NZ618003B2

NZ618003B2 - Method of drug delivery for pth, pthrp and related peptides

Info

Publication number: NZ618003B2
Application number: NZ618003A
Authority: NZ
Inventors: Amy S Determan; Kris J Hansen; Gary Hattersley; Ying Zhang
Original assignee: Kindeva Drug Delivery Lp; Radius Health Inc
Priority date: 2011-04-22
Filing date: 2012-04-20
Publication date: 2016-08-30

Abstract

Disclosed is an aqueous formulation comprising [Glu22,25, Leu23,28,31, Aib29, Lys26,30]hPTHrP(1-34)NH2 and histidine, an aqueous formulation comprising [Glu22,25, Leu23,28,31, Aib29,Lys26,30]hPTHrP(1-34)NH2, wherein said formulation has a viscosity of greater than 500 centipoises and a microprojection array suitable for transdermal drug delivery, wherein said microprojection array comprises a backing material with a plurality of attached microprojections wherein at least one of said microprojections comprises a coating of a formulation comprising [Glu22,25, Leu23,28,31, Aib29, Lys26,30]hPTHrP(1-34)NH2 and histidine. Also disclosed is the use of such compositions and microarrays for the manufacture of a medicament for use in the treatment of conditions such as osteperosis, post-menopausal osteoporosis, one or more fractured bones and osteoarthritis. on array suitable for transdermal drug delivery, wherein said microprojection array comprises a backing material with a plurality of attached microprojections wherein at least one of said microprojections comprises a coating of a formulation comprising [Glu22,25, Leu23,28,31, Aib29, Lys26,30]hPTHrP(1-34)NH2 and histidine. Also disclosed is the use of such compositions and microarrays for the manufacture of a medicament for use in the treatment of conditions such as osteperosis, post-menopausal osteoporosis, one or more fractured bones and osteoarthritis.

Description

METHOD OF DRUG DELIVERY FOR PTH, PTHrP AND RELATED PEPTIDES RELATED APPLICATIONS This application claims the benefit of U.S. Provisional Application No. 61/478,466, filed April 22, 2011 and U.S. Piovisional Application No. 61/578,120, filed December 20, 2011. The entire contents of the above applications are incorporated herein by reference.

BACKGROUND OF THE INVENTION Parathyroid hormone-related protein ("PTHrP") is a 139 to 173 amino acid- protein. PTHrP, especially the C-terminal 1-36 secretory product and certain analogs, are known to be useful for the treatment of osteoporosis and related disorders by stimulating bone formation to improve bone mineral density (BMD).

PTHrP analogues having excellent pharmacological properties and parenteral storage stable compositions thereof are described in hit. Publ. No. WO 2008/063279, the entire contents of which are hereby incorporated by reference.

The effective delivery of PTHrP analogues by routes other than subcutaneous could provide potential advantages such as improved patient satisfaction and compliance.

One alternative to subcutaneous delivery is delivery by a microneedle or microprojection patch ("MNP") route. According to a standard definition, transdermal delivery refers to delivery of a drug substance across the skin. While certain types of drugs can be formulated and delivered using, for example, transdermal patches that allow for the passive diffusion of the drug across the skin, not all drugs perform well in the transdermal venue. One of the common reasons why a particular drug or class of drugs does not effectively penetrate. through the skin to reach systemic circulation is the particular nature of the outermost skin layer.

The outermost skin layer in humans is called the stratum corneum and it is composed primarily of several layers of dead skin cells. The stratum corneum poses a formidable barrier to the transdermal delivery of a drug because unless the drug is capable of diffusing through the stratum comeum layer, it will not efficiently enter the circulation - the stratum corneum is not vascularized. As such, many large molecules or drugs of high water solubility cannot effectively diffuse through the stratum corneum, especially charged macromolecules such as peptides.

It is believed that treatments employing PTHrP analogues are most therapeutic if the pharmacokinetics are controlled, thereby achieving bone anabolic effects without losing efficacy of causing bone loss. As such, use of microprojection patches can result in complicated therapies if effective and reproducible coating of the microprojections is not achieved. Improved methods of delivering PTHrP analogues are needed.

SUMMARY OF THE INVENTION One way for a drug, such as a peptide drug, to bypass the stratum corneum is to use small piercing elements to deliver a drug through the stratum corneum and place the drug into the intradermal space, sometimes referred to as intradermal delivery. For purposes of conveying meaning in the context of this invention description, the terms “transdermal” and “intradermal” are interchangeable when referring to the microprojection or microneedle assisted delivery of the PTHrP, PTHrP analogues 22,25 23,28,31 29 26,30 including [Glu , Leu , Aib , Lys ]PTHrP(1-34)NH . These small piercing elements can take the form of microprojections comprising various materials, shapes and dimensions. In some instances they can take the form of microneedles.

The present invention relates to drug formulations (e.g., aqueous formulations) comprising PTHrP and PTHrP analogues useful for coating microprojections for use in microprojection patch arrays, methods of coating microprojections and microprojection patch arrays, drug-coated microprojections and drug-coated microprojection patch arrays. The present invention also relates to the intradermal delivery of PTHrP and PTHrP analogues and methods of treating osteoporosis, osteopenia, fractured bones and osteoarthritis using transdermal delivery, for example, using drug-coated microprojections and microprojection arrays. In particular, the PTHrP analogue for use 22,25 23,28,31 29 26,30 in embodiments of the invention is [Glu , Leu , Aib , Lys ]PTHrP(1- 34)NH .

According to a first aspect, the present invention provides an aqueous formulation comprising [Glu22,25, Leu23,28,31, Aib29, Lys26,30]hPTHrP(1-34)NH and histidine. 11285858 According to a second aspect, the present invention provides an aqueous 22,25 23,28,31 29 26,30 formulation comprising [Glu , Leu , Aib , Lys ]hPTHrP(1-34)NH , wherein said formulation has a viscosity of greater than 500 centipoises.

According to a third aspect, the present invention provides a microprojection array suitable for transdermal drug delivery, wherein said microprojection array comprises a backing material with a plurality of attached microprojections wherein at least one of said microprojections comprises a coating of a formulation comprising [Glu22,25, Leu23,28,31, Aib29, Lys26,30]hPTHrP(1-34)NH and histidine. 22,25 According to a fourth aspect, the present invention provides the use of [Glu , 23,28,31 29 26,30 Leu , Aib , Lys ]hPTHrP(1-34)NH for the manufacture of a medicament for use in the treatment of a mammal, wherein said medicament is formulated for administration to said mammal by contacting the skin of said mammal with a microprojection array according to the third aspect with sufficient force to cause penetration of one or more of said microprojections comprising a coating of said formulation into the skin of said mammal. 22,25 According to a fifth aspect, the present invention provides the use of [Glu , 23,28,31 29 26,30 Leu , Aib , Lys ]hPTHrP(1-34)NH for the manufacture of a medicament for use in the treatment of osteoporosis in a human in need thereof wherein said 22,25 23,28,31 29 medicament is formulated for administration of [Glu , Leu , Aib , 26,30 Lys ]hPTHrP(1-34)NH once-daily according to the use of the fourth aspect. 22,25 According to a sixth aspect, the present invention provides the use of [Glu , 23,28,31 29 26,30 Leu , Aib , Lys ]hPTHrP(1-34)NH for the manufacture of a medicament for use in the treatment of osteoporosis in a human in need thereof wherein said 22,25 23,28,31 29 medicament is formulated for administration of [Glu , Leu , Aib , 26,30 Lys ]hPTHrP(1-34)NH once-weekly according to the use of the fourth aspect.

According to a seventh aspect, the present invention provides the use of 22,25 23,28,31 29 26,30 [Glu , Leu , Aib , Lys ]hPTHrP(1-34)NH for the manufacture of a medicament for use in the treatment of post-menopausal osteoporosis wherein said 22,25 23,28,31 29 medicament is formulated for administration of [Glu , Leu , Aib , 26,30 Lys ]hPTHrP(1-34)NH to a woman in need thereof by contacting the skin of said woman with a microprojection array according to the third aspect with sufficient force 11285858 to cause penetration of one or more of said microprojections comprising a coating of said formulation into the skin of said woman and wherein said administration 22,25 23,28,31 29 26,30 results in C plasma levels of [Glu , Leu , Aib , Lys ]hPTHrP(1-34)NH max 2 of greater than 200 pg/mL.

According to an eighth aspect, the present invention provides the use of 22,25 23,28,31 29 26,30 [Glu , Leu , Aib , Lys ]hPTHrP(1-34)NH for the manufacture of a medicament for use in the treatment of one or more fractured bones wherein said 22,25 23,28,31 29 medicament is formulated for administration of [Glu , Leu , Aib , 26,30 Lys ]hPTHrP(1-34)NH to a human in need thereof by contacting the skin of said human with a microprojection array according to the third aspect with sufficient force to cause penetration of one or more of said microprojections comprising a coating of said formulation into the skin of said human. 22,25 According to a ninth aspect, the present invention provides the use of [Glu , 23,28,31 29 26,30 Leu , Aib , Lys ]hPTHrP(1-34)NH for the manufacture of a medicament for use in the treatment of osteoarthritis wherein said medicament is formulated for 22,25 23,28,31 29 26,30 administration of [Glu , Leu , Aib , Lys ]hPTHrP(1-34)NH to a human in need thereof by contacting the skin of said human with a microprojection array according to the third aspect with sufficient force to cause penetration of one or more of said microprojections comprising a coating of said formulation into the skin of said human.

The sequence of native hPTHrP (1-34) is as follows: Ala Val Ser Glu His Gln Leu Leu His Asp Lys Gly Lys Ser Ile Gln Asp Leu Arg Arg Arg Phe Phe Leu His His Leu Ile Ala Glu Ile His Thr Ala (SEQ ID NO:1). 11285858 In a particular embodiment, the PTHrP analogue is [G1u 22 ’25 , Leu23 ’28’3 ’ Aib29 , Lys 26 ’30]hPTHrP(1-34)NH 2 (SEQ ID NO.: 2).

In one aspect, the present invention relates to formulations containing PTHrP or PTHrP 1-34 analogues including [G1u 22’25, Leu 23 ’28’31 , Aib29, Lys 26’30]PTHrP(1- 34)NH2 . In particular, these formulations are useful for coating one or more microproj ections or a microproj ection array including a microneedle patch array ("IvINP") with said PTHrP or PTHrP 1-34 analogues including [G1u 2225 , Leu23’28 ’31 , Aib 29 , Lys 26’30]PTHrP(l-34)NH 2 . These formulations can be described by their contents including the percent of PTI-IrP or PTHrP analogue including [G1u 22’25 , Leu23 ’28’31 , Aib29 , Lys 26’30]PTHrP(1-34)NH 2 . The coating formulation refers to the formulation composition that is used to coat the microprojections. By way of a non- limiting example in order to help understand the process and use of the described embodiments, a microprojection array comprises at least one but usually a plurality of microprojections that are typically affixed to a backing material and are coated by a formulation (e.g., an aqueous formulation) that contains a PTI{rP analogue including [Glu 22’25, Leu23 ’28’31 , Aib29, Lys 26’30]PTHrP(1-34)N}1 2 at a defined by weight concentration. The percent by weight in the coating formulation is not typically the percent by weight in the drug delivery device as used since the coating formulation is designed to be useful for coating the drug onto the microprojections and then the coated microprojections are often subject to further processing (e.g. drying) and storage conditions that will likely affect the proportions of ingredients in the final composition. Where the array of microprojections or microneedles is affixed to a flexible backing material, that array is sometimes referred to as a microprojection patch array or microneedle patch array or simply microneedle patch.

The microneedle patch may contain an adhesive material in order to facilitate its staying in place while the drug is released from the projections or needles of the patch.

In one embodiment of this invention, the formulation useful for coating one or more microprojections or a microprojection array is an aqueous formulation comprising at least by weight of [G1u 22 ’25, Leu23 ’28 ’31 , Aib29, Lys26’30]PTHrP(1- 34)NH2.

In a related embodiment, an aqueous formulation useful for coating one or more microprojections or a microprojection array comprising at least 10% by weight of [Glu22 ’25 , Leu 23 ’28 ’31 , Aib 29, Lys26’30]PTHrP(l-34)NH 2 is described. In yet other embodiments, an aqueous formulation useful for coating one or more microprojections or a microprojection array comprising at least 20%, or at least %, or at least 40%, or at least 45% by weight of [G1u 22’25 , Leu23 ’28’31 , Aib29 , Lys 2630]PTHrP(l-34)N}1 2 is described. In certain embodiments of this invention, an aqueous formulation useful for coating one or more microprojections or a microprojection array comprising between 40% and 63% by weight [G1u 2225 , Leu23 ’28’31 , Aib29, Lys"’ ]PTHrP(l-34)NH 2 is described. In certain embodiments of this invention, an aqueous formulation useful for coating one or more microprojections or a microprojection array comprising between 43% and 63% by weight [G1u 22 ’25 , Leu23 ’28’31 , Aib 29, Lys 26 ’30]PTHrP(l-34)N}1 2 is described.

In some embodiments of this invention, an aqueous formulation useful for coating one or more microprojections or a microprojection array comprising 5% to % by weight [G1u 22 ’25 , Leu2328’31 , Aib 29, Lys 26 ’30]PTHrP(l-34)NH 2 is described.

In other embodiments of this invention, an aqueous formulation useful for coating one or more microprojections or a microproj ection array comprising 12.5% to 20% by weight [G1u 22’25, Leu23 ’28’31 , Aib29, Lys 26’30]PTHrP(l-34)NH 2 is described. In other embodiments of this invention, an aqueous formulation useful for coating one or more microprojections or a microprojection array comprising 15% to 60% by weight [G1u 22’25, Leu23 ’28 ’31 , Aib 29, Lys 26 ’30]PTHrP(1-34)NH 2 is described.

In some embodiments of this invention, an aqueous formulation useful for coating one or more microprojections or a microprojection array comprising 43%- 48% by weight [G1u22’25 , Leu 23 ’28 ’31 , Aib 29, Lys2630]PTHrP(l-34)NH 2 is described.

In other embodiments of this invention, an aqueous formulation useful for coating one or more microprojections or a microprojection array comprising 46%-52% by weight [G1u 22’25, Leu 23 ’28’31 , Aib29 , Lys 26 ’30]PTHrP(1 -34)NH2 is described.

In some embodiments of this invention, an aqueous formulation useful for coating one or more microprojeetions or a microprojection array comprising 40%- 48% by weight [G1u 22’25, Leu23 ’28 ’31 , Aib29, Lys 26 ’30]PTHrP(l-34)NT4 2 is described.

In other embodiments of this invention, an aqueous formulation useful for coating one or more microprojections or a microprojection array comprising 40%-46% by weight [G1u 22’25, Leu 23 ’2831 , Aib29, Lys 26’30]PTHrP(l-34)NH2 is described. In other embodiments of this invention, an aqueous formulation useful for coating one or more microproj ections or a microprojeetion array comprising 40%-52% by weight [G1u22 ’25, Leu23 ’28 ’31 , Aib29, Lys 26’30]PTHrP(1-34)NI-1 2 is described.

In some embodiments of this invention, an aqueous formulation useful for coating one or more microprojections or a microprojection array comprising 50%- 62% by weight [G1u 22’25 , Leu23 ’28’31 , Aib29, Lys26 ’30]PTHrP(l-34)NH 2 is described.

In other embodiments of this invention, an aqueous formulation useful for coating one or more microprojections or a microprojection array comprising 52%-60% by weight [G1u 22 ’25, Leu23 ’2831 , Aib 29, Lys26 ’30]PTHrP(l-34)NH 2 is described. In other embodiments of this invention, an aqueous formulation useful for coating one or more microprojections or a microprojection array comprising 54%-5 8% by weight [G1u22’25, Leu23 ’28’31 , Aib29 , Lys 26’30]PTHrP(l-34)NH 2 is described.

In other embodiments of this invention, an aqueous formulation useful for coating one or more microprojections or a microprojection array comprises 54% by weight [G1u 22’25 , Leu23’28’31 , Aib29, Lys 26 ’30]PTHrP(l-34)NH 2 and 46% by weight PBS. In some embodiments of this invention, an aqueous formulation useful for coating one or more microprojections or a microprojection array comprises 58% by weight [G1u 22 ’25, Leu23 ’28 ’31 , Aib 29, Lys26 ’30]PTHrP(I-34)NH2 and 42% by weight PBS.

It should be appreciated that for purposes of describing this invention unless , Aib29 , otherwise stated, the percent by weight of peptide such as [G1u 22’25, Leu 23 ’28 ’31 Lys 26’30 ]PTHrP(1 -34)NH2 refers to normalized peptide content and excludes the presence of various co-excipients, counterions, etc. Percent by weight refers to percent weight of peptide content over the total weight of the formulation being discussed. So for example, when a peptide is synthesized it may contain water, cosolvents (such as acetic acid), counter ions, water, etc. In order to adjust for batch to batch variance, it is preferred in the present context to refer to the pure peptide content meaning content exclusive of said additional cosolvents, counter ions, water, and other non-peptidic components.

In certain embodiments of this invention, the term "suitable for coating a microprojection array" means that the formulation is useful for coating a microprojection array. The term useful in this context means that the aqueous formulation is useful for coating the array in a manner that is consistent with that arrays eventual use in a mammal, preferably a human. The formulations may be coated on a microneedle or a inicroprojection array using various techniques known in the art such as dip-coating by dipping the array into a formulation, brushing a formulation onto an array, or applying aliquots of a fonnuation onto an array.

Examples of coating microneedle arrays can be found, for example, in United States Patent Application Publication No. 2008/0051699.

The aqueous formulation comprising [G1u22’25, Leu2328’31 , Aib29 26’30]PTHrP(l-34)NH 2 in any of the concentration ranges described may further comprise additional excipients. Additional excipients can include, for example, stabilizing agents, buffers and/or amphiphilic surfactants.

In some embodiments, one or more saccharides or polysaccharides are included as excipients in the aqueous formulation. In certain embodiments, the polysaccharide hydroxyethyl cellulose (HEC) is an added excipient. In another embodiment, the aqueous formulation comprises sucrose.

In some embodiments, buffered saline solutions are included in the aqueous formulation. Suitable buffered saline solutions include phosphate buffered saline (PBS), Tris buffered saline (TBS), saline-sodium acetate buffer (SSA), and saline- sodium citrate buffer (SSC). In one embodiment, the aqueous formulation comprising [G1u 22’25, Leu23 ’28’31 , Aib29, Lys 2630]PTHrP( 1-3 4)NH2 may further comprise phosphate buffered saline (PBS buffer). In one aspect of this embodiment, the PBS buffer used in the aqueous formulation has a pH of from 6.6 to 8.2. In another aspect of this embodiment, the PBS used in the aqueous formulation has a pH of from 6.8 to 8, or from 7.0 to 7.8, or from 7.2 to 7.6, or about 7.4, or 7.4. Inyet another aspect of this embodiment, the PBS buffer is from 0.5X to lOX buffer concentration, or from 0.5X to 5X, or lx. In a particular embodiment, the aqueous formulation useful for coating one or more microprojections or a microprojection array comprises [G1u 22 ’25, Leu23 ’28’31 , Aib29, Lys26’30]PTHrP(l-34)NH2 and PBS as the sole excipient. In a specific aspect of this embodiment, the PBS has a 1X buffer concentration. In a more particular embodiment, the aqueous formulation useful for coating one or more microprojections or a microprojection array comprises [Glu 22’25 , Leu23 ’2831 , Aib29, Lys2630]PTHrP(1-34)NH2 and 1X PBS as the sole excipient wherein the peptide is present at about 50%-62% by weight, such as 52%-60% by weight such as 54%-58% by weight. In another particular embodiment, the aqueous formulation useful for coating one or more microprojections or a microprojection array comprises [G1u 22’25, Leu23 ’28’31 , Aib29, Lys 26’30]PTHrP(1-34)NH2 and 1X PBS as the sole excipient wherein the peptide is present at about 58% by weight and the PBS is present at about 42% by weight.

In certain embodiments of this invention, the microneedle coating formulations can be characterized by their final pH. One of ordinary skill in the art will appreciate that the pH of the final coating formulation can be different from the pH of the buffer used to co-formulate the peptide, such as [Glu 22’25, Leu2328’31 , Aib29, Lys26 ’30]PTHrP(l-34)NH 2, especially when the peptide is highly concentrated and/or contains significant amounts of other pH-affecting co-solutes such acetic acid. In particular, the coating formulations of peptides such as [Glu 22 ’25, Leu23 ’28’31 , Aib29 , 26’30]PTHrP(1-34)NH 2 may have pH values lower than the pH of the included buffer, such as an included PBS buffer. For example, some embodiments of the coating formulations of this invention may have a pH that falls between 3 and 8, or 3 and 7,or3.5 and 6.5, or 4 and 6, or 4.5 and 5.5.

In some embodiments, the [G1u 22 ’25, Leu 23 ’28’31 , Aib 29, Lys26 ’30]PTHrP(l- 34)NH2 used in the preparation of aqueous formulation solutions suitable for the preparation of one or more drug-coated microprojections or drug-coated microprojection arrays may further contain from 3% to 20% acetate present as the acetate ion and/or acetic acid by weight - in the aqueous coating formulation. In other embodiments, the [G1u 22 ’25, Leu23 ’28 ’31 , Aib 29, Lys 26’30]PTHrP(1-34)NH2 may contain from 3% and 15% acetate present as the acetate ion and/or acetic acid by weight used in the aqueous formulation. In certain embodiments, the [G1u 22’25 , Leu 23 ’28’31 , Aib 29, Lys 26 ’30]PTHrP(l-34)NH 2 used in the preparation of aqueous formulation solutions suitable for the preparation of one or more drug-coated microprojections or drug-coated microprojection arrays may contain from 4% and % acetate present as the acetate ion and/or acetic acid by weight in the aqueous formulation.

In certain embodiments, the [G1u 22’25, Leu23 ’28 ’31 , Aib 29, Lys 26 ’30]PTHrP(1- 34)NH 2 used in the preparation of aqueous formulation solutions suitable for the preparation of one or more drug-coated microprojections or drug-coated microprojection arrays may further contain from 1% to 15% trifluoroacetic acid present as the trifluoroacetate ion and/or trifluoroacetic acid by weight in the aqueous formulation. In other embodiments, the [G1u 22’25, Leu23 ’28’31 , Aib29, Lys26’30JPTHrP(1-34)N}1 2 may further contain from 1% to 10% trifluoroacetic acid present as the trifluoroacetate ion and/or trifluoroacetic acid by weight in the aqueous formulation.

In certain embodiments, the [G1u 22’25 , Leu23 ’28’31 , Aib 29, Lys26 ’30]PTHrP( 1- 34)NH2 used in the preparation of aqueous formulation solutions suitable for the preparation of one or more drug-coated microprojections or drug-coated microprojection arrays may further contain from 1% to 15% histidine by weight in the aqueous formulation. In other embodiments, the [G1u 22’25 , Leu 2328 ’31 , Aib29 , Lys26’30]PTHrP(1-34)NH 2 may further contain from 1% to 10% histidine by weight in the aqueous formulation. In other embodiments, the [G1u 22 ’25 , Aib 29 , , Leu23’28 ’31 Lys26’30]PTHrP(l-34)NH 2 may further contain from 1% to 7% histidine by weight in the aqueous formulation. In certain embodiments, the aqueous formulations suitable for the preparation of one or more drug-coated microprojections or drug-coated microprojection arrays may further contain 3% histidine or about 3% histidine. In some embodiments, the aqueous formulations suitable for the preparation of one or more drug-coated microprojections or drug-coated microprojection arrays may further contain 5% histidine or about 5% histidine. In some embodiments, the aqueous formulations suitable for the preparation of one or more drug-coated microprojections or drug-coated microprojection arrays may further contain 10% histidine or about 10% bistidine.

YS21,30 In certain embodiments, the [G1u 22’25 , Leu23’28 ’31 , Aib 29, L ]PTFIrP(I- 34)NH2 used in the preparation of aqueous formulation solutions suitable for the preparation of one or more drug-coated microprojections or drug-coated microprojection arrays may further contain from 1% to 15% potassium chloride by weight in the aqueous formulation. In other embodiments, the [G1u , Leu 23’28 ’31 , 22 ’25 Aib 29 , Lys 26’30]PTHrP(1-34)NH2 may further contain from 2% to 10% potassium chloride by weight in the aqueous formulation. In some embodiments, the [G1u 22’25 , Leu 23 ’28 ’31 , Aib29 , Lys 26 ’30]PTHrP(1-34)NH 2 may further contain 9% potassium chloride by weight in the aqueous formulation. In certain embodiments, the [G1u 22’25 , Leu23 ’28’31 , Aib 29, Lys 26 ’30]PTHrP(l-34)NH 2 may further contain about 9% potassium chloride by weight in the aqueous formulation.In certain embodiments, the [Glu 2225 Leu23 ’28 ’31 , Aib 29 , Lys 26’30]PTHrP(l-34)NI-1 2 used in the preparation of aqueous formulation solutions suitable for the preparation of one or more drug-coated microprojections or drug-coated microprojection arrays may further contain from 1% to 15% arginine by weight in the aqueous formulation. In other embodiments, the [G1u22’25 , Leu23 ’28’31, Aib29, Lys 26’30]PTHrP(1-34)NH2 may further contain from 1% to 7% arginine by weight in the aqueous formulation. In certain embodiments, the aqueous formulations suitable for the preparation of one or more drug-coated microprojections or drug-coated microprojection arrays may further contain 3% arginine or about 3% arginine. In some embodiments, the aqueous formulations suitable for the preparation of one or more drug-coated microproj ections or drug- coated microprojection arrays may further contain % arginine or about 5% arginine.

In some embodiments of this invention, the viscosity of the aqueous formulation comprising [Glu 22’25, Leu23 ’28 ’31 , Aib 29, Lys 26’30] PTHrP( 1 -34)NH 2 suitable for coating microprojections is between 500 centipoises and 10,000 centipoises at room temperature and a high shear rate. In additional embodiments of this invention, the viscosity of the formulation containing [Glu 22’25, Leu23 ’28’31 , Aib29 , Lys 26’30]PTHrP(1-34)NH 2 suitable for coating microprojections is between 500 centipoises and 750 centipoises at room temperature and a high shear rate. In yet additional embodiments of this invention, the viscosity of the formulation containing [Glu22’25 , Leu 23 ’2831 , Aib29, Lys 26 ’30]PTHrP(1-34)NH 2 suitable for coating microprojections is between 500 centipoises and 1000 centipoises at room temperature and a high shear rate. In some embodiments of this invention, the viscosity of [G1u 22 ’25, Leu23 ’28’31 , Aib 29, Lys 26 ’30]PTHrP(1-34)NH2 of the aqueous formulation for the coating of the microprojections is between 1000 centipoises and 2000 centipoises at room temperature and a high shear rate. In some embodiments of this invention, the viscosity of [Glu 26 ’30]PTHrP(l- 22 ’25, Leu23 ’28’31 , Aib29, Lys 34)NH 2 of the aqueous formulation for the coating of the microprojections is between 1000 centipoises and 10,000 centipoises at room temperature and a high shear rate.

As used herein, "room temperature" means a temperature in the the range from 20 C to 25 C, inclusive. In some aspects, the temperature is 23 C or 25 C.

As used herein, "a high shear rate" means a shear rate equal to or greater than 100 s - In some embodiments, the shear rate is 100 s_ i or 128 s.

In some embodiments of this invention, the viscosity of the aqueous formulation comprising [G1u 22’25 , Leu 23 ’28’31 , Aib 29, Lys26’30]PTHrP(l -34)NH 2 suitable for coating microprojections is greater than 500 centipoises when measured at 23C and a shear rate of 128 s_ i . In some embodiments of this invention, the viscosity of the formulation containing [G1u 22 ’25, Leu23 ’28’31 , Aib29, Lys 26’30]PTHrP(1- 34)NH2 suitable for coating microprojections is greater than 600 centipoises at 23C and a shear rate of 128s 1 . In certain embodiments of this invention, the viscosity of the formulation containing [G1u 22’25 , Leu23 ’28 ’31 , Aib 29, Lys26’30]PTI{rP(1-34)NH 2 suitable for coating microprojections is greater than 700 centipoises at 23C and a 1 shear rate of 128s . In certain embodiments of this invention, the viscosity of the formulation containing [G1u 22 ’25 , Leu 23 ’2831 , Aib 29, Lys 26 ’30]PTHrP(1-34)NH 2 suitable for coating microprojections is greater than 800 centipoises at 23C and a shear rate of 128 s* In certain embodiments of this invention, the viscosity of the formulation containing [G1u22’25, LeU21,21’11 , Aib, Lys 26’30] PTHrP( 1 -34)NH 2 suitable for coating microprojections is greater than 1000 centipoises at 23C and a shear rate of 128 s 1 . In still yet additional embodiments of this invention, the viscosity of the formulation containing [G1u 22’25, Leu 23 ’28 ’31 , Aib29 , Lys26’30]PTHrP( 1- 34)NH2 suitable for coating microprojections is greater than 1250 centipoises at 23C and a shear rate of 128 s. In certain embodiments of this invention, the viscosity of the formulation containing [G1u 22 ’25, Leu23 ’28’31 , Aib29, Lys 26’30]PTHrP(l- 34)NH2 suitable for coating microprojections is greater than 1500 at 23 C and a shear rate of 128 s’. In certain embodiments of this invention, the viscosity of the formulation containing [G1u 22’25, Leu23 ’28’31 , Aib29, Lys 26’30]PTHrP( 1 -34)NH2 suitable for coating microprojections is greater than 2500 at 23C and a shear rate of 128s 1 . In certain embodiments of this invention, the viscosity of the formulation containing [G1u 22’25 , Leu23 ’28 ’31 , Aib29, Lys 26 ’30]PTHrP(l-34)NH 2 suitable for coating microprojections is greater than 3500 at 23C and a shear rate of 128s. In certain embodiments of this invention, the viscosity of the formulation containing [G1u 22 ’25 , Leu23 ’28’31 , Aib29, Lys26’30]PTHrP(1-34)NH 2 suitable for coating microprojections is greater than 4500 at 23C and a shear rate of 128s. In certain embodiments of this invention, the viscosity of the formulation containing [01u 22’25, Leu23 ’28’31 , Aib29 , Lys 26’30]PTHrP(l-34)NH 2 suitable for coating microprojections is greater than 5500 at 23C and a shear rate of 128s 1 . In yet still additional embodiments of this invention, the viscosity of the formulation containing {G1u 22’25, Leu23 ’28’31 , Aib 29 , Lys 26’30]PTHrP(1-34)NH suitable for coating microprojections is between 500 centipoises and centipoises at 23C and a shear rate of 128s 1 . In yet additional embodiments of this invention, the viscosity of the formulation containing [G1u 22’25 , Leu 3 ’28 ’31 , Aib29 , Lys2630]PTHrP(1-34)NH 2 suitable for coating microprojections is between 500 centipoises and 1000 centipoises at 23C and a shear rate of 128s 1 . In some embodiments of this invention, the viscosity of [G1u 22’25, Leu23’28’31 , Aib29, Lys26’30]PTHrP(l-34)NH 2 of the aqueous formulation for the coating of the microprojections is between 1000 centipoises and 2000 centipoises at 23C and a shear rate of 128s 1 . In some embodiments of this invention, the viscosity of [G1u22’25, Leu 23 ’28 ’31 , Aib 29, Lys 26’30]PTHrP(1-34)NH 2 of the aqueous formulation for the coating of the microprojections is between 1000 centipoises and 10,000 centipoises at 23C and a shear rate of 128s- .

In some embodiments of this invention, the viscosity of the aqueous formulation comprising [G1u22’25, Leu 23 28’31 , Aib29 , Lys 26’30]PTHrP(1-34)NH 2 suitable for coating microprojections is greater than 500 centipoises when measured at 25 C and a shear rate of 100 s_ I . In some embodiments of this invention, the viscosity of the formulation containing [G1u 22’25, Leu23 ’28 ’31 , Aib 29, Lys 26’30]PTHrP(1- 34)NH2 suitable for coating microprojections is greater than 600 centipoises at 25 C and a shear rate of 100 s* In certain embodiments of this invention, the viscosity of the formulation containing [G1u 22’25, Leu 23 ’28’31 , Aib 29, Lys 26’30 ]PTHrP( 1 -34)NH2 suitable for coating microprojections is greater than 700 centipoises at 25 C and a shear rate of 100 s* In certain embodiments of this invention, the viscosity of the formulation containing [G1u22’25, Leu23 ’28 ’31 , Aib29, Lys 26’30]PTHrP( 1 -34)NH2 suitable for coating microprojections is greater than 800 centipoises at 25 C and a shear rate of 100 s - 1 . In certain embodiments of this invention, the viscosity of the formulation containing [G1u 22’25, Leu23’28’31 , Aib 29 , Lys 26 ’30]PTHrP(1-34)NH 2 suitable for coating microprojections is greater than 1000 centipoises at 25 C and a shear rate of 100 s. In still yet additional embodiments of this invention, the viscosity of the formulation containing [G1u 22 ’25 , Leu 23 ’2831 , Aib29, Lys 2630]PTHrP(1- 34)NH2 suitable for coating microprojections is greater than 1250 centipoises at 25 C and a shear rate of 100 s - 1 . In certain embodiments of this invention, the viscosity of the formulation containing [G1u 22 ’25 , Leu 2328 ’31 , Aib 29, Lys 26 ’30]PTHrP( 1- 34)NH2 suitable for coating microprojections is greater than 1500 at C and a shear rate of 100 s - 1 . In certain embodiments of this invention, the viscosity of the formulation containing [G1u 22’25 , Leu 23 ’28’31 , Aib 29, Lys26’30]PTHrP(1-34)NH2 suitable for coating microprojections is greater than 2500 at 25 C and a shear rate of 100 s* In certain embodiments of this invention, the viscosity of the formulation containing [G1u 22 ’25 , Leu23 ’28’31 , Aib 29, Lys 26 ’30]PTHrP(1-34)NH 2 suitable for coating microprojections is greater than 3500 at 25 C and a shear rate of 100 In certain embodiments of this invention, the viscosity of the formulation containing [G1u 22 ’25 , Leu2328 ’31 , Aib29 , Lys 26’30]PTHrP(1-34)NH 2 suitable for coating microprojections is greater than 4500 at 25 C and a shear rate of 100 s* In certain embodiments of this invention, the viscosity of the formulation containing [Glu 22 ’25, Leu23’28’31 , Aib29 , Lys 26 ’30]PTHrP(1-34)NH 2 suitable for coating microprojections is greater than 5500 at 25 C and a shear rate of 100 s - 1 . In yet still additional embodiments of this invention, the viscosity of the formulation containing [Glu 22’25, Leu23 ’28’31, Aib 29, Lys26’30]PTHrP(1-34)NH2 suitable for coating microprojections is between 500 centipoises and 750 centipoises at 25 C and a shear rate of 100 s 1 . In yet additional embodiments of this invention, the viscosity of the formulation containing [G1u 2225 , Leu23 ’28’31 , Aib29, Lys2630]PTFJrP(l-34)NH 2 suitable for coating microprojections is between 500 centipoises and 1000 centipoises at 25 C and a shear rate of 100 s.

In some embodiments of this invention, the viscosity of [Glu 22’25, Leu23 ’28’, Aib29 , Lys 26’30 ]PTHrP( 1 -34)NH2 of the aqueous formulation for the coating of the microprojections is between 1000 centipoises and 2000 centipoises at 25 C and a shear rate of 100 s - 1 . In some embodiments of this invention, the viscosity of [Glu22’25, Leu23 ’28 ’31 , Aib29, Lys 26 ’30]PTHrP(l -34)NH2 of the aqueous formulation for the coating of the microprojections is between 2000 centipoises and 3000 centipoises at 25 C and a shear rate of 100 In some embodiments of this invention, the viscosity of [G1u 22 ’25, Leu23 ’28 ’31 , Aib29,Lys26 ’30]PTHrP(1-34)NH2 of the aqueous formulation for the coating of the microprojections is between 1000 centipoises and 3000 centipoises at 25 C and a shear rate of 100 s 1 . In some embodiments of this invention, the viscosity of [Glu 22 ’25 , Aib29 , , Leu 23’28’31 Lys 26 ’30]PTHrP(1-34)NH 2 of the aqueous formulation for the coating of the microprojections is between 2000 centipoises and 2500 centipoises at 25 C and a shear rate of 100 In some embodiments of this invention, the viscosity of [Glu’25, Leu23 ’28’31 , Aib 29, Lys 26’30]PTHrP(1-34)NI-12 of the aqueous formulation for the coating of the microprojections is between 1000 centipoises and 10,000 centipoises at 25 C and a shear rate of 100 s_ The shear viscosity is a measurement of the resistance of a fluid to being deformed by shear stress. Various instruments can be used for viscosity testing, including rheometers, for example rheometers from TA Instruments (New Castle, DE).

In some aspects, the invention described herein relates to a drug delivery device comprising a microprojection array comprising a plurality of microprojections wherein one or more of said microprojections is coated with [G1u 22’25, Leu23 ’28’31 , Aib29, Lys 26’30]PTHrP(1-34)NH2. In certain embodiments of this invention, the microprojections are more than 100 microns but less than 1,000 microns in length. In certain embodiments of this invention, the microprojections are more than 250 microns in length. In some microns but less than 750 embodiments of this invention, the microproj ections are between 400 and 600 microns in length. In certain embodiments, the microprojections are about 500 microns in length. In some embodiments, the microprojections are 500 microns in length.

In some embodiments of this invention, the [Glu 22 ’25, Leu 2328 ’31 , Aib 29, Lys26 ’30 ]PTHrP(l -34)NH2 coated microprojections are microneedles. For the purpose of this invention, the term microneedle means a microprojection that has a base and a tip wherein said tip has a lesser diameter, width, perimeter or circumference than said base. In one embodiment of this invention, the microneedles have a tapered design meaning that the microneedle from base to tip reflects a relatively constant narrowing over the length. In certain aspects of this invention, the microneedles have the greatest diameter, width, perimeter or circumference at the base compared to anywhere else on said microneedle. In certain embodiments of this invention, the ratio of the width at the base of the microneedle to the width at tip of the microneedle is greater than 2. In related embodiments, of this invention, the diameter, width, perimeter or circumference at the base of the microneedle to the diameter, width, perimeter or circumference at tip of the microneedle ratio is greater than 4. In related embodiments, of this invention, the diameter, width, perimeter or circumference at the base of the microneedle to the diameter, width, perimeter or circumference at tip of the microneedle ratio is greater than 6. In some embodiments, the needles have a generally circular perimeter about the axis that is broader at the base than the tip. In certain embodiments, the microneedles are pyramidal in shape, with an approximately rectangular base that tapers to an apex wherein said apex is approximately rectangular. In certain embodiments, the microneedles are pyramidal in shape, with a square base that tapers to an apex wherein said apex is approximately square. In certain embodiments, the microneedles are pyramidal in shape with a rectangular or square base and a shape that is not readily characterized as rectangular or square at the top.

In some embodiments of this invention, the microprojection array comprises a backing sheet or member wherein the plurality of microprojections are affixed to said backing sheet or member. In certain embodiments of this invention, the vertical axis of said microprojections extend at an angle of at least 45 degrees from the backing sheet or member. In certain embodiments, said microprojections extend at an angle of at least 60 degrees from the backing sheet or member. In some embodiments, the microprojections are perpendicular to said sheet or member. In certain embodiments, the microprojection arrays of this invention comprises a plurality of microprojections that are made from the same material as the backing sheet or member. In certain embodiments, the microneedle arrays of this invention comprises a plurality of mieroneedles that are made from the same material as the backing sheet or member. In some embodiments, the microprojection arrays of this invention comprises a plurality of microprojections that are integral with the backing sheet or member. In some aspects, the microprojection arrays of this invention comprises a plurality of microprojections that are made by an injection molding process. In certain embodiments, the microprojection arrays of this invention comprises a plurality of microprojections that are made from the same material as the backing sheet or member wherein said microprojection array is made by a molding process. In certain embodiments, the microneedle arrays of this invention comprises a plurality of microneedles that are made from the same material as the backing sheet or member wherein said microprojection array is made by an injection molding process.

In certain embodiments of this invention, the microprojections and/or microneedles are made from carbon containing polymers wherein said microprojections and/or needles can be defined according to their flexural modulus.

In some embodiments, this invention comprises arrays comprising microprojections and/or microneedles coated with [Glu 22 ’25, Leu 23 28 ’31 , Aib 29, Lys26 ’30]PTHrP(1- 34)NH2 wherein said microprojections and/or microneedles are made from carbon containing polymers having a flexural modulus of greater than 1,000 MPa (ISO 178). In certain embodiments, this invention comprises arrays comprising microprojections and/or microneedles made from carbon containing polymers having a flexural modulus of greater than 2,000 MPa (ISO 178). In yet other embodiments, this invention comprises arrays comprising microprojections and/or micro needles made from carbon containing polymers having a flexural modulus of greater than 3,000 MPa (ISO 178). In yet other embodiments, this invention comprises arrays comprising microprojections and/or microneedles made from carbon containing polymers having a flexural modulus of between 3,000 MPa (ISO 178) and 15,000 MPa (ISO 178). In some embodiments, this invention comprises arrays comprising microprojections and/or microneedles made from carbon containing polymers having a flexural modulus of between 5,000 MPa (ISO 178) and 12,000 MPa (ISO 178). In some embodiments, this invention comprises arrays comprising microprojections and/or microneedles made from carbon containing polymers having a flexural modulus of between 8,000 MPa (ISO 178) and 12,000 MPa (ISO 178). In some embodiments, this invention comprises arrays comprising microprojections and/or microneedles made from carbon containing polymers having a flexural modulus of between 9,000 MPa (ISO 178) and 10,000 MPa (ISO 178).

As used herein, "ISO 178" refers to ISO test standards for determination of flexural properties of plastics.

One embodiment of this invention includes a microprojection array comprising a plurality of microneedles wherein one or more of said microneedles is coated with [G1u 2225, Leu23 ’28 ’31 , Aib 29, Lys 26 ’30]PTHrP(1-34)NH2 wherein said microprojection array has a density of needles of between 20 and 1,000 needles per cm2 . In certain embodiments of this invention, a microprojection array comprising a plurality of microneedles wherein one or more of said microneedles is coated with {G1u22’25, Leu23 ’28 ’31 , Aib29 ]PTHrP(l-34)NH2 has a density of needles of , Lys 26 ’30 between 100 and 500 needles per cm2.

In some embodiments of this invention, a [G1u 22 ’25, Leu23 ’28’31 , Aib29 , Lys 26’30]PTHrP(1-34)NH 2 coated microprojection array suitable for the intradermal delivery of an effective amount of [G1u 22’25 , Leu2328 ’31 , Aib 29, Lys26’30]PTHrP(l- 34)NH2 contains between 50 and 600 microprojections. In certain embodiments of this invention, a [G1u 22 ’25 , Leu 23’2831 , Aib 29, Lys26 ’30]PTHrP(l-34)NH 2 coated microprojection array suitable for the intradermal delivery of an effective amount of [G1u 22’25 , Leu 23 ’2831 , Aib29, Lys 26 ’30 ]PTHrP(l -34)NH2 contains between 100 and 500 microprojections is described. In certain embodiments, this invention includes a [G1u22’25 , Leu 23 ’28’31 , Aib29, Lys 26’30]PTHrP(l-34)NH 2 coated microprojection array suitable for the intradermal delivery of an effective amount of [G1u 22’25, Leu23’28’3 Aib29, Lys 2630 ]PTHrP(1 -34)NT-12 containing between 250 and 400 microprojections.

In some embodiments, this invention comprises a [G1u 22 ’25, Leu23 ’28’31 , Aib 29, Lys26’30]PTHrP(l-34)NH 2 coated microprojection array suitable for the intradermal delivery of an effective amount of [G1u 22’25 , Leu23 ’28’31 , Aib29, Lys 26 ’30]PTHrP(l- 34)NH 2 and containing between 300 and 375 microprojections. In certain embodiments, this invention comprises a [Glu 22’25, Leu23 ’28 ’31 , Aib 29 , Lys26’30]PTHrP(l-34)NH 2 coated microprojection array suitable for the intradermal delivery of an effective amount of [G1u 22’25 , Leu23 ’28 ’31 , Aib29, Lys 26’30]PTHrP(l- 34)NH 2 and containing about 366 microprojections. In some embodiments of this invention, a [G1u 22’25, Leu23 ’2831 , Aib 29, Lys 26’30]PTHrP(1-34)NH 2 coated microprojection array suitable for the intradermal delivery of an effective amount of [Glu2225 , Leu 23 ’28 ’31 , Aib29 , Lys 2630]PTHrP(1-34)NH2 and containing 366 microprojections is described. In certain embodiments, this invention comprises a [G1u22’25 , Leu 23 ’28 ’31 , Aib29, Lys 26 ’30]PTHrP(1-34)NH 2 coated microprojection array suitable for the intradermal delivery of an effective amount of [G1u 22’25 , Leu23 ’28 ’31 , Aib 29, Lys 26 ’30]PTHrP(1-34)NH 2 and containing about 316 microprojections. In certain embodiments, this invention comprises a {G1u 22’25, Leu23 ’28 ’31 , Aib 29 , Lys 26 ’30]PTHrP(1 -34)NH 2 coated microprojection array suitable for the intradermal delivery of an effective amount of [Glu 22’25, Leu 23 ’28’31 , Aib29, Lys 2630]PTHrP( 1- 34)NH2 and containing about 320 microprojections. In some embodiments, the microprojections are microneedles.

In some embodiments of this invention, the term "coated" means that one or more of the microprojections or microneedles of a microprojection array comprise [G1u22 ’25 , Leu23 ’28’31 , Aib 29, Lys26’30]PTHrP(1-34)NH2 on at least part of the surface of said microprojection or microneedle. In some embodiments, more than 1% and less than 50% of the total microprojections or microneedle surface area is coated by the aqueous formulation comprising [Glu 22’25, Leu 23 ’28’31 , Aib 29, Lys 26 ’30] PTHrP( 1- 34)NH 2 . In certain embodiments, more than 2% and less than 40% of the total microprojections or microneedle surface area is coated by the aqueous formulation comprising [Glu2225 , Leu23 ’28’31 , Aib29, Lys 26’30]PTHrP(1-34)NH2. In certain embodiments, more than % and less than 35% of the total microprojections or microneedle surface area is coated by the aqueous formulation comprising [G1u 22’25 , Leu 23 ’28’31 , Aib29 , Lys 26 ’30]PTHrP(1-34)NH2. In certain embodiments, more than % and less than 50% of the total microprojections or rnicroneedle surface area is coated by the aqueous formulation comprising [Glu 22’25 , Aib 29 , , Leu 2 ’2831 Lys 26 ’30 ]PTHrP( 1-3 4)NH2. In certain embodiments, the aqueous formulation comprising [G1u 22 ’25, Leu23 ’28’31 , Aib 29, Lys 26’30]PTHrP(l-34)NH2 coats from about 30% to about 50% of the top of the microprojections or microneedle (as used herein, "top" means the end of the microprojection or microneedle which would contact the skin),In the context of this description, the term total microprojections or microneedle surface area means the microprojections or microneedle surface area of all of the microprojections or microneedles present on a microprojections or microneedle array where said array comprises a plurality of microprojections or microneedles. In certain embodiments of this invention, said coated microprojections or microneedles are prepared by dipping an array comprising said microprojections or microneedles into an aqueous formulation comprising [G1u 22 ’25 , Leu23 ’28’31 , Aib 29, Lys 26 ’30]PTHrP(l-34)NH 2 and then removing said array and allowing the array to dry. In some embodiments, accelerated drying conditions are applied to said array. In certain embodiments, said accelerated drying conditions include one or more of providing a circulating air flow, desiccants, vacuum and/or heat.

In some embodiments, this invention comprises a microprojection array comprising a plurality of [G1u 22’25, Leu23 ’28 ’31 , Aib 29, Lys 26’30]PTHrP(l-34)NH 2 coated microprojections wherein said microprojection array comprises at least 63.75 tg of [G1u22 ’25 , Leu23 ’28’31 , Aib29, Lys 26 ’30]PTHrP(l-34)NH 2. In some embodiments, this invention describes a microprojection array comprising a plurality of [Glu, 22’25 Leu23 ’2831 , Aib 29, Lys 2630}PTHrP(1-34)NH 2 coated microprojections wherein said microprojection array comprises between 63.75 and 86.25 .tg of [G1u 22’25, Leu23 ’28 ’31 , Aib29 , Lys 26 ’30]PTHrP(1-34)NH 2 . In some embodiments, this invention describes a microprojection array comprising a plurality of [Glu 2225 , Leu23’2831 , Aib29, Lys 26 ’30 ]PTHrP( I -34)NH2 coated microprojections wherein said microprojection array comprises about 75 g of [G1u22’25 , Leu23 ’2831 , Aib 29, Lys26’30]PTHrP(l- 34)NH2. In certain embodiments, this invention describes a microprojection array comprising a plurality of [G1u 22 ’25 , Leu2328’31 , Aib 29, Lys2630]PTHrP(1-34)NH 2 coated microprojections wherein said microprojection array comprises 75 tg of [G1 u22’25, Leu2328’31 , Aib 29, Lys 26 ’30]PTHrP(l-34)NH2. In some embodiments said microprojection array is a microneedle array.

In certain aspects, this invention comprises a microprojection array comprising a plurality of [G1u 22’25, Leu23 ’28’31 , Aib 29, Lys26’30]PTHrP(l-34)NH 2 coated microprojections wherein said microprojection array comprises at least 85 tg of [G1u 22’25, Leu232831 , Aib29, Lys 26 ’30]PTHrP(l-34)NH 2 . In some embodiments, this invention describes an array comprising a plurality of [G1u 22 ’25, Leu2328’31 , Aib 29 , Lys 26’30]PTHrP(1-34)NH 2 coated microprojections wherein said microprojection array comprises between 85 j.g and 115 jtg of [G1u 22’25, Leu23 ’28’31 , Aib29 , 26 ’30]PTHrP(l-34)N}1 2 . In some embodiments, this invention describes a microprojection array comprising a plurality of [Glu 2225 , Leu23’28 ’31 , Aib29, Lys 26’30]PTI-IrP(l -34)NH 2 coated microprojections wherein said array comprises about 100 ig of [G1u 22’25, Leu23 ’28 ’31 , Aib 29, Lys 26’30]PTHrP(1-34)NH2. In certain embodiments, this invention describes a microprojection array comprising a plurality of [G1u 22 ’25, Leu238 ’31 , Aib29, Lys 26’30]PTHrP(1-34)NH2 coated microprojections wherein said microprojection array comprises 100 tg of [Glu 22’25 , Leu23’28’31 , Aib29 , Lys 26’30]PTHrP(l-34)NH 2. In some embodiments said microprojection array is a microneedle array. In certain aspects, this invention comprises a microprojection array comprising a plurality of [G1u , Leu23 ’2831 , 2225 Aib29, Lys 26 ’30]PTI-IrP(1-34)NH 2 coated microprojections wherein said array comprises at least 106.25 tg of [Glu 22’25 , Leu23 ’28’31 , Aib 29, Lys 26’30]PTHrP(l- 34)NH2. In some embodiments, this invention describes a microprojection may comprising a plurality of [Glu 22’25, Leu 23 ’28’31 , Aib 29, Lys 26’30]PTI-IrP(l -34)NH2 coated microprojections wherein said microprojection array comprises between 106.25 jtg and 143.75 jig of [G1u 2225 , Leu23 ’28’31 , Aib29, Lys2630]PTHrP(l-34)NH 2 .

In some embodiments, this invention describes a microprojection array comprising a plurality of [G1u22’25 , Leu23 ’2831 , Aib 29 , Lys 26’30]PTHrP(l-34)NH2 coated microprojections wherein said microprojection array comprises about 125 jig of [Glu22 ’25 , Leu23 ’28’31 , Aib 29 , Lys 26’30]PTHrP(1-34)NH 2 . In certain embodiments, this invention describes a microprojection array comprising a plurality of [G16 22 ’25 , Leu23 ’28 ’31 , Aib 29, Lys 26 ’30]PTHrP(1-34)NH 2 coated microprojections wherein said array comprises 125 jig of [G1u 22’25 , Leu23’2831 , Aib 29 , Lys 26’30]PTHrP(l-34)NT-1 2. In some embodiments said microprojection array is a microneedle array.

In some embodiments, this invention describes a microprojection array comprising a plurality of [G1u 22 ’25, Leu2328’31 , Aib 29, Lys 26’30]PTHrP(l-34)NH 2 coated microprojections wherein said microprojection array comprises at least 127.5 jig of [G1u22 ’25 , Leu23 ’28’31, Aib 29, Lys26 ’30]PTHrP(1-34)NH2 . In some embodiments, this invention describes a microprojection array comprising a plurality of [G1u 22’25 , Leu23’28’3 Aib 9, Lys 2630 ] PTHrP( 1 -34)NH2 coated microproj ections wherein said microprojection array comprises between 127.5 jig and 172.5 jig of [G1u 22 ’25 , Leu 23’28 ’31 , Aib 29 , Lys 26’30]PTHrP(1-34)NH2 . In some embodiments, this invention describes a microprojection array comprising a plurality of [G1u 22 ’25 , Leu23 ’28’31 , Aib 29, Lys 26 ’30 ]PTHrP(1 -34)NH2 coated microprojections wherein said microprojection may comprises about 150 jig of [Glu22 ’ 5, Leu 23 ’28’31 , Aib29 , Lys26 ’30]PTHrP(l-34)NH 2 . In certain embodiments, this invention describes a microprojection array comprising a plurality of [G1u 22 ’25, Leu2328’31 , Aib29, Lys 26’30 ] PTHIP( 1 -34)NH 2 coated microproj ections wherein said microproj ection array comprises 150 jig of [G1u 22’25 , Leu23 ’28’31 , Aib29, Lys 26’30]PTHrP(1-34)NH 2. In some embodiments said microprojection array is a microneedle array.

In some embodiments, this invention describes a microprojection array comprising a plurality of [G1u 22’25, Leu23 ’28’31 , Aib29, Lys 26 ’301PTHrP(l-34)NH 2 coated microprojections wherein said microprojection array comprises at least 170 jig of [G1u 22 ’25, Leu23 ’28 ’31 , Aib29, Lys2630]PTHrP(l-34)NH 2 . In some embodiments, this invention describes a microprojection array comprising a plurality of [G1u 22’25 , Leu23 ’28 ’31 , Aib29 , Lys 26 ’30]PTHrP(1-34)NH 2 coated microprojections wherein said microprojection array comprises between 170 .xg and 230 tg of [G1u 2225 , Leu23 ’28 ’31 , Aib29 , Lys 26 ’30 ]PTJ-IrP(1 -34)NH2. In some embodiments, this invention describes a microproj ection array comprising a plurality of [G1u 22’25, Leu 23 ’2831 , Aib29 , Lys26’30 ]PTHrP( 1-3 4)NH 2 coated microproj ections wherein said microproj ection array comprises about 200 tg of [G1u 22’25, Leu23 ’28’31 , Aib29, Lys 2630]PTHrP(1- 34)NH 2 . In certain embodiments, this invention describes a microprojection array comprising a plurality of [G1u 22 ’25 , Leu 23 ’28’31 , Aib29, Lys 26 ’30]PTHrP( 1 -34)NH2 coated microprojections wherein said microprojection array comprises 200 xg of [01u22’25, Leu 23 ’28’31 , Aib29 , Lys 26’30]PTHrP(l-34)NH 2 . In some embodiments said microprojection array is a microneedle array.

In some aspects of these embodiments, aqueous formulations comprising % [G1u22’25, Leu 23’28’31 , Aib29, Lys26’30]PTHrP(1-34)NH 2 are used to prepare a microprojection array comprising 20 jig of [G1u 22 ’25, Leu23 ’28 ’31 , Aib29 , Lys 26 ’30]PTHrP(1-34)NH 2. In other aspects of these embodiments, aqueous formulations comprising 12.5-20% [G1u 22’25, Leu23’28’31 , Aib 29, Lys 26’30]PT}-IrP(1- 34)NH 2 are used to prepare a microprojection array comprising 40 jig of [G1u 22’25 , Leu23 ’28 ’31 , Aib29, Lys 26’30]PTHrP(l-34)NH 2 . In some aspects of these embodiments, aqueous formulations comprising 15-60% [G1u 22’25, Leu23 ’28’31 , Aib29 , 26,31] Lys PTHrP( 1-3 4)NH are used to prepare a microproj ection array comprising from 80 to 450 jig of [G1u 22 ’25 , Leu 23 ’28’31 , Aib29, Lys 26 ’301PTHrP(1-34)NH 2 .

In some embodiments, this invention comprises a method of treating osteoporosis in a subject in need thereof comprising the less than daily administration of a microprojection array comprising one or more [G1u 2225 , Leu23 ’2831 , Aib29 , Lys 26’30]PT1-hP(1-34)NI-1 2 coated microprojections wherein said administration comprises contacting one or more of said [G1u 22’25 , Leu23 ’2831 , Aib29 , Lys26’30]PTHrP(1-34)NH 2 coated microprojections with the skin of the subject using sufficient force to cause penetration of one or more [Glu 22’25, Leu23 ’28 ’31 , Aib 29 , Lys 26’30]PTHrP(1-34)NH 2 coated microprojections into the skin. For example, it is believed that an anabolic effect on bone could be achieved by a once per every two days application, once per every three days application, or even a once per week application.

In some embodiments, this invention comprises a method of treating osteoporosis in a subject in need thereof comprising the daily administration of a microprojection array comprising one or more [G1u 22’25 , Leu23’28’31 , Aib 29 , Lys 26’30 ] PTHrP( 1 -34)NH 2 coated microprojections wherein said administration comprises contacting one or more of said [G1u 22 ’25 , Leu23 ’28’31 , Aib29 , Lys26’30 ]PTHrP( 1-3 4)NH2 coated microproj ections with the skin of the subject using sufficient force to cause penetration of one or more [G1u 22’25, Leu23 ’28 ’31 , Aib29 , Lys 26’30]PTHrP(1-34)NH 2 coated microprojections into the skin. In certain embodiments, the array is left in place with one or more microprojections embedded in the subject’s skin for a period of more than 10 minutes and less than 1 hour. In some embodiments, the array is left in place with one or more microprojections embedded in the subject’s skin for a period of from 10 minutes to 30 minutes. In certain embodiments, the array is left in place with one or more microprojections embedded in the subject’s skin for a period of about 15 minutes. In certain embodiments, the array is left in place with one or more microprojections embedded in the subject’s skin for a period of 15 minutes. In some embodiments said microprojection array is a microneedle array.

In certain embodiments, this invention comprises a method of treating osteoporosis in a subject in need thereof comprising the daily administration of a microprojection array comprising one or more [G1u 22’25, Leu 23’28’31 , Aib29 , Lys26 ’30]PTHrP(l -34)NH 2 coated microprojections wherein said administration comprises contacting the one or more of said [G1u 22’25, Leu23 ’28’31 , Aib 29 , Lys2630]PTHrP(1-34)NH2 coated microprojections with the skin of the subject using sufficient force to cause penetration of said one or more [G1u 22 ’25, Leu 23 ’28’31 , Aib29 , Lys26 ’30]PTHrP(l-34)NH 2 coated microprojections into the skin. In certain embodiments, the array is left in place with one or more microprojections embedded in the subject’s skin for a period of from 3 seconds to 10 minutes. In certain embodiments, the microprojection array is left in place with one or more microprojections embedded in the subject’s skin for a period of from 3 seconds to minutes. In certain embodiments, the microprojection array is left in place with one or more microprojections embedded in the subject’s skin for a period of from 5 seconds to 3 minutes. In certain embodiments, the microprojection array is left in place with one or more microprojections embedded in the subject’s skin for a period of from seconds to 1 minute. In some embodiments, the microprojection array is left in place with one or more microprojections embedded in the subject’s skin for a period of from 5 seconds to 30 seconds. In certain preferred embodiments, the microproj ection array is left in place with one or more microproj ections embedded in the subject’s skin for a period of about 15 minutes. In some preferred embodiments, the microprojection array is left in place with one or more microprojections embedded in the subject’s skin for a period of about 5 minutes. In other preferred embodiments, the microprojection array is left in place with one or more microprojections embedded in the subject’s skin for a period of about 1 minute. In some embodiments, the microprojection array is left in place with one or more microprojections embedded in the subject’s skin for a period of about 30 seconds. In certain embodiments, the microprojection array is left in place with one or more microprojections embedded in the subject’s skin for a period of about 15 seconds. In certain embodiments, the microprojection array is left in place with one or more microprojections embedded in the subject’s skin for a period of about 10 seconds. In certain embodiments, the microprojection array is left in place with one or more microprojections embedded in the subject’s skin for a period of about 5 seconds. In certain embodiments, the microprojection array is left in place with said microprojections embedded in the subject’s skin for a period of 5, 10 or 15 seconds, seconds, 1 minute, 5 minutes, 10 minutes, 15 minutes or 3 0 minutes. In some embodiments, the microprojection array is fixed in place for the duration of their residency time on the subject’s skin. In certain embodiments, the microprojeetion array is fixed in place by the presence of an adhesive material on the microprojection array such that the adhesive material adheres to the subject’s skin and the microprojection array thereby reducing the possibility that the microprojection array will move substantially during its residency time on said subject’s skin. In some embodiments said microprojection array is a microneedle array.

, Leu23 ’28 ’31 , Aib 29 , In some embodiments, the administration of [Glu 22 ’25 Lys 26 ’30]PTHrP(1-34)NH 2 by microprojection array is applied with sufficient force to cause one or more of said microprojections to penetrate the subject’s skin to a depth of at least 50 micrometers. In some embodiments, the administration of [G1u 22 ’25 , Leu 23 ’28 ’31 , Aib29, Lys26 ’30]PTHrP(l -34)NH2 by microprojection array is applied with sufficient force to cause one or more of said microprojections to penetrate the subject’s skin to a depth of at least 100 micrometers. In some embodiments, the administration of [G1u 22 ’25, Leu23 ’28 "31 , Aib 29, Lys 26 ’30]PTFIrP(1-34)NH 2 by microprojection array is applied with sufficient force to cause one or more of said microprojections to penetrate the subject’s skin to a depth of at least 200 micrometers.

In certain embodiments, the force applied to the array is applied manually wherein said array is held in the administering person’s hand, who may or may not be the person receiving the drug, and applied to the site of administration. In some embodiments, the force applied to the array is applied manually to an applicator wherein said applicator is affixed to the array. In certain embodiments, said applicator is capable of storing a fixed force and said force can be released to the array with sufficient energy to administer the drug in accordance with the principles of this invention. In some embodiments, the microprojection array is applied using force by discharging a spring-loaded applicator. Applicators suitable for the administration of microproj ection arrays in accordance with the methods of this invention are known to those of ordinary skill in the art. For example, suitable applicators are described in U.S. Patent Application Publications No. 2009/0198189 2005/0096586, the entire contents of each of which are herein incorporated by reference.

In certain embodiments, the drug-coated microproj ection arrays described herein are useful for the treatment of osteoporosis. In some embodiments, the drug coated microprojection arrays described herein are useful for the treatment of postmenopausal osteoporosis. In certain embodiments, the drug coated arrays described herein are useful for the treatment of glucocorticoid induced osteoporosis in men or women. In certain embodiments, the methods of treating osteoporosis described herein can be applied to a patient or patient population characterized as being at an elevated risk for bone fracture. In some embodiments, said patient or patient population can be characterized as having bone mineral density at one or more skeletal sites of >1 standard deviation below the norm. In some embodiments, the methods of treating osteoporosis described herein can be applied to a patient or patient population characterized by bone mineral density at one or more skeletal sites of >2 standard deviations below the norm. In some embodiments, the methods of treating osteoporosis described herein can be applied to a patient or patient population characterized by bone mineral density at one or more skeletal sites of >2.5 standard deviations below the norm. In some embodiments, the methods of treating osteoporosis described herein can be applied to a patient or patient population characterized by bone mineral density at one or more skeletal sites of >3 standard deviations below the norm. In certain embodiments, the methods of treating osteoporosis described herein can be applied to patients who have had one or more previous bone fractures. Where said patient has had one or more prior fractures they may also present with a bone mineral density at or below the mean, for example, said patient may have bone mineral density at one or more sites that is at least 1 standard deviations below the mean, or at least 2 standard deviations below the mean, or at least 2.5 standard deviations below the mean or at least 3 standard deviations below the mean. In addition, the methods of treating osteoporosis described herein may be applied to any patient at potentially increased risk of fracture wherein said patient may have one or more characteristics that identify them as being at increased risk such as smoking, consumption of alcohol, use of glucocorticoids, use of tricyclic antidepressants, are at increased risk of falling, have asthma, chronic liver disease, rheumatoid arthritis, type 2 diabetes, endocrine problems, familial history of fractures, poor nutrition or nutritional disorders.

In some embodiments, this invention includes a method of treating osteoporosis comprising daily administration of a microprojection array comprising , Leu232831, Aib a plurality of [G1u 22’25 29, Lys26 ’30]PTHrP(l-34)NH 2 coated microprojections to a subject in need thereof wherein said administration comprises contacting one or more of said microproj ections of the microproj ection array with sufficient force to penetrate the subject’s skin and wherein said microproj ections are coated with 75 jtg or about 75 tg of [G1u22’25, Leu 23 ’28 ’31 , Aib 29 , Lys 26 ’30]PTHrP(l. 34)NH2 .

In some embodiments, this invention includes a method of treating osteoporosis comprising daily administration of a microprojection array comprising a plurality of [G1u 22’25 , Leu23 ’28’31 , Aib 29, Lys 26’30]PTHrP(l-34)NH 2 coated microprojections to a subject in need thereof wherein said administration comprises contacting one or more of said microprojections of the microprojection array with sufficient force to penetrate the subject’s skin and wherein said microprojections are coated with from 85 g to 115 .ig of [G1u 22’25 , Leu23 ’2831 , Aib 29, Lys 26’30]PTHrP(1- 34)NH2.

In some embodiments, this invention includes a method of treating osteoporosis comprising daily administration of a microprojection array comprising a plurality of [G1u 22’25 , Leu23’28’3 Aib29, Lys 26’30 ]PTHrP( 1 -34)NH2 coated microprojections to a subject in need thereof wherein said administration comprises contacting one or more of said microprojections of the microprojection array with sufficient force to penetrate the subject’s skin and wherein said microprojections are coated with 100 tg or about 100 tg of [G1u 22’25, Leu23 ’28’31 , Aib29, Lys 26’30]PTHrP(1 - 34)NH2 .

In some embodiments, this invention includes a method of treating osteoporosis comprising daily administration of a microprojection array comprising a plurality of [Glu 22’25, Leu23 ’28 ’31 , Aib29 , Lys 26 ’30]PTHrP(l-34)NH 2 coated microprojections to a subject in need thereof wherein said administration comprises contacting one or more of said microprojections of the microprojection array with sufficient force to penetrate the subject’s skin and wherein said microprojections are coated with from 106.25 g to 143.75 tg of [G1u 22 ’25, Leu23 ’28’31 , Aib 29 , Lys 26’30 ]PTHrP( 1 -34)NH2.

In some embodiments, this invention includes a method of treating osteoporosis comprising daily administration of a microprojection array comprising a plurality of [G1u 22’25, Leu 23 ’28 ’31 , Aib29 , Lys 26 ’30]PTHrP(1-34)NH 2 coated microprojections to a subject in need thereof wherein said administration comprises contacting one or more of said microprojections of the microprojection array with sufficient force to penetrate the subject’s skin and wherein said microprojections are coated with 125 jig or about 125 jig of [G1u 22 ’25, Leu 23 ’28’31 , Aib 29, Lys 26 ’30]PTHrP(1 - 34)NH 2 .

In some embodiments, this invention includes a method of treating osteoporosis comprising daily administration of a microprojection array comprising a plurality of [G1u 22’25, Leu23 ’28 ’31 , Aib29, Lys 26’30]PTHrP(1-34)NH 2 coated microprojections to a subject in need thereof wherein said administration comprises contacting one or more of said microprojections of the microprojection array with sufficient force to penetrate the subject’s skin and wherein said microprojections are coated with from 127.5 jig to 172.5 jig of[G1u 22’25, Leu23 ’28 ’31 , Aib 29 , Lys26 ’30 ]PTHrP( 1 -34)NH2.

In some embodiments, this invention includes a method of treating osteoporosis comprising daily administration of a microprojection array comprising a plurality of [G1u 22 ’25, Leu23 ’2831 , Aib 29, Lys26 ’30]PTHrP(l-34)NH 2 coated microprojections to a subject in need thereof wherein said administration comprises contacting one or more of said microprojections of the microprojection array with sufficient force to penetrate the subject’s skin and wherein said microprojections are coated with 150 jig or about 150 tg of [G1u 22 ’25, Leu 23 ’28 ’31 , Aib29, Lys 26 ’30]PTHrP( 1- 34)NH2 .

In some embodiments, this invention includes a method of treating osteoporosis comprising daily administration of a microprojection array comprising a plurality of [G1u 22 ’25 , Leu2328 ’31 , Aib 29, Lys 26 ’30]PTHrP(1-34)NH 2 coated microprojections to a subject in need thereof wherein said administration comprises contacting one or more of said microprojections of the microprojection array with sufficient force to penetrate the subject’s skin and wherein said microprojections are coated with from 170 tg to 230 tg of [Glu 22 ’25, Leu23 ’28’31 , Aib 29 , Lys 26 ’30]PTHrP(1- 34)NH2 .

In some embodiments, this invention includes a method of treating osteoporosis comprising daily administration of a microprojection array comprising a plurality of [Glu22 ’25 , Leu 2328 ’31 , Aib29 , Lys 26 ’30JPTHrP(1-34)NH 2 coated microprojections to a subject in need thereof wherein said administration comprises contacting one or more of said microprojections of the microprojection array with sufficient force to penetrate the subject’s skin and wherein said microproj ections are coated with 200 jig or about 200 jig of [G1u 22 ’25, Leu23 ’28 ’31 , Aib 29 , Lys26 ’30 ] PTHrP( 1-3 4)NH2.

In certain therapeutic arenas, the drug coated arrays of this invention are useful for improving the healing process in people who have suffered from one or more fractures or breaks of one or more bones in their bodies, including either vertebral fractures or non-vertebral fractures (for example, hip or femur fractures).

Such improvement is evidenced by an increase in fracture healing rate and/or quality of bone associated with the fractured site and/or patient-reported symptomatic outcomes including such indices of fracture healing such as reduced discomfort, increased flexibility and/or mobility and/or strength. People who have suffered a bone fracture may or may not suffer from concomitant low bone mineral density, but they can benefit from the increased rate of bone formation that the use of the drug coated arrays of this invention can provide. In certain embodiments of this invention, the dosages and administration schedules as described herein for preventing or treating osteoporosis are useful for improving the fracture healing process in people who have experienced bone fractures. In some embodiments, the methods for improving the healing process in people who have suffered from one or more fractures or breaks of one or more bones in their bodies described herein can be applied to a patient with one or more vertebral fractures. In some embodiments, the methods for improving the healing process in people who have suffered from one or more fractures or breaks of one or more bones in their bodies described herein can be applied to a patient with one or more femoral fractures. In some embodiments, the methods for improving the healing process in people who have suffered from one or more fractures or breaks of one or more bones in their bodies described herein can be applied to a patient with one or more radial fractures.

In some embodiments of this invention, a drug coated microprojection array is applied twice daily, or once daily, or once every two days, once every three days or once per week. Therefore, in some embodiments of this invention, a drug coated microprojection array is applied once per day wherein said array is coated with an amount of drug deemed useful for the indication with the amount recommended being those amounts that are useful for preventing or treating osteoporosis as has been otherwise described in this specification. Said daily applications can begin any time after a fracture is detected. In some embodiments, the application of the drug coated microprojection arrays of this invention is started no later than 6 months after a fracture has occurred or is detected. In certain embodiments, said application is started no later than 3 months after a fracture has occurred or is detected. In some embodiments, said application is started no later than 1 month after a fracture has occurred or is detected. In some embodiments, said application is started no later than 2 weeks after a fracture has occurred or is detected. In certain embodiments, said application is started no later than 1 week after a fracture has occurred or is detected. It is recommended that to most effectively utilize the method of treating people with one or more fractured bones is for that treatment to begin soon after a fracture is detected. It should be appreciated that the duration of treatment is contingent upon a number of variables including the extent of the injury, the location of the injury, the rate and degree of recovery, the patient’s overall bone health including bone mineral density at other anatomical sites, the discretion of the treating physician and more. Therefore, the treatment of fracture can vary from as little as one or a few once-daily applications up to one or even more than one year of once-daily applications. In some embodiments, the treatment period wilibe at least 1 application of a drug coated microprojection array as described in this invention.

In certain embodiments, the treatment period will be at least one week of once-daily applications. In some embodiments, the treatment period will be at least two weeks of once-daily applications. In some embodiments, the treatment period will be at least four weeks of once-daily applications. In certain embodiments, the treatment period will be at least eight weeks of once-daily applications. In some embodiments, the treatment period will be at least twelve weeks of once-daily applications. In certain embodiments, the treatment period will be at least twenty four weeks of once-daily applications. In some embodiments, the treatment period will be at least one year of once-daily applications.

In certain embodiments, this invention comprises a method of treating fractures or accelerating fracture healing in a subject in need thereof comprising the daily administration of a microprojection array comprising one or more [G1u 22 ’25 , Leu23 ’28’31 , Aib 29, Lys26’30]PTHrP(l-34)NH 2 coated microprojections wherein said administration comprises contacting the one or more of said [G1u 22’25, Leu23 ’2831 , Aib 29 , Lys 26 ’30 ]PTHrP(1 -34)NH2 coated microprojections with the skin of the subject using sufficient force to cause penetration of said one or more [G1u 22’25, Leu23’28’3 , Aib29, Lys 26 ’30]PTHrP(l -34)NH 2 coated microprojections into the skin. In certain embodiments, the array is left in place with one or more microprojections embedded in the subject’s skin for a period of from 3 seconds to 10 minutes. In certain embodiments, the microprojection array is left in place with one or more microprojections embedded in the subject’s skin for a period of from 3 seconds to 5 minutes. In certain embodiments, the microprojection array is left in place with one or more microprojections embedded in the subject’s skin for a period of from 5 seconds to 3 minutes. In certain embodiments, the microprojection array is left in place with one or more microprojections embedded in the subject’s skin for a period of from 5 seconds to 1 minute. In some embodiments, the microprojection array is left in place with one or more microprojections embedded in the subject’s skin for a period of from 5 seconds to 30 seconds. In certain embodiments, the microprojection array is left in place with one or more microprojections embedded in the subject’s skin for a period of about 15 minutes. In certain embodiments, the microprojection array is left in place with one or more microprojections embedded in the subject’s skin for a period of about 5 minutes. In some embodiments, the microprojection array is left in place with one or more microprojections embedded in the subject’s skin for a period of about 1 minute. In some embodiments, the microprojection array is left in place with one or more microprojections embedded in the subject’s skin for a period of about 30 seconds. In certain embodiments, the microprojection array is left in place with one or more microprojections embedded in the subject’s skin for a period of about 15 seconds. In certain embodiments, the microprojection array is left in place with one or more microprojections embedded in the subject’s skin for a period of about 10 seconds. In certain embodiments, the microprojection array is left in place with one or more microprojections embedded in the subject’s skin for a period of about 5 seconds. In certain embodiments, the microproj ection array is left in place with said microproj ections embedded in the subject’s skin for a period of , 10 or 15 seconds, 30 seconds, 1 minute, 5 minutes, minutes, 15 minutes or 30 minutes. In some embodiments, the microprojection array is fixed in place for the duration of their residency time on the subject’s skin.

In certain embodiments, the microprojection array is fixed in place by the presence of an adhesive material on the microprojection array such that the adhesive material adheres to the subject’s skin and the microprojection array thereby reducing the possibility that the microprojection array will move substantially during its residency time on said subject’s skin.

In some embodiments, this invention includes a method of treating fractures or accelerating fracture healing in a subject comprising daily administration of a microprojection array comprising a plurality of [G1u 2225 , Leu232831 , Aib29, Lys26 ’30]PTHrP(l-34)NH 2 coated microprojections to a subject in need thereof wherein said administration comprises contacting one or more of said microprojections of the microprojection array with sufficient force to penetrate the subject’s skin and wherein said microprojections are coated with about 75 tg of [Glu2225 , Leu23’28’3 Aib 29, Lys 26 ’30]PTI-IrP( 1 -34)NH2.

In some embodiments, this invention includes a method of treating fractures or accelerating fracture healing in a subject comprising daily administration of a , Leu23 ’28 ’31 , Aib29 , microprojection array comprising a plurality of [G1u 22’25 Lys26’30]PTHrP(l-34)NH2 coated microprojections to a subject in need thereof wherein said administration comprises contacting one or more of said microprojections of the microprojection array with sufficient force to penetrate the subject’s skin and wherein said microprojections are coated with between 85 tg and 115 jig of [G1u22’25, Leu23’28 ’31 , Aib29, Lys 26’30]PTHrP(l -34)NH2.

In some embodiments, this invention includes a method of treating fractures or accelerating fracture healing in a subject comprising daily administration of a , Leu 23 ’28’31 , Aib29, microprojection array comprising a plurality of [Glu 22’25 Lys 26’30]PTHrP(1-34)NH 2 coated microprojections to a subject in need thereof wherein said administration comprises contacting one or more of said microprojections of the microprojection array with sufficient force to penetrate the subject’s skin and wherein said microprojections are coated with about 100 jig of [G1u22’25, Leu23 ’28’31 , Aib29, Lys 26’30]PTHrP( 1-3 4)NH2.

In some embodiments, this invention includes a method of treating fractures or accelerating fracture healing in a subject comprising daily administration of a microproj ection array comprising a plurality of [Glu 22 ’25, Leu23 ’28’31 , Aib29, Lys 26’30]PTHrP(1-34)NH 2 coated microprojections to a subject in need thereof wherein said administration comprises contacting one or more of said microprojections of the microprojection array with sufficient force to penetrate the subject’s skin and wherein said microprojections are coated with between 106.25 jig and 143.75 jig of [Glu 22’25, Leu 23 ’28’31 , Aib 29, Lys 26 ’30]PTHrP(1-34)NB2.

In some embodiments, this invention includes a method of treating fractures or accelerating fracture healing in a subject comprising daily administration of a 22 ’25, Leu23 ’28’31 5 Aib29 , microprojection array comprising a plurality of [Glu Lys 26’30]PTHrP(1-34)NH 2 coated microprojections to a subject in need thereof wherein said administration comprises contacting one or more of said microprojections of the microprojection array with sufficient force to penetrate the subject’s skin and wherein said microprojections are coated with about 125 jig of , Leu 23 ’28’31 , Aib29, Lys 26 ’30]PTHrP( 1-3 4)NH2.

[G1u22 ’25 In some embodiments, this invention includes a method of treating fractures or accelerating fracture healing in a subject comprising daily administration of a microprojection array comprising a plurality of [G1u 22’25 , Leu23 ’28’31 , Aib29 , Lys 26’30 ]PTHrP(l -34)NH2 coated microprojections to a subject in need thereof wherein said administration comprises contacting one or more of said microprojections of the microprojection array with sufficient force to penetrate the subject’s skin and wherein said microprojections are coated with between 127.5 jig and 172.5 tg of [G1u 22’25, Leu 23 ’28’31 , Aib 29 , Lys26 ’30]PTHrP(1 -34)NH 2 .

In some embodiments, this invention includes a method of treating fractures or accelerating fracture healing in a subject comprising daily administration of a microprojection array comprising a plurality of {G1u 22’25 , Leu23 ’28’31 , Aib29 , 26 ’30 JPTHrP(1 -34)NH2 coated microprojections to a subject in need thereof wherein said administration comprises contacting one or more of said microprojections of the microprojection array with sufficient force to penetrate the subject’s skin and wherein said microprojections are coated with between 150 g of [G1u22 ’25, Leu2328’31 , Aib 29, Lys 26’30 ]PTHrP( I -34)NH 2 .

In some embodiments, this invention includes a method of treating fractures or accelerating fracture healing in a subject comprising daily administration of a microprojection array comprising a plurality of [G1u 22’25, Leu 23 ’28’31 , Aib29 , Lys26 ’30]PTHrP(1-34)N}1 2 coated microprojections to a subject in need thereof wherein said administration comprises contacting one or more of said microprojections of the microprojection array with sufficient force to penetrate the subject’s skin and wherein said microprojections are coated with between 170 jig and 230 tg of [G1u22’25 , Leu23’28 ’31 , Aib29, Lys 26’30]PTI-lrP(1-34)NH 2 .

In some embodiments, this invention includes a method of treating fractures or accelerating fracture healing in a subject comprising daily administration of a microprojection array comprising a plurality of [G1u 22’25, Leu2328’31 , Aib29, Lys 26’30]PTHrP(1-34)NH 2 coated microprojections to a subject in need thereof wherein said administration comprises contacting one or more of said microprojections of the microprojection array with sufficient force to penetrate the subject’s skin and wherein said microprojections are coated with about 200 jig of [G1u22 ’25 , Leu 23 ’28’31 , Aib 29, Lys 26 ’30 ]PTHrP( 1-3 4)NH2.

In some embodiments, the microprojection arrays useful for the method of treating fractures or accelerating fracture healing in a subject comprise microneedles.

The drug-coated microprojection or microneedle arrays of this invention may also be used for the prevention and/or treatment of osteoarthritis. It is recognized that osteoarthritis is accompanied by the loss of cartilage, particularly at the joints.

In some cases, the lost cartilage is replaced by bone or bony deposits. The drug coated microprojection arrays of this invention provide methods of treating people with agents that promote the bone remodeling process possibly including the increased production of cartilage and/or the diminution of bony deposits through acceleration of a normal bone remodeling process. Increasing the amount of cartilage in worn joints can have a laudatory effect on the individual measurable by numerous quality of life improvements including decreased pain and increased freedom of motion around the affected joint. The method of treating an individual suffering from osteoarthritis will typically comprise the administration of a drug coated microprojection or microneedle array of this invention typically in a once per day setting. The dosages applied will be typically the same as those dosages that are useful for the prevention and/or treatment of osteoporosis as described herein. Since the signs and symptoms of osteoarthritis are often different than osteoporosis, the treatment of osteoarthritis by the arrays of this invention will take that into account.

In particular, while it is envisioned that a once daily administration of the arrays of this invention will remain an important choice, the duration of treatment including the adjudication of a successful outcome will be different. In particular, whereas the effect of an osteoporosis treatment can be readily ascertained by acute temporal effects on bone mineral density and reduction in fracture risk, the effect of treatment for osteoarthritis can be most readily detected via a patient reported reduction of symptoms. In this regard, the treatment of osteoarthritis can be started upon the observation of one or more symptoms of osteoarthritis and may be continued for a time sufficient for the diminution or elimination of one or more of the observed symptoms. Alternatively, the patient can have their treatment monitored by X-ray analysis of the affected joint(s) and the X-ray images interpreted by a qualified examiner in order to help determine if the treatment is having the desired effect.

Due to the complexity of osteoarthritis and the ambiguity of correlating X-ray images with patient perception of pain or affected movement, the patient together with their medical practitioner will often decide together whether the treatment regimen is working or whether it should be adjusted.

In certain embodiments of this invention, the drug coated microproj ection or microneedle arrays are applied once daily for a time sufficient to achieve a satisfactory reduction in symptoms such as pain, inflammation, swelling and edema.

In some embodiments, the drug coated microprojection arrays are applied once daily for a period of at least one week. In certain embodiments, the drug coated microprojection arrays are applied once daily for a period of at least two weeks. In some embodiments, the treatment period will be at least four weeks of once-daily applications. In certain embodiments, the treatment period will be at least eight weeks of once-daily applications. In some embodiments, the treatment period will be at least twelve weeks of once-daily applications. In certain embodiments, the treatment period will be at least twenty four weeks of once-daily applications. In some embodiments, the treatment period will be at least one year of once-daily applications. Regardless of the length of any course of treatments, it should be appreciated that retreatment can be commenced if the symptoms return or worsen or if other indices of the disease indicate that an additional round of treatment could be beneficial.

In certain embodiments, this invention comprises a method of treating osteoarthritis in a subject in need thereof comprising the daily administration of a microprojection array comprising one or more [G1u 22’25 , Leu23 ’28’31 , Aib29, Lys26 ’30 ]PTHrP( I -34)NH2 coated microproj ections wherein said administration comprises contacting the one or more of said [G1u 22 ’25 , Leu23283 , Aib29, Lys 26 ’30]PTHrP(1-34)NH2 coated microprojections with the skin of the subject using sufficient force to cause penetration of said one or more [Glu 2225 , Leu2328 ’31 , Aib 29 , Lys 26’30]PTHrP(l-34)N}1 2 coated microprojections into the skin. In certain embodiments, the array is left in place with one or more niicroprojections embedded in the subject’s skin for a period of from 3 seconds to 10 minutes. In certain embodiments, the microprojection array is left in place with one or more microprojections embedded in the subject’s skin for a period of from 3 seconds to 5 minutes. In certain embodiments, the microprojection array is left in place with one or more microprojections embedded in the subject’s skin for a period of from seconds to 3 minutes. In certain embodiments, the microprojection array is left in place with one or more microprojections embedded in the subject’s skin for a period of from seconds to 1 minute. In some embodiments, the microprojection array is left in place with one or more microprojections embedded in the subject’s skin for a period of from 5 seconds to 30 seconds. In certain embodiments, the microprojection array is left in place with one or more microprojections embedded in the subject’s skin for a period of about 15 minutes. In certain embodiments, the microprojection array is left in place with one or more microprojections embedded in the subject’s skin for a period of about 5 minutes. In some embodiments, the microprojection array is left in place with one or more microprojections embedded in the subject’s skin for a period of about 1 minute. In some embodiments, the microprojection array is left in place with one or more microprojections embedded in the subject’s skin for a period of about 30 seconds. In certain embodiments, the microprojection array is left in place with one or more mieroprojections embedded in the subject’s skin for a period of about 15 seconds. In certain embodiments, the microprojection array is left in place with one or more microprojections embedded in the subject’s skin for a period of about 10 seconds. In certain embodiments, the microprojection array is left in place with one or more microprojections embedded in the subject’s skin for a period of about 5 seconds. In certain embodiments, the microprojection array is left in place with said microprojections embedded in the subject’s skin for a period of 5, 10 or 15 seconds, 30 seconds, 1 minute, 5 minutes, minutes, 15 minutes or 30 minutes. In some embodiments, the microprojection array is fixed in place for the duration of their residency time on the subject’s skin.

In some embodiments, this invention includes a method of treating osteoarthritis comprising daily administration of a microprojection array comprising a plurality of [G1u 22 ’25, Leu23 ’28 ’31 , Aib29, Lys 26 ’30]PTHrP(1-34)NH2 coated microprojections to a subject in need thereof wherein said administration comprises contacting one or more of said microprojections of the microprojection array with sufficient force to penetrate the subject’s skin and wherein said microprojections are coated with about 75 .ig of [G1u 22’25 , Leu 23 ’28’31 , Aib29, Lys26 ’30]PTHrP(1-34)NH 2 .

In some embodiments, this invention includes a method of treating osteoarthritis comprising daily administration of a microprojection array comprising a plurality of [G1u 22’25 , Leu 23 ’28 ’31 , Aib29 , Lys2630]PTI-IrP(1-34)NH 2 coated microprojections to a subject in need thereof wherein said administration comprises contacting one or more of said microprojections of the microprojection array with sufficient force to penetrate the subject’s skin and wherein said microproj ections are U23,28,31, Aib29, coated with between 85 Vig and 115 tg of [G1u22’25, Lys26’30]PTHrP(1 -34)NH2.

In some embodiments, this invention includes a method of treating osteoarthritis comprising daily administration of a microproj ection array comprising a plurality of [G1u 22 ’25, Leu 23 ’28 ’31 , Aib29 , Lys 26’30]PTHrP(1-34)N1-12 coated microprojections to a subject in need thereof wherein said administration comprises contacting one or more of said microprojections of the microprojection array with sufficient force to penetrate the subject’s skin and wherein said microprojections are coated with about 100 jig of [G1u 22’25, Leu23 ’2831 , Aib29 , Lys 26’30]PTHrP(1-34)NH2 .

In some embodiments, this invention includes a method of treating osteoarthritis comprising daily administration of a microprojection array comprising a plurality of [G1u 22’25 , Leu 23 ’28’31 , Aib 29, Lys 26’30]PTHrP(1-34)NH 2 coated microprojections to a subject in need thereof wherein said administration comprises contacting one or more of said microprojections of the microprojection array with sufficient force to penetrate the subject’s skin and wherein said microproj ections are coated with between 106.25 pg and 143.75 jig of [G1u 22 ’25, Leu23 ’28’31 , Aib29, Lys26’30]PTHrP(1-34)NJ-1 2 .

In some embodiments, this invention includes a method of treating osteoarthritis comprising daily administration of a microprojection array comprising a plurality of [G1u 22’25 , Leu 23 ’2831 , Aib 29 , Lys 26’30]PTHrP(1-34)NH 2 coated microprojections to a subject in need thereof wherein said administration comprises contacting one or more of said microprojections of the microprojection array with sufficient force to penetrate the subject’s skin and wherein said microprojections are coated with about 125 jig of [G1u 22 ’25 , Leu23 ’28 ’31 , Aib 29 , Lys 26’30]PTHrP(1-34)NH2.

In some embodiments, this invention includes a method of treating osteoarthritis comprising daily administration of a microprojection array comprising a plurality of [01u 22’25 , Leu23 ’28 ’31 , Aib29, Lys 26’30]PTHrP(l-34)N}1 2 coated microprojections to a subject in need thereof wherein said administration comprises contacting one or more of said microprojections of the microprojection array with sufficient force to penetrate the subject’s skin and wherein said microprojections are coated with between 127.5 p.g and 172.5 g of[Glu 22’25, Leu 23 ’28 ’31 , Aib 29, Lys 26’30 ]PTHrP( 1 -34)NH.

In some embodiments, this invention includes a method of treating osteoarthritis comprising daily administration of a microprojection array comprising a plurality of [G1u 22 ’25 , Leu2328’31 , Aib 29, Lys26 ’30]PTHrP(l-34)NH 2 coated microprojections to a subject in need thereof wherein said administration comprises contacting one or more of said microprojections of the microprojection array with sufficient force to penetrate the subject’s skin and wherein said microprojections are coated with between 150 j.g of [G1u 22 ’25 , Leu 23 ’28 ’31 , Aib 29, Lys 26 ’30]PTHrP(l- 34)NH 2 .

In some embodiments, this invention includes a method of treating osteoarthritis comprising daily administration of a microprojection array comprising a plurality of [Glu 22’25, Leu 23 ’28 ’31 , Aib29, Lys26 ’30]PTHrP(1-34)NH 2 coated microprojections to a subject in need thereof wherein said administration comprises contacting one or more of said microprojections of the microprojection array with sufficient force to penetrate the subject’s skin and wherein said microproj ections are coated with between 170 ig and 230 p.g of [G1u 22 ’25 , Leu 23 ’28’31 , Aib 29, Lys 26 ’30 ]PTHrP( 1 -34)NH 2 .

In some embodiments, this invention includes a method of treating osteoarthritis comprising daily administration of a microprojection array comprising a plurality of [G1u 22 ’25, Leu 23 ’28 ’31 , Aib29, Lys26 ’30]PTHrP(l-34)NH 2 coated microprojections to a subject in need thereof wherein said administration comprises contacting one or more of said microprojections of the microprojection array with sufficient force to penetrate the subject’s skin and wherein said microprojections are coated with about 200 j.tg of [G1u22 ’25 , Leu 23 ’28’31 , Aib 29, Lys 26 ’30]PTHrP(l-34)NH 2 .

In some embodiments, the microprojection arrays useful for the treating osteoarthritis comprise microneedles.

In some embodiments, this invention comprises a method of increasing bone mineral density in a subject in need thereof comprising the administration of a microprojection array comprising one or more [G1u 22’25 , Leu23’2831 , Aib29 , Lys26’30] PTHrP( 1 -34)NH 2 coated microproj ections wherein said administration comprises contacting one or more of said [G1u 22 ’25, Leu23 ’28 ’31 , Aib29 , Lys26 ’30]PTHrP(l-34)NH 2 coated microprojections with the skin of the subject using sufficient force to cause penetration of one or more [G1u 22’25, Leu23’28 ’31 , Aib 29 , Lys 26 ’30]PTHrP(l-34)NH 2 coated microprojections into the skin. For example, it is believed that an anabolic effect on bone could be achieved by a once per every two days application, once per every three days application, or even a once per week application. In particular embodiments, a method of increasing bone mineral density in a subject in need thereof comprise the administration of a microprojection array comprising one or more [G1u 22 ’25, Leu 23 ’28’31 , Aib 29, Lys 26 ’30]PTHrP(l-34)NH 2 coated microprojections in doses and dosing schedules as set forth herein for the treatment of osteoporosis, and/or for treating fractures or accelerating fracture healing, and/or for the treatment of osteoarthritis.

BRIEF DESCRIPTION OF THE DRAWINGS FIG. I is a graph comparing a representative microneedle array pharmacokinetics (PK) profile (09RAD010 Group 1), adjusted to a 20 igIkg dose, graphed together with the reference subcutaneous (SC) profile. is an image of a liquid crystal polymer (LCP) microarray. is a side view with dimensions of the microstructures of the LCP array. is a graph showing the mean concentrations of [Glu 22 ’25, Leu 2328 ’31 , Aib29, Lys 26 ’30]hPTHrP(1-34)NH 2 in serum versus time after a single microneedle array application (155342-041, 124 jtg). is a graph showing the mean concentrations of [G1u 22 ’25, Leu 23 28’31 , Aib29, Lys 26’30]hPTHrP(1-34)NH 2 in serum versus time after single microneedle array application (155342-0 16, 103 p.g). is a graph showing the mean concentrations of [G1u 22 ’25, Leu23 ’28 ’31 , 29 26 30 Aib , Lys ]hPTHrP(1-34)NH 2 (ng/mL) n serum after a single microneedle array i application (155342-064, 56 jig). is a graph showing the mean concentrations of [G1u 22 ’25, Leu23 ’28’31 , Aib29, Lys26 ’30]hPTHrP(1-34)NH 2 in serum after a single microneedle array application (155342-033, 211 xg). is a graph showing the mean concentrations of [G1u 22 ’25, Leu23 ’28’31 , Aib29, Lys26 ’30]hPTHrP(1-34)NH 2 (ng/mL) in serum after single microneedle array application (152986-035, 13.6 .ig).

FIG 9 is a figure showing change in femoral metaphysis bone mineral density in the osteopenic rat following repeat application of [G1u 22’25, Leu23 28’31 , Ai b 29, Lys2630]hPTHrP(1 -34)NH2-microneedle arrays FIG 10 is a figure showing change in lumbar spine bone mineral density in the osteopenic rat following repeat application of [G1u 22’25, Leu 23 ’28’31 , Aib 29, Lys26’30 ]hPTHrP( 1 -34)NH2-microneedle arrays is a graph comparing plasma exposure levels of [G1u 22’25 , Leu 23 ’28’31 , Aib 29, Lys26 ’30]hPTHrP(l-34)NH 2 in pG/mL after periumbilical application with 100 tg array (15 minute contact and 10 second contact time) and 80 ig subcutaneous administration of [G1u 22’25, Leu 23 ’28’31 , Aib 29, Lys 26 ’30]hPTHrP(l-34)NH 2 . is a graph comparing plasma exposure levels of [Glu 22’25, Leu 23 ’2831 , Aib29, Lys 26’30]hPTHrP(1-34)N}1 2 in pg/mL after upper thigh application with 100 j.tg array (15 minute contact and 10 second contact time) and 80 g subcutaneous administration of [G1u 22’25, Leu 23 ’28 ’31 , Aib 29, Lys 26 ’30]hPTI-[rP(1-34)NH 2 . is a graph showing mean change from baseline collagen type I cross-linked C-telopeptide (CT)() concentrations following Glu 22 ’25, Leu23 ’28’31 , Aib29 , Lys 26 ’30]hPTHrP(l-34)NH 2 study groups and placebo on days 1, 3, and 7 (Study Period 2) - Linear Scale is a graph showing mean change from baseline CTX concentrations following G1u 22’25, Leu 23 ’28’31 , Aib29, Lys 26’30]hPTHrP(1-34)NH2 study groups on days 1, 3, and 7 (Study Period 3) - Linear Scale is a graph showing mean change from baseline procollagen type 1 amino-terminal propeptide (PINP) concentrations following G1u 22’25, Leu23 ’28’31 , Aib 29 , Lys 26 ’30]hPTHrP(l -34)NH2 study groups and placebo on Days 1, 3, and 7 (Study Period 2) - Linear Scale is a graph showing mean change from baseline P1NP concentrations following G1u 22’25, Leu2328’31 , Aib29, Lys 26 ’30]hPTHrP(l-34)NH2study groups on days 1, 3, and 7(Study Period 3) - Linear Scale DETAILED DESCRIPTION OF THE INVENTION The present invention relates to the use of PTHrP or PTHrP analogues for the prevention or treatment of osteoporosis, osteopenia, osteoporosis, osteoarthritis, or bone fracture or to accelerate bone fracture healing. In particular, the preferred compound for use in the various embodiments of this invention is [G1u 22’25 , Leu23 ’2831 , Aib 29, Lys 2630]hPTHrP(l-34)NH2 or a salt thereof. The bone anabolic ]hPTHrP(l-34)NH2 has been described in agent [G1u 22’25, Leu23 ’28’31 , Aib29, Lys 26’30 previous publications including mt. Pubi. No. , US Patent Appin Pubin. 2009/0227498 and US Pat No. 5,969,095.

The term "treating" or "treatment" of a mammal, preferably a human is understood to include treating, preventing, or ameliorating the symptoms associated with, or reducing the incidence of, reducing the pathogenesis of, facilitating the recovery from or delaying the onset of the condition being considered including osteopenia, osteoporosis, osteoarthritis, bone fracture, and so forth.

The term "preventing" as used herein is understood to mean preventing or delaying the disease or symptom from occurring in a subject which may be predisposed to the disease or symptom but has not yet been diagnosed as having it.

As used herein, the unit microgram may be represented by either "meg" or" jig"; polycarbonate maybe represented by the term "PC", and phosphate buffered saline (PBS).

With regard to osteopenia or osteoporosis, it will not matter if the osteoporosis or risk of osteoporosis from which the subject suffers finds its roots in immobilization, age, low gonadal state (e.g. postmenopausal women, testosterone deficient males - including chemically-induced low gonadal like states induced through use of aromatase inhibitors, anti-androgens, gonadotropin agonist/antagonists and the like), endocrinological disorders (e.g. diabetes, adrenal insufficiency, cushing’s syndrome), malnutrition including vitamin D and/or calcium deficiency, rheumatoid arthritis, renal insufficiency, various cancers including myelomas and leukemias, certain inherited forms of osteoporosis and osteoporosis caused by concomitant administration of medicines known or suspected to cause bone loss (e.g. cortico steroids, peroxisome proliferator-activated receptor gamma (PPARgamma) agonists, thyroid medications, lithium therapy, anti- depressants, proton pump inhibitors, etc). Whatever the source, osteoporosis risk is most broadly identified by identifying at risk populations but more specifically can be identified by looking at individual risk factors including low bone mineral density and/or prior incidence of fracture in the individual in question. It should be appreciated that the compositions, products, devices and methods of this invention can be applied to at-risk populations or individuals. Because of the highly bone anabolic nature of the compositions and methods of this invention there is particular value in treating populations at especially high risk, including those with bone mineral density at more than 1 standard deviation below the mean, or more than 2 standard deviations below the mean or more than 2.5 standard deviations below the mean. Alternatively or in addition, the compositions and methods of this invention are of particular value for those who have had one or more previous bone fractures, particularly those who have suffered from one or more previous fragility fractures.

With regard to treatment of bone fracture or the acceleration of bone fracture healing, the fractures may be either non-traumatic or traumatic factures, including for example, fragility or osteoporotic fractures, and may occur in either vertebral or nonvertebral bones. In particular, osteoporotic fractures may occur at the hip, spine, wrist, or forearm, though they are not limited to these sites.

The previous published reports relating specifically to [Glu 22 ’25, Leu23 28’31 , Aib29, Lys 26 ’30]hPTHrP(1-34)NH 2 have described the administration to a patient in need thereof by subcutaneous injection (e.g. ), preferably a daily subcutaneous injection. Due to the particular nature of the anabolic effects of PTH and PTHrP and analogues, it is generally believed that their pharmacokinetics has to be fairly tightly controlled in order to achieve bone anabolic effects without losing efficacy or possibly even leading to bone loss. In particular, it has been noted that a transient, daily exposure to an adequate amount of a PTH, PTI-IrP or PTHrP analogue can induce anabolic effects on bone with a lag in bone resorption resulting in a net increase in bone density and a corresponding reduction in fractures (see, for example, Neer, et al. New England Journal of Medicine, vol 344; 1434-1441, May , 2001). However, the drawbacks of PTH therapy as currently available include side effects such as hypercalcemia even at a low daily dose of 20 g per day and the inconvenience of requiring patients to inject themselves subcutaneously every day with the drug. These challenges are compounded by the fact that the patient population most likely to benefit from the therapy are often the elderly and infirm.

In this regard, it is worth noting that the PTHrP analogue [G1u 22 ’25, Leu23 2831 , Aib 29 , Lys 26 ’30]hPTI-hP(1-34)NH 2 is a bone anabolic agent that is particularly efficacious at increasing bone mineral density in osteoporotic patients and of particular interest is its reduced tendency to induce hypercalcemia in patients even at very high doses (e.g. 80 tg sc per day). However, the problem with the inconvenience of a daily injection remains. For this reason, the exciting discovery that a very viable and alternative delivery of the PTHrP analogue [G1u 2225 , Leu23 ’28 ’31 , Aib29 , Lys 26 ’30]hPTHrP(1-34)NH 2 as reported herein is particularly noteworthy.

The alternative delivery described in this patent application relates to the use of microproj ection, including microneedle, arrays coated with the PTHrP analogue [Glu22 ’25, Leu23 ’28 ’31 , Aib 29 , Lys 26 ’30]hPTHrP(1-34)NH 2. In general, the advantages of a microprojection array over a subcutaneous administration of the drug relate to the fact that the mieroprojections in the array do not need to completely penetrate the dermis in order to effectively deliver the drug substance, thereby providing a relatively painfree delivery route to the patient. Microprojection arrays typically consist of a plurality of microprojections, for example microneedles, fixed to a support material. The microprojections, for example microneedles, are often described as containing a reservoir or channel or mechanism such that the very tiny microprojections, for example microneedles, can transfer enough of the drug substance into the subject undergoing treatment. In some instances, the microprojections, for example microneedles, have been reported to be useful where the microprojections do not contain a separate reservoir but rather are directly coated with the drug substance (see, for example, US Pat Appin Publn No. 2005/0256045).

In this latter mode of operation, the technology that has been described to date works best when the drug has a high enough potency so that the very tiny, coated microprojections, for example microneedles, can convey enough of the drug to effectively treat the patient. For the specific example of PTH 1-34 (teriparatide), work has been disclosed using the compound on microneedle arrays where those arrays are coated with enough drug to approximate the exposure of a 20 ig subcutaneous dose (or less) of teriparatide, which is the approved and marketed dose for that compound. While every drug poses its own challenges with regard to any particular form of drug delivery, some challenges can be greater than others. In particular, for the directly coated microprojections, for example microneedles, containing the PTHrP analogue [Glu 2225 , Leu2328 ’3 , Aib 29, Lys 26 ’30]IiPTHrP(l- 34)NH2 , doses higher than the 20 jig currently marketed dose of teriparatide are preferred. For example, it has been discovered that subcutaneous doses as high as 80 tg of [G1u 22 ’25, Leu 23 ’28 ’31 , Aib 29 , Lys 26 ’30]hPTHrP(l-34)NH 2 are highly effective and well-tolerated. Without the aid of some sort of drug retaining reservoir or channel, there are legitimate questions of whether such a large dosing volume can be effectively and reproducibly coated onto the microprojections (e.g., microneedles) and moreover, whether such a large dosing volume can be effectively and reproducibly delivered in a manner that is consonant with the requirement of tightly controlled pharmacokinetics. Beyond the questions associated with the higher dose of this particular drug are the problems inherent to delivering any polypeptide through the skin. While the delivery of teriparatide by an intradermal route has been documented, one should be especially cautious in attempting to extrapolate those results to completely different polypeptides. Differences in solubility, stability, polarity, ionization and many other factors make any comparisons or predictions from one class of compounds to another suspect. In accordance with the features of this invention, the various aspects will be presented both separately and in combination though it should be appreciated that the invention is not limited to the specific combinations described.

In a first aspect of this invention, a formulation for coating the microprojection (e.g., microneedle) delivery device is described. As mentioned previously, the coating formulation ideally provides a suitable concentration, viscosity and stability of the drug and furthermore, the excipients used (if any) in the coating formulation must not be excessively irritating or allergenic to the skin of the animal being treated, especially where the treated animal is a human. In this regard, it has been quite surprisingly discovered that the compounds useful in this invention can be effectively coated onto the microprojections (e.g., microneedles) with or without the addition of traditional stabilizing excipients and still maintain very good drug stability. For purposes of evaluation, several coating formulations containing containing different concentrations of drug and excipient were prepared, and the formulations used to coat polycarbonate or liquid crystalline polymer solid microstructured transdermal system ("sMTS") microprojection arrays with 500 im square pyramid needle structures spaced 550 .tm apex to apex. After coating the drug substance onto the microneedles, the formulation was dried and the stability evaluated.

In Table 1, stability results for aqueous formulations of [G1u 22 ’25, Leu2383 ’ Aib29, Lys2630]hPTHrP( I -34)NH 2 with only a PBS buffer IX (pH 7.4) as an excipient coated on a polycarbonate array after drying are displayed. As can be seen from Table 1, good stability was observed with both coating concentrations as well as good stability independent of final loading doses.

Table 1: Stability of [G1u 22 ’25, Leu 23 ’28’, Aib 29, Lys 26 ’30]hPTHrP(1-34)NH2 on array with only PBS Buffer as excipient Weight % Storage Conditions Initial 2 week 4 week mcg*/a rray) Content ( 35.0 32.3 32.9 Std.Dev. 4.1 1.9 4.7 % of Initial Content 100 100 100 Content (mcg/array) 32.3 32.2 33.0 25C Std. Dev. 4.1 1.7 2.0 /o aqueous solution 32 meg / array % of Initial Content 100 100 100 Content (meg/array) 141.9 166.7 166 Std. Dev. 17.0 20.0 11.7 % of Initial Content 100 100 100 Content (meg/array) 141.9 133.3 169.6 25C Std. Dev. 17.0 11.6 29.4 60% aqueous solution 142 meg 100 / array % of Initial Content 100 94 Content (meg/array) 386.5 368.8 361.7 4C Std. Dev. 57.0 58.9 7.2 % of Initial Content 100 95 94% Content (meg/array) 386.5 390.8 291.3 25C Std, Dev. 57.0 35.4 18.1 60% aqueous solution 387 meg / array % of Initial Content 100 100 75% *mcg = p.g = microgram The reported weight percentages in Table 1 refer to crude peptide weight including acetic acid, trifluoroacetic acid and small amounts of water. The actual weight content normalized to peptide is approximately 85% of the listed amount.

Additional experiments were performed for different loading concentrations of [Glu22 ’25, Leu 23 ’28’31 , Aib29, and excipients.

Lys26’30IhPTHrP(1-34)NH2 Table 2 summarizes some of those findings. The formulations in Table 2 refer to the formulation concentration and excipients used to coat the microneedle arrays. As was performed previously, the formulation solution was coated onto the microneedle array and the coated microneedle arrays dried prior to the stability evaluation.

Table 2: Stability of [Glu 22 ’25, Leu 23 ’28 ’31 , Aib 29 , Lys 26 ’30] hPTHrP(1-34)NH 2 with only PBS and with PBS and other excipients. Storage was at approximately 4 degrees Celsius and ambient RH.

Formulation % of initial % of initial Glu225 , Leu’28 ’ ’, Aib 29 , Lys 26 ’ 30]hPTHrP(1-34)NH 2 Desiccant (1 week) (2 week) aqueous formulation No 91.5 93.2 50% aqueous formulation Yes 101.6 95.4 % aqueous with 30% sucrose no 99.1 94.3 % aqueous with 30% sucrose yes 101.6 98.6 % aqueous with 4.5% EIEC* no 91.3 86,5 % with 4.5% HEC yes 87.5 86.5 % aqueous with 17.5% sucrose and 2% 1-fEC no 85.7 86.5 % aqueous with 17.5% sucrose and 2% HEC yes 98.9 102.3 *Hydroxyethylcellulose The reported weight percentages in Table 2 refer to crude peptide weight including acetic acid and water. The actual weight content normalized to peptide is approximately 80% to 90% of the listed amount (that is, acetic acid and water account for 10% to 20% of the crude peptide weight).

In Table 3, stability results for [Glu 22 ’25, Leu23 ’28’31 , Aib 29 Lys26’30]hPTHrP(1 -34)NH 2 on an LCP (liquid crystal polymer) microneedle array, with 3% histidine, 5% histidine or 9% potassium chloride as an excipient are displayed. The formulations in Table 3 refer to the excipients used to coat the microneedle arrays. As was performed previously, the formulation solution was coated onto the microneedle array and the microneedle array packaged in the presence or absence of a desiccant prior to the stability evaluation. Desiccants suitable for pharmaceutical applications include silica gel and molecular sieves.

As can be seen from Table 3, good microneedle array coating and [G1u 22’25 , Leu23 ’28 ’31 , Aib29, Lys 26’30]hPTHrP(l-34)NH 2 stability was observed in formulationswith on PBS as an excipient, or in formulations containing PBS and the additional excipients histidine, or potassium chloride, and stability was enhanced by the presence of a desiccant in the packaging.

Table 3: Stability of Glu 22’25 , Leu 23’28’31, Aib29, Lys 26 ’301hPTHrP(1-34)NH2 coated microneedle arrays with and without desiccant Time (Months) 4C/Ambient 40C/75% Ri-I 25C160% RH Formulation Test Initial 0.5M IM 2M IM 2M IM Content - 124 118 102 91 124 89 126 (mcg/array) Control* Purity (%) 95.4 92.1 91.1 95.2 92.5 98.3 97.7 98.9 Content 112 128 98 124 119 125 97 122 Control with (meg/array) Desiccant 97.9 97.4 98.6 98.3 Purity (%) 98.9 97.6 96 94.3 Content 94 125 123 136 135 122 89 138 (mcg/array) 3% 1-listidine 99.2 99.2 Purity (%) 99.5 98.3 96.8 95.8 98.7 97.6 Content 137 135 101 139 119 138 104 3% Histidine with (mcg/array) Desiccant 99.3 99.2 Purity (%) 99.5 98.5 97.4 96.1 98.9 98.3 Content 120 66 134 125 108 39 115 69 (mcg/array) % 1-listidine 99.1 Purity (%) 99.5 98.4 97.3 96.3 98.7 98 99.1 Content 44 113 70 120 86 134 130 117 % Histidine with (mcgfarray) Desiccant 99.2 99.2 Purity (%) 99.5 98.5 98 97.5 98.9 98.7 Content III 94 90 58 96 57 109 74 9% Potassium (meg/array) Chloride ________________ 93.4 89.9 98.8 97.5 Purity (%) 99.4 94.3 92.7 90.5 Content 9% I I Potassium Ill 108 105 87 I 05 88 105 75 (mcg/array) Chloride with I I I I I Desiccant Purity (%) 99.4 98.2 97.5 96.4 98.8 98.3 98.9 99.2 * control formulation includes PBS as sole excipient Certain drug coated microarrays were tested in vivo in a preclinical model using Sprague Dawley rats. These studies assessed transdermal delivery of [Glu22 ’25 , Leu2 ’ 8 ’31 , Aib29, Lys 26’30]hPTHrP(l-34)NH2 using microneedle arrays in Sprague U22,21, Dawley rats. Application of [GI Leu 23 ’28 ’31 , Aib29, Lys260]hPTHrP( 1 -34)NH2- microneedle arrays to the skin with only short contact times (1-5 minutes) achieved , Lys 26 ’30]hPT1-frP(1-34)NH2 and a systemic exposure of [G1u22’25, Leu23 ’28 ’31 , Aib29 rapid absorption from the array and rapid elimination.

Table 4: Studies with microneedle arrays comprising polycarbonate Lys26iOlhPTHrP(1_34)NH2 rnicroneedles coated with G1u 22 ’25 1 Leu 23 ’28"31 , Aib29, Formulation Peptide Dose Level Study umber of Content1 Group Number Animals (j.tg/kg) (kg) Peptide HEC 09RAD005 1 9 20.0 5.0 4.5 72 09RAD006 1 10 31.0 15.0 4.0 104 09RAD006 2 10 22.0 10.0 4.5 76 09RADOIO 1 26.2 12.5 4.5 83 09RADOIO 2 8 57.7 12.5 4.5 178 09RADOI1 1 8 67.7 16.7 4.0 227 09RADOI 1 2 8 45.6 20.5 3.5 09RAD017 1 8 27.0 16.7 4.0 78 09RADOI7 2 8 27.0 16.7 4.0 79 09RADOI7 3 8 27.0 16.7 4.0 .0 3.5 94 09RADOI7 4 8 32.0 0,0 433 09RADO18 1 8 141.9 59.3 1189 09RADO18 2 8 386.5 59.3 0.0 09RAD030 1 2 27.0 16.7 4.0 105 09RAD030 2 3 32.0 20.0 3.5 125 09RAD030 3 1 26.2 12.5 4.5 4.0 103 09RAD030 4 2 27.0 16.7 .0 3.5 120 09RAD030 5 3 32.0 09RAD030 6 1 26.2 12.5 4.5 98 Formulation Peptide Study Number of Dose Level Content Group Number Animals (p.g/kg) (jig) Peptide HEC 09RAD048 1 12 9.8 49 0.0 37 09RAD048 2 12 54.0 49 0.0 178 09RAD053 1 6 141.9 59.3 0.0 529 09RAD053 2 1 386,5 59.3 1470 Peptide ([G1u’, Aib4’, Lys’ 3 ]hPTHrP(l-34)NH 2 ) content calculated based on total peptide content including water and acetic acid. Actual peptide content is approximately 80% - 90% of the stated amount.

Materials and Methods for studies RAD 005, 006, 010, 011, 017, 018, 030, 048, 053 of Table 4 Animals Male Sprague Dawley rats with jugular vein catheters were purchased from Charles River Laboratories. Once received, they were acclimated for at least 24 hours prior to dosing. Animals were singly housed in polycarbonate ventilated (45 ACH) cages. All animals were provided certified rodent diet (2918 from Harlan Tekiad) and water ad libitum. The housing environment was maintained between 18-26 C with 30-70% relative humidity with a 12 hr light: 12 hr dark cycle.

Test Article Table 5: Microneedle arrays used for studies RAD 005, 006, 010, 011, 017, 018, 030, 048, 053 Microneedle arrays Polycarbonate arrays Material of Construction Polycarbonate ("PC’) Number of Microneedles .366 Flexural Modulus (by, ISO 178) 2300 Grade Class VI, medical grade polymer Surface area .5 cm2 or 27 mm in diameter Depth of Penetration (DOP) 250+!- 10 Height of Microneedles 500gm Spacing between Microneedles apart (tip to tip) 550i1m The finished ([G1u 22 ’25, Leu23 ’28 ’31 , Aib 29, Lys 26 ’30]hPTHrP(l-34)NH2) - microneedle array is sealed in a packaging system that insures moisture and light are controlled to maintain a biostatic environment (an environment in which microorganisms can not proliferate). Further, the ([G1u , Aib29 , 22’25, Leu23 ’28’31 Lys 26 ’30]hPTHrP( 1 -34)NH2) -microneedle array Finished Drug Product is stored under refrigerated conditions until dosing. Microbial release specifications for the drug product are based on the acceptance criteria described in PhEur 5.1.4 and USP <1111>, USP <61>, and <62>. The drug product also meets the endotoxin specifications in Ph.Eur. 2.6.14 and USP <85> and <161>.

Based on the manufacturing processes designed to insure microbial control and on the release specifications governing the release of the drug product prior to use in humans, the ([G1u 22’25 , Leu23 ’28 ’31 , Aib 29, Lys 26’30]hPTHrP(1-34)NH 2) - microneedle array Finished Drug Product is defined as an ultra low bioburden product.

Microneedle arrays coated with ([Glu 22’25, Leu 2 .3 ’28’31 , Aib29 , Lys 26 ’30]hPTHrP(1-34)NH2) were manufactured by dip-coating the microneedle array into an aqueous, PBS buffered solution having the disclosed concentration of ([G1u22’25, Leu23 ’28’31 , Aib29 , Lys 26’30]hPTHrP(1-34)NH 2) by weight and additional excipients as noted in Table 4. Other methods of coating microneedles are known in the art. After a dipping step, the arrays are air dried. Various lots of ([G1u 22’25 , Leu23 ’28 ’31 , Aib 29, Lys26 ’30]hPTHrP(l-34)NI-1 2-microneedle arrays were tested in which the percent (w/w) of([G1u 22 ’25, Leu 23 ’28’31 , Aib29, .Lys26 ’ ]hPTHrP(1-34)NH2 and hydroxyethyl cellulose (HEC) in the formulation, and the amount of compound coated on the array was varied. Details of the different microneedle arrays lots are given in Table 4. The microneedle arrays are supplied individually packaged in a light protective foil .pouch, some with a desiccant and some without and stored at 4C. Typically, one hour prior to dosing microneedle arrays were removed from refrigeration (approximately 4C) and allowed to equilibrate to room temperature.

In studies 09RAD005 and 09RAD006, the microneedle arrays were applied immediately after removal from the refrigerator, without sufficient time to reach room temperature.

Dose Administration Transdermal dose delivery was assessed by application of ([G1u 22 ’25 , Leu 23 ’28’31 , Aib 29, Lys26 ’30]hPTHrP(1-34)NH 2-microneedle arrays to the skin of rats.

The standard procedure for skin preparation and microneedle array application is as follows.

One day prior to dosing, an area just above the hind legs on the dorsal Nairﬁ surface of the rat was shaved using electric clippers. hair removal lotion (Church & Dwight Co.) was then applied to the area for 5 to 8 minutes to remove remaining fur stubble. The Nair ﬁ lotion was then thoroughly removed using a damp cloth. The next day a microneedle array was applied using a spring-loaded applicator. The microneedle array was left in contact with skin for five minutes, before being removed. During array application and contact time the rats were manually restrained.

Throughout these studies variations to the procedure for microneedle application were explored.

Table 6 summarizes the dosing and application conditions for each study in this set.

Table 6: Array contact time, temperature and skin preparation Array Study Array Group Skin Preparation Number Temperature* Contact Time 09RAD005 1 4C 5 Minutes Clippers and Nair 09RAD006 1 4C 5 Minutes Clippers and Nair 09RAD006 2 4C 5 Minutes Clippers and Nair 09RADO 10 1 22C Minutes Clippers and Nair 09RADO10 2 22C 5 Minutes Clippers and Nair 09RADO 11 1 22C 5 Minutes Clippers and Nair 09RADO 11 2 22C 5 Minutes Clippers and Nair 09RADO 17 1 22C Minutes Clippers and Nair 09RADO 17 2 22C 1 Minute Clippers and Nair 09RADO17 3 22C 5 Minutes Clippers. 09RADO17 4 22C 5 Minutes Clippers and Nair 09RAD0I8 1 22C Minutes Clippers and Nair 09RADO 18 2 22C Minutes Clippers and Nair 09RAD030 1 22C 1 Minute Clippers 09RAD030 2 22C Clippers 1 Minute 09RAD030 3 22C 1 Minute Clippers 09RAD030 4 22C 5 Minutes Clippers 09RAD030 5 22C 5 Minutes Clippers 09RAD030 6 22C 5 Minutes Clippers 09RAD048 1 22C 5 Minutes Clippers 09RAD048 2 22C 5 Minutes Clippers 09RAD053 I 22C 5 Minutes Clippers Array Study Array Group Skin Preparation Number Temperature* Contact Time 09RAD053 2 22C Minutes Clippers * Microneedle arrays applied to rats immediately after removal from refrigerator are designated as "4C." Microneedle arrays allow to first equilibrate to room temperature are designated as "22C." Serum Collection 09RAD005, O9RADOO6, O9RADO1O, 09RAD011, 09RAD017, O9RADO18: Blood was collected at three time points from each animal out of a possible total of five time destinations (5 minutes, 15 minutes, 30 minutes, 45 minutes, 90 minutes) from each rat on a staggered schedule so that all time points would be represented with extra sampling at 15 minutes without overdrawing from any animal. Approximately 1 mL of blood was collected via the catheter from the jugular vein using a syringe and needle from rats for their first two blood draws. For the terminal blood collection, animals were euthanized via CO 2 chamber and approximately I mL of blood was collected via cardiac puncture. The blood was immediately transferred to a serum separator tube that contained 25 1iL of a mg/ml aprotinin (Sigma) solution.

Blood draw schedule for 09RAL030: Blood was collected from each rat , 10, 15, 30 and 45 minutes post dose.

Approximately 600 l.LL of blood was collected via the catheter from the jugular vein using a syringe and needle from rats for their first four blood draws. For the terminal blood collection, animals were euthanized via CO2 chamber and approximately 600 jtL of blood was collected via cardiac puncture. The blood was immediately transferred to a serum separator tube that contained 12 1iL of a 2.5 mg/mi aprotinin (Sigma) solution.

Blood draw schedule for 09RAD048: Blood was collected three or four times from each rat at the time points depicted in the tables below. Approximately 1 mL of blood was collected via the catheter from the jugular vein using a syringe and needle from rats for any non- terminal time points. For the terminal blood collection, animals were euthanized via CO2 chamber and approximately 1 ml, of blood was collected via cardiac puncture.

The blood was immediately transferred to a serum separator tube that contained 20 pL of a 2.5 mg/ml aprotinin (Sigma) solution.

Blood draw schedule for 09RAD053: Blood was collected from each rat 45, 90 and 120 minutes post , 15, 30, dose. Approximately 500 ttl, of blood was collected via the catheter from the jugular vein using a syringe and needle from rats for their first five blood draws. For the terminal blood collection, animals were euthanized via CO2 chamber and approximately 500 j.tL of blood was collected via cardiac puncture. The blood was immediately transferred to a serum separator tube that contained 10 of a 2.5 i.tL mg/ml aprotinin (Sigma) solution.

Residual ([G1u 22’25, Leu 23’28’31, Aib 29, Lys 26’30/hPTHrP(1-34)NH2 Analysis Residual ([G1u 2225 , Leu 23 ’28 ’31 , Aib29, Lys 26’30]hPTHrP(1-34)NH2was eluted from all ([G1u 22 ’25 , Leu23 ’28’31 , Aib29, Lys 26 ’30]hPTHrP(l-34)NH 2-microneedle arrays used to dose studies 09RADO 10 and 09RADO 11. In addition, at least two microneedle arrays from each group that were not used to dose, to confirm initial array drug content, and two uncoated arrays (placebo-microneedle arrays) were , Lys26 ’30]hPTHrP(1- eluted. In study 09RADO18, ([G1u 22 ’25, Leu 23 ’28’31 , Aib 29 34)NH2was eluted from one ([G1u 2225, Leu 23 ’2831 , Aib 29, Lys26’30]hPTHrP(l-34)NH2- microneedle array per group prior to dosing. ([G1u 22’25 , Leu23 ’28’31 , Aib 29 , Lys 26’30]hPTHrP(l -34)NH2 elution was performed according to the following protocol.

The microneedle array was removed from its adhesive backing using forceps, and was placed, needles down, in a 5 mL snap-cap vial (Nalgene). 1 mL of PBS- Tweenﬁ 80 extraction solution (0.2 g TweenlL PBS) was added to the vial so that the array was completely immersed. The vial was placed on an orbital shaker set at 100-150 oscillations per minute for 30 minutes. The array was then removed from the vial and discarded. The vials containing eluted ([Glu 22 ’25, Leu23 ’28’31 , Aib29 , Lys 26’30]hPTHrP(l-34)NH2 in the PBS-Tween 80 solution from studies 09RADO10 and 09RADO1 1 were stored at -20C. Samples were then used for HPLC analysis of 2 content. The vials ([G1u22’25, Leu2328 ’3] , Aib29, Lys 26 ’30]hPTHrP(l -34)NH , Aib29, Lys2630]hPTHrP( I -34)NH2 in the PBS- containing eluted ([G1u 22 ’25 , Leu 23’28 ’31 Tween 80 solution from study 09RADO18 were stored at 4C. Samples were then sent for I-IPLC analysis of([G1u 22’25, Leu 23 ’28 ’31 , Aib 29 , Lys 26 ’30]hPTHrP(l-34)NH2 content.

The initial drug content of each group of arrays was determined to be the average of the at least two two arrays that were not used to dose. The residual content is the average amount of([G1u 2225 , Leu 23 ’28 ’31 , Aib 29, Lys26’30]hPTHrP(l- 34)NH2 on the remaining arrays. The percent of drug load released was then calculated as: %Released = Peptide Peptide Peptide INITIAL- RESIDUAL)/ INITIAL Sample Handling and Storage Blood was kept at room temperature in serum separator tubes containing aprotinin for approximately 45 minutes to allow it to clot. Once clotted, the blood was centrifuged at 2500 rpm for 10 minutes. Serum was transferred to microcentrifuge tubes for storage at -80C until analysis of([G1u 22’25, Leu 23 ’28 ’31 , Aib 29 , Lys 26 ’30]hPTHrP(l -34)NH2 content by radioimmunoassay, as described below.

([G1u 22’25 , Leu 23’28 ’31, Aib29 , Lys 26’30] hPTHrP(1 -34)NH2 Radioimmunoassay Assay Buffer Preparation: 2.00 g of bovine serum albumin (BSA, Sigma) was dissolved in 750 mL of deionized water. 17.4 g of potassium phosphate, dibasic (EMD), 9.0 g of sodium chloride (Sigma), 0.50 g of sodium azide (Sigma), and 1.00 mL of Triton X-100 (Sigma) were added. The pH was adjusted to 7.4 with 1.0 M potassium phosphate (Fisher) and the final volume was adjusted to 1.0 L.

Standard Curve Preparation: A 0.1 mg/mL aliquot of([G1u 22’25 , Leu23 ’28’31 , Aib 29 , Lys26 ’30]hPTHrP(1-34)NH 2 in 0. IN acetic acid was thawed on ice. A 2000 ng/mL dilution was made in rat serum (Innovative Research) containing aprotinin (0.1 mg/mL, Sigma). This dilution was further diluted to 250 nglmL in the same serum.

The 250 ng/mL solution was used to make an 8 ng/mL solution of ([G1u 22’25 , Leu 23 ’28 ’31 , Aib 29, Lys 26 ’30]hPTHrP(1-34)NH 2 in the same serum. Finally, this solution was serially diluted 2-fold to obtain the following concentrations: 4, 2, 1, 0.5, 0.25, 0.125, 0.063, 0.031 ng/mL. All dilutions were made and kept on ice until ethanol extraction.

Sample Preparation: Study serum samples were thawed on ice and diluted in pooled rat serum containing aprotinin (0.1 mg/mL). Based on historical data dilutions were picked to give a final expected concentration between 0.25-2.0 ng/mL.

Ethanol Extraction: 250 4L of standard (in duplicate), diluted sample, or blank serum (for non-specific and matrix binding) was put in a microcentrifuge tube. To each sample, standard, or blank 1 mL of room temperature 95% ethanol was added with a repeat pipette. All of these tubes were vortexed for 2 minutes and stored at 4C for 30 minutes. The samples were then centrifuged at 3600 rpm at 4C for 30 minutes. The supernatant was removed from each tube and transferred into a new microcentrifuge tube. All samples were vacuum evaporated for 3 hours at the highest temperature setting (approximately 60C). Once dry the samples were stored at -80C overnight.

Reconstitution: Samples were removed from the freezer and placed at 4C for 30 minutes. While working on ice, 100 tL of assay buffer was added to each tube.

Samples were vortexed for 3 minutes and then stored at 4C for 30 minutes.

Antibody Addition: A 1:11,000 dilution of([G1u22 ’25, Leu 23 ’28 ’31 , Aib29 , Lys26 ’30]hPTHrP(l-34)NH 2 rabbit antiserum, Ipsen) was made in the assay buffer. 100 j.tL of this antibody solution was added to all reconstituted samples except for non-specific binding tubes. Samples were vortexed for 30 seconds and stored at 4C for 20-24 hours.

Probe Addition: A stock of [ 1251]-Tyro- ([G1u22 ’25, Leu23 ’28 ’ 31 , Aib 29 , Lys 26 ’30]hPTHrP(l-34)NH 2 that was less than 30 days old was removed from the freezer and thawed. The stock was diluted in assay buffer until 100 1.tL of probe solution read between 9,500-11,000 cpms when counted for 1 minute in 10 ml, of scintillation fluid. 100 j.tL of this solution was added to all sample tubes. The tubes were vortexed for 30 seconds and stored at 4C for 20-24 hours.

N-Propanol Extraction: 1 ml, of cold n-propanol was added to each sample. The tubes were vortexed for 30 seconds and then stored at 4C for 15 minutes. Tubes were centrifuged at 3600 rpm at 4C for 30 minutes. Finally, the supernatant was poured off into a waste container.

Liquid Scintillation Counting of Samples: 200 1tL of 0.2N NaOH was added to each sample. Samples were vortexed for approximately 5 minutes until the pellet - .54 - was completely solubilized. Samples were then transferred into 10 mL of scintillation fluid. 100 tL of glacial acetic acid was added to each scintillation vial to neutralize the solution. All samples were counted for one minute on a Beckman Coulter LS6500.

Data Analysis: The BIB 0 value was found for each standard and unknown sample in the RIA by using the following equation in Microsoft ' Excel 2008: BIB,, = [(YNSB)/(MBNSB)]* 100 where: BIB,, = Percent of radio-labeled ([’ 251]-Tyro- ([G1u 22’25 , Leu 23 ’28’31 , Aib 29 , Lys 26’30]hPTHrP(l-34)NH 2 bound to the antibody Y = standard or unknown samples’ binding (epm) MB = matrix binding, or zero concentration (cpm) NSB = non-specific binding (cpm) The B/B 0 values of the standards were plotted versus the logarithm of the GraphPad' concentration in Prism 4 and a fitted curve was made using the sigmoidal dose-response (variable slope) analysis. From this curve the unknown sample values were extrapolated. In Excel, the extrapolated values were converted to ng/mL and multiplied by the dilution factor to determine the original concentration of each serum sample. All samples for a given rat that fell in the linear range of the assay before being multiplied by the dilution factor were averaged to determine the reported concentration. In the case that all dilutions for a sample fell outside of the linear range of the assay, the sample was reported as above or below the limit of detection and was excluded from average values.

Pharmacokinetic (PK) Analysis The average serum [G1u 22 ’25, Leu 23 ’28’31 , Aib 29, Lys 26’30]hPTHrP(l-34)NH 2 concentrations at each time point were used to create a pharmacokinetic profile for each dosing group from which pharmacokinetie parameters could be determined.

The exception to this was study 09RAD030. In this study, the group sizes were too small (n=l -3) to reliably determine differences in exposure from varied array contact time. In order to have a higher number of samples per group, the Leu232831, average serum [’251]-Tyro- ([G1u 22 ’25 , Aib 29, Lys 26 ’30]hPTHrP(l-34)NH2 concentrations were mathematically adjusted to a standard 20 meg/kg dose and then all of the one minute array application animals were averaged together. In a likewise manner, the five minute array application animals also became one group.

The resulting curves were used to determine the pharmacokinetic parameters.

From the pharmacokinetic profile the maximum concentration (C m ), the time to maximum concentration (T m ), the area under the curve (AUCo), and the half-life (T 112 ) were calculated using Microsoft ' Excel 2008 using the PK functions add-in (Allergan). The relative bioavailability (%F) was calculated using the following equation: %F = AUC0 t/[AUC5c*(Dose/20)] where: %F = Bioavailability relative to a 20 [tg/kg subcutaneous dose; AUC0 = area under the curve of the microneedle array pharmaco kinetic mirjmL) ; profile (ng* AUCsc = area under the curve of historic 20 fig/kg subcutaneous ng*minlmL) ; pharmacokinetie profile ( Dose = [G1u22’25 , Leu23 ’28’31 , Aib29. Lys 26 ’30]hPTHrP(l-34)NH 2 content on microneedle array divided by the average body weight (.tgIkg).

Results and Discussion Blood samples were collected at various time points following [G1u 22’25 , Leu 23 ’28 ’31 , Aib 29, Lys 26’30 ]hPTHrP( 1 -34)NH -microneedle array skin application.

Samples were diluted in pooled blank rat serum to enable reliable determination of [G1u 22 ’25 , Leu 2328 ’31 , Aib 29, Lys 26 ’30]hPTHrP(l-34)NH 2 content by radio immunoassay. The concentration of[G1u 22’25, Leu23 ’28 ’31 , Aib29, Lys26 ’30]hPTHrP(l-34)NH 2 in each sample dilution was determined by extrapolation from a control standard curve generated on the same day. The linear range of each standard curve varies slightly between assays, but is typically 0.25 to 2.0 ng/mL.

Samples that fell outside of the linear range of their assay were excluded from analysis.

The concentration of [G1u 22’25, Leu 23 ’28 ’31 , Aib29, Lys 26’30]hPTHrP( 1-3 4)NH2 in individual serum samples and the average and standard deviation for each time point is listed in Tables 7-16. The average values can be used to create pharmacokinetic curves from which PK parameters are calculated.

Comparison of the PK profiles from several studies demonstrate that the [Glu 2’, Leu23 ’28 ’3 , Aib 29 , Lys 26 ’30]KPTHrP(l-34)NH2 -microneedle arrays result in a similar and consistent exposure profile with rapid absorption and elimination of [G1u 22 ’25, Leu 23 ’28’31 , Aib 29, Lys 26 ’30]hPTHrP(1-34)NH 2 . For the [G1u22’25, Leu 23 ’28’31 , Aib29, Lys 26 ’30]hPTHrP(1-34)N}-J 2 -microneedle array lots across the nine studies, the Tm occured between and 15 minutes and the t1,2 is 14-27 minutes, with the exception of study 09RAD005 were the half-life was calculated to be 43 minutes.

In addition to being consistent between [G1u 22’25, Leu23 ’28 ’31 , Aib 29 , Lys26’30]hPTHrP(1-34)NH2 -microneedle lots, these profiles are comparable to historical reference SC injection PK data. Figure 1 is a representative microneedle array PK profile (09RADO10 Group 1), adjusted to a 20 jig/kg dose, graphed together with the reference SC profile. For this reference SC data, the t112 is 31 minutes and the T ,, ma 10 minutes.

The relative bioavailability of [Glu 22 ’25, Leu23 ’28’31 , Aib 29, Lys 26 ’30]hPTHrP(1- 34)NH2 delivered by sMTS arrays was compared to SC injection (Table 17).

Cm values are generally proportional to bioavailability. When the Cmx, adjusted to a standard 20 g /kg dose, the [G1u 22’25 , Leu 23 ’28 ’31 , Aib 29 , Lys 26’30]hPTHrP(1-34)NH 2 -microneedle arrays from 09RAD005 and 09RAD006 had an average Cmv, of 4.2 – 0.7 nglmL, which is 47 percent of the with a 20 Cm a., .tg 1kg SC dose (8.9 ng/mL). However, the average C m from the 09RAD010, 09RADOI 1, 09RADOI7, and 09RAD030 [Glu 22’25, Leu23 ’31 , Aib 29 , Lys26 ’30]hPTHrP(l-34)NH 2 -microneedle arrays is 8.9 – 1.8 ng/mL, which is approximately 100 percent of subcutaneous injection.

For Tables 7 through 17, "Peptide" refers to [G1u 22’25, Leu23 ’28 ’31 , Aib 29, Lys 26’30]hPTHrP(l-34)NH 2 ; NA indicates no serum sample was collected, ND means value not determined, LLOQ means lower limit of quantification, and ULOQ means upper limit of quantification.

Table 7: 09RAD005: Concentrations of Peptide (ng/mL) in Serum after Single Pentide-Micrnneedk A rrv A nn1ieitinn Time 20.Opg Peptide, 5.0% Formulation, 4C Arrays, 5 Minute Application, Clippers and Nair (mm) Rat 1 Rat 2 Rat 3 Rat 4 Rat 5 Rat Rat 7 Rat 8 Rat 9 Mean SD 7.21 11.80 6.46 6.52 14.70 NA NA NA NA 9.34 3.73 5.58 8.88 7.82 6.73 12.12 12.42 13.93 18.00 11.94 5.44 22.02 4.94 6.52 .93 5.63 8.96 NA NA NA NA 6.40 1.54 NA NA NA NA NA 5.09 9.57 7.29 7.12 6.54 1.87 NA NA NA NA NA 3.09 3.62 3.71 3.14 2.13 0.73 Table 8: 09RAD006: Concentrations of Peptide (ng/mL) in Serum after Single Peptide-Micro needle Application 31.Opg Peptide, 15.0% Formulation, 4C Arrays, 5 Minute Application Clippers and Nair Time Rat 1 Rat 2 Rat 3 Rat 4 Rat 6 Rat 7 Rat 8 Rat 9 Mean SD (mm) 14.59 20.39 .64 32.56 8.29 NA NA NA NA NA 20.29 9.43 19.33 27.92 24.52 45.96 8.37 15.65 34.29 22.98 20.43 16.35 23.58 10.59 9.54 11.45 13.26 22.40 5.99 NA NA NA NA NA 12.53 6.14 45 NA NA NA NA NA 2.64 6.69 4.66 5.20 4.48 4.73 1.46 90 NA NA NA NA NA 1.04 1.27 1.08 1.14 0.67 1.04 0.22 22.Opg Peptide, 10.0% Formulation, 4C Arrays, 5 Minute Application, Clippers and Nair Time Rat Rat Rat Rat Rat Rat (mm) Rat 11 Rat 12 Rat 13 Rat 16 Mean SD 14 15 17 18 19 20 24,92 6.97 21.50 14.68 17.58 NA NA NA 17.13 NA NA 6.88 18.22 7.02 13.25 12.80 11.06 .74 32.74 11.63 9.06 10.15 13.17 7.71 5.79 3.53 10.30 6.50 6.17 NA NA NA NA 6.46 2.44 45 NA NA NA NA NA 1.34 .76 3.15 2.80 3.69 3.35 1.61 90 NA NA NA NA NA 0.29 1.31 0.71 0.59 1.08 0.80 0.40 NA No serum sample was collected.

Table 9: 09RADO1O: Concentrations of Peptide (nglmL) in Serum after Single Peptide-Microneedle Array Application Time 26.2pg PEPTIDE, 12.5% Formulation, 22C Arrays, 5 Minutes Application, Clippers and Nair (mm) Rat 1 Rat 2 Rat 3 Rat 4 Rat 5 Rat 6 Rat 7 Rat 8 Mean SD 30.01 23.97 40.60 37.68 41.01 NA NA NA 34.65 7.43 NA NA NA 71.00 28.44 39.18 51.08 30.15 43.97 17.58 14.63 8.45 20.51 NA NA NA 26.97 16.01 17.31 6.91 .87 35.06 NA 10.18 .18 7.85 NA NA 13.83 12.08 90 NA NA 2.37 NA NA 1.99 2.39 2.13 2.22 0.19 57.7pg PEPTIDE, 12.5% Formulation, 22C Arrays, 5 Minutes Application, Clippers and Nair Time (mm) Rat Rat 10 Rat 11 Rat 12 Rat 13 Rat 14 Rat 15 Rat 16 Mean SD 57.28 42.27 28.20 49.32 38.50 NA NA NA 43.11 11.00 NA NA NA 63.85 77.29 60.79 62.67 71.93 28.19 19.18 31.16 33.13 16.86 NA NA NA 40.14 101.44 18.13 35.05 45 50.12 45.01 NA 15.49 15.49 14.53 NA NA 28.13 17.84 90 >ULOQ* NA NA 3.52 NA NA 4.79 3.72 0.98 2.86 No serum sample was collected.

NA Samples> ULOQ were excluded from the average and standard deviation.

Table 10: 09RADO11: Concentrations of Peptide (ng/mL) in Serum after Single Peptide-Microneedle Array Application 67.7pg Peptide, 16.7% Formulation, 22C Arrays, 5 Minutes Application, Clippers and Nair Time (mm) Rat 1 Rat 2 Rat 3 Rat 4 Rat 5 Rat 6 Rat 7 Rat 8 Mean SD 49.82 96.12 39.27 90.38 48.71 NA NA NA 64.86 26.32 NA NA NA 114.02 73.79 61.42 112.59 51.88 82.74 28.97 47.29 63.24 55.76 NA NA NA 63.65 26.58 51.30 15.35 21.77 25.81 NA 26.49 11.25 13.22 NA NA 19.71 7.09 90 NA NA 4.95 NA NA 3.09 16.58 5.79 7.60 6.09 45.6pg Peptide, 20.5% Formulation, 22C Arrays, 5 Minutes Application, Clippers and Nair Time (mm) Rat 9 Rat 10 Rat 11 Rat 12 Rat 13 Rat 15 Rat 16 Mean SD 65.04 >ULOQ* >ULOQ* 120.77 78.95 NA NA NA 88.25 29.01 NA NA 98.02 83.13 67.94 54.31 76.94 76.07 16.37 21.54 22.25 >ULOQ* 24.13 NA NA NA 76.66 36.15 27.03 45 16.78 >ULOQ* 13.58 NA 22.91 63.85 NA NA 29.28 23.37 90 NA NA 3.31 NA NA >ULOQ* 2.22 8.83 4.79 3.54 NA No serum sample was collected.

Samples> ULOQ were excluded from the average and standard deviation.

Table 11: 09RAD017: Concentrations of Peptide (ng/mL) in Serum after Single Peptide-Microneedle Array Application Time 27.oig Peptide, 16.7% Formulation, 22C Arrays, 5 Minutes Application, Clippers and Nair (mm) Rat 1 Rat 2 Rat 3 Rat 4 Rat 5 Rat 6 Rat 7 Rat 8 Mean SD 21.97 12,91 .. 22.89 .04 29.03 NA NA NA 20.37 6.48 NA NA NA 16.66 27.09 32.52 34.7 44.15 31.02 10.12 16.70 .43 16.3 NA NA NA 26.29 25.81 18.11 8.55 45 9.18 3.13 NA 6.07 ND 9.65 NA NA 7.01 3.03 90 NA NA 1.51 NA NA 2.86 2.85 2.26 0.70 1.81 27.Opg Peptide, 16.7% Formulation, 22C Arrays, 1 Minute Application, Clippers and Nair Time (mm) Rat Rat 10 Rat 11 Rat 13 Rat 14 Rat 15 Rat 16 Mean SD 28.25 36.64 29.63 33.75 34.54 NA NA 32.56 NA 3.51 NA 34.82 NA .30 38.39 NA 63.49 37.14 41.83 12.19 8.24 15.67 14.69 NA NA NA 11.19 16.03 13.16 3.35 .08 8.72 NA 19.30 13.59 9.09 NA NA 11.16 5.46 NA NA 2.49 NA NA 2.16 2.52 3.42 2.65 0.54 27.0Jg peptide, 16.7% Formulation, 22C Arrays, 5 Minutes Application, Clippers Time (mm) at 17 at 18 Rat 19 Rat 21 Rat 22 Mean Rat 23 Rat 24 SD 30.25 23.99 31.73 36.63 30.88 NA NA NA 30.70 4.51 NA NA NA 50.74 37.31 37.26 43.22 33.29 40.36 6.80 16.55 8,11 24.13 NA NA NA 34.64 20.01 20.69 9.78 .99 9.29 NA 21.07 11.81 17.55 NA NA 14.14 4.96 90 NA NA .37 NA NA .10 5.63 4.49 5.15 0.49 Time 32.Opg Peptide, .0% Formulation, 22C Arrays, 5 Minutes Application, Clippers and Nair (mm) Rat 25 Rat 26 Rat 27 Rat 28 Rat 29 Rat 30 Rat 31 Rat 32 Mean 37.27 65.27 36.54 38.57 48.21 NA NA NA 45.17 12.18 NA NA NA 40.05 63.34 35.48 65,64 41.70 49.24 14.13 11.12 25.01 .29 NA NA NA 26.60 21.55 18.91 7.72 .57 17.45 NA 13.33 14.29 12.44 NA NA 13.62 2.54 NA NA 4.03 NA NA 4.96 6.40 4.73 5.03 1.00 No serum sample was collected.

Value not determined for this sample.

Table 12: 09RAD018: Concentrations of Peptide (ng/mL) in Serum after Single Peptide-Microneedle Array Application Time 141.9ig Peptide, 59.3% Formulation, 22C Arrays, 5 Minutes Application, Clippers and Nair (mm) Rat 1 Rat 2 Rat 3 Rat 4 Rat 5 Rat 6 Rat 7 Rat 8 Mean SD 106.49 195.93 225.47 150.49 250.49 NA NA NA 185.77 57.87 NA NA NA 126.21 316.07 182.28 265.36 259.68 229.92 75.15 103.52 222.88 240.82 NA NA NA 261.04 264.60 218.57 66.47 45 85.34 129.88 NA 50.93 102.01 90.99 NA NA 91.83 28.58 NA NA 19.81 NA NA 12.33 15.98 46.54 23.67 15.55 Time 386.5pg Peptide, 59.3% Formulation, 22C Arrays, 5 Minutes Application, Clippers and Nair (mm) Rat Rat 10 Rat 11 Rat 12 Rat 13 Rat 14 Rat 15 Rat 16 Mean SD 37,50* 138.64 70.87 164.17 76.41 NA NA NA 97.52 52.18 NA NA NA 196.20 108.08 77.48 116.62 168.28 133.33 47.98 79.65 107.15 31.48 NA NA NA 79.86 78.65 75.36 27.32 45 45.92 57.53 NA 55.94 29.86 21.69 NA NA 42.19 15.89 7 . 50* 90 NA NA 7 . 50* NA NA 7.50 7.62 7.53 0.06 NA No serum sample was collected.

Samples < LLOQ. Reported as equal to the dilution factor times the LLOQ (0.25 ng/ml).

Table 13: 09RAD030: Concentrations of Peptide (ng/mL) in Serum after Single Peptides Microneedle Array Application 27.Opg Peptide, 16.7% Formulation, 22C Arrays, Time 1 Minute Application, Clippers (mm) Rat 1 Rat 2 Mean SD 17.13 25.55 21.34 5.96 ND 58.30 58.30 NA 28.85 30.55 29.70 1.20 12.19 2.56 14.00 10.37 45 12.45 9.10 4.73 .76 .Opg Peptide, 20.0% Formulation, 22C Arrays, Time 1 Minute Application, Clippers (mm) Mean SD Rat 3 Rat 5 Rat 6 20.19 ND 25.07 6.91 29.96 36.24 ND 32.49 34.36 2.65 44.12 29.62 28.20 33.98 8.81 23.48 13.76 16,11 17.78 5.07 45 19.78 8.47 9.73 12.66 6.20 26.2pg Peptide, 12.5% Formulation, 22C Arrays, Time 1 Minute Application, Clippers (mm) Rat Mean SD 41.15 41.15 NA ND NA NA 42.82 42.82 NA 17.40 NA 17.40 12.48 NA 45 12.48 27.Opg Peptide, 16.7% Formulation, 22C Arrays, Time Minute Application, Clippers (mm) Rat Rat Mean SD 34.89 19.92 27.41 10.59 31.54 15.19 23.37 11.56 33.48 28.67 31.08 3.40 15.02 9.85 12.43 3.65 45 7.89 6.08 6.99 1.28 32.Opg Peptide, 20.0% Formulation, 22C Arrays, Time Minute Application, Clippers (mm) Mean SD Rat 9 Rat 11 Rat 12 32.69 35.12 45.46 37.76 6.78 29.94 4.15 25.74 34.05 30.05 37.48 13.61 42.39 47.95 22.10 .99 1.18 15.22 17.34 15.40 8.39 0.97 45 9.23 8.62 7.33 32.Opg Peptide, Formulation, 22C Arrays, .0% Time Minute Application, Clippers (mm) Rat Rat 11 Rat 12 Mean SD 26.2ig Peptide, 12.5% Formulation, 22C Arrays, Time Minute Application, Clippers (mm) Rat 10 Mean SD 45.29 45.29 NA 26.74 26.74 NA 59.72 59.72 NA 20.15 20.15 NA 45 11.63 11.63 NA ND Value not determined for this sample.

NA Parameter cannot be calculated.

Table 14: 09RAD030 Concentrations of Peptide (ng/mL) in Serum after Single Peptide-Microneedle Array Application Adjusted to 20 [tg/kg Time 1 Minute Application Animals Adjusted to a 20 pg/kg Dose (mm) Rat 1 Rat 2 Rat 3 Rat 4 Rat 5 Rat 6 Mean SD 4.92 2.07 3.30 4.79 3.28 8.36 4.87 ND ND 10.93 ND ND 5.06 7.29 3.18 .89 5.56 5,72 8.70 4.81 4.39 6.06 1.61 7.17 2.70 1.94 3.81 3.53 2.24 2.51 2.79 0.74 45 2.40 1.08 3.21 2.54 1.38 1.51 2.02 0.82 pg/kg Dose Time 5 Minute Application Animals Adjusted to a (mm) Rat 7 Rat 8 Rat 9 Rat 10 Rat 11 Rat 12 Mean SD 7.64 6.45 1.86 6.64 3.90 5.48 9.27 5.77 6.00 2.97 5.47 5.60 5.05 4.90 1.11 4.31 6.37 5.61 7.10 12.22 7.88 3.72 7.15 2.86 0.72 2.86 1.93 2.55 4,12 2.85 2.59 2.82 45 1.50 1.42 1.54 0.43 1.19 1.55 2.38 1.23 ND Value not determined for this sample.

Table 15: 09RAD048 Concentrations of Peptide (ng/mL) in Serum after Single Peptide-Microneedle Array Application 22*C 9.8pg Peptide, 50% Formulation, Arrays, 5 Minute Application, Clippers Time (mm) Rat 1 Rat 2 Rat 3 Rat 4 Rat 5 Rat 6 Rat 7 Rat 8 Rat 9 Rat 10 Rat 11 Rat 12 Mean 1415 582 5.21 20.6 11.42 14.79 NA NA NA NA NA NA 12.00 5.85 NA NA NA NA NA NA 17.16 11.33 8.82 5.87 7.42 7.29 9.65 4.12 4.92 2.54 2.73 7.00 .79 6.75 NA NA NA NA NA NA 4.96 1.94 NA NA NA NA NA NA 1.61 2.38 1.79 1.58 2.24 2.84 2.07 0.50 60 NA NA NA NA NA NA 1.82 1.37 1.24 1.34 1.68 1.34 1.47 0.23 90 0.63 0.30 0.36 0.83 0.73 0.85 NA NA NA NA NA NA 0.62 0.24 120 0.51 0.15 0.22 0.45 0.42 0.54 NA NA NA NA NA NA 0.38 0.16 22*C 54pg Peptide, 50% Formulation, Arrays, 5 Minute Application, Clippers Rat 13 CIN Rat 14 Rat 15 Rat 16 Rat 17 Rat 18 Rat 19 Rat 20 Rat 22 Rat 23 Rat 24 Mean SD Time (mm) 12.34 19.45 33.03 19.15 6.64 8.28 NA NA NA NA NA NA 16.44 9.71 NA NA NA 64.23 46.83 64.88 25.65 49.79 14.91 NA NA NA 42.24 5492 17.62 20.41 32.65 13.11 2.08 16.95 NA NA NA NA NA NA 17.14 9.95 NA 14.36 6.60 9.37 3.69 45 NA NA NA NA NA 4.53 9.08 12.79 8.85 3.68 60 NA NA NA NA NA NA 3.54 9.02 12.02 7.41 11.12 3.41 7.75 0 .65* 1.45 0.90 90 3.17 1.36 1.55 0.85 1.11 NA NA NA NA NA NA 0 . 13* 0.31 0.22 0.31 0.32 0.14 0.76 NA NA NA NA NA NA 0.23 No serum sample was collected.

NA Samples < LLOQ. Reported as equal to the dilution factor times the LLOQ (0.13 ng/mI). 10191 E Table 16: 09RAD053: Concentrations of [G1u 22 ’25, Leu23’28 ’31, Aib29, Lys 26 ’30]hPTHrP(1- 34)NH 2 (ng/mL) in Serum after Single Peptide-Microneedle Array Application 141 .9pg Peptide, 59.3% Formulation, 22C Arrays, 5 Minutes Application, Time Clippers (mm) Rat 1 Rat 2 Rat 3 Rat 4 Rat 5 Rat 6 Mean SD 32.75 66.63 47.47 71.45 39.91 51.47 51.65 15.07 233.66 311.26 132.89 122.56 46.41 153.74 100.23 75.65 138.55 144.30 108.00 84.37 20.03 48.51 90.63 49.55 45 64.65 63.12 65.58 39.47 8.93 23.27 44.17 24.24 90 10.15 11.38 5.84 4.72 1.31 3.20 6.10 3.94 120 4.34 4.62 2.50 2.18 0.55 1.73 2.65 1.56 386.5pg Peptide, 59.3% Formulation, 22C Minutes Application, Arrays, 5 Time Clippers (mm) Rat 7 Mean SD 74.28 74.28 ND 179.02 179.02 ND 148.40 148.40 ND 45 58.80 58.80 ND 90 6.84 6.84 ND 2.88 2.88 ND ND Parameter cannot be calculated.

Table 17: Pharmacokinetic Parameters of [G1u 22 ’25, Leu23 ’28’31, Aib29 , Lys 26 ’30]hPTHrP(1-34)NH 2 Exposure in Rats Dosed with a Single [Glu 22 ’25, Leu’28 ’31 , Aib 29 , Lys 26 ’30JhPTHrP(1-34)NH 2-Microneedle Array Application Study (20 pg/kg Number Dose Formulation AUC Q Dose) Tmax T1 Cmax 20.0 5.0 4.5 576 .1194 15 43 47 3.36 09RA000 31.0 15.0 4.0 750 23.58 4.58 15 17 42 22.0 10.0 4.5 465 17.13 4.51 5 19 36 09RADO1 26.2 12.5 4.5 1447 15 18 101 43.97 10.60 57.7 12.5 4.5 2505 60.79 6.83 15 18 82 09RADO1 67.7 16.7 4.0 2890 7.29 22 74 82.74 15 45.6 .5 3.5 2920 88.25 11.24 5 20 108 27.0 16.7 4.0 1022 31.02 7.95 15 20 76 09RADO1 27.0 16.7 4.0 1277 20 94 41.83 10.59 15 27.0 16.7 4.0 1508 40.36 10.09 15 26 109 32.0 20.0 3.5 1647 49.24 10.48 15 25 102 09RADO1 141.9 59.3 0.0 15 21 139 10369 229.92 10.60 386.5 59.3 0.0 4533 118.39 2.24 15 18 22 1 minute groups adjusted to 20 09RAD03 pg/kg 69 166 7.29 7.29 10 18 0 5 minute groups adjusted to 20 pg/kg 166 7.15 7.15 15 14 69 09RAD04 49.0 9.8 0. 343 12.00 6.49 5 22 49 64 - Study Cmax Number %F* Dose Formulation AUC, T 1 Cm,, Dose) Tma,, 54.0 49.0 0 1378 49.79 5,59 15 24 37 09RAD05 141.9 59.3 0 5199 153.74 15 17 51 .81 386.5 59.3 0 6899 179.02 2.44 15 16 24 AUC from 0-90 minutes for all studies exceot 09RAD030. 09R.AD048. and 09RAD053. A(JC for 09RAD030 is from 0-45 ninutes. AUC for 09RAD048 Group 1 and 09RAD053 is 0-120 minutes and 09RAD048 Group 2 is 0-180 minutes.

Evaluation of different array materials and array contact times in Sprague Dawley rats Study Design Several additional single dose phannacokinetic studies were performed in Sprague- Dawley rats. The studies investigated the effect of different skin contact times for polycarbonate (PC) and liquid crystal polymer (LCP) microneedle arrays and the effect of different microneedle array dose loads. Microneedle arrays were coated with aqueous formulations of 40 to 60 wt-% [G1u 22 ’25, Leu23 ’28 ’31 , Aib 29, Lys2630JPTHrP(1-34)NH2 and phosphate buffered saline.

General characteristics of PC and LCP microneedles are shown below in Table 18, and present results from depth of penetration tests performed with uncoated microneedle patches (i.e., arrays did not contain any peptide drug loading).

Table 18: Polycarbonate ("PC") Microneedle Arrays and Liquid Crystal Polymer ("LCP") Microneedle Arrays Microneedle Arrays Material of Construction Polycarbonate . ." . Liquid Crystal Polymer Number of Microneedles 366 FIŁxral Modulus (by ISO 178) 2300 Grade Class VI, medical grade polymer Class VI, medical grade polymer Surface area 5.5 cm2 or -27 mm in diameter 5.5 cm 2 or -27 mm in diameter Depth of Penetration (DOP) 250+1-1 250+7-I Oh.tm Height of Microneedles 50011m 500 jim Spacing between Microneedles 550 jim apart (tip to tip) 550 jim apart (tip to tip) The LCP microneedle array is injection molded USP Class VI rated liquid crystal polymer resin (Ticona, Vectraﬁ MT1300). The array is a circular disc with an overall surface area of 1.27 cm or -12.7 n -mi in diameter, containing approximately 316 pyramid- shaped microstructures on one side of the disc. An image of the LCP microarray is set forth in Figure 2.

For the LCP array, each microstructure is approximately 500tm tall. The microstructures are spaced approximately 550tm apart (tip to tip) in a geometric pattern. As side view with dimension of the microstructures is set forth in Figure 3.

Dose Administration Typically, one day prior to dosing, an area just above the hind legs on the dorsal side Nairﬁ of the rat was shaved using electric clippers. hair removal lotion was then applied to the area for 5 to 8 minutes to remove remaining hair stubble. The Nair lotion was removed completely using a cloth dampened with water. The next day the microneedle array was applied using the supplied spring loaded applicator. The microneedle array was left in contact with the skin for either five minutes before removal or removed almost immediately (typically 2 - 3 seconds after skin contact). During microneedle application and contact, the rats were manually restrained.

Table 19: Studies RAD021, RAD022, RAD024 Array Skin Contact Number Peptide Study Material Time (mm) Lot Number Contents Number Animals (mcg) IORAD02I 5 6 155342-016 ORAD022 6 155342-041 124 LCP 5 IORAD024 6 155342-064 56 IORAD026 0.05 6 155342-016 1ORAD026 6 0.05 155342-041 124 LCP 0.05 1ORAD026 6 155342-064 PC 5 IORAD02I 5 152986-035 13.6 PC 0.05 10RAD021 5 152986-035 13.6 PC 5 IORAD021 6 155342-033 IORAD02I 0.05 - 6 - 155342-033 211 , LeuUJ2SuI, Aib § Peptide ([GIu 222 29, Lys 2630]hPTHrP(l-34)NH 2 ) content calculated based on total peptide content including water and acetic acid. Actual peptide content is approximately 80% - 90% of the stated amount.

Serum Sample Collection Blood was collected from each rat at 5, , 30, 45 and 90 minutes after application of microneedle arrays, for LCP-microneedle arrays and at 1, 5, 15 and 30 minutes after application for PC-microneedle arrays. Approximately 600 j.tL of blood was collected via the catheter from the jugular vein using a syringe and needle from rats for their first four blood draws. For the last blood collection, animals were euthanized via CO 2 chamber and Ireffs approximately 600 iL of blood was collected via cardiac puncture. The blood was immediately transferred to a serum separator tube that contained 12 .LL of a 2.5 mg/ml aprotinin (Sigma) solution.

Surprisingly, application of the 155342-04 1 [G1u22’25, Leu 23 ’28’31 , Aib29 , Lys26 ’30 ]hPTHrP(1 -34)NH2-LCP-microneedle arrays to the rat for either minutes or approximately 3 seconds (0.05 minutes) resulted in a similar PK profile, based on Cm x, Tmax, AUC and T112.

Similar results comparing a 5 minute application time with 0.05 minutes were obtained with two other LCP arrays (155342-0 16 and 155342-064) and two PC-microneedle arrays (155342-033 and 152986-035). Furthermore, comparison of individual animal data values between 0.05 and 5 minute wear suggests that variability is not necessarily increased with the short application time. This indicates that times of patch application wherein the patch is left in place after administration are useful through a wide range of drug doses.

In the following tables, BLQ means Below the Limit of Quantitation.

, Leu232831, Aib TaIle 20: Concentrations of [G1u 22 ’25 29, Lys26 ’30]hPTHrP(1-34)NH2 (ng/mL) in Serum after Single Microneedle Array Application (lot 155342-041; 14 mcg) minute Microneedle Array Skin Contact Time [Time Rat 1 Rat 2 Rat 3 Rat 4 Rat 5 Rat 6 Mean SD 42.4 20.3 33.6 62.7 <BLQ 12.1 34.2 19.7 96.2 63.3 98.8 92.4 84.9 <BLQ 73.9 15.6 92.5 30.1 43.1 59.7 <BLQ 41.4 53.4 24.3 38.2 14.2 24 27.5 <BLQ 19.9 24.8 9 18.9 4.8 8.5 12.8 <BLQ 7.7 10.5 5.5 63.3 98.8 92.4 73.9 Cmax 96.2 84.9 15.6 15 15 Tmax 15 0 1878 AUC 590 2961 3478 2375 4374 3013 .8 22.3 26.5 23.4 11/2 30.1 24.6 3.7 0.05 minute Microneedle Array Skin Contact Time Time (mm) Rat 1 Rat 2 Rat 3 Rat 4 Rat 5 Rat 6 Mean SD 87.9 41.1 53.6 18.3 15.9 33.4 41.8 26.5 197.5 76 117.4 52.2 33.4 94.1 88.8 58.4 119.1 52 80.4 37.9 18.8 82.3 65.1 36.1 61.5 22.3 41.6 23.8 11.2 55.9 36 20.1 .6 3.6 NA NA 1.5 10.9 6.6 4.8 76 117.4 52.2 33.4 Cmax 197.5 88.8 94.2 58.4 15 15 15 Tmax 15 0 2686 3253 1496 AUC5 90 1146 4432 6779 3299 2081 16.6 20 26.5 16.6 23.4 1112 17.6 .1 4.1 NA No serum sample was collected.

Table 21: Concentrations of [G1u 22’25, Len23’28’31, Aib 29, Lys 26’30]hPTHrP(1-34)NH2 (ng/mL) in Serum after Single Microneedle Array Application (lot 155342-016; 103 mcg) minute Microneedle Array Skin Contact Time Time (mm) Rat 1 Rat 2 Rat 3 Rat 4 Mean SD Rat 5 Rat 6 42.4 20.3 33.6 62.7 <BLQ 12.1 34.2 19.7 96.2 63.3 98.8 92.4 84.9 15.6 <BLQ 73.9 92.5 .1 43.1 59.7 <BLQ 41.4 53.4 24.3 45 38.2 14.2 24 27.5 <BLO 19.9 24.8 9 90 18.9 4.8 8.5 12.8 <BLQ 7.7 10.5 5.5 63.3 98.8 92.4 73.9 Cmax 96.2 84.9 15.6 15 15 Tmax 15 0 1878 2961 3478 2375 AUC5.90 4374 3013 970 .8 22.3 26.5 23.4 T112 30.1 24.6 3.7 0.05 minute Microneedle Array Skin Contact Time Time (mm) Rat 1 Rat 2 Rat 3 Rat 4 Rat 5 Rat 6 Mean SD 87.9 41.1 53.6 18.3 15.9 33.4 41.8 26.5 197.5 76 117.4 52.2 33.4 88.8 94.1 58.4 119.1 52 80.4 37.9 18.8 82.3 65.1 36.1 45 61.5 22.3 41.6 23.8 11.2 55.9 36 20.1 .6 3.6 NA NA 6.6 4.8 1.5 10.9 76 117.4 52.2 33.4 88.8 Cmax 197.5 94.2 58.4 15 Tmax 15 15 15 0 2686 3253 1496 1146 4432 AUC590 6779 3299 2081 16.6 20 26.5 16.6 23.4 LT1/2 17.6 .1 4.1 NA No serum sample was collected.

Table 22: Concentrations of [G1u 22 ’25, Len23’28 ’31, Aib 29, Lys 26’30]hPTHrP(1-34)N112 (ng/mL) in Serum after Single Microneedle Array Application (lot 155342-064; 56 mcg) minute Microneedle Array Skin Contact Time Time (mm) Rat 1 Rat 2 Rat 3 Rat 4 Rat 5 Rat 6 Mean SD 31.8 32.3 39.2 29.7 29.7 14.8 30.1 8.0 31.3 57.2 58.5 34.7 43.2 .6 57.1 16.4 26.8 49.5 55.9 21.0 10.7 31.7 26.6 17.4 8.5 21.1 15.4 9.0 4.3 7.9 11.0 6.1 90 4.6 .2 3.9 2.5 0.9 2.5 3.3 1.6 Cmax 31.8 57.2 58.5 34.7 20,6 57.1 43.3 16.3 Tmax 5 15 13 15 15 15 4 AUC5 90 1309 2352 2317 1225 643 1556 1567 666 T112 27.5 20.7 18.1 19.8 16.9 16.9 20.0 4.0 31.8 32.3 39.2 29.7 14.8 30.1 29.7 8.0 0.05 minute Microneedle Array Skin Contact Time Time (mm) Rat 1 Rat 2 Rat 3 Rat 4 Rat 5 Rat 6 Mean SD .3 23.6 25.7 14.5 16.8 25.6 21.9 5.0 .8 29.8 57.0 24.7 33.9 44.7 36.8 11.9 16.6 16.1 33.8 11.3 19.2 28.3 20.9 8.5 9.9 10.2 20.0 7.2 9.6 13.4 11.7 4.5 90 1.6 1,5 5.2 1.9 2.6 2.3 2.5 Cmax 30.8 29.8 57.0 24.7 33,9 44.7 36.8 11.9 Tmax 15 15 15 15 15 15 0 AUC590 1092 1073 2067 810 1291 1142 1563 451 11/2 17.8 17.5 21.9 21.0 20.3 17.1 19.3 2.0 Table 23: Concentrations of [Glu 22’25, Leu 23 ’28 ’31, Aib29, Lys 26 ’30J hPTHrP(1 -34)N112 (ng/mL) in Serum after Single Microneedle Array Application (lot 155342-033; 211 meg) minute Microneedle Array Skin Contact Time Time (mm) Rat I Rat 2 Rat 3 Rat 4 Rat 5 Rat 6 Mean SD 98.5 58.9 36.4 39.8 <6LQ 49.1 48.8 29.4 149.5 55.5 55.6 128.1 <BLQ 66.0 77.4 51.8 211.6 41.4 36.8 135.0 18.9 86.1 88.3 73.6 Cmax 211.6 58.9 55.6 135 18.9 86.1 94.4 69.2 Trnax 5 30 30 30 23 11 AUC530 4195 1446 1244 2912 338 1996 1839 1365 0.05 minute Microneedle Array Skin Contact Time Time (mm) Rat 1 Rat 2 Rat 3 Rat 4 Rat 5 Rat 6 Mean SD 1 11.3 16.5 12.8 34.9 49.5 26.7 25.3 14.9 33.4 34.8 21.3 72.1 54.1 40.2 42.6 17.9 51.9 47.7 43.0 164.3 89.3 156.9 71.9 56.1 75.3 50.2 42.4 195.1 143.1 95.0 64.2 60.8 Cmax 75.3 50.2 43.0 195.1 156,9 98.7 71.9 62.3 Tmax 30 15 30 15 15 23 8 AUC 5.30 1475 1258 1036 4108 3537 1729 2190 1298 Table 24: Concentrations of [G1u 22 ’25, Leu 23 ’28 ’31 , Aib29, Lys 26 ’30]hPTHrP(1-34)NH2 (ng/mL) in Serum after Single Microneedle Array Application (lot 152986-035; 13.6 meg) minute Microneedle Array Skin Contact Time Time (mm) Rat 1 Rat 2 Rat 3 Rat 4 Rat 5 Mean SD 1 1.45 2.68 5.18 2.5 1.82 1,33 1.6 9.55 7.90 11.16 9.72 5.91 8.8 2.0 10.81 7.10 14.40 7.81 3.04 8.6 4.3 8.08 4.47 10.73 4.45 2.35 6.0 3.3 C max 10.8 7.9 14.4 9.7 5.9 9.7 3.2 Tmax 15 5 15 5 9 AUC5.90 266 184 352 204 100 221 94 Time 0.05 minute Microneedle Array Skin Contact Time (mm) Rat 1 Rat 2 Rat 3 Rat 4 Rat 5 Mean 1 7.68 5.49 4.76 7.15 5.91 6.2 1.2 12.11 12.21 11.28 12.13 11.23 11.8 0.5 8.90 10.00 7.71 14.41 11.25 10.5 2.6 7.1 7.39 7.97 4.66 9.38 6.11 1.8 C max 12.1 12.3 1.3 12.2 11.3 14.4 11.3 Tmax 9 5 5 5 15 15 AUC5.90 J 271 284 222 280 282 47 euUizt , Graphs showing the mean concentrations of [Glu’’, L Aib’ Lys 26 ’30]hPTHrP(1-34)NH 2 (nglmL) in serum versus time after single microneedle array application for the data in Tables 20-24 is presented in Figures 4-8.

Evaluation of changes in bone mineral density and bone microstructure after repeat application of [GIn 22’25, Len 23 ’28’31 , Aib 29 , Lys26’30] hPTHrP(1-34)NH2 PC Microneedle Arrays and [G1u 22’25, Len 23’28’31 , Aib29 , Lys 26’30 ] hPT11rP(1-34)NH2 LCP-Microneedle Arrays to osteopenic rats Study Design This study investigated the effect of [G1u 22 ’25 , Aib29, Lys 26 ’30]hPTHrP( 1- , Leu 23 ’28 ’31 34)NH2-PC and LCP-microneedle arrays in an ovariectomy (OVX)-induced bone loss model in Sprague Dawley rats. Effects on the skeleton were assessed by measurement of changes in bone mineral density (BMD), using dual energy x-ray absorptiometry (DEXA) and bone micro-architecture, by micro-computed tomography (microCT).

Microneedle arrays were coated with aqueous formulations of [G1u 22 ’25, Leu23 ’28 ’31 Aib29 , Lys 26 ’30]PTHrP(1-34)NH 2 and phosphate buffered saline.

Table 25: Study treatment groups Surgery Number of Rats Route of Dose Adminsitration Dose (.tg) SHAM 0 (Placebo) 11 - OVX 0 (Placebo) 10 Pc microneedle array OVX 13.6 10 Pc microneedle array OVX 8.8 6 LCP microneedle array OVX 0 (Placebo) 11 sc Injection OVX 12.7 11 sc Injection Animals Fifty nine female Sprague Dawley rats (CRL:CD; Charles River Laboratories) were singly housed in polycarbonate ventilated (45 ACH) cages. All rats were provided certified rodent diet (2918 from Harlan Tekiad) and water ad libitum. The housing environment was maintained between 18-26C with 30-70% relative humidity and a 12 hour light: 12 hour dark cycle. Rats underwent either ovariectomized or sham ovariectomy surgery at approximately 18 weeks of age.

Dose Administration All rats starting approximately 6-weeks post surgery were acclimated to the experimental procedures by daily handling and restraint to simulate microneedle array application.

Acclimation was continued for 4 weeks before a baseline assessment of BMD by DEXA and randomization into treatment groups based on femur BMD. Daily dose administration of either [G1u 22’25 , Leu 23 ’28 ’31 , Aib 29, Lys 26 ’30]hPTHrP(1-34)NH2-PC-microneedle arrays, or [G1u 22’25 , Leu23 ’28 ’ 31 , Aib 29 , Lys 26’30]hPTJ-IrP(1-34)NH 2-LCP-microneedle arrays or placebo microneedle arrays, or [G1u 22’25 , Leu23 ’28’31 , Aib 29, Lys 26’30]hPTHrP(1-34)NH 2 by subcutaneous injection or placebo subcutaneous injection as outlined in Table 25.

Microarrays were left in contact with the skin for one minute before being removed. Dosing was performed for 14 days, and then all rats were euthanized for sample collection.

Serum Sample Collection On day 14 of dosing approximately 3 mL of blood was collected 15 minutes post dose. The blood was immediately transferred to a serum separator tube that contained 60 L of a 2.5 mg/mL aprotinin (Sigma) solution. The blood was kept at room temperature for approximately 45 minutes to allow it to clot. Once clotted, the blood was centrifuged at 2500 rpm for 10 minutes. Serum was stored at -80C. Prior to quantification [G1u 22 ’25, Leu23 ’28’31 , Aib29 , Lys2630]hPTHrP( 1 -34)NH2 by radioimmunoassay.

Bone Mineral Density (BMD) On the first day of test article dosing and on the day of sacrifice, BMD for all animals was assessed by DEXA (PIXImus, Lunar Corp/GE). The images were analyzed using the provided software to determine the BMD of the L3-L5 region of the spine and the left femur.

The baseline and end of study scans were used to calculate the percent change in BMD after 14-days of treatment.

Micro-Computed Tomography At necropsy the left femur and the L4-L5 vertebrae were removed and dissected of free soft tissue. The bones were stored in 70% ethanol at -80C. Prior to microCT analysis the femurs were cut through the midshaft and loaded into the sample analysis tube. Additionally, one vertebra from each rat was wrapped in ethanol soaked gauze and stacked in the sample tube for scanning. Qualitative 3D evaluation was preformed using the Scanco mCT40 system (Scanco, CH). For analysis of femur trabecular bone 250 slices of the distal femur metaphysis were scanned. 150 of these slices were contoured for evaluation. Analysis was started at the first slice where the right and left condyles were no loner visible. This ensured that there is no contribution from cortical bone or growth plate. Analysis continued towards the midshaft of the bone. For analysis of lumbar spine trabecular bone sections were analyzed starting at the first slice where the growth plate was no longer visible and continued until the growth plate appeared on the other side of the vertebra. Trabecular parameters analyzed included bone volume density (By/TV), connectivity density (ConnD.), trabecular number (Tb.N), trabecular thickness (Tb.Th), trabecular spacing (Tb.Sp), and apparent bone density (ABD).

Results Ovariectomy of female rats resulted in an approximately 10% decrease in whole femur BMD at baseline, relative to sham surgery controls, and approximately a % decrease in lumbar spine BMD, confirming the effect of ovariectomy to induce osteopenia in rats (Figure 9). Repeat daily application of [Glu 2225 , Leu23’28 ’31 , Aib29, Lys" -"] hPTHrP(1-34)NH2 PC microneedle arrays or [Glu 22 ’25, Leu232831 , Aib 29, Lys2630] hPTHrP(l-34)NH2 LCP microneedle arrays resulted in a marked increase in whole femur BMD (Figure 9) and lumbar spine BMD (Figure 10) after 14 days, compared to the corresponding placebo microneedle array control. Similar increase in femur and lumbar spine BMD was observed with [G1u 22’25 , Leu 23 ’28’31 , Aib 29, Lys26 ’30 ] hPTHrP(1 -34)NH 2 subcutaneous injections (Figures 9 and 10).

The rapid recovery in bone mineral density clearly indicate the utility of the arrays containing [G1u22 ’25 , Leu2328’31 , Aib29, Lys 26 ’30 ] hPTHrP(1-34)NH 2 for the prevention and treatment of disorders relating to decreased bone mineral density such as osteoporosis and due to the particular rapidity of the effect and the anabolic nature of the product, the healing of bone fractures and/or breaks.

Trabecular bone microstructure parameters evaluated by microCT, including By/TV, Tb.N and Tb.Th are decreased, while Tb. Sp is increased at baseline in the femoral metaphysis of OVX rats compared to Sham controls (Table 26). Similar changes in baseline OVX rats are observed in bone microstructure parameters in the lumber spine (Table 27). Repeat daily application for 14 days of [Glu 2225, Leu2328 ’31 , Aib29, Lys 26 ’30] hPTHrP(1-34)NH2 PC or [Glu 22 ’25 , Leu23 ’28 ’31 , Aib29, Lys 2630] hPTHrP(l-34)NH 2 LCP microneedle arrays partially reversed these changes with increases in By/TV, TB. N and Tb Th, while Tb. Sp was decreased in both the femoral metaphysis and lumbar spine (Tables 26 and 27). The magnitude of changes on these bone microstructure parameters was similar to those observed with repeat daily administration of [G1u 22’25 , Leu 23 ’28 ’31 , Aib 29, Lys26’30] hPTI-lrP(l-34)NH2 by subcutaneous injection (Tables 26 and 27). Additionally bone density measured by microCT ] hPTHrP(1- was also increased following application of [GI u 22’25 , Leu23 ’28 ’31 , Aib29, Lys26 ’30 34)NH2 PC or [G1u 22’25 , Leu23 ’28’31 , Aib 29, Lys26 ’30] hPTHrP(l -34)NH2 LCP microneedle arrays in bone the femoral metaphysis and lumbar spine (Tables 26 and 27). ] hPTHrP(l-34)NH2 was Serum concentration of [G1u 22’25, Leu232831 , Aib 29, Lys 26’30 measured 15 minutes post dose and for rats treated with [G1u 22 ’25 , Leu23 ’28’31 , Aib29, Lys2630] hPTHrP(l -34)NH 2 PC microneedle arrays the serum concentration was 17.2 – 5.9 pg/mI, for rats treated with .[G1u 22’25, Leu2328 ’31 , Aib29, Lys 26’30] hPTHrP(l-34)NH2 LCP microneedle , Aib 29, arrays the serum concentration was 14.0 – 9.2 pg/mi and for [G1u 22’25, Leu23’28’31 21,31] Lys hPTHrP(l-34)NH2 subcutaneous injection was 10.8 – 3.6 pg/mI.

Table 26: Change in Trabecular Bone Microstructure in the Osteopenic Rat Distal Leu 2 ’28 ’ , Aib29 , Femur Metaphysis Following Repeat Application of [G1u 22’25, Lys 26 ’30]hPTHrP(1 -34)NH 2-Microneedle Arrays OVX OVX SHAM OVX OVX OVX LCP Sc SC PC PC Parameters - Placebo 13.6 .tg 8.8 j.tg Placebo 12.7 jig BV/TV 0.240 – 0.05* 0.203 – 0.04 0.253 – 0.05* 0.554 – 0.14 0.172 – 0.04 0.227 – 0.06* (ratio) 0.101–0.01* 0.104–0.01* 0.108–0.01* Tb.Th 0.130–0.03 0.089–0.01 0.095–0.01 (mm) 2.33 – 0.53 Tb.N 5.51 – 0.85 1.72 – 0.30 2.21 – 0.70 2.14 – 0.37* 2.13 – 0.60 (#1mm) 0.471 – 0.11 TbSp 0.156 – 0.04 0.632 – 0.12 0.513 – 0.16 0.507 – 0.12 0.532 – 0.16 (mm) Conn.D 122–11 122–8 130–23 126–9 122–6 124–15 (#/mm 3 ) 215–46* 222–44* ABD 202–54* 179–31 466– 112 152–39 * p <0.05 compared to treatment corresponding placebo control Table 27: Change in Trabecular Bone Microstructure in the Osteopenic Rat Lumbar Spine Following Repeat Application of [Glu 22 ’25, Leu’28 ’31 , Aib 29, Lys26 ’30]hPTHrP(1- 34)NH2-Microneedie Arrays OVX OVX OVX SE-JAM OVX OVX LCP SC SC PC PC Placebo Parameters - Placebo 12.7 pg 13.6 pg 8.8 pg BV/TV 0.470 – 0.04 0.520 – 0.05* 0.604 – 0.07 0.472 – 0.07 0.520 – 0.04 0.500 – 0.03 (ratio) Th.Th 0.125 – 0.01 0.117–0.01 0.132– 0.01* 0.134 – 0.02 0.119 – 0.01 0.131 – 0.01* (mm) Tb.N 4.00 – 0.28 4.02 – 0.39 4.86 – 0.39 3.94 – 0.39 4.00 – 0.38 4.00 – 0.37 (#1mm) 0.224 – 0.03 TbSp 0.186 – 0.02 0.223 – 0.02 0.225 – 0.02 0.227 – 0.02 0.231 – 0.03 (mm) 46–8 Conn.D 44–12 49–7 44–10 48–6 48–9 73 - (#1mm 3 ) ABD 507–57 451–28* 391–53 432– 14 400–30 451–43* (mgHAJmm 2) * p <0.05 compared to treatment corresponding placebo control Clinical study evaluation of pharmacokinetics of [Gin 22’25 , Leu 23’28 ’31 , Aib29 , Lys26’30J hPTHrP(1-34)NH polycarbonate-coated inicroarrays in postmenopausal women Study Design Table 28: Polycarbonate arrays used in clinical study Arrays Polycarbonate arrays Material of Construction Poly carbonate Number of Microneedles Flexural Modulus (by ISO 178) 2300 Grade Class VI, medical grade polymer Surface area .5 cm 2 or 27 mm in diameter Depth of Penetration (DOP) 250+/-10.tm Height of Microneedies Spacing between Microneedles 550i.tm apart (tip to tip) Arrays were prepared using aqueous formulations of 54 to 58 wt-% [G1u22 ’25, Leu23 ’2831 , Aib29, Lys26 ’30]PTHrP(l-34)NH 2 and phosphate buffered saline.

Array loading dosages tested Array 1: 100 j.tg per array +1- 15 p.g per array (90 .tg per array mean) Array 2: 150 –g per array +1- 22.5 g per array (149 p.g per array mean) Array 3: 200 jtg per array +1-30 g per array (211 g per array mean) Study Design and Methodology: This is a randomized, double-blind, placebo-controlled, ascending single-dose safety, pharmacokinetic and tolerability study of [G1u 22’25, Leu 23 ’28 ’31 , Aib 29, Lys26’30]hPTHrP(l - 34)NH 2 presented as a coated transdermal microarray in healthy postmenopausal women.

Enrolled subjects will undergo up to 3 single dose exposures to [G1u 22’25, Leu23 ’28’31 , Aib29 , Lys 26 ’30]hPTHrP( 1 -34)NH or [G1u 22’25 , Leu23 ’28 ’3 , Aib 9, Lys26 ’30]hPTHrP( 1 -34)NH 2-sMTS- Placebo or [Glu22’25, Leu 23 ’28 ’31 , Aib29, Lys 26’30]hPTHrP(1-34)NH 2 80 .ig subcutaneous (Sc) injection over the course of the study.

Three study Periods and 13 study Groups are planned, with subjects being randomized prior to each dosing. In the first study Period, 4 wear time variable Groups will be completed, as will 6 subjects who will receive 80 4g [G1u 22’25, Leu23 ’28’31 , Aib 29 , Lys 26’30]hPTHrP(1-34)NH 2 for injection administered subcutaneously. In study Periods 2 and 3 there will be three Groups receiving an escalating dose. Within the first study Group, 32 subjects will be randomized into one of four sub-Groups of varying wear time for the transdermal microarray. The potential wear times of the TD microarray are , 15, 30, and 60 minutes while the concentration of the [G1u 22’25 , Leu23 ’28 ’31 , Aib 29 , Lys 26’30]hPTHrP(1-34)N}1 2 -microneedle array will remain constant at 100 pig. Within each of the 5 subgroups (Study Period 1), 6 subjects will receive [G1u 22’25, Leu23 ’28 ’31 , Aib 29 , Lys 26’30]hPTHrP(1-34)NH 2 - microneedle array via a transdermal microarray and two subjects will receive a corresponding [Glu22 ’25 , Leu23 ’28 ’31 , Aib 29, Lys 2630]hPTHrP(1-34)NH -microneedle array-Placebo, and six subjects will receive [G1u 22’25, Leu 23 ’2831 , Aib 29, Lys26 ’30]hPTHrP(1-34)NH2 80 jig for injection, administered subcutaneously. Prior to proceeding to the next dose safety, tolerability, and pharmacokinetic data from subjects enrolled in earlier Groups will be reviewed for suitability to escalate to the next higher dose. In study Group 2 which will enroll 24 subjects, 18 will be randomly assigned to receive [G1u 22 ’25 , Leu2328’31 , Aib29, Lys26 ’30]hPTJ-IrP(1 -34)NH -microneedle array via transdermal microarray, 4 will receive a corresponding [G1u22’25 , Leu23 ’28’31 , Aib29 , Lys26’30]hPTHrP(1-34)NH 2 -microneedle array- Placebo, and 2 will receive [Glu 2225, Leu23 ’2831 , Aib 29 , Lys 26 ’30]hPTHrP(1-34)NH2 administered as a SC injection of [G1u 22’25, Leu23 ’28 ’31 , Aib 29 , Lys 26’30]hPTHrP(l-34)NH 2 80 jg for injection administered subcutaneously. In Group 3 which will enroll 16 subjects, 2 Groups of 6 will be randomly assigned to receive [G1u 22’25, Leu 23 ’28’31 , Aib 29, Lys26’30]hPTHrP(l-34)NJ-1 2 -microneedle array applied to the periumbilical region or upper outer arm, while 2 will receive a corresponding [Glu 22’25, Leu 23 ’28’31 , Aib 29, Lys26 ’30]hPTHrP(l-34)NH -microneedle array-placebo, one at each of these sites. In addition, 2 additional subjects will receive a standard SC administration of [Glu 22’25 , Leu23 ’28 ’31 , Aib29 , Lys 2630]hPTHrP(1-34)NH 2 80 tg for injection administered subcutaneously.

If the bioavailability of the 100 tg [G1u 22 ’25, Leu 23 ’28’31 , Aib 29 , Lys 26 ’30]hPTHrP(l- 34)NH2 -microneedle array is greater than 50%, the 200 gg dose will not be administered; if greater than 66%, the 150 ig dose will not be administered.

The doses and the number of subjects that are planned for enrollment per Period and Group are shown in Table 29.

Table 29: Schedule of dosages, sites and wear time Number of Subiects Randomized Period I Microarrpy Subcutaneous Study Frequency Application or Wear Time Group of Dosing Dose Injection Site Peptide- Microneedle 80 pg Peptide for Total if aMTS Array-Placebo injection Once 100 pg Periumbilical min 6 2 N/A 8 lb Once 100 pg Periumbilical 15 min 6 2 N/A 8 I Once 100 pg Periumbitical 30 min 6 2 N/A Id Once 100 jig Periumbilical 60 min 6 2 N/A 8 Ic Once Periumnbilical 80 pg N/A N/A N/A 6 6 Total; 24 8 6 38 Period 2 Mjcroarray Subcutaneous Study Frequency Application Wear Time’ Group of Dosing Dose Site Peptide.

Peptide- 80 pg Peptide for Total if microneed microneedle injection Ic array array-Placebo Once 150 pg Periumbilical TBD 6 1 N/A 7 Once ISO pg Upper Anterior TBD 6 I N/A 7 Thigh Once 100 pg Periumbilical 24 Hours 6 2 N/A 8 Once 80 pg Periumbilical N/A N/A N/A 2 2 Total: 18 4 2 24 Period 3 Ivljeroarray Subcsttaneosss Study Frequency Application Wear Time Group of Dosing Dose Site Peptide- Peptide- 80 jig Peptide for Total if microneed microneedle injection Ic array array-Placebo 3a Once 200 pg Periumbiticat TBD 6 1 N/A 7 3b Once 200 pg Upper Outer TBD 6 I N/A 7 Arm (deltoid) 3c Once 80 jig Periuinbilical N/A N/A N/A Total: 12 2 2 16 The wear times-in Study Periods 2 and 3 will be based upon the results obtained in Study Period I Standard safety assessments are included to ensure the safety of subjects. These safety evaluations include physical examinations, vital signs, 12-lead digital ECGs, clinical laboratory tests, and monitoring and recording of local tolerance and adverse events.

For pharmacokinetic (PK) analysis, a total of 15 venous blood samples across 24 hours will be taken to measure [G1u 22’25 , Leu23 ’28’31 , Aib 29, Lys 26 ’30]hPTHrP(1-34)NH2 plasma concentrations at the following times: pre-dose and , 10, 15, 20, 30, 60 minutes, 1.5, 2, 3, 4, 6, 8, and 12 hours post-dose. A final sample will be taken 24 hours after the last dose of study medication.

Number of subjects: A sufficient number of eligible subjects will be enrolled to achieve 38 subjects who complete treatment and study procedures.

Treatments Administered: [G1u22 ’25 , Leu23 ’2831 , Aib 29, Lys 26 ’30]hPTHrP( 1 -34)NH 2-sMTS (100 j.tg, 150 Vg and 200 g) will be supplied as a coated, transdermal array attached to a self- adhesive patch for use with an applicator.

[G1u 22 ’25 , Leu23 ’28 ’31 , Aib 29, Lys26 ’30]hPTHrP(1 -34)NH 2-microneedle array-Placebo will be similarly supplied in a coated, transdermal array attached to a self-adhesive patch for use with a spring-loaded applicator.

[G1u22 ’25 Drug Product for Injection , Leu23 ’28 ’3 , Aib29, Lys 26 ’30]hPTHrP(1-34)NH 2 80 .tg is supplied as a multi-dose cartridge mL) containing 2 mglmL [Glu 22 ’25 , Leu23 ’28 ’31 , (1.5 Aib29, Lys 26 ’30]hPTHrP(l-34)NH 2 mg/mL tn-hydrate sodium acetate and 5 (free base) in 5 mg/mL of phenol (preservative) adjusted at pH 5.1 with acetic acid.

The pen injector is a modified version of the Becton Dickinson Pen II device and has in its pre- been validated for use with [G1u 22 ’25, Leu23 ’28 ’31 , Aib 29, Lys 26 ’30]hPTHrP(1 -34)NH 2 filled cartridge.

Data Analysis: Pharmacokinetic analysis: 26 ’30]hPTHrP(1- Individual plasma concentrations of [Glu 22 ’25 , Leu23 ’28 ’31 , Aib 29, Lys 34)NH2 will be tabulated separately for each dose Group and sampling time and summarized descriptively. Individual and summary profiles will also be plotted for each dose. The plasma concentration-time profiles of [G1u 22 ’25, Leu 23 ’28 ’ 3 1 , Aib 9, Lys 26 ’30]hPTHrP( 1- 34)NH2will be analyzed using non-compartmental methods. For each dose level, relative bioavailability will be calculated as the ratio of dose normalized AUCinf values: [AUCinf(transdermal)/Dose(transdermal)]/[AUCinf(SC)/Dose(SC)].

Selection of Study Population Number of Subjects A sufficient number of eligible subjects will be enrolled to achieve 38 subjects who complete treatment and study procedures.

Inclusion Criteria Subjects must meet all of the following inclusion criteria to be eligible to participate in this study.

The subject is a healthy postmenopausal woman from 50 to 80 years of age, inclusive.

For the purposes of this study, postmenopausal is defined as? 24 months of spontaneous amenorrhea (not relating to eating disorders or other causes) or? 6 months of spontaneous amenorrhea with serum follicle-stimulating hormone (FSH) levels ? 40 mIU/mL or 6 weeks postsurgical bilateral oophorectomy with or without hysterectomy.

The subject is in good general health as determined by medical history and physical examination (including vital signs) and without evidence of clinically significant abnormality, in the opinion of the Investigator.

The subject has a hemoglobin value greater than 12.0 g/dL during the screening Period.

The subject has a serum phosphorus, PTH(l -84) and a serum total calcium within the normal range during the screening Period.

The subject has a normal serum alkaline phosphatase during the screening visit or, if abnormal but not clinically significant, a normal serum bone-specific alkaline phosphatase The subject has a 25-hydroxyvitamin D of > 9 ng/mL.

The subject has all other screening and baseline clinical laboratory tests without any clinically significant abnormality, in the opinion of the Investigator.

The resting 12-lead electrocardiogram obtained during screening shows no clinically significant abnormality of the following intervals: PR:? 120 and < 220 ms; QRS < 120 ms: QTc (Bazett’s correction) 470 ms. Incomplete right bundle branch block (IRBBB) and left anterior hemiblock (LAH) are acceptable.

The subject’s systolic blood pressure is? 100 and 155 mmHg, diastolic blood pressure is? 40 and < 95 mmHg, and heart rate is ? 45 and 90 bpm during screening.

The subject weighs at least 120 pounds (54.5 kg) and is within 25% and +30% of her ideal body weight (at screening) based on height and body frame according to the Metropolitan Life Insurance Company table.

The subject has read, understood, and signed the written informed consent form.

Exclusion Criteria Subjects who meet any of the following exclusion criteria will not be eligible to participate in the study.

General exclusion criteria: The subject has a history of clinically significant chronic or recurrent renal, hepatic, pulmonary, allergic, cardiovascular, gastrointestinal, endocrine, central nervous system, hematologic or metabolic diseases, or immunologic, emotional and/or psychiatric disturbances.

The subject has been diagnosed with osteoporosis, Paget’s disease, or other metabolic bone diseases (e.g., vitamin D deficiency or osteomalacia) or has had a non-traumatic fracture that occurred within one year prior to the initial screening visit.

The subject has a history of urolithiasis within the past five years.

The subject has a history of gout or a uric acid value> 7.5 mg/dL during the Screening Period.

The patient has a decrease of 20 mmHg or more in systolic blood pressure or 10 mmHg or more in diastolic blood pressure from supine to standing (5 minutes lying and 3 minutes standing) and/or any symptomatic hypotension.

The subject has an acute illness which, in the opinion of the Investigator, could pose a threat or harm to the subject or obscure laboratory test results or interpretation of study data.

The subject has donated blood, or has had a blood loss of more than 50 mL within weeks prior to study Day 1, or has had a plasma donation (apheresis) within 7 days prior to Day 1.

The subject is known to be positive for Hepatitis B, Hepatitis C, human immunodeficiency virus (HIV)-1 or HIV-2 or have positive results at screening for Hepatitis B surface antigen (HBsAg), Hepatitis C antibody (HCV-Ab), or HIV.

The subject has been previously randomized, dosed and discontinued in this study for any reason.

Medication related exclusion criteria: The subject has a known history of hypersensitivity to any of the test materials or related compounds.

The subject uses any medication on a chronic basis, including bisphosphonates and estrogens or estrogen derivatives, with the exception of certain medications The subject received any medication, including over-the-counter, non-prescription preparations or herbal or homeopathic supplements, with the exception of certain medicines, within 72 hours prior to administration of the first dose of study medication.

The subject received a general anesthetic or an investigational other than [Glu’ 25 , Leu23 ’28 ’ 31 , Aib 29 , Lys26 ’30]hPTHrP(l-34)NH 2 within 90 days prior to the initial dose of study medication.

Unwillingness or inability to understand study procedures or commitments as judged by the Medical Investigator.

Lifestyle related exclusion criteria: The subject has an abnormal nutritional status (abnormal diets, excessive or unusual vitamin intakes, malabsorption, significant recent weight change).

The subject smokes more than 10 cigarettes per day. Subjects will not be allowed to consume any nicotine-containing products while they are confined to the clinical facility.

The subject has a history of alcohol abuse, illegal drug use or drug abuse within 24 months of the screening visit.

The subject has a positive urine drug/alcohol screen.

Withdrawal of Subjects Subjects will be informed that they have the right to withdraw from the study at any time for any reason, without prejudice to their medical care. The Investigator also has the right to withdraw subjects from the study for any of the following reasons: Adverse events.

Refusal of treatment.

Subject request.

Inability to complete study procedures.

Lost to follow-up.

Non-compliance.

If a subject is withdrawn or discontinued from the study, the reason for withdrawal from the study is to be recorded in the source documents and on the case report form. All subjects withdrawn prior to completing the study should be encouraged to complete postdose study evaluation scheduled for the Study Group. Subjects who withdraw from the study for administrative reasons after study medication has been administered may be replaced at the discretion of the Investigator after consultation with the Medical Monitor.

Replacement of Subjects If there are insufficient subjects to achieve enrollment of 38, 24, and 16 subjects per dose Group respectively in Groups 1, 2, and 3, additional subjects may be recruited.

[G1u22 ’25, Leu 23 ’28’31 , Aib 29, Lys 26’30]hPTHrP(l-34)NH2-microneedle array and [Glu22 ’25 , Leu23 ’28 ’31 , Aib29, Lys 26’30]hPTHrP(l-34)NH 2-microneedle array-Placebo will be supplied. Transdermal microarrays, cartridges and needles for administration of study medications will also be supplied to the study site. Study drug will be prepared for individual patients by the pharmacist.

[Glu22’25, Leu 23 ’28’31 has been formulated with , Aib 29, Lys 26 ’30]hPTHrP(l-34)NH 2 phosphate buffered saline (PBS) alone to deliver either 100, 150, or 200 tg of [Glu 2225 Leu23 ’28’31 , Aib 29, Lys26 ’30]PTHrP(l-34)NH 2 per array for transdermal administration using a microneedle array. The microneedle array is a 366 microneedle (500 jim tall) array designed to be drug coated and applied directly to the skin to achieve systemic delivery. The array patch has an overall surface area of .5 cm2 or -P27 mm in diameter. 23,28,31, The [G1u22’25, Le Aib29, Lys26’30]hPTHrP(l-34)NH 2 -coated microneedle array ({G1u22’25 , Leu23 ’2831 , Aib29 , Lys2630]hPTHrP(l-34)NH2 - microneedle array) will be enclosed in a collar assembly for loading onto a spring loaded applicator. The [G1u 22’25, Leu23 ’28’31 , Aib29 , Lys 26 ’30 ]hPTJ-JrP(l-34)NH2 - microneedle array will be removed from refrigeration one hour prior to application. Then, the [G1u 22 ’25, Leu 23 ’28 ’31 , Aib29, Lys 26 ’30]hPTHrP(l- 34)NH2 microneedle array will be loaded onto the applicator by the pharmacist or study personnel for subject dosing. Each [G1u 22’25, Leu23 ’28’31 , Aib29 , Lys 26’30]hPTHrP(l-34)NH 2 microneedle array is coated with either 100 [tg, 150 tg or 200 tg of [Glu 22’25 , Leu23 ’2831 , Aib29 , Lys 26’30]hPTHrP( 1 -34)NH 2 .

[G1u22’25 , Leu23’28’3 Aib29, Lys 26 ’30 ]hPTHrP( 1 -34)NH2-microneedle array-Placebo: Phosphate Buffered Saline (PBS) has been formulated as a placebo for transdermal administration using a microneedle array. The PBS-coated microneedle array (Placebo microneedle array) will be enclosed in a collar assembly for loading onto a spring loaded applicator. The Placebo microneedle array will be removed from refrigeration one hour prior to application. Then the Placebo microneedle array will be loaded onto the applicator by the pharmacist or study personnel for subject dosing.

Study Medication Administration [Glu22’25 , Leu 23 ’28 ’31 , Aib29, Lys 26’30 ]hPTHrP( 1 -34)NH2-microneedle array and [G1u22 ’25, Leu23 ’28 ’31 , Aib29, Lys 2630]hPTHrP(l-34)N}i 2 -microneedle array-Placebo will be administered in a double-blinded fashion. Subjects will fast overnight for a minimum of 8 hours prior to receiving study medication.

In Group 1 at the appropriate time, each subject will be given study medication via a single application of the transdermal microarray or single subcutaneous injection into the periumbilical region by study personnel. Subjects participating in Group 1 will be randomized to receive [G1u 22’25, Leu23 ’2831 , Aib29 , Lys 26’30]hPTHrP(1-34)NH 2-microneedle array or [Glu 22’25, Leu23 ’28’31 , Alb 29, Lys 26 ’30]hPTHrP(l-34)NH 2-microneedle array-Placebo administered transdermally or [G1u 22’25, Leu23 ’28 ’31 , Aib29, Lys2630]hPTHrP(l-34)NH2 80 jig administered subcutaneously. The subjects randomized to the [G1u 22’25, LŒu 23 ’28’31 , Aib 29 , Lys 26’30 ]hPTHrP( 1 -34)NH2-microneedle array or [G1u 22’25, Leu 23 ’28’31 , Aib29, Lys26 ’30 ]hPTHrP(1 -34)NH2-microneedle array-Placebo trarisdermal application will be assigned to one of 4 wear times (5, 15, 30, and 60 minutes, 6 active treatment and 2 placebo in each Group). Six subjects will also be randomized to [G1u , Leu23 ’28 ’31 , Aib 29 , 22’25 Lys26 ’30]hPTHrP(l -34)NH 2 for injection 80 g administered subcutaneously.

Subjects in Group 2a will be randomized to receive either [G1u 22 ’25 , Leu23 ’28’31 , Aib29, 26’30]hPTHrP(1 -34)NH2-microneedle may delivered transdermally or [G1u 22’25, Leu23 ’28 ’31 , Aib29 , Lys 26 ’30]hPTHrP(1-34)NH2 for injection 80 .tg administered subcutaneously. If the bioavailability of the 100 j.tg [G1u 22’25, Leu23’28 ’31 , Aib29, Lys 26’30]hPTHrP(1-34)NH2- dose will not be administered. Those microneedle array is greater than 66%, the 150 randomized to the transdermal application will receive either [G1u 22’25, Leu 23 ’28’31 , Aib 29 , Lys26 ’30]hPTHrP(1-34)NH2-microneedle array 150 g or [Glu 22 ’25, Leu 23 ’28 ’31 , Aib 29 , Lys 26’30]hPTHrP(l -34)NH2-mieroneedle array-Placebo in one of two anatomical locations.

Six subjects will be randomized to wear the microarray in the periumbilical region (Group 2a), and 6 subjects will be randomized to receive the microarray on the upper anterior thigh (Group 2b). One placebo patient will be randomized to each of the anatomical sites, for a total of 12 active, 2 placebo subjects in Group 2a. Eight further subjects will be randomized , Leu23 ’28’31 , Aib 29 , to Group 2c, and of these subjects, six will receive either [G1u 22’25 , Leu23’28’31 , Aib 29 , Lys26 ’30]hPTHrP(l-34)NH 2-microneedle array or [Glu 22’25 Lys26 ’30]hPTHrP(1-34)NH 2-microneedle array-Placebo at a dose of 100 1g via transdermal delivery for 24 hours applied to the periumbilical region.

Prior to the administration of study drug, the application site should be examined in order to assure that the areas are not compromised. Each application site will be graded immediately upon removal of the transdermal device or post injection, at one hour and 24 hours after the microarray application or subcutaneous injection was performed. For patients in Group 2c, who were randomized to a wear time of 24 hours, the patient will need to return to the clinic for a final local tolerance assessment 24 hours after removal of the microarray.

For any administration sites rated with a grade of 3, evaluations will continue at 24 hour intervals until the skin irritation has stabilized or resolved.

Before loading the transdermal microarray and collar onto the applicator, the microarray should be visibly inspected. If any of the microarrays or collars appear to be damaged that microarray should not be used and a new array should be chosen.

Concomitant Medications Vitamin D ( 800 lU/day), calcium supplements (< 1000 mg/day), and low dose aspirin (< 81 mg/daily for prophylaxis of cardiovascular disease) are acceptable as long as the subject has been on a stable dose for 1 month prior to the initial screening visit and remains on the same dose(s) throughout the study. Thyroid replacement therapy is allowed if the subject has been on a stable dose for at least 6 months and remains on the same dose throughout the study. Statins for lowering blood cholesterol levels are allowed as long as the subject has been on a stable dose for at least 3 months and remains on the same dose throughout the study.

Subjects should not take any other medications, including over-the-counter medications, herbal medications, or mega-doses of vitamins during the study without prior approval of the Investigator. The occasional use of over-the-counter medications (e.g., ibuprofen or acetaminophen) for headache or minor discomfort is allowed if discussed with the Investigator and recorded in the CRF.

If it becomes necessary for a subject to take any other medication during the study, the specific medication(s) and indication(s) must be discussed with the Investigator. All concomitant medications taken during the course of the study must be recorded in the source documents and transcribed into the subject’s case report form.

Prohibited Medications Subjects cannot take any medications, including over-the-counter, non-prescription medication, with the exception of those noted (Concomitant Medications), within 72 hours prior to dosing on Day 1.

In addition, subjects are ineligible for the study if they received general anesthesia within the past 3 months, received an investigational drug within 90 days prior to the initial dose of study medication, take any medications on a chronic basis (other than allowed in Section 6. 1), or have an abnormal nutritional status (abnormal diets, excessive or unusual vitamin intakes, malabsorption).

Blood Sample Collection 22 ’25, Leu23 ’28 ’31 , A total of 15 venous blood samples will be taken to measure [G1u plasma concentrations. PK blood samples should be Aib29, Lys 26 ’30]hPTHrP(1 -34)NH 2 mL samples will be collected collected as close to the exact time point as possible. Two 5 into vacutainer tubes and put into an ice water bath immediately after collection. Exact procedures for centrifuging, storage, and shipping of plasma samples will be detailed in a separate document. Plasma samples will be stored at -80’C before shipment to the bioanalytical laboratory. Venous blood samples will be taken as follows: Days Pi-Di, P2-Di and P3-Di Pre-dose and at 5, 10, 15, , 30, 60 mm, 1.5, 2, 3, 4, 6, 8 and 12 hours post-dose.

Days P1-D2, P2-D2 and P3-D2 A single venous blood sample will be taken in the morning 24 hours after study medication administration.

The actual time of each blood collection will be recorded.

Pharmacodynamic (PD) Assessments Blood Sample Collection Venous blood samples will be collected for the determination of total calcium and phosphorous at the following time points: Days Pi-Di, P2-Di and P3-Di Pre-dose and at 0.5, 1, 2, 3, 4, 6, 8 and 12 hours post-dose.

Days PI-D2, - P2-D2 and P3-D2 A single venous blood sample will be taken in the morning 24 hours after study medication administration.

Venous blood samples for determination of 1.25 hydroxyvitamin D at the following time points: Days Pi-DI, P2-D1 and P3-DI Pre-dose and at 3 and 12 hours post-dose.

Days Pl-D2, P2-D2 and P3-D2 A single venous blood sample will be taken in the morning 24 hours after study medication administration.

PHARMACOKINETIC ANALYSIS nNonlinTM PK parameters will be derived using noncompartmental methods with Wi Professional Version .01, or higher, (Pharsight Corp, Cary, North Carolina) and SASTM Version 9. 1, or higher (SAS Institute, Inc., Cary, North Carolina).

The following PK parameters will be estimated: The peak plasma concentration (Cm) The empirical time Of Cm (T,,) as well as the time of the last sample with quantifiable concentration of [G1u 22 ’25 , Leu23 ’28 ’31 , Aib 29, Lys 26’30]hPTHrP(1- 34)NH2 The apparent elimination rate constant (?), estimated by linear regression of the terminal phase of the semilogarithmic plasma level curve, when it is clearly defined The apparent elimination half-life (t 1 12), determined as ln2/2 The area under the plasma concentration time curve from time 0 to the last experimental point (AUCo), estimated by the linear-log trapezoidal rule The area under the plasma concentration time curve from time 0 to (AUC0 ) estimated by the linear-log trapezoidal rule. AUC0 = AUC 0 t+C t/X, where C t is the last measurable concentration The area under the plasma concentration time curve from time 0 to the 24 hr (AUC), estimated by the linear-log trapezoidal rule The extravascular plasma clearance (CL/F), calculated as: = Dose! AUC0 The extravascular volume of distribution (Vd/F), calculated as: = CL!F/?z.

Moreover, for each dose level, relative bioavailability will be calculated as the ratio of dose normalized AUC0 values: [AUC 0 . (transdermal)/Dose(transdermal)]/[ AUC0 (SC)/Dose(SC)] Analytical Methods The quantification of [G1u 22’25 , Leu 23 ’28’31 , Aib29, Lys26’30]hPTHrP(l-34)NH 2 in human plasma will be performed using a validated immunoassay method.

Table 30: Results of study with [G1u 22’25, Leu 23 ’28’31, Aib29 , Lys 26’30]hPTHrP(1-34)NH2 using PCS-transdermal system LS Means Pharmacokinetic Mean Comparison Parameters Test Reference Ratio P-Value Treatment lAversus Peptide for C, (pg/mL) 298.19 504.01 59.16 0.0546 Injection 80 pg (pg*hr/mL) UC 0. 1 64.78 655.94 9.88 <.0001 (pg*h r/m L) 88.54 699.06 12.67 <. . 0001 Treatment 1 B versus Peptide for C,, (pg/mL) 366.47 504.01 72.71 0.2346 Injection 80 pg UC (pghr/mL) 112.14 655.94 17.10 0.0002 (pg*h r/m L) 122.48 699.06 17.52 <.0001 Treatment 1C versus Peptide for C, (pg/mL) 237.56 504.01 47.13 0.0074 Injection 80 pg WC 0 . 1 (pghr!mL) 62.04 655.94 9.46 <.0001 - LS Means Pharmacokinetic Mean Comparison P Parameters rest Reference Ratio (pg*hr/mL) UC0.1, 77.67 699.06 11.11 <.0001 Treatment ID versus Peptide for 58.09 0.0471 C, (pg/mL) 292.78 504.01 I njection 80 pg (pg*hr/mL) 655.94 12.57 <.0001 UC 82.48 18.25 0.0001 \UC1 (pghr/mL) 127.57 699.06 Treatment 2C versus Peptide for (pg/mL) 226.31 504.01 44.90 0.0390 Cm Injection 80 pg (pg*hr/mL) 13.24 0.0017 \UC 1 86.85 655.94 \UC.int (pg*hr/mL) 107.84 699.06 15.43 0.0013 Treatment 1A: 1 x 100 pg Peptide-array administered into the periumbilical region via a TD delivery system (TD microarray) with minutes wear time (test) Treatment 18:1 x 100 pg Peptide-array administered into the perlumbilical region via a TD delivery system (TD mlcroarray) with minutes wear time (test) Treatment 1C: delivery system (TD microarray) with 1 a 100 pg Peptide-array administered into the perlumbilical region via a TD minutes wear time (test) Treatment 1D: 1 a 100 vg Peptide-array administered into the periumbilical region via a TD delivery system (TD microarray) with 60 minutes wear time (test) Treatment 1 E: 1 x 80 pg Peptide administered Into the perlumbllical region In a single Sc injection (reference) microarray) with Treatment 2C: 1 a 100 pg Peptide-array administered into the periumbilical region via a ID delivery system (ID 24 hours wear time (test) AN OVA.

Values for Treatments are the least-squares means (LS Means) from the Parameters were In-transformed prior to analysis.

LS Means are calculated by exponentlating the LS Means from the ANOVA.

% Mean Ratio = 1 00(test/reference) Data from all 10 subjects combined from the 3 periods were used for the SC dose (Treatment 1 E). ]hPTHrP(l-34)NH2 exposure from [G1u 22’25 , Peak [G1u 22 ’25, Leu23 ’28’31 , Aib 29, Lys 26 ’30 -microneedle array 100 jig, as determined from Leu23 ’28’31 , Alb 29, Lys 26’30]hPTHrP(1-34)NH 2 , Aib29, 22’25 , Leu23 ’2831 ranged from 45% to 73% of the reference treatment ([G1u Cmax, Lys 26’30]hPTHrP(1-34)NH 2 for Injection 80 jig). Total exposure, as determined from AUCO was 11% to 18% of the reference treatment. 22’25 , The differences in mean C,,,,,,, AUCo, and AUC0 values between the [G1u , Lys 26’30]hPTHrP(I-34)NH2-microneedle array treatments and the reference Leu 23 ’28’31 , Aib 29 treatment were statistically significant (p-values <0.05) in most cases. 22 ’25, Len 23 ’28 ’31 , Aib29, Table 31: Statistical Comparisons of Plasma [G1u 22 ’25 , Leu23 ’28’’, Lys 26 ’30] hPTHrP(1 -34)NH 2Pharmacokinetic Parameters Following [G1u Aib29, Lys 26’30]hPTHrP(1-34)NH2 Treatments (Period 2): Effect of Application Site LS Means Mean Pharmacokinetic - % P-Value Parameters Test Reference Ratio Comparison 1504.01 62.48 0.1034 Treatment 2A versus Peptide for (pglmL) 314.89 Cmax Injection 80 pg (pg *h rlm L) 16.30 0.0003 \UC, 106.91 655.94 (pg*hr/mL) 0.0003 118.72 699.06 16.98 UC 0. 1, 0.9621 311.97 314.89 99.07 Ireatment2Bversus Cm,,(pg/mL) Ireatment 2A LS Means Mean Pharmacokinetic % Comparison P-Value Parameters rest Reference Ratio 0.3246 UC (pgThr/mL) 142.85 106.91 133.62 UC 54 (pgThr/mL) 157.42 118.72 132.60 0.3202 Treatment 2B versus Peptide for 504.01 61.90 0.0972 C, (pg/mL) 311.97 Injection 80 pg (pg*hr/mL) 0.0015 \UC04 142.85 655.94 21.78 0.0014 UCo40 (pghr/mL) 157.42 699.06 22.52 Treatment 2A: 1 x 150 pg Peptide-microneedle array administered into the perlumbilical region via a ID delivery system (TD microarray) with 15 minutes wear time a TO delivery system Treatment 29: 1 x 150 pg Peptide-microneedle array administered into the upper anterior thigh region via (TO microarray) with 15 minutes wear time Treatment 2D: 1 x 80 pg Peptide administered into the periumbilical region In a single SC injection Values for Treatments are the least-squares means (LS Means) from the ANOVA.

Parameters were In-transformed prior to analysis.

LS Means are calculated by exponentiating the LS Means from the ANOVA. 1 00*(test/reference) % Mean Ratio = Data from all 10 subjects combined from the 3 periods were used for the SC dose (Treatment 20).

LysBo]hPTHrP(134)NH2 exposure from Glu, Peak [G1u, Leu’’, Aib, Leu 23 ’28’31 -microneedle array 150 .ig, as determined from , Aib29, Lys 26’30]hPTHrP(1-34)NH2 , Leu23 ’28’31 , Aib29 , Cm, was about 62% of the reference treatment ([G1u 22’25 Lys 26’30]hPTHrP(1 -34)NH2 for Injection 80 rig). Total exposure, as determined from AUCO was 17% to 23% of the reference treatment. 22 ’25 , The differences in mean Cm AUC0 1, and AUC0 values between the [G1u 22’25 , Leu 23 ’28 ’31 , Aib29, Lys 26 ’30]hPTHrP(1 -34)NI-1 2-microneedle array treatments and [Glu Leu23 ’28’31 , Aib29, Lys 26’30]hPTHrP(1-34)NH 2 for Injection 80 .tg were statistically significant (p-values <0.05) in most cases. ]hPTHrP(1-34)NH2 exposure from [G1u 2225 , Peak [G1u 22’25, Leu23 ’28’31 , Aib29, Lys 26 ’30 ]hPTHrP(1 -34)NH2- microneedle array 150 .tg administered into Leu 23 ’28 ’31 , Aib29, Lys 2630 the upper anterior thigh region, as determined from Cm, was about 99% of the reference ]hPTHrP(1-34)NH2- microneedle array 150 .tg treatment ([G1u 2225, Leu2328’31 , Aib29, Lys 2630 3 was administered into the periumbilical region). Total exposure, as determined from AUCO 133% of the reference treatment. 2225 , The differences in mean AUC0 1, and AUC0 values between [Glu Leu 23 ’28 ’31 , Aib29, Lys 26 ’30]hPTHrP(1-34)NH2- microneedle array 150 j.tg administered into the periumbilical region and [G1u 22’25 , Leu23 ’28 ’31 , Aib29, Lys 26 ’30]hPTHrP(1-34)NH2- microneedle array 150 .tg administered into the upper anterior thigh region were not statistically significant (p-values> 0.05).

Aib29, 22’25, Leu 23’28 ’31 , Table 32: Statistical Comparisons of Plasma [G1u 22’25 , Leu23’’ 31 , Pharmacokinetic Parameters Following LGIU Lys 26 ’301 hPT11rP(1 -34)NH 2 Treatments (Period 3): Effect of Application Site Aib29, Lys 26’30IhPTHrP(1-34)NH2 LS Means % Mean Pharmacokinetic Ratio P-Value Test Reference Comparison Parameters 0.3255 66.78 (pg/mL) 336.59 504.01 Treatment 3A versus Peptide for Cm Injection 80 pg 14.86 0.0009 97.45 655.94 WC0., (pghr/mL) 0.0004 (pg*hr/mL) 699.06 15.66 UCi 109.50 0.2017 145.42 Cmax (pg/mL) 489.45 336.59 reatment 3B versus Treatment 3A WC0. (pg*hr/mL) 0.1267 97.45 171.17 166.79 g*h r/mL) 0.0802 109.50 173.66 190.16 UCo.rnr (p 0.9423 97.11 489.45 504.01 Treatment 3B versus Peptide for Cr .. (pglmL) Injection 80 pg _ _____________ ________ 0.0101 655.94 25.43 UC0., (pghr/mL) 166.79 0.0065 WC0.w (pg*hrlmL) 127.20 190.16 1699.06 Treatment 3A: 1 x 200 pg Peptide-microneedle array administered Into the periumbilical region via a TD delivery system (TO microarray) with 15 minutes wear time Treatment SB: 1 x 200 jig Peptide-microneedle array administered into the upper outer arm (deltoid) region via a TO delivery system (TD microarray) with 15 minutes wear time Treatment SC: 1 x 80 pg Peptide administered Into the periumbilical region in a single SC injection Values for Treatments are the least-squares means (LS Means) from the ANOVA.

Parameters were In-transformed prior to analysis.

LS Means are calculated by exponentiating the LS Means from the ANOVA.

% Mean Ratio = 1 O0*(test/reference) Data from all 10 subjects combined from the 3 periods were used for the SC dose (Treatment SC). l2eXpOSUre irorn Luiu Lys’ jflFII-lrl-ij-i’f)INX- Peak Li1u’’, Leu’’’, Aib’, ]hPTHrP( 1 -34)NH- microneedle array 200 pig, as determined from Leu23 ’28 ’31 , Aib29, Lys 26’30 , Aib29, 22 ’25 , Leu23 ’28’31 ranged from 67% to 97% of the reference treatment ([G1u Cm,,,, ]hPTHrP(i-34)NH2 for Injection 80 ig). Total exposure, as determined from AUCo, Lys26 ’30 was 16% to 27% of the reference treatment. 22’25 , and AUC0 values between the [G1u The differences in mean AUCO 3 Cmax, 22’25 , ]hPTHrP(l-34)NH2- microneedle array treatments and [G1u Leu23 ’28 ’31 , Aib29, Lys 26’30 ]hPTHrP(1-34)NH2 for Injection 80 tg were statistically significant , Aib29, Lys 26’30 Leu 23 ’28 ’31 (p-values <0.05) in most cases. 22 ’25 , ]hPTHrP(1-34)NH2 exposure from [G1u , Lys26 ’30 Peak [G1u 22’25, Leu23 ’28’31 , Aib29 26’30]hPTHrP(1 -34)NH2- microneedle array 200 xg administered into the Leu23 ’28 ’3 1, Aib, Lys upper outer arm (deltoid) region, as determined from Cm, was about 145% of the reference ]hPTHrP(1-34)NH2- microneedle array 200 tg , Aib29, Lys26’30 treatment ([G1u 22 ’25, Leu23 ’28’31 administered into the periumbilical region). Total exposure, as determined from ATJCO.O, was 174% of the reference treatment. 22 ’25 , AUCo-, and AUCo values between [G1u The differences in mean Cmax, ]hPTHrP(1-34)NH2- microneedle array 200 p.g administered into the Leu23 ’28 ’31 , Aib29, Lys 26 ’30 1hPTHrP(1-34)NH2- microneedle , Lys 26 ’30 , Leu23 ’28 ’31 , Aib29 periumbilical region and [G1u 22 ’25 array 200 pg administered into the upper outer arm (deltoid) region were not statistically significant (p-values > 0.05).

Relative Bioavailability (F ret): The results of relative bioavailability (F ret) of -sMTS treatments compared to [G1u 22’25 , Leu23 ’28 ’31 , Aib29 , Lys 26’30]hPTHrP(l-34)NH 2 for Injection 80 p.g administered into the periumbilical region in a single SC injection are presented in the following table.

Table 33: Relative Bioavailability of [G1u 22’25, Leu 23 ’28’31 , Aib 29, Lys 26’30]hPTHrP(1- Aib29 , 34)NH2-Microneedle Array Treatments Compared to [G1u 22 ’25 , Leu 23’28’31 , Lys 26 ’30]hPTHrP(1-34)NH 2 for Injection 80 tg Mean Dose Normalized AUCO-Inf sMTS Doses SC Dose Study Treatment Period Mean N Mean N Fret 0.108 1A 1 1.00 5 9.25 10 0.151 1 1 1.39 9.25 10 IC - 1 1.11 9.25 10 0.120 10 0.204 1 1.89 5 9.25 2A 2 0.83 6 9.25 10 0.090 9.25 10 0.134 2B 2 1.24 6 0.151 2C 2 1.40 6 9.25 0.063 3A 3 0.58 6 9.25 10 3B 10 0.122 3 1.13 19.25 Data from all 10 subjects combined from the 3 periods were used for the SC dose.

Relative bioavailability of [Glu 22’25, Leu23 ’28 ’31 , Aib29, Lys 26 ’30]hPTHrP( 1 -34)NH2- , Aib29, Lys 26 ’30]hPTHrP(l- microneedle array treatments compared to [Glu 22’25 , Leu23’28’31 34)NH 2 for Injection 80 .ig administered into the periumbilical region in a single SC injection ranged from approximately 6% following 200 j.g [G1u 22 ’25, Leu23 ’28’31 , Aib29 , Lys 26 ’30]hPTHrP(l-34)NH 2 administered to the periumbilical region with 15 minutes wear time (Treatment 3A) to about 20% following 100 tg [G1u22 ’25, Leu23 ’28 ’31 , Aib 29 , Lys26’30]hPTHrP(l -34)NH2 administered in the periumbilical region with 60 minutes wear time (Treatment 1 D).

Dose Proportionality Analysis , Aib29 , The results of dose proportionality analysis of [Glu 22’25, Leu 23’28 ’31 Lys 2630]hPTHrP(l -34)NH 2-sMTS treatments are presented in the following table. 22’25, Leu 23’28’31 , Aib 29 , Table 34: Dose Proportionality Analysis of [G1u Lys 26’30] hPTHrP(1-34)NH 2Pharmacokinetics Parameters Following 100, 150, and 200 jig [G1u 22 ’25, Leu23’28’31 , Aib29, Lys 26’30] hPTHrP(1-34)NH2-Microneedle Array Treatments _89 - Pharmacokinetic Standard Parameters 95% Cl Slope Error (pg/mL) -.2522 0.2944 (-0.88, 0.37) Cmax (pg*hr/mL) UC0.., (-1.10, 0.49) -.3069 0.3735 (pg*hr/mL) \UC0.1 .2791 10.3563 (-1.03, 0.48) Period 1:1 a 100 pg Peptide -microneedle array administered into the periumbilical region via a TO delivery system (TO microarray) with 15 minutes wear time Period 2: 1 a 150 pg Peptide-microneedle array administered into the periumbilical region via a ID delivery system (TD mlcroarray) with 15 minutes wear time Period 3: 1 x 200 pg Peptide-microneedle array administered into the perlumbilical region via a TO delivery system (ID microarray) with 15 minutes wear time Parameters and dose were In-transformed prior to analysis.

Dose Proportionality is concluded if the Cl for the In-transformed parameters includes the value of 1.

The 95% CIS for the PK parameters did not contain the value of 1, indicating lack of , Lys 26’30]hPTHrP(1 - dose proportionality of the 3 treatments ([G1u 22 ’25 , Leu 23 ’28 ’31 , Aib 29 34)NH2-microneedle array 100 j.tg, Treatment 1B, [Glu 22’25 , Leu2328’31 , Aib29 , .tg Treatment 2A, and [G1u 22’25, Leu23 ’28’31 , Lys26 ’30]hPTHrP(1-34)NH 2-microneedle array 150 Aib29, Lys 26’30]hPTHrP(1-34)NH2-microneedle array 200 pg Treatment 3A) administered into periumbilical region with 15 minutes’ wear time. Moreover, the dose ratio, the expected and observed exposure ratios, the negative slopes of the regression lines for the PK parameter, .., and AUC0 versus [Glu 22’25, Leu23 28’31 , and the display of the PK parameters Cm, A1JC o Aib29, Lys 26’30]bPTHrP(1-34)NH2-microneedle array doses, indicate that the exposure to ]hPTHrP(l -34)NH2 was less than proportional to the [G1u 22’25 , Leu23’28’3 Aib, Lys 26 ’30 , Aib29, Lys 26 ’30]hPTHrP(1-34)NH2-microneedle array doses. administered [G1u 22’25, Leu 23 ’28 ’31 Pharmacodynamic Results: In presenting the results for the PD markers, the term baseline-adjusted is used to refer to change from baseline.

Total Serum Calcium 2-Microneedle Leu 23 ’28 ’3 11 , Aib 9 , Lys 26 ’30] hPTHrP(1 -34)NH Study Period 1 and [Glu 22 ’25, From Study Period 2 Array 100 ftg With 24 Hours Wear Time (Treatment 2C) 22 ’25 , Baseline-adjusted total serum calcium concentrations following the [G1u -microneedle array 100 .tg with wear times Leu 23 ’28 ’31 , Aib 29, Lys 26’30]hPTHrP(1-34)NH 2 22’25 , minutes to 24 hours administered into the periumbilical region and [G1u ranging from 5 ]hPTHrP(l-34)NH2 for Injection 80 tg (Treatment IE), stayed Leu 23 ’28 ’31 , Aib29, Lys 26’30 above the baseline levels for most parts of the sampling interval and up to about 8 hours postdose above the placebo levels. Baseline-adjusted total serum calcium concentrations were highest following Treatment 1E compared to other treatments for about 8 hours postdose.

Mean baseline-adjusted total serum calcium concentration ranged from -0.1 to 0.3 mg/dL following [G1u , Lys 26 ’30]hPTHrP(1-34)NH 2-microneedle array 22 ’25 , Leu23 ’28 ’31 , Aib 29 treatments, ranged from 0.1 to 0.4 mg/dL following Treatment 1E, and -0.1 to 0.3 mgldL following placebo. The mean maximum change from baseline in total serum calcium , Aib 29, concentrations ma) was 0.3 to 0.5 mg/dL following [Glu 22’25, Leu23 ’28’31 Lys26 ’30]hPTHrP(1-34)NH 2-microneedle array treatments, 0.5 mg/dL following Treatment I E, and 0.0 following placebo.

Study Period 2 22 ’25 , Baseline-adjusted total serum calcium concentrations following the [G1u , Aib29 2-microneedle arrays 150 tg (administered into Leu23 ’28’31 , Lys 26’30]hPTHrP(1 -34)NH the periumbilical region [Treatments 2A] and into the upper anterior thigh region [Treatments 213]) and [Glu 2225, Leu23 ’28’31 , Aib 29, Lys26 ’30]hPTI-IrP(1-34)NI-12 for Injection 80 .tg (Treatment 2D) generally stayed above the baseline levels for up to about 8 hours postdose.

The highest baseline-adjusted total serum calcium concentrations resulted following Treatment 2D. Baseline-adjusted total serum calcium concentration was generally higher following the administration of Treatment 2A compared to administration of Treatment 213, both with 15 minute wear times.

Mean baseline-adjusted total serum calcium concentration ranged from 0.0 to 0.3 ]hPTHrP(1-34)NH2-microneedle arrays mg/dL following [G1u22’25 , Leu23 ’28 ’31 , Aib 29, Lys 26 ’30 mg/dL following Treatment 21), and 0.0 to 0.,3 mg/dL 150 .tg, ranged from 0.2 to 0.5 following placebo. The mean maximum change from baseline in total serum calcium 22’25, Leu23 ’28’31 , Aib 29 , concentrations (A max) ranged from 0.3 to 0.4 mg/dL following [G1u Lys 2630]hPTHrP(1-34)NH2-microneedle arrays 150 .tg, 0.6 mg!dL following Treatment 2D and 0.2 mg/dL following placebo.

Mean baseline-adjusted total serum calcium concentration ranging from 0.0 to 0.3 A.a, value at 0.4 mg/dL mg/dL were similar following Treatments 2A and 2B. The mean value following Treatment 213 at following Treatment 2A was comparable to the mean Amax 0.3 mgtdL.

Study Period 3 Baseline-adjusted total serum calcium concentrations following the [G1u 22 ’25 , Leu 23 ’28’31 , Aib29 , Lys 26 ’30]hPTHrP(l-34)NH 2-mjcroneedle array 200 g (administered into the periumbilical region [Treatments 3A] and into upper outer arm [deltoid] region, [Treatments 313]) and [G1u 22’25 , Leu23 ’2831 , Aib 29, Lys 26’30]hPTHrP(l-34)NH2 for injection 80 tg (Treatment 3C), mostly remained around the baseline levels throughout the sampling interval and for up to about 8 hours postdose above the placebo level. Baseline-adjusted total serum calcium concentrations were generally higher following the administration of Treatment 313 compared to the administration of Treatment 3A, both with 15 minute wear times.

Mean baseline-adjusted total serum calcium concentration ranged from 0.0 to 0.3 mg/dL following [G1u 22 ’25 , Leu23 ’28 ’31 , Aib 29, Lys 26 ’30]hPTHrP(1-34)NH2 -microneedle array 200 j.tg, -0.5 to 0.1 mg/dL following Treatment 3C, and -0.3 to 0.2 mg/dL following placebo.

The mean maximum changes from baseline in total serum calcium concentrations were (max) 0.0 and 0.3 mg/dL following [G1u 22’25, Leu 2328 ’31 , Aib 29, Lys26’30]hPTHrP(1-34)N1F12- microneedle array 200 .tg, -0.5 mg/dL following Treatment 3C, and 0.0 following placebo.

Mean baseline-adjusted total serum calcium concentrations ranged from -0.2 to 0.3 mg/dL following Treatment 3A and ranged from 0.0 to 0.3 mg/dL following Treatment 3B.

Mean A values were 0.0 following Treatment 3A and 0.3 mgldL following Treatment 3B.

Serum Phosphorus 26 ’30]hPTHrP(1-34)NH2- Study Period 1 and [Glu 22 ’25, Leu 23 ’28’31 , Aib 29, Lys microneedle array 100 tg with 24 hours wear time (Treatment 2C) From Study Period 2 Baseline-adjusted serum phosphorus concentrations following the [Glu 22 ’25, Leu23 ’28’31 , Aib29 -microneedle array 100 tg with wear times ranging from 5 , Lys26’30]hPTHrP(1-34)NH 2 22 ’25, Leu23 ’28 ’31 , Aib29 , minutes to 24 hours administered into the periumbilical region and [Glu Lys 26 ’30]hPTHrP(1-34)NH 2 for Injection 80 j.tg (Treatment 1E) fluctuated around baseline levels for about 8 hours postdose and rose above baseline levels thereafter. Baseline-adjusted serum phosphorus concentrations following the [Glu 22’25, Leu23 ’28 ’31 , Aib 29 , Lys 26 ’30]hPTHrP(1-34)NH 2-microneedle arrays 100 g and Treatment 1E were generally above those of the placebo.

Mean baseline-adjusted serum phosphorus concentrations ranged from -0.2 to 0.8 mg/dL following [G1u 22 ’25 , Lys 26 ’30]hPTHrP( 1-3 4)NH 2-microneedle arrays , Leu 23 ’28 ’31 , Aib 29 100 ig, -0.2 to 0.4 mg/dL following Treatment lB. and -0.3 to 0.5 mg/dL following placebo.

The mean maximum change from baseline serum phosphorus concentrations (L max) ranged from 0.3 to 0.9 mg/dL following [G1u 22’25, Leu23 ’28 ’31 , Aib29, Lys 26 ’30]hPTHrP(1-34)NH 2- microneedle arrays 100 jtg, 0.3 mg/dL following Treatment 1E, and 0.4 mg/dL following placebo.

Study Period 2 Baseline-adjusted serum phosphorus concentrations following the [G1u 22’25, Leu23 ’28 ’31 , Aib29 , Lys 26 ’30]hPTI-frP(l-34)NH 2 -mjcroneedle arrays 150 ptg (administered into the periumbilical region [Treatments 2A] and into the upper anterior thigh region [Treatments 213]) and [G1u22 ’25, Leu 23 ’28 ’31 , Aib29 , Lys 26 ’30]hPTHrP(l-34)NH 2 for Injection 80 tg (Treatment 2D) mostly fluctuated around the baseline levels for about 8 hours postdose and rose above the baseline levels thereafter. Baseline-adjusted serum phosphorus concentrations following Treatment 2B and Treatment 2D were generally above the placebo levels.

Moreover, baseline-adjusted serum phosphorus concentrations were higher following Treatment 2B compared to Treatment 2A, both with 15 minute wear times.

Mean baseline-adjusted serum phosphorus concentrations ranged from -0.1 to 1.0 mg/dL following [Glu 22’25, Leu23 ’2831 , Aib29, Lys 26’30]hPTHrP( 1 -34)NH 2-microneedle arrays 150 tg, -0.3 to 0.6 mg/dL following Treatment 2D, and -0.1 to 0.4 mg/dL following placebo.

The mean maximum change from baseline serum phosphorus concentrations (imax) ranged from 0.2 to 1.0 mg/dL following [Glu 22’25, Leu 23 ’28 ’31 , Aib 29, Lys 26 ’30]hPTHrP(1-34)N112- microneedle arrays 150 j.ig, 0.6 mg/dL following Treatment 2D, and 0.4 mg/dL following placebo.

Mean baseline-adjusted serum phosphorus concentrations ranged from -0.2 to 0.3 mgldL following Treatment 2A and ranged from -0.1 to 1.0 mg/dL following Treatment 2B.

The mean Amax values were 0.2 mgldL following Treatment 2A and 1.0 mg/dL following Treatment 2B.

Study Period 3 Baseline-adjusted serum phosphorus concentrations following the [G1u 22 ’25, Leu23 ’28’31 , Aib29, Lys 26’30]hPTHrP(l-34)NH 2 -microneedle arrays 200 ig (administered into the periumbilical region [Treatments 3A] and into upper outer arm [deltoid] region, [Treatments 313]) and [Glu 22’25 , Leu 23 ’2831 , Aib29, Lys 26 ’30]hPTHrP(l-34)NH 2 for Injection 80 tg (Treatment 3C), fluctuated around the baseline levels for about 8 hours postdose and rose above the baseline levels thereafter. Baseline-adjusted serum phosphorus concentrations following [G1u 2225 , Leu23 ’28 ’31 , Aib29, Lys 26 ’30]hPTHrP(1-34)NH 2 -microneedle arrays 200 tg and Treatment 3C were generally above the placebo level. Baseline-adjusted serum phosphorus concentrations were generally higher for Treatment 3B compared Treatment 3A.

Mean baseline-adjusted serum phosphorus concentrations ranged from -0.4 to 0.6 mg/dL following [G1u 22’25, Leu23 ’28 ’31 , Aib29, Lys26 ’30]hPTHrP(l-34)NH 2-microneedle arrays 200 tg, -0.7 to 0.4 mg/dL following Treatment 3C, and -0.3 to 0.3 following placebo. The mean maximum change from baseline serum phosphorus concentrations (im ax) were 0.4 and 0.6 mg/dL following [G1u 22’25, Leu 23 ’28 ’31 , Aib29 , Lys2630] hPTHrP( I -34)NH2-microneedle arrays 200 jig, -0.7 mg/dL following Treatment 3C, and 0.2 mg/dL following placebo.

Mean baseline-adjusted serum phosphorus concentrations ranged from -0.4 to 0.6 mg/dL following Treatment 3A and -0.1 to 0.6 mg!dL following Treatment 313. Mean Amax values were 0.4 mg/dL following Treatment 3A and 0.6 mg/dL following Treatment 3B. 1, 25-dihydroxyvitamin D Study Period 1 and [G1u 2225, Leu 23 ’28 ’31 , Aib 29 , 26 ’ ] hPTHrP(1-34)NH 2 -Microneedle Arrays 100 p.g with 24 hours wear time (Treatment 2C) From Study Period 2 Baseline-adjusted serum 1, 25-dihydroxyvitamin D concentrations following the [G1u22’25 , Leu 23 ’28’31 , Aib29, Lys26 ’30]hPTHrP(l-34)NH 2-sMTS 100 jig with wear times ranging from 5 minutes to 24 hours administered into the periumbilical region and [G1u 22’25 , Leu23 ’28 ’31 , Aib 29, Lys 26’30]hPTHrP(1-34)NH 2 for injection 80 jig (Treatment 1E) stayed above the baseline levels. The highest baseline-adjusted serum 1, 25-dihydroxyvitamin D concentrations resulted after 3 hours postdose following Treatment I.E.

Mean baseline-adjusted serum 1, 25-dihydroxyyitamin D concentrations ranged from to 16.1 pg/mL following [G1u 22’25, Leu23 ’2831 , Aib29, Lys 26 ’30]hPTHrP( 1 -34)NH2- microneedle array 100 jig, -0.6 to 26.2 pg/mL following Treatment 1E, and 1.1 to 7.1 pg/mL following placebo. The mean maximum change from baseline serum 1 ,25-dihydroxyvitamin D concentration (A max) ranged from 2.9 to 27.1 pg/mL following [G1u 22 ’25 , Leu23 ’28 ’31 , Aib 29 , Lys 26 ’30]hPTHrP(1-34)NH 2 -microneedle array 100 jig, 30.2 pg/mL following Treatment 1E, and 8.0 pg/mL following placebo.

Study Period 2 Baseline-adjusted serum 1, 25-dihydroxyvitamin D concentrations following the [Glu 22’25 , Leu 23 ’28 ’3 , Aib 29, Lys 26 ’30]hPTHrP( 1 -34)NH2- microneedle array 150 jig (administered into the periumbilical region [Treatments 2A] and into the upper anterior thigh region [Treatments 213}) and [G1u 22 ’25, Leu 23 ’28’31 , Lys2630]hPTHrP(1-34)NH 2 for , Aib29 injection 80 p.g (Treatment 2D) mostly remained above the baseline levels. The highest baseline-adjusted serum 1, 25-dihydroxyvitamin D concentrations resulted following Treatment 2D.

Mean baseline-adjusted serum 1, 25-dihydroxyvitamin D concentrations ranged from -14.2 to 11.0 pg/mL following [G1u 2- 22’25 , Leu23 ’28 ’31 , Aib29, Lys 26’30]hPTHrP(1 -34)NH microneedle array 150 jig, 7.6 to 32.2 pg/mL following Treatment 2D, and 3.4 to 14.9 pg/mL following placebo. The mean maximum change from baseline serum 1, 25-dihydroxyvitamin D level (A max ) ranged from -4.5 to 0.3 pg/mL following [G1u 22 ’25 , Leu23 ’28 ’31 , Aib29 , Lys26’30]hPTHrP(l-34)NH 2- microneedle array 150 p.g, 32.2 pg/mL following Treatment 2D, and 17.0 pglmL following placebo.

Mean baseline-adjusted serum 1, 25-dihydroxyvitamin D concentrations ranged from -14.2 to 11.0 pg/mL and from to 11 pglmL following Treatments 2A and 213, -2.5 respectively. Mean A ,, values were -4.5 pglmL following Treatment 2A and 0.3 pg/mL following Treatment 2B.

Study Period 3 Baseline-adjusted serum 1, 25-dihydroxyvitamin D concentrations following the [G1u22 ’25, Leu23 ’28’31 , Aib 29, Lys26 ’30]hPTHrP(1-34)NH 2- microneedle array 200 .Lg (administered into the periumbilical region [Treatments 3A] and into upper outer arm , Lys26 ’30]hPTHrP(1-34)NH2 [deltoid] region, [Treatments 3B]) and [G1u 22 ’25, Leu23 ’28’31 , Aib29 for Injection 80 jtg (Treatment 3C) mostly remained above the baseline levels and, after 8 hours postdose, above the placebo levels. Baseline-adjusted serum I, 25-dihydroxyvitamin D concentrations were generally higher following Treatment 3B compared to Treatment 3A.

Mean baseline-adjusted serum 1, 25-dihydroxyvitarnin D concentrations ranged from -5.1 to 22.5 pg/mL following [Glu 22’25, Leu 23 ’28 ’31 , Aib29, Lys 26 ’ 30]hPTHrP(1-34)NH2- microneedle array 200 [tg, -0.2 to 25.9 pg/mL following Treatment 3C, and -0.7 to 19.0 pg/mL following placebo. The mean maximum changes from baseline serum 1, 25- dihydroxyvitamin D concentrations (A m ) were 9.0 and 22.6 pg/mL following [G1u 22 ’25 , Leu 23 ’28 ’ 31 , Aib 29 - microneedle array 200 tg, 30.2 pg/mL , Lys 26 ’30]hPTHrP(1-34)NH2 following Treatment 3C, and 10.5 pg!mL following placebo.

Mean baseline-adjusted serum 1, 25-dihydroxyvitamin D concentrations ranged from -5.1 to 11.5 pglmL following Treatment 3A and 7.2 to 22.5 pg/mL following Treatment 3B.

Mean A m a,, values were 9.0 pglmL following Treatment 3A and 22.6 pg/mL following Treatment 3B.

Pharmacokjnetjcs: Peak [G1u 22’25, Leu 23 ’28 ’31 , Aib 29 , Lys 26’30]hPTHrP(1-34)NH 2 exposure from [01u 22’25 , Leu23 ’28’31 , Aib 29, Lys2630]hPTHrP(1-34)NH 2 - microneedle array 100 tg, as determined from ranged from Cmax, 45% to 73% of the reference treatment ([Glu 22’25 , Leu23 ’28’31 , Aib29 , Lys 26’30]hPTHrP(1-34)NH2 for Injection 80 jig). Total exposure, as determined from AUCO was 11% to 18% of the reference treatment.

Peak [G1u 22’25, Leu23 ’28 ’31 , Aib 29 , Lys 26’30]hPTHrP(1-34)NH2 exposure from [Glu 22’25 , Leu23 ’28’31 , Aib29, Lys 26’30]hPTHrP(1-34)NH 2 - microneedle array 150 Vtg, as determined from Cmax, was about 62% of the reference treatment ([G1u 22’25, Leu 23 ’28’31 , Aib29, Lys 26 ’30]hPTHrP(1-34)NH 2 for Injection 80 .tg). Total exposure, as determined from AUC0., was 17% to 23% of the reference treatment.

Peak [G1u 22’25 , Leu23 ’28’3 1 , Aib29, Lys 26’30]hPTHrP(1 -34)NH 2 exposure from [G1u 22’25 , Leu23 ’28 ’31 , Aib 29 , Lys26’30]hPTHrP(1-34)N}1 2- microneedle array 200 tg, as determined from Cm, ranged from 67% to 97% of the reference treatment ([G1u 22 ’25 , Leu23 ’28 ’31 , Aib29, Lys 26’30]hPTHrP(1-34)NT-1 2 for Injection 80 pg). Total exposure, as determined from AUCO was 16% to 27% of the reference treatment.

Mean relative bioavailability of [G1u 22’25 , Leu 23’28’31 , Aib29, Lys 26’30]hPTHrP(1- 34)NH2- microneedle array 100 g ranged from about 11% to 20%, of [G1u 22’25 , Leu 23 ’2831 , Aib29 , Lys 26’30]hPTHrP(1-34)NH 2- microneedle array 150 j.tg was 9% (when administered into the periumbilical region) and 13% (when administered into the upper anterior thigh region), and of [01u22’25 , Leu2328’31, Aib29, Lys 26’30]hPTHrP(1-34)N11 2- microneedle array 200 pg was about 6% (when administered into the periumbilical region) and 12% (when administered into the upper outer arm [deltoid] region) when compared to [G1u 22’25 , Leu23 ’28’31 , Aib 29, Lys 26 ’30]hPTHrP(1-34)NH2 for Injection 80 rig.

Relationship between wear time and exposure to [Glu 22 ’25, Leu 23 ’28’31 , Aib29 , Lys 26 ’30]hPTHrP(1-34)NH2 was not apparent from the results of this investigation. The relative bioavailability ranged from about 6% to 20% irrespective of wear time.

The mean relative bioavailability was comparable following [G1u 2225, Leu23 ’28’31 , Aib29, Lys 26 ’30]hPTHrP(l-34)NH 2 - microneedle array 150 .ig administration between the periumbilical region and the upper anterior thigh region. Peak [Glu 22’25, Leu23 ’28 ’31 , Aib29 , Lys2630 ]hPTHrP( 1 -34)NH2 exposures from [G1u 22’25, Leu 23 ’28 ’31 , Aib 29, Lys 26 ’30]hPTHrP( 1- 34)NH2- microneedle array 150 j.g administered into the periumbilical region and upper anterior thigh region, as determined from C m , were about 62% of the reference treatment ([G1u22’25, Leu 23 ’28 ’31 , Aib29, Lys26 ’30]hPTHrP(1-34)NH2 for Injection 80 tg). Total exposures, as determined from AUC O3 were 17% and 23% of the reference treatment, respectively.

The mean relative bioavailability was higher following [G1u 22’25 , Leu232831 , Aib 29, Lys 26 ’30]hPTHrP(1 -34)NH 2- microneedle array 200 tg administration to the deltoid region than to the periumbilical region. Peak [G1u 2225, Leu 23 ’28 ’31 , Aib 29, Lys 26’30 .PTHrP(l-34)NH2 exposures from [G1u 22’25 , Leu23’28’3 , Aib29, Lys 26 ’30]hPTHrP(l -34)NH2- microneedle array 200 j.g administered into the periumbilical and the deltoid regions, as determined from C , Leu23 ’28 ’31 , Aib 29 , were about 67% and 97% of the reference treatment ([G1u 22’25 Lys26 ’30]hPTHrP(l-34)NH 2 for Injection 80 tg), respectively. Total exposures, as determined from AUCO 3 were 16% and 27% of the reference treatment, respectively.

Pharmacodynamics: Baseline-adjusted total serum calcium concentrations either marginally or transiently increased following [G1u 22 ’25 , Leu 23 ’231 , Aib29, Lys 2630]hPTHrP(1-34)NH2- microneedle array treatments and [G1u 22 ’25 , Leu 23 ’28 ’31 , Aib29, Lys 26 ’30]hPTHrP(l-34)NH2 for Injection 80 tg that remained within the normal laboratory range, or remained around the baseline levels. Baseline-adjusted total serum calcium concentrations rose above the placebo levels up to about 8 hours postdose and either fell below the placebo levels or overlapped with the placebo afterwards.

Baseline-adjusted total serum calcium concentrations were higher following the application of [G1u 22’25, Leu23 ’2831 , Aib29, Lys26 ’30]hPTHrP( 1 -34)NH2- microneedle array 150 jig to the periumbilical region compared to the upper anterior thigh region and were higher following the application of [G1u 22’25 , Aib29, Lys 26 ’30]hPTHrP(l-34)NH2- , Leu23 ’2831 microneedle array 200 jig to the upper outer arm (deltoid) region compared to the , Aib 29 , periumbilical region, indicating the effect of the site of [Glu 2225 , Leu23 28 ’31 Lys 26 ’30]hPTHrP(l-34)NH 2 administration on total serum calcium concentrations.

Baseline-adjusted serum phosphorus concentrations following [G1u 22 ’25 , Leu23 ’28 ’31 , , Leu23 ’28 ’31 , Aib29, Lys 26’30]hPTHrP(l-34)NH2- microneedle array treatments and [Glu 22 ’25 for Injection 80 jig fluctuated around the baseline levels for Aib 29, Lys 26 ’30]hPTHrP(l-34)NH 2 approximately 8 hours postdose and rose above the baseline levels for the remainder of the sampling interval. Serum phosphorus concentrations were generally above the placebo levels and at times overlapped with the placebo.

Baseline-adjusted serum phosphorus concentrations were higher following the application of [G1u 22’25 , Leu23 ’28’31 , Aib 29, Lys 2630]hPTHrP(1-34)NH2 - microneedle array 150 Vg to the upper anterior thigh region compared to the periumbilical region and were higher following the application of [Glu 22’25, Leu 23 ’28 ’31 , Aib 29, Lys26’30]hPTHrP(1-34)NH 2- microneedle array 200 tg to the upper outer arm (deltoid) region compared to the periumbilical region, indicating the effect of the site of [G1u 22’25, Leu23 ’28’31 , Aib 29, Lys 26 ’30]hPTHrP(l-34)NH 2 administration on serum phosphorus concentrations.

Baseline-adjusted serum 1, 25-dihydroxyvitarnin D concentrations increased following [G1u 22 ’25, Leu23’28’31 , Aib29, Lys26’30]hPTHrP(l-34)NH 2- microneedle array treatments and [G1u22’25, Leu23 ’28’31 , Aib 29, Lys 2630]hPTHrP(1-34)NH2 for Injection 80 .ig compared to baseline levels. Baseline-adjusted serum I, 25-dihydroxyvitamin D concentrations were either above the placebo levels or overlapped with the placebo.

While there was no clear trend in serum 1, 25-dihydroxyvitamin D concentrations following the application of [G1u 22’25, Leu23 ’28 ’31 , Aib 29, Lys 26’30]hPTHrP(l-34)NH 2- microneedle array 150 fig to periumbilical region and the upper anterior thigh region, baseline-adjusted serum 1, 25-dihydroxyvitamin D concentrations were generally higher following application of [G1u22 ’25 , Leu23 ’28’31 , Aib29, Lys2630]hPTHrP(l-34)NH 2- microneedle array 200 Vg to the upper outer arm (deltoid) region and remained above the baseline level during the entire sampling time compared to the periumbilical region.

Safety: Single-dose administration of up to 200 tg [G1u22’25, Leu232831 , Aib29 , Lys26’30]hPTHrP(l-34)NH 2- microneedle array TD microarray patch and 80 jg [GIu 2225 , Leu 23’28’31 , Aib 29 , Lys 26’30]hPTHrP(l -34)NH 2 for Injection appeared to be safe and generally well tolerated by this group of healthy postmenopausal female volunteers.

[Glu22 ’25, Leu 23 ’28 ’31 , Aib 29, Lys 26’30]hPTHrP(1-34)NH2- microneedle array was well tolerated at the application site, with minor irritation consisting mostly of mild erythema and swelling. Note that the comparison of the composite irritancy score between subjects receiving active TD microarray versus placebo indicated that irritancy was not associated with the amount of the active component [Glu 22’25, Leu23 ’28 ’31 , Aib 29, Lys 26’30]hPTHrP(1- 34)NH2 .

Clinical Study Clinical study evaluation of pharmacokinetics of [G1u 22’25 , Leu23 ’28 ’31 , Aib29 , Lys26 ’30]hPTHrP(1-34)NH 2 (ng/mL) LCP-coated microarrays in postmenopausal women.

Study Design Table 35: Arrays used Mmicroneedle Array Description Maxorial of Construction Liquid Crystal Polymer (LCP) Number of Microneedles Flexural Modulus (by ISO 178) 9100 Grade Class VI, medical grade polymer Surface area .5 cm or -27 mm in diameter Depth of Penetration (DOP) 250+/-I0im Height of Microneedles 500im Spacing between Microneedles 550im apart (tip to tip) array loading dosages tested Array 1: 100 jig per array +1- 15 jig per array (104 lLg per array mean) Array 2: 150 jig per array +1- 22.5 jig per array (146 jig per array mean) Arrays were prepared using aqueous formulations of 54 to 58 wt-% [G1u2225 , Leu23 ’28 ’31 , Aib2 , Lys 26’30]PTHrP(1-34)NH 2 and phosphate buffered saline.

A second phase 1 clinical study was conducted utilizing [G1u 22’25 , Aib29 , , Leu238’31 Lys26’30]hPTHrP(l-34)NH 2 coated LCP microarrays in postmenopausal women. The study was designed to evaluate the utility of a new array material (LCP) and shorter application time (10 seconds and 15 minutes) as well as to evaluate the site of administration on relative bioavailability and C m values and pharmacodynamic parameters as occurred in the PCS study discussed above in the previous example.

This second study was a randomized, double-blind, placebo-controlled, single- and multiple-dose safety, PK, and tolerability study of [G1u 22’25, Leu 23 ’28’31 , Aib 29 , Lys26’30]hPTHrP( 1-3 4)NH coated LCP arrays administered transdermally to healthy postmenopausal women.

This study was conducted at 1 study site and consisted of 3 study periods. In Study Period 1, subjects were to receive a single administration of the following: [G1u 22 ’25 , Leu 23 ’28 ’31 , Aib29, Lys 26 ’30]hPTHrP(1-34)NH 2 coated LCP array 100 jig, [G1u 22’25 , Leu 23 ’28 ’31 , Aib29, Lys 26’30]hPTHrP(1-34)NH 2 coated LCP array-Placebo, or a single SC administration of [Glu22 ’25, Leu23 ’28’31 , Aib29, Lys 26 ’30]hPTHrP(I -34)NH 2 for Injection 80 jig. Application sites IMIA were to be either periumbilical or upper thigh regions each with 2 wear times of 10 seconds and 15 minutes. Subjects enrolled in Study Period 2 were to receive [G1u 22 ’25, Leu 232831 , Aib29 , Lys 26 ’30]hPTHrP(1-34)NH 2 coated LCParray 100 or 150 tg or [G1u 22 ’25, Leu238 ’31 , Aib29, Lys 26 ’30]hPTHrP(1 -34)NH coated LCP array -Placebo for 7 consecutive days.

Application sites were to be either periumbilical with 10 second and 15 minute wear times or upper thigh regions with a 15 minute wear time. Subjects enrolled in Study Period 3 were to receive [G1u 22 ’25 , Leu23 ’2831 , Aib29, Lys26 ’30]hPTHrP(1-34)NH 2 coated LCP array 150 tg or [01u22 ’25, Leu23 ’28 ’ 31 , Aib29, Lys 26 ’30]hPTHrP(l-34)NH 2 coated LCP array-Placebo over a range of application times for 7 consecutive days. Application times were to included seconds, 1, 5, 15, 60 minutes, and 24 hours. New subjects were to be enrolled in each study period.

Standard safety evaluations were to be included in this study to ensure the safety of subjects. These safety evaluations were to include physical examinations, vital signs, 12-lead ECGs, clinical laboratory tests, and monitoring and recording of local tolerance and AEs. As a precaution and to ensure that the study procedures were to be performed according to protocol, subjects were to remain under direct supervision during the PK and PD. assessment periods and were not to be released from the clinical facility until the Principal Investigator determined that it was safe to do so.

To facilitate safety and tolerability assessments and to reduce bias in interpretation of results, a randomized, double-blind, placebo-controlled design was utilized. A [G1u 22 ’25 , Leu23 ’28 ’31 , Aib29, Lys 26 ’30]hPTHrP(1-34)N11 2 coated LCP array group size of 6 or 8 subjects per dose level (6 active or 6 active/2 placebo) was chosen as appropriate for an early phase clinical trial of safety and tolerability in which clinical judgment was to be used to determine the enrollment of subjects into subsequent periods. The lowest dose, 100 tg, was administered in the first period. Subjects in subsequent periods were to receive 100 or 150 rig, subject to the safety and tolerability of [Glu 22 ’25, Leu23 ’28 ’31 , Aib29 , Lys26 ’30]hPTHrP(1-34)NH 2 coated LCP array -Active in the preceding period.

Table 36: Arrays used I I Period . . . __. .......... .

Study Frequency Application or WearTime Group of Dosing Dose injection Site Once 100 pg Periumbilical 10 seconds Once 100 pg Periumbilical minutes ic Once 100 pg Upper Thigh 10 seconds id Once lOOpg UpperThigh 15 minutes le Once 80 pg Perlumbllical N/A _100 - Total: Period 2 Study Frequency Application Site Wear Time Group of Dosing Dose Daily X 7 150 pg Periumbillcal 10 seconds Daily X 7 150 pg Periumbilical 15 minutes Daily X 7 100 pg Upper thigh 15 minutes Total: Period 3 __________________ Study Frequency Application Site Wear Time Group of Dosing Dose 3a Daily X 7 150 pg Upper Thigh 5 minutes on Days 1 -6, seconds on Day 7 3b Daily X 7 150 pg Upper Thigh 1 minute on Days 1 -6, 60 minutes on Day 7 3c Daily X 7 150 pg or Upper Thigh 150 pg: Day 1 24 hours 15 Placebo minutes on Day 7.

Placebo: Day 1 24 hours, Days 2, and 3, 4, 5, and 6 for 60, 15 5 1 minute, and 30 seconds, respectively Study Period 1 was to include 4 study groups (1A, 1B, 1C, and 1D) receiving [G1u22’25 , Leu23 ’28’31 , Aib29, Lys 26’30]hPTHrP(1-34)NH 2 coated LCP array 100 jig with embedded [G1u 22’25 , Leu 23 ’28 ’31 , Aib29, Lys 26 ’30]hPTHrP(1-34)NH2 coated LCP array placebo within 2 (lB and 1D) of the 4 study groups and a fifth group (1E) to receive [G1u 22’25 , Leu23 ’2831 , Aib 29, Lys26 ’30]hPTHrP(1 -34)NH 2 for Injection 80 jig. The major purpose of the 4 [G1u22’25 , Leu23’28 ’31 , Aib29, Lys 26’30]hPTHrP(1-34)NH 2 coated LCP array 100 jig study groups was to define the impact of wear time (10 seconds and 15 minutes) and application site , Aib 29 , (periumbilical and upper thigh) on relative bioavailability of [G1u 22’25, Leu23 ’28 ’31 Lys 26 ’30]hPTHrP(1-34)NH2 coated LCP array compared to [G1u 22’25 , Leu23 ’28’31 , Aib29 , Lys26 ’30]hPTHrP(1 -34)NH2 for Injection 80 jig. [G1u 22’25, Leu23 ’28 ’31 , Aib29 , Lys 26 ’30]hPTHrP(1-34)NH 2 for Injection 80 jig administered SC (fifth group, Study Group 1 E) was to serve as a positive control group since this dose has been demonstrated to exhibit relevant in vivo activity. There were to be 6 active and 2 placebo subjects in Study Groups 1B and 1D and only 6 active subjects in each of Study Groups 1A, 1C, and [G1u 22 ’25, Leu2328’31 , Aib29, Lys 26 ’30]hPTHrP(1-34)NH 2 for Injection 80 jig (1E). Pooled placebo treatments from 2 [G1u22’25, Leu 23 ’28’31 , Aib29, Lys 26’30]hPTHrP(1-34)Nl-1 2 coated LCP array groups (lB and 1D) were to serve as control for the safety evaluation.

Study Period 2 was to examine a 50% higher [G1u 22’25, Leu23 ’28 ’31 , Aib 29, Lys26 ’30]hPTHrP( 1 -34)NH2 coated LCP array dose (150 jig) in 2 of 3 study groups. Six (6) subjects in Study Group 2A were to receive [G1u 22 ’25 , Leu 23 ’28’31 , Aib29, Lys 26 ’30]hPTHrP(1- 34)NH2 coated LCP array and 8 subjects in Study Group 2B were to receive [Glu 2225 , Leu23 ’28 ’31 , Aib 29 , Leu 23 ’2831 , , Lys26’30]hPTHrP(1-34)NH 2 coated LCP array and [G1u 22 ’25 Aib 29 , Lys 26’30]hPTHrP(1-34)NH 2 coated LCP array -Placebo for 7 consecutive days with a 6:2 allocation (randomized, double blind). The major goal was to compare 2 different wear times (10 seconds and 15 minutes, administered into the periumbilical region) following single (Day 1) and 7 consecutive days of [G1u 22’25, Leu 23 ’28 ’31 , Aib 29, Lys26 ’30]hPTHrP(1- 34)NH 2 coated LCP array multiple dosing. Additionally, the relative bioavailability of [Glu2 ’2 , Leu23 ’28 ’3 , Aib 29 , Lys 26 ’30]hPTHrP(1-34)NH 2 coated LCP array following Study Groups 2A and 2B was to be compared to [Glu 2225 , Leu 23 ’28 ’31 , Aib 29, Lys26 ’30]hPTHrP(1- 34)NH 2 for Injection 80 .tg (Study Group IE, Study Period 1). A third group [Study Group 2C] involved the [G1u 22’25 , Leu23 ’28 ’31 , Aib 29, Lys 26’30]hPTHrP(1-34)NH 2 coated LCP array 100 jig dose (as in Study Period 1) with 6 subjects receiving [G1u 22’25 , Leu23 ’28 ’31 , Aib29, Lys26 ’30]hPTHrP(1-34)NH 2 coated LCP array dose with a 15 minute wear time for 7 consecutive days.

In Study Period 3, the same 150 tg [G1u 22 ’25, Leu 23 ’28 ’31 , Aib 29, Lys26’30]hPTHrP(1- 34)NH 2 coated LCP array dose as in Study Period 2 (Study Groups 2A and 2B) was further investigated but was administered in the upper thigh region (instead of periunibilical region) with varying wear times. The main goal was to describe the effect of application site and varying wear times on relative bioavailability of [G1u 22’25 , Leu23 ’28’31 , Aib 29, Lys26 ’30]hPTHrP(1-34)NH 2 coated LCP array compared to [G1u 22’25 , Leu 23 ’28’31 , Aib 29, Lys26 ’30]hPTHrP(1-34)NH 2 for Injection 80 Vg (Study Group lB. Study Period 1). Moreover, the effect of varying wear times was to be compared. Subjects in Study Period 3 (Study Group 3A [N = 6] and Study Group 3B [N = 6]) were to receive 150 jig [Glu 22’25 , Leu 23 ’28’31 , Aib 29 , Lys 26 ’30]hPTHrP(1 -34)NH 2 coated LCP array doses with 5 and 1 minute wear times, respectively on Days 1 through 6 and 30 second and 60 minute wear times, respectively, on Day 7. The 8 subjects in Study Group 3C were to receive [G1u 22 ’25, Leu2328 ’31 , Aib29 , Lys26 ’30]hPTHrP(1-34)NH2 coated LCP array and [Glu 22’25 , Leu 23 ’28 ’31 , Aib 29 , Lys 26 ’30]hPTHrP(1-34)NH 2 coated LCP array-Placebo with a 6:2 allocation (randomized, 22’25 , double blind) with a 24 hour wear time on Day 1. All 8 subjects were to receive [G1u Leu2328 ’31 , Aib29, Lys26’30]hPTHrP(1-34)NH2 coated LCP array-Placebo on Days 2, 3, 4, 5, and 6 with 60, 15, 5, and 1 minute, and 30 second wear times, respectively. All 8 subjects were to receive 150 jig [Glu 22’25, Leu23 ’28’3 ’, Aib29, Lys 26 ’30]hPTHrP( 1 -34)NH2 coated LCP array doses on Day 7 with a 15 minute wear time.

Subjects were to meet all of the following inclusion criteria to be eligible to participate in this study.

The subject was to be a healthy postmenopausal woman from 50 to 80 years of age, inclusive. For the purposes of this study, postmenopausal was defined as 2 24 months of spontaneous amenorrhea (not relating to eating disorders or other causes),? 6 months of spontaneous amenorrhea with serum follicle-stimulating hormone (FSH) levels? 40 mIU/mL, or 6 weeks postsurgical bilateral oophorectomy with or without hysterectomy.

In the opinion of the Principal Investigator, the subject was to be in good general health as determined by medical history and physical examination (including vital signs) and without evidence of clinically significant abnormality.

The subject was to have a hemoglobin value> 12.0 g!dL during the screening period.

The subject was to have a serum phosphorus, PTH(1 -84), and a serum total calcium within the normal range during the screening period.

The subject was to have a normal serum alkaline phosphatase (ALP) during the screening visit or, if abnormal but not clinically significant, a normal serum bone-specific ALP.

The subject was to have a 25-hydroxyvitamin D of> 20 nglmL.

In the opinion of the Principal Investigator, the subject was to have all other screening and baseline clinical laboratory tests without any clinically significant abnormality.

The resting 12-lead ECG obtained during screening was to show no clinically significant abnormality of the following intervals: PR: 120 and 220 msec; QRS 120 msec; QTc (Bazett’s correction) < 470 msec. Incomplete right bundle branch block (IRBBB) and left anterior hemiblock (LAB) were acceptable.

The subject’s systolic blood pressure (SBP) was to be? 100 and 155 mmHg, diastolic blood pressure (DBP) was to be 2 40 and 95 mmHg, and heart rate was to be? 45 and < 90 bpm during screening.

. The subject was to weigh at least 120 pounds (54.5 kg) and was to be within 25% and +30% of her ideal body weight (at screening) based on height and body frame.

The subject was to read, understand, and sign the written ICF.

Subjects who met any of the following exclusion criteria were not eligible to participate in the study.

General exclusion criteria: The subject had a history of clinically significant chronic or recurrent renal, hepatic, 40 pulmonary, allergic, cardiovascular, gastrointestinal, endocrine, CNS, hematologic or metabolic diseases, or immunologic, emotional, and/or psychiatric disturbances.

The subject was diagnosed with osteoporosis, Paget’s disease, or other metabolic bone diseases (e.g., vitamin D deficiency or osteomalacia) or was to a non-traumatic fracture that occurred within 1 year prior to the initial screening visit. 45 3.

The subject had a history of urolithiasis within the past 5 years. 4.

The subject had a history of gout or a uric acid value> 7.5 mg/dL during the screening period.

The subject had a decrease of 20 mmHg or more in SBP or 10 mmHg or more in DBP from supine to standing (5 minutes lying and 3 minutes standing) and/or any symptomatic hypotension.

The subject had an acute illness which, in the opinion of the Principal Investigator, could have posed a threat or harm to the subject or obscure laboratory test results or interpretation of study data.

The subject had donated blood, had a blood loss of more than 50 mL within 8 weeks prior to study Day 1, or had a plasma donation (apheresis) within 7 days prior to Day 1. 8.

The subject was known to be positive for hepatitis B, hepatitis C, human immunodeficiency virus (HIV)-1 or HIV-2 or had positive results at screening for hepatitis B surface antigen (HBsAg), hepatitis C antibody (HCV-Ab), or HIV.

The subject had been previously randomized, dosed, and discontinued in this study for any reason.

Medication related exclusion criteria: The subject had a known history of hypersensitivity to any of the test materials or related compounds. 11. The subject used any medication on a chronic basis, including bisphosphonates and estrogens or estrogen derivatives. 12. The subject received any medication, including over-the-counter (OTC), non-prescription preparations or herbal or homeopathic supplements, within 72 hours prior to administration of the first dose of study medication. 13. The subject received a general anesthetic or an investigational product other than [G1u22 ’25, Leu23 ’28 ’31 , Aib29, Lys 26 ’30]hPTHrP(l-34)NH 2 within 90 days prior to the initial dose of study medication. 14. Unwillingness or inability to understand study procedures or commitments as judged by the Principal Investigator.

Lifestyle related exclusion criteria: The subject had an abnormal nutritional status (abnormal diets, excessive or unusual vitamin intakes, malabsorption, or significant recent weight change).

The subject smoked more than 10 cigarettes per day; Subjects were not allowed to consume any nicotine-containing products while they were confined to the clinical facility. 17. The subject had a history of alcohol abuse, illegal drug use, or drug abuse within 40 24 months of the screening visit.

The subject had a positive urine drug/alcohol screen.

Subjects were informed that they had the right to withdraw from the study at any time for any reason, without prejudice to their medical care. The Principal Investigator also had 45 the right to withdraw subjects from the study for any of the following reasons: Adverse events Refusal of treatment Subject request Inability to complete study procedures Lost to follow-up Non-compliance Administrative reasons If a subject was withdrawn or discontinued from the study, the reason for withdrawal from the study was to be recorded in the source documents and on the case report form (CRF). All subjects withdrawn prior to completing the study were to be encouraged to complete the postdose study evaluation scheduled for the study group. All ABs were to be followed to resolution.

Subjects who withdrew from the study for administrative reasons after study medication had been administered may have been replaced at the discretion of the Principal Investigator after consultation with the Medical Monitor.

According to the study protocol, the term study group will be used instead of treatment in the tables, figures, and the text of the report.

The [GIu’25 , Leu23 ’28 ’31 , Aib29, Lys2630]hPTHrP(l-34)NH 2 coated LCP array ([01u22 ’25, Leu23 ’28’31 , Aib 29 , Lys 26’30]hPTHrP(1-34)NH 2 coated LCP array, 100, 150, and 200 jig) ([G1u 22’25, Leu23 ’28 ’31 , Aib 29 , Lys26 ’30]hPTHrP(l-34)NH 2 coated LCP array) was to be supplied in an enclosed collar assembly for loading onto a spring loaded applicator.

The phosphate buffered saline (PBS)-coated array (Placebo-array) was to be similarly supplied in an enclosed collar assembly for loading onto a spring loaded applicator.

[G1u22’25, Leu 23 ’28’3 , Aib29, Lys2630]hPTHrP(l-34)NH 2 for Injection 80 jig was to be supplied as a multi-dose cartridge (1.5 mL) containing 2 mg/mL [Glu 22 ’25, Leu23 28 ’31 , Aib29, Lys26 ’30]hPTHrP(1-34)NH 2 (free base) in mg/mL tn-hydrate sodium acetate and 5 mglmL of phenol (preservative) adjusted at pH 5.1 with acetic acid.

The pen injector is a modified version of the Becton Dickinson Pen II device and has been validated for use with [G1u 22’25, Leu23 ’28 ’31 , Aib29, Lys 26 ’30]hPTHrP(1 -34)NH2 in its pre- filled cartridge.

Study Period I Study Group 1A = 1 x 100 jig [G1u22’25, Leu23 ’28 ’31 , A1b29, Lys 26’30]hPTHrP(1-34)NH2 -sMTS was to be administered into the periumbilical region via a TD delivery system (TD microarray) with 10 second wear time.

Study Group I = I x 100 p.g [G1u 22 ’25, Leu 23 ’28 ’31 , Aib29, Lys2630]hPTHrP(l-34)NH2 -sMTS was to be administered into the periumbilical region via a TD delivery system (TD microarray) with 15 minute wear time.

Study Group 1C = I x 100 jtg [G1u 22 ’25 , Aib 29, Lys 26 ’30]hPTHrP(1-34)NH2 -sMTS , Leu 2328’31 was to be administered into the upper thigh region via a TD delivery system (TD microarray) with 10 second wear time.

Study Group 1D = I x 100 Vig [G1u , Lys 26’30]hPTHrP(1-34)NH2 -sMTS 22 ’25, Leu 23 ’2831 , Aib 29 was to be administered into the upper thigh region via a TD delivery system (TD microarray) with 15 minute wear time.

, Lys26 ’30]hPTHrP(1-34)NH2 was to be Study Group 1E = I x 80 g [G1u 22’25, Leu23 ’28 ’31 , Aib29 administered into the periumbilical region in a single SC injection.

Placebo = placebo was to be administered into the periumbilical/upper thigh region via a TD delivery system (TD microarray) with 15 minute wear time.

Study Period 2 Study Group 2A = 1 x 150 jig [G1u 22 ’25 , Leu23 ’28 ’31 , Aib 29, Lys26 ’30]hPTHrP(1-34)NH2 -sMTS was to be administered into the periumbilical region via a TD delivery system (ID microarray) with 10 second wear time daily for 7 days.

Study Group 2B = 1 x 150 tg [G1u 22’25, Leu2328’31 , Aib 29, Lys 26 ’30]hPTHrP(1-34)NH2 -sMTS was to be administered into the periumbilical region via a ID delivery system (TD microarray) with 15 minute wear time daily for 7 days.

, Aib 29, Lys 26 ’30]hPTHrP(l-34)NH2 -sMTS Study Group 2C = 1 x 100 p.g [G1u 22’25, Leu 23 ’28 ’31 was to be administered into the upper thigh region via a TD delivery system (TD microarray) with 15 minute wear time daily for 7 days.

Placebo = placebo was to be administered into the periumbilical region via a TD delivery system (TD microarray) with 15 minute wear time daily for 7 days.

Study Period 3 Study Group 3A = 1 x 150 .ig [G1u22’25 , Leu23 ’28 ’31 , Aib 29, Lys 26’30]hPTHrP(1-34)NH 2 -sMTS was to be administered into the upper thigh region via a TD delivery system (TD microarray) with minute wear time on Days 1 through 6 and 30 second wear time on Day 7.

Study Group 3B = 1 x 150 tg [G1u 22’25, Leu2328 ’31 , Aib 29 , Lys 26 ’30]hPTHrP(1-34)NH 2 -sMTS was to be administered into the upper thigh region via a TD delivery system (TD microarray) with 1 minute wear time on Days 1 through 6 and 60 minute wear time on Day 7.

Study Group 3C = I x 150 tg [G1u 22’25 , Leu23 ’28 ’31 , Aib 29, Lys 26 ’30]hPTHrP( 1 -34)NH 2 -sMTS was to be administered into the upper thigh region via a TD delivery system (TD microarray) with 24 hour wear time on Day 1 and 15 minute wear time on Day 7.

Placebo = placebo was to be administered into the upper thigh region via a TD delivery system (ID microarray) with 24 hour wear time on Day 1 and 60, 15, 5, 1 minute, and 30 second wear times on Days 2, 3, 4, , 6, respectively.

Method of Assigning Patients to Treatment Groups The study employed a double randomization procedure. A specific study group was assigned to subjects according to the subject number and randomization code. This assignment was not blinded. Secondly, the subject was assigned to active drug versus placebo and this assignment was double blind.

A total of 34 subjects planned for Study Period 1 were assigned to 5 study groups.

The study groups included 4 groups (1A, 1B, 1C, and 1D) who received [G1u 22 ’25 , Leu23 ’28’31 , Aib 29 , Lys 2630]hPTHrP(1-34)N}1 2 -sMTS 100 ptg with varying wear times (10 seconds and 15 minutes) and applications sites (periumbilical and upper thigh). Six subjects were randomly assigned to each of Study Groups 1 A and IC and 8 subjects were randomly assigned to each of Study Groups I and 1D. While 6 subjects in each of Study Groups 1 and 1D were randomized to receive [G1u 22 ’25, Leu23 ’28’31 , Aib29, Lys 26’30]hPTHrP(l-34)NH2-sMTS 100 gg, 2 subjects in each group were randomly assigned to receive [G1u 22’25, Leu23 ’28’31 , Aib 29 , Lys2630 ]hPTHrP(1 -34)NH2 -sMTS-Placebo. A fifth group (Study Group 1 E, N = 6) was randomized to receive [G1u 22 ’25 , Leu23 ’28’31 , Aib29, Lys 26 ’30]hPTHrP(l-34)NH 2 for Injection 80 Twenty (20) Subjects planned for Study Period 2 were randomly assigned to 3 study groups. Six (6) subjects were assigned to Study Group 2A to receive [G1u 22’25 , Leu23 ’28 ’31 , Aib 29 , Lys 26’30]hPTFIrP(1-34)NJ-1 2 -sMTS 150 ig in the periumbilical region with a 10 second wear time for 7 consecutive days. Eight (8) subjects were assigned to Study Group 2B, 6 subjects received [G1u 22 ’25, Leu232831 , Aib 29, Lys 26’30]hPTHrP(1-34)NH 2 -sMTS 150 ftg in the periumbilical region with a 15 minute wear time and 2 subjects received a corresponding [G1u 22’25 , Leu 23 ’28’3 , Aib29 , Lys 26’30]hPTFIrP(1-34)NH 2 -sMTS-Placebo for 7 consecutive days. Six (6) subjects were assigned to Study Group 2C to receive [G1u 22’25 , Leu23 ’28 ’31 , Aib29, Lys26 ’30]hPTHrP(1-34)NH 2 -sMTS 100 ig in the upper thigh with a 15 minute wear time for 7 consecutive days.

Twenty (20) subjects planned for Study Period 3 were randomly assigned to 3 study groups. Six (6) subjects were assigned to Study Group 3A to receive [G1u 22’25 , Leu23 ’28 ’31 , Aib29, Lys 26’30]hPTHrP(1-34)NH 2 -sMTS 150 ig in the upper thigh for 7 consecutive days with a 5 minute wear time (Days 1 - 6) and a 30 second wear time (Day 7). Six (6) subjects were assigned to Study Group 3B to receive [G1u 22’25, Leu23 ’28’31 , Aib29, Lys26’30]hPTHrP(1- 34)NH2 -sMTS 150 .tg in the upper thigh for 7 consecutive days with a 1 minute wear time (Days 1 - 6) and 60 minute wear time (Day 7). Subjects in Study Group 3C (N = 8) were randomized to receive 1 application of [G1u 22’25, Leu23 ’28’31 , Aib29, Lys 26 ’30]hPTHrP(1 -34)NH2 -sMTS 150 ptg (N = 6) or [G1u 22 ’25, Leu23 ’28 ’31 , Aib29, Lys 26’30]hPTHrP(1-34)NH 2 -sMTS- Placebo (N = 2) with a wear time of 24 hours administered to the upper thigh on Day 1.

These 8 subjects subsequently received 5 consecutive days of [G1u 22’25 , Leu23 ’28 ’31 , Aib29, Lys 26’30]hPTHrP( 1 -34)NH 2 -sMTS-Placebo application administered to the upper thigh over a range of wear times (60, 15, , 1 minutes and 30 seconds on Days 2- 6, respectively), followed by a single dose of [G1u 22’25 , Leu 23 ’28’31 , Aib 29, Lys 26 ’30]hPTHrP(1-34)NH2 -sMTS 150 .1g (N = 8) with a wear time of 15 minutes applied to the upper thigh on Day 7.

Study Periods I and 2 were separated by approximately 28 days to allow for a safety review, analysis of PK samples, and calculation of bioavailability. Study Periods 2 and 3 were separated by an approximately 7-day interval to review safety. New subjects were to be enrolled for each period. All study subjects for Study Periods 2 and 3 had a maximum of 7 study drug administrations.

Selection of Doses in the Study [G1u22’25 , Leu 23 ’28 ’31 , Aib 29, Lys 26 ’30]hPTHrP(1-34)NH 2 -sMTS Active and [G1u22’25, Leu23 ’28 ’31 , Aib29, Lys 26’30 ]hPTHrP( 1 -34)NH2 -sMTS-Placebo [G1u22 ’25, Leu 23 ’28 ’31 , Aib 29, Lys 26’30]hPTHrP( 1 -34)NH 2 -sMTS The [G1u22’25 , Leu 23’28 ’31 , Aib 29, Lys 26’30]hPTHrP(l-34)NH 2 -coated sMTS microneedle array was enclosed in a collar assembly for loading onto a spring loaded applicator. The [Glu 22’25 , Leu 23 ’28 ’31 , Aib 29 , Lys 26’30]hPTHrP(l-34)NH 2 -sMTS was removed from refrigeration 1 hour prior to application and was loaded onto the applicator by the pharmacist or qualified study personnel for subject dosing. Each [G1u 22’25, Leu23 ’28 ’31 , Aib29 , Lys 26 ’30]hPTHrP(1-34)NH -sMTS was coated with 100 or 150 .tG[Glu 22 ’25 , Leu 23 ’28’31 , Aib 29 , Lys 26 ’30]hPTHrP(1 -34)NH [G1u22 ’25 , Leu23’28’3 , Aib 9, Lys 26’30]hPTHrP( 1 -34)NH 2 .-sMTS-Placebo The PBS was formulated as a placebo for TD administration using an sMTS. The PBS-coated sMTS (Placebo-sMTS) was enclosed in a collar assembly for loading onto a spring loaded applicator. The Placebo-sMTS was removed from refrigeration 1 hour prior to application and was loaded onto the applicator by qualified study personnel for subject dosing.

[Glu 22 ’25 , Leu 23 ’28 ’31 , Aib 29, Lys 26 ’30]hPTHrP(1-34)NH 2 for Injection 80 tg Each multi-dose cartridge contained 2 mg/mL [Glu 22’25, Leu23’28’3 , Aib2, Lys26 ’30]hPTHrP(1-34)NH 2 (free base) in 5 mg/mL tn-hydrate sodium acetate and mg/ml, of phenol (preservative) adjusted at pH 5.1 with acetic acid. [G1u 22’25, Leu238’31 , Aib29 , Lys26 ’ 30]hPTHrP(1-34)NH for Injection 80 jtg was supplied as a liquid in a 1.5 mL Type 1 glass cartridge and was stored refrigerated at – 3C. The multi-dose cartridge was designed to deliver a dose of 80 .ig of [Glu 22 ’25, Leu23 ’28 ’31 , Aib29 , Lys 26 ’30]hPTHrP(1-34)NH 2 in 40 ml, of fluid when inserted into the pen injector device (BD Pen II). The multi-dose cartridge was designed to deliver a dose of 80 pg of [0lu 22’25, Leu23’28’31 , Aib29 , Lys 26 ’30]hPTHrP(1-34)NH2 in 40 mL of fluid when inserted into the pen injector device (BD Pen II). The 80 tg cartridge was removed from refrigeration 1 hour prior to application.

Selection and Timing of Dose for Each Patient In Study Period 1, 34 subjects were randomized into I of 5 study groups of varying application sites and wear times for [Glu 22’25, Leu23 ’28’31 , Aib29, Lys 26 ’30]hPTHrP(1-34)NH 2- sMTS 100 rig, or into a study group that received [G1u 22’25, Leu 23 ’28’31 , Aib29 , Lys 26 ’30]hPTHrP(1-34)NH 2 for Injection 80 tg. The application sites were in the periumbilical region and the upper anterior thigh and the wear times for [G1u 22’25, Leu23 ’28 ’31 , Aib 29, Lys26 ’30 ]hPTHrP(l-34)NH 2 sMTS 100 jig were 10 seconds and 15 minutes. For all subjects in this period randomized to the Glu 22 ’25 , Leu23’28’31 , Aib29, Lys26’30]hPTHrP(1- 34)NH2 -sMTS groups, there was a single application and the dose of G1u 22 ’25, Leu23 ’28 ’31 , Aib 9 , Lys 26’30]hPTHrP([-34)NH 2 ..sMTS was to remain constant at 100 jig. In Study Group 1A, 6 subjects were administered Glu 22 ’25, Leu23 ’28’31 , Aib29, Lys 26’30]hPTHrP(1- 34)NH2-sMTS 100 jig in the periumbilical region for 10 seconds. In Study Group 1B, 6 subjects were randomized to receive G1u 22 ’25 , Leu 23 ’28 ’31 , Aib29, Lys 26 ’30]hPTHrP(l- 34)NH2-sMTS 100 jig applied in the periumbilical region for 15 minutes and 2 subjects received a corresponding sMTS-Placebo, also administered in the periumbilical region for 15 minutes. In Study Group 1C, 6 subjects were administered G1u 22 ’25, Leu23 ’28’31 , Aib29 , 26’30]hPTHrP(1-34)NH 2 100 jig in the upper thigh for 10 seconds, In Study Group 1D, 6 subjects were randomized to receive G1u 22’25, Leu 23’28 ’31 , Aib 29, Lys 26’30]hPTHrP(l-34)NH 2- sMTS 100 jig applied to the upper thigh for 15 minutes and 2 subjects received a corresponding G1u 22’25 , Leu 23 ’28 ’31 , Aib29 , Lys 26’30]hPTHrP(1-34)NH2-sMTS-Placebo, also administered in the upper thigh for 15 minutes. In addition, 6 subjects were to receive Glu22’25, Leu23 ’28’31 , Aib 29 , Lys26’30]hPTHrP(1-34)NH 2 for Injection 80 jig, administered SC (Study Group I E) into the periumbilical region.

Prior to proceeding to the next dose, safety and tolerability data from subjects enrolled in earlier periods were reviewed for suitability to escalate to the next higher dose. If the bioavailability of the single-dose administration of Glu 22 ’25, Leu23 ’28 ’31 , Aib29 , Lys 26’30]hPTHrP(1-34)NH2 sMTS 100 jig was greater than 66% of the SC 80 jig dose in Study Period 1, the 150 jig dose was not administered.

In Study Period 2, 20 subjects were dosed once daily for 7 consecutive days with G1u 22 ’25, Leu 23 ’28 ’31 Aib29, Lys26’30]hPTHrP(l-34)NH 2 9 -sMTS 100 or 150 jig. In Study Group 2A, 6 subjects were randomized to receive Glu 2225 , Leu23 ’28 ’3 , Aib29, Lys 26’30]hPTHrP(1- 34)NH2 -sMTS 150 jig applied to the periumbilical region with a wear time of 10 seconds. In Study Group 2B, 6 subjects were randomized to receive Glu 22’25, Leu23 ’28’31 , Aib 29 , Lys 26 ’30]hPTHrP(l-34)NH 2 -sMTS 150 jig applied to the periumbilical region for 15 minutes and 2 subjects received a corresponding G1u 22’25, Leu23 ’28 ’31 , Aib 29, Lys 26’30]hPTHrP(l- 34)NH2-sMTS-Placebo, also administered in the periumbilical region for 15 minutes. In addition, 6 subjects in Study Group 2C were to be randomly assigned to receive G1u 22’25 , Leu2328 ’31 , Aib 29, Lys 26’30]hPTHrP(l-34)NH 2-sMTS 100 jig at an application site (either periumbilical or upper thigh) and for a wear time (either 10 seconds or 15 minutes) to be determined by the PK results obtained from Study Period 1.

Prior to proceeding to the next dose, safety and tolerability from subjects enrolled in earlier periods were reviewed for suitability to escalate to the next higher dose. If the bioavailability of the single-dose administration of G1u 22’25 , Leu2328’31 , Aib29 , Lys26’30]hPTHrP(1-34)NH 2-sMTS 100 Vg was greater than 50% of the SC 80 [tg dose in Study Period 1, the 200 .ig dose was not to be administered.

Protocol Amendment 4 was enacted to conduct a time-course study to optimize the duration of G1u 2225 , Leu23 ’28 ’31 , Aib 29, Lys 2630]hPTHrP(l-34)NH2-sMTS application within the G1u22’25, Leu2328 ’31 , Aib 29 , Lys 26’30]hPTHrP(1-34)NH2-sMTS 150 ig dose groups.

Study Period 3 was to dose a total of 20 subjects. Subjects randomized to Study Group 3A (N = 6) were to receive Glu 2225, Leu 23 ’28’31 , Aib29, Lys 2630]hPTHrP(l-34)NH2 150 gig administered in the upper thigh with a wear time of 5 minutes for 6 consecutive days, followed by a single administration of Glu 22’25, Leu 23 ’28’31 , Aib29, Lys 26’30]hPTHrP(1- 34)NH2150 [tg with a wear time of 30 seconds, also applied to the upper thigh on Day 7.

Subjects randomized to Study Group 3B (N = 6) were to receive Glu 22’25, Leu2328 ’31 , Aib 29 , Lys26 ’30 ]hPTHrP(l -34)NH2-sMTS 150 gig administered to the upper thigh with a wear time of 1 minute for 6 consecutive days followed by a single administration of G1u , Leu23’28 ’31 , 22’25 Aib29, Lys 26’30]hPTHrP(l-34)NH 2-sMTS 150 gig with a wear time of 60 minutes, also applied to the upper thigh on Day 7. Subjects randomized to Study Group 3C (N = 8) received I application of Glu 22’25, Leu 23 ’28’31 , Aib29, Lys 26 ’30]hPTHrP(1-34)NH2-sMTS 150 gig (N = 6) or sMTS-Placebo (N = 2) with a wear time of 24 hours applied to the upper thigh on Day 1.

These 8 subjects subsequently received 5 consecutive days of placebo application over a range of wear times (30 seconds and 1, 5, 15, and 60 minutes), followed by a single dose of G1u 22’25, Leu23 ’28’31 , Aib 29 , Lys 26’30]hPTHrP(1-34)NH 2-sMTS 150 gig (N = 8) with a wear time of 15 minutes applied to the upper thigh on Day 7.

Prior and Concomitant Therapy Vitamin D (< 800 IIJ/day), calcium supplements (< 1000 mg/day), and low-dose aspirin ( 81 mg/daily for prophylaxis of cardiovascular disease) were acceptable as long as the subject had been on a stable dose for 1 month prior to the initial screening visit and remained on the same dose(s) throughout the study. Thyroid replacement therapy was allowed if the subject had been on a stable dose for at least 6 months and remained on the same dose throughout the study. Statins for lowering blood cholesterol levels were allowed as long as the subject had been on a stable dose for at least 3 months and remained on the same dose throughout the study.

Subjects were not to take any other medications, including OTC medications, herbal medications, or mega-doses of vitamins during the study without prior approval of the Principal Investigator. The occasional use of OTC medications (e.g., ibuprofen or acetaminophen) for headache or minor discomfort was allowed if discussed with the Principal Investigator and recorded in the CRF.

If it became necessary for a subject to take any other medication during the study, the specific medication(s) and indication(s) were to be discussed with the Principal Investigator.

All concomitant medications taken during the course of the study were to be recorded in the source documents and transcribed into the subject’s CRF.

In addition, subjects were ineligible for the study if they received general anesthesia within the past 3 months, received an investigational drug within 90 days prior to the initial dose of study medication, took any medications on a chronic basis, or had an abnormal nutritional status (abnormal diets, excessive or unusual vitamin intakes, or malabsorption).

Treatment Compliance In order to evaluate the safety, tolerability, and PK of the study drug, it was critical that subjects received each dose of study medication as directed. The date and time that each dose of study drug was administered was to be recorded. All doses of study medication were to be administered at the clinical facility by qualified personnel under direct observation.

If a subject did not wear the microarray for the intended duration or take all study medication, the reason for the missed dosing was to be recorded on the CRF and in the source documents.

Primary Pharmacokinetic and Pharmacodynamic Parameters Pharmacokinetics The following PK parameters were to be calculated from individual plasma concentration-time G1u 22 ’25, Leu23 ’28 ’31 , Aib 29, Lys 26 ’30]hPTHrP(l-34)NH2 data based on actual time using noncompartmental methods using WinNonlin Version .0.1 and SAS ﬁ Version 9.1: Study Periods 1, 2, and 3 - Day 1 (Single Dose) Area under the drug concentration-time curve, calculated using linear trapezoidal summation from time zero to time t, where t was the time of the last measurable concentration (C 1).

AUCOO Area under the drug concentration-time curve from time zero to infinity.

AUC AUC 1 where X, was the terminal elimination rate = + constant. The parameter was be displayed as AUC O1nf in SAS.

AUCR Ratio of AUC 11 to AUCO3 Cm8x Maximum observed drug concentration Tmax Time of the observed maximum drug concentration TIast Time of the last quantifiable drug concentration Apparent elimination rate constant, estimated by linear regression of the terminal linear portion of the log concentration versus time curve. The parameter was displayed as Lambda _z in SAS.

Apparent elimination half-life, calculated as ln(2)IX CL/F Apparent clearance, calculated as Dose/AUC Vd/F Apparent volume of distribution (Vd/F), calculated as CUF/?.

Relative Relative bloavailability was to be calculated as the ratio of dose bloavailability normalized AUC values: [AUC 0., (F rei ) (transdermal)/Dose(transdermal)}/[Mean AU C (SC)iDose(SC)]-Study 0 ..

Periods 1 2, and 3 - Day 1.

Study Periods 2 and 3 Day 7 (Multiple Dose) In addition to the above parameters (except AUC0), the following PK parameters were to be computed using the same method: Area under the drug concentration-time curve, calculated using linear trapezoidal AUC O., summation from time zero to time x, where t was the dosing interval (24 hr).

AR, Accumulation ratio (AR 1 ), calculated as C Day 7/C m5x , Day I - Study Period 2 max , (2a, 2b, and 2c) only.

AR, Accumulation ratio (AR Day 7/AUC, Day I - Study 2), calculated as AUC O3 Period 2 (2a, 2b, and 2c) only.

Linearity factor (LF) = AUC Day 7/AUC O, Day 1 - Study Period 2 (2a, 2b, and Moreover, CL SS/F and V SS/F were to be calculated following multiple dosing for Day respectively. 7, wherever applicable but were to be presented as CL/F and Vd/F, The following footnotes were to be added, wherever applicable, on Day 7 PK parameter tables.

CL/F following multiple dosing was computed as Dose/AUC0 VdIF following multiple dosing was computed as MRT*CL SS Pharmacodynamics The following PD parameters were to be computed for total serum calcium and serum phosphorus using SAS ﬁ Version 9.1: Study Periods 1, 2, and 3 - Days 1 and 7 Original/Change From Parameter Description Baseline Data Original C,,,,jm , Minimum and maximum observed serum concentration Original Time of the first occurrence of the minimum or maximum serum concentration Change From Baseline Maximum change from predose (0 hour). Note: Day 1 Amax predose was to be used as baseline.

The parameter was to be displayed as Delta Max in SAS.

Change From Baseline Tma, Time of maximum change from predose (0 hour). The - parameter was to be displayed as T mox in SAS.

Note: For 1,25-dihydroxyvitamin D, CTX, and PIN?, Day 1 predose was to be used to compute change from baseline for Days 3 and 7.

Table 37 Summary of Plasma G1u 22’25, Leu23’28’31, Aib29, Lys 26’30JhPTHrP(1- 34)NH2Pharmacokinetjc Parameters Following Glu 22’2 , Len 23’28’31 , Aib29, )NH2Study Groups and GIn 22’25 , Aib29, Lys 26’30 , Len 23 ’28 ’31 IhPTHrP( 1.34 Lys 26’30JhPTHrP(1-34)NH 2 for Injection 80 jig (Study Period 1) Study Group lA Study Group LB Study Group IC Study Group ID Study Group 1E Pharmacokinetic Mean – SD Mean :L SD Mean – SD Mean – SD Mean :L - SD Parameters (N) (N) (N) (N) C. (pglmL) 292–167 401 –212 303– 139 676–257 452– 189 (6) (6) (6) (6) T.., (hr) 0.130 (0.0775. 0.164) 0.163 (0.0856, 0.160 (0.0808, 0.163 (0.161, 0.422 (0.246, 1.01) 0.175) 0.166) 0.170) (6) (6) (6) (6) (6) 1.42– 1.32 fl,,, (hr) 1.09–0.363 1.26–0.693 1.85–0.701 3.51 –0.546 (6) (6) (6) (6) (6) (pg*hr/m L) AUC 0.1 126–89.9 132–66.6 134– 105 247–66.4 5841219 (6) (6) (6) (6) 142.1 – 10 1. 7 142.4 – 67.94 150.8 – 116.4 268.9– 74.31 633.3 – 226.2 (pg *hr/mL) (6) (6) (6) (6) AUC0., 142.1110 1. 6 633.1 – 226.0 142.4 – 67.92 150.7 – 116.3 268.8 – 74.16 (pg*hr/mL) (6) (6) (6) (6) AUC0.1,.1/dose 1.42–1.02 1.42–0.679 1.51 – 1.16 2.69–0.743 7.92–2,83 (pg*hr/m1Jjg) (6) (6) (6) (6) (6) ’UCo.jdose 1.42– 1.02 1.42–0.679 1.51+ 1.16 1 2.69–0.742 7.91 –2.83 (pg*hrlm L/jIg) (6) (6) (6) (6) (6) to (hr) 0.466 – 0.417 0.302 – 0.0821 0.405 – 0.196 0.571 – 0.297 0.970– 0.185 (6) (6) (6) (6) (6) Lambda_z (1/hr) 2.38.+1.49 2.5311.05 2.29-+1.60 1.46–0.621 0.744–0.185 (6) (6) (6) (6) (6) AUCR 0.877 – 0.0317 0.915 – 0.0309 0.871 -10.0616 0.919 – 0.0138 0.916 – 0.0471 (6) (6) (6) (6) (6) CL/F (L/hr) 1143 – 999.5 869.5 – 457.3 1114 – 819.5 402.6 – 138.0 140.6 – 49.21 (6) (6) (6) (6) (6) Vd/F (L) 491.1 – 207.7 337.4 – 96.41 467.3 – 159.7 297.9 – 86.25 197.0 – 86.21 (6) (6) (6) (6) (6) T. is presented as Median (Minimum, Maximum) Study Group IA: 1 x 100 jig Glu 12 , Leu2283 , Aib 29, Lys 26’30]hPTHrP(1- 34)NH2sMTS, 10 Second Wear Time (Periumbilical) LCU 21.29.3 Study Group IB: I x 100 jig GIu222, Aib 29, Lys 26’30]hFTHrP(1- 34)Nl-I 2 sMTS, 15 Minute Wear Time (Periumbilical) Study Group IC: I x 100 jig GIu 22 ’2 , Leu 2328 ’31 , Aib 29, Lys 2630JhPTHrP(1.34)NH 2 sMTS), 10 Second Wear Time (Upper Thigh) Study Group ID: I x 100 jig G1u 22’25 , Leu 23 ’283 , Aib 29, Lys 2630]hPTHrP(I -34)NH 2 sMTS, 15 Minute Wear Time (Upper Thigh) Leu2),2i3t, Study Group IE: I x 80 jig G1u 22 ’2’, A09, Lys 26’30]hPTHrP(1-34)NH 2 SC injection (Periumbilical) G1u22’25 , Leu 23 ’28 ’31 , Aib29, Lys26 ]hPTHrP(1-34)NH 2 was characterized by a rapid absorption as mean C,,, a,, was achieved within 0.163 hours (-40 minutes) following G1u 22’25 , Leu 23 ’28’31 , Aib 29 , Lys 26’30]hPTHrP(1-34)NT-1 2-sMTS 100 [ig study groups and at 0.422 hours (-’25 minutes) following G1u 22’25, Leu23 ’28’31 , Aib29, Lys 26’30]hPTHrP(1-34)NH2for Injection 80 tg (Study Group IE). Moreover, [G1u 22 ’25, Leu232831 , Aib 29, Lys 26’30]hPTHrP(1-34)NH2 had a short half-life with mean t112, ranging from 0.302 hours (--18 minutes) to 0.571 hours (-34 minutes) following the G1u 22’25 , Leu23 ’28’31 , Aib 29, Lys26 ’30]hPTHrP(1-34)NH 2-sMTS study groups and at 0.970 hours (--’58 minutes) following Study Group 1E.

Mean peak exposure as measured by at 401 pg/mL following G1u 22 ’25, Leu23’28 ’31 , Cmax Aib 9, Lys 26’30 ]hPTHrP( 1 -34)NH2-sMTS 100 tg administered to periumbilical region with 15 minute wear time (Study Groups 1 B) was relatively comparable to mean peak exposure following G1u22’25 , Leu23 ’2831 , Aib29, Lys 26’30]hPTHrP(l-34)NH 2 for Injection 80 g (Study Group 1E) at 452 pg/mL, but was higher compared to GIn 22 ’25, Leu23 ’28’31 , Aib29, 26’30]hPTHrP(1-34)NH 2-sMTS 100 jg applied to periumbilical or upper thigh regions with 10 second wear time (Study Groups 1A and 1C) at 292 pglmL and 303 pg/mL, respectively.

The highest mean peak exposure at 676 pg/mL was observed following Glu 22’25 , Leu23 ’28’31 ,Aib29, Lys 26’30]hPTHrP(l-34)NH2-sMTS 100 tg administered to upper thigh region with 15 minutes wear time (Study Group 1D). Subject 110 with a peak concentration of 1140 pglmL (-2 times the average peak values of other subjects in this study group), probably contributed to the high Cm value of Study Group 1 D.

The highest mean total exposure (as measured by AUCo) resulted following G1u 22’25 , Leu23 ’28 ’31 , Aib 29, Lys 26’30]hPTHrP(1-34)NH 2 for Injection 80 g (Study Group 1E) at pg*/mL pg*hr/mL, Study Group 1C, at 633.3 followed by Study Group 1D, at about 268.9 pg*hrlmL, pg*hr/mL.

The lower 150.8 and Study Groups 1A and lB at approximately 142 clearance value for Study Group 1E might been the result of higher total exposure for this study group as compared to Glu , Aib29, Lys26 ’30]hPTHrP(1-34)NH2-sMTS 22 ’25, Leu23 ’28 ’31 study groups.

Mean time to the last detectable plasma G1u 22 ’25 , Leu23’28’31 , Aib29, Lys26’30]hPTHrP(l- 34)NH2 concentrations ranged from 1.09 to 1.86 hours following G1u22 ’25 , Leu 23 ’28 ’31 , Aib29, Lys 26’30]hPTHrP(l.-34)NH2-sMTS study groups and was 3.51 hours following Study Group 1E.

Apparent total body clearance ranged from 402.6 to 1143 L/hr following G1u 22 ’25 , Leu23 ’28 ’31 , Aib29 , Lys 26 ’30]hPTJ-frP(1-34)NH2..sMTS study groups and was lower at 140.6 L/hr following Study Group 1E (SC injection).

Plasma G1u22 ’25 , Leu 23 ’28 ’31 , Aib 29 , Lys26’30]hPTHrP(l-34)NI-12 PK parameters following G1u22 ’25, Leu 23 ’28’31 , Aib29, Lys 26’30]hPTHfP(l-34)NH2-sMTS study groups on Days 1 and in Study Period 2 are summarized in Tables 38 and 39.

Table 38 Summary of Plasma G1u 22’25, Leu 23’28’31 , Aib 29, Lys 26’301hPTHrP(1-34)NH2 Pharmacokinetic Parameters Following Gin 22’25, Leu2 ,28,31, Aib29, Lys 26’30 JhPTHrP(1-.34)NH2Study Groups (Study Period 2) - Day 1 __________ Study Group 2A Study Group 2B Study Group 2C Pharmacokinetic Mean – SD Mean – SD – Mean SD Day Parameters (N) (N) (N) 1 C. (pg/mL) 380–191 4701203 317–80.6 (6) (5) (hr) 0.164 (0.0836, 0.248) 0.179 (0.164, 0.242) 0.201 (0.0856, 0.348) (6) (5) (6) IT,.,, (hr) 1.69–1.27 2.83-+1.92 1.28–0.424 ____________ (6) (5) (6) WCO.L (pg*hr/mL) 236–229 462 – 577 154 – 69.3 (6) (5) (6) UC0.1,1 (pgthr/mL) 268.6 – 264.7 236.8 – 102.3 176.9 – 86.89 (6) (4) (4) AUCO thU (pghr/mL) 268.3 – 264.2 236.8 – 102.3 176.8 – 86.84 (6) (4) (4) AUCos/dose(pg*hr/mLJ 1i g) 1.79–1.76 1.58–0.682 1.7710.869 (6) (4) (4) /dose (pg*hr/m1J1g) AUC() 1.79 – 1.76 1.58 – 0.682 1.77 – 0.868 (6) (4) (4) ti,, (hr) 0.568–0.471 0.761 –0.361 0.402–0.126 (6) (4) (4) Lambdaz (1/hr) 2.09+ 1.57 1.06 – 0.436 1.84 – 0.495 (6) (4) (4) AUCR 0.883 – 0.0201 0.873 – 0.0332 0.898 – 0.0169 (6) (4) (4) CL/F(L/hr) 1167–1046 716.3–264.9 666.2–284.4 (6) (4) (4) Vd/F (L) 516.4 – 112.7 718.2– 224.1 365.8 – 127.8 (6) (4) (4) T_ is presented as Median (Minimum, Maximum) 23253t Study Group 2A = I x 150 ltg G1u 2225, Leu , Aib 29, Lys’6 ’]hPTJ-lrP(l -34)NH - sMTS, 10 Second Wear Time Daily for 7 Days (Periumbilical) Leu2328,31, Study Group 2B = I x 150 sg Glu"’ 5, Aib29, Lys2630]hPTHrP(1-34)NH -sMTS, 15 min Wear Time Daily for 7 Days (Periumbilical) LeuSSS&S, Study Group 2C = I x 100 ig Glu 1225 , Aib29, Lys" 30]hPTHrP(1-34)NFI 2 -sMTS, 15 min Wear Time Daily for 7 Days (upper thigh) Subject 204 was excluded from summary statistics for having un-measurable and missing concentration values.

= Value missing or not reportable.

Table 39 Summary of Plasma G1u 22’25 , Leu 23’28’31 , Aib 29, Lys 26’301hPTHrP(1 -34)NTI2 Pharrnacokinetic Parameters Following G1u 22’25, Leu2 ,28,31 Aib29, Lys 26’30]hPTHrP(1-34)NH2Study Groups (Study Period 2) - Day Study Group 2A Study Group 2B 2C Study Group Pharmacokipetic Mean – SD – – Mean SD Mean SD Day Parameters (N) (N) (N) 7 , (pg/mL) 144–180 412– 172 359– 125 (6) (6) (6) ’,,, (hr) 0,166 (0.161. 0.179) 0.172 (0.0978, 0.203) 0.159 (0.0839. 0.220) (5) (6) T i..,(hr) 1.091- 1.19 2.37+ 1.37 1.51 – 0.526 (5) (6) (6) (pg*hr/mL) AUC0. 1 99.2 -1 168 260 – 209 165 – 67.4 (6) (6) (6) (pg*hr/mL) UC0. 219.3 – 215.2 318.1 – 283.3 184.3 – 69.95 (3) (4) (6) (pg*hr/mL/pg) ’UCo.Idose 1.46– 1.43 2.12– 1.89 1.84–0.699 (3) (4) (6) t (hr) 0.572–0.292 0.593–0.419 0.489–0.169 (3) (4) (6) Lambda _z (1/hr) 1.47 -10.796 1.78 – 1.38 1.64 + 0.810 (3) (4) 1/F (L/hr) 1778– 2027 809.9 + 597.1 679.2 – 462.2 (3) (4) (6) Vd/F (L) 957,5 – 697.6 455.2 – 146.9 406.5 – 106,5 (3) (4) (6) 0.2939 – 0.2544 1.175 – 0.9195 1.188 – 0.5306 (6) (5) 0.4485 – 0.2636 2.097:k 1,620 1.076 – 0.6683 (3) (4) 0.4482:h 0.2633 2.097 – 1.622 1.075 – 0.6684 (3) (3) (4) T,, is presented as Median (Minimum, Maximum) following multiple dosing was computed as Dose/AUCo.

Vd/F following multiple dosing was computed as MRT*CLss Study Group 2A = 1 x 150 sg Glu225, 23231, Aib 19 , Lys 26’30]hPTHrP( I -34)NH2- 5MTS, 10 Second Wear Time Daily for 7 Days (Periumbilical) Study Group 2B = I x 150 ig Glu 22 ’ 5, Leu 2328’31, Aib 29, Lys 26’30JhPTHrP(!-34)NH 2- sMTS, 10 Second Wear Time Daily for 7 Days (Periumbilical) Study Group 2C = I x ISO jig Glu 22 ’25, Leu 23 ’28", Aib 29, Lys 26" ]hPTHrP( 1 -34)NH2 - sMTS, 10 Second Wear Time Daily for 7 Days (Periumbilical) Subject 204 was excluded from summary statistics for having un-measurable and missing concentration values.

Value missing or not reportable.

Mean peak exposure (at 470 pg/mL and 412 pg/mL on Days 1 and 7, respectively) was higher following G1u22’25 , Leu23’28’31 , Aib29, Lys 26 ’30]hPTHrP(1-34)NH2---sMTS 150 j.tg applied to the periumbilical region with 15 minute wear time (Study Group 213) compared to the G1u 22 ’25, Leu 23 ’28’31 , Aib 29, Lys 26’30]h.PTHrP(1-34)NH2sMTS 150 ig administered to periumbilical region with 10 second wear time (Study Group 2A) at 380 pg/mL and 144 pg/mL on Days 1 and 7, respectively. The lowest mean peak exposure at 317 pglmL resulted following Glu 22 ’25 -34)NH2sMTS 100 , Leu23 ’28’31 , Aib29, Lys26’30]hPTHrP( 1 administered to upper thigh region with 15 minute wear time (Study Group 2C) on Day 1.

The second highest mean peak exposure at 359 pg/mL resulted following Study Group 2C on Day 7. Mean total exposure values as measured by AUC0 on Day 1 and AUCo on Day 7 pg*hr/m were 268.8 and 219.3 L, respectively, following Study Group 2A, were 236.8 and 318.1 pg*h L, respectively, following Study Group 2B, and were 176.9 and 184.3 pg*h L, respectively, following Study Group 2C.

The median Tm, occurred at approximately 11 minutes, was similar among the study groups. The mean t112 value was 34 minutes following Study Group 2A, and ranged from 36 to 46 minutes following Study Group 2B, and 24 to 29 minutes following Study Group 2C.

The mean time to the last detectable plasma G1u 22’25, Leu23 ’28 ’31, Aib29 , Lys2630]hPTHrP(l -34)NH 2 concentrations ranged from 1.28 hours following Study Group 2C to 2.83 hours following Study Group 2B on Day 1 and from 1.09 hours following Study Group 2A to 2.37 hours following Study Group 2B on Day 7.

The highest apparent total body clearance at 1167 and 1’778 L/hr on Days 1 and 7, respectively, resulted following Study Group 2A followed by Study Group 2B at 716.3 and 809.9 L/hr, and Study Group 2C at 666.2 and 679.2 LIhr. Total body clearance values were relatively consistent between Days 1 and 7 following each study group.

Accumulation ratios (AR 1 and AR 2) and linearity factor (LF) values were 0.2939, 0.4485, and 0.4482, respectively, following Study Group 2A, 1.175, 2.097, and 2.097, respectively, following Study Group 2B, and 1.188, 1.076, and 1.075, respectively, following Study Group 2C.

Plasma Glu 22’25, Leu 23 ’28 ’31 , Aib29, Lys26 ’30]hPTHrP(l-34)NH 2 PK parameters following Glu 22 ’25 , Leu23 ’28 ’31 , Aib 29, Lys 26’30]hPTHrP(1-34)NH2-sMTS study groups on Days 1 and 7 in Study Period 3 are summarized in Tables 40 and 41.

Table 40 Summary of Plasma G1u 22’25, Leu 23’28’ ’, Aib 29 , Lys 26’30JhPTHrP(1 - 34)NH2Pharmacokinetic Parameters Following G1u22’25 , Leu23’28’1, Aib29 , Lys26’30]hPTHrP(1-34)N112 Study Groups (Study Period 3) - Day 1 Study Group 3A Study Group 3B Study Group 3C Pharmacokinetic Mean – SD Mean :k SD Mean + SD Parameters (N) (N) (N) I Cm., (pg/mL) 347–117 261–135 345–96.0 (6) (6) T m (hr) 0.163 (0.0817, 0.168) 0.167 (0.0994, 0.178) 0.169 (0.157, 0.216) (6) (6) (6) r (hr) 1.43 – 0.499 1.42 – 0.493 1.60 – 0.880 (6) (6) (6) AUC01 (pg*hr/mL) 153– 80.1 120–66.2 165–85.1 (6) (6) (pg*hr/mL) _ WC0. 172.2–79.69 137.3–66.34 198.5–98.76 (6) (6) (5) AUC0 (pghr/mL) 172.1 – 79.62 137.2– 66.32 198.4–98.71 (6) (5) AUCo/dose (pg*hr/mL/j.Lg) rE 1.15 – 0.531 0,915 0.442 1.32– 0.658 (6) (6) (5) AUCo./dose (pg*hr/mL.41g) 1.15 – 0.531 0.915 – 0.442 1.32 – 0.658 (6) (6) (5) t (hr) 0.484–0.151 0.538–0.171 0.570–0.351 (6) (6) Lambda z(l/hr) 1.56–0.520 1.42–0.509 1.84– 1.51 (6) (6) (5) AUCR 0.868 – 0.104 0.846 – 0.103 0.884 – 0.0245 (6) (6) (5) L/F (L/hr) 1046 – 478.8 1308 – 567.0 921.4 – 431.9 (6) (6) (5) VdJF (L) 701.9– 361.6 1013 – 632.8 641.8–317.5 (6) (6) (5) is presented as Median (Minimum, Maximum) Study Group 3A = I x 150 jig G1u 22 ’25, Leu 231 , Aib29, Lys 26’30]hPTHrP(1 -34)NH2 -sMTS, Wear Time: 5 Minute Days 1 - 6, 30 Second Day 7 (Upper Thigh) Study Group 3B = I x 150 jig G1u 22 ’25, Leu 23 ’28’31, Aib29, Lys 2630]hPl’HrP(1-34)NH 2 -sMI’S, Wear Time: I Minute Days I - 6, 60 Minute Day 7 (Upper Thigh) Study Group 3C = I x 150 jig G1u 22’25, Leu 23 ’2831 , Aib 29 , Lys26’30JhPTHrP(1-34)NH2 - MTS, Wear Time: 24 Hour Day 1, 15 Minute Day 7 (Upper Thigh) = Value missing or not reportable.

Table 41 Summary of Plasma G1u 22’25, Len 23’28’31 , Aib 29, Lys 26 ’30JhPTHrP(1- Leu2328M, 34)Nll2Pharmacokinetic Parameters Following Glu22’25, Aib29, Lys 26’30 Study Groups (Study Period 3) - Day 7 IhPTHrP(1-34 )NH2 Study Group 3A Study Group 3B Study Group 3C FPharmacokinetic Mean – SD Mean – – SD Mean SD ameters (N) (N) 381 – 174 319–129 334–222 (6) (6) (8) - 0.168 (0.0844, 0.186) 0.171 (0.0942, 0.254) 0.168 (0.0789, 0.189) _______ (6) (6) ______ (hr) i 2.18 –0.934 2.01 – 0.550 1.44–0.864 _______ (6) (6) AUC01 (pghr/mL) 229– 121 179– 67.3 153–107 (6) (6) (8) AUC 1,.1 (pghrImL) 169.2 – 113.5 (.) (8) (pg*hr/mL) AUC0. 1. 5 – 125.5 205.3 – 66.54 169.2 – 113.4 (6) (8) AUCo/dose (pg*hr/mL/pg) . . 1.13 – 0.756 1.44(.) 1 (8) (pg*hr/mLlpg) WCa.Idose 1.676:h 0.8367 1.369 – 0.4436 1.13 – 0.756 (6) (8) ti,, (hr) 0.671 – 0.280 0.737 – 0.138 0.454 10.224 (6) (8) Lambda _z (1/hr) 1.13 – 0.295 0.970– 0.196 1.95 – 1.06 (6) (8) UCR . . 0.862 – 0.102 L/F (L/hr) 723.1 – 322.8 813.6 – 332.1 1578–1430 (6) (6) (8) Vd/F(L) 644.5–241.6 878.9–454.1 743.7–439.8 (6) (6) (8) . is presented as Median (Minimum, Maximum) CL/F following multiple dosing was computed as Dose/AUC a.

Vd/F following multiple dosing was computed as MRT*CLss Study Group 3A = I x 150 pg G1u 1225, Leu 232831 , Aib 29 , Lys" 0)hPTHrP(1 -34)NH2 -sMTS, Wear Time: 5 Minute Days I - 6, 30 Second Day 7 (Upper Thigh) Study Group 38 = 1 x 150 jig G1u 22 ", Leu’2 ’ 1 , Aib". Lys26 ]hPTHrP(l-34)NH -sMTS, Wear Time. 1 Minute Days I - 6, 60 Minute Day 7 (Upper Thigh) Study Group 3C = I x ISO pg Glu 2225 , Lcu 23’2831 , Aib 29 , Lys26 ’ JhPTHrP( I -34)NH2 - sMTS, Wear Time: 24 Hour Day I, 15 Minute Day 7 (Upper Thigh) = Value missing or not reportable.

Day 1 Peak and total exposure values were comparable between G1u 22 ’25, Leu23 ’28 ’31 , Aib29, Lys26 ’30JhPTHrP(1-34)NH 2 -sMTS 150 g applied to the upper thigh region with 5 minute and 24 hour wear times (Study Groups 3A and 3C, respectively), but were higher than the corresponding values of G1u 22’25 , Leu 23 ’28 ’31 , Aib29, Lys 2630]hPTHrP(l-34)NH2-sMTS 150 j.tg applied to the upper thigh with 1 minute wear time (Study Group 213).

Median time to reach Cmax (i.e., Tmax) at approximately 10 minutes and t112 at approximately 30 to 35 minutes were similar or comparable among the 3 study groups.

Furthermore, mean time to the last detectable plasma Glu 22’25, Leu 23 ’28 ’31 , Aib 29, Lys 26’30]hPTHrP(l-34)NH2 concentration (i.e., ranging from 1.42 to 1.60 hours were TIast) comparable among the 3 study groups.

Apparent total body clearance value of 1308 L/hr on Day I following the 1 minute wear time (Study Group 3B) was higher compared to those following the 5 minute wear time (Study Group 3A) and 24 hour wear time (Study Group 3C) which were 1046 and 921.4 LIhr, respectively.

Mean peak and total exposure to G1u 22’25, Leu 23 ’28’31 , Aib 29, Lys 26’30]hPTHrP(l- 34)NH2were generally higher following Study Group 3A (30 second wear time), followed by Study Group 3B (60 minute wear time), and Study Group 3C (15 minute wear time). As on Day 1, median T on Day 7 of about 10 minutes was similar and t1,2 ranging from 27 to 44 minutes was relatively comparable among the 3 study groups. Time of the last detectable plasma G1u 22 ’25, Leu23 ’28’31 , Aib29 , Lys26’30]hPTHrP(1-34)NH2 concentration (i.e., approximately 2 hours following 30 second and 60 minute wear times, which was somewhat later compared to the T1 value following the 15 minute wear time of approximately 1.5 hours.

The apparent total body clearance value of 1578 L/hr following the 15 minute wear time (Study Group 3C) was approximately 2 times higher compared to those following the second wear time (Study Group 3A) and 60 minute wear time (Study Group 3B) at 723 and 814 L/hr, respectively.

The results of the relative bioavailability (F rei) of Glu2225 , Le 1 , Aib 29 , Lys26’30]hPTHrP(1-34)NH 2 -sMTS study groups for Day 1 in Study Periods 1, 2, and 3 Leu232831, compared to G1u22’25 , Aib 29, Lys 26’30]hPTHrP(1-34)NH 2 for Injection 80 jig are presented in Table 42.

Table 42 Summary of relative bioavailability rei) of G1u 22’25, Aib 29 , (F Leu 23’28 ’31 , Lys 26 ’30]hPTHrP(1-34)NH 2 -sMTS study groups for Day 1 in Study Periods 1, 2, and 3 compared to G1u 22’25 , Leu 23’28’31 , Aib 29, Lys 26 ’30JhPTHrP(l-34)NH2 for Injection 80 ttg Mean Dose Normalized AUCO-inf sMTS Dose SC Dose Treatment Study Period Mean N Mean N Fret 1 1.42 6 7.92 6 0.180 1 1.42 6 7.92 6 o.igo IC I 1.51 6 7.92 6 0.190 I 2.69 6 7.92 6 0.340 2 1.79 6 7.92 6 0.226 2B 2 1.58 4 7.92 6 0.199 2 1.77 4 7.92 6 0.223 3A 1.15 6 7.92 6 0.145 3B 3 0.92 6 7.92 6 0.116 3C Day 1 3 1.32 7.92 6 0.167 3CDay7 1.13 8 7.92 6 0.143 1A= Ix 100 tgGlu 22 ’25, Leu 23 ’28 ’31, Ai7 , Lys 26 ’301hPTHrP(1-34)NH 2-sMTS, 10 Second WearTime (Periumbilical) ]B = I x 100 ig G lu 22 ’25, Leu 23 ’2831 , Aib 29, Lys2630] hPTI-JrP( 1-3 4)NH 2-sMTS, 15 Minute Wearlime (Periumbilical) 1C= lx 100 gGlu 22 ’25 , Leu232831 , Aib 29, Lys 26 ’30]hPTI-IrP(1-34)NH 2-sMTS, 10 Second WearTirne(Upper Thigh) ID = 1 x 100 tg G1u 22 ’25 , Leu 23 ’28 ’31 , Aib29 , Lys26 ’30]hPTHrP( 1-3 4)NH 2-sMTS, 15 Minute WearTime (Upper Thigh) 22,15 2A= I x 150 ltgGIU , Leu23 ’28 ’31 , Aib 29, Lys2630]hPTHrP( 1 -34)NH 2-sMTS, 10 Second Wear Time Daily for 7 Days (Periumbilical) 2B = 1 x 150 ig G1u 2225 , Leu 2328 ’ 3 1, Aib29 , Lys 26 ’30JhPTHrP( 1-3 4)NH 2-sMTS, 15 Minute Wear Time Daily for 7 Days (Periumbilical) 2C= I x 100 g G1u 2225, Leu23 ’28 ’31 , Aib29 , Lys 26 ’30]hPTHrP( 1 -34)NH 2-sMTS, 15 Minute Wear Time Daily for 7 Days (Upper Thigh) 3A = I x 150 jig G1u 22 ’25, Leu 23 ’28 ’31 , Aib29, Lys 26 ’30]hPTHrP( 1 -34)NH 2-sMTS, WearTime: 5 MInute Days 1 - 6,30 Second Day (Upper Thigh) 3B =1 x 150 ig G1u22’25, Leu 23 ’28 ’31 , Aib 29, Lys26 ’30]hPTHrP( 1-3 4)NH 2-sMTS, Wear Time: 1 Minute Days 1 -6, 60 Minute Day 7 (Upper Thigh) 3C= I x 150 ligG1u 22 ’25, Leu2328 ’31 Aib 29, LYS 2630]hPTHFP( 1-3 4)NH 2-sMTS, WearTime: 24 Hour Day 1,15 Minute Day 7 (Upper Thigh) Serum CTX (collagen type 1 cross-linked C-telopeptide) Predose samples were obtained on Days 1, 3, and 7 in Study Periods 2 (Study Groups 2A, 213, 2C, and placebo) and 3 (Study Groups 3A and 3B) for the determination of serum CTX concentrations. Predose serum concentrations on Day I were used as baseline to compute the change from baseline concentrations for Days 3 and 7.

The mean change from baseline CTX concentrations following G1u 22’25, Leu23 ’28’31 , Aib29, Lys26’30]hPTHrP(1-34)NH 2 -5MTS study groups on Days 1, 3, and 7 in Study Period 2 are presented in Figure 13.

With the exception of G1u 22’25 , Leu23 ’28’31 , Aib29, Lys 26 ’30]hPTHrP(1-34)NH2 G1u22 25 Leu 23 ’28 ’31 , Aib29, Lys 26 ’30]hPTHrP(1-34)NH 2 -sMTS 150 tg applied to the periumbilical region with 15 minute wear time (Study Group 2B) on Day 3, mean CTX concentrations in serum following G1u 22’25 , Leu23 ’28 ’31 , Aib 29 , Lys 26 ’30]hPTHrP(1-34)NH2-sMTS study groups remained below the baseline levels on Days 3 and 7. Mean CTX concentrations in serum were at or above the placebo levels on Day 3 and were below the placebo levels on Day 7.

Mean change from baseline serum CTX concentrations were 0.0 and -0.1 ng/mL on Days 3 and 7, respectively, following G1u 22’25, Leu23 ’28 ’31 , Aib29, Lys2630]hPTHrP(l - 34)NH2-sMTS 150 jig applied into the periumbilical region with 10 second wear time (Study Group 2A); 0.0 and -0.1 ng/mL following G1u 22 ’25, Leu23’28 ’31 , Aib 29, Lys26’30]hPTHrP(1- 34)NH 2 G1u 22’25, Leu 23 ’28’31 , Aib 29 , Lys 26’30]hPTHrP(1-34)NH 2 G1u22 ’25, Leu23 ’28’31 , Aib 29, Lys 26 ’30JhPTHrP( I -34)NH G1u 22 ’25, Leu 23 ’28 ’31 , Aib29, Lys 26’30]hPTHrP( I -34)NH2-sMTS 150 .tg (Days I and 7, respectively) applied into the periumbilical region with 15 minute wear time (Study Group 2B); 0.0 and -0.1 ng/mL following G1u 22’25 , Leu23 ’28’3 , Aib29 , Lys 26 ’30 ]hPTHrP( I -34)NH2-sMTS 100 tg applied into the upper thigh region with 15 minute wear time (Study Group 2C); and 0.0 ng/mL following placebo.

The mean change from baseline CTX concentrations following [G1u 22’25 , Leu2328 ’31 , Aib29, Lys 26 ’30 ]hPTHrP(1-34)NH 2 -sMTS study groups on Days 1, 3, and 7 in Study Period 3 are presented in the Figure 14 While mean CTX concentrations in serum following G1u 22’25, Leu23 ’28’31 , Aib29, Lys 26 ’30 ]hPTHrP(1-34)NT-I2 sMTS 150 tg applied to the upper thigh region with 5 minute wear time on Day I and 30 second wear time on Day 7 (Study Group 3A) remained at baseline levels on Days 3 and 7, those following Glu 22’25, Leu23 ’28’31 , Aib 29 , Lys26 ’30]hPTHrP(1-34)NH2 -sMTS 150 i.g applied to the upper thigh region with 1 minute wear time on Day 1 and 60 minute wear time on Day 7 (Study Group 3B) decreased below the baseline levels on Days 3 and 7.

Mean change from baseline serum CTX concentration values were 0.0 ng/mL following Study Group 3A and -0.1 nglmL following Study Group 3B.

The mean maximum change from baseline in serum CTX concentrations (A max) were 0.0 ng/mL following Study Group 3A and -0.1 ng/mL following Study Group 3B.

Serum P1NP (procollagen type 1 amino-terminal propeptide) Predose samples were obtained on Days 1, 3, and 7 in Study Periods 2 (Study Groups 2A, 2B, 2C, and placebo) and 3 (Study Groups 3A and 3B) for the determination of serum P I NP concentrations. Predose serum concentrations on Day 1 were used as baseline to compute the change from baseline concentrations for Days 3 and 7.

The mean change from baseline P1NP concentrations following G1u 22’25, Leu 23 ’2831 , Aib 29, Lys26 ’30]hPTHrP(1-34)NH 2 sMT5 study groups on Days 1, 3, and 7 in Study Period 2 are presented in Figure 15.

Based on change from baseline values, mean P1NP concentrations in serum following G1u22 ’25 , Leu2328’31, Aib 29 , Lys26 ’30]hPTHrP(l-34)NH 2-sMTS study groups remained above the baseline and placebo levels on Days 3 and 7. The mean values were higher on Day 7 compared to Day 3.

Mean change from baseline serum PINP concentrations were 2.8 and 6.2 nglmL on Days 3 and 7, respectively, following Glu 22 ’25 , Leu 23 ’28’31 , Aib29, Lys 26’30]hPTHrP(1- 34)NH2-sMTS 150 tg applied into the periumbilical region with 10 second wear time (Study Group 2A);.6 and 7.2 ng/mL on Days 3 and 7, respectively, following Glu 22 ’25 , Leu2328 ’31 , Aib 29, Lys26 ’30]hPTJ-IrP(1-34)NH 2 -sMTS 150 tg applied into the periumbilical region with 15 minute wear time (Study Group 2B); 3.2 and 8.8 nglmL on Days 3 and 7, respectively, following G1u 22’25, Leu23 ’28 ’31 , Aib29, Lys 26’30]hPTHrP( 1 -34)NlsMTS 100 ig applied into the upper thigh region with 15 minute wear time (Study Group 2C); and 2.0 ng!mL following placebo.

The mean maximum change from baseline in serum P1 NP concentrations were (\m) ng/mL following Study Group 2A, 7.8 ng/mL following Study Group 2B, 8.8 ng/mL following Study Group 2C, and 1.0 ng/mL following placebo.

The mean change from baseline P1NP concentrations following Glu 22 ’25, Leu 23 ’28 ’31 , Aib29 , Lys 26’30JhPTHrP(1-34)NH2 -sMTS study groups on Days 1, 3, and 7 in Study Period 3 are presented in Figure 16.

Based on change from baseline values, mean P1NP concentrations in serum following G1u22’25, Leu 23’28’31 , Aib29 , Lys26’30JhPTHrP(l-34)NH 2-sMTS study groups increased above the baseline level (Day 1 predose) and were higher on Day 7 compared to Day 3.

Mean change from baseline serum P1NP concentrations were 1.0 and 4.2 ng/mL following G1u 22’25, Leu 23 ’28 ’31 , Aib29 , Lys2630]hPTHrP(1-34)NH 2-sMTS 150 jig applied to the upper thigh region with minute wear time on Day 1 and 30 second wear time on Day 7 (Study Group 3A) and were 5.6 and 9.8 nglmL following G1u 22 ’25, Leu 23 ’28 ’31 , Aib29, Lys26 ’30]hPTHrP(1-34)NH 2 -sMTS 150 j.g applied to the upper thigh region with 1 minute wear time on Day 1 and 60 minute wear time on Day 7 (Study Group 3B).

The mean maximum change from baseline in serum P1NP concentrations (A max) were 4.7 ng!mL following Study Group 3A and 10.4 nglmL following Study Group 2B.

The systematic delivery of [Glu’ , Leu23 ’28 ’31 , Aib29, Lys26 ’30]hPTHrP(1-34)NH2 using microneedle technology has been clearly demonstrated in preclinical models (rats) and postmenopausal women. The release profile appears to be extremely rapid with high Cmax values that were quickly reached. The levels obtained, bone marker response and increases in bone mineral density clearly indicate the clinical utility of the many embodiments of this invention.

While this invention has been particularly shown and described with references to example embodiments thereof, it will be understood by those skilled in the art that various changes in form and details may be made therein without departing from the scope of the invention encompassed by the appended claims.

Claims

WE CLAIM:

1. An aqueous formulation comprising [Glu , Leu , Aib , 26,30 Lys ]hPTHrP(1-34)NH and histidine. 22,25 23,28,31 29

2. An aqueous formulation comprising [Glu , Leu , Aib , 26,30 Lys ]hPTHrP(1-34)NH , wherein said formulation has a viscosity of greater than 500 centipoises.

3. The aqueous formulation according to claim 1 or 2, wherein said formulation 22,25 23,28,31 29 comprises at least 5%, 40%, or 45% by weight of [Glu , Leu , Aib , 26,30 Lys ]hPTHrP(1-34)NH .

4. The aqueous formulation according to claim 1 or 2, wherein said formulation comprises between 40% and 63%, between about 50% and about 62%, or 22,25 23,28,31 29 between about 46% and about 48% by weight [Glu , Leu , Aib , 26,30 Lys ]hPTHrP(1-34)NH .

5. The aqueous formulation according to any one of the preceding claims, wherein said formulation has a viscosity of greater than 500 or 600 centipoises at 25 °C and a shear rate of 100 s .

6. The aqueous formulation according to any one of the preceding claims, wherein said formulation has a viscosity of greater than 1,000 centipoises at 25 °C and a shear rate of 100 s .

7. The aqueous formulation according to any one of the preceding claims, wherein said formulation has a viscosity of greater than 1,250 centipoises at 25 °C and a shear rate of 100 s . 11285858

8. The aqueous formulation according to any one of the preceding claims, wherein said formulation has a viscosity of greater than 1,500 centipoises at 25 °C and a shear rate of 100 s .

9. The aqueous formulation according to any one of claims 1-4, wherein said formulation has a viscosity of between 1,000 centipoises and 3,000 centipoises at 25 °C and a shear rate of 100 s .

10. The aqueous formulation according to any one of the preceding claims, further comprising acetate and/or acetic acid.

11. The aqueous formulation according to any one of the preceding claims, further comprising from 4% to 10% by weight acetate.

12. The aqueous formulation according to any one of the preceding claims, further comprising from 1% to 15% by weight histidine.

13. The aqueous formulation according to claim 12, wherein said histidine is 3% by weight.

14. The aqueous formulation according to claim 12, wherein said histidine is 5% by weight.

15. The aqueous formulation according to any one of the preceding claims, further comprising from 2% to 10% by weight potassium chloride.

16. The aqueous formulation according to claim 15, wherein said potassium chloride is 9% by weight.

17. The aqueous formulation according to any one of the preceding claims, further comprising an amphiphilic surfactant. 11285858

18. The aqueous formulation according to any one of the preceding claims, further comprising an uncharged amphiphilic surfactant.

19. The aqueous formulation according to any one of the preceding claims, further comprising a polysaccharide.

20. The aqueous formulation according to any one of the preceding claims, further comprising sucrose or hydroxyethyl cellulose.

21. The aqueous formulation according to any one of the preceding claims, further comprising a buffer.

22. The aqueous formulation according to any one of the preceding claims, further comprising a buffered saline solution.

23. The aqueous formulation according to any one of the preceding claims, further comprising a 1X phosphate buffered saline solution.

24. The aqueous formulation according to any one of the preceding claims, wherein said aqueous formulation has a pH from 3.0 to 8.0.

25. The aqueous formulation according to any one of the preceding claims, wherein said aqueous formulation has a pH from 3.0 to 7.0.

26. The aqueous formulation according to any one of the preceding claims, wherein said aqueous formulation has a pH from 3.5 to 6.5.

27. The aqueous formulation according to any one of the preceding claims, wherein said aqueous formulation has a pH from 4.0 to 6.0.

28. The aqueous formulation according to any one of the preceding claims, wherein said aqueous formulation has a pH from 4.5 to 5.5. 11285858

29. A microprojection array suitable for transdermal drug delivery, wherein said microprojection array comprises a backing material with a plurality of attached microprojections wherein at least one of said microprojections comprises a 22,25 23,28,31 29 coating of a formulation comprising [Glu , Leu , Aib , 26,30 Lys ]hPTHrP(1-34)NH and histidine.

30. The microprojection array according to claim 29, wherein said coating is manufactured by a process step comprising application of an aqueous formulation described in any one of claims 1-28.

31. The microprojection array according to claim 30, wherein said process step comprising application is followed by a process step comprising drying of said coating.

32. The microprojection array according to any one of claims 29-31, wherein said microprojections comprise a carbon containing polymeric material.

33. The microprojection array according to any one of claims 29-32, wherein said microprojections comprise a polycarbonate polymer.

34. The microprojection array according to any one of claims 29-33, wherein said microprojections comprise a liquid crystal polymer.

35. The microprojection array according to any one of claims 29-34, wherein said microprojections comprise a base with a width greater than two times the width at the tip.

36. The microprojection array according to any one of claims 29-35, wherein said microprojections comprise a base with a width greater than four times the width at the tip. 11285858

37. The microprojection array according to any one of claims 29-36, wherein said microprojections comprise a base with a width greater than six times the width at the tip.

38. The microprojection array according to any one of claims 29-37, wherein said microprojections are microneedles.

39. The microprojection array according to any one of claims 29-38, wherein said microprojections are pyramidal in shape.

40. The microprojection array according to any one of claims 29-39, wherein said microprojections have a rectangular base and rectangular tip.

41. The microprojection array according to any one of claims 29-39, wherein said microprojections have a square base and square tip.

42. The microprojection array according to any one of claims 29-41, wherein said microprojections have a flexural modulus of greater than 1,000 MPa (ISO 178).

43. The microprojection array according to any one of claims 29-42, wherein said microprojections have a flexural modulus of greater than 2,000 MPa (ISO 178).

44. The microprojection array according to any one of claims 29-43, wherein said microprojections have a flexural modulus of greater than 3,000 MPa (ISO 178).

45. The microprojection array according to any one of claims 29-44, wherein said microprojections have a flexural modulus from about 3,000 MPa to about 15,000 MPa (ISO 178).

46. The microprojection array according to any one of claims 29-45, wherein said microprojections have a flexural modulus from about 5,000 MPa to about 12,000 MPa (ISO 178). 11285858

47. The microprojection array according to any one of claims 29-46, wherein said microprojections have a flexural modulus from about 8,000 MPa to about 12,000 MPa (ISO 178).

48. The microprojection array according to any one of claims 29-47, wherein said microprojections have a flexural modulus from about 9,000 MPa to about 10,000 MPa (ISO 178).

49. The microprojection array according to any one of claims 29-48, wherein said microprojections have a flexural modulus of between 9,000 MPa and 9,500 MPa (ISO 178).

50. The microprojection array according to any one of claims 29-49, wherein said microprojections are more than 100 microns and less than 1,000 microns in length.

51. The microprojection array according to any one of claims 29-50, wherein said microprojections are more than 250 microns and less than 750 microns in length.

52. The microprojection array according to any one of claims 29-51, wherein said microprojections are more than 400 microns and less than 600 microns in length.

53. The microprojection array according to any one of claims 29-52, wherein said microprojections are about 500 microns in length.

54. The microprojection array according to any one of claims 29-53, wherein said array has a microprojection density between 20 and 1,000 microprojections per cm . 11285858

55. The microprojection array according to any one of claims 29-54, wherein said array has a microprojection density between 100 and 500 microprojections per cm .

56. The microprojection array according to any one of claims 29-55, wherein said array comprises between 50 and 600 microprojections.

57. The microprojection array according to any one of claims 29-56, wherein said array comprises between 100 and 500 microprojections.

58. The microprojection array according to any one of claims 29-57, wherein said array comprises between 250 and 400 microprojections.

59. The microprojection array according to any one of claims 29-58, wherein said array comprises between 300 and 375 microprojections.

60. The microprojection array according to any one of claims 29-59, wherein said array comprises about 366 microprojections.

61. The microprojection array according to any one of claims 29-59, wherein said array comprises about 316 microprojections.

62. The microprojection array according to any one of claims 29-61, wherein said 22,25 23,28,31 array comprises from about 63.75 g to about 86.25 g of [Glu , Leu , 29 26,30 Aib , Lys ]hPTHrP(1-34)NH .

63. The microprojection array according to any one of claims 29-62, wherein said 22,25 23,28,31 29 26,30 array comprises about 75 g of [Glu , Leu , Aib , Lys ]hPTHrP(1- 34)NH .

64. The microprojection array according to any one of claims 29-61, wherein said array comprises from about 85 g to about 115 g, about 20 µg to about 386 µg, 11285858 22,25 23,28,31 29 or about 85 µg to about 230 µg of [Glu , Leu , Aib , 26,30 Lys ]hPTHrP(1-34)NH .

65. The microprojection array according to any one of claims 29-61 and 64, wherein 22,25 23,28,31 29 said array comprises about 100 g of [Glu , Leu , Aib , 26,30 Lys ]hPTHrP(1-34)NH .

66. The microprojection array according to any one of claims 29-61, wherein said 22,25 array comprises from about 106.25 g to about 143.75 g of [Glu , 23,28,31 29 26,30 Leu , Aib , Lys ]hPTHrP(1-34)NH .

67. The microprojection array according to any one of claims 29-61 and 66, wherein 22,25 23,28,31 29 said array comprises about 125 g of [Glu , Leu , Aib , 26,30 Lys ]hPTHrP(1-34)NH .

68. The microprojection array according to any one of claims 29-62, wherein said 22,25 23,28,31 array comprises from about 127.5 g to about 172.5 g of [Glu , Leu , 29 26,30 Aib , Lys ]hPTHrP(1-34)NH .

69. The microprojection array according to any one of claims 29-61 and 68, wherein 22,25 23,28,31 29 said array comprises about 150 g of [Glu , Leu , Aib , 26,30 Lys ]hPTHrP(1-34)NH . 22,25 23,28,31 29 26,30

70. Use of [Glu , Leu , Aib , Lys ]hPTHrP(1-34)NH for the manufacture of a medicament for use in the treatment of a mammal, wherein said medicament is formulated for administration to said mammal by contacting the skin of said mammal with a microprojection array according to any one of claims 29-69 with sufficient force to cause penetration of one or more of said microprojections comprising a coating of said formulation into the skin of said mammal.

71. The use of claim 70, wherein said mammal is a human. 11285858

72. The use of claim 71, wherein said human has osteopenia or osteoporosis.

73. The use of any one of claims 71-72, wherein said human is a post-menopausal woman.

74. The use of any one of claims 71-73, wherein said human has glucocorticoid- induced osteopenia or osteoporosis. 22,25 23,28,31 29 26,30

75. Use of [Glu , Leu , Aib , Lys ]hPTHrP(1-34)NH for the manufacture of a medicament for use in the treatment of osteoporosis in a human in need thereof wherein said medicament is formulated for administration 22,25 23,28,31 29 26,30 of [Glu , Leu , Aib , Lys ]hPTHrP(1-34)NH once-daily according to the use of any one of claims 71-74. 22,25 23,28,31 29 26,30

76. Use of [Glu , Leu , Aib , Lys ]hPTHrP(1-34)NH for the manufacture of a medicament for use in the treatment of osteoporosis in a human in need thereof wherein said medicament is formulated for administration 22,25 23,28,31 29 26,30 of [Glu , Leu , Aib , Lys ]hPTHrP(1-34)NH once-weekly according to the use of any one of claims 71-74.

77. The use of claim 75 or 76, wherein said microprojection array is formulated for contact on the surface of the stomach area of said human.

78. The use of claim 75 or 76, wherein said microprojection array is formulated for contact on the surface of the deltoid area of said human.

79. The use of claim 75 or 76, wherein said microprojection array is formulated for contact on the surface of the thigh of said human.

80. The use according to any one of claims 70-79, wherein said microprojection array is left in place with one or more of said microprojections embedded in the 11285858 skin after said contacting for a period of from about 10 seconds to about 24 hours.

81. The use of claim 80, wherein said period is from about 10 seconds to about 1 hour.

82. The use of claim 80, wherein said period is from about 10 seconds to about 30 minutes.

83. The use of claim 80, wherein said period is from about 10 seconds to about 15 minutes.

84. The use of claim 80, wherein said period is from about 10 seconds to about 5 minutes.

85. The use of claim 80, wherein said period is about 10 seconds.

86. The use of claim 80, wherein said period is about 30 seconds.

87. The use of claim 80, wherein said period is about 1 minute.

88. The use of claim 80, wherein said period is about 5 minutes.

89. The use of claim 80, wherein said period is about 15 minutes.

90. The use of claim 80, wherein said period is about 30 minutes. 22,25 23,28,31 29 26,30

91. Use of [Glu , Leu , Aib , Lys ]hPTHrP(1-34)NH for the manufacture of a medicament for use in the treatment of post-menopausal osteoporosis wherein said medicament is formulated for administration of 22,25 23,28,31 29 26,30 [Glu , Leu , Aib , Lys ]hPTHrP(1-34)NH to a woman in need thereof by contacting the skin of said woman with a microprojection array as 11285858 described in any one of claims 29-69 with sufficient force to cause penetration of one or more of said microprojection members into the skin of said woman and 22,25 23,28,31 wherein said administration results in C plasma levels of [Glu , Leu , 29 26,30 Aib , Lys ]hPTHrP(1-34)NH of greater than 200 pg/mL.

92. The use of claim 91, wherein said administration results in C plasma levels of 22,25 23,28,31 29 26,30 [Glu , Leu , Aib , Lys ]hPTHrP(1-34)NH of greater than 300 pg/mL.

93. The use of claim 91, wherein said administration results in C plasma levels of 22,25 23,28,31 29 26,30 [Glu , Leu , Aib , Lys ]hPTHrP(1-34)NH of greater than 400 pg/mL.

94. The use of claim 91, wherein said administration results in C plasma levels of 22,25 23,28,31 29 26,30 [Glu , Leu , Aib , Lys ]hPTHrP(1-34)NH of greater than 500 pg/mL.

95. The use of any one of claims 91-94, wherein the plasma T occurs at less than one hour post-administration time.

96. The use of any one of the claims 91-95, wherein the plasma T occurs at less than ½ hour post administration time. 22,25 23,28,31 29 26,30

97. Use of [Glu , Leu , Aib , Lys ]hPTHrP(1-34)NH for the manufacture of a medicament for use in the treatment of one or more fractured 22,25 bones wherein said medicament is formulated for administration of [Glu , 23,28,31 29 26,30 Leu , Aib , Lys ]hPTHrP(1-34)NH to a human in need thereof by contacting the skin of said human with a microprojection array as described in any one of claims 29-69 with sufficient force to cause penetration of one or more of said microprojection members into the skin of said human.

98. The use of claim 97, wherein said administration is a once-daily administration. 11285858

99. The use of any one of claims 97 or 98, wherein said microprojection array is left in place with one or more of said microprojections imbedded in the skin after said contacting for a period of from about 10 seconds to about 24 hours.

100. The use of claim 99, wherein said period is from about 10 seconds to about 1 hour.

101. The use of claim 99, wherein said period is from about 10 seconds to about 30 minutes.

102. The use of claim 99, wherein said period is from about 10 seconds to about 15 minutes.

103. The use of claim 99, wherein said period is from about 10 seconds to about 5 minutes.

104. The use of claim 99, wherein said period is about 10 seconds.

105. The use of claim 99, wherein said period is about 30 seconds.

106. The use of claim 99, wherein said period is about 1 minute.

107. The use of claim 99, wherein said period is about 5 minutes.

108. The use of claim 99, wherein said period is about 15 minutes.

109. The use of claim 99, wherein said period is about 30 minutes.

110. The use of any one of claims 97-109, wherein said administration results in C 22,25 23,28,31 29 26,30 plasma levels of [Glu , Leu , Aib , Lys ]hPTHrP(1-34)NH of greater than 200 pg/mL. 11285858

111. The use of any one of claims 97-110, wherein said administration results in C 22,25 23,28,31 29 26,30 plasma levels of [Glu , Leu , Aib , Lys ]hPTHrP(1-34)NH of greater than 300 pg/mL.

112. The use of any one of claims 97-111, wherein said administration results in C 22,25 23,28,31 29 26,30 plasma levels of [Glu , Leu , Aib , Lys ]hPTHrP(1-34)NH of greater than 400 pg/mL.

113. The use of any one of claims 97-112, wherein said administration results in C 22,25 23,28,31 29 26,30 plasma levels of Glu , Leu , Aib , Lys ]hPTHrP(1-34)NH of greater than 500 pg/mL.

114. The use of any one of claims 97-113, wherein the plasma T occurs at less than one hour post-administration time.

115. The use of any one of the claims 97-114, wherein the plasma T occurs at less than ½ hour post administration time.

116. The use of any one of claims 97-115, wherein said microprojection array is formulated for contact on the surface of the stomach area of said human.

117. The use of any one of claims claim 97-115, wherein said microprojection array is formulated for contact on the surface of the deltoid region of said human.

118. The use of any one of claims 97-115, wherein said microprojection array is formulated for contact on the surface of the thigh of said human.

119. The use of any one of claims 97-118, wherein said one or more fractured bones was detected within 3 months from the time that said treatment begins. 11285858

120. The use of any one of claims 97-119, wherein said one or more fractured bones was detected within 1 month from the time that said treatment begins.

121. The use of any one of claims 97-120, wherein said one or more fractured bones was detected within two weeks from the time that said treatment begins. 22,25 23,28,31 29 26,30

122. Use of [Glu , Leu , Aib , Lys ]hPTHrP(1-34)NH for the manufacture of a medicament for use in the treatment of osteoarthritis wherein 22,25 23,28,31 29 said medicament is formulated for administration of [Glu , Leu , Aib , 26,30 Lys ]hPTHrP(1-34)NH to a human in need thereof by contacting the skin of said human with a microprojection array as described in any one of claims 29-69 with sufficient force to cause penetration of one or more of said microprojection members into the skin of said human.

123. The use of claim 122, wherein said administration is a once-daily administration.

124. The use of claim 122 or 123, wherein said microprojection array is left in place with one or more of said microprojections embedded in the skin after said contacting for a period of from about 10 seconds to about 24 hours.

125. The use of claim 124, wherein said period is from about 10 seconds to about 1 hour.

126. The use of claim 124, wherein said period is from about 10 seconds to about 30 minutes.

127. The use of claim 124, wherein said period is from about 10 seconds to about 15 minutes.

128. The use of claim 124, wherein said period is from about 10 seconds to about 5 minutes. 11285858

129. The use of claim 124, wherein said period is about 10 seconds.

130. The use of claim 124, wherein said period is about 30 seconds.

131. The use of claim 124, wherein said period is about 1 minute.

132. The use of claim 124, wherein said period is about 5 minutes.

133. The use of claim 124, wherein said period is about 15 minutes.

134. The use of claim 124, wherein said period is about 30 minutes.

135. The use of any one of claims 122-134, wherein said administration results in 22,25 23,28,31 29 26,30 C plasma levels of [Glu , Leu , Aib , Lys ]hPTHrP(1-34)NH of max 2 greater than 200 pg/mL.

136. The use of any one of claims 122-134, wherein said administration results in 22,25 23,28,31 29 26,30 C plasma levels of [Glu , Leu , Aib , Lys ]hPTHrP(1-34)NH of max 2 greater than 300 pg/mL.

137. The use of any one of claims 122-134, wherein said administration results in 22,25 23,28,31 29 26,30 C plasma levels of [Glu , Leu , Aib , Lys ]hPTHrP(1-34)NH of max 2 greater than 400 pg/mL.

138. The use of any one of claims 122-134, wherein said administration results in 22,25 23,28,31 29 26,30 C plasma levels of [Glu , Leu , Aib , Lys ]hPTHrP(1-34)NH of max 2 greater than 500 pg/mL.

139. The use of any one of claims 122-134, wherein the plasma T occurs at less than one hour post-administration time. 11285858

140. The use of any one of claims 122-134, wherein the plasma T occurs at less than ½ hour post administration time.

141. The use of any one of claims 122-140, wherein said microprojection array is formulated for contact on the surface of the stomach area of said human.

142. The use of any one of claims 122-140, wherein said microprojection array is formulated for contact on the surface of the deltoid region of said human.

143. The use of any one of claims 122-140, wherein said microprojection array is formulated for contact on the surface of the thigh of said human.

144. The use of any one of claims 122-140, wherein said microprojection array is formulated for contact on the surface of the upper chest of said human. Radius Health, Inc. 3M Innovative Properties Company By the Attorneys for the Applicant SPRUSON & FERGUSON Per: 11285858