Title:  Method and composition for delivering zinc to the nasal membrane

United States Patent:  6,673,835

Issued:  January 6, 2004

Inventors:  Hensley; Charles (Woodland Hills, CA); Davidson; Robert Steven (Woodland Hills, CA)

Assignee:  Zicam LLC (Phoenix, AZ)

Appl. No.:  388816

Filed:  September 1, 1999

Abstract

A viscous gel for delivering minor effective amounts of active substances through the nasal membrane into the body.

Description of the Invention

This invention relates to compositions and methods for delivering minor effective amounts of a substance to the blood in a body.

More particularly, the invention relates to a method and composition for delivering a minor effective amount of a substance to the nasal membrane.

In a further respect, the invention relates to a composition which maintains zinc in an ionic state for delivery to the nasal membrane.

In another respect, the invention relates to a composition which maintains a substance in direct contact with the nasal membrane for an extended period of time.

The common cold is one of the most frequently occurring human illnesses and is responsible for substantial morbidity and economic loss. Ionic zinc is a known effective anti-rhinovirus agent in vitro and in vivo.

In one in vivo study reported in 1991, a double-blind clinical trial demonstrated the effectiveness of orally administered zinc gluconate/glycerine lozenges. The lozenges used in the study contained twenty-three milligrams of zinc provided by 179 milligrams of zinc gluconate trihydrate which provided a 13.1 millimolar ionic zinc concentration in the oral cavity. During the study, lozenges administered at two hour intervals resulted in a forty-two percent reduction in mean cold duration and in a marked reduction in both the number and severity of symptoms if treatment with the lozenges was initiated within two days of the onset of cold symptoms. A second study reported in 1992 (Zarmebo J. E., Godfrey J. C., Godfrey N., J Pharm Sci 1992; 81: 128-130) confirmed the findings of the 1991 study. Soon after the results of these studies became widely known, a number of companies began marketing their own versions of the zinc lozenge cold remedy.

While zinc lozenges are usually beneficial in treating a cold, the lozenges have several drawbacks. First, the majority of zinc in a zinc gluconate lozenge is released in the oral cavity. The principal site, however, of antiviral activity is believed to be the nasal cavity (Novick S. G., Godfrey J. C., Godfrey N. J., Wilder H. R., Medical Hypothesis 1996; 46: 295-302). It is surmised that some ionic zinc released by a lozenge in the oral cavity makes its way to nasal passages where the zinc binds to viral ICAM-1 receptors and inhibits rhinovirus from binding to and infecting nasal mucosal cells. The difficulty encountered by ionic zinc or another substance in a lozenge in attempting to travel from the oral cavity to the nasal cavity limits the effectiveness of lozenges. Further, in a congested individual the route from the oral cavity to the nasal cavity may be completely blocked, rendering the lozenges ineffective.

A second disadvantage associated with zinc lozenges is the production of significant side effects. In one study, twenty percent of the subjects complained of nausea and eight percent complained of bad taste reactions (Novick S. G., Godfrey J. C., Godfrey N. J., Wilder H. R., Medical Hypothesis 1996; 46: 295-302). With respect to the nausea, it is well established that excessive zinc in the intestinal tract interferes with copper absorption and that preventing the absorption by the body of sufficient quantities of copper can lead to a variety of undesirable pathological states. The overuse of zinc lozenges may contribute to copper depletion.

We have discovered a novel gel composition and method for delivering ionic (negatively charged) zinc and other active substances to the nasal epithelial membrane without encountering the disadvantages normally associated with lozenges. The composition maintains ionic zinc or another active substance in direct contact with the nasal membrane, preferably for an extended period of time of at least one-quarter hour, and delivers zinc or another active substance into the nasal membrane and into blood in the nasal membrane.

When the gel composition is a homeopathic composition, it includes from 75% to 99.999% by weight of at least one carrier and a minor effective amount of an active substance. The minor effective amount in the gel composition includes from 0.0000001% to 5.0% by weight of the active substance.

When the gel composition is a pharmaceutical composition, it includes from 75% to 99.999% by weight of at least one carrier and a minor effective amount of an active substance. The minor effective amount includes from 0.0000001% to 10.0% by weight in the composition of the active substance. As would be appreciated by those of skill in the art, small concentrations of active substances may not be deemed homeopathic but can still be beneficial to the body. Such "non-homeopathic" concentrations of an acitve substance are herein deemed to produce a pharmaceutical composition.

When the gel composition is a homeopathic composition and zinc is the active substance, the composition includes from 0.185% to 2.8% by weight (from about 4 mM to 60 mM), preferably 0.9% to 2.0% by weight (from about 20 mM to 44 mM), zinc gluconate. Each 0.1% by weight zinc gluconate in the composition produces a concentration of approximately 0.014% by weight ionic zinc (i.e., of about 2.2 mM ionic zinc). At least a 4 mM concentration of ionic zinc is preferred in the gel composition to insure that a sufficiently high concentration of ionic zinc is produced by the composition at the interface between the composition and the nasal membrane.

The composition has a viscosity in the range of 2,500 to 40,000 centipoise, preferably 5,000 to 20,000 centipoise. The viscosity of the composition is important because it facilitates maintenance of the composition in the nasal cavity in contact with the nasal membrane or with mucous on the membrane. When the viscosity is less than about 2,500 centipoise, the composition tends to be drawn by gravity out of the nasal cavity. If the viscosity is in excess of about 40,000 centipoise, the thickness of the composition interferes with the diffusion of ionic zinc through the composition to the nasal membrane. During the development of the composition of the invention, nasal sprays were considered and discarded because the low viscosity of the liquids comprising such sprays allows the liquids to flow under gravity out of the nasal cavity, preventing the sprays from contacting the nasal membrane for an extended period of time. The effectiveness of a nasal spray usually substantially dissipates in less than five minutes. Similarly, applying the composition on a swab or nose plug is not believed efficient because the swab or nose plug, which may for example be made of cotton or of a sponge material retain the composition and interferes with the delivery of an additional supply of the composition into contact with the nasal membrane following dissipation of the composition which is on the surface of the swab or plug and is in direct contact with the nasal membrane.

As noted, nasal sprays were avoided during development of the invention. By way of background with respect to zinc--bearing nasal sprays, U.S. Pat. No. 5,688,32 concerns antiallergic spray preparations and discloses and claims a method for the treatment of an allergic condition in which a spray solution is applied to the eye or respiratory tract of a mammal having the allergic condition. The spray solution includes a non-toxic, anti-allergy effective amount of ionic zinc in a concentration below that which causes irritation to mucus membranes. The majority of the ionic zinc in the spray solution is unchelated zinc and is in the form of free ionic solution, wherein the solution has a zinc ion content of between about 0.002 and about 0.12%(w/v). The allergic condition treated with the spray solution can comprises hay-fever and asthma. The spray solution can be selected from the group consisting of essentially aqueous and essentially saline solutions; can have a zinc ion content of about 0.04% (w/v); can comprise a mineral acid salt of zinc as solute; can comprise a solute selected from the group consisting of zinc sulfate and zinc chloride; can be dispensed in aliquots of about either 0.05 to 0.5 ml or 0.2 ml; and/or, can include at least one other pharmaceutically acceptable ingredient. The other pharmaceutically acceptable ingredient can be selected from the group consisting of antihistamines, scenting agents and active ingredients; or, can comprise ascorbate. U.S. Pat. No. 5,688,532 also discloses and claims an improvement in a method for treatment of an allergic condition by the administration of a zinc compound to a mammal possessed of an allergic condition. The improvement consists essentially of spraying a solution comprising a non-toxic, anti-allergy effective amount of ionic zinc to the eye or respiratory tract of a mammal possess of the allergic condition. The solution comprises a concentration of ionic zinc below that which causes irritation to mucus membranes. The majority of the ionic zinc in the spray is unchelated zinc and is in the form of free ionic solution. The solution has a zinc ion content of between about 0.002 and 0.12%(w/v).

U.S. Pat. No. 5,622,724 discloses and claims a method for the treatment of the symptoms of the common cold comprising administering a spray of a solution containing a non-toxic, symptom effective treating amount of a solution of a substantially unchelated ionic zinc compound. The solution contains substantially unchelated zinc ions in a concentration of from about 0.004 to about 0.12% (w/vol), to the nostrils and respiratory tract of a patient in need thereof. The solution can be selected from the group consisting of aqueous and saline solutions; can further comprises an effective amount of a flavor and/or odor enhancing agent; can have an unchelated zinc ion content of about 0.04% (w/v); or, can consist essentially of the substantially unchelated ionic zinc compound and at least one pharmaceutically acceptable carrier. The substantially unchelated ionic zinc compound can comprise a mineral acid salt of zinc; can comprise a salt selected from the group consisting of zinc sulfate and zinc chloride; or, can comprise zinc sulfate. Utilization of zinc chloride at concentrations greater than 0.2%, especially greater than 0.4% is not preferred because, as is well known in the art, the zinc chloride is caustic. The carrier utilized in the invention can include 0.05% to 5.0% by weight glycerine. The glycerine is important and is presently preferred because it allows zinc to remain in an ionic state until the zinc contacts the nasal membrane and/or mucous on the nasal membrane. One problem encountered during development of the invention was identifying a carrier which maintains zinc in an ionic state.

The gel composition of the invention which utilizes zinc as the active substance preferably permits ionic zinc to diffuse through the composition to the nasal epithelial membrane or mucous on the epithelial membrane. This facilitates the availability of a continuous supply of ionic zinc because the composition will continue via diffusion to supply zinc without requiring that the portion of the composition adjacent the nasal epithelial membrane (on mucous on the membrane) dissolve or dissipate and expose a fresh portion of the composition containing ionic zinc. As noted, composition viscosities in excess of about 40,000 centipoise are believed to interfere with the diffusion of zinc through the composition. Viscosity measurements recited herein were obtained using the Brookfield Syncho-Lectric Viscometer for the measurement of the apparent Viscosity of Newtonian and Non-Newtonian materials at low shear rates at given rotational speeds (ASTM D1824-87). See also ASTM D1084-88, ASTM D2196-86 and other ASTM protocols concerning the measurement of viscosity.

We have also discovered a method of delivering minor effective amounts of a metal into the blood. The metal is the active substance. The method includes the step of providing a viscous delivery composition. The delivery composition includes 90% to 99.995% by weight of at least one carrier and less than 1.5% by weight of the metal. The composition has a viscosity in the range of 2,500 to 40,000 centipoise. The method includes the additional steps of applying the delivery composition in the nasal cavity in direct contact with the nasal membrane, and maintaining the delivery composition in contact with the nasal membrane for at least one-sixth hour.

In another embodiment of the invention, we provide an improved method of delivering minor effective amounts of an active substance into the blood. The method includes the step of providing a viscous delivery composition including 75% to 99.999% by weight of at least one carrier, and a minor effective amount of the active substance. The composition has a viscosity in the range of 2,500 to 40,000 centipoise. The method also includes the step of applying the delivery composition in the nasal cavity. The nasal cavity includes mucous, cilia and a nasal membrane. The delivery composition is applied such that a first portion of the composition directly contacts at least the nasal membrane, a second portion of the composition directly contacts at least mucous in the nasal cavity, and at least a third portion of the composition directly contacts at least cilia in the nasal cavity. The method also includes the step of maintaining the first portion of the delivery composition in contact with the nasal membrane for at least ten minutes.

In a further embodiment of the invention, we provide an improved method of delivering a minor effective amount of an active substance to the blood and of reducing the time required to deliver the substance into the blood by increasing the ability of the active substance to penetrate the body. The improved method comprises the steps of providing at least one carrier; providing at least one active substance; and, providing at least one permeation enhancer to facilitate passage of the active substance through a nasal membrane in a nasal cavity. The nasal cavity also includes mucous and cilia. The improved method further includes the step of combining the carrier, active substance, and permeation enhancer to produce a viscous delivery composition including 75% to 99.999% by weight of said carrier, including a minor effective amount of the active substance, and including a minor effect amount of the permeation enhancer. The composition has a viscosity in the range of 2,500 to 40,000 centipoise. The method also includes the step of applying the delivery composition in the nasal cavity such that a first portion of the composition directly contacts at least the nasal membrane, such that a second portion of the composition directly contacts at least the mucous in the nasal cavity, and at least a third portion of the composition directly contacts the cilia in the nasal cavity; and, maintaining the first portion of said delivery composition in contact with the nasal membrane for at least ten minutes.

In still another embodiment of our invention, we provide an improved method of delivering a minor effective amount of an active substance to the blood and of reducing the time required for the active substance to pass through membrane into the blood by increasing the surface area over which the active substance contacts the body. The improved method includes the step of providing a viscous delivery composition including 75% to 99.999% by weight of at least one carrier, and a minor effective amount of the active substance. The composition has a viscosity in the range of 2,500 to 40,000 centipoise. The method also includes the step of applying the delivery composition in the nasal cavity. The nasal cavity includes a nasal membrane, cilia and mucous. A first portion of the composition directly contacts at least the nasal membrane, a second portion of the composition directly contacts at least said mucous in the nasal cavity, and at least a third portion of the composition directly contacts at least the cilia in the nasal cavity. The improved method also includes the step of increasing the action of the cilia in the nasal cavity.

In yet a further embodiment of our invention, we provide an improved method for controlling the rate at which minor effective amounts of an active substance are delivered into the blood. The improved method includes the step of providing a viscous delivery composition including 75% to 99.999% by weight of at least one carrier, and a minor effective amount of the active substance. The composition has a viscosity in the range of 2,500 to 40,000 centipoise. The method also includes the steps of determining the carrier diffusion rate at which the active substance diffuses through the carrier at a selected temperature and a selected pressure; determining the membrane diffusion rate at which the active substance penetrates a nasal membrane when the delivery composition contacts the nasal membrane at the selected temperature and pressure; selecting at least one of a diffusion rate pair comprising the carrier diffusion rate, and the membrane diffusion rate;and, adding a component to the viscous delivery composition to produce a modified viscous delivery composition in which the diffusion rate of the one of the diffusion rate pair is altered.

Claim 1 of 6 Claims

We claim:

1. A method of delivering minor effective amounts of an active substance into the blood, comprising the steps of

(a) providing a viscous gel delivery composition including

(i) 75% to 99.999% by weight of at least one carrier, and

(ii) a minor effective amount of the active substance comprising zinc,

(b) applying said delivery composition in the nasal cavity, said nasal cavity including mucous, cilia and a nasal membrane, said delivery composition being applied such that a first portion of said composition directly contacts at least the nasal membrane, a second portion of said composition directly contacts at least mucous in the nasal cavity, and at least a third portion of said composition directly contacts at least cilia in the nasal cavity; and,

(c) maintaining said first portion of said delivery composition in contact with the nasal membrane for at least ten minutes.

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