MXPA00005047A - Method and composition for delivering zinc to the nasal membrane - Google Patents

Abstract

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

Description

METHOD AND COMPOSITION TO DISTRIBUTE ZINC TO THE NASAL MEMBRANE This invention relates to compositions and methods for distributing minor, effective amounts of a substance to the blood in a body. More particularly, the invention relates to a method and composition for distributing a lesser, effective amount of a substance to the nasal membrane. In a further aspect, the invention relates to a composition that maintains zinc in an ionic state for distribution to the nasal membrane. In another aspect, the invention relates to a composition that maintains a substance in direct contact with the nasal membrane for a prolonged period of time. The common cold is one of the most frequently occurring human diseases, and is responsible for substantial morbidity and economic loss. Ionic zinc is an effective anti-inovirus agent, known in vitro and in vivo.

In an in vivo study reported in 1991, a double-blind clinical trial demonstrated the effectiveness of zinc glycerin / glycerin tablets, administered orally. The tablets used in the study contained twenty-three milligrams of zinc provided by 179 milligrams of zinc gluconate trihydrate that provided an ionic zinc concentration, millimolar of 13.1 in the oral cavity. During the study, the pills were administered at two-hour intervals resulting in a reduction of forty-two percent in the average duration of the cold and a marked reduction in both the number and the severity of the symptoms without treatment with the Pills started within two days of the onset of cold symptoms. A second study reported in 1992 (Zarmebo JE, Godfrey JC, Godfrey N., J. Pharm Sci 1992; 81: 128-130) confirmed the findings of the 1991 study. Shortly after the results were widely known From these studies, several companies began to market their own versions of the cold remedy with zinc pills.

While zinc pills are usually beneficial in the treatment of a cold, the pills have several disadvantages. First, most zinc in a zinc gluconate pill is released into the oral cavity. However, the main site 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 assumed that some of the ionic zinc released by a pill in the oral cavity makes its way to the nasal passages where zinc binds to the viral ICAM-1 receptors and prevents the rhinovirus from binding to mucosal, nasal, and respiratory cells. infect The difficulty encountered by ionic zinc or another substance in a pill when attempting to travel from the oral cavity to the nasal cavity limits the effectiveness of the pills. In addition, in a congested individual, the route from the oral cavity to the nasal cavity may be completely blocked, rendering the pills ineffective. A second disadvantage associated with zinc pellets is the production of significant side effects. In one study, twenty percent of subjects complained of nausea and eight percent complained of unpleasant reactions (Novick SG, Godfrey J. C, Godfrey NJ, Wilder HR, Medical Hypothesis 1996; 46-: 295-302 ). With regard to nausea, it is well established that excess zinc in the intestinal tract interferes with the absorption of copper and prevents the absorption by the body of sufficient amounts of copper and can lead to a variety of undesirable pathological states. Excessive use of zinc tablets can contribute to depletion in copper. A new gel composition has been discovered and methods for distributing ionic zinc (negatively charged) that and other active substances to the nasal epithelial membrane without encountering the disadvantages normally associated with the pellets. The composition keeps the ionic zinc or other active substance in direct contact with the nasal membrane, preferably for a prolonged period of at least a quarter of an hour, and distribute the zinc or other active substance in the nasal membrane and in the 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 minimum effective amount of an active substance. The minimum effective amount in the gel composition includes from 0.0000001% to 5.0% by weight of the active substance. When the composition in Ge is a pharmaceutical composition, it includes from 75% to 99.999% by weight of at least one porker and a smaller, 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 will be appreciated by those skilled in the art, small concentrations of active substances may not seem homeopathic, but may still be beneficial to the body. These "non-homeopathic" concentrations of an active substance are estimated in the present 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 m), preferably from 0.9% to 2.0% by weight ( from about 20 mM to 44 mM), of zinc gluconate. Each 0.1% by weight of zinc gluconate in the composition produces a concentration of approximately 0.014% by weight of ionic zinc (i.e., approximately 2.2 m ionic zinc) At least a concentration of 4 mM ionic zinc is preferred in the gel composition to ensure that a sufficiently high concentration of ionic zinc is produced by the composition in 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 the maintenance of the composition in the nasal cavity in contact with the nasal membrane or with the mucus of the membrane. When the viscosity is less than about 2,500 centipoise, the composition tends to fall 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 due to the low viscosity of the liquids comprising these dispersions or aerosols that allows liquids to flow under gravity out of the nasal cavity, preventing the aerosols from entering. in contact with the nasal membrane for a prolonged period of time. The effectiveness of a nasal spray usually dissipates substantially in less than five minutes. Similarly, the application of the composition in a cotton or nose cap is not believed to be efficient because the cotton or nose cap, which for example can be made of cotton or a spongy material requires a composition and interferes with the distribution of an additional supply of the composition in contact with the nasal membrane after the dissipation of the composition that is on the surface of the cotton or plug and is in direct contact with the nasal membrane. As noted, nasal sprays were avoided during the development of the invention. As a background with respect to nasal sprays containing zinc, U.S. Patent No. 5,688,532 relates to anti-allergic aerosol preparations and describes and claims a method for the treatment of an allergic condition in which applies an aerosol solution to the eye or respiratory tract of a mammal having the allergic condition. The aerosol solution includes an effective amount, anti-allergy, non-toxic ionic zinc at a lower concentration than that which causes irritation to the mucous membranes. The majority of the ionic zinc in the aerosol solution is non-chelated zinc and is in the form of a 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 aerosol solution may include hay fever and asthma. The aerosol solution can be selected from the group consisting of essentially aqueous and essentially saline solutions; it can have an ionic zinc content of approximately 0.04% (w / v); it may comprise a zinc mineral acid salt as a solute; it may comprise a solute selected from the group consisting of zinc sulfate and zinc chloride; it can be distributed in aliquots of approximately 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 anti- i-t-aminics, flavoring agents and active ingredients; or, it may comprise ascorbate. In U.S. Patent No. 5,688,532 also describes and claims an improvement in a method for the treatment of an allergic condition by administering a zinc compound to a mammal having an allergic condition. The improvement consists essentially of a spray or spray of a solution comprising an effective, anti-allergic, non-toxic amount of ionic zinc to the eye or respiratory tract of a mammal having the allergic condition. The solution comprises a concentration of ionic zinc below which causes irritation to the mucous membranes. The majority of the ionic zinc in aerosol is not chelated and is in the form of a free ionic solution. The solution has an ionic zinc content of between about 0.002 and 0.12% (w / v). U.S. Patent No. 5,622,724 discloses and claims a method for treating the symptoms of the common cold which comprises administering an aerosol or spray of a solution containing an effective, non-toxic amount of symptom treatment, and no solution. of an ionic zinc compound, substantially non-chelated. The solution contains zinc ions substantially not chelated at a concentration of about C.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; may additionally comprise an effective amount of a flavor and / or odor enhancing agent; it may have a non-chelated zinc ion content of approximately 0.04% (w / v); or, may - consist essentially of the zinc, ionic, substantially non-chelated compound and at least one pharmaceutically acceptable carrier. The substantially non-chelated ionic zinc compound may comprise a zinc mineral acid salt; may comprise a salt selected from the group consisting of zinc sulfate and zinc chloride; or, it may comprise zinc sulfate. The use of zinc chloride at concentrations greater than 0.2%, especially and greater than 0.4% is not preferred because, as is well known in the art, zinc chloride is caustic. The carrier used in the invention can include 0.05% to 5.0% by weight of glycerin. Glycerin is important and is currently preferred because it allows zinc to be retained in an ionic state until zinc contacts the nasal membrane and / or mucus in the nasal membrane. A problem encountered during the development of the invention was the identification of the carrier that maintains the zinc in an ionic state. The gel composition of the invention using zinc as in the active substance preferably allows the ionic zinc to diffuse through the composition to the epithelial, nasal or mucus membrane in the epithelial membrane. This facilitates the availability of a continuous supply of ionic zinc because the composition will continue via diffusion to be delivered without requiring that the portion of the composition adjacent to the nasal epithelial membrane (in the mucus in the membrane) dissolve or dissipate and expose a fresh portion of the composition containing the ionic zinc. As noted, viscosities of the composition in excess of about 40,000 centipoise are believed to interfere with the diffusion of zinc through the composition. The viscosity measurements cited herein were obtained using a Brookfield Syncho-Lectric Viscometer for the measurement of the apparent viscosity of Newtonian and non-Newtonian materials at low cutting speeds at given rotational speeds (ASTM D1824-87). See also ASTM D1084-88, ASTM D2196-86 and other ASTM protocols that relate to viscosity measurement. A method for distributing smaller, effective amounts of a metal in the blood has also been discovered. The metal is the active substance. The method includes the step of providing a viscous distribution composition. The distribution composition includes between 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 distribution composition in the nasal cavity in direct contact with the nasal membrane, and maintaining the distribution composition in contact with the nasal membrane for at least one sixth of an hour.

In another embodiment of the invention, an improved method is provided for the distribution of minor, effective amounts of an active substance in the blood. The method includes the step of providing a viscose distribution composition that includes 75% to 99.999% by weight of at least one carrier, a minor, effective amount of the effective 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 composition and distribution in the nasal cavity. The nasal cavity includes mucus, cilia and a nasal membrane. The distribution 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 the mucus in the nasal cavity, and at least a third portion of the nasal membrane. the composition directly contacts at least the cilia in the nasal cavity. The method also includes the step of maintaining the first portion of a composition and distribution in contact with the nasal membrane for at least ten minutes. In a further embodiment of the invention, there is provided an improved method for the distribution of a lower, effective amount of an active substance in the blood and a reduction in the time required for the distribution of the substance in the blood, by increasing the capacity of the blood. the active substance to penetrate the body. The improved method comprises the steps of providing at least one carrier; provide at least one active substance; and providing at least one permeation enhancer to facilitate the passage of the active substance through a nasal membrane into a nasal cavity. The nasal cavity also includes mucus and cilia. The improved method further includes the step of combining the carrier, the active substance and the permeation enhancer to produce a viscous composition and distribution that includes 75% to 99.999% by weight of the carrier, which includes a minor, effective amount of the substance. active, and that includes a smaller, effective amount of the permeation enhancer. The composition of a viscosity in the range of 2,500 to 40,000 centipoise. The method also includes the step of applying the composition and distribution in the nasal cavity such that in the first portion of the composition it directly contacts at least the nasal membrane, such that a second portion of the composition directly contacts at least one nasal membrane. the mucus in the nasal cavity, and at least a third portion of the composition directly contacts > _on the cilia in the nasal cavity; and maintaining the first portion of the distribution composition in contact with the nasal membrane for at least ten minutes. In yet another embodiment of the invention, there is provided an improved method for distributing a lesser, effective amount of an active substance to the blood and reducing the time required for the active substance to pass through the membrane into the blood, by increasing the surface area over which the active substance makes contact with the body. The improved method includes the steps of providing a viscous distribution composition that includes 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 distribution composition in the nasal cavity. The nasal cavity includes a nasal membrane, cilia and mucus. The first portion of the composition directly contacts at least the nasal membrane, a second portion of the composition directly contacts at least the mucus in the nasal cavity, and at least a third portion of the composition directly contacts at least one 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 still a further embodiment of the invention, an improved method for controlling the rate at which the effective, smaller amounts of an active substance is distributed in the blood is provided. The improved method includes the step of providing a viscous distribution composition which includes 75% to 99.999% by weight and 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 maintaining the diffusion rate of the carrier to which the active substance is diffused through the carrier at a selected temperature and a selected pressure; determining the rate of diffusion of the membrane at which the active substance penetrates a nasal membrane when the distribution composition contacts the nasal membrane at the selected temperature and pressure; selecting at least one of a pair of diffusion rates comprising the rate of diffusion of the carrier, and the rate of diffusion of the membrane; and, adding a component to the viscous distribution composition to produce a viscous, modified distribution composition in which the diffusion rate of the pair of diffusion rates is altered. The following examples represent the presently preferred embodiments of the invention for the purposes of illustrating the practice thereof and not of limiting the scope of the invention. The examples, all proportions are by weight, unless stated otherwise.

EXAMPLE 1 A liter of a gel composition is prepared by mixing together purified water, glycerin, carbopol, and zinc gluconate. The gel includes: Component Percent by weight PURIFIED WATER 97.0 GLICERINA U.S.P. 2.0 CARBOPOL 940 nf 0.5 ZINC GLUCONATE (source of 1.5 (concentration 33.3 zinc ion) miiimolar) * * E1 molecular weight of zinc gluconate, approximately 450 g / mol, multiplied sometimes 0. 0333 moles per liter of zinc gluconate gives a weight of about 15 grams per liter of the gel composition.

The concentration of zinc gluconate in the gel composition of the invention is preferably in the range of 0.185% to 2.8% by weight (from about 4 mM to 60 m), preferably from 0.9% to 2.0% by weight (from approximately 20 mM to 44 mM) of zinc gluconate. The carrier in the gel composition can vary as desired, but currently includes preferably 90.0 to 99.0% purified water, and 0.05% to 5.0% by weight glycerin (a thickener that also works to allow zinc maintain its ionic state), and from 0.000001% to 5.0% by weight, preferably from 0.1% to 3.0% by weight, of a carbohydrate or other thickener. A carbohydrate thickener is currently preferred. Other thickeners that can be used include: carrageenan gum, sugar, guar gum, and methylcellulose. The glycerin in the carrier produces a matrix that allows zinc ions to diffuse easily through it. Glycerin is also preferred because it has the ability to dissolve and permeate the raoco and nasal epithelial membrane, transporting ionic zinc with it.

EXAMPLE 2 Two hundred fifty milliliters of the zinc gel of Example 1 are placed in a nasal passage of a male, thirty-nine-year-old, healthy patient. Two hundred fifty microliters of zinc gel from Example 1 are then placed in the other nasal passage of the patient. Consequently, a total of 500 microliters of gel is placed in the patient's nose. A first portion of the gel makes contact with at least a portion of the epithelial, nasal membrane. A second portion of the gel contacts at least a portion of the mucus in the patient's nose. A third portion of the gel contacts at least the cilia in the patient's nose. The gel remains in contact with at least a portion in the epithelial membrane, nasal, cilia, or mucus in the membrane. After four hours, the zinc gel has completely dissipated.

EXAMPLE 3 Example 2 is repeated, except that the individual is a twenty-four-year-old African American patient who has experienced benign symptoms of cold for a day. The gel remains in contact with at least a portion of the epithelial, nasal membrane or the mucus layer in the membrane. After four hours the zinc gel has completely dissipated and the patient perceives a marked reduction in the severity of his cold symptoms.

EXAMPLE 4 Example 3 is repeated, except that the zinc gel of the invention is not administered to the African American patient of twenty-four years of age or age, nor is any other medication administered. After four hours, he does not perceive any reduction in the safety of the symptoms of the cold.

EXAMPLE 5 Examples 3 and 4 are repeated, except that the treated individual is a fifteen-year-old Japanese girl who has been suffering from mild cold symptoms for a day. Similar results are obtained.

EXAMPLE 6 Examples 3 and 4 are repeated, except that the treated individual is a fifty-year-old Caucasian man who has been suffering from cold symptoms for two days. Similar results are obtained.

EXAMPLE 7 Example 2 is repeated except that the concentration of zinc in the nasal mucosa is measured just prior to the insertion of the zinc gel; and, it is measured ten minutes later, thirty minutes, one hour, two hours, three hours and four hours after the gel is inserted into the individual's nasal cavity. The following results are obtained.

EXAMPLE 8 Examples 1 through 6 are repeated, except that the concentration of the ionic zinc in the composition is 20 mM instead of 33.3 millimolar. Similar results are obtained.

EXAMPLE 9 Example 1 to 6 is repeated, except that the concentration of the ionic zinc in the composition is 44 mM instead of 33.3 millimolar. Similar results are obtained.

EXAMPLE 10 Examples 1 to 6 are repeated, except that the concentration of the ionic zinc in the composition is 10 mM instead of 33.3 mmo. Similar results are obtained.

EXAMPLE 11 Example 1 is repeated, except that the zinc gel composition is prepared using 1.5% by weight of NATROSOL (MR) (hydroxyethylcellulose) instead of carbopol and 96% by weight of purified water instead of 97% by weight of purified water. The weight percent of each of the glycerin and zinc gluconate in the gel composition is unchanged.

Example 12 Examples 2 to 7 are repeated, except that the zinc gel composition of Example II is used in place of the zinc gel composition of Example 1. Similar results are obtained.

Example 13 Examples 8 to 10 are repeated except that the zinc gel composition of Example 11 is used in place of the zinc gel composition of Example 1, and the concentration of the ionic zinc in the zinc gel composition of Example 11 is altered as specified in each of Examples 8 to 10. Similar results are obtained. The NATROSOL used in Example 11 is obtained from Hercules Corporation of 1313 North Market Street, Limington, Delaware 19894. Hydroxyethylcellulose is obtained from other vendors. One of the objects of the invention is the distribution in the blood via the nasal membrane of homeopathic concentrations of metals, chemical elements or other active substances. This ordinarily requires the distribution of titrated, selected, specific concentrations (ie, effective, minor amounts) of a substrate. If an active substance or component is distributed to the bloodstream at a concentration that is also too high, this can have an adverse effect on the body. The distribution of minor, effective amounts of the active substances to the bloodstream via the nasal membrane according to the invention is believed to be highly advantageous because it offers a rapid distribution in the blood stream of effective, minor, dosed amounts, selected from a metal, chemical element (s), composition (s), or other active substance. The attempt to orally distribute titrated, homeopathic quantities of chemical elements or compositions is often not believed to be practical due to the degradation of the chemical elements that occurs in the oral cavity. As noted above, as used herein, homeopathic concentrations of an active substance in the gel composition of the invention occur when the active substance is in the gel composition in a minor amount, effective at a concentration in the range from 0.0000001% to 5.0%.

As used herein, a metal, chemical element, or other chemical component or composition is estimated to be an active substance if the mental, chemical element, etc., produces a beneficial physiological effect on the body. An active substance produces a physiological, beneficial effect on the body if the substance after entering the body of a patient the active substance or benefits the skeletal system, the digestive system, the respiratory system, the circulatory system, the reproductive system, the urinary system , the endocrine system, the skin, or the nervous system of the body. One way in which an active substance can produce a beneficial physiological effect is by helping the body fight against the disease. Otherwise it is by helping the body to heal itself. Another way is to improve the functioning of a system in the body. As will be appreciated by those skilled in the art, the active substance can comprise any of a large list of chemical compositions that include, but are not limited to vitamins, minerals, insulin and other polypeptides, nicotine, genes, substances that alter genes or that facilitate gene formation or that disable the genes, and pharmaceutical and homeopathic substances. Nicotine can function as an active substance when used to compensate nicotine in cigarettes in order to make it easier for a person to stop smoking cigarettes. This benefits the lungs and other systems and organs in the body. As used herein, the carrier comprises all components in the gel, nasal composition different from the active substance (s) in the nasal gel. Accordingly, the carrier includes the fluid component of the gel composition (ie, water, oil, alcohol, etc.), includes any thickener in the nasal gel (i.e., glycerin, carrageenan gum, sugar, guar gum). , methyl cellulose, etc.), include permeation int ensifiers (ie, liposomes, chitosan, cyclodextrin, etc.), and includes any other component besides the active substance. As used herein, a permeation enhancer functions to facilitate the passage of the active substance through the nasal membrane, to protect an active substance from being damaged or altered as it passes through the nasal membrane, and / or to transport an active substance to a desired target in the body after the active substances pass through the nasal membrane. Examples of membrane permeation enhancers include liposomes, chitosan and cyclodextrin. A liposome can encapsulate a drug or other active substance and can protect the drug from damage or disruption when the liposome passes through the epithelial, nasal membrane. The liposome can also facilitate passage through the epithelial, nasal membrane upon entering, passing through, and leaving a cell comprising a portion of the nasal membrane. A liposome can be constructed to be a "secret" liposome that can not be "seen" by the liver and degraded by the liver. For example, putting polyethylene glycol in a small concentration in a liposome returns to the liposome a "secret" liposome that can not be "seen" and degraded by the liver. The liposome can also be directed to a specific site in the body. For example, an antigen can be removed from cardiac tissue and used to make an antibody. The antibody is placed in the liposome that carries the active substance. When the liposome passes through the nasal membrane and enters the body, the antibody together with the liposome of the active substance carried in the liposome, will look for an antigen in the heart that corresponds to the class of antigen used to produce the antibody. The protease inhibitor can function as a permeation enhancer by altering the physical characteristics of a liposome or the nasal membrane in order to facilitate the passage of an active substance through the nasal membrane. The permeation inducers are present in the nasal gene at a concentration in the range of 0.000001% to 5.0%. As used herein, the matrix includes the liquid (i.e., water, oil, alcohol, etc.) and the thickener (carragahen, sugar, guar gum, etc.). Zinc in the nasal cavity acts as a decongestant, improving the discharge of mucus and inhibiting the generation of new mucus. Menthol is also a decongestant and can be incorporated into the composition of the invention at a concentration of 0.000001% to 0.10% by weight. Menthol is a bronchial dilator, which works to open the air passages in the lungs and help lift the mucus. When the zinc gel of the invention is applied to the nasal cavity, the zinc ions diffuse from the gel matrix into the mucus or mucous membrane in the nasal cavity. It is believed that the concentration of zinc in the mucus or mucus membrane creates a barrier that inhibits viral infection of the epithelial membrane, nasal As the ionic zinc is absorbed from the gel in the mucous membrane and other nasal epithelial cells, the gel matrix allows the new zinc to diffuse into the nasal membrane. The gel matrix has micelle cell-like properties that facilitate the diffusion of zinc through the gel matrix. The homeopathic concentration of the zinc ions in the zinc gel of the invention is from 4 millimolar (mM) to 60 millimolar, preferably from 20 mM to 44 Mm. Zinc concentrations in excess of 44 mM are not preferred unless an antioxidant or other component is included in the gel composition to protect the epithelial, nasal membrane from the abnormally high zinc concentrations. Examples of antioxidants include ascorbic acid and SOD. The concentration of an antioxidant in the gel composition of the invention is in the range of 0.000001% to 5.0%. In the liquid component (s) in the carrier can be water, one (some) oil (s) and / or one (some) alcohol (s). The liquid component can be from 0% to 100% water, from 0% to 100% oil, or from 0% to 100% alcohol. Examples of oil are polyunsaturated oils, omega 3 and omega 6 monosaturated oils and DHA. An example of an alcohol is ethanol. The use of an oil, either alone or in combination with water and / or alcohol, may be desirable when the active substance is soluble fat. An example of a soluble, active fat is vitamin A. Soluble, fat active ingredients are typically included in the gel, nasal composition of the invention in a concentration in the range of 0.000001% to 4% by weight. Emulsifiers can be included in the nasal gel composition of the invention, especially when the carrier includes water and oil. Glycerol is an example of an emulsifier because it helps to combine the oil with water and protects the membrane when wetting it. The concentration of the emulsifiers in the gel composition, ñ s? Al is preferably currently in the range of 0.000001% to 5.0%. The proteins, polypeptides, nucleic acids, and amino acids are additional examples of active substances, potential for the gel, nasal composition of the invention. A polypeptide is not a protein, but is a polyamide that is obtained by partial hydrolysis of the proteins or by synthesis. A polypeptide produces amino acids in hydrolysis but has a much lower molecular weight than a protein. The nasal membrane in general has no affinity for proteins and tends to prevent proteins and polypeptides, even the smallest polypeptides, from passing to and through the nasal membrane. The nasal membrane may also tend to prevent the passage of amino acids; however, in some cases, the nasal membrane does not prevent the passage of amino acids because there are transporters in the nasal membrane for certain amino acids. Sometimes enzymes are polypeptides. Hormones such as insulin, growth hormones and secretin are polypeptides. Insulin is a polypeptide.

Enzymes such as protease inhibitors can function as intmeators of the permeation because they facilitate the passage of the active ingredients through the nasal membrane. Hydroxycellulose or other thickeners or components can be used, if desired, to form colloidal solutions (ie, suspensions) in order to increase the viscosity of the carrier in the nasal gel composition. The currently preferred concentration for the thickeners is from 0.000001% to 5.0% by weight. Permeation enhancers can, by enlarging or loosening the firm junctions between the cells in the nasal membrane, facilitate the passage of an active substance, a liposome, or another permeation enhancer through the nasal membrane. By way of example, and not limitation, EDTA can chelate calcium. By removing calcium from the cell junctions, EDTA can loosen the functions to facilitate the passage of an active substance, liposome, etc., through the junction. The liquid permeation enhancer includes ascorbic acid in water, glycerol in water, chitosa in water, and lysophosphotidylcholine in oil. The concentration of the permeation inducers in the nasal gel is in the range of 0.00001% to 5.0%. Other anti oxidants that can be used in the gel of the invention include green tea catech, epigallate and selenium. The currently preferred concentration range for an antioxidant in the gel composition is from 0.000001% to 5.0%. The variation of the diffusion rate of an active substance through the carrier, the mucous, epithelial, nasal membrane, or through the mucus in the nose is important in the practice of the invention. In order to increase the rate of diffusion of an active substance through the nasal membrane, the concentration of a permeation activator such as vitamin C or liposome can be increased. Permeation enhancers such as vitamin C or liposomes can be included in the nasal gel at concentrations in the range of 0.000001% to 5.0% by weight. By making the nasal gel less viscous, it is another way to increase the diffusion of an active substance through the nasal membrane. Normally, an active substance or permeation enhancer that carries the active substance can move more freely through the nasal gel when the gel is less viscous. Similarly, the rate of diffusion of an active substance through the nasal gel itself can be increased by decreasing the viscosity of the nasal gel or by using ui. iiposome or another chemical component that facilitates the diffusion of an active substance through the nasal gel either by transporting the active substance or by interacting with the nasal gel to facilitate the passage and diffusion of the active substance through the nasal gel. The rate of diffusion of an active substance through the nasal gel itself is important when the concentration of the active substance in the gel becomes lower near or in the gel-nasal membrane interface. When the concentration in the gel of the active substance near or in the gel-nasal membrane interface becomes less than the concentration of the active substance in the rest of the gel, it is desirable for the active substance to diffuse easily through the gel to replenish the concentration of the active substance in or near the gel tracer-nasal membrane. The concentration of the active substance at or near the interface of the nasal membrane becomes less when the active substance is absorbed from the gel on the nasal membrane. t.n liposomes and other chemical components can be included in the nasal gel at concentrations in the range of 0.000001% to 5.0% by weight. The rate of diffusion of an active substance through the mucus in the nasal passage can be increased by using in the gel composition an agent such as zinc or salt that facilitates the breakage and drying of mucus in the nose or when used in the composition in gel a component that actually facilitates the trip of an active substance through the mucus. The mucus is a protein and has different properties than the epithelial membrane, nasal Agents such as zinc or salt may be included in the nasal gel in concentrations in the range of 0.000001% to 5.0% by weight. Another method to facilitate the diffusion of an active substance in the nasal membrane is to spread the nasal gel over a larger surface area of the nasal membrane. One way in which it is facilitated is by improving the action of cilia that tend to hit or carry mucus or foreign substances in the nose towards the back of the throat. Chemical components such as lipozymes can be included in the nasal gel in concentrations in the range of 0.00001% to 5.0% by weight to increase the action of the cilia and therefore to increase the speed at which the gel composition is transported. backwards, after it is inserted into the patient's nose, from the nose down through the nasal passage to the back of the patient's throat. The increase in the action of the cilia works to increase the speed at which the nasal gel has a greater surface area in the nasal passage. As used herein, the nasal passage begins behind the nose at a point about a quarter of an inch to a half inch from the opening in each nostril extending to the back of a patient's throat. The nasal passage includes portions of each nostril of a patient's nose. The absorption of an active substance in the gel of the invention in the lungs or nasal membrane can be facilitated by sublimation. For example, canfor or iodine can be mixed with the nasal gel of the invention sometime before inserting the gel into the nose of the patient. The content of a sublimation active substance may vary as desired, but is typically in the range of 0.00001% to 5.0% by weight. In the nasal gel, it is sometimes important to maintain an active substance such as zinc in its ionized state. One way to increase the likelihood that an active substance will remain in its ionized state is by increasing the viscosity of the nasal gel. An additional way to increase the probability that an active substance will remain in its ionized state is by using a thickener that will not bind with the active substance when the active substance is in an ionized state. For example, carbopol does not bind with zinc and in general is therefore not a preferred thickener in gel compositions in which it is desired to keep zinc in its ionized state. Most thickeners do not bind with zinc ions. Ascorbic acid also binds with zinc. Therefore, ascorbic acid is not ordinarily used in combination with a gel composition that includes ionic gel as an active substance. Glycerin works to help keep zinc and other components in their ionic state. When the nasal gel includes zinc ions and is being used to treat rhinoviruses, it is important to use the gel in both nostrils of the patient's nose. In other circumstances, for example, the distribution of a vitamin in the patient's bloodstream is not necessary since the gel is placed in both nostrils. The use of just one nostril may be enough. One may wish to use a nasal gel composition that thickens when placed in a patient's nostril. Using a component that is sensitive to temperature and thickens due to the increased temperature in the patient's nose is a way to produce an increased viscosity when the nasal gel is applied to the patient's nose. Another way is to mix two or more components just before applying the nasal gel to the patient's nose. The two components produce a composition that has a higher viscosity than any component separately. The nasal gel of the invention can be packaged in a capsule or other excipient that dissolves upon insertion into the nose. When the excipient dissolves, the gel makes contact with the nasal membrane. The capsule can be made of gelatin, from a water soluble material, foldable, soft paper type, or from any other desired material that dissolves or disintegrates or degrades otherwise when placed in the nasal cavity.

Example 14 One liter of a gel composition is prepared by mixing together purified water, glycerin, carbopol, liposomes, and insulin. The gel includes: Component Percent by weight PURIFIED WATER 96.5 GLICERINA U.S.P. 2.0 CARBOPOL 940 nf 0.5 INSULIN 0.5 LIPOSOMES (carrier for 0.5 insulin) EXAMPLE 15 Two hundred milliliters of the gel of Example 14 is placed in the nasal passage of a Caucasian male patient, thirty-nine years old, healthy. Two hundred milliliters of the zinc gel of Example 1 are then placed in the other nasal passage of the patient. Consequently, a total of 400 milliliters of the gel is placed in the patient's nose. A first portion of the gel makes contact with at least a portion of the epithelial, nasal membrane. A second portion of gel contacts at least a portion of the mucus in the patient's nose. A third portion of the gel contacts at least the cilia in the patient's nose. The gel remains in contact with at least a portion of the epithelial membrane, nasal, cilia, or mucus membrane. After four hours, the zinc gel has completely dissipated.

Example 16 One liter of a gel composition is prepared by mixing together purified water, oil, glycerin, carbopol, liposomes, and vitamin A. The gel includes: Component Percent by weight PURIFIED WATER 86.5 OMEGA 6 (MONOSATURATED OIL) 10.0 GLYCERIN U.S.P. 2.0 CARBOPOL 940 nf 0.5 VITAMIN A 0.5 LIPOSOMES (carrier for 0.5 vitamin A) EXAMPLE 17 Three hundred milliliters of the gel of Example 16 are placed in a nasal passage of a healthy, female Chinese female, twenty-eight years of age. Consequently, a total of 300 milliliters of the gel is placed on the patient's nose. A first portion of the gel makes contact with at least a portion of the epithelial, nasal membrane. A second portion of the gel contacts at least a portion of the mucus in the patient's nose. A third portion of the gel contacts at least the cilia of the patient's nose. The gel remains in contact with at least a portion of the epithelial membrane, nasal, cilia, or mucus in the membrane. After four hours the zinc gel has completely dissipated.

EXAMPLE 18 One liter of a gel composition is prepared by mixing together purified water, water, alcohol, glycerin, carbopol, and nicotine. The gel includes: Component Percent by weight PURIFIED WATER 87.25 ALCOHOL 10.0 GLYCERIN U.S.P. 2.0 CARBOPOL 940 nf 0.5 NICOTINE 0.25 EXAMPLE 19 One hundred fifty milliliters of gei-in Example 18 are placed in a nasal passage of a healthy, female African-American patient, fifty years of age. Consequently, a total of 150 microliters of the gel is placed in the patient's nose. A first portion of the gel makes contact with at least a portion of the epithelial, nasal membrane. A second portion of the gel contacts at least a portion of the mucus in the patient's nose. A third portion of the gel contacts at least the cilia in the patient's nose. The gel remains in contact with at least a portion of the epithelial membrane, nasal, cilia, or mucus in the membrane. After three hours the zinc gel has completely dissipated.

EXAMPLE 20 One liter of a gel composition is prepared by mixing together purified water, glycerin, carbopol, zinc gluconate, and SOD. The gel composition includes: * The molecular weight of zinc gluconate, approximately 450 g / mol, increased by 0.05 mol per liter of zinc gluconate gives a weight of approximately 22.5 grams per liter in the gel composition.

The anti-oxidant SOD works to protect the epithelial, nasal membrane where it owed to high concentrations of zinc ion in the nasal gel.

EXAMPLE 21 Examples 2 to 7 are repeated using the gel composition of Example 20 in place of the gel composition of Example 1. Similar results are obtained.

EXAMPLE 22 Example 7 is repeated except that the patient has a layer of mucus about one-sixteenth of an inch thick that covers the nasal mucosa. Similar results are obtained.

EXAMPLE 23 Example 22 is repeated except that the gel composition of Example 1 also includes 1.0% by weight of NaCl and that the weight percent of purified water in the gel composition is 96% instead of 97%. The weight percent of glycerin, carbopol, and zinc gluconate in the gel composition of Example 1 remains the same. The salt is included in the gel composition in order to facilitate the diffusion of the zinc through the mucus layer. The results obtained in this Example 23 are similar to those of Example 22, except that the concentration of zinc in the nasal mucosa increases more rapidly in Example 23 because the salt facilitates drying and dissipation of the mucus layer.

EXAMPLE 24 Example 7 is repeated except that the gel composition of Example 1 is inserted into the nasal passage of the nose and instead of measuring the concentration of zinc in the nasal mucosa just before the administration of the zinc gel, ten minutes after the administration of the zinc gel, half an hour after the administration of the zinc gel, etc., the distance of the zinc gel that has turned back in the nasal cavity by the cilia in the nasal cavity after ten is measured minutes, half an hour, etc.

EXAMPLE 25 Example 24 is repeated except that the gel composition of Example 1 also includes 0.5 wt% lysozyme and that the weight percent of the purified water is 96.5% instead of 97%. The weight percent of glycerin, carbopol and zinc gluconate in the gel composition of Example 1 remains the same. The lysozyme included in the gel composition increases the activity of the cilia in the nose and as a result, increases the speed at which the cilia transport the zinc gel from the inside of the nose back through the nasal cavity towards the nose. back of the patient's throat. The results obtained in Example 25 are similar to those obtained in Example 24, except that in Example 25 the cilia transport the zinc gel more rapidly towards the back of the patient's throat.

EXAMPLE 26 The gel composition of Example 1 is placed against a surface that removes the zinc from the gel in the gel-surface interface at a selected ratio. The rate of diffusion of zinc from a selected point (the point that is a distance selected from the interface) to the interface is measured.

EXAMPLE 27 Example 26 is repeated, except that the viscosity of the gel composition of Example 1 is reduced by reducing the concentration of carbopol to 0.25 weight percent and reciprocally increasing the concentration of purified water to 97.25%. The concentration of glycerin and zinc gluconate remains the same. The results obtained are similar, except that the diffusion rate of zinc ions is higher in this Example 27 than in Example 26 due to the reduced viscosity in the gel composition.

EXAMPLE 28 Example 15 is repeated, except that the concentration of insulin in the nasal membrane is measured at 10, 20 and 30 minutes.

EXAMPLE 29 Example 28 is repeated except that the liposomes are removed from the gel composition of Example 14 and the concentration of the purified water. it increases reciprocally to 97% by weight. Liposomes are peri-growth enhancers and are added to enhance or improve the ability of insulin to permeate the epithelial, nasal membrane. The concentration of glycerin, carbopol, and insulin in the gel composition of Example 14 remains the same. The results obtained in this Example 29 are different from those obtained in Example 28, because the concentration of insulin in the nasal mucosa increases more slowly due to the permeation inducers of the liposomes that are not present for a longer time. the gel composition. Having described the present invention in these terms to feel that those skilled in the art understand and practice it, and having identified the presently preferred embodiments thereof, it is claimed:

Claims (4)

1. CLAIMS 1. A method for distributing minor, effective amounts of an active substance in the blood, comprising the steps of: (a) providing a viscous distribution composition that includes: (i) from 75% to 99.999% by weight of at least one carrier, and (ii) an effective, lower amount of an active substance, the composition has a viscosity in the range of 2,500 to 40,000 centipoise; (b) applying the distribution composition in the nasal cavity, the nasal cavity including mucus, cilia and a nasal membrane, the distribution composition being 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 one mucus in the nasal cavity, and at least a third portion of the composition directly contacts at least the cilia in the nasal cavity; and (c) maintaining the first portion of the contact and distribution composition with the nasal membrane for at least ten minutes.
2. 2. A method for distributing an effective, lesser amount of an active substance to the blood and reducing the time required to distribute the substance in the blood by increasing the ability of the active substance to penetrate the body, comprising the steps of: a) providing at least one carrier including an effective amount, less than at least one gel permeation enhancer in the carrier to facilitate the passage of an active substance through a nasal membrane into a nasal cavity, the nasal cavity including snot and cilia; (b) providing at least one active substance; (c) combining the carrier of the active substance to produce a viscous distribution composition, which includes: (i) from 75% to 99.999% by weight of the carrier, and (ii) an effective, lower amount of an active substance, this composition having a viscosity in the range of 2,500 to 40,000 centipoise; (d) applying the distribution composition in the nasal cavity 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 the mucus in the nasal cavity, and at least a third portion of the composition directly contacts the cilia in the nasal cavity; and (e) maintaining the first portions of the dispensing composition in contact with the nasal membrane for at least ten minutes.
3. 3. A method for distributing an effective, lesser amount of an active substance to the blood and to reduce the time required for the active substance to pass through the membrane in the blood by increasing the surface area over which the active substance makes contact with the body, comprising the steps of: (a) providing a viscous distribution composition, which includes: (i) from 75% to 99.999% by weight of at least one carrier, and (ii) an effective amount, minor of the active substance, the composition having a viscosity in the range of 2,500 to 40,000 centipoise; (b) applying the distribution composition in the nasal cavity, (i) the nasal cavity including a nasal membrane, cilia and mucus; (ii) a first portion of the composition directly contacts at least the nasal membrane, a second portion of the composition directly contacts at least the mucus in the nasal cavity, and at least a third portion of the composition makes contact directly with at least the cilia in the nasal cavity; and (c) increase the activity of the cilia in the nasal cavity.
4. 4. A method for controlling the rate at which effective, lesser amounts of an active substance is distributed in the blood, comprising the steps of a) providing a viscous distribution composition, which includes: (i) 75% a 99.999% by weight of the least one carrier, and (ii) an effective, smaller amount of the active substance, the composition having a viscosity in the range of 2,500 to 40,000 centipoise; (b) determining the rate of diffusion of the carrier to which the active substance is diffused through the carrier at a selected temperature and to a selected portion; (c) determining the membrane diffusion rate at which the active substance penetrates a nasal membrane when the distribution composition contacts the nasal membrane at the selected temperature and pressure, (d) selecting at least one of a pair of velocities of fusion, comprising: (i) the rate of diffusion of the carrier, and (ii) the rate of membrane diffusion; (e) adding a component to the viscous distribution composition to produce a viscous, modified distribution composition in which the diffusion rate of a pair of diffusion rates is altered.