Patent Abstract:
several variations of formulations are used as a water base solution to disperse oil soluble pharmaceuticals , including cannabis extract , suitable for use with a vmn . common elements include added small amount of sodium electrolytes to facilitate the nebulization process and ethanol in controlled amount as needed to dilute or dissolve thick waxy substances such as found in some cannabis extracts . surfactants , co - surfactants and / or emulsifiers to include but not limited to acconon ™, ethanol , hydroxylated soy lecithin and / or sodium lauryl sulfate are used . the ingredients are sonicated to obtain a uniform respirable liposomal suspension that could be delivered in low micron range using a vmn for efficient absorption into the blood stream by oral inhalation .

Detailed Description:
an aerosol precursor is a substance that is capable of being dispersed into a system of solid or liquid particles suspended in air or other gaseous environment . aerosols can vary in size and composition depending on the substrate used and the delivery system deployed . the “ entourage effect ” refers to the interaction of various compounds in cannabis . cannabis , unlike most modern day medicine , contains a wide range of chemical compounds . scientists have identified over 60 unique molecules in cannabis known as cannabinoids , which include thc and cbd . many other non - cannabinoid compounds are produced by the plant that also have regulatory effects . for example , terpenes , the molecules responsible for marijuana &# 39 ; s smell , have been shown to block some cannabinoid receptor sites in the brain while promoting cannabinoid binding in others . as a result , terpenes are believed to affect many aspects of how the brain takes in thc or cannabidiol ( cbd ), while offering various therapeutic benefits of their own . while thc , the psychoactive molecule within cannabis has gotten most of the attention , studies suggest many of the compounds in cannabis work together to produce a synergy of effects . this is known as the “ entourage effect ”. hemp oil or hempseed oil is an oil extracted from the hemp plant . all plants in the cannabis genus can produce the oil , but usually only industrial hemp is used to make hemp oil . industrial hemp is a hemp variety which has been cultivated specifically for industrial production , and it has a minimum of psychoactive substances associated with the genus , most notably a - 9 - tetrahydrocannabinol ( thc ). the oil could be used to dilute a concentrated cannabis extract . cannabis , also known as marijuana among several other names , is a preparation of the cannabis plant intended for use as a psychoactive drug or medicine . a single unit dose is herein defined as a maximum dose of the medication that can be taken at any one time or within a specified dosage period . the term titratable dose is defined as meaning that the patient is provided with a medication that is in such a form that smaller doses of the formulation can be taken . titration of doses is beneficial to the patient as they are able to take smaller doses of the medication until the drug is efficacious . not all patients will require exactly the same dose of medication . dependent factors could include but not limited to body size , metabolic rate , renal and / or hepatic clearance , genetics , and the state of the drug / tissue interface during absorption . the benefits of delivering cannabis extracts using vmn over other dosage forms are evident as smaller aliquots could be used and without the lengthy wait times of up to 2 hours for peak response as in the oral route . decarboxylation is a chemical reaction that releases carbon dioxide ( co 2 ). this refers to a chemical reaction that takes place in which carboxylic acids loose a carbon atom from a carbon chain . this process for example , converts thca ( acid form of thc found in abundance in growing and harvested cannabis and is a biosynthetic precursor of thc ) to thc . thc is the active compound with many medicinal and psychoactive effects . when the cannabis plant dries , it very slowly begins to decarboxylate and converts thca to thc . mmad refers to mass median aerodynamic diameter defined as the diameter at which 50 % of the particles by mass are larger and 50 % are smaller . a cascade impactor is strictly a measurement - related device . in addition to measuring the range of substances moved through an opening by aerosol , the impactor can also be used to determine the particle size of the distributed substance . sample formulations are set forth in table 1 below used to deliver a continuous or an intermittent nebulization of cannabis extract using a palladium mesh vmn capable of generating mean particle sizes of under 5 microns . the cannabis or hemp oil extract in various concentrations is added to a water base solution containing surfactants , co - surfactants and / or emulsifiers and then put through a simple sonicator or ultrasonic homogenizer . a more sophisticated fluidizer could also be used to enhance the stability of the emulsion . a gentle agitation of the solution prior to use is recommended to prevent separation upon long term standing . like nebulization , smoking cannabis results in a more rapid onset of action , higher blood levels of cannabinoids , and a shorter duration of pharmacodynamic effects compared to oral administration ( 1 ). the amount of δ 9 - thc delivered from cannabis cigarettes is variable ( 1 ). factors contributing to this variability include the plant source together with the efficiency and method of smoking used by the patient ( 1 , 3 ). smokers often claim that they can titrate their δ 9 - thc intake by adapting their smoking behavior to obtain the desired effect ( 4 , 5 ). δ 9 - thc absorption by smoke inhalation is fast and variable , with a bioavailability of 2 - 56 % depending on depth of inhalation , puff duration , and breath hold ( 6 , 7 ). in practice , a maximum of 25 - 27 % of the thc content in a cannabis cigarette is absorbed or delivered to the systemic circulation from the total available amount ( 2 , 8 ). vaporization of cannabis generally requires a heat source in the form of a heating coil or plate . for drug particles to be absorbed by the pulmonary route , they must be carried deep into the alveolar sacs and into the alveoli terminal of the bronchioles where there are over 100 meter square of absorptive surface area in an adult . vaporization allows this to happen by heating the cannabis extract to release vapor and often using propylene glycol and / or glycerol as a solvent vehicle . the potential advantages of vaporization include the formation of a smaller quantity of toxic by - products such as carbon monoxide , polycyclic aromatic hydrocarbons ( pahs ), and tar , as well as a more efficient extraction of δ 9 - thc from the cannabis material ( 4 , 9 , 10 , 11 , 12 ). the subjective effects and plasma concentrations of δ 9 - thc obtained by vaporization of cannabis are comparable to those obtained by smoking cannabis , with absorption being somewhat faster with the vaporizer compared to smoking , according to one study ( 4 ). in addition , the study reported that the vaporizer was well tolerated with no reported adverse effects , and was preferred over smoking by the test subjects ( 4 ). while vaporization has been reported to be amenable to self - titration ( as has been claimed for smoking ) ( 4 , 11 ), the proper use of the vaporizer for optimal administration of cannabis for therapeutic purposes needs to be established in more detail ( 12 ). the amount and type of cannabis placed in the vaporizer , the vaporizing temperature and duration of vaporization , and the balloon volume are some of the parameters that can affect the delivery of δ 9 - thc ( 11 ). whereas the central nervous system and physiological effects occur within minutes by the smoking route or by vaporization ( 13 , 14 ), these effects proceed much slower in the case of oral ingestion ( 14 , 15 ). oral administration results in a slower onset of action , lower peak blood levels of cannabinoids , and a longer duration of pharmacodynamic effects compared to smoking ( 1 ). the psychotropic effect or “ high ” occurs much more quickly by the smoking than by the oral route , which is the reason why smoking appears to be the preferred route of administration by many , especially recreational users ( 16 ). for orally administered prescription cannabinoid medicines such as synthetic δ 9 - thc ( dronabinol , marketed as marinol ®), only 10 - 20 % of the administered dose enters the systemic circulation indicating extensive first - pass metabolism ( 5 ) δ 9 - thc can also be absorbed orally by ingestion of foods containing cannabis ( e . g . butters , oils , brownies , cookies ), and teas prepared from leaves and flowering tops . absorption from an oral dose of 20 mg δ 9 - thc in a chocolate cookie was described as slow and unreliable ( 3 ), with a systemic availability of only 4 - 12 % ( 3 ). following a single oro - mucosal administration of nabiximols ( sativex ®) ( four sprays totaling 10 . 8 mg δ 9 - thc and 10 mg cbd ), mean peak plasma concentrations of both thc and cbd typically occur within 2 - 4 h . when administered oro - mucosally , blood levels of δ 9 - thc and other cannabinoids are lower than those achieved by inhalation of the same dose of smoked cannabis , but δ 9 - thc blood levels were comparable to those seen with oral administration of dronabinol ( 108 , 290 ). oro - mucosal administration of nabiximols is amenable to self - titration ( 19 , 20 , 21 , 22 ). while δ 9 - thc itself is not absorbed through the rectal route , the pro - drug δ 9 - thc - hemisuccinate is absorbed ; this fact , combined with decreased first - pass metabolism through the rectal route , results in a higher bioavailability of δ 9 - thc by the rectal route ( 52 - 61 %) than by the oral route ( 23 , 24 , 25 , 26 , 27 ). plasma concentrations of δ 9 - thc are dose and vehicle - dependent , and also vary according to the chemical structure of the thc ester ( 26 ). the rectal route is less desirable but offers an alternative for patients lacking conscious coordination . cannabinoids are highly hydrophobic , making transport across the aqueous layer of the skin the rate - limiting step in the diffusion process ( 1 ). no clinical studies exist regarding the percutaneous absorption of cannabis — containing ointments , creams , or lotions . however , some research has been carried out on transdermal delivery of synthetic and natural cannabinoids using a dermal patch ( 28 , 29 ). permeability of various cannabinoids vary such that cannabidiol ( cbd ) and cannabinol ( cbn ) was found to be 10 - fold more permeable through the skin than for δ 8 - thc ( 30 ). in the 1970s , scientists proposed using liposomes for the delivery of drugs . today we have a variety of drugs in use given in liposomal form for direct injection into our blood stream . liposomes , spherical vesicles , having at least one lipid layer , are formed when surfactant , co - surfactant , emulsifiers and / or minute detergents are added with a fat soluble substance in water . liposomes can be prepared by disrupting biological membranes such as by sonication . such a structure formed can be used as a vehicle for the administration of fat soluble pharmaceutical drugs for direct delivery into the blood stream by injection . liposomes vary in size , typically in the low microns . we have formulated a medicinal cannabis extract solution with electrolytes suitable for nebulization using the most advanced hand held vmn today that could deliver particle sizes below 5 micron for deposition deep into the pulmonary tree . to deliver cannabis oil extract effectively through the most advanced hand held nebulizer on the market today , the extract containing but not limited to entities listed in appendix a must be emulsified using respirable emulsifiers and / or surfactants that could carry the extracts in a stable liposomal form in a water base solution to be inhaled deep into the lung for deposition and immediate absorption . vmn technology is not new . its deployment has steadily improved over the course of the past ten years . but it is only recently that the designs have improved so significantly as evidenced by the filing of patent application with the united states patent and trademark office # 29 / 552 , 887 ; # 29 / 552 , 888 and 29 / 552 , 885 that such devices could have a broad consumer appeal . by using the present invention , the cannabis extract is able to be formulated into a deliverable form for use in vmn that can produce particle sizes of less than 5 micron capable of being deeply inhaled to produce the desired effects with a much lower dose . in this format , titration of dose requirement could easily be achieved . 1 : propellant dependent devices such as meter dose inhalers using hydroxyfluroalkane as the propellant 3 : nebulizers : pneumatic type ( fig2 ), ultrasonic type ( fig2 ) ( 1 . 6 - 1 . 8 mhz , 2 . 4 - 2 . 5 mhz ) or the vibrating mesh ultrasonic type (& gt ; 20 khz ) while our pharmaceutical formulation of claim 1 could be used in all types of nebulizers , it is with particular interest that we want to formulate a solution that will be efficiently discharged from the mesh ultrasonic type of nebulizers known to nebulize solution particle sizes in the below 5 micron range without clogging up the mesh apparatus . pulmondary deposition for the traditional nebulizers are inferior to the vmn today ( fig3 ). the vmn uses mesh deformation to push the liquid drug through the mesh . an annular piezo element , which is in contact with the mesh , is used to produce vibration around the mesh , and the liquid drug is in direct contact with the mesh . holes in the mesh have a conical structure , with the largest cross - section at the cone in contact with the liquid drug . the mesh deforms into the liquid side , thus pumping and loading the holes with liquid . this deformation on the other side of the liquid - drug reservoir ejects droplets through the holes , which can be inhaled by the patient . our formulation forms composite structures of liposomes with cannabis extracts emulsified in a stable form using surfactants , electrolytes , emulsifiers and / or co - surfactants and is able to be delivered in particle sizes in the low micrometers for inhalation using vmn . a histogram for the device used in testing our invention is shown in fig3 . while a preferred embodiment of the invention has been described and illustrated above , it should be understood that it is exemplary of the invention is not to be considered as limiting . additions , omissions , substitutions , and other modifications can be made without departing from the spirit or scope of the present invention . accordingly , the invention is not to be considered as limited by the foregoing . various changes and modifications may be made in the concentration , composition and compounding of the formulations described above which fall within the spirit of this invention and all such changes and modifications coming within the scope of the appended claims are embraced thereby . sample list of some commonly found cannabinoids , terpenes and flavonoids in cannabis ( 31 ): 1 : huestis , m . a . 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