WO2012075375A1 - Administration d'hormones parathyroïdiennes par des systèmes de micro-injection - Google Patents

Administration d'hormones parathyroïdiennes par des systèmes de micro-injection Download PDF

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Publication number
WO2012075375A1
WO2012075375A1 PCT/US2011/063034 US2011063034W WO2012075375A1 WO 2012075375 A1 WO2012075375 A1 WO 2012075375A1 US 2011063034 W US2011063034 W US 2011063034W WO 2012075375 A1 WO2012075375 A1 WO 2012075375A1
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WIPO (PCT)
Prior art keywords
parathyroid hormone
formulation
hormone formulation
teriparatide
subject
Prior art date
Application number
PCT/US2011/063034
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English (en)
Inventor
Anthony P. Deasey
Patrick Frankham
Wolfgang Renz
Thomas Lang
Original Assignee
Lanco Biosciences, Inc.
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Application filed by Lanco Biosciences, Inc. filed Critical Lanco Biosciences, Inc.
Publication of WO2012075375A1 publication Critical patent/WO2012075375A1/fr

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Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61M—DEVICES FOR INTRODUCING MEDIA INTO, OR ONTO, THE BODY; DEVICES FOR TRANSDUCING BODY MEDIA OR FOR TAKING MEDIA FROM THE BODY; DEVICES FOR PRODUCING OR ENDING SLEEP OR STUPOR
    • A61M37/00—Other apparatus for introducing media into the body; Percutany, i.e. introducing medicines into the body by diffusion through the skin
    • A61M37/0015—Other apparatus for introducing media into the body; Percutany, i.e. introducing medicines into the body by diffusion through the skin by using microneedles
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • A61K38/17—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
    • A61K38/22—Hormones
    • A61K38/29—Parathyroid hormone, i.e. parathormone; Parathyroid hormone-related peptides
    • 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
    • A61K9/0019—Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner
    • A61K9/0021—Intradermal administration, e.g. through microneedle arrays, needleless injectors
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61M—DEVICES FOR INTRODUCING MEDIA INTO, OR ONTO, THE BODY; DEVICES FOR TRANSDUCING BODY MEDIA OR FOR TAKING MEDIA FROM THE BODY; DEVICES FOR PRODUCING OR ENDING SLEEP OR STUPOR
    • A61M37/00—Other apparatus for introducing media into the body; Percutany, i.e. introducing medicines into the body by diffusion through the skin
    • A61M37/0015—Other apparatus for introducing media into the body; Percutany, i.e. introducing medicines into the body by diffusion through the skin by using microneedles
    • A61M2037/0023—Drug applicators using microneedles
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61M—DEVICES FOR INTRODUCING MEDIA INTO, OR ONTO, THE BODY; DEVICES FOR TRANSDUCING BODY MEDIA OR FOR TAKING MEDIA FROM THE BODY; DEVICES FOR PRODUCING OR ENDING SLEEP OR STUPOR
    • A61M37/00—Other apparatus for introducing media into the body; Percutany, i.e. introducing medicines into the body by diffusion through the skin
    • A61M37/0015—Other apparatus for introducing media into the body; Percutany, i.e. introducing medicines into the body by diffusion through the skin by using microneedles
    • A61M2037/003—Other apparatus for introducing media into the body; Percutany, i.e. introducing medicines into the body by diffusion through the skin by using microneedles having a lumen
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61M—DEVICES FOR INTRODUCING MEDIA INTO, OR ONTO, THE BODY; DEVICES FOR TRANSDUCING BODY MEDIA OR FOR TAKING MEDIA FROM THE BODY; DEVICES FOR PRODUCING OR ENDING SLEEP OR STUPOR
    • A61M37/00—Other apparatus for introducing media into the body; Percutany, i.e. introducing medicines into the body by diffusion through the skin
    • A61M37/0015—Other apparatus for introducing media into the body; Percutany, i.e. introducing medicines into the body by diffusion through the skin by using microneedles
    • A61M2037/0061—Methods for using microneedles

Definitions

  • Osteoporosis is a disease of the bone that can lead to an increased risk of bone fracture.
  • the bone mineral density is reduced, bone microarchitecture is disrupted, and the amount and variety of proteins in bone is altered.
  • osteoporosis The underlying mechanism in all cases of osteoporosis is an imbalance between bone resorption and bone formation.
  • bone multicellular units B Us. See, e.g. , KM. Frost and C.C. Thomas, "Bone Remodeling Dynamics", Springfield, IL ( 1963). Bone is resorbed by osteoclast cells (which derive from the bone marrow), after which new bone is deposited by osteoblast cells.
  • osteoporosis Mechanisms by which osteoporosis develops include inadequate peak bone mass (the skeleton develops insufficient mass and strength during growth), excessive bone resorption and inadequate formation of new bone during remodeling. Interplay of these mechanisms can underlie the development of fragile bone tissue. See L. Raisz, "Pathogenesis of osteoporosis: concepts, conflicts, and prospects," J. Clin. Invest. 1 15 (12), 33 18-25 (2005).
  • Parathyroid hormone (PTH), parathormone or parathyrin, is secreted by the parathyroid glands as a polypeptide containing 84 amino acids. It acts to increase the concentration of calcium (Ca 2+ ) in the blood, whereas calcitonin (a hormone produced by the parafollicular cells (C cells) of the thyroid gland) acts to decrease calcium concentration.
  • PTH acts to increase the concentration of calcium in the blood by acting upon parathyroid hormone receptor in three parts of the body: the half-life of PTH half-life is about 4 minutes. It has a molecular mass of 9,400 daltons ("Da").
  • Teriparatide (trade name Forteo®) is a recombinant form of parathyroid hormone that can be used in the treatment of some forms of osteoporosis.
  • Teriparatide is a portion of human PTH, amino acid sequence 1 through 34, of the complete molecule (containing 84 amino acids).
  • PTH can increase serum calcium by increasing bone resorption. While chronically elevated PTH can deplete bone stores, intermittent exposure to PTH can activate osteoblasts more than osteoclasts. A once-daily injection of teriparatide can have a net effect of stimulating new bone formation, leading to increased bone mineral density.
  • An aspect of the invention provides a system comprising a microinjection device and a parathyroid hormone formulation, the microinjection device comprising a microneedle array having one or more hollow tips for delivering a parathyroid hormone formulation; a housing having the microneedle array and a skin-contacting face defining an opening that can be positioned at or adjacent to a target site; and a driver for moving the microneedle array toward the target site.
  • the parathyroid hormone formulation includes teriparatide or a pharmaceutically acceptable derivative of teriparatide.
  • the parathyroid hormone formulation has a pH between about 2.0 and 7.0.
  • the parathyroid hormone formulation has a pH between about 2.5 and 6.0.
  • the parathyroid hormone formulation has a pH between about 3.0 and 5.5. In another embodiment, the parathyroid hormone formulation has a pH between about 3.5 and 4.5. In another embodiment, the parathyroid hormone formulation has a parathyroid hormone concentration between about 0.01 mg in 1 mL and 0.50 mg in 1 mL of the parathyroid hormone formulation.
  • Another aspect of the invention provides a method for delivering a parathyroid hormone to a subject, comprising providing a microinjection device comprising a microneedle array and a parathyroid hormone-containing formulation; and delivering the parathyroid hormone-containing formulation to the subject with the aid of the microinjection device.
  • the parathyroid hormone-containing formulation includes teriparatide or a pharmaceutically acceptable derivative of teriparatide.
  • the parathyroid hormone-containing formulation has a pH between about 2.0 and 7.0.
  • the parathyroid hormone-containing formulation has a pH between about 2.5 and 6.0.
  • the parathyroid hormone-containing formulation has a pH between about 3.0 and 5.5.
  • the parathyroid hormone-containing formulation has a pH between about 3.5 and 4.5. In another embodiment, the parathyroid hormone-containing formulation has a parathyroid hormone concentration between about 0.01 mg in 1 mL and 0.50 mg in 1 mL of the parathyroid hormone-containing formulation.
  • Another aspect of the invention provides a method for treating osteoporosis, comprising using a microinjection device comprising a microneedle array and a parathyroid hormone formulation to administer to a subject the parathyroid hormone formulation.
  • the parathyroid hormone formulation is administered to the subject on a daily basis.
  • the parathyroid hormone formulation is administered to the subject at a concentration of between about 0.01 mg in 1 mL and 0.50 mg in 1 mL of the parathyroid hormone formulation.
  • the parathyroid hormone formulation is delivered to the subject in a length of time between about 0.1 seconds and 10 minutes.
  • the parathyroid hormone formulation is delivered to the subject in a length of time between about 30 seconds and 8 minutes.
  • the parathyroid hormone formulation is delivered transdermal ly. In another embodiment, the parathyroid hormone formulation is delivered intradermally. In another embodiment, the parathyroid hormone formulation has a pH between about 2.0 and 7.0. In another embodiment, the parathyroid hormone formulation has a pH between about 2.5 and 6.0. In another embodiment, the parathyroid hormone formulation has a pH between about 3.0 and 5.5. In another embodiment, the parathyroid hormone formulation has a pH between about 3.5 and 4.5. In another embodiment, the parathyroid hormone formulation includes teriparatide or a pharmaceutically acceptable derivative of teriparatide.
  • Another aspect of the invention provides a system comprising an application device and a parathyroid hormone formulation, the application device comprising a housing having a skin-contacting face defining an opening that can be positioned at a target site, the housing having a microneedle array; and an impactor for impacting the microneedle array and accelerating the microneedle array toward the target site, the microneedle array configured to deliver the parathyroid hormone formulation to the subject.
  • the impactor is configured to move along a substantially arcuate path to move the microneedle array toward the target site.
  • the parathyroid hormone formulation comprises teriparatide or a pharmaceutically acceptable derivative of teriparatide.
  • the parathyroid hormone formulation has a pH between about 2.0 and 7.0. In another embodiment, the parathyroid hormone formulation has a pH between about 2.5 and 6.0. In another embodiment, the parathyroid hormone formulation has a pH between about 3.0 and 5.5. In another embodiment, the parathyroid hormone formulation has a pH between about 3.5 and 4.5. In another embodiment, the parathyroid hormone formulation has a parathyroid hormone concentration between about 0.01 mg in 1 mL and 0.50 mg in 1 mL of the parathyroid hormone formulation.
  • Another aspect of the invention provides a microinjection device having a parathyroid hormone formulation.
  • the microinjection device is configured to deliver said parathyroid hormone formulation to a subject.
  • the parathyroid hormone formulation comprises teriparatide or a pharmaceutically acceptable derivative of teriparatide.
  • the parathyroid hormone formulation has a pH between about 2.0 and 7.0.
  • the parathyroid hormone formulation has a pH between about 2.5 and 6.0.
  • the parathyroid hormone formulation has a pH between about 3.0 and 5.5.
  • the parathyroid hormone formulation has a pH between about 3.5 and 4.5.
  • the parathyroid hormone formulation has a parathyroid hormone concentration between about 0.01 mg in 1 mL and 0.50 mg in 1 mL of the parathyroid hormone formulation.
  • a microinjection device for subcutaneous, transdermal or intradermal delivery of a parathyroid hormone formulation, comprising a microneedle array for delivering a parathyroid hormone formulation to a subject; and one or more chambers in fluid communication with the microneedle array, the one or more chambers having a parathyroid hormone formulation.
  • the microneedle array comprises microneedles having hollow tips.
  • the parathyroid hormone formulation comprises teriparatide or a pharmaceutically acceptable derivative of teriparatide.
  • the parathyroid hormone formulation has a pH between about 2.0 and 7.0.
  • the parathyroid hormone formulation has a pH between about 2.5 and 6.0.
  • the parathyroid hormone formulation has a pH between about 3.0 and 5.5. In another embodiment, the parathyroid hormone formulation has a pH between about 3.5 and 4.5. In another embodiment, the parathyroid hormone formulation has a parathyroid hormone concentration between about 0.01 mg in 1 mL and 0.50 mg in 1 mL of the parathyroid hormone formulation.
  • Another aspect of the invention provides a system for the administration of a parathyroid hormone to a subject, comprising a parathyroid hormone formulation; and a drug delivery device configured to deliver the parathyroid hormone formulation to said subject by microneedle injection, hydration, ablation of the subject's skin, follicular delivery, ultrasound, iontophoresis or electroporation.
  • the parathyroid hormone formulation comprises teriparatide or a pharmaceutically acceptable derivative of teriparatide.
  • the parathyroid hormone formulation has a pH between about 2.0 and 7.0.
  • the parathyroid hormone formulation has a pH between about 2.5 and 6.0.
  • the parathyroid hormone formulation has a pH between about 3.0 and 5.5.
  • the parathyroid hormone formulation has a pH between about 3.5 and 4.5. In another embodiment, the parathyroid hormone formulation has a parathyroid hormone concentration between about 0.01 mg in 1 mL and 0.50 mg in 1 mL of the parathyroid hormone formulation.
  • Another aspect of the invention provides a system for applying a microneedle array to a subject's skin, comprising a parathyroid hormone formulation; a housing having a skin- contacting face defining an opening that can be positioned at a target site, the housing having a microneedle array; and an impactor for impacting the microneedle array and accelerating the microneedle array toward the target site, the microneedle array configured to deliver a parathyroid hormone formulation to the subject.
  • the impactor is configured to move along a substantially arcuate path to move the microneedle array toward the target site.
  • the parathyroid hormone formulation comprises teriparatide or a pharmaceutically acceptable derivative of teriparatide.
  • the parathyroid hormone formulation has a pH between about 2.0 and 7.0. In another embodiment, the parathyroid hormone formulation has a pH between about 2.5 and 6.0. In another embodiment, the parathyroid hormone formulation has a pH between about 3.0 and 5.5. In another embodiment, the parathyroid hormone formulation has a pH between about 3.5 and 4.5. In another embodiment, the parathyroid hormone formulation has a parathyroid hormone concentration between about 0.01 mg in 1 mL and 0.50 mg in 1 mL of the parathyroid hormone formulation.
  • Another aspect of the invention provides a system for subcutaneous, transdermal or intradermal delivery of a parathyroid hormone to a subject, comprising a parathyroid hormone formulation; a microneedle array for delivering the parathyroid hormone formulation to a subject; and one or more chambers in fluid communication with the microneedle array, the one or more chambers configured to hold the parathyroid hormone formulation.
  • the parathyroid hormone formulation comprises teriparatide or a pharmaceutically acceptable derivative of teriparatide.
  • the parathyroid hormone formulation has a parathyroid hormone concentration between about 0.01 mg in 1 mL and 0.50 mg in 1 mL.
  • the parathyroid hormone formulation has a parathyroid hormone concentration between about 0.10 mg in 1 mL and 0.30 mg in 1 mL. In another embodiment, the parathyroid hormone formulation has a pH between about 2.0 and 7.0. In another embodiment, the parathyroid hormone formulation has a pH between about 2.5 and 6.0. In another embodiment, the parathyroid hormone formulation has a pH between about 3.0 and 5.5. In another embodiment, the parathyroid hormone formulation has a pH between about 3.5 and 4.5.
  • Another aspect of the invention provides a system for delivering a parathyroid hormone formulation to a subject, comprising a parathyroid hormone formulation; a microneedle array having one or more hollow tips for delivering the parathyroid hormone formulation; a housing having the microneedle array and a skin-contacting face defining an opening that can be positioned at or adjacent to a target site; and a driver for moving the microneedle array toward the target site.
  • the parathyroid hormone formulation comprises teriparatide or a pharmaceutically acceptable derivative of teriparatide.
  • the parathyroid hormone formulation has a parathyroid hormone concentration between about 0.01 mg in 1 mL and 0.50 mg in 1 mL.
  • the parathyroid hormone formulation has a parathyroid hormone concentration between about 0.10 mg in 1 mL and 0.30 mg in 1 mL. In another embodiment, the parathyroid hormone formulation has a pH between about 2.0 and 7.0. In another embodiment, the parathyroid hormone formulation has a pH between about 2.5 and 6.0. In another embodiment, the parathyroid hormone formulation has a pH between about 3.0 and 5.5. In another embodiment, the parathyroid hormone formulation has a pH between about 3.5 and 4.5.
  • the parathyroid hormone formulation comprises teriparatide or a pharmaceutically acceptable derivative of teriparatide.
  • the parathyroid hormone formulation has a pH between about 2.0 and 7.0.
  • the parathyroid hormone formulation has a pH between about 2.5 and 6.0.
  • the parathyroid hormone formulation has a pH between about 3.0 and 5.5.
  • the parathyroid hormone formulation has a pH between about 3.5 and 4.5.
  • the parathyroid hormone formulation has a parathyroid hormone concentration between about 0.01 mg ⁇ in 1 mL and 0.50 mg in 1 mL of the parathyroid hormone formulation.
  • Another aspect of the invention provides a method for subcutaneous, transdermal or intradermal delivery of a parathyroid hormone formulation to a subject, comprising
  • the parathyroid hormone formulation comprises teriparatide or a pharmaceutically acceptable derivative of teriparatide.
  • the parathyroid hormone formulation has a parathyroid hormone concentration between about 0.01 mg in 1 mL and 0.50 mg in 1 mL. In another embodiment, the parathyroid hormone formulation has a parathyroid hormone concentration between about 0.10 mg in 1 mL and 0.30 mg in 1 mL.
  • the parathyroid hormone formulation has a pH between about 2.0 and 7.0. In another embodiment, the parathyroid hormone formulation has a pH between about 2.5 and 6.0. In another embodiment, the parathyroid hormone formulation has a pH between about 3.0 and 5.5. In another embodiment, the parathyroid hormone formulation has a pH between about 3.5 and 4.5. [0019] In another aspect, a method for subcutaneous, transdermal or intradermal delivery of a parathyroid hormone formulation to a subject comprises administering the parathyroid hormone formulation to the subject by microneedle injection, hydration, ablation of the subject's skin, follicular delivery, ultrasound, iontophoresis or electroporation.
  • the parathyroid hormone formulation is administered to the subject by microneedle injection. In another embodiment, the parathyroid hormone formulation is administered to the subject by iontophoresis. In another embodiment, the parathyroid hormone formulation comprises teriparatide or a pharmaceutically acceptable derivative of teriparatide. In another embodiment, the parathyroid hormone formulation has a parathyroid hormone concentration between about 0.01 mg in 1 mL and 0.50 mg in 1 mL. In another embodiment, the parathyroid hormone formulation has a parathyroid hormone concentration between about 0.10 mg in 1 mL and 0.30 mg in 1 mL. In another embodiment, the parathyroid hormone formulation has a pH between about 2.0 and 7.0.
  • the parathyroid hormone formulation has a pH between about 2.5 and 6.0. In another embodiment, the parathyroid hormone formulation has a pH between about 3.0 and 5.5. In another embodiment, the parathyroid hormone formulation has a pH between about 3.5 and 4.5.
  • Another aspect of the invention provides a method for treating osteoporosis, comprising using a microinjection device comprising a microneedle array and a parathyroid hormone formulation to administer to a subject the parathyroid hormone formulation.
  • the parathyroid hormone formulation comprises teriparatide or a pharmaceutically acceptable derivative of teriparatide.
  • the parathyroid hormone formulation has a parathyroid hormone concentration between about 0.01 mg in 1 mL and 0.50 mg in 1 mL.
  • the parathyroid hormone formulation has a parathyroid hormone concentration between about 0.10 mg in 1 mL and 0.30 mg in 1 mL.
  • the parathyroid hormone formulation has a pH between about 2.0 and 7.0.
  • the parathyroid hormone formulation has a pH between about 2.5 and 6.0. In another embodiment, the parathyroid hormone formulation has a pH between about 3.0 and 5.5. In another embodiment, the parathyroid hormone formulation has a pH between about 3.5 and 4.5.
  • Another aspect of the invention provides a system for the administration of a parathyroid hormone to a subject, comprising a parathyroid hormone formulation; and a microinjection device configured to subcutaneously, intradermally or transdermal ⁇ deliver the parathyroid hormone formulation to the subject.
  • the parathyroid hormone formulation comprises teriparatide or a pharmaceutically acceptable derivative of teriparatide.
  • the parathyroid hormone formulation has a parathyroid hormone concentration between about 0.01 mg in 1 mL and 0.50 mg in 1 mL.
  • the parathyroid hormone formulation has a parathyroid hormone concentration between about 0. 10 mg in 1 mL and 0.30 mg in 1 mL.
  • the parathyroid hormone formulation has a pH between about 2.0 and 7.0. In another embodiment, the parathyroid hormone formulation has a pH between about 2.5 and 6.0. In another embodiment, the parathyroid hormone formulation has a pH between about 3.0 and 5.5. In another embodiment, the parathyroid hormone formulation has a pH between about 3.5 and 4.5.
  • Another aspect of the invention provides a system for delivering a parathyroid hormone formulation to a subject, comprising a parathyroid hormone formulation having an excipient; and a microinjection device configured to deliver the parathyroid hormone formulation.
  • the microinjection device is configured to deliver at least about 0.1 mg, or 0.2 mg, or 0.25 mg of parathyroid hormone in 1 mL of the parathyroid hormone formulation.
  • the parathyroid hormone formulation comprises teriparatide or a pharmaceutically acceptable derivative of teriparatide.
  • the parathyroid hormone formulation has a parathyroid hormone concentration between about 0.01 mg in 1 mL and 0.50 mg in 1 mL.
  • the parathyroid hormone formulation has a parathyroid hormone concentration between about 0.10 mg in 1 mL and 0.30 mg in 1 mL. In another embodiment, the parathyroid hormone formulation has a pH between about 2.0 and 7.0. In another embodiment, the parathyroid hormone formulation has a pH between about 2.5 and 6.0. In another embodiment, the parathyroid hormone formulation has a pH between about 3.0 and 5.5. In another embodiment, the parathyroid hormone formulation has a pH between about 3.5 and 4.5. In another embodiment, the excipient includes one or more of glacial acetic acid, sodium acetate, mannitol, metacresol, hydrochloric acid, sodium hydroxide and water. In another embodiment, the excipient is a pharmaceutically acceptable excipient.
  • FIG. 1 A is a perspective view of a microinjection device having a microneedle assembly, in accordance with an embodiment of the invention
  • FIG. I B is a perspective side view of an array of microneedles, in accordance with an embodiment of the invention
  • FIG. 2 is a schematic cross-sectional side view of a microinjection device having an array of microneedles, in accordance with an embodiment of the invention
  • FIG. 3 is a schematic cross-sectional side view of a portion of the microinjection device of FIG. 2, in accordance with an embodiment of the invention
  • FIG. 4 is a schematic perspective side view of a microneedle device comprising a patch, in accordance with an embodiment of the invention.
  • FIG. 5A is a perspective side view of an array of microneedles, in accordance with an embodiment of the invention.
  • FIG. 5B is a cross-sectional side view of a microneedle in the array of FIG. 5 A, in accordance with an embodiment of the invention;
  • FIG. 6 is a schematic side view of a microneedle application device, in accordance with an embodiment of the invention.
  • FIG. 7 is a schematic cross sectional side view of the microneedle application device of FIG. 6, in accordance with an embodiment of the invention.
  • FIG. 8 is a schematic cross sectional side view of a collar of the microneedle application device of FIGs. 6 and 7, in accordance with an embodiment of the invention.
  • FIG. 9A is a schematic perspective view of an applicator device having peelable seals, in accordance with an embodiment of the invention.
  • FIG. 9B is a schematic perspective view of the applicator of FIG. 9 A with the peelable seals removed, in accordance with an embodiment of the invention.
  • FIG. 9C is a schematic cross-sectional view of the applicator of FIGs. 9A and 9B in a loaded position, in accordance with an embodiment of the invention.
  • FIG. 9D is a schematic cross-sectional view of the applicator of FIGs. 9A and 9B in a partially released position, in accordance with an embodiment of the invention.
  • FIG. 9E is a schematic cross-sectional view of the applicator of FIGs.
  • FIG. 9F is a schematic cross-sectional view of the applicator of FIGs. 9A and 9B being removed from a microneedle array that has been deployed onto a target surface, in accordance with an embodiment of the invention
  • FIG. 10 is a schematic cross-sectional side view of an applicator device, in accordance with an embodiment of the invention.
  • FIG. 1 1 is a schematic perspective view of a portion of the applicator device of FIG. 10, in accordance with an embodiment of the invention
  • FIG. 12 is a schematic perspective view of an applicator device having a patch, in accordance with an embodiment of the invention.
  • FIG. 13 is a schematic partial cross-sectional side view of a microneedle array cartridge mounted on an applicator device, in accordance with an embodiment of the invention.
  • parathyroid hormone can include any substance, compound or species that includes or overlaps with all or a portion of the chemical structure of sequence of human parathyroid hormone (h-PTH).
  • a parathyroid hormone can include polymeric materials having amino acid monomers (or subunits).
  • a parathyroid hormone can include recombinant parathyroid hormone.
  • a parathyroid hormone can include or overlap with all or a portion of h-PTH, which can include a sequence of eighty four amino acids.
  • a parathyroid hormone can include or overlap with thirty four amino acids of h-PTH.
  • a parathyroid hormone can include amino acid sequence 1 through 34 of h-PTH.
  • a parathyroid hormone can include teriparatide or a pharmaceutically acceptable derivative of teriparatide.
  • a parathyroid hormone can include other medically active or inactive species, compounds, or formulations.
  • a parathyroid hormone can be administered to a subject using a parathyroid hormone formulation (e.g., teriparatide formulation) having the parathyroid hormone (e.g., teriparatide).
  • the terms "transdermal” and "transdermal ly”, as used herein, can refer to transdermal drug delivery.
  • transdermal drug delivery can include delivering a drug or formulation to a subject across the subject's skin.
  • transdermal drug delivery can include delivering a drug or formulation to a subject across the subject's skin and into a blood vessel.
  • intradermal and “intradermally”, as used herein, can refer to intradermal drug delivery.
  • intradermal drug delivery can include delivering a drug or formulation to a subject in or into the subject's skin.
  • subcutaneous injection can refer to an injection that is administered as a bolus into the subcutis, i.e., the layer of skin directly below the dermis and epidermis (collectively referred to as the cutis).
  • An aspect of the invention provides parathyroid hormone compounds (also called parathyroid hormone compounds (also
  • parathyroid hormones herein) that can be used to treat osteoporosis.
  • parathyroid hormones include teriparatide or pharmaceutically acceptable derivatives of teriparatide.
  • an injection solution comprising a parathyroid hormone compound can be filled into primary packaging, such as an injection or microinjection apparatuses, as described below.
  • Primary packaging such as an injection or microinjection apparatuses, as described below.
  • Parathyroid hormone compounds and formulations of embodiments of the invention can be administered to one or more subjects with the aid of injection or microinjection apparatuses of embodiments of the invention.
  • a parathyroid hormone compound such as a teriparatide compound
  • a formulation that further comprises other compounds or agents, such as other pharmacological agents.
  • parathyroid hormone compounds including teriparatide
  • parathyroid hormone compounds are provided for use in the treatment of osteoporosis, osteopenia, osteomalacia, osteogenesis imperfecta, osteosarcoma or Paget's Disease.
  • Parathyroid hormones of embodiments of the invention can be prescribed for use with subjects who are at increased risks for osteosarcoma. This can include those with Paget's Disease of bone or unexplained elevations of serum alkaline phosphate, open epiphysis, or prior radiation therapy involving the skeleton.
  • Parathyroid hormones of embodiments of the invention can aid in treating osteoporosis by stimulating new bone formation.
  • parathyroid hormone compounds include compounds including or overlapping with a portion of the chemical structure or sequence of human parathyroid hormones (h-PTH).
  • a parathyroid hormone compound includes teriparatide, having the formula C181 H291N55O51 S2, and the following structure:
  • a parathyroid hormone can include or sequentially overlap with all or a portion of human parathyroid hormone.
  • a parathyroid hormone can include teriparatide having the following sequence of amino aci :
  • a parathyroid hormone can include teriparatide having recombinant human parathyroid hormone (1-34), [rhPTH(l-34)] (or "PTH( l-34)"), which can have an identical sequence to the 34 N-terminal amino acids (the biologically active region) of the 84-amino acid human parathyroid hormone.
  • a parathyroid hormone can include PTH(l -37), PTH(l -38) or PTH(1 -41).
  • a parathyroid hormone can include one or more parathyroid hormones provided by U.S. Patent No. 6,590,081 to Zhang (“Crystalline teriparatide”), which is entirely incorporated herein by reference.
  • a parathyroid hormone compound can have an average molecular weight between about 1 ,000 daltons and 40,000 daltons, or 2,000 daltons and 20,000 daltons, or 3,000 daltons and 10,000 daltons, or 3,500 daltons and 5,000 daltons, or 4,000 daltons and 4,500 daltons.
  • a parathyroid hormone compound in another embodiment, can have an average molecular weight less than about 1 ,000 daltons, or less than about 1 ,500 daltons, or less than about 2,000 daltons, or less than about 2,500 daltons, or less than about 3,000 daltons, or less than about 3,500 daltons, or less than about 4,000 daltons, or less than about 4,500 daltons, or less than about 5,000 daltons, or less than about 5,500 daltons, or less than about 6,000 daltons, or less than about 6,500 daltons, or less than about 7,000 daltons, or less than about 7,500 daltons, or less than about 8,000 daltons.
  • a parathyroid hormone compound can have an average molecular weight of about 41 17.7150 g mol and a monoisotropic molecular weight of about 41 15.1309 g/mol.
  • a parathyroid hormone can include a teriparatide compound having an average molecular weight between about 1 ,000 daltons and 40,000 daltons, or 2,000 daltons and 20,000 daltons, or 3,000 daltons and 10,000 daltons, or 3,500 daltons and 5,000 daltons, or 4,000 daltons and 4,500 daltons.
  • a parathyroid hormone can include a teriparatide compound having an average molecular weight less than about 1 ,000 daltons, or less than about 1 ,500 daltons, or less than about 2,000 daltons, or less than about 2,500 daltons, or less than about 3,000 daltons, or less than about 3,500 daltons, or less than about 4,000 daltons, or less than about 4,500 daltons, or less than about 5,000 daltons, or less than about 5,500 daltons, or less than about 6,000 daltons, or less than about 6,500 daltons, or less than about 7,000 daltons, or less than about 7,500 daltons, or less than about 8,000 daltons.
  • a parathyroid hormone compound can include teriparatide having an average molecular weight of about 41 17.7150 g/mol and a monoisotropic molecular weight of about 41 15.1309 g/mol.
  • a parathyroid hormone-containing formulation can be configured for one or more of subcutaneous delivery, intradermal delivery and transdermal delivery to a subject (e.g., patient).
  • a parathyroid hormone-containing formulation can be delivered to a subject with the aid of microinjection or microneedle devices, as described below.
  • parathyroid hormone compounds can have an average molecular weight of less than about 10,000 daltons ("Da"), or less than about 9,000 Da, or less than about 8,000 Da, or less than about 7,000 Da, or less than about 6,000 Da, or less than about 5,000 Da.
  • At least 50%, or at least 55%, or at least 60%, or at least 65%, or at least 70%, or at least 75%, or at least 80%, or at least 85%, or at least 90%, or at least 95% of all chains in the parathyroid hormone compound have a molecular weight less than about 5,000 Da.
  • a teriparatide compound can have an average molecular weight of less than about 10,000 daltons ("Da"), or less than about 9,000 Da, or less than about 8,000 Da, or less than about 7,000 Da, or less than about 6,000 Da, or less than about 5,000 Da. In another embodiment, at least 50%, or at least 55%, or at least 60%, or at least 65%, or at least 70%, or at least 75%, or at least 80%, or at least 85%, or at least 90%, or at least 95% of all chains in the teriparatide compound have a molecular weight less than about 5,000 Da.
  • a parathyroid hormone formulation can have a pH between about 2.0 and 7.0, or between about 2.5 and 6.0, or between about 3.0 and 5.5, or between about 3.5 and 4.5.
  • a parathyroid hormone formulation can have a pH of about 3.0, or 3.1 , or 3.2, or 3.3, or 3.4, or 3.5, or 3.6, or 3.7, or 3.8, or 3.9, or 4.0, or 4.1 , or 4.2, or 4.3, or 4.4, or 4.5, or 4.6, or 4.7, or 4.8, or 4.9, or 5.0.
  • a teriparatide-containing formulation can have a pH between about 2.0 and 7.0, or between about 2.5 and 6.0, or between about 3.0 and 5.5, or between about 3.5 and 4.5.
  • a teriparatide-containing formulation can have a pH of about 3.0, or 3.1 , or 3.2, or 3.3, or 3.4, or 3.5, or 3.6, or 3.7, or 3.8, or 3.9, or 4.0, or 4.1 , or 4.2, or 4.3, or 4.4, or 4.5, or 4.6, or 4.7, or 4.8, or 4.9, or 5.0.
  • a parathyroid hormone formulation can be lyophilized and formed into an aqueous solution suitable for subcutaneous, transdermal or intradermal injection.
  • a parathyroid hormone formulation can be formulated in any of the forms known in the art for preparing oral, nasal, buccal, or rectal formulations of peptide drugs.
  • Parathyroid hormone formulations such as teriparatide-containing formulations, can be combined or modified with various substances or components, including, without limitation, glidants, lubricants, antioxidants, antimicrobial agents, enzyme inhibitors, stabilizers (including pH stabilizers), retarding agents, preservatives and modifiers.
  • Parathyroid hormone formulations can include other pharmaceutically active or inactive ingredients. Such ingredients can be added to provide a desirable fluid property of the formulation, such as a desirable viscosity for administering the formulation using a microinjection device.
  • a parathyroid hormone formulation can include one or more excipients (inactive ingredients), such as dyes, flavors, binders, emollients, fillers, lubricants and preservatives.
  • a teriparatide-containing formulation can include one or more excipients, such as dyes, flavors, binders, emollients, fillers, lubricants and preservatives.
  • a parathyroid hormone formulation can include one or more of cornstarch, lactose, talc, magnesium stearate, sucrose, gelatin, calcium stearate, silicon dioxide, shellac and glaze.
  • a teriparatide-containing formulation can include one or more of cornstarch, lactose, talc, magnesium stearate, sucrose, gelatin, calcium stearate, silicon dioxide, shellac, glaze and microcrystalline cellulose.
  • a parathyroid hormone formulation can include one or more of lactose, microcrystalline cellulose, pregelatinized starch, hypromellose, magnesium stearate, titanium dioxide, triacetin, and iron oxide yellow.
  • a teriparatide formulation can include one or more of lactose, microcrystalline cellulose, pregelatinized starch, hypromellose, magnesium stearate, titanium dioxide, triacetin, and iron oxide yellow.
  • a parathyroid hormone formulation can include one or more of aspartame, gelatin, mannitol, methylparaben sodium and propylparaben sodium.
  • a parathyroid hormone formulation can include one or more of citric acid anhydrous, purified water, sodium benzoate, sodium citrate and sorbitol.
  • a teriparatide formulation can include one or more of aspartame, gelatin, mannitol, methylparaben sodium and propylparaben sodium.
  • a teriparatide formulation can include one or more of citric acid anhydrous, purified water, sodium benzoate, sodium citrate and sorbitol.
  • a parathyroid hormone or teriparatide-containing formulation can include one or more excipients selected from lactose, dextrose, sucrose, sorbitol, mannitol, starches, gum acacia, calcium phosphate, alginates, tragacanth, gelatin, calcium silicate, microcrystalline cellulose, polyvinylpyrrolidone, cellulose, sterile water, syrup and methyl cellulose.
  • a parathyroid hormone or teriparatide-containing formulation can also include one or more of lubricating agents (such as talc); magnesium stearate; mineral oil; wetting agents;
  • a parathyroid hormone formulation can include one or more of mannitol, edentate disodium dihydrate, trisodium citrate dihydrate and citric acid monohydrate.
  • a parathyroid hormone formulation can include one or more of citric acid anhydrous, hypromellose, lactose, magnesium stearate, cellulose (or microcrystalline cellulose), polyethylene glycol, polysorbate, sodium starch glycolate and titanium dioxide.
  • a parathyroid hormone formulation can include one or more of mannitol, phenol, acetate and water.
  • a parathyroid hormone formulation can include one or more of sodium
  • a teriparatide formulation can include one or more of mannitol, edentate disodium dihydrate, trisodium citrate dihydrate and citric acid monohydrate.
  • a teriparatide formulation can include one or more of citric acid anhydrous, hypromellose, lactose, magnesium stearate, cellulose (or microcrystalline cellulose), polyethylene glycol, polysorbate, sodium starch glycolate and titanium dioxide.
  • a teriparatide formulation can include one or more of mannitol, phenol, acetate and water.
  • a teriparatide formulation can include one or more of sodium metabisulfate, benzyl alcohol, sodium hydroxide and water.
  • a parathyroid hormone formulation can include, in addition to the parathyroid hormone, one or more of glacial acetic acid, sodium acetate, mannitol, metacresol, hydrochloric acid, sodium hydroxide and water.
  • a parathyroid hormone formulation can include, in addition to the parathyroid hormone, one or more of methanol, ethanol, iso-propanol, sodium citrate, hydrochloric acid, ethylene glycol, polyethylene glycol, glycine buffer, maleate, glycerol and ammonium sulfate.
  • a teriparatide-containing formulation can include, in addition to teriparatide or derivative of teriparatide, one or more of glacial acetic acid, sodium acetate, mannitol, metacresol, hydrochloric acid, sodium hydroxide and water.
  • a teriparatide-containing formulation can include, in addition to teriparatide or derivative of teriparatide, one or more of methanol, ethanol, iso-propanol, sodium citrate, hydrochloric acid, ethylene glycol, polyethylene glycol, glycine buffer, maleate, glycerol and ammonium sulfate.
  • a parathyroid hormone-containing formulation can include, in addition to parathyroid hormone, one or more of the following excipients: up to and including about 0.45 mg/1 mL acetic acid; up to and including about 0.20 mg/1 mL sodium acetate; up to and including about 46 mg 1 mL mannitol; up to an including about 4 mg/1 mL metacresol; hydrochloric acid; sodium hydroxide; and water.
  • a parathyroid hormone-containing formulation can include about 0.25 mg 1 mL parathyroid hormone, about 0.41 mg 1 mL acetic acid, about 0.
  • hydrochloric acid 1 mg/1 mL sodium acetate, about 45.4 mg/1 mL mannitol, about 3 mg/1 mL metacresol, hydrochloric acid, sodium hydroxide and water.
  • the quantity (or concentration) of each of hydrochloric acid and sodium hydroxide can be adjusted to yield a desirable pH (see above).
  • other acids and bases can be used in addition to, or in place of, hydrochloric acid and sodium hydroxide.
  • a teriparatide-containing formulation can include, in addition to teriparatide or derivative of teriparatide, one or more of the following excipients: up to and including about 0.45 mg/1 mL acetic acid; up to and including about 0.20 mg/1 mL sodium acetate; up to and including about 46 mg/1 mL mannitol; up to an including about 4 mg/1 mL metacresol; hydrochloric acid; sodium hydroxide; and water.
  • a teriparatide-containing formulation can include about 0.25 mg/1 mL teriparatide, about 0.41 mg/1 mL acetic acid, about 0.1 mg/1 mL sodium acetate, about 45.4 mg/1 mL mannitol, about 3 mg/1 mL metacresol, hydrochloric acid, sodium hydroxide and water.
  • the quantity (or concentration) of each of hydrochloric acid and sodium hydroxide can be adjusted to yield a desirable pH (see above).
  • other acids and bases can be used in addition to, or in place of, hydrochloric acid and sodium hydroxide.
  • a parathyroid horomone formulation in which each 1 mL includes about 0.25 mg of a parathyroid hormone (corrected for acetate, chloride, and water content), 0.41 mg glacial acetic acid, 0.1 mg sodium acetate (anhydrous), 45.4 mg mannitol, 3 mg metacresol, and water for injection.
  • a hydrochloric acid solution (10%) and/or a sodium hydroxide solution (10%) can be added to adjust the product pH to about 4.
  • a teriparatide formulation in which each 1 mL includes about 0.25 mg of teriparatide (corrected for acetate, chloride, and water content), 0.41 mg glacial acetic acid, 0.1 mg sodium acetate (anhydrous), 45.4 mg mannitol, 3 mg metacresol, and water for injection.
  • a hydrochloric acid solution (10%) and/or a sodium hydroxide solution (10%) can be added to adjust the product pH to about 4.
  • Parathyroid hormone formulations and teriparatide-containing formulations of embodiments of the invention can be combined or modified with other parathyroid hormone formulations and methods for forming parathyroid hormone formulations, such as, for example, compounds, formulations and/or methods provided by U.S. Patent Nos. 6,590,081 to Zhang (“Crystalline teriparatide”) and 7,144,861 to Chang et al. (“Stabilized teriparatide solutions”), and U.S. Patent Publication Nos. 2006/0189533 to Quay et al.
  • injection systems are provided for the delivery parathyroid hormone compounds of embodiments of the invention.
  • injection systems include microinjection systems.
  • Microinjection systems of embodiments of the invention can be configured for subcutaneous, transdermal or intradermal drug delivery.
  • Microinjection systems of embodiments of the invention can provide for improved delivery efficiency and absorption times in relation to traditional syringes.
  • Microinjection systems of embodiments of the invention can include one or more microneedles configured to deliver parathyroid hormone formulations or drug formulations, such as, for example, a formulation comprising teriparatide or derivatives of teriparatide.
  • a microinjection system can include a solid microneedle system having one or more solid microneedles, wherein at least a portion of the one or more solid microneedles are coated with a parathyroid hormone drug formulation, such as teriparatide.
  • a microinjection system can include a hollow microneedle system having one or more hollow microneedles. The one or more hollow microneedles can include fluid passages for directing a formulation having a parathyroid hormone drug formulation from a reservoir to a subject.
  • solid microneedle systems having one or more microneedles (or microneedle assemblies).
  • the solid microneedle systems can be configured for the delivery of parathyroid hormone drug formulations, up to and including about 0.001 milligrams ("mg"), or 0.002 mg, or 0.003 mg, or 0.004 mg, or 0.005 mg, or 0.006 mg, or 0.007 mg, or 0.008 mg, or 0.009 mg, or 0.010 mg, or 0.01 1 mg, or 0.012 mg, or 0.013 mg, or 0.014 mg, or 0.015 mg, or 0.016 mg, or 0.017 mg, or 0.018 mg, or 0.019 mg, or 0.020 mg, or 0.021 mg, or 0.022 mg, or 0.023 mg, or 0.024 mg, or 0.025 mg, or 0.026 mg, or 0.027 mg, or 0.028 mg, or 0.029 mg, or 0.030 mg, or 0.031 mg
  • the solid microneedle systems can be configured for the delivery of teriparatide drug formulations, up to and including about 0.001 mg, or 0.002 mg, or 0.003 mg, or 0.004 mg, or 0.005 mg, or 0.006 mg, or 0.007 mg, or 0.008 mg, or 0.009 mg, or 0.010 mg, or 0.01 1 mg, or 0.012 mg, or 0.013 mg, or 0.014 mg, or 0.015 mg, or 0.016 mg, or 0.017 mg, or 0.018 mg, or 0.019 mg, or 0.020 mg, or 0.021 mg, or 0.022 mg, or 0.023 mg, or 0.024 mg, or 0.025 mg, or 0.026 mg, or 0.027 mg, or 0.028 mg, or 0.029 mg, or 0.030 mg, or 0.031 mg, or 0.032 mg, or 0.033 mg, or 0.034 mg, or 0.035 mg, or 0.036 mg, or 0.037 mg, or
  • microinjection systems comprising microinjection devices having parathyroid hormone or parathyroid hormone-containing formulations are provided.
  • a microinjection system is provided for delivering to a subject the equivalent of at least about 0.01 mg, or 0.02 mg, or 0.03 mg, or 0.04 mg, or 0.05 mg, or 0.06 mg, or 0.07 mg, or 0.08 mg, or 0.09 mg, or 0.10 mg, or 0.1 1 mg, or 0.12 mg, or 0.13 mg, or 0.14 mg, or 0.15 mg, or 0.16 mg, or 0.17 mg, or 0.18 mg, or 0.19 mg, or 0.20 mg, or 0.21 mg, or 0.22 mg, or 0.23 mg, or 0.24 mg, or 0.25 mg, or 0.26 mg, or 0.27 mg, or 0.28 mg, or 0.29 mg, or 0.30 mg, or 0.31 mg, or 0.32 mg, or 0.33 mg, or 0.34 mg, or 0.35 mg, or 0.36 mg, or 0.37 mg, or 0.38 mg, or 0.39 mg
  • a microinjection system for delivering to a subject the equivalent of at least about 0.01 mg, or 0.02 mg, or 0.03 mg, or 0.04 mg, or 0.05 mg, or 0.06 mg, or 0.07 mg, or 0.08 mg, or 0.09 mg, or 0.10 mg, or 0.1 1 mg, or 0.12 mg, or 0.13 mg, or 0.14 mg, or 0.15 mg, or 0.16 mg, or 0.17 mg, or 0.18 mg, or 0.19 mg, or 0.20 mg, or 0.21 mg, or 0.22 mg, or 0.23 mg, or 0.24 mg, or 0.25 mg, or 0.26 mg, or 0.27 mg, or 0.28 mg, or 0.29 mg, or 0.30 mg, or 0.31 mg, or 0.32 mg, or 0.33 mg, or 0.34 mg, or 0.35 mg, or 0.36 mg, or 0.37 mg, or 0.38 mg, or 0.39 mg, or 0.40 mg, or 0.41 mg, or 0.42 mg, or 0.43 mg, or 0.44 mg, or 0.45 mg, or 0.46 mg,
  • solid microneedle systems can include between about 300 and 1500 solid microneedles. Each microneedle can have a height between about 250 and 700 ⁇ tall. In another embodiment,. each microneedle can be coated with a parathyroid hormone- containing drug or vaccine, such as a drug formulation comprising teriparatide. In an embodiment, the tip of each microneedle can be coated with a parathyroid hormone drug formulation.
  • a solid microneedle system can be integrated into a user-wearable device. Upon application, the microneedles penetrate stratum corneum for delivery of the parathyroid hormone drug formulation.
  • the microneedles can remain in the skin for a desirable or predetermined period of time, such as a length of time selected to permit the delivery of the parathyroid hormone-containing drug to a subject. Such time can be between about 30 seconds and 60 minutes.
  • Parathyroid hormone drug formulations can be kept in a dry state, which can enhance stability, allowing for room temperature storage of the formulations.
  • Solid microneedle system can be configured for single or multiple uses.
  • a microinjection device having one or more hollow microneedles is provided.
  • the one or more hollow microneedles can be configured to deliver parathyroid hormones of embodiments of the invention.
  • microinjection devices can include a plurality of hollow microneedles.
  • a hollow microneedle system can be configured for the delivery of a parathyroid hormone drug formulation in liquid form, from about 0.01 mL up to and including about 5 mL of a parathyroid hormone drug formulation, such as at least about 0.01, 0.02, 0.03, 0.04, 0.05, 0.06, 0.07, 0.08, 0.09, 0.1, 0.1 1 ,
  • 0.46 0.47, 0.48, 0.49, 0.50, 0.51 0.52, 0.53, 0.54, 0.55, 0.56, 0.57, 0.58, 0.59, 0.60, 0.61 0.62,
  • 0.63 0.64 0.65, 0.66, 0.67, 0.68, 0.69, 0.70, 0.71 , 0.72, 0.73 0.74, 0.75, 0.76, 0.77, 0.78 0.79,
  • 0.80 0.81 0.82, 0.83, 0.84, 0.85 0.86, 0.87, 0.88, 0.89, 0.90, 0.91 , 0.92, 0.93, 0.94, 0.95 0.96,
  • a hollow microneedle system can be configured for the delivery of a parathyroid hormone drug formulation in liquid form, from about 0.01 ml to 6 mL, or 0.01 mL to 3 mL, or 0.02 mL to 2 mL of a parathyroid hormone drug formulation.
  • hollow microneedle systems can include about 18 hollow microneedles per cm . Each microneedle can have a height of about 900 ⁇ .
  • a hollow microneedle system can be integrated into user-wearable device. Upon application, the microneedles penetrate the skin. Small channels in each microneedle allow for the flow of a fluid having a parathyroid hormone drug formulation from the device into the skin.
  • the delivery time can be between about 0.1 seconds and 2 hours, or between about 10 seconds and 1 hour, or between about 30 seconds and 40 minutes, or between about 1 minute and 30 minutes.
  • the infusion time can be dependent on the viscosity and volume of the parathyroid hormone-containing fluid.
  • a microinjection device having one or more hollow microneedles having one or more hollow microneedles.
  • the one or more hollow microneedles can be configured to deliver teriparatide.
  • microinjection devices can include a plurality of hollow microneedles.
  • a hollow microneedle system can be configured for the delivery of a teriparatide drug formulation in liquid form, from about 0.01 mL up to and including about 5 mL of a teriparatide drug formulation, such as at least about 0.01, 0.02, 0.03, 0.04, 0.05, 0.06, 0.07, 0.08, 0.09, 0.1, 0.11, 0.12, 0.13, 0.14, 0.15, 0.16, 0.17, 0.18, 0.19, 0.20, 0.21, 0.22, 0.23, 0.24, 0.25, 0.26, 0.27, 0.28, 0.29, 0.30, 0.31, 0.32, 0.33, 0.34, 0.35, 0.36, 0.37, 0.38, 0.39, 0.40, 0.41, 0.42, 0.43, 0.44, 0.45, 0.46, 0.47, 0.48, 0.49, 0.50, 0.51, 0.52, 0.53, 0.54, 0.55, 0.56, 0.57, 0.58, 0.59, 0.60, 0.61, 0.62, 0.63,
  • a hollow microneedle system can be configured for the delivery of a teriparatide-containing drug formulation in liquid form, from about 0.01 ml to 6 mL, or 0.01 mL to 3 mL, or 0.02 mL to 2 mL of a teriparatide-containing drug formulation.
  • hollow microneedle systems can include about 18 hollow microneedles per cm 2 . Each microneedle can have a height of about 900 ⁇ .
  • a hollow microneedle system can be integrated into user-wearable device. Upon application, the microneedles penetrate the skin. Small channels in each microneedle allow for the flow of a fluid having a teriparatide-containing drug formulation from the device into the skin.
  • the delivery time can be between about 0.1 seconds and 2 hours, or between about 10 seconds and 1 hour, or between about 30 seconds and 40 minutes, or between about 1 minute and 30 minutes.
  • the infusion time can be dependent on the viscosity and volume of the teriparatide-containing fluid.
  • a microinjection device comprises a plurality of hollow microneedles configured to deliver a parathyroid hormone formulation to a subject.
  • each microneedle is formed of a polymeric material.
  • each microneedle is formed of a metallic material, such as an elemental metal or a metal alloy.
  • each microneedle is formed of a semiconductor material.
  • each microneedle is formed of an insulating material.
  • each microneedle is formed of one or more of a metallic material, a semiconductor material and an insulating material.
  • a system for subcutaneous, transdermal or intradermal delivery of a parathyroid hormone to a subject comprises a parathyroid hormone formulation; a microneedle array for delivering the parathyroid hormone formulation to a subject; and one or more chambers in fluid communication with the microneedle array, the one or more chambers configured to hold the parathyroid hormone formulation.
  • the system can be configured to deliver to a subject a formulation comprising teriparatide or derivatives of teriparatide.
  • FIG. 1 A illustrates a microinjection device configured to deliver parathyroid hormones, in accordance with an embodiment of the invention.
  • the microinjection device includes a handle portion configured to permit a user to hold or grip the microinjection device.
  • FIG. I B illustrates an array of microneedles mountable to the microinjection device of FIG. 1 A, in accordance with an embodiment of the invention.
  • the microneedles can penetrate the skin of a subject with minimal discomfort. Small channels in each microneedle can allow for fluid flow from the device into the subject's skin.
  • FIG. 2 illustrates a microinjection device having an array of microneedles (also "microneedle array application device” herein), in accordance with an embodiment of the invention.
  • the application device includes a patch 20, microneedle array 22, collar 34, actuator 36, piston 42, driver 44, holding tabs 50 and distance sensors 60.
  • the actuator 36 of the device has not been engaged.
  • the driver 44 has stored energy and the piston 42 is not in contact with the patch 20, which is retained within the collar 34 of the application device.
  • the application device has distance sensors 60 that sense distances "B” and "C” between the sensor and a skin surface 38.
  • a user can bring the applicator in proximity to the skin surface 38 so that the distances "B” and “C” 40 can be adjusted so that a distance, "x", between the end of the collar 34 and the skin surface 38 can be as desired.
  • the application device can be triggered.
  • FIG. 3 illustrates a portion of the application device of FIG. 2, in accordance with an embodiment of the invention.
  • the application device is in the second released or triggered position, where the actuator 36 has been engaged, allowing the driver 44 to move the piston 42 towards the patch 20, thereby removing the patch from the holding tabs 50, propelling the patch 20 beyond an open distal end 48 of the collar 34 and pressing the microneedle array 22 and a skin facing adhesive 24 against the skin 38.
  • the piston 42 can then be removed from contact with the patch 20, thereby leaving the patch 20 in place on the skin 38.
  • the piston 42 can propel the patch 20 and array 22 from the application device and the patch 20 and array 22 can travel part of the distance in air (not shown) before impacting with the skin surface 38.
  • FIG. 4 illustrates a microneedle device comprising a patch 20 in the form of a combination of an array 22, pressure sensitive adhesive 24 and backing 26, in accordance with an embodiment of the invention.
  • a portion of the array 22 is illustrated with microneedles 10 protruding from a microneedle substrate surface 14.
  • the microneedles 10 can be arranged in any desired pattern or distributed over the microneedle substrate surface 14 randomly.
  • the microneedles 10 are configured for delivering a parathyroid hormone- containing formulation, such as a teriparatide-containing formulation, to a subject. As shown, the microneedles 10 are arranged in uniformly spaced rows.
  • arrays of the present invention have a skin-facing surface area of more than about 0.1 cm 2 and less than about 20 cm 2 , or more than about 0.5 cm 2 and less than about 5 cm 2 .
  • a portion of the substrate surface 16 of the patch 20 is non-patterned.
  • the non-patterned surface has an area of more than about 1 percent and less than about 75 percent of the total area of the device surface that faces a skin surface of a subject.
  • the non-patterned surface can have an area of more than about 0.10 square inch (0.65 cm 2 ) to less than about 1 square inch (6.5 cm 2 ).
  • the microneedles can be disposed over substantially the entire surface area of the array 22.
  • microneedle devices useful in various embodiments of the invention can comprise any of a variety of configurations, such as the structures and configuration disclosed in U.S. Patent Publication No. 2003/0045837 to Delmore et al., U.S. Patent Publication No.
  • a microinjection device having an array of microneedles, wherein the microneedles in the array include tapered structures that include at least one channel formed in the outside surface of each microneedle.
  • the microneedles can include bases that are elongated in one direction.
  • the channels in microneedles with elongated bases can extend from one of the ends of the elongated bases towards the tips of the
  • microneedles The channels formed along the sides of the microneedles can optionally be terminated short of the tips of the microneedles.
  • the microneedle arrays can also include conduit structures formed on the surface of the substrate on which the microneedle array is located. The channels in the microneedles can be in fluid communication with the conduit structures.
  • each of the microneedles can include a truncated tapered shape and a controlled aspect ratio.
  • microneedles can include bladelike microprotrusions for piercing the skin.
  • microneedles can include a hollow central channel.
  • each of the microneedles can be hollow and include at least one longitudinal blade at the top surface of tip of a microneedle.
  • FIG. 5A an array of microneedles is shown, in accordance with an embodiment of the invention.
  • FIG. 5B shows a cross-section of a microneedle in the array, in accordance with an embodiment of the invention.
  • the microneedles can be formed of a polymeric material, such as a medical-grade polymeric material. They can be configured to overcome the barrier properties of the stratum corneum to deliver to a subject parathyroid hormones of embodiments of the invention, such as teriparatide.
  • microneedles can be modeled as mini hypodermic needles, each having a height between about 100 um and 1000 ⁇ , or between about 300 ⁇ and 950 ⁇ , or between about 500 ⁇ and 900 ⁇ .
  • the array can include 18 microneedles in an array area of about 1 cm .
  • Each microneedle can include a fluid passage for delivering parathyroid hormones, each fluid passage running the length of a microneedle.
  • Each microneedle can include a tip portion configured to pierce a subject's skin.
  • FIG. 6 illustrates a microneedle application device 30 and a skin surface 32, in accordance with an embodiment of the invention.
  • the microneedle device 30 can be used to deliver parathyroid hormone compounds of embodiments of the invention, such as teriparatide.
  • the microneedle device 30 can be used to deliver a teriparatide-containing formulation.
  • the microneedle device 30 can be used to deliver a teriparatide-containing formulation, which can include other active or inactive ingredients (see above).
  • the microneedle application device 30 can be used to deploy patches that include a microneedle array to a surface, such as to the skin surface 32.
  • the device 30 includes a housing 34 with a gripping portion 36, a trigger 38 and a collar 40.
  • the collar 40 defines an outward-facing contact portion 42.
  • the collar 40 is detachable from the housing 34, and can be disposable or reusable.
  • the collar 40 is a unitary member of generally cylindrical shape, and contact portion 42 is generally annular in shape.
  • the collar 40 can have nearly any shape and configuration.
  • the collar 40 can have a rectangular, triangular, oval, or other shape or combination of shapes.
  • the contact portion 42 will typically have a shape corresponding to the shape of the collar 40.
  • the collar 40 need not be unitary, and can be configured to form a number of discrete feet or supports that collectively define the contact portion 42.
  • FIG. 7 is a cross sectional side view of the microneedle application device 30 of FIG. 6, in accordance with an embodiment of the invention.
  • the device 30 includes a microneedle array patch 52; the device 30 is positioned against the skin surface 32.
  • the device 30 includes a support member or actuator.
  • the support member or actuator can be a piston 44 having a pad 46 and a shaft 48.
  • any type of mechanical, electromechanical, pneumatic, or other type of support member or actuator can be used.
  • a driver 50 capable of storing energy engages the shaft 48 of the piston 44, and can accelerate the piston 44 to a desired velocity.
  • the driver 50 can be in the form of a mechanical spring (e.g., a coil spring, leaf spring, etc.), compressed resilient member (e.g., rubber, etc.), compressed fluids (e.g., air, liquids, etc.), piezoelectric structure, electromagnetic structure, etc.
  • the collar 40 can hold a patch 52, carrying a microneedle array, prior to patch application.
  • the microneedle application device 30 can be positioned with the collar 40 near a desired application site.
  • the contact portion 42 of the collar 40 is placed in contact with the skin surface 32, and the contact portion 42 defines a target patch application site 54 on the skin surface 32.
  • a user can apply force to the microneedle application device 30 at the gripping portion 36 of the housing 34. At least a portion of that force can be transmitted through the collar 40 to the skin 32. That force can be referred to as a "pushdown force".
  • a "dome” 56 is generally created at the target site 54, as the skin 32 responds to the pushdown force. This "dome” has parameters of height and firmness.
  • Both of these parameters of the dome can be dependent upon the force applied to the applicator during microneedle application device 30 positioning.
  • the depth of penetration of a microneedle array is related to the application site, i.e., soft and fatty areas of a body versus firm muscular areas of the body. Skin characteristics can vary from one individual to another, and particular characteristics of skin can vary across subjects (e.g., patients) and across selected application sites on individual subjects. Such variations can affect characteristics of the dome 56.
  • a "pushback force" is exerted by the skin 32 in response to the pushdown force. The pushback force is generally directed in a direction directly opposed to the direction of the pushdown force, although specific relationships can be complex and will vary depending on the particular application site.
  • a force sensor can be coupled to the piston 44 at either end or anywhere along the length of piston 44, for example, at location 58A, 58B and/or 58C (jointly referred to as sensor 58).
  • the sensor 58 can be capable of sensing applied mechanical forces, such as pushback force at the piston 44.
  • the sensor 58 can be a strain gauge, variable capacitance sensor, or variable resistance sensor.
  • the sensor 58 can comprise a variable resistance member having a semi-conducting polymer disposed between conductive layers or grids, where the resistance of the variable resistance member varies according to applied force.
  • variable resistance member can be further configured in a voltage divider, which converts the resistance of the member into a voltage signal output that can be measured to detect force applied to the sensor 58.
  • a voltage divider which converts the resistance of the member into a voltage signal output that can be measured to detect force applied to the sensor 58.
  • An example of such a variable resistance member is disclosed in U.S. Patent No. 5,209,967, which is herein incorporated by reference in its entirety.
  • Other examples of aspects of such a variable resistance member are disclosed in U.S. Patent Nos. 5,904,978 and 5,573,626, which are entirely incorporated herein by reference.
  • the piston 44 is moveable between a stored position and an extended position. In the stored position, energy is stored in the driver 50, and an actuator 38 secures the piston 44 in its stored position.
  • the actuator 38 allows an operator to trigger the release of energy stored in the driver 50 to accelerate the piston 44 through the collar 40 and toward the patch 52.
  • the microneedle application device 30 can be used to deliver the microneedle array patch 52 to the skin surface 32, in order to pierce the stratum corneum at the target application site 54 on a subject's skin.
  • the patch application device can be used to deliver a parathyroid hormone formulation through the skin in a variation on transdermal delivery, or to the skin for intradermal or topical treatment, such as, e.g., vaccination.
  • the patch application device can be used to deliver a teriparatide formulation through the skin in a variation on transdermal delivery, or to the skin for intradermal or topical treatment, such as, e.g., vaccination.
  • the microneedle array patch 52 can be used to pierce the stratum corneum before or after a pharmacological agent is applied to the skin surface in a separate step, thus being used as a pre- or post-treatment step.
  • FIG. 8 shows an enlarged cross sectional view of the collar 40 of the microneedle application device 30 of FIGs. 6 and 7, positioned against the skin surface 32, in accordance with an embodiment of the invention.
  • the collar 40 includes obstructions 70 on an interior portion thereof.
  • the obstructions 70 can be configured to retain patches, such as the patch 52.
  • Patch 52 can include a backing 72, an adhesive 74 (e.g., a pressure sensitive adhesive), and a microneedle array 76.
  • a desired patch application path 78 is defined through the collar 40.
  • the path 78 is substantially perpendicular to a plane in which the microneedle array 76 is retained by the obstructions 70 within the collar 40, and is generally perpendicular to the target application site 54.
  • the patch 52 is moved along the patch application path 78.
  • This patch movement can be accomplished by mechanically pushing the patch 52 with the piston 44.
  • the microneedle application device 30 can use other means for moving the patch 52.
  • the patch 52 can be moved pneumatically, without contacting a piston.
  • FIG. 9A is a perspective view of an applicator device 120 having a housing 122 that includes a base 124 and an upper cover structure 126, in accordance with an embodiment of the invention.
  • the device is elongate in shape and has a first, tapered end 127 and a second end 129.
  • the second end 129 has a top and bottom sealed by a top peelable seal 131 having a tab 133 and a bottom peelable seal 132 having a tab 135 (only tab 135 is visible in FIG. 9A).
  • FIG. 9B shows the applicator device after the peelable seals 13 1 , 132 have been removed.
  • a trigger 1 37 is integrally formed in the top surface of the housing 122.
  • the trigger is connected to the top surface of the housing at a single attachment point 139, thus allowing the trigger to be deflected downward by thumb or finger pressure (see FIG. 9D).
  • FIG. 9C is a cross-sectional view of the device of FIGs. 9A, showing a patch 172 mounted on an impactor 1 70, in accordance with an embodiment of the invention.
  • the impactor 1 70 is integrally formed with a drive member 166 having a length extending from a fixed end 167 attached to the housing 122 to a movable end 169.
  • the drive member 166 is bendable along its length.
  • a holding mechanism in the form of a latch uses a hook 125 attached to the housing 122. The hook 125 engages with a slot 1 71 in the movable end 169 of the drive member 1 66 to hold the movable end 169 of the drive member 1 66 away from the skin-contacting face 124 of the housing 122.
  • the drive member can be any elongate, bendable member, such as, for example, a leaf spring.
  • a target surface such as a skin surface (not shown).
  • FIG. 9E shows the drive member 1 66 fully deployed, having propelled the patch 1 72 past the skin- contacting face 124 so that the patch is pressed against the skin surface (not shown).
  • FIG. 9F shows the device 120 being removed from the skin surface 1 81 , leaving a patch 1 72 with a microneedle array 174 in place on the skin surface 181.
  • the impactor 170 is shown as a curled end of a leaf spring, as this allows for a convenient means for providing a holding mechanism (via the slot 171 in the movable end 169 of the leaf spring) while also providing a separate patch contacting and holding surface.
  • any variety of suitable shapes can be used for the movable end 169 of the drive member 166, including a flat leaf spring having no curled end.
  • FIG. 10 illustrates an applicator device 20 having a housing 22 that includes a base 24 and an upper cover structure 26, in accordance with an embodiment of the invention.
  • the applicator device 20 is configured to deliver a parathyroid hormone formulation to a subject.
  • the applicator device 20 is configured to deliver a teriparatide- containing formulation to a subject.
  • the base 24 can be rectangular in shape, and include a recess 28 located on a bottom face 30 thereof.
  • a generally circular opening 32 is defined in the recess 28 of the base 24.
  • a raised portion 34 is formed on an upper face 36 of the base 24 for holding a patch accelerating or patch applicator assembly 38.
  • a mounting structure or retaining portion of the applicator device 20 is formed by a pair of retainers 40, also referred to as a first retainer and a second retainer, connected to the base 24 (only one retainer 40 is visible in FIG. 10).
  • the retainer members 40 are generally elongate and each have a substantially flat upper surface 42 that is generally parallel to and facing a bottom portion 44 of the recess 28, and is spaced from the bottom face 30 (i.e., the skin-contacting face) of the base 24.
  • the pair of retainer members 40 are located on opposite sides of the opening 32 and are connected to the base 24 at one side of the recess 28.
  • the retainer members 40 define an opening 46 at one end for accepting patches between the retainer members 40 and the bottom portion 44 of the recess 28.
  • the upper surfaces 42 of the retainer members 40 can be non-stick or release surfaces.
  • a non-stick or release surface can be achieved, for example, by a non-stick or release coating applied to the upper surfaces 42.
  • the non-stick or release coating can be selected according to the desired use of the applicator device 20.
  • a release coating such as a low surface energy silicone, fluoropolymer, or fluoro-silicone release coating, can be selected based upon the adhesives used with patches applied using the patch application device 20.
  • a blade or other cutting means can be provided as part of the mounting structure, for separating portions of items from patches mounted on the applicator.
  • the upper cover structure 26 is connected to the base 24 at or near a perimeter of the base 24.
  • the upper cover structure 26 is shaped to fit on the base 24, and defines a volume, which is selected to provide space for the patch accelerating assembly 38.
  • the housing 22 can also provide space for storing patches (e.g., a roll of patches) for eventual deployment by the applicator device 20.
  • a slot 48 is defined in a side portion of the upper cover structure 26. In the illustrated embodiment of FIG. 10, the slot 48 is arcuate in shape and generally resembles a half circle, with the open portion of the half circle facing the base 24 of the housing 22. Both the base 24 and the upper cover structure 26 can be formed of a polymeric material.
  • FIG. 1 1 is a perspective view of a portion of the applicator device 20 of FIG. 10 with the upper cover portion 26 omitted to show interior portions of the device 20.
  • the patch acceleration assembly 38 includes a frame member 60, an impactor 62, a handle 64, a bracket 66, and a torsion spring 68.
  • the torsion spring 68 serves as a drive member to bias the impactor relative to the housing.
  • the bracket 66 is mounted to the raised portion 34 of the base 24 of the housing 22 and pivotally retains the frame member 60. In some instances the bracket 66 can be directly affixed to the base 24, for example, if the base has sufficient thickness to allow for placement of the torsion spring 68.
  • the frame member 60 can be a wire formed as a rectangular loop.
  • the impactor 62 is attached to the frame member 60 opposite the bracket 66, and is the portion of the patch acceleration assembly 38 that interfaces with a patch to move it (i.e., to accelerate it), that is, it is the patch contacting portion of the device.
  • the impactor 62 has a patch contacting surface 70 that is configured according to characteristics of a desired application, for instance, based upon the shape of a patch to be applied. In the embodiment shown in FIG. 10, the patch contacting surface 70 is configured so that it is generally parallel to and aligned with the frame member 60. Furthermore, it will be generally aligned with the bottom face 30 of the device 20 when fully deployed.
  • the patch contacting surface 70 can be configured so that it is at another angle with respect to the frame member 60, and with respect to the bottom face 30 of the device 20 when fully deployed. Other such angles are possible.
  • the patch contacting surface 70 can be aligned so as to form an angle of between 4 and 1 5 degrees with the plane of the frame member.
  • the angle of the patch contacting surface 70 can be selected so that it is aligned with the back of the a patch resting on retaining members 40 when the patch contacting surface 70 contacts the patch.
  • the impactor 62 can be formed of a polymer material.
  • the handle 64 extends from the impactor 62, and can be integrally formed with the impactor 62.
  • FIG. 10 represents one configuration for manipulating the patch acceleration assembly 38.
  • a slot can be provided on the upper cover portion 26, thereby allowing the handle 64 or any other suitable actuation protrusion tb protrude through the upper cover portion 26.
  • the method for manipulating the patch acceleration assembly 38 need not be by means of a direct mechanical connection.
  • various linkages or gears can be provided such that a button or knob on the exterior of the housing 22 can be pressed or turned to manipulate the patch acceleration assembly 38.
  • the patch acceleration assembly 38 can be moved by a motor or solenoid that is electrically controlled by a button or knob on the exterior of the housing 22.
  • the torsion spring 68 biases the frame 60 of the patch acceleration assembly 38 relative to the base 24 of the housing 22.
  • the torsion spring 68 can be a conventional coiled spring steel torsion spring.
  • the torsion spring 68 biases the frame 60, and therefore also the impactor 62, toward the opening 32 in the base 24 of the housing 22.
  • the impactor In a substantially de-energized state, the impactor is at rest and positioned near the opening 32 in the base 24 of the housing 22.
  • an operator can store potential energy in the torsion spring 68.
  • Energy stored in the torsion spring 68 can be used to accelerate the impactor 62 toward a patch and also to accelerate a patch that has contacted the impactor 62.
  • the amount of energy stored in the torsion spring 68 will vary depending on the amount of displacement of the impactor 62 away from the opening 32 and along the arcuate path.
  • the appropriate torsion spring constant will depend upon a number of parameters, including the mass of the patch acceleration assembly, the mass of the patch, the arc length through which the patch acceleration assembly travels, and the desired speed of the patch on impact with a surface.
  • the torsion spring constant can be more than about 0.5 Newton*mm/degree, or more than about 2.0 Newton*mm/degree.
  • the torsion spring constant can be less than about 5.0
  • the impactor 62 can be held at various points along the arcuate path either manually or, in some embodiments, with holding means (not shown) that engage and temporarily secure the handle 64 along the slot 48 in the upper cover structure 26 of the housing 22.
  • demarcations or other indicators e.g., a force readout display
  • the range of angular travel of the patch acceleration assembly will often be less than about 170 degrees and sometimes less than about 1 10 degrees.
  • the range of angular travel of the patch acceleration assembly will often be more than about 10 degrees and sometimes more than about 60 degrees.
  • the mass of the patch acceleration assembly will often be more than about 1 gram and sometimes more than about 5 grams.
  • the mass of the patch acceleration assembly will often be less than about 100 grams and sometimes less than about 30 grams.
  • FIG. 12 is a perspective view of a patch 72 (e.g., a patch 72 carrying a microneedle array 74) mounted on the applicator device 20, in accordance with an embodiment of the invention.
  • the applicator device 20, including the patch 72 is configured to deliver a parathyroid hormone formulation to a subject.
  • applicator device 20 is configured to deliver a teriparatide-containing formulation to a subject.
  • the patch 72 is disposed between the retainer members 40 and the bottom portion 44 of the recess 28 in the base 24 of the housing 22.
  • the microneedle array 74 faces away from the opening 32 in the base 24 of the housing 22.
  • the patch 72 which can have adhesive surrounding the microneedle array 74 on the surface facing away from the patch application device 20, contacts the upper surfaces 42 of the retainer members 40, but is generally not adhered firmly to the retainer members 40 due to the release character of the upper surfaces 42.
  • microneedle array carried on the patch 72 is generally aligned relative to the opening 32 in the base 24 of the housing 22 (the opening 32 is not visible in FIG. 12).
  • the retainer members 40 have cutaway portions 76 that provide an enlarged, partially circular open region that is generally aligned with the opening 32 on the bottom portion 44 of the recess 28 of the base 24 of the housing 22.
  • the wider, open region defined by the cutaway portions 76 facilitates patch application by reducing the amount of deflection of the patch 72 required during deployment to move the patch 72 from a mounted position on the applicator device 20 to a target location.
  • Such cutaway portions 76 can be omitted if, for example, the patch has a generally rectangular shape.
  • FIG. 13 is a partial cross-sectional view of a microneedle array cartridge 80, having a patch 72 and a cover 82, mounted on an applicator device 20.
  • the applicator device 20 is similar to the applicator device of FIG. 12.
  • the microneedle array cartridge 80 includes a microneedle array 74.
  • the microneedle array 74 is configured to deliver parathyroid hormone formulations to a subject. Mounting the patch 72 on the applicator device 20 includes the following steps. The cartridge 80 is partially slid onto the retainer members 40.
  • Microinjection methods, devices and systems of embodiments of the invention can be combined or modified with other injection or microinjection methods, devices and systems, including methods, devices and systems for manufacturing microinjection devices and components (such as, e.g., microneedles).
  • microneedle devices provided herein can be combined or modified with devices, apparatuses, systems and methods (including methods of manufacturing) described in U.S. Patent Publication Nos. 2003/0045837 to Delmore et al., 2003/0135161 to Fleming et al., 2005/0143713 to Delmore et al., 2005/0187521 to Fleming et al., 2005/0261631 to Clarke et al., 2006/0195067 to Wolter et al., 2007/0083151 to Carter, 2007/0191761 to Boone et al., 2008/000981 1 to Cantor, 2008/0009825 to Ringsred et al., 2008/0039805 to Frederickson et al., 2008/0051699 to Choi et al., 2008/0088066 to Ferguson et al., 2008/0102192 to Johnson et al., 2008/0108958 to Carter e
  • microneedle (or microinjection) devices provided herein can be combined or modified with devices, apparatuses, systems and methods (such as methods of manufacturing) described in U.S. Patent Publication No. 2004/0249339, U.S. Patent Publication No.
  • microinjection devices are used to deliver parathyroid hormone formulations (or drug formulations) to subjects.
  • Microinjection devices for delivering parathyroid hormone formulations can be selected from any microinjection or microneedle devices provided herein.
  • a microinjection device having one or more microneedles is used to deliver a parathyroid hormone formulation to a subject.
  • a microinjection device having a plurality of microneedles can be used to deliver a teriparatide-containing formulation to a subject.
  • the teriparatide-containing formulation is delivered to a subject subcutaneously. In another embodiment, the teriparatide-containing formulation is delivered to a subject in a transdermal fashion (or “transdermal ly”). In another embodiment, the teriparatide- containing formulation is delivered to a subject in an intradermal fashion (or “intradermally”).
  • a microinjection device having a parathyroid hormone formulation can be used to treat one or more of osteoporosis, osteopenia, osteomalacia, osteogenesis imperfecta, osteosarcoma and Paget's Disease.
  • a microinjection device having a teriparatide formulation can be used to treat one or more of osteoporosis, osteopenia, osteomalacia, osteogenesis imperfecta, osteosarcoma and Paget's Disease.
  • a parathyroid hormone is administered to a subject by
  • subcutaneous, transdermal or intradermal administration is by drug vehicle interaction.
  • subcutaneous, transdermal or intradermal administration is by the use of ion pairs or coacervates.
  • subcutaneous, transdermal or intradermal administration is by vesicles and particles.
  • subcutaneous, transdermal or intradermal administration is by liposomes and analogues.
  • subcutaneous, transdermal or intradermal administration is with the use of high velocity particles.
  • subcutaneous, transdermal or intradermal administration is by removing, bypassing or modifying the stratum corneum.
  • subcutaneous, transdermal or intradermal administration is by hydration. In still another embodiment, subcutaneous, transdermal or intradermal administration is with the use of chemical enhances. In still another embodiment, subcutaneous, transdermal or intradermal administration is by microneedle injection. In still another embodiment, subcutaneous, transdermal or intradermal administration is by ablation. In still another embodiment, subcutaneous, transdermal or intradermal administration is by follicular delivery. In still another embodiment, subcutaneous, transdermal or intradermal administration is by electrically assisted methods. In still another embodiment, subcutaneous, transdermal or intradermal administration is by ultrasound. In still another embodiment, subcutaneous, transdermal or intradermal administration is by iontophoresis. In still another embodiment, subcutaneous, transdermal or intradermal administration is by electroporation.
  • a parathyroid hormone is administered subcutaneously, transdermally or intradermally with the aid of iontophoresis, which can involve non-invasively propelling high concentrations of a charged substance, such as a parathyroid hormone formulation, subcutaneously, transdermally or intradermally by a repulsive electromotive force using a small electrical charge applied to an iontophoretic chamber containing a similarly charged active agent, such as a parathyroid hormone, and its vehicle.
  • teriparatide is administered subcutaneously, transdermally or intradermally with the aid of iontophoresis.
  • a device having one or more chambers filled with a solution containing a parathyroid hormone is provided.
  • the parathyroid hormone can be provided in the one or more chambers with a solvent to aid in (or facilitate) delivery.
  • the device can include one or both of a positively charged chamber for repelling a positively charged chemical and a negatively charged chamber for repelling a negatively charged chemical into the skin of a subject.
  • a parathyroid hormone is administered subcutaneously, transdermally or intradermally with the aid of ultrasound or ultrasonic energy (also "ultrasound” herein).
  • teriparatide is administered subcutaneously, transdermally or intradermally with the aid of ultrasound.
  • the application of ultrasound to the skin can increase the permeability of skin to a parathyroid hormone, which can enable the delivery of a parathyroid hormone, such as teriparatide, through the skin.
  • a parathyroid hormone is administered subcutaneously, transdermally or intradermally with the aid of electroporation.
  • teriparatide is administered subcutaneously, transdermally or intradermally with the aid of electroporation.
  • a device is provided for applying an electric field to an area of a subject's body in which transdermal administration of a parathyroid hormone is desired, such as, for example, a portion of a subject's arm. The application of the electric field can facilitate the transdermal delivery of the parathyroid hormone, such as teriparatide, to the subject.
  • a parathyroid hormone is administered subcutaneously, transdermally or intradermally by microneedle injection.
  • teriparatide is administered subcutaneously, transdermally or intradermally by microneedle injection.
  • Microneedle injection can include use of a microneedle device, such as a microneedle device of various embodiments of the invention.
  • a first user employs a microinjection device having a parathyroid hormone formulation, such as teriparatide, to deliver the parathyroid hormone formulation to a subject.
  • a parathyroid hormone formulation such as teriparatide
  • the first user is a doctor or healthcare professional and the subject is a patient.
  • the first user is a caregiver and the second user is a subject under the caregiver's care.
  • the first user is a friend or relative of the subject.
  • a subject employs a microinjection device having a parathyroid hormone formulation to self-administer the parathyroid hormone formulation.
  • a subject employs a microinjection device having a teriparatide formulation to self-administer the teriparatide formulation.
  • the term "user”, as used herein, can refer to an individual using a microinjection device to administer a parathyroid hormone formulation to another individual, such as a subject, or to an individual using the microinjection device to administer the parathyroid hormone formulation to her or himself.
  • the term "subject”, as used herein, can refer to an individual under treatment by another individual, such as a healthcare provider (e.g., physician, physician's assistant, nurse) or a care provider, or to an individual administering the parathyroid hormone formulation to himself or herself (i.e., self administration).
  • a "subject” includes asymptomatic individuals and symptomatic individuals, such as a patient.
  • a microinjection device is used to deliver to a subject the equivalent of 0.01 mg, or 0.02 mg, or 0.03 mg, or 0.04 mg, or 0.05 mg, or 0.06 mg, or 0.07 mg, or 0.08 mg, or 0.09 mg, or 0.10 mg, or 0.1 1 mg, or 0.12 mg, or 0.13 mg, or 0.14 mg, or 0.15 mg, or 0.16 mg, or 0.17 mg, or 0.18 mg, or 0.19 mg, or 0.20 mg, or 0.21 mg, or 0.22 mg, or 0.23 mg, or 0.24 mg, or 0.25 mg, or 0.26 mg, or 0.27 mg, or 0.28 mg, or 0.29 mg, or 0.30 mg, or 0.31 mg, or 0.32 mg, or 0.33 mg, or 0.34 mg, or 0.35 mg, or 0.36 mg, or 0.37 mg, or 0.38 mg, or 0.39 mg, or 0.40 mg, or 0.41 mg, or 0.42 mg, or 0.43 mg, or 0.44 mg, or 0.45 mg, or 0.46 mg,
  • a microinjection device is used to deliver to a subject the equivalent of 0.01 mg, or 0.02 mg, or 0.03 mg, or 0.04 mg, or 0.05 mg, or 0.06 mg, or 0.07 mg, or 0.08 mg, or 0.09 mg, or 0.10 mg, or 0.1 1 mg, or 0.12 mg, or 0.13 mg, or 0.14 mg, or 0.15 mg, or 0.16 mg, or 0.17 mg, or 0.1 8 mg, or 0.19 mg, or 0.20 mg, or 0.21 mg, or 0.22 mg, or 0.23 mg, or 0.24 mg, or 0.25 mg, or 0.26 mg, or 0.27 mg, or 0.28 mg, or 0.29 mg, or 0.30 mg, or 0.31 mg, or 0.32 mg, or 0.33 mg, or 0.34 mg, or 0.35 mg, or 0.36 mg, or 0.37 mg, or 0.38 mg, or 0.39 mg, or 0.40 mg, or 0.41 mg, or 0.42 mg, or 0.43 mg, or 0.44 mg, or 0.45 mg, or 0.46 mg, or 0.47
  • a parathyroid hormone formulation (or parathyroid hormone- containing formulation) can have a parathyroid hormone concentration (mg parathyroid hormone / mL formulation) of about 0.01 mg 1 mL, or 0.02 mg/1 mL, or 0.03 mg/1 mL, or 0.04 mg/1 mL, or 0.05 mg 1 mL, or 0.06 mg/1 mL, or 0.07 mg/1 mL, or 0.08 mg/1 mL, or 0.09 mg/1 mL, or O.
  • mg parathyroid hormone / mL formulation of about 0.01 mg 1 mL, or 0.02 mg/1 mL, or 0.03 mg/1 mL, or 0.04 mg/1 mL, or 0.05 mg 1 mL, or 0.06 mg/1 mL, or 0.07 mg/1 mL, or 0.08 mg/1 mL, or 0.09 mg/1 mL, or O.
  • a parathyroid hormone formulation can have a parathyroid hormone concentration between about 0.01 mg/1 mL and 0.50 mg/1 mL, or between about 0.10 mg/1 mL and 0.30 mg/1 mL, or between about 0.19 mg/1 mL and 0.26 mg/1 mL.
  • a teriparatide formulation (or teriparatide-containing formulation) can have a teriparatide concentration (mg teriparatide / mL formulation) of about 0.01 mg/1 mL, or 0.02 mg/1 mL, or 0.03 mg/1 mL, or 0.04 mg/1 mL, or 0.05 mg/1 mL, or 0.06 mg/1 mL, or 0.07 mg/1 mL, or 0.08 mg/1 mL, or 0.09 mg/1 mL, or 0.10 mg 1 mL, or 0.1 1 mg/1 mL, or 0.12 mg/1 mL, or 0.13 mg/1 mL, or 0.14 mg/1 mL, or 0.15 mg/1 mL, or 0.16 mg/1 mL, or 0.17 mg 1 mL, or 0.18 mg/1 mL, or 0.19 mg/1 mL, or 0.20 mg/1 mL, or 0.21 mg/1 mL, or 0.22 mg/1 mL
  • a teriparatide formulation can have a teriparatide concentration between about 0.01 mg 1 mL and 0.5 mg 1 mL, or between about 0.10 mg/1 mL and 0.30 mg 1 mL, or between about 0.1 mg/1 mL and 0.26 mg/1 mL.
  • formulation volumes when used in association with doses (mg), are used to illustrate concentrations and may not necessarily be the volumes of formulations delivered to subjects.
  • a microinjection device is loaded with about 2 mL of a parathyroid hormone formulation having a parathyroid hormone concentration of about 0.22 mg in 1 mL.
  • the parathyroid hormone formulation can include an excipient.
  • a microinjection device such as any device provided herein, is used to deliver a parathyroid hormone, including teriparatide, to a subject from once a day to once a month.
  • a microinjection device such as any device provided herein, is used to deliver teriparatide to a subject from once a day to once a week.
  • a microinjection device such as any device provided herein, is used to deliver a parathyroid hormone, such as teriparatide, to a subject once a day, once every two days, once every three days, once every four days, once every five days, once every six days, once a week, once every two weeks, once every three weeks, once a month, once every two months, once every three months, once every four months, once every five months, once every six months, once a year, or more.
  • a microinjection device such as any device provided herein, is used to deliver a parathyroid hormone to a subject from once a day to once every other day.
  • a microinjection device such as any device provided herein, is used to deliver a parathyroid hormone, such as teriparatide, to a subject once a day, or twice a day, or three times per day, or four times per day, or five times per day, or six times per day, or seven times per day, or eight times per day, or nine times per day, or ten times per day, or eleven times per day, or twelve times per day, or thirteen times per day, or fourteen times per day, or fifteen times per day, or sixteen times per day, or seventeen times per day, or eighteen times per day, or nineteen times per day, or twenty times per day, or twenty one times per day, or twenty two times per day, or twenty three times per day, or twenty four times per day.
  • a parathyroid hormone such as teriparatide
  • a microinjection device such as any device provided herein, is used to deliver a teriparatide formulation to a subject from once a day to once a month.
  • a microinjection device such as any device provided herein, is used to deliver teriparatide to a subject from once a day to once a week.
  • a microinjection device such as any device provided herein, is used to deliver a teriparatide formulation to a subject once a day, once every two days, once every three days, once every four days, once every five days, once every six days, once a week, once every two weeks, once every three weeks, once a month, once every two months, once every three months, once every four months, once every five months, once every six months, once a year, or more.
  • a microinjection device such as any device provided herein, is used to deliver teriparatide formulation to a subject from once a day to once every other day.
  • a microinjection device such as any device provided herein, is used to deliver a teriparatide formulation to a subject once a day, or twice a day, or three times per day, or four times per day, or five times per day, or six times per day, or seven times per day, or eight times per day, or nine times per day, or ten times per day, or eleven times per day, or twelve times per day, or thirteen times per day, or fourteen times per day, or fifteen times per day, or sixteen times per day, or seventeen times per day, or eighteen times per day, or nineteen times per day, or twenty times per day, or twenty one times per day, or twenty two times per day, or twenty three times per day, or twenty four times per day.
  • a microinjection device is used to deliver a parathyroid hormone or a parathyroid hormone formulation to a subject at a dose (mg parathyroid hormone) of at least about 0.001 mg, or 0.002 mg, or 0.003 mg, or 0.004 mg, or 0.005 mg, or 0.006 mg, or 0.007 mg, or 0.008 mg, or 0.009 mg, or 0.010 mg, or 0.01 1 mg, or 0.012 mg, or 0.013 mg, or 0.014 mg, or 0.015 mg, or 0.016 mg, or 0.017 mg, or 0.018 mg, or 0.019 mg, or 0.020 mg, or 0.021 mg, or 0.022 mg, or 0.023 mg, or 0.024 mg, or 0.025 mg, or 0.026 mg, or 0.027 mg, or 0.028 mg, or 0.029 mg, or 0.030 mg, or 0.03 1 mg, or 0.032 mg, or 0.033 mg, or 0.034 mg,
  • a microinjection device is used to deliver teriparatide or a teriparatide formulation to a subject at a dose (mg teriparatide) of at least about 0.001 mg, or 0.002 mg, or 0.003 mg, or 0.004 mg, or 0.005 mg, or 0.006 mg, or 0.007 mg, or 0.008 mg, or 0.009 mg, or 0.010 mg, or 0.01 1 mg, or 0.012 mg, or 0.013 mg, or 0.014 mg, or 0.01 5 mg, or 0.016 mg, or 0.017 mg, or 0.01 8 mg, or 0.019 mg, or 0.020 mg, or 0.021 mg, or 0.022 mg, or 0.023 mg, or 0.024 mg, or 0.025 mg, or 0.026 mg, or 0.027 mg, or 0.028 mg, or 0.029 mg, or 0.030 mg, or 0.031 mg, or 0.032 mg, or 0.033 mg, or 0.034 mg,
  • a microinjection device is used to deliver a parathyroid hormone or a parathyroid hormone-containing formulation to a subject at a regimen (volume) of at least about 0.1 mL, or 0.2 mL, or 0.3 mL, or 0.4 mL, or 0.5 mL, or 0.6 mL, or 0.7 mL, or 0.8 mL, or 0.9 mL, or 1.0 mL, or 1.1 mL, or 1.2 mL, or 1.3 mL, or 1.4 mL, or 1.5 mL, or 1.6 mL, or 1.7 mL, or 1 .8 mL, or 1.9 mL, or 2.0 mL, or 2.1 mL, or 2.2 mL, or 2.3 mL, or 2.4 mL, or 2.5 mL, or 2.6 mL, or 2.7 mL, or 2.8 mL, or 2.9 mL, or 3.0 mL, or 2.0 mL
  • a microinjection device is used to deliver teriparatide or a teriparatide- containing formulation to a subject at a regimen (volume) of at least about 0.1 mL, or 0.2 mL, or 0.3 mL, or 0.4 mL, or 0.5 mL, or 0.6 mL, or 0.7 mL, or 0.8 mL, or 0.9 mL, or 1.0 mL, or 1.1 mL, or 1.2 mL, or 1.3 mL, or 1.4 mL, or 1.5 mL, or 1.6 mL, or 1.7 mL, or 1.8 mL, or 1.9 mL, or 2.0 mL, or 2.1 mL, or 2.2 mL, or 2.3 mL, or 2.4 mL, or 2.5 mL, or 2.6 mL, or 2.7 mL, or 2.8 mL, or 2.9 mL, or 3.0 mL, or
  • a microinjection device is used to deliver a parathyroid hormone to a subject at a dose of at least about 0.001 mg/day, or 0.002 mg/day, or 0.003 mg/day, or 0.004 mg/day, or 0.005 mg/day, or 0.006 mg/day, or 0.007 mg/day, or 0.008 mg/day, or 0.009 mg/day, or 0.010 mg/day, or 0.01 1 mg/day, or 0.012 mg/day, or 0.013 mg/day, or 0.014 mg/day, or 0.015 mg/day, or 0.016 mg/day, or 0.017 mg/day, or 0.01 8 mg/day, or 0.019 mg/day, or 0.020 mg/day, or 0.021 mg/day, or 0.022 mg/day, or 0.023 mg/day, or 0.024 mg/day, or 0.025 mg/day, or 0.026 mg/day, or 0.027 mg/day, or 0.028
  • a microinjection device is used to deliver teriparatide to a subject at a dose of at least about 0.001 mg/day, or 0.002 mg/day, or 0.003 mg/day, or 0.004 mg/day, or 0.005 mg/day, or 0.006 mg/day, or 0.007 mg/day, or 0.008 mg/day, or 0.009 mg/day, or 0.010 mg/day, or 0.01 1 mg/day, or 0.012 mg/day, or 0.013 mg/day, or 0.014 mg/day, or 0.015 mg/day, or 0.016 mg/day, or 0.017 mg/day, or 0.018 mg/day, or 0.019 mg/day, or 0.020 mg/day, or 0.021 mg/day, or 0.022 mg/day, or 0.023 mg/day, or 0.024 mg/day, or 0.025 mg/day, or 0.026 mg/day, or 0.027 mg/day, or 0.028
  • a microinjection device is used to deliver a parathyroid hormone to a subject at a dose of about 0.001 mg or less, or 0.002 mg or less, or 0.003 mg or less, or 0.004 mg or less, or 0.005 mg or less, or 0.006 mg or less, or 0.007 mg or less, or 0.008 mg or less, or 0.009 mg or less, or 0.010 mg or less, or 0.01 1 mg or less, or 0.012 mg or less, or 0.013 mg or less, or 0.014 mg or less, or 0.01 5 mg or less, or 0.016 mg or less, or 0.017 mg or less, or 0.018 mg or less, or 0.019 mg or less, or 0.020 mg or less, or 0.021 mg or less, or 0.022 mg or less, or 0.023 mg or less, or 0.024 mg or less, or 0.025 mg or less, or 0.026 mg or less, or 0.027 mg or less, or 0.028 mg
  • a microinjection device is used to deliver a parathyroid hormone to a subject at a dose of at least about 0.01 mg, or 0.02 mg, or 0.03 mg on a daily basis. In another embodiment, a microinjection device is used to deliver a parathyroid hormone to a subject once a day at a dosage of about 0.1 mg, or 0.15 mg, or 0.2 mg, or 0.25 mg, or 0.3 mg in a 1 mL formulation having parathyroid hormone.
  • a microinjection device is used to deliver teriparatide to a subject at a dose of about 0.001 mg or less, or 0.002 mg or less, or 0.003 mg or less, or 0.004 mg or less, or 0.005 mg or less, or 0.006 mg or less, or 0.007 mg or less, or 0.008 mg or less, or 0.009 mg or less, or 0.010 mg or less, or 0.01 1 mg or less, or 0.012 mg or less, or 0.013 mg or less, or 0.014 mg or less, or 0.015 mg or less, or 0.016 mg or less, or 0.017 mg or less, or 0.018 mg or less, or 0.019 mg or less, or 0.020 mg or less, or 0.021 mg or less, or 0.022 mg or less, or 0.023 mg or less, or 0.024 mg or less, or 0.025 mg or less, or 0.026 mg or less, or 0.027 mg or less, or 0.028 mg or
  • a microinjection device is used to deliver teriparatide to a subject at a dose of at least about 0.01 mg, or 0.02 mg, or 0.03 mg on a daily basis. In another embodiment, a microinjection device is used to deliver teriparatide to a subject once a day at a dosage of about 0.1 mg, or 0.15 mg, or 0.2 mg, or 0.25 mg, or 0.3 mg in a 1 mL formulation having teriparatide.
  • the length of time in which a given dosage of a parathyroid hormone is delivered to a subject using a microinjection device is dependent on various fluid and delivery properties, such as the volume of a parathyroid hormone formulation, the viscosity of the formulation, the flow rate of the formulation from the microinjection device, the diameter of any fluid channels in any microneedles included in the microinjection device, and the pressure drop across fluid channels in any hollow microneedles included in the microinjection device.
  • a microinjection device can be used to deliver a parathyroid hormone formulation to a subject in a time period between about 0.
  • a microinjection device can be used to deliver a parathyroid hormone formulation to a subject in a time period up to an including 1 minute, or 2 minutes, or 3 minutes, or 4 minutes, or 5 minutes, or 6 minutes, or 7 minutes, or 8 minutes, or 9 minutes, or 10 minutes, or 30 minutes, or 1 hour, or 2 hours, or 3 hours, or 4 hours, or 5 hours, or 6 hours, or 7 hours, or 8 hours, or 9 hours, or 10 hours, or 1 5 hours, or 20 hours, or 24 hours.
  • the length of time in which a given dosage of teriparatide is delivered to a subject using a microinjection device is dependent on various fluid and delivery properties, such as the volume of a teriparatide-containing formulation, the viscosity of the formulation, the flow rate of the formulation from the microinjection device, the diameter of any fluid channels in any microneedles included in the microinjection device, and the pressure drop across fluid channels in any microneedles included in the microinjection device.
  • a microinjection device can be used to deliver a teriparatide formulation to a subject in a time period between about 0.1 seconds and 60 minutes, or between about 30 seconds and 30 minutes, or between about 1 minute and 7 minutes, or between about 2 minutes and 6 minutes, or between about 3 minutes and 5 minutes.
  • a microinjection device can be used to deliver a teriparatide formulation to a subject in a time period up to an including 1 minute, or 2 m inutes, or 3 minutes, or 4 minutes, or 5 minutes, or 6 minutes, or 7 minutes, or 8 minutes, or 9 minutes, or 10 minutes, or 30 minutes, or 1 hour, or 2 hours, or 3 hours, or 4 hours, or 5 hours, or 6 hours, or 7 hours, or 8 hours, or 9 hours, or 10 hours, or 15 hours, or 20 hours, or 24 hours.
  • a microinjection device such as any device provided herein, can be used to deliver a parathyroid hormone, including teriparatide, to a subject at a dosage, in a 1 .0 mL formulation of the parathyroid hormone, of about 0.01 mg, or 0.02 mg, or 0.03 mg, or 0.04 mg 3 or 0.05 mg, or 0.06 mg, or 0.07 mg, or 0.08 mg, or 0.09 mg, or 0.10 mg, or 0.1 1 mg, or 0.12 mg, or 0.13 mg, or 0.14 mg, or 0.
  • a microinjection device such as any device provided herein, can be used to deliver a parathyroid hormone to a subject every 1 hour, or 2 hours, or 3 hours, or 4 hours, or 5 hours, or 6 hours, or 7 hours, or 8 hours, or 9 hours, or 10 hours, or 1 1 hours, or 12 hours, or once a day.
  • a microinjection device such as any device provided herein, can be used to deliver a parathyroid hormone to a subject over a time period of about 0. 1 seconds to 60 minutes, or about 1 second to 30 minutes, or about 5 seconds to 5 minutes, or about 10 seconds to 1 minute, or about 1 5 to 45 seconds.
  • a parathyroid hormone can be delivered to a subject over a period of 1 minute or less, or 2 minutes or less, or 3 minutes or less, or 4 minutes or less, or 5 minutes or less, or 6 minutes or less, or 7 minutes or less, or 8 minutes or less, or 9 minutes or less, or 10 minutes or less, or 30 minutes or less, or 1 hour or less, or 2 hours or less, or 3 hours or less, or 4 hours or less, or 5 hours or less, or 6 hours or less, or 7 hours or less, or 8 hours or less, or 9 hours or less, or 10 hours or less, or 1 1 hours or less, or 12 hours or less, or 13 hours or less, or 14 hours or less, or 15 hours or less, or 16 hours or less, or 1 7 hours or less, or 1 8 hours or less, or 1 9 hours or less, or 20 hours or less, or 21 hours or less, or 22 hours or less, or 23 hours or less, or 24 hours or less.
  • a microinjection device such as any device provided herein, can be used to deliver a parathyroid hormone to a subject at a dosage of about 0.25 mg in a 1 mL formulation once a day over a period less than about 1 hour, or less than about 30 minutes, or less than about 10 minutes, or less than about 1 minute.
  • a microinjection device such as any device provided herein, can be used to deliver a parathyroid hormone to a subject in a time period of about 30 seconds, or 1 minute, or 1.5 minutes, or 2 minutes, or 2.5 minutes, or 3 minutes, or 3.5 minutes, or 4 minutes, or 4.5 minutes, or 5 minutes, or 5.5 minutes, or 6 minutes, or 7.5 minutes, or 8 minutes, or 8.5 minutes, or 9 minutes, or 9.5 minutes, or 10 minutes, or 1 0.5 minutes, or 1 1 minutes, or 1 1.5 minutes, or 1 2 minutes, or 12.5 minutes, or 13 minutes, or 1 3.5 minutes, or 14 minutes, or 14.5 minutes, or 15 minutes, or 1 5.5 minutes, or 1 6 minutes, or 16.5 minutes, or 1 7 minutes, or 1 7.5 minutes, or 1 8 minutes, or 1 8.5 minutes, or 19 minutes, or 19.5 minutes, or 20 minutes, or 20.5 minutes, or 21 minutes, or 21 .5 minutes, or 22 minutes, or 22.5 minutes, or 23 minutes, or 23..5 minutes, or
  • a microinjection device such as any device provided herein, can be used to deliver teriparatide to a subject at a dosage, in a 1.0 mL formulation having the teriparatide, of about 0.01 mg, or 0.02 mg, or 0.03 mg, or 0.04 mg, or 0.05 mg, or 0.06 mg, or 0.07 mg, or 0.08 mg, or 0.09 mg, or 0.10 mg, or 0.1 1 mg, or 0.12 mg, or 0.13 mg, or 0.14 mg, or 0.15 mg, or 0.16 mg, or 0.17 mg, or 0.1 8 mg, or 0.19 mg, or 0.20 mg, or 0.21 mg, or 0.22 mg, or 0.23 mg, or 0.24 mg, or 0.25 mg, or 0.26 mg, or 0.27 mg, or 0.28 mg, or 0.29 mg, or 0.30 mg, or 0.31 mg, or 0.32 mg, or 0.33 mg, or 0.34 mg, or 0.35 mg, or 0.36 mg, or 0.37 mg, or 0.38 mg, or
  • a microinjection device such as any device provided herein, can be used to deliver teriparatide to a subject every 1 hour, or 2 hours, or 3 hours, or 4 hours, or 5 hours, or 6 hours, or 7 hours, or 8 hours, or 9 hours, or 10 hours, or 1 1 hours, or 12 hours, or once a day.
  • a microinjection device such as any device provided herein, can be used to deliver teriparatide to a subject over a time period of about 0.1 seconds to 60 minutes, or about 1 second to 30 minutes, or about 5 seconds to 5 minutes, or about 10 seconds to 1 minute, or about 15 to 45 seconds.
  • teriparatide can be delivered to a subject over a period of 1 minute or less, or 2 minutes or less, or 3 minutes or less, or 4 minutes or less, or 5 minutes or less, or 6 minutes or less, or 7 minutes or less, or 8 minutes or less, or 9 minutes or less, or 10 minutes or less, or 30 minutes or less, or 1 hour or less, or 2 hours or less, or 3 hours or less, or 4 hours or less, or 5 hours or less, or 6 hours or less, or 7 hours or less, or 8 hours or less, or 9 hours or less, or 10 hours or less, or 1 1 hours or less, or 12 hours or less, or 13 hours or less, or 14 hours or less, or 15 hours or less, or 16 hours or less, or 1 7 hours or less, or 1 8 hours or less, or 19 hours or less, or 20 hours or less, or 21 hours or less, or 22 hours or less, or 23 hours or less, or 24 hours or less.
  • a microinjection device such as any device provided herein, can be used to deliver teriparatide to a subject at a dosage of about 0.25 mg in a 1 mL formulation once a day over a period less than about I hour, or less than about 30 minutes, or less than about 10 minutes, or less than about 1 minute.
  • a microinjection device such as any device provided herein, can be used to deliver teriparatide to a subject in a time period of about 30 seconds, or 1 minute, or 1.5 minutes, or 2 minutes, or 2.5 minutes, or 3 minutes, or 3.5 minutes, or 4 minutes, or 4.5 minutes, or 5 minutes, or 5.5 minutes, or 6 minutes, or 7.5 minutes, or 8 minutes, or 8.5 minutes, or 9 minutes, or 9.5 minutes, or 10 minutes, or 10.5 minutes, or 1 1 minutes, or 1 1.5 minutes, or 12 m inutes, or 12 5 minutes, or 13 m inutes, or 13 5 minutes, or 14 minutes, or 14.5 minutes, or 1 5 m inutes, or 1 5 5 minutes, or 1 6 m inutes, or 1 6 5 minutes, or 1 7 minutes, or 17.5 minutes, or 1 8 m inutes, or 18 5 minutes, or 19 m inutes, or 19 5 minutes, or 20 minutes, or 20.5 minutes, or 21 m inutes, or 21 5
  • a microinjection device such as any device provided herein, can be used to deliver a parathyroid hormone to a subject once a day at a dose of about 0.001 mg, or 0.002 mg, or 0.003 mg, or 0.004 mg, or 0.005 mg, or 0.006 mg, or 0.007 mg, or 0.008 mg, or 0.009 mg, or 0.010 mg, or 0.01 1 mg, or 0.012 mg, or 0.013 mg, or 0.014 mg, or 0.015 mg, or 0.016 mg, or 0.017 mg, or 0.01 8 mg, or 0.019 mg, or 0.020 mg, or 0.021 mg, or 0.022 mg, or 0.023 mg, or 0.024 mg, or 0.025 mg, or 0.026 mg, or 0.027 mg, or 0.028 mg, or 0.029 mg, or 0.030 mg, or 0.031 mg, or 0.032 mg, or 0.033 mg, or 0.034 mg, or 0.035
  • a microinjection device can be used to deliver 0.020 mg (20 ⁇ g) of a parathyroid hormone per dose to a subject once a day for up to 28 days.
  • a microinjection device such as any device provided herein, can be used to deliver teriparatide to a subject once a day at a dose of about 0.001 mg, or 0.002 mg, or 0.003 mg, or 0.004 mg, or 0.005 mg, or 0.006 mg, or 0.007 mg, or 0.008 mg, or 0.009 mg, or 0.010 mg, or 0.01 1 mg, or 0.012 mg, or 0.013 mg, or 0.014 mg, or 0.015 mg, or 0.016 mg, or 0.017 mg, or 0.018 mg, or 0.019 mg, or 0.020 mg, or 0.021 mg, or 0.022 mg, or 0.023 mg, or 0.024 mg, or 0.025 mg, or 0.026 mg, or 0.027 mg, or 0.028
  • the equivalent of 0.1 mg, or 0.15 mg, or 0.2 mg, or 0.25 mg, or 0.3 mg of a parathyroid hormone formulation in a 1.0 mL solution is delivered to a subject once a day.
  • the equivalent of 0.1 mg, or 0.15 mg, or 0.2 mg, or 0.25 mg, or 0.3 mg of a parathyroid hormone formulation in a 1.0 mL solution is delivered to a subject once a day and over a time period up to and including 1 minute, or 2 minutes, or 3 minutes, or 4 minutes, or 5 minutes, or 6 minutes, or 7 minutes, or 8 minutes, or 9 minutes, or 10 minutes, or 20 minutes, or 30 minutes, or 40 minutes, or 50 minutes, or 1 hour, or 2 hours, or 3 hours, or 4 hours, or 5 hours, or 6 hours, or 7 hours, or 8 hours, or 9 hours, or 10 hours, or 1 1 hours, or 12 hours, or 13 hours, or 14 hours, or 15 hours, or 16 hours, or 1 7 hours, or
  • a microinjection device such as any device provided herein, is loaded with a parathyroid hormone formulation having a parathyroid hormone concentration of about 0.10 mg/1 mL, or 0.15 mg/1 mL, or 0.20 mg/1 mL, or 0.25 mg 1 mL, or 0.30 mg/1 niL.
  • the microinjection device can be used to deliver the parathyroid hormone formulation to a subject over a predetermined time period, such as a time period up to and including 1 minute, or 2 minutes, or 3 minutes, or 4 minutes, or 5 minutes, or 6 minutes, or 7 minutes, or 8 minutes, or 9 minutes, or 10 minutes, or 20 minutes, or 30 minutes, or 40 minutes, or 50 minutes, or 1 hour, or 2 hours, or 3 hours, or 4 hours, or 5 hours, or 6 hours, or 7 hours, or 8 hours, or 9 hours, or 10 hours, or 1 1 hours, or 12 hours, or 13 hours, or 14 hours, or 15 hours, or 16 hours, or 17 hours, or 18 hours, or 19 hours, or 20 hours, or 21 hours, or 22 hours, or 23 hours, or 24 hours.
  • a time period up to and including 1 minute, or 2 minutes, or 3 minutes, or 4 minutes, or 5 minutes, or 6 minutes, or 7 minutes, or 8 minutes, or 9 minutes, or 10 minutes, or 20 minutes, or 30 minutes, or 40 minutes, or 50 minutes
  • a subject can apply a microinjection device having a parathyroid hormone formulation with a parathyroid hormone concentration of about 0.10 mg/1 mL, or 0.15 mg/1 mL, or 0.20 mg/1 mL, or 0.25 mg/1 mL, or 0.30 mg/1 mL to the subject's arm for delivery of parathyroid hormone on a daily basis.
  • the equivalent of 0.1 mg, or 0.15 mg, or 0.2 mg, or 0.25 mg, or 0.3 mg of teriparatide in a 1.0 mL solution is delivered to a subject once a day.
  • the equivalent of 0.1 mg, or 0.15 mg, or 0.2 mg, or 0.25 mg, or 0.3 mg of teriparatide in a 1.0 mL solution is delivered to a subject once a day and over a time period up to and including 1 minute, or 2 minutes, or 3 minutes, or 4 minutes, or 5 minutes, or 6 minutes, or 7 minutes, or 8 minutes, or 9 minutes, or 10 minutes, or 20 minutes, or 30 minutes, or 40 minutes, or 50 minutes, or 1 hour, or 2 hours, or 3 hours, or 4 hours, or 5 hours, or 6 hours, or 7 hours, or
  • a microinjection device such as any device provided herein, is loaded with a teriparatide-containing formulation having a teriparatide concentration of about 0.10 mg/1 mL, or 0.15 mg/1 mL, or 0.20 mg/1 mL, or 0.25 mg/1 mL, or 0.30 mg/1 mL.
  • the microinjection device can be used to deliver the teriparatide-containing formulation to a subject over a predetermined time period, such as a time period up to and including 1 minute, or 2 minutes, or 3 minutes, or 4 minutes, or 5 minutes, or 6 minutes, or 7 minutes, or 8 minutes, or
  • a subject can apply a microinjection device having a teriparatide-containing formulation with a teriparatide concentration of about 0.10 mg/1 mL, or 0.15 mg/1 mL, or 0.20 mg/1 mL, or 0.25 mg/1 mL, or 0.30 mg/1 mL to the subject's arm for delivery of the
  • a microinjection device having a deliverable parathyroid hormone formulation is provided.
  • a parathyroid hormone, parathyroid hormone-containing, teriparatide or teriparatide-containing formulation can be delivered by subcutaneous, transdermal or intradermal injection.
  • a user places the device adjacent another user's skin or adjacent the user's skin, if self administration is desired, to deliver the parathyroid hormone formulation.
  • the user employs the microinjection device to deliver the parathyroid hormone formulation to another user or the user (self administration). The user then removes the microinjection device from the skin.
  • the microinjection device is a single use device and is be disposed of after it is used.
  • the microinjection device can be used for a future administration of the parathyroid hormone formulation, such as with a replaceable cartridge or with additional doses provided in the original cartridge having the parathyroid hormone formulation.

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Abstract

Cette invention concerne des systèmes et des dispositifs utilisés pour administrer des hormones parathyroïdiennes à un sujet, lesdites hormones pouvant être administrées par voie sous-cutanée, transdermique ou intradermique. Dans certains cas, les préparations d'hormones parathyroïdiennes comportent du tériparatide ou des préparations contenant du tériparatide.
PCT/US2011/063034 2010-12-02 2011-12-02 Administration d'hormones parathyroïdiennes par des systèmes de micro-injection WO2012075375A1 (fr)

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* Cited by examiner, † Cited by third party
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WO2012130193A1 (fr) * 2011-03-31 2012-10-04 Zentiva, K.S. Complexes solubles non covalents de tériparatide contenant des polysaccharides et forme pharmaceutique de tériparatide pour administration orale
EP2818159A1 (fr) * 2013-06-25 2014-12-31 LTS LOHMANN Therapie-Systeme AG Dispositif doté d'un système thérapeutique transdermique, d'une aide au positionnement et d'une aide à la pénétration
US20160220486A1 (en) * 2013-06-28 2016-08-04 Amgen Inc. Stable liquid formulation of amg 416 (velcalcetide)
US9555014B2 (en) 2010-05-12 2017-01-31 Radius Health, Inc. Therapeutic regimens
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US10385008B2 (en) 2017-01-05 2019-08-20 Radius Pharmaceuticals, Inc. Polymorphic forms of RAD1901-2HCL
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