Injection solution for intramuscular and subcutaneous administration to animals

An injection solution for subcutaneous or intramuscular administration to an animal, and a method of producing same, are provided. The injection solution is substantially free of chloride ions and employs a basic amino acid as a pH-adjusting agent, characteristics that make the injection solution more physiologically tolerable upon injection. Preferably, the injection solution comprises 5 to 30 g of oxytetracycline per 100 ml of injection solution, where the oxytetracycline is provided in a magnesium complex; 0 to 25 g of polyvinylpyrrolidone per 100 ml of injection solution; a basic amino acid in an amount sufficient to adjust a pH of the injection solution to from 5.5 to 9.5; and an additive in an aqueous/organic solvent phase.

This application is a 371 of PCT/EP94/01696 filed May 25, 1994. 
FIELD OF THE INVENTION 
The invention relates to an injection solution for subcutaneous or 
intramuscular administration to animals and a process for the production 
thereof. 
BACKGROUND OF THE INVENTION 
Tetracycline antibiotics are the agents of first choice in many countries 
for numerous therapeutic indications in the veterinary sector. Moreover, 
oxytetracycline (OTC) is the tetracycline used most for parenteral 
administrations. 
Nevertheless, a number of serious problems is associated with the use of 
tetracyclines. Thus, parenteral use is restricted by their poor solubility 
and low stability in aqueous media. In addition, they lead to severe 
irritation at the injection site on intramuscular or subcutaneous 
injection. 
Many attempts have been made to solve the problem of the low solubility of 
tetracyclines in water by using water-miscible solvents and cosolvents. 
Examples which may be mentioned are polyethylene glycol, 1,2-propanediol 
and N,N-dimethylacetalide, which in their turn are highly irritant and 
have haemolytic effects, NOUWS, Vet. Quart., 1984, 6, 2, 80-84; NOUWS, 
Vet. Quart., 1990, 12, 3, 129-138; RASMUSSEN et al., Res. vet. Sci., 1976, 
20, 55-60; HAPKE et al., DTW, 1983, 90, 161-200 and 216-218. 
Better pharmaceutical solutions are obtained by using water-miscible and 
better tolerated pyrrolidone derivatives which are employed as 
solubilizers, solvents or cosolvents in aqueous parenteral tetracycline 
compositions. Reference should be made in this connection to 
polyvinylpyrrolidone, 2-pyrrolidone, N-methylpyrrolidone and 
2-hydroxyethylpyrrolidone. These derivatives permit oxytetracycline 
formulations of high concentration to be produced. 
The advantage of highly concentrated oxytetracycline formulations with 20% 
OTC is that an antimicrobially effective serum level which persists for up 
to 72 hours after injection--so-called long-acting formulations 
(oxytetracycline LA)--can be produced with a single intramuscular 
injection of a dose of 20 mg per kg of body weight. LA formulations are 
very popular for administration in veterinary medicine for practical 
reasons. 
Solutions, which are suitable for parenteral, oral and local 
administration, of oxytetracycline-magnesium complexes in up to 25% 
strength aqueous polyvinylpyrrolidone with an oxytetracycline content of 
up to 15% are disclosed in GB-A-1 131 007. The solutions described therein 
have a pH in the range from 8.0 to 9.5. The pH is adjusted with the aid of 
sodium hydroxide, ammonia, ethanolamine or ethylenediamine. Solutions of 
this type are relatively well tolerated but have the disadvantage that the 
OTC concentration cannot be adjusted to higher than 10% in formulations 
suitable for parenteral administration. The LA effect of other 20% 
strength formulations cannot be achieved thereby. 
DE-A-26 15 140 discloses an active substance formulation for topical 
transdermal administration having a vehicle system composed of 
N-methylpyrrolidone and 2-pyrrolidone in a ratio of 1:4 to 4:1. The 
vehicle system in the composition described therein is intended to promote 
passage through the skin of the active substance applied to the skin. 
Administration of formulations of this type by injection is not intended. 
DE-A-26 59 152 describes formulations, which are suitable for injection, of 
a tetracycline complex in aqueous 2-pyrrolidone, which may additionally 
contain polyvinylpyrrolidone. However, the solutions described therein 
have proved to be exceptionally irritant for tissues. The injections are 
frequently painful for the animals and lead to undesired necroses. The 
tissue irritation leads to high and long-lasting residue levels in the 
tissue and result in undesirably long withdrawal periods (Nouws; Rasmussen 
et al.). 
EP-A-0 096 942 describes an oxytetracycline composition in which 10 to 30 
parts by weight of oxytetracycline in the form of an alkaline earth metal 
complex and 2.5 to 10 parts by weight of polyvinylpyrrolidone are 
dissolved together with antioxidants and bases in aqueous 
N-methylpyrrolidone at a pH of 6.0 to 9.5. The solutions described therein 
are intended for intramuscular injection but show the same poor local 
tolerability as the 2-pyrrolidone formulations described above (Nouws; 
Rasmussen et al.). 
Furthermore, EP-B-0 271 374 describes the use of 
N-hydroxyethyl-2-pyrrolidone as solubilizer for tetracyclines and, in 
particular, also for oxytetracycline. No investigations of the 
tolerability have yet been published. 
Another OTC formulation in aqueous/organic solvents has been marketed under 
the name Tridox. The organic solvent component is a mixture of 
approximately equal parts of N-methylpyrrolidone and 2-pyrrolidone. The 
mixture contains polyvinylpyrrolidone to increase the solubility and 
improve the tolerability. This formulation, which was intended for 
intramuscular administration, also led to irritation at the injection 
site. The absorption and the serum levels were not optimal, also because 
of the irritation. 
In all these formulations, the particular tetracycline is first complexed 
with an alkaline earth metal ion, after which the formulation is adjusted 
to an advantageous pH. Both serve to improve the chemical and physical 
stability of the tetracycline solution. It should be noted in this 
connection that the optimal pH for the various tetracycline derivatives 
may vary widely and is, for example, for oxytetracycline between 7.5 and 
9.5. 
Other formulations which correspond in essential points to those indicated 
above have been disclosed in the past and reflect the many years of 
research activity in this sector. 
The commonest side effect is local irritation at the injection site, which 
may lead to necroses and encapsulations and reduce or delay the absorption 
of the active substance. In consequence, long withdrawal periods up to the 
time of slaughter and, in some cases, a prohibition of use of the tissue 
lying around the injection site also result. 
Veterinary officers and inspectors of slaughter-houses are very familiar 
with this problem. It is concluded that compositions which lead to severe 
necroses in muscle tissue no longer meet the current requirements for 
veterinary medical practice (Vet. Quarterly, 1984, 6, 2, 80-84; ibid., 
1990, 12, 3, 129-138). According to these publications, only a single 
injectable oxytetracycline composition is adjusted to have sufficiently 
little irritation, namely that described in GB-A-1 131 007. With these 
compositions, the damage to muscles at the injection site is small and has 
completely disappeared after a few weeks. However, it has emerged in 
practice that these solutions can be injected only up to an 
oxytetracycline content of up to 10%, because of their high viscosity. 
The inventors have found that the pharmacokinetic results with the known 
products also vary widely and substantially correlate with the local 
irritation in each case. Thus, the serum levels reached on intramuscular 
administration of these formulations sometimes fall rapidly and sometimes 
persist for longer but are in each case connected with the more or less 
severe irritation at the injection sites. The same varying results have 
also been described in the veterinary medical literature, see MEVIUS et 
al., Vet. quart., 1986, 8, 4, 285-294; NOUWS, Proc. 2nd Congr. Eur. Assoc. 
vet. Pharmacol. & Toxicol., Toulouse, France, 1982, 195-198; XIA et al., 
J. vet. Pharmacol. Ther., 1983, 6, 113-120. 
Despite intense research activity, however, it has not to date been 
possible completely to control the local side effects of LA-OTC product. 
However, irritation-free long-acting OTC products are very desirable in 
veterinary practice, not only for reasons of good veterinary practice in 
respect of the animal to be treated, but also because only they guarantee 
a safe and reliable shape of the serum curve and allow losses of the 
injection sites in the carcass to be avoided. 
The known LA-oxytetracycline formulations contain the oxytetracycline 
completed with magnesium, as already mentioned. oxytetracycline 
hydrochloride and magnesium chloride are often used for the production. 
The final pH of the formulations is adjusted with organic bases, 
frequently with mono- or diethanolamiine. In many cases, hydrochloric acid 
is also added for fine adjustment of the pH. Low polyvinylpyrrolidone 
concentrations are used to improve the local tolerability, but the amount 
is limited by the simultaneous increase in the viscosity. 
It has now emerged that there is a number of causes of the local irritation 
at the injection site. The presence of magnesium chloride is an important 
factor in this connection. Magnesium chloride present in the formulation 
may, moreover, be attributable to incomplete complexation of magnesium 
ions or the addition of hydrochloric acid to adjust the pH. 
SUMMARY OF THE INVENTION 
The object of the invention is to provide OTC injection solutions with 
reduced tendency to produce local irritation on intramuscular or 
subcutaneous injection. At the same time, these solutions are intended to 
ensure serum levels which are at least equivalent to previously known 
products and to ensure that excretion from the body is as complete as 
possible. 
This object is achieved by an injection solution for subcutaneous or 
intramuscular administration to animals, according to the present 
invention. The injection solution has a content, based on 100 ml of 
solution, of 5 to 30 g of oxytetracycline as magnesium complex, 0 to 25 g 
of polyvinylpyrrolidone, the required amount of an organic base to adjust 
a pH of 5.5 to 9.5, and conventional additives in a physiologically 
tolerated aqueous/organic solvent phase. The injection solution is 
adjusted to be essentially free of chloride ions and contains a basic 
amino acid as organic base to adjust the pH.

DESCRIPTION OF EMBODIMENTS 
An injection solution for subcutaneous or intramuscular administration to 
animals, and a process for producing same, are provided according to the 
present invention. The injection solution comprises, based on 100 ml of 
solution, 5 to 30 g of oxytetracycline as magnesium complex, 0 to 25 g of 
polyvinylpyrrolidone, the required amount of an organic base to adjust a 
pH of 5.5 to 9.5, and conventional additives in a physiologically 
tolerated aqueous/organic solvent phase. 
The use of chloride ions is avoided in the formulation according to the 
invention, i.e. neither the oxytetracycline nor the magnesium compound 
used or the complexation is added as chloride. Likewise, hydrochloric acid 
is not used to correct the pH. The oxytetracycline is expediently added as 
base, in particular as dihydrate. Magnesium oxide MgO is preferably used 
as magnesium compound. 
To improve the local tolerability of the injection solutions according to 
the invention further it may be advantageous to employ less than the 
stoichiometric amount of the magnesium used for complexation of the OTC, 
for example in a ratio of 0.75:1 to &lt;1:1, preferably in an amount of 
0.80:1 to 0.95:1, in each case relative to oxytetracycline. Higher 
concentrations of free magnesium compounds and, in particular, also MgO 
are likewise irritant for tissue. 
It is known that polyvinylpyrrolidone may improve the local tolerability of 
tetracyclines. It is therefore worth mentioning that the injection 
solutions according to the invention show a better local tolerability, 
even without the addition of polyvinylpyrrolidone, than known products 
which contain polyvinylpyrrolidone. It might be particularly advantageous 
to dispense with the addition of polyvinylpyrrolidone because the 
viscosity of the injection solution increases with such an addition. The 
injectability of the formulation is made difficult by too high a 
viscosity. 
If polyvinylpyrrolidone is added, it expediently has a molecular weight in 
the range from 5000 to 30,000. Molecular weights from 10,000 to 17,000 are 
particularly preferred. Those which are particularly suitable are ones 
with K values of 12 to 30, for example K12 to K17. 
The injection solutions according to the invention contain 
polyvinylpyrrolidone in an amount of 0 to 0.25 g/100 ml, preferably in an 
amount of 2.5 to 20 g/100 ml, of solution. A polyvinylpyrrolidone with a 
low molecular weight is most suitable for the injection solution, for 
example Kollidon 12 PF from BASF with a K value of 12, in a concentration 
of about 2.5 to 10 g/100 ml. 
It has proved advantageous, in order to increase the tolerability of the 
injection solutions according to the invention, to dissolve the 
polyvinylpyrrolidone in water under pressure at a temperature to more than 
115.degree. C. This autoclaving process should last at least about 15 min, 
expediently at least about 30 min. For stabilization and prevention of 
discoloration it is possible during the autoclaving process to add to the 
solution sodium metabisulphite, for example in an amount up to 0.5% by 
weight and preferably of about 0.1% by weight based on the 
polyvinylpyrrolidone. The autoclaving of the solution additionally 
improves the injectability even of highly concentrated solutions by about 
up to 20%. 
The oxytetracycline active substance is present in the injection solutions 
according to the invention in an amount of 5 to 30 g, but in particular in 
an amount of about 20 g/100 ml of solution. 
In the formulations patented to date, organic bases were used to adjust the 
pH, predominantly mono- or diethanolamine. These products are very 
irritant, as is evident from studies by T. SADO (Nippon Nogeikagaku 
Raishi, 1961, 35, 1164-1177). It has been found that basic amino acids 
such as L-arginine, L-lysine or L-ornithine are suitable replacement 
products with excellent local tolerability. 
The pH in the range from 5.0 to 9.5, preferably 6.0 to 9.5, which is 
required for the injection solution according to the invention is adjusted 
according to the invention with a basic amino acid. It is possible to use 
naturally occurring or synthetic amino acids, with the L form, which is 
more physiologically tolerable, being preferred in each case. A basic 
amino acid means according to the invention one which contains at least 2 
amino groups together with at least one acidic group, with the number of 
amino groups exceeding that of the acidic groups. An acidic group means, 
as a rule, a carboxylic acid group, but other acidic groups may also 
fulfill the desired purpose, for example a sulphonic acid group. 
The use of the natural basic amino acids L-arginine, L-lysine and 
L-ornithine is particularly preferred. The potential irritation associated 
with the use of sodium hydroxide or organic amines is avoided in this way. 
It has emerged that the use of basic amino acids distinctly improves the 
tolerability of the formulations produced therewith. However, it may be 
expedient to add additional conventional bases in small amounts in order 
to facilitate the pH adjustment or to prevent the precipitation of the 
amino acid because the solubility has been exceeded. 
The good tolerability of the injection solutions according to the invention 
is furthermore determined by the use of starting materials free of 
chloride ions. The terms "free of chloride ions" or "essentially free of 
chloride ions" used here mean that the content of chloride ions is of an 
order of magnitude at which physiological irritation can no longer be 
caused. 
In principle, the solutions according to the invention can be produced from 
any desired starting materials, even those containing chloride. It is then 
necessary, for adjustment to freedom from chloride ions, to take measures 
for removing disadvantageous amounts of chloride from the finished 
solution. This can take place, for example, by in fact preparing the 
magnesium complexes starting from starting materials which contain 
chloride ions, such as hydrochlorides and magnesium chloride, but removing 
the chlorides produced thereby, for example by crystallization. In order 
to obtain a product which is essentially free of chloride ions, however, 
it is always preferable to use a magnesium salt which is free of chloride 
ions, in particular magnesium oxide. Oxytetracycline is preferably 
employed in the form of the free base, in particular as dehydrate. It is 
furthermore possible to use salts which are free of chloride ions and 
whose tolerability and low irritation is known. 
The injection solutions according to the invention are preferably adjusted 
to an injection viscosity of less than 70 cps. An injection viscosity of 
less than 40 cps is particularly preferred. 
Conventional organic solvents can be employed for the aqueous/organic 
solvent phase for oxytetracycline formulations. Their physiological 
tolerability is a precondition. Pyrrolidone and its derivatives, in 
particular N-methylpyrrolidone, 2-pyrrolidone and 
N-(2-hydroxyethyl)pyrrolidone have proved suitable. Mention should also be 
made of N,N-dimethylacetamide, hydroxyethylacetamide and other 
conventional amide derivatives, glycerol formal, polyethylene glycol and 
polypropylene glycol. Preferred aqueous/organic solvents are 
N-methyl-pyrrolidone and 2-pyrrolidone. 
The injection solutions according to the invention can be produced both 
with the individual solvents and with mixtures thereof. It has been found 
that, in particular, mixtures of two different solvents of the pyrrolidone 
type further improve the absorption characteristics compared with the use 
of the particular solvent alone. References to this effect are to be found 
in DE-A-2 615 140, but for the case of transdermal formulations therein. 
However, the same effect also occurs on subcutaneous or intramuscular 
administration. 
The injection solutions according to the invention expediently contain 8 to 
66 g of solvent per 100 ml of solution. 
Formulations with an oxytetracycline content of about 10 to 30 g, in 
particular about 20 g, per 100 ml of solution have proved particularly 
suitable for intramuscular administration. A preferred formulation 
contains in the solvent phase 20 to 60 g of N-methylpyrrolidone and 
2-pyrrolidone in a mixing ratio of 92:8 to 70:30. To stabilize the 
solution and increase the tolerability it is possible to add 2.5 to 10 g 
of polyvinylpyrrolidone per 100 ml of solution. 
In this case the weight ratio of N-methyl-pyrrolidone to 2-pyrrolidone is 
preferably less than 90:10 and larger than 80:20 and is, in particular, 
about 5:1 to 4:1. It has emerged that, when these limits are observed, an 
optimum dissolving effect with good injectability and good tolerability is 
achieved. At the same time, the mixture guarantees good absorption of the 
pharmaceutical after intramuscular or subcutaneous injection, so that the 
desired high serum levels are reached at an early time. Tissue residues 
are completely broken down within a short time so that the result is a 
shortening of the withdrawal periods which have had to be observed to 
date. 
The excellent pharmacokinetic properties of the injection solutions 
according to the invention have been confirmed by examination of classical 
serum curves, The serum creatine phosphokinase levels (CK) showed an 
excellent local tolerability which was superior to previously disclosed 
products and was confirmed by the known Shintani test. 
The pharmacokinetic properties of the solutions according to the invention 
have been investigated by determining the classical serum curves in 
calves. Determination of serum oxytetracycline in this case took place by 
means of high pressure liquid chromatography. 
It is known that damage to the skeletal muscle causes an increase in serun 
CK activity. The increase in the CK activity depends on the extent of the 
traumatization, for example also of the intramuscular injection of certain 
pharmaceuticals (veterinarmedizinische Laboruntersuchungen fur die 
Diagnose und Verlaufskontrolle veterinary medical laboratory tests for 
diagnosis and monitoring progress!, Boehringer Mannheim; UCELLI et al., 
Rec. med. vet., 1988, 164, 11, 939-943). 
The increase in the CK levels was investigated in calves after a single 
intramuscular administration of various products. 4 calves in each trial 
group were selected at random, with the sex (female), breed (black and 
white) and body weight (110.+-.2 kg) being consistent. The animals 
received a single intramuscular treatment, the therapeutic dose being one 
ml of product per 10 kg of body weight (20 mg of oxytetracycline per kg of 
body weight). Blood samples were taken immediately before and 8, 12, 24, 
48, 60, 72 and 96 hours after the injection. The CK determinations took 
place by automatic analysis as described by Boehringer Mannheim with a 
BM/Hitachi 704 apparatus. The formulation of Example 7 according to the 
invention was compared with a commercially available product (20% of 
oxytetracycline in aqueous 2-pyrrolidone). 
______________________________________ 
Hours after injection 
______________________________________ 
CK levels in IU/l 
0 8 12 24 48 72 96 
(means) 
Formula 18 79 55 34 23 22 20 
Example 7 
Non-commercial 
22 291 163 98 58 49 26 
Oxytetracycline 
20% in 2-pyrr. 
______________________________________ 
It is evident from the results that the injection solution according to 
Example 7 resulted in only an approximately 4-fold increase in the CK 
levels, which had essentially disappeared completely after 48 hours. By 
contrast, an approximately 13-fold increase in the CK levels occurred in 
the comparison product and did not disappear again until 92 hours had 
elapsed. 
A check by the Shintani test (Shintani et al., Tox. appl. Pharmacol., 1967, 
11, 293-301) confirmed the results of the CK test. The degree of 
irritation was determined on the basis of a macroscopic assessment of the 
injection site after intramuscular administration to rabbits. 
______________________________________ 
SHINTANI SCORE Hours after injection 
(Mean of 3 animals in each case) 
48 72 
______________________________________ 
Formula 3.00 2.00 
Example 3 (*) 
Commercial oxytetracycline 
4.33 3.33 
20% N-methylpyrrolidone 
______________________________________ 
The Shintani criteria are: 
______________________________________ 
no reaction: 0 to 0.4 
slight reaction: 0.5 to 1.4 
mild reaction: 1.5 to 2.4 
moderate reaction: 
2.5 to 3.4 
strong reaction: 3.5 to 4.4 
serious reaction: 
4.5 to 5 
______________________________________ 
(*) 3.00 only because of yellow precipitation. The injection site was, 
however, free of necroses. 
The formulations according to the invention are preferably produced by a 
process in which, in a first step, the required amount of 
polyvinylpyrrolidone is dissolved in water and autoclaved at a temperature 
of more than 115.degree. C. for a period of at least 15 min, in a second 
step this solution is, after cooling, mixed with one or more organic 
solvents which are physiologically advantageous, stabilizers and a 
chloride-free magnesium salt in each case in the required amounts, and 
stirred to homogeneity, and thien, in a third step, the required amount of 
oxytetracycline or oxytetracycline derivative, which is free of chloride 
ions, is stirred in, with the required pH being adjusted by adding the 
basic amino acid. In the case where no polyvinylpyrrolidone is present in 
the formulation according to the invention, of course, the autoclaving 
step is dispensed with. 
The invention is explained in detail by the following examples. 
Production process 
The following Examples 1 to 8 were carried out with the following 
production process. 
Where present, the polyvinylpyrrolidone was mixed together with the sodium 
metabisulphite in about 25 ml of water for injection and autoclaved at 
121.degree. C. for 30 min. After cooling to room temperature, the organic 
solvent phase (2-pyrrolidone and/or N-methylpyrrolidone) was mixed in, 
followed by the magnesium oxide. Mixing was continued until a homogeneous 
suspension was obtained. 
The resulting mixture was subsequently mixed with sodium formaldehyde 
sulphoxylate and the basic imino acid. The mixture was heated to 
50.degree. C. and oxytetracycline dihydrate was slowly added, while 
continuing the stirring. Heating was continued until the oxytetracycline 
was completely complexed. 
After cooling to room temperature, the mixture was diluted to 100 ml with 
water for injections. The solution was sterile filtered and dispensed into 
ampoules under nitrogen as protective gas. 
______________________________________ 
Example 1 
Oxytetracycline dihydrate 
21.600 g 
(equivalent to 20 g of oxytetracycline) 
Magnesium oxide 1.600 g 
Polyvinylpyrrolidone (K17) 
5.000 g 
Sodium metabisulphite 0.005 g 
2-Pyrrolidone 8.880 g 
N-Methylpyrrolidone 41.200 g 
Sodium formaldehyde sulphoxylate 
0.400 g 
L-Arginine 3.250 g 
Water for injections to 100 ml 
The pH of the solution was 8.90. 
Example 2 
Oxytetracycline dihydrate 
21.600 g 
(equivalent to 20 g of oxytetracycline) 
Magnesium oxide 1.600 g 
Polyvinylpyrrolidone (K17) 
5.000 g 
Sodium metabisulphite 0.005 g 
2-Pyrrolidone 50.000 g 
Sodium formaldehyde sulphoxylate 
0.400 g 
L-Arginine 3.650 g 
Water for injections to 100 ml 
The pH of the solution was 8.74. 
Example 3 
Oxytetracycline dihydrate 
21.600 g 
(equivalent to 20 g of oxytetracycline) 
Magnesium oxide 1.600 g 
Polyvinylpyrrolidone (K17) 
8.000 g 
Sodium metabisulphite 0.008 g 
2-Pyrrolidone 8.880 g 
N-Methylpyrrolidone 41.200 g 
Sodium formaldehyde sulphoxylate 
0.400 g 
L-Arginine 3.250 g 
Water for injections to 100 ml 
The pH of the solution was 8.90. 
The viscosity at 25.degree. C. was 45 cst. 
Example 4 
Oxytetracycline dihydrate 
21.600 g 
(equivalent to 20 g of oxytetracycline) 
Magnesium oxide 1.450 g 
2-Pyrrolidone 8.880 g 
N-Methylpyrrolidone 41.200 g 
Sodium formaldehyde sulphoxylate 
0.400 g 
L-Arginine 3.750 g 
Water for injections to 100 ml 
The pH of the solution was 8.73. 
Example 5 
Oxytetracycline dihydrate 
21.600 g 
(equivalent to 20 g of oxytetracycline) 
Magnesium oxide 1.600 g 
Polyvinylpyrrolidone (K17) 
8.000 g 
Sodium metabisulphite 0.008 g 
2-Pyrrolidone 8.880 g 
N-Methylpyrrolidone 41.200 g 
Sodium formaldehyde sulphoxylate 
0.400 g 
L-Cystein 0.025 g 
L-Arginine 3.250 g 
Water for injections to 100 ml 
The pH of the solution was 8.77. 
The viscosity at 25.degree. C. was 44 cst. 
Example 6 
Oxytetracycline dihydrate 
21.600 g 
(equivalent to 20 g of oxytetracycline) 
Magnesium oxide 1.450 g 
Polyvinylpyrrolidone (K12) 
8.000 g 
Sodium metabisulphite 0.008 g 
2-Pyrrolidone 8.880 g 
N-Methylpyrrolidone 41.200 g 
Sodium formaldehyde sulphoxylate 
0.400 g 
L-Arginine 3.750 g 
Water for injections to 100 ml 
The pH of the solution was 8.77. 
Example 7 
Oxytetracycline dihydrate 
21.600 g 
(equivalent to 20 g of oxytetracycline) 
Magnesium oxide 1.450 g 
Polyvinylpyrrolidone (K17) 
2.500 g 
Sodium metabisulphite 0.002 g 
2-Pyrrolidone 8.880 g 
N-Methylpyrrolidone 41.200 g 
Sodium formaldehyde sulphoxylate 
0.400 g 
L-Arginine 3.750 g 
Water for injections to 100 ml 
The pH of the solution was 8.83. 
Example 8 
Oxytetracycline dihydrate 
33.570 g 
(equivalent to 30 g of oxytetracycline) 
Magnesium oxide 2.300 g 
Polyvinylpyrrolidone (K17) 
8.000 g 
Sodium metabisulphite 0.008 g 
2-Pyrrolidone 9.000 g 
N-Methylpyrrolidone 49.000 g 
Sodium formaldehyde sulphoxylate 
0.400 g 
L-Arginine 6.500 g 
Water for injections to 100 ml 
The pH of the solution was 8.60. 
______________________________________