Drug – bio-affecting and body treating compositions – Antigen – epitope – or other immunospecific immunoeffector – Conjugate or complex
Reexamination Certificate
1999-02-22
2001-08-28
Lilling, Herbert J. (Department: 1651)
Drug, bio-affecting and body treating compositions
Antigen, epitope, or other immunospecific immunoeffector
Conjugate or complex
Reexamination Certificate
active
06280737
ABSTRACT:
This application is a 371 of PCT/DE97/00591 filed Mar. 21, 1997.
Due to many years of experience, tea preparations or extracts, respectively, from roots of devil's claw (radix harpagophyti) have been employed in the case of dyspeptic conditions as well as in the treatment of rheumatoid diseases (Sticher, O., DAZ 117 (1977), 1279-1284). The drug is composed of the underground parts and mainly of the secondary storage roots of Harpagophytum procumbens (Volk, O.H., DAZ 104 (1964), 573-576; F.C. Czygan, Zeitschrift fur Phytotherapie 8 (1987), 17-20).
M. Caprasse, J. Pharm. BeIg., 1980, 35, 2, 143-149, reviews Harpagophytum procumbens and its properties. The finely pulverized root was extracted with methanol, the resulting extract was evaporated, the residue added with water, and the resulting aqueous solution was extracted 3 times with a 4:1 mixture of methylene chloride and n-butanol.
R.E. Moati, FR-A-2 614 791, describes a composition of 400 mg of Harpagophytum procumbens, 20 mg of selenium and 25 mg of zinc for the treatment of rheumatism and inflammations.
The commission E of the former Bundesgesundheitsamt took the reports and clinical observations into account by publishing a positive monography “Radix harpagophyti” in 1989. According to this publication, preparations from devil's claw roots are employed in the case of dyspeptic conditions (daily dose of 1.5 g of the drug) and in the supportive therapy of degenerative diseases of the motoric system (daily dose of 4.5 g of the drug) (Bundesanzeiger No. 43 of 02/03/1989). To date it has not been possible to attribute the efficacy to particular ingredients.
As the essential ingredients of the extracts there have been mentioned iridoid glycosides, in particular harpagoside, and also harpagide and procumbide. Furthermore, they contain high amounts of sugar (50-60%), fats, waxes, and sterines (Steinegger, Hänsel, Lehrbuch der Pharmakognosie und Phytopharmazie, Springer Verlag Berlin, Heidelberg, New York 1988, pp 608-610). Particularly, tea preparations (R. Jaspersen-Schib, DAZ 130 (1990), 71-73; F.-C. Czygan in M. Wichtl, Teedrogen WVA Stuttgart 1989, pp 495-497) as well as capsule and tablet preparations for oral administration containing simple aqueous or aqueous alcoholic extracts (Chrubasik et al., Forsch. Komplementarmed. 1996:3:57-63) are commercially available.
Recently, an antirheumatic effectivity has been shown in a clinical double-blind study. For this purpose, extracts have been employed ensuring a dosage of 50 mg of harpagoside per day (S. Chrubasik, R. Ziegler in Phytopharmaka 2—Forschung und klinische Anwendung—Loew, Rietbrock, eds., Steinkopf Verlag Danrstadt 1996 (pp 101-114)).
The conventional pharmaceutical preparations containing simple extracts show harpagoside contents of 1 to 3% (Chrubasik et al., Forsch. Komplementärmed. 1996:3:6-11) so that as high amounts of extract as 1500 to 4500 mg would be necessary to ensure an administration of 50 mg harpagoside/day. This again would require large drug formulations or a frequent or repeated intake of the preparation thereby leading to a decrease in patient compliance.
The object of the present invention is to provide novel extracts enriched in harpagoside content in which ingredients without or with undesired pharmacological effects have been depleted. It is a further object of the invention to provide methods for the preparation of such extracts as well as drug formulations containing those extracts.
The inyention is based on the surprising finding that aqueous or aqueous alcoholic primary extracts generally having a harpagoside content of only 1 to 3% may be strongly enriched in harpagoside according to the invention by stirring with neat aliphatic alcohol or aliphatic keton or mixtures thereof up to values of at least 5% while ingredients having a stimulatory effect on the synthesis of thromboxane B
2
and cysteinyl-leucotrienes are reduced or eliminated.
The term “aqueous alcoholic primary extracts” refers to extracts obtained by extracting radix harpagophyti with a mixture of water and ethanol. The aliphatic alcohols contain from 1 to 4 C atoms, the aliphatic ketons contain from 3 to 4 C atoms. Preferably, for stirring there are used methanol, ethanol, propanol, isopropanol, n-butanol, isobutanol, tert butanol, aceton, butanon and the mixtures thereof. Ethanol is especially preferred. The stirring is performed at a temperature in the range of about 5 to 25° C. The term “stirring” refers to intimate mixing by stirring.
In a preferred embodiment the ground drug is extracted with 20% ethanol/water. Subsequently a concentration step is carried out, and the resulting primary extract is stirred with ethanol 96% at room temperature. The soluble fraction is separated from the insoluble fraction and dried. It contains at least 5% of harpagoside.
In a preferred embodiment the ground drug is extracted with 20% ethanol/water. Subsequently a concentration step is carried out, and the resulting primary extract is stirred with ethanol 96% at room temperature. The soluble fraction is separated from the insoluble fraction and dried. It contains at least 5% of harpagoside.
A further surprising finding was that extracts prepared according to the method described have a higher pharmacological activity in comparison to primary extracts but also to pure harpagoside. Conventional primary extracts have been found to contain ingredients leading to a potent stimulation of the synthesis of pro-inflammatory lipid mediators and thereby counteracting the desired antiphlogistic effects. These ingredients are depleted in the extracts of the invention. The depletion or removal, respectively, of these undesired ingredients is performed by the stirring according to the invention of the primary extract with the alcohol or keton or the mixtures thereof.
The extracts according to the invention may be used to prepare orally applicable solid or liquid drug preparations having an antirheumatic and antiphlogistic activity by adding conventional pharmaceutical adjuvants in a known manner.
REFERENCES:
patent: 2031386 (1990-12-01), None
patent: 3940092 (1991-06-01), None
patent: 0 524 873 A1 (1993-01-01), None
patent: 2614791 (1988-11-01), None
English Translation of Purchase Order No. 211138, Jan. 12, 1995.
English Translation of Invoice from Salus-Haus for Purchase Order No. 211138, Nov. 12, 1995.
English Translation of Client Information regarding purchases by Salus-Haus, Oct. 12, 1992.
English Translation of Specification of the Salus-Haus product 13RT183, Nov. 1995.
English Translation of Declaration of Dr. Ernst Schneider, Mar. 15, 2000.
Chrubasik et al., (1996)Forsch Komplementarmed, vol. 3, pp. 57-63.
Purchase order no. 211138, Jan. 12, 1995.
Invoice from Salus-Haus for Purchase order No. 211138, Nov. 12, 1995.
Client Information Regarding purchases by Salus-Haus, Oct. 12, 1992.
Specification of the Salus-Haus product 13RT183, Nov. 1995.
Declaration of Dr. Ernst Schneider, Mar. 15, 2000.
Caprasse, M.,J. Pharm. Belg., 35, 2, 143-149(1980).
Mousard et al.,Chemical Abstracts, 117, p. 34, Abstract No. 117:163533z (1992).
Erdos et al.,Planta Medica, 34, 97-108, (1978).
Database WPI, Derwent Publications Ltd., Abstract of KR9205686, (Jul. 1992).
Jaggy Hermann
Koch Egon
Oschmann Rainer
Simmet Thomas
Stumpf Karl-Heinz
Dr. Willmar Schwabe GmbH & Co.
Lilling Herbert J.
McDonnell & Boehnen Hulbert & Berghoff
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