Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Carbohydrate doai
Reexamination Certificate
1999-09-29
2002-04-30
Geist, Gary (Department: 1623)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Carbohydrate doai
C514S058000
Reexamination Certificate
active
06380172
ABSTRACT:
FIELD OF THE INVENTION
This invention relates to a pharmaceutical composition comprising a lipophilic oligosaccharide antibiotic in a substantially monomeric form.
BACKGROUND OF THE INVENTION
Lipophilic oligosaccharide antibiotics such as the everninomicins, curamycins, avilamycins and flambamycins are members of the orthosomycin family of antibiotics which contain at least one acidic phenolic hydrogen, and two orthoester linkages associated with carbohydrate residues. See, A. K. Ganguly in “Kirk-Othmer, Encyclopedia of Chemical Technology” (1978), Volume 2, pp. 205-209, Third Edition, John Wiley and Sons and W. D. Ollis et al.,
Tetrahedron
(1 979), Volume 35, pp. 105-127. These lipophilic oligosaccharide antibiotics exhibit broad spectrum biological activity against gram positive and gram negative bacteria in various in vitro assays, and in vivo activity in animal models such as mice. However, the injection of these lipophilic oligosaccharide antibiotics can cause an adverse reaction syndrome in mice. The symptoms of the adverse reaction syndrome include: incoordination, ataxia, lateral recumbency, urination, hind leg rigidity, labored breathing, and cardiac arrest.
The art has experimented with the use of cyclodextrins to enhance the solubility and bioavailability of drugs to avoid the adverse reaction syndrome. Cyclodextrins are modified starches made from glucopyranose units and include &agr;-cyclodextrin consisting of six glucopyranose units, &bgr;-cyclodextrin consisting of seven glucopyranose units, and &ggr;-cyclodextrin consisting of eight glucopyranose units. The &agr;-, &bgr;- and &ggr;-cyclodextrins and derivatives thereof have an inside surface or cavity which is lipophilic and an outer surface which is hydrophilic. This combination of a hydrophobic cavity and a hydrophilic outer surface has led to the use of cyclodextrins and derivatives thereof for the molecular complexation or encapsulation of many hydrophobic and/or unstable drugs of suitable dimensions, thereby improving solubility, stability and bioavailability of such drugs. Derivatives of &agr;-, &bgr;-, and &ggr;-cyclodextrins such as the hydroxypropyl-&bgr;-cyclodextrins, are disclosed by Jozsef Szejtli in
Pharmaceutical Technology
, June 1991, pp. 36-40. Complexes of &agr;-, &bgr;-and &ggr;-cyclodextrins, mixtures and derivatives thereof are disclosed in, U.S. Pat. No. 4,983,586 to Bodor. Specifically, U.S. Pat. No. 4,983,586 discloses a method of decreasing the incidence of precipitation of a lipophilic or water labile drug occurring at/or near the injection site and/or in the lungs following parenteral administration, by parenterally administering said drug in an aqueous solution containing a large quantity, i.e., 20 to about 50 weight percent of hydroxypropyl-&bgr;-cyclodextrin.
U.S. Pat. No. 4,727,064 and
The International J. of Pharmaceutics
, (1986) 29, 73-82 disclose the use of a concentrated, i.e., 40-60 weight percent, aqueous solution of hydroxypropyl-&bgr;-cyclodextrin to solubilize various drugs such as acetaminophen, sex steroids, cardiac glycosides such as digoxin, as well as retinoic acid and acid salts thereof. See also, Pitha, U.S. Pat. No. 4,596,795 which discloses the administration of testosterone, progesterone and estradiol as complexes with poly-&bgr;-cyclodextrin or hydroxypropyl-&bgr;-cyclodextrin.
Janssen Pharmaceutica N.V. International Patent Application No. PCT/EP84/00417 published under International Publication No. WO 85/02767 on Jul. 4, 1985 discloses pharmaceutical compositions comprising complexes of drugs which are unstable or only sparingly soluble in water with partially etherified &bgr;-cyclodextrin (“&bgr;-CD”) of the Formula (&bgr;-CD)-OR wherein the residue R is hydroxyethyl, hydroxypropyl, dihydroxypropyl and part of the residue R may optionally be alkyl groups, especially methyl or ethyl.
U.S. Pat. No. 5,624,914 teaches lipophilic oligosaccharide compositions, containing a lipophilic oligosaccharide antibiotic, NMG, cyclodextrins, a non-ionic surfactant, and optionally mannitol, sodium chloride, or glucose which are useful in avoiding the adverse reaction syndrome. Finally, U.S. Pat. No. 5,776,912 discloses oligosaccharide antibiotic compositions containing said oligosaccharide antibiotic, human serum albumin as a binding agent and optionally a tonicity agent such as mannitol. Said compositions avoid the adverse reaction syndrome. The human serum albumin is said to be a cheaper, generally recognized as safe (GRAS) alternative to cyclodextrins.
Surprisingly, Applicants have discovered an oligosaccharide antibiotic composition wherein said oligosaccharide antibiotic is in a substantially monomeric form. Said substantially monomeric form prevents the occurrence of the adverse reaction syndrome.
DEFINITIONS AND USAGES OF TERMS
The term “particles of monomeric form”, as used herein, means that the oligosaccharide antibiotic is in particle form, and said particles have a hydrodynamic radius of about 5 to 50 Angstroms (Å). Specifically, said particles of monomeric form have a hydrodynamic radius of about 5 to 50 Å, preferably 7 to 40 Å; most preferably 10 to 30 Å.
The term “substantially monomeric”, as used herein means that the particles of monomeric form contribute 35% to 100% of the total intensity of the linewidth distribution function. This means that about 80 to 100% of the drug by weight is present in particles of monomeric form. The remaining drug is present in other forms (dimer, trimer, multimer).
The term “tonicity agent”, as used herein, means an agent which allows the pharmaceutical compositions of the present invention to have an osmolarity compatible with human serum. Typically, suitable tonicity agents, which may be present in the pharmaceutical compositions of the present invention, include mannitol, sodium chloride, glycine and dextrose. The preferred tonicity agent (when one is used) is mannitol but any pharmaceutically acceptable tonicity agent would also be acceptable.
The term “uniformity agent”, as used herein, means a compound that increases the relative population of monomers in solution. Uniformity agents can be surfactants such as the nonionic, cationic, anionic, and amphoteric surfactants.
The terms “amphoteric” and “zwitterionic” are used interchangeably herein.
The terms “particles of monomeric form” and “monomeric form” are used interchangeably herein.
All percentages are weight percentages unless otherwise indicated.
SUMMARY OF THE INVENTION
The present invention relates to an aqueous pharmaceutical composition comprising an oligosaccharide antibiotic in substantially monomeric form.
DETAILED DESCRIPTION OF THE INVENTION
The present invention relates to an aqueous pharmaceutical composition comprising an oligosaccharide antibiotic in substantially monomeric form.
Specifically, Applicants' composition, wherein the antibiotic is blended with selected bases, tonicity agents, uniformity agents, and cyclodextrins, stabilizes the antibiotic in solution in a substantially monomeric form. In its substantially monomeric form 80-100% of the antibiotic is in monomeric form. The substantially monomeric form of the oligosaccharide antibiotic in the present invention maintains the antibiotic in soluble form. Specifically, the oligosaccharide antibiotic is maintained in particles of monomeric form having a hydrodynamic radius of 5-50 Å. Thus, the adverse reaction syndrome is avoided because the antibiotic does not aggregate and it stays in solution.
The “substantially monomeric” nature of the oligosaccharide of the present invention is experimentally measured using quasielastic light scattering technique. Quasielastic light scattering, is also known as photon correlation spectroscopy (PCS), as described in Madani and Kaler (Part. Part. Syst. Charact., Vol. 8, pp. 259-266, (1991)), Berne and Pecora (“Dynamic Light Scattering”, John Wiley, New York, 1976) and/or D. H. Everett (“Basic Principles of Colloid Science”, Royal Society of Chemistry, London, 1988). This can be accomplished using a variety of commercially a
Ganguly Ashit Kumar
Kaler Eric W.
McNemar Charles W.
Reichert Paul
Weber Patricia C.
Albanese Peggy
Geist Gary
Korsen Elliott
Schering Corporation
White Everett
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