Intradermal delivery of substances

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 he 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. Nos. 3,964,482; 5,250,023; 5,876,582; 5,591,139; 5,801,057; 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 99/84580 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 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 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



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 Was a 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 our 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. Nos. 5,957,895; 5,250,023; WO 96/175.18; 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 t: 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 1.0-12 mm. The needle was constructed in a delivery device similar to that described in U.S. Pat. No. 5,957,395, with infusion pressure on the insulin reservoir provided by a plastic Belleville spring and gravimetrically measured flow rates of 9 U/hr (90 μL/hr). The corresponding flow rates for SC control infusions were set using MiniMed 507 insulin infusion pumps and Disetronie 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 concommitant 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 la 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 Humelog™ (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 pharmaceutically 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
  • 1. A method for administration of insulin to a human subject, comprising delivering the insulin 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, wherein the outlet has an exposed height of about 0 to 1 mm; and(b) delivering the insulin through the lumen of the needle with the application of pressure in an amount effective to control the rate of delivery of the insulin,
  • 2. The method of claim 1, wherein the needle is selected from the group consisting of a microneedle, a catheter needle, and an injection needle.
  • 3. The method of claim 1, wherein a single needle is inserted.
  • 4. The method of claim 1, wherein multiple needles are inserted.
  • 5. The method of claim 1, wherein the needle is about 300 μm to 2 mm long.
  • 6. The method of claim 1, wherein the needle is about 500 μm to 1 mm long.
  • 7. The method of claim 1, wherein the outlet is at a depth of about 250 μm to 2 mm when the needle is inserted.
  • 8. The method of claim 1, wherein the outlet is at a depth of about 750 μm to 1.5 mm when the needle is inserted.
  • 9. The method of claim 1, wherein the outlet has an exposed height of about 0 to 300 μm.
  • 10. The method of claim 1, wherein the delivery rate or volume is controlled by spacing of multiple needles, needle diameter or number of needles.
Parent Case Info

This application is a divisional application of U.S. patent application Ser. No. 13/866,381, filed Apr. 19, 2013, which is a divisional of U.S. patent application Ser. No. 09/606,909, filed Jun. 29, 2000, now U.S. Pat. No. 8,465,468, issued Jun. 18, 2013, all of which are hereby incorporated by reference in their entirety.

US Referenced Citations (104)
Number Name Date Kind
2619962 Rosenthal Dec 1952 A
3814097 Ganderton et al. Jun 1974 A
3964482 Gerstel et al. Jun 1976 A
4270537 Romaine Jun 1981 A
4440207 Genatempo et al. Apr 1984 A
4512767 Denance Apr 1985 A
4592753 Panoz Jun 1986 A
4655762 Rogers Apr 1987 A
4886499 Cirelli et al. Dec 1989 A
5003987 Grinwald Apr 1991 A
5098389 Cappucci Mar 1992 A
5156591 Gross et al. Oct 1992 A
5242425 White et al. Sep 1993 A
5250023 Lee et al. Oct 1993 A
5279544 Gross et al. Jan 1994 A
5279552 Magnet Jan 1994 A
5340359 Segura Badia Aug 1994 A
5417662 Hjertman et al. May 1995 A
5484417 Waitz et al. Jan 1996 A
5505694 Hubbard et al. Apr 1996 A
5527288 Gross et al. Jun 1996 A
5536258 Folden Jul 1996 A
5567495 Modak et al. Oct 1996 A
5582591 Cheikh Dec 1996 A
5591139 Lin et al. Jan 1997 A
5741224 Milder et al. Apr 1998 A
5792120 Menyhay Aug 1998 A
5800420 Gross et al. Sep 1998 A
5801057 Smart et al. Sep 1998 A
5807375 Gross Sep 1998 A
5820622 Gross et al. Oct 1998 A
5848990 Cirelli et al. Dec 1998 A
5848991 Gross Dec 1998 A
5876582 Frazier Mar 1999 A
5879326 Godshall et al. Mar 1999 A
5925739 Spira et al. Jul 1999 A
5928207 Pisano et al. Jul 1999 A
5957895 Sage et al. Sep 1999 A
5997501 Gross et al. Dec 1999 A
6007821 Srivastava Dec 1999 A
6056176 Aftanas et al. May 2000 A
6056716 D'Antonio May 2000 A
6099504 Gross et al. Aug 2000 A
6200291 Di Pietro Mar 2001 B1
6256533 Yuzhakov et al. Jul 2001 B1
6319224 Stout et al. Nov 2001 B1
6334856 Allen et al. Jan 2002 B1
6346095 Gross et al. Feb 2002 B1
6482176 Wich Nov 2002 B1
6494865 Alchas Dec 2002 B1
6537242 Palmer Mar 2003 B1
6569143 Alchas et al. May 2003 B2
6591133 Joshi Jul 2003 B1
6607513 Down et al. Aug 2003 B1
6611707 Prausnitz Aug 2003 B1
6623457 Rosenberg Sep 2003 B1
6679870 Finch et al. Jan 2004 B1
6743211 Prausnitz et al. Jun 2004 B1
6808506 Lastovich et al. Oct 2004 B2
7722595 Pettis et al. May 2010 B2
8465468 Pettis et al. Jun 2013 B1
8708994 Pettis et al. Apr 2014 B2
8986280 Pettis et al. Mar 2015 B2
8998877 Pettis et al. Apr 2015 B2
9005182 Pettis et al. Apr 2015 B2
20010056263 Alchas et al. Dec 2001 A1
20020038111 Alchas et al. Mar 2002 A1
20020095134 Pettis et al. Jul 2002 A1
20020156453 Pettis et al. Oct 2002 A1
20030073609 Pinkerton Apr 2003 A1
20030093032 Py et al. May 2003 A1
20030100885 Pettis et al. May 2003 A1
20040028707 Pinkerton Feb 2004 A1
20040073160 Pinkerton Apr 2004 A1
20040082934 Pettis et al. Apr 2004 A1
20040170654 Pinkerton Sep 2004 A1
20040175360 Pettis et al. Sep 2004 A1
20040175401 Pinkerton Sep 2004 A1
20050008683 Mikszta et al. Jan 2005 A1
20050010193 Laurent et al. Jan 2005 A1
20050096330 Boettcher et al. May 2005 A1
20050096331 Das et al. May 2005 A1
20050096332 Jung et al. May 2005 A1
20050096630 Pettis et al. May 2005 A1
20050096631 Pettis et al. May 2005 A1
20050096632 Pettis et al. May 2005 A1
20050124967 Kaestner et al. Jun 2005 A1
20050147525 Bousquet Jul 2005 A1
20050181033 Dekker, III et al. Aug 2005 A1
20050196380 Mikszta et al. Sep 2005 A1
20050245594 Sutter et al. Nov 2005 A1
20050256182 Sutter et al. Nov 2005 A1
20050256499 Pettis et al. Nov 2005 A1
20080118465 Pettis et al. May 2008 A1
20080118507 Pettis et al. May 2008 A1
20080119392 Pettis et al. May 2008 A1
20080138286 Pettis et al. Jun 2008 A1
20080140050 Pettis et al. Jun 2008 A1
20080147042 Pettis et al. Jun 2008 A1
20080234656 Pettis et al. Sep 2008 A1
20090124997 Pettis et al. May 2009 A1
20110190725 Pettis et al. Aug 2011 A1
20140200547 Pettis et al. Jul 2014 A1
20149299547 Pettis et al. Jul 2014
Foreign Referenced Citations (36)
Number Date Country
2349431 May 2000 CA
0692270 Jan 1996 EP
0429842 Aug 1996 EP
1086718 Mar 2001 EP
1086719 Mar 2001 EP
1088642 Apr 2001 EP
1092444 Apr 2001 EP
1246668 Oct 2002 EP
1296740 Nov 2007 EP
A 113862 Mar 1999 JP
WO 9423777 Oct 1984 WO
WO 8700441 Jan 1987 WO
WO 9317754 Sep 1993 WO
WO 9617648 Jun 1996 WO
WO 9637155 Nov 1996 WO
WO 9637256 Nov 1996 WO
WO 9721457 Jun 1997 WO
WO 9943350 Sep 1999 WO
WO 9964580 Dec 1999 WO
WO 0009186 Feb 2000 WO
WO 0016833 Mar 2000 WO
WO 0067647 Nov 2000 WO
WO 0074763 Dec 2000 WO
WO 0139772 Jun 2001 WO
WO 0202178 Jan 2002 WO
WO 0202179 Jan 2002 WO
WO 0211669 Feb 2002 WO
WO 02083231 Oct 2002 WO
WO 02083232 Oct 2002 WO
WO 03002175 Jan 2003 WO
WO 03015787 Feb 2003 WO
WO 03057143 Jul 2003 WO
WO 2004098676 Nov 2004 WO
WO 2004101023 Nov 2004 WO
WO 2005086773 Sep 2005 WO
WO 2005115360 Dec 2005 WO
Non-Patent Literature Citations (89)
Entry
Agrawal et al., 1991, “Pharmacokinetics, Biodistribution, and Stability of Oligodeoxynucleotide Phosphorothioates in Mice,” Proc. Natl. Acad. Sci. USA 88:7595-7599.
Anon, 2004, “Flu vaccine: skin injection method effective in younger people,” American Health Line: Research Notes (Nov. 4, 2004).
Autret et al., 1989, “Comparison of Pharmacokinetics and tolerance of Calcitonine administered by Intradermal or Subcutaneous Route,” Fundamental Clinical Pharmacology 3(2):170-171.
Autret et al., 1991, “Comparaison des concentrations plasmatiques et de la tolerance d'une dose unique de calcitonine humaine administree par voie intradermique et sous-cutanee,” Therapie 46:5-8 (with English Translation).
Ba Wu et al., 1989, “Pharmacokinetics of Methoxyflurane after its Intra-Dermal Inection as Lecithin-Coated Microdroplets,” Journal of Controlled Release 9:1-12.
Bader, 1980, “Influenza vaccine experience in Seattle,” Am. J. Public Health 70(5):545.
Belshe et al., 2004, “Serum antibody responses after intradermal vaccination against influenza,” New England Journal of Medicine 351(22):2286-2294.
Benoni et al., 1984, “Distribution of Ceftazidime in Ascitic Fluid”, Antimicrobial Agents and Chemotherapy 25(6):760-763.
Bickers et al., editors, 1984, “Clinical Pharmacology of Skin Disease”, Churchill Livingstone, Inc.:57-90.
Bocci et al., 1986, “The Lymphatic Route. IV. Pharmacokinetics of Human Recombinant Interferon a2 and Natural Interferon β Administered Intradermally in Rabbits”, International Journal of Phamaceutics 32:103-110.
Branswell, 2004, “Vaccine stretching may be an option for future shortages, pandemics: studies,” Canadian Press News Wire (Nov. 3, 2004).
Bresolle et al., 1993, “A Weibull Distribution Model for Intradermal Administration of Ceftazidime”, Journal of Pharmaceutical Sciences 82(11):1175-1178.
Bronaugh et al., 1982, “Methods for in Vitro Percutaneous Absorption Studies. II. Animal Models for Human Skin,” Toxicol. and Applied Pharmacol. 62(3):481-488.
Brooks et al., 1977, “Intradermal administration of bivalent and monovalent influenza vaccines,” Ann. Allergy 39(2):110-112.
Brown et al., 1977, “The immunizing effect of influenza A/New Jersey/76 (Hsw1N1) virus vaccine administered intradermally and intramuscularly to adults,” J. Infect. Dis. 136 Suppl: S466-71.
Burkoth et al., 1999, “Transdermal and Transmucosal Powered Drug Delivery,” Critical Review in Therapeutic Drug Carrier Systems 16(4):331-384.
Callen, 1981, “Intralesional Corticosteriods”, Journal of the American Academy of Dermatology, University of Louisville School of Medicine, 149-151.
Communication of a Notice of Opposition to EP 1296740 (Aug. 14, 2008) and Opposition Brief in its entirety.
Communication of a Notice of Opposition to EP 1296740 (Jul. 18, 2008) and Opposition Brief in its entirety.
Corbo et al., 1989, “Transdermal Controlled Delivery of Propranolol from a Multilaminate Adhesive Device,” Pharm. Res. 6(9):753-758.
Cossum et al., 1993, “Disposition of the C-Labeled Phosphorothioate Oligonucleotide ISIS 2105 after Intravenous Administration to Rats”, The Journal of Pharmacology and Experimental Therapeutics 267(3):1181-1190.
Cossum et al., 1994, “Pharmacokinetics of C-Labeled Phosphorothioate Olignucleotide, ISIS 2105 after Administration to Rats”, The Journal of Pharmacology and Experimental Therapeutics, 269(1):89-94.
Crooke et al., 1994, “A Pharmacokinetic Evaluation of C-Labeled Afovirsen Sodium in Patients with Genital Warts”, Clinical Pharmacology & Therapeutics 56(6):641-646.
Crowe, 1965, “Experimental comparison of intradermal and subcutaneous vaccination with influenza vaccine,” Am. J. Med. Technol. 31(6):387-396.
Decision of Opposition Division Revoking EP 1296742 (Mar. 27, 2008).
Erstad et. al., 1993, “Influence of Injection Site and Route on Medication Absorption,” Hospital Pharmacy 28(9), 853-854, 872-873.
Firooz et al., 1995, “Benefits and Risks of Intralesional Corticosteroid Injection in the Treatment of Dermatological Diseases”, Clinical and Experimental Dermatology 20(5):363-370.
First Page of Lantus draft Product Insert submitted to the FDA (Apr. 2000).
Fjerstad, 2004, “U. Minnesota professor uses alternative flu vaccine technique,” FSView & Florida Flambeau via U-Wire (Nov. 15, 2004).
Foy et al., 1970, “Efficacy of intradermally administered A2 Hong Kong vaccine,” JAMA 213(1):130.
Glenn et al., 1999, “Advances in vaccine delivery: transcutaneous immunisation,” Exp. Opin. Invest. Drugs 8(6):797-805.
Goodarzi et al., 1992, “Organ Distribution and Stability of Phosphorothioted Oligodeoxyribonucleotides in Mice,” Biopharmaceutics & Drug Disposition 13(3):221-227.
Gramzinski et al., 1998, “Immune response to a hepatitis B DNA vaccine in Aotus monkeys: a comparison of vaccine formulation, route, and method of administration,” Mol. Med. 4(2):109-118.
Halperin et al., 1979, “A comparison of the intradermal and subcutaneous routes of influenza vaccination with A/New Jersey/76 (swine flu) and A/Victoria/75: report of a study and review of the literature,” Am. J. Public Health. 69(12):1247-1250.
Haynes et al., 1985,“Ultra-long-duration Local Anesthesia Produced by Injection of Lecithin-coated Methoxyflurane Microdroplets”, Anestheiology 63(5):490-499.
Henry et al., 1998, “Microfabricated Microneedles: A Novel Approach to Transdermal Drug Delivery”, Journal of Pharmaceutical Sciences 87(8):922-925.
Herbert et al., 1979, “Comparison of responses to influenza A/New Jersey/76-A/Victoria/75 virus vaccine administered intradermally or subcutaneously to adults with chronic respiratory disease,” J. Infect. Dis. 140(2):234-238.
International Search Report mailed Apr. 21, 2006 from the International Searching Authority for PCT/US2004/014469, filed May 6, 2004.
International Search Report mailed Dec. 11, 2001 from the International Searching Authority for PCT/US2001/020763, filed Jun. 29, 2001.
International Search Report mailed Dec. 11, 2001 from the International Searching Authority for PCT/US2001/020782, filed Jun. 29, 2001.
International Search Report mailed Dec. 14, 2006 from the International Searching Authority for PCT/US2004/014033, filed May 6, 2004.
International Search Report mailed Dec. 6, 2006 from the International Searching Authority for PCT/US2005/07412, filed Mar. 8, 2005.
International Search Report mailed Oct. 6, 2003 from the International Searching Authority for PCT/US2002/040841, filed Dec. 23, 2002.
International Search Report mailed Sep. 18, 2006 from the International Searching Authority for PCT/US2005/016424, filed May 11, 2005.
International Search Report mailed Sep. 2, 2002 from the International Searching Authority for PCT/US2001/50436, filed Dec. 28, 2001.
International Search Report mailed Sep. 3, 2002 from the International Searching Authority for PCT/US2001/50440, filed Dec. 28, 2001.
International Standard ISO 9626, Stainless steel needle tubing for the manufacture of medical devices, p. 2 (Table 2—Dimensions of Tubing) of ISO 9626, 1st Edition, Sep. 1, 1991, Amendment 1, Jun. 1, 2001.
Jakobson et al., 1977, “Variations in the Blood Concentration of 1,1,2-Trichloroethane by Percutaneous Absorption and Other Routes of Administrtion in the Guinea Pig”, Acta Pharmacologica et Toxicologica 41(5):497-506.
Jarratt et al., 1974, “The Effects of Intradermal Steriods on the Pituitary-Adrenal Axis and the Skin”, Journal of Investigative Dermatology 62(4):463-466.
Kaushik et al., 1999, “Transdermal Protein Delivery Using Microfabricated Microneedles”, 1 page.
Kenny et al., 2004, “Dose sparing with intradermal injection of influenza vaccine,” New England Journal of Medicine 351(22):2295-2301.
Kirkpatrick et al., 1987, “Local Anesthetic Efficacy of Methoxyflurane Microdroplets in Man”, Anesthesiology 67(3A):A254.
Knox et al., 2004, “New research shows intradermal rather than intramuscular vaccine injection could stretch flu vaccine supplies,” National Public Radio: All Things Considered (Nov. 3, 2004).
Kohn, 2004, “Flu shot technique yields more doses, studies find; critics say injecting skin rather than muscle is too difficult for common use,” The Baltimore Sun: Telegraph 3A (Nov. 4, 2004).
Leroy et al., 1984, “Pharmacokinetics of Ceftazidime in Normal and Uremic Subjects”, Antimicrobal Agents and Chemotherapy 25(5):638-642.
Majeski et al., 2004, “Technique could stretch vaccine; changing the way shots are given means the current supply of flu vaccine could immunize 10 times as many people, two Minnesota physicians say” Saint Paul Pioneer Press: Main 1A (Oct. 27, 2004).
Majeski, 2004, “Alternate flu shot less effective in elderly; doctors proposed method to stretch vaccine supply,” Saint Paul Pioneer Press: Main 17A (Nov. 4, 2004).
Marian et al., 2001, “Hypoglycemia activates compensatory mechanism of glucose metabolism of brain,” Acta Biologica Hungarica 52(1):35-45.
McAllister et al., 1999, “Solid and Hollow Microneedles for Transdermal Protein Delivery,” Proceed. Int'l. Symp. Control. Rel. Bioact. Mater. 26:192-193.
McAllister et al., 1999, “Thee-Dimensional Hollow Microneedle and Microtube Arrays,” Conference: Solid-State Sensors and Actuators Transducers-Conference 12:1098-1103.
McElroy et al.. 1969, “Response to intradermal vaccination with A2, Hong Kong variant, influenza vaccine,” N. Engl. J. Med. 281(19):1076.
McGugan et al., 1963, “Adrenal Suppression from Intradermal Triamcinolone”, Journal of Investigative Dermatology 40:271-272.
Merriam-Webster's Collegiate Dictionary, 10th Edition, 1998, Merriam-Webster, Inc., Springfield, MA, p. 306.
Montagne et al., 2004, “Intradermal influenza vaccination—can less be more?” New England Journal of Medicine 351(22):2330-2332.
Niculescu et al., 1981, “Efficacy of an adsorbed trivalent split influenza vaccine administered by intradermal route,” Arch. Roum. Path. Exp. Microbiol. 40(1):67-70.
Park, 1993, “Pharmacokinetics and Pharmacodynamics in the critically ill patient,” Xenobiotica 23(11):1195-1230.
Payler, 1974, “Letter: Intradermal influenza vaccination,” Br. Med. J. 2(921):727.
Payler, 1977, “Intradermal influenza vaccine using Portojet 1976,” Br. Med. J. 2(6095):1152.
Pinski, 2000, p. 192 of “Soft tissue augmentation for the new millennium,” Dermatological Therapy 13:192-197.
Product Brochure of Terumo Insulin Syringe (Oct. 6, 1990).
Puri et al., 2000, “An investigation of the intradermal route as an effective means of immunization for microparticulate vaccine delivery systems,” Vaccine 18:2600-2612.
Rindfleisch et al., 2004, “La Crosse finding could curtail flu vaccine shortages,” Wisconsin State Journal D9 (Nov. 14, 2004).
Scott et al., 1981, “Toxicity of Interferon,” British Medical Journal 282:1345-1348.
Sebastien et al., 1998,“Microfabricated Needles: A Novel Approach to Transdermal Drug Delivery,” Journal of Pharmaceutical Sciences 87(8):922-925.
Shute, 2004, “Second thoughts on the flu vaccine,” Science & Society Public Health 137(17):80.
Smith, 2004, “Low-dose vaccine helps block flu, study says younger adults seen benefiting,” The Boston Globe: National/Foreign A2 (Nov. 4, 2004).
Supersaxo et al., 1988, “Recombinant Human Interferon Alpha-2a: Delivery to Lymphoid Tissue by Selected Modes of Application,” Pharmaceutical Research 5(8):472-476.
Sutherest, 1979, “Treatment of Pruritus Vulvae by Multiple Intradermal Injections of Alcohol. A Double-Blind Study,” British Journal of Obstetrics and Gynecology 86:371-373.
Sveinsson, 1939, Investigation on the Influence of Insulin and Adrenalin in Rabbits with Alimentary Fatty Liver and Muscles and on the Content of Fat and Sugar in Blood:66-86.
Tauraso et al., 1969, “Effect of dosage and route of inoculation upon antigenicity of inactivated influenza virus vaccine (Hong Kong strain) in man,” Bull. World Health Organ 41(3):507-516.
The American Heritage College Dictionary, 2000, 3rd Edition; Houghton Mifflin Company, Boston, New York, p. 368.
The Merck Manual of Diagnosis and Therapy (17th Ed.) 1999.
The Merck Manual of Diagnosis and Therapy, 1999, 17th Edition, Beers & Berkow, ed., Merck Research Laboratories, Division of Merck & Co., Inc., Whitehouse Station, NJ, pp. 2559-2567.
Tuft, 1931, “Active Immunization against Thyroid Fever, with Particular Reference to an Intradermal Method”, Journal of Laboratory and Clinical Medicine:552-556.
Ward et al., 1975, “Pruritus Vulvae: Treatment by Multiple Intradermal Alcohol Injections,” British Journal of Dermatology 93(2):201-204.
Written Opinion mailed by the International Searching Authority on Apr. 21, 2006 for PCT/US2004/014469, filed May 6, 2004.
Written Opinion mailed by the International Searching Authority on Dec. 14, 2006 for PCT/US2004/014033, filed May 6, 2004.
Written Opinion mailed by the International Searching Authority on Sep. 18, 2006 for PCT/US2005/016424, filed May 11, 2005.
Zaynoun et al., 1973, “The Effect of Intracutaneous Glucocorticoids on Plasma Cortisol Levels,” British Journal of Dermatology 88(2):151-156.
Related Publications (1)
Number Date Country
20150182705 A1 Jul 2015 US
Divisions (2)
Number Date Country
Parent 13866381 Apr 2013 US
Child 14657746 US
Parent 09606909 Jun 2000 US
Child 13866381 US