WO1996021432A1

WO1996021432A1 - Delivery of active substances by way of mucosal surfaces of pharyngeal and esophageal regions

Info

Publication number: WO1996021432A1
Application number: PCT/US1996/000566
Authority: WO
Inventors: Gary W. Cleary; Subbu Venkatraman; James E. Biegajski; Ann M. Scott; Peter Watts
Original assignee: Cygnus, Inc.
Priority date: 1995-01-11
Filing date: 1996-01-11
Publication date: 1996-07-18

Abstract

A method for delivering a therapeutically active substance to a subject includes contacting mucosal tissues of the subject's pharyngeal region and/or esophageal region with mucoadhesive particles containing a pharmaceutically effective amount of the active agent. Also, a composition for delivery of an active substance to a subject has the form of a preparation of particles containing the active substance, the particles adhering to mucosal surfaces of the pharyngeal or esophageal regions of the subject. Also, a method for treating 'acid stomach' or reflux esophagitis in a subject includes administering to the subject a swallowable liquid composition including mucoadhesive particles containing a pharmaceutically effective amount of an antacid agent; and such a swallowable liquid composition.

Description

DELIVERY OF ACTIVE SUBSTANCES BY WAY OF MUCOSAL SURFACES OF PHARYNGEAL AND ESOPHAGEAL REGIONS

Technical Field

This invention relates to controlled systemic and local delivery of therapeutical ly active agents.

Background

The literature in the drug delivery art includes various suggestions for administering the drug in particulate form, for improved control of the drug delivery rate or improved localization of the delivery site within the subject. In one mode of delivery, the lungs are the delivery site, and the drug- containing particles are inhaled, by way of either the nose or the mouth. For review, see. for example, F. Moren et al, Eds. (1993), Aerosols in Medicine: Principles, Diagnosis and Therapy, Elsevier, 2d Revised Edition. Some understanding has been reached regarding deposition and retention of particulate matter in the airways and alveoli (see particularly P.E. Morrow et al, Chapter 6); and some general recommendations have emerged for the form and formulation of aerosol dosage forms for delivery of drugs to the upper respiratory tract (that is, the nasal cavity) or the lower respiratory tract (particularly bronchi or alveoli) by either oral or nasal inhalation (see particularly F. Moren. Chapter 13, in F. Moren et al. (1993)). For delivery of particulates to the lower respiratory tract, particle size must be kept within a range of small aerodynamic sizes. For example, dust particles in the size range having an aerodynamic diameter smaller than about 100 μm are generally known to be inhalable; particles in the approximate size range 1-

10 μm diameter are able to pass beyond the upper airways and bronchi to the alveolar regions (see D.C. F. Muir et al, Chapter 16, in F. Moren et al. (1993)).

Thus, for delivery of particulates to the lower respiratory tract, particle sizes in size ranges below about 10 μm diameter are preferred, as deposition upstream is advantageously avoided. For example, British Patent Publication GB 2237150 describes delivery of bioadhesive microspheres in the size range 0.1-1.0 μm by nasal inhalation.

For delivery through the nasal mucosa, the emphasis is on deposition and retention of the particles in the nasal cavity. U.S. Patent No. 5,204,108, for example, describes a composition in microsphere form for delivery of a peptide drug having molecular weight greater than about 6,000. The microspheres gel upon contact with the moist surface of mucosal membranes, and are intended for use in delivery of the peptide drug to the mucosal membrane of the nasal cavity, the vagina, or the eye. The '108 patent particularly emphasizes the importance of retention of the particles in the nasal cavity for transmucosal systemic delivery of the peptide drug across the nasal cavity mucosa.

Delivery of active agents by administering the agent into the mouth and swallowing has long been known, and a variety of dosage forms have been developed. For a review, see, for example, C.G. Wilson et al (1989), Physiological Pharmaceutics: Biological Barriers to Drug Absorption, John

Wiley & Sons. Generally, esophageal transit times vary according to the dosage form and the position of the subject, falling usually in the range about 10 to 14 seconds. Solid dosage forms such as tablets or capsules may have longer transit times, depending upon their size and composition. Adhesion of solid dosage forms to the esophagus is generally regarded as presenting problems (see particularly C.G. Wilson et al. Chapter 3).

The publications referred to herein, above and below, are hereby incorporated herein by reference.

Disclosure of the Invention

We have discovered that the pharyngeal and esophageal regions can be advantageously employed as a platform from controlled and sustained local or systemic release of active substances. According to the invention, sustained and controlled local or systemic release of active agents can be achieved by causing mucoadhesive particles containing the active agent to adhere to a mucosal surface of the pharyngeal and/or esophageal regions (including broadly the nasopharynx, the oral pharynx and the laryngeal pharynx; the esophagus; and the soft palate, the epiglottis, the rear part of the tongue, and associated tissues).

Accordingly, the invention features methods for delivery of a therapeutical ly active agent to a subject, by contacting mucosal tissues of the pharyngeal region or the esophageal region, or some portion thereof, with mucoadhesive particles containing the active agent. In some embodiments the active agent-containing mucoadhesive particles dissolve or disperse in the fluid milieu of the mucosal tissue to which the particles adhere.

In some embodiments the active agent passes from the mucoadhesive particles to the mucosal surface on which the particles adhere; in some embodiments the active agent passes into fluids within the mucosa-lined body cavity in which the particles are situated, and is carried in the fluid to other mucosal surfaces that are bathed by the fluids. The active agent can have its therapeutic effect either locally within the mucosal tissues to which they are delivered, or upon ihe mucosal tissues and underlying tissues. Or, additionally or alternatively, the active agent can be delivered systemically, by passing transmucosally into the bloodstream. Where the active agent is carried in fluids within the mucosa-lines body cavity, the agent can have its effect at least in part by changing a condition (such as for example the pH) of the fluid itself. The invention can be employed for delivery of a single pharmaceutically active agent to the subject. Or, two or more pharmaceutically active agents can be delivered to the subject concurrently according to the invention, for example, by depositing particles that each contain more than one agent, or by concurrently depositing a mixture of different particles containing different agents. According to the particular particle formulation, the invention can provide for rapid onset of drug delivery, and can provide for sustained delivery following onset at controlled rates. Particles that dissolve or disperse quickly in the milieu in which they are deposited can provide for rapid, short term delivery of the active agent into the fluids of the body cavity or into the mucosal tissues to which they adhere. Particles that dissolve or disperse more slowly and continue to adhere to the mucosal surface for an extended time can provide for sustained delivery of the active agent. Particles having different dissolution or dispersion characteristics can according to the invention be used concurrently to control the delivery profile of one or more active agents. In one general aspect, the invention features a method for delivery of a therapeutically active agent to a subject, including steps of contacting mucoadhesive particles containing a pharmaceutically effective amount of the active agent with a mucous surface of the pharyngeal or esophageal region.

In another general aspect, the invention features particles containing an active agent, the particles adhering to mucous surfaces of the pharyngeal or esophageal region. Preferred mucoadhesive particles according to the invention contain, in addition to the active agent or agents, a polymer which is mucoadhesive itself or in combination with the active agent in particulate form. Preferred such polymers include, for example, polyethylene oxide and polyacrylic acid.

In some embodiments the particles dissolve or disperse over a generally predetermined time in the fluid milieu of the mucous surface to which they adhere. In some embodiments the particles are microparticles; or are microspheres; or are microcapsules.

In another general aspect the invention features a method for treating "acid stomach" or reflux esophagitis in a subject animal, by administering to the subject a swallowable liquid composition including mucoadhesive particles containing a pharmaceutically effective amount of an antacid agent: and in another aspect the invention features such a swallowable composition. In preferred embodiments the liquid composition is in a suspension of the antacid agent-containing mucoadhesive particles in a liquid. Preferably the antacid agent-containing mucoadhesive particles are substantially insoluble in the liquid, and preferred liquids include, for example, glycerol. miglyol; any safely ingestible liquid (preferably GRAS- or NF- certified; or food grade) that can be swallowed and that passes reasonably rapidly through the esophagus may be suitable. Liquids that are suitable for use in forming suspensions or dispersions of particles made from any particular polymer may be selected as a matter of routine; and preferably the particles remain freely dispersed in the liquid. Also preferably for delivery to the lower esophagus, the liquid is sufficiently viscous so as not to disperse too early after administration; propylene glycol, for example is insufficiently swallowable because it may disperse too rapidly following administration at the back of the tongue, so that the microparticles hydrate and gelate on the tongue itself rather than passing to the esophagus before they begin to swell. Preferred antacid agents include, for example, aluminum hydroxide, magnesium hydroxide; and any safely ingestible acid-neutralizing agent can be suitable, as is well-known in the art of treating gastric acid-induced distress. The swallowable liquid preparation can additionally include, for example, flavorants or flavorings, as are well-known in the art of formulating swallowable dosage forms. The particles for use in treatment of reflux esophagitis according to the invention may be made by coating suitably dimensioned particles of the antacid agent with the mucoadhesive polymer, or, as may be preferred, by mixing the antacid agent with the polymer and forming particles from the mixture, as described generally above and in further detail below.

Brief Description of the Drawings Fig. 1 is a diagrammatic sketch in lengthwise sectional view of a device for use in delivery of a dry powder to the pharyngeal region according to the invention.

Fig. 2 is a plot from a scintigraphic study comparing clearance from the pharynx of a radiolabelled swallowable liquid composition including mucoadhesive microparticles in liquid suspension according to the invention, and a radiolabelled Mylanta (antacid) preparation.

Fig. 3 is a plot from a scintigraphic study comparing clearance from the esophagus of a radiolabelled swallowable liquid composition including mucoadhesive microparticles in liquid suspension according to the invention, and a radiolabelled Mylanta (antacid) preparation.

Modes for Carrying out the Invention According to the invention, the active agent to be delivered to the subject is contained in mucoadhesive particulate form, and the particles are deposited onto a mucosal surface of one or more of the pharyngeal and the esophageal regions of the subject.

Particles for administration according to the invention can be made by uniformly mixing the active substance with a bioerodible mucoadhesive polymer. Or, alternatively, the particles can be made by forming a core of the active substance and coating the active substance core with a bioerodible mucoadhesive polymer layer.

The rate of release of the active substance form the particles can be established by choosing an appropriate polymer or polymers in the construction of the particles. For example, where a particle is formed as a drug-containing core having a mucoadhesive coating, the mucoadhesive coating can be made of a polymer that dissolves slowly in the fluid milieu, resulting in retention of the active substance on the mucosal surface for an extended time. And, for example, a particle can be made by mixing the active substance with a bioerodible polymer, and the delivery profile of the active substance is controlled by the rate of dissolution or dispersion of the polymer in the milieu in which the particle is deposited. And, for example, a core of active-containing material can be coated with a layer of a material across which the diffusion of the active material is limited; such materials include, by way of example, certain of the Eudragit ® family of acrylic resin polymers, manufactured by Rohm GMBH.

Preferred materials for use in construction of active substance-containing particles according to the invention are acceptable for ingestion by humans (that is, they are preferably GRAS- or NF-certified). The particles, whether formed by mixing the active substance with other materials or by coating an active substance- containing core with a material, preferably adhere quickly upon contact with a mucosal surface of a pharyngeal or esophageal region. Preferred materials include for example, and without limitation, poly glycolic lactic acid (PLGA), poly lactic acid (PLA), prolamincs, poly ethylene oxide (PEO), poly vinyl pyrollidone (PVP), poly vinyl acetate (PVA), cellulose derivatives such as hydroxy propyl cellulose (HPC), carboxy methyl cellulose (CMC), hydroxy propyl methyl cellulose

(HPMC) and the like, gelatin, malto dextrin. Various combinations of these materials may be used, such as for example: PEO and PVA; PEO and certain of the Eudragit family of acrylic resin polymers; PEO and ethyl cellulose. As is well known in the art of formulations using such materials, the rate of dispersion or dissolution in the fluid milieu can be altered by selection of certain of materials in selected proportions.

Moreover, where the active substance can be delivered both by diffusion out from the particle and by way of the dissolution or dispersion of the particle, the extent of delivery to the mucosal surface to which the particles adhere as compared to delivery into the fluid of the body cavity can be controlled. That is, where some substantial degree of diffusion occurs, transmucosal delivery to the underlying mucosa can be relatively greater than where little or no diffusion occurs, and the extent of delivery to the fluids of the body cavity can be limited by limiting the rate of dissolution or dispersion of the surface of the particles. On the other hand, where the rate of permeation of the particular active substance through the tissue membranes is rate limiting, that is where the rate of the active substance through the cell membranes of the mucosa is relatively lower than the rate of movement of the active substance from the particles, whether by diffusion or by dissolution or dispersion of the particle, local delivery into fluid of the body cavity can predominate over transmucosal systemic deliver}'. Additionally, where the active substance is poorly soluble in aqueous media, but relatively readily passes through biological membranes such as mucosa, the active substance may preferentially pass through the mucosa rather than into the fluid milieu.

General ly. the mucosa of the esophageal and pharyngeal regions has a higher permeability to drugs, and provides for more rapid onset of delivery than by use of transdermal routes, for example.

According to the invention, in use the particles adhere principally to a mucosal surface of the pharyngeal and/or esophageal region. To ensure that the particles are mucoadhesive. a mucoadhesive composition can be used in the construction of the particle, or a drug-containing particulate core can be at least partly coated with a mucoadhesive composition. The device for administration can be adapted to direct the particles principally to the pharyngeal and/or esophageal region, where they adhere upon contact. Additionally, or alternatively, physical characteristics of the particles, such as particle size, can be selected to ensure that the particles are deposited principally to the pharyngeal and/or esophageal region. Particularly, for example, administration by oral inhalation of dry powder compositions having particles in the size range between about 10 and about 100 μm can result in deposition of the particles in the pharyngeal region, while depositing only a negligible proportion of the particles in the forward part of the oral cavity, or the lower respiratory tract. The particles can be deposited onto the mucous surface of the pharynx using any of various inhalation drug delivery techniques; many such techniques, and apparatus for carrying them out, are conventional in the inhalation drug delivery art. Such techniques include, for example, dry powder inhalation, using for example a breath actuated inhaler or a passive inhaler; propellant or non- propellant based metered dose inhalation; and nebulization.

Commercially available inhalation devices that may be used in or may be adapted for use in delivering particles to the esophageal or pharyngeal region according to the invention include devices manufactured by BESPAK; and by PFEIFFER. A simple illustration of a device for administration of particles in an air stream is given below as Example 1.

Alternatively, the particles can be deposited onto the mucous surface of the lower portions of the pharyngeal region and the esophagus by administration in a swallowable form. as. for example, by suspension of the particles in a liquid. Or, for example, the particles may be included in a chewable tablet or a lozenge; here, the lozenge may be held in the mouth and sucked, or the tablet may be chewed, releasing the particles post- orally, where they adhere to the oral pharynx or laryngeal pharynx and esophagus and related sites. The invention can be used for systemic or local administration of any of a variety of active substances, and the terms "active substance" and "active agent" as used herein is intended to include any substance the administration of which to a subject for an effect in the subject is desired. Thus, active substances and active agents that can be delivered according to the invention include, for example, drugs, nutritional components including for example vitamins and nutritional supplements, agents for adjustment of pH, flavors, deodorants, etc.

The following examples further illustrate the invention. These examples are not intended to limit the invention in any manner. Examples

Example I

In this example, a simple device for projecting a stream of dry powder onto the rear of the throat (principally, onto the soft palate and oral pharynx) is described by way of illustration. As shown in the Fig., the device 10 includes a generally cylindrical barrel 12 and a plunger 14 having a close-fitting piston 15.

Plunger 14 can be moved slidably within barrel 12 in piston-and cylinder fashion. A small opening 16 at one end 18 of barrel 12 provides for escape of air from the chamber 2fl within the barrel as the plunger is moved within the barrel toward the end 18. A suitably close sliding engagement between the circumference of piston 15 and the inner wall of barrel 12 ensures that substantially no air escapes between the piston and the barrel as the piston is moved within the barrel. A suitable quantity of the dry powder to be delivered is placed within the chamber 20. For use, the barrel is placed in the mouth, with the opening 16 situated rearward and well back in the mouth, and then the plunger is moved within the barrel toward barrel end 18 to project a stream of air, containing at least a portion of the dry powder, out through the opening 16 and onto the back of the throat. Example II

This example illustrates construction of mucoadhesive particles for use according to the invention.

In this example, the particles include a core constituting a particle of the active substance to be delivered, and a coating that provides for adhesion of the particle to the mucosa of the pharynx and/or esophagus; additionally, optionally, the particles include a rate-controlling layer between the active substance core and the adhesive, to limit the rate of release of the active substance from the particle. Various exemplary compositions for use in making such particles, for use by way of example in delivering benzocaine locally for relief of sore throat pain, are set out in Table I below. The particles can be administered in an air stream, either by inhalation or by projecting onto the pharyngeal region a jet of air containing the particles.

Techniques for particle coating are well-known in the art. The technique for making the particles in the examples shown here employs a Glatt Fluidized Bed

(Glaft Air Techniques, Inc., Ramsey NJ, USA), used generally according to the manufacturer's instructions. In this method, the drug is first introduced to the apparatus in particulate form, and then the coating or coatings are added in sequence, the apparatus dries the coatings on the particles while preventing agglomeration.

The resulting powder can be sieved to obtain a suitable size fraction. The particle sizes are to some extent determined by the sizes of the active substance core particles upon which the coatings are deposited. In these examples, adhesion of the particles on mucosal surfaces was tested in an in vitro model. In this example the benzocaine was provided as a "fine powder" having particles ranging broadly in size between about 10 μm and about 400 μm. Following introduction of the benzocaine core particles to the apparatus, the materials forming the further layers (Eudragit polymer, providing release control; adhesive) were introduced serially in aqueous solution. In some instances, as indicated, one or more of the aqueous solutions was warmed, to reduce the viscosity; alternatively, a more dilute solution of the component can be used.

In some instances, triethyl citrate was added as a plasticiser.

The following formulations were used for coating benzocaine particles in the Glaft apparatus.

Table I

1. Eudragit L30D-55 (to 50% weight increase)

PVP 90F (to 1 1.25% weight increase)

(PVP was added as a 15% aqueous solution, 60 °C)

2- Eudragit L30D-55 (to 50% weight increase)

Gelatin (to 1 1.25% weight increase)

(Gelatin was added as a 15% aqueous solution, 80 °C)

3. Eudragit L30D-55 (to 50% weight increase) HPC EF (to 1 1.25% weight increase) (HPC EF was added as a 15% aqueous solution, 60 °C)

4. Eudragit L30D-55 (to 50% weight increase) 7.5% Gelatin PS 200, 7.5% PVP 90F in water (Gelatin and PVP were added as an aqueous solution, 85 °C)

5. Eudragit L30D-55 (to 50% weight increase) Na CMC (to at least 10% weight increase) (Na CMC was added as an aqueous solution at between 60 °C and 90 °C Faxample HI

This example illustrates delivery of benzocaine in mucoadhesive particulate form to the back of the throat, for long-lasting relief of sore throat pain.

Benzocaine-containing coated particles made generally as described in

Example II above were delivered in an airstream to the back of the throat of a subject suffering from sore throat pain. The subject reported a sensation of relief from sore throat pain with rapid onset and lasting for about one-half hour.

For relief of sore throat pain, other medications may be used as active substance; clonidine may be used, for example.

Exampl g IV

This example illustrates use of the invention for delivery of an antacid to the upper gastrointestinal tract for relief of "acid stomach".

As an antacid, aluminum hydroxide is provided as an antacid in a powder form, preferably sieved or otherwise size-sorted to provide core particles having about 100 μm diameter. The core particles are then coated, using particle coating techniques known in the art, such as are described above in Example II, with a mucoadhesive polymer such as, for example, polyethylene oxide, and, optionally, with a release rate-controlling layer. The coated core particles are then delivered in an airstream by inhalation, to deposit the coated particles on mucous surfaces of the pharyngeal region of the subject. Thereafter as the subject swallows normally, the adhering particles gradually over time erode away from the pharyngeal surface, and are carried down the esophagus to the stomach. - H -

Example V

This example illustrates use of the invention for delivery of mucoadhesive microparticles to the lower esophagus, where they are retained for an extended time. In this approach, the bioadhesive microparticles are suspended in a nonsolvent liquid and swallowed, and retention of the microparticles at various points in the esophagus was compared with retention of a preparation "Mylanta", a commercial antacid product. Mylanta is an antacid medicine sold over the counter in the U.S. (Johnson & Johnson — Merck Consumer Pharmaceuticals). The reported active ingredients in Mylanta are aluminum hydroxide (40 mg/ml), magnesium hydroxide (40 mg/ml) and simethicone (4 mg/ml).

For purposes of illustration, the preparations of Mylanta and of the mucoadhesive microparticles of the invention were radiolabelled using neutron irradiated samarium oxide, and a scintigraphic record in the each subject's esophagus was made over time after the subject swallowed the preparation.

Preparation of mucoadhesive microparticles. Radiolabelled mucoadhesive microparticles were prepared having the following composition: 1.83% w/w samarium oxide (Sigma) bound to 96.34% w/w polyethyleneoxide ("Polyox" WSR NF, lot C280 NF, Union Carbide) using 1.83% w/w ethylcellulose ("Ethocel", 45 viscosity, lot 930224-1 Dow), as follows. 475 mg ethlycellulose was dissolved in

25 ml of ethanol, and 475 mg of samarium oxide was suspended in the ethylcellulose solution. The Polyox was sieved through a 75 μm sieve, and the ethylcellulose/samarium oxide suspension (25 ml) was thoroughly mixed into 25 g of the sieved Polyox. The resulting wet mass of Polyox/ethlycellulose/samarium oxide was then transferred to a foil tray and dried overnight at 40 °C. The dried material was milled in a Waring pulverizer unit and sieved to collect particles in the size range 45-106 μm. The resulting Polyox microparticles were neutron irradiated 48 h prior to administration to the subjects; neutron irradiation generates gamma-emitting ¹⁵³Sm. On the morning of dosing, the irradiated microparticles (6.25 g) were suspended in 24.5 g of glycerol (lot 3 A, Boots Company, Nottingham). The resulting formulation constituted 250 mg/ml Polyox microparticles suspended in glycerol (equivalent to 4.6 mg/ml samarium oxide), Preparation of Mylanta. The radiolabelled Mylanta preparation was made as follows. 150 mg of samarium oxide powder was neutron irradiated 48 h prior to administration to generate ⁵ Sm. On the morning of dosing, the samarium oxide powder was mixed into 30 ml of Mylanta suspension (lot LSF226). The resulting formulation constituted 5 mg/ml samarium oxide suspended in Mylanta Administration. Volunteers received a Mylanta preparation or a mucoadhesive microparticle preparation in a single dose on each study day, and received different preparations on different days. Particularly, each of eight healthy human volunteers received 2 ml of radiolabelled Mylanta preparation on a first study day, and 2 ml of radiolabelled microparticles suspended in glycerol on a second study day. Each preparation was dispensed at the back of the tongue, and the volunteer was then instructed to swallow the preparation. In each instance, approximately equal amounts of the preparation were administered, providing standard levels of radioactivity.

Scintigraphic imaging. A gamma camera was used to image the mouth, the neck, and the esophagus. Images were then recorded at intervals over a period of

30 minutes, or until the image showed that all the radioactivity had been cleared from the mouth, pharynx, and esophagus. Particularly, prior to administration of the preparation, the volunteer was aligned in front of the camera such that the side of the face was pressed against the camera head, and the camera head was positioned to capture activity from the throat to the lower esophagus.

Approximately 2 seconds prior to administration of the preparation a 10-minute dynamic imaging sequence was started. The radiolabelled formulation was administered from a syringe onto the back of the tongue, and the volunteer was instructed to swallow.

Thereafter, and for the duration of the imaging period, volunteers were instructed to swallow at will. Four images per second were recorded over the first thirty seconds, followed by four images per minute for the remaining 9.5 minutes.

After the 10-minute dynamic image had been completed, further images (1 minute in duration) were recorded at 5-minute intervals. Imaging was completed 30 minutes post-dose. If all the activity had left the throat and esophagus before 30 minutes, imaging was stopped. Data were processed as follows. The number of radioactive counts in each of the images from the 10-minute dynamic schedule were computed. The image with the highest number of counts was taken to represent 100% of the dose.

Regions of interest (pharynx and esophagus) were superimposed onto the scintigraphic images and the radioactivity in each region was computed. All data were corrected for radionuclide decay and background. The amount of activity in each region with time was expressed as a percentage of the total amount of activity administered.

In addition, data were processed using a "condensed image" program. A condensed image format showing the transit of the formulations over the first 30 seconds and first ten minutes was produced. The image is produced by adding the collected data across the field of view of the camera detector to form a single column of data for each frame. By placing all of the columns in sequence, a condensed image is generated. Further information on this technique can be found in A.C. Perkins et al. (1994), Gut, Vol. 35, pp. 1363-67. Results. The clearance data are presented in Figs. 2 and 3. Both formulations were well tolerated by the subjects. The Polyox/glycerol preparation had a bland, slightly sweet taste. A number of anomalous figures appeared in the raw Mylanta data (raw data not shown), where the activity decreased in one image but then increased in the next. This was largely a consequence of the low amount of activity present in some of the Mylanta images. As a result, fluctuations in background activity (which was subtracted from each image) significantly affected the activity attributed to the Mylanta.

The activity of the Mylanta was less than expected because the irradiation efficiency of the samarium oxide powder, used to radiolabel the formulation, was lower than anticipated. Consequently, each subject received approximately 0.5 Mbq of activity with Mylanta and 1 Mbq with Polyox/glycerol.

Referring now to Fig. 2, surprisingly, Mylanta was cleared more slowly from the pharynx than was the Polyox/glycerol formulation. At 10 minutes, approximately 12% of the Mylanta remained in the pharynx, compared to 3% of the Polyox microparticles. Mylanta contains both carboxymethycellulose and hydroxypropyl methlycellulose, which could act as bioadhesives, and such may account for the greater retention of the Mylanta preparation in the pharynx.

The picture in the esophagus, Fig. 3, was very different. The mean time for clearance of 50% of each formulation was calculated. For the Mylanta, this was the time taken for the activity resident in the esophagus to fall from 56.6% to 28.3%. The 50% clearance time was 4 minutes. For the Polyox particles, the mean time taken for the percentage of activity resident in the esophagus to fall from 81.2% to 40.6% was 10.4 minutes. Thus, the mean residence time for the Polyox formulation in the esophagus was approximately 2.5 fold greater than for the Mylanta preparation. By 15 minutes following administration, Mylanta remained in the esophagus in just two of the subjects (mean amount of dose remaining =

3.6%). In contrast, substantial amounts of the Polyox formulation remained in the esophagus in 7 of the 8 volunteers (mean amount of dose remaining = 20.9%). These results demonstrate that prolonged esophageal residence can be achieved using a swallowable liquid formulation based on mucoadhesive particles (e.g., polyethylene oxide) suspended in a liquid (e.g., glycerol) that quickly traverses the esophagus and that is a non-solvent for the particles. After 15 minutes following administration in this study, more than 20% of the particles remained in the esophagus. Significantly, the formulation appeared to accumulate at the lower end of the esophagus, which is the target area for treatment of reflux esophagitis.

It will be appreciated, of course, that for treatment of reflux esophagitis, suspensions of mucoadhesive articles containing an antacid agent, such as for example aluminum hydroxide, made generally as described above, would be used; and the preparation need not be radioactive, as the radioactivity was employed in this example solely for purposes of illustrating the retention of the preparations in the esophagus. As described above, the composition of the microparticles as well as of the vehicle (e.g., selection for viscosity, water miscibility) may be adjusted to control the hydration rate and therefore the deposition pattern of the Polyox microparticles.

Modifications of the above-described modes for carrying out the invention that are obvious to those of skill in the fields of chemistry, transdermal drug delivery, pharmacology and related fields are intended to be within the scope of the following claims.

Claims

We claim

1. A method for delivering a therapeutically active agent to a subject, comprising contacting mucosal tissues of the subject's pharyngeal region or esophageal region with mucoadhesive particles containing a pharmaceutically effective amount of the active agent.

2. The method of claim 1. wherein the active agent-containing mucoadhesive particles dissolve or disperse in the fluid milieu of the mucosal tissue to which the particles adhere.

3. The method of claim 1 , said particles having a diameter in the range about 10 μm to about 100 μm.

4. The method of claim 3, said particles having a diameter in the range about 20 μm to about 100 mm.

5. The method of claim 1. wherein the mucoadhesive particles are deposited on the mucosal tissues in an air stream.

6. The method of claim 5, wherein the mucoadhesive particles are administered by inhalation.

7. The method of claim 5, wherein an air stream containing the mucoadhesive particles is projected toward the mucosal surface.

8. The method of claim 1 , wherein the particles are administered in a liquid suspension.

9. The method of claim 8, wherein the liquid suspension is swallowed.

10. The method of claim 1, wherein the particles are administered in the form of chewable tablet or lozenge.

1 1. A composition for administration of an active substance to a subject, the composition comprising particles containing the active substance, said particles being mucoadhesive. and said particles having a diameter in the range about 10 μm to about 200 μm.

12. The composition of claim 10, said particles dissolving or dispersing in the fluid milieu of a mucosal surface of the pharyngeal or the esophageal region of the subject.

13. The composition of claim 10. said particles having a diameter in the range about 10 μm to about 100 μm.

14. The composition of claim 10. said particles having a diameter in the range about 20 μm to about 200 μm.

15. The composition of claim 10, said particles having a diameter in the range about 20 μm to about 100 μm.

16. A swallowable liquid composition for treatment of a condition at the lower esophagus, the composition including mucoadhesive particles, said particles containing an active substance that is effective in treating the condition.

17. The liquid composition of claim 16, comprising said particles in suspension in a liquid, said particles being substantially insoluble in said liquid.

18. The liquid composition of claim 16, wherein said condition results from reflux of stomach acid into the lower esophagus, and wherein said active agent is an antacid agent.

1 . The liquid composition of claim 17, wherein said liquid comprises glycerin.

20. A method for treatment reflux esophagitis in a subject, comprising orally administering to the subject for swallowing a liquid composition of claim 18.