U.S. patent application number 10/044504 was filed with the patent office on 2002-12-19 for method of intradermally injecting substances.
Invention is credited to Alchas, Paul G., Laurent, Philippe Emile Fernand.
Application Number | 20020193740 10/044504 |
Document ID | / |
Family ID | 27023822 |
Filed Date | 2002-12-19 |
United States Patent
Application |
20020193740 |
Kind Code |
A1 |
Alchas, Paul G. ; et
al. |
December 19, 2002 |
Method of intradermally injecting substances
Abstract
A method of making an intradermal injection using a drug
delivery device containing the substance to be injected. A device
for practicing the method includes a needle cannula having a
forward tip and a limiter portion having a skin engaging surface
surrounding the needle cannula. The needle cannula is in fluid
communication with the substance and the tip of the needle cannula
extends beyond the skin engaging surface a distance equal to
approximately 0.5 mm to 3.0 mm. The needle cannula includes a fixed
angle of orientation relative to the plane of the skin engaging
surface. The skin engaging surface limits penetration of the needle
tip into the skin so that the substance can be expelled through the
needle tip into the dermis layer. Preferably, the fixed angle of
orientation of the needle cannula is generally perpendicular
relative to the skin surface, and the skin engaging surface is
generally flat.
Inventors: |
Alchas, Paul G.; (Wayne,
NJ) ; Laurent, Philippe Emile Fernand; (Oullins,
FR) |
Correspondence
Address: |
HOWARD & HOWARD ATTORNEYS, P.C.
THE PINEHURST OFFICE CENTER, SUITE #101
39400 WOODWARD AVENUE
BLOOMFIELD HILLS
MI
48304-5151
US
|
Family ID: |
27023822 |
Appl. No.: |
10/044504 |
Filed: |
January 10, 2002 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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10044504 |
Jan 10, 2002 |
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09835243 |
Apr 13, 2001 |
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09835243 |
Apr 13, 2001 |
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09417671 |
Oct 14, 1999 |
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Current U.S.
Class: |
604/117 ;
604/507 |
Current CPC
Class: |
Y02A 50/412 20180101;
Y02A 50/39 20180101; A61M 5/3278 20130101; Y02A 50/401 20180101;
Y02A 50/464 20180101; A61M 5/282 20130101; Y02A 50/388 20180101;
Y02A 50/466 20180101; A61M 2202/0445 20130101; A61K 39/00 20130101;
Y02A 50/484 20180101; A61K 2039/54 20130101; A61M 5/3202 20130101;
A61B 17/205 20130101; A61M 37/00 20130101; Y02A 50/396 20180101;
A61M 5/158 20130101; Y02A 50/30 20180101; A61K 2039/53 20130101;
A61M 5/46 20130101 |
Class at
Publication: |
604/117 ;
604/507 |
International
Class: |
A61M 031/00 |
Claims
What is claimed is:
1. A method of making an intradermal injection into the skin of an
animal to obtain systemic delivery or an immune response comprising
the steps of: providing a drug delivery device including a needle
cannula having a forward needle tip and said needle cannula being
in fluid communication with a substance contained in said drug
delivery device and including a limiter portion surrounding said
needle cannula and said limiter portion including a skin engaging
surface, with said needle tip of said needle cannula extending from
said limiter portion beyond said skin engaging surface a distance
equal to approximately 0.5 mm to approximately 3.0 mm and said
needle cannula having a fixed angle of orientation relative to a
plane of the skin engaging surface of the limiter portion;
inserting said needle tip into the skin of an animal and engaging
the surface of the skin with said skin engaging surface of said
limiter portion such that the skin engaging surface of the limiter
portion limits penetration of the needle tip into the dermis layer
of the skin of the animal; and expelling the substance from said
drug delivery device through the needle tip into the skin of the
animal to expose the injected substance to the microcirculatory
blood vasculature and the lymphatic plexuses.
2. A method as set forth in claim 1 wherein said substance is
selected from the group consisting of drugs, vaccines and the like
used in the prevention, diagnosis, alleviation, treatment, or cure
of diseases.
3. A method as set forth in claim 1 wherein said fixed angle of
orientation of said needle cannula is further defined as being
generally perpendicular to said plane of said skin engaging surface
of the limiter portion within about fifteen degrees.
4. A method as set forth in claim 3 wherein said fixed angle of
orientation of said needle cannula is further defined as being
ninety degrees relative to said plane of the skin engaging surface
of the limiter portion within about five degrees.
5. A method as set forth in claim 2 wherein said substance includes
a combination of the drugs or vaccines.
6. A method as set forth in claim 5 wherein said substance is
selected from a combination of vaccines against (i) measles, mumps
and rubella, (ii) diphtheria, tetanus and acellular pertussis,
(iii) hepatitis A and hepatitis B, (iv) haemophilus influenza B,
diphtheria, tetanus and acellular pertussis, (v) haemophilus
influenza B, hepatitis B, diphtheria, tetanus and a cellular
pertussis, and (vi) haemophilus influenza B, inactivated polio,
diphtheria, tetanus and acellular pertussis which are commonly
delivered in combination to the subcutaneous and/or intramuscular
space.
7. A method as set forth in claim 1 further including the step of
selecting an injection sight on the skin of the animal.
8. A method as set forth in claim 7 further including the step of
cleaning the injection sight on the skin of the animal prior to
expelling the substance from the drug delivery device into the skin
of the animal.
9. A method as set forth in claim 1 further comprising the step of
filling the drug delivery device with the substance.
10. A method as set forth in claim 1 further including the step of
pressing said skin engaging surface of said limiter portion against
the skin of the animal and applying pressure thereby stretching the
skin of the animal.
11. A method as set forth in claim 1 further including the step of
withdrawing the needle cannula from the skin after injecting the
substance.
12. A method as set forth in claim 1 wherein said step of inserting
said forward tip into the skin is further defined by inserting said
forward tip into the skin to a depth of from approximately 1.0 mm
to approximately 2.0 mm.
13. A method as set forth in claim 1 wherein said step of inserting
said forward tip into the skin is further defined by inserting said
forward tip into the skin to a depth of 1.5 mm.+-.0.2 mm to 0.3
mm.
14. A method as set forth in claim 1 wherein said substance
comprises an influenza vaccine.
15. A method as set forth in claim 1 wherein said substance
comprises a hepatitis B vaccine.
16. A method as set forth in claim 1 wherein said substance
comprises a rabies vaccine.
17. A method as set forth in claim 1 wherein said substance
comprises a cancer vaccine.
18. A method as set forth in claim 1 wherein said substance
comprises a genetic based vaccine.
19. A method as set forth in claim 1 wherein said substance
comprises a tuberculin test substance.
20. A method of making an intradermal injection with a drug
delivery device having a limiter with a skin engaging surface
limiting the depth a needle cannula can be inserted into the skin
of an animal to obtain systemic delivery or an immune response
comprising the steps of: exposing a forward tip of said needle
cannula extending from a limiter beyond a skin engaging surface a
distance equal to approximately 0.5 mm to approximately 3.0 mm and
said needle cannula having a fixed angle of orientation relative to
the skin engaging surface of the limiter; inserting said forward
tip of the needle cannula into the skin of the animal at until said
skin engaging surface contacts the skin of the animal; and
expelling a substance from said device into the dermis layer of the
skin of the animal to expose the injected substance to the
microcirculatory blood vasculature and the lymphatic plexuses.
21. A method as set forth in claim 20 wherein said step of
inserting said forward tip into the skin of the animal is further
defined by inserting said forward tip into the skin at an angle
being generally perpendicular to the skin.
22. A method as set forth in claim 20 wherein said step of
inserting said forward tip into the skin of the animal is further
defined by inserting said forward tip into the skin at an angle of
generally ninety degrees to the skin.
23. A method as set forth in claim 20 wherein said fixed angle of
orientation relative to said skin engaging surface is further
defined as being generally perpendicular within about fifteen
degrees.
24. A method as set forth in claim 23 wherein said drug delivery
device comprises a syringe having a barrel and a plunger received
within said barrel and said plunger being depressable to expel said
substance from said delivery device through the forward tip of said
needle cannula.
25. A method as set forth in claim 24 wherein said step of
expelling the substance from said delivery device is further
defined by grasping said hypodermic needle with a first hand and
depressing said plunger with an index finger of a second hand.
26. A method as set forth in claim 24 wherein said step of
expelling the substance from said delivery device is further
defined by grasping said hypodermic needle with a first hand and
depressing said plunger on said hypodermic needle with a thumb of a
second hand.
27. A method as set forth in claim 24 wherein said step of
inserting the said forward tip into the skin of the animal is
further defined by pressing the skin of the animal with said
limiter.
28. A method as set forth in claim 24 further including the step of
attaching a needle assembly to a tip of said barrel of said syringe
with said needle assembly including said needle cannula and said
limiter.
29. A method as set forth in claim 28 further including the step of
exposing the tip of said barrel before attaching said needle
assembly thereto by removing a cap from said tip of said
barrel.
30. A method as set forth in claim 20 wherein said animal is
human.
31. A method as set forth in claim 24 wherein said step of
inserting said forward tip of said needle into the skin of the
animal is further defined by simultaneously grasping said
hypodermic needle with a first hand and pressing said limiter
against the skin of the animal thereby stretching the skin of the
animal.
32. A method as set forth in claim 31 wherein said step of
expelling the substance is further defined by depressing said
plunger with an index finger of the first hand.
33. A method as set forth in claim 31 wherein said step of
expelling the substance is further defined by depressing said
plunger with a thumb of the first hand.
34. A method as set forth in claim 20 further including the step of
withdrawing said forward tip of said needle cannula from the skin
of the animal after the substance has been injected into the skin
of the animal.
35. A method as set forth in claim 20 wherein said step of
inserting said forward tip into the skin is further defined by
inserting said forward tip into the skin to a depth of from
approximately 1.0 mm to approximately 2.0 mm.
36. A method as set forth in claim 35 wherein said step of
inserting said forward tip into the skin is further defined by
inserting said forward tip into the skin to a depth of 1.5
mm.+-.0.2 mm to 0.3 mm.
37. A method as set forth in claim 20 wherein said step of exposing
said forward tip of said needle cannula is further defined by
removing a cap from said delivery device.
38. A method as set forth in claim 20 wherein said substance is
selected from the group consisting of drugs, vaccines and the like
used in the prevention, diagnosis, alleviation, treatment, or cure
of disease.
39. A method as set forth in claim 38 wherein said drugs 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, Leutenizing hormone,
Leutenizing hormone releasing hormone and analogs, Low molecular
weight heparin, M-CSF, metoclopramide, Midazolam, Monoclonal
antibodies, Narcotic analgesics, nicotine, Non-steroid
anti-inflammatory agents, Oligosaccharides, ondansetron,
Parathyroid hormone and analogs, Parathyroid hormone antagonists,
Prostaglandin antagonists, Prostaglandins, Recombinant soluble
receptors, scopolamine, Serotonin agonists and antagonists,
Sildenafil, Terbutaline, Thrombolytics, Tissue plasminogen
activators, TNF-, and TNF-antagonist, said vaccines, with or
without carriers/adjuvants, include 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 japanese
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, Alzheimers, H. Pylori,
salmonella, diabetes, cancer, herpes simplex, human papilloma and
like other substances include all of the major therapeutics such as
agents for the common cold, Anti-addiction, anti-allergy,
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, sexual hypofunction
and tranquilizers and major diagnostics such as tuberculin and
other hypersensitivity agents.
40. A method as set forth in claim 38 wherein said substance
comprises an influenza vaccine.
41. A method as set forth in claim 38 wherein said substance
comprises a hepatitis B vaccine.
42. A method as set forth in claim 38 wherein said substance
comprises a rabies vaccine.
43. A method as set forth in claim 38 wherein said substance
comprises a cancer vaccine.
44. A method as set forth in claim 38 wherein said substance
comprises a genetic based vaccine.
45. A method as set forth in claim 20 wherein said step of
expelling the substance from said device into the dermis layer of
the skin includes expelling a small volume of air from the device
into the dermis layer before expelling said substance.
46. A method of making an intradermal injection into the skin of an
animal comprising the steps of: providing a drug delivery device
with a prefillable container including a needle cannula having a
forward needle tip and said needle cannula being in fluid
communication with a substance contained in said prefillable
container and including a limiter portion surrounding said needle
cannula and said limiter portion including a skin engaging surface,
with said needle tip of said needle cannula extending from said
limiter portion beyond said skin engaging surface and said needle
cannula having a fixed angle of orientation relative to a plane of
the skin engaging surface of the limiter portion; inserting said
needle tip into the skin of an animal and engaging the surface of
the skin with said skin engaging surface of said limiter portion
such that the skin engaging surface of the limiter portion limits
penetration of the needle tip into the dermis layer of the skin of
the animal; and expelling a small volume of air and the substance
from said drug delivery device through the needle tip into the skin
of the animal to expose the injected substance to the
microcirculatory blood vascularity and the lymphatic plexuses where
the substance can be taken up, absorbed or can interact with the
cells to obtain systemic delivery or an immune response in cases
where the substance is either a drug or one or more vaccines.
47. A method as set forth in claim 46 wherein said step of
inserting said forward tip into the skin of the animal is further
defined by inserting said forward tip into the skin at an angle
being generally perpendicular to the skin within about fifteen
degrees.
48. A method as set forth in claim 47 wherein said step of
inserting said forward tip into the skin of the animal is further
defined by inserting said forward tip into the skin at an angle of
generally ninety degrees to the skin within about five degrees.
49. A method as set forth in claim 46 wherein said limiter portion
has a generally flat skin engaging surface surrounding said needle
tip having an outside diameter of at least 5 mm.
50. A method as set forth in claim 49 wherein said step of
providing a limiter portion is further defined by said forward tip
of said needle cannula extending beyond said skin engaging surface
a distance equal to approximately 0.5 mm to approximately 3.0
mm.
51. A method as set forth in claim 46 wherein said barrel of said
syringe is made of glass.
52. A method as set forth in claim 46 wherein said step of
inserting said forward tip into the skin is further defined by
inserting said forward tip into the skin to a depth of from
approximately 1.0 mm to approximately 2.0 mm.
53. A method as set forth in claim 46 wherein said step of
inserting said forward tip into the skin is further defined by
inserting said forward tip into the skin to a depth of 1.5
mm.+-.0.2 mm to 0.3 mm.
54. A method as set forth in claim 46 wherein said substance is
selected from the group consisting of drugs, vaccines and the like
used in the prevention, diagnosis, alleviation, treatment, or cure
of diseases.
55. A method as set forth in claim 46 wherein said substance is
selected from the group consisting of drugs, vaccines and the like
used in the prevention, diagnosis, alleviation, treatment, or cure
of diseases.
56. A method as set forth in claim 55 wherein said substances
includes a combination of drugs or vaccines.
57. A method as set forth in claim 56 wherein said substance is
selected from vaccine combinations against (i) measles, mumps and
rubella, (ii) diphtheria, tetanus and acellular pertussis, (iii)
hepatitis A and hepatitis B, (iv) haemophilus influenza B,
diphtheria, tetanus and acellular pertussis, (v) haemophilus
influenza B, hepatitis B, diphtheria, tetanus and acellular
pertussis, and (vi) haemophilus influenza B, inactivated polio,
diphtheria, tetanus and acellular pertussis which are commonly
delivered in combination to the subcutaneous and/or intramuscular
space.
Description
REFERENCE TO RELATED APPLICATIONS
[0001] The present application is a continuation-in-part of U.S.
patent application Ser. No. 09/835,243, filed on Apr. 13, 2001,
which is a continuation-in-part of U.S. patent application Ser. No.
09/417,671, filed on Oct. 14, 1999.
FIELD OF THE INVENTION
[0002] The present invention generally relates to a method for
delivering substances such as drugs, vaccines and the like used in
the prevention, diagnosis, alleviation, treatment, or cure of
diseases into the skin of an animal using an injection device
having a needle cannula and a limiter for engaging the surface of
the skin and limiting penetration of the tip of the needle cannula
into the skin, and more specifically to a method for injecting such
substances intradermally, i.e., preferably from approximately 1.0
mm to approximately 2.0 mm, and most preferably around 1.5
mm.+-.0.2 mm to 0.3 mm, such that the substance is injected into
the dermis layer of the animal. In addition, the method of the
present invention includes fixing the orientation of the needle
cannula, i.e., so that the needle cannula is preferably generally
perpendicular to the plane of the skin engaging surface of the
limiter within about fifteen degrees, and the skin engaging surface
is generally flat.
BACKGROUND OF THE INVENTION
[0003] Intradermal injections are used for delivering a variety of
substances. Many of these substances have proven to be more
effectively absorbed into or react with the immune response system
of the body when injected intradermally. Recently, clinical trials
have shown that hepatitis B vaccines administered intradermally are
more imunogenic than if administered intramuscularly. In addition,
substances have been injected intradermally for diagnostic testing,
such as, for example using what is known in the art as the "Mantoux
test" to determine the immunity status of the animal against
tuberculosis and the immediate hypersensitivity status of Type I
allergic diseases.
[0004] An intradermal injection is made by delivering the substance
into the epidermis and upper layers of the dermis. Below the dermis
layer is subcutaneous tissue (also sometimes referred to as the
hypodermis layer) and muscle tissue, in that order. There is
considerable variation in the skin thickness both between
individuals and within the same individual at different sites of
the body. Generally, the outer skin layer, epidermis, has a
thickness between 50-200 microns, and the dermis, the inner and
thicker layer of the skin, has a thickness between 1.5-3.5 mm.
Therefore, a needle cannula that penetrates the skin deeper than
about 3.0 mm has a potential of passing through the dermis layer of
the skin and making the injection into the subcutaneous region,
which may result in an insufficient immune response, especially
where the substance to be delivered intradermally has not been
indicated for subcutaneous injection. Also, the needle cannula may
penetrate the skin at too shallow a depth to deliver the substance
and result in what is commonly known in the art as a "wet
injection" because of reflux of the substance from the injection
site.
[0005] The standard procedure for making an intradermal injection
is known to be difficult to perform, and therefore dependent upon
experience and technique of the healthcare worker. This procedure
is recommended to be performed by stretching the skin, orienting
the bevel of a 26 Gauge short bevel needle cannula upwardly and
inserting the needle cannula to deliver a volume of 0.5 ml or less
of the substance into the skin of an animal with the needle cannula
being inserted into the skin at an angle varying from around 10-15
degrees relative to the plane of the skin to form a blister or
wheal in which the substance is deposited or otherwise contained.
Accordingly, the technique utilized to perform the standard
intradermal injection is difficult and requires the attention of a
trained nurse or medical doctor. This procedure also makes it
essentially impossible to self-administer an intradermal injection.
Inserting the needle to a depth greater than about 3.0 mm typically
results in a failed intradermal injection because the substance
being expelled through the cannula will be injected into the
subcutaneous tissue of the animal. Further, the present method is
not suitable for self-administration of intradermal injections.
[0006] The most frequent cause of a failed intradermal injection is
derived from inserting the needle into the skin at an angle greater
than 15 degrees. A further cause of error is derived from pinching
rather than stretching the skin in the area of the injection, which
is normally done when giving a subcutaneous rather than an
intradermal injection. Pinching increases the likelihood of giving
a subcutaneous injection. Procedural errors as described above
result in delivering the contents of the injection into the
subcutaneous layer, which can reduce the effectiveness of the
injection, as well as possibly deliver the substance in a way not
approved for delivery. Intradermal injections performed by using
the standard procedure also are known to cause a significant amount
of pain to the recipient of the injection because the needle
cannula is inserted into the skin at an angle of about 10-15
degrees. By inserting the needle cannula at this angle, about 5 mm
to about 6 mm of the needle is actually inserted into the skin.
This results in a significant disruption of the pain receptors
dispersed throughout the upper layers of the skin.
[0007] Accordingly, there has been a long felt need for a
simplified method of performing an intradermal injection of
substances which overcomes the problems and limitations associated
with conventional methods, especially including reducing the
probability of error and pain caused from the injection by making
such injections less dependent upon experience and technique. In
addition, there has been a need to limit the depth of penetration
of the needle cannula into the skin of the animal to avoid entry
into the subcutaneous layer of the skin as well as reliably fixing
the orientation of the needle cannula relative to the skin. Also,
there has been a need to apply pressure to the skin of the animal
to facilitate formation of the blister or wheal in the skin in
which the substance is deposited or otherwise contained and avoid
wet injections.
SUMMARY OF THE INVENTION AND ADVANTAGES
[0008] In contrast to the conventional methods discussed above, it
has been found by the applicant that a method of intradermally
injecting substances into the skin to obtain systemic delivery or
an immune response can be used in accordance with the present
invention to effectively and reliably deliver such substances
intradermally. Specifically, the method includes fixing the
orientation of the needle cannula relative to the skin and engaging
the surface of the skin to limit the depth of penetration of the
needle cannula into the skin, i.e., preferably from approximately
1.0 mm to approximately 2.0 mm, and most preferably around 1.5
mm.+-.0.2 mm to 0.3 mm, to avoid entry into the subcutaneous layer.
In addition, the method includes applying pressure to the surface
of the skin to facilitate delivery of the substance, particularly
formation of a blister or wheal in the skin in which the substance
is deposited or otherwise contained. Further, the pressure applied
masks the pain derived from the intradermal injection by
stimulating the muscle fibers to block the pain receptors. Many
substances have proven to be more effective when injected
intradermally in the prevention, diagnosis, alleviation, treatment,
or cure of diseases. These include several drugs and vaccines such
as, for example, influenza vaccines, hepatitis B vaccine, rabies
vaccines tuberculin test substance and many others. These vaccines,
drugs and the like will hereinafter be referred to as substances.
It is also possible to self-administer intradermal injections by
the method of this invention.
[0009] The hypodermic needle assembly set forth above includes the
elements necessary to perform the present invention directed to an
improved method of making an intradermal injection into the skin of
an animal including the steps of providing a drug delivery device
including a needle cannula having a forward needle tip and the
needle cannula being in fluid communication with a substance
contained in the drug delivery device and including a limiter
portion surrounding the needle cannula and the limiter portion
including a skin engaging surface, with the needle tip of the
needle cannula extending from the limiter portion beyond the skin
engaging surface a distance equal to approximately 0.5 mm to
approximately 3.0 mm and the needle cannula having a fixed angle of
orientation relative to a plane of the skin engaging surface of the
limiter portion, inserting the needle tip into the skin of an
animal and engaging the surface of the skin with the skin engaging
surface of the limiter portion, such that the skin engaging surface
of the limiter portion limits penetration of the needle cannula tip
into the dermis layer of the skin of the animal, and expelling the
substance from the drug delivery device through the needle cannula
tip into the skin of the animal to expose the injected substance to
the microcirculatory blood vasculature and the lymphatic
plexuses.
[0010] In the preferred method, the substance is selected from the
group consisting of drugs, vaccines and the like used in the
prevention, diagnosis, alleviation, treatment, or cure of diseases.
In addition, the fixed angle of orientation of the needle cannula
is further defined as being generally perpendicular to the plane of
the skin engaging surface of the limiter portion within about
fifteen degrees, and most preferably within about five degrees,
substantially ninety degrees relative to the plane of the skin
engaging surface of the limiter portion. In addition, the drug
delivery device includes a syringe having a barrel and a plunger
rod preferably including a stopper received within the barrel
therein and the plunger rod being depressable to expel the
substance from the delivery device through the tip of the needle
cannula, with the barrel including a barrel tip and the needle
cannula forms part of a needle assembly attachable to and in fluid
communication with the barrel tip.
[0011] Also, the preferred embodiment of the method includes the
step of selecting an injection sight on the skin of the animal and
includes the step of cleaning the injection sight on the skin of
the animal prior to expelling the substance from the drug delivery
device into the skin of the animal. In addition, the method
includes the step of filling the drug delivery device with the
substance. Further, the method includes the steps of pressing the
skin engaging surface of the limiter portion against the skin of
the animal and applying pressure, thereby stretching the skin of
the animal, and withdrawing the needle cannula from the skin after
injecting the substance. Still further, the step of inserting the
forward tip into the skin is further defined by inserting the
forward tip into the skin to a depth of from approximately 1.0 mm
to approximately 2.0 mm, and most preferably into the skin to a
depth of 1.5 mm.+-.0.2 to 0.3 mm. The preferred substance comprises
an influenza vaccine, a hepatitis B vaccine, a rabies vaccine, a
cancer vaccine, a genetic based vaccine or a tuberculin test
substance.
[0012] The preferred substance includes a combination of the drugs
or vaccines. In addition, the preferred method includes the
addition of a substance selected from a combination of vaccines
against: (i) measles, mumps and rubella, (ii) diphtheria, tetanus
and acellular pertussis, (iii) hepatitis A and hepatitis B, (iv)
haemophilus influenza B, diphtheria, tetanus and acellular
pertussis, (v) haemophilus influenza B, hepatitis B, diphtheria,
tetanus and a cellular pertussis, and (vi) haemophilus influenza B,
inactivated polio, diphtheria, tetanus and acellular pertussis,
which are commonly delivered in combination to the subcutaneous
and/or intramuscular space.
[0013] In addition, the present invention is directed to a method
of making an intradermal injection with a drug delivery device
having a limiter with a skin engaging surface limiting the depth a
needle cannula can be inserted into the skin of an animal to obtain
systemic delivery or an immune response or including the steps of
exposing a forward tip of the needle cannula extending from a
limiter beyond a skin engaging surface a distance equal to
approximately 0.5 mm to approximately 3.0 mm and the needle cannula
having a fixed angle of orientation relative to the skin engaging
surface of the limiter, inserting the forward tip of the needle
cannula into the skin of the animal at until the skin engaging
surface contacts the skin of the animal, and expelling a substance
from the device into the dermis layer of the skin of the animal to
expose the injected substance to the microcirculatory blood
vasculature and the lymphatic plexuses.
[0014] In the preferred embodiment of the method, the step of
inserting the forward tip into the skin of the animal is further
defined by inserting the forward tip into the skin at an angle
being generally perpendicular to the skin within about fifteen
degrees, with the angle most preferably being generally ninety
degrees to the skin, within about five degrees, and the fixed angle
of orientation relative to the skin engaging surface is further
defined as being generally perpendicular. In the preferred
embodiment, the limiter surrounds the needle cannula, having a
generally planar flat skin engaging surface. Also, the drug
delivery device comprises a syringe having a barrel and a plunger
received within the barrel and the plunger being depressable to
expel the substance from the delivery device through the forward
tip of the needle cannula.
[0015] In the preferred embodiment of the method of the present
invention, expelling the substance from the delivery device is
further defined by grasping the hypodermic needle with a first hand
and depressing the plunger with an index finger of a second hand
and expelling the substance from the delivery device by grasping
the hypodermic needle with a first hand and depressing the plunger
on the hypodermic needle with a thumb of a second hand, with the
step of inserting the forward tip into the skin of the animal
further defined by pressing the skin of the animal with the
limiter. In addition, the method may includes the step of attaching
a needle assembly to a tip of the barrel of the syringe with the
needle assembly including the needle cannula and the limiter, and
includes the step of exposing the tip of the barrel before
attaching the needle assembly thereto by removing a cap from the
tip of the barrel. Alternatively, the step of inserting the forward
tip of the needle into the skin of the animal may be further
defined by simultaneously grasping the hypodermic needle with a
first hand and pressing the limiter against the skin of the animal
thereby stretching the skin of the animal, and expelling the
substance by depressing the plunger with an index finger of the
first hand or expelling the substance by depressing the plunger
with a thumb of the first hand. The method further includes
withdrawing the forward tip of the needle cannula from the skin of
the animal after the substance has been injected into the skin of
the animal. Still further, the method includes inserting the
forward tip into the skin preferably to a depth of from
approximately 1.0 mm to approximately 2.0 mm, and most preferably
to a depth of 1.5 mm.+-.0.2 to 0.3 mm. Also, the step of expelling
the substance from the device into the dermis layer of the skin
includes expelling a small volume of air from the device into the
dermis layer before expelling the substance.
[0016] Also, the substance intradermally delivered in accordance
with the method of the present invention is selected from the group
consisting of drugs, vaccines and the like used in the prevention,
diagnosis, alleviation, treatment, or cure of disease, with the
drugs including 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, Leutenizing
hormone, Leutenizing hormone releasing hormone and analogs, Low
molecular weight heparin, M-CSF, metoclopramide, Midazolam,
Monoclonal antibodies, Narcotic analgesics, nicotine, Non-steroid
anti-inflammatory agents, Oligosaccharides, ondansetron,
Parathyroid hormone and analogs, Parathyroid hormone antagonists,
Prostaglandin antagonists, Prostaglandins, Recombinant soluble
receptors, scopolamine, 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 japanese
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, Alzheimers, 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, anti-allergy,
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, sexual hypofunction
and tranquilizers and major diagnostics such as tuberculin and
other hypersensitivity agents.
[0017] Another embodiment of the method of the present invention of
making an intradermal injection into the skin of an animal includes
the steps of providing a drug delivery device with a prefillable
container including a needle cannula having a forward needle tip
and the needle cannula being in fluid communication with a
substance contained in the prefillable container and including a
limiter portion surrounding the needle cannula and the limiter
portion including a skin engaging surface, with the needle tip of
the needle cannula extending from the limiter portion beyond the
skin engaging surface and the needle cannula having a fixed angle
of orientation relative to a plane of the skin engaging surface of
the limiter portion, inserting the needle tip into the skin of an
animal and engaging the surface of the skin with the skin engaging
surface of the limiter portion such that the skin engaging surface
of the limiter portion limits penetration of the needle tip into
the dermis layer of the skin of the animal, and expelling a small
volume of air and the substance from the drug delivery device
through the needle tip into the skin of the animal to expose the
injected substance to the microcirculatory blood vascularity and
the lymphatic plexuses where the substance can be taken up,
absorbed or can interact with the cells to obtain systemic delivery
or an immune response in cases where the substance is either a drug
or one or more vaccines.
BRIEF DESCRIPTION OF THE DRAWINGS
[0018] Other advantages of the present invention will be readily
appreciated and apparent to those skilled in the art as the same
becomes better understood by reference to the following detailed
description when considered in connection with the accompanying
drawings wherein:
[0019] FIG. 1 is an exploded, perspective illustration of a needle
assembly designed according to this invention.
[0020] FIG. 2 is a partial cross-sectional illustration of the
embodiment of FIG. 1.
[0021] FIG. 3 shows the embodiment of FIG. 2 attached to a syringe
body to form an injection device.
[0022] FIG. 4 is a perspective view of one technique for making the
intradermal injection of the present invention.
[0023] FIG. 5 is a perspective view of a second technique for
making the intradermal injection of the present invention.
[0024] FIG. 6 is a perspective view of a third technique for making
the intradermal injection of the present invention.
[0025] FIG. 7 is a perspective view of a fourth technique for
making the intradermal injection of the present invention.
[0026] FIG. 8 is a bar chart showing the B-gal expression levels of
the clinical trials on swine skin.
[0027] FIG. 9 is a histogram showing the results of a survey of the
subjects pain perception relevant from the human clinical
trial.
[0028] FIG. 10 is a flow chart diagram that schematically
illustrates preparation of the device for use in intradermally
injecting substances, including filling the device with the
substance.
DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS
[0029] FIGS. 1-3 of the drawings illustrate an example of a drug
delivery device which can be used to practice the methods of the
present invention for making intradermal injections illustrated in
FIGS. 4-7. The device 10 illustrated in FIGS. 1-3 includes a needle
assembly 20 which can be attached to a syringe barrel 60. Other
forms of delivery devices may be used including pens of the types
disclosed in U.S. Pat. No. 5,279,586, U.S. patent application Ser.
No. 09/027,607 and PCT Application No. WO 00/09135, the disclosure
of which are hereby incorporated by reference in their entirety.
The method of the present invention can be used to intradermally
inject substances, other than food, such as drugs, vaccines and the
like used in the prevention, diagnosis, alleviation, treatment, or
cure of disease into the skin of an animal such as a human,
referred to collectively herein as "substances".
[0030] The needle assembly 20 includes a hub 22 that supports a
needle cannula 24. The limiter 26 receives at least a portion of
the hub 22 so that the limiter 26 generally surrounds the needle
cannula 24 as best seen in FIG. 2.
[0031] One end 30 of the hub 22 is able to be secured to a receiver
32 of a syringe. A variety of syringe types for containing the
substance to be intradermally delivered according to the present
invention can be used with a needle assembly designed, with several
examples being given below. The opposite end of the hub 22
preferably includes extensions 34 that are nestingly received
against abutment surfaces 36 within the limiter 26. A plurality of
ribs 38 preferably are provided on the limiter 26 to provide
structural integrity and to facilitate handling the needle assembly
20.
[0032] By appropriately designing the size of the components, a
distance "d" between a forward end or tip 40 of the needle 24 and a
skin engaging surface 42 on the limiter 26 can be tightly
controlled. The distance "d" preferably is in a range from
approximately 0.5 mm to approximately 3.0 mm, and most preferably
around 1.5 mm.+-.0.2 mm to 0.3 mm. When the forward end 40 of the
needle cannula 24 extends beyond the skin engaging surface 42 a
distance within that range, an intradermal injection is ensured
because the needle is unable to penetrate any further than the
typical dermis layer of an animal. Typically, the outer skin layer,
epidermis, has a thickness between 50-200 microns, and the dermis,
the inner and thicker layer of the skin, has a thickness between
1.5-3.5 mm. Below the dermis layer is subcutaneous tissue (also
sometimes referred to as the hypodermis layer) and muscle tissue,
in that order.
[0033] As can be best seen in FIG. 2, the limiter 26 includes an
opening 44 through which the forward end 40 of the needle cannula
24 protrudes. The dimensional relationship between the opening 44
and the forward end 40 can be controlled depending on the
requirements of a particular situation. In the illustrated
embodiment, the skin engaging surface 42 is generally planar or
flat and continuous to provide a stable placement of the needle
assembly 20 against an animal's skin. Although not specifically
illustrated, it may be advantageous to have the generally planar
skin engaging surface 42 include either raised portions in the form
of ribs or recessed portions in the form of grooves in order to
enhance stability or facilitate attachment of a needle shield to
the needle tip 40. Additionally, the ribs 38 along the sides of the
limiter 26 may be extended beyond the plane of the skin engaging
surface 42.
[0034] Regardless of the shape or contour of the skin engaging
surface 42, the preferred embodiment includes enough generally
planar or flat surface area that contacts the skin to facilitate
stabilizing the injector relative to the animal's skin. In the most
preferred arrangement, the skin engaging surface 42 facilitates
maintaining the injector in a generally perpendicular orientation
relative to the skin surface and facilitates the application of
pressure against the skin during injection. Thus, in the preferred
embodiment, the limiter has dimension or outside diameter of at
least 5 mm. The major dimension will depend upon the application
and packaging limitations, but a convenient diameter is less than
15 mm or more preferably 11-12 mm.
[0035] It is important to note that although FIGS. 1 and 2
illustrate a two-piece assembly where the hub 22 is made separate
from the limiter 26, a device for use in connection with the
invention is not limited to such an arrangement. Forming the hub 22
and limiter 26 integrally from a single piece of plastic material
is an alternative to the example shown in FIGS. 1 and 2.
Additionally, it is possible to adhesively or otherwise secure the
hub 22 to the limiter 26 in the position illustrated in FIG. 2 so
that the needle assembly 20 becomes a single piece unit upon
assembly.
[0036] Having a hub 22 and limiter 26 provides the advantage of
making an intradermal needle practical to manufacture. The
preferred needle size is a small Gauge hypodermic needle, commonly
known as a 30 Gauge or 31 Gauge needle. Having such a small
diameter needle presents a challenge to make a needle short enough
to prevent undue penetration beyond the dermis layer of an animal.
The limiter 26 and the hub 22 facilitate utilizing a needle 24 that
has an overall length that is much greater than the effective
length of the needle, which penetrates the individual's tissue
during an injection. With a needle assembly designed in accordance
herewith, manufacturing is enhanced because larger length needles
can be handled during the manufacturing and assembly processes
while still obtaining the advantages of having a short needle for
purposes of completing an intradermal injection.
[0037] FIG. 3 illustrates the needle assembly 20 secured to a drug
container such as a syringe 60 to form the device 10. A generally
cylindrical syringe body 62 can be made of plastic or glass as is
known in the art. The syringe body 62 provides a reservoir 64 for
containing the substance to be administered during an injection. A
plunger rod 66 has a manual activation flange 68 at one end with a
stopper 70 at an opposite end as known in the art. Manual movement
of the plunger rod 66 through the reservoir 64 forces the substance
within the reservoir 64 to be expelled out of the end 40 of the
needle as desired.
[0038] The hub 22 can be secured to the syringe body 62 in a
variety of known manners. In one example, an interference fit is
provided between the interior of the hub 22 and the exterior of the
outlet port portion 72 of the syringe body 62. In another example,
a conventional Luer fit arrangement is provided to secure the hub
22 on the end of the syringe 60. As can be appreciated from FIG. 3,
such needle assembly designed is readily adaptable to a wide
variety of conventional syringe styles.
[0039] This invention provides an intradermal needle injector that
is adaptable to be used with a variety of syringe types. Therefore,
this invention provides the significant advantage of facilitating
manufacture and assembly of intradermal needles on a mass
production scale in an economical fashion.
[0040] Having described the intradermal delivery device including
the needle assembly 20 and drug container 60, its operation and use
in practicing the methods of the present invention for
intradermally injecting substances is described below.
[0041] Prior to inserting the needle cannula 24, an injection site
upon the skin of the animal is selected and cleaned. Subsequent to
selecting and cleaning the site, the forward end 40 of the needle
cannula 24 is inserted into the skin of the animal at an angle of
generally 90 degrees until the skin engaging surface 42 contacts
the skin. The skin engaging surface 42 prevents the needle cannula
42 from passing through the dermis layer of the skin and injecting
the substance into the subcutaneous layer.
[0042] While the needle cannula 42 is inserted into the skin, the
substance is intradermally injected. The substance may be prefilled
into the syringe 60, either substantially before and stored therein
just prior to making the injection. Several variations of the
method of performing the injection may be utilized depending upon
individual preferences and syringe type. In any event, the
penetration of the needle cannula 42 is most preferably no more
than about 1.5 mm because the skin engaging surface 42 prevents any
further penetration.
[0043] Also, during the administration of an intradermal injection,
the forward end 40 of the needle cannula 42 is embedded in the
dermis layer of the skin which results in a reasonable amount of
back pressure during the injection of the substance. This back
pressure could be on the order of 76 psi. In order to reach this
pressure with a minimal amount of force having to be applied by the
user to the plunger rod 66 of the syringe, a syringe barrel 60 with
a small inside diameter is preferred such as 0.183" (4.65 mm) or
less. The method of this invention thus includes selecting a
syringe for injection having an inside diameter of sufficient width
to generate a force sufficient to overcome the back pressure of the
dermis layer when the substance is expelled from the syringe to
make the injection.
[0044] In addition, since intradermal injections are typically
carried out with small volumes of the substance to be injected,
i.e., on the order of no more than 0.5 ml, and preferably around
0.1 ml, a syringe barrel 60 with a small inside diameter is
preferred to minimize dead space which could result in wasted
substance captured between the stopper 70 and the shoulder of the
syringe after the injection is completed. Also, because of the
small volumes of substance, on the order of 0.1 ml, a syringe
barrel with a small inside diameter is preferred to minimize air
head space between the level of the substance and the stopper 70
during process of inserting the stopper. Further, the small inside
diameter enhances the ability to inspect and visualize the volume
of the substance within the barrel of the syringe.
[0045] Several variations of performing the intradermal injection
of the present invention (present method) were proven effective
during clinical trials, the results of which will be explained
below. As shown in FIG. 8, the syringe 60 may be grasped with a
first hand 112 and the plunger 66 depressed with the forefinger 114
of a second hand 116. Alternatively, as shown in FIG. 9 the plunger
66 may be depressed by the thumb 118 of the second hand 116 while
the syringe 60 is held by the first hand. In each of these
variations, the skin of the animal is depressed, and stretched by
the skin engaging surface 42 on the limiter 26. The skin is
contacted by neither the first hand 112 nor the second hand
116.
[0046] An additional variation has proven effective for
administering the intradermal injection of the present invention.
This variation includes gripping the syringe 60 with the same hand
that is used to depress the plunger 66. FIG. 10 shows the syringe
60 being gripped with the first hand 112 while the plunger is
simultaneously depressed with the thumb 120 of the first hand 112.
This variation includes stretching the skin with the second hand
114 while the injection is being made. Alternatively, as shown in
FIG. 11, the grip is reversed and the plunger is depressed by the
forefinger 122 of the first hand 112 while the skin is being
stretched by the second hand 116. However, it is believed that this
manual stretching of the skin is unnecessary and merely represents
a variation out of habit from using the standard technique.
[0047] In each of the variations described above, the needle
cannula 24 is inserted only about 1.5 mm into the skin of the
animal. Subsequent to administering the injection, the needle
cannula 24 is withdrawn from the skin and the syringe 60 and needle
assembly 20 are disposed of in an appropriate manner. Each of the
variations were utilized in clinical trials to determine the
effectiveness of both the needle assembly 20 and the present method
of administering the intradermal injection.
[0048] The feasibility of the present method was also proven
effective in animal tests on live swine skin. 50 .mu.g of naked
plasmid DNA encoding the reporter gene, b-galactosidase (b-gal), in
fifty .mu.l volume was delivered intradermally via "rapid bolus"
(approximately 2 .mu.l/sec.). Full thickness skin biopsies were
removed at twenty four hours and evaluated for b-gal activity.
Twelve separate sites were administered the intradermal injections
on three separate Yorkshire swine, i.e., four sites were evaluated
for each group on each swine. Negative controls consisted of
delivery of an equivalent dose of an unrelated plasmid DNA.
Background b-gal activity in the control group combines data from
30 Gauge needle cannula delivered with the standard procedure and
26.6 Gauge needle utilizing the limiter 26 and the present method.
There was no discemable difference detected, as there was no
difference in activity between the control groups.
[0049] Mean b-gal activity was determined for both the standard
procedure and the technique of the present method. Mean b-gal
activity is represented by the bars, and activity within individual
skin sites is represented by the dots on the chart shown in FIG. 8.
Although there was high variability in each of the groups, standard
procedure, present method, and control, there was a significant
increase in b-gal activity in the standard procedure and the
present technique compared to the control group. There was no
statistical difference in b-gal activity between the standard
procedure and the present method. Therefore, it was proven during
the animal tests conducted on swine skin that the present method
could be used to deliver an intradermal injection at least as
effectively as the standard procedure.
[0050] Subsequent to the swine studies, a clinical trial was
conducted on human volunteers to evaluate the effectiveness of the
procedure of the present invention. Twelve nurses administered
intradermal injections to 108 healthy subjects. Six of the nurses
were very experienced in giving intradermal injections, and six of
the nurses only occasionally gave intradermal injections in which
case they only had a baseline competency in giving injections prior
to the study. Each of the nurses received training in the form of
videos and practice upon a rubber arm on both techniques for making
the intradermal injection prior to initiating the trial.
[0051] The subjects comprised various ethnic groups to determine if
ethnicity would have any impact upon functionality. These groups
included:
1 Ethnicity Number (percent) Caucasian 67 (16.7%) African American
22 (20.4%) Latino 12 (11.1%) Asian/Pacific 7 (6.5%)
[0052] Eighteen (16.7%) of the subjects were older than sixty years
of age.
[0053] A 26 Gauge 3/8 inch needle cannula with an intradermal bevel
was utilized for the standard procedure, which includes inserting
the needle into the skin at a fifteen degree angle in order to
avoid delivering a subcutaneous injection. A 30 Gauge 1/2 needle
with an intradermal bevel was used with the limiter 26 to
administer the intradermal injection utilizing the present method
(generally ninety degree insertion of the needle cannula) for
comparison with the standard procedure. Each of the nurses were
instructed to insert the needle cannula into the skin until the
skin engaging surface 42 made tight contact with the skin,
compressing the skin. Each nurse used one of the variations
associated with the limiter 42 and described above to administer
the intradermal injection using the present method. The variation
chosen by each nurse was based upon individual preference.
[0054] Each syringe was filled with 110 .mu.l of saline solution.
The saline solution was delivered via separate injections into the
volar forearm and deltoid region. To determine the effectiveness of
the injection, the site into which the injection was made was
examined for a satisfactory tense white wheal resulting from the
injection of the saline solution. The existence of a white wheal
indicates a successful injection has been made.
[0055] Other variables were analyzed during the trial including the
amount of pain experienced by each of the subjects following the
saline injection, the subjects preference for the variation used,
and the nurses preferences.
[0056] A tuberculin syringe was filled with 110 .mu.l of saline
solution. The air was purged and the filling needle was removed
prior to attaching the appropriate intradermal needle as defined by
a randomization schedule developed for the trial. Each subject was
administered eight intradermal injections, two with 100 .mu.l of
saline solution into the right and left volar forearms, and two
with 100 .mu.l of saline into the right and left deltoid region.
One injection from each pair was given utilizing the present method
of the instant invention and one injection was given utilizing the
standard procedure. Each of the injections were administered
according to a Randomized Schedule developed for the clinical
trial. Good Clinical Practice and Universal Precautions was adhered
to during each of the procedures.
[0057] An injection was considered acceptable if a tense white
wheal was observed soon after the injection was completed.
Completeness of the injection and post-injection bleeding were also
evaluated immediately following each injection. The pain perceived
by the subject was also evaluated immediately after each injection.
The subjects were also asked which intradermal method was preferred
at the conclusion of the each session.
[0058] The most significant improvement over the standard procedure
was the decrease in the amount of pain perceived by each subject.
Pain was measured on a twenty point, Gracely Box SL Scale. Each
subject was asked to select a point on the table listed below that
corresponds to the amount of pain perceived:
2TABLE 1 Score Sensation 0 No Pain Sensation 1 Faint (pain
sensation) 2 3 4 Very Weak 5 Weak 6 7 Very Mild 8 Mild 9 10 11
Moderate 12 Barely Strong 13 Slightly Intense 14 15 Strong 16
Intense 17 Very Intense 18 Extremely Intense 19 20
[0059] FIG. 9 shows a histogram of the pain perceived by each of
the subjects corresponding to the method used to make the
intradermal injection. The present method proved to be
significantly less painful for the subjects than the standard
method. This is believed to be in part due to the reduction in the
length of needle cannula that is inserted into the skin. The
present method results in only 1.5 mm of needle cannula being
inserted into the skin. The standard procedure, because of the
injection angle of fifteen degrees, results in the needle cannula
being inserted at least twice that amount to reach the depth
required to make the injection. Statistically, the present method
proved much less painful than the standard procedure. The table
below indicates that the mean pain score for the standard procedure
is forty percent higher than present method described above. The
median pain score for the standard procedure proved to be twice
that of the present method.
3 Delivery Method Mean Median Standard Dev. Standard Procedure
7.720 8.000 5.423 Present Method 4.460 4.000 4.580
[0060] A visual inspection of the wheal formation subsequent to
each intradermal injection indicated that there was no discemable
difference in results between the two methods of making the
intradermal injection. A binary analysis was made for each
injection site. If no wheal formed after the intradermal injection
was made, a numerical value of zero was assigned. If a tight white
wheal formed after the intradermal injection was made, a numerical
value of one was assigned. Table 2 listed below indicates the
results of the visual inspection:
4 TABLE 2 Delivery Method Zero One Number of sites Standard
Procedure 42 172 214 Present Method 46 170 216
[0061] The data collected indicates that with respect to forming a
tight white wheal the present method performed generally as well as
the standard procedure.
[0062] Each of the nurses was surveyed with respect to their
preference for the standard procedure or the present method with
respect to a particular injection. The nurses indicated a
substantial preference for the present method in response to
several inquiries. The first was an inquiry as to which intradermal
injection was thought to be best relative to each patient. Table 3
indicates the nurses had a significant overall preference for the
present method:
5 TABLE 3 Delivery Method Number Standard Procedure 24 Present
Method 81 No Preference 3 Total Responses 108
[0063] In response to an inquiry as to the easiest method to
administer an intradermal injection, the nurses indicated a
significant preference for the present method:
6 TABLE 4 Delivery Method Number Standard Procedure 5 Present
Method 99 No Preference 4 Total Responses 108
[0064] In response to an inquiry as to the overall preference
between the standard procedure or the present method the nurses
indicated a significant preference for the present method:
7 TABLE 5 Delivery Method Number Standard Procedure 3 Present
Method 87 No Preference 18 Total 108
[0065] When a preference was requested between the standard
procedure and the present method relative to a particular location
the intradermal injection was made, a significant preference again
was indicated for the present method.
8TABLE 6 Preferred injection Delivery Method Deltoid Volar Total
Standard Procedure 8 9 17 Present Method 38 52 90 No Preference 0 0
1 Total 46 61 108
[0066] A visual inspection was made after each intradermal
injection to determine the amount of leakage of the saline solution
from the injection site. A four point scale was used to rate the
amount of leakage. Zero was selected to indicate no leakage and
three was selected to indicated a significant amount of leakage.
The results indicated there was no statistically discemable
difference between the standard procedure and the present
method.
9TABLE 7 Rating Delivery Method 0 1 2 3 Standard Procedure 142 71 1
0 Present Method 137 68 6 5
[0067] A visual inspection was made of each intradermal injection
site to determine the level of bleeding that resulted from the
injection. The same four point scale used for the leakage
evaluation was used to evaluate the level of bleeding. The data
shown in Table 8 indicates the present method resulted in less
bleeding than the standard procedure did:
10TABLE 8 Rating Delivery Method 0 1 2 3 Standard Procedure 98 109
5 2 Present Method 177 38 0 1
[0068] After the clinical trial was completed, each of the twelve
nurses was surveyed about their overall satisfaction with the
present method when compared to the standard procedure. Each of the
twelve nurses indicated that it was easy to keep the skin engaging
surface 42 against the skin of the subject when administering the
intradermal injection. Eight of the nurses indicated the overall
performance of the present method was excellent. Three indicated
the overall performance was better than acceptable and only one
indicated the performance was less than acceptable. Eleven of the
twelve nurses indicated a preference for the present method while
only one indicated no preference. All twelve of the nurses
indicated the present method was easier to perform than the
standard procedure. The nurses were evenly split as to the ease in
of injecting the saline solution between the two procedures with
two nurses having no preference. All twelve nurses indicated the
present method proved easier to keep the needle in the proper
place. Eleven of the twelve nurses indicated it was preferable to
give an intradermal injection at an angle of ninety degrees than
fifteen degrees. One nurse had no preference. Seven of the nurses
indicated the present method was more effective in delivering a
proper injection. Two nurses indicated the standard procedure was
more effective, and three nurses indicated no preference.
[0069] Accordingly, the method of the present invention may be used
to intradermally inject various substance selected from the group
consisting of drugs, vaccines and the like used in the prevention,
diagnosis, alleviation, treatment, or cure of diseases to expose
the injected substance to the microcirculatory blood vasculature
and the lymphatic plexuses where the substance can be taken up,
absorbed or can interact with the cells to obtain systemic delivery
or an immune response in cases where the substance is either a drug
or one or more vaccines. In this way, by targeting the dermal
space, the immune response, pharmacokinetics (PK) and
pharmacodynamics (PD) parameters of the substance can be
dramatically altered, which, for example, in the case of improved
bioavailability or improved immune response , can result in a
reduction in the amount of the necessary dose of the substance to
be delivered. These substances may include: (i) drugs such as
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, Leutenizing hormone,
Leutenizing hormone releasing hormone and analogs, Low molecular
weight heparin, M-CSF, metoclopramide, Midazolam, Monoclonal
antibodies, Narcotic analgesics, nicotine, Non-steroid
anti-inflammatory agents, Oligosaccharides, ondansetron,
Parathyroid hormone and analogs, Parathyroid hormone antagonists,
Prostaglandin antagonists, Prostaglandins, Recombinant soluble
receptors, scopolamine, Serotonin agonists and antagonists,
Sildenafil, Terbutaline, Thrombolytics, Tissue plasminogen
activators, TNF-, and TNF-antagonists; (ii) vaccines, with or
without carriers/adjuvants, such as 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 japanese
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, Alzheimers, H. Pylori,
salmonella, diabetes, cancer, herpes simplex, human papilloma; and
(iii) other substances in all of the major therapeutics such as
Agents for the common cold, Anti-addiction, anti-allergy,
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, sexual hypofunction
and tranquilizers and major diagnostics such as tuberculin and
other hypersensitivity agents.
[0070] In addition, it should be appreciated that the substance
delivered in accordance with the method of the present invention
can be a combination drugs or vaccines, such as for example
vaccines against (i) measles, mumps and rubella, (ii) diphtheria,
tetanus and acellular pertussis, (iii) hepatitis A and hepatitis B,
(iv) haemophilus influenza B, diphtheria, tetanus and acellular
pertussis, (v) haemophilus influenza B, hepatitis B, diphtheria,
tetanus and acellular pertussis, and (vi) haemophilus influenza B,
inactivated polio, diphtheria, tetanus and acellular pertussis
which are commonly delivered in combination to the subcutaneous
(SQ) and/or intramuscular (IM) space.
[0071] During SQ or IM injections with a needle, it is generally
recommended practice to expel or purge any air that may be
contained within the needle and needle hub prior to the injection.
This practice eliminates the risk of accidentally injecting air
into a blood vessel sufficient to create an air embolism into the
vasculature. For intradermal injections, this risk is eliminated
because the depth at which an intradermal injection is given is not
in the region of large blood vessels into which a needle can
penetrate. Therefore, purging the needle and needle hub of air is
not required prior to an intradermal injection. Furthermore, it is
anticipated that purposely injecting a small volume of air into the
intradermal space just prior to injecting the substance may
facilitate the formation of a wheal, which is the indicator of a
successful intradermal injection. It is believed that this occurs
because during an intradermal injection a reasonably high amount of
pressure needs to be generated to separate the dermal layers and
open a pathway through which the substance can flow. Air, being a
less viscous fluid than a substance such as a drug or vaccine,
flows easier into the dermal space, thereby creating a pathway
downstream to the drug or vaccine. This sequential delivery of air
followed by drug or vaccine is believed to increase the likelihood
of a successful intradermal injection.
[0072] The present invention also includes the use of the above
substances in the preparation of a filled device for making an
intradermal injection into the skin of an animal. Accordingly,
referring now to FIG. 10, an example of a way of preparing the
filled devices designed according to this invention is
schematically illustrated in flow chart format. When the device
includes a syringe of the style illustrated in FIG. 3, the
following basic procedure is useful for preparing prefilling the
syringes with a desired substance for such use.
[0073] A supply of syringe barrels 200 includes the desired form of
syringe, such as those illustrated and discussed above having a
first end and a second end. A locally controlled environment 202
preferably is maintained in a known manner. The locally controlled
environment 202 preferably is situated to immediately accept the
syringes without requiring any intermediate cleaning or sterilizing
steps between the supply 200 and the environment 202.
[0074] In one example, the syringe barrels are washed with air at
204 to remove any particulates from the syringes. The syringes
preferably are then coated at 206 with a lubricant such as a
conventional lubricating silicone oil on the inner surface. The
lubricant facilitates moving the stopper 70 and plunger rod 66
through the syringe during actual use of the device.
[0075] The end of syringes to which the needle assembly 20 will
eventually be attached may be capped with a tip cap within the
environment 202. In one example, tip caps are supplied at 208. The
tip caps are air washed at 210. The cleaned tip caps and syringe
barrels are conveyed to an assembly device 212 where the tip caps
are secured onto the syringes. The syringe barrel assemblies are
then conveyed to a filling station 214 to be filled with the
desired substance.
[0076] Once filled as desired, the stoppers 70 are inserted into
the open end of the syringes at 220. Prior to inserting the
stoppers 70, they preferably are assembled with the plunger rods 66
at 222 and lubricated at 224 with a conventional lubricant in a
known manner. The assembled, filled syringes preferably are
inspected at 226 for defects and discharged from the locally
controlled environment.
[0077] Where feasible, the syringes typically will be sterilized at
230 and packaged at 232 into individual packages or into bulk
packaging depending on the needs of a particular situation.
Suitable sterilization techniques are known and will be chosen by
those skilled in the art depending on the needs of a particular
situation or to accommodate the properties of a given substance.
Sterilizing a device designed according to this invention can be
completed before or after packaging. Typically, vaccines are not
terminally sterilizable, particularly live vaccines.
[0078] Variations of the filling steps are within the scope of this
invention. For example, the stopper can be inserted first, then
fill the syringe, followed by applying a tip cap. Additionally, the
device may be filled just prior to making the injection,
particularly in situations where the substance to be injected is in
a dry or reconstitutable form.
[0079] The actual insertion of the desired substance into the
syringe body can be accomplished in any of several known manners.
Example preparation and filling techniques are disclosed in U.S.
Pat. No. 6,164,044 to Profano et al.; U.S. Pat. No. 6,189,292 to
Odell et al.; U.S. Pat. No. 5,620,425 to Heffernan et al.; U.S.
Pat. No. 5,597,530 to Smith et al.; U.S. Pat. No. 5,573,042 to
DeHaen; U.S. Pat. No. 5,531,255 to Vacca; U.S. Pat. No. 5,519,984
to Beussink et al.; U.S. Pat. No. 5,373,684 to Vacca; U.S. Pat. No.
5,256,154 to Liebert et al.; U.S. Pat. No. 5,207,983 to Liebert et
al.; and U.S. Pat. No. 4,718,463 to Jurgens, Jr. et al., each of
which is incorporated by reference into this specification.
[0080] The description given above provides example implementations
of this invention. Variations and modifications may become apparent
to those skilled in the art that do not necessarily depart from the
basis of this invention. The scope of legal protection given to
this invention can only be determined by studying the following
claims.
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