IL28680A - Stabilized aqueous suspensions of benzathine penicillin - Google Patents

Description

28680 2 Stabilized aqueous suspensions of benzathine penicillin AMERICAN HOME PRODUCTS CORPORATION This invention relates generally to the stabilisation of aqueous suspensions of Ν,Ν'-dibenzylethylenediamine di-penicillin, which suspensions are capable of being stored without refrigeration.

The compound Ν,Ν'-dibenzylethylenediamine di-penicillin, hereinafter referred to as benzathine penicillin G, is described in U.S.A. Patent Specification No» 2 , 627,^91 (and corresponding foreign specifications) and has been firmly established as a standard antibiotic of proven usefulness in the treatment of many infections of the Gram positive type in man, including infections due to strepto-coccal and pneumococcal strains.

As described in said patent specification, benzathine penicillin G may be prepared by slowly adding a solution of Ν,Ν'-dibenzylethylenediamine diacetate in water to a solution of sodium penicillin G in water maintained at a lowered temperature (preferably about 0-½°C), filtering the slurry, washing the residue with cold water, and thereafter drying the residue to obtain the substantially water-insoluble product in the form of needle-like acicular crystals.

Among the problems found in preparing therapeutic compositions containing such crystals of benzathine penicillin G in a liquid medium was that the resulting compositions had excessive viscosities and a tendency to cause blockage of a hypodermic needle when parenteral administration was attempted. It was later discovered that, regardless of which known method was used for isolating the crystalline penicillin product, it was obtained as single needles or as rosettes or dendrites, but always acicular in crystal habit. In such form, the crystals provided therapeutic compositions which had a tendency to block hypodermic needles of 22 gauge (Stubbs) , and even the larger diameter 20 gauge needle. On the other hand, when the crystals were comminuted to small particle sizes, a new problem of excessive viscosity made the resulting compositions exceedingly difficult to use.

As described in U.S.A.patent specification No. 2,7^5,785, (and corresponding foreign specifications) it was subsequently found that, when the penicillin salt is prepared in a forraamide medium in which it is quite soluble, or when the needle-like crystals of the penicillin salt obtained by $he prior method of preparation are recrystallised from a formamide solution, the crystal habit is changed to a predominantly tabular or plate-shaped form of square or rectangulat shape. The size of these plates may be regulated depending on the precise conditions used. Regardless of whether they are large or small, or thick or thin, the platelet or tabular form of crystal has been found superior to the needle form for parenteral compositions. Even in compositions containing both acicular and tabular forms, where the tabular form predominates in the parenteral compositions; excessive viscosities or blockage of a 22 guage needle is satisfactorily avoided as long as the compositions are not stored for any length of time and/or exposed to high temperature conditions (e.g. for a few months at 35°C or higher)* A current typical commercial formulation for an aqueous suspension of a benzathine penicillin preparation in accordance with the Teachings in U.S.A. patent specification No. 2,7^5,785 is given below: FORMULA PER CC.

Benzathine Penicillin G (Micronised, lecithin coated) 300,000 μ Sodium Citrate, Anhydrous 10e0 mg.

Lecithin, R.G. 3»0 mg.

Polyvinylpyrrolidone, (K value 26-36) 3.0 mg.

Carboxymethylcellulose, (Type 7 HP) Sorbitan Monopalmitate Polyoxyethylene Sorbitan Monopalmitate Propylparaben, USP Methylparaben, USP Water for Injection, USP qs.ad Compositions of the above type have shown stability of the penicillin potency when stored at temperatures as high as 35°C. for as long as two years, but as has since been found, not in a practical, usable manner. For example, after only a few months at 3 °C the compositions became unusable because of discolouration and such pronounced gelling, that neither aspiration nor extrusion through conventional hypodermic needles may be effected.

Attempts have been made to obviate the aforesaid disadvantages of the otherwise highly useful benzathine penicillin G preparations of the prior art, which disadvantages are the more pronounced the higher the temperature conditions and or the longer the period of time of the increased temperature conditions to which the compositions are subjected. As suggested in U.S.A. patent specification ^.2,7^51785» lecithin has been included in the previously known formulations for facilitating resuspension and free drainage from a silicone coated vial„ Unfortunately however, although the lecithin increases as the penicillin potency stability, it also increases the gelling propensities of the compositions in an undesirable manner. Moreover, lecithin, being o idisable, causes early discolouration of the compositions. In an attempt to avoid these disadvantages in the use of lecithin, the latter has been omitted in the preparation of certain formulations for therapeutic preparations containing benzathine penicillin G. Although discolouration of the benzathine penicillin G compositions has been reduced to some degree by this expedient, the serious problem of gel thickening has not been obviated thereby.

We have now discovered that both discolouration and the gelling of the otherwise known aqueously suspended benzathine penicillin G preparations may be substantially prevented and a product of surprisingly increased storage stability, as well as of excellent reconstituting characteristics, obtained by the formulation of the present invention. We have found that the substitution of sodium formaldehyde sulphoxylate for lecithin in the vehicle, in conjunction with the inclusion of a particular surface-active combination as referred to hereinafter, results in potency-stable, colour-*stable and gel-stable aqueous suspensions of benzathine penicillin G, which are re-suspendible are fully usable for injection, even after storage for periods at least as long as l8 months at temperatures as high as 35°C.

Accordingly, the present invention provides a stabilised therapeutic composition comprising comminuted crystals of benzathine penicillin G in an aqueous suspending medium which includes polyvinylpyrrolidone and a minor storage-stabilising amount of sodium formaldehyde sulphoxylate, the polyvinylpyrrolidone being present in an amount equal to at least ten times the weight of the sodium formaldehyde sulphoxylate.

In preparing the benzathine penicillin G for inclusion in the aqueous parenteral compositions of the invention, the particle size of the penicillin salt may range from 5 to 150 microns, but preferably at least 60 per cent of the particles should be less than 10 microns in size with approximately 50 per cent of the particles having a particle size from 8 to 10 microns. In accordance with a preferred feature of the present invention, the penicillin particles are pre-coated with a wetting agent to increase the wetting characteristics of the penicillin salt. Eminently suitable for such purpose has been found to be a coating solution containing a mixture of a polyoxyethylene sorbitan - - monolaurate (particularly that obtained commercially as Tween 20) and stearyl alcohol. The coating solution is preferably prepared by dissolving the monolaurate and the alcohol in acetone medium in proportion so that the monolaurate comprises from 1.2 per cent to 1·6 per cent and the alcohol comprises from 0.5 per cent to 0.9 per cent of the solution.

Preferably, the sodium formaldehyde sulphoxylate is included in the aqueous suspensions in amounts which provide from 0,05 per cent to 0.5 per cent of the total compositions on a weight to volume basis. Sodium formaldehyde sulphoxylate, obtainable as white crystals having a melting point of 65°C. , is soluble in water.

The major suspending agent for the penicillin is polyvinylpyrrolidone in an amount equal to at least 10 times and preferably more than 25 times the weight of the sodium formaldehyde sulphoxylate present. Generally therefore, the polyvinylpyrrolidone content of the compositions may be varied from 5«0 per cent to 15.0 per cent by weight thereof. In some instances, if desired, other suspending agents in minor amount may be included to provide the total suspending agent employed.

As additional suspending agents, there may be included in the compositions, in minor amounts, either salts of carboxymethylcellulose, methyl cellulose, gelatin, pectin, agar, gum, tragacanth or gum karaya, or mixtures of these agents. Other suspending agents which are assimilable in the body and which are relatively non-toxic in the amounts used may be used in addition to polyvinylpyrrolidone and in place of those specifically mentioned.

In preparing the storage-stabilised aqueous parenteral compositions of the invention, in addition to the preferably coated particles of penicillin salt as described herein, the sodium formaldehyde sulphoxylate, and the comparatively large portion of polyvinylpyrrolidone as suspending agent, it has been found useful to have a buffering agent present in order to extend the shelf-life, and a preservative to inhibit bacterial or fungal action. Methyl paraben, propyl paraben, sodium benzoate, as well as the alk l-p_-benzoates are useful preservatives; while suitable buffers for the penicillin are sodium citrate, CaCO, , various mixed phosphate buffers or any of the buffers described in U.S.A. Patent Specification No .^", ^38 , 106.

The buffer content may vary in the formulations from 0.5 per cent to 5· 0 per cent by weight, while the preservative content may also be varied within the range of 0.15 per cent to 0„ 25 per cent for the methyl derivative and 0.015 per cent to 0.05 per cent for the propyl derivative.

The following advantageously may be added to the compositions, namely emulsifiers, surface-active and defoaming agents, such as various partial higher fatty acid esters of sorbitan or polyoxyalkylene derivatives thereof known as Spans or Tweens; aryl alkyl polyether alcohols or salts thereof known as Tritons; and the dialkyl esters of sodium sulphosuccinic acid known as Aerosols. Preferred for the compositions of the present invention is Dow Corning Antifoam-AF Emulsion.

While EDTA disodium (ethylenediamine tetraacetic acid disodium salt) is preferred for its anti-foam action complementary to that of the AF Emulsion; there may be used in place thereof, in certain instances, the monolaurate, monostearate or monooleate sorbitans, and or the corresponding polyoxyethylene derivatives thereof. These surfactant agents may be used to the extent of from 0.05 per cent to O.3 per cent by weight. All of these percentages are on a weight basis, in grams per 100 cc. of liquid volume.

The following non-limiting Example illustrates the inventions EXAMPLE The following are added, with agitation, to 666 cc. of water for injection (U . S.P.).

GRAMS Sodium citrate 15«23 Polyvinylpyrrolidone (K value 26-36) 53» 20 Eo De Te A. disodium 1.13 Dow Corning Antifoam-AF Emulsion 0.18 With constant agitation, the resulting mixture is sterilised at 121°C. and 15 lbs. pressure for one hour, and cooled immediately to 60C; 0.21 gram of sterile propylparaben is then added with agitation until dissolved; followed by the addition of 1.82 grams of sterile methylparaben with agitation until dissolved.

After this mixture has cooled to 25°C. , 75 cc. of k per cent weight by volume sterile solution of sodium formaldehyde sulphoxylate, followed by 300,000 Oxford units of sterile micronised benzathine penicillin G tabular crystals (1, 170 units/mgo) (60 per cent of the particles being less than 10 microns) per cc. of final product are added with continuous agitation. The penicillin salt particles are coated previously with a coating solution comprising a mixture of polyoxyethylene sorbitan monolaurate and stearyl alcohol in acetone in proportions so that the solution comprises 1.6 per cent of the former substances and 0.9 per cent of the latter. The coating solution is then used in proportions which furnish 2 0 mg. thereof per 300,000 units of the penicillin salt. The coated penicillin crystals are thereafter vacuum dried and the product is then pulverised in a Fitzmill having a 60 mesh screen. Sufficient quantity of water for injection (U.S.P.) is then added to bring the volume of the suspension to one litreo Agitation is continued for one hour to ascertain a homogenous suspension. The latter is then homogenised in a Bantam Micropulveriser« The resulting therapeutic preparation is a uniform suspension of benzathine penicillin G which is stable and suitable for intramuscular injection into humans or animals. Injection of one mlo of this product furnishes 300,000 Oxford units of crystalline dibenzylethylenediamine di-penicillin G. After 18 months at 35°Co , the potency diminishes less than 5 per cento More importantly, the easily re-suspended compositions are still of suitable colour and viscosity to permit injection with the use of hypodermic needles as thin as 23 gauge.

Claims (12)

AHP-3879-fl HAVING FQ particularly described and ascertained the nature of our said invention and in what manner the same is to be performed, we declare that what we claim is

1. A stabilised therapeutic composition comprising comminuted crystals of benzathine penicillin G (i.e. Ν,Ν'-dibenzylethylenediamine di- penicillin) in an aqueous suspending medium which includes polyvinylpyrrolidone and a minor storage-stabilising amount of sodium formaldehyde sulphoxylate, the polyvinylpyrrolidone being present in an amount equal to at least ten times the weight of the sodium formaldehyde sulphoxylate.

2. A stabilised therapeutic composition as claimed in Claim 1, wherein at least 60$ of the benzathine penicillin G has a size less than 10 microns.

3. A stabilised therapeutic composition' as claimed in Claim 1 or Claim 2, wherein the comminuted crystals of benzathine penicillin G are coated with a coating composition comprising a synthetic wetting agent.

4. , A stabilised therapeutic composition as claimed in Claim 3, wherein the wetting agent is a mixture of polyoxyethylene sorbitan monolaurate and stearyl alcohol.

5. A stabilised therapeutic composition as claimed in any of the preceding claims, wherein the sodium formaldehyde sulphoxylate is present in an amount of from 0.05 to 0.5 by weight of the total composition on a weight to volume basis. — I o

6. A stabilised therapeutic composition as claimed in any of the preceding claims, wherein the polyvinylpyrrolidone is present as 5.0 to 15·0 by weight of the total composition.

7. A stabilised therapeutic composition as claimed in any of the preceding claims, said composition also including one or more additional suspending agents, emulsifiers, surface active agents and/or anti-foaming agents.

8. A stabilised therapeutic composition as claimed in Claim 7» containing a salt of carboxymethylcellulose, methylcellulose, gelatin, pectin, agar, gum tragacanth or gum karaya.

9. A stabilised therapeutic composition as claimed in any of the preceding claims wherein the composition also contains from 0.5 to ·0# by weight of a buffering agent.

10. A stabilised therapeutic composition as claimed in any of the preceding claims, wherein the composition also contains a preservative to inhibit bacterial or fungal action.

11. A stabilised therapeutic composition as claimed in any of the preceding claims, wherein the benzathine penicillin G is present in a proportion affording approximately 300,000 units potency per 1 cc. of total composition*

12. A stabilised therapeutic composition as claimed in Claim 1, having the following formulation: - I I - COMPONENT PER CC. Benzathine Penicillin G, (Micronised, coated with 250 mg. of a solution containing from 1.2-1.6 per cent of a polyoxyethylene sorbitan monolaurate and from 0.5-0.9 per cent of stearyl alcohol) 300,000 μ Sodium Citrate 15.23 mg. Polyvinylpyrrolidone 53.20 mg-. Sodium Formaldehyde Sulphoxylate 1.52 mg. Propylparaben 0.21 mg. Methylparaben 1.82 mg. E.D.T.A. disodium 1.13 ∞g. Dow Corning Antifoam-AF Emulsion 0el8 mg. Water for injection (U.S.P.) to make 1.0 cc. A method of preparing a therapeutic composition as defined in Claim 1, which method comprises first admixing the recited ingredients to form a suspension and therafter homogenising the suspension. A* method as claimed in Claim^i^ substantially as described with reference to the Example. A stabilised therapeutic composition when prepared by the method claimed in Claim 13 or Claim Ik.