AU625276B2 - Pharmaceutical compositions - Google Patents

Abstract

Pharmaceutical product containing (a) a compound with antibacterial activity, and (b) an effective amount of an absorption-promoting 2-component system which contains as first component (b 1) an ether composed of a C6-C18-alcohol and polyoxyethylene glycol and as second component either (b 2-1) a polyoxyethylene glycol C6-C18-carboxylic acid glyceride ester, or (b 2-2) a C6-C18-carboxylic acid or a pharmaceutically utilisable salt thereof, or (b 2-3) an ester composed of two or more C6-C18-carboxylic acids, glycerol and a polyoxyethylene glycol.

Description

I

6 27 S F Ref: 111775 FORM COMMONWEALTH OF AUSTRALIA PATENTS ACT 1952 COMPLETE SPECIFICATION

(ORIGINAL)

FOR OFFICE USE: Class Int Class 0*0 o c~ 0 V Ob Os 0,a Complete Specification Lodged: Accepted: Published: Priority: Related Art: Name and Address of Applicant: F.Hoffmann-La Roche AG 124 Grenzacherstrasse CH-4002, Basel

SWITZERLAND

00 4 0 9 09 09r r. 41 Address for Service: Spruson Ferguson, Patent Attorneys Level 33 St Martins Tower, 31 Market Street Sydney, New South Wales, 2000, Australia 4 Complete Specification for the invention entitled: Pharmaceutical Compositions The following statement is a full description of this invention, including the best method of performing it known to me/us 5845/3 i: m r=;l 1 The present invention relates to a pharmaceutical composition comprising and antibacterial compound and an absorption enhancing amount of a two-component absorption enhancing system made up of a first component which is an ether of an acyclic C 6 to C 18 -alcohol and a polyoxyethylene glycol (PEG) having an average molecular weight from 400 to 600 and a second component selected from among a polyoxyethylene glycol (PEG)- caprylate/caprate glyceride ester, (2)(ii) caprylic or capric acid or pharmaceutically acceptable salt thereof, and (2)(iii) a polyoxyethylene glycol-glycerol cocoate; with or without a pharmaceutically inert carrier.

The term "polyoxyethylene glycol-C 6 to C18 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 o 15 a C 6

-C

18 carboxylic acid and glycerol or with a C 6

-C

18 carboxylic gly ol- 6

C

acid glyceride or glycerides. Resulting from such reactions are, typically, mixtures of a polyoxyethylene glycol-C to C 18 carboxylic acid glyceride ester PEG-glycerol-caprate, PEG-glycerol-caprylate or PEG-glycerol-caprylate/caprate), a polyoxyethylene glycol-C 6 to

C

1 8 carboxylic acid ester PEG-caprate, PEG-caprylate or PEG-caprylate/caprate), and a glyceryl-C 6 to C 18 carboxylic acid Sester glyceryl mono-, di- or tricaprylate, glyceryl mono-, di- or Ttricaprate or glyceryl mono-, di- or tricaprylate/caprate).

o~o TMS/1496u glcrd ese"a sd ncneto wt hsivnto eest thos recinpout eie rmtec-ecino oyxehln 1B glc l(rp l mrzbep eu srthr o ,sc seh ln xd )wt 2as the principal components.

It has been found that the above-identified absorption enhancing system functions to increase the extent of absorption of antibacterial compounds through mucosal tissue and into the bloodstream. This invention thus promotes the absorption and, concomitantly, the bioavailability 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 pharmaceutical :00 compositions of the present invention also promote the .o greater absorption and bioavailability of antibacterial :o ~15 compounds which are otherwise only moderately absorbed through mucosal tissue, thus enhancing the effectiveness of .0 0 such therapeutic compounds also.

This invention encompasses the aforementioned pharmaceutical composition for administration in virtually any dosage form suitable for oral or rectal administration.

o Embraced within its scope are oral and rectal types of 0 e0 pharmaceutical preparations containing effective amounts of an antibacterial compound and an absorption enhancing system 0:000 25 in accordance with the present description, with or without .0.40 an inert carrier and pharmaceutically acceptable adjuvants.

a 0. :V 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 Suseful for combatting a bacterial infection in a host, d ei prepredby hemial ean, o preare bya cobintio ofi micrbialandchemcal rocdure (sei-sntheic) C1j- 3including 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 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

O

0 o oand/or fused with other ring systems which themselves can be substituted or unsubstituted. Exemplary of such beta-lactam antibiotics are penicillins, cephalosporins, penems, S•"d 25 carbapenems and monocyclic beta-lactams.

Especially preferred beta-lactam antibiotics for use in this invention are compounds of the formula t 0 30 I o R 2 ca b -4 in which R1is hydrogen or optionally substitutes alkyl, R is SO 3-M+ where M+ is a proton or cation, R 3is an acylamino group or hydroxyalkyl, or R 1and RH together with the beta-lactam (azetidinone) ring tc which they are bonded represent -x 01 in which X is and Y is group -01 -so 2 -CF or -CH(CH 3 o .4.40

S

.4.44.4 o .45 .4.4 .4 .4.4 .4.4 .4.4 .4 .4 .4 .4 e~4 .4.4 .4 .4.4.4 .4 .4 .4.4.4.4 .3.04 .4 .4 .4 .4 .4 .4.

00 .4 04.

I

.4 4 .4504 .4

CH

3

X/

COOE

X

COOE

COOE

C.

in which R 4 i -SCH 2CH NH 2

NH

-SH2 CH 2

NHCH,

a substituted thio group such as ethylthio, 0 -SCH 2CH2

CH#

S -C(')HCONMe 2

I

or an optionally substituted lower alkyl group such as aminomethyl, acylaminomethyl, 0 halogen, alkoxy or CH2T, with T denoting hydrogen, alkyl pyridinium, carboxamidopyridinium, aminopyridinium, carbamoyloxy, azido, cyano, hydroxyl, the group -S-phenyl which can be substituted or the group -S-het wherein "het" o is an optionally substituted 5- or 6-membered heterocyclic ring, and E is hydrogen, a pharmaceutically acceptable ester Sor at15 group or a salt-forming cation.

h aExamples of the 5- or 6-membered heterocyclic rings encompassed within "het" above are the following: N-N N-N N-N o* i N-N -N CH 3

N

IN N CH 2

C

2

H

H

Especially preferred beta-lactam antibiotics and their pharmaceutically acceptable salts, esters and hydrates Sinclude ceftriaxone, a cephalosporin described in U.S.

i I 6- Patent No. 4,327,210 (Montavon et carumonam, a 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; mezlocillin, a penicillin described in U.S. Patent No. 3,974,142; and cefazolin, a cephalosporin 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, cefazolin, cephalexin, azlocillin, penicillin G, temocillin, sulbenicillin, ticarcillin, mecillinam, amoxicillin, methicillin, carbenicillin, thienamycin, P 15 N-formimidoylthienomycin, sulbactam and azthreonam.

Another preferred beta-lactam antibiotic for use in this invention is the compound, (E)-2-(Isobutoxy carbonyl) ,o -2-pentenyl(6R,7R)-7-[(Z)-2-(2-amino-4-thiazolyl) -2-(methoxyimino)acetamido]-3-(azidomethyl)-8-oxo-5-thia -1-azabicyclo[4.2.0]oct-2-ene-2-carboxylate which is described in European Patent Publication A2-0318767.

oz r Also included within the scope of this invention are 25 antibiotics other than the beta-lactams, for example, vancomycin and gentamicin, the absorption and bioavailability of which are improved by use with the t o: described absorption enhancing systems.

Absorption enhancing system component is the product of an etherification reaction between an alcohol, specifically, an acyclic C 6 to C 18 straight or branched chain alkanol and a polyoxyethylene glycol (PEG). Examples of alcohols suitable for the preparation of component include n-hexyl, P-heptyl, n-octyl, n-decyl, n-dodecyl (lauryl), n-tetradecyl (myristyl), n-hexadecyl (cetyl), 1 i 7 7 n-octadecyl, and so forth. Lauryl alcohol is preferred.

The polyoxyethylene glycol is, typically, a medium to high molecular weight material which preferably has a number average molecular weight in the range from about 200 to about 1500, and more usually from about 400 to about 600.

Component can be prepared by known procedures.

Especially favored for use as component is the material known as Laureth-12 (CTFA designation). A suitable commercially available material is MACOL LA-12, manufactured p' by Mazer Chemicals Company, Gurnee, Illinois.

Ct C Absorption enhancing system component may be the product of an esterification reaction between a polyoxyethylene glycol, glycerol and one or more straight or 0o branched chain C to C 18 carboxylic acids, preferably a S* 6 is monofunctional acid or acids. Alternatively, component may be prepared by oligomerizing or polymerizing ethylene oxide in the presence of an ester of glycerol and one or more of such C 6 to C 18 carboxylic acids (glyceride esters). Still another route, and the preferred one, is by co-reacting the glyceride ester or esters with a fully :i 25 pre-formed polyoxyethylene glycol under conditions sufficient to achieve alcoholysis.

According to a particular preferred procedure, involving J 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 0 C, with continuous stirring commenced at 70 0 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.

-8- Examples of C 6 to C18 carboxylic acids, saturated or 6 18 unsaturated, which are useful for the preparation of absorption enhancing system component are caproic, caprylic, capric, lauric, myristic, oleic, palmitic and stearic. 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 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.

o0 0 0 15 A material which is suitable for use as absorption 15 enhancing system component will most preferably o° have the following characteristics: c P:4 Organoleptic Properties: it:6: @444w o 40o 44 4 40 8 0 4 4 .44.

4or 4444 4 t Appearance: Odor: Color: clear oily liquid faint pale yellow to yellow Physical and Chemical Properties: Acid Value: Sulfate' .Lb- Saponifi n index: Iodine i .x: Moistut~ ntent: Free glycerin content: Monoglyceride content: 20 Density (d 2 4e 20) Refractive index (nD 0.2 0.6 less than 0.05% 85 105 less than 2 less than 0.05% approx. 2% approx. 6 to 8% 1.062 1.068 g/cc 1.458 1.462 *t f o 0o *e o c o 0 00 0 0 o* 9 Suitable absorption enhancing system components for use in this invention which are commercially available are LABRASOL, produced by Gattefosse Corporation, Paris, France (PEG-8 caprylate/caprate glyceride esters), and SOFTIGEN 767, produced by Dynamit Nobel, West Germany (PEG-6 caprylate/caprate glyceride esters).

The C 6 to C18 carboxylic acid or its salt which constitutes absorption enhancing system component is derived from an acyclic carboxylic acid, which may be straight or branched chain. Examples include caproic, caprylic, capric, lauric, myristic, oleic, palmitic and stearic. Most favored for the purposes of this invention are caprylic and capric acids.

These salts 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 's 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 invention are sodium salts, chiefly because of their ready availability.

*Ooo o 0 V 00 0 oc 0 0c Absorption enhancing system component is derived from a mixture of two or more carboxylic acids of 6 to 18 carbon atoms, glycerol and a polyoxyethylene glycol.

The acids may be straight or branched chain, and saturated or unsaturated.

Suitable acids include saturated carboxylic acids such as n-hexyl, n-heptyl, n-octyl, n-decyl, lauryl, myristyl, i i

~I

i 1~ ii ij r! i i Yt i 'i j i: 1 j.t cetyl and n-octadecyl, and unsaturated enoic oleic) and dienoic linoleic) acids.

Preferred are mixtures comprised of several C to 6

C

18 fatty acids, such as found in vegetable oils and fats, and most preferably coconut oil, which is composed of major amounts of saturated and minor amounts of unsaturated fatty acids of up to 18 carbon atoms.

Preferably, the polyoxyethylene glycol employed for absorption enhancing system component is characterized by a number average molecular weight in the range from about 200 to about 1500, and more usually from about 300 to about 600.

Absorption enhancing agents useful as absorption enhancing system component can be prepared by 2 those skilled in the art using conventional esterification procedures. A suitable material is available commercially from Capital City Products, Janesville, Wisconsin under the trade designation ACCONON CON (a PEG glycerol cocoate).

The relative proportions of the two components which comprise the absorption enhancing system can be varied to achieve optimum results for a particular embodiment of the invention. Preferably, the weight ratio of to or is in the range from about 1:50 to about 50:1, more preferably from about 1:10 to about 10:1, and most preferably from about 1:4 to about 4:1.

The effective amount of the absorption enhancing system, component in the composition of this invention will 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 11 a.

o o 00 o oa a o o a a a* Go a 0.

a a a G a e o a a a p

CI

invention, it is preferred to employ from about 50 to about 1000 milligrams and more preferably from about 100 to about 500 mg of the absorption enhancing system, for each unit dose of the composition. These compositions will usually contain the antibacterial compound in amounts from about 10 to about 500 mg, and more usually fromi about 50 to about 250 mg, per unit dose.

Rectal dosage form compositions in accordance with this invention will usually contain from about 50 to about 1500 mg, more preferably from about 75 to about 600 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 to about 15 3000 mg, and more usually from about 100 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 25 stated amount of drug.

The described antibacterial compound and absorption enhancing system, components and respectively, can be incorporated into a 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 3iI, i rl i" i.

1i 12 of this invention are mixtures of m no- di- and acids, preferably vegetable fatty acids having an even number of, carbon atoms (C C C etc.).

12' 14' 16' 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.

acids, preferabyIf utilized, the vehicle will generally be present in t5 Ehose amounts which are conventional for pharmaceutical The preferred method of orally administering thein the art.

ente" carrier materials and which can be reasonably and safely administered.

filled into a hard- or soft-shell capsule or, if the makThe preferred method of orally administering the combination of antibacterial compound and absorption enhancing system in accordance with this invention is in the Sencapsulatedform of an enteric coated entity, and more specifically, an Usage of enteric coated solid dosage form. The formulation can berves filled into a hard- or soft-shell capsule or if therial 25 formulation is a liquid, absorbed onto a suitable carrier to ompound together with the absorptin enhancing system towhich may thereafter be tenapsulated in an enteric coatedn capsule.

Usage of enteric coating materials in this manner serves .to protect the antibacterial compound from the gastric fluid 0compound together with the absorption enhancing system to the intestine. The enteric coating material is, for the 's I V I l lll i, 13 most part, resistant to the gastric fluid and is unaffected 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 cellulose acetate trimellitate hydroxypropyl methylcellulose phthalate hydroxypropyl methylcellulose phthalate succinate 0 15 polyvinyl acetate phthalate S* methacrylic acid methacrylic acid esters 00 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 25 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, the total capsule or tablet weight. Examples of suitable Senteric coating formulations are given below.

ii I 1 1 1 1 P I mehcyi aci 1 5845/3 14 Enteric Coating Formulations ingredients

W/W

Preparation A: Hydroxypropyl methylcellulose phthalate (HPMCP) Triacetin Methylene chloride Denatured alcohol 47.25 47.25 04~0 4*A~ o 0Q 00 0 0~0 0 0 8 40 0 0 044 0 0 o oti 15 Preparation

B:

HPMCP

Titanium dioxide Dimethyl polysiloxane Acetone Denatured alcohol 10. 0 0.2 0.05 44.875 44.875 040 0 00 0 4004 Preparation C: Cellulose acetate phthalate (CAP) Diethyl phthalate Titanium dioxide Acetone Denatured alcohol 0.2 44 .9 44.9 Preparation D: Polyvinyl acetate phthalate Acetylated glycerides Methylene chloride Denatured alcohol 0.8 47. 1 47. 1 4 f i ii I 15 Preparation E: Methacrylic acid or methacrylic acid ester (Eudragit S or L, Rohm Pharma, GMBH, Wetterstadt, West Germany) Acetone Anhydrous alcohol Plasticizer 46.0 46.0 q.s.

00 0a *0 0 C*4* 0 OU4O 0* 0 4* 00*4k4

C

Oral dosage form compositions in accordance with this invention can also be formulated to additionally contain conventional additives or supplementary ingredients, in the usual amounts for such materials. By way of illustration, 15 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.

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 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 i!1 t j I:ii ri ii i i I i 1 1-' i i I -i i "~'Li*lj 16 conventional amounts.

In vivo tests were utilized to evaluate the enhanced mucosal tissue absorption of antibiotics administered in accordance with this invention.

IN VIVO (RATS) ENTERAL i 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 to expose the intestine. Administration of an antibiotic was carried out using a solution dosage form. The solutions o 15 were prepared by dissolving 5 mg of antibiotic in water with or without absorption enhancer and diluting to the desired Sconcentration.

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

25 Plasma Levels of Antibiotic in Rats

V

S' 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 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.

v I A 1 I 1 1 17 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 H 0. Any antibiotic not bound by plasma was diluted in H 0 and assayed against standards prepared 2 in H 0. 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 with a dilution factor of 1:12 and assaying against a standard curve diluted in H20. Antibiotic levels were assayed on o* nunc plates employing the appropriate agar seeded with 15 bacteria, as listed below.

e AA a 4 4

N'.

18 Assay organismT Range o' Standard Curves (incg/ml) Bioassay Media Vo I ne

(MCI)

Antibiotic Carumonam Ampicillin Cefamandol Cefotaxime CefoxitinI Ceftriaxon Cefazol in 1 15 Moxalactam Penicillin Meziocilli Gentamnicin Vanccmyci n

E.

M.

e M.

E.

S.

ie E.

S.

B.

aE.

G n M.

K.

B.

coli1. 1346 lutea ATCC 9341 lutea ATCC 9341 coli. 1346 aureus MB2 786 coli. 1346 aureus ATCC 25923 subtilis spores coli. 1346 lutea ATCC 9341 lutea ATCC 9341 pnellmuniae A cereus ATCC 11778 32-1 8-0.25 32-i 8-0.25 or 16-0.5 64-4 4-0. 125 32-1 32-2 50-1.56 8-0.5 16-1 80-2.5 64-2 AA# I AAP1 3

BHI

MNA 1 AA# l 4

MH

SA8 itt' 4 4, ~4 C 4 0 L~ U, 4, 4 J I 4*4 Ga C Gal 4 a 444 4 044.06 0.

*4L C c t 1 Antibiotics protein bound in rat plasma.

2 MAi antibiotic agar 11 (Difco).

3 HI =Brain Heart Infusion Media (Difco).

4* MH Mueller Hinton Agar (Difco).

25 5 AA8 =antibiotic agar #8 (Difco).

mcg/ml =micrograms per milliliter mcl microliters The plates were incubated overnight at 370 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 were as follows: LUL.LUUe U:L.LLL1A&I.1=, a UCVYLLdLUbULL&A UCDULLLPU LLL U.D.

~%gCgy~Ew~Uuu~~~ 19- TABLE 1 ENTERAL ABSORPTION IN RATS With and Without Absorption Enhancers Dose 5 mg/0.5 ml Onax (micrograms per milliliter) (Control) Acconon Con Labrasol Sodiuin Caprylate Antibiotic Water Laureth-12* Laureth-12* Laureth-12* 15 Carumonam 0.0 0.0 1.2 1.4 11.7 3.8 6.3 2.4 Cefamandole 1.3 2.5 6.4 0.6 8.4 2.6 18.1 3.7 Cefazolin 0.0 0.0 42.9 3.0 62.2 25.2 40.7 i 7.2 Cefoxitin 0.0 0.0 7.7 2.8 9.1 3.4 16.2 4.6 **Cefotetan 0.0 0.0 9.5 2.8 21.2 5.8 26.1 11.4 20 Gentamicin 3.9 15.4 2.3 9.6 1.9 14.1 6.9 Mezlocillin 0.0 0.0 0.6 t 1.0 1.4 1.4 6.7 1.7 Moxalactam 0.0 0.0 9.6 2.2 16.2 1.8 19.9 Penicillin G 0.5 0.1 3.5 1.0 5.2 1.6 7.4 2.4 9O 9 Vancomycin 2.9 0.6 0.0 0.0 6.9 1.0 9.8 Ceftriaxone 2.4 1.9 38.8 22.6 10S.5 23.0 53.7 13.3 099999 0 9 *Weight Ratio of Other Absorption Enhancer Component to Laureth-12 was 8:1 20 IN VIVO (DOGS) ENTERAL Six male beagle dogs, weighing about 10 to 16 kilograms each, were chronically fitted with a modified Thomas cannula implanted in the distal duodenum. Each dog received 2 hard shell gelatin capsules containing 210 mg of ceftriaxone sodium salt in 280 mg of a base (WITEPSOL H15), with absorption enhancer (157.5 mg of Labrasol and 52.5 mg of Laureth-12). Administration of the capsules in each instance was enteral through the modified Thomas cannula into the proximal jejunum. Drug dosage was 20 to 50 mg of ceftriaxone per kilogram of dog body weight.

Blood plasma concentrations of ceftriaxone were .o0 15 determined prior to administration and at 10, 20, 40, a* 120, 180 and 240 minutes after administration. Measurements were made by withdrawing blood at these time intervals, centrifuging, separating the plasma and assaying by High Performance Liquid Chromatography (HPLC), reverse phase method, or by bioassay (the same procedure as previously described for the Bioassay of Plasma Samples).

o To establish a standard curve, ceftriaxone was diluted with normal dog plasma, then deproteinized in the same 25 manner as described previously. Calculations were conducted using a Waters 840 Computer System. Through the use of an Sappropriate computer program, the area under the curve (AUC) was determined for each route of administration. From these S: determinations, the bioavailability was computed using the C t( following equation: rAUC Enterall Bioavailability [A x 100 [AUC I.V.] Whenever intravenous data were not available for the same dose level used enterally, the following equation was employed: 21 B [AUC Enteral] I Dose] SBioavailability [AUC x [Enteral Dose] x 100 The results were 45.4 18.2% Bioavailability and 19.5 6.5 mcg/ml Cmax for the absorption enhanced formulation, compared to 0% Bioavailability and 0.5 mcg/ml J Cmax for the control (a solution of ceftriaxone in water equivalent to 25 mg/kg, no absorption enhancers).

IN VIVO (BABOONS) ORAL Adult baboons (Papio anubis and Papio hamadryas), ranging in weight from 12 to 30 kilograms, were used in this study. The baboons were fasted overnight, then sedated with ketamine hydrochloride by intramuscular injection prior to 15 administration of the antibiotic. Each baboon received four hard shell gelatin capsules through a gastric tube. Each capsule contained the following: 0*9 o Ceftriaxone sodium salt 300 mg Labrasol 225 mg Laureth-12 75 mg Witepsol H15 380 mg .o 980 mg 25 Enteric coating: polyvinyl acetate phthalate Sapproximately 8% of total capsule weight) t One-milliliter blood samples were taken from the femoral Sregion of each baboon using a heparinized 3-ml syringe.

Samples were taken prior to ceftriaxone administration and at 15, 30, 60, 120, 240, 360, 480, 600 and 720 minutes following ceftriaxone administration. The samples were centrifuged at 12,000 rpm for one minute and the plasma was separated and bioassayed for antibiotic content after deproteinization with acetonitrile, using the same procedure described previously for the Bioassay of Plasma Samples.

i1 i, ri I'Th~f 22 The results were 10.0 6.5% Bioavailability and 5.5-59.8 mcg/ml Cmax range, compared to 0% Bioavailability and 0 mcg/ml Cmax for the control (ceftriaxone sodium salt, 300 mg, in the same enteric coated capsule, no absorption enhancers).

Absorption was also evaluated using a formulation composed of 300 mg of ceftriaxone sodium salt, 200 mg of sodium caprylate, 75 mg of Laureth-12 and 415 mg of Witepsol H15. The Bioavailability of this formulation was 15.7 9.9% and 15.0-66.3 mcg/ml Cmax range, compared to 0% Bioavailability and 0 mcg/ml Cmax for the control (same as above).

oo 0s o o0 0 000 0 0000, 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 capsules through a gastric tube. Each capsule contained the following: 0004 o 00r e 00 o o,

C

10 C I* 0 0' Ceftriaxone sodium salt Labrasol Laureth-12 Witepsol H15 300 mg 225 mg 75 mg 380 mg 980 mg Enteric coating: polyvinyl acetate phthalate (approximately 8% of total capsule weight) Blood plasma concentrations of ceftriaxone were determined prior to administration and at 10, 20, 40, 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 ij 23- Samples method.

The results were 34.2 14.0% Bioavailability and 21.6 7.6 mcg/ml Cmax for the above formulation, 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).

Absorption was also evaluated using a formulation composed of 300 mg of ceftriaxone sodium salt, 200 mg of sodium caprylate, 75 mg of Laureth-12 and 415 mg of Witepsol Bioavailability was 22.4 13.5% and Cmax was 14.4 8.4 mcg/ml, compared to 0% and 0 mcg/ml, respectively, for the control (same as above).

o 0 4 IN VIVO (BABOONS) RECTAL 0 Male and female adult baboons (Papio anubis and Papio hamadryas), ranging in weight from 12 to 27 kilograms, were used in this study. The baboons were fasted for 24 hours prior to administration of antibiotic, then sedated with ketamine hydrochloride by intramu3cular injection prior to administration of the antibiotic. Suppositories made up of a the formulations shown below were administered to the t 25 baboons and the rectal openings were then taped closed to prevent expulsion and leakage of the suppository mass.

Antibiotic 500 mg SLaureth-12 125 mg Labrasol 250 mg Witepsol H15 1125 mg Total: 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 L A ILL YUiLLLCaOLP, LJUL UJLCA. y

A

,1 24 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 were as follows: TABLE 2 Antibiotic Bioavailability and Cmax Range in Baboons After Rectal Administration

CR,.

C CR CO C C OR CC Ca C C C C C C 40 CO C CCQ 0 CR44 With Absorption Enhancer System Antibiotic Ceftriaxone Cefamandole Cefoxitin Penicillin G Bioavailability 31.5 13.1 46.5 16.6 77.0 22.5 38.2 26.1 Cmax Range mcq/ml 18.2-49.6 5.9-16.4 4.7-10.8 2.0-11.1 Control-No Absorption Enhancer System Bioavail- Cmax Range ability mcg/ml 4.3 2.8 0.3-9.0 6.0 2.3 2.3-4.6 0 0 17.4 8.0 1.2-2.4 0044 0 C *4 C o C O CO .440.4 OCOCit Sf11 I' ft I I I I Ii Absorption was also evaluated using a formulation composed of 600 mg of ceftriaxone sodium salt, 200 mg of sodium caprylate, 125 mg of Laureth-12 and 1075 mg of 25 Witepsol H15 (total: 2000 mg). The Bioavailability was 49.3 13.7% and the Cmax range was 68.1-102.8 mcg/ml, compared to 4.3% Bioavailability and 0.3-9.0 mcg/ml Cmax range for the control (600 mg of ceftriaxone sodium salt in suppository vehicle with no absorption enhancers).

By way of illustration, some suitable formulations for various dosage forms in accordance with this invention are set forth below. While ceftriaxone, the preferred antibiotic for this invention, is used to illustrate these formulations, it should be understood that other antibiotics may be substituted in appropriate amounts.

i *1

I!

I 7> 25 ORAL DOSAGE FORMS ercapsu'le A) Ceftriaxofle (sodium) 60 Labrasol 225 Laureth~-12 75 Witepsol H15 340 B) Ceftriaxone (sodium) 60 Sodium cap' ±Late 200 Laureth-12 75 Witepsol H15 365 C) Ceftriaxone (sidium) 60 Acconon Con 225 Laureth-12 75 Witepsol H15 340 D) Ceftriaxofle (sodium) 60 Softigeri 767 225 Laureth-12 75 Witepsol H15 340 120 225 75 340 120 200 75 365 120 225 75 340 120 225 75 340 210 Mg 300 Mg 225 75 340 210 200 75 365 210 225 75 340 210 225 75 340 225 340 300 200 365 300 225 340 300 225 340 .9.9% 9.

.9.9% 9 9.

4 9.9 *9 99 44 9

I

99.

4 9 9 499% *99% .49% 9 4~ .4 9 94 9 9 9 9% o 9.

94 9. 9.

9 9.

99. 9.

99 I (9 RECTAL DOSAGE FORMS per suppository A) Ceftriaxofle (sodium)180 mg 300 mg 600 mg 1200 mg Labrasol 250 mg 250 mg 250 mg 500 mg Laureth-12 125 Mg 125 Mg 125 mg 250 Mg Witepsol H15 1445 Mg 1325 Mg 1025 Mg 2050 Mg B) Ceftriaxofle (sodium)180 Sodium caprylate 200 Laureth-12 125 Witepsol H15 1495 300 200 125 1375 600 200 125 1075 1200 400 250 2150 the intestine. ne enLuerL oL.U i~~ 26 C) Ceftriaxone (sodium)180 Acconon Con 250 Laureth-12 125 Witepsol H15 1445 D) Ceftriaxone (sodium)180 Softigen 767 250 Laureth-12 125 Witepsol H15 1445 300 mg 250 mg 125 mg 1325 mg 300 mg 250 mg 125 mg 1325 mg 600 mg 250 mg 125 mg 1025 mg 600 mg 250 mg 125 mg 1025 mg 1200 mg 500 mg 250 mg 2050 mg 1200 mg 500 mg 250 mg 2050 mg The above dosage forms can be prepared as follows:

PROCEDURES

a I a a a 0 04 0 44 a Oral I J The base (Witepsol H15) is warmed to 55 0 C and the absorption enhancer system components are added to the melt with mixing. The melt is then cooled to 45 0 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 filled into gelatin capsules, sealed if necessary, and the capsules are enteric coated.

0 0 4 i t 4 4 t t r C Rectal 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 0 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.

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Claims (5)

1. A pharmaceutical composition comprising and antibacterial compound and an absorption enhancing amount of a two-component absorption enhancing system made up of a first component which is an ether of an acyclic C 6 to C18-alcohol and a polyoxyethylene glycol (PEG) having an average molecular weight from 400 to 600 and a second component selected from among a polyoxyethylene glycol (PEG)- caprylate/caprate glyceride ester, (ii) caprylic or capric acid or pharmaceutically acceptable salt thereof, and (iii) a polyoxyethylene glycol-glycerol cocoate; with or without a pharmaceutically inert carrier.

2. A composition according to Claim 1, in which the absorption enhancing system is made up from an ether of lauryl alcohol and PEG 12 and a PEG-8 .15 caprylate/caprate glyceride ester.

3. A composition according to Claim 1 in which the absorption enhancing 0 system is made up from an ether of lauryl alcohol and PEG12 and sodium o. caprylate.

4. A composition according to Claim 1, in which the absorption enhancing system is made up from an ether of lauryl alcohol and PEG 12 and a PEG glycerol cocoate. A composition according to any one of claims 1 to 4, 25 in which the antibacterial compound is a beta-lactam. S6. A composition according to claim 5 in which the beta-lactam is of the formula R RI 0 R2 Cc- f o 2 0> Ff\'/ 28 in Which R I is hydrogen or optionally substituted alkyl, 'R is so 3-M+i where M+ is a proton or cation, R 3is an acylamino group or hydroxyalkyl, or R and R 2tgte with the beta-lactam (azetidinone) ring to which they are bonded represent in which X is -SO, -SO 2 -CH 2 or -CH(CH3 and Y is group 0 0 9 *oo0 COCE COOE 00 0 49 4 44 0044 9 40 44 0 0444 COCE in which R is a substituted thio group selected from 4 among ethylthio, -SCH 2CHR NH 2 NH 0 CR NHCH, SCH CH2 2'N -L OONMe 2 2 22

29- or an optionally substituted lower alkyl group selected from among aminomethyl, acylaminomethyl, or a substituted oxy group consisting of carbamoyloxy 0 (-OCNH2), and the carbon atom which carries the ,CCOOE group is bonded to the nitrogen atom of the beta-lactam ring, Z is hydrogen, halogen, alkoxy or CH2T, with T denoting hydrogen, alkyl 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, o 0, and E is hydrogen, a pharmaceutically acceptable ester group 9 09 o or a salt-forming cation. oo 0 04 6 o 7. A composition according to claim 6 in which the antibacterial compound is (E)-2-(Isobutoxy carbonyl) -2-pentenyl(6R,7R)-7-[(Z)-2-(2-amino-4-thiazolyl) -2-(methoxyimino)acetamido]-3-(azidomethyl)-8-oxo-5-thia -l-azabicyclo[4.2.0]oct-2-ene-2-carboxylate. 8.A composition according to claim 7 in which the antibacterial compound is ceftriaxone or a pharmaceutically S< acceptable salt, ester or hydrate thereof. 9. A composition according to any one of claims which is in an enteric coated oral dosage form. A composition according to any one of claims 1-8 which is in a rectal dosage form. Cc A) U- 1 J.1~' 30 11. The novel pharmaceutical compositions substantially as hereinbefore described. DATED this THIRTY-FIRST day of MARCH 1992 F.Hoffmann-La Roche AG Patent Attorneys for the Applicant SPRUSON FERGUSON 0900 0999 o o~o @0 0 o o'. 00 00 00 0 0 0 0 b@ 00 000 0 9004 99 0 a 00 a 00 0000 0 00 00 9 4-9. 0 Ce.. 4~ 4 O t T4' 0 TMS/1496u