WO1996001109A1

WO1996001109A1 - Clavulanate pharmaceutical formulations

Info

Publication number: WO1996001109A1
Application number: PCT/EP1995/002609
Authority: WO
Inventors: Patrick John Crowley
Original assignee: Smithkline Beecham Plc
Priority date: 1994-07-05
Filing date: 1995-07-03
Publication date: 1996-01-18
Also published as: GB9413542D0

Abstract

Pharmaceutical formulations comprising in combination clavulanate and an acid neutralising material and/or an adsorbent material, methods of preparation of the same, and their use.

Description

CLAVULANATE PHARMACEUTICAL FORMULATIONS

This invention relates to pharmaceutical formulations comprising derivatives of clavulanic acid, and to their use. Clavulanic acid is a β-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 β-lactam antibiotics, to increase their resistance to the β-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 β-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, for example in diarrhea, which 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.

Co-formulations of clavulanate with various substances have been investigated. For example Int. J. Clin. Pharmacol. Ther. Toxicol 23, 154-157, (1985) describes the co-administration of cimetidine, aluminium hydroxide and mill- on the bioavailability after oral administration of a 1 : 2 potassium clavulanate : amoxycillin formulation. This paper concludes that aluminium hydroxide has no effect on the clavulanic acid components of this combination.

In oral formulations clavulanate is normally made up into tablets in a co- formulation with amoxycillin, as described in GB 2005538 A. The tablets described therein comprise potassium clavulanate and amoxycillin trihydrate, together with various excipients etc. GB 2005538 A discloses the use of calcium carbonate and magnesium carbonate in a generally known way as fillers. The quantities of calcium and magnesium carbonate used in the tablets disclosed in GB 2005538 are generally quite small, as is generally the case with tablet fillers, e.g respectively 175 and 110 mg co-formulated with a 1 : 2 weight ratio of 125 mg free acid equivalent of potassium clavulanate and 250 mg free acid equivalent of amoxycillin trihydrate. The present invention is based upon a novel effect observed with co- formulations or co-administrations of clavulanate with various materials, and novel formulations based upon this effect.

According to this invention, a pharmaceutical formulation is provided, comprising in combination clavulanate and an acid neutralising material and/or an adsorbent material, provided that when the formulation is a potassium clavulanate : amoxycillin trihydrate formulation with a clavulanate : amoxycillin ratio of 1 : 2 (expressed as free acids equivalent) then (i) the acid neutralising material and/or adsorbent material is other than aluminium hydroxide in an acid neutralising form, and (ii) the ratio acid neutralising material and/or adsorbent material : clavulanate (expressed as free acid equivalent) is greater than 1.4 : 1 when the said material is calcium carbonate, and greater than 0.88 : 1 when the said material is magnesium carbonate. The invention also provides a method of use of clavulanate, and an acid neutralising and/or an adsorbent material together in the manufacture of an antibacterial medicament formulation, provided that when the formulation is a potassium clavulanate : amoxycillin trihydrate formulation with a clavulanate : amoxycillin ratio of 1 : 2 (expressed as free acids equivalent then (i) the acid neutralising material and/or adsorbent material is other than aluminium hydroxide in an acid neutralising form, and (ii) the ratio acid neutralising material and/or adsorbent material : clavulanate (expressed as free acid equivalent) is greater than 1.4 : 1 when the said material is calcium carbonate, and greater than 0.88 : 1 when the said material is magnesium carbonate. The invention also provides a method for the preparation of a pharmaceutical formulation as defined above, which method comprises admixing the combination of clavulanate acid and the said acid neutralising material and/or an adsorbent material.

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 a method of suppressing the gastro intestinal intolerance associated with the oral dosing of clavulanate-containing products, the method comprising co-administration of clavulanate in combination with an acid neutralising material and/or an adsorbent material. The invention also provides a pharmaceutical formulation including clavulanate, in which the gastro intestinal intolerance associated with the oral dosing of clavulanate-containing products, is suppressed by an acid neutralising and/or an adsorbent material.

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

In the above formulations and methods, 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 the acid neutralising and adsorbent material may be the same material, ie an acid neutralising material which also has an adsorbent ability, or an adsorbent material that also has an acid neutralising ability. Alternatively materials which have solely or substantially only an acid neutralising or an adsorbent ability may be used. Such materials may be used singly or in combination, e.g. two or more acid neutralising materials, or two or more adsorbent materials, or an acid neutralising material together with an adsorbent material.

The term "acid neutralising material" used herein includes pharmaceutically acceptable alkalis and bases, i.e. compounds which can combine with acids to produce a salt of the acid plus water. More specifically the term includes materials normally referred to as "antacids", i.e. having the ability to chemically neutralise e.g. by an acid-base reaction, or otherwise reduce gastric acidity. The term

"adsorbent material" as used herein includes pharmaceutically acceptable materials which are capable of adsorbing organic molecules from aqueous suspension or solution.

Suitable generic classes and specific examples of acid neutralising materials and/or adsorbent materials include the following generally water insoluble materials: Group II metal bases such as carbonates, hydrogen carbonates, oxides (other than calcium oxide), hydroxides (other than calcium hydroxide) and silicates, such as magnesium carbonate, calcium carbonate and calcium silicate; Group ELI metal bases such as carbonates, hydrogen carbonates, oxides, hydroxides and silicates, such as alumimum carbonate, aluminium hydrogen carbonate, aluminium oxide, aluminium hydroxide and aluπiinium silicate (e.g. Kaolin); molecular sieves, celluloses; Group ϋ/III metal silicates such as calcium aluminosilicates and other clays, and charcoal. Such materials may be used singly or in mixtures with other acid neutralising materials and/or adsorbent materials, for example a magnesium carbonate/magnesium hydroxide mixture, for example that having the overall stoichiometry (MgCO3)4.Mg(OH)2.5H2O. Forms of aluminium hydroxide which have no acid neutralising ability can be suitable, as alternatively can forms of alumimum hydroxide which have an acid neutralising ability.

Preferred acid neutralising and/or adsorbent materials are magnesium carbonate, aluminium hydroxide, and especially calcium carbonate, which can be particularly effective in suppression of the undesirable effects discussed above. It should be noted however that magnesium salts can themselves cause diarrhea, and the use of magnesium compounds in quantities known to cause diarrhea should be avoided. In the above formulations and methods, the clavulanate is normally also co- formulated with an antibiotic compound, as the principal function of clavulanate is to increase the resistance of antibiotic compounds to the β-lactamase enzymes produced by certain microorganisms. The antibiotic compound is suitably a β- lactam antibiotic such as a penicillin or cephalosporin. A preferred β-lactam antibiotic is amoxycillin, e.g. in the form of its trihydrate or sodium salt, for example the anhydrous crystalline form of sodium amoxycillin disclosed in EP 0131147.

Other suitable β-lactam antibiotics include penicillins 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, and ticarcillin; and cephalosporins suitable for oral administration selected from: cefaclor, cefadroxil, cefatrizine, cefclidine, cefamandole, cefazolin, cefbuperazone, cefcanel daloxate, cefdinir, cefepime, cefetamet pivoxil, cefixime, ceftninox, cefininoxime, 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.

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 1:15, for example between 1:1 to 1:8, e.g. 1: 4 to 1:7 by weight.

A preferred formulation of the invention is therefore one which contains potassium clavulanate, magnesium carbonate, aluminium hydroxide, or especially calcium carbonate, and amoxycillin, e.g in the form of its trihydrate or as sodium amoxycillin, within the weight ratio clavulanate : amoxycillin 1 : 4 to 1 : 7.

In the formulations and methods of the present invention the clavulanate, acid neutralising material and/or adsorbent material and the optional antibiotic material are preferably formulated together for oral administration, and are preferably administered together by this route. Alternatively the clavulanate and optional antibiotic material may be formulated and/or administered together and the acid neutralising and/or adsorbent material may be separately formulated for oral administration and separately orally administered.

The constituents comprising such an oral formulation, ie clavulanate, acid neutralising or adsorbent material and antibiotic, may be formulated for oral presentation in various ways.

The constituents may for example 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. Alternatively the constituents may be formulated into a compacted tablet, for example including conventional excipients such as fillers, diluents, compaction aids, disintegrants, lubricants, wetting agents, flavours, colourants etc. Such tablets may also include an effervescent couple (provided the couple does not interfere with the acid neutralising or adsorbent material), and/or a chewable base. Such tablets may be made by processes well known in the art, for example blending of powdered constituents, optionally with excipients, 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.

Alternatively the formulation may be made up as a liquid form, for example in an oily solution, suspension, emulsion, syrup or elixir, or may be provided as a dry product for reconstitution as a liquid formulation with water or an appropriate vehicle before use.

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. Suitable quantities of the acid neutralising material and/or an adsorbent material 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 acid neutralising material and/or an adsorbent material. Suitable ratios of acid neutralising and/or adsorbent material : clavulanate in oral formulations for human patients may be between 0.8 : 1 and 1.5 : 1 in the case of calcium carbonate and magnesium carbonate. 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.

Consequently the total quantity of the acid neutralising material and/or an adsorbent material included in a single tablet may suitably be around 25 - 500 mg, for example around 125 - 250 mg. Suitably the quantity of the acid neutralising material and/or an adsorbent material may comprise 0.5 - 50 wt% of the solid dosage form such as a compacted tablet, for example 10 - 50 wt% .

For example reduction of gastrointestinal intolerance may be observed on oral coadministration of clavulanate together with amoxycillin and the above- mentioned acid neutralising material and/or an adsorbent material in ratios of clavulanate : acid neutralising material and/or an adsorbent material 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 2005538A 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.

The invention will now be described by way of example only with reference to Figs. 1 to 6 which show: Fig. 1: Comparison of effects of inorganic salts including antacids/adsorbents on basal fluid accumulation in the conscious rat.

Fig. 2: Dose dependent effects on basal fluid accumulation in the conscious rat.

Fig. 3: Comparison of effects of inorganic salts including antacids/adsorbents on basal fluid accumulation in the conscious rat.

Fig. 4: Comparison of the effects of acid-neutralizing and non acid- neutralizing aluminium compounds on fluid accumulation in the conscious rat. Fig. 5: Comparison of effects of amoxycillin (200mg/kg) vs potassium clavulanate (100 mg/kg) vs the combination on fluid accumulation in the conscious rat.

Fig. 6: Comparison of effects of inorganic salts including antacids/adsorbents on fluid accumulation in the conscious rat.elicited by the combination of amoxycillin and potassium clavulanate in the concious rat. Example 1: Summary of a Single Oral Dose Study in Mice to Investigate the effect of Co-administration of Potassium clavulanate with Acid Neutralising /

Adsorbent materials. Introduction: An early series of experiments carried out to investigate gastro-intestinal irritancy of oral administered potassium clavulanate included a study in mice which incorporated co-administration of antacids to counteract low gastric pH. It was found that MgCO3 completely protected against the lethality of potassium clavulanate, which when dosed without the antacid caused 100% deaths at 6g/kg of clavulanate. In addition, the other antacid AI2O3 reduced the lethality, though to a much lesser extent. Since these results could have implications for the development of formulations of potassium clavulanate which cause less G.I intolerance in the clinic, the antacid study was repeated to determine whether the results are reproducible.

Study Design: After a 6-day acclimatisation period, groups of 8 male CD-I mice received potassium clavulanate as a solution in 40 ml/kg body weight of purified water at doses of 6000, 4200, 2940 or 2058 mg/kg as pure free acid (pfa) by oral gavage. Similar groups received potassium clavulanate at the same doses as suspensions in 40 ml/kg body weight of 4% w/v AI2O3 or 10% w/v MgCO3 (these being of equivalent hydrogen ion neutralising activity). Measurements: Clinical observations and body weight were assessed throughout the study. All animals were necropsied and macroscopic findings recorded.

Results: There were 13/32 deaths in mice receiving potassium clavulanate alone, 9/32 deaths in mice receiving potassium clavulanate in 4% w/v AI2O3 and 0/32 deaths in mice receiving potassium clavulanate in 10% w/v MgCO3- The mortality pattern in those receiving potassium clavulanate alone showed no dose- relationship, with 7/8 animals dying at 2940 mg/kg and only 3/8 at 6000 mg/kg. This lack of dose-relationship has been seen previously with this compound and is therefore not unexpected. Adverse clinical observations comprised reduced activity, hunched posture, watery eyes, ataxia, brown anal staining, prostration and laboured breathing. The frequency and severity of these signs were related to dose and treatment, with the greatest number and severity being in those receiving potassium clavulanate alone. In the mice receiving potassium clavulanate in 10% w/v MgCO3, the only observation was brown anal staining on day 1 at 6000 mg/kg.

There was no effect on body weight in survivors, other than a slight reduction in those receiving potassium clavulanate alone at 6000 mg/kg. Discussion/Conclusion:

Since there were more deaths in those receiving potassium clavulanate alone, compared with when administered with AI2O3 or MgCO3, it can be said that co- administration with an antacid reduces the lethality of this compound. The total protection provided by 10% w/v MgCO3, in that there were no deaths, and only very minor clinical observations, confirms the findings of the previous study. Both 4% w/v AI2O3 and 10% w/v MgCO3 have similar acid neutralising properties.

Therefore, co-administration with an antacid reduces the acute oral toxicity of potassium clavulanate in male mice, especially MgCO3 which offers complete protection.

Example 2: Evaluation of Effects of Antacids on Intestinal Fluid Secretion in the Rat.

Materials:

Potassium clavulanate and amoxycillin trihydrate (SB Pharmaceuticals, Bristol, Tennessee) were prepared in water. Aluminum hydroxide (Al(OH)₃ Johnson Matthey, Ward Hill, Massachusetts, or Alhydrogel, Sergeant Pulp & Chemical Co., Inc., Clifton, New Jersey), magnesium hydroxide (Mg(OH)₂ Aldrich Chemical Co., Milwaukee, Wisconsin), magnesium carbonate ((MgCO₃)₄-Mg(OH)₂ pentahydrate Sigma Chemical Co., St. Louis, Missouri), calcium carbonate (CaCO₃ Sigma Chemical Co., St. Louis, Missouri), Kaolin (hydrated aluminum silicate, Sigma Chemical Co., St. Louis, Missouri).

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 milligrams of fluid/centimeter of intestine. Acid Neutralizing Capacity:

The acid-neutralizing capacity of antacid preparations was determined using a Radiometer titration unit (TTT80 Titrator; ABTJ80 Autoburette; PHM84 Research pH meter, Radiometer America, Westlake, OH). The procedure employed was < 301 > ACID-NEUTRALIZING CAPACITY from USP XXII with the exception that tests were performed at room temperature rather than 37 °C as specified. Antacids tested were liquid suspensions (with the exception of a TUMS E-X^® tablet of that was first dissolved in 70 ml Milli-Q water) for which target amounts of 10 mEq were calculated and added to 70 ml H2O. To this mixture, 30 ml of 1.0 N HCl was added. The solution was stirred for 15 min and then titrated with 0.5 N NaOH to pH 3.5. Reagents:

1.0 N HCL (Mallinckrodt; lot 7741 KDPX) - A 1.0 N solution was prepared by diluting 86.2 ml concentrated HCl (11.6 N) to 1L with Milli-Q water.

0.5 N NaOH (Mallinckrodt; lot KMHY) - 20 g of NaOH was dissolved in 1 L of Milli-Q water.

Al(OH)3 (e.g. Alhydrogel, MW=78.00) - This was supplied as a 3% solution and 8.7 ml (~ 10 mEq) were assayed for neutralizing capacity.

Al(OH)3 (Alfa, MW=78.00; purity=76.5%) - A 3% suspension in Milli-Q water was prepared (3.92 g/100 ml based on purity) and 8.7 ml (~ 10 mEq) were assayed for neutralizing capacity.

Mg(OH)2 (MW=58.33; purity=95%) - A suspension of 3.54 g/100 ml in Milli-Q water was prepared and 8.7 ml (~ 10 mEq) were assayed for neutralizing capacity.

TUMS E-X One tablet ( ~ 15 mEq) was dissolved in 70 ml Milli-Q water and assayed for neutralizing capacity.

( Cθ3)4-M (OH)2*5H2θ (MW=485.7) - A suspension of 8.48 g/100 ml in Milli-Q water was prepared and 4.8 ml ( — 8 mEq) were assayed for neutralizing capacity.

CaCθ3 (MW= 100.1) - A suspension of 8.6 g/100 ml Milli-Q water was prepared and 5.8 ml (~ 10 mEq) were assayed for neutralizing capacity. Results:

The effects of a number of antacids on fluid accumulation elicited by clavulanate were determined in the rat model. Prior to dosing animals, the neutralizing capacity of the antacids employed were determined employing the USP method as described above (Methods). Ten mEq, or 15 mEq in the case of TUMS E-X, of the various antacid suspensions (Alhydrogel is actually an adjuvant suspension and not an antacid) were added to 70 ml H2O, and the volume of 0.5 N NaOH required to titrate to pH 3.5 was determined. The results (average of duplicate determinations) are presented in Table 1. As can be seen in Table 1, the solutions were generally within 20-30% of the calculated values with the Alhydrogel having no neutralizing capacity.

Table 1. Determination of acid neutralizing capacity of agents employed in the rat enteropooling assay.

H2Ω Alhvdrogel Mg(OH>2 AHOHtø initial pH 5.5 5.0 10.2 5.5 pH w/ HCl 0.60 0.60 0.78 0.79

NaOH (ml) 62.7 62.2 41.5 43.9 calc. mEq 0 0 8.0 7.0

MgCθ3_ CaCOs TUMS E-X initial pH 10.5 9.9 8.0 pH w/ HCl 0.72 0.77 0.83

NaOH (ml) 43.7 39.7 32.1 calc. mEq 7.0 8.8 12.1

The target concentrations of antacids for these studies were 10 mEq with the exception of TUMS E-X which was 15 mEq.

Initially, effects of inorganic salts, including antacids, on 'basal' fluid accumulation were determined. As shown in Fig. 1, animals administered water alone have a 'basal' fluid accumulation of 7.5 ± 0.3 mg/cm at 1 hr post dosing. Adniinistration of two forms of aluminum hydroxide, one neutralizing and one non-neutralizing (Alhydrogel), at doses of 11 mg/kg had no effect on 'basal' fluid accumulation (6.9 ± 0.4 mg/cm and 6.0 ± 1.1 mg/cm, respectively) . Fluid accumulation resulting from administration of Kaolin

(aluminium silicate, 30 mg/kg), magnesium hydroxide (11 mg/kg), magnesium carbonate (85 mg/kg) or calcium carbonate (86 mg/kg) ranged between 5.7 and 11.5 mg/cm. Only magnesium carbonate produced significant increases in 'basal' fluid accumulation. Dose-dependence of the increase in 'basal' fluid accumulation was completed with aluminum hydroxide, magnesium carbonate and calcium carbonate. The results shown in Fig. 2 indicate that aluminum hydroxide produced marginal and not clearly dose-dependent changes in fluid accumulation while magnesium carbonate produced a greater change in 'basal' fluid accumulation when compared to either aluminum hydroxide or calcium carbonate.

In addition to determination of the effects of these antacids on 'basal' fluid accumulation, their ability to reverse the increase in fluid accumulation elicited by potassium clavulanate was examined. As shown in Fig. 3 the neutralizing and non-neutralizing forms of aluminum hydroxide reduced the fluid accumulation elicited by potassium clavulanate from 22.0 + 0.8 mg/cm to 14.4 ± 1.1 mg/cm and 18.9 ± 1.3 mg/cm, respectively, although the decrease produced by the non-neutralizing form (Alhydrogel) was significantly less. The neutralizing form of aluminum hydroxide did not show any dose- dependent effect in reducing fluid accumulation between 5.6 and 30 mg/kg (Fig. 4). Calcium carbonate (86 mg/kg) and the acid neutralizing form of aluminum hydroxide significantly reduced the fluid accumulation elicited by potassium clavulanate (Fig. 3). These data indicate that the acid neutralizing form of aluminum hydroxide is an effective agent in reducing fluid accumulation elicited by potassium clavulanate. It should be noted that calcium carbonate produced a similar reduction in the fluid accumulation elicited by potassium clavulanate although the acid neutralizing capacity (e.g. mEq dose) required was 4 times greater.

Amoxycillin (200 mg/kg) and potassium clavulanate (100 mg/kg) were dosed alone or in combination and fluid accumulation determined at 1 hr. While administration of amoxycillin alone produced no significant effect on 'basal' fluid accumulation, the combination of amoxycillin and potassium clavulanate produced a significantly greater amount of fluid accumulation (26.1 ± 0.7 mg/cm) than that seen with potassium clavulanate alone ( 22.0 ± 0.8 mg/cm) (Fig. 5). In the light of these findings, effects of antacids on fluid accumulation elicited by the combination of amoxycillin and potassium clavulanate were determined. The neutralizing form of aluminum hydroxide (11 mg/kg), Kaolin (30 mg/kg) and magnesium hydroxide (11 mg/kg) reduced the fluid accumulation elicited by the combination of amoxycillin and potassium clavulanate by a small extent (23.3 ± 1.0 mg/cm, 24.3 ± 2.0 mg/cm, 24.3 ± 2.0 mg/cm respectively) (Fig.6). Co-administration of magnesium carbonate (85 mg/kg) or calcium carbonate (86 mg/kg) reduced the fluid accumulation elicited by amoxycillin and potassium clavulanate to 19.7 ± 1.4 mg/cm and 17.8 ± 0.9 mg/cm, respectively. Thus, calcium carbonate was able to inhibit fluid accumulation produced by potassium clavulanate alone or the combination of potassium clavulanate and amoxycillin. Conclusion.

In summary, data from the rat enteropooling assay suggests that specific antacid salts may be useful in reducing fluid secretion stimulated by the combination of potassium clavulanate and amoxycillin. Of the antacids studied, calcium carbonate and magnesium carbonate inhibited fluid accumulation elicited by the combination of amoxycillin and potassium clavulanate. Although the dose-response for this inhibition is similar, the greater effect of magnesium carbonate on 'basal' fluid accumulation in the rat enteropooling assay may compromise any potential benefits. Co-administration of calcium carbonate does not completely reverse fluid accumulation produced by amoxycillin and clavulanate in the rat enteropooling assay, but the reduction observed may be sufficient to reduce the incidence of intolerance.

The reduction in fluid accumulation seen with antacids does not appear to be due solely to acid neutralization based on the observations that aluminum hydroxide (dosed at 0.43 mEq/kg neutralizing capacity, within the standard human dose range), magnesium carbonate (dosed at 1.8 mEq/kg neutralizing capacity) and calcium carbonate (dosed at 1.7 mEq/kg neutralizing capacity) produced similar reductions in fluid accumulation in response to potassium clavulanate. In addition, doses of aluminum hydroxide from 5.6 to 30 mg/kg produced the same change in fluid accumulation in response to potassium clavulanate. The effect may be due to these antacid materials also acting as an adsorbent.

Example 3: Evaluation of Effects of Antacids on Gastric Fluid Secretion in the Rat.

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

K. clavulanate (100) +

+Al(OH)3 (5.6) 14.81 1.87 6

+Al(OH)₃ (11.2) 14.39 1.12 12

+Al(OH)₃ (30) 15.85 1.06 12

+ Alhydrogel (11.2) 18.92 1.30 9

+MgCO₃ (84.8) 18.78 0.92 22 0.27 0.04 7

+CaCO3 (86) 16.73 0.70 37 0.44 0.06 15

+CaCO₃ (50) 16.35 1.58 5 0.42 0.05 5

+CaCO₃ (25) 17.13 2.61 4 0.44 0.10 4

+ Charcoal (75) 19.30 1.09 6

Amox. /K.clav. (200/100) 25.57 0.50 133 1.39 0.13 31

Amox. /K.clav. (200/100) +

+Al(OH)₃ (11.2) 23.26 0.98 11

+Al(OH)₃ (30) 22.81 0.84 6

+Mg(OH)₂ (11.2) 23.32 1.54 10

+MgCO₃ (42.4) 24.10 1.20 11

+MgCO₃ (84.8) 19.68 1.38 17

+MgCO₃ (170) 24.64 2.77 5

+CaCO3 (43) 22.18 1.99 6

+CaCO₃ (86) 18.55 0.87 28 0.44 0.07 10

+CaCO3 (170) 18.61 1.55 6

Example 4: Tablet Formulation.

A tablet formulation of this invention suitable for administration to humans is listed below.

Formulation 1:

Component mg per tablet

Amoxycillin trihydrate 875.00¹

Potassium clavulanate 125.00¹ Calcium carbonate USP 250.00

Sodium starch glycollate NF 30.00

Magnesium stearate NF 15.00

Microcrystalline cellulose NF qsad 1500.00

Note: ^l weight expressed as free acid equivalent.

This formulation was made into compacted tablets using standard methods known in the art, suitably those disclosed in GB 2005538A.

Claims

Claims:

1. A pharmaceutical formulation comprising in combination clavulanate and an acid neutralising material and/or an adsorbent material, provided that when the formulation is a potassium clavulanate : amoxycillin trihydrate formulation with a clavulanate : amoxycillin ratio of 1 : 2 (expressed as free acids equivalent) then (i) the acid neutralising material and/or adsorbent material is other than aluminium hydroxide in an acid neutralising form, and. (ii) the ratio acid neutralising material and/or adsorbent material : clavulanate (expressed as free acid equivalent) is greater than 1.4 : 1 when the said material is calcium carbonate, and greater than 0.88 : 1 when the said material is magnesium carbonate.

2. A pharmaceutical formulation according to claim 1 characterised in that the clavulanate is potassium clavulanate.

3. A pharmaceutical formulation according to claim 1 or claim 2 characterised in that the acid neutralising material and/or adsorbent material is selected from Group II or Group in metal bases, Group WJR metal silicates, celluloses, molecular sieves and charcoal.

4. A pharmaceutical formulation according to claim 3 characterised in that the acid neutralising material and/or adsorbent material is selected from Group II or Group in metal carbonates, hydrogen carbonates, oxides (other than calcium oxide) or hydroxides (other than calcium hydroxide).

5. A pharmaceutical formulation according to claim 4 characterised in that the acid neutralising material and/or adsorbent material is selected from calcium carbonate, magnesium carbonate, and aluminium hydroxide.

6. A pharmaceutical formulation according to claim 1 characterised in that the clavulanate is co-formulated with an antibiotic compound.

7. A pharmaceutical formulation according to claim 6 characterised in that the antibiotic compound is amoxycillin.

8. A pharmaceutical formulation according to claim 1 in unit dosage form, characterised by containing from 12.5 to lOOOmg (expressed as the free acid) of clavulanate, from 125 to 3000 mg of amoxycillin (expressed as the free acid), and 25 - 500 mg of the acid neutralising material and/or an adsorbent material.

9. A method for the preparation of a pharmaceutical formulation according to claim 1, comprising admixing the combination of clavulanate acid and the said acid neutralising material and/or an adsorbent material.

10. A pharmaceutical formulation according to claim 1 for use as an active therapeutic substance, particularly in the treatment of bacterial infections in humans or animals.

11. A method of use of clavulanate, and an acid neutralising and/or an adsorbent material together in the manufacture of an antibacterial medicament formulation, provided that when the formulation is a potassium clavulanate : amoxycillin trihydrate formulation with a clavulanate : amoxycillin ratio of 1 : 2 (expressed as free acids equivalent) then (i) the acid neutralising material and/or adsorbent material is other than aluminium hydroxide in an acid neutralising form, and (ii) the ratio acid neutralising material and/or adsorbent material : clavulanate (expressed as free acid equivalent) is greater than 1.4 : 1 when the said material is calcium carbonate, and greater than 0.88 : 1 when the said material is magnesium carbonate.

12. A method of suppressing the gastro intestinal intolerance associated with the oral dosing of clavulanate-containing products, the method comprising co- administration of clavulanate in combination with an acid neutralising material and/or an adsorbent material.

13. A pharmaceutical formulation including clavulanate, in which the gastro intestinal intolerance associated with the oral dosing of clavulanate-containing products, is suppressed by an acid neutralising and/or an adsorbent material.

14. A method of treatment of bacterial infections in humans, which comprises the oral administration to a patient in need of treatment an effective amount of a pharmaceutical formulation as claimed in claim 1.