WO2017155866A1 - Osmotic therapeutic agent delivery device - Google Patents

Abstract

Disclosed herein are osmotic therapeutic agent delivery devices and methods of using same to treat a patient.

Description

OSMOTIC THERAPEUTIC AGENT DELIVERY DEVICE

Cross-Reference to Related Applications

This application claims priority pursuant to 35 U.S.C. §1 19(e) to the filing date of U.S. Provisional Application No. 62/304,801 , filed March 7, 2016, the disclosure of which is incorporated herein by reference.

Field

The present disclosure relates to osmotically driven therapeutic agent delivery devices. In certain embodiments, the delivery devices are adapted for implantation into the body, for example at the site of a surgical wound, and can deliver a therapeutic agent directly to the surgical site to improve tissue healing.

Introduction

The nasal passageway is the central path for ventilation and drainage for the paranasal sinuses (maxillary, frontal, sphenoid and ethmoid). Any blockages or constrictions in these areas can cause mucus stasis resulting in infection (sinusitis) and inflammation of the mucosal lining. If these constrictions persist, the infection can be become chronic. In cases where the disease state becomes chronic and the patient is failing medical management, surgical intervention (referred to as functional endoscopic sinus surgery or FESS) is used to improve ventilation and drainage. In FESS, the surgeon opens the blocked passageway(s) by cutting and removing diseased tissue and bone from within the nose. The procedures most commonly used to improve ventilation and drainage are ethmoidectomy (anterior, posterior and total) and frontal sinusotomy. An

ethmoidectomy is a surgical procedure to remove infected tissue and bone in the ethmoid sinuses, also called ethmoid air cells, blocking natural drainage. Typical endoscopic frontal sinus surgery focuses on removing obstructing disease within the frontal recess thereby restoring drainage of the frontal sinus. In either an

ethmoidectomy or a frontal sinusotomy, the surgeon views the diseased tissues with an endoscope, and typically uses a microdebrider to precisely remove affected tissue and bone, without damaging healthy tissue. The procedure is commonly done intranasally, i.e., by inserting the endoscope and the microdebrider through the patient's nostril. In these procedures, there is a chance of scarring, polyposis, mucosal thickening, or tissue ingrowth causing re-narrowing of the nasal passageway, particularly if the surgical area is not properly cared for. To prevent these re-narrowing events from happening, surgeons will protect the lining of the new opening by packing the surgical area and prescribing an anti-inflammatory or antibiotic medication. The packing used could be in the form of a non-bioresorbable or bioresorbable sinus stent, spacer, nasal dressing pack, or the like. The anti-inflammatory and/or antibiotic prescribed are either in an oral systemic dosage form, or a local dosage form such as a topical spray applied directly to the tissue or applied to the packing material. To date there are still occurrences of re- narrowing caused by scarring or inflammation requiring one or more additional surgical procedures.

In addition to the nasal cavity, there are many other anatomical sites, such as blood vessels, the urethra, sinus cavities (maxillary, ethmoid and sphenoid), the Eustachian tube, the ear (canal, middle and inner), the oral cavity (sublingual, buccal and

periodontal), the eye (intraocular and behind the eye), the esophagus, the stomach, the intestines (small and large), the rectum, the bladder, the prostate, the urethra (both male and female), the vagina and the uterus, where long term localized therapeutic agent delivery, to a surgical site or otherwise, would be desirable.

Summary

Therefore, there still is a need for a conformable packing solution that will provide a sustained and localized (i.e., non-systemic) therapeutic agent release, for example throughout the critical healing period following surgery. The present disclosure addresses these needs.

In one aspect, an osmotically driven therapeutic agent delivery device for delivering a therapeutic agent to a patient is provided. The device comprises a water-permeable polymeric matrix, the matrix having a shape with a surface, a surface area and a volume such that a ratio of the surface area to the volume is 0.3 mm²/mm³ or more (e.g., at least 0.3 mm²/mm³). The matrix has a plurality of osmotically-driven therapeutic agent pumps contained therein. Each of the pumps comprises (i) a solid core containing a therapeutic agent, an osmotically active agent and optionally one or more excipients, (ii) a semipermeable membrane surrounding the core, and (iii) a therapeutic agent delivery orifice through the semipermeable membrane. The pumps are oriented in the matrix such that the delivery orifices face the surface. Upon exposure of the matrix to water, the device delivers the therapeutic agent through the orifices at a controlled rate and over an extended period of time. In another aspect, an osmotically driven therapeutic agent delivery device for delivering a therapeutic agent to a patient is provided. The device comprises a water-permeable polymeric matrix, the matrix having a shape with a surface, a surface area and a volume such that a ratio of the surface area to the volume is 0.3 mm²/mm³ or more (e.g., at least 0.3 mm²/mm³). The matrix has a plurality of osmotically-driven therapeutic agent pumps in the form of small beads contained therein. Each of the beads releases the therapeutic agent by an osmotic bursting mechanism. Each of the beads comprises (i) a solid core containing a therapeutic agent, an osmotically active agent and optionally one or more excipients, and (ii) a continuous semipermeable membrane surrounding the core. The osmotic beads are placed within cavities in the matrix. Delivery orifices are made, e.g., by drilling, in the matrix at each small cavity such that the orifices connect the cavities to the biological environment. Typically, the orifices are on the side of the matrix that will make contact with tissue. Upon exposure of the matrix to water, water enters the device through the orifices and through absorption from the matrix itself, and is imbibed by osmosis into the beads. The beads then swell and burst thereby releasing the therapeutic agent through the orifices placed in the matrix. Timing of the beads' bursting is controlled by the composition of the semipermeable membranes surrounding the cores of the beads. In certain embodiments, the beads will have a plurality of semipermeable membrane thicknesses, causing beads to burst at different times. In this way the delivery device can be designed to release the therapeutic agent over a predetermined, and in some cases an extended (e.g., many days or weeks) predetermined, period of time. In another aspect, the therapeutic agent is released from the device over a period of from 1 to 300 days. In another aspect, the device is a spacer which fits into a space formed by removal of tissue and or bone during an ethmoidectomy or a frontal sinusotomy, the

therapeutic agent is selected from an inorganic salt, an anti-inflammatory drug, an antibiotic, an antifungal, a cilia growth promoter and combinations thereof, and the therapeutic agent is released from the device over a period of at least 2 days.

In yet another aspect, methods of treating a patient using one of the devices described herein are provided.

Before embodiments of the present disclosure are described in greater detail, it is to be understood that these embodiments are not limited to the particular aspects described, and as such may, of course, vary. It is also to be understood that the terminology used herein is for the purpose of describing particular embodiments only, and is not intended to be limiting, since the scope of the embodiments is embodied by the appended claims Where a range of values is provided, it is understood that each intervening value, to the tenth of the unit of the lower limit unless the context clearly dictates otherwise, between the upper and lower limit of that range and any other stated or intervening value in that stated range, is encompassed within embodiments of the present disclosure. The upper and lower limits of these smaller ranges may independently be included in the smaller ranges and are also encompassed within the embodiments, subject to any specifically excluded limit in the stated range. Where the stated range includes one or both of the limits, ranges excluding either or both of those included limits are also included in the embodiments. Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs. Although any methods and materials similar or equivalent to those described herein can also be used in the practice or testing of the present

embodiments, representative illustrative methods and materials are now described. It is noted that, as used herein and in the appended claims, the singular forms "a", "an", and "the" include plural referents unless the context clearly dictates otherwise. It is further noted that the claims may be drafted to exclude any optional element. As such, this statement is intended to serve as antecedent basis for use of such exclusive

terminology as "solely," "only" and the like in connection with the recitation of claim elements, or use of a "negative" limitation.

As will be apparent to those of skill in the art upon reading this disclosure, each of the individual embodiments described and illustrated herein has discrete components and features which may be readily separated from or combined with the features of any of the other several embodiments without departing from the scope or spirit of the present invention. In addition, it will be readily apparent to one of ordinary skill in the art in light of the teachings herein that certain changes and modifications may be made thereto without departing from the spirit and scope of the appended claims. Any recited method can be carried out in the order of events recited or in any other order which is logically possible.

All publications and patents cited in this specification are herein incorporated by reference as if each individual publication or patent were specifically and individually indicated to be incorporated by reference and are incorporated herein by reference to disclose and describe the methods and/or materials in connection with which the publications are cited. To the extent such publications may set out definitions of a term that conflict with the explicit or implicit definition of the present disclosure, the definition of the present disclosure controls. The citation of any publication is for its disclosure prior to the filing date and should not be construed as an admission that the present invention is not entitled to antedate such publication by virtue of prior invention. Further, the dates of publication provided may be different from the actual publication dates which may need to be independently confirmed. Brief Description of the Figures

Fig. 1 is a partial cutaway view of a human head showing the positions of the frontal sinuses (FS), the maxillary sinuses (MS) and the nasal cavity (NC) which is divided into right side and left side portions by the nasal septum (NS);

Fig. 2 is a sectional view of a portion of a human head showing the positions of the right frontal sinus (FS) and the right ethmoid air cells (EAC) prior to an ethmoidectomy;

Fig. 3 is a sectional view of a portion of a human head showing the surgically created ethmoidectomy cavity following an ethmoidectomy;

Fig. 4 is the view shown in Fig. 3 with a spacer positioned within the surgically created ethmoidectomy cavity;

Fig. 5 is a frontal sectional view of a portion of a human head showing the ethmoid air cells (EAC) prior to an ethmoidectomy;

Fig. 6 is a side view of an ethmoidectomy cavity spacer, according to embodiments of the present disclosure;

Fig. 7 is a cross sectional view of the ethmoidectomy cavity spacer shown in Fig. 6, taken along line VII-VII;

Fig. 8 is a frontal sectional view of a portion of a human head showing the surgically created ethmoidectomy cavity 1 1 and a section view of an ethmoidectomy cavity spacer positioned therein;

Fig. 9 is a perspective view of an ethmoidectomy cavity spacer, according to

embodiments of the present disclosure;

Fig. 10 is an end view of the spacer shown in Fig. 9;

Fig. 1 1 is a perspective view of an ethmoidectomy cavity spacer, according to

embodiments of the present disclosure;

Fig. 12 is an end view of the spacer shown in Fig. 1 1 ;

Fig. 13 is a perspective view of a surgical cavity spacer, according to embodiments of the present disclosure;

Fig. 14 is a perspective view of a surgical cavity spacer, according to embodiments of the present disclosure; Fig. 15 is a sectional view of a portion of a human head showing the surgically created cavity following a frontal sinusotomy;

Fig. 16 is the view shown in Fig. 15 with a spacer, shown in cross-section, positioned in the surgically created frontal sinusotomy cavity;

Fig. 17 is a perspective view of a surgical cavity spacer having an array of osmotic drug delivery drivers with a pattern described in Example 1 ;

Fig. 18 is a perspective view of a surgical cavity spacer described in Example 1 , after a forming step;

Fig. 19 is a perspective view of osmotic tablets during semipermeable membrane dip coating as described in Example 5;

Fig. 20 is a perspective view of the mucosal facing side of a nasal cavity spacer described in Example 5;

Fig. 21 is a perspective view of the non-mucosal facing side of a nasal cavity spacer described in Example 5;

Fig. 22 is a perspective view of the nasal cavity spacer shown in Figs. 20 and 21 after forming into a U-shaped cross section;

Fig. 23 is a graph plotting in vitro cumulative mometasone furoate release versus time for both individual osmotic pumps and the nasal cavity spacers containing the pumps, for the testing described in Example 10;

Fig. 24 is a graph plotting in vivo cumulative mometasone furoate release versus time for both individual osmotic pumps and the nasal cavity spacers containing the pumps, for the testing described in Example 10;

Fig. 25 is a graph plotting in vitro and in vivo cumulative mometasone furoate release versus time for individual osmotic pumps contained in nasal cavity spacers tested as described in Example 10; and

Fig. 26 is a graph plotting in vitro and in vivo cumulative mometasone furoate release versus time for nasal cavity spacers tested as described in Example 10.

Detailed Description

Disclosed herein is a device that can be placed in the body, either through implantation or placed in a body cavity such as the nasal cavity, which provides osmotically driven therapeutic agent delivery over an extended period of time (i.e., 1 to 300 days) to body tissues located at the site of the device placement. As an example, and by way of illustration only, the following description of an osmotic delivery device suitable for use in the nasal cavity is provided. This device comprises a matrix that is in the form of a sheet, which is then further bent into a shape have a U-shaped cross section, and is used as ethmoidectomy cavity spacer. An ethmoidectomy cavity spacer is also commonly referred to in the art as a stent. The spacer or stent is placed in the ethmoidectomy cavity following an ethmoidectomy. The spacer is designed to be left in the ethmoidectomy cavity for a period of days following surgery during which the tissue healing occurs. In some embodiments, the spacer is designed to be left in the ethmoidectomy cavity for a period of 3 to 10 days, though in certain cases it may be desirable to leave the spacer in the ethmoidectomy cavity for longer periods of time, e.g., up to two weeks, four weeks or even up to eight weeks following surgery. The sheet-shaped matrix is comprised of a water permeable polymeric material in sheet form, although the sheet can be formed (e.g., folded) in situ or preformed into shapes such as a tube having an O-shaped cross section, a U-shaped cross section, or a tear drop-shaped cross section, or other shapes. The water permeable polymer is selected from either a hydrophilic polymer in porous or nonporous form, or a porous hydrophobic polymer having sufficient porosity to allow water to permeate therethrough. Optionally the polymeric matrix may be comprised of a polymeric mesh having openings that are large enough to allow water and/or therapeutic agent to cross the mesh, but small enough to keep the osmotic pumps contained within the matrix. Suitable hydrophilic polymers include aliphatic polyether polyurethanes with equilibrium moisture content in the range of 20 to 900 weight percent, polyvinyl alcohol, hydroxyalkyl methacrlyate hydroxyethyl methacrylate, hydroxyethyl methacrylate methyl methacrylate copolymer, and cellulose, or blends of these polymers. Additional water permeable polymers include cellulose derivatives blended with pore forming agents or cellulose gauze fabric. Cellulose derivatives include cellulose acetate or ethyl cellulose. Water-soluble pore formers for these cellulosic derivatives include, sorbitol, triacetin, polyethylene glycol, glycerol, and ethylene oxide:propylene oxide:ethylene oxide tri-block copolymers, hydroxypropyl cellulose, hydroxypropyl methyl cellulose, methyl cellulose, polyvinyl pyrrolidone, and pegylated fatty acids such as polyethylene oxide (40) stearate.

Suitable porous hydrophobic polymers include aliphatic polyether polyurethanes with equilibrium moisture content in the range of 20 weight percent or less, aliphatic polycarbonate polyurethanes, aromatic polyether polyurethanes, silicones,

polydialkylsiloxane, polydimethylsiloxane, polyethylene, ethylene vinyl acetate, polyvinyl acetate, polytetrafluoroethylene, polyisobutylene, polyamides, polyimides, ethyl acrylate methyl methacrylate copolymer, polyisoprene, polyether block amides, chitin, chitin derivatives, chitosan, and silk, or combinations threof, optionally blended with water soluble pore formers.

In certain embodiments, the sheet-shaped matrix is comprised of a hydrophilic polyurethane film. Suitable polyurethane films can be made from the extrusion / molding grade, or solution grade, polyurethanes sold by The Lubrizol Corporation of Wickliffe, OH under the tradename Tecophilic, and particularly those resins which exhibit equilibrium water absorptions of 100 wt% and 150 wt%, respectively, as well as blends thereof. Because the Tecophilic films are hydrophilic, the spacers made from these films easily absorb water upon insertion into the ethmoidectomy cavity which acts as a driving force for the osmotic therapeutic agent delivery.

The water permeable polymeric matrix contains a plurality of osmotically driven therapeutic agent pumps. Each of the pumps comprises (i) a solid core containing a therapeutic agent, an osmotically active agent and optionally one or more excipients, (ii) a semipermeable membrane surrounding the core, and (iii) a therapeutic agent delivery orifice through the semipermeable membrane. The pumps are oriented in the matrix such that the delivery orifices face the surface of the device which is adjacent the tissues being treated. In use, water from the patient's nasal cavity and nasal mucosal membranes is absorbed by the water permeable polymeric matrix. The water is thereby in contact with the semipermeable membrane coatings of the osmotic pumps. Due to the presence of the osmotically active agent in the core of each of the pumps, water permeates through the semipermeable membranes and into the cores to achieve osmotic equilibrium. As the water permeates into the cores, the therapeutic agent is forced out of the pump via the orifice.

Osmotically driven therapeutic agent pumps are typically one of two types, depending on the water solubility of the therapeutic agent being delivered. For therapeutic agents having high water solubility (e.g., antibiotics), the osmotic pump used is typically an elementary osmotic pump with the core components being evenly mixed throughout the core. For therapeutic agents having low water solubility (e.g., corticosteroids), the osmotic pump used is typically a push-pull osmotic pump with the core comprising two separate layers; a first layer containing an osmotically active agent and a water swellable polymer and a second layer containing the therapeutic agent to be delivered. Both types of osmotic pumps are disclosed for example in US Patents 4,484,921 (discloses elementary osmotic pumps) and 6,387,403 (discloses push-pull osmotic pumps), the disclosures of which are incorporated herein by reference.

In certain embodiments, the portion of the matrix having the pumps therein has at least 0.5 pumps per cm² of the matrix portion surface area. In some embodiments, the portion of the matrix having the pumps therein has at least 0.67 pumps per 3 cm² of the matrix portion surface area. In some embodiments, the portion of the matrix having the pumps therein has at least 1 pumps per 3 cm² of the matrix portion surface area. In some embodiments, the portion of the matrix having the pumps therein has at least 1 .5 pumps per 3 cm² of the matrix portion surface area. In some embodiments, the portion of the matrix having the pumps therein has at least 2 pumps per 3 cm² of the matrix portion surface area. In some embodiments, the portion of the matrix having the pumps therein has at least 2.5 pumps per 3 cm², or at least 3 pumps per 3 cm², or at least 3.5 pumps per 3 cm², or at least 4 pumps per 3 cm², or at least 4.5 pumps per 3 cm², or at least 5 pumps per 3 cm² of the matrix portion surface area.

In those embodiments in which the matrix is in the form of a film or sheet that is folded upon insertion into the ethmoidectomy cavity, the device can be an approximately rectangularly-shaped spacer 20, as shown in Fig. 6, with dimensions that are adapted to fit within the surgically created ethmoidectomy cavity 1 1 and contact at least those portions of the ethmoidectomy cavity walls that were directly impacted by the removal of ethmoid tissue and/or bone when the spacer 20 is folded along its length, i.e., in a way that the fold line is parallel to the length of the spacer 20. Thus, the spacer 20 can have a length 3 to 4 cm and a width of 1 to 3 cm. Spacer 20 optionally has one or more drainage holes 21 therethrough with a diameter of about 0.5 to 1 cm at locations along the fold line, for example a single hold 21 at the location shown in Fig. 6. The hole 21 is adapted to be placed adjacent the frontal sinus recess when in position in the

ethmoidectomy cavity 1 1 and allow drainage from the frontal sinus as is described in more detail herein. In other embodiments, the spacer 20 is one having a sock or boot shape with a "toe" portion 22 as shown in Fig. 6.

Fig. 7 shows a cross sectional view of spacer 20 taken along line VII-VII in Fig. 6. The spacer is comprised of a gasket 23 having openings therein to accept insertion of the osmotic pumps 30. The gasket 23 is sandwiched between a bottom sheet 24 and a top sheet 25. The top sheet 25 has openings 26, 27, 28 and 29 therein. The gasket 23 and the sheets 23 and 25 are made from water permeable materials, and in certain embodiments are made from the same water permeable material, e.g., hydrophilic polyurethane.

Each of the osmotic pumps 30 comprises a compressed core 31 which contains a therapeutic agent, an osmotically active agent and optionally one or more excipients. Each of the cores 31 has a semipermeable membrane 32 surrounding the core. A therapeutic agent delivery orifice 33 is provided through each of the semipermeable membranes 32. In the embodiment shown in Figs. 6 and 7, each of the delivery orifices 33 are oriented to pump therapeutic agent out of the same side/surface of spacer 20.

In order to assemble the spacer 20, the gasket 23 and the sheets 24 and 25 are all laminated together using heat and pressure. Next, the individual osmotic pumps 30 are inserted through the openings 26-29 in the top sheet 25, again with the orifices 33 pointing away from the bottom sheet 24. In other embodiments, the spacer 40 can be one that is preformed into a trough-like shape having a tear drop-shaped cross-section as shown in Figs. 9 and 10. Spacer 40 optionally has a drainage hole 41 with a diameter of about 0.5 to 1 cm at the location shown in Fig. 9, whose function is the same as hole 31 . In other embodiments, the spacer 50 can be one that is preformed into a trough-like shape having a U-shaped cross-section as shown in Figs. 1 1 and 12. Spacer 50 optionally has a drainage hole 51 with a diameter of about 0.5 to 1 cm at the location shown in Fig. 1 1 , whose function is the same as hole 31 .

In other embodiments, the spacer 60 can have a tube-like shape as shown in Fig. 13. Spacer 60 can be formed by rolling and heat setting a sheet matrix having the configuration of spacer 20 or spacer 30. Spacer 60 optionally has a drainage hole 61 with a diameter of about 0.5 to 1 cm at the location shown in Fig. 13, whose function is the same as hole 31 when used in an ethmoidectomy cavity. When used in a frontal sinusotomy cavity, the hole 61 need not be present as drainage occurs primarily through the open space within spacer 60. In other embodiments, the spacer 70 can have a tapered tube-like shape as shown in Fig. 14. Spacer 70 can be formed by rolling and heat setting a sheet matrix having the configuration of spacer 20 or spacer 30. Spacer 70 optionally has a drainage hole 71 with a diameter of about 0.5 to 1 cm at the location shown in Fig. 14, whose function is the same as hole 31 when used in an ethmoidectomy cavity. When used in a frontal sinusotomy cavity, the hole 71 need not be present as drainage occurs primarily through the open space within spacer 70. The spacers 20, 40, 50, 60 and 70 can each have a thickness of 0.7 to 3.2 mm.

Referring now to Figs. 1 and 2, there is shown a human patient 10 prior to an

ethmoidectomy, showing the positions of the frontal sinuses (FS), the maxillary sinuses (MS) and the nasal cavity (NC). The nasal cavity (NC) is divided into a right side and a left side by the nasal septum (NS). Fig. 2 shows the ethmoid air cells (EAC), also referred to herein as the ethmoid sinus, which consists of numerous thin-walled cavities forming a honeycomb like structure. The ethmoid sinus (EAC) is situated in the ethmoidal labyrinth and completed by the frontal, maxilla, lacrimal, sphenoidal, and palatine bones. The ethmoid air cells lie between the upper parts of the nasal cavities and the orbits, and are separated from these cavities by thin bony laminae.

As is clearly shown in Fig. 2, the frontal sinus (FS), and ethmoid sinus (EAC) can be accessed by way of the patient's nostril openings (NO). Similarly, the maxillary sinuses (MS, shown in Fig. 1 ) and sphenoid sinuses can also be accessed by way of the patient's nostrils. For example, the right ethmoid sinus (EAC) can be accessed via the patient's right nostril opening (NO) and right nasal cavity (NC) whereas the left ethmoid sinus can be accessed via the patient's left nostril opening and left nasal cavity (not shown in Fig. 2). Also shown in Fig. 2 is the Agger Nasi air cell (AN) and the sphenoid sinus (SS) which are not typically disturbed or removed in an ethmoidectomy. Fig. 3 shows a similar view of the nasal cavity (NC) shown in Fig. 2, but immediately following removal of the ethmoid air cells (EAC) by an ethmoidectomy. The

ethmoidectomy creates an ethmoidectomy cavity 1 1 where the ethmoid air cells (EAC) had been before being surgically removed. Depending upon the extent of the ethmoidectomy surgery, cavity 1 1 typically has a length of about 2 to 4 cm and a width of about 0.5 to 1 .2 cm and a height (at least measured from the ceiling of the

ethmoidectomy cavity to the point where the ethmoidectomy cavity opens to the greater nasal cavity) of up to about 1 cm.

Fig. 5 shows a frontal sectional view of the patient's paranasal sinuses and adjacent structures including the eye orbits (EO). Fig. 5 shows the portion of the ethmoid sinus (EAC) to be removed during an ethmoidectomy in a polka dot overlay pattern.

In use, and as best shown in Figs. 4, 6 and 8, the spacer 20 is folded and then inserted through the patient's nostril into the ethmoidectomy cavity 1 1 such that one side of the spacer is against the medial turbinate and the other side is against the lateral wall of the nasal cavity. In those spacer 20 embodiments having a hole 21 , the spacer 20 is positioned such that the hole 21 is adjacent the frontal sinus recess, as best shown in Fig. 4, so that drainage from the frontal sinus (FS) is not blocked by the spacer 20. Upon insertion, the folded spacer 20 tends to unfold and exert an outward pressure against the nasal cavity walls. Water absorption by the spacer 20 described earlier, also causes the spacer 20 to soften and expand. As the spacer 20 presses against the nasal cavity walls, the softened spacer 20 better conforms to the irregularities in the bone and tissue surfaces lining the cavity 1 1 . Thus, the spacer 20 self-seats after being inserted, and eventually conforms intimately to the contacted cavity 1 1 walls. The self-seating property of spacer 20 is best shown in Fig. 8 where the flexible and conformable nature of the spacer, in combination with the softening of the polymer upon absorption of aqueous fluid from the nasal cavity (NC), causes the polymer film to gently press against the bone and tissue lining the ethmoidectomy cavity 1 1 and conform to the irregular shape thereof.

Referring back to Figs. 1 and 2, there is shown a human patient 10 prior to a frontal sinusotomy, showing the positions of the frontal sinuses (FS), and the blocked frontal sinus recess (FR). Fig. 2 shows the blockage occurring between the ethmoid air cells (EAC) or ethmoid sinus, and the Agger Nasi air cell (AN).

Fig. 15 shows a similar view of the nasal cavity (NC) shown in Fig. 2, but immediately following removal of the Agger Nasi air cell (AN) and the anterior portion of the ethmoid air cells (EAC) by a frontal sinusotomy. The frontal sinusotomy creates a cavity 12 where the anterior ethmoid air cells (EAC) and the Agger Nasi air cell (AN) had been before being surgically removed. Depending upon the extent of the frontal sinusotomy surgery, cavity 12 typically has a length of about 2 to 4 cm and a variable width. Such a surgical cavity can be treated with a spacer having a tapered-tube like, or frustum or bell-like shape that is open at both ends to allow flow of mucus therethrough while the spacer is in place in cavity 12. In use, and as best shown in Fig. 16, a spacer 80 having a frustum shape is inserted through the patient's nostril into the cavity 12 formed by the frontal sinusotomy such that the end of the spacer having the smaller diameter inserted furthest into the frontal recess, optionally reaching the frontal sinus cavity itself, and the spacer end with the larger diameter is open to the nasal cavity. The frustum shape lends itself to wedging the spacer 80 firmly in place within the cavity 12. After insertion of spacer 80, water is absorbed causing the spacer to soften and expand. As the spacer 80 presses against the nasal cavity walls, the softened, expanded spacer 80 better conforms to the irregularities in the bone and tissue surfaces lining the cavity 12. Thus, the spacer 80 self-seats after being inserted, and eventually conforms intimately to the contacted cavity 12 walls.

In those embodiments where the osmotic therapeutic agent delivery device is for use in the nasal cavity, the device can be designed to release a therapeutic agent during and up to the entire period of time the device sits in the nasal cavity. In those embodiments, the therapeutic agent can be an inorganic salt such as sodium chloride and/or magnesium sulfate hydrate (Epsom salts). Alternatively, the therapeutic agent can be a drug, particularly an anti-inflammatory drug, an antibiotic, a drug that promotes cilia growth or combinations thereof. Examples of suitable anti-inflammatory drugs include mometasone, budesonide, fluticasone, belclomethasone, triamcinolone and

pharmaceutically acceptable salts and esters thereof. Examples of suitable antibiotics include tobramycin, vancomycin, levomycin, gentamycin, ciprofloxacin, levofloxacin and pharmaceutically acceptable salts and esters thereof. Examples of antifungal drugs include amphotericin B, ketoconazole and fluconazole. Examples of drugs that promote cilia growth include retinoic acid, minoxidil and pharmaceutically acceptable salts and esters thereof.

In one embodiment, the device matrix contains a plurality of osmotically driven pumps which deliver the anti-inflammatory drug mometasone furoate, a furoate ester prodrug of mometasone, having low water solubility (~1 1 ng/ml). The device can have a

mometasone furoate loading in the range of 350 to 4000 μg. In certain embodiments, the device releases the mometasone furoate in vitro into the ethmoidectomy cavity over a period of at least 3 days. In other embodiments, the spacer releases the mometasone furoate in vitro into the ethmoidectomy cavity over a period of at least 5 days. In still other embodiments, the spacer releases the mometasone furoate in vitro into the ethmoidectomy cavity over a period of at least 7 days.

Because the nasal mucosal tissues are hydrophilic, the mometasone furoate requires a solubility enhancer such as a surfactant to affect its release from the spacer, particularly when using elementary osmotic pumps. The surfactant in certain embodiments is one that is solid at room and body temperatures. One suitable surfactant that is solid at room and body temperatures is Lutrol F127 sold by BASF Corporation of Mount Olive, NJ. Lutrol F127 is a nonionic triblock copolymer composed of a central hydrophobic chain of polyoxypropylene (polypropylene oxide)) flanked by two hydrophilic chains of polyoxyethylene (poly(ethylene oxide).

As can be appreciated from the disclosure provided above, the present disclosure has a wide variety of applications. Accordingly, the following examples are offered for illustration purposes and are not intended to be construed as a limitation on the invention in any way. Those of skill in the art will readily recognize a variety of noncritical parameters that could be changed or modified to yield essentially similar results. Thus, the following examples are put forth so as to provide those of ordinary skill in the art with a complete disclosure and description of how to make and use the present invention, and are not intended to limit the scope of what the inventors regard as their invention nor are they intended to represent that the experiments below are all or the only experiments performed. Efforts have been made to ensure accuracy with respect to numbers used (e.g. amounts, temperature, etc.) but some experimental errors and deviations should be accounted for. Unless indicated otherwise, parts are parts by weight, molecular weight is weight average molecular weight, temperature is in degrees Celsius, and pressure is at or near atmospheric. Examples

Example 1

Fabrication of the device is as follows. First, an osmotic tablet granulation is prepared. The granulation comprises the therapeutic agent, tablet binder, and a tablet lubricant. Optionally, the granulation may include more or more osmotic agents if the neat drug lacks sufficient osmotic activity. Next, the osmotic granulation is compressed into mini- tablets. The tablet configuration is biconvex round with diameters in the range of 1 .3 to 4.0 mm. The aspect ratio of the tablet ranges from 1 .0 to 4.0. For example, the aspect ratio is 1 .2 to 1 .4. Next, the tablet is enclosed within a semipermeable membrane. This membrane may be enrobed around the tablet from a sheet, dissolved in a solvent and dip coated from solution or spray coated from solution. In certain embodiments, the method is to spray coat the membrane composition from solution in a fluidized bed coater. The coated tablet is then dried to remove residual processing solvent. Next, a delivery port is formed in the resulting semipermeable membrane. The port can be formed by drilling with a drill bit and drill press. The port can alternately be formed by compressing the tablet granulation with a wire located within and protruding from the compressed tablet. The wire/tablet assembly is dip coated into a membrane forming solution using the wire as the handle to dip coat the tablet. After sufficient coating is applied, the wire is pulled out thus forming the delivery port across the coated membrane. Diameter of the resulting delivery port can be selected by using a wire having a diameter equal to the target diameter of the port. The connection point between the tablet and the wire forms a conical structure between the tablet surface and the wire as the coating builds up preferentially at this site. When the wire is removed, a micro-nozzle is formed. In certain embodiments, the method of drilling is to ablate a port using a laser driller. In certain embodiments, the location of the port is in the center of the face of the round tablet. In certain embodiments, the number of ports is one. The diameter of the port ranges from 3 to 30 mils, for example a range of 5 to 15 mils. Yet another means for manufacturing the micro-nozzle is to cut the wire handle used in dip coating to a short length such that 1 to 2 mm protrude above the surface of the tablet. When such a mini-tablet with a protruding wire end is spray coated, the protruding end of wire is coated with the membrane-forming solution. This process thus forms a small, generally conical feature on the surface of the coated tablet. The tip of the feature can be cut and the underlying wire removed to form micro-nozzle.

The flexible membrane is next fabricated from three parts; an outer membrane, an inner membrane, and a gasket. First, the gasket is fabricated. Medical grade elastomeric polymer is extruded to a thin sheet. In certain embodiments, the polymer is Tecophilic HP-93A-100 polyurethane extruded to a thickness in the range of 25 to 40 mils. In certain embodiments, the thickness is about 33 mils. A sheet is then die cut or laser cut from the extruded sheet to form the outside dimensions and shape of the device. In certain embodiments, the configuration for use in the ethomoidectomy cavity is a rectangular shape having a width of 20 mm and a length of 28 mm. Optionally, a rounded feature, or toe, can be present on a corner of the rectangular sheet as part of the overall shape. This feature can be 4 mm wide by 12 mm long. When the toe feature is present, the outline of the resulting device resembles a boot configuration. Next, an array of circular holes is punched or laser drilled in the sheet. In certain embodiments, the diameter of the holes is about 2.8 mm. The number of holes can be 2 to 400, and in certain embodiments 6 to 30 and in still other embodiments, the range for the number of holes is 12 to 24. The pattern of the array can be a regular linear grid pattern, a polka dot pattern, or the like. In certain embodiments, the pattern is illustrated in Fig. 17. This completes fabrication of the gasket.

Next, the outer membrane is fabricated. A thin sheet of polymer having the same composition as the gasket is formed. The sheet can be formed by spray coating, casting, extrusion or compression molding. In certain embodiments, the method is to first extrude Tecophilic to 33 mils thickness and then compression mold that sheet to a thinner sheet of a target thickness using heat and pressure. To accomplish this, a metallic shim of the target thickness is first made. Within the shim is present a cutout having a length and width that exceed the dimensions of the finished spacer. Then, a section of the 33 mil sheet stock is cut and placed upon a sheet of siliconized

polyethylene terephthalate (PET). The siliconized side of the PET sheet faces the sample to be compressed. The shim is next placed over the siliconized PET such that the sample to be thinned is within the cutout. Next, a second sheet of siliconized PET is placed on the sample to be thinned with the siliconized surface facing the sample. The 3 layer stack is next compressed with heat and pressure. This thinner sheet is then die cut or laser cut into the same configuration as the outline of the gasket. In certain embodiments, the range of thickness for the resulting outer membrane is 10 mils to 12 mils. Next, an array of holes is die punched or laser cut in this outer membrane. The center point of these holes matches the center point of the holes in the gasket. The diameters of the holes in this membrane are smaller than the holes of the gasket. In certain embodiments, the diameter of the holes in the outer membrane is about 25 to 50% of the diameter of the holes in the gasket. The diameter of these holes is about 30 mils. This completes fabrication of the outer membrane.

Next, the back membrane is fabricated. The material and fabrication steps and are the same as those used to fabricate the outer membrane except that no holes are formed. Next, these three components of the flexible membrane and the osmotic mini-tablets are assembled. First, the outer membrane and gasket are aligned such that the outline of each is the same. Two sheets of siliconized PET were punched with a die. These siliconized sheets have the same outer dimensions and outline as the gasket and outer membrane. Next, the gasket and outer membrane are placed between the two sheets of siliconized PET such that the siliconized sides face the Tecophilic components. The four layer assembly is next placed in a shim having a thickness of about 55 mils? This shim has a cutout that matches the size and configuration of the boot. The two components are next laminated with heat and light pressure for a short duration. In certain

embodiments, the conditions are 100 °C under a 5 gram weight for 2 minutes. The 5 gram weight was machined from aluminum and was made with a boot configuration that matched the size and configuration of the boot. The siliconized sheets are peeled off of the resulting outer membrane/gasket laminate.

Next, 24 of the coated and drilled osmotic mini-tablets are inserted into the 24 cavities of the gasket. The min-tablets are oriented such that the delivery ports face the outer membrane. Then, the inner or back membrane is placed over the mini-tablets. Sheet of siliconized PET die cut to the dimensions of the boot is placed under the outer membrane. Another sheet of siliconized PET is then placed over the inner membrane. The entire assembly is next placed into the boot-shaped cut out of the 55 mil thick shim. The 5 g boot-shaped weight is next placed over the assembly within the cut out and the assembly is heated on the platen of a Carver press at 100 °C for two minutes to bond and laminate the assembly. The resulting device is cooled to room temperature.

The cooled device is next removed from the cut out placed in a forming mandrel or forming channel and heated for 30 minutes at 100 °C. After this treatment, the device is cooled to room temperature. The forming process created a lengthwise fold. Cross section of the device has the configuration of a "V", "U" or "tear drop". An example of the device is shown in Fig. 18. Tablets of resulting spacer device can be formulated with therapeutic agent or therapeutic agent with osmotic agents. When placed in the cavity formed by an ethomoidectomy, the osmotic mini-tablets of the device imbibe water from the biological environment. The resulting hydrostatic pressure within the coated tablets causes the therapeutic agent to be released from the delivery ports of the mini-tablets at controlled rates for prolonged time directly to the mucosal tissue. The prolonged release of therapeutic agent promotes a therapeutic response which response is greater than had the spacer not had mini-tablets releasing therapeutic agent. Example 2

The spacer with osmotic tablets is placed in saline at 37 °C. Water is imbibed by osmosis into the tablet reservoirs to produce an osmotic driving force. The osmotic driving force is given by Equation 2:

Δ Π = n_d - n_s Eq. 2

Δ Π = 10 atmospheres where n_d = the osmotic pressure of the simulated drug, lactose = 18 atm; and n_s = osmotic pressure of saline = 8 atm

As water is imbibed into the reservoirs, the lactose and blue dye dissolve. The resulting solution is osmotically pumped through the delivery orifice present in the outer membrane of the spacer driven by the osmotic gradient. Blue dye is released at a controlled rate over a prolonged time. Osmotic pressures of selected osmotic agents are listed in Table 1 .

The device delivers at a constant (i.e., zero order) rate in the aqueous environment. The fraction of drug delivered at zero order can be calculated according to Equation 3

Mzo / M_t = 1 - [S_d / p_d] Eq. 3 where M_zo = mass of drug delivered at zero order rate

M_t = total mass of drug in tablet

S_d = solubility of drug

Pd = density of drug

Substituting the values for the simulated drug, lactose, into Equation 3 yields

- [(0.248 g/cc ) / (1 .53 g/cc)]

Mzo / M_t = 0.84 indicating that 84% of the dose initially formulated within each tablet will be delivered at zero order rate. (Ref: for lactose solubility J. Machado, et. al, "Solid-liquid Equilibrium of a-lactose in ethanol water, Fluid Phase Equilibria 173 (2000) pp 121 -134. Ref: for lactose density Merck Index 1 1 ^th Ed., p. 5224).

Table 1

Osmotic pressures of Saturated Aqueous Solutions

Saturated Solute P (atm)

H2O

sodium phosphate dibasic.12 31

H2O

sodium phosphate dibasic.7 31

H2O

sodium phosphate 29

dibasic.anhydrous

lactose 18

Example 3

An osmotic spacer is made according to the procedures described in Example 2 except the osmotic tablets are additionally coated with a semipermeable membrane

composition before being placed within the spacer. The semipermeable membrane composition is 95/5 cellulose acetate 398-10/poloxamer 407 spray coated from a 5% solids solution in acetone. The tablets are coated in a pharmaceutical fluidized bed coater with the solution until a coating thickness of 5 mils is applied. The tablets are then dried in forced air at 50 °C for 2 days to remove residual coating solvent. Thirteen of the resulting coated tablets are inserted in the thirteen cavities of a spacer reservoir layer. The reservoir layer is laminated with the outer membrane 1 and the back membrane 2. Finally, each coated osmotic tablet of the spacer is laser drilled with a carbon dioxide laser through the outer membrane 1 and into the cellulose acetate coating such that an orifice is formed in the outer membrane over each osmotic tablet and in each cellulose acetate coating. The orifice diameter is 10 mils. The spacer is shaped into a U-shaped configuration. The orifices are drilled through the Tecophilic and cellulose acetate membranes that are located on the outside of the bend.

When placed in an aqueous environment, water is imbibed into the 13 osmotic engines by osmosis. A small hydrostatic pressure is built up inside each osmotic engine which pressure is vented through the orifices. A narrow stream of blue dye solution is visibly released at controlled rate over prolonged time. This simulates controlled release of soluble drug at a controlled rate over a prolonged time from the outside surface of the spacer that would be in contact with mucosal tissue.

Example 4

An osmotic spacer is fabricated according to the procedures and materials described in Example 2. The tablets are again 4 mm in diameter but are bilayer rather than single layer. One tablet layer comprises 10 mg of 64/30/5/1 Polyox 303/sodium

chloride/hydroxypropyl E5/magnesium stearate. This layer functions as a swellable push layer. The second layer comprises the simulated drug layer weighing 20 mg. The simulated drug layer may comprise a soluble drug with standard tableting excipients such as a binder and a lubricant. Alternatively, the simulated drug layer may comprise water insoluble drug, a suspending agent, and standard tableting excipients.

The osmotic tablets formulated with water soluble drug in the drug layer are drilled with ports across the cellulose acetate membrane having a diameter of 7 mils. The osmotic tablets formulate with water insoluble drug in the drug layer are drilled with ports across the cellulose acetate membrane have a diameter of about 20 to 40 mils.

When placed in an aqueous environment, such as in the cavity formed after an ethomoidectomy, water is imbibed from the biological tissues by osmosis into the osmotic tablets. The swellable push layer within each coated osmotic tablet expands and expels the drug layer at controlled rate from the spacer to the tissue in need of medication. Example 5

An osmotic granulation was prepared by drying 25 grams of sodium chloride in a forced air oven set at 50 °C for 2 hours. The resulting dried sodium chloride was ground in a mortar with pestle to a finely divided size and passed through a 100 mesh sieve. 23.125 grams of the dried and sized sodium chloride was weighed into a 250 ml beaker. Next, 1 1 cc of anhydrous ethyl alcohol formula SDA3A was dispensed into a 20 cc glass scintillation vial. 1 .25 grams of the tablet binder, polyvinyl pyrrolidone (PVP), were weighed into the 20 cc scintillation vial. The PVP was commercially available as

Kollidon 90 F and supplied by the BASF Corporation, Ludwigshafen, Germany. The vial was tumble mixed to form a solution of the PVP. Then, 375 mg of FD and C Brilliant Blue Dye #1 was weighed and added to the solution. The vial was then tumble mixed until the dye had dissolved. The resulting blue binder solution was next slowly stirred into the beaker of salt with a spatula to form a uniform damp mass. 1 cc of anhydrous ethanol was added to the vial to rinse residual blue dye remaining in the vial and the rinsate was added with stirring to the damp mass. The resulting damp mass was passed through a 40 mesh sieve to form granules which granules were dried in a fume hood overnight. The dried granules were next passed through a 40 mesh sieve forming finely divided and free-flowing granules. Finally, 250 mg of the tablet lubricant, magnesium stearate, was passed through an 80 mesh sieve over the granules. The composition was transferred to a 120 cm³ screw capped jar. Then, the composition was tumble mixed for 1 minute to uniformly distribute the lubricant within the blend.

The resulting osmotic granulation was compressed into osmotic mini-tablets. The mini- tablets were compressed at a nominal weight of 14 mg of the osmotic granulation on a Carver press at 100 to 150 pounds force using 2.6 mm diameter round concave core rod tooling. The core rod consisted of a 10 mil diameter Nitinol wire. During the compression cycle, the wire was centered in the round face of the compressed tablet. The wire had a length of 3 inches. At the completion of each compression cycle, the end of the 3 inch long core Nitinol wire was attached to each tablet. The wire was thus embedded within the compressed tablet. The wire spanned the distance within the tablet from tablet dome to tablet dome. Twenty-four mini-tablets were compressed.

Next, a coating solution was prepared for use in forming the semipermeable membrane coating on the mini-tablets. 5 grams of pharmaceutical grade cellulose acetate 398-10 (CA) was weighed. The cellulosic polymer has an acetyl content of 39.8 weight percent and a falling ball viscosity of 10 seconds. The cellulose acetate is supplied by Eastman Chemical, Kingsport, Tennessee. 95 grams of anhydrous acetone was dispensed into a 120 cm³ screw capped jar. A magnetic stir bar was added to the solvent. The stirring continued until a clear solution had formed.

Next, the mini-tablets were coated with the CA semipermeable membrane. Prior to dip coating, the 2-3 mm length of wire that protruded from the surface of one side of the tablet was pressed flush to the surface and then pulled such that then end of the wire was just under the surface of the dome. Using dome of the tablet and then pulled just under the surface of the dome. Using the wire as a handle, the tablets were dipped in the 5% CA 398 solution to a depth of about 1 .5 cm and quickly removed. The drip at the bottom was quickly blotted off on paper toweling and the tablet was dried in a current of warmed air using a heat gun (Steinel Electronic Heat Gun model HL 2010 E) set at a temperature of 120 °F and an air flow setting "III" in a fume hood. The mini-tablets were dipped 20 times to form a coating thickness of 6 mils. Fig. 19 illustrates the appearance of three dip coated mini-tablets still attached to the ends of the 3-inch wires. A conical structure comprising cellulose acetate had formed at the point of where the 10 mil wire was attached to the tablet. This conical point will later form a micro-nozzle for use in drug delivery.

The twenty-four mini-tablets were installed within a Tecophilic spacer. The wires attached to the mini-tablets were used to position the mini-tabs such that the delivery ports of each mini-tab were facing in the same direction. This direction will face mucosal tissue once the spacer is installed in a patient. The positioning of the mini-tabs was accomplished by the method described in Example 1 . After an array of twenty-four mini-tablets was installed within the flexible spacer, the Nitinol wires were pulled out of the cellulose acetate membrane. This resulted in the formation of a 10 mil diameter delivery port centered in each of the twenty-four osmotabs. The tip of the conical attachment point was shaved off using a mechanical mill such that the end of the conical nozzle was flush with the top of the Tecophilic base material. The diameter of the micro-nozzle at the base where it was connected to the membrane surface was about 35 mils. Figs. 20 and 21 illustrate the mucosal and non- mucosal sides, respectively, of the array of mini-tablets incorporated into the spacer with each with micronozzle facing the same direction. Fig. 22 shows the array after forming the spacer into a U-shaped cross section. When placed in water, the above device imbibes water by osmosis through the

Tecophilic and cellulose acetate membranes into the osmotabs and generates a small hydrostatic pressure within the osmotic pumps. The resulting pressure causes the blue dye to be dispensed from the osmotic pumps through the micronozzles to the external environment. The visible release of blue dye from array of individual osmotabs over prolonged time simulates the unidirectional release of drug from the device to mucosal tissue over a prolonged period of time.

Example 6

A spacer is fabricated according to the procedures described in Example 5 except the tablets are formulated with tobramycin base. Also, the delivery ports of the 24 osmotabs are formed using a different process. In this process, the 10 mil diameter core rod wire is partially withdrawn such that the end of the wire is flush with the surface of the tablet on one side of the tablet and the 3 inch length is protruding from the opposite side. Next, the protruding wire is cut off such that the length protruding is reduced to a nib of 1 .5 mm. The resulting tablets with 1 .5 mm nibs are next placed in a fluid bed coater. The osmotabs are fluidized in a current of air warmed to 34 °C and the membrane composition is spray coated onto the osmotabs. During the coating process, a continuous coating is applied to the tablet and the nib. The spray coating of the nib forms a generally conical feature where the uncoated wire had been. After a nominal coating thickness of 4 mils is applied, the tablets are dried in the current of warm air for 30 minutes and are removed from the coater. The now coated and still protruding wires are pulled out of the tablets to form the conical micronozzles.

Example 7

A spacer having an array of osmo-tabs is fabricated according to the procedures detailed in Example 6 except the delivery ports are formed with delivery ports without nozzles. In this process, a core rod Nitinol wire having a diameter of 15 mils is used to compress the mini-tablets. The core rod is then completely removed from the mini- tablets. Removing the wire leaves behind a shaft through the tablet that spans the distance between the tablet domes. The resulting tablets with central shafts are spray coated in a fluidized bed coater. The atomized spray coating solution coats the tablet surface except at the two holes on the tablet surface formed by the shaft. A coating thickness of about 5 mils is applied uniformly over the tablet except at these two points. The two points of uncoated membrane become delivery ports for the device. Example 8

A spacer having an array of osmo-tabs is fabricated according to the procedures detailed in Example 6 except the delivery ports are formed by laser drilling. The mini- tablets are first installed within the gasket of a Tecophilic spacer which gasket is pre-cut with a laser to have an array of 20 circular holes. The diameter of each hole present in the gasket is 1 15 mils. This diameter provides a snug fit for the osmotabs when they are installed in the gasket. The fixed orientation of the mini-tablets defined by the pattern of the array allows a laser driller to be programmed on the x-y plane such that the center of each coated mini-tablet can be laser drilled with an exit port. Example 9

Osmotic spacers designed to be used for in vivo testing in rabbits were fabricated with pharmaceutical grade excipients as follows. Bilayer osmotic mini-tablets having a length of 6 mm and an oval cross section were first fabricated. One layer comprised an mometasone furoate (MF) composition while the adjoining layer comprised an expandable push composition. The drug layer was formulated with hydrogel-forming and drug solubility-enhancing polymer (poloxamer), an osmotic agent (sodium chloride), a pH 4.5 buffer system (citrates) and miscellaneous tableting excipients. The solubility of MF is enhanced in the presence of poloxamer. The push layer was formulated with high molecular weight hydrogel-forming polymer (polyethylene oxide), an osmotic agent (sodium chloride), red pigment (ferric oxide) and miscellaneous tableting excipients. The bilayer mini-tablets were coated with a semipermeable rate controlling membrane. The coating process involved first drilling a 10 mil diameter hole in the dome of the push layer to a depth of 30 mils. A 10 mil Nitinol wire with a length of about 45 mm was next inserted into this hole. Using the wire as a handle, each of the mini-tablets was fully immersed into a solution of cellulose acetate dissolved in acetone. The mini-tablets were then lifted from the solution, inverted 180 degrees, and air dried. This dip coating process was repeated multiple times until the target membrane thickness of 13-14 mils, as measured by the increase in the major axis dimension, was reached. The wire was then removed and the resulting hole was sealed with the cellulose acetate membrane coating solution. Small delivery ports were then drilled through the membrane. The ports were located on the drug layer side near the dome of each of the tablets on one face of the tablet. When placed in the spacer, the pumps were oriented such that the delivery ports would face mucosal tissue to pump directionally to the mucosa.

The spacers were designed with two pockets due to the small size of the test animals' maxillary sinus cavities. A miniature osmotic delivery system was inserted into each pocket. The spacer had been pre-formed from a thin, flat sheet of compliant,

biocompatible, elastomeric medical grade polyurethane into a generally rounded configuration having a horse shoe-shaped cross section. Each pocket was designed with a window comprising surgical grade mesh fabric.

Example 10

The performance of the spacers made in Example 9 were tested in vivo and in vitro. The in vivo portion of this study was conducted in three New Zealand white rabbits and with three residence durations; 2, 4, and 8 days. The New Zealand white rabbits were chosen since they are an accepted model for measuring drug release into the nasal cavity. The extent of cumulative mometasone furoate release was also estimated qualitatively by visually measuring the reduction in drug layer thickness over time as the red push layer expanded and displaced the white drug layer. Cumulative release was determined quantitatively by measuring residual drug content at a particular residence time compared to the average content value at time zero. Drug content for both in vivo and in vitro samples was measured by HPLC. The prototype devices of the present study were placed bilaterally into the maxillary sinus cavities of the rabbits by first creating a side osteotomy through which the stent was inserted. The devices had an arched configuration (Figure 1 ) which when placed in vivo assumes a more tubular configuration. The length of each of the spacers was about 12 mm. The diameter of each spacer, once placed, was about 5 mm. Each spacer was charged with two osmotic pumps.

The rabbits were fasted for at least 12 hours prior to surgery. Water was provided ad libitum. Thirty minutes prior to initiating surgical procedures, gentamicin (1 mg/kg IV) and enrofloxacin (5 mg/kg SQ) were administered. The animals were then anesthetized with ketamine (50 mg/kg IM) and xylazine (4 mg/kg IM) and maintained with inhalant isoflurane via endotracheal tube to allow unobstructed access to the nasal cavities. The animals were monitored while under the plane of anesthesia. A dorsal midline incision was made through periosteal, subcutaneous tissue and skin to approach the maxillary sinuses. Direct access to the maxillary sinuses through the skull was facilitated by boring a 1 cm x 1 cm port over both sinus cavities using a cutting burr. An osmotic spacer was placed bilaterally in each port. Dates and times of placements were recorded. The administered dose of MF was 446.8 ug MF per rabbit (106.6 ug per osmotic pump x 2 pumps per spacer x 2 spacers per rabbit = 426.4 ug MF). The spacers were positioned such that patency of the maxillary sinus outflow tract was maintained and were oriented such that the delivery ports of the osmotic pumps were facing mucosal tissue and distal to the nasal cavity. Once the spacers were placed, the incision was closed with 4-0 suture.

During the terminal procedures at 2, 4, and 8 days later, the spacers were retrieved. Date and times of retrieval were recorded. Once a spacer was retrieved, the individual osmotic pumps in each spacer were carefully removed by slipping them through the insertion slit located in the back membrane of the spacer. The retrieved pumps and retrieved spacers were then gently wiped with gauze to remove surface debris.

Lengths of the drug layer and push layers were measured at 20X magnification with a Toolmakers Microscope. The samples were then frozen in 20 cc scintillation vials at -20 °C until assay.

When placed in vivo, the mesh of the spacers faced the mucosal tissue. Thus, this window of open mesh provided access for absorption of mucosal water into the osmotic pump and an access for drug release out to mucosal tissue. The mesh further provided a barrier to mass transport of the gelled drug which barrier served to both disperse the gelled drug onto the mucosa and to slow delivery rate of drug to the mucosa. When placed in the animals, the miniature pumps imbibed water from the biological environment by osmosis, causing the viscous push layer to expand within the rigid membrane shell and thereby extrude the gelled drug layer at controlled rate through the ports over a prolonged time. The released gel next was deposited into the mesh window from which it diffused to tissue.

Twelve osmotic pumps / six nasal cavity spacers were evaluated in three animals over a duration of 8 days. Performance of the pumps was independent of location in vivo; spacers inserted into the right and left sinuses yielded equivalent mometasone furoate (MF) release results. Cumulative MF release from spacers in the medial position showed no trend of being higher or lower than spacers implanted in the lateral position.

As demonstrated in Fig. 25, in vivo performance of the individual osmotic pumps correlate well to performance in vitro. The majority of the cumulative MF release was during the first 3-4 days. The remaining cumulative MF release was during the final 4 to 8 days. Likewise, in vivo performance of the spacers correlated well to in vitro performance, as demonstrated in Fig. 26. Again, the majority of the cumulative MF release was during the first 3-4 days. The remaining cumulative MF release was during the final 4 to 8 days. No degradation products were observed in the residual pumps tested in vivo or in vitro. The mechanism of in vivo drug release from the osmotic spacers used in the present study is as follows. The osmotic pumps first deliver drug to the spacer and then the spacer diffuses drug to the nasal mucosa. 30% of the MF loaded into the spacer is retained within the pumps and then 25% of the MF load is retained in the spacer. Net MF delivered to the tissue was therefore 45% of drug initially loaded. The released gelled drug spreads and disperses over the spacer and mucosa.

Example 11

A configuration of osmotic spacer comprising osmotic beads rather than osmotic tablets is fabricated. The mechanism of drug release is by osmotic bursting over prolonged periods of time. First, a batch of osmotic beads is fabricated. 175 grams of sodium chloride crystals are dried overnight in a forced air oven set at 50 °C. The dried sodium chloride is next ground to a fine power with a mortar and pestle and passed through a stainless steel sieve having mesh with 100 wires per inch. 200 grams of microcrystalline cellulose having a nominal particle size of 50 microns is then blended with the sodium chloride in a beaker with a spatula. The microcrystalline cellulose is commercially available as Avicel PH 101 from FMC Corporation, Philadelphia, PA. Next, 120 grams of micronized poloxamer 407 is added to the mixture and blended for 5 minutes. The poloxamer is available as Kolliphor P407 micro and is supplied by the BASF

Corporation, Florham Park, NJ. Finally, 5 grams of the steroid drug, fluticasone propionate, micronized to a nominal particle size of 5 microns is added to the powder mixture and blended for 5 minutes. The powder mixture is next transferred to the mixing bowl of a small high shear mixer-granulator. The mixer is started and de-ionized water as a liquid binder is added slowly during mixing until the resulting wet mass forms a doughy consistency. The mixing bowl is removed and the screw extruder and safety cover is attached to the base unit. The wet mass is fed into the extruder until the batch is extruded through an extrusion plate having a grid of round holes with diameters of 31 mils. The resulting extrudate is added to a spheronizer bowl, the unit is run between 400 rpm and 600 rpm for about 1 to 2 minutes until the extrudate is converted into rounded beads approximately the same diameter as the extrudate. The resulting batch of rounded beads is dried in a fluid bed coater at 40 °C for 2 hours. The batch is passed through ASTM E1 1 sieves size number 20 having 33 mil openings to remove the oversized and through sieve size number 25 with 28 mil openings to remove the under sized beads. Average weight of a bead in the batch from the 20/25 sieve cut is typically about 2 mg. Average drug content of a bead is about 20 micrograms.

Next, the batch of dried bare beads is transferred to a bottom spray fluidized bed coater fitted with a Wurster column and a 40 mesh sieve mounted on the distribution plate to retain the beads within the column of the coater. A coating solution comprising 3 weight percent ethyl cellulose in anhydrous SDA 3A ethyl alcohol is prepared. The ethyl cellulose is supplied by Dow Chemical, Midland, Ml as ETHOCEL™ Ethylcellulose Standard Premium 7 cps viscosity. The bed of beads is fluidized in the column of the coater in a current of warm air. Next, the coating solution is sprayed onto the bed of beads through an atomizing nozzle using 1 bar pressure of clean dry air. At selected times, the coating process is interrupted and samples of coated beads are removed. This process is continued until five equal portions of coated beads are collected. The sampling is performed such that each of the five samples comprises the same number of coated beads. The samples collected earlier have thinner membrane coatings and the samples collected later in the coating process have thicker membrane coatings. The coating composition forms a semipermeable membrane on each bead. The average coating thickness of the beads of the five in process samples are 1 mil, 2 mils, 3 mils, 4 mils, and 5 mils, respectively. Therefore, the nominal diameter of the coated beads in the five in process samples are 33 mils, 35 mils, 37 mils, 39 mils, and 41 mils, respectively. After the coating is completed, the five fractions of beads are dried in a forced air oven at 45 °C overnight to remove residual coating solvent. Finally, the five fractions of beads are tumble mixed in a V-blender for 5 minutes to form a uniform blend of the five fractions. This completes the fabrication of the osmotic beads containing fluticasone propionate.

Next, a rectangular gasket is laser cut from a sheet of 32 mil thick sheet of extruded hydrophilic polyurethane sheet. Length of the sheet is 1 .1 inch and width of the sheet is 0.85 inch. The polyurethane is supplied by Thermedics Polymer Products, Wilmington, MA, as Tecophilic HP-93A-100. The 128 cavities are laser cut within the rectangular sheet as illustrated in Figure 27. Each cavity has a diameter of 43 mils and center-to- center spacing of the cavities is 65 mils. This completes fabrication of the gasket. Next, a front membrane is fabricated. A sheet of the extruded 32 mil Tecophilic HP-93A- 100 is compression molded in a 12 mil thick shim with heat and pressure to form a 12 mil thick coupon (the term "coupon" in the polymer field denotes an easily handled sized piece of polymer sheet material). The coupon is then laser cut to the same rectangular length and width dimensions as the gasket. 128 ports are laser cut in the front membrane with the same pattern as the gasket using 65 mil center-to-center spacing. The diameters of the ports are 13 mils.

Then, a back membrane is laser cut from the 12 mil thick Tecophilic HP 93A-100 coupon. The back membrane is of the same rectangular dimensions as the front membrane and no ports are formed.

Next, the back membrane and gasket are laminated with heat and pressure on a Carver press with heated platens. The cavities of the resulting sheet are filled with 128 beads of the coated bead blend described earlier. Next, the front membrane is laminated to the gasket using heat and pressure to seal the beads within the Tecophilic sheet. In the resulting construction, each bead is encapsulated within the Tecophilic sheet and a delivery port is present in the front membrane over each bead. This completes fabrication of the osmotic bead device. When placed in an aqueous biological environment, for example when in contact with mucosal tissue, water is transmitted across the drilled ports and diffuses through the Tecophilic membrane and is imbibed across the semipermeable membrane coating of the beads into the osmotic core of the beads. The thinner coatings imbibe water faster than the thicker coatings. As water is imbibed, a hydrostatic pressure develops within the membrane shell of the beads causing the shell to stretch and expand outwardly. The beads continue to imbibe water and the pressure within the beads increases to the point that the walls of the coating stretches beyond the elongation at break value of the hydrated semipermeable membrane. At this point, the shell ruptures and forms an in situ delivery port at the site of the rupture. Thinner shells rupture first, shells with intermediate thickness rupture next, and thicker shells rupture last. In each instance, the contents of the beads are released from the in situ formed port and are delivered through the laser drilled port of the front membrane directionally to the biological tissue. Thus, 2,560 ug fluticasone propionate (128 beads x 20 ug/bead) is released locally over a prolonged period time to the mucosal tissue in need of anti-inflammatory treatment. Example 12

Osmotic spacers are made according to the procedures described in Example 9 except each spacer was fitted with four osmotic pumps and the mesh is formed by laser cutting a polymer film rather than using an off-the-shelf surgical mesh. First, polymeric coupons are formed by re-processing 32 mil thick extruded Tecophilic HP 93A-100 sheets to thinner sheets. 1 .3 grams of the extruded sheet stock is compression molded on a Carver press fitted with heated platens using heat, pressure and shims. The shims are stainless steel, 17 mils thick, and have 2.5 inch by 2.5 inch cut outs.

Front membranes are laser cut from the resulting 17 mil sheet stock. The configuration of the front membrane is boot-shaped as illustrated in Figure 17. Four sets of grids are laser cut in the front membrane as illustrated in Figure 28. Each grid comprises 24 laser cut holes and each hole is roughly of square proportions of 25 mils by 25 mils. The cut corners of the square cut outs are slightly radiused. Additionally, two round laser cut holes each having a diameter of 100 mils are laser cut in the center of the sheet which holes serve as drainage conduits for mucosal flow from the frontal sinus when the device is in operation. Next, a back membrane is laser cut from the 17 mil sheet stock. Outer dimensions of the back membrane and drainage holes are identical to that of the front membrane. The back membrane is laser cut with four slots as illustrated in Figure 29. Each slot is cut in a dumb bell configuration having an overall length of 120 mils with 30 mil diameter bulbs at each end and a 12 mil wide slit in the middle connecting the two bulbs. Four 303 grade stainless steel molding tablets are machined on a computer numerical control (CNC) mill. The tablets are milled to the same dimensions as the coated mini- tablets having oval cross sections as described in Example 9. The length of the metal tablet is 256 mils, cross section dimension of the major axis is 142 mils, and cross section dimension of the minor axis is 81 mils. Also machined on a CNC mill is a 4- cavity stainless steel upper mold and a 4-cavity stainless steel lower mold. The locations of the cavities of the molds match the locations of where the osmotic pumps will be present in the finished spacer. The size and shape of the cavities match the size and shape of metal molding tablets but are machined to have slightly larger inside dimensions than the metal molding tablet. The larger cavity dimensions are to

accommodate the 17 mil membranes that will be formed around the metal molding tablets within the cavities.

A spacer is next fabricated using the laser cut front and back membranes, the 4-cavity upper mold, the 4-cavity lower mold, and four metal molding tablets. First, a 16 mil stainless steel shim having a cutout equivalent to the boot shaped outline of the spacer is placed on the lower 4-cavity mold. The shim is designed with two positioning holes that serve to locate the shim in the proper location on the positioning posts of the mold during the molding process. The 17 mil front membrane is next placed within the cut out of the shim. Next, the four metal molding tablets are placed on the front membrane and positioned within the four cavities of the lower mold. The upper 4-cavity mold is next placed on top of the four metal molding tablets. The upper mold is designed with two positioning holes to accommodate the two positioning posts of the lower mold such that the cavities in the upper and lower molds align during the molding process. The assembly is next placed on a Carver press with heated platens and compressed for one minute at 225 °F at 600 lbs force. The assembly is then removed from the press and cooled at room temperature for 5 minutes. The front membrane is next removed from the mold. This process pre-forms the four half cavities in the front membrane.

Next, the four half cavities are pre-formed in the back membrane. The 16 mil shim is placed on the lower mold using the two positioning pins to fix it to the proper location. The shim in this step is placed in a mirror image configuration to what was used for the front membrane. The 17 mil Tecophilic back membrane is placed within the boot- shaped cut out of the shim such that the four pre-formed half cavities nest within the four cavities of the lower mold. Next, the four metal molding tablets are placed in the four cavities of the back membrane. The upper 4-cavity mold is next placed on top of the four metal molding tablets. The assembly is then placed on a Carver press with heated platens and compressed for one minute at 225 °F with 600 lbs force. The assembly is next removed from the press and cooled at room temperature for 5 minutes. The back membrane is removed from the mold. This process pre-forms the four half cavities in the back membrane.

Finally, the front and back membranes with pre-formed half cavities are laminated together. A 32 mil stainless steel shim with a cut out having the boot-shaped outline of the front and back membranes is placed on the lower mold. This shim has two positioning holes that fit onto the two positioning posts to fix it to the proper location on the shim during the lamination process. Next, the back membrane is placed within the cut out such that the half cavities nest within the cavities of the lower mold. The four metal molding tablets are then placed within each half cavity of the back membrane. Then, the front membrane is positioned over the back membrane such that the half cavities nest onto the metal molding tablets. The upper mold is next placed over the assembly such that the cavities of the upper mold nest onto the metal molding tablets. The assembly is then placed in a Caver press with platens heated to 225 °F and compressed for 5 minutes at 600 lbs force. Next, the molded assembly is removed and cooled at room temperature for 5 minutes. The laminated system is then removed from the mold. Finally, the metal molding tablets are removed through the elastic slits in the back membrane. This forms the spacer with four empty cavities. Four osmotic pumps fabricated as describe in Example 9 are inserted through the elastic slits in the back membrane. The osmotic pumps are oriented such that the delivery ports face the laser cut grid of each cavity of the front membrane. This completes fabrication of the osmotic spacer.

When placed in an aqueous biological environment, water permeates through the matrix and through the laser drilled grids and is imbibed by the osmotic pumps. The osmotic pumps dispense the drug formulation into the laser cut grids from where it diffuses to tissue in need of therapeutic agents.

The preceding merely illustrates the principles of the disclosure. All statements herein reciting principles, aspects, and embodiments of the disclosure as well as specific examples thereof, are intended to encompass both structural and functional equivalents thereof. Additionally, it is intended that such equivalents include both currently known equivalents and equivalents developed in the future, e.g., any elements developed that perform the same function, regardless of structure. The scope of the present disclosure, therefore, is not intended to be limited to the exemplary embodiments shown and described herein. Rather, the scope and spirit of present disclosure is embodied by the appended claims.

Claims

Claims

1 . An osmotically driven therapeutic agent delivery device for delivering a therapeutic agent to a patient, the device comprising:

a water-permeable polymeric matrix, the matrix having a shape with a surface, a surface area and a volume such that a ratio of the surface area to the volume is

0.3 mm²/mm³ or more, the matrix having a plurality of osmotically-driven therapeutic agent pumps contained therein, each of the pumps comprising (i) a solid core

containing a therapeutic agent, an osmotically active agent and optionally one or more excipients, (ii) a semipermeable membrane surrounding the core, and (iii) a therapeutic agent delivery orifice through the semipermeable membrane, the pumps being oriented in the matrix such that the delivery orifices face the surface;

whereby the device delivers the therapeutic agent through the orifices at a controlled rate and over an extended period of time upon exposure of the matrix to water.

2. The device of claim 1 , wherein the water permeable polymer is selected from:

(a) a hydrophilic polymer selected from aliphatic polyether polyurethanes with equilibrium moisture content in the range of 20 to 900 weight percent, polyvinyl alcohol, hydroxyalkyi methacrlyate hydroxyethyl methacrylate, hydroxyethyl methacrylate methyl methacrylate copolymer, and cellulose; and

(b) a porous hydrophobic polymer selected from aliphatic polyether

polyurethanes with an equilibrium moisture content in the range of 20 weight percent or less, aliphatic polycarbonate polyurethanes, aromatic polyether polyurethanes, silicones, polydialkylsiloxane, polydimethylsiloxane, polyethylene, ethylene vinyl acetate, polytetrafluoroethylene, polyisobutylene, polyamides, polyimides, ethyl acrylate methyl methacrylate copolymer, polyisoprene, chitin, chitin derivatives, chitosan, and silk.

3. The device of claim 1 , wherein the semipermeable membrane is comprised of a material selected from cellulose ester, cellulose acetate, cellulose acetate butyrate, cellulose propionate, cellulose ether, ethyl cellulose, sulfonated polystyrene, polyamides, polyimides, polysulfones, polyethersulfones, polyphenylsulfones, and polycarbonate, chitin, chitin derivatives and chitosan.

4. The device of claim 1 , wherein the osmotically active agent is selected from water soluble salts, organic acids, low molecular weight starches, low molecular weight polyvinyl pyrrolidone and sugars.

5. The device of claim 1 , wherein the portion of the matrix having the pumps therein has at least 0.67 pumps per cm² of the matrix portion surface area.

6. The device of claim 1 , wherein the portion of the matrix having the pumps therein has at least 2 pumps per 3 cm² of the matrix portion surface area.

7. The device of claim 1 , wherein each of the cores comprises a compressed tablet.

8. The device of claim 7, wherein each of the semipermeable membranes comprises a coating on the core.

9. The device of claim 1 , wherein the therapeutic agent delivery orifices are formed in situ during operation of the device through bursting of the semipermeable membranes due to osmotic pressure developing within the pumps.

10. The device of claim 9, wherein the semipermeable membranes on the pumps have variable coating thicknesses.

1 1 . The device of claim 1 , wherein the matrix comprises a coating on a substrate, the pumps being oriented in the coating with the delivery orifices pointing away from the substrate.

12. The device of claim 1 , wherein the matrix is in a shape selected from a sheet, a rod, a tube, a disc, a sphere, a ring, a wedge and a cone.

13. The device of claim 1 , wherein the matrix is a sheet and the sheet is in a shape having a U-shaped, O-shaped or tear drop-shaped cross section.

14. The device of claim 1 , wherein the matrix comprises a mesh.

15. The device of claim 1 , having a ratio of the surface area to the volume of

1 mm²/mm³ or more.

16. The device of claim 1 , having a ratio of the surface area to the volume of less than 5 mm²/mm³.

17. The device of claim 1 , having at least 2 osmotically driven pumps.

18. The device of claim 1 , having at least 5 osmotically driven pumps.

19. The device of claim 1 , having at least 10 osmotically driven pumps.

20. The device of claim 1 , wherein the therapeutic agent has low water solubility and each of the cores comprises a bi-layer tablet comprised of a first layer containing the therapeutic agent and a second layer comprising a polymer that expands upon hydration, wherein the therapeutic agent containing layer is adjacent to the orifice.

21 . The device of claim 1 , wherein the device is adapted to be placed in a location in a body of a patient, the location having sufficient moisture to provide an osmotic driving force for the therapeutic agent delivery.

22. The device of claim 21 , wherein the body location is a surgical wound site.

23. The device of claim 1 , wherein the therapeutic agent is a drug.

24. The device of claim 1 , wherein the extended period of time is from 1 to 300 days.

25. The device of claim 1 , wherein the controlled rate is zero order.

26. The device of claim 21 , wherein the body location is the nasal cavity, the matrix is a sheet having a roughly rectangular shape with a U-shaped cross-section, and the therapeutic agent is selected from an inorganic salt, an anti-inflammatory drug, an antibiotic, an antifungal, a cilia growth promoter and combinations thereof.

27. The device of claim 26, wherein the therapeutic agent is selected from sodium chloride, mometasone, tobramycin, amphotericin B, retinoic acid and any

pharmaceutically acceptable salts and esters thereof.

28. The device of claim 27, wherein the therapeutic agent is mometasone furoate and the excipient comprises an ethylene oxide propylene oxide block copolymer.

29. The device of claim 26, wherein the device releases the mometasone furoate in vivo over a period of at least 3 days.

30. A method of treating a subject, comprising placing a device of claim 1 in the subject.