Microneedle injection apparatus comprising an inverted actuator.

(54) Title: MICRO-NEEDLE INJECTION DEVICE INCLUDING AN INVERTED ACTUATOR.

(54) Title: MICRONEEDLE INJECTION APPARATUS COMPRISING AN INVERTED ACTUATOR.

(57) Summary

A microneedle injection apparatus (100) comprising an inverted actuator. The apparatus may include a housing (102) having a base and a cavity and a microneedle unit holder (106) configured to retain a microneedle unit (107) within the cavity of the housing. The microneedle unit holder can be moveable between a retracted position and an extended position. The apparatus may further include an actuator (104) movable with respect to the housing and holder of the microneedle unit between a first position and a second position to cause the holder of the microneedle unit to move from the stowed position to the extended position. At least a portion of the actuator can be located on one side of the apparatus facing the skin (for example, adjacent to the base of the housing) and can be configured to move from the first position to the second position in response to pressure from the apparatus towards the skin surface.

(57) Abstract

A microneedle injection apparatus (100) comprising an inverted actuator. The apparatus can include a housing (102) having a base and a cavity, and a microneedle array holder (106) configured to hold a microneedle array (107) within the cavity of the housing. The microneedle array holder can be movable between a retracted position, and an extended position. The apparatus can further include an actuator (104) movable with respect to the housing and the microneedle array holder between a first position and a second position to cause the microneedle array holder to move from the retracted position to the extended position. At least a portion of the actuator can be located on a skin-facing side of the apparatus (eg, adjacent the base of the housing) and can be configured to be moved from the first position to the second position in response to the apparatus being pressed toward the skin surface.

<img file="MX353241B_D0001.tif" />

PATENT TITLE No. 353241

Headlines): 3M INNOVATIVE PROPERTIES COMPANY

D micilio:

3M Center, Saint Paul, Minnesota, 55144-1000, USA

D nomination:

Classification:

INVERTED ACTUATOR INJECTION DEVICE.

CIP: A61M5 / 32; A6 ^ Vlá7 / Üp /_;

CPC: A6WI5 / 322rA6ÍM37 / 0015

MICRO NEEDLES INCLUDING A

Inventor (s):

Number:

MX / a / 2015/015565

Country;

US

SCOTT A. BURTON; CHIN-YE

<img file="MX353241B_D0002.tif" />

%

International:

Number:

61 / 829,632 'I heard

JA w

V £ n $ imient &amp; 2Í d &amp; Wtayo sheet of £ 2Θ3

Expedition sheet f 4 dé tei ^ »r &lt;^ 2018

The patent of reference is ^ rga with furtáarfte ^ p in the active and ^ Wsje l * 4 ^ ¿ie the Rnjpie ^ rindustnal.

In accordance with the artfgtáo'i * of the Law ^ deJa Prop! Edj! ¡Jnlta | 44P¿ Agency of twenty rf ^ Albftirrogables, counted from the date of presentíbt ^ ® the solidWiflterpacidqrf and &amp;. nnart ^ er viger ^ fes ydWbchos.

Whoever subscribes to the present title is subject to the provisions of the 6th section III and 7&gt; 2 of the Industrial Property Law (Official Gazette of the Federation · # ®φ127 / 96 «99irWpnnla βΐ1Β2Β8ί1994, 26 /, '26 / 12/1 ^ ΜΪ &lt;β5 / 1999, 01/26/2004, 06/16/2005,

25/01/2006, 06/05/2009,06/01/2010, )8/156/^40, _:06/28 / 20.ipj27 / Cj / 2012&gt; t (Wai1 / 2012f af °, 3 ^ ra ^^^^ ia), 4^or and 12th fraction s i and I II of

Regulations of the Mexican Institute iíí5a&gt; gQjietÍad leéet® * (^ O&gt;. ^. Ϊ́λΐ2ί1899, | ¿| o articles 1^or, 3°, 4^or, 5^or fraction V subsection a), ... - - 12/27/1999, amended on 10/10/2002, 29/0 /

Deputy Generals, Coordinator, Directors

Departmental and other subordinates of the Institute

08/04/2004 and 09/13/2007).

Validity: Twenty years j · irmaHa el ^ átoai1994,&gt; / ^_, 12/26 / W? MW / 1999, 01/26/2004, 06/16/2005,&gt; 7 / Α / 20121ΐ% 0 | / 2012 »af °, 3 ^ rañ &amp; f ^ &amp; ^ a), 4^or and 12th fractions I and III of

1 «jXlS? 9, il 01 # 7 ^ ί) 2; .ΐφ7 / 2004 07/28/2004 and 09/07/2007);

III and '3OTftbeitio ^ rgán¡S0MltflnstrtúnMe &lt;beno of Industrial Property (Addendum DOF that delegates powers to the Directors, Divisional Deputy Directors, Coordinators NíSh 2/1999, amended on 02/04/2000, 07/29/2004,

<img file="MX353241B_D0003.tif" />

<img file="MX353241B_D0004.tif" />

This letter is signed with an advanced electronic signature (FIEL), based on articles 7 BIS 2 of the Industrial Property Law; 3 of its Regulations, and 1 fraction III, 2 fraction V, 26 BIS and 26 TER of the Agreement establishing the guidelines for the use of the Electronic Payment and Services Portal (PASE) of the Mexican Institute of Industrial Property, in the procedures indicated.

THE DIVISIONAL DIRECTOR OF PATENTS

NAHANNY CANAL REYES

<img file="MX353241B_D0005.tif" />

Original string:

NAHANNY MARISOL CANAL REYES | 00001000000403252793 | Administration Service

Tax | 1695 || MX / 2018/2558 | MX / a / 2015/015565 | PCT patent title | 1223 | GAGV | Page (s) 1 | PgEv7FaLGH + / gSAWj6FN7oz1g44 =

Digital stamp:

mv9sb5fCOEAeSdrUVMud9vwV1H9F5hlDuRCMYeals + j40n / vm2yq4ZtzndAdth2LHF6sdxXI + 75zpcRQUenw9JuOYg efhdgg6krShKi0csWvEHevzv37g0GO / 7HjzJ / JyTefG2ufPKBBnEpC9Bm5QkO87fizj4aYZMF6YTuLn4dfpBLT1f0Z vwZvWs / UN12quE4DK3fMmSain1l91RMISInTdUeiz¡YRbeYzPkDus1ZkhAZqoq7irxwaX83ErnXtFXq1HdNDW + vmbf d4Vh8f¡FOUM9QAg1 \ / pfxgxb / nQobf4VVm3PCOOXuthaOsdGJvOmyCaV \ / == 5vaKnn4B8yqlXXgJr + A

Arenal No. 550 Floor 1. Santa María Tepepan Town, Xochimilco, 16020. Mexico City.

('55) 53340700 www gob.mx/impi

<img file="MX353241B_D0006.tif" />

353541

IMPI 0¾¾

MICRO NEEDLE INJECTION DEVICE THAT '^ JÓ ^ &amp; ÉSfíÉ

INDUSTRIAL

INVERTED ACTUATOR

FIELD OF THE INVENTION

The present disclosure generally relates to microneedle injection devices for applying microneedles to the skin and / or delivering an active agent to the skin.

BACKGROUND OF THE INVENTION

The active agents (or drugs) are conventionally administered orally or by injection. Unfortunately, many agents can be ineffective or their effectiveness is radically reduced when administered orally as they are not absorbed or negatively affected before entering the bloodstream and therefore do not have the desired activity. Also, orally administered agents may not work as quickly as injected agents. Furthermore, while direct injection of the agent into the bloodstream ensures that the agent is not modified during administration, this is a difficult, inconvenient, painful, and uncomfortable procedure that the patient sometimes does not adequately adhere to.

Transdermal delivery can provide a method of administering active agents that must otherwise be delivered through hypodermic injection or

Ref.:261770 intravenous infusion. Further,

<img file="MX353241B_D0007.tif" />

orally, transdermal delivery prevents the hostile environment of the digestive tract, prevents gastrointestinal metabolism of the drug, reduces first-pass effects, and prevents deactivation that can be caused by digestive and liver enzymes.

However, in some cases, the amount of molecules that can be effectively delivered via transdermal delivery may be limited by the barrier properties of the skin. The main barrier to the transport of molecules through the skin is the stratum corneum (the outermost layer of the skin).

Several different skin treatment methods have been proposed to increase the permeability or porosity of the outermost layers of the skin, such as the stratum corneum, and thereby improve delivery to or through these layers. The stratum corneum is a complex structure of compact keratinized cell debris separated by lipid domains. The stratum corneum is made up of keratinocytes, which make up most of the epidermal cells, lose their nuclei, and transform into corneocytes. These dead cells comprise the stratum corneum, which is only about 10-30 microns thick and protects the body from invasion by exogenous substances and outward migration of endogenous fluids and dissolved molecules.

<img file="MX353241B_D0008.tif" />

Various methods of treating i

INSTITIIT .MtXICANΛ incÍuyfeft skin^TRei microneedles, laser ablation, ab 1 ion — ρ · &lt;?. · Γ.Γ, thermal, sonophoresis, iontophoresis, or a combination of these.

The matrices of microneedles or microperforators, also mentioned, sometimes as microstructured transdermal systems (MTS), allow intradermal delivery of active agents that would not otherwise penetrate the stratum corneum.

The sharp tip of the microneedle is designed to penetrate the stratum corneum layer of the skin,

<td colspan="2">but it's short enough</td><td>how</td><td>not to</td><td colspan="2">pierce the</td>

<td>nerve endings and,</td><td>of</td><td>this</td><td>way,</td><td>I know</td><td>reduces or</td>

<td>eliminates the pain produced</td><td>by</td><td colspan="2">insertion.</td><td>Without</td><td>embargo,</td>

Often, penetrating microneedles to precise levels into skin tissue and with adequate reproducibility is challenging. Therefore, unlike the application of traditional patch delivery systems, some MTS require the aid of external energy to ensure efficient and reproducible penetration of microneedles into biological tissue to desired depths. This can be accomplished by an apparatus device that can be used after positioning the microneedle unit on the skin surface or the apparatus device can be integrated with a microneedle unit and, when activated, can supply the microneedle unit To the skin.

The

<img file="MX353241B_D0009.tif" />

MEXICAH INSTITUTE? mic / Ó ^ W

<img file="MX353241B_D0010.tif" />

create microchannels in the skin that, in some modalities, can facilitate the supply of an active ingredient. In some constructions, the active component (s) may be coated in the microneedle unit and supplied directly through microneedles pierce the stratum corneum.

the skin when

An advantage of MTS systems compared to other skin treatment methods is a mode of delivery that causes less pain.

SUMMARY OF THE INVENTION

Some embodiments of the present invention provide a microneedle injection apparatus that may include a housing having a base and a cavity extending through the base to define an opening in the base, where the base of the housing is configured to position yourself towards a surface of the skin. The apparatus may further include a microneedle unit holder configured to retain a microneedle unit within the cavity of the housing. The microneedle unit holder can be configured so that it is located at least partially in the housing cavity and is movable with respect to the opening in the housing base between (i) a stowed position in which the microneedle unit is retracted into the housing so that the microneedle unit does not enter

IM P |

OE M ¿i '_TO.» ^? in contact with the skin surface when iá ^^ fí ^ se ^ TáéíA · * housing is positioned on the surface of the microneedle unit engages the support of the microneedle unit, and (ii) an extended position in which At least a portion of the microneedle contacting unit is positioned with the skin surface through the opening when the base of the microneedle positions on the skin surface and microneedles.

movable second unit with housing unit is attached to the

The apparatus may support include, with respect to the housing of the unit in addition, an actuator and the support of the microneedle between a first position to cause the microneedles to move from the extended one. At least one adjacent location being configured for second position on the surface to move position support portion position and one of the unit retracted to the base actuator position of the housing and skin responsive.

can can first position the appliance pressure to the towards

Other characteristics and aspects of the present description will be evident when considering the detailed description and accompanying figures.

BRIEF DESCRIPTION OF THE FIGURES

FIG. 1 is an assembled front perspective view of a microneedle injection apparatus in accordance with one embodiment of the

<img file="MX353241B_D0011.tif" />

UHSTJTl ITO MEXiCANC, DE LA ΚΟΡΙΕpresen &amp; fesT the device includes a cover and an injection unit, and an infusion unit.

Figure 2 is a side view of the apparatus of Figure 1.

Figure 3 is a side cross-sectional view of the apparatus of Figures 1 and 2.

Figure 4 is a partially diagrammatic top and front perspective view of the apparatus of Figures 1-3.

Figure 5 is a front and bottom partially diagrammatic perspective view of the apparatus of Figures 1-4.

Figure 6 is a front and top diagrammatic perspective view of the apparatus of Figures 1-5.

Figure 7 is a side cross-sectional view of the apparatus of Figures 1-6; the appliance is shown in a first condition with the cover removed.

Figure 8 is a close up upper and rear partial perspective view of the apparatus of Figures 1-7; the appliance is shown in the first condition with the cover removed.

Figure 9 is a side cross-sectional view of the apparatus of Figures 1-8; the apparatus is shown in a second condition.

Figure 10 is a close-up top and rear partial perspective view of the apparatus of Figures

1-9; the apparatus is shown in the second condition.

Figure 11 is a view in

<img file="MX353241B_D0012.tif" />

side of the apparatus of Figures 1 -IG ··; ol ~ —apa-rai-n is shown in a third condition.

Figure 12 is a close-up top and rear partial perspective view of the apparatus of Figures

1-11; the apparatus is shown in the third condition.

<td>The</td><td>Figure 13</td><td>is</td><td>a section view</td><td>cross</td>

<td>side</td><td colspan="2">of the apparatus</td><td>Figures 1-12; the</td><td>appliance is</td>

<td>shows</td><td colspan="3">in a fourth condition.</td><td></td>

<td>The</td><td>Figure 14</td><td>is</td><td>a section view</td><td>cross</td>

<td>frontal,</td><td>close up</td><td>of the</td><td colspan="2">apparatus of Figures 1-13; the</td>

<td>apparatus</td><td>it shows</td><td>in the</td><td>fourth condition.</td><td></td>

<td>The</td><td>Figure 15</td><td>is</td><td>a section view</td><td>cross</td>

<td>frontal,</td><td>close up</td><td>of the</td><td colspan="2">apparatus of Figures 1-14; the</td>

apparatus is shown in a fifth condition.

<td>The</td><td>Figure 16</td><td>is</td><td>a view in</td><td>section</td><td colspan="2">cross</td>

<td>side</td><td>of the appliance</td><td>of</td><td>the figures</td><td>1-15; the</td><td>apparatus</td><td>I know</td>

<td>shows</td><td>in the fifth</td><td colspan="2">condition.</td><td></td><td></td><td></td>

<td>The</td><td>Figure 17</td><td>is</td><td>a view in</td><td>section</td><td colspan="2">cross</td>

<td>side</td><td>of the appliance</td><td>of</td><td>the figures</td><td>1-16; the</td><td>apparatus</td><td>I know</td>

<td>shows</td><td>in a sixth</td><td colspan="2">condition.</td><td></td><td></td><td></td>

<td>The</td><td>Figure 18 is</td><td>a</td><td colspan="2">top flat view of</td><td>apparatus</td><td>of</td>

Figures 1-17; the apparatus is shown in the sixth condition.

Figure 19 is a close-up side cross-sectional view of the apparatus shown in Figure 9, 1.? ·.

taken from the portion marked with the circle ^ ÍEÍÍi ^ dxóXdó as; 19 in Figure 9.

Figure 20 is a close-up side cross-sectional view of the apparatus shown in Figure 11, taken from the portion marked with the circle indicated as 20 in Figure 11.

Figure 21 is a close-up side cross-sectional view of the apparatus shown in Figure 17, taken from the portion marked with the circle indicated 21 in Figure 17.

Figure 22 is a side cross sectional view of the apparatus of Figures 1-21; the apparatus is shown in a seventh condition.

Figure 23 is a top plan view of the apparatus of Figures 1-20; the apparatus is shown in the seventh condition.

Figure 24 is a top perspective view of the cover of Figures 1-6.

Figure 25 is a bottom perspective view of the cover of Figures 1-6 and 24.

Figure 26 is a top cross sectional view of a portion of an infusion unit in accordance with another embodiment of the present invention.

Figure 27 is a close-up side cross-sectional view of an illustrative microneedle unit.

<img file="MX353241B_D0013.tif" />

INSTITUTE μ; · · -, // 7 / -. that can be used with the Fillet machine l-25j&gt; the microneedle unit is shown with ..... the .....- jui.cxiaag.uj.añ .. pointing upwards.

DETAILED DESCRIPTION OF THE INVENTION

Before explaining in detail any embodiment of the present invention, it will be understood that it is not limited in its application to the details of construction and to the arrangement of components set forth in the following description or illustrated in the following figures. The invention may have other embodiments and may be practiced or carried out in various ways. Furthermore, it will be understood that the phraseology and terminology used in the present description are for the purpose of description and should not be considered as limiting. In the present description, the use of including, comprising or having and its variants is intended to encompass the elements indicated after these expressions and the equivalents of these as well as additional elements. Unless otherwise specified or limited, the terms mounted, supported, and coupled and variations thereof are widely used and encompass direct and indirect mounting, mounting, and coupling. It should be understood that other modalities may be used and that structural or logical changes may be made without departing from the scope of the present description. Furthermore, terms such as front, back, top, bottom and the like are used only to describe the eÍ®fneri.tc) ¿c &amp; mp s © · 'relate to each other, but are in no way intended to establish specific orientations of the apparatus, indicate or imply necessary orientations required of the apparatus or specify how the invention described in the present description will be used, mounted, displayed or positioned during use.

The present disclosure generally relates to microneedle injection apparatus and methods of using them. The apparatuses of the present invention can include a microneedle unit that can be applied to the skin (or to a biological membrane) to treat the skin (i.e., create small holes or perforations or micropores in the skin) and, in addition, can supply a active agent to the skin. The apparatuses of the present invention particularly include an inverted actuator to trigger release of a microneedle unit holder to which a microneedle unit can be attached, to allow the microneedle unit to impact and penetrate a patient's skin when is desired. Such an actuator may be movable with respect to the housing and holder of the microneedle unit (for example, when the holder of the microneedle unit is in a retracted position) between a first position and a second position to cause the holder of the microneedle unit is moved from a retracted position to an extended position in which the microneedle unit is

<img file="MX353241B_D0014.tif" />

with the patient's skin. Particularly, in the apparatus of the present invention, at least a portion of the actuator may be located adjacent a base of an apparatus housing, i.e., on a skin-facing side of the apparatus, and may be actuated in response to the apparatus that pressed to or onto the skin surface. Such a configuration is referred to in the present description as an 'inverted actuator'. Several advantages of using a 'reverse actuator' are described in more detail below.

Some embodiments of the apparatus of the present invention can be configured to be activated by a simple actuation to automatically and reliably penetrate (or inject) a patient's skin with a microneedle unit (eg, a hollow microneedle unit) and, then automatically releasing and supplying it with a stored fluid (eg, an active agent) from a receptacle (eg, a ready-to-use drug cartridge) in a controlled manner from an infusion device integrated into the skin via the microneedles. That is, in some embodiments, the inverted actuator can be configured to initiate injection and infusion without the need for the user to perform additional steps after simple initial actuation.

The phrase hollow microneedle refers to a specific microscopic structure that includes a

The hollow microneedles of the present to traverse the stratum corneum to

INSTHW&gt; ΜΓΧΙΟι ·: · /. TO

DELA Ι · Λ ·&gt; ΠΕ0ΑΩ lumen formedá'dó'fen ¿IS-ar descriperé facilitate the delivery of active agents through the skin, for example, through each lumen. As an example, microneedles can include needles or needle-like structures, in addition to other structures that can traverse the stratum corneum and deliver the active agent. Other details about the microneedles that can be used with the apparatus of the present invention are described in more detail below.

Some embodiments of the present invention can be configured to synchronize and organize a sequence of events after actuation, such as, for example, that the microneedles are in place, and penetrate the skin, before the start of delivery or release of the agent from the integrated infusion device. For example, in some embodiments, the apparatus of the present invention may include an injection unit or device that includes a microneedle unit holder and an infusion unit or device that includes a cartridge that defines a receptacle configured to contain an active agent. . An actuator can be actuated to cause the injection device to inject microneedles into the skin and to initiate infusion of the active agent from the injection device through the injection device into the skin. In some embodiments, the injection device is in a retracted position until the actuator causes the infusion device to move and release the injection device. Just as an example and as described in more detail below, the actuator can be moved from a first position to a second position, so that a shuttle is released from the infusion device that holds and transports the cartridge, which in turn releases at least a portion of the injection device (eg, the microneedle unit holder). In some embodiments, the shuttle can continue to move after the injection device penetrates the skin to move the cartridge to an infusion position, where the cartridge holder is in continuous communication with a fluid path (eg, that includes hollow microneedles that penetrate the skin). The active agent can then be forced out of the cartridge receptacle into the fluid path to deliver the active agent to the skin.

The apparatuses of the present invention may be useful when applied to the skin as a pretreatment step, that is, when applied to the skin to alter the layer of the stratum corneum of the skin and then removed. Thereafter, the altered area of ​​the skin may be useful to allow for the improved delivery of a topical composition (eg, a solution, a cream, a lotion, a gel, a

<img file="MX353241B_D0015.tif" />

ointment or the like) or patch comprising an active agent · applied to the disturbed area.

The invention may further be useful when providing the microneedles with a dry coating comprising an active agent that dissolves from the microneedles after they are inserted into the skin. As a result, the apparatuses of the present invention may be useful for improving the delivery of molecules to the skin, such as in dermatological treatments, the delivery of vaccines, or in enhancing the immune response of vaccine adjuvants. In addition, in some embodiments, the active agent can be applied to the skin (for example, in the form of a solution that is applied with a swab to the surface of the skin or as a cream, lotion, gel, ointment, or the like. , which is rubbed on the skin surface) before applying the microneedles of the apparatus of the present invention.

When a patch is applied to the treated or altered site, the patch can be provided in various forms and can include a drug receptacle comprising an active agent to deliver to the treated site. For the continuous transdermal delivery of a therapeutically effective amount of an appropriate drug, any suitable transdermal patch can be used. Suitable transdermal patches include gel or liquid receptacles, such as those in US Pat. USA no.

IΜ ΡI

4,834,979 (Gale), called patches of ^ot patches containing attached drive enclosures? . a,, 1¾ skin by an adjacent adhesive layer, such as in US Pat. USA no. 6,004,578 (Lee et al.), Called unit patches; and patches containing pressure sensitive adhesive (PSA) receptacles, such as in US Patents. USA nos. 6,365,178 (Venkateshwaran et al.), 6,024,976 (Miranda et al.), 4,751,087 (Wick), and 6,149,935 (Chiang et al.), Referred to as adhesive drug patches, the disclosures of which are incorporated herein by reference. In some embodiments, the drug receptacle can be provided in the form of a drug-containing unit layer; The unit layer adheres to a skin contact adhesive on the patch. Such a unit may be a layer of adhesive. Alternatively, the unit layer may be non-adhesive or weakly adhesive and depend on the surrounding rim of the skin contact adhesive on an adhesive patch to secure the patch in place and keep the drug container in contact with the skin surface. .

In another embodiment, the drug receptacle may be provided in the form of solid particles incorporated on the surface or within the skin contact adhesive of the patch. In particular, these particles can be hydrophilic

<img file="MX353241B_D0016.tif" />

with exposed aqueous fluid on the surface of the treated skin will cause them to dissolve or disintegrate and therefore release drug to the skin.

In another embodiment, the drug receptacle may be provided within the skin contact adhesive of the patch. The drug can be mixed with the skin contact adhesive prior to forming the patch or can be applied to the skin contact adhesive of the patch in a separate process step. Examples of suitable methods of applying drug to an adhesive layer can be found in US Patent Application Publication. USA no.

2003/054025 (Cantor et al.) And in US Pat. USA

no. 5,688,523 (Garbe et al.), The disclosures of which are incorporated herein by reference.

The time between (i) microneedle treatment of the skin to increase permeability and (ii) the placement of the active agent in contact with the treated skin area may vary. In some modalities, this time can be kept to a minimum to avoid any chance that the skin barrier will form again through a healing process. The minimum time can generally be governed by the time necessary to remove the apparatus of the present invention from the skin and apply the active agent, for example, apply a solution with a swab, rub a cream or patch coating, and apply your adhesive on the treated site (for example, if a patch is used), etc. This time can be less than about 1 minute, less than about 30 seconds, less than about 10 seconds, or less than about 5 seconds. However, there is no reason why this time cannot be extended to many minutes or hours if desired. Generally, it is known that the length of time the skin will become increasingly patent after treatment depends on the type of treatment and whether or not the skin becomes blocked after treatment. In some cases, increased permeability can be maintained for up to several days as long as the treated site remains blocked, and even without that block the skin may have greater permeability for several hours. Therefore, if there is any clinical benefit or advantage, the site could be treated and delay the delivery of an active agent / ingredient through the use of some type of dressing on the treated site until such time as delivery is desired. of the active agent, at which time the active agent could be applied to the treated skin.

When describing the apparatus of the present invention, the term "downward" and variations thereof are sometimes used to describe the direction in which the microneedles are pressed into the skin and upward /

wnrr · '· ·.' '\' σ: '.' -&gt;

to describe the opposite direction. Without '^ emJóar'qp,. The..-⁷ Those of skill in the art will understand that they are used when microneedles are pressed into the skin at an angle to the direction of earth's gravity or even in a direction contrary to that of earth's gravity, and these terms are used only to simplify and clarify when describing relative directions.

Figures 1-25 illustrate a microneedle injection apparatus 100 in accordance with an embodiment of the present invention. As shown, in some embodiments, apparatus 100 may include an injection unit (or device) 101 and an infusion unit (or device) 103, which may be an integrated infusion device. Although the illustrated embodiment includes both the injection unit 101 and the infusion unit 103, in some embodiments, the apparatus 100 may include only the injection unit 101 and does not include an integrated infusion device such as the infusion unit 103 that It houses an active agent that will be delivered to the skin through hollow microneedles.

The phrase "integrated infusion device" generally refers to a unit or device that can deliver an active agent to the microneedles of injection unit 101 for delivery to a patient's skin and that forms a portion of or couples to and which can be used with injection unit 101.

In some ways, it is mentioned as a controlled, fluid libero apparatus.

I read injection unit

101 it may be further mentioned as a microneedle apiicator or apiicator and the infusion unit 103 may be further mentioned as a fluid storage and supply system or unit.

The apparatus

100 may also include accommodation

102, an actuator 104, a microneedle unit holder 106 configured to contain and transport a microneedle unit 107 comprising a plurality of microneedles 108, a cartridge 110 defining a receptacle

111 configured to contain an active agent and a cover

113 . As shown in Figures 1, 2, 4, and 5, in some embodiments, housing 102 may include a ridged or textured surface or portion 117 to facilitate manual holding and / or handling of apparatus 100.

In some embodiments, cartridge 110 can be installed by manufacturers, assemblers, or users. Furthermore, cartridge 110 and microneedle unit 107 can be replaced and thus allow reuse of apparatus 100. Replaceable cartridges can provide the advantage of allowing cleaning, sterilization, charging, and recharging compared to microneedle devices that they have fixed or specific cartridges that are formed integrally with them.

IM

INST1T1 ··?

OF THE ; '' '

As shown in Figure 3, the unit

101 it can include the microneedle unit holder 106 and a microneedle unit 107 (that is, when coupled to the microneedle unit holder 106) and the infusion unit 103 can include the cartridge 110.

In some embodiments, apparatus 100 may further include a fluid path 123 in continuous communication with or that includes microneedle unit 107 (for example, any surface or distributor thereof, in addition to hollow microneedles 108), when the Microneedle unit 107 couples to the holder of microneedle unit 106. As a result, fluid path 123 can deliver an active agent to and through hollow microneedles 108. Such a fluid path 123 can provide continuous communication between injection unit 101 and infusion unit 103 and, therefore, in some embodiments, can be described as a path that forms a portion of either unit or as a connection between the units.

In some embodiments, at least a portion of fluid path 123 may be formed by a conduit or channel positioned to continuously connect cartridge 110 and microneedles 108. In some embodiments, that conduit may be provided by flexible tubing 129 (see Figures 3, 4 and 6). In some modalities, one end of

<img file="MX353241B_D0017.tif" />

mrrnuTo those pipes can be attached to the m unit and can be moved with the micraagj.ijas unit,, l, ü7_or., .. £ .and ... £ j__

<td>support</td><td>of</td><td>the unit of</td><td>microneedles</td><td> 106</td><td>). Such</td><td colspan="2">pipeline</td>

<td>flexible</td><td> 129</td><td>can allow</td><td colspan="2">that an element</td><td>stinging</td><td> 175</td><td>in</td>

<td colspan="2">communication</td><td>continue with</td><td>the journey</td><td>of</td><td>fluid</td><td> 123</td><td>and</td>

<td colspan="2">configured</td><td>to go through</td><td>or pierce</td><td colspan="2">the cartridge</td><td> 110</td><td>I know</td>

keep in a fixed location within housing 102. As such, piercing element 175 need not move with microneedle unit 107 and bracket 106. Such tubing 129 may be formed from various materials including, but not limited to , polymeric materials, such as polypropylene, polyethylene, silicone, other suitable polymeric materials, or a combination of these. However, in some embodiments, piercing element 175 may be fixedly coupled to support 106, apparatus 100 does not necessarily include flexible tubing 129, and piercing element 175 may be movable in housing 102 with microneedle unit 107 and the support 106.

Infusion unit 103 may further include a shuttle 125 configured to contain and transport cartridge 110 in continuous communication with fluid path 123. Actuator 104 may be used to drive injection and, in some embodiments, may also drive the movement of the shuttle 125 (and, consequently, the cartridge 110) and the infusion of the active agent in the path

<img file="MX353241B_D0018.tif" />

MSMW INSTITUTE *. , OíLAPRuHEL-AU fluid 123 and outside the hollow microneedles 1 wqstrjal

In some embodiments, the oto-108 microneedles can be configured to treat the skin (i.e., create small or micropore holes or perforations in the skin) and / or deliver an active agent through the skin, particularly the skin of a mammal and, particularly, transdermally. Various microneedles that can be used in the apparatus and methods of the present disclosure are described in more detail below. In embodiments in which microneedles 108 are hollow and configured to deliver an active agent, each hollow microneedle 108 includes a lumen 127 (see Figures 14 and 15). While a plurality of microneedles 108 are described herein, it should be understood that not all microneedles 108 in a given unit 107 need penetrate the skin (or be coated with an active agent in modalities in which microneedles 108 include a coating) in a certain use.

The term transdermal and variants thereof is generally used to refer to any type of delivery of an active ingredient that passes through any portion of skin. That is, transdermal can generally include systemic delivery (i.e., when the active ingredient is transported from one side to the other or substantially through the dermis, so that the active ingredient is delivered to the bloodstream), in addition to intradermal and active supply

<img file="MX353241B_D0019.tif" />

<img file="MX353241B_D0020.tif" />

partially through the dermis, for example TOT of¹Another of the outer layer (stratum corneum) of the skin, where the active ingredient is supplied to the skin, for example to treat psoriasis or to supply a local anesthetic). That is, the transdermal supply, as used in

<td>the present</td><td>description,</td><td>It includes</td><td>the</td><td colspan="2">supply of</td>

<td>ingredient</td><td>asset that</td><td>transports</td><td>of</td><td>a</td><td>side to side</td>

<td>through</td><td>at least one</td><td>portion</td><td>of</td><td>the</td><td>skin (but</td>

necessarily all layers of skin), rather than simply topically applied to an outer layer of skin.

In some embodiments, housing 102 may be self-contained and compactly constructed to provide a relatively low profile and relatively small footprint to, among other factors, facilitate patient use and comfort. The term footprint generally refers to the surface area occupied by an element (eg, apparatus 100), eg, on a skin surface. The footprint of a given element can be thought of as the area occupied by a contour of the element's outer dimensions. In some embodiments, low profile may refer to an apparatus 100 generally wide relative to its height. That is, a low-profile device may be a device that has a dimension that extends along the surface of the skin that is greater than a dimension that extends iNSTi.-U &lt;'&gt;.

Generally normal to (and far from) the skin surface, that is, low profile may refer to a dimension that extends parallel to the skin that is greater than its dimension that extends normal to the skin.

As shown, apparatus 100 and housing 102 can be elongated along a longitudinal axis L (see, eg, Figures 1 and 2) and can be configured to be oriented substantially parallel with respect to a skin surface when are in use. Such a configuration can provide a low profile for apparatus 100. A low profile can reduce the likelihood of microneedles 108 becoming misplaced during penetration and / or infusion and can facilitate hands-free use. While apparatus 100 is designed such that longitudinal axis L will generally be oriented parallel to a patient's skin surface during use, a compact, low profile design can be provided to allow for other orientations.

In some embodiments, housing 102 can be formed from more than one portion. In some embodiments, housing 102 may include a first portion (or upper portion) 120 adapted to engage (eg, removably or permanently) with a second portion (or lower portion) 122, so that first portion 120 can function as a cover for

<img file="MX353241B_D0021.tif" />

To the second portion 122.

At least a portion (fé ^ rSlá- ^ artii.ento

<img file="MX353241B_D0022.tif" />

or more light transmitting windows 124 which, in some embodiments, may allow a user to observe the progress of at least a portion of the infusion process. For example, as shown in Figures 18 and 23 and as described in more detail below, in some embodiments, infusion unit 103 may include one or more indicators 126 to indicate the progress of the infusion, and such indicators 126 may be visible through window 124. Window (s) 124 need not be fully transparent, but must be at least partially transmitting at wavelengths in the visible spectrum (i.e., from about 400nm to about 700 nm) to allow visual detection of indicator (s) 126 through window (s) 124.

Second portion 122 of housing 102 can be configured to contain and retain the injection unit

101 and infusion unit 103. The first portion 120 and the second portion 122 of the housing may include one or more retaining walls 105. The first portion 120 and the second portion 122 of the housing 102 may be configured to couple together by various means coupling including, but not limited to, snap fit coupling (also sometimes referred to as friction fit coupling or

INSTITUTO MEXICZN · ';

DB LA FRjPltDAO 3KL

INDUSTRIAL snap fit coupling by snap, magnets, hook and loop fasteners, adhesives, cohesives, clamps, points, staples, screws, nails, rivets, tacks, corrugations, retainers, welding (eg sonic welding (for eg, ultrasonic)) any thermal bonding technique (eg, heat and / or pressure applied to one or both of the components to be coupled), other suitable coupling means, or combinations thereof. Just as an example, in the modalities of the

Figures 1-25, the first portion 120 and the second portion

122 they are configured to be welded together by ultrasound. Furthermore, housing 102 is shown divided along its length into first portion 120 and second portion 122; however, other configurations are possible that further facilitate assembly and / or use of apparatus 100.

In some embodiments, housing 102 (eg, second portion 122 of housing 102) may include a base 112 (see, eg, Figures 3-5) configured to position toward a skin surface 50 (see, eg For example, the Figure

Base 112 can be configured to touch skin surface 50 during injection and / or infusion and can include a skin contact adhesive.

However, base 112 of the modality illustrated in the

Figures 1-25 does not include an adhesive and is a non-surface

<img file="MX353241B_D0023.tif" />

adhesive.

AJ ('' '' hee

INSTITUTO Mí.x, 'Can:&gt; * A

The base 112 of the accommodation 102 can &lt;fé^w^^ élídeís ^ 4 / and along the entire length of the ai ojami eni-n i 02, but the base 112 of the housing 102 mentioned in the present description refers, particularly, to the base 112 or portion thereof located adjacent to injection unit

101 and actuator 104, projecting outwardly from base 112, as described in more detail below. Particularly, the base 112 of the housing 102 mentioned in the present description is generally provided or defined by a projection 119 that protrudes (for example, downwards) in relation to the rest of the housing 102 (see Figures 4 and 5).

In the attached figures, apparently, a trailing or tail end of apparatus 100 (for example, adjacent to infusion unit 103 and opposite the location where injection unit 101 is located) rises off the surface of the skin 50. While this may be the case, it is certainly possible that the tail end of the apparatus 100 rests further against the surface of the skin 50 during use. For example, the rear end of apparatus 100 may be angled downward toward skin 50 to facilitate support of the rear end on skin 50. In addition, in some embodiments, base 112 of housing 102 in that region (or extending along the apparatus 100) may further include a skin contact adhesive and may adhere to the skin. Also the projection 119 ^ é / ^^ gtrá solo&gt;

as an example; however, you should pnt-pndprge gye the ι ~^η100 it may be configured so as not to include such projection 119 and, in some embodiments, the entire base 112 of housing 102 may be at skin level 50 or it may be configured to adhere to skin, eg, after actuation.

Housing 102 may further include or define a cavity (or chamber or cavity or recess, etc.) 114. As shown, base 112 may define an opening 115, which opens into cavity 114. That is, the cavity 114 can extend through base 112 to define opening 115. Housing 102 and particularly cavity 114 (or a portion thereof) can be configured to accommodate at least a portion of the microneedle unit holder 106 and the microneedle unit 107 (for example, when coupled to the holder 106) that is, before the application of the microneedles 108 to the skin 50.

The microneedle unit holder 106 can be configured to be at least partially located in cavity 114 of housing 102 and can be configured to retain a microneedle unit 107 within cavity 114 of housing 102. The microneedle unit holder 106, in addition, it can be movable with respect to housing 102 (i.e., with respect to opening 115 in housing 102) to supply microneedles 108 to a substrate of interest

IM 7 ~ (for example, skin). As shown in lTY ^ áígá &amp; aMSf.

micro-needle unit support i oqPG. '¹ JIÍX ^a it can be configured to be positioned towards a skin surface, that is, oriented towards the skin, and it can be configured to receive the microneedle unit

107.

As an example only, a microneedle unit

107 coupling means (eg, removably coupled) of the microneedle unit 106 may be coupled to the bracket by various means including, but not limited to, snap fit coupling (furthermore, sometimes referred to as friction fit coupling) or interference fit coupling), snap coupling, magnets, hook and loop fasteners, adhesives, cohesives, clamps, points, staples, screws, nails, rivets, tacks, corrugations, seals, welding (eg sonic welding (eg ultrasonic)), any thermal bonding technique (eg heat and / or pressure applied to one or both components to be coupled), other suitable coupling means or combinations of these.

The microneedle unit 107 may include the microneedles 108 and any supporting structure or substructure used to support the microneedles 108 and / or to couple the microneedle unit 107 to other structures or components of the apparatus 100, such as the support of the unit of microneedles 106. Per unit of carrier or base microneedles) 109

<img file="MX353241B_D0024.tif" />

INDUSTRIAL 's; example, in some modalities,

107 may include fCT substrate from which microneedles protrude

108, in addition to additional layers or carriers. In the embodiment illustrated in Figures 1-25, the microneedles 108 are integrally formed with the substrate 109. However, it should be understood that additional layers may be used in the microneedle unit

107, and that other suitable configurations are possible.

For example, in some modalities, microneedles

108 can be formed directly on the substrate

109 which can then be coupled (eg mechanically and by fluids) to an additional base or layer.

In some embodiments, apparatus 100 does not include microneedle unit 107, but rather, apparatus 100 can be configured to retain microneedle unit 107 and to deliver microneedle unit 107 to the skin in accordance with specific parameters, for example , at a predetermined speed and / or impact force.

Such specific parameters, for example, can be used to ensure delivery of the microneedles 108 to a predetermined penetration depth.

The microneedle unit 107 (for example, the substrate

116 comprising the microneedles 108 and a second side 118 opposite the first side

116. The first side 116 can include a first surface can be oriented towards the base 112 sa ¡í t&gt; y »i ϊ * A Jk.

! N &lt;Tjn «TO MriXfCAÍO Dt L&gt; r ';:

say to be oriented main orient (eg, illustrated mode) of 108. The first side 116 of the housing 102 (is toward the skin surface 50). That is, a microneedle unit 107 can be coupled to the microneedle unit holder 106 such that the second side 118 is oriented towards the microneedle unit holder 106 and the first side 116 is oriented towards the base 112 of the housing 102 , i.e. positioned to face the skin surface 50, or may face the skin.

The housing 102, the actuator 104, the holder of the microneedle unit 106 and / or the microneedle unit 107 (for example, the substrate 109), the cover 113 and the shuttle 125 can be formed of various materials including, but not they are limited to thermoformed plastics (eg, acetal resin available under the trade designation DELRIN® DuPont Corporation, Wilmington, DE; other suitable thermoformed plastics or combinations thereof), thermoplastics (eg, polyethylene, polypropylene, other suitable thermoplastics, or combinations thereof), or combinations thereof.

Actuator 104 may include an internal portion 130 configured to receive in (or extend into) cavity 114 of housing 102 and to interact and / or engage injection unit 101 and, in some

IMPI

MEXICAN INSTITUTE C tl ^ A fKJPIti'AL ·

<img file="MX353241B_D0025.tif" />

modalities, the infusion unit 103. The JHTT actuator may further include an outer portion 1 ^ 2 coupled to inner portion 130 and configured to extend out of cavity 114 of housing 102 and through opening 115 of housing 102 so that outer portion 132 can projecting out of housing 102 and residing at least partially on the outside of housing 102 to allow a user to manually manipulate and control actuator 104. For example, as shown, in some embodiments, outer portion 132 may include or function as a button or other manually dockable portion or element. The outer portion 132 is illustrated as an example as a push button. As an example, inner portion 130 and outer portion 132 of actuator 104 of Figures 1-25 are integrally formed.

Actuator 104 may be movable with respect to housing 102 (eg, with respect to opening 115 in base 112 of housing 102) and the microneedle unit holder 106 between a first position Pi (see Figures 3-5 , 7 and 8) and a second position P2 (see Figures 9-13, 16-17 and 22) to cause the holder of the microneedle unit 106 to move, respectively, between a first position folded Hi (see, for example, Figures 3, 4 and 7-12), in which the microneedle unit 107 (when coupled to the support of the

<img file="MX353241B_D0026.tif" />

INSTITUTE 'to microneedles 106) retracts into the housing Vft ^ é ^^ uílOá / J.yZ®' 'the actuator 104, as described more abag-n) „anda, manp-ra g ^ jq the microneedle unit 107 no comes into contact with skin 50 when apparatus 100 is positioned on skin 50; and (ii) a second extended (or impact or treatment) position H₂ (see, eg, Figures 15-17 and 22), in which at least a portion of the microneedle unit 107 (when coupled to the holder of the microneedle unit 106) is positioned to contact the skin 50 (eg, through opening 115) when the apparatus is positioned on skin 50.

In some embodiments, movement of the support 106 from the retracted position H₂ may be damped by one or more shock absorbers or shock absorbing elements or materials, which is illustrated in Figures 13-15 and described

<td>below</td><td colspan="2">with regard</td><td>to a to</td><td>Lmort iguador</td><td colspan="2">163, as I know</td>

<td>shows in</td><td>the figures</td><td> 6,</td><td>14 and 15.</td><td></td><td></td><td></td>

<td>How</td><td>it shows,</td><td>in</td><td>some</td><td>modalities,</td><td>the</td><td>actuator</td>

<td>104 can</td><td>move from</td><td>its</td><td>first</td><td>Pi position</td><td>to</td><td>his second</td>

position P₂ against diversion of a diversion element 128.

As such, actuator 104 may deviate to its first position Pi (eg, downward) and may require a user to overcome the deviation of deviation element 128 to operate apparatus 100. That is, the deviation force presented by the deviation element 128 represents the force

<img file="MX353241B_D0027.tif" />

MTOCáa INSTITUTE&gt;

that a user should overcome to operate

This deflection force can be controlled dp way gneno ..... either, too high nor too low. If the deflection force is too low, the apparatus 100 may be too sensitive and the apparatus 100 may actuate prematurely, for example, when a user simply attempts to adhere the apparatus 100 to the skin 50. However, if the deflection force is too high, apparatus 100 may not be operable when pressed on soft skin. In some embodiments, the deflection force (eg, provided by the deflection element 128), and therefore, in addition, the driving force of the apparatus 100, may be at least 5 N, in some embodiments, at least 6 N and, in some modalities, is 8 N. In some modalities, the deflection force (and therefore the driving force) may be not greater than 15 N, in some modalities, not greater than 12 N and, in some modalities, not greater than 10 N.

As shown, the microneedle unit holder 106 can be movable between the Hi retracted position and the H extended position₂regardless of any portion of the infusion unit 103, such as cartridge 110 and shuttle 125, which can minimize the amount of structure that must move to impact skin 50 with microneedles 108. That is, injection unit 103 and portions of it are generally not movable with the ιμρι ^ 3 microneedle unit holder 106 retracted Hi and the extended position H2. As a result, injection unit 101 can be decoupled and operate separately from infusion unit 103, even though injection unit 101 and infusion unit 103 can form a portion of general apparatus 100 that allows each unit to be specific to its respective functions.

In some embodiments, the infusion unit 103 (eg, shuttle 125 and cartridge 110) can be configured so that it does not move independently of housing 102 at an appreciable level in a normal or substantially normal oriented direction with respect to the surface of the skin 50. That is, in some embodiments, infusion unit 103 can be configured so that it does not move independently of housing 102 toward or away from skin surface 50 at any appreciable level. As in the illustrated embodiment, in some embodiments, the infusion unit 103 can move toward the skin surface 50 with the housing 102 as the apparatus 100 is operated, without the infusion unit 103 moving separately from the housing 102 in this direction. In some embodiments, infusion unit 103 can be located in a portion (eg, an elongated portion, such as a handle or extension) of apparatus 100 that can be pressed to the skin surface 50 along with the rest of apparatus 100 when

<img file="MX353241B_D0028.tif" />

skin 50 to drive the actuator modalities, the infusion unit 103 can be configured so that it does not move relative to the housing 102 in a direction towards or away from the surface of the skin 50.

The first position folded Hi and the second position extended H₂ they can be separated from each other by a distance along an actuation axis A '(see Figures 3, 7 and 16), so that the support of the microneedle unit 106 can move along an actuation axis A ', for example, in relation to housing 102 and actuator 104 (for example, after actuator 104 has moved to its second position P₂), between the first retracted position Hi and the second extended position H₂.

The drive shaft A 'can generally be oriented substantially normal with respect to the skin surface 50 (and the first side 121 of the support 106, in addition to the first side 116 of the microneedle unit 107 when coupled to the support 106) , but not necessarily so. Rather, in some embodiments, drive shaft A 'may be arched or otherwise defined as nonlinear path (s), etc. Drive shaft A 'simply refers to movement between the first stowed position

Hi and the extended second position H₂.

Actuator 104 may further include a base 133 configured to be positioned toward the

<img file="MX353241B_D0029.tif" />

«MSTmT:» MEXICAN ιλ, '.'. Η, &amp;. Ο superf íciet-'Gl · ®

<img file="MX353241B_D0030.tif" />

and a cavity (or chamber or recess or cavity - or ori-f-Íe-io) ..... 134. extending through base 133 of actuator 104 to form an opening 135 (see, for example, Figure 7) in base 133 of actuator 104. Base 133 may be defined at least partially by outer portion 132 of actuator 104 and cavity 134 may be defined at least partially by internal portion 130 dimensioned to be received in cavity 114 of housing 102.

As can be seen by comparing Figures 7 and 9, in some embodiments, actuator 104 (eg, base 133 thereof) can move relative to base 112 of housing 102, such that when the actuator 104 is in the first position Pi, an outermost surface (eg, base 133) of actuator 104 may extend beyond base 112 of housing 102 at a first distance di (eg, see Figure 7); and when actuator 104 is in the second position P2, the outermost surface of actuator 104 no longer extends beyond base 112 of housing 102 (eg, is leveled with or retracted relative to base 112) or the outermost surface of actuator 104 extends beyond base 112 of housing 102 at a second distance d2 (eg, see Figure 9) that is less than the first distance di. That is, in some modalities, the actuator

104 can move between the first position ^^Ti ^^ úí | ia. position P2 with respect to base 112 'of housing 102 inside and outside opening 115 formed in base 112 of housing 102. That is, in some embodiments, when actuator 104 is in the first position Pi, at least a portion Actuator 104 may protrude from or through opening 115 in base 112 of housing 102 and may define a first surface (eg, base 133) configured to engage skin surface 50. Such a first surface may include a skin contact adhesive 150, as described below.

The configuration of the actuator 104 is shown located on a skin-facing surface of the apparatus 100, that is, adjacent to the base 112 of the housing 102. That is, the outer (attachable) portion 132 of the actuator 104 is shown located on and projected from a lower portion (i.e., second portion 122) of housing 102. That is, actuator 104 is an example of an 'inverted actuator' compared to conventional systems, in which actuator 104 is located on a lower side of apparatus 100. Such a configuration allows for easy operation of apparatus 100, and particularly allows movement of actuator 104 from first position Pi to second position P₂ in response to pressure from apparatus 100 toward skin surface 50 by pressure on an unoriented portion

INSTITurf) m:

πκττηιτπυ · t toward the skin or upper portion of the apparatus because it is not oriented toward the skin or portion (eg, housing 102) not necessarily directly opposite actuator 104. That is, the non-skin-oriented portion or upper portion may be located in an off-axis portion with respect to an actuation axis or central longitudinal axis of actuator 104.

The term off-axis generally refers to a position, direction, or axis of movement not aligned with the central longitudinal or actuation axis of actuator 104. For example, actuator 104 may move from the first position Pi to the second position. P₂ in a first direction along a drive axis in a first direction, along a drive axis A '' (see Figure 7), which, in the embodiment illustrated in Figures 1-25 is, in addition , its central longitudinal axis. Such actuation or movement of actuator 104 may be caused by a force exerted along a second direction that is not directly opposite to the second direction or that is not aligned with actuation axis A '' of actuator 104. Rather, Such movement of actuator 104 may be caused by a force oriented at an oblique angle with respect to the actuation axis A '' of actuator 104. In some embodiments, the second direction or axis may intersect the first direction or drive axis A '' of the actuator

<img file="MX353241B_D0031.tif" />

<img file="MX353241B_D0032.tif" />

&lt;1 rif INSTITUTO MEXICaN '»1,,, DELA PROHEDaD,

104 (for example, at an oblique angle), or the second ^ di or axis may be parallel with respect to the · - · ** je ^ -Iong-i teudinal · actuator central 104 without being directly in line with the axis drive A ''.

By allowing off-axis actuation of apparatus 100, apparatus 100 can offer more reliable actuation, greater user comfort, and improved economy, for example, if apparatus 100 can be actuated without requiring a user to dock or manipulate a location or specific element of the apparatus 100. For example, at least one portion (eg, the first portion (or upper portion) 120 of housing 102) may be configured to be pressed into skin 50 with the use of any part of one hand, such as the palm or fist of the user, rather than requiring the precise dexterity of finger handling. Such a configuration may provide an advantage, for example, for arthritis patients and / or older patients. Furthermore, the off-axis drive enables the apparatus 100 to be operated in various ways, contrary to a single option, clearly understood by a user, for example, by means of an intuitive design or configuration.

While 'inverted actuator' 104 in the illustrated embodiment is further shown to provide opening 135 through which microneedle unit 107 will deploy to impact and penetrate a skin surface, in

ΙΜ? Ϊ ^r '· Η »» ητυτσ MExif.-iio -' some modalities, can even be used ^nE'í ^; A / ^ ctcuia.dior' 'inverted, i.e. on a lower side or ladp. Qr.i.entLa £ ka .. towards the skin of the apparatus 100 and housing 102, without the actuator 104 further defining a cavity 134 or opening 135 through which the microneedle unit 107 and the support of the the microneedle unit 106 (as is the case in the illustrated embodiment, as described below). That is, in some embodiments, actuator 104 may even be reversed, but not positioned directly adjacent to the opening through which microneedles 108 extend when the holder of microneedle unit 106 is in its extended position H2. However, particular advantages can be obtained from the use of an actuator 104 such as that illustrated when the support of the microneedle unit 106 is movable also within the cavity 134 of the actuator 104, such as a compact design.

In some embodiments, as shown in the illustrated embodiment, actuator 104 can be configured to be located only in a portion of apparatus 100 that can locate the actuation of apparatus 100 to a precise area, even without the need for use to manipulate apparatus 100 in a precise way. For example, as shown, in some embodiments, general apparatus 100 may have or define a first footprint having a first area and actuator 104 may have a second footprint having a second area and

<img file="MX353241B_D0033.tif" />

In some modalities, the second area may be less than half (that is, less than 50%) of the first area. In some embodiments, the second area may be less than a quarter (that is, less than 25%) of the first area.

As shown in Figures 1-6 and 24-25, cover 113 can be configured to cover opening 115 in base 112 of housing 102. As shown in Figures 3-6 and described in more detail below with respect to Figures 24 and 25, in some embodiments, cover 113 may be a 'double cover' including a first portion 140 configured to cover the minus a portion of base 112 of housing 102 adjacent opening 115 and a second portion 142 configured to be received at least partially in cavity 114 of housing 102 and further configured to cover the plurality of microneedles 108 in the microneedle unit 107. In embodiments such as the illustrated embodiment using an 'inverted actuator' 104, the cover 113 may further be configured to cover the opening 135 for the cavity 134 of the actuator 104 (see, for example, Figure 3). Cover 113 (eg, second portion 142 thereof) can be configured to maintain sterility of microneedles 108 and fluid path 123 (i.e., in modalities using infusion unit 103). In modalities in which the microneedle unit

<img file="MX353241B_D0034.tif" />

ό. 7. and.

aroTwrr ·· r ·. ·

107 will unfold through the opening⁷· / Actuator 104, cover 113 (eg ^ H »pXa._and«~ -« 4a ^ '- &lt;' P'E-ime'r-a'- ~ - · * portion 140 of this) can also be configured to cover and protect actuator 104 before use and can be used to inhibit or avoid accidental premature actuation of actuator 104. In embodiments in which microneedle unit 107 will deploy through opening 115 in housing 102, but not necessarily through opening 135 in actuator 104, cover 113 (eg, first portion 140 of this ) can be configured to cover and protect at least the portion of base 112 of housing 102 configured to engage a surface of the skin. Cover 113 is further described in US patent application Ser. USA copendiente no. 61 / 829,659, filed on May 31, 2013, incorporated herein by reference.

As shown in Figure 5, in some embodiments, actuator base 133 may include skin contact adhesive 150 (described in more detail below) and apparatus 100 may further include an optional release liner. 152 (described in more detail below) which can protect skin contact adhesive 150 before use and during assembly, storage and shipping of apparatus 100. Release liner 152 can be removed before applying apparatus 100 to the skin. The

J. '·'. ·. ...: ·. IM

ΙΝΪΤΗΙΓ '¹ '

Ofu release liner 152 can be configured to 'be released or can be configured to present⁷¹Release characteristics * * ”” for skin contact adhesive 150, so that apparatus 100 can be attached to release liner 152 during storage and shipping and can be easily detached from release liner 152 during application of the apparatus 100. As an example only, release liner 152 may include a tab 155 (see Figures 4 and 5) positioned to facilitate removal of release liner 152 from skin contact adhesive 150 when desired. As shown, tab 155 may include one or more folds 153 to allow shortening of tab 155 during storage, but elongation when it is desired to facilitate removal of release liner 152.

In use, release liner 152 may be removed (if used) from skin contact adhesive 150 and adhesive base 133 of actuator 104 may be attached to skin 50. Actuation of actuator 104 may occur immediately after coupling of the base 133 of the actuator 104 to the skin 150 or even substantially simultaneously with the coupling of the base 133 to the skin 150. The base 133 of the actuator 104 can be kept coupled to the skin 50 throughout the injection and, optionally, the infusion. As a result, in some embodiments, the apparatus

INSTITUI&gt;,&gt; τ.

Own; . Cí.;.¹ ;

100 can be configured to be used by W^J '^,^ 'aciérité'^&gt;During fluid infusion / injection in such modalities, apparatus 100 can be applied directly to the skin of a patient 50 to accommodate ambulatory movement while maintaining microneedles 108 at a suitable depth of penetration. That is, even in modalities in which housing 102 itself does not include skin contact adhesive 150, housing 102 (i.e., apparatus 100 as a whole, including actuator 104, housing 102, and elements of the infusion unit 103) can be configured to remain coupled to the skin surface 50 after the microneedle unit 107 pierced the skin 50 and during the infusion. For example, in such embodiments, housing 102 may be configured to adhere to skin 50 through skin contact adhesive 150 on actuator 104.

In some embodiments, as shown, the microneedle unit holder 106 can be located and movable in cavity 134 of actuator 104 between the Hi retracted position and the extended H2 position. As such, in some embodiments, actuator 104 can be configured to at least partially surround microneedle unit 107 when microneedle unit 107 engages support 106, at least when support 106 is in the extended H2 position. In some embodiments, actuator 104 may be configured

IMPI

INSTITUTO mex.Cam ·. i

Say LA VRONFnAD to - *! - &lt;nx-r; r. i &lt;i ·.-..- - .. · .. '· that at least a portion of the actuator 104. ^ per external portion 132) surrounds the unit of my CTüagirj'd'a¹¹ fOT-- f and / or the microneedle unit holder 106) on all sides, or surrounds the microneedle unit 107 (and / or the microneedle unit holder 106), at least when the microneedle unit holder 106 is in the extended H2 position.

As shown in Figures 7 and 9, in modes in which actuator 104 is inverted and located adjacent to the same opening 115 through which microneedle unit 107 will contact skin 50 and when actuator 104 is in the first position Pi and the support of the microneedle unit 106 is in the retracted position Hi, the base 133 of the actuator 104 can be positioned at a first distance x_x of the first side (or base) 121 of the microneedle unit support 106 (and / or the first side (or base) 116 of the microneedle unit 107) see Figure 7. When the actuator 104 is in the second position P2 , the base 133 of the actuator 104 can be positioned at a second distance x₂ of the first side (or base) 121 of the microneedle unit holder 106 (and / or the first side (or base) 116 of the microneedle unit 107), see Figure 9, and the second distance X2 may be less than the first distance xi. As a result, the distance between the base 133 of the actuator 104 and the first side 121 of the support of the microneedle unit 106 (or the first side 116 of the microneedle unit 107) can be reduced moves from the first position Pi to

INSTITUTE ^ .F.X'Can.x .....

when eP * »_i^_J^,3 ^ $ acfóí ^ &lt;ÍO4 ^ '* ·&gt;

the second ... position ._P₂ ·,

As an example only in the embodiments illustrated in Figures 1-25, at least a portion of cavity 114 in housing 102 may be in the form of a cylindrical bore, at least a portion of actuator 104 may include an annular transverse shape (for example, when the cross section is considered substantially parallel with respect to the base 133) and the internal portion

130 of actuator 104 may be substantially tubular in shape and have the dimension to be received in the shaped cavity

<td colspan="2">hole</td><td>cylindrical 114</td><td>of the</td><td>accommodation</td><td> 102 .</td><td>Besides, the</td>

<td>cavity</td><td> 134</td><td colspan="2">defined at least</td><td>partially</td><td>by</td><td>Serving</td>

<td>internal</td><td> 130</td><td>actuator</td><td> 104</td><td>can have</td><td>the</td><td>shape of a</td>

<td>orifice</td><td colspan="2">cylindrical. How</td><td colspan="3">example only,</td><td>axes</td>

shape of central longitudinals of cavities with holes 114 and 134 defined by the housing

102 and the actuator

104, respectively, can be substantially aligned and the drive shaft A '(see Figures

3, 7 and 16) of the support of the microneedle unit 106 can also be substantially aligned with the central longitudinal axes of the cavities 114 and 134.

In some embodiments, the drive shaft A 'and the center longitudinal axes of cavities 114 and 134 may not all align exactly, but may be

I1M MM ¡Ν3Τ) Τυτ-1?,.&gt; '' Á substantially parallel one with respect to some modalities, the axis of action

106 can be oriented substantially parallel with respect to the drive

A '' of actuator 104, as shown in the illustrated embodiment. Furthermore, in some embodiments, as shown, drive A 'of bracket 106 may be substantially aligned (i.e., in line with) with drive shaft A' 'of driver 104.

When the holder of the microneedle unit 106 is in the first retracted position Hi, the holder 106 may be retracted into the housing 102 and the actuator 104, such that the holder 106 (and the microneedle unit 107, when coupled to the support 106) does not extend beyond base 112 of housing 102 or base 133 of actuator 104. The microneedle unit 107 can be movable with the support 106 throughout the entire distance between the retracted position and the extended position Hi and H₂of the support. That is, when the microneedle unit holder 106 is in the first retracted position Hi and a microneedle unit 107 is attached to the holder 106, the microneedle unit 107 may also be in a first retracted position Mi (see, for example, Figures 3, 7, 9 and 11), for example, in which the microneedle unit 107 is retracted into the housing 102 and the actuator 104 so that the microneedle unit 107 does not come into contact (or does not is positioned to

You? ' Λ-

- - . .·

ΙΝ3ΤΓΠΠ '· h-fib - enter coritowtw skin surface when base

104 it is positioned on the skin surface 50. The microneedle unit 107 may be housed within cavity 114 of housing 102 and cavity 134 of actuator 104, and may be retracted from base 112 of housing 102 and base 133 of actuator 104 in its retracted position Mi.

Also, when the microneedle unit holder 106 is in the second extended position H₂ and a microneedle unit 107 is coupled to the support 106, the microneedle unit 107 may also be in a second extended position M₂ (see, eg, Figures 15-17 and 22), for example, in which at least a portion of the microneedle unit 107 is positioned to contact the skin surface 50 when the actuator base 133 104 is positioned on the skin surface 50.

When the holder of the microneedle unit 106 and the microneedle unit 107 are in their second positions H₂ and M₂ respective, at least a portion of the microneedle unit 107 (and, potentially, a portion of the holder of the microneedle unit 106) may extend beyond the base 133 of the actuator 104. However, this is not necessarily the case and, in some modalities, it may be preferred that this is not the case. Rather, in some embodiments, microneedles 108 can be positioned sufficiently

<img file="MX353241B_D0035.tif" />

IMPI ~

MEXICAN INSTITUTE OF INDUSTRIAL MONEDAD near base 133 of actuator 104 (while still retracted within housing 102 and actuator 104 and not extending beyond base 133 of actuator 104), so that when base 133 is depressed On the surface of the skin 50, the skin 50 is deformed or rounded up through the opening 135 of the actuator 104 and into the cavity 134 to a position in which the skin 50 contacts the microneedles 108.

The portions of the housing 102 that define the cavity 114 and / or portions (for example, the internal portion 130) of the actuator 104 that define the cavity 134 can retain and / or guide the support of the microneedle unit 106 for the displacement to the along a path generally perpendicular to base 133 of actuator 104 (and / or base 112 of housing 102), as indicated by arrow A in Figure 7. The drive axis A 'of the support of the microneedle unit 106 can be generally normal or perpendicular to the longitudinal axis L of the apparatus 100. While in an illustrative embodiment, the movement of support 106 may be substantially 90 degrees from base 133 (and / or base 112), it will be appreciated that the generally normal path may deviate from 90 degrees to assume orientations that they can penetrate deep enough to deliver an intended dosage.

The support of the microneedle unit 106 (and a microneedle unit 107 coupled to the folded position Hi (and Mi) a by a first device

<img file="MX353241B_D0036.tif" />

operable to release its potential energy to apply force to the support of the microneedle unit 106 in a generally normal direction to the base 133 (and / or the base 112), for example downwards, in the direction of the skin surface 50 In some embodiments, such an actuated force allows the movement of the support 106 in a controlled manner, and thus ensures the application of the necessary forces so that the microneedles 108 penetrate the skin of a patient. As a result, apparatus 100 can reliably and consistently deliver microneedle unit 107 to the skin at a desired rate of impact, eg, to achieve the desired depth (s) of penetration.

In some embodiments, the first stored energy device 138 may be operable to apply force to the support 106 to achieve a velocity of the microneedle unit 107 before impact (i.e., before the microneedle unit 107 retained by the support 106 impact on a patient's skin) ranging from about 2 to about 20 m / s. More typically, microneedle unit 107 can strike a patient's skin at a speed prior to impact ranging from about 4 to about 12 m / s, in some embodiments, at a speed before impact of at least 5 m / s and , ΐΝ.ιτιτυτη K-.xir.AN&gt;

in algüHáSíu ^ f ^ Baí ^ sS'ásfe ',' '' at a speed before impact of approxirppdairientfi 6, m / s. ..

In some embodiments, the first stored energy device 138 may include a bypass element (eg, a spring) and is shown as a spiral spring as an example only in the illustrated embodiment. However, the stored energy devices of the present disclosure may include at least one stored energy device from a group consisting of: diversion elements (eg, springs), propellants, chemicals, motors, electrical devices, and combinations of these.

The microneedle unit holder 106 is deflected downwardly on apparatus 100 to its extended Hi position. As a result, a microneedle unit 107, when coupled to support 106, further deviates into its extended position Mi.

The holder of the microneedle unit 106 is prepared or maintained under load or against diversion (for example, when a diversion element is used as the stored energy device 138) when it is in the Hi retracted position, so that when the The microneedle unit holder 106 is released from the retention, the stored energy device

138 will provide the necessary forces to move the support of the microneedle unit 106 to its extended position H₂ and particularly at a desired speed.

In some embodiments, a portion of the actuator 104

I. ..

ΙΝ5ΤΠ'ΡΟ - ./-:.-.-7; . &lt;·&gt; **

Say, 7 ''; · * .- v? ·. - .., / can retain the microneedle unit holder ~^,!ltl6 é'ñ ~ éü 'position retracted Hi until the actuator ”1'04' '§e' ha m'óVi¿Jo to its second position P₂, at which point the actuator 104 no longer retains the microneedle unit holder 106 and the microneedle unit holder 106 is free to be driven by the stored energy device 138.

However, in some embodiments, as shown in the illustrated embodiment, an intermediate component, i.e., between actuator 104 and support 106, may be actuated to move (or be released) by moving actuator 104 to its second position. P₂, and when that intermediate component is actuated or allowed to move, it moves to a position where it no longer holds the support 106 in its retracted position Hi, and the support of the microneedle unit 106 is free to be driven by the stored energy device 138. As a result, in some embodiments, the support of the microneedle unit 106 is held within the housing 102 in its retracted position Hi by means of an element, component or structure of the apparatus 100 other than the actuator 104.

In the illustrated embodiment, that intermediate component is an element of the infusion unit 103, that is, shuttle 125. Shuttle 125 may be movable (eg, substantially along the longitudinal axis L of apparatus 100) between:

<img file="MX353241B_D0037.tif" />

(i) a first position of no in ^^^ fííxSi^x&lt;; tysjí¿r^;·· for example, Figures 3,

<img file="MX353241B_D0038.tif" />

receptacle 111 of cartridge 110 is not in continuous communication with fluid path 123 (i.e., in which cartridge 110 is not in continuous communication), and (ii) a second infusion position S2 (see, for example, Figures 17 and 22) in which the receptacle 111 of the cartridge 110 is in continuous communication with the fluid path 123.

As a result, in some embodiments, movement of actuator 104 to its second position P2 (i.e. actuation of actuator 104) can drive (i) movement of shuttle 125 (i.e. cartridge 110) to its second position S₂ and movement of the microneedle unit holder 106 to the extended position H2.

Since shuttle 125 in the illustrated embodiment is configured to contain and transport cartridge 110, the first and second positions Si and S2 of shuttle 125 further define cartridge positions.

110 .

As a result, the shuttle positions described in the present disclosure may further refer to cartridge positions.

110. However, in modalities that do not use the infusion unit

103, apparatus 100 may still include an intermediate element, i.e., shuttle 125 that is movable in response to movement of actuator 104 to its second position P₂ to a second position S₂ in^{, w}Ia '^{TO THE}what is the microneedle unit holder

<img file="MX353241B_D0039.tif" />

The position in which the support of the microneedle unit 106 is released is described below as the third position S3, which is intermediate to the first position of the shuttle Si and the second position of the shuttle S₂; however, in modes that do not include a cartridge 110 or the other elements of infusion unit 103, the second position S₂ The shuttle 125 can be described as the position in which the microneedle unit holder 106 is released.

The shuttle 125 can be prepared or kept under load in this first position Si and can be diverted to its second position S₂, such that when shuttle 125 is released by actuator 104, the shuttle is free to move and begins to move to its second position S₂. The use of the separate shuttle 125 carrying the cartridge 110 and operating between the actuator 104 and the microneedle unit holder 106 can provide a sequence of events that ensures a sufficient delay between impact (i.e., movement of the holder of the the microneedle unit 106 into its extended position H₂) and infusion (for example, at least when shuttle 125 moves to its second position S₂, where fluid communication is established between receptacle 111 and fluid path 123). That is, the support of the microneedle unit 106 can move to its extended position H2 before completing its movement to its modalities, as is the case.

IMPI ^^ 5

Xstituto mi'.xícan -&gt;

M THE INDUSTRIAL PFOPlíLtAD that the shuttle 125 has second position S2. In some of the illustrated embodiment, shuttle 125 may begin to move to its second position S2 before the microneedle unit holder 106 can reach its extended position H2, but apparatus 100 can be configured such that shuttle 125 does not will have fully reached its second position S2 (i.e. the point of establishing continuous communication between the cartridge

110 and fluid path 123) before microneedle unit 107 has pierced skin 50.

That is, even though the actuator 104 drives the movement of the shuttle 125 and the support of the microneedle unit 106, the support of the microneedle unit 106 may be in its extended position H2 when the shuttle 125 reaches its second position S2, such that there is a delay or delay between the time when the microneedle unit 107 is inserted into the skin 50 and the time when the receptacle

111 it is placed in continuous communication with the microneedle unit 107. If this were not the case, the active agent could begin to drip from the microneedles 108 before the microneedles 108 penetrate the skin 50. In some embodiments, this delay can be adjusted to a period of time in which microneedle unit 107 may experience some waviness as it impacts the skin

<img file="MX353241B_D0040.tif" />

<img file="MX353241B_D0041.tif" />

50, which can be from about 8 to about 10 milliseconds. Generally, it may be advantageous to provide continuous communication between fluid path 123 and cartridge 110 after microneedle unit 107 (and holder 106) has reached a steady state condition and no longer bounces off the skin surface 50 .

Shuttle 125 can be configured to be movable between its first position Si and its second position S₂in a direction or along an axis oriented at a non-zero angle with respect to the drive axis A 'of the support 106 and / or the drive axis A^z 'of actuator 104. That is, in some embodiments, the microneedle unit holder 106 may be movable between the retracted position Hi and the extended position H₂ along a first axis (i.e. its drive axis A '), actuator 104 may be movable between the first position Pi and the second position P₂ along a second axis and the shuttle 125 can be movable between the first position Si and the second position S₂ along a third axis and the third axis can be oriented at a non-zero angle with respect to one or both axes, the first axis and the second axis. Particularly, in embodiments using a low profile configuration, shuttle 125 can be configured to move in a direction substantially parallel to the skin surface 50 which, in addition, in some embodiments can be

-A- -K- A l _F '-nINSTITUTO MEXlCAN ·' ·

OF U PROPERTY

INI&gt; U3T. &lt;IAL can be oriented substantially perpendicular to one of both axes, the first axis and the second axis.

The shuttle

125 can be configured to interact with the microneedle unit holder

106 to retain support 106 in its stowed position

Hi until shuttle 125 reaches an intermediate position (i.e. a third position S3 - see, for example, Figure 13) between the first position Si and the second position S2, in which the holder of the microneedle unit 106 is released from its stowed position Hi by means of shuttle 125. Figures 11 and 12 show shuttle 125 after it started moving from its first position Si, but before it reaches third position S3, in which support 106 is released.

The movement of the shuttle 125 between its first and its second position Si and S2 can be accomplished or powered by one or more stored energy devices. In the illustrated embodiment, two stored energy devices are used to fully move the shuttle 125 from the first position Si to the second position S2. As an example, in the illustrated embodiment, a second stored energy device 144 (see Figures 3, 6, 7, 9, 11, 13, 16, 17, and 22) can initiate movement of shuttle 125, for example, move shuttle 125 from first position Si to third position S₃, wherein the holder of the microneedle unit 106 can be released from its

<img file="MX353241B_D0042.tif" />

As an additional example in modality i

<td colspan="2">device</td><td colspan="2">Energy</td><td>i stored</td><td> 146</td><td>(see</td><td>the</td><td>Figures 3,</td><td> 6,</td>

<td>7, 9 and 11,</td><td> 13,</td><td> 16,</td><td> 17</td><td>and 22) can</td><td colspan="3">complete the</td><td>movement</td><td>of</td>

<td colspan="2">the shuttle</td><td> 125</td><td>to</td><td>his second</td><td colspan="2">position</td><td>S2,</td><td>where</td><td>the</td>

<td>receptacle</td><td colspan="2"> 111</td><td>of the</td><td>cartridge:</td><td>MESS</td><td>this</td><td>in</td><td colspan="2">communication</td>

<td colspan="2">continue with</td><td>the</td><td colspan="3">fluid path</td><td> 123</td><td>and,</td><td colspan="2">Furthermore, you can</td>

<td>start and</td><td colspan="3">to complete</td><td>The infussion</td><td>of</td><td>a</td><td colspan="2">active agent</td><td>of the</td>

receptacle 111 of cartridge 110 to fluid path 123 and outside of hollow microneedles 108.

Cartridge 110 may include a movable piston 148 in receptacle 111 of cartridge 110 to force active agent out of cartridge 110 into fluid path 123 and out of hollow microneedles 108. Piston 148 may be in a slip and seal relationship with respect to the interior walls of the cartridge 110. This can provide a suitable seal for a fluid stored in an internal variable volume chamber formed between piston 148 and an openable end 151 of cartridge 110. Piston 148 can be moved or pressed into cartridge 110 by a plunger 149 that can engage and move with shuttle 125 and cartridge 110, until shuttle 125 reaches its second position S2, after which plunger 149 can be moved with respect to housing 102, shuttle 125, cartridge 110, etc. to actuate the piston

<img file="MX353241B_D0043.tif" />

ΙΝ'.ΠΤυΤΟ MEXICAN □ f THE PROfTEUAlX

148 and supply the active agent. I mean ~^DLbin^L

<img file="MX353241B_D0044.tif" />

modalities, infusion unit 103 can contiguUÍ'áT'S'e tte¹so that the piston 148 (and the piston 14 9) is not movable in the receptacle 111 with respect to the shuttle 125 until the shuttle is in its second position S2. That is, in some embodiments, infusion unit 103 can be configured such that piston 148 is inhibited or prevented from moving to its second position until shuttle 125 is in its second position S2.

Piston 148 and plunger 149 may be movable together between (i) a first position (non-supply or non-delivery) in which the active agent is not forced out of receptacle 111 and into fluid path 123 (i.e., in which active agent is contained within receptacle 111); and (ii) a second position or delivered position in which the active agent is forced out of receptacle 111 and into fluid path 123.

Given the variability of the volume of the receptacle 111 of the cartridge 110, the cartridge 110 can be configured to adapt to any dosing volume. Such a cartridge 110 may be of the type of cartridges in which the pre-filled drugs are ready for use. Cartridge 110 may be of the type of cartridges that meet standards, including international standards, such as standards established by the International Organization for Standardization (ISO).

<img file="MX353241B_D0045.tif" />

which can be relatively easy to 1 implar ..... and · 'eofee'r-áÍé-Z'ftgτ

The present disclosure further contemplates the use of valve mechanisms to open the openable end 151 of cartridge 110 to allow transfer of an active agent to fluid path 123. For example, a valve member retained by cartridge 110 it can be opened from a locked or closed condition by causing it to cooperate with the structure (not shown), such as a cannula, as the two are operatively coupled. Suitable valve mechanisms include, but are not limited to, those described in International Publication No. W02005 / 018705 issued to Cindrich et al.

Again with reference to piston 148, it is adapted to travel along a length of receptacle 111 (eg, which can be oriented substantially along longitudinal axis L) until the active agent is fully forced or expressed (or almost completely) from there. Typically, piston 148 can be made of materials that seal against the body of cartridge 110 but are, in addition, inert with respect to the active agent. For example, typically purified elastomeric materials, such as halobutyl rubber and silicone rubber materials, can be used for the pistons, but, in addition, other materials are contemplated, such as non-elastomeric materials. In addition, piston 148

<img file="MX353241B_D0046.tif" />

<img file="MX353241B_D0047.tif" />

Various materials, including construcGÚ ^ a «®- ^ LaiaÍaaGla®» ~~ £ Í ~ ^ although the illustrated embodiment uses one type of piston, other types of piston may be used, including those contoured in such a way that they substantially coincide with the interior shape of the openable end 151.

Other means are contemplated to reduce the empty space in the cartridge. For example, the receptacle lll can include small spherical objects. When the piston 148 moves forward and pushes the active agent out of the cartridge 110, small spherical objects can also be pushed forward into the neck of the cartridge 110 and around the piercing element 175. The spherical objects are preferably larger than the fluid path 123 in the piercing element 175 to prevent plugging of the fluid path 123. Instead, the spherical objects can be packaged around the piercing element 175 and displace the active agent in the cartridge neck gap. The spherical objects may be made of metal, plastic, glass, ceramic, or other material compatible with the active agent in the receptacle III.

Cartridge 110 has a longitudinal axis that can generally be oriented along the longitudinal axis L of apparatus 100 and / or that can be generally oriented parallel to skin 50 during use. In other modes, the cartridge ί "

110 can be arranged at angles mTTrnjTo-μ ex.íc / · .- ·· &lt;· _. . I heard THE rfcOPJE'l · &lt;· · ,. · -. ' ..

nonzero ^ í® &lt;Dh'-_rspit to the skin

SW.

In modalities on the low profile for apparatus 100 (or at least the infusion unit

103 thereof), the longitudinal axis of the cartridge 110 may generally be parallel to the major plane (eg, of the first side 116) of the microneedle unit 107 (when attached to the holder of the microneedle unit 106). Cartridge 110 may be a glass drug cartridge (eg, which is transparent). Such a glass drug cartridge may be of a commercially available type, such as those from Schott North America, Elmsford, NJ, USA and West Pharmaceutical Services, Inc. of Lionsville, PA, USA. Other types of cartridges that have similar properties are within the scope of the description.

When made of glass, cartridge 110 may further be advantageous with respect to improving the versatility of the delivery systems of the present disclosure. A potential advantage is that cartridge 110 can conform to sizes and shapes already known in the pharmaceutical field that, for example, can be easily loaded with the use of commercial equipment. Furthermore, since cartridge 110 can be packaged separately from apparatus 100, users may be able to use adapted receptacles and easily install them in apparatus 100 at the time of use. As shown in

<img file="MX353241B_D0048.tif" />

IWSTÍTUTO Μ

Figure 6, in some modalities it can be used¹* covered_door 147 to allow access άίΓβαΧώ ~ -Α. · ~ 1 ^ ~ ιώί4θ &amp; ο £ όη .. of infusion unit 103 in which cartridge 110 can be positioned. In addition, the ability to use known drug cartridges allows users to Patients use a wide variety of drugs and dosages supplied in a manner particularly suited to them and not rely on a manufacturer for dispensers that have fixed cartridges.

A typical glass drug cartridge that can be used with the apparatus of the present invention can have dimensions of 2 cm to approximately 8 cm in length and can have internal diameters of 4 mm to 12 mm. More typically, the lengths can be from 4 cm to 6 cm and the internal diameters from 6 mm to 10 mm. The present description contemplates other dimensions that depend, for example, on the volume of the active agent to be supplied. While a clear glass drug cartridge can be used, it is also possible to use other materials. The materials and construction of cartridge 110 are generally compatible with the desired active agent to be delivered and capable of withstanding the pressures generated during use.

In some modalities, the volume of active agent to be delivered or infused may be at least 0.1 mL, in some modalities at least 0.2 mL, and in some modalities at least 0.5 mL. In some embodiments, the volume may be no greater than

INSTITUTE, 'A mL, in some modalities, not in some modes, not greater than 5 mL and, in some modalities, not greater than 3 mL. In some modalities, the volume can be from 0.1 mL to mL, in some modalities, from

0.1 mL to 10 mL and, in some modalities, 0.1 to 5 mL. In some modalities, the volume can be from 0.5 mL to 3 mL.

As an example only, in the illustrated embodiment, the same third stored energy device 146 that completes the movement of shuttle 125 to its second position S2 may, in addition, initiate and complete the infusion process, i.e., initiate and complete movement of the piston 149 and the piston 148, accordingly, to supply the active agent.

In some embodiments, the second and third stored energy devices 144 and 146 each may include a spring or bypass element and each is shown as a coil spring as an example only in the illustrated embodiment. However, any of the above stored energy devices can be used for each of the second and third stored energy devices 144 and 146. In embodiments in which a bypass element is used, shuttle 125 may be prepared or held under load, for example, against bypass bypass elements 144 and 146 when the shuttle is in the first Si position.

That is, the shuttle 125 can deviate in or towards its second position S2 For example, the shuttle 125 can ιχίτπυτο MEXICANA

FROM THE INDUSTRIAL ERC'PIEE'AL 'deviate by means of one or both devices, the second stored energy device 144 and the third stored energy device 146, for example, if one or both of these devices, the second and third Stored energy device 144 and 146 include a diverter element. Shuttle 125 can be held in its first position Si until actuator 104 has moved to its second position P₂. As an example, in the illustrated embodiment, actuator 104 includes a portion that maintains shuttle 125 in its first position Si until actuator 104 has moved to its second position P₂.

Specifically, in some embodiments, as shown in Figures 8, 10, and 12, actuator 104 may include one or more shuttle stops (or catch hooks or retainers) 154 that can be moveable with actuator 104 when the actuator is moves between its first and its second

<td>position</td><td>Pi and</td><td>P₂.</td><td>Usually,</td><td>the</td><td colspan="2">apparatus 100</td><td>is</td><td>symmetrical</td>

<td>respect</td><td>of the</td><td>axis</td><td>longitudinal</td><td>L.</td><td colspan="2">As such,</td><td>the</td><td>modality</td>

<td>illustrated</td><td>uses</td><td>two</td><td colspan="3">shuttle stops 154,</td><td>one</td><td>in</td><td>each side</td>

of the apparatus 100; however, only one is shown in Figures 8, 10, and 12. However, it should be understood that, in some embodiments, apparatus 100 may include only one shuttle stop 154. In embodiments where more than one stop is used. of shuttle 154, it should be understood that the description of the present description can be applied in

IM ^r; :’^Λ' '^:S :,

Í715TJTVTO .tí&gt; ·&gt;. '. A

Give the way equivalent to additional caps. .........

Shuttle stop 154 ​​is configured ^,pⁱaffa^{to go}'Cabbage^,indaL 'engaging at least a portion of the shuttle 125. As a result, the stop of the shuttle 154 can be coupled to or formed by at least a portion of the actuator 104 and can be movable, with the actuator 104, between:

(i) a first position Ti with respect to the housing 102, the shuttle 125 and the support of the microneedle unit 106 (see Figure 8) in which the stop of the shuttle 154 is positioned to engage at least a portion of the shuttle 125 to hold shuttle 125 in its first position Si, and (ii) a second position T₂ with respect to housing 102, shuttle 125, and microneedle unit holder 106 (see Figures 10 and 12) in which shuttle stop 154 ​​is no longer positioned to engage at least a portion of shuttle 125 to keep shuttle 125 in its first position Yes, so that when the stop of shuttle 154 is in the second position T₂, shuttle 125 is free to move to its second position S₂for example, by the second and third stored energy devices 144 and 146.

In Figures 7 and 8, the actuator 104, the shuttle

125, the microneedle unit holder 106 and the piston

148 (and plunger 149) are all in their first positions

<img file="MX353241B_D0049.tif" />

IMPI

MEXICAN INSTITUTE

Of LA FXOPir.lAD

INl-USTIUAL respective, respective positions. In these first shuttle 125, support the microneedle unit 106 and keep the piston stored propelled

<td> 148</td><td>(and</td><td>the</td><td>plunger</td><td> 149)</td><td>can be prepared 0</td>

<td>low</td><td>a</td><td colspan="2">load ready</td><td>for</td><td>soar, that is,</td>

<td>by</td><td colspan="2">means, medium</td><td>of the</td><td colspan="2">power devices</td>

<td> 138,</td><td> 144</td><td>me</td><td> 146.</td><td></td><td></td>

the and 10, actuator 104 is in its

In Figures 9 second position

P2 and the stop of shuttle 154 is in its second position

T₂, but shuttle 125 has not yet started to move to its second S2 position. In Figures 11 and 12, the actuator

104 is in his second position P₂ and the stop of the shuttle

154 it is in its second position T2, and shuttle 125 has started to move to its second position S2, but the microneedle unit holder 106 has not yet been released from its retracted position Hi.

As shown in the Figures

8, 10 and 12, the shuttle

125 may include one or more extensions, teeth, or projections

156, each of which is configured to engage and interact with a stop of shuttle 154. Extensions 156 are shown, as an example, as side extensions that extend along side sides of apparatus 100 and are elongated, generally , along longitudinal axis L. Each extension 156 includes a first portion (or surface, for example, a lateral or front surface in the illustrated embodiment) that may have indentations or

<img file="MX353241B_D0050.tif" />

include an actuator shuttle configured flange 154 move out of engagement

MEXICAN INSTITUTE t '1 to engage until the actuator engages with shuttle 125, for example, until actuator 104 moves to the second position P₂ and, in this way, moves the stop of shuttle 154 to its second position T₂.

Each extension 156 may further include a second portion (or surface, for example, a top surface in the illustrated embodiment) that can be configured to engage the stop of shuttle 154 after actuator 104 has moved to its second position. P₂ to hold actuator 104 in second position P₂ after he moved to his second P position₂. As a result, as actuator 104 moves to its second position P₂, shuttle 125 is released; and shuttle 125 can be configured such that as shuttle 125 moves to its second position S₂, shuttle 125 catches actuator 104 and holds actuator 104 in its second position P₂.

Such a configuration can inhibit actuator 104 from being forced back into its first position Pi after actuation, for example, which could potentially dislodge microneedles 108 from skin 50 during use. Accordingly, each stop of shuttle 154 may include a first portion (or surface, eg, a lateral or rear surface in the illustrated embodiment)

<img file="MX353241B_D0051.tif" />

IMPI

MEXICAN INSTITUTE

DE LA fX'JELEDAD configured to inhibit the movement of the lance ^ era ~ TÍ5 from its first position Si and a second portion To the surface (for example, a lower surface in the illustrated mode) configured to inhibit the movement of the actuator 104 of its second position P2 once actuator 104 moves to its second position P₂. However, this arrangement and interaction between shuttle 125 and actuator 104 is shown as an example only. In some embodiments, the stop of the shuttle 154 on the actuator 104 can be configured to engage a different element when it is in its second P2 position to hold the actuator 104 in its second P2 position after it has moved to its second P2 position.

As shown, for example, in Figures 4, 6 and 7-

13, in some embodiments, the microneedle unit holder 106 may include one or more extensions or teeth 158 configured to engage one or more stops of the holder 160 on the shuttle 125. Similar to the stop of the shuttle 154 on the actuator 104, the stop of the support 160 is movable with the shuttle 125, between:

(iii) a first position Ri with respect to the housing 102, the actuator 104 and the support of the microneedle unit 106 (see Figures 7-10) in which the stop of the support 160 is positioned to engage at least a portion of the support of the microneedle unit 106 (i.e. the /

_ _ l · ··.

INSTTTVTi? MEXIC- · !! &lt;&gt; ί extension 158) to retain the dad support. _of.

microneedles 106 in their retracted position Hi, and. _Jt,_ ,._;7:.

(iv) a second position R₂ with respect to the housing 102, the actuator 104 and the support of the microneedle unit 106 (see Figure 13) in which the stop of the

<td>support</td><td> 160</td><td>no longer</td><td>I know</td><td colspan="3">positions for</td><td>couple to</td><td>less</td><td>a</td>

<td>portion</td><td>of the</td><td>support</td><td>of</td><td>the</td><td>Unit</td><td>of</td><td>microneedles</td><td> 106</td><td>for</td>

<td>keep</td><td>the</td><td>support</td><td>of</td><td>the</td><td>Unit</td><td>of</td><td>microneedles</td><td colspan="2">106 in his</td>

<td>position</td><td colspan="2">withdrawn</td><td>Hi,</td><td>of</td><td>way</td><td colspan="2">that when the</td><td>stop</td><td>of the</td>

support 160 is in second position R₂, the microneedle unit holder 106 is free to move into its extended position H₂for example by the first stored energy device 138.

Figures 11 and 12 illustrate shuttle 125 before it has almost reached its third intermediate position S₃, in which the support of the microneedle unit 106 is released and is capable of moving towards its extended position H₂, shown in Figure 13. As mentioned above and described in more detail below with respect to Figures 14 and 15, Figure 13 illustrates an optional damped position of support 106 before support 106 has fully reached your extended position H₂, shown in Figures 15-17 and 22.

The stop (s) of the support 160 in the shuttle 125 can (can) be coupled to or formed by a portion of the

<img file="MX353241B_D0052.tif" />

shuttle

125. Like '' T and r. '* - * Λ *

-Λ. -TO- ,

INSTITUTO MÍXICAN J L&gt; t LA PROPIEDAD INDUSTRIAL example only, extension shown

158 on the support 106 as a vertical projection. Extension 158 may be notched or include a flange (for example, so that extension

158 include an abutment with the bottom surface) configured to stop the support 160 (for example, an extend a predetermined distance along the longitudinal axis L of the apparatus 100, so that when the stop of the support 160 has moved to its second position R₂, extension 158 in bracket 106 has unclogged the top of bracket 160, is no longer engaged with the top of bracket 160, and bracket 106 is free to be driven by the first stored energy device 138 to its extended position H2. As another example, the stop of the support 160 can be formed or defined by one or more extensions, teeth or projections 162. Specifically, in the illustrated embodiment, shuttle 125 includes two extensions 162 that generally extend along the longitudinal axis L of apparatus 100 and include a lower protrusion or flange that includes an upper surface defining the stop of bracket 160. In the illustrated embodiment, the stop of the support 160 is formed, specifically, by two of those projections on which the extension 158 of the support 106 rests or against which it is forced, when the support 106 is kept under load in its position withdrawn Hi. I mean the

<img file="MX353241B_D0053.tif" />

INSTrn.'TnMíXICANO '

PE LA ΤΧΟΓΈιΆί), - i _ ⁷ ext ens'i'OTT *¹5 stops of the support 160 slide one in relation to each other as the shuttle 125 moves to the housing 102, generally, along the longitudinal axis L of the apparatus 100 towards its second position S₂, until the stop of the support 160 reaches its second position R₂ (i.e. until shuttle 125 reaches its third position S3, located between its first position Si and its second position S₂) .

As shown in Figures 6 and 14-15, in some embodiments, apparatus 100 may include one or more dampers 163 positioned between the microneedle unit holder 106 and actuator 104 (or housing 102 in modes in which support 106 does not move to its extended position H₂ adjacent to actuator 104). The dampers 163 can be configured to deform at least partially in response to the inertia of the microneedle unit holder 106 as the holder 106 is driven by the first stored energy device 138 to its extended position H₂ and, in this way, dampens or reduces the speed of the support 106 as it comes to a stop in its extended position H₂. In the illustrated embodiment, damper 163 includes a wire formed in an incomplete circle (see Figure 6) positioned in a recess within cavity 134 of actuator 104 and located between base 133 of actuator

<img file="MX353241B_D0054.tif" />

<img file="MX353241B_D0055.tif" />

104 and a lower part of the support 106

Figure 15 illustrates support 106 at the end of ..... its' re COÍlTdó ”(ie, with support 106 fully in position

H2 and the microneedle unit 107 fully in its extended position M2), with its guide rails resting on the ends of the guides formed within the actuator 104. The damper 163 in Figure 15 has been deformed and forced into a lower recess 164 by means of support 106.

In the illustrated embodiment, the recess 164 to which the damper 163 is forced is defined by the actuator 104; however, in modalities in which the support 106 does not move to the actuator 104, this recess could be provided by means of the housing

102 another element of the apparatus

100. The illustrated shock absorber

163 and the relative configuration between support 106 and actuator 104 are shown only as an example; however, any energy or shock absorbing element or material can be used, and other configurations are possible and are within the spirit and scope of the present description.

While the microneedle unit 107 impacts the skin 50, the shuttle 125 continues its movement along the longitudinal axis L towards its second position S2 (as shown in Figures 17 and 22). In the illustrated embodiment, as shown in Figures 13, 16, 17, and 22, gauge 126 may include a first portion (or body⁷⁵ IMPI

IN.ITm.iTC MEXICANO DE LA fltlWDAD IM U .- 'TRIAL principal) 126a and a second portion (or tail) 126b

<img file="MX353241B_D0056.tif" />

configured to be removably coupled to each other, for example, by means of one or more latches or retainers 166.

The second stored energy device 144 (eg, a spring) may be located within one or more retaining walls or tubes 168 (see, eg, Figure 13), which are provided by means of or are fixedly attached to housing 102. As an example, retaining wall 168 is generally tubular, generally centrally located in housing 102 with respect to shuttle 125 and indicator

126 and is generally oriented along the longitudinal axis

L. Retaining wall 168 can define a recess (or hole or chamber) 173, for example, that can receive at least a portion of the second stored energy device 144. In addition, the first indicator portion 126a and the second indicator portion 126b of the illustrated embodiment each include internal (eg, concentric and forward projecting) walls (or teeth or projections) 170a and 170b, respectively, coupled to each other removably (for example, at their respective leading ends) through the hitch 166 and together define a generally tubular recess 172 (see Figure 13) configured to receive the retaining wall 168. As an example, in the illustrated embodiment, the inner wall 170b of the second portion Indicator 126b is formed by a series of teeth (spaced

<img file="MX353241B_D0057.tif" />

<img file="MX353241B_D0058.tif" />

WWnT'rroMW &lt;. «Nio 'm LA FXOFiívAD circumferentially) configured to dispose of the inner circumference defined by the wall“ ^ ri't'éíffiaΎΤΰ a of the first indicating portion 126a when the first and second indicating portion 126a and 126b couple together through hook 166. Accordingly, the inner wall 170a of the first indicator portion 126a may include a series of notches or openings configured to receive at least a portion of the inner wall 170b, i.e. the portion (s) of one or more teeth formed by one or more hooks 166.

As the shuttle 125, together with the indicator 126, initially moves from its first position Si by means of the second stored energy device 144, the internal walls 170a and 170b, removably coupled by the hitch 166, travel or move they slide along the retaining wall 168 (and the remaining wall 168 is received within the recess 172 defined by the inner walls 170a and 170b). At this stage, the retaining wall 168 inhibits inward bending or deflection of the inner walls 170a and 170b, and thus keeps the hitch 166 in a closed or hooked configuration and keeps the inner walls 170a and 170b coupled together. .

Retaining wall 168 extends only (for example, along longitudinal axis L of apparatus 100) a relatively short distance forward from a rear wall 169 of housing 102. Therefore, as shuttle 125 and the indicator

<img file="MX353241B_D0059.tif" />

MEXICAN INSTITUTE '&gt;

<img file="MX353241B_D0060.tif" />

displacement in housing 102, the

170a and 170b of the first indicator portion 126a and the second indicator portion 126b move beyond the retaining wall 168 to a place where the internal walls 170a and 170b can flex with respect to each other. Particularly, in the illustrated embodiment, at this point, the inner wall 170b of the second indicator portion 126b is free to flex inward, i.e. relative to the inner wall 170a of the first indicator portion 126a. The third stored energy device 146 can now provide (or help provide) the energy necessary to overcome the hitch or retainer 166 to allow the first and second indicator portions 126a and 126b to separate, as shown in Figure 16. The third stored energy device 146 is positioned to couple at least a portion of the second indicator portion 126b to cause the second indicator portion 126b to move in a direction opposite to shuttle 125 and the first indicator portion 126a, for example, toward back in the housing 102 in the direction of the rear wall 169, with the inner wall 170b traveling along and receiving the retaining wall 168.

In some embodiments, at least a portion of indicator 126 may be in adjoining relationship with shuttle 125. For example,

IMPIOS

MEXICAN INSTITUTE

FROM FROHSDAD C. “« = »Aí '· W' as shown in 'l ^' ^ gurh ^ Tj, before shuttle 125 reaches its segtUKla · pusfelón 'S₂, "The second indicator portion 126b may be in abutting relationship with a rear end of the first indicator portion 126a and a rear end of the shuttle 125, ie, until the first indicator portion 126a and the second indicator portion 126b are separated .

After the first indicator portion 126a and the second indicator portion 126b are separated, the second stored energy device 144 and the third stored energy device 146 are positioned to continue the movement of shuttle 125 and the first indicator portion 126a in the housing 102 towards the second position of shuttle S₂. The second stored energy device 144 is positioned to continue pushing the plunger 149, while the third stored energy device 146 is positioned to move the first indicator portion 126a, which engages the plunger 149 (eg, through the wall internal 170a). Plunger 149 is positioned to contact and push piston 148 to pressurize receptacle 111 of cartridge 110 and a leading end (i.e. openable end 151) of cartridge 110 is positioned to contact an internal surface of shuttle 125 to continue actuation of shuttle 125 to its second position S₂

ΙΜΠ

INSTITUTE ΜΧΧΙΓλ.λ: M la nonsoAD industrial ___ __ y 22). In some (as shown in the embodiment Figures, the fluid within the cartridge 110 is not pressurized until this stage, that is, until the apparatus 100 is actuated and the resulting series of events includes the pressurization of the cartridge 110. For example, In the illustrated embodiment, the second stored energy device 144 is responsible for deploying shuttle 125 (and cartridge 110) to its second position S₂, and the third stored energy device 146, which is configured to provide greater forces than the second stored energy device 144, completes the movement of the shuttle 125, pressurizes and energizes the cartridge 110 and moves the piston 148 in the receptacle 111 of the cartridge 110.

The second indicator portion 126b that is configured to be removably coupled to the first indicator portion 126a is described as a portion of indicator 126 as an example only. Instead, this element can be described as a portion of shuttle 125 or as a completely separate element that is configured to removably engage at least indicator 126 or shuttle 125.

As an example only, plunger 149 in the illustrated embodiment engages with or is provided by (eg, integrally formed with) gauge 126, so gauge 126 includes (i) an internal portion

IMPI

MIXICANC INSTITUTE. FROM INDUSTRIAL MOPIH'AD —fr - - ftlB-iii 'TL — Τ-- A engage piston 149), of which at least a portion is responsible for engaging and moving piston 148 in cartridge

110; and (ii) an external portion 187 configured to travel along an external surface or wall

188 of shuttle 125 to be visible through window 124 to show the progress of active agent infusion (see

Figures 13, 16,

Specifically, in the illustrated embodiment, the outer portion 187 of indicator 126 is dimensioned to be received between a retaining wall 105 of the housing.

102 and the outer surface or wall

188 from the shuttle

125. That is, the outer portion

187 of the indicator 126 can be dimensioned to receive at least a portion of the shuttle 125, so that after the shuttle 125 has moved to its second position S2, the indicator 126 can be moveable with respect to the shuttle

Furthermore, in the illustrated embodiment, plunger 149 includes or defines an internal recess or chamber.

171 and the second stored energy device 144, for example, in the case where a spring is used as the second stored energy device 144, can be dimensioned to be received at least partially in the recess 173 defined by the retaining wall 168 and extends at least partially into internal chamber 171 to actuate or divert piston 149

<img file="MX353241B_D0061.tif" />

<img file="MX353241B_D0062.tif" />

back wall 169 of the

IMPI

MEXICAN INSTITUTE

OF. THE PROPltDAÜ ', - —INDUSTRIAL AM 102.

Furthermore, in the illustrated embodiment, the diameter of the indicator 126 includes a first external recess or chamber 190 defined between an internal surface or wall of the external portion 187 of the indicator 126 and the external surface or wall 188 of the Shuttle 125, the first outer recess 190 opens rearward. The first external recess 190 can be dimensioned to receive the third stored energy device 146 (eg, when a spring is used as the third stored energy device 146). As such, the third stored energy device 146 can be positioned to drive or deflect a front or front end of the indicator.

126 forward into housing 102, away from rear wall 169 of housing 102. In some embodiments, as shown, outer portion 187 of indicator 126 may further include a second outer recess 191 dimensioned to receive at least a portion of shuttle 125, second outer recess 191 opens forward.

In addition, in some embodiments, as shown, the internal portion 185 of indicator 126 may further include or define an internal recess or chamber 192 sized to receive at least a portion of cartridge 110.

<td>Particularly,</td><td>the</td><td>rebate</td><td>internal 192 can</td><td>receive a</td>

<td>closed end</td><td>of the</td><td>cartridge</td><td>110 (for example</td><td>what includes</td>

<td>piston 148),</td><td>by</td><td>example,</td><td>in a coupling</td><td>adjustment to</td>

Pressure. As shown

IMPI

ΙΝ.ΠΤΤυΤ MLX'CAN · .;

Of the cartridge 110 the cartridge 110 can be positioned in the internal recess 192 so that the piston 148 adjoins a front or front end of the piston 149.

As shown in Figure 17, the combined forces provided by the second stored energy device 144 and the third stored energy device 146 can complete the movement of shuttle 125 to its second infusion position S2, where receptacle 111 of the Cartridge 110 is placed in continuous communication with fluid path 123. As an example, as described above, fluid path 123 may include or engage sharpening element 175 (eg, a hollow needle) which, as an example only, can be held stationary with respect to housing 102 and shuttle 125. As another For example, cartridge 110 can be adjusted with a cover 176 and a septum 177 that can be accessed through cover 176. In some embodiments, the cartridge 110 may include a glass cylinder and the open or openable end 151 may be closed and sealed with the cap 176. The cap 176 may include a metal cap, such as an aluminum cap that may be corrugated to the open end 151 of the cartridge 110 in a known manner. Cap 176 may contain septum 177 which seals the otherwise open end 151 of cartridge 110.

Septum 177 can be made of many materials

ΙΝΓΠΤυΤΛ yFXrAA.IO

FROM FZCr'ítl'A! » different,

...... I that include those used t í¿íítd3Mént'§ ~^;:Receptacles (eg cartridges for 'drugCUET ^ - ”ET septum 177 can be manufactured with an elastomeric seal or septum, which can be punctured and resealed, which is securely mounted with or without being corrugated, through the open end 151 cartridge 110. In some embodiments, septum 177 (eg, formed from an elastomer) may be corrugated over one end of cartridge 110 with a malleable cap 176 formed, for example, from aluminum. For the septum other similar materials and ways can be used to secure it to the open end 151 of the cartridge 110. For example, a septum molded into the body of a cylinder can be used, such as the CZ series available from West Pharmaceutical Services, Inc, Lionville, PA, a cap, such as a standard syringe luer cap, or a molded end thin enough to puncture. Suitable materials can be punctured with sufficient puncturing force and maintain their seal after punctures. As noted above, septum 177 can be punctured during use and sealed around piercing element 175 with sufficient force to prevent leakage during depressurization and transfer of active agent from receptacle 111. Certain septate materials allow for resealing of septum 177 after piercing element 175 is removed after use. The present description contemplates the opening of the seal or

<img file="MX353241B_D0063.tif" />

INSTITUTE V :.

PF. M í'RCi'itj abertursr'uael

<img file="MX353241B_D0064.tif" />

closed in any other way 177 by divopoee-mófeodos

When shuttle 125 moves to its second position S2, piercing element 175 can pierce or pierce septum 177 and thereby place fluid path 123 (i.e., through piercing member 175) in communication Continues with receptacle 111 of cartridge 110, as shown in Figure 17. At this point, as further shown in Figure 17, the open end 151 of the cartridge 110 (for example, and the lid 176) adjoins a base 178 of the piercing element 175 defining the second position S₂ of shuttle 125. As a result, shuttle 125 and cartridge 110 come to a stop within housing 102. Now, the third stored energy device 146, one end of which is positioned to engage one end of indicator 126, can transfer its remaining stored energy to move indicator 126 (i.e., the first indicator portion 12 6a), along with the plunger 14 9, for actuating piston 148 within receptacle 111 and forcing the active agent into fluid path 123 through piercing element 175 into hollow microneedles 108. Figure 18 shows when indicator 126 begins to be seen through window 124 of housing 102 as the infusion process begins. Indicator 126 may be colored or in any other way visible relative to the other components of apparatus 100

<img file="MX353241B_D0065.tif" />

to make it clearly visible to a user

In the illustrated modality, the first larloΤ2 · 1 ΰ.εΊ ·· 'Βuparte

106 and the second side 118 of the microneedle unit 107 can be configured to be separated by a distance when the microneedle unit 107 is coupled to the support 106 to define a receptacle or distributor 180 therebetween (see Figures 14, 15, 17 and 22). Particularly, when the microneedle unit 107 is coupled to the holder 106, the second side 118 of the microneedle unit 107 or a portion thereof, a distance from the first side (or base) 121 of the holder 106 can be spaced to define the receptacle 180 As shown in Figures 14 and 15, the receptacle 180 can be configured to close on all sides to inhibit leakage. Other sealing members can be used as needed. Fluid path 123 may include or be in continuous communication with receptacle 180 and receptacle

180 it may be in continuous communication with the hollow microneedles 108 (ie, through the second side 118 of the microneedle unit 107). That is, in some embodiments, substrate 109 may include one or more channels positioned to extend through them to provide continuous communication between first side 116 and second side 118 of microneedle array 107. As a result, as the active agent is driven out of the receptacle

111 cartridge 110 and fluid path 123, the active agent moves to the receptacle

INSTITUTE MSXT-N 'οε ι.λ' ¹ &gt; INDUSTíV / O.

180 positioned to supply or feed the active agent to the plurality ...... 3 ~ hollow microneedles 108 to, in turn, deliver the active agent to the skin 50 through the microneedles 108. Other configurations are possible to provide continuous communication between the stinging element

175 (eg, the remainder of fluid path 123) and microneedles 108, and receptacle 180 is shown only as

Figures 7, 9, 11, 13, 16, example.

and 19-21 illustrate a sterility seal 182 positioned to enclose and maintain the sterility of piercing element 175 prior to piercing septum 177 and positioning piercing element 175 in continuous communication with receptacle 111 of cartridge 110. Particularly, Figures 19-21 show close-up cross-sectional views of the piercing element 175 and the sterility seal 182 and, particularly, show close-up views of the piercing element 175 and the sterility seal 182 of Figures 9, 11 and 17 , respectively, prior to perforation of seal 182, as seal 182 is perforated, and after seal 182 is perforated and falls.

As the shuttle 125 moves the cartridge 110 to the second position S2, the septum 177 which is positioned on the open end 151 of the cartridge 110 contacts and deforms the seal 182 until the piercing element 175 punctures or pierces the seal 182 (see Figure 20). While the shuttle

125 (and cartridge 110)

<img file="MX353241B_D0066.tif" />

INSTjmr · m continues its movement ^ ·

<img file="MX353241B_D0067.tif" />

Stabbing 175 continues the movement through-the-seal, 18.2.

as it pierces septum 177. That is, the seal 182 can be configured to deform and fall toward the base 178 of the piercing element 175 and, furthermore, can be configured to remain in a dropped configuration after it is punctured (eg, cannot return to its original position or configuration), as shown in Figure 21.

In some embodiments, seal 182 may be formed of materials similar to those described above with respect to septum 177 that allow seal 182 to be punctured during use and sealed around piercing element 175 with sufficient force to prevent leakage during pressurization and transfer. of active agent from receptacle lll or at least until piercing element 175 punctures septum 177 and septum 177 can prevent leakage. In some embodiments, the seal 182 simply falls around the piercing element 175 and is not sealed around the piercing element 175.

As further shown in Figures 19-21, sterility seal 182 can be configured to change from a first state (see Figure 19) in which sterility seal 182 defines a chamber (eg, a sterile chamber) 184 configured to house the piercing element 175 into a second state (see Figure 21) in which the sterility seal 182 has already been punctured by the piercing element 175 and has fallen, particularly

<img file="MX353241B_D0068.tif" />

the lid 176 or the open end 151 of the cartridge 110) and the base 178 of the piercing element 175. Figure 20 illustrates a third state or intermediate condition between those shown in Figures 19 and 21, in which the seal 182 is puncture by means of the piercing element 175.

As mentioned above, piston 148 and plunger 149 can move together between a first non-supplied position (for example, as shown in Figure 17) and a second supplied position (for example, as shown in Figure 22). , respectively. Figures 22 and 23 illustrate apparatus 100 with piston 148 and piston 149 in their respective second positions. That is, after continuous communication is established (see Figure 17) between fluid path 123 and receptacle 111 of cartridge 110, shuttle 125 is held in its second position S₂, and the third stored energy device 146 continues to drive the indicator 126 in the housing 102, by

<td>example,</td><td>to</td><td>the length</td><td>of the</td><td>axis</td><td colspan="2">longitudinal L which, in addition,</td>

<td>drives</td><td>the</td><td>piston 149</td><td colspan="2">¹ what to</td><td>turn it moves the</td><td>piston 148</td>

<td colspan="2">inside of the</td><td>cartridge</td><td> 110</td><td>for</td><td>force the agent</td><td>active at</td>

<td>journey</td><td>of</td><td>fluid 123.</td><td>The</td><td colspan="2">Figure 23 illustrates what</td><td>an user</td>

would see when the infusion or delivery of the active agent is complete and the apparatus 100 can be removed from the skin 50.

In use, cover 113 and release liner

152 can be removed. The contact adhesive at the base 133 of the actuator 104 (and / or eji. The b ^? E .112. ΗαΊ housing 102) can be applied to the skin 50. An upper portion (eg, the first portion 120) of the housing 102 of apparatus 100 can be pressed into skin 50 to cause actuator 104 to move from its first position Pi (as shown in Figures 7 and 8, illustrating a first condition of apparatus 100) to its second position P₂ (as shown in Figures 9 and 10, which illustrate a second condition of the apparatus 100), for example, against deflection of the deflection element 128.

The movement of actuator 104 to its second position P₂ releases shuttle 125 (i.e., by movement of shuttle stop 154) to allow shuttle 125 to begin moving to its second position S₂ (as shown in Figures 11 and 12, illustrating a third condition of apparatus 100), for example, as a result of being driven by the second stored energy device 144 (as shown in Figure 11). After shuttle 125 moves to a third position S3 located between its first and second position Si and S₂, the stop of the holder 160 in the shuttle 125 is no longer positioned to retain the holder of the microneedle matrix 106 in its retracted position Hi, so that the holder 106 is released and the first stored energy device 138 can

<img file="MX353241B_D0069.tif" />

<img file="MX353241B_D0070.tif" />

begin to provide forces to drive the microneedle unit holder 106 into its extended position H2 (as shown in Figures 13-14, illustrating a fourth condition of apparatus 100). In the illustrated embodiment, Figures 13 and 14 show a damped position of the support 106 and the support 106 can continue to its fully extended position H2 (and, accordingly, the microneedle unit 107 can continue to its extended position M2), as shown in Figures 15 and 16, which illustrate a fifth condition of apparatus 100. However, some embodiments do not use damper 163 or damped position of bracket 106 illustrated in Figures 13 and 14. The shuttle 125 then continues movement to its second position S2 and the first indicator portion 126a and the second indicator portion 126b are allowed to separate (as shown in Figure 16), at which point the third stored energy device 146 may provide or assist in providing forces to continue the movement of shuttle 125 to the second position S2.

When shuttle 125 reaches its second position S2 (as shown in Figure 17, illustrating a sixth condition of apparatus 100), receptacle 111 of cartridge 110 of infusion unit 103 is placed in continuous communication with the fluid path 123 and particularly with microneedles 108 in injection unit 101.

IMPI

Furthermore, at this point, indicator 126 '} “INDUSTRIAL

126a) may start to move in first indicator portion relative to shuttle

125, which can actuate the piston

148 in the receptacle 111 (for example, with the piston 149) and the advancement of the piston 148 can be displayed to a user by means of the indicator

126, which can be visible through window 124 in housing 102 (as shown in piston 148 and plunger 149 (and gauge 126) reach their respective second positions (as shown in Figures 22 and 23 , illustrating a seventh condition of apparatus 100), the infusion of the active agent is complete. This indication may be provided to a user with indicator 126, which may be visible through window 124 of housing 102, for example, when indicator 126 is shown to fill window 124.

Figures 24 and 25 illustrate cover 113 in greater detail. As mentioned above, cover 113 may include (i) a first portion (eg, outer portion) 140 configured to cover at least a portion of base 112 of housing 102 adjacent opening 115, in addition to base 133 of actuator 104; and (ii) a second portion (eg, internal portion) 142 configured to be received in cavity 114 of housing 112 and, furthermore, configured to cover the plurality of microneedles 108 in microneedle unit 107 when the support of the unit of microneedles τ 7ΚΛ Π τ '* *' *

Ικλ χ a.

106 is in the stowed position Hi. The signal ^ Q ^^ / ^ pfpÍQíi Λ42 ·: industrial 'can be further configured to be received in the cavity 134 of the actuator 104, for example, in modalities using an actuator 104 through which the microneedle unit 107 is deployed In addition, the first portion 140 can cover the base 133 of the actuator 104 adjacent the opening 135 in embodiments using an actuator 104 through which the microneedle unit 107 is deployed.

As mentioned above, base 133 of actuator 104 and / or base 112 of housing 102 may include skin contact adhesive 150 and any optional release liner 152. In such embodiments, cover 113 (i.e., first portion 140 thereof) can be configured to cover at least the portion of base 133 (and / or base 112) that includes the skin contact adhesive 150 and, optionally any release liner 152 used, particularly when actuator 104 is in the first Pi position. However, in some embodiments, after the apparatus 100 has been used and removed from the skin 50, the cover 113 can be used to again cover the actuator 104 and the base 112 of the housing 102, with the actuator 104 in this second position P₂.

In the illustrated embodiment, the first portion 140 and the second portion 142 of the cover 113 are integrally formed together. However, in some modalities, the

<img file="MX353241B_D0071.tif" />

irviJIUlU MUIIAI.'Ü Λ first and second portion 14 0 and 142 removably put together (for example, by any of the removable coupling means described above), which may allow coating and / or removal of the coating from the base 133 (and / or base 112) independently of microneedles 108.

As an example only, second portion 142 is generally illustrated as a tubular shaped portion, so that second portion 142 can extend through opening 135 (and / or opening 115) at base 133 (and / or or base 112) and to cavity 134 of actuator 104 (and / or cavity 114 of housing 112).

As shown in Figure 25, the first portion 140 may include or define a recess (or chamber or cavity) 195 (i.e., with a closed end 197) with dimensions suitable to receive at least a portion of the base 133 of the actuator 104 and / or at least a portion of base 112 of housing 102. In embodiments in which cover 113 covers actuator 104, closed end or base 197 of recess 195 may be spaced a distance from base 133 of actuator 104 when cover 113 is coupled to apparatus 100, so that actuator 104 is already it is not undesirably or prematurely actuated 104 prior to use.

As further shown, second portion 142 may include or define a recess (or chamber or cavity) 196 (i.e., with a closed end 198

IN'TIT'JT · with the dimensions á

<img file="MX353241B_D0072.tif" />

receiving the plurality of microneedles 108 which - &amp; protrude - from ~ the first main surface of the first side 116 of the microneedle unit 107. Recess 196 (eg, closed end 198) in second portion 142 may be defined at least partially by an inner surface, and the inner surface of recess 196 and first side 116 of microneedle unit 107 may together define a chamber. sterile to accommodate the plurality of microneedles 108 after assembly of apparatus 100 and before use. Such a sterile chamber can allow free access of the sterilizing agent (s) to the enclosed volume and, at the same time, prevent the entry of contaminants into the chamber after sterilization.

As further shown in Figure 25, in some embodiments, the second portion 142 of the cover 113 may

<td colspan="2">include</td><td>at least</td><td>a</td><td>projection or a</td><td>undercut and the first</td><td>side</td>

<td> 116</td><td>of</td><td>unit</td><td>of</td><td>microneedles 107</td><td>(and / or the first side</td><td> 121</td>

<td>of the</td><td colspan="2">support 106)</td><td colspan="2">may include the</td><td>minus a recess or</td><td>a</td>

projection, respectively, with the dimensions suitable to receive the projection and / or project into the recess of the second portion 142 of the cover 113. Such an arrangement can allow the second portion 142 to be mated with the microneedle unit 107 (and / or support 106) and facilitate housing and protection of microneedle unit 107 with second portion 142 of cover 113.

IMPI

<img file="MX353241B_D0073.tif" />

As shown in Figures 3 and 25, in the illustrated embodiment, a recess facing the microneedle (eg, facing upward) 199 is illustrated in the second portion

142 of cover 113 as an example. As shown, the first side 116 of the microneedle unit 107 may include a deck facing recess (eg, facing downward) 139 surrounding the plurality of microneedles 108. As shown in Figures 3, 4, and 6, a sealing member 136 with dimensions suitable to be received in recess 199 in second portion 142 of cover 113 and recess 139 in microneedle unit 107 can be used to sealing or closing the chamber configured to house the microneedles 108 and providing additional separation between the closed end 198 of the recess 196 of the second portion 142 of the cover 113 and the first side 116 of the microneedle unit 107. This specific arrangement is shown as an example only, but generally, the second portion 142 of the cover 113 can be configured to somehow engage the first side 116 of the microneedle unit 107 (and / or the support 106) to enclose and protect the plurality of microneedles 108 prior to use, i.e., to maintain sterility of the microneedles 108. In some embodiments, the sealing member 136 and / or a portion of the cover 113 may be permeable to the sterilizing agent and, at the same time, inhibit the entry of contaminants after sterilization. In such embodiments, the member may include or provide such arrangements, the sealing member of · —seal ..... 13-6 - -Ea.

136 it can be integrally formed with cover 113 and configured to engage at least the first side 116 of the microneedle unit 107 or the first side 121 of the microneedle unit holder 106.

As mentioned above, housing 102 may include a projection 119 that defines or includes base 112. Actuator 104 (eg, outer portion 132 thereof) may extend outward (eg, downward) from the projection, for example, when actuator 104 is in its first position Pi. The recess 195 in the first portion 140 of the cover 113 may have the dimensions suitable for

<td>to receive</td><td>the</td><td>projection</td><td>of accommodation 119 and / or</td><td>at least</td><td>a</td>

<td>portion</td><td>of</td><td colspan="2">the external portion 132 of the actuator</td><td> 104 .</td><td></td>

<td>The</td><td colspan="2">cover 113</td><td>can be configured to</td><td>mate</td><td>to the</td>

<td colspan="2">accommodation</td><td>102 (by</td><td>example the projection</td><td>119) and / or</td><td>to the</td>

actuator 104 by any of the coupling means described above. Cover 113 may further be configured to abut a portion of housing 102 from which projection 119 projects, which may facilitate inhibition of cover 113 from depressing actuator 104 when cover 113 is coupled to apparatus 100 to avoid premature actuation of actuator 104.

Although the modality of Figures 1-25 uses a configuration and arrangement of elements

11V1. -i

ÍNST'T '.' Tr MVJCan- · Of LA stored energy devices for and, optionally, infusion, it should be understood that the variations for the specific structures and arrangements shown in the illustrated modality are within the spirit and scope of the present description.

For example, the

Figure 26 illustrates an apparatus 100 'in accordance with another embodiment of the present invention and, particularly, a portion of an infusion unit 103' in accordance with another fashion of the present invention.

In some embodiments, as shown in Figure 26, the third stored energy device 146 'can be configured to directly engage (rather than indirectly) plunger 149' and / or piston 148 ', and gauge 126' (for example , the outer portion 187 'of this) may still include an outer recess 190' configured to receive at least a portion of the shuttle 125 'and can slide along the outer surface of the shuttle 125' between the shuttle 125 'and a or more retaining walls 105 'of the housing 102' so that it is visible through a window of the housing

102 'to indicate the progress of the infusion.

For example, in such embodiments, the third stored energy device 146 'may be located within the internal chamber 171' of the internal portion 185 'of the indicator 126' defining the plunger 149 '(i.e., opposite

<img file="MX353241B_D0074.tif" />

to the location between an outer surface of shuttle 125 and outer portion 187 'of gauge 126). A front end or wall of the plunger 149 'may still be in contact with the piston 148'. Furthermore, in such modalities, the second stored energy device 144 'can still initiate the movement of the shuttle 125', in addition to the decoupling of the first and the second indicating portion 125a 'and 125b'. Similar to apparatus 100 of Figures 1-25, in apparatus 100 ', the first indicator portion 126a' is located between shuttle 125 'and the second indicator portion 126b' (and provides coupling between them). Furthermore, pointer 126 '(or a portion thereof, particularly first pointer portion 126a'), can be moved with shuttle 125 'until shuttle 125' reaches its second position after which, outer portion 187 'can reaching a longitudinal location along longitudinal axis L 'that is beyond a retaining wall 193, allowing the walls that form the outer portion 187' of indicator 126 'to flex outward. At that point, the third stored energy device 146 'can provide forces to overcome a hitch or catch 194 that couples the indicator 126' (i.e., the first indicator portion 126a ') and the shuttle 125', allowing the indicator 126 'begins to move along longitudinal axis L', relative to shuttle 125 ', so that shuttle

125'

INSTITUTO MEX-.CA, so V'-J *) may 'inside the outer portion

187 '(i.e. external recess 190') to drive piston 148 'in cartridge

110 'and infuse an active agent.

Each embodiment shown in the figures is illustrated as a separate embodiment to clarify the illustration of various features of the apparatus of the present invention. However, it should be understood that any combination of elements and features of any embodiment illustrated in the figures and described in the present description can be used in the apparatus of the present invention.

The following descriptions of application time, microneedles, skin contact adhesive, release liner, and active agents can be applied to any embodiment of the apparatus of the present invention.

In some embodiments, the time during which the appliances of the present invention can be kept on the skin 50 may be an extended time, however, the appliances of the present invention are more likely to remain on the skin 50 for shorter periods. For example, in some embodiments, the apparatus of the present invention may remain on the skin for a treatment period of at least 1 second, in some embodiments, at least 5 seconds, in some embodiments, at least 10 seconds, in some embodiments , at least 15 seconds and, in some modalities,

100

<img file="MX353241B_D0075.tif" />

IMPI

INSTITUTD MtXICAN ·, DE LA PK., PIEDAD INDUSTRIAL at least 30 seconds. In some modalities, the device can be kept on the skin for a period of time no greater than 1 hour, in some modalities no more than 30 minutes, in some modalities no more than 20 minutes, in some modalities no more than 10 minutes and, in some modalities, not more than 5 minutes. In some modalities, the devices can be kept on the skin for a treatment period of 1 second to 1 hour, in some modalities from 10 seconds to 10 minutes, and in some modalities from 30 seconds to 5 minutes.

In some embodiments, apparatus 100 can be configured to deliver an active agent over an infusion period of at least 1 second, in some embodiments, at least 5 seconds, in some embodiments, at least 10 seconds, in some embodiments, at least 15 seconds and, in some modalities, at least 30 seconds. In some embodiments, the apparatuses of the present invention may include infusion periods of no more than 1 hour, in some embodiments, not greater than 30 minutes, in some embodiments, not greater than 20 minutes, in some embodiments, not greater than 10 minutes and, in some modalities, no longer than 5 minutes. In some modalities, the devices can be kept on the skin for a treatment period of 1 second to 1 hour, in some modalities from 10 seconds to 10 minutes, and in some modalities from 30 seconds to 5 minutes.

101 with the

Skin contact adhesive

ΙΜΡΪ

INSTITUTE of or. ·. ·:. · '

In some embodiments, the skin contact adhesive 150 can cover the entire actuator base 133

104 (and / or in some modalities, the skin contact adhesive

150 may cover eg including intermittent application of skin contact adhesive 150 to create gaps (eg, randomly or in a pattern) and / or a full ring of skin contact adhesive

150 having a width less than the width of base 133 (and / or base 112).

Skin contact adhesive

150 it is generally a pressure sensitive adhesive, and particularly a pressure sensitive adhesive capable of securely but removably adhering or bonding to skin (eg, mammalian skin). The skin contact adhesive 150 is, moreover, generally safe, non-toxic.

The skin contact adhesive layers will generally be selected in accordance with the desired end use of apparatus 100.

In some embodiments, apparatus 100 may include more than one skin contact adhesive

150. When apparatus 100 comprises more than one layer of skin contact adhesive 150, each layer of skin contact adhesive 150 can be selected independently of one another with respect to the material and thickness used. The examples

102 Suitable adhesives include

<img file="MX353241B_D0076.tif" />

rubber --- uahuraX., __ polyisobutylenes, synthetic rubber, copolymers, and mixtures of these.

Acrylates and silicones may be preferred skin contact adhesives 150. Generally, skin contact adhesive 150 should cause little or no skin irritation or sensitization during the period of intended use.

In some embodiments, the skin contact adhesive 150 may be an acrylate (or methacrylate) copolymer. Acrylates will typically have an inherent viscosity of greater than about 0.2 dL / g and will comprise one or more polymerized primary monomers and, optionally, one or more polar comonomers. Suitable primary monomers for use include alkyl acrylates containing 4 to 12 carbon atoms in the alkyl group, and alkyl methacrylates containing 4 to 12 carbon atoms in the alkyl group.

Examples of suitable alkyl acrylates and methacrylates include n-butyl, n-pentyl, nhexyl, isoheptyl, n-nonyl, n-decyl, isohexyl, 2-ethyloctyl, isooctyl, and 2-ethylhexyl acrylates and methacrylates. In some embodiments, the alkyl acrylates can include isooctyl acrylate, 2-ethylhexyl acrylate, n-butyl acrylate, and cyclohexyl acrylate. Suitable polar monomers for use can include those that have hydroxyl, amide or carboxylic, sulfonic or phosphonic acid functionality. The examples

103 Representatives include acrylamide me t ac ri 1 amide; - N ^ vini pyrrolidone, 2-hydroxyethyl acrylate, 2 hydroxypropyl acrylate, acrylic acid, methacrylic acid, pyrrolidonyl ethyl acrylate and alkoxyethyl acrylates, such as 2-carboxyethyl acrylate. In some embodiments, the amount by weight of polar monomer will not exceed approximately 40% of the total weight of all monomers to avoid excessive firmness of the final PSA product. Typically, polar monomers can be incorporated in the range of from about 1% to about 20% by weight. In some embodiments, the polar monomer can be acrylamide.

In some embodiments, the acrylate copolymer may comprise the reaction product of primary and polar monomers and additional optional monomers that, when present, are included in the polymerization reaction in amounts that will not make the adhesive composition sticky.

Optional additional monomers can be added, for example, to improve performance, reduce cost, or for other purposes. Examples of such optional monomers include vinyl esters, such as vinyl acetate, vinyl chloride, vinylidene chloride, styrene, and macromonomers copolymerizable with the other monomers.

Suitable macromonomers include polymethylmethacrylate, styrene / acrylonitrile copolymer, polyether, and polystyrene. Examples of macromonomers

104

<img file="MX353241B_D0077.tif" />

IMSTJTlbr

ÜF LA --.-. 7 / J ^v : 's useful and their preparation are described in the_gpatertté 'dé lóüs'-EK *.

USA no. 4,693,776 (Krampe et al.), The degcTi'preion of · la-ctral · · ^ is incorporated herein by reference.

Pressure sensitive silicone or polysiloxane adhesives include pressure sensitive adhesives based on two main components: a polymer or rubber and a tackifying resin. Polysiloxane adhesive can be prepared

<td colspan="2">by crosslinking</td><td>of</td><td>the</td><td>rubber,</td><td>typically a</td>

<td>by organosiloxane</td><td>of</td><td>high</td><td>weight</td><td>molecular</td><td>, with the resin,</td>

<td>to produce a</td><td colspan="2">structure</td><td>of</td><td>silicate</td><td>three-dimensional to</td>

through a condensation reaction in a suitable organic solvent. The ratio of the resin to the polymer can be adjusted to modify the physical properties of the polysiloxane adhesives. In some embodiments, the use of capped (or amine compatible) polysiloxanes may be preferred to increase drug stability and reduce degradation. Other details and examples of pressure sensitive silicone adhesives that may be useful are described in US Pat.

USA

nos.

4,591,622 (Blizzard et al.), 4,584,355 (Blizzard et al.),

4,585,836 (Homan et al.) And 4,655,767 (Woodard et al.).

Suitable pressure sensitive silicone adhesives are commercially available and include the silicone adhesives sold under the trademarks BIO-PSA® by Dow Corning

Corporation, Medical Products, Midland, Michigan.

105

Another description of in the patents of the

USA USA

nos. 5.65'6 '; 28Έ&gt; ..... (ΜΐϊοΠΤΰΡ¹ ("T al.), 5,223,261 (Nelson et al.) And 5,380,760 (Wendel et al.), The disclosures of which are incorporated herein by reference. In some embodiments, the thickness of the skin contact adhesive 150 may be at least about pm, in some embodiments, at least about 20 pm, and, in some embodiments, at least about 40 pm.

In some embodiments, the thickness of the skin contact adhesive 150 may be less than about 2 mm (0.07874 inches), in some modes less than about 1 mm (0.03937 inches), and in some modes less than about

150 miorones (5906 microinches).

In some embodiments, a medical grade may be preferred for the skin adhesive contact adhesive 150.

Such a medical grade skin contact adhesive 150 may have physical properties and characteristics that allow it to maintain intimate skin contact 50 before, during, and after actuation of apparatus 100. Attachment of actuator 104 (or housing 102) to skin 50 can help keep microneedles 108 inserted into skin 50. Release liners

Release liners that can be used as at least a portion of release liner 152 (in addition

106 of other coatings

<img file="MX353241B_D0078.tif" />

a portion of base 112) 'S'é'CaiT to cover at least available from various manufacturers in a wide variety of proprietary formulations. Those skilled in the art will typically test these coatings under simulated use conditions against an adhesive of choice to obtain a product with the desired release characteristics. Coatings that can be suitably used in the apparatus of the present invention can be made from kraft papers, polyethylene, polypropylene, polyester, or composites of any of these materials. The coating material can be coated with release agents or low adhesion coatings, such as fluorochemicals or silicones. For example, US Patent No. USA no. 4,472,480 (Olson), the disclosure of which is incorporated herein by reference, discloses low surface energy perfluorochemical coatings. The coatings can be papers, polyolefin films, or polyester films coated with silicone release materials. Examples of commercially available silicone coated release papers are POLYSLIK® silicone release papers available from Loparex (Willowbrook, IL). Active agent

As mentioned above, in some embodiments, the active ingredients or agents (eg drugs)

<img file="MX353241B_D0079.tif" />

107

IMPI can be supplied through microneedles 108 (eg, through solid or hollow microneedles). Any substance that can be formulated in a fluid or supplied via hypodermic injection can be used as the active agent, including any pharmaceutical, nutraceutical, cosmeceutical, diagnostic therapeutic agent (collectively referred to herein as drug).

The present disclosure contemplates that even a gaseous fluid can be used.

Examples of drugs that can be incorporated into the apparatus of the present invention are those capable of achieving a local or systemic effect when administered to the skin. Some examples include buprenorphine, clonidine, diclofenac, estradiol, granisetron, isosorbide dinitrate, levonorgestrel, lidocaine, methylphenidate, nicotine.

Nitroglycerin, oxybutynin, rivastigmine, rotigotine, scopolamine, selegiline, testosterone, tulobuterol, and fentanyl, commercially available in the form of transdermal devices. Other examples include example, hydrocortisone, prednisolone, triamcinolone) and non-steroids (eg, naproxen, piroxicam);

bacteriostatic agents (eg, chlorhexidine, hexylresorcinol);

antibacterial (eg penicillins such as penicillin V, cephalosporins such as

108 cephalexin, erythromycin, sulfathiazole, nitrofurantoin, and quinoiones' taies corfio ñorfloxacin, flumequine, and ibafloxacin); antiprotozoa (eg, calcium channel (eg, nifedipine, diltiazem);

bronchodilators (for example theophylline, pyrbuterol, salmeterol, isoproterenol); enzyme inhibitors, such as collagenase inhibitors, protease inhibitors, acetylcholinesterase inhibitors (eg, donepezil), elastase inhibitors, lipoxygenase inhibitors (eg, A64077), and angiotensin converting enzyme inhibitors (eg, captopril, lisinopril); other antihypertensive drugs (eg, propranolol); leukotriene antagonists (eg ICI204,219); anti-ulcers such as H2 antagonists; steroid hormones (eg, progesterone); antivirals and / or immunomodulators (eg, 1-isobutyl-lH-imidazo [4,5-c] quinolin-4-amine, 1- (2-hydroxy-2-methylpropyl) -lH-imidazo [4,5-c ] quinolin-4amine, N- [4 - (4-amino-2-ethyl-1H-imidazo [4,5-c] quinolin-1yl) butyl] methanesulfonamide and acyclovir); local anesthetics (eg benzocaine, propofol, tetracaine, prilocaine); cardiotonics (eg, digitalis, digoxin); antitussives (eg codeine, dextromethorphan); antihistamines (eg diphenhydramine, chlorpheniramine,

109 terfenadine);

narcotic pain relievers

<img file="MX353241B_D0080.tif" />

Institute .

DE 1 / Mí.7-7., Ik, ej empló; ^;TO4notf «iá7 fentanyl citrate, sufentanil, —- -el · o-yh i di · ato - '^' Tder” * '· hydromorphone); peptide hormones (eg, human or animal growth hormones, LHRH, parathyroid hormones); cardioactive products such as atropeptides; agents

<td>antidiabetic</td><td>(eg insulin, exanatide); enzymes</td>

<td>(for example,</td><td>antiplaque enzymes, lysozyme, dextranase);</td>

<td>anti-nausea;</td><td>anticonvulsants (eg carbamazine);</td>

immunosuppressants (eg, cyclosporine);

sedative psychotherapeutics (eg, diazepam) (eg, phenobarbital); anticoagulants (eg, heparin, enoxaparin sodium); pain relievers (eg, acetaminophen);

antimigraine agents (eg ergotamine, melatonin, sumatriptan, zolmitriptan) antidiarrheal agents (eg flecainide); antiemetics (eg, metaclopromide, ondansetron, granisetron hydrochloride); anticancer agents (eg, methotrexate); neurological agents such as anxiolytic drugs; hemostatic; anti-obesity agents; dopamine agonists (eg, apomorphine); GnRH agonists (eg, leuprolide, goserelin, napharelin); fertility hormones (eg hCG, hMG, urofolitropin); interferons (eg interferon-alpha, interferon-beta, interferon-gamma, pegylated interferon-alpha); and the like, in addition to pharmaceutically acceptable salts and esters thereof. The amount

110

<img file="MX353241B_D0081.tif" />

of drug constituting an effective quantity cannot be easily determined ρρτ- Ί in matter with due consideration of the particular drug, the particular carrier and the desired therapeutic effect.

In some embodiments, peptide therapeutic agents (natural, synthetic, or recombinant) can be delivered through microneedles 108 (eg, through solid or hollow microneedles). Examples of peptide therapeutic agents that can be incorporated into the apparatus of the present invention include parathyroid hormone (PTH), parathyroid hormone related protein, calcitonin, lysozyme, insulin, insulinotropic analogues , glatiramer acetate, goserelin acetate, somatostatin, octreotide, leuprolide, vasopressin, desmopressin, thymosin alfa-1, atrial natriuretic peptide (ANP, endorphin, vascular endothelial growth factor (VEGF), fibroblast growth factor (FGF) erythropoietin (EPO), protein bone morphogenetics (BMP), epidermal growth factor (EFG), granulocyte colony stimulating factor (G-CSF), colony stimulating factor of

111

<img file="MX353241B_D0082.tif" />

OF ΙΑ &lt;.&gt;! * Macrophages and granulocytes (GM-CSF), factor of¹'¹ -insulin growth hormone (IGF), £ ut'L'üT tte platelet derived growth (PDGF), growth hormone releasing hormone (GHRH) ), dornase alpha, tissue plasminogen activator (tPA), urokinase, ANP clearance inhibitors, luteinizing hormone-releasing hormone (LHRH), melanocyte-stimulating hormones ( Alpha and beta msh), pituitary hormones (hGH), adrenocorticotropic hormone (ACTH), human chorionic gonadotropin (hCG), streptokinase, interleukins (eg IL2, IL-4, IL-10, IL-12, IL-15, IL-18), protein C, protein

S, angiotensin, angiogenin, endothelin, pentigetide, brain natriuretic peptide (BNP), neuropeptide Y, islet amyloid polypeptide (IAPP), vasoactive intestinal peptide (VIP) in English), hirudin, glucagon, oxytocin and derivatives of any of the above peptide therapeutic agents.

In some embodiments, drugs that are of a high molecular weight can be delivered transdermally. Increasing the molecular weight of a drug can cause a reduction in unassisted transdermal delivery. The

112

ΙΝίΠ.ι'ϊ- ί ·· '.! ··. &lt;·_ζ *. * 4 examples of such large molecules ^ ncluyéñrZ / J ^ Xdt &amp; íjQ ^ g ^ '' peptides, monoclonal nucleotide sequences, vaccines, polysaccharides, such as heparin, and antibiotics, such as ceftriaxone. Examples of suitable vaccines include therapeutic cancer vaccines, anthrax vaccine, influenza vaccine, Lyme disease vaccine, rabies vaccine, measles vaccine, mumps vaccine, chickenpox vaccine, vaccine. against smallpox, hepatitis vaccine, hepatitis A vaccine, hepatitis B vaccine, hepatitis C vaccine, whooping cough vaccine, rubella vaccine, diphtheria vaccine, encephalitis vaccine, Japanese encephalitis vaccine, respiratory syncytial virus vaccine, yellow fever vaccine, recombinant protein vaccine, DNA vaccines, polio vaccine, therapeutic cancer vaccine, herpes vaccine, vaccine against human papillomavirus, pneumococcal vaccine, meningitis vaccine, whooping cough vaccine, tetanus vaccine, typhoid vaccine, cholera vaccine, tuberculosis vaccine, severe acute respiratory syndrome (SARS) vaccine, HSV-1 vaccine, HSV-2 vaccine, HIV vaccine, and combinations of these. The term

113 Vaccine therefore includes, but i A fi ^ Dí'isé, - .Yii-ím'ít-á /, -a'zx ΐΜΟυ .'- ΓίΐΐΛί '-s ·· —l: —— antigens in the forms of weakened or exterminated proteins, polysaccharides, oligosaccharides or viruses. Other examples of suitable vaccines and vaccine adjuvants are described in US Patent Publication. USA no. 2004/0049150 (Dalton et al.), The disclosure of which is incorporated herein by reference.

In another embodiment, small molecule drugs may be used that are otherwise difficult or impossible to deliver by passive transdermal delivery. Examples of such molecules include salt forms, ionic molecules, such as bisphosphonates, including alendronate or sodium pamedronate, and molecules with physicochemical properties not conducive to passive transdermal delivery.

Microneedles

The microneedle arrays useful for practicing the present disclosure may have various configurations and characteristics, such as those described in the following patents and patent applications , the disclosures of which are incorporated herein by reference. One embodiment for the microneedle arrays includes the structures described in US Patent Application Publication. USA no. 2005/0261631 (Clarke et al.), Which describes microneedles that have a conical shape

114

<img file="MX353241B_D0083.tif" />

INSTITUTE Vi&gt; 2; .vx&gt;

truncated and a controlled aspect ratio. ° O ^^ fj ^ dálida ^ .. for the microneedle matrices includes_ the structures described in US Pat. USA no. 6,091,975 (Daddona et al.), Which describes blade-type microprojections to puncture the skin. Still another embodiment for the microneedle matrices includes the structures described in US Pat. USA no. 6,312,612 (Sherman et al.), Which describes conical shaped structures that have a hollow central channel. Still another embodiment for the microneedle matrices includes the structures described in US Pat. USA no. 6,379,324 (Gartstein et al.), Which describes hollow microneedles that have at least one longitudinal blade on the upper surface of the microneedle tip. Another embodiment for microneedle arrays includes the structures described in the US patent application publications. USA nos. US2012 / 0123387 (González et al.) And US2011 / 0213335 (Burton et al.), Which describe hollow microneedles. Another embodiment for microneedle arrays includes the structures described in US Pat. USA nos. 6,558,361 (Yeshurun) and 7,648,484 (Yeshurun ​​et al.), Which describe hollow microneedle matrices and methods of making them.

Various modalities of microneedles that can be used in the microneedle arrays of the present disclosure are described in PCT publication no. WO 2012/074576 (Duan et al.), Which describes liquid crystalline polymer (LCP, microneedles,

115 for its acronym in English)

2012/122162 (Zhang et al.), Which describes a .various-eks types - and different compositions of microneedles that can be used in microneedles

In some of the present description.

In modalities, the microneedle material may be (or include) silicon, glass, or a metal such as stainless steel, titanium, or nickel-titanium alloy. In some embodiments, the microneedle material may be (or include) a polymeric material, such as a medical grade polymeric material. Illustrative types of medical grade polymeric materials include liquid crystalline polymer polycarbonate (LCP), polyether ether ketone (PEEK), cyclic olefin copolymer (COC) , Polybutylene Terephthalate (PBT). Particularly useful types of medical grade polymeric materials include polycarbonate and LCP.

In some embodiments, the microneedle material can be (or include) a biodegradable polymeric material, particularly, a medical grade biodegradable polymeric material. Illustrative types of biodegradable medical grade materials include polylactic acid (PLA), polyglycolic acid (PGA), copolymer of PGA and PLA, polyester amide polymer (PEA) in English).

116

<img file="MX353241B_D0084.tif" />

From a dissolved material, degrade yourself B-iatoegrabla, ee- -or ·· and are referred to herein as dissolved microneedles. A dissolved, degradable, or disintegrable material is any solid material that dissolves, degrades, or disintegrates during use.

In particular, a dissolvable microneedle dissolves, degrades, or disintegrates sufficiently in the tissue underlying the stratum corneum to allow the release of a therapeutic agent into the tissue.

The therapeutic agent can be coated on or incorporated into a dissolvable microneedle. In some embodiments, the dissolvable material is selected from a carbohydrate or a sugar.

In some embodiments, the dissolvable material is polyvinylpyrrolidone (PVP).

In some embodiments, the dissolvable material is selected from the group consisting of hyaluronic acid, carboxymethyl cellulose, hydroxypropyl methyl cellulose, methyl cellulose, polyvinyl alcohol, sucrose, glucose, dextran, trehalose, maltodextrin, and a combination of these.

In some embodiments, the microneedles can be made from more of any of the materials mentioned above. For example, the tip of a microneedle may be a dissolvable material, while the remainder of the microneedle is a medical grade polymeric material.

117 and · &lt;· description can have various forms capable of puncturing the stratum corneum. In some embodiments, one or more of the plurality of microneedles may have a square pyramidal shape, a triangular pyramid shape, a step pyramid shape, a conical shape, a microblade shape, or the shape of a hypodermic needle. In some embodiments, a stepped triangular pyramidal plurality or plurality more than the

<td>plurality of</td><td colspan="2">microneedles can</td><td>to have</td><td>form</td>

<td colspan="3">square. In some modalities,</td><td>one or</td><td>more than</td>

<td>microneedle</td><td>can have</td><td>a</td><td>shape</td><td>pyramidal</td>

<td>In some</td><td>modalities,</td><td>a</td><td colspan="2">or more than</td>

<td>microneedle</td><td>can have</td><td>a</td><td>shape</td><td>pyramidal</td>

<td>In some</td><td>moda1i dade s,</td><td>a</td><td colspan="2">or more than</td>

<td>microneedle</td><td>can have</td><td>a</td><td>shape</td><td>conical. In</td>

some modalities, one or microneedles can have one some modalities, one or

<td>plus</td><td>of</td><td>the</td><td>plurality</td><td>of</td>

<td>shape</td><td>of</td><td colspan="2">microblade.</td><td>In</td>

<td>plus</td><td>of</td><td>the</td><td>plurality</td><td>of</td>

The microneedles may be in the shape of a hypodermic needle.

shape can be symmetric or asymmetric. The shape may be truncated (eg, the plurality of microneedles may have a truncated pyramid shape or a truncated cone shape).

In some embodiments, the plurality of microneedles in a microneedle unit are solid microneedles (i.e., the microneedles are solid in their

118 whole). In some modalities, • ia^{W! &lt;T}^ K'ííi-á3: ida; d? £ .de&gt; · '»lAilví, ....'. L --— solid microneedles in a unit of solid microneedles can have a square pyramidal shape, a triangular pyramidal shape, a stepped pyramidal shape, a conical shape, or a microblade shape. In a preferred embodiment, each plurality of solid microneedles in a unit of solid microneedles has a square pyramid shape.

In some embodiments, the plurality of microneedles in a microneedle unit are hollow microneedles (ie, the microneedles contain a hollow hole through the microneedle). The hollow hole may be extending from the base of the microneedle to the tip of the microneedle or the hole may extend from the base of the microneedle to a position offset from the tip of the microneedle. In some embodiments, one or more of the plurality of hollow microneedles in a hollow microneedle unit may have a conical shape, a cylindrical shape, a square pyramid shape, a triangular pyramid shape, or the shape of a hypodermic needle.

In some embodiments, one or more of the plurality of hollow microneedles in a hollow microneedle unit may have a conical shape. In some embodiments, one or more of the plurality of hollow microneedles in a hollow microneedle unit may have a cylindrical shape. In some embodiments, one or more of the plurality of hollow microneedles in a hollow microneedle unit may have a shape

119

<img file="MX353241B_D0085.tif" />

square pyramid. In some modalities7 *^STSS ^^ C. máé ^ / déifla w υ u; rr x ¡al * · * · * —12: - plurality of hollow microneedles in a unit of hollow microneedles may have a triangular pyramidal shape. In some embodiments, one or more of the plurality of hollow microneedles in a hollow microneedle unit may be in the form of a hypodermic needle. In a preferred embodiment, each plurality of hollow microneedles in a hollow microneedle unit may be in the form of a conventional hypodermic needle.

Figure 27 shows a portion of the microneedle unit 107 including four microneedles 108 (of which two are mentioned in Figure 27) positioned on a microneedle substrate 109. Each microneedle 108 has a height h, which is the length from the tip of the microneedle 108 to the base of the microneedle on the substrate 109. Either the height of a single microneedle or the average height of all the microneedles in the microneedle unit can be mentioned as the height of the microneedle, h. In some embodiments, each plurality of microneedles (or the average of the entire plurality of microneedles) has a height of from about 100 to about 3,000 microns, in some modes, from about 100 to about 1,500 micrometers, in some modes, from about 100 to approximately 1200 micrometers and, in some embodiments, approximately 100 to approximately

1000 micrometers.

120

<img file="MX353241B_D0086.tif" />

(or the average of all the pluralities of microneedles)

<td>you</td><td>at a height</td><td>of</td><td>approximately</td><td> 200</td><td>to</td><td>approximately</td>

<td> 1200</td><td>micrometers,</td><td>of</td><td>approximately</td><td> 200</td><td>to</td><td>approximately</td>

<td> 1000</td><td>micrometers,</td><td>of</td><td>approximately</td><td> 200</td><td>to</td><td>approximately</td>

<td> 750</td><td>micrometers or</td><td>of</td><td>approximately</td><td> 200</td><td>to</td><td>approximately</td>

600 micrometers.

In some embodiments, each plurality of microneedles (or the average of all the pluralities of microneedles)

<td>has</td><td>: a height</td><td>of</td><td>approximately</td><td>250 to</td><td>approximately</td>

<td> 1500</td><td>micrometers,</td><td>of</td><td>approximately</td><td>500 to</td><td>approximately</td>

<td> 1000</td><td>micrometers or</td><td>of</td><td>approximately</td><td>500 to</td><td>approximately</td>

750 micrometers.

In some embodiments, each plurality of microneedles (or the average of all the pluralities of microneedles) has a height of from about 800 to about 1400 microns.

In some embodiments, each plurality of microneedles (or the average of all the pluralities of microneedles) is approximately 500 micrometers high.

In some embodiments, each plurality of microneedles (or the average of all the pluralities of microneedles) is less than about 3000 micrometers in height. In other embodiments, each plurality of microneedles (or the average of all the pluralities of microneedles) has a

121 height less than about

IMPI &lt;

INSTITUTO MÍ.XICM * i DE LA PROrMFí'AD

150 0 ni icr ómdti'O'feT *

<img file="MX353241B_D0087.tif" />

Other modalities, each plurality of "TtrlL'lüayu jas - '(or ··' cl · ·· - average of all the pluralities of microneedles) has a height less than about 1200 micrometers. In still other embodiments, each plurality of microneedles (or the average of all the pluralities of microneedles) is less than about 1000 microns in height. In other embodiments, each plurality of microneedles (or the average of all the pluralities of microneedles) is less than about 750 microns in height. In still other embodiments, each plurality of microneedles (or the average of all the pluralities of microneedles) is less than about 600 microns in height.

In some embodiments, each plurality of microneedles (or the average of all the pluralities of microneedles) has a height of at least about 100 microns. In other embodiments, each plurality of microneedles (or the average of all the pluralities of microneedles) has a height of at least about 200 microns. In still other embodiments, each plurality of microneedles (or the average of all the pluralities of microneedles) has a height of at least about 250 microns. In still other embodiments, each plurality of microneedles (or the average of all the pluralities of microneedles) has a height of at least about 500 microns. In even

<img file="MX353241B_D0088.tif" />

122 In other embodiments, each plurality of microneedles (or the average of all the pluralities of microneedles) has a height of at least about 800 microns.

In some embodiments using solid microneedles, each plurality of solid microneedles (or the average of all the pluralities of solid microneedles) has a

<td colspan="4">height of about 100</td><td>to</td><td></td><td>approximately</td>

<td> 1500</td><td>micrometers,</td><td>of</td><td>approximately</td><td> 100</td><td>to</td><td>approximately</td>

<td> 1200</td><td>micrometers,</td><td>of</td><td>approximately</td><td> 200</td><td>to</td><td>approximately</td>

<td> 1000</td><td>micrometers,</td><td>of</td><td>approximately</td><td> 200</td><td>to</td><td>approximately</td>

<td> 750</td><td>micrometers,</td><td>of</td><td>approximately</td><td> 200</td><td>to</td><td>approximately</td>

600 micrometers or approximately 500 micrometers.

In some embodiments using hollow microneedles, each plurality of hollow microneedles (or the average of all the pluralities of hollow microneedles) is from about 100 to about 3000 microns, about 800 to about 1400 microns, or about 500 microns in height.

In some embodiments, each plurality of hollow microneedles (or the average of all pluralities of hollow microneedles) has a height of from about 900 to about 1000 microns. In other embodiments, each plurality of hollow microneedles (or the average of all the pluralities of hollow microneedles) has a height of from about 900 to about 950 microns. In even

123 the average of all the pluralities of m-ieyoagu ja »hollow) · has a height of approximately 900 mierometers.

A single microneedle or the plurality of microneedles in a microneedle unit can be further characterized by their aspect ratio. The aspect ratio of a microneedle is the ratio of the height of the microneedle, h to the width (at the base of the microneedle), w (as shown in Figure

27). The aspect ratio can be presented as h: w. In some embodiments, each plurality of microneedles (or the average of all the pluralities of microneedles) has (have) an aspect ratio in the range of 2: 1 to 5: 1. In some of these embodiments, each plurality of microneedles (or the average of all the pluralities of microneedles) has (have) an aspect ratio of at least 3: 1.

In some embodiments, the microneedle unit contains from about 100 to about 1500 microneedles per cm.² of the microneedle unit.

In some embodiments using solid microneedles, the solid microneedle unit contains from about 100 to about 1500 solid microneedles per cm² of the solid microneedle unit.

In some embodiments, the solid microneedle unit contains from about 200 to about 500 solid microneedles per cm.² of the microneedle unit

124

IMPI

<img file="MX353241B_D0089.tif" />

solid.

In some embodiments, the solid microneedle unit contains from about 300 to about 400 solid microneedles per cm² of the solid microneedle unit.

In some embodiments using hollow microneedles, the hollow microneedle unit contains from about 3 to about 30 hollow microneedles per unit of hollow microneedles.

In some embodiments, the hollow microneedle unit contains from about 10 to about 30 hollow microneedles per hollow microneedle unit.

In some embodiments, the hollow microneedle unit contains from about 3 to about 20 hollow microneedles per unit of hollow microneedles.

In some embodiments, the hollow microneedle unit contains from about 13 to about 20 hollow microneedles per unit of hollow microneedles.

In some embodiments, the hollow microneedle unit contains from about 8 to about 18 hollow microneedles per hollow microneedle unit.

In some embodiments, the hollow microneedle unit contains approximately 18 hollow microneedles per hollow microneedle unit.

In some embodiments, the hollow microneedle unit

125

IMPIí

INSTITUTO MUICANri 7 'DE LA ηΟΗΓ.Ι ΛΙ1 &lt;contains approximately 12 microneedles Ruecas íJt9i?^Tlutfni i '¹

<img file="MX353241B_D0090.tif" />

hollow microneedles.

In some embodiments, each plurality of microneedles (or the average of all the pluralities of microneedles) in a microneedle unit can penetrate the skin to a depth of about 50 approximately

1500 micrometers, approximately approximately

400 micrometers or approximately

250 micrometers.

In some embodiments, each plurality of microneedles (or the average of all the pluralities of microneedles) in a microneedle unit can penetrate the skin to a depth of from about 100 to about 400 microns or from about 100 to about 300 microns.

In some embodiments, each plurality of microneedles (or the average of all the pluralities of microneedles) in a microneedle unit can penetrate the skin to a depth of from about 150 to about 1500 microns or from about 800 to about 1500 microns.

In some embodiments, each plurality of microneedles (or the average of all the pluralities of microneedles) in a microneedle unit can penetrate the skin to a depth of about 400 to about

126

800 micrometers.

<img file="MX353241B_D0091.tif" />

<img file="MX353241B_D0092.tif" />

For all of the above modalities, -SW depth of penetration (DOP) of each plurality of microneedles (or the average of all pluralities of microneedles) in a unit of microneedles may not be the total length of the microneedles properly the.

In some embodiments, the microneedle unit 107 in accordance with the present disclosure may be in the form of a patch, which may include the microneedle unit 107, a skin contact adhesive, such as those described above, and optionally a reinforcement. Whether in a patch or not, microneedles 108 can be arranged in any desired pattern or arrangement. For example, microneedles 108 may be arranged in evenly spaced rows that may be aligned or offset. In some embodiments, the microneedles 108 may be arranged in a polygonal pattern such as a triangle, square, rectangle, pentagon, hexagon, heptagon, octagon, or trapezoid.

In other embodiments, the microneedles 108 may be arranged in a circular or oval pattern.

In some embodiments, the surface area of ​​the microneedle-covered substrate 109 may be approximately 0.1 cm² to about 2 0 cm². In some of these modalities, the surface area of ​​the substrate 109 covered with microneedles 108 is approximately 0.5 cm² to

127

<img file="MX353241B_D0093.tif" />

about 5 cm². modalities, the area of ​​microneedles 108 approximately 3 cm². In still other of these modalities, the surface area of ​​the substrate 109 covered with microneedles

108 it is about 1cm² to about 2 cm².

In some embodiments, microneedles 108 of the present disclosure may be disposed over substantially the entire surface of unit 107 (eg, substrate 109). In other embodiments, a portion of the substrate 109 may not be provided with microneedles 108 (i.e., a portion of the substrate

109 it is not structured). In some of these modalities, the unstructured surface has an area greater than about 1 percent and less than about 75 percent of the total surface area of ​​the device facing the skin surface 50. In another of these modalities, the unstructured surface has an area greater than about 0.65 cm² (0.10 square inches) to an area less than about 6.5 cm² (1 square inch).

For hollow microneedles, a channel or hollow hole extends through substrate 109 and microneedles 108. In some embodiments, the hole exits a channel opening at or near the tip of the hollow microneedle. The channel preferably exits an opening near the tip of the hollow microneedle. Most preferably, the

128 channel or hole continues to

IMPI R / 3 ΐΗ $ τιτυτη,!

FROM THE MQí'if.W), along up axis ^lG^tand^;ñtral ''^rGive - d: a microneedle but, similarly to a —ha hi-podérmrtraT it exits on a sloping side wall of the microneedle to help prevent blockage of the canal by tissue when insertion occurs. In some embodiments, the diameter of the channel hole is from about 10 to about 200 microns. In other embodiments, the diameter of the channel hole is from about 10 to about 150 microns. In still other embodiments, the diameter of the channel hole is from about 30 to about 60 microns.

In some modalities of hollow microneedles, the average cross-sectional area of ​​the canal hole is

<td>approximately</td><td>75 to approximately 32,000 micrometers. In</td>

Other modalities of hollow microneedles, the average cross-sectional area of ​​the canal hole is approximately 75 to

<td>approximately</td><td>18,000 micrometers. In still other modalities</td>

<td>microneedle</td><td>hollow, the average cross-sectional area of</td>

<td>hole of</td><td>channel is about 70 0 to</td>

<td>approximately</td><td>3,000 micrometers.</td>

<td>In some</td><td>hollow microneedle matrix modalities,</td>

the average spacing between adjacent microneedles (such as

<td>it is measured from the</td><td>tip of one microneedle to the tip of another</td>

<td>microneedle) is</td><td>from about 0.7 mm to about</td>

<td>20 mm. In others</td><td>hollow microneedle matrix modalities,</td>

129 the separation approximately

IMPI

INSTIT! ΙΤΠ MELICA_N..

average between adjacent microneedles is

Of LA FÍcwnÚ, INDUSTRIAL VT

0.7mm to about 10mm. In still other forms of hollow microneedle arrays, the average spacing between adjacent microneedles is from about 2mm to about 20mm. In still other forms of hollow microneedle arrays, the average spacing between adjacent microneedles is from about 2mm to about 10mm. In a preferred embodiment of hollow microneedle arrays, the average spacing between adjacent microneedles is approximately 2 mm.

In some forms of hollow microneedle arrays, the average gap between adjacent microneedles (as measured between the tip of one microneedle and the tip of another microneedle) is greater than about 0.7 mm. In other forms of hollow microneedle arrays, the average spacing between adjacent microneedles is greater than about 2 mm.

In some forms of hollow microneedle arrays, the average spacing between adjacent microneedles is less than about 20 mm. In other forms of hollow microneedle arrays, the average spacing between adjacent microneedles is less than about 10 mm.

In some forms of solid microneedle arrays, the average spacing between adjacent microneedles (as measured between the tip of a microneedle and the tip of

130

<img file="MX353241B_D0094.tif" />

another microneedle) is approximately

200 micrometers and approximately 2000 micrometers. In other forms of solid microneedle arrays, the average spacing between adjacent microneedles is from about 200 microns to about 600 microns. In still other forms of solid microneedle arrays, the average spacing between adjacent microneedles is from about 200 microns to about 300 microns. In still other forms of solid microneedle arrays, the average spacing between adjacent microneedles is from about 500 microns to about 600 microns.

In some forms of solid microneedle arrays, the average separation between adjacent microneedles (as measured between the tip of one microneedle and the tip of another microneedle) is greater than about 200 microns. In other forms of solid microneedle arrays, the average spacing between adjacent microneedles is greater than about 500 microns.

In some forms of solid microneedle arrays, the average spacing between adjacent microneedles is less than about 2000 microns. In other forms of solid microneedle arrays, the average spacing between adjacent microneedles is less than about 1000 microns. In still other modalities of

131

<img file="MX353241B_D0095.tif" />

IMPI

INSTITUTO MEXICANO DE LA ΡΧΟΡΙ £ Γ; Λί&gt; INDUSTRIAL solid microneedle matrices, the average separation between adjacent microneedles is less than approximately

600 micrometers. In still other forms of solid microneedle arrays, the average spacing between adjacent microneedles is less than about 300 microns.

The microneedle matrices can be manufactured in any suitable way, such as by injection molding, compression molding, metal injection molding, stamping, photolithography, or extrusion. In one embodiment, the hollow microneedle arrays can be manufactured by thermocycling injection molding of a polymer, such as medical grade polycarbonate or LCP, followed by laser drilling to form the channels of the microneedles.

The following embodiments are intended to be illustrative and not limiting of the present disclosure. Modalities

one. A microneedle injection apparatus comprising:

a housing having a base and a cavity extending through the base to define an opening in the base, where the base of the housing is configured to position toward a skin surface;

a microneedle unit holder configured to contain a microneedle unit within the cavity of the housing; the microneedle unit holder is

132 of the housing and to be movable C'Oir ^ 'TSSpffCT'O the opening at the base of the housing between a retracted position in which the microneedle unit is retracted into the housing so that the microneedle unit does not come into contact with the skin surface when the housing base is positioned on the skin surface and the microneedle unit engages the microneedle unit holder, and an extended position in which at least a portion of the microneedle unit is positioned to contact the skin surface through the opening when the housing base is positioned on the skin surface and the skin unit. microneedle is attached to the microneedle unit holder; and an actuator movable with respect to the housing and holder of the microneedle unit between a first position and a second position to cause the holder of the microneedle unit to move from the retracted position to the extended position, where at least one portion of the actuator is located adjacent to the base of the housing and

<td>configure</td><td colspan="2">to move</td><td>of</td><td>the first position to</td><td colspan="2">the second</td>

<td>position</td><td>in</td><td>answer</td><td>to</td><td>appliance pressure</td><td>against</td><td>the</td>

<td colspan="2">surface of</td><td>the skin.</td><td></td><td></td><td></td><td></td>

<td> 2 .</td><td>The</td><td>apparatus</td><td>of</td><td>modality 1, in</td><td>where</td><td>the</td>

133 the · support

IMPI

INSTITUTO MEXICANO D € LA INDUSTRIAL FORMATION configured for actuator includes a base configured towards the skin surface, where the microneedle unit includes a base positioned towards the skin surface, and where the distance between the actuator base and the base The microneedle unit holder decreases when the actuator moves from the first position to the second position.

3. The mode 1 or 2 apparatus, wherein the actuator includes a base configured to position toward the skin surface, where the microneedle unit holder includes a base configured to position toward the skin surface, where the actuator base is positioned at a first distance from the base of the microneedle unit holder when the actuator is in the first position, wherein the base of the actuator is positioned a second distance from the base of the microneedle unit holder when the actuator is in the second position, and where the second distance is less than the first distance.

Four. The apparatus of any embodiment 1-3, wherein the actuator is located on one side of the apparatus facing the skin.

5. The apparatus of any embodiment 1-4, wherein the actuator is movable between the first position and the second position in relation to the housing and the support

134

<img file="MX353241B_D0096.tif" />

IMPI

MEXICAN INSTITUTE

FROM THE INDUSTRIAL PROPERTY of the microneedle unit when the microneedle υ holder is in the retracted position.

6. The apparatus of any embodiment 1-5, wherein the apparatus has a footprint having a first area, and where the actuator has a footprint having a second area and where the second area is less than half of the first area .

7. The apparatus of any embodiment 1-6, further comprising a cartridge located within the housing; the cartridge defines a receptacle configured to contain an active agent.

8. The mode 7 apparatus, wherein the microneedle unit holder is movable independently of the cartridge.

9. The mode 7 or 8 apparatus, wherein the cartridge is movable between a first position in which the receptacle is not in continuous communication with a fluid path and a second position in which the receptacle is in continuous communication with the path of fluid.

10. The apparatus of any modality 7-9, where the movement of the actuator to the second position activates

<td>both (i)</td><td>the</td><td colspan="2">bracket movement</td><td>of</td><td>the</td><td>Unit</td><td>of</td>

<td>microneedles</td><td>to</td><td>the extended position</td><td>how</td><td>(ii)</td><td>the</td><td colspan="2">movement</td>

<td>cartridge</td><td>to</td><td>the second position.</td><td></td><td></td><td></td><td></td><td></td>

<td>11. The</td><td colspan="2">modality apparatus</td><td>9th</td><td> 10,</td><td>than</td><td colspan="2">understands,</td>

<td>in addition, a</td><td colspan="2">shuttle configured for</td><td colspan="2">contain</td><td>the</td><td>cartridge</td><td>in</td>

135

<img file="MX353241B_D0097.tif" />

<img file="MX353241B_D0098.tif" />

t

MfiXtCAH5 INSTITUTE

LA PRf&gt; P'F. ''. AO cartridge * · between^INrNday^t •, housing and transport position and second position.

12. The mode 11 apparatus, wherein the shuttle is configured to retain the actuator in the second position after the actuator has moved to the second position.

13. The apparatus of any embodiment 1-12, further comprising an infusion device.

14. The apparatus of any embodiment 1-13, wherein the microneedle unit includes a first main surface and a plurality of microneedles protruding from the first main surface.

fifteen. The apparatus of any embodiment 1-14, wherein the plurality of microneedles are hollow, and further comprising a cartridge including a receptacle configured to contain an active agent, wherein the receptacle and at least some of the plurality of microneedles Hollows are configured to be in continuous communication when the microneedle unit is attached to the microneedle unit holder and the microneedle unit holder is in the extended position, but not when the microneedle unit holder is in the retracted position.

16. The apparatus of mode 15, wherein the cartridge is transported by a shuttle movable between a first position, in which the receptacle is not in continuous communication with the plurality of microneedles and a second

136

OF THE P-'OP'LDAD

INDUS'íHJAL

<td>position</td><td>in</td>

<td>keep going</td><td>with</td>

<td> 17.</td><td>The</td>

at least shuttle apparatus some of the plurality of microneedles.

of modality 16, where when it is in the second position, the shuttle is positioned to keep the actuator in the second position.

.

The mode apparatus 17, wherein the shuttle is configured to retain the actuator in the second position after the actuator moved the second position.

19.

The apparatus of any modality

1-18, where the support of the microneedle unit is held in the position retracted by a shuttle, and where the shuttle is movable between a first position in which the shuttle is positioned to maintain the support of the microneedle unit in the retracted position and a second position in which the microneedle unit holder is free to move to the extended position.

twenty. The apparatus of mode 19, wherein the shuttle deviates to the second position and where the movement of the shuttle to the second position is restricted by the actuator until the actuator is in the second position.

twenty-one. The apparatus of mode 19 or 20, wherein when the actuator is in its second position, the shuttle is free to move to its second position.

22. The apparatus of modality 19 or 20, where

137

<img file="MX353241B_D0099.tif" />

<img file="MX353241B_D0100.tif" />

minus a portion of the shuttle is eg the: i '- r _ν sets pS ^ á * to stop '' '' the actuator in the second position of 'sp1iéé'^mtTe "''^,That the actuator moved to the second position.

2. 3. The apparatus of any embodiment 1-22, wherein the actuator is located at least partially in the cavity of the housing.

24. The apparatus of any embodiment 1-23, wherein the actuator is movable with respect to the base of the housing, and where when the actuator is in the first position, an outermost surface of the actuator extends beyond the base of the housing along a first distance and when the actuator is in the second position, the outermost surface of the actuator does not extend beyond the base of the housing or extend beyond the base of the housing along a second distance that is less than the first distance.

25. The apparatus of either embodiment 1-24, wherein the actuator has an annular transverse shape and defines an internal bore, and wherein the microneedle unit holder is movable in the hole as the microneedle unit holder is moves between the retracted position and the extended position.

26. The apparatus of any embodiment 1-25, wherein the actuator includes a base and a cavity that extends

138

<img file="MX353241B_D0101.tif" />

<img file="MX353241B_D0102.tif" />

through the actuator base to form an opening in the actuator base and where the microneedle unit holder is movable in the actuator cavity independently of the cartridge when the microneedle unit holder moves between the position retracted and extended position.

27. The apparatus of embodiment 26, wherein at least a portion of the actuator is movable with respect to the base of the housing into and out of the opening formed in the base of the housing.

28. The apparatus of any one embodiment 1-27, wherein at least a portion of the actuator extends into the cavity of the housing.

29. The apparatus of either embodiment 1-28, wherein the actuator includes a base and an opening formed in the base, and wherein at least a portion of the microneedle unit extends through the opening in the actuator and beyond the actuator base when the microneedle unit holder is in the extended position.

30. The mode 29 apparatus, wherein the actuator base is configured to engage the skin surface.

31. The apparatus of embodiment 29 or 30, wherein the actuator base includes a skin contact adhesive.

32. The apparatus of any modality 1-31, where at

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<img file="MX353241B_D0103.tif" />

<img file="MX353241B_D0104.tif" />

at least a portion of the actuator is located in the housing cavity and is positioned to at least partially surround the microneedle unit, at least when the microneedle unit holder is in the extended position.

33. The apparatus of any embodiment 1-32, wherein at least a portion of the actuator is located adjacent to the opening at the base of the housing, and where at least a portion of the microneedle unit extends beyond the actuator when the bracket of the microneedle unit is in the extended position.

3. 4. The apparatus of any embodiment 1-33, wherein the microneedle unit holder is movable along a first drive axis between the retracted position and the extended position, and wherein the actuator is movable between the first position and the second position along a second drive shaft, and wherein the first drive shaft and the second drive shaft are substantially parallel to each other.

35. The mode 34 apparatus, wherein at least a portion of the actuator extends beyond the base of the housing when the actuator is in the first position.

36. The 34 or 35 mode apparatus, wherein the first drive shaft and the second drive shaft are substantially aligned.

37. The apparatus of any modality 1-36, where

140 ¡7 T '· A c i' ·; / ;, i - 'k

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011./· go »! ti μ n IMDUSTtIAL the actuator is configured to stay in the second position after it is moved from the second position.

38. The apparatus of any embodiment 1-37, further comprising:

a bypass element positioned to bypass the actuator in the first position, wherein the actuator is movable from the first position to the second position against the bypass of the first bypass element; and a stored energy device operable to drive the microneedle unit holder from the retracted position to the extended position as a result of movement of the actuator to the second position.

39. The apparatus of any embodiment 1-38, further comprising:

a first deflection element positioned to deflect the actuator in the first position, wherein the actuator is movable from the first position to the second position against deflection of the first deflection element; and a second deflection element positioned to deflect the microneedle unit holder in the extended position, where the microneedle unit holder is held against deflection of the diverter element when the microneedle unit holder is in the folded position, and where the microneedle unit holder is released from the

141 retention against diversion of the

<img file="MX353241B_D0105.tif" />

detour like

INSTTT '.' T '·' · MJ-XXA-XCi DE LA PR PlFHAn IND '.' STRIAL result of actuator being moved to second position.

40. The apparatus of any embodiment 1-39, wherein the support of the microneedle unit is deflected in the extended position.

41. The apparatus of any embodiment 1-40, further comprising a deflection element positioned to deflect the microneedle unit holder in the extended position, wherein the microneedle unit holder is retained against deviation of the deviation when the microneedle unit holder is in the retracted position, and wherein the support of the microneedle unit is released from the hold against deflection of the deflection element as a result of the actuator being moved to the second position.

42. The apparatus of any embodiment 1-41, wherein the actuator is bypassed in the first position.

43. The apparatus of any embodiment 1-42, wherein the microneedle unit holder is held in the retracted position, and where the microneedle unit holder is released from the retracted position as a result of the actuator being moved to the second position.

44. The apparatus of any embodiment 1-43, wherein the actuator includes a skin contact adhesive and wherein the housing is configured to engage the

142

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INSTITUTO MLZíCaí ^ 'DI LA PR-'jHthAL) &lt;INDUSTRIAL skin surface at least through the skin contact adhesive on the actuator.

Four. Five. The apparatus of any embodiment 1-44, wherein the actuator includes a skin contact adhesive.

46. The apparatus of any embodiment 1-45, wherein when the actuator is in the first position at least a portion of the actuator projects from the opening into the base of the housing and defines a base configured to engage the skin surface.

47. The mode 46 apparatus, wherein the actuator base includes a skin contact adhesive.

48. The apparatus of any embodiment 1-47, wherein the microneedle unit holder includes a base configured to be positioned toward a skin surface and further comprising the microneedle unit, wherein the microneedle unit is coupled to the base of the microneedle unit holder and is movable with the holder of the microneedle unit between the retracted position and the extended position.

49. The apparatus of any embodiment 1-48, wherein at least a portion of the actuator is located in a skin-facing portion of the apparatus and is configured to move from the first position to the second position in response to pressure of the apparatus against a skin surface by pressing on a portion of the apparatus

143 not oriented towards the skin.

IMPI

MEXICAN INSTITUTE. ·.

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fifty. The apparatus of mode 49, wherein the non-skin-facing position of the apparatus is located at an offset position from the axis with respect to an actuation axis of the actuator.

51. The apparatus of any embodiment 1-50, wherein at least a portion of the actuator is located in a lower portion of the housing and where the actuator is configured to move from the first position to the second position in response to the pressure of the apparatus against a skin surface by means of pressure on an upper portion of the housing.

52. The apparatus of mode 51, wherein the upper portion of the housing is located in an offset position from the axis with respect to an actuation axis of the actuator.

53. The apparatus of any embodiment 1-52, wherein the actuator is configured to move from the first position to the second position when a non-skin-oriented portion of the housing is pressed.

54. The apparatus of embodiment 53, wherein the non-skin-facing portion of the housing is not located directly opposite the actuator portion located adjacent to the base of the housing.

55. The apparatus of either embodiment 53 or 54, wherein the non-oriented portion of the housing is located in a

144 offset position of the shaft with actuator actuation.

56. The apparatus of any embodiment 1-55, wherein at least a portion of the housing is configured to be depressed with the use of any part of the hand.

The modalities described above and illustrated in the figures are presented by way of example only and are not intended to be a limitation on the concepts and principles of the present description. As such, a person of ordinary skill in the art will understand that various changes in the elements and their configuration and arrangement are possible without departing from the spirit and scope of the present invention.

All references and publications cited in the present disclosure are expressly incorporated herein by reference in their entirety in this disclosure.

Various features and aspects of the present invention are set out in the following claims.

It is noted that in relation to this date, the best method known by the applicant to put the aforementioned invention into practice is the one that is clear from the present description of the invention.

as above, it

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