Classifications

• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
  • A61K47/02—Inorganic compounds
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K33/00—Medicinal preparations containing inorganic active ingredients
  • A61K33/06—Aluminium, calcium or magnesium; Compounds thereof, e.g. clay
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
  • A61P31/04—Antibacterial agents

Definitions

• 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.
• gastrointestinal intolerance 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.
• 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.
• a solid pharmaceutical formulation for oral administration 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 ⁇ 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.
• salt-like derivative refers to salts and derivatives in which acid groups in the acid are ionically associated with metal cations in any way.
• 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.
• 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.
• phosphoric acid as used herein includes higher oxo-acids of phosphorus, including orthophosphoric acid (H3PO4, generally called “phosphoric acid”), and metaphosphoric acids.
• H3PO4 orthophosphoric acid
• 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.
• salts include calcium sulphate, dibasic calcium phosphate, calcium chloride and magnesium sulphate. Calcium sulphate and dibasic calcium phosphate are preferred.
• 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 prefe ⁇ ed 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.
• 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, cef
• 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.
• 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 prefe ⁇ ed 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.
• 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.
• 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.
• 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.
• 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.
• 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.
• 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.
• the weight of the antibiotic compound may co ⁇ espond 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.
• 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.
• an inorganic acid such as calcium sulphate, dibasic calcium phosphate, calcium chloride and magnesium sulphate
• 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
• 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.
• 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.
• 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.
• 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.
• 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:
• 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:
• 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.
• 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.
• amoxycillin may comprise from 5 to 80 wt%, e.g.
• 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 co ⁇ esponding 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.
• a mediator as hereinbefore defined, preferably
• 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 inco ⁇ orated 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..
• 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.
• 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 dia ⁇ hoea. 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.
• 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.
• a substantially air-tight container such as a bottle or sachet
• this container may suitably include a desiccant to protect the potassium clavulanate from degradation by atmospheric water vapour.
• Example 1 Tablet Formulations.
• Amoxycillin Trihydrate (equiv to amoxycillin fa) 400.00 200.00
• Xanthan gum (thickening agent) 15.42 17.50
• 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.
• Suitable mediators were defined as those which satisfied the following criteria:
• the initial pH was in the range 4.0 -6.0, preferably 4.6 to 5.8;
• 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.

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• 1996
  • 1996-08-12 WO PCT/EP1996/003565 patent/WO1997006798A2/en not_active Application Discontinuation
  • 1996-08-12 EP EP96928455A patent/EP0843552A2/de not_active Withdrawn
  • 1996-08-12 JP JP9508930A patent/JPH11510811A/ja active Pending

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