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(12) Patent Application Publication (10) Pub. No.: US 2007/0104741 A1 Murty Et Al

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(12) Patent Application Publication (10) Pub. No.: US 2007/0104741 A1 Murty Et Al US 20070 104741A1 (19) United States (12) Patent Application Publication (10) Pub. No.: US 2007/0104741 A1 Murty et al. (43) Pub. Date: May 10, 2007 (54) DELIVERY OF TETRAHYDROCANNABINOL Publication Classification (51) Int. Cl. (75) Inventors: Ram B. Murty, Lexington, KY (US); A6II 3 L/353 (2006.01) Santos B. Murty, Lexington, KY (US) A6IR 9/00 (2006.01) A6II 3 L/655 (2006.01) Correspondence Address: (52) U.S. Cl. ........................... 424/400: 514/454: 514/151 TOWNSEND & BANTA (57) ABSTRACT fo PORTFOLIO P A self-emulsifying drug delivery system to improve disso PO BOX S2OSO lution, stability, and bioavailability of drug compounds of MINNEAPOLIS, MN 55402 (US) dronabinol or other cannabinoids. The drug compound(s) are dissolved in an oily medium (e.g. triglycerides and/or (73) Assignee: Murty Pharmaceuticals, Inc., Lexing mixed glycerides and/or free fatty acids containing medium ton, KY and/or long chain Saturated, mono-unsaturated, and/or poly Appl. No.: 11/592,393 unsaturated free fatty acids) together with at least one (21) Surfactant. The Surfactant promotes self-emulsification, (22) Filed: Nov. 3, 2006 thereby promoting targeted chylomicron delivery and opti mal bioavailability to a mammalian intestinal lumen. A dosage form can optionally include co-solvents, anti-oxi Related U.S. Application Data dants, viscosity modifying agents, cytochrome P450 meta bolic inhibitors, P-GP efflux inhibitors, and amphiphilic/ (60) Provisional application No. 60/734,160, filed on Nov. non-amphiphilic solutes to induce semi-solid formation for 7, 2005. targeted release rates. -0-Formulation (i) -H-Formulation (ii) SO -A-Formulation (iii) de-Formulation (iv) 40 - -ie- Formulation (v) O Marketed Product O 20 40 60 8O Time (min) Patent Application Publication May 10, 2007 Sheet 1 of 3 US 2007/0104741 A1 120 100 - 8 O -0-Formulation (i) -HFormulation (ii) 6 O -A-Formulation (iii) -X-Formulation (iv) 4 O --Formulation (v) O Marketed Product 2 O O 20 40 60 80 Time (min) Fig. 1 Patent Application Publication May 10, 2007 Sheet 2 of 3 US 2007/0104741 A1 80 C SB 60 () is 40 S. CD n 20 O O 100 200 300 400 Time (min) Fig. 2 Patent Application Publication May 10, 2007 Sheet 3 of 3 US 2007/0104741 A1 O 60 120 18O 240 300 360 Time (min) Fig. 3 US 2007/01 04741 A1 May 10, 2007 DELIVERY OF TETRAHYDROCANNABINOL reported that another limitation of orally administered THC is the large inter-Subject variability in absorption. RELATED APPLICATION DATA 0008. Other postulated mechanisms for the biopharma 0001) This application claims the benefit of U.S. Provi ceutical anomalies can be attributed to the physical-chemical sional application No. 60/734,160, filed on Nov. 7, 2005. properties of A-THC. This compound is highly lipophilic, essentially water insoluble, and potentially acid labile within FIELD OF THE INVENTION the stomach. This compound is also sensitive to environ 0002 The present invention relates in general to a deliv mental storage and stress conditions. For instance, this ery system to improve administration of cannabinoids compound is thermolabile and photolabile, and long-term (THC) to patients and, more particularly, to a self-emulsi storage can lead to a cumulative decrease in A-THC content fying drug delivery system. The drug delivery system of the by an oxidation reaction forming cannabinol (CBN). present invention optimizes THC dissolution properties and 0009. It is well known that in mammals certain areas of avoids hepatic first-pass metabolism, thereby enhancing the alimentary canal have a venous drainage, which does not bioavailability through the gastrointestinal tract. The deliv involve a first pass through the liver. The avoidance of the ery system of the present invention can be administered as first pass effect is the rationale for the use of rectal, buccal, either a liquid or semi-solid matrix within a capsule shell for nasal, and Sublingual formulations. A A-THC and canna immediate or Sustained release rates. bidiol combination have been formulated as a buccal spray. Some of the disadvantages associated with nasal, Sublingual BACKGROUND OF THE INVENTION and buccal routes of administration are that the nasal mucosa 0003 Cannabinoids are compounds derived from the may cause pain or reflex Sneezing and, in extreme cases, cannabis sativa plant commonly known as marijuana. The may cause irritation and damage to the nasal mucosa. plant contains more than 400 chemicals and approximately Sublingual formulations may stimulate the flow of saliva, 60 cannabinoids. The most active chemical compound of the making it difficult for patients to avoid Swallowing when naturally occurring cannabinoids is tetrahydrocannabinol Substantial amounts of saliva are produced. Also, buccal formulations may be subject to the same limitations as (THC), particularly A-THC. Sublingual formulations. 0004 Currently, A-tetrahydrocannabinol, also known as dronabinol, is available commercially in MarinolR soft 0010 Both sublingual and buccal formulations depend gelatin capsules which have been approved by the Food and on the efficient transfer of medicament from a hydrophilic Drug Administration (FDA) for the control of nausea and vehicle to the mucous membrane of the sublingual or buccal Vomiting associated with chemotherapy and for appetite mucosa. Transfer of medicament through the interstices stimulation of AIDS patients suffering from the wasting between or through epithelial cells is governed principally syndrome. A-tetrahydrocannabinol shows other biological by the lipid solubility of the medicament. When a drug is activities, which lend themselves to possible therapeutic water insoluble as in the case with cannabinoids, this pre applications, such as in the treatment of glaucoma, migraine sents a further barrier to absorption from the sublingual area. headaches, spasticity, anxiety, analgesia, and drug addiction. 0011. In an effort to improve local drug delivery of THC, 0005. In Marinol R, A-THC is dissolved in sesame oil researchers have tried to develop a transdermal delivery and encapsulated in gelatin capsules for oral administration. system. The bioactive material administered dermally, how After oral administration, Dronabinol has an onset of action ever, may show erratic and irregular absorption. Hence, the of approximately 0.5 to 1 hour, with a peak effect of 2-4 need exists for the addition of absorption enhancers which in hours. The duration of action for psychoactive effects is 4-6 Some cases may be detrimental to the skin due to local side hours, but the appetite stimulant effect may continue for 24 effects. hours or longer after administration. The maximal plasma 0012. Other delivery systems for THC or cannabinoids levels after oral dosing of 20 mg THC in a sesame oil described in the patent literature, include: Metered dose formulation are around 10 ng/ml. inhaler using non-CFC propellants (U.S. Pat. Nos. 6,509, 0006. At the present time, some cancer patients manage 005 and 6,713,048); Pump action spray (U.S. Pat. No. to obtain prescriptions for marijuana in order to alleviate 6,946,150); Microsphere nasal delivery system (U.S. Pat. pain as well as nausea and vomiting due to chemotherapy. No. 6,383,513); Water soluble prodrugs for intranasal This latter situation arises due to poor or partial response administration (U.S. Patent No.: 6,380,175); Topical lini from oral therapy, which often requires oral administration ment (U.S. Pat. No. 6,949.582); Cyclodextrin complexes two to three times a day to obtain equivalent acute psycho with cannabinoids (U.S. Patent Application No. logical and physiological effects obtained from Smoking 20050153931); and Solid lipid compositions for oral admin marijuana. istration (U.S. Pat. Nos. 5,891, 469 and 5,989,583). 0007 When administered orally, THC or dronabinol is 0013 This solid lipid composition involves a method for almost completely absorbed (90-95%) after a single oral delivering a non-psychoactive cannabinoid (i.e. dexanab dose. However, due to the combined effect of first pass inol) in a dry lipid mixture to greatly enhance oral bioavail hepatic metabolism and high lipid solubility, only about ability when compared to known formulations. With 10-20% of an administered dose reaches systemic circula enhanced absorption characteristics of oral delivery systems, tion with highly variable maximal concentrations. It has the patentees anticipated that treatment could be directed been found that fasting or food deprivation may decrease the towards brain damage associated with stroke, head trauma, rate of absorption of THC from the sesame oil capsules and cardiac arrest. This, however, required sufficient bio currently available in the market. Previous studies have availability of the drug compound. Oral THC or dronabinol US 2007/01 04741 A1 May 10, 2007 therapy would be greatly benefited by improved bioavail 0020. Another object of the present invention is to pro ability for treating a variety of conditions described above. mote drug absorption through alternate gastrointestinal path Oral dosage forms are designed to enable sufficient avail ways, outside the conventional hepatic portal vein transport ability of the active compound at its site of action. The mechanism, which results in a high first-pass effect. bioavailability of a drug depends on several parameters, i.e., the physicochemical nature of the active compound, the SUMMARY OF THE INVENTION dosage form, as well as physiological factors. The cannab inoid compounds, being hydrophobic by nature, show wet 0021. The inventors herein, after extensive investigation ting difficulties and poor dissolution in the gastrointestinal and research, unexpectedly discovered an oral dosage form region. In addition, THC or dronabinol undergo extensive of cannabinoids which achieve the above objectives of the hepatic first-pass metabolism. These properties represent present invention. barriers to drug absorption from oral dosage forms. These 0022. The present invention provides an isotropic phased barriers in turn cause a Subsequent reduction in the bioavail and chemically stabilized oral delivery system of dronabinol ability.
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