IL31148A - Antibacterial compositions containing sulfisoxazole and ampicillin or hetacillin - Google Patents

Description

Antibacterial compositions containing sulfiaoxazole and ampicillin or hetacillin BRISTOL-MYERS OOMPAHY C: 29358 This invention relates to antibacterial compositions possessing both low toxicity and a broad spectrum of antibacterial activity. More particularly, this invention relates to mixtures of one part of sulfisoxazole with from about 0.10 to about 0.5 parts by weight of ampicillin or of hetacillin. The compositions of the present invention are of great value in the treatment of bacterial infections in animals, particularly man.

Ampicillin is the generic name for D-(-)-a- aminobenzylpenicillin. As used herein, the term ampicillin includes the free acid (i.e., amphoteric) form, the anionic salts with acids such as hydrochloric acid, the cationic salts with bases such as sodium hydroxide and the hydrates of that penicillin. Their preparation and properties have been described, inter alia, in United States Patents Nos. 2, 98 ,6 8; 3,140, 282 ; 3,144, 5 ; 3, 157,640 and 3, 180, 862.

Hetacillin is the generic name for 6- (2, 2- dimethyl-5-oxo-4-phenyl-l-imidazolidinyl)penicillanic acid which has the structure s used herein, the term hetacillin includes the "free acid" illustrated above and its nontoxic, pharmaceutically acceptable cationic salts of the acidic carboxylic acid group and its nontoxic, pharmaceutically acceptable acid addition anionic salts (i.e., salts of the basic nitrogen). Their preparation and properties are described in U. S. Patent 3, 198, 804- .

Ampicillin and hetacillin are both classified as "broad-spectrum" penicillanic acids since both exhibit excellent activity against a large number of Gram-positive and Gram-negative bacteria. Both hetacillin and ampicillin suffer from the disadvantage of being susceptible to inactivation by Staphylococcus penicillinase and thus being ineffective in the treatment of bacterial infections in which such staphylococci are present.

In addition to the usually excellent activity against most Gram-positive organisms, both possess good bacteriocidal activity against many Gram-negative organisms among which are Haemophilus in luenzae, Escherichia coli, Shigella, Salmonella, Klebsiella and some Proteus .

Sulfisoxazole, also known as Gantricin, is a bacteriostatic drug that is official in the United States Pharmacopeia ( 1965 ) . It is commonly used in the treatment of a large variety of Gram-positive and Gram-negative bacteria, a few examples of which are streptococci, staphylococci, pneumonococci, gonococci, meningococci, bacillary dysentery and influenza bacilli.

It was an object of the present invention to provide an imp rved nontoxic antibacterial composition with a broadened spectrum of activity against both Gram- positive and Gram-negative bacteria. It was a further object to provide a composition that would exhibit an improved hetacillin or ampicillin resistance to penicillinase.

The objects of: the present invention were achieved by the provision according to the present invention, of a broad-spectrum penicillanic acid derivative in combination with sulfisoxazole, which comprises a mixture of about one part by weight (250 mg. to 750 mg.) of sulfisoxazole to about 0.10 to 0.5 parts by weight of ampicillin or hetacillin.

The present invention also provides a process for the preparation of nontoxic, stable, uniform anti-bacterial compositions which comprises intimately admixing one part by weight of sulfisoxazole, but preferably 250 mg. to 750 mg. of sulfisoxazole, and most preferably 500 mg. of sulfisoxazole per unit dosage, with about 0. 10 to 0.50 parts by weight of hetacillin or ampicillin, but most preferably 125 mg. of hetacillin or ampicillin per unit dosage, either with or without inert diluents, flavors, suspending agents, preservatives, buffering agents, sweetening agents, colors and anti-oxidants.

It was discovered the above compositions exhibit a synergistic effect in the treatment of certain bacterial infections. Most specifically, the hetacillin-sulfisoxazole or ampicillin-sulfisoxazole combination was unexpectedly synergistic in its bacteriostatic-bacteriocidal effect against Pseudomonas aeruginosa.

The combination of sulfisoxazole-hetacillin 1 was found to "be most efficacious for the treatment of 2 a broad spectrum of bacterial infections. As expected 3 the combination was additive with regard to the bacterial spectrum of each. Each drug continued to perform well within its own individual bacterial 6 spectrum. In particular the combination is most 7 popular for the treatment of urinary tract infections, 8 the bacteria of which infections are. usually most 9 susceptible to sulfa therapy, and even more susceptible to sulfa-penicillin therapy. 11 An unexpected result of the combination, 12 however, was the synergistic effect observed for the 13 hetacillin-sulfisoxazole combination against strains 1 of Pseudomonas. Pseudomonas infections are most difficult 5 to treat and cure. There are few good or effective 16 nontoxic agents that are commercially available for the 17 treatment of such infections. As such the discovery 18 of the synergistic effect of the hetacillin-sulfisoxazole 19 combination is of significant therapeutic importance.

The Minimum Inhibitory Concentrations (M.I.C.) 21 of the individual components of the mixtures and of the 22 mixtures themselves, were determined by the usual 23 procedures. The M.I.C. 's of the mixtures were inter- ^ preted for any synergistic effects according to the procedure of Maccacaro as specified in "Progress in 26 Industrial Microbiology", 3, p. 173 (1961). 2? Table I is representative of a number of pQ co organisms that were studied to determine the effective- 2^ ness of a hetacillin-sulfisoxazole combination as com- J pared to the individual drugs alone.

A B LE I ANTIBACTERIAL ACTIVITY OF HETACILLIN-SULFISOXAZ Table I continued: A. Minimum Inhibitory Concentration B.

Test Combination 1:4 Hetacillin Organism Hetacillin Sulfisoxazole Hetacillin/Sulfisoxazole 10 (mcR./ml. ) Pseudomonas species 5230 >200 >800 200/800 M 7 5 >200 400 50/200 M 7 6 >200 400 50/200 7 7 >200 400 100/400 M4760 >200 400 50/200 M4765 >200 400 100/400 M4773 >200 400 50/200 4788 >200 400 50/200 M4865 >200 400 50/200 ATCC 9027 >200 400 100/400 Resistant Incomplete Inhibition Column A represents the Minimum Inhibitory Con- centratlons of hetacillin alone, sulfisoxazole alone and a 1:4 combination of both. Column B represents the zones of inhibition for the drugs alone and in combination. R = resist- ant to drug and I = incomplete inhibition. 6 As can be seen from both the M.I.C. and zone inhib- ition data, the only organisms showing a consistent syner- 8 gistic response to the combination are the Pseudomonas species. 9 Most of the Pseudomonas species show little or no 0 growth inhibition when treated with hetacillin or sulfisoxazole 1 alone. However, a combination of the hetacillin and sulfisoxa-2 zole results in markedly improved M.I.C. and inhibitory disc responses. All the data confirms the synergistic activity of 4 a hetacillin-sulfisoxazole combination against a wide variety 9 of Pseudomonas strains. 6 7 8 9 0 1 2 > A B L E II MINIMUM INHIBITORY CONCENTRATION TESTS WITH VARYING CONCENTRATIONS OF SULFISOXAZOIE TO HE Test Combination 1:4 Comb Organism Hetacillin Sulf isoxazole Hetacillin/Sulf isoxazole Hetacilli (meg. /ml. ) Pseudomonas species Klebslella-Aerobacter M6025 400 >i6oo > 200/>800 >100 6038 100 >l6oo 200/800 >ioo Escherichia coli M6651 50 >1600 25/100 25 1 Table II shows the limiting factor of the synergistic 2 effect is the sulfisoxazole concentration. While the concen- 3 tration of the hetaclllln can be varied appreciably, the con- centration of the sulfisoxazole must remain relatively con- 5 stant to achieve synergistic inhibition of the Pseudomonas 6 species . 7 The synergistic action of the hetacillin-sulfisoxazole 8 combination against Pseudomonas is reproducable with an amp- 9 icillln-sulfisoxazole combination. Both ampicillin and heta- 10 cillin are comparable in their spectrum of activity and are 11 known to be equivalent in biological effeet except for some 12 minor idiosyncrasies such as rate of absorption, blood levels, 13 etc. This is not too surprising inasmuch as hetaclllln de-l^ composes into ampicillin in the presence of water.

A preferred embodiment of the present invention 16 Is a therapeutic composition in unit dosage form comprising 17 a mixture of 250 mg. to 7 0 mg. of sulfisoxazole per unit 18 dosage with about 0. 10 parts to 0.5 parts by weight per unit 19 dose of a member selected from the group consisting of ampi- 20 cillin and hetaclllln. 21 A more preferred embodiment of the present invention 22 Is a therapeutic composition In unit dosage form comprising 2j~> a mixture of about 500 mg. of sulfisoxazole per unit dose 2k with about 75 mg. to 250 mg. per unit dose of a member selected 2r from the group consisting of hetacillin and ampicillin. 26 Another preferred embodiment of the present invention 27 is the process for treating a bacterial disease in animals 2o which comprises administering to the bacterial host a thera- 1 mg. per unit dose of a member selected from the group, 2 consisting of hetacillin and ampicillin . j5 A most preferred embodiment of the present invention is a therapeutic composition in unit dosage form comprising a mixture of about 500 mg. of sulfisoxazole per unit dose 6 with about 125 mg. per unit dose of a member selected from 7 the group consisting of hetacillin and ampicillin. 8 In the present invention and particularly in the 9 examples, hetacillin free acid is taken as the standard with an activity of 1000 mcg./mgm. and when other salts are used, 11 the weight taken is that which gives an equivalent amount of 12 activity, i.e., 1096 mgms. of potassium hetacillin are equiv- 15 alent in activity to 1000 mgms. of hetacillin free acid. The 1 relationship is stoichiometric.

Vj In the case of ampicillin the standard with an activity 16 of 1000 mcg./mgm. is anhydrous ampicillin . Ampicillin trihydrate 17 has a potency of 865 mcg./mgm. 18 In the actual formulations use is often made as is 19 customary in this field of an overfill, e.g., of ten percent, of each active ingredient as compared to labelled potency. 21 The compositions of the present invention are of 22 value in vitro, as in sterilizing laboratory glassware or the walls of hospital rooms, as well as in vivo in the treat-2i\ ment of bacterial infections in animals, Including man. 23 The compositions of the present invention may be 26 embodied in any of the known pharmaceutical forms for oral, 27 parenteral, topical or rectal administration. The combinations m 2f be prepared in eolid compositions for oral administration 1 compounds may be prepared for oral administration also. 2 Sterile suspensions or solutions may be prepared for parenti eral use. When desirable, the compound may be incorporated in suppositories for rectal administration.

The term unit dosage form as used in the specification 6 and claims means a physically distinct entity suitable -as 7 a unitary dosage for administration, each unit containing a 8 predetermined quantity of the composition of the present 9 invention. The quantity of the compound contained in the 0 . unit dosage form is directly dependent upon the considerations 1 which are well-known in the art of compounding a pharmaceut-2 ically active material for therapeutic use. The character- istlcs of the active compound, the particular therapeutic | effect to be achieved, the route of administration and the 1 mechanism of the action of the material in the host are 6 important considerations in determining the quantity of the 7 active compound included in the unit dosage form. Examples 8 of suitable oral unit dosage forms are capsules, pills, 9 tablets, cachets and powder packets for solid compositions, 0 and teaspoonfuls, dropperfuls, ampoules and vials for liquid oral dosage forms. 2 The tablets or pills can be laminated or otherwise compounded to provide for time-release action of the active /| compound. For example , the tablet or pill can comprise an 9 inner portion constituting one unit dose and an outer 6 portion constituting another unit dose, the outer portion 7 being in the form of an envelope encompassing the inner portion. 9 Examples of oral liquid dosage forms include aqueous 1 suspensions and emulsions wherein the product is dissolved 2 or dispersed in a pharmaceutically acceptable carrier or 3 vehicle. Flavoring agents may be added to increase the 4 palatability of the dosage form. Examples of vehicles are cottonseed oil, sesame oil, peanut oil and the like and 6 acceptable dispersing agents for aqueous suspensions include 7 synthetic and natural gums such as tragacanth, acacia, dextran, 8 methyl cellulose and the like. 9 For many reasons, i.e., administration to children 0 and the aged, the physician prefers to use a pleasantly 11 flavored aqueous suspension of an antibiotic and, as a prac- 12 tical matter, it is desirable that this suspension be stable 13 under ordinary conditions of storage and without refrlger-1^1 ation for a substantial period of time .

Vj In the case of a powder for reconstitution into a 16 suspension for oral administration, the resultant suspension 17 should be stable for a minimum of 2 weeks at room temperature 18 after reconstitution with water . The suspensions of the 19 present invention fulfill this requirement.

The pharmaceutical elegance, appearance, suspension 21 characteristics, palatability and general stability of the 22 product as a whole is greatly enhanced by the addition of 2j~> adjuvants to the basic formula; i.e. suspending agents, 2k buffering agents, sweetening and flavoring agents, antl- 25 oxidants, preservatives and coloring agents. 26 As used herein the term "finely powdered" shall 27 mean materials pulverized to particle sizes smaller than 250 2o microns in diameter and preferably in the range of 5 to 80 29 microns. 1 The following terms are defined as listed below 2 for the purpose of the instant invention. While in the 3 following definitions and examples of various embodiments 4 of this invention have been set forth in specific detail and are elaborated for the purpose of illustration, it will 6 be apparent to those skilled in the art that these defin- 7 itions are susceptible to other embodiments and that many 8 of the definitions and details can be varied widely with- out departing from the basic concept and the spirit and scope of the invention. 11 1. Suspending agents shall mean any pharmaceutically 12 acceptable organic or inorganic agents, suitable for internal 13 use, that are capable of increasing or contributing to the 14 uniform suspendability of the finely divided insoluble partly icles of the suspension. Examples of such agents are gum 16 tragacanth, gum acacia, sodium alginate, carboxymethylcel- 17 lulose, bentonite, gum karaya, or their functional equivalents. 18 2. Buffering agents shall mean any pharmaceutically 19 acceptable organic or inorganic agents, suitable for Internal use, that are capable of maintaining the pH within the pre- 21 scribed range of the suspension of. the instant invention. 22 Examples of such buffering agents are lithium, sodium, potassium, 23 ammonium and calcium hexametaphosphate, citrate, acetate, tar-2 ! trate and phosphate. 3 · Sweetening agents shall mean any pharmaceutically 26 acceptable organic agents, suitable for internal use, that will 27 impart a sweet taste to the suspension. Preferred examples of 2o such agents include sodium saccharin, sodium or calcium cycla-29 mate, sucrose, lucose or their functional e uivalents. ·ν·' ing or flavoring, real or imitation, that is approved acceptable for internal use in the food or pharmaceutical industry.

. Anti-oxidants shall mean any pharmaceutically acceptable organic or inorganic agent, suitable for internal use, that will protect the ampicillin or hetacillin, or any of the ingredients, or the suspension as a whole from decomposition due to oxidation, i.e., sodium metabisulfite, sodium bisulfite, sodium hypo-phosphite, sodium sulfoxylate, or their equivalents. 6. Preservatives shall mean any agent that is approved acceptable for use in the food or pharmaceutical industry. Examples of such agents will include sodium benzoate, methyl and propyl paraben, or their functional equivalents.

The compositions of the present invention are of value in vitro, as in sterilizing laboratory glassware or the walls of hospital rooms, as well as in vivo in the treatment of bacterial infections in animals, including man.

In the treatment of bacterial infections in man, the composition of this invention is administered topically, orally, rectally and parenterally, but preferably orally, in accordance with conventional pro-cedures for antibiotic administration.

The dosages of the compositions of this invention are dependent on such factors as the size of the patient and the severity of the disease, and are dosage range per day for human adults by oral administration is 0.2 grams to 2.000 grams of hetacillin or ampicillin in combination with 1.00 grams to 3.00 grams of sulfisoxazole administered in divided doses three to four times a day. The preferred average dosage consists of 125 mg. of hetacillin or ampicillin in combination with 500 mg. of sulfisoxazole administered orally four times a day. 1 Description of The Preferred Embodiments 2 The following examples are given to Illustrate 3 but not to limit the present Invention.

Example I Hetacillin (125 mg. hetacillin activity )-Sulfisoxazole (500 mg. ) Capsules, 6 7 Per Capsule 8 Hetacillin (free acid) ♦0.1513 gram of activity 9 Sulfisoxazole O.500 gram ιό Magnesium Stearate 0.004 gram 11 (to compact) 12 Magnesium Stearate 0.016 gram (to aid encapsulation) 13 Solka-Floc BW 200 O.060 gram 14 Corn Starch O.065 gram Lactose, U.S. P. q^s.. if necessary 16 17 * Represents 5$ over label claim of 125 mg. activity per capsule. 18 19 Mix the Hetacillin, SulfIsoxazole, Magnesium Stearate (to compact), Solka-Ploc BW 200 and the Corn Starch. 21 Slug this mixture and mill to obtain granulation suitable for 22 filling capsules. Add the remaining Magnesium Stearate and 23 Lactose if necessary. Mix and fill into capsules. 24 26 27 Example II Hetaclllin (125 mg. hetaclllin activity ) -Sul Isoxazole (500 mg. ) Tablets? 1 Per Tablet Hetaclllin (free acid) ♦0.1313 Gram of activity Sulfisoxazole O.5000 Gram Magnesium Stearate (to slug) Ο.Οθ4θ Gram Magnesium Stearate ( to compress) O.OO30 Gram Solka-Ploc (B 200) O.I250 Gram * This figure represents $ over label claim of 125 mg. of Hetaclllin Activity. 1. Granulate the sulfisoxazole . 2. Pass the dried granules through a Fitzmill. 3. Blend the sulfisoxazole with the hetaclllin and magnesium stearate. 4. Slug mixture and screen.

- Weigh the mixture, add the calculated magnesium stearate for compressing and blend. 6. Compress into tablets.

Example III Hetaclllin ( 250 mg. Hetaclllin activity), Sulflsoxazole ( 1 gram) BOft gelatin capsules.

Per capsule Hetaclllin, mlcronized * 0.2625 gram Hetaclllin activity Sulfisoxazole, micropulverlzed 1.000 gram Soy Bean Oil Refined 0.480 gram ♦♦mixture used Lecithin, Soya 0.015 gram ¾s.

Sodium Lauryl Sulfate U.S. P. XV O.030 gram * Represents over label claim of 250 mg.

Hetaclllin activity per .capsule.

** This mixture is used to q.s. for proper fill per capsule. 1 . Dissolve the Lecithin in the Soy Bean Oil with mixing. 2. Incorporate the Sodium Lauryl Sulfate. 3 . Incorporate all the remaining ingredients. 4. Pass the suspension through a premier mill.

. Deaerate. 6. Pill into capsules using a soft gelatin encapsulating machine.

Example IV Hetaclllln (125 mg.) and SulfIsoxazole (500 mg.) per ml. Powder For Oral Suspension Per 60 Ml.

Hetaclllln, non sterile, micropulverized... Grams Activity , , . 6.00 Grams Gram Gram , , 0.80 Gram , .. 0.06 Ml.

Gram Gram Grams *This figure represents Hetaclllln activity and includes a 10$ excess.

**The amount of Hexamic Acid used Bhould be adjusted in order to obtain a reconstituted pH of 2.3 to 2.8 (preferably 2.5). 1. Standardize the size of the sucrose, hetaclllln, sulfisoxazole and hexamic acid. 2. Place approximately 20$ of the Sucrose (to the nearest kilogram) in a suitable mixer and, while mixing at slow speed, slowly add the ween 40. Mix for twenty min-utes. 3. Pass the mix from Step 2 through a 10 mesh screen to break up any lumps which may have formed due to 1 add the screened mix from Step 3, the Hetaclllin, Sulfisox- 2 azole, Sodium Saccharin, Sodium Cyclamate, Sodium Benzoate, Flavor, Dye, Carrageenan. Blend for one hour.

. Standardize the mixture size in a Pitzmill. 6. On a small scale, determine the amount of 6 Hexamic Acid necessary to adjust the pH to 2.3 to 2.8. 7 Use 1.05 ml. of Purified Water, U.S.P. for each gram of 8 blend used in this determination. 9 7. Return the mix to the blender. Add the milled Hexamic Acid and blend for thirty minutes. 11 8. Check the pH of the final blend using 9.7 12 Grams of blend and 10.0 ml. of Purified Water, U.S. P. 13 pH should be 2.3 to 2.8. 14 9. · Crop from the blender. Sample, weigh and Vj pack. Prior to use add sufficient deionlzed water to make 16 60 ml. of suspension. Each 5 ml. of resulting suspension 17 contains 125 mg. of hetaclllin activity and 500 mg. of sulf- 18 isoxazole. 19 0 1 2 23 k 6 7 8 1 Example V 2 Ampicillin Trihydrate (125 mg. ampicillin activit )- Sulfisoxazole (500 mg.) Tablets Per Tablet 4 Ampicillin Trihydrate, micropulverized ' *0.l627 Gram of Activity 6 Sulfisoxazole 0.5000 Gram 7 Polyvinylpyrrolidone 0.000177 Gram 8 Solka Ploc 0.1250 Gram 9 Magnesium Stearate 0.0070 Gram 0 Methylene chloride 0.2000 ml. 1 *This O.I627 gram of Ampicillin Trihydrate is equivalent to O.1375 gram of Ampicillin 2 activity which is a 10 excess over label claim of 125 mg. of Ampicillin activity per 3 tablet based on a standard potency of 8 5 mcg./mg. 4 1. Standardize the ampicillin trihydrate and 6 sulfisoxazole size. 7 2. Blend the ampicillin trihydrate, sulfisoxazole 8 and 3/4 of the Solka-Ploc, and granulate using the polyvinyl-9 pyrrolldone dissolved in the methylene chloride. Standardize 0 the granule size. 1 3. Add the remaining Solka-Ploc and the magnesium 2 stearate. Blend for 30 minutes. ? 4. Compress into tablets. The usual dose is one >-\ . tablet three to four times a day. 6 7 8 Example VI Ampiclllln Trlhydrate (125 mg. ampiclllln activity) and Sulfisoxazole ( 500 mg.) per 5 ml. Powder for Oral Suspension.

Per 60 Ml.

Ampicllll Trlhydrate, micropulverized * 1.65 Gram of activity Sulfisoxazole, micropulverized 6.00 Grams Sodium Saccharin 0. 16 Gram Sodium Sucaryl 1.60 Grams Sodium Citrate 0.14 Gram Sodium Benzoate 0.06 Gram Gum Acacia 1.50 Grams Tween 40 O.06 Ml.

Sucrose 22.00 Grams Vanillin 0.04 Gram Flavor *This figure represents Amplcillin Trlhydrate activity and includes a 10$ excess. 1. Standardize the size of the sucrose, ampiclllln trlhydrate and sulfisoxazole. 2. Place approximately 20$ of the Sucrose (to the nearest Kilogram) in a suitable mixer and, while mixing at slow speed, slowly add the Tween 40 and flavors. Mix for twenty minutes . 3. Pass the mix from Step 2 through a 10 mesh screen to break up any lumps which may have formed due to addition of the Tween and flavors. 4. To the remainder of the Sucrose, in a blender, add the screened mix from Step 3 the Amplcillin, Sulfisoxazole, 1 5. Pass the blend through a Pltzmlll equipped 2 with a No. 4 screen, knives forward, high speed. 3 6. Return the mix to the blender. Blend for 4 thirty minutes. 7. Drop from the blender. Sample, weigh, and 6 pack . 7 Example VII 8 Ampicillin Trihydrate (125 mg. of ampicillin activity) Sulfisoxazole (750 mg.) Tablets. 9 Per Tablet 11 Ampicillin Trihydrate *0.l627 Gram 12 Sulfisoxazole 0.750 Gram 13 Magnesium Stearate 0.007 Gram 14 Solka-Floc BW 200 0.060 Gram Vj Corn Starch qs. 16 17 *This 0.1627 Gram of ampicillin trihydrate is equivalent to Ο.Γ575 Gram of ampicillin activity 18 which is 10$ excess over label claim of 125 mg. of ampicillin activity per tablet. 19 0 Standardize the powder sizes. Compact the ampicillin 1 trihydrate, sulfisoxazole, Solka-Ploc and the corn starch. 2 Slug the mixture and mill to obtain granulation suitable for 23 making tablets. Compress into tablets. k Usual daily dose is one tablet three to four times a day. 6 7 8 Example VIII Hetaclllin (50 mg. of hetacillln activity) -Sulfisoxazole (500 mg.) Capsules.

Per Capsule Hetacillin * 0.055 Gram Sulfisoxazole 0.500 Gram Magnesium stearate 0.06 Gram Solka-Floc BW200 Ο.θβ Gram Corn starch I ¾s.

Lactose ) * $ excess over label claim.

Standardize the. powder sizes. Compact the hetacillln, sulfisoxazole, Solka-Floc, corn starch and magnesium stearate. if necessary with lactose and fill capsules.

Usual dose is one capsule three to four time Example IX He aclllin (125 mg.) and Sulfisoxazole (500 mg.) per Ml. Powder for Oral Suspension.

Per 60 Ml.

Hetaclllin, non-sterile, micropulverized *1.65 Grams Activity Sulfisoxazole, micropulverized 6.00 Grams Sodium Saccharin 0.16 Oram Sodium Cyclamate 1.00 Oram Hexamic Acid** O.JO Oram Tween 40 , 0.06 Ml.

Sodium Benzoate 0 , 06 Grams Sucrose 22.6 Grams Tragacanth ...... 0.18 Gram Vanillin 0.005 Gram PPW Antibiotic Flavor.. 0.005 Ml.

Quintaldehyde Imitation Pineapple 0.001 Ml.

FD&C Red No. 2 Dye Trituration \ 0.60 Gram *Thls figure represents Hetaclllin activity and includes a 10$ excess.

**The amount of Hexamic Acid used should be adjusted in order to obtain a reconstituted pH of 2.3 to 2.8 (preferably 2 .5 ) . 1. Pass the sucrose through a Fitzmill equipped with a No. IB screen, knives forward, high speed. 2. Check the physical appearance of the Hetaclllin. If lumpy, pass through a Fitzraill equipped with a No.l screen, impact forward, high speed. 3. Check the physical appearance of the Sulfisoxazole.

If lum ass throu h a Fitzmill e ui ed with a No. 1 screen 1 4. Place approximatel 20$ of the Sucrose (to the 2 nearest kilogram) in a suitable mixer and while mixing at 3 slow speed, slowly add the Tween 40, antibiotic flavor BM6, and quintaldehyde imitation pineapple. Mix for 20 minutes. 5 . Pass the mix from Step No. 4 through a 10 mesh 6 screen to break up any lumps which may have formed due to 7 addition of the Tween and flavors. 8 6. To the remainder of the Sucrose, in a. blender, 9 add the screened mix from Step No. 5 * the Hetacillin, Sulf- 10 isoxazole, Sodium Saccharin, Sodium Cyclamate, Sodium Benzoate> 11 tragacanth, vanillin, and PD&C red No. 2 dye trituration 1%. 12 Blend for one hour. 13 7. Pass the blend through a Fitzmill equipped with a 1 No. 4 screen, knives forward, high speed.

Vj 8. Weigh. 16 9 . On a small scale, determine the amount of Hexamic Acid 17 necessary to adjust the pH to 2.3 to 2.8. Use 1. 13 ml. of 18 Purified Water, U.S.P. for each gram of blend used in this 19 determination. 10 · Paes the required amount of Hexamic Acid through 21 a Fitzmill equipped with a No.9 screen, imact forward, high 22 speed. 23 11. Return the mix to the blender. Add the milled k Hexamic Acid and blend for thirty minutes. 12. Check the pH of the final blend using 8.9 Grams of 6 blend and 10.0 ml. of Purified Water, U.S. P. pH should be 2.3 to 27 2.8. c 13 . Drop from the blender. Sample, weigh and pack. 9 Example X Sugarless Hetaclllln (125 mg.) and SulfIsoxazole (500 mg.) per 5 Ml. Powder for Oral Suspension.

Per 60 ML.

Hetaclllln, non-sterile, micropulverized .... *1.65 Grams activity Sulfisoxazole, micropulverized 6.00 Grams Sodium Saccharin O.30 Gram Sodium Cyclamate I.30 Grams Hexamic Acid** 0.40 Gram Sodium Benzoate O.06 Gram Tragacanth 0.36 Gram Polak imitation Candied Sugar Flavor 0.900 Gram Spray Dried Oil of Peppermint 0.100 Gram Dolcoseal Special Lemon Flavor 0.400 Gram FD&C Yellow No. 5 Dye Trituration 1 0.008 Gram *This figure represents Hetaclllln activity and includes a 10$ excess.

**The amount of Hexamic Acid used should be adjusted in order to obtain a reconstituted pH of 2.5 to 2.8 (preferably 2.5 ) . 1. Check the physical appearance of the Hetaclllln. If lumpy, pass through a Fitzmill equipped with a No.l screen, impact forward, high speed. 2. Check the physical appearance of the Sulfisoxazole.

If lumpy, pass through a Fitzmill equipped with a No. 1 screen, impact forward, high speed.

. Place in a blender the Hetaclllln, Sulfisoxazole.

Sodium Saccharin, Sodium Cyclamate, Sodium Benzoate, Tragacanth, flavors and FD&C Yellow No. 5 dye trituration \ . Blend for one hour No. 4 screen, knives forward, high speed.

. Weigh. 6. On a small scale, determine the amount of hexamic acid necessary to adjust the pH to 2.3 to 2.8. Use . 5 ml. of purified water, U.S. P. for each gram of blend used in this determination. 7. Pass the required amount of hexamic acid through a Fitzmill equipped with a No. 0 screen, impact forward, high speed. 8. Return the mix to the blender. Add the milled hexamic acid and blend for thirty minutes. 9. Check the pH of the final blend using 2.13 grams of blend and 10.0 ml. of purified water, U.S. P.. pH should be 2.3 to 2.8.

. Drop from the blender. Sample, weigh and pack.

While in the foregoing specification various embodiments of this invention have been set forth in specific detail and elaborated for the purpose of illustration, it will be apparent to those skilled in the art that this invention is susceptible to other embodiments and that many of the details can be varied widely without departing from the basic concept and the spirit and scope of the invention.

Claims (11)

1. An antibacterial composition comprising a mixture of about one part by weight of sulfisoxazole with about 0.10 parts to about 0.50 parts by weight of ampicillin or hetacillin,

2. An antibacterial composition as claimed in claim 1, in unit dosage form, comprising from about 250 mgm. to about 750 mgm. of sulfisoxazole per unit dose.

3. An antibacterial composition as claimed in claim 2, comprising about 500 mg. of sulfisoxazole per unit dose.

4. An' antibacterial composition as claimed in any one o the preceding claims, in unit dosage form, comprising from about 75 mg. to about 250 mg. of hetacillin or ampicillin per unit dose.

5. An antibacterial composition as claimed in claim 4, comprising about 125 mg, of ampicillin or hetacillin per unit dose.

6. An antibacterial composition as claimed in any one of the preceding claims, wherein the composition further comprises one or more of an inert diluent, a flavouring agent, a suspendin agent, a preservative, a buffering agent, a sweetening agent, a coloring agent and an antioxidant.(

7. A antibacterial composition as claimed in claim 1 and substantially as hereinbefore described in any one of the Examples.

8. A capsule, tablet or powder for oral suspension comprising a composition as claimed in any one of the preceding claims.!:

9. A method of Inhibiting the growth of bacteria which method comprisee applying to the habitat of the bacteria an effective amount of an antibacterial composition as claimed in any one of claims 1 to 7, or a capsule, tablet or orally suspended powder as claimed in claim 8.

10. A method for treating a bacterial disease in an anima which method comprises administering to the bacterial host a therapeutic amount of an anti-bacterial compositio as claimed iii anyone of claims 1 to 7? or a capsule, tablet, or, orally suspended powder as claimed in claim 8.

11. A method of sterilizing laboratory glassware, which method comprises applying to the glassware an effective amount of a composition as claimed in any one of claims 1 to 7» For the Applicants WD/ru