Pharmaceutical compositions are described that contain one agent for treatment of sinusitis and a surfactant. The compositions are prepared to have a surface tension that renders the composition effective for treatment of sinusitis.

SUMMARY OF THE INVENTION

Provided are pharmaceutical compositions that include one or more active ingredients such as anti-infective, anti-inflammatory and mucolytic agents. Such compositions preferably are formulated as a solution in a unit dose or multi-dose vial for aerosol administration to the nasal sinuses. It is contemplated that such formulations are packaged with labels or inserts or other forms of directions for their use in the treatment of sinusitis.

In a preferred embodiment, the surface tension of the solution is between about 10 to 70 dynes/cm, in order to yield an aerosol having a preferred Mass Median Aerodynamic Diameter within the range of about 1.0 to 4.0 microns. The use of such an aerosolized spray has minimal systemic side effects. Surface tension of a given formulation may be adjusted by adding a surfactant in addition to the active ingredients in order to bring it into the preferred range.

Generally, it is contemplated that formulations according to the present invention will preferably have a pH in the range of about 3.0 to 8.5; an osmolality of the solution between about 150 mOsm/kg to 880 mOsm/kg; and a NaCl equivalency to the solution is preferably between about 0.9% NaCl to 3.0% NaCl.

Preferred anti-infective agents include Penicillins, Cephalosporins, Macrolides, Sulfonamides, Quinolones, Aminoglycosides, BetaLactam antibiotics, Linezolid, Vancomycin, Amphotericin B, and Azole antifungals. Preferred anti-inflammatory agents include Glucocorticoids, Disodium Cromoglycate and Nedcromil Sodium. Preferred mucolytic agents are Acetylcysteine and Dornase Alpha. Preferred decongestant agents are Phenylephrine, Naphazoline, Oxymetazoline, Tetrahydrozoline and Xylometoazoline.

Exemplary pharmaceutical compositions contain one or more active ingredients selected from the group consisting of anti-infective, anti-inflammatory and mucolytic agents, wherein the surface tension of the solution is between about 10 to 70 dynes/cm, said composition being formulated as a solution in a unit dose for aerosol administration to the nasal sinuses and being packaged with directions for its use in the treatment of sinusitis. The pH of the composition typically ranges from about 3.0 to 8.5. The osmolality typically ranges from 300 mOsm/kg to 880 mOsm/kg, where the NaCl equivalency to the solution is generally between about 0.9% NaCl to 3.0% NaCl. The compositions also contain a surfactant. The compositions can additionally contain other active agents for treatment of sinusitis, such as a decongestant.

In one embodiment, the agent is an anti-infective agent and the sinusitis is caused by a pathogen selected from among Alpha Hemolytic streptococci, Beta Hemolytic streptococci, Branhamella Catarrhalis, Diptheroids, Haemophilis influenzae (beta-lactamase positive and negative), Moraxella species, Pseudomonas aeruginosa, Pseudomonas maltophilia, Serratia marcescens, Staphylococcus aureus, Streptococcus pneumonia, Aspergillosis, Mucor and Candida Albicans, Fusarium, Curvularia, cryptococcus, coccidioides, and histoplasma. The anti-infective agent can be selected from among Penicillins, Cephalosporins, Macrolides, Sulfonamides, Quinolones, Aminoglycosides, BetaLactam antibiotics, Linezolid, Vancomycin, Amphotericin B, and Azole antifungals. The surfactant can be a polysorbate, such as polysorbate 20 to polysorbate 85.

The compositions can be formulated as an aerosol. In one embodiment, at least about 85% of the aerosolized particles have a Mass Median Aerodynamic Diameter within the range of about 1.0 to 4.0 microns. These aerosols can be effective to kill at least about 90% of susceptible sinusitis-causing pathogens present in the sinus passages of a sinusitis patient within about 14 days following an every 8 hr (TID), every 12 hr (BID), or every 24 hr (AD) administration protocol.

Kits containing the compositions are provided. In a one embodiment, a kit is described that provides the various equipment and attachments useful in administering the formulations of the present invention by using the disclosed nebulizer devices. In one embodiment, the kits contain a nebulizer cup with a nasal adapter for delivering the composition in aerosolized form to the nasal sinuses. This kit can be combined with a nebulizer device.

Methods of treatment a patient suspected or diagnosed as having chronic sinusitis are provided. Preferred administration protocols also are described. The pharmaceutical composition, for example, can be administered to the patient 1 3 times a day for a total of 14 21 days. These methods can include the step of administering to the pharmaceutical composition by aerosolization using a nebulizer, which delivers aerosol particles of between about 1 to 5 .mu.m in average diameter. Nebulizers that deliver aerosol particles between about 1 to 5 .mu.m in average diameter are known in the art (see U.S. Pat. No. 5,508,269). One exemplary nebulizer is a PARI nebulizer with a nasal adapter. The nebulizer can be connected to a PARI SinuNEB compressor which is an exemplary device to generate an airflow to deliver the composition. The nebulizer can deliver a majority of aerosolized particles in the size range of abut 3.0 to 3.5 .mu.m in diameter.

DETAILED DESCRIPTION OF THE INVENTION

I. General Description

The present invention involves the topical delivery of medications to the nasal cavity and sinuses by aerosolizing aqueous solutions of these medications. The present invention is based in part on the surprising finding that aerosolized ant-infective particles are surprisingly effective therapeutically when they have a mass median aerodynamic diameter (MMAD) of about 3.0 to 3.5 .mu.m for deposition in the sinuses in a preferred size range. The present invention provides an apparatus for delivery of such optimally sized anti-infective particles into the sinuses. The present invention is also based in part on the finding that the addition of a surfactant to formulations increases the deposition, retention, and penetration of anti-infectives or other active ingredients into the sinuses. The present invention provides guidance for therapy schedule and dosage as discussed in detail below.

As described in greater detail below, the pharmaceutical formulations will be aerosolized/atomized prior to administration to a patient to form an aerosol cloud with particles of aerosolized/atomized H.sub.2O and medication that have a MMAD (Mass Median Aerodynamic Diameter) of preferably between about 0.5 and 5.0 microns, more preferably between about 1.0 to 4.0 microns and most preferably between about 2.0 to 3.5 microns. It is also preferable to have the maximum number of particles over 5.0 microns be less than 20% of the total particles.

A surprising discovery made by the inventors was that the surface tension of the solution prepared for inhalation needed to be adjusted to achieve optimal results. To achieve effective deposition of medication within the sinuses it is preferable to have the surface tension of the solution for aerosolization be adjusted with surfactants to between 10 dynes/cm and 70 dynes/cm, more preferably between about 20 to 60 dynes/cm, and most preferably between about 30 to 50 dynes/cm.

Contemplated pharmaceutical compositions will include one or more active ingredients such as anti-infective, anti-inflammatory and mucolytic agents. Appropriate medications to be used in the methods according to the present invention are listed in Table 1. These medications may be administered for the treatment of sinusitis, particularly chronic sinusitis, by resolving infection, reducing inflammation or reducing congestion in the nasal cavity and sinuses.

These compositions ideally will be formulated as a solution in a unit dose or multi-dose vial for aerosol administration to the nasal cavity and sinuses and packaged with directions for its use in the treatment of sinusitis. Appropriate compositions for this purpose will be formulated by using surfactants, NaCl or other chemicals entities to adjust the solution for administration to have the following properties: surface tension preferably between about 10 to 70 dynes/cm, more preferably between about 20 to 60 dynes/cm, and most preferably between about 30 to 50 dynes/cm. osmolality between about 300 mOsm/kg to 880 mOsm/kg, more preferably between about 400 mOsm/kg to 700 mOsm/kg and most preferably between about 500 mOsm/kg to 600 mOsm/kg. NaCl equivalency of the solution preferably between about 0.9% NaCl and 3.0% NaCl, more preferably between about 1.1% NaCl and 1.8% NaCl and most preferably between about 1.3% NaCl and 1.7% NaCl. pH preferably between about 3.0 and 8.5, but may vary according to the properties of the medication used.

A. Surface Tension

The present inventors have found that the surface tension and, to a lesser degree, particle size are critical factors in getting optimal deposition of the formulation in the nasal cavity and sinuses. For example, particles that are too large will deposit in the nasal cavity, but are unlikely to enter the sinuses. Having too low a surface tension increases an aerosolized particle's chance of deposition on the first surface that it comes in contact with, which generally would be tissue or structures in the nasal cavity proximal to the sinuses. In contrast, if the surface tension is too high, much of the aerosolized medication is not deposited within the patient's sinuses and ultimately is deposited in the lungs. If the surface tension is too low most of the aerosolized medication is deposited in the nasal cavity and does not reach the sinuses.

For purposes of preparing formulations according to the present invention, surface tension may be measured by using a Ring Tensiometer or the capillary rise measure method which consists of a capillary tube of known diameter placed into the solution and a measurement of capillary rise taken to provide surface tension. Surface tension will then be adjusted using surfactants to fall within a preferred range in dynes/cm.

B. Osmotic Pressure

Optimal osmotic pressure helps to reduce damage to the epithelia cilia of the sinuses. Although often not present in chronic sinusitis patients, epithelia cilia perform a useful function in the sinuses by moving mucosal fluid out of the sinuses.

For purposes of preparing formulations according to the present invention, osmolality may be measured by using an Osmometer. If necessary, osmolality may then be raised to fall within a preferred range by adding NaCl to the solution.

C. Sodium Chloride Equivalency

Optimal NaCl equivalency (tonicity) works to reduce swelling in the sinuses and nasal cavity by drawing water from the nasal and sinus epithelia, reducing swelling. NaCl equivalency below 0.9% (hypotonic) may cause swelling in the epithelia of the nasal cavity and sinuses. NaCl equivalency above 3.0% would raise the tonicity and osmotic pressure above desirable levels and may cause a burning sensation.

For purposes of preparing formulations according to the present invention, NaCl equivalency will closely follow osmotic pressure and can be measured using the methods described in section B above.

D. pH

In general, the pH would be adjusted if a given medication is either more stable or more effective at a certain pH. American Hospital Formulary Service (AFHS) published yearly or the Hand Book of Injectable Drugs by Lawrence A. Trissel, .COPYRGT. 1994 American Society of Hospital Pharmacists, Inc., which are herein incorporated by reference, provide information regarding the stability or effectiveness of a medication at certain pH.

For the purposes of preparing formulations according to the present invention the pH of the various solutions may need to be adjusted to achieve stability or increase effectiveness. A pH meter, where a probe is placed into the solution and the device gives the pH, will be used to measure pH or pH paper will be used to estimate pH by placing solution on the tape and then comparing to a predeveloped chart of pH colorations. When necessary, pH will then be adjusted to arrive at the most preferable range of pH needed for nasal aerosolization by adding buffering agents.

E. General Preparation of a Unit Dose and Production of Aerosol with Optimal Particle Diameter

After determining the medications to be used in the formulation, each ingredient is weighed/measured out individually, added together and dissolved in sterile water for injection. The preparation is then tested to ensure that it is within the parameters established for surface tension, osmolality, pH, and sodium chloride equivalency. This is done by using the appropriate equipment for each test as noted in Sections A to D above. To prepare a unit dose, the ingredients of such formulations generally will be dissolved in a solvent such as water or saline solution, in a volume between about 0.5 and 6.0 mls, more preferably between about 2 and 4 mls and most preferably between about 2.5 and 3.5 mls.

F. Surfactants

The surface tension of a fluid is the tendency of the fluid to "stick" to itself when there is a surface between the liquid and the vapor phase (known as an interface). A good example is a drop of water falling in air. The drop assumes a spherical shape due to surface tension forces, which minimize its surface given the volume. Molecules at the surface of a liquid exert strong attractive forces on other molecules within their vicinity. The resultant force acting perpendicular to a line of unit length in the surface is known as surface tension, usually measured in Dynes/Centimeter.

Surfactants can be used as dispersing agents, solubilizing agents and spreading agents. Some examples of surfactants are: Polyethylene glycol 400; Sodium lauryl sulfate; sorbitan laurate, sorbitan palmitate, sorbitan stearate (available under the tradename SPAN.RTM. 20-40-60 etc.); polysorbates including, but not limited to, polyoxyethylene (20) sorbitan monolaurate, polyoxyethylene (20) sorbitan monopalmitate, polyoxyethylene (20) sorbitan monostearate (available under the tradename TWEEN.RTM. 20-40-60 etc.); and Benzalkonium chloride. The purpose of using surfactants in the preferred formulations of the present invention is to adjust the surface tension of the aerosolized particles so that the maximum amount of medication is deposited in or near the middle meatus ostea. If the surface tension is reduced too much, the majority of the particles will deposit in the nasal cavity, conversely if the surface tension is too high the particles go directly to the lungs without depositing in the nasal sinuses.

The HLB (hydrophile-lipophile-balance) is used to describe the characteristics of a surfactant. The system consists of an arbitrary scale to which HLB values are experimentally determined and assigned. If the HLB value is low, the number of hydrophilic groups on the surfactant is small, which means it is more lipophilic (oil soluble).

Surfactants can act as solubilizing agents by forming micelles. For example, a surfactant with a high HLB would be used to increase the solubility of an oil in an aqueous medium. The lipophilic portion of the surfactant would entrap the oil in the lipophilic (interior) portion of the micelle. The hydrophilic portion of the surfactant surrounding of oil globule would, in turn, be exposed to the aqueous phase.

An HLB value of 10 or higher means that the agent is primarily hydrophilic, while an HLB value of less than 10 means it would be lipophilic. For example, SPANs have HLB values ranging from 1.8 to 8.6, which is indicative of oil soluble for oil dispersible molecules. Consequently, the oil phase will predominate and a water/oil emulsion will be formed. TWEENs have HLB values that range from 9.6 to 16.7, which is characteristic of water-soluble or water dispersible molecules. Therefore, the water phase will predominate and oil/water emulsions will be formed.

Emulsifying agents are surfactants that reduce the interfacial tension between oil and water, thereby minimizing the surface energy through the formation of globules. Wetting agents, on the other hand, aid in attaining intimate contact between solid particles and liquids.

Detergents are also surfactants that reduce the surface tension and wet the surface as well as the dirt. When a detergent is used, the dirt will be emulsified, foaming may occur and the dirt will then wash away.

G. Pathogens Known to Produce Acute and Chronic Sinus Infections

A retrospective review of sinus cultures obtained over a 4-year period from a consecutive series of patients who underwent endoscopic sinus surgery (ESS) was conducted by Niel Bhattacharyya M.D. et al.; Archives of Otolaryngology-Head and Neck surgery Vol. 125 No. 10, October 1999. A wide range of bacteria may be present in the infected post-ESS sinus cavity, with a considerable population of gram-negative organisms, including Pseudomonas species. Fungal infections of the sinuses have a nonspecific clinical presentation, is refractory to standard medical treatment and may produce expansion and erosion of the sinus wall. Various factors have been implicated in the development of fungal sinusitis: anatomical factors in the osteomeatal complex, tissular hypoxia, traumatic factors, massive exposure to fungal spores, allergy and immunosuppression.

The most common bacterial organisms found are the following: Alpha Hemolytic streptococci, Beta Hemolytic streptococci, Branhamella Catarrhalis, Diptheroids, Haemophilis influenzae (beta-lactamase positive and negative), Moraxella species, Pseudomonas aeruginosa, Pseudomonas maltophilia, Serratia marcescens, Staphylococcus aureus and Streptococcus pneumonia.

The most common fungal organisms found are the following: Aspergillosis, Mucor and Candida Albicans, Fusarium, Curvularia, cryptococcus, coccidioides, and histoplasma.

The optimum treatment modality is for the physician to obtain a culture from the sinus cavities via endoscope. The culture is sent to a laboratory where it is tested for minimum inhibitory concentration for several antibiotics and then the correct antibiotic can be chosen based on the sensitivities provided by the laboratory. Current therapy by most Otolaryngologists is to determine the best antibiotic by using their clinical experience in treating sinus infections. This is called empiric therapy.

The anti-fungal therapy is done similarly in that it can also be cultured and sent to the lab for identification allowing the most effective agent to be prescribed, or empiric therapy is performed by the physician.

The kill rate is determined by the susceptibility of the organism to the antibiotic or antifungals. If culture and sensitivities are performed and the correct antibiotic is prescribed the kill rate occurs between a period of one to three weeks. The kill is determined/measured by a repeat culture and sensitivity test showing no bacterial or fungal growth (as appropriate).

II. Specific Embodiments

A. Pharmaceutical Compositions and Formulations

Preferred anti-infective agents include Penicillins, Cephalosporins, Macrolides, Sulfonamides, Quinolones, Aminoglycosides, BetaLactam antibiotics, Linezolid, Vancomycin, Amphotericin B, and Azole antifungals. Preferred anti-inflammatory agents include Glucocorticoids, Disodium Cromoglycate and Nedcromil Sodium. Preferred mucolytic agents are Acetylcysteine and Dornase Alpha. Preferred decongestant agents are Phenylephrine, Naphazoline, Oxymetazoline, Tetrahydrozoline and Xylometoazoline. These agents may be found in the American Hospital Formulary Service published by American Society of Hospital Pharmacists, Inc., which is incorporated herein by reference.

As an example of a contemplated formulation, Cefuroxime is formulated in dosages of 285 mg in 3 ml sterile water for injection per dose, to produce an antibiotic for aerosol administration. This formulation may be compounded under a Laminar Flow hood by performing the following steps: 1) weigh out sufficient cefuroxime to provide 21 doses of 285 mg each (5985 mg), with 5% overage to account for that lost in compounding; 2) QS ad (add up to) to 63 ml with sterile water, with 5% overfill for loss in compounding; and 3) adding 0.1 ml of polysorbate 20 per 100 ml solution.

The formulation is tested using a Ring Tensiometer or the Capillary Rise test to determine the surface tension of the solution. The preferable range is 10 to 70 dynes/cm. The formulation may be adjusted with a surfactant if necessary using, for example, polysorbate 20. Using a pH meter, the formulation is tested for the desirable pH, preferably in the range of about 3.0 to 8.5. The pH is adjusted with appropriate acids, bases and appropriate buffers as needed according to conventional compounding practices.

Preferably the formulation will also be evaluated using E tables from sources known to practitioners skilled in the pharmaceutical arts, such as Remington: The Science and Practice of Pharmacy or other suitable pharmaceutical text to calculate its sodium chloride equivalence to ensure that it is in the preferred range of 0.9% to 3.0%. Similarly, the osmolality is checked to ensure that it falls within the preferred range of about 300 to 880 mOsm/kg. If osmolality falls outside of this range, the polysorbate 20 component may be decreased until the preferred conditions are met.

As a second example, Ciprofloxacin is formulated in dosages of 90 mg unit dose in 3 ml of sterile water for injection per dose. Because compounds of this antibiotic class (i.e., Fluoroquinolones) do not have inherent surfactant activities, a surfactant preferably is added to lower the surface tension of the final product.

This formulation may be compounded under a Laminar Flow hood by performing the following steps: 1) weighing out a sufficient quantity of Ciprofloxacin powder to prepare 28 doses (2520 mg) with 5% overage to account for loss during compounding; 2) QS ad to 74 ml sterile water for injection (add 5% overage for loss in compounding); and 3) adding 0.25 ml polysorbate 20 for every 100 ml of solution.

The formulation is tested as described above and adjustments made to bring surface tension, pH, sodium chloride equivalence and osmolality within preferred ranges or to preferred levels.

As a third example, Amphotericin B is formulated in 10 mg unit doses along with Hydrocortisone sodium succinate in 50 mg unit doses in 3 ml sterile water to provide an antifungal agent together with an anti-inflammatory agent.

This formulation may be compounded under a Laminar Flow hood by performing the following steps: 1) weighing out sufficient powder of Amphotericin B to make 28 doses (280 mg) of 10 mg each allowing 5% overage for loss in compounding; 2) weighing out sufficient powder of Hydrocortisone sodium succinate to make 28 doses (1400 mg) of 50 mg each allowing 5% overage for loss of compounding; 3) combining powders; and 4) QS ad sterile water for injection to 84 ml plus 5% for loss in compounding. The formulation is tested as described above and adjustments made to bring surface tension, pH, sodium chloride equivalence and osmolality within preferred ranges or to preferred levels.

As a fourth example, Ofloxacin is formulated in 90 mg unit doses along with Acetylcystiene in 100 mg unit doses in 3 ml of sterile water to provide an antibiotic together with a mucolytic agent for injection.

This formulation is compounded under a Laminar Flow Hood by performing the following steps: 1) weighing out sufficient powder of Ofloxacin to make 28 doses (2520 mg) of 90 mg each allowing 5% overage for loss in compounding; 2) weighing out sufficient powder of Acetylcysteine to make 28 doses (2800 mg) of 100 mg each allowing 5% overage for loss in compounding; and 3) combining the powders and QS ad to 84 ml with sterile water for injection allowing 5% overage for loss during compounding. The formulation is tested as described above and adjustments made to bring surface tension, pH, sodium chloride equivalence and osmolarity within preferred ranges or to preferred levels.

As a fifth example, Tobramycin is formulated in 100 mg unit doses in 2.5 ml of saline solution to provide an alternative antibiotic formulation. The formulation is compounded under a Laminar Flow hood by performing the following steps: 1) weighing out the tobramycin powder sufficient to provide 42 doses of 100 mg per dose (4200 mg), allowing for 5% overage due to losses during compounding; 2) QS ad with 105 ml of sterile water for injection, allowing for 5% overage due to losses during compounding; and 3) adding 0.15 ml polysorbate 20 to adjust surface tension. The formulation is tested as described above and adjustments made to bring surface tension, pH, sodium chloride equivalence and osmolality within preferred ranges or to preferred levels.

As a sixth example, Cefoperazone and Oxymetazoline are formulated in 3 ml of Sterile water for injection to provide an antibiotic formulated with a decongestant. This formulation is prepared under a Laminar Flow Hood by following these steps: 1) weighing out sufficient powder of Cefoperazone to make 28 doses of 600 mg each (16.8 gm) allowing 5% overage for compounding loss; 2) weighing out sufficient powder of Oxymetazoline to make 28 doses of 0.5 mg each (14 mg) allowing 5% overage for compounding loss; 3) combining the powders together; 4) QS ad with sterile water to 84 ml allowing 5% overage for compounding loss; 5) adding Benzalkonium Chloride 0.02% (0.02 gm/100 ml of solution). The formulation is tested as described above and adjustments made to bring surface tension, pH, sodium chloride equivalence and osmolarity within preferred ranges or to preferred levels.

B. Determination of the Course of Treatment

In general, the course of treatment for any given patient will be determined by his or her physician. Thus, if the organisms found in a patient's sinuses are cultured by known techniques and their sensitivities are determined, the most appropriate antibiotic will be ordered. However, if no cultures and sensitivities are done, then the patient also may be treated empirically with the antibiotic chosen by the physician using his or her experience based on what bacteria or fungus is suspected. If the anatomical structures inside the nasal passageways are swollen or inflamed due to allergy or flu symptoms, an anti-inflammatory agent or a decongestant agent also may be administered if the patient is not otherwise using nasal sprays or oral medication separately.

Example of a Patient Treatment Scenario

1. Patient contracts what they feel is a sinus infection and goes to their Otolaryngologist for diagnosis. After determining the diagnosis of sinusitis, a culture is obtained endoscopically and sent to the laboratory.

2. The laboratory determines the bacteria/fungus sensitivities by drug and reports its findings to the physician.

3. The physician faxes the report to the pharmacy along with a prescription for the antibiotic most appropriate for the infection. The formulation is prepared as described above and dispensed in 2.5 ml containers. Generally, the container will be labeled: "Store in Refrigerator."

4. The physician will call patient and discuss the treatment and any pertinent data necessary to enhance the treatment outcome.

C. Contemplated and Preferred Treatment Regimens

The preferred treatment is the antibiotic (adjusted for the proper surface tension, pH, sodium chloride equivalence, and osmolality) that most effectively kills the bacteria or fungus as determined by culture and sensitivity, administered once to three times per day for a duration of 5 to 10 minutes per each treatment (See Table 1).

The total number of days needed to rid the infection preferably is determined by reculturing until no growth is noted. However, when the physician does not do culturing, the conventional standard of practice is two weeks of therapy until patient generally would be expected to have become asymptomatic plus an additional 7 days of therapy.

D. Monitoring Efficacy

The typical Otolaryngologist when treating chronic sinusitis prescribes antibiotics until the patient is symptom free by physical exam plus an additional seven days. The problem that occurs with respect to sinus infections is that, if the infection is not completely resolved, the patient will have a recurrence the next time their immune system is challenged, i.e., they contract the flu, go through a stressful time in their life or need chemotherapy treatments. Thus, the preferred method of determining resolution of the infection is to reculture the sinuses endoscopically and have the laboratory report come back negative, i.e., reporting no growth of pathogenic microorganisms. The present inventors have discovered that aerosolization should lead to less resistance exhibited by bacteria due to the fewer times they are exposed to the antibiotic, and such exposure occurs at lower dosages and for shorter periods of time of aerosolized administration (typically 1 3 weeks) as compared to oral (typically 3 weeks to several months) and intravenous treatment (typically 3 6 weeks).

E. Equipment for Aerosolized Delivery of Pharmaceutical Composition

Equipment for aerosolized delivery of pharmaceutical compositions are well known to the skilled artisan. O'Riordan et al., Journal of Aerosol Medicine, 20(I):13 23 (1997), reports the delivery of aerosolized tobramycin by a jet nebulizer and an ultrasonic nebulizer. U.S. Pat. No. 5,508,269, issued Apr. 16, 1996, compares the characteristics of three different nebulizers: the Ultraneb 99 (DeVilbiss) ultrasonic nebulizer, the Medicaid Sidestream jet nebulizer, and the Pari LC jet nebulizer.

The preferred equipment for aerosolized delivery of pharmaceutical solutions is depicted in FIG. 1. This nebulizer manufactured by Pari Respiratory Equipment, Inc for the inventors produces the desired particle size for effective administration of the solutions in this invention to the sinuses. To use this nebulizer preferably 1 ml to 5 ml of medication solution, more preferably 2 ml to 4 ml and most preferably 2.5 ml to 3.5 ml of medication solution is placed in the nebulizer at A. The nebulizer is then connected to a compressor or other source of 4 liter/minute airflow at B with tubing supplied. When the airflow is turned on the patient places the nose piece C under their nostrils and breathes normally until the medication solution in the nebulizer begins to sputter and no mist comes out at C. This will usually take 8 to 10 minutes.

 

Claim 1 of 47 Claims

1. An aerosolized pharmaceutical solution, comprising: aerosolized particles of the solution, which contains an antibiotic for treating sinusitis, and a surfactant, wherein: the solution is formulated for nasal administration as an aqueous solution; the solution as formulated has an osmolality of about 300 mOsm/kg to about 880 mOsm/kg; the solution as formulated has a surface tension of about 30 to about 50 dynes/cm, wherein the surface tension is effective for retention of the solution in the nasal sinuses; the solution as formulated contains at least about 0.02% (w/v) surfactant; the antibiotic for treating sinusitis is selected from the group consisting of aminoglycosides; and wherein at least about 80% of the aerosolized particles of the pharmaceutical solution have a mass median aerodynamic diameter (MMAD) in the size range of about 0.5 .mu.m to about 5.0 .mu.m in diameter, whereby the aerosolized pharmaceutical solution is effective for treatment of chronic sinusitis.

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