CN110200953B - Use of cannabinoids in the manufacture of a medicament for inhalation administration - Google Patents
Use of cannabinoids in the manufacture of a medicament for inhalation administration Download PDFInfo
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- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/045—Hydroxy compounds, e.g. alcohols; Salts thereof, e.g. alcoholates
- A61K31/05—Phenols
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- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
- A61K31/35—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having six-membered rings with one oxygen as the only ring hetero atom
- A61K31/352—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having six-membered rings with one oxygen as the only ring hetero atom condensed with carbocyclic rings, e.g. methantheline
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- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/0012—Galenical forms characterised by the site of application
- A61K9/007—Pulmonary tract; Aromatherapy
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- A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
- A61P1/08—Drugs for disorders of the alimentary tract or the digestive system for nausea, cinetosis or vertigo; Antiemetics
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- A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
- A61P1/14—Prodigestives, e.g. acids, enzymes, appetite stimulants, antidyspeptics, tonics, antiflatulents
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- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/08—Antiepileptics; Anticonvulsants
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
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- A61P25/00—Drugs for disorders of the nervous system
- A61P25/24—Antidepressants
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
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- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P27/00—Drugs for disorders of the senses
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- A61P27/06—Antiglaucoma agents or miotics
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
Abstract
The invention discloses an application of cannabinoid in preparing an inhalation drug, wherein the inhalation drug has short time, the inhalation drug administration time of a patient is less than 1 minute, the drug effect is rapidly exerted, the peak reaching time of blood concentration is short, and the bioavailability of the drug is high.
Description
Technical Field
The invention belongs to the field of biomedicine, and particularly relates to application of cannabinoids in preparation of an inhalation drug.
Background
Cannabis sativa L, a name of Cannabis sativa L, is a plant of the genus Cannabis of the family Moraceae, and has a long history of use as a medicine. In 1997, the National Institute of Health (NIH) published a report "works hop on the Medical Utility of Marijuana" outlining useful scientific data on cannabis for therapeutic applications, suggesting studies that support the potential use of cannabis in the following Medical indications: appetite stimulation and/or cachexia, nausea and vomiting following anti-cancer therapy, neurological and movement disorders, pain, and glaucoma. A report "Marijuana and Medicine, assembling the Science Base" was subsequently published in 1999, which provides a review of the actual and potential therapeutic uses of cannabinoids, which, in addition to identifying these medical uses of cannabis, underscores the need for a fast-acting, non-smoking, safe and reliable cannabinoid delivery system.
Cannabinoids are a specific class of substances in cannabis plants and are the main active ingredients in cannabis plants, and research on cannabinoids is a hot spot of cannabis research. The main cannabinoids in the cannabis plant include Cannabinol (CBN), Cannabidiol (CBD), Cannabidivarin (CBDV), Cannabigerol (CBG), Tetrahydrocannabidivarin (THCV), Tetrahydrocannabinol (THC), etc. The THC can cause people to be fantastic addicted, can be used as a drug, and is prohibited for a long time, but because the hemp has extremely high economic and medicinal values, the raw material hemp specially used for industrial application is called industrial hemp for short, the THC content in the hemp flowers and leaves in the growth period is less than three thousandth, and the THC has no value of extracting toxic component tetrahydrocannabinol or can be directly sucked as the drug, so that the THC can be legally planted in a large scale and can be industrially developed and utilized. The hemp as referred to in the present invention is industrial hemp. The above phenolic substances have been proved to have strong pharmacological activity, especially CBD, is becoming research focus more and more due to its multiple pharmacological activities, CBD has no neurotoxicity, it can hinder the influence of THC on human nervous system, and has obvious pharmacological activities such as antispasmodic, antirheumatic arthritis, antianxiety, etc., it has great industrial development value; CBD and THCV may affect lipid and carbohydrate metabolism and may be a new option for controlling blood glucose in type 2 diabetic patients; CBDV has good anti-epileptic activity, and studies show that CBDV can relieve nausea symptoms and help to treat gastrointestinal problems.
With the increasing importance of pharmacological and physiological activities of cannabinoids by the world, pharmaceutical preparations containing cannabinoids have been widely studied. Patent document CN200880106135.9 discloses a pharmaceutical formulation comprising cannabinoids Tetrahydrocannabivarin (THCV) and Cannabidiol (CBD), which is in the form of a tablet, capsule, powder, dispersible granule, pill, suspension or emulsion, etc. In the prior art, the medicines containing cannabinoids are rarely prepared into inhalable dosage forms.
Inhalable drugs, i.e. drugs for respiratory and systemic treatment by pulmonary administration. Compared with injection, transdermal administration and oral administration, the pulmonary administration has many advantages, the medicine can directly act on the lesion part, has the advantages of obvious curative effect, small dosage, quick response, less side effect, convenient use and the like, has high local medicine concentration in the respiratory tract, can avoid or reduce the medicine used by the whole body, and has greater attraction to patients and doctors.
The inhalation administration mode provides a non-invasive administration method, and the patients only need to cooperate to ensure the exertion of the drug effect, so the inhalation administration mode becomes an ideal administration route at present. First, inhalation administration enables effective pulmonary targeted drug delivery for the treatment of relatively common respiratory diseases such as asthma, emphysema, bronchiectasis, and chronic bronchitis; secondly, inhalation administration takes effect quickly, close to intravenous injection, faster than oral or subcutaneous injection, and this mode of administration is beneficial for the treatment of pain, epilepsy, panic or anxiety attacks, hypertensive crisis, allergic reactions and parkinson's disease; finally, inhalation instead of oral administration avoids gastrointestinal problems such as poor solubility, low bioavailability, irritation of the digestive tract, unwanted metabolism, food effects and dose variation.
At present, the lung is inhaled to give preparations in three types, namely powder inhalation, water inhalation and aerosol inhalation. The powder inhalation is a dosage form which is used for systemic or local action of one or more medicaments which enter corresponding parts of lungs in a dry powder aerosol form through a special inhalation administration device. The inhalation powder has the advantages of convenient use and easy filling. The disadvantages are large dosage, uneven particle size distribution, and large part of particle size, which is not easy to be absorbed by alveolus. The physiological structure of the lung is such that only fine mist particles having a particle size of 1 to 5 μm of the drug particles can reach the bronchi or alveoli.
The inhalation aerosol is a mixed solution composed of a drug solution or a suspension and a proper propellant, which are packaged in a pressure-resistant tank with a specific valve device, when in use, the liquid in the tank is sprayed out in the form of aerosol by the pressure of the propellant, and the aerosol is inhaled by a patient independently, so that the drug is deposited at the corresponding part of the lung. Has the advantages of convenient use and carrying, and has the defects of extra burden on the lung and uneven particle size due to the addition of a propellant and other auxiliary materials.
The inhalation of the aerosol is to dissolve the raw material medicines in water or disperse the raw material medicines in corresponding media to prepare aqueous solution or suspension. Then the aerosol is formed by atomization of the atomizer, and the patient actively inhales the aerosol, so that the medicine is deposited at the corresponding part of the lung. The inhalation aerosol is mainly used for treating respiratory diseases, especially asthma patients, and has the advantages of small and uniform particles, most of the particle diameters meeting the requirement of 1-5 mu m, no propellant, high dosage delivery, no special hand-lung coordination, normal breathing, less effort of patients and suitability for patients of any age or emergency treatment. The disadvantage is that only one dose can be delivered, and the treatment needs about 20min once and is long in time.
US patent application US20040034108a1 describes a pharmaceutical formulation comprising a cannabinoid, a solvent and a co-solvent, which can be used for administration using a spray pump, useful solvents being described including C1-C4 alcohols, including ethanol as the preferred solvent. The cosolvent comprises dihydric alcohol, sugar alcohol, carbonate and chlorinated hydrocarbon. The viscosity of the formulation is critical in order to obtain the desired particle size suitable for administration as an aerosol with a spray pump, and therefore, the ratio of solvent: the working range of co-solvents is rather narrow.
Patent document CN200680021401.9 discloses a pharmaceutical composition comprising a cannabinoid active pharmaceutical ingredient crystalline trans- (±) - Δ 9-tetrahydrocannabinol comprising mixing an effective amount of crystalline trans- (±) - Δ 9-tetrahydrocannabinol and a pharmaceutically acceptable carrier to provide a composition for delivery to the lungs of the mammal using a mechanical device, preferably selected from the group consisting of a powder inhaler, a unit dose inhaler, a metered dose inhaler, a spray pump and a nebulizer.
US patent 6747058 describes compositions for inhalation therapy in which the Δ 9-THC is formulated in a semi-aqueous solvent comprising an alcohol, water and a pharmaceutically acceptable glycol in a "judiciously selected" volume ratio, such as 35: 10: 55 ethanol: water: propylene glycol.
U.S. patent application publication No. US20030229027a1 discloses a formulation in which a cannabinoid compound is incorporated into a glassy sugar (glass) or glassy sugar alcohol (glass), a natural cannabinoid compound is dissolved in a water-soluble organic solvent, and the sugar is dissolved in water. The two solutions are combined to form a mixture, which is then freeze dried, spray dried, vacuum dried or dried with a supercritical fluid. Freeze drying produces a porous cake which can be processed into a powder for tableting or pulmonary administration.
US patent US6713048 describes a Δ 9-THC solution metered dose inhaler containing a composition comprising a hydrofluoroalkane propellant and Δ 9-THC. Suitable propellants include 1,1,1, 2-tetrafluoroethane and 1,1,1,2,3,3, 3-heptafluoropropane. In addition, the formulation may also contain an organic solvent (e.g. ethanol) to solubilize the Δ 9-THC.
Based on the prior art, the invention provides the application of cannabinoid in preparing the medicine for inhalation administration, which has the following advantages: 1) the medicine has uniform grain diameter and meets the requirement of pulmonary administration and inhalation. 2) Without the adjunct, the adjunct can be removed by the apparatus prior to inhalation. 3) The administration time is short, the atomization administration can be completed within a few minutes, the administration time is much shorter than the administration time of 20min by using a conventional atomizer, the drug effect is quickly exerted, the peak reaching time of the blood concentration is short, and the bioavailability of the drug is high.
Disclosure of Invention
The object of the present invention is to provide the use of a cannabinoid for the manufacture of a medicament for administration by inhalation, said medicament being administered for a period of less than 1 minute; in another aspect, the present invention also provides a cannabinoid-containing composition further comprising a pharmaceutical carrier, wherein said composition is vaporized and/or aerosolized by heating at 100 ℃ and 400 ℃; the invention also provides a method of administering a cannabinoid comprising heating the cannabinoid to produce a gas, filtering the gas and cooling the gas for administration by inhalation.
In a first aspect, the use of a cannabinoid for the manufacture of a medicament for inhalation administration, said medicament for inhalation administration having an inhalation administration time of less than 1 minute.
Preferably, the inhalation administration time of the inhalation administration medicine is less than 10 seconds
Preferably, the inhalation administration time of the inhalation administration medicine is 1 to 8 seconds.
More preferably, the inhalation administration time of the inhalation administration drug is 1 to 3 seconds.
The inhalation drug is a liquid drug or a solid drug, preferably, the drug is a solid drug, and the inhalation drug is a drug which can be heated, vaporized and/or atomized at the temperature of 100 ℃ and 400 ℃.
More preferably, the inhalation drug is a drug that can be vaporized and/or atomized by heating at 150 ℃ and 300 ℃.
The solid medicament is a pharmaceutical preparation in the following form: tablet, pill, capsule, pellicle, and granule.
The particle size of the inhalation drug after heating vaporization and/or atomization is 0.1-20 μm, preferably 0.5-15 μm, and more preferably 0.5-10 μm. Preferably, the medicament also comprises a medicament carrier with a melting point close to that of the cannabinoid, and preferably, the melting point of the medicament carrier is +/-0-20 ℃ different from that of the cannabinoid.
More preferably, the pharmaceutical carrier and cannabinoid have melting points within a range of + -0-10 deg.C.
The medicinal carrier is easily soluble in water, and is selected from one or more of PEG, poloxamer, xylitol, sorbitol, lactitol, isomalt, mannitol, dextrin, starch, gelatin, carrageenan, tragacanth, bletilla gum, guar gum, konjac gum, karaya gum, pectin, agar, gum ghatti, tamarind gum, and locust bean gum.
Preferably, the drug carrier is selected from PEG and/or poloxamer, and the PEG is selected from one or the combination of more than two of PEG4000, PEG5000, PEG6000, PEG7000, PEG7500 and PEG 8000.
In a preferred embodiment of the invention, the drug carrier is PEG 6000.
The mass percent of the cannabinoid in the inhalation drug is 1-99%, preferably, the mass percent of the cannabinoid in the inhalation drug is 1-50%, and more preferably, the mass percent of the cannabinoid in the inhalation drug is 20%.
The cannabinoids of the present invention may be chemically synthesized products, biosynthetic products, plant extracts or prepared in other ways. The cannabinoid comprises one or more of Cannabidiol (CBD), Cannabidivarin (CBDV), Cannabigerol (CBG), Tetrahydrocannabivarin (THCV), cannabichromene (CBC), and Cannabinol (CBN).
Preferably, the mass percentage of CBD in the cannabinoid is not less than 60%, preferably, the mass percentage of CBD in the cannabinoid is not less than 90%, and most preferably, the mass percentage of CBD in the cannabinoid is not less than 99.7%.
The inhalational administration medicine of the present invention is a medicine for preventing and/or treating nausea, vomiting, HIV wasting syndrome, anorexia, multiple sclerosis, spinal cord injury, epilepsy, pain, arthritis, dyskinesia, glaucoma, asthma, hypertension, mental disorder, dementia, systemic inflammation, gastrointestinal tract diseases, acute stress disorder, depression, anxiety disorder (generalized anxiety disorder, social anxiety disorder, phobia, obsessive compulsive disorder, panic disorder, post-traumatic stress disorder), premenstrual syndrome, attention deficit disorder, obesity, eating disorder, flushing due to vasoconstriction, cocaine and alcohol addiction, sexual dysfunction and related diseases, functional disorder, neurological disorder.
The inhalant drug of the present invention may also be an inhalant drug for non-therapeutic purposes.
In a second aspect, a composition comprises a cannabinoid and a pharmaceutical carrier having a melting point close to that of the cannabinoid, preferably within a range of ± 0 ℃ to 20 ℃ of the melting point of the cannabinoid.
More preferably, the pharmaceutical carrier and cannabinoid have melting points within a range of + -0-10 deg.C.
Preferably, the mass percent of cannabinoid in the composition is 1-99%, preferably, the mass percent of cannabinoid is 1-50%, more preferably, the mass percent of cannabinoid is 20%.
The cannabinoid comprises one or more of cannabidiol, cannabidivarin, cannabigerol, tetrahydrocannabivarin, cannabichromene, and cannabinol. Preferably, the mass percentage of CBD in the cannabinoid is not less than 60%, preferably, the mass percentage of CBD in the cannabinoid is not less than 90%, and most preferably, the mass percentage of CBD in the cannabinoid is not less than 99.7%.
The medicinal carrier is water-soluble one or more of PEG, poloxamer, xylitol, sorbitol, lactitol, isomalt, mannitol, dextrin, starch, gelatin, carrageenan, tragacanth gum, bletilla gum, guar gum, konjac gum, karaya gum, pectin, agar, gum ghatti, tamarind gum, and locust bean gum.
Preferably, the drug carrier is selected from PEG and/or poloxamer, and the PEG is selected from one or the combination of more than two of PEG4000, PEG5000, PEG6000, PEG7000, PEG7500 and PEG 8000.
In a preferred embodiment of the invention, the pharmaceutical carrier is selected from PEG 6000.
The composition is a pharmaceutical formulation in the form of: tablet, pill, capsule, spray, oil solution, pellicle, granule, and suspension.
Preferably, the composition is a pharmaceutical formulation in the form of: tablet, pill, capsule, pellicle, and granule.
In a preferred embodiment of the invention, the pharmaceutical composition is a pill.
Preferably, the composition also comprises one or more of an antioxidant, a buffering agent, a preservative, a lubricant, a binder, a coloring agent and a pH regulator as a pharmaceutical adjuvant.
In a preferred embodiment of the invention, the composition is a unit formulation comprising an appropriate amount of the active ingredient cannabinoid, which may vary or be adjusted from 0.001mg to 1000mg of the active ingredient in the unit formulation depending on the pharmaceutical potency of the cannabinoid component in the unit formulation and the disease to be treated accordingly.
In the present invention, the content of cannabinoid in the unit preparation is 0.1-1000mg, and preferably, the content of cannabinoid in the unit preparation is 10-100 mg.
The composition can be heated to vaporize and/or atomize at the temperature of 100-400 ℃, and preferably, the drug composition can be heated to vaporize and/or atomize at the temperature of 150-300 ℃. The particle size after vaporization and/or atomization by heating is 0.1-20 μm, preferably 0.5-15 μm, and more preferably 0.5-10 μm.
The administration mode of the composition is inhalation administration, and the inhalation administration time is less than 1 minute.
Preferably, the inhalation administration time of the inhalation administration medicine is less than 10 seconds
Preferably, the inhalation administration time of the inhalation administration medicine is 1 to 8 seconds.
More preferably, the inhalation administration time of the inhalation administration drug is 1 to 3 seconds.
In a third aspect, a method of administering a cannabinoid comprising heating the cannabinoid to vaporize and/or atomize the cannabinoid, filtering the cannabinoid to cool, and then inhaling the cannabinoid, preferably further comprising a pharmaceutical carrier that approximates the melting point of the cannabinoid.
The difference between the melting points of the drug carrier and the cannabinoid is + -0-20 deg.C, preferably, the difference between the melting points of the drug carrier and the cannabinoid is + -0-10 deg.C.
Preferably, the method for administering cannabinoid comprises heating cannabinoid and pharmaceutical carrier in heating device for vaporization and/or atomization, passing gas and/or aerosol through delivery device into filtering and cooling device, filtering to remove gas and/or aerosol generated by heating pharmaceutical carrier and/or pharmaceutical adjuvants, and inhaling the rest cannabinoid gas and/or aerosol by patient through inhalation device.
The heating temperature of the heating device is 100-400 ℃, and preferably 150-300 ℃.
The cannabinoid and the pharmaceutical carrier are heated for vaporization and/or atomization to have a particle size of 0.1-20 μm, preferably in the range of 0.5-15 μm, and more preferably in the range of 0.5-10 μm.
Preferably, the gas and/or mist particles generated by heating, vaporizing and/or atomizing are filtered and cooled by a filtrate selected from water, more preferably, the water temperature is 1-40 ℃, most preferably, the water temperature is 1-25 ℃.
The cannabinoid comprises one or more of Cannabidiol (CBD), Cannabidivarin (CBDV), Cannabigerol (CBG), Tetrahydrocannabivarin (THCV), cannabichromene (CBC) and Cannabinol (CBN). Preferably, the mass percentage of CBD in the cannabinoid is not less than 60%, preferably, the mass percentage of CBD in the cannabinoid is not less than 90%, and most preferably, the mass percentage of CBD in the cannabinoid is not less than 99.7%.
The medicinal carrier is easily soluble in water, and is selected from one or more of PEG, poloxamer, xylitol, sorbitol, lactitol, isomalt, mannitol, dextrin, starch, gelatin, carrageenan, tragacanth, bletilla gum, guar gum, konjac gum, karaya gum, pectin, agar, gum ghatti, tamarind gum, and locust bean gum.
Preferably, the drug carrier is selected from PEG and/or poloxamer, and the PEG is selected from one or the combination of more than two of PEG4000, PEG5000, PEG6000, PEG7000, PEG7500 and PEG 8000.
In a preferred embodiment of the invention, the drug carrier is PEG 6000.
The methods may be used for therapeutic or non-therapeutic purposes.
The present invention has the advantage of providing the use of cannabinoids in the manufacture of a medicament for inhalation administration which is short in time, preferably inhaled by the patient within 10 seconds, and which has a rapid onset of action, a short peak time for blood levels and a high bioavailability of the medicament. The cannabinoid-containing formulation can be a unit formulation, with a single administration of precise dosage; because the melting point of the drug carrier is similar to that of the cannabinoid, but the solubility of the drug carrier and the cannabinoid is different in the same medium, the gas generated by the drug carrier can be removed by a filter device after vaporization and/or atomization, and the pure cannabinoid gas can be used for inhalation administration.
Detailed Description
The technical solutions in the embodiments of the present invention will be clearly and completely described below, and it is obvious that the described embodiments are only some embodiments of the present invention, and not all embodiments. All other embodiments, which can be derived by a person skilled in the art from the embodiments given herein without making any creative effort, shall fall within the protection scope of the present invention.
Example 1 preparation of a cannabinoid (20%) containing pellet formulation
a, adding 20 parts of cannabinoid (the mass percentage of CBD is 99.7%) and 600080 parts of drug carrier PEG into a stirring container, heating to 65 ℃ while stirring, melting the added materials into feed liquid, and stirring for 30min until the feed liquid is uniform;
b, injecting the feed liquid into a spherical mold with the diameter of 10mm prepared in advance, and cooling the spherical mold to room temperature for molding;
and c, removing the mold after 1h, and taking out the formed spherical pills.
Example 2 preparation of a cannabinoid (50%) containing pellet formulation
adding 50 parts of cannabinoid (the mass percentage of CBD is 99.7%) and 600050 parts of drug carrier PEG into a stirring container, heating to 65 ℃ while stirring, melting the added materials into feed liquid, and stirring for 30min until the feed liquid is uniform;
b, injecting the feed liquid into a spherical mold with the diameter of 10mm prepared in advance, and cooling the spherical mold to room temperature for molding;
and c, removing the mold after 1h, and taking out the formed spherical pills.
Example 3 preparation of a cannabinoid (90%) containing pellet formulation
a, adding 90 parts of cannabinoid (the mass percentage of CBD is 99.7%) and 600010 parts of drug carrier PEG into a stirring container, heating to 60 ℃ while stirring, melting the added materials into feed liquid, and stirring for 30min until the feed liquid is uniform;
b, injecting the feed liquid into a spherical mold with the diameter of 10mm prepared in advance, and cooling the spherical mold to room temperature for molding;
and c, removing the mold after 1h, and taking out the formed spherical pills.
Example 4 preparation of a cannabinoid (90%) containing pellet formulation
a, adding 90 parts of cannabinoid (the mass percentage of CBD is 60.6%, CBDV is 30.8%, CBN is 30.1%) and 10 parts of drug carrier poloxamer into a stirring container, heating to 60 ℃ while stirring, melting the added materials into feed liquid, and stirring for 30min until the materials are uniform;
b, injecting the feed liquid into a spherical mold with the diameter of 10mm prepared in advance, and cooling the spherical mold to room temperature for molding;
and c, removing the mold after 1h, and taking out the formed spherical pills.
Example 5 preparation of cannabinoid containing pellets
a, adding 20 parts of cannabinoid (the mass percentage of CBD is 99.7%) and 400080 parts of drug carrier PEG into a stirring container, heating to 65 ℃ while stirring, melting the added materials into feed liquid, and stirring for 30min until the feed liquid is uniform;
b, injecting the feed liquid into a spherical mold with the diameter of 10mm prepared in advance, and cooling the spherical mold to room temperature for molding;
and c, removing the mold after 1h, and taking out the formed spherical pills.
Example 6 preparation of cannabinoid containing pellets
a, adding 20 parts of cannabinoid (the mass percentage of CBD is 99.7%) and 80 parts of drug carrier mannitol into a stirring container, heating to 65 ℃ while stirring, melting the added materials into feed liquid, and stirring for 30min until the feed liquid is uniform;
b, injecting the feed liquid into a spherical mold with the diameter of 10mm prepared in advance, and cooling the spherical mold to room temperature for molding;
and c, removing the mold after 1h, and taking out the formed spherical pills.
EXAMPLE 7 selection of drug Carriers in the pellets
According to the preparation method and material ratio disclosed in example 1, cannabinoid pills with mannitol, PEG4000 and PEG6000 as drug carriers were prepared respectively under the condition of no cannabinoid change, and the results are shown in Table 1 by examining the formability, surface smoothness, solubility of drug carrier in water, cannabinoid transfer rate and other indexes of 3 pills. Heating the cannabinoid pill in a heating device to 300 deg.C, atomizing the cannabinoid pill, filtering and cooling the gas generated by atomization with a filter to remove the gas generated by heating the drug carrier, selecting the filtrate from water of 10 deg.C, and detecting the ratio of cannabinoid to gas generated by the drug carrier in the filtered and cooled gas, the results are shown in Table 2.
TABLE 1 drug Carrier screening in cannabinoid pill preparation
TABLE 2 drug carrier screening in cannabinoid pill administration
| Drug carrier | Filtering gaseous cannabinoid content | Filtering the content of gas carrier |
| Mannitol | 80％ | 13％ |
| PEG4000 | 90％ | 6％ |
| PEG6000 | 96％ | 1％ |
According to the test results, it can be seen that when the drug carrier is mannitol, PEG4000 or PEG6000, the drug transfer rates of the cannabinoid pellets are all the same, and the pill-forming surface smoothness is affected due to the higher viscosity of mannitol. In addition, the solubility of the drug carrier in water, PEG6000 in water, is the best. The pill is heated and atomized, the generated gas passes through a filtering and cooling device, and when the drug carrier is PEG6000, the content of cannabinoid in the filtered gas is highest and reaches 96%.
Example 8 selection of cannabinoid pill Loading
PEG6000 is selected as a drug carrier, 10%, 20%, 30% and 50% of cannabinoid by mass are respectively added, cannabinoid pills are prepared according to the preparation method disclosed in example 1, the best drug loading rate of the cannabinoid pills is screened through two indexes of demoulding effect and pill forming performance, and the result is shown in Table 3.
TABLE 3 cannabinoid pill drug load screening
Through the experimental results, the content of the cannabinoid has certain influence on the preparation of the pill, when the content of the cannabinoid is too high, such as 50%, the demoulding effect in the preparation process of the pill is poor, the pill is not shaped, when the content of the cannabinoid is 30%, the pill demoulding effect and the formability are still poor, and when the content of the cannabinoid is 20%, the maximum drug loading rate which is smooth in demoulding and good in pill formability can be realized.
Example 9 comparative cannabinoid-containing pill odor test
The cannabinoid pellets prepared in examples 1-6 were heat atomized and tested for gaseous odor and cannabinoid controls were used. The cannabinoid formulation was heated in a heating apparatus at 300 c, the mist was filtered through water after atomization, and the odor generated during heating was recorded, with the results shown in table 4.
TABLE 4 results of heat-baking test for different dosage forms of cannabinoid drugs
| Drug carrier | Taste of the product | Results | |
| Example 1 | PEG6000(80％) | Is tasteless | Qualified |
| Example 2 | PEG6000(50％) | Is tasteless | Qualified |
| Example 3 | PEG6000(10％) | Is tasteless | Qualified |
| Example 4 | Poloxamer (10%) | Is tasteless | Qualified |
| Example 5 | PEG4000(80％) | Is tasteless | Qualified |
| Example 6 | Mannitol (80%) | Is tasteless | Qualified |
| Cannabinoid | Is free of | Is tasteless | Qualified |
According to the above experimental results, it can be seen that, when the drug carrier is PEG, mannitol or poloxamer, the gas generated after the heating of the cannabinoid drug formulation is odorless, and the content of PEG as the drug carrier has no influence on the odor generated after the heating of the drug, compared to the cannabinoid without the carrier.
Effects of the embodiment
1.1 Condition of the subject
180 patients in the department of sleeping in a hospital are randomly selected, the age is 26-45 years, the duration of the disease is 3-14 months, and the insomnia factor is sleep disorder caused by anxiety. Subjects were randomized into the cannabinoid pill, spray, and placebo groups, each group containing 30 patients with a male to female ratio of approximately 1: 1.
1.2 inclusion and exclusion criteria
1.2.1 inclusion criteria: the diagnosis standard of insomnia in the third edition of Chinese mental disorder classification and diagnosis standard is met; all patients signed informed consent.
1.2.2 exclusion criteria: eliminating the patients with insomnia accompanied by other organic lesions; patients with allergic constitution and patients allergic to the drugs used in the study were excluded; eliminating patients with heart, liver and renal dysfunction; and people who suffer from insomnia caused by physical diseases or abuse or dependence of psychotropic drugs are excluded.
1.3 therapeutic Agents
Cannabinoid pill 1 group: cannabinoid pellets with 20% cannabinoid content prepared in example 1 were heated to 300 ℃ in a heating device for nebulization, the gas was filtered through a filter device for cooling, and the subjects were inhaled through an inhalation device for 3 seconds per subject.
Cannabinoid pill 2 group: cannabinoid pellets with 20% cannabinoid content prepared in example 1 were heated to 300 ℃ in a heating device for nebulization, the gas was filtered through a filter device for cooling, and the subjects were inhaled through an inhalation device for 10 seconds per subject.
Cannabinoid pill 3 group: cannabinoid pellets with 20% cannabinoid content prepared in example 1 were heated to 300 ℃ in a heating device for nebulization, the gas was filtered through a filter device for cooling, and the subjects were inhaled through an inhalation device for 5 minutes per subject.
Cannabinoid pill 4 group: cannabinoid pellets with 20% cannabinoid content prepared in example 1 were heated to 300 ℃ in a heating device for nebulization, the gas was filtered through a filter device for cooling, and the subjects were inhaled through an inhalation device for 20 minutes per subject.
Cannabinoid spray set: cannabinoid spray with cannabinoid content of 20% was prepared according to the methods disclosed in the prior art, and was self-administered to the mouth of the patient when needed. The cannabinoid spray is prepared as follows: 20 parts of cannabinoid and 80 parts of solvent, wherein the solvent is a mixture of ethanol and propylene glycol (v/v is 1:1), the cannabinoid is dissolved in the solvent, the mixture is evenly mixed by vortex, and the liquid is filled into a spray bottle with the volume of 120ml for standby.
Placebo group: blank pellets, in which cannabinoid was replaced by PEG6000, were prepared according to the preparation method disclosed in example 1, the blank pellets were heated to 300 ℃ in a heating device for atomization, the gas was filtered and cooled by a filtering device, and the subjects were inhaled by an inhalation device, and the inhalation time of each subject was 3 seconds.
1.4 methods of treatment
The subject is required to take the drug 1h before going to bed every night, 1 time/day, 4 mg/time, and 7 days continuously.
1.5 therapeutic efficacy determination
The treatment effect judgment standard is as follows: after treatment, the patient can sleep normally, or sleep for more than 6h at night, and the patient can wake up and has vigorous energy; the effect is shown: the sleep state of the patient is improved after treatment, and the sleep time is increased by more than or equal to 3 hours compared with that before treatment; the method has the following advantages: the sleep condition of the patient is improved after treatment, the sleep time is increased compared with that before treatment, but the increase time is less than 3 h; and (4) invalidation: the sleep condition of the patient is not improved or even aggravated after the treatment.
1.6 statistical treatment
The data are analyzed by SPSS 18.0 statistical software, t test is adopted, X2 test is adopted for counting data, and the difference is statistically significant when P is less than 0.05.
2 results of the test
Data for time to sleep, duration of sleep, and number of nighttime awakenings for each test group are shown in Table 5.
TABLE 5 comparison of time to sleep, duration of sleep, number of nighttime awakenings
As can be seen from the table above, the proportion of the patients who fall asleep for less than 15min, have sleep duration for more than or equal to 6h and are not aroused at night in the cannabinoid pill 1-2 groups is significantly higher than that in the placebo group, the difference has statistical significance (P is less than 0.05), and although the cannabinoid spray group has a certain treatment effect compared with the placebo group, the cannabinoid pill group without inhalation administration has a good treatment effect. Compared with the treatment effect of the groups 1-4 of the cannabinoid pill, the effect of tranquilizing and improving sleep is best when the administration time is 3 seconds or 10 seconds, and the treatment effect is equivalent to that of the spray administration when the administration time is as long as 20 minutes. Therefore, when the inhalation administration time of the cannabinoid pill prepared by the invention is 3-10 seconds, the inhalation administration effect has obvious effects on tranquilizing and allaying excitement, helping sleep and relieving anxiety.
Finally, it should be noted that: the above embodiments are only used to illustrate the technical solution of the present invention, and not to limit the same; while the invention has been described in detail and with reference to the foregoing embodiments, it will be understood by those skilled in the art that: the technical solutions described in the foregoing embodiments may still be modified, or some or all of the technical features may be equivalently replaced; and the modifications or the substitutions do not make the essence of the corresponding technical solutions depart from the scope of the technical solutions of the embodiments of the present invention.
Claims (10)
1. Use of a cannabinoid in the manufacture of a medicament for administration by inhalation, said medicament being administered by inhalation for a period of less than 1 minute; wherein the drug is composed of cannabinoid and a drug carrier with a melting point close to that of the cannabinoid, the difference between the melting points of the drug carrier and the cannabinoid is +/-0-20 ℃, the drug carrier is a water-soluble drug carrier, and the drug carrier is selected from one or a combination of more than two of PEG, poloxamer and mannitol;
the inhalation drug is a solid drug.
2. The use according to claim 1, wherein the solid medicament is a pharmaceutical formulation in the form of: tablet, pill, capsule, pellicle, and granule.
3. The use according to claim 1, wherein the medicament is a medicament which is capable of being vaporized and/or atomized by heating at 100-400 ℃.
4. Use according to claim 3, wherein the drug is vaporized and/or atomized by heating and has a particle size of 0.1-20 μm.
5. The use according to claim 1, wherein the PEG is selected from one or a combination of two or more of PEG4000, PEG5000, PEG6000, PEG7000, PEG7500, and PEG 8000.
6. A composition is administered by inhalation, and comprises cannabinoid and water-soluble drug carrier with melting point within + -0-20 deg.C, wherein the drug carrier is selected from one or more of PEG, poloxamer and mannitol;
the composition is a pharmaceutical formulation in the form of: tablet, pill, capsule, pellicle, and granule.
7. The composition of claim 6, wherein the pharmaceutical composition is capable of being vaporized and/or aerosolized by heating at a temperature of about 100 ℃ to about 400 ℃.
8. The composition of claim 6, wherein the melting point of the pharmaceutical carrier is within the range of ± 0-10 ℃ from that of the cannabinoid, the percentage by mass of the cannabinoid in the composition is 1-99%, the pharmaceutical carrier is selected from the group consisting of PEG and/or poloxamer, and the PEG is selected from the group consisting of PEG4000, PEG5000, PEG6000, PEG7000, PEG7500, and PEG 8000.
9. The composition of claim 6, wherein the pharmaceutical carrier is selected from the group consisting of: PEG6000, the composition is a unit preparation, and the content of cannabinoid is 0.1-1000 mg.
10. The composition of claim 6, wherein the composition is a pill.
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