DESCRIPTION
FIELD OF THE INVENTION
The present invention relates to the pharmaceutical composition comprising an aminoglycoside and the protectants which reduces the Nephrotoxicity and ototoxicity.
PRIOR ART TO THE INVENTION
JP 2289522 (A) is directed to the use of selected organic acid polymer protectants to inhibit the nephrotoxicity associated with the use of antibiotic aminoglycosides. The invention also covers pharmaceutical compositions comprising such protectants and aminoglycosides for clinical use when coadministration is desired.
JP 2003261459 (A) relates to nephrotoxicity inhibitor of the aminoglucoside-based antibiotics containing a megalin (LRP-2)-binding substance consisting at least one of lysozyme, aprotinin, cytochrome C, a partial peptide of the cytochrome C and a partial peptide of N-WASP of megalin (LRP-2) substrates, and the antibacterial preparation consists of the nephrotoxicity inhibitor having the nephrotoxicity-inhibiting activity and the aminoglucoside-based antibiotic material. Especially, the aminoglucoside-based antibiotic material consists preferably of at least one of gentamicin, amikacin, kanamycin, streptomycin, tobramycin, arbekacin, isepamicin and netilmicin.
JP 4282315 (A) discloses aminoglycoside composition comprising a compound of formula I to formula II (R1 and R2 are each a 2-6C alkyl, cyclohexyl, alkoxyalkyl or hydroxyalkyl; A is a <=4C hydrocarbon group substitutable with methyl; at least one of R3 and R4 is a group of formula III and the other is H or a <=6C aliphatic hydrocarbon group which is interrupted with an oxygen atom having <= two carbon chains or is substitutable with one oxygen atom or two hydroxyl groups; R6 is a 1-3C alkyl; ; (n) is an integer of 2-5), preferably one or more compounds selected from 1,3-di-n-butyl-7-(2-oxopropyl)xanthine and 7-(3-oxobutyl)-1,3-di-n-butylxanthine and is capable of reducing nephrotoxicity of an aminoglycoside such as gentamicin, amikacin, kanamycin and neomycin, especially neomycin.

OBJECTIVES OF THE INVENTION
The object of the present invention is to provide the pharmaceutical combination for the effective treatment of various bacterial infections. Yet another object of the invention is to provide the combination of Amikacin which significantly reduces the nephrotoxicity of Amikacin. Yet another object of the invention is to provide the combination of Amikacin which significantly reduces the ototoxicity of Amikacin.
Another object of the invention is to provide safe and effective pharmaceutical combination for treating bacterial infections.
DETAILED DESCRIPTION OF THE INVENTION
Amikacin is a semisynthetic antibiotic of the aminoglycoside group. It possesses a broad antimicrobial spectrum, but the greatest activity is against the Gram-negative bacteria (E. coli, Proteus, Klebsiella) etc. The drug is active also against some staphylococcus strains (Staphylococcus epidermidis and aureus). Amikacin has a bactericidal action which is due to the inhibition of the protein synthesis in the cells of the microorganisms. It produces errors in genetic code reading during the process of translation and interferes with the ordering of amine acids in the peptic chain and leads to production of "useless proteins". The presence of a remnant of -hydroxybutyrate acid in the Amikacin's molecule makes this drug insensitive to the enzymes, produced by Pseudomonas and enterobacteria, resistant to the other aminoglycosides.
Amikacin is indicated for the treatment of infections of: central nervous system, urogenital system, biliary and intestinal tracts, skin and subcutaneous tissues, intraabdominal infections, pneumonia, caused by Gram-negative microorganisms, secondary infections after combustion, bacterial septicemia, infections of the bones and joints (caused by sensitive to Amikacin microorganisms).
Amikacin is an excellent broad spectrum antibiotic which is effective in a variety of bacterial infections caused by various microorganisms, but its use is very much limited due to its serious side effects.
There is a Black Box warning on amikacin concerning the risk of severe nerve damage, kidney problems, and permanent hearing loss that can occur during treatment and even after treatment has been stopped. Amikacin is not recommended to be used more than 14 days. Patients with preexisting kidney

problems or hearing loss may be at a higher risk for deafness, vertigo, numbness, muscle twitching, convulsions, and skin tingling side effects from this medication. Amikacin should not be used in combination with any other medications that cause nerve, kidney, or hearing problems. Patients of advanced age or those experiencing dehydration may also be at an increased risk for serious side effects.
Thus, the present invention directs to safe and effective combination of amikacin that reduces the serious side effects and makes the medication safer to the patients.
The present invention discloses the pharmaceutical combination comprising amikacin or its pharmaceutically acceptable salts, protectants preferably L-aspartic acid or L-arginine or L-glutamine, preferably L-aspartic acid and ototoxicity reducing agent N-acetyl cysteine.
L-aspartic acid is one of the non-essential amino acids commonly occurring in the L-form. It is found in animals and plants, especially in sugar cane and sugar beets. It may be a neurotransmitter. L-Aspartic Acid is widely used in food and pharmaceutical industry as an important amino acid. It is used as dietetic supplement, additive for kinds of soft drink. In medicine, it is used as ammonia detoxicating agent hepar function accelerator and fatigue refresher. Aspartic acid is one of two acidic amino acids. Aspartic acid and glutamic acid play important roles as general acids in enzyme active centers, as well as in maintaining the solubility and ionic character of proteins. Proteins in the serum are critical to maintaining the pH balance in the body; it is largely the charged amino acids that are involved in the buffering properties of proteins. Aspartic acid is alanine with one of the ß hydrogens replaced by a carboxylic acid group. The pKa of the ß carboxyl group of aspartic acid in a polypeptide is about 4.0. Note that aspartic acid has an a-keto homolog, oxaloacetate, just as pyruvate is the a-keto homolog of alanine. Aspartic acid and oxaloacetate are interconvertable by a simple transamination reaction, just as alanine and pyruvate are interconvertible.
N-Acetyl Cysteine (NAC) is a metabolite of the sulfur-containing amino acid, Cysteine. Cysteine is found in high protein foods, N-Acetyl Cysteine is not. N-Acetyl Cysteine is produced within the human body. Cysteine plays a role in the sulfation cycle, acting as a sulfur donor in phase II detoxification and as a

methyl donor in the conversion of homocysteine to methionine. Cysteine also
helps synthesize glutathione, one of the body's most important natural
antioxidants and detoxifiers. N-Acetyl-Cysteine is the acetylated form of L-
Cysteine.
N-Acetyl Cysteine is rapidly metabolized to intracellular glutathione. Glutathione
acts as a powerful antioxidant in the body. Glutathione also detoxifies chemicals
into less harmful compounds. N-Acetyl Cysteine also protects the body from
acetaminophen toxicity and is used in hospitals for patients with acetaminophen
poisoning. It has also been shown to be effective at treating liver failure from
other causes as well.
Heavy metals like lead, mercury and arsenic are detoxified and removed from
the body by N-Acetyl Cysteine . It also increases the excretion of zinc and other
essential minerals when taken over an extended period. It is therefore
necessary to supplement zinc, copper and other trace minerals when taking N-
Acetyl Cysteine.
Glutathione is known to aid in the transport of nutrients to lymphocytes and
phagocytes, two major classes of immune cells, and to protect cell membranes.
While purified glutathione is available as a dietary supplement, absorption is
low, and N-Acetyl Cysteine is thought to be a better method of boosting cellular
glutathione levels. N-Acetyl Cysteine is being investigated as a treatment for
AIDS.
N-Acetyl Cysteine cleaves disulfide bonds by converting them to two sulfhydryl
groups. This action results in the breakup of mucoproteins in lung mucus,
reducing their chain lengths and thinning the mucus, improving conditions such
as bronchitis and flu. Double-blind research has found that N-Acetyl Cysteine
supplements improved symptoms and prevented recurrences in people with
chronic bronchitis.
N-Acetyl Cysteine has been shown to reduce the proliferation of certain cells
lining the colon and may reduce the risk of colon cancer in people with recurrent
polyps in the colon. Its action as an antioxidant and a glutathione precursor may
also contribute to a protective effect against cancer.
It was found that when N acetyl cysteine was combined with amikacin, the
ototoxicity related to amikacin was reduced.

Amikacin present in the said invention ranges from 75 mg to 600 mg, preferably 100 mg to 500 mg. N-acetyl cysteine present in the said invention is 200 mg to 600 mg and L-aspartate present in the said formulation is 30 mg to 100 mg.

CLAIMS
1. A pharmaceutical formulation comprising Amikacin, N-Acetyl cysteine
and L aspartate, with the pharmaceutically acceptable excipients.
2. Amikacin, as claimed in claim 1, is present in the range from 75 mg to
600 mg, preferably 100 mg to 500 mg.
3. N-acetyl cysteine, as claimed in claim 1, is present in the range of 200
mg to 600 mg.
4. L-aspartate, as claimed in claim 1, is present in the range from 30 mg to
100 mg.
5. The pharmaceutical formulation, as claimed in claim 1, is preferably injectable formulation.