US 20070078414 A1
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.
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.
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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 of
25. The device of
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 of
28. The method of manufacturing a device for transdermal delivery of an agent of
29. The method of manufacturing a device for transdermal delivery of an agent of
30. The method of manufacturing a device for transdermal delivery of an agent of
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 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.
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.
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.
The invention may be better understood from the following illustrative description with reference to the following drawings.
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 devices 10) for delivering agents across biological barriers. Each agent delivery device 10 includes a microneedle (generally referred to as microneedle 100) with integrated agent reservoirs 102 according to illustrative embodiments of the invention. Microneedles 100 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. The microneedle 100 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 microneedle 100 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 the microneedle 100 is formed of biodegradable polymers, however, this mechanical requirement is less stringent, since the microneedle 100 or the tip thereof can break off, for example in the skin, and will biodegrade. Therefore, biodegradable microneedles 100 can provide an increased level of safety, as compared to nonbiodegradable ones. Nonetheless, even a biodegradable microneedle 100 still needs to remain intact at least long enough for the microneedle 100 to serve its intended purpose (e.g, its delivery function). The microneedle 100 should preferably be sterilizable using standard methods.
In general, one benefit of delivering an agent via a microneedle 100 is that while the microneedle 100 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 a microneedle 100 typically is less painful than standard injection delivery devices. To this end, the height (or length) of the microneedle 100 generally is between about 100 μm and about 3 mm. In transdermal applications, the “insertion depth” of the microneedle 100 is preferably between about 100 μm and about 1 mm, so that insertion of the microneedle 100 into the skin does not penetrate through the lower dermis. In such applications, the actual length of the microneedle 100 may be longer, since some portion of the microneedle 100 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, the microneedle 100 is formed to be between 10 μm and about 2 mm wide, preferably between 100 and 300 μm wide. A microneedle 100 will be generally planar, cylindrical, conical, or rectangular in shape, though other polygonal and irregular shapes are also suitable. The distal end of the microneedle 100 preferably tapers to a point.
The agent delivery device 10 a illustrated in
To prevent the base element 104 from widening the wound in a patient's skin during insertion, the delivery device 10 b includes a depth guard 106. The depth guard 106 includes a rigid member that extends from the base element 104 toward the distal end of the microneedle 100 b to a point beyond the base element 104. In an alternative embodiment, the depth guard 106 extends out directly from the microneedle 10 b, substantially perpendicular to the length of the microneedle 100 b. In both embodiments, upon application of the microneedle 100 b to the skin of a patient, the depth guard 106 acts as a barrier and prevents the microneedle 100 b from being inserted so deep within the skin that the wider base element 104 further disrupts the skin surface. In embodiments in which the base element 104 is not substantially wider than the microneedle 100 b, the depth guard 106 prevents the microneedle 100 b from penetrating too deeply.
In another embodiment of the delivery device 10 d, depicted in
The microneedles 100 a in the two-dimensional microneedle array 200 a are attached to a substrate 108. The microneedles 100 a may be integrally formed with the substrate 108 or they may be physically attached, for example with an adhesive, to the substrate 108. In the two-dimensional array 200 a, the substrate 108 serves as a depth guard 106. In other implementations, one or more of the microneedles 100 a on the two-dimensional array 200 a include independent depth guards 106.
In the two-dimensional microneedle array 200 a depicted in
Two-dimensional microneedle array 200 a may also include a feature in which the substrate 108 is coated with an adhesive for adhering to the patient's skin. The adhesive keeps the integrated reservoirs 102 of the microneedles 100 beneath the skin for extended periods of time, for example, to allow for gradual absorption of agents stored in the reservoir 102.
One class of agents 202 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 agents 202 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 biologically active agents 202 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 agents 202 (such as ethers, esters, amides, etc.), which are easily hydrolyzed at body pH, enzymes, etc., can be employed.
Additional agents 202 may be stored in the same integrated reservoir 102 as a therapeutic agent 202, or they may be stored in integrated reservoirs 102 integrated into separate microneedles 100. For example, the integrated reservoir 102 may contain a viscosity enhancing agent 202 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.
Additional potential agents 202 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 as Tween 20 and Tween 80, other sorbitan derivatives, such as sorbitan laurate, and alkoxylated alcohols, such as laureth-4.
Still other useful agents 202 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 agents 202 compatible for use in the integrated reservoir 102 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.
Stabilizing agents 202, which can comprise, without limitation, a non-reducing sugar, a polysaccharide or a reducing sugar, may be stored in the integrated reservoir 102. 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 agents 202 include “pathway patency modulators”, which can comprise, without limitation, osmotic agents 202 (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, the integrated reservoir 102 includes a solubilising/complexing agent 202, 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.
Additional useful agents 202 include non-aqueous solvents, such as ethanol, isopropanol, methanol, propanol, butanol, propylene glycol, dimethysulfoxide, glycerin, N,N-dimethylformamide and polyethylene glycol 400.
In order to facilitate filling of the integrated reservoir 102, hydrophilic compounds can be applied to the surfaces of the microneedle 100 defining the integrated reservoir 102. 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 the microneedle 100.
Microneedles 100, as depicted in
In similar methods, the microneedle injection mold 402 is formed from a transparent material. Light sensitive material is injected into the microneedle injection mold 402 is then set by the application of, for example, ultraviolet light. After the material is set, the microneedle injection mold 402 is opened to yield the microneedle 100 a.
In additional implementations of the methods described in relation to
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 mask 604 corresponding to the exterior outline of the microneedle 100. A dry etch removes the unmasked material of the substrate 604. Subsequently, the process includes applying a second mask 604 leaving an area of the microneedle 100 exposed for forming the integrated agent reservoir 102. Various etching methods and etching times are then employed to form the reservoir 102.
The processes described above with respect to
When depositing agents 202 into one-dimensional microneedle arrays 200 c, the process may include multiple dispensing devices 704 corresponding to each microneedle 100 or to subsets of microneedles in the one-dimensional array. The multiple fluid dispensing devices 704 may all hold the same agent, or they may hold different agents. Microneedles 100 can be filled prior to attachment to a substrate or to other microneedles, or they may be filled subsequent to such attachment.
As depicted in
In operation, the microneedle 1002 begins in a retracted position, as depicted in
This retractable microneedle medical device 1000 can be used in situations in which an agent is administered over a prolonged period of time. For example, the device 1008 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.