WO2008023389A1 - Dispositif hormonal intra-utérin pour l'administration de lévonorgestrel - Google Patents

Dispositif hormonal intra-utérin pour l'administration de lévonorgestrel Download PDF

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Publication number
WO2008023389A1
WO2008023389A1 PCT/IN2007/000350 IN2007000350W WO2008023389A1 WO 2008023389 A1 WO2008023389 A1 WO 2008023389A1 IN 2007000350 W IN2007000350 W IN 2007000350W WO 2008023389 A1 WO2008023389 A1 WO 2008023389A1
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WIPO (PCT)
Prior art keywords
maleic anhydride
styrene maleic
anhydride copolymer
active
dmso
Prior art date
Application number
PCT/IN2007/000350
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English (en)
Inventor
Sujoy Kumar Guha
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Pregna International Ltd.
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Publication of WO2008023389A1 publication Critical patent/WO2008023389A1/fr

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    • 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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/56—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids
    • A61K31/57—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids substituted in position 17 beta by a chain of two carbon atoms, e.g. pregnane or progesterone
    • 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
    • C—CHEMISTRY; METALLURGY
    • C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
    • C08F—MACROMOLECULAR COMPOUNDS OBTAINED BY REACTIONS ONLY INVOLVING CARBON-TO-CARBON UNSATURATED BONDS
    • C08F257/00—Macromolecular compounds obtained by polymerising monomers on to polymers of aromatic monomers as defined in group C08F12/00
    • C08F257/02—Macromolecular compounds obtained by polymerising monomers on to polymers of aromatic monomers as defined in group C08F12/00 on to polymers of styrene or alkyl-substituted styrenes
    • C—CHEMISTRY; METALLURGY
    • C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
    • C08L—COMPOSITIONS OF MACROMOLECULAR COMPOUNDS
    • C08L51/00—Compositions of graft polymers in which the grafted component is obtained by reactions only involving carbon-to-carbon unsaturated bonds; Compositions of derivatives of such polymers
    • C08L51/003—Compositions of graft polymers in which the grafted component is obtained by reactions only involving carbon-to-carbon unsaturated bonds; Compositions of derivatives of such polymers grafted on to macromolecular compounds obtained by reactions only involving unsaturated carbon-to-carbon bonds

Definitions

  • the present invention relates to a hormonal intrauterine device for delivery of levonorgestrel.
  • the intrauterine device [IUD] is well known for its use as a female contraceptive. To have safer and more effective contraception, its vertical arm is provided with hormone release means called matrix and such IUD is known as hormonal IUD.
  • the known hormonal IUD comprises of a porous tubing of silicone rubber and a matrix again of silicone rubber provided on its vertical arm.
  • the active ingredient levonorgestrel is provided in said matrix. It has been found that the active ingredient - levonorgestrel in a known hormonal IUD releases by diffusion process.
  • the main drawback of such known hormonal IUD is that the release of active ingredient - levonorgestrel is non-uniform, that is, it is relatively faster in initial stage and relatively slower at a later stage, and hence the hormonal device is more effective at initial stage and less effective at later stage meaning thereby the probability of achieving effective and safer contraception is reduced at later stage.
  • hormonal IUD wherein the active ingredient - levonorgestrel is provided in a matrix which is active in nature so as to release the active ingredient - levonorgestrel by active process so as to achieve substantially complete release of active ingredient - levonorgestrel to avoid wastage thereof meaning thereby the hormonal IUD should be more economical for commercial use and should be replaced only on substantially complete release of active ingredient - levonorgestrel.
  • the main object of the present invention is to provide a hormonal IUD for delivery of active ingredient - levonorgestrel which can deliver the active ingredient in controlled and uniform manner, that is, can uniformly release active ingredient till the active ingredient is substantially completely released from the hormonal IUD, that is the hormonal IUD has substantially same contraceptive activity at initial stage as it has at the later stage meaning thereby the probability of achieving effective and safer contraception is approximately substantially same at later stage as it is at the initial stage.
  • the another main object of the present invention is to provide a hormonal IUD for delivery of active ingredient - levonorgestrel wherein the active ingredient - levonorgestrel is provided in an active matrix complex to release the active ingredient - levonorgestrel by active process, and hence, achieves substantially complete release of active ingredient - levonorgestrel to avoid wastage thereof meaning thereby the hormonal IUD for delivery of active ingredient - levonorgestrel is more economical for commercial use and is replaced only on substantially complete release of active ingredient - levonorgestrel.
  • FIG. 1 illustrates spraying of active ingredient on active complex of SMA-DMSO in accordance with one of the preferred embodiments of the present invention.
  • Figure 2 illustrates microinjection of active ingredient on active complex of SMA-DMSO in accordance with one of the preferred embodiments of the present invention.
  • FIG. 3 illustrates active matrix comprising active ingredient and active complex of SMA-DMSO in accordance with one embodiment of the present invention.
  • Figure 4 illustrates active matrix comprising active ingredient and active complex of SMA-DMSO in accordance with another embodiment of the present invention.
  • FIG. 5 illustrates active matrix comprising active ingredient and active complex of SMA-DMSO in accordance with still another embodiment of the present invention.
  • Figure 6 illustrates active matrix comprising active ingredient and active complex of SMA-DMSO in accordance with yet another embodiment of the present invention.
  • Figure 7 illustrates hormonal IUD comprising a T' provided with active matrix comprising active ingredient and active complex of SMA-DMSO in accordance with one embodiment of the present invention.
  • Figure 8 illustrates hormonal IUD comprising a T' provided with active matrix comprising active ingredient and active complex of SMA-DMSO in accordance with another embodiment of the present invention.
  • Figure 9 illustrates hormonal IUD comprising a T' provided with active matrix comprising active ingredient and active complex of SMA-DMSO in accordance with still another embodiment of the present invention wherein the active matrix is covered by a silicon tube.
  • Figure 10 illustrates hormonal IUD comprising a T' provided with active matrix comprising active ingredient and active complex of SMA-DMSO in accordance with yet another embodiment of the present invention.
  • Figure 11 illustrates hormonal IUD comprising a T' provided with active matrix comprising active ingredient and active complex of SMA-DMSO in accordance with further embodiment of the present invention.
  • Figure 12 illustrates proton Nuclear Magnetic Resonance [NMR] of SMA copolymer in accordance with one of the embodiments of the present invention.
  • Figure 13 illustrates formation of bulging in the active matrix in accordance with one of the embodiments of the present invention.
  • the known hormonal IUD devices have limitations in achieving controlled and uniform and complete release of an active ingredient to have safer and effective contraception and being economical for commercial use. It has been observed that for safer and effective contraception and other medical applications, the hormonal IUD device is required to be capable of releasing the active ingredient uniformly at a controlled rate in the range varying from about 10 ⁇ g/day to about 60 ⁇ g/day for a period varying upto about 6 years.
  • release rate with variation of about + 20% should be capable of having safer and effective contraception.
  • the hormonal IUD device with release rate of about 10 ⁇ g/day to 60 ⁇ g/day with variation of about 20% is expected to have safer and effective contraception. Further, such release rate is required to be controlled and maintained till substantially complete active ingredient is released.
  • the known hormonal IUD devices have been found unsuitable for achieving controlled, uniform and complete release of an active ingredient, and hence, have been found unsuitable for achieving safer and effective contraception and still being economical for commercial use.
  • hormonal IUD devices Based on the teaching of known hormonal IUD devices, it is not possible to arrive at hormonal IUD device having controlled and uniform release of active ingredient for a longer period. Further, it is also difficult to arrive at hormonal IUD device having controlled and uniform release of active ingredient with variation of about + 20% for a period varying upto about 6 years.
  • hormonal IUD device capable of releasing substantially completely the active ingredient so as to render it suitable for replacement only on target time, and hence, make it economical for commercial use.
  • the aim of the present invention is to provide hormonal IUD device satisfying above requirements and being suitable to have in-vivo control of release rate of active ingredient by having a suitable mechanism capable of controlling the in-vivo release of active ingredient, and having a matrix which itself is capable of controlling the in-vivo release of active ingredient to achieve not only its controlled and uniform release, but also the continuous release till the active ingredient is substantially completely released for achieving safer and effective contraception and still being economical for commercial use.
  • the present invention relates to a hormonal IUD comprising active matrix capable of releasing active ingredient - levonorgestrel in controlled and uniform manner till the active ingredient is substantially completely released from the hormonal IUD, that is the presently disclosed hormonal IUD has substantially same contraceptive activity at initial stage as it has at the later stage meaning thereby the' probability of achieving more effective and safer contraception is approximately substantially same at later stage as it is at the initial stage.
  • the presently disclosed hormonal IUD for delivery of active ingredient - levonorgestrel comprises active matrix to release active ingredient - levonorgestrel by active process, and hence, achieves substantially complete release of active ingredient - levonorgestrel to avoid wastage thereof meaning thereby the presently disclosed hormonal IUD for delivery of active ingredient - levonorgestrel is more economical for commercial use and is replaced only on substantially complete release of active ingredient - levonorgestrel.
  • the present invention relates to a hormonal intrauterine device [IUD] for controlled and uniform delivery of active ingredient - levonorgestrel comprising an active matrix provided on or provided in vertical arm of the intrauterine device, wherein the active matrix comprises active complex and active ingredient, wherein active complex consists of styrene maleic anhydride copolymer [SMA] and dimethyl sulfoxide [DMSO].
  • IUD hormonal intrauterine device
  • active matrix comprises active complex and active ingredient
  • active complex consists of styrene maleic anhydride copolymer [SMA] and dimethyl sulfoxide [DMSO].
  • the active complex, active matrix, active ingredient and intrauterine device [T'] for presently disclosed hormonal intrauterine device [IUD] are characterized by following novel and inventive features.
  • Another aim of the present invention is to solve this problem of commercially available SMA by proposing specific SMA, which can also solve the problems of non-uniform release and incomplete release of active ingredient.
  • the present invention is based on the finding that a straight chain styrene maleic anhydride copolymer is capable of releasing an active ingredient faster than the cross-linked styrene maleic anhydride copolymer, therefore, if straight chain styrene maleic anhydride copolymer is used the active ingredient has been found to be released at a faster rate, thereby, resulting in achieving the contraception at faster rate, but for shorter duration, which requires early replacement of hormonal IUD, and if cross- linked styrene maleic anhydride copolymer is used the active ingredient has been found to release at a slower rate which has been found to be insufficient to achieve safer and effective contraception and this finding makes it possible, by a judicious choice, to have a synergistic mixture of straight chain styrene maleic anhydride copolymer and cross-linked styrene maleic anhydride copolymer which has been surprisingly found to be capable of releasing the active ingredient
  • an active complex of SMA-DMSO which is suitable for controlled and uniform release of active ingredient in abovementioned range having abovementioned variation for a longer period varying upto about 6 years to have safer and effective contraception on one hand, and capable of maintaining uniform release of the active ingredient till active ingredient is substantially completely released to have economical device for commercial use on another hand
  • styrene maleic anhydride copolymer in active complex judiciously, comprises straight chain styrene maleic anhydride copolymer, however, not exceeding a certain limit beyond which the active complex will release the active ingredient at a faster rate, thereby, result in achieving the contraception at faster rate, but for shorter duration and will require early replacement of hormonal IUD, and cross-linked styrene maleic anhydride copolymer, however again this also, not exceeding a certain limit beyond which the active complex will release the active ingredient at a slower rate, thereby, resulting in in-effective contraception for a longer
  • the styrene maleic anhydride copolymer in active complex of present invention consisting of styrene maleic anhydride copolymer and DMSO comprises synergistic mixture of straight chain styrene maleic anhydride copolymer and cross- linked styrene maleic anhydride copolymer in an amount which is capable of releasing the active ingredient at a controlled and uniform rate so as to achieve availability of desired amount of active ingredient at controlled and uniform rate which is suitable for achieving safer and effective contraception not only at controlled and uniform rate, but also for a longer duration.
  • the styrene maleic anhydride copolymer in active complex comprises higher amount of straight chain styrene maleic anhydride copolymer and lower amount of cross-linked styrene maleic anhydride copolymer so that the release rate of active ingredient is capable of achieving safer and effective contraception not only at faster rate, but also for a longer duration.
  • the styrene maleic anhydride copolymer in active complex comprises straight chain styrene maleic anhydride copolymer in an amount varying from about 55% to about 85% of the total styrene maleic anhydride copolymer.
  • the styrene maleic anhydride copolymer in active complex comprises cross-linked styrene maleic anhydride copolymer in an amount varying from about 15% to about 45% of the total styrene maleic anhydride copolymer amount.
  • the styrene maleic anhydride copolymer in active complex comprises straight chain styrene maleic anhydride in an amount varying from about 65% to about 75% of the total styrene maleic anhydride and cross-linked styrene maleic anhydride in an amount varying from about 25% to about 35% of the total styrene maleic anhydride amount.
  • the styrene maleic anhydride copolymer predominantly comprising straight chain styrene maleic anhydride copolymer was mixed with DMSO wherein it was observed that straight chain styrene maleic anhydride copolymer partially converts to cross-linked styrene maleic anhydride copolymer and forms complex of SMA-DMSO, wherein the styrene maleic anhydride copolymer comprises straight chain styrene maleic anhydride copolymer as well as cross-linked styrene maleic anhydride copolymer.
  • this complex does not comprise sufficient amount of cross-linked styrene maleic anhydride copolymer required for controlled and uniform release of active ingredient from the active matrix prepared from such complex.
  • the styrene maleic anhydride copolymer predominantly comprising straight chain styrene maleic anhydride copolymer is mixed with
  • the active complex of SMA-DMSO may be used either as gel or used as powder after drying the gel form of SMA-DMSO complex.
  • the present invention relates to a process for preparation of active complex of styrene maleic anhydride copolymer [SMA] and DMSO, comprising mixing styrene maleic anhydride copolymer predominantly comprising straight chain styrene maleic anhydride copolymer with DMSO from which active complex of SMA-DMSO in the form of gel is precipitated out by addition of water, wherein the styrene maleic anhydride copolymer in the active complex comprises straight chain styrene maleic anhydride copolymer as well as cross-linked styrene maleic anhydride copolymer.
  • SMA styrene maleic anhydride copolymer
  • the styrene maleic anhydride copolymer comprising straight chain styrene maleic anhydride copolymer and cross-linked styrene maleic anhydride copolymer on mixing with DMSO forms gel form of active complex of SMA-
  • the present invention relates to a process for preparation of active complex of styrene maleic anhydride copolymer [SMA] and DMSO, comprising mixing styrene maleic anhydride copolymer comprising straight chain styrene maleic anhydride copolymer and cross-linked styrene maleic anhydride copolymer with DMSO to form gel form of active complex of SMA-DMSO.
  • SMA styrene maleic anhydride copolymer
  • DMSO cross-linked styrene maleic anhydride copolymer
  • the styrene maleic anhydride copolymer comprising straight chain styrene maleic anhydride copolymer and cross-linked styrene maleic anhydride copolymer on mixing with DMSO forms gel form of active complex SMA- DMSO, which on spraying water followed by drying results in preparation of powder form of active complex of SMA-DMSO.
  • the present invention relates to a process for preparation of active complex of styrene maleic anhydride copolymer [SMA] and DMSO, comprising mixing styrene maleic anhydride copolymer comprising straight chain styrene maleic anhydride copolymer and cross-linked styrene maleic anhydride copolymer with DMSO to form gel form of active complex of SMA-DMSO, which on spraying water followed by drying results in preparation of powder form of active complex of SMA-DMSO.
  • SMA styrene maleic anhydride copolymer
  • the styrene maleic anhydride copolymer and DMSO are taken in a ratio varying from about 1:1 to about 1:4 weight (in mg) /volume (in ⁇ l), preferably in a ratio of about 1:3 weight (in mg) /volume (in ⁇ l).
  • the styrene maleic anhydride copolymer is mixed with DMSO in a ratio varying from about 1: 1 to about 1:4 weight/ volume, preferably in a ratio of about 1:3 weight/ volume.
  • the SMA to DMSO ratio has been found to influence the corsslinking during formation of active complex of SMA-DMSO and to hold the active ingredient in the active matrix prepared from such active complex.
  • the former increasing with lower ratio and the later increasing with higher ratio have been found to give balance of both requirements.
  • the active complex is in any one of the forms selected from a group of gel form, powder form and layer form.
  • the viscous SMA-DMSO active complex is spread on a flat platform, preferably on a cleaned glass plate to form a SMA-DMSO active complex layer.
  • the SMA employed in present invention is free of styrene maleic acid copolymer.
  • styrene maleic acid copolymer upto 5% of the SMA does not create any problem.
  • the relative amounts of straight chain styrene maleic anhydride copolymer and cross-linked styrene maleic anhydride copolymer in the styrene maleic anhydride copolymer can be controlled by any means. However, in accordance with present invention, it can be controlled by controlled hydrolysis of straight chain styrene maleic anhydride copolymer to cross-linked styrene maleic anhydride copolymer by addition of water which has been found to cause hydrolysis of the maleic groups resulting in physical crosslinking by hydrogen bonds. Such crosslinking has been found to have advantage of entrapping active ingredient in the spaces formed between SMA chains.
  • amount of water to be added to complex of SMA-DMSO is determined by visual observation of formation of a white coloured complex. Accordingly, the present invention is not restricted by amount of water for hydrolysis of SMA-DMSO complex to produce a SMA-DMSO active complex comprising synergistic mixture of straight chain styrene maleic anhydride and cross-linked styrene maleic anhydride copolymers. It has been observed that even if water is added in excess, it does not cause any damage to the SMA-DMSO complex during hydrolysis.
  • the relative amounts of straight chain styrene maleic anhydride copolymer and cross-linked styrene maleic anhydride copolymer in the styrene maleic anhydride copolymer can be estimated by any means. It may be noted that techniques of measurement of crosslink density in high molecular weight polymers all have limitations in specificity, accuracy and precision. Therefore, the relative amounts of straight chain styrene maleic anhydride copolymer and cross-linked styrene maleic anhydride copolymer in the styrene maleic anhydride copolymer are estimated by three techniques, i.e., viscosity measurements, swelling capability and proton NMR spectroscopic techniques.
  • SMA copolymer predominantly comprising straight chain SMA copolymer was mixed with DMSO in 1:3 weight/volume ratio to form a gel form of complex, from which active complex of SMA-DMSO was precipitated by addition of water in a ratio of 1:1.
  • the crosslinking density was measured at SMA, SMA-DMSO complex and SMA-DMSO active complex stages and it was found that crosslink density increases from the SMA stage to SMA-DMSO complex stage, and thereafter, to SMA-DMSO active complex stage.
  • the relative viscosity on dilution in tetrahydrofuran in the ratio of about l:100::wt:vol was found to be about 2.2 for SMA stage, about 2.9 for SMA-DMSO complex stage, and about 4.6 for SMA-DMSO active complex stage.
  • the greater crosslink density was found to result in more retractive force, and thus, a smaller swelling, which is confirmed by decreasing swelling capability from SMA stage to SMA-DMSO complex stage, and thereafter, to SMA-DMSO active complex stage.
  • the swelling capability measured in toluene was found to be about 3.9 times for SMA stage, about 2.7 times for SMA-DMSO complex stage, and about 2.1 times for SMA- DMSO active complex stage confirming increasing crosslinking from SMA stage to SMA-DMSO complex stage and then to SMA-DMSO active complex stage when measured by applying the Flory-Rehner equation.
  • the peak [110] of benzene group in the 6 to 8 ppm region was analyzed, which had shown about 20% reduction in width of band in the 6-8 ppm region from SMA stage to SMA-DMSO complex stage and further reduction in width of about 15% from SMA-DMSO complex stage to SMA-DMSO active complex stage confirming increasing crosslinking from SMA stage to SMA-DMSO complex stage and then to SMA-DMSO active complex stage.
  • the active ingredient may be incorporated in the active complex of the present invention by any means.
  • the active ingredient is added in active complex comprising styrene maleic anhydride copolymer and DMSO, wherein styrene maleic anhydride copolymer predominantly comprises straight chain styrene maleic anhydride copolymer [the first embodiment of preparation of active complex of styrene maleic anhydride [SMA] and dimethyl sulfoxide [DMSO]] from which active matrix of SMA- DMSO-active ingredient in the form of gel is directly precipitated out by addition of water, wherein the styrene maleic anhydride copolymer of the active matrix has been found to comprise straight chain styrene maleic anhydride copolymer as well as cross-linked styrene maleic anhydride copolymer.
  • the active matrix of SMA- DMSO-active ingredient may be used either as gel or used as powder after drying the gel form of SMA-DMS O-active ingredient matrix.
  • straight chain styrene maleic anhydride copolymer undergoes controlled hydrolysis on addition of water in the complex of straight chain styrene maleic anhydride copolymer, DMSO and active ingredient by controlled hydrolysis of the maleic groups to form physical crosslinking by hydrogen bonds, which has been found to have advantage of entrapping the active ingredient in the spaces formed between the SMA chains.
  • the present invention relates to active matrix of SMA-DMSO-active ingredient.
  • it also relates to a process for preparation of active matrix of SMA-DMSO complex and active ingredient comprising adding the active ingredient in active complex comprising styrene maleic anhydride copolymer and DMSO, wherein styrene maleic anhydride copolymer predominantly comprises straight chain styrene maleic anhydride copolymer from which active matrix of SMA-DMSO-active ingredient in the form of gel is directly precipitated out by addition of water, wherein the styrene maleic anhydride copolymer in precipitated active matrix comprises straight chain styrene maleic anhydride copolymer and cross-linked styrene maleic anhydride copolymer, and the active matrix produced by this process has been found to have advantage of being capable of use, either as gel or as powder after drying the gel form of SMA-DMSO-active ingredient matrix.
  • amount of water to be added to complex of SMA-DMSO-active ingredient is also determined by visual observation of formation of a white coloured complex. Accordingly, the present invention is not restricted by amount of water for precipitation of SMA-DMSO-active ingredient active matrix. It has been observed that even if water is added in excess, it does not cause any damage to the SMA-DMSO-active ingredient active matrix.
  • the active ingredient may be added to active complex by any means.
  • the active ingredient may be added to active complex by means of spraying gun, microinjector or automizer.
  • the active ingredient [1] - levonorgestrel [LNG] is provided in SMA-DMSO active complex [2] by spraying [for example with the help of spray nozzle (3)] it onto the SMA-DMSO active complex layer [Figure 1] so that the active ingredient [4] is uniformly distributed and suitably embedded into SMA- DMSO active complex layer [5] [ Figure 3] thereby resulting in formation of a active matrix of SMA-DMSO-active ingredient [6] which when packed in or applied on the vertical arm of the IUD has been found to be capable of uniformly releasing active ingredient from SMA-DMSO active complex for achieving safer and effective contraception on implantation of presently disclosed hormonal IUD in the uterus.
  • the active ingredient - levonorgestrel [LNG] is provided in SMA-DMSO active complex by microinjecting [for example with the help of micro-injector (7) provided with a micro-needle (8)] it into the SMA-DMSO active complex layer [2] [ Figure 2] so that the active ingredient is uniformly distributed and suitably embedded into SMA-DMSO active complex layer [ Figure 3] thereby resulting in formation of active matrix of SMA-DMSO-active ingredient which when packed in or applied on the vertical arm of the IUD has been found to be capable of uniformly releasing active ingredient from SMA-DMSO active complex layer for achieving safer and effective contraception on implantation of presently disclosed hormonal IUD in the uterus.
  • the active ingredient - levonorgestrel [LNG] is embedded in SMA-DMSO active complex by employing an automiser to form active matrix of SMA- DMSO-active ingredient which when packed in or applied on the vertical arm of the IUD has been found to be capable of uniformly releasing active ingredient from SMA-DMSO active complex layer for achieving safer and effective contraception on implantation of presently disclosed hormonal IUD in the uterus.
  • the active ingredient - levonorgestrel [LNG] consists of micro-sized particles which are added preferably by microinjecting or spraying the micro-sized particles of the active ingredient into the SMA-DMSO active complex layer under a pressure sufficient to cause embedding of micro-sized particles of active ingredient into the SMA-DMSO active complex layer to form active matrix of SMA-DMSO-active ingredient which when packed in or applied on the vertical arm of the IUD has been found to be capable of uniformly releasing active ingredient from SMA-DMSO active complex layer for achieving safer and effective contraception on implantation of presently disclosed hormonal IUD in the uterus.
  • microinjection or spray of micro-sized particles of active ingredient - levonorgestrel [LNG] results in better uniform distribution of active ingredient within the SMA-DMSO active complex layer which when packed or applied on the vertical arm of the IUD has been found to be capable of uniformly releasing active ingredient from SMA-DMSO active complex layer for achieving safer and effective contraception on implantation of presently disclosed hormonal IUD in the uterus.
  • the active ingredient - levonorgestrel is sprayed or microinjected into the SMA-DMSO active complex layer after dissolving in an organic solvent preferably chloroform for achieving uniform distribution and better embedding of active ingredient into the SMA-DMSO active complex layer thereby resulting in formation of a active matrix which when packed in or applied on the vertical arm of the IUD is capable of uniformly releasing active ingredient from SMA-DMSO active complex layer for achieving safer and effective contraception on implantation of presently disclosed hormonal IUD in the uterus.
  • the solvent preferably chloroform has been found to have advantage of providing a solution of active ingredient without altering its chemical structure and still having suitable viscosity which enables microinjection or spraying of active ingredient.
  • a layer of active ingredient - levonorgestrel [LNG] [10] is provided on the SMA-DMSO active complex layer [11] to produce active matrix [12] [ Figure 4] of the present invention.
  • a layer of active ingredient - levonorgestrel [10/13] is provided on the SMA- DMSO active complex layer [11/14] to produce active matrix [12] as shown in Figure 4 which is optionally provided with another layer of SMA-DMSO active complex [15] on its side opposite to SMA-DMSO active complex layer to produce active matrix [16] [ Figure 5] of the present invention.
  • active matrix [17] comprising a layer of active ingredient - levonorgestrel [18] and SMA-DMSO active complex [19], or a layer of active ingredient [18] sandwiched between two layers of SMA-DMSO active complex [19 8B 20] is optionally formed as a zig-zag structure [Figure 6], which is capable of stretching to a straight form before insertion and capable of regaining its zigzag structure after insertion of the hormonal IUD in the uterus.
  • the zig-zag structure has been observed to cause increase in surface area available for release of active ingredient - levonorgestrel.
  • the active ingredient and active complex may be mixed in any ratio.
  • the active ingredient and active complex are taken in a ratio varying from about 1:0.8 to about 1:1.5, preferably in a ratio of about 1:1.3.
  • the T' is conventionally available T' [30] as one is employed in hormonal IUD of the present invention shown in accompanying Figure 7 comprising a vertical arm [31] provided with active matrix of SMA-DMSO-active ingredient [32] of the present invention.
  • the T' is specially designed T' [33] having a central vertical hole [34] and one or more horizontal holes [35] in its vertical arm [36] as one is employed in hormonal IUD of the present invention shown in accompanying Figure 8.
  • the T' is conventionally available T' [60] having a zig-zag shape vertical arm [61] as one is employed in hormonal IUD of the present invention shown in accompanying Figure 10.
  • T' is specially designed T' having a zig-zag shape vertical arm as one is employed in hormonal IUD of the present invention shown in accompanying
  • Figure 10 and provided with a central vertical hole and one or more horizontal holes in its zig-zag shaped vertical arm.
  • the T' is conventionally available T' [70] having a zig-zag shape vertical arm [71] as one is employed in hormonal IUD of the present invention shown in accompanying Figure 11.
  • the T is specially designed T' having a zig-zag shape vertical arm as one is employed in hormonal IUD of the present invention shown in accompanying Figure 11 and provided with a central vertical hole and one or more horizontal holes in its zig-zag shaped vertical arm.
  • the vertical arm of the T' has zig-zag structure all through its length [Figure 10 and Figure 11] or in its middle portion or only in its lower half portion or only in its upper half portion.
  • the hormonal IUD of present invention may be prepared from presently disclosed active matrix comprising active complex and active ingredient in any manner.
  • the hormonal IUD is prepared from active matrix comprising active complex of SMA-DMSO and active ingredient, wherein active matrix is prepared by adding active ingredient in active complex comprising styrene maleic anhydride copolymer and DMSO, wherein styrene maleic anhydride copolymer predominantly comprises straight chain styrene maleic anhydride copolymer [the first embodiment of preparation of active complex of styrene maleic anhydride [SMA] and dimethyl sulfoxide [DMSO]] from which active matrix of SMA- DMSO-active ingredient in the form of gel is directly precipitated out by addition of water, wherein the styrene maleic anhydride copolymer of the active matrix has been found to comprise straight chain styrene maleic anhydride copolymer as well as cross-linked styrene maleic anhydride copolymer, and the active matrix of SMA-DMSO-active ingredient thus produced may be used either as
  • the present invention relates to hormonal IUD comprising active matrix of SMA-DMSO- active ingredient applied on vertical arm of IUD, wherein active matrix of SMA-DMSO-active ingredient is prepared by adding the active ingredient in active complex comprising styrene maleic anhydride copolymer and DMSO, wherein styrene maleic anhydride copolymer predominantly comprises straight chain styrene maleic anhydride copolymer from which active matrix of SMA-DMSO-active ingredient in the form of gel is directly precipitated out by addition of water, wherein the styrene maleic anhydride copolymer of the active matrix has been found to comprise straight chain styrene maleic anhydride copolymer as well as cross-linked styrene maleic anhydride copolymer, and the active matrix of SMA-DMSO-active ingredient thus produced can be used either as gel or as powder after drying the gel form of SMA-DMSO-active ingredient matrix,
  • the active matrix of the present invention comprising SMA-DMSO active complex and active ingredient - levonorgestrel [LNG] is applied onto vertical arm of the IUD to form hormonal IUD [Figure 7] for uniform release of active ingredient - levonorgestrel. Accordingly, in accordance with second embodiment of the present invention, the active matrix comprising SMA- DMSO active complex and active ingredient - levonorgestrel is applied onto vertical arm of the IUD to produce hormonal IUD [Figure 7] of the present invention for uniform and effective release of active ingredient - levonorgestrel.
  • the active matrix of the present invention comprising SMA-DMSO active complex and active ingredient - levonorgestrel is packed in vertical arm of the IUD provided with a central vertical hole and one or more horizontal holes to form hormonal IUD [Figure 8] for uniform release of active ingredient - levonorgestrel. Accordingly, in accordance with third embodiment of the present invention, the active matrix comprising SMA- DMSO active complex and active ingredient - levonorgestrel is packed in vertical arm of the IUD provided with a central vertical hole and one or more horizontal holes to form hormonal IUD [Figure 8] of the present invention for uniform and effective release of active ingredient - levonorgestrel.
  • the active matrix [40] comprising SMA-DMSO active complex and active ingredient - levonorgestrel is applied on the vertical arm [41] of the IUD [42] and optionally provided with a layer of inactive material [43], for example of silicone rubber [Figure 9] thereby avoiding any damage to the active matrix of the present invention before its implantation in the uterus.
  • the silicone tube is provided with pores or holes preferably of size varying from about 0.02 mm to about 0.5 mm diameter preferably at a distance of about 0.02 mm to about 0.5 mm.
  • the active matrix comprising a layer of active ingredient - levonorgestrel provided on the SMA-DMSO active complex layer [Figure 4] is packed in [ Figure 8] or applied on [ Figures 7, 9, 10, 11] the vertical arm of the IUD to produce hormonal IUD of the present invention for uniform and effective release of active ingredient - levonorgestrel.
  • the active matrix comprising a layer of active ingredient - levonorgestrel sandwiched between two layers of SMA-DMSO active complex [Figure 5] is packed in [ Figure, 8] or applied on [ Figures 7, 9, 10, 11] the vertical arm of the IUD to produce hormonal IUD of the present invention for uniform and effective release of active ingredient - levonorgestrel.
  • the active matrix comprising a layer of active ingredient - levonorgestrel sandwiched between two layers of SMA-DMSO active complex and having a zig-zag shape [Figure 6] is packed in [not shown] or applied on [ Figure 10] the vertical arm of the IUD to produce hormonal IUD of the present invention for uniform and effective release of active ingredient - levonorgestrel.
  • the active matrix comprising a layer of active ingredient - levonorgestrel provided on the SMA-DMSO active complex layer [Figure 4] is applied on the vertical arm of the IUD and is optionally provided with a layer of inactive material, for example of silicone rubber.
  • the active matrix comprising a layer of active ingredient - levonorgestrel sandwiched between two layers of SMA-DMSO active complex [Figure 5] is applied on the vertical arm of the IUD and is optionally provided with a layer of inactive material, for example of silicone rubber.
  • the active matrix comprising a layer of active ingredient - levonorgestrel sandwiched between two layers of SMA-DMSO active complex formed in a zig-zag structure [Figure 6] is applied on the vertical arm of the IUD and is optionally provided with a layer of inactive material, for example of silicone rubber.
  • the layer of inactive material [43] is provided in the form of a tube [ Figure 9] comprising pores or holes [44] preferably of size varying from about 0.02 mm to about 0.5 mm diameter preferably at a distance of about 0.02 mm to about 0.5 mm thereby avoiding any damage to the active matrix of the present invention before its implantation in the uterus.
  • hormonal IUD devices for delivery of active ingredient on contact with water it absorbs water resulting in formation of pouches or bulging [50] in the matrix which comes out of the pores [35] provided in vertical arm of the T' [ Figure 8 and Figure 13] or silicone rubber tubing [Figure 9 and Figure 13] and the active ingredient is released out of these pouches formed on contact with water.
  • the absorbed water causes swelling of the active matrix thereby resulting in pumping of active ingredient therefrom confirming active nature of the active matrix of the present invention.
  • the pouches or bulging formed are observed to degrade which result in release of active ingredient trapped even in cross-linked copolymer thereby resulting in complete and uniform release of active ingredient from the active matrix of the presently disclosed hormonal IUD for achieving safer and more effective contraception, which confirms that active matrix of present invention is capable of releasing substantially completely the active ingredient.
  • the length of the tubing of the inactive material provided onto the active matrix is shorter than the length of active matrix covering vertical arm of the T' thereby resulting in release of active ingredient - levonorgestrel from the top and bottom ends of the active matrix provided around the vertical arm of the T'.
  • the active ingredient - levonorgestrel not only releases from the pores provided in the silicone tube, but also from the top and bottom ends of the active matrix provided around the vertical arm of the T'.
  • the release from bottom end has been observed to produce changes in cervix so that the sperms entering from cervix become inactive on contact with active ingredient, wherein the active ingredient acts on mucosa of cervix so that mucosa becomes hostile to sperms and the release of active ingredient from the top end, which is close to zygote implantation site in upper part known as fundus of the uterus, makes fundus hostile to zygote thereby resulting in enhanced activity of the presently disclosed hormonal IUD.
  • the SMA copolymer is mixed in DMSO having purity of about 98% in 1:3 weight/volume ratio while stirring for about two days in inert environment of dry nitrogen to form about 800 mg of SMA-DMSO complex in gel form.
  • SMA-DMSQ-LNG Active Matrix About 1 to 1.5 ml of distilled water, the volume of which is determined by visual observation of formation of a white coloured complex was microinjected into the SMA-DMSO-LNG complex to form SMA-DMSO-LNG active matrix on hydrolysis of SMA to have required level of cross-linked SMA.
  • the SMA-DMSO-LNG active matrix obtained in preceding step may be used directly or after drying. Accordingly, it is subjected to vacuum drying for about four days. For achieving complete drying the matrix is cut into small pieces after about two days of vacuum drying.
  • the SMA-DMSO-LNG active matrix may be packed or applied onto vertical arm of T' in any of the manners described herein or may be packed or applied onto vertical arm of T' after granulation and converting to powder form after drying step, wherein the powder form is screened through 200 BSS sieve.
  • the sieved fine powder of the active matrix is then compacted or moulded and packed onto vertical arm of T, which is covered by swollen silicon membrane followed by sealing of ends to form in hormonal IUD which is ready for implantation.
  • the release of LNG was tested using an apparatus suitable for providing controlled temperature of about 37 0 C and rotation of about 100 rpm. After every 24 hrs, dissolute solution was subjected to analytical measurement by HPLC and was found that LNG releases in a controlled and uniform manner.
  • SMA and DMSO and the terms active matrix [or active matrix complex] as employed herein is intended to define the complex of SMA, DMSO and active ingredient. However, such terms have been used in a generic and descriptive sense only and not for purpose of limitation.
  • the complex of SMA and DMSO, and complex of SMA, DMSO and active ingredient may be described by other similar terms.
  • the word "about” as used herein is intended to include the practical errors in achieving the respective value of any of the respective parameter.
  • the active ingredient - levonorgestrel as referred herein is a drug required to be delivered in the target site.
  • the present invention has been described by selecting levonorgestrel as active ingredient to form the active matrix complex of present invention.
  • the presently disclosed active complex comprising SMA-DMSO complex may also be employed for release of other active ingredients, that is may also employ other active ingredients required to be released at uniform rate for a longer duration. Therefore, in one embodiment of this invention, such active matrix complexes comprising active complex of the present invention are also intended to be included within the scope of the present invention.
  • the present invention is not restricted by thickness of the active complex SMA-DMSO layer and/or LNG layer.

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Abstract

La présente invention concerne un dispositif hormonal intra-utérin (42) destiné à l'administration régulée et uniforme d'un principe actif. Le dispositif est constitué d'une matrice (40) active composée d'un complexe et d'un principe actif, ledit complexe actif comportant un copolymère de styrène - anhydride maléique [SAM] et du sulfoxyde de diméthyle [DMSO].
PCT/IN2007/000350 2006-08-21 2007-08-17 Dispositif hormonal intra-utérin pour l'administration de lévonorgestrel WO2008023389A1 (fr)

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Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2013061341A1 (fr) * 2011-10-28 2013-05-02 Sujoy Kumar Guha Dispositif contraceptif intra-utérin amélioré
US10028858B2 (en) 2011-07-11 2018-07-24 Medicines360 Intrauterine systems, IUD insertion devices, and related methods and kits therefor

Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3679653A (en) * 1968-09-27 1972-07-25 Monsanto Co Hormonally-active reaction product of a polymer with a hormone
DE2363963A1 (de) * 1972-12-27 1974-07-11 Alza Corp Koerper zur verzoegerten abgabe von aktiven mitteln
WO1997006787A2 (fr) * 1995-08-17 1997-02-27 Dyer, Alison, Margaret Produits a liberation controlee
US20030236514A1 (en) * 2002-06-19 2003-12-25 Schwarz Marlene C. Implantable or insertable medical devices for controlled delivery of a therapeutic agent

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3679653A (en) * 1968-09-27 1972-07-25 Monsanto Co Hormonally-active reaction product of a polymer with a hormone
DE2363963A1 (de) * 1972-12-27 1974-07-11 Alza Corp Koerper zur verzoegerten abgabe von aktiven mitteln
WO1997006787A2 (fr) * 1995-08-17 1997-02-27 Dyer, Alison, Margaret Produits a liberation controlee
US20030236514A1 (en) * 2002-06-19 2003-12-25 Schwarz Marlene C. Implantable or insertable medical devices for controlled delivery of a therapeutic agent

Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US10028858B2 (en) 2011-07-11 2018-07-24 Medicines360 Intrauterine systems, IUD insertion devices, and related methods and kits therefor
US11090186B2 (en) 2011-07-11 2021-08-17 Medicines360 Methods for using intrauterine systems and IUD insertion devices
US12004992B2 (en) 2011-07-11 2024-06-11 Medicines360 Kits for intrauterine systems and IUD insertion devices
WO2013061341A1 (fr) * 2011-10-28 2013-05-02 Sujoy Kumar Guha Dispositif contraceptif intra-utérin amélioré

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