US20020197212A1 - Aerosolized anti-infectives, anti-inflammatories, and decongestants for the treatment of sinusitis - Google Patents

Aerosolized anti-infectives, anti-inflammatories, and decongestants for the treatment of sinusitis Download PDF

Info

Publication number
US20020197212A1
US20020197212A1 US10193081 US19308102A US2002197212A1 US 20020197212 A1 US20020197212 A1 US 20020197212A1 US 10193081 US10193081 US 10193081 US 19308102 A US19308102 A US 19308102A US 2002197212 A1 US2002197212 A1 US 2002197212A1
Authority
US
Grant status
Application
Patent type
Prior art keywords
method
mg
composition
nebulizer
sinusitis
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Abandoned
Application number
US10193081
Inventor
Robert Osbakken
Mary Hale
Frederick Leivo
James Munk
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Naryx Pharma Inc
Original Assignee
Sinuspharmacycom Inc
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date

Links

Images

Classifications

    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL, OR TOILET PURPOSES
    • A61K9/00Medicinal preparations characterised by special physical form
    • A61K9/0012Galenical forms characterised by the site of application
    • A61K9/007Pulmonary tract; Aromatherapy
    • A61K9/0073Sprays or powders for inhalation; Aerolised or nebulised preparations generated by other means than thermal energy
    • A61K9/0078Sprays or powders for inhalation; Aerolised or nebulised preparations generated by other means than thermal energy for inhalation via a nebulizer such as a jet nebulizer, ultrasonic nebulizer, e.g. in the form of aqueous drug solutions or dispersions
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL, OR TOILET PURPOSES
    • A61K31/00Medicinal preparations containing organic active ingredients
    • A61K31/56Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives, e.g. steroids
    • A61K31/57Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives, e.g. steroids substituted in position 17 beta by a chain of two carbon atoms, e.g. pregnane, progesterone
    • A61K31/573Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives, e.g. steroids substituted in position 17 beta by a chain of two carbon atoms, e.g. pregnane, progesterone substituted in position 21, e.g. cortisone, dexamethasone, prednisone or aldosterone
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL, OR TOILET PURPOSES
    • A61K9/00Medicinal preparations characterised by special physical form
    • A61K9/0012Galenical forms characterised by the site of application
    • A61K9/0043Nose
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61MDEVICES FOR INTRODUCING MEDIA INTO, OR ONTO, THE BODY; DEVICES FOR TRANSDUCING BODY MEDIA OR FOR TAKING MEDIA FROM THE BODY; DEVICES FOR PRODUCING OR ENDING SLEEP OR STUPOR
    • A61M11/00Sprayers or atomisers specially adapted for therapeutic purposes
    • A61M11/06Sprayers or atomisers specially adapted for therapeutic purposes of the injector type
    • YGENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y10TECHNICAL SUBJECTS COVERED BY FORMER USPC
    • Y10STECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y10S514/00Drug, bio-affecting and body treating compositions
    • Y10S514/853Decongestant

Abstract

Pharmaceutical compositions are described that comprise one or more active ingredients selected from the group consisting of anti-infective, anti-inflammatory and mucolytic agents, and particularly to compositions formulated as a solution in a unit dose for aerosol administration to treat chronic sinusitis.

Description

    RELATED APPLICATIONS
  • This application is a divisional of U.S. application Ser. No. 09/577,623, to Osbakken et al., entitled “AEROSOLIZED ANTI-INFECTIVES, ANTI-INFLAMMATORIES, AND DECONGESTANTS FOR THE TREATMENT OF SINUSITIS.” This application claims priority under 35 U.S.C. §119(e) to U.S. provisional application Ser. Nos. 60/142,618, 60/142,620, 60/142,621, 60/142,622, 60/142,624, 60/142,741, and 60/142,881, all filed on Jul. 6, 1999, and to U.S. provisional application Ser. Nos. 60/194,078, 60/193,509, 60/193,508, 60/193,507 and 60/193,510, all filed Apr. 3, 2000. The disclosures of the above-referenced utility and provisional applications are hereby incorporated by reference in their entireties.[0001]
  • FIELD
  • The present invention relates to pharmaceutical compositions comprising one or more active ingredients selected from the group consisting of anti-infective, anti-inflammatory and anti-mucolytic agents, and particularly to compositions formulated as a solution in a unit dose or multi-dose vials for aerosol administration to treat chronic sinusitis. [0002]
  • BACKGROUND
  • There are a number of air-filled cavities called sinuses in the skull ([0003] Stedman's Medical Dictionary, 27th Edition, page 1644, (1999), Lippincott Williams & Wilkins, Baltimore, Md.). Four pairs of sinuses known as the paranasal sinuses, connect the space (known as the nasal passage) running from the nostrils and up through the nose. These four pairs of paranasal sinuses are the frontal sinuses, the maxillary sinuses, the ethmoid sinuses, and the sphenoid sinuses. They are located, respectively, in the forehead, behind the cheekbones, between the eyes, and behind the eyes. A membrane lining the sinuses secretes mucus, which drains into the nasal passage from a small channel in each sinus. Healthy sinuses are sterile and contain no bacteria. In contrast, the nasal passage, normally contains many bacteria that enter through the nostrils as a person breathes.
  • A number of factors and/or processes are involved in maintaining healthy sinuses. The mucus secreted by the membrane lining must be fluid but sticky, in order to flow freely yet absorb pollutants and entrap bacteria. It must also contain sufficient amounts of bacteria-fighting substances, such as antibodies. Additionally, small hair-like projections called cilia, located in the nostril, must beat in unison to propel mucus outward, in order to expel bacteria and other particles. Moreover, the mucous membranes themselves must be intact, and the sinus passages must be open to allow drainage and the circulation of air through the nasal passage. When one or more of these processes or factors are amiss, causing obstruction of the sinus passage, an infection called sinusitis develops. [0004]
  • Sinusitis is an inflammation of the membrane lining one or more paranasal sinuses. There are three different types of sinusitis: acute, recurrent acute, and chronic. Acute sinusitis is characterized as lasting less than three weeks or occurring less than four times a year. Acute sinusitis can be successfully treated using antibiotics, leaving no damage to the linings of the sinus tissue. Recurrent acute sinusitis occurs more often but leaves no significant damage. Chronic sinusitis lasts longer than three weeks and often continues for months. In cases of chronic sinusitis, there is usually tissue damage. According to the Center for Disease Control (CDC), thirty seven million cases of chronic sinusitis are reported annually. [0005]
  • Causes of Sinusitis
  • The most common cause for sinusitis is a viral cold or flu that infects the upper respiratory tract and causes obstruction. Obstruction creates an environment that is hospitable for bacteria, the primary cause of acute sinusitis (Etkins et al., 1999 Nidus Information Services, Inc. [0006] Well-Connected Report. Sinusitis. June 1999. (Online) www.well-connected.com.). The bacteria most commonly found in acute sinusitis are Streptococcus pneumoniae (also called pneumococcal pneumonia or pneumococci), H. influenzae (a common bacteria associated with many respiratory infections in young children), and Moraxella (or Branhamella) catarrhalis. Less common bacterial culprits include other streptococcal strains including Staphylococcus aureus.
  • Fungi are an uncommon cause of sinusitis, but its incidence is increasing. The fungus Aspergillus is the common cause of fungal sinusitis. Others include [0007] Curvularia, Bipolaris, Exserohilum, and Mucormycosis. Fungal infections can be very serious and should be suspected in people with sinusitis who also have diabetes, leukemia, AIDS, or other conditions that impair the immune systems. Fungal infections can also occur in patients with healthy immune systems. There have been a few reports of fungal sinusitis caused by Metarrhizium anisopliae which is used in biological insect control.
  • Chronic or recurrent acute sinusitis can be a lifelong condition and may result from untreated acute sinusitis that causes damage to the mucous membranes, medical disorders that cause chronic thickened stagnant mucus, or abnormalities in the nasal passage such as polyps, enlarged adenoids, cleft palate, or tumors. The same organisms that cause acute sinusitis are often present in chronic sinusitis. In addition, about 20% of chronic sinusitis cases (Etkins et al., 1999, Id.) are caused by [0008] Staphylococcus aureus (commonly called Staph infection). Along with these bacteria, certain anaerobic bacteria, particularly the species Peptostreptococcus, Fusobacterium, and Prevotella, are found in 88% of cultures in chronic sinusitis cases (Etkins et al., 1999, Id.). Fungi can also cause chronic and recurrent sinusitis. An uncommon form of chronic and highly recurrent sinusitis is caused by an allergic reaction to fungi, usually, aspergillus, growing in the sinus cavities. Fungal sinusitis usually occurs in younger people with healthy immune systems and is more likely to be found in warm climates.
  • Symptoms of Sinusitis
  • In acute sinusitis, symptoms almost always present are nasal congestion and discharge which is typically thick and contains pus that is yellowish to yellow-green. Severe headache occurs, and there is pain in the face. A persistent cough occurs particularly during the day. Other upper respiratory symptoms and fever may be present. Sneezing, sore throat, muscle aches, and fatigue are rarely caused by sinusitis itself, but may result from symptoms or causes, such as muscle aches caused by fever, sore throat caused by post-nasal drip, and sneezing resulting from allergies. [0009]
  • The symptoms of recurrent acute and chronic sinusitis tend to be vague and generalized, last longer than eight weeks, and occur throughout the year, even during nonallergy seasons. Nasal congestion and obstruction are common. Yellowish discharge, chronic cough, bad breath, and postnasal drip may occur. Sufferers do not usually experience facial pain unless the infection is in the frontal sinuses, which results in a dull, constant ache. However, facial tenderness or pressure may be present. [0010]
  • Site-specific symptoms depend on the location of the infection. Frontal sinusitis causes pain across the lower forehead. Maxillary sinusitis causes pain over the cheeks and may travel to the teeth, and the hard palate in the mouth sometimes becomes swollen. Ethmoid sinusitis causes pain behind the eyes and sometimes redness and tenderness in the area across the top of the nose. Sphenoid sinusitis rarely occurs by itself. When it does, the pain may be experienced behind the eyes, across the forehead, or in the face. Rare complications of sinusitis can produce additional symptoms which may be severe or even life threatening. [0011]
  • Treatments of Sinusitis
  • The primary objectives for treatment of sinusitis are reduction of swelling, eradication of infection, draining of the sinuses, and ensuring that the sinuses remain open. Less than half of patients reporting symptoms of sinusitis need aggressive treatment and can be cured using home remedies and decongestants alone. Steam inhalation and warm compresses applied over the sinus are often sufficient to relief discomfort. Many over-the-counter decongestants are available, either in tablet form or as sprays, drops, or vapors, which bring the medication into direct contact with nasal tissue. [0012]
  • Antibiotics are prescribed if decongestants fail to relieve symptoms or if other problems exist, including signs of infection (such as yellowish nasal discharge). They prevent complications, relieve symptoms, and reduce the risk of chronic sinusitis. Most patients with sinusitis caused by bacteria can be successfully treated with antibiotics used along with a nasal or oral decongestant. [0013]
  • Chronic sinusitis is often difficult to treat successfully, however, as some symptoms persist even after prolonged courses of antibiotics. The usefulness of antibiotics in treating chronic sinusitis is debated. Steroid nasal sprays are commonly used to treat inflammation in chronic sinusitis. For patients with severe chronic sinusitis, a doctor may prescribe steroids, such as prednisone. Since oral steroids can have serious side effects, they are prescribed only when other medications have not been effective. [0014]
  • When medical treatment fails, surgery may be the only alternative in treating chronic sinusitis. Studies suggest that the most patients who undergo surgery have fewer symptoms and better life. Presently, the most common surgery done is functional endoscopic sinus surgery, in which the diseased and thickened tissues from the sinuses are removed to allow drainage. This type of surgery is less invasive than conventional sinus surgery, and serious complications are rare. [0015]
  • Considerations and Concerns of Treatments
  • Sprays, drops, and vapors work quickly but often require frequent administration. Nasal decongestants may dry out the affected areas and damage tissues. With prolonged use, nasal decongestants become ineffective. The tendency is to then increase the frequency of use to as often as once an hour. Withdrawal from the drugs after three to five days of over-frequent use can itself cause symptoms of sinusitis and the return of nasal congestion phenomenon known as rebound effect. Short-acting nasal decongestants may cause rebound effect after only eight hours. Rebound effect leads to dependency when the patient takes the decongestant to treat the rebound effect, the drug becomes ineffective, the patient withdraws, and the condition rebounds again, with the nasal passages becoming swollen and burning. Eventually, the condition can become worse than before the medication was taken. Nasal decongestants are generally recommended for no more than one to three days of use because of this risk. [0016]
  • Some oral decongestants may cause constriction of other vessels in the body, temporarily raising blood pressure in people with hypertension. Other side effects of oral decongestants include insomnia, agitation, abnormal heart rhythms (particularly in people with existing cardiac problems), and urinary retention in men with enlarged prostates. Decongestant sprays and drops, too, are absorbed into the body and can sometimes cause these side effects. [0017]
  • The most common side effect for nearly all antibiotics is gastrointestinal distress. Antibiotics also double the risk for vaginal infections in women. Certain drugs, including some over-the-counter medications, interact with antibiotics, and all antibiotics carry the risk for allergic reactions, which can be serious in some cases. Thus, patients should inform their physician of all medications they are taking and of any drug allergies. [0018]
  • Oral antibiotics are usually prescribed for 7 to 10 days. Patients must take all of the tablets prescribed; failure to do so may increase the risk for reinfection and also for development of antibiotic-resistant bacteria. It should be noted, however, that even after antibiotic treatments, between 10% and 25% of patients still complain of symptoms. [0019]
  • Of major concern to physicians and the public is the emergence of bacterial strains that have become resistant to common antibiotics due to frequent exposure. It should be noted that the average person is not yet endangered by this problem. The risk is greatest in hospitals and nursing homes, but it is still not high. Nonetheless, the prevalence of such antibiotic-resistant bacteria has increased dramatically worldwide, and caution should be exercised. [0020]
  • Nebulization Therapy
  • Nebulization is a conventional treatment for pulmonary infections related to cystic fibrosis, because it is relatively easy and safe to use, and because it delivers antibiotics topically to the site of infection, with little systemic absorption of the antibiotics. Nebulization has also been known to have been used for sinus infections and pulmonary infections, related to bronchiectasis. Thus, there are few systemic side effects. [0021]
  • Small Aerosolized Particles for Treating Sinusitis
  • Yokota et al., [0022] Japanese Journal of Antibiotics 609(15):48 (1995) reports administration of cefmenoxime using a nebulizer to treat sinusitis patients. These authors evaluated cefmenoxime against clinical isolates from sinusitis patients, and found that minimum inhibitory concentrations were lower when a one percent (1%) solution was used with a nebulizer. The paper speculates that sufficient concentrations exceeding such minimum inhibitory concentrations would be obtained by nebulizer treatment using a cefmenoxime nasal solution.
  • Guevara et al., [0023] Anales O.R.L. Iber. -Amer. XVIII, 3:231-238 (1991), describes aerosol therapy for treating patients suffering from chronic sinusitis. The disclosed aerosol therapy involves delivery of a therapeutic composition comprising 500 mg of Cefotaxime, 5 mg metilprednisolone, and 1.5 ml N-acetilcisteina using an air-jet nebulizer for 15-20 minutes, every 8 hours, over a total period of 15 days. The air-jet nebulizer produces aerodynamic particle diameters of average mass of four microns. Guevara et al. reports a success rate of 96%. However, Guevara et al. does not disclose adding a surfactant to assist deposition, penetration, and retention of the antibiotic in the sinuses. It is also noted that the aerosol therapy of Guevara et al. requires frequent treatments over a long period of time.
  • Kondo et al., [0024] Acta Otolaryngol Suppl. 525:64-67 (1996), reports treatment of paranasal sinusitis using fosfomycin (FOM) aerosol. Kondo et al. describes delivery of 4 ml of 3% FOM solution using either a jet-type nebulizer or a ultrasonic nebulizer. The jet-type nebulizer produces aerosol particles having about 0.5 to 0.7 μm in diameter, while the ultrasonic-type nebulizer produces particles having about 2-4 μm in diameter. The results of Kondo et al. indicate that the ultrasonic-type nebulizer delivers a higher concentration of FOM to the maxillary sinus surface and is therefore more effective in treating paranasal sinusitis than the jet-type nebulizer. Although Kondo et al. suggests that the preferred aerosol particle size is about 2-4 μm in diameter for deposition of a higher level of antibiotic in the maxillary sinus, Kondo et al. does not disclose an administration schedule or the addition of a surfactant to the FOM solution to further increase the deposition of FOM in the sinuses.
  • Small Aerosolized Particles for Pulmonary Treatment
  • Smith et al., U.S. Pat. No. 5,508,269, discloses the use of aminoglycoside aerosol formulations to treat patients suffering from endobronchial infection. Smith et al. describes delivery of the aminoglycoside formulation using a jet or ultrasonic nebulizer that produces aerosol particle size between 1 and 5 μm. The formulation comprises 200 to 400 mg of aminoglycoside dissolved in about 5 ml of solution containing 0.225% sodium chloride and it has a pH between 5.5 to 6.5. Although Smith teaches delivery of aminoglycoside to the endobronchial space using a nebulizer for the treatment endobronchial infection, Smith does not teach an aerosol formulation for treatment of sinusitis and does not disclose a treatment schedule. It is also noted that the aerosol particle size disclosed in Smith et al. is a broad range. It is not predictable what fraction of the aerosol particles between 1 to 5 μm will deposit in the sinuses, and what fraction of the aerosol particles will have a diameter of 1 μm, 2 μm, etc. [0025]
  • Rubin et al., U.S. Pat. No. 5,925,334, describes the use of aerosolized surfactant to promote pulmonary airway clearance. The method of Rubin et al. comprises administering a formulation containing a surfactant using a PARI LC Jet nebulizer for 15 minutes, 3 times a day for 14 consecutive days, to patients suffering from bronchitis or cystic fibrosis. However, Rubin does not teach the use of aerosolized antibiotic or aerosolized antibiotic and surfactant combination to treat sinusitis. [0026]
  • Schmitt et al., U.S. Pat. No. 4,950,477, teaches a method of preventing and treating pulmonary infection by fungi using aerosolized polyenes. The method comprises administering to a patient suffering from pulmonary infection by Asperigillus about 0.01 mg/kg to 6.0 mg/kg of a polyene in an aerosol of particles having an aerodynamic diameter between about 0.5 μm to about 8 μm. Schmitt et al. specifically discloses the administration of amphotericin B. Although Schmitt et al. teaches aerosolized polyenes for treatment of pulmonary infection, Schmitt et al. does not provide guidance for using aerosolized polyenes for treating sinusitis. [0027]
  • O'Riordan et al., [0028] Journal of Aerosol Medicine, 20(1):13-23 (1997), reports the effect of nebulizer configuration on delivery of aerosolized tobramycin to the lung. O'Riordan et al. discloses the delivery of tobramycin using either an ultrasonic nebulizer delivering aerosol particles having between 1.45 to 4.3 μm or a jet nebulizer delivering aerosol particles having between 1.25 μm. The results of O'Riordan et al. show that nebulizer configuration affects both the amount of aerosolized tobramycin inhaled as well as the particle size. Specifically, nebulizers that produce large particles are prone to considerable deposition on tubing and connections. O'Riordan et al. recommends that nebulizer configuration be specified in treatment protocols.
  • Large Particle Aerosolization
  • In contrast to the references discussed above, Negley et al., [0029] ENT Jounal, 78(8):550-554 (1999), and Desrosiers et al., (presented at the ENT Academy Meeting, May 1999) teach large particle nebulization therapy for treatment of sinusitis. Negley observes that deposition of medication into the sinuses is best achieved when the aerosolized particles are 1 6 to 25 μm in size. Desrosiers et al. reports that large particle saline aerosol therapy alone is effective in treating refractory sinusitis and that the addition of tobramycin to the saline solution had minimal benefit.
  • The journal articles and patents discussed above teach various aerosol therapies for the treatment of sinusitis. However, there does not appear to be agreement among the various authors as to the optimal size or size distribution of the aerosolized particles or even whether antibiotics are effective in treating sinusitis. What has been needed is a clinically effective anti-infective treatment protocol for sinusitis, a more optimal therapy schedule, and an appropriate nebulizer configuration for the deposition of aerosolized anti-infective particles into the sinuses for the successful and consistent treatment of chronic sinusitis. [0030]
  • SUMMARY
  • 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. [0031]
  • 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. [0032]
  • 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 osmotic pressure 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. [0033]
  • 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. [0034]
  • In a preferred embodiment of the invention, 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. [0035]
  • Preferred administration protocols also are described.[0036]
  • BRIEF DESCRIPTION OF THE DRAWINGS
  • FIG. 1 discloses the preferred equipment for aerosolized delivery of pharmaceutical solutions. 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 medication is placed in the nebulizer at A. The nebulizer is then connected to a compressor or other source 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.[0037]
  • DETAILED DESCRIPTION
  • I. General Description [0038]
  • 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 μm 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. [0039]
  • 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[0040] 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. [0041]
  • 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. [0042]
  • 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: [0043]
  • 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. [0044]
  • osmotic pressure 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. [0045]
  • 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. [0046]
  • pH preferably between about 3.0 and 8.5, but may vary according to the properties of the medication used. [0047]
  • A. Surface Tension [0048]
  • 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. [0049]
  • 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. [0050]
  • B. Osmotic Pressure [0051]
  • 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. [0052]
  • For purposes of preparing formulations according to the present invention, osmotic pressure may be measured by using an Osmometer. If necessary, osmotic pressure may then be raised to fall within a preferred range by adding NaCl to the solution. [0053]
  • C. Sodium Chloride Equivalency [0054]
  • 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. [0055]
  • 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. [0056]
  • D. pH [0057]
  • In general, the pH would be adjusted if a given medication is either more stable or more effective at a certain pH. [0058] American Hospital Formulary Service (AFHS) published yearly or the Hand Book of Injectable Drugs by Lawrence A. Trissel, ® 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. [0059]
  • E. General Preparation of a Unit Dose and Production of Aerosol with Optimal Particle Diameter [0060]
  • 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, osmolarity, 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 mis, more preferably between about 2 and 4 mis and most preferably between about 2.5 and 3.5 mis. [0061]
  • F. Surfactants [0062]
  • 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. [0063]
  • Surfactants can be used as dispersing agents, solubilizing agents and spreading agents. Some examples of surfactants are: PEG 400, Sodium lauryl sulfate, Spans (20-40-60 etc), Tweens (polysorbates, 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. [0064]
  • The HLB (hydrophille-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). [0065]
  • Surfactants can act as a solubilizing agent 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 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. [0066]
  • 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. [0067]
  • 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. [0068]
  • 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. [0069]
  • G. Pathogens Known to Produce Acute and Chronic Sinus Infections [0070]
  • 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 [0071] 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: [0072] 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: [0073] 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. [0074]
  • 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. [0075]
  • 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). [0076]
  • II. Specific Embodiments [0077]
  • A. Pharmaceutical Compositions and Formulations [0078]
  • 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 [0079] 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. [0080]
  • 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. [0081]
  • 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 Osmolarity is checked to ensure that it falls within the preferred range of about 300 to 880 mOsm/kg. If Osmolarity falls outside of this range, the polysorbate 20 component may be decreased until the preferred conditions are met. [0082]
  • 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. [0083]
  • 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. [0084]
  • 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. [0085]
  • 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. [0086]
  • 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 osmolarity within preferred ranges or to preferred levels. [0087]
  • 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. [0088]
  • 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. [0089]
  • 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 osmolarity within preferred ranges or to preferred levels. [0090]
  • 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 μm) allowing 5% overage for compounding loss; 2) weighing out sufficient powder of Oxymetazonline 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 μm/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. [0091]
  • B. Determination of the Course of Treatment [0092]
  • 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. [0093]
  • 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. [0094]
  • 2. The laboratory determines the bacteria/fungus sensitivities by drug and reports its findings to the physician. [0095]
  • 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.” [0096]
  • 4. The physician will call patient and discuss the treatment and any pertinent data necessary to enhance the treatment outcome. [0097]
  • C. Contemplated and Preferred Treatment Regimens [0098]
  • The preferred treatment is the antibiotic (adjusted for the proper surface tension, pH, sodium chloride equivalence, and osmolarity) 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). [0099]
  • 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. [0100]
  • D. Monitoring Efficacy [0101]
  • 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). [0102]
  • E. Equipment for Aerosolized Delivery of Pharmaceutical Composition [0103]
  • Equipment for aerosolized delivery of pharmaceutical compositions are well known to the skilled artisan. O'Riordan et al., [0104] Journal of Aerosol Medicine, 20(1):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. [0105]
  • In light of the foregoing general discussion, the specific examples presented below are illustrative only and are not intended to limit the scope of the invention. Other generic and specific configurations will be apparent to those persons skilled in the art. [0106]
  • EXAMPLES Example 1
  • Patient A [0107]
  • A female in her forty's had been suffering from sinusitis for most of her adult life. These sinusitis episodes seemed to be triggered by allergies. She historically had three-four (3-4) episodes of sinusitis each year, which were treated with oral antibiotics for four-eight (4-8) weeks per episode. These oral antibiotic regimens produced yeast infections, which were treated with Diflucan® (fluconazole). Relief from the headaches, malaise, facial pressure and pain, yellow-green nasal discharge, coughing and fever took up to six weeks and were treated with narcotic and non narcotic analgesics, decongestants, decongestant nasal sprays, cough suppressants, and nasal rinses. Her allergies were treated with antihistamines and anti-inflammatory agents. [0108]
  • In an effort to reduce the duration of her sinusitis episodes, a nose drop of tobramycin 80 mg/ml was administered. This treatment did not seem to work. The medication was irritating; and in order to administer the drops and try to get them into the sinus cavity, the patient had to hold her head back. This caused intolerable pain resulting in the discontinuation of the therapy. A nose drop of Bactoban® was tried. It was not efficacious; it was very viscous. The administration of this drop produced similar pain on administration, and this therapy was also discontinued. [0109]
  • In order to eliminate the pain caused by holding her head back when administering nose drops, a nose drop of tobramycin was administered after the patient had been on oral antibiotics for a period of time. This did not seem to work. The drop did not seem to penetrate into the sinus cavities. [0110]
  • Thereafter, a preparation of tobramycin 80 mg/ml was administered using 3 ml in a Pari LC Star® nebulizer cup with adult mask attached and a Pari Proneb® compressor. The medication was nebulized three (3) times daily. After four days of therapy, the patient experienced a “dumping” of green, purulent nasal discharge. The therapy was continued for a total of seven (7) days. It seemed at this point that the sinus infection had been eliminated, but a relapse was experienced within a month. Another seven (7) day regimen of nebulized tobramycin was given to the patient. Again the sinus infection seemed to be eliminated, but it reoccurred within two (2) months. [0111]
  • A preparation of cefuoxime 285 mg in 2.5 ml sterile water for injection was administered three (3) times daily using a Pari LC Star® nebulizer cup with adult mask attached and a Pari Proneb® compressor. The time of nebulization was extensive and the medication did not seem to be completely nebulized. After one day of therapy, a Pari Turbo® compression was substituted for the Pari Proneb® compressor. The patient experienced a “dumping” of green, purulent nasal discharge after (3) days of therapy. The therapy was continued for a total of seven (7) days, again she contracted a yeast infection and was given Diflucan®. [0112]
  • After the seven (7) days of treatment with nebulized cefuroxime using the Pari Turbo® compressor and the Pari LC Star® nebulizer cup with mask, the patient has remained free of sinus infections for nine (9) months. She has continued to experience problems with her allergies, and while in the past these allergies triggered sinus infections, this time no such infection has recurred. [0113]
  • Example 2 Patient B
  • A male in his forty's had been experiencing sinus infections off and on during his adult life. He was treated with cefuoxime 285 mg in 2.5 ml of sterile water for injection three (3) times daily using a Pari LC Star® nebulizer cup with adult mask attached and a Pari Turbo® compressor. The patient experienced a “dumping” of green, purulent nasal discharge after eight (8) treatments. The therapy was continued for a total of seven (7) days. No other antibiotics were given. This patient has been free from sinus infections for six (6) months. [0114]
  • Example 3 Patient C
  • A female aged mid-50s had been suffering from sinusitis off and on for most of her adult life. These sinusitis episodes seemed to be triggered by allergies. The patient took antihistamines and decongestants when allergies triggered headaches and/or a clear nasal discharge. Historically, she would have one or more sinus infections a year requiring twenty or more days of oral antibiotics. [0115]
  • She was treated with cefuoxime 285 mg in 2.5 ml of sterile water for injection three (3) times daily using a Pari LC Star® nebulizer cup with adult mask attached and a Pari Turbo® compressor. The patient experienced a “dumping” of green, purulent nasal discharge after eight (8) treatments. The therapy was continued form a total of seven (7) days. No other antibiotics were given. This patient has been free from sinus infections for six (6) months. [0116]
  • It should be understood that the foregoing discussion and examples merely present a detailed description of certain preferred embodiments. It therefore should be apparent to those of ordinary skill in the art that various modifications and equivalents can be made without departing from the spirit and scope of the invention. All journal articles, other references, patents and patent applications that are identified in this patent application are incorporated by reference in their entirety. [0117]
    TABLE 1
    Agents and Dosages
    More Most Most
    Brand Preferable Preferable Preferable Preferable
    Generic Name Name Class Range Range Range Dose
    Amikacin Amikin Aminoglycoside 50- 75-300 mg 100- 166 mg
    500 mg 200 mg Q8-12H
    Amphptericin B Fungizone Antifungal 2.5-45 mg 4-30 mg 7.5-15 mg 10 mg
    Q12H
    Azithromycin Zithromax Macrolide 50- 75-300 mg 150- 167 mg
    400 mg 200 mg Q12H
    Aztreonam Azactam Monobactam 250- 300- 475- 450 mg
    1000 mg 900 mg 750 mg Q8H
    Cefazolin Ancef, Cephlasporin 250- 300- 575- 650 mg
    Kefzol (Gen I) 1000 mg 900 mg 700 mg Q8H
    Cefepime Maxipime Cephlasporin 125- 200- 575- 650 mg
    (Gen IV) 1000 mg 900 mg 700 mg Q12H
    Cefonicid Moniacid Cephlasporin 250- 300- 575- 600 mg
    (Gen II) 1000 mg 900 mg 700 mg Q24H
    Cefoperazone Cefobid Cephlasporin 250- 300- 575- 600 mg
    (Gen III) 1000 mg 900 mg 700 mg Q12H
    Cefotaxime Claforan Cephlasporin 250- 300- 575- 600 mg
    (Gen III) 1000 mg 900 mg 700 mg Q8-12H
    Cefotetan Cefotan Cephlasporin 250- 300- 575- 600 mg
    (Cephamycin) 1000 mg 900 mg 700 mg Q8-12H
    Cefoxitin Mefoxin Cephlasporin 250- 300- 575- 600 mg
    (Cephamycin) 1000 mg 900 mg 700 mg Q12H
    Ceftazidime Fortaz, Cephlasporin 250- 300- 475- 550 mg
    Ceptaz (Gen III) 1000 mg 900 mg 750 mg Q12H
    Ceftizoxime Cefizox Cephlasporin 250- 300- 575- 600 mg
    (Gen III) 1000 mg 900 mg 700 mg Q8-12H
    Ceftriaxone Rocephin Cephlasporin 250- 300- 575- 650 mg
    (Gen III) 1000 mg 900 mg 700 mg Q12H
    Cefuroxime Ceftin Cephlasporin 100- 200- 250- 285 mg
    (Gen II) 600 mg 520 mg 400 mg Q8H
    Cephapirin Cefadyl Cephlasporin 250- 300- 575- 650 mg
    (Gen I) 1000 mg 900 mg 700 mg Q12H
    Ciprofloxacin Cipro Quinolone 25- 50-175 mg 75-110 mg 90 mg
    200 mg Q12H
    Clindamycin Cleocin Lincosamide 50- 75-500 mg 125- 225 mg
    600 mg 300 mg Q12H
    Doxycycline Vibramycin Tetracycline 10- 15-80 mg 25-65 mg 27 mg
    100 mg Q12H
    Fluconazole Diflucan Antifungal 12.5- 20-70 mg 25-50 mg 30 mg
    150 mg Q12H
    Gentamycin Garamycin Aminoglycoside 10- 30-150 mg 80-120 mg 95 mg Q8-
    200 mg 12H
    Itraconzaole Sporanox Antifungal 12.5- 20-70 mg 25-50 mg 30 mg
    150 mg Q12H
    Levofloxacin Levaquin Quinolone 40- 50-150 mg 60-80 mg 70 mg
    200 mg Q12H
    Meropenem Merrin Carbapenem 200- 250- 300- 333 mg
    750 mg 700 mg 500 mg Q8H
    Mezlocillin Mezlin Penicillin 300- 375- 750- 833 mg
    1500 mg 1000 mg 950 mg Q6H
    Miconazole Monistat Antifungal 12.5- 30-200 mg 50-100 mg 60 mg
    300 mg Q12H
    Nafcilin Nafcil Penicillin 100- 125- 250- 460 mg
    1000 mg 750 mg 600 mg Q6H
    Ofloxacin Floxin Quinolone 25- 50-175 mg 75-110 mg 90 mg
    200 mg Q12H
    Piperacillin Pipracil Penicillin 100- 125- 250- 460 mg
    1000 mg 750 mg 600 mg Q6H
    Rifampin Rafadin Miscellaneous 500- 1000- 1500- 2250 mg
    5000 mg 4000 mg 3500 mg Q12H
    Ticarcillin + Timentin Penicillin 500- 1000- 1500- 2250 mg
    Clavulanate 5000 mg 4000 mg 3500 mg Q6-8H
    Tobramycin Nebcin Aminoglycoside 10- 30-150 mg 80-120 mg 95 mg Q8-
    200 mg 12H
    Vancomycin Vancocin Antifungal 50- 75-325 mg 125- 166 mg
    400 mg 250 mg Q6-8H

Claims (38)

    What is claimed is:
  1. 1. A method of treating a patient suspected or diagnosed as having chronic sinusitis, comprising nasally administering an aerosolized/atomized composition comprising an agent for treatment of sinusitus, wherein the composition has a surface tension that results in penetration or adhesion of the agent in the sinuses.
  2. 2. The method of claim 1, wherein the surface tension is about 10 to about 70 dynes/cm.
  3. 3. The method of claim 1, wherein the composition comprises a surfactant.
  4. 4. The method of claim 1, wherein the agent is an anti-infective, an anti-inflammatory or a mucolytic agent.
  5. 5. The method of claim 1, wherein the composition is administered via a nebulizer.
  6. 6. The method of claim 1, wherein the agent is selected from the group consisting of anti-infective, anti-inflammatory and mucolytic agents;
    the surface tension of the composition is between about 10 to about 70 dynes/cm; and
    the composition is formulated as a solution in a unit dose for aerosol administration to the nasal sinuses by aerosolization using a nebulizer that delivers aerosol particles of between about 1 to about 5 μm in average diameter.
  7. 7. The method of claim 1, herein the composition is packaged with directions for its use in the treatment of sinusitis.
  8. 8. The method of claim 5, wherein the nebulizer is a nebulizer with a nasal adapter.
  9. 9. The method of claim 5, wherein the nebulizer is connected to a compressor.
  10. 10. The method of claim 5, wherein the nebulizer delivers a majority of aerosolized particles in the size range of about 3.0 to about 3.5 μm in diameter.
  11. 11. The method claim 1, wherein the pharmaceutical composition is administered to the patient 1-3 times a day for a total of 14-21 days.
  12. 12. The method of claim 1, wherein the composition has a pH in the range of about 3.0 to about 8.5.
  13. 13. The method of claim 1, wherein the osmotic pressure of the composition is between about 300 mOsm/kg to about 880 mOsm/kg.
  14. 14. The method of claim 1, wherein the NaCl equivalency to the composition is between about 0.9% NaCl to about 3.0% NaCl.
  15. 15. The method of claim 1, wherein the composition further comprises a decongestant.
  16. 16. The method of claim 1, wherein the composition, when administered as an aerosolized spray, has minimal systemic side effects.
  17. 17. The method of claim 1, wherein said active ingredient is an anti-infective agent and the sinusitis is caused by a pathogen selected from the group consisting of 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.
  18. 18. The method of claim 17, wherein said anti-infective agent is selected from the group consisting of Penicillins, Cephalosporins, Macrolides, Sulfonamides, Quinolones, Aminoglycosides, BetaLactam antibiotics, Linezolid, Vancomycin, Amphotericin B, and Azole antifungals.
  19. 19. The method of claim 2, wherein said surfactant is a polysorbate.
  20. 20. The method of claim 5, wherein the nebulizer delivers a majority of aerosolized particles in the size range of about 1.0 to about 4.0 μm in diameter.
  21. 21. The method of claim 5, wherein the nebulizer delivers a majority of aerosolized particles in the size range of about 0.5 to about 5.0 μm in diameter.
  22. 22. The method of claim 5, wherein the nebulizer delivers a majority of aerosolized particles in the size range of about 2.0 to about 3.5 μm in diameter.
  23. 23. The method of claim 5, wherein the maximum number of particles delivered by the nebulizer over about 5.0 microns is less that 20% of the total particles.
  24. 24. The method of claim 1, wherein the surface tension of the composition is between about 20 to about 60 dynes/cm.
  25. 25. The method of claim 1, wherein the surface tension of the composition is between about 30 to about 50 dynes/cm.
  26. 26. The method of claim 1, wherein the osmotic pressure of the composition is between about 150 mOsm/kg to about 880 mOsm/kg.
  27. 27. The method of claim 1, wherein the osmotic pressure of the composition is between about 400 mOsm/kg to about 700 mOsm/kg.
  28. 28. The method of claim 1, wherein the osmotic pressure of the composition is between about 500 mOsm/kg to about 600 mOsm/kg.
  29. 29. The method of claim 1, wherein the NaCl equivalency to the composition is between about 1.1 % NaCl to about 1.8% NaCl.
  30. 30. The method of claim 1, wherein the NaCl equivalency to the composition is between about 1.3% NaCl to about 1.7% NaCl.
  31. 31. The method of claim 4, wherein the anti-inflammatory agent is a glucocorticoid, disodium cromoglycate or nedcromil sodium.
  32. 32. The method of claim 4, wherein the mucolytic agent is acetylcysteine or dornase alpha.
  33. 33. The method of claim 15, wherein the decongestant is phenylephrine, naphazoline, oxymetazoline, tetrahydrozoline or xylometoazoline.
  34. 34. The method of claim 1, wherein the agent is amikacin, amphotericin B, azithromycin, aztreonam, cefazolin, cefepime, cefonicid, cefoperazone, cefotaxime, cefotetan, cefoxitin, ceftazidime, ceftizoxime, ceftriaxone, cefuroxime, cephapirin, ciprofloxacin, clindamycin, doxycycline, fluconazole, gentamycin, itraconazole, levofloxacin, meropenem, meziocillin, miconazole, nafcilin, oflaxacin, piperacillin, rifampin, ticarcillin+clavulanate, tobramycin or vancomycin.
  35. 35. The method of claim 2, wherein the surfactant is PEG 400, sodium lauryl sulfate, span 20, span 40, span 60, Tween 20, Tween 40, Tween 60 or benzalkonium chloride.
  36. 36. The method of claim 2, wherein the surfactant has a hydrophile-lipophile-balance (HLB) of between about 1.8 to about 8.6.
  37. 37. The method of claim 2, wherein the surfactant has a hydrophile-lipophile-balance (HLB) of between about 9.6 to about 16.7.
  38. 38. The method of claim 2, wherein the surfactant is Tween 20.
US10193081 1999-07-06 2002-07-09 Aerosolized anti-infectives, anti-inflammatories, and decongestants for the treatment of sinusitis Abandoned US20020197212A1 (en)

Priority Applications (14)

Application Number Priority Date Filing Date Title
US14262499 true 1999-07-06 1999-07-06
US14262099 true 1999-07-06 1999-07-06
US14261899 true 1999-07-06 1999-07-06
US14288199 true 1999-07-06 1999-07-06
US14262299 true 1999-07-06 1999-07-06
US14274199 true 1999-07-06 1999-07-06
US14262199 true 1999-07-06 1999-07-06
US19350700 true 2000-04-03 2000-04-03
US19407800 true 2000-04-03 2000-04-03
US19350800 true 2000-04-03 2000-04-03
US19351000 true 2000-04-03 2000-04-03
US19350900 true 2000-04-03 2000-04-03
US09577623 US6576224B1 (en) 1999-07-06 2000-05-25 Aerosolized anti-infectives, anti-inflammatories, and decongestants for the treatment of sinusitis
US10193081 US20020197212A1 (en) 1999-07-06 2002-07-09 Aerosolized anti-infectives, anti-inflammatories, and decongestants for the treatment of sinusitis

Applications Claiming Priority (1)

Application Number Priority Date Filing Date Title
US10193081 US20020197212A1 (en) 1999-07-06 2002-07-09 Aerosolized anti-infectives, anti-inflammatories, and decongestants for the treatment of sinusitis

Related Parent Applications (1)

Application Number Title Priority Date Filing Date
US09577623 Division US6576224B1 (en) 1999-07-06 2000-05-25 Aerosolized anti-infectives, anti-inflammatories, and decongestants for the treatment of sinusitis

Publications (1)

Publication Number Publication Date
US20020197212A1 true true US20020197212A1 (en) 2002-12-26

Family

ID=27584535

Family Applications (4)

Application Number Title Priority Date Filing Date
US09577623 Expired - Fee Related US6576224B1 (en) 1999-07-06 2000-05-25 Aerosolized anti-infectives, anti-inflammatories, and decongestants for the treatment of sinusitis
US10193081 Abandoned US20020197212A1 (en) 1999-07-06 2002-07-09 Aerosolized anti-infectives, anti-inflammatories, and decongestants for the treatment of sinusitis
US10231804 Expired - Fee Related US7128897B2 (en) 1999-07-06 2002-08-28 Aerosolized anti-infectives, anti-inflammatories, and decongestants for the treatment of sinusitis
US11532043 Abandoned US20070031344A1 (en) 1999-07-06 2006-09-14 Aerosolized anti-infectives, anti-inflammatories, and decongestants for the treatment of sinusitis

Family Applications Before (1)

Application Number Title Priority Date Filing Date
US09577623 Expired - Fee Related US6576224B1 (en) 1999-07-06 2000-05-25 Aerosolized anti-infectives, anti-inflammatories, and decongestants for the treatment of sinusitis

Family Applications After (2)

Application Number Title Priority Date Filing Date
US10231804 Expired - Fee Related US7128897B2 (en) 1999-07-06 2002-08-28 Aerosolized anti-infectives, anti-inflammatories, and decongestants for the treatment of sinusitis
US11532043 Abandoned US20070031344A1 (en) 1999-07-06 2006-09-14 Aerosolized anti-infectives, anti-inflammatories, and decongestants for the treatment of sinusitis

Country Status (5)

Country Link
US (4) US6576224B1 (en)
EP (1) EP1207912A4 (en)
JP (2) JP2003507325A (en)
CA (1) CA2375748A1 (en)
WO (1) WO2001002024A9 (en)

Cited By (15)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20020061281A1 (en) * 1999-07-06 2002-05-23 Osbakken Robert S. Aerosolized anti-infectives, anti-inflammatories, and decongestants for the treatment of sinusitis
US6759434B2 (en) 1999-09-22 2004-07-06 B. Ron Johnson Anti-infective compositions, methods and systems for treating disordered tissue
US20040166066A1 (en) * 2002-09-13 2004-08-26 Tim Clarot Compositions to reduce congestion and methods for application thereof to the nasal membrane
US20060073173A1 (en) * 2004-10-04 2006-04-06 Maria Banach Large-scale manufacturing process for the production of pharmaceutical compositions
US20060276483A1 (en) * 2005-05-18 2006-12-07 Surber Mark W Aerosolized fluoroquinolones and uses thereof
US8173709B2 (en) 1999-09-22 2012-05-08 Quadex Pharmaceuticals, Llc Anti-infective methods for treating pathogen-induced disordered tissues
US8357696B2 (en) 2005-05-18 2013-01-22 Mpex Pharmaceuticals, Inc. Aerosolized fluoroquinolones and uses thereof
WO2012094381A3 (en) * 2011-01-05 2013-06-20 Hospira, Inc. Spray drying vancomycin
US8629139B2 (en) 2008-10-07 2014-01-14 Mpex Pharmaceuticals, Inc. Topical use of Levofloxacin for reducing lung inflammation
US8815838B2 (en) 2008-10-07 2014-08-26 David C. Griffith Aerosol fluoroquinolone formulations for improved pharmacokinetics
US9125911B2 (en) 2013-03-14 2015-09-08 Quadex Pharmaceuticals, Llc Combined systemic and topical treatment of disordered tissues
US9428291B2 (en) 2013-03-15 2016-08-30 Choon Teo Method and system for producing high purity vancomycin hydrochloride
US9463180B2 (en) 2013-03-14 2016-10-11 Quadex Pharmaceuticals, Llc Treatment of molluscum contagiosum
US9549930B2 (en) 2013-03-14 2017-01-24 Quadex Pharmaceuticals, Llc Combined systemic and topical treatment of disordered and/or prodromal stage tissue
US9700564B2 (en) 2009-09-04 2017-07-11 Horizon Orphan Llc Use of aerosolized levofloxacin for treating cystic fibrosis

Families Citing this family (73)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US7135191B2 (en) * 1997-09-04 2006-11-14 Zsolt Istvan Hertelendy Urogenital or anorectal transmucosal vaccine delivery system
US6576224B1 (en) * 1999-07-06 2003-06-10 Sinuspharma, Inc. Aerosolized anti-infectives, anti-inflammatories, and decongestants for the treatment of sinusitis
US8336545B2 (en) 2000-05-05 2012-12-25 Novartis Pharma Ag Methods and systems for operating an aerosol generator
US7971588B2 (en) 2000-05-05 2011-07-05 Novartis Ag Methods and systems for operating an aerosol generator
US20040022740A1 (en) * 2001-07-10 2004-02-05 Baker William R. Macrolide formulations for inhalation and methods of treatment of endobronchial infections
JP2004517127A (en) 2000-12-21 2004-06-10 ネクター セラピューティックス Pulmonary delivery of polyene antifungal agent
US7214364B2 (en) 2000-12-27 2007-05-08 Corus Pharma, Inc. Inhalable aztreonam lysinate formulation for treatment and prevention of pulmonary bacterial infections
WO2003026559A3 (en) 2001-09-28 2003-11-06 Kurve Technology Inc Nasal nebulizer
US20030133925A1 (en) * 2001-09-28 2003-07-17 Shawar Ribhi M. Monobactam compositions and methods of use thereof
WO2003099359A1 (en) * 2002-05-09 2003-12-04 Kurve Technology, Inc. Particle dispersion chamber for nasal nebulizer
DE10239321B3 (en) 2002-08-27 2004-04-08 Pari GmbH Spezialisten für effektive Inhalation Aerosol therapy device
WO2004027027A3 (en) 2002-09-18 2004-05-21 Univ Pennsylvania Method of inhibiting choroidal neovascularization
CA2518960C (en) 2003-03-14 2013-08-27 Sinexus, Inc. Sinus delivery of sustained release therapeutics
US7361376B2 (en) * 2003-04-11 2008-04-22 International Flavors & Fragrances Inc. Alkyldienamides exhibiting taste and sensory effect in flavor compositions
US7632531B2 (en) * 2003-04-11 2009-12-15 International Flavors & Fragnances Inc. Alkyldienamides exhibiting taste and sensory effect in flavor compositions
US7141686B2 (en) 2003-07-10 2006-11-28 International Flavors & Fragrances Inc. E2, E4, Z8-undecatrienoic acid and ester and carboxamide derivatives thereof, organoleptic uses thereof and processes for preparing same
WO2005023334A3 (en) * 2003-09-05 2005-07-28 Kurve Technology Inc Nasal adapter for the base of the nose
EP1673123A2 (en) * 2003-09-05 2006-06-28 Kurve Technology, Inc. Integrated nebulizer and particle dispersing chamber for delivery of medicament
CN1882338A (en) * 2003-09-18 2006-12-20 马库赛特公司 Transscleral delivery
US8007839B2 (en) * 2003-10-03 2011-08-30 International Flavors & Fragrances Conjugated dienamides, methods of production thereof, compositions containing same and uses thereof
US7544204B2 (en) * 2003-10-15 2009-06-09 Valam Corporation Control of halitosis-generating and other microorganisms in the non-dental upper respiratory tract
WO2006060027A3 (en) * 2004-09-20 2007-12-13 Corus Pharma Inc A method for improvement of tolerance for therapeutically effective agents delivered by inhalation
US7452523B2 (en) * 2004-01-27 2008-11-18 Gilead Sciences, Inc. Targeted delivery of lidocaine and other local anesthetics and a method for treatment of cough and tussive attacks
US7452524B2 (en) * 2004-01-27 2008-11-18 Gilead Sciences, Inc. Method for improvement of tolerance for therapeutically effective agents delivered by inhalation
US20060045849A1 (en) * 2004-08-24 2006-03-02 Farhan Taghizadeh Method of customizing the fragrance of nasal medications
WO2006036180A1 (en) * 2004-09-20 2006-04-06 Corus Pharma, Inc. Targeted delivery of lidocaine and other local anesthetics and a method for treatment of cough and tussive attacks
US7731678B2 (en) 2004-10-13 2010-06-08 Hyprotek, Inc. Syringe devices and methods for mixing and administering medication
US8663639B2 (en) 2005-02-09 2014-03-04 Santen Pharmaceutical Co., Ltd. Formulations for treating ocular diseases and conditions
EP3025713A1 (en) 2005-02-09 2016-06-01 Santen Pharmaceutical Co., Ltd Liquid formulations for treatment of diseases or conditions
WO2007070875A1 (en) * 2005-12-15 2007-06-21 Aerosol Science Laboratories, Inc. Treatment of active infections and related compositions
WO2007079466A3 (en) * 2006-01-04 2008-12-04 August K Doner Air driven delivery system for sprayable media
DE102006001113B3 (en) 2006-01-09 2007-06-28 Pari GmbH Spezialisten für effektive Inhalation Aerosol therapy device comprises an atomizer, an aerosol generator, a nosepiece for delivering aerosol to one nostril, a device for creating flow resistance in the other nostril, and a connector that imparts pressure fluctuations
US20070173463A1 (en) * 2006-01-20 2007-07-26 Brechtelsbauer Paul B Method and composition for treating otitis media
WO2007092620A3 (en) 2006-02-09 2009-03-26 Macusight Inc Stable formulations, and methods of their preparation and use
JP2009526003A (en) * 2006-02-10 2009-07-16 パーリ・ファルマ・ゲーエムベーハー Spray-like antibiotic for inhalation therapy
CA2645488C (en) 2006-03-23 2014-09-02 Macusight, Inc. Formulations comprising rapamycin and methods using same for vascular permeability-related diseases or conditions
US7993675B2 (en) 2006-05-10 2011-08-09 Medtronic Xomed, Inc. Solvating system and sealant for medical use in the sinuses and nasal passages
US20070264296A1 (en) * 2006-05-10 2007-11-15 Myntti Matthew F Biofilm extracellular polysachharide solvating system
US7959943B2 (en) 2006-05-10 2011-06-14 Medtronics Xomed, Inc. Solvating system and sealant for medical use in the middle or inner ear
US7976873B2 (en) 2006-05-10 2011-07-12 Medtronic Xomed, Inc. Extracellular polysaccharide solvating system for treatment of bacterial ear conditions
CA2698137A1 (en) 2006-08-30 2008-03-06 Kurve Technology, Inc. Aerosol generating and delivery device
US8414525B2 (en) 2006-11-20 2013-04-09 Lutonix, Inc. Drug releasing coatings for medical devices
US8414526B2 (en) 2006-11-20 2013-04-09 Lutonix, Inc. Medical device rapid drug releasing coatings comprising oils, fatty acids, and/or lipids
US8998846B2 (en) 2006-11-20 2015-04-07 Lutonix, Inc. Drug releasing coatings for balloon catheters
US8425459B2 (en) 2006-11-20 2013-04-23 Lutonix, Inc. Medical device rapid drug releasing coatings comprising a therapeutic agent and a contrast agent
US8414909B2 (en) 2006-11-20 2013-04-09 Lutonix, Inc. Drug releasing coatings for medical devices
US9700704B2 (en) 2006-11-20 2017-07-11 Lutonix, Inc. Drug releasing coatings for balloon catheters
US8414910B2 (en) 2006-11-20 2013-04-09 Lutonix, Inc. Drug releasing coatings for medical devices
US9737640B2 (en) 2006-11-20 2017-08-22 Lutonix, Inc. Drug releasing coatings for medical devices
US20080276935A1 (en) 2006-11-20 2008-11-13 Lixiao Wang Treatment of asthma and chronic obstructive pulmonary disease with anti-proliferate and anti-inflammatory drugs
US8088095B2 (en) 2007-02-08 2012-01-03 Medtronic Xomed, Inc. Polymeric sealant for medical use
DE502007002037D1 (en) 2007-04-11 2009-12-31 Pari Gmbh Aerosol therapy device
US20080265343A1 (en) * 2007-04-26 2008-10-30 International Business Machines Corporation Field effect transistor with inverted t shaped gate electrode and methods for fabrication thereof
US9522097B2 (en) 2007-10-04 2016-12-20 Hyprotek, Inc. Mixing/administration syringe devices, protective packaging and methods of protecting syringe handlers
US8002737B2 (en) * 2007-10-04 2011-08-23 Hyprotek, Inc. Mixing/administration syringe devices, protective packaging and methods of protecting syringe handlers
WO2009079418A3 (en) 2007-12-18 2009-12-30 Sinexus, Inc. Self-expanding devices and methods therefor
CA2727432C (en) * 2008-06-12 2016-10-11 Medtronic Xomed, Inc. Method for treating chronic wounds with an extracellular polymeric substance solvating system
US8763222B2 (en) 2008-08-01 2014-07-01 Intersect Ent, Inc. Methods and devices for crimping self-expanding devices
US8430055B2 (en) 2008-08-29 2013-04-30 Lutonix, Inc. Methods and apparatuses for coating balloon catheters
WO2010042427A3 (en) 2008-10-06 2010-07-01 Microbial Defense Systems, Llc Antimicrobial composition and methods of making and using same
US20120016011A1 (en) 2009-03-19 2012-01-19 Merck Sharp & Dohme Corp. RNA Interference Mediated Inhibition of Connective Tissue Growth Factor (CTGF) Gene Expression Using Short Interfering Nucleic Acid (siNA)
EP2408915A2 (en) 2009-03-19 2012-01-25 Merck Sharp&Dohme Corp. RNA INTERFERENCE MEDIATED INHIBITION OF GATA BINDING PROTEIN 3 (GATA3) GENE EXPRESSION USING SHORT INTERFERING NUCLEIC ACID (siNA)
EP2408458A1 (en) 2009-03-19 2012-01-25 Merck Sharp&Dohme Corp. RNA INTERFERENCE MEDIATED INHIBITION OF SIGNAL TRANSDUCER AND ACTIVATOR OF TRANSCRIPTION 6 (STAT6) GENE EXPRESSION USING SHORT INTERFERING NUCLEIC ACID (siNA)
US20120016010A1 (en) 2009-03-19 2012-01-19 Merck Sharp & Dohme Corp RNA Interference Mediated Inhibition of BTB and CNC Homology 1, Basic Leucine Zipper Transcription Factor 1 (BACH1) Gene Expression Using Short Interfering Nucleic Acid (siNA)
WO2010111464A1 (en) * 2009-03-27 2010-09-30 Merck Sharp & Dohme Corp. RNA INTERFERENCE MEDIATED INHIBITION OF APOPTOSIS SIGNAL-REGULATING KINASE 1 (ASK1) GENE EXPRESSION USING SHORT INTERFERING NUCLEIC ACID (siNA)
US20120022143A1 (en) 2009-03-27 2012-01-26 Merck Sharp & Dohme Corp RNA Interference Mediated Inhibition of the Thymic Stromal Lymphopoietin (TSLP) Gene Expression Using Short Interfering Nucliec Acid (siNA)
US20120022142A1 (en) 2009-03-27 2012-01-26 Merck Sharp & Dohme Corp. RNA Interference Mediated Inhibition of Signal Transducer and Activator of Transcription 1 (STAT1) Gene Expression Using Short Interfering Nucleic Acid (siNA)
WO2010111468A3 (en) 2009-03-27 2010-11-18 Merck Sharp & Dohme Corp. RNA INTERFERENCE MEDIATED INHIBITION OF THE NERVE GROWTH FACTOR BETA CHAIN (NGFß) GENE EXPRESSION USING SHORT INTERFERING NUCLEIC ACID (SINA)
EP2411517A2 (en) 2009-03-27 2012-02-01 Merck Sharp&Dohme Corp. RNA INTERFERENCE MEDIATED INHIBITION OF THE INTERCELLULAR ADHESION MOLECULE 1 (ICAM-1)GENE EXPRESSION USING SHORT INTERFERING NUCLEIC ACID (siNA)
US8802058B2 (en) * 2010-04-19 2014-08-12 Gelmed, Llc Pharmaceutical compositions and methods for administering the same
US9265967B2 (en) 2011-08-05 2016-02-23 Lumimed, Llc Apparatus and method for treating rhinitis
WO2015157038A1 (en) * 2014-04-08 2015-10-15 Aradigm Corporation Liposomal ciprofloxacin formulations with activity against non-tuberculous mycobacteria
US20180071281A1 (en) * 2016-08-19 2018-03-15 Gerbe Labs Inc. Treating chronic rhinosinusitis

Citations (19)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4438100A (en) * 1980-04-25 1984-03-20 A/S Orthana Kemisk Fabrik Sterilized preserved, stable mucine-containing solutions
US4693999A (en) * 1984-07-30 1987-09-15 Aktiebolaget Draco Liposomes containing steroid esters
US4917951A (en) * 1987-07-28 1990-04-17 Micro-Pak, Inc. Lipid vesicles formed of surfactants and steroids
US4944949A (en) * 1986-12-18 1990-07-31 T.I.L. Medical Ltd. Pharmaceutical delivery systems
US5004611A (en) * 1984-03-08 1991-04-02 Phares Pharmaceutical Research Nv Pro-liposome compositions
US5397771A (en) * 1990-05-10 1995-03-14 Bechgaard International Research And Development A/S Pharmaceutical preparation
US5428006A (en) * 1990-05-10 1995-06-27 Bechgaard International Research And Development A/S Method of administering a biologically active substance
US5431902A (en) * 1993-05-25 1995-07-11 Adir Et Compagnie New medicament aerosol formulation based on fusafungine
US5843881A (en) * 1997-02-13 1998-12-01 The Procter & Gamble Company Spray compositions
US5925334A (en) * 1997-08-27 1999-07-20 Rubin; Bruce K. Use of surface active agents to promote mucus clearance
US5976573A (en) * 1996-07-03 1999-11-02 Rorer Pharmaceutical Products Inc. Aqueous-based pharmaceutical composition
US6126930A (en) * 1997-02-13 2000-10-03 The Procter & Gamble Company Spray compositions
US6207703B1 (en) * 1997-10-22 2001-03-27 Jens Ponikau Methods and materials for treating and preventing inflammation of mucosal tissue
US6274634B1 (en) * 1997-05-14 2001-08-14 Senju Pharmaceutical Co., Ltd. Aqueous suspension preparations with excellent redispersibility
US20020061281A1 (en) * 1999-07-06 2002-05-23 Osbakken Robert S. Aerosolized anti-infectives, anti-inflammatories, and decongestants for the treatment of sinusitis
US6395746B1 (en) * 1998-09-30 2002-05-28 Alcon Manufacturing, Ltd. Methods of treating ophthalmic, otic and nasal infections and attendant inflammation
US6395300B1 (en) * 1999-05-27 2002-05-28 Acusphere, Inc. Porous drug matrices and methods of manufacture thereof
US20020102294A1 (en) * 1998-11-12 2002-08-01 H. William Bosch Aerosols comprising nanoparticle drugs
US20030031631A1 (en) * 1999-07-06 2003-02-13 Osbakken Robert S. Aerosolized anti-infectives, anti-inflammatories, and decongestants for the treatment of sinusitis

Family Cites Families (62)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US103157A (en) 1870-05-17 Improvement in spoke-tenoning and hub-boring machines
US52338A (en) 1866-01-30 Improvement in glass-molds
US65244A (en) 1867-05-28 George lawton
US4424216A (en) 1979-07-31 1984-01-03 The Rockefeller University Method for the reduction of mucin viscosity
US4593089A (en) 1980-07-30 1986-06-03 Abbott Laboratories Fluorescent polarization immunoassay utilizing substituted triazinylaminofluorescein aminoglycosides
US4468513A (en) 1980-09-22 1984-08-28 Eli Lilly And Company 2'-N-Acylated and 2'-N-alkylated derivatives of 4-O-substituted-2-deoxystreptamine aminoglycosides
US4312860A (en) 1980-10-24 1982-01-26 Regents Of The University Of California Lung surfactant compositions
JPS634812B2 (en) 1980-12-04 1988-02-01 Teijin Ltd
DE3206725A1 (en) 1981-05-13 1982-12-02 Merck Patent Gmbh Sparingly soluble salts of aminoglycoside antibiotics
JPS58213774A (en) 1982-06-04 1983-12-12 Kowa Co Novel aminoglycoside
US4493831A (en) 1982-10-25 1985-01-15 Fujisawa Pharmaceutical Co., Ltd. Aminoglycoside derivatives
US5169637A (en) 1983-03-24 1992-12-08 The Liposome Company, Inc. Stable plurilamellar vesicles
US4478822A (en) 1983-05-16 1984-10-23 Merck & Co., Inc. Drug delivery system utilizing thermosetting gels
JPS6042394A (en) 1983-08-18 1985-03-06 Kowa Co Novel aminoglycoside and its preparation
US4684643A (en) 1983-08-22 1987-08-04 Eli Lilly And Company Pharmaceutical compositions for storage in plastic containers and process therefor
US5141674A (en) 1984-03-08 1992-08-25 Phares Pharmaceutical Research N.V. Methods of preparing pro-liposome dispersions and aerosols
US4656160A (en) 1984-11-29 1987-04-07 Fujisawa Pharmaceutical Co., Ltd. Aminoglycoside derivatives
US5110806A (en) 1985-06-26 1992-05-05 The Regents Of The University Of California Lung surfactant compositions
JPS6253997A (en) 1985-09-03 1987-03-09 Kowa Co Novel amino glycoside and pharmaceutical preparation containing same
US5049388A (en) 1986-11-06 1991-09-17 Research Development Foundation Small particle aerosol liposome and liposome-drug combinations for medical use
US4767612A (en) * 1987-01-23 1988-08-30 Rorer Pharmaceutical Corporation Triamcinolone acetonide for the treatment of allergic rhinitis
US5112804A (en) 1987-04-01 1992-05-12 Temple University Of The Commonwealth System Of Higher Education Pharmaceutical composition and method of intranasal administration
US4950477A (en) 1988-08-23 1990-08-21 Memorial Hospital For Cancer And Allied Dieseas Method of preventing and treating pulmonary infection by fungi using aerosolized polyenes
US5049389A (en) 1988-12-14 1991-09-17 Liposome Technology, Inc. Novel liposome composition for the treatment of interstitial lung diseases
US4906476A (en) 1988-12-14 1990-03-06 Liposome Technology, Inc. Novel liposome composition for sustained release of steroidal drugs in lungs
US5006343A (en) 1988-12-29 1991-04-09 Benson Bradley J Pulmonary administration of pharmaceutically active substances
WO1990013327A1 (en) 1989-04-28 1990-11-15 Riker Laboratories, Inc. Dry powder inhalation device
US5614216A (en) 1990-10-17 1997-03-25 The Liposome Company, Inc. Synthetic lung surfactant
US5039666A (en) 1990-10-30 1991-08-13 Hoechst-Roussel Pharmaceuticals Inc. Aminoglycoside composition having substantially reduced nephrotoxicity induced by the aminoglycoside
GB9027255D0 (en) 1990-12-17 1991-02-06 Minnesota Mining & Mfg Closure system for inhalers
US5145684A (en) 1991-01-25 1992-09-08 Sterling Drug Inc. Surface modified drug nanoparticles
FR2674756B1 (en) 1991-04-05 1993-06-25 Diffusion Tech Francaise Sarl Device for controlling the mano-sonic functions of a therapeutic nebuliser.
US5900406A (en) 1991-07-09 1999-05-04 Nzym, Inc. Use of antibiotics of the type 2-deoxystreptamine substituted with aminosugars to inhibit growth of microorganisms containing group I introns
GB9120005D0 (en) 1991-09-19 1991-11-06 Wellcome Found Method of administering phospholipid dispersions
US5167506A (en) 1991-10-24 1992-12-01 Minnesota Mining And Manufacturing Company Inhalation device training system
US5525329A (en) 1992-05-21 1996-06-11 The Johns Hopkins University Inhibition of phosphodiesterase in olfactory mucosa
US5510339A (en) 1993-02-02 1996-04-23 Mayo Foundation For Medical Education And Research Method for the treatment of bronchial asthma by administration of topical anesthetics
EP0694310B1 (en) 1993-04-16 2000-02-16 Wakamoto Pharmaceutical Co., Ltd. Reversible, thermally gelling water-base medicinal composition
US5512269A (en) 1993-06-09 1996-04-30 Burroughs Wellcome, Co. Method of treating retained pulmonary secretions
US5631004A (en) 1993-09-30 1997-05-20 Alcon Laboratories, Inc. Use of sustained release antibiotic compositions in ophthalmic surgical procedures
US5595977A (en) 1993-10-27 1997-01-21 Dumex-Alpharma A/S Salts of amino glycosides
US5522385A (en) 1994-09-27 1996-06-04 Aradigm Corporation Dynamic particle size control for aerosolized drug delivery
US5508269A (en) 1994-10-19 1996-04-16 Pathogenesis Corporation Aminoglycoside formulation for aerosolization
US5861275A (en) 1995-09-28 1999-01-19 The University Of Maryland Lantibiotic mutants and chimeras of enhanced stability and activity, leader sequences therefor, genes encoding the same, and methods of producing and using the same
US6423694B1 (en) 1996-02-21 2002-07-23 Inspire Pharmaceuticals, Inc. Method of treating otitis media with uridine triphosphates and related compounds
US6420347B1 (en) 1997-03-27 2002-07-16 Inspire Pharmaceuticals, Inc. Method of treating ciliary dyskinesia with uridine triphosphates and related compounds
US6083922A (en) 1996-04-02 2000-07-04 Pathogenesis, Corp. Method and a tobramycin aerosol formulation for treatment prevention and containment of tuberculosis
US5789391A (en) 1996-07-03 1998-08-04 Inspire Pharmaceuticals, Inc. Method of treating sinusitis with uridine triphosphates and related compounds
US5906198A (en) 1996-07-16 1999-05-25 Flickinger; William J. Nasal nebulizer
US6180604B1 (en) 1996-08-21 2001-01-30 Micrologix Biotech Inc. Compositions and methods for treating infections using analogues of indolicidin
JPH10130148A (en) 1996-09-04 1998-05-19 Senju Pharmaceut Co Ltd Composition for nebulizer
US5685291A (en) 1996-11-15 1997-11-11 Marsh; Jean Ann Nebulizer adapter system for premature babies
US6921755B2 (en) 1998-02-06 2005-07-26 Inspire Pharmaceuticals, Inc. Method of treating dry eye disease with purinergic receptor agonists
US5900407A (en) 1997-02-06 1999-05-04 Inspire Pharmaceuticals, Inc. Method of treating dry eye disease with uridine triphosphates and related compounds
WO1998056379A1 (en) * 1997-06-11 1998-12-17 Alcon Laboratories, Inc. Compositions and methods for treating glaucoma
US5883084A (en) 1998-06-08 1999-03-16 Clarion Pharmaceuticals Inc. Treatment of respiratory diseases utilizing α-tocopheryl-phosphocholine
US6241969B1 (en) 1998-06-26 2001-06-05 Elan Corporation Plc Aqueous compositions containing corticosteroids for nasal and pulmonary delivery
US6274855B1 (en) * 1998-11-17 2001-08-14 Ngk Spark Plug Co., Ltd. Heating resistor for ceramic heaters, ceramic heaters and method of manufacturing ceramic heaters
EP1161247A4 (en) 1998-12-17 2002-05-15 Chiron Corp Method for the treatment of severe chronic bronchitis (bronchiectasis) with an aerosolized antibiotic
ES2166278B2 (en) 1999-09-14 2003-06-16 Univ Madrid Complutense Process for preparing nasal spray powders using insoluble, absorbent excipients as nasal absorption promoters.
US6277855B1 (en) 2000-04-21 2001-08-21 Inspire Pharmaceuticals, Inc. Method of treating dry eye disease with nicotinic acetylcholine receptor agonists
US6448276B1 (en) 2000-05-17 2002-09-10 Inspire Pharmaceuticals, Inc. Method for treating vaginal dryness with nicotinic acetylcholine receptor agonists

Patent Citations (29)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4438100A (en) * 1980-04-25 1984-03-20 A/S Orthana Kemisk Fabrik Sterilized preserved, stable mucine-containing solutions
US5004611A (en) * 1984-03-08 1991-04-02 Phares Pharmaceutical Research Nv Pro-liposome compositions
US4693999A (en) * 1984-07-30 1987-09-15 Aktiebolaget Draco Liposomes containing steroid esters
US4944949A (en) * 1986-12-18 1990-07-31 T.I.L. Medical Ltd. Pharmaceutical delivery systems
US4917951A (en) * 1987-07-28 1990-04-17 Micro-Pak, Inc. Lipid vesicles formed of surfactants and steroids
US5693608A (en) * 1990-05-10 1997-12-02 Bechgaard International Research And Development A/S Method of administering a biologically active substance
US5397771A (en) * 1990-05-10 1995-03-14 Bechgaard International Research And Development A/S Pharmaceutical preparation
US5428006A (en) * 1990-05-10 1995-06-27 Bechgaard International Research And Development A/S Method of administering a biologically active substance
US5431902A (en) * 1993-05-25 1995-07-11 Adir Et Compagnie New medicament aerosol formulation based on fusafungine
US6375984B1 (en) * 1996-07-03 2002-04-23 Rorer Pharmaceuticals Products Inc. Aqueous-based pharmaceutical composition
US5976573A (en) * 1996-07-03 1999-11-02 Rorer Pharmaceutical Products Inc. Aqueous-based pharmaceutical composition
US6143329A (en) * 1996-07-03 2000-11-07 Rorer Pharmaceutical Products Inc. Aqueous-based pharmaceutical composition
US5843881A (en) * 1997-02-13 1998-12-01 The Procter & Gamble Company Spray compositions
US6126930A (en) * 1997-02-13 2000-10-03 The Procter & Gamble Company Spray compositions
US6274634B1 (en) * 1997-05-14 2001-08-14 Senju Pharmaceutical Co., Ltd. Aqueous suspension preparations with excellent redispersibility
US5925334A (en) * 1997-08-27 1999-07-20 Rubin; Bruce K. Use of surface active agents to promote mucus clearance
US20010006944A1 (en) * 1997-10-22 2001-07-05 Jens Ponikau Methods and materials for treating and preventing inflammation of mucosal tissue
US20010002400A1 (en) * 1997-10-22 2001-05-31 Jens Ponikau Methods and materials for treating and preventing inflammation of mucosal tissue
US6291500B2 (en) * 1997-10-22 2001-09-18 Jens Ponikau Methods and materials for treating and preventing inflammation of mucosal tissue
US20010031779A1 (en) * 1997-10-22 2001-10-18 Jens Ponikau Methods and materials for treating and preventing inflammation of mucosal tissue
US20020052390A1 (en) * 1997-10-22 2002-05-02 Jens Ponikau Methods and materials for treating and preventing inflammation of mucosal tissue
US6207703B1 (en) * 1997-10-22 2001-03-27 Jens Ponikau Methods and materials for treating and preventing inflammation of mucosal tissue
US6555566B2 (en) * 1997-10-22 2003-04-29 Mayo Foundation For Medical Education And Research Methods and materials for treating and preventing inflammation of mucosal tissue
US6395746B1 (en) * 1998-09-30 2002-05-28 Alcon Manufacturing, Ltd. Methods of treating ophthalmic, otic and nasal infections and attendant inflammation
US20020102294A1 (en) * 1998-11-12 2002-08-01 H. William Bosch Aerosols comprising nanoparticle drugs
US6395300B1 (en) * 1999-05-27 2002-05-28 Acusphere, Inc. Porous drug matrices and methods of manufacture thereof
US20030031631A1 (en) * 1999-07-06 2003-02-13 Osbakken Robert S. Aerosolized anti-infectives, anti-inflammatories, and decongestants for the treatment of sinusitis
US20020061281A1 (en) * 1999-07-06 2002-05-23 Osbakken Robert S. Aerosolized anti-infectives, anti-inflammatories, and decongestants for the treatment of sinusitis
US20040204399A1 (en) * 2001-08-31 2004-10-14 Osbakken Robert S. Aerosolized decongestants for the treatment of sinusitis

Cited By (27)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20020061281A1 (en) * 1999-07-06 2002-05-23 Osbakken Robert S. Aerosolized anti-infectives, anti-inflammatories, and decongestants for the treatment of sinusitis
US6759434B2 (en) 1999-09-22 2004-07-06 B. Ron Johnson Anti-infective compositions, methods and systems for treating disordered tissue
US8173709B2 (en) 1999-09-22 2012-05-08 Quadex Pharmaceuticals, Llc Anti-infective methods for treating pathogen-induced disordered tissues
US20040204399A1 (en) * 2001-08-31 2004-10-14 Osbakken Robert S. Aerosolized decongestants for the treatment of sinusitis
US7714011B2 (en) 2002-09-13 2010-05-11 Zicam, Llc Compositions to reduce congestion and methods for application thereof to the nasal membrane
US20040166066A1 (en) * 2002-09-13 2004-08-26 Tim Clarot Compositions to reduce congestion and methods for application thereof to the nasal membrane
US20060073173A1 (en) * 2004-10-04 2006-04-06 Maria Banach Large-scale manufacturing process for the production of pharmaceutical compositions
US20060276483A1 (en) * 2005-05-18 2006-12-07 Surber Mark W Aerosolized fluoroquinolones and uses thereof
US8524735B2 (en) 2005-05-18 2013-09-03 Mpex Pharmaceuticals, Inc. Aerosolized fluoroquinolones and uses thereof
US7838532B2 (en) 2005-05-18 2010-11-23 Mpex Pharmaceuticals, Inc. Aerosolized fluoroquinolones and uses thereof
US8357696B2 (en) 2005-05-18 2013-01-22 Mpex Pharmaceuticals, Inc. Aerosolized fluoroquinolones and uses thereof
US8524734B2 (en) 2005-05-18 2013-09-03 Mpex Pharmaceuticals, Inc. Aerosolized fluoroquinolones and uses thereof
US8546423B2 (en) 2005-05-18 2013-10-01 Mpex Pharmaceuticals, Inc. Aerosolized fluoroquinolones and uses thereof
US9326936B2 (en) 2008-10-07 2016-05-03 Raptor Pharmaceuticals, Inc. Aerosol fluoroquinolone formulations for improved pharmacokinetics
US8629139B2 (en) 2008-10-07 2014-01-14 Mpex Pharmaceuticals, Inc. Topical use of Levofloxacin for reducing lung inflammation
US8815838B2 (en) 2008-10-07 2014-08-26 David C. Griffith Aerosol fluoroquinolone formulations for improved pharmacokinetics
US9717738B2 (en) 2008-10-07 2017-08-01 Horizon Orphan Llc Aerosol fluoroquinolone formulations for improved pharmacokinetics
US9700564B2 (en) 2009-09-04 2017-07-11 Horizon Orphan Llc Use of aerosolized levofloxacin for treating cystic fibrosis
US8709310B2 (en) 2011-01-05 2014-04-29 Hospira, Inc. Spray drying vancomycin
US9023258B2 (en) 2011-01-05 2015-05-05 Hospira, Inc. Spray drying vancomycin
WO2012094381A3 (en) * 2011-01-05 2013-06-20 Hospira, Inc. Spray drying vancomycin
US9763997B2 (en) 2011-01-05 2017-09-19 Hospira, Inc. Spray drying vancomycin
US9545408B2 (en) 2013-03-14 2017-01-17 Quadex Pharmaceuticals, Inc. Combined systemic and topical treatment of disordered tissues
US9549930B2 (en) 2013-03-14 2017-01-24 Quadex Pharmaceuticals, Llc Combined systemic and topical treatment of disordered and/or prodromal stage tissue
US9463180B2 (en) 2013-03-14 2016-10-11 Quadex Pharmaceuticals, Llc Treatment of molluscum contagiosum
US9125911B2 (en) 2013-03-14 2015-09-08 Quadex Pharmaceuticals, Llc Combined systemic and topical treatment of disordered tissues
US9428291B2 (en) 2013-03-15 2016-08-30 Choon Teo Method and system for producing high purity vancomycin hydrochloride

Also Published As

Publication number Publication date Type
JP2008013580A (en) 2008-01-24 application
EP1207912A4 (en) 2006-03-15 application
US6576224B1 (en) 2003-06-10 grant
US20070031344A1 (en) 2007-02-08 application
EP1207912A1 (en) 2002-05-29 application
US20030031631A1 (en) 2003-02-13 application
JP2003507325A (en) 2003-02-25 application
WO2001002024A9 (en) 2002-09-06 application
WO2001002024A1 (en) 2001-01-11 application
US7128897B2 (en) 2006-10-31 grant
CA2375748A1 (en) 2001-01-11 application

Similar Documents

Publication Publication Date Title
Ebbens et al. Amphotericin B nasal lavages: not a solution for patients with chronic rhinosinusitis
Cochereau-Massin et al. Efficacy and tolerance of intravitreal ganciclovir in cytomegalovirus retinitis in acquired immune deficiency syndrome
Hashimoto et al. Depletion of alveolar macrophages decreases neutrophil chemotaxis to Pseudomonas airspace infections
Marple et al. Safety review of benzalkonium chloride used as a preservative in intranasal solutions: an overview of conflicting data and opinions
Daviskas et al. Inhalation of dry powder mannitol improves clearance of mucus in patients with bronchiectasis
Vaughan et al. Use of nebulized antibiotics for acute infections in chronic sinusitis
Singhi et al. Efficacy of nebulized budesonide compared to oral prednisolone in acute bronchial asthma
Eisenberg et al. A comparison of peak sputum tobramycin concentration in patients with cystic fibrosis using jet and ultrasonic nebulizer systems
US5925334A (en) Use of surface active agents to promote mucus clearance
US20080058295A1 (en) Nasal pharmaceutical formulations and methods of using the same
US20050244339A1 (en) Pharmaceutical aerosol composition
US5993781A (en) Fluticasone propionate nebulizable formulations
Robinson et al. The effect of inhaled mannitol on bronchial mucus clearance in cystic fibrosis patients: a pilot study
Coates et al. The choice of jet nebulizer, nebulizing flow, and addition of albuterol affects the output of tobramycin aerosols
US20060110331A1 (en) Compositions comprising azelastine and methods of use thereof
Stead et al. Inhaled ceftazidime compared with gentamicin and carbenicillin in older patients with cystic fibrosis infected with Pseudomonas aeruginosa
Geller et al. Efficiency of pulmonary administration of tobramycin solution for inhalation in cystic fibrosis using an improved drug delivery system
US20070020330A1 (en) Compositions comprising azelastine and methods of use thereof
US6702997B2 (en) Albuterol inhalation solution, system, kit and method for relieving symptoms of pediatric asthma
US20100152147A1 (en) Compositions Comprising Azelastine and Methods of Use Thereof
US6297227B1 (en) Methods and compositions for treating sinusitis, otitis media and other related disorders using antihistamines
Deterding et al. Phase 2 randomized safety and efficacy trial of nebulized denufosol tetrasodium in cystic fibrosis
US6083922A (en) Method and a tobramycin aerosol formulation for treatment prevention and containment of tuberculosis
JP2001520188A (en) Methods and materials for treating and preventing inflammation of mucosal tissue
Taylor et al. Ultrasonic nebulisers for pulmonary drug delivery

Legal Events

Date Code Title Description
AS Assignment

Owner name: SINUSPHARMACY.COM, INC., CALIFORNIA

Free format text: ASSIGNMENT OF ASSIGNORS INTEREST;ASSIGNORS:OSBAKKEN, ROBERT S.;HALE, MARY ANNE;LEIVO, FREDERICK T.;AND OTHERS;REEL/FRAME:013979/0144

Effective date: 20000616

AS Assignment

Owner name: NARYX PHARMA, INC., CALIFORNIA

Free format text: CHANGE OF NAME;ASSIGNOR:SINUSPHARMA, INC.;REEL/FRAME:017321/0768

Effective date: 20050317