Field of the invention
The technical field of the present invention relates to oral dosage forms comprising p-lactam antibiotic and P-lactamase inhibitor prepared by granulation process. More particularly, the present invention relates to oral dosage forms comprising amoxicillin and clavulanic acid prepared by wet granulation process.
Background of the invention
p-lactam antibiotics such as amoxicillin, ampicillin, flucloxacillin are widely used in the treatment of bacterial infections. To enhance the antibacterial effects, p-lactam antibiotics are generally used in combination with p-lactamase inhibitors like clavulanic acid or its salts.
The combination of amoxicillin and potassium clavulanate is available as immediate release tablets and powder for oral suspension under the trade name Augmentin® and extended release tablets under the trade name Augmentin XR® in the US. The combination is used as a broad spectrum antibiotic for the treatment of commonly occurring bacterial infections.
Commercially available tablets marketed under the trade name Augmentin® contain 250/125, 500/125, 500/62.5, and 875/125 mg of amoxicillin/clavulanic acid (in the form of potassium clavulanate) as active ingredients and excipients such as colloidal silicon dioxide, hypromellose, magnesium stearate, microcrystalline cellulose, polyethylene glycol, sodium starch glycolate and titanium dioxide.
Pharmaceutical industry employs various methods for compounding substances in tablet formulation. In particular granulation is one of the most prevalent methods. Granulation is a process whereby granules are formed from a bulk drug substance with or without excipients to improve the properties of the bulk drug or formulation. Granules are preparations consisting of solid, dry agglomerates of powder particles sufficiently robust to withstand handling.
Wet granulation is distinguished from dry granulation in that a granulating liquid, such as water, organic solvents or mixtures thereof, are used in wet granulation to produce granules. The advantages of wet granulation include improvement of the cohesiveness and compactability of powders, increase in density, good distribution providing uniform content of micronized drugs, reduction of dust and airborne contamination, and prevention of segregation of components.
Given below are the patents/patent publications, which disclose pharmaceutical compositions of amoxicillin:
US 4,537,887 discloses composition comprising amoxicillin, clavulanic acid and colloidal silica.
US 4,950,484 discloses granulate comprising amphoteric p-lactam antibiotic, up to 0.5 wt % of a wet binding substance, based on the weight of the antibiotic, and a cellulose product prepared by mixing beta-lactam antibiotic with water and a cellulose product, granulating the resulting wet mass to form a granulate.
US 5,851,550 and its family disclose a process for the manufacture of a tablet comprising amoxicillin, clavulanic acid by dry roller compaction.
US 5,948,422 discloses a process for the preparation of a granulate comprising moistening the antibiotic with an aqueous solution containing 0-0.5 wt % of a wet granulation binding agent the percentage based on the granulate; screening the mass through a 2 mm sieve; drying the product; and screening the dry product through an at least 0.71 mm sieve using 10-35% based on the weight of the antibiotic of the aqueous solution.
US 6,051,255 discloses a process for preparing an aqueous film coated tablet comprising a compacted mixture of amoxicillin and clavulanate.
US 6,177,421 discloses a unit-dose composition comprising p-lactam antibiotic in combination with at least one p-lactamase inhibitor, together with a
pharmaceutical^ acceptable carrier, wherein said composition does not comprise an extra-granular disintegrant and is prepared by slugging.
US 2006/0159741 discloses formed particles comprising amoxicillin and clavulanic acid, wherein the particles are obtained by wet granulation using an organic solvent or with binder dispersion in an organic solvent.
WO 2006/066930 discloses formulation comprising a granulate comprising amoxicillin and excipients, clavulanic acid prepared by dry granulation.
WO 2007/059916 discloses a solid dosage form comprising a p-lactam antibiotic and having a film coating comprising a p-lactamase inhibitor.
The above prior art references disclose various compositions of p-lactam antibiotic in combination with p-lactamase inhibitor prepared by dry granulation or wet granulation using organic solvent. The use of organic solvents is not preferable as it generates toxic vapor which cause explosions and even the traces of solvent should be carefully eliminated to avoid the odour of solvent. And also some of the above prior art references further disclose that wet granulation is avoided in compositions comprising p-lactamase inhibitors such as clavulanic acid as they are moisture sensitive and degrades quickly in presence of water. During our continuous efforts, it was observed that stable compositions can be obtained by granulating amoxicllin using aqueous solvent and mixing clavulanic acid extra granularly.
Objective of the invention
Accordingly, the main objective of the present invention is to provide oral dosage forms comprising p-lactam antibiotic and p-lactamase inhibitor prepared by simple and cost effective wet granulation process.
Yet another objective of the present invention is to provide oral dosage forms comprising P-lactam antibiotic and p-lactamase inhibitor prepared by wet granulation process in such a way that the dosage forms will comply with the
reference product in terms of in vivo parameters like Cmax, tmaK and AUC and in vitro parameters like dissolution, disintegration and etc.
Summary of the invention Accordingly, the present invention provides oral dosage form comprising p-lactam antibiotic and p-lactamase inhibitor prepared by a process, which comprises the steps of:
i) granulating p-lactam antibiotic and one or more intragranular excipients using 0.5-10% w/w of aqueous binder solution/dispersion,
ii) drying the granules obtained in step (i),
iii) blending the dried granules obtained in step (ii) with P-lactamase inhibitor and one or more extragranular excipients,
iv) processing the blend of step (iii) into solid dosage form.
Detailed description of the invention In an embodiment of the present invention, the p-lactam antibiotic is amoxicillin and the P-lactamase inhibitor is potassium clavulanate.
The term amoxicillin used according to the present invention includes amoxicillin trihydrate, amoxicillin sodium or mixture of both.
In another embodiment, the intragranular excipients include one or more of diluent, binder, disintegrant, release retarding polymers.
In another embodiment, the oral solid dosage form comprises about 50% to about 75%w/w of p-lactam antibiotic, 3% to about 15% w/w of diluent, about 1% to about 5% w/w of disintegrant as intragranular excipients.
In another embodiment, the extragranular excipients include one or more of diluent, disintegrant, glidant and lubricant.
Suitable diluents used according to the present invention are selected from spray-dried monohydrate or anhydrous lactose, sucrose, dextrose, mannitol, sorbitol, starch, microcrystalline cellulose, silicified microcrystalline cellulose, dihydrated or anhydrous dibasic calcium phosphate and the like or combination thereof.
The binders used according to the present invention are either water soluble or water insoluble. Suitable water soluble binders include polyvinylpyrrolidone, pregeltinised starch, hydroxypropyl cellulose, hydroxypropylmethylcellulose, starch and the like, and water insoluble binders include ethylcellulose, polymethacrylates and the like.
Suitable disintegrants used according to the present invention are selected from pregelatinised starch, cross linked polyvinylpyrrolidone, sodium starch glycolate, and croscarmellose sodium and the like or combination thereof.
Suitable release retarding polymers of the present invention include methylcellulose, ethylcellulose, hydroxypropylcellulose, carboxymethylcellulose and its salts, hydroxypropylmethylcellulose, polyvinylalcohols, polyoxyethylene glycols, polyethylene oxide, povidone, acrylic acid copolymers, carbopol, xanthan gum, alginates and its salts and the like.
Suitable glidants of the present invention include calcium silicate, magnesium carbonate, talc, magnesium oxide, magnesium silicate, colloidal silicon dioxide and the like.
Suitable lubricants used according to the present invention are selected from magnesium stearate, calcium stearate, sodium stearyl fumerate, vegetable oils, stearic acid, fumaric acid, glyceryl behenate and the like.
The compositions of the present invention may be in the form of immediate release or sustained release, preferably containing from 250 to 1000 mg of amoxicillin and the appropriate amount of clavulanic acid. They may be prepared as 250/125, 500/125, 500/62.5, 875/125mg and 1000/62.5 mg unit dosage forms and the ratio of amoxicillin to clavulanic acid may vary between 1:1 to 20:1 preferably 1:1,2:1,4:1 and 7:1.
The dosage forms prepared according to present invention may be administered twice or three times daily depending on the severity of the infection.
The immediate release dosage forms prepared according to present invention releases more than 90% of amoxicillin and clavulanate within 30 minutes when the dissolution is carried out in 900 ml of purified water as medium according to the procedure described in the USP, Apparatus USP 11/900 ml, Paddle, @ 75 rpm speed.
In a preferred embodiment, the oral dosage form comprising p-lactam antibiotic and P-lactamase inhibitor prepared by a process, which comprises the steps of:
(i) granulating about 25% to about 85%w/w of p-lactam antibiotic, about 3% to about 15% w/w of diluent, about 1% to about 10% w/w of disintegrant using about 0.5% to about 10% w/w of aqueous binder solution/dispersion,
(ii) drying the granules obtained in step (i),
(iii) blending the dried granules of step (ii) with 3% to about 25% w/w of p- lactamase inhibitor, about 3% to about 15% w/w of diluent, about 0% to about 0.5% w/w of disintegrant, about 0.5% to about 5% w/w of glidant and about 0.5% to about 5% w/w of lubricant and
(iv) processing the granules obtained in step (iii) into solid dosage form. Potassium clavulanate is blended with a diluent such as Avicel
(Microcrystalline cellulose) or Syloid (Colloidal silicon dioxide) in a ratio of 1:1. This blend is directly used for preparing dosage forms according to present invention.
In another preferred embodiment, the oral dosage forms comprising amoxicllin and potassium clavulanate prepared by a process, which comprises the steps of:
(i) granulating about 25% to about 85%w/w of amoxicillin, about 3% to about 15% w/w of diluent selected from microcrystalline cellulose, lactose; about 1% to about 10% w/w of disintegrant selected from sodium starch glycolate, crospovidone or combination thereof, using about 0.5% to about 10% w/w of aqueous binder solution/dispersion selected from ethylcellulose, pregelatinised starch,
(ii) drying the granules obtained in step (i),
(iii) blending the dried granules of step (ii) with 3% to about 25% w/w of potassium clavulanate; about 3% to about 15% w/w of diluent selected from microcrystalline cellulose, lactose; about 0% to about 0.5% w/w of disintegrant selected from sodium starch glycolate, crospovidone; about 0.1% to about 5% w/w of glidant selected from colloidal silicon dioxide, talc and about 0.1% to about 5% w/w of lubricant selected from magnesium stearate, sodium stearyl fumerate and
(iv) processing the granules obtained in step (iii) into solid dosage form. In another preferred embodiment, the oral dosage form comprises
(a) 25% to about 85%w/w of p-lactam antibiotic,
(b) about 3% to about 25% w/w of diluent, about 0.5% to about 10% w/w of ethyl cellulose, about 1% to about 10% w/w of disintegrant as intragranular excipients,
(c) 3% to about 25% w/w of p-lactamase inhibitor,
(d) about 3% to about 25% w/w of diluent, about 0% to about 0.5% w/w of disintegrant, about 0.5% to about 5% w/w of glidant and about 0.5% to about 5% w/w of lubricant as extragranular excipients.
In another preferred embodiment, the oral dosage form comprises about 25% to about 85%w/w of amoxicillin; 3% to about 25% w/w of potassium clavulanate; 3% to about 20% w/w of microcrystalline cellulose; about 1% to about 10% w/w of disintegrant selected from sodium starch glycolate, crospovidone or combination thereof; about 0.5% to about 10% of ethyl cellulose; about 0.1% to about 5% w/w of colloidal silicon dioxide; and about 0.1% to about 5% w/w of magnesium stearate.
The solid oral dosage forms include tablets and capsules and the tablets may be uncoated or optionally coated.
In yet another embodiment of the present invention, film coating composition comprises a solution / suspension of film coating polymers and one or more excipients such as lactose, titanium dioxide, surfactant and antisticking agent.
In yet another embodiment, the present invention also provides method of treating bacterial infections such as upper respiratory tract infections, lower respiratory tract infections, genito-urinary tract infections and skin and soft tissue infections by administering dosage form prepared according to present invention.
The following examples further exemplify the invention and are not intended to limit the scope of the invention. It is obvious to those skilled in the art to find out the composition for other dosage forms and substitute the equivalent excipients as described in this specification or with the one known to
the industry. Example 1
Ingredients Qty (mg)
Intragranular
Amoxicillin Trihydrate 1000.4
Microcrystalline cellulose 79.37
Crospovidone 14.7
Sodium starch glycolate 14.7
Binder solution
Ethyl cellulose 28.7
Purified water QS
Extra granular
Clavulanate Potassium + Avicel (1:1) 277.77
Colloidal Silicon Dioxide 14.7
Magnesium Stearate 14.7
Film coating
Hypromellose 15.4
Polyethylene glycol 4.540
Titanium dioxide 14.7
Tween 80 0.35
Purified water 14.7

The processing steps involved in manufacturing compositions given in example 1 are given below:
i) Amoxicillin trihydrate, microcrystalline cellulose, crospovidone, sodium starch glycollate, were sifted and blended,
ii) aqueous dispersion of ethyl cellulose was prepared,
iii) granulated the blended material of step (i) with dispersion of step (ii),
iv) the granules obtained in step (iii) were dried and the dried granules were blended with extragranular potassium clavulanate, microcrystalline cellulose and colloidal silicon dioxide,
v) the blend of step (iv) was lubricated with magnesium stearate and
vi) the lubricated blend was compressed to obtain tablets or filled into capsules.
The compositions given in examples 2 & 3 were prepared using similar procedure as described in example 1.
Example 2
Ingredients Qty (mg)
Intragranular
Amoxicillin Trihydrate 573.920
Microcrystalline cellulose 45.35
Crospovidone 8.4
Sodium starch glycolate 8.4
Binder solution
Ethyl cellulose 16.4
Purified water Qs
Extra granular
Clavulanate Potassium + Avicel (1:1) 277.77
Colloidal Silicon Dioxide 9.630
Magnesium Stearate 9.630
Film coating
Hypromellose 10.067
Polyethylene glycol 2.974
Titanium dioxide 9.610
Tween 80 0.229
Purified water Qs

Example 3
Ingredients Qty (mg)
Intragranular
Amoxicillin Trihydrate 286.96
Microcrystalline cellulose 22.675
Crospovidone 4.20
Sodium starch glycolate 4.20
Binder solution
Ethyl cellulose 8.20
Purified water Qs
Extra granular
Clavulanate Potassium + Avicel (1:1) 277.77
Colloidal Silicon Dioxide 6.248
Magnesium Stearate 6,247
Film coating
Hypromellose 6.539
Polyethylene glycol 1.932
Titanium dioxide 6.241
Tween 80 0.149
Purified water Qs
Example 4
Ingredients Qty (mg)
Intragranular
Amoxicillin Trihydrate 1004.360
Microcrystalline cellulose 71.020
Crospovidone 14.70
Sodium starch glycolate 14.70
Binder solution
Ethyl cellulose 18.5
Purified water Qs
Extra granular
Clavulanate Potassium + Avicel (1:1) 297.620
Crospovidone 14.70
Colloidal Silicon Dioxide 14.70
Magnesium Stearate 14.70
Film coating
Hypromellose 20.791
Polyethylene glycol 6.122
Titanium dioxide 20.248

Purified water Qs
Example 5
Ingredients Qty (mg)
Intragranular
Amoxicillin Trihydrate 573.920
Microcrystalline cellulose 40.582
Crospovidone 8.4
Sodium starch glycolate 8.4
Binder solution
Ethyl cellulose 10.570
Purified water Qs
Extra granular
Clavulanate Potassium + Avicel (1:1) 297.620
Colloidal Silicon Dioxide 10.169
Crospovidone 10.169
Magnesium Stearate 10.70
Film coating
Hypromellose 13.791
Polyethylene glycol 4.054
Titanium dioxide 13.407
Purified water Qs

The processing steps involved in manufacturing compositions given in example 4 & 5 are given below:
i) Amoxicillin trihydrate, microcrystalline cellulose, crospovidone, sodium starch glycollate, were sifted and blended,
ii) aqueous dispersion of ethyl cellulose was prepared,
iii) granulated the blended material of step (i) with dispersion of step (ii),
iv) the granules obtained in step (iii) were dried and the dried granules were blended with extragranular potassium clavulanate, microcrystalline cellulose, crospovidone and colloidal silicon dioxide,
v) the blend of step (iv) was lubricated with magnesium stearate and
vi) the lubricated blend was compressed to obtain tablets or filled into capsules.
The compositions given in examples 6 to 10 were prepared using similar procedure as described in example 4.
Example 6
Ingredients Qty (mg)
Intragranular
Amoxicillin Trihydrate 286.960
Microcrystalline cellulose 20.291
Crospovidone 4.2
Sodium starch glycolate 4.2
Binder solution
Ethyl cellulose 5.285
Purified water Qs
Extra granular
Clavulanate Potassium + Avicel (1:1) 297.620
Colloidal Silicon Dioxide 7.148
Crospovidone 7.148
Magnesium Stearate 7.148
Film coating
Hypromellose 9.052
Polyethylene glycol 2.674
Titanium dioxide 8.846
Purified water Qs
Example 7
Ingredients Qty (mg)
Intragranular
Amoxicillin Trihydrate 1004.360
Microcrystalline cellulose 56.42
Crospovidone 14.70
Sodium starch glycolate 29.30
Binder solution
Ethyl cellulose 18.5
Purified water Qs
Extra granular
Clavulanate Potassium + Avicel (1:1) 297.620
Crospovidone 14.70
Colloidal Silicon Dioxide 14.70
Magnesium Stearate 14.70
Film coating
Hypromellose 20.791

Polyethylene glycol 6.122
Titanium dioxide 20.248
Purified water Qs
Example 8
Ingredients Qty (mg)
Intragranular
Amoxicillin Trihydrate 1012.46
Microcrystalline cellulose 61.2
Crospovidone 14,70
Sodium starch glycolate 14.70
Binder solution
Ethyl cellulose 17.5
Purified water Qs
Extra granular
Clavulanate Potassium + Avicel (1:1) 299.04
Colloidal silicon dioxide 14.70
Magnesium Stearate 14.70
Film coating
Hypromellose 17.60
Polyethylene glycol 4.16
Titanium dioxide 9.92
Tween 80 0.32
Purified water Qs
Example 9
Ingredients Qty
Intragranular
Amoxicillin Trihydrate 580.15
Microcrystalline cellulose 21.99
Crospovidone 8.40
Sodium starch glycolate 8.40
Binder solution
Ethyl cellulose 10.00
Purified water Qs
Extra granular
Clavulanate Potassium + Avicel (1:1) 301.8
Colloidal Silicon dioxide 9.63
Magnesium stearate 9.63
Film coating

Hypromellose 10.067
Polyethylene glycol 2.974
Titanium dioxide 9.610
Tween 80 0.229
Purified water Qs
Example 10
Ingredients Qty (mg)
Intragranular
Amoxicillin Trihydrate 290.07
Microcrystalline cellulose 12.25
Crospovidone 4,2
Sodium starch glycolate 4.2
Binder solution
Ethyl cellulose 5.0
Purified water Qs
Extra granular
Clavulanate Potassium + Avicel (1:1) 301.8
Colloidal Silicon Dioxide 6.24
Magnesium Stearate 6.24
Film coating
Hypromellose 7.266
Polyethylene glycol 2.146
Titanium dioxide 6.934
Tween 80 0.166
Purified water Qs

The following table shows the dissolution profile of the amoxicillin-clavulanate tablets prepared according to the present invention carried out in 900 ml of purified water as medium according to the procedure described in the USP, Apparatus USP 11/900 ml, Paddle, @ 75 rpm speed. The release profile (% of drug released in minutes) is given in tables 1.
Table 1
Time in minutes Example 4 Example 5
% of drug dissolved
Amoxicillin Clavulanate Amoxicillin Clavulanate
10 89 96 86 95
20 99 97 100 98
30 103 97 103 99

Table 2
Time in minutes Example 6 | Example 7
% of drug dissolved
Amoxicillin Clavulanate Amoxicillin Clavulanate
10 72 94 78 94
20 93 101 91 101
30 99 101 95 102

Table 3
Time in minutes Example 8 Example 9
% of drug dissolved
Amoxicillin Clavulanate Amoxicillin Clavulanate
10 77 57 88 100
20 97 92 99 100
30 98 92 100 100
Table 4
Time in minutes Example 10
% of druj » dissolved
Amoxicillin Clavulanate
10 85 98
20 96 98
30 98 98

Claims:
1. An oral dosage form comprising (5-lactam antibiotic and p-lactamase inhibitor prepared by a process, which comprises the steps of:
i) granulating p-lactam antibiotic and one or more intragranular excipients using 0.5-10% w/w of aqueous binder solution/dispersion,
ii) drying the granules obtained in step (i),
iii) blending the dried granules obtained in step (ii) with p-Iactamase inhibitor and one or more extragranular excipients,
iv) processing the blend of step (iii) into solid dosage form.
2. The dosage form of claim 1, wherein the p-lactam antibiotic is amoxicillin and the P-lactamase inhibitor is potassium clavulanate.
3. The dosage form as claimed in claim 1, wherein the intragranular excipients comprise diluent, binder and disintegrant.
4. The dosage form of claim 1, wherein the extra granular excipients comprise diluent, disintegrant, glidant and lubricant.
5. The dosage form of claims 3 and 4, wherein the diluent is selected from spray-dried monohydrate or anhydrous lactose, sucrose, dextrose, mannitol, sorbitol, starch, microcrystalline cellulose, silicified microcrystalline cellulose, dehydrated and anhydrous dibasic calcium phosphate or mixture thereof.
6. The dosage form of claim 1, wherein the binder is selected from starch, ethylcellulose, hydroxypropyl cellulose, hydroxypropylmethylcellulose, polyvinylpyrrolidone and pregelatinized starch.
7. The dosage form of claims 3 and 4, wherein the disintegrant is selected from pregelatinised starch, cross linked polyvinylpyrrolidone, sodium starch glycolate and croscarmellose sodium.
8. An oral dosage form comprising about 25% to about 85%w/w of amoxicillin; 3% to about 25% w/w of potassium clavulanate; 3% to about 20% w/w of microcrystalline cellulose; about 1% to about 10% w/w of disintegrant selected from sodium starch glycolate, crospovidone or combination thereof;
about 0.5% to about 10% of ethyl cellulose; about 0.1% to about 5% w/w of colloidal silicon dioxide; and about 0.1% to about 5% w/w of magnesium stearate.
9. An oral dosage form comprising (3-lactam antibiotic and p-lactamase inhibitor prepared by a process, which comprises the steps of:
(i) granulating about 25% to about 85%w/w of p-lactam antibiotic, about 3% to about 15% w/w of diluent, about 1% to about 10% w/w of disintegrant using about 0.5% to about 10% w/w of aqueous binder solution/dispersion,
(ii) drying the granules obtained in step (i),
(iii) blending the dried granules of step (ii) with 3% to about 25% w/w of p- lactamase inhibitor, about 3% to about 15% w/w of diluent, about 0% to about 0.5% w/w of disintegrant, about 0.5% to about 5% w/w of glidant and about 0.5% to about 5% w/w of lubricant and
(iv) processing the granules obtained in step (iii) into solid dosage form.
10. An oral dosage form comprising amoxicllin and potassium clavulanate prepared by a process, which comprises the steps of:
(i) granulating about 25% to about 85%w/w of amoxicillin, about 3% to about 15% w/w of diluent selected from microcrystalline cellulose, lactose; about 1% to about 10% w/w of disintegrant selected from sodium starch glycolate, crospovidone or combination thereof, using about 0.5% to about 10% w/w of aqueous binder solution/dispersion selected from ethylcellulose, pregelatinised starch,
(ii) drying the granules obtained in step (i),
(iii) blending the dried granules of step (ii) with 3% to about 25% w/w of potassium clavulanate; about 3% to about 15% w/w of diluent selected from microcrystalline cellulose, lactose; about 0% to about 0.5% w/w of disintegrant selected from sodium starch glycolate, crospovidone; about 0.1% to about 5% w/w of glidant selected from colloidal silicon dioxide, talc and about 0.1% to
about 5% w/w of lubricant selected from magnesium stearate, sodium stearyl fumerate and
(iv) processing the granules obtained in step (iii) into solid dosage form.