Note: Descriptions are shown in the official language in which they were submitted.
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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
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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
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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-
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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-
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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
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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~
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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
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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
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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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lo A 2 0 994
Example I
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
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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
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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
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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
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