WO2003092785A1 - Arrays of microneedles comprising porous calcium phosphate coating and bioactive agents - Google Patents

Arrays of microneedles comprising porous calcium phosphate coating and bioactive agents Download PDF

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Publication number
WO2003092785A1
WO2003092785A1 PCT/CA2003/000577 CA0300577W WO03092785A1 WO 2003092785 A1 WO2003092785 A1 WO 2003092785A1 CA 0300577 W CA0300577 W CA 0300577W WO 03092785 A1 WO03092785 A1 WO 03092785A1
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WO
WIPO (PCT)
Prior art keywords
calcium phosphate
skin
coating
bioactive agent
porous
Prior art date
Application number
PCT/CA2003/000577
Other languages
French (fr)
Inventor
Morteza Shirkhanzadeh
Original Assignee
Morteza Shirkhanzadeh
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Filing date
Publication date
Priority to GB0209813.5 priority Critical
Priority to GB0209813A priority patent/GB0209813D0/en
Priority to GB0212352.9 priority
Priority to GB0212352A priority patent/GB0212352D0/en
Application filed by Morteza Shirkhanzadeh filed Critical Morteza Shirkhanzadeh
Priority claimed from GB0316870A external-priority patent/GB0316870D0/en
Publication of WO2003092785A1 publication Critical patent/WO2003092785A1/en

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    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61MDEVICES 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
    • A61M37/00Other apparatus for introducing media into the body; Percutany, i.e. introducing medicines into the body by diffusion through the skin
    • A61M37/0015Other apparatus for introducing media into the body; Percutany, i.e. introducing medicines into the body by diffusion through the skin by using microneedles
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL, OR TOILET PURPOSES
    • A61K47/00Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/02Inorganic compounds
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL, OR TOILET PURPOSES
    • A61K9/00Medicinal preparations characterised by special physical form
    • A61K9/0012Galenical forms characterised by the site of application
    • A61K9/0014Skin, i.e. galenical aspects of topical compositions
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL, OR TOILET PURPOSES
    • A61K9/00Medicinal preparations characterised by special physical form
    • A61K9/0012Galenical forms characterised by the site of application
    • A61K9/0019Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner
    • A61K9/0021Intradermal administration, e.g. through microneedle arrays, needleless injectors
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61MDEVICES 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
    • A61M37/00Other apparatus for introducing media into the body; Percutany, i.e. introducing medicines into the body by diffusion through the skin
    • A61M37/0015Other apparatus for introducing media into the body; Percutany, i.e. introducing medicines into the body by diffusion through the skin by using microneedles
    • A61M2037/003Other 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
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61MDEVICES 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
    • A61M37/00Other apparatus for introducing media into the body; Percutany, i.e. introducing medicines into the body by diffusion through the skin
    • A61M37/0015Other apparatus for introducing media into the body; Percutany, i.e. introducing medicines into the body by diffusion through the skin by using microneedles
    • A61M2037/0053Methods for producing microneedles

Abstract

A device for delivering bioactive agents through skin comprising: a plurality of skin-piercing members; a porous calcium phosphate coating adapted as a carrier and disposed upon at least a portion of said skin-piercing members, wherein the coating includes at least one bioactive agent. In one preferred embodiment, the calcium phosphate coating further includes a supplementary material such as trehalose in dry form to improve the mechanical stability of the calcium phosphate coating during penetration of the skin-piercing members through skin. The supplementary material is preferably a water-soluble carbohydrate containing a bioactive agent. In another preferred embodiment, the coated skin-piercing members described above are adapted as electrodes for subjecting the skin cells (e.g., the Langerhans cells) to a high electric field for efficient transfer of bioactive agents into cells.

Description

Arrays of Microneedles Comprising Porous Calcium Phosphate Coating and Bioactive Agents

Field of the Invention

This invention is related to devices for the delivery of bioactive materials across tissue barriers such as the stratum corneum (SC) layer in the human skin. In particular, the invention is related to the arrays of microneedles and microblades used for the transdermal transfer of bioactive agents through skin. The invention is further related to electroporation devices using microneedles and microblades as electrodes for efficient delivery of bioactive agents into skin cells.

Background of the Invention

A common method for delivering therapeutic and biological molecules across skin is the use of conventional needles and catheters. It is known, however, that the administration of drugs by needles and catheters generally causes pain, local damage to the tissue, and may result in disease transmission. Another alternative method commonly used for the transdermal delivery of drugs is the use of transdermal patches that rely on the passive diffusion of the drug across skin. The problem with this method is that the rate of the passive diffusion of drugs through the skin is too slow due to the poor permeability of the skin. The rate of the passive diffusion of drugs can be improved by the application of permeation enhancers and by modifying the physiochemical properties of drugs. However, currently there are only a limited number of drugs that have the required physiochemical properties to be effectively delivered through skin by passive diffusion.

There are also devices for delivering pharmaceutical agents comprising arrays of microneedles or microblades that pierce the outermost layer of the skin known as the stratum corneum. These skin-piercing elements in general create pathways into the skin and thereby enhance the delivery of therapeutic agents. Devices comprising arrays of skin piercing elements with liquid or solid reservoirs containing therapeutic agents have been disclosed in PCT publication No. WO 02 / 07813, US patent application No 0020177839, US patent application No. 0020061589, US Pat. No. 5,879,326, WO 98/29298, WO 98/29365, and WO 00/05339 all incorporated by reference in their entirety. The piercing elements generally extend perpendicularly from a flat member such as a pad or sheet. The piercing elements in some of these devices are extremely small, some having a length of about 25 to 400 micrometer and a diameter (e.g., microneedle diameter) of only about 1-3 micrometer.

Devices comprising arrays of skin- piercing microprojections coated with a solid biodegradable reservoir containing therapeutic agents have been disclosed in PCT publication No. WO 02/07813. Preferred biodegradable solid reservoirs comprise sugars, and in particular stabilizing sugars that form a glass such as lactose, raffinose, trehalose or sacrose. Once the coated microprojections have pierced the stratum corneum layer and come to contact with body fluid, the agent can be released into the skin tissue as a result of biodegradation of the solid reservoir. The potential advantage of this system is that the reservoir containing the agent is in a solid form and thus the agent may be stored at room temperature for a relatively long time without losing its effectiveness.

US patent application No. 0020177839 also describes a device including a plurality of stratum corneum-piercing elements that are coated with a solid and biocompatible carrier containing at least one beneficial agent. The biocompatible carrier is selected from the group consisting of human albumin, bio-engineered albumin, dextran sulfate, pentosan polysulfate, polyglutamic acid, polyaspartic acid, polyhistidine and non-reducing sugars.

The solid reservoirs in devices disclosed in the PCT publication No. WO 02 / 07813 and US patent application No. 0020177839 must have a combination of desired properties in order to be effective for their intended function. Firstly, the reservoir media should be capable of adhering to the skin-piercing elements to a sufficient extent that the reservoir remains physically stable and attached during prolonged storage. The reservoir should also remain substantially intact during the administration procedure when the coated piercing elements cut through the stratum corneum. Secondly, the reservoir must also be capable of holding an effective amount of the agent, and ideally should be capable of stabilizing the agent over the period of storage. Thirdly, for certain applications such as vaccines, the reservoir media should facilitate rapid release of the pharmaceutical agent into skin tissue over a short period of time, preferably 30 seconds or less.

In the prior art, physical means have been used to increase the surface area of the reservoir to enhance the release of the agent in the skin. For example, it is disclosed in PCT publication No. WO 02 / 07813 that the skin-piercing members may be coated first with an aqueous solution of an agent and water-soluble polyol followed by lyophilisation to give a porous coating with a high solubility rate. The problem with this method, however, is that lyophilised formulations are known to be mechanically weak and unstable and, therefore, the reservoir processed in this way may disintegrate or break off during the penetration of the skin-piercing elements into skin.

Another alternative method for enhancing the dissolution rate of the reservoir is to employ thin films of reservoir disposed upon skin-piercing members having rough, porous, or textured surfaces. This would create an interface with a large surface area that is necessary for rapid dissolution of the solid reservoir in the skin. Conventional techniques available for texturing and for creating rough surfaces include chemical and photochemical etching, mechanical milling (e.g., diamond milling, abrading, roughening), high energy milling (e.g., ablation or etching with high energy beams such as with plasma, laser diodes and the like), and electrical discharge machining (EDM). There are also other treatments that are capable of creating porous surfaces such as electrochemical oxidation process (e.g., anodization of the silicon in a hydrofluoric acid electrolyte). However, given the small dimensions of the skin-piercing elements commonly used, it is understandable that such treatments would create significant stress concentrations at the surface that may weaken the mechanical strength of these tiny elements. As a result, skin- piercing elements with micro-porous and textured surfaces may easily break off (especially near the tips) following insertion or removal from skin. Furthermore, broken parts may be left in the skin tissue that may cause inflammation and other undesirable complications. It would be desirable, therefore, to provide means for increasing the surface area of the skin-piercing elements that would facilitate the fast release of the agent into skin tissue without having the problems discussed above.

Skin-piercing microneedles and microblades have also been used as tiny electrodes for the electroporation of skin cells for a more efficient transfer of bioactive materials into cells. PCT publication No. WO 00/44438 discloses skin-piercing elements coated with therapeutic agents and adapted as electrodes. Therapeutic agents attached to electrodes are intended to be released and driven into cells as a result of the application of voltage signals between electrodes. A problem associated with this method, however, is that electrode reactions can result in significant changes in the pH of the tissue close to the skin-piercing elements. Toxic species may also be released from the skin-piercing elements as a result of the electrochemical reactions that may cause adverse effects such as burning sensation, irritation, blister formation, skin necrosis, and cell death. Electrode reactions may also cause biochemical degradation of the drugs (e.g., DNA molecules) that may be attached to the skin-piercing elements, and thus may reduce the therapeutic effects of these agents. It would, therefore, be desirable to provide skin-piercing electrodes that would have the means for minimizing the side effects discussed above. In particular it would be desirable to provide skin-piercing electrodes having the means for minimizing the biochemical degradation of therapeutic agents attached to the skin-piercing electrodes.

It is also known in the literature that the transfer of biological molecules (e.g., DNA molecules) into skin cells can be enhanced by the use of the calcium phosphate transfection method. The calcium phosphate transfection method is based on the formation of fine DNA/calcium phosphate particles that attach to the cell surface and are then transported into the cytoplasm via endocytosis (Loyter et al., Exp. Cell Res., Vol. 139, pp 223 - 234 (1982)). Once the fine DNA calcium phosphate particles are located inside the cells, the nucleic acids are transferred to the nucleus by means of an endosomal-lysosomal vesicular transport system (Orrantia et al., Exper. Cell Res., Vol. 190, pp 170 -174 (1990). While the prior art indicates that electroporation can be used in conjunction with skin-piercing elements for the delivery of DNA into cells, the prior art does not teach or suggest a device that would deliver DNA molecules into cells by combining electroporation and the calcium phosphate transfection method together. Thus, it would be desirable to provide a device comprising plurality of skin-piercing elements that would allow efficient delivery of DNA molecules into skin cells by combining electroporation and the calcium phosphate/DNA transfection method.

SUMMARY OF THE INVENTION

The present invention provides for improved devices that can rapidly and efficiently release pharmaceutical agents through the stratum corneum without having the problems and limitations of the prior art. A preferred embodiment of the present invention consists of a device for delivering bioactive agents through skin comprising a plurality of skin-piercing members, a porous calcium phosphate coating adapted as a carrier disposed on at least a portion of the skin-piercing members, wherein the coating includes at least one bioactive agent. The porous calcium phosphate coating in the present invention is intended to act as an effective porous matrix with a large surface area to facilitate rapid release of the bioactive agent in the skin tissue. Furthermore, the porous calcium phosphate is intended to provide a novel means for increasing the amount of bioactive agent that can be delivered by the individual skin-piercing members. In another preferred embodiment, the skin-piercing members coated with the porous calcium phosphate coating as described above are adapted as electrodes for the electroporation of skin cells for a more efficient transfer of bioactive agents into skin cells (e.g., the Langerhans cells). In this embodiment, the porous calcium phosphate is intended to act as a solid buffer for minimizing pH changes close to electrodes as well as an effective porous carrier for delivery of bioactive agents (e.g., DNA molecules) into cells.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. la is a Scanning Electron Microscope (SEM) image (X300) of a single microneedle having a porous calcium phosphate coating according to one embodiment of the present invention.

FIG. lb is another Scanning Electron Microscope (SEM) image of the coated microneedle showing the porous interconnected network of the calcium phosphate coating of the present invention at a higher magnification (X 4000).

DETAILED DESCRIPTION OF THE INVENTION

The device of the present invention in general has a plurality of skin-piercing members (preferably about 100 to 1000 members per device) of various shapes and sizes to pierce the stratum corneum. The piercing elements may extend perpendicularly from the surface or edges of a flat member such as a sheet. The piercing members may be in the form of microneedles or microblades and may have a length of about 25 to 800 micro-meter and a diameter (e.g., microneedle diameter ) of about 1 to 25 micro-meter or more. The length of the skin-piercing members should be appropriately selected in order to deliver the bioactive agents into defined layers of skin such as dermis. The skin-piercing members can be manufactured by methods know in art, including methods described in Annual Rev. Biomed.Eng., 2000,289 -313 ( McAllister et al), Journal of Pharmaceutical Sciences, 1998, 922-925 (Henry et al) ; US 5,879,326 ; WO 97/ 48440; WO 97/48442; US. Pat. No. 6, 038, 196 ; U.S. Pat. No. 6,050, 988 ; U.S. Pat. No. 6, 091, 975; and WO 98/28037. The skin-piercing members may be constructed from any material with sufficient mechanical strength including metals, ceramics, plastics, semiconductors or composite materials. For example, skin-piercing members may be made of stainless steel, titanium, palladium, and palladium alloys charged with hydrogen.

The porous calcium phosphate coating in the present invention is disposed on at least a portion of the skin-piercing members and preferably has an average thickness less than 10 micrometer, and more preferably an average thickness less than 5 micrometer. The porous calcium phosphate coating may be amorphous, crystalline, nano-crystalline or partially crystalline. The term "amorphous" used here is intended to include a material with significant amorphous character that is characterized by a broad featureless X-ray diffraction pattern. The term "porous calcium phosphate" used herein is intended to include calcium phosphate coatings that are porous throughout their structure or partially porous. For example, pores may be predominantly located at the surface of the coating. Thus, the coating may be characterized by having tiny three-dimensional features at the surface such as open pores, craters, recess, and empty spaces between tiny crystals that would increase the surface area of the coating. Pores may be uniform in size or they may be of different sizes. For example, the porous calcium phosphate coating in the present invention may have a meso-porous, a nano-porous, or a micro-porous three- dimensional framework structure. Alternatively, the calcium phosphate coating may be characterized by a structure that is, for example, partially meso-porous or nano-porous and partially micro-porous. The calcium phosphate coating may be, for example, a composite coating consisting of more than one coating layer each having a different microstructure and composition. Preferably, pores in the coating are less than 5 micrometer in size, and more preferably less than 1 micrometer and even more preferably less than 200 nanometers.

In the preferred embodiments, the Ca/P molar ratio of the coating is less than 1.67, and more preferably less than 1.5. Specific examples of calcium phosphate compounds suitable in the present invention are amorphous calcium phosphate (ACP), Brushite, α- and β- Tricalcium Phophate , Calcium-deficient Hydroxyapatite, Carbonated Apatite, Octa Calcium Phosphate ( OCP), stoichiometric Hydroxyapatite, Flouro- and Chloro-apatite and mixtures thereof. Such compositions are generally known to be biocompatible and non-toxic to cells and tissues. In a preferred embodiment, the calcium phosphate compound is formulated to be biodegradable. The term " biodegradable" used herein is intended to include calcium phosphate compounds that are capable of becoming soluble upon hydrolysis (or decomposition) in the presence of enzymes or other substances present in the skin tissue. In a preferred embodiment, the calcium phosphate coating is intended to completely dissolve in the skin tissue in less than 30 minutes, and more preferably in less than 5 minutes.

Calcium phosphate compounds in the present invention may additionally include ions such as magnesium, sodium, potassium, fluoride, silicate, carbonate, and bicarbonate ions. Additionally, calcium phosphate may be used in combination with oxides such as CaO, MgO , and glass forming solid compounds containing silicon, oxygen, calcium, and phosphate. In one preferred embodiment, the porous calcium phosphate coating is composed of calcium-deficient hydroxyapatite with a general chemical formula: Ca (io -x) (P0 ) (6) (OH) (2_χ) (HPO ) x , where x is less than 2.

As shown in figures la and lb, in one embodiment of the invention the porous calcium phosphate coating may comprise a mass of randomly oriented plate-like crystals of Ca-deficient hydroxyapatite and/or octa calcium phosphate (OCP) having dimensions in the range of 1 to 5 μm, more preferably less than 1 micrometer. Such a porous coating would provide a large surface area necessary for the effective loading of individual microneedles with the bioactive agents. In another preferred embodiment of the invention, the micro-porous coating comprises an array of densely spaced needle-like crystals of ca-deficient hydroxyapatite having a height of about 5 to 10 μm and a packing density of about 10 needle crystals per cm .

Bioactive agents that may be incorporated in the calcium phosphate coating of the present invention may include agents known in the prior art including pharmaceutical agents, therapeutic and prophylactic agents, cells, bacteria, viruses, Iipids, proteins, polypeptides, oligosaccharides, polysaccharides, nucleic acids including DNA, RNA, DNA fragment, enzymes, polynucleotide molecules, anti- infection agents, hormones, growth factors, anti-cancer drugs, and vaccines. Suitable vaccines include, but are not limited to, vaccines effective against influenza, measles, mumps, rubella, and combinations thereof.

Bioactive agents may be incorporated in the calcium phosphate coating in varying amounts and in a variety of physical forms. For example, the bioactive agent may be a particulate or liquid agent that is intimately mixed with the calcium phosphate of the present invention. Thus, the calcium phosphate coating may serve as a matrix for the bioactive agent that is embedded or dispersed throughout the matrix. The bioactive agent may also be located within the pores of the coating. In this case, the bioactive agent may be in a liquid form, gel form, or a solid form including substantially dry particles in micro- and nano-meter size. For example, the bioactive agent may be nanometer size particles of calcium phosphate carrying DNA molecules. In one embodiment, the bioactive agent is incorporated in a specific region of the coating. For example, the bioactive agent may be located only in a region of the porous coating close to the tips of the skin-piercing members. In a preferred embodiment, the porous calcium phosphate coating is composed of fine calcium phosphate crystals and the bioactive agent is adsorbed on these crystals in a substantially dry form.

The calcium phosphate coating in the present invention may further include one or more supplementary materials. The supplementary material is selected based upon its compatibility with calcium phosphate and the bioactive agents and its ability to impart chemical, physical, biological, or mechanical properties to the calcium phosphate coating. The supplementary material may be made of one material or may be a composite material having more than one component. The supplementary material may be selected, for example, to act as a binder to improve the adhesion of the coating to the skin-piercing elements, improve the mechanical stability of the coating, and prevent the coating from being dislodged during penetration of the skin-piercing members into skin. The supplementary material may have an affinity for calcium, phosphate, or calcium phosphates that would enhance the strength of the calcium phosphate/ supplementary material interface or would modify the morphology of the calcium phosphate coating. In preferred embodiments, the supplementary material used to enhance the mechanical strength of the calcium phosphate coating is selected from the group consisting of monosaccharides, disaccharaids, trisaccharides, and oligosaccharides. The supplementary material may be a non-reducing carbohydrate such as raffinose, dextran, sucrose, and sugar alcohols or may be a reducing carbohydrate such as glucose, maltose, and lactose. Preferably, the supplementary material is a stabilizing polyol such as trehalose. It has been discovered now that the porous structure of the calcium phosphate coating of the present invention can be stabilized for a long time during storage by contacting the calcium phosphate coating with a dilute solution of polyol followed by drying at low temperatures. The supplementary material may also be selected to modify the chemical stability of the coating, increase or decrease the release rate of the bioactive agent in vivo, protect the bioactive agent during storage of the device, or improve the therapeutic efficacy of the bioactive agent. For example, the supplementary material may be a polyol or a nucleic acid vector. In embodiments where the skin-piercing elements are adapted as electrodes for electroporation of cells and tissues, the supplementary material may be an electrolyte that would modify the ionic conductivity of the tissue in contact with the electrodes. The electrolyte may be formulated in any conventional form including aqueous form, solid form, gel, paste, and cream.

The supplementary material selected in the present invention is desirably biocompatible, that is, there is no detrimental reaction induced by the material when introduced into skin tissue. In many instances, it is desirable that the supplementary material also be bioresorbable. Suitable bioresorbable supplementary materials may include, but are not limited to, collagen, glycogen, cellulose, keratins, nucleic acids, polyglycolic acid, polylactic acid, and copolymers thereof. In addition phosphate glasses and bioactive glass compositions such as compositions including Si02, Na20, CaO, P2O5, A12O3 and/or CaF2 may be used in combination with the calcium phosphate composition of the invention.

The supplementary material may be incorporated in the calcium phosphate coating in varying amounts and in a variety of physical forms. For example, the supplementary material may be a particulate or liquid agent that is intimately mixed with the calcium phosphate of the present invention. Thus, the calcium phosphate coating may serve as a matrix for the supplementary material that is embedded or dispersed throughout the matrix. The supplementary material may also be substantially located within the pores of the coating. In this case, the supplementary material may be in a liquid form or may be in a dry form such as a dry film or solid particles including micro- and nano-meter size particles. For example, the supplementary material may be applied as a thin film onto the porous calcium phosphate coating as a post-fabrication coating to impart various desirable properties, including improving the adhesion of the calcium phosphate coating to the skin-piercing members. In one preferred embodiment, the supplementary material and the bioactive agent are added in proportions not to block the pores in the calcium phosphate coating, but in quantities sufficient to produce a porous interconnected network extending throughout the calcium phosphate coating.

In one embodiment, a highly water-soluble material is used as a supplementary material to act as a binder to improve the mechanical stability of the calcium phosphate coating during penetration of the skin-piercing elements into skin. Preferably, the supplementary material is a water-soluble material with an amorphous or glassy structure and with sufficient solubility in water such that upon penetration of the skin-piercing members into skin, the supplementary material is rapidly dissolved. The water-soluble supplementary material can be selected from any water-soluble material known in the art that forms a strong interface with calcium phosphates including, but not limited to, carbohydrates and carbohydrates derivatives. The term "carbohydrates" used herein includes, but is not limited to, monosaccharides, disaccharaids, trisaccharides, and oligosaccharides. The supplementary material may be a non-reducing carbohydrate such as raffinose, dextran, sucrose, and sugar alcohols or may be a reducing carbohydrate such as glucose, maltose, and lactose.

Preferably, the supplementary material that improves the mechanical stability of the calcium phosphate coating is a stabilizing polyol such as trehalose in a dry form. The stabilizing polyol may additionally contain one or more bioactive agents. The bioactive agent may be dissolved or suspended within the stabilizing polyol. In one preferred embodiment, the bioactive agent present in the stabilizing polyol is different from the bioactive agent that may be directly incorporated in the calcium phosphate matrix. The polyol may further contain additives such as inhibitors to prevent losses of the agent activity or may contain modifiers to alter the glass transition temperature of trehalose. The stabilizing polyol containing the bioactive agent may be applied as a dry thin film onto the porous calcium phosphate coating, for example, as a post-fabrication coating to improve the mechanical stability of the calcium phosphate during storage and during penetration of the skin-piercing members into skin. The supplementary material may also be in the form of a multilayer film, each layer having a different chemical composition and imparting different properties to the calcium phosphate coating.

Various forms of drug delivery can be realized by varying the form and the composition of calcium phosphate and the supplementary material used in the present invention. In one preferred embodiment, the porous calcium phosphate coating is composed of fine calcium phosphate crystals carrying at least one bioactive agent (e.g., vaccine) in dry form. Additionally, a highly water-soluble material (e.g., a stabilizing polyol) is used as a supplementary material to act as a binder to improve the mechanical stability of the porous coating and to ensure that the calcium phosphate crystals remain strongly bonded to the skin-piercing members during the penetration into skin. In this case, upon penetration of the skin-piercing members into skin, the water-soluble polyol is dissolved rapidly and, upon withdrawal of the skin-piercing members from skin, fine particles of calcium phosphate crystals carrying the bioactive agent would be substantially dislodged and left in the skin. Fine calcium phosphate crystals left in the skin could then gradually degrade and release the bioactive agent over a period of time.

In one preferred embodiment, the calcium phosphate crystals carrying the bioactive agent will dissolve in the skin in less than 5 minutes. In another embodiment, calcium phosphate is formulated to dissolve over a period longer than 24 hours. For a more efficient delivery of bioactive agents, the size of calcium phosphate crystals carrying bioactive agents could be controlled to promote uptake by microphages. In a preferred embodiment, the size of the calcium phosphate crystals that remain in the skin is less than 1 micrometer. In this case, the phagocytosis of the calcium phosphate crystals could be rapid, being essentially completed within 24 hours. In a preferred embodiment, skin-piercing members are fabricated to have a smooth surface. This would allow calcium phosphate crystals to be dislodged more easily from the skin-piercing members and to be left behind in the skin upon withdrawal of the skin-piercing members from skin. It has been discovered now that water- soluble polyols such as trehalose, when added as a supplementary material, in fact facilitate dislodging of the calcium phosphate crystals upon withdrawal of the skin- piercing members from skin. Without wishing to be bound by any theory, it is believed that this effect is associated with the formation of strong hydrogen bonds between polyols and the calcium phosphate crystals.

In another alternative method, skin-piercing members coated in accordance with the present invention may be left in the skin for a pre-determined period during which the bioactive agent could be slowly released from the porous calcium phosphate coating. In another embodiment, the porous calcium phosphate coating is intended to release the bioactive agent into the skin tissue in a short time but remain intact and attached to the skin- piercing members during the withdrawal of the skin-piercing members from the skin. The skin-piercing members in this case may be provided with the means for mechanically anchoring porous calcium phosphate coating. For example, skin-piercing members may be roughened, textured, or provided with channels or cavities for retaining the calcium phosphate coating. Alternatively, biocompatible supplementary materials such as proteins with a high molecular weight may be incorporated in the coating to substantially reduce the solubility of the calcium phosphate crystals in the skin and to increase the mechanical stability of the coating.

A booster effect can be realized if, in addition to the calcium phosphate, the stabilizing polyol used as supplementary material is also loaded with bioactive agents. In this case, upon penetration of the skin-piercing elements into skin, the water-soluble polyol is first dissolved rapidly to give an initial dosing effect. The initial dosing effect is then followed by a more slow release of the agent from the calcium phosphate crystals. This type of the release pattern may be particularly useful for vaccine delivery. In one preferred embodiment, the bioactive agent present in the water-soluble polyol is different from the bioactive agent carried by the calcium phosphate crystals.

In another embodiment, the skin-piercing members are adapted as electrodes and the device of the present invention is used for the electroporation of skin cells, particularly the Langerhans cells. In this embodiment, the calcium phosphate coating disposed on the skin-piercing members is intended to act as a solid buffer as well as a carrier for the bioactive agent. Thus, an important feature of the present invention resides in the capability of the calcium phosphate coating to effectively neutralize the extreme acid and alkaline pH close to the electrodes during the application of electrical pulses. This feature of the invention is useful for eliminating skin burns and other tissue injuries that normally occur close to the electrodes as a result of extreme acidic and alkaline pH. This feature of the invention is also important for stabilizing bioactive agents (e.g., DNA molecules) attached to the electrodes that may be sensitive to pH changes.

In another embodiment, the skin-piercing members are adapted as electrodes and the coating disposed on the skin-piercing members comprises calcium phosphate and DNA. In this embodiment, the skin-piercing members are used as electrodes for dissociating calcium phosphate/DNA mixture and forming fine calcium phosphate/ DNA precipitates in vivo for transfecting skin cells with nucleic acid. In use, the skin-piercing members (electrodes) coated with calcium phosphate / DNA are inserted into skin to a sufficient depth, and then the first electrical waveform comprising one or more electrical pulses is delivered to the electrodes. The pulse waveforms may be delivered to all electrodes or a group of electrodes. The first electrical waveform is selected to have sufficient intensity such that the calcium phosphate /DNA disposed on electrodes is at least partially dissociated and calcium ions, phosphate ions, and DNA molecules are released from the electrodes. After this, the second electrical waveform comprising one or more electrical pulses is delivered to the electrodes. The second electrical waveform is selected to create sufficient electrical field between electrodes such that the released calcium ions, phosphate ions, and DNA molecules are repelled and distributed within the treated area and form calcium phosphate/DNA precipitates for transfection of skin cells.

A suitable first electrical waveform that causes calcium phosphate/DNA on electrodes to dissociate is, for example, a train of bipolar rectangular pulses. The intensity, polarity, pulse length, and the intervals between the pulses may be selected to effectively dissolve the calcium phosphate/DNA mixture on electrodes. During the application of bipolar pulses, protons (H +) are generated electrochemically as a result of the electrochemical reactions on electrodes. This would result in the dissociation of the calcium phosphate/DNA mixture. In practice, any electrical stimulus that can generate protons can be used to dissociate the calcium phosphate - DNA mixture present on the electrode surface. The electrical stimulus may be a direct current, alternating current, pulsed alternating current, pulsed direct current, variable direct current waveforms, variable alternating current waveforms, square bipolar pulses with variable intensity and pulse length, etc. The second electrical waveform that is required for repelling calcium ions, phosphate ions, and DNA molecules from the electrodes is a waveform that would create a high electric field required for the electromigration and electrorphoretic transport of ions and DNA molecules away from electrodes. Examples of electrical waveforms required for the electromigration and electrophoretic transport of ions and DNA in the present invention are unipolar and bipolar rectangular pulses. Alternatively, a train of electrical pulses may be used to effectively transport the ions and the DNA molecules within the target tissue.

The characteristics of the electrical waveform such as the polarity of pulses, pulse intensify, pulse duration, intervals between pulses, and number of pulses can be selected such that ions and DNA molecules are uniformly distributed within the target tissue. These characteristics should be selected such that the calcium ions, phosphate ions, and DNA molecules are uniformly distributed so that the fine particles of calcium phosphate / DNA are formed uniformly within a target tissue site for the effective transfection of cells with DNA. Electrical fields of about 200 V/cm or less would be sufficient for the distribution of calcium ions, phosphate ions and DNA molecules within the target tissue.

In one preferred embodiment of the invention, the first electrical waveform required for the dissociation of calcium phosphate / DNA is also capable of generating sufficient electrical field with appropriate polarify for repelling calcium ions (positively charged), phosphate ions (negatively charged) and DNA molecules from the electrodes. In another preferred embodiment, the first or the second electrical waveform is also selected to have sufficient intensify and duration to cause electropermeabilization of cells and to cause the DNA molecules released from the electrodes to be delivered into cells.

In yet another preferred embodiment, the power supply required for generating said first and second electrical waveforms comprises a pulse generator capable of delivering a sequence of programmable pulses with predetermined shape, intensify, and pulse length, such as the systems PA - 2000 and PA-4000, both from Cyto Pulse Sciences, Inc., Columbia, MD, USA.

In another preferred embodiment, in addition to DNA, other biologically active materials may be incorporated into micro-porous calcium phosphate coating including DNA fragment, RNA, proteins, enzymes, polysaccarides, polynucleotide molecules, anti-infection agents, hormones, growth factors, anti-cancer drugs, and the like. Such bioactive molecules entrapped within pores of the calcium phosphate coating may be released from the electrodes on demand in response to electrical stimuli.

Porous calcium phosphate coatings may be applied to the skin-piercing members using a variety of conventional techniques known in the art including, but not limited to, the sol-gel method, electrophoretic process, and electrodeposition. In a preferred embodiment of the present invention, the calcium phosphate coating is applied to the skin-piercing members using the electrodeposition method. This method is preferred since it allows fabrication of porous calcium phosphate coatings with controlled pore size and crystallinify at low temperatures (See, for example "Electrochemical preparation of bioactive calcium phosphate coatings on porous substrates by the periodic pulse technique", M.Shirkhanzadeh , J. Mater. Sci. Lett. (1993), 12(1), 16-19; " Biocompatible delivery systems for osteoinductive proteins: Immobilization of L-lysine in micro-porous hydroxyapatite coatings", Shirkhanzadeh et al., Mater.Lett. (1994), 21(1), 115-118; "Direct formation of nanophase hydroxyapatite on cathodically polarized electrodes" Shirkhanzadeh,M., Materials science: Materials in Medicine (1998), 9(7) , 385 - 391 ; and " Method for depositing bioactive coatings on conductive substrates", Shirkhanzadeh,M, PCT Int. Appl.(1992), WO 9213984 Al).

Thus, in accordance with one aspect of the invention, there is provided a process for forming a porous calcium phosphate coating on at least a portion of skin-piercing members. The process comprising the steps of:

(a) Contacting at least a portion of the skin-piercing members with an aqueous electrolyte containing Ca- and P-bearing ions; and

(b) Passing a cathodic current of selected strength and waveform through the electrolyte to said skin-piercing members for sufficient time so as to allow electro-deposition of a calcium phosphate coating of desired thickness.

The pH of the electrolyte may be adjusted, preferably between 3 to 8 and most preferably between 4 and 7. The electrolyte may additionally contain ions such as F ", CO3 " ", HCO3 ", CI". The electrolyte may also contain bioactive agents including therapeutic and diagnostic agents, DNA and the like. In another preferred embodiment the electrolyte further contains supplementary materials selected from the group consisting of bioresorbable polymers, proteins, reducing carbohydrates, and non-reducing carbohydrates. The temperature of the bath is preferably kept constant at 25 to 85 degrees centigrade, most preferably about 65 to 80 degree centigrade. The process of electrodepositing calcium phosphate coating on the skin-piercing members can be carried out using an electrolytic cell having at least one counter electrode made of, for example, platinum or graphite and equipped with a programmable power supply. The programmable power supply is preferably capable of producing constant voltages and constant currents of a selectably programmable intensity, and pulsed waveforms such as square pulses with selectably programmable pulse duration and peak intensities. In one preferred embodiment, the skin-piercing members are partially immersed in the electrolyte during the coating process. The skin-piercing members may be immersed in the electrolyte in vertical or horizontal positions. The rate of calcium phosphate formation on the skin-piercing members would depend on the intensity of current during the electrodeposition process. Suitable calcium phosphate coatings with sufficient thickness can be obtained in a short time and at relatively low temperatures.

In one embodiment, the micro-porous calcium phosphate coating deposited on the skin-piercing members comprises a mass of randomly oriented plate-like crystals of Ca-deficient hydroxyapatite and/or octa calcium phosphate (OCP) having dimensions in the range of 0.2 to 1 μm. In a more preferred embodiment of the invention, the micro-porous coating comprises an array of densely spaced microneedles of ca-deficient hydroxyapatite having heights of about 5 to 10 μm and a packing density of about 107 needles per cm2.

In one embodiment, the porous calcium phosphate coating is first formed on a portion of the skin-piercing members (step 1) and then the coating is loaded with at least one bioactive agent (step 2). The bioactive agent(s) may be selected from the group consisting of pharmaceutical agents, therapeutic and prophylactic agents, cells, bacteria, viruses, lipids, proteins, polypeptides, oligosaccharides, polysaccharides, nucleic acids including DNA, RNA, DNA fragment, enzymes, polynucleotide molecules, anti-infection agents, hormones, growth factors, anti- cancer drugs, and vaccines. Suitable vaccines include, but are not limited to, vaccines effective against influenza, measles, mumps, rubella, and combinations thereof. To load the porous coating with the bioactive agent, the coating is contacted with a solution or suspension of bioactive agent and subsequently dried at a low temperature. The bioactive agent does not have to be dissolved in a solvent. It can remain as a suspension. The solvent may be, for example, water or an organic solvent. Conventional processes such as electrophoresis may be used to assist loading the porous coating with bioactive agents. In one embodiment, the bioactive agent is incorporated in a specific region of the porous coating. For example, the bioactive agent may be located only in a region of the porous coating close to the tips of the skin-piercing members. The porous coating loaded with the bioactive agent may be further contacted with a solution or suspension of a supplementary material such as a solution containing 100 g of trehalose per litre followed by drying at a low temperature to improve the mechanical stability of the coating (step 3). The supplementary material may be selected from the group consisting of proteins, monosaccharides, disaccharaids, trisaccharides, oligosaccharides, trehalose, raffinose, dextran, sucrose, glucose, maltose, and lactose. In a preferred embodiment, the solution containing the supplementary material further contains at least one bioactive agent that may be different from the bioactive agent used in step 2. The bioactive agent(s) may be selected from the group consisting of pharmaceutical agents, therapeutic and prophylactic agents, cells, bacteria, viruses, lipids, proteins, polypeptides, oligosaccharides, polysaccharides, nucleic acids including DNA, RNA, DNA fragment, enzymes, polynucleotide molecules, anti- infection agents, hormones, growth factors, anti-cancer drugs, and vaccines. Suitable vaccines include, but are not limited to, vaccines effective against influenza, measles, mumps, rubella, and combinations thereof. In another alternative method for loading the porous calcium phosphate coating with the bioactive agent, the coating is first formed on a portion of the skin-piercing members as in step 1. The porous coating is then contacted with a solution or suspension containing both the bioactive agent and the supplementary material followed by drying at a low temperature.

Although the invention has been described in terms of certain embodiments, it should be understood that other variations would be apparent to those skilled in the art. For instance, one skilled in the art would readily recognize that the device of the present invention can be useful in the transport of material into or across all forms of biological barriers including skin, blood vessels and cell membranes. Furthermore, the electrode elements in the present invention may be used for other applications involving the transfer of electrical energy and signals to or from tissues in human, animals, plants and embryo and the like. It is recognized that other equivalents, alternatives, and modifications aside from those expressly stated here, are possible and within the scope of the appended claims.

Claims

CLAIMS:
1. A device for delivering bioactive agents through skin, the device comprising: a plurality of skin-piercing members; a porous calcium phosphate coating adapted as a carrier and disposed upon at least a portion of said skin- piercing members, wherein the coating includes at least one bioactive agent.
2. A device according to claim 1 wherein said porous coating is composed of a calcium phosphate selected from the group consisting of amorphous calcium phosphate (ACP), Brushite, α- and β- Tricalcium Phosphate , Calcium- deficient Hydroxyapatite, Carbonated Apatite, Octa Calcium Phosphate( OCP), stoichiometric Hydroxyapatite, Flouro- and Chloro-apatite and mixtures thereof.
3. A device according to claim 1 wherein said porous calcium phosphate coating is biodegradable and dissolves in the body in less than 5 minutes.
4. A device according to claim 1 wherein said calcium phosphate coating has a porous structure selected from the group consisting of nano-porous, micro- porous and mixture thereof.
5. A device according to claim 1 wherein the pores in said porous calcium phosphate coating have a diameter less than 1 micrometer.
6. A device according to claim 1 wherein said porous calcium phosphate coating has a thickness less than 5 micrometer.
7. The device of claim 1 wherein said coating is substantially composed of calcium-deficient hydroxyapatite having a chemical formula Ca (io-x) ( P ) ( 6 - x) (OH) ( 2 -x ) (HPO ) x , where x is less than 2.
8. The device of claim 1 wherein said coating is crystalline and consists of platelike crystals or needle-like crystals having dimensions less than about 1 μm.
9. The device of claim 1 wherein said coating is a micro-porous coating comprising an array of densely spaced micro-needles composed of calcium- deficient hydroxyapatite and having heights of about 5 to 10 μm and a packing density of about 10 needles per cm .
10. A device according to any of the claims 1 to 9 wherein said bioactive agent is selected from the group consisting of pharmaceutical agents, therapeutic and prophylactic agents, cells, bacteria, viruses, lipids, proteins, polypeptides, oligosaccharides, polysaccharides, nucleic acids including DNA, RNA, DNA fragment, enzymes, polynucleotide molecules, anti-infection agents, hormones, growth factors, anti-cancer drugs, and vaccines.
11. A device according to claim 10 wherein said bioactive agent is a particulate or a liquid agent dispersed throughout the calcium phosphate coating.
12. A device according to claim 10 wherein said bioactive agent is located within the pores of the coating in a form selected from the group consisting of nanoparticles, liquid, and gel.
13. A device according to claim 10 wherein said bioactive agent is in the form of a thin dry film.
14. A device according to claim 10 wherein said bioactive agent is adsorbed on the calcium phosphate crystals.
15. A device according to claims 1 to 14 wherein said porous calcium phosphate coating further includes at least one supplementary material selected from the group consisting of monosaccharides, disaccharaids, trisaccharides, and oligosaccharides.
16. A device according to claims 1 to 14 wherein said porous calcium phosphate coating further includes a supplementary material selected from the group consisting of trehalose, raffinose, dextran, sucrose, glucose, maltose, and lactose.
17. A device according to claim 15 and 16 wherein the supplementary material is in the form of a dry film.
18. A device according to claim 17 wherein said supplementary material further contains at least one bioactive material selected from the group consisting of pharmaceutical agents, therapeutic and prophylactic agents, cells, bacteria, viruses, lipids, proteins, polypeptides, oligosaccharides, polysaccharides, nucleic acids including DNA, RNA, DNA fragment, enzymes, polynucleotide molecules, anti-infection agents, hormones, growth factors, anti-cancer drugs, and vaccines.
19. A device according to claim 18 wherein the bioactive agent present in the supplementary material is substantially different from the bioactive agent directly adsorbed on the calcium phosphate crystals.
20. A device according to any of the claims 1 to 19 wherein the skin-piercing members are electrically conductive and adapted as electrodes for electroporation of skin cells.
21. A process for forming a porous calcium phosphate coating containing at least one bioactive agent on a portion of skin-piercing members comprising the steps of:
(a) Contacting a portion of the skin-piercing members with an aqueous electrolyte containing Ca- and P-bearing ions,
(b) Passing a cathodic current of selected strength and waveform through the electrolyte to said skin-piercing members for sufficient time so as to allow electrodeposition of a calcium phosphate coating of desired thickness on at least a portion of the skin-piercing members, and
(c) Loading the porous calcium phosphate coating with at least one bioactive agent by contacting the coating with a liquid containing said bioactive agent.
22. A process according to claim 21 wherein the bioactive agent is selected from the group consisting of pharmaceutical agents, therapeutic and prophylactic agents, cells, bacteria, viruses, lipids, proteins, polypeptides, oligosaccharides, polysaccharides, nucleic acids including DNA, RNA, DNA fragment, enzymes, polynucleotide molecules, anti-infection agents, hormones, growth factors, anti-cancer drugs, and vaccines.
23. A process according to claim 22 wherein step (b) further comprises: drying the coating prior to loading the coating with the bioactive agent.
24. A process according to claims 22 and 23 wherein step [c] further comprises: drying the coating loaded with the bioactive agent at a low temperature.
25. A process according to claim 24 wherein step [c] further comprises: contacting the loaded coating with a liquid containing at least one supplementary material followed by drying at a low temperature.
26. A process according to claim 25 wherein the supplementary material is selected from the group consisting of monosaccharides, disaccharaids, trisaccharides, oligosaccharides, trehalose, raffinose, dextran, sucrose, glucose, maltose, and lactose.
27. A process according to claim 25 wherein said liquid containing said supplementary material further contains at least one bioactive agent selected from the group consisting of pharmaceutical agents, therapeutic and prophylactic agents, cells, bacteria, viruses, lipids, proteins, polypeptides, oligosaccharides, polysaccharides, nucleic acids including DNA, RNA, DNA fragment, enzymes, polynucleotide molecules, anti-infection agents, hormones, growth factors, anti-cancer drugs, and vaccines.
28. A process according to claim 24 wherein said liquid containing the bioactive agent further contains a supplementary material selected from the group consisting of monosaccharides, disaccharaids, trisaccharides, oligosaccharides, trehalose, raffinose, dextran, sucrose, glucose, maltose, and lactose.
PCT/CA2003/000577 2002-04-30 2003-04-23 Arrays of microneedles comprising porous calcium phosphate coating and bioactive agents WO2003092785A1 (en)

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GB0209813.5 2002-04-30
GB0209813A GB0209813D0 (en) 2002-04-30 2002-04-30 Electroporation device comprising solid buffer for minimizing tissue injury
GB0212352.9 2002-05-29
GB0212352A GB0212352D0 (en) 2002-04-30 2002-05-29 Method for in vivo formation of dna/calcium phosphate precipitates for gene therapy and dna vaccination

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GB0316870A GB0316870D0 (en) 2003-04-23 2003-07-18 Method for coating skin piercing microprojections using ink jet printing

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