CA2024887A1 - Pharmaceutical preparations - Google Patents
Pharmaceutical preparationsInfo
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- CA2024887A1 CA2024887A1 CA002024887A CA2024887A CA2024887A1 CA 2024887 A1 CA2024887 A1 CA 2024887A1 CA 002024887 A CA002024887 A CA 002024887A CA 2024887 A CA2024887 A CA 2024887A CA 2024887 A1 CA2024887 A1 CA 2024887A1
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- composition according
- carboxylic acid
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/02—Suppositories; Bougies; Bases therefor; Ovules
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
- A61K31/425—Thiazoles
- A61K31/429—Thiazoles condensed with heterocyclic ring systems
- A61K31/43—Compounds containing 4-thia-1-azabicyclo [3.2.0] heptane ring systems, i.e. compounds containing a ring system of the formula, e.g. penicillins, penems
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/54—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one sulfur as the ring hetero atoms, e.g. sulthiame
- A61K31/542—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one sulfur as the ring hetero atoms, e.g. sulthiame ortho- or peri-condensed with heterocyclic ring systems
- A61K31/545—Compounds containing 5-thia-1-azabicyclo [4.2.0] octane ring systems, i.e. compounds containing a ring system of the formula:, e.g. cephalosporins, cefaclor, or cephalexine
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/70—Carbohydrates; Sugars; Derivatives thereof
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
- A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
- A61K47/12—Carboxylic acids; Salts or anhydrides thereof
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
- A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
- A61K47/14—Esters of carboxylic acids, e.g. fatty acid monoglycerides, medium-chain triglycerides, parabens or PEG fatty acid esters
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P31/04—Antibacterial agents
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- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Epidemiology (AREA)
- General Chemical & Material Sciences (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Engineering & Computer Science (AREA)
- Oil, Petroleum & Natural Gas (AREA)
- Communicable Diseases (AREA)
- Oncology (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Organic Chemistry (AREA)
- Molecular Biology (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Medicinal Preparation (AREA)
- Plural Heterocyclic Compounds (AREA)
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
Abstract
ABSTRACT OF THE DISCLOSURE
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- or three-component absorption enhancing system made up of a polyoxyethylene glycol- C6 to C18 glyceride ester, a C6 to C18 carboxylic acid and, optionally, a C6 to C18 carboxylic acid salt. A carrier and adjuvants are usually included. These compositions can be administered in oral or rectal dosage forms such as capsules, beadlets and suppositories.
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- or three-component absorption enhancing system made up of a polyoxyethylene glycol- C6 to C18 glyceride ester, a C6 to C18 carboxylic acid and, optionally, a C6 to C18 carboxylic acid salt. A carrier and adjuvants are usually included. These compositions can be administered in oral or rectal dosage forms such as capsules, beadlets and suppositories.
Description
2~2~7 ~ ~
, . ...................................... .
.
RAN 4600/62 .
This invention relates to pharmaceutical compositions compeising ~a) an antibacterial compound and (b) an absorption enhancing amount of an absorption enhancing ~ -~
system made up of (l) a polyoxyethylene glycol - C6 to Cl~ carboxylic acid glyceride ester and (Z) a C6 to Clb carboxylic acid, with or without a C6 to Cl8 `~-carboxylic acid salt. Optionally, a pharmaceutically inert carrier can also be included.
:,., :., The term ~polyoxyethylene glycol-C6 to Cl8 16 carboxylic acid glyceride ester~ as used in connection with thi~ invention refers to those reaction products derived from the co-reaction of polyoxyethylene glycol (or polymerizable precursor thereof, such as ethylene oxide) with a C6-Cl8 carboxylic acid and glycecol or with a C6-Cl8 carboxylic acid glyceride or glycerides.
Re~ulting ~rom such reaction~ are, ty~ically, mixtures of a ~olyoxyethylene glycol-C6 to C18 carboxylic acid ~;
glyceride e~ter ~e.g., PEa-glycerol-caprate, pEa-glycer caprylate or PEG-glycerol-caprylate/caprate), a polyoxyethylene glycol-C6 to C18 cacboxylic acid ester te.g., PEG-caprate, pEa-caprylate or pEa-caprylate/caprate)~
and a glyceryl-C6 to Cl8 carboxylic acid ester (e.g., glyceryl mono-, di- or tricaprylate, glyceryl mono-, di- or ^ --tricaprate or glyceryl mono-, di- or tricaprylate~ caprate), ;
a8 the principal components.
More s~ecifically, it has been discovered that the above-identi~ied absorption enhancing ~ystem functions to lncrease the extent of absorption of antibacterial compounds through mucosal tissue and into the bloodstream. This Grn/27.6.90 ;. ' ~,'. ~'' ' .
~ 2~2~7 invention thus promotes the absorption and provides adequate blood levels of antibacterial compounds which, when administered without the absocption enhancer by means other than parenteral, are only poorly absorbed or not absocbed to any appreciable deqree. The preparation and use of a greater vaeiety of dosage forms for such compounds are thus enabled. The invention also eromotes 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.
16 The invention includes oral and rectal types of pharmaceutical ~reparations containing effective amounts of an antibacterial compound and an absorption enhancing system in accocdance with the present description, with or without an inert carrier and pharmaceutically acceptable adjuvants.
The terms "antibacterial" and l'antibiotic~ are used intecchangeably throughout this disclosure to refer to bacteeicidal or bacterio~tatic compounds which have been metabolically deri~ed from a microorganism, synthetically 2S ~repared 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 moderaeely absorbed upon non-in3ected or non-infused administration.
However, this lnvention finds its greatest usefulness when employed to enhance the absorption and bioavailability of 3S antibiotics which, for the most pact, can be effectively administered only by in3ection or in~usion due to non- or ' ~ .
~'~
,.' ' ~. :~
2~2~87 :
_ 3 -poor absorbability via other routes of administration.
Among the most preferred antibacterial compounds suitable for use as the therapeutic 6ubstance 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 ' "
'10 1 1 `'' D--N
O
which can be substituted at various positions on the ring and/or ~used 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 ~ormula ~2 in which al is hydrogen or optionally substituted alkyl, R2 is S03-M+ where M+ is a proton or cation, R3 is an `acylamino group or hydroxyalkyl, or Rl and R2 together with the beta-iactam (azetidinone) ring to which they are bonded re~resant 202~g~7 R~
o in which X is -S-, -O, -SO-, -SO2, -CH2 or -CH(CH3) and Y is group . ' C~3 \ / or I or / \ C~3 ~ Z .
/ COOE
C~l COOE
",:
,~4 ~ :`
: COOE
, .., .:
2~ ~
:: in whic~ R4 is a substituted thio group such as ethylth1o, 2CH2NH2' :~
-SCH2CH2;, -SCH2CH~OCNH2. '~i~CONMe~
or an o~tionally substituted lower alkyl group such as aminom-thyl, acylaminomethyl, 3~ ' .'"';'".''"
. . ......
,, ""
,., ., ~ ,. .", ~ 2~2~7 -... .
_ 5 -~ ' ' o~ - ', or a substituted oxy group such as carbamoyloxy (-O~H2), the carbon atom which carries the -COOE group is bonded to the nitrogen atom of the beta-lactam eing, Z is hydrogen, halogen, alkoxy or CH2T, with T denoting hydrogen, alkyl :
-CO-O-, pyridLnium, carboxamidopyridinium, aminopyridinium, carbamoyloxy, azido, cyano, hydroxyl, the group -S-phenyl which can be ~ubstituted or the qroup -S-het wherein l'het"
is an optionally substituted 5- or 6-membered heterocyclic eing, and E i~ hydrogen, a pharmaceutically acceptable ester group or a salt-forming cation.
Exam~les of the 5- or 6-membered heterocyclic rings encompassed within "het" above are the ~ollowing:
N--N N N N N : ; .
~S~ CHI ~ N ~N~ :
CH3 CH2 CH2N~CH3)2 2~5 :
H :
_<--N ~--IN~\N CH3~ ~N~
Es~ecially preferred beta-lactam antibiotics and their 36 ~harmaceutically acce~table salts, esters and hydrates include ceftriaxone, a cephalosporin described in U.S.
Patent No. 4,327,210 (Montavon et al.); carumonam, a 202~~7 monocyclic beta-lactam described in Eucopean Patent No. EP
73061: piperacillin, a penicillin described in U.S. Patent No. 4,11Z,090; cefamandole, a cephalosporin described in U.S. Patent No. 3,641,021; and cefazolin, a cephalosporin described in U.S. Patent No. 3,516,997, the disclosures of all of which are incocporated herein by reference. Further included are cefoxitin, cefmetazole, cefotetan, moxalactam, eefuroxime, ceforamide, eefoperazone, eeftizoxime, cefotaxime, eefmenoxime, eeftazidime, cefsulodin, cephalexin, azloeillin, penieillin G, temocillin, sulbenicillin, ticarcillin, mecillinam, amoxicillin, methicillin, carbenieillin, thienamycin, N-foemimidoyl~hienomycin, sulbactam and azthreonam.
Also included within the seope of this invention are aneibioties other than the beta-laetams, for exam~le, vaneomyein, the absor~tion and blood levels of whieh are improved by use with the deseribed absorption enhaneing systems.
':
Absorption enhancing system component (b)~l) may be the produet of an sterifieation reaetion between a polyoxyethyl-n- glyeol, qlyeerol and one or more straight or branehed ehain C6 to Cl~ earboxylie aeids, preferably a monofunetional aeid or aeids. Alteenatively, eom~onent ~b~tl) may be ~cepared by oligomerizing or polymerizing ; ;
ethylene oxide in the presenee of an ester of glyeerol and ; one or more of sueh C6 to Cl~ carboxylie acids ~glyceride esters). Still another route, and the preferred one, is by co-reacting the glyceride ester or esters~ with a ~ "~
fully ~re-formed polyoxyethylene glycol under condition~
sufficient to achieve alcoholysis.
Aceording to a particulae ~referred ~rocedure, involving alcoholysis, a reaction vessel is charged with stoichiometeic quantities of a glyceryl-fatty acid ester or esters and a polyethylene glycol. The vessel iB closed and ~''"''' ''"'~
2~2~7 : .:
heated at atmospheric pressure to 200C, with continuous stirring commenced at 70C. for a period of 12 to 24 hours or until the reaction i8 completed. The vessel is allowed to cool and the reaction product is then separated from the reaction mixture by filtration.
Examples of C6 to C18 carboxylic acids, saturated or unsaturated, which are useful for the preparation of absorption enhancing system component (b)(l) 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 1S f absorption enhancing system component (b)(l) is, typically, a medium to high molecular weight material, ~referably having a number average molecular weight in the range from about 200 to about lSOO, and more preferably from about 300 to about 600.
' ""
A material which is suitable for use as absor~tion enhancing system com~onent (b)~l) will most ~refecably have the ~ollowing characteristics~
Organole~tic Pro~erties:
Appearance: clear oily liquid Odor: faint Color: pale yellow to yellow Physical and Chemical Properties:
~ 2û24~87 : ~
Acid Value 0 2 - 0 6 Sulfated ash less than 0 05%
Saponification index 85 - 105 Iodine index less than Z
Moisture content less than 0 05%
Free qlycerin content appcox 2%
appcox 6 to 8 Denslty (dq ) 1 062 - 1 068 g/cc aesractive lndex (nD) 1 458 - 1 462 ' 10 '~ ' " '~ "
Suitable absorption enhancing system components ~or use --~ -as (b)(l) in this inYention which are commercially available are LA~aA80L, produc-d by aatte~osse Corpocation, Pacis, France (P~G-~ ca~rylate/caprate glyceride estecs), and 1~ 80~T~aEN 767, ~roduced by Dynamit Nobel, West Germany (PEG-6 i`
; ca~eylat-/ca~cat- glycerid- e~ter~
~ The C6 to ClEi caeboxylic acid Or absorption i `~r '~ enhancing ~y~t-m com~on-nt (b)(2) i~ derived from an -5~ æo all~hatlc cacboxyllc acld, which may be ~traight or branched chain ~xam~ includ- ca~roic, ca~rylic, ca~ric, lauric, yrl~tlc, ol-ic, ~almitic and ~tearic acids Mo~t Savoced ;;;
tor th- ~u~or-- oS~thl~ lnY-ntion i~ oa~cyllc acid 2~ ~ Th- C6 to Cl~ carboxyllc acld ~alt, Which optionally `
la am~loy-d with th- acid, aan b- ~re7ared in a conventional minn-r and u-ing known techniguei by reacting the acid with'~A'':7''''.'''~:.i' ~!,D ;`~I a~ba-- ha~ing~a non-toxic, ~har~acologically and ~harmaceutically acce~table cation In genecal, any base which will ~orm a salt with a carboxylic acid and the ha&~àcological ~ro~er;tie~ Or which will not cause an ' advelB- ~hy~iiological!eSSect when ingested by or otherwi~e ;
ad~inl~t-r-d to a waem-blooded ani~al i- suitable Such l~if,--ba~-r thur inalude, ror exa~le, alkali metal and alkaline ~arth metal hydfcoxide~ or carbonate~, such as sodium ~ hydcoxide, ~otas~ium hydroxide, calclum hydroxide, ~otas~ium iln ; carbonate, and the like Particularly ~ce~erred for this ; ,",, , ;~:
~',.'', . ""~ ~ ' i'':
2~2~8~7 _ 9 _ invention are sodium salts, chiefly becau6e of their ready availability. Sodium caprylate is especially preferred.
The C6 to Cl8 carboxylic acid salt is useful as a stabilizing agent for the C6 to Cl8 carboxylic acid, and is especially de~irable in formulations where ceftriaxone is present as the antibiotic.
The relative proportions of the components which comprise the absorption enhancing system can be varied to achieve optimum results for a particular embodiment of the invention. Por the two-component absorption enhancer system, prefecably, component (b)(l) is present in an amount from about 20 to about 80 percent and the carboxylic acid is 16 present in an amount from about 80 to about 20 percent, based on the total weight (lOOt) of these two components comblned. A more preferred embodiment will comprise from about 40 to about 60 percent of component (b)(l) and from about 60 to about 40 percent of the carboxylic acid, based on the total weight of the two components. Still more peQte~red are those absorption enhancer systems consisting ot about 50 pereent of com~onent (b)(l) and about 50 percent ot the earboxylie acld, based on the eombined weight of the two eomponents.
Preferably, for the three-eomponent absorption enhaneer system, eomponent (b)(l) is present in an amount from about 20 to about 80 pereent, more preferably from about 40 to about 60 percent, and most preferably about 50 percent, based on the total weight (100%) of the three absorp~tion enhancer system components combined. The carboxylic acid preferably is present in an amount from about 10 to about 40 pereent, more preferably from about 15 to about 25 percent, and most prefecably about 25 percent of the total weight.
The carboxylic acid salt is present in an amount from about lO to about 40 percent, more preferably from about 25 to about 35 percent, and most preferably about 25 percent of A,''.,~` . ,' . ' ' . . . . ', ` ' . , ., . . . ` ' , .. , . , .,, . ' . ,: , .. . ' 202~887 :
., .
the total weight.
The effective amount of the absoretion enhancing system, component (b), in the composition of this invention will 5 vacy depending on such factors as the particulae -antibacterial compound being employed and its amount, as well as the age of the sub3ect being treated.
In general, for oral dosage form compositions of this 10 invention, it i8 preferred to employ from about ;
50 milligrams (mg) to about 1000 mg, and more preferably from about 100 mg to about 500 mg of the absorption enhancing system, Cor each unit dose of the compo~ition.
These compo~itions will usually eontain the antibacterial 16 compound in amount~ from about 10 mg to about 500 mg, and more usually from about 50 mg to about 250 mg, pec unit dose.
Rectal dosage form com~ositions in aecordance with this ~; ~
invention will usually eontain from about 25 mg to about ~` ` `
1500 mg, more preSerably feom about 100 mg to about 500 mg of the absorption enhancing system, for eaeh unit dose of th- eompo~ltlon. Sueh eomposltlons wlll usually contaln the antlbaeteclal eompound ln amounts from about ~0 mg to about ~`~ 3000 mg, and more usually from about 100 mg to about ~ , 2B l500 mg, per unlt dose.
~; The term ~unit do~e~ is used here in the eonventional , ~ ;-sense to mean a single applieation or administration of the ` ;~
drug to the sub3eet being treated in an amount as stated above, but it 8hould be understood that the amount ean be glven in the form of a single pill, tablet, eapsule, U~uository~ etc., or alternatively, in multiples of two or more of such dosage unit~ with the total adding up to the stated amount of drug.
The described antibaeterial eompound and absorption enhaneing ~ystem, respeetively, can be incorporated in a ', ~; ~ `' .
2~2~
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 of mono-, di- and triglycerides of C12 to C18 natural saturated fatty acids, preferably vegetable fatty acids having an even number of carbon atoms (C12, C14, C16, etc.). E6pecially suitable and preferred are the pharmaceutical bases of Dynamit Nobel having the trade 16 de~ignation ~WITEPSOL~.
Still other pharmaceutically compatible carrier mate~ials may be employed as desired and depending upon pacticular requirements, the selection of which is within the knowledge of those skilled in the art.
If utillzed, the vehicle will generally be present in those amounts which are conventional for pharmaceutical carrier materials and which can be reasonably and safely 2~ ad~ini~tered.
The preferred method of orally administerinq 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 i~ 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 compcund mixed with the -, , 2~2~7 ab60rption enhancing system which may thereafter be encapsulated in an enteric coated capsule.
: ''' .
Usage of enteric coating materials in this manner serves to peotect 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, resi~tant to the gastric fluid and is unaffected by it but di~solves in the intestinal fluid to cause release of the drug.
The effec~iveness of particular enteric coating materials can be measured using known USP procedures. By 16 way of illustration, suitable enteric coating materials for purpo~es of this invention include but are not limited to the following:
cellulose acetate phthalate cellulose acetate trimellitate hydroxypro~yl methylcellulose phthalate hydroxy~ro~yl methylcellulo~e ~hthalate succinate ~olyvinyl acetate phthalate ~
` methacrylic acld -methacrylic acid ester~ -: ~ " ', .' These enteric coating materials may be applied with or ~~
without plasticizers, such as acetylated glycerides or diethylphthalate, usinq methods kr.own to those skilled in ! 30 the art.
.," ~,., .:.::
The ~ercentage of enteric coatlng a~plied is usually b~tween about 1 and about 10 percent by weight, or more, and most desirably from about 2 to about ~ percent by weight, 3S based on the total weight of the unit dosage form, i.e., the "
total capsule or tablet weight. Examples of suitable . ~, ~,'~', ',, ~ 202~8~ :
.., enteric coating formulations are given below.
Enteric Coatina Formulations S -- .
Ingcedients % W/W
. ...
PreDaration A:
Hydroxypropylmethylcellulose phthalate (HPMCP) 5.0 Triacetin 0-5 Methylene chloride 47.25 15 Denatured alcohol 47.25 PreDaration B: .
HPMCP lO.o 20 Titanium dioxide 0.2 Trlethyl citrate 1.5 .
Acetone 44.15 Denatured alcohol 44.15 P~eDaration C:
Cellulo~e acetate phthalate (CAP) 8.5 Diethyl phthalate 1.5 ~-Titanium dioxide 0.2 ! 30 IAcetone 4'4-9 Denatured alcohol 44.9 2~2~&.~7 Preparation D:
Polyvinyl acetate phthalate 5.0 Acetylated glycerides 0.8 5 Methylene chloride 47.1 Denatured alcohol 47.1 , PreDaration E: . .
,' ' :' ' "":
10 Methacrylic acid or methacrylic acid ester (Eudragit S or L, 8.0 Rohm Pharma, GM8H, Wetterstadt, ::
west Germany) '', ~, '' ',, ' Triacetin 1.0 . ::
15 Acetone 45.5 Anhydrous alcohol 45.s Oral dosage form compositions in accordance with this invention can also be formulated to additionally contain conventional additives or sup~lementary ingredients, in the usual amounts for such materials. By way of illustration, :
such additi~es or su~lements include thickening agents, such as silicic acid (for instance, the trade designated "Aerosil~' products); bentonites: colloidal clay:
X5 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 . ;~
30 (for instance, stearic or palmitic acids, or stearic or ~ ;
cetyl alcohols): waxes: monoglycerides of saturated or unsaturated hiqh fatty acid~ such as stearic acid, ~almitic acid or oleic acid: gelling agents, such as alumlnum steaeate: dispersing agents, such as ionic, non-ionic or cationic surfactants: emulsifying agents, such a~ lecithin, and 80 forth.
: ':
.'', ~ 202~8~
- 15 _ The compositions of this invention can also contain pharmaceutically acceptable adjuvant6, such a6 binders or lubricant~i foc tabletting, stabilizinq agents, antioxidant6, flowing agents (to enhance pourability or flowability during pcocessing)~ pre6ervative6, flavoling agent6, coloring agents and bu~fering agents. Any of the6e can be selected ~eom among materials known for such purpose6 and u6ed in conventional amounts.
In vivo tests were utilized to evaluate the enhanced mucosal tis6ue absorption of antibiotics admini6tered in accordance with this invention.
IN VIV0 tRATS) - ENTERAL
Adult Sprague-Dawley female rats tCharles River Breeding Laboratories, Kingston, New York), weighing about 250 grame each, were fasted overnight and anesthetized with metofane.
With each rat, an incision wa~ made on the ventral surface to ex~o~e the intestine. Administration of an antibiotic wa~ carried out using a solution dosage form. The solutions were QreQared by dis~olving antibiotic in water with or without absorption enhancer 80 as to deliver 20 milligrams per kilogram, appeoximately 5 mg pec cat.
2~ ~
Each solution of antibiotic in water was administered ~ -enterally by in3ecting with a syringe into the duodenum directly below the pyloric valve. For purposes of comparison, the solution was alternatively adminieitered ;~
~intcavenously by in3ecting with a syringe into a tai!l vein.
a LeYel~ of Antibiotic in Rat~
Tbe concentration of antibiotic in rat plasma wae 3S determined at various time intecvals aftec intcavenous oc entecal administration. Blood eamples were collected from the tail of each test animal prior to administration of the ,'.~' ..','':': ~'.
'~ ,.: .~ ' ' " 202~87 :
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 ~he plasma was withdrawn and frozen until assayed. -:.
: .
~ioassaY of Plasma SamDles Most of the antibiotics tested had exhibited some degree of protein binding when drug-seiked rat plasma was assayed against drug in H20. Any antibiotic not bound by plasma was diluted in H20 and assayed against standards prepared in H20. For bound antibiotics, the influence of protein binding wa~ negated by diluting all standards and samples in pooled rat plasma. In the case of ceftriaxone and ~ ~.
16 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 H20. Antibiotic levels were assayed on ~ :
nunc plates employing the appropriate agar seeded with : :
20 bacteria, as listed below in Table 1. ..
.
2 0 2 ~ 8 ~ 7 ~ ~
Ass y RangQ of Standard 3ioassay Volume Antiblotlc Or~anlsm Curv~s ~mcc~ml~ ~Qdla (mcl) C~rtrlPu~n E coll 1346 32-1 AA~12 20 Amp~clllln ~ lut~ ~TCC 9341 0-0 25 AA~l 20 C f~m~ndol ~ lute~ ATCC 93-1 32-1 AA~l 20 C fot~lm~ E eoli 1346B 0 25 or 16-0 5 AA~l 20 C fo~1t1n S ur us rB21B6 64-4 BHI3 20 C~ftrl~on~l E eoll lS 6 ~ 0 125 ~A~l 20 C fu olln S ~ur u~ ATCC 2S923 32-1 A~l 50 B subtlli~ Dpor s 32-2 A~l 50 Act~ E col~ 1346 S0L1 56 AAJl 50 P nic~llln Gl ~ lut~ ATCC g341 ~-0 5 AA~l 20 V~ncorycln B c r us AT0C 1177B 64-2 ~35 50 i ~
', '' " '~ " .
1 Antibiotic~ i?cotein bound in rat ~la~a AA~l . antibiotic agar ~1 (Dl~co) HI Brain H-art In~usion M-dia ~Dieco) MH . Muell-e Hlnton Agar (Di~co) ;;
AA~ . antibiotic agar ~ ~Di~co) mcg~l . miceogcams i?-r mllliliter cl . ~icrolit-rs The i?lates were incubated overnight at 37C and the zone~ ;
o~ inhibition were read to the nea~e~t 0 1 mm Calculation~
SO ~were made u~ing an autoas~ay machine (ailes Scientific, l ;
Inc , New York) For re~erence, see J~ V Bennett et al , ; ~;
A~lied Microbiology ~, 170-177 (1966) ,;
, ~ ,., .. ~
The results are ~re~ented in Table Z ;
, ''~' '. "", ;. . . ~
:. , ,..- ....
~;~
202~7 _18 _ TA~LE 2 ENTERAL ABSORPTICN IN RATS -~i~h and ~ithout Absorp~ien Enhaneers Doso ~ S m~/O S ml Cm3x (microarams p~r millilitQr) ~Control) Labrasol ~Labrasol ~ Caprylit Acid Antlbiotle ~ator CaPrvlle Aeid~ Sodium Caprvlat~*~
C~ruror m 0 13 6 ~ 2 9 10 9 1 1 4 CofamandDlo1 3 ~ 2 55 4 l S !s S ~ 6 8 C~fuolln 0 - 17 5 ~ S 7 cQfoxltln O - 12 B ~ 1 7 C~fo~etan 0 1? 8 4 9 20 4 ~ 4 9 ~e~ e~am O - 15 8 1 1 3 Ponleillin G 0 5 ~ 0 1 7 2 0 7 2 9 ~ 1 6 Vaneomyeln2 9 0 6 8 0 2 3 5 3 2 1 C~f~rl~xon~2 4 ~ 1 9 57 0 ~ 10 252 2 ~ æ.s ~lght Ratlo of L~Drasol C~Drylle Aeld ~as 2 1 ~*~lght Ratlo of LuDrasol C4prylle Aeld Sodlum C4Dryla~o ~as 4 1 1 ~ ' '".
202'18~
IN VIVO (DOGS) - ORAB
Male beagle dogs weighing approximately 10-14 kilograms were used in this study The dogs received Z or 3 hard shell enteric coated capsules orally Each capsule contained either of the following formulations A B
Cefteiaxone sodium salt~315 mg 315 mg Babrasol 225 mg 225 mg Caprylic acid 200 mg loO mg Sodium caprylate -- 100 mg Witep~ol H15 210 ma 210 mc 950 mg 950 mg ; ~ `
~315 mg o~ ce~triaxone sodium salt is eguivalent to 250 mg o~ ce~teiaxone as ~ree acid plu8 5% excess Enteric coating ~olyvinyl acetate phthalate (approximately ~% of total capsule weight) Blood pla~ma concentratlon~ of ceftriaxone were determined prlor to admini~tration and at 10, 20, 40, 60, 120, 180 and 240 minute~ a~t-r admlni~tratlon M-a~urement~ were made by withdrawlng blood at th-~- tlme lnterval~, separatlng the ;~ ~la~ma, deprot-lnlzlng, and a~aylng by Hlgh Performance lquid Chromatography (HPBC), reverse phase method, or by the !` 1 ; previou81y de~cribed Bioassay of Plasma Samples method !~ 1 30 i The results were 27 7 ~ 12 7% Bioavailabllity and 10 to ;
39 5 mcg/ml Cmax Range for Formulation A, 31 0 ~ 19 8% ;
Bioavailabllity and 3~ 6 ~ 23 2 mcg/ml Cmax for Formulation B, and Ot Bioavailabillty and O mcg/ml Cmax for the control tceftriaxone ~odlum salt, 300 mg, in the ~ame enterlc coated 35 ca~ule, no absor~tion enhancer~) ;
. .
,~
F~
~ 2~2~7 ~
, ~
IN VIVO ~BABOONS) - RECTAL
Male and female adult baboons (PaDio anubis and PaDio hamadrYas), ranging in weight from 12 to 27 kilograms, were used in this ~tudy. The baboons were fasted overnight prior to administration of antibiotic, then sedated with ketamine hydrochloride by intramuscular in3ection prior to administration o~ the antibiotic. Suppositories made up of the formulation shown below were administered to the baboons and the rectal openings were then taped closed to prevent expulsion and leakage of the suppository mass.
C D
Antibiotic (active form) 500 mg 500 mg Labrasol 250 mg 250 mg Caprylic acid 200 mg 100 mg 8Odium caprylate -- 100 mg Witepsol H15 1050 ma 1050 ma 2000 mg 2000 mg ~ ''' ' To mea~ure antlbiotic absorption into the bloodstream, blood ~ampl-~ wer- taken trom the femoral region of each baboon, u~ing heparlnized 3~ yringe~, pcior to antibiotic ad~ini~tratlon and at 15, 30, 60, 120, 240, 360 and 480 minute~ after antibiotic admini~tration. The withdrawn `~` cam~le~ were centrifuged at 12,000 rpm for one minute and ~` bioassayed by the previously de~ccibed Bioassay of Plasma ~-8ample~ method. The results are presented in Tables 3 and 3A:
:
:
': ' ;~.. ~'' ~ ~:
202~87 TABLE ~
~ , Antlbiotlc Bioavai labl 1 lty and CmaX Ranqe in Baboons Aftvr R~ctal Adlllnistration ~ ;
~Ith 2~nponont ~bsorptlonControl~o Absorptlon Enh~ncor Syst~ ~Fonnulatlon C) Enhancer System % Bloavall- Cm~x Rang-% Bioavall- C~ Rang~
AntibiotkabllitY mc~m1 abllitv mco/ml Ccftrlu~on~ 17.3 ~ 4.B 21.6 - 46.6 4.3 ~ 2.B 0.3 - 9.0 Cefotot n11.4 ~ 7.4 4.3 - 21.t4.9 ~ 3.1 2.4 - 10.1 ~ntibiotic Bioavai labi l it~
and C~x ~n9' In ~boons A~y R ct~ n!_~tion ~lth 3 r0ponont Absorp~lonControl-No Absorptlon Enh~nc~r S~t~ ~Fomul~tlon 0) Enh~ncrr Syct m % 8io~v~ Cm~X Rango S Blo vall- Cm~x Rang i ~ ~ Antiblotle abllltvmcc~ml abll!tv mca~ml Co-triuton~ lt.l ~ 5.0 16.3 - 38.3 4.3 ~ 2.B 0.3 - 9.0 Cofototan 24.1 ~ 12.B 2.5 - 61.5 4.9 ~ 3.1 2.4 - 10.1 ~0 -, ' ' 202~8~7 By way of illustration, ~ome ~uitable 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 descciption can be substituted, in appropriate amounts, without departing from the scope of the invention.
ExamD l e 1 ' 10 Oral Pormulation (Hard Gelatin Capsule) ma/caDsule 16 Inaredients Ceftriaxone Sodium~ 120 mg 300 mg 120 mg 300 mg ~abrasol 90 mg 225 mg 90 mg 225 mg Sodium caprylate -- -- 40 mg 100 mg 20 Ca~rylic acid 80 mg 200 mg 40 mg 100 mg Wite~sol H15 84 ma 210 ma 84 ma 210 ma 374 mg 935 mg 374 mg 935 mg ~ Eguivalent to 100 mg and 250 mg, respectively, of free acid Procedure The base (Witepsol H15) i8 warmed to 55C and the absoeption enhancer system components are added to the melt ~` 30 `with mixing. The melt is then cooled to 45C and the drug (ceftriaxone sodium) is added to the molten mass and mixed .
2 0 2 ~ 7 until uniformly distributed and free of any aggregates. The mass is homogenized, if nece~sary, to obtain a uniform suspension. The suspension is then ~illed into capsules and allowed to cool and congeal. The capsules are sealed with a 6 gelatin band and coated with an enteric polymer (PVAP).
A~proximately 8t of enteric coating is applied.
~ . ~
ExamDle 2 Oral Formulation -(Soft Gelatin Capsule) ma/caD~ule ~ ;
Inaredients Co~triaxone Sodium~ 120 mg300 mg 120 mg 300 mg ;
Labcasol 90 mg 225 mg90 mg 225 mg Sodium caprylate -- -- 40 mg 100 mg ; Caprylic acid 80 mg 200 mg40 mg 100 mg 20 WiteP~ol H15 84 ma 210 ma84 ma 210 ma 374 mg 935 mg374 mg 935 mg ; ~, . ;:i, ., Eguivalent to 100 mg and 250 mg, respectively, o~ ~ree acid i ~
.;
Procedure The base (Witepsol N15) is warmed to 55C and the -~
absorption enhancer system components are added to the melt ;~ 4;~
with mixing. The melt is then cooled to 45C and the drug ` ~ 30 `~ce~triaxone sodium) is added to the molten mass and mixed ;~
until uniformly distributed and free o~ any aggregates. The ~: ~"','.. ' .'~'',~,,''`'`.' ' ' .' ' .~. . -.
202~
:
mass is homogenized, if necessary, to obtain a uniform su~pension. 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) ' 10 ma/dose Inaredients Ceftciaxone Sodium* 150 mg 300 mg150 mg300 mg 16 Labra8ol 90 mg 180 mg90 mg 180 mg Sodium caprylate -- -- 40 mg ao mg Caprylic acid 80 mg 160 mg40 mg 80 mg Witepsol H15 150 mq 300 ma150 ma300 ma 470 mg 940 mg470 mg940 mg Equivalent to 125 mg and 250 mg, respectively, of free acid ~rocedure The base ~Witepsol H15) iB warmed to 55C and the absorption enhancer ~ystem components are added to the melt with mixing. The melt is then cooled to 45C 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 spray chilled for conversion ., . .. . , . ,.. -. .. .. , .: . .. ..
2~2~87 - 25 - ~ :
into micro6pheres. The microspheres are placed in a capsule : ,~
shell and coated with an enteric polymer as described in Example l.
' 10 :; ";'"
` .
' .~; ,.. :, '~.` ~ '' `~ "'' -:
, . . .
'' .' " ," ,.
,, i, ,''~" . '"
"",."'' ,' , 36 '''~,' ' ',' ' ~ 202~87 f~alDlQ 4 - RQctal f~ latlon (Suppos~tory) In~rQdl~nts m~/suD~osltorv C~ftrl~ion~ Sodlu~* 120 mg 300 rg 600 mg 120 mg 300 mg 600 mg L~r,tsol 250 mg 250 mg 250 mg 250 mg 250 mg 250 mg Sodiu~ capryl~tQ -- -- -- 100 mg 100 mg 100 mg C~pryl1c ~c~d20a mg 200 mg 200 mg 100 mg 100 mg 100 mg ol H15 1430 m~ ~ ~ 1430 m~ ~3~ ,~
2000 mg2000 mg 2aoo mg 2000 mg 2000 mg 2000 mg .
15 ~ Equlv~l~nt to lOO mg, 250 mg ~nd S00 mg, rQsp~ct~vQly, of frQ cld Procedure The base tWitePsOl H15) i8 warmed to 55C and the absor~tion enhancer system components are added to the melt with mixing. The melt is then cooled to 45C and the drug (ce~triaxone ~odium) is added to the molten mas~ and mixed until uniformly distributed and ~cee o~ any aggregates. The mass 18 homogenized. i~ nece~sary, to obtain a uni~orm ~us~ension. The sus~ension i~ then filled into suQpository shell~ and allowed to cool and congeal.
' ' ;' ':
,: 30 ' ' '
, . ...................................... .
.
RAN 4600/62 .
This invention relates to pharmaceutical compositions compeising ~a) an antibacterial compound and (b) an absorption enhancing amount of an absorption enhancing ~ -~
system made up of (l) a polyoxyethylene glycol - C6 to Cl~ carboxylic acid glyceride ester and (Z) a C6 to Clb carboxylic acid, with or without a C6 to Cl8 `~-carboxylic acid salt. Optionally, a pharmaceutically inert carrier can also be included.
:,., :., The term ~polyoxyethylene glycol-C6 to Cl8 16 carboxylic acid glyceride ester~ as used in connection with thi~ invention refers to those reaction products derived from the co-reaction of polyoxyethylene glycol (or polymerizable precursor thereof, such as ethylene oxide) with a C6-Cl8 carboxylic acid and glycecol or with a C6-Cl8 carboxylic acid glyceride or glycerides.
Re~ulting ~rom such reaction~ are, ty~ically, mixtures of a ~olyoxyethylene glycol-C6 to C18 carboxylic acid ~;
glyceride e~ter ~e.g., PEa-glycerol-caprate, pEa-glycer caprylate or PEG-glycerol-caprylate/caprate), a polyoxyethylene glycol-C6 to C18 cacboxylic acid ester te.g., PEG-caprate, pEa-caprylate or pEa-caprylate/caprate)~
and a glyceryl-C6 to Cl8 carboxylic acid ester (e.g., glyceryl mono-, di- or tricaprylate, glyceryl mono-, di- or ^ --tricaprate or glyceryl mono-, di- or tricaprylate~ caprate), ;
a8 the principal components.
More s~ecifically, it has been discovered that the above-identi~ied absorption enhancing ~ystem functions to lncrease the extent of absorption of antibacterial compounds through mucosal tissue and into the bloodstream. This Grn/27.6.90 ;. ' ~,'. ~'' ' .
~ 2~2~7 invention thus promotes the absorption and provides adequate blood levels of antibacterial compounds which, when administered without the absocption enhancer by means other than parenteral, are only poorly absorbed or not absocbed to any appreciable deqree. The preparation and use of a greater vaeiety of dosage forms for such compounds are thus enabled. The invention also eromotes 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.
16 The invention includes oral and rectal types of pharmaceutical ~reparations containing effective amounts of an antibacterial compound and an absorption enhancing system in accocdance with the present description, with or without an inert carrier and pharmaceutically acceptable adjuvants.
The terms "antibacterial" and l'antibiotic~ are used intecchangeably throughout this disclosure to refer to bacteeicidal or bacterio~tatic compounds which have been metabolically deri~ed from a microorganism, synthetically 2S ~repared 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 moderaeely absorbed upon non-in3ected or non-infused administration.
However, this lnvention finds its greatest usefulness when employed to enhance the absorption and bioavailability of 3S antibiotics which, for the most pact, can be effectively administered only by in3ection or in~usion due to non- or ' ~ .
~'~
,.' ' ~. :~
2~2~87 :
_ 3 -poor absorbability via other routes of administration.
Among the most preferred antibacterial compounds suitable for use as the therapeutic 6ubstance 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 ' "
'10 1 1 `'' D--N
O
which can be substituted at various positions on the ring and/or ~used 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 ~ormula ~2 in which al is hydrogen or optionally substituted alkyl, R2 is S03-M+ where M+ is a proton or cation, R3 is an `acylamino group or hydroxyalkyl, or Rl and R2 together with the beta-iactam (azetidinone) ring to which they are bonded re~resant 202~g~7 R~
o in which X is -S-, -O, -SO-, -SO2, -CH2 or -CH(CH3) and Y is group . ' C~3 \ / or I or / \ C~3 ~ Z .
/ COOE
C~l COOE
",:
,~4 ~ :`
: COOE
, .., .:
2~ ~
:: in whic~ R4 is a substituted thio group such as ethylth1o, 2CH2NH2' :~
-SCH2CH2;, -SCH2CH~OCNH2. '~i~CONMe~
or an o~tionally substituted lower alkyl group such as aminom-thyl, acylaminomethyl, 3~ ' .'"';'".''"
. . ......
,, ""
,., ., ~ ,. .", ~ 2~2~7 -... .
_ 5 -~ ' ' o~ - ', or a substituted oxy group such as carbamoyloxy (-O~H2), the carbon atom which carries the -COOE group is bonded to the nitrogen atom of the beta-lactam eing, Z is hydrogen, halogen, alkoxy or CH2T, with T denoting hydrogen, alkyl :
-CO-O-, pyridLnium, carboxamidopyridinium, aminopyridinium, carbamoyloxy, azido, cyano, hydroxyl, the group -S-phenyl which can be ~ubstituted or the qroup -S-het wherein l'het"
is an optionally substituted 5- or 6-membered heterocyclic eing, and E i~ hydrogen, a pharmaceutically acceptable ester group or a salt-forming cation.
Exam~les of the 5- or 6-membered heterocyclic rings encompassed within "het" above are the ~ollowing:
N--N N N N N : ; .
~S~ CHI ~ N ~N~ :
CH3 CH2 CH2N~CH3)2 2~5 :
H :
_<--N ~--IN~\N CH3~ ~N~
Es~ecially preferred beta-lactam antibiotics and their 36 ~harmaceutically acce~table salts, esters and hydrates include ceftriaxone, a cephalosporin described in U.S.
Patent No. 4,327,210 (Montavon et al.); carumonam, a 202~~7 monocyclic beta-lactam described in Eucopean Patent No. EP
73061: piperacillin, a penicillin described in U.S. Patent No. 4,11Z,090; cefamandole, a cephalosporin described in U.S. Patent No. 3,641,021; and cefazolin, a cephalosporin described in U.S. Patent No. 3,516,997, the disclosures of all of which are incocporated herein by reference. Further included are cefoxitin, cefmetazole, cefotetan, moxalactam, eefuroxime, ceforamide, eefoperazone, eeftizoxime, cefotaxime, eefmenoxime, eeftazidime, cefsulodin, cephalexin, azloeillin, penieillin G, temocillin, sulbenicillin, ticarcillin, mecillinam, amoxicillin, methicillin, carbenieillin, thienamycin, N-foemimidoyl~hienomycin, sulbactam and azthreonam.
Also included within the seope of this invention are aneibioties other than the beta-laetams, for exam~le, vaneomyein, the absor~tion and blood levels of whieh are improved by use with the deseribed absorption enhaneing systems.
':
Absorption enhancing system component (b)~l) may be the produet of an sterifieation reaetion between a polyoxyethyl-n- glyeol, qlyeerol and one or more straight or branehed ehain C6 to Cl~ earboxylie aeids, preferably a monofunetional aeid or aeids. Alteenatively, eom~onent ~b~tl) may be ~cepared by oligomerizing or polymerizing ; ;
ethylene oxide in the presenee of an ester of glyeerol and ; one or more of sueh C6 to Cl~ carboxylie acids ~glyceride esters). Still another route, and the preferred one, is by co-reacting the glyceride ester or esters~ with a ~ "~
fully ~re-formed polyoxyethylene glycol under condition~
sufficient to achieve alcoholysis.
Aceording to a particulae ~referred ~rocedure, involving alcoholysis, a reaction vessel is charged with stoichiometeic quantities of a glyceryl-fatty acid ester or esters and a polyethylene glycol. The vessel iB closed and ~''"''' ''"'~
2~2~7 : .:
heated at atmospheric pressure to 200C, with continuous stirring commenced at 70C. for a period of 12 to 24 hours or until the reaction i8 completed. The vessel is allowed to cool and the reaction product is then separated from the reaction mixture by filtration.
Examples of C6 to C18 carboxylic acids, saturated or unsaturated, which are useful for the preparation of absorption enhancing system component (b)(l) 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 1S f absorption enhancing system component (b)(l) is, typically, a medium to high molecular weight material, ~referably having a number average molecular weight in the range from about 200 to about lSOO, and more preferably from about 300 to about 600.
' ""
A material which is suitable for use as absor~tion enhancing system com~onent (b)~l) will most ~refecably have the ~ollowing characteristics~
Organole~tic Pro~erties:
Appearance: clear oily liquid Odor: faint Color: pale yellow to yellow Physical and Chemical Properties:
~ 2û24~87 : ~
Acid Value 0 2 - 0 6 Sulfated ash less than 0 05%
Saponification index 85 - 105 Iodine index less than Z
Moisture content less than 0 05%
Free qlycerin content appcox 2%
appcox 6 to 8 Denslty (dq ) 1 062 - 1 068 g/cc aesractive lndex (nD) 1 458 - 1 462 ' 10 '~ ' " '~ "
Suitable absorption enhancing system components ~or use --~ -as (b)(l) in this inYention which are commercially available are LA~aA80L, produc-d by aatte~osse Corpocation, Pacis, France (P~G-~ ca~rylate/caprate glyceride estecs), and 1~ 80~T~aEN 767, ~roduced by Dynamit Nobel, West Germany (PEG-6 i`
; ca~eylat-/ca~cat- glycerid- e~ter~
~ The C6 to ClEi caeboxylic acid Or absorption i `~r '~ enhancing ~y~t-m com~on-nt (b)(2) i~ derived from an -5~ æo all~hatlc cacboxyllc acld, which may be ~traight or branched chain ~xam~ includ- ca~roic, ca~rylic, ca~ric, lauric, yrl~tlc, ol-ic, ~almitic and ~tearic acids Mo~t Savoced ;;;
tor th- ~u~or-- oS~thl~ lnY-ntion i~ oa~cyllc acid 2~ ~ Th- C6 to Cl~ carboxyllc acld ~alt, Which optionally `
la am~loy-d with th- acid, aan b- ~re7ared in a conventional minn-r and u-ing known techniguei by reacting the acid with'~A'':7''''.'''~:.i' ~!,D ;`~I a~ba-- ha~ing~a non-toxic, ~har~acologically and ~harmaceutically acce~table cation In genecal, any base which will ~orm a salt with a carboxylic acid and the ha&~àcological ~ro~er;tie~ Or which will not cause an ' advelB- ~hy~iiological!eSSect when ingested by or otherwi~e ;
ad~inl~t-r-d to a waem-blooded ani~al i- suitable Such l~if,--ba~-r thur inalude, ror exa~le, alkali metal and alkaline ~arth metal hydfcoxide~ or carbonate~, such as sodium ~ hydcoxide, ~otas~ium hydroxide, calclum hydroxide, ~otas~ium iln ; carbonate, and the like Particularly ~ce~erred for this ; ,",, , ;~:
~',.'', . ""~ ~ ' i'':
2~2~8~7 _ 9 _ invention are sodium salts, chiefly becau6e of their ready availability. Sodium caprylate is especially preferred.
The C6 to Cl8 carboxylic acid salt is useful as a stabilizing agent for the C6 to Cl8 carboxylic acid, and is especially de~irable in formulations where ceftriaxone is present as the antibiotic.
The relative proportions of the components which comprise the absorption enhancing system can be varied to achieve optimum results for a particular embodiment of the invention. Por the two-component absorption enhancer system, prefecably, component (b)(l) is present in an amount from about 20 to about 80 percent and the carboxylic acid is 16 present in an amount from about 80 to about 20 percent, based on the total weight (lOOt) of these two components comblned. A more preferred embodiment will comprise from about 40 to about 60 percent of component (b)(l) and from about 60 to about 40 percent of the carboxylic acid, based on the total weight of the two components. Still more peQte~red are those absorption enhancer systems consisting ot about 50 pereent of com~onent (b)(l) and about 50 percent ot the earboxylie acld, based on the eombined weight of the two eomponents.
Preferably, for the three-eomponent absorption enhaneer system, eomponent (b)(l) is present in an amount from about 20 to about 80 pereent, more preferably from about 40 to about 60 percent, and most preferably about 50 percent, based on the total weight (100%) of the three absorp~tion enhancer system components combined. The carboxylic acid preferably is present in an amount from about 10 to about 40 pereent, more preferably from about 15 to about 25 percent, and most prefecably about 25 percent of the total weight.
The carboxylic acid salt is present in an amount from about lO to about 40 percent, more preferably from about 25 to about 35 percent, and most preferably about 25 percent of A,''.,~` . ,' . ' ' . . . . ', ` ' . , ., . . . ` ' , .. , . , .,, . ' . ,: , .. . ' 202~887 :
., .
the total weight.
The effective amount of the absoretion enhancing system, component (b), in the composition of this invention will 5 vacy depending on such factors as the particulae -antibacterial compound being employed and its amount, as well as the age of the sub3ect being treated.
In general, for oral dosage form compositions of this 10 invention, it i8 preferred to employ from about ;
50 milligrams (mg) to about 1000 mg, and more preferably from about 100 mg to about 500 mg of the absorption enhancing system, Cor each unit dose of the compo~ition.
These compo~itions will usually eontain the antibacterial 16 compound in amount~ from about 10 mg to about 500 mg, and more usually from about 50 mg to about 250 mg, pec unit dose.
Rectal dosage form com~ositions in aecordance with this ~; ~
invention will usually eontain from about 25 mg to about ~` ` `
1500 mg, more preSerably feom about 100 mg to about 500 mg of the absorption enhancing system, for eaeh unit dose of th- eompo~ltlon. Sueh eomposltlons wlll usually contaln the antlbaeteclal eompound ln amounts from about ~0 mg to about ~`~ 3000 mg, and more usually from about 100 mg to about ~ , 2B l500 mg, per unlt dose.
~; The term ~unit do~e~ is used here in the eonventional , ~ ;-sense to mean a single applieation or administration of the ` ;~
drug to the sub3eet being treated in an amount as stated above, but it 8hould be understood that the amount ean be glven in the form of a single pill, tablet, eapsule, U~uository~ etc., or alternatively, in multiples of two or more of such dosage unit~ with the total adding up to the stated amount of drug.
The described antibaeterial eompound and absorption enhaneing ~ystem, respeetively, can be incorporated in a ', ~; ~ `' .
2~2~
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 of mono-, di- and triglycerides of C12 to C18 natural saturated fatty acids, preferably vegetable fatty acids having an even number of carbon atoms (C12, C14, C16, etc.). E6pecially suitable and preferred are the pharmaceutical bases of Dynamit Nobel having the trade 16 de~ignation ~WITEPSOL~.
Still other pharmaceutically compatible carrier mate~ials may be employed as desired and depending upon pacticular requirements, the selection of which is within the knowledge of those skilled in the art.
If utillzed, the vehicle will generally be present in those amounts which are conventional for pharmaceutical carrier materials and which can be reasonably and safely 2~ ad~ini~tered.
The preferred method of orally administerinq 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 i~ 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 compcund mixed with the -, , 2~2~7 ab60rption enhancing system which may thereafter be encapsulated in an enteric coated capsule.
: ''' .
Usage of enteric coating materials in this manner serves to peotect 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, resi~tant to the gastric fluid and is unaffected by it but di~solves in the intestinal fluid to cause release of the drug.
The effec~iveness of particular enteric coating materials can be measured using known USP procedures. By 16 way of illustration, suitable enteric coating materials for purpo~es of this invention include but are not limited to the following:
cellulose acetate phthalate cellulose acetate trimellitate hydroxypro~yl methylcellulose phthalate hydroxy~ro~yl methylcellulo~e ~hthalate succinate ~olyvinyl acetate phthalate ~
` methacrylic acld -methacrylic acid ester~ -: ~ " ', .' These enteric coating materials may be applied with or ~~
without plasticizers, such as acetylated glycerides or diethylphthalate, usinq methods kr.own to those skilled in ! 30 the art.
.," ~,., .:.::
The ~ercentage of enteric coatlng a~plied is usually b~tween about 1 and about 10 percent by weight, or more, and most desirably from about 2 to about ~ percent by weight, 3S based on the total weight of the unit dosage form, i.e., the "
total capsule or tablet weight. Examples of suitable . ~, ~,'~', ',, ~ 202~8~ :
.., enteric coating formulations are given below.
Enteric Coatina Formulations S -- .
Ingcedients % W/W
. ...
PreDaration A:
Hydroxypropylmethylcellulose phthalate (HPMCP) 5.0 Triacetin 0-5 Methylene chloride 47.25 15 Denatured alcohol 47.25 PreDaration B: .
HPMCP lO.o 20 Titanium dioxide 0.2 Trlethyl citrate 1.5 .
Acetone 44.15 Denatured alcohol 44.15 P~eDaration C:
Cellulo~e acetate phthalate (CAP) 8.5 Diethyl phthalate 1.5 ~-Titanium dioxide 0.2 ! 30 IAcetone 4'4-9 Denatured alcohol 44.9 2~2~&.~7 Preparation D:
Polyvinyl acetate phthalate 5.0 Acetylated glycerides 0.8 5 Methylene chloride 47.1 Denatured alcohol 47.1 , PreDaration E: . .
,' ' :' ' "":
10 Methacrylic acid or methacrylic acid ester (Eudragit S or L, 8.0 Rohm Pharma, GM8H, Wetterstadt, ::
west Germany) '', ~, '' ',, ' Triacetin 1.0 . ::
15 Acetone 45.5 Anhydrous alcohol 45.s Oral dosage form compositions in accordance with this invention can also be formulated to additionally contain conventional additives or sup~lementary ingredients, in the usual amounts for such materials. By way of illustration, :
such additi~es or su~lements include thickening agents, such as silicic acid (for instance, the trade designated "Aerosil~' products); bentonites: colloidal clay:
X5 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 . ;~
30 (for instance, stearic or palmitic acids, or stearic or ~ ;
cetyl alcohols): waxes: monoglycerides of saturated or unsaturated hiqh fatty acid~ such as stearic acid, ~almitic acid or oleic acid: gelling agents, such as alumlnum steaeate: dispersing agents, such as ionic, non-ionic or cationic surfactants: emulsifying agents, such a~ lecithin, and 80 forth.
: ':
.'', ~ 202~8~
- 15 _ The compositions of this invention can also contain pharmaceutically acceptable adjuvant6, such a6 binders or lubricant~i foc tabletting, stabilizinq agents, antioxidant6, flowing agents (to enhance pourability or flowability during pcocessing)~ pre6ervative6, flavoling agent6, coloring agents and bu~fering agents. Any of the6e can be selected ~eom among materials known for such purpose6 and u6ed in conventional amounts.
In vivo tests were utilized to evaluate the enhanced mucosal tis6ue absorption of antibiotics admini6tered in accordance with this invention.
IN VIV0 tRATS) - ENTERAL
Adult Sprague-Dawley female rats tCharles River Breeding Laboratories, Kingston, New York), weighing about 250 grame each, were fasted overnight and anesthetized with metofane.
With each rat, an incision wa~ made on the ventral surface to ex~o~e the intestine. Administration of an antibiotic wa~ carried out using a solution dosage form. The solutions were QreQared by dis~olving antibiotic in water with or without absorption enhancer 80 as to deliver 20 milligrams per kilogram, appeoximately 5 mg pec cat.
2~ ~
Each solution of antibiotic in water was administered ~ -enterally by in3ecting with a syringe into the duodenum directly below the pyloric valve. For purposes of comparison, the solution was alternatively adminieitered ;~
~intcavenously by in3ecting with a syringe into a tai!l vein.
a LeYel~ of Antibiotic in Rat~
Tbe concentration of antibiotic in rat plasma wae 3S determined at various time intecvals aftec intcavenous oc entecal administration. Blood eamples were collected from the tail of each test animal prior to administration of the ,'.~' ..','':': ~'.
'~ ,.: .~ ' ' " 202~87 :
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 ~he plasma was withdrawn and frozen until assayed. -:.
: .
~ioassaY of Plasma SamDles Most of the antibiotics tested had exhibited some degree of protein binding when drug-seiked rat plasma was assayed against drug in H20. Any antibiotic not bound by plasma was diluted in H20 and assayed against standards prepared in H20. For bound antibiotics, the influence of protein binding wa~ negated by diluting all standards and samples in pooled rat plasma. In the case of ceftriaxone and ~ ~.
16 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 H20. Antibiotic levels were assayed on ~ :
nunc plates employing the appropriate agar seeded with : :
20 bacteria, as listed below in Table 1. ..
.
2 0 2 ~ 8 ~ 7 ~ ~
Ass y RangQ of Standard 3ioassay Volume Antiblotlc Or~anlsm Curv~s ~mcc~ml~ ~Qdla (mcl) C~rtrlPu~n E coll 1346 32-1 AA~12 20 Amp~clllln ~ lut~ ~TCC 9341 0-0 25 AA~l 20 C f~m~ndol ~ lute~ ATCC 93-1 32-1 AA~l 20 C fot~lm~ E eoli 1346B 0 25 or 16-0 5 AA~l 20 C fo~1t1n S ur us rB21B6 64-4 BHI3 20 C~ftrl~on~l E eoll lS 6 ~ 0 125 ~A~l 20 C fu olln S ~ur u~ ATCC 2S923 32-1 A~l 50 B subtlli~ Dpor s 32-2 A~l 50 Act~ E col~ 1346 S0L1 56 AAJl 50 P nic~llln Gl ~ lut~ ATCC g341 ~-0 5 AA~l 20 V~ncorycln B c r us AT0C 1177B 64-2 ~35 50 i ~
', '' " '~ " .
1 Antibiotic~ i?cotein bound in rat ~la~a AA~l . antibiotic agar ~1 (Dl~co) HI Brain H-art In~usion M-dia ~Dieco) MH . Muell-e Hlnton Agar (Di~co) ;;
AA~ . antibiotic agar ~ ~Di~co) mcg~l . miceogcams i?-r mllliliter cl . ~icrolit-rs The i?lates were incubated overnight at 37C and the zone~ ;
o~ inhibition were read to the nea~e~t 0 1 mm Calculation~
SO ~were made u~ing an autoas~ay machine (ailes Scientific, l ;
Inc , New York) For re~erence, see J~ V Bennett et al , ; ~;
A~lied Microbiology ~, 170-177 (1966) ,;
, ~ ,., .. ~
The results are ~re~ented in Table Z ;
, ''~' '. "", ;. . . ~
:. , ,..- ....
~;~
202~7 _18 _ TA~LE 2 ENTERAL ABSORPTICN IN RATS -~i~h and ~ithout Absorp~ien Enhaneers Doso ~ S m~/O S ml Cm3x (microarams p~r millilitQr) ~Control) Labrasol ~Labrasol ~ Caprylit Acid Antlbiotle ~ator CaPrvlle Aeid~ Sodium Caprvlat~*~
C~ruror m 0 13 6 ~ 2 9 10 9 1 1 4 CofamandDlo1 3 ~ 2 55 4 l S !s S ~ 6 8 C~fuolln 0 - 17 5 ~ S 7 cQfoxltln O - 12 B ~ 1 7 C~fo~etan 0 1? 8 4 9 20 4 ~ 4 9 ~e~ e~am O - 15 8 1 1 3 Ponleillin G 0 5 ~ 0 1 7 2 0 7 2 9 ~ 1 6 Vaneomyeln2 9 0 6 8 0 2 3 5 3 2 1 C~f~rl~xon~2 4 ~ 1 9 57 0 ~ 10 252 2 ~ æ.s ~lght Ratlo of L~Drasol C~Drylle Aeld ~as 2 1 ~*~lght Ratlo of LuDrasol C4prylle Aeld Sodlum C4Dryla~o ~as 4 1 1 ~ ' '".
202'18~
IN VIVO (DOGS) - ORAB
Male beagle dogs weighing approximately 10-14 kilograms were used in this study The dogs received Z or 3 hard shell enteric coated capsules orally Each capsule contained either of the following formulations A B
Cefteiaxone sodium salt~315 mg 315 mg Babrasol 225 mg 225 mg Caprylic acid 200 mg loO mg Sodium caprylate -- 100 mg Witep~ol H15 210 ma 210 mc 950 mg 950 mg ; ~ `
~315 mg o~ ce~triaxone sodium salt is eguivalent to 250 mg o~ ce~teiaxone as ~ree acid plu8 5% excess Enteric coating ~olyvinyl acetate phthalate (approximately ~% of total capsule weight) Blood pla~ma concentratlon~ of ceftriaxone were determined prlor to admini~tration and at 10, 20, 40, 60, 120, 180 and 240 minute~ a~t-r admlni~tratlon M-a~urement~ were made by withdrawlng blood at th-~- tlme lnterval~, separatlng the ;~ ~la~ma, deprot-lnlzlng, and a~aylng by Hlgh Performance lquid Chromatography (HPBC), reverse phase method, or by the !` 1 ; previou81y de~cribed Bioassay of Plasma Samples method !~ 1 30 i The results were 27 7 ~ 12 7% Bioavailabllity and 10 to ;
39 5 mcg/ml Cmax Range for Formulation A, 31 0 ~ 19 8% ;
Bioavailabllity and 3~ 6 ~ 23 2 mcg/ml Cmax for Formulation B, and Ot Bioavailabillty and O mcg/ml Cmax for the control tceftriaxone ~odlum salt, 300 mg, in the ~ame enterlc coated 35 ca~ule, no absor~tion enhancer~) ;
. .
,~
F~
~ 2~2~7 ~
, ~
IN VIVO ~BABOONS) - RECTAL
Male and female adult baboons (PaDio anubis and PaDio hamadrYas), ranging in weight from 12 to 27 kilograms, were used in this ~tudy. The baboons were fasted overnight prior to administration of antibiotic, then sedated with ketamine hydrochloride by intramuscular in3ection prior to administration o~ the antibiotic. Suppositories made up of the formulation shown below were administered to the baboons and the rectal openings were then taped closed to prevent expulsion and leakage of the suppository mass.
C D
Antibiotic (active form) 500 mg 500 mg Labrasol 250 mg 250 mg Caprylic acid 200 mg 100 mg 8Odium caprylate -- 100 mg Witepsol H15 1050 ma 1050 ma 2000 mg 2000 mg ~ ''' ' To mea~ure antlbiotic absorption into the bloodstream, blood ~ampl-~ wer- taken trom the femoral region of each baboon, u~ing heparlnized 3~ yringe~, pcior to antibiotic ad~ini~tratlon and at 15, 30, 60, 120, 240, 360 and 480 minute~ after antibiotic admini~tration. The withdrawn `~` cam~le~ were centrifuged at 12,000 rpm for one minute and ~` bioassayed by the previously de~ccibed Bioassay of Plasma ~-8ample~ method. The results are presented in Tables 3 and 3A:
:
:
': ' ;~.. ~'' ~ ~:
202~87 TABLE ~
~ , Antlbiotlc Bioavai labl 1 lty and CmaX Ranqe in Baboons Aftvr R~ctal Adlllnistration ~ ;
~Ith 2~nponont ~bsorptlonControl~o Absorptlon Enh~ncor Syst~ ~Fonnulatlon C) Enhancer System % Bloavall- Cm~x Rang-% Bioavall- C~ Rang~
AntibiotkabllitY mc~m1 abllitv mco/ml Ccftrlu~on~ 17.3 ~ 4.B 21.6 - 46.6 4.3 ~ 2.B 0.3 - 9.0 Cefotot n11.4 ~ 7.4 4.3 - 21.t4.9 ~ 3.1 2.4 - 10.1 ~ntibiotic Bioavai labi l it~
and C~x ~n9' In ~boons A~y R ct~ n!_~tion ~lth 3 r0ponont Absorp~lonControl-No Absorptlon Enh~nc~r S~t~ ~Fomul~tlon 0) Enh~ncrr Syct m % 8io~v~ Cm~X Rango S Blo vall- Cm~x Rang i ~ ~ Antiblotle abllltvmcc~ml abll!tv mca~ml Co-triuton~ lt.l ~ 5.0 16.3 - 38.3 4.3 ~ 2.B 0.3 - 9.0 Cofototan 24.1 ~ 12.B 2.5 - 61.5 4.9 ~ 3.1 2.4 - 10.1 ~0 -, ' ' 202~8~7 By way of illustration, ~ome ~uitable 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 descciption can be substituted, in appropriate amounts, without departing from the scope of the invention.
ExamD l e 1 ' 10 Oral Pormulation (Hard Gelatin Capsule) ma/caDsule 16 Inaredients Ceftriaxone Sodium~ 120 mg 300 mg 120 mg 300 mg ~abrasol 90 mg 225 mg 90 mg 225 mg Sodium caprylate -- -- 40 mg 100 mg 20 Ca~rylic acid 80 mg 200 mg 40 mg 100 mg Wite~sol H15 84 ma 210 ma 84 ma 210 ma 374 mg 935 mg 374 mg 935 mg ~ Eguivalent to 100 mg and 250 mg, respectively, of free acid Procedure The base (Witepsol H15) i8 warmed to 55C and the absoeption enhancer system components are added to the melt ~` 30 `with mixing. The melt is then cooled to 45C and the drug (ceftriaxone sodium) is added to the molten mass and mixed .
2 0 2 ~ 7 until uniformly distributed and free of any aggregates. The mass is homogenized, if nece~sary, to obtain a uniform suspension. The suspension is then ~illed into capsules and allowed to cool and congeal. The capsules are sealed with a 6 gelatin band and coated with an enteric polymer (PVAP).
A~proximately 8t of enteric coating is applied.
~ . ~
ExamDle 2 Oral Formulation -(Soft Gelatin Capsule) ma/caD~ule ~ ;
Inaredients Co~triaxone Sodium~ 120 mg300 mg 120 mg 300 mg ;
Labcasol 90 mg 225 mg90 mg 225 mg Sodium caprylate -- -- 40 mg 100 mg ; Caprylic acid 80 mg 200 mg40 mg 100 mg 20 WiteP~ol H15 84 ma 210 ma84 ma 210 ma 374 mg 935 mg374 mg 935 mg ; ~, . ;:i, ., Eguivalent to 100 mg and 250 mg, respectively, o~ ~ree acid i ~
.;
Procedure The base (Witepsol N15) is warmed to 55C and the -~
absorption enhancer system components are added to the melt ;~ 4;~
with mixing. The melt is then cooled to 45C and the drug ` ~ 30 `~ce~triaxone sodium) is added to the molten mass and mixed ;~
until uniformly distributed and free o~ any aggregates. The ~: ~"','.. ' .'~'',~,,''`'`.' ' ' .' ' .~. . -.
202~
:
mass is homogenized, if necessary, to obtain a uniform su~pension. 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) ' 10 ma/dose Inaredients Ceftciaxone Sodium* 150 mg 300 mg150 mg300 mg 16 Labra8ol 90 mg 180 mg90 mg 180 mg Sodium caprylate -- -- 40 mg ao mg Caprylic acid 80 mg 160 mg40 mg 80 mg Witepsol H15 150 mq 300 ma150 ma300 ma 470 mg 940 mg470 mg940 mg Equivalent to 125 mg and 250 mg, respectively, of free acid ~rocedure The base ~Witepsol H15) iB warmed to 55C and the absorption enhancer ~ystem components are added to the melt with mixing. The melt is then cooled to 45C 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 spray chilled for conversion ., . .. . , . ,.. -. .. .. , .: . .. ..
2~2~87 - 25 - ~ :
into micro6pheres. The microspheres are placed in a capsule : ,~
shell and coated with an enteric polymer as described in Example l.
' 10 :; ";'"
` .
' .~; ,.. :, '~.` ~ '' `~ "'' -:
, . . .
'' .' " ," ,.
,, i, ,''~" . '"
"",."'' ,' , 36 '''~,' ' ',' ' ~ 202~87 f~alDlQ 4 - RQctal f~ latlon (Suppos~tory) In~rQdl~nts m~/suD~osltorv C~ftrl~ion~ Sodlu~* 120 mg 300 rg 600 mg 120 mg 300 mg 600 mg L~r,tsol 250 mg 250 mg 250 mg 250 mg 250 mg 250 mg Sodiu~ capryl~tQ -- -- -- 100 mg 100 mg 100 mg C~pryl1c ~c~d20a mg 200 mg 200 mg 100 mg 100 mg 100 mg ol H15 1430 m~ ~ ~ 1430 m~ ~3~ ,~
2000 mg2000 mg 2aoo mg 2000 mg 2000 mg 2000 mg .
15 ~ Equlv~l~nt to lOO mg, 250 mg ~nd S00 mg, rQsp~ct~vQly, of frQ cld Procedure The base tWitePsOl H15) i8 warmed to 55C and the absor~tion enhancer system components are added to the melt with mixing. The melt is then cooled to 45C and the drug (ce~triaxone ~odium) is added to the molten mas~ and mixed until uniformly distributed and ~cee o~ any aggregates. The mass 18 homogenized. i~ nece~sary, to obtain a uni~orm ~us~ension. The sus~ension i~ then filled into suQpository shell~ and allowed to cool and congeal.
' ' ;' ':
,: 30 ' ' '
Claims (12)
1. A pharmaceutical composition comprising:
(a) an antibacterial compound;
(b) an absorption enhancing amount of an absorption enhancing system comprising (1) a polyoxyethylene glycol (PEG)- C6 to C18 glyceride ester and (2) a C6 to C18 carboxylic acid, with or without a C6 to C18 carboxylic acid salt; and optionally (c) a pharmaceutically inert carrier.
(a) an antibacterial compound;
(b) an absorption enhancing amount of an absorption enhancing system comprising (1) a polyoxyethylene glycol (PEG)- C6 to C18 glyceride ester and (2) a C6 to C18 carboxylic acid, with or without a C6 to C18 carboxylic acid salt; and optionally (c) a pharmaceutically inert carrier.
2. A composition according to claim 1, which is in an oral dosage form.
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 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 weight of the two substances combined.
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 C6 to C18 carboxylic acid is caprylic acid, and the C6 to C18 carboxylic acid salt is 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 R1 is hydrogen or optionally substituted 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 group 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, barboxamidopyeidinium, 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.
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, barboxamidopyeidinium, 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.
11. A composition according to claim 10, in which the antibacterial compound is ceftriaxone or a pharmaceutically acceptable salt, ester or hydrate thereof.
12. The novel pharmaceutical compositions as described hereinbefore.
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US40549489A | 1989-09-11 | 1989-09-11 | |
| US405,494 | 1989-09-11 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CA2024887A1 true CA2024887A1 (en) | 1991-03-12 |
Family
ID=23603936
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA002024887A Abandoned CA2024887A1 (en) | 1989-09-11 | 1990-09-07 | Pharmaceutical preparations |
Country Status (8)
| Country | Link |
|---|---|
| EP (1) | EP0418674A1 (en) |
| JP (1) | JPH03106827A (en) |
| AU (1) | AU6236090A (en) |
| CA (1) | CA2024887A1 (en) |
| HU (1) | HU207216B (en) |
| IE (1) | IE903285A1 (en) |
| IL (1) | IL95614A0 (en) |
| ZA (1) | ZA906186B (en) |
Families Citing this family (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US5136105A (en) * | 1991-03-28 | 1992-08-04 | Union Carbide Chemicals & Plastics Technology Corporation | Oxidation of terminal olefins to aldehydes |
| SI9400338A (en) * | 1994-08-31 | 1996-04-30 | Lek D D | Vancomycin hydrochloride suspensions for peroral use and for filling into soft ,gelatine capsules. |
| GB9516268D0 (en) * | 1995-08-08 | 1995-10-11 | Danbiosyst Uk | Compositiion for enhanced uptake of polar drugs from the colon |
| GB2318056B (en) * | 1995-08-08 | 1999-05-26 | Danbiosyst Uk | Composition for enhanced uptake of polar drugs from the colon |
| JP2007042005A (en) * | 2005-08-05 | 2007-02-15 | Toppan Forms Co Ltd | Email address collection method, information processing server, and email address collection system |
Family Cites Families (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4525339A (en) * | 1982-10-15 | 1985-06-25 | Hoffmann-La Roche Inc. | Enteric coated oral dosage form |
| EP0126348A2 (en) * | 1983-05-19 | 1984-11-28 | Kyoto Pharmaceutical Industries, Ltd. | Composition for rectal administration and method of promoting rectal drug absorption |
| CA1256799A (en) * | 1984-02-22 | 1989-07-04 | Walter Fuller | Suppositories |
-
1990
- 1990-08-06 ZA ZA906186A patent/ZA906186B/en unknown
- 1990-09-07 EP EP90117309A patent/EP0418674A1/en not_active Withdrawn
- 1990-09-07 CA CA002024887A patent/CA2024887A1/en not_active Abandoned
- 1990-09-07 IL IL95614A patent/IL95614A0/en unknown
- 1990-09-07 HU HU905823A patent/HU207216B/en unknown
- 1990-09-10 AU AU62360/90A patent/AU6236090A/en not_active Abandoned
- 1990-09-10 JP JP2239807A patent/JPH03106827A/en active Pending
- 1990-09-10 IE IE328590A patent/IE903285A1/en unknown
Also Published As
| Publication number | Publication date |
|---|---|
| EP0418674A1 (en) | 1991-03-27 |
| JPH03106827A (en) | 1991-05-07 |
| IE903285A1 (en) | 1991-04-10 |
| IL95614A0 (en) | 1991-06-30 |
| HUT56269A (en) | 1991-08-28 |
| ZA906186B (en) | 1991-06-26 |
| HU905823D0 (en) | 1991-03-28 |
| AU6236090A (en) | 1991-03-14 |
| HU207216B (en) | 1993-03-29 |
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Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| FZDE | Discontinued |