EP1478337A1 - Systeme d'administration de medicaments par voie transvaginale - Google Patents

Systeme d'administration de medicaments par voie transvaginale

Info

Publication number
EP1478337A1
EP1478337A1 EP02700512A EP02700512A EP1478337A1 EP 1478337 A1 EP1478337 A1 EP 1478337A1 EP 02700512 A EP02700512 A EP 02700512A EP 02700512 A EP02700512 A EP 02700512A EP 1478337 A1 EP1478337 A1 EP 1478337A1
Authority
EP
European Patent Office
Prior art keywords
delivery system
drug
tampon
following
ibuprofen
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Withdrawn
Application number
EP02700512A
Other languages
German (de)
English (en)
Inventor
Simon Benita
Ram Kluger
Theodor Stern
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Yissum Research Development Co of Hebrew University of Jerusalem
Hi Gienic Intra Vaginal Technologies Ltd
Original Assignee
Yissum Research Development Co of Hebrew University of Jerusalem
Hi Gienic Intra Vaginal Technologies Ltd
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Yissum Research Development Co of Hebrew University of Jerusalem, Hi Gienic Intra Vaginal Technologies Ltd filed Critical Yissum Research Development Co of Hebrew University of Jerusalem
Publication of EP1478337A1 publication Critical patent/EP1478337A1/fr
Withdrawn legal-status Critical Current

Links

Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61F—FILTERS IMPLANTABLE INTO BLOOD VESSELS; PROSTHESES; DEVICES PROVIDING PATENCY TO, OR PREVENTING COLLAPSING OF, TUBULAR STRUCTURES OF THE BODY, e.g. STENTS; ORTHOPAEDIC, NURSING OR CONTRACEPTIVE DEVICES; FOMENTATION; TREATMENT OR PROTECTION OF EYES OR EARS; BANDAGES, DRESSINGS OR ABSORBENT PADS; FIRST-AID KITS
    • A61F13/00—Bandages or dressings; Absorbent pads
    • A61F13/15—Absorbent pads, e.g. sanitary towels, swabs or tampons for external or internal application to the body; Supporting or fastening means therefor; Tampon applicators
    • A61F13/20—Tampons, e.g. catamenial tampons; Accessories therefor
    • A61F13/2051—Tampons, e.g. catamenial tampons; Accessories therefor characterised by the material or the structure of the inner absorbing core
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0034—Urogenital system, e.g. vagina, uterus, cervix, penis, scrotum, urethra, bladder; Personal lubricants
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L15/00—Chemical aspects of, or use of materials for, bandages, dressings or absorbent pads
    • A61L15/16—Bandages, dressings or absorbent pads for physiological fluids such as urine or blood, e.g. sanitary towels, tampons
    • A61L15/42—Use of materials characterised by their function or physical properties
    • A61L15/44—Medicaments
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61M—DEVICES FOR INTRODUCING MEDIA INTO, OR ONTO, THE BODY; DEVICES FOR TRANSDUCING BODY MEDIA OR FOR TAKING MEDIA FROM THE BODY; DEVICES FOR PRODUCING OR ENDING SLEEP OR STUPOR
    • A61M31/00—Devices for introducing or retaining media, e.g. remedies, in cavities of the body
    • A61M31/002—Devices for releasing a drug at a continuous and controlled rate for a prolonged period of time
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0034—Urogenital system, e.g. vagina, uterus, cervix, penis, scrotum, urethra, bladder; Personal lubricants
    • A61K9/0036—Devices retained in the vagina or cervix for a prolonged period, e.g. intravaginal rings, medicated tampons, medicated diaphragms
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L2300/00—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices
    • A61L2300/40—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices characterised by a specific therapeutic activity or mode of action
    • A61L2300/402—Anaestetics, analgesics, e.g. lidocaine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L2300/00—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices
    • A61L2300/40—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices characterised by a specific therapeutic activity or mode of action
    • A61L2300/41—Anti-inflammatory agents, e.g. NSAIDs
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L2300/00—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices
    • A61L2300/40—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices characterised by a specific therapeutic activity or mode of action
    • A61L2300/43—Hormones, e.g. dexamethasone
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L2300/00—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices
    • A61L2300/40—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices characterised by a specific therapeutic activity or mode of action
    • A61L2300/432—Inhibitors, antagonists
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61M—DEVICES FOR INTRODUCING MEDIA INTO, OR ONTO, THE BODY; DEVICES FOR TRANSDUCING BODY MEDIA OR FOR TAKING MEDIA FROM THE BODY; DEVICES FOR PRODUCING OR ENDING SLEEP OR STUPOR
    • A61M2210/00—Anatomical parts of the body
    • A61M2210/14—Female reproductive, genital organs
    • A61M2210/1475—Vagina

Definitions

  • This invention relates to a system and method for transvaginal drug delivery.
  • Transvaginal drug delivery is a well known means of administering drugs to a female (Woolfson, A.D., Malcolm, R.K. and Gallagher, R. (2000) Critical Reviews in Therapeutic Drug Carrier Systems 17:509-555).
  • the transvaginal route has several advantages: (1) it is non-invasive; (2) the vagina consists of highly perfused tissue with a well-developed blood supply; (3) it avoids first-pass metabolism in the liver.
  • the transvaginal route may be used both for local drug treatment as well as systemic drug absorption.
  • Transvaginal drug delivery systems may be classified in two main groups: those adapted from semisolid topical systems and those designed specifically for intravaginal use.
  • Known systems include the following:
  • Mucoadhesive gels and hydrogels are weakly crosslinked polymers which are able to swell in contact with water and spread onto the surface of mucus. These have been used for cervical ripening, spermicidal contraception, vaccination and treatment of vaginal infections;
  • Vaginal tablets They may be formulated with mucoadhesive polymers in order to increase intravaginal residence time. They have been used for cervical ripening, spermicidal contraception, pregnancy termination, analgesia and urge incontinence;
  • Vaginal pessaries and suppositories These are substances such as natural gums, fatty acids, alum and rock salts which were originally used by the ancient Egyptians as contraceptives. They have been used for cervical ripening, treatment of vaginal infections, pregnancy termination and progesterone therapy; • Microspheres for the delivery of peptide and protein drugs; • Intravaginal rings. These are torus-shaped polymeric devices designed to release one or more incorporated drugs in a controlled fashion. They have been used for steroidal and spermicidal contraception, and estrogen replacement therapy.
  • U.S. Patent No. 3,918,452 discloses vaginal sponges and/or tampons impregnated with contraceptive compositions.
  • the composition comprises microcapsules containing a contraceptive drug and which provide sustained release of the drug before, during and/or after coitus.
  • U.S. Patent No. 4,309,997 discloses a medicated tampon in the form of a soft, porous foam ball of spherical configuration.
  • the tampon is impregnated with a contraceptive drug and/or an antibiotic for control of venereal disease.
  • the tampon is inserted into the vagina to cover the cervical area while permitting intercourse to take place.
  • U.S. Patent No. 5,201,326 discloses a rod-shaped medical tampon for releasing an active substance.
  • the tampon includes a core of compressed fibers and a cover surrounding the core and glued thereto, the cover comprising hardened collagen foam or hardened gelatin foam impregnated with a retardant, such as a fatty substance, including the dissolved active substance to be released.
  • the active substance may be antibiotics, sulfonamides, antimycotics, fungicides or hormones.
  • 5,417,224 discloses a tampon comprising a porous spherical member having an inner region configured radially within an outer region, a cord extending through a passage extending through the spherical member, a spermicide within the pores of the inner region and a lubricant within the pores of the outer region.
  • U.S. Patent No. 6,086,909 discloses devices and methods for the treatment of dysmenorrhea which comprise an intravaginal drug delivery system containing an appropriate pharmaceutical agent which is released into the vagina and absorbed through the vaginal mucosa via lymphatic and venous channels to the uterus.
  • the drug delivery system may include a tampon device, vaginal ring, pessary, tablet, vaginal suppository, vaginal sponge, bioadhesive tablet, bioadhesive microparticle, cream, lotion, foam, ointment, solution or gel.
  • the system may additionally include a muco-adhesive agent and/or a penetration enhancer.
  • the device is an absorbent vaginal tampon
  • one end of the tampon has a means for delivering the pharmaceutical agent while the other end has means for conveying fluid discharged from the uterus (such as menses fluid) to the tampon, thereby preventing contact of the fluid with the agent.
  • Non-steroidal anti-inflammatory drugs are marketed worldwide as over the counter (OTC) analgesics and antipyretics, of which, the most commonly used are aminophen, aspirin, ibuprofen and naproxen.
  • PGHS is the key rate-limiting enzyme in the production of prostanoids. This enzyme catalyzes the conversion of arachidonic acid to PGH 2 via a two-step reaction mechanism involving sequential cyclooxygenase and peroxydase activities.
  • OTC analgesics are regarded as safe for the majority of patients.
  • adverse effects have been reported and are mainly associated with the oral administration of NSAIDs, occurring mostly in the gastrointestinal tract. Dyspepsia appears to be the most common side effect, but serious adverse effects such as bleeding, ulceration and perforation can also occur.
  • the potential of adverse renal effects have also been reported, although for some NSAIDs this relationship remains controversial. Most adverse renal effects, however, are reversible on prompt discontinuation of the analgesics.
  • Numerous studies have dealt with the controlled release of NSAIDs from capsules, matrices, or gels. Colloidal liposomal carriers in an injectable 25% poloxamer gel were used to investigate the release properties of ibuprofen.
  • Poloxamer gel was also used for the epidural injection of lidocaine and ibuprofen.
  • Biodegradable matrices such as poly lactic acid (PLA) were also used for the controlled release of analgesics.
  • Gel-yielding egg albumin-based matrices were used to study drug release kinetics.
  • Other sustained release formulations consisted of hydroxypropyl methylcellulose (HPMC) matrices or matrices of synthetic crosslinked polymeric resins, as for example crosslinked poly acrylic acid. It is estimated that 30 to 50% of the women of childbearing age in the US, are affected by painful menstrual periods or dysmenorrhea and 10 to 15% of those women are incapacitated for 1 to 3 days each month.
  • PGE2 prostaglandin E2
  • PGF2 ⁇ prostaglandin F2 ⁇
  • NSAIDs are successful as analgesics in 77 to 80% of dysmenorrhea patients, ibuprofen, naproxen, or naproxen sodium being the usual initial choices.
  • transvaginal drug delivery system comprising:
  • a deposition comprising an effective amount of the drug and, optionally, a wetting agent; and (b) a polymeric support on which the deposition is deposited.
  • transvaginal includes both local delivery to the vagina (intravaginal) as well as through the vagina to other target tissues in the body, including systemic effects.
  • the drug used in the delivery system of the invention may be any drug which either is released and acts locally or which is absorbed through the vaginal mucosa to other locations in the body.
  • examples of such drugs include non-steroidal anti-inflammatory drugs (NSAID), anti-prostaglandins, prostaglandin inhibitors, COX-2 inhibitors, local anaesthetics, calcium channel blockers, potassium channel blockers, ⁇ -adrenergic agonists, leukotriene blocking drugs, smooth muscle inhibitors, vasodilators, hormone replacement drugs, androgenic hormones and drugs capable of inhibiting dyskinetic muscle contraction.
  • NSAID non-steroidal anti-inflammatory drugs
  • anti-prostaglandins prostaglandin inhibitors
  • COX-2 inhibitors local anaesthetics
  • calcium channel blockers potassium channel blockers
  • ⁇ -adrenergic agonists ⁇ -adrenergic agonists
  • leukotriene blocking drugs smooth muscle inhibitors
  • vasodilators hormone replacement drugs
  • Non-limiting examples of NSAIDs suitable for use in the method of the invention include Aspirin, Ibuprofen, Indomethacin, Phenylbutazone, Bromfenac,
  • Fenamate Sulindac, Nabumetone, Ketorolac, and Naproxen.
  • local anesthetics include Lidocaine, Mepivacaine, Etidocaine, Bupivacaine,
  • 2-Chloroprocaine hydrochloride 2-Chloroprocaine hydrochloride, Procaine, and Tetracaine hydrochloride.
  • calcium channel antagonists include Diltiazem, KAm, Nimodipine,
  • potassium channel blockers include Defetilide, E-4031, Almokalant, Sematilide, Ambasilide, Azimilide, Tedisamil, RP58866, sotalol, Piroxicam, and Ibutilide.
  • ⁇ -adrenergic agonists examples include Terbutaline, Salbutamol,
  • Vasodilators which are believed to relieve muscle spasm in the uterine muscle, include nitroglycerin, isosorbide dinitrate and isosorbide mononitrate.
  • COX-2 inhibitors are Celecoxib, Meloxicam and Flosulide.
  • hormone replacement drugs are estrogen or estradiol and progestogen.
  • androgenic hormones are testosterone and other androgenic hormones.
  • the drug may be present in the system in combination with a biocompatible excipient or carrier acceptable for application of the drug to the vaginal epithelium.
  • a biocompatible excipient or carrier acceptable for application of the drug to the vaginal epithelium may be present in the system in combination with a biocompatible excipient or carrier acceptable for application of the drug to the vaginal epithelium.
  • excipients such as wetting agents or surfactants in the formulation
  • an effective amount in this specification means an amount sufficient to attain a therapeutically effective amount of the drug in the target tissue or system.
  • the drug is absorbable through the vaginal mucosa and thereby transmitted via venous and lymphatic channels to the uterus or to the general blood circulation.
  • the deposited drug or drug composition may include any polymer capable of producing and facilitating a coherent deposition on the polymeric support material.
  • polymers include but are not limited to polyesters, olefins, cellulose and cellulose derivatives, PVA and PVP.
  • the polymeric support may be any polymeric material capable of serving as a support for the deposited material, and includes non-woven as well as woven materials.
  • support material include polypropylene, polyethylene, cellulose and cellulose derivatives or any other polymer which can be processed as a fiber.
  • a preferred shape of the polymeric support is a rectangular strip, which preferably consists of one or more layers, for example, 2-16 layers. Other shapes for the strip are also contemplated as part of the invention.
  • wetting agents which may be used in the drug delivery system of the invention include glycerol, polyethylene glycol (PEG), polypropylene glycol (PPG) and surfactants with an HLB ranging from 10 to 18 such as Tween 80.
  • PEG polyethylene glycol
  • PPG polypropylene glycol
  • surfactants with an HLB ranging from 10 to 18 such as Tween 80.
  • Preferred wetting agents are glycerol and PEG-8000.
  • the delivery system of the invention is preferably used together with a catamenial tampon, as will be explained in more detail below.
  • a catamenial tampon Preferably, more than one delivery system will be placed in a tampon on different sides, so as to release the drug in all directions.
  • the delivery system of the invention for releasing a drug to the surrounding environment of the female urogenital tract is the contribution both to the economy of the manufacturing process of the tampon as well as to its reproducibility.
  • the amount of drug necessary to use in the system to obtain a given effect may be significantly less than in systemic methods of drug administration.
  • catamenial tampon for insertion in a human vagina comprising:
  • the delivery system is positioned between the inner core and the outer layer.
  • the tampon further comprises a polymeric water-impermeable film behind the strips of the delivery system, e.g. between the delivery system and the inner core.
  • the film is comprised of high-density polyethylene (HDPE).
  • the drug is a NSAID such as naproxen or ibuprofen.
  • Figs, la and 2a are perspective top views of a folded-type tampon in its flat form with two different embodiments of a delivery system in accordance with the invention
  • Figs, lb and 2b are perspective views of a folded-type tampon in its final folded and pressed form;
  • Figs, lc and 2c are sectional views along lines lc — lc and 2c — 2c in Figs, lb and 2b, respectively;
  • FIGs. 3a and 4a are perspective top views of a rolled-type tampon in its flat form with two different embodiments of a delivery system in accordance with the invention
  • Figs. 3b and 4b are perspective views of a rolled-type tampon in its final, rolled and pressed form
  • Figs. 3c and 4c are sectional views along lines 3c — 3c and 4c — 4c in Figs. 3b and 4b, respectively.
  • Fig. 5 shows release profiles of formulated tampons containing either 50 mg or 25 mg ibuprofen, in net enclosure permitting different fluid volume absorption
  • Figs. 6a and 6b show embodiments of alternate structures of the delivery system with a polymeric film backing: a split arrangement (Fig. 6a) and a continuous arrangement (Fig. 6b);
  • Fig. 7 shows release profiles of tampons, enclosed in a tight net, containing lOOmg of Ibuprofen and 25% glycerol with the delivery system attached to HDPE substrate type A (results of two replicas);
  • Fig. 8 shows release profiles of tampons, enclosed in a tight net, containing lOOmg of Ibuprofen and 10% Tween-80 with the delivery system attached to HDPE substrate type A ( ⁇ ) and type B (•); and
  • Fig. 9 shows release profiles of tampons, enclosed in a tight net, containing 150mg of Ibuprofen, 20% glycerol and 20% PEG-900 (without HDPE substrates) (results of two replicas a (B) and b (•)).
  • the delivery system of the invention is composed of a polymeric support, such as a non-woven polymer material, on which a deposition is deposited.
  • the deposition comprises a drug which may be released to the surrounding environment. Examples of such drugs are listed above in the summary of the invention.
  • the drug is dissolved in a solvent which is applied to the support.
  • the deposition is deposited by evaporation of the solvent
  • the polymeric support is placed near the surface of the tampon.
  • the delivery system is positioned between the inner absorbent core of the tampon and its outer covering layer.
  • the polymeric support may be in any geometrical form or shape.
  • the support is in the form of rectangular strips of material, although other shapes are also possible. A plurality of these strips may be placed on different sides of the tampon in order to release the drug in all directions.
  • tampons prepared according to the invention.
  • Tampons which undergo both radial and longitudinal expansion are generally manufactured for use with various types of applicator devices.
  • the longitudinal expansion is generally more than 10% of its unexpanded length.
  • This type of tampon comprises an inner core of absorbent material, such as cellulose fibers and/or cotton fibers, enveloped by an outer layer of liquid-permeable material such as a non-woven polymer, as for example polypropylene, polyethylene, polyester, cellulose, cellulose derivatives, or any combination of the above.
  • This type of tampon is referred to in this specification as a "folded-type' ' ' tampon.
  • a folded-type tampon according to one embodiment of the invention is illustrated in Fig. la, in which can be seen a tampon 2 in its flat form comprising a body 4 and a withdrawal cord 6.
  • the body 4 of the tampon comprises an outer layer 8 enveloping an inner absorbent core 10.
  • the outer layer is held to the inner core in ways well known in the art, such as sewing or welding.
  • the flat body has an upper 12 and a lower 14 surface.
  • a delivery system according to the invention in the form of three rectangular polymeric strips are positioned between the outer layer and the inner core, in parallel to the longitudinal axis of the body.
  • One relatively wide strip 16 is on the upper surface 12 of the body (under the outer layer 8) and two narrow strips 18 are on the lower surface 14.
  • the length of the strips may be approximately equal to the length of the flat body, and preferably equal to it.
  • the width of the wide strip is approximately twice the width of the narrow strips.
  • Typical, non-limiting dimensions may be as follows: length and width of flat tampon - 5-9.5 and 4-5 cm, respectively; widths of wide and narrow strips - 1.5-2.5 cm and 0.7-1.5 cm, respectively.
  • Example 2 in which can be seen the inner core 10, the outer layer 8 and the wide 16 and narrow 18 strips below the outer layer. It may be seen from the figure that the edges of the wide strip 16 are folded within the folds of the inner core 10, thereby releasing the drug absorbed therein to within the tampon as well as to the surrounding environment.
  • Example 2
  • Fig. 2a In another embodiment, illustrated in Fig. 2a, three strips are positioned at spaced intervals between the outer layer 22 and the inner core 24 of the flat tampon 28, perpendicularly to the longitudinal axis of the flat body 26 of the tampon.
  • the strips are wound around the width of the body 26 and then excised at the lateral edges 30 of the body so that there are 3 strips 20 on the upper surface 32 of the body and 3 corresponding strips 34 on the underside of the body.
  • the length of each of the strips is equal to the width of the flat tampon.
  • the strips are positioned closer to the front end 36 of the tampon, opposite the withdrawal cord 38, since this is the end with which the menstrual fluid first comes into contact.
  • the folded tampon 40 is illustrated in Fig. 2b, in which can be seen the annular strips 20.
  • Fig. 2c shows how the strips 20,34 appear near the outer surface of the tampon between the outer layer 22 and the inner core 24, as well as within the folds of the inner core.
  • a typical tampon which undergoes primarily radial expansion ( ⁇ 10% longitudinal expansion, if at all) is referred to in this specification as a "rolled-type" tampon and is shown in Figs. 3a-3c.
  • the folded-type tampon described above it comprises an inner core of absorbent material, as in Example 1, enveloped by an outer layer of liquid-permeable material, as in Example 1.
  • the rolled-type tampon differs from the folded-type tampon, inter alia, in their dimensions as well as in the manner of forming of the tampon. These differences affect the placement of the strips.
  • the flat tampon 48 comprises an absorbent layer 50 on which is placed an outer layer 52.
  • the absorbent layer 50 is in the form of an extended rectangular ribbon.
  • the material of the outer layer 52 is generally heat sealed to the upper side of the absorbent layer near one of its ends 54, an extension 56 of the outer layer partly extending beyond the end 54 of the absorbent layer.
  • the length of the extension 56 is substantially equivalent to the circumference of the tampon in its final, folded form.
  • three parallel spaced rectangular polymeric strips 58 are positioned equidistantly from each other, perpendicular to the longitudinal axis of the outer layer, and between the absorbent layer 50 and the outer layer 52.
  • the ends of the strips are distanced from the longitudinal edges of the outer layer, and the strip 60 closest the end 54 of the absorbent layer is inwardly displaced from that end.
  • the distance from the strip 62 farthest from the end 54 of the absorbent layer to that end is approximately equal to the circumference of the tampon in its folded form.
  • Typical, non-limiting dimensions of the various tampon components are given below for exemplary purposes only: length, width and thickness of absorbent layer - 20-30 cm, 4-6 cm and 0.4-1.0 cm, respectively; length and width of outer layer - 5-15 cm and 4-4.5 cm; circumference of tampon - 3-4.5 cm; length of strips - 3.5-5.5 cm.
  • Fig. 3b shows the tampon 64 in its folded form comprising the body 66 and withdrawal cord 68.
  • the absorbent layer of the flat tampon (Fig. 3 a) is rolled up onto itself along its longitudinal axis towards the end on which the strips and outer layer are placed, and the extension 56 of the outer layer is heat welded to the opposite end of the outer layer, thus enveloping the absorbent layer which now forms the core of the tampon.
  • Two of the three strips 58 may be seen in Fig. 3b through the outer layer, with the third strip out of sight behind the body of the tampon.
  • Fig. 3 c shows the three components of the tampon according to the invention: the rolled up inner absorbent core 50, the outer layer 52 and the strips 58.
  • Figs. 4a-4c the strips are placed parallel to the longitudinal axis of the outer layer rather than perpendicular thereto.
  • Fig. 4a illustrates the absorbent layer 60 and outer layer 62 of the flat tampon 63 as in the previous example.
  • Three parallel equidistant strips 64 are placed between the two layers in parallel to the longitudinal axis of the outer layer. The length of each strip is equal to the circumference of the tampon in its final form.
  • the strips are placed proximate to the anterior end of the folded tampon.
  • Figs. 4b and 4c show the tampon 66 in its folded form comprising the inner core 60, the outer layer 62 and the strips 64.
  • SINK conditions originated from the fact that the drug concentration gradient between the external and internal epithelial layer is always maximal, and that the tissue or blood acts as a natural 'sink', i.e. the drug is instantaneously absorbed the moment it dissolves. Therefore, under in vivo conditions, there is no concentration buildup and hence the retarding effect of low and/or moderate concentration gradient in unlikely to occur.
  • in vitro dissolution or release kinetics studies are usually conducted using a large volume of dissolution or release medium, so that the solute concentration never reaches more than 5-10% of its maximum solubility under identical experimental conditions. If such conditions are maintained, the low aqueous solubility of the drug does not represent anymore a rate -limiting factor. All in vitro tests in this specification were conducted under sink conditions using 10% of maximum solubility concentration, unless otherwise specified.
  • each one of the drugs was first dissolved in ethanol, at a concentration determined by the drug dosage per tampon, and glycerol was added to a percentage of 15% calculated on drug weight basis.
  • Glycerol acts as a wetting agent. The co-inclusion of other wetting agents or surfactants in the formulation may be necessary at times.
  • the formulation was loaded on non-woven (NW) strip (7.5-8.5x2.5 cm) (i.e. the delivery system), by immersing the NW in an ethanol solution, containing the formulation, and eventually evaporating the solvent. Both ethanol and acetone were found suitable for this method, nevertheless, ethanol was chosen due to its significantly lower toxicity.
  • the fonnulation-containing strips of the folded-type were folded 2 times around the axial direction and 7.5 cm-long strips were prepared by pressing the folded material at 1 ton/cm 2 for 30 seconds. 4 layered strips were obtained by using a single PP/PE (NW). One 2.5cm strip and two 1.25cm strips were attached to a tampon in the longitudinal direction as shown in Fig. la.
  • the release medium used for these experiments was the Sorensen -Walbum buffer, chosen here due to its lack of absorbance in the UV range, thus causing less interference with the analytical drug detection process.
  • the buffer consisted of glycine (0.1 M) and NaCl (0.1 M), adjusted to pH 7.4 with NaOH (0.1M).
  • the saturation concentration of Ibuprofen under these conditions was 100 ⁇ g/ml. Accordingly, the SINK conditions concentration was set to 10 ⁇ g/ml. It is worth mentioning that a significantly higher saturation concentration can be reached by first dissolving the drug in a small quantity of ethanol and then mixing it with the buffer solution. Nevertheless, these are not the conditions under which the drug is released in vitro or in vivo.
  • Ibuprofen concentrations were determined by means of high performance liquid chromatography (HPLC), using the method described in Pharmaceutical Research (1998) 15:482-487.
  • Isocratic mobile phase acetonitrile: 0.1M sodium acetate (35:65 v/v), adjusted to pH 6.2 with glacial acetic acid.
  • UV detector at 222 run.
  • Detection limit 0.05 ⁇ g/ml.
  • Naproxen under the release kinetics experimental conditions, was determined, in the same manner as described before for Ibuprofen. A large excess of Naproxen was added to 50 ml of the Sorensen buffer and agitated in a sealed flask at 37°C, for a period of 24 hours.
  • the saturation concentration of Naproxen under these conditions was 109 ⁇ g/ml, only slightly higher than that of Ibuprofen. Accordingly, the sink conditions concentration was set to 10.9 ⁇ g/ml, which is 10% of the saturation conditions.
  • Naproxen concentrations were determined by HPLC using the method described in Acta Pharmacol, et Toxicol. (1980) 47:267-273. Column: RP-Cis , 5 ⁇ m 25mm, (Merck) at ambient temperature.
  • Isocratic mobile phase acetonitrile : lOOmM ammonium acetate (40:60 v/v), adjusted to pH 5.5 with glacial acetic acid.
  • UV detector at 280 nm. Detection limit: 0.02 ⁇ g/ml.
  • Formulated tampons (with either ibuprofen or naproxen) were enclosed in a flexible plastic net.
  • the net was firmly tied around the tampons, so that it allowed a maximum absorption of 6 ml of the release medium, which is close to the absorption volume of menstrual fluids under physiological conditions.
  • the extent of net tightness was decreased to allow a final absorption volume of 8-10 ml.
  • Fig. 5 summarizes the ibuprofen release results obtained comparing the effect of two parameters - fluid absorption and amount of formulation - on the drug release profile.
  • the formulated delivery system was attached to a thin film of high-density polyethylene (HDPE) which is a relatively inert and hydrophobic material, impermeable to water.
  • HDPE high-density polyethylene
  • the main concept of placing a thin HDPE substrate attached to the formulated chip was to facilitate the outward diffusion of the drug by minimizing the inward flow.
  • the HDPE substrate was attached to the delivery system by sewing the edges with a cotton thread.
  • the chip was mounted on the tampon with the HDPE substrate facing inward.
  • the saturation concentrations obtained with the 1% and 3% albumin containing buffer solutions were approximately 730 ⁇ g/ml and 2100 ⁇ g/ml, respectively. These concentrations are respectively 7 to 21 times higher than the 100 ⁇ g/ml saturation concentration obtained with the Sorensen buffer alone. It is believed that either a complexation process between the protein and drug molecules, or a change in the solubility parameters of the solution led to such a significant increase in the drug saturation concentration.
  • SINK conditions were set at 6.8% and 14% for formulated tampons containing 50 mg and 100 mg of ibuprofen, respectively, in a volume of 1 liter of releasing medium containing 1% bovine serum albumin. 5.
  • the in vitro experimental conditions were set as follows: Drug release from formulated tampons was performed in a dissolution apparatus, consisting of 6 1 -liter glass vessels immersed in a controlled temperature water bath and equipped with a controlled mechanical stirring system (130 rpm). Albumin concentration in the releasing medium was 1% and the solution was kept at a constant temperature of37°C.
  • Formulated tampons were enclosed in a tight plastic net, restricting the maximum fluid absorption to 5-6 ml.
  • the tampons were immersed into the releasing medium head down, held vertically by the string. A small glass weight was attached to the tampon, in order to prevent floating. All experiments were carried out in two replicas. Samples were taken in duplicates and treated as described in the previous section.
  • the tampons were washed with 50 ml of ethanol in order to extract the residual amounts of drug present in the tampon at the end of the process.
  • the sum of the residual and the released amounts was considered as the total amount of drug originally present in the formulated tampon.
  • the release profiles of the different formulated tampons are presented in Figs. 7, 8 and 9.
  • the release profiles of formulation numbers (b) and (c), shown in Fig. 8 clearly indicate that the use of Tween 80 as wetting agent instead of glycerol, does not increase the release rate and even slows it down. No significant difference in the release profiles was observed when using either split or continuous HDPE substrates.

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Abstract

L'invention concerne un système d'administration de médicaments par voie transvaginale, ce système comprenant : (a) un produit de dépôt comprenant une dose efficace de médicament et, éventuellement, un agent mouillant ; et (b) un support polymère sur lequel est appliqué ledit produit de dépôt. L'invention concerne également un tampon hygiénique à insérer dans le vagin, ce tampon comprenant : (a) un noyau central comprenant une matière absorbante ; (b) une couche externe comprenant une matière perméable aux liquides ; et (c) un système d'administration conforme à l'invention. L'invention concerne en outre une méthode d'administration de médicaments par voie transvaginale.
EP02700512A 2002-02-24 2002-02-24 Systeme d'administration de medicaments par voie transvaginale Withdrawn EP1478337A1 (fr)

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US20100130907A1 (en) 2008-11-21 2010-05-27 Linkel Stephan M Article of manufacture used in contact with human body surfaces

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US4340055A (en) * 1980-10-01 1982-07-20 Sneider Vincent R Impregnated tampon and method of fabricating same
DE3928677C2 (de) * 1989-08-30 1998-05-14 Kimberly Clark Gmbh Tampon für medizinische oder hygienische Zwecke sowie Verfahren zu seiner Herstellung
JPH0394218U (fr) * 1990-01-18 1991-09-26
JPH07450A (ja) * 1991-05-04 1995-01-06 Mitsugi Takahashi 座薬機能を持った生理用タンポン
US6197327B1 (en) * 1997-06-11 2001-03-06 Umd, Inc. Device and method for treatment of dysmenorrhea
GB0009914D0 (en) * 2000-04-20 2000-06-07 Metris Therapeutics Limited Device
IL138183A0 (en) * 2000-08-31 2001-10-31 Rostam Ltd Ph reducing formulation and delivery system for a tampon
US6888043B2 (en) * 2001-12-21 2005-05-03 Kimberly-Clark Worldwide, Inc. Feminine care products for the delivery of therapeutic substances

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See references of WO03070216A1 *

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WO2003070216A1 (fr) 2003-08-28
AU2002233588B2 (en) 2008-01-31
JP2005535563A (ja) 2005-11-24
AU2002233588A1 (en) 2003-09-09
CA2477109A1 (fr) 2003-08-28
IL163614A0 (en) 2005-12-18
CA2477109C (fr) 2010-11-16

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