COMPOSITION AND METHODS TO IMPROVE STABILITY, DOSING, PHARMACODYNAMICS AND PRODUCT SHELF LIFE OF ENDOCANNABINOIDS, PHYTOCANNABINOIDS AND SYNTHETIC CANNABINOIDS DELIVERED BY NASAL INHAER

Abstract

An inhaler-delivery-device-packaged homogenate of solid heterogeneous-lipid particulates carrying lipophilic cannabinoid receptor agonists and/or antagonists, wherein the solid heterogeneous-lipid particles comprises: one (or more) lipid(s) whose melting point(s) is (are) substantially above room temperature; in combination with, one (or more) lipid(s) whose melting point(s) is (are) substantially less than room temperature.

Claims

1. An inhaler-delivery-device-packaged homogenate of solid heterogeneous-lipid particulates carrying lipophilic cannabinoid receptor agonists and/or antagonists, said solid heterogeneous-lipid particles comprising: a. one (or more) lipid(s) whose melting point(s) is (are) substantially above room temperature; in combination with, b. one (or more) lipid(s) whose melting point(s) is (are) substantially less than room temperature.

2. The inhaler-delivery-device-packaged homogenate according to claim 1, comprising solid lipid particle of a homogenate selected from the group comprising: a. Solid lipid particle homogenate based on a compounded excipient comprised of a formulation of mutually compatible lipids including a first lipid having a melting point substantially greater than room temperature, and a second lipid having a melting point substantially below room temperature; or, b. Solid lipid particle homogenate of lipid phytoextracts fats/oils containing a first lipid having a melting point substantially greater than room temperature, and a second lipid having a melting point substantially below room temperature; or, c. A combination thereof.

3. The inhaler-delivery-device-packaged homogenate according to claim 2 wherein said first lipid comprises one or more saturated fatty acid(s), and said second lipid comprises one or more unsaturated fatty acid(s).

4. The inhaler-delivery-device-packaged homogenate according to claim 3, wherein said first lipid includes one or more of the group of unsaturated fatty acids comprising palmitic acid and stearic acid.

5. The inhaler-delivery-device-packaged homogenate according to claim 3, wherein said second lipid includes one or more of the group of saturated fatty acids comprising oleic acid and linoleic acid.

6. The inhaler-delivery-device-packaged homogenate according to claim 2, is a solid lipid particle homogenate of lipid phytoextracts fats/oils.

7. The inhaler-delivery-device-packaged homogenate according to claim 6, wherein said solid lipid particle homogenate of lipid phytoextracts fats/oils comprises one or more of the group selected from solid lipid particle homogenate of extracted cannabis fats/oils; or, solid lipid particle homogenate of one or more vegetable oils.

8. The inhaler-delivery-device-packaged homogenate includes a solid lipid particle homogenate of extracted cannabis-endogenous fats/oils, and further comprises cannabis-endogenous essential oils.

9. The inhaler-delivery-device-packaged homogenate according to claim 8, wherein said essential oils are cannabis phytoterpenoids, and include one or more of the group selected from limonene, myrcene, α-pinene, linalool, β-caryophyllene, caryophyllene oxide, nerolidol and phytol.

10. The inhaler-delivery-device-packaged homogenate according to claim 1, wherein said device is selected from one of the group comprising: propellant or inspiration of dry solid lipid particulate homogenate devices; or “wet” pumped aerosols of solid lipid particle homogenate devices.

11. The inhaler-delivery-device-packaged homogenate according to claim 10, wherein said device is a “wet” pumped aerosols of solid lipid particle homogenate device and said solid lipid particles include one or more of the group selected from microparticles and nanoparticles.

12. A lipophilic active pharmaceutical ingredient, lipophilic bioactive nonessential nutrient agent or lipophilic essential nutrient, in combination with a carrier comprised of mutually compatible lipids including a first crystalized lipid providing a crystalline structure with a second lipid interstitially disposed within said structure and in close-packing-interfering relation with first lipid crystals thereof, and wherein said first lipid is a solid at room temperature, and said second lipid is a liquid at a temperature of about 21 degrees centigrade.

13. The combination according to claim 12, wherein said first lipid has a melting point higher than normal internal human body temperature i. *Note for description: or higher: must be low enough so that its melting does not result in substantial damage to a temperature labile API, e.g. cannabinoid.

14. The combination according to claim 12, wherein said first lipid is stearic acid and said second lipid is sunflower oil.

15. The combination according to claim 12, wherein the ratio of said first lipid to said second lipid is about 70 parts to 30 parts by weight.

16. The combination according to claim 12, further comprising an antioxidant.

17. The combination according to claim 16, wherein the antioxidant is alpha tocopherol

18. The combination to claim 12, in an aqueous excipient-in-water emulsion including a surfactant.

19. The combination according to claim 18, wherein said emulsion is a polysorbate surfactant emulsion.

20. The combination according to claim 18 comprising a pre-homogenate aqueous, emulsifier-stabilized, uniform emulsion of liquid phase first and second excipient lipids.

21. The combination according to claim 18, comprising a homogenate of said pre-homogenate aqueous emulsion.

22. The combination according to claim 21, at a temperature below the melting point of at least said first lipid, and formed of solid lipid particulates of excipient-borne active pharmaceutical ingredient.

23. The combination according to claim 22, wherein said solid lipid particulate excipient-borne active pharmaceutical ingredient includes a substantial proportion of numbers of particles in the micrometer and/or nanometer size ranges.

24. The combination according to claim 23, wherein said particulates form a dry, friable powder.

25. The combination according to claim 24, wherein said particulates are lyophilized.

26. The combination according to claim 12, wherein said lipophilic active pharmaceutical ingredient, lipophilic bioactive nonessential nutrient agent or lipophilic essential nutrient, comprises 30 to 96% by weight of said combination.

27. A packaged product comprising the combination according to claim 12.

28. A packaged product comprising the combination according to claim 27, wherein said package is one of the group selected from dry dispense packaging; wet pump dispense packaging, blister packaging; gel cap dispensing.

29. The packaged product according to claim 28, wherein said package is a metered dose dispenser.

30. The packaged product according to claim 28 is an intra nasal dispenser.

31. The combination of claim 12, wherein said lipophilic active pharmaceutical ingredient, lipophilic bioactive nonessential nutrient agent or lipophilic essential nutrient is one or more of the group selected from the lipophilic vitamins; opiates, endogenous cannabinoids, synthetic cannabinoids, solvent extracted (eg especially ethanol extracted) phytocannabinoids from (e.g. and preferably cannabis via carbon dioxide extracted) plant extracts, essential oils of cannabis plant cannabinoids and/or terpenoids, a cannabinoid receptor agonist, and cannabinoid receptor antagonist.

32. The combination of claim 31, wherein the API includes an opiate.

33. The combination of claim 32, wherein the opiate is selected from the group comprising methadone or morphine.

34. The combination of claim 32 or 33, comprising an opiate with a (phyto-cannabinoid extract predominantly containing) a THC/cannabidiol combination (with minor proportions of other phyto-canabinoids and/or phyto-terpenoids (or synthetic equivalents thereof)) (“entourage effect” is the sum of/between multiple synergies), wherein the proportion of opiate is a moderated dose in proportion to a moderating effect of the phyto-cannabinoid extract. (subclinical opiate doses)

35. The combination according to claim 34, wherein said API comprises 30 to 96% by weight of said API and lipid excipient combination.

36. A method for producing a solid lipid particle pre-homogenate, comprising: a. heating a mixture comprising: i. a heterogeneous lipid combination including: 1. one (or more) lipid(s) whose melting point(s) is (are) substantially above room temperature; in combination with, 2. one (or more) lipid(s) whose melting point(s) is (are) substantially less than room temperature, and ii. one or more of a group selected from lipophilic API, lipophilic bioactive nonessential nutrient, or lipophilic essential nutrient b. to above the melting point which is substantially above room temperature sufficient to melt said lipids and reduce said mixtures viscosity; c. pre-homogenizing said heated mixture to produce a stable pre-homogenate.

37. The method according to claim 35, further comprising the addition of surfactant stabilizer to said mixture.

38. The method according to claim 36, wherein said surfactant is a non-ionic surfactant, preferably selected from the group consisting of polysorbates or poloaxmers.

39. The method according to claim 35 wherein said mixing is carried out for about 10 minutes at about 20,000 rpm.

40. A method of preparing a solid lipid particle homogenate comprising heating/homogenizing the heated pre-homogenate according to claim 35, at about 500 to 1500 bar at least once and preferably twice to produce a further heated homogenate, and then cooling the heated homogenate to about room temperature, to produce a solid lipid homogenate.

41. The method according to claim 39, wherein said homogenization carried out to produce solid lipid microparticles and/or nanoparticles in said room temperature homogenate.

42. The method according to claim 40, wherein said room temperature homogenate is then lyophilized.

43. The method according to claim 35 wherein said mixture comprises a cannabis carbon dioxide extract wherein said heterogeneous lipids are comprised of cannabis fats and oils from said cannabis extract.

44. The method according to claim 35, wherein a selected API comprises a carbon dioxide cannabis extract, containing cannabis extracted phytocannabinoids.

45. The method according to claim 43 wherein said cannabis extracted phytocannabinoids is a carbon dioxide cannabis extract residual following ethanolic extraction thereof, and said heterogeneous lipid combination is comprised of lipids from sources other than cannabis.

46. A co-therapeutic combination comprising a subclinical dose of morphine together with a compensatory dose of one or more cannabinoid receptor agonist(s) and or antagonist(s).

47. A co-therapeutic combination comprising a subclinical does or methadone together with a compensatory dose of one or more cannabinoid receptor agonist(s) and of antagonist(s).

Description

BRIEF DESCRIPTION OF DRAWINGS

[0111] FIG. 1 is a plan view of the top and bottom panels of a high oxygen barrier polymer composite laminate pharmaceutical blister package in which the bottom panel contains molded dose compartments in accordance with an embodiment of this invention. FIG. 1 depicts a side view of a pharmaceutical blister package consisting of an upper, low oxygen permeable flat composite laminate sheet whose exterior surface is comprised of aluminum foil, whose middle layer is comprised of high oxygen barrier polymer and whose inner layer is comprised of oxygen scavenging polymer and a lower composite laminate sheet of the same composition which contains multiple individual molded dose compartments wherein the oxygen scavenger polymer layer forms the inside of each molded dose compartment.

[0112] FIG. 1 “A” depicts a side view of a Package 35 consisting of a separate flat upper sheet of composite polymer of aluminum foil 20, oxygen barrier polymer 30 and oxygen scavenger polymer 40 and a separate lower sheet of the same composite polymer containing individual moulded dose compartments 100 wherein oxygen scavenger polymer layer 40 forms the inside of each moulded dose compartment 100. Each dose compartment 100 contains a sachet of oxygen scavenger 41 and a dose of sensitive API 60 in close proximity or in direct contact with the two oxygen scavengers. FIG. 1 “B” depicts a side view of a sealed Package 35, consisting of an upper sheet of composite laminate heat sealed to a lower sheet of similar composite laminate that is formed into low O2 permeable dose pockets 100. Oxygen scavenging polymer 40 must comprise the two inner layers of sealed package 35 and be adjacent to or in direct contact with packaged cannabinoid 40 to scavenge residual head space oxygen and oxygen that over time may permeate through the semi-permeable composite laminate package 35, conferring protection against oxidative degradation of cannabinoids thereby extending their shelf life from 20 days to 60 days.

[0113] In another embodiment, package 35, may contain an additional oxygen scavenger sachet 41 placed in cavity pocket 100 of laminate package 35 or be adhered to oxygen scavenger polymer 40 so that oxygen scavenger 41 is in close proximity or direct contact with packaged cannabinoid 60 such that head space oxygen or oxygen that over time may permeate semi-permeable package 35 conferring protection from oxidative degradation of cannabinoids and other API and extending the shelf life of package 20 cannabinoids up to 60 days.

[0114] In a preferred embodiment of Package 35, prior to sealing the top panel 10 to the formed bottom panel 10A of package 35, cannabinoid is placed in the cavity pocket beside oxygen scavenger 41 in a modified gas atmosphere while the top and bottom panels of package 35 are adhered together in a gas tight manner by heat sealing or adhesive to form the final Package 35. This method extends cannabinoid shelf life by reducing head space oxygen and moisture during the fill-seal-cut process. Residual head space oxygen or oxygen that remains resident in the head space or permeates through semi-permeable package 35 is scavenged by oxygen scavengers 40 and 41. In this manner, package 35 protects sensitive cannabinoids from light, oxygen and water vapour, reducing degradation and extending shelf life of packaged cannabinoids up to 60 days.

[0115] A Preferred Formulation: A particularly preferred form of the present invention comprises a formulation (ANA-131), of a CBD, CBG predominant preparation with CBD/THC ratio being equal. Addition of β carophylline, limonene and linalool at concentrations of 0.05% each improved nasal absorption and synergistically increased the efficacy of ANA-131 in treatment of IBS via its targeted action on CB1 and CB2 receptors. Cannabinoids and terpenoids proved to be highly bio-available with an average pulmonary uptake of 70% and intra nasal uptake of over 80%. Both routes avoid first pass hepatic uptake. From earlier studies, it was found that the inclusion of 0.05% limonene and pinene increased the absorption of ANA-131 through the nasal mucosa. The nasal inhaler doses of ANA-131 ranged from 2 mg/dose to 16 mg/dose. In these small trials, the most effective dose was 8 mg/dose BID. It appears that the Cannabis plant is not just a carrier for the active cannabinoids. The combination of “active” and ‘inactive’ synergists are responsible for the “entourage effect” seen when comparing the activity of pure THC from Cannabis extract vs. the same amount of pure THC—which also suggests why greater observed effects of whole extract on vs pure THC—CBD purified combinations in the treatment of IBS. It is believe, without wishing to be necessarily bound, hat one or more of several synergistic interactions arise between cannabinoids and terpenoids: (a) potentiation; (b) antagonism; (c) improved dissolution, solubility, bioavailability; (d) improved anti-bacterial action; (e) modulation of complex adverse events in IBS. In any case, there are biochemical, pharmacological and phenomenological distinctions observed between Cannabis ‘strains’ related to the relative content and ratios of cannabinoids and terpenoids, and this too suggests a botanical basis for the observed synergistic effects seen in IBS treatment with different ratios of phytocannabinoids and terpenoids. A blend of CBD, THCV, CBCR, CBV and terpenoids is an effective anti-inflammatory agent to control joint inflammation with no THC. With the addition of THC=CBD, the blend is 10× more effective than cortisone and 20× more effective than NSAID's without the serious adverse effects (heart attacks and strokes) associated with inhibition of COX-1 or COX-2 enzymes by NSAID's. Caryophyllene is a selective full agonist of CB2, synergistic with the cannabinoid-terpenoid blend in Anandamide hence it is included therein to increase efficacy. Given the lack of psychoactivity of CB2 agonists, caryophyllene offers great promise as a therapeutic compound. This is an example of true synergy as the THC-cannabinoid-terpenoid combination provides a greater effect than the sum of the effects of THC and the other cannabinoids and terpenes separately.

IBS Treaments:

[0116] A cohort of 5 IBS subjects diagnosed with IBS-C, IBS-D or intractable IBS and who had not found a satisfactory treatment modality inhaled 8 mg doses of ANA-131 BID for 180 days. 4 of 5 subjects reported a reduction in IBS symptoms and diminution of depression as scored using the Hamilton Depression scale. The results indicated 4 of 5 subjects Hamilton Depression Scores had returned to normal and the subjects felt they were emotionally able to discontinue their antidepressants.

[0117] One subject, a previously healthy 66 year old male who had been diagnosed with advanced prostate cancer. He received 1 year of lutenizing hormone blocking agent (Zoladex) therapy and 42 E-beam radiation treatments (69.7 Grey units of radiation) 80% of which were directed toward the abdomen. During recovery, the subject developed radiation induced colitis with a galaxy of symptoms similar to IBS-A. He was treated with 8 mg ANA-131 BID for 45 days at which time the supply of clinical trial nasal inhalers became exhausted. After a week without treatment, the IBS symptoms returned. The subject then began to smoke marijuana and has been doing so since then. He reports his radiation induced colitis has not returned in the one year period following the end of treatment.

Alcoholism

[0118] A cohort of 6 alcoholic subjects (defined as imbibing 14 oz per day ethanol) inhaled 8 mg doses of ANA-131 twice a day for 30 days. 5 of 6 subjects reported a reduction in alcohol related craving and drinking. This suggests ANA-131 can modulate the reinforcing properties of alcohol and could be a useful adjunct in treatment of chronic alcohol addiction, alcohol withdrawal and alcoholism treatment relapses.

[0119] The present invention also extends to a co-therapeutic combination comprising a subclinical dose of morphine together with a compensatory dose of one or more cannabinoid receptor agonist(s) and or antagonist(s).

[0120] The combination of cannabinoids and morphine in cannabinoid-morphine SLP for intra nasal inhalation decreases morphine's addiction potential, respiratory depression, opiate-induced constipation and reduces the dose of morphine required. This combination provides synergistically enhanced analgesia for near immediate pain relief in management of severe break-through pain in terminal cancer, post-surgical recovery, cholecystitis, cholelithiasis, pancreatitis, renal calculi, polymyalgia rheumatica, myofascial neurogenic pain and intractable neurogenic pain syndrome. The synergistic effects of the morphine-cannabinoid combination is quite significant and specific as morphine acts directly on its endogenous morphinan receptors, whereas cannabinoids act directly on their endogenous CB1 and CB2 receptors. Such a method offers a significant advance in the pharmaceutical art of cannabinoids and opiates.

[0121] In a case of bBreakthrough pain control in terminal cancer, a 68 year old male subject was diagnosed with terminal pancreatic cancer. Palliative treatment consisted of a liquid diet and 20 mg morphine q4 h. Constipation was a minor side effect compared to the loss of reasoning, violence and paranoid ideation the subject was suffering from. The subject was weaned off high dose morphine as 125 mg THC dosed cigarettes replaced the morphine to control break through pain. Cigarettes dosed with 125 mg of THC contained in a Cannabis extract was tried and produced better results than the THC alone. This is due to the entourage effect other cannabinoids in the extract exert on THC, synergistically increasing its analgesic efficacy while modulating its psychotropic side effects. Cigarettes were smoked ad libitum. This regimen proved highly effective in controlling breakthrough pain, improved the subjects communication abilities, arrested paranoid ideation and improved the overall level of comfort of the subject.

[0122] In yet another aspect of the present invention, there is provided a co-therapeutic combination comprising a subclinical does or methadone together with a compensatory dose of one or more cannabinoid receptor agonist(s) and of antagonist(s). The combination of cannabinoids and methadone is unique as together they can reduce the significant addiction liability, respiratory depression and constipation associated with methadone, but retain and improve the control of opiate withdrawal and craving and act as a superior substitute for Methadone use in opiate addiction maintenance programs. Methadone blocks the acute symptoms of withdrawal in opiate addicts, but with a cost, as methadone is a dysphoric whose effects are generally considered as unpleasant. In large part, this is the reason for the limited success of methadone maintenance programs. By combining methadone and cannabinoids, the dysphoric effect of methadone is replaced by a mild feeling of well-being. The synergy between cannabinoid and methadone improves the addicted patient's experience with methadone, making the combination a more effective substitute treatment for opiate addiction than methadone alone. Methadone can be readily repurposed with cannabinoids as cannabinoid-methadone SLP for nasal inhaler administration. In a poorly controlled study undertaken in a street drug clinic setting, the combination reduced acute withdrawal symptoms with one-half the dose of methadone and was more effective than methadone alone in weaning opiate addicts from their opiate dependence. Such an invention is suitable for use in chronic maintenance treatment programs and would be a desirable replacement for the significantly larger methadone dose currently employed at street clinics. Such a method offers a significant advance in the pharmaceutical art of the cannabinoids.

[0123] In opiate addiction therapy trials, a cohort of 6 opiate addicted subjects on Methadone maintenance programs inhaled 8 mg dose of ANA-131 twice a day for 30 days. All subjects reported a reduction in opiate craving, opiate-related stimuli and opiate use. This suggests ANA-131 can effectively modulate the reinforcing properties of opiates and could be a useful adjunct in the treatment of opiate addiction. An unexpected side effect of the ANA-131 treatment was the subjects reported that although they still took Methadone periodically, the effects of ANA-131 were preferred over those of Methadone.