WO2012119261A1

WO2012119261A1 - Enhanced artificial mucus composition comprising hyaluronan for the treatment of rhinitis

Info

Publication number: WO2012119261A1
Application number: PCT/CA2012/050146
Authority: WO
Inventors: Wesley Mark DOMAREKI; Ilan HOFMANN
Original assignee: Biocia Inc.
Priority date: 2011-03-10
Filing date: 2012-03-12
Publication date: 2012-09-13

Abstract

A composition for use in the treatment of rhinitis and sinus or nasal disorders which comprises at least one hydrophillic biologically compatible compound, such as hyaluronan. The composition has an optimized rheological profile.

Description

ENHANCED ARTIFICIAL MUCUS COMPOSITION COMPRISING

HYALURONAN FOR THE TREATMENT OF RHINITIS

CROSS-REFERENCE TO RELATED APPLICATIONS AND DOCUMENTS

[0001] This application claims priority from U.S. provisional patent application 61/451 ,585 filed on March 10, 201 1 , the content of which is incorporated by reference in its entirety.

TECHNICAL FIELD

[0002] The present application generally relates to a composition for the prevention and treatment of nasal and sinus conditions related to discomfort, bleeding, excessive dryness and adverse physiological factors including disease.

BACKGROUND ART

[0003] Rhinitis is the medical term describing irritation and inflammation of some internal areas of the nose. The primary symptom of rhinitis is nasal dripping. It is caused by chronic or acute inflammation of the mucous membrane of the nose due to viruses, bacteria, surgery, trauma, pharmaceutical treatments, oxygen therapy or irritants. The inflammation results in the generation of excessive amounts of mucus, commonly producing the aforementioned runny nose, as well as nasal congestion and post-nasal drip.

[0004] Rhinitis has also been found to adversely affect more than just the nose, throat, and eyes. It has been associated with sleeping problems, ear conditions, and even learning problems (King and Rubin, Rheology of airway mucus: Relationship with clearance function; Chapter 7 of: Takishima T, Shimura S, eds. Airway Secretion: Physiological Bases for the Control of Mucus Hypersecretion (Lung Biology in Health and Disease Series) New York: Marcel Dekker, 1994, 283-314). Rhinitis is caused by an increase in histamine, which is often triggered by airborne allergens. These allergens may affect an individual's nose, throat, or eyes and cause an increase in fluid or mucus production within these areas.

[0005] Rhinitis is categorized into three types: (i) infective rhinitis includes acute and chronic bacterial infections; (ii) non-allergic (vasomotor) rhinitis which includes autonomic, hormonal, drug-induced, atrophic, and gustatory rhinitis, as well as rhinitis medicamentosa; and (iii) allergic rhinitis, the reaction triggered by pollen, mold, animal dander, dust and other similar inhaled allergens.

[0006] Airway mucus derives from the goblet cells of the epithelial surface layer and the mucous cells of the submucosal glands. The mucous secretion is a non-homogeneous, viscoelastic fluid containing glycoproteins, proteins, and lipids in a watery matrix. The mucus along with serous fluid forms the airway surface fluid (ASF) that provides a protective milieu for the airways. The composition and physical characteristics of ASF allow for normal ciliary activity and airway protection. When disruption of normal secretory or mucocilliary clearance processes occurs, respiratory secretions can accumulate and impair pulmonary function, reduce lung defenses and increase the risk for infection and possibly neoplasia.

[0007] The viscoelasticity of mucus is important for its interaction with the cilia which directly effects mucocilliary clearance. Mucus with inadequate viscosity will be runny, and is likely to either drip out of the nose through the nostrils or run down the throat. Such runny mucus will also be less able to effectively act as a filter and trap airborne particles and infectious agents. Also, the beating cilia will be unable to move mucus which does not have adequate elasticity and/or viscosity. Similarly, if the mucus is too viscous, the beating cilia will be unable to move it, and the mucus will tend to clog the nasal tract, which can make breathing difficult, whilst also being extremely uncomfortable and difficult to breathe and or sleep. Such thick mucus may also be less efficient in absorbing and trapping particles and infectious agents.

[0008] Mucus factors affecting the rate of mucocilliary transport clearance are the mucus depth and mucus viscoelastic properties (King and Rubin, Rheology of airway mucus: Relationship with clearance function; Chapter 7 of: Takishima T, Shimura S, eds. Airway Secretion: Physiological Bases for the Control of Mucus Hypersecretion (Lung Biology in Health and Disease Series) New York: Marcel Dekker, 1994, 283-314; King M. Mucus, mucociliary clearance and coughing. In: Bates D V. Respiratory Function in Disease, 3rd ed. Philadelphia: Saunders, 1989: 69-78). When the mucus layer is too thick, and clearance by the cilia is hindered, clearance by coughing takes over. Mucus needs to be both viscous and elastic. The elasticity of mucus is important for clearance by cilia because it efficiently transmits the momentum of the cilia during their forward stroke without energy loss. The increased viscosity of mucus results in energy loss, but it is necessary so that mucus can be displaced and either expectorated or swallowed. A Theological balance between these factors must be maintained for optimal clearance.

[0009] Current treatments for rhinitis and related mucosal disorders address symptoms and primarily attempt to restore moisture to the affected area.

[0010] U.S. patent No. 5,376,365 describes a method alleviating dry nose by administering a composition which consist essentially of a high-viscosity isotonic mixture, in gel form having non-Newtonian rheological properties, of an humectant in the form of an isotonic amount of glycerin or a polyalkylene glycol, and 0.2-1 .0 weight % of a physiologically acceptable anionic polymer having a molecular weight of 500,000 to 5 million, wherein the composition contains less than 1 .5 mM of any inorganic salt.

[0011] International application publication No. WO 2006/040596 teaches a dry powder natural mucus enhancer (for administration in the nasal tract) comprising cellulose, and in particular hyroxypropylmethylcellulose (HPMC). It is suggested that administration of HPMC to the nasal cavity is capable of enhancing natural mucus while at the same time delivering therapeutic agents. It is suggested that compositions comprising certain grades of HPMC are capable of controlling the humidity in the nasal tract, (and gel forming when they are administered to the nasal tract), and are thus useful in the treatment and/or prevention of certain allergic conditions, such as allergic rhinitis, asthma and atopic eczema, of infections caused by inhaled infectious agents, such as bacteria and viruses, and of medical conditions associated with poor or abnormal natural mucus production. Further to this, the use of these grades of powdered cellulose in compositions for intra-nasal administration avoids the disadvantages associated with other intranasal applied compositions, such as the drying out of the nasal mucosa and the associated discomfort and irritation. The authors suggest that mucocilliary clearance can be normalized (that is, can be adjusted to a normal rate) by administering compositions comprising HMPCs which are capable of controlling the humidity in the nasal tract.

[0012] U.S. patent No. 6,641 ,799 teaches a hypertonic, alkaline nasal spray that avoids the use of vasoconstrictors and aids in the decongesting and moisturizing of the nose through osmotic activity, thinning and decreasing the viscosity of mucus, and increasing ciliary function. One component of the composition is a ciliary stimulant in order to keep the nasal passages clear of mucus. It is noted that if cilia function is subnormal, mucus will build up and contribute to congestion of the nasal passages. The basis of this composition is a saline solution. Another aspect described therein is the increase of the moisture and lubrication inside the nose as the inside of the nose can become irritated and dry due to natural forces or in response to medications. Some people naturally have a dry nose which can lead to cracking and scaling within the nose. The composition described in U.S. patent No. 6,641 ,799 addresses these issues by including glycerin as a moisturizer and lubricant. The glycerin also aids in achieving the hypertonic nature of the composition. Preferably the U.S. P. grade of glycerin is 99.5%.

[0013] U.S. application publication No. 2008/0058421 describes a biologically active composition for cleaning and disinfecting a nasal tract and a sinus cavity, comprising one or more organic acidifying agents, one or more inorganic acidifying agents, one or more anionic surface-active agents, and one or more solubilizing agents. The organic acidifying agents include an acid selected from the group consisting of adipic acid, ascorbic acid, benzoic acid, citric acid, dehydroacetic acid, erythorbic acid, fumaric acid, glutaric acid, gluconic acid, hyaluronic acid, hydroxyacetic acid, lactic acid, malic acid, succinic acid, tannic acid, tartaric acid, pimelic acid, suberic acid, azelaic acid, sebacic acid, carboxylic acid polymers, homo- or hetero-polymerized carboxylic acid such as poly lactic acid, polylactic glycolic acid, and mixtures thereof. Soothing agents such as eucalyptol can be included

[0014] There remains a need to be provided with a highly effective composition which addresses more than the symptoms of mucosal disorders and conditions.

SUMMARY

[0015] In accordance with the present invention there is now provided a therapeutic composition for use in the treatment of rhinitis and related sinus/nasal disorders which comprises one or more biologically compatible compounds which together have a calibrated rheological profile which optimizes the composition's pseudoplasticity, elasticity and viscosity in order to increase mucocilliary transport clearance and nasal ciliary function of the composition when administered to nasal and/or sinus regions of an animal.

[0016] It is also provided a method of treating rhinitis and sinus/nasal disorders and increasing post-operative nasal and sinus health in a patient which comprises administering to the nasal or sinus regions of the patient a therapeutically effective amount of one more biologically compatible compounds which together have a rheological profile which optimizes said composition's pseudoplasticity, elasticity and viscosity in order to increase nasal ciliary function and mucocilliary transport clearance.

[0017] It is further provided a composition for use in the treatment of rhinitis and sinus/nasal disorders which comprises at least one hydrophilic biologically compatible compound and a carrier, the composition having an optimized rheological profile.

[0018] In an embodiment, the at least one hydrophilic biologically compatible compound is lipophilic. [0019] In another embodiment, the at least one hydrophilic biologically compatible compound is a glycosaminoglycan, a physiological salt thereof or a derivative thereof.

[0020] The glycosaminoglycan can be a hyaluronan, a physiological salt thereof or a derivate thereof.

[0021] In another embodiment, the at least one hydrophilic biologically compatible compound is a polymer consisting of hyaluronic acid or a hyaluronate salt having a molecular weight of at least 1 .2 million Da.

[0022] Alternatively, the polymer has a molecular weight from 1 .2 million to 7 million Daltons.

[0023] In a further embodiment, the at least one hydrophilic biologically compatible compound is a cellulose derivative.

[0024] The cellulose derivative can be Carboxymethylcellulose, Hydroxyethyl cellulose, Hydroxypropyl methylcellulose, Methylcellulose, Dextran , Gelatin, Polyols liquid, Polyethylene glycol, Polyethylene glycol , Polysorbate , Propylene glycol, Polyvinyl alcohol, or Povidone.

[0025] In a further embodiment, the composition further comprises hydrophobic and lipophilic demulcent glycerin.

[0026] In an embodiment, the composition comprises a hyaluronan and glycerin.

[0027] In an additional embodiment, the ratio of hyaluronan to glycerin is by weight between 15:1 to 1 :20; or the ratio of hyaluronan to glycerin is by weight between 1 :2 to 2:1 .

[0028] In an embodiment, the composition has a dynamic elastic modulus of G' (Pa) 0.5 @ 10 Hz.

[0029] In another embodiment, the composition further has a dynamic viscous modulus G" (Pa) 0.8 @ 2 Hz. [0030] In another embodiment, the composition has an intrinsic viscosity of at least 10 cP.

[0031] The composition can also comprise at least one soothing agent, one anti-inflammatory agent, one anti-microbial agent, one anti-neoplastic agent, one decongestant or one anti-histamine agent.

[0032] The anti-microbial, antibiotic, anti-fungal, antiviral agent can be an analgesic agent, an emollient, or a disinfecting agent.

[0033] In an embodiment, the composition facilitates and increase mucocilliary transport clearance (MTC) and nasal ciliary function.

[0034] It is also provided a method of treating rhinitis and sinus disorders in a patient which comprises administering to the nasal or sinus regions of the patient a therapeutically effective amount of a composition as defined herein.

[0035] It is further disclosed a method of enhancing patient comfort post- nasal/sinus surgery which comprises administering to the nasal or sinus regions of the patient a therapeutically effective amount of a composition as defined herein.

[0036] It is additionally provided the use of a composition as defined herein for treating rhinitis and sinus disorders.

[0037] It is also provided the use of a composition as defined herein in the manufacture of a medicament for treating rhinitis and sinus disorders.

DETAILED DESCRIPTION

[0038] It is provided a composition which is the first formulation that addresses the critical problem of compromised mucocilliary transport clearance and nasal ciliary function. The composition is specifically Theologically calibrated by design to increase and optimize mucocilliary transport clearance and nasal ciliary function and to maintain its residence time in situ for long acting effects. It is the first and only artificial mucus replacement and stabilizer/natural mucus enhancer which can be used to treat patients with rhinitis and other nasal/sinus conditions such as excessive dryness or bleeding where the function of delicate internal tissue is compromised and/or impeded due to a lack of mucus, compromised quality of mucus, dryness, disease, drugs, oxygen therapy or noxious environmental conditions. More specifically, the artificial mucus replacement/stabilizer enhancement described herein is composed of compounds of natural origin to insure that it is biocompatible, safe and Theologically ideal to optimize the proper function of nasal cilia and other internal nasal/sinus tissue which is vital to proper health and elimination of bacteria, virus, noxious contaminants and nasal healing.

[0039] One particular feature of the composition described herein is the unique rheologically-specified range of pseudoplasticity, elasticity and viscosity which allow the delicate function and "beating" of nasal cilia which can become impeded by using frequent washes and/or moisturizers or thick petrolatum- based gels plus other negative factors including excessive dryness, oxygen therapy, use of various drug therapy and physiological disorders. It is designed to provide lasting relief with fewer applications compared to commonly used washes or moisturizers.

[0040] The composition described herein is intended to be used as a substitute for frequently used moisturizing agents and saline-based solutions which may irritate delicate nasal tissue and cilia with repeated use, thereby exacerbating pre-existing conditions. The health and proper functioning of nasal cilia is critical and is not adequately addressed in currently available "moisturizing" therapies which generally simply "wet" affected tissue for temporary periods of duration. The composition described herein, in contrast, serves a dual function as an artificial mucus replacement/stabilizer and an enhancer/restorer of healthy ciliary function.

[0041] Also described is the use of the composition described herein to mitigate the effects of noxious environmental factors including pollution and dryness and also temporary or chronic bleeding, especially in arid climates including desert and mountain locations as well as artificially heated and/or cooled buildings, hospitals, nursing homes and general residential dwellings. It is thus provided a Theologically calibrated mucus replacement/stabilizer composition of natural origin which, when administered to an animal with nasal and/or sinus disorders or conditions such as but not limited to: deviated septum, external nasal deformity, turbinate hypertrophy, nasal valve collapse, inflammation of the mucous membrane lining the nose other anatomical problems associated with turbinate and maxillary sinus cavities, excessive dryness due to colds, flu or medications, oxygen, etc., bleeding during and following surgery or post-surgery treatment; optimizes mucocilliary transport clearance and ciliary function.

[0042] As used herein, "animal" means any member of the animal kingdom, including all mammals and most preferably humans.

[0043] As used herein "mucocilliary transport clearance", or MTC, refers to the process of and/or time it takes for natural elimination of contaminants from the nasal and sinus regions. Such clearance is an important physiological function of nasal cavity that helps in protecting the lower respiratory tract from undesirable organic and inorganic matter including the microorganisms. Nasal mucocilliary transport efficiency depends primarily on two factors: the ciliary beating of the epithelial cells and the physical properties of mucus secreted by erous and mucous glands.

[0044] Nasal hair, nose hair or olfactory cilia are small hair-like cells found in the nose, located mostly near the nostrils. The purpose of these cells is to act as a filter, keeping dust and dirt out of the nasal passages. They also draw liquid mucus up from the epithelium by capillary action. In this way, they help to maintain humidity in the air passages and stop them from drying out. In addition, the hairs (cilia) trap moisture as air is breathed out. The evaporation of trapped moisture on the hairs increases the humidity of air as it is breathed in.

[0045] Cilia are in constant motion, with healthy cilia beating up to 16 times a second. This movement pushes mucus back in towards the oropharynx where it can be either swallowed or ejected. The cilia in the ear canal remove cerumen (and other detritus) in much the same way. Exposure to cold is thought to slow the movement of the cilia, leading to the build-up of mucus; pollutants and allergens are thought to have similar effect. Similarly, other nasal and sinus disorders and conditions can later and compromise the critical function of cilia. Loss of nasal cilia due to alopecia areata (a form of hair loss that causes bald spots) has been linked to increased severity of asthma, seasonal allergy and atopic dermatitis (skin irritation caused by hereditary hyper-sensitivity). Smoking is also believed to upset ciliary function.

[0046] As used herein, the terms "effective" or "therapeutically effective", are intended to qualify the amount of the composition administered to an animal, in particular a human, in order to elicit a biological or medical response of a tissue, system, animal or mammal that is being sought by the person administering the composition and which amount achieves one or more of the following goals:

• treating and reducing symptoms and conditions associated with rhinitis;

• treating and reducing symptoms and conditions associated with noxious environmental conditions including dryness, sick building syndrome, pollution, airborne irritants such as pollen, animal dander, mites, allergens of various sources and dust, and artificial heating and or cooling of buildings where people spend extended periods of time;

• treating and reducing symptoms associated with nose bleeding;

• improving post-operative nasal and sinus functionality;

• providing an artificial mucus replacement/stabilizer;

• enhancing MTC;

• enhancing and/or restoring ciliary function;

• augmenting mucus quantity; and

• augmenting mucus quality.

[0047] The present description discloses a composition for the treatment of rhinitis and other related sinus/nasal disorders which comprises one more biologically compatible compounds which together have a rheological profile which optimizes the composition's pseudoplasticity, elasticity and viscosity in order to facilitate nasal ciliary function and mucocilliary transport clearance (MTC) of the composition when administered to nasal or sinus regions of an animal.

[0048] As used herein, an optimized rheological profile the property of the composition to enhance or mimic mucus rheology and in turn optimize mucocilliary transport clearance (MTC) and nasal ciliary function due to exhibiting superior elasticity (C) and viscosity (G") and water-imbibing characteristics compared to other commonly marketed nasal solutions.

[0049] In order to achieve the desired rheological profile, the composition so created, in an embodiment, has an elasticity of at least G' (Pa) 0.5 @ 10 Hz and a viscosity of at least G" (Pa) 0.8 @ 2 Hz.

[0050] In another embodiment, the ingredients comprised in the composition are used in combination or alone with cross-linked hyaluronan in any form as derived from any source and any cross-linking process or method.

[0051] With these minimum rheological parameters relating to elasticity and viscosity, ciliary function is protected and optimized under periodic adverse physiological and/or environmental conditions. The objective is simply to enable the delicate cilia to properly function by providing a 'theologically calibrated" mucus environment compared to abnormal mucus which is often associated with dryness, bleeding, disease, drugs or devices. Abnormal mucus can mechanically, pharmacologically, and physiologically impede proper ciliary function due to inadequate or abnormal mucus which may be dry, callous, runny or otherwise compromised so as to prevent proper ciliary function which requires vibrant innervations of the ever-delicate cilia in an ideal rheological environment of healthy mucus.

[0052] Preferably, in order to achieve the desired rheological profile, the composition comprises at least one biologically compatible, highly hydrophilic compound and at least one biologically compatible compound which are both hydrophilic and lipophilic. More preferably, the composition comprises at least one biologically compatible, high molecular weight, highly hydrophilic compound and at least one biologically compatible low molecular weight mucoadhesive compound which is both hydrophilic and lipophilic.

[0053] The high molecular weight, highly hydrophilic compound can be high molecular weight acidic glycosaminoglycans and their physiological salts and derivatives thereof. The compound can be a polymer consisting of hyaluronan (HA) and physiological salts and derivates thereof. Preferably, the ideal nasal profile can be comprised of either soluble and/or insoluble, crosslinked and/or non-crosslinked hyaluronan to achieve an optimal rheological profile for use in the nose and/or sinus relative to the indications discussed herein.

[0054] Naturally occurring hyaluronan (hyaluronic acid or hyaluronate salts or HA) is a glycosaminoglycan with a repeating disaccharide unit of N- acetylglucosamine and glucuronic acid with an average molecular weight of 5-6 million Da but molecular weight can be enhanced through partial or complete crosslinking methods so as to reach a molecular weight of up to 25 million Da. It has been used for many years topically as an eye drop because of its therapeutic benefits which provide lasting moisturizing, lubrication and protection of corneal tissue of the eye, especially for the treatment of dry eye conditions from natural causes as a result of refractive or other surgical procedures. It has also been used in the eye during surgery to maintain the anatomical shape of the eye and in the joint to restore vital physical properties including high elasticity and viscosity as a medical device or drug to restore function due to degradation of the rheological profile of naturally occurring fluid within the eye and joint.

[0055] HA is composed of only two molecules: D-glucuronic acid and 2- acetamido-2-deoxy-D-glucose, which repeats for up to 25,000 times. In solution, HA does not maintain a rigid tertiary structure, but instead, typically has a random coil configuration, familiar to most polymer scientists and engineers. The coil may be held semi-rigidly in its configuration by hydrogen bonds, but these are weak and can easily be disrupted. The polymer typically exists at physiological pH, at which the carboxyl groups are dissociated, conferring a polyanionic character to the molecule. In other words, for every disaccharide unit, there is a strong negative charge.

[0056] HA is a critical component of connective tissue and typically exists in a state of strong association with proteins and other glycosoaminoglycans (GAGs) such as Heparin and Chondroitin Sulfate.

[0057] Despite the fact that the chemical identity of the molecule never changes, (i.e., it always contains the same linear repeating disaccharide units), the number of repeating units can vary greatly by source or as a result of processing, purification or from environmental conditions such as heat, light, radiation etc... Table 1 shows the molecular weight of hyaluronic acid isolated from various sources.

[0058]

Table 1

Molecular weight of hyaluronic acid isolated from various sources

Source Molecular Weight, Daltons

Human umbilical cord 3.4 x 10 ⁶

Bovine vitreous humor 7.7 χ 10 -1 .7 χ 10 ⁶

Bovine synovial fluid 14 x 1 0 ⁶

Human synovial fluid (Normal) 6 x 10 ⁶

Human synovial fluid (Rheumatoid) 2.7-2.5 χ 10 ⁶

Rooster Comb 1 .2 x 10 ⁶

Streptococcal cultures 0.93 χ 1 0 ⁶

[0059] HA have very unique properties when it is in its solution form. In particular, at very low concentrations in water (<1 %) viscosities can exceed 50,000 cps, and the solution has significant non-Newtonian behavior in its elasticity, shear thinning, and cohesiveness. [0060] In order to achieve the desired Theological profile, the composition comprises HA which has a molecular weight of at least 1 .2 million to 7 million Daltons in its native form and most preferably from 1 .2 million to 3 million Daltons in the non-crosslinked form and up to 25 million if a combination of either soluble and/or insoluble crosslinked hyaluronan is blended into a given formulation to facilitate and optimize MTC (mucocilliary transport clearance).

[0061] Preferably, the composition comprises sterile HA, which is formulated in its sodium, potassium, calcium, zinc or other salt forms with a concentration of the HA varying from 0.05 to 3.0 percent and with a molecular weight ranging from 1 .2 million Daltons to 7 million Daltons in its native form and up to 25 million Daltons in its cross-linked form.

[0062] It is preferred to use glycerin as a co-ingredient with HA with its character as a hydrophobic and lipophilic demulcent to replace and/or enhance compromised mucus in rhinitis patients or patients with other nasal/sinus conditions. By inclusion of glycerin, or functionally similar compounds lipids are attracted and bound, forming natural healthy mucus.

[0063] Key features of the composition described herein are:

-Long residence time compared to other nasal solutions (i.e. saline solution)

o Mucoadhesive:

• due to LMW (low molecular weight) glycerin or functionally similar compound

o Pseudoplastic:

• Not rapidly eliminated (i.e. blowing the nose or swallowing)

o Elastic:

• Fortifies watery mucus to minimize runny noise

• Easily delivered into nasal/sinus cavity

o Viscous:

• Thickens and fortifies watery mucus (runny nose) • High molecular weight Hyaluronan + Glycerin (or functionally similar compounds) provide a stabilized water layer on inner tissue surfaces to prevent desiccation)

-Exhibits ideal rheological properties to optimize MTC

o Pseudoplastic

• High molecular weight Hyaluronan, or a functionally similar compound (allows delicate undulating cilia to function at low shear)

o Elastic

• High molecular weight Hyaluronan, or a functionally similar compound - (allows delicate undulating cilia to function at low shear)

o Viscous

• High molecular weight Hyaluronan, or a functionally similar compound

o provides a protective "cilia water barrier" to inner tissue surfaces

o prevents crusting, scaling and bleeding of tissue surfaces

-Does not dry out nasal tissue with repeated use compared to repeatedse of simple saline solutions

-Contains safe and well-documented ingredients of a natural origin:

^■ Glycerin, or a functionally similar compound, which exhibits both hydrophilic and lipophilic properties.

^■ Hyaluronan which is a natural cellular constituent of the intercellular matrix and other body fluids (vitreous, aqueous, synovial fluids, etc.) or a functionally similar compound

^■ Other optional constituents including but not limited to soothing agents (for example: eucalyptus, menthol, aloe vera, mentholatum, sesame oil, heart leaf, sida, oregano, ginger, capsaicin, tea-tree or mint for comfort), steroidal and non-steroidal anti-inflammatory agents, decongestants (such as but not limited to Oxymetazoline, phenylephrine etc.), antihistamines (such as but not limited to: azelastin, olopatadine, etc .. ) anti-neoplastic agents (such as but not limited to: alkylating agents, antimetabolites, anthracyclines, plant alkaloids, topoisomerase, etc .. ) antimicrobial/antibiotic agents including but not limited to zinc and/or silver, analgesics, disinfecting agents and as a protein and non-protein drug and vaccine delivery agent. -Sterile for safety.

-Ideal for use following nasal, functional endoscopic sinus surgery also referred to as and trans-nasal sinus surgery to protect delicate tissue, minimize post-operative bleeding, and prevent scaling or unwanted tissue adhesions while allowing for optimal function of ciliary function, especially during the immediate post-operative period.

[0064] Phosphate or other buffering agents are advantageously incorporated in the composition to maintain a pH varying from 5.0 to 8.0. Sodium chloride or other salts are also advantageously incorporated in the composition, which will maintain osmolality ranging from 250 to 370 mOsmol/kg.

[0065] In an embodiment, the ratio of HA or derivative thereof to glycerin is (by weight) between 15: 1 to 1 :20, more preferably in the range of 1 :2 to 2: 1 .

[0066] It may also be safely used as a nasal spray or nasal gel with preservatives including but not limited to benzalkonium chloride, etc. or without preservatives depending on desired shelf life and other packaging considerations.

[0067] The composition described herein may be delivered in a pumping device for direct application to the nostril(s) to optimize ease of use and hygienic application without direct contact with the affected area. Even though this product can also be delivered in a tube-type configuration or a container, the use of a pumping device offers superior hygienic coverage of the affected area and ease of use without the need to directly contact the affected area.

[0068] As may be appreciated, hyaluronan and/or its derivatives may be used as a nasal spray or nasal gel product(s) for the treatment of dry nasal conditions by moisturizing, protecting and lubricating nasal tissue (cilia) for a longer period of time compared to commonly used saline solutions or commonly used nasal demulcents. Such is achieved when HA and/or its derivatives are delivered into the nasal passages, because HA imbibes water to a higher degree compared to other commonly used biomaterials such as but not limited to Cellulose derivatives such as but not limited to Carboxymethylcellulose, Hydroxyethyl cellulose, Hydroxypropyl methylcellulose, Methylcellulose and Dextran, Gelatin, Polyols, liquid: Glycerin, Polyethylene glycol , Polyethylene glycol, Polysorbate, Propylene glycol, Polyvinyl alcohol, Povidone, etc.

[0069] In an aspect of the present description, the composition attains the desired rheological effects by the combination of Hyaluronan and glycerin:

-The use of glycerin as a combined hydrophobic and lipophilic demulcent to replace and/or enhance compromised mucus in rhinitis patients or patients with other nasal/sinus conditions by attracting and binding lipids as a natural constituent of healthy mucus

-It does not contain the use of harmful preservatives which can irritate and harm delicate nasal/sinus tissue.

-The use of glycerin in ranges of 0.2% to 1 % as a mucoadhesive biomaterial for lasting residence time to allow for fewer applications compared to simple moisturizers, washes and/or drugs which are rapidly eliminated.

-Both Hyaluronan and glycerin components are formulated at in concentrations > 0.1 % but < 0.5% concentration.

-To avoid the use of hydrophobic petrolatum-based gels which are uncomfortable and difficult to apply and which interfere with the normal ciliary function. -To have a spray applicator that allows for safe and hygienic administration into the nose, sinus to minimize chance of contamination.

-Delivered sterile for use following surgery of the nose or sinus. -Bacterial endotoxins less than or equal to 0.51 lU/mg -pH range: 5.0-8.0

[0070] The purpose of the description is to provide a biocompatible nasal mucus replacement/stabilizer enhancement for rhinitis and other patient indications due to compromised nasal/sinus conditions. A form of the composition encompassed herein has the following features and benefits:

1 ) To be used as a prophylaxis against bacterial and viral infection and noxious environmental contaminants such as pollution, dust, smoke, contaminated air in vessels of mass transport including trains, buses, planes, etc., heating, air-conditioning in buildings or homes and use in iatrogenically induced conditions such as use of oxygen therapy and administration of allergy medications.

2) To restore the normal functioning of the nasal cilia in rhinitis patients and other nasal/sinus conditions to increase the normal elimination of noxious contaminants, bacteria, and virus by improving ciliary function and optimize nasal healing.

3) To provide lasting soothing relief both during the day and night hours when administration is difficult or impractical

4) To improve quality of sleep during night hours

5) To allow patients to live and work with fewer disruptions as a result of frequent applications compared to other nasal solutions, moisturizers, washes, drugs, etc...

6) To prevent cilia from being damaged and further compromised by the use of frequent washes, hydrophobic ointments and/or moisturizers due to the restoration of normal rheological properties when compared to nasal moisturizers and washes which are watery, to viscous or hydrophobic ointments which do not exhibit these properties.

7) To optimize, stabilize and enhance natural mucus by attracting lipids and water as a natural component of healthy mucus which can become degraded due to disease, infection and/or noxious environmental conditions. This effect is not found in other nasal moisturizers that do not exhibit this feature.

8) To provide soothing relief due to the use of a safe herbal components, such as eucalyptus, mint or menthol

9) To be clear and free from particulate matter

10) To be free from perfumes and odour other than the mild scent of eucalyptus, mint or menthol

1 1 ) To restore health without the use of active drugs which can be habit- forming and debilitating (as sometimes found in certain commonly- used nasal decongestants)

12) To allow for unlimited use without adverse effects or damage to delicate nasal tissues compared to frequent use of washes, moisturizers or drugs

[0071] This is achieved by administering to an animal, a non-toxic and therapeutically effective amount of a compound or composition as described herein.

[0072] The amount of the compounds within the composition which are required to achieve the desired effects will, of course, depend on a number of factors such as the particular compound chosen and the delivery vehicle.

[0073] The compositions described herein are preferably administered in amounts of between 20 μΙ_ and 500 μΙ_ per nostril. Preferably, the dose is between 100 μΙ_ to 200 μΙ_. [0074] Without limiting the generality of the foregoing, the composition of the present invention may be mixed with various carriers or adjuvants or excipients to assist in delivery and administration. In order to appreciate the various possible vehicles of the delivery of the composition, the following non-limiting examples are provided.

[0075] The present disclosure will be more readily understood by referring to the following examples which are given to illustrate embodiments rather than to limit its scope.

EXAMPLE I

Various formulations

Table 2

INGREDIENTS

Purified water

dibasic sodium phosphate

Polysorbate

Triglyceride soluble

Hyaluronan (native form or cross-linked)

Sodium chloride

Monobasic potassium phosphate

Eucalyptol

Benzalkonium chloride Table 3

INGREDIENTS

Purified water

Dibasic sodium phosphate

Glycerin

Hyaluronan (native form or cross-linked)

Sodium chloride

Monobasic potassium phosphate

Eucalyptol

Benzalkonium chloride

[0076] While the description has been described in connection with specific embodiments thereof, it will be understood that it is capable of further modifications and this application is intended to cover any variations, uses, or adaptations of the embodiments following, in general, the principles of the invention and including such departures from the present disclosure as come within known or customary practice within the art to which the invention pertains and as may be applied to the essential features hereinbefore set forth, and as follows in the scope of the appended claims.

Claims

WHAT IS CLAIMED IS:

1 . A composition for use in the treatment of rhinitis and sinus/nasal disorders which comprises at least one hydrophilic biologically compatible compound and a carrier, said composition having an optimized rheological profile.

2. The composition of claim 1 , wherein the at least one hydrophilic biologically compatible compound is lipophilic.

3. The composition of claim 1 , wherein the at least one hydrophilic biologically compatible compound is a glycosaminoglycan, a physiological salt thereof or a derivative thereof.

4. The composition of claim 3, wherein the glycosaminoglycan is a hyaluronan, a physiological salt thereof or a derivate thereof.

5. The composition of claim 1 , wherein the at least one hydrophilic biologically compatible compound is a polymer consisting of hyaluronic acid or a hyaluronate salt having a molecular weight of at least 1 .2 million Da.

6. The composition of claim 5, wherein the polymer has a molecular weight from 1 .2 million to 7 million Daltons.

7. The composition of claim 2, wherein the at least one hydrophilic biologically compatible compound is a cellulose derivative.

8. The composition of claim 7, wherein the cellulose derivative is Carboxymethylcellulose, Hydroxyethyl cellulose, Hydroxypropyl methylcellulose, Methylcellulose, Dextran , Gelatin, Polyols liquid, Polyethylene glycol , Polyethylene glycol , Polysorbate , Propylene glycol, Polyvinyl alcohol, or Povidone.

9. The composition of any one of claims 1 -8, further comprising hydrophobic and lipophilic demulcent glycerin.

10. The composition of claim 1 , comprising a hyaluronan and glycerin.

1 1 . The composition of claim 10, wherein the ratio of hyaluronan to glycerin is by weight between 15: 1 to 1 :20.

12. The composition of claim 10, wherein the ratio of hyaluronan to glycerin is by weight between 1 :2 to 2: 1 .

13. The composition of any one of claims 1 -12, said composition having a dynamic elastic modulus of G' (Pa) 0.5 @ 10 Hz.

14. The composition of any one of claims 1 -12, said composition having a dynamic viscous modulus G" (Pa) 0.8 @ 2 Hz.

15. The composition of any one of claims 1 -14, said composition having an intrinsic viscosity of at least 10 cP.

16. The composition of any one of claims 1 -15, additionally comprising at least one soothing agent, one anti-inflammatory agent, one antimicrobial agent, one anti-neoplastic agent, one decongestant or one anti-histamine agent.

17. The composition of claim 16, wherein the anti-microbial, antibiotic, antifungal, antiviral agent is an analgesic agent, an emollient, or a disinfecting agent.

18. The composition of any one of claims 1 -17, said composition facilitate and increase mucocilliary transport clearance (MTC) and nasal ciliary function.

19. A method of treating rhinitis and sinus disorders in a patient which comprises administering to the nasal or sinus regions of said patient a therapeutically effective amount of a composition as defined in any one of claims 1 -18.

20. A method of enhancing patient comfort post-nasal/sinus surgery which comprises administering to the nasal or sinus regions of said patient a therapeutically effective amount of a composition as defined in any one of claims 1 -18.

21 . Use of a composition as defined in any one of claims 1 -18 for treating rhinitis and sinus disorders.

22. Use of a composition as defined in any one of claims 1 -18 in the manufacture of a medicament for treating rhinitis and sinus disorders.