EP0843552A2 - Pharmaceutical formulations - Google Patents

Pharmaceutical formulations

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Publication number
EP0843552A2
EP0843552A2 EP19960928455 EP96928455A EP0843552A2 EP 0843552 A2 EP0843552 A2 EP 0843552A2 EP 19960928455 EP19960928455 EP 19960928455 EP 96928455 A EP96928455 A EP 96928455A EP 0843552 A2 EP0843552 A2 EP 0843552A2
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EP
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Patent type
Prior art keywords
clavulanate
acid
salt
amoxycillin
formulations
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Withdrawn
Application number
EP19960928455
Other languages
German (de)
French (fr)
Inventor
Patrick John. Crowley
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
SmithKline Beecham PLC
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SmithKline Beecham PLC
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Classifications

    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL, OR TOILET PURPOSES
    • A61K47/00Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/02Inorganic compounds
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL, OR TOILET PURPOSES
    • A61K33/00Medicinal preparations containing inorganic active ingredients
    • A61K33/06Aluminium, calcium or magnesium; Compounds thereof, e.g. clay

Abstract

Pharmaceutical formulations comprising clavulanate and an intolerance mediator which is a pharmaceutically acceptable salt-like derivative of a Group II metal ion and an inorganic acid are useful in treating bacterial infections, with reduced incidence of gastro-intestinal intolerance.

Description

Pharmaceutical Formulations

This invention relates to pharmaceutical formulations comprising derivatives of clavulanic acid, and to their use. Clavulanic acid is a beta-lactamase inhibitor, and its pharmaceutically acceptable salts (herein individually and collectively referred to as "clavulanate" unless specific salts are identified) may be formulated in antibacterial medicament formulations with antibiotics, particularly beta-lactam antibiotics, to increase their resistance to the beta-lactamase enzymes produced by certain microorganisms. A widely used pharmaceutically acceptable salt of clavulanic acid is potassium clavulanate, which is commercially co-formulated with the beta-lactam antibiotic amoxycillin, generally in the form of amoxycillin trihydrate, in oral formulations.

Some incidence of gastrointestinal intolerance have been observed in patients to whom clavulanate, such as potassium clavulanate, has been administered. This intolerance is manifested in various ways, and may be a result of intestinal fluid accumulation. The precise cause of this intolerance is not understood, and many causes have been suggested. Whatever the cause, the intolerance is seen as a self - limiting nuisance which does not normally prejudice the use of clavulanate, in view of the substantial counter balancing benefits of clavulanate in combating bacterial resistance.

It is an object of this invention to provide formulations including clavulanate, for oral dosing, having reduced gastrointestinal intolerance. The present invention is based upon a novel effect observed with co-formulations or co-administrations of clavulanate with various salts and salt-like derivatives of inorganic acids. Certain Group LI metal salts of inorganic acids are known for use as tablet fillers, for example WO 92/19227 mentions the use of dicalcium phosphate as a filler in a tablet which includes potassium clavulanate and amoxycillin.

According to this invention, a solid pharmaceutical formulation for oral administration is provided, comprising in combination clavulanate and a pharmaceutically acceptable salt or salt-like derivative of a Group II metal ion with an inorganic acid; excluding formulations comprising Group II carbonates and bicarbonates, and tablet formulations comprising dicalcium phosphate in a proportion of 10wt% or less of the tablet weight. The invention also provides a method for preparing a pharmaceutical formulation as defined above, which method comprises admixing the combination of clavulanate and the said pharmaceutically acceptable salt or salt-like derivative of a Group π metal ion with an inorganic acid. The invention also provides a pharmaceutical formulation as defined above for use as an active therapeutic substance, particularly in the treatment of bacterial infections in humans or animals.

The invention also provides for the use of clavulanate and a pharmaceutically acceptable salt or salt-like derivative of a Group LI metal ion with an inorganic acid in the manufacture of a solid antibacterial medicament formulation associated with a reduced propensity to cause gastro intestinal intolerance.

The invention also provides a method of treatment of bacterial infections in humans, which comprises the administration to a patient in need of treatment an effective amount of a pharmaceutical formulation as defined above.

The invention also provides a method of suppressing the gastro intestinal intolerance associated with oral dosing of clavulanate-con taining products, the method comprising oral co-administration of clavulanate in combination with a pharmaceutically acceptable salt or salt-like derivative of a Group II metal ion with an inorganic acid.

The solid pharmaceutical formulations of this invention include tablets, pills, granules, powders etc., including such solid formulations which are intended to be reconstituted to form liquid suspensions for administration to patients, and powder or granulate formulations which are intermediate products for subsequent compaction into tablets.

The term "salt-like derivative" refers to salts and derivatives in which acid groups in the acid are ionically associated with metal cations in any way.

In the formulations and methods of this invention, the clavulanate is preferably the potassium salt of clavulanic acid, ie potassium clavulanate. Salts of clavulanic acid are very hygroscopic. Therefore potassium clavulanate should be handled under dry conditions, preferably under conditions of low relative humidity, e.g. 30% RH or less, in the manufacture of formulations of this invention.

In the formulations and methods of this invention a single pharmaceutically acceptable salt or salt-like derivative of a Group LI metal ion with an inorganic acid may be used, or two or more of such may be used in combination. The one or more salt or salt-like derivative(s) may be used by themselves, or may be used in combination with other compounds or materials which are themselves known or believed to reduce GI inolerance of clavulanate when orally administered in combination with clavulanate. Suitable Group II metal salts include calcium and magnesium salts of sulphuric, hydrochloric and phosporic acids, i.e. the respective metal sulphates, chlorides and phosphates. The term "phosphoric" acid as used herein includes higher oxo-acids of phosphorus, including orthophosphoric acid (H3PO4, generally called "phosphoric acid"), and metaphosphoric acids. When the inorganic acid contains more than one acid hydrogen atom, one or more, up to all, of these may be replaced by a metal ion. Examples of such salts include calcium sulphate, dibasic calcium phosphate, calcium chloride and magnesium sulphate. Calcium sulphate and dibasic calcium phosphate are preferred. In the above formulations and methods, the clavulanate is preferably also co- formulated with an antibiotic compound. The antibiotic compound is suitably a beta- lactam antibiotic such as penicillins, which term as used herein includes antibiotic compounds having a nucleus derived from the penicillin ring system, such as penems and carbapenems; or cephalosporins, which term as used herein includes antibiotic compounds having a nucleus derived from the cephalosporin ring system, such as carbacephs. A prefeπed beta-lactam antibiotic is amoxycillin, e.g. in the form amoxycillin trihydrate or the sodium salt of amoxycillin, for example the anhydrous crystalline form of sodium amoxycillin disclosed in EP 0131147 A.

Other suitable antibiotics include those suitable for oral admistration selected from: ampicillin, apalcillin, aspoxicillin, azidocillin, azlocillin, aztreonam, benzylpenicillin, bacampicillin, carbenicillin, cloxacillin, cyclacillin, dicloxicillin, epicillin, flucloxacillin, lenampicillin, mecillinam, methicillin, mezlocillin, phenoxymethylpenicillin, piperacillin, pivampicillin, propicillin, sulbenicillin, talampicillin, ticarcillin, cefaclor, cefadroxil, cefatrizine, cefclidine, cefamandole, cefazolin, cefbuperazone, cefcanel daloxate, cefdinir, cefepime, cefetamet pivoxil, cefixime, cefminox, cefminoxime, cefmetazole, cefonicid, cefoperazone, cefotaxime, cefotetan, cefotiam, cefotiam hexetil, cefoxitin, cefpimizole, cefpiramide, cefrirome, cefpodoxime proxetil ,cefprozil, ceftazidime, ceftibuten, ceftizoxime, ceftriaxone, cefuroxime axetil, cefuroxime, cephacetrile, cephalexin, cephaloridine, cephalothin, cephamanadole nafate, cephapirin, cephoperazone, cefsulodin, cefuzonam, cephradine, loracarbef, DQ 2556, ME1207, S-1006, SCE-2787 and moxalactam.

Such a formulation which includes an antibiotic compound is effective as a therapeutic or prophylactic treatment for bacterial infections.

The weight ratio clavulanate : antibiotic compound in the formulations and methods of this invention may vary within a wide range, e.g. 1:1 to 1:30, expressed in terms of the free acids. In the case of amoxycillin the said ratio may for example be between 1:1 to 1: 20, for example between 1:1 to 1:8, e.g. 1: 4 to 1:7 by weight. A prefeπed formulation of the invention is therefore one which contains potassium clavulanate and amoxycillin, e.g in the form of its trihydrate or as sodium amoxycillin, within the weight ratio range clavulanate : amoxycillin 1:2 to 1:20., suitably 1:2 to 1:12, typically 1:4 to 1:8.

It is generally prefeπed to administer the pharmaceutically acceptable salt or salt-like derivative of a Group II metal ion with an inorganic acid at, around the same time as, or before the administration of the clavulanate. In the formulations and methods of the present invention the clavulanate, the optional antibiotic material, and the pharmaceutically acceptable salt or salt-like derivative of a Group LT metal ion with an inorganic acid are preferably formulated together for oral administration, and are preferably administered together by this route. Altematively the clavulanate and optional antibiotic material may be formulated and/or administered together and the pharmaceutically acceptable salt or salt-like derivative of a Group II metal ion with an inorganic acid may be separately formulated for oral administration and separately orally administered.

The constituents comprising such an oral formulation, ie clavulanate, pharmaceutically acceptable salt or salt-like derivative of a Group II metal ion with an inorganic acid may be formulated for oral presentation in various ways. Suitable presentations include compacted tablets.

Such tablets may also comprise conventional excipients such as fillers, diluents, compaction aids, disintegrants, lubricants, wetting agents, flavours, colourants etc. as are known in the art. Such tablets may also include an effervescent couple, and/or a chewable base. Such tablets may be made by processes well known in the art, for example blending of powdered constituents, granulation eg by slugging or roller compaction, then compaction into a tablet form in a conventional tablet press. Such sachets, capsules or tablets may suitably comprise a unit dosage form, each containing a unit dose of the active constituents.

The constituents may for also be formulated simply as a dry powder or granules comprising the constituents, and methods of preparing such a formulation will be apparent to those skilled in the art. Such powders or granules may be presented for example in a dry form in a sachet or capsules. When the formulations of this invention are presented in unit dosage form, the amount of clavulanate and any antibiotic compound such as amoxycillin included in the formulation may be generally the same as that contained in known formulations containing these. Typically therefore the formulation may contain from 12.5 to lOOOmg (expressed as the free acid), preferably from 12.5 to 250mg of clavulanate, e.g. 12.5, 25, 50, 75, 100, 125, 150, 200 or 250mg of potassium clavulanate.

Typically the amount of the antibiotic, for example amoxycillin may be in the range from 125 to 3000 mg (expressed as the free acid), suitably from 125 to lOOOmg. Suitably the weight of the antibiotic compound may coπespond generally to the amounts in which it is generally used in solid, e.g tablet or granule formulations. Suitable quantities of the pharmaceutically acceptable salt or salt-like derivative of a Group LI metal ion with an inorganic acid for use in the formulations and methods of the present invention vary between wide limits and may be determined by experimentation, for example by clinical trials observing symptoms of gastrointestinal intolerance with various combinations of clavulanate, antibiotic and the pharmaceutically acceptable salt or salt-like derivative of a Group LT metal ion with an inorganic acid. It is generally desirable to limit the weight of a pharmaceutical tablet intended for swallowing by a patient to a reasonable size to facilitate swallowing, e.g around 1-2 g maximum per tablet, 1.5 g generally being a comfortable maximum in practice.

The total quantity of the pharmaceutically acceptable salt or salt-like derivative of a Group LT metal ion with an inorganic acid included in a single tablet may suitably be around 25 - 500 mg, for example around 125 - 250 mg, and for example these quantities may be combined with 125 - 250 mg of the above-described acid neutralising and/or adsorbent materials. Suitably the quantity of the pharmaceutically acceptable salt or salt-like derivative of a Group II metal ion with an inorganic acid may comprise 0.5 - 50 wt% of the solid dosage form such as a compacted tablet, for example 10 - 50 wt%.

Reduction of gastrointestinal intolerance may be observed on oral coadministration of clavulanate together with amoxycillin and the above-mentioned pharmaceutically acceptable salt or salt-like derivative of a Group II metal ion with an inorganic acid, such as calcium sulphate, dibasic calcium phosphate, calcium chloride and magnesium sulphate, in ratios of clavulanate : pharmaceutically acceptable salt or salt-like derivative of a Group LI metal ion with an inorganic acid in the range 10 : 1 to 1 : 10, relative to the gastrointestinal intolerance observed with the oral administration of these amounts of clavulanate and amoxycillin without the salt¬ like derivative.

The remaining bulk of the dosage form may be made up to 100 wt% by the above mentioned excipients, which may be used in conventional proportions as known in the art. General methods of making a compacted tablet comprising potassium clavulanate and an antibiotic such as amoxycillin trihydrate, together with the abovementioned excipients are well known, for example as disclosed in GB 2005538 A and WO92/19227 which disclose methods and formulations such as dry compaction of powders, granulation of the amoxycillin and clavulanate and compaction of the granules or inclusion of the powdered ingredients or granules in a sachet.

Formulations may also be provided as a dry product for reconstitution as a liquid formulation with water or an appropriate vehicle before use; such presentations being especially suitable for paediatric presentations Accordingly, in a further aspect, the present invention provides a pharmaceutical formulation adapted for oral administration in the form of a liquid aqueous suspension, comprising: (i) amoxycillin trihydrate and potassium clavulanate in combination, in a weight ratio (expressed as the free parent acids amoxycillin and clavulanic acid, this manner of expression being used throughout) between 2:1 and 15:1; and (ii) a mediator which is a pharmaceutically acceptable salt-like derivative of a Group LT metal ion with an inorganic acid.

Such formulations are preferably provided in the form of a dry powder or granule formulation for reconstitution into an aqueous suspension with water or other suitable aqueous media, shortly before administration. The present invention covers such dry powder and granule formulations as well as liquid aqueous preparations. Suitable total quantities of mediator to be included in a formulation adapted for oral administration in the form of a liquid aqueous suspension may be around 25 - 500 mg/5ml of liquid suspension, for example around 100 - 300 mg/5ml of liquid suspension. These quantities may be combined with 5 - 300, preferably 100 - 300 mg/5ml of liquid suspension of the above-described acid neutralising material. Suitably the quantity of the mediator may comprise 0.5 - 50 wt% of the formulation, suitably 10 - 50 wt%.

Formulations of this invention may be adapted for use as paediatric formulations or for administration to adults. As used herein, the term 'paediatric' means suitable for administration to children up to about 12 years of age, including children under 2 years of age and neonates.

Formulations adapted for oral administration in the form of a liquid aqueous suspension are provided for twice daily (bid) or three times daily (tid) administration, which ideally may comprise two administrations at 12 hour dosage intervals or three administrations at 8 hour dosage intervals, respectively, although a greater or lesser interval between administrations may be used.

Suitably, formulations adapted for oral administration in the form of a liquid aqueous suspension are provided in amounts such that the liquid aqueous suspension contains in a convenient volume, typically within the range 2 to 10ml, preferably about 5ml, of suspension, a unit dosage of amoxycillin and potassium clavulanate. The volume may be measured by any conventional measuring device such as a spoon, syringe or graduated measuring cup. Unit dosages typically lie within the range 50 to 800mg of amoxycillin plus pro rata amounts of potassium clavulanate. It will be appreciated that the appropriate unit dosage will be at the discretion of the physician and will depend inter alia upon the age and weight of the patient and the nature and severity of the infection to be treated. Suitable ratios of amoxycillin and potassium clavulanate include 2:1, 4:1, 7:1, 8:1 and 14:1.

It is found to be convenient to provide paediatric formulations in a lower and a higher strength formulation, for treating mild to moderate and serious infections respectively. The suitable formulations, when made up as aqueous liquid suspensions, will contain from 100 to 400mg or 200 to 800mg amoxycillin per 5ml of suspension plus pro rata amounts of potassium clavulanate. Representative examples and appropriate dosage regimens are given in the following table:

amoxycillin* potassium dosage clavulanate* regimen

125 31.3 tid

250 62.5 tid

200 29 bid

400 57 bid

*5ml suspension, within a tolerance of ±10%.

In a representative example, for a unit dosage of 5ml, the suspension is made up to a total volume of 100ml. It will however be appreciated that a range of total volumes may be used, to adjust the amount in a 5ml unit dose to an amount appropriate for the individual patient.

Suitable adult ranges include:

amoxycillin* potassium dosage clavulanate* regimen

400 57 tid

500 125 bid

875 125 bid

*5ml suspension, within a tolerance of ±10%.

For paediatric tid administration formulations adapted for oral administration in the form of a liquid aqueous suspension will normally comprise amoxycillin trihydrate and potassium clavulanate, in a weight ratio of 4: 1 , for use at a dosage of between 15 and 40mg/kg/day, preferably 20 or 30mg/kg/day of amoxycillin trihydate and pro rata amounts of potassium clavulanate, or, for more severe infections, between 35 and 70mg/kg/day, preferably 40 or 60mg kg/day of amoxycillin trihydate and pro rata amounts of potassium clavulanate.

For paediatric bid administration formulations adapted for oral administration in the form of a liquid aqueous suspension will comprise amoxycillin trihydrate and potassium clavulanate, in a weight ratio of between 6:1 and 8:1, preferably about 6.5:1 to 7.5:1, more preferably about 7:1, for use at a dosage of between 15 and 80mg/kg/day, preferably between 20 and 75mg/kg/day of amoxycillin trihydate and pro rata amounts of potassium clavulanate. Representative daily amounts of amoxycillin/potassium clavulanate include 25/3.2, 35/5, 45/6.4 and 70/10mg/kg/day. Suitably, amoxycillin may comprise from 5 to 80 wt%, e.g. 10 to 50 wt%, and potassium clavulanate may comprise from 0.5 to 30 wt%, of the solid dosage form. Formulations adapted for oral administration in the form of a liquid aqueous suspension may therefore usefully comprise from 100 to 400 or 200 to 800 mg of amoxycillin per 5 ml of suspension and coπesponding pro rata amounts of potassium clavulanate, in a ratio of from 2:1 to 14:1 and from 25 to 500mg/5ml, preferably, 100 to 300mg/5ml of liquid suspension, of a mediator as hereinbefore described and optionally from about 5 to 300mg/5ml of liquid suspension of an acid neutralising material. Preferred formulation adapted for oral administration in the form of a liquid aqueous suspension comprise: amoxycillin (200mg/5ml (±10%) of liquid suspension) and potassium clavulanate (29mg/5ml (±10%) of liquid suspension); amoxycillin (400mg/5ml (±10%) of liquid suspension) and potassium clavulanate (57mg/5ml (±10%) of liquid suspension) ; amoxycillin (125mg/5ml (±10%) of liquid suspension) and potassium clavulanate (31.3mg 5ml (±10%) of liquid suspension); or amoxycillin (250mg/5ml (±10%) of liquid suspension) and potassium clavulanate (62.5mg/5ml (±10%) of liquid suspension); and a mediator as hereinbefore defined, preferably calcium sulphate, preferably present in the range from 25 to 500mg/5ml, more preferably about 250mg/5ml of liquid suspension.

Formulations adapted for oral administration in the form of a liquid aqueous suspension will normally further comprise excipients which are conventionally used for formulations adapted for reconstitution into oral suspensions, including paediatric suspensions. These will be incoφorated in generally conventional proportions, using conventional particle sizes and grades etc.. These excipients may comprise suspending aids, glidants (to aid filling), diluents, bulking agents, flavours, sweeteners, stabilisers, preservatives etc.. In addition, dry formulations adapted for make up to aqueous suspension will noramally further comprise an edible desiccant to assist preservation of the potassium clavulanate against hydrolysis by atmospheric moisture on storage. Potassium clavulanate is normally supplied in admixture with silicon dioxide as diluent Suitable excipients for use include xanthan gum (suspension aid), colloidal silica (glidant), aspartame (sweetener), hydroxypropylmethylcellulose (suspension aid) and silicon dioxide (desiccant, diluent for potassium clavulanate and bulking agent). Flavours may comprise common flavours such as orange, banana, raspberry and golden syrup, or mixtures thereof, to suit local requirements. It is found that further agents, hereinafter referred to as 'pH modifiers', may be required to optimise the pH of the suspension following initial reconstitution and or storage, to minimise undesirable degradation of clavulanic acid. The pH of the aqueous medium of the suspension is a significant factor which can affect SIS. It is preferable for the pH of the initial suspension to be in the range 4.6 to 5.8 and the pH at the end of the in-use reconstituted shelf-life to be equal to or less than 6.0. Suitable pH modifiers include organic acids and salts thereof, for instance succinic acid, citric acid, lactic acid, pectic acid (including Mexpectins such as grades LAI 10 and LA910), benzoic acid and propionic acid and salts thereof. The level of pH modifier required will depend on the individual substance and also the amounts of amoxycillin and potassium clavulanate present in the suspension.

An important requirement for liquid formulations is the need to ensure the microbiological quality of the product throughout the shelf-life and in use period. To achieve this, it may be necessary to include a preservative in the product. Suitable preservatives for use in formulations according to the present invention include sodium benzoate (0.1 to 0.5% w/v), calcium benzoate (0.1% w/v) and calcium sorbate (0.1 to 0.25% w/v).

Mannitol and sorbitol are often used in pharmaceutical formulations as excipients. They are however recognised to have, at least at certain levels, a diuretic effect and have been given orally to remove fluid by causing osmotic diaπhoea. It has found to be advantageous to avoid the use of excessive amounts of mannitol or sorbitol in formulations comprising amoxycillin/potassium clavulanate, as it is thought that this may be associated with reduced levels of gastric irritancy. Accordingly, the present invention provides for a pharmaceutical formulation as hereinbefore defined and which is substantially mannitol- or sorbitol-free.

Generally the proportion of active materials amoxycillin trihydrate and potassium clavulanate in a dry formulation for make up with aqueous media into a suspension formulation of the invention may be around 25-60, e.g. 35-50 wt%.

Dry, unreconstituted formulations according to the present invention may be provided in a substantially air-tight container such as a bottle or sachet, and this container may suitably include a desiccant to protect the potassium clavulanate from degradation by atmospheric water vapour.

The invention will now be described by way of example only with reference to the following examples. Example 1: Tablet Formulations.

Formulation 1:

Component mg per tablet Amoxycillin trihydrate 875.001

Potassium clavulanate 125.001

Calcium sulphate USP 250.00

Sodium starch glycollate NF 30.00

Magnesium stearate NF 15.00 Microcrystalline cellulose NFqsad 1500.00

Formulation 2:

Component mg per tablet

Amoxycillin trihydrate 500.001 Potassium clavulanate 125.001

Magnesium sulphate USP 250.00

Sodium starch glycollate NF 21.00

Magnesium stearate NF 10.50 Microcrystalline cellulose NFqsad 1050.00

Note: l weight expressed as free acid equivalent.

These formulations were made into compacted tablets using standard methods known in the art, suitably those disclosed in GB 2005538A.

Example 2: Liquid Aqueous Suspension Formulations

Ingredient A B mg/5ml mg/5ml

Amoxycillin Trihydrate (equiv to amoxycillin fa) 400.00 200.00

Potassium clavulanate (equiv to clavulanic acid) 59.85 29.93

Calcium sulphate (mediator) 250.00 250.00

Xanthan gum (thickening agent) 15.42 17.50

Aspartame (sweetener) 12.50 12.50

Succinic acid (pH modifier) 0.85 0.85

Colloidal Silicon Dioxide (flow aid) 25.00 25.00

Hydroxypropylmethylcellulose (thickener) 79.65 79.65

Orange flavour 26.25 26.25

Raspberry dry flavour 22.50 22.50

Golden syrup dry flavour 23.75 23.75

Silicon dioxide NF (desiccant, diluent) to 1186.00 to 1046.00

Corresponding formulations may also be prepared comprising 125 mg/5ml calcium sulphate, rather than 250mg 5ml.

Further formulations were also prepared , using the same quantities as given for A and B but comprising the following amounts of amoxycillin/clavulanate: 250/62.5 mg/5ml; 125/31.3 mg/5ml; 600/42.9 mg 5ml; 400/50 mg/5ml; and 200/25 mg/5ml; and comprising calcium sulphate at 250 mg/5ml and 125 mg/5ml.

Stability data

Method: A known and predetermined volume of water was added to bottles previously filled to a known weight with a dry powder (coπesponding to formulation A with 250 mg of test mediator) for suspension. The suspension was shaken to form a consistent mixture. Representative samples were taken at the "initial" time point, diluted and analysed by a suitable liquid chromatographic analytical method. The bottles were stored at 5°C and resampled and reanalysed after a known period of storage. Results for the content of amoxycillin and clavulanate after storage were compared with "initial" results. Results

Suitable mediators were defined as those which satisfied the following criteria:

(a) the clavulanate activity did not fall below 80%, preferably 88% of the initial value after 4 days at 5°C;

(b) the initial pH was in the range 4.0 -6.0, preferably 4.6 to 5.8; and

(c) the pH after 4 days storage at 5°C was in the range 5.0 to 6.4, preferably 5.5 to 6.3.

Evaluation of Effects of Agents on intestinal and gastric fluid secretion in the gastro-intestinal system of the rat.

This is accepted as a guide to gastro intestinal intolerance as manifested by diarrhea, a reduction in the amount of fluid accumulation being generally regarded as indicating a likelihood of reduction of diarrhea.

Materials: Potassium clavulanate and amoxycillin trihydrate (SB Pharmaceuticals, Bristol, Tennessee) were prepared in water.

Enteropooling Assay: Male Sprague-Dawley rats weighing 200-300 g were housed in individual wire-bottomed cages to restrict coprophagia. Animals were food deprived for 24 hr prior to experimentation with water provided ad libitum. Using a protocol similar to that described previously for dimethyl PGE2 (Robert et al., 1976; Fondacaro et al., 1989), test agents dissolved or suspended in Mili-Q water were administered to conscious rats by gavage at a dose volume of 1 ml. Animals were sacrificed at 60 min following dosing. The abdomen was opened and the small intestine clamped at the pyloric sphincter and ileocaecal junction; the intestinal segment thus isolated was carefully removed from the abdominal cavity, the length measured and then weighed, emptied of its fluid contents, and reweighed. Enteropooling is expressed as mg. of fluid / cm. of intestine.

Gastric Fluid Accumulation: Gastric fluid secretion or gastric enteropooling was determined according to the following methods. Male Sprague-Dawley rats weighing 200-300 g were housed in individual wire-bottomed cages to restrict coprophagia. Animals were food deprived for 24 hr prior to experimentation with water provided ad libitum. Test agents dissolved or suspended in water were administered to conscious rats by gavage at a dose volume of 1 ml. Animals were sacrificed at a standard time, usually 60 min, following dosing. The abdomen was opened and the stomach clamped at the pyloric sphincter and lower esophagal sphincter; the stomach thus isolated was carefully removed from the abdominal cavity, weighed, emptied of its fluid contents and reweighed. Enteropooling is expressed as total grams of fluid.

Assay results of intestinal enteropooling and stomach fluid accumulation are tabulated below. (Amox. = amoxycillin, K.clav. = potassium clavulanate).

Intestinal Stomach Agent (mg/kg) Mean SEM n Mean SEM n

Water 7.58 0.27 71 0.27 0.04 10 amoxycillin (200) 8.84 0.61 11 0.29 0.06 5

K. clavulanate (100) 21.29 0.39 182 1.23 0.08 109

Effect of agents:

JL clavulanate (100) 21.29 0.39 182 1.23 0.08 109

K. clavulanate (100)+

+ Ca sulphate (100) 15.49 0.75 15 0.71 0.16 13

+ Mg sulphate (100) 18.57 0.30 5 0.75 0.20 4

Claims

Claims
1. A solid pharmaceutical formulation for oral administration, comprising in combination clavulanate and a pharmaceutically acceptable salt or salt-like derivative of a Group LT metal ion with an inorganic acid; excluding formulations comprising Group II carbonates and bicarbonates, and tablet formulations comprising dicalcium phosphate in a proportion of 10wt% or less ofthe tablet weight
2. A pharmaceutical formulation adapted for oral administration in the form of a liquid aqueous suspension, comprising:
(i) amoxycillin trihydrate and potassium clavulanate in combination, in a weight ratio
(expressed as the free parent acids amoxycillin and clavulanic acid, this manner of expression being used throughout) between 2:1 and 15:1; and (ii) a mediator which is a pharmaceutically acceptable salt-like derivative of a Group
LT metal ion with an inorganic acid.
3. A formulation according to claim 1 or 2 wherein the said pharmaceutically acceptable salt or salt-like derivative of a Group II metal ion with an inorganic acid is selected calcium and magnesium salts of sulphuric, hydrochloric and phosporic acids.
4. A formulation according to claim 3 wherein the said pharmaceutically acceptable salt or salt-like derivative of a Group II metal ion with an inorganic acid is selected from calcium sulphate and magnesium sulphate.
5. A formulation or method according to any one of claims 1 to 4 wherein the clavulanate is potassium clavulanate.
6. A formulation according to any one of claims 1 to 5 wherein the clavulanate is co-formulated with amoxycillin.
7. A process for preparing a pharmaceutical formulation as claimed in any one of claims 1 to 6 which process comprises admixing the combination of clavulanate and the said pharmaceutically acceptable salt or salt-like derivative of a Group II metal ion with an inorganic acid;a long with any other excipients or ingredients.
8. A method of suppressing the gastro intestinal intolerance associated with oral dosing of clavulanate-containing products, the method comprising oral co- administration of clavulanate in combination with a pharmaceutically acceptable salt or salt-like derivative of a Group II metal ion with an inorganic acid.
9. The use of clavulanate and a pharmaceutically acceptable salt or salt-like derivative of a Group LT metal ion with an inorganic acid in the manufacture of a solid antibacterial medicament formulation associated with a reduced propensity to cause gastro intestinal intolerance.
EP19960928455 1995-08-12 1996-08-12 Pharmaceutical formulations Withdrawn EP0843552A2 (en)

Priority Applications (5)

Application Number Priority Date Filing Date Title
GB9516584A GB9516584D0 (en) 1995-08-12 1995-08-12 Pharmaceutical formulations
GB9516584 1995-08-12
GB9604447 1996-03-01
GB9604447A GB9604447D0 (en) 1996-03-01 1996-03-01 Pharmaceuticals
PCT/EP1996/003565 WO1997006798A3 (en) 1995-08-12 1996-08-12 Pharmaceutical formulations

Publications (1)

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EP0843552A2 true true EP0843552A2 (en) 1998-05-27

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WO (1) WO1997006798A3 (en)

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GB9815532D0 (en) * 1998-07-17 1998-09-16 Lek Pharmaceutical & Cvhemical Pharmaceutical suspension formulation
EP1414457B1 (en) 2001-08-10 2007-06-20 Purdue Research Foundation Chiral dinapsoline
WO2003084517A3 (en) * 2002-04-09 2004-04-01 Flamel Tech Sa Oral suspension of amoxicillin capsules

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GB8608962D0 (en) * 1986-04-12 1986-05-14 Beecham Group Plc Beta-lactam antibiotics
GB9109862D0 (en) * 1991-05-08 1991-07-03 Beecham Lab Sa Pharmaceutical formulations
EP0723452B1 (en) * 1993-10-13 2004-12-29 Warner-Lambert Company LLC Antacid pharmaceutical composition

Non-Patent Citations (1)

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Title
See references of WO9706798A2 *

Also Published As

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WO1997006798A2 (en) 1997-02-27 application
WO1997006798A3 (en) 1997-04-10 application
JPH11510811A (en) 1999-09-21 application

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