The drug is in tablet form with a polymer coating containing amoxicillin and clavulanate

 

(57) Abstract:

The invention can be used in medicine for treatment of bacterial infections. The composition of tablets: tablets mixture 750-950 mg amoxicillin and clavulanate when the mass ratio respectively of from 6:1 to 8:1. The tablet has a film coating of polymers, applied technology application of aqueous film coating. A method of treating bacterial infections in humans or animals include oral administration of the drug no more than twice a day. The method of producing tablets for oral administration include tableting mixture above, and applying the obtained tablet film coating contains hypromellose and polyethylene glycol. The invention eliminates the use of toxic organic solvents during application of the film coating on the core tablets. 4 C. and 10 C.p. f-crystals, 1 table.

The present invention relates to oral medications destination for treatment of bacterial infections containing amoxicillin and salt clavulanate acid.

Amoxicillin and its derivatives, e.g., amoxicillin-trihydrate, are known (for example, patent Velikobritaniya bacterial infections. Clavulanate acid and its derivatives such as its salts, such as clavulanate potassium, are known (for example, patent UK 1508977) as-lactamase inhibitors, which inhibit the activity obtained from bacteria-lactamase enzymes, and which give resistance to the antibiotic at destruction-lactam antibiotics, such as amoxicillin. If not specified, when used herein, the terms "amoxicillin" and "clavulanate" include both related free acid and derivatives such as their salts. Using clavulanate in combination with amoxicillin increases in the effectiveness of amoxicillin.

In the United Kingdom patent 2005538 describes the use of clavulanate potassium in combination with amoxicillin trihydrate when the ratio of amoxicillin: clavulanate acid from 1:1 to 6:1 (expressed by weight related compounds amoxicillin or clavulanate acid, and, if not specified, this terminology is used throughout the description). Clavulanate potassium is an extremely difficult material to include in the composition due to excessive hygroscopicity and sensitivity to moisture. In the presence of water and the aquatic environment legcom three times a day (i.e. "three times"-dosing). If it is desired to inter alia patient comfort and compliance with treatment, these drugs are intended to receive two times a day (i.e., "double-dosing). Also highly desirable that such drugs were compatible bioavailability of the active ingredients of clavulanate and amoxicillin.

Issued drug amoxicillin/clavulanate, which provides dosing twice, and also has the unexpected advantage is especially compatible bio-availability, in particular clavulanate. In such cases, the drug may be increased bioavailability.

According to the present invention provides a drug in the form of a pill, which medicine oral assignments for the treatment of bacterial infections, and the tablet contains preformed mixture of 750-950 mg amoxicillin and number of clavulanate when the mass ratio of amoxicillin:clavulanate from 6:1 to 8:1, inclusive, and has a film coating of polymers, which may be caused by the technology of application of aqueous coatings.

The corresponding derivative of amoxicillin are amoxicillin trihydrate, anhydrous slider clavulanate acids are alkali metal salts clavulanate acid, such as potassium clavulanate. It is preferable to use amoxicillin-trihydrate and potassium clavulanate in combination in the composition of the tablets of this invention containing both, and this combination was regularly presented for approval and has special advantages.

Accordingly tablet contains nominally 875 mg amoxicillin for 10% and 125 mg clavulanate 10%, i.e. at a ratio of amoxicillin:clavulanate 7:1. The tablet of the invention may accordingly contain 50% wt. or more, for example, about 65-75% by weight. combination of amoxicillin and clavulanate, for example, typically 70 2 wt.%.

The drug is in the form of tablets of this invention can be used generally for the treatment of bacterial infections, such as one or more inter alia infections of the upper respiratory tract, lower respiratory tract infections, urinary tract infections, and infections of skin and soft tissues. Formulation of tablets of this invention are typically suitable for the treatment of infections caused by microorganisms that are sensitive to-lactam antibiotics, and may also be effective for some microorganisms resistant to penicillin.

Declared a tablet may include one or more deleteone dosage forms may contain one or more conventional diluents, such as microcrystalline cellulose (which can also function as teletrauma additives), for example, in an amount of about 20-35% by weight of the tablet, for example, 25-30% wt.; disintegrant, such as matrikamantra, for example, comprising from 0.5 to 3.5% by weight of the tablet, for example, 1,75-2,25% wt.; lubricating agents such as magnesium stearate, for example, constituting 0.5 to 1.5% by weight of the tablet, for example, 0,75-1,25% wt.; and slip additives, such as colloidal silicon dioxide, for example, components of 0.25 to 1.0% by weight of the tablet, for example, 0.5 to 0.9% by weight. Although the above classes and examples of fillers together with the active ingredients can be up to 100% by weight of uncoated core tablets, the tablets may optionally contain fragrances, colorants, preservatives, drying retardants and so on, traditional for this pharmaceutical form, in the amount of 100% by weight of uncoated core tablets.

The claimed tablet can be obtained by traditional technologies for tablets, for example, by mixing the ingredients, followed by dry pressing, graining, and then pelletizing the granulate to obtain tablets core tablets. Sousounis on rollers typically includes screening, which can lead to a more narrow distribution of particle size with smaller particles at any limit size range. The pressing rollers can be better suitable for large and continuous granulate, which is obtained from a tablet, because, although the pharmaceutically clumping and pressing rolls are usually considered as fully equivalent, the tablet pressing rolls is an unexpected increase of the agreed bioavailability and therefore is preferred. The appropriate way of pressing rollers is applied using a known roller pressing unit "Chilsonator". Description this installation included, for example, in "theory and Practice of Industrial Pharmacy"; Lachan et al., 3rd. Edn. Lea 2 Febiger (1986), pp. 318-320. It is also preferable to obtain formulations of the invention occurred in conditions of low humidity, for example, less than 30% relative humidity, more suitable, less than 20% relative humidity, ideally as low as possible, which contributes to maintaining high sensitivity to moisture of clavulanate, in particular ChoicePoint.

Polymers that can be applied in the form of aqueous film coating, can the resulting need to use organic solvents. Appropriate polymers include hydroxypropylcellulose, hypromellose, ethylcellulose (for example, ethylcellulose in latex compositions provided EF Em C Corporation under the trademark Aqua-Coat"), methylhydroxyethylcellulose, polyvinylpyrrolidon (PVP, for example, supplied under the trade mark Povidone, sodium carboxymethyl cellulose and activities polymers (e.g., the esters of methacrylic acid, supplied under the trade mark "Eudragit").

The preferred polymer is hypromellose (HPMC), suitable in combination with polyethylene glycol (PEG). Low molecular weight PEG' and (rows 200-600) are liquid at room temperature and find use as plasticizers. High molecular weight (900-8000) PEG' and are solid wax at room temperature and used in combination with low-molecular PEG AMI with other polymers, such as HPMC, for modification of film properties and contribute to making gloss tablet.

The preferred polymer, which can be caused by the technology of application of aqueous film coating is one or more hydroxypropylmethylcellulose in Combi liquids, and also in the water, do not prevent the disintegration of the tablets of the drug, solubility or availability of drugs, the formation of an elastic film, free from unpleasant taste or odor, are resistant to heat, light, air, moisture, compatible with stabilizers, dyes, mufflers, and have a gloss. The hypromellose acts as a foaming agent, and the polyethylene glycol acts as a plasticizer. The ratio hypromellose: polyethylene film coating is suitable from 7.5:1 to 5.5:1, for example, about 6.5:1 to 10%. Accordingly, the hypromellose is used in the form of a mixture of hydroxypropylmethylcellulose with a viscosity of 6 JV and with a viscosity of 15 SP in a ratio of about 2: 1 to 4:1, for example, about 3:1 to 10%. Accordingly, the polyethylene glycol is applied in the form of a mixture of polyethylene glycol 4000+and 6000+in the ratio of about 1:2 to 2:1, e.g. about 1:1 (in the USA these materials are supplied as polyethylene glycol 3350 and 6000 respectively). The film coating may also be suitable to include a muffler, for example, titanium dioxide (white). Accordingly, the muffler may be present in the film coating in a 1:1 ratio of 10% with hydrox is the application of aqueous film coating, since the application in this way gives the film's nature, which also contributes to improved compatibility in biological availability. The corresponding dry matter content for aqueous film coating is approximately 10-30% wt./about., usually 10-20%, for example 15 2%.

Accordingly, the film coating is applied so that the deposited mass of dry film materials, about 1.0-4.0% by weight. the total mass of coated tablets.

Preferred dosage forms of the medicinal drug of the invention are packaged in a container, which slows down the penetration of atmospheric moisture, such as bubble wrap or tightly closed bottles, etc. that are used traditionally. Preferably, the bottles also contain a desiccant material to save clavulanate.

The unit dosage form (s) of the medicinal drug of the invention can be designed accordingly for oral administration, for example, at intervals of 6 hours or more 8 hours or more, for example, after about 12 hours. Although particularly suitable is a double-dosing, formulation of tablets of this invention may also be appointed to receive with greater frequency, i.e., three times the existing total daily dose of amoxicillin are within 900-1800 mg / day, preferably 1000-1750 mg inclusive per day. The appropriate total daily dose clavulanate acid are within 200-300 mg per day, preferably 250 10 mg inclusive daily. When the above total daily dose for oral assignments twice a day tablet of the invention can be used orally at intervals of about 8-12 hours.

The invention additionally provides a method of treating bacterial infections in humans or animals, including oral application by a person or animal in need of such treatment, the above-described drug no more than twice a day.

The invention also provides a method of obtaining a medicinal product in the form of a pill, which drug for the treatment of bacterial infections, which includes the tableting mixture 750-950 mg amoxicillin and number of clavulanate mass ratio of amoxicillin: clavulanate from 6: 1 to 8: 1 including coating the preformed film coating mixture, which contains hydroxypropylmethylcellulose and glycols.

Appropriate and preferred forms of this method are as described above, use as an active therapeutic substance claimed the drug in tablet form.

The invention also provides a method of treating a bacterial infection in humans, which includes receiving an effective amount of amoxicillin and clavulanate contained in the tablet, as described above.

Example of getting a tablet composition shown in the table, see the end of the description.

Notes to table:

1) These quantities depend on the potential active components and is based on 86% of the amoxicillin and 82% of ChoicePoint (ChoicePoint 41% is part of a 1: 1 mixture with microcrystalline cellulose). Constant mass of the tablet is supported by adjusting the amount of microcrystalline cellulose in accordance with the activity of the active components.

2) Comprising a film coating can be supplied in the form of a dry powder mixtures, or, for example, Colorcon, in the form of Opadry white YS-1-7700 in the United States or Opadry white OY-S-7300 in Europe. Weight percents of the components of film coatings are expressed as percentage of weight Opadry film.

3) polyethylene glycol 3350 and 8000 are supplied in Europe as poliatilenglikole the coating is applied to 100% by weight of the core tablet.

Tablets are obtained by mixing amoxicillin, clavulanate and parts microcrystalline cellulose and magnesium stearate, the pressing rollers (Silantieva) of this mixture, then mix with other ingredients prior to pelletizing traditional tablet press and coating. The method is described in more detail below.

All components are sifted or loaded into the mixer through a vibratory feeder, equipped with a 4 sieve mesh, or through a sieve mixer 14 mesh and through the mill, unless otherwise specified. The mill operates at 1500 rpm, knives forward, with a perforated plate with holes of 2.4 mm

Approximately 2/3 of a portion of the microcrystalline cellulose is loaded into an appropriate mixer. Approximately 1/5 portion of amoxicillinclavulanate is loaded into the mixer. In the mixer through a 14 mesh sieve loaded half of the magnesium stearate. The mixture is mixed for 2 minutes. Other 2/5 portions of amoxicillinclavulanate and 1/2 mixture ChoicePoint/microcrystalline cellulose is loaded into the mixer. The mixture is mixed for 3 minutes. Then in the mixer is loaded the rest of amoxicillinclavulanate and the mixture ChoicePoint/microcrystalline cellulose. The mixture smachivaetsya pressure of 6895 kPa. Then is discharged through the mill Fitzmill operating at 1800 rpm, knives forward, with a perforated plate with holes 2-2,8 mm, with subsequent screening vibrating screen with top 14 mesh sieve and the bottom sieve 18 mesh, recycling and re-pressing of the granules until such time as an acceptable cutoff reaches 98% load.

Approximately 10% of the portion of the granules are loaded into the mixer, biassou mill. Colloidal silicon dioxide, matrikamantra and the remaining part of magnesium stearate and microcrystalline cellulose are loaded into the mixer, and the mixture is mixed for 5 minutes. The rest of the granulate is loaded into the mixer, biassou mill and mixed for 15 minutes.

The mixture tabletroute using the appropriate tabletiruemogo press with capsulorraphy stamps 9 x 21.5 mm to produce tablets having a weight of 1,450 g, hardness and thickness within the regulations for pharmaceutical tablets.

Core tablets then covered with a water film coating in a bath of 300 kg in the form of 1500 mm, the Preferred coating process requires dehydration of the incoming air at a sufficient temperature, which can give consider the years of study showed reduced interregional flexibility. Despite the fact that this was especially shown by the tablet of example, this effect can also be observed for pharmaceutically equivalent tablets having the composition, in which the proportions of the ingredients were different, for example, plus 10%, for example, +5% from the values given in this example.

1. The composition of the tablets representing drug oral administration for the treatment of bacterial infections, including preformed mixture of 750 - 950 mg of amoxicillin and clavulanate when the mass ratio amixicillin: clavulanat from 6:1 to 8:1, inclusive and film coating of polymers, applied technology application of aqueous film coating.

2. The composition of the tablets under item 1, characterized in that amoxicillin is amoxicillinwhere and clavulanat - clavulanate potassium.

3. The composition of the tablets under item 1 or 2, characterized in that the tablet contains 875 mg% of amoxicillin and 125 mg% clavulanate, for example, at a nominal ratio of amoxicillin: clavulanate 7:1.

4. The composition of the tablets of PP.1 to 3, characterized in that it further comprises microcrystalline cellulose, comprising 20 to 35 wt.% tablets, cromargan sodium, for example the work of 0.25 - 1.0 wt.% tablets, which together with the active ingredients is 100% by weight of uncoated core tablets.

5. The composition of the tablets of PP.1 to 4, characterized in that the tablet is produced by pelletizing of the granules obtained by the pressing rolls.

6. The composition of the tablets of PP.1 to 5, characterized in that the coating includes hydroxypropylcellulose, hypromellose or acrylate polymers.

7. The composition of the tablets under item 6, wherein the film coating comprises hydroxypropylcellulose in combination with polyethylene glycol.

8. The composition of the tablets under item 7, characterized in that the ratio of the hypromellose: polyethylene glycol in the film is from 7.5:1 to 5.5: 1.

9. The composition of the tablets under item 8, characterized in that the glycol is a mixture of polyethylene glycol 4000 and 6000 in the ratio from 1:2 to 2:1.

10. The composition of the tablets of PP.1 to 9, characterized in that the mass of the dry film material is about 1.0 to 4.0 wt.% the total mass of film-coated tablets.

11. A method of treating bacterial infections in humans or animals by oral administration of a medicinal product on the PP.1 - 11 not more than two times the change for the treatment of bacterial infections characterized in that it comprises tableting mixture of 750 - 950 mg of amoxicillin and clavulanate when the mass ratio of amoxicillin: clavulanate from 6:1 to 8:1 including applying a film coating, which contains hypromellose and polyethylene glycol.

13. The composition of the tablets of PP.1 - 10 for obtaining a medicinal product for the treatment of bacterial infections.

14. A method of treating bacterial infections in a patient person, which includes a step of introducing an effective amount of amoxicillin and clavulanate in the form of a tablet composition according to PP.1 - 10.

 

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