MXPA01002002A - Oral mucoadhesive compositions containing gastrointestinal actives - Google Patents

Abstract

The present invention relates to mucoadhesive compositions comprising a safe and effective amount of a gastrointestinal active;from about 1.5%to about 10%, by weight of the composition, of a clay component;and from about 0.01%to about 1%, by weight of the composition, of a gum component. Alternatively, the clay component can be a titanium dioxide or a silicone dioxide component. The mucoadhesive compositions also preferably comprise up to about 2%by weight of the composition, of a non-ionic component such as methyl cellulose. The present invention also relates to methods of prevention and treatment of gastrointestinal tract disorders in humans or lower animals by orally administering a composition of the present invention.

Description

ORAL MUCOADHESIVE COMPOSITIONS CONTAINING GASTROINTESTINAL ASSETS BACKGROUND OF THE INVENTION The present invention relates to gastrointestinal pharmaceutical compositions having improved retention, suitable for oral administration to humans or lower animals. The compositions of the present invention are widely used to treat a variety of gastrointestinal disorders such as nausea, heartburn and diarrhea. Some patent references, such as the patent of E.U.A. No. 4,940,695, to Coveney et al., Which is incorporated herein by reference in its entirety, discloses gastrointestinal pharmaceutical products containing bismuth such as Pepto-Bismol® (marketed by Procter &Gamble Company). Additionally, there are many other known gastrointestinal compositions. However, the gastrointestinal compositions of the prior art have limited mucoadhesive properties. The prolonged coating is desirable since it protects the mucosa and the underlying tissue against irritating or harmful agents and / or accelerates the healing of inflamed or damaged tissue. Additionally, the extended coating also provides a matrix for enhanced delivery of the gastrointestinal active to the coated tissue resulting in higher efficacy and / or low side effects.

Therefore, there remains a need for a consumer acceptable gastrointestinal composition, which has improved mucoadhesion for exceptional coating and efficacy in the gastrointestinal tract. Through careful formulation, gastrointestinal compositions having improved mucoadhesion as well as viscosities and aesthetics acceptable to the consumer have been created. These mucoadhesive compositions comprise a gastrointestinal active, a clay / particulate component, a rubber component, and optionally a non-ionic component. These and other formulations of the present invention will be readily apparent from the detailed description that follows. All percentages and ratios used herein are by weight and all measurements are at room temperature, unless otherwise indicated. As used herein, "mi" means milliliters, "mm" means millimeters, "mg" means mg, and "nm" means nanometers.

BRIEF DESCRIPTION OF THE INVENTION The present invention relates to mucoadhesive compositions comprising a safe and effective amount of a gastrointestinal active; from 1.5% to about 10% by weight of the composition, of a clay component; and from 0.01% to about 1%, by weight of the composition, of a gum component. Alternatively, the clay component can be a component of titanium dioxide or silicon dioxide. The mucoadhesive compositions also preferably comprise up to 2% by weight of the composition, of a non-ionic component such as methylcellulose. The present invention also relates to methods of prevention and treatment of gastrointestinal tract disorders in human or lower animals by oral administration of a composition of the present invention.

BRIEF DESCRIPTION OF THE DRAWING Figure 1 is an idealized rheogram that is useful for graphically displaying a number of terms and concepts that are used in the present invention. Figure 1 is a graph of the logarithm of the shear stress applied to the logarithm of the viscosity. A represents the viscosity of zero shear stress. B represents the yield stress, and C represents a high shear viscosity.

DETAILED DESCRIPTION OF THE INVENTION Figure 1 shows the logarithm of the shear stress applied to the logarithm of the viscosity. Figure 1 is a representative rheogram resulting from the test of a viscous liquid material that is thin with shear stress in a controlled stress rheometer. In the tension ramp testids , initially very low shear stress is applied to the sample, and gradually but continuously the shear stress is increased, all the time determining the constant stress regime resulting in the sample. Figure 1 is useful for defining terms related to the viscosity and flow properties of liquid materials, in particular the shear thinning liquclaimed herein. The term "shearing thinning", as used herein, refers to a liquid having a higher viscosity when the applied shear stress is very low. At higher shear forces, a thinner liquid with shear stress has a lower viscosity. This characteristic low viscosity of a shear thinning composition under high shear stress is called the "high shear viscosity" C. since the structure in the liquid is largely undisturbed by the initial stress of low shear applied in the test, the viscosity of the composition does not change to a wide degree. However, as the shear stress increases, there will be a disproportionate increase in the shear rate as the internal structure in the fluid decomposes, and correspondingly, the viscosity decreases. The shear stress applied to the fluid at which the rapid flow only begins to occur is called the "yield stress", or "yield value" B.

The "zero shear viscosity" is a measure of the internal structure in the liquid formulation and is the viscosity when the stress below the yield stress is applied A. The shear stress viscosity can be determined exactly by the flow compliance method using a sensitive, controlled voltage rheometer. This method is described in the book "A Practical Approach to Rheology and Rheometry", by Gebhard Schramm, 1994, page 107, which is incorporated herein by reference in its entirety. Approximately 0.9 ml volume of the liquid sample is placed on the rheometer plate (Haake R150), and a 35 mm cone, 4 degree angle is lowered to the measuring position. An equilibrium shear stress of approximately 20 per second is applied for 10 seconds, then no tension is applied for 2 minutes. At the end of 2 minutes, an instantaneous shear stress is applied and held constant for 5 minutes (hereinafter referred to as "yield stress"). This yield stress must be below the yield stress. A graph of stress induced elongation in the sample on the Y axis is generated against the time the yield stress is applied on the X axis. This graph will exhibit a large instantaneous increase in shear elongation at the beginning of the test, and After some period of curvature the graph will show that the elongation of shear stress increases proportionally in a straight line with time. The calculated slope of this shear-time elongation line is divided into the applied yield stress to give a viscosity. As long as the yield stress is below the yield value of the liquid, then the viscosity determined in this way is the viscosity of zero shear stress. Other terms useful herein are defined below. In addition, terms used in the art, as well as general concepts, are further described in "The Language of Coolloid and Interface Science" by Laurier L. Schramm, American Chemical Society, 1993, which is incorporated herein by reference in its entirety The term "shear stress" as used herein is the deformation ratio of a fluid when subjected to a mechanical shear stress. In shear stress of simple fluid, successive layers of fluid move in relation to each other so that the displacement of any layer is proportional to its distance from a reference layer. The relative displacement of any two layers divided by their separation distance from one another is called "shear stress" or "shear strain". The rate of change with time of shear is called "the shear rate". A certain applied force is needed to produce deformation in a fluid. For a flat area around some point in the fluid and at the limit of the area that decreases, the component of deformation forces per unit area that acts parallel to the plane is the "shear stress".

The "viscosity" of a viscous material, also called the viscosity index, is defined as the ratio of the shear stresses applied to the material, divided by the resultant shear velocity. Materials of higher viscosity have a higher resistance to flow, or forces that can induce flow, than a material of lower viscosity. All viscosities listed herein are at a shear rate of about 50 per second unless otherwise indicated. The viscosities given herein can be measured in a controlled voltage rotary viscometer, for example Haake RS 150 namely by Haake GmbH, Karisruhe, Germany, Carrimed CSL 500 Controlled Stress Rheometer by TA Instruments, New Castle, Delaware, and Rheometric SR5, by Rheometric Scientific, Piscataway, NJ. The present invention relates to mucoadhesive oral formulations comprising colloidal suspensions that form a coating matrix on the epithelium of the gastrointestinal tract. The term "colloidal" as used herein refers to finely divided solid material in which the Ti? 2, SiO2) and / or clay particles are dispersed in a liquid phase and have a particle size of generally less of 10 microns, or the particles have at least one dimension between 1 and 1000 nm. The particle size of the solid particles of the present invention are of colloidal dimension, from about 1 nm to 10 microns, preferably 1, 000 nm or smaller. The use of small particle sizes increases the surface area for improved absorption or bridge formation of the particle to mucin. The term "colloidal suspension" as used herein refers to a system in which essentially solid colloidal particles are dispersed in a continuous phase of composition or different state, for example water. The colloidal suspensions of the present invention form a coating matrix on the epithelium of the mucosa of the gastrointestinal tract. The colloidal suspensions of the present invention should have a high viscosity of zero shear stress. The zero shear viscosity of the compositions present should be at least 2000 pascal seconds, preferably greater than 7500 pascal seconds, more preferably greater than 25,000 pascal seconds. The term "gastrointestinal tract" as used herein refers to the mouth, pharynx, esophagus, upper and lower gastrointestinal tract, including the stomach and the large and small intestines. The term "gastrointestinal disorder" as used herein, encompasses any infection, disease or other disorder of the gastrointestinal tract that is treatable or prevented by oral administration of gastrointestinal actives. Examples of such disorders include heartburn, indigestion, nausea, vomiting, altered stomach, diarrhea, traveler's diarrhea, abdominal pain / colic, constipation, gastritis, ulcers, and / or gastroesophageal reflux diseases. The term "gastrointestinal fluid" as used herein refers to saliva, gastric juice, intestinal fluid, and mixtures thereof.

The term "pharmaceutically acceptable" as used herein means that the components present in the compositions of the present invention are compatible and suitable for oral administration to a human or lower animal. The term "compatible" as used herein, means that the components of the pharmaceutical compositions are capable of being blended with one another in a manner that there is no interaction that would substantially reduce the safety or pharmaceutical efficacy of the pharmaceutical compositions under ordinary use situations. The term "mucoadhesive" or "bioadhesive" as used herein refers to the phenomenon where a natural or synthetic substance applied to an epithelium of the mucosa, adheres, usually creating a new interface, to the mucosal layer. (CRC Critical Reviews in Ther Druq Carrier, Vol. 5 issue 1 (1988) pp. 21). In general, mucoadhesion can be eved through physical or chemical procedures or both. This mechanism is described in Journal of Controlled Relay, Vol. 2 (1982) pp. 257 and Journal of Controlled Relay, Vol. 18 (1992) pp. 249. The above references are incorporated by reference herein in their entirety. The "mucoadhesive" compositions of the present invention have mucorretentive properties. The term "mucorretentive" (or retentive) as used herein refers to a degree of resistance to the normal physiological propelling mechanism that involves the contraction of longitudinal and circular muscle fiber, which transports substances through the gastrointestinal tract, i.e. resistance to peristalsis. In addition, mucorretentive refers to a degree of resistance of a composition to washing forces and fluid solvents in the gastrointestinal tract. The inventors used a test that measures the tendency of a liquid formulation to be coated on gastrointestinal tissue and to resist shear forces and rinsing of gastrointestinal fluid. This test was based on a method to evaluate the ability of gastrointestinal therapeutic formulations to bind and be retained on the esophageal mucosa (LR Fitzpatrick et al., Gastroenterology, "A Comparison of Sucralfate and Bismuth Subsalicylate Formulation in Rabbit Esophageal Models", Vol. 108, 1995 p.A94, incorporated herein by reference in its entirety). In this method, a freshly collected esophagus from a rabbit or rat is cut into 2 cm long sections. The tissue is turned inside out on a glass rod so that the surface of the mucosa is facing outward. This surface of the mucosa can then be immersed in the formulation. Formulations with preferred rheology properties will tend to spread over the mucosa and then to form a coherent coating layer. Resistance to mechanical strength and washing can be determined by vertically immersing the coated tissue in gastrointestinal fluid over and over again by reciprocation. The amount of formulation remaining coated on the tissue at the end of rinses in gastrointestinal fluid or saliva has been determined to be a useful number to determine whether a formulation has mucorretentive properties. This can be quantified by measurement using a specific chemical analytical technique for a component of the formulation, or by incorporation of an easily measured colloidal non-diffusion marker material into the formulation prior to testing. The mucorretentive compositions of the present invention have, after 30 rinses in sham saliva, 80% of the initial amount still adhered to the tissues, preferably 85%, more preferably 90% or greater. The simulated saliva used for this retention test was adapted from Fusayama et al (Fusayama, T., Katayori, S., Nomoto, S., "Corrosion of gold and amalgam placed in contact with eother", J. Dent. 42, 1963, 1183-1197) and contains on a mg / ml basis: KCI 0.4; NaCI 0.4; Na2SO4 0.013; MgCl2 0.018; K2HPO4 4.2; KH2PO4 3.2; KOH 0.19; and 4.0 of submaxillary mucin coil. The simulated saliva used to determine the viscosity triggered ratio was more concentrated to count for the dilution that occurs in the rheology test. It contains on a mg / ml basis an 8.3 times higher concentration of ingredients than the previous simulated saliva, except that the salivary mucin was 83 mg / g. More preferably, when treating gastrointestinal disorders, the compositions of the present invention have, after 30 rinses in simulated gastric fluid, 80% of the initial amount still adhered to the tissues, preferably 85%, more preferably 90% or greater. The simulated gastric fluid useful in this test can be manufactured according to the instructions found in U.S. Pharmacopoeia 23, 1995, US Pharmacopeial Convention, Rockville, MD, p. 2053, which is incorporated herein by reference in its entirety. The term "glycoprotein" as used herein, refers to a class of conjugated proteins comprising a protein with a carbohydrate group. The glycoproteins yield, in decomposition, a product capable of frequently reducing alkaline solutions of cupric oxide. Glycoproteins include mucins, mucoids, and the condoproteins. The term "mucin" as used herein, includes that which is contained in the saliva, gastrointestinal fluid, and / or associated with the surface of the gastrointestinal tissue. Mucin is produced inside the body and provides lubrication and protection to mucous surfaces. It consists of a protein base structure, on which many polysaccharide chains are attached. In the dry state, the mucin material is 70 to 80% by weight, carbohydrate. Mucin, with its high molecular weight, forms filament-like chains as long as 4-6 microns long, and can be effective for bridging a colloidal suspension of particles that absorb it. In order to provide suspensions with acceptable aesthetics, it is desirable that the suspensions are thinned when agitated and / or poured into a spoon, feeder, or other dosing device. Said agitation and pouring subject the suspensions at a shear rate of about 10 to 1,000 per second. Additionally, when ingested, a liquid is subjected to a shear rate of 10 to 100 per second. It is also critical that suspensions are significantly thinned when ingested in order to achieve adequate dispersion and coating of the gastrointestinal tract. Specifically, when subjected to a constant shear rate of about 100 per second, the liquid compositions present have a viscosity of less than 1.5 seconds pascal, preferably less than 75 seconds pascal, more preferably less than 0.5 seconds pascal. The solid particles of the present invention must be selected and formulated so that contacting and mixing a formulation of the present invention (hereinafter "the formulation") to a mucosal surface such as the gastrointestinal tract triggers the conversion of the formulation to a more viscous gel-like mixture. In other words, after the formulation is mixed with gastrointestinal fluid, the viscosity of the formulation is greater than the viscosity of the formulation before mixing, or of the mixture of gastrointestinal fluid alone. The value of the viscosity ratio triggered from the formulation ("T") is useful in determining the degree to which a composition exhibits the gelling characteristic described above. The formula and the procedure for determining the triggered viscosity ratio is discussed below. It is desirable that the compositions of the present invention exhibit a fired viscosity ratio of at least 1.2, more preferably at least 1.4, and more preferably at least 1.5 where the fired viscosity is defined by the following formula: T = wherein? g = viscosity of the gel where? t = viscosity of the formulation of the present invention. As used herein, the term "gel" describes the substance that results from the combination of a mixture of mucin saliva and the formulation. To determine the viscosity ratio triggered herein, the mucin saliva mixture is formed by mixing a commercial supply of mucin and a concentrated form of saliva. For use in the present test, mucin saliva comprises, on a mg / ml basis, KCI 3.32, NaCl 3.32, Na2SO0108, MgCl2 0.150, K2HP04 34.86, KH2PO4 26.56, KOH 1.57, and submaxillary mucin coil 83. Submaxillary mucin coil is available commercially from Sigma Chemical Co., St. Louis, MO, as submaxillary mucin type I coil, catalog # M4503. The triggered viscosity ratio of a formulation can be determined by the following method. First, the viscosity of the formulation (? F) is determined in a rheometer using a shear rate of 50 per second. For the determination of? F, 0.9 ml of the formulation are placed on the plate of a Haake RS150 rheometer. The temperature is controlled in the typical room temperature scale, approximately 23 ° C. A cover is used on the measuring system to prevent evaporation of water from the sample during the test. A 4-degree angle cone measurement system, 35 mm in diameter, is lowered onto the sample, and an equilibrium shear force of approximately 20 per second is applied for 20 seconds. After a rest period in which no tension is applied for 2 minutes, a constant shear rate of 50 per second is applied for 65 seconds. The viscosity? F is read from the instrument at the time point of 60 seconds. For the determination of? G, 0.5 ml of the mucin saliva mixture defined above are combined with 4.5 ml of the formulation and the two are mixed together gently for 5 minutes. The mixture is then loaded onto the plate of the same rheometer used for the measurement of? F except that the temperature is controlled at the normal body temperature of a human, 37 ° C. An identical rheometer measurement program is used for the determination of? F. The activated viscosity factor is calculated from? F and? G as described above.

Sedimentation Volume Ratio Another essential feature of the compositions of the present invention is that the compositions have a sedimentation volume ratio greater than 0.90, preferably greater than 0.95, more preferably greater than 0.98 and even more preferably approximately 1 (after approximately 48 hours). The sedimentation volume ratio is determined by carefully filling a sample of the formulation in a graduated cylinder of clear glass, covering the cylinder to prevent any evaporation, and allowing the formulation to remain undisturbed and free of significant vibration. After at least 48 hours, determine the total volume occupied in the cylinder (V0) and the final volume of any sediment that may have been formed by settling the components of the suspension below the total volume (Vu). (This procedure is explained in "Coarse Dispersions," chapter 18 in "Physical Pharmacy," A. Martin, Lea and Febiger, Malvern, PA, 1993, p. 480). The ratio of sedimentation volume is then the ratio of the final volume to the volume occupied (Vu / V0).

Components The pharmaceutical compositions of the present invention are formulated to provide a safe and effective amount of the components defined below. Specifically, as used herein, the phrase "safe and effective amount" means an amount of particulate component, clay, gum component, and / or gastrointestinal active, sufficiently high to significantly (positively) modify the condition which will be treated or effect the desired result, but low enough to avoid serious side effects (at a reasonable benefit / risk ratio), within the scope of sound medical judgment. The safe and effective amount will vary with the particular condition or disease that is being treated, the age and physical condition of the patient being treated, the severity of the condition, the duration of the treatment, the nature of the concurrent therapy, the specific to the particles or active agent used, the particular vehicle from which the particles or active agent are applied, and similar factors within the knowledge of the attending physician or one skilled in the art.

Clays Clay is present at a level of 1.5% to 10% by weight of the composition, preferably 2.5% to 6.5%, more preferably 3.5% to 4.5% by weight. The clays are composed of fine particles of mineral clays that are anhydrous layer-type silicates (containing hydroxyl structural groups) of aluminum, magnesium, potassium, iron and other less abundant elements, particularly alkalis and ferrous alkali metals. Silicates of aluminum, magnesium and iron are preferred. Aluminum silicates are more preferred. Magnesium aluminum silicate (or magnesium aluminum silicate), which occurs naturally in such smectite minerals such as colerainite, saponite and safirin, is preferred. The refined magnesium aluminum silicates useful herein are already available as Veegum, manufactured by R.T. Vanderbilt Company, Inc. Clay can also contain varying amounts of minerals other than clay such as quartz, calcite, feldspar and pyrite.

Preferred clays useful herein are clays that swell with water. The term "clay", as used herein, includes but is not limited to kaolin minerals such as kaolinite, china clay, dike, nacrite, halloysite, serpentine minerals such as lizardite, aloisite, chrysolite, antigorite, carlosturanite , amestita, cronstedita, chamosita, bertierina, garieríta; talcum powder; pyrophyllite; ferriphophyllite; smectites such as montmorilonitas, beidelita, nontronita, hectorita, saponita, sauconita, medmontita, pimelita, bentonita; lita minerals such as lediqueta, bravaisite, degraded mica, hydromica, hydromuscovita, anhydrous lita, anhydrous mica, K-mica, micaceous clay, and sericite; mica such as pegmatite, muscovite, and phlogopite; brittle mica such as daisy, and clintonite; glauconite; celadonite; chlorite and vermiculite such as penina, clinochlora, chamosite, nimite, baileyclora, donbasita, coquita, sudoite, franklinfurnaceita, paligorskite and sepiolite minerals such as attapulgite; allophan and imogolite; mixed-layer clay minerals such as talc-chlorite; and mixtures thereof. The preferred clays are selected from the group consisting of kaolin minerals, smectites, mica and mixtures thereof. Most preferred are clays selected from the group consisting of laponite, bentonite, hectorite, saponite, montmorillonites and mixtures thereof. Any of the available forms are acceptable for use in the present invention such as colloidal clay, for example magnesium aluminosilicate, magnesium bentonite, attapulgite, sodium bentonite magma, etc. Clays that are useful in the present invention include mined, naturally occurring clays as well as synthetic clays. The clays must be pharmaceutically acceptable. A more detailed description of the clays and clay minerals useful herein can be found in the following three references, each of which is incorporated by reference in its entirety: Kirk-Othmer, Encvclopedia of Chemical Technology, Fourth Edition, Vol 6 pages 381-423; Dell, D.J. "Smectite Clays in Personal Care Products", Cosmetics & Toiletries, Vol. 108, May 1993, pages 79-85; and Theng B.K.G., Formation and Properties of Clav-Polvmer Complexes, Developments in Soil Science, Vol. 9.

Particulate Component: Through the present invention, a particulate component selected from the group consisting of silicon dioxide components and / or titanium dioxide components can be replaced by the clays. Mixtures of clays and particulate components can also be used. However, clays are preferred.

Silicon dioxide (silica): Silicon dioxide is present at a level of 2% to 50% by weight of the composition, preferably 3% to 20%, more preferably 4% & to 9% by weight. Any of the available forms are acceptable for use in the present invention such as fuming silicon dioxide, precipitated silicon dioxide, colloidal silicon dioxide, coacervate or gels. The fuming silicon dioxide is especially effective from 5% to 20% by weight. These silica particles can be chemically modified surface, for example with methyl siloxane, to improve the tissue barrier properties of the coating to hydrophilic substances.

Titanium dioxide: Titanium dioxide is present at a level of 2% to 50% by weight of the composition, preferably from 3% to 20%, more preferably from 4% to 9% by weight. Any of the available pharmaceutical grade forms of titanium dioxide are acceptable for use in the present invention as long as said forms achieve the mucin interaction described by the present invention and efficiently achieve an acceptable settling volume ratio specified in I presented.

Such forms include rutile, crystalline anatase form, amorphous form, and any other form that is acceptable for the purposes of the present invention. These titanium dioxide particles may preferably be chemically modified surface, for example with alumina, silica, or other stabilizing agent, to improve the tissue barrier properties of the coating to hydrophilic substances. The two main procedures used in the manufacture of titanium dioxide are sulfate and chloride. The procedures are usually followed by modification of the particle surface with treatments and coatings. Certain additives are used to modify the titanium dioxide which affect the surface properties, for example zinc salts that form zinc titanate on the glass surfaces, coatings of alumina, silica, and titania in aqueous dispersions. In addition, the titanium dioxide can be further modified by organic surface treatments. Organic surface treatments include surface active agents, saturated and unsaturated fatty acid, oleic acid, dehydrated castor oil acid, and derivatives of those compounds and mixtures thereof. Additional details of surface properties of titanium dioxide are found in H.S. Ritter, "Surface Properties of Titanium Dioxide Pigments", Piqment Handbook. Chemical Division, PPG Industries (1973), Volume 3, 169-84. Preference is given to titanium dioxide of small particle size, ie titanium dioxide having an average particle size of less than 1 miera. Preferably, the uncoated titanium dioxide having average particle sizes of 20 nm to 400 nm, still more preferably 50 nm, is used. The uniform uncoated and spherical titanium dioxide useful herein, which has principal diameters of particle size of about 50 nm, can be synthesized by the method described in N. Kallay and E. Matijevic, Langmvir 1, p. 195, 1985, which is incorporated herein by reference in its entirety.

Rubber Component: The term "rubber component", as used herein, refers to a component selected from the group consisting of xanthan gum, guar gum, locust bean gum, carrageenan gum, tragacanth gum, and carbomer . Xanthan gum is preferred. Xanthan gum is available as "Rhodigel" from R. T. Vanderbilt Corp. Norwalk, CT. The gum component should be included in the present invention from 0.01% to 1% by weight of the composition, preferably from 0.05% to 0.5%, more preferably from 0.1% to 0.3%. The compositions of the present invention should comprise clay and rubber component so that the ratio of clay to rubber component is from 10: 1 to 100: 1. It is preferred that the ratio of clay to rubber component be from 12: 1 to 65: 1, more preferred from 35: 1 to 45: 1.

Gastrointestinal Active: The compositions of the present invention also comprise a safe and effective amount of at least one pharmacologically active gastrointestinal agent. For example, the compositions of the present invention may comprise from 0.01% to 50% of gastrointestinal active, by weight of the composition, preferably from 0.1% to 20%, more preferably from 0.5% to 5%, and more preferably from 0.7% at 3% by weight of the composition. Examples of gastrointestinal agents useful in the present invention include but are not limited to: antacids, anticholinergics, bismuth compounds, prostaglandin analogs, H2 receptor antagonists, laxatives, gastroprotectors, gastrokinetic and prokinetic agents, proton pump inhibitors, antidiarrheals, agents that are bacteriostatic or bactericidal to the ulcer-inducing organism Heliobacter pylori, topical anesthetics, topical analgesics and polyanionic materials useful for the treatment of ulcers and other gastrointestinal disorders. Preferred for use herein are gastrointestinal agents including antacids, H2 receptor antagonists, gastroprotectors, proton pump inhibitors, antidiarrheals, and polyanionic materials useful for the treatment of ulcers or other gastrointestinal disorders. Antacids, gastroprotectors, and antidiarrheals are more preferred. Examples of anticholinergics useful herein include but are not limited to atropine, clidinium and dicyclomin. Examples of antacids useful herein include but are not limited to aluminum hydroxide. Other examples of antacids can be found in 21 CFR 331.11 which is incorporated herein by reference. Examples of H2 receptor antagonists useful herein include but are not limited to cimetidine, famotidine, nizatidine and ranitidine. The H2 receptor antagonist compounds useful herein are further described in the U.S.A. 5,294,433, Singer et al, March 15, 1994, which is incorporated herein by reference in its entirety. Examples of laxatives useful herein include but are not limited to bisacodyl, picosulfate, and casantrol. Other examples of laxatives can be found in the Federal Registry, vol. 50, no. 10, January 15, 1985, pages 2152-2158 which is incorporated herein by reference. Examples of gastroprotectors useful herein include but are not limited to sucralfate and wet sulfate gel. Examples of gastrokinetic and procinthetic agents useful herein include but are not limited to cisapride, metoclopramide and eisaproda. Examples of proton pump inhibitors useful herein include but are not limited to omeprazole. Examples of useful antidiarrheals herein include but are not limited to bismuth diphenoxylate, attapulgite, and loperamide subsalicylate. Examples of agents that are bacteriostatic or bactericidal to the Heliobacter pylori ulcer-inducing organism useful herein include but are not limited to amoxicillin, metronidazole, erythromycin, and nitrofurantoin. Those and other agents for treating H. pylori are described in the U.S. Patent. No. 5,256,684, to Marshall, issued October 26, 1993, which is hereby incorporated by reference in its entirety. Examples of topical anesthetics useful herein include but are not limited to lidocaine and benzocaine. Examples of topical analgesics useful herein include but are not limited to menthol, acetaminophen, salicylates including aspirin (acetylsalicylic acid), ibuprofen and naproxen. These are described more fully in the following: US Pat. 4,749,720 to Sunshine et al, issued June 7, 1988, U.S. Patent. 4,747,711 to Sunshine et al, issued June 7, 1988, U.S. Patent. 4,749,697 to Sunshine et al, issued June 7, 1988, U.S. Patent. 4,783,465 to Sunshine et al, issued November 8, 1988, Patent of U.S.A. 4,619,934 to Sunshine et al, issued October 28, 1986, U.S. Patent. 4,552,899 to Sunshine et al, issued November 12, 1985, all of which are incorporated by reference herein, in their entirety. Examples of polyanionic materials useful for the treatment of ulcers and other gastrointestinal disorders useful herein include but are not limited to amylopectin, carrageenan, sulfated dextrins, inositol hexaphosphate, or other similar agents. Extracts of plants or other natural substances known to be effective in any of the above disorders can also be supplied from the mucoadhesive matrix. Examples of each of the aforementioned gastrointestinal actives are additionally described, together with suitable dosages, in Facts and Comparisons, 1998, p. 242-260, 291-326h, and 601-607, which is incorporated herein by reference in its entirety.

Bismuth: The preferred gastrointestinal agent for use in the present invention is bismuth. As used herein, the amount of bismuth is by weight of elemental bismuth. In the present invention, the term "bismuth" as used herein, includes bismuth in the form of a pharmaceutically acceptable salt, bismuth or bismuth salt in the form of an organic or other complex containing bismuth as an active ingredient and mixtures thereof. the same. Such organic complexes include 2,2'-spirobi [1, 32-benzodoxabismole]. A pharmaceutically acceptable salt is preferred. Said bismuth salts include bismuth aluminate, bismuth subcarbonate, bismuth subcitrate, bismuth citrate, ranitidine bismuth citrate complex, tripotassium dicitrate bismut, bismuth subgalate, bismuth subnitrate, bismuth tartrate, bismuth subsalicylate, and mixtures thereof. Bismuth citrate, bismuth ranitidine citrate complex, bismuth subcitrate, tripotassium dicitrate bismuthate, bismuth tartrate, bismuth subsalicylate, and mixtures thereof are preferred bismuth salts for use in this invention. When used in the compositions of the present invention, the bismuth preferably comprises from 0.8% to 7% bismuth, more preferably from 1% to 3% by weight of the composition.

Nonionic Component: The nonionic components are optionally present at a level of 0.0% to 2% by weight of the composition, preferably from 0.05% to 0.5%. The nonionic components useful in the present invention are selected from the group consisting of methylcellulose, ethylcellulose, hydroxyethylcellulose, hydroxypropylcellulose, hydroxypropylmethylcellulose, carboxymethylcellulose, polyvinylpyrrolidone, acacia, propylene glycol alginate, sodium alginate, and sodium starch glycolate. Methylcellulose is preferred.

Optional consistency aids: Optionally, consistency aids are present at a level of 0.1% to 50% by weight of the composition, preferably from 1% to 30%, more preferably from 2% to 20% by weight. These consistency auxiliaries are mono and polyols of low molecular weight and are selected from the group consisting of monosaccharides such as glucose (dextrose), fructose (levulose); disaccharides such as sucrose, lactose, maltose, cellobiose and other sugars, ribose, glycerin, sorbitol, xylitol, inositol, propylene glycol, galactose, mannose, xylose, rhamnose, glutaraldehyde, invert sugars, ethanol, honey, mannitol, polyethylene glycol, glycerol, and mixtures thereof; Preferably, the polyols are selected from the group consisting of honey, sorbitol, glycerin, glycerol and mixtures thereof. These compounds help provide physical stability to the compositions. In addition to that compound, such as low molecular weight polyols, it is preferred to provide the proper consistency of the composition prior to administration so that an optimal degree of dispersion on the mucosa is achieved after administration. Specifically, these polyols will reduce or retard the rate at which the particles in the dispersion bridge or are absorbed by the mucosal glycoproteins. This allows the composition to spread better and coat the fabric before the triggering causes the viscosity of the composition to increase.

Pharmaceutically acceptable excipients: The liquid phase of the colloidal suspensions of the present invention is generally water.

These compositions comprise from 5% to 98%, preferably from 70% to 95% by weight of the composition, of water. Optionally, these aqueous compositions also contain suitable amounts of preservatives, emulsifying agents, suspending agents, diluents, natural or artificial sweeteners, flavor masking agents, coloring agents, and flavoring agents, to provide an appetizing and pleasant looking final product. . In addition, the compositions may comprise antioxidants, for example, butylated hydroxy anisol or butylated hydroxy toluene, and preservatives, for example, methyl or propyl paraben or sodium benzonate, to prolong and improve shelf life. Antimicrobials may also be optionally added to the compositions of the present invention. Additionally, optionally useful herein are sensory agents selected from the group consisting of fresheners, salivating agents, warming agents. If present, these agents comprise from 0.001% to 10%, preferably from 0.1% to 1%, by weight of the composition. Suitable cooling agents include but are not limited to carboxyamide paramentan agents such as N-ethyl-p-menthane-3-carboxamide, menthol, 3-1-menthoxypropane-1,2-diol glycerol acetal menthone, menthyl lactate, and cyclic sulfones and sulfoxides, salivating agents useful herein include Jambu® manufactured by Takasago Perfumery Co., Ltd., Tokyo, Japan. Heating agents include capsicuma and nicotinate esters, such as benzyl nicotinate.

The compositions of the present invention also preferably but optionally contain from 0.005% to 3%, preferably from 0.7% to 1.5% of substituted or unsubstituted short chain organic acids or water soluble salts thereof, including citric, tartaric, acetic , malic, maleic, and succinic to provide consistent dispersion of the solid particles thus improving stability. Specific examples of pharmaceutically acceptable carriers and excipients that can be used to formulate oral dosage forms are described in U.S. Pat. 3,903,297, Robert, issued September 2, 1975, incorporated by reference herein.

Methods of use The compositions of the present invention should be administered orally in a safe and effective amount for the treatment and / or prevention of gastrointestinal disorders. An example of a method of treatment and / or prevention may comprise oral administration to a human or animal less than 1 ml to 100 ml, preferably 20 ml to 50 ml per dose of the compositions of the present invention. The compositions of the present invention are dosed as necessary, preferably no more than 30 times a day, more preferably no more than 15 times a day, and more preferably no more than 8 times a day. Said oral administration of the compositions of the present invention provides a top coating system (the combination claimed herein as a component of clay and / or particulate material, and the rubber component) that can help protect the mucosa and tissue underlying against irritating or harmful agents and / or accelerate the healing of inflamed or damaged tissue. Additionally, this top coating system allows for improved delivery of the gastrointestinal active to the coated tissue resulting in higher efficacy and / or lower side effects.

Manufacturing method These compositions can be prepared by the following method: Using high shear mixing, disperse the clays and / or particulate components in water. With continuous mixing, add the rubber component. Where it is included in the formulation, add one or more non-ionic components with mixing (it may be useful to first prepare a dilute solution of the non-ionic components). Where are included, in the formulation, sweeteners such as corn syrup, or sorbitol are now added. Those steps form the main mix. Separately, combine water and dye to form a color premix. Prepare a second premix by combining the gastrointestinal active (s) together with other optional ingredients such as flavors, excipients, preservatives, etc. with a small amount of water. Create a colored master mix by adding the color premix to the main mix with mixing. Add the second premix slowly to the colored main mix with gentle mixing. Add water to bring the final weight of the batch. Mix until homogeneous. The following are non-limiting examples that illustrate the methods and uses of the present invention.

EXAMPLES EXAMPLE 11 A man who has diarrhea accompanied by nausea and vomiting orally takes a dose of 30 ml of a composition as shown in example 6. Soon after, the symptoms have subsided and the man feels normal again.

EXAMPLE 12 A woman eats too much at dinner and therefore has indigestion. Orally take a dose of 40 ml of a composition as shown in any of the examples 1-8 and 10, and your indigestion is relieved.

EXAMPLE 13 A woman knows that eating spicy foods routinely causes heartburn. Therefore, before eating too much of those foods, orally take a dose of 35 ml of a composition as shown in any of the examples 1-8 and 10. This action covers your gastrointestinal tract and prevents you from suffering from heartburn as a result to eat spicy food.

Claims (20)

NOVELTY OF THE INVENTION CLAIMS

1. A liquid mucorretentive aqueous pharmaceutical composition, comprising: a) a safe and effective amount of a gastrointestinal active in which the gastrointestinal active is selected from the group consisting of antacids, anticholinergics, bismuth compounds, prostaglandin analogues, H2 receptor antagonists , laxatives, gastroprotectors, gastrokinetic and prokinetic agents, proton pump inhibitors, antidiarrheals, agents that are bacteriostatic or bactericidal to the organism that induces Heliobacter pylori ulcer, topical anesthetics, and polyanionic materials useful for the treatment of ulcers and other gastrointestinal disorders; b) from 1.5% to 10% by weight of the composition, of clay in which the clay is not magnesium trisilicate; and c) from 0.01% to 1% by weight of the composition, of a gum component selected from the group consisting of xanthan gum, guar gum, locust bean gum, carrageenan gum, tragacanth gum, and carbomer; and wherein the clay and the rubber component are in a ratio of 10: 1 to 100: 1 and in which the aqueous liquid composition is administered perorally or orally.

2. The pharmaceutical composition according to claim 1, further characterized in that it additionally comprises a nonionic component selected from the group consisting of methylcellulose, ethylcellulose, hydroxyethylcellulose, hydroxypropylcellulose, hydroxypropyl methylcellulose, carboxymethylcellulose, polyvinylpyrrolidone, acacia, propylene glycol alginate, alginate sodium, and sodium starch glycolate.

3. The pharmaceutical composition according to claim 1, further characterized in that the clay and the rubber component are in a ratio of 35: 1 to 65: 1.

4. The pharmaceutical composition according to claim 1, further characterized in that the pharmaceutical composition has a zero shear viscosity of at least 2000 pascal seconds.

5. The pharmaceutical composition according to claim 1, further characterized in that the pharmaceutical composition has a sedimentation volume ratio of greater than 0.90 when measured after 48 hours.

6. The pharmaceutical composition according to claim 1, further characterized in that the pharmaceutical composition has a triggered viscosity ratio of at least 1.2.

7. The pharmaceutical composition according to claim 2, further characterized in that it comprises from 3.5% to 4.5% by weight of the composition, of the clay and in which the pharmaceutical composition has a sedimentation volume ratio of greater than 0.95. when measured after 48 hours.

8. - The pharmaceutical composition according to claim 2, further characterized in that the gastrointestinal active is one or more bismuth salts.

9. The pharmaceutical composition according to claim 3, further characterized in that it comprises from 0.05% to 0.5% by weight of the composition of the rubber component.

10. An aqueous, mucorretentive liquid pharmaceutical composition, comprising: a) a safe and effective amount of a gastrointestinal active in which the gastrointestinal active is selected from the group consisting of antacids, anticholinergics, bismuth compounds, prostaglandin analogs, antagonists of H2 receptor, laxatives, gastroprotectors, gastrokinetic and prokinetic agents, proton pump inhibitors, antidiarrheals, agents that are bacteriostatic or bactericidal to the organism that induces Heliobacter pylori ulcer, topical anesthetics, and polyanionic materials useful for the treatment of ulcers and other disorders gastrointestinal; b) from 2% to 50% by weight of the composition, of a particulate component selected from the group consisting of silicon dioxide and titanium dioxide; and c) from 0.01% to 1% by weight of the composition, of a gum component selected from the group consisting of xanthan gum, guar gum, locust bean gum, carrageenan gum, tragacanth gum, and carbomer; wherein the aqueous liquid composition is administered perorally or orally.

11. - The pharmaceutical composition according to claim 10, further characterized in that it additionally comprises a non-ionic component selected from the group consisting of methylcellulose, ethylcellulose, hydroxyethylcellulose, hydroxypropylcellulose, hydroxypropyl methylcellulose, carboxymethylcellulose, polyvinylpyrrolidone, acacia, propylene glycol alginate, sodium alginate, and sodium starch glycolate.

12. The pharmaceutical composition according to claim 10, further characterized in that the pharmaceutical composition has a zero shear viscosity of at least 2000 pascal seconds.

13. The pharmaceutical composition according to claim 10, further characterized in that the pharmaceutical composition has a viscosity of less than 0.75 pascal seconds when subjected to a constant shear rate of 100 per second.

14. The pharmaceutical composition according to claim 10, further characterized in that the pharmaceutical composition has a triggered viscosity ratio of at least 1.2.

15. The pharmaceutical composition according to claim 10, further characterized in that the pharmaceutical composition has a sedimentation volume ratio of greater than 0.90 when measured after 48 hours.

16. - A pharmaceutical composition according to claim 11, comprising from 5% to 20% by weight of the composition, of the particulate component.

17. A pharmaceutical composition according to claim 11, further characterized in that it comprises from 0.05% to 0.5% by weight of the composition, of the rubber component.

18. The use of a composition according to claim 1, for the manufacture of a medicament to be administered orally for the treatment or prevention of a gastrointestinal disorder by coating the gastrointestinal tract in a human or lower animal.

19. The use of a composition according to claim 8, for the manufacture of a medicament that will be administered orally for treatment or prevention of a gastrointestinal disorder by coating the gastrointestinal tract in a human or lower animal.

20. The use of a composition according to claim 10, for the manufacture of a medicament that will be administered orally for treatment or prevention of a gastrointestinal disorder by coating the gastrointestinal tract in a human or lower animal.