Drug – bio-affecting and body treating compositions – Nonspecific immunoeffector – per se ; or nonspecific...
Reexamination Certificate
1999-10-08
2004-06-08
Swartz, Rodney P (Department: 1645)
Drug, bio-affecting and body treating compositions
Nonspecific immunoeffector, per se ; or nonspecific...
C424S009100, C424S009200, C424S184100, C424S234100, C424S238100, C424S245100, C424S247100, C424S265100, C435S243000, C435S842000, C435S843000, C514S028000, C514S030000, C514S450000, C549S364000
Reexamination Certificate
active
06746677
ABSTRACT:
BACKGROUND OF THE INVENTION
Macrolide compounds including macrocyclic lactones such as LL-F28249&agr;-&lgr; compounds, 23-oxo or 23-imino derivatives of LL-F28249&agr;-&lgr; compounds, milbemycin compounds such as milbemycin D and milbemycin oxime, avermectin compounds such as abamectin, ivermectin and doramectin, and mixtures thereof are useful for the prevention and control of helminthiasis and infection by acarids and arthropod endo- and ectoparasites in warm-blooded animals. Subcutaneous injection of aqueous compositions is one of the preferred methods for administering those compounds.
Vaccines are used to protect warm-blooded animals from a variety of diseases and are also administered by subcutaneous injection. However, a vaccine composition containing both a macrolide compound and antigens is not known. The primary reason for the lack of such a combination vaccine is due to the fact that aqueous injectable compositions of macrolide compounds contain dispersing agents which are known to interact with proteins and affect the permeability of the outer membrane of bacterial cells. Such interaction can denature or otherwise disrupt proteins such as antigens.
GB-A-2030043 describes injectable compositions which comprise tetramisole or its levorotatory isomer and a vaccine. However, that application does not disclose a combination vaccine which includes a complex macrolide compound. Further, that application does not describe the use of a dispersing agent, an important component in aqueous macrolide injectable compositions.
It is therefore an object of the present invention to provide stable vaccine compositions comprising macrolide compounds and antigens. It is also an object to provide stable compositions of macrolide compounds in the absence of an antigen.
It is also an object of the present invention to provide a method for preventing or controlling helminthiasis, infection by acarid and arthropod endo- and ectoparasites and bacterial and viral disease in warm-blooded animals.
It is a further object of the present invention to provide a process for the preparation of stable vaccine compositions.
These and other objects and features of the present invention will become more apparent from the detailed description thereof set forth below.
SUMMARY OF THE INVENTION
The present invention relates to stable vaccine compositions. The compositions comprise, on a weight to volume basis, about 0.05% to 2.5% of a macrolide compound as hereinafter defined; about 0.1% to 6% of a water soluble organic solvent; about 1% to 8% of a dispersing agent; about 10% to 50% of an adjuvant; at least one antigen; up to about 0.1% of a preservative; and saline or water or a mixture thereof.
Surprisingly, it has been found that the vaccine compositions of the present invention are stable in the presence of a dispersing agent and may be stored for prolonged periods of time without loss of antigen and macrolide potency.
DETAILED DESCRIPTION OF THE INVENTION
In accordance with the present invention, the stable vaccine compositions comprise a macrolide compound as hereinafter defined, a water soluble organic solvent; a dispersing agent; an adjuvant; at least one antigen; optionally, a preservative, and saline or water or a mixture thereof. The invention also provides a method for protecting or controlling helminthiasis, infection by acarid and arthropod endo- and ectoparasites and disease in warm-blooded animals.
Preferred stable vaccine compositions of the present invention comprise, on a weight to volume basis, about 0.1% to 1% of an LL-F28249&agr;-&lgr; compound, a 23-oxo or 23-imino derivative of an LL-F28249&agr;-&lgr; compound, a milbemycin compound, an avermectin compound or mixtures thereof; about 0.2% to 2.5% of a water soluble organic solvent; about 2% to 7% of a dispersing agent; about 20% to 40% of an adjuvant; at least one antigen; up to about 0.1% of a preservative; and saline or water or a mixture thereof.
The macrolide compounds useful in the invention include macrocyclic lactone compounds, milbemycin compounds, avermectin compounds and mixtures thereof described below.
The macrocyclic compounds include but are not limited to those described in U.S. Pat. Nos. 5,019,589; 4,886,828; 5,108,992; 5,030,650 and 5,055,486, incorporated herein by reference.
The preferred macrocyclic lactone compounds include the compounds designated LL-F28249&agr;-&lgr; which are (collectively) isolates from the fermentation broth of the microorganism
Streptomyces cyaneogriseus
subspecies noncyanogenus, deposited in the NRRL under deposit accession No. 15773. The method for preparation of LL-F28249&agr; is disclosed in U.S. Pat. No. 5,106,994 and its continuation, U.S. Pat. No. 5,169,956, incorporated herein by reference.
The LL-F28249&agr;-&lgr; compounds are represented by the following structural formula:
LL-F28249&agr;-&lgr;
LL-F28249
R
1
R
2
R
3
R
4
R
5
R
6
R
5
+ R
6
A-B
B-C
alpha
CH(CH
3
)
2
H
CH
3
CH
3
—O—CH
2
—
CH—CH
CH═C
beta
CH
3
H
CH
3
CH
3
—O—CH
2
—
CH—CH
CH═C
gamma
CH
3
CH
3
CH
3
CH
3
—O—CH
2
—
CH—CH
CH═C
delta
CH
3
CH
3
CH
3
CH
3
OH
CH
2
OH
CH—CH
CH═C
epsilon
CH(CH
3
)
2
H
H
CH
3
—O—CH
2
—
CH—CH
CH═C
zeta
CH
2
CH
3
H
CH
3
CH
3
—O—CH
2
—
CH—CH
CH═C
eta
CH(CH
3
)
2
H
CH
3
CH
3
—O—CH
2
—
C═CH
CH—CH
theta
CH(CH
3
)
2
H
CH
3
CH
2
CH
3
—O—CH
2
—
CH—CH
CH═C
iota
CH(CH
3
)
2
H
CH
2
CH
3
CH
3
—O—CH
2
—
CH—CH
CH═C
kappa
CH
3
CH
3
CH
3
CH
3
H
CH
3
CH—CH
CH═C
lambda
CH(CH
3
)
2
CH
3
CH
3
CH
3
—O—CH
2
—
CH—CH
CH═C
The 23-oxo and 23-imino derivatives of LL-F28249&agr;-&lgr; compounds, useful in the stable vaccine compositions of this invention, are disclosed in U.S. Pat. No. 4,916,154, incorporated herein by reference.
A preferred LL-F28249&agr;-&lgr; compound and 23-imino derivative of an LL-F28249&agr;-&lgr; compound useful in the vaccine compositions of this invention have the following structural formulas:
LL-F28249&agr;
and 23-(O-methyloxime)-LL-F28249&agr; (moxidectin)
Milbemycin compounds suitable for use in the stable vaccine compositions of this invention include but are not limited to milbemycin D, milbemycin oxime and those compounds described in U.S. Pat. Nos. 3,950,360 and 4,346,171 and 4,547,520, incorporated herein by reference. Preferred milbemycin compounds for use in this invention are milbemycin D and milbemycin oxime.
Avermectin compounds which are suitable for use in the invention compositions include but are not limited to abamectin, ivermectin, doramectin and those compounds described in U.S. Pat. Nos. 4,199,569 and 4,310,519, incorporated herein by reference, with ivermectin, abamectin and doramectin being preferred. Doramectin and a method for its preparation are described in U.S. Pat. No. 5,089,480, incorporated herein by reference.
Antigens suitable for use in the compositions of the present invention include antigens derived from bacterial and viral pathogens of warm-blooded animals including but not limited to those derived by recombinant DNA technology. Preferred antigens include
Clostridium perfringens
type A, B, C and D,
Clostridium septicum, Clostridium tetani, Clostridium chauvoei, Clostridium novyi
type B,
Clostridium sordelli, Clostridium haemolytica,
Pasteurella,
Pasteurella maltocida
and
Corynebacterium pseudotuberculosis
which are used in the treatment of diseases such as Lamb dysentery, Pulpy Kidney disease (enterotoxaemia), Malignant Oedema (blood poisoning), Tetanus, Blackleg disease, Black disease, caseous lymphadenitis, and pasteurellosis.
The present invention also provides a process for the preparation of the stable vaccine compositions which comprises:
a) blending a dispersing agent with water to form a first solution;
b) adding to the first solution, a second solution comprising a macrolide compound as defined above or mixtures thereof in a water soluble organic solvent to form a third solution;
c) adding the third solution to a first suspension comprising at least one antigen, an adjuvant and a saline solution to form a second suspension; and
d) adjusting the pH of the second suspension to a
Cobb Ramune Marija
Schwartzkoff Christopher Leigh
Lences Barbara L.
Levis John F.
Renda Barbara L.
Swartz Rodney P
Wyeth Holdings Corp.
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