BE523745A - - Google Patents

Description

       

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  AMERICAN HOME PRODUCTS CORPORATION, residing in NEW YORK.



  METHOD FOR MANUFACTURING COMPOSITIONS OF PENICILLIN.



   The present invention relates to the manufacture of penicillin compositions and more particularly to the manufacture of therapeutic compositions containing an N-N'disubstituted alkylene diamine salt of penicillin.
These penicillin salts have been found to be both therapeutically active and relatively insoluble in water compared to the alkali metal salts of penicillin. In fact, comparisons with procaine-penicillin indicate that the diamine salt is significantly less soluble than the procaine salt and therefore exerts a more prolonged action when compositions containing the diamine-penicillin salt are administered orally or parenterally.

   It has been found that, whatever the type of composition used, for oral or parenteral route, the compositions according to the invention exert, under conditions of use similar to those applied to procaine-penicillin, an action which is prolongs at least two to four times more than that of procaine-penicillin.



   Among the problems posed by the preparation of the compositions containing the diamine salt is that of the preparation of a crystalline salt capable of being satisfactorily suspended in a liquid vehicle, in particular by avoiding excessive viscosities. , and that of the development of a composition that does not tend to block hypodermic guillas.



   It has been found that, whatever the method of preparation applied hitherto, the diamine salt of penicillin is always obtained in the form of large needle-like crystals, isolated or in the form of twins or dendrites, but always of crystal type acicular. If one attempts to use these crystalline materials in parenteral injection compositions. there is always a tendency for hypoder- needles to clog

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 mics of about 45 hundredths of a millimeter.

   One always comes up against the problem of plugging by needle crystals when using naturally formed crystals, regardless of the manufacturing process or treatment applied and, if: These crystals are reduced to a fine particular dimension, we come up against a new problem, namely the excessive viscosity of the solutions which makes their use extremely difficult.



   Attempts to obtain non-acicular crystalline structures which do not clog the standard hypodermic needles normally used for penicillin injections and do not collapse too much have been carried out on various recrystallization processes, after the different reaction modes have been carried out. failed to produce an acceptable product. Many known commercial solvents have been tried without success, either because of the insolubility of the salt in the solvent or because of the formation of predominantly circular crystals when the compound was appreciably soluble.



   It was found, quite unexpectedly, that if one prepares the salt of penicillin within formamide, in which it is very soluble, or if one recrystallizes the salt of penicillin in a needle in the breast of formamide, the crystalline type changes mainly to square or rectangular tablets or lamellae. The size of these lamellar crystals can be determined by the conditions applied. However, regardless of the size and thickness of the lamellae, this crystalline form is superior to the needle form for compositions intended for parenteral injections.

   In parenteral compositions containing both the acicular and lamellar forms with a predominance of the lamellar form, excessive viscosities or the plugging of the 45/100 mm needle are also satisfactorily avoided. . No other solvent has been shown to be as good as formamide in producing the diamine salt in an essentially lamellar form.



   The following example is an illustration of the method of preparing the acicular form of the penicillin salt described above.



    Example 1.



   About 63 g of potassium penicillin G are dissolved in 160 cc of water.



   It is also dissolved in 160 cc. water about 30 g. of N, N'-dibenzylethylene diamine diacetate.



   The two solutions are mixed dropwise, adding at the same time about 280 cc. of water, stirring during the addition, which takes about two hours. The crystallized product is filtered off and washed with water, then with acetone and dried. The crystals obtained are substantially needle-like, mainly in the form of twins and isolated needles. However, due to the slow addition, relatively thick crystals with a substantial length / width ratio can be obtained.



   The following examples illustrate processes for obtaining the novel lamellar form according to the invention of N.N-di-benzylethylene diamine-di-penicillin G.



    Example 2.



   100 g are dissolved. of penicillin potassium in 300 cc. 50% aqueous formamide.



   37 g are added. of N, N'-dibenzylethylene diamine to 2 liters of formamide and neutralized by adding 18.5 g. glacial acetic acid.



  To this solution heated to 55 ° C. is added with stirring the solution of potassium penicillin. Then slowly added 650 cco of water so as to cause crystallization. The mixture was cooled to 5 ° C. and the crystals were filtered off, washed with water, acetone and ether, then dried in a vacuum desiccator. The crystals obtained are

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 in the form of regular lamellae with an apparent density of 0.4. This product is satisfactory in the form of an aqueous suspension for injection.



    Example 3.



   100 g of potassium penicillin G are dissolved at room temperature in 360 cc. formamide adjusted to approximately pH 6.8.
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  The mixture is heated to 360C. and one agitates moderately.



   240 cc is mixed. of 1.25 N dibenzylethylene diamine diacetate to 36 Co with 290 cc. of formamide of approximately pH 6.8 and this mixture is slowly added to the solution of potassium penicillin. About 300 cc is then added. of distilled water and the complete mixture is cooled to 5 ° C. before
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 to separate by filtration the crystals of NoN'-dibenzyJéJ.è # diamine-dipenicillin G formed, 'The crystals are washed with acetone and 1 ethero. These crystals can, if desired, be coated with lecithin by washing using an ethereal solution of lecithin In the uncoated state, these crystals generally have the shape of dense and regular rectangular lamellae, with very few fine crystals.



  Example 4.



   100 Go of potassium penicillin G are dissolved in 2 liters of formamide at 55 Ce
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 To the stirred solution of penicillin-potassium hydroxide was slowly added 53.5 g. of NoN'-clibenZYlethylene diamine diacetata (110% of the theoretical amount) in 1100 cc. of water, at 50'DG ,. Crystallization occurs before all of the NoN'-dibenzyLethylene diamine diacetate solution has been added. The mixture is cooled in an ice bath before filtration. The crystals are washed with water, acetone and ether.



   The crystals are in the form of square, fairly regular lamellae.



   In the previous examples, a small amount of acetone (about one tenth of the volume of formamide) can be added to the solution of
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 penicillin-formamide so as to reduce its viscosity and facilitate filtration
The use of a predominantly anhydrous medium during the reaction results in thicker and denser crystals than those normally obtained in the presence of larger amounts of water.
In examples 2 and 3, it should be noted that either acid is added to formamide (example 2), or formamide is adjusted to a
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 pH close to neutral, that is to say around 6.8 (Example 3). It has been found that formamide generally contains ammonia, especially after standing, which decreases the yield of penicillin salt.

   Significantly better yields are obtained when formamide is treated with an acid so as to reduce the basicity to neutrality or even acidity.
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 said light. Any acid can be used, but it is preferable to choose an acid giving the same salt as the salt being treated. For example, if a diacetate of an alkylene diamine is used, it is preferable to use glacial acetic acid for the neutralization.



   Although the above examples relate to crystallization from a medium formed of formamide and water, the latter acting to decrease the solubility of the diamine salt in solution, accelerate crystallization and increase the yield, the lamellar crystals according to the invention can also be obtained in substantially pure formamide by reducing the temperature of a relatively hot solution of the penicillin salt in formamide.

   Conversely, although the examples relate to crystallization in a medium where formamide is in excess, which constitutes
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 the preferred process, it is still possible to obtain lamellar crystals even when the water content of the medium is such that the formamide content does not exceed

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 not about 15% by volume. However, if the water is in excess, the lamellar crystals are thin and are not as satisfactory as the thicker lamellae produced in excess formamide.



   The agitation of the solution during the formation of the crystals should not be too rapid if it is desired to obtain large and thick crystals.



  The anchor-shaped stirrer is suitable. Homogenizing type stirring produces excessive shear which results in particles that are too small. Relatively low temperatures during crystallization also give small lamellar crystals. Although one can use
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 temperatures reaching approximately 60 C. to form the penicillin salt, it is preferable to use a temperature of approximately 20 to 45 C. During crystallization, the solutions can be cooled to between 0 and 20 C.



   Examples 2 to 4 illustrate the crystallization of the penicillin salt from formamide containing a certain proportion of water in order to reduce the solutibility of the penicillin salt, and it has already been noted that One could operate in the presence of a weak offer of an alternative solvent to mechanically improve filtration. It is, however, also possible to carry out the crystallization from a mixture of solvents so as to obtain the desired lamellar crystals, on the condition that there is a significant proportion of formamide. We can thus obtain, at
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 using a mixture of formamide and dimethylformamide, penicillin crystals of the lamellar type provided that there is at least about 50% formamide in the solvent mixture.



   The following examples illustrate the recrystallization in lamellar form of crystals initially of the acicular type Example 5
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 25 g are dissolved. of NoN'-dibenzylethylenediamine-dipenicillin G in 500 cc of 60 Co formamide, and slowly added with stirring 150 cc. of water so as to precipitate la-dlbenzylethylene diamine -penicillin. When the addition of water is complete, the mixture is cooled to onc, filtered, washed with water, acetone and ether and dried in vacuo. Crystallized dibenzyl ethylene diamine penicillin is in the form of short square and rectangular lamellae.



  Example 6.
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 Dissolved at 60 ° C. 5 g. of penicillin potassium in the following solvent mixture:
Formamide 50 cc.



   Isopropanol 50 cc.



   Water 2.5 cc.



   Slowly add 1.20 cc (110%) of a 1.25 N aqueous solution.
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 of dibenzyléthy3.éne diamine diacetate to the stirred solution of potassium penicillin, then 50 cc. of water to complete crystallization. The mixture is cooled to 0 ° C. in an ice bath, filtered, washed with water, acetone and ether and dried under vacuum. The product titrated 1170 units per milligram. The crystals are in the form of square lamellae and short rectangles.



   Other solvents than isopropanol can be used, such as,
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 for example, methanol, ethanol, methyl cyanide, iacetone-alcohol, crystals of NN1-dibenzylethylene-diamine-dipEnicillin G suitable for the compositions for parenteral injections according to the invention, as obtained. in preparations 2 to 6 above, have the following physical and optical properties:
1. Crystalline form: lamellar (square or rectangular)
2. Crystal system: orthorhombic

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 3. Slow length or positive elongation.
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  .o Index of refraction parallel to the length s I956o 5. Index of refraction perpendicular to the length: a 19530
6. Strong birefringence (0.035).



   7. Parallel extinction 9 which indicates that the optical axes are parallel to the crystallographic axes
The process described above for obtaining the crystalline lamellar form instead of the acicular form is applied essentially to the preparation of parenteral compositions.



   Another aspect of the invention comprises the application of the method
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 described in the preparation of N.Nl-dibenzylethylene diamine-clipenillin to obtain the desired crystalline form in the preparation of special combinations having important medical properties.



   One process that has proven to be very interesting is the preparation
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 a combination of NoN'-dibenzylethylene diamine-dipenicillin and a relatively more water soluble salt of penicillin to achieve a high initial blood level, associated with a prolonged blood level. Another aspect of
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 the invention is the use of a combination of antibiotics so as to act on a wide range of bacteria. For example, the combination of iOH'-dIben2ylethylènēd amine -dlpenlellline with the sulfonamides has been shown to be surprisingly effective due to its unusually prolonged effect.



   Procaine-penicillin was the first penicillin-based antibiotic found to exert a prolonged action relative to the earlier well-known water-soluble penicillin salts. It appears, for example, that the effect of procaine-penicillin by injection is prolonged for at least 48 hours when injected at normal doses. Although the duration of action of procaine-penicillin has been recognized to be very advantageous in the treatment of many bacterial diseases, a composition was sought which would ensure higher blood levels during the same time.

   As a result of recent studies, compositions have been proposed containing a combination of procaine-penicillin with a water-soluble penicillin salt such as penicillin potassium. Attempts have been made to achieve the relatively higher blood level provided by the water-soluble penicillin salt;

  , combined with the prolonged concomitant action of the part formed by procaine-penicillin.,
It has been found, however, that although the combination of penicillin potassium and procaine-penicillin gives a higher blood level than procaine-penicillin only the duration of action of the composition is considerably reduced compared to that which would normally be expected. hope based on the action of procaine-penicillin itself In effect, the water-soluble salts of penicillin appear to act as solubilizing agents of less soluble forms of penicillin, greatly reducing the duration of action of procaine-penicillin.



  In fact, the duration of action of these compositions is reduced by 50%. To remedy this solubilizing effect, it then appears necessary to use appreciably larger proportions of procaine-penicillin so as to be able to maintain the initial effect at 48 hours. Repeated experiments have verified this phenomenon, which leads to the conclusion that the effect of any relatively water-soluble penicillin salt on a less soluble salt
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 is to reduce the normal duration of action of the latter salt.However, it has been found that, although the solubilizing effect is clear in the combinations of alkaline salts of penicillin and pxaeaâne pé = nicillin, some new compositions comprising a relatively soluble penicillin salt in water, combined with a relatively water insoluble penicillin salt,

   do not have the drawbacks noted for
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 the above-mentioned compositions It has been found that if we prepare corn #

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 positions of penicillin by using a special form of NoN'-dibenzylethylene diamine-dipenicillin, one can obtain compositions exerting a particularly prolonged action, with a high Initial blood level.
The compositions according to the invention do not show - or only insignificantly - a reduction in the prolonged action of the more soluble element of the composition. The compositions within the scope of the invention not only give the high initial blood levels produced by the most water soluble element of the composition, but also retain their action for a long time.

   There was thus prepared a composition containing a diamine salt and a relatively water soluble penicillin salt. Since the diamine salt could be expected
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 chosen by itself gives a certain blood level. for about 14 days, and the combination with the more soluble salt gives an effective level without
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 guin not exceeding about 7 days but a high initial level, the composition was unexpectedly found to give a high initial blood level and an effective duration of action of about twelve days.



   In order to prepare the combinations within the scope of the invention, one begins by preparing the suitable crystal form of the diamine salt of penicillin. As has been said, it is the lamellar crystalline form which. is best for just about any composition.

   A suitable control of the conditions, for example of the temperature, makes it possible to obtain lamellar crystals of various sizes and thicknesses.
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 However, whether the lamellae are large or small-, thick or- thin, they are superior to needles or acicular forms-for- parenteral compositions and, surprisingly, it is still the cs- even- when the lamellae have a dimension not exceeding 5 to 10 microns, because the excessive viscosities which are seen in the case of needle-like crystals do not
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 do not occur when the particle size s- of the lamellae is reduced to a low value.



   It should be mentioned that the penicillin crystals in the
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 Needle or acicular type are useful in "compositions whose potency is substantially less than 300,000 units per cubic centimeter. Excessive viscosities or bouchange can be avoided by using this type of crystals if potency is .. effectively maintained. at 2000000 u-
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 nlties per cubic centimeter or less. If one seeks a greater power, of the order of 300,000 units or more, the lamellar form of the crystals is essential.
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  It should be noted that while the lamellar form of the crystals is required for the injectable compositions, the needle penicillin crystals can be used for the aqueous drinkable or absorbable compositions. tablets. It will be noted that the compositions according to the invention can be used in the form of injectable compositions in suspension-liquid or in the dry state to be suspended at the time of use; they can also be used in the form of an aqueous suspension or in the dry state to be suspended at the time of use, to be absorbed orally. In addition, the compositions can be put in the form of tablets to be absorbed orally.

   Although the oral absorbable compositions have less prolonged effects than the injectable compositions, they are more easily administered and they provide
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 a higher blood level and a more prolonged effect than any of the compositions known until now.



     In general, all the compositions according to the invention
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 These include an N oN '-disubstituted alkylene diamine salt of penicillin in combination with a more water soluble penicillin salt. It is preferable to mix NoN'-dibenzylethylene diamine-penicillin or FoN'-di (alpha-methylbenzYl.) - eliblene diamine-penicillin with a more water soluble penicillin salt.

   or we can mix the two d1.WJ1inic salts so
In the case of dibenzylethylene diamine-penicillin, suitable compositions are prepared comprising an alkaline salt of penicillin.

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 or procaine -penicillin, or combinations of these three salts of penicillin Another composition according to the invention uses dibenzyl-
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 ethylenediamine-penicillin and NoN 'di- (alpha-methylbenzyl) -ethylene diamine-dipenillin. Another combination coming within the scope of the invention is a combination of the latter salt with an alkaline salt of penicillin in the form of a two-component mixture, or of an alkaline salt of penicillin with the dibenzylethylene diamine-penicillin.



   When preparing liquid suspensions for parenteral injections, an aqueous or oily suspension can be used, but the aqueous suspension is preferable. If an oily vehicle is used, it may consist of one or more vegetable oils, preferably
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 for $ 1 peanut oil or sesame oil.



   Whether the liquid is oily or aqueous, it is often desirable to use a suspending agent, but this is not always necessary. When an oily suspension is considered desirable a suitable suspending agent may be beeswax, hydrogenated vegetable oil or aluminum monostearate. In the case of aqueous vehicles, suitable suspending agents are hydrophilic products such as natural gums such as gum arabic, gum tragacanth.
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 icasaya gum, pectin, gelatin, agar-agar, dextrin, 9 etc. or hydrophilic synthetic agents and in particular carboxymethyl-cellulose salts, methyl-cellulose,

     polyvinyl-pyrrolidone or dextrano The term polyvinyl-pyrrolidone is understood here to mean the material described under this name, in the publication published in 1951 by General Aniline and Film
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 Corp and Development Dept o Nen Yoxs9 New Yor) 6 and dealing with its preparation, properties and applications.

   Of course, the suspending agents used must be substantially inert and harmless, in the proportions used in the compositions,
Injectable or drinkable compositions. regardless of salt
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 penicillin and the suspension agent (s) therein usefully contain a stabilizing or buffering agent intended to prolong the possible storage life and a preservative intended to inhibit bacterial or fungicidal action.

   Benzyl alcohol, sodium benzoate,
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 as well as the alkyl p-hydroxy benzoates are valuable preservatives, and calcium carbonate, the various phosphate buffer mixtures or any of the agents described in the patent.
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 United States of America No. 2 <> 438 106s of March 23, 1948, are suitable buffering agents.

   From mffma9 if other properties are desired, the penicillin particles can be coated with a wetting agent such as lecithin so as to increase the wetting characteristics.
 EMI7.8
 penicillin salt, and emulsifying agents, surfactants and anti-foaming agents can also be added such as, for example, various higher fatty acid partial esters of sorbitant or polyoxyalkylene known under the names of "Spans" or of "Tweens", alkyl-arylpo-
 EMI7.9
 lyether alcohols or their salts known as "tritons", dialkyl esters of sodium sultosuccinate known as "aerosols" and the like.

   The parenteral compositions can also contain a substance intended to make them isotonic, for example sodium chloride. For drinkable suspensions, coloring, sweetening and perfumes can be incorporated in order to make them acceptable to children.



   In the case of oily or aqueous suspensions intended for
 EMI7.10
 parenteral injections, the particle size of the penicillin salts may streak between approximately $ and 150 microns, a proportion of 95% of the particles preferably being less than 10 microns in size and a proportion of 50% being between 8 and 10 microns approximately. If he's
 EMI7.11
 question of a dry mixture. to be suspended in water at the time of use9, the particle sizes may be between about 5 and 150 microns, at least 50% of the particles being between about 20 and 40 microns.

   For drinkable compositions, of the aqueous type, the dimensions per

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   ticular s are substantially marls than for injectable aqueous suspensions.



   We can, for drinkable compositions, use the form
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 needle-like or lamellar crystal form of the penicillin salt, the lamellar form being preferable for liquid compositions. to avoid high viscosities. The particle sizes can, that is to say between approximately 5 and 150 microns. In the case of li-
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 In this case, relatively small particle sizes are used, about 50% of the particles having a size of 8-10 microns, while in
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 that of the tablets to be absorbed by mouth, one. can use sizes from 5 to 150 microns.



  Drinkable liquid compositions utilizing to1'-dibenzyl ethylene dlamine-dlpenlllline are remarkably valuable in infant therapy, especially for children who, due. of their young age, cannot swallow tablets. Drinkable compositions comprising this penicillin salt in a slightly scented aqueous vehicle have become very popular because of their ease of administration. So far all
 EMI8.4
 the known penicillin salts, and even procalne-penieillin, were sufficiently soluble in water to impart to the medication the characteristic bitter taste of penicillin.



   No fragrance agent was strong enough or oral enough to mask the bitterness of the penicillin. On the contrary, drinkable suspensions containing the diamine salt are of used insolubility in water such that they are practically tasteless.



   As with the injectable composition, any of the suspending agents described above, which are normally useful with an aqueous vehicle, the sodium salt of carboxymethyl cellulose, can be used for the drinkable liquid composition. again being the suspension agent of choice.



   The following examples illustrate the invention, but are of course in no way limiting.



  Example 7.



     An injectable therapeutic composition is prepared as follows:
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 37ibenzyl.ethylene d3amine-c3ipenicillin 3,000,000 units (lamellar crystals) (80% powdered) (20% uicronized} Penicillin potassium 100,000 units
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 The above composition is mixed with carbozymethylcellulose and sodium carafe, pulverized and "micronized" The product is sieved to an average particle size of about 70 microns, then it is sterilized. , in an aqueous vehicle, forms a suspension suitable for medical and veterinary uses.



  Example 8.



   A therapeutic composition is prepared in dry form suitable for being placed in an aqueous medium at the time of use, in accordance with the following formula:
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 Dibenzye1iethylene diami.nS-dipénicillne G 150,000 units (lamellar, pulverized) Frocaine-penioillin G (pulverized) 15? OpC1 units Penicillin potassium G 100,000 units
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<tb> (sprayed <SEP>) <SEP>
<tb>
 

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This composition is mixed with sodium citrate as above and sterilized. Flasks are filled with this dry and stable material so as to obtain a therapeutic preparation containing approximately 4,000,000 units of penicillin per cubic centimeter.
 EMI9.1
 



  Example 9o A therapeutic composition of the following formula is prepared: Dibenzylétbylene diamine-dipénictI .; L1.ine G 2,400,000 units (lamellar, pulverized) Dibenzylét.ethylene diamine-dipenicillin G 600,000 units
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<tb> (micronized <SEP> lamellar)
<tb> Procaine-penicillin <SEP> 3000000 <SEP> units
<tb>
<tb> (sprayed)
<tb>
 
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 This composition is mixed with carboxymethylellulose and sodium citrate and sterilized in the usual manner. Adding 2 cc of water to form a single dose gives a stable suspension for intramuscular injection for medical or veterinary use.



  Example 10.



   An aqueous suspension of a product prepared by the association of 300 million Oxford units of lamellar micronized crystals is prepared.
 EMI9.4
 of dibenzylethylene dlamine-dlpenicillin G and 100 million Oxford units of procaine-penicillin crystals sprayed with sodium citrate, lecithin, polyvinylpyrrolidone of carboxymethylellulose, sorbitant monopalmitate and polyoxyethylene-sorbitor monopalmitate, with the addition of benzoate as a preservative and enough water to obtain a volume of 1 liter.



   This therapeutic preparation is a regular suspension of
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 dlbenzylethylene diamine-dipenicillin G and procaine-penicillin G, stable and suitable for intramuscular injections for medical or veterinary purposes. Injection of 1 cco of this product provides 300,000 Oxford units of di-
 EMI9.6
 crystallized benzylethylene amine-dipenicillin G and 100,000 Oxford units of procaine-penicillin Go Example 11 A therapeutic composition is prepared in the dry state for subsequent suspension in aqueous suspension for injection, according to the formula:

   
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 Dîbenzylethylene diamine-dipenicillin G 1,500,000 units (pulverized lamellar) 13i- (alphanetlaylbenzyl) -ethyLene diamine-
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<tb> dipenicillin <SEP> G <SEP> (spray) <SEP> 150o000 <SEP> units
<tb>
 Mix thoroughly with sodium citrate and car-
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 boxymethylcellulose and sterilize the above composition, then put it in a vial, added with 1 cc. of water, it provides 300,000 units of penicillin for intramuscular injection for medical and veterinary uses. Example 12.



   A therapeutic composition is prepared in the form of a suspension.
 EMI9.10
 aqueous solution of marl as described in # 3mple 109 except that the penicillin elements are modified. In this case, 500,000 units of dibenzylethylene diamiI-d1pen1cl1line G are used instead of the 3,000,000 units indicated e1iap. instead of proQa'in-penici111ne G9 150,000 units of dî -, (alpha-methylbenzyl) -ethylene diamine-dipepicillin G in powdered state and coated with lecithin

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 Example 13.



   A therapeutic composition for the oral route is prepared by mixing 180 million Oxford units of "micronized" lamellar crystals of dibenzylethylene diamine-dipenicillin G with 180 million units of.
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 proaa! ne-penicillin Go To these antibiotics are added sucrose, a coloring matter, sodium citrate, carboXIII-ce1Jnlose and a benzoate as a preservative. Then add enough water
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 so that every fraction of 5 ce. The suspension provides approximately 300,000 Oxford units.



   We can replace procaine-penicillin G, in the example
 EMI10.3
 above, by penicillin potassium G or NoN '-di- (alpha-methylbenzyl) - ethylene diamine-dipenicillin Go Another drinkable composition may include a combination of dibenzyl salt, di- (alpha-methylbenzyl salt ) and penicillin potassium Go Other combinations falling within the scope of the invention will readily come to the mind of specialists.
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  The "micronisaT.i, on.l1 of the penicillin lamellae is effected by very fine grinding of the penicillin salt using a jet of pressurized air, which causes the fragmenting to a generally particle size. of the order of about 5 to 20 microns, but usually reading less than about 10 microns Spraying is carried out using a hammer device giving a relatively coarse fragmentation, of the order of over About 20 microns
 EMI10.5
 As stated in the above examples, suitable compositions can be prepared with or without suspending agents, but it is preferable to include them, and the preferable and main suspending agent is. carboxymethylcellulose The amount of this material which can be used in the above formulas can be between 0 and 1% by weight approximately.

   Polyvinylpyrrolidone can be used in a proportion
 EMI10.6
 tion up to 1.5%, agar-agar up to about 0.5%, dextrin, dextran, acacia gum up to about 8-, Karaya gum or Irish moss gel up to about 2%. Met2piceIIuIose with a viscosity of 1500 cpso, pectin and tragacanth can also be used in a proportion which can reach approximately 1%. Gelatin can be used up to approximately 4% and sodium alginate up to approximately 098.



  The content of stabilizing agent may also vary and the amount of sodium or potassium citrate may range from about 0.15 to about 5% by weight. Sodium phosphate, mono- or dibasic, is also effective and usable in an amount of about 0.05 to 2%.



   Regarding wetting agents, one can appeal
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 sorbitans and polyoxyaleoylene s well known derivatives. Mention will in particular be made of monolaurate, monopalmitatele monostearate and monooleate, in a proportion of between 0.05 and 0.3% approximately. When lecithin is added to the suspension, its proportion is between 0.1 and 3% approximately; in the form of a coating deposited on the penicillin, it is approximately 0.5 to 6% by weight.



   When we use preservatives, we can appeal
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 phenol, benzyl alcohol, sodium benzoate or lower alkyl p-hydroxybenzoate. The proportion of phenol can be understood
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 between Ofl25 and 0.5% by weight, that of benzyl alcohol and sodium benzoate between 0.5 and 1% by weight, that of methyl benzoate between 0.12 and 0.25% and that of propyl benzoate and butyl between 0.013 and 0.05% by weight, approximately.



   In the drinkable compositions, one can use a perfume, a coloring material or any sweetening agent, such as sucrose, sucaryl or saccharin. The proportion of sucrose can thus be from 5 to 30% by weight and that of - = aryl or of saccharin - from 32 to 260 mg.

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   All the above percentages express weights per unit volume of base, for example grams per 100 cc. The compositions according to the invention as described produce exceptionally prolonged blood levels with a high initial therapeutic effect. The more water soluble component of penicillin has not been found to significantly reduce the prolonged duration of action of the less soluble penicillin salt.
As has been pointed out, the bacterial spectrum can also be widened and for this purpose various sulfonamides can be combined with diamine-penicillin salts. It has been found that the combination of these compounds with the alumina gel gives unexpected results.



   It is generally accepted that adsorbents reduce the rate of absorption of oral drugs, in part by limiting their availability, in part by ensuring their access to absorbent surfaces (Sollmann,
A Manual of Pharmacology, 1948). It was therefore assumed that the simultaneous administration of a drug and an adsorbent by the buccal route lowered the rate and duration of action of the drug by opposing maximum absorption before elimination from the digestive tract.
It has been found that the improved antibiotic activity of a combination of sulfonamide and penicillin can be maintained for a longer period of time than has heretofore been possible.



   It has further been found that this combination can be provided in an acceptable drinkable form, either as an aqueous suspension or as a tablet. These results were obtained by the unexpected discovery that the incorporation of a combination of sulfonamide and penicillin in a vehicle consisting essentially of hydrated alumina as a long-acting agent improved the antibiotic activity of said combination.



   Further, due to the prolonged action exerted by such an adsorbent in this combination, it was believed that water-repellent oily materials, eg mineral oil, would enhance this long-acting effect by delaying solubilization. and absorption of the drug.

   This is not the case in fact, and it was unexpectedly found that the hydrated alumina associated with the antibiotic combination, in principle free of water-repellent oily materials, prolonged the duration of the therapeutic activity of the combination. with respect to a composition containing oily water-repellent materials
Although the present invention may concern only a single sulfonamide or a combination of several sulfonamides with therapeutic activity,

   it has usually been found desirable to use two or more sulfonamides to obtain the benefits of superior antibiotic activity and less risk of anuria etc. Particularly interesting results have been obtained by using, in the combination according to the invention, a triple combination comprising sulfadiazine (2-sulfanilamide-pyrimidine). sulfamerazine (2-sulfaniamido-4-methylpyrimidine) and sulfamethazine (2-sulfanilmido-4,6-dimethy;

  [uriomidne). Other well known sulfonamides can be used instead of the preceding ones. Thus, in the following combination, the invention is equally effective. Therapeutically active sulfonamides such as sulfaquinidine, sulfapidinela sulfasu; xidine, suflathalidne \ 1 sulfathiazole and sulfisoxi- xol.



     It has also been found that the use of substituted alkylene diamine salts of penicillin in the combination makes it possible to take advantage of the exceptional properties of these compounds to prepare drinkable drugs with high therapeutic activity and acceptable. . For example, one of the main objections to the use of the various penicillin salts in drinkable preparations is their characteristic bitter taste. the substituted alkylenediamine salts of penicillin are so insoluble

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 that their aqueous suspensions are practically tasteless and can be easily accepted orally.

   The relative insolubility and stability of these penicillin salts are also very advantageous in that the therapeutic inactivity is longer due to absorption.
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 slower, the stability with respect to deactivation by gastric secretions allows infrequent dosing to be administered ;, regardless of the gastric content, without risk of deactivation prior to absorption, and in that the increased stability prolongs the possible storage time.



   As has been said, the product according to the invention can be prepared in the form of dry tablets or in the form of an aqueous suspension.



  In the case of tablets :, the main ingredients are powdered hydrated alumina, a substituted alkylenediamine salt of penicillin (preferably dibenzylethylene diamine-dipenicillin G or "Benzé.; ..
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  1ibacillf) of su1.1 "adiazine of sulfamerazine, sulfamethazins9 with binders, excipients and coloring matter The main ingredients of the aqueous suspension are the salts of the supermenic penicillin.
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 agents, sulfonamides, aqueous alumina gel (preferably free from oily substances) preservatives; ,, scent materials and suspending agents ,,
The following example describes the preparation of a preferred composition according to the invention, but this example is of course purely il-
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 1.ustra'tive and not limiting, EMM] 21st LL.



   To 3 million units of dibenzylethylene diamine-dipenicilline G (in micronized lamellar crystals) are added 3.33 gb of sulfadiazine, sulfamerazine and sulfamethazine each. These antibiotics are mixed with 35 cc of gel of alumina. The mixture is then added to the mixture of magnesium aluminum silicate, hydrated with sugar, fragrances, glycerin and a benzoate as a preservative. Sufficient water is added to make 100 cc.



   It can be seen that the above composition, including 5 ce. contains
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 nent 150,000 Oxford units of diamond-penicillium and 0916 g of each of the sulfonamide, is effective in medical and veterinary therapy.



   Although the above examples illustrate the preparation of enhanced compositions ensuring a high initial blood level together with a prolonged action and also the preparation of a long-acting composition of penicillin and sulfonamides, the operator is in a position to prepare a simple composition containing only one antibiotic of the diamine type, when the aim is only for a prolonged action without seeking to reinforce the antibacterial action or to broaden the bacterial spectrum, and the invention is capable of variants without qu 'we move away from our frame and our minds
The following example relates to an oily composition
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 jectable using only lamellar crystals of N.N'-dibenzyl- ethylene eliamine-èli,

  penicillin & to Example 15
20 g are added to one liter of peanut oil. of powdered aluminum monostearate. The mixture is stirred slowly and heated, increasing the temperature by only 50 ° C. per minute at most. We heat
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 3usqu. To 125 Co with continued agitation, then the heating was stopped but continued. stir slowly until the gel has cooled to room temperature.



   Add 300 million Oxford units of lamellar crystals
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 dibenzylethylene diamine-dipenicillin G (of which 95% of the particles are

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 less than 10 microns) at 700 cc. peanut oil with 2% * aluminum monostearate, stirring slowly. A sufficient amount of peanut oil gel containing 2% aluminum monqstearate is then added to bring the volume of the suspension to 1 liter. The mixture is stirred for one hour so as to make a homogeneous suspension.
This therapeutic preparation is a homogeneous suspension of dibenzylethylene diamine-dipenicillin G,

   stable and suitable for administration by infra-muscular injection in humans and animals The injection of 1 cc. supplies 3,000,000 Oxford units of dibenzyl-ethylenediamine-dipenicillin G.


    

Claims (1)

All the compositions described obtained according to the methods of preparation described are effective in the treatment of bacterial diseases sensitive to the action of penicillin or desulfonamides. The particular interest of the invention is the prolongation of the action of the antibiotics and the detectable blood levels of penicillin which have been found in many cases after two weeks and even more, of course depending on the dose administered. . Process for the preparation of penicillin compositions, characterized by the following, singly or in combinations: 1) N, N′-dibenzylethylenediamine-dipenicillin is crystallized. in a medium comprising mainly formamide, said medium is isolated from lamellar crystals of. penicillin salt, these crystals are sprayed to obtain a particle size of less than about 150 microns and these crystalline particles are mixed with a carrier; 2) said carrier comprises a harmless salt of carboxymethylcellulose; 3) the penicillin salt is combined with another antibiotic of the penicillin type or of the suflonamide type; 4) dibenzylethylene diamine-dipenicillin G is associated with a more water-soluble salt of penicillin y 5) said more soluble salt is a) N.N'- dj- (alpha-methylbenzyl) -ethylene-diamine-dipenicillin; b) penicillin potassium G; c) procaine-penicillin G; 6) the penicillin salt is combined with at least one sulfamide.