FORM 2
THE PATENTS ACT 1970
(39 OF 1970)
COMPLETE SPECIFICATIONS
(SECTION 10)
"PROLONGED RELEASE PHARMACEUTICAL COMPOSITIONS
OF CLARITHROMYCIN"
UNICHEM LABORATORIES LIMITED, A COMPANY
REGISTERED UNDER THE INDIAN COMPANIES ACT, 1956,
HAVING ITS REGISTERED OFFICE LOCATED AT UNICHEM
BHAVAN, PRABHAT ESTATE, OFF S. V. ROAD, JOGESHWARI
(WEST), MUMBAI-400 102,
MAHARASHTRA, INDIA
The following specification particularly describes the invention and the manner in which it is to be performed.

"PROLONGED RELEASE PHARMACEUTICAL COMPOSITIONS OF CLARITHROMYCIN"
FIELD OF INVENTION
[0001] The present invention relates to the pharmaceutical compositions of prolonged
release tablets of Clarithromycin and methods for its manufacture thereof, useful for the treatment of microbial infection.
BACKGROUND OF THE INVENTION
[0002] Clarithromycin is an anti-bacterial drug belonging to the class of semi-synthetic macrolide antibiotics. Its chemical name is 6-O-methylerythromycin. It has a molecular formula of C38H69NO13 with a molecular weight of 747.96.
Clarithromycin is a semi-synthetic derivative of erythromycin A. It exerts its antibacterial action by binding to the 50s ribosomal sub-unit of susceptible bacteria and suppresses protein synthesis. It is highly potent against a wide variety of aerobic and anaerobic gram-positive, gram-negative micro organisms as well as on most of Mycobacterium avium complex (MAC) microorganisms. The minimum inhibitory concentrations (MICs) of Clarithromycin are generally two-fold lower than the MICs of erythromycin. The 14-hydroxy metabolite of Clarithromycin also has antimicrobial activity. The MICs of this metabolite are equal or two-fold higher than the MICs of the parent compound, except for H. influenzae where the 14-hydroxy metabolite is twofold more active than the parent compound.
[0003] Clarithromycin is commercially available as, immediate release systems in the form of tablets of 250 mg & 500 mg strengths, granules for oral suspension of 125 mg/5 ml &250 mg/5 ml strengths, extended release tablets of 500 mg strength and as Powder for Solution for Injection at a strength of 500 mg/vial.
[0004] Immediate release systems of Clarithromycin in the form of tablets are currently marketed by Abbott Laboratories under the brand names of Biaxin in 250 mg & 500 mg strengths in the USA and as Klaricid 250 tablets & Klaricid 500 tablets for 250 mg & 500 mg strengths in Europe.

[0005] Clarithromycin Granules for Oral Suspension are currently marketed by Abbott Laboratories under the brand name of BIAXIN® Granules in 125 mg/5 ml & 250 mg/5ml strength in the USA. In Europe, it is marketed under the brand names of Klaricid Pediatric Suspension in 125 mg/5 ml & 250 mg/5ml strengths and as Klaricid Adult Sachet in 250 mg/5ml strength.
[0006] Powder for Solution for Injection of Clarithromycin is marketed by Abbott Laboratories under the brand name Klaricid IV or Clarithromycin 500 mg/vial in Europe.
[0007] Extended release tablets of Clarithromycin of 500 mg strength are currently marketed by Abbott Laboratories under the brand name of BIAXIN XL FILMTAB® 500mg in the USA & as KLARICID XL 500mg tablets or Clarithromycin of 500 mg Modified Release Tablets in Europe.
[0008] US 6,010,718 (Laman Al-Razzak et al.; January 4, 2000); US 6,551,616 Bl (Gerard F Notario et al.; April 22, 2003) & US 2005/0064033 Al (Gerard F Notario et al.; March 24, 2005); discloses method of reducing gastrointestinal adverse effects of Clarithromycin by developing the extended release pharmaceutical composition of Clarithromycin. Manufacturing process involves preparation of drug granulates by aqueous wet granulation technique and by utilization of Hydroxypropyl methyl cellulose intragranularly. This results in the generation of hard granules leading to compressibility issues.
[0009] US 6,642,276 B2 (Hardeep Wadhwa; November 4, 2003) discloses preparation, isolation, characterization of soluble and stable citrate salt of macrolides. Preparation and isolation of citrate salt of macrolide utilizes organic solvents. It also discloses release pharmaceutical composition for controlled release of marcolides. In addition, manufacturing process involves aqueous wet granulation technique utilizing Hydroxypropyl methyl cellulose intragranularly which leads to hard drug granules and therefore lead to compressibility issues. In addition, utilization of organic solvents in the preparation and isolation of citrate salt of macrolide increases the manufacturing cost.

[00010] WO 03/082241 A2 (Rampal Ashok et al.; October 9, 2003) discloses extended release pharmaceutical composition of Clarithromycin. Disclosed process utilizes micronization of Clarithromycin alone or co-micronization of Clarithromycin with one or more pharmaceutical carriers. This increases number of unit operations and hence increases manufacturing period as well as manufacturing cost of the drug product. In addition, the disclosed process employs aqueous wet granulation technique utilizing Hydroxypropyl methyl cellulose intragranularly leading to formation of hard drug granules and ultimately leading to compressibility issues.
[00011] US 2003/0091627 Al (Vinay Sharma; May 15, 2003) discloses pharmaceutical composition for rate controlled delivery of marcolides. Disclosed process utilizes costlier excipients like β-cyclodextrins and employs hot melt extrusion technique, microfluidization technique for preparing the particle of the formulation. These techniques require specialty equipment than the regularly used manufacturing equipment and hence increase the manufacturing cost.
[00012] US 2004/0048814 Al (Francis Vanderbist et al.,; March 11, 2004) discloses pharmaceutical oral sustained release composition of Clarithromycin containing coated pellets comprising each a core containing Clarithromycin and sustained release coating surrounding the core, in which the sustained release coating comprises at least a water insoluble polymer which is substantially pH independent. Manufacturing process employed for manufacturing Clarithromycin containing core pellets is Extrusion spheronization technique. This technique utilizes costlier specialty equipments rather than regular machinery and hence increases manufacturing costs.
[00013] US 2007/0015719 Al (Scott Jenkins & Gary G Liversidge; January 18, 2007) discloses method of formulating and manufacturing Nanoparticulate Clarithromycin compositions and methods of treatment using the compositions. The process of preparing the Nanoparticulate Clarithromycin compositions involves unit operations like milling, wet milling, homogenizing, precipitation, freezing, supercritical fluid particle generation techniques, emulsion techniques or a combination of these unit operations. Increased number of unit operations and requirement of specialized equipment increases the manufacturing cost of the drug product and hence making not affordable to common needy people.

OBJECT OF THE INVENTION
[00014] The object of the present invention is to provide prolonged release pharmaceutical compositions of Clarithromycin and process for preparation thereof.
SUMMARY OF THE INVENTION
[00015] The present invention relates to an prolonged release pharmaceutical composition for oral drug delivery system in form of matrix system comprising pharmaceutically effective amount of Clarithromycin or its pharmaceutically acceptable salt, solvate, enantiomers or mixtures thereof, one or more of enteric or non-enteric release retarding agents or combination of both along with pharmaceutically acceptable excipients
[00016] Further, the present invention also provides process for the preparation of composition which comprises the steps of:
a. Sifting of drug and pharmaceutically acceptable excipients.
b. Dry mixing or granulation of ingredients
c. Blending and lubrication.
d. Compression of the lubricated blend of step (c) into tablets.
e. Film coating of the compressed tablets.
BRIEF DESCRIPTION OF THE DRAWINGS
[00017] Figure 1: Comparative dissolution profiles of the formulation of Example 1 and KLARICID XL in Phosphate Buffer pH 6.8 with 0.5% SLS.
[00018] Figure 2: Comparative dissolution profiles of the formulation of Example 1 in Phosphate Buffer pH 6.8 with 0.5% SLS stored at accelerated storage conditions (40°C/75%RH).
[00019] Figure 3: Comparative dissolution profiles of the formulation of Example 2 and KLARICID XL in Phosphate Buffer pH 6.8 with 0.5% SLS.

[00020] Figure 4: Comparative dissolution profiles of the formulation of Example 2 in Phosphate Buffer pH 6.8 with 0.5% SLS stored at accelerated storage conditions (40°C/75%RH).
[00021] Figure 5: Comparative dissolution profiles of the formulation of Example 3 and KLARICID XL in Phosphate Buffer pH 6.8 with 0.5% SLS.
[00022] Figure 6: Comparative dissolution profiles of the formulation of Example 3 in Phosphate Buffer pH 6.8 with 0.5% SLS stored at accelerated storage conditions (40°C/75%RH).
DETAILED DESCRIPTION OF THE INVENTION
[00023] The present invention relates to an prolonged release pharmaceutical
compositions of Clarithromycin, which is useful for once a daily administration. [00024] The present invention also describes the manufacturing process for the
preparation of prolonged release pharmaceutical compositions of Clarithromycin. [00025] In accordance with the present invention, the prolonged release pharmaceutical
composition is in the form of matrix tablet systems. [00026] In accordance with the present invention, prolonged release pharmaceutical
composition comprises:
(1) Compressed core, which essentially contains,
(i) Active pharmaceutical ingredient.
(ii) Pharmaceutically acceptable diluents,
(iii) Pharmaceutically acceptable acidulants,
(iv) Pharmaceutically acceptable binders.
(v) Pharmaceutically acceptable enteric and/or non-enteric release retardant
polymers, (vi) Pharmaceutically acceptable glidants and lubricants &
(2) Film Coating around the said core tablet, which consists of a protective layer of
pharmaceutically acceptable water soluble polymer.
[00027] In accordance with the present invention, manufacturing methods used are one or more of wet granulation technique, dry granulation technique or direct compression of active pharmaceutical ingredient along with one or more of pharmaceutically acceptable excipients, preferably wet granulation technique.

[00028] Method of manufacturing by wet granulation method includes, preparation of drug granulates comprising, active pharmaceutical ingredient, one or more of pharmaceutically acceptable excipients by using granulating solution with or without binder. Wet granulation method includes, spray granulation using fluidized bed processor or conventional wet granulation using rapid mixer granulator. After drying, milling and sieving, the resulted drug granulates are mixed with one or more of other extra granular pharmaceutically acceptable excipients, lubricated and then compressed into tablets.
[00029] Method of manufacturing by dry granulation method includes, preparation of drug granulates by slugging the uniformly blended mixture of active pharmaceutical ingredient and one or more of pharmaceutically acceptable excipients. After sieving. the resulted drug granulates are mixed with one or more of other extra granular pharmaceutically acceptable excipients, lubrication and then compression into tablets.
[00030] Method of manufacturing by direct compression includes mixing of active pharmaceutical ingredient with other pharmaceutically acceptable excipients, lubrication, and then compression into tablets
[00031] In accordance with the present invention, prolonged release pharmaceutical composition comprises, pharmaceutically effective amount of Clarithromycin and at least one or more pharmaceutically acceptable excipients viz., Enteric and/or non-enteric release retardant polymers, diluents, acidulants, glidants. binders, lubricants and one or more of coating agents for protecting the drug from external environment.
[00032] Non-enteric release retardant polymers used in the present invention may be one or more of cellulose derivatives like hydroxy! ethyl cellulose, ethyl cellulose, methyl cellulose, hydroxypropyl methylcellulose, hydroxypropyl cellulose, preferably hydroxypropyl methylcellulose and hydroxyl ethyl cellulose; natural polysaccharide gums comprise one or more of guar gum, xanthan gum, karaya gum, gellan gum, hupu gum, carob gum, caramania gum, sodium alginate, carrageenan, ceratonia, sodium calcium alginate and alginic acid, preferably sodium alginate and sodium calcium alginate.
[00033] Hydroxypropyl methylcellulose used as cellulose derivative is of nominal viscosity of about 3 cps to 200000cps.
[00034] A prolonged release pharmaceutical composition, wherein cellulose derivatives comprises between about 1 % to about 20% w/w.

[00035] A prolonged release pharmaceutical composition, wherein polysaccharide gums comprises between about 1 % to about 20% w/w.
[00036] Enteric release retardant polymers used in the present invention may be one or more of poly (butyl methacrylate, (2-dimethyl amino methyl) methacrylate, methyl methacrylate) 1:2:1, poly (methacrylic acid, methyl methacrylate) 1:1, poly (methacrylic acid, ethyl acrylate,) 1:1, poly (methacrylic acid, methyl methacrylate) 1:2, poly (ethyl acrylate, methyl methacrylate, trimethyl ammonio-ethyl methacrylate chloride) 1:2:0.2. poly (ethyl acrylate. methyl methacrylate, trimethyl ammonio-ethyl methacrylate chloride) 1:2:0.1, cellulose acetate phthalate, hydroxypropyimethyl cellulose phthalate, hydroxypropyimethyl cellulose acetate succinate, dimethyl phthalate, diethyl phthalate, dibutyl phthalate, and mixture thereof, preferably hydroxypropyl methyl cellulose phthalate and poly(methacrylic acid-co-ethyl acrylate) 1:1.
[00037] A prolonged release pharmaceutical composition, wherein enteric release retardant polymers comprises between about 1 % to about 20 % w/w.
[00038] Diluents used in the present invention are at least one or more of the microcrystalline cellulose, silicified microcrystalline cellulose, lactose monohydrate, anhydrous lactose, directly compressible lactose, starch 1500, calcium phosphate (dibasic/tribasic), calcium sulphate, calcium sulphate dihydrate, fructose, sucrose. sorbitol, xylitol, dextrose, compressible sugar, dextrates, dextrin, starch, powdered cellulose, sodium alginate, tragacanth, sodium chloride, potassium chloride, magnesium sulfate, magnesium chloride, sodium sulfate, lithium sulfate, urea, inositol, lactose, mannitol, magnesium succinate, potassium acid phosphate and the like, preferably lactose monohydrate and microcrystalline cellulose. [00039] Acidulants used in the present invention are at least one or more of ascorbic
acid, fumaric acid, citric acid anhydrous & the like, preferably citric acid anhydrous. [00040] Binders used in the present invention may be at least one or more of povidone, pyrrolidone, co-povidone, acacia gum, guar gum, xanthan gum, karaya gum, gellan gum, hupu gum, carob gum, caramania gum, gelatin, glucose, sugar, dextrin, sorbitol, maltose, pregelatinised starch, carboxymethyl cellulose sodium, methyl cellulose, hydroxypropyl cellulose, low substituted hydroxypropyl cellulose, hydroxypropyl methyl cellulose, ethyl cellulose, hyroxyethyl cellulose, cellulose acetate, agar, alginic acid, sodium alginate, carbomers, carrageenan, ceratonia, chitosan, poloxamer,

polyethylene oxide, magnesium aluminum silicate, preferably povidone and sodium alginate.
[00041] Granulating solvents used in the present invention may be at least one or more of water, acetone, isopropyl alcohol and ethanol, preferably water and acetone.
[00042] A prolonged release pharmaceutical composition, wherein granulating solvents comprises between about 15 % to about 75 % w/w.
[00043] Glidants used in the present invention may be at least one or more of colloidal silicon dioxide, talc, magnesium stearate, calcium stearate, hydrogenated castor oil, sodium lauryl sulfate, precipitated silicon dioxide and starch etc. preferably talc.
[00044] Lubricants used in the present invention are one or more of magnesium stearate, calcium stearate. stearic acid, talc, sodium stearyl fumarate, hydrogenated vegetable oils, magnesium lauryl sulfate, wax, polyethylene glycol, glyceryl behenate, glyceryl palmitostearate, palmitic acid, poloxamer, sodium benzoate and sodium lauryl sulfate, preferably magnesium stearate, talc and stearic acid.
[00045] In accordance with the present invention, the tablet is film coated, wherein film coating is applied for protecting the drug from degradation due to external environment. The coating layers over the tablet may be applied as dispersion/solution of coating ingredients by using any technique known as spray coating, dip coating and conventional pan coating.
[00046] In accordance with the present invention, coating composition comprises one or more of film forming agents, opacifiers, plasticizers, coloring agents, solvents and other pharmaceutically acceptable excipients etc.
[00047] In accordance with the present invention, film forming agents used includes one or more of polyethylene glycol, polyvinyl alcohol, povidone, chitosan, maltodextrin, isomalt ammonium alginate, gelatin, carrageen, ethyl lactate, cellulose derivatives such as hydroxypropyl methyl cellulose, ethyl cellulose, hydroxymethyl cellulose, hydroxyethyl cellulose, hydroxypropyl cellulose, methyl cellulose, preferably hydroxypropyl methyl cellulose. [00048] Opacifiers used in the present invention may be one or more of titanium dioxide, ethylene glycol palmitostearate, acetates such as zinc acetate, silicates such as talc and aluminium silicate, carbonates such as magnesium carbonate, calcium carbonate etc., stearates such as aluminium stearate and zinc stearate etc.. sulfates such as calcium sulfate, oxides such as magnesium oxide and hydroxides such as aluminiuim hydroxides, preferably titanium dioxide.

[00049] Plasticizers used in the present invention may be one or more of polyethylene glycols, propylene glycol, glycerine, caster oil, acetyltriethyl citrate, benzyl benzoate, chlorbutanol, dextrin, acetyltributyl citrate, dimethyl phthalate, diethyl phthalate, dibutyl phthalate, dibutyl sebacate, glyceryl monooleate, glyceryl monostearate. 2-pyrrolidone, sorbitol, stearic acid, palmitic acid, triacetin, tributyl citrate, triethyl citrate, triethanolamine, surfactants like polysorbates, sorbitan esters and organic acid esters and mixtures thereof, preferably polyethylene glycol.
[00050] Suitable coloring agents include one or more colors approved by FDA.
[00051] Suitable solvents used for coating solution/dispersion include one or more of water, ethyl acetate, acetone, isopropyl alcohol, n-propanol, ethanol and mixtures thereof.
[00052] A prolonged release pharmaceutical composition, wherein solvents used for coating solution/dispersion comprises between about 15 % to about 45 % w/w.
[00053] According to the present invention, Prolonged release pharmaceutical composition may contain 40 to 60% of active pharmaceutical ingredient, \ to 50% of one or more of enteric and/or non-enteric release retardant polymers, 1 to 50% of diluents, from about I to 20% of acidulants, from about 1 to 15% of binders, from about 0.1 to 5% of glidants, from about 0.1 to 5% of lubricants and from about 0.5 to 15% of coating agents.
[00054] According to present invention; Prolonged release pharmaceutical composition wherein coating comprises about 0.5 % to about 5.0 % w/w of film forming agent; about 0.1 % to about 3.0 % w/w of opacifier; about 0.05 % to about 1.0 % of plasticizers
[00055] Prolonged release pharmaceutical composition of the present invention contains the active ingredient in the range of from about 400 lug to about 1200 mg. The 'active ingredient' refers to Clarithromycin.
[00056] A prolonged release tablet of the present invention releases, not more than 20% at 2 hours, between 45 % and 80 % at 12 hours & not less than 80%o at 24 hours, as measured in 0.05M Phosphate Buffer pH 6.8 with 0.5% SL-S maintained ar37±2°C using USPType I apparatus.
[00057] In another embodiment, process for forming a film coated prolonged release matrix system includes:

1. Sifting of Clarithromycin, sodium alginate, sodium calcium alginate, povidone, lactose monohydrate and citric acid anhydrous through ASTM mesh #20 and dry mixing in the rapid mixer granulator.
2. Preparation of solvent mixture of Purified water and Isopropyl alcohol (Purified water: Isopropyl alcohol - 1:1) or Purified water and Acetone (Purified water: Acetone - 1:1).
3. Granulation of Step-1 dry mix using Step-2 solvent mixture.
4. Drying of Step-3 granules.
5. Sifting of Ste-p-4 dried granules through ASTM # 20 mesh.
6. Sifting of talc, stearic acid and magnesium stearate through ASTM mesh #40 and mixing with Step-5 granules in a blender.
7. Compression of the Step-6 lubricated blend to form matrix tablets.
8. Preparation of the aqueous coating dispersion containing water-soluble polymer.
9. Coating of Step-7 matrix tablets with step-8 coating dispersion.
[00058] The Prolonged release pharmaceutical composition of the present invention
may be administered to the mammals. Preferably the mammal is a human, and the
composition is administered as prolonged release tablet. Preferably, the pharmaceutical
composition of present invention containing clarithromycin may be used in the
treatment of microbial infection. The amount of the Clarithromycin in the prolonged
release pharmaceutical composition of present invention is preferably an amount that
provides a therapeutically effective amount of Clarithromycin.
[00059] Although the present invention has been described with reference to specific
embodiments, this description is not meant to be construed in a limiting sense. Various
modifications of the disclosed embodiments, as well as alternate embodiments of the
invention, will become apparent to persons skilled in the art upon reference to the
description of the invention. It is therefore contemplated that such modifications can be
made without departing from the spirit or scope of the present invention as defined.
EXAMPLES
[00060] The following examples are presented for illustration only, and are not intended to limit the scope of the invention or appended claims

Example 1
Table 1: Composition of Example 1
Sr. No. | Ingredients | Qty./tab (mg)
Core Composition:
1 Clarithromycin 500.000
2 Citric acid anhydrous 128.000
3 Povidone 50.000
4 Lactose monohydrate 98.500
5 Hydroxypropyl methyl cellulose (4000 cps) 40.000
6 Hydroxypropyl methyl cellulose (5 cps) 70.000
7 Microcrystalline cellulose 88.500
S Magnesium Stearate 10.000
9 Purified water q.s.
Weight of Core Tablet (mg) 985.000
Coating Composition:
10 Hydroxypropyl methyl cellulose (6 cps) 18.750
11 Titanium Dioxide 5.255
12 Quinoline Yellow Aluminium Lake 4.118
13 PEG 400 1.875
14 FD & C Blue # 2 / Indigo Carmine Aluminium Lake 0.002
15 Purified water q.s.
Weight of Coated Tablet (mg) 1015.000
Uriel Manuf
1. Si
th
2. Pr
3. G
4. D
5. Si acturing Procedure:
fting of clarithromycin through ASTM #20 mesh & rough ASTM #80 mesh and dry mixing in the rapid mi
eparation of binder solution by dissolving povidone in
-anulation of Step-1 dry mix using Step-2 binder soluti
-ying of Step-3 granules.
fting of Step-4 dried granules through ASTM # 16 mes citric acid anhydrous xer granulator.
purified water.
on.
sh.

6. Sifting of lactose monohydrate, hydroxypropylmethyl cellulose (4000 cps). hydroxypropylmethyl cellulose (5 cps) and microcrystalline cellulose through ASTM mesh #40 and mixing with Step-5 granules in a blender.
7. Sifting of magnesium stearate through ASTM #60 mesh and blending with Step-6 blend in a blender.
8. Compression of the Step-7 lubricated blend to form matrix tablets.
9. Preparation of the aqueous coating dispersion.
10. Coating of Step-8 matrix tablets with Step-9 coating solution/dispersion.
[00061] Dissolution studies of tablets of example 1 and Klaricid XL were carried out in USP Type 1 apparatus using 900 ml of 0.05M Phosphate Buffer pH 6.8 with 0.5% SLS, as dissolution medium maintained 37±2°C with the basket speed of 100 RPM. and the comparative dissolution profiles are given in Table 2 and Fig 1.
Table 2: Comparative dissolution profiles of the formulation of Example 1 and KLARICID XL in Phosphate Buffer pH 6.8 with 0.5% SLS

Time
(Hrs.) Percent Clarithromycin Released

KLARICID XL Example 1
0 0 0
9 6.2 8.9
4 15.8 20.3
6 27.1 31.6
8 40.8 41.4
12 63.7 59.7
16 80.0 74.8
20 91.4 84.9
24 97.9 90.3
[00062] Chemical Studies were con tablets. The results analysis was performed for the ma
ducted for assay, Loss on drying
of these studies are shown in Table nufactured clarithromycin tablets. and related substances in these ;:3.

Table 3: Physicochemica! parameters of compos ition of Example: 1
Sr. No. Parameters Results
1. Assay (%) 98.7
2. Loss on drying (%) 6.2
3. Related Substances

Impurity A (%) 0.16

Impurity B (%) Below Detection Limit

Impurity C (%) Below Detection Limit

Impurity D (%) 0.16

Impurity E {%) 0.57

Impurity F (%) 0.21

Impurity G (%) 0.09

Impurity H (%) Below Detection Limit

Impurity I (%) Below Detection Limit

Impurity J (%) Below Detection Limit

Impurity K (%) 0.19

Impurity L (%) Below Detection Limit

Impurity M (%) Below Detection Limit

Impurity N (%) Below Detection Limit

Impurity O (%) Below Detection Limit

Impurity P (%) Below Detection Limit

Any unknown impurity (%) Below Disregard Limit
Total impurities (%) 1.38
[00062] Stability studies were also conducted for the tablets of Example 1 after packing in PVC-PVDC blister for 6 months at accelerated conditions <40°C/75% RH) to evaluate the changes in related substances as well as changes in the dissolution profile in USP Type-1 apparatus run at the basket speed of 100 rpm by using 900 ml of 0.05M Phosphate Buffer pH 6.8 with 0.5% SLS maintained at 37±2°C. The results of these studies are shown in Table 4 to 5 and Fig, 2.

Table 4: Accelerated stability stu dy results of tablets of Example 1
Sr. No. Parameters Accelerated conditions (40°C/75% RH)


1 month 2 month 3 month 6 month
1. Assay (%) 102.8 98.4 96.9 96.8
2. Loss on drying
(%) * 4.90 6.7 6.5 4.9
3. Related Substances

Impurity A (%) 0.13 0.18 0.18 0.15

Impurity B (%) BDL BDL 0.13 BDL

Impurity C (%) BDL BDL 0.05 BDL

Impurity D (%) BDL 0.19 0.26 0.20

Impurity E (%) 0.54 0.63 0.50 0.70

Impurity F (%) 0.30 0.12 BDL 0.23

Impurity G (%) 0.05 0.08 0.06 0.03

Impurity H (%) BDL 0.04 0.03 0.06

Impurity 1 (%) 0.34 0.37 0.40 0.43

Impurity J (%) BDL BDL 0.02 BDL

Impurity K (%) 0.16 0.14 0.32 BDL

Impurity L (%) BDL BDL BDL BDL

Impurity M (%) BDL BDL BDL BDL

Impurity N (%) BDL BDL BDL BDL

Impurity 0 (%) BDL BDL BDL BDL

Impurity P (%) BDL BDL 0.38 BDL

Any unknown impurity (%) Below Disregard
Limit Below
Disregard Limit Below
Disregard
Limit 0.15

Total impurities 1.52 1.71 2.28 1.92
B
T
co DL: Below Detection Limit
able 5: Dissolution profile of tablets of Example 1 stored at accelerated storage ndition (40°C/75%RH)
Time Percent Clarithromycin Released
(Hrs.) 1 month 2 month 3 month 6 month
0 0 0 0 0

2 12.1 7.5 9.1 10.5
12 60.8 57.1 54.5 57.4
24 86.3 86.9 90.0 87.4
Example 2
Table 6: Composition of Example 2
Sr. No. Ingredients Qty./tab (mg)
Core Composition:
1 Clarithromycin 500.000
2 Citric acid anhydrous 128.000
3 Povidone 30.000
4 Lactose monohydrate 100.000
5 Sodium Alginate 120.000
6 Sodium Calcium Alginate 15.000
7 Magnesium Stearate 10.000
8 Talc 30.000
9 Stearic acid 21.000
10 Purified water q.s.
11 Isopropyl alcohol q.s.
Weight of Core Tablet (mg) 954.000
Coating Composition:
12 Hydroxypropyl methyl cellulose (6 cps) 16.250
13 Titanium Dioxide 4.560
14 Quinoline Yellow Aluminium Lake 3.570
15 PEG 400 1.620
16 FD & C Blue ft 2 / Indigo Carmine Aluminium Lake 0.002
17 Purified water q.s.
Weight of Coated Tablet (mg) 980.000
Brief Manufa
1. Si lac an cturing Procedure:
fting of clarithromycin, sodium alginate, sodium calciu tose monohydrate and citric acid anhydrous through d dry mixing in the rapid mixer granulator. m alginate, povidone. ASTM mesh #20 mesh

2. Preparation of solvent mixture of purified water and isopropyl alcohol.
3. Granulation of Step-1 dry mix using Step-2 solvent mixture.
4. Drying of Step-3 granules.
5. Sifting of Step-4 dried granules through ASTM # 20 mesh.
6. Sifting of talc, stearic acid and magnesium stearate through ASTM mesh #60 and mixing with Step-5 granules in a blender.
7. Compression of the Step-6 lubricated blend to form matrix tablets.
8. Preparation of the aqueous coating dispersion.
9. Coating of Step-7 matrix tablets with Step-8 coating dispersion.
[00063] Dissolution studies of tablets of example 2 and Klaricid XL were carried out in USP Type 1 apparatus using 900 ml of 0.05M Phosphate Buffer pH 6.8 with 0.5% SLS, as dissolution medium maintained 37±2°C with the basket speed of 100 RPM. and the comparative dissolution profiles are given in Table 7 and Fig 3.

Table 7: Comparative dissolution profiles of the formulation of Example 2 and KLARJCID XL in Phosphate Buffer pH 6.8 with 0.5% SLS
Time
(Hrs.) Percent Clarithromycin Released

KLAR1CID XL Example 2
0 0 0
2 6.2 7.0
4 15.8 17.5
6 27.1 30.5
8 40.8 44.9
12 63.7 68.7
16 80.0 83.3
20 91.4 91.5
24 97.9 95.4
[ S
T 00064] Chemic tudies were cond he results of these al analysis was performed for the m jcted for assay. Loss on drying and ; studies are shown in Table: 8. anufactured clarithromycin tablets related substances in these tablets

Table 8 Physicochemical parameters of composition of Example: 2
Sr.
No. Parameters Results
1. Assay (%) 98.2
2. Loss on drying (%) 7.2
3. Related Substances

Impurity A (%) 0.28

Impurity B (%) Below Detection Limit

Impurity C (%) Below Detection Limit

Impurity D {%) Below Detection Limit

Impurity E {%) 0.35

Impurity F (%) 0.11

Impurity G (%) Below Detection Limit

Impurity H (%) 0.06

Impurity I (%) Below Detection Limit

Impurity J (%) Below Detection Limit

Impurity K (%) Below Detection Limit

Impurity L (%) Below Detection Limit

Impurity M {%) Below Detection Limit

Impurity N (%) Below Detection Limit

Impurity O (%) Below Detection Limit

Impurity P (%) Below Detection Limit

Any unknown impurity (%) Below Detection Limit
Total impurities (%) 0.80
[00065] Stability studies were also conducted for the tablets of Example 2 after
packing in PVC-PVDC blister for 6 months at accelerated conditions (40°C/75% RH) to evaluate the changes in related substances as well as changes in the dissolution profile in USP Type-1 apparatus run at the basket speed of 100 rpm by using 900 ml of 0.05M Phosphate Buffer pH 6.8 with 0.5% SLS maintained at 37±2°C. The results of these studies are shown in Table 9 to 10 and Fig. 4.

Table9 : Accelerated stability s tudy results of tablets of Example 2
Sr.
No. Parameters Accelerated conditions (40°C/75% RH)

1 month 2 month 3 month 6 month
1. Assay (%) 96.8 99.0 97.2 98.1
2. Loss on drying
(%) 8.4 7.0 9.0 9.29
3. Related Substances

Impurity A (%) 0.31 0.32 0.30 0.30

Impurity B (%) BDL BDL 0.13 BDL

Impurity C (%) BDL BDL BDL BDL

Impurity D (%) 0.42 0.26 0.24 BDL

Impurity E (%) 0.38 0.29 0.29 0.25

Impurity F (%) 0.32 0.29 0.21 0.14

Impurity G (%) BDL BDL 0.04 BDL

Impurity H (%) 0.06 0.07 0.06 0.06

Impurity I (%) BDL BDL BDL BDL

Impurity J (%) 0.12 BDL BDL BDL

Impurity K (%) BDL BDL BDL BDL

Impurity L (%) BDL BDL BDL BDL

Impurity M (%) BDL BDL BDL BDL

Tmpurity N (%) BDL BDL BDL 0.21

Impurity O (%) BDL BDL BDL BDL

Impurity P (%) BDL BDL BDL BDL

Any unknown impurity (%) BDL Below
Quantification Limit 0.10 Below
Quantification
Limit

Total impurities (%) 1.61 1.23 1.33 1.10
BDL: Below Detection Limit
Table 10: Dissolution profile of tablets of Example 2 stored at accelerated storage condition (40°C/75%RH).
Time (Hrs) Percent clarithromycin released

1 month 2 month 3 month 6 month
0 0 0 0 0
2 5.7 6.5 10.0 9.0

12 53.7 57.5 74.3 58.8
24 91.4 91.2 100.2 90.0
Example
Table 11: 3
Composition of Example 3
Sr. No . Ingredients Qty./tab (mg)
Core Co mposition:
I Clarithromycin 500.000
2 Citric acid anhydrous 128.000

3 Povidone 30.000
4 Lactose monohydrate 100.000
5 Sodium Alginate 120.000
6 Sodium Calcium Alginate 15.000
7 Magnesium Stearate 10.000
8 Talc 30.000
9 Stearic acid 21.000
10 Purified water q.s.
11 Acetone q.s.
Weight of Core Tablet (mg) 954.000
Coating Composition:
12 Hydroxy propyl methyl cellulose (6 cps) 16.250
13 Titanium Dioxide 4.560
14 Quinoline Yellow Aluminium Lake 3.570
15 PEG 400 1.620
16 FD & C Blue # 2 / Indigo Carmine Aluminium Lake 0.002
17 Purified water q.s.
Weight of Coated Tablet (mg) 980.000
Brief Manuf
1. Si
lac
an
2. Pr acturing Procedure:
fting of clarithromycin, sodium alginate, sodiu ;tose monohydrate and citric acid anhydrous th d dry mixing in the rapid mixer granulator.
eparation of solvent mixture of purified water z n calcium alginate, po rough ASTM mesh #2
tnd acetone. vidone, 0 mesh

3. Granulation of Step-1 dry mix using Step-2 solvent mixture.
4. Drying of Step-3 granules.
5. Sifting of Step-4 dried granules through ASTM # 20 mesh.
6. Sifting of talc, stearic acid and magnesium stearate through ASTM mesh #60 and mixing with Step-5 granules in a blender.
7. Compression of the Step-6 lubricated blend to form matrix tablets.
8. Preparation of the aqueous coating dispersion.
9. Coating of Step-7 matrix tablets with Step-8 coating dispersion.
[00066] Dissolution studies of tablets of example 3 and Klaricid XL were carried out in USP Type 1 apparatus using 900 ml of 0.05M Phosphate Buffer pH 6.8 with 0.5% SLS, as dissolution medium maintained 37±2°C with the basket speed of 100 RPM, and the comparative dissolution profiles are given in Table 12 and Fig 5.
Table 12: Comparative dissolution profiles of the formulation of Example 3 and KLARICID XL in Phosphate Buffer pH 6.8 with 0.5% SLS

Time (Hrs.) Percent Clarithromycin Released

KLAR1CID XL Example 3
0 0 0
2 6.2 9.6
4 15.8 21.1
6 27.1 33.6
8 40.8 46.4
12 63.7 68.1
16 80.0 84.0
20 91.4 93.6
24 97.9 98.1
[00067] Chemical Studies were cond The results of thes analysis was performed for the ucted for assay, Loss on drying and e studies are shown in Table: 13. manufactured clarithromycin tablets. related substances in these tablets.

Table 13 ; Physicochemical parameters of composition of Example: 3
Sr. No. Parameters Results
1. Assay (%) 102.4
2. Loss on drying (%) 4.14
3. Related Substances

Impurity A (%) 0.32

Impurity B (%) Below Detection Limit

Impurity C (%) Below Detection Limit

Impurity D (%) 0.04

Impurity E (%) 0.24

Impurity F (%) 0.20

Impurity G (%) Below Detection Limit

Impurity H (%) 0.06

Impurity I (%) Below Detection Limit

Impurity J (%) Below Detection Limit

Impurity K (%) Below Detection Limit

Impurity L (%) Below Detection Limit

Impurity M (%) Below Detection Limit

Impurity N (%) Below Detection Limit

Impurity O (%) Below Detection Limit

Impurity P (%) Below Detection Limit

Any unknown impurity (%) Below Quantification Limit

Total impurities (%) 0.82
[00068] Stability studies were also conducted for the tablets of Example 3 after packing in PVC-PVDC blister for 3 months at accelerated conditions (40oC/75% RH) to evaluate the changes in related substances as well as changes in the dissolution profile in USP Type-! apparatus run at the basket speed of 100 rpm by using 900 ml of 0.05M Phosphate Buffer pH 6.8 with 0.5% SLS maintained at 37±2°C. The results of these studies are shown in Table 14 to 15 and Fig. 6.

Table 14: Accelerated stability study resu lts of tablets of Example 3
Sr. No. Parameters Accelerated conditions (40°C/75% RH)

1 month 2 month 3 month
1. Assay (%) 101.2 101.2 103.2
2. Loss on drying (%) 5.77 7.36 8.16
3. Related Substances

Impurity A {%) BDL BDL 0.37

Impurity B (%) BDL BDL BDL

Impurity C (%) BDL BDL BDL

Impurity D (%) BDL 0.16 0.19

Impurity E (%) 0.13 0.19 0.21

Impurity F (%) 0.13 0.11 0.17

Impurity G (%) BDL BDL BDL

Impurity H (%) 0.06 0.10 0.07

Impurity I (%) BDL BDL BDL

Impurity J (%) BDL BDL BDL

Impurity K (%) BDL BDL BDL

Impurity L (%) BDL BDL BDL

Impurity M (%) BDL 0.11 BDL

Impurity N (%) BDL BDL BDL

Impurity 0 {%) BDL BDL BDL

Impurity P (%) BDL BDL BDL

Any unknown impurity (%) Below
Quantificatio
n Limit Below
Quantificati on Limit Below
Quantification
Limit

Total impurities (%) 0.26 0.67 1.01
BDL: Below
Table 15: Detection Limit
Dissolution profile of tablets of Example 3 stored at accelerated storage Condition (40°C/75%RH).
Time (Hrs.) Percent Clarithromycin Released

1 month 2 month 3 month
0 0 0 0
2 8.4 !1.7 13.9

12 57.2 78.3 87.3
24 93.5 100.8 103.4
Example 4
Table 16: Co mposition of Example 4
Sr. No. Ingredients Qty./tab (mg)
Core Composition:
1 Clarithromycin 500.000
2 Citric acid anhydrous 128.000
3 Povidone 50.000
4 Lactose monohydrate 73.500
5 Hydroxyethyl cellulose 25.000
6 Hydroxypropylmelhyl cellulose (4000 cps) 40.000
7 Hydroxypropylmethyl cellulose (5cps) 70.000
8 Microcrystalline cellulose 88.500
9 Magnesium Stearate 10.000
10 Purified water q.s.
Weight of Core Tablet (mg) 985.00
Coating Co mposition:
11 Hydroxypropyl methyl cellulose (6 cps) 18.750
12 Titanium Dioxide 5.255
13 Quinoline Yellow Aluminium Lake 4.118
14 PEG 400 1.875
15 FD & C Blue # 2 / Indigo Carmine Aluminium Lake 0.002
16 Purified water q.s
Weight of Coated Tablet (mg) 1015.000
Brief Manufacturing Procedure:
1. Sifting of clarithromycin through ASTM mesh #20 and citric acid anhydrous through ASTM mesh #80 and dry mixing in the rapid mixer granulator.
2. Preparation of binder solution by dissolving povidone in purified water.
3. Granulation of Step-1 dry mix using Step-2 binder solution.
4. Drying of Step-3 granules.

5. Sifting of Step-4 dried granules through ASTM # 16 mesh.
6. Sifting of hydroxyethyl cellulose, lactose monohydrate, microcrystalline cellulose, hydroxypropyl methyl cellulose (4000 cps), & hydroxypropyl methyl cellulose (5 cps) through ASTM mesh #40 and mixing with Step-5 granules in a blender.
7. Sifting of magnesium stearate through ASTM #60 mesh and blending with Step-6 blend in a blender.
8. Compression of the Step-7 lubricated blend to form matrix tablets.
9. Preparation of the aqueous coating dispersion.
10. Coating of Step-8 matrix tablets with Step-9 coating dispersion.
Example 5
Table 17: Composition of Example 5

Sr. No. Ingredients Qty./tab (mg)
Core Com position:
1 Clarithromycin 500.000
2 Citric acid anhydrous 128.000
3 Povidone 50.000
4 Lactose monohydrate 73.500
5 Polyfmethacryiic acid, ethyl acrylate) 25.000
6 Hydroxypropylmethyl cellulose (4000 cps) 40.000
7 Hydroxypropylmethyl cellulose (5cps) 70.000
8 Microcrystailine cellulose 88.500
9 Magnesium Stearate 10.000
10 Purified water q.s.
Weight of Core Tablet (mg) 985.000
Coating C omposition:
11 Hydroxypropyl methyl cellulose (6 cps) 18.750
12 Titanium Dioxide 5.255
13 Quinoline Yellow Aluminium Lake 4.1 18
14 PEG 400 1.875

15 FD & C Blue it 2 / Indigo Carmine Aluminium Lake 0.002
16 Purified water q.s.
Weight of Coated Tablet (mg) 1015.000
Brief Manufacturing Procedure:
1. Sifting of clarithromycin through ASTM mesh #20 and citric acid anhydrous through ASTM mesh #80 and dry mixing in the rapid mixer granulator.
2. Preparation of binder solution by dissolving povidone in purified water.
3. Granulation of Step-1 dry mix using step-2 binder solution.
4. Drying of Step-3 granules.
5. Sifting of Step-4 dried granules through ASTM # 16 mesh.
6. Sifting of lactose monohydrate. poly(methacrylic acid, ethyl acrylate). microcrystalline cellulose, hydroxypropylmethyl cellulose (4000 cps), & hydroxypropyl methyl cellulose (5 cps) through ASTM mesh #40 and mixing with step-5 granules in a blender.
7. Sifting of magnesium stearate through ASTM #60 mesh and blending with Step-6 blend in a blender.
8. Compression of the Step-7 lubricated blend to form matrix tablets.
9. Preparation of the aqueous coating dispersion.
10. Coating of Step-8 matrix tablets with Step-9 coating dispersion.
Example 6
Table 18: Composition of Example 6

Sr. No. Ingredients Qry./tab (mg)
Core Com position:
1 Clarithromycin 500.000
2 Citric acid anhydrous 128.000
Povidone 50.000
4 Lactose monohydrate 73.500
5 Hydroxypropyl methyl cellulose phthalate 25.000

6 Hydroxypropylmethyl cellulose (4000 cps) 40.000
7 Hydroxypropylmethyl cellulose (5cps) 70.000
8 Microcrystalline cellulose 88.500
9 Magnesium Stearate 10.000
10 Purified water q.s.
Weight of Core Tablet (mg) 985.000
Coaling Composition :
11 Hydroxypropyl methyl cellulose (6 cps) 18.750
12 Titanium Dioxide 5.255
13 Quinoline Yellow Aluminium Lake 4.118
14 PEG 400 1.875
15 FD & C Blue # 2 / Indigo Carmine Aluminium Lake 0.002
16 Purified water q.s.
Weight of Coated Tablet (mg) 1015.000
Brief Manufacturing Procedure:
1. Sifting of Clarithromycin through ASTM mesh #20 and Citric acid anhydrous through ASTM mesh #80 and dry mixing in the rapid mixer granulator.
2. Preparation of binder solution by dissolving povidone in purified water.
3. Granulation of Step-1 dry mix using Step-2 binder solution.
4. Drying of Step-3 granules.
5. Sifting of Step-4 dried granules through ASTM # 16 mesh.
6. Sifting of hydroxypropyl methyl cellulose phthalate. lactose monohydrate, microcrystalline cellulose, hydroxypropylmethyl cellulose (4000 cps), & hydroxypropyl methyl cellulose (5 cps) through ASTM mesh #40 and mixing with Step-5 granules in a blender.
7. Sifting of magnesium stearate through ASTM #60 mesh and blending with Step-6 blend in a blender.
8. Compression of the Step-7 lubricated blend to form matrix tablets.
9. Preparation of the aqueous coating dispersion.
10. Coating of Step-8 matrix tablets with Step-9 coating dispersion.

We Claim
1. A prolonged release pharmaceutical composition for oral drug delivery system in form of matrix system comprising pharmaceutically effective amount of Clarithromycin or its pharmaceutically acceptable salt, solvate, enantiomers or mixtures thereof, one or more of enteric or non-enteric release retarding agents or combination of both along with pharmaceutically acceptable excipients.
2. A prolonged release pharmaceutical composition of claim 1, wherein dosage form comprises of film coated prolonged release tablets of Clarithromycin.
3. A prolonged release pharmaceutical composition of claim 1, wherein tablet dosage form prepared by either wet granulation or dry granulation or direct compression method, more preferably by wet granulation method.
4. A prolonged release pharmaceutical composition of claim 1, wherein the non-enteric release retarding agents comprises one or more cellulose derivatives, polysaccharide gums
5. A prolonged release pharmaceutical composition of claim 1, wherein cellulose derivatives comprises one or more of ethyl cellulose, hydroxy ethyl cellulose, hydroxypropylmethyl cellulose, hydroxypropyl cellulose, and methylcellulose, preferably hydroxy-propyl methylcellulose and hydroxyl ethyl cellulose.
6. A prolonged release pharmaceutical composition of claim 5, wherein hydroxypropyl methylcellulose used of nominal viscosity of about 3 cps to 200000cps.
7. A prolonged release pharmaceutical composition of claim 4, wherein cellulose derivatives comprises between about 1 % to about 20% w/w.
8. A prolonged release pharmaceutical composition of claim 4, wherein polysaccharide gums comprise one or more of guar gum, xanthan gum, karaya gum, gellan gum, hupu gum, carob gum. caramania gum, sodium alginate, carrageenan, ceratonia, sodium calcium alginate and alginic acid, preferably sodium alginate and sodium calcium alginate.

9. A prolonged release pharmaceutical composition of claim 8,. wherein polysaccharide
gums comprises between about 1 % to about 20% w/w.
10. A prolonged release pharmaceutical composition of claim 1. wherein enteric release retardant polymers comprise one or more of poly (butyl methacrylate, (2-dimethy! aminomelhyl) methacrylate, methyl methacrylate) 1:2:1, poly (methacrylic acid. methyl methacrylate) 1:1. Poly(methacrylic acid, ethyl acrylate) 1:1, poly (methacrylic acid, methyl methacrylate) 1:2, poly (ethyl acrylate, methyl methacrylate. trimethyi ammonio-ethyl methacrylate chloride) 1:2:0.2, poly (ethyl acrylate. methyl methacrylate, trimethyi ammonio-ethyl methacrylate chloride) 1:2:0.1. cellulose acetate phthalate, hydroxypropylmethyl cellulose phthalate, hydroxypropylmethyl cellulose acetate succinate, dimethyl phthalate, diethyl phthalate, dibuty! phthalate, and mixture thereof, preferably hydroxypropyl methyl cellulose phthalate and poly(methacrylic acid-co-ethyl acrylate) 1:1.
11. A prolonged release pharmaceutical composition of claim 10, wherein enteric release retardant polymers comprises between about 1 % to about 20% w/w.
12. A prolonged release pharmaceutical composition of claim 1, wherein pharmaceutical!)' acceptable excipients further comprises one or more of diluents, acidulants, binders, glidants, lubricants, granulating solvents and film coating agents.
13. A prolonged release pharmaceutical composition of claim 12, wherein diluents comprises at least one or more of microcrystalline cellulose, silicified microcrystalline cellulose, lactose monohydrate, anhydrous lactose, directly compressible lactose, starch 1500, calcium phosphate (dibasic/tribasic), calcium sulphate, calcium sulphate dihydrate, fructose, sucrose, sorbitol, xylitol, dextrose, compressible sugar, dextrates, dextrin, starch, powdered cellulose, tragacanth, sodium chloride, potassium chloride, magnesium sulfate, magnesium chloride, sodium sulfate, lithium sulfate, urea, inositol, lactose, mannitol, magnesium succinate, potassium acid phosphate, preferably lactose monohydrate and microcrystalline cellulose.
14. A prolonged release pharmaceutical composition of claim 12, wherein acidulant comprises at least one or more of ascorbic acid, fumaric acid, citric acid anhydrous, preferably citric acid anhydrous.

15. A prolonged release pharmaceutical composition of claim 12, wherein, binders comprises at least one or more of povidone, pyrrolidone. co-povidone. acacia gum, guar gum. xanthan gum. karaya gum, gellan gum, hupu gum, carob gum, caramania gum. gelatin, glucose, sugar, dextrin, sorbitol, maltose, pregelatinized starch, carboxymethyl cellulose sodium, methyl cellulose, hydroxypropyl cellulose, low substituted hydroxypropyl cellulose, hydroxypropyl methyl cellulose, ethyl cellulose, hyroxyethyl cellulose, cellulose acetate, agar, alginic acid, sodium alginate. carbomers, carrageenan, ceratonia, chitosan, poloxamer, polyethylene oxide, magnesium aluminum silicate, preferably povidone and sodium alginate.
16. A prolonged release pharmaceutical composition of claim 12, wherein glidants comprises of one or more of colloidal silicon dioxide, talc, magnesium stearate, calcium stearate, hydrogenated castor oil. sodium lauryl sulfate, precipitated silicon dioxide and starch, preferably talc.
17. A prolonged release pharmaceutical composition of claim 12, wherein lubricant comprises of one or more of magnesium stearate, talc, calcium stearate, stearic acid. sodium stearyl fumarate, hydrogenated vegetable oils, magnesium lauryl sulfate, wax, polyethylene glycol, glyceryl behenate, glyceryl palmitostearate. palmitic acid. poloxamer, sodium benzoate and sodium lauryl sulfate, preferably magnesium stearate, talc and stearic acid.
18. A prolonged release pharmaceutical composition of claim 12, wherein granulating solvent comprises one or more of water, acetone, isopropyl alcohol and ethanol. preferably water and acetone.
19. A prolonged release pharmaceutical composition of claim 23, wherein granulating
solvents comprises between about 15 % to about 75 % w/w,
20. A prolonged release pharmaceutical composition of claim 1. wherein matrix system
comprises between 40 to 60% of active ingredient, between 1 to 50% of the enteric or
non enteric release retarding agents or combination of both, between 1 to 50% of the
diluents, between 1 to 20% of the acidulant, between 1 to 15% of the binders, between
0.1 to 5% of glidants, between 0.1 to 5% oflubricants and between 0.5 to 15% of the
coating agents.

21. A prolonged release pharmaceutical composition of claim 2. wherein the composition of film coating comprises one or more of film forming agents, opacifiers, plasticizers, coloring agents & solvents.
22. A prolonged release pharmaceutical composition of claim 12, wherein film forming agents comprises one or more of polyethylene glycol, polyvinyl alcohol, povidone, chitosan, maltodextrin, isomalt, ammonium alginate, gelatin, carrageen, ethyl lactate, cellulose derivatives like hydroxypropyl methyl cellulose, ethyl cellulose, hydroxymethyl cellulose, hydroxyethyl cellulose, hydroxypropyl cellulose, methyl cellulose, preferably hydroxypropyl methyl cellulose.
23. A prolonged release pharmaceutical composition of claim 2, wherein opacifiers comprises of titanium dioxide, ethylene glycol palmitostearate. acetates such as zinc acetate, silicates such as talc and aluminium silicate, carbonates such as magnesium carbonate, calcium carbonate, stearates such as aluminium stearate and zinc stearate, sulfates such as calcium sulfate, oxides such as magnesium oxide and hydroxides such as alumimuim hydroxides, preferably titanium dioxide.
24. A prolonged release pharmaceutical composition of claim 2, wherein plasticizers comprises of one or more of polyethylene glycols, propylene glycol, glycerine, caster oil, acetyltriethyl citrate, benzyl benzoate, chlorbutanol, dextrin, acetyltributyl citrate, dimethyl phthalate, diethyl phthalate, dibutyl phthalate, dibutyl sebacate, glyceryl monooleate, glyceryl monostearate, 2-pyrrolidone. sorbitol, stearic acid, palmitic acid, triacetin, tributyl citrate, triethyl citrate, triethanolamine, surfactants like polysorbates, sorbitan esters and organic acid esters and mixtures thereof, preferably polyethylene glycol.
25. A prolonged release pharmaceutical composition of claim 2, wherein coloring agents used may be one or more of colors approved by FDA.
26. A prolonged release pharmaceutical composition of claim 2. wherein solvents used for coating solution/dispersion comprises of water, ethyl acetate, acetone, isopropyl alcohol, n-propanol, ethanol or mixtures thereof.
27. A prolonged release pharmaceutical composition of claim 2, wherein solvents used for coating solution/dispersion comprises between about 15 % to about 45 % w/w.

28. A prolonged release pharmaceutical composition of claim 2. wherein coating comprises about 0.5 % to about 5.0 % w/w of film forming agent; about 0.1 % to about 3.0 % w/w of opacifier; about 0.05 % to about 1 .0 % of plasticizers.
29. A prolonged release pharmaceutical composition of claim I prepared by process comprising;
a. Sifting of drug and pharmaceutically acceptable excipients.
b. Dry mixing or granulation of ingredients.
c. Blending and lubrication.
d. Compression of the lubricated blend of step (c) into tablets &
e. Film coating of the compressed tablets.
30. A prolonged release pharmaceutical composition of claim 1, wherein the dosage form releases, not more than 20% at 2 hours, between 45 % and 80 % at 12 hours & not less than 80% at 24 hours, as measured in 0.05M Phosphate Buffer pH 6.8 with 0.5% SLS maintained at 37±2°C using USP Type 1 apparatus.
31. A prolonged release pharmaceutical composition of claim 1 wherein the dosage form is used for the treatment of microbial infection.
32. A prolonged release pharmaceutical composition of claim I wherein the dosage form is administered once a daily.
33. A prolonged release pharmaceutical composition substantially as herein described and illustrated with reference to the accompanying examples.