U.S. patent application number 11/030259 was filed with the patent office on 2005-07-21 for delivery of oral drugs.
This patent application is currently assigned to Vectura Limited. Invention is credited to Staniforth, John, Tobyn, Michael.
Application Number | 20050158394 11/030259 |
Document ID | / |
Family ID | 26243754 |
Filed Date | 2005-07-21 |
United States Patent
Application |
20050158394 |
Kind Code |
A1 |
Staniforth, John ; et
al. |
July 21, 2005 |
Delivery of oral drugs
Abstract
Disclosed is a system for delivery of a drug comprising a
multiple unit dosing device comprising a housing and an actuator,
said device containing multiple doses of multiparticulates
comprising drug particles, said device upon actuation delivering a
unit dose of said multiparticulates, said drug particles having a
mean diameter of greater than 10 .mu.m to about 1 mm such that an
effective dose of said drug cannot be delivered into the lower lung
of a human patient. Also disclosed are novel methods, devices and
dosage forms for delivering a drug.
Inventors: |
Staniforth, John; (Bath,
GB) ; Tobyn, Michael; (Trowbridge, GB) |
Correspondence
Address: |
DAVIDSON, DAVIDSON & KAPPEL, LLC
485 SEVENTH AVENUE, 14TH FLOOR
NEW YORK
NY
10018
US
|
Assignee: |
Vectura Limited
Chippenham
GB
|
Family ID: |
26243754 |
Appl. No.: |
11/030259 |
Filed: |
January 6, 2005 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
|
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11030259 |
Jan 6, 2005 |
|
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09793304 |
Feb 26, 2001 |
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Current U.S.
Class: |
424/489 |
Current CPC
Class: |
A61M 15/0081 20140204;
A61K 9/0065 20130101; A61J 7/0084 20130101; A61J 1/035 20130101;
A61M 15/0048 20140204; A61M 2202/064 20130101; A61M 15/0055
20140204; A61M 15/0051 20140204; A61M 15/0066 20140204; A61M
15/0003 20140204; A61J 7/0076 20130101; A61J 7/0053 20130101; A61M
15/008 20140204; A61M 15/0043 20140204; A61J 7/02 20130101; A61K
9/0073 20130101; A61J 7/0038 20130101; A61K 9/145 20130101; A61M
15/0068 20140204; A61M 15/0071 20140204; A61K 9/0075 20130101 |
Class at
Publication: |
424/489 |
International
Class: |
A61K 009/14 |
Foreign Application Data
Date |
Code |
Application Number |
Feb 28, 2000 |
GB |
0004701.9 |
Apr 12, 2000 |
GB |
0009023.3 |
Claims
1. A drug delivery system for gastrointestinal deposition,
comprising a multiple unit dosing device comprising a housing and
an actuator, said device containing multiple doses of
multiparticulates comprising drug particles, said device upon
actuation delivering a unit dose of said multiparticulates, said
drug particles having a mean diameter of greater than about 50
.mu.m to about 1 mm such that an effective dose of said drug cannot
be delivered into the lower lung of a human patient.
2. The system of claim 1 wherein said delivery is by administering
in vivo said unit dose into the oral cavity of said patient.
3. The system of claim 1 wherein said delivery is by dispensing ex
vivo said unit dose into an intermediate receptacle.
4. The system of claim 1 wherein said unit dose is in the form of a
discrete unit.
5. The system of claim 1, wherein said device administers said unit
dose onto the tongue of said patient.
6. (canceled)
7. The system of claim 1 wherein said multiparticulates further
comprise a pharmaceutically acceptable excipient.
8. The system of claim 7 wherein said excipient is coated with said
drug.
9. The system of claim 7 wherein said drug is coated with said
excipient.
10. The system of claim 7 wherein said excipient comprises a taste
masking agent.
11. The system of claim 7 wherein said excipient comprises a
sweetening agent, flavoring agent or combination thereof.
12. The system of claim 7 wherein said excipient comprises a
salivary stimulant, an effervescent agent or a combination
thereof.
13. The system of claim 7 wherein said excipient comprises a
controlled release material.
14. The system of claim 13 wherein said excipient is less than
about 20% by weight of said multiparticulates.
15. The system of claim 1 wherein said multiple doses are contained
in a reservoir.
16. The system of claim 15 further comprising a metering component
to meter a unit dose of said drug from said reservoir upon
actuation of said system.
17-23. (canceled)
24. The system of claim 1 wherein said device comprises a
mouthpiece.
25. The system of claim 24 wherein said mouthpiece is of sufficient
length to minimize moisture exposure of the multiparticulates from
outside the device.
26. The system of claim 24 wherein said device further comprises a
mouthpiece cap to minimize moisture exposure of the
multiparticulates from outside the device.
27. The system of claim 1 further comprising a desiccant to
minimize moisture exposure of the multiparticulates from outside
the device.
28. The system of claim 1 wherein said doses are individually
metered prior to said actuation.
29. The system of claim 28 further comprising blisters on a
substrate base, each blister containing said individually metered
unit dose, said blisters covered by a seal.
30. The system of claim 29 wherein said blisters are aligned
linearly in the form of a strip.
31. The system of claim 30 wherein said strip is in the form of a
roll.
32. A device for delivery of a drug, for gastrointestinal
deposition, comprising a housing and an actuator, said device
capable of containing multiple doses of multiparticulates
comprising drug particles, said device upon actuation capable of
delivering a unit dose of said multiparticulates wherein said drug
particles have a mean diameter of greater than about 50 .mu.m to
about 1 mm such that an effective dose of said drug cannot be
delivered into the lower lung of a human patient.
33. The device of claim 32 wherein said delivery is by
administering in vivo said unit dose into the oral cavity of said
patient.
34. The device of claim 32 wherein said delivery is by dispensing
ex vivo said unit dose into an intermediate receptacle.
35. The device of claim 32 wherein said unit dose is in the form of
a discrete unit.
36. The device of claim 32 wherein said device administers said
unit dose onto the tongue of said patient.
37-48. (canceled)
49. A method for delivery of a drug for gastrointestinal
deposition, comprising delivering multiparticulates comprising drug
particles via the use of a multiple unit dosing device comprising a
housing and an actuator, said device upon actuation delivering a
unit dose of said multiparticulates, and thereafter re-using said
device to deliver additional unit doses of said drug at appropriate
dosing intervals, said drug particles having a mean particle size
of greater than about 50 .mu.m to about 1 mm such that an effective
dose of said drug cannot be delivered into the lower lung of a
human patient.
50. The method of claim 49 wherein said delivery is by
administering in vivo said unit dose into the oral cavity of a
patient.
51. (canceled)
52. The method of claim 49 wherein said unit dose is in the form of
a discrete unit.
53. The method of claim 49 wherein said device administers said
unit dose onto the tongue of said patient.
54. (canceled)
55. A drug delivery device for administering a drug in
multiparticulate form into the oral cavity of a patient for
gastrointestinal deposition, said device including a mouthpiece
having an outlet for delivering said multiparticulates and an inlet
for receiving said multiparticulates, wherein the mouthpiece
protrudes downward from the drug delivery device at an angle
greater than about 15 degrees measured from a horizontal baseline
when the drug device is in an upright position, in order to direct
the multiparticulates onto the tongue of said patient, said drug
particles having a mean diameter of greater than 10 .mu.m to about
1 mm.
56. The mouthpiece of claim 55 wherein the outlet of the mouthpiece
faces downward to administer said multiparticulates onto the tongue
of said patient.
57. The mouthpiece of claim 55 wherein the mouthpiece is conical in
shape and has an outlet having a larger diameter than an inlet
wherein the multiparticulates enter said mouthpiece.
58. The mouthpiece of claim 57 wherein the diameter of the outlet
is 25% greater than the diameter of the inlet.
59. The mouthpiece of claim 57 wherein the diameter of the outlet
is 50% greater than the diameter of the inlet.
60. The mouthpiece of claim 57 wherein the diameter of the outlet
is 100% greater than diameter of the inlet.
61. The mouthpiece of claim 55 wherein the mouthpiece is
rectangular in shape, having side walls which extend outward from
an inlet at opposite angles, to provide an outlet having a larger
area than the inlet area where the multiparticulates enter said
mouthpiece.
62. The mouthpiece of claim 61 wherein the outlet area is 25%
greater than the inlet area.
63. The mouthpiece of claim 61 wherein the outlet area is 50%
greater than the inlet area.
64. The mouthpiece of claim 61 wherein the outlet area is 100%
greater than the inlet area.
65. The mouthpiece of claim 61 having top and bottom walls which
are convex on their outer edges.
66-68. (canceled)
69. A device for delivering multiple unit doses of a drug in
multiparticulate form, for gastrointestinal deposition, comprising
a housing for containing multiple unit doses of multiparticulates
comprising drug particles, said housing having an opening for
delivering a unit dose of said multiparticulates; said drug
particles having a mean diameter of greater than 10 .mu.m to about
1 mm; a metering component operable between a first position in
which it receives a unit dose from said housing and a second
position in which it delivers said unit dose to said opening in
said housing; said unit dose being delivered from said metering
component to the exterior of the device through said opening of
said housing with an air flow of less than about 20 litres/min.
70. The device of claim 69 wherein said device does not include a
propellant to facilitate the delivery of the unit dose.
71. The device of claim 69 wherein said unit dose is delivered
through said opening substantially by gravitational force.
72-84. (canceled)
85. A device for delivering multiple unit doses of a drug in
multiparticulate form for gastrointestinal deposition, comprising a
housing to contain multiple unit doses of a drug in
multiparticulate form comprising drug particles; said drug
particles having a mean diameter of greater than about 50 .mu.m to
about 1 mm, said housing having a mouthpiece for delivering a unit
dose of said multiparticulates into the oral cavity of a patient;
means for removing a unit dose of said multiparticulates from said
housing and transporting said unit dose to said mouthpiece, said
mouthpiece having a drug receiving end connected to said means and
a drug delivery end through which said unit dose is delivered
outside the device, said mouthpiece being positioned on said device
such that drug expelled through said mouthpiece can be deposited in
the oral cavity of a patient substantially without deposition of
said particulates into the lungs of said patient.
86. A device for delivering multiple unit doses of a drug in
multiparticulate form for gastrointestinal deposition, comprising a
housing to contain multiple unit doses of a drug in
multiparticulate form comprising drug particles; said housing
having a mouthpiece for delivering a unit dose of said
multiparticulates into the oral cavity of a patient; a meterer for
removing a unit dose of said multiparticulates from said housing
and transporting said unit dose to said mouthpiece, said mouthpiece
having a drug receiving end connected to said metering device and a
drug delivery end through which said unit dose is delivered outside
the device, said drug particles having a mean diameter of greater
than about 50 .mu.m to about 1 mm, said mouthpiece being positioned
on said device such that drug expelled through said mouthpiece can
be deposited in the oral cavity of a patient substantially without
deposition of said particulates into the lungs of said patient.
87-91. (canceled)
92. The system of claim 1, wherein said device comprises two
reservoirs, wherein one reservoir contains said medicament and the
other reservoir contains a liquid.
93. The system of claim 92, wherein said device comprises two
reservoirs, wherein one reservoir contains said medicament and the
other reservoir contains a liquid.
94. The system of claim 92 wherein each reservoir has a dispensing
hole and a retaining strip, the retaining strip covering the
dispensing hole and sealing said the reservoir when the retaining
strip is in a first position, the dispensing hole being uncovered
when the retaining strip is in a second position.
95. The system of claim 92 wherein the reservoir is disposable.
96. The system of claim 92 wherein the reservoirs are permanently
affixed to one another.
97. The system of claim 1, wherein said device comprises two
reservoirs, each reservoir containing said medicament.
98. The system of claim 1, wherein said device comprises two
reservoirs, wherein one reservoir contains said medicament and the
other reservoir contains a different medicament.
99. The system of claim 97 wherein each reservoir has a dispensing
hole and a retaining strip, the retaining strip covering the
dispensing hole and sealing said the reservoir when the retaining
strip is in a first position, the dispensing hole being uncovered
when the retaining strip is in a second position.
100. The system of claim 97 wherein each reservoir is
disposable.
101. The system of claim 97 wherein the reservoirs are permanently
affixed to one another.
102. The system of claim 1, wherein said device further comprises:
a disk, the disk having a plurality of cavities arranged about on
the periphery of the disk; the disk rotating about a central axis
to position the cavities in alignment with a piercing member; and
the piercing member for penetrating each of the cavities to expel a
unit dose of said multiparticulates from the cavity.
103. The system of claim 102 wherein the multiparticulates from the
cavity are dispensed into a delivery conduit affixed to the
piercing member.
104. The system of claim 102 wherein the delivery conduit is
coupled to a mouthpiece, the mouthpiece for dispensing the unit
dose into the oral cavity of the patient.
105. The system of claim 103, wherein the delivery conduit
comprises a hollow tube.
106. The system of claim 104, wherein the delivery conduit
comprises a hollow tube.
107. The system of claim 102 wherein the device is disposable.
108. The system of claim 102 wherein the disk is replaceable.
109. The system of claim 1, wherein said device further comprises:
a disk, the disk having a plurality of blisters arranged about on
the periphery of the disk, each blister comprising a premetered
dose of the medicament; the disk rotating about a central axis to
position each blister in alignment with a piercing member; and the
piercing member for penetrating each aligned blister to expel the
premetered dose from the aligned blister.
110. The system of claim 109 wherein the premetered dose from the
blister is dispensed into a delivery conduit affixed to the
piercing member.
111. The system of claim 110 wherein the delivery conduit is
coupled to a mouthpiece, the mouthpiece for dispensing the unit
dose into the oral cavity of the patient.
112. The system of claim 110, wherein the delivery conduit
comprises a hollow tube.
113. The system of claim 111, wherein the delivery conduit
comprises a hollow tube.
114. The system of claim 1, wherein the medicament is stored in a
plurality of containers, each container sealed via a removable
seal.
115. The system of claim 92 wherein the medicament and the liquid
are alternatively mixed within the device prior to
administration.
116. The system of claim 92 wherein said device comprises two
reservoirs, wherein one reservoir contains said medicament and the
other reservoir contains a liquid, and wherein the medicament and
the liquid are mixed in an intermediate receptacle.
117. The system of claim 97, wherein said device comprises two
reservoirs, each of the reservoirs containing a different dose of
said medicaments.
Description
FIELD OF THE INVENTION
[0001] The present is directed to a delivery device and method for
the oral administration of therapeutic agents in powder form for
gastrointestinal deposition.
BACKGROUND OF THE INVENTION
[0002] The most prominent mode of delivery of therapeutic agents is
by the oral route by means of solid dosage forms such as tablets
and capsules. Oral administration of solid dosage forms is more
convenient and accepted than other modes of administration, e.g.
parenteral administration. However, the manufacture, dispensing and
administration of solid dosage forms are not without associated
problems and drawbacks.
[0003] With the manufacture of solid dosage forms, in addition to
the active agent, it is necessary to combine other ingredients in
the formulations for various reasons, such as to enhance physical
appearance, to provide necessary bulk for tableting or capsuling,
to improve stability, to improve compressibility or to aid in
disintegration after administration. However, these added
excipients have been shown to adversely influence the release,
stability and bioavailability of the active ingredient. The added
excipients are a particular problem with drugs which require a high
dose in order to provide a therapeutic effect, e.g., biphosphonate
drugs. The inclusion of the additional excipient can make the final
tablet extremely large which could result in esophogeal damage due
to the physical characteristics of the dosage form if it is not
swallowed properly. Esophogeal damage can also be caused by
toxicity caused by the drug itself, if the tablet becomes lodged in
the throat or has an increased transit time through the esophagus,
due to its increased size.
[0004] Further, the tableting of certain drugs has many associated
production problems. In particular, many drugs, e.g.,
acetaminophen, have poor compressibility and cannot be directly
compressed into solid dosage forms. Consequently, such drugs must
either be wet granulated or manufactured in a special grade in
order to be tableted which increases manufacturing steps and
production costs.
[0005] The adherence to good manufacturing practices and process
controls is essential in order to minimize dosage form to dosage
form and batch to batch variations of the final product. Even
strict adherence to these practices still is not a guarantee that
acceptable variation will occur.
[0006] With the high cost of industrial scale production and
governmental approval of solid dosage forms, such formulations are
often available in a limited number of strengths, which only meet
the needs of the largest sectors of the population. Unfortunately,
this practice leaves many patients without acceptable means of
treatment and physicians in a quandary with respect to
individualizing dosages to meet the clinical needs of their
patients.
[0007] The dispensing of oral solid dosage forms also makes the
formulations susceptible to degradation and contamination due to
repackaging, improper storage and manual handling.
[0008] There are also many patients who are unable or unwilling to
take conventional orally administered dosage forms. For some
patients, the perception of unacceptable taste or mouth feel of a
dose of medicine leads to a gag reflex action that makes swallowing
difficult or impossible. Other patients, e.g., pediatric and
geriatric patients, find it difficult to ingest typical solid oral
dosage forms, e.g., due to tablet size.
[0009] Other patients, particularly elderly patients, have
conditions such as achlorhydria which hinders the successful use of
oral solid dosage forms. Achlorhydria is a condition wherein there
is an abnormal deficiency or absence of free hydrochloric acid in
the gastric secretions of the stomach. This condition hinders the
disintegration and/or dissolution of oral solid dosage forms,
particularly dosage forms with high or insoluble excipient
payloads
[0010] Flavored solutions/suspensions of some therapeutic agents
have been developed to facilitate the oral administration of oral
agents to patients normally having difficulty ingesting
conventional solid oral dosage forms. While liquid formulations are
more easily administered to the problem patient, liquid/suspension
formulations are not without their own significant problems and
restrictions. The liquid dose amount is not as easily controlled
compared with tablet and capsule forms and many therapeutic agents
are not sufficiently stable in solution/suspension form. Indeed,
most suspension type formulations are typically reconstituted by
the pharmacist and then have a limited shelf life even under
refrigerated conditions. Another problem with liquid formulations
which is not as much a factor with tablets and capsules is the
taste of the active agent. The taste of some therapeutic agents is
so unacceptable that liquid formulations are not a viable option.
Further, solution/suspension type formulations are typically not
acceptable where the active agent must be provided with a
protective coating, e.g. a taste masking coating or an enteric
coating to protect the active agent from the strongly acidic
conditions of the stomach.
[0011] Another alternative to oral dosage forms for certain
medications is aerosol dosage forms which administer therapeutic
agents for deposition to the pulmonary systern. The use of aerosol
dosage forms has many advantages for the patient. The packaging of
the active agent is convenient and easy to use, generally with
limited manual manipulation. As the medicine is sealed within the
device, direct handling of the medication is eliminated and the
contamination of the contents from air and moisture can be kept to
a minimum. Further, a metering valve can be included in the device
in order to individualize the dose for particular patients.
However, such formulations also have drawbacks such as decreased
bioavailability of the drug due to improper administration by the
patient. For example, if a patient's breathing is not coordinated
with the activation of the device, the active agent will not reach
its intended site of action which will lead to a decrease in
therapeutic benefit.
[0012] Another alternative is dry powder dosage forms. For example,
International Patent Application WO 94/04133, hereby incorporated
by reference, describes a powder composition for inhalation which
contains a microfine drug such as salbutamol sulfate and a carrier
containing an anti-static agent. The carrier is calcium carbonate
or a sugar, especially lactose. The amount of carrier is 95-99.99
weight percent. The compositions are said to be useful for delivery
of the active agent to the lungs while providing reduced side
effects such as nausea by maximizing its proportion of drug
reaching the lungs.
[0013] U.S. Pat. No. 4,590,206, hereby incorporated by reference,
describes capsules, cartridges or aerosol containers containing
spray-dried sodium cromoglycate in finely divided and
un-agglomerated form. A substantial proportion of the individual
drug particles have sizes and shapes which allow deep penetration
into the lung and yet are free-flowing so as to allow capsule
filling.
[0014] International Patent Application WO 93/25198, hereby
incorporated by reference, is directed to an ultrafine powder for
inhalation. The powder comprises a drug and hydroxypropyl cellulose
and/or hydroxypropylmethylcellulose. More than 80 weight percent of
the particles in the powder are said to have a particle diameter of
0.5-10 microns. The powder is said to be able to reach the lower
windpipe and bronchi.
[0015] Due to the disadvantages of known drug delivery discussed
above (as well as other disadvantages) there exists a need in the
art for the development of a device and method for facilitating
delivery of a wide range of therapeutic agents for gastrointestinal
deposition and which minimize pulmonary deposition of materials
having undesirable or unknown pulmonary toxicology but which are
approved for oral delivery.
OBJECTS OF THE INVENTION
[0016] It is an object of the invention to provide a method and
system for the delivery of a dose of a therapeutic agent in
multiparticulate form for gastrointestinal deposition.
[0017] It is an object of the invention to provide a method and
system for the oral administration of a dose of a therapeutic agent
in multiparticulate form into the oral cavity of a patient for
gastrointestinal deposition.
[0018] It is an object of the invention to provide a method and
system for the dispensing of a dose of a therapeutic agent in
multiparticulate form, for subsequent administration into the oral
cavity for gastrointestinal deposition.
[0019] It is a further object of the invention to provide a method
and system for delivery of multiple doses of a therapeutic agent in
multiparticulate form which minimizes the need for inert
pharmaceutical excipients.
[0020] It is a further object of the invention to provide a method
and system for delivery of multiple doses of a therapeutic agent in
multiparticulate form for fast, standard, sustained, controlled, or
targeted release.
[0021] It is a further object of the invention to provide a method
and system for the delivery of a dose of a therapeutic agent for
gastrointestinal deposition which protects the active ingredient
from contamination and moisture.
[0022] It is a further object of the invention to provide a method
and system for the delivery of a dose of a therapeutic agent for
gastrointestinal deposition which allows for the dosing to be
adjustable based on the needs of an individual patient or patient
population.
[0023] It is a further object of the invention to provide a method
and system for the delivery of a dose of a therapeutic agent for
gastrointestinal deposition which can be used for a wide variety of
agents for a wide variety of therapies, e.g. to treat systemic
and/or local conditions.
[0024] It is a further object of the invention to provide a method
and system for the delivery of two or more different drugs in
multiparticulate form simultaneously or at different times. The
device of the system can hold the 2 or more drugs in separate
compartments or together in the same compartment.
[0025] It is a further object of the invention to provide a method
and system for the delivery of a dose of a therapeutic agent for
gastrointestinal deposition which provides an acceptable
variability from dose to dose and batch to batch.
[0026] It is a further object of the invention to provide a method
of producing a unit dose of a drug without limitation to the
compressibility or dose amount of the drug.
[0027] It is a further object of the invention to provide a method
and system for the delivery of a dose of a therapeutic agent for
gastrointestinal absorption which can be administered and swallowed
without the aid of a fluid.
[0028] It is a further object of the invention to provide novel
oral dosage forms in multiparticulate form.
[0029] The above objects of the invention and others are achieved
by virtue of the present invention, which in certain embodiments
provides a drug delivery system for delivery of a drug for
gastrointestinal deposition. The system comprises a multiple unit
dosing device comprising a housing and an actuator, the device
containing multiple doses of multiparticulates comprising drug
particles, the device upon actuation delivering a unit dose of the
multiparticulates for gastrointestinal deposition, the
multiparticulates having a mean particle size of greater than 10
.mu.m and preferably less than about 1 mm in order to minimize
pulmonary deposition of the multiparticulates and such that an
effective dose of the drug cannot be delivered into the lower lung
of a human patient. The drug delivery system can be used to
administer the unit dose of multiparticulates into the oral cavity
of the patient (in-vivo) or to dispense the unit dose into an
intermediate receptacle (ex-vivo) for subsequent gastrointestinal
deposition.
[0030] In certain embodiments, the invention provides a device for
delivery of a drug comprising a housing and an actuator, the device
capable of containing multiple doses of multiparticulates
comprising drug particles, the device upon actuation capable of
delivering a unit dose of the multiparticulates wherein the
multiparticulates have a mean diameter of greater than 10 .mu.m,
and preferably less than about 1 mm in order to minimize pulmonary
deposition of the multiparticulates and such that an effective dose
of the drug cannot be delivered into the lower lung of a human
patient. The device can be used to administer the unit dose of
multiparticulates into the oral cavity of the patient (in-vivo) or
to dispense the unit dose into an intermediate receptacle (ex-vivo)
for subsequent gastrointestinal deposition.
[0031] In certain embodiments, the invention provides a device for
delivering multiple unit doses of a drug in multiparticulate form
comprising a housing for containing multiple unit doses of a
multiparticulates comprising drug particles, the housing having an
opening for delivering a unit dose of the multiparticulates; a
metering component operable between a first position in which it
receives a unit dose from said housing and a second position in
which it delivers the unit dose of drug to the opening in the
housing; the unit dose being delivered from the device to the
exterior of the device through the opening of the housing with an
air flow of less than about 20 litres/min. In preferred embodiments
the device does not include a propellant to facilitate the delivery
of the unit dose and preferably the unit dose is delivered through
the opening substantially by gravitational force.
[0032] In certain embodiments, the invention provides a device for
delivering multiple unit doses of a drug in multiparticulate form
comprising a housing to contain multiple unit doses of
multiparticulates comprising drug particles, the housing having a
mouthpiece for delivering a unit dose of the multiparticulates into
the oral cavity of a patient; means for removing a unit dose of the
multiparticulates from the housing and delivering the unit dose to
the mouthpiece, the mouthpiece having a drug receiving end
connected to the removing means and a drug delivery end through
which the unit dose is delivered outside the device, the mouthpiece
being positioned on the device such that drug particles expelled
through the mouthpiece can be deposited in the oral cavity of a
patient substantially without deposition of drug particles into the
lungs of the patient.
[0033] In certain embodiments, the invention provides a device for
delivering multiple unit doses of a drug in multiparticulate form
comprising a housing to contain multiple unit doses of
multiparticulates comprising drug particles; the housing having a
mouthpiece for delivering a unit dose of the multiparticulates into
the oral cavity of a patient; a metering component for removing a
unit dose of the multiparticulates from the housing and delivering
the unit dose to the mouthpiece, the mouthpiece having a drug
receiving end connected to the metering component and a drug
delivery end through which the unit dose is delivered outside the
device, the mouthpiece being positioned on the device such that
drug particles expelled through the mouthpiece can be deposited in
the oral cavity of a patient substantially without deposition of
the drug particles the lungs of the patient.
[0034] In certain embodiments, the invention provides a method of
preparing a drug delivery system for delivering multiple doses of a
drug for gastrointestinal deposition comprising preparing a
multiparticulate drug formulation in a manner to provide particles
which when placed in the oral cavity and swallowed are deposited to
the gastrointestinal tract and not deposited in any substantial
amount to the lungs; and placing multiple unit doses of said drug
formulation in a device which meters a single unit dose for
delivery.
[0035] In certain embodiments, the invention provides a method of
treating a patient in need of multiple doses of a drug for
gastrointestinal deposition comprising preparing multiparticulates
comprising drug particles in a manner wherein the drug particles
when placed in the oral cavity and swallowed are deposited to the
gastrointestinal tract and not deposited in any substantial amount
to the lungs; placing multiple unit doses of the multiparticulates
in a device which meters a single unit dose for delivery; and
either (a) administering the unit dose into the oral cavity of a
patient or(b) dispensing the unit dose into an intermediate
receptacle and thereafter administering the unit dose into the oral
cavity of the patient.
[0036] In certain embodiments, the invention provides a drug
formulation for gastrointestinal deposition comprising a
non-compressed free flowing plurality of particles comprising a
drug and a pharmaceutically acceptable excipient, the particles
having a mean diameter of greater than 10 .mu.m to about 1 mm, the
particles comprising at least about 80% drug, preferably at least
about 90% drug.
[0037] In certain embodiments, the drug formulation can further
comprise a facilitating agent (e.g., an absorbability enhancer, a
texture modifier, a taste masking agent, a sweetener, a flavorant,
a salivary stimulant, an effervescent compound or combinations
thereof) which enhances the oral administrability of the unit
dose.
[0038] In certain embodiments, the drug formulation can further
comprise a material to provide fast, standard, sustained,
controlled, or targeted release.
[0039] In certain embodiments, the invention provides a method for
delivery of a drug comprising delivering multiparticulates
comprising drug particles via the use of a multiple unit dosing
device comprising a housing and an actuator, the device upon
actuation delivering a unit dose of the multiparticulates, and
thereafter re-using said device to deliver additional unit doses of
multiparticulates at appropriate dosing intervals, the drug
particles having a mean diameter of greater than 10 .mu.m, and
preferably less than about 1 mm to minimize pulmonary deposition
and such that an effective dose of the drug cannot be delivered
into the lower lung of a human patient. In certain embodiments of
the method, upon actuation, the delivery is by administering the
unit dose into the oral cavity of the patient (in vivo).
Alternatively upon actuation, the delivery is the dispensing of the
unit dose into an intermediate receptacle (ex vivo) for subsequent
gastro-intestinal deposition.
[0040] In certain embodiments of the invention, greater than about
80% of the unit dose is deposited in the gastrointestinal tract,
preferably greater than about 90% or greater than about 95%, and
most preferably, about 100% of the unit dose is deposited in the
gastrointestinal tract.
[0041] In preferred embodiments of the invention, the unit dose
comprises a discreet collection of multiparticulates. For purposes
of the invention, a "discreet collection" means that the
multiparticulates are in the form of a non-compressed free flowing
unit and not dispersed in a cloud or mist, which effectively
minimizes inhalation of the active agent into the lungs of the
patient. The unit dose can be, e.g., from about 0.01 mg to about
1.5 g, depending on the dose of the active agent being delivered.
For example, the unit dose can be from about 1 mg to about 100 mg
or from about 10 mg to about 50 mg. Preferably, the unit dose is
administered to the tongue, most preferably towards the front of
the tongue behind the teeth, where it can be easily swallowed with
or without the need for an additional fluid. However the invention
does contemplate delivery to any portion of the tongue, taking into
account, e.g., the taste sensations of different sections of the
tongue and/or individual patient preference associated with
comfort, e.g. mouth position.
[0042] In certain embodiments of the invention, the mean diameter
of the drug particles is of a size which mininizes their capacity
to be inhaled into the lower lung. Typically, the agglomerate mean
particle size of the drug particles is greater than 10 .mu.m,
preferably greater than about 50 .mu.m or greater than about 75
.mu.m. In certain embodiments of the invention, the mean particle
size range of the drug particles is from about 100 .mu.m to about 1
mm. In preferred embodiments, greater than 80% of the drug
particles have the above disclosed diameter (not mean diameter),
e.g. 80% of the drug particles have a diameter of greater than 10
.mu.m, or a diameter of from about 100 .mu.m to about 1 mm. In
other embodiments, greater than about 90% of the drug particles
have the above disclosed diameter.
[0043] In certain embodiments of the invention, the mean diameter
of the drug particles does not vary by greater than about 20%,
preferably not greater than about 15% and most preferably not
greater than about 10%.
[0044] In certain embodiments of the invention, the
multiparticulates comprise a pharmaceutically acceptable excipient.
The excipient preferably does not comprise more than about 20% of
the multiparticulates by weight, preferably not more than about 10%
by weight.
[0045] In certain embodiments of the invention, the excipient is
coated with the drug, or the drug is coated with the excipient.
Alternatively, the drug and the excipient can be a mixture of
powders, each preferably being greater than 10 .mu.m, preferably
greater than about 50 .mu.m or greater than about 75 .mu.m.
[0046] In certain embodiments of the invention, the excipient can
provide taste masking of the drug. In taste masking embodiments and
other embodiments, the excipient can include flavors and/or
sweeteners. In other embodiments, the excipient can provide a
sustained or delayed release of the drug.
[0047] In certain embodiments of the invention, the multiple doses
of the drug are contained in a reservoir. The reservoir can contain
an amount of multiparticulates to provide any number of unit doses,
e.g. from about 2 doses to about 400 doses. For ease in patient
compliance, the reservoir has a sufficient quantity of to provide
e.g. a days supply, a months supply or a years supply of doses,
e.g. 30 or 365 for once daily dosing for a month or year,
respectively.
[0048] In certain embodiments, the system can contain multiple
dosing mechanisms in order to provide different dosage amounts for
different times. For example, the system can comprise two dosing
mechanisms which can provide a different dosage amount in the
morning and the evening. In other embodiments, the dosing mechanism
can be adjusted in order to increase or decrease the size of the
dose.
[0049] In certain embodiments, the system can contain more than one
reservoir, each containing a different drug or enantiomeric form of
drug. Upon actuation, the desired amount of each drug is metered
out for delivery, such metering being present in the factory or
other place, e.g., a pharmacy. Such a system would be beneficial
for combination therapy and would eliminate the need for multiple
systems and would allow a much wider range of possible doses and
dose combinations than hereto possible.
[0050] In certain embodiments of the invention, the system delivers
up to about 80%, preferably up to about 90% of the doses supplied
in the system, thus eliminating waste by providing an efficient
system.
[0051] In certain embodiments of the invention, the variability
between dose to dose is not greater than 5%. In certain embodiments
of the invention, the delivery of the unit dose is facilitated by a
gas, which may be provided by the patients own breath maneuvers or
which can be contained in the system in the form of pressurized gas
or liquid gas. Alternatively, the delivery of the unit dose can be
facilitated by a liquid carrier. In such an embodiment, the liquid
and the unit dose are mixed during or after the unit dose is
discharged from the reservoir.
[0052] In certain embodiments of the invention, the device
comprises a mouthpiece. Preferably, the mouthpiece is of sufficient
length to minimize moisture exposure of the reservoir from outside
the device. Preferably, the mouthpiece comprises a mouthpiece cap
or closure to minimize the ingress of moisture (e.g., from saliva
or humidity) into the device. In order to minimize moisture
exposure of the reservoir, the invention can also include a
desiccant. Further measures can be taken by making the device from
a material which has water repellant properties to inhibit the
accumulation of moisture. For example, the device can consist of a
non-wetting material such as silicone, which if contaminated with
moisture, would promote the formation of droplets which would run
off and not adhere to the surface of the device and would not
result in the accumulation of water. In certain embodiments, the
device (especially the mouthpiece) can comprise a silver containing
plastic or other material resistant to microbial growth.
[0053] In order to aid in patient compliance, certain embodiments
of the invention include a counter or indicator to display the
number of doses remaining in the system or the number of doses
actuated.
[0054] In certain embodiments of the invention, the unit doses are
individually metered prior to actuation, e.g., in the form of
capsules or blisters, wherein each blister contains one individual
unit dose. The system can be capable of containing any multiple of
pre-metered unit doses, e.g. from about 2 to about 400
blisters.
[0055] In certain embodiments of the invention, the system is
capable of being reloaded with additional doses (in reservoir or
pre-metered form) upon full or partial depletion. Alternatively,
the system can be manufactured wherein the device is disposable and
is not capable of being reloaded with additional unit doses.
[0056] The present invention is also directed to a method of
administering a drug to a patient for gastrointestinal deposition
comprising formulating the drug in multiparticulate form;
containing the multiparticulates in a drug delivery device capable
of delivering multiple unit doses of the multiparticulates into the
oral cavity; administering a unit dose of the multiparticulates to
the oral cavity of the patient wherein greater than about 80% of
the drug is deposited in the gastrointestinal tract. This method
can be achieved, e.g., by controlling at least one at least one of
the following factors: a) formulating the multiparticulates to have
a mean diameter of greater than 10 .mu.m; b) administering the
multiparticulates with a device having a mouthpiece which directs
the multiparticulates onto the tongue of the patient; c)
administering the multiparticulates with a device which delivers
the unit dose as a discreet collection; and d) administering the
multiparticulates with a device having a flared mouthpiece.
[0057] The invention is also directed to methods of delivery (e.g.,
in vivo administration and ex vivo dispensing) and methods of
treatment utilizing any of the disclosed embodiments directed to
compositions of matter. The invention is also directed to methods
of preparation of all of the disclosed embodiments.
[0058] The present invention is also directed to systems which
contain particles greater than 10 .mu.m of a particulate drug and
particles of 10 .mu.m or less of the same or a different drug which
upon actuation, deliver a unit dose for oral and pulmonary
administration.
[0059] The present invention is also directed to mouthpieces
adapted to fit onto a drug delivery device for administering a drug
in multiparticulate form into the oral cavity of a patient, the
improvement being that the mouthpiece protrudes from the drug
delivery device at an angle in order to direct the
multiparticulates onto the tongue of the patient.
[0060] The present invention is also directed to mouthpieces which
are conical or rectangular in shape and which provide a flared
opening, wherein the area of the outlet of the mouthpiece is larger
than the area of the inlet of the mouthpiece. This reduces the
velocity of the delivered multiparticulates in order to minimize
pulmonary deposition.
[0061] The present invention is also directed to mouthpieces and
devices which drop the unit dose vertically onto the tongue with
minimal or no horizontal velocity. This action directs the unit
dose down to the tongue and minimizes movement of particles toward
the back of the throat in order to minimize or avoid pulmonary
deposition. In preferred embodiments, when the device is utilized
as intended, greater than 80% of the unit dose is administered from
the device in a downward direction from about 45 degrees to about
135 degrees based on a vertical baseline independent of the device.
Preferably greater than 90% of the drug follows this direction.
[0062] The invention is also directed to methods of providing a
therapeutic effect to a patient comprising administering to the
patient a unit dose of a drug utilizing the systems, devices and
formulations disclosed herein. The invention is also directed to
methods of preparing the systems, devices and formulations
disclosed herein.
[0063] The invention is also directed to novel powders for oral
administration which are disclosed herein.
[0064] For purposes of the present invention, the term "device"
refers to an apparatus capable of delivering a unit dose of
drug.
[0065] The term "system" refers to a drug delivery device in
combination with the disclosed multiparticulate drug having the
specifications disclosed herein, e.g. drug particle size, excipient
type, etc.
[0066] The term "discreet collection" refers to a non-compressed
free flowing unit of multiparticulates with minimal particulate
matter being dispersed in the surrounding environment (e.g., as a
cloud or mist).
[0067] The term "drug" refers to any agent which is capable of
providing a therapeutic effect to a patient upon gastrointestinal
deposition. This encompasses all drugs which are intended for
absorption for a systemic effect (regardless of their actual
bioavailability) as well as drugs intended for a local effect in
the gut and/or oral cavity, e.g. nystatin, antibiotics or local
anesthetics.
[0068] The term "particle size" refers to the diameter of the
particle.
[0069] The term "deposition" means the deposit of the unit dose at
the intended point of absorption and/or action. For example,
gastrointestinal deposition means the intended deposit of the unit
dose in the gastrointestinal system for e.g., absorption for a
systemic effect or to exert a local effect. Pulmonary deposition
means the intended deposit of drug into the lungs in order to
provide a pharmaceutical effect, regardless that the unit dose may
enter the oral cavity prior to pulmonary deposition.
[0070] The term "dispense", when used in connection with the
devices and systems of the present invention, means that the device
or system delivers the unit dose ex vivo with the intent of
subsequent administration to a mammal. For example, the device or
system can dispense the unit dose into a food, a liquid, a spoon,
or another intermediate receptacle.
[0071] The term "administer", when used in connection with the
devices and systems of the present invention, means that the device
or system delivers the unit dose in vivo, i.e., directly into the
gastrointestinal tract of a mammal.
[0072] The term "deliver" is meant to cover all ex vivo and in vivo
delivery, i.e.; dispensing and administering, respectively.
[0073] The term "patient" refers to humans as well as other mammals
in need of a therapeutic agent, e.g., household pets or livestock.
This term also refers to humans or mammals in need of or receiving
prophylactic treatment.
[0074] In certain embodiments, the particulates are defined
functionally with respect to the fact that they are of a size such
that an effective dose cannot be delivered into the lower lung of a
human patient. However, this definition should be understood to
mean that a small percentage of drug (but not an amount effective
to render a therapeutic effect) may in fact be inadvertently
delivered to the lungs of the patient. Also, this definition is
meant to define the particles, but not to limit the use of the
invention to the treatments of humans only. The invention may be
used for delivering doses of drugs to other mammals as well.
BRIEF DESCRIPTION OF THE DRAWINGS
[0075] FIG. 1 is a schematic side view of a delivery device
according to the invention in an upright position; and
[0076] FIG. 2 is a schematic side view of the device of FIG. 1 in
the inverted (delivery) position.
[0077] FIG. 3 is a vertical section through another form of
delivery device according to the invention having a mouthpiece;
[0078] FIG. 4 is a front view of the device of FIG. 3, with the
mouthpiece folded into a storage position;
[0079] FIG. 5 is a vertical section through a third form of
delivery device according to the invention, having a
mouthpiece;
[0080] FIG. 6 is a front view of the device of FIG. 5 with the
mouthpiece folded into a storage position; and
[0081] FIG. 7 is a vertical section through a fourth form of
delivery device according to the invention.
[0082] FIG. 8 is an illustration of an embodiment of the invention
comprising a drum reservoir.
[0083] FIG. 9 is an illustration of an embodiment of the invention
having a rotatable member outside of the reservoir.
[0084] FIG. 10 is an illustration of is an illustration of an
embodiment of the invention having a rotatable wheel outside of the
reservoir.
[0085] FIG. 11 is an illustration of an embodiment of the invention
having a rotatable plate mechanism.
[0086] FIG. 12 is an illustration of an embodiment of the invention
having a slidable plate mechanism.
[0087] FIG. 13 is an illustration of an embodiment of the invention
having an archimedean screw.
[0088] FIG. 14 is an illustration of an embodiment of the invention
having a slidable member mechanism.
[0089] FIG. 15 is an illustration of an embodiment of the invention
having a slidable reservoir mechanism.
[0090] FIG. 16 is an illustration of an embodiment of the invention
having a pull cord mechanism.
[0091] FIG. 17 is an illustration of a blister pack.
[0092] FIG. 18 is an illustration of an opening mechanism for a
blister strip or roll
[0093] FIG. 19 is an illustration of a piercing mechanism for a
blister strip or roll.
[0094] FIGS. 20 and 20A are illustrations of circular blister
packs.
[0095] FIG. 21 is an illustration of a powder delivery device
comprising a lifting rod.
[0096] FIG. 22 is an illustration of a powder delivery device with
an optionally coupled powder feeder.
[0097] FIG. 23 is an illustration of a powder delivery device with
an internal reservoir.
[0098] FIG. 24 is an illustration of an angled mouthpiece.
[0099] FIG. 25 is an illustration of a curved mouthpiece.
[0100] FIG. 26 is an illustration of a straight angled
mouthpiece.
[0101] FIG. 27 is an illustration of a conical mouthpiece.
[0102] FIG. 28 is an illustration of a rectangular mouthpiece.
[0103] FIG. 29 is an illustration of a fanlike rectangular
mouthpiece.
DETAILED DESCRIPTION
[0104] In general, it has been recognized in the art that dry
powder inhalation or insufflation formulations must consist of
particles of a size of about 2 microns in diameter in order for the
particles, when inhaled, to reach the peripheral or "deep" lung,
including alveoli. Particles larger than 10 microns in diameter are
not able to reach the deep lung when inhaled because they are
collected on the back of the throat and upper airways in humans.
Therefore, known powder delivery systems have been formulated with
particle sizes of less than 10 microns in order for the particles
to reach the intended site of action, the pulmonary system. Known
powder delivery devices have not contemplated delivery of particles
from a multi-dose delivery device to achieve gastrointestinal
deposition, and therefore have avoided the use of drug particles
having a large size, e.g. greater than 10 microns. By virtue of the
present invention, it has been a surprising discovery that drug
particles greater than 10 microns can be delivered from a multi-use
drug delivery device for gastrointestinal deposition in a patient
in order to minimize the inhalation of the drug particles into the
lungs, in order to have substantially all of the dose deposited in
the gastrointestinal system.
[0105] The present invention is directed to a system comprising a
device containing multiple doses of a drug which is in
multiparticulate form. When the system is actuated, the device
delivers a unit dose, preferably by administration into the oral
cavity of a patient, for the unit dose to be deposited in the
gastrointestinal system of the patient for subsequent absorption
and/or action. Preferably, the unit dose is subsequently swallowed
by the patient for absorption and/or action in the stomach and/or
intestines. However, the system can be used to deliver a unit dose
of drug intended for sublingual or buccal absorption and/or
action.
[0106] In order to increase gastrointestinal deposition and reduce
pulmonary deposition, the unit dose is preferably administered as a
discreet collection. Administration of the unit dose as a discreet
collection ensures that the multiparticulates are aggregated
together and there is no dispersion or "mist" which forms in the
oral cavity which would tend to be aspirated into the lungs.
[0107] The mean drug particle size of the unit dose is greater than
10 .mu.m and preferably greater than about 50 .mu.m in order to
minimize pulmonary aspiration of the drug such that an effective
dose of said drug cannot be delivered into the lower lung of a
human patient. For example, the drug particles can be greater than
about 75 .mu.m, or greater than about 100 .mu.m. A preferred range
of the mean drug particle size is about 100 .mu.m to about 500
.mu.m, although drug particles of 1 mm and above would still be
functional in the present invention. Preferably, any inactive
particle in the unit dose is also greater than 10 .mu.m in order to
minimize pulmonary aspiration of such particles.
[0108] In order to achieve the desired mean particle size, the
active material can be incorporated into larger particles if the
active agent itself is less than 10 .mu.m. This can be performed by
known procedures in the art, e.g., by granulation, coating,
agglomeration or spray coating. The larger particles may include
excipients suitable for use in pharmaceutical formulations.
[0109] The present invention is also directed to systems which
contain drug particles greater than 10 .mu.m and drug particles of
less than 10 .mu.m of the same or a different drug which upon
actuation, administer a unit dose for oral and pulmonary
administration. For example, when gastrointestinal deposition is
desired the drug will formulated, e.g., to have at least 95% by
weight of the gastrointestinal dose being of aerodynamic diameter
of at least 50 .mu.m. For the inhalable dose, the drug will be in
the form of multiparticulates of which at least 90% by weight of
the inhalable dose has an aerodynamic diameter of not more than 10
.mu.m. These particles can be arranged as to be releasable from
larger carrier particles.
[0110] The gastric dose and the inhalable dose can be incorporated
into a single formulation comprising carrier particles; the
inhalable drug being on the surface of the carrier particles and
releasable therefrom on inhalation from the device; and the larger
particles being for gastrointestinal deposition. The two doses can
be contained in the same reservoir or can be contained separately
and co-administered upon actuation.
[0111] In preferred embodiments of the invention, the mean drug
particle size of the multiparticulates does not vary by more than
about 20%, more preferably no more than about 15% and most
preferably by no more than about 10%. Preferably, any inactive
particles will also be within this range.
[0112] In preferred embodiments, greater than about 80% of the drug
particles fall within the above disclosed variance, more preferably
greater than 90% and most preferably about 100% of the drug
particles fall within the above disclosed ranges. For example, in a
preferred embodiment, about 90% of the drug particles of the unit
dose would have a mean particle size of about 450 to about 550
.mu.m, although this example is not meant to be limiting.
Preferably, any inactive particles also fall within this range.
[0113] The size of the unit dose is dependent on the amount of drug
needed to provide the intended therapeutic effect and the amount of
any pharmaceutically acceptable excipient which may be necessary.
Typically, a unit dose of from about 0.01 mg to about 1.5 g would
be sufficient to contain a therapeutically effective amount of the
drug to be delivered, however, this range is not limiting and can
be smaller or higher, depending on the amount of drug and excipient
that is necessary. Generally, the unit dose should not be so large
that it is not capable of being swallowed by the patient without
much difficulty. It is preferred that the unit dose is of a small
enough quantity that it can be swallowed without the necessity of
an additional liquid, however, the invention is not limited to such
quantity and doses which may require a liquid are contemplated by
the invention. Preferably the unit dose is from about 1 mg to about
100 mg, or from about 10 mg to about 50 mg, depending on the
potency of the active agent. In situations where the unit dose is
too large to be easily swallowed, it is contemplated that the
system can be actuated multiple times for subsequent delivery in
order to administer divided doses of the intended dose, which are
more easily swallowed by the patient.
[0114] When it is contemplated for the unit dose to be swallowed
without the use of an additional liquid, certain embodiments of the
invention provide that the multiparticulates comprise an effective
amount of an agent which stimulates the production of saliva in
order to facilitate the swallowing of the unit dose. Such agents
include any acid which is safe for human consumption and includes
food acids, acid anhydrides and acid salts. Food acids include
tartaric acid, malic acid, fumaric acid, adipic acid, and succinic
acids and fruit-acids, e.g., citric acid. Acid anhydrides of the
above described acids may also be used. Acid salts may include
sodium, dihydrogen phosphate, disodium dihydrogen pyrophosphate,
acid citrate salts and sodium acid sulfite.
[0115] In other embodiments of the invention, the multiparticulates
can comprise an effervescent compound or composition which provides
a pleasing organoleptic effect which can substantially mask the
taste of unpalatable active ingredients in the powder. The
effervescent action also acts as a stimulant to saliva production.
Effervescent agents include compounds which evolve gas. The
preferred effervescent agents evolve gas by means of chemical
reactions which take place upon exposure to a liquid such as saliva
in the mouth. This bubble or gas generating chemical reaction is
most often the result of the reaction of an acid (e.g. the saliva
stimulant acids listed above) and an alkali metal
carbonate/dicarbonate or base. The reaction of these two general
classes of compounds produces carbon dioxide gas upon contact with
saliva.
[0116] The use of acids and/or effervescent ingredients is
particularly useful in patients with achlorhydria or other patients
with a problem swallowing the unit dose without the use of a
liquid.
[0117] For ease of swallowing and in order to minimize pulmonary
aspiration of multiparticulates, the system preferably is
configured to dispense the unit dose onto the tongue of the
patient. The tongue can be stuck out in order to facilitate the
deposit of the unit dose thereon or preferably, the dispenser can
be configured in order to deposit the unit dose on the tongue
without the necessity of the patient sticking out the tongue.
Preferably, the system is of such a configuration that the unit
dose is deposited behind the teeth towards the front of the tongue.
The front of the tongue is preferred in order to stimulate the
natural swallowing of the unit dose into the esophagus. This
reduces the possibility of any individual particles becoming
airborne and inhaled into the pulmonary system and facilitates the
swallowing of the unit dose by initiating a more natural swallowing
reflex. However, the unit dose should be able to be placed anywhere
on the tongue, including the deposit on the back of the tongue
without stimulating the soft palate to cause a gag reflex.
[0118] As with most pharmaceutical formulations, it is often
necessary to add a pharmaceutically acceptable excipient to the
drug. For example, when formulating an agent into tablets or
capsules, a bulking agent is used in order to provide enough mass
to tablet or capsule the agent. This results in many of the
drawbacks of solid dosage forms which were discussed above.
[0119] With the present invention, however, it is not necessary to
have a large percent of the formulation consisting of excipient as
it is preferable to have the unit dose which is deposited on the
tongue of the patient as small as possible in order to facilitate
swallowing. The use of excipient is used in the present invention,
e.g., to improve flowability, to taste mask, to stimulate flow of
saliva for swallowing or to provided a modified release of the
drug. In preferred embodiments the excipient is less than about 20%
by weight of the multiparticulates and more preferably less than
about 10% by weight of the multiparticulates. These preferred
percent weights of excipients are not meant to be limiting. For
example, with a micro-dose drug such as digoxin or levothyroxine,
the percent of excipient may need to be more than 20% in order to
provide enough bulk for acceptable flow or dose metering
characteristics.
[0120] The pharmaceutical acceptable excipient of the
multiparticulates can coat the drug. In such an embodiment, the
excipient can provide a modified release of the drug. For example,
such a multiparticulate can be formulated to provide a delayed
release wherein the drug is released in the intestine.
Multiparticulate with an excipient coating can also be formulated
in order to provide a sustained release of the drug over time in
the gastrointestinal tract. Coating the drug with excipient can
also be done in order to mask the bitter taste of certain
drugs.
[0121] Alternatively, the excipient can be used as a substrate and
the drug can be coated onto the excipient. This formulation option
can be used in order to provide desired flow capabilities and to
provide a critical mass of the drug particles in order to minimize
lung aspiration.
[0122] The excipient can also be used in a mixture with the in
order to provide the desired properties (e.g., flow properties) to
allow the unit dose to be delivered as a discreet unit, with
minimal multiparticulates suspended in the air.
[0123] When the multiparticulates are formulated as controlled
release powders, the drug may be combined with a polymer which may
be soluble, insoluble, permeable, impermeable or biodegradable. The
polymers may be polymers or copolymers. The polymer may be a
natural or synthetic polymer. Natural polymers include
polypeptides, polysaccharides and alginic acid. A suitable
polypeptide is zein and a suitable polysaccharide is cellulose. The
drug/polymer combination can be formed by known methods such as
granulating, spray coating or agglomerating.
[0124] Representative synthetic polymers include alkyl celluloses,
hydroxyalkyl celluloses, cellulose ethers, cellulose esters, nitro
celluloses, polymers of acrylic and methacrylic acids and esters
thereof, polyamides, polycarbonates, polyalkylenes, polyalkylene
glycols, polyalkylene oxides, polyalkylene terephthalates,
polyvinyl alcohols, polyvinyl ethers, polyvinyl esters, polyvinyl
halides, polyvinylpyrrolidone, polyglycolides, polysiloxanes and
polyurethanes and co-polymers thereof. The polymer to be used is
governed by its toxicity and its compatibility with the particular
active ingredient being used and can be selected without difficulty
by those skilled in the art.
[0125] Particularly suitable polymers include: methyl cellulose,
ethyl cellulose, hydroxypropyl cellulose, hydroxypropyl methyl
cellulose, hydroxybutyl methyl cellulose, cellulose acetate,
cellulose propionate (lower, medium or higher molecular weight),
cellulose acetate propionate, cellulose acetate butyrate, cellulose
acetate phthalate, carboxymethyl cellulose, cellulose triacetate,
cellulose sulphate sodium salt, poly(methyl methacrylate),
poly(ethyl methacrylate), poly(butylmethacrylate), poly(isobutyl
methacrylate), poly(hexylmethacrylate), poly(isodecyl
methacrylate), poly(lauryl methacrylate), poly(phenyl
methacrylate), poly(methyl acrylate), poly(isopropyl acrylate),
poly(isobutyl acrylate), poly(octadecyl acrylate), poly(ethylene),
poly(ethylene) low density, poly(ethylene) high density,
poly(propylene), poly(ethylene glycol), poly(ethylene oxide),
poly(ethylene terephthalate), poly(vinyl alcohol), poly(vinyl
isobutyl ether), poly(vinyl acetate), poly(vinyl chloride) and
polyvinylpyrrolidone. Especially suitable co-polymers include:
butyl methacrylate/isobutyl methacrylate co-polymer, high molecular
weight, methylvinyl ether/maleic acid co-polymer, methylvinyl
ether/maleic acid, monoethyl ester co-polymer, methylvinyl
ether/maleic anhydride co-polymer and vinyl alcohol/vinyl acetate
co-polymer.
[0126] Representative biodegradable polymers include, polylactides,
polyglycolides, poly(ethylene terephthalate), polyhydroxy-butyrate,
polyhydroxy-valerate and polyurethane.
[0127] Representative acrylates and methacrylates are polyacrylic
and methacrylic polymers such as those sold under the Trademarks
Eudragit. Amberlite and Carbopol.
[0128] Classes of drugs which are suitable in the present invention
include antacids, anti-inflammatory substances, coronary dilators,
cerebral dilators, peripheral vasodilators, anti-infectives,
psychotropics, anti-manics, stimulants, anti-histamines, laxatives,
decongestants, vitamins, gastro-intestinal sedatives,
anti-diariheal preparations, anti-anginal drugs, vasodilators,
anti-arrhythmics, anti-hypertensive drugs, vasoconstrictors and
migraine treatments, anti-coagulants and anti-thrombotic drugs,
analgesics, anti-pyretics, hypnotics, sedatives, anti-emetics,
anti-nauseants, anti-convulsants, neuromuscular drugs, hyper- and
hypoglycemic agents, thyroid and anti-thyroid preparations,
diuretics, anti-spasmodics, uterine relaxants, mineral and
nutritional additives, anti-obesity drugs, anabolic drugs,
erythropoietic drugs, anti-asthmatics, bronchodilators,
expectorants, cough suppressants, mucolytics, drugs affecting
calcification and bone turnover and anti-uricemic drugs.
[0129] Specific drugs include gastro-intestinal sedatives such as
metoclopramide and propantheline bromide; antacids such as aluminum
trisilicate, aluminum hydroxide, ranitidine and cimetidine;
anti-inflammatory drugs such as phenylbutazone, indomethacin,
naproxen, ibuprofen, flurbiproferi, diclofenac, dexamethasone,
prednisone and prednisolone; coronary vasodilator drugs such as
glyceryl trinitrate, isosorbide dinitrate and pentaerythritol
tetranitrate; peripheral and cerebral vasodilators such as
soloctidilum, vincamine, naftidrofuryl oxalate, co-dergocrine
mesylate, cyclandelate, papaverine and nicotinic acid;
anti-infective substances such as erythromycin stearate,
cephalexin, nalidixic acid, tetracycline hydrochloride, ampicillin,
flucloxacillin sodium, hexamine mandelate and hexamine hippurate;
neuroleptic drugs such as flurazepam, diazepam, temazepam,
amitryptyline, doxepin, lithium carbonate, lithium sulfate,
chlorpromazine, thioridazine, trifluperazine, fluphenazine,
piperothiazine, haloperidol, maprotiline hydrochloride, imipramine
and desmethylimipramine; central nervous stimulants such as
methylphenidate, ephedrine, epinephrine, isoproterenol, amphetamine
sulfate and amphetamine hydrochloride; antihistamic drugs such as
diphenhydramine, diphenylpyraline, chlorpheniramine and
brompheniramine; anti-diarrheal drugs such as bisacodyl and
magnesium hydroxide; the laxative drug, dioctyl sodium
sulfosuccinate; nutritional supplements such as ascorbic acid,
alpha tocopherol, thiamine and pyridoxine; anti-spasmodic drugs
such as dicyclomine and diphenoxylate; drugs affecting the rhythm
of the heart such as verapamil, nifedipine, diltiazem,
procainamide, disopyramide, bretylium tosylate, quinidine sulfate
and quinidine gluconate; drugs used in the treatment of
hypertension such as propranolol hydrochloride, guanethidine
monosulphate, methyldopa, oxprenolol hydrochloride, captopril and
hydralazine; drugs used in the treatment of migraine such as
ergotamine; drugs affecting coagulability of blood such as epsilon
aminocaproic acid and protamine sulfate; analgesic drugs such as
acetylsalicylic acid, acetaminophen, codeine phosphate, codeine
sulfate, oxycodone, dihydrocodeine tartrate, oxycodeinone,
morphine, heroin, nalbuphine, butorphanol tartrate, pentazocine
hydrochloride, cyclazacine, pethidine, buprenorphine, scopolamine
and mefenamic acid; anti-epileptic drugs such as phenytoin sodium
and sodium valproate; neuromuscular drugs such as dantrolene
sodium; substances used in the treatment of diabetes such as
tolbutamide, disbenase glucagon and insulin; drugs used in the
treatment of thyroid gland dysfunction such as triiodothyronine,
thyroxine and propylthiouracil, diuretic drugs such as furosemide,
chlorthalidone, hydrochlorthiazide, spironolactone and triamterene;
the uterine relaxant drug ritodrine; appetite suppressants such as
fenfluramine hydrochloride, phenternine and diethylproprion
hydrochloride; anti-asthmatic and bronchodilator drugs such as
aminophylline, theophylline, salbutamol, orciprenaline sulphate and
terbutaline sulphate; expectorant drugs such as guaiphenesin; cough
suppressants such as dextromethorphan and noscapine; mucolytic
drugs such as carbocisteine; anti-septics such as cetylpyridinium
chloride, tyrothricin and chlorhexidine; decongestant drugs such as
phenylpropanolamine and pseudoephedrine; hypnotic drugs such as
dichloralphenazone and nitrazepam; anti-nauseant drugs such as
promethazine theoclate; haemopoietic drugs such as ferrous
sulphate, folic acid and calcium gluconate; uricosuric drugs such
as sulphinpyrazone, allopurinol and probenecid; and calcification
affecting agents such as biphosphonates, e.g., etidronate,
pamidronate, alendronate, residronate, teludronate, clodronate and
alondronate.
[0130] Drugs which possess taste and/or odor characteristics which,
when administered orally without any excipients, render the drug or
therapeutic agent unpalatable to a subject and would be candidates
for taste masking in the present invention include, but are not
limited to, H.sub.2 receptor antagonists, antibiotics, analgesics,
cardiovascular agents, peptides or proteins, hormones,
anti-migraine agents, anti-coagulant agents, anti-emetic agents,
anti-hypertensive agents, narcotic antagonists, chelating agents,
anti-anginal agents, chemotherapy agents, sedatives,
anti-neoplastics, prostaglandins, antidiuretic agents and the like.
Typical drugs include but are not limited to nizatidine,
cimetidine, ranitidine, famotidine, roxatidine, etinidine,
lupitidine, nifentidine, niperitone, sulfotidine, tuvatidine,
zaltidine, erythomycin, penicillin, ampicillin, roxithromycin,
clarithromycin, psylium, ciprofloxacin, theophylline, nifedipine,
prednisone, prednisolone, ketoprofen, acetaninophen, ibuprofen,
dexibuprofen lysinate, flurbiprofen, naproxen, codeine, morphine,
sodium diclofenac, acetylsalicylic acid, caffeine, pseudoephedrine,
phenylpropanolamine, diphenhydramine, chlorpheniramine,
dextromethorphan, berberine, loperamide, mefenamic acid, flufenamic
acid, astemizole, terfenadine, certirizine, phenytoin, guafenesin,
N-acetylprocainamide HCl, pharmaceutically acceptable salts thereof
and derivatives thereof.
[0131] Dry powder inhalation devices require high air flow to
create shear conditions sufficient to isolate discrete drug
particles in the pulmonary system. The greater the air flow, the
more the device disperses the powdered drug into smaller, more
respirable particles. This air flow is in the range of about 20
litres/min. to about 150 litres/min. and results in high shear
forces on agglomerates of drug and causes collisions between the
agglomerates of powdered drug both of which tend to deagglomerate
the large agglomerates into the desired primary particles for
pulmonary deposition. In certain embodiments of the present
invention, the air flow provided is enough to facilitate the unit
dose of drug out of the device, but not-enough in order to project
the particles into a "mist" for inhalation into the pulmonary
system. This air flow is less than 20 litres/min, preferably less
than about 10 litres/min. In the present invention, devices from
the prior art can be modified in order to provide the desired less
than 20 litres/min. airflow. In alternate embodiments, there is
minimal air flow and the powder dispenses from the device into the
oral cavity through gravitational force or mechanical action. In
certain embodiments, the unit dose is metered and mechanically
moved to the dispensing hole of the device (against or in the
direction of gravity) prior to dispensing.
[0132] In certain embodiments, the multiparticulates are contained
in a reservoir. Preferably, the reservoir contains multiple doses
of the multiparticulates in order to provide a multiplicity of unit
doses. The number of unit doses contained in the reservoir and
capable of being delivered by the system depends on, among other
factors, the frequency of dosing and the duration of therapy of the
drug being dispensed. For example, for acute therapy, the system
can be configured to deliver 30 unit doses of an antibiotic being
prescribed three times daily for 10 days. Alternatively for chronic
therapy, the system can be configured to contain 30, 100 or even
365 doses of an antihypertensive drug administered once daily.
[0133] In certain embodiments, the system of the invention can be
configured wherein the reservoir is replaceable, e.g., in the form
of a replaceable cartridge, or wherein the reservoir is capable of
being refilled, e.g., by including a removable plug wherein bulk
powder can be introduced. However, in embodiments wherein the
system is capable of being refilled, it is preferable that the
system utilizes a replaceable system such as the previously
disclosed cartridge device rather than refilling the system with
bulk powder through an unplugged hole as the latter may be more
prone to human error, e.g., loss of powder due to spilling or
improper manipulation. Further, the handling of bulk powders may
result in contamination of the reservoir, powder or both with
moisture and/or contaminants.
[0134] In other embodiments the system can be disposable, wherein
after administration of all of the unit doses, the system is not
capable of being replaced with additional unit doses of the drug.
This embodiment can be beneficial for many reasons. Most
prominently, a disposable system will give the patient, the
prescriber and the manufacturer, greater assurances that the
patient is receiving a proper dosage from a functional system that
has not been subjected to improper handling and/or internal
friction for a long duration of time. Such a disposable device may
also reduce the overall cost of manufacture, as the device would
only have to be manufactured to provide an accurate dose for a
finite period of time. With refillable systems, greater care would
have to be taken in the manufacturing process and materials
selected in order to assure that the device is capable of providing
an accurate dose for a longer period of time, e.g. over a year. As
a compromise between the disposable and refillable system, a
refillable system can be manufactured wherein the patient is
informed that after a certain amount of time and/or courses of
therapy, the system should be replaced with a new device. Such a
system would be beneficial to the patient, prescriber and
manufacturer by reducing manufacturing cost, improving patient
convenience by being able to refill the device and assuring to all
parties that a patient will not be using a device which may be
non-functional due to internal friction and/or improper
handling.
[0135] In certain embodiments, a counter can be included in the
system which can improve compliance of the patient. This is done by
the count or indicator being utilized to know how many doses have
been taken for those patients who sometimes forget if they have
taken a previous dose. With solid dosage forms, if a patient has
forgotten if a previous dose has been taken, it is often necessary
to count the remaining doses to see if one was taken. This creates
problems such as contamination and also the likelihood of
miscounting wherein the patient might take a double dose or skipped
dose due to a counting error. The counter will also keep the user
apprised as to when the drug will run out and will help to improve
proper planning for the patient to frequent a pharmacy in a timely
manner. This can reduce the likelihood of a patient being
"surprised" when the system does not provide any unit doses. The
device can alternatively count the doses delivered by counting up,
or can count down to show the number of unit doses remaining in the
system. The counter can be an electrical or mechanical mechanism
which are commonly known in the art. The indicator can also be a
visual mechanism, e.g., the powder could fall below a colored
marker which would indicate the number of doses remaining, the
device can expose the internal powder to view in a window, or other
mechanisms known in the art.
[0136] In the present invention, unlike tablets or capsules which
have patient instruction labels on secondary containers, the system
of the present invention has a label permanently affixed to the
container by the manufacturer, prescriber or dispenser. As the drug
is not separated from the container, the label in not disassociated
from the drug and the label can be seen at or between each
dose.
[0137] In certain embodiments, the unit dose of multiparticulates
is metered out of the reservoir and expelled from the device.
Preferably the unit dose exits the reservoir into a delivery
conduit which transports the unit dose out of the device to the
oral cavity of the patient or an intermediate receptacle. The
delivery conduit can be in the form of a hollow tube, or a molded
conduit with a hollow center wherein the unit dose can be
transported. In certain embodiments, the unit dose passes through
the deliver conduit into the oral cavity due to gravity wherein it
is necessary to hold the unit in an upright position during
actuation and delivery. However, it is contemplated in certain
embodiments of the invention that delivery out of the reservoir and
throughout the conduit for delivery of the unit dose can be
facilitated by use of a gas or aqueous carrier. For example a gas
can be released upon actuation to facilitate the outward motion of
the unit dose out of the device. The gas can be pressurized and
located in an additional reservoir in the system or it can be
compressed in the same reservoir as the multiparticulates. The
pressurized gas can be compressed air or liquid gas which becomes a
gas upon release from the container. In another embodiment, a
liquid can be released from a separate reservoir wherein the
multiparticulates and the liquid mix after actuation and a liquid
suspension of the multiparticulates is deposited into the oral
cavity of the patient.
[0138] In preferred embodiments, the system administers the unit
dose against gravity by mechanical means. In such an embodiment,
the reservoir or blister containing the unit dose is at a point
below the mouth prior to administration and upon actuation, the
unit dose is moved against gravity to the output cavity, where it
is deposited onto the tongue. At the point of deposit, gravity may
be used. This provides a more comfortable and convenient motion for
the patient, rather than the alternative where the unit dose is at
a point higher than the oral cavity and is transported with, or
assisted by gravity to the point of output. For example, a sipping
straw has a more comfortable and convenient feel to a user when the
contents are drawn up to the tongue, rather than drawn down from
the point of origin, e.g., the reservoir.
[0139] It is also contemplated that the unit dose can be
mechanically expelled from the device, e.g., by action of a
plunger, auger or similar mechanism. This can be used in order to
assure that all of the unit dose is expelled from the device. For
example, if there is moisture contamination at the point of
expulsion, an amount of the unit dose may stick to the device. A
plunger, auger or similar mechanism would minimize or remove this
possible situation.
[0140] As previously disclosed, it is contemplated that the unit
dose may in some circumstances be expelled not into the oral
cavity, but into a beverage, food, holder (e.g., a spoon), or other
suitable intermediate receptacle prior to ingestion.
DETAILED DESCRIPTION OF CERTAIN EMBODIMENTS
[0141] With reference to FIG. 1, a delivery device 1 has a housing
2, which includes a base 3 and an outlet portion 4. Within the
housing is a chamber 5 of circular cross section. The chamber
encloses a batch 6 of a particulate pharmaceutical preparation, for
example, a powder or granular preparation, which comprises an
orally active drug. At the upper extremity of chamber 5 is a
delivery conduit 7 which communicates with a delivery outlet 8. A
cap 9 can cover the outlet 8, and may be attachable by friction fit
or snap fit means (not shown in the drawings) to the
circumferential surface of the housing 2. A metering device 10 is
provided at the periphery of the chamber 5 for the purpose of
metering a dose of the preparation from the chamber 5 and
discharging the metered dose into the delivery conduit 7. The
metering device, which is not shown in FIG. 1, may for example be
of a kind used for metering dry powder formulations in dry powder
inhalers. One suitable form of such a metering device is described
in European Patent Specification No. 0 661 071 B, the disclosure of
which is incorporated herein by reference.
[0142] FIG. 2 shows the device of FIG. 1 in the inverted position.
As a result of inversion, the preparation is located immediately
adjacent to, the delivery conduit 7 and metering device 10. On
actuation of the metering device (in the case of devices such as
that of EP 0 661 071B, by rotation), a dose of the preparation is
metered and discharged into delivery conduit 6, through which it
falls under the influence of gravity to delivery outlet 8. If
desired, the dispersed dose may be collected in a receptacle
11.
[0143] In the use of rotatable metering devices such as those known
in the art of dry powder inhalers, it is frequently necessary for
the user to employ both his or her hands to use the device, as a
result of the twisting action required to actuate the metering
device. It is envisaged that the device of the invention might be
provided with a gearing means communicating between the rotatable
device and a remote actuation device on the device housing, the
remote actuation device being arranged to permit actuation using
the hand in which the device is held. The remote actuation means
may be, for example, operable by pressing or squeezing or a tab or
button.
[0144] Referring to FIG. 3, in another form of device according to
the invention the drug may be delivered directly into the patient's
mouth. The device of FIGS. 3 and 4 has an elongate housing 21, in
which is mounted a shallow drum-shaped reservoir 22 containing the
particulate material 23 to be dispensed. The axis of the reservoir
22 extends transversely across the elongate housing and the
reservoir 22 has a diameter that is greater than the width of the
housing 21, so that the extremities of the reservoir extend beyond
the sides of the housing. The reservoir 22 is rotatable and may be
arranged to meter the particulate material 23 in an analogous
manner to that described above in relation to FIGS. 1 and 2. A
delivery conduit 24 is provided in the housing underneath the
reservoir 22 to receive metered doses of material therefrom, for
delivery to an opening 25. A mouthpiece 26 is positioned against
the housing about the opening 25.
[0145] A pathway 27 defined within the mouthpiece 26 communicates
with the opening 25 for receiving the particulate material
therefrom. An air opening, with a valve (neither is shown) is
provided in the housing 21 and also so communicates with the
delivery conduit 24 that air can be drawn in through that air
opening when a patient sucks through the mouthpiece. The valve is
so arranged that it permits only a limited amount of air, in
general less than 20 cm3, to be drawn in through the opening during
a single sucking action of the patient, the valve closing after
that amount of air has passed to prevent further air being drawn
in.
[0146] The mouthpiece 26 has an elongate portion 28 immediately
adjacent to the opening 25. Extending from the elongate portion 28
at the distal end relative to the housing 21 is a flared portion 29
which defines a downwardly facing delivery outlet 30. Underneath
the elongate portion 28 is provided a stop member 31 which serves
to indicate to the user the correct depth of insertion into the
mouth of the mouthpiece 26. The mouthpiece 26 is mounted on a pivot
32, about which the mouthpiece is pivotable from the working
position to a storage position. The storage position is indicated
in FIG. 3 by broken lines. When the mouthpiece 26 is in the storage
position, the opening 25 at the outlet of the delivery conduit 24
may be closed by means of a slidable closure plate 33, which
protects against ingress of moisture into the reservoir 22 between
dispensing operations. On release of the mouthpiece 26 from the
storage position, actuation means (not shown) are operable to
actuate the dispensing mechanism (including the reservoir 22) and a
dose counter. In FIG. 4, the device is shown with the mouthpiece 26
in the storage position.
[0147] The configuration and relative dimensions of the mouthpiece
26 of the device of FIGS. 3 and 4 are chosen so as to ensure that
substantially all of the dispersed particulate material 23 is
delivered to, and deposited in, the patient's mouth. In particular,
they are chosen with the object of preventing accidental inhalation
of material. Thus, the elongate portion 28 of the mouthpiece 26
defines a flow channel 27a of relatively small cross-section (for
example, of circular cross-section of diameter 5 mm), which at the
distal end flares outwardly into a delivery outlet 30 at which the
pathway 27b is of much greater cross-section. Furthermore, the
delivery outlet 30 is oriented downwardly. The flaring of the
distal portion of pathway 27b tends to cause a deceleration of
airborne material received from the channel 27a, and that
deceleration in combination with the orientation of the outlet 30
promotes the deposit of the material within the patient's mouth and
especially on the tongue. In addition, as discussed further below,
the particulate material will preferably be so formulated as to
minimize the amount of material that will remain airborne on
administration, and thus to minimize inhalation.
[0148] The device 34 of FIGS. 5 and 6 is similar to that of FIGS. 3
and 4, and parts present in FIGS. 3 and 4 are designated by the
same reference numerals in FIGS. 5 and 6. In addition to the
structures already described in relation to FIGS. 3 and 4, the
device of FIG. 5 contains an additional reservoir 35 with
associated metering means (not shown) and associated delivery
conduit 36. The delivery conduits 24 and 36 communicate with the
pathway 27 in the mouthpiece 26 for delivery of particulate
material thereto from respective reservoirs 22 and 35. In FIG. 6,
the device of FIG. 5 is shown with the mouthpiece 26 in the storage
position. The reservoir 35 will usually contain a particulate
material 37 comprising an orally active drug that is different from
the orally active drug in the particulate material 23, although it
will be appreciated that, if desired, material 37 could contain the
same orally active drug, for use as a reserve source or for use in
a different dosage. For example, one of the reservoirs may contain
a glitazone drug, whilst the other might then contain a
sulphonylurea. The choice of further combinations is a matter of
routine for those skilled in the art, having regard to the known
activities of drugs and any relevant contra-indications.
[0149] The device 38 of FIG. 7 is in some respects similar to the
device 20 of FIGS. 3 and 4, and parts present in FIGS. 3 and 4 are
designated by the same reference numerals in FIG. 7. In the case of
the device 38, however, there is additionally present a reservoir
39 and metering means (not shown) for a second particulate material
40 comprising a drug for inhalation. The device has a delivery
conduit 41, into which material metered from the reservoir 39
enters in use. The delivery conduit communicates with an inhalation
airway 42, which is arranged to receive material from the conduit
41. The path from reservoir 22 via delivery conduit 24 into
mouthpiece 26 and the path from reservoir 39 via delivery conduit
41 into airway 42 are independent of one another. Whereas, as
described in relation to the device 20 of FIGS. 3 and 4, the
delivery conduit 24 communicates with an air opening having a valve
that limits the intake of air, the delivery conduit 41 communicates
with a separate air opening in the housing which permits
essentially unrestricted admission of air on inhalation of the
patient via airway 42. The device includes selection means (not
shown), which are operable by the patient to select which of the
materials 23 or 40 is to be administered. According to the
selection made by the patient, the air path communicating with the
delivery conduit of the non-selected material is closed.
[0150] In contrast to the flared outlet 30 of the mouthpiece 26,
the airway 42 of device 38 is of substantially constant, or even
tapering cross-section and is inclined only slightly downwardly. As
a result, the airflow in the airway 42 tends to flow at a
relatively high velocity, and possibly even to be accelerated.
That, in combination with the orientation of the outlet of the
airway, tends to promote inhalation of the particulate material.
Suitable combinations of particulate materials for use in the
reservoirs 22 and 39 include those comprising any of the orally
active drugs already mentioned above (in the case of reservoir 22)
and those comprising any drug that is suitable for administration
by inhalation (in the case of reservoir 39), provided of course
that the selected drugs are compatible in use. Drugs suitable for
inhalation will include, but are not limited to, those for use in
the treatment or prevention of respiratory disease.
[0151] The device of FIG. 7 is especially suitable for
administration where there is a need for both a rapid response and
for continuing action. For example, in the case of pain control,
there is frequently a need for fast relief from pain on commencing
treatment, with pain relief then being maintained. A further
potential area of use is the treatment of respiratory disease by
means of an inhalable drug during the day, and by means of a
slower-acting orally active drug for use at night.
[0152] In certain embodiments as demonstrated in FIG. 8, the system
comprises a device which comprises a drum 81 having an inner cavity
82 disposed therein for containing the multiparticulates 83. The
drum having an outer lining 84, a rotatable inner lining 85
disposed immediately within the outer lining and a stationary
retaining strip 86 located immediately within a portion of the
inner lining. The outer lining has a dispensing hole 87 at a point
behind the retaining strip to dispense the unit dose and the
rotating inner lining has a filling hole 88 disposed therein. The
rotating inner lining has a first position 89 where the filling
hole is not adjacent to the retaining strip to allow a unit dose of
the multiparticulates to be filled therein; and a second position
810 where said filling hole is adjacent to the retaining strip and
in communication with the outer hole. Upon actuation, the inner
lining is moved from the first position to the second position and
the unit dose is delivered from the reservoir to the dispensing
hole and expelled from the device for delivery to the patient. In
this embodiment, the drum which holds the multiparticulates can be
spherical or cylindrical.
[0153] In another embodiment as demonstrated in FIG. 9, the system
comprises a device which comprises a reservoir 90 containing the
multiparticulates 91 which has an exit hole therein 92; a rotatable
member 93 outside the reservoir having an external cavity 94 in
communication with the exit hole when the rotatable member is in a
first position, to allow a unit dose of the multiparticulates to be
filled therein; a stationary retaining housing 95 immediately
covering the rotating member, the retaining housing having a
dispensing hole 96 disposed therein; the rotatable member having a
second position wherein the external cavity of the rotatable member
is in communication with the dispensing hole wherein upon
actuation, the rotatable member is moved, from the first position
to the second position whereby the unit dose is delivered from the
reservoir to the dispensing hole and expelled from the device for
delivery to the patient.
[0154] In another embodiment as demonstrated in FIG. 10, the system
comprises a device which comprises a reservoir 101 to contain the
multiparticulates 102, the reservoir having an exit hole 103
therein; a rotatable member 104 outside the reservoir having a
plurality, of external cavities 105; a stationary retaining housing
106 immediately covering the rotating member, the retaining housing
having a dispensing hole 107 disposed therein; the rotatable member
in position wherein one external cavity is in communication with
the exit hole, to be filled with a unit dose of the
multiparticulates and one external cavity is in communication with
the dispensing hole; the rotating member being rotatable to advance
each cavity to the exact position of the next adjacent cavity
wherein a unit dose of the multiparticulates is delivered from the
dispensing hole when a cavity containing a unit dose is advanced to
be in communication with the dispensing hole.
[0155] In another embodiment as demonstrated in FIG. 11, the system
comprises a device which comprises a reservoir 111 to contain the
multiparticulates 112, the reservoir having an exit hole 113
therein; a movable plate 114 having a filling hole 115 disposed
therein, the movable plate, having a first position wherein the
filling hole is in communication with the exit hole of the
reservoir; a stationary retaining plate 116 immediately under the
movable plate to form a filling cavity with the filling hole, to be
filled with a unit dose of multiparticulates when the movable plate
is in the first position, the stationary retaining plate having a
dispensing hole 117; the movable plate having a second position
wherein the filling hole is in communication with the dispensing
hole. Upon actuation, the moving plate moves from the first
position to the second position and a unit dose is delivered from
the reservoir to the dispensing hole, where it is expelled from the
device and administered to the patient. In an alternate embodiment,
the device has a stationary upper plate 118 immediately over the
movable plate, the upper plate having a hole therein in
communication with the reservoir hole and the filling hole in order
to retain the unit dose in the cavity during transmission from the
first to the second hole. In certain embodiments, as shown in FIG.
11, the movable plate 114 is circular and rotatably moves from the
first position to the second position. In other embodiments as
demonstrated in FIG. 12, the movable plate 114 is rectangular and
slidably moves from the first position to the second position.
[0156] In another embodiment of the invention, the system comprises
a device comprising an archimedean screw 131 capable of reciprocal
movement to dispense a unit dose of multiparticulates from the
reservoir 132 to be discharged from the device into the oral cavity
of the patient.
[0157] In another embodiment of the invention as demonstrated in
FIG. 14, the system comprises a device comprising a shaft 141 in
communication with a reservoir 142 and a delivery conduit 143 in
communication with the shaft, wherein said device is capable of
providing a unit dose of the drug from the reservoir to the
delivery conduit. In a certain embodiments, the device further
comprises a slidable member 144 within the reservoir and the shaft,
the slidable member having a filling cavity 145 disposed therein,
the slidable member having a first position with the filling cavity
located in the reservoir and a second position with the filling
cavity located in the shaft and in communication with the delivery
outlet. Upon actuation, the slidable member moves from the first
position to the second position, and a unit dose of the drug is
discharged from the reservoir into the delivery conduit and
subsequently into the oral cavity of the patient. In preferred
embodiments, a mechanism, e.g. a spring, 146 returns the slidable
member to the first position after release of the unit dose. In an
alternate embodiment as demonstrated in FIG. 15, the slidable
member is the reservoir 147 which is enclosed within a housing
148.
[0158] In another embodiment of the invention as demonstrated in
FIG. 16, the system comprises a device comprising an elongated tube
161 having an internal cord 162, the cord having a plurality of
evenly spaced nodules 163 which plug the tube to form a plurality
of evenly spaced air pockets 164 within the tube, each of which
contains a unit dose of the multiparticulates 165; wherein upon
actuation, the cord is pulled to expose a single air pocket and the
unit dose is dispensed from the system and subsequently dispensed
to the oral cavity of the patient.
[0159] In certain embodiments of the invention, the unit doses are
individually metered prior to actuation. FIG. 17 illustrates an
embodiment comprising unit doses contained in blisters 171 on a
substrate base 172, each blister containing a unit dose, the
substrate base and the blisters covered by a seal 173. In certain
embodiments the blisters are aligned linearly in the form of a
strip, and in alternate embodiments, the strip is in the form of a
roll
[0160] In certain embodiments of the system comprising premetered
blisters as demonstrated by FIG. 18, upon actuation, the blister
strip or roll is advanced by a gear mechanism 180, an amount of
seal covering one blister is taken up by a first take up roller 181
and an equal portion of substrate base is taken up by a second take
up roller 182, whereby a unit dose-of multiparticulates is expelled
from the strip and dispensed from the system into the oral cavity
of the patient. Preferably, pinch rollers 183 are utilized in order
to straighten the substrate base to facilitate the rolling and
storage of the used blister substrate.
[0161] In other embodiments of the system comprising premetered
blisters as demonstrated by FIG. 19, the system further comprises a
piercing member 191, wherein the strip is advanced to have a
blister aligned with the piercing member wherein upon actuation,
the piercing member penetrates the blister and a unit dose of
multiparticulates is expelled from the strip and dispensed from the
system into the oral cavity of the patient.
[0162] In embodiments of the system comprising premetered blisters,
the substrate base is disk shaped with the blisters arraigned on
the periphery of the disk. The blisters being equidistant from each
other and from the center of the pack as demonstrated by FIG. 20,
wherein upon actuation the substrate base rotates about its central
axis and positions a blister in alignment with a piercing member.
The piercing member penetrating the blister to expel the unit dose
from the blister to be dispensed from the system into the oral
cavity of the patient. In alternate embodiments, the blisters can
be arranged as a matrix as demonstrated by Fog. 20a, which would
require a more complex mechanism in order to advance the blisters
to the piercing member, or vice versa.
[0163] Another embodiment of the invention as demonstrated in FIG.
21 is directed to a device for depositing a unit dose of
multiparticulates comprising a drug to the tongue of a patient
comprising a housing 211 having an inner cavity 212 formed therein
for containing multiple doses of the multiparticulates 213, the
housing having a tapered top end 214 with an opening therein 215
and a tapered bottom end 216; a lifting rod 217 fitted at a first
position 218 within the tapered bottom end of the housing which is
movable to a second position 219 within the tapered top end of the
housing, the lifting rod comprising an elongated cylinder 220 with
a top end 221 and an inner push rod 222 within the elongated
cylinder which terminates at a point below the top end of the
cylinder to form a filling cavity 223 when the lifting rod is in
the first position (b), the inner push rod movable to terminate at
a point above the top end of the cylinder when the lifting rod is
at the second position (d); wherein when the device is upright in
the first position, the filling cavity is filled with a unit dose
of the multiparticulates and when the lifting rod is moved to the
second position, the inner push rod moves to a point above the top
end of the cylinder and the unit dose of drug is expelled from the
housing onto the tongue of the patient (f). This embodiment of the
invention can further comprising an endcap 224 covering the opening
of the tapered top end or at least one shutter 225 covering the
opening of the tapered top end, wherein the at least one shutter
opens when the lifting rod is in the second position. This
embodiment of the invention can further comprise an inner ridge 226
in the opening of the tapered top end, the inner ridge configured
to engage and stop the motion of the elongated cylinder and not the
inner push rod, allowing the inner push rod to terminate at a point
above the top end of the cylinder to expel the unit dose. The
placement of the inner push rod in the elongated cylinder at the
first position is preferably adjustable in order to vary the volume
of the filling cavity and individualize the dose of the drug.
Preferably, the top tapered end is of sufficient length to allow
the dose to deposit onto the back of the tongue of the patient. In
certain embodiments, the device can be loaded with drug and cocked
at a position between the first and second position prior to
actuation as demonstrated in (c).
[0164] Another embodiment of the invention as demonstrated by FIG.
22 is directed to a device for depositing a drug onto the tongue of
a patient comprising an elongated housing 221 having an inner
cavity 223, the housing having an opening 224 connecting the inner
cavity to outside of the housing, the housing adapted to fit within
the oral cavity of a human patient with the opening facing the
tongue of the patient; a movable member 225 within the inner
cavity, the movable member having a filling aperture 226 capable of
containing a dose of drug, the filling aperture enclosed by the
housing when the movable member is in a first position (e), the
movable member capable of being positioned to a second position (f)
wherein the filling aperture is in communication with the housing
opening to load the drug into the aperture or to discharge the drug
onto the tongue of the patient. In certain embodiments, the movable
member is horizontally slidable from the first position to the
second position or is rotatable within the elongated housing and
rotates from the first position to the second position (h, i).
Preferably, the elongated housing is of sufficient length to allow
the drug to deposit on the back of the tongue of the patient. This
embodiment can also comprise a powder feeder 227 coupled to the
opening of the housing to deposit a unit dose of drug into the
aperture when the movable member is in the second position, the
powder feeder being completely removable from the housing in order
to allow for the deposit of the dose onto the tongue of the
patient. In preferred embodiments, the powder feeder is attached to
the housing by a folding member (e.g. a hinge, spring, flexible
strip or similar mechanism) which provides a closed position and an
open position. When the housing and the powder feeder are in the
closed position, the powder feeder is coupled to the opening of the
housing and is in position to deposit a unit dose of drug into the
filling aperture 226 with the movable member is in the second
position. In the open position, the housing and the powder feeder
are in a spatial relationship which allows the housing to dispense
the unit dose into the mouth of the user without hindrance due to
the presence of the powder feeder. In order to reduce steps
involved in dispensing the drug, the folding action from the open
position to the closed position, or vice versa, can actuate a step
in the dispensing process. For example, the opening of the device
could trigger the filling of the aperture and/or the movement of
the movable member from the second position to the first position.
Alternatively, the opening of the device could trigger the filling
of the aperture, the movement of the movable member from the second
position to the first position during the initial opening, and the
movement of the movable member back to the first position for
dispensing, during the end of the opening action, when the
subsequent dispensing is unhindered by the powder feeder. The
powder feeder can comprise any mechanism for metering powder,
including any of the above disclosed reservoir systems, e.g., the
powder feeder can comprise a housing 228 forming an inner reservoir
229 to hold multiple doses of the drug in powder form 230, a shaft
231 in communicating with the reservoir and a delivery outlet 232
in communication with the shaft, wherein the powder feeder is
capable of providing a unit dose of the drug from the reservoir to
the delivery outlet. In one embodiment, the powder feeder further
comprises a slidable member 233 within the inner reservoir and the
shaft having a filling cavity 234 disposed therein, the slidable
member having a first position 235 with the filling cavity located
in the reservoir and a second position 236 with the filling cavity
located in the shaft and in communication with the delivery outlet,
wherein upon movement of the slidable member from the first
position to the second position, a unit dose of the drug is
discharged from the powder feeder into the filling aperture of the
movable member.
[0165] Another embodiment of the invention as demonstrated by FIG.
23 is directed to a device for depositing a drug onto the tongue of
a patient comprising a housing 231 forming a reservoir 232 and a
shaft 233 in communication with the reservoir, the housing having
an opening 234 connecting the shaft to outside of the housing, the
housing adapted to fit within the oral cavity of a human patient
with the opening facing the tongue of the patient; a movable member
235 having a filling aperture 236 capable of containing a dose of
drug, the movable member fitted within the shaft in a first
position (b) wherein the filling aperture is in communication with
the reservoir and capable of being filled with the dose, the
movable member capable of being positioned to a second position (d)
with the filling aperture in communication with the housing opening
wherein the dose of drug is discharged onto the tongue of the
patient. In certain embodiments the movable member is horizontally
slidable from the first position to the second position or is
rotatable within the elongated housing and rotates from the first
position to the second position. The device can further comprise a
locking mechanism 237 to keep the position of the filling aperture
at a location between the first and second position (c).
Preferably, the device comprises a mechanism, e.g. a spring 238, to
position the movable member to the second position upon release of
the locking mechanism. Preferably, the top tapered end is of
sufficient length to allow the dose to deposit onto the back of the
tongue of the patient and has a removable cap 239.
[0166] The systems and device of the present invention should
contain the powder in order to prevent contamination from the
outside environment as well as to assure a closure to prevent loss
and waste of powder. This can be accomplished by elastomeric
sealing gaskets which can provide a seal between the reservoir and
the other components to prevent leakage or escape of powder from
the reservoir. Alternatively, this can be accomplished by biasing
the components with, e.g. a screw, in order to provide tight
frictional engagement between the drug containing components.
[0167] Another aspect of the invention is directed to novel
mouthpieces which aid in the coordination of the unit dose into the
oral cavity.
[0168] In certain embodiments, the mouthpiece initially protrudes
from the device in a similar manner as a traditional mouthpiece on
a standard inhaler. However, after the initial protrusion, the
mouthpiece angles downward in order to direct the unit dose onto
the tongue of the user as shown in FIG. 24. This is to assure that
as close to 100% as possible of the unit dose is subsequently
absorbed by the gastrointestinal tract and not inhaled into the
pulmonary system. The angled mouthpiece can have a sharp angle
(FIG. 24) or can be curved as shown in FIG. 25.
[0169] In another embodiment, rather than having the angled or
curved mouthpiece, the mouthpiece can be straight, but can protrude
from the device, when the device is in an upright position at an
angle (FIG. 26) in order to direct the unit dose onto the tongue
and also to reduce any deflection in the mouthpiece from the angle
and curved mouthpiece which may result in some drug being retained
and not delivered by the system.
[0170] Another novel feature of the mouthpiece of the present
invention is to have a flared mouthpiece which reduces the velocity
of the multiparticulates and prevents the scattering and dispersion
of the dose which may lead to pulmonary infiltration. In the prior
art, narrowed or venturi style mouthpieces result in an increased
velocity during delivery which is beneficial for pulmonary
inhalation. By virtue of the flared mouthpiece of the present
invention, the velocity of the multiparticulates is not increased,
thereby increasing the percent of drug deposited
gastrointestinally. As shown in FIG. 27, the flared mouthpiece can
be conical in shape 270, wherein diameter of the outlet of the
mouthpiece 271 is large than the internal entrance 272 wherein the
unit enters the mouthpiece. In preferred embodiments, the outlet
diameter is 25%, 50% or 100% greater than the inlet diameter of the
mouthpiece. However these percentages are not meant to be
limiting.
[0171] In other embodiments as demonstrated in FIG. 28, the
mouthpiece can be rectangular 281, with the horizontal top 282 and
bottom 283 being longer than the sides 284 in order to fit within
the mouth of a patient. Similarly to the conical mouthpiece the
outlet of the opening 285 will be greater than the inlet opening
286. For example, the surface area of the outlet opening van be
25%, 50% or 100% larger than the inlet opening.
[0172] In other embodiments with a rectangular style mouthpiece as
depicted in FIG. 29, the outward protrusion of the mouthpiece 291
can be fanlike. In such an embodiment the side walls 292 of the
mouthpiece extend outward from the beginning of the mouthpiece 293
as angles, e.g. 15 degrees, going in opposite direction from each
other to provide the flare. When the walls reach the desired
distance, the top and bottom of the mouthpiece 294 are convex on
their outer edges 295 in order to provide the fanlike
appearance.
[0173] In certain embodiments of the invention, drug delivery
devices known in the art, e.g., powder inhaler art, can be
modified/adapted in order to have the capacity and the capability
to actuate a unit dose of particles having a size suitable for
gastrointestinal delivery with minimal inhalation into the
pulmonary system. Such devices are described in the above mentioned
WO 94/04133, U.S. Pat. No. 4,590,206 and WO 93/25198, hereby
incorporated by reference,. Other devices are described below:
[0174] One such device is known as the Bespak device described in
PCT publication WO 92/00771, hereby incorporated by reference,
available from Innovata Biomed Limited. The device described
therein includes a storage chamber for storing a powdered drug to
be administered and a metering member having metering cups in which
individual doses of the powdered drug are placed. Air is inhaled
through an inhalation passage at one end of the device and directed
into contact with the metering cup that has been filled with the
powdered drug. The metering cup is oriented upwardly open to face
the air stream and to enable the powder to be released from the
cup. Upon inhalation, the dose is mixed with the air flow and
continues through the mouthpiece to be inhaled. The metering cups
on the metering member are arranged on an outer frusto-conical wall
so that each metering cup is positioned to be upwardly open and
face the air flow during inhalation. The metering member rotates so
that the metering cups move between a position in which the cup
receives a dose of the powered drug from the storage chamber to a
position in which the cup is exposed to the air flow. As one cup is
exposed to the air flow, another cup is aligned with the storage
chamber and is being filled with powder. After the dose is blown
from the metering cup, and upon subsequent rotation of the metering
member, the cup is wiped and cleaned by a wiping element to remove
any undispersed powder and then dried via a moisture absorbent
material.
[0175] Another device for delivery of inhalation powders is
described in U.S. Pat. No. 2,587,215 (Priestly), hereby
incorporated by reference. Priestly describes an inhaler having a
storage chamber containing a powdered drug, a mixing chamber and
means to move a set dose of drug from the storage chamber to the
mixing chamber. The dose is mixed with air in the mixing chamber
and inhaled through a mouthpiece.
[0176] Yet another inhalation device suitable for delivering
powdered inhalation drugs is described in U.S. Pat. No. 4,274,403
(Struve), hereby incorporated by reference. Struve describes an
inhaler for administering a powdered drug nasally, which includes
storage means for containing a quantity of the drug therein. The
storage means includes a feed hole through which the powdered drug
may be received from the storage means. The device further includes
a dispensing head operatively coupled to the storage means for
dispensing the powdered drug more nasally. The dispensing head of
the Struve inhaler includes a nozzle, a body portion, a dispensing
cylinder and a vent means. The nozzle is shaped to be received in
the nasal passage of the user. The nozzle includes a dispensing
passageway for dispensing the dose into the nasal cavity of
patient. The body portion is located adjacent the nozzle and has a
traverse bore therein. The traverse bore operatively connects the
dispensing passageway in the nozzle with the feed hole leading to
the drug storage means. The feed hole and the dispensing passageway
are transversely offset relative to one another at the points where
they enter the transverse bore.
[0177] The dispensing cylinder includes a metering chamber. The
metering chamber may be selectively aligned with either the feed
hole or the dispensing passageway. The dispensing cylinder is
slidably received in the transverse bore for movement between a
first transverse position in which the metering chamber is aligned
with the feed hole and a second transverse position in which the
metering chamber is aligned with the dispensing passageway. In its
first position, the metering chamber can be filled with a charge of
the powdered drug when the inhaler is manipulated. In the second
position, places the charge of the powdered drug into the
dispensing passageway for inhalation by the user. The vent means is
formed as part of the dispensing cylinder and is capable of venting
the metering chamber to atmosphere only in the second position of
the cylinder, i.e. when the powder disposed in the device such that
it may be inhaled by the user.
[0178] Another inhaler device is disclosed in U.S. Pat. No.
4,524,769 (Wetterlin), hereby incorporated by reference. Wetterlin
describes a dosage inhaler for administering a micronized
pharmacologically active substance to a patient. The inhaler
includes a gas conduit means through which gas passes for carrying
the micronized substance to be administered. The inhaler further
includes a membrane having a plurality of preselected perforated
portions, each portion adapted to hold and dispense a reproducible
unit dose of less than 50 mg of said active substance, in dry
powder form. The powder particles have a particle size of less than
5 micrometers. The membrane is movably connected to the gas conduit
means so that one of the preselected portions can be positioned
within the gas conduit means so that the substance held in the
preselected portion may be dispensed. The remaining preselected
portion can be in a position external to said gas conduit means to
receive said active substance. The membrane is movable through a
plurality of positions whereby each preselected portion of the
membrane can be successively positioned within the gas conduit to
dispense the unit dose of the active substance held therein. Each
preselected portion from which the active substance has been
dispensed can be moved to said external position to receive active
substance.
[0179] GB Patent Application No. 2,041,763, hereby incorporated by
reference, describes an inhaler having a powder storage chamber and
a rotatable metering member having dosing holes which open to the
storage chamber in one position and open to the mixing chamber in
another position. Upon rotation of the metering member, the powder
is carried from the storage chamber to the mixing chamber to be
inhaled.
[0180] EP 0 079 478, hereby incorporated by reference, describes an
inhaler having a storage chamber, inhalation air passage and
rotatable delivery member having a cavity formed therein. The
delivery member is rotated from one position in which the cavity
receives powder from the storage chamber to another position in
which the powder falls from the cavity by the effect of gravity
into a collector positioned in the air passage.
[0181] U.S. Pat. No. 4,860,740 (Kirk et al.), hereby incorporated
by reference, describes an inhaler having a rotatable metering
member with recesses formed therein. The recesses contain a
powdered drug. Upon rotation of the metering member, one of the
recesses in exposed to the air inhalation passage to be entrained
in the air stream and inhaled.
[0182] The Easyhaler.TM., described in PCT publication WO 92/09322,
hereby incorporated by reference, available from Boehringer
Ingelheim is illustrative of another suitable device which can be
adapted/modified for delivering the formulations of the present
invention. The device includes a supply of a pulverized medical
substance and a "dosing means", which is a rotatable cylinder
having five uniform recesses arranged around the periphery of the
cylinder. The cylinder is rotated such that one recess aligns with
the supply of drug and is filled by a quantity of the drug while
another recess aligns with an air channel connected to the
mouthpiece. The filled recess is then rotated to another position
in the direct path of an inhalation air flow. The dose is pre-set
by the recessed portion of the rotatable dosing means and is
flushed clean by the direct air flow through the inhalation
chamber. To operate the device, the rotating dosing means is turned
so that a full dosing chamber (having already been filled up after
the previous use) is rotated into alignment with the air channel
leading to the mouthpiece. Upon inhalation by the user, air is
drawn through apertures and nozzles directly into the dosing
chamber. The air flow flushes the dosing chamber causing the drug
to be carried with the air in the direction of the inhalation
through the mouthpiece. The axis of the air channel is arranged at
an angle to the axis of the dosing means of between 70.degree. and
110.degree., but preferably 90.degree. (perpendicular).
[0183] U.S. Pat. No. 5,176,132, hereby incorporated by reference,
discloses a device for the administration to the lung by inhalation
of a drug in powdered form. The device includes a mouthpiece, a
drug reservoir communicating with said mouthpiece, and metering
means for dispensing a dose of drug from the reservoir. The
reservoir contains a compacted body of powdered drug including an
active ingredient having a particle size of from 1 to 10 .mu.m when
in loose powder form. The metering means includes a rotatable
helical blade for abrading the compacted body. Thus when actuated,
the helical blade abrades the compacted powdered drug into
particles capable of being inhaled into the respiratory tract of a
patient.
[0184] International patent applications, PCT/EP93/01157 and
PCT/EP93/01158 (assigned to GGU), hereby incorporated by reference,
are directed to an inhalation device and to a annular tablet,
respectively. GGU's device includes a drug reservoir body situated
in a mouthpiece. The body forms the beginning of an inhalation tube
through which the drug is inhaled. The drug is in a compacted and
annular (ring) form. In use, a face mill cutter rotates, generating
particles of the drug. Upon inhalation, air flows through air inlet
openings in the casing and in the area of the cutting edges of the
face mill cutter. Together with depressions situated between the
cutting edges, the inlet openings and the depressions form an air
channel leading to the mouthpiece, through which the drug particles
are inhaled.
[0185] The quantity of each dose is determined by the amount of
rotations of the face mill cutter. A spring presses the inhalation
tube and thus the drug body toward the face mill cutter. In
operation, a wind-up button is rotated to load the spring. By
pressing the trigger mechanism, the spring is released thereby
rotating the upper portion to which is connected the face mill
cutter.
[0186] Other representative inhalers for medications are those
described in, for example, U.S. Pat. Nos. 3,157,179; 3,178,748;
3,183,907; 3,356,088; 3,361,306; 3,456,644; 3,456,646; 3,565,070;
3,656,070; 3,636,949; 3,658,059; 3,732,864; 3,789,843; 3,814,297;
3,991,761; 3,826,413; 4,206,758; 4,414,972; 4,484,577; 4,534,345;
4,592,348; 4,817,822; 4,484,577; 4,926,852; 4,790,305; 4,210,155;
4,852,561; 4,644,107; 4,677,975; 4,803,978; 4,934,358; 4,955,371;
5,020,527; 5,048,514; 5,060,643; 5,224,471; 5,250,287; 5,284,133;
and 5,351,683. Representative of nasal-pharyngeal inhalers for
large mammals such as a horse is that described in U.S. Pat. No.
5,062,423.
[0187] Representative devices for handling powder forms of medicine
are shown and described in several U.S. Patents, including U.S.
Pat. Nos. 6,142,146; 6,116,238; 6,073,818; 6,071,498; 6,065,471;
6,029,663; 6,006,747; 5,934,273; 5,875,776; 5,871,010; 5,785,049;
5,577,497; 5,694,920; 5,642,728; 5,568,807; 5,546,932; 5,524,613;
5,476,093; 5,447,151; 5,383,850; 5,372,128; 5,301,666; 5,287,850;
5,263,475; 5,042,472; 4,889,114; 4,860,740; 4,846,168; 4,338,931;
5,458,1351; 5,388,572; 5,349,947; 5,042,472; 3,507,277; 3,518,992;
3,635,219; 3,831,606; 3,948,264; 3,971,377; and 4,147,166. Dry
powder inhalers include dose inhalers, for example the single dose
inhaler known by the trade mark Monohaler.RTM. and multi-dose
inhalers, for example a multi-dose, breath-actuated dry powder
inhaler such as the inhaler known by the trade mark
Turbohaler.RTM.. Many of these prior art devices use powdered
medicine contained in a gelatin capsule or blister with a separate
dose contained in each capsule or blister. For example, in U.S.
Pat. Nos. 3,507,277; 3,518,992; 3,635,219; 3,795,244; and
3,807,400, inhalation devices are described having means for
piercing of a capsule containing a powdered drug, which upon
inhalation is drawn out of the pierced capsule and into the user's
mouth. In U.S. Pat. No. 2,517,482, a device is described having a
powder containing capsule placed in a lower chamber before
inhalation, where it is pierced by manual depression of a piercing
pin by the user. After piercing, inhalation is begun and the
capsule is drawn into an upper chamber of the device where it moves
about in all directions to cause a dispensing of powder through the
pierced holes and into the inhaled air stream. One well known dry
powder inhaler, the Diskhaler, described in U.S. Pat. No.
4,627,432, uses individual drug doses sealed within blisters on a
blister disk. A plunger pierces the blisters, to release each dose.
The disk is advanced by a knob with each successive dose. The
Spiros inhaler, described in U.S. patent application Ser. No.
08/681,103 is a dry powder inhaler which also uses a blister disk.
Another inhaler described in PCT application No. PCT/US93/09751
contains individual medicine doses stored within a plurality of
apertures in a medicine containing cartridge. The cartridge is
manually advanced to successive doses by rotating the medicine
containing cartridge. U.S. Pat. Nos. 5,327,883, and 5,577,497,
describe an inhaler having a spinning impeller.
[0188] Known devices for delivering aerosol medication for
inhalation by a patient include metered dose inhalers that are
manually operated and breath actuated. Some Examples of devices for
delivering aerosol medication for inhalation are described in U.S.
Pat. Nos. 5,960,792; 5,848,587; 5,738,087; 5,666,948; 5,617,844;
5,505,194; 5,394,866; 5290,539; 5,165,391; 5,027,806; 4,955,371;
4,852,561; 4,790,305; 4,509,515; 5,954,047; 5,755,218; 5,724,986;
5,622,162; 5,544,647; 5,505,194; 5,392,768; 5,304,125; 4,852,561;
3,187,748; 3,565,070; 3,814,297; 3,826,413; 4,592,348; 4,648,393;
4,803,978; 4,896,832; a product available from 3M Healthcare known
as Aerosol Sheathed Actuator and Cap; and a product available from
Raker Laboratories known as Autohaler.
[0189] Some Examples of fixed aerosol actuator devices of one-piece
construction are described in U.S. Pat. Nos. 3,918,451; 3,991,761;
4,011,864; 4,069,819; 4,227,522; 4,265,236; 4,454,877; 4,576,157;
4,648,393; 4,860,740; 5,002,048; 5,012,804; 5,115,803; 5,134,993;
5,134,993; 5,161,524; and 5,178,138.
[0190] Devices which are articulated and which can be folded or
telescoped for convenient carrying in a pocket or purse are
described in U.S. Pat. Nos. 3,739,950; 3,788,316; 3,927,806;
3,994,421; 4,130,116; 4,292,966; 4,509,515; 4,637,528; and
4,641,644.
[0191] Breath activated inhalers differ from pressurized aerosol
inhalers in that breath activated inhalers are activated by
inhalation of the user so that the drug is reliably drawn into the
distal regions of the lung. Typical breath activated inhalers are
described in U.S. Pat. Nos. 6,102,036; 5,483,954; 4,846,168;
4,524,769. Other systems also include a means of triggering the
medication release by the start of inhalation. Such devices have
been described in U.S. Pat. Nos. 4,664,107; 4,803,978 and
4,739,754.
[0192] Some disposable, breath-actuated inhalers are described in
WO 89/01348, U.S. Pat. No. 4,265,236. Other disposable inhalers are
described in U.S. Pat. Nos. 6,102,035, 6,062,213, 5,660,169,
5,533,505, 4,955,371.
[0193] Other more recent improvements in inhalers are described in
U.S. Pat. Nos. 6,149,892; 6,143,277; 6,131,566; 6,116,234;
6,062,213; 6,083,514; 6,074,668; and 5,878,917.
[0194] All of the disclosures of these aforementioned patents are
hereby incorporated by reference in their entireties.
* * * * *