US20070078414A1 - Methods and devices for delivering agents across biological barriers - Google Patents

Abstract

The invention provides for microneedle devices for delivering agents across biological barriers. The microneedles include agent reservoirs integrated into the bodies of the microneedles, themselves.

Description

BACKGROUND
• Numerous drugs and therapeutic agents have been developed in the battle against disease and illness. However, a frequent therapeutic limitation of these drugs is their delivery: how to transport drugs across biological barriers in the body (e.g., the skin, the oral mucosa, the blood-brain barrier), which normally do not transport drugs at rates that are therapeutically useful.
• Drugs are commonly administered orally as pills or capsules. However, many drugs cannot be effectively delivered in this manner due to degradation in the gastrointestinal tract and/or elimination by the liver. Moreover, some drugs cannot effectively diffuse across the intestinal mucosa. Patient compliance may also be a problem, for example, in therapies requiring that pills be taken at particular intervals over a prolonged period.
• Another common technique for delivering drugs across a biological barrier is the use of a needle, such as those used with standard syringes or catheters, to transport drugs across (through) the skin. While effective for this purpose, needles generally cause pain; local damage to the skin at the site of insertion; bleeding, which increases the risk of disease transmission; and a wound sufficiently large to be a site of infection.
• An alternative delivery technique is the transdermal patch, which usually relies on diffusion of the drug across the skin. However, this method is not useful for many drugs, due to the poor permeability (i.e., effective barrier properties) of the skin. The rate of diffusion depends in part on the size and hydrophilicity of the drug molecules and the concentration gradient across the stratum corneum. Few drugs have the necessary physiochemical properties to be effectively delivered through the skin by passive diffusion. Iontophoresis, electroporation, ultrasound, and heat (so-called active systems) have been used in an attempt to improve the rate of delivery. While providing varying degrees of enhancement, these techniques are not suitable for all types of drugs, failing to provide the desired level of delivery. In some cases, they are also painful and inconvenient or impractical for continuous controlled drug delivery over a period of hours or days. Attempts have been made to design alternative devices for active transfer of drugs through the skin.
• Thus, there remains a need for better drug delivery devices, which make smaller incisions, deliver drug with greater efficiency (greater drug delivery per quantity applied) and less variability of drug administration, and/or are easier to use.
SUMMARY
• It is therefore an object of the present invention to provide a microneedle device for relatively painless, controlled, safe, convenient delivery of a variety of drugs across one or more biological barriers. In one aspect, the invention relates to a delivery device which includes a microneedle with an integrated agent reservoir. The integrated reservoir may include, for example, an opening extending through the entirety of the width or depth of the needle or a depression in one side of the needle. In such a configuration, when an agent is placed within the integrated reservoir and the microneedle is applied to the biological barrier (e.g., the skin, the oral mucosa barrier, the blood-brain barrier, etc.) of a patient, the agent, being located predominantly within the interior volume of the microneedle, is largely protected from contacting the barrier as the microneedle passes through the barrier. This greatly reduces the loss of the agent cause by contact with the barrier. Such loss can be significant given the small quantity of agent delivered by microneedle technologies and can affect the therapeutic effectiveness of the agent.
• In one embodiment, the integrated reservoir encompasses between 20% -50% of the volume of the microneedle. In other embodiments, integrated reservoir encompasses as little as 10% or and as much as 70% of the volume of the first microneedle. The integrated reservoir is filled, in one embodiment with a biologically active agent, such as a drug or a vaccine.
• In various embodiments, the microneedle is made of, for example and without limitation, stainless steel, titanium, or a biodegradable polymer. The microneedle can be between 150 and 3000 microns long, and between 10 and 2000 microns wide.
• Additional features of the invention include microneedles with depth guards and the use of base elements, which in some embodiments are wider than the microneedles, themselves. The base elements provide for greater structural stability for longer microneedles. The depth guard prevents the wider base elements from entering the biological barrier, which would enlarge the disruption in the barrier caused by the microneedle.
• In another embodiment, microneedles are combined into arrays. The arrays of microneedles allow for administration of larger volumes of agent and for concurrent administration of multiple agents. The microneedles in the array may be attached to a substrate.
• In another aspect, the invention relates to manufacturing the delivery devices described above. The method of manufacture may include dipping the microneedle into a solution containing the agent. In an alternative embodiment, a predetermined volume of the agent is dispensed into the integrated reservoir.
• In another aspect, the invention relates to methods of administering an agent across a biological barrier. The administration method includes applying one of the microneedle devices described above against a biological barrier, thereby puncturing the barrier and positioning the integrated reservoir beyond the barrier. In one embodiment, the method includes providing a plurality of microneedles coupled to a substrate. At least one of the microneedles includes an opening which defines an integrated reservoir. The reservoir is filled with an agent. The plurality of microneedles are applied against the skin of a patient, puncturing the skin and positioning the integrated reservoir beneath the surface of the skin. The puncture depth is limited by a depth guard coupled to at least one of the microneedles.
BRIEF DESCRIPTION OF THE FIGURES
• The invention may be better understood from the following illustrative description with reference to the following drawings.
• FIGS. 1A through 1D depict microneedles with integrated drug reservoirs according to several illustrative embodiments of the invention.
• FIGS. 2A through 2C depict arrays of microneedles with integrated drug reservoirs according to illustrative embodiments of the invention.
• FIG. 3 depicts a microneedle with an integrated drug reservoir which is filled with an agent according to an illustrative embodiment of the invention.
• FIGS. 4A through 4C depict a method of forming a microneedle with an integrated drug reservoir using injection molding according to an illustrative embodiment of the invention.
• FIGS. 5A through 5C depict a method of forming a microneedle with an integrated drug reservoir using a stamping process according to an illustrative embodiment of the invention.
• FIGS. 6A through 6C depict a method of forming a microneedle with an integrated drug reservoir using a chemical etching technique according to an illustrative embodiment of the invention.
• FIGS. 7A and 7B depict two methods of filling microneedle integrated agent reservoirs according to two embodiments of the invention.
• FIGS. 8 and 9 illustrate methods of administering an agent transdermally to a patient according to two embodiments of the invention.
• FIGS. 10A-10E depict a medical device incorporating a microneedle with an integrated agent reservoir and an external reservoir, and a method of using the same, according to an illustrative embodiment of the invention.
DESCRIPTION OF ILLUSTRATIVE EMBODIMENTS
• Throughout the description below reference to ranges of values are intended to refer to the specified range, and any smaller range, or single value within that range. Thus, a range of 1 to 10 refers, for example, to the ranges 1 to 10, 3 to 7, or 5. In addition, like reference numerals refer to like elements.
• The devices disclosed herein are useful in transport of material into or across biological barriers including the skin (or parts thereof); the blood-brain barrier; mucosal tissue (e.g., oral, nasal, ocular, vaginal, urethral, gastrointestinal, respiratory); blood vessels; lymphatic vessels; or cell membranes (e.g., for the introduction of material into the interior of a cell or cells). The biological barriers could be in humans or other types of animals, as well as in plants, insects, or other organisms, and embryos.
• For internal tissues, application of the microneedle devices can be achieved with the aid of a catheter or laparoscope. For certain applications, such as for drug delivery to an internal tissue, the devices can be surgically implanted.
• Skin is a biological barrier of particular use with the microneedle device disclosed herein. However, skin is only one example of a biological barrier. It will be understood that any biological barrier can be substituted for “skin” thoughout.
• Specifically with respect to skin, the stratum corneum is the outer layer, generally between 10 and 50 cells, or between 10 and 20 μm thick. Unlike other tissue in the body, the stratum corneum contains “cells” (called keratinocytes) filled with bundles of cross-linked keratin and keratohyalin surrounded by an extracellular matrix of lipids. It is this structure that is believed to give skin its barrier properties, which prevents therapeutic transdermal administration of many drugs.
• Below the stratum corneum is the viable epidermis, which is between 50 and 100 μm thick. The viable epidermis contains no blood vessels, and it exchanges metabolites by diffusion to and from the dermis. Beneath the viable epidermis is the dermis, which is between 1 and 3 mm thick and contains blood vessels, lymphatics, and nerves.
• FIGS.1A-C depict three versions of agent delivery devices (generally referred to as agent delivery devices10) for delivering agents across biological barriers. Each agent delivery device10 includes a microneedle (generally referred to as microneedle100) withintegrated agent reservoirs102 according to illustrative embodiments of the invention.Microneedles100 include microprotrusions, microabraders, microblades, and other elements on the submicron to millimeter scale used to pierce, cut, or otherwise disrupt the surface of a biological barrier. Themicroneedle100 can be constructed from a variety of materials, including metals, ceramics, semiconductors, organics, polymers (e.g., biodegradable polymers), and composites. Preferred materials of construction include medical grade stainless steel, gold, titanium, nickel, iron, gold, tin, chromium, copper, alloys of these or other metals, silicon, silicon dioxide, and polymers. Representative biodegradable polymers include polymers of hydroxy acids such as lactic acid and glycolic acid polylactide, polyglycolide, polylactide-co-glycolide, and copolymers with PEG, polyanhydrides, poly(ortho)esters, polyurethanes, poly(butyric acid), poly(valeric acid), and poly(lactide-co-caprolactone). Representative non-biodegradable polymers include polycarbonate, polymethacrylic acid, ethylenevinyl acetate, polytetrafluorethylene (TEFLON™), and polyesters.
• Generally, a microneedle100 should have the mechanical strength to remain intact for delivery of an agent, while being inserted into the barrier, while remaining in place for up to a number of days, and while being removed. In embodiments where themicroneedle100 is formed of biodegradable polymers, however, this mechanical requirement is less stringent, since themicroneedle100 or the tip thereof can break off, for example in the skin, and will biodegrade. Therefore,biodegradable microneedles100 can provide an increased level of safety, as compared to nonbiodegradable ones. Nonetheless, even abiodegradable microneedle100 still needs to remain intact at least long enough for themicroneedle100 to serve its intended purpose (e.g, its delivery function). Themicroneedle100 should preferably be sterilizable using standard methods.
• In general, one benefit of delivering an agent via amicroneedle100 is that while themicroneedle100 disrupts a patient's skin, thereby providing access to the blood flow of a patient, it does not disrupt the skin deep enough to generate a response from the patient's nerves. Thus agent delivery via amicroneedle100 typically is less painful than standard injection delivery devices. To this end, the height (or length) of themicroneedle100 generally is between about 100 μm and about 3 mm. In transdermal applications, the “insertion depth” of themicroneedle100 is preferably between about 100 μm and about 1 mm, so that insertion of themicroneedle100 into the skin does not penetrate through the lower dermis. In such applications, the actual length of themicroneedle100 may be longer, since some portion of themicroneedle100 distal the tip may not be inserted into the skin; the uninserted length depends on the particular device design and configuration.
• In order to reduce injury and the risk of infection to the patient, themicroneedle100 is formed to be between 10 μm and about 2 mm wide, preferably between 100 and 300 μm wide. A microneedle100 will be generally planar, cylindrical, conical, or rectangular in shape, though other polygonal and irregular shapes are also suitable. The distal end of themicroneedle100 preferably tapers to a point.
• Theagent delivery device10aillustrated inFIG. 1A, includesmicroneedle100a.Microneedle100aincludes anintegrated reservoir102 for holding agents to be delivered across a biological barrier, such as the skin. Theintegrated reservoir102 consists of an opening that passes through a side of themicroneedle100a. Theintegrated reservoir102 encompasses a substantial portion of the volume of themicroneedle100a. For example, thereservoir102 encompasses between 10% and 70% of the volume of themicroneedle100a. In other configurations, theintegrated reservoir102 encompasses between 20 and 50% of the volume of themicroneedle100a. Thus, the exposed surface area of any agent stored in theintegrated reservoir102 is relatively low in relation to the total volume of the stored agent. Theintegrated reservoir102 is contained wholly within the physical bounds of themicroneedle100a. Theintegrated reservoir102 can take on virtually any shape, whether it be polygonal, irregular, circular, or elliptical.
• FIG. 1B depicts a secondagent delivery device10bfor delivering agents across biological barriers. Thedelivery device10bincludes a microneedle100bwith anintegrated reservoir102 according to a second embodiment of the invention. Themicroneedle100bis coupled to abase element104. Thebase element104 can be wider than themicroneedle100bto provide additional strength and stability.
• To prevent thebase element104 from widening the wound in a patient's skin during insertion, thedelivery device10bincludes adepth guard106. Thedepth guard106 includes a rigid member that extends from thebase element104 toward the distal end of themicroneedle100bto a point beyond thebase element104. In an alternative embodiment, thedepth guard106 extends out directly from the microneedle10b, substantially perpendicular to the length of themicroneedle100b. In both embodiments, upon application of themicroneedle100bto the skin of a patient, thedepth guard106 acts as a barrier and prevents themicroneedle100bfrom being inserted so deep within the skin that thewider base element104 further disrupts the skin surface. In embodiments in which thebase element104 is not substantially wider than themicroneedle100b, thedepth guard106 prevents themicroneedle100bfrom penetrating too deeply.
• FIG. 1C depicts a third illustrative embodiment of adelivery device10caccording to an illustrative embodiment of the invention.Delivery device10cincludesmicroneedle100cwith anintegrated reservoir102. In addition to the features of thedelivery devices10aand10bdepicted inFIGS. 1A-1B, thedelivery device10cincludes asubstrate108 to which thebase element104 is coupled. In the illustrative embodiment, thesubstrate108 is formed integrally with thebase element104,microneedle100c, anddepth guard106. The substrate can be, for example, between 300 μm -500 μm wide and between about 400 μm and about 1 mm long. As shown, thesubstrate108 is generally parallel to thebase element104 andmicroneedle100c, though in other embodiments, thesubstrate108 is generally perpendicular to, or at an angle to thebase element104 andsubstrate108. Thesubstrate108 includes twoalignment holes110 for aligning a plurality ofmicroneedles100cinto an array. The alignment holes110 can be, for example, spaced between about 100 μm to about 300 μm apart, and be between about 50 μm to about 200 μm in diameter.
• In another embodiment of thedelivery device10d, depicted inFIG. 1D, themicroneedle100dincludes anintegrated reservoir102d, which does not pass through the entirety of the side of themicroneedle100d. Instead, theintegrated reservoir102dis formed by creating a depression into one or more sides of themicroneedle100dinto which an agent can be placed. As with the version of theintegrated reservoir102 in which the reservoir passes through the entirety of a side of a microneedle100a, described above in relation toFIG. 1A, the depression integratedreservoir102dpreferably takes up a substantial portion of the volume of themicroneedle100d. Theintegrated reservoir102dcan take on virtually any shape, whether it be polygonal, irregular, circular, or elliptical.
• FIGS. 2A-2C illustrate arrays of microneedles according to three illustrative embodiments of the invention. Microneedle arrays (generally microneedle arrays200) are useful, for example and without limitation, in at least the three following circumstances: 1) if thereservoir102 of asingle microneedle100 may not be able to hold a sufficient volume of an agent to be effective; 2) if it desired to deliver the agent or agents to a greater surface area of a biological barrier; and 3) if multiple agents are to be administered concurrently and the multiple agents are not sufficiently compatible to store or administer in asingle microneedle100integrated reservoir102.
• FIG. 2A depicts a delivery device10eincluding a two-dimensional microneedle array200aaccording to an illustrative embodiment of the invention. The two-dimensional microneedle array200aincludes fourmicroneedles100a, as described in relation toFIG. 1A. The inclusion of only fourmicroneedles100ain the two-dimensional microneedle array200ais for illustrative purposes only. The two-dimensional microneedle array200amay include a smaller or larger number ofmicroneedles100a. For example, the two-dimensional microneedle array200amay include as few as threemicroneedles100a. The dimensionality of themicroneedle array200arefers to the geometric relationship among themicroneedles100ain the array, and thus, two microneedles by definition could only form a one dimensional array. The two-dimensional microneedle array can include as many as sixteenmicroneedles100a, or more.Other microneedle100 implementations, for example and without limitation,microneedles100b-100d, may be incorporated into the two-dimensional microneedle array200a.
• Themicroneedles100ain the two-dimensional microneedle array200aare attached to asubstrate108. Themicroneedles100amay be integrally formed with thesubstrate108 or they may be physically attached, for example with an adhesive, to thesubstrate108. In the two-dimensional array200a, thesubstrate108 serves as adepth guard106. In other implementations, one or more of themicroneedles100aon the two-dimensional array200ainclude independent depth guards106.
• In the two-dimensional microneedle array200adepicted inFIG. 2A, two of themicroneedles100ainclude afirst agent202astored in their correspondingintegrated reservoirs102 and two of themicroneedles100ainclude a different agent202b(agents will be referred to hereinafter generally as agents202).
• Two-dimensional microneedle array200amay also include a feature in which thesubstrate108 is coated with an adhesive for adhering to the patient's skin. The adhesive keeps theintegrated reservoirs102 of themicroneedles100 beneath the skin for extended periods of time, for example, to allow for gradual absorption of agents stored in thereservoir102.
• FIG. 2B depicts a second illustrative embodiment of a delivery device10fhaving a two-dimensional microneedle array200b. Two-dimensional microneedle array200bincludes fourmicroneedles100d.Microneedles100dresemblemicroneedles100awith the addition ofalignment holes110, as previously depicted inmicroneedle100c. In this two-dimensional array200b,alignment elements204 pass through the alignment holes110 of themicroneedles100dand intobase structure206. Spacers208 can be placed on the alignment elements between themicroneedles100cto keep them apart and firmly in place.
• FIG. 2C depicts a delivery device10gincluding a one-dimensional microneedle array200caccording to an illustrative embodiment of the invention. The one-dimensional microneedle array200cincludes tenmicroneedles100c. The one-dimensional microneedle array200cmay have fewer than tenmicroneedles100c(as few as two) or it can includeadditional microneedles100c. The one-dimensional microneedle array200cmay be formed by manufacturing a single integrated set of microneedles, or each microneedle100cmay be formed independently and then joined together. Themicroneedles100ccan be joined using, for example, adhesives, bonding, oralignment elements204.
• FIG. 3 depictsdelivery device10bdepicted inFIG. 1B having anagent202 place in theintegrated reservoir102. The term agent refers to asingle agent202 or a combination ofseveral agents202. Theagents202 may be biologically active or biologically inactive.Sample agents202 include, without limitation, drugs, vaccines, allergens, antigens, excipients, anti-coagulants, surfactants, radiological dyes or markers, toxins, or any other agent, compound or substance suitable for introduction into a biological barrier. As stored, theagents202 may be, for example, dry (e.g., a film), or in a semi-solid gel.
• One class ofagents202 includes therapeutic agents in all the major therapeutic areas including, but not limited to, anti-infectives, such as antibiotics and antiviral agents; analgesics, including fentanyl, sufentanil, remifentanil, buprenorphine and analgesic combinations; anesthetics; anorexics; antiarthritics; antiasthmatic agents such as terbutaline; anticonvulsants; antidepressants; antidiabetic agents; antidiarrheals; antihistamines; anti-inflammatory agents; antimigraine preparations; antimotion sickness preparations such as scopolamine and ondansetron; antinauseants; antineoplastics; antiparkinsonism drugs; antipruritics; antipsychotics; antipyretics; antispasmodics, including gastrointestinal and urinary; anticholinergics; sympathomimetrics; xanthine derivatives; cardiovascular preparations, including calcium channel blockers such as nifedipine; beta blockers; beta-agonists such as dobutamine and ritodrine; antiarrythmics; antihypertensives such as atenolol; ACE inhibitors such as ranitidine; diuretics; vasodilators, including general, coronary, peripheral, and cerebral; central nervous system stimulants; cough and cold preparations; decongestants; diagnostics; hormones such as parathyroid hormone; hypnotics; immunosuppressants; muscle relaxants; parasympatholytics; parasympathomimetrics; prostaglandins; proteins; peptides; psychostimulants; sedatives; and tranquilizers. These agents may take the form of peptides, proteins, carbohydrates (including monosaccharides, oligosaccharides, and polysaccharides), nucleoproteins, mucoproteins, lipoproteins, glycoproteins, nucleic acid molecules (including any form of DNA such as cDNA, RNA, or a fragment thereof, oligonucleotides, and genes), nucleotides, nucleosides, lipids, biologically active organic or inorganic molecules, or combinations thereof.
• Further specific examples of agents202 include, without limitation, growth hormone release hormone (GHRH), growth hormone release factor (GHRF), insulin, insultropin, calcitonin, octreotide, endorphin, TRN, NT-36 (chemical name: N-[[(s)-4-oxo-2-azetidinyl]carbonyl]-L-histidyl-L-p-rolinamide), liprecin, pituitary hormones (e.g., HGH, HMG, desmopressin acetate, etc), follicle luteoids, aANF, growth factors such as growth factor releasing factor (GFRF), bMSH, GH, somatostatin, bradykinin, somatotropin, platelet-derived growth factor releasing factor, asparaginase, bleomycin sulfate, chymopapain, cholecystokinin, chorionic gonadotropin, erythropoietin, epoprostenol (platelet aggregation inhibitor), gluagon, HCG, hirulog, hyaluronidase, interferon alpha, interferon beta, interferon gamma, interleukins, interleukin-10 (IL-10), erythropoietin (EPO), granulocyte macrophage colony stimulating factor (GM-CSF), granulocyte colony stimulating factor (G-CSF), glucagon, leutinizing hormone releasing hormone (LHRH), LHRH analogs (such as goserelin, leuprolide, buserelin, triptorelin, gonadorelin, and napfarelin, menotropins (urofollitropin (FSH) and LH)), oxytocin, streptokinase, tissue plasminogen activator, urokinase, vasopressin, deamino [Val4, D-Arg8] arginine vasopressin, desmopressin, corticotropin (ACTH), ACTH analogs such as ACTH (1-24), ANP, ANP clearance inhibitors, angiotensin II antagonists, antidiuretic hormone agonists, bradykinn antagonists, ceredase, CSI's, calcitonin gene related peptide (CGRP), enkephalins, FAB fragments, IgE peptide suppressors, IGF-1, neurotrophic factors, colony stimulating factors, parathyroid hormone and agonists, parathyroid hormone antagonists, parathyroid hormone (PTH), PTH analogs such as PTH (1-34), prostaglandin antagonists, pentigetide, protein C, protein S, renin inhibitors, thymosin alpha-1, thrombolytics, TNF, vasopressin antagonists analogs, alpha-1 antitrypsin (recombinant), and TGF-beta.
• The biologicallyactive agents202 can also be in various forms, such as free bases, acids, charged or uncharged molecules, components of molecular complexes or nonirritating, pharmacologically acceptable salts. Further, simple derivatives of the active agents202 (such as ethers, esters, amides, etc.), which are easily hydrolyzed at body pH, enzymes, etc., can be employed.
• Additional agents202 may be stored in the sameintegrated reservoir102 as atherapeutic agent202, or they may be stored inintegrated reservoirs102 integrated intoseparate microneedles100. For example, theintegrated reservoir102 may contain aviscosity enhancing agent202 such as maleic acid, malic acid, malonic acid, tartaric acid, adipic acid, citraconic acid, fumaric acid, glutaric acid, itaconic acid, meglutol, mesaconic acid, succinic acid, citramalic acid, tartronic acid, citric acid, tricarballylic acid, ethylenediarninetetraacetic acid, aspartic acid, glutamic acid, carbonic acid, sulfuric acid, phosphoric acid, hydrochloric acid, hydrobromic acid, nitric acid, sulfuric acid, benzene sulfonic acid, methane sulfonic acid, glycolic acid, gluconic acid, glucuronic acid, lactic acid, pyruvic acid, tartronic acid, propionic acid, pentanoic acid, carbonic acid, adipic acid, citraconic acid, and levulinic acid.
• Additionalpotential agents202 include surfactants, such as zwitterionic, amphoteric, cationic, anionic, or nonionic, including, without limitation, sodium lauroamphoacetate, sodium dodecyl sulfate (SDS), cetylpyridinium chloride (CPC), dodecyltrimethyl ammonium chloride (TMAC), benzalkonium, chloride, polysorbates such asTween20 and Tween80, other sorbitan derivatives, such as sorbitan laurate, and alkoxylated alcohols, such as laureth-4.
• Still otheruseful agents202 include include polymeric materials or polymers that have amphiphilic properties, for example and without, cellulose derivatives, such as hydroxyethylcellulose (HEC), hydroxypropylmethylcell—ulose (HPMC), hydroxypropycellulose (HPC), methylcellulose (MC), hydroxyethylmethylcellulose (HEMC), or ethylhydrox-ethylcellulose (EHEC), as well as pluronics.
• Further agents202 compatible for use in theintegrated reservoir102 include biocompatible carriers, which include, without limitation, human albumin, bioengineered human albumin, polyglutamic acid, polyaspartic acid, polyhistidine, pentosan polysulfate, polyamino acids, sucrose, trehalose, melezitose, raffinose and stachyose.
• Stabilizingagents202, which can comprise, without limitation, a non-reducing sugar, a polysaccharide or a reducing sugar, may be stored in theintegrated reservoir102. Suitable non-reducing sugars for use in the methods and compositions of the invention include, for example, sucrose, trehalose, stachyose, or raffinose. Suitable polysaccharides for use in the methods and compositions of the invention include, for example, dextran, soluble starch, dextrin, and insulin. Suitable reducing sugars for use in the methods and compositions of the invention include, for example, monosaccharides such as, for example, apiose, arabinose, lyxose, ribose, xylose, digitoxose, fucose, quercitol, quinovose, rhamnose, allose, altrose, fructose, galactose, glucose, gulose, hamamelose, idose, mannose, tagatose, and the like; and disaccharides such as, for example, primeverose, vicianose, rutinose, scillabiose, cellobiose, gentiobiose, lactose, lactulose, maltose, melibiose, sophorose, and turanose, and the like.
• Other agents202 include “pathway patency modulators”, which can comprise, without limitation, osmotic agents202 (e.g., sodium chloride), zwitterionic compounds (e.g., amino acids), and anti-inflammatory agents, such as betamethasone 21-phosphate disodium salt, triamcinolone acetonide 21-disodium phosphate, hydrocortamate hydrochloride, hydrocortisone 21-phosphate disodium salt, methylprednisolone 21-phosphate disodium salt, methylprednisolone 21-succinaate sodium salt, paramethasone disodium phosphate and prednisolone 21-succinate sodium salt, and anticoagulants, such as citric acid, citrate salts (e.g., sodium citrate), dextrin sulfate sodium, aspirin and EDTA.
• In yet another embodiment of the invention, theintegrated reservoir102 includes a solubilising/complexing agent202, for example, alpha-cyclodextrin, beta-cyclodextrin, gamma-cyclodextrin, glucosyl-alpha-cyclodextrin, maltosyl-alpha-cyclodextrin, glucosyl-beta-cyclodextrin, maltosyl-beta-cyclodextrin, hydroxypropyl beta-cyclodextrin, 2-hydroxypropyl-beta-cyclodextrin, 2-hydroxypropyl-gamma-cyclodextrin, hydroxyethyl-beta-cyclodextrin, methyl-beta-cyclodextrin, sulfobutylether-alpha-cyclodextrin, sulfobutylether-beta-cyclodextrin, sulfobutylether7 beta-cyclodextrin, and sulfobutylether-gamma-cyclodextrin.
• Additionaluseful agents202 include non-aqueous solvents, such as ethanol, isopropanol, methanol, propanol, butanol, propylene glycol, dimethysulfoxide, glycerin, N,N-dimethylformamide and polyethylene glycol400.
• In order to facilitate filling of theintegrated reservoir102, hydrophilic compounds can be applied to the surfaces of themicroneedle100 defining theintegrated reservoir102. The hydrophilic compound can be selected from the following group: hydroxyethyl starch, dextran, poly(vinyl alcohol), poly(ethylene oxide), poly(2-hydroxyethylmethacrylate), poly(n-vinyl pyrolidone), polyethylene glycol and mixtures thereof, and like polymers. A hydrophobic compound, such as TEFLON™, silicon or other low energy material, can be applied to the remainder of themicroneedle100.
• Microneedles100, as depicted inFIGS. 1A-1C, can be formed using a variety of microfabrication techniques known in the art. For example, themicroneedles100 can be fabricated using lithography; etching techniques, such as wet chemical, dry, and photoresist removal; thermal oxidation of silicon; electroplating and electroless plating; diffusion processes, such as boron, phosphorus, arsenic, and antimony diffusion; ion implantation; film deposition, such as evaporation (filament, electron beam, flash, and shadowing and step coverage), sputtering, chemical vapor deposition (CVD), epitaxy (vapor phase, liquid phase, and molecular beam), electroplating, screen printing, and lamination. See generally Jaeger, Introduction to Microelectronic Fabrication (Addison-Wesley Publishing Co., Reading Mass. 1988); Runyan, et al., Semiconductor Integrated Circuit Processing Technology (Addison-Wesley Publishing Co., Reading Mass. 1990); Proceedings of the IEEE Micro Electro Mechanical Systems Conference 1987-1998; Rai-Choudhury, ed., Handbook of Microlithography. Micromachining & Microfabrication (SPIE Optical Engineering Press, Bellingham, Wash. 1997).
• More particularly,FIGS. 4A-6C depict specific methods of formingmicroneedles100 withintegrated agent reservoirs102 as described in relation to FIGS.1A-C.
• FIG. 4A depicts a method of forming a microneedle100 using an injection molding technique according to an illustrative embodiment of the invention. The first step, depicted inFIG. 4A, includes providing amicroneedle injection mold402. Themicroneedle injection mold402 can be formed using one or more of the microfabrication processes mentioned above. The interior of themicroneedle injection mold402 includes the relevant features of themicroneedle100. In the second step, depicted inFIG. 4B, a molten material, for example, a molten metal or plastic, is injected into themicroneedle injection mold402. After the molten material solidifies, themicroneedle injection mold402 is opened yielding themicroneedle100adepicted inFIG. 4C.
• In similar methods, themicroneedle injection mold402 is formed from a transparent material. Light sensitive material is injected into themicroneedle injection mold402 is then set by the application of, for example, ultraviolet light. After the material is set, themicroneedle injection mold402 is opened to yield themicroneedle100a.
• FIGS. 5A-5C depict a method of forming a microneedle100 with anintegrated reservoir102 using a stamping process according to one illustrative embodiment of the invention. The first step, depicted inFIG. 5A includes providing amicroneedle stamping mold502. As with themicroneedle injection mold502 described with respect toFIG. 4A, themicroneedle stamping mold502 can be fabricated using one or more of the microfabrication techniques described above. As depicted inFIG. 5B, themicroneedle stamping mold502 is then stamped into thematerial504 being used to form themicroneedle100. The material may be heated to a semi-solid or liquid state prior to stamping. If the material is heated prior to stamping, the material is allowed to cool before themicroneedle stamping mold502 is removed. After themicroneedle stamping mold502 is removed, excess material, if any, is removed, resulting in themicroneedle100 with anintegrated reservoir102 depicted inFIG. 5C. The stamping process can be used to form a strip or a sheet of microneedles. In addition, a substrate can be processed in a reel-to-reel fashion resulting in a continuous chain of microneedles.
• In additional implementations of the methods described in relation toFIGS. 4A-5C,microneedles100 can be formed using a multi-step process that may include both injection molding and stamping steps. For example the exterior shape of themicroneedle100, i.e., themicroneedle100 without areservoir102, is formed using injection molding or a first stamping step. Subsequently, a stamp may puncture themicroneedle100 to form theintegrated reservoir102.
• FIGS. 6A-6C depict a method of forming a microneedle100 with anintegrated agent reservoir102 using an etching process according to an illustrative embodiment of the invention. Asubstrate602 is provided from which themicroneedle100 is to be formed, as depicted inFIG. 6A. Thesubstrate602 may formed from a semiconductor material, such as silicon oxide, or any other semiconductor material suitable for insertion into a patient.FIG. 6B illustrates the application to thesubstrate602 of a mask604 defining the features of themicroneedle100. For example, the mask includes a reservoir portion606. The chemical composition of the mask604 depends upon the chemistry being used in the etch. Such mask/etch chemistry combinations are well known in the art of semiconductor substrate processing. See, e.g., Jansen, et al., “The Black Silicon Method IV: The Fabrication of Three-Dimensional Structures in Silicon with High Aspect Ratios for Scanning Probe Microscopy and Other Applications,” IEEE Proceedings of Micro Electro Mechanical Systems Conference, pp. 88-93 (1995). In the sample illustrated inFIGS. 6A-6C, reactive ions etch away portions of thesubstrate602 not protected by the mask604, thereby yielding themicroneedle100 depicted inFIG. 6C. Etching can be used tomultiple microneedles100 at the same time. For example, masks corresponding tomultiple microneedles100 can be deposited linearly or in two dimensions across a substrate.
• In other embodiments, the etching process includes a wet chemical etch or a combination of wet and dry etching. For example, in a first step, the process includes applying a first mask604 corresponding to the exterior outline of themicroneedle100. A dry etch removes the unmasked material of the substrate604. Subsequently, the process includes applying a second mask604 leaving an area of themicroneedle100 exposed for forming theintegrated agent reservoir102. Various etching methods and etching times are then employed to form thereservoir102.
• The processes described above with respect toFIGS. 4A-6C can also be used to form microneedle arrays200. In particular, the one-dimensional microneedle array200ccan readily be formed using a dry etching technique by applying a mask corresponding to the entire array shape.
• FIGS. 7A and 7B depict methods of fillingintegrated reservoirs102 according to illustrative embodiments of the invention. Theintegrated reservoirs102 can be either wholly or partially filled. InFIG. 7A, theintegrated reservoirs102 are filled using a dip process. The dip process includes physically dipping a microneedle100 into a solution702aof water or other solvent, which includes theagent202. The solution can be either in a liquid or semi-solid gel-like state. The dipping process is well suited for filling one- and two-dimensional microneedle arrays200. As described with respect toFIG. 3, the interior surface of theintegrated reservoir102 can be coated with ahydrophilic compound701 while the remaining surface area of themicroneedle100 can be coated with ahydrophobic compound703. As a result of the coatings and surface tension forces, when themicroneedle100 is removed from the solution, a volume of the aqueous solution702aremains within theagent reservoir102 but the remaining surface area of themicroneedle100 is substantially free of the aqueous solution702a. In alternative embodiments, no coatings are applied, and residual aqueous solution702afalls from themicroneedle100 due to gravity, while theintegrated reservoir102 remains filled due to surface tension forces.
• FIG. 7B depicts a deposition reservoir filling process according to an illustrative embodiment of the invention. The process includes providing a microneedle100 with anintegrated reservoir102. A dispensing device704 (e.g., a micropipette or a syringe) deposits a predetermined volume of an aqueous solution702bincluding the desiredagent202 into theintegrated reservoir102. The aqueous solution702bdries or forms a gel within theintegrated reservoir102. As described above, the exterior surfaces of themicroneedle100 and the surfaces of theintegrated reservoir102 may be coated with hydrophobic and hydrophilic compounds to aid in the deposition process.
• When depositingagents202 into one-dimensional microneedle arrays200c, the process may includemultiple dispensing devices704 corresponding to each microneedle100 or to subsets of microneedles in the one-dimensional array. The multiplefluid dispensing devices704 may all hold the same agent, or they may hold different agents.Microneedles100 can be filled prior to attachment to a substrate or to other microneedles, or they may be filled subsequent to such attachment.
• FIGS. 8A-9C depict methods of administeringagents202 using amicroneedle100 having anintegrated agent reservoir102 according to illustrative embodiments of the invention. For illustrative purposes, the biological barrier illustrated in the figures is the skin of a patient. The illustrated methods also apply to administering agents across other biological barriers.FIGS. 8A-8C depict three steps of administering anagent202 using a microneedle100athat does not have adepth guard106, while themicroneedle100binFIGS. 9A-9C has adepth guard106. While theFIGS. 8A-9C depict transdermal delivery usingsingle microneedles100aand100b, the methods illustrated therein also apply to transdermal delivery using microneedle arrays200.
• As depicted inFIG. 8A, an exemplary administration process includes providing a microneedle100ahaving anintegrated reservoir102 filled with anagent202. A microneedle applier (e.g., a patient, doctor, nurse, certified nurse's assistant, etc.) then applies themicroneedle100ato theskin802 of the patient such that themicroneedle100apierces theskin802. Themicroneedle100amay be applied manually or by using an impacting device which forces themicroneedle100aagainst the skin. Upon application, themicroneedle100aextends to a depth great enough such that theintegrated reservoir102 is located beneath the surface of theskin802, but not deep enough to trigger a pain response in the patient, as depicted inFIG. 8B. The bloodstream of the patient absorbs theagent202 in theagent reservoir102, as depicted inFIG. 8C.
• FIGS. 9A-9C are similar toFIGS. 8A-8C, though themicroneedle100binFIGS. 9A-9C includes adepth guard106. Thus, when the microneedle applier applies themicroneedle100bto theskin902 of the patient, themicroneedle100bpierces theskin902 to the depth at which thedepth guard106 rests upon the surface of theskin902. As with the method illustrated inFIGS. 8A-8C, this depth is great enough that theintegrated reservoir102 sits beneath the surface of theskin902 and shallow enough such that the application of themicroneedle100bdoes not trigger a pain response in the patient. As depicted inFIG. 9B, thedepth guard106 also prevents thewider base element104 from expanding the puncture wound904 caused by the application of themicroneedle100b.
• FIGS. 10A-10E depict amedical device1000 incorporating a microneedle1002 with anintegrated agent reservoir1004 and anexternal reservoir1006, and a method of using the same, according to an illustrative embodiment of the invention. Themedical device1000 includes aexternal reservoir1006 storing at least oneagent1008. Themicroneedle1002 is retractably mounted to the interior of theexternal reservoir1006 such that theintegrated agent reservoir1004 of themicroneedle1002 can be withdrawn into the interior of theexterior reservoir1006 and such that it can be forced out of theexterior reservoir1006. Theexterior reservoir1006 is sealed such that themicroneedle1002 can move back and forth through theseal1010 without theagent1008 leaking from theexternal reservoir1006.
• In operation, themicroneedle1002 begins in a retracted position, as depicted inFIG. 10A, such theintegrated reservoir1004 is positioned within theexternal reservoir1006 and is exposed to theagent1008. Themedical device1000 then forces themicroneedle1002 out of theexternal reservoir1006 and through abiological barrier1012, as depicted inFIG. 10B. A volume ofagent1008 remains within theintegrated reservoir1004 of themicroneedle1002 as a result of capillary forces, thereby transporting theagent1008 across thebiological barrier1012. After a predetermined time, during which theagent1008 in theintegrated reservoir1004 is absorbed into the target biological tissue, themicroneedle1002 is withdrawn to the initial position (seeFIG. 10C) such that theintegrated reservoir1004 fills with an additional volume of theagent1008. The process then repeats (seeFIGS. 10D and 10E).
• This retractable microneedlemedical device1000 can be used in situations in which an agent is administered over a prolonged period of time. For example, thedevice1008 can be implanted within a patient, allowing continuous internal administration of accurately dosed agents without the need for external intervention.
• The invention may be embodied in other specific forms without departing from the spirit or essential characteristics thereof. The foregoing embodiments are therefore to be considered in all respects illustrative, rather than limiting of the invention.

Claims (33)

1. A device for delivering an agent across a biological barrier comprising:

a first microneedle;

a first reservoir integrated into the microneedle for holding the agent.

2. The device ofclaim 1, wherein the biological barrier is skin.

3. The device ofclaim 1, wherein the first reservoir comprises an opening through one of the width and depth of the microneedle.

4. The device ofclaim 1, wherein the first reservoir comprises a depression in the microneedle.

5. The device ofclaim 1, wherein the first reservoir takes up a substantial portion of the volume of the first microneedle.

6. The device ofclaim 5, wherein the portion is between about 5% and about 70% of the volume of the first microneedle.

7. The device ofclaim 5, wherein the portion is about 20% -50% of the volume of the first microneedle.

8. The device ofclaim 1, wherein the first microneedle comprises one of stainless steel and titanium.

9. The device ofclaim 1, wherein the first microneedle is between about 150 μm to about 3000 μm long.

10. The device ofclaim 1, wherein the first microneedle is between about 300 μm to about 1500 μm long.

11. The device ofclaim 1, wherein the first microneedle is about 10 μm to about 2000 μm wide.

12. The device ofclaim 1, wherein the first microneedle is about 100 μm to about500 μm wide.

13. The device ofclaim 1, wherein the agent is suitable for intradermal delivery.

14. The device ofclaim 1, wherein the agent contains a drug.

15. The device ofclaim 1, wherein the agent contains a vaccine.

16. The device ofclaim 1, wherein the reservoir is filled with the agent.

17. The device ofclaim 1, comprising a second microneedle having a second reservoir integrated into the second microneedle.

18. The device ofclaim 17, wherein the first reservoir contains a first agent and the second reservoir contains the same agent.

19. The device ofclaim 17, wherein the first reservoir contains a first agent and the second reservoir contains a different agent.

20. The device ofclaim 17, wherein the first microneedle extends from a first base element, the second microneedle extends from a second base element, and wherein the first and second base elements are coupled to a common substrate.

21. The device ofclaim 1, comprising a depth guard for limiting the depth to which to the first microneedle can pierce the skin of a user.

22. The device ofclaim 21, wherein the depth guard extends from one of the first microneedle, a substrate from which the first microneedle extends, and a base element from which the first microneedle extends.

23. The device ofclaim 21, comprising a base element having a proximal end and a distal end, the base element being wider at its proximal end than at distal end, wherein:

the first microneedle extends from the distal end of the base element, and

the depth guard extends beyond the base element towards the distal end of the first microneedle.

24. The device ofclaim 1, comprising one of a biodegradable stent, wherein the first microneedle is coupled to the biodegradable stent for delivering the agent across a vascular barrier.

25. The device ofclaim 1, comprising a surgical tool, wherein the microneedle is coupled to the surgical tool for delivering the agent across an internal biological barrier.

26. A method of manufacturing a device for delivering an agent across a biological barrier:

providing a microneedle having an integrated agent reservoir; and

filling the integrated agent reservoir with the agent.

27. The method of manufacturing a device for transdermal delivery of an agent ofclaim 26 wherein filling the integrated agent reservoir comprises dipping the microneedle into a solution containing the agent.

28. The method of manufacturing a device for transdermal delivery of an agent ofclaim 26 wherein filling the integrated agent reservoir comprises depositing a predetermined volume of a solution containing the agent into the integrated agent reservoir.

29. The method of manufacturing a device for transdermal delivery of an agent ofclaim 26 wherein filling the integrated agent reservoir comprises applying a hydrophilic compound to the interior of the integrated agent reservoir and applying a hydrophobic compound to a remainder of the microneedle.

30. The method of manufacturing a device for transdermal delivery of an agent ofclaim 26 further comprising

providing a second microneedle having a second integrated agent reservoir;

coupling the first microneedle and the second microneedles to a substrate; and

filling the second integrated agent reservoir with the agent.

31. A method of delivering an agent transdermally comprising:

providing a microneedle having an integrated agent reservoir filled with the agent;

applying the microneedle against the skin of a patient, thereby piercing the skin and positioning the integrated reservoir beneath the surface of the skin.

32. A device for transdermal agent delivery comprising:

a substrate;

a plurality of microneedles extending from corresponding base elements coupled to the substrate, wherein the microneedles include openings, which take up between 20-50% of the volume of a corresponding microneedle, and which define integrated agent reservoirs; and

a depth guard extending from at least one of the base elements for limiting the depth to which the plurality of microneedles can be inserted into a surface.

33. A method of delivering an agent transdermally comprising:

providing a plurality of microneedles coupled to a substrate, wherein at least one of the plurality of microneedles includes an opening defining an integrated reservoir holding the agent;

applying the substrate to the skin of a patient, thereby puncturing the skin to a depth allowed by a depth guard coupled to at least one of the microneedles such that the integrated reservoir is below the surface of the skin.

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