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United States Patent (19) 11 Patent Number: 6,113,907 Khwaja Et Al

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United States Patent (19) 11 Patent Number: 6,113,907 Khwaja Et Al USOO6113907A United States Patent (19) 11 Patent Number: 6,113,907 Khwaja et al. (45) Date of Patent: *Sep. 5, 2000 54). PHARMACEUTICAL GRADE ST. JOHNS Cott. J. In Vitro Receptor Binding and Enzyme Inhibition by WORT Hypericum perforatum Extract. Pharmacopsychiatry 30(Supplement 2)108-112, 1997. 75 Inventors: Tasneem A. Khwaja, Corona Del Mar; Muller W. In Vitro Study of Hypericum Extract, Hypericine Elliot P. Friedman, Montecito, both of and Camphor Oil as Antidepressants. Deutsche Apotherker Calif. Zeitung 136(13)1015-1022, Mar. 1996. 73 Assignees: University of Southern California, English translation of Georgiev E. Los Angeles; Pharmaprint Inc., Irvine, English translation of Chatterjee, EP 0599 307. both of Calif. Colegate S. Bioactive Natural Products. CRC Press, Boca Raton FL, pp. 3, 200–201, 1993. * Notice: This patent issued on a continued pros Steinback R. Problems in Purifying and Standardizing a ecution application filed under 37 CFR Phytopharmaceutical, For Example Hypericum. J of Applied 1.53(d), and is subject to the twenty year Phytotherapy Vol. 6, pp. 221-224, English translation pro patent term provisions of 35 U.S.C. vided, 1981. 154(a)(2). Liao J. Evaluation with Receptor Binding Assay on the Water Extracts of Ten CNS Active Chinese Herbal Drugs. 21 Appl. No.: 08/956,602 Proc National Science. 19(3) 151-158, 1995. Rossi, G. Biological Testing, Chapter 31. Remington's Phar 22 Filed: Oct. 23, 1997 maceutical Sciences, Phila College of Pharmacy and Sci ence 16th Ed., 1980. Related U.S. Application Data Khwaja T. Recent Studies on the Anticancer Activities of Mistletoe and Its Alkaloids. Oncology 43(Sup 1)42-50, 63 Continuation-in-part of application No. 08/838,198, Apr. 15, 1986. 1997, abandoned. Dingermann T., Phytopharmaceuticals in Old Age, Phar (51) Int. Cl." ..................................................... A61K 35/78 mazeutische Zeitung 140(23)9–14, 16, Jun. 1995. Rocha L., An Antifungal Pyrone and Xanthones with Monoamine Oxodase Inhibitory Activity from Hypericum 52 U.S. Cl. ........................................................... 424/195.1 Brasiliense 36(6)1381–1385, Jun. 1994. Nissen, H., Quality Control of Phytopharaca with HPLC, 58 Field of Search ............................................ 424/195.1 GIT Fachz Lab 31(4)293–5, Apr. 1987. 56) References Cited Seabra R., Analysis of Commerically Available Hypericum Extracts, Rev Port Farm 41(3)39–42, Mar. 1992. U.S. PATENT DOCUMENTS Han G., The Screening of Chinese Traditional Drugs by 5,401,502 3/1995 Wunderlich et al. ................ 424/195.1 Biological ASSay and the Isolation of Some Active Compo 5,716,928 2/1998 Benet et al. .............................. 514/11 nents, Int J of Chinese Medicine 16(1)1-17, Mar. 1991. 5,780,037 7/1998 Khwaja ........ 424/195.1 Killmer L., How LC/MS Can Help Solve Your Pharmaceu 5,798,101 8/1998 Haveson ....... 424/195.1 tical Analysis Problems, Today's Chemist at Work, Feb. 5,849,734 12/1998 Tehim et al. ............................ 514/217 1996. FOREIGN PATENT DOCUMENTS Muller et al., “Johanniskraut-In-vitro-Studie uber Hyperi cum-Extract, Hypericin und Kampferol als. Antidepressiva', O 599 307 A1 11/1993 European Pat. Off.. Deutsche Apotheker Zeitung (136 Jahrgang), No. 13, pp. 0 702 957 A1 9/1994 European Pat. Off.. 17–24 (1015-1022), Mar. 28, 1996. (English translation also 39 35 772 4/1991 Germany. provided.) WO 96/32122 10/1996 WIPO. Raffa, “Screen of Receptor and Uptake-Site Activity of WP 97/13489 4/1997 WIPO. Hypericin Component of St. John's Wort Reveals O Recep OTHER PUBLICATIONS tor Binding, Life Sciences, vol. 62, No. 16, pp. PL Georgiev E. Nauchn Tr Plovoiv 32(1)257–63, 1985. 265-270, 1998. Baureithel K. Inhibition of Benzodiazepine Binding in vitro by Amentoflavone, A Constituent of Various Species of Primary Examiner Ralph Gitomer Hypericum. Pharmaceutica Acta Helvetiae 72(3)153-157, Attorney, Agent, or Firm-Lyon & Lyon LLP Mar. 1997. 57 ABSTRACT Stephenson F. Purification and Characterization of the Brain GABA/Benzodiazepine Receptor. Structural and Functional The present invention relates generally to St. John's Wort Properties, Alan R. Liss, Inc. 261-274, 1986. materials and methods for making Such materials in medici Scholfield P. Sequence and Functional Expression of the nally useful and pharmaceutically acceptable forms. More GABA Receptor Shows a Ligand Gated Receptor Super particularly, the present invention relates to the use of Family. Nature 328 221-227, Jul. 1987. compositional and activity fingerprints in the processing of Chatterjee S. Hyperforin as a Possible Antidepressant Com St. John's Wort materials to produce drugs which qualify as ponent of Hypericum Extracts. Life Sciences 63(6)499–510, pharmaceutical grade compositions which are Suitable for 1998. use in clinical or Veterinary Settings to treat and/or amelio Denke A. Biochemical Activites of Extracts from Hyperi rate diseases, disorders or conditions. cum perforatum L. Arzneim Forsch/Drug Res 49(2)109-114, 1999. 2 Claims, 6 Drawing Sheets U.S. Patent Sep. 5, 2000 Sheet 1 of 6 6,113,907 IDENTIFYING AND SEPARATING MARKERS BOACTIVITY ASSAY OF MARKERS COMPONENTS HAVING A NACTIVE SUBSTANTIAL PORTION OF COMPONENTS ACTIVITY ESTABLISHING FINGERPRINT 5 FIG.1 U.S. Patent Sep. 5, 2000 Sheet 2 of 6 6,113,907 BOTANICAL 21 MATERIAL PROCESSED MATERIAL 22 QA/STANDARDIZATION PROCEDURES MODIFY: REJECT APPROVE AEEE REAGENT 26 24 25 FIG.2 U.S. Patent Sep. 5, 2000 Sheet 3 of 6 6,113,907 PLANT/HERB PULVERIZED AFTER FREEZING AT LIQUID NITROCENTEMPERATURE EXTRACT WITH DISTILLED WATER RESIDUE WATER EXTRACT EXTRACT WITH ETHER ETHER EXTRACT (SEPONINS, TERPENOIDS) AQUEOUS PHASE FREEZE DRY RESIDUE (DRY) DISSOLVE IN WATER AND BRING pH TO 8.5 EXTRACT WITH CHLOROFORM CHLOROFORM EXTRACT AQUEOUS PHASE (ALKALOIDS) ADDAMMONUM SULPHATE (70%) PRECIPITATION WATER EXTRACT (PROTEINS) CARBOHYDRATES FIG.3 U.S. Patent Sep. 5, 2000 Sheet 4 of 6 6,113,907 U.S. Patent Sep. 5, 2000 Sheet 6 of 6 6,113,907 2 d S2 a co CD 4. - C 5 e li a Se i Se C gLU 2 HSNS 5 | | | | | | | | | NS 5 | | | | | | | | | S s 6,113,907 1 2 PHARMACEUTICAL GRADE ST. JOHNS 6.4.6 MISCELLANEOUS COMPOUNDS IN ST. JOHNS WORT WORT 647 ANALYTICAL METHODS OF ANALYSIS This is a continuation-in-part of U.S. Ser. No. 08/838, 6.4.8 THIN LAYER CHROMATOGRAPHY (TLC) OF 198, filed on Apr. 15, 1997 now abandoned. 5 HYPERICIN AND PSEUDOHYPERICIN Sample Preparation TABLE OF CONTENTS 1. FIELD OF THE INVENTION Standard Preparation 2. BACKGROUND OF THE INVENTION Stability of Standards/Sample Solutions 21 ST JOHNS WORT 1O Stop Test 22 CLINICAL STUDIES OF ST. JOHNS WORT Chromatographic Conditions 2.2.1 MILD-TO-MODERATE DEPRESSION 6.4.9 HIGH PERFORMANCE LIQUID CHROMATOG Animal Studies RAPHY (HPLC) OF HYPERICIN AND PSEUDOHY 222 ANTIVIRAL ACTIVITY PERICIN 22.3 WOUND-HEALING EFFECTS 15 Limits of Quantitation and Detection 2.24 MISCELLANEOUS EFFECTS HPLC (Flavonoids, Hypericin and Pseudohypericin) 3. SUMMARY OF THE INVENTION Extraction 3.1. DEFINITIONS 6.4.10 UV/VIS SPECTROS COPIC METHOD 4 BRIEF DESCRIPTION OF THE DRAWINGS (HYPERICIN/PSEUDOHYPERICIN) SAMPLE 5. DETAILED DESCRIPTION OF THE INVENTION PREPARATION 5.1. METHODS OF PHARMAPRINTING(R) 6.5 HPLC ANALYSIS OF ST. JOHNS WORT COMPO 5.1.1. METHODS OF DEVELOPING A PHAR NENTS HYPEROSIDE, RUTIN, QUERCETIN, MAPRINTOR) QUERCITRIN, HYPERICIN, MANGIFERIN 5.12. ALTERNATIVE METHODS OF DEVELOPING A 6.6 CONTRIBUTION OF COMPONENTS TO TOTAL PHARMAPRINTOR) 25 ACTIVITY OF ST. JOHNS WORT 5.13 ADDITIONAL VARIATIONS ON THE METHOD OF DEVELOPING A PHARMAPRINTOR) 1. FIELD OF THE INVENTION 5.2. METHODS OF PROCESSING AND EXTRACTING BOTANICAL MATERIALS The present invention relates generally to botanical mate 5.2.1 LIQUID EXTRACTS OF PLANT MATERIALS rials and methods for transforming Such materials into AND POWDERED PLANT MATERIALS medicinally useful and pharmaceutically acceptable forms. 5.3 SEPARATION OF FRACTIONS More particularly, the present invention relates to the use of 54 ESTABLISHMENT OF APPROPRIATE BIOASSAYS compositional and activity fingerprints in the processing of 541. ENZYMATIC AND RECEPTOR BASED ASSAYS St. John's Wort to produce botanical drugs which qualify as 542 CELL CULTURE AND OTHER ASSAYS 35 pharmaceutical grade compositions which are Suitable for 5.43. ANTICANCERACTIVITY use in clinical Settings to treat and/or ameliorate diseases, 5.44. ANTIVIRAL ACTIVITY disorders and/or conditions. 5.5. ANALYTICAL METHODS FOR ANALYZING 2. BACKGROUND OF THE INVENTION CHEMICAL COMPONENTS 5.6. ANALYSIS OF FRACTIONS 40 Pharmaceutical manufacturing is based on control over 5.7. METHODS OF USE OF PHARMAPRINTED(R) the composition and bioactivity for each manufactured MATERIALS batch. This Standardization and control provides reproduc 58. PHARMPRINTOR OF ST. JOHNS WORT ible material in the predictable and consistent treatment of 5.8.1. BIOLOGICAL PHARMAPRINTOR) patients. Herbal medicines, produced from botanical 5.8.2. CHEMICAL COMPONENTS 45 materials, have presented a unique problem for manufactur 58.3. CONVERSION RATIO erS desiring the control, reproducibility, and Standardization 6. EXAMPLE: ST JOHNS Wort, Hypericum perforatum that are required of pharmaceuticals. This problem is pri 6.1 COMMERCIAL SUPPLIERS/PRODUCT NAMES marily due to the plurality of components contained in an 6.2 FRACTIONAL ANALYSIS ON A SILICA GEL COL herbal medicine and the large variation in composition and UMN 50 potency due to the growing, harvesting and processing 6.3 BIOLOGICALACTIVITY ANALYSIS MONOAMINE conditions of raw materials. OXIDASE, SEROTONIN TRANSPORTER ASSAY, Plants have been, and continue to be, the Source of a wide OTHER ASSAYS variety of medicinal compounds. For centuries, various 6.3.1 BIOASSAY FOR GABA BINDING forms of botanically derived materials have been used to 6.3.2 BIOASSAY FOR NMDAAGONIST SITE BINDING 55 treat countleSS different ailments. The botanical materials 6.3.3 BIOASSAY FOR M BINDING have typically been in the form of powders made from one 6.3.4 MONOAMINE OXIDASE-A (MAO) or more plants or plant parts or extracts derived from whole 6.3.5 MONOAMINE OXIDASEB plants or Selected plant parts.
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