US20020198509A1 - Intradermal delivery of vaccines and gene therapeutic agents via microcannula - Google Patents

Intradermal delivery of vaccines and gene therapeutic agents via microcannula Download PDF

Info

Publication number
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
Authority
US
United States
Prior art keywords
vaccine
skin
delivery
microneedle
mammal
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Abandoned
Application number
US10/185,717
Inventor
John Mikszta
Jason Alarcon
Paul Alchas
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Becton Dickinson and Co
Original Assignee
Becton Dickinson and Co
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Priority claimed from US09/417,671 external-priority patent/US6494865B1/en
Priority claimed from US09/834,438 external-priority patent/US6843781B2/en
Priority claimed from US09/835,243 external-priority patent/US6569143B2/en
Priority claimed from US10/044,504 external-priority patent/US20020193740A1/en
Application filed by Becton Dickinson and Co filed Critical Becton Dickinson and Co
Priority to US10/185,717 priority Critical patent/US20020198509A1/en
Assigned to BECTON, DICKINSON AND COMPANY reassignment BECTON, DICKINSON AND COMPANY ASSIGNMENT OF ASSIGNORS INTEREST (SEE DOCUMENT FOR DETAILS). Assignors: ALCHAS, PAUL G., ALARCON, JASON B., MIKSZTA, JOHN A.
Publication of US20020198509A1 publication Critical patent/US20020198509A1/en
Priority to US10/679,038 priority patent/US7473247B2/en
Priority to US11/118,916 priority patent/US20060018877A1/en
Abandoned legal-status Critical Current

Links

Images

Classifications

    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61MDEVICES FOR INTRODUCING MEDIA INTO, OR ONTO, THE BODY; DEVICES FOR TRANSDUCING BODY MEDIA OR FOR TAKING MEDIA FROM THE BODY; DEVICES FOR PRODUCING OR ENDING SLEEP OR STUPOR
    • A61M5/00Devices for bringing media into the body in a subcutaneous, intra-vascular or intramuscular way; Accessories therefor, e.g. filling or cleaning devices, arm-rests
    • A61M5/14Infusion devices, e.g. infusing by gravity; Blood infusion; Accessories therefor
    • A61M5/158Needles for infusions; Accessories therefor, e.g. for inserting infusion needles, or for holding them on the body
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K39/00Medicinal preparations containing antigens or antibodies
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K39/00Medicinal preparations containing antigens or antibodies
    • A61K39/12Viral antigens
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K39/00Medicinal preparations containing antigens or antibodies
    • A61K39/12Viral antigens
    • A61K39/145Orthomyxoviridae, e.g. influenza virus
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61MDEVICES FOR INTRODUCING MEDIA INTO, OR ONTO, THE BODY; DEVICES FOR TRANSDUCING BODY MEDIA OR FOR TAKING MEDIA FROM THE BODY; DEVICES FOR PRODUCING OR ENDING SLEEP OR STUPOR
    • A61M37/00Other apparatus for introducing media into the body; Percutany, i.e. introducing medicines into the body by diffusion through the skin
    • A61M37/0015Other apparatus for introducing media into the body; Percutany, i.e. introducing medicines into the body by diffusion through the skin by using microneedles
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61PSPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/04Antibacterial agents
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61PSPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/12Antivirals
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61PSPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/12Antivirals
    • A61P31/14Antivirals for RNA viruses
    • A61P31/16Antivirals for RNA viruses for influenza or rhinoviruses
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61PSPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00Drugs for immunological or allergic disorders
    • A61P37/02Immunomodulators
    • A61P37/06Immunosuppressants, e.g. drugs for graft rejection
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61BDIAGNOSIS; SURGERY; IDENTIFICATION
    • A61B17/00Surgical instruments, devices or methods, e.g. tourniquets
    • A61B17/20Surgical instruments, devices or methods, e.g. tourniquets for vaccinating or cleaning the skin previous to the vaccination
    • A61B17/205Vaccinating by means of needles or other puncturing devices
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61DVETERINARY INSTRUMENTS, IMPLEMENTS, TOOLS, OR METHODS
    • A61D7/00Devices or methods for introducing solid, liquid, or gaseous remedies or other materials into or onto the bodies of animals
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K39/00Medicinal preparations containing antigens or antibodies
    • A61K2039/51Medicinal preparations containing antigens or antibodies comprising whole cells, viruses or DNA/RNA
    • A61K2039/525Virus
    • A61K2039/5252Virus inactivated (killed)
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K39/00Medicinal preparations containing antigens or antibodies
    • A61K2039/51Medicinal preparations containing antigens or antibodies comprising whole cells, viruses or DNA/RNA
    • A61K2039/53DNA (RNA) vaccination
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K39/00Medicinal preparations containing antigens or antibodies
    • A61K2039/54Medicinal preparations containing antigens or antibodies characterised by the route of administration
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K39/00Medicinal preparations containing antigens or antibodies
    • A61K2039/545Medicinal preparations containing antigens or antibodies characterised by the dose, timing or administration schedule
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K39/00Medicinal preparations containing antigens or antibodies
    • A61K2039/555Medicinal preparations containing antigens or antibodies characterised by a specific combination antigen/adjuvant
    • A61K2039/55511Organic adjuvants
    • A61K2039/55566Emulsions, e.g. Freund's adjuvant, MF59
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K39/00Medicinal preparations containing antigens or antibodies
    • A61K2039/555Medicinal preparations containing antigens or antibodies characterised by a specific combination antigen/adjuvant
    • A61K2039/55511Organic adjuvants
    • A61K2039/55572Lipopolysaccharides; Lipid A; Monophosphoryl lipid A
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61MDEVICES FOR INTRODUCING MEDIA INTO, OR ONTO, THE BODY; DEVICES FOR TRANSDUCING BODY MEDIA OR FOR TAKING MEDIA FROM THE BODY; DEVICES FOR PRODUCING OR ENDING SLEEP OR STUPOR
    • A61M37/00Other apparatus for introducing media into the body; Percutany, i.e. introducing medicines into the body by diffusion through the skin
    • A61M37/0015Other apparatus for introducing media into the body; Percutany, i.e. introducing medicines into the body by diffusion through the skin by using microneedles
    • A61M2037/0061Methods for using microneedles
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61MDEVICES FOR INTRODUCING MEDIA INTO, OR ONTO, THE BODY; DEVICES FOR TRANSDUCING BODY MEDIA OR FOR TAKING MEDIA FROM THE BODY; DEVICES FOR PRODUCING OR ENDING SLEEP OR STUPOR
    • A61M2202/00Special media to be introduced, removed or treated
    • A61M2202/04Liquids
    • A61M2202/0413Blood
    • A61M2202/0445Proteins
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61MDEVICES FOR INTRODUCING MEDIA INTO, OR ONTO, THE BODY; DEVICES FOR TRANSDUCING BODY MEDIA OR FOR TAKING MEDIA FROM THE BODY; DEVICES FOR PRODUCING OR ENDING SLEEP OR STUPOR
    • A61M37/00Other apparatus for introducing media into the body; Percutany, i.e. introducing medicines into the body by diffusion through the skin
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61MDEVICES FOR INTRODUCING MEDIA INTO, OR ONTO, THE BODY; DEVICES FOR TRANSDUCING BODY MEDIA OR FOR TAKING MEDIA FROM THE BODY; DEVICES FOR PRODUCING OR ENDING SLEEP OR STUPOR
    • A61M5/00Devices for bringing media into the body in a subcutaneous, intra-vascular or intramuscular way; Accessories therefor, e.g. filling or cleaning devices, arm-rests
    • A61M5/46Devices for bringing media into the body in a subcutaneous, intra-vascular or intramuscular way; Accessories therefor, e.g. filling or cleaning devices, arm-rests having means for controlling depth of insertion
    • CCHEMISTRY; METALLURGY
    • C12BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12NMICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
    • C12N2760/00MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA ssRNA viruses negative-sense
    • C12N2760/00011Details
    • C12N2760/16011Orthomyxoviridae
    • C12N2760/16111Influenzavirus A, i.e. influenza A virus
    • C12N2760/16134Use of virus or viral component as vaccine, e.g. live-attenuated or inactivated virus, VLP, viral protein
    • YGENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y02TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
    • Y02ATECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE
    • Y02A50/00TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE in human health protection, e.g. against extreme weather
    • Y02A50/30Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change

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.[0001]
  • BACKGROUND OF THE INVENTION
  • 1. Field of the Invention [0002]
  • The present invention relates to methods and devices for administration of vaccines and gene therapeutic agents into the intradermal layer of skin. [0003]
  • 2. Background Information [0004]
  • 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. [0005]
  • 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. [0006]
  • 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, see [0007] 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 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. [0008]
  • 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, [0009] 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. [0010]
  • 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. [0011]
  • 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. [0012]
  • 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. [0013]
  • Virtually all of the human vaccines currently on the market are administered via the IM or SC routes. Of the [0014] 32 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. [0015]
  • SUMMARY OF THE INVENTION
  • 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. [0016]
  • 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. [0017]
  • 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. [0018]
  • 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 [0019]
  • 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. [0020]
  • 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. [0021]
  • 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. [0022]
  • 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.[0023]
  • BRIEF DESCRIPTION OF THE DRAWINGS
  • 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. [0024]
  • 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. [0025]
  • 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. [0026]
  • 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. [0027]
  • 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. [0028]
  • 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. [0029]
  • 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. [0030]
  • 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. [0031]
  • 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. [0032]
  • 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. [0033]
  • 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. [0034]
  • DETAILED DESCRIPTION OF THE INVENTION
  • 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. [0035]
  • 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). [0036]
  • 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. [0037]
  • 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 about [0038] 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.
  • 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. [0039]
  • 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. [0040]
  • 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. [0041]
  • 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. [0042]
  • 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. [0043]
  • 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. [0044]
  • 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. [0045]
  • 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. [0046]
  • 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. [0047]
  • 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 [0048] 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 about [0049] 250 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. [0050]
  • 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. [0051]
  • 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. [0052]
  • 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. [0053]
  • 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,[0054] 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. [0055]
  • 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. [0056]
  • 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. [0057]
  • 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. [0058]
  • 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. [0059]
  • 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. [0060]
  • In a particularly preferred embodiment, the kit of the invention comprises a hub portion being attachable to the prefillable reservoir storing the vaccine; [0061]
  • at least one microneedle supported by said hub portion and having a forward tip extending away from said hub portion; and [0062]
  • 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. [0063]
  • 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. [0064]
  • 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. [0065]
  • 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 [0066] EP 1 092 444 A1 was also used in some Examples.
  • EXAMPLE 1 ID Delivery and Expression of Model Genetic Therapeutic/prophylactic Agents, Guinea Pig Model.
  • 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). [0067]
  • 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. [0068]
  • EXAMPLE 2 ID Delivery and Expression of Model Genetic Therapeutic/prophylactic Agents, Rat Model.
  • 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. [0069]
  • 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. [0070]
  • EXAMPLE 3 ID Delivery and Expression of Model Genetic Therapeutic/prophylactic Agents, Pig Model.
  • 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. [0071]
  • 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. [0072]
  • 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. [0073]
  • 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. [0074]
  • 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. [0075]
  • EXAMPLE 4 Indirect Measurement of Localized Tissue Damage Following ID Delivery
  • 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. [0076]
  • 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. [0077]
  • EXAMPLE 5 Induction of Immune Response to Influenza DNA Vaccine Following ID Delivery in Rats
  • 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 ([0078] days 0, 21 and 42) with plasmid DNA in PBS solution (50 μg per rat in 50 μl volume delivered by rapid bolus injection) ID using the MDD device as described in Example 2 or IM into the quadriceps using a conventional 30G needle and 1cc syringe. As a negative control, DNA was applied topically to untreated skin. Sera were collected at weeks 3, 5, 8 and 11 and analyzed for the presence of influenza-specific antibodies by ELISA. Briefly, microtiter wells (Nalge Nunc, Rochester, N.Y.) were coated with 0.1 μg of whole inactivated influenza virus (A/PR/8/34; Charles River SPAFAS, North Franklin, Conn.) overnight at 4° C. After blocking for 1hr at 37° C. in PBS plus 5% skim milk, plates were incubated with serial dilutions of test sera for 1 hr at 37° C. Plates were then washed and further incubated with horse radish peroxidase conjugated anti-rat IgG, H+L chain (Southern Biotech, Birmingham, Ala.) for 30 min at 37° C. and were then developed using TMB substrate (Sigma, St. Louis, Mo.). Absorbance measurements (A450) were read on a Tecan Sunrise™ plate reader (Tecan, RTP, NC).
  • 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. [0079]
  • 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 [0080] 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.
  • EXAMPLE 6 Induction of Immune Response to Influenza DNA/virus “Prime-boost” Following ID Delivery in Rats
  • 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 [0081] 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 at weeks 13 and 17 by ELISA as described above. Both ID delivery and IM injection induced a potent booster effect (FIG. 7). 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 [0082] 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 at weeks 13 and 17 by ELISA as described above. Both ID delivery and IM injection induced a potent booster effect (FIG. 8). Mean titers in the ID delivery group were greater than via IM injection following the virus boost; at 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.
  • EXAMPLE 7 Induction of Immune Response to Influenza Virus Vaccine Following ID Delivery in Rats
  • 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 ([0083] days 0, 21 and 42); serum was collected and analyzed for influenza-specific antibodies by ELISA as above on days 21, 35 and 56; n=4 rats per group.
  • 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. [0084]
  • EXAMPLE 8 Induction of Immune Response to Influenza Vaccine Following ID Delivery Via in Pigs
  • 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 [0085] 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.
  • 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. [0086]
  • EXAMPLE 9 In Delivery of Lower Doses of Influenza Vaccine
  • 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. [0087]
  • 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 ([0088] days 0, 21 and 42) and were analyzed for serum anti-influenza antibodies at days 21, 35 and 56 (n=4 rats per group). Data shown in FIG. 11 reflect titers at day 56, although similar trends were observed at day 21 and day 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. [0089]
  • 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. [0090]
  • 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. [0091]
  • 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. [0092]
  • 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. [0093]
  • 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. [0094]
  • 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. [0095]
  • 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. [0096]

Claims (60)

What is claimed is:
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.
US10/185,717 1999-10-14 2002-07-01 Intradermal delivery of vaccines and gene therapeutic agents via microcannula Abandoned US20020198509A1 (en)

Priority Applications (3)

Application Number Priority Date Filing Date Title
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
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

Related Parent Applications (1)

Application Number Title Priority Date Filing Date
US10/044,504 Continuation-In-Part US20020193740A1 (en) 1999-10-14 2002-01-10 Method of intradermally injecting substances

Related Child Applications (1)

Application Number Title Priority Date Filing Date
US10/679,038 Continuation-In-Part US7473247B2 (en) 1999-10-14 2003-10-02 Intradermal delivery of vaccines and gene therapeutic agents via microcannula

Publications (1)

Publication Number Publication Date
US20020198509A1 true US20020198509A1 (en) 2002-12-26

Family

ID=26721644

Family Applications (2)

Application Number Title Priority Date Filing Date
US10/185,717 Abandoned US20020198509A1 (en) 1999-10-14 2002-07-01 Intradermal delivery of vaccines and gene therapeutic agents via microcannula
US10/679,038 Expired - Lifetime US7473247B2 (en) 1999-10-14 2003-10-02 Intradermal delivery of vaccines and gene therapeutic agents via microcannula

Family Applications After (1)

Application Number Title Priority Date Filing Date
US10/679,038 Expired - Lifetime US7473247B2 (en) 1999-10-14 2003-10-02 Intradermal delivery of vaccines and gene therapeutic agents via microcannula

Country Status (8)

Country Link
US (2) US20020198509A1 (en)
EP (1) EP1416986A4 (en)
JP (1) JP2004531578A (en)
CN (1) CN1253220C (en)
BR (1) BR0210628A (en)
CA (1) CA2451816A1 (en)
MX (1) MXPA03011611A (en)
WO (1) WO2003002069A2 (en)

Cited By (37)

* Cited by examiner, † Cited by third party
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
EP1592443A1 (en) * 2003-02-13 2005-11-09 Becton, Dickinson and Company Improved anthrax vaccines and delivery methods
US20050271684A1 (en) * 2004-04-13 2005-12-08 Trautman Joseph C Apparatus and method for transdermal delivery of multiple vaccines
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
US20090157041A1 (en) * 2001-09-12 2009-06-18 Pettis Ronald J Microneedel-based pen device for drug delivery and method for using same
US20100222743A1 (en) * 2005-06-27 2010-09-02 Frederickson Franklyn L 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
US20110112508A1 (en) * 2009-11-09 2011-05-12 David Panzirer Drug Delivery Devices, Systems, and Methods
US8057842B2 (en) 2004-11-18 2011-11-15 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
US8414959B2 (en) 2004-11-18 2013-04-09 3M Innovative Properties Company Method of contact coating a microneedle array
US8900194B2 (en) 2002-07-19 2014-12-02 3M Innovative Properties Company Microneedle devices and microneedle delivery apparatus
US8961477B2 (en) 2003-08-25 2015-02-24 3M Innovative Properties Company Delivery of immune response modifier compounds
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
US20150217089A1 (en) * 2014-01-31 2015-08-06 Gary Chuang Systems and methods for using a microcannula introducer for skin & soft tissue augmentation
US9119945B2 (en) 2006-04-20 2015-09-01 3M Innovative Properties Company Device for applying a microneedle array
US9174035B2 (en) 2004-11-18 2015-11-03 3M Innovative Properties Company Microneedle array applicator and retainer
US10035008B2 (en) 2005-04-07 2018-07-31 3M Innovative Properties Company System and method for tool feedback sensing
US10315021B2 (en) 2005-06-24 2019-06-11 3M Innovative Properties Company Collapsible patch and method of application
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
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
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
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

Families Citing this family (35)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20050010193A1 (en) * 2002-05-06 2005-01-13 Laurent Philippe E. Novel methods for administration of drugs and devices useful thereof
CA2451816A1 (en) * 2001-06-29 2003-01-09 Becton, Dickinson And Company Intradermal delivery of vaccines and gene therapeutic agents via microcannula
US20040120964A1 (en) * 2001-10-29 2004-06-24 Mikszta John A. Needleless vaccination using chimeric yellow fever vaccine-vectored vaccines against heterologous flaviviruses
JP2006516006A (en) * 2003-01-16 2006-06-15 ベクトン・ディキンソン・アンド・カンパニー Intradermal cell delivery using a fine gauge microcannula
KR20060009303A (en) * 2003-05-06 2006-01-31 벡톤 디킨슨 앤드 컴퍼니 A method for altering insulin pharmacokinetics
WO2005086773A2 (en) * 2004-03-08 2005-09-22 Becton Dickinson And Company A method for delivering therapeutic proteins to the intradermal compartment
US20090004222A1 (en) * 2004-11-03 2009-01-01 O'hagan Derek Influenza Vaccination
US20070292386A9 (en) * 2004-12-02 2007-12-20 Campbell Robert L Vaccine formulations for intradermal delivery comprising adjuvants and antigenic agents
CN101687094B (en) * 2005-09-06 2012-09-26 谢拉杰克特股份有限公司 Solid solution perforator containing drug particle and/or drug-adsorbed particles
US8986253B2 (en) 2008-01-25 2015-03-24 Tandem Diabetes Care, Inc. Two chamber pumps and related methods
US8506966B2 (en) 2008-02-22 2013-08-13 Novartis Ag Adjuvanted influenza vaccines for pediatric use
US9028463B2 (en) * 2008-06-30 2015-05-12 Hisamitsu Pharmaceutical Co., Inc. Microneedle device, and method for enhancing the efficacy of influenza vaccine by using microneedle device
US8408421B2 (en) * 2008-09-16 2013-04-02 Tandem Diabetes Care, Inc. Flow regulating stopcocks and related methods
WO2010033878A2 (en) 2008-09-19 2010-03-25 David Brown Solute concentration measurement device and related methods
US9278126B2 (en) 2009-02-10 2016-03-08 Seqirus UK Limited Influenza vaccines with reduced amounts of squalene
US20100286600A1 (en) * 2009-05-08 2010-11-11 Bommannan D Bommi Transdermal patch device
US8641671B2 (en) 2009-07-30 2014-02-04 Tandem Diabetes Care, Inc. Infusion pump system with disposable cartridge having pressure venting and pressure feedback
GB201007207D0 (en) * 2010-04-29 2010-06-16 Univ Cork Method
EP2691101A2 (en) 2011-03-31 2014-02-05 Moderna Therapeutics, Inc. Delivery and formulation of engineered nucleic acids
DK2750705T3 (en) * 2011-08-31 2023-01-23 Perosphere Tech Inc Methods for effectively and rapidly desensitizing allergic patients
CA3018046A1 (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
RS63237B1 (en) 2012-11-26 2022-06-30 Modernatx Inc Terminally modified rna
AU2013374345A1 (en) 2013-01-17 2015-08-06 Moderna Therapeutics, Inc. Signal-sensor polynucleotides for the alteration of cellular phenotypes
US20160024181A1 (en) 2013-03-13 2016-01-28 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
JP2017500865A (en) 2013-12-19 2017-01-12 ノバルティス アーゲー Compositions and formulations of leptin mRNA
AU2015274367B2 (en) 2014-06-13 2020-11-26 Beth Israel Deaconess Medical Center, Inc. Products and methods to isolate mitochondria
US20170151287A1 (en) 2015-11-30 2017-06-01 Flagship Ventures Management, Inc. Methods and compositions of chondrisomes
AU2017208013B2 (en) 2016-01-15 2022-12-01 Beth Israel Deaconess Medical Center, Inc. Therapeutic use of mitochondria and combined mitochondrial agents
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)

* Cited by examiner, † Cited by third party
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
US5279552A (en) * 1993-01-11 1994-01-18 Anton Magnet Intradermal injection device
US5279544A (en) * 1990-12-13 1994-01-18 Sil Medics Ltd. Transdermal or interdermal drug delivery devices
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
US5879327A (en) * 1994-04-06 1999-03-09 Moreau Defarges Alain Needleless jet injection device
US5879326A (en) * 1995-05-22 1999-03-09 Godshall; Ned Allen Method and apparatus for disruption of the epidermis
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
US6090082A (en) * 1998-02-23 2000-07-18 Becton, Dickinson And Company Vial retainer interface to a medication delivery pen
US6090080A (en) * 1996-07-05 2000-07-18 Disetronic Licensing Ag Injection device for injection of liquid
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
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
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
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)

* Cited by examiner, † Cited by third party
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
US4886499A (en) 1986-12-18 1989-12-12 Hoffmann-La Roche Inc. Portable injection appliance
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
TW279133B (en) 1990-12-13 1996-06-21 Elan Med Tech
US5156591A (en) 1990-12-13 1992-10-20 S. I. Scientific Innovations Ltd. Skin electrode construction and transdermal drug delivery device utilizing same
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
CA2213682C (en) 1995-03-07 2009-10-06 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
DE69837211T2 (en) * 1997-08-28 2007-12-06 Cheil Jedang Corp. AN APPROVED VERO CELLS JAPANESE ENZEPHALITIS VIRUS AND A VACCINATE AGAINST JAPANESE ENZEPHALITIS
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
AU2002254901A1 (en) * 2001-02-23 2002-10-03 Smithkline Beecham Biologicals S.A. Influenza vaccine formulations for intradermal delivery
US20040096463A1 (en) * 2001-02-23 2004-05-20 Nathalie Garcon Novel vaccine
JP2004528896A (en) * 2001-04-13 2004-09-24 ベクトン・ディキンソン・アンド・カンパニー How to inject a substance intradermally
US20060058736A1 (en) * 2001-04-27 2006-03-16 Alchas Paul G Novel vaccine
BRPI0307434B8 (en) * 2002-02-04 2021-06-22 Becton Dickinson Co device for applying or removing a substance through the skin.

Patent Citations (99)

* Cited by examiner, † Cited by third party
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
US5312335A (en) * 1989-11-09 1994-05-17 Bioject Inc. Needleless hypodermic injection device
US5503627A (en) * 1989-11-09 1996-04-02 Bioject, Inc. Ampule for needleless injection
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
US5279544A (en) * 1990-12-13 1994-01-18 Sil Medics Ltd. Transdermal or interdermal drug delivery devices
US5527288A (en) * 1990-12-13 1996-06-18 Elan Medical Technologies Limited Intradermal drug delivery device and method for intradermal delivery of drugs
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
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
US5891085A (en) * 1995-01-09 1999-04-06 Medi-Ject Corporation Nozzle assembly with lost motion connection for medical injector assembly
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)

* Cited by examiner, † Cited by third party
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
US7473247B2 (en) 2009-01-06
CN1253220C (en) 2006-04-26
CN1520318A (en) 2004-08-11
MXPA03011611A (en) 2004-07-01
WO2003002069A3 (en) 2003-08-14
EP1416986A2 (en) 2004-05-12
BR0210628A (en) 2004-08-10
US20040131641A1 (en) 2004-07-08
WO2003002069A2 (en) 2003-01-09
JP2004531578A (en) 2004-10-14
EP1416986A4 (en) 2005-12-14
CA2451816A1 (en) 2003-01-09

Similar Documents

Publication Publication Date Title
US20020198509A1 (en) Intradermal delivery of vaccines and gene therapeutic agents via microcannula
EP1439870B1 (en) Device for the delivery of a substance
US20090012494A1 (en) Intradermal delivery of biological agents
ES2643606T3 (en) Matrix of hollow microneedles
US7582069B2 (en) Method and device for the delivery of a substance
KR100897148B1 (en) Microneedle for delivering a substance into the dermis
US20050271684A1 (en) Apparatus and method for transdermal delivery of multiple vaccines
US20050112135A1 (en) Ultrasound assisted transdermal vaccine delivery method and system
JP2004525712A (en) Method and apparatus for delivery of high molecular weight substances
TW200539907A (en) Delivery of polymer conjugates of therapeutic peptides and proteins via coated microprojections
US20040115167A1 (en) Drug delivery device and method having coated microprojections incorporating vasoconstrictors
US11844920B2 (en) Microneedle immunotherapeutic multi-component system and a method for vaccination
US20060018877A1 (en) Intradermal delivery of vacccines and therapeutic agents
Kim Skin vaccination methods: gene gun, jet injector, tattoo vaccine, and microneedle
AU2002327186A1 (en) Intradermal delivery of vaccines and gene therapeutic agents via microcannula
Kumar et al. Cutaneous DNA Immunization: Enhancing Penetration by Hair Follicle Modification or Microneedle Application
WO2023201224A2 (en) Stabilized spike protein and method of use thereof as a coronavirus disease 2019 (covid-19) vaccine

Legal Events

Date Code Title Description
AS Assignment

Owner name: BECTON, DICKINSON AND COMPANY, NEW JERSEY

Free format text: ASSIGNMENT OF ASSIGNORS INTEREST;ASSIGNORS:MIKSZTA, JOHN A.;ALARCON, JASON B.;ALCHAS, PAUL G.;REEL/FRAME:013230/0546;SIGNING DATES FROM 20020813 TO 20020815

STCB Information on status: application discontinuation

Free format text: ABANDONED -- FAILURE TO RESPOND TO AN OFFICE ACTION