cell lines was captured at 400 and 600 fold magnification, respectively. The use of rabbit polyclonal antibodies as controls showed minimal light background fluorescence with or without CBD treatment of 10 μg/mL (fig. 5B). Figure 5B, line 1, shows control rabbit antibody immunostaining on vehicle control treated cells. FIG. 5B, line 2, shows control rabbit antibody immunostaining on CBD 10 μg/mL treated cells. Figure 5B, line 3, shows rabbit LC3A/B antibody immunostaining in vehicle control treated cells, showing variable staining of the cytoplasm. FIG. 5B, line 4, shows rabbit LC3A/B immunostaining in cells treated with 10 μg/mL CBD, showing punctate autophagosomes in the cytoplasm of the cells.
When LC3A/B rabbit polyclonal antibodies were used, there was a slightly diffuse cytoplasmic staining in methanol vehicle control treated cells, regardless of the cell line used. When subjected to 10 μg/mL CBD treatment with LC3A/B antibody for immunofluorescence, both CMT12 and D17 cells showed multiple discrete punctate strong staining vesicles, consistent with localization of LC3 protein to autophagosomes or autophagy lysosomes (fig. 5B).
Analysis
The purpose of the study was to examine whether CBD and its naturally acidic form (CBDA) caused similar cytotoxic effects in a selected number of common canine cancers that represent mesenchymal, circular and epithelial origins. According to many human cell line studies, the results show that CBD results in uniform death of canine-like cancer cells, whereas CBDA has limited effect at the concentrations used, except for the light effect on lymphoma cell lines at the highest concentrations. These assays were allowed to incubate for 48 hours, which typically required more than 24 hours to induce cytotoxicity, similar to other natural product studies.
The results also demonstrate that canine cancer cell proliferation is significantly reduced when treated with CBD concentrations in the range of 2.5 to 10 μg/mL and has a similar effect on all 5 cell lines examined. CBD enriched whole cannabis extracts used in this study resulted in a significant reduction in cancer cell proliferation at the lowest CBD concentration ranging from 0.67 to 10 μg/mL. When whole cannabis extracts were used, the same CBD concentrations as used in the pure CBD experiments were chosen. In the presence of CBDA and/or other phytocannabinoids and terpenes at lower concentrations, the lethality of CBD may enhance the whole plant extract effect in this study. This synergistic discovery is often reported as a "satellite effect" in which a mixture of cannabinoids and terpenes can act synergistically to produce an enhanced effect.
When treated with 10 to 15 μg/mL CBD, the cell proliferation response of the 17-71, CMT12 and D17 cell lines resulted in apoptosis as demonstrated by annexin V staining and cleaved caspase 3 immunoblotting (fig. 3A), and occurred within 8 hours of treatment. FIG. 3A is an image of immunoblots of cleaved caspase 3 (17 kDa) after CBD treatment for 8 and 16 hours compared to methanol vehicle control, showing cleaved caspase in all cell lines at two time points. In addition, autophagy responses were observed, as well as proportional phase shift of LC3-I relative to the phosphoethanolamine LC3-II moiety of the protein, p62 degradation and localization of autophagy-related LC3 proteins. In combination with this increase in LC3-II, the autophagy vector aptamer SQSTM1/p62 was concomitantly decreased.
Cell signaling mechanisms evaluation did not show significant changes in signaling pathways through AKT or mTOR signaling. However, phosphorylation of MAP kinase pathways, particularly ERK and JNK signaling, is reproducibly and dramatically increased with minimal impact on p38 phosphorylation and activation.
When canine cancer cells are treated with conventional chemotherapy in combination with CBD, synergistic and antagonistic results with respect to cancer cell proliferation are significant. The combination of vincristine and CBD consistently enhanced the decrease in cell viability compared to either treatment alone, demonstrating a significant synergistic response at the lethal to sublethal doses of both CBD and vincristine. Importantly, combination treatment with doxorubicin and CBD produced both synergistic and antagonistic results depending on the specific concentrations of each compound used. Based on the results, as more lethal doses of CBD and doxorubicin are utilized, there may be addition of a synergistic response, whereas at sub-lethal doses the effect may be antagonistic. The dose of doxorubicin used in these in vitro assays was observed at the higher end of the dose in the serum of dogs during intravenous infusion when treating CMT12 and D17 cell lines (1-2 μm), whereas the 17-71 cell lines were much more sensitive to doxorubicin treatment at concentrations approaching 1/10. Similarly, the 17-71 cell line is more sensitive to vincristine than the D17 and CMT12 cell lines, and all concentrations used were 5-20 times lower than the effective concentrations of about 20 to 40nM observed in canine clinical use.
Example 16:
canine atopy study
Studies were conducted to determine the efficacy of cannabis extracts in treating dog atopy.
The study was a double blind, prospective, placebo controlled, randomized study. Comprising a dog owned by a customer suffering from atopic dermatitis (cAD). According to published guidelines, a qualified dog with cAD is diagnosed. Owner consent was obtained for each case prior to the study. Parasitic and infectious etiologies of itch were excluded by negative combing, skin scraping and cytologic examination. Dogs in the study showed no improvement in the first two months of hydrolysis or the novel protein exclusion diet. For each case, a dermatological examination was performed and lesions and itching were evaluated using a validated scoring system. Only cases of local and mild to moderate cAD are included. Mild to moderate cAD are defined as those patients with a pruritus visual analog scale (pVAS) score of between 3 and 7, and those with a canine atopic dermatitis degree and severity index-4 (CADESI-4) score of between 10 and 35.
Cyclosporine (trade name: atoptic or general microemulsion) is not allowed to be administered simultaneously, and patients who received this drug in the past two months are excluded. For patients who received this treatment at least one year prior to the initial study, simultaneous administration of injectable or sublingual allergen-specific immunotherapy is allowed. For patients who received these drugs at least two months prior to the initial study, simultaneous administration of olantinib (oclacetinib), oral glucocorticoids, ketoconazole (ketoconazole) and other imidazoles was allowed. Patients who received injection of tertoxel (Cytopoint) within three months of the initial study were excluded. No other treatments, concomitant medications or drug changes were allowed during the study. During the study, the typical bathing program of the patient was not allowed to change. Dietary changes were not allowed during the study.
The investigator blinded the group. Group a consisted of those patients receiving oral oil-based CBD: CBDA products twice daily at a dose of 2mg/kg in capsule form. Group B consisted of those patients who received matching placebo oil in capsule form. Dogs with concomitant complications such as renal failure, liver disease, endocrinopathy or other immune dysfunction (ITP, I MHA) are excluded. The study involved 29 dogs with cAD (17 in the treatment group and 12 in the control group). The CBD product was orally administered at a dose of about 2mg/kg twice daily for twenty-eight days. The owner is required to administer the medication with meals.
The dose of drug allowed that the patient received prior to the study remained unchanged for the duration of the study. In addition, the drug dose was unchanged within 21 days prior to the start of the study.
Procedure
The customer is required to sign an agreement. On day (0), each dog received a preliminary consultation of the investigator, including a comprehensive medical history and physical examination. Treatment was started as described above and follow-up was performed at weeks 2 and 4. The change in perception of the extent and severity of atopic dermatitis by the host was evaluated using pVAS. The range and severity of atopic dermatitis was assessed by veterinary-based CADESI-4. The benchmark separating normal/remission from mild, moderate and severe cAD using CADESI-4 was 10, 35 and 60, respectively, as suggested by the validation study. Prior to the beginning of the survey, all participating researchers were trained on how to evaluate and interpret the CADESI-4, which included evaluating clinical case instances. 1cc of serum from visits 0 and 4 was stored at-20 ℃ for future cytokine analysis and used for serum CBD testing.
Analysis
Current efficacy analysis shows that if there is a 2.5 standard deviation and a 2.0 variation in the host's VAS score, the necessary population for statistical significance is found to be approximately 13 patients. To ensure adequate cohort and complete the trial, 18 dogs were cohorted based on a random number generator, and up to 36 patients were assigned to either group a or group B. After data collection and cleaning, all scores and blood parameters were assessed using a mixed model anova comprising time effects, treatment, concomitant medication, and random effects in dogs with significant alpha sets of 0.05 or less. If a discrepancy is found, a Tukey post-hoc analysis is performed to evaluate the discrepancy between the time points.
Results
Figure 6A shows the VAS scores for the treatment and control groups. Figure 6B shows the CADESI scores for the treatment and control groups at zero and 4 weeks. Significant differences are marked with asterisks at zero and 4 weeks.
Fig. 7A shows alkaline aminotransferase levels in dogs treated with CBD treatment or placebo. Values of both zero and 4 weeks are shown. Fig. 7B shows alkaline phosphatase levels in dogs treated with CBD treatment or placebo. Values of both zero and 4 weeks are shown.
FIG. 8 shows alkaline phosphatase levels in dogs when CBD treatment was combined with various other drugs as shown, or when CBD treatment was administered without other drugs (right-most column).
FIG. 9A shows serum levels of monocyte chemotactic protein-1 (MCP-1) of study participants at zero and 4 weeks. Figure 9B shows serum levels of IL-6 in study participants at zero and 4 weeks.
Figure 10A shows serum levels of IL-31 for study participants at zero and 4 weeks. Figure 10B shows serum levels of IL-34 for study participants at zero and 4 weeks.
Further features and advantages of the invention will be appreciated by those skilled in the art based on the above-described embodiments. Accordingly, the invention is not to be limited by what has been particularly shown and described, except as indicated by the appended claims. All publications and references cited herein are hereby incorporated by reference in their entirety.

Claims (161)

1. A method for treating a recurrent diarrhea disease in a veterinary subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of cannabis extract.
2. The method of claim 1, wherein the veterinary subject is a primate.
3. The method of claim 2, wherein the primate is a non-human primate.
4. The method of claim 3, wherein the non-human primate is a macaque.
5. The method of any one of the preceding claims, wherein the recurrent diarrhea disease comprises idiopathic diarrhea.
6. The method of any one of the preceding claims, wherein the cannabis extract is administered orally.
7. The method of any one of the preceding claims, wherein the cannabis extract is administered in the form of a chew, marshmallow, fudge, or by syringe.
8. The method of any one of the preceding claims, wherein the cannabis extract is administered at a dose of about 2mg/kg, about 4mg/kg, or about 8 mg/kg.
9. The method of any one of the preceding claims, wherein the cannabis extract is administered until the fecal score of the veterinary subject is less than or equal to 2 for 3 days or for 21 days.
10. The method of any one of the preceding claims, wherein the cannabis extract is administered once a day, twice a day, three times a day, or four times a day.
11. A method for treating inflammation in a veterinary subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of cannabis extract.
12. The method of claim 11, wherein the veterinary subject is a dog.
13. The method of claim 11 or 12, wherein the cannabis extract comprises CBD, CBDA, or a combination thereof.
14. The method of any one of claims 11 to 13, wherein the cannabis extract modulates neutrophil function, reactive oxygen species production, phagocytosis, eicosanoid concentration, chemotaxis, cytokine production and/or fibroblast response.
15. A method for treating noise aversion to a veterinary subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of cannabis extract.
16. The method of claim 15, wherein the veterinary subject is a dog.
17. The method of claim 15 or 16, wherein the noise aversion disorder is phobia.
18. The method of claim 17, wherein the phobia is a storm phobia or a noise phobia.
19. The method of claim 15, wherein the noise aversion disorder is to fireworks or thunderstorms.
20. A method for treating dehairing in a veterinary subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of cannabis extract.
21. The method of claim 20, wherein the veterinary subject is a bird.
22. The method of claim 20 or 21, wherein the cannabis extract comprises CBD, CBDA, or a combination thereof.
23. The method of claim 22, wherein the cannabis extract comprises 70mg/mL total cannabinoids.
24. The method of claim 23, wherein the cannabis extract comprises 60mg/mL CBD and CBDA.
25. The method of any one of claims 20 to 24, wherein the cannabis extract is administered twice daily at a dose of 60mg/kg for three months.
26. A method for treating lameness in a veterinary subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of cannabis extract.
27. The method of claim 26, wherein the veterinary subject is a horse.
28. The method of claim 26 or 27, wherein the cannabis extract comprises CBD, CBDA, or a combination thereof.
29. The method of any one of claims 26 to 28, wherein the cannabis extract is administered every 12 hours at a dose of 1 mg/kg.
30. A method for promoting wound healing in a veterinary subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of cannabis extract.
31. The method of claim 30, wherein the cannabis extract is topically applied.
32. The method of claim 30 or 31, wherein the veterinary subject is a dog.
33. The method of any one of claims 30-32, wherein the cannabis extract comprises CBG and CBGA.
34. The method of claim 33, wherein 20mg CBG and CBGA are applied to the wound.
35. The method of claim 34, wherein the CBG and CBGA are applied to the wound every 12 hours.
36. A method for treating cancer in a veterinary subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of cannabis extract.
37. The method of claim 36, wherein the veterinary subject is a dog.
38. The method of claim 36 or 37, wherein the cannabis extract comprises CBD, CBDA, or a combination thereof.
39. A method for treating sepsis in a veterinary subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of cannabis extract.
40. The method of claim 39, wherein the cannabis extract is topically applied.
41. The method of claim 39 or 40, wherein the veterinary subject is a dog.
42. The method of any one of claims 39-41, wherein the cannabis extract comprises CBD and CBG.
43. The method of claim 42, wherein 40mg CBD and CBG are applied to the site of the pyoderma.
44. The method of any one of claims 42 or 43, wherein the CBD and CBG are applied every 12 hours to the site of sepsis.
45. A method for treating atopy in a veterinary subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of cannabis extract.
46. The method of claim 45, wherein the veterinary subject is a dog.
47. The method of claim 45 or 46, wherein the cannabis extract comprises CBD and CBDA.
48. The method of any one of claims 45-47, wherein the cannabis extract is administered orally.
49. The method of claim 48, wherein the cannabis extract is administered by a capsule.
50. The method of any one of claims 45-49, wherein the cannabis extract comprises CBD and CBDA, and wherein the cannabis extract is administered such that a dose of about 2mg/kg of CBD and CBDA is administered.
51. The method of any one of claims 45-50, wherein the cannabis extract is administered once every 12 hours.
52. A method for treating a neurological condition in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of cannabis extract.
53. The method of claim 52, wherein the subject is a human.
54. The method of claim 52, wherein the subject is a veterinary subject.
55. The method of any one of claims 52-54, wherein the neurological condition comprises traumatic nerve injury or degenerative neurological disease.
56. The method of any one of claims 52 to 55, wherein the cannabis extract comprises THCA.
57. A method for treating arthritis in a veterinary subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of cannabis extract.
58. The method of claim 57, wherein the subject is a rabbit.
59. The method of any one of claims 57-58, wherein the cannabis extract comprises CBD, CBDA, or a combination thereof.
60. The method of any one of claims 57-59, wherein the cannabis extract is administered at a dose of 10mg/kg to 25 mg/kg.
61. The method of any one of claims 57-60, wherein the cannabis extract is administered at a dose of about 15 mg/kg.
62. The method of any one of claims 57-61, wherein the cannabis extract is administered at a dose of about 20 mg/kg.
63. The method of any one of claims 57-62, wherein the cannabis extract is administered twice daily.
64. The method of any one of the preceding claims, wherein the cannabis extract comprises:
cannabidiol; and
cannabidiol;
wherein the ratio of cannabidiol to cannabidiol is from about 0.6:1 to about 1:0.6.
65. The method of claim 64, wherein the cannabis extract further comprises:
cannabigerol acid;
Δ9-tetrahydrocannabinol; and
cannabichromene.
66. The method of any one of the preceding claims, wherein the cannabis extract comprises:
cannabidiol;
cannabidiol;
cannabigerol acid;
Δ9-tetrahydrocannabinol; and
cannabichromene;
wherein the ratio of cannabidiol to cannabidiol is from about 0.6:1 to about 1:0.6.
67. The method of any one of claims 64-66, wherein the cannabis extract further comprises:
Alpha-pinene;
beta-myrcene;
beta-pinene;
delta-limonene;
linalool;
beta-caryophyllene;
alpha-lupulin;
nerolidol 2;
guaifenesin;
a caryophyllene oxide; and
alpha-bisabolol.
68. The method of any one of claims 64 to 67, wherein the concentration of Δ9-tetrahydrocannabinol is insufficient to produce a psychotropic effect.
69. The method of any one of claims 64-68, wherein the ratio of Δ9-tetrahydrocannabinol to other cannabinoids is about 1:25.
70. The method of any one of claims 64-69, wherein the concentration of Δ9-tetrahydrocannabinol is less than about 1mg/mL.
71. The method of any one of claims 64-70, wherein the concentration of Δ9-tetrahydrocannabinol is less than about 0.5mg/mL.
72. The method of any one of claims 64-71, wherein the concentration of Δ9-tetrahydrocannabinol is less than about 0.3mg/mL.
73. The method of any one of claims 64-72, wherein the concentration of Δ9-tetrahydrocannabinol is less than about 0.2mg/mL.
74. The method of any one of claims 64-73, wherein the concentration of Δ9-tetrahydrocannabinol is less than about 0.1mg/mL.
75. The method of any one of claims 64-74, wherein the concentration of Δ9-tetrahydrocannabinol is about 0mg/mL.
76. The method of any one of claims 64-75, wherein the cannabis extract comprises:
about 1-10mg/mL cannabidiol;
about 1-10mg/mL cannabidiol;
about 0.05-0.2mg/mL cannabigerol acid;
about 0.1-0.3mg/mL of Δ9-tetrahydrocannabinol; and
about 0.1-0.4mg/mL cannabigerol.
77. The method of claim 64, wherein the cannabis extract comprises:
about 5mg/mL cannabidiol;
about 5mg/mL cannabidiol;
about 0.11mg/mL cannabigerol acid;
about 0.25mg/mL of Δ9-tetrahydrocannabinol; and
about 0.27mg/mL cannabigerol.
78. The method of any one of claims 64-77, wherein the cannabis extract comprises:
about 0.09% to about 0.13% α -pinene;
about 0.23% to about 0.44% of beta-myrcene;
about 0.04-0.09% beta-pinene;
about 0.05-0.09% delta-limonene;
about 0.03% to about 0.06% linalool;
about 0.04-0.07% beta-caryophyllene;
about 0.02-0.04% of alpha-lupulin;
about.04% to about 0.07% nerolidol 2;
about 0.04% to about 0.08% caryophyllene oxide; and
about 0.01-0.04% alpha-bisabolol.
79. The method of claim 78, wherein the cannabis extract further comprises:
Camphene;
beta-ocimene;
eucalyptol;
isopulegol; and/or
Nerolidol 1.
80. The method of claim 79, wherein the cannabis extract comprises:
about 0.02% camphene;
about 0.02% to about 0.03% of beta-ocimene;
from about 0.02% to about 0.05% eucalyptol;
about 0.02% isopulegol; and/or
About 0.02-0.04% nerolidol 1.
81. The method of any one of claims 64-80, wherein the cannabis extract is formulated in a carrier.
82. The method of claim 81, wherein the carrier is selected from the group consisting of: hemp seed oil, linseed oil, olive oil, fish oil, salmon oil, coconut oil, catmint oil, sesame oil, MCT oil and grape seed oil.
83. The method of claim 82, wherein the carrier is grape seed oil.
84. The method according to claim 82, wherein the carrier is catmint oil.
85. The method of claim 82, wherein the carrier is sesame oil.
86. The method of any one of claims 76-85, wherein the cannabis extract comprises lecithin.
87. The method of claim 86, wherein the lecithin is sunflower lecithin.
88. The method of claim 87, wherein the sunflower lecithin comprises up to 40%.
89. The method of any one of claims 64-88, wherein the cannabis extract further comprises NF-971P.
90. The method of claim 89, wherein the NF-971P weight/volume ratio is at most 2%.
91. The method of any one of claims 64-90, wherein the cannabis extract comprises nepetalactone.
92. The method of any one of claims 64-91, wherein the cannabis extract comprises taurine.
93. The method of any one of claims 1-63, wherein the cannabis extract comprises:
cannabidiol;
cannabidiol;
cannabigerol acid;
Δ9-tetrahydrocannabinol; and
cannabichromene;
wherein the carrier is grape seed oil.
94. The method of claim 93, wherein the ratio of cannabidiol to cannabidiol is selected from the group consisting of: about 1:100, about 1:50, about 1:10, and about 1:1.
95. The method of claim 93 or 94, wherein the ratio of cannabidiol to cannabidiol is about 1:1.
96. The method of any one of claims 93-95, wherein the concentration of Δ9-tetrahydrocannabinol is insufficient to produce a psychotropic effect.
97. The method of any one of claims 93-96, wherein the ratio of Δ9-tetrahydrocannabinol to other cannabinoids is about 1:25.
98. The method of any one of claims 93-95, wherein the concentration of Δ9-tetrahydrocannabinol is less than about 1mg/mL.
99. The method of any one of claims 93-96, wherein the concentration of Δ9-tetrahydrocannabinol is less than about 0.5mg/mL.
100. The method of any one of claims 93-97, wherein the concentration of Δ9-tetrahydrocannabinol is less than about 0.3mg/mL.
101. The method of any one of claims 93-100, wherein the cannabis extract comprises:
about 1-10mg/mL cannabidiol;
about 1-10mg/mL cannabidiol;
about 0.05-0.2mg/mL cannabigerol acid;
about 0.1-0.3mg/mL of Δ9-tetrahydrocannabinol; and
about 0.1-0.4mg/mL cannabigerol.
102. The method of claim 101, wherein the cannabis extract comprises:
about 5mg/mL cannabidiol;
about 5mg/mL cannabidiol;
about 0.11mg/mL cannabigerol acid;
about 0.25mg/mL of Δ9-tetrahydrocannabinol; and
about 0.27mg/mL cannabigerol.
103. The method of any one of claims 93 to 102, wherein the cannabis extract comprises:
Alpha-pinene;
beta-myrcene;
beta-pinene;
delta-limonene;
linalool;
beta-caryophyllene;
alpha-lupulin;
nerolidol 2;
guaifenesin;
a caryophyllene oxide; and
alpha-bisabolol.
104. The method of claim 103, wherein the cannabis extract comprises:
about 0.09% to about 0.13% α -pinene;
about 0.23% to about 0.44% of beta-myrcene;
about 0.04-0.09% beta-pinene;
about 0.05-0.09% delta-limonene;
about 0.03% to about 0.06% linalool;
about 0.04-0.07% beta-caryophyllene;
about 0.02-0.04% of alpha-lupulin;
about 0.04-0.07% nerolidol 2;
about 0.02% to about 0.04% guaifenesin;
about 0.04% to about 0.08% caryophyllene oxide; and
about 0.01-0.04% alpha-bisabolol.
105. The method of claim 103 or 104, wherein the cannabis extract further comprises:
camphene;
beta-ocimene;
eucalyptol;
isopulegol; and/or
Nerolidol 1.
106. The method of claim 104, wherein the cannabis extract comprises:
about 0.02% camphene;
about 0.02% to about 0.03% of beta-ocimene;
from about 0.02% to about 0.05% eucalyptol;
about 0.02% isopulegol; and/or
About 0.02-0.04% nerolidol 1.
107. The method of any one of the preceding claims, wherein the cannabis extract is administered in a dosage form comprising: one or more pharmaceutically acceptable additives, flavoring agents, surfactants and adjuvants.
108. The method of claim 107, wherein the flavoring is selected from the group consisting of: peppermint oil, mango extract, beef, poultry and seafood.
109. The method of claim 107, wherein the flavoring is selected from the group consisting of: peanut butter, catmint oil, chicken liver powder, poultry meat extract, maltodextrin, butter and bacon.
110. The method of claim 107, wherein the flavoring is chicken liver powder.
111. The method of claim 107, wherein the flavoring is molasses or dry molasses.
112. The method according to claim 109, wherein the flavoring is catmint oil.
113. The method of claim 109, wherein the flavoring is peanut butter.
114. The method of claim 107, wherein the dosage form comprises nepetalactone.
115. The method of claim 107, wherein the dosage form comprises taurine.
116. The method of claim 107, wherein the dosage form is formulated as a sublingual spray.
117. The method of claim 107, wherein the dosage form is formulated as a water, alcohol, polyethylene glycol, or glycerin-soluble solution or cream for topical or transdermal application.
118. The method of claim 107, wherein the dosage form is formulated as a gel for buccal or mucosal administration.
119. The method of claim 107, wherein the dosage form is formulated as a paste for buccal or mucosal administration.
120. The method of claim 107, wherein the dosage form is formulated as a powder.
121. The method of claim 107, wherein the dosage form is formulated as a solution for subcutaneous injection.
122. The method of claim 107, wherein the dosage form is formulated as a tablet.
123. The method of claim 107, wherein the dosage form is formulated as a capsule.
124. The method of claim 107, wherein the dosage form is formulated as a hard chewable.
125. The method of claim 107, wherein the dosage form is formulated as a soft chewable.
126. The method of claim 107, wherein the dosage form is formulated for administration using a nebulizer.
127. The method of claim 107, wherein the dosage form is formulated for inhalation.
128. The method of claim 107, wherein the dosage form is formulated for administration using a pet collar.
129. The method of claim 107, wherein the composition is formulated as an edible product for oral administration.
130. The method of claim 107, wherein the dosage form is formulated as a chew for oral administration.
131. The method of claim 130, wherein said chew is produced using cold extrusion.
132. The method of claim 131, wherein the chew weighs between about 0.5-10g.
133. The method of claim 132, wherein the chew weighs about 4g, about 6g, about 9g, or about 10g.
134. The method of claim 132, wherein the chew weighs about 4g.
135. The method of claim 134, wherein said chew comprises:
about 7mg cannabidiol;
about 6mg cannabidiol;
about 0.12mg cannabigerol acid;
about 0.32mg Δ9-tetrahydrocannabinol; and
about 0.36mg cannabigerol.
136. The method of claim 107, wherein the dosage form is formulated in a carrier for oral administration.
137. The method of claim 136, wherein the carrier is selected from the group consisting of: hemp seed oil, linseed oil, olive oil, fish oil, salmon oil, coconut oil, catmint oil, sesame oil, MCT oil and grape seed oil.
138. The method of claim 137, wherein the carrier is grape seed oil.
139. The method according to claim 137, wherein the carrier is catmint oil.
140. The method of claim 137, wherein the carrier is sesame oil.
141. The method of claim 107, wherein the dosage form comprises:
HCl glucosamine;
chondroitin sulfate (76%);
beer yeast;
acacia gum;
guar gum;
a flavoring agent;
Verdilox；
Previon；
cannabis sativa extract;
glycerol;
sunflower lecithin; and
and (3) water.
142. The method of claim 141, wherein the dosage form comprises:
about 12-17% HCl glucosamine;
about 1-4% chondroitin sulfate (76%);
about 29-33% brewer's yeast;
about 3-6% acacia;
about 0.5-2% guar gum;
about 12-16% flavoring agent;
about 0.01% to about 0.1% Verdilox;
about 0.5-1.5% Previon;
about 3-6% cannabis extract;
About 13-17% glycerol;
about 3-7% sunflower lecithin; and
about 3-7% water.
143. The method of claim 141 or 142, wherein the dosage form comprises: about 15.6% HCl glucosamine;
about 2.6% chondroitin sulfate (76%);
about 30% brewer's yeast;
about 4.7% acacia;
about 0.9% guar gum;
about 14.2% flavoring agent;
about 0.05% Verdilox;
about 0.9% Previon;
about 4.7% cannabis extract;
about 15.1% glycerol;
about 5.7% sunflower lecithin; and
about 5.7% water.
144. The method of claim 107, wherein the dosage form comprises:
HCl glucosamine;
hyaluronic acid;
beer yeast;
acacia gum;
guar gum;
a flavoring agent;
Verdilox；
Previon；
cannabis sativa extract;
glycerol;
sunflower lecithin; and
and (3) water.
145. The method of claim 144, wherein the dosage form comprises:
about 12-17% HCl glucosamine;
about 0.01-1% hyaluronic acid;
about 29-33% brewer's yeast;
about 3-6% acacia;
about 0.5-2% guar gum;
about 12-16% flavoring agent;
about 0.01% to about 0.1% Verdilox;
about 0.5-1.5% Previon;
About 3-6% cannabis extract;
about 13-17% glycerol;
about 3-7% sunflower lecithin; and
about 3-7% water.
146. The method of claim 144 or 145, wherein the dosage form comprises: about 16% HCl glucosamine;
about 0.1% hyaluronic acid;
about 30.6% brewer's yeast;
about 4.8% acacia;
about 0.97% guar gum;
about 14.5% flavoring agent;
about 0.05% Verdilox;
about 0.97% Previon;
about 4.8% cannabis extract;
about 15.5% glycerol;
about 5.8% sunflower lecithin; and
about 5.8% water.
147. The method of claim 107, wherein the dosage form comprises:
cannabis sativa extract;
peanut butter;
rice bran;
HCl glucosamine;
sweet potato;
dry molasses;
sorbic acid;
beer yeast;
sugar;
water;
glycerol;
potato starch;
dehydrated peanut butter;
rice starch; and
guar gum.
148. The method of any one of claims 147, wherein the dosage form comprises: about 3.0-10.0% cannabis extract;
about 10.0-20.0% peanut butter;
about 10.0% to about 15.0% rice bran;
about 5.0% to about 15.0% HCl glucosamine;
about 4.0-10.0% sweet potato;
About 6.0% to about 13.0% dry molasses;
about 0.5-5.0% sorbic acid;
about 2.0-8.0% brewer's yeast;
about 3.0-8.0% sugar;
about 5.0% to about 15.0% water;
about 8.0% to about 18.0% glycerol;
about 1.0% to about 8.0% potato starch;
about 0.5% to about 5.0% dehydrated peanut butter;
about 1.0% to about 5.0% rice starch; and
about 1.0-5.0% guar gum.
149. The method of claim 147 or 148, wherein the dosage form comprises: about 5.0% cannabis extract;
about 15.0% peanut butter;
about 12.5% rice bran;
about 12.75% HCl glucosamine;
about 5.5% sweet potato;
about 8.0% dry molasses;
about 1% sorbic acid;
about 5.0% brewer's yeast;
about 6.0% sugar;
about 9.25% water;
about 13.0% glycerol;
about 2.0% potato starch;
about 1.0% dehydrated peanut butter;
about 2.0% rice starch; and
about 2.0% guar gum.
150. The method of claim 147 or 148, wherein the dosage form comprises: about 5.0% cannabis extract;
about 15.0% peanut butter;
about 13.0% rice bran;
about 8.5% HCl glucosamine;
about 6.0% sweet potato;
about 9.0% dry molasses;
about 1% sorbic acid;
About 5.0% brewer's yeast;
about 6.0% sugar;
about 9.5% water;
about 13.0% glycerol;
about 4.0% potato starch;
about 1.0% dehydrated peanut butter;
about 2.0% rice starch; and
about 2.0% guar gum.
151. The method of claim 107, wherein the dosage form comprises: cannabis sativa extract;
peanut butter;
rice bran;
HCl glucosamine;
sweet potato;
dry molasses;
sorbic acid;
beer yeast;
sugar;
water;
glycerol;
potato starch;
dehydrated peanut butter;
DigestaWellPET；
rice starch; and
guar gum.
152. The method of claim 151, wherein the dosage form comprises: about 3.0-10.0% cannabis extract;
about 5.0% to about 20.0% peanut butter;
about 10.0% to about 15.0% rice bran;
about 5.0% to about 15.0% HCl glucosamine;
about 4.0-10.0% sweet potato;
about 6.0% to about 13.0% dry molasses;
about 0.5-5.0% sorbic acid;
about 2.0-8.0% brewer's yeast;
about 3.0-8.0% sugar;
about 5.0% to about 15.0% water;
about 8.0% to about 18.0% glycerol;
about 1.0% to about 8.0% potato starch;
about 0.5% to about 5.0% dehydrated peanut butter;
about 0.1-3.0% DigestaWell PET;
about 1.0% to about 8.0% rice starch; and
about 1.0-5.0% guar gum.
153. The method of claim 151 or 152, wherein the dosage form comprises: about 5.0% cannabis extract;
about 10.0% peanut butter;
about 12.0% rice bran;
about 12.75% HCl glucosamine;
about 5.5% sweet potato;
about 8.0% dry molasses;
about 1% sorbic acid;
about 5.0% brewer's yeast;
about 6.0% sugar;
about 7.25% water;
about 10.0% glycerol;
about 5.0% potato starch;
about 4.0% dehydrated peanut butter;
about 0.5% DigestaWell PET;
about 6.0% rice starch; and
about 2.0% guar gum.
154. The method of claim 151 or 152, wherein the dosage form comprises: about 5.0% cannabis extract;
about 10.0% peanut butter;
about 12.5% rice bran;
about 8.5% HCl glucosamine;
about 8.0% sweet potato;
about 9.0% dry molasses;
about 1% sorbic acid;
about 5.0% brewer's yeast;
about 6.0% sugar;
about 6.0% water;
about 10.0% glycerol;
about 6.0% potato starch;
about 4.0% dehydrated peanut butter;
about 0.5% DigestaWell PET;
about 6.5% rice starch; and
about 2.0% guar gum.
155. The method of claim 107, wherein the dosage form comprises: cannabis sativa extract;
Peanut butter;
rice bran;
HCl glucosamine;
sweet potato;
dry molasses;
sorbic acid;
beer yeast;
sugar;
water;
glycerol;
potato starch;
dehydrated peanut butter;
chondroitin;
DigestaWell PET；
rice starch; and
guar gum.
156. The method of claim 155, wherein the dosage form comprises:
about 3.0-10.0% cannabis extract;
about 5.0% to about 20.0% peanut butter;
about 10.0% to about 15.0% rice bran;
about 5.0% to about 15.0% HCl glucosamine;
about 4.0-10.0% sweet potato;
about 6.0% to about 13.0% dry molasses;
about 0.5-5.0% sorbic acid;
about 2.0-8.0% brewer's yeast;
about 3.0-8.0% sugar;
about 5.0% to about 15.0% water;
about 8.0% to about 18.0% glycerol;
about 1.0% to about 8.0% potato starch;
about 0.5% to about 5.0% dehydrated peanut butter;
about 0.5-5.0% chondroitin;
about 0.1-3.0% DigestaWell PET;
about 1.0% to about 8.0% rice starch; and
about 1.0-5.0% guar gum.
157. The method of claim 155 or 156, wherein the dosage form comprises: about 5.0% cannabis extract;
about 10.0% peanut butter;
about 12.0% rice bran;
about 12.75% HCl glucosamine;
about 5.5% sweet potato;
about 8.0% dry molasses;
About 1% sorbic acid;
about 5.0% brewer's yeast;
about 6.0% sugar;
about 7.25% water;
about 10.0% glycerol;
about 4.0% potato starch;
about 4.0% dehydrated peanut butter;
about 2.5% chondroitin;
about 0.5% DigestaWell PET;
about 4.5% rice starch; and
about 2.0% guar gum.
158. The method of claim 155 or 156, wherein the dosage form comprises:
about 5.0% cannabis extract;
about 10.0% peanut butter;
about 12.5% rice bran;
about 8.5% HCl glucosamine;
about 8.0% sweet potato;
about 9.0% dry molasses;
about 1% sorbic acid;
about 5.0% brewer's yeast;
about 6.0% sugar;
about 6.0% water;
about 10.0% glycerol;
about 5.0% potato starch;
about 4.0% dehydrated peanut butter;
about 2.5% chondroitin;
about 0.5% DigestaWell PET;
about 5.0% rice starch; and
about 2.0% guar gum.
159. The method of any one of the preceding claims, wherein the cannabis extract, dosage form, or pharmaceutical composition is packaged to provide one or more doses of cannabis extract per package.
160. The method of claim 159, wherein the package is resealable.
161. The method of claim 159, wherein a dose of cannabis extract is a therapeutically effective amount.
CN202280024699.8A 2021-02-11 2022-02-11 Compositions and methods comprising cannabis extracts for treating animals in need thereof Pending CN117062606A (en)

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US202163197179P 2021-06-04 2021-06-04
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PCT/US2022/070630 WO2022174255A1 (en) 2021-02-11 2022-02-11 Compositions and methods comprising hemp extract for the treatment of animals in need

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