DEVICE CAPABLE OF DELIVERY OF HIGHLY SOLUBLE PHARMACEUTICAL

DOSE FORMS INTO BODY SPACES

GOVERNMENTAL SPONSORSHIP [0001] None.

RELATED APPLICATION

[0002] This application claims priority to U.S. Provisional Patent Application, Serial Number 60/678,125, entitled "DEVICE CAPABLE OF DELIVERY OF HIGHLY SOLUBLE PHARMACEUTICAL DOSE FORMS INTO BODY SPACES" filed on May 5, 2005, the entire content of which is hereby incorporated by reference.

BACKGROUND

[0003] This invention relates to a device for delivering medicaments or medical devices into body spaces. More specifically, this invention pertains to an apparatus for administering pills or tiny medical devices into a body cavity while protecting the pill or medical device from the aqueous environment in the body cavity until the pill or medical device is positioned properly in the body cavity.

[0004] With the discovery and use of highly active pharmaceuticals and biologicals in human and veterinary medicine, solid or semisolid dose forms of these pharmaceuticals and biologicals may be the most suitable and stable formulation for a pharmaceutical composition. Additionally, solid or semisolid dose forms may be used to achieve a desired local pharmacological effect while avoiding the potential adverse effects accompanying systemic administration of a pharmaceutical or biological. The production of multiple sizes, concentrations and dose forms of these pharmaceuticals and biologicals may not be practical or cost efficient for manufacturers; therefore, there is occasion in medical practice where delivery of a subdivision of a highly soluble solid or semisolid dose form may be required to achieve the proper dose and clinical outcome for a treatment or procedure.

[0005] Delivery of solid or semisolid dose forms is as old as the history of medicine. The preparation and application of medicinal inorganic (clays) and organic (herbs) dose forms has been accepted medical practice in many cultures. These dose forms were delivered by hand to assure accurate placement on or in the patient. Accurate delivery and placement of solid or semisolid dose forms still requires the skilled hand of a well trained practioner. In veterinary medicine the inter-uterine placement of sulfa powders and boluses to prevent or treat infection and assist with uterus involution are common practice. The instillation of solid or semisolid dose forms of pharmaceuticals in body spaces and cavities is still common medical practice today. The advent of laparoscopic and endoscopic surgical procedures and diagnostic techniques may allow new uses and require new delivery methods for solid and semisolid pharmaceutical dose forms. Medical devices such as radiological markers and micro or nano scale medical devices could benefit from an accurate location delivery system.

[0006] Many of the new solid dose forms are highly soluble to allow for rapid local absorption. These solubility and absorption characteristics are desirable to rapidly initiate the desired local pharmacological effect and then allow the body to rapidly clear the pharmaceutical from the treated tissues. Many of these solid dose forms are presented in the form of a coated tablet or suppository. When one subdivides the original dose form, then the solubility of this fraction is dramatically increased because the coating is incomplete. When the practioner tries to accurately place the fraction dose form by hand, dissolution may began prior to the placement of the dose in the proper location resulting in an insufficient dose being delivered at the proper location.

[0007] The described device will assist the skilled practioner in accurately placing solid or semisolid dose forms in or on the patient while preventing premature dissolution of the fraction dose form. This device or modifications of this device may also facilitate the manufacture and delivery of unit-dose solid, powdered or semisolid pharmaceutical products. This device and its modifications can overcome all the premature dissolution and accurate hand placement problems associated with currently practiced procedures and techniques used to deliver solid or semisolid dose forms in human and veterinary

medicine. Additionally this device and its modifications may be adapted for use in minimally invasive surgical procedures including, but not limited to orthopedic, laparoscopic and endoscopic procedures for delivery of solid or semisolid dose forms. Radiological markers, micro or nano scale medical devices, or other solid medical devices could benefit from an accurate location delivery system.

SUMMARY

[0008] This present invention relates to a medicinal applicator for delivering compositions or tiny medical devices into body spaces. The medicinal applicator is used for administering therapeutic compositions or devices (e.g. pills, micro- or nano- scale medical devices, or parts thereof) into a body cavity while preventing the therapeutic composition or device from contacting the aqueous environment in the body cavity until the precise placement of the therapeutic composition or device has been located.

[0009] A first aspect of this invention is a medicinal applicator that includes a flexible tube with a bore hole or lumen traversing the entire length of the flexible tube from a proximal end of the flexible tube to a distal end of the flexible tube; a plunger traversing the bore hole or lumen of the flexible tube; an elastic membrane having a self-sealing watertight opening and covering the bore hole or lumen forming a delivery end of the flexible tube; and a removable finger retaining loop. In a first preferred embodiment, the delivery end of the flexible tube and the plunger form a therapeutic holding chamber that remains watertight until the plunger is depressed at the proximal end mechanically propelling the mendicant through the watertight opening of the elastic membrane. The flexible tube can be made from medicinal grade metals, plastics, or composite materials (e.g. stainless steel, HDPE, silicon, plastic coated material, or silicon coated materials). The length of the flexible tube is in the range of about 5 cm to about 1 ,000 cm, preferably in the range of about 15 cm to about 50 cm. The diameter of the flexible tube is in the range of about 1 mm to about 30 mm, preferably the range of about 3 mm to about 10 mm. The elastic membrane having a self- sealing and relatively watertight opening is preferably silicone, but can be made from other materials having similar mechanical properties, such as plastic, synthetic or natural rubber. In a preferred embodiment, the medicinal applicator further comprises a camera. This camera or similar device can be used to confirm the placement location of the mendicant. Additionally, the medicinal applicator may further comprise a palm bar. This palm bar is capable of being adjustably connected along the entire length of the flexible tube.

[0010] A second aspect of the current invention is a method of administering a medicinal product into a body cavity of a mammal using a medicinal applicator described above. The method includes loading the medicinal product into the therapeutic holding chamber, forming a primed medicinal applicator; placing the delivery end of the primed medicinal applicator in a desired location in the body cavity of the mammal; depressing the plunger at the proximal end and mechanically propelling the medicinal product through the watertight opening of the self-sealing elastic membrane at the delivery end; returning the plunger to a position capable of allowing the self-sealing elastic membrane to reseal. Once the medicament has been delivered, the medicinal applicator is removed from the body cavity of the mammal. In a preferred embodiment the medicinal product comprises a pill, medical device, a marker, or a dye.

BRIEF DESCRIPTION OF THE DRAWINGS

[0011] The following drawings form part of the present specification and are included to further demonstrate certain aspects of the present invention. The invention may be better understood by reference to one or more of these drawings in combination with the detailed description of specific embodiments presented herein.

[0012] FIGURE 1 shows the basic design and components of one embodiment of the device.

[0013] FIGURE 2 shows two views of the delivery end of one embodiment of the device, 2A shows a front view, and 2B shows a side view with a medicament being propelled through the re-sealable watertight opening.

[0014] FIGURE 3 shows the basic design of one embodiment of the device and having a finger loop. (10) flexible applicator rod; (11 ) removable palm bar; (20) plunger; (21) beveled end for deployment; (22) end of plunger; (30) substantially water tight holder; (31 ) medicament or device; (32) reservoir space; (40) removable finger loop; (41) finger device attachment; (42) finger hole.

[0015] FIGURE 4 shows the basic design and palm bar.

[0016] FIGURE 5 shows the device inserting a medicament into the vaginal fornix of a mammal.

DETAILED DESCRIPTION OF PREFERRED EMBODIMENTS

[0017] The medicinal applicator of this invention can be used in different procedures for delivery of a medicament (e.g. pills, tiny medical devices, markers, dyes, etc.) to specific areas of different types of body cavities, body spaces, wounds, or injuries in different mammals (e.g. companion animals, research animals, feed animals, and humans).

[0018] The present invention relates to a medicinal applicator consisting of a tubular structure containing a plunger placed in one end of the tube that when partially withdrawn allows placement an object in the opposite end of the tubular structure and when advanced would push the object out of the opposite end of the tubular structure. On the distal end of the tubular structure is a flexible membrane shaped reservoir that can be manually opened, but when released reforms into a near-fluid-tight membrane, which prevents fluids under physiological conditions from entering the re-sealable membrane into the reservoir. The reservoir would be of sufficient size and shape to accommodate an object being placed therein, such as a solid or semisolid pharmaceutical dose form or medical device. The plunger would be of sufficient length to clear any object(s) in the tube and membrane shaped reservoir end and cause the object(s) to be pushed out and positioned just outside the membrane covered end. When the plunger is withdrawn the membrane would immediately close behind the plunger end, thus depositing the object(s) immediately at the end of the tubular device.

[0019] This device can be used for delivering a medicament after locating the proper position for delivery by hand. For example, the tubular device is presented for use with a stretchable finger loop that is adjustable along the tube so that the practitioner can tightly secure the device to a finger and can palpate with that finger for the proper anatomical location for dose form delivery. The delivery is achieved by advancing the entire device to the proper location and then advancing the plunger to discharge the solid or semisolid dose form from the reservoir onto the tissue at the desired location. Additionally, there is a palm bar that also is adjustable in location along the tubular device to fit the practitioner's hand. This bar allows the advancement of the tubular device with the thumb of

the same hand or fine adjustment of the device membrane tip without the use of the practitioner's other hand. The plunger can then be advanced with the thumb of the palpating hand, the practitioner's other hand or with the assistance of another party, object or machine.

[0020] This device is useful for delivering a medicament during minimally invasive surgical procedures including arthroscopic, endoscopic and laparoscopic procedure, the tubular device would be of optimal diameter and sufficient length to fit through the trocar sheath and deliver the solid or semisolid dose form, or radiological marker or other solid medical device accurately to the desired tissue structure or organ in the body cavity or tissue space desired.

[0021] One of ordinary skill in the art will recognize that there are many different types of arthroscopic, endoscopic and laparoscopic procedures. For example, an endoscope is a device that is usually used with an attached light, for looking inside a body cavity or organ. Typically, the endoscope is inserted through a natural opening, such as the mouth during a bronchoscopy, the rectum for a sigmoidoscopy, or the vagina for a cystoscopy. However, a medical procedure using any type of endoscope is called endoscopy (e.g. bronchoscopy, cystoscopy, colonoscopy, cystourethroscopy, ERCP, esophagogastroduodenoscopy, gastroscopy, laryngoscopy, proctosigmoidoscopy, sigmoidoscopy), these procedures are well known in the art.

[0022] One aspect of the present invention relates to the delivery of a portion of a tablet that has been sub fractionated to more accurately dose a local tissue structure or organ by surface delivery. When a sub fractionated tablet is exposed to body fluids as it is being advanced within the body space for specific location placement, dissolution begins immediately and this dissolution may be premature or at the wrong location to achieve the proper dose and clinical outcome desired. The described device will protect the tablet or part thereof, from contact with body tissues or fluids until the plunger is advanced at the proper location and the tablet or part thereof, is pushed through the split membrane end of the tubular device.

[0023] Another embodiment of the present invention relates to a device that incorporates the finger loop and membrane tip and is used for intrauterine installation of solid or semisolid dose forms in domestic animals. The tubular device would have to be approximately 1 meter in length and obviously would not need a palm bar, but might incorporate a similar structure near the plunger end to facilitate the movement of the tubular device with the shoulder, mouth or other hand of the practioner for accurate placement of the dose in the uterine horn or other body cavity or tissue structure.

[0024] For veterinary applications, the device can be constructed from any suitable material (e.g. metal, plastic, or composite materials, or a combination thereof). For applications in human medicine, the device tubular structures would be made from materials that are approved by the US/FDA for tissue and pharmaceutical contact as listed in the 21 C. F. R. The preferred embodiment would have the tubular and plunger structures molded, formed or prefabricated from medical grade high density polyethylene (HDPE). The reservoir membrane and finger loop would be made from medical grade silicone. The palm bar can be made from a combination of silicone and HDPE. The devices components could be sterilized by methods using heat, ethylene oxide or other suitable gas sterilent. The device would be presented in "clear-on-one-side" packaging for clinic, delivery or operating room use.

EXAMPLES

[0025] The following examples are provided to further illustrate the construction and uses of this invention and the manner in which it may be carried out. It will be understood, however, that the specific details given in the examples have been chosen for purposes of illustration only and not be construed as limiting the invention.

EXAMPLE 1

[0026] The basic design and components of one embodiment of the device are illustrated in Figure 1. The tubular component (10) may be of any length required by the distance from the body surface to the location of the tissue

to be treated. These lengths could be substantially different for humans or domesticated animals. The tube might incorporate a roughened or flared grip area (11) that would facilitate holding the device by the practioner. The plunger (20) would be flared on one end (21). The plunger would be of a sufficient length to be able to push out the object (1) placed in the other end of the tube. On the other end of the tube is a reservoir membrane (30) for holding the medicament. The reservoir membrane (30) has two ends, the first end connects the reservoir to the end of the tube, which forms the void for holding the medicament. The second end contains an opening that allows the medicament to be loaded into the device and also allows the medicament to be released at the desired location. The preferred reservoir membrane contains a slit (31) in the second end of the membrane for loading and unloading the medicament, but forms a near-fluid-tight seal that can be opened manually to allow one to place the dose form inside the reservoir space (32).

[0027] When the proximal end of the plunger is advanced by a user, the distal end of the plunger (22) would push out any object(s) contained in the tube and/or reservoir space by forcing the object out the split end (31) as illustrated in Figure 2. When the object (1) is pushed out of the split end of the reservoir (32) and the plunger end (22) is retracted, then the reservoir membrane (30) immediately reassumes its substantially fluid-tight form and isolates the object (1) delivered from the reservoir and the device. Thus the dose is delivered. The reservoir membrane is made from a material that will not allow the dose form to adhere to it in sufficient quantity to effectively alter the desired local dose or location of the dose or solid medical device delivered.

EXAMPLE 2

[0028] One embodiment of the present invention relates to the device that incorporates a finger loop (40) component that is adjustable along the tube near the reservoir membrane (Figure 3). The finger loop component would consist of a tube loop (41) to go around the tubular part of the device (10) and a connected finger loop (42) of flexible and expandable material to allow the operator to insert his finger. This specific embodiment would be used for

intrauterine installation of solid or semisolid dose forms in humans and in domestic animals. The tubular device would vary from approximately 10 cm to approximately 1 meter in length and may or may not incorporate a palm bar (50). The palm bar would consist of a tube loop (51) to make the bar adjustable along the length of the tube (10) and a flat rectangular piece (52) to rest against the palm of the operator. For domestic animal use, a variant device might incorporate a similar bar structure near the plunger end of the tube to facilitate the movement of the tubular device with the shoulder, mouth or other hand of the practioner for accurate placement of the dose in the uterine horn or other structure in animals.

EXAMPLE 3

[0029] Accurate delivery of a portion of a tablet (misoprostol) solid dose form to the posterior fornix of the vagina is the most effective placement for inducing labor in pregnant humans. The use of this prostaglandin E-1 analog and this procedure have become common in obstetrics practice. This tablet is very soluble. When the tablet is subdivided it becomes even more soluble because the tablet coating is incomplete. When the practioner tries to manually place the dose at the proper anatomical location using a gloved finger, the dose starts dissolving immediately when it comes in contact with fluids or moist tissues. Patient comfort is of great importance at all times. It is a common complaint that accurate placement of cervical ripening agents with fingers is often uncomfortable for patients and difficult for the practitioner. Use of this device would allow the practioner to accurately deliver the solid dose form to the correct anatomical location with ease and without the dose starting to dissolve. This device design is very safe in these applications because the membrane reservoir end is soft and would not cause tissue damage or penetration when used by a practioner skilled in the art and practice of obstetrics.

EXAMPLE 4

[0030] The size and depth of a domestically animal (horse, cow) uterus following fetal delivery is problematic for the veterinary obstetrics practioner. If there is incomplete placental detachment or contamination of the uterus during

assisted fetal deliveries, it is general practice to place antibiotic solid dose forms in the uterus. On many occasions the practioner would like to place these dose forms in the deepest recesses of the uterus and/or uterine horns. This device is capable of solid or semisolid dose form delivery at distances of greater than 1 meter and would be of great assistance in the postpartum management of these animals. Additionally, animals with uterine infections will usually benefit from deep installation of intrauterine antibiotic solid or semisolid dose forms as well as systemic antibiotics. This device would allow the veterinary practioner to utilize a wider range of intrauterine antibiotic dose forms and place them deeper into the uterus and associated structures. This device design is very safe in these applications because the membrane reservoir end is soft and would not cause tissue damage or penetration when used by a practioner skilled in the art and practice of veterinary medicine.

[0031] One skilled in the art readily appreciates that this invention is well adapted to carry out the objectives and obtain the ends and advantages mentioned as well as those inherent therein. Pharmaceutical compositions, treatments, methods, procedures and techniques described herein are presently representative of the preferred embodiments and are intended to be exemplary and are not intended as limitations of the scope. Changes therein and other uses will occur to those skilled in the art which are encompassed within the spirit of the invention or defined by the scope of the pending claims.

REFERENCES CITED

[0032] The following references, to the extent that they provide exemplary procedural or other details supplementary to those set forth herein, are specifically incorporated herein by reference.

U.S. PATENT DOCUMENTS:

United States Patent 3,042,030 issued to Read on July 3, 1962, titled "Spherical Type Insert Plug for Body Passageway and Tool Thererfore."

United States Patent 3,757,781 issued to Smart on September 11 , 1973, titled "Tool for Administering Pills to Animals."

United States Patent 6,123,683 issued to Propp on September 26, 2000, titled "Pill Delivery Apparatus."

OTHER REFERENCES:

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2. Prostaglandin E2 gel versus misoprostol for cervical ripening in patients with premature rupture of membranes after 34 weeks. Obstet Gynecol. 2002 Feb; 99(2):206-10.

3. Kulier R, Gulmezoglu AM, Hofmeyr GJ, Cheng LN, Campana A., Medical methods for first trimester abortion. Cochrane Database Syst Rev. 2004.

4. Gulmezoglu AM, Forna F, Villar J, Hofmeyr GJ. Prostaglandins for prevention of postpartum hemorrhage. Cochrane Database Syst Rev. 2004;(1).

5. Obstetrics: Normal and Problem Pregnancies, Gabbe: pg 1038-1046.

6. Williams Obstetrics, Williams: pg 1230-1234.

7. Joy et al. Misoprostol during the third stage of labor. Inter J Ob&Gyn. 2003 82. 143-152.

8. Grimes et al. Induced abortion. Annals of lnt Med. 2004. 140(8).620-627.

9. Lokugamage AU, Refaey HE, Rodeck CH. Misoprostol and pregnancy: ever-increasing indications of effective usage.Curr Opin Obstet Gynecol. 2003 Dec; 15(6):513-8. Review.

10. Hofmeyr GJ, Gulmezoglu AM. Vaginal misoprostol for cervical ripening and induction of labour. Cochrane Database Syst Rev. 2003 ;( 1):CD000941. Review.

11. Wing et al. A Benefit-Risk Assessment of Misoprostol for cervical Ripening and Labor Induction. Drug Safety 2002:25 (9):665-676.

12. Tenore et al. Methods for Cervical Ripening and Induction of Labor. American Family Physician, 2003:67 (10):2123-2128.

13. Chund, et al. A Prospective randomized controlled trial that compared misoprostol, Foley catheter, and combination for labor induction. Am J Obstetrics and Gynecology. 2003:189 (4): 1031 -1035.

14. Villar, et al. Systematic review of randomized controlled trials of misoprostol to prevent PPH. Ob&Gyn. 2002:100 (6)1301-1312.