WO2006102438A2

WO2006102438A2 - Methods and compositions for irrigation of mucosal tissues

Info

Publication number: WO2006102438A2
Application number: PCT/US2006/010448
Authority: WO
Inventors: Robert D. Christensen; Diane Lambert
Original assignee: Ihc Intellectual Asset Management, Llc
Priority date: 2005-03-23
Filing date: 2006-03-23
Publication date: 2006-09-28
Also published as: WO2006102438A3

Abstract

Formulations for irrigating tissues and reducing mucosal infection with aqueous alkaline and alkaline earth salts with and without human albumin at an orally acceptable pH and methods for using the same are disclosed. The formulations and methods are also useful for preventing and treating iatrogenic infections, particularly in infants, relieving dry mouth, and lubricating tissues of patients receiving respiratory assistance.

Description

METHODS AND COMPOSITIONS FOR IRRIGATION OF MUCOSAL TISSUES

TECHNICAL FIELD The present invention relates to methods and compositions for irrigation of body tissues, the treatment of dry mouth, and lubrication of patients who are intubated with an endotracheal tube or receiving some form of mechanical ventilation or other assistance. The invention also relates to methods and formulations for preventing, treating, and reducing infections, including mucosal infections in patients, including infants.

BACKGROUND

Patients requiring intubation or other ventilation assistance for extended periods often suffer from a high rate of nosocomial infections (See Pediatr Infect Dis J. 1998 Jul;17(7):593-8). This tendency is particularly marked among small and ill neonates, patients with immune dysfunction, and patients requiring therapy that reduces innate immunity (such as cancer chemotherapy). Many infections in these groups of patients are caused by organisms of low virulence in healthy adults, such as Candida albicans and Staphylococcus epidermitis. The poor immunologic barrier function in the trachea, nose, and mouth, arising from the presence of an endotracheal tube, a nasal canula, other respiratory support equipment, or subject to nasal continuous positive airway pressure (CPAP) or invasive mechanical assistance, likely contributes to the high incidence of these infections. Normal human saliva, nasal secretions, and tracheal effluent have antimicrobial properties that inhibit colonization of the upper airway by Candida albicans and other infectious agents and protect the upper airway from infection.

Intensive care unit workers and caregivers periodically irrigate the endotracheal tube or other similar lumens of patients who require mechanical ventilation. This treatment is needed to prevent tracheal secretions from building up and occluding the lumen of the endotracheal tube and thereby impeding ventilation and oxygenation. Caregivers also periodically moisten the mucosal tissues of these patients, because the presence of an endotracheal tube prevents lip apposition and therefore results in a dry mouth. Similarly, patients on nasal CPAP or nasal canula oxygen require occasional irrigation of the nose to treat or prevent thick secretions from occluding the nasal passages.

Conventional practices in care facilities involve periodic irrigation with sterile 0.9% saline, dispensed from plastic, disposable "bullet tubes" of patients receiving ventilation assistance. These treatments are generally given by the respiratory therapist or the bed side nurse, as often as hourly or as infrequently as every 6 to 8 hours in accordance with local policy and practice, and according to need, as judged by the volume and viscosity of the secretions in the patient's trachea, mouth, and nose. Salivary and tracheal secretions include an important component called

"LL37," a 37 amino acid peptide (MoI Cell 2:397-403). LL37 also known as human cathelicidin, has widespread antimicrobial properties. LL37 and proteins like it reduce colonization of the airway by pathogenic microorganisms. Research reported by Welsh (AmJ. Respir.Cell Mol.Biol., 1999;20:872-879), teaches that the electrolyte composition of airway surface liquid (ASL) influences antimicrobial activity of innate host defense and proposes delivery of nonionic osmolytes to draw water to airway surface liquids.

SUMMARY OF THE INVENTION The present invention is directed to liquid formulations for irrigation and lubricating tissues including patient airways, which reduces mucosal infections and is effective in treating dry mouth. In another aspect, the liquid formulations do not impair the innate immunity of the upper airway, do not dispose the patient to airway infections, and also assist to prevent lumen occlusion.

Formulations and methods for periodic airway care and for relieving dry mouth are disclosed. In one embodiment, an aqueous mucosal tissue irrigant and lubricant includes less than about 0.3% sodium chloride. In another embodiment, the irrigant includes recombinant or purified albumin. In still another embodiment, the irrigant includes an aqueous solution of alkaline and alkaline earth metal salts. Optionally the anions of the salts are selected from one or more of chloride, phosphate and sulfate. The formulations exhibit sufficient lubricity to prevent or wash away mucosal buildup causing occlusion in and around respiratory equipment without deactivating the antimicrobial activity of innate host defense. In some embodiments the formulations are substantially free of any endogenous human proteases. In other embodiments, the formulations have endogenous human proteases. In embodiments with human albumin, the albumin may be recombinant albumin. In other embodiments with human albumin, the albumin may be purified albumin. In some embodiments, one or more optional therapeutically active agents are present such as an antifungal agent, an antiviral agent, an antibacterial agent, a corticosteroid and a lysozyme. In more specific embodiments, LL37 acts as a therapeutically agent.

The methods for reducing infections and for relieving dry mouth include contacting a tissue such as a mucosal tissue with an aqueous irrigant or lubricant of the formulations described. In some embodiments, the method includes periodic application of an irrigant formulation.

DETAILED DESCRIPTION OF THE INVENTION Definitions While the terminology used in this application is standard within the art, the following definitions of certain terms are provided to assure clarity.

Units, prefixes, and symbols may be denoted in their SI accepted form. Unless otherwise indicated, nucleic acids are written left to right in 5' to 3' orientation. Numeric ranges recited herein are inclusive of the numbers defining the range and include and are supportive of each integer within the defined range.

Amino acids may be referred to herein by either their commonly known three letter symbols or by the one-letter symbols recommended by the IUP AC-IUBMB Nomenclature Commission. Nucleotides, likewise, may be referred to by their commonly accepted single-letter codes. Unless otherwise noted, the terms "a" or "an" are to be construed as meaning "at least one of." The section headings used herein are for organizational purposes only and are not to be construed as limiting the subject matter described. All documents, or portions of documents, cited in this application, including but not limited to patents, patent applications, articles, books, and treatises, are hereby expressly incorporated by reference in their entirety for any purpose. In the case of any amino acid or nucleic sequence discrepancy within the application, the figures control. As used herein, the term "xerostomia" means a condition in which the salivary glands do not produce sufficient quantities of saliva and is more often referred to as "dry mouth." Xerostomia can be associated with various kinds of disorders, including Sjorgren's syndrome, a disorder characterized by a combination of dry eyes and dry mouth. Additional problems with mastication, swallowing (dysphagia), digestion, speech (dysphonia), and the like as well as inflammation, infection, ulceration and pain of the oral tissues arise from dry mouth. Xerostomia may arise from physiological causes (e.g., age, menopause, postoperative conditions, dehydration), as well as psychological causes (nervousness) and pharmacological causes (e.g., as a common side effect of many medications, including antihypertensives, diuretics, anti-arthritics and anti-depressants) or as a side effect of radiotherapy.

As used herein, the term "saliva" means the watery mixture of secretions from the salivary and oral mucous glands that lubricates chewed food, moistens the oral walls, and contains ptyalin. Ptyalin is a form of amylase in the saliva of humans and some animals that catalyzes the hydrolysis of starch into maltose and dextrin.

As used herein, the term "endogenous" means natively produced within an organism, tissue, or cell. Endogenous does not include recombinant or purified substances. The term "tissue" means an aggregation of morphologically similar cells and associated intercellular matter acting together to perform one or more specific functions in an organism's body. Examples of tissues include mucosal tissues and connective tissues.

The terms "mucosal tissue" or "mucosal tissues" means tissues found within the upper airways including the oral (mouth), sinus (nose), and throat including the larynx, esophagus, and trachea.

The term "infant" means a child including newborns, neonates as well as toddlers before the age of 5 years old.

The term "ionic strength" (I) means half of the total sum of the concentration (C₁) of every ionic species (i) in the solution times the square of its charge (Z₁); i.e.

For example, the ionic strength of a 0.1 M solution of CaCl₂ is 0.5 x (0.1 x 22 + 0.2 x 12)=0.3 M. Concentration may be expressed in terms of molarity, molality, or any other concentration measure. The term "osmole" means a unit of measure for the molecular weight of a solute, in grams, divided by the number of ions or particles into which it dissociates in solution. For example, a 300 millimolar solution of glucose, a 300 millimolar solution of urea, and a 150 millimolar solution of NaCl each have the same osmolarity.

The term "equivalents" means a unit of measure for concentration of ions. The equivalents of an ion is equal to the molarity times the number of charges per molecule. Thus equivalents is a measure of charge concentration.

The term "iatrogenic" means induced in a patient by a physician's or other medical caregiver's activity, manner, or therapy.

The term "nosocomial" means of or relating to a hospital or other clinical treatment environment, including homecare environments.

The terms "respiratory support equipment" and "mechanical ventilation" mean devices or equipment including, but not limited to, endotracheal tubes, nasal canula, nasal continuous positive airway pressure (CPAP), and the like.

The term "mucin" means any of a group of glycol proteins found especially in the secretions of mucous membranes.

The term "surfactant" means a surface-active substance that reduces the surface tension of a fluid. The term "respiratory surfactant" means a surface-active substance that serves to maintain the stability of pulmonary tissues by reducing the surface tension of fluids coating pulmonary tissue.

The phrase "reducing infection" means reducing the incidence of infection, reducing the severity of infection, or both. The present invention relates to formulations for the irrigation of mucosal tissues, for the relief of dry mouth, and/or the prevention or treatment of infections, including iatrogenic and nosocomial infections. The present formulations are effective in restoring and maintaining moisture in mucosal tissues when insufficient native secretions are produced or when invasive objects such as endotracheal tubes and the like must pass through an oral cavity or other lumen.

Conventional irrigation of mucosal tissue has been carried out with saline solutions of 0.9% sodium chloride. Sodium and chloride in saline solutions are common electrolytes found in biological systems. Such systems must maintain electrolytic balance for continued vitality. Electrolytes attract fluids by osmosis. The selection of sodium chloride concentration in solutions applied to tissues has been correlated with the typical physiological sodium chloride concentrations found within cells. When hypertonic saline solutions envelope a cell, osmotic pressure drives water across the cell membrane and outside the cell causing cells to crenate or shrink. When hypotonic saline solutions envelop a cell, osmotic pressure drives water across the cell membrane and inside the cell causing cells to swell and possibly lyse. Isotonic solutions do not alter the osmotic equilibrium across the cell membrane. Drinking water and distilled water are examples of hypotonic solutions. Seawater is an example of a hypertonic solution. Medical practitioners consequently treat patients with isotonic solutions including when irrigating mucosal tissues. The isotonic level of sodium chloride in cells is typically 0.9%.

The present formulations include aqueous solutions of alkaline and alkaline earth salts at a physiologically compatible pH. The formulations may be hypotonic, hypertonic or isotonic relative to the concentration of alkaline and alkaline earth metals and salts found in the mucosal tissue secretions of patients. In one aspect, the formulations are isotonic to native irrigant secretions. Optionally, the alkaline and alkaline earth salts are chloride, sulfate, and/or phosphate salts. The formulations may also optionally contain proteins. In some embodiments with proteins, proteins not found in tracheal effluent such as salivary amylase and other proteases are absent. In some embodiments, the formulations are free of protein. In other embodiments, the formulations are tree of proteases. Native saliva includes classes of proteins including histatins, statherins, lysozme, praline-rich proteins, carbonic anhydrases, amylases, peroxidases, lactoferrin, mucin 1 (MGl), mucin 2 (MG2) and slgA. Inasmuch as these proteins are present in tracheal effluent, they may be optionally included in the formulations for irrigation.

Native saliva and normal secretions of the trachea and nose contain about 8 mEq of sodium per liter of fluid. In contrast, 0.9% saline contains 154 mEq sodium per liter. This extremely high concentration of sodium and chloride in the trachea, nose, and mouth following the irrigation with 0.9% saline inactivates the innate immunity of the airway and render patients more vulnerable to infection.

The formulations and methods described herein may be employed to ameliorate innate host defense compared to conventional applications of 0.9% saline in the mouth and the upper airways of patients. Mucosal tissues serve as an important barrier to foreign pathogens. Innate host defense includes the production of antimicrobial factors including cationic antimicrobial protein of 18 ItDa (CAP 18), its C-terminal domain LL37 subunit whether conjugated or independent, other cathelicidins, lysozyme and lactoferrin. The inventive formulations do not deactivate the antimicrobial activity of native proteins or flora in innate host defense. In addition, the formulations are physiologically compatible with native salivary, tracheal, nasal, and other mucosal secretions.

Solution constituents for substitute or supplemental irrigants may include one or more of the following ingredients: sodium in an amount up to about 21.9 mEq/L and more preferably from about 0.9 to about 14.9 mEq/L and even more preferably from about 4.4 to about 11.4 mEq/L; potassium from about 8.9 to about 34.1 mEq/L and more preferably from about 15.2 to about 27.8 mEq/L and even more preferably from about 18.4 to about 24.7 mEq/L; chloride in an amount up to about 82.9 mEq/L and more preferably from about 9.4 to about 58.4 mEq/L and even more preferably from about 21.7 to about 46.2 mEq/L; calcium in an amount up to about 4.2 mEq/L and more preferably from about 0.6 to about 3.0 mEq/L and even more preferably from about 1.2 to about 2.4 mEq/L; magnesium in an amount up to about 1.6 mEq/L and more preferably from about 0.1 to about 1.1 mEq/L and even more preferably from about 0.4 to about 0.9 mEq/L; phosphate in an amount up to about 6.6 mEq/L and more preferably about 2.1 to about 3.9 mEq/L; and, protein in an amount up to about 508 mg/dL and more preferably from about 37 to about 351 mg/dL and even more preferably from about 117 to about 272 mEq/L. The solutions have a pH from about 5.5 to about 6.7 and more preferably from about 6 to about 6.3.

The sodium concentration as a single component or in combination with other alkaline and alkaline earth metal cations should not exceed an amount that it deactivates or significantly reduces innate host antimicrobial activity. For example, the concentration of sodium by itself or in conjunction with other alkaline and alkaline earth metal cations should not deactivate or significantly reduce antimicrobial activity of LL-37.

In some embodiments, the maximum sodium concentration is less than about 0.5% (about 85 mEq/L). In other embodiments, the maximum sodium concentration is less than about 0.4% (about 68 mEq/L). In still other embodiments, the maximum sodium concentration is less than about 0.35% (about 60 mEq/L). In further embodiments, the maximum sodium concentration is less than about 0.3% (about 51 mEq/L). In additional embodiments, the maximum sodium concentration is less than about 0.25% (about 43 mEq/L).

Furthermore, the concentration of sodium as a single component or in combination with other alkaline and alkaline earth metal cations should not be so hypotonic that chronic application of a formulation causes airway closure. The hypotonic formulations of the present invention can be administered in acute applications without causing airway closure or significant airway closure. Where chronic irrigation is indicated, application of formulations that are isotonic is preferred.

In some embodiments, the minimum sodium concentration is greater than about 0.01% (about 1.7 mEq/L). In other embodiments, the minimum sodium concentration is greater than about 0.03% (about 5.1 mEq/L). In additional embodiments, the minimum sodium concentration is greater than about 0.05% (about 8.5 mEq/L). In further embodiments, the minimum sodium concentration is greater than about 0.1% (about 17 mEq/L). In still further embodiments, the minimum sodium concentration is greater than about 0.15% (about 25.5 mEq/L). In still other embodiments, the minimum sodium concentration is greater than about 0.2% (about 34 mEq/L).

Tracheal aspirates may be drawn periodically to monitor for inflammatory responses to hypotonic conditions. Inflammatory responses may indicate development of airway closure. Typically, tracheal aspirates could be drawn (1) at the time of intubation (or within 30 minutes of intubation) for information relative to congenital respiratory inflammation, (2) when an ET (endotracheal) tube is changed for any reason (within 30 minutes of placing the new tube), for information regarding tracheal colonization (as opposed to ET tube colonization), (3) when the character of the ET secretions change substantially, having become yellow, thick, and/or copious, looking for a dominant isolate with accompanying inflammatory cells, and (4) as part of the diagnostic evaluation (along with CBC, blood culture, chest X-ray, and CRP), when pneumonia is suspected in an intubated patient (to supply information relative to a dominant isolate with accompanying inflammatory cells). Culture, gram stain, and leukocyte estimation tests may be examined for indications of airway inflammation and closure.

In some embodiments, the maximum alkaline and alkaline earth metal cation concentration should not exceed an amount that deactivates or significantly reduces innate host antimicrobial activity. For example, the concentration of alkaline and alkaline earth metal cations should not deactivate or significantly reduce antimicrobial activity of LL-37.

In some embodiments, the maximum alkaline and alkaline earth metal cation concentration is less than about 0.5%. In other embodiments, the maximum alkaline and alkaline earth metal cation concentration is less than about 0.4%. In still other embodiments, the maximum alkaline and alkaline earth metal cation concentration is less than about 0.35%. In further embodiments, the maximum alkaline and alkaline earth metal cation concentration is less than about 0.3%. In additional embodiments, the maximum alkaline and alkaline earth metal cation concentration is less than about 0.25%.

Furthermore, the concentration of alkaline and alkaline earth metal cations should not be so hypotonic that chronic application of a formulation causes airway closure. The hypotonic formulations of the present invention can be administered in acute applications without causing airway closure or significant airway closure. Where chronic irrigation is indicated, application of formulations that are isotonic is preferred.

In some embodiments, the minimum alkaline and alkaline earth metal cation concentration is greater than about 0.01%. In other embodiments, the minimum alkaline and alkaline earth metal cation concentration is greater than about 0.03%. In additional embodiments, the minimum alkaline and alkaline earth metal cation concentration is greater than about 0.05%. In further embodiments, the minimum alkaline and alkaline earth metal cation concentration is greater than about 0.1%. In still further embodiments, the minimum alkaline and alkaline earth metal cation concentration is greater than about 0.15%. In still other embodiments, the minimum alkaline and alkaline earth metal cation concentration is greater than about 0.2%. Tracheal aspirates may be drawn periodically to monitor for inflammatory responses to hypotonic conditions. In some formulation embodiments, the alkaline and alkaline earth metal cations include sodium, potassium, calcium, and magnesium cations. In other formulation embodiments, the alkaline and alkaline earth metal cations include potassium, calcium, and magnesium cations. In additional formulation embodiments, the alkaline and alkaline earth metal cations include potassium and calcium cations. In still other formulation embodiments, the alkaline and alkaline earth cations include potassium and magnesium cations.

In other formulation embodiments, the alkaline and alkaline earth metal cations include sodium, calcium, and magnesium cations. In additional formulation embodiments, the alkaline and alkaline earth metal cations include sodium and calcium cations. In still other formulation embodiments, the alkaline and alkaline earth metal cations include sodium and magnesium cations.

In other formulation embodiments, the alkaline and alkaline earth metal cations include sodium, potassium, and calcium cations. In additional formulation embodiments, the alkaline and alkaline earth metal cations include sodium, potassium, and magnesium cations.

In other formulation embodiments, the alkaline and alkaline earth metal cations include alkaline cations such as sodium by itself, potassium by itself or sodium and potassium. In additional formulation embodiments, the alkaline and alkaline earth metal cations include alkaline earth metal cations such as calcium by itself, magnesium by itself, or calcium and magnesium.

In embodiments where alkaline metal cations are present, the concentration of alkaline metal cations should not exceed an amount that it deactivates or significantly reduces innate host antimicrobial activity. For example, the total concentration of sodium and potassium should not deactivate or significantly reduce antimicrobial activity of LL-37.

In some embodiments, the maximum sodium concentration is less than about 0.5% (about 85 niEq/L). In other embodiments, the maximum sodium concentration is less than about 0.4% (about 68 mEq/L). In still other embodiments, the maximum sodium concentration is less than about 0.35% (about 60 mEq/L). In further embodiments, the maximum sodium concentration is less than about 0.3% (about 51 mEq/L). In additional embodiments, the maximum sodium concentration is less than about 0.25% (about 43 mEq/L). Furthermore, the concentration of alkaline metal should not be so hypotonic that chronic application of a formulation causes airway closure. The hypotonic formulations of the present invention can be administered in acute applications without causing airway closure or significant airway closure. Where chronic irrigation is indicated, application of formulations that are isotonic is preferred.

In some embodiments, the minimum alkaline metal cation concentration is greater than about 0.01% (about 1.7 mEq/L). In other embodiments, the minimum alkaline metal cation concentration is greater than about 0.03% (about 5.1 mEq/L). In additional embodiments, the minimum alkaline metal cation concentration is greater than about 0.05% (about 8.5 mEq/L). In further embodiments, the minimum alkaline metal cation concentration is greater than about 0.1% (about 17 mEq/L). In still further embodiments, the minimum alkaline metal cation concentration is greater than about 0.15% (about 25.5 mEq/L). In still other embodiments, the minimum alkaline metal cation concentration is greater than about 0.2% (about 34 mEq/L).

Tracheal aspirates may be drawn periodically to monitor for inflammatory responses to hypotonic conditions.

Optionally, the formulations may also contain one or more therapeutically active agents. Such therapeutically active agents may include recombinant or purified proteins, over-the-counter and prescription drugs, antifungal agents, antiviral agents, antibacterial agents, corticosteroids, lysozme, saliva production agents, oral antiseptics, anticariogenic agents, oral mucosa protective agents, and the like.

Solution constituents for substitute or supplemental irrigants could also be expressed in terms of total osmolarity of from about 10 to about 660 milliosmoles, from about 64 to about 461 milliosmoles, and from about 164 to about 381 milliosmoles.

In another aspect, the irrigant formulations have a total ionic osmolarity of less than about 154 milliosmoles/L. In some embodiments, the total ionic osmolarity is less than about 120 milliosmoles/L. In additional embodiments, the total ionic osmolarity is less than about 100 milliosmoles/L. In other embodiments, the total ionic osmolarity is less than about 85 milliosmoles/L. In still other embodiments, the total ionic osmolarity is less than about 80 milliosmoles. In even other embodiments, the total ionic osmolality is less than about 75 milliosmoles/L. In yet other embodiments, the total ionic osmolarity is less than about 70 milliosmoles/L.

These formulations can provide both acute and long term relief from dry mouth including xerostomia and act as lubricants for patients receiving ventilation assistance. The formulations may be swallowed to provide relief to the upper digestive track, including the esophagus. The formulations may also be applied through the nasal and sinus cavities.

The formulations may also be used to prevent or wash away mucosal build ups including tracheal build ups, which may partially or completely occlude the lumen of respiratory support equipment (thus washing open an occlusion). The formulations provide an aqueous mucosal tissue irrigant with sufficient lubricity to prevent, wash away, or wash open mucosal occlusion in and around respiratory equipment without deactivating the antimicrobial activity of innate host defense. Optionally, one or more saliva production agents or stimulants such as citric acid and malic acid may be included to cause direct stimulation of saliva secretion. The irrigant formulations can include between 0.01 and 0.3% and preferably between 0.1 and 0.3% saliva production agents with respect to the total weight/volume. Optionally, one or more oral antiseptics such as triclosan may be included for their antiseptic activity against pathogenic microorganisms. The irrigant formulations can include between 0.01 and 2.0% and preferably between 0.1 and 0.3% antiseptic, with respect to the total weight/volume.

Optionally, one or more anticariogenic agents such as fluoride compounds, including sodium fluoride (NaF) and sodium monofluorophosphate, also known as NaMFP, may be included. The irrigant formulations can include between 0.01% and 2.0% and preferably between 0.1 and 0.3% anticariogenic agents, with respect to the total weight/volume. Xylitol also can act as an anticariogenic agent to inhibit the growth of certain bacteria present in the mouth and also help reduce demineralization of tooth enamel.

Optionally, one or more protective agents for the oral mucosa, particularly the gingival mucosa may be included. These protective agents include vitamin E acetate and the like to improve blood circulation and inhibit inflammation. Panthenol is a pantothenic acid derivative that promotes the healing process by epidermal stimulation without causing sensitization or irritation. The extracts of Aloe Vera are natural products of proven efficacy that inhibit inflammation and improving the healing of wounds. The irrigant formulations may include between 0.01% and 1.0% and preferably between 0.1 and 0.3% mucosa protective agents, with respect to the total weight/volume.

The irrigants may serve as irrigant formulations and can further include water and/or polyols acceptable for human consumption, among them glycerin, sorbitol, and/or propylene glycol, as well as with other nonessential ingredients of those conventionally used in oral liquid formulations.

In another aspect, the formulations may further include mucins. Mucins are a family of large, heavily glyclosulated proteins. Some mucins of biological origin may be secreted freely into a biological fluid such as those that are secreted on mucosal surfaces and saliva. Typically mucins are secreted as massive aggregates by prosglandins with molecular masses of roughly 1 to 10 million Daltons (Da.).

Within these aggregates, monomers are linked to one another mostly by noncovalent interactions, although intermolecular disulfide bonds may also play a role in the aggregation. Presently there are at least 19 human mucin genes that have been distinguished by cDNA cloning, i.e., MUC 1, 2, 3A, 3B, 4, 5AC, 5B, 6-9, 11-13 and 15-19. The major secreted airway mucins are MUC 5AC and MUC 5B, while MUC 2 is secreted mostly in the intestine and may also be found in the airway.

In another aspect, the formulations may also include a surfactant. In some embodiments, the surfactant is a respiratory surfactant. Surfactants may be used to affect the surface tension of a fluid. Surface tension is the tendency of molecules in a fluid to be pulled toward the center of the fluid. Examples of surfactants include but are not limited to phospholipids, proteins, cholesterols. The surfactant may be ionic or non-ionic. Protein surfactants may be surfactant-associated proteins (such as SP-A to SP-D). The surfactants may be synthetic or natural. Natural surfactants are derived from animal sources. Synthetic surfactants can include complex combinations of phospholipids, neutral lipids, lipid proteins or alcohols.

Examples for artificial surfactants are Exosurf Neonatal (a synthetic surfactant composed of dipalmitoylphosphatidylcholine, hexadecanol, and tyloxapol), Lucinactant (Surfaxin®, Discovery Laboratories, Inc., Warrington, Pathologic., USA) (a mixture of dipalmitoylphosphatidylcholin-e, palmitoyloleoylphosphatidylglycerol, palmitic acid, and KL₄) or Lusupultide (Venticute©, Altana Pharma, Konstanz, Germany) (a mixture of phospholipids and recombinant SP-C). Exemplary natural surfactants include Curosurf®, Survanta©, or Alveofact®, however, other preparations of surfactant could be used equally. Curosurf® (Chiesi company, Italy) is a lipid extract from whole minced porcine lung tissue. Survanta® (Abbott GmbH, Wiesbaden, Germany) is prepared from minced bovine lung extract with added DPPC, triacylglycerol, and palmitic acid. Alveofact® (Boehringer Ingelheim Pharma KG, Ingelheim, Germany) is produced by lipid extraction from bovine lung lavage.

In yet another aspect, the formulations may also include an optional flavoring agent. The flavoring agent may be used to affect the taste of the irrigant solution.

The formulations may be delivered in a variety of manners including with "bullet tubes" as previously practiced or by volumetric syringes, metered dose devices, droppers or other devices. As mentioned earlier, the formulations contemplated may be presented in a variety of forms including mouthwashes, sprays and oral gels.

In addition to water, polyhydroxylated compounds such as glycerin or glycols (e.g., propylene glycol, nonionic surfactants, etc.) and other additives to improve appearance, flavor, and preservation can be included.

The sprays are formulations equal or similar to mouthwashes but dispensed in spray bottles for convenient application of the dose needed to moisten and protect the mouth or nose without requiring subsequent rinsing. Oral gel formulations of the substitute saliva can include polymers that impart gel qualities and texture to the formulations. Oral gels may be administered by direct application to the oral cavity. Such polymers include polycarbopb.il and carbomer, since they keep the gel structure stable for very prolonged times under extreme temperature conditions. The formulations are prepared by conventional mixing techniques, well known to those skilled in the art, and can provide fast and effective relief to individuals suffering from dry mouth. The formulations described may be administered to a patient suffering from dry mouth in particular, or to infants to reduce infections including iatrogenic nosocomial infections. Therefore, a method for providing an oral lubricant to a patient includes orally administering an effective amount of a liquid formulation of the following ingredients: sodium in an amount up to about 21.9 mmol/L and more preferably from about 0.9 to about 14.9 mmol/L and even more preferably from about 4.4 to about 11.4 mmol/L; potassium from about 8.9 to about 34.1 mmol/L and more preferably from about 15.2 to about 27.8 mmol/L and even more preferably from about 18.4 to about 24.7 mmol/L; chloride in an amount up to about 82.9 mmol/L and more preferably from about 9.4 to about 58.4 mmol/L and even more preferably from about 21.7 to about 46.2 mmol/L; calcium in an amount up to about 4.2 mmol/L and more preferably from about 0.6 to about 3.0 mmol/L and even more preferably from about 1.2 to about 2.4 mmol/L; magnesium in an amount up to about 1.6 mmol/L and more preferably from about 0.1 to about 1.1 mmol/L and even more preferably from about 0.4 to about 0.9 mmol/L; and, phosphate in an amount up to about 6.6 mmol/L and more preferably about 2.1 to about 3.9 mmol/L; and, protein in an amount up to about 508 mg/dL and more preferably from about 37 to about 351 mg/dL and even more preferably from about 117 to about 272 mmol/L. The solutions have a pH from about 5.5 to about 6.7 and more preferably from about 6 to about 6.3. When desired, the formulations may be swallowed or expectorated. When swallowed or otherwise advanced to the gastrointestinal tract, the formulations may be used to lavage the gastrointestinal tract. The formulations may be administered at periodic intervals.

In some embodiments, the methods of irrigation can include contacting a mucosal tissue with any of the formulations with alkaline and alkaline earth metal cations and concentration ranges described above.

In additional embodiments, the methods of irrigation can include contacting a mucosal tissue with a solution with a lower ionic strength than conventional irrigants. By irrigating mucosal areas with lower ionic strength fluids, endogenous antimicrobials maintain antimicrobial activity to impart innate host defense.

In other embodiments, the methods can include contacting a mucosal tissue with a solution with a lower sodium chloride concentration than conventional irrigants. By irrigating mucosal areas with lower sodium chloride concentration fluids, endogenous antimicrobials maintain activity in contributing to innate host defense.

In still other embodiments, the methods can include contact a mucosal tissue with a solution with low levels of sodium chloride and alkaline earth metal salts. By irrigating mucosal areas with lower sodium chloride concentration and alkaline earth metal salts, endogenous antimicrobials maintain or improve activity in contributing to innate host defense.

Caregivers can irrigate and lubricate the endotracheal tube or other similar conduits as well as the airway in patients who require mechanical ventilation. The methods and formulations described can prevent tracheal and other similar secretions from building up and occluding the lumens of the endotracheal tube and airway. Furthermore, the methods and formulations described prevent tracheal abrasion from respiratory equipment, which may further irritate or inflame both mucosal and adjoining tissues. Applying the formulations can reduce the ionic concentration of sodium chloride and other salts, which grows as a result of evaporation, and the lack of Hp apposition. Furthermore, the methods and formulations described herein avoid the problems associated with iatrogenically adding excessive sodium and/or alkaline and alkaline earth metal cations that deactivate innate host defense. The methods described deliver water to mucosal surfaces at physiologically salt acceptable concentrations while at the same time providing both an irrigating and lubricating function.

It is contemplated that the irrigant formulations described herein can be used to irrigate or lubricate a variety of tissues and area's of an organisms body. These tissues and organisms include, but are not limited to the mouth, lips, teeth, gums, tongue, sinus passages, lungs, esophagus, throat, nose, Eustachian tubes, ears, eyes, larynx, and the like. Examples

Example 1

To a sterile container was added 1.957 mL of 4 mEq/niL of sodium chloride 4 mEq/mL, 10.75 mL of 2 mEq/mL of potassium chloride, 2.7 mL of 100 mg/mL calcium chloride, 0.3 mL of 4.06 mEq/mL of magnesium sulfate, 1 mL of 3 of potassium phosphate, 7.76 mL of 25% albumin and a quantity sufficient of sterile water to take the solution to a volume of IL. This solution had a pH of 6.1+0.5. The resulting solution had the concentration values as shown in Table 1

Table 1.

Example 2

An irrigation solution with the constituents and their relative proportions displayed in Table 2 was prepared with a pH of 6.5.

Table 2.

The irrigation solution was stored in a refrigerated cabinet at 36 to 46° F. Aliquots of the stored solution were weekly sampled for four weeks for bacterial culture by plating on enriched thioglycollate medium and/or by refractive index measurement. No bacterial growth was detected. No change in refractive index or change in pH was observed.

Ten newborn infants on the first day of life who were intubated with an endotracheal tube for mechanical ventilation were treated with the irrigation solution. The irrigation solution was instilled at intervals determined by respiratory therapists consistent with the practice for and intervals for use with conventional 0.9% NaCl solutions. A protocol was followed for the instillation and suctioning maneuvers. The protocol involved assessing the need for suctioning, rather than using a set suctioning schedule. Briefly, an inline suction catheter was used with suction pressure between 80 and 100 cm H₂O. The suction depth was 0.5 cm past the endotracheal tube tip for infants <1000 grams and 1.0 cm past the tip for those >1000grams. The volume of irrigation solution to be instilled was set at approximately 0.5 mL. Once the catheter was in place, suction was applied for 2 seconds and then the catheter was withdrawn with suction applied. Preoxygenation and reoxygenation were used as indicated. For each subject, the study was concluded when the patient was extubated, and data on possible systemic effects were tabulated through discharge to home.

Patients were observed for signs of immediate intolerance including coughing, oxyhemoglobin desaturation, bradycardia, tachycardia, hypotension, hypertension, or appearance of cutaneous rash. No signs of immediate intolerance were observed during or after administration of the irrigant solutions for any of the ten patients.

Patients were observed for signs of systemic toxicity. Laboratory tests of renal, hematologic, and hepatic function, from the ten patients, were compared with values from a historic cohort comparison group of 479 other patients. The comparison group received airway care using 0.9% conventional saline. The cohort group comprised patients with an endotracheal tube, with a date of birth from January 1, 2003 through December 31, 2004, cared for in the McKay-Dee Hospital NICU in Davis County, Utah. Sixty-five percent of the historic comparison group (310/479) were intubated for three days or less. The intubation period for the historic comparison group ranged from 1 to 88 days. Ninety-eight percent (469/479) of the comparison group and all 10 the patients survived to be discharged home. Table 3 lists laboratory findings during the entire hospitalization among the ten study subjects and the cohort patients. The table lists whether an elevated creatinine, a low platelet or neutrophil count, or an elevated total or direct bilirubin, ALT or AST were observed during the hospitalization. Compared with the cohort, the study subjects did not have a higher than anticipated occurrence of abnormalities of these laboratory values. Table 3. Laboratory tests among the study subjects and the historic cohort.

VO

In the table, Great refers to creatinine; ANC refers to absolute neutrophil count; bili refers to bilirubin; ALT refers to alanine amino transferase; AST refers to aspartate amino transferase.

Additional Examples

Irrigant solutions with varying constituent concentrations can be prepared as summarized by the examples in Table 4. All concentrations are expressed in terms of mEq/L except for albumin which is expressed in units of mg/L.

Table 4.

In the examples displayed in Table 4, charge balance can be adjusted for stoiciometric purposes using a an appropriate buffer and pH.

While the invention has been particularly shown and described with reference to the foregoing embodiments, it will be understood by those skilled in the art that various other changes in the form and details may be made without departing from the scope of the invention.

Claims

CLAIMSWhat is claimed is:

1. An aqueous tissue irrigant consisting of less than about 0.3% sodium chloride.

2. An aqueous tissue irrigant comprising less than about 0.3% sodium chloride and recombinant or purified albumin.

3. An aqueous tissue irrigant consisting essentially of an aqueous solution of alkaline and alkaline earth metal salts, wherein the anions of the salts are selected from one or more of chloride, phosphate and sulfate, and exhibiting sufficient lubricity to prevent or wash open mucosal occlusion in and around respiratory equipment without deactivating the antimicrobial activity of innate host defense, wherein the total concentration of sodium chloride, if present, is less than about 0.3% and the formulation is substantially free of any endogenous human protease.

4. An aqueous tissue irrigant consisting essentially of an aqueous solution of alkaline and alkaline earth metal salts and human albumin, wherein the anions of the salts are selected from one or more of chloride, phosphate and sulfate, and exhibiting sufficient lubricity to prevent or wash open mucosal occlusion in and around respiratory equipment without deactivating the antimicrobial activity of innate host defense, wherein the total concentration of sodium chloride, if present, is less than about 0.3% and the formulation is substantially free of any endogenous human protease.

5. The irrigant according to claim 4, wherein the human albumin is recombinant or purified albumin.

6. A tissue irrigant consisting essentially of an aqueous solution comprising: (a) sodium from about 0.1 to about 21.9 mEq/L;

(b) potassium from about 8.9 to about 34.1 mEq/L;

(c) calcium from about 0.1 to about 4.2 mEq/L;

(d) magnesium from about 0.1 to about 1.6 mEq/L; (e) chloride from about 0.1 to about 82.9 mEq/L;

(f) phosphate from about 0.1 to about 6.6 mEq/L;

(g) albumin from about 0.1 to about 508 mg/dL; exhibiting sufficient lubricity to prevent or wash open mucosal occlusion in and around respiratory equipment without deactivating the antimicrobial activity of innate host defense and wherein the solution has a pH from about 5.5 to about 6.7 and is substantially free of endogenous human protease proteins found in saliva.

7. A tissue irrigant consisting essentially of an aqueous solution comprising:

(a) sodium from about 0.9 to about 14.9 mEq/L; (b) potassium from about 15.2 to about 27.8 mEq/L;

(c) calcium from about 0.6 to about 3.0 mEq/L;

(d) magnesium from about 0.1 to about 1.1 mEq/L;

(e) chloride from about 9.4 to about 58.4 mEq/L;

(f) phosphate from about 1.2 to about 4.8 mEq/L; (g) albumin from about 37 to about 351 mg/dL; exhibiting sufficient lubricity to prevent or wash open mucosal occlusion in and around respiratory equipment without deactivating the antimicrobial activity of innate host defense and wherein the solution has a pH from about 5.8 to about 6.4 and is substantially free of endogenous human protease proteins found in saliva.

8. A tissue irrigant consisting essentially of an aqueous solution comprising:

(a) sodium from about 4.4 to about 11.4 mEq/L;

(b) potassium from about 24.7 to about 18.4 mEq/L;

(c) calcium from about 1.2 to about 2.4 mEq/L; (d) magnesium from about 0.4 to about 0.9 mEq/L;

(e) chloride from about 21.7 to about 46.2 mEq/L; (f) phosphate from about 2.1 to about 3.9 mEq/L;

(g) albumin from about 116.5 to about 271.5 mg/dL; exhibiting sufficient lubricity to prevent or wash open mucosal occlusion in and around respiratory equipment without deactivating the antimicrobial activity of innate host defense and wherein the solution has a pH from about 6.0 to about 6.3 and is substantially free of endogenous human protease proteins found in saliva.

9. The irrigant according to any one of claims 2-8, further comprising a mucin.

10. The irrigant according to any one of claims 2-8, further comprising a surfactant.

11. The irrigant according to any one of claims 2-8, further comprising a therapeutically active agent.

12. The irrigant according to any one of claims 2-8, further comprising a therapeutically active agent selected from the group consisting of: an anti-fungal agent, an antiviral agent, an antibacterial agent, a corticosteroid and a lysozyme.

13. The irrigant according to any one of claims 11 and 12, wherein the therapeutically active agent is LL37.

14. A method of reducing mucosal infection by contacting a mucosal tissue with an irrigant comprising an aqueous solution consisting of less than about 0.3% sodium chloride.

15. A method of reducing mucosal infection by contacting a mucosal tissue with an irrigant comprising an aqueous solution comprising less than about 0.3% sodium chloride and recombinant or purified albumin.

16. A method of reducing mucosal infection by contacting a mucosal tissue with an irrigant consisting essentially of an aqueous solution of alkaline and alkaline earth metal salts, wherein the anions of the salts are selected from one or more of chloride, phosphate and sulfate, and exhibiting sufficient lubricity and the total concentration of sodium chloride, if present, is less than about 0.3%, and wherein the irrigant does not include an endogenous human protease.

17. A method of reducing mucosal infection by contacting a mucosal tissue with an irrigant consisting essentially of an aqueous solution of alkaline and alkaline earth metal salts and human albumin, where the anions of the salts are selected from one or more of chloride, phosphate and sulfate and the total concentration of sodium chloride, if present, is less than about 0.3%, and wherein the irrigant does not include an endogenous human protease.

18. The method according to claim 17 wherein the human albumin in the irrigant is recombinant or purified albumin.

19. A method of reducing mucosal infection by contacting a mucosal tissue with an irrigant consisting essentially of an aqueous solution comprising:

(a) sodium from about 0.1 to about 21.9 mEq/L; (b) potassium from about 8.9 to about 34.1 mEq/L;

(c) calcium from about 0.1 to about 4.2 mEq/L;

(d) magnesium from about 0.1 to about 1.6 mEq/L;

(e) chloride from about 0.1 to about 82.9 mEq/L;

(f) phosphate from about 0.1 to about 6.6 mEq/L; (g) albumin from about 0.1 to about 508 mg/dL; exhibiting sufficient lubricity to prevent or wash open mucosal occlusion in and around respiratory equipment without deactivating the antimicrobial activity of innate host defense and wherein the solution has a pH from about 5.5 to about 6.7 and is substantially free of endogenous human protease proteins found in saliva.

20. A method of reducing mucosal infection by contacting a mucosal tissue with an irrigant consisting essentially of an aqueous solution comprising:

(a) sodium from about 0.9 to about 14.9 mEq/L;

(b) potassium from about 15.2 to about 27.8 mEq/L;

(c) calcium from about 0.6 to about 3.0 mEq/L; (d) magnesium from about 0.1 to about 1.1 mEq/L;

(e) chloride from about 9.4 to about 58.4 mEq/L;

(f) phosphate from about 1.2 to about 4.8 mEq/L;

(g) albumin from about 37 to about 351 mg/dL; exhibiting sufficient lubricity to prevent or wash open mucosal occlusion in and around respiratory equipment without deactivating the antimicrobial activity of innate host defense and wherein the solution has a pH from about 5.8 to about 6.4 and is substantially free of endogenous human protease proteins found in saliva.

21. A method of reducing infection by contacting a mucosal tissue with an irrigant consisting essentially of an aqueous solution comprising:

(a) sodium from about 4.4 to about 11.4 mEq/L;

(b) potassium from about 24.7 to about 18.4 mEq/L;

(c) calcium from about 1.2 to about 2.4 mEq/L;

(d) magnesium from about 0.4 to about 0.9 mEq/L; (e) chloride from about 21.7 to about 46.2 mEq/L;

(f) phosphate from about 2.1 to about 3.9 mEq/L;

22. The method according to any one of claims 14-21, wherein the irrigant further comprises a mucin.

23. The method according to any one of claims 14-21, wherein the irrigant further comprises a surfactant.

24. The method according to any one of claims 14-21, wherein the irrigant further comprises a therapeutically active agent.

25. The method according any one of claims 14-21, wherein the irrigant further comprises a therapeutically active agent selected from the group consisting of: an anti-fungal agent, an antiviral agent, an antibacterial agent, a corticosteroid and a lysozyme.

26. The method according to any of claims 24 and 25, wherein the therapeutically active agent is LL37.

27. The method according to any one of claims 14-26, wherein the irrigant is applied to the mucosal tissue at periodical intervals.

28. A method for treating dry mouth by contacting a tissue with an aqueous solution consisting of less than about 0.3% sodium chloride.

29. A method for treating dry mouth by contacting a tissue with an irrigant comprising an aqueous solution comprising less than about 0.3% sodium chloride and recombinant or purified albumin.

30. A method for treating dry mouth by contacting a tissue with an irrigant consisting essentially of an aqueous solution of alkaline and alkaline earth metal salts, where the anions of the salts are selected from one or more of chloride, phosphate and sulfate and exhibiting sufficient lubricity and the total concentration of sodium chloride, if present, is less than about 0.3%, and wherein the irrigant does not include an endogenous human protease.

31. A method for treating dry mouth by contacting a tissue with a formulation consisting essentially of an aqueous solution of alkaline and alkaline earth metal salts and human albumin, where the anions of the salts are selected from one or more of chloride, phosphate and sulfate and exhibiting sufficient lubricity and the total concentration of sodium chloride, if present, is less than about 0.3%, and wherein the irrigant does not include an endogenous human protease.

32. The method according to claim 31 wherein the human albumin in the formulation is recombinant or purified albumin.

33. A method for treating dry mouth by contacting a tissue with an irrigant consisting essentially of an aqueous solution comprising:

(a) sodium from about 0.1 to about 21.9 mEq/L;

(b) potassium from about 8.9 to about 34.1 mEq/L; (c) calcium from about 0.1 to about 4.2 mEq/L;

(d) magnesium from about 0.1 to about 1.6 mEq/L;

(e) chloride from about 0.1 to about 82.9 mEq/L;

(f) phosphate from about 0.1 to about 6.6 mEq/L;

34. A method for treating dry mouth by contacting a tissue with an irrigant consisting essentially of an aqueous solution comprising:

(a) sodium from about 0.9 to about 14.9 mEq/L;

(b) potassium from about 15.2 to about 27.8 mEq/L;

(c) calcium from about 0.6 to about 3.0 mEq/L;

(d) magnesium from about 0.1 to about 1.1 mEq/L; (e) chloride from about 9.4 to about 58.4 mEq/L;

(f) phosphate from about 1.2 to about 4.8 mEq/L;

35. A method for treating dry mouth by contacting a tissue with an irrigant consisting essentially of an aqueous solution comprising:

(a) sodium from about 4.4 to about 11.4 mEq/L; (b) potassium from about 24.7 to about 18.4 mEq/L;

(e) chloride from about 21.7 to about 46.2 mEq/L;

(f) phosphate from about 2.1 to about 3.9 mEq/L;

(g) albumin from about 116.5 to about 271.5 mg/dL; exhibiting sufficient lubricity to prevent or wash open occlusion in and around respiratory equipment without deactivating the antimicrobial activity of innate host defense and wherein the solution has a pH from about 6.0 to about 6.3 and is substantially free of endogenous human protease proteins found in saliva.

36. The method according to any one of claims 29-35, wherein the irrigant further comprises a mucin.

37. The method according to any one of claims 29-35, wherein the irrigant further comprises a surfactant.

38. The method according to any one of claims 29-37, wherein the irrigant further comprises a therapeutically active agent.

39. The method according any one of claims 29-37, wherein the irrigant further comprises a therapeutically active agent selected from the group consisting of: an anti-fungal agent, an antiviral agent, an antibacterial agent, a corticosteroid and a lysozyme.

40. The method according to any of claims 38 and 39, wherein the therapeutically active agent is LL37.