WO2014123880A1 - Anneau intravaginal pour l'administration de combinaisons uniques de compositions antimicrobiennes - Google Patents

Anneau intravaginal pour l'administration de combinaisons uniques de compositions antimicrobiennes Download PDF

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Publication number
WO2014123880A1
WO2014123880A1 PCT/US2014/014633 US2014014633W WO2014123880A1 WO 2014123880 A1 WO2014123880 A1 WO 2014123880A1 US 2014014633 W US2014014633 W US 2014014633W WO 2014123880 A1 WO2014123880 A1 WO 2014123880A1
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WIPO (PCT)
Prior art keywords
water
ring
molecular weight
weight water
soluble
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PCT/US2014/014633
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English (en)
Inventor
Thomas M. Zydowsky
Shweta Ugaonkar
Samantha Seidor
Original Assignee
The Population Council, Inc.
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Filing date
Publication date
Priority claimed from US13/759,981 external-priority patent/US20130150810A1/en
Application filed by The Population Council, Inc. filed Critical The Population Council, Inc.
Priority to CN201480020245.9A priority Critical patent/CN105555281A/zh
Priority to EP14705007.4A priority patent/EP2953629A1/fr
Priority to RU2015136769A priority patent/RU2015136769A/ru
Priority to BR112015018701A priority patent/BR112015018701A2/pt
Priority to AU2014215459A priority patent/AU2014215459A1/en
Publication of WO2014123880A1 publication Critical patent/WO2014123880A1/fr

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0034—Urogenital system, e.g. vagina, uterus, cervix, penis, scrotum, urethra, bladder; Personal lubricants
    • A61K9/0036—Devices retained in the vagina or cervix for a prolonged period, e.g. intravaginal rings, medicated tampons, medicated diaphragms
    • 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
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • 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
    • A61K33/00—Medicinal preparations containing inorganic active ingredients
    • A61K33/24—Heavy metals; Compounds thereof
    • A61K33/30—Zinc; Compounds thereof
    • 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
    • A61K47/36—Polysaccharides; Derivatives thereof, e.g. gums, starch, alginate, dextrin, hyaluronic acid, chitosan, inulin, agar or pectin

Definitions

  • Carrageenans are polysaccharides obtained from the red algae commonly known as seaweed. They are a structural component of seaweed and are extracted as three main types, namely iota, kappa and lambda, although there are other types as well, including kappa-II, mu and nu carrageenans. Carrageenans have been used extensively in the food, pharmaceutical and cosmetics industries as thickeners, gelling agent, and stabilizing and dispersing agents. Extensive pharmacological and toxicological studies have been conducted. Carrageenan has been found to be non-toxic by oral, dermal, and inhalation routes of administrations even at extremely high doses.
  • the carrageenans were therefore classified as "generally recog nized as safe” (GRAS) by the FDA in 1972 2 . Further extensive oral pharmacokinetic studies conducted in pigs, rats, mice, gerbils, guinea pigs, ferrets, hamsters, dogs, and monkeys 3 11 showed that the breakdown of the carrageenans in the gastrointestinal tract were minimal at best and that absorption was virtually non-existent
  • Sci., 101, 8, 2833 discloses intravaginal delivery of microbicide combinations which once again include separate pods which are imbedded in the vaginal ring itself and in which multiple pods can thus release multiple drugs thereby.
  • This author discloses forming pellets as a drug core which is then coated with a release polymer such as polylactic acid. The search has therefore continued for more efficient mechanisms for delivering these compounds, preferably at a zero order rate of release.
  • Applicants have discovered that a certain carrageenan or mixtures or combinations of various carrageenans possess specific physical and chemical properties and that when they are formulated for vaginal administration, they provide a prolonged antimicrobial effect and inhibit or reduce the possibility of transmission of a sexually transmitted infection (STI). Applicants have also discovered a novel delivery system for the intravaginal delivery of these types of compounds.
  • STI sexually transmitted infection
  • a first aspect of the present invention is directed to an aqueous antimicrobial composition, comprising an effective amount of an antimicrobial agent comprising carrageenans (referred to herein as “the carrageenans” or a “carrageenan mixture”) which are lambda carrageenan in an amount of at least about 50% by dry weight of said carrageenans, remainder of said carrageenans being at least one non-lambda carrageenan, and a physiologically acceptable pH controlling agent.
  • the term "antimicrobial” is meant to embrace anti-bacterial and/or antiviral activity.
  • a related aspect of the present invention is directed to a sexually transmitted infection (STI) inhibiting composition, comprising an effective amount of an antimicrobial agent comprising carrageenans which are lambda carrageenan in an amount of at least about 50% by dry weight of said carrageenans, remainder of said carrageenans being at least one non-lambda carrageenan, and a physiologically acceptable pH controlling agent.
  • STI sexually transmitted infection
  • compositions may further include another antimicrobial agent and/or a vaginally administrable drug, in which case the carrageenan component may be a lambda carrageenan, without any non-lambda carrageenan.
  • the additional agent may be in admixture and/or associated with the carrageenans such as in the form of a complex.
  • a further aspect of the present invention is directed to aqueous antimicrobial composition, comprising: (a) a physiologically acceptable pH controlling agent; and (b) an effective amount of an antimicrobial agent comprising a complex of a lambda carrageenan or carrageenans which are lambda carrageenan in an amount of at least about 50% by dry weight of said carrageenans, remainder of said carrageenans being at least one non-lambda carrageenan, and an antimicrobial, physiologically acceptable water-soluble cationic metal salt.
  • a further aspect of the present invention is directed to an aqueous antimicrobial composition, comprising: (a) a physiologically acceptable pH controlling agent; (b) an effective amount of an antimicrobial agent comprising a complex of a lambda carrageenan or carrageenans which are lambda carrageenan in an amount of at least about 50% by dry weight of said carrageenans, remainder of said carrageenans being at least one non-lambda carrageenan; and (c) a lignosulfonic acid.
  • a further aspect of the present invention is directed to an aqueous antimicrobial composition, comprising: (a) a physiologically acceptable pH controlling agent; (b) an effective amount of an antimicrobial agent comprising a complex of a lambda carrageenan or carrageenans which are lambda carrageenan in an amount of at least about 50% by dry weight of said carrageenans, remainder of said carrageenans being at least one non-lambda carrageenan; and (c) a vaginally administrable drug such as a contraceptive agent or an agent for hormone replacement therapy.
  • a further aspect of the present invention is directed to an aqueous antimicrobial composition
  • an antimicrobial agent comprising a polyanionic microbicide, such as carrageenans which are lambda carrageenans in an amount of at least about 50% by dry weight of the carrageenans, the remainder of the carrageenans being at least one non-lambda carrageenan, a physiologically acceptable water soluble cationic metal salt, and a non-nucleoside reverse transcriptase inhibitor or a nucleoside reverse transcriptase inhibitor.
  • a polyanionic microbicide such as carrageenans which are lambda carrageenans in an amount of at least about 50% by dry weight of the carrageenans, the remainder of the carrageenans being at least one non-lambda carrageenan, a physiologically acceptable water soluble cationic metal salt, and a non-nucleoside reverse transcriptase inhibitor or a nucleoside reverse transcriptase inhibitor.
  • a further aspect of the present invention is directed to a method of processing, refining or stabilizing the carrageenans of the present invention.
  • the method entails mixing a lambda carrageenan or the carrageenans in anhydrous or powdery form with the dry form of the PH controlling agent, followed by hydration of the carrageenans e.g., by the addition of water or another aqueous solution.
  • the method overcomes several disadvantages associated with current techniques for processing high concentrations of carrageenans into homogenous aqueous solutions and facilitates further processing into pharmaceutical formulations such as the aforementioned compositions and complexes.
  • the present invention is also directed to a vaginal ring for the delivery of water-soluble compounds
  • a vaginal ring for the delivery of water-soluble compounds
  • the water-soluble polymer comprises a high molecular weight water-soluble polymer.
  • the outer layer comprises an extruded polymeric ring, and the inner layer is encased within the extruded polymeric ring whereby the outer layer comprises the only layer encasing the inner layer.
  • the non-water-swellable elastomer is capable of controllably diffusing a water-insoluble compound therethrough.
  • the high molecular weight water-soluble polymer is free of any polymeric coating or layer which would prevent the release of the high molecular weight water-soluble polymer therefrom.
  • the inner layer is encased in a separate sheath, which may or may not include an active agent, for separating the inner layer from other components and/or active agents within the IVR.
  • the extruded polymeric ring comprises a thermosetting or thermoplastic polymer such as EVA or silicone polymers.
  • the outer layer comprises an extruded polymeric ring and the vaginal ring includes a polymeric sheath surrounding the inner layer such that the at least one aperture is provided in both the outer layer and the polymeric sheath.
  • the polymeric sheath can include an active agent such as the water soluble or water insoluble compounds discussed in more detail below.
  • the extruded polymeric ring itself can include at least one water insoluble compound which is preferably compounded with the non-water-swellable elastomer which constitutes the ring itself.
  • the outer layer can include a plurality of these water insoluble compounds.
  • these water insoluble compounds can comprise and NNRTI, such as MIV-150, either alone or combined with other water insoluble compounds, such as in a preferred embodiment, contraceptives such as levonorgestrel and the like.
  • these embodiments include an inner layer which, aside from the water soluble compounds hereof, can also include one or more of these water insoluble compounds.
  • the polymeric sheath can preferably comprise a non-water-swellable elastomer, and most preferably the same as the elastomer of the non-water-swellable elastomer of the outer layer, which can be free of any additional components such as water insoluble compounds, or contain such active agents including such water insoluble compounds.
  • the inner layer comprises a compressed core of the high molecular weight water-soluble polymer.
  • the high molecular weight water-soluble polymer comprises carrageenan.
  • the outer layer includes at least one water-insoluble compound. Preferably, this water-insoluble compound is compounded with the non-water-swellable elastomer.
  • the at least one water- insoluble compound comprises MIV-150.
  • the inner layer includes a low molecular weight water-soluble compound, such as a zinc salt.
  • the inner layer comprises a pair of inner layers, preferably a first inner layer comprising a compressed core of the high molecular weight water-soluble polymer and a second inner layer comprising a core of the low molecular weight water-soluble compound.
  • the second inner layer includes an elastomeric polymer which enables the sustained release of the low molecular weight water-soluble compound therefrom.
  • the outer layer is in the form of a ring, the ring including the at least one aperture extending substantially transversely through at least a portion of the ring, and wherein the inner layer comprises a compressed pellet of the high molecular weight water-soluble polymer disposed in the at least one aperture.
  • the ring includes a plurality of the apertures, and the inner layer comprises a plurality of the compressed pellets of the high molecular weight water-soluble polymer disposed in the plurality of apertures.
  • the ring includes a plurality of the apertures
  • the inner layer comprises at least one compressed pellet of the high molecular weight water-soluble polymer disposed in at least one of the plurality of apertures, and at least one pellet of a low molecular weight water-soluble compound disposed in at least one other of the plurality of apertures.
  • the at least one pellet of the low molecular weight water-soluble compound includes an elastomeric polymer which enables sustained release of the low molecular weight water-soluble compound therefrom.
  • the ring includes at least one low molecular weight water-insoluble compound, most preferably MIV-150.
  • the outer layer comprises at least one ring of the non-water-swellable elastomer
  • the inner layer comprises a compressed core of the high molecular weight water-soluble polymer contained within the center of the ring.
  • the ring includes an upper surface and a lower surface
  • the outer surface includes a pair of outer sheets of non-water-swellable elastomer disposed on the upper and lower surfaces of the ring, the at least one aperture extending through at least one of the pair of outer sheets.
  • the non-water-swellable elastomer of the ring and the non-water-swellable elastomer of the pair of sheets comprises the same non-water-swellable elastomer.
  • these water-impermeable polymers comprise EVA or a silicone polymer.
  • the outer layer comprises a plurality of rings of the non-water-swellable elastomer and the inner layer comprises a plurality of compressed cores of the high molecular weight water-soluble polymer contained within the centers of each of the plurality of rings.
  • the outer layer comprises a plurality of rings of the non-water-swellable elastomer and the inner layer comprises a plurality of compressed cores of the high molecular weight water-soluble polymer contained within the centers of each of the plurality of rings.
  • the outer layer comprises a plurality of rings of the non-water-swellable elastomer and the inner layer comprises at least one inner layer comprising a compressed core of the high molecular weight water-soluble polymer disposed in at least one of the plurality of rings and at least one other inner layer of a core of a low molecular weight water-soluble compound disposed in at least one other of the plurality of rings.
  • the core of low molecular weight water-soluble compound includes an elastomeric polymer which enables the sustained release of the low molecular weight water-soluble compound therefrom.
  • the vaginal ring of the present invention includes a separate ring encompassing the at least one ring.
  • the separate ring comprises a polymer such as a thermoplastic or thermosetting elastomer and includes a low molecular weight water-insoluble compound therein.
  • the low molecular weight water-insoluble compound is compounded with the polymer comprising the separate ring.
  • a further aspect of the present invention is directed to a method of preparing a vaginal ring for delivery of a water-soluble compound.
  • this aspect of the present invention comprises preparing an outer layer of a non-water-swellable elastomer, preparing an inner layer of the water-soluble compound, disposing the inner layer within the outer layer, and providing at least one aperture in the outer layer whereby the water-soluble compound can only be delivered through the at least one aperture.
  • the water-soluble compound comprises a high molecular weight water-soluble polymer.
  • preparing the outer layer comprises forming the outer layer in the form of a ring.
  • preparing the inner layer of the high molecular weight water-soluble polymer comprises leaving the outer surface of the inner layer free of any polymeric coating or layer which would prevent the release of the high molecular weight water-soluble polymer therefrom.
  • the inner layer can be contained within a polymeric sheath to separate any other active agents within the sheath from active agents otherwise within the IVR.
  • preparing the inner layer of the water soluble polymer comprises disposing the inner layer within a polymeric sheath.
  • the polymeric sheath preferably comprises either a water- swellable or non-water-swellable polymer, preferably a non-water-swellable polymer and most preferably the same non-water-swellable polymer that comprises the outer layer constituting the ring.
  • the polymeric sheath can also include an active agent, such as a water insoluble compound.
  • the providing of at least one aperture in the outer layer thus includes providing the at least one aperture also in the polymeric sheath, again so that the water soluble compound in the inner layer can be delivered through the at least one aperture, in this case through these two layers.
  • preparing the outer layer comprises forming a portion of the ring including an inner surface and an outer surface and preparing a second portion of the ring including an inner surface and an outer surface, and combining the first and second portions of the ring by juxtaposing the inner surfaces of the first and second portions to fully form the ring.
  • the method includes providing at least one groove in the inner surface of one of the first and second portions of the ring.
  • the method includes disposing the high molecular weight water-soluble polymer in the at least one groove prior to combining the first and second portions of the ring.
  • the method includes providing at least one groove on the inner surfaces of each of the first and second portions of the ring.
  • this method includes disposing the high molecular weight water-soluble polymer in one of the at least two grooves and disposing a low molecular weight water-soluble compound in the other of the at least two grooves.
  • the low molecular weight water-soluble polymer preferably includes an elastomer, either hydrophilic or hydrophobic, which provides for the sustained release of the low molecular weight water-soluble compound therefrom.
  • the method includes providing the at least one aperture transversely through the ring.
  • the at least one aperture substantially traverses the depth of the ring.
  • disposing the inner layer within the outer layer comprises inserting a compressed pellet of the inner layer within the at least one aperture.
  • the method includes providing a plurality of the apertures transversely through the ring. Preferably, this plurality of apertures substantially transverses the depth of the ring.
  • disposing of the inner layer within the outer layer comprises inserting the high molecular weight water-soluble polymer within the plurality of apertures.
  • the method includes combining the non-water-swellable elastomer with a low molecular weight water-insoluble compound.
  • disposing the inner layer within the outer layer comprises inserting the high molecular weight water-soluble polymer in at least one of the plurality of apertures, and includes inserting a low molecular weight water-soluble compound in at least one other of the plurality of apertures.
  • the high molecular weight water-soluble polymer comprises carrageenan and the low molecular weight water-soluble compound comprises a zinc salt.
  • disposing the inner layer within the outer layer comprises providing the compressed high molecular weight water-soluble polymer within the center of the ring.
  • the ring includes an upper surface and a lower surface
  • the providing of the outer layer comprises providing a first sheet of non-water-swellable elastomer on the upper surface of the ring and providing a second sheet of non-water-swellable elastomer on the lower surface of the ring, and wherein the at least one aperture is disposed in one of the first and second sheets.
  • preparation of the outer layer comprises forming a plurality of outer layers in the form of a plurality of rings.
  • preparation of the inner layer comprises compressing a plurality of cores of the high molecular weight water-soluble polymer.
  • disposing of the inner layers within the outer layers comprises providing the plurality of compressed cores of the high molecular weight water-soluble polymer within the centers of the plurality of rings.
  • preparation of the inner layer comprises compressing at least one core of the high molecular weight water-soluble polymer and including disposing the at least one core of the high molecular weight water-soluble polymer in at least one of the plurality of rings, and including providing at least one core of the low molecular weight water-soluble compound and disposing the at least one core of the low molecular weight water-soluble compound in another of the plurality of rings.
  • Fig. 1 is a graph showing long-term activity of a composition containing the carrageenans of the present invention. Mice were challenged with a 95-100% infectious dose of HSV-2 at various time intervals after application of the composition. The composition retains some level of activity against HSV-2 even after 24 hours. This suggests that a woman could be protected even if considerable time elapsed between use of the composition and coitus.
  • Fig. 2 is a graph of Southern Blot hybridization of RT PCR products from RNA extracted from the spleens. Lane 2 and 3 are positive controls. Lanes 4 to 8 are from mice that were pretreated with a composition containing the carrageenans of the present invention, 5 minutes before viral challenge. Lanes 9 to 14 are from mice inoculated vaginally with HIV.
  • Fig. 3 is a bar graph showing p24 (HIV) concentration versus concentration of a composition containing the carrageenans of the present invention, another composition of the present invention that contains a complex of the carrageenans and a water-soluble zinc salt ("zinc-carrageenan”), and lignosulfonic acid (LSA).
  • HIV p24
  • Fig. 4 is a graph showing comparison between a composition of the present invention containing the carrageenans and LSA, and a composition of the present invention containing the carrageenans, in the HSV-2/Mouse system. The results show that the composition containing LSA and the carrageenans is more efficacious than a composition containing the carrageenans alone.
  • Fig. 5 is a plot of the percent inhibition by LSA of viral replication as measured by p24 ELISA.
  • Fig. 6 is a graph of the efficacy of a composition containing the carrageenans of the present invention, and another composition of the present invention that contains zinc-carrageenan, in preventing plaque formation of HSV-2 in Vero cells as a function of dose.
  • Fig. 7 is a graph showing the efficacy of a composition containing the carrageenans of the present invention, and another composition of the present invention that contains zinc-carrageenan, in protecting mice from infection from HSV-2, following vaginal challenge.
  • Fig. 8 is a graph showing the comparison of long-term activity of a composition of the present invention containing zinc-carrageenan compared to two known products, Conceptrol and Advantage S, at a viral challenge dose of 10 4 or 100% infection dose of HSV-2.
  • Fig. 9 is a graph showing protection against viral challenge by a composition containing the carrageenans of the present invention, and another composition of the present invention that contains zinc-carrageenan.
  • Fig. 10 is a graph of the amount of Nestorone released from a composition containing the carrageenans of the present invention.
  • Fig. 11 is a bar graph comparing the effectiveness of various dilutions of carrageenan compositions of the present invention in protecting mice from infection by HSV-2. Results show that even when the carrageenans are diluted 1:200, they still were able to provide 40% protection from infection.
  • Fig. 12 is a top elevational view of a portion of the vaginal ring in accordance with the present invention.
  • Fig. 13 is a side elevational view of the vaginal ring shown in Fig. 12.
  • Fig. 14 is a top elevational view of the portion of the vaginal ring shown in Fig. 12 including a wire for creating a groove therein.
  • FIG. 15 is top elevational view of the portion of the vaginal ring shown in Fig. 12 including the groove produced therein.
  • Fig. 16 is a side elevational view of the completed vaginal ring of the present invention including the inner groove containing an inner core of compressed material.
  • FIG. 17 is a top elevational view of a completed vaginal ring in accordance with the present invention including a plurality of apertures through the surface thereof for connection with the groove therein.
  • Fig. 18 is a side perspective view of another embodiment of the vaginal ring of the present invention.
  • Fig. 19 is a top elevational view of another embodiment of the vaginal ring of the present invention.
  • Fig. 20 is a top, elevational view of another embodiment of the vaginal ring of the present invention.
  • Fig. 21 is a top, elevational view of a mold for producing one embodiment of the vaginal ring of the present invention.
  • the polyanionic microbicides used in the compositions and in the intravaginal rings (IVRs) of the present invention are microbicides which interfere with viral attachment so as to reduce HIV transmission across mucosal surfaces.
  • These polyanionic microbicides include compounds such as PRO 2000, Buffergel, dextrin sulfate, cellulose sulfate, and most preferably the carrageenans.
  • the carrageenans present in compositions of the present invention include a lambda carrageenan.
  • the carrageenans mixture contains at least about 50% (and preferably at least 50%) of lambda carrageenan, based on total dry weight of the carrageenans in the composition.
  • the amount of lambda carrageenan is at least about 75, 76, 77, 78, 79, 80, 81, 82, 83, 84, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94, 95, 96, 97, 98, or 99 % of the total dry weight of the carrageenans (i.e., lambda and non-lambda carrageenans).
  • Other preferred amounts are at least 75%, at least about 85%, at least about 95%, about 85 to about 99%, and from about 94 to about 97% lambda carrageenan.
  • Lambda carrageenan is commercially available (FMC Corp., Philadelphia).
  • lambda carrageenan can be produced from diploid (sporophyte) seaweed plants e.g., Gigartina radula, Gigartina skottsbergii, Gigartina chamissoi, Gigartina stellata, Iridaea cordata, Chondrus chrispus and Sarcothalia crispata.
  • Isolation of the carrageenan from the seaweed is conducted in accordance with standard techniques. For example, the seaweed is separated, cleaned and then dried.
  • Lambda carrageenan is extracted in hot dilute sodium hydroxide, yielding a paste that contains as much as 4% concentration of lambda carrageenan.
  • the resulting paste is clarified by centrifugation and filtration to yield a clear, lambda carrageenan solution. Water is removed by any combination of evaporation, alcohol precipitation or washing, and drying.
  • the remainder of the carrageenans in compositions of the present invention may include at least one non-lambda carrageenan.
  • non-lambda carrageenan any carrageenan other than lambda carrageenan, such as kappa-c&rr&geen&n, iota carrageenan, kappa-II carrageenan (which contains kappa and iota carrageenans), mu carrageenan, and nu carrageenan.
  • Non- lambda carrageenans are also available commercially (e.g., FMC Corp.) or may be extracted from seaweed in accordance with standard techniques.
  • kappa-II carrageenan is also naturally present in the species of seaweed described above.
  • the non-lambda carrageenans include kappa carrageenan, iota carrageenan, and kappa-II carrageenans, and mixtures of any two or more thereof.
  • the non-lambda carrageenan includes kappa-II carrageenan.
  • the non-lambda component of the carrageenans constitutes less than about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24 or about 25% of the total dry weight of the carrageenans.
  • the non-lambda component is about less than about 25%, less than about 15%, less than about 5 %, about 1 to about 15%, or about 3 to about 6% of the total dry weight of the carrageenans.
  • the carrageenan mixture is substantially or entirely free of dextrose, an ingredient commonly found in carrageenans used in the food industry.
  • the lambda carrageenan or the carrageenans are generally present in amounts of about 1 to about 5%, based on total weight of the composition. In preferred embodiments, the carrageenans are present in amount of about 3% by total weight of the composition.
  • antimicrobial or “antimicrobial effect” it is meant that the composition inhibits or reduces the likelihood of transmission of a sexually transmitted infection caused by a bacterium, another microbe or a virus.
  • the compositions of the present invention useful in protection against sexually transmitted infections e.g., by inhibiting infection by HIV, HPV, HSV-2 and Neisseria gonorrhoeae.
  • the terms “antimicrobial” and “antimicrobial effect” are not meant to convey, imply or be limited to any particular means by which the inhibition of transmission of the infection is accomplished.
  • compositions containing the lambda carrageenan or the carrageenans in amounts less than 1% or greater than 5% may be used, so long as that they provide an antimicrobial effect and retain vaginal acceptability.
  • vaginal acceptability it is meant that the rheological properties such as viscosity of composition allow it to be used for its intended purpose (e.g., the composition maintains a viscosity so that it can be applied by the user and be retained in the vaginal vault, as well as providing aesthetic properties such as being substantially odorless, smoothness, clarity, colorlessness and tastelessness).
  • the viscosity is selected so as to enable the composition to evenly coat the epithelial lining of the vaginal vault.
  • the viscosity of the compositions is about 10,000 to about 50,000 cP, preferably about 20,000 to about 50,000 cP, and more preferably about 30,000 to about 50,000 cP.
  • Carrageenan has a continuum of molecular weights.
  • the carrageenan mixtures of the present invention may have a molecular weight of up to about 2 x 10 6 daltons with less than about 1% of carrageenan molecules having an average molecular weight of 1 x 10 5 daltons (as determined by gas permeation chromatography and light scattering). More particularly, a lambda carrageenan in the invention has a weight average molecular weight of about 600,000 to about 1,200,000 daltons. This physical property imparts non- absorbability to the final formulation that in turn provides prolonged anti-microbial activity.
  • polyanionic microbicides other than the carrageenans, which can also be used in the compositions of the present invention, is PRO 2000.
  • This microbicide is a vaginal microbicide for HIV prevention.
  • other such polyanionic microbicides include Buffergel, a microbicidal spermicide which provides buffering activity to maintain the mild, protective acidity of the vagina in the presence of semen.
  • dextrin sulfate, a polyanion which blocks the entry of HIV at the surface of the cell, and cellulose sulfate can also be utilized therefor.
  • the composition further contains a physiologically acceptable pH controlling agent such as phosphate buffered saline (PBS).
  • a physiologically acceptable pH controlling agent such as phosphate buffered saline (PBS).
  • PBS phosphate buffered saline
  • the pH controlling agent prevents or reduces any change of the change in the composition once it is introduced into the body where the pH can vary significantly. Vaginal pH can range between 3.5 to 5.5. Thus, the presence of the pH controlling agent extends the antimicrobial effect of the carrageenans.
  • the compositions include from bout 0.001% to about 1.0% of the pH-controlling agents.
  • the compositions formulation may further contain other active agents and/or inert ingredients, depending upon the intended use (as described below).
  • the carrageenans of the present invention provide several other benefits. They remain stable if exposed to freezing, ambient, or boiling temperatures. The mixture is compatible with the human vaginal environment. Without intending to be bound by any particular theory of operation, it is believed that the carrageenans are compatible with the human vaginal environment and do not act as a substrate or otherwise cause or stimulate growth of natural vaginal flora, nor are they toxic so as to disrupt the natural floral balance in the vagina. Aside from the properties attributable to the carrageenans of the present invention, their antimicrobial activity extends over a period of time because they are not systemically absorbed or degraded to any absorbable by-products detrimental to humans.
  • Zinc carrageenate is an inhibitor of such sexually transmitted pathogens as HIV and HSV-2.
  • Zinc acetate and zinc sulfate have been shown to inhibit HIV infection in cell culture, and HSV-2 in both cell culture and laboratory animals.
  • Zinc salts have been shown to be effective in blocking infection by HIV in vitro 39 , foot-and-mouth virus, human rhinovirus, influenza A and B, semliki forest virus and Sindbis virus 40 . Haraguchi, et al.
  • Zinc chloride did not exhibit significant cytotoxicity when present in concentrations of up to 550 ⁇ g/mL.
  • Water-soluble zinc salts useful in the present invention include both inorganic salts and organic salts that exhibit anti-microbial properties without causing unacceptable irritation when used in accordance with the present invention.
  • Preferred water-soluble zinc salts include zinc acetate, zinc propionate, zinc butyrate, zinc formate, zinc gluconate, zinc glycerate, zinc glycolate, zinc lactate, zinc sulfate, zinc chloride, and zinc bromide.
  • Copper and silver counterpart salts are also useful in the present invention provided that they are non-irritating in vivo and do not cause degradation to any absorbable by-products detrimental to humans.
  • compositions of this invention will thus include between about 0.03% and 1.5% of the water-soluble metal salts, preferably from about 0.3% to 1.0%.
  • the anti-microbial activity of the composition is greater than a formulation containing the carrageenans as the only antimicrobial agent.
  • there is a significant increase in anti-microbial activity it is believed that the anti-microbial activity of the formulation is enhanced because the rate at which the metal salt is absorbed by the body is relatively controlled and at the same time, the irritation of the metal salt is reduced.
  • the complexes of the present invention may be prepared by standard processes whereby the metal ions replace cations that are naturally present on the backbone of the polysaccharide.
  • zinc carrageenan (which refers to a complex between zinc cations and the carrageenans of the present invention) is a compound synthesized by a procedure whereby zinc (11) is non-covalently attached to the sulfate groups of the carrageenans.
  • Carrageenan is a polysaccharide consisting of repeating D-galactose and 3,6- anhydro D-galactose units arranged in a linear fashion. The polymer is highly sulfated having 3 SO 3 groups per each disaccharide unit.
  • the binding of zinc to the carrageenans is accomplished by a chemical process developed to replace sodium bound to native carrageenan with zinc.
  • An aqueous solution of a highly soluble zinc salt (such as zinc acetate) is used in this process as a source of zinc cations.
  • the carrageenans are dialyzed against a concentrated solution of zinc acetate allowing positively charged zinc ions to diffuse and complex with the negative sulfate groups of the carrageenans. Excess of zinc is then removed by dialysis against water.
  • the inclusion of a complex of zinc II metal cations with the carrageenans in the present invention can be achieved by the use of zinc II carrageenate.
  • Zinc carrageenate is synthesized by substitution of the natural carrageenan cations (sodium, potassium, calcium) by zinc cations.
  • Zinc carrageenate is traditionally prepared by dialysis of a solution of carrageenan against a concentrated solution of zinc II acetate. Excess zinc cations are then removed by dialysis against water, before concentrating, and for example, freeze drying.
  • the use of zinc II carrageenate can avoid the use of anions such as lactate or acetate in the present invention.
  • Another process entails (a) soaking the carrageenans in about a 2.5% zinc lactate (or other suitable soluble zinc salt) in 50:50 alcohokwater liquor for two hours, (b) separated, and (c) washed with alcohol before drying. Steps (a) through (c) may need to be repeated several times to achieve the desired metal content in the carrageenans. Two cycles are normally required to achieve over 50% zinc carrageenan on an equivalent basis.
  • a combination of the complex between a water soluble metal salt and carrageenans along with specific antiretroviral agents provides unexpected advantages and synergistic properties. Most particularly, this particular combination of ingredients has been found to provide unexpected results in terms of inhibition of sexually transmitted infections and particularly in blocking vaginal SHIV-RT infections (simian/human immunodeficiency virus-reverse transcriptase).
  • Antiretroviral agents are drugs used for the treatment of infection by retroviruses, primarily HIV.
  • NRTIs non-nucleoside reverse transcriptase inhibitors
  • NRTIs nucleoside reverse transcriptase inhibitors
  • integrase inhibitors fusion inhibitors
  • CCR5 antagonists CCR5 antagonists
  • NNRTIs are compounds which attach themselves to reverse transcriptase and prevent the enzyme from converting RNA to DNA so that HIV's genetic material cannot be incorporated into the healthy genetic material of cells and the cells can be prevented from producing new viruses.
  • drugs such as nevirapine, delavirdine, efavirenz, etravirine, MIV-150, MIV-160, MIV-170, dapivirine (TMC-120), and UC-781.
  • the NNRTI would be MIV-150, an NNRTI developed by Medivir for use as an antiviral therapeutic.
  • MIV-150 is a tight-bonding HIV-RT enzyme inhibitor characterized by a rapid formation and slow dissociation rate that is effective at inactivating chemical isolates of HIV at very low concentrations.
  • water-soluble metal salts preferably such as zinc
  • NNRTIs such as MIV-150
  • this specific combination has been found to be significantly more effective than the individual combination of the carrageenans with water-soluble metal salts such as zinc; or the carrageenans with NNRTIs, or the carrageenans themselves.
  • the combination of the carrageenans of the present invention, the water- soluble metal salts, and the NNRTI preferably include the carrageenans discussed above, including lambda carrageenan in amounts of at least about 50% by dry weight of the carrageenans with the remainder of the carrageenans being at least one non-lambda carrageenan, and most preferably a combination of 95% lambda carrageenan and 5% kappa carrageenan, with the overall composition in the form of a gel including between 1% and 5% carrageenan, preferably about 3% carrageenan; the compositions include the water- soluble metal salts preferably comprising zinc salts, most preferably in the form of zinc acetate or zinc lactate, including from about 0.1wt.% and 1.5 wt.% of the metal, such as zinc, in the overall composition, most preferably about 0.3 wt.% thereof; and include the NNRTIs, most preferably MIV-150, in amounts of from between 5
  • NRTIs are compounds which are incorporated into the DNA of the virus to stop the building process. They thus result in incomplete DNA that cannot create a new virus. These include drugs such as abacavir, tenofovir and zidovudine.
  • LSA lignosulfonic acid
  • LSA-carrageenan a lambda carrageenan or the carrageenans
  • LSA-carrageenan a lambda carrageenan or the carrageenans
  • the secondary cell wall contains another very abundant material called lignin which is the polysaccharide that makes plants stiffer.
  • lignin is the polysaccharide that makes plants stiffer.
  • LSA water soluble lignosulfonic acid
  • the usefulness of commercial lignosulfonate comes from its dispersing, binding, complexing and emulsifying properties.
  • the aromatic ring structure of lignosulfonic acid confers on plants the ability to resist attacks from microbes.
  • LSA has been shown to have in vitro anti-HIV activity.
  • Formulations comprising the carrageenans and LSA can be prepared by adding LSA to the carrageenans, generally in an LSA-total carrageenan weight ratio of from about 20: 1 to about 1:20.
  • a solid buffer salt can be mixed with the carrageenans, usually in a weight ratio of from about 1: 1 to about 10: 1.
  • the resultant mixture is then solubilized in an aqueous solution.
  • the pH of the carrageenan-LSA formulation may then be adjusted to be from about 6.0 to about 8.0 by adding an acid such as HC1, or a base such as NaOH.
  • LSA in aqueous solutions yields a tan to brown coloration.
  • a whitening agent such as titanium dioxide may be included in the composition.
  • the whitening agent is present in an amount of about 0.1 to about 3.0% based on total weight of the composition.
  • the whitening agent may also contribute to the antimicrobial effect.
  • LSA also functions as a dispersing agent for the carrageenans, and disentangles and elongates them, thus creating greater density of this material and greater anti-microbial potency.
  • the carrageenans provide the preferred rheological properties necessary for acceptable and effective vaginal (and even rectal) administration, which cannot be achieved by LSA in and of itself because it is rather watery in nature.
  • the combination of the carrageenans and LSA acts synergistically in preventing or inhibiting sexually transmitted infections.
  • compositions of the present invention may also contain a vaginally administrable drug in the aqueous formulation along with the pH controlling agent and the lambda carrageenan or the carrageenans.
  • Preferred drugs are contraceptive agents, such as steroid hormones, disclosed in Saleh, et ah , U.S. Patent 5,972,372 ("Saleh”), the disclosure of which is hereby incorporated by reference.
  • contraceptive agents useful in the present invention include progestins, ACTH, androgens, estrogens, gonadotropin, human growth hormone, menotropins, progesterone, progestins (e.g., levonorgestrel, norethindrone, 3-keto-desogestrel and gestodene), progestogen, urofollitropin, vasopressin and combinations thereof.
  • Preferred agents include progestational compounds (e.g., norethindrone acetate and NESTORONETM ("NES"). (i.e., 16-methylene-17.alpha.- acetoxy-19-norpregnene-3,20-dione)), and progestins (e.g., levonorgestrel (LNG)).
  • a preferred contraceptive agent is Nestorone 16-methylene- 17a-acetoxy- 19- norpregn-4-ene-3, 20-dione (hereinafter "NES"), which has been identified in the literature as “ST- 1435 ".
  • NES was found to have progestational activity 100 times higher than that of progesterone and 10 times higher than that of levonorgestrel 53 . Therefore, smaller amounts of NES are required to achieve ovulation inhibition.
  • NES has been shown to undergo rapid metabolism and inactivation upon oral administration making it suitable for use in nursing women when given via implants or vaginal rings ' .
  • a preferred delivery dose of NES when combined with the ⁇ / ⁇ carrageenan mixture in gel form is between about 75 and about 100 ⁇ g per day, which will reach plasma levels of NES around 200 pmol/L and achieve good bleeding patterns during menses.
  • Other preferred vaginally administrable drugs include agents for hormone replacement therapy such as estrogenic substances (e.g., ethynylestradiol) and other steroidal compounds.
  • the carrageenans possess a dual function of imparting microbicidal properties while providing a prolonged release delivery system for a contraceptive agent or agent for hormone replacement therapy, thus enhancing the activity of the agent.
  • compositions described herein may further contain at least one physiologically inert ingredient, such as a physiologically acceptable preservative.
  • a physiologically acceptable preservative include alkyl esters of para-hydroxybenzoic acid, such as methyl paraoxybenzoate, propyl paraoxybenzoate, hydantoin derivatives, parabens, such as methyl paraben, propioniate salts, triclosan tricarbanilide, tea tree oil, alcohols, farnesol, farnesol acetate, hexachlorophene and quaternary ammonium salts, such as benzolconjure, zinc and aluminum salts, sodium benzoate, benzyl alcohol, benzalkonium chloride and chlorobutanol.
  • the preservative is present in an amount up to about 0.3% based on the total weight of the composition.
  • the preservative prevents any deleterious effects that might occur to the active agents in the composition due to the presence of normal body flora once the composition is introduced into the body. This will prolong the length of time that the active agents in the composition remain active.
  • compositions of the present invention e.g., containing the carrageenans as the sole antimicrobial agent, with or without a vaginally administrable drug, and the rings, foams, films, suppositories and gels that contain an additional antimicrobial agent such as the cationic metal salt or LSA, are administered vaginally.
  • the present invention also includes rectal administration.
  • the compositions may be suitably formulated e.g., into gels, creams, foams, films and suppositories, in accordance with standard techniques in the pharmaceutical industry.
  • the gel formulations can be administered prior to sexual activity such as intercourse, usually within about one hour before such time.
  • the application of the carrageenan-based formulation in human prevents or inhibits transmission of a sexually transmitted infection (STI), such as Neisseria gonorrhoeae, human papillomavirus, HSV-2 and HIV.
  • STI sexually transmitted infection
  • IVR intravaginal ring
  • administration of the water-soluble polymers of the present invention can also include low molecular weight water-soluble compounds.
  • these low molecular weight water-soluble compounds include, for example, polyurethane elastomers such as the thermoplastic silicone polyether urethane known as PURSIL.
  • the term "active agent" has been utilized. This is intended to broadly refer to each of the water soluble and water insoluble compounds discussed herein, including the high molecular weight water soluble polymers, and the low molecular weight water insoluble and water soluble compounds. Each of the specific such compounds discussed herein thus have pharmaceutical utilities, as drug compounds, antimicrobials, antiretrovirals, antiobiotics, etc. [ 0083 ]
  • the novel IVRs which have now been discovered can thus directly employ the preferred high molecular weight water-soluble polymers in a compressed or compacted form, directly in or associated with the IVR itself.
  • these water-soluble compounds are incorporated directly into the IVRs themselves. A number of methods of doing so are disclosed in this application. In general, however, these high molecular weight compounds are incorporated directly into the IVR ring structure and/or are pelletized, with the pellets being incorporated into the ring structure and/or into a complementary film or sheath of non- water- swellable elastomer, either the same as that of the ring structure itself, or another such non-water-swellable elastomer sheet or film which is compatible with that of the ring structure.
  • these high molecular weight water soluble polymers themselves, these can be considered to be macromolecules including sulfated polysaccharides such as carrageenan, particularly lambda carrageenan, and particularly the carrageenans discussed above, which in a preferred embodiment includes, at least about 50% lambda carrageenan on a dry weight basis, with the remainder of the carrageenans being at least one non-lambda carrageenan.
  • carrageenan particularly lambda carrageenan
  • the carrageenans discussed above which in a preferred embodiment includes, at least about 50% lambda carrageenan on a dry weight basis, with the remainder of the carrageenans being at least one non-lambda carrageenan.
  • macromolecules can also include proteins, including but not limited to lectins, such as griffithsin, glycoproteins, peptides/polypeptides, peptide hormones, such as insulin, nucleic acid derivatives, including oligonucleotides and aptamers, glucoaminoglycans (GAGs), HIV-1 envelope proteins, HSV envelope proteins, therapeutic antibodies and the line, polyacrylic acids, like carbopol, as well as polypyrroles.
  • proteins including but not limited to lectins, such as griffithsin, glycoproteins, peptides/polypeptides, peptide hormones, such as insulin, nucleic acid derivatives, including oligonucleotides and aptamers, glucoaminoglycans (GAGs), HIV-1 envelope proteins, HSV envelope proteins, therapeutic antibodies and the line, polyacrylic acids, like carbopol, as well as polypyrroles.
  • lectins such as griffi
  • the inner layer of high molecular weight water-soluble polymer is preferably prepared by simply compressing these compounds under significant pressure.
  • the degree of compression itself can effect the release rates obtained, but as noted above, the present invention can lead to substantially zero order release rates.
  • pellets of these high molecular weight water-soluble polymers can either be utilized alone or in combination with other ingredients, such as the low molecular weight water-soluble compounds discussed herein.
  • These low molecular weight water-soluble compounds include the water-soluble metal salts discussed above, including metal salts such as zinc salts.
  • These zinc salts include both inorganic and organic salts which exhibit antimicrobial properties, preferably including zinc acetate, zinc sulfate, zinc lactate, and the like.
  • Other such water-soluble compounds include compounds such as probiotics, including lactobacilli, HIV-1 envelope proteins, HSV envelope proteins, therapeutic antibiotics and the like, pseudovirions such as HVP, HIV, HSV and HSV pseudovireones and antigens and/or other immunogens and combinations of any two or more thereof.
  • the low molecular weight water- insoluble molecules of the present invention can include the NNRTIs discussed in this application, including drugs such as navirapine, delavirdine, efavirenz, estrairine, MIV-150, MTV- 160, MIV-170, dapivirine (TMC-120), and UC-781, and most preferably the MIV-150 which is highly preferred in combination with the complex between a water-soluble metal salt and the water-soluble carrageenans discussed above.
  • the inner layer of water-soluble compounds hereof are preferably free to diffuse out of these IVRs upon contact with water.
  • they are neither contained within a separate protective container or pod nor covered by a separate polymeric coating, cover or sheath. However, in one embodiment they are contained within a sheath, which is preferably identical to or comparable to the non-water-swellable elastomer of the IVR itself, primarily for the purpose of physically separating the inner layer from the active agents in the IVR.
  • Those high molecular weight water-soluble compounds such as the carrageenans discussed above, can preferably be used in a dry form without the need for admixing additional components, since they are compressible in that form. This is also true for the zinc-carrageenan mixtures discussed herein. However, even with certain of the zinc- carrageenan mixtures with high zinc contents, this may begin to negatively impact the compressibility of these compounds. Furthermore, there are others of the high molecular weight water-soluble compounds discussed above which will not be amenable to simple compression and under compression will not compact sufficiently to maintain their integrity in the manner required by this invention.
  • the water-soluble compounds of the present invention comprise low molecular weight water-soluble compounds
  • the elastomeric polymers comprise hydrophilic or water-swellable elastomers. These include aliphatic thermoplastic urethanes, such as the poly(ether urethane)s or silicone poly(ether urethane)s disclosed in International Application No. WO 2013/013172, in Paragraphs [00021] through [00023], which are incorporated herein by reference thereto.
  • hydrophilic poly (ether urethane)s such as the TECOPHILICS, thermoplastic silicone-polyether urethanes such as the PURSIL ALs, thermoplastic polyether urethanes such as the ELASTHANEs and PELLETHANEs, and the like.
  • these can include non-swellable or hydrophobic elastomers, such as poly (ether urethane)s and the TECOFLEXs, all of which are incorporated herein by reference thereto.
  • the inner layer of high molecular weight water-soluble polymer can also include an amount of low molecular weight water insoluble molecules, which can also be included in the outer layer of water-impermeable polymeric compound.
  • These low molecular weight and primarily water-insoluble compounds include intravaginally administrable drugs such as cervical anesthetics, contraceptives, anti-endometriosis drugs, estrogen receptor modulators, preterm labor drugs, overactive bladder drugs, morning sickness drugs, osteoporosis drugs, antimicrobials, vaccines, and the like.
  • useful intravaginally administrable substances include, but are not limited to, cervical anesthetics such as lidocaine, contraceptives such as 17a-ethinyl-levonogestrel-17b-hydroxy-estra- 4,9,ll-trien-3-one, estradiol, etonogestrel, levonogestrel, medroxyprogesterone acetate, NESTORONE, norethindrone, progesterone, estrogen receptor modulators such as RU-486, anti-endometriosis drugs such as Terbutaline, antivirals such as acyclovir and gancyclovir; blood flow increasing drugs like Sildenafil; labor-inducing drugs like misoprostol; preterm labor drugs like indomethacin; overactive bladder drugs like oxybutynin; morning sickness drugs such as Bromocriptine; osteoporosis drugs like human parathyroid hormone; drugs and/or substances for vaginal dryness such as glycerol
  • the vaginal rings of the present invention can be more fully appreciated with reference to the drawings.
  • the IVRs themselves are well known and are generally made from non-water-swellable elastomers, which can be either thermosetting or thermoplastic elastomers.
  • Thermoplastics include, but are not limited to, polyurethanes and ethylene vinyl acetate (EVA).
  • Thermosetting resins include, but are not limited to, the class of silicone polymers.
  • IVRs can also be made from a mixture of any two or more polymers and generally have a toroidal shape.
  • the ring includes an inner layer of low and/or high molecular weight water-soluble polymer embedded within the ring itself.
  • One method of producing this product is as follows: One half of such a ring 100 is shown in Figs. 12 and 13. It is generally injection molded, and has a bottom surface 101 having the shape of the ring and an upper planar surface 102. In order to embed the high molecular weight water-soluble polymer within the ring, a groove is produced in the upper surface 102. One method of doing this is to embed a heated wire 104, such as a brass wire, onto the upper surface 102, and applying pressure thereto in order to create a groove 110 in the upper surface 102 of the ring 100. This is shown in Fig. 14, and the groove 110 is then created in the upper surface 102 of the ring 100.
  • a heated wire 104 such as a brass wire
  • FIG. 21 An alternate method of preparing the groove 110 can be seen by using the mold shown in Fig. 21.
  • the mold half on the left side of Fig. 21 shows mold half 116 which includes a number (six in this case) of ring molds 118, each connected to a central source of polymer for filling the mold.
  • the right hand mold 120 shown in Fig. 21 includes a circular projection 122 corresponding to each of the ring molds 118.
  • the result is half of a ring including a groove 110 in the upper surface 102 thereof.
  • the ring itself is then completed by producing a second half of the ring identical to that shown in Figs. 12 and 13 by injection molding in the normal manner where the second half of the ring is injection molded over the first half. Molding the entire ring thus produces an IVR which contains an inner layer of either the compressed high molecular weight water-soluble polymer or the low molecular weight water-soluble compound admixed with an elastomeric polymer, imbedded within the ring itself, as shown in Fig. 16.
  • this combination of high molecular weight water-soluble polymer and low molecular weight water-soluble compound comprises the mixture of carrageenan and zinc salt discussed more fully in this application.
  • the IVR 123 including a groove 110 as shown in Fig. 15 containing the compressed high molecular weight water-soluble polymer therein. It is then possible to produce the second half of the IVR 123, again including a groove 110 therein as shown in Fig. 15, but in this case in which the groove is filled with the low molecular weight water-soluble compound admixed with the elastomeric polymers discussed above.
  • the two halves of the ring are then combined either by heat treatment or using a biocompatible adhesive or the like.
  • the aperture or apertures 124 can then be provided so as to contact both of the filled grooves containing both the high molecular weight water-soluble polymer and the low molecular weight water-soluble compound discussed herein.
  • the outer layer includes a pair of polymer layers, including the non-water-swellable elastomer of the ring itself and the polymeric sheath surrounding the inner layer.
  • the polymeric sheath which can be either a water- swellable elastomer or a non-water-swellable elastomer, but preferably a non-water-swellable elastomer, and most preferably the same non-water-swellable elastomer as that of the ring itself, can include a water soluble and/or a water insoluble compound, such as those discussed herein.
  • the polymeric sheath can, on the other hand, be free of any active agents.
  • the outer layer comprising the non-water-swellable elastomeric polymers will include at least one and possibly additional water insoluble compounds.
  • this outer layer (the non-water-swellable elastomer) can include an NNRTI, preferably one such as MIV-150, either alone or combined with a contraceptive, such as levonorgestrel or the like.
  • the inner layer can also include a water insoluble compound, such as those included in the outer layer of non- water- swellable elastomer.
  • FIG. 18 Another embodiment of the vaginal ring of this invention is shown in Fig. 18.
  • the ring 127 is a conventional ring, including a conventional sheath produced in the normal manner.
  • a series of apertures or cavities 128 are cut or drilled into one of the surfaces of the ring 127, preferably to a substantial depth, but preferably not entirely through the ring 127.
  • each of these apertures can then be filled with pellets of compressed high molecular weight water-soluble polymer of the present invention either alone or combined with other high molecular weight water- soluble polymers, low molecular weight water-soluble compounds, and/or low molecular weight water-insoluble compounds.
  • some of these apertures can be filled with pellets of low molecular weight water-soluble compounds of the present invention, combined with the elastomeric polymers discussed above, for sustained release therefrom.
  • the release of these high molecular weight water-soluble polymers and/or the low molecular weight water-soluble compounds and/or other components contained in the compressed pellets can be controlled by the size of the apertures, the number of apertures, and the size of the pellets in each of the apertures.
  • FIG. 19 Yet another embodiment of the vaginal ring of the present invention is shown in Figs. 19 and 20.
  • a conventional ring of a small size (approximately 20 mm x 2 mm) 130 is produced by conventional means.
  • a pellet of compressed high molecular weight water-soluble polymer is then produced for placement in the center 132 of the ring 130.
  • the compressed inner layer of high molecular weight water- soluble polymer preferably fits snuggly within the center 132 of the ring 130 and is retained therein.
  • a pellet of low molecular weight water-soluble compound can be produced, again combined with an elastomeric polymer for enabling the sustained release of the low molecular weight water-soluble compound and then be placed in the center 132 of the ring 130.
  • the inner layer of low molecular weight water-soluble compound is made to fit snuggly within the center 132 of the ring 130 and be retained therein.
  • a pair of substantially planar sheets 134 and 136 of the non-water-swellable elastomer are affixed to the upper and lower surfaces of the ring 130, thus enclosing the pellet 134 therewithin.
  • the materials of the substantially planar sheets (134, 136) can be the same material used to produce the ring 130 itself, or they can constitute membranes made from any other non- water- swellable elastomers that are non-reactive with the enclosed mixtures.
  • an aperture 138 is drilled through at least one of the planar sheets, in this case sheet 136. This can include a single aperture 138 of a preferred size, or a number of apertures 138 of various or constant sizes for controlling release of the compressed high molecular weight water-soluble polymer therefrom. Referring to Fig. 20, the entire structure shown in Fig. 19 is duplicated so that two such structures (140, 142) with apertures 138 corresponding to the aperture shown in Fig. 19 shown therein.
  • These devices are then contained within a larger or conventional- sized ring 146 (normally 55 to 60 mm x 4 mm) so that they can be used for implantation as is the case with normal IVRs.
  • the smaller rings can be affixed to the larger IVR by either using a bioadhesive or by physically creating hooks in the larger IVR, or injection molding a larger IVR into which the edge of the smaller IVR can be fixed.
  • the IVR matrix itself for the large ring 146 also include low molecular weight water-insoluble compounds which are preferably compounded with the polymer of the ring and are dispersed therein for diffusion through the outer surface of the sheath of the ring 146.
  • Yet another aspect of the present invention is directed to a method for refining a non-absorbable, carrageenan.
  • the formulation is typically prepared by mixing a solid buffer salt and lambda carrageenan, or the carrageenan mixture, in a weight ratio of from about 1:1 to about 10:1.
  • the mixture of solid buffer salt and carrageenan is then solubilized in water or in an aqueous solution, to make the formulation.
  • the pH of the formulation is then adjusted to be from about 6.0 to about 8.0. This is typically achieved by the addition of an acid, such as HC1 or a base, such as NaOH.
  • the viscosity of the formulation is from about 20,000 to about 100,000 CPS, preferably from about 30,000 to about 35,000 CPS.
  • At least one physiologically acceptable preservative can be added to the formulation.
  • the preservative can be present in the proportions indicated in the various pharmacopoeias, and in particular in a weight ration to the carrageenans of from about 80:1 to about 10:1, preferably from 40:1 to about 15:1.
  • Solid buffer salts include solid alkaline metal salts of acetic acid, citric acid, phosphoric acid, and lactic acid.
  • the solid alkaline metal phosphate buffer includes solid mixture of tri-basic and di-basic alkali salts of phosphate, preferably in anhydrous form, wherein alkaline metal includes, but is not limited to, potassium and sodium. Any physiologically acceptable buffer can be used. However, in the case where water-soluble zinc salts are utilized, the phosphates are less preferred, and in these formulations, the acetates, citrates and lactates are more preferred. In preferred embodiments, these buffer solutions comprise mixtures of acetic acid and sodium acetate; citric acid and sodium citrate; and lactic acid and sodium lactate.
  • the carrageenans are dry powders that are extremely hygroscopic when exposed to the atmosphere.
  • the uptake of atmospheric moisture into the dry ingredient causes clumping of the material.
  • the solid buffer salt absorbs the atmospheric moisture that the carrageenans would have absorbed when exposed to the atmosphere, thus preventing or substantially reducing clumping of the carrageenans.
  • the process serves to increase the solubility of carrageenans in water, and achieves stabilization of the pH.
  • Production Vessel - IKA, EMA 9/500AIUTL is a water jacket production vessel that allows for rapid heating and cooling of solution during production.
  • Phosphate buffer saline [containing: NaCl - 120 mmol/L, KC1 - 2.7 mmol/L, Phosphate buffer (potassium phosphate monobasic and sodium phosphate dibasic) - 10 mmol/L - (Sigma Aldrich, Saint Louis MO);
  • Control Test #1 Complete incorporation and even distribution
  • the testing sample should be cooled to 25°C + 2 (a range of 23°C to 27°C) for testing.
  • the pH should be 7.0 ⁇ 0.1 (a range of 6.9 to 7.1). This indicates that the solution's pH is uniform and the solution is "PASS”. If the solution is not within the acceptable pH range (6.9 to 7.1) the solution is "FAIL”. If the solution is "FAIL", the solution needs to be adjusted, as needed with either 10% HC1 (to decrease the pH) or IN NaOH (to increase the pH) in 25 mL increments until the solution is "PASS”. With each incremental addition of either acid or base, thorough stirring (stirring and vacuum condition step #9, no added heat) is needed to ensure even distribution throughout batch before re- testing the pH. Recheck solution after stirring/vacuum for 0.5 hour. Continue in this manor until solution is "PASS”.
  • the testing sample should be heated to 35°C ⁇ 2° (a range of 33°C to 37°C). To optimize performance, the viscosity should be about 30,000 to about 40,000 cP. Viscosity measurements indicate that the solution's viscosity is uniform with the PC Reference sample and CCS production batches and the solution is 'PASS". If the solution is "FAIL" obtain testing samples from the top and the bottom of production vessel and conduct Control Test #2, pH and Control Test #3, Viscosity on each sample. If the solution is still "FAIL", repeat step #9 and step #12 and retest the solution for Control Test 3#, Viscosity. If solution is "FAIL" an Out of Specifications Study shall be undertaken to determine the source of out of specification production.
  • the final formulation has a pH of about 7.0 which was adjusted by adding
  • Carrageenan has been shown to block HIV and other enveloped viruses by several laboratories including the laboratory of the PI15-19. Several different types of target cells and strains of HIV have been employed in these studies. Generally, 50% blocking is observed at a few micrograms/mL. This result is similar to other sulfated polysaccharides such as heparin and dextran sulfate.
  • the HSV-2/mouse (Balb/C) system is widely utilized by most investigatory groups engaged in the development of a microbicide.
  • An important difference between the system established by Phillips 20-22 and other systems is the utilization of viral dose range comparison.
  • the standard viral challenge dose, 100% infection dose or 104 pfu, used by others for evaluation of a microbicide is rate limiting.
  • the large majority of the microbicides under development, as well as many of the OTC spermicides will show a significant rate of protection against HSV-2 infection at this viral challenge doses.
  • Phillips has utilized a virus concentration method that will enable evaluation at viral challenge doses of 105, 106, and 1,000 x 100% infection dose.
  • compositions of the present invention containing the K-11/ ⁇ carrageenan mixture (also referred to herein as the " ⁇ / ⁇ carrageenan composition")
  • comparative test formulations were: microbicides under development such as BufferGelTM and No Fertil, OTC spermicides: K-Y Plus® Gynol II®, and Advantage STM; OTC vaginal lubricants: Replens® and K-Y Jelly®; and possible placebo formulations: 2.5% Carbopol® and 2.5% methyl cellulose.
  • Test formulations fell into three categories with respect to efficacy in protecting mice from vaginal HSV-2 infection.
  • At the viral challenge dose of 104 pfu with the exception of K-Y Jelly, Carbopol and methyl cellulose, all formulations provided a significant level of protection against infection from HSV-2.
  • At the viral challenge dose of 105 with the exception of the K-11/ ⁇ carrageenan composition, all formulations only provided a minimum level of protection.
  • the K-11/ ⁇ carrageenan composition was the only formulation still affording a level of protection against viral infection at the viral challenge dose of 106 pfu 20
  • the resulting data was the first demonstration of the unexpected high level of protection against viral infection that the K-11/ ⁇ composition provides.
  • HSV-2/mouse system can be employed as a means by which candidate microbicides can be evaluated and compared under the same testing conditions to identify potential effective microbicides.
  • a microbicide that was effective in protecting against infection by HIV could be used rectally as well as vaginally.
  • an intra- rectal viral challenge modification of the HSV-2-/mouse system an evaluation of the efficacy and safety of a microbicide was explored.
  • mice can not be infected with HIV, it has been shown that when active or inactivated virus is instilled into the vagina of mice, virus can be subsequently detected in the lymph lodes by the use of reverse transcriptase polymerase chain reaction (RT-PCR)24 Evidence has been presented that dendritic cells played a role in the uptake of virus and subsequent transport to the lymph nodes. This conclusion is in agreement with studies implicating dendritic cells in the initial stage of sexual transmission of HIV25.
  • RT-PCR reverse transcriptase polymerase chain reaction
  • [ 0160 ] HIV transport using a mouse system and AldritholTM-2 inactivated virus were used. This is a standard method for inactivating HIV that does not alter the viral envelope.
  • the spleen and the lymph nodes were assayed for the detection of HIV in order to establish the spleen as an alternate repository site for HIV.
  • the spleen (as opposed to the lymph nodes) allows for obtaining relatively larger amounts of RNA for performing RT- PCR for the detection of HIV.
  • extraction of spleens is less time consuming than removal of the lymph nodes thereby lessening the probability of RNA degradation.
  • mice were randomized into three groups: 1) non-treated PBS control mice; 2) mice pre-treated with methyl cellulose (inert placebo); and 3) mice pretreated with the K-11/ ⁇ carrageenan composition. Results are shown on the Southern Blot in Fig. 2 and the table below.
  • mice received only a vaginal inoculation of macrophages, the recipient animals had an average of 55 labeled donor's cells in the draining lymph nodes and of 558 cells in the spleen, respectively.
  • mice that received a vaginal pre-inoculation of K-11/ ⁇ carrageenan composition indicated in table above as "K-11/ ⁇ carrageenan" an average of only 4 cells were counted in the draining lymph nodes, and an average of only 28 were observed in the spleen. The difference between untreated and K-11/ ⁇ carrageenan composition-treated animals was significant.
  • the K-11/ ⁇ carrageenan composition has also been proven effective on blocking bovine papillomavirus (BPV) foci formation in vitro (data not shown).
  • the K-11/ ⁇ carrageenan composition is efficacious in preventing human papillomavirus (HPV) from transforming human vaginal explants in a xenograft system.
  • HPV human papillomavirus
  • the SKID mouse xenograph system employs explants of human vaginal tissue rolled into cylindrical tubes that are grafted subcutaneously on NOD/SKID (immunodeficient) mice29. The grafts are allowed to heal for two weeks, at which time one end of the tube is opened and a test compound is instilled followed by HPV challenge.
  • the ⁇ / ⁇ carrageenan mixture is also effective at high dilutions as demonstrated in the HSV-2 mouse system.
  • a 3% ⁇ - ⁇ / ⁇ carrageenan composition was diluted in PBS to make 1: 1, 1 :5, 1:25, 1:50, 1: 100, and 1 :200 dilutions.
  • Dilute solutions were vaginal administered to mice followed by 104 (100% infection dose) of HSV-2.
  • the results from these experiments are unexpected. Instead of observing a dose dependent decrease in the anti-viral protection rate the K-11/ ⁇ carrageenan composition dilution of 1:50 retained most of the anti-viral protection rate as less dilute solutions. Furthermore, significant activity was retained even with the 1:200 solution. See Fig. 11.
  • LSA-carrageenan was compared to the K-11/ ⁇ carrageenan composition alone at a viral challenge dose of 106 pfu, in three separate experiments. LSA-carrageenan was significantly more effective than the K-11/ ⁇ carrageenan composition alone in all experiments.
  • the addition of other sulfated polymers to K-11/ ⁇ carrageenan composition did not increase the effectiveness of the formulation.
  • the addition of 5% dextran sulfate or 5% heparin to K-11/ ⁇ carrageenan composition had no effect on efficacy against HSV-2 infection in mice.
  • HSV-2 106 pfu viral dose is equivalent to 100 times the viral dose that would infect all unprotected mice. It is necessary to use such high doses of virus because carrageenan is extremely effective at inhibiting viral infection.
  • Each formulation is initially tested in a total of 20 mice. Compounds or formulations that show a blocking effect are assayed again in another 20 mice. The number of mice infected is an average.
  • the viral dose is 100 times the 100% infection rate and no compound other than the minimal effect of 3% carrageenan has had any effect at such a high virus dose.
  • LSA was assayed without Carrageenan to better evaluate its inhibitory properties.
  • LSA was added to the inert thickener, methylcellulose, to maintain the same viscosity that vaginal products (lubricants, spermicides, and microbicides) generally have. (Data shown below.)
  • LSA is effective as a microbicide against HSV-2 infection, HIV, and other STI's, with or without carrageenan.
  • the sulfated polymer LSA is effective in protecting epithelial cells in vitro against HIV infection and mice from HSV-2 infection.
  • the inhibitory effect may be observed with other enveloped viruses such as the human pathogen, human T cell leukemia virus.
  • epithelial cells are protected against the human papillomavirus, which is not an enveloped virus.
  • the inhibitory efficaciousness of LSA may thus extend to a broader range of STI's.
  • the testing results are shown in Fig. 5.
  • Zn-carrageenan has also been evaluated in the HSV-2/mouse system (see Fig. 7).
  • HSV-2 viral challenge doses ranging from 103 pfu or 50% infection dose, to 107 pfu or 1,000 x 100% infection dose was also used.
  • Applicants had determined that K-11/ ⁇ carrageenan composition could protect some animals at a viral challenge dose of 106 pfu or 100 x 100% infection dose. No other candidate microbicide tested was able to afford protection at this viral dose.
  • a microbicide that was able to be effective even if administered following exposure to a virus would extend product use to include women who were not able to use the product until after intercourse had already occurred e.g., women who fell victim to rape.
  • researchers have been unable to identify a microbicide that might afford such protection.
  • Zn-carrageenan is able to afford protection against HSV-2 infection in mice post-viral challenge.
  • Zn-carrageenan is exceptional in that it demonstrated activity for up to 4 hours post- viral exposure (see Fig. 9). This finding is remarkable in light of Applicants' observations that K-11/ ⁇ carrageenan composition did not prevent infection post viral challenge unless administered immediately following HSV-2 challenge.
  • Example 17 Contraceptive Microbicide for Dual Protection
  • the ⁇ - ⁇ / ⁇ carrageenan composition remains in the vagina for up to 24 hours, enabling a once-daily application for protection against HIV and its use as a vaginal delivery system for a contraceptive hormone.
  • the feasibility of delivering various steroids vaginally has been thoroughly investigated with the recent development of contraceptive vaginal rings43. It has been shown that steroids applied directly to the vaginal mucosa are quickly absorbed, and only very small doses are needed to achieve the desired contraceptive effect 48-52. In addition, vaginal delivery is usually accompanied by diminished undesirable side effects that are often associated with oral contraceptives.
  • the vaginal formulations of the present invention provide dual protection as a combination microbicide/contraceptive that have a further advantage of enhancing user motivation for compliance.
  • the contraceptive hormone NES is a preferred contraceptive agent. This synthetic progestin has been shown to be an exceptionally potent molecule. Using classic bioassays of measuring the progestational potency, NES has proven to be 100 times more active than progesterone and only very small quantities of NES are required to suppress luteal activity. Additionally, extensive toxicology studies of NES have been conducted.
  • the Erlenmeyer flask was heated to 60°C with stirring to afford a clear solution, and the contents of the flask were immediately added to the zinc-carrageenan water mixture contained in the 700 ml mixing jar.
  • the mixture was stirred for two hours at ambient temperature at which time 5 mL of an MIV-150/DMSO stock solution prepared by dissolving 18.5 mg of MIV-150 in 10 mL of dimethyl sulfoxide were added to the contents of the 700 mL mixing jar. This mixture was then stirred at 300 rpm for 35 minutes at ambient temperature, and 26 grams of sterile purified water was then added to the mixing jar and the contents were stirred for 30 minutes at ambient temperature.
  • Macaques were injected with Depo-Provera and three week later given 2 mL of the gel prepared as discussed above per day for two weeks prior to being challenged with 1,000 TC1D50 of SHIV-RT at the indicated times after the last gel was applied.
  • the numbers of infected animals as set forth in Table 1 below reflect the number with typical viremia (SIV RNA copies in plasma).
  • a half-sized macaque IVR (20 mm x 2 mm) was created using a conventional brass cavity mold having two halves of equal dimensions. A flat brass plate was placed against one half of the mold. Thus, instead of creating a full-sized IVR (20 mm x 4 mm) in which both of the cavity molds are joined together and the polymer is injection molded, the flat brass plate provided a half macaque IVR by injection molding.
  • the polymer used was EVA 28, Scientific Polymer Products, which was injection molded at 127°C.
  • the final step of producing the full ring could include a different polymer from that of the step used to produce the half ring.
  • the final ring can instead employ any other thermoplastic elastomer that can fuse with the polymer used in the first half of the IVR.
  • the final step in producing a full ring can also include the creation of two halves, both with grooves for containing water-soluble polymer, and/or compounds and then sealing the two halves using a heat seal or bioadhesives.
  • the ring itself can be compounded or loaded with various low molecular weight water-insoluble compounds described above.
  • Another embodiment of the present invention was prepared by first extruding a full-sized macaque EVA ring under normal conditions with a dual mold at 210°C.
  • the ring was produced from the EVA polymer, and preferably is compounded with MIV-150.
  • two macaque IVRs (20 mm x 4 mm) were produced using conventional injection molding, based on EVA polymers. These IVRs were then placed in the mold and the central cavity within the IVRs was filled with nearly 200 mg of carrageenan. The molds were then closed and subjected to three tons of pressure using the Arbor press for nearly one minute. In this manner, a compressed disk of carrageenan was formed within the ring. The compressed carrageenan disk remained whole and sustained its integrity upon removal from the molds. The reservoirs were made with carrageenan alone and with carrageenan-zinc acetate mixtures. With increased amounts of zinc acetate, however, the compression properties were negatively impacted.
  • a first IVR half such as that shown in Fig. 15 was produced, in this case using the six-member mold of Fig. 21 and the projections 122 shown in Fig. 21 on the right-hand side to produce the grooves within the IVR halves.
  • the IVR halves were again made from EVA-28 and extruded at around 151°C.
  • a hydrophilic polyurethane resin identified as PURSIL AL-2075 was loaded with zinc acetate as a low molecular weight water-soluble compound using the solvent casting method. Since the addition of the zinc acetate lowered the extrusion temperature of the PURSIL AL-2075 significantly, this allowed extrusion of this loaded resin at relatively low temperatures.
  • an incision was made through the outer wall of the half of the IVR to permit the extruded resin to enter into the groove from the center of the mold. In this manner hot molten resin was enabled to flow into the grooves.
  • a flat plate was placed upon the top of the left-hand side of the mold shown in Fig. 21.
  • the IVR was then sealed using a normal extrusion process using EVA polymer to create the second half of the ring.
  • a second IVR half including a groove can be produced, and the groove filled either in the same manner as the first half, or with a different core, such as including a high molecular weight water-soluble polymer such as carrageenan or the like.
  • the two halves can then be sealed together to form the IVR.
  • ICM Intercellular adhesion molecules
  • Luscombe, D.K. & Nicholls, P.J. Acute and subacute oral toxicity of AHR-2438B, a purified sodium lignosulphonate in rats. Fd. Cosmet. Toxicol. 11, 229-237 (1973).
  • Pentosan polysulfate a sulfated oligosaccharide
  • ATSDR Ad for Toxic Substances and Disease Registry. Toxological Profile for Zinc. Agency for Toxic Substances and Disease Registry, U. S. Public Health Service, Atlanta, GA. 121 pp (2001).

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Abstract

L'invention concerne des compositions destinées à inhiber la transmission d'une infection sexuellement transmissible qui contient un ou plusieurs microbicides, comme des carraghénanes, notamment le carraghénane lambda, ainsi que des sels de métaux hydrosolubles et des agents antirétroviraux spécifiés comprenant des INNTI et des INTI. Elle concerne également des procédés de préparation et d'utilisation des compositions. Elle concerne aussi des anneaux intravaginaux pour l'administration de composés hydrosolubles, et de préférence des polymères hydrosolubles de haut poids moléculaire essentiellement à une vitesse d'ordre zéro. Les anneaux comprennent une couche externe d'élastomère qui ne gonfle pas dans l'eau et de préférence un polymère hydrosoluble de haut poids moléculaire et une couche interne du polymère hydrosoluble, qui est incluse dans la couche externe et une ouverture à travers la couche externe pour sa libération uniquement par cette ouverture.
PCT/US2014/014633 2013-02-05 2014-02-04 Anneau intravaginal pour l'administration de combinaisons uniques de compositions antimicrobiennes WO2014123880A1 (fr)

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CN201480020245.9A CN105555281A (zh) 2013-02-05 2014-02-04 用于递送抗菌组合物的独特结合的阴道环
EP14705007.4A EP2953629A1 (fr) 2013-02-05 2014-02-04 Anneau intravaginal pour l'administration de combinaisons uniques de compositions antimicrobiennes
RU2015136769A RU2015136769A (ru) 2013-02-05 2014-02-04 Внутривагинальное кольцо для доставки уникальных комбинаций противомикробных композиций
BR112015018701A BR112015018701A2 (pt) 2013-02-05 2014-02-04 anel vaginal para dispensação de um polímero solúvel em água, e, método para fabricar um anel vaginal para dispensação de um polímero solúvel em água
AU2014215459A AU2014215459A1 (en) 2013-02-05 2014-02-04 Intravaginal ring for the delivery of unique combinations of antimicrobial compositions

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CN106474147A (zh) * 2016-10-14 2017-03-08 上海颉隆投资管理有限公司 一种预防和控制人乳头状瘤病毒感染的敷料及其制备方法
WO2017139854A1 (fr) * 2016-02-17 2017-08-24 Ent Technologies Pty Ltd Compositions et méthodes de traitement des troubles et des pathologies des sinus
US20190388590A1 (en) * 2016-05-12 2019-12-26 Merck Sharp & Dohme Corp. Drug delivery system for the delivery of antiviral agents
CN113677326A (zh) * 2019-02-19 2021-11-19 粒子科学公司 隔室化药物递送装置

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