Abstract:
A method of delivering one or more therapeutic agents comprising providing a suppository comprising one or more therapeutic agents and a biocompatible carrier medium and shaped to be capable of cooperating with the periurethral musculature to retain the suppository in place in the urethra, inserting the suppository into the urethra, and retaining the suppository within the urethra by the action of the periurethral musculature for a period of time sufficient to permit the therapeutic agent to diffuse substantially into the urethra, the referred suppository comprising a shaft having a first end and a second end and shaped to be capable of cooperating with the action of the periurethral musculature to retain the suppository within the urethra and a substantially ellipsoidal knob extending from the second end of the shaft and sized to prevent insertion into the urethra.

Description:
FIELD OF THE INVENTION  
         [0001]    This invention relates to a method of delivering therapeutic agents to the urethra, bladder and related structures and an urethral suppository for use in delivering therapeutic agents thereto.  
           [0002]    In the treatment of various ailments affecting the urethra, bladder and related structures, it is generally not desirable to deliver therapeutic agents systemically. When delivery of such agents is accomplished in a systemic fashion such as, for example, orally of by way of a remote intravenous, intramuscular, subcutaneous or transdermal route, relatively high dosages are required in order to deliver an amount to the affected areas sufficient to have the desired therapeutic effect. The requirement for such relatively high dosages results from the dilution and dissipation effects attendant to such delivery methods as well as the loss of efficacy that can result from biochemical interactions between the therapeutic agent and unrelated systems. Further, due to the relatively high dosages required by systemic delivery methods, the risks of triggering both adverse reactions and unwanted side effects are increased. Accordingly, it is known to employ delivery methods which provide for the local application of therapeutic agents in the treatment of urethral, bladder and related ailments in order to administer relatively small dosages to achieve delivery of relatively high concentrations of such agents to the affected areas.  
           [0003]    While the local application of therapeutic agents permits the use of smaller dosages, and can avoid certain of the drawbacks associated with systemic delivery methods as mentioned hereinabove, a different set of problems arise with respect thereto. In the context of treating conditions affecting the urethra, bladder and related structures, for example, it is of primary importance that the local application of therapeutic agents be accomplished in a manner compatible with the anatomical structures involved. Accordingly, it is known to employ suppositories as delivery devices for therapeutic agents. Such suppositories are designed to be inserted into the urethra and to release therapeutic agents contained therein or applied thereon to the mucosal lining of the urethra. The release of therapeutic agents occurs upon liquefaction of the suppository which results from the transfer to the suppository of the body heat of the patient into whose urethra the suppository has been placed.  
           [0004]    Various prior art suppositories, however, have been designed in such a manner that they are difficult to retain in position within the urethra where the precise delivery of therapeutic agents is desired. Experience has shown that such suppositories tend either to advance inwardly into the bladder or to be expelled out of the urethra prior to the complete decomposition within the urethra. In either case, the desired result of a precise placement of the specific dosage of the selected therapeutic agents within the urethra is not realized.  
         REPORTED DEVELOPMENTS  
         [0005]    In order to address these shortcomings, it is known to configure urethral suppositories in the form disclosed in U.S. Pat. No. 5,085,650 to Giglio (the &#39;650 patent). The &#39;650 patent discloses an urethral suppository comprising a bulbous head and a conical tail joined by a narrow cylindrical shaft. As taught by the &#39;650 patent, upon insertion of the suppository into the urethra of a human female patient, the bulbous head thereof is advanced through the entire length of the urethra and penetrates into the bladder to anchor the suppository at the bladder neck. The conical tail of the suppository prevents the further advance of the suppository into the bladder. More specifically, once the suppository is positioned within the urethra, the portion of the bulbous head of the suppository which curves inwardly toward the shaft is designed to prevent the suppository from expulsion by its contact with the bladder walls at the bladder neck where the bladder narrows to the meet the proximal end of the urethra. At the same time, the flared portion of the conical tail, having an increasingly larger diameter than the shaft of the suppository as well as the urethra itself, is designed to prevent the suppository from overinsertion by contact with the edges of the urethral orifice at the distal end thereof. It is through this combination of contact surfaces that the suppository disclosed in the &#39;650 patent is intended to be held in position during the liquefaction thereof.  
           [0006]    While suppositories configured with bulbous heads, conical tails and narrow cylindrical shafts, as disclosed in the &#39;650 patent, aid in the placement and retention of suppositories within the urethra as compared with purely cylindrical suppositories that lack such features, such configurations permit, nonetheless, some slippage and, moreover, present certain other disadvantages. Because retention of the suppository is effected, in part, by the contact between the inwardly curved portion of the bulbous head with the bladder neck, it is required that the bulbous head of the suppository advance beyond the urethra and invade into the bladder itself. As a result, where therapeutic agents are infused throughout the material comprising the suppository, the portion of the dosage contained within the material comprising the bulbous head thereof is not positioned so that it is in direct physical contact with the mucosal lining of the urethra and thus is not absorbed readily therein. As a result, the precise delivery of a specific dosage through absorption by the urethra cannot be realized effectively. Further, insofar as the conical tail section of the suppository disclosed in the &#39;650 patent has a flat base, it is difficult to manipulate after insertion as it provides no projections which can be grasped readily. Moreover, the roundness of the conical tail renders the distal end of the suppository less than fully compatible with the anatomical structure of the labia. As a result, the comfort of the patient is compromised.  
           [0007]    The present invention relates to the provision of an improved method for delivering a therapeutic agent to the urethra and an easily manipulatable urethral suppository which is designed to overcome disadvantages associated with prior art suppositories.  
         SUMMARY OF THE INVENTION  
         [0008]    In accordance with one aspect of the present invention, there is provided a method for delivering a therapeutic agent to the urethra, bladder and related structures comprising the steps of providing a suppository comprising one or more therapeutic agents and a biocompatible carrier medium and shaped to be capable of cooperating with the action of the periurethral musculature to retain the suppository within the urethra, inserting the suppository into the urethra, and retaining the suppository within the urethra by the action of the periurethral musculature for a period of time sufficient to permit the therapeutic agent to diffuse substantially into the urethra. The suppository utilized in the method of the present invention may be of any shape capable of being inserted into the human female urethra and of cooperating with the periurethral musculature in retaining the suppository within the urethra.  
           [0009]    In accordance with another aspect of the present invention, there is provided an urethral suppository shaped to be capable of cooperating with the action of the periurethral musculature to retain the suppository within the urethra. Preferably, the suppository comprises a shaft having a rounded first end tapering along a longitudinal axis to a second end, and a substantially ellipsoidal knob extending from the second end of the shaft and sized to prevent insertion into the urethra, said shaft and knob comprising a composition of at least one therapeutic agent and a biocompatible carrier medium. More preferably, the substantially ellipsoidal knob of the suppository has a major axis which is substantially perpendicular to the longitudinal axis of the shaft. It is also preferred that the biocompatible carrier medium is capable of forming a relatively soft, pliable and smooth suppository so that the need for a lubricant to aid insertion can be eliminated and the risk of patient discomfort can be minimized.  
           [0010]    The tapered shaft of the preferred suppository of the present invention provides a profile to the suppository which is particularly well suited to work in concert with the normal action of the periurethral musculature found in human females. So configured, the naturally occurring pressure exerted by the periurethral musculature is most advantageously utilized in retaining the suppository entirely within the urethra. This retention permits the complete delivery of a precise dosage of one or more therapeutic agents to the mucosal lining thereof without invasion into the bladder.  
       
    
    
     BRIEF DESCRIPTION OF THE DRAWINGS  
       [0011]    [0011]FIG. 1 shows a profile view of a preferred suppository of the present invention.  
         [0012]    [0012]FIG. 2 shows a cross-sectional view of a preferred suppository of the present invention as shown from line  2 - 2  of FIG. 1.  
     
    
     DETAILED DESCRIPTION OF THE INVENTION  
       [0013]    The urethra of the adult human female is a substantially tubular structure which serves as the outlet for urine from the bladder. While the urethra of the adult human female has some degree of variation in size across any given population, it is generally about 3 to about 4.5 centimeters in length and about 0.8 to about 1.5 centimeters in diameter upon full expansion. The flow of urine from bladder is controlled by certain muscles which surround the urethra and exert forces inwardly to constrict the urethra. It will be understood that as used herein the muscles which surround and impinge upon the urethra will be referred to herein collectively as the periurethral musculature.  
         [0014]    The forces applied by the periurethral musculature, however, are not exerted evenly along the length of the urethra. Rather, due to the physical arrangement of the periurethral musculature with respect to the urethra, these forces are applied differentially. Considering an average adult human female urethra of about 4 centimeters in 1 centimeter intervals beginning at the bladder, the forces exerted by the periurethral musculature increase substantially from the first to the second centimeter, increase further to a maximum within the third centimeter, and drop off significantly in the last centimeter. This profile of urethral pressures is substantially the same from patient to patient as it is a direct consequence of the anatomical configuration and location of the human female periurethral musculature.  
         [0015]    In view of this specific pressure profile, a key feature which serves to retain the suppositories disclosed in the &#39;650 patent within the urethra, namely the inwardly curving portion of the bulbous head, is designed to do so at a region of low urethral pressure. In contrast, the present invention takes advantage of the naturally occurring forces exerted by the periurethral musculature in holding the suppository in place. It is designed specifically to work in concert with the distinctive pressure profile of the human female periurethral musculature. As a result, slippage of the present suppository within the urethra is minimized and precise delivery of the therapeutic agent thereto is achieved.  
         [0016]    The provision of a suitably shaped suppository is important to the practice of the method of the present invention. While the suppository utilized in the method of the present invention may be provided in any of a variety of shapes which are capable of insertion into the human female urethra, it is important that the shape of the suppository also be such that it is capable of cooperating with the pressure profile of the human female periurethral musculature to secure the suppository within the urethra. More specifically, and as described more fully hereinabove, the periurethral musculature exerts inward forces upon the urethra in a differential manner with the greatest inward forces being located at a region approximately three centimeters distal to the bladder. Accordingly, it is important that the suppository provided in the method of the present invention have a shape which, upon insertion into the urethra, permits the region of greatest urethral pressure to impinge thereon in a manner which promotes the secure placement and retention of the suppository within the urethra. In a preferred embodiment of the method of the present invention, the suppository provided will be of a shape as shown substantially in FIGS. 1 and 2.  
         [0017]    The therapeutic agents suitable for use in the suppository provided in the method of the present invention may be any of a wide variety of compounds, substances, pharmaceuticals, and the like which are capable of being absorbed through the mucosal lining of the human female urethra, either alone or in combination with biocompatible absorption aids, and which have been approved or which will be approved for the diagnosis, treatment, prophylaxis, cure or mitigation of any disease of the urethra, bladder or associated structures. Such therapeutic agents include, without limitation, antibiotics, antimicrobials, antifungal agents, analgesics, steroidal and non-steroidal antiinflammatory agents, hormones such as estrogen and progesterone, mucous production stimulators such as pentosan polysulfate sold under the trademark Elmiron® by Alza Corporation, anti-spasmodics such as oxybutynin chloride sold under the trademark Ditropan® by Hoechst Marion Roussel, Inc., and the like. The urethral suppositories employed in the method of the present invention are particularly well suited to the treatment of various infections, incontinence, uninhibited neurogenic or reflex neurogenic bladder (i.e., urgency, frequency, urinary leakage, urge incontinence, dysuria), and non-specific urethritis, as well as post-menopausal urethral and bladder symptoms.  
         [0018]    The therapeutic agents suitable for use in the suppository provided in the method of the present invention may also comprise compounds or substances used in conjunction with medical procedures such as catheterization, cystoscopy, or transurethral surgery. Such therapeutic agents include, for example, antimicrobials, steroidal and non-steroidal anti-inflammatory agents, and topical anaesthetics such as lidocaine, procaine, benzocaine, xylocaine and the like.  
         [0019]    The biocompatible carrier medium suitable for use in the suppository employed in the method of the present invention may be selected from any of a wide variety of biocompatible materials which are capable of being combined with the desired therapeutic agents. With respect to the physical characteristics of the biocompatible carrier media, it is important that such media are capable of becoming sufficiently rigid at room temperature to be inserted into the human female urethra and of liquefying within a relatively short period of time upon insertion therein. Preferably, the biocompatible carrier medium is capable of being formed into relatively soft, pliable and smooth suppository so that comfort of the patient and ease of use is optimized. In certain preferred embodiments, the biocompatible carrier medium is also self-lubricating, water-soluble, substantially non-staining and substantially free of parabens.  
         [0020]    Biocompatible carrier media suitable for use in the suppository provided in the method of the present invention include a wide variety of polymers which are soluble in body fluids such as, for example, vegetable gums such as carrageenan, modified celluloses such as hydroxypropylcellulose or hydroxypropylmethylcellulose, polyvinyl alcohol, polyvinylpyrrolidone, polyacrylamide, polyethylene glycol, poly(phosphoester-urethanes), ethylenoxide polymers, and the like. Preferably, the biocompatible carrier medium is selected so that the entire mass thereof is completely liquified within the urethra within about 10 minutes, and even more preferably within about 5 minutes.  
         [0021]    The concentration of therapeutic agents found in the suppository employed in the method of the present invention will vary in accordance with, among other things, the nature of the therapeutic agents, their physiologic role, the desired therapeutic effect, and the manner in which the therapeutic agents and the biocompatible carrier medium are combined. Thus, for example, the concentration of female hormones, such as estrogen or progesterone, will likely be different from the concentration of an anaesthetic or dialator used in connection with the performance of a medical procedure.  
         [0022]    The insertion step of the method of the present invention may be accomplished by any means suitable for effecting the placement of the suppository within the urethra. Such means may include, for example, manual or instrument-assisted insertion either by a health care professional or the patient herself.  
         [0023]    The urethral suppository of the present invention comprises a therapeutic agent and a biocompatible carrier medium which are combined and formed into a shape suitable for insertion into the human female urethra and capable of cooperating with the action of the periurethral musculature to retain the suppository within the urethra. While the therapeutic agent or agents as well as the biocompatible carrier medium may be selected from any of a wide variety of materials appropriate for inclusion in an urethral suppository as set forth more fully hereinabove, it is important that the urethral suppository of the present invention have certain shape characteristics. It is by means of these shape characteristics that the urethral suppository of the present invention advantageously utilizes the action of the periurethral musculature in securing the position of the suppository within the urethra, provides for ease of insertion and manipulation, and promotes the comfort of the patient through compatibility with the external structures of the human female genital anatomy.  
         [0024]    In accordance with a preferred embodiment of the present invention, and with reference to FIG. 1, the suppository  10  comprises a shaft  12  having a rounded first end  13  tapering along a longitudinal axis  14  to a second end  15  and a substantially ellipsoidal knob  16  sized to prevent insertion into the urethra which extends from the second end  15  which has a major axis  17  wherein the major axis  17  of the knob  16  is substantially perpendicular to the longitudinal axis  14  of the shaft  12 . As shown in FIG. 2, the shaft  12  is substantially circular. It is by means of the tapering of the shaft  12  that retention substantially entirely within the urethra by cooperation with the periurethral musculature is advantageously realized. More specifically, upon insertion of the suppository into the urethra, the first end  13  (where the diameter of the shaft  12  is at its greatest) corresponds to the proximal end of the urethra (where the urethra meets the bladder) at which the force of the periurethral musculature is the lowest. As the force exerted by the periurethral musculature increases from a minimum at the proximal end of the urethra to a maximum at about three centimeters distal thereto, the diameter of the shaft  12  decreases. The tapering of the shaft  12  continues to the second end  15  at which a substantially ellipsoidal knob  16  extends substantially perpendicular to the longitudinal axis  14  of the shaft  12  thereby preventing overinsertion thereof.  
         [0025]    As a result of this configuration, the region of strongest urethral pressure contributes substantially to the retention of the suppository within the urethra. In order for the suppository to be withdrawn, the force applied to the suppository must overcome the incrementally increasing resistance offered by the region of greatest urethral pressure on the increasing diameter of the shaft  12 . This interplay between the region of greatest urethral pressure and narrowest shaft diameter yields a significant improvement over urethral suppositories found in the prior art with respect to the retention of the suppository within the urethra. Accordingly, the precise delivery of therapeutic agents to and absorption by the mucosal lining of the urethra is advantageously achieved.  
         [0026]    The ellipsoidal knob  16  also contributes to the anchoring of the suppository within the urethra. Insofar as the major axis  17  of the knob  16  extends substantially perpendicularly to the longitudinal axis  14  of the shaft  12 , and is sized to prevent insertion into the urethra, the knob  16  serves to prevent the advance of the suppository into the bladder. More specifically, the inwardly curved surface  18  of the knob  16  which extends circumferentially about the second end  15  of the shaft  12 , as shown in FIG. 2, prevents overinsertion of the suppository by its contact with the urethral orifice (not shown). Moreover, due to its ellipsoidal shape, the knob  16  is easily palpable by the person performing the insertion. If subsequent manipulation is required, either to effect repositioning or early withdrawal, the knob  16  provides means for grasping the suppository readily. Finally, as a result of the substantially ellipsoidal shape of the knob  16 , the suppository is compatible with the external anatomy of the human female. More specifically, the ellipsoidal nature of the knob  16  permits the alignment of the major axis  17  with the contours of the labia minora of the patient so as to afford greater comfort in the use of the suppository.  
         [0027]    It will be understood that the dimensions of the various portions of the suppository of the present invention are important to the successful practice of the invention. That is, the suppository must be of such a size that it is properly retainable within the urethra while not be so large as to cause undue discomfort to the patient during insertion and use. Within such bounds, however, and depending on the particular dimensions of the urethra into which the suppository will be inserted, variations in the dimensions of the various portions of the suppository may occur.  
         [0028]    In certain preferred embodiments it has been found that the shaft of the suppository will have an longitudinal axial length of about 3.5 to about 5 centimeters, preferably about 4 to about 4.5 centimeters, a diameter at the first end thereof of about 0.8 to about 1.5 centimeters, preferably about 0.8 to about 1.2 centimeters, and a diameter at the second end thereof of about 0.4 to about 1 centimeters, preferably about 0.5 to about 0.7 centimeters. In such preferred embodiments, the ellipsoidal knob will have a major axis of about 1 to about 2 centimeters, preferably about 1.3 to about 1.7 centimeters.  
         [0029]    With respect to the manner in which the therapeutic agents and the biocompatible carrier medium are combined in the suppository of the present invention, the therapeutic agent loading level for a given suppository will vary in accordance with, among other things, whether such therapeutic agent is chemically bound to the selected biocompatible carrier medium, physically mixed therewith prior to formation into a suppository, or coated on the surface thereof after formation into a suppository or combinations thereof. For those embodiments in which the therapeutic agent is chemically bound to the selected biocompatible carrier medium, the concentration of the therapeutic agent can be as high as the stoichiometric ratio of one therapeutic agent molecule per biocompatible carrier medium bonding site.  
         [0030]    For those embodiments in which the therapeutic agent is physically mixed with the selected biocompatible carrier medium prior to formation into an urethral suppository or applied as a coating on a preformed urethral suppository, the concentration of the therapeutic agent will vary in accordance with the particular agents that are employed and the application for which the suppository is used. In certain embodiments, the therapeutic agent will be applied differentially to the surface of the biocompatible carrier medium. More specifically, in embodiments in which the therapeutic agent forms a coating on the surface of the biocompatible carrier medium which has already been formed into a suppository, the concentration of the therapeutic agent will vary along the length thereof. In this manner, the precise delivery of different amounts of a therapeutic agent to different portions of the urethra may be realized. In any event, the desired amount of a particular therapeutic agent to be used, and the preferred manner in which the therapeutic agent is combined with the selected carrier medium will be readily ascertainable by one of ordinary skill in the art for each particular application.