Polygala senega compositions and methods of use

Details Polygala senega compositions and methods of use Polygala senega compositions and methods of use

1998-08-06

2001-06-05

Page, Thurman K. (Department: 1615)

Drug, bio-affecting and body treating compositions

Preparations characterized by special physical form

Implant or insert

C424S435000, C424S195110, C424S278100, C530S214000

Reexamination Certificate

active

06241995

ABSTRACT:

TECHNICAL FIELD
The present invention relates generally to adjuvants for use in pharmaceutical compositions. In particular, the invention relates to
Polygala senega
saponin adjuvant compositions and methods of using the same.
BACKGROUND OF THE INVENTION
Many vaccine compositions include immunological adjuvants in order to increase antigenic potency. Immunological adjuvants act to augment cell-mediated and humoral immune responses. Such adjuvants include depot adjuvants, compounds which adsorb and/or precipitate administered antigens and which serve to retain the antigen at the injection site. Typical depot adjuvants include aluminum compounds and water-in-oil emulsions. However, depot adjuvants, although increasing antigenicity, often provoke severe persistent local reactions, such as granulomas, abscesses and scarring, when injected subcutaneously or intramuscularly. Other adjuvants, such as lipopolysacharrides and muramyl dipeptides, can elicit pyrogenic responses upon injection and/or Reiter's symptoms (influenza-like symptoms, generalized joint discomfort and sometimes anterior uveitis, arthritis and urethritis). Accordingly, there is a continued need for effective and safe adjuvants for use in a variety of pharmaceutical compositions.
Saponins are high molecular weight, glycosidic, natural plant surfactants, consisting of an aglycone ring linked to one or more sugar chains. Although saponins share common properties, they are structurally diverse. For example, the aglycone can be steroid, triterpenoid or a steroidalalkaloid and the number of sugars attached to the glycosidic bonds varies greatly.
Numerous pharmacological properties have been attributed to saponins, including anti-inflammatory (Shibata, S. (1977) in
New Natural Products and Plant Drugs with Pharmacological, Biological or Therapeutic Activity
(Wagner, H. and Wolff, P. eds, Springer, Berlin) pp. 177-196); antiviral (Amoros et al.,
Antiviral Res
. (1987) 8:13-25); molluscicidal (Hostettmann, K., Helv.
Chim. Acta
. (1980) 63:606-609); contraceptive (Bhargava, S. K.,
Int. J. Crude Drug Res
. (1988) 26:229-233); antibacterial (Chowdhury et al.,
J. Bangladesh Acad. Sci
. (1987) 11:75-82); and fungicidal activities (Anisimov et al.,
Izv. Akad. nauk SSSR, Ser. Biol
. (1979), 570-575 (Chem. Abstr. 107:108725).
More recently, saponins have been found to exhibit adjuvant and immunostimulating properties. See, e.g., Kensil et al.,
J. Immunol
. (1991) 146:431-437. For example, the triterpene glycoside saponins extracted from the South American tree,
Quillaja saponaria
, termed Quil A (U.S. Pat. No. 5,057,540; International Publication No. WO 88/09336, published Dec. 1, 1988) have been used as immunological adjuvants in vaccine compositions against a variety of infectious diseases.
Roots of the plant Polygala senega (commonly known as “snakeroot”), contain at least 6-10 triterpenoid saponins. Hostettmann and Marston, 1995 in
Chemistry and Pharmacology of Natural Products: Saponins
(Phillipson, J. D., ed. Cambridge University Press, New York) p. 323, the main saponins being senegin II, III and IV (Shoji et al.,
Chem. Pharm. Bull
. (1973) 21:791-799; Tsukitani and Shoji,
Chem. Pharm. Bull
. (1973) 21:1564-1574; and Yoshikawa et al.,
Chem. Pharm. Bull
. (1995) 43:350-352. These saponins differ from Quil A saponins in (a) the number of sugars present in the side chains of the molecules, and (b) the presence of different functional groups in the triterpenoid aglycone. Thus, the
P. senega
saponins are chemically distinct from the
Quillaja saponaria
saponins.
P. senega
saponins have been reported to exhibit hypoglycemic effects (Kako, et al.,
Biol. Pharm. Bull
. (1995) 18:1159-1161 and Yoshikawa et al.,
Chem. Pharm. Bull
. (1995) 43:2115-2122); reduce blood triglyceride levels (Masuda et al.,
Biol. Pharm. Bull
. (1996) 19:315-317); and reduce alcohol absorption (Yoshikawa et al.,
Chem. Pharm. Bull
. (1995) 43:350-352 and Yoshikawa et al.,
Chem. Pharm. Bull
. (1995) 43:2115-2122). However, the use of Polygala senega saponins as immunological adjuvants has not been previously described.
DISCLOSURE OF THE INVENTION
The present invention is based on the surprising discovery that
P. senega
saponins are able to act as immunological adjuvants to enhance immune responses to a co-administered antigen.
In one embodiment, the subject invention is directed to a composition comprising:
(a) a
P. senega
saponin extract comprising at least one
P. senega
saponin capable of potentiating an immunological response;
(b) a selected antigen; and
(c) a pharmaceutically acceptable vehicle.
In another embodiment, the invention is directed to a composition comprising:
(a) a
P. senega
saponin extract comprising at least one
P. senega
saponin capable of potentiating an immunological response, wherein said
P. senega
saponin extract is obtained by a method comprising:
(i) providing roots of a
P. senega
L plant;
(ii) extracting a crude saponin mixture from the roots with methanol;
(iii) extracting the crude mixture from (ii) with n-butanol;
(iv) performing column chromatography on the butanolic extract; and
(v) obtaining fractions from step (iv) with hemolytic activity;
(b) a selected antigen; and
(c) a pharmaceutically acceptable vehicle.
In other embodiments, the invention is directed to methods for stimulating an immunological response in a vertebrate subject. The methods comprise administering an effective amount of the pharmaceutical compositions above to the subject.
In another embodiment, the invention is directed to a method for stimulating an immunological response in a vertebrate subject, wherein the
P. senega
saponin, comprising at least one
P. senega
saponin capable of potentiating an immunological response, can be administered with the antigen or administered in a separate composition.
In still a further embodiment, the invention is directed to a method of making a composition. The method comprises combining a
P. senega
saponin extract comprising at least one
P. senega
saponin capable of potentiating an immunological response, with a selected antigen.
These and other embodiments of the present invention will readily occur to those of ordinary skill in the art in view of the disclosure herein.


REFERENCES:
patent: 4501734 (1985-02-01), Tanaka et al.
patent: 5057540 (1991-10-01), Kensil et al.
patent: 5700787 (1997-12-01), Tzianabos et al.
patent: 2 202 683A (1974-05-01), None
patent: WO 88/09336 (1988-12-01), None
Amoros et al., “in vitro Antiviral Acitivity of a Saponin fromAnagallis Arvensis, Primulaceae, Against Herpes Simplex Virus and Polivirus,”Antiviral Res.8:13-25 (1987).
Anisimov et al., “Chemical Structure and Antifungal Activity of a Number of Triterpenoids,”Izv. Akad. Nauk SSSR, Ser. Biol. Chem.Abstr. 107: 570-575, 108725 (1979).
Bhargava, S.K., “Antifertility Effects ofSapindus TrifoliatusL. Fruit Extract in Rats,”Int. J. Crude Drug Res.26:229-233 (1988).
Chowdhury et al., “Biological Activity of the Alcohol Extract and the Glycosides ofHydrocotile AsiaticaLinn.,”J. Bangladesh Academy Science11:75-82 (1987).
Hostettmann, Kurt, “Saponins with Molluscicidal Activity fromHedera HelixL.,” Helv. Chim. Acta. 63:606-609 (1980).
Hostettmann and Marston, 1995 inChemistry and Pharmacology of Natural Products: Saponins(Phillipson, J.D., ed. Cambridge University Press, New York) p. 323.
Kako et al., “Effect of Senegin-II On Blood Glucose in Normal and NIDDM Mice,”Biol. Pharm. Bull.18(8):1159-1161 (1995).
Kenarova et al., “Immunomodulating Acitivity of Ginsenoside RG fromPanax Ginseng,” Japan J. Pharmacol.54:447-454 (1990).
Kensil et al., “Separation and Characterization of Saponins with Adjuvant Activity fromQuillaja saponariaCortex,”The Journal Immunol.146:431-437 (1991;.
Masuda et al., “Intraperitoneal Administration of Senegae Radix Extract and Its Main Component, Senegin-II, Affects Lipid Metabolism in Normal and Hyperlipidemic Mice,”Biol. Pharm. Bull.19(2):315-317 (1996).
Mita et al., “Enhancement and Suppression of IgM-Antibody in Mice Treated With Purified Saponins,”Biomedicine31(8):223

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