WO2009107136A2

WO2009107136A2 - Drug delivery device, system and method

Info

Publication number: WO2009107136A2
Application number: PCT/IL2009/000224
Authority: WO
Inventors: Tidhar Shalon; Tadmor Shalon; Guy Kotlizky
Original assignee: SVIP 3 LLC
Current assignee: SVIP 3 LLC
Priority date: 2008-02-29
Filing date: 2009-02-26
Publication date: 2009-09-03
Anticipated expiration: 2010-08-29
Also published as: WO2009107136A3

Abstract

A device for delivering an active agent to or through the anal canal or rectum is provided. The device is configured for spanning an anal canal of the subject.

Description

DRUG DELIVERY DEVICE, SYSTEM AND METHOD

FIELD AND BACKGROUND OF THE INVENTION

The present invention relates to devices and methods suitable for delivering therapeutic agents to or through anal or rectal tissue.

Medications may be administered via the rectal route for local or systemic effect.

Such delivery is typically effected using a suppository or a catheter delivery system.

Local administration can be used to treat fissures, hemorrhoids, and the like, while delivery systems designed for systemic administration can be used to treat nausea, vomiting or seizures or for sedation, analgesia, or antipyresis.

Rectal administration provides rapid absorption of many drugs and may be a suitable alternative to the intravenous route, having the advantage of being relatively painless, and usually no more threatening to children than taking a temperature.

The mechanisms of rectal absorption of drugs are not significantly different from those in the upper part of the gastrointestinal tract. The rectal absorption of sulphonamides with perfusion techniques has been studied in rats. On rectal administration, drugs may be absorbed across the epithelial cell (transcellular) or via the tight junctions interconnecting the mucosal cells (paracellular). After rectal administration, the drug is absorbed via passive transport, which is believed to be the main mechanism of absorption. Such transport is mainly dependent on the molecular weight, liposolubility and degree of ionization of molecules; basic drugs are absorbed faster in the presence of anions like sodium laurylsulphate.

Several local host factors may influence absorption in the rectum: fecal matter present in the rectum, the mucous layer, the variable volume of rectal fluid, the basal cell membrane, the tight junctions and the intracellular compartments may each constitute local barriers to drug absorption, depending on histological factors and on the molecular structure of the administered drug. The pharmaceutical formulation and access to mucosa at the location of delivery may therefore play a major role in the rectal absorption and consequently in the systemic distribution and pharmacokinetics of rectally delivered drugs.

The rate and extent of rectal drug absorption are dictated by the rectal formulation (solid vs. liquid, nature of the suppository base). This relation between formulation and drug uptake has been clearly demonstrated for drugs like diazepam, paracetamol (acetaminophen), indomethacin, methadone and diflunisal. For a number of drugs the extent of rectal absorption has been reported to exceed oral values. This phenomenon has been reported for morphine, metoclopramide, ergotamine, lidocaine (lignocaine) and propranolol. High rectal absorption may reflect partial avoidance of hepatic first-pass metabolism after rectal delivery. It is known that drugs administered high in the rectum (drained by the superior rectal veins) are usually carried directly to the liver and, thus, are subject to metabolism. However, drugs administered low in the rectum are delivered systemically by the inferior and middle rectal veins before passing through the liver thus avoiding first pass metabolism.

Although rectal drug administration can be advantageous, currently used delivery systems can lead to inefficient or irregular drug uptake and variability in absorption of systemic drugs. In addition, local irritation is increasingly being acknowledged as a possible complication of rectal drug therapy. Drug delivery for local treatment is further limited by current delivery approaches such as suppositories and ointments.

Since suppositories are pushed into the rectum and melt within minutes and dispersing the active agent into the upper rectum (Linksvan Hoogdalem EJ et al, Pharmacokinetics of Rectal Drug Administration, Clinical Pharmacokinetics, VoI 21, Issue 21,1991/07, 1 1-26), use thereof in treatment of disorders associated with the anal canal such as hemorrhoids or fissures can be ineffective. Although suppositories or ointments are used in treatment of anal canal disorders such as fissures, poor retention of the active agent in the site of treatment in the anal canal results in limited dosing and thus requires repeated applications. While reducing the present invention to practice, the present inventors have devised a drug delivery device which can be effectively retained in the anal canal without inducing discomfort and used for controlled and effective delivery of both local and systemic drugs.

BRIEF DESCRIPTION OF THE DRAWINGS

The invention is herein described, by way of example only, with reference to the accompanying drawings. With specific reference now to the drawings in detail, it is stressed that the particulars shown are by way of example and for purposes of illustrative discussion of the preferred embodiments of the present invention only, and are presented in the cause of providing what is believed to be the most useful and readily understood description of the principles and conceptual aspects of the invention. In this regard, no attempt is made to show structural details of the invention in more detail than is necessary for a fundamental understanding of the invention, the description taken with the drawings making apparent to those skilled in the art how the several forms of the invention may be embodied in practice.

In the drawings: FIG. 1 is an illustration of the anatomy of the anal canal and associated tissues.

FIGs. 2 A-B illustrate the dosing of drugs with existing rectal administration and the dosing possible with the drug delivery device of the present invention.

FIGs. 3 A-C illustrates the delivery and positioning of the drug delivery device of the present invention. FIGs. 4 A-C illustrate one configuration of the present drug delivery device that has a dissolvable top portion.

FIGs. 5 A-B illustrate one configuration of the present drug delivery device that has a drug-releasing lower portion.

FIGs. 6 A-B illustrate one configuration of the present drug delivery device which is introduced into the anal canal without an applicator as an elongated solid body having a solid core that melts at body temperature.

FIG. 7 illustrates the position of an in-situ formed vinyl polysiloxane (VPS) plug within an anal canal and rectum.

DESCRIPTION OF THE PREFERRED EMBODIMENTS

The present invention is of devices, systems and methods which can be used to treat systemic disorders as well as disorders associated with the anal or rectal canals. The principles and operation of the present invention may be better understood with reference to the drawings and accompanying descriptions. Before explaining at least one embodiment of the invention in detail, it is to be understood that the invention is not limited in its application to the details of construction and the arrangement of the components set forth in the following description or illustrated in the drawings. The invention is capable of other embodiments or of being practiced or carried out in various ways. Also, it is to be understood that the phraseology and terminology employed herein is for the purpose of description and should not be regarded as limiting. Although suppositories capable of delivering local or systemic drugs are widely used, such devices are limited in their ability to deliver drugs to or through the anal canal due to the fact that they melt and quickly diffuse and disperse away from the target tissue of interest.

The present inventors have postulated that a drug delivery device devised for positioning mostly within the anal canal while being capable of maintaining the anal canal free of fecal solids or liquids would be advantageous over prior art suppositories. In addition, the present inventors have also postulated that unlike suppositories which slowly dissolve in the rectum, the present device should maintain its location and drug release profile throughout use. In order to design a drug delivery device capable of anchoring and sealing at the anal canal, the present inventors formed impressions of the anal canal using an injectable vinyl polysiloxane (VPS) impression material. VPS material was introduced into the rectum and anal canal as a liquid and polymerized in situ into a solid "plug" that formed a highly ridged and thin "stem" in the anal canal and a small "cap" in the lower rectum. These plugs, made with approximately 1.5 ml of VPS were imperceptible and stayed in place until the next bowel movement. A plug made with 10 ml or more of VPS formed a large "cap" in the rectum and was not easily tolerated by the user. The shapes of the expelled drug delivery devices demonstrated that anal canal walls are highly folded (see Figure 7 for example which depicts the 1.5 ml plug) thus suggesting that a drug delivery device capable of effectively anchoring in the anal canal, staying in place, and yet be tolerable must have a minimal profile, maximum volume of less than 10 ml, and be soft and flexible so that it conforms to the anatomy of the anal canal and does not put any pressure against the lateral rectal walls. If the device of the present invention is too big, rigid or bulky, it would cause significant discomfort and would not be tolerated by patients..

As is further described hereinunder, the present inventors generated several designs which incorporate features derived from the VPS impressions. While testing these drug delivery devices it was further uncovered that by using a soft and elastic drug delivery device body, a single universal drug delivery device design can fit most if not all patients, including smaller sizes for pediatric patients.

As is further described herein, the drug delivery device of the present invention is preferably constructed from a soft silicone shell which is capable of releasing an agent contained therein or coated thereon.

Thus, according to one aspect of the present invention there is provided a drug delivery device which is designed for:

(i) residing primarily in the anal canal with a small top or cap portion being in the hemorrhoidal or lower rectum region and a small bottom portion that rests against the external peri-anal tissues and connected to the top or cap portion through an elongated body that spans the anal canal;

(ii) sized and shaped to fit the natural anatomy of the anal canal and/or the lower rectum; (iii) being of sufficiently soft and elastic material or covered by or filled with a soft material such that it is essentially imperceptible and conforms to the anatomy of the anal canal and lower rectum, even during movement;

(iv) optionally elastically stretchable in order to fit various anal canal lengths;

(v) optionally elastically stretchable in order to provide an elastic biasing force to help in anchoring and sealing; and

(vi) is constructed from a material that ensures that the device body does not substantially disintegrate, degrade, dissolve or melt in the body when in use (hours to a few days).

Such features ensure that the drug delivery device of the present invention effectively anchors along the length of the anal canal and in the lower rectum thereby providing cooperative anchoring and sealing. In addition, the fact that the present drug delivery device is designed for following the anatomy of the anal canal and optionally rectum enables it to stay in place and seal without applying any perceptible pressure on the walls of the anal canal and/or rectum, even as the latter fills with fecal matter. Furthermore, since the total volume of the drug delivery device is less than 10 ml and since the drug delivery device body resides below the side walls of the rectum, it does not trigger sensory receptors present in rectal tissue and thus does not cause discomfort.

In order to accomplish the functionality described above, the drug delivery device of the present invention is preferably characterized by several distinct features. It includes an elongated body (also referred to hereinbelow as stem portion 12) at least a portion of which is preferably capable of elastically stretching to accommodate several lengths of anal canals (and thus fit different individuals). This elasticity also enables administration of a cap portion (referred to hereinunder as cap portion 14) above the intended rectal position thereof and thus enables proper seating of the cap portion which is introduced into the anal canal concave down due to drag forces during insertion and assumes a concave up configuration once the elastic force pulls it back down into position during applicator 50 withdrawal.

With reference to FIGs 3A-C and 6A-B, drug delivery device (also referred to herein as device 10) includes at least one, preferably two protrusions, one at each end of the elongated body; the first protrusion (also referred to herein as cap portion 14) mainly functions in anchoring, whereas the second protrusion (also referred to hereinbelow as biasing cap 21) functions in maintaining the drug delivery device within the anal canal (by providing a force countering upward movement of drug delivery device 10 into the rectum). The embodiments of the present drug delivery device described hereinbelow provide more detail as to specific elements of drug delivery device 10 and their function.

Stem portion 12 can reside fully in the anal canal with no part of it exposed, or can extend below the anal canal and a portion exposed between the patient's legs, allowing the patient to pull stem portion 12 and seat cap portion 14 against the lower rectum or remove drug delivery device 10 altogether from the rectum. Stem portion 12 can include within it or be comprised of a non-elastic drawstring that is over-molded by cap portion 14 and perhaps also parts of stem portion 12 itself. Preferably, at least some part of stem portion 12 is axially flexible and radially elastic to enable it to conform the various and dynamic curvatures of the anal canal as explained more fully below.

Stem portion 12 can also include a biasing cap 21 attached opposite cap portion 14. Biasing cap 21 functions in securing drug delivery device 10 within the anal canal and preventing drug delivery device 10 from riding up into the rectum. As such, when drug delivery device is positioned within the anal canal (using the steps shown in FIGs 3 A-C) and cap portion 14 anchored in the lower rectum, biasing cap 21, which resides outside the anal canal (against the peri-anal skin) applies a gentle pulling force on stem portion 12 thereby causes slight stretching and adjustment of its length to correspond to that of the anal canal. Following positioning, biasing cap 21 resides against the external surface of the anus and/or buttocks effectively providing a counter force of 100 grams force or less to the anchoring of cap portion 14. Such a biasing force is distributed over a few square centimeters of soft material of biasing cap 21 and hence is a very gentle and effectively imperceptible counter force which can be tolerated for many hours or even days without discomfort as demonstrated in the examples below. Since the anal canal does not like to be occupied and tends to push out any foreign objects, drug delivery device 10 would tend to be pushed outward and out of the body and end up between the patient's buttocks without the anchoring of cap portion 14. Likewise, without biasing cap 21, drug delivery device 10 would tend to be pushed up into the rectum. The balance of forces between cap portion 14 and biasing cap 21 through an elastic element allows for stable and self-contained positioning of drug delivery device 10 in the anal canal at all times, without the need for external tubes, tape, adhesive elements, string or other anchoring schemes which may cause discomfort.

Cap portion 14 and biasing cap 21 can be separately shaped, for example, as an inverted cone with the tip contiguous with stem portion 12, as a diamond-profiled head with conical surfaces on the top and bottom, as a spherical or conical balloon (which can be fully or partially filled with fluid, gas, particles or a gel), a ring, or as a cupped or flat disc or set of disks with a circular or elliptical transverse cross section or as a bowl.

Cap portion 14 can have a fixed, detachable or dissolvable nose cone on the top of it to facilitate easier entry into the anal canal. Cap portion 14 or a portion thereof can be a disk 15 with thickness of 10-3000 microns, with or without stiffening and shaping rings, ridges or ribs. Disk 15 folds backwards into the anal canal and once in the rectum folds forward and seats in the lower rectum to provide additional sealing and anchoring capabilities to drug delivery device 10. Cap portion 14 can take the form of an inverted umbrella biased open by elastic ribs or via a mechanism activated through the applicator. Cap portion 14 can be made of two or more elements, for example as a balloon for anchoring and flat or pleated skirt for sealing or a series of discs of variable diameter arranged one on top of the other. The diameter of cap portion 14 can range between 0.5 to 5 cm. Cap portion 14 can have sufficient size and rigidity so as to not migrate downward into the anal canal, but still be small enough to not be felt and to be evacuated easily. A cross sectional area in the range of 0.5-5 sq cm should be sufficient for this purpose. The overall volume of drug delivery device 10 can range between 0.5 to 10 ml, preferably 1-3 ml.

Biasing cap 21 is constructed so as to provide external anchoring which maintains a slight pulling force on cap portion 14. In addition, since biasing cap 21 resides outside the anus and against external tissues of the subject, it should be configured for maintaining tissue contact while providing the necessary (although minimal) pulling force and enough surface area such that it is not pulled into the anal canal and distributes the pulling force over sufficient tissue area to prevent discomfort (for example a disk -2.5 cm in diameter, 1 mm thick, made of shore A 3 silicone). Thus, biasing cap 21 can be fabricated from soft thin material as a flat, yet foldable sheet which can be, for example, disc-shaped. Drug delivery device 10 does not need to appreciably change in volume or girth following introduction thereof into the anal canal. This feature of drug delivery device of the present invention ensures that it does not exert any appreciable radial pressure on the walls of the rectum or anal canal and as such does not cause sensation or discomfort when in use. Cap portion 14 occupies a small volume of up to a few ml. in the lower rectum, preferably within 30 mm, and more preferably within 15mm above the anal canal. Furthermore, the small size of drug delivery device 10 ensures that it can be evacuated naturally without any user intervention during a bowel movement or manually by pulling on any element of drug delivery device 10.

As is mentioned hereinabove, drug delivery device 10 relies on anchoring at the stem and/or cap portions. When anchored at both the stem and cap portions, cooperative anchoring is achieved by the combination of two separate anchoring mechanisms, a downward force biasing cap portion 14 against the neck-like structure above the anal canal and an adherence/frictional force between stem portion 12 (and optionally cap portion 14) and the surface of the anal canal wall in which stem portion 12 resides. Additionally, cap portion 14 can be designed such that fecal matter and liquids accumulating on top of cap portion 14, thereby serving to better anchor drug delivery device 10 in place by applying a downward force thereupon, and therefore also improve the seal against the lower rectum to prevent fecal matter from entering the region where the active agent is being released. This is in contrast to suppositories which prior to melting can be dislodged by filling of the rectum by fecal matter, antegrade or retrograde peristalsis, or general movement of the tissue. In addition, use of biasing cap 21 in preferred configurations of drug delivery device 10 ensures that stem portion 12 is maintained in place and that drug delivery device 10 does not ride up and into the rectum especially in cases where stem portion 12 has to be stretched to maintain correct anatomical fit. The anal canal tends to squeeze out foreign objects. Without biasing cap 21, drug delivery device 10 would be more prone to migration into the rectum, whereas without cap 14 drug delivery device 10 would be more susceptible to migration out of the anus. Therefore a design having a lower (biasing) cap and an upper (anchoring) cap balance the forces and keeps stem portion 12 stably located in the anal canal without the need for further anchoring or securing using external means such as tubes, tape, string, etc. Such anchoring schemes ensure that drug delivery device 10 remains secured in place and enables compensation for temporary loss of anchoring (e.g. during anal canal movement). Human subjects that have used the present device report no problem in passing gas around the drug delivery device despite the fact that the drug delivery device 10 is not permeable to gas. Therefore, it is believed that gas escapes around drug delivery device 10 by temporarily detaching a region of cap portion 14 from the tissue, but since drug delivery device 10 is also anchored at stem portion 12 and at other regions of cap portion 14, such escaped gas will simply travel as a wave along the length of drug delivery device 10 and not completely dislodge drug delivery device 10 from its position. An additional advantage to such an anchoring scheme is the ability to self eject drug delivery device 10 upon defecation or to easily remove drug delivery device 10 manually.

Since drug delivery device 10 of the present invention does not rely on a radial force or a large diameter anchor for anchoring, the act of voluntary defecation naturally dilates the anal canal, thereby detaching the top anchoring of drug delivery device 10 and enabling effortless self-ejection thereof along with the fecal matter. Furthermore, since device 10 does not exert any significant forces on the tissue lining the anal canal and rectum it can be utilized over extended time periods (days) making long-term drug release possible. Prior art anal plug devices such as the ProCon 2 are typically limited to 8 hour use periods since extended use can lead to capillary blood flow blocking and tissue necrosis. Drug delivery device 10 can be constructed as a hollow or solid structure or a combination of hollow and solid portions. For example, stem portion 12 can be constructed as a hollow or solid rod while cap portion 14 can be fabricated as a solid cone or disc or as a hollow sphere (e.g. balloon) or vice versa. Any hollow spaces can be filled with a liquid, gel, gas, foam or solid particles, all capable of containing active agents.

Stem portion 12 can be an elongated body of ranging in diameter from 0.5 mm to 10 mm, giving a circumference of roughly 1.5 mm to 30 mm. To get contact between drug delivery device 10 to sufficient surface area of the mucosa of the anal canal for adequate drug flux, it is beneficial to have stem portion 12 stretch the anal canal to a circumference within this range, which is another function of the elongated body or stem portion 12. Therefore, with a length of 2-5 cm, stem portion 12 in the form of a soft and flexible elongated body can contact directly between 0.3-15 cm² of mucosal surface area of the anal canal. Areas of the folded mucosal surfaces not in contact with drug delivery device 10 will also be exposed to the active agent through diffusion over short distances. Cap portion 14 is preferably configured to facilitate insertion into the anal canal, it may also coated with a lubricant on its upper surface. Cap 14 may have a top surface of a low friction material, such as talc, microspheres of silica or a polymer such as PMMA, or PTFE deposited directly onto the surface using vapor deposition techniques, or as a separate sheet overlaid onto the top of cap portion 14. The advantage of this method of reducing friction during drug delivery device insertion, as opposed to liquid or gel lubricants, is a lower chance of accidental drug delivery device evacuation due to the residual lubricant in the anal canal causing very low friction between the drug delivery device and the anal canal long after the insertion process.

Stem portion 12 can include an element to provide stiffness to aid in the insertion of drug delivery device 10 into the anus. Such an element can be used to stiffen stem portion 12 thus facilitating insertion of drug delivery device 10, as well as acting as a protective sheath for a drug delivery device applicator (further described hereinbelow with respect to applicator designs) thereby minimizing the chances that such an applicator perforates stem portion 12 or cap portion 14. The stiffening element can be longer than stem portion 12 and therefore extend outside the anus and serve as a handle and drawstring for manual removal of drug delivery device 10. The stiffening element can also be used to facilitate an applicator-free positioning as is further described hereinbelow.

Experiments conducted by the present inventors have determined that a drug delivery device of the geometry shown in FIGs 3A-C was slightly uncomfortable when made of silicone of Shore A 40 and harder, but essentially unnoticeable when made of a silicone of Shore A 3. Therefore, in order to be comfortable and usable over extended time periods, drug delivery device 10 is constructed having minimal surface hardness required to maintain its basic shape and maximal compliance to surface and tissue anatomy. Such properties can be achieved by fabricating solid structures from soft materials such as low Shore silicone (e.g. < 40 Shore A value), silicone-latex, open or closed cell foams (e.g. silicone or polyurethane) or by constructing drug delivery device 10 as a partially or fully fluid, gel or gas-filled hollow structure. Partial filling allows for the drug delivery device surface to fold and/or invaginate and better conform to mucosal folds. Preferably, drug delivery device 10 is also elastic such that it conforms to the shape of the anal canal during movement thus being effective in sealing while being compliant to tissue movement over extended time periods (hours to days). Drug delivery device 10 can also be constructed from a rigid yet partially elastic material which is coated with a soft material such as Shore A 3 silicone. Conversely drug delivery device 10 can be constructed from a higher shore material filled with a gel or comprised of a foam structure which lowers the effective shore to a comfortable level. As is mentioned hereinabove, stem portion 12 is preferably elastic so as to enable fitting of drug delivery device 10 to individuals of varying anal canal lengths. Such elasticity ensures that drug delivery device 10 can be stretched to accommodate anal canals of varying lengths. Stem portion 12 can be fabricated with variable elasticity along its length such that a lower region of stem portion 12 stretches more than an upper region (adjacent to cap portion 14) when drug delivery device 10 is administered.

The latter configuration ensures that drug delivery device 10 can accommodate various anal canal lengths by stretching at a lower region thereof and not an upper region. Enabling drug delivery device 10 length accommodation without stretching or distorting an upper region of stem portion 12 as well as cap portion 14 attached thereto, ensures that the anchoring function of stem upper region 17 and cap portion 14 are maintained. Anal canal length ranges from about 2-5 cm (Morren G.L., British Journal of

Surgery, 2001, 88, 1506-1512" and "Gold, D.M., British Journal of Surgery, 1999, 86, 365-370). Thus, stem region 12 is configured to elastically stretch so as to accommodate such variance in canal length without affecting the diameter and shape of cap portion 14. Children have even shorter anal canals and thus would require smaller sized devices which would accommodate anal canal lengths of 1-2 cm. Thus, pediatric device 10 configurations can have a stem length of 0.5-2cm, a cap portion diameter of 0.5-2cm and a biasing cap diameter of 0.5-2cm.

It will be appreciated that although the stem-cap configurations described above is presently preferred, configurations in which the stem portion is considerably shorter (e.g. 0.5-2 cm) or configurations which only include the stem portion or the cap portions separately are also envisaged. In a further embodiment, the cap portion can be connected to a fine elastic stem which itself is anchored to a biasing cap element that remains outside the anal canal between the legs of the subject. The very small diameter stem, shaped like an elastic string, acts as an elastic tether between the cap portion and the external biasing cap thereby applying a predetermined force on the cap portion against the neck region of the lower rectum.

In a further embodiment, drug delivery device is shaped as a 3-5 cm long cylinder (stem portion 12) on top of biasing cap 21 without a larger diameter cap portion 14 altogether. Stem portion 12 can be hollow with a thin external shell that does not melt at body temperature and filled with a meltable core. When introduced in the anal canal, the meltable core melts and the fluid is squeezed upwards towards the top of stem portion 12 which rests 0.5-2 cm above the anal canal and is either a fully non-meltable portion or bulges the external shell outwards due to the presence of the fluid being squeezed up through the resting tone of the anal sphincters. This top portion of stem portion 12 acts effectively as cap portion 14 to anchor drug delivery device 10 in the lower rectum, even though it may be the same diameter of stem portion 12 during insertion in the anus. Not having cap portion 14 and keeping the diameter of stem portion 12 small helps make insertion easier.

The external shell of stem portion 12 can be porous to allow for controlled release of the active agent which can be formulated into the meltable core of stem portion 12. The pores of the external shell can be large enough to allow the small molecule or low molecular weight active agent to diffuse out, but too small to allow the large molecules of the meltable core to escape, thus preventing the emptying of the molten core from the device. Furthermore, the osmolality of the meltable or hydratable core can be controlled so that there is a net influx of water into drug delivery device 10 increasing its volume slightly, and then a net outflow of active agent diffusing through the pores. The hydration or volume expansion can change the size of the pores as well, allowing for the initiation of release of the active agent just when drug delivery device is exposed to the heat and humidity of the anal canal.

In a further embodiment, drug delivery device 10 can have no cap portion 14 or biasing cap 21 altogether, as long as stem portion 12 is designed to have sufficient friction or fit with the anal canal to stay stably positioned in the anal canal. Such friction or fit can be achieve through surface properties, mucoadhesion, self polymerizing (like VPS or alginate) or gelling surfaces, or mechanical features such as stacked upward pointing conical chevron elements, to obviate the need for cap portion 14 and biasing cap 21 altogether. Stem portion 12 can be desiccated (in the size and form comparable to a matchstick for example) and contain within it the active agent. In this embodiment, stem portion 12 is inserted into the anus directly and when hydrated becomes soft, and may increases in volume in the form of a hydrogel for example, and releases the active agent which was kept desiccated along with the structural component of stem portion 12. Drug delivery device 10 in this embodiment comprises stem portion 12 alone and is then removed during normal defecation.

In a further embodiment, drug delivery device 10 is introduced in the anus in liquid or gel form and self-polymerizes or hardens in the anal canal. See FIG. 7 for an example of a VPS plug created according to this embodiment. The active agent can be premixed within the VPS material and be eluted out of it at a know rate. Another class of materials suitable for such an application are alginate and pluronic gel. Reference is made to PCT/IL2008/001450 by the present inventors for more examples of such in situ polymerizing materials.

In a further embodiment, and as depicted in FIG 4A-C, cap portion 14 can be over-molded onto stem 12 and cap portion 14 can be in its entirety meltable or dissolvable over time, thereby releasing the active agent and also gradually disappearing. In FIG 4B, device 10 is shown inserted into the anal canal where biasing cap 21 and stem portion 12 essentially keep cap portion 14 located in the lower rectum/anal canal regions until cap portion 14 has completely melted or dissolved. As depicted in FIG. 4C, once completely melted or dissolved, cap portion 14 disappears and all that is left of device 10 is elastic stem 12 which can be a thin rubber-band like element, and biasing cap 21 which can be a soft disc or rod, which are removed manually or eliminated with the next bowel movement. Device 10 can be introduced into the anal canal with a finger, an internal or external applicator, or with a stiff stem portion 12 that then softens over time in the anal canal. Drug delivery device 10, or portions/layers thereof, can be made of a hydrophobic material, in which case an open-cell foam will allow for gas to vent through the drug delivery device without the passage of liquid or solid fecal matter, or a hydrophilic material, in which case a closed cell foam would be preferable. In general, a hydrophobic material is preferable to minimize seepage of liquid between the tissue and drug delivery device surface.

In a further embodiment, drug delivery device 10 or portions thereof are made of a material that can degrade naturally in the waste water of the sewage system or septic tanks. Such water degradation properties can occur over weeks or months, but not affect the ability of drug delivery device 10 to function and withstand the humid environment of the rectum for hours or even days. Example materials include collagen, gelatin, gum, agarose, hydrogels, materials used in denture adhesive, or the like.

Dissolution of the biodegradable material comprising device 10 or portions thereof can proceed from the surface. The dissolved polymers can fit within the smallest of mucosal folds, as long as the viscosity of the dissolved polymer is sufficiently high and lubrication is controlled. Other biodegradable materials include derivatized cellulosics, for example hydroxy methyl cellulose or polyvinyl alcohol. Such materials can be formulated in a hydrogel, hydrated and cross-linked or alternatively in a non- hydrogel, desiccated or non-crosslinked state (with appropriate moisture control packaging). Additionally, biodegradable or hydrolysable polymers can be made to have slow degradation times and generally degrade by bulk hydrolytic mechanisms. Such materials include as polylactic or glycol acids. Typical degradation times would be in days or weeks, over which time such material would lose its mechanical properties.

Other degradable materials include certain polycarbonates or polyanhydrides, polymers and copolymers of phthalic acid, isophthalic acid with compounds like caprolactone or valerolactone, maleic anhydride or phthalic anhydride and the like. All materials listed above can be made in a soft formulation. Device 10 can be made of combinations of biodegradable materials. For example inner sleeve 23 can be a hard plastic such as polylactic acid (PLA) encased in a softer gelatin or cellulosic outer drug delivery device.

Drug delivery device 10 or portions thereof can be fabricated by a compound that softens, plasticizes or even molds itself under humid conditions, at body temperature or under other conditions present or caused during drug delivery device 10 insertion, thereby increasing compliance to the natural tissue anatomy.

Drug delivery device 10 or portions thereof can be made of a solid core with a gel, liquid or gas filled blistered surface that allows for adequate surface conformation/invagination with the solid core provides structural rigidity.

Drug delivery device 10 can also be coated with a gel or gelling material (e.g. desiccated hydrogel). Such coating can swell upon contact with body fluids, as well as provide additional surface impressibility (conformity to surface anatomy, e.g. folds of anal canal wall), better sealing and adhesion for improved anchoring and resistance to drug delivery device migration.

Drug delivery device 10 can also be filled with gel or fluid that exudes out of pores of the drug delivery device body to improve sealing, anchoring or to release an active agent.

Drug delivery device 10 can also be fabricated from an inelastic core which is overmolded with elastic soft material. For example, hydrated or dehydrated gelatin, agarose or other deformable, elastic or moldable polymer or hydrogel can be overmolded on an axially inelastic backbone, such as a string or collapsible tube.

For example, drug delivery device 10 can be dry coated with a layer of desiccated carboxymethyl cellulose which upon contact with anal and/or rectal tissue hydrates into a gel layer which follows the microscopic and macroscopic contours of the tissue folds. Drug delivery device 10 or portions thereof can be coated with a high viscosity hydrophobic agent that might soften but does not flow at body temperature, such as various forms of grease or wax. High viscosity gel layers will stay in the anal canal for an extended period of time, slowly releasing the active agent formulated within. It will be appreciated that drug delivery device 10 coated with a hydrogel can be fabricated from a higher shore material since such a coating can provide the necessary compliance with tissue surface morphology.

Polymers that are suitable for use in construction of the present drug delivery device include the following: Poly(urethanes) for elasticity, Poly(siloxanes) or silicones for insulating ability, Poly(methyl methacrylate) for physical strength and transparency,

Poly(vinyl alcohol) for hydrophilicity and strength, Poly(ethylene) for toughness and lack of swelling, Poly(vinyl pyrrolidone) for suspension capabilities. Additional materials include Poly(2-hydroxy ethyl methacrylate), Poly(N-vinyl pyrrolidone), Poly(methyl methacrylate), Poly(acrylic acid), Polyacrylamide, Poly(ethylene-co-vinyl acetate), Poly(ethylene glycol), Poly(methacrylic acid), Polylactides (PLA),

Polyglycolides (PGA), Poly(lactide-co-glycolides) (PLGA), Polyanhydrides and

Polyorthoesters, and various hydrocolloids and carbohydrate-based polymers.

As is mentioned hereinabove, the present device is designed for delivery of drugs and active agents to or through the anal or rectal tissue.

As such, the drug delivery device of the present invention includes an active agent which can be used in local or systemic therapy or for diagnostics.

The active agent can be contained within or coated upon the device and is released over time into the rectum or anal canal region during use of drug delivery device 10. The present drug delivery device functions as a fully-contained drug reservoir and drug delivery system for local or systemic delivery through the mucosal surface of the anal or rectal tissues.

The present drug delivery device provides several advantages over currently used delivery approaches: i. Due to its reservoir and slow release design, it increases the amount of drug available locally or systemically. ii. Due to its sealing and anchoring capabilities, no drug is lost by dispersion of the drug through the anus or up into the rectum and colon as is the case with ointments and suppositories. iii. Since it resists migration, it enables sustained drug delivery to the affected tissue. iv. It can be used to deliver several drugs, including the automatic sequencing and release of drugs in a predetermined or controlled order and dosing schedule. v. It provides increased residence time since it does not dissolve and disperse like a suppository. vi. It can increase compliance due to reduced number of applications

(suppositories and ointments require multiple applications a day), vii. It is convenient and disposable and does not require direct patient contact with the anus. viii. It is easy to dispose of unused drug and terminate drug exposure by removing the device manually, ix. The device shields the target tissue from fecal matter which improves access of the active agent to the target tissue. x. Anal canal/rectal positioning ensures that the drug delivered systemically avoids first pass metabolism by the liver, thereby increasing bioavailability; xi. It can be used to deliver a desiccated form of the drug which is stable in formulation and has a long shelf life. Contact with the anal mucosa or puncturing of an internal ampoule during drug delivery device insertion can be used to hydrate the drug and initialize delivery; xii. The drug delivery device can release the drug directly at the mucosal surface which increases the effective concentration of the drug and therefore increases bioavailability as compared to enemas and suppositories in which the drug is diluted in a larger volume and therefore most of the drug is not at the mucosal interface, and therefore not available for absorption. xiii. The drug formulation can be much simplified as compared to enemas and suppositories that need additives in order to achieve specific stability, melting and spreading behavior. Much of the mucosal irritation related to rectal drug delivery has been caused by such additives. xiv. It can be used along with local monitoring of various parameters (e.g. power source and sensor provided in drug delivery device which measures glucose levels in fluids present in the anal canal and releases insulin, temperature sensor which releases drugs to lower fever, or a remote control activation for on-demand release of morphine or anti- emetics based on patient control within a limited range of dosing) and thus be configured as a closed loop system for delivery of dose sensitive drugs.

FIG. 2A illustrates that typical drug delivery using prior art rectal administration approaches can lead to rapid absorption of the drug and a spike in systemic or local levels of the drug following dosing.

FIG. 2B illustrates one form of dosing possible with the present drug delivery device. The rate of release of the drug can be zero order which is the optimal level for longer time periods, providing a proper and steady systemic dosing of a systemic drug, or longer and more sustained relief from peri-anal conditions such as anal fissures and hemorrhoids. The drug delivery system of the present invention allows for much greater control of the area under the curve (total dose), maximum concentration, minimum concentration, rise time, decay time, half-life and steady state dosing. Furthermore, as opposed to ointments or suppositories, the dosing can be stopped at any time via manual removal of the drug delivery device.

Generally a zero order kinetic release is preferred in the release of an active agent from a device. Such a release is characterized by a constant active agent elution amount with time during the life time of the device. Simple approaches of incorporating the active agent into the polymer, such as incorporating the active agent directly into the polymer of manufacture of the device, for example silicone, will likely produce a nonzero order release kinetics with a release more typically characterized by a pseudo first order profile or described by a linear release with the square root of time. Such pseudo first order drug release profiles may be advantageous in specific applications where an initial high initial dose is desired (for example pain relief).

An additional parameter to control is to reservoir the active agent at the appropriate concentration for the intended duration of delivery. Although some active agents will be released at amounts that are sufficiently small that loading capacities are not a concern, other active agents will require significant loadings to provide the desired active agent concentration for the intended period of use.

One approach for the attainment of a zero order release is described below. Drug delivery device 10 is made out of molded structural polymer (such as silicone) and contains an internal reservoir of the desired active agent. The reservoir consists of at least two components and more probably three or more components. In the simplest form the pure active agent is coated or encased with a rate releasing polymer film that allows for the controlled release of the active agent from the reservoir into the surrounding structural polymer from which drug delivery device 10 is made (or through holes or perforations made in the structural polymer for this purpose). The polymer film may consist of a wide variety of various polymers which will allow for the controlled diffusion of the active agent. The polymer chosen would be appropriate for the type of active agent employed, whether hydrophilic or hydrophobic, and the compatibility with the structural polymer from which drug delivery device 10 is manufactured. Examples of such polymers include but are not limited to: ethylene vinyl acetate, ethylene vinyl acetate vinyl alcohol copolymers, poly vinyl pyrrolidone, poly acrylates, poly butylene, poly isobutylene and poly isoprene although many other polymers may be employed as would be understood by those skilled in the art. Additionally the polymers may be used in either a linear or a crosslinked form. Crosslinking of the polymeric material also allows for a change in the release kinetics and as such may be employed to modify the release rate and profile of the intended active agent from the reservoir. The method described herein would be appropriate for the zero order release of an active agent such as nitroglycerin, for example.

In many cases the use of a pure active agent is undesirable in the reservoir and therefore the active agent to be delivered is mixed into another carrier material from which the active agent may elute. In such cases the reservoir may or may not include a separate outer membrane for the controlled release of the active agent. In certain cases the material in which the active agent is contained may serve as the rate controlling release material itself where the diffusion into the surrounding structural polymer material is governed by the reservoir material. The polymers previously described as well as others known to those skilled in the art may be employed for the reservoir of the active agent.

In yet other cases the reservoir is coated with a material that will allow bonding of the reservoir to the structural polymer of the device. This may be necessary is cases where the reservoir is not an integral part of the device and as such shows unexpected release kinetics since there may be gaps between the body of the device and the reservoir preventing the continuous diffusion and elution of the active agent from the reservoir into the structural polymer of the device. Such materials will be selected to allow for interphase compatibility of the structural polymer material of the device and the reservoir material. Some examples of such materials would be block copolymers of silicones and the respective reservoir polymer. Additionally other interphase compatible materials may be used to allow for the intimate compatibility of the two different materials and would include such materials as low molecular weight poly butylenes, poly acrylates and the like.

Another example of a means of providing for controlled release of an active agent from a structural polymer include particles which may be comprised of an active agent dissolved in a carrier material that may include other polymeric materials; active agent dissolved in a device polymer incompatible fluid; or in some cases pure active agent particles itself. All such approached employ the concept of an active agent reservoir within the structural polymer constituting the bulk of drug delivery device 10. Active agent release kinetics are controlled by the partitioning of the active agent into the polymer phase from the active agent reservoirs. The active agent reservoir phase is intended to serve as high concentration phase where active agent concentration within the reservoir remains high during the course of the time that active agent treatment is desired and the chemical activity of the active agent effectively remains.

The dispersion of active agent reservoirs within the polymer matrix can be accomplished during the fabrication of the device and may require the use of added agents to allow for homogeneous dispersion as is known to those skilled in the art. The size of the active agent reservoirs is calculated to provide sufficient active agent reservoir for the intended duration of active agent delivery based upon the release kinetics, desired released active agent concentration and the partitioning of the active agent into the structural polymer of the drug delivery device. Such calculations would be known and understood by those skilled in the art. One may combine the approaches discussed above. In such a combined approach active agent reservoirs are deposited in a rate controlling polymer membrane. Such an approach may be required if phase incompatibilities between the active agent reservoir and the structural polymer of the drug delivery device do not allow for the facile diffusion of the active agent. Although more complicated, such a device construction allows for additional control of active agent delivery and a wider range of active agents that can be released from the device.

Release of two or more active agent may be required in cases where multiple symptoms are present and the controlled delivery of the active agent to the localized area is preferable, for example separate agents to act as muscle relaxant, pain reliever and increase blood perfusion in the case of anal fissures.

Other compounds that would also be used in such a system are those that are combined with the active agent or device to enhance the effectiveness of the active agent being delivered. Another example would include compounds that provide for better penetration of the active agent into the endothelium of the surrounding tissue. In yet another example would be the use of a solvent that allows for the dissolution of the active agent in the active agent reservoir thus overcoming the issue of active agent dissolution becoming part of the active agent release kinetics. In yet another example would be compounds that are included to plasticize a polymer used in the construction of the device thereby altering the diffusion of the active agent through the device. Many examples of compounds would be known to those skilled in the art.

Drug delivery device 10 can be used to deliver drugs formulated for local or systemic applications and having a short or an extended/delayed release pattern. Such drugs can be small molecules, peptides or polypeptides (specific examples described hereinunder). Several approaches can be used to deliver active agents from the drug delivery device of the present invention. The active agent can be co-formulated with a polymer matrix system and slowly diffuse out of the polymer. Alternatively, the active agent can reside in a reservoir and diffuse out to the tissue through microchannels or pores in a polymeric membrane with controlled diffusion characteristics. An additional alternative is to design the drug delivery device so that it is incapable of releasing its agent or agents until it is exposed to the moisture in the anal canal and rectum. Swelling-controlled release systems are initially dry and, when placed in the body, will absorb water or other body fluids and swell. The swelling increases the aqueous solvent content within the formulation as well as the polymer mesh size, enabling the drug to diffuse through the swollen network into the external environment. Most of the materials used in swelling-controlled release systems are based on hydrogels, which are polymers that will swell without dissolving when placed in water or other biological fluids. These hydrogels can absorb a great deal of fluid and, at equilibrium, typically comprise 60-90% fluid and only 10-30% polymer.

"Smart" hydrogel system can further limit or control the release of drug based on additional environmental or controllable parameters. Table 1 below lists some of the parameters or stimuli that can control the timing, rate or amount of drug released into the body by the present device.

Table 1- Parameters controllin dru di usion rom a h dro el matrix

For systemic delivery applications, a drug releasing configuration of drug delivery device 10 preferably includes an internal reservoir within cap portion 14 and optionally top region (neck) of stem portion 12. In one embodiment, cap portion 14 is configured for allowing intake of water from the anal canal/rectum to hydrate the desiccated drug. In the hydrated form, the drug can then leach out of a drug-releasing surface of drug delivery device 10 which is situated between the bottom of cap portion 14 and above the neck region of stem portion 12 opposite the internal hemorrhoids which represent an attractive target for venous absorption. The top of cap portion 14 prevents feces from accessing the bottom and side-facing drug releasing surface of drug delivery device 10 which contacts the rectal and anal mucosa. Such mixing is a major limitation of drugs introduced via enemas or suppositories which mix together with rectal fluids and fecal matter and are therefore diluted and not absorbed. Sealing of the anal sphincters around stem portion 12 prevents downward migration of the released drug much as fluids in the rectum are retained, effectively creating a clean, sealed and controlled area of mucosa and drug release for optimal drug absorption. It is estimated that the area of a target tissue covered by such a device can be up to 10 square centimeters. This is at least 3x times higher than the starting area of contact of suppositories which melt over time, diffuse up into the rectum and colon, mix with fecal matter, and thus lead to a decrease in area of contact and a decrease in the available effective dose.

For local delivery of drugs, such as for example for proctitis, the active agent can be an antibody, antiviral, steroid, anti-inflammatory (e.g. 5-aminosalicyclic acid otherwise known as 5 ASA) or anti-diarrheals, and it can be released from the top of cap portion 14 into the lower rectum to treat the affected tissues directly. Similarly, for internal hemorrhoid conditions, the active agent can be released from the bottom of cap portion 14 and/or stem portion 12 which is in contact with the internal hemorrhoids. In the case of external hemorrhoids, the active agent can be released from the bottom of stem portion 12 or the top surface of biasing element 21 which is in contact with the external hemorrhoids. The duration of release and release profile can be controlled far more precisely as compared to enemas or suppositories.

An anal fissure is a tear in the mucosal lining of the distal anal canal leading to excruciating pain, especially during defecation. Anal fissure is one of the most common causes of anorectal pain. The pain is mainly due to the intense spasm of the internal anal sphincter muscle. Acute fissures which do not heal with the standard of care, becomes chronic anal fissures or anal ulcers. Hypertonicity of the internal anal sphincter and/or muscle spasms and mucosal ischemia are thought to play the major role in the pathophysiology of chronic anal fissures.

In hemorrhoids, the cushions located internally near the dentate line and external near the anal opening becomes enlarged, and the veins internal and external to the anus and lower rectum bulge resulting in pain, burning/itch, and bleeding, especially during bowel movement. While low grade hemorrhoid diseases can benefit from the standard of care, surgical procedures such as rubber band ligation, hemorrhoidectomy, etc. are effective in treating more severe hemorrhoid disorders.

With both hemorrhoids and anal fissures, resting pressure of the anal canal is usually elevated. In one study, the average resting pressure of the internal sphincter was significantly higher (120mm Hg) in patients with a chronic anal fissure versus normal controls (83 mmHg) (Keck, JO, et. al. Dis Colon Rectum 1995; 38:72). Furthermore, fissures are correlated with decreased blood perfusion in at least some portion of the internal anal sphincter muscle. Therefore, objective clinical endpoints that can be measured and used to assess, monitor and control the efficacy or dosing of treatment by the device of the present invention can include a reduction of resting pressure in the anal canal over time, increased blood perfusion, as well as a reduction of subjective clinical symptoms, mainly pain.

Thus, both anal fissures and hemorrhoids condition can benefit from reducing internal anal sphincter pressure to improve local blood circulation and facilitate healing as well as from direct relief of pain and inflammation and improved drainage. The goals of therapy are to break the cycle of sphincter spasm and tearing of the anal mucosa, and to promote healing of the fissure. In that respect, drug delivery device 10 can be configured to release a muscle relaxant or a paralytic agent such as Botox or Acetyl Hexapeptide-3, in addition to a therapeutic agent such as nitroglycerin to increase blood perfusion.

In cases where a muscle relaxant or paralytic agent is used, fecal incontinence may result due to the reduced tone of the internal and/or external anal sphincters. The resulting incontinence could be dealt with concurrently with the drug treatment by the sealing capabilities of drug delivery device 10.

Inflammatory bowel diseases (IBD) including Crohn's disease and ulcerative colitis are debilitating chronic inflammatory diseases of the intestinal linings. Crohn's disease is a condition in which the lining of the digestive tract becomes inflamed, causing severe diarrhea and abdominal pain. The inflammation often spreads deep into the layers of affected tissue. Ulcerative colitis also causes chronic inflammation of the digestive tract. Ulcerative colitis usually affects one continuous section of the inner lining of the colon beginning with the rectum instead of patches of inflamed tissues seen in Crohn's disease. Like Crohn's disease, ulcerative colitis can be debilitating and sometimes can lead to life-threatening complications.

While there's no known medical cure for Crohn's disease or ulcerative colitis, therapies can reduce the signs and symptoms of both diseases and even bring about a long-term remission. Effective medical treatments include anti-inflammatory drugs (Sulfasalazine (Azulfidine), Mesalamine (Asacol, Rowasa), Corticosteroids, etc.), immunosuppressants (Azathioprine (Imuran) and mercaptopurine (Purinethol), Infliximab (Remicade), Adalimumab (Humira), Certolizumab pegol (Cimzia), Methotrexate (Rheumatrex), Cyclosporine (Neoral, Sandimmune). Natalizumab (Tysabri), etc. In order to treat fistulas and abscess either associated with IBD or due to other causes, antibiotics, such as Metronidazole (Flagyl) or Ciprofloxacin (Cipro) may be used. A sustained release drug delivery device could provide additional therapeutic advantages to the use of these drugs by minimizing the systemic exposure, and yet, maintaining a constant local drug level, thus improving efficacy and prolong remission of IBD via using the device.

The drug delivery device of the present invention can also be used to treat additional local disorders. Examples of other local rectal disorders treatable with locally or regionally applied drugs include proctitis (which can be treated with 5-ASA, corticosteroids, turmeric, tacrolimus, infliximab, anti-CD3 antibodies, selective integrin blockers, anti-IL-2 antibodies and PPAR-γ agonists for example), fistulas (which can be treated by antibiotics and an immunosuppressive agents such as azathioprine or mercaptopurine), colorectal polyps (which can be treated with NSAIDS), rectal cancer and the like on an acute or chronic basis. The drug delivery device of the present invention can be useful for relieving constipation, whether acute or chronic. The active agent that can be released from device 10 for relieving constipation can be water, saline, glycerin, stool softeners, or any one of the many constipation relieving drugs on the market or in clinical development.

In general, the volume of the released agent can be greater than the volume of the drug delivery device body by virtue of having drug delivery device 10 serve as a tolerable anchor for a tube that is connected to an external reservoir not in the vicinity of the anus. Such an embodiment of device 10 is further described hereinbelow.

Additional drugs useful for anal or peri-anal disorders include witch hazel, pramoxine, zinc phosphate, Tucks® (pramoxine HCl), Preparation H ®, topical starch (such as Anusol ®) used to temporarily form a protective coating over inflamed tissues to help prevent drying of tissues, aloe vera, hamemelis, chamomille, minera oil, zinc oxide, hydrocortisone or hydrocortisone acetate to relieve itching (at dosages of roughly 0.4-12 micrograms per cm² to the perianal skin and up to lcm into the anal canal), corticosteroids, Butcher's Broom extract (ruscus aculeatus), horse-chestnut extract (aesculus hippocastanum), saponins, aescin, bilberry extract (vaccinium myrtillus), anthocyanoside bioflavonoid, tribenoside, lidocaine or other members of the "caine" family, nitric oxide donors such as arginine, glyceryl trinitrate, nitroglycerin isosorbide dinitrate etc, bethanechol, calcium channel blockers such as diltiazem, nifedipine and the dihydropuridine class of calcium channel blockers, verapamil, selective and non- selective phosphodiesterase inhibitors including caffeine, aminophylline, sildenafil, zapraniast, etc, potassium channel openers and vasodilating compounds such as minoxidil, smooth muscle relaxants, vasoconstrictive compounds such as phenylephrine and other alpha-blockers, anti-inflammatory compounds such as Sulfasalazine (Azulfidine), Mesalamine (Asacol, Rowasa), corticosteroids, hydrocortisone, PDE inhibitors, and all other drugs used to treat such conditions in topical or suppository formulations, immunosuppressants such as (Azathioprine (Imuran) and mercaptopurine (Purinethol), Infliximab (Remicade), Adalimumab (Humira), Certolizumab pegol (Cimzia), Methotrexate (Rheumatrex), Cyclosporine (Neoral, Sandimmune), Natalizumab (Tysabri), anti-emetic agents, stool softeners, and anti-neoplastic agents.

The conditions described above are treatable with prior art creams or suppositories, however, since such treatment approaches are poorly retained at the tissue site, they require frequent dosing which leads to a spiked pharmacokinetic (PK) drug profile and limited bioavailability. For example, nitroglycerine or other NO donors when applied as a cream or suppository produce spiked pharmacokinetics which leads to rapid systemic spread. The result is low blood pressure and headaches as side effects, limiting the use of this effective therapy for anal fissures. Therefore a local and sustained release of a much smaller amount of drug to the anal tissue while keeping systemic levels of the drug low is greatly preferred.

On the other hand, drugs like lidocaine which can be used to deal with the pain of inserting the device into an anal canal with fissures, for example, could be used for immediate relief and to increase compliance of device use. Therefore, lidocaine might be added to the lubricant used to coat the device, and perhaps also released steadily at a lower rate to help in muscle relaxation and increase blood perfusion.

Drugs like steroids would also benefit from sustained slow release since their bioavailability would be enhanced and healing will take place faster. Certain drugs, such as corticosteroids that are transferred through skin patches can accumulate in the skin, but cannot do so through mucosal tissues, therefore sustained and controlled release is important in such cases. Complex drug release profiles are possible with the device of the current invention (by layering drug release layers for example), and would further increase the clinical utility of this mode of treatment.

For hemorrhoids and anal fissures, specific active agents, drug concentrations and drug release rates which can be used with the drug delivery device of the present invention are listed in Table 2 below.

Table 2. Active agents for use in hemorrhoid and fissure treatment

Pharmaceutically Concentration Rate of Preferred Rate of Drug

Active Agent in the Matrix (w/v) Drug Delivery Delivery

Nitroglycerin 0.01% - 0.4% 0.01 nig-0.6 mg /Hr 0.05mg-0.3 mg/Hr

Nifedipine O.l%-4% 0.05 mg-2.0 mg/Hr 0.2mg- 1.0 mg/Hr

Theophylline 1.0%-20% 0.5 mg-60 mg/Hr 0.5mg-10 mg/Hr

Minoxidil 0.1%-5.0% 0.1 mg- 3.0 mg/Hr 0.1 mg- 1.0 mg/Hr Systemic drugs are also delivered via suppositories and suffer from the same short term bioavailability and spiked PK described above.

Drug delivery device 10 can also be used to deliver systemic drugs to treat fever, hormone imbalance (e.g. by delivering insulin, growth hormone etc), bone loss (e.g. osteoporosis - calcitonin), to control cholesterol levels (e.g. by delivering statins), to provide sedation (e.g. by delivering Benzodiazepines) or anesthesia, to treat hypertension (e.g. by delivering propanolol), to control epileptic seizures, to treat microbial infections (e.g. by delivering anti-viral or antibacterial agents), to control or treat pain (e.g. opioids such as morphine), to treat panic attacks, to induce sleep, to treat addiction (e.g. nicotine, alcohol, drugs), to treat cardiovascular disease, to treat erectile dysfunction, to treat nausea and motion sickness (e.g. anti-emetics or scopolamine), to provide chemotherapeutic agents, to treat neurological disorders (e.g. Parkinson's, Alzheimer's), to quickly treat migraine attacks (e.g. Sumatriptan), to provide vaccines, to treat asthma and other pulmonary and immunological disorders. Such drugs can be formulated as dry particles or liquid/gel preparations and disposed within drug delivery device 10 or coated thereon. The drug can be released using osmotic, positive pressure, or hydration forces and the rate of release controlled by orifice size or pore size of the reservoir coating or by the characteristics of the drug formulation itself. For example, the active agent can be desiccated in the reservoir and when rehydrated by the body fluids in the rectum or anal canal, the drug can diffuse out of a molecular membrane coating, such that the rate of release of the drug is controlled by pore size of the membrane. Such drug delivery systems are well known in the art. The formulations can also include absorption enhancers such as Tween, sodium octanoate, sodium hexanoate, glyceryl- 1-monooctanoate, and mucoadhesives such as hydroxypropylcellulose, polyvinylpyrrolidone, carbopol, polycarbophilor sodium alginate, as well as a thermal gelling polymer such as pluronic ™ , poloxamer 407 or poloxamer 188.

Although the present drug delivery device can maintain its position within the anal canal for extended time periods, an additional anchoring force can be provided by a drug-containing matrix which includes a muco-adhesive (e.g. one or more biocompatible polymer adhesives), a co-solvent and a pharmacologically active agent. The amount of adhesive is sufficient to maintain the device in constant contact with the skin or mucosal membrane before the next administration and yet is easily detached while removing the device. For mucosal membrane, the drug containing adhesive matrix comprising at least one pharmacologically active agent, and one or more adhesive polymers copolymers and matrix material such as anhydrous lactose NF, carbomer 934P, hypromellose USP, magnesium stearate NF, lactose monohydrate NF, polycarbophil USP, colloidal silicon dioxide NF, starch NF and talc USP. In an ano- dermal adhesive composition embodiment of the invention, a multiple polymer adhesive system comprising of a blend of 0.5-96% by weight of an acrylate polymer and 4-98% by weight of a polymer of siloxane, the multiple polymer adhesive system being in an amount of about 50-99% by weight of the dermal adhesive composition. The ratio of the two polymer adhesives can be adjusted to provide proper load of the active agent, the sufficient release of the active agents, and the optimal adhesion to the dermal tissues. This is combined with a pharmacologically active agent in the amount of 0.1-20% by weight of the total dermal adhesive composition. Optional additives, such as co-solvent for the active agent (up to 30% by weight) and enhancers (up to 10% by weight) may be included in the dermal adhesive composition.

Suitable adhesives for use as the drug matrix include polysiloxanes, polyacrylates, polyurethanes, tacky rubbers such as polyisobutylene, and the like. Particularly preferred contact adhesives for use as the drug reservoir herein are cross- linked acrylates and methacrylates.

In a further embodiment, the active agent can be incorporated into a phase change material that is used to fill a hollow device 10 wherein the material can be stiff under room temperature and liquid at body temperature. The active agent can be eluted from the external surfaces of drug delivery device 10, or it can be co-formulated with the phase change material and exit the surface of drug delivery device 10 through an opening or pores at a controlled or predetermined rate. Such materials can include, for example, 70% poloxamer 188 (P 188) and 30% propylene glycol, paraffin wax, polyester wax, solid fats such as polyglycerol ester of fatty acids (PGEFs for example: decaglycerol heptabehenate HB750 and hexaglycerol pentastearate PS500), beeswax, and Witepsol™ hard fats.

Drug delivery device 10 can be configured for positioning within the anal canal without use of an applicator. Biasing cap 21 of this embodiment of drug delivery device 10 is elastically connected to either stem portion 12 or directly and independently to cap portion 14. The latter option prevents the elasticity of biasing cap 21 from being affected by the stiffness of stem portion 12. Stem portion 12 includes a core which is made from a hydratable material such as PVA microporous foam. Cap portion 14 includes a top opening through which liquids can come in contact with the core. This opening ensures that once device 10 is positioned within the anal canal, the top portion of the core wicks liquid from the lower rectal environment and into and along the length of the core thereby hydrating it and transforming it from rigid to soft. The final softness and elasticity of the core when wet can be configured to provide the proper mechanical properties.

Drug delivery device 10 of this configuration can be inserted in a manner similar to a stiff suppository by holding it at the bottom (biasing cap 21 region) and pushing it into the anal canal (with cap portion 14 protruding into the lower rectum). Once positioned, the core hydrates and softens within a minute or two making drug delivery device 10 softer and more elastic. The liquid that hydrates the core can also dissolve the active agent, which can then wick out of opening or pores in the surface of cap portion 14 or stem portion 12. Alternatively, adjacent to the core within stem portion 12 is a liquid ampoule that is burst upon entry of the drug delivery device into the anal canal and thereby softens the core within a preset time and also acts to rehydrate the active agent.

In a further embodiment, drug delivery device 10 is inflated by an injected drug solution and such inflation forms the body of drug delivery device 10 according to a preformed envelope shape, including optionally into cap portion 14 which serves as an anchor. The syringe is then discarded and the drug in drug delivery device 10 is trapped via a one way valve and can only emerge into the rectum through the desired surfaces of drug delivery device 10 through a controlled pore size under the pressure of the solution in the elastic drug delivery device envelope or by the pressure of the anal sphincter compressing stem portion 12 of drug delivery device 10.

Drug delivery device 10 can also include a connectable bulb-type reservoir either directly or via a thin tube that can be compressed by the user or pumped by a pump to deliver the drug through pores in cap region 14. Such a configuration, as well as, the syringe configuration described above can be used to deliver the drug through cap portion 14 in a spray/mist form. Such delivery can be used to target tissue regions above cap portion 14.

In a further embodiment, drug delivery device 10 can form a stable positioning platform for a first end of a tube that is used to deliver active agents over time. The tube, which can be 0.5-5 mm in diameter, can be connected at its second end to a reservoir of the active agent that is located elsewhere on the patient's body (or in proximity to the patient) and the active agent is delivered through the tube due to a controllable pressure differential between the reservoir and the rectum or via positive displacement.

FIGs 3A-C illustrate a system which includes drug delivery device 10 fitted with an internal sleeve and an internal applicator 100 which is designed to engage an internal bore of the internal sleeve.

This configuration of applicator 100 includes a finger hold which is designed to be fitted over a finger (e.g. index finger) and a rod 104 which is attached to the finger hold and is designed for fitting within the sleeve of drug delivery device 10. In that respect, rod 104 can be any shape and dimension suitable for insertion into the sleeve.

Preferably rod 104 is cylindrical in shape and is either hollow or solid in construction.

Rod 104 is typically 1-10 cm in length and 0.1-5 mm in diameter. Applicator 100 can be constructed from a polymer such as polypropylene, polycarbonate, acetal, polybutylene terephtalate, polylactic acid or similar using known molding techniques and be either disposable or reusable.

The finger hold of applicator 100 can be designed to accommodate any finger size by providing an adjustment (spring-loaded) tab within the finger-engaging portion.

The diameter of the index finger first joint ranges between 1.5-2.3 cm for most individuals and thus a single design can be used to accommodate such a finger size range. An index finger application is preferred since this finger is the most developed with respect to kinesthetic feedback (proprioception), and thus most everyone can use this finger to guide drug delivery device 10 to the anal orifice.

As is mentioned hereinabove, the sleeve serves two functions, to prevent rod 104 from puncturing through drug delivery device 10 (and potentially damaging anal mucosa or rectal tissue) and to provide the upper region of stem portion 12 with the rigidity necessary to maintain its configuration even when drug delivery device 10 is stretched to accommodate anal canals of varying lengths. FIGs 3A-C illustrate drug delivery device 10 administration using applicator 100. Drug delivery device 10 is positioned over an illustration of the anal canal to indicate drug delivery device position with respect to the canal at every stage of insertion. Due to its flimsiness, cap portion 14 folds backwards axially around applicator 100 to reduce the cross sectional area of cap portion 14 during insertion in the anal canal. Lubrication of the top surface of cap portion 14 can be used to ease insertion. When applicator 100 is removed, cap portion 14 can return to its original shape due to its inherent elasticity or some other shape-retention mechanism and the elastic outer rim 15 of cap portion 14 rests in the lower rectum and seals the region from fecal matter accreting on top of it. Therefore the target tissue right underneath cap portion 14 is clean and accessible to the active agent being released. The inner surface of stem portion 12 of drug delivery device 10 and applicator 100 and/or portions thereof can also be pre-lubricated for easier removal of applicator 100 following insertion of drug delivery device 10. A detent can be provided within the internal sleeve. Such a detent can interface with a ball feature at the tip of rod 104 and provide friction preventing drug delivery device 10 from falling off applicator 100 when held upside down. Such friction can be low enough to still enable release when applicator 100 is removed following insertion of drug delivery device 10 into the anus.

Applicator 100 can include a mechanism that is sensitive to the pressing of the linger hold up against the external opening of the anus, and thereby providing the user tactical or auditory feedback of proper insertion position. For example, a click can be heard when applicator 100 is exposed to sufficient pressure from the front or the sides that also serves to collapse or otherwise disable rod 104 to prevent reuse and/or release drug delivery device 10 from applicator 100 and tells the user that applicator 100 is in far enough and that it can be withdrawn. Alternative feedback mechanisms can include a fluid filled balloon that is disposed between applicator 100 and drug delivery device 10 and emits a sound when exposed to pressure of a predetermined threshold. Tactile feedback can be provided by using the finger hold design which facilitates tactile feedback. For example, the finger hold can include an exposed or thin membrane- covered window which transmits sensation to the operating finger such that the user can feel when drug delivery device 10 is fully inserted. Alternatively, the finger hold can be provided with elements (e.g. rubber rods) that project through the surface of the finger hold and can transmit tactile feedback from the exterior surface of the finger hold to the finger of the user.

Applicator 100 can be a single use applicator and be fabricated from a biodegradable material or a dissolvable material which can be flushed down the toilet. Applicator 100 can include a reservoir for containing a gel, fluid or gas which can be pumped into drug delivery device 10 during or after insertion into the rectum, either manually or by pre-stored energy source.

For example, drug delivery device 10 designed as a collapsed balloon can be positioned via applicators 100 and inflated inside the rectum with fluid, gas, particles or a gel, including a reverse thermal gelation (RTG) gel such as Pluronic™ that will retain their shape at body temperature, or a hardening moldable compound such as VPS.

Drug delivery device 10 when filled with a fluid, gas, particles or gel can be configured so as to enable transfer of the filling material between regions of drug delivery device 10 which are then maintained in the proper internal geometry during movement of the anal canal and rectum. Optionally, drug delivery device 10 has within it one or more one way valves that prevent transferred fluid, gel or gas from moving backwards and deflating the acquired shape.

Applicator 100 and drug delivery device 10 form a part of a system which is preferably co-packaged as a drug delivery kit. The kit can include a reusable applicator and several disposable drug delivery devices or it can include disposable applicator-drug delivery device pairs. The kit can contain a specific size of drug delivery device 10 and/or applicator 100 (e.g. small, medium or large) or it can include an assortment of sizes. Such a kit can include a disposal bag and/or a moist wipe or disposable gloves to help keep the drug delivery device insertion process as hygienic as possible even if not performed at home.

In an additional embodiment, an applicator which is designed for attaching to biasing cap 21 can be used with a drug delivery device 10 configuration which can be inserted into the anal canal without use of an inner or outer rod-type applicators such as those described above (applicator 100). In such cases, drug delivery device 10 can include elements for stiffening stem portion 12 to thereby enable stem portion to be rigid enough for self insertion. It will be appreciated that such configurations can also be inserted into the anal canal without use of any applicator simply by holding drug delivery device 10 at biasing cap 21 and pushing it into the anal canal.

Several configurations for stiffening stem portion 12 are envisaged herein. Stem portion 12 can be a hollow tube which is filled with a gas, liquid or gel which stiffens stem portion 12. Following insertion into the anal canal, the gas, liquid or gel can be released from stem portion 12 allowing it to conform to anal canal anatomy and stretch to accommodate anal canal length.

Alternative, applicator-less configurations of drug delivery device 100 can include an inner sleeve (in stem portion 12) which covers only the lower region of stem portion 12 and thus provides the stiffening and yet does not affect drug delivery device elasticity. Stem portion 12 can also include a stiff dry foam (e.g. microporous polyvinyl alcohol - PVA) or a desiccated hydrogel core which provides rigidity and yet following insertion into the anal canal hydrates and softens. A port can be provided in cap portion 14 to enable liquid transfer into the dry core from the rectum, or via the puncturing of an internal liquid ampoule. A coil core can also be used, in which case, compressing the coil for insertion provides rigidity from the stacked coils, following insertion, the coil relaxes and provides the elasticity necessary from stem portion 12. Alternatively, a stacked coil made of paper or a polymer can provide the necessary rigidity and be pulled out (while being unraveled) of the drug delivery device following insertion to allow for drug delivery device elasticity.

A phase change material can also be used in stem portion 12 and optionally cap portion 14; the material can be stiff under room temperature and soft at body temperature. Device 100 can be filled with such a material and deformed while molten (e.g. by stretching the drug delivery device from its ends) to as to form a more deliverable structure with reduced cap portion diameter when the material sets. Once in the body, the material melts and device 100 assumes its natural configuration providing the required anchoring.

An example configuration of such a drug delivery device is shown in FIGs 6A-B. External shell 19 is made of 0.4 mm thick silicone shore A 40 filled with molten Witespol™ hard fat. Optionally, the drug delivery device is stretched and allowed to cool and harden while elongated as shown in FIG. 6A, thereby minimizing the cross sectional area of the drug delivery device 10. Additional example materials include 70% poloxamer 188 (P 188) and 30% propylene glycol, paraffin wax, polyester wax, solid fats such as polyglycerol ester of fatty acids (PGEFs for example: decaglycerol heptabehenate HB750 and hexaglycerol pentastearate PS500), and beeswax. The meltable material does not need to come into contact with the body and can be fully sealed inside drug delivery device 10. Drug delivery device 10 can be kept under tension or in this stretched state in the packaging so even if exposed to temperatures above body temperature during transportation and storage, the elongated drug delivery device 10 will still maintain its elongated shape upon cooling. Drug delivery device 10 can have multiple chambers, some of which fully seal the phase change materials and other chambers with or without a phase change material that release an active agent to the target tissue.

Drug delivery device 10 of the present invention may, if desired, be presented in a pack or dispenser device, such as an FDA approved kit, which may contain one or more units of drug delivery device 10. The pack may, for example, comprise metal or plastic foil. The pack or dispenser device may be accompanied by instructions for administration and use in treating rectal, anal or systemic disorders. The pack or dispenser device may also be accompanied by a notice in a form prescribed by a governmental agency regulating the manufacture, use, or sale of drug devices.

As used herein the term "about" refers to ± 10 %.

It is appreciated that certain features of the invention, which are, for clarity, described in the context of separate embodiments, may also be provided in combination in a single embodiment. Conversely, various features of the invention, which are, for brevity, described in the context of a single embodiment, may also be provided separately or in any suitable subcombination.

Additional objects, advantages, and novel features of the present invention will become apparent to one ordinarily skilled in the art upon examination of the following examples, which are not intended to be limiting. Additionally, each of the various embodiments and aspects of the present invention as delineated hereinabove and as claimed in the claims section below finds experimental support in the following example. EXAMPLES

Reference is now made to the following examples, which together with the above description illustrate the invention in a non limiting fashion.

EXAMPLE 1

Internal hemorrhoid drug delivery device

The drug delivery device configuration shown in FIGs 6A-B was used to deliver preparation H. In this specific example, the external shell 19 of the hollow silicone drug delivery device is made of silicone shore A 40 with wall thickness 0.4mm, which was filled through the bottom of stem portion 12 with a molten Preparation H ® suppository (active ingredients cocoa butter 85.39% as a protectant, phenylephrine HCl 0.25% as a vasoconstrictor, and shark liver oil 3.0% as a protectant). The drug delivery device was elongated upside down while the suppository material was still molten by hanging a weight of 100 grams from it and allowing the suppository material to cool. The device was then sealed with a silicone RTV adhesive at the bottom of the stem portion 12 in order to keep the meltable core material fully contained in the external shell of drug delivery device 10. Once solidified, four 0.5 mm long slits radially distributed every 90 degrees were punched through the external shell 19 on the sides of cap portion 14 of device 10 to allow the suppository ingredients to seep out slowly when molted. Device 10 was inserted into the anal canal by a male subject suffering from internal hemorrhoids. The subject reported that device 10 was imperceptible during 8 hours of use and that no movement upwards into the rectum or downwards out of the body was perceived or noted. The subject also reported significant relief from symptoms during this 8 hour period. The drug delivery device was ejected during a bowel movement. Examination of the ejected device revealed that the core material was liquified due to the exposure to body temperature. Any active agent would thus have been slowly leaked out of device 10 and absorbed through the mucosal surfaces it was exposed to during these 8 hours.

EXAMPLE 2 External hemorrhoid drug delivery device

A drug delivery device having a biasing cap portion which includes a phenylephrine-containing hydrocolloid gel pad 1.5 cm in diameter and 1 mm thick (pad 30 in FIGs 5A-B) was used in treatment of external hemorrhoids. The device was self inserted into the anal canal by a human subject suffering from external hemorrhoids using a fingertip applicator. In this configuration of the present drug delivery device, cap portion 14 serves as a passive anchor to position the biasing cap containing pad 30 with the active agent up against the perianal skin. Phenylephrine released from the pad 30 induced vasoconstriction and reduced the volume of the external hemorrhoid cushion, the pain, discomfort, and bleeding of the subject for the 6 hours the device was used until it was removed manually by the patient.

EXAMPLE 3

Anal fissure drug delivery device

A drug delivery device containing a 4 ml drug reservoir with pores of 200 microns in diameter along the surface of stem portion 12 was loaded with Nifedipine solubilized in an aqueous or hydroalcoholic gel matrix (methyl cellulose or carbopol polymer matrix at the concentration of 1%). Insertion of this drug-containing device into the anal canal leads to release of therapeutically effective amounts of nifedipine from the reservoir matrix located at the top of the stem of the device. The released drug induces relaxation of the internal anal sphincter muscle, thus relieves the anal pain associated with anal fissures.

Although the invention has been described in conjunction with specific embodiments thereof, it is evident that many alternatives, modifications and variations will be apparent to those skilled in the art. Accordingly, it is intended to embrace all such alternatives, modifications and variations that fall within the spirit and broad scope of the appended claims. AU publications, patents and patent applications mentioned in this specification are herein incorporated in their entirety by reference into the specification, to the same extent as if each individual publication, patent or patent application was specifically and individually indicated to be incorporated herein by reference. In addition, citation or identification of any reference in this application shall not be construed as an admission that such reference is available as prior art to the present invention.

Claims

WHAT IS CLAIMED IS:

1. A drug delivery device comprising a cap portion positionable in a region within a rectum and an attached biasing cap being positionable outside an anal canal when the device is in use, the drug delivery device being configured for releasing an active agent.

2. The drug delivery device of claim 1, wherein said cap portion and said biasing cap are interconnected via an elongated body being designed for residing within an anal canal when the device is in use.

3. The drug delivery device of claim 1, further comprising an active agent being releasable from the device.

4. The drug delivery device of claim 3, wherein said active agent is selected suitable for treatment of fissures, hemorrhoids, constipation, proctitis, colitis, anal fistulas or inflammatory diseases.

5. The drug delivery device of claim 1, wherein the drug delivery device is designed such that said cap portion does not extend more than 20 mm above the pectinate line when said biasing cap is positioned outside said anal canal.

6. The drug delivery device of claim 3, wherein the device is at least partially hollow and said active agent is contained within the device.

7. The drug delivery device of claim 2, wherein the device is configured for releasing said active agent from said cap portion, said elongated body or said biasing cap.

8. The drug delivery device of claim 3, wherein at least some portion of the device is formulated to phase change following positioning of the drug delivery device in a body.

9. The drug delivery device of claim 3, wherein the drug delivery device is devoid of a fluid communication port.

10. The drug delivery device of claim 3, being designed for enabling hydration of said active agent following insertion of the drug delivery device into the body.

11. The drug delivery device of claim 3, wherein said active agent elutes from an outer surface of the drug delivery device.

12. The drug delivery device of claim 6, wherein the drug delivery device is capable of controllably releasing said active agent.

13. The drug delivery device of claim 8, wherein said active agent is formulated as a solid reservoir designed for melting following positioning of the drug delivery device in said body.

14. The drug delivery device of claim 8, wherein said phase change alters a shape of the drug delivery device.

15. A drug delivery device comprising a device body being positionable within an anal canal and including an active agent, said device body being capable of residing in an anal canal without a substantial change to a volume thereof over a time period of at least 1 hour.

16. The drug delivery device of claim 15, wherein said active agent is formulated as a solid reservoir that disintegrates, melts or dissolves in the body.

17. The drug delivery device of claim 16, wherein disintegration, melting or dissolving of said solid reservoir releases said active agent.

18. A drug delivery device comprising a device body being positionable within an anal canal, said device body including at least two active agents selected from:

(i) a muscle relaxant/paralytic agent; (ii) a blood perfusion enhancer; and (iii) an analgesic or an anesthetic agent.

19. The drug delivery device of claim 18, wherein said device body is positionable within said anal canal by positioning a first end of said device body in a region of a rectum and a second end of said device body at peri-anal tissue.

20. The drug delivery device of claim 18, wherein said device body is designed for releasing said active agents in the anal canal.

21. A method of delivering an active agent to or through an anal canal or rectum comprising administering a device body including an active agent to an anal canal thereby initiating delivery of the active agent from said device body without concomitant disintegration of said device body.

22. The method of claim 21, wherein said administering is effected by positioning a first end of said device body in a region of a rectum and a second end of said device body at peri-anal tissue.

23. The method of claim 21, wherein said active agent is selected suitable for treatment of fissures, hemorrhoids, constipation, proctitis, colitis, anal fistulas, or inflammatory diseases.