WO2013013172A1 - Intravaginal devices for drug delivery - Google Patents
Intravaginal devices for drug delivery Download PDFInfo
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- WO2013013172A1 WO2013013172A1 PCT/US2012/047649 US2012047649W WO2013013172A1 WO 2013013172 A1 WO2013013172 A1 WO 2013013172A1 US 2012047649 W US2012047649 W US 2012047649W WO 2013013172 A1 WO2013013172 A1 WO 2013013172A1
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
- A61K47/34—Macromolecular compounds obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyesters, polyamino acids, polysiloxanes, polyphosphazines, copolymers of polyalkylene glycol or poloxamers
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61F—FILTERS IMPLANTABLE INTO BLOOD VESSELS; PROSTHESES; DEVICES PROVIDING PATENCY TO, OR PREVENTING COLLAPSING OF, TUBULAR STRUCTURES OF THE BODY, e.g. STENTS; ORTHOPAEDIC, NURSING OR CONTRACEPTIVE DEVICES; FOMENTATION; TREATMENT OR PROTECTION OF EYES OR EARS; BANDAGES, DRESSINGS OR ABSORBENT PADS; FIRST-AID KITS
- A61F6/00—Contraceptive devices; Pessaries; Applicators therefor
- A61F6/06—Contraceptive devices; Pessaries; Applicators therefor for use by females
-
- 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
-
- 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
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
- A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
- A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
- A61K31/52—Purines, e.g. adenine
- A61K31/522—Purines, e.g. adenine having oxo groups directly attached to the heterocyclic ring, e.g. hypoxanthine, guanine, acyclovir
-
- 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
- A61K31/567—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 substituted in position 17 alpha, e.g. mestranol, norethandrolone
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/56—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids
- A61K31/57—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids substituted in position 17 beta by a chain of two carbon atoms, e.g. pregnane or progesterone
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/66—Phosphorus compounds
- A61K31/675—Phosphorus compounds having nitrogen as a ring hetero atom, e.g. pyridoxal phosphate
-
- 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
- A61K31/70—Carbohydrates; Sugars; Derivatives thereof
- A61K31/715—Polysaccharides, i.e. having more than five saccharide radicals attached to each other by glycosidic linkages; Derivatives thereof, e.g. ethers, esters
- A61K31/731—Carrageenans
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/02—Inorganic compounds
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/0012—Galenical forms characterised by the site of application
- A61K9/0034—Urogenital system, e.g. vagina, uterus, cervix, penis, scrotum, urethra, bladder; Personal lubricants
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/0012—Galenical forms characterised by the site of application
- A61K9/0034—Urogenital system, e.g. vagina, uterus, cervix, penis, scrotum, urethra, bladder; Personal lubricants
- A61K9/0036—Devices retained in the vagina or cervix for a prolonged period, e.g. intravaginal rings, medicated tampons, medicated diaphragms
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61M—DEVICES FOR INTRODUCING MEDIA INTO, OR ONTO, THE BODY; DEVICES FOR TRANSDUCING BODY MEDIA OR FOR TAKING MEDIA FROM THE BODY; DEVICES FOR PRODUCING OR ENDING SLEEP OR STUPOR
- A61M31/00—Devices for introducing or retaining media, e.g. remedies, in cavities of the body
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61M—DEVICES FOR INTRODUCING MEDIA INTO, OR ONTO, THE BODY; DEVICES FOR TRANSDUCING BODY MEDIA OR FOR TAKING MEDIA FROM THE BODY; DEVICES FOR PRODUCING OR ENDING SLEEP OR STUPOR
- A61M31/00—Devices for introducing or retaining media, e.g. remedies, in cavities of the body
- A61M31/002—Devices for releasing a drug at a continuous and controlled rate for a prolonged period of time
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- 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
- A61P15/02—Drugs for genital or sexual disorders; Contraceptives for disorders of the vagina
-
- 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
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
Definitions
- the present technology generally relates to intravaginal drug delivery devices. More specifically, intravaginal devices such as intravaginal rings are disclosed, which are capable of providing a zero order release of loaded drugs, including hydrophilic drugs, over extended periods of time. Methods of making and using the devices are also disclosed, including prevention and/or treatment of diseases, disorders and sexually transmitted infections.
- intravaginal devices such as intravaginal rings are disclosed, which are capable of providing a zero order release of loaded drugs, including hydrophilic drugs, over extended periods of time.
- Methods of making and using the devices are also disclosed, including prevention and/or treatment of diseases, disorders and sexually transmitted infections.
- Intravaginal drug delivery devices including intravaginal rings (IVRs) are typically formed from biocompatible polymers and contain a drug released by diffusion through the polymer matrix. The devices may be inserted into the vaginal cavity and the drug may be absorbed by the surrounding body fluid through the vaginal tissue.
- the drug is uniformly dispersed or dissolved throughout the polymer matrix (monolithic system). In other designs, the drug may be confined to an inner core within the ring (reservoir system).
- Monolithic systems are expected to show Fickian diffusion- controlled drug release whereby the release rate decreases with time. Reservoir systems may exhibit a zero order release of loaded drugs.
- poly(ethylene-co-vinyl acetate), or pEVA e.g., in NuvaRing ®
- poly(dimethyl siloxane) e.g., in Estring ® , Femring ® and in Population Council's progesterone -releasing ring
- silicone e.g., in Estring ® , Femring ® and in Population Council's progesterone -releasing ring
- silicone IVRs are fabricated with larger cross- sectional diameters to achieve the retractive forces required for retention in the vaginal cavity, which may affect ring user acceptability. Consequently, the manufacturing costs associated with these IVRs are considerable.
- pEVA and silicone are not suitable for delivery of highly water-soluble drugs and macromolecules, e.g., proteins, due to the hydrophilic nature and/or macroscopic size of such drugs.
- the present technology provides intravaginal drug delivery devices, including intravaginal rings (IVRs), methods for making the devices, and methods of using the devices.
- Each device includes a reservoir of one or more vaginally administrable drugs, wherein the reservoir is surrounded at least in part by a hydrophilic elastomer or non- swellable elastomer.
- the devices are suitable for delivery of a wide variety of substances, including but not limited to hydrophilic drugs, hydrophobic drugs, and macromolecules. Because the core does not need to be heated during device fabrication, the present devices can deliver biologies, which are often susceptible to thermal degradation.
- the present technology thus provides a broad range of intravaginal devices, including intravaginal rings, rods, tablets, tampons, and pessaries.
- FIG. 1 A shows an illustrative embodiment of a single segment reservoir
- FIG. IB shows an illustrative embodiment of a two segment reservoir IVR.
- FIG. 2A shows in vitro release of tenofovir from a reservoir IVR of the present technology.
- FIG. 2B shows the force required to compress exemplary IVRs of the present technology, 25% of outer diameter as described in Example 1.
- FIG. 3. shows the daily release rate of LNG from the IVRs for various LNG core loadings and polymers, as described in Example 2.
- FIG. 4 shows daily release rate of LNG from IVRs for various LNG tubing wall loadings, as described in Example 3.
- FIG. 5 shows the HPLC-derived daily release rates of TFV from the IVRs described in Example 11.
- FIG. 6 illustrate the effects of varying ratios of Tecophilic ® HP-93A-100 and
- Tecophilic ® HP-60D-60 in tubing comprising the two polymers with respect to percentage swelling.
- FIG. 7 shows the 30-day average drug/active pharmaceutical ingredient
- FIG. 8A is a graph showing the difference in TFV release rates (mg/day) over time with and without the osmotic agent glycerol (33 wt%) in the core of a hydrophilic tubing reservoir IVR (Tecophilic ® HP-60D-35) as described in Example 33.
- FIG. 8B is a graph showing the steady- state (average from day 5 to day 14) release rate of TFV (mg/day) from Tecophilic ® tubing reservoir IVRs as a function of thermal conditioning time at 40°C as described in Example 37.
- FIG. 8C shows the equilibrium (average from day 5 to day 14) release rate of TFV (mg/day) as a function of polymer equilibrium swelling ratio for various polymers and polymer blends (see Example 37).
- FIG. 9 is a graph showing the release profile over time for a hydrophobic small molecule drug, IQP-0528 from an IVR of the present technology as described in Example 26.
- FIG. 10 is a graph showing the release profile over time for tenofovir disoproxil fumarate (TDF) from an IVR composed of a 20 wt% swellable hydrophilic polyether urethane tubing (HydroThaneTM), with a reservoir containing a drug and sodium chloride mixture as described in Example 33.
- TDF tenofovir disoproxil fumarate
- FIG. 11 is a graph showing the release rate over time of TDF from the same
- FIG. 12A is a graph showing the release rate of elvitegravir (EVG) from the reservoir of a hydrophilic polyurethane ring.
- the EVG was part of a 63/5/32 wt% mixture of TFV/EVG/glycerol-water.
- the polyurethane was a 35 wt% swelling hydrophilic polyurethane single segment tubing with 5.5 mm cross-sectional diameter and 0.7 mm wall thickness.
- FIG. 12B shows the release profile of dapivirine (DPV) from the same ring with a 63/5/32 wt% mixture of TFV/DPV/glycerol-water. (See Example 38.)
- FIG. 13A is a graph showing the release rate of TFV from a hydrophilic polyurethane tubing reservoir segment of a dual-segment IVR as a function of time.
- the segment comprised a 35 wt% swelling hydrophilic polyurethane tube with 5.5 mm cross- sectional diameter and 0.7 mm wall thickness.
- FIG. 13B is a graph showing the release rate of LNG from a hydrophobic solid-core polyurethane reservoir segment, with 5.5 mm cross- sectional diameter and 0.1 mm wall thickness, of the same dual-segment IVR.
- the core comprised a poly(ether urethane) similar to Tecoflex EG-85A with LNG molecularly dissolved at 1.3 wt%.
- the outer membrane comprised a poly(ether urethane) similar to Tecoflex EG-65D and Tecoflex EG-60D. (See Example 29.)
- Intravaginal drug delivery devices including intravaginal rings, are provided herein. Also provided are methods for making the devices and methods of using the devices to prevent or treat a biological condition.
- the devices include a reservoir of one or more vaginally administrable drugs, wherein the reservoir is surrounded at least in part by a hydrophilic elastomer.
- the present devices are especially suited for, though not limited to, delivery of macromolecules and small hydrophilic molecules that are not compatible with the hydrophobic polymers widely used in current intravaginal rings due to insufficient solubility of the API/macromolecule in the hydrophobic polymer and therefore limited diffusion of hydrophilic API and macromolecules through the polymer.
- the present devices therefore provide a cost-effective, user-adherent/patient compliant means of providing a sustained delivery of drugs which heretofore were challenging to deliver intravaginally, including drugs that prevent the transmission of HIV or other viruses.
- the intravaginal devices of the present technology include a hydrophilic elastomer surrounding, at least in part, a drug reservoir, e.g., a drug-containing core.
- Hydrophilic elastomers of the present technology are permeable to water and the drugs contained in the reservoir, including hydrophilic drugs. Hydrophilic elastomer swellable by water may be employed in the devices. In some embodiments, the hydrophilic elastomer swells from about 20% to about 100% by weight. Examples of the amount of swelling that the hydrophilic elastomer may undergo include about 20%>, about 25%, about 30%, about 35%, about 40%, about 45%, about 50%, about 55%, about 60%, about 65%, about 70%, about 75%, about 80%, about 85%, about 90%, about 95%, about 100%, and ranges between and including any two such values.
- Hydrophilic elastomers that may be used in intravaginal devices of the present technology include but are not limited to hydrophilic polyurethanes, e.g., multiblock poly(ether urethane)s, or silicone poly(ether urethane)s.
- Polyurethanes used in the present devices offer control of processing temperature, mechanical properties and drug release by modifying their components and ratios. The presence of a microphase separation leading to hard and soft domains imparts flexibility and strength to the polymer.
- poly(ether urethane)s composed of a polymeric diol and short chain diol connected by urethane linkages through diisocyanates are practically non-degradable up to three years.
- Hydrophilic silicone poly(ether urethane)s have advantage of silicone-like surface properties, proven biocompatibility, lower process flow temperature, enhanced light and moisture stability and protection from oxidative degradation.
- poly(ether urethane)s may be used in the present devices.
- Such poly(ether urethane)s can be the reaction product of a polymeric diol, a short chain diol, and a diisocyanate.
- Diisocyanates include, but are not limited to, symmetrical molecules such as methylene-bis-cyclohexyl diisocyanates, 1 ,4 cyclohexyl diisocyanate, and dicyclohexyl methane diisocyanate (HMDI).
- Short chain diols include, but are not limited to, 1 ,4 butane diol or similar symmetrical diols or asymmetrical diols like 1 ,2 propane diol.
- the polymeric diols include, but are not limited to, poly(tetra methylene ether glycol) (PTMEG) and poly(ethylene glycol) (PEG).
- PTMEG poly(tetra methylene ether glycol)
- PEG poly(ethylene glycol)
- the PTMEG ranges in molecular weight from about 500 to about 10,000 (e.g., 500, 1 ,000, 2,000, 3,000, 4,000, 5,000, 7,500, 10,000 and a range between and/or including any two such values).
- the PEG ranges in molecular weight from about 100 to about 10,000 (e.g., 100, 250, 500, 1 ,000, 2,000, 3,000, 4,000, 5,000, 7,500, 10,000 and a range between and/or including any two such values).
- the poly(ether urethane) is water- swellable and includes poly(ethylene glycol).
- the poly(ether urethane) comprises the reaction product of dicyclohexyl methane diisocyanate, a PTMEG having a molecular weight of between about 500 and about 10,000, and 1 ,4 butane diol.
- the PTMEG has a molecular weight of about 1 ,000 to about 2,000.
- the number of moles of dicyclohexyl methane diisocyanate is equal to the sum of the number of moles of PTMEG and the number of moles of 1,4 butane diol and the molar ratio of 1,4 butane diol to PTMEG is between about 1 to 1 and about 1.5 to 0.5.
- the polyurethane has an average molecular weight of about 60,000 to about 180,000 (e.g., 60,000, 80,000, 100,000, 120,000, 140,000, 150,000, 160,000, 180,000 and a range between and/or including any two such values ) and a weight average molecular weight of about 120,000 to about 335,000 (e.g., 120,000, 160,000, 200,000, 240,000, 285,000, 290,000, 295,000, 300,000, 310,000, 320,000, 330,000 and a range between and/or including any two such values).
- These polyurethanes and their synthesis are described in detail in U.S. Pat. No. 4,523,005, which is hereby incorporated by reference in its entirety.
- These polyurethanes are also commercially available as non-swellable polyurethanes (Tecoflex ® family) manufactured by Lubrizol Advanced Materials (Wickliffe, OH).
- Tecoflex ® is a family of aliphatic polyether-based polyurethanes manufactured in several grades including but not limited to EG-80A, EG-85A, EG-93A, EG-100A, EG-60D, EG- 65D, EG-68D, EG-72D.
- the EG-80A and EG-85A polyurethanes use a PTMEG-2000 molecular weight polyol component while the EG-93A, EG-100A, EG-60D, EG-65D, EG- 68D and EG-72D polyurethanes use a PTMEG- 1000 molecular weight polyol component.
- the devices include a poly(ether urethane) selected from Tecoflex ® EG-80A, Tecoflex ® EG-85A, or Tecoflex ® EG-93A.
- hydrophobic polymers that may be used include, e.g., ChronoThaneTM (an aliphatic ether based polyurethane elastomer from AdvanSource Biomaterials, Wilmington, MA) T75A , T75B, T75C, and T75D, and Quadraflex ® (Biomerics, Salt Lake City, UT) ALE- 75A, 80A, 85A, 90A, 93A, 95A, 55D, and 72D.
- ChronoThaneTM an aliphatic ether based polyurethane elastomer from AdvanSource Biomaterials, Wilmington, MA
- T75A , T75B, T75C, and T75D T75A , T75B, T75C, and T75D
- Quadraflex ® Biomerics, Salt Lake City, UT
- poly(ether urethane)s include, but are not limited to, the Tecophilic ® , and Tecothane ® family of polyurethanes manufactured by Lubrizol Advanced Materials.
- Tecophilic ® is a family of aliphatic polyether-based polyurethanes, including hydrophilic water-swellable poly(ether urethane)s, manufactured by Lubrizol.
- Tecophilic ® poly(ether urethanes) have similar composition to Tecoflex ® with the addition of polyethylene glycol to impart water swellable characteristics and is available as Tecophilic ® HP-60D-20, HP- 60D-35, HP-60D-60, or HP-93A-100.
- Tecothane ® is a family of aromatic polyether-based polyurethanes manufactured in several grades including TT-1074A, TT-1085A, TT-1095A, TT-1055D, TT-1065D, and TT-1075D-M.
- polyurethanes that may be used include those manufactured by DSM Biomedical (Berkeley, CA), such as PurSil ® , CarboSil ® , Elasthane ® , BioSpan ® , and Bionate ® , those manufactured by Biomerics (Salt Lake City, UT), such as Quadraphilic TM ALC- and ALE- 90A-20, 90A-70, 90A-120, 55D-25, 55D-60, 55D-100, 65D-25, and 65D-60, and those manufactured by AdvanSource Biomaterials (Wilmington, MA), such as HydroThane TM AL, 80A or 93 A. Any of the polyurethanes described above may be used alone or in combination to form the
- the intravaginal devices of the present technology may further comprise additional components, including, but not limited to, other polymers or pharmaceutically compatible agents.
- the devices further comprise PEG.
- PEG may be present at varying amounts, including, but not limited to, amounts ranging from about 5% w/w to about 35% w/w, where w/w refers to the weight ratio of PEG to the total weight of the hydrophilic elastomer, such as, but not limited to poly(ether urethane).
- the hydrophilic poly(ether urethane) is
- Tecophilic ® HP-60D-35 Tecophilic ® HP-60D-60, Tecophilic ® HP-93A-100, or blends thereof with varying ratios.
- a variety of pharmaceutically compatible agents may be used, including, but not limited to, those disclosed in U.S. Patent No. 6,951,654.
- the present technology provides intravaginal devices that include a reservoir of one or more vaginally administrable drugs, wherein the reservoir is surrounded at least in part by a non-swellable elastomer (e.g., a hydrophobic elastomer).
- a non-swellable elastomer e.g., a hydrophobic elastomer
- the non-swellable elastomer may be any of the multiblock poly(ether urethane) or a silicone poly(ether urethane) non-swellable elastomers disclosed herein.
- the non-swellable elastomer may be a poly( ether urethane) selected from Tecoflex ® EG- 80A, Tecoflex ® EG-85A, or Tecoflex ® EG-93A, or ChronoThaneTM T75A, T75B, T75C or T75D polyurethane.
- the device may have any of the structures or
- the intravaginal devices of the present technology also include a reservoir.
- the reservoir can hold (or contain) a liquid, solid or semi-solid composition that includes one or more intravaginally administrable drugs.
- compositions can, but need not, include a pharmaceutically acceptable carrier or excipient.
- Non-limiting examples of such carriers and excipients include glycerol, cellulose (including but not limited to
- the reservoir holds a solid selected from powders or pellets, or a combination thereof.
- the solid may include one or more diluents, densification agents, bulking agents, lubricating agents or glidants, or osmotic agents.
- the solid include one or more selected from the group consisting of cellulose, starch, sugar, sodium salt, potassium salt, calcium salt, and magnesium salt.
- the reservoir is filled with a solid drug-containing polymer, e.g., as pellets or as a single core.
- the drug-containing reservoir can include a non-swellable elastomer such as Tecoflex ® or a hydrophilic elastomer, including but not limited to hydrophilic poly(ether urethane)s such as Tecophilic ® -HP-60D-60 at weight fractions ranging from 30% to 95% w/w (e.g., 30%, 40%, 50%, 60%, 70%, 80%, 90%, 95% or a range between and including any two such values) to aid in mechanical reinforcement and/or processability.
- water-soluble porogens such as salt crystals, are incorporated into the tubing wall during extrusion.
- the drug composition includes a macromolecule and porogen.
- the elastomer at least partially surrounding the reservoir includes the drug as well.
- the drug may be mixed with the elastomer during fabrication. Alternatively, the drug migrates into the elastomer during thermal conditioning of the device after loading of the reservoir.
- hydrophilic polymers or of one or more hydrophilic polymers and one or more hydrophobic polymer may be blended and used to fabricate a single segment or multiple segments of IVDs of the present technology. Such mixtures allow control of the overall polymer percent swelling, polymer elastic moduli, polymer phase separation, and drug flux.
- devices may include mixtures of two or more hydrophilic polymers with different shore hardness and swelling indices to fabricate tubing with intermediate properties.
- hydrophilic and hydrophobic poly(ether urethanes) described herein may be used including, but not limited to Tecophilic HP-60D-20, -35 and -60, HP-93A-100 and TG-500 and -2000 and HydroThaneTM 80A and 93 A (5 wt% to 25 wt% swelling) and Tecoflex ® EG-80A, 85A, 93A, 60D, 65D, 68D and 72D and
- ChronoThaneTM T75A to 75D For example, a 1 : 1 mixture of Tecophilic ® HP 60D-35 resin (35 wt% swelling) and Tecoflex ® EG-85A resin may be used to make tubing with 21 wt% swelling. In another example, a 3: 1 mixture of Tecophilic ® HP 60D-35 resin (35 wt% swelling) and Tecoflex ® EG-85A resin may be used to make tubing with 27 wt% swelling.
- a 3: 1 mixture of Tecophilic ® HP-60D-60 resin (60 wt% swelling) and Tecophilic ® HP-93A-100 resin (100 wt% swelling) may be used to make tubing with intermediate swelling.
- the present devices may further include a portion of the intravaginally administrable drug dispersed in the hydrophilic elastomer surrounding the reservoir. Such embodiments avoid a lag period after the device has been placed in the vagina before drug can diffuse out from the reservoir core into the vagina.
- the amount of drug dispersed in the elastomer is about 0.05 wt% to about 10 wt% of the elastomer.
- Examples of the amount of drug dispersed in the elastomer include about 0.05 wt%, about 0.1 wt%, about 0.2 wt%, about 0.3 wt%, about 0.5 wt%, about 0.75 wt%, about 1 wt%, about 2 wt%, about 3 wt%, about 4 wt%, about 5 wt%, about 6 wt%, about 7 wt%, about 8 wt%, about 9 wt%, about 10 wt%, and ranges between and including any two such values.
- macromolecule a molecule having a molecular weight of more than 2,000.
- macromolecules include but are not limited to synthetic polymers, proteins, polysaccharides, and certain peptides.
- hydrophilic small molecule is meant a molecule with a molecular weight of 2,000 or below and having a water solubility of about 0.1 mg/mL or greater.
- Hydrophilic small molecules also include smaller peptides and many drugs.
- Non-limiting examples of intravaginally administrable drugs include microbicides, contraceptive agents, hormones, estrogen receptor modulators, post-menopausal hormones, antiviral agents, anticancer agents and agents for prevention of endometriosis or uterine fibroids.
- the microbicide is an antiviral such as an anti-HIV, anti-HSV, anti-HBV, or an anti-HPV agent.
- the microbicide may be an anti- HIV agent selected from the group consisting of non-nucleoside reverse transcriptase inhibitors (NNRTIs), nucleoside reverse transcriptase inhibitors (NRTIs), HIV protease inhibitors, NCP7 inhibitors, HIV integrase inhibitors, and HIV entry inhibitors.
- NRTIs non-nucleoside reverse transcriptase inhibitors
- NRTIs nucleoside reverse transcriptase inhibitors
- HIV protease inhibitors NCP7 inhibitors
- HIV integrase inhibitors HIV entry inhibitors.
- the NNRTI is selected from tenofovir (( ⁇ [(2i?)-l-(6-amino-9H-purin-9- yl)propan-2-yl]oxy ⁇ methyl)phosphonic acid) and/or adefovir.
- the NRTI is selected from zidovudine, didanosine, zalcitabine, stavudine, lamivudine, abacavir, emtricitabine, entecavir, and/or apricitabine.
- the NNRTI is selected from efavirenz, nevirapine, delavirdine, etravirine, rilpivirine, dapivirine, and/or lersivirine.
- the protease inhibitor is selected from saquinavir, ritonavir, indinavir, nelfmavir, amprenavir, lopinavir, atazanavir, fosamprenavir, tipranavir, and/or darunavir.
- the integrase inhibitor is selected from elvitegravir, raltegravir, GSK-572, and/or MK-2048.
- the entry inhibitor is maraviroc and/or enfuvirtide.
- Other anti-HIV agents may be used, including but not limited to, AMD-3100, BMS-806, BMS-793, C31G, carrageenan, CD4-IgG2, cellulose acetate phthalate, cellulose sulphate, cyclodextrins, dextrin-2-sulphate, efavirenz, etravirine (TMC- 125), mAb 2G12, mAb bl2, Merck 167, nonoxynol-9, plant lectins, poly naphthalene sulfate, poly sulfo-styrene, PRO2000, PSC-Rantes, rilpivirine (TMC-278), dapivirine (TMC-120), SCH-C, SCH-D, T-20, TMC-125, UC-781, UK-427, UK-857, and Viramune.
- the microbicide may also be an anti-HSV agent, including, but not limited to acyclovir, gangcyclovir, valacyclovir, and famciclovirm penciclovir, imiquimod, and/or resiquimod.
- the microbicide may be an anti-HPV agent, including, but are not limited to pyrrole polyamides and lopinavir.
- Other representative microbicides that may be used in the present devices include, but are not limited to, those disclosed in U.S. Patent No. 6,951,654.
- Contraceptive agents, hormones, and estrogen receptor modulators may be delivered with the present devices.
- the contraceptive, hormone or estrogen receptor modulator is loaded into a segment of the device separate from other drugs.
- the separate segment may be formed of any suitable polymer, including a hydrophobic elastomer.
- Contraceptive agents that may be delivered with the present devices include, but are not limited to, 17a-ethinyl-levongestrel-17b-hydroxy-estra-4,9,l l-trien-3- one, estradiol, etono-progestin alonegestrel, levongestrel, medroxyprogesterone acetate, nestorone, norethindrone, norgestrienone, progesterone, RU-486, etonogestril (3-keto- desogestrel), progestin, megestrol, 17-acetoxy-16-methylene-19-norprogesterone, and nestorone.
- Representative hormones that may be delivered include, but are not limited to gonadatropin releasing hormone agonists and leuprolide acetate.
- Representative estrogen receptor modulators include, but are not limited to, afimoxifene (4-hydroxytamoxifen), arzoxifene, clomifene, femarelle (DT56a), lasofoxifene, ormeloxifene, raloxifene, tamoxifen, toremifene, mifepristone (RU486), VA2914, ulipristal, Proellex, Asoprisnil, and CDB-4124.
- vaginally administrable drugs include anticancer drugs such as, e.g., fluorouracil, cisplatin, doxorubicin, leuprolide acetate, and paclitaxel; lidocaine, a cervical anaesthetic; Terbutaline, for dysmenorrhea and endometriosis; Sildenafil, for increased blood flow to the uterus in preparation for embryo implantation; Misoprostol, for the induction of labor, cervical ripening, and pregnancy termination; Oxybutynin, for overactive bladder; Indomethacin, for the treatment of preterm labor; Bromocriptine, for the treatment of prolactinoma in those intolerant of nausea/vomiting side effects.
- anticancer drugs such as, e.g., fluorouracil, cisplatin, doxorubicin, leuprolide acetate, and paclitaxel
- lidocaine a cervical anaesthetic
- vaginally administrable drugs include agents to treat fungal infections, bacterial vaginosis, antibacterial agents. These include metronidazole, clotrimazole, miconazole terconazole, imidazole, " and clindamycin.
- the one or more drugs is selected from the group consisting of 1 -(cyclopent-3-enylmethyl)-6-(3,5-dimethylbenzoyl)-5-ethylpyrimidine- 2,4(1 H,3H)-dione, l-(cyclopentenylmethyl)-6-(3,5-dimethylbenzoyl)-5- isopropylpyrimidine-2,4(lH,3H)-dione, l-(cyclopent-3-enylmethyl)-6-(3,5- dimethylbenzoyl)-5-isopropylpyrimidine-2,4(lH,3H)-dione, l-(cyclopropylmethyl)-6-(3,5- dimethylbenzoyl)-5-isopropylpyrimidine-2,4(lH,3H)-dione, l-(4-benzoyl-2,2- dimethylpiperazin-l-yl)-2-(3H-pyrimidine- 2,4(1
- the devices of the present technology include one or more vaginally administrable drugs.
- the devices are adapted to deliver pharmaceutically effective amounts of such drugs.
- pharmaceutically effective it is meant an amount which is sufficient to effect the desired physiological or pharmacological change in the subject. This amount will vary depending upon such factors as the potency of the particular drug, the desired physiological or pharmacological effect, and the time span of the intended treatment. Those skilled in the pharmaceutical arts will be able to determine the pharmaceutically effective amount for any given drug in accordance with standard procedures.
- the drug is present in the devices in an amount ranging from about 1 mg to about 2,000 mg of drug per device.
- amounts of drug loaded into the device include about 1 mg, about 2 mg, about 3 mg, about 4 mg, about 5 mg, about 6 mg, about 8 mg, about 10 mg, about 15 mg, about 20 mg, about 25 mg, about 30 mg, about 40 mg, about 50 mg, about 75 mg, about 100 mg, about 200 mg, about 500 mg, about 1,000 mg, about 1,500 mg, about 2,000 mg, and ranges between and including any two such values.
- the drug is present in an amount ranging from about 0.01% w/w to about 50% w/w, where w/w refers to the weight ratio of the drug to the total weight of the device.
- the drug is tenofovir and is present in an amount of about 500 mg to about 2000 mg per device. In other embodiments, the drug is levonorgestrel and is present in an amount ranging from about 1 mg to about 10 mg per device.
- the intravaginal devices of the present technology are capable of providing sustained delivery of one or more vaginally administrable drugs in a substantially zero order release profile.
- substantially zero order it is meant that a substantially constant amount of drug is released over a given period of time.
- the devices exhibit a substantially zero order release profile of the drug over at least one day.
- the devices exhibit a substantially zero order release profile of the drug over at least several days (e.g., over at least 2, 3, 4, 5, or 6 days), over at least a week, over at least one month, or over more than a month (e.g., over at least 45, 60, or 90 days).
- the release rate of drug from the devices of the present technology may be modified by changing the initial loading of the poly(ether urethane) matrix with drug or by modifying the components or composition of the poly(ether urethane) to make the polymer more or less hydrophobic. Additionally, changing device geometry such as surface area and tubing thickness or core excipient can be used to modify the drug release rate. In some embodiments, the devices exhibit a substantially zero order release profile of the drug over at least several days (e.g., over at least 2, 3, 4, 5, or 6 days), over at least a week, over at least one month, or over more than a month (e.g., over at least 45, 60, or 90 days).
- the core loading may not affect the release rate, but will instead affect the release duration.
- the devices exhibit release rates ranging from about 5 ⁇ g of drug per day to about 50 mg of drug per day. This release rate is expected to be sufficient to achieve the desired therapeutic concentration of drugs, including, e.g., anti-HIV agents, in the vagina to prevent sexual transmission of HIV.
- the devices exhibit release rates of about 5 ⁇ g, about 10 ⁇ g, about 25 ⁇ g, about 50 ⁇ g, about 75 ⁇ g, about 100 ⁇ g, about 150 ⁇ g, about 200 ⁇ g, about 500 ⁇ g, about 750 ⁇ g, about 1 mg, about 2 mg, about 3 mg, about 4 mg, about 5 mg, about 10 mg, about 15 mg, about 20 mg, about 30 mg, about 40 mg, about 50 mg of drug per day and ranges between and including any two such values.
- the intravaginal device includes tubing having an interior space that that makes up the reservoir.
- the tubing may be a single segment or may include two or more segments, at least one of which includes the reservoir.
- devices of the present technology may have separate segments to deliver different drugs if so desired.
- at least one segment of the device includes a swellable hydrophilic elastomer.
- at least one segment of the device may also be a non-swellable hydrophobic elastomer.
- the device includes at least a segment including a swellable hydrophilic elastomer and a segment including a non-swellable hydrophobic elastomer.
- the non-swellable hydrophobic elastomer may be selected from the group consisting of hydrophobic poly(ether urethane), poly(ethylene-co-vinyl acetate), polyether amide copolymer, silicone, silicone-poly(carbonate urethane), poly(carbonate urethane), and silicone-poly(ether urethane).
- the two or more segments may be joined by a polymer end-cap (i.e., a solid piece of polymer such as, e.g., a plug, rod, or disk) substantially impermeable to the drug in at least one of the segments.
- Multi-segment devices may include one or more tubular segments and/or one or more solid polymeric segments. Each segment may contain one or more APIs that may be different for each segment. Between each segment there may exist polymeric end caps to prevent diffusion of drug(s) into the other adjacent segments. These end caps include polymers that are substantially (i.e., completely or almost completely) impermeable to small molecule diffusion, including but not limited to ChronoThaneTM T65D and Tecoflex ® EG- 65D polyether urethane. The length of the end cap can be adjusted so that no significant amount of API travels from one API-loaded segment to another during device storage.
- end caps will be attached to the segment ends using a variety of techniques including, but not limited to injection molding or overmolding, induction welding, solvent welding, or an adhesive. Subsequently or simultaneously, segments with end caps in between may be joined together using a variety of techniques such as injection molding/overmolding, induction welding, solvent welding, or an adhesive.
- the intravaginal devices further include one or more orifices connecting the reservoir to an outer surface of the device.
- the orifices could be slits or pores.
- the pores may be of any suitable shape including, but not limited to circular, oval, square or rectangular.
- the one or more orifices may be pores with a diameter or width from about 0.1 mm to about 2 mm.
- the intravaginal devices of the present technology may encompass a variety of shapes and sizes provided the device is compatible with vaginal administration to the subject and with the requirements imposed by drug delivery kinetics.
- the device may therefore be an intravaginal ring, rod, tablet, tampon or pessary. Tablets, pessaries, and rods may be adhered to the mucosal epithelium as disclosed in U.S. Patent Number 6,951,654.
- the intravaginal device may be strengthened by use of a mesh, braid or spring.
- woven or braided tubing is commonly used in medical tubing applications such as catheters to give the wall sufficient strength and rigidity and prevent tube kinking as disclosed in U.S. Patent Number 5,059,375.
- the device of the present technology is an intravaginal ring (IVR).
- IVR intravaginal ring
- the dimensions of the IVR may vary depending upon the anatomy of the subject, the amount of drug to be delivered to the patient, the time over which the drug is to be delivered, the diffusion characteristics of the drug and other manufacturing
- the IVR should be flexible enough to enable bending and insertion inside the vaginal cavity and rigid enough to withstand the expulsive forces of the vaginal musculature without causing abrasion to the vaginal epithelium.
- the outer diameter of the IVRs may range, e.g., from about 45 mm to about 65 mm (including but not limited to any diameter within that range such as 50 mm, 55 mm, 60 mm and so forth).
- the cross-sectional diameter of the IVRs may range, e.g., from about 1.5 mm to about 10 mm (e.g., about 3, about 4, about 5, about 6, about 7, about 8, about 9, or about 10 mm and ranges between and including any two such values).
- the cross-sectional diameter of the reservoir core may range from about 1 mm to about 8 mm.
- the thickness of the hydrophilic elastomer surrounding the reservoir may vary from about 0.1 mm to about 2 mm (e.g., about 0.1, about 0.2, about 0.3, about 0.4, about 0.5, about 0.6, about 0.7, about 0.8, about 0.9, about 1, about 1.1, about 1.25, about 1.5 about 1.75, or about 2 mm, and ranges between and including any two such values).
- the intravaginal ring may be a single segment or it may include at least two segments.
- one of the segments includes a second intravaginally administrable drug different from the first.
- one segment may include any of the drugs discussed herein (e.g., an antiviral), and the second drug may be a contraceptive.
- the present technology also provides methods of making the intravaginal devices disclosed herein.
- the methods include loading the reservoir of an intravaginal device or a precursor thereto with an intravaginally administrable drug, wherein the reservoir is surrounded at least in part by a hydrophilic elastomer.
- the reservoir may be loaded with a composition comprising the intravaginally administrable drug and a pharmaceutically acceptable carrier and/or excipient.
- the methods further include forming the precursor into a shape suitable for intravaginal drug delivery.
- the precursor may be a tube of a hydrophilic elastomer.
- Such a tube may be formed into an intravaginal (hollow) rod by simply sealing off each end of the tube or into an intravaginal ring by joining the two ends to each other.
- the device or precursor thereto may be formed by coaxial extrusion or injection molding of any of the polymers discussed herein, including but not limited to poly(ether urethane)s.
- the present devices may be thermally conditioned, i.e., heated to allow the drug to diffuse into the elastomer (preventing lag times in drug release) and/or to provide increased physical/structural stability to the elastomer after fabrication.
- the device is heated from 1 to 30 days, in others, from 7 to 28 days, in still others, from 7 to 14 days. Heating must be gentle enough not to degrade the drug.
- the device is heated to a temperature from about 30 to about 60 °C.
- thermal conditioning temperatures include about 30°C, about 35 °C, about 40°C, about 45°C, about 50°C, about 55°C, about 60 °C, and ranges between and including any two of these values.
- a portion of the drug may also be dispersed in the hydrophilic elastomer itself (e.g., 0.05 wt% to 10 wt% of the total weight of the elastomer in the outer tube or 5 wt% to 70 wt% in the drug reservoir as a core).
- API may be incorporated into the polymer by adding API and polymer resin to a twin-screw extruder at desired feed rates using manual, gravimetric, or volumetric feeders, and extruding at a desired elevated temperature to melt and mix the polymer with API. The resultant mixture leaves the extruder as a homogenous drug-incorporated into the polymer extrudate.
- the ring may be formed by extruding a hydrophilic elastomer of the present technology using a crosshead die connected to an extruder known to those skilled in the art.
- the extruded tube is sectioned and the ends of the cut tube are joined to form a ring by a number of welding techniques including induction welding, butt welding, sonic welding and solvent welding.
- Two or more segments, each containing a reservoir including a different drug may be joined together in a similar fashion.
- the additional segment(s) may be solid and have drug(s) dispersed throughout the polymer (e.g., homogenous ly) rather than contained in a reservoir.
- Each of these steps may be carried out under a variety of conditions, including, but not limited to those described in the Examples.
- the present technology further provides methods of using the intravaginal devices disclosed herein.
- the methods comprise releasing the drug from any of the intravaginal devices disclosed herein while the device resides in a subject's vagina.
- the devices may be used to treat or prevent a variety of biological conditions.
- biological condition refers not only to diseases and disorders but conditions for which medical treatment may be desirable.
- the devices may be used to treat or prevent biological conditions, including, but not limited to a sexually transmitted disease, pregnancy and a post-menopausal condition.
- the devices may also be used to prevent or treat other biological conditions such as the bacterial, fungal, viral and/or protozoal infections disclosed in U.S. Patent No. 6,591,654.
- the biological condition is a sexually transmitted disease, including, but not limited to HIV, HSV, HBV or HPV.
- the methods further comprise retainably positioning the intravaginal device within the vaginal tract of the subject.
- the methods comprise retaining the intravaginal device in place for a period of time, including, but not limited to, about one day, about several days, about one month, or more than a month.
- Tecophilic ® hydrophilic aliphatic extrusion grade thermoplastic polyurethane was obtained (supplied by Lubrizol Advanced Materials, Wickliffe, OH), in particular HP- 60D grades with 60, 35, and 20 wt% equilibrium swelling. These polymers have a durometer (shore hardness) ranging from 41 to 43D and flexural modulus ranging from 4000 - 4300 psi.
- the various polymer resins were mixed with the opacifier titanium dioxide (anatase form, USP grade, Spectrum Chemicals, Gardena, CA, item number Til 40, CAS number 13463-67-7) at a titanium dioxide concentration around 0.75 wt%.
- the different mixtures were then hot-melt extruded using a tubing crosshead (Guill Tool, West Warwick, RI) mounted on a 3 ⁇ 4 inch 25: 1 L/D single screw extruder (C.W. Brabender, South Hackensack, NJ).
- the extrudate was then cut to 155.5 mm length using a Loctite ® precision o-ring cut and splice tool (Henkel, Rocky Hill, CT).
- Solid core cylindrical plugs of 4.1 mm cross- sectional diameter were extruded using the same material as tubing and subsequently cut to approximately 1 cm long to serve as a mating/joining interface for the tubing ends.
- the plug was placed in both ends of a filled tubing segment so that the tubing ends touched each other with the plug centered roughly in-between.
- An RF transistorized solid state induction heating unit, HPS-20, with pneumatic air and water-cooling was used to melt and join the tubing ends and plug to create a sealed IVR (PlasticWeld Systems, Inc., Newfane, NY).
- the ring joint to be welded was placed in a 6 mm long hardened stainless steel split die with outer diameter of 5.5 mm.
- the split die closed around the joint interface and 55% power was applied to the split die for 10 seconds, followed by 10 seconds of chilled air cooling. The split die then opened and the joined ring was removed, resulting in a sealed IVR with final dimensions of 55 mm outer diameter and 5.5 mm cross-sectional diameter.
- IVRs may adopt a non-circular conformation.
- IVRs are placed in a 12-cavity temperature controlled aluminum mold to shape anneal the rings in a circular shape and alleviate tube kinking. The mold is heated to 65°C for 15 minutes followed by 5 minutes at 10°C.
- TFV tenofovir
- IVR mechanical studies were conducted to evaluate device performance. IVRs were incubated in pH 4.2 sodium acetate buffer and placed in a 37°C, 80 rpm shaker for up to 120 days. Sink conditions were maintained throughout the entire experiment, and release media was changed daily.
- Quantification of amount of TFV released was determined using high performance liquid chromatography (HPLC) (aqueous mobile phase gradient method on reverse phase CI 8 column, Agilent 1200 series HPLC). Mechanical properties of the rings over time were measured by compressing rings 25% of their initial outer diameter at a rate of 1 mm/sec using an Instron 3342 mechanical testing system (Norwood, MA) with custom machined aluminum probe. The TFV release rapidly attained steady-state, and release was dependent on polymer equilibrium swelling. The 35 wt% polymer was able to maintain steady- state release through 105 days. Also, the ring mechanical properties changed little with time, even after all drug was released. (See FIG. 2.)
- TFV-containing paste is prepared similarly to that described above, with the exception that water is incorporated and the final composition is 65/33/2
- IVRs were incubated in sodium acetate buffer (pH 4.2) and placed in a 37°C, 80 rpm shaker for up to 90 days. Sink conditions were maintained throughout the entire experiment, and release media was changed daily. Quantification of amount of LNG released was determined using high performance liquid chromatography (HPLC) (aqueous/organic mobile phase gradient method on reverse phase CI 8 column, Agilent 1200 series HPLC). Steady-state LNG release was achieved, although it took approximately 21 days to achieve. Loading- dependent release was attained and 2 formulations maintained steady-state release through 90 days. (See FIG. 3.)
- HPLC high performance liquid chromatography
- the API at low wt% and polymer and titanium dioxide are premixed and extruded into tubing as described in Example 2.
- the tubing core composed of low wt% API is then filled as described in Example 3, with or without another API such as TFV or with excipient filler such as ethyl cellulose.
- hydrophobic antiretroviral small molecules e.g., IQP-0528, UC-
- API at a high wt% (1 wt% or greater) is compounded with polymer in a twin screw extruder and extruded into tubing per Example 1.
- API is then mixed at a high wt% (10 wt% or greater) with glycerol and filled as described in Example 1 , with or without another API, such as TFV or with excipient filler such as ethyl cellulose.
- IVRs adapted to deliver other hydrophilic small molecules such as TDF,
- SAMT-10, acyclovir, or adefovir are prepared as in Example 1.
- a high wt% swelling polymer such as Tecophilic HP-93A-100 is used as the tubing polymer.
- Fast-dissolving porogens which do not melt at extrusion temperature and which are insoluble in the polymer but demonstrate high aqueous solubility are used to create holes and channels in the tubing wall once placed in aqueous environment and therefore increase API release rate.
- One such example is sodium chloride which is premixed with the polymer pellets as well as titanium dioxide and hot-melt extruded to create tubing as described in Example 1.
- the extruded tubing additionally may have holes created via laser cutting to allow for increased drug release if necessary. The size, shape, and number of holes are varied depending on required API release rate.
- the API and plasticizing/lubricating agent are subsequently mixed and filled into the tubing to create a ring as described in Example 1.
- the TFV-filled tubing may also be manufactured using an alternative coaxial extrusion method.
- a 12 mm twin screw extruder (C.W. Brabender) is fed TFV from a powder feeder (model K-CL-SFS-MT12 pharma twin-screw microfeeder, K-Tron, Pitman, NJ) and glycerol from a liquid feeder peristaltic pump (K-Tron).
- the tubing polymer is fed into a 3/4" single screw extruder (C.W. Brabender).
- the two material streams meet in a custom-made coextrusion crosshead (Guill Tool).
- the coextrusion crosshead inner core is liquid cooled to near room temperature to prevent the TFV/glycerol from heating. Near the end of the crosshead, the two materials meet and interface and leave the crosshead. Sections of the co-extruded product are cut and joined as described in Example 1 to create an IVR.
- Example 9 Improved IVR Manufacturing Process
- Tecophilic ® HP-60D-60 tubing was cut to 171 mm in length and one end of each tube was heat sealed closed to create a plug using a HPS-EM tip forming induction welding machine with a polytetrafluoroethylene-coated stainless steel bonding die (Plastic Weld Systems Inc., Newfane, NY).
- TFV/glycerol/water (65/33/2 wt%) paste was loaded into a Model 2400 Higher Pressure Filling System (Dymax, Torrington, CT) with a 150 mm stainless steel nozzle. Tubes with one end sealed were slid over the nozzle and the paste was backfilled in the tube, leaving 15 mm of the tube end free.
- 100% TFV powder was filled into tubes instead of the 65/33/2 wt% paste. Each method filled at least 1.5 g of TFV per device. Subsequently, for all filled tubes, the HPS-EM tip forming machine was used to seal the second tube end. The sealed tube ends were then welded together to form rings using the HPS-20 ring bonding induction welding system described above. Additional IVRs using other types of Tecophilic ® tubing were manufactured according to this procedure.
- a multi-segment ring wherein different APIs are delivered from different polymeric segments, is created.
- a TFV/glycerol filled tubing segment is made as described in Examples 1, 8 or 9.
- Another segment is fabricated using the same or different method(e.g., the additional segment may be a solid polymeric segment).
- Solid polymeric segments may be matrix-type (extruded or injection molded) or reservoir-type (coaxially extruded rate controlling membrane over API-loaded core).
- Tubular and solid polymeric reservoir-type segments may or may not contain drug within their rate controlling membrane, which would be incorporated during hot-melt extrusion or during device storage via diffusion from the drug-loaded core to the rate controlling membrane.
- Each segment will contain one or more API. It may be advantageous to formulate APIs in separate segments for various reasons such as independent control of each API's release rates, and chemical or physical incompatibility between the APIs or corresponding excipients.
- Segments may be joined together using a variety of techniques including, but not limited to induction welding, solvent welding, or an adhesive.
- the multiple segments are joined to a piece of high modulus polymer such as Tecoflex ® EG- 65D hydrophobic polyurethane (shore hardness 60D, flexural modulus 37,000 psi) as this polymer is highly impermeable and has been shown to minimize diffusion of API from one segment to another.
- Tecoflex ® EG-65D segment(s) are then joined to the other segments to create an IVR.
- APIs include, but are not limited to antimicrobial and antiviral agents, antiretroviral agents, antibacterial agents, antifungal agents, contraceptives, hormonal agents, selection progesterone receptor modulators (SPRMs, such as telapristone), and selective estrogen receptor modulators (SERMs, such as raloxifene and tamoxifen, and phytoserms from botanical source).
- SPRMs selection progesterone receptor modulators
- SERMs selective estrogen receptor modulators
- the mixed agonist/antagonist activity results in selective stimulation or inhibition of progesterone-like action in divergent tissue.
- SERMs selectively stimulate or inhibit estrogen-like action in various tissues.
- SPRMs and SERMs can be delivered locally intravaginally as doses ranging between 10 ⁇ g to 100 mg.
- These agents can be effective therapeutics for including, but not limited to endometriosis, uterine fibroids, post-menopausal symptoms, hormone replacement therapy, anti-cancer benefits, thrombosis, and osteroporosis benefits.
- These agents can be delivered intravaginally over a short (1 to several days) or long (up to three months) period. Benefits of delivering these agents intravaginally include, but not limited to lower dosing, more directed therapy, and lower side-effect profile.
- TFV was compounded at approximately 40%
- the coating material was formed by compounding TFV at approximately 5% (w/w) into HPU 20, a custom-designed hydrophilic polyurethane which exhibits approximately 20% equilibrium aqueous swelling (w/w), using a twin-screw extruder to form cylindrical strands approximately 2 mm in diameter, which were subsequently milled in a strand pelletizer.
- the HPU 20 / TFV was used to jacket HPU 60 / TFV using a twin-screw extruder and crosshead die.
- the ring described in Example 11 is manufactured using gravimetric (loss- in-weight) feeding and coaxial extrusion.
- the core and coating materials are pre-fabricated using a twin-screw extruder.
- the hydrophilic polyurethane or other water-swellable polymer are fed using a gravimetric (loss-in-weight) feeder in to a twin- screw extruder while TFV is fed, down-barrel, into the same twin-extruder using a separate gravimetric loss-in-weight feeder.
- Material is passed through a narrow (1 - 2 mm) circular strand die at the end of the extruder barrel.
- the relative outputs of the two feeders are adjusted to produce the desired mass fraction of TFV in the extrudates.
- the ratio of equilibrium aqueous mass fractions (after swelling) of the core polymer to the coating polymer are approximately between 1.5 and 5.
- the mass fraction of TFV in the coating polymer is optimized to produce a burst release similar to the zero-order release profile dictated by the swelling behavior of the coating polymer and the cross-sectional geometry of the device.
- Both extrudates are milled into pellet form using a strand pelletizer.
- the core extrudate is starve-fed into a twin-screw extruder using a gravimetric feeder while the coating extrudate is flood-fed into a single-screw extruder.
- Both extruders are connected using a heated crosshead die in order to produce a coaxially extruded strand.
- the outer diameter and wall thickness of the extrudate are controlled by the relative screw speeds of the two extruders.
- the resulting reservoir strands are cut and joined at the ends using induction welding methods similar to those described in Examples 1 and 9, to form a ring with desired outer diameter, approximately 50 - 60 mm.
- Example 13 Formation of IVR with Combination of Drugs and Drug-Impregnated Polymeric Core
- a ring is prepared as described in Example 12 whereby a low weight fraction of levonorgestrel or other synthetic progestin is mixed with TFV prior to pre-fabrication of the core and coating extrudates in order to produce a dual protection contraceptive - microbicide IVR.
- Example 14 Formation of IVR including Acyclovir and Tenofovir
- a ring is prepared as described in Example 12, whereby a desired weight fraction of acyclovir (ACV), a hydrophilic HSV-RT inhibitor, is mixed with TFV prior to pre-fabrication of the core and coating extrudates in order to produce a microbicide IVR for the prevention or treatment of HIV and HSV infections.
- ACCV acyclovir
- HSV-RT inhibitor a hydrophilic HSV-RT inhibitor
- a ring is prepared as described in Example 12, whereby TFV is replaced by
- ACV to be investigated for simultaneous contraception and protection against HSV infection.
- a ring is prepared as described in Example 14 whereby TFV and ACV are loaded in to separate core and coating extrudates, each coaxially extruded separately in to cylindrical strands of equal outer cross-sectional diameter.
- the core mass fractions of each API are generally greater than 30%.
- the wall thickness and relative lengths of each strand are selected to produce a desired release rate.
- Two coaxially extruded strands, one containing TFV and one containing ACV, are joined via two induction welds to form a ring of similar dimensions to Example 11.
- Example 17 Formation of IVR including Tenofovir and Contraceptive
- a ring is prepared as described in Example 16 whereby ACV is replaced by a low ( ⁇ 1%) mass fraction of levonorgestrel or other synthetic progestin for the same indication as the ring in Example 13.
- Example 18 Formation of IVR including Acyclovir and Contraceptive
- a ring is prepared as described in Example 16 whereby TFV is replaced by a low ( ⁇ 1%) mass fraction of levonorgestrel or other synthetic progestin for the same indication as the ring in Example 14.
- a ring is prepared as described Example 13 whereby the synthetic progestin is replaced by a non-nucleoside reverse transcriptase inhibitor (NNRTI) of HIV- 1 such as UC781, MIV-170, MIV-150, dapivirine, efavirenz or IQP-0528, or an HIV-1 cell entry inhibitor such as maraviroc, an HIV-1 protease inhibitor such as saquinavir or ritonavir, or an HIV-1 integrase inhibitor such as darunavir or raltegravir.
- NRTI non-nucleoside reverse transcriptase inhibitor
- a ring is prepared as described in Example 16 whereby ACV is replaced by a low mass fraction ( ⁇ 10%) of a non-nucleoside reverse transcriptase inhibitor (NNRTI) of HIV-1 such as UC781, MIV-170, efavirenz or IQP-0528, or an HIV-1 cell entry inhibitor such as maraviroc, an HIV-1 protease inhibitor such as saquinavir or ritonavir, or an HIV-1 integrase inhibitor such as darunavir or raltegravir.
- NRTI non-nucleoside reverse transcriptase inhibitor
- Example 21 Formation of IVR including NRTI
- a ring is prepared as described in Example 13 whereby TFV is replaced by a hydrophilic nucleoside analogue reverse transcriptase inhibitor (NRTI) of HIV-1, such as emtracitibine (FTC), or an alternative NRTI such as tenofovir disoproxil fumarate (TDF).
- NRTI hydrophilic nucleoside analogue reverse transcriptase inhibitor
- FTC emtracitibine
- TDF tenofovir disoproxil fumarate
- Example 22 Formation of IVR including NRTI
- a ring is prepared as described in Example 16 whereby TFV is replaced by a hydrophilic nucleoside analogue reverse transcriptase inhibitor (NRTI) of HIV-1 such as emtracitibine (FTC), or an alternative NRTI such as tenofovir disoproxil fumarate (TDF).
- NRTI hydrophilic nucleoside analogue reverse transcriptase inhibitor
- FTC emtracitibine
- TDF tenofovir disoproxil fumarate
- a ring is prepared as described in Example 17 whereby TFV is replaced by a hydrophilic nucleoside analogue reverse transcriptase inhibitor (NRTI) of HIV- 1 such as emtracitibine (FTC), or an alternative NNRTI such as tenofovir disoproxil fumarate (TDF).
- NRTI hydrophilic nucleoside analogue reverse transcriptase inhibitor
- FTC emtracitibine
- TDF tenofovir disoproxil fumarate
- Example 24 Formation of IVR including NRTI
- a ring is prepared as described in Example 19 whereby TFV is replaced by a hydrophilic nucleoside analogue reverse transcriptase inhibitor (NRTI) of HIV- 1 such as emtracitibine (FTC), or an alternative NRTI such as tenofovir disoproxil fumarate (TDF).
- NRTI hydrophilic nucleoside analogue reverse transcriptase inhibitor
- FTC emtracitibine
- TDF tenofovir disoproxil fumarate
- Example 25 Formation of IVR including NRTI
- a ring is prepared as described in Example 20 whereby TFV is replaced by a hydrophilic nucleoside analogue reverse transcriptase inhibitor (NRTI) of HIV- 1 such as emtracitibine (FTC), or an alternative NRTI such as tenofovir disoproxil fumarate (TDF).
- NRTI hydrophilic nucleoside analogue reverse transcriptase inhibitor
- FTC emtracitibine
- TDF tenofovir disoproxil fumarate
- Example 26 Formation of IVR including Drug in Core and Wall of Ring
- An IVR as described in Examples 1, 2, 3, and 9 is manufactured by premixing hydrophobic small molecule API (such as IQP-0528, UC-781, or levonorgestrel) with non-swellable polymer (such as Tecoflex ® ) and titanium dioxide.
- the tubing is then extruded as described above using a single screw extruder and tubing crosshead.
- the tubing may or may not incorporate reinforced/braided tubing or metallic springs to mechanically support the wall.
- the tubing is then filled with the API and excipient(s) mixture and joined to make a ring as described above.
- FIG. 9 shows a tubular device for hydrophobic small molecule, IQP-0528, a pyrimidinedione.
- the core is composed of 48 wt% drug and 52 wt% glycerol paste filled in a hydrophobic tubing (Tecoflex ® EG85A) preloaded with 4.7 wt% drug.
- a hydrophobic tubing Tecoflex ® EG85A
- approximately 600 ⁇ g of IQP-0528 was released daily for 30 days.
- Tecophilic ® HP- 60D grades with 60, 35, and 20 wt% equilibrium swelling are used. These polymers have a durometer (shore hardness) ranging from 41 to 43D and flexural modulus ranging from 4000 - 4300 psi.
- the various polymer resins are mixed with the opacifier titanium dioxide (anatase form, USP grade, Spectrum Chemicals, Gardena, CA, item number Til 40, CAS number 13463-67-7) at a titanium dioxide concentration around 0.75 wt%.
- the different mixtures are then hot-melt extruded using a tubing crosshead (Guill Tool, West Warwick, RI) mounted on a 3 ⁇ 4 inch 25: 1 L/D single screw extruder (C.W. Brabender, South
- the extrudate is then cut to 155.5 mm length using a Loctite ® precision o-ring cut and splice tool (Henkel, Rocky Hill, CT).
- Micronized ACV is manually mixed with a spatula with the
- plasticizing/lubricating agent glycerol USP grade, Spectrum Chemicals, Gardena, CA, item number G1016, CAS number 56-81-5) at ratios of 70/30 and 50/50 wt%.
- the tubing cores are then filled with the ACV/glycerol mixture by manually packing the mixture in with a 3 mm diameter brass rod.
- the IVR segments are weighed before and after filling, and approximately 3 g of ACV/glycerol mixture is added to each IVR.
- Solid core cylindrical plugs of 4.1 mm cross-sectional diameter are extruded using the same material as tubing and subsequently cut to approximately 1 cm long to serve as a mating/joining interface for the tubing ends.
- the plug is placed in both ends of a filled tubing segment so that the tubing ends touch each other with the plug centered roughly in-between.
- An RF transistorized solid state induction heating unit, HPS-20, with pneumatic air and water-cooling is used to melt and join the tubing ends and plug to create a sealed IVR (PlasticWeld Systems, Newfane, NY).
- the ring joint to be welded is placed in a 6 mm long hardened stainless steel split die with outer diameter of 5.5 mm.
- the split die closes around the joint interface and 55% power is applied to the split die for 10 seconds, followed by 10 seconds of chilled air cooling.
- the split die is then opened and the joined ring removed, resulting in a sealed IVR with final dimensions of 55 mm outer diameter and 5.5 mm cross-sectional diameter.
- Example 28 Formation of IVR including Contraceptive and Antiretroviral agents
- Tecophilic hydrophilic polyurethane is used to deliver both the
- LNG is premixed at a low concentration (0.05 - 0.2 wt%) with the hydrophilic polyurethane pellets in addition to the opacifier titanium dioxide.
- the mixture is then hot-melt extruded to create tubing as described in Example 27.
- ACV/glycerol at a ratio of 70/30 wt% is mixed together for the core, along with a small amount (milligrams) of LNG.
- the tubing cores are then filled with the ACV/LNG/glycerol mixture, amounting to approximately 2.0 g of ACV and 1 - 10 mg LNG in each IVR core.
- the filled tube ends are then joined using the same procedure described in Example 27.
- Example 29 Formation of Dual-Segment IVR from hydrophilic and hydrophobic polymers
- Example 29A A dual-segment ring is made, wherein TFV and/or including, but not limited to, hydrophilic antiviral API (e.g., ACV, FTC) is/are delivered from a hydrophilic tubing reservoir segment and levonorgestrel and/or other contraceptive API is/are delivered from a coaxially extruded hydrophobic solid core reservoir segment.
- hydrophilic antiviral API e.g., ACV, FTC
- levonorgestrel and/or other contraceptive API is/are delivered from a coaxially extruded hydrophobic solid core reservoir segment.
- an TFV/glycerol filled tubing segment is made as described in Example 9. Another segment is fabricated using a coaxial extrusion setup known to those skilled in the art.
- Tecoflex ® EG-85A is added to a twin screw extruder at a drug loading of around 1 wt%
- Tecoflex ® EG-65D shore hardness 60D, fiexural modulus 37,000 psi
- the two molten polymer feeds meet in a coaxial crosshead (Guill Tool) where the cylindrical core composed of the LNG in Tecoflex ® EG-85A is coated by the Tecoflex ® EG-65D with approximately 100 ⁇ coating thickness which serves as a rate-controlling membrane.
- the two segments are joined to an injection-molded plug composed of a high modulus polymer such as Tecoflex ® EG-65D as this polymer is highly impermeable and has been shown to minimize diffusion of API from one segment to another.
- Tecoflex ® EG-65D plug segment(s) are then joined to the other segments to create an IVR.
- Joining methods include induction welding, solvent welding, or an adhesive.
- Example 29B In a further example, a TFV/glycerol/water (65/33/2 wt%) semi-solid paste was loaded into the hydrophilic tubing reservoir segment and LNG was dissolved in the hydrophobic solid core reservoir segment of a dual segment IVR made according to Example 29A (using similar polyurethane tubing). The resulting IVR was subjected to in vitro drug release testing in an aqueous buffer sink for 90 days. Zero-order release of TFV, following a brief (1 day) lag period (see Fig 13 A), and near-zero-order release of LNG (see Fig 13B) were observed for 90 days.
- Example 29C A dual segment ring, is made as in example 29A, where the contraceptive(s) is/are replaced by one or more polymer-soluble antiviral API (e.g. DPV, EVG, IQP-0528, GS-7340) present between 1 and 20 wt%.
- polymer-soluble antiviral API e.g. DPV, EVG, IQP-0528, GS-7340
- a high wt% swelling polymer such as Tecophilic ® HP-93A-100 is used as the tubing polymer.
- the polymer tubing is extruded as described in Example 27.
- Fast- dissolving porogens which do not melt at extrusion temperature and which are insoluble in the polymer but demonstrate high aqueous solubility are used to create holes and channels in the tubing wall once placed in aqueous environment and therefore increase carrageenan release rate.
- One such example is sodium chloride which is premixed with the polymer pellets as well as titanium dioxide and hot-melt extruded to create tubing as described in Example 27.
- the extruded tubing additionally may have holes created via laser cutting to allow for increased drug release if necessary.
- the size, shape, and number of holes are varied depending on required drug release rate.
- Carrageenan and an excipient such as glycerol are mixed together at a ratio of approximately 70/30 wt%.
- carrageenan is compressed into pellets using a pharmaceutical pellet press.
- the carrageenan formulation is subsequently filled into the tubing and welded to create a ring as described in Example 27.
- Example 31 Creation of tubing and devices from a mixture of polyurethane resins to obtain varying swelling
- Example 1 The procedure of Example 1 was followed to prepare tubing for a single or multi-segment IVD except that a blend of polymers of varying hydrophilicity was used.
- a 1 : 1 wt/wt mixture of Tecophilic ® HP 60D-35 resin (35 wt% swelling) and Tecoflex ® EG-85A resin (hydrophobic) is extruded to make tubing with 21 wt% swelling.
- a 3 1 wt/wt mixture of Tecophilic ® HP 60D-35 resin (35 wt% swelling) and
- Tecoflex ® EG-85A resin is extruded to make tubing with 27 wt% swelling.
- Example 32 A tubular device with solid (dry) filling
- Single or multi-segment tubular devices may be filled with one or more drugs or APIs of the same or different class of compounds in the form of a powder or pellet.
- Devices also may be composed of one drug or API as a powder and/or pellets or two to three different drugs or APIs as powder or individual pellets depending on the desired delivery rate for each drug.
- Drug/ API may or may not be micronized or milled or ground to a certain particle size before filling.
- the drug/ API may be mixed or granulated with an excipient including, but not limited to diluents, densification, or bulking agent such as cellulose derivatives including microcrystalline cellulose, methyl cellulose, ethyl cellulose and hydroxyl propyl methyl cellulose; sugars, such as lactose and mannitol; calcium and magnesium salts, such as calcium or magnesium carbonate, di- or tribasic calcium phosphate and magnesium oxide and starch; lubricating agent and glidants to improve powder flow properties, such as magnesium, calcium or zinc stearate, talc, starch, calcium phosphate and colloidal silicon dioxide; and osmotic agents, such as salts like sodium chloride, sodium acetate, and sugars such as sucrose, mannitol, xylitol.
- an excipient including, but not limited to diluents, densification, or bulking agent such as cellulose derivatives including microcrystalline cellulose, methyl cellulose,
- Granulation may be done by wet or dry techniques and includes, single pot mixing, high shear mixing, spray granulation and drying, fluidized bed process, direct compression, roller compaction. Granules may be produced in various sizes, shapes, hardness, friability and possessing differing density, dissolution, and disintegration rates.
- the device may have one or more segments filled with immediate and delayed release formulations of same or multiple drugs/APIs, so that sufficient drug is available. Also, addition of a delayed release formulation may control the drug/ API release rate from a tubing device. Delayed release formulations may be prepared by granulation or by melt extrusion followed by pelletization. FIG. 7 shows the 30-day average drug/ API release from a tubular device with dry filling.
- a 3 : 1 mixture of granulated and free drug/ API was filled in hydrophilic tubing for sustaining drug release over 30 days.
- Granules were prepared by wet granulation of drug with microcrystalline cellulose, dried and mixed in a 3 : 1 ratio with the API.
- Example 33 A tubular device with osmotic agents or osmo-attractants to reduce lag time
- Single or multi-segment tubular devices may contain an osmotic agent or osmo-attractant along with one or multiple APIs in the core.
- an osmotic agent may be incorporated in the tubing wall during extrusion or injection molding. Addition of an osmotic agent to the tubular device results in rapid entry of water into the tubing lumen and results in drug release when the device is in physiological conditions. In the absence of an osmotic agent, water entry is dependent on the rate of polymer swelling and aqueous solubility of the API resulting in delayed drug release. Higher water swelling polymers and APIs in their salt form show lower lag times.
- Osmotic agents include, but not limited to, low molecular weight polyvinyl pyrrolidone, polyvinyl alcohol, polyethylene glycol and polyacrylic acid.
- Osmotic agents also include water soluble salts, but not limited to salts of sodium and potassium, such as sodium and potassium chloride and acetate, sugars such as glucose, fructose, sucrose, trehalose, mannitol, xylitol and sorbitol and alcohols such as glycerol, ethylene glycol, propylene glycol and tetraethylene glycol
- FIG. 8A shows the comparative TFV release rate profiles for a hydrophilic tubing reservoir IVR comprised of Tecophilic® HP-60D-35 filled with either a 65/33/2 wt% TFV/glycerol/water paste or 100% TFV powder. Rings with 100% TFV in the core do not achieve steady state TFV release rates by 28 days, whereas rings with the osmotic agent glycerol in the core (33 wt%) achieve steady state TFV release rates by 3 days .
- FIG. 10 shows the release profile for TDF from an IVR composed of a 20 wt% swellable hydrophilic polyether urethane tubing (HydroThaneTM), with core composed of a drug and sodium chloride mixture.
- Sodium chloride (15 wt% of total drug content) acts as an osmo-attractant and aids in decreasing the lag time for equilibrium swelling.
- Example 34 A tubular device for delivery of nucleotide analogue reverse
- transcriptase inhibitor tenofovir and its prodrugs
- a vaginal device of the present technology may be used to deliver a nucleotide analogue reverse transcriptase inhibitor, tenofovir or its prodrugs, tenofovir disoproxil fumarate and GS-7340, directly to the female genital tract in prophylactic doses to prevent HIV and HSV (and HPV) infections.
- TDF and GS-7340 are well-suited for local delivery to vaginal tissues, because of their increased hydrophobicity and therefore result in relatively higher tissue uptake in comparison to TFV. This also reduces the overall amount of the drug required for protection eventually making it possible to deliver relevant quantities up to 30 days with one time device insertion.
- the amount of drug delivered form the device may include 0.1 - 20 mg/day.
- a device is produced by the method of Examples 1, 9 or 26.
- Tubing may be composed of hydrophilic aliphatic polyether urethane or its combination with hydrophobic polyether urethane.
- Hydrophilic polyether urethanes may include, but not limited to Tecophilic ® HP-60D-20, -35 and -60, HP-93A-100 and TG-500 and -2000 and
- HydroThaneTM 80A and 93A (5 wt% to 25 wt% swelling) and hydrophobic polyether urethanes may include, but not limited to Tecoflex ® EG-80A, 85A, 93 A, 60D, 65D, 68D and 72D and ChronoThaneTM T75A to 75D.
- Tubing dimensions are variable and wall thickness may range from 0.6 mm to 1.2 mm and diameter from 4 mm to 5.5 mm.
- Tubing may be filled with solid drug or formulations in the reservoir.
- Drug may be micronized or milled to desired particle size before filling.
- the reservoir may be filled with 100% drug or combined with an excipient.
- the amount of drug filled in the core may be from 1 mg to 2000 mg.
- the core may contain from 0 to 80 wt% excipients.
- Excipients include, but not limited to diluent or bulking agent, such as cellulose derivatives, microcrystalline cellulose, methyl cellulose and ethyl cellulose; sugars, lactose, mannitol; calcium and magnesium salts, calcium or magnesium carbonate, di- or tri-basic calcium phosphate, and magnesium oxide; starch; lubricating agents and glidants to improve powder flow properties; such as magnesium, calcium or zinc stearate, talc, starch, calcium phosphate; colloidal silicon dioxide; and osmotic agents to reduce lag time, such as salts such as sodium chloride, sodium acetate and sugars like sucrose, mannitol, xylitol.
- diluent or bulking agent such as cellulose derivatives, microcrystalline cellulose, methyl cellulose and ethyl cellulose
- sugars, lactose, mannitol such as cellulose derivatives, microcrystalline cellulose, methyl cellulose and ethyl
- tubing may be filled with semi-solid formulation as a paste.
- Paste can be prepared with water, alcohols such as glycerol, ethylene glycol, propylene glycol, polyethylene glycol.
- Paste can also be made with oils for example, castor oil, or silicones, such as dimethicone using a high shear homogenizer and may include osmotic agents and excipients. Since prodrugs are susceptible to hydrolytic degradation, use of water or hygroscopic agents should be avoided.
- Tubing may be filled with solid or semi-solid formulation using auger or gravimetric filling techniques. Total weight of the filled material may be from 100 mg to 2000 mg. Tubes may be sealed and device may be fabricated using induction welding, solvent welding or by use of plugs held by adhesive, induction or solvent welded.
- Example 35 A tubular device for delivery of agents to promote vaginal health and treat vaginal conditions
- the vaginal device is made from polymer tubing with a drug filled reservoir.
- Tubing may be composed of hydrophilic aliphatic polyether urethane or its combination with hydrophobic polyether urethane.
- Hydrophilic polyether urethanes may include, but not limited to Tecophilic ® HP-60D-20, -35 and -60, HP-93A-100 and TG- 500 and -2000 and HydroThaneTM 80A and 93A (5 wt% to 25 wt% swelling) and hydrophobic poly(ether) urethanes may include, but not limited to Tecoflex ® EG-80A, 85A, 93A, 60D, 65D, 68D and 72D and ChronoThaneTM T75A to 75D.
- Tubing dimensions are variable and wall thickness may range from 0.06 mm to 1.2 mm and diameter from 4 mm to 5.5 mm.
- APIs may include agents that promote or improve vaginal health conditions.
- vaginal health and conditions and vaginal microflora including antibiotics, menopause (or estrogen decline), oral contraceptives, spermicides, and/or diabetes.
- Use of tubular devices to deliver agents such as probiotics and prebiotics intravaginally will promote improved vaginal health and replace or replenish health microflora.
- Delivery of probiotics including, but not limited to stains of Lactobacillus, Lactobacillus rhamnosus, Lactobacillus reuteri, and Lactobacillus fermentum for maintaining healthy vaginal flora can be accomplished using such tubular intravaginal devices.
- Prebiotics including, but not limited to particular fructooligosaccharides, galactooligosaccharides, and lactulose also could promote vaginal health when delivered intravaginally.
- Example 36 A tubing device with API incorporated in the wall at elevated
- devices may be stored at elevated temperature ranging from 40°C to 70°C, depending on drug stability, for a predetermined amount of time to accelerate diffusion of the API from the tubing lumen to the tubing wall. After a predetermined time/temperature storage, the API loading in the device wall be equilibrated and the device will show minimal or no lag-time in drug release.
- This approach works for APIs which show some solubility in the rate-controlling polymer. Also, in certain instances this approach may negate the need for an osmotic agent.
- TDF tenofovir disoproxil fumarate
- TFV steady-state release rate has been observed to be significantly lower if devices were first stored at room temperature for several weeks prior to in vitro release testing. This example ensures acceleration of the polyurethane phase separation during the last manufacturing step so that the device is thermodynamically stable thereafter.
- TFV IVRs are prepared as described in Example 1 or Example 9, using variety of hydrophilic poly(ether) urethane (Tecophilic) tubing, including blended materials described in Example 31.
- IVRs are then placed in a vapor- flex flat barrier bag, type VF42 PET/FOIL/LLDPE (LPS Industries, Moonachie, NJ).
- the pouches are heat sealed using an impulse sealer Model AIE 300 A.
- the pouches are placed in a 40°C oven for various time.
- the rings are then evaluated for TFV release kinetics using methodology described in Example 1.
- hydrophobic compounds can be delivered from hydrophilic polyurethane tubing reservoir rings at high sub-milligram/day levels in vitro for over 28 days.
- Elvitegravir (EVG), TFV, and glycerol (63/5/32 wt% TFV/EVG/glycerol-water, where glycerol was premixed as a 33/2 wt% stock solution) was loaded into the lumen of 35 wt% swelling hydrophilic polyurethane single-segment tubing with 5.5 mm cross-sectional diameter and 0.7 mm wall thickness.
- dapivirine (DPV) was formulated in various equilibrium swelling hydrophilic polyurethane tubing lumens (all with 5.5 mm cross-sectional diameter and 0.7 mm wall thickness) at 63/5/32 wt%
- the DPV release rates from the various hydrophilic polyurethane rings ranged from approximately 300 to 1000 ⁇ g/day (depending on polyurethane utilized), after a lag time of approximately two weeks (FIG. 12B).
- the highest DPV flux was achieved by polymers with the lowest swelling, indicating that DPV diffused primarily through the hydrophobic blocks of the polyurethane and thus the hydrophobic API release rate can be tailored to achieve a desired release rate.
- Both DPV and EVG rings described above were tested for in vitro release immediately after ring fabrication.
- a ring delivering hydrophobic APIs should show little or no lag time in releasing the drug after adequate storage time, since the API should partition into the tubing wall on ring storage.
- TFV release from HTPU 35 and 60% swelling rings was not noticeably affected by the presence of DPV and EVG (TFV steady- state release rates were approximately 13 and 22 mg/day, respectively).
- a dual-segment IVR (Tecophilic ® 75/25 HP-60D-60/HP-93A-100;
- Tecoflex ® EG-85A coated with EG-65D containing both TFV and LNG, was fabricated as described in Example 29A/B.
- Example 29B where thermal conditioning was used to eliminate lag time to achieve steady- state LNG release rate
- Example 37 where thermal conditioning is used to provide a thermodynamically stable TFV release rate upon storage, the entire IVR (not just one of the segments) was thermally conditioned at 40°C for 14 days.
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Abstract
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Priority Applications (11)
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AU2012283837A AU2012283837B2 (en) | 2011-07-20 | 2012-07-20 | Intravaginal devices for drug delivery |
JP2014521836A JP6170044B2 (en) | 2011-07-20 | 2012-07-20 | Intravaginal device for drug delivery |
EP12815417.6A EP2734262B1 (en) | 2011-07-20 | 2012-07-20 | Intravaginal rings for drug delivery |
KR1020147004240A KR20140074281A (en) | 2011-07-20 | 2012-07-20 | Intravaginal devices for drug delivery |
BR112014001450A BR112014001450A2 (en) | 2011-07-20 | 2012-07-20 | intravaginal drug delivery devices |
RU2014106067A RU2607179C2 (en) | 2011-07-20 | 2012-07-20 | Intravaginal device for drug delivery |
CN201280040764.2A CN103796708A (en) | 2011-07-20 | 2012-07-20 | Intravaginal devices for drug delivery |
MX2014000765A MX357598B (en) | 2011-07-20 | 2012-07-20 | Intravaginal devices for drug delivery. |
CA2842550A CA2842550C (en) | 2011-07-20 | 2012-07-20 | Intravaginal devices for drug delivery |
US14/233,692 US20140209100A1 (en) | 2011-07-20 | 2012-07-20 | Intravaginal devices for drug delivery |
ZA2014/01269A ZA201401269B (en) | 2011-07-20 | 2014-02-19 | Intravaginal devices for drug delivery |
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TWI640306B (en) * | 2013-06-21 | 2018-11-11 | 德派信迪思公司 | Films and methods of manufacture |
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Also Published As
Publication number | Publication date |
---|---|
RU2014106067A (en) | 2015-08-27 |
KR20140074281A (en) | 2014-06-17 |
ZA201401269B (en) | 2020-05-27 |
CA2842550A1 (en) | 2013-01-24 |
EP2734262A1 (en) | 2014-05-28 |
AU2012283837B2 (en) | 2017-04-27 |
US20140209100A1 (en) | 2014-07-31 |
BR112014001450A2 (en) | 2017-07-18 |
AU2012283837A1 (en) | 2014-02-27 |
JP6170044B2 (en) | 2017-07-26 |
EP2734262B1 (en) | 2018-02-28 |
MX2014000765A (en) | 2014-09-25 |
MX357598B (en) | 2018-07-16 |
CN103796708A (en) | 2014-05-14 |
CA2842550C (en) | 2020-03-24 |
JP2014520896A (en) | 2014-08-25 |
EP2734262A4 (en) | 2014-12-31 |
RU2607179C2 (en) | 2017-01-10 |
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