IL30684A - Therapeutic compositions containing ampicillin or hetacillin and nystatin - Google Patents

Description

30684/3 κ o'V'aan ninpli »*i*i∑ n 7»Doo*ai ' 'san Therapeutic compositions containing arapiclllin or iietacillin and nystatin BRISTOL-rMYERS COMPANY C:28912 This Invention relates to antibacterial compositions possessing both low toxicity and a broad spectrum of antibacterial activity andj moro particularl , to mixtures of ono part of nystat with -f-rom about one to about four parts of ampioillln or of heta- •eillift.

The nystatin referred to erein is a polyene antibiotic of broad antifungal activity and is of a quality comparable to that described in the United States Pharmacopeia (U.S. P. - i960) and in all cases contains not less than 2000 U.S. P. nystatin units per mg.

Ampicillin is the generic name for D-( -)-a-aminobenzyl-penicillln. 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 U.S. patents 2,985 , 648, 3, 140,282, 3, 144, 445, 3,157, 640 and 5,180,862.

Hetacillin is the generic name for 6-(2,2-dimethyl-5-oxoi-4-phenyl-l-imldazolidinyl)penicillanlc acid which has the structure As used herein, the term hetacillin includes the "free acid" toxic, pharmaceutically acceptable acid addition anionic salts, (i.e. salts of the basic nitrogen). Their preparation and prop-erties are described in U. S. Patent 3 , 198, 8o .

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.

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 influenzae, Escherichia coli, Shigella, Salmonella, Klebsiella and some Proteus.

A major disadvantage in the use of antibiotics possessing good, "broad-spectrum" activity however, is the- commonly caused upset in the balance of the normal body's resident bacterial flora. Disturbing this balance by the destruction or suppression of one or more of these normal bacterial species often results in serious alimentary and mucous membrane changes, and Just as often vitamin deficiencies. An individual in such a condition is then very susceptible to fungal infestation, such as moniliasis of the intestines, vagina, oral cavity etc. Such infestations can quite often lead to death.

It is well known that many pathogens, Candida, etc., oft live as a part of the normal flora of the mouth, intestines, vagina mucous membranes, etc., without causing pathological manifestations People with lowered resistance however, such as those suffering from malnutrition, diabetes mellitus, infections, etc., are quite susceptible to tissue invasion by monilia. Because of this 'v. 30684/3 There exists a need, therefore, to provide stable cbmpositions of an antifungal agent in combination with a broad spectrum penicillin, e.g. nystatin-ampicillln, nystatin-hetacillin. Prior to the discovery of the broad spectrum penicillins such a combination was unanticipated and unnecessary. nystatin, also known as Mycostatin, is a good fungistatic agent that has found wide use in the treatment of fungal and yeast infections β οΐι as moniliasis, Candida albicans, Coccidiodes immltis, and the organisms blastomycosis and histoplasmosis. Nystatin is usually administered orally and is relatively nontoxic by this route. Parenteral administeration is sometimes practiced but commonly results in violent side effects.

U.S. Patent Wo. 2,903,356 shows the state of the art in regard to compositions of penicillin with nystatin and the use of nystatin in the treatments prophylaxis of monilial Infections.

According to the preeent invention there is provided a therapeutic composition for the treatment of bacterial infection which composition comprises a mixture of about 100,000 to 550,000 nystatin units per unit dose with about 100 mg to 600 mg per unit dose 1 active ingredient as compared to labelled potency. 2 The compositions of the present invention are of value in 3 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. 6 For many reasons, i.e., administration to children and the 7 aged, the physician prefers to use a pleasantly flavored aqueous sue- 8 pension of an antibiotic and, as a practical matter, it is desirable 9 that this suspension be stable under ordinary conditions of storage 0 and without refrigeration for a substantial period of time. 1 In the case of a powder for reconstitution into a suspension 2 for oral administration, the resultant suspension should be stable 3 for a minimum of 2 weeks at room temperature after reconstitution with water. Obviously, the longer the duration of stability, ie. 5 four to six weeks or more, the more desirable the product. 6 To be considered stable, such a suspension must show less 7 than a 20$ loss in potency on storage at room temperature during 8 the duration of its use following reconstitution. Products show-9 ing a greater loss of potency are not released for sale by the 0 Federal Food & Drug Administration without satisfactory explan-1 atlon or short-term out-dating. 2 Prior to the discovery of ampicillin and hetacillin^ 3 penicillin therapy rarely produced the bacterial imbalance most i commonly caused by "broad-spectrum" antibiotic therapy. For this reason such a composition of a penicillin-antifungal com-^ position was neither desirable or needed until said effects were clinically encountered. o The formulation of a hetacillin- or ampicillin-nystatin combination as a suspension presented several problems, the most 30684/2 mediaj said ingredients usually losing their therapeutic potency in 2 weeks or less.

The out-date as required by The Food and Drug Administration on the commercially available amplcillin trlhydrate and ampicillin •anhydrate suspensions is but one week at room temperature. A one week out-date was also required on the .previously marketed nystatin suspension of E. R. Squibb, now withdrawn from the marketplace.

Currently marketed nystatin-tetracycline combinations for reconstitution into aqueous suspensions are also out-dated two weeks after reconstitution.

The suspensions of the present invention are novel because of the greatly prolonged stability of the bioactive principles, i.e., hetacillin, ampicillin and nystatin.

The nystatin-ampicillin or hetacillin formulations for reconstitution are prepared by mixing together finely powdered nystatin, ampicillin (or hetacillin) with a sequestering agent, and a buffering agent to place and keep the pH in the desired pH range of about 5.0 to 8.0 after reconstitution by the addition of water.

The pharmaceutical elegance, appearance, suspension characteristics, palatability and general stability of the product as a whole is greatly enhanced by the addition of adjuvants to the basic formula; i.e. suspending agents, buffering agents, sweetening and flavoring agents, antioxidants, preservatives and coloring agents.

As used herein the term "finely powdered" shall mean materials pulverized to particle sizes smaller than 250 microns in diameter and preferably in the range of 5 to 80 microns. 30684/2 ·' : Λβ used heroin the term "oequaater:Uig agent" shall mean any p.iarmacoutically acceptable nontoxio organio or . inorganic compound suitable for internal use, oapable of contributing to the stability of the nystatin in the · formulation by physical or chemical means. The preferred eequestering-buffering agents are lithium, sodium, potassium* oaloium or ammonium hexamotaphosphate. ' " Phoophate anions other than the preferred hoxamotaphosphates' are capable of acting as sequestering agents in the present invention; While the preferred embodiment gives the greatest improvement in stability, some useful improvement' is obtained by the ' use of other phosphate anions such as metaphoophate, tripoiy-. phosphate, tetrametaphoapbate, orthophosphato, trimotaphoophat and polymetaphosphato. ' The orthophosphates are not ' . ' ·" particularly useful as sequestering agents although' they 1 · are .good buffering agents." li51'r'' "τ"-'-'·. ? :ι) ·*" V·"·* ■V ι*' · ·other substantially equivalent oequeotoring agents include the tartrates, citrates» ethyienediami etotraacotates or concentrated sucrose syrupi either, alone or in combination with a supplemental buffering agent.. '•■•*":: l''a 'i _ ·'···« ;.iyfr ii¾.a. ""* ·Λ!Λ'5¾β suspending agents employed in the present · ' invention oomprise the pharmaceutically acceptable organic or inorganic agents, suitable for internal use, that are capable of increasing or contributing to the unifora suspendability of the finely divided insoluble .particles of t tj BUSpension*' Examples of such agents are gum tragaoanthV gum acaoia, .sodium alginate, ccirboxyoethyioelluloee». behonit©, , · " ¾>:' : , gum karay.tt* ;;·, ..■· ''. ■■,'"■[' .

The buf ering' agents employed . in' he present invention V 1 hetacillin) in the suspension of the preferred embodiment of the 2 present invention is attributed to the addition of the sequestering 3 buffering agent, sodium hexametaphosphate, and to the adjustment ^ of the pH to within the range of about 5.0 to 8.0.

The addition of a different sequestering agent such as 6 a tartrate, citrate, ethylenediaminetetraacetate, etc., at a 7 buffered pH of about 5 .0 to 8.0, likewise Imparts enhanced 8 stability to the aqueous suspensions. For maximum stability how- 9 ever, the suspension of the present invention should contain the 10 three essential elements of a sequestering agent buffering agent H and a pH in the range of about 5 .0 to 8.0. 12 It has been found that the rate of nystatin decomposition 13 in aqueous formulations is very dependent upon the pH of the i4 suspension.

Table I 16 Nystatin Suspension of Example I 17 18 % Decomposition of Nystatin 19 56° C • 45° C.

PH 1 wk. 2 wk. 3 wk. 1 mo. 2 mo. 21 4.0 67 , 90 100 40 90 22 .0 14 40 65.4 ■ 25 56.8 6.0 0 24 1.9 14 4 5 .8 7.0 5.8 5.8 8 0 ^ 1.9 26 P7 As is apparent from the table above, nystatin is most 2Q stable at a pH above 5.0, and preferably at a pH in the range 2g of about pH 6 to 7.

As mentioned previously, the commeridally available suspensions of ampicillin all have short out-dates of about one week at room temperature (24° C). A typical rate of decomposition of ampicillin in these products is shown in Table II., Table II Temperature 24° C. - pH 6.

Time 125 mg/ml. 250 ma/ml .

*The ampicillin anhydrate suspension utilized in this experiment is commercially available as Wyeth's Omnipen which is described in the product literature as: I II Omnipen for Oral Suspension (Wyeth ampicillin). Omnipen contains 2 grams or 4 grams of ampicillin for reconstltutlon with water to make 8o cc. of a palatable suspension containing in each 5 cc. 125 mg. or 250 mg. of ampicillin.

As is apparent from the above table II,. the commercially available ampicillin suspensions are not stable for periods of more than several days.

Table III is illustrative of the stability of various formulations of the present invention.

TABLE III RECONSTITUTED STABILITY OF VARIOUS AMPICILLIN TRIHYDRATE - NYSTATIN POWDERS FOR ORAL SUSPENSION Reconstituted Stability $ loss/ at 24°C, pH 5.5-6.5.

Example One Week Two Weeks Three Weeks Four Weeks Amp. Nyst. Amp. Nyst. Amp. Nyst. Amp. Nyst.

As can be seen, there Is a vast Improvement In the stability of both the amplclllin and nystatin from a period of less time than ,one week to a period of greater than four weeks.

The objectives of the present invention have been achieved, by the provision according to the present invention, of the process for the preparation of nontoxic, stable, uniform compositions comprising a) ampicillin or hetaclllln, b) nystatin, c) a buffering agent and d) a sequestering agent, said composition producing a nystatin-ampicillin (or hetaclllln) stable suspen.- sion u on the addition of water said ension havin a in the range of about 5 to 8.

In a preferred embodiment of the process, a quantity of nystatin is used to produce a final concentration of nystatin In the range of 5 , 000 to 200, 000 units/ml.; a quantity of ainpicillin or hetacillin to produce a final concentration in the range of 15 mg. to 125 mg./ml.; a quantity of a sequestering agent, preferably sodium hexametaphosphate, to produce a concentration of about 0.2 to 15.0 and when the sequestering agent used is other than a hexametaphosphate, the composition may contain a buffering agent such as trisodium phosphate or some functional equivalent to adjust the pH of the final suspension to a pH of about 5 to 8.

In a more preferred embodiment of the process, a quantity of nystatin is used to produce a final concentration of nystatin in the range of 20, 000 to 125 , 000 units/ml.; a quantity of ampicillin or hetacillin to produce a final concentration in the range of 25 mg. to 50 mg./ml., a quantity of sodium hexametaphosphate to adjust the pH of the final suspension to a pH of about 5 .5 to 6.5 .

The pharmaceutical elegance, appearance, suspension characteristics, palatability and general stability may be enhanced by the addition of adjuvants to the basic formula; i.e., suspending agents, buffering agents, sweetening and flavoring agents, antioxidants, preservatives and coloring agents.

The dosage forms of the present invention include, but are not limited to, oral dosage forms such as capsules, tablets and powders for dilution into suspensions. The nystatin and ampicillin or hetacillin may be compounded into the above Description of the Preferred Embodiments with the exception of Example 1 1 The following examples/are given to illustrate 2 but not to limit the present invention. 3 Example 1 4 Sugarless Nystatin Oral Suspension Tween 85 1.6 ml. 6 Sodium hexametaphosphate 320.5 g. 7 Qum tragacanth 80.O g. 8 Methylparaben (preservations) 12.8 g. 9 Propylparaben (preservations) 3.2 g. 0 Sodium saccharin 80.O g. 1 Sodium cyclamate 480.0 g. 2 Flavoring q.s. 3 Sodium benzoate 16.0 g. 4 Micropulverlzed nystatin 112.0 g.

Distilled water 13.0 1. 6 Concentrated phosphoric 7 acid or to adjust pH. 18.75$ Sodium hydroxide solution Distilled water, q.s. ad 16.1 Add the gum tragacanth to 11.2 liters, of purified water U.S. P. over a five minute period with rapid stirring, heat to 60 - 650 C. for 15 minutes. Cool the resultant sol4 ution to 25° C. and while continuing the rapid stirring add " the Tween 85 and all the other ingredients. Stir for 15 minutes, ^ adjust the pH to 6.0 and q.s. the volume to l6.0 liters. Pass ^ the suspension through a 100 - 200 mesh screen and then stir 8 vigorously for one hour. Deaerate for 15 - JO minutes and 9 bottle under nitrogen.

Without the sodium hexametaphosphate in this formulation, the nystatin will decompose even faster; e.g., 70$ at pH 5 for one week at 56° C.

Example 2 AMPICILLIN TRIHYDRATE-NYSTATIN SUGAR FREE POWDER FOR ORAL SUSPENSION (250 mg./5 ml. ampicillin activity as the Trihydrate plus 260.000 units of nystatin/5 ml.) Ampicillin Trihydrate 3 .88 gm.

Nystatin, N.F. 3 , 450, 000 units of activity Flavor, Sodium Benzoate 0.06 gm.

Sodium Saccharin, Granular, ( 60 mesh) 0.3 gm.

Sodium Cyclamate, granular 1.494 gm.

Sodium Hexametaphosphate 1.2 gm.

Gum Tragacanth (mlcropulverized) 0.3 gm.

To prepare the suspension qs ad water to 60.O ml. The components of the formulation are finely ground and mixed with a Pony mixer. The mix may be passed through a 10 mesh screen to break up any lumps formed by the addition of the flavors. Following additional blending, the product is passed through a Fitzmill equipped with a No. 4 screen.

After additional blending the product is subdivided AMPICILLIN TRIHYDRATE-NYSTATIN FOR ORAL SUSPENSION (125 mg. amplclllln Activity + 125*000 units nystatin per 5 ml.) per 60 Ml.

Bottle Ampicillin Trlhydrate, micro- pulverized 1.8640 Grams Sodium Saccharin, N.F. 0. l6 Gram Sodium Cyclamate, N.F. 1.60 Grams Sodium Citrate Tribasic, anhydrouB, U.S.P. 0.14 Gram Sodium Benzoate, U.S.P. 0.06 Gram Acacia, U.S.P. 1.50 Grams Tween 40 0. o6 ml.

Flavor Sucrose, U.S.P. 20,895 Grams Nystatin NF, micropulverized 1, 725 , 000 units To prepare suspension qs ad water to 60.00 ml.

Prepare as in Example 2.

Example 4 AMPICILLIN TRIHYDRATE + NYSTATIN FOR ORAL SUSPENSION mg. amplclllln activity + 250, 000 units nystatin per 5 ml.) Per 60 ml.

Bottle Amplclllln Trihydrate, mlcropulverlzed 3 .90 grams Sodium Saccharin, N.F. 0.16 gram Sodium Cyclamate, N.F. I.60 grams Sodium Citrate, tribasic, anhydrous, 0.14 gram U.S. P.

Sodium Benzoate, U.S. P. O.06 gram Acacia, . U.S .P. I.50 grams Sucrose, U.S. P. 21.406 grams Nystatin, N.F., mlcropulverlzed 3 , 450, 000 units Flavor o^s 9 . s.

To prepare suspension qs with water to 60.00 ml.

Prepare as in Example 2.

Example 5 AMPICILLIN TRIHYDRATE-NYSTATIN SUQAR FREE POWDER iPOR ORAL SUSPENSION (125 mg./5 ml. amplclllit activity as the Trl- hydrate plus 125.000 units of aystatin/ 5 ml.") Per 80 ml.

Bottle Ampicillin Trihydrate, micro- pulverized 2.586 Grams Nystatin, N.F., mlcropulverlzed 2,500, 000 units of activity Flavor Sodium Benzoate O.08 Gram Sodium Saccharin, granular 0.4 Gram Sodium cyclamate, granular I.992 Grams Sodium Hexametaphosphate 1.6 Grams Gum Tragacanth, mlcropulverlzed 0.4 Gram To prepare suspension qB ad water to 80.O ml. Prepare as in Example 2. r 1 Example 6 2 AMPICILLIN TRIHYDRATE-NYSTATIN SUGAR FREE POWDER 3 FOR ORAL SUSPENSION ^ (125/mg/5ml. ampicillin activity as the trlhydrate plus 125.000 units of nystatin/5ml. ) 6 Ampicillin Trlhydrate, micropulverized 1.864 gms. 7 Nystatin, N.F., micropulverized 1,725,000 units 8 Sodium Cyclamate, N.F. 1.80 gm. 9 Sodium Hexametaphosphate 1.200 gm.

Sodium Benzoate O.060 gm. 11 Gum Tragacanth O.360 gm. 12 Flavor «J..s. 13 Sodium Saccharin, N.F. 0.30 gm. Il÷ To Prepare suspension qs ad water to 60.00 ml.

Prepare as in Example 2. 6 Example 7 17 HETACILLIN - NYSTATIN SUGAR FREE POWDER FOR ORAL SUSPENSION 18 (250 mg/5ml hetacillin and 250,000 units of n statin/5mI7T 19 Hetacillin, micropulverized 3.30 gm. 21 Nystatin, N.F. 3,450,000 units of activity 22 Flavor, ¾e 23 Sodium Benzoate O.06 gram 24 Sodium Saccharin, Granular, 0.3 gram (60 mesh) 26 Sodium Cyclamate, Granular 1.494 grams 27 Sodium Hexametaphosphate 1.2 grams 28 Gum Tragacanth (micropulverized) 0.3 gram Example 8 HETAC LLIN - NYSTATIN SUGAR FREE POWDER FOR ORAL SUSPENSION (125 mg./5ml. hetacillin plus 125, 000 units of nystatin/ 5 ml.j Per 80 ml.

Bottle Hetacillin, micropulverized 2.20 gm.

Nystatin, N.F., micropulverized 2,300, 000 units of activity Flavor Sodium Benzoate Sodium Saccharin, granular, ( 60 mesh) 0.4 Gram Sodium Cyclamate, granular 1 .992 Grams Sodium Hexametaphosphate 1.6 Grams Gum Tragacanth, micropulverized 0.4 Gram To prepare suspension qs ad water to 80.0 ml.

Prepare as in Example 2.

Example 9 AMPICILLIN TRIHYDRATE ..-n NYSTATIN CAPSULES ( 250 Mg. ampiclllin Activity as ampiclllin Trihydrate and 250.000 units nystatin Activity per Capsule) Per Capsule Ampiclllin Trihydrate, Compacted O.J047 Gm.

Nystatin, U.S. P., Non Sterile 287, 500 units Magnesium Stearate, U.S. P. Ο.ΟΟ65 Gm.

Lactose, U.S. P. (if neceesary) 0.05 Gm.

Add the Nystatin Ampiclllin Trihydrate and the Magnesium stearate to a suitable blender, mix well for thirty minutes. Mix this composition with lactose, U.S. P. if nec 1 Example 10 2 HETACILLIN - NYSTATIN CAPSULES (250 mg. hetacillin and 250.000 units nystatin activity per Capsule « Hetacillin, compacted 0.2575 gm 6 Nystatin, N.P. 287,500 units 7 Magnesium Stearate, U.S. P. Ο.ΟΟ65 gm. 8 Lactose, U.S. P. (if necessary) 0.05 gm. 9 Prepare as in Example 9. 11 12 While in the foregoing specification various embodi- 13 ments of this invention have been set forth in specific detail Ik and elaborated for the purpose of illustration, it will be apparent to those skilled in the art that this invention is sus 16 ceptible to other embodiments and that many of the details can 17 be varied widely without departing from the basic concept and 18 the spirit and scope of the invention. 19 . 1 2 k 6 7 8 30684/3

Claims (6)

1. A therapeutic composition for the treatment of bacterial infection by oral administration comprising a mixture of about 100,000 to 550,000 nystatin units per unit dose with about 100 mg to 600 mg of amplcillln or hetaclllin per unit does with a pharmaceutically acceptable carrier.

2. A therapeutic composition according to Claim 1, for dilution with water, into a stable suspension of nystatin with ampleillin or hetaclllin for the treatment of bacterial infections by oral administration, which composition comprises a mixture of about 100,000 to 275,000 units of nystatin per unit dose, about 100 mg to 300 mg of ampicillin or hetacillin per unit dose, a sequestering agent and a buffering agent, the composition having, after dilution with water, a pH in the range of about 5.0 to 8.0.

3. A therapeutic composition as claimed in Claim 2 wherein a combination sequestering-buf ering agent is used.

4. A therapeutic composition as claimed in Claim 3 wherein about 0.2 to 15$ by weight of sodium hexametaphos-phate is used as the combination sequestering-bufferin agent.

5. A therapeutic composition as claimed in Claim 4 wherein there is also added a suspending agent.

6. A therapeutic composition as claimed in Claim 5 wherein the suspending agent is gum tragacanth or gum acacia.