IL31431A - Therapeutic compositions containing penicillin derivatives - Google Patents

Description

'I'V's jD. nn m o»^»3&¾, ^'na ^n δ»;ΐ 3ΐ» Therapeutic compositions containing enicillin derivatives BRISTOL-MTERS COMPAHY Ct 29673 31431/2 This Invention relates to compositions having value as antibacterial agents useful in the treatment of infectious diseases caused by Gram-positive and Gram-negative bacteria. More particularl , this, invention relates" to compositions containing alpha-aminobenzyl- penicillin trlhydrate which can be administered intramuscularly and to the process for making such compositions.

■ Alpha-aminobenzylpencillln trlhydrate is also known in the technical literature as amplcillin trlhydrate ' and has been found useful in the treatment of both Gram- positive and Gram-negative bacterial infections., Alpha- aminobenzylpenicillin can be administered either orally in the form of capsules, tablets or aqueous suspensions, or, intramuscularly in the form of aqueous suspensions.

Alkali metal salts such as the sodium salt of alpha- aminobenzylpeniclllin. ! have been found to be more soluble- in water and thus are more readily adaptable to be used in aqueous compositions which can be administered either intravenously or intramuscularly. The sodium salt- ,of alp'ha-aminobenzylpenicillin has ;been preferred for use in compositions which are intramuscularly administered due / '''' . ' to its ' increased solubility in water..

Although sodium alpha-aminobenzylpenicillln exhibits physical properties which in some respects makes It .preferable fpr use in intramuscular or intravenous compositions, it suffers from the serious drawback1 of/ eing •la- relatively unstable and 'quickly losing its potency. This requires that sodium alpha-aminobenzylpenicillin aqueous solutions which have been reconstituted from powder form must be administered within one hour afte the reconstitu-tion. This instability seriously limits the use of sodium alpha-aminobenzylpencillin in aqueous compositions since the required dosages must be made up individually just prior to expected use and this can result in either a great deal of lost time in preparation of a large number of dosages or i excessive spoilage of the product.

It is an object of the present invention to provide ( · compositions containing alpha-aminobenzylpenicillin tri- I hydrate which can be administered intramuscularly. It is another object of the present invention to provide compositions having improved stability when reconstituted with water. It is a further object of the present invention to provide compositions which quickly release a high amount of alpha-aminobenzylpenicillin in the bloodstream of animals including man, thus producing high serum levels of the penicillin and which also produce prolonged high serum levels of the penicillin.

In accordance with the present invention, a composition,.is provided which can be employed to producie intra-muscularly administrable aqueous suspensions. The compo-sltions contain particulate alpha-aminobenzylpenicillin 31431/2 trihydrate having a Bize less than about 100 mesh and having the formula: The particulate alpha-aminobenzyl- . penicillin is coated with physiologically acceptable hydrophilic and lipophilic surfactants.

' A method for preparing alpha-aminobenzylpenicillin trihydrate is described in U. S. Patent No. 3j 157*6^0.

The present invention provides a process for the preparation of an antibacterial composi'tion suitable for recohstitution with water to form a suspension. for intra- • muscular use, characterized in that particulate alpha- trihydrate aminobenzylpenicillin/naving a size less than about 100 mesh is mixed with an organic solvent solution of a physio- ' logically acceptable hydrophilic surface active agent and a physiologically acceptable lipophilic surface active agent, followed by evaporation of the solvent to produce trihydrate particulate alpha-aminobenzylpenicillin which is coated with a,mixture of said surface active agents, and pulverizing said coated material so that not more than 1 by weight is ^ larger than 200 mesh. - Suitable lipophilic surface active agents which can be employed include lecithin, esters derived by reacting fatty acids such as laurlc, palmitic, stearic;' oleic, or mixtures thereof, with hexital anhydrides derived from sorbitol; and' mixtures thereof. Specific examples 31431/2 4 of such esters include Span 40 (sorbitan monopalmitate ) and Span 85 (sorbitan trioleate) marketed by Atlas Chemical Company. Suitable hydrophilic surface active agents which can be employed include ester-ethers derived by reacting ethylene oxide, fatty acids and hexitol anhydrides to produce ester-ethers such as Tween 40 (sorbitan monopalmitate polyoxyalkylene derivative) and Tween 85 (sorbitan trioleate polyoxyalklene derivative) marketed by Atlas Chemical Company. Such surfactants are well known in the art. · It has been found that the . compositions of the present invention can be readily reconstituted to form aqueous suspensions. The resultant suspensions are charac-. terized by excellent fluidity, slow settling, easy resuspen- sion and, when employed for intramuscular administration from presently available silicone coated vials, by excellent drainage therefrom. Furthermore, the compositions of the present invention, after being' reconstituted, exhibit excellent stability allowing a minimum use life of 14 days when stored at 25° C.

Coated penicillins preparations are known, e.g. from British Patent Specifications 660,551, 655,519 and 709,108 and from US Patent Specifications 2,694,665 and 2,793,156. The penicillin in all those known preparations is Penicillin G or' a salt thereof, and in the coating of the penicillin particles, use is made of either a hydrophilic surfactant (e.g. tweens) or a hypophilic one (e.g. lecithin). It has been found that the coating, of ampicillin trihydrate in accordance with these known processes, did not result in effective stabilization of aqueous suspensions of hypophilic surfactants was used in accordance with this invention.

The compositions of the present invention are prepared by coating or mixing particulate alpha-aminobenzyl- penicillin trihydrate having a size less than about 100 mesh and preferably having a size so that at least about 99 weight percent is less than about 200 mesh with a solution of physiologically acceptable surfactants containing a hydrophilic surfactant and a lipophilic surfactant. The coating solvent employed is one which will dissolve the surfactants to form true solutions rather than suspensions and thus promote homogeneous mixing with the alpha-amino- benzylpenicillin trihydrate. Solvents suitable for use in this invention will be apparent to those skilled in the art; such solvents include chloroform, methylene chloride, trichlorethylene, ether and petroleum ether. The amount of surfactant solution employed is that which will adequately coat the alpha-aminobenzylpenicillin trihydrate particules upon removal of the solvent while not being so much as to seriously dilute the antibacterial properties of alpha-aminobenzylpenicillin trihydrate. Accordingly, the surfactant solution and alpha-aminobenzylpenicillin trihydrate preferably are mixed so that the resultant solvent-free material contains between about 1.0 and about 10.0 weight percent, preferably between about 1.5 and about 6.0 weight percent surfactants based upon the weight of alpha-aminobenzylpenicillin trihydrate. After the solution and alpha-aminobenzylpenicillin trihydrate have been intimately mixed, the solvent is removed therefrom as for example by air drying at 40-50° C. for 2 hours. The coated particulate material from which the solvent has been substantially completely removed is then pulverized so that not more than about 1 weight percent thereof is larger than 200 mesh.

The compositions of this invention, prior to being mixed with aqueous mediums, can be mixed with physiologically acceptable preservatives which assist in maintaining sterility of the reconstituted product. It is preferred to employ preservatives which are particularly effective in aqueous mediums. Suitable preservatives which can be employed include methyl-p-hydroxybenzoate, propyl-p-hydroxybenzoate, sodium benzoate and or mixtures thereof.

These materials in powder form are added to the coated - mixtures are blended to obtain a homogeneous solid particulate mixture. Furthermore, since the preservatives are in particulate form, they can be first mixed with the alpha-aminobenzylpenicillin trihydrate and the resultant mixture blended with the surfactant solution. The final composition is then obtained in the manner described above by removing the solvent .

The compositions of this invention can be mixed with aqueous mediums to form a suspension which can be intramuscularly administered to animals including human beings. It is most convenient to store the compositions of this invention in vials having the internal surface coated with materials which facilitate removal of the composition therefrom, such as silicone polymers. The powdered composition and- the aqueous medium are mixed and agitated. to form an aqueous suspension of the powder. The suspension can be easily intramuscularly administered with a syringe.

It is to be understood that the process for making the compositions of this invention can be conducted under aseptic conditions to eliminate or greatly reduce the possibility of pathogens being associated with the com— positions of this invention.

It is also to be understood that the compositions of the present invention can contain additional ingredients which enhance the use thereof in intramuscularly adminis-trable compositions. Thus, physiologically acceptable materials which suppress color formation such as dodecyl gallate or ascorbic acid (or its sodium salt) can be employed. Furthermore, physiologically acceptable buffers such as sodium citrate, sodium phosphate or sodium hexametaphosphate can "be added to these compositions as well as other ingredients such as sodium acetate, sodium chloride, methylcellulose, or polyvinylpyrrolidone.

In use, the effectiveness of these compositions, will- depend upon various factors including age, weight, sex and physical condition of the patient. Usually, in practice the composition is given preliminarily in small dosages, and the increasingly larger dosages until satisfactory effectiveness is obtained without significant side effects. Normally, the dosage of active alpha-aminobenzylpenicillin trihydrate will be in the range of from about 50 to about 500 milligrams and at a frequency of 1 to 4 times per day. These variables can be adjusted to the need of the patient by gradually increasing dosages.

The following examples are intended to illustrate the present invention and are not intended to limit the same.

EXAMPLE 1 Alpha-aminobenzylpenicillin trihydrate was pulverized through a water cooled sterile mill equipped with a 100 mesh screen and run at 85ΟΟ rpm at the rate of kilograms per hour. The pulverized product was sufficiently small to pass through a 100 mesh screen with about 25 being sufficiently small to pass through a 200 mesh screen and was collected in a sterile container. A separate batch of alpha-aminobenzylpenicillin trihydrate was micronized to contain a particulate product having a size less than 20 microns. The pulverized and micronized. alpha-aminobenzylpenicillin trihydrate were mixed in amounts of three arts of micronized roduct to one art of ul blender which was adapted for liquid addition, which had been rendered sterile by spraying with peracetic acid and exposure to ethylene oxide gas to 16 hours prior to use. After the mixture was. added, the blender was run two minutes to assure homogeneous blending thereof. A chloroform solution of surfactants shown in Table I was then added in five equal parts to the alpha-aminobenzylpenicillin trihydrate mixture.

Table I Weight % of Total Ampicillin Used Lecithin 2.5 Span kO 1.2 ■ Tween 40 2.0 After each addition of solution, the resultant mixture was agitated to obtain a homogeneous mixture. At the' termination of each blending period, the pressure developed during the blending process was released and vacuum was applied to remove chloroform vapors. To aid in the evaporation and removal of vapors, heat was applied to the shell by circulating hot water through the walls to maintain a mixture temperature of '32-33° C.

After all the solution had been added and blended and the vapors removed therefrom, the residue was removed from the blender and trayed for drying. The residue was placed in covered trays in an air atmospheric oven and dried for six hours at a temperature of between -3° C and 4-9° C. After six hours of heating, the heat was turned off and air was circulated over the tra s for 10 hours to assure complete drying of the surfactant on the particulate alpha-aminobenzylpenicillin trihydrate. The coated material was removed from the trays and repulverized to obtain particles of a size less than 200 mesh. The coated pulverized alpha-aminobenzylpenicillin trihydrate was added in portions to a sterile mixture of particulate methyl-p-hydroxybenzoate, propyl-p-hydroxybenzoate and methylcellulose of a particle size less than 200 mesh. The entire blending process took about two hours to complete. The weight ratio of coated alpha-aminobenzylpenicillin trihydrate to the sterile mixture was about 5 to 1.

The mixture was then used to fill silicone coated vials under aseptic conditions so that each vial contained the following dosage : Table II 1 Dose Vial Alpha-aminobenzylpenicillin trihydrate (200 mesh) 0.0625 grams (25 ) Alpha-aminobenzylpenicillin trihydrate (micronized) O.I875 grams (75$) Lecithin 0.00β grams Span 0 O.OO3 grams Tween -0 O.OO5 ml.

Methyl-p-hydroxybenzoate O.OOO9 grams Propyl-p-hydroxybenzoate 0.0001 gram Methyl Cellulose 0.002 grams . The above formulation, when mixed with water and agitated, produced suspensions which were readily adaptable for intramuscular administration. Furthermore, the aqueous suspension showed the following stability when tested' under the following temperature conditions.

Powder Stability; 1.8$ loss after months at 5β° C. 6.9$ loss after 6 months at 5° C.

Reconstituted Stability; 2$ loss after 1 month at room temperature or 4° C.

EXAMPLE 2 According to the method set forth in Example 1, five-dose vials of the following composition were prepared: Table III Dose Vial Alpha-aminobenzylpenicillin trihydrate (200 mesh) 0.3125 grams (25$) Alpha-aminobenzylpenicillin trihydrate (micronized) 0.9375 grams (75$) Lecithin 0.03 grams Span 40 O.OI5 grams Tween 40 O.025 ml.

Methyl-p-hydroxybenzoate 0.0045 grams Propy1-p-hydroxybenzoate O.OOO5 -grams Methyl Cellulose 0.01 gram The above formulations when mixed with water and agitated produced suspensions which were readily adaptable for intramuscular administration. Furthermore, the aqueous suspension showed the following stability when tested under Powder Stability; 6 loss after 4 months at 5° C.

Reconstituted Stability: Less than 5 loss after 1 month at room temperature or 4° C.

EXAMPLE 3 According to the method set forth in Example 1, five-dose vials of the following compositions were prepared: Table IV Dose Vial Alpha-aminobenzylpenicillin trihydrate (200 mesh) 0.625 grams (50$) Alpha-aminobenzylpenicillin trihydrate (micronized) 0.625 grams ( 0 ) Lecithin 0.03 grams Span 40 0.015 grams Tween 0 0.025 ml.

Methyl-p-hydroxybenzoate 0.0045 grams Propy1-p-hydroxybenzoate 0.0005 grams Methyl Cellulose 0.01 gram The above formulations when mixed with water and agitated produced suspensions which were readily adaptable for intramuscular administration. Furthermore , the aqueous suspension showed the following stability when tested under the following temperature conditions.

Powder Stability: 6. $ loss after 6 months at 45° C.

Reconstituted Stability: 0% loss after 1 month at room temperature or 4° C.

EXAMPLE 4 According to the method set forth in Example 1, five-dose vials of the following composition were prepared, Sterile polyvinylpyrrolidone was substituted for methyl cellulose and no Span 40 was employed.

Table V Dose Vial Alpha-aminobenzylpenicillin trihydrate (200 mesh) 0.3125 gram ( 5 ) Alpha-aminobenzylpenicillin trihydrate (micronized) 0.9375 gram (75$) Lecithin 0.03 gram Tween 0 Ο.Ο37 ml.

Methyl-p-hydroxybenzoate 0.004-5 gram Propy1-p-hydroxy enzoate O.OOO5 gram Polyvinylpyrrolidone 0.5 gram The above formulations when mixed with water and agitated produced suspensions which were readily adaptable for intramuscular administration. Furthermore3 the aqueous suspension shows good storage stability.

EXAMPLE 5 Formulation A was prepared in accordance with the procedure set forth below.

Table VI Formulation A Per 5 Dose Vial Alpha-aminobenzylpenicillin trihydrate (200 mesh) 1.497 grams Lecithin 0.027β5 grams Span 40 O.OI305 grams Tween 40 0.03β7 grams Carboxymethylcellulose O.OI975 grams Anhydrous Sodium Citrate Ο.Ο2252 grams Formulation A was prepared by blending particulate alpha-aminobenzylpenicillin trihydrate and carboxymethylcellulose and passing the mixture twice through a 200 mesh screen. The lecithin^ Span 40 and Tween 40 were dissolved in 20-30 milliliters of chloroform and this solution was used to triturate the alpha-aminobenzylpenicillin trihydrate-carboxymethylcellulose mixture. The result material was air-dried for 20 hours at 5° C. and thereafter passed through a 200 mesh screen. The material was recovered and blended with sodium citrate by mixing in a blender for one half hour and passing the resultant mixture through a 200 mesh screen. This blending and screening operation was repeated three times.

A second formulation "B" was prepared by adding t Formulation A methyl-p-hydroxybenzoate and propyl-p-hydroxy benzoate to obtain a 5 dose formulation shown in Table VII.

Table VII Formulation B Per 5 Dose Vial Alpha-aminobenzylpenicillin trihydrate (200 mesh) I.4 7 grams Formulation B Per 5 Dose Vial Lecithin 0.027β5 grams Span 40 O.OI305 grams Tween 40 0.03674 grams Carboxymethylcellulose O.OI975 grams Anhydrous Sodium Citrate O.02252 grams Methyl-p-hydroxybertzoate 0.0045 grams Propyl-p-hydroxybenzoate O.OOO5 grams The formulations set forth in Tables VI and VII were reconstituted with .3-9 milliliters each of sterile water, resulting in 5 milliliters of a 250 mg. of ampicillin activity per milliliter suspension of alpha-aminobenzyl-penicillin trihydrate. The suspensions in each of the vials were tested at room temperature (24° C.) and with ice (4° C. ) to determine the stability thereof. Each of the suspensions were sampled to determine the stability by diluting 0.5 ml. of the suspension to 50 milliliters with a sterile 1% solution of pH 6.0 phosphate buffer.

Table VIII Room Temperature (25° C. ) 1 4 7 14 21 Formulation Orig. Day_ Days Days Days Days meg. /ml. A 25ΟΟ 25ΟΟ 2475 26ΟΟ 2500 2500 Loss - 0 -1 +4 0 0 meg./ml. B 2350 2400 2500 2600 25ΟΟ 2 00 fo Loss +2.1 +6.4 +10.6 +6.4 +6.4 ICE (4° C. ) . Formulation Orig. 1 week 2 weeks 3 weeks meg./ml. A 2350 26ΟΟ 25ΟΟ 2500 me ./ml. B 2600 2500 2475 2450 Loss _ 3.85 4.8 5.8 EXAMPLE 6 According to the method set forth in Example K} 16 dose vials of the following composition were prepared.

Table IX 16 Dose Vial Alpha-aminobenzylpenicillin trihydrate (200 mesh) 4.73 grams Lecithin 0.064 grams Tween 40 O.08 ml.

Meth l-p-hydroxybenzoate 0.0144 grams Propyl-p-hydroxybenzoate O.OOI6 grams Polyvinylpyrrolidone 1.6 grams Sodium Chloride O.096 grams The above formulation when mixed and shaken with sufficient water to give 200 mg./ml. ampicillin activity results in a suspension which was readily adaptable for intramuscular administration. This suspension was stable with less than 10$ loss for at least one month at room temperature or 4° C. Similar concentrations of sodium ampicillin in water must be used within 1 hour and show greater than 60$ loss for 2 hours at room temperature. In Table X there are presented serum levels obtained after intramuscular and oral administration of sodium ampicillin and ampicillin trihydrate in human subjects. The intramuscular ampicillin trihydrate formulation shown therein was the coated material prepared according to this invention and described in Table IX.

Since prior art has shown that salts or derivatives of antibiotics having low solubility give extremely low initial serum levels and low prolonged serum levels following intramuscular injection which are inferior to the oral dosage counterpart, it is a novel and unexpected result that the initial serum levels obtained after the intramuscular injection of the ampicillin trihydrate composition of this invention are equivalent to the initial serium levels obtained after oral administration of the very soluble sodium ampicillin salt and more than twice as high as the initial serum levels obtained after oral administration of ampicillin trihydrate. Also, after having these high initial serum levels, it is equally unexpected that high prolonged serum levels continue to exist after intramuscular administration of the ampicillin trihydrate composition through twelve hours after injection. In addition the prolonged high serum levels obtained after intramuscular injection of the ampicillin trihydrate composition are non-existant after oral administration of sodium ampicillin and ampicillin trihydrate or the intramuscular injection of sodium ampicillin.

Table X Human serum levels obtained after intramuscular and oral a and Ampicillin Trihydrate.

Dose (Ampicillin S ^Prepared according to Example 6 and shown in Table IX Example 7 According to the method set forth in Example vials of the following compositions were prepared •H H H Φ Φ -P -p O £ . oj oj •H CO O O £ CD' N N Φ C a a ft Φ Φ 0 H O x> XI T3 iO !» •H N 0J H Φ o O O ■a Φ X> Φ .■a ■ΰ O -P > O ΰ <& ■G ft H •d 1 1 H ε ¾ o a > ft ft > •H -=* 1 1 a 1 Λ J H H •rl Per On 2-Does V Alpha-aminobenzylpenicillin Trihydrate (200 mesh) O.7OO Gr Lecithin 0.012 Gr Tween 40 OIOI5 Ml Methyl-p-hydroxybenzoate O.OOI8 G Propyl-p-hydroxybenzoate 0.0002 G Polyvinylpyrrolidone 0.1 Gram Sodium Chloride 0.012 Gr Table XIII Alpha-aminobenzyl enicill'in Trihydrate (200 mesh) 0.375 Gram Ο.7 Ο Gr Lecithin O.OO6 Gram 0.012 Gr Tween 40 Ο.ΟΟ75 Ml. O.OI5 Ml Methyl-p-hydroxybenzoate O.OOO9 Gram O.OOI8 G Propyl-p-hydroxybenzoa e 0.0001 Gram 0.0002 G Polyvinylpyrrolidone 0.04 Gram 0.08 Gra Sodium Chloride O.OO6 Gram 0.012 Gr Table XIV Per one 5-dose vial Alpha-aminobenzylpenicillin Trihydrate (200 mesh) 2.5 Grams Lecithin 0.0395395 G-ram Span 40 0.0186615 Gram Tween 40 Ο.Ο5 382 Gram Sodium Citrate,, anhydrous, 100 mesh O.O322036 Gram Methy1-p-hydroxybenzoate 0.0045 Gram Propyl-p-h droxybenzoate O.OOO5 Gram Carboxymethylcellulose Ο.Ο282425 Gram Table XV Per 1 dose vial Alpha-aminobenzylpenicillin Trihydrate (200 mesh) O.5OO Gram Lecithin O.OO79079 Gram Span 0 Ο.ΟΟ373 3 Gram Tween 40 O.OIO5076 Gram Sodium Citrate, anhydrous, 100 mesh 0.0064407 Gram Methyl-p-hydroxybenzoate O.OOO9 Gram Propy1-p-hydroxybenzoate 0.0001 Gram Carboxymethylcellulose 0.0056485 Gram -22- 31431/2 The formulations' set forth in Tables XI - XV are reconstituted with sterile water -to give, suspensions readily adaptable for intramuscular administration containing 300 mg./nil. 350 mg./l.O ml. and 375 mg./l.O ml. ampicillin activity respectfully. The suspensions show good storage stability.

Claims (10)

-23- 31431 2 CLAIMS : ,

1. A process for the preparation of an antibacterial ·'.·.. composition suitable for reconstitution with water to form a suspension for intramuscular, use, characterized in that trihydrate particulate alpha-aminobenzylpenicillin having a size less . than about 100 mesh is mixed with an organic solvent solution of a physiologically acceptable hydrophilic surface active agent and a physiologically acceptable lipophilic surface active agent, followed by evaporation of the solvent to produce trihydrate particulate' alpha-aminobenzylpenicillin /which is coated with a mixture of said surface 'active agents, and pulverizing said coated material so that not more than 1$ by weight is larger than 200.mesh. »

2. The process of Claim 1 wherein the lipophilic surface active agent is lecithin, sorbitan monopalmitate, ■ • 1 1 sorbitan trioleate or a mixture thereof. j ■ ' I

3. ! 3. The process' of Claim 2 wherein the hydrophilic surface active agent is a polyoxyalkylene derivative of sorbitan monopalmitate or sorbitan trioleate.

4. The process of Claim 3 wherein the solvent is •selected from chloroform,, methylene chloride, trichloroethylene, ether' and petroleum ether.

5.. An antibacterial composition comprising a mixture of a particulate alpha-aminobenzylpenicillin trihydrate. having a size less than about 100 mesh and represented by the formula: -24- 5X A/ 2 a physiologically acceptable hydrophilic surface active agent » and a physiologically acceptable lipophilic surface active agent, said surface active agents being present in an amount which is sufficient to form a surface coating on the particulate components in said mixture.

6. The composition of Claim 5 containing a physiologically acceptable preservative for the alpha-aminobenzylpenicillin tri-hydrate.

7. The composition of Claim 6, wherein said preservative is coated with said surfactants.

8. A material comprising the composition of Claim 5 in aqueous suspension.

9. A . composition comprising the composition of Claim 6 in aqueous suspension*

10. A composition comprising the composition of Claim 7 I aqueous suspension. KDied