FORM 2
THE PATENT ACT 1970
(39 of 1970)
&
The Patents Rules, 2003
COMPLETE SPECIFICATION
(See section 10 and rule13)
1. TITLE OF THE INVENTION:
IMPROVED SEQUENTIAL STEP DOWN THERAPY FOR TREATING RESISTANT BACTERIAL INFECTIONS CAUSED BY ESBLs PRODUCING STRAIN.
2. APPLICANT (S)
(a) NAME: WOCKHARDT LTD.
(b) NATIONALITY: INDIAN
(c) ADDRESS: Wockhardt Towers, Bandra-Kurla Complex, Bandra
(East), Mumbai -400 051.
3. PREAMBLE TO THE DESCRIPTION
The present invention provides method of treating resistant bacterial infections caused by Extended Spectrum Beta-Lactamase (ESBLs) producing strains using a improved Sequential step down therapy, wherein therapeutic options comprises parenterally administering a therapeutically effective amount of cefepime and sulbactam followed by oral third generation cephalosporin with a suitable (3 lactamase inhibitor.
The following specification particularly describes the invention and the manner in which it is to be performed.
4. DESCRIPTION
The present invention provides method of treating resistant bacterial infections caused by Extended Spectrum Beta-Lactamase (ESBLs) producing strains using a improved Sequential step down therapy, wherein therapeutic options
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compriseis parenterally administering a therapeutically effective amount of cefepimei and sulbactam followed by oral third generation cephalosporin with a suitable (3 lactamase inhibitor.
Cefepime is a semi-synthetic, broad spectrum, fourth generation cephalosporin antibiotic. Cefepimei is commercially available as hydrochloride salt (Formula I) under the trade name of Maxipime®. It is chemically 1-[[(6R, 7R)-7-[2-(2-amino-4-thiazolyl) -glyoxylamido] -2-carboxy-8-oxo-5-thia-1-azabicyclo [4.2.0] oct-2-en-3-yl] methyl]-1-methylpyrrolidinium chloride, 72 - (Z)-(O-methyloximei), monohydrochloride monohydrate.
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Cefepime exerts antibacterial functions on G+ve bacteria, such as staphylococcus aureus, staphylococcus epidermidis, streptococcus pyogenes, pathogenesis staphylococcal bacteria, streptococcus pneumoniae and other hemolytic streptococcus etc. It also has good antibacterial functions on G -ve bacteria, such as pseudomonas aeruginosa, Escherichia coli, Klebsiella, enteric bacilli, bacillus proteus, hemophilus, neisseria, salmonella, serratia, shigaella, and yersinia, etc., but it is ineffective against P.Maltophilia. In addition, it has good antibacterial functions on anaerobic bacteria, such as bacteroid and Cl.perfringens, etc. but it's ineffective to bacteroides fragilis and Clostridium difficile.
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Cefepime follows linear pharmacokinetics over the range of 250 mg-2g (IV) and 500 mg- 2g (IM). Its average steady state Vd is 18.0 (± 2.0) L and serum protein binding is approximately 20%. It is principally eliminated via renal excretion, average (±SD) half-life of cefepime is 2.0 (± 0.3) hours and total body clearance is 120.0 (± 8.0) mL/min. It is metabolized to N-methylpyrrolidine (NMP), which is rapidly converted to the N-oxide (NMP-N-oxide). Cefepime hydrochloride is indicated in the treatment of infections like Pneumonia (moderate to severe), Uncomplicated and Complicated Urinary Tract Infections (including pyelonephritis), Uncomplicated Skin and Skin Structure and Complicated Intra-abdominal Infections (used in combination with metronidazole).
Sulbactam, a derivative of the basic penicillin nucleus, is an irreversible beta-lactamase inhibitor. Sulbactam is commercially available as sodium salt (Formula II) in combination with ampicillin (P lactam antibiotic) under the trade name of Unasyn. It is chemically (2S, 5R)-3,3-dimethyl-7-oxo-4-thia-1-azabicyclo [3.2.0] heptane-2-carboxylate 4,4-dioxide. The mean serum half-life of sulbactam is approximately 1 hour and approximately 75 to 85% of sulbactam is excreted unchanged in the urine. It is given in combination with beta-lactam antibiotics to overcome beta-lactamase enzyme that destroys the antibiotics.

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Third-Generation oral Cephalosporinsi have excellent activity against Enterobacteriaceae, Orally active third generation cephalosporin include cefdinir, cefditoren, cefixime, cefpodoxime, cefprozil and ceftibuteni.
Cefdinir (Formula III), an extended-spectrum, semisynthetic cephalosporin, is [6R-[6_,7_(Z)]]-7-[[(2-amino-4-thiazolyl) (hydroxyimino)acetyl]amino]-3-ethenyl-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid. The empirical formula is C14H13N505S2and the molecular weight is 395.42.
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Cefditoren pivoxil, semi-synthetic cephalosporin for oral administration is a prodrug, which is hydrolyzed by esterases during absorption, and the drug is distributed in the circulating blood as active cefditoren. Chemically, cefditoren pivoxil (Formula IV) is (-)-(6R,7R)-2,2- dimethylpropionyloxymethyl 7-[(Z)-2-(2-aminothiazol-4-yl)-2-methoxyiminoacetamido]-3-[(Z)-2-(4-methylthiazol-5-yl)ethenyl]- 8-oxo-5-thia-1 -azabicyclo[4.2.0] oct-2-ene-2-carboxylate.
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Cefixime Formula IV Cefixime (Formula V) is a semisynthetic, cephalosporin antibiotic is (6R,7R)-7-[2-(2-Amino-4-thiazolyl)glyoxylamido]-8-oxo-3-vinyl-5-thia-1-azabicyclo[4.2.0] oct-2-ene-2-carboxylic acid, 72-(Z)-[0-(carboxymethyl)-oxime] trihydrate.
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## STR(

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Cefpodoxime proxetil (Formula VI) is an orally administered extended spectrum, semi-synthetic antibiotic of the cephalosporin class. The chemical name is (RS)-1(isopropoxycarbonyloxy)ethyl (+)-(6R,7R)-7-[2-( 2-amino-4-thiazolyl)-2-{(Z) methoxyimino}acetamido]-3-methoxymethyl-8-oxo-5-thia-1-azabicyclo [4.2.0] oct-2-ene-2- carboxylate. Its empirical formula is C21H27N5O9S2

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Ceftibuten dihydrate (Formula VII) is a semisynthetic cephalosporin antibiotic for oral administration. Chemically, it is (+)-(6R,7R)-7-[(Z)-2-(2-Amino-4-thiazolyl) -4-carboxycrotonamido]-8-oxo-5-thia-1-azabicycio [4.2.0]oct-2-ene-2-carboxylic acid, dihydrate. Its molecular formula is C 15 H 14 N 4 O 6 S 2 -2H 2 O.

Formula VII
Cefprozil (Formula VIII) is a cis and trans isomeric mixture (> 90% cis). The chemical name for the monohydrate is (6R,7R)-7-((R)-2-amino-2-(p-hydroxy-phenyl)acetamido) -8-oxo-3-propenyl-5-thia-1 -azabicyclo (4.2.0)oct-2-ene-2-carboxylic acid monohydrate

Tazobactam sodium (Formula IX), a derivative of the penicillin nucleus, is a penicillanic acid sulfone. Its chemical name is sodium (2 S ,3 S ,5 R )-3-methyl-7-oxo-3-(1 H -1,2,3-triazol-1-ylmethyl)-4-thia-1-azabicyclo[3.2.0]heptane-2-carboxylate-4,4-dioxide. The chemical formula is C 10 H 11 N 4 NaO 5 S and the molecular weight is 322.3.

In subjects with long-standing severe infections related to resistant Extended Spectrum Beta-Lactamase strain (hereinafter refered as ESBLs), antibiotic therapy is continued for longer period so as to avoid recrudescence. The limitations of parenteral therapy like it requires a skilled or trained person to administer; they need to be sterile; pain and cell necrosis associated with them, all these factors contribute to increased hospital stay which in turn increase the expenses.

In one of the aspects of the present invention there is provided a method for treating a resistant bacterial infections caused by ESBLs producing strain in a subject in need thereof, which comprises
a) Administering a pharmaceutical dosage form comprising cefepime in combination with sulbactam and pharmaceutically acceptable excipients via parenteral route, followed by
b) Oral third generation cephalosporin with a suitable (3 lactamase inhibitor after a suitable interval.
In yet another aspects of the present invention there is provided a method for treating a resistant bacterial infection caused by ESBLs producing strain in a subject in need thereof, which comprises administering oral third generation cephalosporin in the ratio of 1:1 to 1:4 with a suitable (3 lactamase inhibitor.
In yet another aspects of the present invention there is provided a method for treating a resistant bacterial infection caused by ESBLs producing strain, which comprises administering oral third generation cephalosporin optionally include one of cefdinir, cefditoren, cefixime, cefpodoxime, cefprozil ceftibuten and the like along with a suitable (b lactamase inhibitor like sulbactam or tazobactam.
In yet another aspects of the present invention there is provided a method for treating a resistant bacterial infection caused by ESBLs producing strain, which comprises oral dosage form, which optionally include tablets, powder, capsule or granules to be reconstituted before administration.
In yet another aspects of the present invention there is provided a method for treating a resistant bacterial infection caused by ESBLs producing strain in a subject, wherein the said subject is mammal.
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While the present invention has been described in terms of its specific embodiments, certain modifications and equivalents will be apparent to those skilled in the art and are intended to be included within the scope of the present invention
EXAMPLE 1-6 Table 1-cefepime and sulbactam combinations

Example No. Cefepime/ CefepimeHydrochloride/Cefepime HydrochlorideHydrate(Calculated on the basis offree Cefepime base in gm) Sulbactam sodium(gm) L-arginine (gm) Sterile waterfor injection/normal saline/5% dextrose(mL)
1 5 0.5 3.625 q.s
2 5 2.5 3.625 q.s
3 5 5 3.625 q.s
4 10 10 7.25 q.s
5 10 15 7.25 q.s
6 10 20 7.25 q.s
The composition of each batch is provided in Table 1. The general procedure used for preparation of the dosage form is provided below:
Procedure: As mentioned in the examples (i.e. Example Nos. 1-6), suitable quantity of Cefepime/ Cefepime Hydrochloride/ Cefepime Hydrochloride Hydrate, sulbactam sodium and L-arginine were mixed under aseptic and clean conditions and proceeded according to the preparation process sequence of dry powder injection preparation to prepare 10 units of powder injection to be reconstituted with suitable solvents like sterile water for injection, normal saline, 5% dextrose before administration.
EXAMPLE 7-8 Table 2 Cefdinirand Sulbactam sodium suspension.

Sr.no Ingredients Example 7 Example 8
Each 5 ml contains Each 5 ml contains
1 Cefdinir 130 130
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2 sulbactam sodium 136.79 273.58
3 sucrose 2308.6 2172
4 citric acid 0.3 0.5
5 sodium citrate 0.1 0.2
6 sodium benzoate 0.2 0.2
7 xanthan gum 5 5
8 guar gum 1 1
9 Colloidal silicon dioxide 8 8
10 dry flavour 8 8
11 magnesium stearate 2 2
2599.99 2600.48
The composition of each batch is provided in Table 2. The general procedure used for preparation of the dosage form is provided below: Procedure: Cefdinir, sulbactam sodium, sucrose, citric acid, sodium citrate, sodium benzoate, xanthan gum, guar gum, Colloidal silicon dioxide were sifted through ASTM mesh # 40 and mixed thoroughly using suitable blender. The suitable flavor was incorporated to prepare 5 bottles of powder for oral suspension, which is ready to be reconstituted with water before administration.
EXAMPLE 9-10
Table 3-Cefditoren and Tazobactam Tablet

Sr.n o Ingredients Example 9 Example 10
Mg/tablet Mg/tablet
1 Cefditoren pivoxil 245.06 245.06
2 Tazobactam sodium 218.86 437.72
3 Cros carmellose sod. 50 60
4 Sod.Caseinate 70 75
5 D mannitol 180 225
6 Sod.tripoly phosphate 20 20
7 HPMC 10 10
8 HPC 75 100
9 Magnesium stearate 2 4
10 Cros carmellose sod. 25 35
11 Magnesium stearate 4 6
899.92 1217.78

The composition of each batch is provided in Table 3. The general procedure used for preparation of the dosage form is provided below: Procedure: Cefditoren pivoxil, tazobactam sodium, crosi carmellose sodium, Sodium caseinate, D mannitol, Sodium tripoly phosphate, HPMC, HPC were sifted through ASTM mesh # 40 and mixed thoroughly using suitable blender. The blend was compacted to get the granules. The granules were further lubricated with magnesium stearate and cross carmellose sodium. The granules so obtained can be compressed into tablets or filled in pouch.
EXAMPLE 11-14 Table 4- Cefixime and Sulbactam tablets

Sr.n o. Ingredients Example 11 Example 12 Example 13 Example 14
Mg/tablet Mg/tablet Mg/tablet Mg/tablet
1 cefixime tri hydrate 223.81 223.81 447.62 447.62
2 Sulbactum Sodium 218.86 437.72 437.72 875.44
3 MCC 100 150 300 400
4 Cros carmellose sodium 40 60 160 220
5 HPC 35 45 90 150
6 Colloidal silicon dioxide 3 5 10 20
7 Magnesium stearate 3 4 6 12
8 Colloidal silicon dioxide 5 7 15 20
9 Magnesium stearate 7 9 14 20
635.67 941.53 1480.34 2165.06
The composition of each batch is provided in Table 4. The general procedure used for preparation of the dosage form is provided below: Procedure: Cefixime trihydrate, Sulbactum Sodium, MCC, cros carmellose sodium, HPC, Colloidal silicon dioxide and magnesium stearate were sifted through ASTM mesh # 40 and mixed thoroughly using suitable blender. The blend was compacted to get the granules. The granules were further lubricated with magnesium stearate and cross carmellose sodium. The granules so obtained can be compressed into tablets or filled in pouch.
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EXAMPLE 15-18
Table 5- Cefpodoxime and Sulbactam tablets

Sr. No Ingredients Example 15 Example 16 Example 17 Example 18
Mg/tablet Mg/tablet Mg/tablet Mg/tablet
1 Cefpodoxime proxetil 134.5 134.5 269 26 9
2 Sulbactam sod 109.43 218.86 218.86 437.72
3 Sod. Lauryl sulfate 10 10 20 20
4 Lactose mono hyd 100 125 200 . 300
5 Calcium CMC 50 75 75 100
6 HPC(LH-11) 40 55 55 60
7 HPMC 10 10 10 10
8 Mag stearate 1 2 3 6
9 HPC(LH-11) 20 30 30 30
10 Mag stearate 3 4 6 10
477.93 664.36 886.86 1242.72
The composition of each batch is provided in Table 5. The general procedure used for preparation of the dosage form is provided below: Cefpodoxime proxetil, sulbactam sodium, sodium lauryl sulfate, lactose mono hydrate, Calcium CMC, HPC, HPMC, magnesium stearate were sifted through ASTM mesh # 40 and mixed thoroughly using suitable blender. The blend was compacted to get the granules. The granules were further lubricated with magnesium stearate and cross carmellose sodium. The granules so obtained can be compressed into tablets or filled in pouch.
EXAMPLE 19-22
Table 6- Cefprozil and Sulbactam tablet

Sr. No Ingredients Example 19 Example 20 Example 21 Example 22
Mg/tablet Mg/tablet Mg/tablet Mg/tablet
1 Cefprozil monohydrate 264.41 264.41 528.82 528.82
2 sulbactam sodium 273.58 547.12 547.12 1094.2
3 MCC 100 150 200 300
4 Methocel 10 10 20 20
5 sod.starch glucolate 35 60 70 120
6 HPC 40 50 80 100
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7 Magnesium stearate 3.5 5 7 10
8 sodium.starch glucolate 10 20 20 40
9 Magnesium stearate 4 6 8 12
total 740.49 1112.53 1480.94 2225.02
The composition of each batch is provided in Table 6. The general procedure used for preparation of the dosage form is provided below:
Procedure: Cefprozil monohydrate, sulbactam sodium, MCC, Methocel, sodium Starch glucolate, HPC, magnesium stearate, sodium starch glycolate were sifted through ASTM mesh # 40 and mixed thoroughly using suitable blender. The blend was compacted to get the granules. The granules were further lubricated with magnesium stearate and cross carmellose sodium. The granules so obtained can be compressed into tablets or filled in pouch.
EXAMPLE 23 Table 7- Ceftibuten and Sulbactum Capsule

Sr. No Ingredients EXAMPLE 23
Mg/capsule
1 Ceftibuten Dihydrate 435.11
2 Sulbactum Sodium 437.72
3 Microcrystalline Cellulose 252
4 Sodium Starch Glycolate 40
5 Magnesium Sterate 5
6 Sodium Starch Glycolate 10
7 Magnesium Sterate 6
750.72
The composition of each batch is provided in Table 7. The general procedure used for preparation of the dosage form is provided below:
Procedure: Ceftibuten Dihydrate, sulbactum sodium, microcrystalline cellulose, sodium starch glycolate, magnesium sterate, sodium starch glycolate,
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magnesium sterate were sifted through ASTM mesh # 40 and mixed thoroughly using suitable blender. The blend was compacted to get the granules. The granules were further lubricated with magnesium stearate and cross carmellose sodium. The granules so obtained can be filled in pouch or capsules of suitable size.
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WE CLAIM:
1. A method for treating a resistant bacterial infections caused by ESBLs
producing strain in a subject in need thereof, which comprises
a) administering a pharmaceutical dosage form comprising cefepime in combination with sulbactam and pharmaceutically acceptable excipients via parenteral route, followed by
b) oral third generation cephalosporin with a suitable p lactamase inhibitor after a suitable interval.

2. The method according to claim 1, wherein ratio of oral third generation cephalosporin to suitable p lactamase inhibitor is between 1:1 to 1:4.
3. The method according to claim 1, wherein oral third generation cephalosporin comprises of cefdinir, cefditoren, cefixime, cefpodoxime, cefprozil, ceftibuten
4. The method according to claim 1, wherein suitable p lactamase inhibitor is sulbactam or tazobactam or pharmaceutically acceptable salt thereof.
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5. The method according to claim 1, wherein the oral dosage form comprises of tablets, capsules, powder, granules or suspension.
6. The method according to claim 1, wherein the said subject is mammal.
Dated this 28th day of April 2006
For Wockhardt Limited
(Kodgule, Mandar Madhukar) Authorized Signatory
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