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Home , Cefazedone

United States Patent [191 [11] Patent Number: 4,582,830 Richardson [45] Date of Patent: Apr. 15, 1986

[54] PHARMACEUTICAL COMPOSITIONS Rybachuk, D. V. et al., Farm Zh, 1978, (3), 71-73, [75] Inventor: Betty L. Richardson, Harrow, (Abstract). England Rybachuk, D. V. et al., Farm Zh, 1978, (4), 87-89, (Abstract). [73] Assignee: Glaxo Group Limited, London, Sykulska, Z. et al., Farm Pol, 1966, 22, 510-4, (Ab England stract). [21] Appl. No.: 530,655 Hoevernaars, P. C., Pharm Weekly, 1965, 100, 1151-62, (Abstract). _ [22] Filed: Sep. 9, 1983 Sykulska, A., Acta Pol Pharm, 1965, 22, 133-39, (Ab [30] Foreign Application Priority Data stract). Kurchenko, I. N., Farm Zh, 1976, 31 (2), 86-87, (Ab Sep. 10, 1982 [GB] United Kingdom ...... 8225853 stract).

[51] Int. Cl.4 ...... A61K 31/545 Litovkina, E. G., Farm Zh, 1978, 12 (3), 123-7, (Ab [52] US. Cl...... 514/203 stract). [58] Field of Search ...... 424/246; 514/203 Parenteral Drug Association, Parenteral Dosage Forms, 1959-1963. [56] References Cited Remington’s Pharmaceutical Sciences, Philadelphia U.S. PATENT DOCUMENTS ‘ College of Pharmacy and Science, 1980, 1480-1481. Modern Pharmaceutics, G. S. Banker and .C. T. Rhodes, 4,128,715 12/1978 Sharp ...... 424/246 pp. 429 and 456. 4,160,829 7/1979 Heijboer et'al...... 424/246 4,258,041 3/1981 O’Callaghan et a1...... 424/246 Primary Examiner-Jerome D. Goldberg 4,329,453 5/1982 ' Brodie et a1...... 424/246 Attorney, Agent, or Firm-Bacon & Thomas FOREIGN PATENT DOCUMENTS [57] ABSTRACT 1380741 1/1975 United Kingdom . A solid pharmaceutical composition comprising one or more B-lactam in acid or amphoteric form in OTHER PUBLICATIONS association with at least one physiologically acceptable Whitter, T. D., Symposium on drug stability, 19th In base in the presence of a gaseous atmosphere containing ternational Congress of Pharmaceutical Sciences, 1959, a stabilizing amount of carbon dioxide at a concentra (Abstract). tion greater than that of atmospheric air. The composi , Freudenstein, H., J. Biol. Stand., 1978, 6 (3), 243-53, tions exhibit enhanced stability. A preferred (Abstract). for the compositions is or a hydrate thereof, Wisniewski, W., Math Naturwiss Reihe, 1967, 16 (2), and a preferred base is sodium carbonate or a mixture 243-45, (Abstract). . _ , thereof with one or more other bases. Rybachuk, D. V. et al., Khim Farm Zh, 1979, 13 (1), 85-86, (Abstract)._ 20 Claims, No Drawings 4,582,830 1 2 tions containing mixtures of antibiotics may for example PHARMACEUTICAL COMPOSITIONS contain two such antibiotics, such as a mixture of amox ycillin and or of and ?uclox This invention concerns improvements in or relating acillin. ' to pharmaceutical compositions. In particular, the in The B-lactam compounds will normally be present in vention relates to pharmaceutical compositions contain a form capable of reacting with a base, i.e. in an acidic ing B-lactam antibiotics. or amphoteric form, which may optionally be solvated B-Lactam antibiotics are often administered by injec e.g. hydrated. It will be appreciated that where compo tion as a solution in a sterile aqueous vehicle. The antibi sitions according to the invention contain more than otics are commonly amphoteric or acidic compounds one B-lactam antibiotic it is possible that only one of the which are relatively insoluble in water and are advanta antibiotic compounds is in an acidic or amphoteric geously present in such solutions as water-soluble salts form. formed with bases, e.g. the sodium salts. It has been B-Lactam antibiotics which may be particularly pre proposed to formulate B-lactam antibiotics with a solid ferred for formulating into compositions according to base such as sodium carbonate so that on dissolution in the invention include, for example, ceftazidime, cepha a sterile aqueous injection medium, a water-soluble salt loridine hydronitrate, , , cef is formed by reaction between the antibiotic and the sulodin, and V. base. This may be done for example, where no stable Bases which may be used in the compositions accord water-soluble physiologically acceptable salt of the ing to the invention include, for example, alkali metal antibiotic has been found. However, it has been found carbonates such as sodium or potassium carbonate; al that even such formulations can be unstable on large kali metal bicarbonates such as sodium bicarbonate; scale handling and subsequent storage even with exclu alkali metal or ammonium phosphates such as sodium sion of oxygen by using an atmosphere of nitrogen. phosphate; ammonium carbonate; guanidine carbonate; We have now surprisingly found that the stability of organic bases such as phenylethylbenzylamine, diben solid compositions containing a B-lactam antibiotic and 25 zylethylenediamine, ethanolamine, diethanolamine, N a base can be signi?cantly improved by formulating the _ methylglucosamine, N-methylglucamine, sodium glyci compositions with an atmosphere containing carbon nate, lysine, lysine acetate, tromethamine, guanidine dioxide. A marked effect on stability can be observed and arginine; and mixtures thereof. In general, the base even with gas mixtures, e.g. nitrogen, containing carbon component preferably includes at least one base capable dioxide at concentrations as low as 10% by volume or of reacting with carbon dioxide and water; thus, for even less. example, a carbonate may react in this way to form a Thus, the invention provides a solid pharmaceutical bicarbonate, or a strong organic base, such as arginine, composition comprising one or more B-lactam antibiot may react to form a carbonate. ics in acidic or amphoteric form in association with at A preferred composition of the invention contains least one physiologically acceptable base in the pres 35 ceftazidime, which may advantageously be present in ence of a gaseous atmosphere containing a stabilising the form of a hydrate e.g. the crystalline pentahydrate amount of carbon dioxide at a concentration greater described in British Patent Speci?cation No. 2063871, than that of atmospheric air. together with sodium carbonate, advantageously in an B-Lactam antibiotics which may be incorporated into anhydrous form. the compositions according to the invention include, for 40 The ratio of base to B-lactam antibiotic in the compo example, compounds such as cefaman sitions of the invention is desirably in the range of (0.8 to dole, , cephalexin, cephaloglycin, cephalothin, 6.0) equivalents of base to one equivalent of antibiotic cephapirin, cephradine, , , , and preferably about 0.9 to 4.021. In some cases ratios of , cefazoflur, cefazedone, , cefsulo base to B-lactam as low as 0.5 may be useful. As indi din, , cephacetrile, cephanone, , cated above, a mixture of bases may be used in which cephoxazole, , ', , one component is generally capable of reacting with cefoperazone, , cefotaxime, cefmenoxime, cef carbon dioxide and water. It may thus be convenient to tizoxime, , , , lamoxac use mixtures of sodium carbonateand bicarbonate. In tam, in the form of an acid addition salt, mixtures of bases the component capable of reacting e.g. the hydronitrate, ceftazidime, (6R,7R)-3-acetox 50 with carbon dioxide and water is preferably present in ymethyl-7-[(Z)-2-(fur-2-yl)-2-methoxyiminoacetamido] an amount of at least 0.05 equivalents per equivalent of ceph-3-em-4-carboxylic acid, (6R,7R)‘-7-[(Z)-2-(2 antibiotic. aminothiazol-4-yl)-2-cyclopropylmethox The amount of carbon dioxide in the compositions yiminoacetamido1-3-(l-pyridiniummethyl)ceph-3-em-4~ according to the invention may vary over wide limits. carboxylate, (6R,7R)-7-[(Z)-2-(2-aminothiazol-4-yl)-2 55 When the carbon dioxide is present in an atmosphere cyclopropylmethoxyiminoacetamido]-3-carbamoylox comprising a mixture of gases e.g. with air, the level of ymethylceph-3-em-4-carboxylic acid, and (6R,7R)-7 carbon dioxide will, of course, be substantially higher [(Z)-2-(1-carboxycyclobut-l-oxyimino)-2-(fur-2 than the concentration of 0.03% by volume normally yl)acetamido]~3-carbamoyloxymethylceph-3-em-4-car found in air. Thus, the atmosphere preferably contains boxylic acid; such as penicillin G, penicillin 60 at least 1%, more preferably at least 4% by volume of V, amoxycillin, ampicillin, , , carbon dioxide. In general, however, we have found , ?ucloxacillin, , , oxacil that the greatest stabilising effect is achieved with con lin, phenethicillin and ; clavulanic acid; centrations of carbon dioxide greater than about 10% such as N-formimidoylthienamycin; by volume. In practice, it may be convenient to use monocyclic B-lactams such as azthreonam; and mix 65 higher concentrations of carbon dioxide, such as 50% tures thereof. Antibiotics such as ceftazidime which or greater e.g. about 90% by volume. contain basic groups may also be in the form of their The amount of carbon dioxide present is preferably acid addition salts, e.g the hydrochlorides. Composi sufficient to combine together with the base with any 4,582,830 3 4 water present. The presence of water may arise by tions of the invention can be as little as a quarter of that adsorption from the atmosphere, abrasion of crystalline of a blend in a vial with a nitrogen headspace. hydrates or as residual solvent from the production The invention will now be illustrated in the following process. non-limiting Examples: The compositions according to the invention are preferably provided in sealed containers e.g. ampoules EXAMPLE 1 or vials or bulk storage containers. Ampoules or vials Formula per blend ‘ are conveniently such as to provide a unit dose of the Ceftazidime pentahydrate: 14.818 kg (on anhydrous active ingredient e.g. for constitution with a sterile vehi basis) cle for injection, such as pyrogen-free water. The dos Sodium carbonate (anhydrous): 1.725 kg age units will generally contain conventional amounts The ceftazidime pentahydrate was blended asepti of the antibiotic substance(s). For example, dosage units cally with the sodium carbonate in a powder mixer. may conveniently contain 50 to 2000 mg of the active Quantities of this blend equivalent to 250 mg anhydrous ingredient. The dosage of active ingredient employed ceftazidime were ?lled into glass vials. In each case the for adult human treatment will preferably range from vial headspace was purged with carbon dioxide and the 500 to 6000 mg per day depending on the antibiotic used vial was closed using a rubber plug and a metal overseal and the route and frequency of administration. applied by crimping. All operations were performed The invention also extends to mixtures of the compo under sterile conditions. nents occurring during blending, handling and ?lling The product may be constituted shortly before ad into sealed containers such as ampoules or vials. ministration by dissolving the powder in water for in The compositions according to the invention may be jections. prepared by bringing at least one acidic or amphoteric EXAMPLE 2 B-lactam antibiotic in solid form, at least one physiolog ically acceptable base in solid form and an atmosphere Formula per blend containing a stabilising amount of carbon dioxide at a Ceftazidime pentahydrate: 15.200 kg (on anhydrous concentration greater than that of atmospheric air into basis) association. For example, the B-lactam antibiotic and Sodium carbonate (anhydrous): 1.7695 kg the base, both in particulate form, may be blended to The ceftazidime pentahydrate was blended asepti gether in air to give a homogeneous particulate mixture cally with the sodium carbonate in a powder mixer with which is then ?lled into appropriate containers which a blanket of sterile carbon dioxide. Quantities of this are subsequently purged with carbon dioxide or a gas blend equivalent to 250 mg anhydrous ceftazidime were mixture containing it. Alternatively, the solid compo ?lled into glass vials. In each case the vial headspace nents may be blended together in an atmosphere com was purged with carbon dioxide and the vial was closed using a rubber plug and a metal overseal applied by prising carbon dioxide, and may if desired be subse 35 quently ?lled into containers also in an atmosphere crimping. comprising carbon dioxide. The product may be constituted, shortly before ad In a further method, one of the solid components is ministration by dissolving the powder in water for in ?lled into the container, followed by ?lling with the jections. other solid component without mixing (the so-called EXAMPLE 3 “double-?lling” method), the two ?llings optionally being effected in the presence of carbon dioxide. The Formula per vial containers may then, if necessary, be purged with car Ceftazidime pentahydrate: 260 mg (on anhydrous basis) bon dioxide. It will be appreciated that the compositions Sodium carbonate (anhydrous): 30 mg The ceftazidime pentahydrate and sodium carbonate prepared by this method will not comprise a homogene 45 ous mixture of the solid components. were accurately weighed into a glass vial and the head In a still further method, the containers may be ?lled space purged with carbon dioxide. A rubber plug was with a solution of the base which is then dried, e.g. by then inserted and a metal overseal applied by crimping. freeze drying, before adding the active ingredient and The product may be constituted shortly before ad purging with carbon dioxide. Alternatively, when the ministration by dissolving the powder in water for in base to be used is sodium carbonate, the containers may jections. be ?lled with sodium bicarbonate in dry form or in EXAMPLE 4 solution which is then heated to form solid sodium carbonate before adding the active ingredient and purg General Method ing with the carbon dioxide. 55 The antibiotic was blended with the base using in When the compositions are in powder form, it will be each case the quantities given in Table l. Quantities of appreciated that the carbon dioxide may be in the inter the blend equivalent to 250 mg of the anhydrous antibi stices between particles of the active ingredient and the otic were ?lled into glass vials. In each case the vial base as well as in any headspace above the solid compo headspace was purged with carbon dioxide. The vial nents. was then closed using a rubber plug and a metal over The ,B-lactam antibiotic and base starting materials seal applied by crimping. are preferably substantially free from water, other than TABLE 1 water of crystallisation. Weight Weight As indicated above, we have found that the stability Antibiotic (g) Base (g) of B-lactam antibiotic in the compositions of the inven 65 Ceftazidime 15 Sodium carbonate 1.500 tion may be surprisingly improved. For example, we pentahydrate have found that in storage tests at elevated tempera Cephaloridine 10 Sodium carbonate 1.61 tures, the rate of degradation of ceftazidime in composi hydronitrate 4,582,830 5 6 TABLE l-continued EXAMPLE 3 Weight Weight Formula per vial Antibiotic (g) Base (g) ‘ ' Cefoperazone 9 Sodium carbonate 0.89 5 (6R’7R)_7[(2)T2'(2'amm9th‘am1'4'yi)'?'?y°1°' cefotaxime 7 Sodium carbonate L14 propylmethoxyimmoacetamido]3-(l-pyr1dm1umme 9 Sodium carbonate 1.08 thynceph-ii-em Cefmenoxime 9 Sodium carbonate 1.49 4-carboxylate, bishydrochloridez 363 mg ' Ceftazidime l0 Guanidine carbonate 1.70 Sodium carbonate anhydrous; 65.5 mg 7 pentahydfm ‘ The cephalosporin antibiotic and the sodium carbon- ' iill’hi‘gsag‘mh draw ‘ 1(5) $2 10 ate anhydrous were accurately weighed into a glass vial cefgroxime y 10 Sodium carbonate 1:75 and the headspace was purged with carbon dioxide. A ' cephalothin 10 sodium carbonate L60 rubber plug was. then inserted and a metal overseal Compound A‘ 10 Sodium carbonate 1.49 aPPheq by cnmPmg Compound B+ 10 Sodium carbonate 2.27 15 I claim: Ceftazidime 10 Potassium carbonate 2.08 1. A solid pharmaceutical composition comprising an pentahyfir?te _ _ effective amount of ceftazidime in association with at 553K552‘; 15 A’gmme 4‘43 least one physiologically acceptable base in the pres- ' Cephoxazole 10 Sodium carbonate 1.27 .ence ofa. gaseous aimosphere S‘Qmtammg carbim. dloxlde cef?zoxime 9 Sodium carbonate L74 20 in sufficient quantity to stabilize the ceftazidime and Pencillin v - 10 sodium carbonate 2.27 present at a concentration greater than the concentra ‘Compound A - (6R,7R)-3-acetoxymethyl-7-[(Z-2-(fur-2-yD-2- “on of carbon @{Oxlde "1 atmosphemf am _ methoxyiminoacetamido]ceph-3-em-4-carboxylic acid. 2. A composition accordmg to claim 1 wherein the +C°T|1P°u?d B-<6R.7R)-7-l(Z)-2-(l-carboxycyclobut-wxyiminw- atmosphere contains at least 1% by volume of carbon 2-(fur-Z-yl)acetamid0]-3-ca.rbamoyloxymethylceph-3-em-4-carboxylic dioxide. acid. 25 .3. _ A composition. . according. to claim. 2 wherein. the atmosphere contains at least 4% by volume of carbon EXAMPLE 5 dioxide. . . . 4. A composition according to claim 3 wherein the A powder ‘.Jlend of ceftazidlme Rentahyqrate and atmosphere contains at least 10% by volume of carbon anhydrous sodium carbonate m a weight ratio of 10:1 30 dioxida was weighed into glass vials “.Sing a? target ?ll Weigh?“ 5. A composition according to claim 3 which con 1-333 8- The headspace of each V131 was purged Wlth tains from 0.8 to 6.0 equivalents of base to one equiva standard gas mixtures of carbon dioxide in nitrogen 161“ of ceftazidime. before being closed by using a rubber plug and a metal 6_ A composition according to claim 5 which con. overseal applied by crimping. The gas mixtures con- 35 tains from 0.9 to 4 equivalents of base to one equivalent .sisted of 20, 10, 8, 6, 4 and 2% v/v carbon dioxide in of ceftazidime. nitrogen. Vials were also filled using 100% carbon diox- 7- A Composition according to claim 1 wherein the idc_ base is arginine. 8. A composition according to claim 1 wherein the EXAMPLE 6 _ 40 base is an alkali metal carbonate. ;..Formu1a per blend 9. A composition according to claim 8 wherein the Ceftazidime pentahydrate: 1975 g carbm‘ate ‘5 S°d.“¥m carbml‘tte- . . Arginine: 525 g a 10.. A composition according to claim 1 wherein cef Sodium carbonate anhydrous- 19 73 g 45 mldlme ls m a hydrated form' . . ‘ ' . 11. A composition according to claim 10 wherein the v The ceftazidime pentahydrate was blended with the hydrate is ceftazidime pentahydrate. argmme and the sodufm carbonic “1 3 Powder mixer‘ 12. A composition according to claim 2 which con The blend was ?ned Into glass vlals’ usmg'a target ?n tains from 0.8 to 6.0 equivalents of base to 1 equivalent weight of 773. mg per vial. Then the vial headspace was of ceftazidime_ purged with carbon dioxide and the vial closed vusing a 50 13_ I A composition according to claim 3 which con. rubber plug and a metal overseal applied by crimping. tains from 0.9 to 4 equivalents of base to one equivalent The product was dissolved, as for administration, by of ceftazidime. the addition of 1.5 ml Water for Injections. ‘ i 14. A composition according to claim 12 wherein the base is arginine. EXAMPLE 7 55 15. A composition according to claim 12 wherein the Formula per via] . base is an alkali metal carbonate. ‘ _ ceftazidime pentahydrate: 1212 g 162A composition according to claim 13 wherein the Tmmethamine: Q2790 g base 1s sodium carbonate. . _ _ sodium carbonate anhydrous: 00121 g 60 17. Acomposition according to claim 14 wherein the ~ The ceftazidime penhtaydrate, tromethamine and ceftzzldlme 1S a .pFmahydmc‘ltF therecffi 15 h . h sodium carbonate were accurately weighed into a glass 1 ' ‘.A‘FOmPOSmOH accor mg to 6 mm W “cm t e ' 1 and the heads ace ur ed with carbon dioxide. A ceftazldlme ls a ydmte theljeof' - ~ “a P I.) g 19. A composition according to claim 16 wherein the rubber plug was then inserted and a metal overseal ceftazidime is a hydrate thereof. applied by cnmpmg. » 65 20. A composition according to claim 19 wherein the The product was dissolved, as for administration, by hydrate is ceftazidime pentahydrate. the addition of 3 ml Water for Injections. ll! *