FIELD OF INVENTION BACKGROUND:

Two hundred million Baby Boomers suffer from arthritis lending support to the relevance of advances in cannabinolic acid pharmacology for pain and arthritis by providing more effective, safer, longer lasting analgesia, reduced inflammation, neuroprotection and mild mood enhancement without any of the serious side effects associated with chronic NSAID and NSAID-Opioid use.

Research on effects of marijuana led to discovery of an endocannabinoid system in humans that plays a crucial role in the regulation of body physiology, inflammatory processes, mood and everyday experience by regulating release of endogenous cannabinoids, Anandamide and 2AG produced by the brain.

Cannabis is the source of phytocannabinoids that activate or modify the endocannabinoid system.

It is known the carboxy acid derivatives of cannabinoids: THCA, CBDA, CBNA, CBGa, CBC, CBL, CBV, THCV, CBDV, CBCV, CBGV, CBGM, CBE and CBT exist in fresh Cannabis and that their pharmacological profiles are significantly different from neutral cannabinoids.

It is further known that the cannabinolic acid THCA (delta-9 tetrahydrocannabinolic acid) and CBDA (cannabidiolic acid) are plant precursors of THC, the primary psychotropic cannabinoid and CBD, the primary non-psychotropic, anti-inflammatory cannabinoid. Cannabinolic plant acids were once thought to be pharmacologically inactive despite evidence suggesting Mayans employed fresh Cannabis to relieve joint pain and the Egyptian Ebers Papyrus (c.1550 BC) which prescribes marijuana applied directly to control inflammation. Fresh Cannabis contains THCA and CBDA and other plant acids which decarboxylate to neutral cannabinoids on exposure to heat (THCA decarboxylates at 122°C - 125°C; CBDA decarboxylates at 138°C -145°C), as well as drying, curing, smoking and cooking. Decarboxylation also occurs on exposure to alkaline conditions.

Jung, J. et al., in Detection of Delta 9-tetrahydrocannabinolic acid A in Human Urine and Blood Serum by LC-MS/MS., J Mass Spectrom 2007: Mar; 42(3): 354-60 teaches mammalian enzyme systems do not decarboxylate THCA or CBDA into THC or CBD.

Takeda, S. et al., in Cannabidiolic Acid as a Selective Cyclooxygenase-2 Inhibitory Component in Cannabis., Drug Metab Disp. 2008; 36(9): 1917-21 teaches that in vitro, THCA and CBDA blocks cyclooxygenase enzymes (COX- 1 and COX-2) which are known mediators of joint inflammation and pain.

Ruhaak. 201 1 teaches THCA and CBDA are more potent inhibitors of COX-1 and COX-2 enzymes than THC or CBD and that the metabolites of THCA and CBDA are not pharmacologically active.

Cascio and Pertwee., in “Known Pharmacological Actions of Nine Non- Psychotropic Phytocannabinoids” Pertwee, Ed.: Handbook of Cannabis London: Oxford U. Press., 2014 discloses, that in vitro, THCA and CBDA activate cation channel receptors which play important roles in signal transduction of pain and inflammation in“vanilloid” type receptors (TRPV1 and TRPV4);“ankyrin” type receptors (TRPA1 ) and in“melastatin” type receptors (TRPM8).

Wohlfarth, A. et al., Rapid isolation procedure for A9-tetrahydrocannabinolic acid A (THCA) from Cannabis sativa using dual flash chromatography systems. J. Chromatogr Analyt. Technol., Biomed Life Sci. 201 1 Oct 15;879(28):3059-64 teaches a method whereby THCA and CBDA can be extracted and purified from Cannabis extract by use of the full capability of a sophisticated chemical lab to separate THCA and CBDA from other cannabinoids and terpenes. The method is slow, costly and inefficient and recovers a low percentage of total acid cannabinoids.

Wohlfarth, supra , also teaches extraction of THCA and CBDA from fresh Cannabis by cold pressing plant material. This method is slow, cumbersome and inefficient, recovering less than half the total acid cannabinoids.

Mechoulam.1969 teaches cannabinoid carboxylic acids can be made synthetically by carboxylation of neutral cannabinoids. (Chem. Communications, 1969, 343-344.) This process results in expensive final products.

Herkenroth US9376367 B2 teaches a method to produce synthetic carboxylic acid cannabinoids by organic chemical reactions or by extraction of natural carboxylic acids from dried Cannabis sativa. The synthetic method has a low yield resulting in an expensive product, whereas the extraction method has a low yield as it relies on extraction of dried Cannabis, separation of neutral and acid cannabinoids and use of organic solvents that are known human carcinogens rendering the product unsafe for human consumption.

Clarke teaches Cannabis acids can be recovered by placing plant leaves in a freezer for 15 minutes. From the freezer, the Cannabis leaves are soaked in ice-water at 0.5°C, stirred periodically and permitted to settle. Residual leaf material is removed by coarse sieving, the cold water is filtered and the filtrate allowed to air dry. The resultant amber/brown residue smells and tastes like Cannabis. (High Times, 1994, lce-o-Lator). The Clarke process is slow, inefficient and leaves more cannabinolic acids behind in the residual plant material than it extracts.

GrowingMarijuana.com. 2017 teaches freeze drying is a poor method to dry marijuana as trichomes become too brittle and fall off.

Baugh et al, US 20160245588 teaches a modular configuration of freeze drying (of tea for example), using multiple chambers to freeze dry botanicals to extend product shelf life, cure raw plant products and improve C0 ₂ extraction efficiency. Baugh also discloses botanical and herbal products are conventionally dried and cured using control of temperature and humidity over a period of weeks, months, or even years for some teas. This is attended by loss of product value due to mold and mildew infestation, loss of volatile terpenes (essential oils), browning of the plant material and darkening of the extract, among other price point indicators. However, as supercritical C02 extraction is hampered by high moisture content, such drying and curing processes are practiced despite their shortcomings. In particular, Baugh mentions tobacco which must be cured to reduce its moisture and to allow the slow oxidation and degradation of carotenoids in tobacco leaf. This results in production of a group of compounds in tobacco leaves that give cured tobacco its sweet hay, tea, rose oil, or fruity aromatic flavor that contributes to the "smoothness" of the consumed products. Baugh also mentions curing Cannabis is widely practiced to convert THCA into neutral THC, the target recreational product to improve the smoking experience.

Abascal et al., Effect of Freeze-drying and its Implications for Botanical Medicine., Phytother. Res. 19, 655-660 (2005) discloses that most drying methods affect the content of volatile essential oils and that freeze-drying has the most pronounced effect and fails to preserve volatile essential oil profiles of fresh plant material. Abscal notes that even in the occasional circumstance when total volatiles were not changed, freeze-drying changed the relative concentrations of volatile compounds, usually failing to preserve the volatiles that give the studied plant its unique aromatic characteristics. In general, Abscal discloses that freeze-drying has unanticipated and significant effects on the constituent profiles of medicinal plants and puts into question whether freeze-drying is appropriate for use in preserving the essential oils of botanical medicines.

Peebles, US1799478 discloses apparatus and methods for flash drying of a liquid such as milk, using a series of flash heaters under vacuum. Freezedry, US5822882 teaches freeze drying of specimens with tray heaters and temperature controllers that control the amount of heat which the specimen is exposed to enhance the rate of sublimation under the prevailing vacuum conditions.

Vacuum-assisted sublimation of water requires operating at mid-vacuum (from a few milliBars into the microBar range) to sublime frozen water. Vacuum increases the mass transfer of water vapor to the condenser because of the temperature gradient between the Cannabis and the colder condenser. For rapid freeze drying, the boundary between solid and vapor phase must be approached or crossed to enhance the rate of drying.

For reasons such as these, all process variables must be controlled and optimized. Thickness of plant material on lyophillizer shelves should not exceed 1.5 to 2.0 cm for optimal results.

There is an unmet medical need for an improved protocol to treat arthritis and pain. To this end, there follows a short treatise on arthritis.

Kingsley, The 1000’s Genomes Project, 2016 teaches the GDF5 gene in man is linked to shorter height and increased prevalence of osteoarthritis, a degenerative joint disease that affects 10% of European and American populations. Risk increases with age and while arthritis is sometimes considered the result of wear and tear, there is also a strong genetic component.

To better understand the GDF5 gene, Kingsley studied DNA sequences that alter how the gene is expressed by studying gene promoters and gene enhancers. From this research, Kingsley discovered a previously unidentified region he called GROW1 .

Kingsley searched for evidence of GROW1 in the 1 ,000 Genomes Project database - an enormous database of genetic sequences of human populations worldwide and found a single change common in European and Asian populations and hardly ever seen in Africans. Kingsley introduced this genetic change in mice and found it led to reduced bone activity and bone growth.

Kingsley then looked at changes in the GROW1 variant over the course of human evolution and found it became more prevalent after Homo sapiens left the African continent 50,000 to 100,000 years ago. Kingsley concluded the benefits of being shorter in a colder climate probably outweighed the risk of developing osteoarthritis later in life.

“Because evolutionary fitness requires successful reproduction, gene alleles that confer benefits during younger reproductive ages may be positively selected in populations, even if they have some deleterious consequences in post-reproductive ages. This change in GDF5 may help explain why osteoarthritis is rarely seen in Africans, but effects 10% of other populations.” - Kingsley.

10% of 6.2 Billion (the total global population less Africa) is a very large number making osteoarthritis the world’s leading cause of disability. The U.S. health care cost for pain and osteoarthritis exceeds $50 Billion a year. The primary affected population are the 200 million Baby Boomer’s who have reached maturity in their aging process and pain and arthritis have begun to take their toll. This is corroborated by the fact that Baby Boomer’s, the world’s wealthiest sector are also the largest consumers of over the counter and prescription drugs for treatment of pain and arthritis.

Examples are over-the-counter (OTC) arthritis drugs such as aspirin, ibuprofen, acetaminophen, naproxen, Excedrin ^® and Tylenol ^® [nonsteroidal anti- inflammatory drugs (NSAIDs)] and counter irritant creams like Capsaicin. The relatively low price and ease of acquisition of OTC NSAID’s discourages development and marketing of new pain and arthritis drugs.

An exception is the new biologic anti-nerve growth factor (NGF) pain treatments, Tanezumab and Fulranumab introduced in 2016. Despite the considerable hype surrounding their launch, these drugs have significant life- threatening risks which limits their use to treat pain and arthritis.

The largest product segment in the entire pharmaceutical industry is the pain market. 26% of the pain market consists of nonsteroidal anti-inflammatory drugs (NSAIDs) and the NSAID- Opioid combinations.

There is an unmet medical need for improved treatment of osteoarthritis, a degenerative joint disease affecting 10% of the world population (excluding Africa).

This makes arthritis the world’s leading cause of disability.

Chronic use of NSAID’s damages the gastrointestinal and cardiovascular systems. Chronic Opioid-NSAID use shares these damaging side effects and creates an “addicted” patient population. 10% of Opioid-NSAID patients metabolize codeine more rapidly than was originally thought. This loophole led to the U.S. becoming the world’s most addicted population with all of its attendant difficulty. High addiction liability and the need for improved pain control makes the development of a new class of non-addictive analgesic, anti- inflammatory drugs of immense importance.

SUMMARY OF THE INVENTION:

According to the present invention, lyophilization is used to concentrate and preserve the medicinal properties of the cannabinolic acids in Cannabis, including THCA and CBDA, inter alia,· a lyophilized concentrate of cannabinolic acids can be derived from freshly harvested Cannabis flower and leaves which can be formulated into an excellent anti-inflammatory and analgesic drug that has been demonstrated to be highly effective in reducing inflammatory processes in arthritic joints, obtunding the associated pain and leaving the patient with a mild feeling of well-being. For greater clarity, medicinal herein is employed in reference to healing properties generally (e.g. curative, healing, remedial, therapeutic, restorative, corrective, health-giving; medical) and also prophylactics

(e.g. intended to help prevent disease - preventative, precautionary, protective, inhibitory), and in connection with animal, mammalian and particularly human applications.

Clinical trials with 50 mg and 100 mg. of freeze dried cannabinolic acids taken orally twice a day has been shown to reduce joint inflammation, pain and anxiety in human seniors. It produces a mild feeling of well-being with no other side effects. Amelioration of pain begins in 20 minutes after ingestion and lasts 4 to 6 hours. Cannabinolic acids last longer than NSAIDs or NSAID-OPIOID combinations because they are more potent inhibitors of the COX-1 and COX- 2 enzymes. The mechanism of action of THCA and CBDA in reduction of inflammation and pain is mediated via inhibition of the COX-1 and COX-2 enzymes responsible for inflammation and is independent of the mechanism of action of the neutral cannabinoids, THC and CBD which act via CB1 receptors in brain and spinal cord and CB2 receptors in intestine, spleen, prostate and other anatomical areas.

It is of interest to note the 2 - carboxy acid group seems a prerequisite for inhibition of COX-1 and COX-2 enzymes as THCA, CBDA and the NSAIDs all contain carboxylic acid groups in their molecular structure.

In accordance with the present invention a method to concentrate thermally/oxidatively labile cannabinolic acids and terpenes from freshly harvested Cannabis has been developed which uses lyophilization to remove moisture, block decarboxylation, concentrate THCA, CBDA and other plant acids and preserve 40% to 60% of the entourage terpenes. See for example, Figure 2 of the drawings.

This lyophilized concentrate has been clinically demonstrated to reduce arthritic joint inflammation, pain and depression in seniors. In a two-year clinical trial, six subjects, ranging in age from 70 to 88 ingested 100 mg of THCA, CBDA, other plant acids and terpenes twice a day. All subjects demonstrated marked reduction in joint inflammation, associated pain and reported improved mood. No behavioral effect or impairment was reported. Reduced inflammation is mediated via cannabinolic acid inhibition of COX-1 and COX-2 enzymes whereas mood improvement is mediated by CBDA activation of brain serotonin receptors.

Some constituents of Cannabis are unstable, making it is difficult to extract, concentrate and preserve such cannabinoids and terpenes for manufacture of a drug with a commercially viable shelf life. According to the present invention, lyophilization is employed to freeze hydrous materials under vacuum and remove frozen water contained therein by sublimation.

Accordingly, lyophilization is selected as the method of choice for the manufacture of a cannabinolic acid-terpene drug formulation that is sensitive to heat, light, oxygen and humidity. Lyophilization employs a series of integrated steps to ensure product consistency and maximize efficiency and has been demonstrated to substantially capture and concentrate cannabinolic acids and many of the entourage terpenes in fresh Cannabis.

In accordance with the practice of aspects of the present invention, it is preferred that the cannabinolic acids and terpenes be sourced from chemovar strains high in THCA and CBDA as opposed to hemp fiber strains containing less CBDA and terpenes and very little THCA. By the premature floral stage of a plant’s development, simple cannabinoid phenotypes may be determined based on THC/CBD biosynthesis activity, whereby in this incipient floral stage each plant has already established its basic fiber or bud strain type. Hemp fiber strains rarely have the potential to produce more than 2% decarboxylated THC (ie: neutral THC) even under ideal agricultural conditions. This indicates different chemovar strains produce varying amount of THCA (up to 20%) and CBDA (up to 17%) and are termed a Cannabis strain. Some strains produce practically no THCA and some CBDA and are termed hemp fiber strains in accordance with the plant’s genetic predisposition. It is further preferred that cannabinolic acids and terpenes be sourced from female seeds to enhance floral production. In all cases, it is preferred that the plant material be freshly harvested. In accordance with aspects of the present invention, fresh and freshly or the like are terms variously employed to connote practices of cooling harvested plant material to less than 20° C and preferably to about 10° C within an hour and preferably within minutes following harvesting from the field. It is therefore preferred that at least some in-field temperature reduction be practiced although this could also be accomplished by harvesting smaller amounts that are taken directly to a cooled processing facility.

Preferably the plant material is harvested following the plants early vegetative stages (pre-senescent), prior to the onset of senescence to reduce the content of neutral THC and CBD. More particularly, it is the preferred order that the plant material be harvested during early and at peak floral stages with peak floral stage harvesting being particularly preferred.

In addition, mechanized or hand harvesting of individual plants is preferred over massed crop harvests.

The cannabis plant is comprised of structures that are common among other flowering species of plants. The cola is a tight bud cluster with smaller colas occurring along the budding sites of lower branches, with the main cola (or “apical bud”) at the very top of the plant. The pistil embodies the reproductive parts of a flower, with hair-like strands called stigmas serving to collect pollen from male plants. The stigmas initial white coloration progressively darkens through yellows, oranges, reds, and browns during progressive stages of plant maturation. While significant to reproduction, the stigmas contribute little to cannabinoid acid or terpenoid production. The bract, which encapsulates the female plant’s reproductive parts, are green tear-shaped “leaves”. These leaves are heavily covered in resin glands that produce the highest concentration of cannabinoids of all the plant’s parts. The bracts enclose the calyx: an initially translucent layer covering the ovule at a flower’s base. Calyx production follows two basic patterns. In one, the percentage of calyxes climbs gradually and levels out during the peak floral stage, followed by a decline in the late floral stage, and leaf production increases as calyx production ceases. Other strains continue to produce calyxes at the expense of leaves, and the calyx percentage increases steadily throughout maturation. In both cases, there is some tendency for calyx percentage to level out during the peak floral stage irrespective of whether leaf growth accelerates or calyx growth continues at a later stage. Resins generally accumulate steadily while the plant matures, but strains vary as to the stage of peak resin secretion. Seed percentage increases exponentially with time if the crop is well fertilized, but Cannabis grown domestically for cannabinolic acid and terpene concentration are seedless, unpollinated female plants. General, to determine dry weight, Cannabis plant samples are harvested, labeled, and air dried until the central stem of the floral cluster will snap when bent. In plant research, dry weight is done in ovens at higher temperatures, but these higher temperatures would ruin the Cannabis. The dry floral cluster is weighed. The outer leaves, inner leaves, calyxes, seeds, and stems are segregated and each group weighed individually. The percentage is determined by dividing the individual dry weights by the total dry weight. Calyx percentage ranges from 30 to 70% of the dry weight of the seedless floral clusters, depending on variety and harvest date. Inner leaf percentages fluctuate between 15 and 45% of dry weight; stems range from 10 to 30%.

Trichomes are diminutive glandular bodies that produce a resin secretion from their translucent, mushroom-shaped glands on the leaves, stems, and calyxes. The resin is comprised of aromatic terpenes, sesquiterpenes essential oils and cannabinoids. There are three principle types of cannabis plant trichomes. Bulbous trichomes are the smallest of the three, and they appear on the surface of the entire plant. Bulbous trichomes are as small as 10-15 microns. Capitate sessile trichomes are slightly larger and contain both a head and a stalk as well as being significantly more abundant than bulbous trichomes. Capitate-stalked trichomes however, range in size from 50 mm -100 mm wide with a structure consisting of a stalk comprised of epidermal and hypodermic feels that build up to a basal cell attached to a large gland head. This gland head, held together by a waxy cuticle layer, serves as the epicenter for cannabinoid and terpenoid synthesis, and while all three trichome types produce cannabinoids, the capitate-stalked trichomes that appear in abundance in and around to the calyxes of budding flowers tend to produce the highest concentration of essential oils. Cannabinoid synthesis within the trichome begins as cannabis plants move into their flowering phases - in which trichomes form along the outer surface of the above ground plant vegetation and begin to transport vacuoles and plastids from their stalk into the gland head. At this point, cells within the gland head begin the plants metabolic process by forming cannabinoid precursors.

During the plant’s vegetative stage, leaf and stem production abound without any significant reproductive structures in evidence. During premature floral stage, floral development progresses slightly beyond primordial features and only a few clusters of immature pistillate flowers appear at the tips of limbs in addition to the primordial pairs along the main stems. By this stage, stem diameter within the floral clusters is very nearly maximum. The stems are easily visible between the nodes and form a strong framework to support future floral development. Larger vegetative leaves (5-7 leaflets) predominate and smaller tri-leaflet leaves are beginning to form in the new floral axis. A few narrow, tapered calyxes may be found nestled in the leaflets near the stem tips and the new pistils appear as thin, feathery, white filaments. During this stage, the surfaces of the calyxes are lightly covered with fuzzy, hair-like, non-glandular trichomes, but only a few bulbous, capitate glandular trichomes have begun to develop. Resin secretion is minimal, as indicated by small resin heads and few if any capitate-stalked, glandular trichomes. There is no flower yield from plants at this premature stage since THC production is low, and there is little or no economic value in the fiber and leaf.

Terpene production starts as the glandular trichomes begin resin secretion but premature floral clusters have little terpene aroma and total cannabinoid production is low. The floral clusters now show very small amounts of THC and CBC whereas CBD production begins when the seedling is very small. THC production also begins when the seedling is very small, particularly in chemovar strains, however, at this stage, THC levels rarely exceed 2% until the early floral stage and rarely produce enough THC to potentially elicit significant“high” effects until the peak floral stage.

In the early floral stage, floral clusters begin to form as calyx production increases and internode length decreases. Tri-leaflet leaves are the predominant type and usually appear along the secondary floral stems within the individual clusters. Many pairs of calyxes appear along each secondary floral axis and each pair is subtended by a tri-leaflet leaf. Older pairs of calyxes visible along the primary floral axis during the premature stage now begin to swell, the pistils darken as they lose fertility, and some resin secretion is observed in trichomes along the veins of the calyx. The newly produced calyxes show few if any capitate-stalked trichomes, but due to low resin production, (total potential for neutral THC less than 3%) are not high enough to produce more than a subtle effect.

During the peak floral stage, elongation growth of the main floral stem ceases, and floral clusters gain most of their size through the addition of more calyxes along the secondary stems until they cover the primary stem tips in an overlapping spiral. Small reduced mono-leaflet and tri-leaflet leaves subtend each pair of calyxes emerging from secondary stems within the floral clusters. These subtending leaves are correctly referred to as bracts. Outer leaves begin to wilt and yellow as the pistillate plant reaches its reproductive peak. In the primordial calyxes, the pistils have turned brown; however, all but the oldest of the flowers are fertile and the floral clusters are white with many pairs of ripe pistils. Resin secretion is advanced in some of older infertile calyxes, and young pistillate calyxes are rapidly producing capitate-stalked glandular trichomes to protect the precious unfertilized ovule.

Under wild conditions the pistillate plant would be starting to form seeds and the cycle would be ending. When Cannabis is grown for cannabinoid and terpene production, the cycle is interrupted. Pistillate plants remain unfertilized and begin to produce capitate-stalked trichomes and accumulate resins in an effort to remain viable. Since capitate-stalked trichomes now predominate, resin and CBDA and THCA production increases. The elevated resin heads appear clear, since fresh resin is still being secreted from the cellular head of the trichome. At this stage, CBDA and THCA production is at its peak and CBDA levels begin to fall as CBDA is rapidly converted to THCA. At this point, THCA synthesis has not been active long enough for a high level of CBNA to build up from oxidative degradation of THCA initiated by oxygen, light and heat. Terpene production is nearing its peak and polymerization of terpene molecules has begun creating the characteristic aroma of Cannabis. This is the point of optimum harvest. Additional calyx growth has ceased. In certain strains, a subsequent flush of new calyx growth may occur and the plant will continue ripening into the late floral stage.

By the late floral stage plants are well past the main reproductive phase and their health has begun to decline. Many of the larger leaves have dropped off, and some of the small inner leaves begin to change color. Autumn colors (purple, orange, yellow, etc.) begin to appear in the older leaves and calyxes at this time; many of the pistils turn brown and begin to fall off. Only the last terminal pistils are still fertile and swollen calyxes predominate. Heavy layers of protective resin heads cover the calyxes and associated leaves.

Production of additional capitate-stalked glandular trichomes slows. Some trichomes may still elongate and secrete resins. As secreted resins mature, they change color due to terpene polymerization into a more viscous, darker colored resin. The weight yield of floral clusters is usually highest at this point.

THCA decarboxylates to THC which decomposes to CBN when exposed to atmospheric conditions and hot sun. Thus, THC can be substantially replaced by CBN once the metabolic processes have ceased. Cannabis that favors high THCA will demonstrate rising neutral THC and CBN. Some CBDA may accumulate if there is insufficient energy to complete the conversion to THCA. Age related senescence begins after a pistillate plant finishes floral maturation, production of pistillate calyxes ceases and the plant continues to decline towards death. Senescence may be evident by color changes. Leaves, calyxes and stems may display auxiliary pigments ranging in color from yellow through red to deep purple. Eventually brown predominates as the plant dies.

To harvest peak levels of cannabinolic acids with low levels of decarboxylated THC, the capitate-stalked glandular trichome resin color must be mostly clear with small amounts of light amber colored resin.

In other aspects of the present invention, freshly harvested flowers are separated from leaves and frozen to - 5° C to -10° C or colder. The frozen flowers are quartered and placed on respective trays. Depending on process requirements, leaves may also be frozen to similar temperature and placed on trays. The frozen, quartered flowers and leaves are then separately carried through the lyophilization process. The resultant cryo-dessicated plant material is then sieved or otherwise processed to remove stems and fine vein structures and ball milled at - 5° C to yield a powder with a particle size of less than 1 mm.

In accordance with the present invention there is provided a novel method to concentrate THCA, CBDA, other plant acids and terpenes from freshly harvested Cannabis by lyophillization to yield a cryo-dessicated plant residue containing 98% of the 2 - carboxy plant acids and 40% to 50% of the terpenes contained in the fresh Cannabis feedstock.

There are numerous conventions used for the measurement of vacuum. For the sake of clarity, the vacuum unit referred to in this patent is the millibar or mbar, where 1 mbar = 1/1000 of a bar and standard atmospheric pressure is 1013.25 mbar.

BRIEF DESCRIPTION OF THE DRAWINGS

Fig. 1 shows Torr and mBar scales. Both scales indicate four decades of pressure and can be read easily in each decade of the scale. Fig. 2 is a flow chart showing processing options.

DESCRIPTION

Cannabis flowers and leaves undergo several transformations during freezing, primary and secondary drying. To optimize drying and product consistency each step in the heat transfer process is monitored. Once the parameters are identified and dialed in, automated controls may be employed if desired.

On a commercial scale, lyophilization is accomplished in a freeze-drying machine. Freshly harvested Cannabis flowers and leaves are frozen (e.g. at - 20°C) to lower the plant material below its eutectic point. This blocks decarboxylation of the plant acids, reduces loss of terpenes and ensures sublimation rather than melting in later stages.

Pre-frozen plant material is placed on material trays in a freeze dryer rack and the rack is lifted into a pre-cooled freeze dryer held at, for example, minus 20°C. During the primary drying phase, vacuum is lowered to a few millibars and heat (for example, 5°C) is supplied to the plant material-supporting trays to assist the ice to sublime. It is important to note at a vacuum of a few millibars, heat is transferred by conduction or radiation, with the convection effect negligible due to low air density. The initial drying phase removes preferably about 95% of the moisture in fresh Cannabis. Cold condenser plates provide surfaces for water vapor to solidify on. The condenser plays no role in keeping the plant material frozen, it is there to prevent water vapor from reaching the vacuum pump which can cause damage. Condenser temperatures are typically held at - 50 °C.

If required, the secondary drying phase removes 2% to 3% of additional moisture. This part of the freeze-drying process is governed by the adsorption isotherms of the plant material. In this phase, tray temperature is raised from 5°C to 18°C to break the physicochemical interaction between water molecules and frozen plant material while vacuum is lowered from a few (5 or less) milliBars into the microBar range (i.e below one milliBar). Once freeze-drying is complete, the vacuum is broken with an inert dry gas, such as nitrogen before the material is sealed. Use of nitrogen at this stage reduces cycle time, energy demand and labor cost.

At the end of the process, residual water content in desiccated Cannabis flowers and leaves is preferably about 1 % to 4%. To avoid problems handling a cannabinoid rich powder which may be sticky at ambient temperature, the desiccated plant material is cold milled at - 1 °C to -5°C and screened (e.g. to #18 mesh) to result in a powder with a particle size < 1 mm or some other desired size distribution. The addition of any diluent and encapsulation is also carried out at - 1°C to - 5°C. Note in this connection that in an aspect of the present invention, the lyophilized leaf product stream may be added back into the lyophilized bud product stream to adjust the cannabinoid acid content of the final mixture. Moreover, it is preferred that the final mixture contain no more than 0.05% by weight of the encapsulated product, of neutral THC. In the event that the component constituency of the products (or their mixtures) exceed this amount, adjustment using high pressure low temperature chromatographic separation may be needed to extract the excess.

Lyophilization delivers stable concentrations of THCA, CBDA, other plant acids and terpenes in a capsule form. The process is scalable from bench to 1000 Kg. per shift or more. At such low moisture levels (< 4%), biological growth and chemical reactions are retarded, ensuring long product shelf life.

A two-year clinical trial of 6 human subjects was undertaken to investigate the effects of natural THCA, CBDA, other plant acids and terpenes on seniors with inflamed, arthritic joints, pain and mild depression. 100 mg capsules were dosed twice daily. All subjects reported joint tenderness decreased, pain obtunded and the despondency commonly seen in association with chronic pain was replaced by a mild sense well-being with no other behavioral effects reported. This trial demonstrates the combination of naturally occurring THCA, CBDA, other plant acids and terpenes are effective modulators of joint inflammation, pain and mild depression in seniors with no adverse side effects.

After multiple human trials using different combinations of freezing rate, tray temperature and vacuum, it was determined that large scale lyophilization is an effective method to concentrate and preserve the molecular and medicinal qualities of THCA, CBDA, other plant acids and terpenes for production of nutraceutical and pharmaceutical products for treatment of osteoarthritis and pain and is superior to all other methods.

It would be a valuable addition to the art to recover 98% of acid cannabinoids and 40% of terpenes in fresh Cannabis in an efficient manner on an industrial scale.

It would be a valuable addition to the art to provide animal, mammalian and especially human seniors that suffer joint inflammation, pain, mild depression and hopelessness with a stable formulation of cannabinoid plant acids and terpenes that has been clinically demonstrated to reduce joint inflammation, pain and generate a mild feeling of well-being.

It would be a valuable addition to the art to introduce THCA, CBDA and terpenes as a drug to treat joint inflammation, pain and mild depression that is a safer alternative to NSAID’s whose well-documented adverse effects on gastrointestinal and cardiovascular systems are major drawbacks of these drugs.

It would be a valuable addition to the art to produce stable THCA, CBDA and terpenes that are generally superior, and perhaps orders of magnitude (e.g.100s) times more effective than NSAID’s in modulating joint inflammation and pain (particularly in connection with co-extracted terpenoids). Research in accordance with the present invention into cannabinolic acids of Cannabis as potential analgesic, anti-inflammatory drugs reveals that with no addictive, toxic or adverse effects, THCA and CBDA have been demonstrated to be more effective than NDAID’s or NSAID-Opioid combinations in the treatment of pain and osteoarthritis. The mechanism of action of THCA, CBDA and the other plant acids on pain may also be mediated via direct or indirect THCA activation of morphinan receptors, although this is not a completely established fact. The anti-inflammatory effects of THCA and CBDA are mediated via inhibition of COX-1 and COX-2 enzymes found in joints. Because the cannabinolic acids do not attach to CB1 cannabinoid receptors in the brain, they do not produce the “high” associated with THC. As a result, Cannabinolic acids lack addiction liability. Rather, they provide a positive impact on older patients by acting as a mild anti-depressant. This effect is mediated via CBDA activation of brain serotonin receptors in the brain.

It would be a valuable addition to the art to introduce THCA, CBDA and terpenes as a drug to treat joint inflammation, pain and mild depression that is a much safer alternative to Opioid-NSAID combinations whose adverse effects include gastrointestinal and cardiovascular disturbance and a high addiction liability which is a major drawback of these drugs.

It would be a valuable addition to the art to produce stable THCA, CBDA and terpenes by concentrating the plants natural constituents and package the API in capsules in a cost-effective manner.

It would be a valuable addition to the art to produce an API which consists of THCA, CBDA, other plant acids and terpenes for wider medical application in treatment of inflammation, pain, chronic pain, neurogenic pain, phantom limb syndrome, muscle spasm, improved sleep, control of tics in Tourette syndrome, anorexia, migraine, fibromyalgia, rheumatoid arthritis, pain control during palliative care, neurological problems, movement problems, multiple sclerosis, amyotrophic lateral sclerosis, posttraumatic stress disorder, inflammatory bowel disease, pre-menstrual tension and as an libido enhancer in post- menopausal woman. Ref erring now to Figure 2 of the appended drawings, there is depicted a flow chart showing processing options according to aspect of the present invention.

The process of various aspects of crop management and harvesting have been described hereinabove. Options for processing the harvest include processing a consolidated harvest of both leaves and bud/flower materials - but in an aspect of the present invention these materials are processed separately through respective stage 1 lyophilizations and optionally through respective stage 2 lyophilizations, followed by cold milling steps with optional recombination’s of the separately processed leaves and bud/flowers streams - all followed by encapsulation.

Note too, that although it is not depicted in the flow chart for this embodiment of the present invention, in an aspect of the present invention a step is included for removing decarboxylated neutral THC from the lyophilized cannabinolic acids. It is preferred that in the event that the concentration of neutral THC exceeds 1.0%" dry weight - that at least some of THC may be removed. In one embodiment, the product according to the present invention contains natural plant cannabinolic acids, terpenes, sesquiterpenes and less than 1 .0% neutral THC. The presence of neutral THC above 1.0% may result in some degree of intoxication - particularly if multiple doses are consumed - so an especially preferred form would be desirable to have the neutral THC concentration between 0.03% and 1 .0%, but preferably not to exceed 1.0%.