Drug – bio-affecting and body treating compositions – Preparations characterized by special physical form
Reexamination Certificate
1999-11-05
2001-04-10
Page, Thurman K. (Department: 1615)
Drug, bio-affecting and body treating compositions
Preparations characterized by special physical form
C424S489000, C424S497000
Reexamination Certificate
active
06214359
ABSTRACT:
“This application is the national stage of PCT/GB97/02235, filed Aug. 19, 1997, which application claims priority from the United Kingdom application 9617780.3, filed Aug. 24, 1996”.
This invention relates to an empiric method of treatment for bacterial infections potentially caused by drug resistant
Streptococcus pneumoniae
using formulations comprising amoxycillin and a salt of clavulanic acid (hereinafter termed “clavulanate” unless a specific salt is identified).
The combination of amoxycillin and clavulanate is an effective empirical treatment for bacterial infections and may be administered by oral dosing, for instance in the form of tablets, and, for paediatric formulations, aqueous solutions or suspensions, typically as a flavoured syrup.
Clavulanate is a &bgr;-lactamase inhibitor and is included with the &bgr;-lactam antibiotic amoxycillin to counter a &bgr;-lactamase mediated resistance mechanism. Some microorganisms such as
Streptococcus pneumoniae
have resistance mechanisms which are not &bgr;-lactamase mediated. WO94/16696 discloses generally that potassium clavulanate may enhance the effectiveness of beta-lactam antibiotics such as amoxycillin against microorganisms having a resistance mechanism which is not &bgr;-lactamase mediated.
Streptococcus pneumoniae
is an important pathogen in respiratory tract infection in the community.
S. pneumoniae
is the most commonly implicated bacterium in the important respiratory tract infections of otitis media in paediatrics and sinusitis in patients of all ages and acute exacerbations of bronchitis and pneumococcal pneumonia in adults. There have been increasing reports in Europe and the US of the emergence of DRSP (drug-resistant
Streptococcus pneumoniae
) with decreased suspectibility to &bgr;-lactam and other antibiotics.
Whilst confirmed cases of DRSP infection may be successfully treated with relatively high levels of amoxycillin, there still remains the need to develop effective empiric treatments, where DRSP may be suspected, for instance in an area with a high prevalence of DRSP, but where other, &bgr;-lactamase producing, organisms may also be present.
International Application WO 97/09042 (SmithKline Beecham Corp) (published after the priority date of the present application) describes formulations for treating DRSP comprising potassium clavulanate and amoxycillin characterised by a relatively high amount of amoxycillin and a twice daily (bid) dosage regimen. Preferred formulations comprise a ratio of 14:1(amoxycillin:clavulanate), with a typical dosage regimen for paediatrics being 90/6.4 mg/kg/day and for adults 3500/250 mg/day, taken as as two equal dosages, 12 hours apart (bid).
International Application WO 96/34605 (SmithKline Beecham plc/Corp) (published after the priority date of the present application) describes paediatric formulations comprising a 7:1 ratio of amoxycillin and clavulanate, for use in a twice daily dosing regimen (bid), such that the total daily dosage is 70/10 mg/kg/day.
International Application WO 95/28927 (SmithKline Beeecham Corp) describes tablets comprising 875 mg amoxycillin and 125 mg clavulanate, for use in a bid regimen, such that the total daily dosage is 1750/250 mg/day.
SmithKline Beecham markets in France a paediatric formulation (‘Nourrisson’) comprising amoxycillin and clavulanate in an 8:1 ratio for use in a thrice daily dosing regimen (tid), such that the total daily dosage is 80/10 mg/kg/day.
It has now been found that empiric treatment of infections potentially caused by DRSP may also be successfully treated with formulations of amoxycillin/clavulanate taken three times a day (tid), rather than two times a day, using a lesser ratio of amoxycillin to clavulanate.
Accordingly, the present invention provides a method of treatment of infections potentially caused by DRSP which method comprises administering to a patient in need thereof a pharmaceutical formulation adapted for oral administration comprising either:
for an adult or older child patient, from 2500 to 3250 mg/kg amoxycillin per day and from 350 to 400 mg/kg clavulanate per day in a weight ratio between 6:1 and 10:1 inclusive; or
for a paediatric patient, from 75 to 125 mg/kg amoxycillin per day and from 12 to 18 mg/kg clavulanate per day in a weight ratio between 6:1 and 10:1 inclusive;
in combination with a pharmaceutically acceptable carrier or excipient.
Suitably, the method is used for the empiric treatment of infections, potentially caused by DRSP, in particular respiratory tract infections such as otitis media in paediatrics, sinusitis and pneumonia in patients of all ages and acute exacerbations of bronchitis in adults.
The invention also provides for the use of amoxycillin and clavulanate in the manufacture of a medicament for the empiric treatment of infections potentially potentially caused by DRSP which medicament comprises:
for an adult or older child patient, from 800 to 1100 mg amoxycillin and from 100 to 150 mg clavulanate in a weight ratio between 6:1 and 10:1 inclusive; or
for a paediatric patient, from 30 to 40 mg/kg body weight of amoxycillin and from 3 to 8 mg/kg body weight of clavulanate in a weight ratio between 6:1 and 10:1 inclusive;
the medicament being taken three times a day (tid).
Suitably, the dosage is administered tid, for example in three, preferably equal, unit doses per day, suitably around eight hours apart.
The weight ratios of amoxycillin:clavulanate expressed herein are as free acid equivalent. Preferred amoxycillin:clavulanate ratios are between 6.5:1 to 7.5:1 inclusive, especially about 7:1 or between 7.5:1 and 8.5:1, especially about 8:1.
In the formulations of the invention the arnoxycillin is preferably in the form of amoxycillin trihydrate, although sodium amoxycillin, for example the crystalline form of sodium amoxycillin which is disclosed in EP 0131147 A may also be used.
Clavulanate is preferably in the form of potassium clavulanate. Potassium clavulanate is extremely moisture-sensitive and should be stored and handled in conditions of 30% RH or less, ideally as low as possible. Solid dosage forms should be packaged in atmospheric moisture-proof containers, and such forms and/or their containers may contain a desiccant.
Suitably, the dosage is administered in three, preferably equal, unit doses per day, suitably around 8 hours apart
The formulations of the invention may be made up into solid dosage forms for oral administration by a method conventional to the art of pharmaceutical technology, e.g. tablets or powder or granular products for reconstitution into a suspension or solution. Suitable ingredients and suitable methods for making such tablets are disclosed in for example GB 2 005 538-A, WO 92/19227 and WO 95/28927. Powder or granular formulations, such as paediatric suspension formulations, may be manufactured using techniques which are generally conventional in the field of manufacture of pharmaceutical formulations and in the manufacture of dry formulations for reconstitution into such suspensions. For example a suitable technique is that of mixing dry powdered or granulated ingredients for loading into a suitable container.
For paediatric dosing, the formulations of the invention are preferably made up into a sweet flavoured aqueous syrup formulation of generally conventional formulation (except for its novel amoxycillin:clavulanate ratio and intended use) containing a suitable weight of the amoxycillin and clavulanate in a unit dose volume, e.g. 5 ml or 2.5 ml of the syrup. Because of the water-sensitivity of clavulanate it is preferred to provide such a syrup formulation as dry powder or granules contained in an atmospheric moisture-proof container or sachet for make up with water or other suitable aqueous medium shortly prior to use.
The formulation of this invention will normally, in addition to its active materials amoxycillin trihydrate and potassium clavulanate, also include excipients which are standard in the field of formulations for oral dosing and used in generally standard proportions, and at generally standard particle sizes and gra
Di Nola-Baron Liliana
Dinner Dara L.
Kinzig Charles M.
Page Thurman K.
SmithKline Beecham p.l.c.
LandOfFree
Use of a combination of amoxycillin and clavulanate in the... does not yet have a rating. At this time, there are no reviews or comments for this patent.
If you have personal experience with Use of a combination of amoxycillin and clavulanate in the..., we encourage you to share that experience with our LandOfFree.com community. Your opinion is very important and Use of a combination of amoxycillin and clavulanate in the... will most certainly appreciate the feedback.
Profile ID: LFUS-PAI-O-2471218