WO2008029351A2

WO2008029351A2 - A modified release formulation comprising amoxicillin and clavulanate

Info

Publication number: WO2008029351A2
Application number: PCT/IB2007/053563
Authority: WO
Inventors: Nidhi Singh; Vivek Mahendra Kumar Dubey; Romi Barat Singh
Original assignee: Ranbaxy Laboratories Limited
Priority date: 2006-09-04
Filing date: 2007-09-04
Publication date: 2008-03-13
Also published as: WO2008029351A3

Abstract

The present invention relates to a modified release formulation comprising amoxicillin and clavulanate, processes of preparation thereof and methods of treating bacterial infection using these formulations. The formulation comprises an immediate- release phase comprising amoxicillin sodium and clavulanate and a slow-release phase comprising amoxicillin trihydrate.

Description

A MODIFIED RELEASE FORMULATION COMPRISING AMOXICILLIN

AND CLAVULANATE

Field of the Invention

Background of the Invention Pharmaceutical formulations comprising amoxicillin and clavulanate approved for marketing in U.S. are immediate -release and modified-release formulations. These formulations contain various weight ratios of amoxicillin and potassium clavulanate ranging from 2:1 to 16: 1. For instance, conventional swallow tablets comprising 250 mg/125 mg, 500 mg/125 mg, 500 mg/62.5 mg, and 875 mg/125 mg amoxicillin/clavulanic acid (in the form of potassium clavulanate). Such tablets comprise amoxicillin and clavulanic acid in the ratios 2: 1, 4:1, 8:1 and 7:1, respectively. The 875 mg/125 mg tablet was developed to provide a tablet formulation, which could be administered in a b.i.d. (twice daily) dosage regimen. It is also marketed for t.i.d. (three times daily) dosing, in Italy and Spain. The 500 mg/62.5 mg tablet was also developed to provide a tablet formulation, which could be administered in a b.i.d. dosage regimen, two such tablets being taken every 12 hours, in preference to a single 1000 mg/125 mg tablet. A 1000 mg/125 mg single dosage is also available, in France, but as a single dosage sachet rather than a tablet. Typically, the approved regimen provides a single dosage of 125 mg of potassium clavulanate. Various controlled-release preparations involving multilayered tablets are described in literature. For example, U.S. Patent No. 6,372,255 discloses a multilayer tablet comprising at least two superposed layers, wherein: a first outer layer comprises a mixture of excipients and a first active substance, wherein the first layer allows immediate-release of the first active substance; a second layer, which is in contact with the first layer, comprises at least one non-biodegradable, inert porous polymeric matrix in which a second active substance is dispersed; wherein the second active substance is identical to the first active substance.

U.S. Patent No. 6,294,200 discloses a tablet comprising a three layered core covered by a partial coating layer, said core having an upper layer consisting of active substance and suitable excipients to allow a fast release of the active substance when the tablet comes into contact with an aqueous medium; an intermediate layer whose composition comprises polymeric material suitable to form a barrier able to determine a time interval between the release of the active substance contained in the upper layer and the active substance contained in the lower layer, a lower layer comprising one or more active substances and having the same or a different composition as the upper layer, said lower layer allowing the controlled release of said active substances; and wherein said partial coating layer consists of granulated polymeric substances, adjuvant substances and plasticizing agents applied by compression on the whole lateral surface and on the lower base of said three layered core thus forming an impermeable barrier which resists dissolution for a predetermined period of time while allowing for the release of the active substance both from the upper layer and from the lower layer, said polymeric substances being selected from hydroxypropyl methylcellulose having viscosity between 4,000 and 100,000 cp when measured at 20 ⁰C in a 2 % aqueous solution.

PCT Publication No. WO 95/20946 discloses layered tablets comprising amoxicillin and, optionally, potassium clavulanate, having a first layer, which is an immediate-release layer and a second layer, which is a slow-release layer. The ratio of amoxicillin to clavulanic acid disclosed therein ranges from 30:1 to 1: 1, with a preferred range of 8: 1 to 1 : 1. The formulations disclosed therein have a pharmacokinetic profile such as there is no early burst of amoxicillin, but a much more protracted release over a period of time as reflected by a lower C_max value.

U.S. Patent No. 6,136,345 discloses a tablet formulation for oral administration comprising amoxicillin and clavulanate in a ratio of 30:1 to 1:1 in which a portion of the amoxicillin is in a central core which is surrounded by a release-retarding coating layer and the remainder of the amoxicillin and all of the clavulanate is in a casing layer surrounding the core, such that there is an initial quick release of amoxicillin and clavulanate from the casing layer and a sustained release of amoxicillin from the core. The release retarding coating is an enteric coating so that the second phase of the release after the immediate -release takes place in the intestine.

U.S. Patent No. 5,910,322 discloses a pharmaceutical tablet formulation, comprising: a matrix which comprises a beta-lactam antibiotic and a beta-lactamase inhibitor, and dispersed within said matrix, granules in a delayed-release form which comprise a beta-lactam antibiotic and a beta-lactamase inhibitor, and dispersed within said matrix granules in a rapid-release form which comprise a beta-lactam antibiotic and a beta-lactamase inhibitor. The delayed release form refers to enteric polymer coated granules. U.S. Patent No. 6,878,386 discloses a modified release pharmaceutical formulation comprising 1000 mg amoxicillin and 62.5 mg potassium clavulanate in which all of the potassium clavulanate and a first part of amoxicillin are formulated with pharmaceutically acceptable excipients which allow for immediate -release of the potassium clavulanate and the first part of amoxicillin, to form an immediate-release phase, and further comprising a second part of amoxicillin formulated with pharmaceutically acceptable excipients which allow for slow-release of the second part of amoxicillin, to form a slow-release phase. The slow-release phase comprises a release retarding excipient. Xanthan gum and organic acid are the preferable release retarding excipients. This patent teaches that the portion of amoxicillin, which is released immediately, is preferably amoxicillin trihydrate and the portion of amoxicillin, which is released slowly, is preferably sodium amoxicillin. The intimate contact between the organic acid and the salt of amoxicillin in the pharmaceutical formulation is believed to cause some form of interaction which modifies the release of the amoxicillin component from the formulation and thus achieve enhanced T> MIC (time above minimum inhibitory concentration) of amoxicillin. In view of the above, there remains a need for novel formulations that achieve desired pharmacokinetic profiles.

Summary of the Invention

We have surprisingly found that it is possible to achieve desired pharmacokinetic profile with modified release formulations containing immediate-release phase and slow- release phase such that the immediate-release phase comprises amoxicillin sodium and the slow-release phase comprises amoxicillin trihydrate. The modified release formulations of the present invention containing 16:1 ratio of amoxicillin and potassium clavulanate may be bioequivalent to formulations of Augmentin-XR (approved by the U.S. Food and Drug Administration containing 16: 1 ratio of amoxicillin and potassium clavulanate).

Thus provided herein are modified release pharmaceutical formulations comprising amoxicillin and clavulanate in a weight ratio of 16:1, wherein the formulation comprises: a) an immediate-release phase comprising amoxicillin sodium, potassium clavulanate and one or more disintegrants, and, b) a slow-release phase comprising amoxicillin trihydrate and one or more release retarding agents. The formulations can include one or more of the following embodiments. For example the amount of amoxicillin can range from about 1000 mg to about 2000 mg and the amount of clavulanate can range from about 62.5 mg to about 125 mg. In another embodiment, the amount of amoxicillin is 1000 mg ± 5 % and the amount of clavulanate is 62.5 mg ± 5 %. The disintegrant can be selected from one or more of croscarmellose sodium, sodium starch glycolate, crospovidone, hydroxypropyl cellulose, pregelatinised starch, microcrystalline cellulose or mixtures thereof. The amount of the disintegrant can range from about 0.2 to about 10 % w/w based on the weight of the immediate-release phase.

The release retarding agent can be selected from one or more of gums, hydrophobic polymers, hydrophilic polymers or mixtures thereof. Suitable gums can be selected from one or more of xanthan gum, guar gum, agar, carrageenan, tragacanth, acacia or mixtures thereof. Suitable hydrophobic polymers can be selected from one or more of cellulose derivatives, shellac, zein or mixtures thereof. Suitable hydrophilic polymers comprises one or more of cellulose derivatives selected from carboxymethylcellulose, hydroxypropyl cellulose or hydroxypropyl methylcellulose; polyvinylalcohol, polyvinylpyrrolidone, polyethylene oxide, alginic acid, alginic acid salts or mixtures thereof.

The amount of the release retarding agent can range from about 0.5 to about 50 % w/w based on the weight of the slow-release phase. The slow-release phase and/or the immediate-release phase can further comprise one or more pH modifiers. The amount of the pH modifier can range from about 1 to about 20 % w/w based on the weight of the slow-release phase. In another embodiment, the amount of the pH modifier can range from about 0.1 to about 5 % w/w based on the weight of the immediate-release phase. pH modifiers can be selected from one or more of acids, bases or mixtures thereof. Acids can be selected from one or more of citric acid, ascorbic acid, tartaric acid, malic acid, malonic acid, succinic acid, fumaric acid, maleic acid, adipic acid, lactic acid, levulinic acid, sorbic acid, polyacrylic acid, or salts thereof, or mixtures thereof. Bases can be selected from one or more of sodium carbonate, sodium bicarbonate, magnesium carbonate, magnesium oxide, calcium carbonate, calcium oxide, aluminium hydroxide, magnesium hydroxide, sodium hydroxide or sodium dihydrogen phosphate. The immediate-release phase and the slow-release phase can further comprise one or more pharmaceutically acceptable excipients. Suitable pharmaceutically acceptable excipients can be selected from one or more of diluents, binders, lubricants or glidants.

The modified release formulations can be in the form of tablet, capsule or sachet. Tablets can be bilayered.

Brief description of the Drawing

Figure 1 shows an in vitro release profile of tablets of Example 8, 10 & 11 compared with the release profile of Augmentin®-XR tablets by Smithkline Beecham.

Detailed Description of the Invention

Provided are modified release pharmaceutical formulations comprising an immediate-release phase comprising amoxicillin sodium and potassium clavulanate; and a slow-release phase comprising amoxicillin trihydrate. The formulation contains amoxicillin and clavulanate in a ratio of 16:1.

The immediate-release phase can comprise amoxicillin sodium, potassium clavulanate and one or more disintegrants; and the slow-release phase can comprise amoxicillin trihydrate and one or more release retarding agents. The immediate-release phase can also comprise amoxicillin sodium, potassium clavulanate and one or more disintegrants; and the slow-release phase can comprise amoxicillin trihydrate, one or more release retarding agents and one or more pH modifiers.

The immediate-release phase can also comprise amoxicillin sodium, potassium clavulanate, one or more disintegrants and one or more pH modifiers; and the slow-release phase can comprise amoxicillin trihydrate, one or more release retarding agents and one or more pH modifiers.

The modified release formulation can be in the form of bilayered tablet, which comprises 1000 mg ± 5 % of amoxicillin and 62.5 mg ± 5 % of clavulanate in a weight ratio of 16:1, comprising: a) a first layer which includes an immediate-release phase comprising amoxicillin sodium, potassium clavulanate and about 0.2 - 10 % w/w of one or more disintegrants based on the weight of the immediate -release phase, and, b) a second layer which includes a slow-release phase comprising amoxicillin trihydrate and about 0.5 - 50 % w/w of one or more release retarding agents based on the weight of the slow-release phase.

The modified release formulation can also be in the form of bilayered tablet, which comprises 1000 mg ± 5 % of amoxicillin and 62.5 mg ± 5 % of clavulanate in a weight ratio of 16:1, comprising: a) a first layer which includes an immediate-release phase comprising amoxicillin sodium, potassium clavulanate and about 0.2 - 10 % w/w of one or more disintegrants based on the weight of the immediate -release phase, and, b) a second layer which includes a slow-release phase comprising amoxicillin trihydrate, about 0.5 - 50 % w/w of one or more release retarding agents and about 1 - 20 % w/w of one or more pH modifiers based on the weight of the slow-release phase. The modified release formulation can also be in the form of bilayered tablet, which comprises 1000 mg ± 5 % of amoxicillin and 62.5 mg ± 5 % of clavulanate in a weight ratio of 16:1, comprising: a) a first layer which includes an immediate-release phase comprising amoxicillin sodium, potassium clavulanate, about 0.2 - 10 % w/w of one or more disintegrants and about 0.1 - 5 % w/w of one or more pH modifiers based on the weight of the immediate-release phase, and, b) a second layer which includes a slow-release phase comprising amoxicillin trihydrate, about 0.5 - 50 % w/w of one or more release retarding agents and about 1 - 20 % w/w of one or more pH modifiers based on the weight of the slow-release phase.

Also provided are methods of treating bacterial infections in humans, which comprise administering to a patient in need thereof a modified release formulation disclosed herein. Also provided herein are modified release formulations comprising amoxicillin and clavulanate in a weight ratio of 16:1. The amount of amoxicillin may range from about 1000 mg to about 2000 mg and the amount of clavulanate may range from about 62.5 mg to about 125 mg. Preferably, the amount of amoxicillin is 1000 mg ± 5 % and the amount of clavulanate is 62.5 mg ± 5 %. The term "amoxicillin," as used herein, refers to amoxicillin, or alkali, alkaline, or acid salts, hydrates, solvates or mixtures thereof. Preferably, amoxicillin may be in the form of amoxicillin trihydrate or amoxicillin sodium. Clavulanate may be in the form of potassium clavulanate.

Unless otherwise indicated, weights of amoxicillin and potassium clavulanate ("clavulanate") refer to the equivalent weights of the corresponding free acids. In addition, it will be appreciated that in practice, weights of amoxicillin and clavulanate to be incorporated into a formulation can be further adjusted, in accord with conventional practice, to take account of the potency of the amoxicillin and clavulanate.

As used herein, the term "immediate-release" refers to the release of the majority of the active material content within a relatively short time, for example within 1 hour, preferably within 30 minutes, after oral ingestion. Examples of such immediate -release formulations include conventional swallow tablets, dispersible tablets, chewable tablets, single dose sachets and capsules, or effervescent forms thereof.

As used herein, the term "modified release" refers to the release of a drug substance from a pharmaceutical formulation, at a slower rate than from an immediate - release formulation. Preferably the modified release formulation includes both an immediate-release phase and a slow-release phase. Modified release formulations are well-known in the art, for example, as described in Remington: The Science and Practice of Pharmacy, Nineteenth Edn, 1995, Mack Publishing Co, Pennsylvania, USA.

Modified release formulations described herein may be in the form of tablets, capsules, granules, sachet or any other suitable oral dosage form. Tablet dosage forms may be bilayered, trilayered or multilayered. In one embodiment, tablet dosage forms are preferably bilayered. Such layered tablets may contain one or more barrier layers with or without one or more active ingredients. Modified release formulations may contain immediate and slow-release phases together in one tablet or in the form of different tablets containing immediate and slow-release phase.

The modified release pharmaceutical formulations disclosed herein can comprise two phases, an immediate-release phase and a slow-release phase. Preferably the immediate-release phase comprises amoxicillin and potassium clavulanate and the slow- release phase comprises amoxicillin alone. The immediate-release phase comprises amoxicillin sodium and the slow-release phase comprises amoxicillin trihydrate. The immediate and slow-release phases may be incorporated in one layer or different layers of the tablet.

The immediate-release phase comprises one or more disintegrants and optionally other pharmaceutically acceptable excipients. The slow-release phase comprises one or more release retarding agents and optionally other pharmaceutically acceptable excipients. The immediate -release phase/slow-release phase may be in the form of granule, powder or mixtures thereof, filled into capsule or compressed into one or more layers of the tablet.

Suitable release retarding agents may be selected from one or more of gums, hydrophobic polymers or hydrophilic polymers or mixtures thereof. Suitable gums include, for example, xanthan gum, guar gum, agar, carrageenan, tragacanth or acacia.

The hydrophobic polymers may be cellulose derivatives for e.g., ethylcellulose, shellac or zein. The hydrophilic polymer may be cellulose derivatives, polyvinylalcohol, polyvinylpyrrolidone, polyethylene oxide, alginic acid or salts thereof. The cellulose derivatives used as hydrophilic polymer may be carboxymethylcellulose, hydroxypropyl cellulose or hydroxypropyl methylcellulose (for e.g., the product used under the trade names Methocel K4MCR, Methocel E5). The amount of the release retarding agent may range from about 0.5 - 50 % w/w based on the weight of the slow-release phase.

Suitable disintegrants may be selected from one or more of croscarmellose sodium, sodium starch glycolate, crospovidone, hydroxypropyl cellulose, pregelatinised starch, microcrystalline cellulose or mixtures thereof. The amount of the disintegrant may range from about 0.2 - 10 % w/w based on the weight of the immediate-release phase.

Suitable pH modifiers may be selected from one or more of acids, bases or mixtures thereof. Suitable acids may be selected from one or more of citric acid, ascorbic acid, tartaric acid, malic acid, malonic acid, succinic acid, fumaric acid, maleic acid, adipic acid, lactic acid, levulinic acid, sorbic acid, polyacrylic acid (for e.g., the product used under the trade names Carbopol 934P) or salts thereof; and suitable bases may be selected from one or more of sodium carbonate, sodium bicarbonate, magnesium carbonate, magnesium oxide, calcium carbonate, calcium oxide, aluminium hydroxide, magnesium hydroxide, sodium hydroxide, sodium dihydrogen phosphate or mixtures thereof. Preferably the pH modifier is citric acid, sodium citrate, polyacrylic acid, sodium dihydrogen phosphate, sodium bicarbonate or mixtures thereof. The amount of the pH modifier may range from about 0.1 - 5 % w/w based on the weight of the immediate- release phase and about 1 - 20 % w/w based on the weight of the slow-release phase. Preferably, the pH modifier is a coated citric acid (e.g., the product used under the trade name Citrocoat® N, Citro® DC or Citrocoat® TG) and/or sodium bicarbonate as such or in the coated form (e.g. , coated with sodium carbonate decahydrate) in the immediate- release phase and the pH modifier is a mixture of citric acid and sodium citrate in the slow-release phase.

Suitable pharmaceutically acceptable excipients may be selected from one or more of diluents, binders or lubricant/glidants. Suitable diluents may be selected from one or more of microcrystalline cellulose, lactose, mannitol or calcium phosphate. Suitable binders may be selected from one or more of polyvinylpyrrolidone, pregelatinised starch, methacrylic acid polymers, e.g., Eudragit E 100, gelatin or hydroxypropyl cellulose. Suitable lubricants/glidants may be selected from talc, colloidal silicon dioxide, magnesium stearate or zinc stearate.

The modified release formulation may be prepared by wet granulation, dry granulation or direct compression process. Suitable wet granulation processes can involve use of water or any other suitable solvent. Suitable dry granulation processes may involve use of roller compacter or any suitable technique. The preparation of layered tablets may involve preparing immediate -release and slow-release granules. Such slow and immediate-release granules can then be formulated into immediate or slow-release phases. Preferably the slow-release phase comprises slow-release granule containing amoxicillin trihydrate and immediate-release phase comprises immediate-release granule comprising amoxicillin sodium and/or potassium clavulanate. In the case of bilayer tablets, there may be two layers, one layer containing immediate-release phase and another layer containing slow-release phase each comprising corresponding immediate or slow-release granules comprising active ingredient(s). In case of trilayer tablets, there may be two immediate - release phases and third slow-release phase, each phase comprising the same and/or different active ingredients.

A non-functional coating layer may optionally cover the modified release formulation. The coating layer may comprise polymers, for example, hydroxypropyl cellulose, hydroxyethyl cellulose or hydroxypropyl methylcellulose; plasticizers, for example, polyethylene glycol, triacetin, dibutyl sebecate or diethyl tartrate; opacifying agents, for example, titanium dioxide or talc; colouring agents; or mixtures thereof.

The modified release formulations prepared according to the various embodiments of the specification may be used to treat, for example, bacterial infections caused by the organisms S. pneumoniae (including Drug Resistant S. pneumoniae (DRSP), for instance Penicillin Resistant S. pneumoniae (PRSP)), and/or β-lactamase producing respiratory pathogens, most notably H. influenzae and M. catarrhalis, such as respiratory tract infections, including community acquired pneumoniae (CAP), acute exacerbations of chronic bronchitis (AECB) and acute bacterial sinusitis (ABS), where the higher break points achievable through the improved pharmacokinetic profile will be especially advantageous compared to existing antibacterial agents. Most outpatient respiratory infections are caused by either S. pneumoniae and/or β-lactamase producing bacteria and are treated empirically so there is a continuing need for a method of treatment that provides a spectrum of activity that covers all such pathogens. The duration of therapy will generally be between about 7 to 14 days, typically about 7 days for indications, such as acute exacerbations of chronic bronchitis, but about 10 days for acute bacterial sinusitis.

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 included within the scope of the present invention. The examples are provided to illustrate particular aspects of the disclosure and do not limit the scope of the present invention as defined by the claims.

Examples Examples 1-5

Examples of Amoxicillin and Potassium Clavulanate Extended Release Tablets:

Procedure

1. Preparation of immediate-release phase

A Amoxicillin Sodium immediate-release granules 1. Microcrystalline cellulose, sodium starch gGlycolate, polyvinylpyrrolidone and colloidal silicon dioxide were sifted and loaded in a Planetary mixer along with sifted amoxicillin followed by dry mixing of the ingredients for 15 minutes.

2. The blend of step 1 was lubricated with sifted magnesium stearate in a non-shear blender for lOmin.

3. The blend of step 2 was compacted using a roller compactor and the compacts were milled and sifted to obtain granules

4. The granules were collected and stored in hermetically sealed triple laminated bags placed in suitable drums. B. Potassium Clavulanate immediate-release granules

5. Microcrystalline cellulose, colloidal silicon dioxide and magnesium stearate were dried at 50-60 ⁰C in tray drier at or below an inlet air relative humidity ("RH") of 25 % to achieve equilibrium relative humidity ("ERH") levels of NMT 10 %.

6. The dried materials of step 5 were sifted and blended together with sifted potassium clavulanate and microcrystalline cellulose (1:1) and hypromellose E-

5/polyvinylpyrrolidone (PVP-K-30) in a non-shear blender for 20 minutes.

7. The blend of step 6 was compacted using a roller compactor and the compacts were milled and sifted to obtain granules

8. The granules were collected and stored in hermetically sealed triple laminated bags placed in suitable drums.

C. Extragranular blending

9. The extragranular microcrystalline cellulose and magnesium stearate were dried at 50-60 ⁰C in tray drier at or below inlet air RH of 25 % to achieve ERH levels of

NMT 10 %. 10. The dried microcrystalline cellulose of step 9 was sifted through # 30 BSS (500 m) on a mechanical vibratory sifter.

11. The dried magnesium stearate of step 9 was sifted through # 30 BSS (500 m) on a mechanical vibratory sifter. 12. The granules of step 4 and 8 were blended together with microcrystalline cellulose of step 10 in a non-shear blender for 20 minutes.

13. The magnesium stearate of step 11 was added to the blend of step 12 and blended for 10 minutes. 14. The blend of step 13 was collected and stored in hermetically sealed triple laminated bags placed in suitable drums.

2. Preparation of slow-release phase

D. Amoxicillin trihydrate slow-release granules

15. Amoxicillin trihydrate was sifted and loaded into a Planetary mixer along with sifted hypromellose/xanthan gum, colloidal silicon dioxide, Carbapol-934P/citric acid/sodium citrate, polyvinylpyrrolidone and microcrystalline cellulose followed by dry mixing for 15 minutes.

16. A mixture of ethanol and water (50:50) was prepared.

17. The material of step 15 was granulated using the ethanol + water mixture of step 16.

18. The granulated material of step 17 was dried to achieve ERH level of NMT 10 %. Humidity of air should be NMT 25 %.

19. The dried granules of step 18 were milled.

20. The granules of step 19 was collected and stored in hermetically sealed triple laminated bags placed in suitable drums.

21. Magnesium stearate was dried at 70-80⁰C in tray drier at or below inlet air RH of 25 % to achieve ERH level of NMT 10 %.

22. The material of step 20 was blended together with sifted magnesium stearate of step 21 in a non-shear blender and lubricated for 10 min. 23. The blended material of step 22 was collected in labeled polythene bags inside hermetically sealed triple laminated bags and drums.

E. Bilayer Tablet Compression 24. Bilayer tablets were compressed with the approved blends of steps 14 (first layer) and 23 (second layer) using approved tooling.

F. Film Coating

25. Opadry 03B58965 White and polyethylene glycol (PEG 400) were added to isopropyl alcohol under mechanical stirring followed by methylene chloride and continued stirring for 20-30min to obtain a coating dispersion.

26. The compressed tablets of step 24 were film coated using the coating dispersion of step 25 to a target weight build up of 2.21 % w/w (2.0 - 2.5 % w/w).

Examples 6-7 Examples of Amoxicillin and Potassium Clavulanate Extended Release Tablets:

Procedure

1. Preparation of immediate-release phase

A. Amoxicillin Sodium immediate-release granules

1. Microcrystalline cellulose, sodium starch glycolate, polyvinylpyrrolidone and colloidal silicon dioxide were sifted and loaded in a Planetary mixer along with sifted amoxicillin followed by dry mixing for 15 minutes.

5. Microcrystalline cellulose, colloidal silicon dioxide and magnesium stearate were dried at 50-60 ⁰C in tray drier at or below inlet air RH of 25 % to achieve ERH levels of NMT 10 %. 6. The dried materials of step 5 were sifted and blended together with sifted potassium clavulanate and microcrystalline cellulose (1:1) and Hypromellose E- 5/polyvinylpyrrolidone (PVP-K-30) in a non-shear blender for 20 minutes.

7. The blend of step 6 was compacted using a roller compactor and the compacts were milled and sifted to obtain granules 8. The granules were collected and stored in hermetically sealed triple laminated bags placed in suitable drums.

C. Extragranular blending

9. The extragranular microcrystalline cellulose and magnesium stearate were dried at 50-60 ⁰C in tray drier at or below inlet air RH of 25 % to achieve ERH levels of NMT 10 %.

10. The dried microcrystalline cellulose of step 9 was sifted through # 30 BSS (500 m) on a mechanical vibratory sifter.

13. The magnesium stearate of step 11 was added to the blend of step 12 and blended for 10 minutes.

14. The blend of step 13 was collected and stored in hermetically sealed triple laminated bags placed in suitable drums.

2. Preparation of Slow-release phase

D. Amoxicillin trihydrate slow-release granules 15. Amoxicillin trihydrate, xanthan gum, colloidal silicon dioxide, citric acid/sodium citrate and microcrystalline cellulose was sifted and lubricated with sifted magnesium stearate in a non-shear blender.

16. The blend of step 15 was compacted using a roller compactor and the compacts were milled and sifted to obtain granules

17. The granules were collected and stored in hermetically sealed triple laminated bags placed in suitable drums.

18. Magnesium stearate was dried at 70-80⁰C in tray drier at or below inlet air RH of 25 % to achieve ERH level of NMT 10 %. 19. The material of step 17 was blended together with sifted magnesium stearate of step 18 in a non-shear blender and lubricated for 10 minutes.

20. The blended material of step 19 was collected in labeled polythene bags inside hermetically sealed triple laminated bags and drums.

E. Bilayer Tablet Compression 21. Bilayer tablets were compressed with the approved blends of steps 14 (first layer) and 20 (second layer) using approved tooling.

F. Film Coating

22. Opadry 03B58965 White and polyethylene glycol (PEG 400) were added to isopropyl alcohol under mechanical stirring followed by methylene chloride and continued stirring for 20-30min to obtain a coating dispersion.

23. The compressed tablets of step 21 were film coated using the coating dispersion of step 22 to a target weight build up of 2.21 % w/w (2.0 - 2.5 % w/w). Examples 8-11

Examples of Amoxicillin and Potassium Clavulanate Extended Release Tablets:

Procedure

1. Preparation of immediate-release phase

A. Amoxicillin Sodium immediate-release granules

1. Amoxicillin sodium along with microcrystalline cellulose and polyvinylpyrrolidone (PVP k-30) was granulated with ethanol followed by drying and sizing to obtain granules.

B. Potassium Clavulanate immediate-release granules

2. Potassium clavulanate along with microcrystalline cellulose, colloidal silicon dioxide, sodium starch glycolate, sodium dihydrogen phosphate, magnesium stearate was granulated followed by drying and sizing to obtain granules.

C. Extragranular blending

3. Extragranular ingredients (Colloidal silicon dioxide, sodium starch glycolate, sodium bicarbonate, citric acid, and magnesium stearate) were sifted and blended with the granules of step 1 and 2 to achieve a final blend. 2. Preparation of Slow-release phase

D. Amoxicillin trihydrate slow-release granules

4. Amoxicillin trihydrate, xanthan gum, colloidal silicon dioxide, citric acid, sodium citrate, microcrystalline cellulose and magnesium stearate were sifted and mixed to obtain a blend.

5. The blend of step 4 was compacted and compacts were sized to obtain granules.

6. The extragranular magnesium stearate, microcrystalline cellulose and colloidal silicon dioxide were sifted and blended with the granules of step 5 to achieve a final blend. E. Bilayer Tablet Compression

7. Bilayer tablets were compressed with the final blends of step 3 (first layer) and step 6 (second layer) using approved tooling.

F. Film Coating

8. The compressed tablets of step 7 were film coated with Opadry coating till desired weight buildup is achieved.

The in vitro release of the tablets of Example 8, 10 & 11 in Purified water at 50 rpm USP II, was compared with the release of Augmentin®-XR tablets by Smithkline Beecham. The data is provided in Figure 1.

Example 12 Amoxicillin and Potassium Clavulanate Extended Release Tablets:

Procedure

1. Preparation of immediate-release phase

A. Amoxicillin Sodium immediate-release granules 1. Granulate amoxicillin sodium along with microcrystalline cellulose and polyvinylpyrrolidone (PVP K-30) with ethanol, dry and size to obtain granules.

B. Potassium Clavulanate immediate-release granules

2. Granulate potassium clavulanate along with microcrystalline cellulose, sodium starch glycolate, colloidal silicon dioxide, magnesium stearate, dry and size to obtain granules.

C. Extragranular blending

3. Sift extragranular ingredients (colloidal silicon dioxide, sodium bicarbonate, citric acid, and magnesium stearate) and blend with the granules of step 1 and 2 to achieve a final blend.

2. Preparation of Slow-release phase

D. Amoxicillin trihydrate slow-release granules

4. Sift amoxicillin trihydrate, xanthan gum, colloidal silicon dioxide, citric acid, sodium citrate, microcrystalline cellulose and magnesium stearate and mix to obtain a blend.

5. Compact the blend of step 4 and size the compacts to obtain granules.

6. Sift the extragranular magnesium stearate, microcrystalline cellulose and colloidal silicon dioxide and blend with the granules of step 5 to achieve a final blend.

E. Bilayer Tablet Compression 7. Compress the final blends of step 3 (first layer) and step 6 (second layer) into bilayer tablets using approved tooling.

F. Film Coating

8. Film coat the compressed tablets of step 7 using Opadry coating till desired weight buildup is achieved.

Claims

We Claim: 1. A modified release pharmaceutical formulation comprising amoxicillin and clavulanate in a weight ratio of 16:1, wherein the formulation comprises: c) an immediate-release phase comprising amoxicillin sodium, potassium clavulanate and one or more disintegrants, and, d) a slow-release phase comprising amoxicillin trihydrate and one or more release retarding agents.

2. The modified release formulation according to claim 1 , wherein the amount of amoxicillin ranges from about 1000 mg to about 2000 mg and the amount of clavulanate ranges from about 62.5 mg to about 125 mg.

3. The modified release formulation according to claim 1, wherein the amount of amoxicillin is 1000 mg ± 5 % and the amount of clavulanate is 62.5 mg ± 5 %.

4. The modified release formulation according to claim 1, wherein the disintegrant is selected from one or more of croscarmellose sodium, sodium starch glycolate, crospovidone, hydroxypropyl cellulose, pregelatinised starch, microcrystalline cellulose or mixtures thereof.

5. The modified release formulation according to claim 4, wherein the amount of the disintegrant ranges from about 0.2 to about 10 % w/w based on the weight of the immediate -release phase.

6. The modified release formulation according to claim 1, wherein the release retarding agent is selected from one or more of gums, hydrophobic polymers, hydrophilic polymers or mixtures thereof.

7. The modified release formulation according to claim 6, wherein the gums are selected from one or more of xanthan gum, guar gum, agar, carrageenan, tragacanth, acacia or mixtures thereof.

8. The modified release formulation according to claim 6, wherein the hydrophobic polymers are selected from one or more of cellulose derivatives, shellac, zein or mixtures thereof.

9. The modified release formulation according to claim 6, wherein the hydrophilic polymers comprises one or more of cellulose derivatives selected from carboxymethylcellulose, hydroxypropyl cellulose or hydroxypropyl methylcellulose; polyvinylalcohol, polyvinylpyrrolidone, polyethylene oxide, alginic acid, alginic acid salts or mixtures thereof.

10. The modified release formulation according to claim 6, wherein the amount of the release retarding agent ranges from about 0.5 to about 50 % w/w based on the weight of the slow-release phase.

11. The modified release formulation according to claim 1, wherein the slow-release phase and/or the immediate-release phase further comprises one or more pH modifiers.

12. The modified release formulation according to claim 11, wherein the amount of the pH modifier ranges from about 1 to about 20 % w/w based on the weight of the slow-release phase.

13. The modified release formulation according to claim 11, wherein the amount of the pH modifier ranges from about 0.1 to about 5 % w/w based on the weight of the immediate -release phase.

14. The modified release formulation according to claim 11, wherein the pH modifier is selected from one or more of acids, bases or mixtures thereof.

15. The modified release formulation according to claim 14, wherein the acids are selected from one or more of citric acid, ascorbic acid, tartaric acid, malic acid, malonic acid, succinic acid, fumaric acid, maleic acid, adipic acid, lactic acid, levulinic acid, sorbic acid, polyacrylic acid, or salts thereof, or mixtures thereof.

16. The modified release formulation according to claim 14, wherein the bases are selected from one or more of sodium carbonate, sodium bicarbonate, magnesium carbonate, magnesium oxide, calcium carbonate, calcium oxide, aluminium hydroxide, magnesium hydroxide, sodium hydroxide or sodium dihydrogen phosphate.

17. The modified release formulation according to claim 1, wherein the immediate- release phase and the slow-release phase further comprises one or more pharmaceutically acceptable excipients.

18. The modified release formulation according to claim 17, wherein the pharmaceutically acceptable excipients are selected from one or more of diluents, binders, lubricants or glidants.

19. The modified release formulation according to claim 1, wherein the formulation is in the form of tablet, capsule or sachet.

20. The modified release formulation according to claim 19, wherein the tablet is bilayered.