Drug – bio-affecting and body treating compositions – Plant material or plant extract of undetermined constitution...
Reexamination Certificate
1999-09-22
2003-05-20
Lilling, Herbert J. (Department: 1651)
Drug, bio-affecting and body treating compositions
Plant material or plant extract of undetermined constitution...
Reexamination Certificate
active
06565897
ABSTRACT:
BACKGROUND OF THE INVENTION
1. Field of the Invention
In one of its aspects, the present invention relates to an extract of a species of Nerium, particularly
Nerium Oleander,
and to a method for production thereof. In another of its aspects, the present invention relates to a pharmaceutical composition comprising an extract of a species of Nerium, particularly
Nerium Oleander,
and to a method for production thereof. The pharmaceutical composition is useful, inter alia, in the treatment of the cell-proliferative and immune deficient diseases in mammals, including cancer and AIDS.
2. Description of the Prior Art
A variety of herbal and plant extracts or preparations are available for mankind for treating any number of diseases affecting the human body [1, 4]. U.S. Pat. No. 4,986,895 [Grossman et al.] teaches the use of water soluble plant extracts in the treatment of virus skin infections. U.S. Pat. No. 5,178,865 [Ho et al.] teaches the use of Chinese herbal extracts in the treatment of HIV related disease in vitro. U.S. Pat. No. 5,482,711 [Medenica] teaches the use of the extract of the plant
Nigella Sativa
in the treatment of cancer, viral diseases and protection from side effects of chemotherapy. Many cell anti-proliferative agents are natural products of fungi, plants and marine animals, and these materials are likely to be the primary sources for anti-proliferative agents for the future. Examples of this class of agents include taxol, vincristine and camptothecin.
U.S. Pat. No. 5,135,745 [Ozel, 20], the contents of which are hereby incorporated by reference, teaches the use of the extract of the plant
Nerium Oleander
for the treatment of cell proliferation diseases in animals and humans. Ozel [20]teaches preparing the water extract of the plant
Nerium Oleander
and administering the extract to human subjects in order to ameliorate cell-proliferative diseases such as cancer. As used throughout this specification, the term “cell-proliferative disease” is intended to mean malignant as well as non-malignant cell populations which often appear morphologically to differ from the surrounding tissue. Ozel [20] teaches a screen to be used in determining whether a particular patient would be a suitable candidate to receive a therapeutic regimen of the extract. Specifically, Ozel [20] teaches initial adminstration of an injectable form of the extract following by observation to detect the onset of fever (from about 38° C. to about 41° C.) in the patient. If the fever develops, the patient is deemed to be a suitable candidate for receiving a therapeutic regimen of the extract. Thus, Ozel [20] teaches a nexus between efficacy of the extract and the onset of a fever in the patient during the screening. In other words, Ozel teaches that a patient who fails to develop a fever during the screening will not be a suitable candidate for receiving a therapeutic regimen of the extract.
The plant oleander is a well-known ornamental plant with leathery evergreen leaves and handsome clusters of red or pink or white flowers. The plant originates from the Mediterranean region and is indigenous to the Indo-Pakistan subcontinent. The plant grows as a weed in the southern part of Texas. In the Mediterranean region, the plant previously has been used for a variety of medicinal purposes. For example: (i) the macerated leaves have been used to relieve itchiness and help prevent hair from falling out, (ii) fresh leaves have been applied to treat tumors, (iii) the decoction of leaves and bark has been used to treat syphillis, and (iv) the decoction of leaves has been used as a gargle to strengthen the teeth and gums and as a nose drop for children [1-4].
Oleander is one of the digitalis-like plants. The plant has certain toxic properties due to the presence of digitoxin like steroidal glycosides. It is estimated that as many as 100 chemical substances are present in various parts of the Oleander plant. Various of the compounds that have been identified in
Nerium Oleander
set out in Table 1.
Ozel describes a procedure for the preparation of
Nerium Oleander
Extract (NOE) in water [20, 21]. The specific extraction of the plant
Nerium Oleander
taught by Ozel [20, 21] involves, cooking the leaves and stems of the plant in water for 2-3 hours and filtering off the residues. Some of the chemical constituents have been separated from the aqueous extract and have been analyzed [22]. The extract has been found to comprise several polysaccharides with very potent immune stimulating properties. The various polysaccharides identified in the aqueous NOE set out in Table 2. These polysaccharides can be mixed with various pharaceutically acceptable carriers to form injectables, capsules, tablets and various other administrative forms [22].
TABLE 1
CHEMICAL COMPOUNDS IDENTIFIED IN
NERIUM OLEANDER
No.
Compound Name
Type
Reference
1
Oleandrin
Steroid
[5]
2
Adynerin
Oleanane
[6]
3
Ursolic Acid
Oleanane
[6]
4
Kaneric Acid
Oleanane
[7]
5
Neriucoumaric Acid
Oleanane
[8]
6
Oleanderen
Oleanane
[9]
7
Oleanderol
Oleanane
[10]
8
Kamerin
Oleanane
[17]
9
Dihydroursolic Acid
Oleanane
[18]
10
Kanerocin
Oleanane
[19]
11
Oleanderolic Acid
Oleanane
[11]
12
Kanerodione
Oleanane
[11]
13
Kaneroside
Oleanane
[12]
14
Neriumoside
Oleanane
[12]
15
cis-Karenin
Oleanane
[13]
16
trans-Karenin
Oleanane
[13]
17
Pregnane Saponins
Steroids
[14-16]
18
Cardenolides Saponins
Steroids
[14-16]
TABLE 2
CHEMICAL CONSTITUENTS OF
NERIUM OLEANDER EXTRACT
Poly-
No.
saccharide
Type & Sugars
Molecular Wt.
1
PS-I
Poly &agr; (1→4) D-Galacturonic Acid
30,000-40,000
2
PS-II
Branched polymer D-Galacturonic
10,000-12,000
Acid Arabinose, Rhamnose
Galactose, Xylose Glucose
3
PS-III
Branched polymer D-Galacturonic
5,000-6,000
Acid Arabinose, Rhamnose
Galactose, Xylose Glucose
4
PS-IV
Branched polymer D-Galacturonic
2,500-3,500
Acid Arabinose, Rhamnose
Galactose, Xylose Glucose
While the extract taught by Ozel [20] is a significant advance in the art of treatment of cell-proliferative diseases in humans, there is still room for improvement. Specifically, as described above, Ozel [20] teaches that only patients who develop a fever during the screening procedure are suitable canditates to receive a therapeutic regimen of the extract. Further, there are technical problems in producing the extract in a commercially suitable form for parenteral administration using the process taught by Ozel [20]. In particular, there is a problem regarding the stability, sterility and endotoxin level of the extract during extended periods of use on human subjects. The aqueous NOE extract described in Ozel [20] is relatively unstable at room temperature over any significant period of time. In particular, the aqueous extract described in Ozel [20], loses its potency when stored at ambient temperatures.
Accordingly, it would be desirable to have an improved extract of the Nerium species which could be used with patients who do not develop a fever during initial screening. It would also be desirable if the extract itself had improved stability and could be used to produce a formulation of improved stability.
SUMMARY OF THE INVENTION
It is an object of the present invention to provide a novel extract of a species of Nerium which obviates or mitigates at least one of the above-mentioned disadvantages of the prior art.
It is another object of the present invention to provide a novel process for producing an extract of a species of Nerium.
It is yet another object of the present invention to provide a novel pharmaceutical composition which obviates or mitigates at least one of the above-mentioned disadvantages of the prior art.
It is yet another object of the present invention to provide
Ozel Huseyin Z.
Selvaraj Ulagaraj
Singh Chandra U.
Katten Muchin Zavis & Rosenman
Lilling Herbert J.
Ozelle Pharmaceuticals, Inc.
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