CA2003340A1 - Pharmaceutical compositions - Google Patents

Abstract

ABSTRACT

The absorption of antibiotics given through oral and rectal routes of administration is significantly enhanced by use of the antibiotic in conjunction with a two-component absorption enhancing system made up of an ether of a C6 to C18 alcohol and a polyoxyethylene glycol together with a second component selected from among polyoxyethylene glycol-C6 to C18 glyceride esters, C6 to C18 carboxylic acids or salts thereof, and esters of two or more C6 to C18 carboxylic acids, glycerol and a polyoxyethylene glycol. A
carrier and adjuvants are usually included. These compositions can be administered in any convenient oral or rectal dosage form, including tablets, capsules, beadlets and suppositories.

Description

~0~334'~

The present invention relate6 to phaLmaceutical compo6ition6 compri~ing (a) an antibacterial compound and (b) an ab60rption enhancing amount of a two-component ab60rption enhancing 6ystem made up of a fir6t component which i6 (1) an ether of a C6 to Cl~ alcohol and a polyoxyethylene glycol (PEG) and a 6econd component 6elected from among (2)(i) a polyoxyethylene glycol - C6 to C18 carboxylic acid glyceride e~ter, (2)(ii) a C6 to C18 carboxylic acid or pharmaceutically acceptable 6alt thereof, and (2)(iii) an e6ter of two or more C6 to C18 carboxylic acid6, glycerol and a polyoxyethylene glycol.
Optionally, a pharmaceutically inert carrier can al60 be included.

The term ~polyoxyethylene glycol-C6 to C18 carboxylic acid glyceride e6ter" a6 u~ed in connection with thi6 invention refer6 to tho6e reaction product6 derived from the co-reaction of polyoxyethylene glycol (or polymerizable precur60r thereof, 6uch a6 ethylene oxide) with a C6-C18 carboxylic acid and glycerol or with a C6-C18 carboxylic acid glyceride or glyceride6.
Re6ulting from 6uch reactions are, typically, mixture6 of a polyoxyethylene glycol-C6 to Cl~ carboxylic acid glyceride ester (e.g., PEG-glycerol-caprate, PEG-glycerol-caprylate or PEG-glycerol-caprylate/ca~rate), a polyoxyethylene glycol-C6 to C18 carboxylic acid e6~er (e.g., PEG-caprate, PEG-caprylate or PE~-caprylatetcapcate), and a glyceryl-C6 to C18 carboxylic acid ester (e.g., glyceryl mono-, di- or tricaprylate, glyceryl mono-, di- or tricaprate or glyceryl mono-, di- or tricaprylate/ caprate), Grn/13.9.89 200:~340 as the principal components.

It has been found that the above--identified ab60rption enhancing sy~tem functions to increase the extent of absorption of antibacterial compound6 through muco~al tissue and into the blood6tream. This invention thus promote~ the ab~orption and, concomitantly, the bioavailability of - antibacterial compounds which, when administered without the absorption enhancer by means other than parenteral, are only poorly ab~orbed or not ab60rbed to any appreciable degree.
The preparation and uBe of a greater variety of dosage forms for such compounds are thu~ enabled. The pharmaceutical compoBitionB of the present invention also promote the greater absorption and bioavailability of antibacterial compounds which are otherwise only moderately absorbed through mucosal tissue, thus enhancing the effectivene6s of such therapeutic compounds also.

This invention encompasses the aforementioned pharmaceutical composition for administration in virtually any do~age form suitable for oral or rectal administration.
Embraced within its scope are oral and rectal types of pharmaceutical preparations containing effective amounts of an antibacterial compound and an absorption enhancing system in accordance with the pre6ent description, with or without an inert carrier and pharmaceutically acceptable adjuvant~.

The terms "antibacterial" and "antibiotic" are used interchangeably throughout this disclosure to refer to bactericidal or bacterioBtatic compounds which have been metabolically derived from a microorganism, 6ynthetical1y prepared by chemical means, or prepared by a combination of microbial and chemical procedures (~emi-synthetic).

Contemplated for utilization in the practice of thi6 invention i~ virtually any antibiotic sub6tance which i6 useful for combatting a bacterial infection in a ho6t, ~)0~ e .

including tho6e antibiotic6 which are only moderately ab60rbed 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 infu6ion due to non- or poor absorbability via other routes of administration.

Among the most preferred antibacterial compounds 6uitable for use a6 the therapeutic 6ub6tance in the practice of this invention are beta-lactam antibiotic6, particularly compound6 having a beta-lactam ring a6 the central structure, that is, the structure 1~ n ~N
o which can be substituted at variou6 positions on the ring and/or fused with other ring system6 which them6elve6 can be 6ubstituted or unsub6tituted. Exemplary of 6uch beta-lactam antibiotic6 are penicillin6, cephalo6porins, penems, 2~ carbapenems and monocyclic beta-lactams.

E6pecially preferred beta-lactam antibiotic~ for use in thi6 invention are compounds of the formula Rl R

~ R

i~C!O~

in which Rl iB hydrogen oc optionally substitutes alkyl, R2 is SO3-M+ where M+ is a proton or cation, R3 i6 an acylamino group oc hydroxyalkyl, or Rl and Rz together with the beta-lactam (azetidinone) ring to which they are bonded cepresent R3~T_I

N Y

in which X is -S-, -O, -SO-, -SO2, -CH2 oc -CH(CH3) and Y i8 group \ / or ~ or / CH
20 \ COOE
Cl I
COOE

. COOE

in which R4 is a sub6tituted thio group such as ethylthio, -SCH2CH2NH2, NH O .
-SCH2CH2NHCH, -SCH2CH20CNH2, -S ~ CONMe2 NH

i~O3~40 or an optionally 6ubstituted lower alkyl group 6uch a6 aminomethyl, acylaminomethyl, O
or a 6ubstituted oxy group such a6 carbamoyloxy (-OCNHz), the carbon atom which carries the -COOE group i6 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 sub~tituted or the group -S-het wherein "het"
i6 an optionally substituted 5- or 6-membered heterocyclic ring, and E is hydrogen, a pharmaceutically acceptable e6ter group or a salt-forming cation.

Example6 of the 5- or 6-membered heterocyclic rings encompa66ed within "het" above are the following:

~\CH3~N~ ~ I ~\\N

CH3 CH2-CH2-N(CH3)2 2~

7 N ~ IN~\\N CH3~ ~N~o Especially preferred beta-lactam antibiotics and their pharmaceutically acceptable salt6, esters and hydrate6 include ceftriaxone, a cephalosporin de6cribed in U.S.

~003;~40 Patent No. 4,327,210 (Montavon et al.): carumonam, a monocyclic beta-lactam de6ceibed in European Patent No. EP
73061: piperacillin, a penicillin de6cribed in U.S. Patent No. 4,112,090: cefamandole, a cephalosporin de6cribed in U.S. Patent No. 3,641,021; mezlocillin, a penicillin de6cribed in U.S. Patent No. 3,974,142 and cefazolin, a cephalo6porin de6cribed in U.S. Patent No. 3,516,99~, the di6clo6ures of all of which are incorporated herein by reference. Further included are cefoxitin, cefmetazole, cefotetan, moxalactam, cefuroxime, ceforamide, cefoperazone, ceftizoxime, cefotaxime, cefmenoxime, ceftazidime, cef6ulodin, cefazolin, cephalexin, azlocillin, penicillin G, temocillin, sulbenicillin, ticarcillin, mecillinam, amoxicillin, methicillin, carbenicillin, thienamycin, N-formimidoylthienomycin, 6ulbactam and azthreonam.

Another preferred beta-lactam antibiotic for u6e in thi6 invention i6 the compound, (E)-2-(I60butoxy carbonyl) -2-pentenyl(5R,7R)-7-[(Z)-2-(2-amino-4-thiazolyl) -2-(methoxyimino)acetamido]-3-(azidomethyl)-8-oxo-5-thia -l-azabicyclot4.2.0]oct-Z-ene-2-carboxylate which i6 described in European Patent Publication A2-0318767.

Al60 included within the scope of thi6 invention are antibiotic6 other than the beta-lactam6, for example, vancomycin and gentamicin, the absorption and bioavailability of which are improved by u6e with the de6cribed absorption enhancing sy6tem6.

Ab60rption enhancing 6y6tem component (b)(l) i6 the product of an etherification reaction between an alcohol, specifically, an acyclic C6 to C18 6traight or branched chain alkanol and a polyoxyethylene glycol (PEG). Example6 of alcohol6 suitable for the preparation of component (b)(l) include n-hexyl, n-heptyl, n-octyl, n-decyl, n-dodecyl (lauryl), n-tetradecyl (myristyl), n-hexadecyl (cetyl), ;~00334~

n-octadecyl, and 80 forth. Lauryl alcohol i6 preferred.

The polyoxyethylene glycol iB, typically, a medium to high molecular weight material which preferably ha6 a number aveLage molecular weight in the range from about 200 to about 1500, and more usually from about 400 to about 600.

Component (b)(l) can be prepared by known procedure6.

Especially favored for use as component (b)(l) iB the material known a6 Lauceth-12 (CTFA de6ignation). A suitable commercially available material i6 MACOL LA-12, manufactured by Mazer Chemical6 Company, Gurnee, Illinoi6.

Ab60rption enhancing ~ystem component (b)(2)(i), may be the product of an esterification reaction between a eolyoxyethylene glycol, glycerol and one or more straight or branched chain C6 to C18 carboxylic acid6, preferably a monofunctional acid or acid6. Alternatively, component (b)(2)(i) may be prepared by oligomerizing or polymerizing ethylene oxide in the pre6ence of an ester of glycerol and one or more of such C6 to C18 carboxylic acid6 (glyceride ester6). Still another route, and the preferred one, iB by co-reacting the glyceride ester or e6ter6 with a fully pre-formed polyoxyethylene glycol under condition~
~ufficient to achieve alcoholysi6.

According to a particular preferred procedure, involving alcoholy6is, a reaction veBBel iB charged with stoichiometric quantitie6 of a glyceryl-fatty acid ester or esters and a polyethylene glycol. The veBBel iB closed and heated at atmospheric pre66ure to Zoooc~ with continuou6 stirring commenced at 70C, for a period of 12 to 24 hourfi or until the reaction i6 completed. The ve6Bel iB allowed to cool and the reaction product iB then 6eparated from the reaction mixture by filtration.

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Examples of C6 to C18 carboxylic acid6, saturated or unsaturated, which are useful for the preparation of absorption enhancing system component (b)(2)(i) 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 sy~tem component (b)(2)(i) iB, 10 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 ~uitable for use as absorption enhancing system component (b)(2)(i) will most preferably have the following characteristics:

Organoleptic Properties:

Appearance: clear oily liquid Odor: faint Color: pale yellow to yellow Physical and Chemical Properties:

Acid Value: 0.2 - 0.6 Sulfated ash: le~ than 0.05%
Saponificatior. index: 85 - 105 Iodine index: les6 than 2 Moi6ture content: les6 than 0.05%
Free glycerin content: approx. 2%
Monoglyceride content: approx. 6 to 8%
Den~itY (d4 ): 1.062 - 1.068 g/cc Refractive index (nD ): 1.458 - 1.462 ~oo~.~an Suitable absoeption enhancing sy~tem components for use in this invention which are commercially available are LABRASOL, produced by Gattefos6e Corporation, Paris, France (PEG-8 caprylate/caprate glyceride e6ters), and SOFTIGEN
767, produced by Dynamit Nobel, West Germany (PEG-6 caprylate/caprate glyceride esters).

The C6 to Cl8 carboxylic acid or it6 salt which con6titutes absorption enhancing system component (b)(2)(ii) 0 i5 derived fcom 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 purpo~e6 of thi~ invention are caprylic and capric acids.

The6e 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 pharmaceuticaliy acceptable cation. In general, any ba6e which will form a 6alt with a carboxylic acid and the eharmacological propertie6 of which will not cau6e an adver~e physiological effect when inge6ted by or otherwise administered to a warm-blooded animal is suitable. Such base6 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.

~bsorption enhancing system component (b)(2)(iii) iB
derived from a mixture of two or more carboxylic acids of 6 to 18 carbon atoms, glycerol and a polyoxyethylene glycol.
The acid6 may be straight or branched chain, and saturated or unsaturated.

Suitable acids include zaturated carboxylic acids such as n-hexyl, n-heptyl, n-octyl, n-decyl, lauryl, myristyl, ~0~ 34~

cetyl and n-oc~adecyl, and un6aturated enoic (e.g., oleic) and dienoic (e.g., linoleic) acids.

Preferred are mixture6 compri6ed of ~everal C6 to C18 fatty acids, 6uch as found in vegetable oil6 and fats, and most preferably coconut oil, which is composed of major amount~ of 6aturated and minor amounts of un6atucated fatty acids of up to 18 carbon atom6.

Preferably, the polyoxyethylene glycol employed for absorption enhancing 6ystem component (b)(2)(iii) is chaLactecized by a number average molecular weight in the range from about 200 to about 1500, and more usually from about 300 to about 600.

~ b60cption enhancing agents u6eful as absorption enhancing 6y6tem component (b)(2)(iii) can be prepared by tho6e skilled in the act u6ing conventional e6terification procedure6. ~ 6uitable material i6 available commercially from Capital City Products, Janesville, Wiscon6in under the trade de6ignation ~CCONON CON (a PEG glycerol cocoate).

The relative proportion6 of the two component6 which comprise the absorption enhancing system can be vacied to achieve optimum results for a paLticular embodiment of the invention. Preferably, the weight ratio of (b)(l) to (b)(Z)(i), (b)(Z)(ii) or (b)(2)(iii) is in the range from about 1:50 to about 50:1, more preferably from about 1:10 to about 10:1, and mo6t preferably from about 1:4 to about 4:1.

The effective amount of the ab60rption enhancing system, component (b), in the composition of this invention will vary depending on 6uch factor6 a6 the particular antibacterial compound being employed and it6 amount, a~
well a6 the age of the 6ubject being treated.

In general, for oral do6age form compo6itions of this invention, it i6 prefe~red to employ from about 50 to about 1000 milligram6 (mg), and more preferably from about 100 to about 500 mg of the ab60rption enhancing 6y6tem, for each unit do6e of the compo6ition. The6e compo6itions will u6ually contain the antibacterial compound in amount6 from about 10 to about 500 mg, and more u6ually from about 50 to about 250 mg, per unit do6e.

Rectal dosage form composition6 in accordance with this 10 invention will usually contain from about 50 to about 1500 mg, more preferably from about 75 to about 600 mg of the absorption enhancing 6y6tem, for each unit do6e of the composition. Such compo6ition6 will usually contain the antibacterial compound in amounts from about 10 to about 3000 mg, and more u6ually from about 100 to about 1500 mg, per unit dose.

The term "unit do6e~ i6 u6ed here in the conventional sense to mean a single application or administration of the drug to the 6ubject being treated in an amount a6 6tated above, but it 6hould be understood that the amount can be given in the form of a single pill, tablet, cap6ule, suppository, etc., or alternatively, in multiples of two or more of such do6age units with the total adding up to the 6tated amount of drug.

The described antibacterial compound and ab60lption enhancing system, components (a) and (b), re6pectively, can be incorporated into a vehicle, if de6ired. ~ the vehicle, there can be u6ed any pharmaceutically acceptable 601id, semi-solid or liquid carrier in which the6e components are 601uble or readily di6per6ible. Some examples include but are no~ limited to cocoa butter, polyethylene glycol6, polypropylene glycol6, methylcellulo6e, carboxymethyl-cellulo6e and Suppocire~ semi-6ynthetic base6 (Gattefos6e Corp., Pari6, France). PLeferably, the vehicle i6 a 601id. Favored as a solid vehicle for the compo6ition6 ~U U~ ~4 ~

of thi6 invention are mixture6 of mono-, di- and triglyceride6 of Cl2 to Cl8 natural saturated fatty acid6, preferably vegetable fatty acids having an even number of carbon atom6 (Cl2, Cl4, Cl6, etc.).
Especially suitable and preferred are the pharmaceutical ba6es of Dynamit Nobel having the trade de6ignation "WITEPSOL".

Still other phaemaceutically compatible carrier 10 material6 may be employed as de6ired and depending upon particular requirement6, the selection of which i6 within the knowledge of tho6e 6killed in the art.

If utilized, the vehicle will generally be pre6ent in tho6e amount6 which are conventional for pharmaceutical caerier materials and which can be reasonably and ~afely admini6tered.

The preferred method of orally administering the combination of antibacterial compound and ab60rption enhancing 6y6tem in accordance with thi6 invention i6 in the form of an enteric coated entity, and more specifically, an enteric coated solid do6age form. The formulation can be filled into a hard- or 60ft-shell cap6ule or, if the formulation i5 a liquid, ab60rbed onto a 6uitable carrier ~o make a free flowing powder and then filled into the capsule or, alternatively, compre66ed into a pill or tablet. Still other po66ible do6age forms include microcap6ule or beadlet form6 of the antibacterial compound mixed with the ab60rption enhancing 6y6tem which may thereafter be encap6ulated in an enteric coated capsule.

Usage of enteric coating material6 in thi6 manner 6erves to protect the antibacterial compound from the ga6tric fluid and to achieve optimum delivery of the antibacterial compound together with the absorption enhancing 6y6tem to the inte6tine. The enteric coating material i6, for the ~003340 most part, re6i6tant to the gastric fluid and iB unaffected by it but di6601ve6 in the intestinal fluid to cau6e release of the drug.

The effectivene66 of particular enteric coating material6 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 methylcellulo~e phthalate hydroxypropyl methylcellulose phthalate succinate eolyvinyl acetate phthalate methacrylic acid methacrylic acid ester~

The6e enteric coating material6 may be applied with or without plasticizers, such as acetylated glyceride6 or diethylphthalate, u6ing method6 known to those skilled in the art.

The percentage of enteric coating applied i6 u6ually between about 1 and about lo eercent by weight, or more, and mo6t desirably from about 2 to about 8 percent by weight, ba6ed on the total weight of the unit do6age form, i.e., the total capsule or tablet weight. Examples of suitable enteric coating formulation6 are given below.

~()033~0 _ 14 -Enteric Coatinq Formulations 5 Ingredient6 % w/w Preparation A:

Hydroxypropyl methylcellulose phthalate (HPMCP) 5.0 Triacetin O.S
Methylene chloride 47.25 Denatured alcohol 47.25 Preparation B
HPMCP 10.0 Titanium dioxide 0.2 Dimethyl polysiloxane 0.05 20 Acetone Denatured alcohol 44.875 Preparation C:

25 Cellulose acetate phthalate (CAP) 8.5 Diethyl phthalate 1.5 Titanium dioxide 0.2 Acetone 44.9 Denatured alcohol 44.9 Preparation D:

Polyvinyl acetate phthalate 5.0 Acetylated glycerides 0.8 35 Methylene chloride 47.1 Denatured alcohol 47.1 Z00~340 Pre~aration E:

Methacrylic acid or methacrylic acid ester (Eudragit S or L, 8.0 5 Rohm Pharma, GMBH, Wetterstadt, West Germany) Acetone 46.0 Anhydrou6 alcohol 46.0 Plasticizer q.B.

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 6uch materials. By way of illustration.
such additives or supplements include thickening agents, 6uch as silicic acid (for instance, the trade designated "Aerosil" products) bentonite6 colloidal clay carboxymethyl celluloses modified montmorillonites, such as alkyl ammonium salts of montmorillonites (for instance, the commercial products known as "Bentone"3 organic thickening and structure-forming agent~, such as saturated higher fatty acids and alcohols containing from lZ to 20 carbon atoms (for in6tance, stearic or palmitic acids, or stearic or cetyl alcohols): waxes: monoglycerides of ~aturated or unsaturated high fatty acids such as ~teacic acid, palmitic acid or oleic acid gelling agents, such as aluminum stearate: dispersing agents, such as ionic, non-ionic or cationic surfactants: emul6ifying 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 u~ed in 200~3A0 - ~6 -conventional amount6.

In vivo te6t6 were utilized to evaluate the enhanced mucosal ti6sue ab60rption of antibiotic6 admini~tered in accordance with thi6 invention.

IN VIVo (RATS) - ENTERAL

~dult Sprague-Dawley female rat6 (Charles River Breeding 10 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 inte6tine. ~dministration of an antibiotic wa6 carried out using a 601ution dosage form. The solutions were prepared by dissolving 5 mg of antibiotic in water with or without absorption enhancer and diluting to the de6ired concentration.

Each solution of antibiotic in water was administered enterally by injecting with a syringe into the duodenum below the pyloric valve. For purpo6es of compari60n, the 601ution was alternatively administered intravenously by injecting with a syringe into a tail vein.

Plasma Levels of Antibiotic in Rat~

~ he concentration of antibiotic in rat plasma was determined at various time intervals after intravenous or enteral administration. Blood ~ample6 were collected from the tail of each te6t animal prior to administration of the antibiotic and at 5, lo, 20, 40, 60, lZ0, 240 and 360 minutes after administration, then centrifuged at 3200 rpm for 5 to 10 minutes, after which the pla~ma was withdrawn and frozen until a66ayed.

~003340 Bioassav of Pla6ma Samples Mo6t 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 H2O and a6sayed against 6tandard6 prepared in H2O. For bound antibiotic6, ~he influence of protein binding wa6 negated by diluting all standard6 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 l:12 and a~6aying against a 6tandard curve diluted in H2O. Antibiotic level6 were as6ayed on nunc plate6 employing the appropriate agar seeded with bacteria, as li6~ed below.

2003~4U

Assay Range o' Standard aioassay Volume Antibiotic Organism Curves (mcq/ml) edia (mcl) Carumonam E. coli. 1346 32-1 AA~l 20 Ampicillin M. lutea ATCC 9341 8-O.Z5 AA~l 20 Cefamandole H. lutea ATCC 9341 32-1 AA#l 20 Cefotaxime E. coli. 1346 8-0.25 or 16-0.5 A M 1 20 Cefoxitinl S. aureus MB2786 64-4 BHI3 20 Ceftriaxone E. coli. 1346 4-0.125 AA~l 20 Cefazolin S. aureus ATCC 25923 32-1 AA#l S0 B. subtilis spores 32-2 AAPl 50 Moxalactam E. coli. 1346 50-1.56 AA#l S0 Penicillin G M. lutea ATCC 9341 8-O.S AA~l 20 Mezlocillin M. lutea ATCC 9341 16-1 AA~l S0 Gentamicin K. pneumDniae A 80-2.5 MH4 S0 Vancomycin B. cereus ATCC 11778 64-2 AA#8 S0 Antibiotics protein bound in rat plasma.
AA#l = antibiotic agar ~1 (Difco).
BHI = Brain Heart Infusion YeJia (Difco).
MH = Mueller Hinton Agar (Difco).
AA#8 = antibiotic agar #8 (Difco).

mcg/ml = micrograms per milliliter mcl = microliters 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).

~ he results were as follows:

^200334~) - lg -With and Without Absorption Enhancers Dose = 5 mq/0.5 ml __ ax (microqrams per milliliter) ~Control) Acconon Con Labrasol Sodium Caprylate (30~) I
Antibiotic Water Laureth-12* Laureth-12* Laureth-12 Carumonam 0.0 i 0.0 7.2 i 1.411.7 i 3.8 6.3 ~ 2.4 Cefamandole 1.3 :!: 2.5 6.4 + 0.6 8.4 i 2.6 18.1 i 3.7 Cefazolin 0.0 i 0.0 42.9 i 3.0 62.2 ~ 25.2 40.7 i 7.2 Cefoxitin 0.0 i 0.0 7.7 i2.8 9.1 i3.4 16.2 i 4.6 Cefotetan 0.0 i 0.0 g.S i2.821.2 ~5.8 26.1 i 11.4 Gentamicin 3.9 15.4 i 2.3 9.6 i1.9 14.1 + 6.9 Mezlocillin 0.0 i 0.0 0.6 +1.0 1.4 +1.4 6.7 ~ 1.7 l~oxalactam 0.0 i 0.0 9.6 +2.216.2 i1.8 19.9 ~ 4.5 PenicillinG 0.5 i 0.1 3.5 +1.0 5.2 i1.6 7.4 i 2.4 Vancar~cin 2.9 ~ 0.6 0.0 i 0.0 6.9 i 1.0 9.8 i 3.S
Ceftriaxone 2.4 i 1.9 38.8 + 22.6105.S i 23.0 53.7 i 13.3 ~Weight Ratio of Other Absorption Enhancer Ca~onent to Laureth-12 ~as 8:1 ZO --IN VIVO (DOGS ) - ENTERAL

Six male beagle dog6, weighing about lo to 16 kilograms each, were chronically fitted with a modified Thomas cannula implanted in the distal duodenum. Each dog received 2 hard 6hell gelatin capsules containing 210 mg of ceftriaxone 60dium salt in 2BO mg of a base (WlTEPSOL H15~, with absorption enhancer (157.5 mg of Labrasol and 52.5 mg of Laureth-12). Adminietration of the cap6ule6 in each instance wa~ enteral through the modified Thomas cannula into the proximal jejunum. Drug do6age was 20 to 50 mg of ceftriaxone per kilogram of dog body weight.

Blood plasma concentrations of ceftriaxone were determined prior to administration and at 10, 20, 40, 60, 120, 180 and 240 minutes after administration. Measurement6 were made by withdrawing blood at the6e time interval6, centrifuging, separating the plasma and assaying by High Performance Liquid Chromatography (HPLC), reverse phase method, or by bioas6ay (the same procedure as previou61y described for the Bioassay of Pla6ma Sample6).

To e6tabli~h a standard curve, ceftriaxone was diluted with normal dog plasma, then deproteinized in the same manner as de6cribed previou61y. Calculations were conducted using a Waters 840 Computer Sy~tem. Through the use of an appropriate computer program, the area under the curve (AUC) was determined for each route of administration. From the6e determination6, the bioavailability wa6 computed u6ing the following equation:
% sioavailability = rAUc Enteral 1 X loo Whenever intravenou6 (I.V. ) data were not available for the same do~e level used enterally, the following equation was employed:

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- Zl -. . . [~UC Enterall rI.V. Dosel % Bloavailablllty = [P.UC I .V. ] X [Enteral DoBe]

The results were 45.4 ~ 18.2% Bioavailability and 19.5 i 6.5 mcg/ml Cmax foc the absorption enhanced 5 formulation, compared to 0% Bioavailability and 0.5 mcg/ml Cmax for the control (a solution of ceftriaxone in water equivalent to 25 mg/kg, no absoeption enhancers).

IN VIVO (B~BOONS) - OR~L

~ dult baboonfi (Papio anubi6 and Papio hamadrYas), ranging in weight from 12 to 30 kilograms, were used in this study. The baboons were fasted overnight, then 6edated with ketamine hydrochloride by intramuscular injection prior to 15 administration of the antibiotic. Each baboon received four hard 6hell gelatin cap6ules through a ga6tric tube. Each cap6ule contained the following:

Ceftriaxone sodium salt 300 mg 20 Labrasol Z25 mg Laureth-12 75 mg Witep601 H15 380 mq 980 mg Enteric coating: polyvinyl acetate phthalate (approximately 8% of total capsule weight) One-milliliter blood 6ample~ were taken from the femoral region of each baboon using a heparinized 3-ml syringe.
Sample8 were taken prior to ceftriaxone administration and at 15, 30, 60, 120, 240, 360, 480, 600 and 720 minutes following ceftriaxone admini6tration. The 6ample6 were centrifuged at 12,000 rpm for one minute and the pla6ma wa6 6eparated and bioa66ayed for antibiotic content after deproteinization with acetonitrile, u6ing the same procedure described previously for the Bioassay of Plasma Sample6.

The re~ults were 10.0 + 6.5% Bioavailability and 5.5-59.B mcg/ml Cmax range, compared to 0% Bioavailability and O mcg/ml Cmax for the control (ceftriaxone 60dium 6alt, 300 mg, in the same enteric coated cap6ule, no ab60rption enhancers).

Absorption was also evaluated using a formulation composed of 300 mg of ceftriaxone sodium 6alt, 200 mg of 60dium caprylate, 75 mg of Laureth-12 and 415 mg of Witep601 H15. The Bioavailability of this formulation wa6 15.7 ~ 9~9% and 15.0-66.3 mcg/ml Cmax range, compared to 0% Bioavailability and o mcg/ml Cmax for the control (same as above).

IN VIVO (D9GS) - ORAL

Male beagle dog~ weighing approximately 10-14 kilograms were used in this study. The dog6 received 2 or 3 hard 6hell cap6ules through a ga6tric tube. Each capsule contained the following:

Ceftriaxone 60dium 6alt 300 mg Labra601 225 mg Laureth-12 75 mg Witepsol H15 3BO ma 980 mg Enteric coating: polyvinyl acetate phthala~e (approximately 8% of total capsule weight) Blood plasma concentrations of ceftriaxone were determined prior to admini6~ration and at lo, 20, 40, 60, 120, 180 and 240 minute6 after admini6tration. Mea~urements were made by withdeawing blood at these time intervals, 6eparating the pla6ma, deproteinizing, and assaying by High Performance Liquid Chromatography (HPLC), reverse phase method, or by the previously described Bioassay of Plasma 2~:)033~

Samples method.

The result6 were 34.2 i 14.0% Bioavailability and Zl.6 i 7.6 mcg/ml Cmax for the above formulation, and 0 Bioavailability and o mcg/ml Cmax for the control tceftriaxone 60dium salt, 300 mg, in the same enteric coated capsule, no absorption enhancers).

Ab60rption wa6 al60 evaluated using a formulation composed of 300 mg of ceftriaxone sodium salt, 200 mg of 60dium caprylate, 75 mg of Laureth-12 and 415 mg of Witepeol H15. Bioavailability wa6 Z2.4 ~ 13.5~ and Cmax was 14.4 i 8.4 mcg/ml, compared to 0% and o mcg/ml, respectively, for the control (6ame a6 above).

IN ~IVo (BABOONS? - RECTAL

Male and female adult baboons (Papio anubis and Papio hamadrYas), ranging in weight from lZ to 27 kilograms, were ueed in thie 6tudy. The baboons were fasted for 2~ hour6 prior to admini6tration of antibiotic, then sedated with ketamine hydrochloride by intramu6cular injection prior to admini6tration of the antibiotic. Suppoeitories made up of the formulation6 shown below were admini6tered to the baboon6 and the rectal opening6 were then taped clo6ed to prevent expulsion and leakage of the suppo6itory ma6~.

Antibiotic 500 mg Laureth-12 125 mg 30 Labra601 250 mg Witepsol H15 1125 mg Total: 2000 mg To measure antibiotic ab60rption into the bloodstream, blood sample6 were taken from the femoral region of each baboon, using heparini2ed 3-ml syringe6, prior to antibiotic 20033~0 admini6tration and at 15, 30, 60, lZ0, 240, 360 and 480 minute6 after antibiotic admini6tration. The withdrawn gample6 were centrifuged at 12,000 rpm for one minute and bioas6ayed by the previou61y described Bioas6ay of Pla6ma Sample6 method. The results were as follows:

Antibiotic Bioavailability and Cmax Range in Baboons After Rectal Administration With Absorption Enhancec Control-No Absorption ~ystem Enhancer System ~ Bioavail- Cmax Range % Bioavail- Cmax Range Antibiotic ability mca/ml ability mca/ml Ceftriaxone 31.5 i 13.118.Z-4g.6 4.~ i Z.8 0.3-9.0 Cefamandole 46.5 + 16.65.9-16.4 6.0 ~ Z.3 2.3-4.6 Cefoxitin 77.0 ~ 22.54.7-10.8 0 o Penicillin G 38.2 i 26.12.0-11.1 17.4 i ~.0 l.Z-Z.4 Absorption was also evaluated using a formulation composed of 600 mg of ceftriaxone sodium salt, 200 mg of sodium caprylate, lZ5 mg of Laureth-lZ and 1075 mg of Witep601 H15 (total: Zooo mg). The Bioavailability was 49.3 i 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 6uppository 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, iB used to illustrate the6e 36 formulation6, it should be understood that other antibiotics may be 6ubstituted in appropriate amount6.

20(~33~

OR~L DOSAGE FORMS

per capsule A) Ceftriaxone (sodium) 60 mg120 mg 210 mg 300 mg Labrasol 225 mg2ZS mgZ25 mg225 mg Laureth-lZ 75 mg75 mg 75 mg 75 mg Witepsol H15 340 mg 340 mg340 mg 340 mg B) Ceftriaxone (sodium) 60 mg120 mg 210 mg 300 mg Sodium caprylate 200 mg200 mgZOO mg Z00 mg Laureth-12 75 mg75 mg 75 mg 75 mg Witepsol H15 365 mg 365 mg365 mg 365 mg C) Ceftriaxone (sodium) 60 mg120 mg Z10 mg 300 mg Acconon Con 225 mg225 mgZZ5 mg225 mg Laureth-12 75 mg75 mg 75 mg 75 mg Witepsol H15 340 mg 340 mg340 mg 340 mg D) Ceftriaxone (sodium) 60 mg120 mg Z10 mg 300 mg 20 Softigen 767 ZZ5 mg ZZ5 mg2Z5 mg ZZ5 mg Laureth-lZ 75 mg 75 mg 75 mg 75 mg Witepsol H15 340 mg 340 mg340 mg 340 mg RECTAL DOS~GE FORMS
per SuppO6 i to ry A) Ceftriaxone (sodium)180 mg300 mg 600 mg lZ00 mg Labrasol Z50 mgZ50 mgZ50 mg500 mg Laureth-lZ 125 mg125 mg125 mg250 mg Witepsol H15 1445 mg1325 mg1025 mg 2050 mg B) Ceftriaxone (sodium)180 mg300 mg 600 mg 1200 mg Sodium caprylate 200 mg200 mgZ00 mg 400 mg Laureth-lZ lZ5 mg lZ5 mg lZ5 mg Z50 mg 35 Witepsol H151495 mg1375 mg1075 mgZ150 mg C) Ceftriaxone (~odium)180 mg 300 mg 600 mg 1200 mg Acconon Con 250 mg 250 mg 250 mg500 mg Laureth-12 125 mg 125 mg 125 mg250 mg Witepsol H15 1445 mg 1325 mg1025 mg 2050 mg D) Ceftriaxone (sodium)180 mg300 mg 600 mg 1200 mg Softigen 767 250 mg250 mg 250 mg 500 mg Laureth-12 125 mg 125 mg 125 mg 250 mg Witep601 H15 1445 mg1325 mg1oZ5 mg2050 mg The above dosage form6 can be prepared a6 follow~:

PROCEDURES

Oral The base (Witepsol ~15) i6 warmed to 55DC and the absorption enhancer sy6tem component6 are added to the melt with mixing. The melt is then cooled to 45C and the drug (ceftriaxone sodium) i6 added to the molten mass and mi~ed until uniformly di6tributed and free of any aggregates. The mas6 i6 homogenized, if nece66ary, to obtain a uniform 6uspen6ion. The 6uspen6ion is filled into gelatin capsules, sealed if nece66ary, and the cap~ule~ are enteric coated.

Rectal The ba6e (Witepsol H15) i~ warmed to S5C and the ab60rption enhancer sy6tem components are added to the melt with mixing. The melt iB then cooled to 45C and the drug (ceftriaxone 60dium) i6 added to the molten mass and mixed until uniformly di6tributed and fLee of any aggregates. The ma6s i6 homogenized, if neces6ary, to obtain a uniform 6uspen6ion. The su6penBion iB then filled into suppo6itory 6hells and allowed to cool and congeal.

Claims (14)

1. A pharmaceutical composition comprising (a) an antibacterial compound and (b) an absorption enhancing amount of a two-component absorption enhancing system made up of a first component which is (1) an ether of a C6 to C18 alcohol and a polyoxyethylene glycol and a second component selected from among (Z)(i) a polyoxyethylene glycol (PEG)- C6 to C18 glyceride ester, (2)(ii) a C6 to C18 carboxylic acid or pharmaceutically acceptable salt thereof, and (Z)(iii) an ester of two or more C6 to C18 carboxylic acids, glycerol and a polyoxyethylene glycol, with or without (c) a pharmaceutically inert carrier.

2. A composition according to claim 1, in which the absorption enhancing system is composed of (b)(1) an ether of a C6 to C18 alcohol and a polyoxyethylene glycol and (b)(Z)(i) a polyoxyethylene glycol- C6 to C18 carboxylic acid glyceride ester.

3. A composition according to claim 2, in which (b)(1) is an ether of lauryl alcohol and polyoxyethylene glycol and (b)(2)(i) is a PEG-8 caprylate/caprate glyceride ester.

4. A composition according to claim 1, in which the absorption enhancing system is composed of (b)(1) an ether of a C6 to C18 alcohol and a polyoxyethylene glycol and (b)(2)(ii) a C6 to C18 carboxylic acid or pharmaceutically acceptable salt thereof.

5. A composition according to claim 4, in which (b)(1) is an ether of lauryl alcohol and polyoxyethylene glycol and (b)(2)(ii) is sodium caprylate.

6. A composition according to claim 1, in which the absorption enhancing system is composed of (b)(1) an ether of a C6 to C18 alcohol and a polyoxyethylene glycol and (b)(2)(iii) an ester of two or more C6 to C18 carboxylic acids, glycerol and a polyoxyethylene glycol.

7. A composition according to claim 6, in which (b)(1) is an ether of lauryl alcohol and polyoxyethylene glycol and (b)(2)(iii) is a PEG glycerol cocoate.

8. A composition according to claim 7, in which the antibacterial compound is a beta-lactam.

9. A composition according to claim 8, in which the beta-lactam is of the formula in which R1 is hydrogen or optionally substitutes alkyl, R2 is SO3-M+ where M+ is a proton or cation, R3 is an acylamino group or hydroxyalkyl, or R1 and R2 together with the beta-lactam (azetidinone) ring to which they are bonded represent in which X is -S-, -O-, -SO, -SO2, -CH2 or -CH(CH3) and Y is group or or in which R4 is a substituted thio group selected from among ethylthio, -SCH2CH2NH2.
, , or an optionally substituted lower alkyl group selected from among aminomethyl, acylaminomethyl, or a substituted oxy gcoup consisting of carbamoyloxy , 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 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.

10. A composition according to claim 8 in which the antibacterial compound is (E)-2-(Isbutoxy carbonyl) -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.

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

12. A composition according to any one of claims 1-11, which is in an enteric coated oral dosage form.

13. A composition according to any one of claims 1-11, which is in a rectal dosage form.

14. The novel pharmaceutical compositions as described hereinbefore.