Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Carbohydrate doai
Reexamination Certificate
1999-07-02
2001-05-29
Peselev, Elli (Department: 1623)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Carbohydrate doai
C536S007400
Reexamination Certificate
active
06239112
ABSTRACT:
FIELD OF THE INVENTION
This invention relates to antibiotic compositions suitable for pharmaceutical use and in particular to water miscible solutions of macrolide antibiotics such as azalides.
BACKGROUND OF THE INVENTION
Macrolides, such as azalides, are a class of antibiotics which contain a many-membered lactone ring to which are attached one or more deoxy sugars. Macrolides are generally bacteriostatic, but have been shown to be bacteriocidal in high concentration against very susceptible organisms. Macrolides are most effective against gram-position cocci and bacilli, although they do possess some activity against some gram-negative organism. Macrolides exert their bacteriostatic activity by inhibiting bacterial protein synthesis by binding reversibly to the 50 S ribosomal subunit. (“Goodman & Gillman's the Pharmacological Basis of Therapeutics,” 9th ed., J. G. Hadman & L. E. Limbird, eds., ch. 47, pp. 1135-1140, McGraw-Hill, New York (1996)).
The macrolides as a class are colorless and usually crystalline. Macrolides, such as azalides, are generally stable in near neutral solution, but they only have limited stability in acid or base solutions. The reason for this is because the glycosidic bonds hydrolyze in acid and the lactone ring saponifies in base (“Principles of Medicinal Chemistry,” 2nd ed., W. F. Foye, ed., ch. 31, pp. 782-785, Lea & Febiger, Philadelphia (1981)). Hence, there is a need to prepare stable, water miscible pharmaceutical or veterinary compositions for parenteral, e.g., intravenous, intramuscular, subcutaneous, administration of macrolide antibiotics.
Macrolides as a class, which include azalides, are soluble in many organic solvents but are only slightly water soluble. Solutions of macrolides in organic solvent systems are used in human and veterinary practice for administration by the intramuscular and subcutaneous routes. These solutions cannot be used for intravenous administration because the macrolides precipitate when the solution is introduced into an aqueous medium as into body fluids. Aqueous solutions of salts of macrolides can be prepared but such solutions have such limited stability as to be limited to use for only a short time period after preparation.
A water miscible solution of macrolides, including azalides, which would be stable for an extended period of time would be of great value to both the medical and veterinary professions. It could be used for intravenous administration to rapidly provide therapeutic blood levels for more effective treatment of infectious diseases. A water miscible solution would also allow for more rapid absorption from intramuscular and subcutaneous injection sites leading to higher concentrations in body fluids and more effective control of infectious diseases. Such a solution would also be useful for oral administration to poultry and swine in their drinking water.
SUMMARY OF THE INVENTION
The present invention provides a stable, high potency water miscible formulation of macrolides, such as azalides. The macrolides as a class contain at least one basic nitrogen group which can be converted in non aqueous solutions into stable water miscible compositions by the addition of an acid. The resulting compositions are stable for extended periods of time and do not lead to precipitation of the macrolide, such as azalide, when introduced into an aqueous environment. The acid is added in an amount about equimolar to the number of available nitrogens present. Solutions containing as much as 40% of the macrolide, such as azalide can be prepared in this manner.
These and other embodiments are disclosed or are obvious from and encompassed by, the following Detailed Description.
DETAILED DESCRIPTION
Macrolides as a class include the erythromycin and its derivative as well as other derivatives such as the azalides. Erythromycin (MW 733.94 daltons) is the common name for a macrolide antibiotic produced by the growth of a strain of Streptomyces erythreous. It is a mixture of three erythromycins, A, B and C consisting largely of erythromycin A which is represented by the formula:
Its chemical name is (3R*,4S*,5S*,6R,7R*,9R*,11R*,12R*, 13S*,14R*)-4-[(2,6-dideoxy-3-C-methyl-3-O-methyl-&agr;-L-ribo-hexopyranosyl)-oxy]-14-ethyl-7,12,13-trihydroxy-3,5,7,9,11,13-hexamethyl-6[[3,4,6-trideoxy-3-(dimethylamino)-&bgr;-D-xylo-hexapyranosyl]oxy]oxacyclotetradecane-2,10-dione, (C
37
H
67
NO
13
).
Erythromycin has a broad and essentially bacteriostatic action against many Gram-positive and some Gram-negative bacteria as well as other organisms including mycoplasmas, spirochetes, chlamydiae and rickettsiae. In humans, it finds usefulness in the treatment of a wide variety of infections. It finds wide application in veterinary practice in the treatment of infectious diseases such as pneumonias, mastitis, metritis, rhinitis, and bronchitis in cattle, swine and sheep.
Other derivatives of erythromycins include carbomycin, clarithromycin, josamycin, leucomycins, midecamycins, mikamycin, miokamycin, oleandomycin, pristinamycin, rokitamycin, rosaramicin, roxithromycin, spiramycin, tylosin, troleandomycin, and virginiamycin. As with the erythromycins, many of these derivatives exist as component mixtures. For example, carbomycin is a mixture of carbomycin A and carbomycin B. Leucomycin exists as a mixture of components A
1
, A
2
, A
3
, A
9
, B
1
-B
4
, U and V in various proportions. Component A
3
is also known as josamycin and leucomycin V is also known as miokomycin. The major components of the midecamycins is midecamycin A and the minor components are midecamycins A
2
, A
3
and A
4
. Likewise, mikamycin is a mixture of several components, mikamycin A and B. Mikamycin A is also known as virginiamycin M
1
. Pristinamycin is composed of pristinamycins I
A
, I
B
, and I
C
, which are identical to virginiamycins B
2
, B
13
and B
2
respectively, and pristinamycin II
A
and II
B
, which are identical to virginiamycin M
1
and 26,27-dihydrovirginiamycin M
1
. Spiramycin consists of three components, spiromycin I, II, and III. Virginiamycin is composed of virginiamycin S
1
and virginiamycin M
1
. All these components may be used in this invention. Sources of these macrolides are well known to the practitioner and are described in the literature in references such as “The Merck Index,” 12th ed., S. Budarari, ed., Merck & Co., Inc., Whitehouse Station, N.J. (1996).
Azalides are semisynthetic macrolides antibiotics related to erythromycin A and exhibit similar solubility characteristics. This class includes compounds of the general structure
and the pharmaceutically acceptable salts and esters thereof, and the pharmaceutically acceptable metal complexes thereof, wherein
R
1
is
hydrogen,
hydroxy;
C
1-4
alkoxy;
formyl;
C
1-10
alkylcarbonyl, C
1-10
alkoxycarbonyl, aryloxycarbonyl, C
1-10
aralkoxycarbonyl, C
1-10
alkylsulfonyl, or arylsulfonyl wherein said C
1-10
alkyl group or aryl group is unsubstituted or substituted by 1-3 halo (F, Cl, Br), hydroxy, amino, C
1-5
acylamino or C
1-4
alkyl groups; or
unsubstituted or substituted C
1-10
alkyl, C
2-10
alkenyl or C
2-10
alkynyl wherein said substituents are independently 1-3 of
(a) aryl or heteroaryl optionally substituted by 1-3 halo (F, Cl, Br, I), C
1-4
alkyl, C
1-3
alkoxy, amino, C
1-4
alkylamino, di(C
1-4
alkyl) amino or hydroxy,
(b) heterocyclyl optionally substituted by hydroxy, amino, C
1-4
alkylamino, di(C
1-4
alkyl)amino, C
1-4
alkylcarbonyloxy or C
1-4
alkylcarbonylamino,
(c) halo (F, Cl, Br or I),
(d) hydroxy optionally acylated by a group
wherein
R
a
is hydrogen, C
1-6
alkyl, aryl, heteroaryl, aralkyl, or heteroaralkyl and
R
b
is C
1-6
alkyl or aryl,
(e) C
1-10
alkoxy,
(f) aryloxy or heterocaryloxy optionally substituted by 1-3 halo, hydroxy, amino or C
1-4
alkyl groups,
(g) amino or C
1-10
alkylamino optionally acylated by a group
or R
b
SO
2
, wherein
R
a
and
R
b
are as defined above,
(h) di(C
1-10
alkyl)amino,
(i) arylamino, heteroarylamino, aralkylamino or heteroarylakylamino wherein said aryl or heteroa
Hopponen Raymond E.
Macy Lowell R.
Williams James B.
Wilson Roger A.
Frommer William S.
Frommer & Lawrence & Haug LLP
Kowalski Thomas J.
Merial, Inc.
Peselev Elli
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