AU2013200837B2 - Manufacture of long term drug delivery devices with polyurethane based polymers - Google Patents
Manufacture of long term drug delivery devices with polyurethane based polymers Download PDFInfo
- Publication number
- AU2013200837B2 AU2013200837B2 AU2013200837A AU2013200837A AU2013200837B2 AU 2013200837 B2 AU2013200837 B2 AU 2013200837B2 AU 2013200837 A AU2013200837 A AU 2013200837A AU 2013200837 A AU2013200837 A AU 2013200837A AU 2013200837 B2 AU2013200837 B2 AU 2013200837B2
- Authority
- AU
- Australia
- Prior art keywords
- polyurethane
- active ingredients
- drug delivery
- based polymer
- delivery device
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Ceased
Links
- 229920002635 polyurethane Polymers 0.000 title claims abstract description 98
- 239000004814 polyurethane Substances 0.000 title claims abstract description 98
- 229920000642 polymer Polymers 0.000 title claims abstract description 79
- 238000012377 drug delivery Methods 0.000 title claims abstract description 67
- 238000004519 manufacturing process Methods 0.000 title claims description 15
- 230000007774 longterm Effects 0.000 title description 4
- 239000003814 drug Substances 0.000 claims abstract description 38
- 229940079593 drug Drugs 0.000 claims abstract description 37
- 239000004480 active ingredient Substances 0.000 claims abstract description 35
- 238000000034 method Methods 0.000 claims abstract description 35
- 239000003937 drug carrier Substances 0.000 claims abstract description 10
- 239000000203 mixture Substances 0.000 claims description 37
- 229920001187 thermosetting polymer Polymers 0.000 claims description 34
- 230000008569 process Effects 0.000 claims description 32
- 230000003750 conditioning effect Effects 0.000 claims description 29
- 230000037452 priming Effects 0.000 claims description 28
- 238000007789 sealing Methods 0.000 claims description 26
- 238000009472 formulation Methods 0.000 claims description 25
- 239000004433 Thermoplastic polyurethane Substances 0.000 claims description 15
- 229920002803 thermoplastic polyurethane Polymers 0.000 claims description 15
- 230000002209 hydrophobic effect Effects 0.000 claims description 14
- 238000000338 in vitro Methods 0.000 claims description 13
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 12
- -1 muscle contractants Substances 0.000 claims description 11
- 238000004528 spin coating Methods 0.000 claims description 11
- 239000004970 Chain extender Substances 0.000 claims description 10
- 239000007787 solid Substances 0.000 claims description 10
- 238000009792 diffusion process Methods 0.000 claims description 9
- 238000001125 extrusion Methods 0.000 claims description 9
- 238000004132 cross linking Methods 0.000 claims description 8
- 230000001143 conditioned effect Effects 0.000 claims description 7
- 238000001746 injection moulding Methods 0.000 claims description 7
- 229920005862 polyol Polymers 0.000 claims description 7
- 150000003077 polyols Chemical class 0.000 claims description 7
- 125000005442 diisocyanate group Chemical group 0.000 claims description 6
- 239000002904 solvent Substances 0.000 claims description 6
- 239000004971 Cross linker Substances 0.000 claims description 4
- 230000003444 anaesthetic effect Effects 0.000 claims description 4
- 230000000202 analgesic effect Effects 0.000 claims description 4
- 230000001773 anti-convulsant effect Effects 0.000 claims description 4
- 230000003110 anti-inflammatory effect Effects 0.000 claims description 4
- 230000000078 anti-malarial effect Effects 0.000 claims description 4
- 230000002141 anti-parasite Effects 0.000 claims description 4
- 230000000648 anti-parkinson Effects 0.000 claims description 4
- 230000002921 anti-spasmodic effect Effects 0.000 claims description 4
- 229940125681 anticonvulsant agent Drugs 0.000 claims description 4
- 239000001961 anticonvulsive agent Substances 0.000 claims description 4
- 239000003430 antimalarial agent Substances 0.000 claims description 4
- 229940033495 antimalarials Drugs 0.000 claims description 4
- 239000004599 antimicrobial Substances 0.000 claims description 4
- 239000003096 antiparasitic agent Substances 0.000 claims description 4
- 239000000939 antiparkinson agent Substances 0.000 claims description 4
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 claims description 4
- 210000003169 central nervous system Anatomy 0.000 claims description 4
- 239000000812 cholinergic antagonist Substances 0.000 claims description 4
- 239000002934 diuretic Substances 0.000 claims description 4
- 229940030606 diuretics Drugs 0.000 claims description 4
- 230000002526 effect on cardiovascular system Effects 0.000 claims description 4
- 229940125697 hormonal agent Drugs 0.000 claims description 4
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 4
- 239000003999 initiator Substances 0.000 claims description 4
- 210000003205 muscle Anatomy 0.000 claims description 4
- 229940035363 muscle relaxants Drugs 0.000 claims description 4
- 239000003158 myorelaxant agent Substances 0.000 claims description 4
- 230000003236 psychic effect Effects 0.000 claims description 4
- 239000003204 tranquilizing agent Substances 0.000 claims description 4
- 230000002936 tranquilizing effect Effects 0.000 claims description 4
- 230000000845 anti-microbial effect Effects 0.000 claims description 3
- 235000021355 Stearic acid Nutrition 0.000 claims description 2
- QIQXTHQIDYTFRH-UHFFFAOYSA-N octadecanoic acid Chemical compound CCCCCCCCCCCCCCCCCC(O)=O QIQXTHQIDYTFRH-UHFFFAOYSA-N 0.000 claims description 2
- OQCDKBAXFALNLD-UHFFFAOYSA-N octadecanoic acid Natural products CCCCCCCC(C)CCCCCCCCC(O)=O OQCDKBAXFALNLD-UHFFFAOYSA-N 0.000 claims description 2
- 239000008117 stearic acid Substances 0.000 claims description 2
- 239000000150 Sympathomimetic Substances 0.000 claims 3
- 230000001975 sympathomimetic effect Effects 0.000 claims 3
- 230000015572 biosynthetic process Effects 0.000 claims 1
- 125000001033 ether group Chemical group 0.000 claims 1
- 230000001747 exhibiting effect Effects 0.000 claims 1
- 238000002513 implantation Methods 0.000 claims 1
- 125000003010 ionic group Chemical group 0.000 claims 1
- 239000007943 implant Substances 0.000 abstract description 28
- 230000000144 pharmacologic effect Effects 0.000 abstract description 4
- 230000009885 systemic effect Effects 0.000 abstract description 4
- 150000001875 compounds Chemical class 0.000 abstract description 3
- 241001465754 Metazoa Species 0.000 abstract 1
- 230000000975 bioactive effect Effects 0.000 abstract 1
- 210000000056 organ Anatomy 0.000 abstract 1
- 239000000126 substance Substances 0.000 abstract 1
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 16
- 239000002609 medium Substances 0.000 description 13
- 239000008188 pellet Substances 0.000 description 13
- 239000000969 carrier Substances 0.000 description 10
- 238000010107 reaction injection moulding Methods 0.000 description 8
- 238000010828 elution Methods 0.000 description 7
- HHXHVIJIIXKSOE-QILQGKCVSA-N histrelin Chemical compound CCNC(=O)[C@@H]1CCCN1C(=O)[C@H](CCCNC(N)=N)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](NC(=O)[C@H](CC=1C=CC(O)=CC=1)NC(=O)[C@H](CO)NC(=O)[C@H](CC=1C2=CC=CC=C2NC=1)NC(=O)[C@H](CC=1N=CNC=1)NC(=O)[C@H]1NC(=O)CC1)CC(N=C1)=CN1CC1=CC=CC=C1 HHXHVIJIIXKSOE-QILQGKCVSA-N 0.000 description 7
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 6
- 229960002193 histrelin Drugs 0.000 description 6
- 108700020746 histrelin Proteins 0.000 description 6
- DQCKKXVULJGBQN-XFWGSAIBSA-N naltrexone Chemical compound N1([C@@H]2CC3=CC=C(C=4O[C@@H]5[C@](C3=4)([C@]2(CCC5=O)O)CC1)O)CC1CC1 DQCKKXVULJGBQN-XFWGSAIBSA-N 0.000 description 6
- 229960003086 naltrexone Drugs 0.000 description 6
- 230000000977 initiatory effect Effects 0.000 description 4
- 239000012948 isocyanate Substances 0.000 description 4
- 150000002513 isocyanates Chemical class 0.000 description 4
- 239000011780 sodium chloride Substances 0.000 description 4
- 125000000217 alkyl group Chemical group 0.000 description 3
- 238000000748 compression moulding Methods 0.000 description 3
- 125000000524 functional group Chemical group 0.000 description 3
- 230000007246 mechanism Effects 0.000 description 3
- 125000005373 siloxane group Chemical group [SiH2](O*)* 0.000 description 3
- 239000000243 solution Substances 0.000 description 3
- 238000012360 testing method Methods 0.000 description 3
- GJSURZIOUXUGAL-UHFFFAOYSA-N Clonidine Chemical compound ClC1=CC=CC(Cl)=C1NC1=NCCN1 GJSURZIOUXUGAL-UHFFFAOYSA-N 0.000 description 2
- 101000904173 Homo sapiens Progonadoliberin-1 Proteins 0.000 description 2
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 description 2
- 102100024028 Progonadoliberin-1 Human genes 0.000 description 2
- 101000996723 Sus scrofa Gonadotropin-releasing hormone receptor Proteins 0.000 description 2
- 239000013543 active substance Substances 0.000 description 2
- 239000000853 adhesive Substances 0.000 description 2
- 230000001070 adhesive effect Effects 0.000 description 2
- 239000000556 agonist Substances 0.000 description 2
- 239000007864 aqueous solution Substances 0.000 description 2
- 238000006243 chemical reaction Methods 0.000 description 2
- 229960002896 clonidine Drugs 0.000 description 2
- 230000001276 controlling effect Effects 0.000 description 2
- XLXSAKCOAKORKW-UHFFFAOYSA-N gonadorelin Chemical compound C1CCC(C(=O)NCC(N)=O)N1C(=O)C(CCCN=C(N)N)NC(=O)C(CC(C)C)NC(=O)CNC(=O)C(NC(=O)C(CO)NC(=O)C(CC=1C2=CC=CC=C2NC=1)NC(=O)C(CC=1NC=NC=1)NC(=O)C1NC(=O)CC1)CC1=CC=C(O)C=C1 XLXSAKCOAKORKW-UHFFFAOYSA-N 0.000 description 2
- 239000007788 liquid Substances 0.000 description 2
- 230000003278 mimic effect Effects 0.000 description 2
- 230000035699 permeability Effects 0.000 description 2
- 230000000704 physical effect Effects 0.000 description 2
- 229910052708 sodium Inorganic materials 0.000 description 2
- 239000011734 sodium Substances 0.000 description 2
- 230000003442 weekly effect Effects 0.000 description 2
- VEXZGXHMUGYJMC-UHFFFAOYSA-M Chloride anion Chemical compound [Cl-] VEXZGXHMUGYJMC-UHFFFAOYSA-M 0.000 description 1
- 239000004721 Polyphenylene oxide Substances 0.000 description 1
- 238000010521 absorption reaction Methods 0.000 description 1
- 125000001931 aliphatic group Chemical group 0.000 description 1
- 239000012736 aqueous medium Substances 0.000 description 1
- 210000001367 artery Anatomy 0.000 description 1
- 230000008901 benefit Effects 0.000 description 1
- 239000012620 biological material Substances 0.000 description 1
- 210000001124 body fluid Anatomy 0.000 description 1
- 239000010839 body fluid Substances 0.000 description 1
- 238000010382 chemical cross-linking Methods 0.000 description 1
- 238000013270 controlled release Methods 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 230000007717 exclusion Effects 0.000 description 1
- 238000010579 first pass effect Methods 0.000 description 1
- 230000005484 gravity Effects 0.000 description 1
- 210000003709 heart valve Anatomy 0.000 description 1
- 229960003911 histrelin acetate Drugs 0.000 description 1
- 230000003993 interaction Effects 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 238000000465 moulding Methods 0.000 description 1
- 229920000570 polyether Polymers 0.000 description 1
- 239000011148 porous material Substances 0.000 description 1
- 238000002360 preparation method Methods 0.000 description 1
- 230000002035 prolonged effect Effects 0.000 description 1
- 230000001105 regulatory effect Effects 0.000 description 1
- 239000011347 resin Substances 0.000 description 1
- 229920005989 resin Polymers 0.000 description 1
- 210000002435 tendon Anatomy 0.000 description 1
- 230000001225 therapeutic effect Effects 0.000 description 1
- 229920001169 thermoplastic Polymers 0.000 description 1
- 239000004416 thermosoftening plastic Substances 0.000 description 1
- 210000003462 vein Anatomy 0.000 description 1
Landscapes
- Medicinal Preparation (AREA)
- Materials For Medical Uses (AREA)
Abstract
This invention is related to the use of polyurethane based polymer as a drug delivery device to deliver biologically active compounds at a constant rate for an extended period of time and methods of manufactures thereof The device is very biocompatible and biostable, and is useful as an implant in patients (humans and animals) for the delivery of appropriate bioactive substances to tissues or organs. The drug delivery device for releasing one or more drugs at controlled rates for an extended period of time to produce local or systemic pharmacological effects comprises: 1. a reservoir, said reservoir comprising; 2. at least one active ingredient; and, optionally, 3. at least one pharmaceutically acceptable carrier; a polyurethane based polymer completely surrounding the reservoir.
Description
Regulation 3.2 AUSTRALIA Patents Act 1990 COMPLETE SPECIFICATION DIVISIONAL APPLICATION APPLICANT: ENDO PHARMACEUTICALS SOLUTIONS INC. Invention Title: MANUFACTURE OF LONG TERM DRUG DELIVERY DEVICES WITH POLYURETHANE BASED POLYMERS The following statement is a full description of this invention, including the best method of performing it known to me: TITLE OF INVENTION Manufacture of long term drug delivery devices with polyurethane based polymers. FIELD OF INVENTION 5 The present invention relates to the field of drug delivery devices and more specifically implantable drug delivery devices made of polyurethane based polymers. BACKGROUND OF THE INVENTION Due to its excellent biocompatibility, biostability and physical properties, 10 polyurethane or polyurethane-containing polymers have been used to fabricate a large number of implantable devices, including pacemaker leads, artificial hearts, heart valves, stent coverings, artificial tendons, arteries and veins. See e.g., www.polymertech.com, www.cardiotech-inc.com, and www.thermedicsinc.com. Also see Hsu et al., Soc. Biomaterials Trans., April 15 1998. Known in the art is US 3,975,350 which discloses the use of polyurethanes to make implants containing pharmaceutically active agents. This patent discloses that the active agents are mixed with the polyurethane polymer prior to being cast (or shaped) into a number of forms, including tubes, rods, 20 films, etc. Also known is US 3,993,073 which discloses a delivery device for the controlled and continuous administration of a drug to a body site. The device disclosed therein comprises a reservoir containing a dissolved drug surrounded by a shaped wall which is insoluble in body fluid. 25 US 3,948,254 discloses a drug delivery device for the administration of a drug. The drug is contained within a reservoir and the device comprises pores filled with a liquid which is permeable to the passage of the drug.
-2 The inventors are not aware of any prior art polyurethane based drug delivery devices which can contain a drug in a solid form and which does not require a liquid medium or carrier for the diffusion of the drug at a zero order rate. 5 SUMMARY OF THE INVENTION It is an object of the present invention to provide polyurethane based long term drug delivery devices. It is a further object of the present invention to provide biocompatible and biostable polyurethane based devices for the delivery of drugs ot other 10 compounds in a living organism. This is accomplished through a drug delivery device for releasing one or more drugs at controlled rates for an extended period of time to produce local or systemic pharmacological effects, said drug delivery device having a reservoir comprising: 15 a) a polyurethane based polymer completely surrounding the reservoir; b) at least one active ingredient; and, optionally, c) at least one pharmaceutically acceptable carrier; Preferably, the drug delivery device has a cylindrically shaped reservoir. Preferably also, the polyurethane based polymer is selected from the group 20 consisting of: thermoplastic polyurethane, and thermoset polyurethane. Even more preferably, the thermoplastic polyurethane is made of macrodials, diisocyanates, difunctional chain extenders or mixtures thereof. Preferably, the thermoset polyurethane is made of multifunctional polyps, isocyanates, chain extenders or mixtures thereof.
-3 Preferably also, the thermoset polyurethane comprises a polymer chain and cross-linking members, said thermoset polyurethane contains unsaturated bonds in the polymer chains and appropriate crosslinkers and/or initiators as cross-linking members. 5 Preferably, the drug delivery device is made of polyurethane which comprises functional groups selected from hydrophilic pendant groups and hydrophobic pendant groups. More preferably, the hydrophilic pendant groups are selected from ionic, carboxyl, ether, hydroxyl groups and mixtures thereof. Even more preferably, the hydrophobic pendant groups are selected 10 from alkyl and siloxane groups and mixtures thereof. Another object of the present invention is a process of manufacturing a drug delivery device, said process comprising: a) precision extrusion or injection molding step to produce a hollow tube made of thermoplastic polyurethane with two open ends with desired 15 physical dimensions; b) sealing one of the open ends of the hollow tube; c) loading a reservoir containing a desired formulation containing actives and, optionally, carriers or filling a reservoir with pre-fabricated pellets; 20 d) sealing the second open end of the hollow tube; and e) conditioning and priming of the drug delivery devices to achieve the desired delivery rates for the actives. Preferably, the sealing steps may be carried out by using pre-fabricated plugs which are inserted on the open ends of the hollow tube with heat or solvent -4 or by applying heat or solvent while sealing or any other means to seal the ends, preferably permanently. Yet another object of the present invention is a process of manufacturing drug delivery devices made with thermoset polyurethanes, said process 5 comprising: a) precision reaction injection molding or spin casting a hollow tube having two open ends; b) curing the hollow tube; c) sealing one-end of the hollow tube; 10 d) loading a reservoir containing a desired formulation containing actives and, optionally, carriers or filling a reservoir with pre-fabricated pellets; e) sealing the second end of the hollow tube; and f) conditioning and priming of the drug delivery devices to achieve the 15 desired delivery rates for the actives. Yet another object of the present invention is a process of manufacturing drug delivery devices made with thermoset polyurethanes, said process comprising: a) precision reaction injection molding or spin casting a hollow tube 20 having one open end; b) curing the hollow tube; -5 c) loading a reservoir containing a desired formulation containing actives and, optionally, carriers or filling a reservoir with pre-fabricated pellets; d) sealing the open end of the hollow tube; and 5 e) conditioning and priming of the drug delivery devices to achieve the desired delivery rates for the actives. Another object of the present invention is a process of manufacturing drug delivery devices made with thermoset polyurethanes, wherein the production of the hollow tube and sealing of an open end, is done with an 10 appropriate light-initiated and/or heat-initiated thermoset polyurethane formulation and initiating and curing the light-initiated and/or heat-initiated thermoset polyurethane formulation with light and/or heat or any other means to seal the ends, preferably permanently. Also another object of the present invention involves a process of 15 manufacturing drug delivery devices made with thermoset polyurethanes, wherein the sealing of an open end, is done by inserting a pre-fabricated end plug at the open end of the hollow tube by suitable means, for example, as described in U.S. 5,292,515. Such suitable means are preferably pharmaceutically acceptable adhesives. 20 Yet another object of the invention is a process of manufacturing drug delivery devices made with thermoset polyurethanes, wherein the sealing of an open end, is done by inserting a pre-fabricated end plug at the open end of the hollow tube and by applying an appropriate light-initiated and/or heat initiated thermoset polyurethane formulation on interface between the pre 25 fabricated end plug and the open end and initiating and curing with light and/or heat or any other means to seal the ends, preferably permanently.
-6 In one instance there is provided a drug delivery device for releasing one or more drugs at controlled rates for an extended period of time to produce local or systemic pharmacological effects, said drug delivery device having a reservoir comprising: 5 i. at least one active ingredient; and, optionally, I. at least one pharmaceutically acceptable carrier; and iii. a polyurethane based polymer completely surrounding the reservoir. Preferably the drug delivery device has a cylindrically shaped reservoir. Preferably, the polyurethane based polymer is selected from the group 10 comprising: thermoplastic polyurethane, and thermoset polyurethane. More preferably, the thermoplastic polyurethane is made of macrodials, diisocyanates, difunctional chain extenders or mixtures thereof. Also more preferably, the thermoset polyurethane is made of multifunctional polyols, isocyanates, chain extenders or mixtures thereof. 15 Even more preferably, the thermoset polyurethane comprises a polymer chain and cross-linking members, said thermoset polyurethane contains unsaturated bonds in the polymer chains and appropriate crosslinkers and/or initiators as cross-linking members. Preferably, the polyurethane comprises functional groups selected from 20 hydrophilic pendant groups and hydrophobic pendant groups. More preferably, the hydrophilic pendant groups are selected from ionic, carboxyl, ether, hydroxyl groups and mixtures thereof. Also preferably, the hydrophobic pendant groups are selected from alkyl, siloxane groups and mixtures thereof.
-7 In one instance there is provided for a process of manufacturing drug delivery devices made with thermoplastic polyurethanes, said process comprising: a) precision extrusion or injection molding step to produce a hollow tube 5 made of thermoplastic polyurethane with two open ends with desired physical dimensions; b) sealing one of the open ends of the hollow tube; c) loading a reservoir containing a desired formulation containing actives and, optionally, carriers or filling a reservoir with pre-fabricated 10 pellets; d) sealing the second open end of the hollow tube; e) conditioning and priming of the drug delivery devices to achieve the desired delivery rates for the actives. Preferably, the sealing steps may be carried out by using pre-fabricated plugs 15 which are inserted on the open ends of the hollow tube with heat or solvent or by applying heat or solvent while sealing or any other means to seal the ends, preferably permanently. In one instance there is provided for a process of manufacturing drug delivery devices made with thermoset polyurethanes, said process 20 comprising: a) precision reaction injection molding or spin casting a hollow tube . having two open ends; b) curing the hollow tube; c) sealing one end of the hollow tube; -8 d) loading a reservoir containing a desired formulation containing actives and, optionally, carriers or filling a reservoir with pre-fabricated pellets; e) sealing the second end of the hollow tube; and 5 f) conditioning and priting of the drug delivery devices to achieve the desired delivery rates for the actives. In another instance there is provided for a process of manufacturing drug delivery devices made with thermoset polyurethanes, said process comprising: 10 a) precision reaction injection molding or spin casting a hollow tube having one open end; b) curing the hollow tube; c) loading a reservoir containing a desired formulation containing actives and, optionally, carriers or filling a reservoir with pre-fabricated 15 pellets; d) sealing the open end of the hollow tube; and e) conditioning and priming of the drug delivery devices to achieve the desired delivery rates for the actives. Preferably, the production of the hollow tube and the sealing of an open end 20 are done with an appropriate light-initiated and/or heat-initiated thermoset polyurethane formulation and initiating and curing the light-initiated and/or heat-initiated thermoset polyurethane formulation with light and/or heat or any other means to seal the ends, preferably permanently.
-9 More preferably, the sealing of an open end, is done by inserting a pre fabricated end plug at the open end of the hollow tube by suitable means, for example, as described in U.S. 5,292,515. Such suitable means are preferably pharmaceutically acceptable adhesives. Even more preferably, the sealing of 5 an open end, is done by inserting a pre-fabricated end plug at the open end of the hollow tube and by applying an appropriate light-initiated and/or heat initiated thermoset polyurethane formulation on interface between the pre fabricated end plug and the open end and initiating and curing with light and/or heat or any other means to seal the ends, preferably permanently. 10 DETAILED DESCRIPTION OF THE FIGURES Figure 1 is a side view of an implant with two open ends as used in the present invention. Figure 2 is a side view of the pre-fabricated end plugs used to plug the implants according to the present invention. 15 Figure 3 is a side view of an implant with one open end as used in the present invention. Figure 4 is a graph of the elution rate of histrelin using an implant according to the present invention. Figure 5 is a graph of the elution rate of naltrexone using implants according 20 to the present invention. Figure 6 is a graph of the elation rate of naltrexone from polyurethane implants according to the present invention. Figure 7 is a graph of the elution rate of LHRH agonist (histrelin) from a polyurethane implant according to the present invention.
-10 Figure 8 is a graph of the elution rate of clonidine from a polyurethane implant according to the present invention. DETAILED DESCRIPTION OF THE INVENTION To take the advantage of the excellent properties of polyurethane based 5 polymers, this invention uses polyurethane based polymers as drug delivery devices for releasing drugs at controlled rates for an extended period of time to produce local or systemic pharmacological effects. The drug delivery device is preferably comprised of a cylindrically shaped reservoir surrounded by polyurethane based polymer through which controls the delivery rate of 10 the drug inside the reservoir. The reservoir is comprised of active ingredients and, optionally, pharmaceutically acceptable carriers. The carriers are formulated to facilitate the diffusion of the active ingredients through the polymer and to ensure the stability of the drugs inside the reservoir. The current invention provides a drug delivery device that can achieve the 15 following objectives: a controlled release rate (zero order release rate) to maximize therapeutic effects and minimize unwanted side effects; an easy way to retrieve the device if it is necessary to end the treatment; an increase in bioavailability with less variation in absorption and no first pass metabolism. The release rate of the drug is governed by the Fick's Law of Diffusion as 20 applied to a cylindrically shaped reservoir device (cartridge). The following equation describes the relationship between different parameters: dM 2uhpAC dt In (ro/ri) where: 25 dM/dt : drug release rate; h length of filled portion of device; A C concentration gradient across the reservoir wall; ro/ri ratio of outside to inside radii of device; and p permeability coefficient of the polymer used.
The permeability coefficient is primarily regulated by the hydrophilicity/hydrophobicity of the polymer, the structure of the polymer, and the interaction of drug and the polymer. Once the polymer and the active ingredient are selected, p will be a constant, h, ro, and r; are fixed and kept 5 constant once the cylindrically shaped device is produced. A C is maintained constant by the carriers inside the reservoir. To keep the geometry of the device as precise as possible, the preferably cylindrically shaped device can be manufactured through precision extrusion or precision molding process for thermoplastic polyurethane polymers, and 10 reaction injection molding or spin casting process for thermosetting polyurethane polymers. The cartridge can be made with either one end closed or both ends open. The open end can be plugged with pre-manufactured end plug to ensure a smooth end and a solid seal. The solid actives and carriers can be compressed 15 into pellet form to maximize the loading of the actives. To identify the location of the implant, radiopaque material can be incorporated into the delivery device by inserting it into the reservoir or by making it into end plug to be used to seal the cartridge. Once the cartridges are sealed on both ends with filled reservoir, they are 20 conditioned and primed for an appropriate period of time to ensure a constant delivery rate. The conditioning of the drug delivery devices involves the loading of the actives (drug) into the polyurethane based polymer which surrounds the reservoir. The priming is done to stop the loading of the drug into the 25 polyurethane based polymer and thus prevent loss of the active before the actual use of the implant. The conditions used for the conditioning and priming step depend on the active, the temperature and the medium in which -12 they are carried out. The conditions for the conditioning and priming may be the same in some instances. The conditioning and priming step in the process of the preparation of the drug delivery devices is done to obtain a determined rate of release of a 5 specific drug. The conditioning and priming step of the implant containing a hydrophilic drug is preferably carried out in an aqueous medium, more preferably in a saline solution. The conditioning and priming step of a drug delivery device comprising a hydrophobic drug is usually carried out in a hydrophobic medium such as an oil based medium. The conditioning and 10 priming steps are carried out by controlling three specific factors namely the temperature, the medium and the period of time. A person skilled in the art would understand that the conditioning and priming step of the drug delivery device will be affected by the medium in which the device is placed. As mentioned previously, a hydrophilic drug 15 would be preferably conditioned and primed in an aqueous solution and more preferably, in a saline solution. For example, Histrelin and Naltrexone implants have been conditioned and primed in saline solution, more specifically, conditioned in saline solution of 0.9 % sodium content and primed in saline solution of 1.8% sodium chloride content. 20 The temperature used to condition and prime the drug delivery device may vary across a wide range of temperatures but, in some instances 37*C, has been preferably used. The time period used for the conditioning and priming of the drug delivery devices may vary from a single day to several weeks depending on the 25 release rate desired for the specific implant or drug. A person skilled in the art will understand the steps of conditioning and priming the implants is to optimize the rate of release of the drug contained -13 within the implant. As such, a shorter time period spent on the conditioning and the priming of a drug delivery device results in a lower rate of release of the drug compared to a similar drug delivery device which has undergone a longer conditioning and priming step. 5 The temperature in the conditioning and priming step will also affect the rate of release in that a lower temperature results in a lower rate of release of the drug contained in the drug delivery device when compared to a similar drug delivery device which has undergone a treatment at a higher temperature. Similarly, in the case of aqueous solutions, which are in some cases preferably 10 saline solutions, the sodium chloride content of the solution will also determine what type of rate of release will be obtained for the drug delivery device. More specifically, a lower content of sodium chloride would result in a higher rate of release of drug when compared to a drug delivery device which has undergone a conditioning and priming step where the sodium 15 chloride content was higher. The same conditions apply for hydrophobic drugs where the main difference in the conditioning and priming step would be that the conditioning and priming medium be hydrophobic medium, more specifically an oil based medium. 20 The drug (actives) that can be delivered include drugs that can act on the central nervous system, psychic energizers, tranquilizers, anti-convulsants, muscle relaxants, anti-parkinson, analgesic, anti-inflammatory, anesthetic, antispasmodic, muscle contractants, anti-microbials, anti-malarials, hormonal agents, sympathominmetic, cardiovascular, diuretics, anti-parasitic and the 25 like. The current invention focuses on the application of polyurethane based polymers, thermoplastics or thermosets, to the creation of implantable drug -14 devices to deliver biologically active compounds at controlled rates for prolonged period of time. Polyurethane polymers are preferably made into cylindrical hollow tubes with one or two open ends through extrusion, (reaction) injection molding, compression molding, or spin-casting (see e.g. 5 U.S. patents 5,266,325 and 5,292,515), depending on the type of polyurethane used. Thermoplastic polyurethane can be processed through extrusion, injection molding, or compression molding. Thermoset polyurethane can be processed through reaction injection molding, compression molding, or spin-casting. 10 The dimensions of the cylindrical hollow tube are very critical and need to be as precise as possible. Polyurethane based polymers are synthesized from multi-functional polyols, isocyanates and chain extenders. The characteristics of each polyurethane can be attributed to its structure. 15 Thermoplastic polyurethanes are made of macrodials, diisocyanates, and difunctional chain extenders (e.g. U.S. patents 4,523,005 and 5,254,662). Macrodials make up the soft domains. Diisocyanates and chain extenders make up the hard domains. The hard domains serve as physical crosslinking sites for the polymers. Varying the ratio of these two domains can alter the 20 physical characteristics of the polyurethanes. Thermoset polyurethanes can be made of multifunctional (greater than difunctional) polyols and/or isocyanates and/or chain extenders (e.g. U.S. patents 4,386,039 and 4,131,604). Thermoset polyurethanes can also be made by introducing unsaturated bonds in the polymer chains and appropriate 25 crosslinkers and/or initiators to do the chemical crosslinking (e.g. U.S. patent 4,751,133). By controlling the amounts of crosslinking sites and how they are distributed, the release rates of the actives can be controlled.
-15 Different functional groups can be introduced into the polyurethane polymer chains through the modification of the backbones of polyols depending on the properties desired. When the device is used for the delivery of water soluble drugs, hydrophilic pendant groups such as ionic, carboxyl, ether, and 5 hydroxy groups are incorporated into the polyols to increase the hydrophilicity of the polymer (e.g. U.S. patents 4,743,673 and 5,354,835). When the device is used for the delivery of hydrophobic drugs, hydrophobic pendant groups such as alkyl, siloxane groups are incorporated into the polyols to increase the hydrophobicity of the polymer (e.g. U.S. patent 10 6,313,254). The release rates of the actives can also be controlled by the hydrophilicity/hydrophobicity of the polyurethane polymers. Once the appropriate polyurethane polymer is chosen, the next step is to determine the best method to fabricate the cylindrically shaped implants. For thermoplastic polyurethanes, precision extrusion and injection molding 15 are the preferred choices to produce two open-end hollow tubes (see Figure 1) with consistent physical dimensions. The reservoir can be loaded freely with appropriate formulations containing actives and carriers or filled with pre-fabricated pellets to maximize the loading of the actives. One open end needs to be sealed first before the loading of the formulation into the hollow 20 tube. To seal the two open ends, two pre-fabricated end plugs (see Figure 2) are used. The sealing step can be accomplished through the application of heat or solvent or any other means to seal the ends, preferably permanently. For thermoset polyurethanes, precision reaction injection molding or spin casting is the preferred choice depending on the curing mechanism. Reaction 25 injection molding is used if the curing mechanism is carried out through heat and spin casting is used if the curing mechanism is carried out through light and/or heat. Preferably, hollow tubes with one open end (see Figure 3) are made by spin casting. Preferably, hollow tubes with two open ends are made -16 by reaction injection molding. The reservoir can be loaded in the same way as the thermoplastic polyurethanes. Preferably, to seal an open end, an appropriate light-initiated and/or heat initiated thermoset polyurethane formulation is used to fill the open end and 5 this is cured with light and/or heat. More preferably, a pre-fabricated end plug can also be used to seal the open end by applying an appropriate light initiated and/or heat-initiated thermoset polyurethane formulation on to the interface between the pre-fabricated end plug and the open end and cured it with the light and/or heat or any other means to seal the ends, preferably 10 permanently. The final process involves the conditioning and priming of the implants to achieve the delivery rates required for the actives. Depending upon the types of active ingredient, hydrophilic or hydrophobic, the appropriate conditioning and priming media will be .chosen. Water based media are 15 preferred for hydrophilic actives and oil based media are preferred for hydrophobic actives. As a person skilled in the art would readily know many changes can be made to the preferred embodiments of the invention without departing from the scope thereof. It is intended that all matter contained herein be considered 20 illustrative of the invention and not it a limiting sense. Example 1 Tecophilic polyurethane polymer tubes are supplied by Thermedics Polymer Products and manufactured through a precision extrusion process. Tecophilic polyurethane is a family of aliphatic polyether-based 25 thermoplastic polyurethane which can be formulated to different equilibrium water content contents of up to 150% of the weight of dry resin. Extrusion -17 grade formulations are designed to provide maximum physical properties of thermoformed tubing or other components. The physical data for the polymers is provided below as made available by Thermedics Polymer Product. 5 Tecophilic Typical Physical Test Data ASTM H 20 HP-ED-35 lP-60D-60j H1?493A-100 or Hdness) D2240 43D 42D 41D 83A Spec Gravity D792 1.12 1.12 1.15 1.13 Flex Modulus (psi) D790 4,300 4,000 4,000 2,900 Ultimate Tensile Dry (psi) D412 8,900 7,800 8,300 2,200 Ultimate Tensile Wet (psi) D412 5,100 4,900 3,100 1,400 Elongation Dry (%) D412 430 450 500 1,040 Eongation Wet (%) D412 390 390 300 620 Hp-60D-20 is extruded to tubes with thickness of 0.30 mm with inside diameter of 1.75 mm. The tubes are then cut into 25 mm in length. One side of the tube is sealed with heat using a heat sealer. The sealing time is less 10 than 1 minute. Four pellets of histrelin acetate are loaded into the tube. Each pellet weighs approximately 13.5 mg for a total of 54 mg. Each pellet is comprised of a mixture of 98% histrelin and 2% stearic acid. The second end open of the tube is sealed with heat in the same way as for the first end. The loaded implant is then conditioned and primed. The conditioning takes place 15 at room temperature in a 0.9% saline solution for 1 day. Upon completion of the conditioning, the implant undergoes priming. The priming takes place at room temperatures in a 1.8% saline solution for 1 day. Each implant is tested in vitro in a medium selected to mimic the pH found in the human body. The temperature of the selected medium was kept at approximately 37C during 20 the testing. The release rates are shown on Figure 4.
-18 Histrelin elution rates WEEKS OF ELUTION HP-60D-20(udv 1 451.733 2 582.666 3 395.9 4 310.29 5 264.92 6 247.17 7 215.93 8 201.78 9 183.22 10 174.99 11 167.72 12 158.37 13 153.95 14 146.46 15 139.83 16 129.6 17 124.46 18 118.12 19 120.35 Example 2 HIP-60D-35 is extruded to tubes with thickness of 0.30 mm with inside 5 diameter of 1.75 mm. The tubes are then cut into 32 mm in length. One side of the tube is sealed with heat using a heat sealer. The sealing time is less than 1 minute. Six pellets of naltrexone are loaded into the tubes and both open sides of the tubes are sealed with heat. Each pellet weighs approximately 15.0 mg for a total of 91 mg. The second end open of the tube 10 is sealed with heat in the same way as for the first end. The loaded implant is then conditioned and primed. The conditioning takes place at room temperature in a 0.9% saline solution for 1 week. Upon completion of the conditioning, the implant undergoes priming. The priming takes place at room temperatures in a 1.8% saline solution for 1 week. Each implant is 15 tested in vitro in a medium selected to mimic the pH found in the human body. The temperature of the selected medium was kept at approximately 37*C during the testing. The release rates are shown on Figure 5.
-19 Naltrexone elution rates WEEKS OF RELEASE HP-60D-35 -1 HP-60D-35 -2 HF-60D-35 -3 0 (udday) (udday) _(gday' 1 1529.26 767.38 1400.95 2 1511.77 1280.03 1498.86 3 1456.01 1635.97 | 1449.49 4 1378.27 1607.13 1500.42 5 1393.05 1614.52 1558.37 6 1321.71 1550.39 1436.03 7 1273.07 1424.24 1300.73 8 1172.82 1246.48 1221.57 Example 3 In Figure 6 there is a comparison of the release rates of naltrexone in vitro 5 using two grades of polymer at two different water contents. Three runs were carried out and analyzed where the polymer of the implant had a water content of 24% and three runs were carried out where the polymer of the implant had a water content of 30%. The release rates were plotted against time. The polymer used for the runs at 24% water content was Tecophilic 10 HP-60-D35 from Thermedics. The polymer used for the runs at 30% water content was Tecophilic HP-60-D60 from Thermedics. The data obtained in this example demonstrates the good reproducibility of the implants as prepared according to the present invention. Example 4 15 Figure 7 shows a plot of the release rate of histrelin (LHRH Agonist) versus time. The polymer in this example had a water content of 15%. The polymer used was Tecophilic HP-60-D20 from Thermedics. The data points were taken weekly.
-20 Example 5 Figure 8 shows a plot of the release rate of clonidine versus time. The polymer in this example has a water content of 15%. The polymer used was Tecophilic HP-60-D20 from Thermedics. The data points were taken weekly. Throughout this specification and the claims which follow, unless the context requires otherwise, the word "comprise", and variations such as "comprises" and "comprising", will be understood to imply the inclusion of a stated integer or step or group of integers or steps but not the exclusion of any other integer or step or group of integers or steps. The reference to any prior art in this specification is not, and should not be taken as, an acknowledgement or any form of suggestion that the prior art forms part of the common general knowledge in Australia.
Claims (28)
1. An implantable drug delivery device for releasing one or more active ingredients at a substantially zero order rate in vitro by diffusion through a polyurethane based polymer for an extended period of time, said implantable drug delivery device comprising a polyurethane based polymer configured to provide a cylindrically shaped reservoir, wherein the reservoir is sealed after being charged with an effective amount of a solid formulation comprising one or more active ingredients and wherein the one or more active ingredients and the polyurethane based polymer are selected such that either: (i) both the one or more active ingredients and the polyurethane-based polymer exhibit hydrophilic characteristics, or (ii) both the one or more active ingredients and the polyurethane-based polymer exhibit hydrophobic characteristics, wherein the one or more active ingredients are selected from drugs that can act on the central nervous system, psychic energizers, tranquilizers, anti-convulsants, muscle relaxants, anti parkinson, analgesic, anti-inflammatory, anesthetic, antispasmodic, muscle contractants, antimicrobials, anti-malarials, hormonal agents, sympathomimetic, cardiovascular, diuretics, and antiparasitic.
2. The implantable drug delivery device of claim 1, wherein the polyurethane based polymer is selected from the group consisting of thermoplastic polyurethane and thermoset polyurethane.
3. The implantable drug delivery device of claim 2, wherein the thermoplastic polyurethane comprises macrodiols, diisocyanates, difunctional chain extenders, or mixtures thereof
4. The implantable drug delivery device of claim 2, wherein the thermoset polyurethane comprises multifunctional polyols, diisocyanates, chain extenders or mixtures thereof
5. The implantable drug delivery device of claim 4, wherein the thermoset polyurethane comprises a polymer chain and cross-linking members, said thermoset polyurethane further including unsaturated bonds in the polymer chains and crosslinkers, initiators, or both as cross-linking members. - 22
6. The implantable drug delivery device of claim 1, which is conditioned and primed under one or more parameters selected from the group consisting of time, temperature, and medium, and wherein the medium is selected to influence the desired delivery rates of the one or more active ingredients.
7. The implantable drug delivery device of claim 1, wherein the polyurethane comprises a hydrophilic pendant group selected from the group consisting of: ionic groups, carboxyl groups, ether groups, hydroxyl groups and mixtures of any two or more thereof
8. The implantable drug delivery device of claim 1, wherein the one or more active ingredients and the polyurethane-based polymer are selected such that both the one or more active ingredients and the polyurethane-based polymer exhibit hydrophilic characteristics.
9. The implantable drug delivery device of claim 1, wherein the one or more active ingredients and the polyurethane-based polymer are selected such that both the one or more active ingredients and the polyurethane-based polymer exhibit hydrophobic characteristics.
10. The implantable drug delivery device of claim 1, wherein the solid formulation includes one or more pharmaceutically acceptable carriers that are not required for the substantially zero order release rate in vitro of the one or more active ingredients through the polyurethane-based polymer.
11. The implantable drug delivery device of claim 10, wherein the one or more pharmaceutically acceptable carriers are not required for the substantially zero order release rate in vitro of the one or more active ingredients as governed by Fick's Law of Diffusion.
12. An implantable drug delivery device for releasing one or more active ingredients at a substantially zero order rate in vitro by diffusion through a polyurethane-based polymer for a period of six weeks or more from the time of implantation, said implantable drug delivery device comprising a polyurethane-based polymer configured to provide a cylindrically shaped reservoir, wherein the reservoir is sealed after being charged with an effective amount of a solid formulation comprising one or more active ingredients exhibiting hydrophilic characteristics and the polyurethane-based polymer exhibits a percent equilibrium water content (%EWC) of about 30% or less, wherein the one or more active ingredients are selected from drugs that can act on -23 the central nervous system, psychic energizers, tranquilizers, anti-convulsants, muscle relaxants, anti-parkinson, analgesic, anti-inflammatory, anesthetic, antispasmodic, muscle contractants, anti-microbials, anti-malarials, hormonal agents, sympathomimetic, cardiovascular, diuretics, and antiparasitic.
13. The implantable drug delivery device of claim 12, wherein the polyurethane based polymer exhibits a %EWC ranging from about 15% to about 30%.
14. The implantable drug delivery device of claim 13, wherein the solid formation includes one or more pharmaceutically acceptable carriers that are not required for the substantially zero order release rate in vitro of the one or more active ingredients through the polyurethane-based polymer.
15. The implantable drug delivery device of claim 14, wherein the one or more pharmaceutically acceptable carriers are not required for the substantially zero order release rate in vitro of the one or more active ingredients as governed by Fick's Law of Diffusion.
16. The implantable drug delivery device of claim 14, wherein the solid formulation includes stearic acid.
17. A process for manufacturing a drug delivery device comprising selecting one or more active ingredients; selecting a polyurethane-based polymer formed as a hollow tube; loading a solid formulation comprising the one or more active ingredients into the tube; and sealing the tube; wherein the one or more active ingredients exhibit hydrophilic characteristics, and the polyurethane-based polymer exhibits a percent equilibrium water content (%EWC) of about 30% or less; and wherein the drug delivery device delivers the one or more active ingredients by diffusion through the polyurethane-based polymer at a substantially zero order release rate in vitro.
18. The process of claim 17, wherein the sealing of the hollow tube comprises inserting a pre-fabricated plug into an open end and applying heat or solvent to the prefabricated plug and polyurethane-based polymer. - 24
19. The process of claim 17, wherein the sealing comprises inserting a prefabricated end plug at an open end of the hollow tube; applying an appropriate light-initiated and/or heat initiated thermoset polyurethane formulation into an interface formed between the pre-fabricated end plug and the open end; and curing the polyurethane formulation with light and/or heat to seal the pre-fabricated plug in the end of the tube.
20. The process of claim 17 further comprising conditioning and priming comprises selecting a parameter selected from the group consisting of time, temperature, and medium to influence the substantially zero order release rate in vitro of the one or more active ingredients through the polyurethane-based polymer.
21. The process of claim 17, wherein the one or more active ingredients and the polyurethane-based polymer are selected such that both the one or more active ingredients and the polyurethane-based polymer exhibit hydrophilic characteristics.
22. The process of claim 17, wherein the solid formulation includes one or more pharmaceutically acceptable carriers that are not required for the substantially zero order release rate in vitro of the one or more active ingredients through the polyurethane-based polymer.
23. The process of claim 22, wherein the one or more pharmaceutically acceptable carriers are not required for the substantially zero order release rate in vitro of the one or more active ingredients as governed by Fick's Law of Diffusion.
24. The process of claim 17, wherein the hollow tube is formed by extrusion molding, injection molding, or spin-casting of the polyurethane-based polymer.
25. The process of claim 17, wherein the hollow tube is formed with two open ends.
26. The process of claim 17, wherein the hollow tube is formed with two open ends, and one end is sealed prior to the loading.
27. The process of claim 17, wherein the hollow tube is formed with one open end and one closed end. -25
28. The process of claim 17, wherein the one or more active ingredients are selected from drugs that can act on the central nervous system, psychic energizers, tranquilizers, anti convulsants, muscle relaxants, anti-parkinson, analgesic, anti-inflammatory, anesthetic, antispasmodic, muscle contractants, anti-microbials, anti-malarials, hormonal agents, sympathomimetic, cardiovascular, diuretics, and antiparasitic.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| AU2013200837A AU2013200837B2 (en) | 2003-08-11 | 2013-02-15 | Manufacture of long term drug delivery devices with polyurethane based polymers |
Applications Claiming Priority (4)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US60/494,132 | 2003-08-11 | ||
| CA2,437,639 | 2003-08-18 | ||
| AU2010251786A AU2010251786B2 (en) | 2003-08-11 | 2010-12-14 | Manufacture of long term drug delivery devices with polyurethane based polymers |
| AU2013200837A AU2013200837B2 (en) | 2003-08-11 | 2013-02-15 | Manufacture of long term drug delivery devices with polyurethane based polymers |
Related Parent Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| AU2010251786A Division AU2010251786B2 (en) | 2003-08-11 | 2010-12-14 | Manufacture of long term drug delivery devices with polyurethane based polymers |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| AU2013200837A1 AU2013200837A1 (en) | 2013-03-07 |
| AU2013200837B2 true AU2013200837B2 (en) | 2015-08-27 |
Family
ID=47833497
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| AU2013200837A Ceased AU2013200837B2 (en) | 2003-08-11 | 2013-02-15 | Manufacture of long term drug delivery devices with polyurethane based polymers |
Country Status (1)
| Country | Link |
|---|---|
| AU (1) | AU2013200837B2 (en) |
Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP0200224B1 (en) * | 1985-05-03 | 1992-03-18 | The Du Pont Merck Pharmaceutical Company | Pharmaceutical compositions containing hollow fine tubular drug delivery systems |
| US6375978B1 (en) * | 1997-12-22 | 2002-04-23 | Alza Corporation | Rate controlling membranes for controlled drug delivery devices |
-
2013
- 2013-02-15 AU AU2013200837A patent/AU2013200837B2/en not_active Ceased
Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP0200224B1 (en) * | 1985-05-03 | 1992-03-18 | The Du Pont Merck Pharmaceutical Company | Pharmaceutical compositions containing hollow fine tubular drug delivery systems |
| US6375978B1 (en) * | 1997-12-22 | 2002-04-23 | Alza Corporation | Rate controlling membranes for controlled drug delivery devices |
Non-Patent Citations (1)
| Title |
|---|
| ZONDERVAN G.J. et al. Biomaterials, 1992, vol. 13, no. 3, pages 136-144 * |
Also Published As
| Publication number | Publication date |
|---|---|
| AU2013200837A1 (en) | 2013-03-07 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| AU2009202942B2 (en) | Manufacture of long term drug delivery devices with polyurethane based polymers | |
| US8784865B2 (en) | Long term drug delivery devices with polyurethane-based polymers and their manufacture | |
| US20090208540A1 (en) | Implantable device for the delivery of naltrexone and methods of use thereof | |
| US20130302397A1 (en) | Implantable device for the delivery of histrelin and methods of use thereof | |
| AU2013200837B2 (en) | Manufacture of long term drug delivery devices with polyurethane based polymers | |
| US20150174301A1 (en) | Long term drug delivery devices with polyurethane based polymers and their manufacture | |
| HK1124550A (en) | Manufacture of long term drug delivery devices with polyurethane | |
| HK1091145B (en) | Manufacture of long term drug delivery devices with polyurethane based polymers | |
| HK1160378B (en) | Manufacture of long term drug delivery devices with polyurethane based polymers |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| MK4 | Application lapsed section 142(2)(d) - no continuation fee paid for the application | ||
| NA | Applications received for extensions of time, section 223 |
Free format text: AN APPLICATION TO EXTEND THE TIME FROM 11 AUG 2013 TO 11 MAR 2014 IN WHICH TO PAY A CONTINUATION FEE HAS BEEN FILED . |
|
| NB | Applications allowed - extensions of time section 223(2) |
Free format text: THE TIME IN WHICH TO PAY A CONTINUATION FEE HAS BEEN EXTENDED TO 11 MAR 2014 . |
|
| PC1 | Assignment before grant (sect. 113) |
Owner name: BRAEBURN PHARMACEUTICALS BVBA SPRL Free format text: FORMER APPLICANT(S): ENDO PHARMACEUTICALS SOLUTIONS INC. |
|
| FGA | Letters patent sealed or granted (standard patent) | ||
| PC | Assignment registered |
Owner name: BRAEBURN PHARMACEUTICALS, INC. Free format text: FORMER OWNER WAS: BRAEBURN PHARMACEUTICALS BVBA SPRL |
|
| MK14 | Patent ceased section 143(a) (annual fees not paid) or expired |