WO2002019996A2

WO2002019996A2 - Prevention of acute sinusitis and sinus attack

Info

Publication number: WO2002019996A2
Application number: PCT/IB2001/001522
Authority: WO
Inventors: James T. Angello; Howard M. Druce
Original assignee: Warner Lambert Co LLC
Current assignee: Warner Lambert Co LLC
Priority date: 2000-09-08
Filing date: 2001-08-23
Publication date: 2002-03-14
Anticipated expiration: 2003-03-08
Also published as: JP2004508324A; AU2001279999A1; EP1317259A2; CA2419653A1; WO2002019996A3; MXPA03001437A; BR0113747A

Abstract

Adregnergic alpha agonists such as pseudoephedrine can be used to prevent sinusitus or sinus attack.

Description

PREVENTION OF ACUTE SINUSITIS AND SINUS ATTACK

SPECIFICATION

FIELD OF THE INVENTION This invention relates to the prevention of acute sinusitis and sinus attack, and more specifically to administering a pharmaceutically acceptable composition containing a decongestant in an amount effective and in a timeframe that is early in relation to the natural cycle of the condition such that acute sinusitis and/or sinus attack is prevented.

BACKGROUND OF THE INVENTION The paranasal sinuses are four pairs of bony cavities found symmetrically on either side of the midline of the human nose. The four paranasal sinuses are known as the maxillary, ethmoid, frontal and sphenoid sinuses.

The interior surfaces of each of the sinuses and the airways in general are covered with a mucosallining, which secretes mucus, a thick fluid that lubricates the walls of the nose and throat. The secreted mucus serves to protect the inner surfaces of the airways, including the sinuses, and to trap any small particulates that are suspended in inhaled air, preventing them from reaching the lower airways. In an adult, the glandular mucosal cells of the sinuses have been reported to produce between 1 and 2 liters of secretions in a 24 hour period. See Newton, "Sinusitis in Children and Adolescents," 24(4) Prim. Care 701 -17 (1996).

All of this fluid must drain from the sinuses through small bony channels, called ostia, which connect each of the sinuses with the interior of the nose. The fluid is propelled to the ostia in defined flows via the coordinated movement of thousands of microscopic cilia that project from the cells of the mucosa. Each ostium is approximately 1 to 3 mm in diameter and is several millimeters in length. See, e.g. Mellen et al., "Effects of Phenylpropanolamine on Ostial and Nasal Patency in Patients Treated for Chronic Maxillary Sinus" 101 Acta Otalaryngol. 494-500 (1986); Aust et al., "Experimental Studies of the Gas Exchange through the Ostium of the Maxillary Sinus," 79 Upsala J. Med. Sci. 177-86 (1974); and Willett et al., "Current Diagnosis and Management of Sinusitis," 9(1) J. Gen. Intern. Med. 38-45 (1994). The ostia are the only openings in the sinuses that allow the movement of fluid out of the sinuses and permit air exchange between the sinuses and the nose. The ostial inner surfaces are covered with the same mucosa that lines the sinuses and the airways. The three anterior sinuses (anterior ethmoid, maxillary, and frontal) all drain through ostia that terminate in a confined region of the nose, called the middle meatus. This collection of ostia and the nasal meatus is commonly referred to as the ostiomeatal (or osteomeatal) complex.

If the sinuses are obstructed for any reason, such as from the congestion present during a cold, normal drainage cannot occur and infection of the sinuses can result. Acute sinusitis is inflammation that is usually accompanied by a bacterial infection of the paranasal sinus mucosa that commonly lasts up to twenty-one days.

Chronic sinusitis is a condition characterized by persistence of postnasal or nasal drainage, nasal congestion with pressure, headaches, sinus infections and nasal polyps.

In a typical case of sinusitis, the mucosal tissue lining both the ostia and the sinus swells due to an upper respiratory tract infection (e.g., caused by a cold virus) or allergic rhinitis). This mucosal swelling leads to ostial closure. Once a sinus ostium is partially or completely closed, oxygen flow into the sinus cavity is inhibited. There is good agreement in the literature that the precipitating event for acute sinusitis is closure of the ostia that drains the affected paranasal sinus. See, e.g., Aust et al., supra; Willett et al., supra; Slavin, "Sinusitis -- Present State of the Art," 12(3) Allergy Proc. 163-5 (1991); Diaz et al., "Acute Sinusitis," 10(1) Semin. Respir. Infect. 14- 20 (1995); Drettner, "Pathophysiology of Paranasal Sinuses with Clinical Implications," 5(4) Clin Otolaryngol 277-84 (1980); Godley et al., "Chronic Sinusitis: An Update," 45(5) Am. Fam. Physician 2190-9 (1992); and Oppenheimer "Sinusitis. How to Recognize and Treat it," 91(5) Postgrad. Med. 281-6, 289-92 (1992). There is also good agreement in the literature that subsequent to ostial closure there is decreased oxygen in the affected sinus, which is regarded as the second leading contributor to acute sinusitis.

The low levels of oxygen cause ciliary movement and granulocyte (white blood cell) function to be impaired. The lack of coordinated movement of mucus and drainage through the ostium, along with ongoing mucus secretion (about 1 L/day or more), causes fluid levels to build up in the affected sinus, resulting in deep pain and pressure.

Over time, the mucus stagnates and in combination with the low oxygen levels provides an optimal environment for bacteria to grow. The stagnant mucus thickens, causing destruction of cilia and further impairment of muco-ciliary clearance. The resulting bacterial infection causes a second round of inflammation of sinus and ostial mucosa. This secondary mucosal thickening causes further obstruction and closure of the ostium. Since this terminal event leads right back to the beginning, this sequence is referred to as the "sinusitis cycle." This vicious cycle is unlikely to resolve spontaneously given the fact that the secondary bacterial infection causes more significant mucosal thickening than the initial inflammatory insult, which more significantly impairs sinus fluid drainage through the ostium as well as oxygen movement into the affected sinus.

Treatment of sinusitis is generally sought after symptoms have already surfaced.

Most remedies for the condition focus on drainage of the sinuses. Nasal decongestants (typically in the form of nasal spray or drops), saline nasal spray and other nasal moisturizers, and moist heat work to aid sinus drainage. In addition, physicians will usually prescribe an antibiotic that will kill the bacteria associated with the full-blown condition of sinusitis. Steam inhalation and warm compresses applied over the sinus area, analgesics, and anti-inflammatory agents also act to relieve discomfort. See Druce, "Adjuncts to Medical Management of Sinusitis," 103

Otolaryngol. Head Neck Surg. 880-883 (1990).

Adrenergic alpha agonists or sympathomimetic drugs, such as phenylpropanolamine and pseudoephedrine, have been shown to significantly increase the size of the maxillary ostium in patients suffering from acute maxillary sinusitis. See Melen et al., supra.

For more severe or chronic sinusitis, surgery is often necessary to return the nose and sinuses to normal function, particularly with patients who have undergone years of treatment and still suffer from sinus blockage, or to enlarge the sinuses of patients born with small sinuses and nasal passages. Maxillary sinusitis has also been generally treated with repeated antral lavages.

It would be preferable to avoid the need for such unpleasant and potentially harmful therapies by preventing sinusitis before it takes hold. For example, U.S. Patent No. 5,897,872 to Picciano discloses a method for preventing and/or treating sinusitis comprising administering to a patient a nasal moisturizing saline solution containing at least 0.001% iodine.

Despite the existence of the foregoing treatments for sinusitis, it would be desirable to provide an alternative method for preventing sinusitis and sinus attack before it occurs.

All references cited herein are incorporated herein by reference in their entireties.

SUMMARY OF THE INVENTION The present invention is directed to a method for preventing sinusitis or sinus attack in a human in need of such prevention by administering to said human a therapeutically effective amount of a adrenergic alpha agonist.

The present invention is also directed to a method of reducing the frequency of sinusitis or sinus attack in a human that is subject to sinusitis or sinus attack comprising administering to said human a therapeutically effective amount of a adrenergic alpha agonist.

The invention is further directed to a process of prophylatic treatment for the prevention of sinusitis or sinus attack comprising administering to a human susceptible to sinusitis or sinus attack an effective amount of a adrenergic alpha agonist. The adrenergic alpha agonist used in the present invention can be a member selected from the group consisting of pseudoephedrine, phenylpropanolamine, phenylephrine and ephedrine including the salts, enantiomers and racemic mixtures of these compounds. DETAILED DESCRIPTION OF PREFERRED EMBODIMENTS

The instant invention comprises administering at least one pharmaceutically acceptable agent (referred to sometimes hereinafter as the "primary active agent") in an amount effective to increase the size of the narrowed ostium, thereby directly counteracting the primary initiating step in sinusitis. This counteraction is two-fold. Not only is the path to mucus drainage made clear with a patent ostium which prevents the accumulation of fluid that supports bacterial growth, but so is the path to oxygen flow into the sinus which is needed to maintain normal ciliary and granulocyte function. A dramatic increase in the gas exchange ratio occurs as the diameter of the maxillary ostium increases. See Aust et al., supra. Likewise, the time for 90% gas exchange of a sinus cavity dramatically decreases as the diameter of the maxillary ostium increases.

In addition, the amount of decongestant effective in maintaining a patent ostium is proposed to be administered in a timeframe that precedes or is early in the natural cycle of the full-blown condition. Such early administration of decongestant therapy is a new and unique proposition for preventing sinusitis and/or sinus attack.

The primary active agent must be capable of dilating the ostia and/or preventing constriction of the ostia. Preferred examples of suitable agents include adrenergic alpha agonists or sympathomimetic drugs, such as pseudoephedrine, its salts, its enantiomers and/or racemic mixtures. Other suitable agents include, e.g., phenylpropanolamine, phenylephrine, and ephedrine and their respective salts, enantiomers and racemic mixtures. Pseudoephedrine and phenylpropanolamine have the additional advantage of improving nasal airflow in addition to ostial airflow. This additional effect increases the amount of oxygen that makes its way through the ostium into the affected sinus.

The primary active agent is provided in a pharmaceutically effective composition. The composition is preferably provided in a dosage form adapted for oral administration, but other forms, such as nasal dosage form, are also suitable.

The primary active agent is preferably provided in amounts varying from 15 - 240 mg /day in single or divided doses for pseudoephedrine as well as therapeutically equivalent doses for phenylpropanolamine, phenylephrine and ephedrine, including the salts, enantiomers and racemic mixtures of these compounds.

In addition to the primary active agent, oral dosage forms of the invention can include additional active agents, such as antihistamines, analgesics, non-steroidal and other anti-inflammatory drugs, expectorants, mucolytics, mucokinetic agents, etc. Typical adult dosages for such additional active agents are readily determined experimentally or through a variety of publications.

Examples of non-steroidal anti-inflammatory drugs that could be used in the present invention include such as aspirin, acetaminophen, ibuprofen, ketoprofen, diflunisal, fenoprofen calcium, naproxen, tolmetin sodium, indomethacin, and the like,

Examples of anti-tussives that could be used include benzonatate, caramiphen edisylate, menthol, dextromethorphan hydrobromide, chlophedianol hydrochloride, and the like,

Examples of anti-histamines that could be used include brompheniramine maleate, chlorpheniramine maleate, carbinoxamine maleate, clemastine fumarate, dexchlorpheniramine maleate, diphenhydramine hydrochloride, diphenylpyraline hydrochloride, azatadine meleate, diphenhydramine citrate, doxylamine succinate, promethazine hydrochloride, pyrilamine maleate, tripelennamine citrate, triprolidine hydrochloride, acrivastine, loratadine, brompheniramine, dexbrompheniramine, and the like, Examples of expectorants or mucolytics that could be used include guaifenesin, ipecac, potassium iodide, terpin hydrate, and the like,

Combinations useful in the methods according to the present invention might include pseudoephedrine or phenylpropanolamine and a mucolytic or mucokinetic agent such as carbocysteine. The active ingredients are combined with suitable pharmaceutical diluents, excipients or carriers (collectively referred to herein as "carrier" materials) suitably selected with respect to the intended form of administration, i.e., oral tablets, capsules, elixirs, syrups, etc. and consistent with conventional pharmaceutical practices. For instance, for oral administration in the form of tablets or capsules, the active drug components may be combined with any oral non-toxic pharmaceutically acceptable inert carrier such as lactose, starch, sucrose, cellulose, magnesium stearate, dicalcium phosphate, calcium sulfate, mannitol, ethyl alcohol (liquid forms) and the like. Moreover, when desired or necessary, suitable binders, lubricants, disintegrating agents and coloring agents can also be incorporated in the mixture. Suitable binders include starch, gelatin, natural sugars, corn sweeteners, natural and synthetic gums such as acacia, sodium alginate, carboxymethylcellulose, polyethylene glycol and waxes. Among the lubricants that may be mentioned for use in these dosage forms, boric acid, sodium benzoate, sodium acetate, sodium chloride, etc. Disintegrators include, without limitation, starch, methylcellulose, agar, bentonite, guar gum, etc. Sweetening and flavoring agents and preservatives can also be included where appropriate.

Additionally, the compositions of the present invention may be formulated in sustained release form to provide the rate controlled release of any one or more of the 5 components to optimize the therapeutic effects, while minimizing undesirable side effects. Suitable dosage forms for sustained release include layered tablets containing layers of varying disintegration rates or controlled release polymeric matrices impregnated with the active components and shaped in tablet form or capsules containing such impregnated or encapsulated porous polymeric matrices. o Prophylactic compositions of the invention possess the ability to counteract the initial formation of the sinusitis cycle, provided that the composition is administered early enough (i.e., before the sinusitis cycle has progressed beyond the two initial steps of ostial closure and poor sinus ventilation for a sufficient time period that would allow progression to the subsequent steps of the sinusitis cycle). The compositions can be 5 administered as early as the first sign of sinus pressure, or even before any symptoms are presented (particularly for anticipated allergic reactions, early stages of cold and flu and the like). Interestingly, the inventors are not aware of any studies in which oral decongestants have been studied for their ability to prevent the sinusitis cycle from initiation. Instead, oral decongestants have been studied only for their ability to improve o the resolution of acute sinusitis once it is established.

The invention is not limited to the prevention of sinusitis, but also is effective to prevent sinus attack. Sinus attack differs from acute sinusitis in that patients experience the symptoms of sinus pain and pressure found in acute sinusitis but without an actual bacterial infection in the sinuses. Accordingly, there is no purulent discharge from the affected ostia or the nose.

The invention will be illustrated in more detail with reference to the following Examples, but it should be understood that the present invention is not deemed to be limited thereto.

An example of this usage would be the use of a sustained release 120 mg pseudoephedrine tablet taken on a regular basis at times when a patient is especially susceptible to develop sinus infections. Patient AB is prone to develop sinus infections 3-4 times during the winter months. Her symptoms are similar for each episode. The first sign is a feeling of pressure over the maxillary sinuses (in the cheek area of the face). This develops over a period of several hours to frank pain in the same area associated with obstruction of the nasal passages. If left untreated, a sinus infection where nasal discharge increases, ensues. At this stage, an antibiotic course is needed to resolve the symptoms. Advising this patient to start using the medication on a regular basis prior to any symptoms during the winter months led to a reduction in the number of frank sinus infections and need for antibiotic courses.

While the invention has been described in detail and with reference to specific examples thereof, it will be apparent to one skilled in the art that various changes and modifications can be made therein without departing from the spirit and scope thereof.

Claims

CLAIMS WHAT IS CLAIMED IS:

1. A method for preventing sinusitis or sinus attack in a human in need of such prevention comprising administering to said human a therapeutically effective amount of a adrenergic alpha agonist.

2. The method of claim 1, wherein said adrenergic alpha agonist is a member selected from the group consisting of pseudoephedrine, phenylpropanolamine, phenylephrine and ephedrine including the salts, enantiomers and racemic mixtures of these compounds.

3. A method of reducing the frequency of sinusitis or sinus attack in a human that is subject to sinusitis or sinus attack comprising administering to said human a therapeutically effective amount of a adrenergic alpha agonist.

4. The method of claim 3, wherein said adrenergic alpha agonist is a member selected from the group consisting of pseudoephedrine, phenylpropanolamine, phenylephrine and ephedrine including the salts, enantiomers and racemic mixtures of these compounds.

5. A process of prophylatic treatment for the prevention of sinusitis or sinus attack comprising administering to a human susceptible to sinusitis or sinus attack an effective amount of an adrenergic alpha agonist.

6. The method of claim 5, wherein said adrenergic alpha agonist is a member selected from the group consisting of pseudoephedrine, phenylpropanolamine, phenylephrine and ephedrine including the salts, enantiomers and racemic mixtures of these compounds.