CA1237672A

CA1237672A - Stable aminoglycoside/penicillin formulations for injection

Info

Publication number: CA1237672A
Application number: CA000444209A
Authority: CA
Inventors: Herbert Voege; Peter Stadler; Hans-Joachim Zeiler; Samir Samaan; Karl G. Metzger
Original assignee: Bayer AG
Current assignee: Bayer AG
Priority date: 1982-12-28
Filing date: 1983-12-23
Publication date: 1988-06-07
Also published as: EP0115001B1; EP0115001A2; DE3377064D1; EP0115001A3

Abstract

ABSTRACT OF THE DISCLOSURE
"Stable aminoglycoside/penicillin formulations for injection"

An injectable antibiotic composition comprising an injectable oil, an aminoglycoside and a .beta.-lactam anti-biotic. Following injection, the active ingredients remain in the bloodstream for long periods of time.

Description

The invention relates to formulations for inject lion consisting of at least one oil suitable for inject ton, at least one aminoglycos;de and at least one pent-clown for administration in human and veterinary medic cone, the use of oils suitable for injection for the pro-parathion of stable formulations for injection containing am;noglycosides and pen;c;ll;ns, and the preparation of formulations for injection of this type and novel salts, which are sparingly soluble in water, of aminoglycoside antibiotics.
From the microbiological viewpoint, a product combining penicillins and aminoglycosides would be ox-Tramiel desirable, since it would then be possible to deal with almost the entire spectrum of 6ram-negat;ve and Gram-pos;tive bacteria. Unfortunately, however, at present it us only possible to inject the two active compounds separately at different sites on the body if the intention us to obtain optimal efficacy from the two active compounds. Moreover, the two injection solutions should not be employed together on one syringe before use recommendations for use given by the manufacturers of am;noglycoside solutions or by I. Courses and D.
Kayo, Antimicrobial Agents and Chemotherapy, 13 I
pages 505-508~ Tao The reason for this is chemical incompatibility between penicillins and aminoglycosides~
as has been described by J. Henderson et at., Amer. J.
Hosp. Harm., 38, 1167 (1981).
Antibiotics of the aminoglycoside serves have been used for a long time for controlling bacterial in-fictions in human and veterinary medicine. In d;seasesof this type, there is a desire, especially in voter-nary medicine, for a successful cure to be achieved aft ton only one injection of the active compound. This us quite possible with, for example, pen;c;ll;ns when a lo A 20 994 - " ~2376~2

- 2 suspension of sparingly soluble penicillin salts is in-jetted into the animals, the active compound on thus being only gradually released. This produces an effect live revel of penicillin on the blood persisting over a prolonged period, and multiple repetition of the inject ton us unnecessary.
In the case of aminoglycosides which are nor-molly injected in aqueous solution, the biological half-life us relatively short about 1 hour), so that an on-section has to be undertaken several times a day for an infection.
Thus, it Gould be desirable, and a great relief for the keeper of animals and the veterinarian, of the number of injections during the illness of the animal could be reduced.
Formulations of aminoglycosides for injection which have these properties have not hitherto been known. It us true that, on another connection, drug formulations which release aminoglycosides continuously over a prolonged period have been described. Thus for example, eye drops which release gentamicin in a de-lazed manner are protected in UrS.Patents 4,188,373 and 4~115,544. Moreover, plastic or ceramic drug formula-lions which are implanted on infected bones and which continuously release the am;no3lycoside there are known (see, for example DEMOS (German Published Specification 2,815,934~ DEMOS German Published Specification

3,005~350~ East German Patent 139,942 or DEMOS (German Published Specification) 2,807,132).
The preparation of sparingly soluble salts of am;noglycosides has already been described zoo. However, these are likewise only untended for external use and not for formulations for ;nject;on. Thus, antibiotic salts which are insoluble on water are clammed on DEMOS
(German Published Specification 2,301,633, according to which the salt is prepared from gentamicin or lo A 20 9~4 7~2 polymyxin as the basis and penicillin or cephalospo-fins as the acids. These salts have the disadvantage that the ratio of aminoglycoside to penicillin derive-toe is foxed by the molar ratio and it cannot be adjust ted to suit the bacteriologically sensible optimum.
Moreover using an aminoglycoside formulation~hich releases the active compounds slowly, it would be possible to develop a product combined with ~-lactam antibiotics which Gould be free from the disadvantages of the penic;llin/gentamicin salt described above:
The preparation of a product combining aminogly-cosine and penicillin derivatives has, in fact, already been disclosed in DEMOS (German Published Specification) 2,756,079~ the penicillin being coated with polyvinyl-pyrrolidone and lecithin. Ike dried powder is filled into sterile glass bottles and, before use, can be con vented into a combination product by adding an aqueous solution of aminoglycoside and shaking. However, the preparation of this product is elaborate and costly and a "ready Jo use" suspension cannot be prepared thus.
Surprisingly, according to the invention, it is possible for the first time to prepare formulations for injection which contain active compounds from Roth alas-sues of active compounds and which are chemically stable, so that they can be prepared and employed as a combine-lion product when the active compounds are suspended in an injectable oil in Shea they do not dissolve.
Accordingly, the invention relates to formula-lions for in section consisting of at least one oil suit-able for injection at least one aminoglycos;de and at least one penicillin for administration in human and veterinary medicine.
Particularly suitable as formulation components from the group of aminoglycosides are gentamic;n, silo-Mohican, etomicin, amikacin, bluensomycin, neomycin,paromomycin, lividomyc;n, canamycin, d;bekac;n, nebramy-lo A ZOO 994 ~'~3~7~

Jo - Sweeney ribostamycin~ butirosinO kasugamycin, sagamicin~
apramycin, verdamicin~ xylostasin, destomycin, hygromy-gin, seldomycin, umtamicinD tobra~ycin, spectinomysin and fortimicinn From this group, those which are particularly preferred are, especially, genta~ycin, sisomicin, etomi-gin, amikacin, neomycin, kanamycin~ tobramycin and for-timicin.
From the group of penicillins all biosynthetic or sem;synthetic penicillins can be employed, but in particular benzylpen;cillin, phenoxymethylpenicil-fin, propic;llin~ phenethic;llin, oxacillin, cloxac;l-fin, dicloxac;llin, ampicillin, carbenicillin, Methuselah-fin, me~a~piciLlin, acidocillin, amoxycillin, ticarcil-fin, ticcercillin, talampicill;n~ pivampicill;n, epicil-fin, c;clacillin and inda~ylcarbenic;llin.
Likewise ure;dopen;c;llins, such as, for example, ~ezlocill;n, azloc;llin and piperacillin~
From this group, those which are particularly preferred are, especially, benzylpenicillin, oxacillin, cloxacillin, d;cloxacill;n and ampicillin. The sub-stances from the group of aminoglycosides and the pent-sullenness can both be employed in the form of their free acid or base or in the form of their salts. Salts which only dissolve to a slight extent in water and thus bring about a delayed delivery of active compound can also be employed. In the case of penicillins these are, for example, the procaine salts or benzathine salts.
The invention also relates to salts which are sparingly soluble in water, of aminoglycos;de ant;bio-tics and organic carboxylic or sulphonic acids or hem-esters of polybasic inorganic acids with aliphatic Alcoa hots, Ryan of which have antibiotic activity.
Within the meaning of the present invention, the term "sparingly soluble" is to be interpreted as 1 to 1000 my, preferably 1 to 500, and particularly prefer-lo A 20 994 ___ ~'~37~2 ably 5 to 200 my of the salt dissolving on 1,000 ml of water at 20C .
The suitable aminoglycoside antibiotics suitable according to the invention for the salt formation are preferably the following:
Gentamicin~ sisomicin, etomicin~ am;kac;n, streptomycin, bluensomycin, neomycin, paromomycin~ livid damson, kanamyc;n, dibekacin, nebramycinr ribostamycin, butirosin, kasu~amycin, sagamic;n, apramyc;n~ verdarni-con xylost3s;n, destomycin~ hygromycin, seldomycin,umtamic;n, tobramyc;n~ septinomycin and fortimicin.
From thus group, those which are particularly preferred are especially, gentamicin, sisom;cin, Tom;-Gino amikacin, streptomycin, neomycin, kanamycin~ cobra-Mohican and fort;m;c;n.
Aminoglycos;des which are der;vatised at theirhydroxyl and/or amino groups are also suitable according to the invention. These are for example, derivatives according to DUKES German Published Specification) 2,712,160 (aminogLycosides which have on at least one N
atom, an alkyd or azalea radical having an ether or trio-ether group), DEMOS (German Published Spec;ficat;on~
2~24~659 (aninoglycosides which have, on at least one N
atom, an aminohydroxyalkyl radical), DEMOS (German Pub-lashed Spec;f;cat;on) 2,753~769 (1-N-carbamoyl- and 1-N-alkoxycarbonyl-am;noglycosides), DE OX (German Pub-fished Spec;f;cat;on) 29832,268 (am;noglycos;des which have, on at least one N atom a polyhydroxyalkyl fad;-eel), DEMOS German Published Specification) 29921,973) (1 N-hydroxyalkyLam;noalkyloxycarbonyl-s;somycin), DE-OX (German Published Spec;f;cat;on) 2~928,183 ~sisom;cin which is substituted with secondary alkyd at the 1-N
atom), DEMOS (German Published Spec;f;cation) 3,100,739 Samson substituted by a carbamoyl group at the 5-0 atom) and DEMOS (German Published Specification 3,101,376 (1-hydroxyalkylurethane-s;somic;n) and the lo A 20 994 ~3~7~7~

pseudo disaccharides according to DEMOS (German Published Specification 2,730,372.
Suitable as the acid component of the salts act cording Jo the invention are all organic carboxylic acids or sulphonic acids and hamsters of inorganic acids with aliphatic alcohols which do not themselves have antibiotic activity and which form a salt which us sparingly soluble in water with the particular aminogly-cosine (derivative). Examples which may be mentioned are as follows:
Embank acid or pamoic acid t- 4,~'-methylene b;sC3-hydroxy-2-naphthalenecarboxylic acid), nephew-thalenedisulphonate or higher fatty acids, for example dodecano;c acid, tetradecano;c acid, hexadecanoic acid, octadecanoic acid, erotic acid, oleic acid elaidic acid linoleic acid or -hydroxymyristic acid.
Of these acids, embank acid and optionally us-saturated fatty acids having 8-25 carbon atoms in par-titular 1Z-18 carbon atoms are preferred. Hamsters of dibasic or polybasic inorganic or organic acids with aliphatic alcohols, such as monocetyl sulfite or moo Seattle malonate or ethyl succinate are also suitable Hamsters of long-cha;n (8 25, preferably 12-18 carbon atoms) alcohols are preferred.
The salts according to the invention are prefer-ably employed in combination with -lactam antibiotics, it being possible for the latter to be present both in the form of the free acid and in the form of a salt. In this connection, all ~lactam antibiotics which are known per so are suitable according to the invention, for example penicillins, cephalosporins and oxeyes-fumes The following may be mentioned as examples: am-picillin~ propicillin~ oxacillin, dicloxacillin, car-penicillin, azidocillin~ mezlocillin, azloc;ll;n, pent-clown G, procaine-penicillin G, p;vampicill;nD
amoxixill;n, flucloxacill;n~ ticarcillin, carindacilin~
lo A 20 994 _ cielacillin, ep;c;llin, cefaloridin, cefalothin, suffuse-fin, cefamandole, cefoxitin~ cefuroxime, cephalexin, eel-radiner cefaclor, cefadroxil~ th;enamycin and cefotaxim.
The sparingly soluble salts of the aminoglyco-side antibiotics can be prepared by bringing aqueous so-lotions of free basic aminoglycosides or their neutral salts with inorganic or organic acids to reaction with aqueous solutions of salts, for example, of higher fat-try acids or of embank acid As a rule the reaction temperature is in the range between 5 and 95C, pro-fireball between, 50 and 80C. The sparingly soluble precipitate which us produced us then filtered off with suction, thoroughly washed with water and dried by cuss tumor methods Suitable liquid vehicles are oils and lipids which are suitable for ;nject;on. Injectable owls or lipids are usually lipids which are liquid at room them portray, for example, groundnut maize, almond, olive, castor or sesame oil, or fatty acid esters, for example ether owlet or isopropyl myr;state, Shea can be used as solvents for substances to be injected or for the prepay ration of lipid emulsions to be administered interwoven-ouzel. They must comply with the regulations relating to ";njectables" on the Federal Republic of Germany, that Z5 is to say they must be prepared in accordance with the procedures in the pharmacopoeia yin this context, compare also K. Mainsail, J. Bush and 0.-E. Schultz, Galenisches Praktikum practical Formulation), Wits. VerLagsg2s~ mbH, Stuttgart (1959) and Arzneibereitung drug Formulation), Ferdinand EnkeVerlag, Stuttgart (196~)). According to Swiss Patent Specification 349,750 (dated ~.6~56/15.
12.60; C.1961. 9893), an injectable formulation is pro-pared, for example, by heating 500 9 of olive oil with a mixture of 84 9 of glycerol and 5 9 of sodium hydroxide at 85C for 8 hours. The upper phase, which contains monoglycerides and diglycerides, is separated off, washed lo A 20 994 - ~3'7~

and dried. MUM. A Guerbert (British Patent Specific cation 181,551 dated 31.8.67, French Patent Specification dated 18.2~64; C. A. 67. No. 120~191 (1967)) recommends, as an injectable lipid base vegetable oils, their Alcoa holysis products or halogenated derivatives, in portico-far combined with polyethylene glycol 400 monopalmitate and a tartaric ester of the monoglycerides of cotton seed oil. The following are also suitable: soya bean oil, miglyol 812~, Viscose and Arlacel I.
Suitable and particularly preferred are oils or lipids suitable for injection, for example natural in-glycerides, such as sesame owl, groundnut oil, castor owl, almond owl, maize germ oil or olive oil, or Cynthia tie triglycerides such as, for example, a mixture of triglycerides of saturated vegetable fatty acids of me-drum chain length (C8-C12), and caprylic/capric acid triglyceride.
Other auxiliaries can be added to the suspension formulation, for example wetting agents, such as fee;-thin or polyoxethylene-sorb;tan moonlit, thickening agents, such as aluminum menstruate, preservatives, such as phenols, bouncily alcohol or hydroxybenzoic en-terse The proportions of active compounds and axe lyres used for the preparation of the formulation can vary within the following limits:
The active aminoglycosides can be introduced in-to the vehicle in a range from 0.5 to 30X~ preferably from 1 to 15%, relative to the aminoglycoside base.
The proportion of auxiliaries can vary between 0.05 and 10X~ preferably 0.2 to 5%.
The proportion of penicillins in the combined formulation can be between 1 and 40%, preferably 3 to I
US The preparation of the suspension ready for in section us carried out under aseptic conditions in a L_ A 20 ~94 _ 9 _ manner known on pharmacy.
The desired active compounds are precipitated sterile to a specified particle size or the sterile pro duct is ground under aseptic conditions. In this con-text the particle Sue should be between 2 and 60 ~cm,but preferably between 5 and 3û mum The ground substance is introduced into the sol-veto which has been previously sterilized, and home-jounced under aspic conditions. The homogeneous sup-pension us fulled out under sterile conditions.
The following examples are intended to thus-irate, but not restrict the invention.
The formulation examples detailed below were prepared by the above procedure under a luminary flow hood.
The data relating to the composition are in weight/vo~ume.

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a) Composition Etomicin sulfite, ground and sterile 1 77 9 Penicillin G Potassium, ground 1.55 9 to- 2.5 Molly) Miglyol 812~ (= synthetic triglyceride ad 100 my b) Pro arat;on as described above c) Stabilit~_of the formulation Etomicin sulfite Penicillin 6 determined as base potassiwm,Mill.U

Initial content 0.85% 2.36%
Storage at 20C
for 3 months 0.84% 2.44X
Storage at 35C
for 3 months 0.86% 2.37X
Storage at Z0C
for 6 months 0.89X 2.37%
eye I.
a) Etomicin sulfite, ground and sterile 1.77 9 Procaine penicillin G, ground and sterile 9.79 g Aluminum menstruate 2X gel in sesame oil ad 100 ml by Preparation as described above lo A 20 994 ____ '7Ç~7~

c) Stubbly of the formulation Etomicin sulfite Procaine as base penicillin G K

Initial content 0.93% 10.1%
Storage at 20C
for 3 months 0.90% 'l005%
Storage at 35C
for 3 months 0.85% 10.25%
Storage at 20C
for 6 months 1.05% 9.5%

a) Kiwi Sisomicin sulfite 1.77 9 Oxacill;n sodium 1.50 9 Tocopherol 0.30 9 Groundnut oil ad DO ml b) Preparation as described above c) Stability of the formulation Sisomicin sulfite Oxaci~lin calculated 35 base sodium Initial content 1.0X 1.45X
after storage for 1 month in a refrigerator 0.98% 1.42X
at 20C 1.02% 1u41X
at 30C 1.D7 1r44 a) Etom;cin sulfite 1.77 9 Ampicillin trihydrate 1.50 g Lecithin 0.50 g lo A 20 994 __ _ - Lowe Ethyl owlet ad 100 ml b) c) Stability the formulation Etomicin sulfite Ampicillin as base as acid Initial content 0.97% 1.39%
after storage for 1 month on a refrigerator 0.98X 1.32%
; 10 at 20C 0.99% 1.33 at 30C 0.95% 1.22%
Examples of other stable formulations are as follows:
Example M

15 Etomicin sulfite 5.217 9 (corresponding Jo 3.0 g of base) Procaine penicillin G 30~000 9 Lecithin 0.1 9 M;glyol 812(R) (synthetic triglyceride) ad 100 ml Example N

Gentamicin sulfite 5.115 9 corresponding to 3.0 9 of base) Penicillin G Potassium 9 25 Ethyl owlet ad 10D ml Example 0 Gentamicin embonate 7.000 g corresponds to Z.0 y of base) Penicillin G potassium 1.550 9 lo A 20 994 N,N~-diben~ylethylenediamine salt of penicillin G Acadia 9 Lecithin 2~000 9 Miglyol 81 ad 10D ml Example P

Etom;cin embonate 6.9Z g (I no g of base) Eto0icin sulfite 1~60 g 0 9 of base) lo Procaine penicillin G25000 g Lecithin 0.02 g Caprylic/capric acid triglyceride ad 100 ml The levels of the aminoglycoside in the blood using the formulations were determined in the following manner:
The formulations were administered intramuscu-laxly in appropriate doses to beagle dogs. Blood samples were taken at various times after treatment and the serum was taken by centrifugation~ The content of active compound in the serum was determined microbe-logically using the ajar diffusion test (well test).
The detecting organism used was the strain bacillus sub lilts ATTICS 6633~ and the test medium used was DUST ajar.
The content of active compound in the various serum samples were determined on the basis of a standard in buffer The results see the Table) show that, after administration of the sparingly soluble salts, Thorpe-tidally relevant levels in the blood were achieved over a considerably longer time than with for example the corresponding water-soluble sulfites As a consequence of the marked prolongation of the half-life, these for mullions offer crucial advantages for therapy lo A 70 994 37~7~

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Claims

THE EMBODIMENTS OF THE INVENTION IN WHICH AN EXCLUSIVE
PROPERTY OR PRIVILEGE IS CLAIMED ARE DEFINED AS FOLLOWS:

1. A formulation for injection consisting of at least one oil suitable for injection, at least one aminoglycoside and at least one penicillin for administration in human and veterinary medicine.

2. A formulation for injection according to claim 1, which contains 0.5 to 30% by weight of at least one aminoglycoside, 1 to 40% by weight of at least one penicillin and optionally 0.05 to 10% by weight of other formulating auxiliaries.

3. A formulation for injection according to claim 1, wherein the aminoglycoside and the penicillin are present in the form of their bases or salts.

4. A formulation for injection according to claim 1, 2 or 3, wherein the aminoglycoside and the penicillin have particle sizes between 2 and 60 mcm.

5. A formulation for injection according to claim 1, 2 or 3 wherein the aminoglycoside and the penicillin have particle sizes between 5 and 30 mcm.

6. A formulation for injection according to claim 1, 2 or 3 which contains the following pair of active compounds: Etomicin sulphate and Penicillin G Potassium.

7. A formulation for injection according to claim 1, 2 or 3 which contains the following pair of active compounds: Etomicin sulphate and Procaine Penicillin G.

8. A formulation for injection according to claim 1, 2 or 3 which contains the following pair of active compounds: Sisomicin sulphate and Oxacillin sodium.

9. A formulation for injection according to claim 1, 2 or 3 which contains the following pair of active compounds: Etomicin sulphate and Ampicillin trihydrate.

10. A formulation for injection according to claim 1, 2 or 3 which contains the following pair of active compounds:
Gentamicin sulphate and Procaine penicillin G.

11. A formulation for injection according to claim 1, 2 or 3 which contains, as the oil, sesame oil, groundnut oil, castor oil, almond oil, maize germ oil, olive oil, a synthetic triglyceride of a saturated C8-C12 vegetable fatty acid or a fatty acid ester.

12. A formulation for injection according to claim 1, 2 or 3 which contains, as formulation auxiliaries, one or more wetting agents, thickening agents or preservatives.

13. A formulation according to claim 1, 2 or 3 which contains 0.5-30% by weight of the salt (calculated as aminoglycoside base) and 1-40% by weight of .beta.-Lactam antibiotic.

14. An ampoule containing a formulation for injection as defined in claim 1, 2 or 3.

15. A process for the preparation of formulations for injection containing an aminoglycosides and a penicillin, wherein the active compounds, separately or together, are precipitated sterile to a particle size of 2 to 60 mcm or are ground under aseptic conditions and the active compounds thus pretreated are homogeneously suspended in an injectable oil.

16. A process according to claim 15 wherein the active compounds are Etomicin sulphate and Penicillin G Potassium.

17. A process according to claim 15 wherein the active compounds are Etomicin sulphate and Procaine Penicillin G.

18. A process according to claim 15 wherein the active compounds are Sisomicin sulphate and Oxacillin sodium.

19. A process according to claim 15 wherein the active compounds are Etomicin sulphate and Ampicillin trihydrate.

20. A process according to claim 15 wherein the active compounds are Gentamicin sulphate and Procaine penicillin G.