DE2112049C - Injectable sulfonamide preparation - Google Patents

Description

H.N -

, -SO ₂ -NH-O

The invention relates to an injectable sulfonamide preparation for veterinary purposes.

It is known that the chemotherapeutic, especially the antibacterial effectiveness of sulfonamides and of certain 2,4-diaminopyrimidines can be mutually increased by using them together can.

2,4-Diaminopyrimidines and process for their preparation are for example in British Patents 715 813, 734 801, 875 562, 957 797 and 1 128 234, British patent application 5246/68 and South African patent application 65/5618 described. A significant class of such compounds are 2,4-diaminopyrimidines with one substituted Benzyl group in 5-position or a substituted phenyl group in 5-position, together with a lower alkyl group in the 6-position. The following may be mentioned as specific valuable compounds: Trimethoprim [2,4-diamino-5- (3,4,5-trimethoxybenzyl) pyrimidine], 2,4-diamino-5- (3,4-dimethoxybenzyl) pyrimidine, 2,4-diamino-5- (3 , 4,6-trimethoxybenzyl) pyrimidine, 2,4-diamino-5- (4-chlorobenzyl) -6-ethyipyrimidine, 2,4-diamino-5- (2-methyl-4,5-dimethoxybenzyl) -pyrimidine, 2,4-diamino-5- (3,4-dimethoxy-5 ombenzyO-pyrimidine and pyrimethamine [2,4-diamino-5- (4-chlorophenyl) -6-ethylpyrimidine].

All of these compounds are known to have valuable chemotherapeutic activity and mixtures with sulfonamides have a synergistic effect.

Compounds of the general formula are preferred

R ¹ NH ₂

RV ^x N

.X

-CH,

-N

-NH,

wherein the radicals R ¹ , R *. R ³ and R ^{4 can be} hydrogen atoms, halogen atoms, alkyl groups, alkoxy groups and / or benzyloxy groups or, if the radicals R ¹ and R * are hydrogen atoms, R * and R ⁴ together can form a methy'fdioxy group. Examples of sulfonamides are sulfadiazine [2- (4-aminobenzenesulfonamido) pyrimidine], 4- (4-aminobenzenesulfonamido) -5,6-dimethoxypyrimidine, sulfa · dt met nox in [4- {4-aminobenzenesulfonamido) -2,6- di wherein Q is an optionally substituted pyrimidin -2-yl or -4-yl group or a substituted isoxazolyl group

Usually the ratio of sulfonamide to 2,4-diamino pyrimidine is around a useful, therapeutic

To achieve therapeutic effect, on the order of 5: 1 (wt ^ wt.), with a preferred ratio between 10: 1 and 2: 1, although in certain cases it may be desirable to use high ratios such as 20: 1 ( W / w) or low ratios

as little as 0.5: 1 or even 0.1: 1 should be used.

While such preparations are often administered orally there is also a need for injectable preparations. Making an injectable Preparation that is both a sulfonamide and

as also contains a 2,4-diaminopyrimidine, forms due to the particular solubility properties of the two components, problems. Sulphonamides only form with certain bases are satisfactorily soluble salts, while the basic reacting 2,4-diaminopyrimidines deliver soluble salts only with certain acids. Mixing aqueous and other pharmaceutical compatible ion solutions of the two components leads to precipitation, which makes the production of injectables Makes solutions in this way impossible.

It has been suggested to make mixtures with various solvents other than water, however Such preparations suffer overall from the known disadvantages of the injection preparations in which a a substantial part of the carrier liquid is not aqueous.

Another disadvantage of the known preparations, which are in the form of solutions, is that it is not possible to increase the concentrations of the active ingredients in the solution without simultaneously increase the viscosity of the solution, the increase in viscosity making the solution unsuitable for injections.

Attempts to suspend finely divided particles of 2,4-diaminopyrimidine in an aqueous solution of a salt of a sulfonamide with a strong base were unsuccessful because of the unexpected formation of an equimolar complex between the sulfonamide and the pyrimidine, since the complex crystals in the injectable preparation forms.
It was found that the crystallization

a) causes fluctuations in the concentration of the content of liquid and solid phases, which brings uncertainty into use, because the absorption of these phases by suckers or birds takes place at different rates.

b) is dependent on time, so that varying amounts of the equimolar complex as crystals random size in samples of different ages

6 $ can be present and

c) Crystals of random size are created, which may be used as seed crystals for further use Crystallization work. The suspensions of the-

like solid phases show a multitude of physical properties, the effectiveness of the preparation in none

lischer properties, e.g. B. the viscosity, the way is affected

different reactions when the at least 99% of the particles of the potentiating agent are administered

result in an injectable preparation. means should have a largest dimension of 50 μm

S have. The crystalline growth of the 1/1 complex normally raises the entire particles

thus completely have the particle size distribution of the pre-largest dimension below 50 μτη. It was

ready and makes it un- established for injection purposes that the aim of the invention is very successful

useful. After that, this path did not seem feasible. can be achieved if the degree of under-

It has now been found that, surprisingly, the io division is such that 99.5% of the number of particles

all of these disadvantages have been overcome in a simple manner and have a largest dimension that is less than

can be. The invention relates to water-5 μτη is. However, it will also produce usable results

rige, injectable Sutfonamidzubereitur.gen for vete- obtained when the particles are larger; for example

Medical purposes, characterized in that it is sufficient if 95% of the number of particles

that they have a largest dimension in an aqueous solution of pH 9.75 to 12 15 which is smaller than

of a water-soluble salt of a Sulfortamtd with 5 μπ ?. Preferably 90% of the number of potential

a strong base as a potentiating agent for ornamental particles a maximum dimension of a few

Sulfonamides known 2,4-diaminopyrimidine, welger than 20 μΐη, and in particular 95% of the number of

ehe = due to no group particles which react with strong bases, a maximum dimension of less than

pe is substituted, in a particle size of less ao 20 μτη, it is particularly preferred that 99.5%

contains than 50 μηι in suspended form. the number of particles has a maximum dimension

F, it seems that if the pH of the preparation is less than 20 μm. It is understandable,

tion is increased to a level at which the potential that sufficient percentages of the subdivision for

The agent is essentially non-ionized, provided any particular formulation, easily

small amount of equimolar complex, if at all 35 obtained by simple experiment using ter

such a structure is not sufficient to allow the standard procedures to be determined.

To exceed solubility in the sulfonamide solution. For intravenous injections, an additive is recommended

and that therefore a crystalline regrowth of grain preparation in which all the particles has a largest throughput

plexes does not occur. have a knife of less than 10 μm.

The liquid carrier therefore consists mainly of 30 An advantage of the preparation according to the invention is

V \ .r scr The presence of organic solvents means that a considerably larger amount of

E.g. of alcohol, glycerine and propylene drugs in a given volume of

ghcol is not excluded, but is usually not able to be incorporated, as is the case with formulations that

advantageous. have been proposed so far for this purpose,

ί nter potentiators are the entire 2.4-35 was loaned. According to the invention, a preparation

To understand diaminopyrimidines that are made against bacterial that have a high concentration of them

lr ^r -ktionen of mammals or birds are effective ingredients having the same and a viscosity

and which cannot have groups such as aromatic which are low enough that they are easy

Hulroxy group, which can be injected with the base, are substituted. This is of particular advantage

from which the salt of the sulfonamide is derived, react 40 in veterinary medicine, if so desired

be able. Trimethoprim (2,4- preparation of larger animals such as horses or cattle,

Dianiino-5- [3,4,5-trimethoxybenzyl] pyrimidine). to inject, otherwise undesirably large liquid

In the preparations according to the invention, the keitsvolume is required. It has been found that potentizing agents in the suspension can be produced entirely in such a way that preparations in which the free base is in the form of the free base, ie in non-ionized form, 45 even up to 70% w / v. the preparation from active materials. Depending on the relative solubility of the substance. Usually the upper limit is determined by the equimolar complex, in comparison with the dissolving viscosity of the preparation, which is not so much the potentiating agent itself, one can be sure that the injection through the syringe will lead to the formation of such equimolar complexes - and needle difficult. However, more viscous embossing can. However, this can be prevented by increasing the pH value diluted the suspension immediately before use. The exponentiation becoming. It is noteworthy that the preparations are usually only in a very small degree of the invention, in spite of the fact that they ionize the suspension level, and are suitably stable, as is a particularly suitable composition of the preparations according to the invention over one Set the pH to the medication for oral administration of 9.75. The pH of the preparation is 55 to be dispersed by diluting with drinking water,
often at least 10 and preferably in the range As already mentioned, the sulfonamide is as a salt from 10 to 10.5. The upper limit of the pH is present with a strong base. Suitable substances, not critical and determined by others, those skilled in the art, which can act as bases, are alkali metal hydrocarbons, factors known according to the tolerance of the animal, such as sodium hydroxide. With certain sulfone, which the injectable solution is injected into, 60 amides, it is possible to use certain organic bases. target. In general, it is undesirable to use a suspcr such as monoethanolumin, diethanolamine and trimetha sion with a higher pH than 12. with regard to nolamin. The term "strong inflammation caused in the animal or bird in which the injection of bases" is to be understood in the sense of the invention, such bases; to apply the suitability of a base for any one. 6 $ special suifonamide, can be easily through simple

It was surprisingly found that although attempt was found. The strong base must

one of the components, namely the suifonamide, should be sufficiently strong to react with the suifonamide.

in solution and the other in a solid state and to form a final pH that is high enough

dead, the potentiating agent is sufficiently non-ionized solution is added to the sulfonamide dispersion,

to let so that the amount of equimolar formed with continuous stirring becomes sufficient

Complex, if any, add 30% sodium hydroxide solution to the

it is not sufficient to dissolve the solubility of the sulfonamide complex and _{to exceed a final pH of s} in the sulfonamide solution. More base 5 10.0 to 10.3 to be obtained. Polyoxyethylene sorbitan-J _T

can, in addition to the amount which is then added to react with the monooleate, the mixture is filtered J j _s

Sulphonamide is required to form the required and ^{sterilized at US 1} C for 30 minutes. ί Κ

borrowed high pH value can be added. The trimethoprim is sterilized in that it + ρ

Wetting agents, usually non-ionic wetting agent, for 1 hour at 150 ° C heated in a hot air oven, _<p support the stability of the Fonnulierung. Polyoxyethylene monooleate under the aseptic conditions of a sterilized porcelain can be thought of as being suitable and using the above-mentioned solution under γ netes wetting agent. Likewise, flocculants, e.g. B. Ball mill ground until the majority of the particles ■, sodium citrate, if desired, be included. Sizes under 5 μπι have (where 99%, based ^ _v

It is usually convenient to base the preparations on the number of particles, a maximum dimension |

of the invention by having the 15 that was less than 20 (im was) and then wun! j _s

sterile potentiating agents in a sterile solution of the preparation under aseptic conditions in 50 m! | t

Suitable salt, for example the Ndtrium salt, filled into ampoules ; r

of sulfonamide. under aseptic conditions and The preparation described above was very suitable I

Machined using a ball mill. One can zui ^ for use as an antibacterial preparation

and the sterile, finely distributed in potentiating so intramuscular injection in livestock, particularities _£

a sterile solution of the appropriate sulfone salt for cattle, sheep, pigs and horses. It will _{

amides using a simple mixed method, preferably not administered intravenously or subcutaneously.

dispersing driving. The solution of the sulfonamide follows. <

can be done using conventional methods, bis D ie 1 2 ^:

sterilized such as heating or filtering. 15 \ :

The potentiating agent can be used as a solid sulfadiazine B.P. 244.80 g

sterilized by heating or irradiation or sterile Trimethoprim 48.96 g

getting produced. Polyoxyethylene sorbitan monooleate 0.24 g;

In this way, preparations containing 40% wt / diethanolamine 7.20 g;

Vol. Sulfadoxine and 8% w / v. Trimethoprim equal to sodium hydroxide 33.00 g

hold, are easily made, and even sodium metabisulphite 1.20 g

higher concentrations, for example up to 70% 30% sodium hydroxide solution qs.

Weight / volume Sulfadoxine and 14% w / v Trimetho- methylhydroxibenzoate to 1.20 g

prim possible, although with this highest concentration injection water to 1200.00 ml

tion the preparation for a satisfactory injection, 35

without prior dilution, is too viscous. Ahn- Half of the final water volume for the injection

Licherweise a preparation containing 20% w / v. is heated to 90 C and methyl hydroxibenzoate in it

Sulfadiazine and 4% w / v Contains trimethoprim, dissolved. The solution was allowed to cool and the suI-

getting produced. The sulfonamide sulfamethoxazole fadiazine is suspended in it. Diethanolamine and

can also be done in a similar manner with Trimethoprim 40 sodium hydroxide in one twentieth of the

be used. Dissolved final water volume of the injections, and the

To obtain a preparation with maximum stability and long-term solution, the sulfadiazine suspension is added,

To achieve a longer shelf life, it is desirable to use sodium metabisulphite dissolved in a small amount of

that the potentiating agent has a solubility in the amount of water tion and polyoxyethylene sorbitan mono-

basic solution of the sulfonamide of less than 45 oleate are then added.

0.5% w / v has, since the higher the solubility of the suspension, then the suspension will be sufficiently 30%

Suspended potentiating agent is, the easier sodium hydroxide solution is added to the sulfadiazine

a mass transfer between the phases will take place to dissolve and a pH in the range from 10.0 to

and crystal growth occurs. 10.5 to form. The solution is then filtered and applied

The invention is now brought about by the following 50 a final volume that is less than the

the examples: displacement volume of trimethoprim (assuming that 1 g of trimethoprim 0.75 ml of carrier, vcr-

Example 1 urges). The solution is then through 30 minutes

The following constituents were used: ^lan | ^{it was} sterilized by ^{etching aui 1} J ^C.

55 Trimethoprim is heated aul for one hour 4- (4-aminobenzenesulfonamido) -5,6- I5OC sterilized in a hot air oven. The sterile

diniethoxypyrimidin 4080.0 g _{s he} j th solution and the sterilized trimethoprim advertising '■

Trimethoprim 816.0g then in a sterilized porcelain ball mill

Polyoxyethylene sorbitan monooleate 2.0 g in size until the majority of the particles are below 5 μm

Diethanolamine 60.0 g are 60, with 99% being smaller than 20 μπι. The suspen-

Sodium hydroxide 500.0 g _s j _{on w} j _{r (} j (j _ann "" te, - aseptic conditions in 20 ml

30% sodium hydroxide solution q.s ampoules filled.

Water for injection to 10000.0 ml n _{as o} b _cn described preparation was as antibaktc-

serial preparation, for intramuscular or subcutaneous use

The sulfonamide becomes very useful in about half the Lnd- 65 injection in cats. In dogs, volumes of injection water formed dispersed. Sodium hydroxide and diethanolamine, after subcutaneous injection, are somewhat irritating, but the intramuscular injection of the water in the lunar volume is dissolved, and these actions are well tolerated.

Example 3 The following ingredients were used:

SuIf amethoxazole 20.00 g Trimethoprim 4.00 g

Isethionic acid or methanesulfonic acid qs

Sodium hydroxide q.s.

Polyvinyl pyrrolidone 4.00 g

Polyoxyethylene sorbitan monooleate 0.02 g

Water for injection to 100.00 ml

Trimethoprim was dispersed in a small amount of water for injection and sufficient isethion or methanesulfonic acid is added for neutralization and solution; the solution was then made with water for injection to form a solution having a content of about 10% w / v. diluted.

Sulfamethoxazole was dispersed in approximately one fifth volume of the water for injection and attached sufficient sodium hydroxide to dissolve it, with a sufficient excess to precipitate the Trimethoprims in the next stage and to achieve a final pH value in the range from 10 to 10.5, admitted. Polyvinyl pyrrolides and polyoxyethylene sorbitan monooleate were then dissolved and, using a heavy duty stirrer, the Trimethoprim solution added in an area of high vortex formation, so that in this way the Tnmethoprimbase was precipitated in fine crystalline form (90% of the number of trimethoprim particles had smaller maximum dimensions than 20 μm). The suspension was diluted with water.

The advantage of this process is that all constituents of the formulation can be subjected to sterilization by filtering in the appropriate stages of the preceding process. SB e ί spie 1 4

The following ingredients were used:

2,4-diamino-5- (3,4-dimethoxybenzyl) -

pyrimidine 0.64 g '

2-sulfonamido-quinoraline 2.56 g

Purified water to 100.00 ml

Sodium hydroxide 0.35 g

30% sodium hydroxide q.s.

iS The solid sodium hydroxide was dissolved in approximately three quarters of the final volume of purified water. Sulphonamidoquinoxaline was then added and dissolved using a mechanical stirrer and heated ^{up to 40 ° C. if necessary.}

»O The solution was then passed through a sintered glass filter No. 3 filtered and reduced with purified water added through the filter Volume than it is the displacement volume of the diaminopyrimidine.

The diaminopyrimidine was mixed with a portion of the sulfonamide solution using a porcelain ball mill crushed until 90% of the particles had a largest diameter .geringer than 5 μm. The mill was then emptied and the suspension diluted with the remaining sulfonamide solution. It Sufficient 30% sodium hydroxide solution was added to bring the suspension to a final pH of 10.0.

309619/406

Claims (2)

Patent claims: 1. Aqueous, injectable sulfouamide preparation for veterinary purposes, thereby characterized in that it is soluble in an aqueous solution of pH 9.75 to 12 of a water Salt of a sulfonamide with a strong base a known as a potentiating agent for sulfonamides 2,4-diaminopyrimidine, which by none, with strong base reacting group is substituted in a particle size of less than SO pm in in suspended form 2. Preparation according to claim 1, characterized in that it contains 2,4-dianuno-5- (3,4,5-trimethoxybenzyl) pyrimidine as the potentiating agent. methoxypyrimidine], sulfamethoxazole, [3- <4-aminobenzenesulfonamido) -5-methyusoxazole], 2-sulfonamidoquinoxaiine, and sulfadmidine [2- (4-aminobenzenesulfonamido), -4,6-dimethylpyrimidine]. A preferred class of sulfonamides are compounds of the general a formula