LV13521B - X-ray visible drug delivery device - Google Patents
X-ray visible drug delivery device Download PDFInfo
- Publication number
- LV13521B LV13521B LVP-06-117A LV060117A LV13521B LV 13521 B LV13521 B LV 13521B LV 060117 A LV060117 A LV 060117A LV 13521 B LV13521 B LV 13521B
- Authority
- LV
- Latvia
- Prior art keywords
- core
- implant
- drug delivery
- delivery device
- barium sulphate
- Prior art date
Links
- 238000012377 drug delivery Methods 0.000 title claims abstract description 24
- 239000003433 contraceptive agent Substances 0.000 claims abstract description 14
- 230000002254 contraceptive effect Effects 0.000 claims abstract description 14
- TZCXTZWJZNENPQ-UHFFFAOYSA-L barium sulfate Chemical compound [Ba+2].[O-]S([O-])(=O)=O TZCXTZWJZNENPQ-UHFFFAOYSA-L 0.000 claims description 184
- 239000007943 implant Substances 0.000 claims description 150
- GCKFUYQCUCGESZ-BPIQYHPVSA-N etonogestrel Chemical compound O=C1CC[C@@H]2[C@H]3C(=C)C[C@](CC)([C@](CC4)(O)C#C)[C@@H]4[C@@H]3CCC2=C1 GCKFUYQCUCGESZ-BPIQYHPVSA-N 0.000 claims description 66
- 229940044513 implanon Drugs 0.000 claims description 39
- RTAQQCXQSZGOHL-UHFFFAOYSA-N Titanium Chemical compound [Ti] RTAQQCXQSZGOHL-UHFFFAOYSA-N 0.000 claims description 34
- 239000000463 material Substances 0.000 claims description 23
- 229920001169 thermoplastic Polymers 0.000 claims description 16
- 239000010936 titanium Substances 0.000 claims description 13
- 229910052719 titanium Inorganic materials 0.000 claims description 13
- 238000002657 hormone replacement therapy Methods 0.000 claims description 11
- RPLCPCMSCLEKRS-BPIQYHPVSA-N desogestrel Chemical compound C1CC[C@@H]2[C@H]3C(=C)C[C@](CC)([C@](CC4)(O)C#C)[C@@H]4[C@@H]3CCC2=C1 RPLCPCMSCLEKRS-BPIQYHPVSA-N 0.000 claims description 10
- 229960004976 desogestrel Drugs 0.000 claims description 10
- 235000006679 Mentha X verticillata Nutrition 0.000 claims description 5
- 235000002899 Mentha suaveolens Nutrition 0.000 claims description 5
- 235000001636 Mentha x rotundifolia Nutrition 0.000 claims description 5
- -1 polyethylene vinyl acetate Polymers 0.000 claims description 4
- 229940088597 hormone Drugs 0.000 abstract description 28
- 239000005556 hormone Substances 0.000 abstract description 28
- 238000002560 therapeutic procedure Methods 0.000 abstract 1
- 239000011162 core material Substances 0.000 description 88
- 239000000203 mixture Substances 0.000 description 20
- 239000013078 crystal Substances 0.000 description 18
- 238000001125 extrusion Methods 0.000 description 16
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 14
- 238000002386 leaching Methods 0.000 description 14
- 229960002941 etonogestrel Drugs 0.000 description 13
- 238000000034 method Methods 0.000 description 12
- 239000000835 fiber Substances 0.000 description 10
- 239000008187 granular material Substances 0.000 description 8
- 239000005038 ethylene vinyl acetate Substances 0.000 description 7
- 229920001200 poly(ethylene-vinyl acetate) Polymers 0.000 description 7
- 229920000642 polymer Polymers 0.000 description 7
- 238000000338 in vitro Methods 0.000 description 6
- 238000012360 testing method Methods 0.000 description 6
- 230000005540 biological transmission Effects 0.000 description 5
- 238000004519 manufacturing process Methods 0.000 description 5
- 238000002360 preparation method Methods 0.000 description 5
- 229920001577 copolymer Polymers 0.000 description 4
- 238000010348 incorporation Methods 0.000 description 4
- 238000003780 insertion Methods 0.000 description 4
- 230000037431 insertion Effects 0.000 description 4
- 238000013508 migration Methods 0.000 description 4
- 230000005012 migration Effects 0.000 description 4
- 239000010935 stainless steel Substances 0.000 description 4
- 239000008280 blood Substances 0.000 description 3
- 210000004369 blood Anatomy 0.000 description 3
- DQXBYHZEEUGOBF-UHFFFAOYSA-N but-3-enoic acid;ethene Chemical compound C=C.OC(=O)CC=C DQXBYHZEEUGOBF-UHFFFAOYSA-N 0.000 description 3
- 239000011159 matrix material Substances 0.000 description 3
- 238000002156 mixing Methods 0.000 description 3
- 229910001220 stainless steel Inorganic materials 0.000 description 3
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 3
- WWYNJERNGUHSAO-XUDSTZEESA-N (+)-Norgestrel Chemical compound O=C1CC[C@@H]2[C@H]3CC[C@](CC)([C@](CC4)(O)C#C)[C@@H]4[C@@H]3CCC2=C1 WWYNJERNGUHSAO-XUDSTZEESA-N 0.000 description 2
- 241000320516 Eothenomys eva Species 0.000 description 2
- LYCAIKOWRPUZTN-UHFFFAOYSA-N Ethylene glycol Chemical compound OCCO LYCAIKOWRPUZTN-UHFFFAOYSA-N 0.000 description 2
- 241000282887 Suidae Species 0.000 description 2
- XTXRWKRVRITETP-UHFFFAOYSA-N Vinyl acetate Chemical compound CC(=O)OC=C XTXRWKRVRITETP-UHFFFAOYSA-N 0.000 description 2
- XECAHXYUAAWDEL-UHFFFAOYSA-N acrylonitrile butadiene styrene Chemical compound C=CC=C.C=CC#N.C=CC1=CC=CC=C1 XECAHXYUAAWDEL-UHFFFAOYSA-N 0.000 description 2
- 239000004676 acrylonitrile butadiene styrene Substances 0.000 description 2
- 229920000122 acrylonitrile butadiene styrene Polymers 0.000 description 2
- 238000003556 assay Methods 0.000 description 2
- 238000009826 distribution Methods 0.000 description 2
- 230000000694 effects Effects 0.000 description 2
- 238000003384 imaging method Methods 0.000 description 2
- 238000001727 in vivo Methods 0.000 description 2
- 239000004615 ingredient Substances 0.000 description 2
- 229960004400 levonorgestrel Drugs 0.000 description 2
- 239000000155 melt Substances 0.000 description 2
- 235000016709 nutrition Nutrition 0.000 description 2
- 230000035764 nutrition Effects 0.000 description 2
- BASFCYQUMIYNBI-UHFFFAOYSA-N platinum Chemical compound [Pt] BASFCYQUMIYNBI-UHFFFAOYSA-N 0.000 description 2
- 238000004626 scanning electron microscopy Methods 0.000 description 2
- 238000000550 scanning electron microscopy energy dispersive X-ray spectroscopy Methods 0.000 description 2
- 238000009987 spinning Methods 0.000 description 2
- 238000002604 ultrasonography Methods 0.000 description 2
- 238000012800 visualization Methods 0.000 description 2
- 229910001020 Au alloy Inorganic materials 0.000 description 1
- 206010006187 Breast cancer Diseases 0.000 description 1
- 208000026310 Breast neoplasm Diseases 0.000 description 1
- 229920003345 Elvax® Polymers 0.000 description 1
- 238000012307 MRI technique Methods 0.000 description 1
- 206010028980 Neoplasm Diseases 0.000 description 1
- 206010033128 Ovarian cancer Diseases 0.000 description 1
- 206010061535 Ovarian neoplasm Diseases 0.000 description 1
- 239000004743 Polypropylene Substances 0.000 description 1
- GWEVSGVZZGPLCZ-UHFFFAOYSA-N Titan oxide Chemical compound O=[Ti]=O GWEVSGVZZGPLCZ-UHFFFAOYSA-N 0.000 description 1
- 229920003351 Ultrathene® Polymers 0.000 description 1
- 208000002495 Uterine Neoplasms Diseases 0.000 description 1
- 230000002411 adverse Effects 0.000 description 1
- 229910000416 bismuth oxide Inorganic materials 0.000 description 1
- FACXGONDLDSNOE-UHFFFAOYSA-N buta-1,3-diene;styrene Chemical compound C=CC=C.C=CC1=CC=CC=C1.C=CC1=CC=CC=C1 FACXGONDLDSNOE-UHFFFAOYSA-N 0.000 description 1
- 201000011510 cancer Diseases 0.000 description 1
- TYIXMATWDRGMPF-UHFFFAOYSA-N dibismuth;oxygen(2-) Chemical compound [O-2].[O-2].[O-2].[Bi+3].[Bi+3] TYIXMATWDRGMPF-UHFFFAOYSA-N 0.000 description 1
- 201000010099 disease Diseases 0.000 description 1
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 1
- 238000004090 dissolution Methods 0.000 description 1
- 238000005553 drilling Methods 0.000 description 1
- 239000013536 elastomeric material Substances 0.000 description 1
- 238000005538 encapsulation Methods 0.000 description 1
- 239000003353 gold alloy Substances 0.000 description 1
- WGCNASOHLSPBMP-UHFFFAOYSA-N hydroxyacetaldehyde Natural products OCC=O WGCNASOHLSPBMP-UHFFFAOYSA-N 0.000 description 1
- 229920001684 low density polyethylene Polymers 0.000 description 1
- 239000004702 low-density polyethylene Substances 0.000 description 1
- 229910052751 metal Inorganic materials 0.000 description 1
- 239000002184 metal Substances 0.000 description 1
- 230000037368 penetrate the skin Effects 0.000 description 1
- 230000000704 physical effect Effects 0.000 description 1
- 229910052697 platinum Inorganic materials 0.000 description 1
- 229920000139 polyethylene terephthalate Polymers 0.000 description 1
- 239000005020 polyethylene terephthalate Substances 0.000 description 1
- 229920005644 polyethylene terephthalate glycol copolymer Polymers 0.000 description 1
- 229920001155 polypropylene Polymers 0.000 description 1
- 239000000843 powder Substances 0.000 description 1
- 230000035935 pregnancy Effects 0.000 description 1
- 239000000583 progesterone congener Substances 0.000 description 1
- 229910001256 stainless steel alloy Inorganic materials 0.000 description 1
- 150000003431 steroids Chemical class 0.000 description 1
- 229920000468 styrene butadiene styrene block copolymer Polymers 0.000 description 1
- 238000007920 subcutaneous administration Methods 0.000 description 1
- 229910052715 tantalum Inorganic materials 0.000 description 1
- GUVRBAGPIYLISA-UHFFFAOYSA-N tantalum atom Chemical compound [Ta] GUVRBAGPIYLISA-UHFFFAOYSA-N 0.000 description 1
- OGIDPMRJRNCKJF-UHFFFAOYSA-N titanium oxide Inorganic materials [Ti]=O OGIDPMRJRNCKJF-UHFFFAOYSA-N 0.000 description 1
- WFKWXMTUELFFGS-UHFFFAOYSA-N tungsten Chemical compound [W] WFKWXMTUELFFGS-UHFFFAOYSA-N 0.000 description 1
- 229910052721 tungsten Inorganic materials 0.000 description 1
- 239000010937 tungsten Substances 0.000 description 1
- 206010046766 uterine cancer Diseases 0.000 description 1
- 210000001215 vagina Anatomy 0.000 description 1
- 210000003462 vein Anatomy 0.000 description 1
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K49/00—Preparations for testing in vivo
- A61K49/04—X-ray contrast preparations
- A61K49/0404—X-ray contrast preparations containing barium sulfate
-
- 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
- A61K31/565—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids not substituted in position 17 beta by a carbon atom, e.g. estrane, estradiol
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K49/00—Preparations for testing in vivo
- A61K49/04—X-ray contrast preparations
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K49/00—Preparations for testing in vivo
- A61K49/04—X-ray contrast preparations
- A61K49/0409—Physical forms of mixtures of two different X-ray contrast-enhancing agents, containing at least one X-ray contrast-enhancing agent which is not a halogenated organic compound
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P15/00—Drugs for genital or sexual disorders; Contraceptives
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P15/00—Drugs for genital or sexual disorders; Contraceptives
- A61P15/18—Feminine contraceptives
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P5/00—Drugs for disorders of the endocrine system
- A61P5/24—Drugs for disorders of the endocrine system of the sex hormones
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P5/00—Drugs for disorders of the endocrine system
- A61P5/24—Drugs for disorders of the endocrine system of the sex hormones
- A61P5/32—Antioestrogens
Landscapes
- Health & Medical Sciences (AREA)
- Veterinary Medicine (AREA)
- Public Health (AREA)
- General Health & Medical Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- Life Sciences & Earth Sciences (AREA)
- Epidemiology (AREA)
- Pharmacology & Pharmacy (AREA)
- Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- General Chemical & Material Sciences (AREA)
- Engineering & Computer Science (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Endocrinology (AREA)
- Organic Chemistry (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Diabetes (AREA)
- Reproductive Health (AREA)
- Gynecology & Obstetrics (AREA)
- Medicinal Preparation (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
- Medicines Containing Antibodies Or Antigens For Use As Internal Diagnostic Agents (AREA)
- Materials For Medical Uses (AREA)
- Pyrrole Compounds (AREA)
- Indole Compounds (AREA)
- Addition Polymer Or Copolymer, Post-Treatments, Or Chemical Modifications (AREA)
- Steroid Compounds (AREA)
Description
FIELD OF THE INVENTION
The present invention relates to the field of contraception and hormone replacement therapy.
The present invention relates to an X-ray visible drug delivery device for subdermal (subcutaneous) administration of a contraceptive or hormone replacement therapy.
The device according to the invention is particularly in the form of an implant, and will hereinafter be referred to as an implant.
BACKGROUND OF THE INVENTION
Implanon® is a contraceptive implant that is inserted in the human body for periods up to 3 years. Cases have been reported in vvhich the implants could not easily be removed due to either incorrect insertions by physicians or due to non-insertion of the implant by physicians. Implanon can be visualized in the body using ultrasonography and MRI techniques. Visualization by MRI is not always readily available, relatively complicated and expensive. Visualization by ultrasonography is also not always readily available and may be difficult in the hands of inexperienced physicians especially in the event the implant vvas inserted incorrectly.
The implant should be removed (and replaced) after three years. Furthermore, women may vvant to remove the implant if they vvish to become pregnant. Another reason for removal can be disease, such as cancer, especially breast cancer, ovary cancer or cancer of the uterus.
It vvould therefore be convenient to have an Implanon-like implant which vvill be X-ray visible. This in order to have additional methods to locate and identify the implant, either to facilitate removal of the implant or to be able to reassure the patient that the implant has been inserted.
Such a contemplated X-ray visible implant must be such that the radio-opaque component does not (i) influence the hormone release profilē of the implant and (ii) does not migrate into the body through the open-ended implant.
X-ray visible medical devices, such as stents, catheters, intra-uterine devices such as MultiLoad®, biodegradable implants and dental devices are knovvn. An X-ray visible drug delivery device known in the field of contraception is described in GB 2168257 which shovvs an X-ray visible vaginai ring comprising the progestogen levonorgestrel. GB2168257 does not relate to the influence of the radio-opaque component on the release rāte of levonorgestrel from the ring, nor does such a ring have open-ends.
It is however crucial to ascertain that the hormone release rāte is not signifīcantly affected by a radio-opaque component present in the contraceptive device because that could possibly result in pregnancy, the unwanted effect for a woman using contraception.
Moreover, it is also crucial that a radio-opaque component present in the contraceptive/HRT device does not migrate outside the (open-ended) implant into the body in undesired amounts causing potential radio-opaque component related adverse effects.
Thus, the subject invention provides for a contraceptive and/or HRT X-ray visible implant vvherein the radio-opaque component does not negatively influence the release rāte of hormones from the device and does not migrate into the body.
SUMMARY OF THE INVENTION
The subject invention provides an X-ray visible drug delivery device for subdermal administration of a contraceptive or hormone replacement therapy comprising one compartment consisting of (i) a thermoplastic polymer core loaded with (a) a contraceptively effective or therapeutically effective amount of desogestrel or 3ketodesogestrel and (b) about 4-30% by vveight radio-opaque material and (ii) a nonmedicated thermoplastic polymer skin covering the core.
The subject invention further provides an X-ray visible drug delivery device for subdermal administration of a contraceptive or hormone replacement therapy comprising one compartment consisting of (i) a thermoplastic polymer core loaded with a contraceptively effective or therapeutically effective amount of desogestrel or 3ketodesogestrel and containing an inert mētai wire and (ii) a non-medicated thermoplastic polymer skin covering the core.
FIGURĒS
Figurē 1: X-ray photographs of implants a) without barium sulphate (BaSO4 )(i.e. identical to Implanon); b) vvith 20 wt% BaSO4 in skin; and c) with 11.5 wt% BaSO4 in core.
Figurē 2: X-ray photographs of implants vvithout barium sulphate (sample 8) and vvith 11.5 wt% BaSO4 in core (sample 7) inserted in pig tissue.
Figurē 3: Accelerated release profilēs of implants vvith 0, 8,11.5 and 15 wt% barium sulphate in the core. (The implant vvith 0 wt% is identical to Implanon.)
Figurē 4: Real time release profilēs up to 190 days of implants with 0, 8, 11.5 and 15 wt% barium sulphate in the core. (The implant vvith 0 wt% is identical to Implanon).
Figurē 5: X-ray photographs of implants a) without BaSO4 or titanium wire (i.e. identical to Implanon); and b) vvith 0.5 mm titanium wire.
Figurē 6: X-ray photographs of implants vvithout titanium wire (sample 3) and with a 0.5 mm titanium wire in the core (sample 4) inserted in pig tissue.
Figurē 7: Accelerated release profilēs of implants with a 0.25 mm titanium wire in the core, a 0.50 mm titanium wire in the core and a reference implant (identical to Implanon) with no titanium vvire.
Figurē 8: Real time release profilēs of implants with a 0.25 mm titanium vvire in the core, a 0.50 mm titanium wire in the core and a reference implant (identical to Implanon) vvith no titanium wire.
Figurē 9: Back Scatter Electron (BSE) detector photograph (magnification 350x) of implant vvith 11.5 wt% barium sulphate in the core
Figurē 10: BSE detector photograph (magnification 3500x) of leached implant vvith 11.5 wt% barium sulphate in the core. The dark section on the left is the skin.
Figurē 11: X-ray photographs of implants a) vvithout BaSCL (i.e. identical to Implanon, sample 1); b) vvith 11.5 wt% BaSCL in core (samples 2 and 3); c) vvith 4 wt% BaSCL in core; d) vvith 20wt% BaSCL in core; and e) with 30 wt% BaSCL in core.
Figurē 12: X-ray transmission of implants as function of content BaSCL(wt(%)).
Figurē 13: Accelerated release profilēs of implants with 0, 4, 20 and 30 wt% barium sulphate in the core. (The implant vvith 0 wt% is identical to Implanon.)
Figurē 14: Real time release profilēs up to 76 days of implants vvith 0, 4, 20 and 30 wt% barium sulphate in the core. (The implant with 0 wt% is identical to Implanon).
Figurē 15: Back Scatter Electron (BSE) detector photograph (magnification 350x) of implant with a) 4 wt% barium sulphate in the core; b) 20 wt% barium sulphate in the core; and c) 30 wt% barium sulphate in the core.
Figurē 16: BSE detector photograph (magnification 3500x) of leached implant vvith a) 4 wt% barium sulphate in the core; b) 20 vvt% barium sulphate in the core; and c) 30 wt% barium sulphate in the core. The dark section on the left is the skin.
DETAILED DESCRIPTION OF THE INVENTION
Implanon® is a subdermal contraceptive implant consisting of a coaxial rod. The core of this rod contains a mixture of etonogestrel (3-keto desogestrel) and ethylene vinylacetate (EVA) copolymer, i.e. EVA 28 vvhich has a vinylacetate content of about 28% (m/m). The skin layer also consists of EVA polymer, i.e. EVA 14, vvhich has a vinyl acetate content of about 14% (m/m). Each rod has a mass of 129 mg and contains 68 mg etonogestrel. Implanon has a length of 40 mm and a diameter of 2 mm and has open ends.
The implant may be placed vvithin an applicator consisting of a stainless Steel needle, vvhich is fitted to an acrylonitrile-butadiene-styrene polymer (ABS) applicator. The applicator is a syringe-like apparatus consisting of a body, plunger, needle and polypropylene shield. The loaded applicator may be placed in a polyethylene terephthalate glycol (PETG) tray, vvhich may be subsequently sealed vvith lidding paper.
The object of the invention is to add a radio-opaque element to a contraceptive/HRT implant such as Implanon® providing the possibility to identify and locate it in the body by X-ray techniques vvhile maintaining the hormone release profilē thereof and vvhile ensuring that the radio-opaque component does not migrate outside of the implant in undesired amounts into the body.
One skilled in the art vvill appreciate that a hormone release profilē of a batch of a drug delivery device is never exactly identical to another batch of the same drug delivery device. Therefore, according to the subject invention, vvhen the hormone release profilē of an X-ray visible implant of the invention deviates less than about 15% from the hormone release profilē of Implanon®, these hormone release profilēs are considered identical or equivalent. The deviation can be calculated using a difference factor (Fi) to compare dissolution profilēs. The difference factor (Fj) calculates the percentage difference between two curves at each time point
Λ-dl ļvrtdto’ioo
Where R, is the reference assay at time point t, Tt is the tēst assay at time point t and n is the number of pull points. F1 values up to 15 (0-15) provide assurance of the sameness or equivalence of the tvvo curves. The reference curve is ehosen such that other release controlling parameters, than the one that is tested, are ķept as constant as possible.
When incorporating a radio-opaque element in the skin layer of the implant, X-ray visibility was hardly accomplished. Hovvever, X-ray visibility vvas accomplished vvhen incorporating the radio-opaque element in the core of the implant. Despite the incorporation of the radio-opaque element in the core of the implant which also contains the active hormone material, the hormone release profilē vvas not affected.
When evaluating vvhere the radio-opaque component vvas located in the implant after production thereof, it vvas surprisingly found that almost ali of the radio-opaque component vvas encapsulated vvithin the polymer component and hardly any radio-opaque component vvas encapsulated in the hormone crystals. This vvas unexpected in vievv of the fact that the polymer component represents only about 36 wt% of the implant vvhereas the hormone component comprises about 52.5 wt% of the implant. As a result of the encapsulation vvithin the polymer component, the radio-opaque component crystals could not migrate out of the implant through the open ends of the implant in undesired amounts. Had the radio-opaque component been present in the hormone crystals, it may have been able to migrate outside of the implant in case vvhere the hormone crystals are interconnected.
Thus, the subject invention provides an X-ray visible drug delivery device for subdermal administration of a contraceptive or hormone replacement therapy comprising one compartment consisting of (i) a thermoplastic polymer core loaded vvith (a) a contraceptively effective or therapeutically effective amount of desogestrel or 3LV 13521 ketodesogestrel and (b) about 4-30% by weight radio-opaque material and (ii) a nonmedicated thermoplastic polymer skin covering the core.
In one specific embodiment, the X-ray visible drug delivery device is an implant.
The radio-opaque element can be any such element known in the art, such as barium sulphate, titanium oxide, bismuth oxide, tantalum, tungsten, or platinum. In a specific embodiment, the radio-opaque material is barium sulphate.
In one embodiment, the radio-opaque material is about 4-25% by weight. In another embodiment, the radio-opaque material is about 6-20% by weight. In yet another embodiment, the radio-opaque material is about 4-15% by vveight. In a specific embodiment, the radio-opaque material is about 8-15% by vveight.
The thermoplastic polymer that can be used in practising the invention, may in principle be any thermoplastic polymer or elastomer material suitable for pharmaceutical use, such as low density polyethylene, ethylene-vinylacetate copolymers and styrene-butadienestyrene copolymers. In a specific embodiment, ethylene-vinylacetate copolymer (polyEVA) is used due to its excellent mechanical and physical properties (e.g. solubility of the steroids in the material). The poly-EVA material may be used for the core as vvell as the skin and can be any commercially available ethylene-vinylacetate copolymer, such as the products available under the trade names: Elvax, Evatane, Lupolen, Movriton, Ultrathene, Ateva and Vestypar.
The radio-opaque material in the core does not affect the release of the desogestrel or 3ketodesogestrel from the device and does not migrate out of the implant.
The subject invention further provides an X-ray visible drug delivery device for subdermal administration of a contraceptive or hormone replacement therapy comprising one compartment consisting of (i) a thermoplastic polymer core loaded vvith a contraceptively effective or therapeutically effective amount of desogestrel or 3ketodesogestrel and containing an inert mētai wire and (ii) a non-medicated thermoplastic polymer skin covering the core.
The radio-opaque element may be an inert titanium wire or other inert material such as certain grades of stainless Steel or gold alloys. In a specific embodiment, the inert mētai wire is a titanium wire.
The mētai vvire in the core does not affect the release of the desogestrel or 3ketodesogestrel from the device.
The present invention is further described in the following examples which are not in any way intended to limit the scope of the invention as claimed.
EXAMPLES
EXAMPLE 1 - Preparation of two-layered implant containing barium sulphate in the core
Preparation of two layered implant containing barium sulphate in the core consisted of two steps, i.e. manufacturing of core granulate (pre-mixing and blend extrusion) containing a mixture of etonogestrel (3-keto desogestrel), barium sulphate and EVA-28 copolymer and manufacturing of a co-axial fiber consisting of the core and a skin layer of EVA-14 copolymer.
The core material was prepared by adding the desired amount (e.g. 52.5 wt% etonogestrel, 36 wt% EVA, 11.5 wt% Barium sulphate) of ingredients to a stainless Steel drum after vvhich the povvder mixture vvas pre-mixed by rotating the drum on a rhonrad, or equivalent, at 47 rpm. The povvder mixture was subsequently fed to a Berstorff ZE25 co-rotating twin screvv extruder (or equivalent) and blend extruded at an extrusion temperature of 125°C. Blend extrusion resulted in strands in vvhich etonogestrel (3-keto desogestrel) and barium sulphate were homogeneously dispersed in the EVA-28 matrix. The strands vvere subsequently granulated to core granulate.
The co-extrusion set-up consisted of a skin extruder that processed the skin material and a core extruder that processed the core material as delivered by the blend extruder. The melt flows were combined in a spinneret resulting in a skin-core fibre. The volume flow rāte of both melt flows vvas controlled by a set of separate spinning pumps. An extrusion temperature of 145°C and an extrusion rāte of 1 m/min vvas used. Extrusion lead to a coaxial fiber vvith a diameter of 2 mm and a skin thickness of 60 pm. The fiber vvas cooled down to room temperature in a vvater bath, dried on air and wound on a reel. The coaxial fiber was cut into 4.0 cm rods using a semi-automatic cutter (Diosynth or equivalent).
EXAMPLE 2 - Preparation of tvvo lavered implant containing barium sulphate in the skin
Preparation of two layered implant containing barium sulphate in the skin consisted of three steps, i.e. manufaeturing of core granulate (pre-mixing and blend extrusion) containing a mixture of etonogestrel (3-keto desogestrel) and EVA-28 copolymer, manufaeturing of skin granulate (pre-mixing and blend extrusion) containing a mixture of Barium sulphate and EVA-14 copolymer, and manufaeturing of a co-axial fiber consisting of the core and a skin layer.
The core material (e.g 60 wt% etonogestrel and 40 wt % EVA-28) and skin material (e.g. 20 wt% barium sulphate and 80 wt % EVA-14) vvere prepared by adding the desired ingredients to a stainless steel drum after vvhich the povvder mixtures were pre-mixed by rotating the drum on a rhonrad, or equivalent, at 47 rpm.
The core povvder mixture was subsequently fed to a Berstorff ZE25 co-rotating twin screw extruder (or equivalent) and blend extruded at an extrusion temperature of 125°C. Blend extrusion resulted in strands in vvhich etonogestrel (3-keto desogestrel) was homogeneously dispersed in the EVA-28 matrix. The strands vvere subsequently granulated to core granulate. Essentially the same process, except for a higher extrusion temperature of 150°C, was executed for the skin powder mixture resulting in strands in vvhich barium sulphate was homogeneously dispersed in the EVA-14 matrix. The strands were subsequently granulated to skin granulate.
The co-extrusion set-up consisted of a skin extruder that processed the skin granulate as delivered by the blend extruder and a core extruder that processed the core granulate as delivered by the blend extruder. The melt flovvs vvere combined in a spinneret resulting in a skin-core fibre. The volume flovv rāte of both melt flovvs vvas controlled by a set of separate spinning pumps. An extrusion temperature of 120°C and an extrusion rāte of 1 m/min vvas used. Extrusion lead to a co-axial fiber vvith a diameter of 2 mm and a skin thickness of 60 pm. The fiber vvas cooled dovvn to room temperature in a vvater bath, dried on air and vvound on a reel. The coaxial fiber vvas cut into 4.0 cm rods.
EXAMPLE 3 - comparison of X-ray visibilitv betvveen implant containing barium sulphate in the core, implant containing barium sulphate in the skin and implant vvithout barium sulphate (Implanon)
X-ray photographs vvere taken from implants and subsequently the X-ray visibility betvveen implants having barium sulphate in either core or skin versus x-ray visibility of implants vvithout barium sulphate (Implanon) vvere compared. Figurē 1 demonstrates that incorporation of barium sulphate in the skin layer hardly improved the x-ray visibility vvhen compared to implants vvithout barium sulphate. Hovvever, incorporation of barium sulphate into the core greatly improved the X-ray visibility of the implant.
The x-ray visibility of the implant vvith barium sulphate in the core vvas also tested in vivo in pig tissue. For this purpose implants having barium sulphate in the core and implants vvithout barium sulphate (Implanon) vvere inserted in hind legs of pigs and subsequently X-ray photographs vvere taken. Figurē 2 demonstrates that the barium sulphate containing implant (sample 7) is clearly visible vvhile the Implanon implant is not (sample 8).
EXAMPLE 4 - Hormone release profilē of implant containing barium sulphate in the core in comparison to hormone release profilē of commerciallv available Implanon
In-vitro release rāte profilēs of the implants were tested by tvvo methods. An accelerated release rāte'method vvas performed by testing the implant in an ethanol/vvater (90/10) solution. For the real time release rāte method the in-vitro release profilē vvas tested in vvater. For both tests the release profilē of an implant containing barium sulphate in the core vvas compared to the profilē of Implanon vvithout barium sulphate.
Implants vvere manufactured loaded vvith 8, 11.5 and 15 wt% barium sulphate in the core. The resulting accelerated release profilēs are shovvn in Figurē 3 vvhich demonstrates that ali release profilēs are similar and that vvithin the tested range of barium sulphate content of the core (0-15 wt%) the radio-opaque component does not influence the release of hormones from the device. The same conclusion can be dravvn from the real time release profilēs up to 190 days (Figurē 4), i.e. vvithin the tested range of barium sulphate content of the core (0-15 wt%) the radio-opaque component does not influence the release of hormones from the device.
These conclusions vvere substantiated by calculating Fl values. The Fl values vvere calculated for both accelerated release rāte profilēs (up to and including 18 days) as real time release rāte profilēs (up to and including 190 days) taking the Implanon release profilēs as reference. The results are given in Table 1. Fl values up to 15 (0-15) provide assurance of the sameness or equivalence of the tvvo curves.
Table 1: Fl values for Implants loaded vvith 8, 11.5 and 15 wt% barium sulphate in the core
| barium sulphate (vvt%) | Accelerated release | Real time release |
| 8 | 3.3 | 9.8 |
| 11.5 | 2.4 | 9.7 |
| 15 | 2.1 | 8.7 |
EXAMPLE 5 - Preparation of an implant containing a titanium wire in the core
To prepare implants in which the core contains an inert titanium vvire, Implanon rods with a diameter of 2 mm were adapted such that a titanium wire could be inserted. This was done by carefully drilling a canal in the implants in longitudinal direction. Spiral drills (Guhring Spiralbohre, Germany) with a diameter of either 0.40 or 0.60 mm were applied. A 0.40 mm spiral drill was applied for the implants in vvhich a 0.25 mm titanium wire vvas inserted, vvhereas a 0.60 mm drill vvas used for the implant in vvhich a 0.50 mm titanium wire was inserted. After the canal was prepared, the titanium vvire vvas carefully inserted taking in consideration that the vvire did not penetrate the skin layer. After insertion, the vvire vvas cut at the rod end using a sharp cutter.
EXAMPLE 6: comparison of X-ray visibilitv betvveen implant containing a titanium vvire in the core and implant vvithout a titanium vvire (Implanon)
X-ray photographs vvere taken from implants and subsequently the X-ray visibility betvveen implants having a titanium wire in the core was compared to implants without a titanium vvire (Implanon). As demonstrated in Figurē 5, insertion of a titanium vvire into the core greatly improved the X-ray visibility of the implant.
The x-ray visibility of the titanium vvire implant vvas also tested in vivo in pig tissue. For this purpose implants having a titanium vvire in the core and implants vvithout a vvire (Implanon) vvere inserted in hind legs of pigs and subsequently X-ray photographs vvere taken. Figurē 6 demonstrates that the titanium vvire containing implant (sample 4) is clearly visible vvhile the Implanon implant is not (sample 3).
ΕΧΑΜΡΕΕ 7 - Hormone release profilē of implant containing titanium vvire in core in comparison to hormone release profilē of commerciallv available Implanon
In-vitro release rāte profilēs of Implanon vvere determined by tvvo methods. An accelerated release rāte method vvas performed by testing the implant in an ethanol/vvater (90/10) solution. For the real time release rāte method the in-vitro release profilē was tested in water. For both tests the release profilē of implants containing titanium vvire in the core vvas compared to the profilēs of Implanon without titanium wire. The resulting accelerated release profilēs are shown in Figurē 7 vvhich demonstrates that ali release profilēs are comparable to the Implanon reference implant and that vvithin the tested range of titanium wire diameters (0.25-0.50 mm) the influence on the release of hormones from the device by the radio-opaque component is acceptable.
The same conclusions can be dravvn form the real time release profilēs up to 118 days (Figurē 8), i.e. that ali release profilēs are comparable to the Implanon reference implant and that vvithin the tested range of titanium vvire diameters (0.25-0.50 mm) the influence on the release of hormones from the device by the radio-opaque component is acceptable.
These conclusions vvere substantiated by calculating Fl values. The Fl values were calculated for both accelerated release rāte profilēs (up to and including 18 days) as real time release rāte profilēs (up to and including 118 days) taking the Implanon release profilēs as reference. The results are given in Table 2. Fl values up to 15 (0-15) provided assurance of the sameness or equivalence of the tvvo curves.
Table 2: Fl values for Implants loaded vvith 0.25 and 0.50 mm titanium vvires
| Titanium wire (mm) | Accelerated release | Real time release |
| 0.25 | 2.6 | 8.1 |
| 0.50 | 7.7 | 10.8 |
EXAMPLE 8: Migration of barium sulphate pārticies out of implant with open ends
To reveal the distribution of barium sulphate in the implant and to obtain an impression of the loss of barium sulphate pārticies upon leaching, cryogenic sections vvere made of implants using a ultramicrotome. Subsequently the sections of the implants vvere analyzed using Scanning Electron Microscopy / Energy Dispersed Xspectroscopy (SEM/EDX) before and after leaching. Leaching the implants leads to removal of the etonogestrel crystals from the implant. By examining before and after leaching Information is obtained on the morphology of the barium sulphate/etonogestrel/EVA-28 mixture. A back scatter electron (BSE) detector was used for imaging. In the BSE image the presence of barium sulphate pārticies is easily recognized by the high brightness of the barium sulphate pārticies.
Figurē 9 reveals the morphology of an implant in which the core is loaded vvith about 11.5 wt% barium sulphate. It can be seen that the bright spots, representing barium sulphate, are mainly located in the EVA-28 material, i.e. the irregular shaped grey/black spots, representing etonogestrel crystals, contain no bright spots. Figurē 10 reveals the same sample that vvas leached . The left part is the skin material vvhile the right part shows the leached core. Dark holes are clearly visible. The holes, representing the location at vvhich etonogestrel crystals vvere present before leaching, hardly contain any bright spots.
The content barium sulphate in several batches vvas also tested using incineration before and after leaching (18 days in ethanol/water (90/10)). This gives information on possible migration of barium sulphate crystals out of the implant after the etonogestrel crystals vvere leached out of the implant. The results (table 3) shovv that there is no major change in content of barium sulphate upon leaching. It can therefore be concluded that no or hardly any barium sulphate crystals migrated out of the implant through the open ends.
Combining Figurēs 9 and 10 vvith the results in table 3 it can be concluded that hardly any radio-opaque component (shown by the bright spots) vvas encapsulated by the hormone crystals and that most of the radio- opaque component vvas encapsulated by the polymer EVA-28.
Table 3: Remnant content BaSO4 of implants (average is given and range of 6 samples is given in brackets)
| Batch | untreated [mg BaSCL/implant] | Leached (18 days EtOH/H2O) [mg BaSCL/implant] |
| Core vvith 11.5 vvt% BaSCL | 14.7(14.5-14.8) | 14.9(14.7-15.1) |
| Core vvith 8 wt% BaSCL | 10.3 (10.2-10.4) | 9.5(9.4-9.6) |
| Core vvith 15 vvt% BaSCL | 19.7(19.4-20.1) | 19.5(19.4-19.6) |
EXAMPLE 9 - comparison of X-ray visibilitv betvveen implant containing barium sulphate in the core, and implant vvithout barium sulphate ('Implanon')
X-ray photographs (at 26 KW and 0.6 mAs) vvere taken from implants and subsequently the X-ray visibility betvveen implants having barium sulphate in the core versus x-ray visibility of implants vvithout barium sulphate (Implanon) vvere compared. Figurē 11 demonstrates that incorporation of barium sulphate into the core greatly improved the Xray visibility of the implant. The implant vvith only 4 vvt% barium sulphate content in the core (sample 4) is clearly visible vvhile the Implanon (sample 1) implant vvithout the barium sulphate is not.
The measured transmission of X-ray is a quantitative value for the X-ray visibility of the implants. The number represents the X-ray exposure (pixels per area) of a X-ray camera (transmission X-rays). Table 4 and Figurē 12 shovvthat the amount of X-ray transmission of the implant vvith a lovv barium sulphate content in the core of 4 vvt% (sample 4) is significantly different from the implant vvithout BaSCL (sample 1).
Table 4: X-ray visibility of implant vvith and vvithout BaSCL
| Sample no. | BaS04 content | Transmission ofX-ray [pixels/area] | |
| [wt.%] | Mean [n=4] | SD | |
| 1 | 0 | 1588 | 21 |
| 2 | 11.5 | 736 | 28 |
| 3 | 11.5 | 729 | 29 |
| 4 | 4 | 1140 | 29 |
| 5 | 20 | 486 | 24 |
| 6 | 30 | 292 | 17 |
EXAMPLE 10 - Hormone release profilē of implant containing barium sulphate in the core in comparison to hormone release profilē of commerciallv available Implanon (no barium sulfate)
In-vitro release rāte profilēs of the implants vvere tested by tvvo methods. An accelerated release rāte method vvas performed by testing the implant in an ethanol/vvater (90/10) solution. For the real time release rāte method the in-vitro release profilē was tested in vvater. For both tests the release profilē of an implant containing barium sulphate in the core vvas compared to the profilē of Implanon vvithout barium sulphate.
Implants vvere manufactured loaded vvith 4, 20 and 30 wt% barium sulphate in the core. The resulting accelerated release profilēs are shovvn in Figurē 13 vvhich demonstrates that ali release profilēs are similar and that vvithin the tested range of barium sulphate content of the core (0-30 vvt%) the radio-opaque component does not influence the release of hormones from the device. The same conclusion can be dravvn from the real time release profilēs up to 76 days (Figurē 14), i.e. vvithin the tested range of barium sulphate content of the core (0-30 wt%) the radio-opaque component does not influence the release of hormones from the device.
These conclusions vvere substantiated by calculating F1 values. The F1 values vvere calculated for both accelerated release rāte profilēs (up to and including 18 days) as real time release rāte profilēs (up to and including 76 days) taking the 0 wt% implant release profilēs as reference. The results are given in Table 5. F1 values up to 15 (0-15) provide assurance of the sameness or equi valence of the tvvo curves.
Table 5: F1 values for Implants loaded vvith 4, 20 and 30 wt% barium sulphate in the core
| Barium sulphate [wt%] | Accelerated release | Real time release |
| 4 | 4.2 | 2.9 |
| 20 | 5.8 | 6.9 |
| Barium sulphate [wt%] | Accelerated release | Real time release |
| 30 | 6.8 | 7.5 |
EXAMPLE 11: Migration of barium sulphate pārticies out of implant vvith open ends
To reveal the distribution of barium sulphate in the implant and to obtain an impression ofthe loss of barium sulphate pārticies upon leaching, cryogenic sections vvere made of implants using a ultramicrotome. Subsequently the sections of the implants vvere analyzed using Scanning Electron Microscopy / Energy Dispersed Xspectroscopy (SEM/EDX) before and after leaching. Leaching the implants leads to removal of the etonogestrel crystals from the implant. By examining before and after leaching information is obtained on the morphology of the barium sulphate/etonogestrel/EVA-28 blend. A back scatter electron (BSE) detector vvas used for imaging. In the BSE image the presence of barium sulphate pārticies is easily recognized by the high brightness of the barium sulphate pārticies.
Figurē 15 reveals the morphology of implants in vvhich the core is loaded vvith about 4, 20 and 30 wt% barium sulphate. It can be seen that the bright spots. representing barium sulphate, are mainly located in the EVA-28 material, i.e. the irregular shaped grey/black spots, representing etonogestrel crystals, contain no bright spots. Figurē 16 reveals the same samples that vvere leached . The blank part is the skin material vvhile the part containing the bright spots shovvs the leached core. Dark holes are clearly visible. The holes, representing the location at vvhich etonogestrel crystals vvere present before leaching, hardly contain any bright spots.
The content barium sulphate in several batches vvas also tested using incineration before and after leaching (18 days in ethanol/vvater (90/10)). This gives information on possible migration of barium sulphate crystals out of the implant after the etonogestrel crystals vvere leached out ofthe implant. The results (table 6) shovv that there is no major change in content of barium sulphate upon leaching. It can therefore be concluded that no or hardly any barium sulphate crystals migrated out of the implant through the open ends.
By combining Figurēs 15 and 16 with the results in Table 6 it can be concluded that hardly any radio-opaque component (shovvn by the bright spots) was encapsulated by the hormone crystals and that most of the radio- opaque component was encapsulated by the polymer EVA-28.
Table 6: Remnant content BaSCU of implants (average is given and range of 6 samples is given in brackets)
| Batch | Untreated [mg BaSO4/implant] | Leached (18 days EtOH/H2O) [mg BaSOVimplant] |
| Core with 4 wt% BaSO4 | 5.0(4.9-5.1) | 5.6 (5.5-5.6) |
| Core with 20 wt% BaSO4 | 26.2 (26.0-26.3) | 26.8 (26.6-26.9) |
| Core vvith 30 wt% BaSO4 | 45.6 (45.4-45.8) | 45.2 (45.1 -45.4) |
Claims (13)
1. An X-ray visible drug delivery device for subdermal administration of a contraceptive or hormone replacement therapy comprising one compartment consisting of (i) a thermoplastic polymer core loaded vvith (a) a contraceptively effective or therapeutically effective amount of desogestrel or 3-ketodesogestrel and (b) 4-30% by vveight radio-opaque material and (ii) a non-medicated thermoplastic polymer skin covering the core.
2. An X-ray visible drug delivery device according to claim 1 vvherein the radioopaque material is 6-20% by vveight
3. An X-ray visible drug delivery device according to claim 1 vvherein the radioopaque material is 8-15% by vveight.
4. An X-ray visible drug delivery device according to any one of the preceding claims vvherein the radio-opaque material in the core does not affect the release of the desogestrel or 3-ketodesogestrel from the device.
5. An X-ray visible drug delivery device according to any one of the preceding claims vvherein the radio-opaque pārticies do not migrate out of the implant.
6. An X-ray visible drug delivery device according to any one of the preceding claims vvherein the radio-opaque material is barium sulphate.
7. An X-ray visible drug delivery device according to any one of the preceding claims vvherein the device is an implant.
8. An X-ray visible drug delivery device according to any one of the preceding claims vvherein the thermoplastic polymer is polyethylene vinyl acetate.
9. An X-ray visible drug delivery device for subdermal administration of a contraceptive or hormone replacement therapy comprising one compartment consisting of (i) a thermoplastic polymer core loaded vvith a contraceptively effective or therapeutically effective amount of desogestrel or 3-ketodesogestrel and containing an inert mētai wire and (ii) a non-medicated thermoplastic polymer skin covering the core.
10. An X-ray visible drug delivery device according to claim 9 wherein the mētai wire in the core does not affect the release of the desogestrel or 3-ketodesogestrel from the device.
11. An X-ray visible drug delivery device according to claims 9 or 10 vvherein the inert mētai vvire is a titanium vvire.
12. An X-ray visible drug delivery device according to any one of claims 9-11 vvherein the device is an implant.
13. An X-ray visible drug delivery device according to any one of claims 9-12 vvherein the thermoplastic polymer is polyethylene vinyl acetate.
1/16
Figurē 1
a) No BaSO4 (Implanon)
b) 20wt% BaSO4 in skin c) 11.5 wt% BaSO4 in core
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| AU2017263253B2 (en) * | 2016-05-12 | 2022-04-14 | Merck Sharp & Dohme Llc | Drug delivery system for the delivery of antiviral agents |
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| US10406336B2 (en) | 2016-08-03 | 2019-09-10 | Neil S. Davey | Adjustable rate drug delivery implantable device |
| US9980850B2 (en) | 2016-09-29 | 2018-05-29 | Gesea Biosciences, Inc. | Bioerodible contraceptive implant and methods of use thereof |
| CN119157859A (zh) * | 2017-07-08 | 2024-12-20 | 赫拉健康解决方案公司 | 可生物侵蚀的药物递送植入物 |
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| KR20210013088A (ko) | 2018-05-24 | 2021-02-03 | 셀라니즈 이브이에이 퍼포먼스 폴리머스 엘엘씨 | 거대 분자 약물 화합물의 지속적인 방출을 위한 이식가능 장치 |
| EP3803866A4 (en) | 2018-05-24 | 2022-03-16 | Nureva Inc. | METHOD, APPARATUS, AND COMPUTER READABLE MATERIALS FOR MANAGING SEMI-CONSTANT (PERSISTENT) SOUND SOURCES IN MICROPHONE CATCH/HOME AREAS |
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- 2005-03-14 MX MXPA06010714A patent/MXPA06010714A/es active IP Right Grant
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- 2005-03-14 KR KR1020067021233A patent/KR101086619B1/ko active IP Right Grant
- 2005-03-14 NZ NZ549877A patent/NZ549877A/en unknown
- 2005-03-14 WO PCT/EP2005/051150 patent/WO2005089814A1/en active IP Right Grant
- 2005-03-14 AU AU2005224054A patent/AU2005224054B2/en active Active
- 2005-03-14 RU RU2006136913/15A patent/RU2384347C2/ru active
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- 2005-03-14 CA CA2559250A patent/CA2559250C/en not_active Expired - Fee Related
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