COMPLETE DESCRIPTION

FIELD OF THE INVENTION
The present invention relates to the pharmaceutical dosage form comprising a cephalosporin and a macrolide, which shows the synergistic effect against the infection caused by a variety of microorganisms.
BACKGROUND OF THE INVENTION
The first macrolide antibiotic, erythromycin, was isolated in 1952 from products produced by Streptomyces erythreus. In 1991, two semisynthetic derivatives of erythromycin, azithromycin and clarithromycin , were brought to market. These new agents possess distinct advantages over erythromycin.
Study showed an excellent in vitro activity of azithromycin against Salmonella and Shigella species . Because of its good intracellular activity and relatively low MICs for enteropathogens, this drug may become an important addition to our antimicrobial strategies for the treatment of typhoid fever and also for bacillary dysentery(1).
Another study showed that the single-dose Azithromycin regimen was well tolerated and eradicated the estimated and potential pathogens of nongonococcal urethritis(2).
In mice and in small clinical trials, the causal prophylactic activity of azithromycin appears to be equal to or somewhat better than that of the clinical agent doxycycline. Drugs of the tetracycline class are contraindicated for young children and women with reproductive potential because of interference with skeletal and tooth development. Thus, an additional advantage of azithromycin is that it can be used in a more general patient population than that which can receive tetracyclines. On the other hand, azithromycin is licensed for short-term use, and side effects in

humans because of chronic dosing are as yet unreported. Nevertheless, the activity of azithromycin in comparison with that of doxycycline suggests that azithromycin may have a clinical role in causal prophylaxis against malaria. If causal activity is insufficient, the suppressive prophylactic activity evidenced here and the blood schizonticidal activities demonstrated in other experiments suggest that azithromycin, like the tetracyclines, may have potential as a combined causal and suppressive prophylactic agent(3).
In a study done on cefixime shows that high efficacy and low incidence of side effects make cefixime a drug of choice for treatment of respiratory tract infections(4).
A Comparison of Single-dose Oral Azithromycin with Azithromycin and Cefixime for treatment of uncomplicated gonococcal urethritis shows that Single-dose oral azithromycin and cefixime is a better alternative then only azithromycin for treatment of uncomplicated gonococcal urethritis (5).
The study regarding the administration of both the drugs is available in the prior art, but has the following shortcomings-
a) The drugs present in the combination are administered one after the other and are not administered simultaneously, thereby lowering the chances of their synergistic action.
b) The patient has to take the medicine in the form of two tablets taken one after the other, thereby increasing the patient''s inconvenience.
c) These drugs are not available for the use of general public in the convenient dosage formulation.
OBJECTIVES OF THE INVENTION
The objective of the invention is to provide a combination which is effective against a large number of microorganisms.
Yet another objective of the invention is to minimize the bacterial resistance against the antimicrobial agents.

It is an object of the invention to provide particles comprising Cefixime and Azithromycin which are suitable for the preparation of stable pharmaceutical compositions of Cefixime and Azithromycin.
The present invention also relates to providing the high efficacy formulation to the general public which will be a cost effective option to treat various bacterial infections.
Another object of the present invention is to improve the patient''s compliance.
DESCRIPTION OF THE INVENTION
Rationale of the present invention is as follows-
Typhoid fever is endemic in India. Typhoid fever has the potential to cause complications like Gl bleeding, intestinal perforation, peritonitis etc. Hence it is important that typhoid fever be treated aggressively.
Currently fluoroquinolones and cephalosporins are commonly used in the management of typhoid. As has been said earlier, the resistance to fluoroquinolones is increasing. Recent reports of ciprofloxacin resistance in enteric fever emerged from the Indian subcontinent, where Nalidixic acid resistant Salmonella typhi is endemic7. Clinically it will be very difficult to identify MDR typhoid. Hence many clinicians prefer to use two antibiotics.
Cefixime has been used both in adults and in children for the management of typhoid fever. In fact cefixime is recommended as empiric therapy in the treatment of typhoid. The dose of cefixime suggested in adults is 200-400 mg OD/BID.
Another drug which is commonly used is Azithromycin. Like Cefixime even Azithromycin is recommended to be used in adults and children. In adults, Azithromycin is recommended as empirical treatment (1g per day orally for 5days) as well as in Multidrug-Resistant fever (1g per day orally for 5days or alternately 1g on day 1 followed by 500 mg/d PO for 6 days).
In management of typhoid fever it is important that the drugs used are safe and do not have major adverse effects. Cefixime and Azithromycin are commonly prescribed in the treatment of typhoid fever. Textbook of

Medicine and Pediatrics recommend the use of Azithromycin and cefixime in the treatment of typhoid fever. Both Cefixime and Azithromycin are effective and safe in typhoid fever, and lack the adverse effects of Chloramphenicol (Bone marrow toxicity).
We propose to introduce a combination of Cefixime 200 mg with Azithromycin.500 mg. The proposed dose is 2 tabs OD for 5 days to be used whenever the doctor uses both these drugs separately. The treatment may be followed by plain cefixime as needed. The advantage of this combination is
1. Combination of two effective and safe drugs in typhoid
2. The combination will have the potential to produce faster clinical cure
3. The mode of action of both drugs is different (Cefixime acts on the bacterial cell wall, while Azithromycin acts on Ribosomes) and the combination has the potential to produce synergy. In fact the combination has shown synergy against Neiserria gonorrheae (In vitro activity of Cefixime against N. gonorrhoeae can be enhanced in combination with Azithromycin).
4. Improved patient compliance with the combination- patient has to take only one tablet as against two if prescribed separately
Azithromycin retains the activity of erythromycin against gram-positive organisms but offers increased gram-negative coverage over erythromycin and clarithromycin. It has been demonstrated to be more active than clarithromycin against H. influenzae. However, it has variable activity against the family Enterobacteriaceae. Nonetheless, Salmonella and Shigella species have been shown to be susceptible, as have other diarrheal pathogens such as Yersinia and Campylobacter. Like clarithromycin, azithromycin also has good activity against Legionella and Mycoplasma species. A unique feature of azithromycin is its excellent activity against sexually transmitted pathogens, especially Chlamydia trachomatis.

Azithromycin is indicated for the treatment of mild to moderate infections caused by susceptible strains of the designated microorganisms in the following conditions:
• Acute bacterial exacerbations of chronic obstructive pulmonary disease due to Haemophilus influenzae, Moraxella catarrhalis, or Streptococcus pneumoniae.
• Community-acquired pneumonia of mild severity due to Streptococcus pneumoniae or Haemophilus influenzae
• Streptococcal pharyngitis/tonsillitis due to Streptococcus pyogenes
• Uncomplicated skin and skin structure infections due to Staphylococcus aureus, Streptococcus pyogenes, or Streptococcus agalactiae
• Non-gonococcal urethritis and cervicitis due to Chlamydia trachomatis
• Disseminated Mycobacterium avium complex Disease
Beta - Lactam antibiotics are among the safest and the most frequently prescribed agents in India and worldwide. However, emergence of beta-lactam resistance coupled with extended spectrum betalactamase (ESBL) in clinically important pathogens have increasingly limited their use.
The emergence of ESBL producing Enterobacteriaceae, particularly Escherichia Choli and Klebsiella pneumonia, presents significant diagnostic and therapeutic challenges to the management of infection due to these organisms. ESBL bacteria that produce ESBL enzymes and that mediate resistance to extended spectrum cephalosporins. The presence of ESBL producing organism in a clinical infection can result in treatment failure if one of the above classes of the drug is used.
Cefixime is highly effective against enterobacteriaceae, H.influenzae, Strep, pyogenes, Streptococcus pneumoniae, and is resistant to various'' B-lactamases. However, it is not active on Staphhylococcus aureus and Pseudomonas.
Antibiotics were first discovered through a providential experiment by Alexander Fleming in 1928. His work eventually led to the large-scale

production of penicillin from the mold Penicillium notatum in the 1940s. As early as the late 1940s resistant strains of bacteria began to appear. Currently, it is estimated that more than 70% of the bacteria that cause hospital-acquired infections are resistant to at least one of the antibiotics used to treat them.
Antibiotic resistance continues to expand for a multitude of reasons, including over-prescription of antibiotics by physicians, non-completion of prescribed antibiotic treatments by patients, use of antibiotics in animals as growth enhancers (primarily by the food industry), increased international travel, and poor hospital hygiene.
The present invention relates to the pharmaceutical comprising the pharmaceutically accepted salts of Azithromycin and Cefixime and there formulation thereof.
The present invention comprises of the formulation comprising pharmaceutically acceptable salts of Azithromycin and cefixime and the required excipients thereof and the process of preparing the formulation.
The azithromycin used in the formulation is in the range of 50mg to 1500mg, preferably 200mg to 100mg, more preferably 250 mg to 500mg.
The cefixime used in the present formulation is in the range of 50 mg to 500 mg, preferably 100 mg to 450mg, more preferably 300 mg to 400 mg.
Suitable fillers may be microcrystalline cellulose, powdered cellulose, lactose, starch, pregelatinized starch, or sucrose preferably microcrystalline cellulose and lactose.
Suitable binders are starch, polyvinylpyrrolidone, alginic acid, methylcellulose, hydroxyethyl cellulose, hydroxypropyl cellulose, hydroxypropyl methylcellulose, polymethacrylates, and others preferably hydroxypropyl cellulose, hydroxypropyl methylcellulose and polyvinylpyrrolidone.
Suitable disintegrants are starch, pregelatinized starch, sodium starch glycolate, sodium carboxymethylcellulose, cross-linked sodium carboxymethylcellulose, cross-linked polyvinylpyrrolidone, alginic acid,

sodium alginate, and others preferably sodium starch glycolate, cross-linked sodium carboxymethylcellulose and cross-linked polyvinylpyrrolidone.
Suitable glidants are magnesium stearate, calcium stearate, aluminium stearate, stearic acid, palmitic acid, cetanol, stearol, colloidal silicon dioxide, talc, powdered cellulose, starch and others, preferably, colloidal silicon dioxide.
Suitable lubricants are stearic acid, calcium, magnesium, zinc or aluminium stearate, siliconized talc, glycerol monostearate, and others. Preferred lubricants are calcium or magnesium stearate and stearic acid.
The release of cefixime and azithromycin from the pharmaceutical formulations of the present invention can be immediate or modified, controlled, delayed, sustained, and extended. The release rate for both active drugs can be the same or different.
The pharmaceutical formulations of the present invention may comprise formed particles with the same composition or formed particles with different composition and different release rate of cefixime and azithromycin.
The present invention can be, but not limited to, manufactured through the following process-
1) Following ingredients are weight accurately for tablet-
(Table Removed)
References:
(1) Indian Journal of Medical Microbiology Year: 2009 | Volume : 27 | Issue:
2 | Page: 107-110 (2) Clinical efficacy of azithromycin for male nongonococcal urethritis, Journal
of Infection and Chemotherapy, Volume 14, Number 6 / December, 2008 (3) Antimicrobial agents and chemotherapy, aug. 1994, p. 1862-1863 <4) Infection, Volume 23, Supplement 2 / March, 1995 (5) Rahman M, Hoque M, Mamun SA, Rahman ZA, Sultan Z; International
Conference on AIDS (15th : 2004: Bangkok, Thailand). Int Conf AIDS.
2004 Jul 11-16; 15: abstract no. ThPeC7345.

CLAIMS
1) A pharmaceutical formulation comprising 50 mg to 400 mg of Cefixime, preferably 100 to 200 mg, and Azithromycin 50 mg to 400 mg, preferably 100 to 200 mg, along with pharmaceutically acceptable excipients; useful for the treatment of a variety of bacterial infections.
2) The pharmaceutically acceptable excipients claimed in 1 are selected from diluents, binding agents, disintegrants, and lubricants.
3) The diluents as claimed in claim 2 can be selected from lactose, sucrose, glucose, mannitol, sorbitol, calcium carbonate, and magnesium stearate.
4) The binding agents as claimed in claim 2 can be selected from polyvinylpyrrolidone (PVP), Hydroxy propyl cellulose, polyethylene glycol (PEG), xylitol, sorbitol and maltitol which are mixed with the appropriate solvent.
5) The solvent as claimed in claim 4 can be selected from purified water or isopropyl alcohol or the mixture of both.
6) The disintegrants as claimed in claim 2 can be selected from polyvinylpyrrolidone (crospovidone), crosslinked sodium carboxymethyl cellulose (croscarmellose sodium) and sodium starch glycolate.
7) The lubricants as claimed in claim 2 can be selected from talc or silica, and fats, e.g. vegetable stearin, magnesium stearate or stearic acid.
8) The formulation as claimed in claim 1 can be coated with Hydroxypropyl Methyl Cellulose, along with suitable plasticizer, opacifier, coloring agent and the solvent.
9) A pharmaceutical formulation as claimed in claim 1 can be obtained by the steps as follows-
(Table Removed)