Stable compositions for parenteral administration and their use

Details Stable compositions for parenteral administration and their use Stable compositions for parenteral administration and their use

1994-06-22

2002-01-22

Fonda, Kathleen Kahler (Department: 1623)

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

Carbohydrate doai

C514S012200, C514S030000, C514S450000, C514S964000, C514S965000, C424S490000, C424S493000, C424S502000

Reexamination Certificate

active

06340671

ABSTRACT:

BACKGROUND OF THE INVENTION
Macromolecules such as LL-F28249&agr;-&lgr; compounds, 23-oxo and 23-imino derivatives of LL-F28249&agr;-&lgr; compounds, milbemycin compounds and avermectin compounds are useful for the prevention and treatment of infections and infestations caused by helminths, nematodes, acarids and endo- and ectoparasitic arthropods when parenterally administered to warm-blooded animals. Parenteral compositions are sterilized prior to administration to an animal. Gamma radiation is an effective sterilization process for eliminating microbial contaminants. However, certain macromolecules such as LL-F28249&agr;-&lgr; compounds, 23-oxo and 23-imino derivatives of LL-F28249&agr;-&lgr; compounds, milbemycin compounds and avermectin compounds degrade and lose much of their biological activity when irradiated. This destructive and degradative response to gamma radiation precludes the use of gamma radiation as a means to sterilize certain macromolecule-containing compositions.
It is an object of the present invention to provide stable compositions which can be irradiated that are useful for the prevention or treatment of infections and infestations caused by helminths, nematodes, acarids and endo- and ectoparasitic arthropods when parenterally administered to warm-blooded animals.
It is also an object of this invention to provide a method for introducing and maintaining levels of LL-F28249&agr;-&lgr; compounds, 23-oxo and 23-imino derivatives of LL-F28249&agr;-&lgr; compounds, milbemycin compounds and avermectin compounds in the blood of warm-blooded animals for extended periods of time.
SUMMARY OF THE INVENTION
The present invention relates to stable microsphere compositions which can be irradiation sterilized for parenteral administration. The compositions comprise, on a weight basis, about 20% to 95% of a fat, a wax or a mixture thereof, about 1% to 50% of an LL-F28249&agr;-&lgr; compound, a 23-oxo or 23-imino derivative of an LL-F28249&agr;-&lgr; compound, a milbemycin compound or an avermectin compound, 0 to about 30% of an oil, semi-soft fat, fatty acid derivative or mixtures thereof and about 0.001% to 10% of an antioxidant.
Surprisingly, it has been found that the microsphere compositions of the invention can be sterilized by gamma radiation without degradation of its biological activity. Also unexpectedly, the microsphere compositions can achieve an effective sustained release effect of the water-insoluble, complex macrolides.
DETAILED DESCRIPTION OF THE INVENTION
In accordance with the present invention, the stable, slow release microsphere compositions comprise an LL-F28249&agr;-&lgr; compound, a 23-oxo or 23-imino derivative of an LL-F28249&agr;-&lgr; compound, a milbemycin compound or an avermectin compound; a fat, a wax or a mixture thereof; an antioxidant and, optionally, an oil, a semi-soft fat, a fatty acid derivative or a mixture thereof. The microsphere compositions are parenterally administered by dispersion in a pharmaceutically and pharmacologically acceptable liquid vehicle. The invention also provides a method for introducing and maintaining blood levels of an LL-F28249&agr;-&lgr; compound, a 23-oxo or 23-imino derivative of an LL-F28249&agr;-&lgr; compound, a milbemycin compound or an avermectin compound in warm-blooded animals for an extended period of time.
Preferred stable microsphere compositions of the invention comprise, on a weight basis, about 50% to 90% of a fat, a wax or a mixture thereof; about 5% to 25% of an LL-F28249&agr;-&lgr; compound, a 23-oxo or 23-imino derivative of an LL-F28249&agr;-&lgr; compound, a milbemycin compound or an avermectin compound; 0 to about 20% of an oil, a semi-soft fat, a fatty acid derivative or mixtures thereof and about 0.01% to 5% of an antioxidant.
The compounds designated LL-F28249&agr;-&lgr; 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, which are incorporated herein by reference thereto.
The LL-F28249&agr;-&lgr; compounds are represented by the following structural formula:
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 microsphere compositions of this invention, are disclosed in U.S. Pat. No. 4,916,154 which is incorporated herein by reference thereto.
A preferred LL-F28249&agr;-&lgr; compound and 23-imino derivative of an LL-F28249&agr;-&lgr; compound useful in the microsphere compositions of this invention have the following structural formulas:
and
The wax of the present invention may be defined as set forth in Hawley's
The Condensed Chemical Dictionary
, Eleventh Edition, as a low-melting organic mixture or compound of high molecular weight, solid at room temperature and generally similar in composition to fats and oils except that it contains no glycerides. Some are hydrocarbons; others are esters of fatty acids and alcohols. These compounds include saturated or unsaturated long chain C
10
-C
24
fatty acids, alcohols, esters, salts, ethers or mixtures thereof. They are classed among the lipids. Waxes are thermoplastic, but since they are not high polymers, they are not considered in the family of plastics. Common properties are water repellency; smooth texture; nontoxicity; freedom from objectionable odor and color. They are combustible and have good dielectric properties. They are soluble in most organic solvents and are insoluble in water. The major types are as follows:
I. Natural
1. Animal (beeswax, lanolin, shellac wax, Chinese insect wax)
2. Vegetable (carnauba, candelilla, bayberry, sugar cane)
3. Mineral
(a) Fossil or earth waxes (ozocerite, ceresin, montan)
(b) petroleum waxes (paraffin, microcrystalline) (slack or scale wax)
II. Synthetic
1. Ethylenic polymers and polyol ether-esters (Carbowax®, registered trademark of Union Carbide Corp., New York, N.Y.)
2. Chlorinated naphthalenes
3. Hydrocarbon type via Fischer-Tropsch synthesis
The fat of the invention may be defined as set forth in Hawley's
The Condensed Chemical Dictionary
, Eleventh Edition, as a glyceryl ester of higher fatty acids such as stearic and palmitic. Such esters and their mixtures are solids at room temperatures and exhibit crystalline structure. Lard and tallow are examples. The term “fat” usually refers to triglycerides specifically, whereas “lipid” is all-inclusive.
The fat is preferably a hard fat composed of mono-, di- or triglyceryl esters of long chain C
10
-C
24
fatty acids. The mono-, di- or triglycerides are composed predominantly of stearates, palmitates, laurates, linoleates, linolenates, oleates, and residues or mixtures thereof; those having melting points greater than 50° C. are most preferred (i.e. a “higher melting” fat). Glyceryl tristearate is a most preferred fat. Additionally, lipophilic salts of fatty acids such as magnesium stearate and the like are also suitable.
The oil, semi-soft fat or fatty acid derivative of the invention are agents which are soluble in the molten hard fat and which accelerate physical transformation of the hard fat crystal from less stable forms to more stable forms at or near room temperature after the molten hard fat or wax solidifies. Preferably, the oil or semi-soft fat may include mixtures or relativ

Affiliated with

Also associated with

Rating

Stable compositions for parenteral administration and their use does not yet have a rating. At this time, there are no reviews or comments for this patent.

If you have personal experience with Stable compositions for parenteral administration and their use, we encourage you to share that experience with our LandOfFree.com community. Your opinion is very important and Stable compositions for parenteral administration and their use will most certainly appreciate the feedback.

Rate now

Comments { 0 }

Profile ID: LFUS-PAI-O-2842772