US20020198509A1 - Intradermal delivery of vaccines and gene therapeutic agents via microcannula - Google Patents
Intradermal delivery of vaccines and gene therapeutic agents via microcannula Download PDFInfo
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- US20020198509A1 US20020198509A1 US10/185,717 US18571702A US2002198509A1 US 20020198509 A1 US20020198509 A1 US 20020198509A1 US 18571702 A US18571702 A US 18571702A US 2002198509 A1 US2002198509 A1 US 2002198509A1
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Images
Classifications
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Definitions
- the present invention relates to methods and devices for administration of vaccines and gene therapeutic agents into the intradermal layer of skin.
- Transdermal delivery includes subcutaneous, intramuscular or intravenous routes of administration of which, intramuscular (IM) and subcutaneous (SC) injections have been the most commonly used.
- IM intramuscular
- SC subcutaneous
- the outer surface of the body is made up of two major tissue layers, an outer epidermis and an underlying dermis, which together constitute the skin (for review, see Physiology, Biochemistry, and Molecular Biology of the Skin, Second Edition, L. A. Goldsmith, Ed., Oxford University Press, New York, 1991).
- the epidermis is subdivided into five layers or strata of a total thickness of between 75 and 150 ⁇ m. Beneath the epidermis lies the dermis, which contains two layers, an outermost portion referred to at the papillary dermis and a deeper layer referred to as the reticular dermis.
- the papillary dermis contains vast microcirculatory blood and lymphatic plexuses.
- the reticular dermis is relatively acellular and avascular and made up of dense collagenous and elastic connective tissue.
- Beneath the epidermis and dermis is the subcutaneous tissue, also referred to as the hypodermis, which is composed of connective tissue and fatty tissue. Muscle tissue lies beneath the subcutaneous tissue.
- both the subcutaneous tissue and muscle tissue have been commonly used as sites for administration of pharmaceutical substances.
- the dermis has rarely been targeted as a site for administration of substances, and this may be due, at least in part, to the difficulty of precise needle placement into the intradermal space.
- the dermis, in particular, the papillary dermis has been known to have a high degree of vascularity, it has not heretofore been appreciated that one could take advantage of this high degree of vascularity to obtain an improved absorption profile for administered substances compared to subcutaneous administration. This is because small drug molecules are typically rapidly absorbed after administration into the subcutaneous tissue that has been far more easily and predictably targeted than the dermis has been.
- Dermal tissue represents an attractive target site for delivery of vaccines and gene therapeutic agents.
- the skin is an attractive delivery site due to the high concentration of antigen presenting cells (APC) and APC precursors found within this tissue, in particular the epidermal Langerhan's cells and dermal dendritic cells.
- APC antigen presenting cells
- Several gene therapeutic agents are designed for the treatment of skin disorders, skin diseases and skin cancer. In such cases, direct delivery of the therapeutic agent to the affected skin tissue is desirable.
- skin cells are an attractive target for gene therapeutic agents, of which the encoded protein or proteins are active at sites distant from the skin.
- skin cells e.g., keratinocytes
- bioreactors producing a therapeutic protein that can be rapidly absorbed into the systemic circulation via the papillary dermis.
- direct access of the vaccine or therapeutic agent to the systemic circulation is desirable for the treatment of disorders distant from the skin.
- systemic distribution can be accomplished through the papillary dermis.
- ID intradermal
- the present invention improves the clinical utility of ID delivery of vaccines and gene therapeutic agents to humans or animals.
- the methods employ devices to directly target the intradermal space and to deliver substances to the intradermal space as a bolus or by infusion. It has been discovered that the placement of the substance within the dermis provides for efficacious and/or improved responsiveness to vaccines and gene therapeutic agents.
- the device is so designed as to prevent leakage of the substance from the skin and improve adsorption or cellular uptake within the intradermal space.
- the immunological response to a vaccine delivered according to the methods of the invention has been found to be equivalent to or improved over conventional IM delivery of the vaccine, indicating that ID administration according to the methods of the invention will in many cases provide improved clinical results, in addition to the other advantages of ID delivery.
- the present disclosure also relates to methods and devices for delivering vaccines or genetic material to an individual based on directly targeting the dermal space whereby such method allows improved delivery and/or an improved response to the vaccine or genetic material.
- ID direct intradermal
- dermal-access means for example using microneedle-based injection and infusion systems, or other means to accurately target the intradermal space
- the efficacy of many substances including vaccines and gene therapy agents can be improved when compared to traditional parental administration routes of subcutaneous and intramuscular delivery.
- Yet another object of the invention is to provide a method to improve the availability of a vaccine (conventional or genetic) to APC residing in the skin in order to effectuate an antigen-specific immune response to the vaccine by accurately targeting the ID tissue. This may, in many cases, allow for smaller doses of the substance to be administered via the ID route.
- a vaccine conventional or genetic
- Yet another object of the present invention is to provide a method to improve the delivery of a medicament comprising genetic material for the treatment of skin diseases, genetic skin disorders or skin cancer by accurately targeting the ID tissue.
- the resultant genetic material is subsequently expressed by the cells within the targeted ID tissue.
- Yet another object of the present invention is to provide a method to improve the delivery of a medicament comprising genetic material for the treatment of diseases, genetic disorders, or cancers affecting tissues distant from the skin by accurately targeting the ID tissue.
- the resultant genetic material is subsequently expressed by the cells within the targeted ID tissue, distant therefrom or both.
- FIG. 1 shows reporter gene activity in guinea pig skin following delivery of plasmid DNA encoding firefly luciferase. Results are shown as relative light units (RLU) per mg protein for intradernal delivery by the Mantoux method, the delivery method of the invention, and control group in which topical application of the Plasmid DNA was made to shaved skin.
- RLU relative light units
- FIG. 2 shows reporter gene activity in rat skin following delivery of plasmid DNA encoding firefly luciferase. Results are shown as RLU/mg protein for intradermal delivery by the microdermal delivery method (one embodiment of the invention, MDD), and control group in which an unrelated plasmid DNA was injected.
- MDD microdermal delivery method
- FIG. 3 shows reporter gene activity in pig skin following delivery of plasmid DNA encoding ⁇ -galactosidase. Results are shown as RLU/mg protein for intradermal delivery by the Mantoux method, by ID delivery via perpendicular insertion into skin using MDD device (34 g) or 30 g needle to depths of 1 mm and 1.5 mm , respectively, and negative control.
- FIG. 4 shows total protein content at recovered skin sites in pigs following Mantoux ID and MDD delivery of reporter plasmid DNA. Control (“Negative”) is untreated skin.
- FIG. 5 shows the influenza-specific serum antibody response in rats following delivery of plasmid DNA encoding influenza virus hemagglutinin in the absence of added adjuvant. Plasmid DNA was administered via ID delivery with the MDD device or via intramuscular (IM) injection with a standard needle and syringe. “Topical” indicates control group, where the preparation was topically applied to skin.
- FIG. 6 shows the influenza-specific serum antibody response in rats following delivery of plasmid DNA encoding influenza virus hemagglutinin in the presence of adjuvant. Plasmid DNA was administered via ID delivery with the MDD device or via intramuscular (IM) injection with a standard needle and syringe. “Topical” indicates control group, where the preparation was topically applied to skin.
- FIG. 7 shows the influenza-specific serum antibody response in rats following “priming” with plasmid DNA in the absence of added adjuvant followed by “boosting” with whole inactivated influenza virus in the absence of added adjuvant.
- Plasmid DNA or whole inactivated influenza virus was administered via ID delivery with the MDD device or via intramuscular (IM) injection with a standard needle and syringe.
- IM intramuscular
- Topicical indicates control group, where the preparation was topically applied to skin.
- FIG. 8 shows the influenza-specific serum antibody response in rats following “priming” with plasmid DNA in the presence of added adjuvant followed by “boosting” with whole inactivated influenza virus in the absence of added adjuvant.
- Plasmid DNA or whole inactivated influenza virus was administered via ID delivery with the MDD device or via intramuscular (IM) injection with a standard needle and syringe.
- IM intramuscular
- Topicical indicates control group, where the preparation was topically applied to skin.
- FIG. 9 shows the influenza-specific serum antibody response in rats to a whole inactivated influenza virus preparation administered via ID delivery with the MDD device or via intramuscular (IM) injection with a standard needle and syringe. “Topical” indicates control group, where the preparation was topically applied to skin.
- FIG. 10 shows the influenza-specific serum antibody response in pigs to a whole inactivated influenza virus preparation administered via ID delivery with the MDD device or via intramuscular (IM) injection with a standard needle and syringe.
- FIG. 11 shows the influenza-specific serum antibody response in rats to reduced doses of a whole inactivated influenza virus preparation administered via ID delivery with the MDD device or via IM injection with a standard needle and syringe.
- ID is intended to mean administration of a substance into the dermis in such a manner that the substance readily reaches the richly vascularized papillary dermis where it can be rapidly systemically absorbed, or in the case of vaccines (conventional and genetic) or gene therapeutic agents may be taken up directly by cells in the skin.
- intended target cells include APC (including epidermal Langerhan's cells and dermal dendritic cells).
- intended target cells include keratinocytes or other skin cells capable of expressing a therapeutic protein.
- the intended target cells include those skin cells which may be affected by the disease, genetic disorder or cancer.
- targeted delivery means delivery of the substance to the target depth, and includes delivery that may result in the same response in a treated individual, but result in less pain, more reproducibility, or other advantage compared to an alternate accepted means of delivery (e.g. topical, subcutaneous or intramuscular).
- an “improved response” includes an equivalent response to a reduced amount of compound administered or an increased response to an identical amount of compound that is administered by an alternate means of delivery or any other therapeutic or immunological benefit.
- needle and “needles” as used herein are intended to encompass all such needle-like structures.
- microcannula or microneedles are intended to encompass structures smaller than about 31 gauge, typically about 31-50 gauge when such structures are cylindrical in nature.
- Non-cylindrical structures encompassed by the term microneedles would be of comparable diameter and include pyramidal, rectangular, octagonal, wedged, and other geometrical shapes.
- bolus is intended to mean an amount that is delivered within a time period of less than ten (10) minutes.
- a “rapid bolus” is intended to mean an amount that is delivered in less than one minute.
- “Infusion” is intended to mean the delivery of a substance over a time period greater than ten (10) minutes.
- nucleic acids includes polynucleotides, RNA, DNA, or RNA/DNA hybrid sequences of more than one nucleotide in either single chain or duplex form, and may be of any size that can be formulated and delivered using the methods of the present invention, Nucleic acids may be of the “antisense” type.
- nucleic acid derived entity is meant an entity composed of nucleic acids in whole or in part.
- gene therapeutic agent an agent that is intended to be delivered into or be capable of uptake by cell(s) of the treated individual for incorporation and expression of genetic material.
- the gene therapeutic agent will ordinarily include a polynucleotide that encodes a peptide, polypeptide, protein or glycoprotein of interest, optionally contained in a vector or plasmid, operationally linked to any further nucleic acid sequences necessary for expression.
- the term “simultaneously” is generally means the administration of two dosages within the same 24 hour period, whereas “sequentially” or “subsequently” is intended to mean that the dosages are separated by more than 24 hours . It will be appreciated by those of skill in the art that simultaneous administration will generally refer to dosages administered at the same medical visit, whereas subsequently or sequentially will refer to dosages that may be separated by days, weeks, months, and occasionally years, depending on the effects of a particular vaccine or gene therapeutic. In one preferred embodiment, “sequential” or “subsequent” refers to dosages that are separated by one day to six weeks.
- the desired therapeutic or immunogenic response is directly related to the ID targeting depth.
- These results can be obtained by placement of the substance in the upper region of the dermis, i.e. the papillary dermis or in the upper portion of the relatively less vascular reticular dermis such that the substance readily diffuses into the papillary dermis. Placement of a substance predominately at a depth of at least about 0.025 mm to about 2.5 mm is preferred.
- delivery be at a targeted depth of just under the stratum corneum and encompassing the epidermis and upper dermis (about 0.025 mm to about 2.5 mm).
- the preferred target depth depends on the particular cell being targeted; for example to target the Langerhan's cells, delivery would need to encompass at least in part the epidermal tissue depth typically ranging from about 0.025 mm to about 0.2 mm in humans.
- the preferred target depth would be between, at least about 0.4 mm and most preferably at least about 0.5 mm up to a depth of no more than about 2.5 mm, more preferably, no more than about 2.0 mm and most preferably no more than about 1.7 mm will result delivery of the substance to the desired dermal layer. Placement of the substance predominately at greater depths and/or into the lower portion of the reticular dermis is usually considered to be less desirable.
- the dermal-access means used for ID administration according to the invention is not critical as long as it provides the insertion depth into the skin of a subject necessary to provide the targeted delivery depth of the substance. In most cases, the device will penetrate the skin and to a depth of about 0.5-2 mm.
- the dermal-access means may comprise conventional injection needles, catheters, microcannula or microneedles of all known types, employed singularly or in multiple needle arrays.
- the targeted depth of delivery of substances by the dermal-access means By varying the targeted depth of delivery of substances by the dermal-access means, behavior of the drug or substance can be tailored to the desired clinical application most appropriate for a particular patients condition.
- the targeted depth of delivery of substances by the dermal-access means may be controlled manually by the practitioner, or with or without the assistance of indicator means to indicate when the desired depth is reached.
- the device has structural means for controlling skin penetration to the desired depth within the intradermal space. This is most typically accomplished by means of a widened area or hub associated with the dermal-access means that may take the form of a backing structure or platform to which the needles are attached.
- the length of microneedles as dermal-access means are easily varied during the fabrication process and are routinely produced.
- Microneedles are also very sharp and of a very small gauge, to further reduce pain and other sensation during the injection or infusion. They may be used in the invention as individual single-lumen microneedles or multiple microneedles may be assembled or fabricated in linear arrays or two-dimensional arrays as to increase the rate of delivery or the amount of substance delivered in a given period of time. Microneedles having one or more sideports are also included as dermal access means. Microneedles may be incorporated into a variety of devices such as holders and housings that may also serve to limit the depth of penetration.
- the dermal-access means of the invention may also incorporate reservoirs to contain the substance prior to delivery or pumps or other means for delivering the drug or other substance under pressure. Alternatively, the device housing the dermal-access means may be linked externally to such additional components.
- the dermal-access means may also include safety features, either passive or active, to prevent or reduce accidental injury.
- ID injection can be reproducibly accomplished using one or more narrow gauge microcannula inserted perpendicular to the skin surface.
- This method of delivery (“microdermal delivery” or “MDD”) is easier to accomplish than standard Mantoux-style injections and, by virtue of its limited and controlled depth of penetration into the skin, is less invasive and painful.
- similar or greater biological responses, as measured here by gene expression and immune response can be attained using the MDD devices compared to standard needles.
- Optimal depth for administration of a given substance in a given species can be determined by those of skill in the art without undue experimentation.
- Delivery devices that place the dermal-access means at an appropriate depth in the intradermal space, control the volume and rate of fluid delivery and provide accurate delivery of the substance to the desired location without leakage are most preferred.
- Micro-cannula- and microneedle-based methodology and devices are described in EP 1 092 444 A1, and U.S. application Ser. No. 606,909, filed Jun. 29, 2000.
- Standard steel cannula can also be used for intra-dermal delivery using devices and methods as described in U.S. Ser. No. 417,671, filed Oct. 14, 1999, the contents of each of which are expressly incorporated herein by reference.
- These methods and devices include the delivery of substances through narrow gauge (about 30G) “microcannula” with limited depth of penetration, as defined by the total length of the cannula or the total length of the cannula that is exposed beyond a depth-limiting feature. These methods and devices provide for the delivery of substances through 30 or 31 gauge cannula, however, the present invention also employs 34G or narrower “microcannula” including if desired, limited or controlled depth of penetration means.
- targeted delivery of substances can be achieved either through a single microcannula or an array of microcannula (or “microneedles”), for example 3-6 microneedles mounted on an injection device that may include or be attached to a reservoir in which the substance to be administered is contained.
- vaccines and gene therapeutic agents may be administered as a bolus, or by infusion. It is understood that bolus administration or delivery can be carried out with rate controlling means, for example a pump, or have no specific rate controlling means, for example, user self-injection.
- rate controlling means for example a pump
- rate controlling means for example a pump
- rate controlling means for example, user self-injection.
- the above-mentioned benefits are best realized by accurate direct targeted delivery of substances to the dermal tissue compartment including the epidermal tissue. This is accomplished, for example, by using microneedle systems of less than about 250 micron outer diameter, and less than 2 mm exposed length.
- exposed length it is meant the length of the narrow hollow cannula or needle available to penetrate the skin of the patient.
- Such systems can be constructed using known methods for various materials including steel, silicon, ceramic, and other metals, plastic, polymers, sugars, biological and or biodegradable materials, and/or combinations thereof.
- the large exposed height of these needle outlets causes the substance usually to effuse out of the skin due to backpressure exerted by the skin itself and to pressure built up from accumulating fluid from the injection or infusion.
- the exposed height of the needle outlet of the present invention is from 0 to about 1 mm .
- a needle outlet with an exposed height of 0 mm has no bevel cut (or a bevel angle of 90 degrees) and is at the tip of the needle. In this case, the depth of the outlet is the same as the depth of penetration of the needle.
- a needle outlet that is either formed by a bevel cut or by an opening through the side of the needle has a measurable exposed height.
- the exposed height and for the case of a cannula with an opening through the side, its position along the axis of the cannula contributes to the depth and specificity at which a substance is delivered. Additional factors taken alone or in combination with the cannula, such as delivery rate and total fluid volume delivered, contribute to the target delivery of substances and variation of such parameters to optimize results is within the scope of the present invention.
- controlling the pressure of injection or infusion may avoid the high backpressure exerted during ID administration.
- a more constant delivery rate can be achieved, which may optimize absorption and obtain an improved response for the dosage of vaccine or therapeutic agent delivered.
- Delivery rate and volume can also be controlled to prevent the formation of wheals at the site of delivery and to prevent backpressure from pushing the dermal-access means out of the skin.
- the appropriate delivery rates and volumes to obtain these effects for a selected substance may be determined experimentally using only ordinary skill and without undue experimentation. Increased spacing between multiple needles allows broader fluid distribution and increased rates of delivery or larger fluid volumes.
- the dermal-access means is placed adjacent to the skin of a subject providing directly targeted access within the intradermal space and the substance or substances are delivered or administered into the intradermal space where they can act locally or be absorbed by the bloodstream and be distributed systemically.
- the dermal-access means is positioned substantially perpendicular to the skin surface to provide vertical insertion of one or more cannula.
- the dermal-access means may be connected to a reservoir containing the substance or substances to be delivered.
- the form of the substance or substances to be delivered or administered include solutions thereof in pharmaceutically acceptable diluents or solvents, emulsions, suspensions, gels, particulates such as micro- and nanoparticles either suspended or dispersed, as well as in-situ forming vehicles of the same. Delivery from the reservoir into the intradermal space may occur either passively, without application of the external pressure or other driving means to the substance or substances to be delivered, and/or actively, with the application of pressure or other driving means. Examples of preferred pressure generating means include pumps, syringes, elastomer membranes, gas pressure, piezoelectric, electromotive, electromagnetic pumping, coil springs, or Belleville springs or washers or combinations thereof. If desired, the rate of delivery of the substance may be variably controlled by the pressure-generating means. As a result, the substance enters the intradermal space and is absorbed in an amount and at a rate sufficient to produce a clinically efficacious result.
- anthrax arthritis, cholera, diphtheria, dengue, tetanus, lupus, multiple sclerosis, parasitic diseases, psoriasis, Lyme disease, meningococcus, measles, mumps, rubella, varicella, yellow fever, Respiratory syncytial virus, tick borne Japanese encephalitis, pneumococcus, smallpox, streptococcus, staphylococcus, typhoid, influenza, hepatitis, including hepatitis A, B, C and E, otitis media, rabies, polio, HIV, parainfluenza, rotavirus, Epstein Barr Virus, CMV, chlamydia, non-typeable haemophilus, haemophilus influenza B (HIB), moraxella catarrhalis, human papilloma virus, tuberculosis including BCG, gonorrhoeae
- compositions for genetic immunization are described, for example, in U.S. Pat. Nos. 5,589,466, 5,593,972 and 5,703,055.
- Particularly preferred substances that can be delivered according to the methods of the invention include nucleic acids, nucleic acid derived entities and gene therapeutic agents and the like used in the prevention, diagnosis, alleviation, treatment, or cure of disease.
- Suitable adjuvants for inclusion in vaccines are known to those of skill in the art. Additional agents for enhancing immune response that may be used in the present invention are disclosed in U.S. application Ser. No. 10/142,966, filed May 13, 2002, which is incorporated herein by reference.
- Nucleic acids for use in the methods of the invention may be RNA or DNA, or a combination thereof. They may be in any physical form suitable for ID administration and for uptake and expression by cells. DNA and/or RNA may be contained in a viral vector or liposome, or may be delivered as a free polynucleotide such as a plasmid as is known in the art.
- the nucleic acid will typically be formulated in a pharmaceutically acceptable formulation such as a fluid, gel, or suspension that is compatible with the nucleic acid.
- the narrow gauge, typically 31 to 50 gauge, of the microcannula greatly reduces the volumetric capacity that can traverse the needle into the syringe, for example. This would be inconvenient to most practitioners who are accustomed to rapid transfer of liquids from vials using conventional devices and thus would greatly increase the amount of time the practitioner would spend with the patient. Additional factors to be considered in the widespread use of microdevices include the necessity to reformulate most drugs and vaccines to accommodate the reduced total volume (10-100 ⁇ l) used or delivered by microdevices. Thus it would be desirable to provide for a kit including the device either in combination with or adapted to integrate therewith, the substance to be delivered.
- Kits and the like comprising the instrument of administration and the therapeutic composition are well known in the art.
- the application of minimally invasive, ID microdevices for the delivery of drugs and vaccines clearly present an immediate need for coupling the device with the formulation to provide safe, efficacious, and consistent means for administering formulations for enabling immunogenic and therapeutic responses.
- the kit provided by the invention comprises a delivery device having at least one hollow microneedle designed to intradermally deliver a substance to a depth between 0.025 and 2 mm which is adapted so that the microneedle is or can be placed in fluid connection with a reservoir adapted for containing a dosage of a vaccine or gene therapeutic.
- the kit also contains an effective dosage of a vaccine or gene therapeutic, optionally contained in a reservoir that is an integral part of, or is capable of being functionally attached to, the delivery device.
- the hollow microneedle is preferably between about 31 to 50 gauge, and may be part of an array of, for example,3-6 microneedles.
- the kit of the invention comprises a hub portion being attachable to the prefillable reservoir storing the vaccine
- At least one microneedle supported by said hub portion and having a forward tip extending away from said hub portion;
- connection to the syringe was via an integral Luer adapter at the catheter inlet.
- needles were inserted perpendicular to the skin surface, and were held in place by gentle hand pressure for bolus delivery. Devices were checked for function and fluid flow both immediately prior to and post injection.
- a 30/31 gauge intradermal needle device with 1.5 mm exposed length controlled by a depth limiting hub as described in EP 1 092 444 A1 was also used in some Examples.
- Plasmid DNA was applied topically to shaved skin as a negative control (the size of the plasmid is too large to allow for passive uptake into the skin).
- Total dose was 100 ⁇ g per animal in total volume of 40 ⁇ l PBS delivered as a rapid bolus injection ( ⁇ 1 min) using a 1 cc syringe.
- Full thickness skin biopsies of the administration sites were collected 24 hr. following delivery, were homogenized and further processed for luciferase activity using a commercial assay (Promega, Madison, Wis.).
- FIG. 1 The results demonstrate strong luciferase expression in both ID injection groups. Mean luciferase activity in the MDD and Mantoux groups were 240- and 220-times above negative controls, respectively. Luciferase expression levels in topical controls were not significantly greater than in untreated skin sites (data not shown).
- DNA was injected using the following methods I) via Mantoux method using a 30G needle and syringe, ii) by ID delivery via perpendicular insertion into skin using a 30/31G needle equipped with a feature to limit the needle penetration depth to 1.5 mm, and iii) by ID delivery via perpendicular insertion into skin using a 34G needle equipped with a feature to limit the needle penetration depth to 1.0 mm (MDD device).
- the negative control group consisted of ID delivery by i-iii of an unrelated plasmid DNA encoding firefly luciferase.
- Total reporter gene expression by skin cells was strongest in the ID, 34G, 1 mm (MDD) group at 563,523 RLU/mg compared to 200,788 RLU/mg in the ID, 30G Mantoux group, 42,470 RLU/mg in the ID (30G, 1.5 mm) group and 1,869 RLU/mg in the negative controls.
- ID delivery via perpendicular insertion of a 34G, 1.0 mm needle (MDD) results in superior uptake and expression of DNA by skin cells as compared to the standard Mantoux style injection or a similar perpendicular needle insertion and delivery using a longer (1.5 mm), wider diameter (30G) needle.
- the pig represents an attractive skin model that closely mimics human skin.
- To test ID delivery devices in vaccine delivery Buffalo swine were immunized with an inactivated influenza vaccine as above, comparing ID delivery ID with IM injection. Pigs were immunized on days 0, 21 and 49; serum was collected and analyzed for influenza-specific antibodies by ELISA as above on days 14, 36, 49 and 60. Pig-specific secondary antibodies were obtained from Bethyl Laboratories, Montgomery, Tex.
Abstract
Methods and devices for administration of vaccines and gene therapeutic agents into the intradermal layer of skin.
Description
- This application is a continuation-in-part of application Ser. No. 10/044,504 filed Jan. 10, 2002, which is a continuation-in-part of applications Ser. No. 09/834,438 and 09/835,243, filed Apr. 13, 2001, which are continuations-in-part of application no. 09/417,671, filed Oct. 10, 1999 and claims priority to U.S. provisional application No. 60/301,476, filed Jun. 29, 2001, each of which is incorporated herein by reference.
- 1. Field of the Invention
- The present invention relates to methods and devices for administration of vaccines and gene therapeutic agents into the intradermal layer of skin.
- 2. Background Information
- The importance of efficiently and safely administering pharmaceutical substances for the purpose of prophylaxis, diagnosis or treatment has long been recognized. The use of conventional needles has long provided one approach for delivering pharmaceutical substances to humans and animals by administration through the skin. Considerable effort has been made to achieve reproducible and efficacious delivery through the skin while improving the ease of injection and reducing patient apprehension and/or pain associated with conventional needles. Furthermore, certain delivery systems eliminate needles entirely, and rely upon chemical mediators or external driving forces such as iontophoretic currents or electroporation or thermal poration or sonophoresis to breach the stratum corneum, the outermost layer of the skin, and deliver substances through the surface of the skin. However, such delivery systems do not reproducibly breach the skin barriers or deliver the pharmaceutical substance to a given depth below the surface of the skin and consequently, clinical results can be variable. Thus, mechanical breach of the stratum corneum such as with needles, is believed to provide the most reproducible method of administration of substances through the surface of the skin, and to provide control and reliability in placement of administered substances.
- Approaches for delivering substances beneath the surface of the skin have almost exclusively involved transdermal administration, i.e. delivery of substances through the skin to a site beneath the skin. Transdermal delivery includes subcutaneous, intramuscular or intravenous routes of administration of which, intramuscular (IM) and subcutaneous (SC) injections have been the most commonly used.
- Anatomically, the outer surface of the body is made up of two major tissue layers, an outer epidermis and an underlying dermis, which together constitute the skin (for review, seePhysiology, Biochemistry, and Molecular Biology of the Skin, Second Edition, L. A. Goldsmith, Ed., Oxford University Press, New York, 1991). The epidermis is subdivided into five layers or strata of a total thickness of between 75 and 150 μm. Beneath the epidermis lies the dermis, which contains two layers, an outermost portion referred to at the papillary dermis and a deeper layer referred to as the reticular dermis. The papillary dermis contains vast microcirculatory blood and lymphatic plexuses. In contrast, the reticular dermis is relatively acellular and avascular and made up of dense collagenous and elastic connective tissue. Beneath the epidermis and dermis is the subcutaneous tissue, also referred to as the hypodermis, which is composed of connective tissue and fatty tissue. Muscle tissue lies beneath the subcutaneous tissue.
- As noted above, both the subcutaneous tissue and muscle tissue have been commonly used as sites for administration of pharmaceutical substances. The dermis, however, has rarely been targeted as a site for administration of substances, and this may be due, at least in part, to the difficulty of precise needle placement into the intradermal space. Furthermore, even though the dermis, in particular, the papillary dermis has been known to have a high degree of vascularity, it has not heretofore been appreciated that one could take advantage of this high degree of vascularity to obtain an improved absorption profile for administered substances compared to subcutaneous administration. This is because small drug molecules are typically rapidly absorbed after administration into the subcutaneous tissue that has been far more easily and predictably targeted than the dermis has been. On the other hand, large molecules such as proteins are typically not well absorbed through the capillary epithelium regardless of the degree of vascularity so that one would not have expected to achieve a significant absorption advantage over subcutaneous administration by the more difficult to achieve intradermal administration even for large molecules.
- One approach to administration beneath the surface to the skin and into the region of the intradermal space has been routinely used in the Mantoux tuberculin test. In this procedure, a purified protein derivative is injected at a shallow angle to the skin surface using a 27 or 30 gauge needle and standard syringe (Flynn et al,Chest 106: 1463-5, 1994). The Mantoux technique involves inserting the needle into the skin laterally, then “snaking” the needle further into the ID tissue. The technique is known to be quite difficult to perform and requires specialized training. A degree of imprecision in placement of the injection results in a significant number of false negative test results. Moreover, the test involves a localized injection to elicit a response at the site of injection and the Mantoux approach has not led to the use of intradermal injection for systemic administration of substances.
- Another group reported on what was described as an intradermal drug delivery device (U.S. Pat. No. 5,997,501). Injection was indicated to be at a slow rate and the injection site was intended to be in some region below the epidermis, i.e., the interface between the epidermis and the dermis or the interior of the dermis or subcutaneous tissue. This reference, however, provided no teachings that would suggest a selective administration into the dermis nor did the reference suggest that vaccines or gene therapeutic agents might be delivered in this manner.
- To date, numerous therapeutic proteins and small molecular weight compounds have been delivered intradermally and used to effectively elicit a pharmacologically beneficial response. Most of these compounds (e.g. insulin, Neupogen, hGH, calcitonin) have been hormonal proteins not engineered receptors or antibodies. To date all administered proteins have exhibited several effects associated with ID administration, including more rapid onset of uptake and distribution (vs. SC) and in some case increased bioavailability.
- Dermal tissue represents an attractive target site for delivery of vaccines and gene therapeutic agents. In the case of vaccines (both genetic and conventional), the skin is an attractive delivery site due to the high concentration of antigen presenting cells (APC) and APC precursors found within this tissue, in particular the epidermal Langerhan's cells and dermal dendritic cells. Several gene therapeutic agents are designed for the treatment of skin disorders, skin diseases and skin cancer. In such cases, direct delivery of the therapeutic agent to the affected skin tissue is desirable. In addition, skin cells are an attractive target for gene therapeutic agents, of which the encoded protein or proteins are active at sites distant from the skin. In such cases, skin cells (e.g., keratinocytes) can function as “bioreactors” producing a therapeutic protein that can be rapidly absorbed into the systemic circulation via the papillary dermis. In other cases, direct access of the vaccine or therapeutic agent to the systemic circulation is desirable for the treatment of disorders distant from the skin. In such cases, systemic distribution can be accomplished through the papillary dermis.
- However, as discussed above, intradermal (ID) injection using standard needles and syringes is technically very difficult to perform and is painful. The prior art contains several references to ID delivery of both DNA-based and conventional vaccines and therapeutic agents, however results have been conflicting, at least in part due to difficulties in accurately targeting the ID tissue with existing techniques.
- Virtually all of the human vaccines currently on the market are administered via the IM or SC routes. Of the32 vaccines marketed by the 4 major global vaccine producers in the year 2001 (Aventis-Pasteur, GlaxoSmithKline, Merck, Wyeth), only 2 are approved for ID use (2001 Physicians Desk Reference). In fact, the product inserts for 6 of these 32 vaccines specifically states not to use the ID route. This is despite the various published pre-clinical and early clinical studies suggesting that ID delivery can improve vaccines by inducing a stronger immune response than via IM or SC injection or by inducing a comparable immune response at a reduced dose relative to that which is given IM or SC (Playford, E.G. et al, Infect. Control Hosp. Epidemiol. 23:87, 2002; Kerr, C. Trends Microbiol. 9:415, 2001; Rahman, F. et al., Hepatology 31:521, 2000; Carlsson, U. et al., Scan J. Infect. Dis. 28:435, 1996; Propst, T. et al., Amer. J. Kidney Dis. 32:1041, 1998; Nagafuchi, S. et al., Rev Med Virol., 8:97, 1998; Henderson, E. A., et al., Infect. Control Hosp Epidemiol. 21:264, 2000). Although improvements in vaccine efficacy following ID delivery have been noted in some cases, others have failed to observe such advantages (Crowe, Am. J. Med. Tech. 31:387-396, 1965; Letter to British Medical Journal 29/10/77, p. 1152; Brown et al., J. Infect. Dis. 136:466-471, 1977; Herbert & Larke, J. Infect. Dis. 140:234-238, 1979; Ropac et al. Periodicum Biologorum 103:39-43, 2001).
- A major factor that has precluded the widespread use of the ID delivery route and has contributed to the conflicting results described above is the lack of suitable devices to accomplish reproducible delivery to the epidermal and dermal skin layers. Standard needles commonly used to inject vaccines are too large to accurately target these tissue layers when inserted into the skin. The most common method of delivery is through Mantoux-style injection using a standard needle and syringe. This technique is difficult to perform, unreliable and painful to the subject. Thus, there is a need for devices and methods that will enable efficient, accurate and reproducible delivery of vaccines and gene therapeutic agents to the intradermal layer of skin.
- The present invention improves the clinical utility of ID delivery of vaccines and gene therapeutic agents to humans or animals. The methods employ devices to directly target the intradermal space and to deliver substances to the intradermal space as a bolus or by infusion. It has been discovered that the placement of the substance within the dermis provides for efficacious and/or improved responsiveness to vaccines and gene therapeutic agents. The device is so designed as to prevent leakage of the substance from the skin and improve adsorption or cellular uptake within the intradermal space. The immunological response to a vaccine delivered according to the methods of the invention has been found to be equivalent to or improved over conventional IM delivery of the vaccine, indicating that ID administration according to the methods of the invention will in many cases provide improved clinical results, in addition to the other advantages of ID delivery.
- The present disclosure also relates to methods and devices for delivering vaccines or genetic material to an individual based on directly targeting the dermal space whereby such method allows improved delivery and/or an improved response to the vaccine or genetic material. By the use of direct intradermal (ID) administration means (hereafter referred to as dermal-access means), for example using microneedle-based injection and infusion systems, or other means to accurately target the intradermal space, the efficacy of many substances including vaccines and gene therapy agents can be improved when compared to traditional parental administration routes of subcutaneous and intramuscular delivery.
- Accordingly, it is one object of the invention to provide a method to accurately target the ID tissue to deliver a vaccine or a medicament comprising genetic material to afford an immunogenic or therapeutic response.
- It is a further object of the invention to provide a method to improve the systemic immunogenic or therapeutic response to vaccine (conventional or genetic) or medicament comprising genetic material by accurately targeting the ID tissue
- Yet another object of the invention is to provide a method to improve the availability of a vaccine (conventional or genetic) to APC residing in the skin in order to effectuate an antigen-specific immune response to the vaccine by accurately targeting the ID tissue. This may, in many cases, allow for smaller doses of the substance to be administered via the ID route.
- Yet another object of the present invention is to provide a method to improve the delivery of a medicament comprising genetic material for the treatment of skin diseases, genetic skin disorders or skin cancer by accurately targeting the ID tissue. The resultant genetic material is subsequently expressed by the cells within the targeted ID tissue.
- Yet another object of the present invention is to provide a method to improve the delivery of a medicament comprising genetic material for the treatment of diseases, genetic disorders, or cancers affecting tissues distant from the skin by accurately targeting the ID tissue. The resultant genetic material is subsequently expressed by the cells within the targeted ID tissue, distant therefrom or both.
- These and other benefits of the invention are achieved by directly targeting delivery of the substance to the preferred depth for the particular therapeutic or prophylactic agent. The inventors have found that by specifically targeting delivery of the substance to the intradermal space, the response to vaccines and gene therapeutic agents can be unexpectedly improved, and can in many situations be varied with resulting clinical advantage.
- FIG. 1 shows reporter gene activity in guinea pig skin following delivery of plasmid DNA encoding firefly luciferase. Results are shown as relative light units (RLU) per mg protein for intradernal delivery by the Mantoux method, the delivery method of the invention, and control group in which topical application of the Plasmid DNA was made to shaved skin.
- FIG. 2 shows reporter gene activity in rat skin following delivery of plasmid DNA encoding firefly luciferase. Results are shown as RLU/mg protein for intradermal delivery by the microdermal delivery method (one embodiment of the invention, MDD), and control group in which an unrelated plasmid DNA was injected.
- FIG. 3 shows reporter gene activity in pig skin following delivery of plasmid DNA encoding β-galactosidase. Results are shown as RLU/mg protein for intradermal delivery by the Mantoux method, by ID delivery via perpendicular insertion into skin using MDD device (34 g) or 30 g needle to depths of 1 mm and 1.5 mm , respectively, and negative control.
- FIG. 4 shows total protein content at recovered skin sites in pigs following Mantoux ID and MDD delivery of reporter plasmid DNA. Control (“Negative”) is untreated skin.
- FIG. 5 shows the influenza-specific serum antibody response in rats following delivery of plasmid DNA encoding influenza virus hemagglutinin in the absence of added adjuvant. Plasmid DNA was administered via ID delivery with the MDD device or via intramuscular (IM) injection with a standard needle and syringe. “Topical” indicates control group, where the preparation was topically applied to skin.
- FIG. 6 shows the influenza-specific serum antibody response in rats following delivery of plasmid DNA encoding influenza virus hemagglutinin in the presence of adjuvant. Plasmid DNA was administered via ID delivery with the MDD device or via intramuscular (IM) injection with a standard needle and syringe. “Topical” indicates control group, where the preparation was topically applied to skin.
- FIG. 7 shows the influenza-specific serum antibody response in rats following “priming” with plasmid DNA in the absence of added adjuvant followed by “boosting” with whole inactivated influenza virus in the absence of added adjuvant. Plasmid DNA or whole inactivated influenza virus was administered via ID delivery with the MDD device or via intramuscular (IM) injection with a standard needle and syringe. “Topical” indicates control group, where the preparation was topically applied to skin.
- FIG. 8 shows the influenza-specific serum antibody response in rats following “priming” with plasmid DNA in the presence of added adjuvant followed by “boosting” with whole inactivated influenza virus in the absence of added adjuvant. Plasmid DNA or whole inactivated influenza virus was administered via ID delivery with the MDD device or via intramuscular (IM) injection with a standard needle and syringe. “Topical” indicates control group, where the preparation was topically applied to skin.
- FIG. 9 shows the influenza-specific serum antibody response in rats to a whole inactivated influenza virus preparation administered via ID delivery with the MDD device or via intramuscular (IM) injection with a standard needle and syringe. “Topical” indicates control group, where the preparation was topically applied to skin.
- FIG. 10 shows the influenza-specific serum antibody response in pigs to a whole inactivated influenza virus preparation administered via ID delivery with the MDD device or via intramuscular (IM) injection with a standard needle and syringe.
- FIG. 11 shows the influenza-specific serum antibody response in rats to reduced doses of a whole inactivated influenza virus preparation administered via ID delivery with the MDD device or via IM injection with a standard needle and syringe.
- As used herein, “intradermal” (ID) is intended to mean administration of a substance into the dermis in such a manner that the substance readily reaches the richly vascularized papillary dermis where it can be rapidly systemically absorbed, or in the case of vaccines (conventional and genetic) or gene therapeutic agents may be taken up directly by cells in the skin. In the case of genetic vaccines, intended target cells include APC (including epidermal Langerhan's cells and dermal dendritic cells). In the case of gene therapeutic agents for diseases, genetic disorders or cancers affecting tissues distant from the skin, intended target cells include keratinocytes or other skin cells capable of expressing a therapeutic protein. In the case of gene therapeutic agents for diseases, genetic disorders or cancers affecting the skin, the intended target cells include those skin cells which may be affected by the disease, genetic disorder or cancer.
- As used herein, “targeted delivery” means delivery of the substance to the target depth, and includes delivery that may result in the same response in a treated individual, but result in less pain, more reproducibility, or other advantage compared to an alternate accepted means of delivery (e.g. topical, subcutaneous or intramuscular).
- As used herein, an “improved response” includes an equivalent response to a reduced amount of compound administered or an increased response to an identical amount of compound that is administered by an alternate means of delivery or any other therapeutic or immunological benefit.
- The terms “needle” and “needles” as used herein are intended to encompass all such needle-like structures. The terms microcannula or microneedles, as used herein, are intended to encompass structures smaller than about31 gauge, typically about 31-50 gauge when such structures are cylindrical in nature. Non-cylindrical structures encompassed by the term microneedles would be of comparable diameter and include pyramidal, rectangular, octagonal, wedged, and other geometrical shapes.
- As used herein, the term “bolus” is intended to mean an amount that is delivered within a time period of less than ten (10) minutes. A “rapid bolus” is intended to mean an amount that is delivered in less than one minute. “Infusion” is intended to mean the delivery of a substance over a time period greater than ten (10) minutes.
- The term “nucleic acids” includes polynucleotides, RNA, DNA, or RNA/DNA hybrid sequences of more than one nucleotide in either single chain or duplex form, and may be of any size that can be formulated and delivered using the methods of the present invention, Nucleic acids may be of the “antisense” type. By “nucleic acid derived entity” is meant an entity composed of nucleic acids in whole or in part.
- By “gene therapeutic agent” is meant an agent that is intended to be delivered into or be capable of uptake by cell(s) of the treated individual for incorporation and expression of genetic material. The gene therapeutic agent will ordinarily include a polynucleotide that encodes a peptide, polypeptide, protein or glycoprotein of interest, optionally contained in a vector or plasmid, operationally linked to any further nucleic acid sequences necessary for expression.
- When referring to the administration of vaccines or gene therapeutic agents, the term “simultaneously” is generally means the administration of two dosages within the same 24 hour period, whereas “sequentially” or “subsequently” is intended to mean that the dosages are separated by more than 24 hours . It will be appreciated by those of skill in the art that simultaneous administration will generally refer to dosages administered at the same medical visit, whereas subsequently or sequentially will refer to dosages that may be separated by days, weeks, months, and occasionally years, depending on the effects of a particular vaccine or gene therapeutic. In one preferred embodiment, “sequential” or “subsequent” refers to dosages that are separated by one day to six weeks.
- The desired therapeutic or immunogenic response is directly related to the ID targeting depth. These results can be obtained by placement of the substance in the upper region of the dermis, i.e. the papillary dermis or in the upper portion of the relatively less vascular reticular dermis such that the substance readily diffuses into the papillary dermis. Placement of a substance predominately at a depth of at least about 0.025 mm to about 2.5 mm is preferred.
- In particular, for vaccines, it is preferred that delivery be at a targeted depth of just under the stratum corneum and encompassing the epidermis and upper dermis (about 0.025 mm to about 2.5 mm). For therapeutics that target cells in the skin, the preferred target depth depends on the particular cell being targeted; for example to target the Langerhan's cells, delivery would need to encompass at least in part the epidermal tissue depth typically ranging from about 0.025 mm to about 0.2 mm in humans. For therapeutics and vaccines that require systemic circulation, the preferred target depth would be between, at least about 0.4 mm and most preferably at least about 0.5 mm up to a depth of no more than about 2.5 mm, more preferably, no more than about 2.0 mm and most preferably no more than about 1.7 mm will result delivery of the substance to the desired dermal layer. Placement of the substance predominately at greater depths and/or into the lower portion of the reticular dermis is usually considered to be less desirable.
- The dermal-access means used for ID administration according to the invention is not critical as long as it provides the insertion depth into the skin of a subject necessary to provide the targeted delivery depth of the substance. In most cases, the device will penetrate the skin and to a depth of about 0.5-2 mm. The dermal-access means may comprise conventional injection needles, catheters, microcannula or microneedles of all known types, employed singularly or in multiple needle arrays.
- By varying the targeted depth of delivery of substances by the dermal-access means, behavior of the drug or substance can be tailored to the desired clinical application most appropriate for a particular patients condition. The targeted depth of delivery of substances by the dermal-access means may be controlled manually by the practitioner, or with or without the assistance of indicator means to indicate when the desired depth is reached. Preferably however, the device has structural means for controlling skin penetration to the desired depth within the intradermal space. This is most typically accomplished by means of a widened area or hub associated with the dermal-access means that may take the form of a backing structure or platform to which the needles are attached. The length of microneedles as dermal-access means are easily varied during the fabrication process and are routinely produced. Microneedles are also very sharp and of a very small gauge, to further reduce pain and other sensation during the injection or infusion. They may be used in the invention as individual single-lumen microneedles or multiple microneedles may be assembled or fabricated in linear arrays or two-dimensional arrays as to increase the rate of delivery or the amount of substance delivered in a given period of time. Microneedles having one or more sideports are also included as dermal access means. Microneedles may be incorporated into a variety of devices such as holders and housings that may also serve to limit the depth of penetration. The dermal-access means of the invention may also incorporate reservoirs to contain the substance prior to delivery or pumps or other means for delivering the drug or other substance under pressure. Alternatively, the device housing the dermal-access means may be linked externally to such additional components. The dermal-access means may also include safety features, either passive or active, to prevent or reduce accidental injury.
- In one embodiment of the invention, ID injection can be reproducibly accomplished using one or more narrow gauge microcannula inserted perpendicular to the skin surface. This method of delivery (“microdermal delivery” or “MDD”) is easier to accomplish than standard Mantoux-style injections and, by virtue of its limited and controlled depth of penetration into the skin, is less invasive and painful. Furthermore, similar or greater biological responses, as measured here by gene expression and immune response, can be attained using the MDD devices compared to standard needles. Optimal depth for administration of a given substance in a given species can be determined by those of skill in the art without undue experimentation.
- Delivery devices that place the dermal-access means at an appropriate depth in the intradermal space, control the volume and rate of fluid delivery and provide accurate delivery of the substance to the desired location without leakage are most preferred. Micro-cannula- and microneedle-based methodology and devices are described in
EP 1 092 444 A1, and U.S. application Ser. No. 606,909, filed Jun. 29, 2000. Standard steel cannula can also be used for intra-dermal delivery using devices and methods as described in U.S. Ser. No. 417,671, filed Oct. 14, 1999, the contents of each of which are expressly incorporated herein by reference. These methods and devices include the delivery of substances through narrow gauge (about 30G) “microcannula” with limited depth of penetration, as defined by the total length of the cannula or the total length of the cannula that is exposed beyond a depth-limiting feature. These methods and devices provide for the delivery of substances through 30 or 31 gauge cannula, however, the present invention also employs 34G or narrower “microcannula” including if desired, limited or controlled depth of penetration means. It is within the scope of the present invention that targeted delivery of substances can be achieved either through a single microcannula or an array of microcannula (or “microneedles”), for example 3-6 microneedles mounted on an injection device that may include or be attached to a reservoir in which the substance to be administered is contained. - Using the methods of the present invention, vaccines and gene therapeutic agents may be administered as a bolus, or by infusion. It is understood that bolus administration or delivery can be carried out with rate controlling means, for example a pump, or have no specific rate controlling means, for example, user self-injection. The above-mentioned benefits are best realized by accurate direct targeted delivery of substances to the dermal tissue compartment including the epidermal tissue. This is accomplished, for example, by using microneedle systems of less than about250 micron outer diameter, and less than 2 mm exposed length. By “exposed length” it is meant the length of the narrow hollow cannula or needle available to penetrate the skin of the patient. Such systems can be constructed using known methods for various materials including steel, silicon, ceramic, and other metals, plastic, polymers, sugars, biological and or biodegradable materials, and/or combinations thereof.
- It has been found that certain features of the intradermal administration methods provide the most efficacious results. For example, it has been found that placement of the needle outlet within the skin significantly affects the clinical response to delivery of a vaccine or gene therapy agent. The outlet of a conventional or standard gauge needle with a bevel angle cut to 15 degrees or less has a relatively large “exposed height”. As used herein the term exposed height refers to the length of the opening relative to the axis of the cannula resulting from the bevel cut. When standard needles are placed at the desired depth within the intradermal space (at about 90 degrees to the skin), the large exposed height of these needle outlets causes the substance usually to effuse out of the skin due to backpressure exerted by the skin itself and to pressure built up from accumulating fluid from the injection or infusion. Typically, the exposed height of the needle outlet of the present invention is from 0 to about 1 mm . A needle outlet with an exposed height of 0 mm has no bevel cut (or a bevel angle of 90 degrees) and is at the tip of the needle. In this case, the depth of the outlet is the same as the depth of penetration of the needle. A needle outlet that is either formed by a bevel cut or by an opening through the side of the needle has a measurable exposed height. In a needle having a bevel, the exposed height of the needle outlet is determined by the diameter of the needle and the angle of the primary bevel cut (“bevel angle”). In general, bevel angles of greater than 20° are preferred, more preferably between 25° and 40°. It is understood that a single needle may have more than one opening or outlet suitable for delivery of substances to the dermal space.
- Thus the exposed height, and for the case of a cannula with an opening through the side, its position along the axis of the cannula contributes to the depth and specificity at which a substance is delivered. Additional factors taken alone or in combination with the cannula, such as delivery rate and total fluid volume delivered, contribute to the target delivery of substances and variation of such parameters to optimize results is within the scope of the present invention.
- It has also been found that controlling the pressure of injection or infusion may avoid the high backpressure exerted during ID administration. By placing a constant pressure directly on the liquid interface a more constant delivery rate can be achieved, which may optimize absorption and obtain an improved response for the dosage of vaccine or therapeutic agent delivered. Delivery rate and volume can also be controlled to prevent the formation of wheals at the site of delivery and to prevent backpressure from pushing the dermal-access means out of the skin. The appropriate delivery rates and volumes to obtain these effects for a selected substance may be determined experimentally using only ordinary skill and without undue experimentation. Increased spacing between multiple needles allows broader fluid distribution and increased rates of delivery or larger fluid volumes.
- In one embodiment, to deliver a substance the dermal-access means is placed adjacent to the skin of a subject providing directly targeted access within the intradermal space and the substance or substances are delivered or administered into the intradermal space where they can act locally or be absorbed by the bloodstream and be distributed systemically. In another embodiment, the dermal-access means is positioned substantially perpendicular to the skin surface to provide vertical insertion of one or more cannula. The dermal-access means may be connected to a reservoir containing the substance or substances to be delivered. The form of the substance or substances to be delivered or administered include solutions thereof in pharmaceutically acceptable diluents or solvents, emulsions, suspensions, gels, particulates such as micro- and nanoparticles either suspended or dispersed, as well as in-situ forming vehicles of the same. Delivery from the reservoir into the intradermal space may occur either passively, without application of the external pressure or other driving means to the substance or substances to be delivered, and/or actively, with the application of pressure or other driving means. Examples of preferred pressure generating means include pumps, syringes, elastomer membranes, gas pressure, piezoelectric, electromotive, electromagnetic pumping, coil springs, or Belleville springs or washers or combinations thereof. If desired, the rate of delivery of the substance may be variably controlled by the pressure-generating means. As a result, the substance enters the intradermal space and is absorbed in an amount and at a rate sufficient to produce a clinically efficacious result.
- Substances that may be delivered according to the methods of the invention include vaccines, with or without carriers, adjuvants and vehicles, including prophylactic and therapeutic antigens including but not limited to subunit proteins, peptides and polysaccharides, polysaccharide conjugates, toxoids, genetic based vaccines, live attenuated bacteria or viruses, mutated bacteria or viruses, reassortant bacteria or viruses, inactivated bacteria or viruses, whole cells or components thereof (e.g. mammalian cells), cellular vaccines (e.g., autologous dendritic cells), or components thereof (for example, exosomes, dexosomes, membrane fragments, or vesicles), live viruses, live bacteria, viral and bacterial vectors including but not limited to those derived from adenoviruses, retroviruses alphaviruses, flaviviruses, and vaccinia viruses) in connection with addiction (e.g. cocaine addiction), anthrax, arthritis, cholera, diphtheria, dengue, tetanus, lupus, multiple sclerosis, parasitic diseases, psoriasis, Lyme disease, meningococcus, measles, mumps, rubella, varicella, yellow fever, Respiratory syncytial virus, tick borne Japanese encephalitis, pneumococcus, smallpox, streptococcus, staphylococcus, typhoid, influenza, hepatitis, including hepatitis A, B, C and E, otitis media, rabies, polio, HIV, parainfluenza, rotavirus, Epstein Barr Virus, CMV, chlamydia, non-typeable haemophilus, haemophilus influenza B (HIB), moraxella catarrhalis, human papilloma virus, tuberculosis including BCG, gonorrhoeae, asthma, atherosclerosis, malaria,E. coli, Alzheimer's Disease, H. Pylori, salmonella, diabetes, cancer, herpes simplex, human papilloma, Yersinia pestis, traveler's diseases, West Nile encephalitis, Camplobacter, C. difficile. Suitable exemplary compositions for genetic immunization are described, for example, in U.S. Pat. Nos. 5,589,466, 5,593,972 and 5,703,055. Particularly preferred substances that can be delivered according to the methods of the invention include nucleic acids, nucleic acid derived entities and gene therapeutic agents and the like used in the prevention, diagnosis, alleviation, treatment, or cure of disease. Suitable adjuvants for inclusion in vaccines are known to those of skill in the art. Additional agents for enhancing immune response that may be used in the present invention are disclosed in U.S. application Ser. No. 10/142,966, filed May 13, 2002, which is incorporated herein by reference.
- Particularly preferred gene therapeutic agents include those indicated for the treatment of cancer including but not limited to melanoma, cutaneous T cell lymphoma, Kaposi's sarcoma, cutaneous squamous cell carcinoma and basal cell carcinoma, adenosine deaminase deficiency, hyperproliferative skin diseases including but not limited to psoriasis, genetic skin diseases including but not limited to epidermolytic hyperkeratosis, epidermolysis bullosa, lamellar ichthyosis and X-linked ichthyosis, hemophilia, cystic fibrosis, growth disorders, hormone deficiencies including but not limited to human growth hormone deficiency, atherosclerosis, transferrin deficiency, as well as gene therapeutic agents indicated for wound healing and tissue regeneration. Suitable exemplary compositions for suitable genetic therapeutic agents are described, for example, in U.S. Pat. No. 5,547,932.
- The substance may be delivered into the skin in any pharmaceutically acceptable form. Vaccines to be used in the methods of the invention may include adjuvants and carriers or vehicles that are suitable in particular formulations, as will be familiar to those of skill in the art.
- Pharmaceutically acceptable peptide and polypeptide formulations for use in the invention, including formulations for allergen compositions, are also well known in the art. Nucleic acids for use in the methods of the invention may be RNA or DNA, or a combination thereof. They may be in any physical form suitable for ID administration and for uptake and expression by cells. DNA and/or RNA may be contained in a viral vector or liposome, or may be delivered as a free polynucleotide such as a plasmid as is known in the art. The nucleic acid will typically be formulated in a pharmaceutically acceptable formulation such as a fluid, gel, or suspension that is compatible with the nucleic acid.
- Typically, to administer vaccine or other medicament a practitioner will remove the appropriate volume from a vial sealed with a septa using a syringe. This same syringe is then used administer the vaccine to the patient. However, a microneedle or microcannula, typically between 0.1 and 2 mm in length, in addition to being somewhat unsuitable in length to completely penetrate the septa, is generally too fragile to puncture a septum of a vial to extract medicament while maintaining sufficient sharpness and straightness to subsequently be used on a patient. Use of such microdevices in puncturing septa also may result in clogging of the bore of the needle. In addition, the narrow gauge, typically 31 to 50 gauge, of the microcannula greatly reduces the volumetric capacity that can traverse the needle into the syringe, for example. This would be inconvenient to most practitioners who are accustomed to rapid transfer of liquids from vials using conventional devices and thus would greatly increase the amount of time the practitioner would spend with the patient. Additional factors to be considered in the widespread use of microdevices include the necessity to reformulate most drugs and vaccines to accommodate the reduced total volume (10-100 μl) used or delivered by microdevices. Thus it would be desirable to provide for a kit including the device either in combination with or adapted to integrate therewith, the substance to be delivered.
- Kits and the like comprising the instrument of administration and the therapeutic composition are well known in the art. However, the application of minimally invasive, ID microdevices for the delivery of drugs and vaccines clearly present an immediate need for coupling the device with the formulation to provide safe, efficacious, and consistent means for administering formulations for enabling immunogenic and therapeutic responses.
- The kit provided by the invention comprises a delivery device having at least one hollow microneedle designed to intradermally deliver a substance to a depth between 0.025 and 2 mm which is adapted so that the microneedle is or can be placed in fluid connection with a reservoir adapted for containing a dosage of a vaccine or gene therapeutic. In a preferred embodiment, the kit also contains an effective dosage of a vaccine or gene therapeutic, optionally contained in a reservoir that is an integral part of, or is capable of being functionally attached to, the delivery device. The hollow microneedle is preferably between about 31 to 50 gauge, and may be part of an array of, for example,3-6 microneedles.
- In a particularly preferred embodiment, the kit of the invention comprises a hub portion being attachable to the prefillable reservoir storing the vaccine;
- at least one microneedle supported by said hub portion and having a forward tip extending away from said hub portion; and
- a limiter portion surrounding said microneedle(s) and extending away from said hub portion toward said forward tip of said microneedle(s), said limiter including a generally flat skin engaging surface extending in a plane generally perpendicular to an axis of said microneedle(s) and adapted to be received against the skin of a mammal to administer an intradermal injection of the vaccine, said microneedle(s) forward tip(s) extending beyond said skin engaging surface a distance approximately 0.5 mm to 2.0 mm wherein said limiter portion limits penetration of the microneedle(s) into the dermal layer of skin of the mammal.
- To use a kit as envisioned by the instant invention the practitioner would break a hermetic seal to provide access to the microdevice and optionally, the vaccine or immunogenic or therapeutic composition. The composition may be preloaded within the microdevice in any form including but not limited to gel, paste, oil, emulsion, particle, nanoparticle, microparticle, suspension or liquid. The composition may be separately packaged within the kit package, for example, in a reservoir, vial, tube, blister, pouch or the like. One or more of the constituents of the formulation may be lyophilized, freeze-dried, spray freeze-dried, or in any other reconstitutable form. Various reconstitution media, cleansing or disinfective agents, or topical steriliants (alcohol wipes, iodine) can further be provided if desired. The practitioner would then load or integrate the substance if necessary into the device and then administer the formulation to the patient using the ID injection microdevice.
- Having described the invention in general, the following specific but not limiting examples and reference to the accompanying Figures set forth various examples for practicing the invention.
- A representative example of dermal-access microdevice (MDD device) comprising a single needle were prepared from 34 gauge steel stock (MicroGroup, Inc., Medway, Mass.) and a single 28° bevel was ground using an 800 grit carborundum grinding wheel. Needles were cleaned by sequential sonication in acetone and distilled water, and flow-checked with distilled water. Microneedles were secured into small gauge catheter tubing (Maersk Medical) using UV-cured epoxy resin. Needle length was set using a mechanical indexing plate, with the hub of the catheter tubing acting as a depth-limiting control and was confirmed by optical microscopy. The exposed needle length was adjusted to 1 mm using an indexing plate. Connection to the syringe was via an integral Luer adapter at the catheter inlet. During injection, needles were inserted perpendicular to the skin surface, and were held in place by gentle hand pressure for bolus delivery. Devices were checked for function and fluid flow both immediately prior to and post injection. A 30/31 gauge intradermal needle device with 1.5 mm exposed length controlled by a depth limiting hub as described in
EP 1 092 444 A1 was also used in some Examples. - Uptake and expression of DNA by cells in vivo are critical to effective gene therapy and genetic immunization. Plasmid DNA encoding the reporter gene, firefly luciferase, was used as a model gene therapeutic agent (Aldevron, Fargo, N. Dak.). DNA was administered to Hartley guinea pigs (Charles River, Raleigh, N.C.) intradermally (ID) via the Mantoux (ID-Mantoux) technique using a standard 30G needle or was delivered ID via MDD (ID-MDD) using a 34G steel micro-cannula of 1 mm length (MDD device) inserted approximately perpendicular. Plasmid DNA was applied topically to shaved skin as a negative control (the size of the plasmid is too large to allow for passive uptake into the skin). Total dose was 100 μg per animal in total volume of 40 μl PBS delivered as a rapid bolus injection (<1 min) using a 1 cc syringe. Full thickness skin biopsies of the administration sites were collected 24 hr. following delivery, were homogenized and further processed for luciferase activity using a commercial assay (Promega, Madison, Wis.). Luciferase activity was normalized for total protein content in the tissue specimens as determined by BCA assay (Pierce, Rockford, Ill.) and is expressed as Relative Light Units (RLU) per mg of total protein (n=3 animals per group for Mantoux and Negative control and n=6 for MDD device).
- The results (FIG. 1) demonstrate strong luciferase expression in both ID injection groups. Mean luciferase activity in the MDD and Mantoux groups were 240- and 220-times above negative controls, respectively. Luciferase expression levels in topical controls were not significantly greater than in untreated skin sites (data not shown). These results demonstrate that the method of the present invention using MDD devices is at least as effective as the Mantoux technique in delivering genetic materials to the ID tissue and results in significant levels of localized gene expression by skin cells in vivo.
- Experiments similar (without Mantoux control) to those described in Example 1above were performed in Brown-Norway rats (Charles River, Raleigh, N.C.) to evaluate the utility of this platform across multiple species. The same protocol was used as in Example 1, except that the total plasmid DNA load was reduced to 50 μg in 50 μl volume of PBS. In addition, an unrelated plasmid DNA (encoding b-galactosidase) injected ID (using the MDD device) was used as negative control. (n=4 animals per group). Luciferase activity in skin was determined as described in Example 1 above.
- The results, shown in FIG. 2, demonstrate very significant gene expression following ID delivery via the MDD device. Luciferase activity in recovered skin sites was >3000-fold greater than in negative controls. These results further demonstrate the utility of the method of the present invention in delivering gene based entities in vivo, resulting in high levels of gene expression by skin cells.
- The pig has long been recognized as a preferred animal model for skin based delivery studies. Swine skin is more similar to human skin in total thickness and hair follicle density than is rodent skin. Thus, the pig model (Yorkshire swine; Archer Farms, Belcamp, Md.) was used as a means to predict the utility of this system in humans. Experiments were performed as above in Examples 1 and 2, except using a different reporter gene system, β-galactosidase (Aldevron, Fargo, N. Dak.). Total delivery dose was 50 μg in 50 μl volume. DNA was injected using the following methods I) via Mantoux method using a 30G needle and syringe, ii) by ID delivery via perpendicular insertion into skin using a 30/31G needle equipped with a feature to limit the needle penetration depth to 1.5 mm, and iii) by ID delivery via perpendicular insertion into skin using a 34G needle equipped with a feature to limit the needle penetration depth to 1.0 mm (MDD device). The negative control group consisted of ID delivery by i-iii of an unrelated plasmid DNA encoding firefly luciferase. (n=11 skin sites from 4 pigs for the ID Mantoux group; n=11 skin sites from 4 pigs for ID, 30/31G, 1.5 mm device; n=10 skin sites from 4 pigs for ID, 34G, 1 mm device; n-19 skin sites from 4 pigs for negative control.) For the negative control, data from all 3 ID delivery methods were combined since all 3 methods generated comparable results.
- Reporter gene activity in tissue was determined essentially as described in Example 1, except substituting the b-galactosidase detection assay (Applied Biosystems, Foster City, Calif.) in place of the luciferase assay.
- The results, shown in FIG. 3, indicate strong reporter gene expression in skin following all 3 types of ID delivery. Responses in the ID-Mantoux group were 100-fold above background, compared to a 300-fold increase above background in the ID, 34G, 1 mm (MDD) group and 20-fold increase above background in the ID, 30G, 1.5 mm (30 g, 1.5 mm) group. Total reporter gene expression by skin cells, as measured by reporter gene mean activity recovered from excised skin tissue biopsies, was strongest in the ID, 34G, 1 mm (MDD) group at 563,523 RLU/mg compared to 200,788 RLU/mg in the ID, 30G Mantoux group, 42,470 RLU/mg in the ID (30G, 1.5 mm) group and 1,869 RLU/mg in the negative controls. Thus, ID delivery via perpendicular insertion of a 34G, 1.0 mm needle (MDD) results in superior uptake and expression of DNA by skin cells as compared to the standard Mantoux style injection or a similar perpendicular needle insertion and delivery using a longer (1.5 mm), wider diameter (30G) needle. Similar studies using these 3 devices and methods to deliver visible dyes also demonstrate that the 34G, 1.0 mm needle results in more consistent delivery to the ID tissue than the other 2 needles/methods and results in less “spill-over” of the administered dose into the subcutaneous (SC) tissue.
- These differences were unexpected since all 3 devices and methods theoretically target the same tissue space. However, it is much more difficult to control the depth of delivery using a lateral insertion (Mantoux) technique as compared to a substantially perpendicular insertion technique that is achieved by controlling the length of the cannula via the depth-limiting hub. Further, the depth of needle insertion and exposed height of the needle outlet are important features associated with reproducible ID delivery without SC “spill-over” or leakage on the skin surface.
- These results further demonstrate the utility of the methods of the present invention in delivering gene based entities in larger mammals in vivo, resulting in high levels of gene expression by skin cells. In addition, the similarities in skin composition between pigs and humans indicate that comparable clinical improvements should be obtained in humans.
- Results presented in Example 3 above suggest that there may be unexpected improvements in efficacy attained by MDD-based ID delivery compared to that attained by Mantoux-based injections using standard needles. In addition, the MDD cannula mechanically disrupt a smaller total area of tissue since they are inserted to a reduced depth compared to standard needles and are not laterally “snaked” through the ID tissue like Mantoux-style injections. Tissue damage and inflammation leads to the release of several inflammatory proteins, chemokines, cytokines and other mediators of inflammation.
- Thus, total protein content at recovered skin sites can be used as an indirect measurement of tissue damage and localized inflammation induced by the two delivery methods. Total protein levels were measured in recovered skin biopsies from pig samples presented in Example 3 above (excluding the 30 g, 1.5 mm) using a BCA assay (Pierce, Rockford, Ill.). Both methods of delivery induced an increase in total protein content compared to untreated skin, as shown in FIG. 4. However, total protein levels in recovered skin biopsies from the ID Mantoux group were significantly greater (p=0.001 by t-test) than the corresponding levels in the MDD group (2.4 mg/ml vs. 1.5 mg/ml). These results provide indirect evidence to strongly suggest that delivery by the methods of the present invention induces less mechanical damage to the tissue than the corresponding damage induced by Mantoux-style ID injection.
- The examples presented above demonstrate that narrow gauge microcannula can be used to effectively deliver model nucleic acid based compounds into the skin resulting in high levels of gene expression by skin cells. To investigate the utility of delivering DNA vaccines by the methods of the present invention, rats were immunized with plasmid DNA encoding influenza virus hemagglutinin (HA) from strain A/PR/8/34 (plasmid provided by Dr. Harriet Robinson, Emory University School of Medicine, Atlanta, Ga.). Brown-Norway rats (n=3 per group) were immunized three times (
days weeks - The results (FIG. 5) demonstrate that delivery by the method of the present invention of a genetic influenza vaccine in the absence of added adjuvant induces a potent influenza-specific serum antibody response. The magnitude of this response was comparable to that induced via IM injection at all measured timepoints. No detectable responses were observed in the topical controls. Thus delivery of genetic vaccine by the method of the present invention induces immune responses that are at least as strong as those induced by the conventional route of IM injection.
- To further investigate delivery by the method of the present invention of adjuvanted genetic vaccines, the above described influenza HA-encoding plasmid DNA was prepared using the MPL +TDM Ribi adjuvant system (RIBI Immunochemicals, Hamilton, Mont.) according to the manufacturer's instructions. Rats (n=3 per group) were immunized and analyzed for influenza-specific serum antibody as described above. Titers in the ID delivery group were comparable to IM following the first and second immunization (week 3-5; FIG. 6). After the third dose, however, ID-induced titers were significantly greater (p=0.03 by t-test) than the corresponding titers induced via IM injection (FIG. 6). At
week 11, the mean ID-induced titer was 42,000 compared to only 4,600 attained by IM injection. Topical controls failed to generate an influenza-specific response. Thus, delivery by the method of the present invention of genetic vaccines in the presence of adjuvant induces immune responses that are stronger than those induced by the conventional route of IM injection. - A recently developed vaccination approach for numerous diseases, including HIV, is the so-called “prime-boost” approach wherein the initial “priming” immunizations and secondary “boosters” employ different vaccine classes (Immunology Today, Apr 21(4): 163-165, 2000). For example, one may prime with a plasmid DNA version of the vaccine followed by a subsequent boost with a subunit protein, inactivated virus or vectored DNA preparation. To investigate delivery by the method of the present invention of these types of vaccination methods, the first experiment of Example 5 was continued for an additional 6 weeks. At
week 11, DNA-primed rats were boosted with whole inactivated influenza virus (A/PR/8/34, 100 μg in 50 μl volume of PBS by rapid bolus injection). Virus was obtained from Charles River SPAFAS, North Franklin, Conn. Influenza-specific serum antibody titers were measured atweeks Week 17 mean influenza-specific titers were equivalent (titer =540,000) by both methods of delivery and were significantly greater than the very weak titers observed following unassisted topical delivery (titer =3200). Thus, delivery by the method of the present invention is suitable for “prime-boost” immunization regimens, inducing immune responses that are at least as strong as those induced by the conventional route of IM injection. - To evaluate the effect of adjuvant on the “prime-boost” response, the second experiment described in Example 5 was continued for an additional 6 weeks. At
week 11, DNA-primed rats were boosted with whole inactivated influenza virus (A/PR/8/34, 100 μg in 50 μl volume by rapid bolus injection as above). Influenza-specific serum antibody titers were measured atweeks week 13, the ID-MDD(MDD) mean titer was 540,000 compared to 240,000 by IM injection and 3,200 by unassisted topical application. Thus, delivery by the method of the present invention is suitable for “prime-boost” immunization regimens incorporating adjuvants, inducing immune responses that are stronger than those induced by the conventional route of IM; injection. - To investigate the utility of delivering conventional vaccines by the method of the present invention in, rats were immunized with an inactivated influenza virus preparation as described in Example 6 via ID delivery or intramuscular (IM) injection with a standard needle and syringe. As negative control, vaccine solution was applied topically to untreated skin; the large molecular weight of the inactivated influenza virus precludes effective immunization via passive topical absorption. As above, vaccine dose was 100 μg total protein in 50 μl volume per animal delivered by rapid bolus injection (<1 min). Rats were immunized 3 times (
days days - The results, shown in FIG. 9, indicate that ID delivery induces potent antigen specific immune responses. Similar levels of antibody were induced by the 2 injection routes, IM and ID. Peak geometric mean titers were somewhat higher in the ID-MDD group (MDD); 147,200 compared to 102,400 via IM injection. Topical application of the vaccine stimulated only very weak responses (peak mean titer =500). Thus, ID delivery of conventional vaccines at high doses induces immune responses that are at least as strong as those induced by the conventional route of IM injection.
- As noted above, the pig represents an attractive skin model that closely mimics human skin. To test ID delivery devices in vaccine delivery, Yorkshire swine were immunized with an inactivated influenza vaccine as above, comparing ID delivery ID with IM injection. Pigs were immunized on
days days - The results (FIG. 10) indicate that ID delivery induces potent antigen specific immune responses. Similar levels of antibody were induced by the 2 injection routes, IM and ID. Peak geometric mean titers were slightly higher in the MDD group; 1,333 compared to 667 via IM injection. Thus, ID delivery of conventional vaccines at high doses induces immune responses that are at least as strong as those induced by the conventional route of IM injection.
- In Example 7, rats were immunized with 100 μg of inactivated influenza virus via ID injection, or IM using a conventional needle and syringe. At such a high dose, both delivery methods induced similar levels of serum antibodies, although at the last time-point the ID-induced titer was slightly greater than that induced by IM.
- To further study the relationship between method of delivery and dosage level, rats were immunized with reduced doses of inactivated influenza virus, ranging from 1 μto 0.01 μg per animal, using the ID and IM routes of administration as above. Rats were given 3 immunizations (
days days day 56, although similar trends were observed atday 21 andday 35. ID delivery (MDD) resulted in a significant antibody response that did not differ significantly in magnitude at the 3 doses tested; i.e., delivery of as little as 0.01 μg (10 ng) induced comparable titers to those observed using 100-fold more vaccine (1 μg). In contrast, a significant reduction in titer was observed when the IM dose was reduced from 1 μg to 0.1 μg and again when the dose was further reduced to 0.01 μg. In addition, there was considerably less variability in the titers induced via ID delivery as compared to IM. Notably, no visible side reactions (adverse skin effects) were observed at the ID administration sites. - The results strongly indicate that ID delivery by the method of the present invention enables a significant (at least 100-fold) reduction in vaccine dose as compared to IM injection. Significant immune responses were observed using nanogram quantities of vaccine. Similar benefits would be expected in clinical settings.
- The results described herein demonstrate that ID injection of vaccine and genetic material can be reproducibly accomplished the methods of the present invention. This method of delivery is easier to accomplish than standard Mantoux-style injections or IM and, in one embodiment, by virtue of its limited and controlled depth of penetration into the skin, is less invasive and painful. In addition, this method provides more reproducible ID delivery than via Mantoux style injections using conventional needles resulting in improved targeting of skin cells with resultant benefits as described above.
- In addition, the method is compatible with whole-inactivated virus vaccine and with DNA plasmids without any associated reduction in biological potency as would occur if the virus particles or plasmid DNA were sheared or degraded when passed through the microcannula at the relatively high pressures associated with ID delivery in vivo. The results detailed herein demonstrate that stronger immune responses are induced via ID delivery, especially at reduced vaccine doses, thus potentially enabling significant dose reductions and combination vaccines in humans.
- The results presented above show improved immunization via ID delivery using devices such as those described above as compared to standard intramuscular (IM) injection using a conventional needle and syringe. The dose reduction study (Example 9), shows that ID delivery induces serum antibody responses to an influenza vaccine in rats using at least 100-fold less vaccine than required via IM injection. If applicable in a clinical setting, such dose reduction would reduce or eliminate the problem of influenza vaccine shortages common across the world. In addition, such dose reduction capabilities may enable the delivery of a greater number of vaccine antigens in a single dose, thus enabling combination vaccines. This approach is of particular relevance to HIV vaccines where it likely will be necessary to immunize simultaneously with several genetic variants/sub-strains in order to induce protective immunity.
- Similar benefits are expected with other types of prophylactic and therapeutic vaccines, immuno-therapeutics and cell-based entities by virtue of the improved targeting of the immune system using the methods and devices of the present invention.
- In another embodiment, it is within the scope of the present invention to combine the ID delivery of the present invention with convention methods of administration, for example IP, IM, intranasal or other mucosal route, or SQ injection, topical, or skin abrasion methods to provide improvement in immunological or therapeutic response. This would include for example, vaccines and or therapeutics of the same or different class, and administration simultaneously or sequentially.
- All references cited in this specification are hereby incorporated by reference. The discussion of the references herein is intended merely to summarize the assertions made by their authors and no admission is made that any reference constitutes prior art relevant to patentability. Applicants reserve the right to challenge the accuracy and pertinence of the cited references.
- The embodiments illustrated and discussed in the present specification are intended only to teach those skilled in the art the best way known to the inventors to make and use the invention, and should not be considered as limiting the scope of the present invention. The exemplified embodiments of the invention may be modified or varied, and elements added or omitted, without departing from the invention, as appreciated by those skilled in the art in light of the above teachings. It is therefore to be understood that, within the scope of the claims and their equivalents, the invention may be practiced otherwise than as specifically described.
Claims (60)
1. A method for delivering a vaccine to a mammal, said method comprising intradermally administering the vaccine through at least one hollow needle having an outlet with an exposed height between 0 and 1 mm , said outlet being inserted into the skin to a depth of between 0.5 mm and 2 mm.
2. The method of claim 1 wherein the vaccine is administered with a device comprising
a hub portion being attachable to a prefillable reservoir storing the vaccine;
at least one hollow microneedle supported by said hub portion and having a forward tip extending away from said hub portion; and
a limiter portion surrounding said microneedle(s) and extending away from said hub portion toward said forward tip of said microneedle(s), said limiter including a generally flat skin engaging surface extending in a plane generally perpendicular to an axis of said microneedle(s) and adapted to be received against the skin of a mammal to administer an intradermal injection of the vaccine, said microneedle(s) forward tip(s) extending beyond said skin engaging surface a distance approximately 0.5 mm to 2.0 mm wherein said limiter portion limits penetration of the microneedle(s) into the dermal layer of skin of the mammal.
3. The method of claim 1 wherein delivery of the vaccine occurs at a depth between 0.025 mm and 2.5 mm in the skin of the mammal.
4. The method of claim 1 wherein the delivered vaccine induces an immune response in the mammal that is equal to or greater than the response after delivery of the same amount of vaccine by subcutaneous or intramuscular injection.
5. The method of claim 1 wherein the delivered vaccine induces an immune response in the mammal that is equal to or greater than the response after delivery of a greater amount of vaccine by subcutaneous or intramuscular injection.
6. The method of claim 1 wherein the needle is a microneedle between about 31 to 50 gauge.
7. The method of claim 1 wherein the needle has a bevel angle between 20° and 90°.
8. The method of claim 7 wherein the needle has a bevel angle between 25° and 40°.
9. The method of claim 6 wherein the length of the needle inserted into the skin is to a depth from about 0.5 mm to about 1.7 mm.
10. The method of claim 6 wherein the microneedle is in an array of microneedles.
11. The method of claim 1 wherein the vaccine comprises a live attenuated virus.
12. The method of claim 1 wherein the vaccine comprises a live attenuated bacterium.
13. The method of claim 1 wherein the vaccine comprises an inactivated or killed virus.
14. The method of claim 13 wherein the vaccine additionally comprises an adjuvant.
15. The method of claim 13 wherein the vaccine is an influenza vaccine.
16. The method of claim 1 wherein the vaccine comprises an inactivated or killed bacterium.
17. The method of claim 1 wherein the vaccine comprises a nucleic acid.
18. The method of claim 17 wherein a peptide or protein encoded by the nucleic acid is expressed in the mammal.
19. The method of claim 17 wherein the vaccine additionally comprises an adjuvant.
20. The method of claim 17 wherein the vaccine is an influenza vaccine.
21. The method of claim 1 wherein the vaccine comprises a live nonattenuated bacterium or virus.
22. The method of claim 1 wherein the vaccine comprises mammalian cells or components thereof.
23. The method of claim 1 wherein the vaccine comprises a polysaccharide or polysaccharide conjugate.
24. The method of claim 1 wherein the vaccine comprises a protein or peptide.
25. The method of claim 1 wherein the needle(s) are inserted substantially perpendicularly to the skin.
26. The method of claim 1 that additionally comprises administering a second vaccine intramuscularly, subcutaneously, mucosally, intraperitoneally, intravenously, topically or epidermally.
27. The method of claim 26 wherein the second vaccine is the same composition as said vaccine.
28. The method of claim 26 wherein the second vaccine is a different composition than said vaccine.
29. The method of claim 26 wherein the second vaccine is a different vaccine class from said vaccine.
30. The method of claim 26 wherein said second vaccine is administered simultaneously with said vaccine.
31. The method of claim 26 wherein said second vaccine is administered subsequently to said vaccine.
32. The method of claim 1 that additionally comprises administering a second vaccine through at least one hollow needle having an outlet with an exposed height between 0 and 1 mm , said outlet being inserted into the skin to a depth of between 0.5 mm and 2 mm.
33. The method of claim 32 wherein delivery of the second vaccine occurs at a depth between 0.025 mm and 2.5 mm in the skin of the mammal.
34. The method of claim 32 wherein the second vaccine is administered simultaneously with said vaccine.
35. The method of claim 32 wherein the second vaccine is administered subsequent to said vaccine.
36. The method of claim 35 wherein the second vaccine is administered one day to six weeks after said vaccine.
37. The method of claim 32 wherein the second vaccine is a different vaccine class than said vaccine.
38. The method of claim 32 wherein the second vaccine is the same composition than said vaccine.
39. The method of claim 32 wherein the second vaccine is a different composition than said vaccine.
40. A method for delivering a vaccine to a mammal, said method comprising:
a) contacting the skin of the mammal with a device having a dermal-access means for accurately targeting a dermal space of the skin at a depth between 0.025 mm and 2.5 mm with the vaccine; and
b) delivering the vaccine to the dermal space.
41. The method of claim 40 wherein the delivered vaccine induces an immune response in the mammal that is equal to or greater than the response after delivery of the same amount of vaccine by subcutaneous or intramuscular injection.
42. The method of claim 40 wherein the delivered vaccine induces an immune response in the mammal that is equal to or greater than the response after delivery of a greater amount of vaccine by subcutaneous or intramuscular injection.
43. A method for delivering a gene therapeutic agent to a mammal, said method comprising administering the therapeutic agent through at least one small gauge hollow needle having an outlet with an exposed height between 0 and 1 mm, said outlet being inserted into the skin to a depth of between 0.5 mm and 2 mm.
44. The method of claim 43 , wherein delivery of the therapeutic agent occurs at a depth between 0.025 mm and 2.5 mm in the skin of the mammal.
45. The method of claim 43 wherein a peptide or protein encoded by the gene therapeutic agent is expressed in the mammal.
46. The method of claim 45 wherein expression occurs in skin cells of the mammal.
47. The method of claim 43 wherein the needle is a microneedle between 31 to 50 gauge.
48. The method of claim 43 wherein the needle has a bevel angle between 20° and 90°.
49. The method of claim 48 wherein the needle has a bevel angle between 25° and 40°.
50. The method of claim 43 wherein the needle has a length from about 0.5 mm to about 1.7 mm.
51. The method of claim 47 wherein the microneedle is contained in an array of microneedles.
52. The method of claim 43 wherein the gene therapeutic agent comprises a nucleic acid.
53. The method of claim 43 wherein the needle(s) are inserted substantially perpendicularly to the skin.
54. A kit comprising a delivery device having at least one hollow microneedle designed to intradermally deliver a substance to a depth between 0.025 and 2.5 mm, said delivery device being adapted to receive a reservoir that contains a gene therapeutic agent or vaccine such that the microneedle is in communication therewith.
55. The kit of claim 54 that additionally comprises an effective dosage of a vaccine or gene therapeutic.
56. The kit of claim 55 wherein the dosage is contained in a reservoir that is an integral part of, or is capable of being functionally attached to, the delivery device.
57. The kit of claim 54 wherein the hollow microneedle is between about 31 to 50 gauge.
58. The kit of claim 54 wherein the device comprises an array of microneedles.
59. The kit of claim 54 wherein the device comprises
a hub portion being attachable to a prefillable reservoir storing the vaccine;
at least one microneedle supported by said hub portion and having a forward tip extending away from said hub portion; and
a limiter portion surrounding said microneedle and extending away from said hub portion toward said forward tip of said microneedle, said limiter including a generally flat skin engaging surface extending in a plane generally perpendicular to an axis of said microneedle and adapted to be received against the skin of a mammal to administer an intradermal injection of the vaccine, said microneedle forward tip extending beyond said skin engaging surface a distance approximately 0.5 mm to 2.0 mm wherein said limiter portion limits penetration of the microneedle into the dermal layer of skin of the mammal.
60. A kit comprising a dermal access means designed to intradermally deliver a substance to a depth between 0.025 and 2.5 mm, said dermal access means being adapted to receive a reservoir that contains a gene therapeutic agent or vaccine such that the dermal access means is in communication therewith.
Priority Applications (3)
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US10/185,717 US20020198509A1 (en) | 1999-10-14 | 2002-07-01 | Intradermal delivery of vaccines and gene therapeutic agents via microcannula |
US10/679,038 US7473247B2 (en) | 1999-10-14 | 2003-10-02 | Intradermal delivery of vaccines and gene therapeutic agents via microcannula |
US11/118,916 US20060018877A1 (en) | 2001-06-29 | 2005-04-29 | Intradermal delivery of vacccines and therapeutic agents |
Applications Claiming Priority (6)
Application Number | Priority Date | Filing Date | Title |
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US09/417,671 US6494865B1 (en) | 1999-10-14 | 1999-10-14 | Intradermal delivery device including a needle assembly |
US09/834,438 US6843781B2 (en) | 1999-10-14 | 2001-04-13 | Intradermal needle |
US09/835,243 US6569143B2 (en) | 1999-10-14 | 2001-04-13 | Method of intradermally injecting substances |
US30147601P | 2001-06-29 | 2001-06-29 | |
US10/044,504 US20020193740A1 (en) | 1999-10-14 | 2002-01-10 | Method of intradermally injecting substances |
US10/185,717 US20020198509A1 (en) | 1999-10-14 | 2002-07-01 | Intradermal delivery of vaccines and gene therapeutic agents via microcannula |
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US10/044,504 Continuation-In-Part US20020193740A1 (en) | 1999-10-14 | 2002-01-10 | Method of intradermally injecting substances |
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US10/679,038 Continuation-In-Part US7473247B2 (en) | 1999-10-14 | 2003-10-02 | Intradermal delivery of vaccines and gene therapeutic agents via microcannula |
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EP (1) | EP1416986A4 (en) |
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Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US20040028707A1 (en) * | 2001-06-29 | 2004-02-12 | Pinkerton Thomas C. | Enhanced pharmacokinetic profile of intradermally delivered substances |
US20040096463A1 (en) * | 2001-02-23 | 2004-05-20 | Nathalie Garcon | Novel vaccine |
US20050123565A1 (en) * | 2003-10-31 | 2005-06-09 | Janardhanan Subramony | System and method for transdermal vaccine delivery |
US20050220854A1 (en) * | 2004-04-01 | 2005-10-06 | Yuh-Fun Maa | Apparatus and method for transdermal delivery of influenza vaccine |
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US20060058736A1 (en) * | 2001-04-27 | 2006-03-16 | Alchas Paul G | Novel vaccine |
US20070083151A1 (en) * | 2003-12-29 | 2007-04-12 | Carter Chad J | Medical devices and kits including same |
US20070088414A1 (en) * | 2005-05-25 | 2007-04-19 | Campbell Robert L | Particulate formulations for intradermal delivery of biologically active agents |
US20070118077A1 (en) * | 2005-11-21 | 2007-05-24 | Becton, Dickinson And Company | Intradermal delivery device |
US20070191761A1 (en) * | 2004-02-23 | 2007-08-16 | 3M Innovative Properties Company | Method of molding for microneedle arrays |
US20070237788A1 (en) * | 2001-02-23 | 2007-10-11 | Nathalie Garcon | Non-live trivalent influenza vaccine for one-dose intradermal delivery |
US20080088066A1 (en) * | 2004-12-07 | 2008-04-17 | Ferguson Dennis E | Method Of Molding A Microneedle |
US20080102192A1 (en) * | 2004-11-18 | 2008-05-01 | Johnson Peter R | Masking Method for Coating a Microneedle Array |
US20080226729A1 (en) * | 2006-09-08 | 2008-09-18 | Becton, Dickinson And Company | Stable powder formulations of alum-adsorbed vaccines |
US20080262416A1 (en) * | 2005-11-18 | 2008-10-23 | Duan Daniel C | Microneedle Arrays and Methods of Preparing Same |
US20080294116A1 (en) * | 2005-11-18 | 2008-11-27 | Wolter James T | Coatable Compositions, Coatings Derived Therefrom and Microarrays Having Such Coatings |
US20090012494A1 (en) * | 2006-10-17 | 2009-01-08 | Nanopass Technologies Ltd. | Intradermal delivery of biological agents |
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Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US20020198509A1 (en) * | 1999-10-14 | 2002-12-26 | Mikszta John A. | Intradermal delivery of vaccines and gene therapeutic agents via microcannula |
US20050010193A1 (en) * | 2002-05-06 | 2005-01-13 | Laurent Philippe E. | Novel methods for administration of drugs and devices useful thereof |
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US8986253B2 (en) | 2008-01-25 | 2015-03-24 | Tandem Diabetes Care, Inc. | Two chamber pumps and related methods |
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US8408421B2 (en) | 2008-09-16 | 2013-04-02 | Tandem Diabetes Care, Inc. | Flow regulating stopcocks and related methods |
EP2334234A4 (en) | 2008-09-19 | 2013-03-20 | Tandem Diabetes Care Inc | Solute concentration measurement device and related methods |
CA2751379C (en) | 2009-02-10 | 2018-06-12 | Novartis Ag | Influenza vaccines with reduced amounts of squalene |
US20100286600A1 (en) * | 2009-05-08 | 2010-11-11 | Bommannan D Bommi | Transdermal patch device |
WO2011014704A2 (en) | 2009-07-30 | 2011-02-03 | Tandem Diabetes Care, Inc. | Infusion pump system with disposable cartridge having pressure venting and pressure feedback |
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AU2012236099A1 (en) | 2011-03-31 | 2013-10-03 | Moderna Therapeutics, Inc. | Delivery and formulation of engineered nucleic acids |
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CA2859387A1 (en) | 2011-12-16 | 2013-06-20 | Moderna Therapeutics, Inc. | Modified nucleoside, nucleotide, and nucleic acid compositions |
US9180242B2 (en) | 2012-05-17 | 2015-11-10 | Tandem Diabetes Care, Inc. | Methods and devices for multiple fluid transfer |
US9555186B2 (en) | 2012-06-05 | 2017-01-31 | Tandem Diabetes Care, Inc. | Infusion pump system with disposable cartridge having pressure venting and pressure feedback |
JP6144355B2 (en) | 2012-11-26 | 2017-06-07 | モデルナティエックス インコーポレイテッドModernaTX,Inc. | Chemically modified mRNA |
WO2014113089A2 (en) | 2013-01-17 | 2014-07-24 | Moderna Therapeutics, Inc. | Signal-sensor polynucleotides for the alteration of cellular phenotypes |
WO2014159813A1 (en) | 2013-03-13 | 2014-10-02 | Moderna Therapeutics, Inc. | Long-lived polynucleotide molecules |
US9173998B2 (en) | 2013-03-14 | 2015-11-03 | Tandem Diabetes Care, Inc. | System and method for detecting occlusions in an infusion pump |
CA2906945A1 (en) | 2013-03-15 | 2014-09-18 | Incube Labs, Llc | Multi-stage biodegradable drug delivery platform |
US20160367638A1 (en) | 2013-12-19 | 2016-12-22 | Crystal BYERS | LEPTIN mRNA COMPOSITIONS AND FORMULATIONS |
EP3154694A1 (en) | 2014-06-13 | 2017-04-19 | Children's Medical Center Corporation | Products and methods to isolate mitochondria |
EP3397261A4 (en) | 2015-11-30 | 2019-07-03 | Flagship Pioneering Innovations V, Inc. | Methods and compositions relating to chondrisomes |
CN109152795A (en) | 2016-01-15 | 2019-01-04 | 儿童医学中心公司 | The therapeutical uses of mitochondria and combined mitochondria reagent |
JP7034425B2 (en) * | 2016-04-15 | 2022-03-14 | エーディーエムバイオサイエンス インコーポレイテッド | Nucleic acid film manufacturing method and drug injection device using nucleic acid film |
CN111343970A (en) | 2017-09-13 | 2020-06-26 | 北卡罗莱纳州立大学 | Microneedle patch for locally inducing browning of adipose tissue and treating obesity |
US10973908B1 (en) | 2020-05-14 | 2021-04-13 | David Gordon Bermudes | Expression of SARS-CoV-2 spike protein receptor binding domain in attenuated salmonella as a vaccine |
US11877848B2 (en) | 2021-11-08 | 2024-01-23 | Satio, Inc. | Dermal patch for collecting a physiological sample |
Citations (93)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US1274081A (en) * | 1917-05-10 | 1918-07-30 | Herman A Metz | Hypodermic needle. |
US2559474A (en) * | 1950-03-09 | 1951-07-03 | Sonco Inc | Hypodermic and spinal syringe |
US2876770A (en) * | 1955-10-10 | 1959-03-10 | Raymond A White | Shielded hypodermic syringe |
US3073306A (en) * | 1958-09-03 | 1963-01-15 | Linder Fritz | Hypodermic syringe |
US3400715A (en) * | 1966-01-04 | 1968-09-10 | Halvard J. Pederson | Attachment for injection apparatus |
US3814097A (en) * | 1972-02-14 | 1974-06-04 | Ici Ltd | Dressing |
US3890971A (en) * | 1973-10-23 | 1975-06-24 | Thomas A Leeson | Safety syringe |
US3964482A (en) * | 1971-05-17 | 1976-06-22 | Alza Corporation | Drug delivery device |
US4270537A (en) * | 1979-11-19 | 1981-06-02 | Romaine Richard A | Automatic hypodermic syringe |
US4373526A (en) * | 1979-06-20 | 1983-02-15 | Lothar Kling | Device for injection syringe |
US4468223A (en) * | 1981-08-06 | 1984-08-28 | Terumo Kabushiki Kaisha | Syringe |
US4583978A (en) * | 1983-01-23 | 1986-04-22 | Michael Porat | Syringe |
US4592753A (en) * | 1982-12-13 | 1986-06-03 | Elan Corporation P.L.C. | Drug delivery device |
US4596556A (en) * | 1985-03-25 | 1986-06-24 | Bioject, Inc. | Hypodermic injection apparatus |
US4826687A (en) * | 1985-06-06 | 1989-05-02 | National Institute Of Health | Influenza vaccine |
US4834704A (en) * | 1988-04-13 | 1989-05-30 | Eaton Corporation | Injectable infusion pump apparatus for implanting long-term dispensing module and medication in an animal and method therefor |
US4898588A (en) * | 1988-10-17 | 1990-02-06 | Roberts Christopher W | Hypodermic syringe splatter shield |
US4940460A (en) * | 1987-06-19 | 1990-07-10 | Bioject, Inc. | Patient-fillable and non-invasive hypodermic injection device assembly |
US4941880A (en) * | 1987-06-19 | 1990-07-17 | Bioject, Inc. | Pre-filled ampule and non-invasive hypodermic injection device assembly |
US5003987A (en) * | 1987-09-11 | 1991-04-02 | Grinwald Paul M | Method and apparatus for enhanced drug permeation of skin |
US5015235A (en) * | 1987-02-20 | 1991-05-14 | National Carpet Equipment, Inc. | Syringe needle combination |
US5098389A (en) * | 1990-06-28 | 1992-03-24 | Becton, Dickinson And Company | Hypodermic needle assembly |
US5137516A (en) * | 1989-11-28 | 1992-08-11 | Glaxo Group Limited | Triggered application device for medicament to be more descriptive of the invention |
US5141496A (en) * | 1988-11-03 | 1992-08-25 | Tino Dalto | Spring impelled syringe guide with skin penetration depth adjustment |
US5190521A (en) * | 1990-08-22 | 1993-03-02 | Tecnol Medical Products, Inc. | Apparatus and method for raising a skin wheal and anesthetizing skin |
US5195526A (en) * | 1988-03-11 | 1993-03-23 | Michelson Gary K | Spinal marker needle |
US5222949A (en) * | 1991-07-23 | 1993-06-29 | Intermed, Inc. | Flexible, noncollapsible catheter tube with hard and soft regions |
US5279544A (en) * | 1990-12-13 | 1994-01-18 | Sil Medics Ltd. | Transdermal or interdermal drug delivery devices |
US5279552A (en) * | 1993-01-11 | 1994-01-18 | Anton Magnet | Intradermal injection device |
US5292506A (en) * | 1990-10-30 | 1994-03-08 | Daiichi Pharmaceutical Co., Ltd. | Muramyldipeptide derivatives and influenza vaccine comprising the derivatives |
US5312335A (en) * | 1989-11-09 | 1994-05-17 | Bioject Inc. | Needleless hypodermic injection device |
US5331954A (en) * | 1990-12-21 | 1994-07-26 | Novo Nordisk A/S | Device for nasal delivery of liquid medications |
US5334144A (en) * | 1992-10-30 | 1994-08-02 | Becton, Dickinson And Company | Single use disposable needleless injector |
US5339163A (en) * | 1988-03-16 | 1994-08-16 | Canon Kabushiki Kaisha | Automatic exposure control device using plural image plane detection areas |
US5383851A (en) * | 1992-07-24 | 1995-01-24 | Bioject Inc. | Needleless hypodermic injection device |
US5417662A (en) * | 1991-09-13 | 1995-05-23 | Pharmacia Ab | Injection needle arrangement |
US5431155A (en) * | 1992-06-03 | 1995-07-11 | Elettro Plastica S.P.A. | Single-dose nasal dispenser for atomized liquid drugs |
US5437647A (en) * | 1990-05-09 | 1995-08-01 | Safety Syringes, Inc. | Disposable self-shielding aspirating syringe |
US5480381A (en) * | 1991-08-23 | 1996-01-02 | Weston Medical Limited | Needle-less injector |
US5496286A (en) * | 1994-08-17 | 1996-03-05 | Sterling Winthrop | Hypodermic syringe holder with disposable body |
US5514107A (en) * | 1994-02-10 | 1996-05-07 | Habley Medical Technology Corporation | Safety syringe adapter for cartridge-needle unit |
US5527288A (en) * | 1990-12-13 | 1996-06-18 | Elan Medical Technologies Limited | Intradermal drug delivery device and method for intradermal delivery of drugs |
US5591139A (en) * | 1994-06-06 | 1997-01-07 | The Regents Of The University Of California | IC-processed microneedles |
US5599302A (en) * | 1995-01-09 | 1997-02-04 | Medi-Ject Corporation | Medical injection system and method, gas spring thereof and launching device using gas spring |
US5649912A (en) * | 1994-03-07 | 1997-07-22 | Bioject, Inc. | Ampule filling device |
US5704911A (en) * | 1992-09-28 | 1998-01-06 | Equidyne Systems, Inc. | Needleless hypodermic jet injector |
US5779677A (en) * | 1994-01-17 | 1998-07-14 | Laboratoire Aguettant | Automatic drug injector |
US5861174A (en) * | 1996-07-12 | 1999-01-19 | University Technology Corporation | Temperature sensitive gel for sustained delivery of protein drugs |
US5873856A (en) * | 1995-06-22 | 1999-02-23 | Pharmacia Ab | Limited depth penetration needle housing |
US5876582A (en) * | 1997-01-27 | 1999-03-02 | The University Of Utah Research Foundation | Methods for preparing devices having metallic hollow microchannels on planar substrate surfaces |
US5879326A (en) * | 1995-05-22 | 1999-03-09 | Godshall; Ned Allen | Method and apparatus for disruption of the epidermis |
US5879327A (en) * | 1994-04-06 | 1999-03-09 | Moreau Defarges Alain | Needleless jet injection device |
US5893397A (en) * | 1996-01-12 | 1999-04-13 | Bioject Inc. | Medication vial/syringe liquid-transfer apparatus |
US5912000A (en) * | 1994-09-23 | 1999-06-15 | Zonagen, Inc. | Chitosan induced immunopotentiation |
US5921963A (en) * | 1992-04-29 | 1999-07-13 | Mali-Tech Ltd. | Skin piercing devices for medical use |
US5928207A (en) * | 1997-06-30 | 1999-07-27 | The Regents Of The University Of California | Microneedle with isotropically etched tip, and method of fabricating such a device |
US5944700A (en) * | 1997-09-26 | 1999-08-31 | Becton, Dickinson And Company | Adjustable injection length pen needle |
US6036675A (en) * | 1999-02-03 | 2000-03-14 | Specialized Health Products, Inc. | Safety sterile cartride unit apparatus and methods |
US6053893A (en) * | 1997-09-12 | 2000-04-25 | Disetronic Licensing Ag | Device for the dosed release of an injectable product |
US6056716A (en) * | 1987-06-08 | 2000-05-02 | D'antonio Consultants International Inc. | Hypodermic fluid dispenser |
US6083197A (en) * | 1995-12-19 | 2000-07-04 | Umbaugh; Jerald C. | Spring-actuated needleless injector |
US6090077A (en) * | 1995-05-11 | 2000-07-18 | Shaw; Thomas J. | Syringe plunger assembly and barrel |
US6090080A (en) * | 1996-07-05 | 2000-07-18 | Disetronic Licensing Ag | Injection device for injection of liquid |
US6090082A (en) * | 1998-02-23 | 2000-07-18 | Becton, Dickinson And Company | Vial retainer interface to a medication delivery pen |
US6093170A (en) * | 1999-01-28 | 2000-07-25 | Hsu; Kuo-Chi | Structure safety syringe |
US6099504A (en) * | 1997-10-22 | 2000-08-08 | Elan Corporation, Plc | Pre-filled injection delivery device |
US6200291B1 (en) * | 1998-01-08 | 2001-03-13 | Antonio Di Pietro | Device for controlling the penetration depth of a needle, for application to an injection syringe |
US6210369B1 (en) * | 1997-12-16 | 2001-04-03 | Meridian Medical Technologies Inc. | Automatic injector |
US6334856B1 (en) * | 1998-06-10 | 2002-01-01 | Georgia Tech Research Corporation | Microneedle devices and methods of manufacture and use thereof |
US6346095B1 (en) * | 1996-06-10 | 2002-02-12 | Elan Corporation, Plc | Needle and method for delivery of fluids |
US20020025326A1 (en) * | 2000-06-22 | 2002-02-28 | Blonder Joan P. | Delivery vehicle composition and methods for delivering antigens and other drugs |
US6372223B1 (en) * | 1998-09-15 | 2002-04-16 | Baxter Aktiengesellschaft | Influenza virus vaccine composition |
US20020095134A1 (en) * | 1999-10-14 | 2002-07-18 | Pettis Ronald J. | Method for altering drug pharmacokinetics based on medical delivery platform |
US6525030B1 (en) * | 1989-12-14 | 2003-02-25 | Applied Tissue Technologies, Llc | Gene delivery to periosteal cells by microneedle injection |
US6534065B1 (en) * | 1997-11-28 | 2003-03-18 | West Pharmaceutical Services Drug Delivery & Clinical Research Centre Limited | Influenza vaccine composition with chitosan adjuvant |
US6537242B1 (en) * | 2000-06-06 | 2003-03-25 | Becton, Dickinson And Company | Method and apparatus for enhancing penetration of a member for the intradermal sampling or administration of a substance |
US20030073609A1 (en) * | 2001-06-29 | 2003-04-17 | Pinkerton Thomas C. | Enhanced pharmacokinetic profile of intradermally delivered substances |
US20030093040A1 (en) * | 2001-10-29 | 2003-05-15 | Mikszta John A. | Method and device for the delivery of a substance |
US6569143B2 (en) * | 1999-10-14 | 2003-05-27 | Becton, Dickinson And Company | Method of intradermally injecting substances |
US6569123B2 (en) * | 1999-10-14 | 2003-05-27 | Becton, Dickinson And Company | Prefillable intradermal injector |
US6689118B2 (en) * | 1999-10-14 | 2004-02-10 | Becton Dickinson And Company | Method of intradermally injecting substances |
US20040073160A1 (en) * | 2000-06-29 | 2004-04-15 | Pinkerton Thomas C. | Intradermal delivery of substances |
US20040082934A1 (en) * | 2002-08-30 | 2004-04-29 | Pettis Ronald J. | Method of controlling pharmacokinetics of immunomodulatory compounds |
US20040120964A1 (en) * | 2001-10-29 | 2004-06-24 | Mikszta John A. | Needleless vaccination using chimeric yellow fever vaccine-vectored vaccines against heterologous flaviviruses |
US20040131641A1 (en) * | 1999-10-14 | 2004-07-08 | Mikszta John A. | Intradermal delivery of vaccines and gene therapeutic agents via microcannula |
US6776776B2 (en) * | 1999-10-14 | 2004-08-17 | Becton, Dickinson And Company | Prefillable intradermal delivery device |
US20050008683A1 (en) * | 2000-06-29 | 2005-01-13 | Becton Dickinson And Company | Method for delivering interferons to the intradermal compartment |
US20050096331A1 (en) * | 2001-12-21 | 2005-05-05 | Das Saibal K. | Novel compounds and their use in medicine process for their preparation and pharmaceutical compositions containing them |
US20050096332A1 (en) * | 2003-10-30 | 2005-05-05 | Boehringer Ingelheim International Gmbh | Use of tyrosine kinase inhibitors for the treatment of inflammatory processes |
US20050096330A1 (en) * | 1999-07-22 | 2005-05-05 | Henning Boettcher | N-(indolecarbonyl) piperazine derivatives |
US20050123550A1 (en) * | 2003-05-12 | 2005-06-09 | Laurent Philippe E. | Molecules enhancing dermal delivery of influenza vaccines |
US20050180952A1 (en) * | 2003-08-26 | 2005-08-18 | Pettis Ronald J. | Methods for intradermal delivery of therapeutics agents |
US20050181033A1 (en) * | 2000-06-29 | 2005-08-18 | Dekker John P.Iii | Method for delivering interferons to the intradermal compartment |
Family Cites Families (50)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US1439707A (en) | 1919-07-10 | 1922-12-26 | William C Newell | Automatic heat-controlled cut-out |
US1436707A (en) * | 1921-08-10 | 1922-11-28 | American Platinum Works | Adjustable and safety regulating device for hypodermic needles |
DE596981C (en) | 1931-10-30 | 1934-05-12 | Mario Demarchi Dr | Injection syringe |
FR1001668A (en) * | 1946-06-17 | 1952-02-26 | Syringe for trunk anesthesia of the lower jaw | |
US2619962A (en) | 1948-02-19 | 1952-12-02 | Res Foundation | Vaccination appliance |
US4060073A (en) | 1976-03-19 | 1977-11-29 | Medi-Ray, Inc. | Syringe shield |
US4774948A (en) | 1986-11-24 | 1988-10-04 | Markham Charles W | Marking and retraction needle having retrievable stylet |
DE3642164A1 (en) | 1986-12-10 | 1988-06-23 | Basf Ag | METHOD FOR REMOVING ACID FROM CATHODIC ELECTRO-DIP LACQUER BATHS BY ELECTRODIALYSIS |
CA1283827C (en) | 1986-12-18 | 1991-05-07 | Giorgio Cirelli | Appliance for injection of liquid formulations |
US4955871A (en) | 1987-04-29 | 1990-09-11 | Path | Single-use disposable syringe |
US4790824A (en) | 1987-06-19 | 1988-12-13 | Bioject, Inc. | Non-invasive hypodermic injection device |
US4769003A (en) | 1987-08-19 | 1988-09-06 | Keith Stamler | Wound irrigation splashback shield |
US4978344A (en) | 1988-08-11 | 1990-12-18 | Dombrowski Mitchell P | Needle and catheter assembly |
CA2016734C (en) | 1989-06-02 | 1994-03-22 | Thomas J. Dragosits | Syringe assembly |
EP0423864A1 (en) | 1989-10-16 | 1991-04-24 | Duphar International Research B.V | Training device for an automatic injector |
EP0429842B1 (en) | 1989-10-27 | 1996-08-28 | Korea Research Institute Of Chemical Technology | Device for the transdermal administration of protein or peptide drug |
US5064413A (en) | 1989-11-09 | 1991-11-12 | Bioject, Inc. | Needleless hypodermic injection device |
US5697901A (en) | 1989-12-14 | 1997-12-16 | Elof Eriksson | Gene delivery by microneedle injection |
US5156591A (en) | 1990-12-13 | 1992-10-20 | S. I. Scientific Innovations Ltd. | Skin electrode construction and transdermal drug delivery device utilizing same |
TW279133B (en) | 1990-12-13 | 1996-06-21 | Elan Med Tech | |
US5540664A (en) | 1993-05-27 | 1996-07-30 | Washington Biotech Corporation | Reloadable automatic or manual emergency injection system |
US5830463A (en) * | 1993-07-07 | 1998-11-03 | University Technology Corporation | Yeast-based delivery vehicles |
CA2132277C (en) | 1993-10-22 | 2005-05-10 | Giorgio Cirelli | Injection device |
US5997501A (en) | 1993-11-18 | 1999-12-07 | Elan Corporation, Plc | Intradermal drug delivery device |
US5466220A (en) | 1994-03-08 | 1995-11-14 | Bioject, Inc. | Drug vial mixing and transfer device |
US5368578A (en) | 1994-03-10 | 1994-11-29 | Sterling Winthrop Inc. | Hypodermic syringe holder |
US5519931A (en) | 1994-03-16 | 1996-05-28 | Syncor International Corporation | Container and method for transporting a syringe containing radioactive material |
GB9412301D0 (en) | 1994-06-17 | 1994-08-10 | Safe T Ltd | Hollow-needle drugs etc applicators |
US5582591A (en) | 1994-09-02 | 1996-12-10 | Delab | Delivery of solid drug compositions |
US5582598A (en) | 1994-09-19 | 1996-12-10 | Becton Dickinson And Company | Medication delivery pen with variable increment dose scale |
IE72524B1 (en) | 1994-11-04 | 1997-04-23 | Elan Med Tech | Analyte-controlled liquid delivery device and analyte monitor |
AU696439B2 (en) | 1995-03-07 | 1998-09-10 | Eli Lilly And Company | Recyclable medication dispensing device |
DE19518810A1 (en) | 1995-05-26 | 1996-11-28 | Bayer Ag | Nasal applicator |
US5702717A (en) | 1995-10-25 | 1997-12-30 | Macromed, Inc. | Thermosensitive biodegradable polymers based on poly(ether-ester)block copolymers |
US5801057A (en) | 1996-03-22 | 1998-09-01 | Smart; Wilson H. | Microsampling device and method of construction |
US5993412A (en) | 1997-05-19 | 1999-11-30 | Bioject, Inc. | Injection apparatus |
DK1604685T3 (en) * | 1997-08-28 | 2012-06-18 | Cj Cheiljedang Corp | An attenuated Japanese encephalitis virus |
US7078500B1 (en) * | 1998-01-30 | 2006-07-18 | The General Hospital Corporation | Genetic immunization with nonstructural proteins of hepatitis C virus |
US5957895A (en) | 1998-02-20 | 1999-09-28 | Becton Dickinson And Company | Low-profile automatic injection device with self-emptying reservoir |
US6096010A (en) | 1998-02-20 | 2000-08-01 | Becton, Dickinson And Company | Repeat-dose medication delivery pen |
US6361524B1 (en) * | 1998-04-14 | 2002-03-26 | Becton, Dickinson And Company | Syringe assembly |
US6319230B1 (en) * | 1999-05-07 | 2001-11-20 | Scimed Life Systems, Inc. | Lateral needle injection apparatus and method |
US6623457B1 (en) * | 1999-09-22 | 2003-09-23 | Becton, Dickinson And Company | Method and apparatus for the transdermal administration of a substance |
US6494865B1 (en) * | 1999-10-14 | 2002-12-17 | Becton Dickinson And Company | Intradermal delivery device including a needle assembly |
GB0025577D0 (en) * | 2000-10-18 | 2000-12-06 | Smithkline Beecham Biolog | Vaccine |
US20040096463A1 (en) * | 2001-02-23 | 2004-05-20 | Nathalie Garcon | Novel vaccine |
EP2269639B1 (en) * | 2001-02-23 | 2018-11-28 | GlaxoSmithKline Biologicals s.a. | Influenza vaccine formulations for intradermal delivery |
WO2002083216A1 (en) * | 2001-04-13 | 2002-10-24 | Becton Dickinson And Company | Method of intradermally injecting substances |
GB2386072A (en) * | 2001-04-27 | 2003-09-10 | Becton Dickinson Co | Novel vaccine |
ES2329781T3 (en) * | 2002-02-04 | 2009-12-01 | Becton, Dickinson And Company | DEVICE AND METHOD TO SUPPLY OR REMOVE A SUBSTANCE THROUGH THE SKIN. |
-
2002
- 2002-07-01 US US10/185,717 patent/US20020198509A1/en not_active Abandoned
- 2002-07-01 CA CA002451816A patent/CA2451816A1/en not_active Abandoned
- 2002-07-01 WO PCT/US2002/020780 patent/WO2003002069A2/en active Application Filing
- 2002-07-01 JP JP2003508311A patent/JP2004531578A/en not_active Withdrawn
- 2002-07-01 CN CNB028128230A patent/CN1253220C/en not_active Expired - Fee Related
- 2002-07-01 BR BR0210628-0A patent/BR0210628A/en not_active IP Right Cessation
- 2002-07-01 EP EP02763212A patent/EP1416986A4/en not_active Withdrawn
- 2002-07-01 MX MXPA03011611A patent/MXPA03011611A/en not_active Application Discontinuation
-
2003
- 2003-10-02 US US10/679,038 patent/US7473247B2/en not_active Expired - Lifetime
Patent Citations (99)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US1274081A (en) * | 1917-05-10 | 1918-07-30 | Herman A Metz | Hypodermic needle. |
US2559474A (en) * | 1950-03-09 | 1951-07-03 | Sonco Inc | Hypodermic and spinal syringe |
US2876770A (en) * | 1955-10-10 | 1959-03-10 | Raymond A White | Shielded hypodermic syringe |
US3073306A (en) * | 1958-09-03 | 1963-01-15 | Linder Fritz | Hypodermic syringe |
US3400715A (en) * | 1966-01-04 | 1968-09-10 | Halvard J. Pederson | Attachment for injection apparatus |
US3964482A (en) * | 1971-05-17 | 1976-06-22 | Alza Corporation | Drug delivery device |
US3814097A (en) * | 1972-02-14 | 1974-06-04 | Ici Ltd | Dressing |
US3890971A (en) * | 1973-10-23 | 1975-06-24 | Thomas A Leeson | Safety syringe |
US4373526A (en) * | 1979-06-20 | 1983-02-15 | Lothar Kling | Device for injection syringe |
US4270537A (en) * | 1979-11-19 | 1981-06-02 | Romaine Richard A | Automatic hypodermic syringe |
US4468223A (en) * | 1981-08-06 | 1984-08-28 | Terumo Kabushiki Kaisha | Syringe |
US4592753A (en) * | 1982-12-13 | 1986-06-03 | Elan Corporation P.L.C. | Drug delivery device |
US4583978A (en) * | 1983-01-23 | 1986-04-22 | Michael Porat | Syringe |
US4596556A (en) * | 1985-03-25 | 1986-06-24 | Bioject, Inc. | Hypodermic injection apparatus |
US4826687A (en) * | 1985-06-06 | 1989-05-02 | National Institute Of Health | Influenza vaccine |
US5015235A (en) * | 1987-02-20 | 1991-05-14 | National Carpet Equipment, Inc. | Syringe needle combination |
US6056716A (en) * | 1987-06-08 | 2000-05-02 | D'antonio Consultants International Inc. | Hypodermic fluid dispenser |
US4940460A (en) * | 1987-06-19 | 1990-07-10 | Bioject, Inc. | Patient-fillable and non-invasive hypodermic injection device assembly |
US4941880A (en) * | 1987-06-19 | 1990-07-17 | Bioject, Inc. | Pre-filled ampule and non-invasive hypodermic injection device assembly |
US5003987A (en) * | 1987-09-11 | 1991-04-02 | Grinwald Paul M | Method and apparatus for enhanced drug permeation of skin |
US5195526A (en) * | 1988-03-11 | 1993-03-23 | Michelson Gary K | Spinal marker needle |
US5339163A (en) * | 1988-03-16 | 1994-08-16 | Canon Kabushiki Kaisha | Automatic exposure control device using plural image plane detection areas |
US4834704A (en) * | 1988-04-13 | 1989-05-30 | Eaton Corporation | Injectable infusion pump apparatus for implanting long-term dispensing module and medication in an animal and method therefor |
US4898588A (en) * | 1988-10-17 | 1990-02-06 | Roberts Christopher W | Hypodermic syringe splatter shield |
US5141496A (en) * | 1988-11-03 | 1992-08-25 | Tino Dalto | Spring impelled syringe guide with skin penetration depth adjustment |
US5503627A (en) * | 1989-11-09 | 1996-04-02 | Bioject, Inc. | Ampule for needleless injection |
US5312335A (en) * | 1989-11-09 | 1994-05-17 | Bioject Inc. | Needleless hypodermic injection device |
US5137516A (en) * | 1989-11-28 | 1992-08-11 | Glaxo Group Limited | Triggered application device for medicament to be more descriptive of the invention |
US6525030B1 (en) * | 1989-12-14 | 2003-02-25 | Applied Tissue Technologies, Llc | Gene delivery to periosteal cells by microneedle injection |
US5437647A (en) * | 1990-05-09 | 1995-08-01 | Safety Syringes, Inc. | Disposable self-shielding aspirating syringe |
US5098389A (en) * | 1990-06-28 | 1992-03-24 | Becton, Dickinson And Company | Hypodermic needle assembly |
US5190521A (en) * | 1990-08-22 | 1993-03-02 | Tecnol Medical Products, Inc. | Apparatus and method for raising a skin wheal and anesthetizing skin |
US5292506A (en) * | 1990-10-30 | 1994-03-08 | Daiichi Pharmaceutical Co., Ltd. | Muramyldipeptide derivatives and influenza vaccine comprising the derivatives |
US5527288A (en) * | 1990-12-13 | 1996-06-18 | Elan Medical Technologies Limited | Intradermal drug delivery device and method for intradermal delivery of drugs |
US5279544A (en) * | 1990-12-13 | 1994-01-18 | Sil Medics Ltd. | Transdermal or interdermal drug delivery devices |
US5331954A (en) * | 1990-12-21 | 1994-07-26 | Novo Nordisk A/S | Device for nasal delivery of liquid medications |
US5222949A (en) * | 1991-07-23 | 1993-06-29 | Intermed, Inc. | Flexible, noncollapsible catheter tube with hard and soft regions |
US5480381A (en) * | 1991-08-23 | 1996-01-02 | Weston Medical Limited | Needle-less injector |
US5417662A (en) * | 1991-09-13 | 1995-05-23 | Pharmacia Ab | Injection needle arrangement |
US5921963A (en) * | 1992-04-29 | 1999-07-13 | Mali-Tech Ltd. | Skin piercing devices for medical use |
US5431155A (en) * | 1992-06-03 | 1995-07-11 | Elettro Plastica S.P.A. | Single-dose nasal dispenser for atomized liquid drugs |
US5383851A (en) * | 1992-07-24 | 1995-01-24 | Bioject Inc. | Needleless hypodermic injection device |
US5520639A (en) * | 1992-07-24 | 1996-05-28 | Bioject, Inc. | Needleless hypodermic injection methods and device |
US5704911A (en) * | 1992-09-28 | 1998-01-06 | Equidyne Systems, Inc. | Needleless hypodermic jet injector |
US5334144A (en) * | 1992-10-30 | 1994-08-02 | Becton, Dickinson And Company | Single use disposable needleless injector |
US5279552A (en) * | 1993-01-11 | 1994-01-18 | Anton Magnet | Intradermal injection device |
US5779677A (en) * | 1994-01-17 | 1998-07-14 | Laboratoire Aguettant | Automatic drug injector |
US5514107A (en) * | 1994-02-10 | 1996-05-07 | Habley Medical Technology Corporation | Safety syringe adapter for cartridge-needle unit |
US5649912A (en) * | 1994-03-07 | 1997-07-22 | Bioject, Inc. | Ampule filling device |
US5879327A (en) * | 1994-04-06 | 1999-03-09 | Moreau Defarges Alain | Needleless jet injection device |
US5591139A (en) * | 1994-06-06 | 1997-01-07 | The Regents Of The University Of California | IC-processed microneedles |
US5496286A (en) * | 1994-08-17 | 1996-03-05 | Sterling Winthrop | Hypodermic syringe holder with disposable body |
US5912000A (en) * | 1994-09-23 | 1999-06-15 | Zonagen, Inc. | Chitosan induced immunopotentiation |
US5891085A (en) * | 1995-01-09 | 1999-04-06 | Medi-Ject Corporation | Nozzle assembly with lost motion connection for medical injector assembly |
US5599302A (en) * | 1995-01-09 | 1997-02-04 | Medi-Ject Corporation | Medical injection system and method, gas spring thereof and launching device using gas spring |
US6090077A (en) * | 1995-05-11 | 2000-07-18 | Shaw; Thomas J. | Syringe plunger assembly and barrel |
US5879326A (en) * | 1995-05-22 | 1999-03-09 | Godshall; Ned Allen | Method and apparatus for disruption of the epidermis |
US6213977B1 (en) * | 1995-06-22 | 2001-04-10 | Pharmacia Ab | Limited depth penetration needle housing |
US5873856A (en) * | 1995-06-22 | 1999-02-23 | Pharmacia Ab | Limited depth penetration needle housing |
US6083197A (en) * | 1995-12-19 | 2000-07-04 | Umbaugh; Jerald C. | Spring-actuated needleless injector |
US5893397A (en) * | 1996-01-12 | 1999-04-13 | Bioject Inc. | Medication vial/syringe liquid-transfer apparatus |
US6346095B1 (en) * | 1996-06-10 | 2002-02-12 | Elan Corporation, Plc | Needle and method for delivery of fluids |
US6090080A (en) * | 1996-07-05 | 2000-07-18 | Disetronic Licensing Ag | Injection device for injection of liquid |
US5861174A (en) * | 1996-07-12 | 1999-01-19 | University Technology Corporation | Temperature sensitive gel for sustained delivery of protein drugs |
US5876582A (en) * | 1997-01-27 | 1999-03-02 | The University Of Utah Research Foundation | Methods for preparing devices having metallic hollow microchannels on planar substrate surfaces |
US5928207A (en) * | 1997-06-30 | 1999-07-27 | The Regents Of The University Of California | Microneedle with isotropically etched tip, and method of fabricating such a device |
US6053893A (en) * | 1997-09-12 | 2000-04-25 | Disetronic Licensing Ag | Device for the dosed release of an injectable product |
US5944700A (en) * | 1997-09-26 | 1999-08-31 | Becton, Dickinson And Company | Adjustable injection length pen needle |
US6099504A (en) * | 1997-10-22 | 2000-08-08 | Elan Corporation, Plc | Pre-filled injection delivery device |
US6534065B1 (en) * | 1997-11-28 | 2003-03-18 | West Pharmaceutical Services Drug Delivery & Clinical Research Centre Limited | Influenza vaccine composition with chitosan adjuvant |
US6210369B1 (en) * | 1997-12-16 | 2001-04-03 | Meridian Medical Technologies Inc. | Automatic injector |
US6200291B1 (en) * | 1998-01-08 | 2001-03-13 | Antonio Di Pietro | Device for controlling the penetration depth of a needle, for application to an injection syringe |
US6090082A (en) * | 1998-02-23 | 2000-07-18 | Becton, Dickinson And Company | Vial retainer interface to a medication delivery pen |
US6334856B1 (en) * | 1998-06-10 | 2002-01-01 | Georgia Tech Research Corporation | Microneedle devices and methods of manufacture and use thereof |
US6503231B1 (en) * | 1998-06-10 | 2003-01-07 | Georgia Tech Research Corporation | Microneedle device for transport of molecules across tissue |
US6372223B1 (en) * | 1998-09-15 | 2002-04-16 | Baxter Aktiengesellschaft | Influenza virus vaccine composition |
US6093170A (en) * | 1999-01-28 | 2000-07-25 | Hsu; Kuo-Chi | Structure safety syringe |
US6036675A (en) * | 1999-02-03 | 2000-03-14 | Specialized Health Products, Inc. | Safety sterile cartride unit apparatus and methods |
US20050096330A1 (en) * | 1999-07-22 | 2005-05-05 | Henning Boettcher | N-(indolecarbonyl) piperazine derivatives |
US6569143B2 (en) * | 1999-10-14 | 2003-05-27 | Becton, Dickinson And Company | Method of intradermally injecting substances |
US20020095134A1 (en) * | 1999-10-14 | 2002-07-18 | Pettis Ronald J. | Method for altering drug pharmacokinetics based on medical delivery platform |
US20040131641A1 (en) * | 1999-10-14 | 2004-07-08 | Mikszta John A. | Intradermal delivery of vaccines and gene therapeutic agents via microcannula |
US6569123B2 (en) * | 1999-10-14 | 2003-05-27 | Becton, Dickinson And Company | Prefillable intradermal injector |
US6689118B2 (en) * | 1999-10-14 | 2004-02-10 | Becton Dickinson And Company | Method of intradermally injecting substances |
US6776776B2 (en) * | 1999-10-14 | 2004-08-17 | Becton, Dickinson And Company | Prefillable intradermal delivery device |
US6537242B1 (en) * | 2000-06-06 | 2003-03-25 | Becton, Dickinson And Company | Method and apparatus for enhancing penetration of a member for the intradermal sampling or administration of a substance |
US20020025326A1 (en) * | 2000-06-22 | 2002-02-28 | Blonder Joan P. | Delivery vehicle composition and methods for delivering antigens and other drugs |
US20050008683A1 (en) * | 2000-06-29 | 2005-01-13 | Becton Dickinson And Company | Method for delivering interferons to the intradermal compartment |
US20040073160A1 (en) * | 2000-06-29 | 2004-04-15 | Pinkerton Thomas C. | Intradermal delivery of substances |
US20050181033A1 (en) * | 2000-06-29 | 2005-08-18 | Dekker John P.Iii | Method for delivering interferons to the intradermal compartment |
US20040028707A1 (en) * | 2001-06-29 | 2004-02-12 | Pinkerton Thomas C. | Enhanced pharmacokinetic profile of intradermally delivered substances |
US20030073609A1 (en) * | 2001-06-29 | 2003-04-17 | Pinkerton Thomas C. | Enhanced pharmacokinetic profile of intradermally delivered substances |
US20040120964A1 (en) * | 2001-10-29 | 2004-06-24 | Mikszta John A. | Needleless vaccination using chimeric yellow fever vaccine-vectored vaccines against heterologous flaviviruses |
US20030093040A1 (en) * | 2001-10-29 | 2003-05-15 | Mikszta John A. | Method and device for the delivery of a substance |
US20050096331A1 (en) * | 2001-12-21 | 2005-05-05 | Das Saibal K. | Novel compounds and their use in medicine process for their preparation and pharmaceutical compositions containing them |
US20040082934A1 (en) * | 2002-08-30 | 2004-04-29 | Pettis Ronald J. | Method of controlling pharmacokinetics of immunomodulatory compounds |
US20050123550A1 (en) * | 2003-05-12 | 2005-06-09 | Laurent Philippe E. | Molecules enhancing dermal delivery of influenza vaccines |
US20050180952A1 (en) * | 2003-08-26 | 2005-08-18 | Pettis Ronald J. | Methods for intradermal delivery of therapeutics agents |
US20050096332A1 (en) * | 2003-10-30 | 2005-05-05 | Boehringer Ingelheim International Gmbh | Use of tyrosine kinase inhibitors for the treatment of inflammatory processes |
Cited By (62)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US20040096463A1 (en) * | 2001-02-23 | 2004-05-20 | Nathalie Garcon | Novel vaccine |
US8557251B2 (en) | 2001-02-23 | 2013-10-15 | Glaxosmithkline Biologicals, Sa | Non-live trivalent influenza vaccine for one-dose intradermal delivery |
US20070237788A1 (en) * | 2001-02-23 | 2007-10-11 | Nathalie Garcon | Non-live trivalent influenza vaccine for one-dose intradermal delivery |
US20060058736A1 (en) * | 2001-04-27 | 2006-03-16 | Alchas Paul G | Novel vaccine |
US20040028707A1 (en) * | 2001-06-29 | 2004-02-12 | Pinkerton Thomas C. | Enhanced pharmacokinetic profile of intradermally delivered substances |
US7556615B2 (en) | 2001-09-12 | 2009-07-07 | Becton, Dickinson And Company | Microneedle-based pen device for drug delivery and method for using same |
US8900186B2 (en) | 2001-09-12 | 2014-12-02 | Becton, Dickinson And Company | Microneedle-based pen device for drug delivery and method for using same |
US20090157041A1 (en) * | 2001-09-12 | 2009-06-18 | Pettis Ronald J | Microneedel-based pen device for drug delivery and method for using same |
US10661066B2 (en) | 2001-09-12 | 2020-05-26 | Becton, Dickinson And Company | Microneedle-based pen device for drug delivery and method for using same |
US8900194B2 (en) | 2002-07-19 | 2014-12-02 | 3M Innovative Properties Company | Microneedle devices and microneedle delivery apparatus |
EP1592443A1 (en) * | 2003-02-13 | 2005-11-09 | Becton, Dickinson and Company | Improved anthrax vaccines and delivery methods |
US20070154494A1 (en) * | 2003-02-13 | 2007-07-05 | Becton Dickinson And Company | Anthrax vaccines and delivery methods |
EP1592443A4 (en) * | 2003-02-13 | 2007-02-21 | Becton Dickinson Co | Improved anthrax vaccines and delivery methods |
US8961477B2 (en) | 2003-08-25 | 2015-02-24 | 3M Innovative Properties Company | Delivery of immune response modifier compounds |
US20050123565A1 (en) * | 2003-10-31 | 2005-06-09 | Janardhanan Subramony | System and method for transdermal vaccine delivery |
US20070083151A1 (en) * | 2003-12-29 | 2007-04-12 | Carter Chad J | Medical devices and kits including same |
US20070191761A1 (en) * | 2004-02-23 | 2007-08-16 | 3M Innovative Properties Company | Method of molding for microneedle arrays |
US20050220854A1 (en) * | 2004-04-01 | 2005-10-06 | Yuh-Fun Maa | Apparatus and method for transdermal delivery of influenza vaccine |
US20050271684A1 (en) * | 2004-04-13 | 2005-12-08 | Trautman Joseph C | Apparatus and method for transdermal delivery of multiple vaccines |
US20080102192A1 (en) * | 2004-11-18 | 2008-05-01 | Johnson Peter R | Masking Method for Coating a Microneedle Array |
US8758298B2 (en) | 2004-11-18 | 2014-06-24 | 3M Innovative Properties Company | Low-profile microneedle array applicator |
US8741377B2 (en) | 2004-11-18 | 2014-06-03 | 3M Innovative Properties Company | Method of contact coating a microneedle array |
US8057842B2 (en) | 2004-11-18 | 2011-11-15 | 3M Innovative Properties Company | Method of contact coating a microneedle array |
US9174035B2 (en) | 2004-11-18 | 2015-11-03 | 3M Innovative Properties Company | Microneedle array applicator and retainer |
US8414959B2 (en) | 2004-11-18 | 2013-04-09 | 3M Innovative Properties Company | Method of contact coating a microneedle array |
US8267889B2 (en) | 2004-11-18 | 2012-09-18 | 3M Innovative Properties Company | Low-profile microneedle array applicator |
US7846488B2 (en) | 2004-11-18 | 2010-12-07 | 3M Innovative Properties Company | Masking method for coating a microneedle array |
US8088321B2 (en) | 2004-12-07 | 2012-01-03 | 3M Innovative Properties Company | Method of molding a microneedle |
US8821779B2 (en) | 2004-12-07 | 2014-09-02 | 3M Innovative Properties Company | Method of molding a microneedle |
US8246893B2 (en) | 2004-12-07 | 2012-08-21 | 3M Innovative Properties Company | Method of molding a microneedle |
US20080088066A1 (en) * | 2004-12-07 | 2008-04-17 | Ferguson Dennis E | Method Of Molding A Microneedle |
US10035008B2 (en) | 2005-04-07 | 2018-07-31 | 3M Innovative Properties Company | System and method for tool feedback sensing |
US20070088414A1 (en) * | 2005-05-25 | 2007-04-19 | Campbell Robert L | Particulate formulations for intradermal delivery of biologically active agents |
US10315021B2 (en) | 2005-06-24 | 2019-06-11 | 3M Innovative Properties Company | Collapsible patch and method of application |
US10307578B2 (en) | 2005-06-27 | 2019-06-04 | 3M Innovative Properties Company | Microneedle cartridge assembly and method of applying |
US8784363B2 (en) | 2005-06-27 | 2014-07-22 | 3M Innovative Properties Company | Microneedle array applicator device and method of array application |
US20100256568A1 (en) * | 2005-06-27 | 2010-10-07 | Frederickson Franklyn L | Microneedle cartridge assembly and method of applying |
US9789249B2 (en) | 2005-06-27 | 2017-10-17 | 3M Innovative Properties Company | Microneedle array applicator device and method of array application |
US20100222743A1 (en) * | 2005-06-27 | 2010-09-02 | Frederickson Franklyn L | Microneedle array applicator device and method of array application |
US20080294116A1 (en) * | 2005-11-18 | 2008-11-27 | Wolter James T | Coatable Compositions, Coatings Derived Therefrom and Microarrays Having Such Coatings |
US20080262416A1 (en) * | 2005-11-18 | 2008-10-23 | Duan Daniel C | Microneedle Arrays and Methods of Preparing Same |
US8900180B2 (en) | 2005-11-18 | 2014-12-02 | 3M Innovative Properties Company | Coatable compositions, coatings derived therefrom and microarrays having such coatings |
US9452257B2 (en) | 2005-11-21 | 2016-09-27 | Becton, Dickinson And Company | Intradermal delivery device |
US7842008B2 (en) | 2005-11-21 | 2010-11-30 | Becton, Dickinson And Company | Intradermal delivery device |
US20070118077A1 (en) * | 2005-11-21 | 2007-05-24 | Becton, Dickinson And Company | Intradermal delivery device |
US9119945B2 (en) | 2006-04-20 | 2015-09-01 | 3M Innovative Properties Company | Device for applying a microneedle array |
US20080226729A1 (en) * | 2006-09-08 | 2008-09-18 | Becton, Dickinson And Company | Stable powder formulations of alum-adsorbed vaccines |
US20110159047A1 (en) * | 2006-09-08 | 2011-06-30 | Becton, Dickinson And Company | Stable powder formulations of alum-adsorbed vaccines |
US20090012494A1 (en) * | 2006-10-17 | 2009-01-08 | Nanopass Technologies Ltd. | Intradermal delivery of biological agents |
US11744927B2 (en) | 2009-10-23 | 2023-09-05 | University of Pittsburgh—of the Commonwealth System of Higher Education | Dissolvable microneedle arrays for transdermal delivery to human skin |
US9199034B2 (en) | 2009-11-09 | 2015-12-01 | Becton, Dickinson And Company | Drug delivery devices, systems, and methods |
US20110112508A1 (en) * | 2009-11-09 | 2011-05-12 | David Panzirer | Drug Delivery Devices, Systems, and Methods |
US9962484B2 (en) | 2009-11-09 | 2018-05-08 | Becton, Dickinson And Company | Drug delivery devices, systems, and methods |
JP2015515886A (en) * | 2012-05-01 | 2015-06-04 | ユニバーシティ オブ ピッツバーグ − オブ ザ コモンウェルス システム オブ ハイヤー エデュケイション | Tip-loaded microneedle array for percutaneous insertion |
US9944019B2 (en) | 2012-05-01 | 2018-04-17 | University of Pittsburgh—of the Commonwealth System of Higher Education | Tip-loaded microneedle arrays for transdermal insertion |
US10322264B2 (en) * | 2014-01-31 | 2019-06-18 | United Arab Emirates University | Systems and methods for using a microcannula introducer for skin and soft tissue augmentation |
US20150217089A1 (en) * | 2014-01-31 | 2015-08-06 | Gary Chuang | Systems and methods for using a microcannula introducer for skin & soft tissue augmentation |
US10441768B2 (en) | 2015-03-18 | 2019-10-15 | University of Pittsburgh—of the Commonwealth System of Higher Education | Bioactive components conjugated to substrates of microneedle arrays |
US10737083B2 (en) | 2015-03-18 | 2020-08-11 | University of Pittsburgh—of the Commonwealth System of Higher Education | Bioactive components conjugated to dissolvable substrates of microneedle arrays |
US11672964B2 (en) | 2015-03-18 | 2023-06-13 | University of Pittsburgh—of the Commonwealth System of Higher Education | Bioactive components conjugated to substrates of microneedle arrays |
US11684763B2 (en) | 2015-10-16 | 2023-06-27 | University of Pittsburgh—of the Commonwealth System of Higher Education | Multi-component bio-active drug delivery and controlled release to the skin by microneedle array devices |
US11744889B2 (en) | 2016-01-05 | 2023-09-05 | University of Pittsburgh—of the Commonwealth System of Higher Education | Skin microenvironment targeted delivery for promoting immune and other responses |
Also Published As
Publication number | Publication date |
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BR0210628A (en) | 2004-08-10 |
CN1253220C (en) | 2006-04-26 |
CN1520318A (en) | 2004-08-11 |
WO2003002069A3 (en) | 2003-08-14 |
EP1416986A2 (en) | 2004-05-12 |
US7473247B2 (en) | 2009-01-06 |
EP1416986A4 (en) | 2005-12-14 |
CA2451816A1 (en) | 2003-01-09 |
JP2004531578A (en) | 2004-10-14 |
US20040131641A1 (en) | 2004-07-08 |
WO2003002069A2 (en) | 2003-01-09 |
MXPA03011611A (en) | 2004-07-01 |
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