US20050096630A1 - Intradermal delivery of substances - Google Patents

Intradermal delivery of substances Download PDF

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US20050096630A1
US20050096630A1 US11004778 US477804A US2005096630A1 US 20050096630 A1 US20050096630 A1 US 20050096630A1 US 11004778 US11004778 US 11004778 US 477804 A US477804 A US 477804A US 2005096630 A1 US2005096630 A1 US 2005096630A1
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canceled
delivery
substance
needle
skin
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Ronald Pettis
James Down
Noel Harvey
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Pettis Ronald J.
Down James A.
Harvey Noel G.
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    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61MDEVICES FOR INTRODUCING MEDIA INTO, OR ONTO, THE BODY; DEVICES FOR TRANSDUCING BODY MEDIA OR FOR TAKING MEDIA FROM THE BODY; DEVICES FOR PRODUCING OR ENDING SLEEP OR STUPOR
    • 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
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL, OR TOILET PURPOSES
    • A61K38/00Medicinal preparations containing peptides
    • A61K38/16Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • A61K38/17Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
    • A61K38/22Hormones
    • A61K38/28Insulins
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL, OR TOILET PURPOSES
    • A61K38/00Medicinal preparations containing peptides
    • A61K38/16Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • A61K38/17Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
    • A61K38/22Hormones
    • A61K38/29Parathyroid hormone (parathormone); Parathyroid hormone-related peptides
    • 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
    • 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
    • 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
    • A61M5/178Syringes
    • A61M5/31Details
    • A61M5/32Needles; Details of needles pertaining to their connection with syringe or hub; Accessories for bringing the needle into, or holding the needle on, the body; Devices for protection of needles
    • 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
    • A61M5/178Syringes
    • A61M5/31Details
    • A61M5/32Needles; Details of needles pertaining to their connection with syringe or hub; Accessories for bringing the needle into, or holding the needle on, the body; Devices for protection of needles
    • A61M5/3286Needle tip design, e.g. for improved penetration
    • 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
    • A61M5/178Syringes
    • A61M5/31Details
    • A61M5/32Needles; Details of needles pertaining to their connection with syringe or hub; Accessories for bringing the needle into, or holding the needle on, the body; Devices for protection of needles
    • A61M5/329Needles; Details of needles pertaining to their connection with syringe or hub; Accessories for bringing the needle into, or holding the needle on, the body; Devices for protection of needles characterised by features of the needle shaft
    • A61M5/3291Shafts with additional lateral openings
    • 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
    • A61M5/178Syringes
    • A61M5/31Details
    • A61M5/32Needles; Details of needles pertaining to their connection with syringe or hub; Accessories for bringing the needle into, or holding the needle on, the body; Devices for protection of needles
    • A61M5/3295Multiple needle devices, e.g. a plurality of needles arranged coaxially or in parallel
    • 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
    • A61M2037/0038Other apparatus for introducing media into the body; Percutany, i.e. introducing medicines into the body by diffusion through the skin by using microneedles having a channel at the side surface
    • 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

Abstract

The present invention provides improved methods for ID delivery of drugs and other substances to humans or animals. The methods employ small gauge needles, especially microneedles, placed in the intradermal space to deliver the substance to the intradermal space as a bolus or by infusion. It has been discovered that the placement of the needle outlet within the skin and the exposed height of the needle outlet are critical for efficacious delivery of active substances via small gauge needles to prevent leakage of the substance out of the skin and to improve absorption within the intradermal space. The pharmacokinetics of hormone drugs delivered according to the methods of the invention have been found to be very similar to the pharmacokinetics of conventional SC delivery, indicating that ID administration according to the methods of the invention is likely to produce a similar clinical result (i.e., similar efficacy) with the advantage of reduction or elimination of pain for the patient. Delivery devices which place the needle outlet at an appropriate depth in the intradermal space and control the volume and rate of fluid delivery provide accurate delivery of the substance to the desired location without leakage.

Description

    FIELD OF THE INVENTION
  • The present invention relates to methods and devices for administration of substances into the skin.
  • BACKGROUND OF THE INVENTION
  • Conventional needles have long been used to deliver drugs and other substances to humans and animals through the skin, and considerable effort has been made to achieve reproducible and efficacious delivery through the skin while reducing or eliminating the pain associated with conventional needles. Certain transdermal delivery systems eliminate needles entirely, and rely on chemical mediators or external driving forces such as iontophoretic currents or sonophoresis to breach the stratum corneum painlessly and deliver substances through the skin. However, such transdermal delivery systems are not sufficiently reproducible and give variable clinical results.
  • Mechanical breach of the stratum corneum is still believed to be the most reproducible method of administration of substances through the skin, and it provides the greatest degree of control and reliability. Intramuscular (IM) and subcutaneous (SC) injections are the most commonly used routes of administration. The dermis lies beneath the stratum corneum and epidermis, beginning at a depth of about 60-120 μm below the skin surface in humans, and is approximately 1-2 mm thick. However, intradermal (ID) injection is rarely used due to the difficulty of correct needle placement in the intradermal space, the difficulty of maintaining placement of the needle in the intradermal space, and a lack of information and knowledge of the pharmacokinetic profiles for many drugs delivered ID. In addition, little is known about fluid absorption limits in dermal tissue and the effect of depot time on drug stability. However, ID administration of drugs and other substances may have several advantages. The intradermal space is close to the capillary bed to allow for absorption and systemic distribution of the substance but is above the peripheral nerve net which may reduce or eliminate injection pain. In addition, there are more suitable and accessible ID injection sites available for a patient as compared to currently recommended SC administration sites (essentially limited to the abdomen and thigh).
  • Recent advances in needle design have reduced the pain associated with injections. Smaller gauge and sharper needles reduce tissue damage and therefore decrease the amount of inflammatory mediators released. Of particular interest in this regard are microneedles, which are typically less than 0.2 mm in width and less than 2 mm in length. They are usually fabricated from silicon, plastic or metal and may be hollow for delivery or sampling of substances through a lumen (see, for example, U.S. Pat. No. 3,964,482; U.S. Pat. No. 5,250,023; U.S. Pat. No. 5,876,582; U.S. Pat. No. 5,591,139; U.S. Pat. No. 5,801,057; U.S. Pat. No. 5,928,207; WO 96/17648) or the needles may be solid (see, for example, U.S. Pat. No. 5,879,326; WO 96/37256). By selecting an appropriate needle length, the depth of penetration of the microneedle can be controlled to avoid the peripheral nerve net of the skin and reduce or eliminate the sensation of pain. The extremely small diameter of the microneedle and its sharpness also contribute to reduced sensation during the injection. Microneedles are known to mechanically porate the stratum corneum and enhance skin permeability (U.S. Pat. No. 5,003,987). However, the present inventors have found that, in the case of microneedles, breaching the stratum corneum alone is not sufficient for clinically efficacious intradermal delivery of substances. That is, other factors affect the ability to deliver substances intradermally via small gauge needles in a manner which produces a clinically useful response to the substance.
  • U.S. Pat. No. 5,848,991 describes devices for the controlled delivery of drugs to a limited depth in the skin corresponding to about 0.3-3.0 mm and suggests that such devices are useful for delivery of a variety of drugs, including hormones. U.S. Pat. No. 5,957,895 also describes a device for the controlled delivery of drugs wherein the needle may penetrate the skin to a depth of 3 mm or less. The fluid in the pressurized reservoir of the device is gradually discharged under gas pressure through the needle over a predetermined interval, e.g., a solution of insulin delivered over 24 hrs. Neither of these patents indicates that delivery using the devices produces a clinically useful response. Kaushik, et al. have described delivery of insulin into the skin of diabetic rats via microneedles with a detectable reduction in blood glucose levels. These authors do not disclose the depth of penetration of the microneedles nor do they report any results suggesting a clinically useful glucose response using this method of administration. Further, there is no evidence of accurate or reproducible volume of delivery using such a device. WO 99/64580 suggests that substances may be delivered into skin via microneedles at clinically relevant rates. However, it fails to appreciate that clinical efficacy is dependent upon both accurate, quantitative, and reproducible delivery of a volume or mass of drug substance and the pharmacokinetic uptake and distribution of that substance from the dermal tissue.
  • SUMMARY OF THE INVENTION
  • The present invention improves the clinical utility of ID delivery of drugs and other substances to humans or animals. The methods employ small gauge needles, especially microneedles, placed in the intradermal space to deliver the substance to the intradermal space as a bolus or by infusion. It has been discovered that the placement of the needle outlet within the skin is critical for efficacious delivery of active substances via small gauge needles to prevent leakage of the substance out of the skin and to improve absorption within the intradermal space. ID infusion is a preferred method for delivery according to the invention because lower delivery pressures are required. This also reduces the amount of substance lost to the skin surface due to internal pressure which increases as fluid accumulates within the skin prior to absorption. That is, infusion minimizes effusion of the substance out of the tissue. Infusion also tends to reduce painful swelling and tissue distension and to reduce internal pressure as compared to the corresponding bolus dose. The pharmacokinetics of hormone drugs delivered according to the methods of the invention have been found to be very similar to the pharmacokinetics of conventional SC delivery of the drug, indicating that ID administration according to the methods of the invention is likely to produce a similar clinical result (i.e., similar efficacy) with the advantage of reduction or elimination of pain for the patient. Delivery devices which place the needle outlet at an appropriate depth in the intradermal space and control the volume and rate of fluid delivery provide accurate delivery of the substance to the desired location without leakage.
  • DESCRIPTION OF THE DRAWINGS
  • FIG. 1 illustrates the results of Example 1 for plasma insulin levels during SC and ID infusion of insulin.
  • FIG. 2 illustrates the results of Example 1 for blood glucose levels during SC and ID infusion of insulin.
  • FIG. 3 illustrates the results of Example 1 for plasma PTH levels during SC and ID infusion of PTH.
  • FIG. 4 illustrates the results of Example 2 for plasma insulin levels during SC and ID infusion of insulin at 2 U/hr.
  • FIG. 5 illustrates the results of Example 2 for plasma glucose levels during SC and ID infusion of insulin at 2 U/hr.
  • DETAILED DESCRIPTION OF THE INVENTION
  • The present invention provides delivery of a drug or other substance to a human or animal subject via a device which penetrates the skin to the depth of the intradermal space. The drug or substance is administered into the intradermal space through one or more hollow needles of the device. Substances infused according to the methods of the invention have been found to exhibit pharmacokinetics similar to that observed for the same substance administered by SC injection, but the ID injection is essentially painless. The methods are particularly applicable to hormone therapy, including insulin and parathyroid hormone (PTH) administration.
  • The injection device used for ID administration according to the invention is not critical as long as it penetrates the skin of a subject to a depth sufficient to penetrate the intradermal space without passing through it. In most cases, the device will penetrate the skin to a depth of about 0.5-3 mm, preferably about 1-2 mm. The devices may comprise conventional injection needles, catheters or microneedles of all known types, employed singly or in multiple needle arrays. The terms “needle” and “needles” as used herein are intended to encompass all such needle-like structures. The needles are preferably of small gauge such as microneedles (i.e., smaller than about 25 gauge; typically about 27-35 gauge). The depth of needle penetration may be controlled manually by the practitioner, with or without the assistance of indicator means to indicate when the desired depth is reached. Preferably, however, the device has structural means for limiting skin penetration to the depth of the intradermal space. Such structural means may include limiting the length of the needle or catheter available for penetration so that it is no longer than the depth of the intradermal space. This is most typically accomplished by means of a widened area or “hub” associated with the shaft of the needle, or for needle arrays may take the form of a backing structure or platform to which the needles are attached (see, for example, U.S. Pat. No. 5,879,326; WO 96/37155; WO 96/37256). Microneedles are particularly well suited for this purpose, as the length of the microneedle is easily varied during the fabrication process and microneedles are routinely produced in less than 1 mm lengths. Microneedles are also very sharp and of very small gauge (typically about 33 gauge or less) 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 to increase the rate of delivery or the amount of substance delivered in a given period of time. Microneedles may be incorporated into a variety of devices such as holders and housings which may also serve to limit the depth of penetration or into catheter sets. The devices 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 microneedles may be linked externally to such additional components.
  • It has been found that certain features of the intradermal administration protocol are essential for clinically useful pharmacokinetics and dose accuracy. First, it has been found that placement of the needle outlet within the skin significantly affects these parameters. The outlet of a smaller gauge needles with a bevel has a relatively large exposed height (the vertical “rise” of the outlet). Although the needle tip may be placed at the desired depth within the intradermal space, the large exposed height of the needle outlet allows the substance being delivered to be deposited at a much shallower depth nearer the skin surface. As a result, the substance tends 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. For example, 200 μm microneedles are often cited as suitable means for delivery of substances through the skin. We have found, however, that even if the needle outlet is at the tip of such a microneedle (without any bevel) the substance is deposited at too shallow a depth to allow the skin to seal around the needle and the substance readily effuses onto the surface of the skin. Shorter microneedles such as these serve only to permeabilize the skin and do not give sufficient dose control for clinical utility. In contrast, microneedles according to the invention have a length sufficient to penetrate the intradermal space (the “penetration depth”) and an outlet at a depth within the intradermal space (the “outlet depth”) which allows the skin to seal around the needle against the backpressure which tends to force the delivered substance toward the skin surface. In general, the needle is no more than about 2 mm long, preferably about 300 μm to 2 mm long, most preferably about 500 μm to 1 mm long. The needle outlet is typically at a depth of about 250 μm to 2 mm when the needle is inserted in the skin, preferably at a depth of about 750 μm to 1.5 mm, and most preferably at a depth of about 1 mm. The exposed height of the needle outlet and the depth of the outlet within the intradermal space influence the extent of sealing by the skin around the needle. That is, at a greater depth a needle outlet with a greater exposed height will still seal efficiently whereas an outlet with the same exposed height will not seal efficiently when placed at a shallower depth within the intradermal space. Typically, the exposed height of the needle outlet will be from 0 to about 1 mm, preferably from 0 to about 300 μm. A needle outlet with an exposed height of 0 has no bevel 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 which is either formed by a bevel or by an opening through the side of the needle has a measurable exposed height.
  • Second, it has been found that the pressure of injection or infusion must be carefully controlled due to the high backpressure exerted during ID administration. Gas-pressure driven devices as are known in the prior art are prone to deviations in delivery rate. It is therefore preferable to deliver the substance by placing a constant pressure directly on the liquid interface, as this provides a more constant delivery rate which is essential to optimize absorption and to obtain the desired pharmacokinetics. Delivery rate and volume are also desirably controlled to prevent the formation of weals at the site of delivery and to prevent backpressure from pushing the needle 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. That is, in general the size of the weal increases with increasing rate of delivery for infusion and increases with increasing volume for bolus injection. However, the size and number of microneedles and how closely together they are placed can be adjusted to maintain a desired delivery rate or delivery volume without adverse effects on the skin or the stability of the needle in the skin. For example, increasing the spacing between the needles of a microneedle array device or using smaller diameter needles reduces the pressure build-up from unabsorbed fluid in the skin. Such pressure causes weals and pushes the needle out of the skin. Small diameter and increased spacing between multiple needles also allows more rapid absorption at increased rates of delivery or for larger volumes. In addition, we have found that ID infusion or injection often provides higher plasma levels of drug than conventional SC administration, particularly for drugs which are susceptible to in vivo degradation or clearance. This may, in some cases, allow for smaller doses of the substance to be administered through microneedles via the ID route, further reducing concerns about blistering and backpressure.
  • The administration methods contemplated by the invention include both bolus and infusion delivery of drugs and other substances to human or animal subjects. A bolus dose is a single dose delivered in a single volume unit over a relatively brief time period, typically less than about 5-10 min. Infusion administration comprises administering a fluid at a selected rate (which may be constant or variable) over a relatively more extended time period, typically greater than about 5-10 min. To deliver a substance according to the invention, the needle is placed in the intradermal space and the substance is delivered through the lumen of the needle into the intradermal space where it can act locally or be absorbed by the bloodstream and distributed systemically. The needle may be connected to a reservoir containing the substance to be delivered. Delivery from the reservoir into the intradermal space may occur either passively (without application of external pressure to the substance to be delivered) or actively (with the application of pressure). Examples of preferred pressure-generating means include pumps, syringes, elastomeric membranes, osmotic pressure or Belleville springs or washers. See, for example, U.S. Pat. No. 5,957,895; U.S. Pat. No. 5,250,023; WO 96/17648; WO 98/11937; WO 99/03521. 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. By “clinically efficacious result” is meant a clinically useful biological response resulting from administration of a substance. For example, prevention or treatment of a disease or condition is a clinically efficacious result, such as clinically adequate control of blood sugar levels (insulin), clinically adequate management of hormone deficiency (PTH, Growth Hormone), expression of protective immunity (vaccines), or clinically adequate treatment of toxicity (antitoxins). As a further example, a clinically efficacious result also includes control of pain (e.g., using triptans, opioids, analgesics, anesthetics, etc.), thrombosis (e.g., using heparin, coumadin, warfarin, etc.) and control or elimination of infection (e.g., using antibiotics).
  • EXAMPLE 1
  • ID infusion of insulin was demonstrated using a stainless steel 30 gauge needle bent at the tip at a 90° angle such that the available length for skin penetration was 1-2 mm. The needle outlet (the tip of the needle) was at a depth of 1.7-2.0 mm in the skin when the needle was inserted and the total exposed height of the needle outlet was 1.0-1.2 mm. The needle was constructed in a delivery device similar to that described in U.S. Pat. No. 5,957,895, with infusion pressure on the insulin reservoir provided by a plastic Belleville spring and gravimetrically measured flow rates of 9 U/hr (90 mL/hr). The corresponding flow rates for SC control infusions were set using MiniMed 507 insulin infusion pumps and Disetronic SC catheter sets. Basal insulin secretion in swine was suppressed by infusion of octreotide acetate (Sandostatin®, Sandoz Pharmaceuticals, East Hanover, N.J.), and hyperglycemia was induced by concomitant infusion of 10% glucose. After a two hour induction and baseline period insulin was infused for 2 hr., followed by a 3 hr. washout period. Plasma insulin levels were quantitated via a commercial radio-immunoassay (Coat-A-Count® insulin, Diagnostic Products Corporation, Los Angeles, Calif.), and blood glucose values were measured with a commercial monitor (Accu-chek Advantage®, Boehringer Mannheim Corp, Indianapolis, Ind.). Weight normalized plasma insulin levels and corresponding blood glucose values are shown in FIG. 1 and FIG. 2. Data indicate similar plasma insulin levels and onset periods for infusion via the ID route and via the conventional SC route. The decrease in blood glucose response is also similar between the two. Although 9 U/hr. is a higher administration rate than is typically used medically, these results also demonstrate the ability of dermal tissues to readily absorb and distribute medicaments which are infused via this pathway.
  • A similar experiment was conducted using human parathyroid hormone 1-34 (PTH). PTH was infused for a 4 hr. period, followed by a 2 hr. clearance. Flow rates were controlled by a Harvard syringe pump. Control SC infusion was through a standard 31 gauge needle inserted into the SC space lateral to the skin using a “pinch-up” technique. ID infusion was through the bent 30 gauge needle described above. A 0.64 mg/mL PTH solution was infused at a rate of 75 μL/hr. Weight normalized PTH plasma levels are shown in FIG. 3. This data demonstrates the efficacy of this route of administration for additional hormone drugs, and indicates that ID infusion may actually provide higher plasma levels for drugs that are susceptible to in vivo biological degradation or clearance.
  • EXAMPLE 2
  • ID insulin delivery was demonstrated in swine using a hollow silicon microneedle connected to a standard catheter. The catheter was attached to a MiniMed 507 insulin pump for control of fluid delivery.
  • A hollow, single-lumen microneedle (2 mm total length and 200×100 μm OD, corresponding to about 33 gauge) with an outlet 1.0 μm from the tip (100 μm exposed height) was fabricated using processes known in the art (U.S. Pat. No. 5,928,207) and mated to a microbore catheter commonly used for insulin infusion (Disetronic). The distal end of the microneedle was placed into the plastic catheter and cemented in place with epoxy resin to form a depth-limiting hub. The needle outlet was positioned approximately 1 mm beyond the epoxy hub, thus limiting penetration of the needle outlet into the skin to approximately 1 mm, which corresponds to the depth of the intradermal space in swine. The patency of the fluid flow path was confirmed by visual observation, and no obstructions were observed at pressures generated by a standard 1 cc syringe. The catheter was connected to an external insulin infusion pump (MiniMed 507) via the integral Luer connection at the catheter outlet.
  • The pump was filled with Humalog™ (LisPro) insulin (Lilly) and the catheter and microneedle were primed with insulin according to the manufacturer's instructions. Sandostatin® solution was administered via IV infusion to an anesthetized swine to suppress basal pancreatic function and insulin secretion. After a suitable induction period and baseline sampling, the primed microneedle was inserted perpendicular to the skin surface in the flank of the animal up to the hub stop. Insulin infusion was begun at a rate of 2 U/hr and continued for 4.5 hr. Blood samples were periodically withdrawn and analyzed for serum insulin concentration and blood glucose values using the procedures of Example 1. Baseline insulin levels before infusion were at the background detection level of the assay, as shown in FIG. 4. After initiation of the infusion, serum insulin levels showed an increase which was commensurate with the programmed infusion rates. Blood glucose levels also showed a corresponding drop relative to negative controls (NC) and this drop was similar to the drop observed for conventional SC infusion (FIG. 5).
  • In this experiment, the microneedle was demonstrated to adequately breach the skin barrier and deliver a drug in vivo at pharmaceutically relevant rates. The ID infusion of insulin was demonstrated to be a pharmacokinetically acceptable administration route, and the pharmacodynamic response of blood glucose reduction was also demonstrated. This data indicates a strong probability of successful pharmacological results for ID administration of hormones and other drugs in humans according to the methods of the invention.

Claims (25)

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  23. 23. (canceled)
  24. 24. (canceled)
  25. 25. A method for administration of a substance to a human subject, comprising delivering the substance through the lumen of a hollow needle into an intradermal compartment of the human subject's skin, which method comprises;
    (a) inserting the needle into the subject's skin so that the needle penetrates the intradermal compartment, and the needle's outlet depth and exposed height of the outlet are located within the intradermal compartment; and
    (b) delivering the substance through the lumen of the needle with the application of pressure in an amount effective to control the rate of delivery of the substance,
    so that the substance is delivered through the lumen of the needle into the intradermal compartment and distributed systemically exhibiting a pharmacokinetic profile similar to subcutaneous delivery of the substance, but with a decreased Tmax and a higher maximum plasma concentration (Cmax.)
US11004778 2000-06-29 2004-12-03 Intradermal delivery of substances Abandoned US20050096630A1 (en)

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US11004778 Abandoned US20050096630A1 (en) 2000-06-29 2004-12-03 Intradermal delivery of substances
US11004779 Abandoned US20050096631A1 (en) 2000-06-29 2004-12-03 Intradermal delivery of substances
US11004780 Abandoned US20050096632A1 (en) 2000-06-29 2004-12-03 Intradermal delivery of substances
US12100259 Abandoned US20080234656A1 (en) 1999-10-14 2008-04-09 Method for altering drug pharmacokinetics based on medical delivery platform
US13072824 Active 2021-04-15 US8708994B2 (en) 1999-10-14 2011-03-28 Method for altering drug pharmacokinetics based on medical delivery platform
US13866425 Active US8986280B2 (en) 2000-06-29 2013-04-19 Intradermal delivery of substances
US13866381 Active US9005182B2 (en) 2000-06-29 2013-04-19 Intradermal delivery of substances
US13866446 Active US8998877B2 (en) 2000-06-29 2013-04-19 Intradermal delivery of substances
US14215271 Active US9242052B2 (en) 1999-10-14 2014-03-17 Method for altering drug pharmacokinetics based on medical delivery platform
US14657746 Active US9339613B2 (en) 2000-06-29 2015-03-13 Intradermal delivery of substances
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US12100259 Abandoned US20080234656A1 (en) 1999-10-14 2008-04-09 Method for altering drug pharmacokinetics based on medical delivery platform
US13072824 Active 2021-04-15 US8708994B2 (en) 1999-10-14 2011-03-28 Method for altering drug pharmacokinetics based on medical delivery platform
US13866425 Active US8986280B2 (en) 2000-06-29 2013-04-19 Intradermal delivery of substances
US13866381 Active US9005182B2 (en) 2000-06-29 2013-04-19 Intradermal delivery of substances
US13866446 Active US8998877B2 (en) 2000-06-29 2013-04-19 Intradermal delivery of substances
US14215271 Active US9242052B2 (en) 1999-10-14 2014-03-17 Method for altering drug pharmacokinetics based on medical delivery platform
US14657746 Active US9339613B2 (en) 2000-06-29 2015-03-13 Intradermal delivery of substances
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Cited By (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20030100885A1 (en) * 1999-10-14 2003-05-29 Pettis Ronald J. Methods and devices for administration of substances into the intradermal layer of skin for systemic absorption
US20050256499A1 (en) * 2004-03-03 2005-11-17 Pettis Ronald J Methods and devices for improving delivery of a substance to skin
US20080118507A1 (en) * 2001-06-29 2008-05-22 Pettis Ronald J Methods and devices for administration of substances into the intradermal layer of skin for systemic absorption
US20080118465A1 (en) * 2001-04-13 2008-05-22 Pettis Ronald J Methods and devices for administration of substances into the intradermal layer of skin for systemic absorption
US20110112508A1 (en) * 2009-11-09 2011-05-12 David Panzirer Drug Delivery Devices, Systems, and Methods
US20110190725A1 (en) * 2000-06-29 2011-08-04 Becton, Dickinson And Company Method for altering drug pharmacokinetics based on medical delivery platform

Families Citing this family (63)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20060002949A1 (en) 1996-11-14 2006-01-05 Army Govt. Of The Usa, As Rep. By Secretary Of The Office Of The Command Judge Advocate, Hq Usamrmc. Transcutaneous immunization without heterologous adjuvant
WO2003002069A3 (en) * 2001-06-29 2003-08-14 Becton Dickinson Co Intradermal delivery of vaccines and gene therapeutic agents via microcannula
US20020156453A1 (en) * 1999-10-14 2002-10-24 Pettis Ronald J. Method and device for reducing therapeutic dosage
US20050008683A1 (en) * 2000-06-29 2005-01-13 Becton Dickinson And Company Method for delivering interferons to the intradermal compartment
JP5208347B2 (en) 2001-02-23 2013-06-12 グラクソスミスクライン バイオロジカルズ ソシエテ アノニム The novel vaccine
US9486581B2 (en) 2002-09-11 2016-11-08 Becton, Dickinson And Company Injector device with force lock-out and injection rate limiting mechanisms
DK1432466T3 (en) 2001-09-12 2012-12-03 Becton Dickinson Co Microneedle-based drug delivery penapparat for and method of use thereof
US20040120964A1 (en) * 2001-10-29 2004-06-24 Mikszta John A. Needleless vaccination using chimeric yellow fever vaccine-vectored vaccines against heterologous flaviviruses
US7004928B2 (en) * 2002-02-08 2006-02-28 Rosedale Medical, Inc. Autonomous, ambulatory analyte monitor or drug delivery device
DE60323729D1 (en) 2002-02-11 2008-11-06 Antares Pharma Inc Intradermal injection device
CN2731876Y (en) * 2002-02-19 2005-10-05 交互数字技术公司 Base station for providing biasing criteria for binary decisions
US20050010193A1 (en) * 2002-05-06 2005-01-13 Laurent Philippe E. Novel methods for administration of drugs and devices useful thereof
US20060264886A9 (en) * 2002-05-06 2006-11-23 Pettis Ronald J Method for altering insulin pharmacokinetics
CA2484265C (en) * 2002-05-06 2012-08-07 Becton, Dickinson And Company Method and device for controlling drug pharmacokinetics
US7338465B2 (en) * 2002-07-02 2008-03-04 Patton Medical Devices, Lp Infusion device and method thereof
DE60328039D1 (en) 2002-10-11 2009-07-30 Becton Dickinson Co Insulin delivery system with sensor
DE10330094B4 (en) * 2003-07-03 2008-04-17 Disetronic Licensing Ag Device for administering a fluid product
CA2536669A1 (en) * 2003-08-26 2005-03-17 Becton, Dickinson And Company Methods for intradermal delivery of therapeutics agents
US20050256182A1 (en) * 2004-05-11 2005-11-17 Sutter Diane E Formulations of anti-pain agents and methods of using the same
CA2566032A1 (en) 2004-05-13 2005-12-01 Alza Corporation Apparatus and method for transdermal delivery of parathyroid hormone agents
US7591806B2 (en) * 2004-05-18 2009-09-22 Bai Xu High-aspect-ratio microdevices and methods for transdermal delivery and sampling of active substances
US8048017B2 (en) * 2005-05-18 2011-11-01 Bai Xu High-aspect-ratio microdevices and methods for transdermal delivery and sampling of active substances
US8043250B2 (en) * 2005-05-18 2011-10-25 Nanomed Devices, Inc. High-aspect-ratio microdevices and methods for transdermal delivery and sampling of active substances
JP5082053B2 (en) 2004-08-16 2012-11-28 イノチュア アイ・ピー リミテッド Method of manufacturing a micro-needle or micro-implant
JP5216328B2 (en) 2005-01-24 2013-06-19 アンタレス ファーマ インコーポレイテッド Pre-filled needles auxiliary syringe jet injector
US7645264B2 (en) 2005-04-11 2010-01-12 Becton, Dickinson And Company Injection device with secondary reservoir
EP1940491A4 (en) * 2005-08-22 2016-08-31 Patton Medical Devices Lp Fluid delivery devices, systems and methods
EP1948267A4 (en) * 2005-11-03 2012-12-19 Patton Medical Devices Lp Fluid delivery devices, systems and methods
US7842008B2 (en) 2005-11-21 2010-11-30 Becton, Dickinson And Company Intradermal delivery device
EP2005990B1 (en) 2006-04-07 2013-08-28 Hisamitsu Pharmaceutical Co., Inc. Microneedle device and transdermal administration device provided with microneedles
WO2007131025A1 (en) 2006-05-03 2007-11-15 Antares Pharma, Inc. Injector with adjustable dosing
WO2007131013A1 (en) 2006-05-03 2007-11-15 Antares Pharma, Inc. Two-stage reconstituting injector
US20080214987A1 (en) * 2006-12-22 2008-09-04 Nanomed Devices, Inc. Microdevice And Method For Transdermal Delivery And Sampling Of Active Substances
US9995295B2 (en) 2007-12-03 2018-06-12 Medipacs, Inc. Fluid metering device
US8814834B2 (en) 2008-03-10 2014-08-26 Antares Pharma, Inc. Injector safety device
US8702677B2 (en) 2008-10-31 2014-04-22 Warsaw Orthopedic, Inc. Device and method for directional delivery of a drug depot
WO2010062768A1 (en) * 2008-11-03 2010-06-03 Bayer Healthcare Llc Method for the treatment of hemophilia
JP2012509106A (en) * 2008-11-18 2012-04-19 スリーエム イノベイティブ プロパティズ カンパニー Hollow microneedle arrays and methods
WO2010108116A1 (en) 2009-03-20 2010-09-23 Antares Pharma, Inc. Hazardous agent injection system
US8715223B2 (en) 2009-07-22 2014-05-06 Warsaw Orthopedic, Inc. Device and method for delivery of a drug depot near the nerve
US9238102B2 (en) 2009-09-10 2016-01-19 Medipacs, Inc. Low profile actuator and improved method of caregiver controlled administration of therapeutics
US8454975B1 (en) 2010-01-11 2013-06-04 Elizabeth VanderVeer Method for enhancing skin appearance
US9500186B2 (en) 2010-02-01 2016-11-22 Medipacs, Inc. High surface area polymer actuator with gas mitigating components
WO2012061556A1 (en) 2010-11-03 2012-05-10 Flugen, Inc. Wearable drug delivery device having spring drive and sliding actuation mechanism
WO2012149136A1 (en) * 2011-04-26 2012-11-01 The Board Of Trustees Of The Leland Stanford Junior University Production and delivery of a stable collagen
US9220660B2 (en) 2011-07-15 2015-12-29 Antares Pharma, Inc. Liquid-transfer adapter beveled spike
US8496619B2 (en) 2011-07-15 2013-07-30 Antares Pharma, Inc. Injection device with cammed ram assembly
CN103687643B (en) * 2011-07-27 2016-04-20 久光制药株式会社 Applicator
US20130211289A1 (en) * 2012-01-25 2013-08-15 Tasso, Inc. Handheld Device for Drawing, Collecting, and Analyzing Bodily Fluid
US9486583B2 (en) 2012-03-06 2016-11-08 Antares Pharma, Inc. Prefilled syringe with breakaway force feature
WO2013138524A1 (en) 2012-03-14 2013-09-19 Medipacs, Inc. Smart polymer materials with excess reactive molecules
EP2833957A4 (en) * 2012-04-02 2016-03-09 Capricor Therapeutics Inc Therapy for kidney disease and/or heart failure by intradermal infusion
EP2833944A4 (en) 2012-04-06 2016-05-25 Antares Pharma Inc Needle assisted jet injection administration of testosterone compositions
WO2013169804A1 (en) 2012-05-07 2013-11-14 Antares Pharma, Inc. Needle assisted jet injection device having reduced trigger force
WO2014124464A1 (en) 2013-02-11 2014-08-14 Travanty Michael Needle assisted jet injection device having reduced trigger force
CA2905031C (en) 2013-03-11 2018-01-23 Hans PFLAUMER Dosage injector with pinion system
WO2014165136A1 (en) 2013-03-12 2014-10-09 Antares Pharma, Inc. Constant volume prefilled syringes and kits thereof
EP2976126B1 (en) * 2013-03-22 2018-10-03 3M Innovative Properties Company Microneedle applicator comprising a counter assembly
CN105339024A (en) 2013-06-18 2016-02-17 因内博注射剂有限责任公司 Vial transfer and injection apparatus and method
CN106232137A (en) * 2014-04-25 2016-12-14 赛诺菲 New administration routes of insulin, insulin analogs or derivatives of insulin
EP3248634A4 (en) * 2015-01-20 2018-10-03 Terumo Corp Injection needle assembly and injector provided therewith for injecting drug solution into upper layer of skin
EP3352814A1 (en) * 2015-09-22 2018-08-01 Thomas Jefferson University Continuous subcutaneous insulin infusion catheter
US9827369B2 (en) 2016-03-16 2017-11-28 Baxter International Inc. Percutaneous administration device and method for injecting medicinal substances

Citations (60)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US2619962A (en) * 1948-02-19 1952-12-02 Res Foundation Vaccination appliance
US3814097A (en) * 1972-02-14 1974-06-04 Ici Ltd Dressing
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
US4440207A (en) * 1982-05-14 1984-04-03 Baxter Travenol Laboratories, Inc. Antibacterial protective cap for connectors
US4512767A (en) * 1982-03-30 1985-04-23 Raymond Denance Apparatus for performing intradermal, subcutaneous of intramuscular injections
US4592753A (en) * 1982-12-13 1986-06-03 Elan Corporation P.L.C. Drug delivery device
US4655762A (en) * 1980-06-09 1987-04-07 Rogers Phillip P Ambulatory dialysis system and connector
US4886499A (en) * 1986-12-18 1989-12-12 Hoffmann-La Roche Inc. Portable injection appliance
US5003987A (en) * 1987-09-11 1991-04-02 Grinwald Paul M Method and apparatus for enhanced drug permeation of skin
US5098389A (en) * 1990-06-28 1992-03-24 Becton, Dickinson And Company Hypodermic needle assembly
US5156591A (en) * 1990-12-13 1992-10-20 S. I. Scientific Innovations Ltd. Skin electrode construction and transdermal drug delivery device utilizing same
US5242425A (en) * 1991-11-14 1993-09-07 Gish Biomedical, Inc. Antiseptic catheter coupling septum
US5250023A (en) * 1989-10-27 1993-10-05 Korean Research Institute on Chemical Technology Transdermal administration method of protein or peptide drug and its administration device thereof
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
US5340359A (en) * 1991-01-30 1994-08-23 L'institut Municipal D'assistencia Sanitaria Disinfecting connection for catheters
US5417662A (en) * 1991-09-13 1995-05-23 Pharmacia Ab Injection needle arrangement
US5484417A (en) * 1991-04-19 1996-01-16 Biotime, Inc. Microcannula
US5505694A (en) * 1990-08-22 1996-04-09 Tcnl Technologies, Inc. Apparatus and method for raising a skin wheal
US5527288A (en) * 1990-12-13 1996-06-18 Elan Medical Technologies Limited Intradermal drug delivery device and method for intradermal delivery of drugs
US5536258A (en) * 1994-02-14 1996-07-16 Fresenius Usa, Inc. Antibacterial medical tubing connector
US5567495A (en) * 1993-08-06 1996-10-22 The Trustees Of Columbia University In The City Of New York Infection resistant medical devices
US5582591A (en) * 1994-09-02 1996-12-10 Delab Delivery of solid drug compositions
US5591139A (en) * 1994-06-06 1997-01-07 The Regents Of The University Of California IC-processed microneedles
US5741224A (en) * 1996-04-16 1998-04-21 Implemed, Inc. Iontophoretic material
US5792120A (en) * 1995-02-17 1998-08-11 Menyhay; Steve Z. Method of using a sterile medical injection port and cover
US5801057A (en) * 1996-03-22 1998-09-01 Smart; Wilson H. Microsampling device and method of construction
US5800420A (en) * 1994-11-04 1998-09-01 Elan Medical Technologies Limited Analyte-controlled liquid delivery device and analyte monitor
US5848991A (en) * 1990-12-13 1998-12-15 Elan Medical Technologies Limited Athlone, Co. Intradermal drug delivery device and method for intradermal delivery of drugs
US5848990A (en) * 1993-10-22 1998-12-15 Hoffmann-La Roche Inc. Device for introducing active substance into a patient
US5876582A (en) * 1997-01-27 1999-03-02 The University Of Utah Research Foundation Methods for preparing devices having metallic hollow microchannels on planar substrate surfaces
US5879326A (en) * 1995-05-22 1999-03-09 Godshall; Ned Allen Method and apparatus for disruption of the epidermis
US5925739A (en) * 1994-03-31 1999-07-20 Pharmacia & Upjohn Ab Pharmaceutical formulation for subcutaneous intramuscular or intradermal administration of factor VIII
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
US5957895A (en) * 1998-02-20 1999-09-28 Becton Dickinson And Company Low-profile automatic injection device with self-emptying reservoir
US5997501A (en) * 1993-11-18 1999-12-07 Elan Corporation, Plc Intradermal drug delivery device
US6007821A (en) * 1997-10-16 1999-12-28 Fordham University Method and compositions for the treatment of autoimmune disease using heat shock proteins
US6056716A (en) * 1987-06-08 2000-05-02 D'antonio Consultants International Inc. Hypodermic fluid dispenser
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
US6319224B1 (en) * 1999-08-20 2001-11-20 Bioject Medical Technologies Inc. Intradermal injection system for injecting DNA-based injectables into humans
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
US20020095134A1 (en) * 1999-10-14 2002-07-18 Pettis Ronald J. Method for altering drug pharmacokinetics based on medical delivery platform
US20020156453A1 (en) * 1999-10-14 2002-10-24 Pettis Ronald J. Method and device for reducing therapeutic dosage
US6482176B1 (en) * 1997-11-27 2002-11-19 Disetronic Licensing Ag Method and device for controlling the introduction depth of an injection needle
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
US6623457B1 (en) * 1999-09-22 2003-09-23 Becton, Dickinson And Company Method and apparatus for the transdermal administration of a substance
US6679870B1 (en) * 1999-07-23 2004-01-20 Vasca, Inc. Methods and kits for locking and disinfecting implanted catheters
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
US6743211B1 (en) * 1999-11-23 2004-06-01 Georgia Tech Research Corporation Devices and methods for enhanced microneedle penetration of biological barriers
US20040175360A1 (en) * 2000-06-29 2004-09-09 Pettis Ronald J. Method for altering drug pharmacokinetics based on medical delivery platform
US6808506B2 (en) * 2002-02-04 2004-10-26 Becton, Dickinson And Company Device and method for delivering or withdrawing a substance through the skin
US20050096332A1 (en) * 2003-10-30 2005-05-05 Boehringer Ingelheim International Gmbh Use of tyrosine kinase inhibitors for the treatment of inflammatory processes
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
US20050147525A1 (en) * 2004-01-06 2005-07-07 Bousquet Gerald G. Sanitized tubing termination method and assembly
US20050256499A1 (en) * 2004-03-03 2005-11-17 Pettis Ronald J Methods and devices for improving delivery of a substance to skin

Family Cites Families (40)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US394482A (en) * 1888-12-11 Triple-expansion engine
CA1248832A (en) 1985-07-22 1989-01-17 Francesco Peluso Antibacterial closure system
US5007501A (en) 1989-09-01 1991-04-16 Baston Peter J Apparatus for facilitating the internal inspection and repair of large pressure vessels
US5328483A (en) * 1992-02-27 1994-07-12 Jacoby Richard M Intradermal injection device with medication and needle guard
JPH07299143A (en) * 1994-05-09 1995-11-14 Kenji Tsubota Medical injection needle
US5540657A (en) 1994-07-15 1996-07-30 Collagen Corporation Delivery device for injectable materials
EP0796128B1 (en) 1994-12-09 1999-03-10 Novartis AG Transdermal system
WO1996037256A1 (en) 1995-05-22 1996-11-28 Silicon Microdevices, Inc. Micromechanical patch for enhancing the delivery of compounds through the skin
FR2749172B1 (en) * 1996-05-31 1998-11-06 Multipropulseurs Hypodermic syringe
WO1998011937A1 (en) 1996-09-17 1998-03-26 Deka Products Limited Partnership System for delivery of drugs by transport
DE19717253A1 (en) * 1997-04-24 1998-10-29 Edwin Dr Med Klaus Hypodermic needle preventing coring and introduction of possibly dangerous tissues carrying micro-organisms into body
WO1999003521A1 (en) 1997-07-14 1999-01-28 Novo Nordisk A/S Injection member
EP2286834A3 (en) 1998-02-25 2012-01-25 THE GOVERNMENT OF THE UNITED STATES, as represented by THE SECRETARY OF THE ARMY Use of skin penetration enhancers and barrier disruption agents to enhance transcutaneous immune response
JP2002517300A (en) 1998-06-10 2002-06-18 ジョージア テック リサーチ コーポレイション Microneedle device and a manufacturing method and use thereof
US6428528B2 (en) 1998-08-11 2002-08-06 Antares Pharma, Inc. Needle assisted jet injector
CA2344398A1 (en) 1998-09-18 2000-03-30 The University Of Utah Surface micromachined microneedles
US6159472A (en) 1998-11-16 2000-12-12 Akzo Nobel N.V. Intradermal Avian immunization with inactivated vaccines
US6689103B1 (en) 1999-05-07 2004-02-10 Scimed Life System, Inc. Injection array apparatus and method
US6611707B1 (en) * 1999-06-04 2003-08-26 Georgia Tech Research Corporation Microneedle drug delivery device
US6256533B1 (en) * 1999-06-09 2001-07-03 The Procter & Gamble Company Apparatus and method for using an intracutaneous microneedle array
US6056176A (en) * 1999-06-09 2000-05-02 Jac Products, Inc. Vehicle article carrier having clamping cross bar
DE19934433A1 (en) 1999-07-22 2001-01-25 Merck Patent Gmbh New N-(indolyl-carbonyl)-N'-ethyl-piperazine derivatives, are 5-HT-2A receptor antagonists useful e.g. for treating schizophrenia, depression, Parkinson's disease, Alzheimer's disease or anorexia
US6835184B1 (en) 1999-09-24 2004-12-28 Becton, Dickinson And Company Method and device for abrading skin
US6331266B1 (en) 1999-09-29 2001-12-18 Becton Dickinson And Company Process of making a molded device
US6494865B1 (en) * 1999-10-14 2002-12-17 Becton Dickinson And Company Intradermal delivery device including a needle assembly
US20050181033A1 (en) * 2000-06-29 2005-08-18 Dekker John P.Iii Method for delivering interferons to the intradermal compartment
US20050245594A1 (en) * 2001-06-29 2005-11-03 Sutter Diane E Dermal delivery of anti-pain agents and methods useful thereof
US20050008683A1 (en) * 2000-06-29 2005-01-13 Becton Dickinson And Company Method for delivering interferons to the intradermal compartment
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
CA2392810A1 (en) 1999-12-01 2001-06-07 Natco Pharma Limited A rapid acting freeze dired oral pharmaceutical composition for treating migraine
GB9928578D0 (en) 1999-12-03 2000-02-02 Zeneca Ltd Pharmaceutical formulations
US6607513B1 (en) * 2000-06-08 2003-08-19 Becton, Dickinson And Company Device for withdrawing or administering a substance and method of manufacturing a device
US6591133B1 (en) * 2000-11-27 2003-07-08 Microlin Llc Apparatus and methods for fluid delivery using electroactive needles and implantable electrochemical delivery devices
DE10139410A1 (en) 2001-08-17 2003-02-27 Boehringer Ingelheim Pharma Using BIBN4096 in combination with other drugs for migraine in the treatment of migraine
US6971999B2 (en) * 2001-11-14 2005-12-06 Medical Instill Technologies, Inc. Intradermal delivery device and method
US20050010193A1 (en) 2002-05-06 2005-01-13 Laurent Philippe E. Novel methods for administration of drugs and devices useful thereof
CA2484265C (en) * 2002-05-06 2012-08-07 Becton, Dickinson And Company Method and device for controlling drug pharmacokinetics
US20050196380A1 (en) * 2004-03-08 2005-09-08 Mikszta John A. Method for delivering therapeutic proteins to the intradermal compartment
US20050256182A1 (en) * 2004-05-11 2005-11-17 Sutter Diane E Formulations of anti-pain agents and methods of using the same

Patent Citations (68)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US2619962A (en) * 1948-02-19 1952-12-02 Res Foundation Vaccination appliance
US3964482A (en) * 1971-05-17 1976-06-22 Alza Corporation Drug delivery device
US3814097A (en) * 1972-02-14 1974-06-04 Ici Ltd Dressing
US4270537A (en) * 1979-11-19 1981-06-02 Romaine Richard A Automatic hypodermic syringe
US4655762A (en) * 1980-06-09 1987-04-07 Rogers Phillip P Ambulatory dialysis system and connector
US4512767A (en) * 1982-03-30 1985-04-23 Raymond Denance Apparatus for performing intradermal, subcutaneous of intramuscular injections
US4440207A (en) * 1982-05-14 1984-04-03 Baxter Travenol Laboratories, Inc. Antibacterial protective cap for connectors
US4592753A (en) * 1982-12-13 1986-06-03 Elan Corporation P.L.C. Drug delivery device
US4886499A (en) * 1986-12-18 1989-12-12 Hoffmann-La Roche Inc. Portable injection appliance
US6056716A (en) * 1987-06-08 2000-05-02 D'antonio Consultants International Inc. Hypodermic fluid dispenser
US5003987A (en) * 1987-09-11 1991-04-02 Grinwald Paul M Method and apparatus for enhanced drug permeation of skin
US5250023A (en) * 1989-10-27 1993-10-05 Korean Research Institute on Chemical Technology Transdermal administration method of protein or peptide drug and its administration device thereof
US5098389A (en) * 1990-06-28 1992-03-24 Becton, Dickinson And Company Hypodermic needle assembly
US5505694A (en) * 1990-08-22 1996-04-09 Tcnl Technologies, Inc. Apparatus and method for raising a skin wheal
US5848991A (en) * 1990-12-13 1998-12-15 Elan Medical Technologies Limited Athlone, Co. Intradermal drug delivery device and method for intradermal delivery of drugs
US5279544A (en) * 1990-12-13 1994-01-18 Sil Medics Ltd. Transdermal or interdermal drug delivery devices
US5156591A (en) * 1990-12-13 1992-10-20 S. I. Scientific Innovations Ltd. Skin electrode construction and transdermal drug delivery device utilizing same
US5527288A (en) * 1990-12-13 1996-06-18 Elan Medical Technologies Limited Intradermal drug delivery device and method for intradermal delivery of drugs
US5340359A (en) * 1991-01-30 1994-08-23 L'institut Municipal D'assistencia Sanitaria Disinfecting connection for catheters
US5484417A (en) * 1991-04-19 1996-01-16 Biotime, Inc. Microcannula
US5417662A (en) * 1991-09-13 1995-05-23 Pharmacia Ab Injection needle arrangement
US5242425A (en) * 1991-11-14 1993-09-07 Gish Biomedical, Inc. Antiseptic catheter coupling septum
US5279552A (en) * 1993-01-11 1994-01-18 Anton Magnet Intradermal injection device
US5567495A (en) * 1993-08-06 1996-10-22 The Trustees Of Columbia University In The City Of New York Infection resistant medical devices
US5848990A (en) * 1993-10-22 1998-12-15 Hoffmann-La Roche Inc. Device for introducing active substance into a patient
US5997501A (en) * 1993-11-18 1999-12-07 Elan Corporation, Plc Intradermal drug delivery device
US5536258A (en) * 1994-02-14 1996-07-16 Fresenius Usa, Inc. Antibacterial medical tubing connector
US5925739A (en) * 1994-03-31 1999-07-20 Pharmacia & Upjohn Ab Pharmaceutical formulation for subcutaneous intramuscular or intradermal administration of factor VIII
US5591139A (en) * 1994-06-06 1997-01-07 The Regents Of The University Of California IC-processed microneedles
US5582591A (en) * 1994-09-02 1996-12-10 Delab Delivery of solid drug compositions
US5800420A (en) * 1994-11-04 1998-09-01 Elan Medical Technologies Limited Analyte-controlled liquid delivery device and analyte monitor
US5820622A (en) * 1994-11-04 1998-10-13 Elan Medical Technologies Limited Analyte-controlled liquid delivery device and analyte monitor
US5792120A (en) * 1995-02-17 1998-08-11 Menyhay; Steve Z. Method of using a sterile medical injection port and cover
US5879326A (en) * 1995-05-22 1999-03-09 Godshall; Ned Allen Method and apparatus for disruption of the epidermis
US5801057A (en) * 1996-03-22 1998-09-01 Smart; Wilson H. Microsampling device and method of construction
US5741224A (en) * 1996-04-16 1998-04-21 Implemed, Inc. Iontophoretic material
US6346095B1 (en) * 1996-06-10 2002-02-12 Elan Corporation, Plc Needle and method for delivery of fluids
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
US6007821A (en) * 1997-10-16 1999-12-28 Fordham University Method and compositions for the treatment of autoimmune disease using heat shock proteins
US6099504A (en) * 1997-10-22 2000-08-08 Elan Corporation, Plc Pre-filled injection delivery device
US6482176B1 (en) * 1997-11-27 2002-11-19 Disetronic Licensing Ag Method and device for controlling the introduction depth of an injection needle
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
US5957895A (en) * 1998-02-20 1999-09-28 Becton Dickinson And Company Low-profile automatic injection device with self-emptying reservoir
US6334856B1 (en) * 1998-06-10 2002-01-01 Georgia Tech Research Corporation Microneedle devices and methods of manufacture and use thereof
US6679870B1 (en) * 1999-07-23 2004-01-20 Vasca, Inc. Methods and kits for locking and disinfecting implanted catheters
US6319224B1 (en) * 1999-08-20 2001-11-20 Bioject Medical Technologies Inc. Intradermal injection system for injecting DNA-based injectables into humans
US6623457B1 (en) * 1999-09-22 2003-09-23 Becton, Dickinson And Company Method and apparatus for the transdermal administration of a substance
US20020095134A1 (en) * 1999-10-14 2002-07-18 Pettis Ronald J. Method for altering drug pharmacokinetics based on medical delivery platform
US20020156453A1 (en) * 1999-10-14 2002-10-24 Pettis Ronald J. Method and device for reducing therapeutic dosage
US20030100885A1 (en) * 1999-10-14 2003-05-29 Pettis Ronald J. Methods and devices for administration of substances into the intradermal layer of skin for systemic absorption
US6743211B1 (en) * 1999-11-23 2004-06-01 Georgia Tech Research Corporation Devices and methods for enhanced microneedle penetration of biological barriers
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
US20040175360A1 (en) * 2000-06-29 2004-09-09 Pettis Ronald J. Method for altering drug pharmacokinetics based on medical delivery platform
US20050096631A1 (en) * 2000-06-29 2005-05-05 Pettis Ronald J. Intradermal delivery of substances
US20050096632A1 (en) * 2000-06-29 2005-05-05 Pettis Ronald J. Intradermal delivery of substances
US20040073160A1 (en) * 2000-06-29 2004-04-15 Pinkerton Thomas C. Intradermal delivery of substances
US20080234656A1 (en) * 2000-06-29 2008-09-25 Becton, Dickinson And Company Method for altering drug pharmacokinetics based on medical delivery platform
US20040170654A1 (en) * 2001-06-29 2004-09-02 Pinkerton Thomas C. Enhanced parmacokinetic profile of hydrophobic dopamine agonists administered to the dermis
US20040175401A1 (en) * 2001-06-29 2004-09-09 Pinkerton Thomas C Enhanced parmacokinetic profile of hydrophobic substances
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
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
US6808506B2 (en) * 2002-02-04 2004-10-26 Becton, Dickinson And Company Device and method for delivering or withdrawing a substance through the skin
US20040082934A1 (en) * 2002-08-30 2004-04-29 Pettis Ronald J. Method of controlling pharmacokinetics of immunomodulatory compounds
US20050096332A1 (en) * 2003-10-30 2005-05-05 Boehringer Ingelheim International Gmbh Use of tyrosine kinase inhibitors for the treatment of inflammatory processes
US20050147525A1 (en) * 2004-01-06 2005-07-07 Bousquet Gerald G. Sanitized tubing termination method and assembly
US20050256499A1 (en) * 2004-03-03 2005-11-17 Pettis Ronald J Methods and devices for improving delivery of a substance to skin

Cited By (16)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20030100885A1 (en) * 1999-10-14 2003-05-29 Pettis Ronald J. Methods and devices for administration of substances into the intradermal layer of skin for systemic absorption
US9339613B2 (en) 2000-06-29 2016-05-17 Becton, Dickinson And Company Intradermal delivery of substances
US9242052B2 (en) 2000-06-29 2016-01-26 Becton, Dickinson And Company Method for altering drug pharmacokinetics based on medical delivery platform
US9005182B2 (en) 2000-06-29 2015-04-14 Becton, Dickinson And Company Intradermal delivery of substances
US8998877B2 (en) 2000-06-29 2015-04-07 Becton, Dickinson And Company Intradermal delivery of substances
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US20110190725A1 (en) * 2000-06-29 2011-08-04 Becton, Dickinson And Company Method for altering drug pharmacokinetics based on medical delivery platform
US8708994B2 (en) 2000-06-29 2014-04-29 Becton, Dickinson And Company Method for altering drug pharmacokinetics based on medical delivery platform
US20080118465A1 (en) * 2001-04-13 2008-05-22 Pettis Ronald J Methods and devices for administration of substances into the intradermal layer of skin for systemic absorption
US20080138286A1 (en) * 2001-06-29 2008-06-12 Pettis Ronald J Methods and devices for administration of substances into the intradermal layer of skin for systemic absorption
US20080119392A1 (en) * 2001-06-29 2008-05-22 Pettis Ronald J Methods and devices for administration of substances into the intradermal layer of skin for systemic absorption
US20080118507A1 (en) * 2001-06-29 2008-05-22 Pettis Ronald J Methods and devices for administration of substances into the intradermal layer of skin for systemic absorption
US20050256499A1 (en) * 2004-03-03 2005-11-17 Pettis Ronald J Methods and devices for improving delivery of a substance to 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
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