WO2019232166A1 - Emballage coque à double compartiment et procédés associés - Google Patents

Emballage coque à double compartiment et procédés associés Download PDF

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Publication number
WO2019232166A1
WO2019232166A1 PCT/US2019/034582 US2019034582W WO2019232166A1 WO 2019232166 A1 WO2019232166 A1 WO 2019232166A1 US 2019034582 W US2019034582 W US 2019034582W WO 2019232166 A1 WO2019232166 A1 WO 2019232166A1
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WO
WIPO (PCT)
Prior art keywords
blister
chamber
outlet
composition
package
Prior art date
Application number
PCT/US2019/034582
Other languages
English (en)
Inventor
Johannes Robert ROEBERS
Original Assignee
Novan, Inc.
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Novan, Inc. filed Critical Novan, Inc.
Publication of WO2019232166A1 publication Critical patent/WO2019232166A1/fr

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Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61J—CONTAINERS SPECIALLY ADAPTED FOR MEDICAL OR PHARMACEUTICAL PURPOSES; DEVICES OR METHODS SPECIALLY ADAPTED FOR BRINGING PHARMACEUTICAL PRODUCTS INTO PARTICULAR PHYSICAL OR ADMINISTERING FORMS; DEVICES FOR ADMINISTERING FOOD OR MEDICINES ORALLY; BABY COMFORTERS; DEVICES FOR RECEIVING SPITTLE
    • A61J1/00—Containers specially adapted for medical or pharmaceutical purposes
    • A61J1/05—Containers specially adapted for medical or pharmaceutical purposes for collecting, storing or administering blood, plasma or medical fluids ; Infusion or perfusion containers
    • A61J1/06—Ampoules or carpules
    • A61J1/067—Flexible ampoules, the contents of which are expelled by squeezing
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61J—CONTAINERS SPECIALLY ADAPTED FOR MEDICAL OR PHARMACEUTICAL PURPOSES; DEVICES OR METHODS SPECIALLY ADAPTED FOR BRINGING PHARMACEUTICAL PRODUCTS INTO PARTICULAR PHYSICAL OR ADMINISTERING FORMS; DEVICES FOR ADMINISTERING FOOD OR MEDICINES ORALLY; BABY COMFORTERS; DEVICES FOR RECEIVING SPITTLE
    • A61J1/00—Containers specially adapted for medical or pharmaceutical purposes
    • A61J1/14—Details; Accessories therefor
    • A61J1/20—Arrangements for transferring or mixing fluids, e.g. from vial to syringe
    • A61J1/2093—Containers having several compartments for products to be mixed
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B65—CONVEYING; PACKING; STORING; HANDLING THIN OR FILAMENTARY MATERIAL
    • B65D—CONTAINERS FOR STORAGE OR TRANSPORT OF ARTICLES OR MATERIALS, e.g. BAGS, BARRELS, BOTTLES, BOXES, CANS, CARTONS, CRATES, DRUMS, JARS, TANKS, HOPPERS, FORWARDING CONTAINERS; ACCESSORIES, CLOSURES, OR FITTINGS THEREFOR; PACKAGING ELEMENTS; PACKAGES
    • B65D75/00—Packages comprising articles or materials partially or wholly enclosed in strips, sheets, blanks, tubes, or webs of flexible sheet material, e.g. in folded wrappers
    • B65D75/28—Articles or materials wholly enclosed in composite wrappers, i.e. wrappers formed by associating or interconnecting two or more sheets or blanks
    • B65D75/30—Articles or materials enclosed between two opposed sheets or blanks having their margins united, e.g. by pressure-sensitive adhesive, crimping, heat-sealing, or welding
    • B65D75/32—Articles or materials enclosed between two opposed sheets or blanks having their margins united, e.g. by pressure-sensitive adhesive, crimping, heat-sealing, or welding one or both sheets or blanks being recessed to accommodate contents
    • B65D75/36—Articles or materials enclosed between two opposed sheets or blanks having their margins united, e.g. by pressure-sensitive adhesive, crimping, heat-sealing, or welding one or both sheets or blanks being recessed to accommodate contents one sheet or blank being recessed and the other formed of relatively stiff flat sheet material, e.g. blister packages, the recess or recesses being preformed
    • B65D75/366—Articles or materials enclosed between two opposed sheets or blanks having their margins united, e.g. by pressure-sensitive adhesive, crimping, heat-sealing, or welding one or both sheets or blanks being recessed to accommodate contents one sheet or blank being recessed and the other formed of relatively stiff flat sheet material, e.g. blister packages, the recess or recesses being preformed and forming one compartment
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B65—CONVEYING; PACKING; STORING; HANDLING THIN OR FILAMENTARY MATERIAL
    • B65D—CONTAINERS FOR STORAGE OR TRANSPORT OF ARTICLES OR MATERIALS, e.g. BAGS, BARRELS, BOTTLES, BOXES, CANS, CARTONS, CRATES, DRUMS, JARS, TANKS, HOPPERS, FORWARDING CONTAINERS; ACCESSORIES, CLOSURES, OR FITTINGS THEREFOR; PACKAGING ELEMENTS; PACKAGES
    • B65D81/00—Containers, packaging elements, or packages, for contents presenting particular transport or storage problems, or adapted to be used for non-packaging purposes after removal of contents
    • B65D81/32—Containers, packaging elements, or packages, for contents presenting particular transport or storage problems, or adapted to be used for non-packaging purposes after removal of contents for packaging two or more different materials which must be maintained separate prior to use in admixture
    • B65D81/3283—Cylindrical or polygonal containers, e.g. bottles, with two or more substantially axially offset, side-by-side compartments for simultaneous dispensing
    • B65D81/3288—Cylindrical or polygonal containers, e.g. bottles, with two or more substantially axially offset, side-by-side compartments for simultaneous dispensing composed of two or more separate containers joined to each other
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B65—CONVEYING; PACKING; STORING; HANDLING THIN OR FILAMENTARY MATERIAL
    • B65D—CONTAINERS FOR STORAGE OR TRANSPORT OF ARTICLES OR MATERIALS, e.g. BAGS, BARRELS, BOTTLES, BOXES, CANS, CARTONS, CRATES, DRUMS, JARS, TANKS, HOPPERS, FORWARDING CONTAINERS; ACCESSORIES, CLOSURES, OR FITTINGS THEREFOR; PACKAGING ELEMENTS; PACKAGES
    • B65D2575/00—Packages comprising articles or materials partially or wholly enclosed in strips, sheets, blanks, tubes or webs of flexible sheet material, e.g. in folded wrappers
    • B65D2575/28—Articles or materials wholly enclosed in composite wrappers, i.e. wrappers formed by association or interconnecting two or more sheets or blanks
    • B65D2575/30—Articles or materials enclosed between two opposed sheets or blanks having their margins united, e.g. by pressure-sensitive adhesive, crimping, heat-sealing, or welding
    • B65D2575/36—One sheet or blank being recessed and the other formed or relatively stiff flat sheet material, e.g. blister packages
    • B65D2575/361—Details
    • B65D2575/362—Details with special means for gaining access to the contents

Definitions

  • the present invention relates to blister packaging, and in particular to dual chamber blister packages for separately holding two compounds and/or compositions therein.
  • Blister packaging is used for dispensing consumer products, including
  • Blister packages typically include a cavity or pocket made from a formable web such as thermoformed plastic or breakable aluminum foil that is positioned on a backing of polymer foil or film or a lidding seal of aluminum foil or plastic. Blister packaging may be used to protect pharmaceutical products, including semi-solid or gel based pharmaceutical products, from environmental factors. Blister packaging may also provide convenient, single-dose packaging for consumer use.
  • U.S. Patent No. 8,806,842 to Penn et al. proposes a frangible blister packaging for mixing and dispensing fluid using a mixing flow path that is initiated by compression on an upstream flexible compartment, which forces content fluid to mix into the downstream compartment for dispensing therefrom.
  • a dual chamber blister package includes: a first package unit comprising: a first blister chamber configured to hold a first compound and/or composition; and a first outlet at an end of the first package unit; a second package unit comprising: a second blister chamber configured to hold a second compound and/or composition; and a second outlet at an end of the second package unit; a sealing member sealing the first and second outlets such that when the sealing member is opened, the first compound and/or composition is expelled from the first blister chamber via the first outlet and the second compound and/or composition is expelled from the second blister chamber via the second outlet upon compression of the first and second blister chambers; and a dividing wall between the first and second package units, the dividing wall positioned so as to provide a fluid barrier between the first and second blister chamber such that the first and second compound and/or composition are contacted only after exiting the respective first and second outlet.
  • the first outlet comprises a first cavity having an opening at an end of the first package unit that is opposite the first blister chamber and the second outlet comprises a second cavity having an opening at an end of the second package unit opposite the second blister chamber.
  • a first (optional) frangible seal is between the first outlet and first blister chamber such that the first blister chamber is sealed by the first frangible seal, and when the first blister chamber is compressed, pressure is exerted on the first frangible seal to break the first frangible seal and form a fluid connection between the first blister chamber and the first outlet so that the first compound and/or composition exits the first package unit via the first outlet.
  • a second (optional) frangible seal is between the second outlet and second blister chamber such that the second blister chamber is sealed by the second frangible seal, and when the second blister chamber is compressed, pressure is exerted on the second frangible seal to break the second frangible seal and form a fluid connection between second blister chamber and the second outlet so that the second compound and/or composition exits the second package unit via the second outlet.
  • the dividing wall extends between the first and second frangible seal.
  • the first compound and/or composition comprises aNO- releasing active pharmaceutical ingredient.
  • the second compound and/or composition comprises an aqueous composition (e.g., a hydrogel).
  • aqueous composition e.g., a hydrogel
  • the sealing member comprises a first sealing member on the first outlet and a second sealing member on the second outlet.
  • a method of forming a dual chamber blister package includes: filling a first blister chamber of a first package unit with a first compound and/or
  • first package unit having a first wall
  • filling a second blister chamber of a second package unit with a second compound and/or composition the second package unit having a second wall
  • a method of operating a dual chamber blister package includes providing a dual chamber blister package comprising: a first package unit comprising: a first blister chamber configured to hold a first compound and/or composition; and a first outlet at an end of the first package unit; a second package unit comprising: a second blister chamber configured to hold a second compound and/or composition; and a second outlet at an end of the second package unit; a sealing member sealing the first and second blister outlets; and a dividing wall between the first and second package unit, the dividing wall positioned so as to provide a fluid barrier between the first and second blister chamber.
  • the method includes opening and/or removing the sealing member; and compressing the first and second blister chambers so as to expel the first compound and/or composition from the first outlet and the second compound and/or composition from the second outlet such that the first and second compound and/or composition is contacted only after exiting the respective first and second outlets.
  • FIG. 1 is a perspective view of a dual chamber blister package according to some embodiments.
  • FIG. 2 is a side cross-sectional view of the dual chamber blister package of FIG. 1 in a sealed configuration.
  • FIG. 3 is a side cross-section view of the dual chamber blister package of FIG. 1 in the unsealed configuration with the chambers compressed.
  • FIG. 4 is a perspective view of a package unit of a dual chamber blister package with a frangible seal according to some embodiments.
  • FIG. 5 is a side cross-sectional view of a dual chamber blister package with the package unit of FIG. 4 in a sealed configuration.
  • FIG. 6 is a side cross-section view of the dual chamber blister package of FIG. 5 in the unsealed configuration with the chambers compressed and the frangible seal opened.
  • FIG. 7 is a side cross-sectional view of a dual chamber blister package in a sealed configuration according to some embodiments.
  • FIG. 8 is a side cross-section view of the dual chamber blister package of FIG. 7 in the unsealed configuration with the chambers compressed and the frangible seal opened.
  • phrases such as “between X and Y” and “between about X and Y” should be interpreted to include X and Y.
  • phrases such as “between about X and Y” mean “between about X and about Y.”
  • phrases such as “from about X to Y” mean “from about X to about Y.”
  • spatially relative terms such as “under,” “below,” “lower,” “over,” “upper” and the like, may be used herein for ease of description to describe one element or feature's relationship to another element(s) or feature(s) as illustrated in the figures. It will be understood that the spatially relative terms are intended to encompass different orientations of the device in use or operation in addition to the orientation depicted in the figures. For example, if the device in the figures is inverted, elements described as “under” or “beneath” other elements or features would then be oriented “over” the other elements or features.
  • the exemplary term “under” can encompass both an orientation of "over” and “under.”
  • the device may be otherwise oriented (rotated 90 degrees or at other orientations) and the spatially relative descriptors used herein interpreted accordingly.
  • the terms “upwardly,” “downwardly,” “vertical,” “horizontal” and the like are used herein for the purpose of explanation only unless specifically indicated otherwise.
  • the transitional phrase "consisting essentially of 1 (and grammatical variants) is to be interpreted as encompassing the recited materials or steps "and those that do not materially affect the basic and novel characteristic(s)" of the claimed invention. See , In re Herz, 537 F.2d 549, 551-52, 190 U.S.P.Q. 461, 463 (CCPA 1976) (emphasis in the original); see also MPEP ⁇ 2111.03.
  • the term “consisting essentially of' as used herein should not be interpreted as equivalent to "comprising.”
  • a measurable value such as an amount or concentration and the like
  • variations of up to ⁇ 20% of the specified value such as, but not limited to, ⁇ 10%, ⁇ 5%, ⁇ 1%, ⁇ 0.5%, or even ⁇ 0.1% of the specified value, as well as the specified value.
  • “about X” where X is the measurable value is meant to include X as well as variations of ⁇ 20%, ⁇ 10%, ⁇ 5%, ⁇
  • a range provided herein for a measureable value may include any other range and/or individual value therein.
  • the terms“increase,”“increases,”“increased,”“increasing,” and similar terms indicate an elevation in the specified parameter of at least about 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 100%, 150%, 200%, 300%, 400%, 500% or more.
  • the terms“reduce,”“reduces,”“reduced,”“reduction,”“inhibit,” and similar terms refer to a decrease in the specified parameter of at least about 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 97%, or 100%.
  • an example dual chamber blister package 10 includes a package unit 20 that includes a blister chamber 22 configured to hold a compound and/or composition and an outlet 24 at an end of the blister chamber 22.
  • Another package unit 30 includes a blister chamber 32 configured to hold another compound and/or composition (which may be the same as or different than the compound and/or composition in the blister chamber 22) and a corresponding outlet 34 at an end of the blister chamber 32.
  • a single sealing member 40 seals two outlets 24, 34 such that when the sealing member 40 is opened, one compound and/or composition is expelled from the outlet 24 and the other compound and/or composition is expelled from the outlet 34 upon compression of the blister chambers 22, 32.
  • alternative sealing mechanisms may be used, including two separate sealing members, which may be provided on the respective outlets 24, 34.
  • a dividing wall 50 having two dividing wall layers 50 A, 50B is between the two package units 20, 30. The dividing wall 50 is formed by a panel or layer 50 A from package unit 20 and a panel or layer 50B from package unit 30.
  • the dividing wall 50 is positioned so as to provide a fluid barrier between each of the blister chambers 22, 32 and the respective outlets 24, 34 such that compounds and/or composition(s) held within the respective chambers 22, 32 are contacted only after exiting the respective outlets 24, 34.
  • the outlets 24, 34 include respective cavities 24A, 34A and openings 24B, 34B, such that when the sealing member 40 is removed from the openings 24B, 34B, such as by a twisting and/or pulling movement that causes separation of the sealing member 40 from the openings 24B, 34B, and the chambers 22, 32 are depressed, the contents of the chambers 22, 32 are separated by the dividing wall 50, and the contents of the chambers 22, 32 make fluid contact only upon exiting the openings 24B, 34B.
  • the contents of the chambers 22, 32 may be kept separate from one another until final application when the compound(s) and/or composition(s) finally exit the openings 24B, 34B.
  • the outlets 24, 34 may be of various shapes and forms, and the cavities 24A, 34A may have any suitable width and/or length.
  • the dividing wall 50 is formed of two planar wall layers 50 A, 50B; however, any suitably shaped divider may be used, including curved or bent dividing walls.
  • Blister package units known to those of skill in the art may be used to prepare a dual chamber blister package of the present invention.
  • a blister package unit may be attached and/or mounted to another blister package unit, such as, for example, attaching a flat panel of one blister package unit to a flat panel of another blister package unit.
  • the blister package units may be attached together using any methods known to those of skill in the art such as, for example, chemical (e.g., adhesive and/or glue) and/or mechanical (embossing, crimping, etc.) means.
  • the blister chambers 22, 32 are aligned on the package 10 such that pressure applied to one of the chambers 22, 32 will also apply pressure to the other one of the chambers 22, 32.
  • a blister package unit that may be used to prepare a dual chamber blister package of the present invention may be available from and/or prepared using machinery from Rohrer AG in Mohlin, Switzerland, such as, for example, Blister Sealing Machine RS510, RS570 or R560. As shown in FIG. 4, a package unit 120, which may be used to form a dual chamber blister package, is shown.
  • the package 100 includes a package unit 120 that includes a blister chamber 122 configured to hold a compound and/or composition and an outlet 124 at an end of the package unit 120.
  • An optional frangible seal 126 is positioned between the blister chamber 122 and the outlet 124.
  • Another package unit 130 includes a blister chamber 132 configured to hold another compound and/or composition and a corresponding outlet 134 at an end of the package unit 130.
  • Another, separate frangible seal 136 is positioned between the blister chamber 132 and the outlet 134.
  • Removable sealing members 140A, 140B each seal the respective outlets 124, 134. As illustrated, the sealing members 140A, 140B are pull tabs.
  • a dividing wall 150 formed by layers 150A, 150B is between the two package units 120, 130. It should be understood that in some embodiments, a single layer dividing wall may be used.
  • the frangible seals 126, 136 may provide additional sealing of the
  • an exemplary dual chamber blister package 200 is shown having tubular-shaped outlets 224, 234.
  • the package 200 includes a package unit 220 that includes a blister chamber 222 configured to hold a compound and/or composition and an outlet 224 at an end of the package unit 220.
  • a frangible seal 226 is positioned between the blister chamber 222 and the outlet 224.
  • Another package unit 230 includes a blister chamber 232 configured to hold another compound and/or composition and a corresponding outlet 234 at an end of the package unit 230.
  • Another, separate frangible seal 236 is positioned between the blister chamber 232 and the outlet 234. Sealing members 240A, 240B are provided at an end of the respective outlets 224, 234.
  • a dividing wall 250 is between the two package units 220, 230.
  • the sealing members 240A, 240B are integrated with the outlets 224, 234 and form a sealed end thereof.
  • the outlets 224, 234 form a tubular portion 224A, 234A, and in some embodiments, the sealing members 240A, 240B may be formed of the same material as the tubular portion 224A, 234A.
  • the end sealing members 240A, 240B on the tubular portions 224 A, 234A of Figure 7 may be removed by any suitable means to form respective openings 224B, 224B as shown in Figure 8. In some embodiments, the end sealing members 240A, 240B are cut open by the user.
  • the contents of the chambers 222, 232 may therefore be expelled via the tubular portions 224A, 234A.
  • the tubular portions 224A, 234A of the outlets 224, 234 are held together by a mechanical holder or adhesive so that the contents of the chambers 222, 232 are expelled in close proximity to one another.
  • the tubular portions 224 A, 234 A are formed by a pipe or tube, which may have various shapes and/or be made of various material(s).
  • the outlets 224, 234 may be sealed by any suitable seal, which could include, for example, a cap, a screw cap, or other types of breakable seals.
  • the dual chamber blister packaging may be formed using any suitable materials and manufacturing methods, including materials/methods known to those skilled in the blister packaging forming art.
  • the blister chambers may be formed of a blank of base material, such as a synthetic resin based material, which is then deformed by a“plug” assist formation method to create the blister chambers and/or the outlet.
  • a synthetic resin based material may be preheated to a pliable yieldable temperature as determined by the selection of the resin material (e.g., PYDC/PE film) and thickness thereof for plug assist formation.
  • the base that holds the product is a thinker aluminum/PET/PE laminate film, which may be referred to as cold form film.
  • the top layer and the sealing layer may be a thinner film of similar material of construction, which may be referred to as a lid film.
  • the desired compounds and/or compositions may be separately filled in the formed blister chambers and separately sealed before joining the blister chambers together.
  • a gas e.g., air, nitrogen, etc.
  • the dividing wall may be formed of any suitable material that provides a fluid barrier between the blister chambers, such as a polymer layer, cardboard layer, etc.
  • the dividing wall may include two sealing (wall) layers that are adhered together. That is, the blister chambers may be formed by the “plug” assist formation method and separately sealed by respective wall layers, which are then adhered together, for example, as shown by the layers of the wall 50 in Figure 2.
  • the volume of the blister chambers is about 0.1 or 0.3 mL to about 0.5, 0.75, 1.0, 2.0, 3.0, 5.0, 10, 20 or 30 ml mL.
  • the blister chambers may be compressed manually by pressing on the chambers or a device may be used to exert force on the blister chambers to expel the contents of the chambers from the outlet.
  • the sealing member at the outlets may be configured as a single sealing member, such as is shown by the sealing member 40 of Figure 2 or the two outlets may have separate sealing members, such as is shown by the sealing member 140A, 140B in Figure 5.
  • the sealing members may be a tab ( Figure 2) or plug ( Figure 5) that is removed from the outlet(s) by a twisting, pulling and/or bending movement that opens and/or removes the sealing member from the outlet.
  • the outlets may be formed of the same material as the blister chambers (as shown in Figures 1-3 and 4-6) or the outlets may be formed of a separate piece, such as a tube, that extends away from the dividing wall between the chambers (as shown in Figures 7-8).
  • the outlets 224, 234 are formed of two respective tubes having adjacent openings 224B, 234B.
  • the openings 224B, 234B may be joined together, for example, by an adhesive or mechanical connection, to maintain a close proximity of the openings 224B, 234B during release of the contents of the chambers.
  • a first compound and/or composition comprising a NO-releasing active pharmaceutical ingredient in a first blister chamber and a second compound and/or composition comprising an aqueous composition in the form of a liquid or semi-solid (e.g., a hydrogel) may be used.
  • a liquid or semi-solid e.g., a hydrogel
  • a dual chamber blister package of the present invention may be a single use dosage unit.
  • a blister package unit of the present invention does not comprise ethylene acrylic acid (EAA) copolymers.
  • a blister package may comprise EAA copolymers and optionally EAA copolymers are not in contact with a NO-releasing API and/or a composition of the present invention (e.g., a NO-releasing composition and/or a hydrogel).
  • a blister package unit may comprise aluminum ⁇ e.g., an aluminum foil) and/or a low density polyethylene
  • each package unit of a dual chamber blister package of the present invention may be separately filled with a compound and/or composition (e.g., a NO- releasing composition or a hydrogel).
  • a first package unit may be filled with a compound and/or composition at a different time then when a second package unit is filled with a compound and/or composition.
  • a dual chamber blister package may not be prepared until shipment.
  • a plurality of blister package units comprising a hydrogel may be prepared and a plurality of blister package units comprising a NO-releasing composition may be separately prepared and subsequently attached and/or mounted together to form a dual chamber blister package of the present invention.
  • a blister package of the present invention may comprise a NO-releasing active pharmaceutical ingredient (API).
  • a NO-releasing API is present in a chamber of a blister package (e.g., in a first chamber and/or a second chamber).
  • Nitric oxide releasing active pharmaceutical ingredient and “NO-releasing API,” as used herein, refer to a compound or other composition that provides nitric oxide to the skin (including mucosa) and/or tissue of a subject, but is not gaseous nitric oxide.
  • the NO-releasing API is also not acidified nitrite.
  • the NO-releasing API includes a nitric oxide-releasing compound, hereinafter referred to as a "NO-releasing compound.”
  • a NO-releasing compound includes at least one NO donor, which is a functional group that may release nitric oxide under certain conditions.
  • Any suitable NO-releasing compound may be used.
  • the NO- releasing compound includes a small molecule compound that includes an NO donor group.
  • "Small molecule compound” as used herein is defined as a compound having a molecular weight of less than 500 Daltons, and includes organic and/or inorganic small molecule compounds.
  • the NO-releasing compound includes a macromolecule that includes an NO donor group.
  • a "macromolecule” is defined herein as any compound that has a molecular weight of 500 Daltons or greater. Any suitable macromolecule may be used, including crosslinked or non-crosslinked polymers, dendrimers, metallic compounds, organometallic compounds, inorganic-based compounds, and other macromolecular scaffolds. In some embodiments, the macromolecule has a nominal diameter ranging from about 0.1 nm to about 100 pm and may comprise the aggregation of two or more
  • macromolecules whereby the macromolecular structure is further modified with an NO donor group.
  • the NO-releasing compound includes a diazeniumdiolate functional group as an NO donor.
  • the diazeniumdiolate functional group may produce nitric oxide under certain conditions, such as upon exposure to water.
  • the NO-releasing compound includes a nitrosothiol functional group as the NO donor.
  • the NO donor may produce nitric oxide under certain conditions, such as upon exposure to light. Examples of other NO donor groups include nitrosamine, hydroxyl nitrosamine, hydroxyl amine and hydroxyurea. Any suitable combination of NO donors and/or NO-releasing compounds may also be used in a vaginal suppository as described herein. Additionally, the NO donor may be incorporated into or onto the small molecule or macromolecule through covalent and/or non-co valent interactions.
  • a NO-releasing macromolecule may be in the form of an NO-releasing particle, such as those described in U.S. Patent No. 8,282,967, U.S. Patent No. 8,962,029 or U.S. Patent No. 8,956,658, the disclosures of which are incorporated by reference herein in their entirety.
  • NO-releasing compounds include NO-releasing zeolites as described in United States Patent Publication Nos. 2006/0269620 or 2010/0331968; NO- releasing metal organic frameworks (MOFs) as described in United States Patent Application Publication Nos. 2010/0239512 or 2011/0052650; NO-releasing multi-donor compounds as described in International Application No.
  • NO-releasing macromolecules may be fabricated as described in International Application No. PCT/US2012/022048 entitled “Temperature Controlled Sol-Gel Co- Condensation” filed January 20, 2012, the disclosure of which is incorporated herein by reference in its entirety.
  • a nitric oxide-releasing active pharmaceutical ingredient may include NO-loaded precipitated silica.
  • the NO-loaded precipitated silica may be formed from nitric oxide donor modified silane monomers into a co-condensed siloxane network.
  • the nitric oxide donor may be an N-diazeniumdiolate.
  • the nitric oxide-releasing active pharmaceutical ingredient may comprise, consist essentially of, or consist of a co-condensed siloxane network comprising a diazeniumdiolate (e.g., aN- diazeniumdiolate) .
  • the nitric oxide donor may be formed from an
  • the co-condensed siloxane network may be synthesized from the condensation of a silane mixture that includes an alkoxysilane and the aminoalkoxysilane to form a nitric oxide donor modified co-condensed siloxane network.
  • the "pre-charging method” means that aminoalkoxysilane is“pretreated” or “precharged” with nitric oxide prior to the co-condensation with alkoxysilane.
  • the precharging nitric oxide may be accomplished by chemical methods.
  • the“pre-charging” method may be used to create co-condensed siloxane networks and materials more densely functionalized with NO-donors.
  • the nitric oxide-releasing active pharmaceutical ingredient may comprise, consist essentially of, or consist of a co-condensed silica network synthesized from the condensation of a silane mixture comprising an alkoxysilane and at least one aminoalkoxysilane having an amine substituted by a diazeniumdiolate (e.g., aN- diazeniumdiolate) .
  • the co-condensed siloxane network may be silica particles with a uniform size, a collection of silica particles with a variety of size, amorphous silica, a fumed silica, a nanocrystalline silica, ceramic silica, colloidal silica, a silica coating, a silica film, organically modified silica, mesoporous silica, silica gel, bioactive glass, or any suitable form or state of silica.
  • the alkoxysilane is a tetraalkoxysilane having the formula Si(OR) 4 , wherein R is an alkyl group.
  • R is an alkyl group.
  • the R groups may be the same or different.
  • the tetraalkoxysilane is selected as tetramethyl orthosilicate (TMOS) or tetraethyl orthosilicate (TEOS).
  • the aminoalkoxysilane has the formula: R"-(NH-R')n-Si(OR)3, wherein R is alkyl, R' is alkylene, branched alkylene, or aralkylene, n is 1 or 2, and R" is selected from the group consisting of alkyl, cycloalkyl, aryl, and alkylamine.
  • the aminoalkoxysilane may be selected from N-(6- aminohexyl)aminopropyltrimethoxysilane (AHAP3); N-(2-aminoethyl)-3- aminopropyltrimethoxysilane (AEAP3); (3-trimethoxysilylpropyl)di- ethylenetriamine (DET3); (aminoethylaminomethyl)phenethyltrimethoxysilane (AEMP3); [3- (methylamino)propyl]trimethoxysilane (MAP3); N-butylamino-propyltrimethoxysilane(n- B AP3 ) ; t-butylamino-propyltrimethoxy silane(t-B AP3 ) ;N - ethylaminoisobutyltrimethoxysilane(EAiB3); N-phenylamino-propy
  • the aminoalkoxysilane has the formula: NH [R'-Si(OR)3]2, wherein R is alkyl and R' is alkylene.
  • the aminoalkoxysilane may be selected from bis(3-triethoxysilylpropyl)amine, bis-[3-(trimethoxysilyl)propyl]amine and bis- [(3 -trimethoxysilyl)propyl] ethylenediamine.
  • the aminoalkoxysilane is precharged for NO-release and the amino group is substituted by a diazeniumdiolate.
  • the aminoalkoxysilane has the formula: R"-N(NONO-X+)- R'-Si(OR) 3 , wherein R is alkyl, R' is alkylene or aralkylene, R" is alkyl or alkylamine, and X + is a cation selected from the group consisting of Na + , K + and Li + .
  • composition of the siloxane network (e.g., amount or the chemical composition of the aminoalkoxysilane) and the nitric oxide charging conditions (e.g., the solvent and base) may be varied to optimize the amount and duration of nitric oxide release.
  • the composition of the silica particles may be modified to regulate the half-life of NO release from silica particles.
  • the amino group of aminoalkoxysilane is substituted with a diazeniumdiolate, and the aminoalkoxysilane having a formula of R"-N(NONO-X+)-R'- Si(OR) 3 , wherein: R is alkyl, R' is alkylene or aralkylene, R" is alkyl or alkylamine, and X + is a cation selected from the group consisting of Na + and K + .
  • the NO-releasing API may comprise a co-condensed silica network comprising diazeniumdiolated aminoethylaminopropyl trimethoxy silane (AEAP3) and tetra methyl orthosilicate (TMOS) and/or a co-condensed silica network comprising diazeniumdiolated aminoethylaminopropyl trimethoxy silane (AEAP3) and tetraethyl orthosilicate (TEOS).
  • AEAP3 diazeniumdiolated aminoethylaminopropyl trimethoxy silane
  • TMOS tetra methyl orthosilicate
  • the NO-releasing API may comprise a co- condensed silica network comprising diazeniumdiolated methylaminopropyl trimethoxysilane (MAP3) and tetra methyl orthosilicate (TMOS) and/or a co-condensed silica network comprising diazeniumdiolated methylaminopropyl trimethoxysilane (MAP3) and tetraethyl orthosilicate (TEOS).
  • MAP3 diazeniumdiolated methylaminopropyl trimethoxysilane
  • TMOS tetra methyl orthosilicate
  • the NO-releasing API may comprise a co- condensed silica network comprising diazeniumdiolated methylaminopropyl trimethoxysilane (MAP3), ethylaminoisobutylsiloxane (EAIB3), and tetraethyl orthosilicate (TEOS).
  • MAP3 diazeniumdiolated methylaminopropyl trimethoxysilane
  • EAIB3 ethylaminoisobutylsiloxane
  • TEOS tetraethyl orthosilicate
  • the NO-releasing API may comprise an amorphous polymer.
  • the particle size of a NO-releasing API may be in a range of about 20 nm to about 20 pm or any range therein, such as, but not limited to, about 100 nm to about 20 pm or about 1 pm to about 20 pm.
  • the particle size may be tailored to minimize or prevent toxicity and/or penetration through the epidermis (or compromised dermis) and into the blood vessels.
  • the particle size is distributed around a mean particle size of less than 20 pm, or any range therein, and the size may allow the particle to enter a follicle.
  • a NO-releasing API may have a particle size that is distributed around a mean particle size of about 20, 19, 18, 17, 16, 15, 14, 13, 12, 11, 10, 9, 8, 7, 6, 5, 4, 3, 2, or 1 pm.
  • aNO- releasing API may have a particle size that is distributed around a mean particle size of less than 10 pm, or any range therein, such as, but not limited to about 2 pm to about 10 pm or about 4 pm to about 8 pm.
  • the particle size may be distributed around a mean particle size of greater than 20 pm, or any range therein, and the size may prevent the particle from entering the follicle.
  • a mixture of particles with mean particle sizes distributed around two or more mean particle sizes may be provided.
  • a NO-releasing API may be micronized (e.g., ball and/or jet milled).
  • Methods for providing a desired particle size and/or micronization include, but are not limited to, those described in U.S. Patent Application Publication No. 2013/0310533, which is incorporated herein by reference in its entirety.
  • a NO-releasing API may have a low charge. In some embodiments, charge on a NO-releasing API may be controlled and/or modulated.
  • a NO-releasing API may be present in a composition that is in a chamber of a blister package (e.g., in a first chamber and/or a second chamber) of the present invention.
  • a NO- releasing API may be present in a composition of the present invention in an amount of about 0.1% to about 70% by weight of the composition.
  • a NO- releasing API may be present in a composition of the present invention in an amount of about 0.1% to about 10%, about 0.1% to about 20%, about 20% to about 30%, about 30% to about 40%, about 40% to about 50%, about 50% to about 60%, or about 60% to about 70% by weight of the composition.
  • a NO-releasing API may be present in a composition of the present invention in an amount of about 0.1%, 0.5%, 1%, 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, 11%, 12%, 13%, 14%, 15%, 16%, 17%, 18%, 19%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65% or 70% by weight of the composition.
  • a composition of the present invention may comprise a NO- releasing API and may store and/or release nitric oxide in an amount of about 0.01% to about 10% by weight of the composition, such as, but not limited to, about 0.15% to about 2%, about 0.15% to about 1%, about 0.3% to about 1.2%, about 0.15% to about 6%, about 1% to about 10%, about 3% to about 6%, or about 1% to about 5% by weight of the composition.
  • a composition of the present invention may comprise a nitric oxide- releasing active pharmaceutical and may store and/or release nitric oxide in an amount of about 0.01%, 0.05%, 0.1%, 0.15%, 0.3%, 0.6%, 0.9%, 1%, 1.25%, 1.5%, 1.75%, 2%, 2.25%, 2.5%, 2.75%, 3%, 3.25%, 3.5%, 3.75%, 4%, 4.25%, 4.5%, 4.75%, 5%, 5.25%, 5.5%, 5.75%, 6%, 6.25%, 6.5%, 6.75%, 7%, 7.25%, 7.5%, 7.75%, 8%, 8.25%, 8.5%, 8.75%, 9%, 9.25%, 9.5%, 9.75%, or 10% by weight of the composition.
  • the amount of nitric oxide released may be determined using real time in vitro release testing. In some embodiments, nitric oxide release may be determined using a chemiluminescent nitric oxide analyzer.
  • Exemplary NO-releasing APIs and/or compositions comprising an NO-releasing API include, but are not limited to, those described in U.S. Patent No. 8,282,967 and International Publication Nos. WO 2011/022652, WO
  • a composition of the present invention comprises a NO-releasing API, a viscosity increasing agent (e.g., hydroxypropyl cellulose), an organic solvent (e.g., an alcohol such as, for example, ethanol and/or isopropyl alcohol), a humectant (e.g., hexylene glycol), and a water repelling agent (e.g., a silicone such as, for example, cyclomethicone).
  • the alcohol is ethanol.
  • the alcohol is isopropyl alcohol.
  • a composition comprising a NO-releasing API may be in the form of a liquid or semi-solid.
  • a blister package of the present invention may comprise an aqueous composition that may be in the form of a liquid or semi-solid.
  • the blister package comprises a hydrogel in a chamber of a blister package (e.g., in a first chamber and/or a second chamber) of the present invention.
  • exemplary hydrogels include, but are not limited to, those described in International Publication Nos. WO 2014/134502, WO 2015/021382, WO 2016/022170, WO 2016/007834, WO 2016/160089, WO 2016/010988, WO
  • a blister package of the present invention may provide a desired shelf life for a NO- releasing API and/or a composition of the present invention (e.g., a hydrogel and/or NO- releasing composition).
  • shelf life refers to the length of time a NO-releasing API and/or a composition of the present invention remains effective for its intended purpose and/or remains suitable for administration to a subject.
  • shelf life refers to the length of time the NO-releasing API and/or composition maintains the ability to release a therapeutically effective amount of a therapeutic agent, such as, but not limited to, nitric oxide, in an unopened package stored under recommended storage conditions.
  • the shelf life may, for example, be evidenced by the "use by” or “best if used by” date for the NO-releasing API and/or composition, the manufacturer’s expiration date of the NO-releasing API and/or composition and/or the actual NO-releasing API and/or composition characteristics after the specified period of time.
  • shelf life should be construed as including both an "actual” shelf life of the NO- releasing API and/or composition and a “predicted” shelf life of the NO-releasing API and/or composition unless stated otherwise.
  • the rate of release of nitric oxide for a NO-releasing API and/or composition under packaged and/or stored conditions may be different (i. e. , faster or slower) than the rate of release of nitric oxide when the NO-releasing API and/or composition is in use ( e.g ., administered to a subject or in an opened package).
  • the rate of release of nitric oxide from a NO-releasing API and/or composition of the present invention may be more rapid when the NO-releasing API and/or composition is in use compared to the rate of release of nitric oxide when a NO-releasing API and/or composition was packaged and/or stored.
  • shelf life may be determined by extrapolation of data at accelerated temperatures, such as, for example, by using the Arrhenius equation. In some embodiments, shelf life may be determined using linear regression analysis, such as, for example, when the kinetics of API degradation is not temperature dependent. In some embodiments, shelf life may be evaluated and/or determined by measuring the API (e.g., NO- releasing API), such as, for example, using high pressure liquid chromatography.
  • API e.g., NO- releasing API
  • the shelf life of the NO-releasing API and/or composition is the time that the NO-releasing API and/or composition maintains the ability to release at least 50% of the initial amount of nitric oxide that the NO-releasing API and/or composition may release when packaged. In some embodiments, the shelf life of the NO-releasing API and/or composition is the time that the NO-releasing API and/or composition maintains the ability to release about 60%, at least 70%, at least 80%, at least 90%, at least 95%, or at least 98% of the initial amount of nitric oxide that the NO-releasing API and/or composition may release when packaged.
  • the shelf life of the NO-releasing API and/or composition is the time that the NO-releasing API and/or composition maintains the ability to release a therapeutically effective amount of nitric oxide over a desired period of time.
  • the recommended storage conditions are room temperature.
  • the recommended storage conditions are refrigerated storage conditions.
  • the refrigerated storage conditions are about l°C to about l2°C.
  • a packaged NO-releasing API and/or composition may have a shelf life of at least about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, or 24 months or more, or any range and/or individual value therein.
  • a NO-releasing API and/or composition of the present invention may have a shelf life of at least about 2 years at 25°C/60% room humidity (RH) for 2 years and/or at least about 6 Months at 40°C/75%RH.
  • RH room humidity
  • Some embodiments may provide a packaged NO-releasing API and/or composition of the present invention that has a useful life of about 1, 2, 3, 4, 5, 6, or 7 days after opening the NO-releasing API and/or composition (e.g., after opening the blister package).
  • the useful life is at least about 30 days, at least about 60 days, at least about 90 days, or at least about 1, 2, 3, 4, 5, 6, 8, 9, 12, 24 or 36 months.
  • the packaged NO-releasing API and/or composition may have a useful life of from at least about 60 days to at least about 730 days.
  • useful life refers to the length of time that the NO-releasing API and/or composition maintains the ability to release a therapeutically effective amount of nitric oxide from an opened packaged when applied as recommended and when stored under recommended storage conditions.
  • the useful life may, for example, be evidenced by the manufacturer’s recommended time to dispose of the NO- releasing API and/or composition after opening or measurements of the vaginal suppositories characteristics after opening.
  • a blister package of the present invention provides a single dose of a NO-releasing API and/or NO-releasing composition.
  • the useful life for a blister package of the present invention may be a single use or 1 day.
  • the term "useful life” as used herein should be construed as including an "actual” useful life of the NO-releasing API and/or composition or a “predicted” useful life of the NO-releasing API and/or composition unless stated otherwise.
  • the useful life of the NO-releasing API and/or composition is the time that the NO-releasing API and/or composition maintains the ability to release at least 50% of the initial amount of nitric oxide that the NO-releasing API and/or composition may release when the NO-releasing API and/or composition is opened.
  • the useful life of the NO-releasing API and/or composition is the time that the NO-releasing API and/or composition maintains the ability to release at least 70%, at least 80%, at least 90%, at least 95%, or at least 98% of the initial amount nitric oxide that the NO-releasing API and/or composition may release when the NO-releasing API and/or composition is opened.
  • the recommended storage conditions after opening are room temperature.
  • the recommended storage conditions after opening are refrigerated conditions.
  • there are no recommended storage conditions after opening e.g., when the instructions are for disposal after one use.

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Abstract

Emballage coque à double compartiment comprenant : une première unité d'emballage comprenant : un premier compartiment de coque conçu pour contenir un premier composé et/ou une première composition ; et un premier orifice de sortie au niveau d'une extrémité de la première unité d'emballage ; une seconde unité d'emballage comprenant : un second compartiment de coque conçu pour contenir un second composé et/ou une seconde composition ; et un second orifice de sortie au niveau d'une extrémité de la seconde unité d'emballage ; un élément d'étanchéité fermant hermétiquement les premier et second orifices de sortie de telle sorte que, lorsque l'élément d'étanchéité est ouvert, le premier composé et/ou la première composition sont expulsés du premier compartiment de coque par l'intermédiaire du premier orifice de sortie et le second composé et/ou la seconde composition sont expulsés du second compartiment de coque par l'intermédiaire du second orifice de sortie suite à la compression des premier et second compartiments de coque ; et une paroi de séparation entre les première et seconde unités d'emballage, la paroi de séparation étant positionnée de façon à former une barrière étanche entre les premier et second compartiments de coque de telle sorte que les premier et second composés et/ou les première et seconde compositions sont mis en contact uniquement après leur sortie hors des premier et second orifices de sortie respectivement.
PCT/US2019/034582 2018-05-30 2019-05-30 Emballage coque à double compartiment et procédés associés WO2019232166A1 (fr)

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Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US11077194B2 (en) 2012-03-14 2021-08-03 Novan, Inc. Nitric oxide releasing pharmaceutical compositions
US11285171B2 (en) 2018-03-01 2022-03-29 Novan, Inc. Nitric oxide releasing suppositories and methods of use thereof
US11534382B2 (en) 2017-06-19 2022-12-27 Novan, Inc. Topical compositions and methods of using the same

Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20020122685A1 (en) * 2000-12-13 2002-09-05 3M Innovative Properties Company Package and dispensing actuator for multiple-component compositions
US8806842B1 (en) * 2011-06-20 2014-08-19 The Packaging Consultants Group Disposable multiple compartment mixing and dispensing container

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20020122685A1 (en) * 2000-12-13 2002-09-05 3M Innovative Properties Company Package and dispensing actuator for multiple-component compositions
US8806842B1 (en) * 2011-06-20 2014-08-19 The Packaging Consultants Group Disposable multiple compartment mixing and dispensing container

Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US11077194B2 (en) 2012-03-14 2021-08-03 Novan, Inc. Nitric oxide releasing pharmaceutical compositions
US11534382B2 (en) 2017-06-19 2022-12-27 Novan, Inc. Topical compositions and methods of using the same
US11285171B2 (en) 2018-03-01 2022-03-29 Novan, Inc. Nitric oxide releasing suppositories and methods of use thereof

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