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WO2008053481A1 - Puces à injections - Google Patents

Puces à injections Download PDF

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Publication number
WO2008053481A1
WO2008053481A1 PCT/IL2007/001324 IL2007001324W WO2008053481A1 WO 2008053481 A1 WO2008053481 A1 WO 2008053481A1 IL 2007001324 W IL2007001324 W IL 2007001324W WO 2008053481 A1 WO2008053481 A1 WO 2008053481A1
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WO
WIPO (PCT)
Prior art keywords
microneedles
skin
microneedle array
region
substance
Prior art date
Application number
PCT/IL2007/001324
Other languages
English (en)
Inventor
Tidhar Shalon
Guy Kotlizky
Tadmor Shalon
Original Assignee
Svip 6 Llc
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Svip 6 Llc filed Critical Svip 6 Llc
Publication of WO2008053481A1 publication Critical patent/WO2008053481A1/fr

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Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61M—DEVICES FOR INTRODUCING MEDIA INTO, OR ONTO, THE BODY; DEVICES FOR TRANSDUCING BODY MEDIA OR FOR TAKING MEDIA FROM THE BODY; DEVICES FOR PRODUCING OR ENDING SLEEP OR STUPOR
    • A61M37/00—Other apparatus for introducing media into the body; Percutany, i.e. introducing medicines into the body by diffusion through the skin
    • A61M37/0015—Other apparatus for introducing media into the body; Percutany, i.e. introducing medicines into the body by diffusion through the skin by using microneedles
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61B—DIAGNOSIS; SURGERY; IDENTIFICATION
    • A61B17/00—Surgical instruments, devices or methods
    • A61B17/20—Surgical instruments, devices or methods for vaccinating or cleaning the skin previous to the vaccination
    • A61B17/205—Vaccinating by means of needles or other puncturing devices
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61B—DIAGNOSIS; SURGERY; IDENTIFICATION
    • A61B17/00—Surgical instruments, devices or methods
    • A61B2017/00743—Type of operation; Specification of treatment sites
    • A61B2017/00747—Dermatology
    • A61B2017/00761—Removing layer of skin tissue, e.g. wrinkles, scars or cancerous tissue
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61M—DEVICES FOR INTRODUCING MEDIA INTO, OR ONTO, THE BODY; DEVICES FOR TRANSDUCING BODY MEDIA OR FOR TAKING MEDIA FROM THE BODY; DEVICES FOR PRODUCING OR ENDING SLEEP OR STUPOR
    • A61M37/00—Other apparatus for introducing media into the body; Percutany, i.e. introducing medicines into the body by diffusion through the skin
    • A61M37/0015—Other apparatus for introducing media into the body; Percutany, i.e. introducing medicines into the body by diffusion through the skin by using microneedles
    • A61M2037/003—Other apparatus for introducing media into the body; Percutany, i.e. introducing medicines into the body by diffusion through the skin by using microneedles having a lumen
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61M—DEVICES FOR INTRODUCING MEDIA INTO, OR ONTO, THE BODY; DEVICES FOR TRANSDUCING BODY MEDIA OR FOR TAKING MEDIA FROM THE BODY; DEVICES FOR PRODUCING OR ENDING SLEEP OR STUPOR
    • A61M37/00—Other apparatus for introducing media into the body; Percutany, i.e. introducing medicines into the body by diffusion through the skin
    • A61M37/0015—Other apparatus for introducing media into the body; Percutany, i.e. introducing medicines into the body by diffusion through the skin by using microneedles
    • A61M2037/0046—Solid microneedles
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61M—DEVICES FOR INTRODUCING MEDIA INTO, OR ONTO, THE BODY; DEVICES FOR TRANSDUCING BODY MEDIA OR FOR TAKING MEDIA FROM THE BODY; DEVICES FOR PRODUCING OR ENDING SLEEP OR STUPOR
    • A61M37/00—Other apparatus for introducing media into the body; Percutany, i.e. introducing medicines into the body by diffusion through the skin
    • A61M37/0015—Other apparatus for introducing media into the body; Percutany, i.e. introducing medicines into the body by diffusion through the skin by using microneedles
    • A61M2037/0061—Methods for using microneedles

Definitions

  • the present invention relates to a device, system and method for delivering agents intradermally and, more particularly, to a microneedle array which is designed for cosmetic and dermatologic tissue remodeling.
  • the skin is a protective tissue-layered stratum that encases the body and guards it from potentially harmful intruders. It is the body's first defense against pathogens such as fungi, viruses and bacteria.
  • the constituent components of the skin perform a second major skin function of equal importance, sensation.
  • Encapsulated and free nerve endings, corpuscles (e.g., Meissner's corpuscle), and sensory receptors for touch and pressure found in the dermal layer of skin communicate tactile information to the brain.
  • Skin is made up of two primary layers the epidermis (outermost layer) and its sublayers, and the dermis; below the dermis there is subcutaneous tissue, or the hypodermis which is mainly composed of fat and connective tissue.
  • the two layers are further differentiated by their respective amounts of hair follicle, pigmentation, cell formation, gland makeup, and blood supply.
  • these layers are present in the two general types of skin, thin and hairy, and thick and hairless.
  • the former is more prevalent on the body, while the latter is found on parts of the body that are used heavily and experience extreme friction, like the palm and the heel.
  • the epidermis the outermost layer of skin, is thin but complex. Melanin, which is responsible for skin pigmentation, is found throughout the epidermis.
  • the epidermis also keratinizes to produce nails, hair, sweat, and to regenerate. It is the foremost initiator of cell death and regeneration, the final boundary between body and environment.
  • the epidermis is a stratified squamous epithelium consisting of five keratinocyte layers at various stages of differentiation, the stratum germinativum, stratum spinosum, stratum granulosum, and stratum corneum.
  • stratum germinativum or basal layer is immediately superficial to the dermal-epidermal junction. This single cell layer of keratinocytes is attached to the basement membrane via hemidesmosomes.
  • Keratinization the maturation and migration of skin cells, begins in the innermost layer of the epidermis, the stratum germinativum. Keratinocytes, accumulate and move outward toward the next epidermis layer, the stratum spinosum, where they become dense. As they move into the stratum granulosum, skin cells pick up granules that contain lipids. Lipids assist in the formation of water barriers among the cells of the skin, which, in turn, help to ensure body moisturization. At this point, the cell also becomes flattened, or horny, and the nucleus disappears; what remains is keratin.
  • the stratum lucidum In the next layer, the stratum lucidum, the cell is prepared to move into its final sublayer with the addition of melanin granules. Then, sudden changes in enzyme function cause cell death.
  • the products of this ongoing process form the stratum corneum, which is the outermost epidural layer consisting of neatly packed dead horny cells. When new cells reach the surface, their upward and outward force causes the dead cells to break apart and slough away, a process known as desquamation. It can take anywhere from six to 10 weeks for a cell to mature and journey through the layers of epidermis to its death and expulsion.
  • the stratum corneum may be as thin as a few cells, or as thick as 50 or more cells, again depending on its location on the body.
  • the corneum of the scalp may be very thin, perhaps five cells thick, while that of the elbow is more likely to be upwards of 50 cells thick. So the body provides for high-contact areas by maintaining a thicker and, therefore, more durable layer of protection.
  • the second, larger layer of skin is called the dermis. Its main roles are to regulate temperature and to supply the epidermis with nutrient-saturated blood.
  • the dermis is made up of fibroblasts, which produce collagen connective tissues and which lend elasticity and support to the skin. It is the seat of hair follicles, nerve endings, and pressure receptors. Furthermore, the dermis defends the body against infectious invaders that can pass through the thin epidermis, the first defense against disease.
  • the dermis is also subdivided into two divisions, the papillary dermis, and the reticular layer.
  • the papillary dermis supplies nutrients to select layers of the epidermis and regulates temperature.
  • the reticular layer is much denser than the papillary dermis; it strengthens the skin, providing structure and elasticity. As a foundation, it supports other components of the skin, such as hair follicles, sweat glands, and sebaceous glands. Aging (both photo- and chronological aging) decreases skin function and causes degenerative clinical changes such as wrinkling, color changes (yellowish, patches, pigmentation), and a loss of elasticity and skin thickness.
  • Skin wrinkling is due to a gradual, age-related depletion of collagen and elastin fibers. While skin characterized by decreased content of collagen and elastin contributes to the formation of fine wrinkles, muscles situated below such skin further contribute to the formation of deep wrinkles.
  • invasive surgical procedures such as cosmetic eyelid surgery, tummy tucks and facelifts, can create the most pronounced and currently available long- lasting changes in appearance. They are performed by plastic surgeons with the patient typically under general anesthesia. Due to the limitations inherent to invasive surgical procedures, alternative approaches which are less invasive and can be performed without the need for a surgical staff are constantly sought after.
  • Botulinum Toxin injections e.g.
  • Botox, Dysport into muscle underlying wrinkles around the eyes, mouth and brows.
  • a microneedle array comprising a plurality of microneedles each having a stem region and a tip region, wherein the tip region comprises a substance being capable of promoting remodeling of skin tissue or for treating a dermal disorder.
  • the stem region is devoid of the substance.
  • the substance is formulated as slow release particles.
  • the substance is selected from the group consisting of glycolic acid, lactic acid, combinations thereof and ascorbic acid.
  • the tip region is composed of the substance.
  • each of the microneedles further comprises a linker region between the tip region and the stem region, the linker region being designed for facilitating release of the tip region from the stem region following introduction of the microneedles into skin tissue.
  • the linker region is composed of a biodegradable substance. According to still further features in the described preferred embodiments the linker region is designed for mechanically detaching from the tip region and/or the stem region following introduction of the microneedles into skin tissue.
  • a length of each of the microneedles is selected such that following introduction of the microneedles into skin tissue the tip region resides within a dermal skin layer or subcutaneous fat.
  • microneedles are attached to a support designed for application onto a surface of a skin region predisposed to, or being characterized by wrinkling.
  • the support is fabricated from a material being compressible under load, wherein application of the microneedle array onto a skin region and loading of the material drives the microneedles into the skin region.
  • a microneedle array comprising a plurality of microneedles each comprising a substance (e.g. in the form of particles) within a solid matrix, the substance being capable of promoting remodeling of skin tissue or for treating a dermal disorder.
  • the particles are formulated for slow release.
  • the solid matrix is biodegradable.
  • the particles are composed of a substance selected from the group consisting of poly- glycolic acid, poly-lactic acid, combinations thereof and ascorbic acid.
  • the particles are embedded only within a tip region of the microneedles.
  • a method of preventing or diminishing skin contour irregularities or treating dermal disorders comprising delivering an agent suitable for treatment of skin contour irregularities or dermal disorders under the stratum corneum using a microneedle array thereby preventing or diminishing skin contour irregularities or treating the dermal disorders.
  • the microneedle array is capable of releasing glycolic acid, lactic acid or ascorbic acid.
  • delivery is effected using an applicator capable of accelerating the microneedle array into skin.
  • a device for treating dermal disorders comprising: (a) an applicator head having a surface designed suitable for contacting skin, the surface including microneedles having a length selected capable of penetrating the stratum corneum when the surface contacts the skin; and (b) a mechanism for accelerating the microneedles through the stratum corneum.
  • the device further comprises (c) a reservoir containing at least one agent useful for treating a dermal disorder, the reservoir being in fluid communication with the microneedles.
  • the microneedles are hollow microneedles.
  • microneedles are solid microneedles.
  • a microneedle array comprising a plurality of microneedles each composed of a biodegradable region attached to a non-biodegradable region, wherein the biodegradable region comprises a substance being capable of promoting remodeling of skin tissue or for treating a dermal disorder.
  • the substance is provided as microparticles.
  • the present invention successfully addresses the shortcomings of the presently known configurations by providing a device system and method which can be used to accurately and consistently deliver active agents to a discrete tissue layer of skin, thereby enabling prevention or reduction in skin contour irregularities and treatment of skin disorders.
  • FIG. 1-2 illustrate several embodiments of the microneedle array of the present invention.
  • FIGs. 3a-b illustrate a microneedle array having a compressible support in a non-compressed ( Figure 3a) and compressed ( Figure 3b) states.
  • FIG. 4 illustrates an applicator device for applying the microneedle array of the present invention to skin regions using a vibrating tamper.
  • FIG. 5a-b illustrate treatment of periorbital skin regions using the present system. DESCRIPTION OF THE PREFERRED EMBODIMENTS
  • the present invention is of a microneedle array which can be used for delivering skin tissue remodeling agents into the skin. Specifically, the present invention can be used to prevent or reduce wrinkling of skin.
  • the effectiveness of skin tissue remodeling agent formulations largely depends on skin permeability, site of delivery and the delivered dose. Due to the low permeability of the stratum corneum, active agents such as vitamin C are typically formulated in skin permeabilizing carriers which decrease the effective dose of the active agent. With some active agents such as glycolic acid, the local dose required for a tissue remodeling effect is relatively high while tissue penetration is relatively low and thus they cannot be effectively delivered via topical formulations.
  • gly colic/lactic acid is injected into the skin in the form of biodegradable poly-glycolic acid microparticles (see U.S. Pat. No. 6,716,251 or U.S. Pat. Application No. 10/186183).
  • One commercial example of injectable lactic acid microparticles is Sculptra/NewFillTM which is a suspension of 40- 60 ⁇ m diameter irregularly shaped PLLA particles. Since it is difficult to control the depth of delivery using a syringe, Sculptra/NewFillTM is injected subcutaneously in a matrix pattern. Due to the depth of injection, lidocaine is typically applied prior to injection to reduce patient discomfort and pain.
  • the present device enables intradermal delivery of accurate doses of such agents in a controlled and repeatable manner thereby overcoming the limitations of prior art delivery approaches.
  • microneedle arrays which can be used for reducing the formation or severity of skin contour irregularities or for treating skin disorders.
  • skin contour irregularities refers to fine or deep wrinkles, stretch marks, scars or cellulite of any skin region of a mammal, and in particular a skin region covering the face, neck, hands, arms, legs, abdomen or buttocks of a human. Skin contour irregularities can also result from lipoatrophy (e.g. HIV lipoatrophy), especially in the facial regions.
  • lipoatrophy e.g. HIV lipoatrophy
  • Skin disorders include, but are not limited to, solar elastosis effects, hyperpigmentation, acne, scarring due to acne, dyschromias, melasma, stria distensae, actinic keratosis, acanthosis nigricans, dermatitis, psoriasis and any other disorders of the skin.
  • the microneedle array of the present invention includes a plurality of microneedles.
  • Such microneedles can be needle-shaped microneedles, pyramid- shaped microneedles, prong-shaped microneedles, and the like.
  • Prausnitz Advanced Drug Deliv Rev. 2004 Mar 27;56(5):581-7].
  • each microneedle of the array includes a stem region and a tip region wherein at least the tip region includes a substance which is capable of promoting remodeling of skin tissue.
  • both the stem and tip regions of the microneedles can include the substance, restriction thereof to the tip region is preferred since it enables accurate localized delivery to a discrete tissue layer.
  • Figure 1 illustrates the microneedle array of this aspect of the present invention.
  • the microneedle array which is referred to herein as array 10 includes a support 12 with attached microneedles 14, each including a tip 16 and stem 18 regions.
  • the microneedle array of the present invention preferably includes 10-1000 needles/cm 2 each having a length of about 50 to about 4,500 microns, preferably 200- 800 microns, most preferably 300-600 microns; a width (at the base) of about 20 to about 500 microns, preferably 40-300 microns, and a tapered tip angle of 5-45°.
  • the length of the tip region of each microneedle can be 5-50% of the overall length of the microneedle.
  • the stem region is attached to a planar support (fabricated from polymer, metal etc) or co-molded therewith.
  • the stem and tip region can be fabricated from the same material or from different materials in which case they are reversibly or irreversibly attached (further detail provided hereinbelow).
  • a PDMS mold can be filled with molten PLA that contains a solvent. Upon cooling and solvent evaporation, the PLA tip region shrinks and space is left in the mold above the PLA tip for the molding of a C
  • the surface area of the array, the number and size of microneedles and spacing thereof are selected according to the intended use of the array. For example, a circular or triangular array 0.5-2 cm in diameter with a microneedle density of 50-500 microneedles/cm 2 and a microneedle length of 500 microns can be utilized for treating orbital wrinkles; whereas, one or more square arrays with a total area coverage of 25-36 cm 2 , a microneedle density of 200-1000 microneedles/cm 2 and a microneedle length of about 800 microns can be utilized for treating hand wrinkles.
  • array and microneedle sizes are determined according to parameters (e.g. coverage area, skin thickness) characterizing the specific skin condition and skin type treated.
  • Each skin region can benefit from a support and microneedle shape most suitable for application and precise coverage.
  • regions such as side of mouth to chin ("marionette lines"), labial folds from nose to side of mouth, skin around the upper or lower lip, bulking of the lips themselves, eyebrows, furrow between eyes, hands, chest, neck, abdomen and buttocks can be treated using dedicated array designs.
  • the density and size of the microneedles can be uniform throughout the array or it can vary (e.g. gradient) in a manner that provides spatial dose control. For example, higher density of microneedles or bigger sized microneedles can be provided along the projected centerline of a wrinkle with lower density of microneedles along the periphery of a wrinkle.
  • the microneedles can be fabricated from any material suitable for use in perforating the stratum corneum.
  • suitable materials include, metals such as, stainless steel, titanium, Nitinol, Nickel, polymers such as PMMA, lactic acid, glycolic acid and carbohydrates, calcium hydroxyl appetite, dextran, polyacrylimide, Teflon, as well as silicon.
  • Microarrays made of a metal covered polymer material compatible for the present invention include, for example, the array described by Choi et. al. (An Electrically Active Microneedle Array for Electroporation of Skin for Gene Delivery; 2005 Controlled Release Society 32nd Annual Meeting & Exposition TRANSACTIONS).
  • the array of the present invention can be fabricated using well known techniques such as etching, extrusion, casting and the like. Additional information regarding fabrication of such arrays can be found in McAllister et al. PNAS November 25, 2003 vol. 100 no. 24 13755-13760, Park et al. Journal of Controlled Release 104 (2005) 51-66, or Park et al. Pharmaceutical Research, Vol. 23, No. 5, May 2006. As is further described below, the microneedles of the present invention are preferably fabricated from a combination of materials using single step or multi-step casting approaches.
  • skin tissue remodeling denotes reorganization of cells or matrix of one or more skin layers, preferably, the subcutaneous fat, dermis and epidermis. This includes deposition of new collagen (neocollagenesis), deposition of new elastin and recruitment and proliferation of various cell types including fibroblasts and keratinocytes.
  • Preferred substances include ascorbic acid (vitamin C) and alpha-hydroxy acids (glycolic acid, lactic acid, malic acid and the like); most preferred are ascorbic acid, and polymeric forms of glycolic acid and lactic acid and combinations thereof (e.g. PLA, PGA, PLGA).
  • Additional substances such as gentian violet, an antibacterial that also visually stains holes in the stratum corneum or other delivery markers which outline the region treated can also be delivered from some or all of the microneedles on the array.
  • gentian violet an antibacterial that also visually stains holes in the stratum corneum or other delivery markers which outline the region treated
  • Several approaches can be used to deliver such substances from the tip region of the microneedles.
  • the tip region of the microneedles can be coated with the substance (preferably dry coated) such that when delivered into skin, the substance dissolves off the tip.
  • the tip of the microneedles can be shaped with a reservoir (e.g. a cup) which can be used to deliver liquid or solid (e.g. particles) forms of the substance.
  • microneedles can capture particles of the substance prior delivered on the surface of the skin at the site of delivery and then push them through the stratum corneum into the epidermis and/or dermis.
  • biodegradable encompasses materials which dissolve or degrade in tissue.
  • the entire microneedle or its tip region is fabricated from a biodegradable/dissolvable matrix which releases the substance following introduction of the microneedle into skin tissue.
  • Two configurations can be used to facilitate such release, entrapment of the substance within a biodegradable/dissolvable microneedle, or fabrication of a tip region or of microparticles embedded within a dissolvable matrix from a biodegradable/dissolvable form of the substance, e.g. a microneedle tip which is composed solely from a biodegradable/dissolvable substance (e.g. PLGA) with no additional biologically active agents or substances.
  • a biodegradable/dissolvable substance e.g. PLGA
  • microparticles of vitamin C or glycolic acid in the form of PLGA
  • CMC carboxymethyl cellulose
  • PVP polyvinyl pyrrilidone
  • PEG polyethylene glycol
  • ice or maltose matrix in the shape of a microneedle/tip.
  • the matrix serves to provide structure to the encapsulated microparticles facilitating their penetration into the skin.
  • the substance can be formulated as part of a slow or timed release composition.
  • Preferred forms of slow release formulation include nano or micro sized particles fabricated from poly-Lactic acid or Poly Glycolic acid or combinations thereof. Examples of particles include liposomes [Mantripragada, Prog Lipid Res. 2002 Sep;41(5):392-406], PLA/PGA particles [Tom and Debenedetti, Biotechnol Prog. 1991 Sep-Oct;7(5):403-l l].
  • a microneedle mold made from PDMS with pyramidal needles 800 microns long and 400 microns at their base was filled via centrifugation at 3000 rpm at a radius of 16 cm with PLLA microspheres 30-60 microns in diameter made of PLLA with an inherent viscosity of around 0.3-0.6 dL/g (Brookwood Pharma).
  • Four distinct methods are given by way of example to construct the microneedles.
  • the tip of an ultrasonic horn is pressed against the microparticles with a force of 1 kg and the particles were welded together using 20 pulses of ultrasonic energy at a pulse length of 1 s, duty cycle of 50%, and pulse power of 125 W using a 20-kHz ultrasonic device (Vibracell VC 505, Sonics & Materials, Danbury, CT).
  • the sample is cooled to room temperature and removed from the mold.
  • Such porous microneedle structures are relatively weak as compared to solid microneedles, but strong enough to survive a single accelerated plunge through the skin where they will break off and the welded particles disassociate from one another.
  • Ultrasonic welding can also be used to connect microneedles to a thin flexible polymer base.
  • microneedles composed of a relatively soft matrix can include coated delivery tips (e.g. coated with PLLA) to facilitate their penetration into tissue.
  • a similar approach can utilize maltose powder which is brought to 140 degrees C in a vacuum to make the maltose flowable and then spun in a centrifuge to pack it into the mold.
  • the matrix material can also be a monomer solution of l-Vinyl-2-pyrrolidone with a thermal initiator of 0.5% benzoyl peroxide which flows into the space between the PLLA particles in a vacuum oven and when heated to 80 degrees C for one hour is thermally polymerized to form a stiff gel.
  • An alternative method is to UV cross link the l-Vinyl-2-pyrrolidone using an initiator such as 2,2-Dimethoxy-2- phenylacetophenone under an intense UV light source for one hour.
  • the particles can range in size from 1-5 microns (similar in size to the colored pigments in tattoo inks) or larger.
  • the slow release particles of similar size ranges can agglomerate and form larger particles of hundreds of microns in diameter and therefore evade being removed from the site of injection by macrophages and the like.
  • particles of about 50 microns in diameter are used so that they are not taken up by macrophages and removed from the area of injection.
  • the second configuration is suitable for substances which can be formulated in biodegradable form.
  • substances include glycolic acid and lactic acid which can be formulated as PLGA or agents which are dissolved in microneedles formed from ice (e.g. by freeze molding buffered agent solutions).
  • PLGA or poly(lactic-co-glycolic acid) is a Food and Drug Administration (FDA) approved copolymer which is used in a host of therapeutic devices, owing to its biodegradability and biocompatibility.
  • FDA Food and Drug Administration
  • PLGA is synthesized by random ring-opening co-polymerization of various ratios of glycolic acid and lactic acid. PLGA degrades by hydrolysis of its ester linkages in the presence of water to yield glycolic acid and lactic acid.
  • the microneedles of the array of the present invention can further comprise a mechanism for detaching the stem region from the tip region following administration of the microneedles into the skin. This enables removal of the array shortly following administration of the microneedles.
  • Such a mechanism can be realized through detachable coupling between the tip region and the stem region or stem and support or through the use of a linker region which is designed for mechanical (e.g. controlled breakage) or chemical (e.g. biodegradable linker) detachment.
  • a linker region which is designed for mechanical (e.g. controlled breakage) or chemical (e.g. biodegradable linker) detachment.
  • Coupling can alternatively be effected using a tip region fashioned as an arrowhead or barb and a stem region which slides into a bore configured within the tip region. Following administration of the microneedles, removal of the array (by pulling it out) forces the arrowheads or barbs to disconnect from the stem, leaving the tip region within the tissue to biodegrade over time.
  • Mechanical breakage can be effected using a linker region which supports loads through the longitudinal axis of the microneedle and yet collapses when loaded by a force which angles away from the longitudinal axis. Examples include a groove or notch which would concentrate a bending force and cause the microneedle to break off from the support at the application of a shear force. Furthermore, at a high enough aspect ratio, that is a relatively a tall and slender microneedle, shear stress will concentrate at the junction of the needle and the base and the microneedle will break naturally at the base upon application of a shear force without the need for a linker or special mechanical feature. Therefore the applicator can combine a sequence of downward motion to insert the microneedles, and then a sideways motion to break them off.
  • Figure 2 illustrates a microneedle array 10 having a detachable tip region 16 which is connected to stem region 18 through a linker 20 which is designed for mechanical breakage.
  • Chemical detachment can be effected using a carboxymethyl cellulose (CMC), Polyvinyl pyrrolidone (PVP), sugars such as maltose, maltodextrin or salts such as NaCl linker region.
  • CMC carboxymethyl cellulose
  • PVP Polyvinyl pyrrolidone
  • sugars such as maltose, maltodextrin or salts such as NaCl linker region.
  • Other biocompatible materials that dissolve in tissue and yet have appropriate mechanical properties when dry can be used for this purpose.
  • the detachment material can be doped into or layered between the same material as the tip, but only in the stem region, thereby weakening the stem sufficiently to enable it to preferentially disconnect at the stem.
  • an array for delivery of solid preparations of a tissue remodeling substance provides several advantages over prior art delivery approaches.
  • An array with breakable/dissolvable/biodegradable release mechanisms enables delivery of an accurate dose in a spatially controlled and consistent manner without requiring high operator skills.
  • microneedle arrays can be applied by a nurse, a technician, a cosmetician or by a person the treated individual.
  • such an array can provide long term effects when used with biodegradable formulations of the substance delivered.
  • the microneedle array includes a plurality of hollow microneedles.
  • Such hollow microneedles can be used to deliver an agent such as retinoic acid (and its derivatives), hyaluronic acid, collagen (as a solution/suspension), or glycolic/lactic acid (in the form of PLLA or PLGA) into skin tissue.
  • microneedles can be connected to a reservoir which can be activated to deliver the agent through the microneedles, or alternatively, the microneedles can be preloaded with the agent.
  • the microneedles can be preloaded with the agent (in liquid or solid form) prior to skin penetration and activated to eject the agent out of the microneedles and deliver it into the tissue following tissue penetration.
  • Delivery of a solid form of the agent from hollow microneedles can be effected via several approaches.
  • particles loaded with or composed from the agent can be loaded directly into the microneedles.
  • the agent can be (partially) molded into a shape that can be fitted within the microneedles or attached to a tip region thereof (e.g. arrowhead-shaped dose fitted into end of microneedles).
  • the agent is released therein via one of the release mechanisms described hereinabove (e.g. dissolution, biodegradation).
  • the solid agent can be suspended as particles in an appropriate matrix, such as CMC or PEG, that keeps the solid agent buoyant or flowable through a narrow bore of the microneedle.
  • an appropriate matrix such as CMC or PEG
  • a positive displacement pump or plunger can be used to deliver precise doses of the active agent into the skin, since a passive pressure reservoir will likely cause a surge of material once the resistance to flow has been overcome, thereby making precise dosing difficult.
  • Another embodiment can employ a microvalve in close proximity to the microneedle to prevent and material from surging out of the microneedle in an uncontrolled manner.
  • the microneedles of the array of the present invention can be attached to a planar support which can be elastic, plastic, semi-rigid or rigid in nature.
  • the support facilitates tissue penetration of the microneedles by directing a force applied thereto to the tops of the microneedles.
  • microneedle array configuration having a polymer support mounted with microneedles will be capable of controlled and accurate delivery of the substance, in order to enhance microneedle penetration and preserve microneedle integrity during administration, especially in the configurations having a linker region which is susceptible to breakage, the present inventors have devised a microneedle array configuration which protects and guides microneedles during tissue penetration.
  • a microneedle array which includes microneedles which are at least partially embedded within a support fabricated from a material being compressible under load. Such a support acts to reinforce the microneedles in the direction perpendicular to the axial load to help prevent buckling during the insertion.
  • the support is configured such that application of the microneedle array onto a skin region and loading of the material compresses the support axially and drives the microneedles into the skin region.
  • the support material can be an open cell foam (e.g. polyurethane or polyethylene foam), which is either plastic or elastic, or any material which demonstrates compression along the axis of load applied without substantial deformation in an axis perpendicular to the load. The latter trait is particularly important in that such deformation can lead to buckling of microneedles or deflection of microneedle paths and inefficient or incomplete delivery.
  • Figures 3a-b illustrate a microneedle array having a compressible support, which array is referred to herein as array 30.
  • support 32 of array 30 includes embedded microneedles 34.
  • Microneedles 34 can be any microneedles known in the art or the microneedles described herein. Support 32 also protects microneedles from breaking or scratching the skin during application and array handling.
  • support 32 compresses, exposing microneedles 34 and directing the path of the microneedles along the direction of the load.
  • a compressible support can negate the need for a rigid support (attached to the base of the microneedles)
  • the above described configuration can also include a rigid planar support base for facilitating microneedle insertion and compression of the compressible support. Delivery of any of the array configurations of the present invention can be effected manually, i.e. by applying a force using a finger, a hand, a roller device or the applicator device described hereinunder.
  • microneedle arrays of greater than a few square millimeter area, whether hollow or solid, are not optimized for penetrating the skin due to the so called "bed of nails effect".
  • the force of the array being pressed against the skin is divided by the collective area of all of the needles in the array, and so the force per needle can be below the threshold necessary to pierce the skin.
  • the conventional means to overcome this effect include minimizing the number of needles or maximizing the force applied to the array, both of which have practical limitations.
  • the present inventors have devised an applicator device which can be used along with the microneedle arrays of the present invention in a system for treating skin contour irregularities.
  • Figure 4 illustrates the applicator device of the present system, which is referred to herein as device 40.
  • Device 40 includes an applicator head 42 which has a surface 44 designed for carrying a microneedle array and an element 46 (e.g. frame) for outlining an application site on the skin region.
  • element 46 e.g. frame
  • Device 40 further includes a handle 48 which houses a power supply (not shown) and a mechanism 48 which is capable of accelerating microneedles 14 into the skin at a velocity of 4- 16 m/s.
  • Mechanism 48 includes a free mass that can be accelerated and impacted to the backside of the microneedle array to transfer momentum to it, thereby accelerating the microneedles and causing them to penetrate the skin faster than the skin can move away.
  • Mechanism 48 can include a mass, a return spring, a damper to prevent overshoot and can be driven using springs, solenoids, piezoelectric actuators or pneumatic actuators.
  • Applicator head 42 can also form an airtight seal around a skin region.
  • Device 40 further includes a vacuum generating mechanism that generates vacuum from a manual, internal or external power supply (not shown).
  • a vacuum generating mechanism that generates vacuum from a manual, internal or external power supply (not shown).
  • this configuration of device 40 is loaded with a microneedle array and placed in contact with a skin region.
  • a vacuum is applied to stretch and pull the skin region up and in contact with the microneedle array thereby forcing the microneedles to penetrate into tissue of the skin region.
  • the microneedle array can form a part of the surface of applicator head or it can be removably attached thereto through an adhesive layer, or a magnetic or mechanical coupling mechanism (e.g. a mechanical holder).
  • microneedle array can be included in a multi-array cartridge which is carried by applicator device 40.
  • the cartridge and device 40 can be configured for coordinated dispensing and delivery of microneedle arrays through applicator head 42. This enables repeated accurate delivery of arrays and large area coverage.
  • the microneedle array can be presented to the applicator head in the form of a tape or cartridge or cassette to be laid down along a skin remodeling site.
  • Applicator device 40 can be a tamper that hits the backside of the tape and plunges the microneedles in the skin.
  • the tape can be porous and after application dampened with water to enhance the dissolution of the dissolvable link between the microneedles and the backing tape.
  • Applicator device 40 can also include a vibratory mechanism for vibrating the microneedles and causing breakage of the tip region from the stem region following tissue penetration.
  • Applicator 40 can also incorporate a massaging mechanism, for example at 100 hertz, for distributing the deposited active agents, for example microparticles of PLLA, more uniformly in the skin. Such vibration can also be used for vibratory anesthesia.
  • Applicator 40 can also direct electricity, light, heat or other forms of energy to melt and therefore detach the microneedles close to the base.
  • Applicator device 40 can also include a lock-out mechanism for preventing abuse of device 40.
  • a lock out mechanism would prevent over-dosing of the substance by effectively prohibiting the user, especially when using the device without medical supervision, from using the device too often.
  • An example of one lock out mechanism is a lock out timer, while another can employ a sensing head which can lock out the device when it detect the presence of a co-administered dye which dissipates from the skin over a predetermined time period.
  • the above described applicator and delivery mechanisms can also be used in an applicator configuration which includes a reservoir and hollow microneedles or hollow microneedles preloaded with the agent.
  • an applicator including a reservoir containing PLLA/PLGA microparticles suspended in a liquid carrier and a mechanism for accelerating the applicator head and attached hollow microneedles into skin can be utilized to efficiently and accurately to deliver such microparticles into the dermis or subcutaneous fat layers.
  • the microparticles can be suspended in any liquid carrier including glycerol, PEG, a sugar solution and the like.
  • glycerol glycerol
  • PEG glycerol
  • sugar solution glycerol
  • a 25% PEG400-PBS solution can be used to maintain the particles suspended for delivery.
  • a microneedle array which includes 100 hollow microneedles each having a height of lOOO ⁇ m, a diameter (at the base) of 200 ⁇ m and a bore 20-100 ⁇ m in diameter is mounted by a user on the applicator head.
  • the applicator includes a reservoir which is in fluid communication with the mounted microneedles and a mechanism for accelerating the applicator head and mounted microneedles into tissue.
  • Applicator head is applied onto a skin surface to be treated and the mechanism for accelerating the applicator head is activated to deliver the hollow microneedles tips into the dermal or subcutaneous fat layers.
  • the reservoir is then activated to pump the agent through the microneedles and into the tissue optionally with concurrent manual or automatic (by reversing the mechanism) withdrawal of the microneedles from the tissue.
  • the applicator head is removed from the skin, the microneedle array is replaced and a second delivery round is effected if so desired.
  • the skin region to be treated can be marked with a grid and the device can be repeatedly used within the grid to cover the area to be treated.
  • a wrinkle of interest can be marked with a marker and an applicator device incorporating a sensor can be used to identify the location of these markings on the skin and deliver the agent through hollow microneedles to the areas that are marked.
  • Applicator configurations of the present invention can further include cooling or heating mechanisms for providing local analgesia as well as facilitating delivery of the active agent.
  • an applicator head which incorporates a cooling element can be used to cool the skin region prior to microneedle delivery.
  • agents which can be delivered using the microneedle arrays of the present invention include, but are not limited to, ascorbic acid and its derivatives, glycolic acid [Bernstein et al., Dermatol Surg. 2001 May;27(5):429-33], alpha- tocopherol [Ricciarelli et al. Free Rad Biol Med, 1999; 27: 729-37], phospholipid hydroperoxide glutathione peroxidase (PHGP) [Hoet al., Free Rad Biol Med, 2000; 29:159-69], retinoic acid, ellagic acid derivatives [Zafrilla et al., J Agric Food Chem.
  • ascorbic acid and its derivatives include, but are not limited to, ascorbic acid and its derivatives, glycolic acid [Bernstein et al., Dermatol Surg. 2001 May;27(5):429-33], alpha- tocopherol [Ricciarelli et al. Free Rad Biol Med, 1999;
  • poly-1 lactic acid PLLA
  • amino acids amino acids building blocks for collagen
  • copper peptides copper is essential for collagen production, Malakyan et al., Inflammopharmacology. 2004;12(4):321-51]
  • MMP e.g.
  • collagenase inhibitors such as, doxycycline hyclate (Periostat), growth and trophic factors such as TGF-beta, FGF, PDGF, NGF, NTF [see Fitzpatrick, Dermatologic Surgery Volume 31 Page 827 - July 2005], an exemplary growth factor cocktail is a mixture of multiple growth factors derived from a three-dimensional tissue culture of human fibroblasts (NouriCel-MD, Smith & Nephew, La Jolla, CA, USA or SkinMedica Carlsbad CA USA), lysozyme [Park et al., J Invest Dermatol.
  • corticosteroids e.g. triamcinolone, prednisone, prednisolone, cortisone/hydrocortisone, dexamethasone/betamethasone
  • Stauvidine for inducing adipocyte proliferation
  • 1,4- dihydroxy-2-methoxy-7-methylanthraquinone for inducing ECM deposition from dermal fibroblasts [Kim et al. J Med Food. 2005 Winter;8(4):552-5]
  • collagen-derived peptides produced by enzymatic, e.g.
  • microneedle arrays of the present invention can be used to deliver more than one type of an agent, either simultaneously or sequentially.
  • Multilayered coatings of the micro arrays can be configured to release certain vitamins or growth factors in a preset sequence in the order they dissolve off.
  • an acid e.g. glycolic acid
  • a neutralizing alkaline agent can be coated as an inner layer on top of the needles, such that it is released after the acid.
  • a liquid formulation of these factors can be sequentially released from a device reservoir through hollow microneedles.
  • the arrays of the present invention can also be used to deliver an agent such as aluminum chloride or botulinum toxin or other compounds which inhibit or block sweat gland activity (cholinergic receptor antagonists) in order to treat excessive sweating (hyperhidrosis).
  • an agent such as aluminum chloride or botulinum toxin or other compounds which inhibit or block sweat gland activity (cholinergic receptor antagonists) in order to treat excessive sweating (hyperhidrosis).
  • use of a microneedle array is advantageous in that large area coverage can be easily obtained via a single application.
  • the arrays of the present invention can also be used to treat gum disease as well as gum regression.
  • Disorders of the gingiva affect nearly 80% of people at one point in their life.
  • Some gingiva disorders as well as age dependent gingival degeneration can be attributed to a reduction of the collagen matrix in gingival tissue [Mussig et al., J Orofac Orthop. 2005 Nov;66(6):422-33].
  • preferred agents administered by the arrays of the present invention include those that promote neocollagenesis and fibroblast recruitment.
  • the arrays of the present invention can also be used to deliver a local anesthetic in order to reduce pain associated with dermal procedures.
  • the present invention provides a device, systems and method for treating skin contour irregularities and dermal disorders.
  • Figures 5a-b illustrates periorbital skin region treatment using applicator device 40 described in Figure 4 and a microneedle array 10 having an array support shape and microneedle distribution which is optimized for treatment of such a skin region.
  • Microneedle array 10 includes 1500 microneedles each having a height of 750 ⁇ m, a diameter (at the base) of 100 ⁇ m mounted on a support which is fabricated as a 1.5 cm (h) by 2 cm (base) triangle via molding.
  • Microneedle array 10 is designed having a PLLA tip region 250 ⁇ m in length. The tip is attached to a 500 ⁇ m stem region composed of PEG (30,000 Dalton MW).
  • each microneedle has a mass of approximately 2x10 "3 milligrams and therefore 1500 microneedles distributed over a patch area of 3 cm 2 implies an effective intradermal PLLA dose of 1 mg/cm , which is sufficient to have a significant effect in reducing wrinkles.
  • microneedle array to periorbital regions is as follows, a user attaches microneedle array 10 to applicator head 42 of device 40 or loads a cartridge including several arrays 10 into applicator device 40.
  • the user then applies applicator head 42 onto a skin surface region 78 to be treated (i.e. the periorbital skin region which includes "crows feet” wrinkles) and activates mechanism 48 of device 40, to deliver a single array 10 to the periorbital region ( Figure 5b).
  • a skin surface region 78 to be treated i.e. the periorbital skin region which includes "crows feet” wrinkles
  • mechanism 48 of device 40 to deliver a single array 10 to the periorbital region ( Figure 5b).
  • array 10 is removed from the skin and a second array is applied if necessary.
  • the skin region to be treated can be marked with a grid and the device can be repeatedly used within the grid to cover the area to be treated.
  • the wrinkle of interest can be marked with a marker and an applicator device incorporating a sensor can be used to identify the location of these markings on the skin and deliver microneedles to the areas that are marked.

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Abstract

L'invention concerne une puce à injections (10). La puce à injections (10) comprend une pluralité de micro-aiguilles pleines ou creuses (14) qui sont conçues pour l'administration d'un agent dans la peau pour traiter des irrégularités du contour de la peau ou des troubles de la peau.
PCT/IL2007/001324 2006-11-01 2007-10-30 Puces à injections WO2008053481A1 (fr)

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