IE903285A1 - Pharmaceutical preparations - Google Patents

Abstract

Pharmaceutical preparations containing (a) an antibacterial compound and (b) an effective amount of an absorption-enhancing system containing (1) a polyoxyethylene glycol C6-C18-carboxylic acid glyceride ester, and (2) a C6-C18-carboxylic acid, where appropriate in addition a pharmaceutically utilisable salt of an acid of this type.

Description

This invention relates to pharmaceutical compositions comprising (a) an antibacterial compound and (b) an absorption enhancing amount of an absorption enhancing system made up of (1) a polyoxyethylene glycol - C to 6 C carboxylic acid glyceride ester and (2) a C, to 18 6 C carboxylic acid, with or without a C to C.Q carboxylic acid salt. Optionally, a pharmaceutically inert carrier can also be included.

The term polyoxyethylene glycol-Cg to C 15 carboxylic acid glyceride ester as used in connection with this invention refers to those reaction products derived from the co-reaction of polyoxyethylene glycol (or polymerizable precursor thereof, such as ethylene oxide) with a C -C carboxylic acid and glycerol or with a 6 18 C6~C18 carboxY’11-c aci-d glyceride or glycerides.

Resulting from such reactions are. typically, mixtures of a polyoxyethylene glycol-C to C carboxylic acid 6 18 glyceride ester (e.g., PEG-glycerol-caprate, PEG-glycerolcaprylate or PEG-glycerol-caprylate/caprate), a polyoxyethylene glycol-Cg to Clg carboxylic acid ester (e.g.. PEG-caprate, PEG-caprylate or PEG-caprylate/caprate) and a glyceryl-C to C carboxylic acid ester (e.g., 18 glyceryl mono-, di- or tricaprylate, glyceryl mono-, di- or tricaprate or glyceryl mono-, di- or tricaprylate/ caprate) as the principal components.

More specifically, it has been discovered that the above-identified absorption enhancing system functions to increase the extent of absorption of antibacterial compound through mucosal tissue and into the bloodstream. This Grn/27.6.90 - 2 invention thus promotes the absorption and provides adequate blood levels of antibacterial compounds which, when administered without the absorption enhancer by means other than parenteral, are only poorly absorbed or not absorbed to any appreciable degree. The preparation and use of a greater variety of dosage forms for such compounds are thus enabled. The invention also promotes the greater absorption and results in adequate blood levels of antibacterial compounds which are otherwise only moderately absorbed through mucosal tissue, thus enhancing the effectiveness of such therapeutic compounds too.

The compositions of this invention encompass virtually any dosage form suitable for oral or rectal administration.

The invention includes oral and rectal types of pharmaceutical preparations containing effective amounts of an antibacterial compound and an absorption enhancing system in accordance with the present description, with or without an inert carrier and pharmaceutically acceptable adjuvants.

The terms antibacterial and antibiotic are used interchangeably throughout this disclosure to refer to bactericidal or bacteriostatic compounds which have been metabolically derived from a microorganism, synthetically prepared by chemical means, or prepared by a combination of microbial and chemical procedures (semi-synthetic).

Contemplated for utilization in the practice of this invention is virtually any antibiotic substance which is useful for combatting a bacterial infection in a host, including those antibiotics which are only moderately absorbed upon non-injected or non-infused administration. However, this invention finds its greatest usefulness when employed to enhance the absorption and bioavailability of antibiotics which, for the most part, can be effectively administered only by injection or infusion due to non- or - 3 poor absorbability via other routes of administration.

Among the most preferred antibacterial compounds suitable for use as the therapeutic substance in the practice of this invention are beta-lactam antibiotics, particularly compounds having a beta-lactam ring as the central structure, that is, the structure which can be substituted at various positions on the ring and/or fused with other ring systems which themselves can be substituted or unsubstituted. Exemplary of such beta-lactam antibiotics are penicillins, cephalosporins, penems, penams, carbapenems, carbapenams and monocyclic beta-lactams.

Especially preferred beta-lactam antibiotics for use in this invention are compounds of the formula _/· in which R^ is hydrogen or optionally substituted alkyl.

R„ is SO -M+ where M+ is a proton or cation, 2 3 R3 is an acylamino group or hydroxyalkyl, or R^ and R2 together with the beta-lactam (azetidinone) ring to which they are bonded represent «ί in which X is -S-, -O. -SO-, and Y is group -SO2, -CH2 or -CH(CH3) \ or COOE in which is a substituted thio group such as ethylthio -sch2ch2nh2.

NH tt -SCH CH NHCH, -SCH CH 2 2 2 2 NH o&jh2, S CONMe2 or an optionally substituted lower alkyl group such as aminomethyl, acylaminomethyl. - 5 j O 5 or a substituted oxy group such as carbamoyloxy (-02), the carbon atom which carries the -COOE group is bonded to the nitrogen atom of the beta-lactam ring, Z is hydrogen, halogen, alkoxy or CH2T, with T denoting hydrogen, alkyl -CO-O-, pyridinium. carboxamidopyridinium, aminopyridinium, carbamoyloxy, azido, cyano, hydroxyl, the group -S-phenyl which can be substituted or the group -S-het wherein het is an optionally substituted 5- or 6-membered heterocyclic ring, and E is hydrogen, a pharmaceutically acceptable ester group or a salt-forming cation.

Examples of the 5- or 6-membered heterocyclic rings encompassed within het above are the following: N-N N-N // J CH2-CH2-N(CH2)2 CH2CO2H Especially preferred beta-lactam antibiotics and their pharmaceutically acceptable salts, esters and hydrates include ceftriaxone, a cephalosporin described in U.S.

Patent No. 4.327,210 (Montavon et al.); carumonam, a - 6 monocyclic beta-lactam described in European Patent No. EP 73061; piperacillin, a penicillin described in U.S. Patent No. 4,112,090; cefamandole. a cephalosporin described in U.S. Patent No. 3,641,021; and cefazolin, a cephalosporin 5 described in U.S. Patent No. 3,516,997, the disclosures of all of which are incorporated herein by reference. Further included are cefoxitin, cefmetazole. cefotetan. moxalactam, cefuroxime, ceforamide, cefoperazone. ceftizoxime. cefotaxime, cefmenoxime, ceftazidime, cefsulodin, 1Q cephalexin, azlocillin. penicillin G, temocillin, sulbenicillin, ticarcillin, mecillinam, amoxicillin, methicillin, carbenicillin, thienamycin, N-formimidoylthienomycin. sulbactam and azthreonam.

Also included within the scope of this invention are antibiotics other than the beta-lactams, for example, vancomycin, the absorption and blood levels of which are improved by use with the described absorption enhancing systems .

Absorption enhancing system component (b)(1) may be the product of an esterification reaction between a polyoxyethylene glycol, glycerol and one or more straight or branched chain C, to C. carboxylic acids, preferably a O J-a monofunctional acid or acids. Alternatively, component (b)(1) may be prepared by oligomerizing or polymerizing ethylene oxide in the presence of an ester of glycerol and one or more of such C, to Cno carboxylic acids o lo (glyceride esters). Still another route, and the preferred 3Q one, is by co-reacting the glyceride ester or esters with a fully pre-formed polyoxyethylene glycol under conditions sufficient to achieve alcoholysis.

According to a particular preferred procedure, involving alcoholysis, a reaction vessel is charged with stoichiometric quantities of a glyceryl-fatty acid ester or esters and a polyethylene glycol. The vessel is closed and heated at atmospheric pressure to 200°C. with continuous stirring commenced at 70°C, for a period of 12 to 24 hours or until the reaction is completed. The vessel is allowed to cool and the reaction product is then separated from the reaction mixture by filtration.

Examples of C, to C_ carboxylic acids, saturated or O lo unsaturated, which are useful for the preparation of absorption enhancing system component (b)(1) are caproic, caprylic, capric, lauric, myristic. oleic, palmitic and stearic acids. Especially preferred for this invention are capric and caprylic acids, individually or together.

The polyoxyethylene glycol (PEG) used in the formation of absorption enhancing system component (b)(1) is, typically, a medium to high molecular weight material, preferably having a number average molecular weight in the range from about 200 to about 1500, and more preferably from about 300 to about 600.

A material which is suitable for use as absorption enhancing system component (b)(1) will most preferably have the following characteristics: Organoleptic Properties: Appearance: Odor : Color: clear oily liquid faint pale yellow to yellow Physical and Chemical Properties: Acid Value: 0.2 - 0.6 Sulfated ash: less than 0.05% Saponification index: 85 - 105 Iodine index: less than 2 Moisture content: less than 0.05% Free glycerin content: approx. 2% Monoglyceride content: approx. 6 to 8% . 2 0 Density (d. ): 1.062 - 1.068 g/cc . 20 Refractive index (ηβ ): 1.458 - 1.462 Suitable absorption enhancing system components for use as (b)(1) in this invention which are commercially available are LABRASOL, produced by Gattefosse Corporation, Paris. France (PEG-8 caprylate/caprate glyceride esters), and 15 SOFTIGEN 767, produced by Dynamit Nobel, West Germany (PEG-6 caprylate/caprate glyceride esters).

The C, to C carboxylic acid of absorption 6 18 enhancing system component (b)(2) is derived from an 2q aliphatic carboxylic acid, which may be straight or branched chain. Examples include caproic, caprylic, capric, lauric, myristic, oleic, palmitic and stearic acids. Most favored for the purposes of this invention is caprylic acid. oc The C to Cno carboxylic acid salt, which optionally 18 is employed with the acid, can be prepared in a conventional manner and using known techniques by reacting the acid with a base having a non-toxic, pharmacologically and pharmaceutically acceptable cation. In general, any base which will form a salt with a carboxylic acid and the pharmacological properties of which will not cause an adverse physiological effect when ingested by or otherwise administered to a warm-blooded animal is suitable. Such bases thus include, for example, alkali metal and alkaline earth metal hydroxides or carbonates, such as sodium hydroxide, potassium hydroxide, calcium hydroxide, potassium carbonate, and the like. Particularly preferred for this - 9 invention are sodium salts, chiefly because of their ready availability. Sodium caprylate is especially preferred.

The C to C carboxylic acid salt is useful as a o J_o c stabilizing agent for the C to C carboxylic acid, and 'J ο 18 is especially desirable in formulations where ceftriaxone is present as the antibiotic.

The relative proportions of the components which 1Q comprise the absorption enhancing system can be varied to achieve optimum results for a particular embodiment of the invention. For the two-component absorption enhancer system, preferably, component (b)(1) is present in an amount from about 20 to about 80 percent and the carboxylic acid is 15 present in an amount from about 80 to about 20 percent, based on the total weight (100%) of these two components combined. A more preferred embodiment will comprise from about 40 to about 60 percent of component (b)(1) and from about 60 to about 40 percent of the carboxylic acid, based 2Q on the total weight of the two components. Still more preferred are those absorption enhancer systems consisting of about 50 percent of component (b)(1) and about 50 percent of the carboxylic acid, based on the combined weight of the two components.

Preferably, for the three-component absorption enhancer system, component (b)(1) is present in an amount from about 20 to about 80 percent, more preferably from about 40 to about 60 percent, and most preferably about 50 percent, based on the total weight (100%) of the three absorption enhancer system components combined. The carboxylic acid preferably is present in an amount from about 10 to about 40 percent, more preferably from about 15 to about 25 percent, and most preferably about 25 percent of the total weight.

The carboxylic acid salt is present in an amount from about to about 40 percent, more preferably from about 25 to about 35 percent, and most preferably about 25 percent of - 10 the total weight.

The effective amount of the absorption enhancing system, component (b), in the composition of this invention will 5 vary depending on such factors as the particular antibacterial compound being employed and its amount, as well as the age of the subject being treated.

In general, for oral dosage form compositions of this 10 invention, it is preferred to employ from about milligrams (mg) to about 1000 mg, and more preferably from about 100 mg to about 500 mg of the absorption enhancing system, for each unit dose of the composition. These compositions will usually contain the antibacterial 15 compound in amounts from about 10 rag to about 500 mg. and more usually from about 50 mg to about 250 mg, per unit dose Rectal dosage form compositions in accordance with this invention will usually contain from about 25 mg to about 2q 1500 mg, more preferably from about 100 mg to about 500 mg of the absorption enhancing system, for each unit dose of the composition. Such compositions will usually contain the antibacterial compound in amounts from about 10 mg to about 3000 rag, and more usually from about 100 mg to about 1500 mg. per unit dose.

The term unit dose is used here in the conventional sense to mean a single application or administration of the drug to the subject being treated in an amount as stated above, but it should be understood that the amount can be given in the form of a single pill, tablet, capsule, suppository, etc., or alternatively, in multiples of two or more of such dosage units with the total adding up to the stated amount of drug.

The described antibacterial compound and absorption enhancing system, respectively, can be incorporated in a - 11 vehicle, if desired. As the vehicle, there can be used any pharmaceutically acceptable solid, semi-solid or liquid carrier in which these components are soluble or readily dispersible. Some examples include but are not limited to cocoa butter, polyethylene glycols, polypropylene glycols, © methylcellulose, carboxymethylcellulose and Suppocire semi-synthetic bases (Gattefosse Corp., Paris. France). Preferably, the vehicle is a solid. Favored as a solid vehicle for the compositions of this invention are mixtures jq of mono-, di- and triglycerides of C to natural saturated fatty acids, preferably vegetable fatty acids having an even number of carbon atoms (C,_, C.., C.,, X 2 X 4 X 6 etc.). Especially suitable and preferred are the pharmaceutical bases of Dynamit Nobel having the trade 15 designation WITEPSOL.

Still other pharmaceutically compatible carrier materials may be employed as desired and depending upon particular requirements, the selection of which is within the knowledge of those skilled in the art.

If utilized, the vehicle will generally be present in those amounts which are conventional for pharmaceutical carrier materials and which can be reasonably and safely administered.

The preferred method of orally administering the combination of antibacterial compound and absorption enhancing system in accordance with this invention is in the form of an enteric coated entity, and more specifically, an enteric coated solid dosage form. The formulation can be filled into a hard- or soft-shell capsule or. if the formulation is a liquid, adsorbed onto a suitable carrier to make a free flowing powder and then filled into the capsule or, alternatively, compressed into a pill or tablet. Still other possible dosage forms include microcapsule or beadlet forms of the antibacterial compound mixed with the - 12 absorption enhancing system which may thereafter be encapsulated in an enteric coated capsule.

Usage of enteric coating materials in this manner serves g to protect the antibacterial compound from the gastric fluid and to achieve optimum delivery of the antibacterial compound together with the absorption enhancing system to the intestine. The enteric coating material is, for the most part, resistant to the gastric fluid and is unaffected 1Q by it but dissolves in the intestinal fluid to cause release of the drug.

The effectiveness of particular enteric coating materials can be measured using known USP procedures. By way of illustration, suitable enteric coating materials for purposes of this invention include but are not limited to the following: cellulose acetate phthalate 2Q cellulose acetate trimellitate hydroxypropyl methylcellulose phthalate hydroxypropyl methylcellulose phthalate succinate polyvinyl acetate phthalate methacrylic acid methacrylic acid esters These enteric coating materials may be applied with or without plasticizers, such as acetylated glycerides or diethylphthalate, using methods known to those skilled in the art.

The percentage of enteric coating applied is usually between about 1 and about 10 percent by weight, or more, and most desirably from about 2 to about 8 percent by weight, based on the total weight of the unit dosage form, i.e., the total capsule or tablet weight. Examples of suitable - 13 enteric coating formulations are given below.

Enteric Coatinq Formulations -Ingredients % W/W IQ Preparation A: Hydroxypropylmethylcellulose phthalate (HPMCP) Tr iacetin Methylene chloride 15 Denatured alcohol .0 0.5 47.25 47.25 Preparation B: HPMCP 2Q Titanium dioxide Triethyl citrate Acetone Denatured alcohol Preparation C: Cellulose acetate phthalate Diethyl phthalate Titanium dioxide Acetone Denatured alcohol .0 0.2 1.5 44.15 44.15 (CAP) 8.5 1.5 0.2 44.9 44.9 - 14 Preparation D: Polyvinyl acetate phthalate 5.0 Acetylated glycerides 0.8 Methylene chloride 47.1 Denatured alcohol 47.1 Preparation E: 1θ Methacrylic acid or methacrylic acid ester (Eudragit S or L, 8.0 Rohm Pharma. GMBH. Wetterstadt, West Germany) Triacetin 1.0 Acetone 45.5 Anhydrous alcohol 45.5 Oral dosage form compositions in accordance with this invention can also be formulated to additionally contain 2q conventional additives or supplementary ingredients, in the usual amounts for such materials. By way of illustration, such additives or supplements include thickening agents, such as silicic acid (for instance, the trade designated Aerosil products); bentonites; colloidal clay; carboxymethyl celluloses; modified montmorillonites, such as alkyl ammonium salts of montmorillonites (for instance, the commercial products known as Bentone); organic thickening and structure-forming agents, such as saturated higher fatty acids and alcohols containing from 12 to 20 carbon atoms (for instance, stearic or palmitic acids, or stearic or cetyl alcohols); waxes; monoglycerides of saturated or unsaturated high fatty acids such as stearic acid, palmitic acid or oleic acid; gelling agents, such as aluminum stearate; dispersing agents, such as ionic, non-ionic or cationic surfactants; emulsifying agents, such as lecithin, and so forth. - 15 The compositions of this invention can also contain pharmaceutically acceptable adjuvants, such as binders or lubricants for tabletting, stabilizing agents, antioxidants, flowing agents (to enhance pourability or flowability during g processing), preservatives, flavoring agents, coloring agents and buffering agents. Any of these can be selected from among materials known for such purposes and used in conventional amounts. 1θ In vivo tests were utilized to evaluate the enhanced mucosal tissue absorption of antibiotics administered in accordance with this invention.

IN VIVO (RATS) - ENTERAL Adult Sprague-Dawley female rats (Charles River Breeding Laboratories, Kingston, New York), weighing about 250 grams each, were fasted overnight and anesthetized with metofane. With each rat, an incision was made on the ventral surface 2Q to expose the intestine. Administration of an antibiotic was carried out using a solution dosage form. The solutions were prepared by dissolving antibiotic in water with or without absorption enhancer so as to deliver 20 milligrams per kilogram, approximately 5 mg per rat.

Each solution of antibiotic in water was administered enterally by injecting with a syringe into the duodenum directly below the pyloric valve. For purposes of comparison, the solution was alternatively administered intravenously by injecting with a syringe into a tail vein.

Plasma Levels of Antibiotic in Rats The concentration of antibiotic in rat plasma was determined at various time intervals after intravenous or enteral administration. Blood samples were collected from the tail of each test animal prior to administration of the - 16 antibiotic and at 5. 10, 20, 40. 60, 120, 240 and 360 minutes after administration, then centrifuged at 3200 rpm for 5 to 10 minutes, after which the plasma was withdrawn and frozen until assayed.

Bioassay of Plasma Samples Most of the antibiotics tested had exhibited some degree of protein binding when drug-spiked rat plasma was assayed against drug in H2O. Any antibiotic not bound by plasma was diluted in H20 and assayed against standards prepared in H2O. For bound antibiotics, the influence of protein binding was negated by diluting all standards and samples in pooled rat plasma. In the case of ceftriaxone and cefazolin, the effect of binding was accounted for by deproteinizing plasma samples with acetonitrile using a dilution factor of 1:12 and assaying against a standard curve diluted in H2O. Antibiotic levels were assayed on nunc plates employing the appropriate agar seeded with bacteria, as listed below in Table 1. - 17 TABLE I Antibiotic Assay Orqanism Range of Standard Curves (mcg/ml) Sioassay Media Vol une (mcl) Carumonam Ampicillin’ E. coli. 1346 32-1 8-0.25 AAAI AAAI 20 20 M. lutea ATCC 9341 10 Cefamandole’ Cefotaxime’ Cefoxitin’ Ceftriaxone’ Cefazolin’ M. lutea ATCC 9341 32-1 AAAI 20 E. coli. 1346 8-0.25 or 16-0.5 AAAI 20 S. aureus HB2786 E. coli. 1346 64-4 4-0.125 BHI3 AAAI 20 20 S. aureus ATCC 25923 32-1 AAAI 50 15 Moxalactam’ Penicillin g’ Vancomycin’ B. subtilis spores E. coli. 1346 32-2 50-1.56 AAAI AAAI 50 50 M. lutea ATCC 9341 8-0.5 AAAI 20 8. cereus ATCC 11778 64-2 AAA85 50 „ Antibiotics protein bound in rat plasma. 2AA#1 = antibiotic agar #1 (Difco). 3BHI = Brain Heart Infusion Media (Difco).

MH = Mueller Hinton Agar (Difco).

AA#8 = antibiotic agar #8 (Difco). mcg/ml = micrograms per milliliter mcl = microliters o The plates were incubated overnight at 37 C and the zones of inhibition were read to the nearest 0.1 mm. Calculations were made using an autoassay machine (Giles Scientific, Inc., New York). For reference, see J. V. Bennett et al., Applied Microbiology 14., 170-177 (1966).

The results are presented in Table 2: -18 TABLE 2 ENTERAL ABSORPTION IN RATS With and Without Absorption Enhancers Dose = 5 mq/0.5 mi Qnax (microqrams per milliliter) Antibiotic (Control) Water Labrasol + Caprylic Acid* Labrasol + Caprylic Acid 4· Sod ion Caprylate** Carunonam 0 13.6 ± 2.9 10.9 ± 1.4 Cefamandole 1.3 ± 2.5 5.4 ± 1.5 15.5 ± 6.8 Cefazolin 0 - 17.5 ± 5.7 Cefoxitin 0 - 12.8 ± 1.7 Cefotetan 0 17.8 ± 4.9 20.4 ± 4.9 Noxalactam 0 - 15.8 ± 1.3 Penicillin G 0.5 ± 0.1 7.2 ± 0.7 2.9 ± 1.6 Vancomycin 2.9 ± 0.6 8.0 ± 2.3 5.3 ± 2.1 Ceftriaxone 2.4 ± 1.9 57.0 ± 10.2 52.2 ± 22.5 *Weight Ratio of **Weight Ratio of Labrasol: Caprylic Acid was 2:1 Labrasol: Caprylic Acid: Sodiun Caprylate was 4:1:1 - 19 IN VIVO (DOGS) - ORAL Male beagle dogs weighing approximately 10-14 kilograms were used in this study. The dogs received 2 or 3 hard shell enteric coated capsules orally. Each capsule contained either of the following formulations: A B Ceftriaxone sodium salt* 315 mg 315 rag Labrasol 225 mg 225 mg Caprylic acid 200 mg 100 mg Sodium caprylate -- 100 mg Witepsol H15 210 mq 210 mq 9 50 mg 9 50 mg *315 mg of ceftriaxone sodium salt is equivalent to 250 mg of ceftriaxone as free acid plus 5% excess.

Enteric coating: polyvinyl acetate phthalate 2o (approximately 8% of total capsule weight) Blood plasma concentrations of ceftriaxone were determined prior to administration and at 10, 20, 40, 60, 120, 180 and 240 minutes after administration. Measurements were made by withdrawing blood at these time intervals, separating the plasma, deproteinizing, and assaying by High Performance Liquid Chromatography (HPLC). reverse phase method, or by the previously described Bioassay of Plasma Samples method.

The results were 27.7 ± 12.7% Bioavailability and 10 to 39.5 mcg/ml Craax Range for Formulation A, 31.0 ± 19.8% Bioavailability and 34.6 ± 23.2 mcg/ml Cmax for Formulation B. and 0% Bioavailability and 0 mcg/ml Cmax for the control (ceftriaxone sodium salt, 300 mg, in the same enteric coated capsule, no absorption enhancers). - 20 IN VIVO (BABOONS) - RECTAL Male and female adult baboons (Papio anubis and Papio hamadryas). ranging in weight from 12 to 27 kilograms, were 5 used in this study. The baboons were fasted overnight prior to administration of antibiotic, then sedated with ketamine hydrochloride by intramuscular injection prior to administration of the antibiotic. Suppositories made up of the formulation shown below were administered to the baboons •jq and the rectal openings were then taped closed to prevent expulsion and leakage of the suppository mass.

Antibiotic (active form) Labrasol Caprylic acid Sodium caprylate Witepsol H15 c D 500 mg 500 mg 250 mg 250 mg 200 mg 100 mg -- 100 mg 1050 mg 1050 mq 2000 mg 2000 mg To measure antibiotic absorption into the bloodstream, blood samples were taken from the femoral region of each baboon, using heparinized 3-ml syringes, prior to antibiotic administration and at 15, 30, 60. 120, 240, 360 and 480 minutes after antibiotic administration. The withdrawn samples were centrifuged at 12,000 rpm for one minute and bioassayed by the previously described Bioassay of Plasma Samples method. The results are presented in Tables 3 and 3A -21 TABLE 3 Antibiotic Bioavailabi1ity and C Range in Baboons max After Rectal Administration Antibiotic With 2-component Absorption Enhancer System (Formulation C) I Bioavailability C Range max mcg/ml Control-No Absorption Enhancer System 1 Bioavailability mcg/ml C Range max Ceftriaxone Cefotetan 17.3 ± 4.8 11.4 ± 7.4 21.6 - 46.6 4.3 - 21.1 4.3 ± 2.8 4.9 ± 3.1 0.3 - 9.0 2.4 - 10.1 Antibiotic TABLE 3A Antibiotic Bioavailability and C Range in Baboons max After Rectal Adninistration With 3-component Absorption Enhancer System (Formulation 0) I Bioavail- C Range max ab i1i ty mcg/ml Control-No Absorption Enhancer System 1 Bioavai 1abi1ity mcg/ml C Range max Ceftriaxone 17.1 ± 5.0 16.3 - 38.3 Cefotetan 24.1 ± 12.8 2.5 -61.5 4.3 ± 2.8 4.9 ± 3.1 0.3 - 9.0 2.4 - 10.1 - 22 By way of illustration, some suitable formulations for dosage forms in accordance with this invention as well as procedures for their preparation are set out below. Ceftriaxone is used because it is the preferred antibiotic. However, it is to be understood that other antibiotics within the previous description can be substituted, in appropriate amounts, without departing from the scope of the invention.

Example 1 Oral Formulation (Hard Gelatin Capsule) mg/capsule Ingredients Ceftriaxone Sodium* 120 mg 300 mg 120 mg 300 mg Labrasol 90 mg 225 mg 90 mg 225 mg Sodium caprylate -- -- 40 mg 100 mg Caprylic acid 80 mg 200 mg 40 mg 100 mg Witepsol H15 84 mg 210 mg 84 mq 210 mq 374 mg 935 mg 374 mg 935 mg * Equivalent to 100 mg and 250 mg, respectively, of free ac Procedure The base (Witepsol H15) is warmed to 55°C and the absorption enhancer system components are added to the melt 3Q with mixing. The melt is then cooled to 45°C and the drug (ceftriaxone sodium) is added to the molten mass and mixed •Ε 903285 - 23 until uniformly distributed and free of any aggregates. The mass is homogenized, if necessary, to obtain a uniform suspension. The suspension is then filled into capsules and allowed to cool and congeal. The capsules are sealed with a gelatin band and coated with an enteric polymer (PVAP). Approximately 8% of enteric coating is applied.

Example 2 Oral Formulation (Soft Gelatin Capsule) mg/capsule Ingredients Ceftriaxone Sodium* 120 mg 300 mg 120 mg 300 mg Labrasol 90 mg 225 mg 90 mg 225 mg Sodium caprylate -- -- 40 mg 100 mg Caprylic acid 80 mg 200 mg 40 mg 100 mg Witepsol H15 84 mq 210 mq 84 ma 210 mq 374 mg 935 mg 374 mg 935 mg * Equivalent to 100 mg and ; 250 mg, respectively, of free aci Procedure The base (Witepsol H15) is warmed to 55°C and the absorption enhancer system components are added to the melt with mixing. The melt is then cooled to 45°C and the drug (ceftriaxone sodium) is added to the molten mass and mixed until uniformly distributed and free of any aggregates. The - 24 mass is homogenized, if necessary, to obtain a uniform suspension. The suspension is then filled into soft gelatin capsules. The soft gelatin capsules are dried and coated with an enteric polymer (PVAP) as described in Example 1.

Example 3 Oral Formulation (Coated Beadlets) mcr/dose Ingredients Ceftriaxone Sodium* 150 mg 300 mg 150 mg 300 mg Labrasol 90 mg 180 mg 90 mg 180 mg Sodium caprylate -- -- 40 mg 80 mg Caprylic acid 80 mg 160 mg 40 mg 80 mg Witepsol H15 150 mq 300 mq 150 mg 300 jmg 470 mg 940 mg 470 mg 940 mg * Equivalent to 125 mg and : 250 mg, respectively, of free , acii Procedure The base (Witepsol H15) is warmed to 55°C and the absorption enhancer system components are added to the melt with mixing. The melt is then cooled to 45°C and the drug (ceftriaxone sodium) is added to the molten mass and mixed until uniformly distributed and free of any aggregates. The 3Q mass is homogenized, if necessary, to obtain a uniform suspension. The suspension is spray chilled for conversion - 25 into microspheres. The microspheres are placed in a capsule shell and coated with an enteric polymer as described in Example 1. - 26 Example 4 Rectal Formulation (Suppository) Inqredients mg/suppository Ceftriaxone Sod inn* 120 mg 300 mg 600 mg 120 mg 300 mg 600 mg Labrasol 250 mg 250 mg 250 mg 250 mg 250 mg 250 mg 10 Sodiin caprylate — — — 100 mg 100 mg 100 mg Caprylic acid 200 mg 200 mg 200 mg 100 mg 100 mg 100 mg Witepsol Hl5 1430 mg 1250 mg 950 mg 1430 mg 1250 mq 950 mg 2000 mg 2000 mg 2000 mg 2000 mg 2000 mg 2000 mg 15 * Equivalent to 100 mg, 250 mg and 500 mg, , respectively, of free acid Procedure The base (Witepsol H15) is warmed to 55 °C and the 20 absorption enhancer system components are added to the mel with mixing. The melt is then cooled to 45 °C and the drug (ceftriaxone sodium) is added to the molten mass and mixed until uniformly distributed and free of any aggregates. The mass is homogenized, if necessary, to obtain a uniform suspension. The suspension is then filled into suppository shells and allowed to cool and congeal.

Claims (13)

1. A pharmaceutical composition comprising: (a) an antibacterial compound; 5 (b) an absorption enhancing amount of an absorption enhancing system comprising (1) a polyoxyethylene glycol (PEG)- C to C. glyceride ester and (2) a C, to C, e Oxo 0 18 carboxylic acid, with or without a C to C carboxylic 6 lo acid salt; and 1θ optionally (c) a pharmaceutically inert carrier.

2. A composition according to claim 1, which is in an oral dosage form. 15

3. A composition according to claim 2, in which the oral dosage form is an enteric coated entity.

4. A composition according to claim 3, in which component (a) is present in an amount from about 10 to about 500 2q milligrams and component (b) is present in an amount from about 50 to about 1000 milligrams, per unit dose.

5. A composition according to claim 1, which is in a rectal dosage form.

6. A composition according to claim 5, in which component (a) is present in an amount from about 10 to about 3000 milligrams and component (b) is present in an amount from about 25 to about 1500 milligrams, per unit dose.

7. A composition according to any one of claims 1-6, in which component (b) comprising from about 20 to about 80 percent of the glyceride ester and from about 80 to about 20 percent of the carboxylic acid, based on 100 percent by 35 weight of the two substances combined. - 28

8. A composition according to any one of claims 1-7, in which the polyethylene glycol of component (b)(1) has a number average molecular weight in the range from about 200 to about 1500.

9. A composition according to any one of claims 1-8, in which component (b)(1) is a PEG-8 caprylate/caprate glyceride ester, the C, to C.. carboxylic acid is caprylic acid, and the C, to C carboxylic acid salt is 6 18 1Q sodium caprylate.

10. A composition according to any one of claims 1-9, in which the antibacterial compound is a beta-lactam of the formula in which R^ is hydrogen or optionally substituted alkyl, R is SO -M+ where M+ is a proton or cation, R_ is an 2 3 3 acylamino group or hydroxyalkyl, or R^ and R 2 together with the beta-lactam (azetidinone) ring to which they are bonded represent in which X is -Sand Y is group -O-. -SO. -SO 2 . -CH 2 or -CH(CH 3 ) - 29 10 COOE COOE or a* in which R, is a substituted 4 among ethylthio, -SCH 2 CH 2 NH 2 NH 0 -SCH CH NHCH, -SCH CH OCNH , thio group selected from -S—< }—CONMe 2 NH or an optionally substituted lower among aminomethyl, acylaminomethyl alkyl group selected from or a substituted oxy group consisting of carbamoyloxy p (-0<^NH 2 ). and the carbon atom which carries the -COOE group is bonded to the nitrogen atom of the beta-lactam ring, Z is hydrogen, halogen, alkoxy or CH 2 T, with T denoting hydrogen, alkyl -CO-O-, pyridinium. carboxamidopyridinium, aminopyridinium. carbamoyloxy, azido, cyano. hydroxyl, the group -S-phenyl which can be substituted or the group -S-het wherein het is an optionally substituted 5- or 6-membered heterocyclic ring, and E is hydrogen, a pharmaceutically acceptable ester group or a salt-forming cation. - 30

11. A composition according to claim 10, in which the antibacterial compound is ceftriaxone or a pharmaceutically acceptable salt, ester or hydrate thereof. 5

12. The novel pharmaceutical compositions as described hereinbefore.

13. A pharmaceutical composition according to claim 1, substantially as hereinbefore described and exemplified.