WO2015189853A1 - Dispositif intra-utérin - Google Patents

Dispositif intra-utérin Download PDF

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Publication number
WO2015189853A1
WO2015189853A1 PCT/IN2014/000494 IN2014000494W WO2015189853A1 WO 2015189853 A1 WO2015189853 A1 WO 2015189853A1 IN 2014000494 W IN2014000494 W IN 2014000494W WO 2015189853 A1 WO2015189853 A1 WO 2015189853A1
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Prior art keywords
drug
polymer
intrauterine device
drug reservoir
suture
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PCT/IN2014/000494
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English (en)
Inventor
Rajnikant Gandalal Vyas
Pramod Kumar Minocha
Nilay Mohanlal LAD
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Meril Endo Surgery Private Limited
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Publication of WO2015189853A1 publication Critical patent/WO2015189853A1/fr

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    • 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
    • A61K9/0039—Devices retained in the uterus for a prolonged period, e.g. intrauterine devices for contraception
    • 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
    • A61F6/00—Contraceptive devices; Pessaries; Applicators therefor
    • A61F6/06—Contraceptive devices; Pessaries; Applicators therefor for use by females
    • A61F6/14—Contraceptive devices; Pessaries; Applicators therefor for use by females intra-uterine type
    • A61F6/142—Wirelike structures, e.g. loops, rings, spirals
    • A61F6/144—Wirelike structures, e.g. loops, rings, spirals with T-configuration

Definitions

  • the present invention relates to an Intrauterine system (IUS) / Intrauterine device (IUD) for effective method of contraception which also prevents the pelvic and vaginal infections. More particularly, the invention relates to an (IUS) / (IUD) which comprises T frame made of low density polyethylene (LDPE) which has drug reservoir containing progestogen or a drug with progestogenic activity to provide effective contraception where the lower end of the T frame is provided with a suture thread which is coated with at least one antimicrobial agent capable of preventing pelvic and vaginal infections which are likely to occur post implantation.
  • LDPE low density polyethylene
  • thermoplastics became the materials of choice for first generation IUDs as they possessed sufficient resilience and flexibility.
  • Some scientists added monofilament nylon string to the IUD to facilitate its removal.
  • the efficacy of these plastic devices as contraceptives was not high as the pregnancy rates were much higher.
  • the frequency of bacterial infection post implantation of the device was also significantly high.
  • the invention of the copper IUD in the 1960s with the T shaped design proved most appropriate and this design is now used in modern IUDs. shape works better as this shape is compatible with the shape of the uterus, which forms a T when contracted. This also reduces the incidents of IUD expulsion. It was also established that copper could be an effective spermicide. However, the copper IUDs are reported to cause increased menstrual bleeding, which led to invention of IUDs with hormones (hormonal IUDs) in 1960s and 1970s to prevent this side effect. The hormonal IUDs offered additional benefits over the oral contraceptive pills. The hormonal IUDs delivered the drug locally in the uterus unlike the systemic release in case of oral contraceptive pills (OCP's).
  • IUDs the dose of the drug in IUDs was less compared to OCPs as most of the drug was released where it was most effective. This helped significantly in reducing the side effects caused by higher drug dose of the oral contraceptive pills. None of these IUDs were, however, able to prevent the risk of pelvic and vaginal infection which occur post implantation.
  • the IUDs are provided with suture thread to facilitate its removal.
  • Vagina harbors many microorganisms that can cause many infectious diseases.
  • the suture of IUD extends from uterus to the vagina, the microorganisms grow on this suture thread and carry the infection into uterus causing the pelvic inflammatory disease.
  • STD sexually transmitted disease
  • This risk of infection is very high in the first twenty days after insertion of IUD. Up to 10 women per 1000 who undergo insertion acquire PID and/or STD. The risk reduces considerably after this period (about 1.4 women per 1000 undergoing insertion).
  • PID that occurs after insertion of IUD is caused by polymicrobial infection usually involving anaerobic bacteria from the cervix and vagina causing bacterial vaginosis, cervicitis, and contamination of the endometrial cavity at insertion site (Farley et al., 1992 Mar 28; 339 (8796): 785-8, Walsh et al., Lancet. 1998; 351(9108):1005, Trussell et al., Contraceptive Technology.2007; 19 th edition, Speroff et al., Clinical Guide for Contraception, 2001 ; 3rd ed.).
  • Neisseria gonorrhoeae and Chlamydia trachomatis are the most important causative organisms associated with PID and account for 60-80% of cases in women less than 25 years of age (Mardh et al., microbial etiology of pelvic inflammatory disease, Sex Transm. Dis. 1984; 1 1(S4): 428-9, Westrom et al., "Pelvic inflammatory disease: bacteriology and sequelae", Contraception. 1987; 36: 1 1 1-28, Kirshon et al., "Correlation of ultrasonography and bacteriology of the endocervix and posterior cul-de-sac of patients with severe pelvic inflammatory disease", Sex Transm. Dis. 1988; 15: 103-7, Hoosen et al., "Sexually transmitted pathogens in acute pelvic inflammatory disease” S .Afr. Med. J. 1989; 76: 251-4.)
  • PID pelvic inflammatory disease
  • Antibiotics chosen should be effective against Chlamydia trachomatis and Neisseria gonorrhoeae, as well as against gram-negative facultative organisms, anaerobes, and streptococci.
  • Orally administered drugs used in the therapy consist of compounds from various groups of broad spectrum antibiotics such as macrolides, cephalosporins, tetracycline, lincosamide antibiotics, imidazole ring-based antibiotics, aminoglycosides, penicillin, uricosuric agents etc.
  • Use of drugs other than broad spectrum antibiotics to treat PID like antimicrobial agents has shown little success.
  • the oral route of administration of drugs to treat PID is reported to cause various side effects which include troubled breathing, hives, unusual bleeding or bruising, diarrhea, vomiting, nausea etc.
  • EP 0082894 relates to a method of making an IUD with drug release element comprising a formable silicone rubber as a carrier material and a non-medicated relatively stable platform for intrauterine placement.
  • This invention comprises of levonorgestrel as drug for contraception combined with room temperature vulcanizing silicon rubber encased in silicone tubing. This invention, however, does not teach any method for preventing the risk of PID and pelvic and vaginal infections which occur in the first few weeks after the implantation.
  • US 201 1/0146693 relates , to a method for contraception and for reducing menstrual problems and for inducing amenorrhea wherein an intrauterine device is used for controlled release of a combination of progestogen or a drug having a progestogenic activity and at least one therapeutically active substance capable of preventing or suppressing abnormal and/or irregular endometrial bleeding over a prolonged period of time.
  • US' 693 further describes use of a drug reservoir having a drug with progestogenic activity namely levonorgestrel and a polymer composition of siloxane and therapeutic amount of tranexamic acid. This invention does not teach any method for preventing the risk of PID and/or pelvic and vaginal infections that occur for the first few weeks after the implantation.
  • the object of the present invention is to provide Intrauterine system (IUS) / Intrauterine device (IUD) which can prevent pelvic and vaginal infections which are likely to occur post implantation.
  • IUS Intrauterine system
  • IUD Intrauterine device
  • Another objective of the present invention is to provide an effective method of contraception.
  • Yet another objective of the present invention is to provide an effective method of preventing or suppressing abnormal and/or irregular endometrial bleeding.
  • Yet another objective of the present invention is to provide manufacturing method of such IUS/IUD. '
  • the instant invention provides an Intrauterine system (IUS)/ Intrauterine device (IUD) which comprises T frame made of biocompatible polymer with its lower end consisting a suture thread which is coated with at least one antimicrobial agent capable of preventing pelvic and vaginal infections that are likely to occur post implantation in addition to providing effective method of contraception and preventing or suppressing abnormal and/or irregular endometrial bleeding.
  • IUS Intrauterine system
  • IUD Intrauterine device
  • the IUS/IUD of present invention comprises a T frame made of Low density polyethylene (LDPE) and a drug reservoir mounted on the T frame.
  • the drug reservoir contains a progestogen, or a drug having progestogenic activity, for controlled release over a specific period of time in a concentration required for contraception.
  • one or more therapeutically active substances capable of preventing or suppressing abnormal and/or irregular endometrial bleeding may also be provided in the drug reservoir which also get released over a specific period of time.
  • the drag reservoir is further provided with a permeable polymer membrane on its outer surface.
  • the said T frame has a suture thread tied to it at its lower end.
  • vagina harbors many microorganisms that can cause many infectious diseases.
  • the suture of IUD extends from uterus to the vagina, the microorganisms will grow on this suture thread and carry the infection into uterus causing the pelvic inflammatory disease.
  • This inflammatory disease is conventionally treated with a course of antimicrobial agents, preferably antibiotics and the treatment lasts for two or more weeks.
  • the suture thread attached to the IUD of present invention is coated with sufficient amount of one or more active therapeutic substances capable of preventing PID/pelvic and vaginal infections which may occur post implantation.
  • the active therapeutic substance includes preferably an antimicrobial agent. The said antimicrobial agent is released from the suture in controlled manner over the period of time till the risk of PID/pelvic and vaginal infections becomes very low.
  • Conventional treatment for preventing PID/pelvic and vaginal infections is by oral administration of the antimicrobial agents.
  • the amount of the antimicrobial agents used to coat the suture of the present invention is much lower compared to that prescribed for oral administration.
  • the oral dose varies from 100 mg to 2 gm per day for 14 days. This means that the total drug intake by oral administration will be in the range of 1.4 gm to 28 gm.
  • the total amount of the drug coated on the suture as per present invention is maximum 200 ⁇ g and this drug is released in controlled manner.
  • the antibiotics taken orally in higher doses can cause undesirable side effects due to their systemic circulation in the blood.
  • the present invention contemplates an intrauterine system that not only provides a method of effective contraception and preventing or suppressing abnormal and/or irregular endometrial bleeding but also eliminates the risk of pelvic and vaginal infection, in particular pelvic inflammatory disease post implantation.
  • the invention provides method of making the said intrauterine device and the method of coating a suture with antimicrobial therapeutic agent which provides controlled release.
  • the antimicrobial therapeutic agents used to coat the suture according to the invention are capable of preventing the pelvic and vaginal infections.
  • FIG 1 illustrates the intrauterine system comprising a T frame (1) with a hole at the lower end of the frame for tying the suture (5), the drug reservoir (2), the permeable polymer membrane (3), and the suture (4).
  • FIG 2 illustrates a flow diagram which describes the method of making the intrauterine system as per the present invention.
  • FIG 3 is a graphical representation of the release pattern of triclosan from the device as per the present invention.
  • the present invention provides an Intrauterine system (IUS)/ Intrauterine device (IUD) which comprises T frame with lower end consisting a suture thread which is coated with at least one antimicrobial agent capable of preventing pelvic and vaginal infections that are likely to occur post implantation in addition to providing effective method of contraception and also preventing or suppressing abnormal and/or irregular endometrial'bleeding.
  • IUS Intrauterine system
  • IUD Intrauterine device
  • the invention provides a method of eliminating risk of the pelvic and vaginal infections in addition to an effective method of contraception which method comprises inserting IUD having a T frame (1) made of Low Density Polyethylene (LDPE) with its lower end consisting of a suture thread (4) coated with at least one antimicrobial agent capable of preventing pelvic and vaginal infections to a female in need thereof.
  • LDPE Low Density Polyethylene
  • the invention provides use of an intrauterine device (IUD) having a T frame (1) made of Low Density Polyethylene (LDPE) with its lower end consisting of a suture thread (4) coated with at least one antimicrobial agent for preventing pelvic and vaginal infections to a female in need thereof.
  • IUD intrauterine device
  • T frame (1) made of Low Density Polyethylene (LDPE) with its lower end consisting of a suture thread (4) coated with at least one antimicrobial agent for preventing pelvic and vaginal infections to a female in need thereof.
  • LDPE Low Density Polyethylene
  • the Intrauterine system (IUS) / Intrauterine device (IUD) consists of a T frame (1 in Fig-1) made of Low Density Polyethylene (LDPE) with its lower end provided with a suture thread (4 in Fig-1) coated with at least one antimicrobial agent capable of preventing pelvic and vaginal infections, to a female in need thereof.
  • LDPE Low Density Polyethylene
  • the invention provides an intrauterine device (IUD) which comprises a T frame (1) made of Low Density Polyethylene (LDPE) and a drug reservoir mounted on the T frame.
  • the drug reservoir contains a progestogen or a drug having progestogenic activity for controlled release over a specific period of time in a concentration required for effective contraception.
  • the drug reservoir may contain therapeutically active substances capable of preventing or suppressing abnormal and/or irregular endometrial bleeding.
  • the drug reservoir has a permeable membrane provided on the outer surface.
  • the T frame on its lower end, is provided with a hole where a suture thread coated with sufficient amount of one or more active therapeutic substances capable of preventing PID/pelvic and vaginal infections post implantation is fixed.
  • the T frame is made from low density polyethylene (LDPE) by injection molding process wherein barium sulfate is added in LDPE to get radio opacity for visualization of the device under X-ray imaging and/or ultrasound.
  • LDPE low density polyethylene
  • the IUS/IUD comprises of a T frame and a drug reservoir mounted on the T frame.
  • the drug reservoir contains a , formulation of progestogen or drug having a progestogenic activity in a polymer for effective contraception.
  • the drug reservoir may contain therapeutically active substances capable of preventing or suppressing abnormal and/or irregular endometrial bleeding.
  • the polymer used in the formulation acts as carrier and allows controlled release of the drug.
  • the drug reservoir is surrounded by a permeable polymer membrane to further control the drug release.
  • the carrier polymer and the polymer of permeable membrane are made of elastomers which harden at room temperature following the addition of cross-linking agents and one or more curing catalysts to yield a polymeric matrix.
  • the carrier polymer should be biocompatible and can be biodegradable or bio- stable.
  • the carrier polymers include but are not limited to ethylene vinyl acetate copolymers, polyurethanes, polytetrafluoroethylene (PTFE), polypropylenes, hydrophilic hydrogels, poly (lactic acid), neoprene rubber, room temperature vulcanized (RTV) silicone rubber, copolymers of dimethylsiloxanes, methylvinylsiloxanes, and polysiloxanes.
  • the carrier polymer and permeable polymer used in drug reservoir are polysiloxanes, in particular poly (dimethyl siloxanes) (PDMS).
  • PDMS poly (dimethyl siloxanes)
  • Progestogens are therapeutically active substances having progestogenic activity with contraceptive effect.
  • the progestogenic compound include a steroidal progestogenic compound such as progesterone and its derivatives, desogestrel, etonogestrel, levonorgestrel, lynestrenol, medroxyprogesterone acetate, norethisterone, norethisterone acetate, norgestimate, drospirenone, gestodene, 19- nor-17-hydroxy progesterone esters, 17 a-ethinyltestosterone and derivatives thereof, 17 a-ethinyl- 19-nor-testosterone and derivatives thereof, ethynodiol diacetate, dydrogesterone, norethynodrel, allylestrenol, medrogestone, norgestrienone, ethisterone and dl-norgestrel.
  • a steroidal progestogenic compound such as progesterone and its derivatives, desoges
  • the progestogenic compound is levonorgestrel.
  • the release kinetics of the progestogenic drug can be tailored by choice of the polymer carrier as well as the permeability of the membrane. With right choice of the carrier and the permeability of the membrane, the release of the drug can be achieved at controlled rate over 5 or more years for continued effective contraception.
  • the slow and controlled release of the drug is achieved in two stages. First stage is diffusion of the drug from the carrier polymer matrix. Once the drug has diffused out from the carrier polymer matrix, it has to permeate out through the membrane in a controlled manner.
  • a hole is provided at the lower end of the T frame (5 in Fig 1) wherein a suture thread is tied to facilitate the removal of the IUD from the uterus.
  • This suture thread extends from uterus up to vagina.
  • This suture can be made from biocompatible and bio-stable polymers.
  • the suture thread can be mono filament or multifilament.
  • Bio-stable polymers that can be used to make the suture include but are not limited to silk, polyamide, polypropylene, cotton, polyolefins, polyethylene terephthalate, and polyethylene.
  • the suture thread made from aforesaid non-bioabsorbable polymer is coated with at least one antimicrobial agent which is released in controlled manner in such a way as to prevent the pelvic and vaginal infections for the first few weeks of post implantation of IUD/IUS.
  • the antimicrobial agent includes antibiotics, antiseptics, disinfectants and combinations thereof that are soluble in water or in organic solvents like alcohols, ketones, ethers, aldehydes, acetonitrile, acetic acid, methylene chloride, chloroform etc.
  • Antibiotics that can be used for the antimicrobial coating include tetracyclines like minocycline; rifamycins like rifampin; macrolides like erythromycin; penicillins like nafcillin; cephalosporins like cefazolin; beta-lactam like imipenem and aztreonam; aminoglycosides like gentamicin and TOBRAMYCIN®; chloramphenicol; sulfonamides like sulfamethoxazole; glycopeptides like vancomycin; quinolones like ciprofloxacin; fusidic acid; trimethoprim; metronidazole; clindamycin; mupirocin; polyenes like amphotericin B; azoles like fluconazole; and beta-lactam inhibitors like sulbactam.
  • antiseptics and disinfectants which may be used for the antimicrobial coating include hexachlorophene; cationic biguanides like chlorhexidine and cyclohexidine; iodine and iodophores like povidoneiodine; halo-substituted phenolic compounds like PCMX (i.e. p-chloro-m-xylenol) and triclosan (i.e. 2,4,4'-trichloro2'hydroxy- diphenylether); furan medical preparations like nitrofurantoin and nitrofurazone; methenamine; aldehydes like glutaraldehyde and formaldehyde; and alcohols.
  • PCMX i.e. p-chloro-m-xylenol
  • triclosan i.e. 2,4,4'-trichloro2'hydroxy- diphenylether
  • furan medical preparations like nitrofurantoin and nitrofur
  • triclosan is used as antimicrobial agent.
  • Triclosan and its compositions are known to act as intravaginal micro-biocides for preventing and treating sexually transmitted diseases.
  • Triclosan is also effective against Neisseria gonorrhoeae and Chlamydia trachomatis when used in pharmaceutical preparation/solution in conjunction with other excipients.
  • bio-compatible polymers are used as excipients for the antimicrobial coating.
  • These polymers include but are not limited to polymers of glycolides, lactides, caprolactones, trimethylene carbonate, dioxanones, dioxepanones, and copolymers and combinations thereof.
  • poly (D,L- Lactide) wherein the ratio of poly D-lactide: poly L-lactide in 50:50 is used as excipient.
  • the antimicrobial coating can be applied to the suture as solution in suitable solvent.
  • the solvent used for making this solution should dissolve the antimicrobial agent, should not interact with any polymeric material/s used for the suture and should have low volatility for easy evaporation after the coating process is completed.
  • suitable solvents include alcohols, ketones, ethers, aldehydes, acetonitrile, acetic acid, methylene chloride, chloroform and water.
  • methylene chloride is used as solvent.
  • Preparing the antimicrobial solution is a relatively simple process and can be accomplished by simple blending and mixing of all ingredients till total dissolution occurs.
  • triclosan and excipient polymer are dissolved in methylene chloride by simple mixing operation.
  • the specific polymer used as excipient and its amount used for coating controls the rate of release of the drug from suture.
  • the drug release occurs by drug diffusing out from the polymer matrix.
  • Using a biodegradable polymer will enhance the release rate compared to a biostable polymer. Degradation rate of the polymer will also influence the drug release rate.
  • the drug release rate can be tailored by choice of the polymer and its amount relative to the drug.
  • the T frame reservoir/s may be manufactured simultaneously with the T frame or separately followed by their assembly.
  • the T frame is made preferably from low density polyethylene, compounded with barium sulphate by injection or compression molding.
  • the drug reservoir contains therapeutic agents in polymer matrix.
  • the drug reservoir is in the shape of a hollow cylinder which can be formed by processes such as moulding, casting, extrusion, or by any other appropriate method/s known in the art.
  • the polymer matrix may consist of the polymeric compounds with desired properties.
  • the polymer matrix can be formed from a mixture of components like elastomer/carrier polymer, cross linking agent and the catalyst which can generate polymer with desired properties.
  • Cross linking agents may include compounds like tetramethyl silicate, tetraethyl silicate, tetra-n-propyl silicate, methyltriethoxysilane, n- propyitrimethoxysilane, n-propyltriethoxysilane, and phenyltriethoxysilane.
  • Catalysts may include platinum or tin based catalysts more preferably stannous octoate.
  • the first step in making the drug reservoir is mixing the therapeutic agent/s with the polymer or with the polymer forming components in specific sequence.
  • the mixture is then processed by extrusion or similar process to get desired shape of the reservoir,
  • the mixture to form the drug reservoir may consist of 30% to 65 % by weight of progestogen or any drug having progestogenic activity, 20 % to 60 % by weight of elastomer, 0.5 % to 5 % by weight of cross linking agent, and 0.1 % to 1 % by weight of catalyst.
  • the mixture to form the drug reservoir may contain 40% to 55 % by weight of progestogen or drug having progestogenic activity, 30 % to 55 % by weight of elastomer, 0.1 % to 3 % by weight of cross linking agent, and 0.2 % to 0.7 % by weight of catalyst.
  • the mixture is then extruded to form the drug reservoir in the form of a hollow cylindrical tube.
  • This tube is fixed on the T frame by sliding it over the T frame.
  • its diameter is increased by applying pressure or by swelling it in a suitable solvent such as cyclohexane, diglyme, isopropanol, or in a mixture of these solvents.
  • the reservoir can then be fixed on the T frame by simply sliding it over the shaft of the T frame. When the solvent evaporates, the drug reservoir tightens on the T frame providing adequate grip.
  • the polymer membrane is then mounted on the drug reservoir.
  • the polymer membrane can be fixed onto the drug reservoir by various methods such as (a) by extrusion of this membrane polymer simultaneously with the drug reservoir, (b) by spraying the solution of the membrane polymer in suitable solvent such as methylene chloride on the drug reservoir, followed by evaporation of the solvent or (c) by dipping the reservoir into the solution of the membrane polymer in suitable solvent such as methylene chloride followed by evaporation of the solvent.
  • the polymer membrane can be in the form of prefabricated polymer tubing.
  • This tubing is fixed on the drug reservoir by first increasing its diameter and then simply sliding it over the drug reservoir.
  • the diameter of the permeable polymer tube can be increased mechanically or by swelling in a suitable solvent such as cyclohexane, diglyme, isopropanol, or in a mixture of solvents.
  • the mechanical methods may include use of a suitable device or by pressurizing it using an inert gas or air. The care should be taken not to exceed elastic limit of the tube so that the tube regains the original diameter and grips the reservoir tube on removal of mechanical force or releasing the gas pressure. If the diameter is increased by solvent swelling, the tube regains the original diameter when the solvent evaporates so that the permeable polymer tubing tightens on the drug reservoir with adequate grip.
  • the length of the T frame is normally in the range of 15 to 45 mm, preferably from 30 to 38 mm.
  • the width of the T frame is normally in the range of 20 to 32 mm which corresponds generally to the width of the fundal portion of the endometrial cavity.
  • the diameter of the T frame preferably ranges from 1mm to 2 mm.
  • the length of the drug reservoir of the IUD can be from 5 mm to 30 mm, more preferably from 15 mm to 25 mm.
  • the thickness of the drug reservoir can be in the range of 1.4 mm to 1.8 mm.
  • the thickness of the permeable polymer membrane can be in the range of 0.1mm to 0.5mm depending on the permeability of the polymer.
  • the release rate of levonorgestrel from the intrauterine devices was measured using high performance liquid chromatography (HPLC) and it ranged from 10 micrograms/day to 28 micrograms/day.
  • HPLC high performance liquid chromatography
  • suture 4 is tied at the lower end 5 of the T frame as depicted in Fig 1.
  • This suture is made of biocompatible and bio-stable polymer.
  • the suture thread can be mono filament or multifilament; preferably monofilament.
  • the suture mentioned herein is provided with antimicrobial coating that contains suitable antimicrobial agent like triclosan.
  • suitable antimicrobial agent like triclosan.
  • the amount of the antimicrobial agent in the antimicrobial coating depends upon a number of factors, such as the effectiveness of the agent, the type and composition of the suture, the choice of excipient and release rate of the antimicrobial agent.
  • a formulation of the antimicrobial agent is used for coating the suture.
  • the antimicrobial coating formulation is a solution of the antimicrobial agent and a biocompatible copolymer in a suitable solvent like methylene chloride or toluene. After coating this solution on the suture, the solvent is removed by evaporation.
  • the coating will hence consist of the antimicrobial agent in the polymer matrix.
  • the polymer matrix will provide controlled release of the antimicrobial agent by diffusion process. The rate of release of the antimicrobial agent from the suture depends on the type of polymer used and the concentration of the antimicrobial agent in the polymer matrix.
  • the polymer used for formulation should be biocompatible and can be bio-stable or bio-degradable, preferably biodegradable.
  • the concentration of the antimicrobial agent and the polymer in the solution may vary from 0.01% to 30% and from 10% to 40% respectively.
  • the concentration of the antiseptic compound in the formulation solution was in the range of 0.5% to 15% by weight.
  • the concentration of biocompatible co-polymer in this case ranged from 20% to 35%.
  • the coating formulation solution had 5% to 12% by weight of the chosen antimicrobial agent and 25% to 32% of the biocompatible co-polymer.
  • the antimicrobial agent was triclosan and the biocompatible co- polymer was poly (D,L- Lactide).
  • concentration of triclosan in the formulation solution was in the range of 5% to 10% by weight in methylene chloride as solvent.
  • concentration of polymer in this formulation was 25% to 30% by weight in methylene chloride.
  • the antimicrobial coating herein can be applied to a suture by any suitable process, e.g., by dip coating or by passing the suture through the formulation solution at specific rate to get desired loading of the therapeutic agent and the polymer on the suture uniformly across the entire length of the suture.
  • suitable process e.g., by dip coating or by passing the suture through the formulation solution at specific rate to get desired loading of the therapeutic agent and the polymer on the suture uniformly across the entire length of the suture.
  • Other ways of application are taking the suture past a brush or any other suitable applicator or by spray coating from one or more spray nozzles dispensing the suture coating solution.
  • the suture wetted with the coating solution is subsequently passed through or held in a drying oven for a time and at a temperature sufficient to vaporize and drive off the solvent.
  • the drying parameters are chosen such that there is no adverse effect on the antimicrobial agent.
  • the process parameters can be set to get the total triclosan content on suture ranging from 700-1600 ppm (wt/wt) with respect to suture.
  • the release of triclosan from the suture continued up to minimum 20 days, maximum 25 days.
  • the release rate of triclosan was measured by HPLC method.
  • the release pattern of triclosan was consistent for the range of concentrations given above; the average release pattern is given in Table 1 and represented graphically in Fig.3. Table 1
  • the release kinetics of triclosan can be manipulated such that the effective dose is available for required therapeutic action.
  • One skilled in the art can optimize the type of polymers used for the formulation and the drug to polymer ratio to achieve effective dose of the therapeutic agent to prevent infection causing PID over the time period till the risk becomes minimum.
  • a HDPE monofilament suture of USP 3/0 was used for coating.
  • the coating was done by dip coating process.
  • Antimicrobial coating solution consisted of 30% by weight of poly (D,L- Lactide) and 5% by weight of triclosan in methylene chloride.
  • the coated suture was then kept in drying oven at 60°C to evaporate methylene chloride.
  • the dried suture was then cut into length of 50-60 cm and was fixed onto the T frame by tying it to the hole in the T frame of the intrauterine system described in Example 1.
  • a HDPE monofilament suture of USP 3/0 was coated as described in Example 2.
  • the triclosan loading on the suture was 800 ppm (wt/wt of suture weight) which corresponded to 88 ⁇ g of triclosan.
  • the release rate was measured in-vitro using HPLC. The release pattern is shown in Table -2.
  • HDPE monofilament sutures of USP 3/0 was coated as described in Example 2.
  • the triclosan loading on the suture was 1500 ppm (wt/wt of suture weight) which corresponded to 165 ⁇ g of triclosan.
  • the release rate was measured in-vitro using HPLC.
  • the release pattern is shown in Table-3.

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  • Medicinal Preparation (AREA)

Abstract

La présente invention concerne un système intra-utérin (IUS)/dispositif intra-utérin (IUD) pour une méthode de contraception efficace qui permet également de prévenir les infections pelviennes et vaginales. Plus particulièrement, l'invention concerne un système intra-utérin (IUS)/dispositif intra-utérin (IUD) qui comprend un cadre en T dont l'extrémité inférieure est constituée d'un fil de suture qui est revêtu d'au moins un agent antimicrobien capable de prévenir les infections pelviennes et vaginales qui sont susceptibles de se produire après l'implantation.
PCT/IN2014/000494 2014-06-13 2014-07-28 Dispositif intra-utérin WO2015189853A1 (fr)

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IN1929MU2014 2014-06-13
IN1929/MUM/2014 2014-06-13

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Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP3446664A1 (fr) * 2017-08-21 2019-02-27 Karl-Heinz Kurz Dispositif intra-utérin
EP3727361A4 (fr) * 2017-12-22 2022-01-12 Alyra Biotech Pty Ltd Traitement de la douleur et/ou des symptômes liés à la douleur associés à la dysménorrhée

Citations (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0082894A1 (fr) 1981-12-30 1983-07-06 The Population Council, Inc. Procédé pour la fabrication de dispositifs intra-utérins
US4563485A (en) * 1984-04-30 1986-01-07 The Trustees Of Columbia University In The City Of New York Injection-resistant materials and method of making same through use of nalidixic acid derivatives
US4582052A (en) * 1982-03-23 1986-04-15 Repromed, Inc. Povidone-iodine dispensing fiber
EP0179518A1 (fr) * 1984-10-16 1986-04-30 Akzo N.V. Fil d'extraction pour dispositif intra-utérin
WO1996001092A1 (fr) * 1994-07-05 1996-01-18 Leiras Oy Dispositif de liberation d'un agent actif
WO2007075086A1 (fr) * 2005-12-27 2007-07-05 Willem Arthur Adriaan Van Os Dispositif intra-uterin et applicateur pour l’introduire dans l’uterus
US20110146693A1 (en) 2008-07-03 2011-06-23 Bernd Duesterberg Intrauterine delivery system for contraception

Patent Citations (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0082894A1 (fr) 1981-12-30 1983-07-06 The Population Council, Inc. Procédé pour la fabrication de dispositifs intra-utérins
US4582052A (en) * 1982-03-23 1986-04-15 Repromed, Inc. Povidone-iodine dispensing fiber
US4563485A (en) * 1984-04-30 1986-01-07 The Trustees Of Columbia University In The City Of New York Injection-resistant materials and method of making same through use of nalidixic acid derivatives
EP0179518A1 (fr) * 1984-10-16 1986-04-30 Akzo N.V. Fil d'extraction pour dispositif intra-utérin
WO1996001092A1 (fr) * 1994-07-05 1996-01-18 Leiras Oy Dispositif de liberation d'un agent actif
WO2007075086A1 (fr) * 2005-12-27 2007-07-05 Willem Arthur Adriaan Van Os Dispositif intra-uterin et applicateur pour l’introduire dans l’uterus
US20110146693A1 (en) 2008-07-03 2011-06-23 Bernd Duesterberg Intrauterine delivery system for contraception

Non-Patent Citations (8)

* Cited by examiner, † Cited by third party
Title
DATABASE BIOSIS [online] BIOSCIENCES INFORMATION SERVICE, PHILADELPHIA, PA, US; May 2000 (2000-05-01), GARD P R ET AL: "Use of chlorhexidine-releasing nylon fibres to reduce device-related uterine infections", XP002735280, Database accession no. PREV200000321465 *
HOOSEN ET AL.: "Sexually transmitted pathogens in acute pelvic inflammatory disease", S .AFR. MED. J., vol. 76, 1989, pages 251 - 4
KIRSHON ET AL.: "Correlation of ultrasonography and bacteriology of the endocervix and posterior cul-de-sac of patients with severe pelvic inflammatory disease", SEX TRANSM. DIS., vol. 15, 1988, pages 103 - 7
MARDH ET AL.: "microbial etiology of pelvic inflammatory disease", SEX TRANSM. DIS., vol. 11, no. S4, 1984, pages 428 - 9
SPEROFF ET AL.: "Clinical Guide for Contraception", 2001
TRUSSELL ET AL.: "Contraceptive Technology", 2007
WALSH ET AL., LANCET, vol. 351, no. 9108, 1998, pages 1005
WESTROM ET AL.: "Pelvic inflammatory disease: bacteriology and sequelae", CONTRACEPTION, vol. 36, 1987, pages 111 - 28, XP023167134, DOI: doi:10.1016/0010-7824(87)90064-3

Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP3446664A1 (fr) * 2017-08-21 2019-02-27 Karl-Heinz Kurz Dispositif intra-utérin
EP3727361A4 (fr) * 2017-12-22 2022-01-12 Alyra Biotech Pty Ltd Traitement de la douleur et/ou des symptômes liés à la douleur associés à la dysménorrhée
US11400059B2 (en) 2017-12-22 2022-08-02 Alyra Biotech Pty Ltd Treatment of pain and/or pain related symptoms associated with dysmenorrhea

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