U.S. patent application number 09/897753 was filed with the patent office on 2004-04-15 for intradermal delivery of substances.
Invention is credited to Pinkerton, Thomas C..
Application Number | 20040073160 09/897753 |
Document ID | / |
Family ID | 24430006 |
Filed Date | 2004-04-15 |
United States Patent
Application |
20040073160 |
Kind Code |
A1 |
Pinkerton, Thomas C. |
April 15, 2004 |
Intradermal delivery of substances
Abstract
A method for administration of a substance into the dermis of a
mammal is disclosed. The method involves administration into the
dermis by injection which results in improved systemic absorption
relative to that obtained upon subcutaneous administration of the
substance. The substance administered may be a growth hormone, a
low molecular weight heparin or a dopamine receptor agonist.
Inventors: |
Pinkerton, Thomas C.;
(Kalamazoo, MI) |
Correspondence
Address: |
HARNESS, DICKEY, & PIERCE, P.L.C
7700 BONHOMME, STE 400
ST. LOUIS
MO
63105
US
|
Family ID: |
24430006 |
Appl. No.: |
09/897753 |
Filed: |
June 29, 2001 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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09897753 |
Jun 29, 2001 |
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09606909 |
Jun 29, 2000 |
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Current U.S.
Class: |
604/28 |
Current CPC
Class: |
A61K 38/28 20130101;
A61M 2037/0038 20130101; A61M 37/0015 20130101; A61K 38/29
20130101; A61M 5/32 20130101; A61M 5/46 20130101; A61M 2037/0061
20130101; A61M 5/158 20130101; A61M 5/3286 20130101; A61M 5/3291
20130101; A61P 3/10 20180101; A61M 5/3295 20130101 |
Class at
Publication: |
604/028 |
International
Class: |
A61M 001/00 |
Claims
What is claimed is:
1. A method for directly delivering a substance into an intradermal
space within mammalian skin comprising administering the substance
through at least one small gauge hollow needle having an outlet
with an exposed height between 0 and 1 mm, said outlet being
inserted into the skin to a depth of between 0.3 mm and 2 mm, such
that delivery of the substance occurs at a depth between 0.3 mm and
2 mm.
2. The method according to claim 1 wherein the delivered substance
has improved pharmacokinetics compared to pharmacokinetics after
subcutaneous injection.
3. The method of claim 1 wherein the injecting is through at least
one small gauge hollow needle.
4. The method of claim 1 wherein the needle has an outlet with an
exposed height between 0 and 1 mm.
5. The method of claim 1 wherein injecting comprises inserting the
needle to a depth which delivers the substance at least about 0.3
mm below the surface to no more than about 2 mm below the
surface.
6. The method of claim 1 wherein administering comprises inserting
the needle into the skin to a depth of at least about 0.3 mm and no
more than about 2 mm.
7. The method of claim 2 wherein the improved pharmacokinetics is
increased bioavailability of the substance.
8. The method of claim 2 wherein the improved pharmacokinetics is a
decrease in T.sub.max.
9. The method of claim 2 wherein the improved pharmacokinetics is
an increase in C.sub.max.
10. The method of claim 2 wherein the improved pharmacokinetics is
a decrease in T.sub.lag.
11. The method of claim 2 wherein the improved pharmacokinetics is
enhanced absorption rate.
12. The method of claim 1 wherein the substance is administered
over a time period of not more than ten minutes.
13. The method of claim 1 wherein the substance is administered
over a time period of greater than ten minutes.
14. The method of claim 1 wherein the substance is a protein.
15. The method of claim 1 wherein the substance is administered at
a rate between 1 nL/min. and 200 mL/ min.
16. The method of claim 1 wherein said substance is a hormone.
17. The method of claim 16 wherein said hormone is selected from
the group consisting of insulin and PTH.
18. The method of claim 1 wherein said substance is a nucleic
acid.
19. The method of claim 1 wherein the substance has a molecular
weight of less than 1000 daltons.
20. The method of claim 1 wherein the substance has a molecular
weight greater than 1000 daltons.
21. The method of claim 1 wherein said substance is
hydrophobic.
22. The method of claim 1 wherein said substance is
hydrophilic.
23. The method of claim 1 wherein the needle(s) are inserted
perpendicularly to the skin.
24. A method of administering a pharmaceutical substance comprising
injecting the substance intradermally through one or more
microneedles having a length and outlet suitable for selectively
delivering the substance into the dermis to obtain absorption of
the substance in the dermis.
25. The method of claim 24 wherein absorption of the substance in
the dermis produces improved systemic pharmacokinetics compared to
subcutaneous administration.
26. The method of claim 25 wherein the improved pharmacokinetics is
increased bioavailability.
27. The method of claim 25 wherein the improved pharmacokinetics is
decreased T.sub.max.
28. The method of claim 25 wherein the improved pharmacokinetics is
an increase in C.sub.max.
29. The method of claim 25 wherein the improved pharmacokinetics is
a decrease in T.sub.lag.
30. The method of claim 25 wherein the improved pharmacokinetics is
an enhanced absorption rate.
31. The method of claim 24 wherein the length of the microneedle is
from about 0.5 mm to about 1.7 mm.
32. The method of claim 24 wherein the microneedle is a 30 to 34
gauge needle
33. The method of claim 24 wherein the microneedle has an outlet of
from 0 to 1 mm.
34. The method of claim 24 wherein the microneedle is configured in
a delivery device which positions the microneedle perpendicular to
skin surface.
35. The method of claim 24 wherein the microneedle needle is
contained in an array of microneedles needles.
36. The method of claim 35 wherein the array comprises 3
microneedles.
37. The method of claim 35 wherein the array comprises 6
microneedles.
38. A microneedle for intradermal injection of a pharmaceutical
substance, wherein the microneedle has a length and outlet selected
for its suitability for specifically delivering the substance into
the dermis.
39. The microneedle according to claim 38 wherein the length of the
microneedle is from about 0.5 mm to about 1.7 mm.
40. The microneedle of claim 38 which is a 30 to 34 gauge
needle
41. The microneedle of claim 38 which has an outlet of from 0 to 1
mm
42. The microneedle of claim 38 which is configured in a delivery
device which positions the microneedle perpendicular to skin
surface.
43. The microneedle of claim 42 which is in an array of
microneedles needles.
44. The microneedle of claim 43 wherein the array comprises 3
microneedles.
45. The microneedle of claim 43 wherein the array comprises 6
microneedles.
46. A method for delivering a bioactive substance to a subject
comprising: contacting the skin of the subject with a device having
a dermal-access means for accurately targeting the dermal space of
the subject with an efficacious amount of the bioactive
substance.
47. The method of claim 46 wherein the pharmacokinetics of the
bioactive substance is improved relative to the pharmacokinetics of
the substance when administered subcutaneously.
48. The method of claim 47 wherein the improved pharnacokinetics is
an increase in bioavailability.
49. The method of claim 47 wherein the improved pharmacokinetics is
a decrease
50. The method of claim 47 wherein the improved pharmacokinetics
comprises an increase in C.sub.max of the substance compared to
subcutaneous injection.
51. The method of claim 47 wherein the improved pharmacokinetics is
a decrease in T.sub.lag.
52. The method of claim 47 wherein the improved pharmacokinetics is
an enhanced absorption rate.
53. The method of claim 46 wherein the device has a fluid driving
means including a syringe, infusion pump, piezoelectric pump,
electromotive pump, electromagnetic pump, or Belleville spring.
53. The method of claim 46 wherein the dermal access means
comprises one or more hollow microcannula having a length of from
about 0.5 to about 1.7 mm-mm.
54. The method of claim 46 wherein said dermal access means
comprises one or more hollow microcannula having an outlet with an
exposed height between 0 and 1 mm.
55. A method for delivering a bioactive substance to a subject
comprising: contacting the skin of a subject with a device having a
dermal-access means for accurately targeting the dermal space of
the subject with an efficacious amount of the bioactive substance
at a rate of 1 nL/min. to 200 mL/min.
56. The method of claim 55 wherein the rapid onset pharmacokinetics
of the bioactive substance is substantially improved relative to
subcutaneous injection.
57. The method of claim 56 wherein the bioavailability is
increased.
58. The method of claim 56 wherein the pharmokinetics is a
decreased T.sub.max.
59. The method of claim 56 wherein the pharmokinetics is an
increased C.sub.max.
60. The method of claim 56 wherein the pharmokinetics is a
decreased T.sub.lag.
61. The method of claim 56 wherein the pharmokinetics is an
enhanced absorption rate.
62. The method of claim 55 wherein the dermal access means has one
or more hollow microcannula that inserts into the skin of said
subject to a depth of from about 0.5 to about -2.0 mm.
63. The method of claim 55 wherein the dermal access means has one
or more hollow microcannula having an outlet with an exposed height
between 0 and 1 mm.
Description
CROSS REFERENCE TO RELATED APPLICATIONS
[0001] This application is a continuation-in-part of U.S.
application Ser. No. 09/606,909 filed Jun. 29, 2000.
FIELD OF THE INVENTION
[0002] The present invention relates to methods and devices for
administration of substances into the intradermal layer of
skin.
BACKGROUND OF THE INVENTION
[0003] The importance of efficiently and safely administering
pharmaceutical substances such as diagnostic agents and drugs has
long been recognized. Although an important consideration for all
pharmaceutical substances, obtaining adequate bioavailability of
large molecules such as proteins that have arisen out of the
biotechnology industry has recently highlighted this need to obtain
efficient and reproducible absorption (Cleland et al., Curr. Opin.
Biotechnol. 12: 212-219, 2001). The use of conventional needles has
long provided one approach for delivering pharmaceutical substances
to humans and animals by administration through the skin.
Considerable effort has been made to achieve reproducible and
efficacious delivery through the skin while improving the ease of
injection and reducing patient apprehension and/or pain associated
with conventional needles. Furthermore, certain delivery systems
eliminate needles entirely, and rely upon chemical mediators or
external driving forces such as iontophoretic currents or
electroporation or thermal poration or sonophoresis to breach the
stratum corneum, the outermost layer of the skin, and deliver
substances through the surface of the skin. However, such delivery
systems do not reproducibly breach the skin barriers or deliver the
pharmaceutical substance to a given depth below the surface of the
skin and consequently, clinical results can be variable. Thus,
mechanical breach of the stratum comeum such as with needles, is
believed to provide the most reproducible method of administration
of substances through the surface of the skin, and to provide
control and reliability in placement of administered
substances.
[0004] Approaches for delivering substances beneath the surface of
the skin have almost exclusively involved transdermal
administration, i.e. delivery of substances through the skin to a
site beneath the skin. Transdermal delivery includes subcutaneous,
intramuscular or intravenous routes of administration of which,
intramuscular (IM) and subcutaneous (SC) injections have been the
most commonly used.
[0005] Anatomically, the outer surface of the body is made up of
two major tissue layers, an outer epidermis and an underlying
dermis, which together constitute the skin (for review, see
Physiology, Biochemistry, and Molecular Biology of the Skin, Second
Edition, L. A. Goldsmith, Ed., Oxford University Press, New York,
1991). The epidermis is subdivided into five layers or strata of a
total thickness of between 75 and 150 .mu.m. Beneath the epidermis
lies the dermis, which contains two layers, an outermost portion
referred to at the papillary dermis and a deeper layer referred to
as the reticular dermis. The papillary dermis contains vast
microcirculatory blood and lymphatic plexuses. In contrast, the
reticular dermis is relatively acellular and avascular and made up
of dense collagenous and elastic connective tissue. Beneath the
epidermis and dermis is the subcutaneous tissue, also referred to
as the hypodermis, which is composed of connective tissue and fatty
tissue. Muscle tissue lies beneath the subcutaneous tissue.
[0006] As noted above, both the subcutaneous tissue and muscle
tissue have been commonly used as sites for administration of
pharmaceutical substances. The dermis, however, has rarely been
targeted as a site for administration of substances, and this may
be due, at least in part, to the difficulty of precise needle
placement into the intradermal space. Furthermore, even though the
dermis, in particular, the papillary dermis has been known to have
a high degree of vascularity, it has not heretofore been
appreciated that one could take advantage of this high degree of
vascularity to obtain an improved absorption profile for
administered substances compared to subcutaneous administration.
This is because small drug molecules are typically rapidly absorbed
after administration into the subcutaneous tissue which has been
far more easily and predictably targeted than the dermis has been.
On the other hand, large molecules such as proteins are typically
not well absorbed through the capillary epithelium regardless of
the degree of vascularity so that one would not have expected to
achieve a significant absorption advantage over subcutaneous
administration by the more difficult to achieve intradernal
administration even for large molecules.
[0007] One approach to administration beneath the surface to the
skin and into the region of the intradermal space has been
routinely used in the Mantoux tuberculin test. In this procedure, a
purified protein derivative is injected at a shallow angle to the
skin surface using a 27 or 30 gauge needle (Flynn et al, Chest 106:
1463-5, 1994). A degree of uncertainty in placement of the
injection can, however, result in some false negative test results.
Moreover, the test has involved a localized injection to elicit a
response at the site of injection and the Mantoux approach has not
led to the use of intradermal injection for systemic administration
of substances.
[0008] Some groups have reported on systemic administration by what
has been characterized as "intradernal" injection. In one such
report, a comparison study of subcutaneous and what was described
as "intradernal" injection was performed (Autret et al, Therapie
46:5-8, 1991). The pharmaceutical substance tested was calcitonin,
a protein of a molecular weight of about 3600. Although it was
stated that the drug was injected intradermally, the injections
used a 4 mm needle pushed up to the base at an angle of 60. This
would have resulted in placement of the injectate at a depth of
about 3.5 mm and into the lower portion of the reticular dermis or
into the subcutaneous tissue rather than into the vascularized
papillary dermis. If, in fact, this group injected into the lower
portion of the reticular dermis rather than into the subcutaneous
tissue, it would be expected that the substance would either be
slowly absorbed in the relatively less vascular reticular dermis or
diffuse into the subcutaneous region to result in what would be
functionally the same as subcutaneous administration and
absorption. Such actual or functional subcutaneous administration
would explain the reported lack of difference between subcutaneous
and what was characterized as intradermal administration, in the
times at which maximum plasma concentration was reached, the
concentrations at each assay time and the areas under the
curves.
[0009] Similarly, Bressolle et al. administered sodium ceftazidime
in what was characterized as "intradermal" injection using a 4 mm
needle (Bressolle et al. J Pharm. Sci. 82:1175-1178, 1993). This
would have resulted in injection to a depth of 4 mm below the skin
surface to produce actual or functional subcutaneous injection,
although good subcutaneous absorption would have been anticipated
in this instance because sodium ceftazidime is hydrophilic and of
relatively low molecular weight.
[0010] Another group reported on what was described as an
intradermal drug delivery device (U.S. Pat. No. 5,007,501).
Injection was indicated to be at a slow rate and the injection site
was intended to be in some region below the epidermis, i.e., the
interface between the epidermis and the dermis or the interior of
the dermis or subcutaneous tissue. This reference, however,
provided no teachings that would suggest a selective administration
into the dermis nor did the reference suggest any possible
pharmacokinetic advantage that might result from such selective
administration.
[0011] Thus there remains a continuing need for efficient and safe
methods and devices for administration of pharmaceutical
substances.
SUMMARY OF THE INVENTION.
[0012] The present disclosure relates to a new parenteral
administration method based on directly targeting the dermal space
whereby such method dramatically alters the pharmacokinetics (PK)
and pharmacodynamics (PD) parameters of administered substances. By
the use of direct intradermal (ID) administration means hereafter
referred to as dermal-access means, for example, using
microneedle-based injection and infusion systems (or other means to
accurately target the intradermal space), the pharmacokinetics of
many substances including drugs and diagnostic substances, which
are especially protein and peptide hormones, can be altered when
compared to traditional parental administration routes of
subcutaneous and intravenous delivery. These findings are pertinent
not only to microdevice-based injection means, but other delivery
methods such as needless or needle-free ballistic injection of
fluids or powders into the ID space, Mantoux-type ID injection,
enhanced iontophoresis through microdevices, and direct deposition
of fluid, solids, or other dosing forms into the skin. Disclosed is
a method to increase the rate of uptake for
parenterally-administered drugs without necessitating IV access.
One significant beneficial effect of this delivery method is
providing a shorter T.sub.max.(time to achieve maximum blood
concentration of the drug). Potential corollary benefits include
higher maximum concentrations for a given unit dose (C.sub.max),
higher bioavailability, more rapid uptake rates, more rapid onset
of pharmacodynamics or biological effects, and reduced drug depot
effects. According to the present invention, improved
pharmacokinetics means increased bioavailability, decreased lag
time (T.sub.lag decreased T.sub.max, more rapid absorption rates,
more rapid onset and/or increased C.sub.max for a given amount of
compound administered, compared to subcutaneous, intramuscular or
other non-IV parenteral means of drug delivery.
[0013] By bioavailability is meant the total amount of a given
dosage that reached the blood compartment. This is generally
measured as the area under the curve in a plot of concentration vs.
time. By "lag time" is meant the delay between the administration
of a compound and time to measurable or detectable blood or plasma
levels. T.sub.max is a value representing the time to achieve
maximal blood concentration of the compound, and C.sub.max is the
maximum blood concentration reached with a given dose and
administration method. The time for onset is a function of
T.sub.lag, T.sub.max and C.sub.max, as all of these parameters
influence the time necessary to achieve a blood (or target tissue)
concentration necessary to realize a biological effect. T.sub.max
and C.sub.max can be determined by visual inspection of graphical
results and can often provide sufficient information to compare two
methods of administration of a compound. However, numerical values
can be determined more precisely by analysis using kinetic models
(as described below) and/or other means known to those of skill in
the art.
[0014] Directly targeting the dermal space as taught by the
invention provides more rapid onset of effects of drugs and
diagnostic substances. The inventors have found that substances can
be rapidly absorbed and systemically distributed via controlled ID
administration that selectively accesses the dermal vascular and
lymphatic microcapillaries, thus the substances may exert their
beneficial effects more rapidly than SC administration. This has
special significance for drugs requiring rapid onset, such as
insulin to decrease blood glucose, pain relief such as for
breakthrough cancer pain, or migraine relief, or emergency rescue
drugs such as adrenaline or anti-venom. Natural hormones are also
released in pulsatile fashion with a rapid onset burst followed by
rapid clearance. Examples include insulin that is released in
response to biological stimulus, for example high glucose levels.
Another example is female reproductive hormones, which are released
at time intervals in pulsatile fashion. Human growth hormone is
also released in normal patients in a pulsatile fashion during
sleep. This benefit allows better therapy by mimicking the natural
body rhythms with synthetic drug compounds. Likewise, it may better
facilitate some current therapies such as blood glucose control via
insulin delivery. Many current attempts at preparing "closed loop"
insulin pumps are hindered by the delay period between
administering the insulin and waiting for the biological effect to
occur. This makes it difficult to ascertain in real-time whether
sufficient insulin has been given, without overtitrating and
risking hypoglycemia. The more rapid PK/PD of ID delivery
eliminates much of this type of problem.
[0015] Mammalian skin contains two layers, as discussed above,
specifically, the epidermis and dermis. The epidermis is made up of
five layers, the stratum corneum, the stratum lucidum, the stratum
granulosum, the stratum spinosum and the stratum germinativum and
the dermis is made up of two layers, the upper papillary dermis and
the deeper reticular dermis. The thickness of the dermis and
epidermis varies from individual to individual, and within an
individual, at different locations on the body. For example, it has
been reported that the epidermis varies in thickness from about 40
to about 90 .mu.m and the dermis varies in thickness ranging from
just below the epidermis to a depth of from less than 1 mm in some
regions of the body to just under 2 to about 4 mm in other regions
of the body depending upon the particular study report (Hwang et
al., Ann Plastic Surg 46:327-331, 2001; Southwood, Plast. Reconstr.
Surg 15:423-429, 1955; Rushmer et al., Science 154:343-348,
1966).
[0016] As used herein, intradermal is intended to mean
administration of a substance into the dermis in such a manner that
the substance readily reaches the richly vascularized papillary
dermis and is rapidly absorbed into the blood capillaries and/or
lymphatic vessels to become systemically bioavailable. Such can
result from placement of the substance in the upper region of the
dermis, i.e. the papillary dermis or in the upper portion of the
relatively less vascular reticular dermis such that the substance
readily diffuses into the papillary dermis. It is believed that
placement of a substance predominately at a depth of at least about
0.3 mm, more preferably, at least about 0.4 mm and most preferably
at least about 0.5 mm up to a depth of no more than about 2.5 mm,
more preferably, no more than about 2.0 mm and most preferably no
more than about 1.7 mm will result in rapid absorption of
macromolecular and/or hydrophobic substances. Placement of the
substance predominately at greater depths and/or into the lower
portion of the reticular dermis is believed to result in the
substance being slowly absorbed in the less vascular reticular
dermis or in the subcutaneous region either of which would result
in reduced absorption of macromolecular and/or hydrophobic
substances. The controlled delivery of a substance in this dermal
space below the papillary dermis in the reticular dermis, but
sufficiently above the interface between the dermis and the
subcutaneous tissue, should enable an efficient (outward) migration
of the substance to the (undisturbed) vascular and lymphatic
microcapillary bed (in the papillary dermis), where it can be
absorbed into systemic circulation via these microcapillaries
without being sequestered in transit by any other cutaneous tissue
compartment.
[0017] Another benefit of the invention is to achieve more rapid
systemic distribution and offset of drugs or diagnostic agents.
This is also pertinent for many hormones that in the body are
secreted in a pulsatile fashion. Many side effects are associated
with having continuous circulating levels of substances
administered. A very pertinent example is female reproductive
hormones that actually have the opposite effect (cause infertility)
when continuously present in the blood. Likewise, continuous and
elevated levels of insulin are suspected to down regulate insulin
receptors both in quantity and sensitivity.
[0018] Another benefit of the invention is to achieve higher
bioavailabilities of drugs or diagnostic agents. This effect has
been most dramatic for ID administration of high molecular weight
substances, especially proteins, peptides, and polysaccharides. The
direct benefit is that ID administration with enhanced
bioavailability, allows equivalent biological effects while using
less active agent. This results in direct economic benefit to the
drug manufacturer and perhaps consumer, especially for expensive
protein therapeutics and diagnostics. Likewise, higher
bioavailability may allow reduced overall dosing and decrease the
patient's side effects associated with higher dosing.
[0019] Another benefit of the invention is the attainment of higher
maximum concentrations of drugs or diagnostic substances. The
inventors have found that substances administered ID are absorbed
more rapidly, with bolus administration resulting in higher initial
concentrations. This is most beneficial for substances whose
efficacy is related to maximal concentration. The more rapid onset
allows higher C.sub.Max values to be reached with lesser amounts of
the substance. Therefore, the dose can be reduced, providing an
economic benefit, as well as a physiological benefit since lesser
amounts of the drug or diagnostic agent has to be cleared by the
body.
[0020] Another benefit of the invention is no change in systemic
elimination rates or intrinsic clearance mechanisms of drugs or
diagnostic agents. All studies to date by the applicants have
maintained the same systemic elimination rate for the substances
tested as via IV or SC dosing routes. This indicates this dosing
route has no change in the biological mechanism for systemic
clearance. This is an advantageous from a regulatory standpoint,
since degradation and clearance pathways need not be reinvestigated
prior to filing for FDA approval. This is also beneficial from a
pharmacokinetics standpoint, since it allows predictability of
dosing regimes. Some substances may be eliminated from the body
more rapidly if their clearance mechanism are concentration
dependent. Since ID delivery results in higher C.sub.max, clearance
rate may be increased, although the intrinsic mechanism remains
unchanged.
[0021] Another benefit of the invention is no change in
pharmacodynamic mechanism or biological response mechanism. As
stated above, administered drugs by the methods taught by the
applicants still exert their effects by the same biological
pathways that are intrinsic to other delivery means. Any
pharmacodynamic changes are related only to the difference patterns
of appearance, disappearance, and drug or diagnostic agent
concentrations present in the biological system.
[0022] Using the methods of the present invention, pharmaceutical
compounds may be administered as a bolus, or by infusion. As used
herein, the term "bolus" is intended to mean an amount that is
delivered within a time period of less than ten (10) minutes.
"Infusion" is intended to mean the delivery of a substance over a
time period greater than ten (10) minutes It is understood that
bolus administration or delivery can be carried out with rate
controlling means, for example a pump, or have no specific rate
controlling means, for example user self-injection.
[0023] Another benefit of the invention is removal of the physical
or kinetic barriers invoked when drugs passes through and becomes
trapped in cutaneous tissue compartments prior to systemic
absorption. Elimination of such barriers leads to an extremely
broad applicability to various drug classes. Many drugs
administered subcutaneously exert this depot effect--that is, the
drug is slowly released from the SC space, in which it is trapped,
as the rate determining step prior to systemic absorption, due to
affinity for or slow diffusion through the fatty adipose tissue.
This depot effect results in a lower C.sub.max and longer
T.sub.max, compared to ID, and can result in high inter-individual
variability of absorption. This effect is also pertinent for
comparison to transdermal delivery methods including passive patch
technology, with or without permeation enhances, iontophoretic
technology, sonopheresis, or stratum corneum ablation or disruptive
methods. Transdermal patch technology relies on drug partitioning
through the highly impermeable stratum comeum and epidermal
barriers. Few drugs except highly lipophilic compounds can breach
this barrier, and those that do, often exhibit extended offset
kinetics due to tissue saturation and entrappment of the drugs.
Active transdermal means, while often faster than passive transfer
means, are still restricted to compound classes that can be moved
by charge repulsion or other electronic or electrostatic means, or
carried passively through the transient pores caused by cavitation
of the tissue during application of sound waves. The stratum
corneum and epidermis still provide effective means for inhibiting
this transport. Stratum comeum removal by thermal or laser
ablation, abrasive means or otherwise, still lacks a driving force
to facilitate penetration or uptake of drugs. Direct ID
administration by mechanical means overcomes the kinetic barrier
properties of skin, and is not limited by the pharmaceutical or
physicochemical properties of the drug or its formulation
excipients.
[0024] Another benefit of the invention is highly controllable
dosing regimens. The applicants have determined that ID infusion
studies have demonstrated dosing profiles that are highly
controllable and predictable due to the rapid onset and offset
kinetics of drugs or diagnostic agents delivered by this route.
This allows almost absolute control over the desired dosing regimen
when ID delivery is coupled with a fluid control means or other
control system to regulate metering of the drug or diagnostic agent
into the body. This single benefit alone is one of the principal
goals of most drug or diagnostic agent delivery methods. Bolus ID
substance administration as defined previously results in kinetics
most similar to IV injection and is most desirable for pain
relieving compounds, mealtime insulin, rescue drugs, erectile
dysfunction compounds, or other drugs that require rapid onset.
Also included would be combinations of substances capable of acting
alone or synergistically. Extending the ID administration duration
via infusion can effectively mimic SC uptake parameters, but with
better predictability. This profile is particularly good for
substances such as growth hormones, or analgesics. Longer duration
infusion, typically at lower infusion rates can result in
continuous low basal levels of drugs that is desired for
anticoagulants, basal insulin, and chronic pain therapy. These
kinetic profiles can be combined in multiple fashion to exhibit
almost any kinetic profile desired. An example would be to
pulsatile delivery of fertility hormone (LHRH) for pregnancy
induction, which requires intermittent peaks every 90 minutes with
total clearance between pulses. Other examples would be rapid peak
onset of drugs for migraine relief, followed by lower levels for
pain prophylaxis.
[0025] Another benefit of the invention is reduced degradation of
drugs and diagnostic agents and/or undesirable immunogenic
activity. Transdermal methods using chemical enhancers or
iontophoresis, or sonophoresis or electroporation or thermal
poration require that a drug pass through the viable epidermal
layer, which has high metabolic and immunogenic activity. Metabolic
conversion of substances in the epidermis or sequestration by
immunoglobulins reduces the amount of drug available for
absorption. The ID administration circumvents this problem by
placing the drug directly in the dermis, thus bypassing the
epidermis entirely.
[0026] These and other benefits of the invention are achieved by
directly targeting absorption by the papillary dermis and by
controlled delivery of drugs, diagnostic agents, and other
substances to the dermal space of skin. The inventors have found
that by specifically targeting the intradermal space and
controlling the rate and pattern of delivery, the pharmacokinetics
exhibited by specific drugs can be unexpectedly improved, and can
in many situations be varied with resulting clinical advantage.
Such pharmacokenetics cannot be as readily obtained or controlled
by other parenteral administration routes, except by IV access.
[0027] The present invention improves the clinical utility of ID
delivery of drugs, diagnostic agents, and other substances to
humans or animals. The methods employ dermal-access means (for
example a small gauge needle, especially microneedles), to directly
target the intradermal space and to deliver substances to the
intradermal space as a bolus or by infusion. It has been discovered
that the placement of the dermal-access means within the dermis
provides for efficacious delivery and pharmacokinetic control of
active substances. The dermal-access means is so designed as to
prevent leakage of the substance from the skin and improve
adsorption within the intradermal space. The pharmacokinetics of
hormone drugs delivered according to the methods of the invention
have been found to be vastly different to the pharmacokinetics of
conventional SC delivery of the drug, indicating that ID
administration according to the methods of the invention will
provide improved clinical results. Delivery devices that place the
dermal-access means 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.
[0028] Disclosed is a method to increase the rate of uptake for
parenterally-administered drugs without necessitating IV access.
This effect provides a shorter T.sub.max. Potential corollary
benefits include higher maximum concentrations for a given unit
dose (C.sub.max), higher bioavailability, more rapid onset of
pharmacodynamics or biological effects, and reduced drug depot
effects.
[0029] It has also been found that by appropriate depth control of
the dermal-access means within the intradermal space that the
pharmacokinetics of hormone drugs delivered according to the
methods of the invention can, if required, produce similar clinical
results to that of conventional SC delivery of the drug.
[0030] The pharmacokinetic profile for individual compounds will
vary according to the chemical properties of the compounds. For
example, compounds that are relatively large, having a molecular
weight of at least 1000 Daltons as well as larger compounds of at
least 2000 Daltons, at least 4000 Daltons, at least 10,000 Daltons
and larger and/or hydrophobic compounds are expected to show the
most significant changes compared to traditional parenteral methods
of administration, such as intramuscular, subcutaneous or subdermal
injection. It is expected that small hydrophilic substances, on the
whole, will exhibit similar kinetics for ID delivery compared to
other methods.
DESCRIPTION OF THE DRAWINGS
[0031] FIG. 1 shows a time course of plasma insulin levels of
intradermal versus subcutaneous bolus administration of
fast-acting.
[0032] FIG. 2 shows a time course of blood glucose levels of
intradermal versus subcutaneous bolus administration of fast-acting
insulin.
[0033] FIG. 3 shows a comparison of bolus ID dosing of fast-acting
versus regular insulin.
[0034] FIG. 4 shows the effects of different intradermal injection
depths for bolus dosing of fast-acting insulin on the time course
of insulin levels
[0035] FIG. 5 shows a comparison of the time course of insulin
levels for bolus dosing of long-acting insulin administered
subcutaneously or intradermally.
[0036] FIGS. 6 and 7 show a comparison of the pharmacokinetic
availability and the pharmacodynamic results of granulocyte colony
stimulating factor delivered intradermally with a single needle or
three point needle array, subcutaneously, or intravenously.
DETAILED DESCRIPTION OF THE INVENTION
[0037] The present invention provides a method for therapeutic
treatment by delivery of a drug or other substance to a human or
animal subject by directly targeting the intradermal space, where
the drug or substance is administered to the intradermal space
through one or more dermal-access means incorporated within the
device. Substances infused according to the methods of the
invention have been found to exhibit pharmacokinetics superior to,
and more clinically desirable than that observed for the same
substance administered by SC injection.
[0038] The dermal-access means used for ID administration according
to the invention is not critical as long as it penetrates the skin
of a subject to the desired targeted depth within the intradermal
space without passing through it. In most cases, the device will
penetrate the skin and to a depth of about 0.5-2 mm. The
dermal-access means may comprise conventional injection needles,
catheters or microneedles of all known types, employed singularly
or in multiple needle arrays. The dermal-access means may comprise
needleless devices including ballistic injection devices. The terms
"needle" and "needles" as used herein are intended to encompass all
such needle-like structures The term microneedles as used herein
are intended to encompass structures smaller than about 30 gauge,
typically about 31-50 gauge when such structures are cylindrical in
nature. Non-cylindrical structures encompass by the term
microneedles would therefore be of comparable diameter and include
pyramidal, rectangular, octagonal, wedged, and other geometrical
shapes. Dermal-access means also include ballistic fluid injection
devices, powderjet delivery devices, piezoelectric, electromotive,
electromagnetic assisted delivery devices, gas-assisted delivery
devices, of which directly penetrate the skin to provide access for
delivery or directly deliver substances to the targeted location
within the dermal space. By varying the targeted depth of delivery
of substances by the dermal-access means, pharmacokinetic and
pharmacodynamic (PK/PD) behavior of the drug or substance can be
tailored to the desired clinical application most appropriate for a
particular patient's condition. The targeted depth of delivery of
substances by the dermal-access means may be controlled manually by
the practitioner, or with or without the assistance of indicator
means to indicate when the desired depth is reached. Preferably
however, the device has structural means for controlling skin
penetration to the desired depth within the intradermal space. This
is most typically accomplished by means of a widened area or hub
associated with the shaft of the dermal-access means that may take
the form of a backing structure or platform to which the needles
are attached. The length of microneedles as dermal-access means are
easily varied during the fabrication process and are routinely
produced in less than 2 mm length. Microneedles are also a very
sharp and of a very small gauge, to further reduce pain and other
sensation during the injection or infusion. They may be used in the
invention as individual single-lumen microneedles or multiple
microneedles may be assembled or fabricated in linear arrays or
two-dimensional arrays as to increase the rate of delivery or the
amount of substance delivered in a given period of time.
Microneedles may be incorporated into a variety of devices such as
holders and housings that may also serve to limit the depth of
penetration. The dermal-access means of the invention may also
incorporate reservoirs to contain the substance prior to delivery
or pumps or other means for delivering the drug or other substance
under pressure. Alternatively, the device housing the dermal-access
means may be linked externally to such additional components.
[0039] IV-like pharmacokinetics is accomplished by administering
drugs into the dermal compartment in intimate contact with the
capillary microvasculature and lymphatic microvasculature. In
should be understood that the terms microcapillaries or capillary
beds refer to either vascular or lymphatic drainage pathways within
the dermal area.
[0040] While not intending to be bound by any theoretical mechanism
of action, it is believed that the rapid absorption observed upon
administration into the dermis is achieved as a result of the rich
plexuses of blood and lymphatic vessels in the dermis. However, the
presence of blood and lymphatic plexuses in the dermis would not by
itself be expected to produce an enhanced absorption of
macromolecules. This is because capillary endothelium is normally
of low permeability or impermeable to macromolecules such as
proteins, polysaccharides, nucleic acid polymers, substance having
polymers attached such as pegylated proteins and the like. Such
macromolecules have a molecular weight of at least 1000 Daltons or
of a higher molecular weight of at least, 2000 Daltons, at least
4000 Daltons, at least 10,000 Daltons or even higher. Furthermore,
a relatively slow lymphatic drainage from the interstitium into the
vascular compartment would also not be expected to produce a rapid
increase in plasma concentration upon placement of a pharmaceutical
substance into the dermis.
[0041] One possible explanation for the unexpected enhanced
absorption reported herein is that upon injection of substances so
that they readily reach the papillary dermis an increase in blood
flow and capillary permeability results. For example, it is known
that a pinprick insertion to a depth of 3 mm produces an increase
in blood flow and this has been postulated to be independent of
pain stimulus and due to tissue release of histamine (Arildsson et
al., Microvascular Res. 59:122-130, 2000). This is consistent with
the observation that an acute inflammatory response elicited in
response to skin injury produces a transient increase in blood flow
and capillary permeability (see Physiology, Biochemistry, and
Molecular Biology of the Skin, Second Edition, L. A. Goldsmith,
Ed., Oxford Univ. Press, New York, 1991, p. 1060; Wilhem, Rev. Can.
Biol. 30:153-172, 1971). At the same time, the injection into the
intradermal layer would be expected to increase interstitial
pressure. It is known that increasing interstitial pressure from
values (beyond the "normal range")of about -7 to about +2 mmHg
distends lymphatic vessels and increases lymph flow (Skobe et al.,
J Investig. Dermatol. Symp. Proc. 5:14-19, 2000). Thus, the
increased interstitial pressure elicited by injection into the
intradermal layer is believed to elicit increased lymph flow and
increased absorption of substances injected into the dermis.
[0042] By "improved pharmacokinetics" it is meant that an
enhancement of pharmacokinetic profile is achieved as measured, for
example, by standard pharmacokinetic parameters such as time to
maximal plasma concentration (T.sub.max), the magnitude of maximal
plasma concentration (C.sub.max) or the time to elicit a minimally
detectable blood or plasma concentration (T.sub.lag). By enhanced
absorption profile, it is meant that absorption is improved or
greater as measured by such pharmacokinetic parameters. The
measurement of pharmacokinetic parameters and determination of
minimally effective concentrations are routinely performed in the
art. Values obtained are deemed to be enhanced by comparison with a
standard route of administration such as, for example, subcutaneous
administration or intramuscular administration. In such
comparisons, it is preferable, although not necessarily essential,
that administration into the intradermal layer and administration
into the reference site such as subcutaneous administration involve
the same dose levels, i.e. the same amount and concentration of
drug as well as the same carrier vehicle and the same rate of
administration in terms of amount and volume per unit time. Thus,
for example, administration of a given pharmaceutical substance
into the dennis at a concentration such as 100 .mu.g/ml and rate of
100 .mu.L per minute over a period of 5 minutes would, preferably,
be compared to administration of the same pharmaceutical substance
into the subcutaneous space at the same concentration of 100
.mu.g/ml and rate of 100 .mu.L per minute over a period of 5
minutes.
[0043] The enhanced absorption profile is believed to be
particularly evident for substances which are not well absorbed
when injected subcutaneously such as, for example, macromolecules
and/or hydrophobic substances. Macromolecules are, in general, not
well absorbed subcutaneously and this may be due, not only to their
size relative to the capillary pore size, it may also be due to
their slow diffusion through the interstitium because of their
size. It is understood that macromolecules can possess discrete
domains having a hydrophobic and/or hydrophilic nature. In
contrast, small molecules which are hydrophilic are generally well
absorbed when administered subcutaneously and it is possible that
no enhanced absorption profile would be seen upon injection into
the dermis compared to absorption following subcutaneous
administration. Reference to hydrophobic substances herein is
intended to mean low molecular weight substances, for example
substances with molecular weights less than 1000 Daltons, which
have a water solubility which is low to substantially insoluble
[0044] The above-mentioned PK and PD benefits are best realized by
accurate direct targeting of the dermal capillary beds. This is
accomplished, for example, by using microneedle systems of less
than about 250 micron outer diameter, and less than 2 mm exposed
length. Such systems can be constructed using known methods of
various materials including steel, silicon, ceramic, and other
metals, plastic, polymers, sugars, biological and or biodegradable
materials, and/or combinations thereof.
[0045] It has been found that certain features of the intradernal
administration methods provide clinically useful PK/PD and dose
accuracy. For example, it has been found that placement of the
needle outlet within the skin significantly affects PK/PD
parameters. The outlet of a conventional or standard gauge needle
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 causes the delivered substance to be
deposited at a much shallower depth nearer to 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. That is, at
a greater depth a needle outlet with a greater exposed height will
still seal efficiently where as an outlet with the same exposed
height will not seal efficiently when placed in a shallower depth
within the intradermal space. Typically, the exposed height of the
needle outlet will be from 0 to about 1 mm. A needle outlet with an
exposed height of 0 mm 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 that is either
formed by a bevel or by an opening through the side of the needle
has a measurable exposed height. It is understood that a single
needle may have more than one opening or outlets suitable for
delivery of substances to the dermal space.
[0046] It has also been found that by controlling the pressure of
injection or infusion may avoid the high backpressure exerted
during ID administration. By placing a constant pressure directly
on the liquid interface a more constant delivery rate can be
achieved, which may optimize absorption and obtain the improved
pharmacokinetics. Delivery rate and volume can also be controlled
to prevent the formation of wheals at the site of delivery and to
prevent backpressure from pushing the dermal-access means out of
the skin. The appropriate delivery rates and volumes to obtain
these effects for a selected substance may be determined
experimentally using only ordinary skill. Increased spacing between
multiple needles allows broader fluid distrubtion and increased
rates of delivery or larger fluid volumes. In addition, it has been
found that ID infusion or injection often produces higher initial
plasma levels of drug than conventional SC administration,
particularly for drugs that are susceptible to in vivo degradation
or clearance or for compounds that have an affinity to the SC
adipose tissue or for macromolecules that diffuse slowly through
the SC matrix. This may, in many cases, allow for smaller doses of
the substance to be administered via the ID route.
[0047] The administration methods useful for carrying out the
invention include both bolus and infusion delivery of drugs and
other substances to humans or animals subjects. A bolus dose is a
single dose delivered in a single volume unit over a relatively
brief period of time, typically less than about 10 minutes.
Infusion administration comprises administering a fluid at a
selected rate that may be constant or variable, over a relatively
more extended time period, typically greater than about 10 minutes.
To deliver a substance the dermal-access means is placed adjacent
to the skin of a subject providing directly targeted access within
the intradermal space and the substance or substances are delivered
or administered into the intradermal space where they can act
locally or be absorbed by the bloodstream and be distributed
systematically. The dermal-access means may be connected to a
reservoir containing the substance or substances to be delivered.
The form of the substance or substances to be delivered or
administered include solutions thereof in pharmaceutically
acceptable diluents or solvents, emulsions, suspensions, gels,
particulates such as micro- and nanoparticles either suspended or
dispersed, as well as in-situ forming vehicles of the same.
Delivery from the reservoir into the intradermal space may occur
either passively, without application of the external pressure or
other driving means to the substance or substances to be delivered,
and/or actively, with the application of pressure or other driving
means. Examples of preferred pressure generating means include
pumps, syringes, elastomer membranes, gas pressure, piezoelectric,
electromotive, elecrtomagnetic pumping, or Belleville springs or
washers or combinations thereof. If desired, the rate of delivery
of the substance may be variably controlled by the
pressure-generating means. As a result, the substance enters the
intradermal space and is absorbed in an amount and at a rate
sufficient to produce a clinically efficacious result.
[0048] As used herein, the term "clinically efficacious result" is
meant a clinically useful biological response including both
diagnostically and therapeutically useful responses, resulting from
administration of a substance or substances. For example,
diagnostic testing or prevention or treatment of a disease or
condition is a clinically efficacious result. Such clinically
efficacious results include diagnositic results such as the
measurement of glomerular filtration pressure following injection
of inulin, the diagnosis of adrenocortical function in children
following injection of ACTH, the causing of the gallbladder to
contract and evacuate bile upon injection of cholecystokinin and
the like as well as therapeutic results, such as clinically
adequate control of blood sugar levels upon injection of insulin,
clinically adequate management of hormone deficiency following
hormone injection such as parathyroid hormone or growth hormone,
clinically adequate treatment of toxicity upon injection of an
antitoxin and the like.
[0049] Substances that can be delivered intradermally in accordance
with the present invention are intended to include pharmaceutically
or biologically active substances including include diagnostic
agents, drugs, and other substances which provide therapeutic or
health benefits such as for example nutraceuticals. Diagnostic
substances useful with the present invention include macromolecular
substances such as, for example, inulin, ACTH (e.g. corticotropin
injection), luteinizing hormone-releasing hormone (eg., Gonadorelin
Hydrochloride), growth hormone-releasing hormone (e.g. Sermorelin
Acetate), cholecystokinin (Sincalide), parathyroid hormone and
fragments thereof (e.g. Teriparatide Acetate), thyroid releasing
hormone and analogs thereof (e.g. protirelin), secretin and the
like.
[0050] Therapeutic substances which can be used with the present
invention include Alpha-1 anti-trypsin, Anti-Angiogenesis agents,
Antisense, butorphanol, Calcitonin and analogs, Ceredase, COX-II
inhibitors, dermatological agents, dihydroergotamine, Dopamine
agonists and antagonists, Enkephalins and other opioid peptides,
Epidermal growth factors, Erythropoietin and analogs, Follicle
stimulating hormone, G-CSF, Glucagon, GM-CSF, granisetron, Growth
hormone and analogs (including growth hormone releasing hormone),
Growth hormone antagonists, Hirudin and Hirudin analogs such as
Hirulog, IgE suppressors, Insulin, insulinotropin and analogs,
Insulin-like growth factors, Interferons, Interleukins, Luteinizing
hormone, Luteinizing hormone releasing hormone and analogs,
Heparins, Low molecular weight heparins and other natural,
modified, or syntheic glycoaminoglycans, M-CSF, metoclopramide,
Midazolam, Monoclonal antibodies, Peglyated antibodies, Pegylated
proteins or any proteins modified with hydrophilic or hydrophobic
polymers or additional functional groups, Fusion proteins, Single
chain antibody fragments or the same with any combination of
attached proteins, macromolecules, or additional functional groups
thereof, Narcotic analgesics, nicotine, Non-steroid
anti-inflammatory agents, Oligosaccharides, ondansetron,
Parathyroid hormone and analogs, Parathyroid hormone antagonists,
Prostaglandin antagonists, Prostaglandins, Recombinant soluble
receptors, scopolarnine, Serotonin agonists and antagonists,
Sildenafil, Terbutaline, Thrombolytics, Tissue plasminogen
activators, TNF-, and TNF-antagonist, the vaccines, with or without
carriers/adjuvants, including prophylactics and therapeutic
antigens (including but not limited to subunit protein, peptide and
polysaccharide, polysaccharide conjugates, toxoids, genetic based
vaccines, live attenuated, reassortant, inactivated, whole cells,
viral and bacterial vectors) in connection with, addiction,
arthritis, cholera, cocaine addiction, diphtheria, tetanus, HIB,
Lyme disease, meningococcus, measles, mumps, rubella, varicella,
yellow fever, Respiratory syncytial virus, tick borne j apanese
encephalitis, pneumococcus, streptococcus, typhoid, influenza,
hepatitis, including hepatitis A, B, C and E, otitis media, rabies,
polio, HIV, parainfluenza, rotavirus, Epstein Barr Virus, CMV,
chlamydia, non-typeable haemophilus, moraxella catarrhalis, human
papilloma virus, tuberculosis including BCG, gonorrhoea, asthma,
atheroschlerosis malaria, E-coli, Alzheimer's Disease, H. Pylori,
salmonella, diabetes, cancer, herpes simplex, human papilloma and
the like other substances including all of the major therapeutics
such as agents for the common cold, Anti-addiction, antiallergy,
anti-emetics, anti-obesity, antiosteoporeteic, anti-infectives,
analgesics, anesthetics, anorexics, antiarthritics, antiasthmatic
agents, anticonvulsants, anti-depressants, antidiabetic agents,
antihistamines, anti-inflammatory agents, antimigraine
preparations, antimotion sickness preparations, antinauseants,
antineoplastics, antiparkinsonism drugs, antipruritics,
antipsychotics, antipyretics, anticholinergics, benzodiazepine
antagonists, vasodilators, including general, coronary, peripheral
and cerebral, bone stimulating agents, central nervous system
stimulants, hormones, hypnotics, immunosuppressives, muscle
relaxants, parasympatholytics, parasympathomimetrics,
prostaglandins, proteins, peptides, polypeptides and other
macromolecules, psychostimulants, sedatives, and sexual
hypofunction and tranquilizers.
[0051] Pharmacokinetic analysis of insulin infusion data was
carried out as follows. Stepwise nonlinear least-squares regression
was used to analyze the insulin concentration-time data from each
individual animal. Initially, an empirical biexponential equation
was fit to the insulin concentration-time data for the negative
control condition. This analysis assumed first-order release of
residual insulin, and recovered parameters for the first-order rate
constant for release, the residual insulin concentration at the
release site, a lag time for release, and a first-order rate
constant for elimination of insulin from the systemic circulation.
The parameters recovered in this phase of the analysis are of no
intrinsic importance, but merely account for the fraction of
circulating insulin derived from endogenous sources.
[0052] The second step of the analysis involved fitting an explicit
compartmental model to the insulin concentration-time data during
and after subcutaneous or intradermal infusion. The scheme upon
which the mathematical model was based is shown in the upper part
of FIG. 1. [PK/PD model fig]. Infusion of insulin proceeded from
t=0 to t=240 min; after a lag time (t.sub.lag,2), absorption from
the infusion site was mediated by a first-order process governed by
the absorption rate constant k.sub.a. Insulin absorbed into the
systemic circulation distributed into an apparent volume V
contaminated by an unknown fractional bioavailability F, and was
eliminated according to a first-order rate constant K. The fitting
routine recovered estimates of t.sub.lag,2, k.sub.a, V/F, and K;
parameters associated with the disposition of endogenous insulin
(C.sub.R, t.sub.lag,1, k.sub.R), which were recovered in the first
step of the analysis, were treated as constants.
[0053] Parameter estimates are reported as mean .+-.SD. The
significance of differences in specific parameters between the two
different modes of insulin administration (subcutaneous versus
intradermal infusion) was assessed with the paired Student's
t-test.
[0054] Pharmacodynamic analysis of insulin infusion data was
calculated as follows. Plasma concentrations of glucose were used
as a surrogate for the pharmacological effect of insulin. The
change in response variable R (plasma glucose concentration) with
respect to time t was modeled as 1 R t = k in - E k out
[0055] where k.sub.in is the zero-order infusion of glucose,
o.sub.ut is the first-order rate constant mediating glucose
elimination, and E is the effect of insulin according to the
sigmoid Hill relationship 2 E = E max C EC 50 + C
[0056] in which M.sub.ax is the maximal stimulation of o.sub.ut by
insulin, EC.sub.50 is the insulin concentration at which
stimulation of o.sub.ut is half maximal, C is the concentration of
insulin, and .gamma. is the Hill coefficient of the relationship.
Initial modeling efforts utilized the plasma concentration of
insulin as the mediator of pharmacological response. However, this
approach did not capture the delay in response of plasma glucose to
increasing concentrations of plasma insulin. Therefore, an
effect-compartment modeling approach was finally adopted in which
the effect of insulin was mediated from a hypothetical effect
compartment peripheral to the systemic pharmacokinetic
compartment
[0057] The pharmacodynamic analysis was conducted in two steps. In
the first step of the analysis, initial estimates of the
pharmacokinetic parameters associated with the disposition of
glucose (o.sub.ut and the volume of distribution of glucose,
V.sub.glucose) were determined from the glucose concentration-time
data in the negative control condition. The full integrated
pharmacokinetic-pharmacodynamic model then was fit simultaneously
to the glucose concentration-time data from the negative control
condition and each insulin delivery condition for each animal
(i.e., two sets of pharmacodynamic parameters were obtained for
each animal: one from the simultaneous analysis of the subcutaneous
insulin infusion/negative control data, and one from the
simultaneous analysis of the intradermal insulin infusion/negative
control data). In all pharmacodynamic analyses, the parameters
governing insulin disposition obtained during pharmacokinetic
analysis of insulin concentration-time data from each animal were
held constant.
[0058] All other pharmacokinetic analyses were calculated using
non-compartmental methods using similar sofware programs and
techniques known in the art.
[0059] Having described the invention in general, the following
specific but not limiting examples and reference to the
accompanying Figures set forth various examples for practicing the
dermal accessing, direct targeting drug administration method and
examples of dermal administered drug substances providing improved
PK and PD effects.
[0060] A representative example of dermal-access microdevice
comprising a single needle were prepared from 34 gauge steel stock
(MicroGroup, Inc., Medway, MA) and a single 28.degree. bevel was
ground using an 800 grit carborundum grinding wheel. Needles were
cleaned by sequential sonication in acetone and distilled water,
and flow-checked with distilled water. Microneedles were secured
into small gauge catheter tubing (Maersk Medical) using UV-cured
epoxy resin. Needle length was set using a mechanical indexing
plate, with the hub of the catheter tubing acting as a
depth-limiting control and was confirmed by optical microscopy. For
experiments using needles of various lengths, the exposed needle
lengths were adjusted to 0.5, 0.8, 1, 2 or 3 mm using the indexing
plate. Connection to the fluid metering device, either pump or
syringe, was via an integral Luer adapter at the catheter inlet.
During injection, needles were inserted perpendicular to the skin
surface, and were either held in place by gentle hand pressure for
bolus delivery or held upright by medical adhesive tape for longer
infusions. Devices were checked for function and fluid flow both
immediately prior to and post injection. This Luer Lok single
needle catheter design is hereafter designated SS1.sub.--34.
[0061] Yet another dermal-access array microdevices was prepared
consisting of 1" diameter disks machined from acrylic polymer, with
a low volume fluid path branching to each individual needle from a
central inlet. Fluid input was via a low volume catheter line
connected to a Hamilton microsyringe, and delivery rate was
controlled via a syringe pump. Needles were arranged in the disk
with a circular pattern of 15 mm diameter. Three-needle and
six-needle arrays were constructed, with 12 and 7 mm
needle-to-needle spacing, respectively. All array designs used
single-bevel, 34 G stainless steel microneedles of 1 mm length. The
3-needle 12mm spacing catheter-design is hereafter designated
SS3.sub.--34B, 6-needle 7mm spacing catheter-design is hereafter
designated SS6.sub.--34A.
[0062] Yet another dermal-access array microdevices was prepared
consisting of 11 mm diameter disks machined from acrylic polymer,
with a low volume fluid path branching to each individual needle
from a central inlet. Fluid input was via a low volume catheter
line connected to a Hamilton microsyringe, and delivery rate was
controlled via a syringe pump. Needles were arranged in the disk
with a circular pattern of about5 mm diameter. Three-needle arrays
of about 4 mm spacing connected to a catheter as described above.
Thesedesigns are hereafter designated SS3S.sub.--34.sub.--1,
SS3C.sub.--34.sub.--2, and SS3S.sub.--34.sub.--3 for lmm, 2mm, and
3mm needle lengths respectively.
[0063] Yet another dermal-access ID infusion device was constructed
using a stainless steel 30 gauge needle bent at near the tip at a
90-degree 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 1.0-1.2 mm This
design is hereafter designated SSB1.sub.--30.
EXAMPLE I
[0064] Slow-infusion ID insulin delivery was demonstrated in swine
using a hollow, silicon-based single-lumen microneedle (2 mm total
length and 200.times.100 .mu.OD, corresponding to about 33 gauge)
with an outlet 1.0 .mu.m from the tip (100 .mu.m exposed height),
was fabricated using processes known in the art (U.S. Pat. No.
5,928,207) and mated to a microbore catheter (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 catheter was attached to a MiniMed
507 insulin pump for control of fluid delivery. 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.TM. (Lispro) insulin (Eli Lilly, Indianapolis,
Ind.) and the catheter and microneedle were primed with insulin
according to the manufacturer's instructions.
Sandostatin.RTM.(Sandoz, East Hanover, N.J.) solution was
administered via IV infusion to 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 at a rate of 2 U/hr was
used and maintained for 4 hr. Blood samples were periodically
withdrawn and analyzed for serum insulin concentration and blood
glucose values. Baseline insulin levels before infusion were at the
background detection level of the assay. After initiation of the
infusion, serum insulin levels showed an increase that was
commensurate with the programmed infusion rates. Blood glucose
levels also showed a corresponding drop relative to negative
controls (NC) without insulin infusion and this drop was improved
relative to conventional SC infusion. 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. Calculated PK
parameters for ID infusion indicate that insulin is absorbed much
faster than via than SC administration. Absorption from the ID
space begins almost immediately: the lag time prior to absorption
(t.sub.lag) was 0.88 vs. 13.6 min for ID and SC respectively. Also
the rate of uptake from the administration site is increased by
approximately 3-fold, k.sub.a=0.0666 vs. 0.0225 min.sup.-1 for ID
and SC respectively. The bioavailability of insulin delivered by ID
administration is increasedaproximately 1.3 fold greater than SC
administration.
EXAMPLE II
[0065] Bolus delivery of Lilly Lispro fast acting insulin was
performed using ID and SC bolus administration. The ID injection
microdevice was dermal access array design SS3.sub.--34. 10
international insulin units (U) corresponding to 100 .mu.L volume
respectively, were administered to diabetic Yucatan Mini swine.
Test animals had been previously been rendered diabetic by chemical
ablation of pancreatic islet cells, and were no longer able to
secrete insulin. Test animals received their insulin injection
either via the microneedle array or via a standard 30 G X1/2 in.
needle inserted laterally into the SC tissue space. Circulating
serum insulin levels were detected using a commercial
chemiluminescent assay kit (Immulite, Los Angeles, Calif.) and
blood glucose values were determined using blood glucose strips. ID
injections were accomplished via hand pressure using an analytical
microsyringe and were administered over approximately 60 sec. By
comparison, SC dosing required only 2-3 sec. Referring to FIG. 1,
it is shown that serum insulin levels after bolus administration
demonstrate more rapid uptake and distribution of the injected
insulin when administered via the ID route. The time to maximum
concentration (T.sub.max) is shorter and the maximum concentration
obtained (C.sub.max) is higher for ID vs. SC administration. In
addition, FIG. 2 also demonstrates the pharmacodynamic biological
response to the administered insulin, as measured by the decrease
in blood glucose (BG), showed faster and greater changes in BG
since more insulin was available early after ID administration.
EXAMPLE III
[0066] Lilly Lispro is regarded as fact acting insulin, and has a
slightly altered protein structure relative to native human
insulin.. Hoechst regular insulin, maintains the native human
insulin protein structure that is chemically similar, but has
slower uptake than Lispro when administered by the traditional SC
route. Both insulin types were administered in bolus via the ID
route to determine if any differences in uptake would be discemable
by this route. 5U of either insulin type were administered to the
ID space using dermal access microdevice design SS3.sub.--34. The
insulin concentration verses time data shown in FIG. 3. When
administered by the ID route the PK profiles for regular and
fast-acting insulin were essentially identical, and both insulin
types exhibited faster uptake than Lispro given by the traditional
SC route. This is evidence that the uptake mechanism for ID
administration is less affected by minor biochemical changes in the
administered substance, and that ID delivery provides an
advantageous PK uptake profile for regular insulin that is superior
to SC administered fast-acting insulin.
EXAMPLE IV
[0067] Bolus delivery of Lilly Lispro fast-acting insulin via
microneedle arrays having needles of various lengths was conducted
to demonstrate that the precise deposition of drug into the dermal
space is necessary to obtain the PK advantages and distinctions
relative to SC. Thus, 5U of Lilly Lispro fast-acting insulin was
administered using dermal access design SS3.sub.--34. Additional
microdevices of the same needle array configuration were fabricated
whereby exposed needle lengths of the microdevice array were
lengthened to include arrays with needles lengths of 2 and 3 mm.
The average total dermal thickness in Yucatan Mini swine ranges
from 1.5-2.5 mm. Therefore insulin deposition is expected to be
into the dermis, approximately at the dermal/SC interface, and
below the dermis and within the SC for 1 mm, 2 mm, and 3 mm length
needles respectively. Bolus insulin administration was as described
in EXAMPLE II. Average insulin concentrations verses time are shown
in FIG. 4. The data clearly shows as microneedle length is
increased, the resulting PK profile begins to more closely resemble
SC administration. This data demonstrates the benefits of directly
targeting the dermal space, such benefits include rapid uptake and
distribution, and high initial concentrations. Since the data are
averages of multiple examples, they do not show the increased
inter-individual variability in PK profiles from longer 2 and 3 mm
microneedles. This data demonstrates that since skin thickness may
vary both between individuals and even within a single individual,
shorter needle lengths that accurately target the dermal space are
more reproducible in their PK profile since they are depositing the
drug more consistently in the same tissue compartment. This data
demonstrates longer microneedles that deposit or administer
substances deeper into the dermal space, or partially or wholly
into the SC space, mitigate or eliminate the PK advantages in
comparison to shallow, directly targeted administrations to the
highly vascularized dermal region.
EXAMPLE V
[0068] Bolus delivery of Lantus long-acting insulin was delivered
via the ID route . Lantus is an insulin solution that forms
microprecipitates at the administration site upon injection. These
microparticulates undergo slow dissolution within the body to
provide (according to the manufacturer's literature) a more stable
low level of circulating insulin than other current long-acting
insulin such as crystalline zinc precipitates (e.g. Lente, NPH).
Lantus insulin (10 U dose, 100 uL) was administered to diabetic
Yucatan Mini pigs using the dermal access design SS3.sub.--34 and
by the standard SC method as previously described. Referring to
FIG. 5, when administered via the ID route, similar PK profiles
were obtained relative to SC. Minor distinctions include a slightly
higher "burst" immediately after the ID insulin delivery. This
demonstrates that the uptake of even very high molecular weight
compounds or small particles is achievable via ID administration.
More importantly this supports the fact that the biological
clearance mechanism in the body is not appreciably changed by the
administration route, nor is the way in which that the drug
substance is utilized. This is extremely important for drugs
compounds that have a long circulating half-life (examples would be
large soluble receptor compounds or other antibodies for cancer
treatment, or chemically modified species such as PEGylated drugs).
NEED CLAIM
EXAMPLE VI
[0069] Bolus ID delivery of human granulocyte colony stimulating
factor (GCSF) (Neupogen) was administered via dermal access
microdevice designs SS3.sub.--34B (array) or SS1.sub.--34 (single
needle) to Yucatan minipigs. Delivery rate was controlled via a
Harvard syringe pump and was administered over a 1-2.5 min period.
FIG. 6 shows the PK availability of GCSF in blood plasma as
detected by an ELISA immunoassay specific for GCSF. Administration
via IV and SC delivery was performed as controls. Referring to FIG.
6 bolus ID delivery of GCSF shows the more rapid uptake associated
with ID delivery. C.sub.max is achieved at approximately 30-90
minutes vs. 120 min for SC. Also the bioavailability is
dramatically increased by an approximate factor of 2 as evidenced
by the much higher area under the curve (AUC). Circulating levels
of GCSF are detectable for an extended period, indicting that ID
delivery does not alter the intrinsic biological clearance
mechanism or rate for the drug. These data also show that device
design has minimal effect on the rapid uptake of drug from the ID
space. The data referred to in FIG. 7 also shows the degree and
time course of white blood cell expansion as a result of GCSF
administration with respect to a negative control (no GCSF
administered). White blood cell (WBC) counts were determined by
standard cytometric clinical veterinary methods ID delivery
exhibits the same clinically significant biological outcomes.
Although all delivery means give approximately equal PD outcomes,
this data suggests ID delivery could enable use half the dose to
achieve essentially the same physiological result in comparison to
SC, due to approximately 2-fold bioavailability increase.
EXAMPLE VII
[0070] An ID administration experiment was conducted using a
peptide drug entity: human parathyroid hormone 1-34 (PTH). PTH was
infused for a 4 h period, followed by a 2 h clearance. 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 dermal access microdevice design SSB1.sub.--30
(a stainless steel 30-gauge needle bent at the tip at a 90.degree.
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. A 0.64 mg/mL
PTH solution was infused at a rate of 75 .mu.L/hr. Flow rate was
controlled via a Harvard syringe pump. Weight normalized PTH plasma
levels are shown in Figure XX. {The weight normalized delivery
profiles show a larger area under the curve (AUC) indicating higher
bioavailability, higher peak values at earlier sampling timepoints
(e.g. 15 and 30 min) indicating more rapid onset from ID delivery,
and rapid decrease following termination of infusion (also
indicative of rapid uptake without a depot effect).}
[0071] The above examples and results demonstrate the inventive
delivery method using multi-point array ID administration and
single needle ID administration results in more rapid uptake with
higher C.sub.max than SC injection. ID uptake and distribution is
ostensibly unaffected by device geometry parameters, using needle
lengths of about 0.5 to about 1.7mm, needle number and needle
spacing. No concentration limit for biological absorption was found
and PK profiles were dictated principally by the
concentration-based delivery rate. The primary limitations of ID
administration are the total volume and volumetric infusion-rate
limits for leak-free instillation of exogenous substances into a
dense tissue compartment. Since absorption of drugs from the ID
space appears to be insensitive to both device design and
volumetric infusion rate, numerous formulation/device combinations
can be used to overcome this limitations and provide the required
or desired therapeutic profiles. For example, volume limited dosing
regimens can be circumvented either by using more concentrated
formulations or increasing the total number of instillation sites.
In addition, effective PK control is obtained by manipulating
infusion or administration rate of substances.
[0072] In general, ID delivery as taught by the methods described
hereto via dermal access microneedle devices provides a readily
accessible and reproducible parenteral delivery route, with high
bioavailability, as well as the ability to modulate plasma profiles
by adjusting the device infusion parameters, since uptake is not
ratelimited by biological uptake parameters.
[0073] In the previously described examples, the methods practiced
by the invention demonstrate the ability to deliver a drug in vivo
with greatly improved pharmaceutically relevant rates. This data
indicates an improved pharmacological result for ID administration
as taught by the methods described of other drugs in humans would
be expected according to the methods of the invention.
[0074] All references cited in this specification are hereby
incorporated by reference. The discussion of the references herein
is intended merely to summarize the assertions made by their
authors and no admission is made that any reference constitutes
prior art relevant to patentability. Applicants reserve the right
to challenge the accuracy and pertinency of the cited
references.
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