MXPA06004865A - Suspension of loteprednol etabonate and tobramycin for topical ophthalmic use - Google Patents

Abstract

This invention relates to formulations for topical use comprising antibiotics in combination with anti-inflammatory steroids for treating ophthalmic infections and attendant inflammation. More specifically, this invention relates to pharmaceutical ophthalmic formulations comprising a pH stabilizing amount of tobramycin and the soft steroid loteprednol etabonate.

Description

SUSPENSION OF LOTEPREDNOL AND TOBRAMYCIN ETABONATE FOR TOPICAL OFTALMIC USE FIELD OF THE INVENTION The invention relates to formulations for topical use comprising antibiotics in combination with anti-inflamatory spheroids to treat ophthalmic infections and the consequent inflammation. More specifically, this invention relates to pharmaceutical ophthalmic formulations comprising a stabilizing amount of the pH of tobramycin and the mild spheroid etabonate of loteprednol.

BACKGROUND OF THE INVENTION Topical spheroids such as corticosteroids are commonly used for anti-inflammatory eye therapy, especially for treating inflammatory conditions of the palpebral or bulbar conjunctiva, cornea and anterior segment of the globe. Common therapeutic applications for spheroids include allergic conjunctivitis, acne rosacea, superficial punctate keratitis and iritis, cyclitis. Spheroids can also be used to improve inflammation associated with corneal injury due to chemical or thermal burns, or penetration of foreign bodies. These conditions can be the result of surgery, injury, allergy or eye infection and can cause serious discomfort.

Despite its therapeutic advantages, the ocular topical use of corticosteroids is associated with several complications, including the formation of posterior subcapsular cataracts, elevation of the infraocular pressure, secondary ocular infection, delay of the healing of corneal wounds, uveitis, mydriasis, transient eye discomfort and ptosis. Numerous systemic complications can also arise from the topical ocular application of corticosteroids. These complications include adrenal insufficiency, Cushing's syndrome, peptic ulceration, osteoporosis, hypertension, muscle weakness or atrophy, growth inhibition, diabetes, activation of the infection, mood swings and delayed wound healing. Topical spheroids to treat ocular inflammations can be based on mild drugs. The mild drugs, as is known in the art, are designed to provide maximum therapeutic effect and minimal side effects. By one approach, the synthesis of a "soft drug" can be achieved by structurally modifying a known inactive metabolite of a known active drug to produce an active metabolite that undergoes a foreseeable transformation in vivo of a step back to the parent inactive metabolite (see, U.S. Patent Nos. 6,610,675, 4,996,335 and 4,710,495 for soft spheroids). "Soft drugs" are therefore biologically active chemical components characterized by in vivo predictable metabolism to non-toxic derivatives after providing their therapeutic effect. Formulations of corticosteroids suitable for ophthalmic use are known. For example, U.S. Patents 4,710,495, 4,996,335, 5,540,930, 5,747,061, 5,916,550, 6,368,616 and 6,610,675, the contents of each of which are incorporated herein by reference. document, describe mild spheroids and formulations containing soft spheroids. Antibiotic agents for use in the treatment of ophthalmic infections are also known. For example it is known that penicillins, cephalosporins and aminoglycosides such as ami acine, gentamicin, and tobramycin are useful in the treatment of eye infections. Tobramycin is marketed and is well recognized as an effective antibiotic. This particular anti-infective agent is recognized as active against the common bacterial pathogens of the eye: Staphylococci, including S. aureus and S. epidermidis, including the strains resistant to penicillin, Streptococci, including S. pneumoniae, Pseudomonas aeruginosa, Escherichia coli, Klebsiella pneumoniae, Enterobacter aerogenes, Proteus mirabilis, Morganella morganii, Haemophilus influenzae, H. aegyptius r Acinetobacter calcoaceticus and some species of Neissaria. The antimicrobial activity of tobramycin is provided by its ability to bind to the 30S ribosomal subunit and alter protein synthesis, thereby leading to the death of the microbial organism. It has been previously suggested that the loteprednol spheroid etabonate (LE) can be combined with antibiotics such as tobramycin. However, the amount of tobramycin to be used in combination with LE has not been suggested to provide a desired therapeutic effect of both active agents. Nor has a combined formulation having satisfactory properties for storage and use of the combination of tobramycin and LE been described in detail.

It is known that formulations containing spheroids can experience stability problems. Such stability problems include bunching and other undesirable changes during storage. U.S. Patent No. 5,916,550 describes the use of C2-C7 aliphatic amino acids to control the pH drop of aqueous suspensions of LE in prolonged storage. Therefore, the need to provide pharmaceutical formulations of spheroids that are stable during storage is well recognized. One of the factors used to evaluate the stability of pharmaceutical formulations is pH. When there is a drastic change in the pH of a pharmaceutical formulation over time, the ability of the formulation to efficiently store and retain its pharmaceutical activity after storage becomes questionable. It is known that buffers are added to certain pharmaceutical formulations in an effort to maintain the stability of the formulation during storage. Examples of buffers include borate buffers, phosphate buffers, etc. Although these buffers are useful in stabilizing the pH, they do not show pharmaceutical activity. Therefore, it would be desirable to use a single material to provide the pH stabilizing activity and the desired anti-infection activity to ophthalmic pharmaceutical formulations containing the soft spheroidal etabonate of loteprednol. SUMMARY OF THE INVENTION It has surprisingly been found that the aminoglycoside tobramycin, when present in a pH stabilizing amount, helps to stabilize formulations containing loteprednol etabonate over time to provide better storage characteristics. This invention provides novel compositions of a substance containing a combination of water-soluble and water-insoluble drugs suitable for therapeutic use. The invention provides aqueous suspensions that are stable to pH changes of water insoluble drugs that remain in that state even after prolonged storage periods. More particularly, the invention is directed to aqueous suspensions of mild spheroids such as loteprednol etabonate in combination with aminoglycosides such as tobramycin suitable for therapeutic use in the eye, ear, or nose. The aqueous suspensions of LE and tobramycin are surprisingly stable at pH changes and can remain in a stable state at pH changes during prolonged storage periods. The formulations comprising the broad spectrum antibiotic aminoglycoside tobramycin in combination with the predictably metabolized spheroid of loteprednol etabonate provide pharmaceutical ophthalmic formulations that not only allow the simultaneous treatment of inflammation and infection in a patient in need of treatment thereof. , but also result in a pharmaceutical ophthalmic formulation having increased stability, as measured by the decreased pH change compared to similar formulations that do not contain tobramycin.

Furthermore, in this document, a topical eye drops medication is provided for inflammatory eye conditions sensitive to spheroids for which a corticosteroid is indicated and in which there is ocular infection by superficial bacteria or risk of ocular infection by bacteria. The medication comprises an ophthalmic suspension of loteprednol / tobramycin etabonate 0.5% / 0.3%. The use of this medication is indicated where the risk of superficial ocular infection is high or when several potentially dangerous bacteria are expected to be present in the eye. Also provided herein is a therapeutically effective composition comprising a mild spheroid such as loteprednol etabonate in an amount effective to provide a therapeutic benefit to a patient to whom the composition is administered and an amount of pH stabilizing tobramycin., wherein the tobramycin is present in an amount effective to stabilize the pH of the composition relative to the pH of a similar formulation without the tobramycin. Also provided herein is a method for the treatment of a patient having inflammatory ocular conditions for which a corticosteroid is indicated and in which there is ocular infection by superficial bacteria or risk of an ocular infection by bacteria, the method comprising the application topical to a patient in need of treatment thereof of a therapeutic amount of a pharmaceutical composition comprising the broad spectrum antibiotic aminoglycoside tobramycin in combination with the metabolized spheroid predictably loteprednol etabonate. Having briefly summarized the invention, the invention will now be described in detail by reference to the following specification and non-limiting examples. Unless otherwise indicated, all percentages are by weight and all temperatures are in degrees Celsius. DETAILED DESCRIPTION OF THE INVENTION The therapeutic suspensions of LE for ophthalmic or otolaryngological use are prepared by aseptic preparation. The purity levels of all the materials used in the suspensions of the invention exceed 98%. The suspensions of the invention are prepared by meticulously mixing the smooth spheroid (component (A)), aminoglycoside (component (B)), the suspending agent (component (C)), and a surfactant (component (D)). Optionally, tonicity agents (component (E)) and preservatives (component (F)) can be included. Component (A) spheroids, preferably soft spheroids, more preferably LE, may be employed. Other spheroids such as beclomethasone, betamethasone, fluocinolone, fluorometholone, exednisolone can also be used. The component suspensions (A) of the invention have a particle size of about 0.1-30 μm, preferably about 1-20 μm, more preferably about 2-10 μm of average diameter. The LE in this size range is available in the market from suppliers such as Sipsy Co., (Avrille, France).

The aminoglycoside component (B) is of pharmaceutical quality. Aminoglycosides are a well-characterized family of antimicrobial agents and include, for example, gentamicin, neomycin, paromomycin, ka.namicin, tobramycin, netilmicin and amikacin. Tobramycin of this quality is available in the market from suppliers such as Biogal Pharmaceutical Works (Debrecen, Hungary). Component (B) is preferably present in an amount which is effective to stabilize the pH of the composition relative to the pH of a similar composition without component (B) Therefore, the amount of component (B) may vary depending on the individual composition. The determination of the pH stabilizing amount of an aminoglycoside for a particular composition can be easily achieved through routine experimentation and pertains to the field of one skilled in the art. The non-ionic polymer of component (C) can be any water-soluble nonionic polymer. Typical compounds such as PVP, PVA, HPMC or dextran can be used at a concentration of about 0.01-2%, and preferably between about 0.4 to 1.5%, and more preferably between 0.4 and 1. %. Increased viscosity above that of simple aqueous solutions may be desirable to increase ocular absorption of the active compound, to decrease the variability to administer the formulation, to decrease the physical separation of the components of a suspension or emulsion from the formulation and / or to improve the pharmaceutical formulation in any other way. Said viscosity adjuvants include, as examples, polyvinyl alcohol, polyvinyl pyrrolidone, methyl cellulose, hydroxypropylmethyl cellulose, hydroxyethyl cellulose, carboxymethyl cellulose, hydroxypropyl cellulose or other agents known to those skilled in the art. Povidone is preferably used as a suspending agent in the finished product and the water soluble classes are routinely used in pharmaceutical compositions as a viscosity enhancing agent. The viscosity of the aqueous solutions of the water-soluble povidone classes depends on the average molecular weight. A subtle change in the kind and concentration of the suspending agent can produce the desired characteristics. Povidone is available in various classes, some of which are soluble in water. Povidone K-90 is the highest molecular weight water soluble viscosity class Povidone. This material is cataloged as Povidona, USP 90,000. The povidone of high molecular weight class dissolves much more slowly than the low molecular weight class. Component (D) is a surfactant that is acceptable for ophthalmic or otolaryngological use. Preferably, this surfactant is nonionic. Useful surfactants include, but are not limited to, polysorbate 80, tyloxapol, TWEEN 80 (ICI America Inc., Wilton, Del.), PLURONIC F-68 (from BASF, Ludwigshafen, Germany) and poloxa ero surfactants. These surfactants are condensed non-ionic alkali oxides of an organic compound containing hydroxyl groups. The concentration at which the surfactant can be used is limited only by the neutralization of the bactericidal effects in the accompanying preservatives, or by the concentrations that can cause irritation.

Preferably, the concentration of the component (D) is about 0.05 to 1%, and more preferably 0.1 to 0.6% by weight based on the weight of the suspension. The compositions of the present invention having a molar ratio of (A): (C): (D) between about 1: 20: 1 and about 1: 0.01: 0.5 are completely adequate. The component tonicity agents (E) can be nonionic diols, preferably glycerol, in amounts sufficient to achieve isotonicity. The non-ionic tonicity agents may be present in an amount of about 2 to 2.8% by weight, and preferably about 2.2 to 2.6%. The nonionic polymer compounds of component (C), and the component surfactants (D) have good solubility in water, have a sufficient number of hydroxyl groups to interact with the spheroid, and have slight effects on the viscosity of the suspension. The final viscosity should not exceed 80 centipoise. The suspension of the invention may also include additional therapeutic drugs such as drugs for the treatment of glaucoma, anti-inflammatory drugs, anti-cancer drugs, anti-fungal drugs and antiviral drugs. Examples of anti-glaucoma drugs include, but are not limited to, timolol-base, betaxolol, atenolol, levobunolol, epinephrine, dipivalyl, oxonolol, acetazyl ida-base and metazalomide. Examples of anti-inflammatory drugs include but are not limited to non-steroids such as piroxicam, indomethacin, naproxen, phenylbutazone, ibuprofen and diclofenac.

Sanitary standards in various countries generally require that ophthalmic preparations include a preservative. Many well-known preservatives that have been used in ophthalmic preparations of the prior art, however, can not be used in the preparations of the invention, since these preservatives can no longer be considered safe for ocular use, or they can interact with the surfactant employed in the suspension to form a complex that reduces the bactericidal activity of the preservative. The preservatives of component (F) employed in the suspensions of the invention, therefore, are chosen so as not to interact with the surfactant to the extent that preservatives are prevented from protecting the suspension from microbiological contamination. In a preferred embodiment, benzalkonium chloride can be used as a safe preservative, more preferably benzalkonium chloride with EDTA. Other possible preservatives include, but are not limited to, benzyl alcohol, methyl parabens, propyl parabens, thimerosal, chlorbutanol, and benzethonium chlorides. Typically said preservatives are employed at a level of 0.001% to 1.0% by weight. Preferably, a preservative (or a combination of preservatives) that will transmit conventional antimicrobial activity to the suspension and will protect against the oxidation of the components (A) - (E) is employed. In the formation of compositions for topical administration, the mixtures are preferably formulated as solutions in water of 0.01 to 2.0 weight percent at a pH of 4.5 to 8.0 (the figures refer to the combined presence of loteprednol etabonate and tobramycin). Meanwhile he Precise regimen is left at the discretion of the doctor, it is recommended that the resulting solution be applied topically by depositing one drop on each eye twice a day. A study of bioavailability of LE-tobramycin against the composition of loteprednol etabonate LOTEMAX showed that in the attempt to treat the population was fulfilled bioequivalence was reached in sampling periods of both 40 and 60 minutes. Therefore, the inclusion of tobramycin does not alter the ocular bioavailability of loteprednol etabonate. A study of the microbial death index was undertaken to demonstrate the antimicrobial equivalence between loteprednol etabonate and an ophthalmic suspension of tobramycin, 0.5% / 0.3% and an ophthalmic solution of tobramycin, USP 0.3%. The methods used were based on USP antimicrobial efficacy procedures for the preparation of the inoculum concentration and exposure of the test organisms. The antimicrobial activity of both products was demonstrated against 22 organisms. The in vitxo study showed that tobramycin has equivalent anti-microbial activity as a single agent and when combined with loteprednol etabonate. Without further elaboration, it is believed that one skilled in the art can, using the preceding description, utilize the present invention to its fullest extent. The following preferred specific embodiments thereof, therefore, should be interpreted in a manner merely illustrative, and in no way limiting the remainder of the description. In the following examples, all temperatures are exposed in degrees Celsius; Unless otherwise indicated, all parts and percentage are by weight.

EXAMPLES A study was undertaken to compare a conventional composition of LE-tobramycin having different concentrations of Povidone and different types of Povidone. The compositions of the example also contained conventional pharmaceutical components. Examples III and VI were used as controls (without tobramycin) to observe the effect of tobramycin on the pH of the composition. The materials were mixed with purified water and maintained at a temperature of 28 ° C to represent stability at room temperature and at 40 ° C to represent accelerated stability. The results are given in the following tables.

STABILITY OF THE LE-TOBRAMYCIN MATRIX (with different viscosity) 28 ° C Tobra time. LE pH (months) (mg / ml) (mg / ml) I 0 3,18 4,976 6,49 0, 6% 1 3,076 - 6,32 PVP-C30 2 3,062 4,947 6,28 3 3,113 5,484 6.21 6 3,003 5,155 6.17 II 0 3,165 5,241 6.47 1.5% 1 3.04 - 6.3 PVP-C30 2 2,995 5.08 6.19 3 3.04 5.32 6.14 6 3.008 5.514 6.087 III 0 - 5,576 5.98 1.5% 1 - - 5,54 PVP-C30 2 - 5,411 5,06 Control 3 - 5,706 5,02 6 - 5,134 4,8 IV 0 3,206 5,296 6.71 1.5% 1 3,082 5,156 6.57 PVP-K90 2 3,122 5.29 6.49 3 3.21 5.306 6.47 6 3.146 5.358 6.39 V 0 2.802 4.32 6, 61 0.5% 1 2.754 4.24 6, 48 PVP-K90 2 2,596 4,28 6,38 3 2,811 4,336 6,34 6 2,806 4,365 6,32 VI 0 - 5,426 6,61 1,5% 1 - 5,638 5,033 PVP-K90 2 - 5,67 4,71 Control 3 - 5.67 4.72 6 - 5.727 4.43 STABILITY OF THE MATRIX OF LE-TOBRAMYCIN (with different viscosity) 40 ° C Time Tobra. LE pH (months) (mg / ml) (mg / ml) I 0 3.18 4.976 6.49 0.6% 1 3.15 - 6.23 PVP-C30 2 2,957 5,008 6.06 3 3,036 5,067 5, 95 6 - - - II 0 3,165 5,241 6.47 1.5% 1 3,019 - 6,21 PVP-C30 2 2,91 5,16 5,89 3 2,95 5,37 5,89 6 - - - III 0 - 5,576 5.98 1.5% 1 - - 4.73 PVP-C30 2 - 5,411 4.33 Control 3 - 5,473 4,11 6 - - - IV 0 3,206 5,296 6.71 1.5% 1 2, 94 5,336 6.47 PVP-K90 2 2.84 5,209 6.13 3 3.17 5.17 6.25 6 3.212 5,178 6.097 V 0 2.802 4.32 6.61 0.5% 1 2.588 4.288 6.38 RRP -K90 2 2,64 4,21 6,21 3 2,82 4,2 6,14 6 2,767 4,267 6,04 VI 0 - 5,426 6,61 1,5% 1 - 5,614 4,62 PVP-K90 2 - 5,91 3,93 Control 3 - 5,85 3,83 6 - 5,572 3,53 The above data represent the results of pH stability tests of various compositions with different viscosity. PVP-C30 is Povidone having a molecular weight of about 30,000 and PVP-K90 is Povidone having a molecular weight of about 90,000. Both were obtained from GAF Corporation, United States. In general, a pH between 4.5 and 7.0 is considered acceptable for pharmaceutical ophthalmic use of these compositions. The data demonstrate that the compositions of the present invention having tobramycin exhibit a more gradual decrease in pH over time and a smaller change in total pH over time compared to similar compositions that do not contain tobramycin. The following example is a representative pharmaceutical composition of the invention for topical use which is indicated against inflammation and infection. EXAMPLE 1 Ingredients (per my) 0.5% loteprednol etabonate (5 mg) 2.5% glycerin Povidone, 0.6% K-90 0.3% Tobramycin (3 mg) Benzalkonium Chloride a0, 01% 0.05% tyloxapol 0.01% disodium edetate Purified water (CS up to 100%) Sulfuric acid or sodium hydroxide (to adjust the pH)

Claims (34)

Claims

1. A composition for ophthalmic and otolaryngological anti-inflammatory use comprising: (A) loteprednol etabonate having a particle size of 0.1 to 30 micrometers in diameter in an amount of about 0.2 to 2% by weight; (B) tobramycin in an amount effective to stabilize the pH of the composition relative to the pH of a similar composition without the tobramycin; (C) a nonionic polymer in an aqueous medium; and (D) a nonionic surfactant in an amount sufficient to retain the corticosteroid in suspension, wherein the molar ratio of (A): (C): (D) is between about 1: 20: 1 and about 1: 0.01: 0.5.

2. The composition of claim 1 further comprising: (E) a non-ionic tonicity agent in an amount sufficient to achieve isotonicity.

3. The composition of claim 1, wherein the loteprednol etabonate is present in an amount of about 0.5 to 1% by weight.

4. The composition of claim 1, wherein the loteprednol etabonate has a particle size of less than about fifteen microns.

5. The composition of claim 4, wherein the tobramycin is present in an effective anti-infection amount.

6. The composition of claim 1 further including a preservative to prevent microbial formation in said composition and in an amount of about 0.01 to 0.025 wt%.

7. The composition of claim 6, wherein said preservative is benzalkonium chloride.

8. The composition of claim 7 which further comprises edetate disodium.

9. The composition of claim 1, wherein said nonionic polymer is selected from the group consisting of polyvinylpyrrolidone, polyvinyl alcohol, or dextran and is present in an amount of about 0.2 to 2% by weight and in which the surfactant Nonionic is present in an amount of about 0.05 to 1% by weight.

10. The composition of claim 1, wherein said nonionic polymer is polyvinyl pyrrolidone and is present in an amount of about 0.4 to 1% by weight.

11. The composition of claim 1, wherein said nonionic surfactant is tyloxapol and is present in an amount of about 0.1 to 0.6% by weight.

12. The composition of claim 1 further comprising an additional therapeutic drug mixed with said mild spheroid and tobramycin, wherein said additional therapeutic drug is selected from the group consisting of betaxolol, atenolol, levobunolol, epinephrine, dipivalyl, oxonolol, acetazilumide-base, metazalomide, piroxicam, indomethacin, naproxen, phenylbutazone, ibuprofen, and diclofenac-acid.

13. A composition for anti-inflammatory and ophthalmic and otolaryngological antiinfection use comprising a nonionic polymer in an aqueous medium, a nonionic tonicity agent in an amount effective to achieve isotonicity, and a nonionic surfactant in an amount sufficient to retain the polymer and the tonicity agent in the aqueous medium, tobramycin; and further comprising a smooth spheroid having a particle size of 0.1 to 30 micrometers in diameter in an amount of about 0.2 to 2% by weight, wherein the composition is bioequivalent to a similar etabonate formulation of loteprednol that does not contain tobramycin.

14. The composition of claim 13, wherein said nonionic tonicity agent is a nonionic diol and is present in an amount of about 2 to 2.8% by weight.

15. The composition of claim 13, wherein the nonionic polymer is present in an amount of about 0.2 to 2% by weight; the tonicity agent nonionic is present in an amount of about 2 to 2.8% by weight; and the nonionic surfactant is present in an amount of about 0.05 to 1% by weight.

16. The composition of claim 13 further comprising a preservative of benzalkonium chloride, disodium edetate, and mixtures thereof in an amount of about 0.01 to 0.025% by weight.

17. The composition of claim 13, wherein the nonionic polymer is polyvinyl pyrrolidone and is present in an amount of about 0.4 to 1% by weight, the nonionic tonicity agent is mannitol or a diol and is present in an amount of about 2 to 2.8% by weight, and the nonionic surfactant is tyloxapol and is present in an amount of about 0.1 to 0.6% by weight.

18. The composition of claim 2, wherein the loteprednol etabonate is present in an amount between about 0.01 and 1% by weight.

19. The composition of claim 2, wherein the loteprednol etabonate is present in an amount between about 0.05 and about 0.5% by weight.

20. The composition of claim 2, wherein said nonionic polymer is a water soluble polymer selected from the group consisting of polyvinylpyrrolidone, polyvinyl alcohol, dextran and cyclodextrin.

21. The composition of claim 2, wherein the nonionic polymer is present in an amount of about 0.2 to 2% by weight.

22. The composition of claim 20, wherein said nonionic polymer is polyvinyl pyrrolidone and is present in an amount between about 0.3 to about 1.75% by weight.

23. The composition of claim 2, wherein said nonionic surfactant is tyloxapol and is present in an amount of about 0.05 to about 1% by weight.

24. The composition of claim 2, wherein said nonionic surfactant is a polyoxyethylene sorbitan mono-oleate ester.

25. The composition of claim 22, wherein the non-ionic tonicity agent is present in an amount between about 1 to about 7% by weight.

26. The composition of claim 25, wherein the nonionic tonicity agent is a nonionic polyol and is present in an amount between about 1.5 to about 4% by weight.

27. The composition of claim 26, wherein the non-ionic tonicity agent is glycerol or mannitol.

28. The composition of claim 2 which further includes a preservative to prevent microbial formation in said composition and is present in an amount between about 0.0001 to about 0.025% by weight.

29. The composition of claim 28, wherein said preservative is selected from the group consisting of benzalkonium chloride, disodium edetate and mixtures thereof.

30. The composition of claim 22 further comprising an additional therapeutic drug mixed with said mild spheroid and tobramycin, wherein said additional therapeutic drug is selected from the group consisting of, betaxolol, atenolol, levobunolol, epinephrine, dipivalyl, oxonolol, acetazolamide-base , metazolamide, piroxicam, indomethacin, naproxen, phenylbutazone, ibuprofen and diclofenac.

31. The composition of claim 2, wherein the nonionic polymer is present in an amount between about 0.2 to about 2% by weight; the non-ionic tonicity agent is present in an amount between about 1 to about 7% by weight; and * the nonionic surfactant is present in an amount between about 0.05 to about 1% by weight.

32. The composition of claim 31 further comprising a preservative to prevent microbial formation in said composition and is present in an amount of about 0.0001 to 0.025% by weight.

33. A method for the treatment of ophthalmic or otolaryngological inflammation comprising applying to the inflamed tissue a composition comprising: (A) loteprednol etabonate in an amount of 0.01 to about 2% by weight and having a particle size from about 0.1 to 30 micrometers in diameter to substantially avoid discomfort during the use of the composition for said ophthalmic or otolaryngological anti-inflammatory treatment.; (B) an amount of tobramycin effective to stabilize the pH of the composition relative to the pH of a similar composition without the tobramycin; (C) a nonionic polymer in an aqueous medium; and (D) a nonionic surfactant in an amount sufficient to retain the soft spheroid in suspension; wherein said composition is applied in an amount effective to treat said inflammation and infection.

34. The method of claim 33, wherein the nonionic polymer is present in an amount between about 0.2 to about 2% by weight, the nonionic tonicity agent is present in an amount between about 1 to about 7% by weight, and the Nonionic surfactant is present in an amount between about 0.05 to about 1% by weight, and wherein the molar ratio of (A): (C): (D) is about 1: 0.01. : 0.05 to about 1: 20: 1.