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(12) United States Patent (10) Patent No.: US 6,896,898 B1 Xiong Et Al

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(12) United States Patent (10) Patent No.: US 6,896,898 B1 Xiong Et Al USOO68.96898B1 (12) United States Patent (10) Patent No.: US 6,896,898 B1 Xiong et al. (45) Date of Patent: May 24, 2005 (54) TRANSIDERMAL DELIVERY SYSTEM FOR OTHER PUBLICATIONS ALKALOIDS OF ACONITUM SPECIES Liu J-H et al. (Anti-inflammatory and Analgesic Activities Inventors: Weihong Xiong, Salt Lake City, UT of N-Deacetylappaconitine and Lappaconitine, Acta Phar (75) macologica Sinica, (1987), vol. 8, No. 4, pp. 301-305.* (US); Dinesh C. Patel, Salt Lake City, Mamoru Ono, et al., Pharmacological Studies of Lappac UT (US) onitine. Occurrence of Analgesic Effect Without Opioid (73) Assignee: XEL Herbaceuticals, Inc., Salt Lake Receptor, Research Communication in Chemical Pathology City, UT (US) and Pharmacology, vol. 63, No. 1, Jan. 1989. Xin Guo, et al., Lappaconitine and N-Deacetylappaconitine Notice: Subject to any disclaimer, the term of this Potentiate Footshock-Induced Analgesia in Rats, Life Sci patent is extended or adjusted under 35 ences, vol. 48, pp 1365–1370, 1991. U.S.C. 154(b) by 876 days. Y. Bai, et al. N-Oxides of Some Norditerpenoid Alkaloids, Journal of Natural Products, Vo. 58, No. 6, pp. 929–933, Appl. No.: 09/944,960 Jun. 1995. (21) Guo Xin, et al., Roles of Periaqueductal Gray and Nucleus (22) Filed: Nov. 17, 2000 Raphe Magnus on Analgesia Induced by Lappaconitine, N-Deacetylappaconitine and Morphine, Acta Pharmaco Related U.S. Application Data logica Sinica, vol. 11, (2), pp. 107-112, Mar. 1990. (60) Provisional application No. 60/166,497, filed on Nov. 19, Mamoru Ono, et al., Pharmacological Studies of Lappac 1999. onitine. Analgesia Produced by Intracerebrokventricular, (51) Int. Cl............................ A61K 9/00; A61F 13/00; Intracisternal and Intrathecal Injections, Journal of Phar AO1N 43/42 macobio-Dynamics, 13, 374-377, 1990. (52) U.S. Cl. ........................ 424/449; 424/400; 514/279 M. Ono, et al., Pharmacological Studies of Lappaconitine, (58) Field of Search ................................. 424/449, 400; Arzneimittelforschung, Jul 1988; 38(7):892–5. 514/279 * cited by examiner (56) References Cited Primary Examiner Susan Coe ASSistant Examiner Randall Winston U.S. PATENT DOCUMENTS (74) Attorney, Agent, or Firm Thorpe North & Western, 4,352,796. A 10/1982 Arichi et al. LLP 4,656,178 A 4/1987 Junusov et al. 4,849.224 A 7/1989 Chang et al. (57) ABSTRACT 4,983,395 A 1/1991 Chang et al. 5,122,383 A 6/1992 Heiber et al. The present invention provides a composition of transder 5,290,784. A 3/1994 Ou et al. mally administered aconitine alkaloids for ameliorating pain 5,446,070 A 8/1995. Mantelle and inflammation. In one aspect, an aconitine alkaloid is 5,460.820 A 10/1995 Ebert et al. delivered in a Sufficient amount to achieve and maintain a 5,514,684 A 5/1996 Murayama et al. blood plasma aconitine alkaloid level of about 0.5 ng/mL to 5,547,956 A 8/1996 Ou et al. 5,656.286 A 8/1997 Miranda et al. about 400 ng/mL. Aconitine alkaloids may be delivered by 5,719,197 A 2/1998 Kanios et al. themselves, or in combination with other elements, Such as 5,770,604 A * 6/1998 Murayama .................. 514/279 additional analgesics, other drugs, or positive health pro 6,024.976 A 2/2000 Miranda et al. moting Substances. Various formulations for the transdermal delivery of aconitine alkaloids are disclosed, and may FOREIGN PATENT DOCUMENTS include Selected penetration enhancers. CN 1074117 A 7/1993 JP 1982-4O144 E * 4/1982 5 Claims, No Drawings US 6,896,898 B1 1 2 TRANSIDERMAL DELIVERY SYSTEM FOR which also imparts an anti-inflammatory effect, and which ALKALOIDS OF ACONITUM SPECIES imparts minimal side effects, Such as drug dependency would be advantageous. PRIORITY DATA Plant extracts from different species of Aconitum plant This application claims priority to provisional U.S. patent have been employed in many holistic medicine cultures for application Ser. No. 60/166,497 which was filed on Nov. 19, their various medicinal and positive health properties. For 1999, and which is incorporated herein by reference in its example, traditional Chinese medicine has long used Aconi entirety. tum extracts for their various analgesic, anti-rheumatic, anti-narcotic, and antipyretic properties. These properties FIELD OF THE INVENTION have now been largely attributed to the diterpenoid alkaloids found within the various AcOnitum plant species. The present invention relates generally to a composition Among the AcOnitum plant derived alkaloids, aconitine, and method for ameliorating pain and inflammation. More 3-acetylaconitine, lappaconitine, N-deacetyl-lappaconitine, particularly, the present invention relates to a pain and Songtiening, and bulley aconitine A, have become particu inflammation ameliorating composition, which contains an 15 larly known for their powerful analgesic properties. Further, alkaloid compound extracted from an AcOnitum plant Spe 3-acetylaconitine and lappaconitine have been shown to be CCS. centrally acting analgesics without affinity for opioid recep BACKGROUND OF THE INVENTION torS. Because extracts of Aconite roots have no affinity for Everyone experiences physical pain in one form or opioid receptors, they may be used to expediently relieve another during his or her life. Pain and inflammation accom drug addiction. In fact, lappaconitine and bulleyaconitine A pany most illnesses and physical injury. Pain may be acute dosage regimens have been shown to relieve drug depen or dull, intermittent, or chronic. Because of the great unde dence and remove withdrawal syndrome within 3-4 days. Sirability of pain many remedies and treatments have been Significant results in Such a shortened duration provide a Sought throughout history. Further, ongoing research con 25 great improvement over known treatment using Successively tinues to Seek analgesic and anti-inflammatory compounds less potent opioids. that provide maximum potency with minimal adverse side Accordingly, in the present invention provides a transder effects, Such as chemical dependency. mal formulation for ameliorating pain and inflammation. In Of the various types of pain, chronic pain caused by one aspect, the transdermal formulation includes an amount degenerative or inflammatory diseases is considered to be of an aconitine alkaloid, which is Sufficient to achieve an especially intolerable because of its constant presence. aconitine alkaloid blood plasma level of from about 0.5 to Many diseases, Such as cancer and arthritis, may cause about 400 ng/ml, an inert carrier and, a permeation enhancer chronic pain and inflammation, which is So debilitating that Selected from the group consisting of: fatty acids, fatty acid it virtually incapacitates the afflicted individual. Therefore, 35 esters, fatty alcohols, fatty acid esters of lactic acid, fatty research efforts in the pharmaceutical and medical Sciences acid esters of glycolic acid, amides, amines, pyrrolidones, continually Seek formulations of analgesic and anti glycerol triesters, terpenes, Surfactants, complexing agents, inflammatory compounds, which are capable of long lasting biologics, their Salts, and mixtures thereof. In another aspect, high potency. The duration of potent activity is especially the blood plasma concentration of an aconitine alkaloid important when treating chronic pain in order to minimize 40 achieved is from about 5 to about 200 ng/ml. In another administration frequency. By reducing administration aspect, the transdermal formulation achieves the blood frequency, intermittent pain, which occurs as one dosage plasma level of from about 0.5 to about 400 ng/ml within wears off, and before another is administered, is greatly about 0.25 to about 18 hours after administration of the reduced. formulation. In yet another aspect, the blood plasma level Many analgesics Such as codeine, tramadol, and dextro 45 may be achieved within about 0.5 to about 12 hours after propoxyphene have been used to manage mild to moderate administration. pain. Additionally, for more Severe pain, opioids Such as The transdermal formulation may be configured to pro morphine, methadone, oxycodone, bupre norphine, vide an extended or Sustained aconitine alkaloid release. In hydromorphone, fentanyl, and heroin have been used. one aspect, a Single dosage of the transdermal formulation Unfortunately, heavy use of opioids, or other narcotics often 50 may be Sufficient to achieve and Sustain the aconitine leads to chemical dependence, or addiction. alkaloid blood plasma level of from about 0.5 to 400 ng/ml Chemical dependence is often extremely difficult and for a duration of at least about 24-96 hours. painful to overcome. One common treatment involves Various types of aconitine alkaloids may be effective in administering opioids and opioid analgesics in decreasing ameliorating pain and inflammation. In one aspect, the doses over an extended duration. For example, methadone is 55 aconitine alkaloid may be a member Selected from the group known for treating heroin addiction by being administered in consisting of lappaconitine, N-deacetyl-lappaconitine, gradually decreasing amounts. While Such regimens do tend Songtiening, bulley aconitine A, 3-acetylaconitin, to alleviate many of the withdrawal Symptoms associated isolappaconitine, deoxylappaconitine, neofinaconitine, with detoxification, they take months to complete and are ranaconitine, N-deacetylranaconitine, finaconitine, therefore only marginally Successful in helping the addict 60 N-deacetylfinaconitine, mesaconitine, jesaconitine, and take a permanent Step away from chemical dependence. Salts, analogs, derivatives, prodrugs, and mixtures thereof. In another aspect the aconitine alkaloid may be lappac SUMMARY OF THE INVENTION onitine. In a further aspect, the aconitine alkaloid may be It has been recognized that an analgesic agent Songtiening. In yet another aspect, the aconitine alkaloid formulation, which can be delivered with long lasting 65 may be bulleyaconitine A. In another aspect, the aconitine potency and at infrequent intervals would be advantageous. alkaloid may be ranaconitine. In a further aspect, the Additionally, it has been recognized that an analgesic agent aconitine alkaloid-may be finaconitine. In another aspect, US 6,896,898 B1 3 4 the aconitine alkaloid may be mesaconitine. In yet another tures thereof.
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