MXPA96005055A - Polymer revestible tablet that comprises amoxicillin and clavulan - Google Patents

Abstract

A tablet formulation, which is a medicament for oral administration for the treatment of bacterial infections. The tablet consists of a compacted mixture of 750 to 950 mg of amoxicillin and an amount of clavulanate in a ratio of amoxicillin: clavulanate weight between 5: 1 to 8: 1 inclusive, and which has a polymer film coating, which can be applied by aqueous film coating techniques

Description

'r POLYMER REINFORCED TABLET COMPRISING AMOXICILLIN AND CLAVULANATE BACKGROUND OF THE INVENTION The present invention is preferred to medicaments for oral administration in the treatment of bacterial infections, consisting of oxycillin and salts of clavulanic acid. Amoxycillin and its derivatives, for example amoxicillin trihydrate, are known (eg GB 1241844) as antibacterial agents useful in the treatment of gram-positive and gram-negative bacterial infections. Clavulanic acid and its derivatives, for example its salts such as potassium clavulanate, are known (e.g., GB 1508977) as β-lactamase inhibitors which inhibit the activity of β-lactamase enzymes produced by bacteria and which confer antibiotic resistance by destroying β-lactam antibiotics such as amoxicillin. The terms "amoxicillin" and "clavulanate" used herein unless otherwise specified include both the original acids in free form and derivatives and salts thereof. The use of clavulanate in combination with amoxicillin consequently that enriches the effectiveness of arnoxycillin. The use of potassium clavulanate in combination with amoxicillin trihydrate within the ratio amoxicillin: clavulanic acid 1: 1 to 6: 1, (expressed in terms of weight of the original amoxicillin or clavulanic acid compound, this terminology being used throughout this description unless otherwise mentioned) is described in GB 2005538. Potassium clavulanate is an exceptionally difficult material to formulate, being extremely hydroscopic and sensitive to moisture. Degradation occurs easily in the presence of water and aqueous medium. Known formulations of amoxicillin and clavulanate are provided for administration three times daily (ie, three times a day). It is desirable for among other things, the convenience of the patient and compliance that such formulations are provided with an administration twice a day (twice daily dose). It is also highly desirable that said formulations have a consistent bioability of the active ingredients clavulanate and amoxicillin. A formulation of amoxicillin / clavulanate has been produced which makes dosing possible twice a day, and also has the unexpected benefit of a particularly consistent bioability, particularly of clavulanate. At some distances the formulation may also show increased bioavailability. In accordance with the present invention, it provides a tablet formulation, being a medicament for oral administration for the treatment of bacterial infections. The tablet consists of a compacted mixture of 750-950 mg of amoxicillin and an amount of clavulanate, in a ratio of amoxicillin: clavulanate weight between 6: 1 to 8: 1 inclusive, and having a polymer coating film which can be applied by aqueous reveater film techniques. Suitable amoxicillin derivatives are amoxicillin trihydrate, anhydrous amoxicillin, and alkali metal salts of amoxicillin such as sodium amoxycillin. Suitable derivatives and clavulanic acid are alkali metal salts of clavulanic acid such as potassium clavulanate. It is preferred to use amoxicillin trihydrate and potassium clavulanate in combination in a tablet formulation of this invention that contains both, this combination has regulatory approval, and is particularly advantageous. Suitably, the tablet contains approximately 875 rn of arnoxicillin ± 10% and 125 mg of clavulanate ± 10%, that is, in an arnoxicilinarclavulanate ratio of 7: 1 norninally. The tablet of the invention may suitably contain 50% by weight or more, for example about 65-75% by weight of the combination of amoxycillin and clavulanate, for example typically 70% by weight plus 2% by weight. The formulation of the tablet of this invention can be provided for the treatment of bacterial infections generally, for example one or more of, among others, upper respiratory tract infections, lower respiratory tract infections, binary genital tract reactions and and skin and soft tissue infections. The formulation of the tablet of this invention is generally suitably for the treatment of infections by microorganisms which are susceptible to β-lactam antibiotics, and may also be effective for some microorganisms resistant to penicillin. The formulation of the tablet of the invention may include one or more other additional excipients, etc. - f generally conventional to the dosage in question. For example, tablet dosage forms may contain one or more conventional diluents such as microcrystalline cellulose (which may also function as a compression aid) eg consisting of about 20-35% by weight of the tablet eg 25- 30% by weight; disintegrants such as sodium starch glycolate, e.g., consisting of 0.5-3.5% by weight of the tablet eg, 1.75-2.25% by weight; lubricants co or magnesium stearate, vr.g., consisting of 0.5-3.5% by weight of the tablet, vr.g., 0.75-1.25% by weight and lidants, such as colloidal silicon dioxide v.g., which consists of 0.75-1.0% by weight of the tablet, v.g., 0.5-0.9% by weight. Although the classes and examples of excipients listed above, together with the active ingredients can form 100% of the weight of the uncoated core of the tablet, the tablet forms can also contain coloring flavoring agents, preservatives, desiccants, etc. conventional to the dosage form in question up to 100% of the weight of the uncoated core of the tablet. The tablets of the invention can be made by the conventional tablet manufacturing techniques, eg, in the mixing of the ingredients followed by the dry compaction, granulation and subsequent compaction of the granule to form a compacted tablet core. A suitable granule can be produced, for example, by kneading or roller compaction. Roller compaction generally involves a screening procedure that can perform a narrower particle size distribution, with fewer particles at each end of the size scale. Roller compaction may also be better suited for a long and continuous scale of the granule from which the tablet of the invention is formed, because although pharmaceutical compaction and roll compaction are generally ,. considered completely equivalent, it has been found in the tablet of the invention that roll compaction contributes to an unexpected increase in bioavailability consistency and is therefore preferred. An adequate method of roller compaction is through the use of the "Chilsonate" roller compactor. The description of such roller compactor is included in, for example, "The Tehory and Practice of Industrial Pharmacy" Lachn et al, 3rd Edn. Read Febiger (1986) p. 318-320. It is also preferred that the preparation of the formulations of the invention be carried out under < Low humidity conditions, vr.g. less than 30% RH, more adequately less than 20% RH ideally as little as possible, to assist in the preservation of clavulanate sensitive to high humidity, particularly potassium clavulanate. Polymers that can be applied by aqueous film coating can facilitate application of the film coating by aqueous film coating techniques, thus avoiding the need for organic solvents. Suitable polymers include hydroxypropyl cellulose, hydroxypropyl ethylcellulose, ethylcellulose (for example, ethylcellulose in a latex composition, such as that supplied by the FMC Corporation as "Ñgua-Coat" (trademark)), netril hydroxyethylcellulose, polyvinylpyrrolidone ("PVP", vr.g., as that supplied under the name of Povidone (trademark), sodium carboxymethylcellulose and acrylate polymers (eg, the stearic acid esters supplied under the trade name "Eudragit" (trademark). A preferred polymer is hydroxypropylmethyl cellulose ("HPMC") suitable in combination with a polyethylene glycol ("PEG"). The low molecular weight PEG's (200 to 600 series) are liquid at room temperature and are useful as plasticizers. High molecular weights (900 to 8000) are waxy solids at room temperature and are used in combination with low molecular weight PEG's and other polymers such as HPtlC, to modify the film properties and to contribute to the brightness of the tablet. A preferred polymer that can be applied by aqueous film coating techniques is one or more hydroxypropyl netilceluloses combined with one or more PEG's. HPNC polymers have the advantages of solubility in physiological fluids, as well as water, non-interference such as tablet disintegration, and moderate solubility or availability, formation of a flexible film - * - objectable taste-free state or odor, stability to heat, light, air, humidity, compatibility with stabilizers, dyes, opacifiers, and gloss. Hydroxypropyl methylcellulose functions as a film former, and polyethylene glycol functions as a plasticizer. The ratio hydroxypropyl methylcellulose: polyethylene glycol in the film coating is suitable between 7.5: 1 to 5.5: 1, v.g., about 6.5: 1 more than 10%. Properly, the Hydroxypropyltrilethylcellulose is applied in the form of a mixture of 6 cps and 12 cps and 15 cps of hydroxypropyltrilethylcellulose, in a ratio of about 2: 1 to 4: 1 v.g., about 3: 1 ± 10%. Suitably, the polyethylene glycol is applied in the form of a mixture of polyethylene glycol 4000 * and 6000 * in a ratio between about 1: 2 to 2: 1, v.g. about 1: 1 ("in E.U.A. these materials are supplied as polyethylene glycol 3350 and 6000 * respectively). The film coating may also suitably include an opacifier, for example anhydrous (white) dioxide (white) suitably, the opacifier may be present in a ratio of about 1: 1 ± 10% with the hydroxypropylmethylcellulose in the film coating. The film coating materials are preferably applied by an aqueous film coating process, which in this way forms a film of a nature that also appears to contribute to the improved bioavailability consistency. A Suitable solids content for aqueous film coating is around 10-30% w / v, typically 10-20%, v. g, % ± 2%. Suitably, the film coating is applied to deposit a weight of dry film materials corresponding to about 1.0-4.0% by weight of the total weight of the coated tablet. Preferably, the dosage forms of the medicament or the invention are packaged in a container that inhibits the ingress of atmospheric moisture, vr.g. Blister packs or tightly closed bottles etc., as conventional in the art. Preferably, the bottles also include a dissecting material to preserve the clavulanate. The unit dosage form (s) of the medicament of the invention can be suitably for oral administration, for example at intervals separated by 6 or more hours, vr.g. separated by 8 or more hours, vr.g. separated by up to about 12 hours. Although it is particularly suitable for twice-daily dosing, the tablet formulation of this invention can also be administered at a higher frequency v. G. Dosage 3 times a day, for appropriate indications and within approved dosing limits. Adequate daily total doses of amoxicillin are on the scale of 90O-1800 mg daily, preferably 100-1750 mg inclusive daily. Appropriate total daily doses of clavulanic acid are on the scale of 200-300 rng daily, - "preferably 250 ± 10 mg inclusive daily. Within the total daily doses referred to above, for oral administration twice a day, the tablet of the invention can be administered orally at separate intervals for about 8 to 12 hours. The invention also provides a method of treatment for bacterial infections in humans or animals consisting of oral administration to a human being or to a human .- animal that needs a treatment such a medication as described above no more than twice a day. The invention also provides a method for the preparation of a tablet formulation, being a medicament for oral administration for the treatment of bacterial infections, comprising compacting a mixture of 750-950 mg of amoxicillin and an amount of clavulanate, in a ratio of amoxicillin: clavulanate weight between 6: 1 and 8: 1 inclusive, and coating the compacted with a film coating consisting of hydroxypropyl ethylcelluloses and l-ethylene glycols. Suitable and preferred forms of this process are as mentioned above in reference to the formulation of the tablet itself changing what needs to be changed. The invention also provides a tablet formulation as described above for use as an active therapeutic substance. -. The invention also provides a tablet formulation as described above for use in the treatment of bacterial infections. The invention also provides the use of a tablet formulation as described above in the manufacture of medicaments for use in the treatment of bacterial infections. The invention also provides a method for treating a ^ bacterial infection in a human patient which includes the step of administering an effective amount of amoxicillin and clavulanate consisting of a tablet formulation as described above. The invention will now be described as an example form only.

EXAMPLE 1 A tablet formulation was prepared according to the composition: Ingredient (G? R.) I in weight I melt luef. a std Ojnstituyentes actives: acb. Ammoniline trihydrate 1017.4 70.2 Active EP ingredient (ßcμivalent to 875.00 apararaldehyla potassium clavulanate 152.45 10.5 ingredient G319 (equivalent to 125.0 active clavulanic acid) ÜlKJtJ CCNIRrB? ENSES: magnesium stearate 14.50 1.00 NF glycollate lubricant alirddcn sodf29.00 2.00 disintegrant NF Colloidal silicon dioxide 10.0 0.70 glidant NF Palu-nsa x-crystalline 226.65 15.6 auxiliary to NF ccprarasicn and diluent BES DE LA DELEO EE LA I 1450.00 100.00 TOH EIA REVESEMENIO EE IA FHJDU-A Purified Pgoa ND Solvent USP White opadri YS-1-7700. 32.0 2.2 Coating of ND film "BLaco apadri-S-7700 can be tested as shown: Titanium ed. 13.76 43.0 EP bcrcrprprilprethyl 10.56 33.0 ferrated: film. Cellulose 6cps nidrcB? Prpiíiretil 3.52 11.0 JP cellulose 15 cps polyethilenglicDl 2.08 6.5 plasticizer USNF 33503 polyethylene glycol 2.08 6.5 plasticizer USNF XVII 80003 purified water4: ND! U} . USP solvent step rnr? nal of tat-Leta 1482.00 coated These quantities depend on the potencies of the used assets and are based on 86% for amoxicillin and 82% for potassium clavulanate (41% potassium clavulanate is part of a mixture 1 : 1 with microcrystalline cellulose). The weight of the constant tablet is maintained by adjusting the amount of microcrystalline cellulose in accordance with the potency of the active ingredients. 2The constituents of film coating - 'can be supplied as a dry liquifier powder either, for example Colorcon as white Opadry YS-1-7700 in E.U.A. or white Opadry OY-S-7300 in Europe. The percentage by weight for the film coating constituents is expressed as a percentage of the weight of the Opadry film. 3 Polyethylene glycols 3350 and 8000 are supplied in Europe as polyethylene glycols 4,000 and 6,000 respectively. The purified water is removed during processing. The film coating is processed. The film coating is applied at 100% of the core weight. The tablets were made by mixing amoxicillin, potassium clavulanate and portions of microcrystalline cellulose and magnesium stearate, roller compaction ("chilsonando") this mixture, and then mixing it with other constituents, before tabletting in a conventional tablet press and the coating. The procedure is "described in more detail below.

DETAILED DESCRIPTION OF THE INVENTION All components are screened or charged in the mixer through a biuratory feeder equipped with a four-mesh screen or through a 14-mesh mixing screen and through a mill, unless otherwise noted. The mill is operated at 1500 rpm, with the blades forward, with a perforated plate of 2.36 nm. A portion of about 2/3 of the microcrystalline cellulose is charged into a suitable mixer. A portion of about 1/5 of amoxicillin trihydrate is loaded into the mixer. Half of the magnesium stearate is charged through a 14 mesh screen into the mixer. The mixture is mixed for 2 minutes. Other - "Dixion of 2/5 of amoxicillin trihydrate and a mixture medium of potassium clavulanate / nicrocrystalline cellulose is charged into the mixer. The mixture is mixed for 3 minutes. What remains of the arnoxycillin trihydrate and the mixture of potassium clavulanate / microcrystalline cellulose is then loaded into the mixer. The mixture is mixed for 5 minutes. The mixed contents are passed through a "chilsonator" of appropriate capacity, under a pressure of 703 g / crn2 subsequently discharged through a fitz 4ue mill operating at 1800 rpm, with the blades forward, with a perforated plate of 2-2.77 mra followed by sieving on a vibrating sieve spliced with? n upper sieve of 14 meshes and a lower sieve of 18 meshes recycling and recompacting the granulation of larger and smaller size until the acceptable screening cut is 98% of the load. Approximately a 10% portion of the granulation is charged into the mixer, through the mill. He '' 'Colloidal silicon dioxide, sodium starch glycolate and the remaining portions of magnesium stearate and microcrystalline cellulose are charged into the mixer, and the mixture is mixed for 5 minutes. The remaining granulation is charged into the mixer, passing through the mill, and mixed for 15 minutes. The mixture is compressed, using a suitable tablet press equipped with perforators in the form of a capsule ^ of 10x21. 5 rnm, to form tablets with a weight of 1450 g with hardness and thickness values within the guidelines for the manufacture of pharmaceutical tablets. The tablet cores are then coated with an aqueous film coating to an overall size of 300 kg in a coating pan of 150 crn. The preferred coating process requires the entry of humidified air at a sufficient temperature which can produce an exhaust humidity of less than 12% during the spraying operation.

In a clinical judgment, the tablet of Example 1 showed reduced inter-subject variability. Although it is specifically exemplified by the tablet of example 1 this effect can also be observed with pharmaceutically equivalent tablets having a composition in which the proportions of ingredients differ within eg + 10% vrg. + 5% of the values given in Example 1.

Claims (16)

NOVELTY OF THE INVENTION CLAIMS

1. - A tablet formulation, which is a drug for oral administration for the treatment of bacterial infections. The tablet consists of a compacted mixture of 750 to 950 mg of amoxicillin and an amount of clavulanate in , a weight ratio amoxicillin: clavulanate of between 6: 1 to 8: 1 inclusive, and having a polymer film coating, which is applied by aqueous film coating techniques.

2. A tablet formulation according to claim 1, further characterized in that the amoxicillin is in the form of amoxicillin trihydrate and the clavulanate is in the form of potassium clavulanate.

3. A tablet formulation according to claim 1 or 2, further characterized in that the tablet contains 875 rng of amoxicillin + 10% and 125 rng of clavulanate plus. + 10%, e.g., in amoxicillin ratio: clavulanate ordinarily 7: 1.

4. A tablet formulation according to claim 1, 2 or 3, which additionally contains microcrystalline cellulose comprising 20-35% by weight of the tablet; Sodium starch glycolate comprising 0.5-3.5% by weight of the tablet; magnesium stearate comprising 0.5-1.5% by weight of the tablet, colloidal silicon dioxide comprising j.25-1.0% by weight of the tablet; which together with the active ingredients make 100% of the weight of the uncoated core of the tablet.

5. A tablet formulation according to any of claims 1 to 4, further characterized in that the formulation is made by compaction of a granule prepared by roller compaction.

6.- A tablet formulation in accordance with ^ 'Any of claims 1 to 5, further characterized in that the film coating consists of hydroxypropylcellulose, hydroxypropylmethylcellulose, ethylcellulose, methylhydroxyethylcellulose, polyvinylpyrrolidone, sodium carboxymethylcellulose or acrylate polymers.

7. A tablet formulation according to claim 6, further characterized in that the film coating consists of hydroxypropyltrilethylcellulose in combination with a polyethylene glycol.

8. A tablet formulation according to claim 7, further characterized in that the ratio hydroxypropylmethylcellulose: polyethylene glycol in the film coating is between 7.5: 1 to 5.5: 1.

9. The tablet formulation according to claim 8, further characterized in that the polyethylene glycol is applied in the form of a mixture of polyethylene glycol 4000 and 6000 in a ratio of 1: 2 to 2: 1

10. - A tablet formulation according to any of the preceding claims, further characterized in that the weight of the dry film materials corresponds to about 1.0-4.0% by weight of the total weight of the coated tablet.

11. A tablet formulation according to any of the preceding claims, substantially as or those described hereinabove in reference r, to example 1.

12. A process for preparing a tablet formulation in accordance with any of the previous claims consisting in coating the core of the tablet with a coating of polymer film applied by aqueous film coating techniques.

13. A method according to claim 11, which consists of the preliminary steps , to prepare granules consisting of a mixture of oxycillin and clavulanate by roller compaction; and, subsequently, compacting the granules together with excipients in tablet cores.

14. A process for preparing a tablet formulation, which consists of compacting a mixture of 750 to 950 rng of arnoxiciline and an amount of clavulanate, in a weight ratio amoxicillin: clavulanate of between 6: 1 and 8: 1 inclusive , and coating the compacted with a film coating consisting of hydroxypropyl ethylcelluloses and .oolietilenglicoles.

15. A tablet formulation according to any of claims 1 to 11, for use in the treatment of bacterial infections.

16. - A method for treating a bacterial infection in a human patient, which includes the step of administering an effective amount of amoxicillin and clavulan to consisting of "a tablet formulation according to any of claims 1 to 11.