U.S. patent application number 11/115826 was filed with the patent office on 2005-09-22 for medicament storage and delivery devices.
This patent application is currently assigned to Vectura Limited. Invention is credited to Bowman, Nicholas John, Brook Simpson, David Badley, Howard, Gary Stephen, Staniforth, John Nicholas, Tobyn, Michael, Wright, Matthew.
Application Number | 20050205083 11/115826 |
Document ID | / |
Family ID | 27791705 |
Filed Date | 2005-09-22 |
United States Patent
Application |
20050205083 |
Kind Code |
A1 |
Staniforth, John Nicholas ;
et al. |
September 22, 2005 |
Medicament storage and delivery devices
Abstract
A multiple dose delivery device for delivering a medicament into
an oral cavity of a patient is provided. The device includes a
sachet pack including a plurality of unit doses of a medicament
enclosed between a first strip and a second strip. The device
further includes a sachet advance mechanism and a mouthpiece. Upon
actuation by a user, the sachet advance mechanism, which is engaged
with the sachet pack, separates the first strip from the second
strip to release one of the plurality of the unit doses from the
sachet pack. The mouthpiece includes an opening, and each released
unit dose passes through the opening.
Inventors: |
Staniforth, John Nicholas;
(Bath, GB) ; Tobyn, Michael; (Trowbridge, GB)
; Bowman, Nicholas John; (Royston, GB) ; Wright,
Matthew; (Kentford, GB) ; Howard, Gary Stephen;
(Swavesey, GB) ; Brook Simpson, David Badley;
(Weston, GB) |
Correspondence
Address: |
DAVIDSON, DAVIDSON & KAPPEL, LLC
485 SEVENTH AVENUE, 14TH FLOOR
NEW YORK
NY
10018
US
|
Assignee: |
Vectura Limited
Chippenham
GB
|
Family ID: |
27791705 |
Appl. No.: |
11/115826 |
Filed: |
April 27, 2005 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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11115826 |
Apr 27, 2005 |
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10383408 |
Mar 7, 2003 |
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60362307 |
Mar 7, 2002 |
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60366710 |
Mar 22, 2002 |
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Current U.S.
Class: |
128/200.14 |
Current CPC
Class: |
A61J 1/03 20130101; A61K
9/0056 20130101; A61K 31/454 20130101; A61K 31/661 20130101; A61K
9/5078 20130101; A61J 3/005 20130101; A61K 31/341 20130101; A61J
7/0076 20130101; A61K 9/0007 20130101; A61K 31/44 20130101; A61K
9/5073 20130101; A61K 31/4045 20130101; A61K 9/5047 20130101; A61K
31/4402 20130101; A61K 9/1623 20130101; A61J 7/0061 20130101; A61K
31/165 20130101; A61K 9/1617 20130101; A61K 31/167 20130101 |
Class at
Publication: |
128/200.14 |
International
Class: |
A61M 011/00; B05D
007/14; A61M 015/00 |
Claims
1. A delivery device, comprising: a sachet pack including a
plurality of unit doses of a medicament enclosed between a first
strip and a second strip; a first member; a second member; an
actuator, the actuator pulling the first strip against the first
member and the second strip against the second member to release a
unit dose of the medicament from the a sachet pack; and a
mouthpiece positioned relative to the sachet pack, the first
member, and the second member, to deliver the unit dose of the
medicament to an oral cavity of a patient, wherein the medicament
is in the form of a solid wherein the solid comprises drug
particles of a size such that pulmonary deposition of an effective
dose of said drug is avoided in a human patient.
2. A delivery device, comprising: a sachet pack including a
plurality of unit doses of a medicament enclosed between a first
strip and a second strip; a first roller spaced apart forward from
a second roller, the first strip being wrapped around the first
roller, the second strip being wrapped around the second roller; an
actuator, the actuator, upon actuation by a patient, pulling the
first strip around the first roller and pulling the second strip
around the second roller to release a unit dose of the medicament
from the sachet pack; a mouthpiece positioned relative to the
sachet pack, the first roller, and the second roller, to deliver
the unit dose of the medicament to an oral cavity of the patient,
wherein the medicament is in the form of a solid, wherein the solid
comprises drug particles of a size such that pulmonary deposition
of an effective dose of said drug is avoided in a human
patient.
3. A multiple dose delivery device for delivering a medicament into
an oral cavity of a patient, comprising: a sachet pack including a
plurality of unit doses of a medicament enclosed between a first
strip and a second strip; a sachet advance mechanism engaged with
the sachet pack, the sachet advance mechanism, upon user actuation,
separating the first strip from the second strip to release one of
the plurality of the unit doses from the sachet pack; a mouthpiece
having an opening, each released unit dose passing through the
opening, wherein the medicament is in the form of a solid wherein
the solid comprises drug particles of a size such that pulmonary
deposition of an effective dose of said drug is avoided in a human
patient.
4. A delivery device, comprising: a sachet pack including a
plurality of unit doses of a medicament enclosed between a first
strip and a second strip; a first roller spaced apart forward from
a second roller, the first strip being wrapped around the first
roller, the second strip being wrapped around the second roller; an
actuator that, upon actuation by a patient, causes a predetermined
rotation of the first and second rollers, the predetermined
rotation being selected such that repeated actuation of the
actuator will cause successive ones of the plurality of the unit
doses to be released from the sachet pack; a mouthpiece positioned
relative to the sachet pack, the first roller, and the second
roller, to deliver the unit dose of the medicament to an oral
cavity of the patient, wherein the medicament is in the form of a
solid, wherein the solid comprises drug particles of a size such
that pulmonary deposition of an effective dose of said drug is
avoided in a human patient.
5. A delivery device, comprising: a sachet pack including a
plurality of unit doses of a medicament enclosed between a first
strip and a second strip; a first roller spaced apart forward from
and above a second roller, the first strip being wrapped around the
first roller, the second strip being wrapped around the second
roller; an actuator, the actuator, upon actuation by a patient,
pulling the first strip around the first roller and pulling the
second strip around the second roller to release a unit dose of the
medicament from the sachet pack; a mouthpiece surrounding the first
and second rollers, the mouthpiece having a top surface, a bottom
surface, and a pair of lateral surfaces, the bottom surface having
an opening formed therein, the released medicament passing through
the opening, wherein the medicament is in the form of a solid,
wherein the solid comprises drug particles of a size such that
pulmonary deposition of an effective dose of said drug is avoided
in a human patient.
6. The device of claim 5, wherein the opening has a forward edge, a
rear edge, and a pair of lateral edges, and wherein the forward
edge contacts the first strip and the rear edge contacts the second
strip.
7. The device of claim 6, wherein the first strip separates from
the second strip at a separation point, and wherein the separation
point is approximately midway between the forward and rear
edges.
8. The device of claim 4, wherein the mouthpiece surrounds the
first and second rollers, the mouthpiece having a top surface, a
bottom surface, and a pair of lateral surfaces, the bottom surface
having an opening formed therein, the released medicament passing
through the opening.
9. The device of claim 8, wherein the opening has a forward edge, a
rear edge, and a pair of lateral edges, and wherein the forward
edge contacts the first strip and the rear edge contacts the second
strip.
10. The device of claim 9, wherein the first strip separates from
the second strip at a separation point, and wherein the separation
point is approximately midway between the forward and rear
edges.
11. The device of claim 2, wherein the mouthpiece surrounds the
first and second rollers, the mouthpiece having a top surface, a
bottom surface, and a pair of lateral surfaces, the bottom surface
having an opening formed therein, the released medicament passing
through the opening.
12. The device of claim 11, wherein the opening has a forward edge,
a rear edge, and a pair of lateral edges, and wherein the forward
edge contacts the first strip and the rear edge contacts the second
strip.
13. The device of claim 12, wherein the first strip separates from
the second strip at a separation point, and wherein the separation
point is approximately midway between the forward and rear
edges.
14. The device of claim 3, wherein the mouthpiece has a top
surface, a bottom surface, and a pair of lateral surfaces, the
bottom surface having an opening formed therein, the released
medicament passing through the opening.
15. The device of claim 14, wherein the opening has a forward edge,
a rear edge, and a pair of lateral edges, and wherein the forward
edge contacts the first strip and the rear edge contacts the second
strip.
16. The device of claim 15, wherein the first strip separates from
the second strip at a separation point, and wherein the separation
point is approximately midway between the forward and rear
edges.
17. The device of claim 1, wherein the first member is a first
roller and the second member is a second roller, and wherein the
first roller is spaced apart forward from the second roller.
18-35. (canceled)
36. The device of claim 3, wherein the sachet advance mechanism
includes a first roller spaced apart forward from a second roller,
the first strip being wrapped around the first roller, the second
strip being wrapped around the second roller; an actuator, the
actuator, upon actuation by a patient, pulling the first strip
around the first roller and pulling the second strip around the
second roller to release a unit dose of the medicament from the
sachet pack.
37. The device of claim 3, wherein the sachet advance mechanism
includes a first member; a second member; and an actuator, the
actuator pulling the first strip against the first member and the
second strip against the second member to release a unit dose of
the medicament from the a sachet pack.
38. The device of claim 3, wherein the sachet advance mechanism
includes, a first roller spaced apart forward from a second roller,
the first strip being wrapped around the first roller, the second
strip being wrapped around the second roller; and an actuator that,
upon actuation by a patient, causes a predetermined rotation of the
first and second rollers, the predetermined rotation being selected
such that repeated actuation of the actuator will cause successive
ones of the plurality of the unit doses to be released from the
sachet pack.
39. The device of claim 3, wherein the sachet advance mechanism
includes a first roller spaced apart forward from and above a
second roller, the first strip being wrapped around the first
roller, the second strip being wrapped around the second roller;
and an actuator, the actuator, upon actuation by a patient, pulling
the first strip around the first roller and pulling the second
strip around the second roller to release a unit dose of the
medicament from the sachet pack.
40. The device of claim 1, wherein the actuator includes a stored
energy component; a stored energy initiator coupled to the stored
energy component, wherein the stored energy initiator, upon
actuation, stores energy in the stored energy component; an
actuation trigger which, upon actuation, releases the energy from
the stored energy component; and a draw component coupled to the
stored energy component, the draw component pulling the first strip
against the first member and the second strip against the second
member when the energy is released from the stored energy
component.
41-42. (canceled)
43. The device of claim 2, wherein the actuator includes a stored
energy component; a stored energy initiator coupled to the stored
energy component, wherein the stored energy initiator, upon
actuation, stores energy in the stored energy component; an
actuation trigger which, upon actuation, releases the energy from
the stored energy component; and a draw component coupled to the
stored energy component, the draw component pulling the first strip
against the first member and the second strip against the second
member when the energy is released from the stored energy
component.
44-45. (canceled)
46. The device of claim 4, wherein the actuator includes a stored
energy component, and a stored energy initiator coupled to the
stored energy component, wherein the stored energy initiator, upon
actuation, stores energy in the stored energy component; an
actuation trigger which, upon actuation, releases the energy from
the stored energy component; and a draw component coupled to the
stored energy component, the draw component pulling the first strip
against the first member and the second strip against the second
member when the energy is released from the stored energy
component.
47-48. (canceled)
49. The device of claim 5, wherein the actuator includes a stored
energy component, and a stored energy initiator coupled to the
stored energy component, wherein the stored energy initiator, upon
actuation, stores energy in the stored energy component; an
actuation trigger which, upon actuation, releases the energy from
the stored energy component; and a draw component coupled to the
stored energy component, the draw component pulling the first strip
against the first member and the second strip against the second
member when the energy is released from the stored energy
component.
50-52. (canceled)
53. The device of claim 1, wherein the solid comprises 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.
54-56. (canceled)
57. The device of claim 2, wherein the solid comprises 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.
58-60. (canceled)
61. The device of claim 3, wherein the solid comprises 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.
62-64. (canceled)
65. The device of claim 4, wherein the solid comprises 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.
66-68. (canceled)
69. The device of claim 5, wherein the solid comprises 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.
70-71. (canceled)
72. A method of delivering a unit dose of a medicament to an oral
cavity of a patient for gastrointestinal, esophageal, or oral
cavity administration, comprising: providing a device having a
sachet pack, an actuator, a first roller, a second roller, and
mouthpiece, the sachet pack including a plurality of unit doses of
a medicament enclosed between a first strip and a second strip, the
first roller spaced apart forward from the second roller, the first
strip being wrapped around the first roller, the second strip being
wrapped around the second roller; and upon actuation of the
actuator by a patient, rotating the first and second rollers such
that one of the plurality of the unit doses is released from the
sachet pack and delivered to an oral cavity of the patient for
gastrointestinal, esophageal, or oral cavity absorption or action
via the mouthpiece.
73. The device of claim 1, wherein the unit dose includes a
non-compressed free flowing plurality of particles comprising an
active agent and a water-soluble excipient, said particles having a
mean diameter of greater than about 10 .mu.m to about 1 mm, and
said formulation dissolving or dispersing in a patient's mouth
within 1 minute after administration without the coadministration
of a fluid.
74. The device of claim 1, wherein the unit dose delivered is
substantially independent of the orientation of the device.
75. The device of claim 1, wherein the first strip separates from
the second strip at a separation point; wherein the device includes
a window located adjacent a path of the first strip, downstream of
the separation point; and wherein an interior surface of the first
strip includes sequential dose numbering, such that a number
corresponding to a next dose to be delivered is on the interior
surface and visible to a user of the device through the window.
76. The device of claim 1, wherein the device includes a housing,
and wherein the actuation input is a lever which actuated by a user
squeezing the lever towards the housing.
77. The device of claim 74, wherein the wherein the first strip
separates from the second strip at a separation point, and wherein
the separation point is directly above an opening in the
mouthpiece.
78. The device of claim 1, wherein the solid comprises 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.
79. The device of claim 2, wherein the solid comprises 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.
80. The device of claim 3, wherein the solid comprises 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.
81. The device of claim 4, wherein the solid comprises 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.
82. The device of claim 5, wherein the solid comprises 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.
Description
[0001] This application claims priority from U.S. Provisional
Application Nos. 60/362,307 filed on Mar. 07, 2002 and No.
60/366,710 filed Mar. 22, 2002, the entire disclosures of which are
hereby incorporated by reference.
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 that 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 if
the dosage form is not swallowed properly. 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 compressible 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.
[0004] 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.
[0005] 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.
[0006] The dispensing of oral solid dosage forms also makes the
formulations susceptible to degradation and contamination due to
repackaging, improper storage and manual handling.
[0007] 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.
[0008] 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
[0009] 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.
[0010] Another alternative to oral dosage forms for certain
medications is aerosol dosage forms, which administer therapeutic
agents for deposition to the pulmonary system. 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.
[0011] 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.
[0012] 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.
[0013] 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.
[0014] 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.
[0015] Oral drug delivery systems, devices and methods for oral
powders are disclosed in PCT/IB01/00251, hereby incorporated by
reference in its entirety for all purposes.
SUMMARY OF THE INVENTION
[0016] In accordance with a first embodiment of the present
invention, a multiple dose delivery device for delivering a
medicament into an oral cavity of a patient is provided. The device
includes a sachet pack including a plurality of unit doses of a
medicament enclosed between a first strip and a second strip. The
device further includes a sachet advance mechanism and a
mouthpiece. Upon actuation by a user, the sachet advance mechanism,
which is engaged with the sachet pack, separates the first strip
from the second strip to release one of the plurality of the unit
doses from the sachet pack. The mouthpiece includes an opening, and
each released unit dose passes through the opening. The sachet
advance mechanism may be constructed in a variety of ways. For
example, the sachet advance mechanism may be constructed using
known techniques using gears, cams, levers, linkages, pulleys,
pistons, augers, slides, torsion elements, and the like.
[0017] In accordance with a second embodiment of the present
invention, a delivery device is provided which includes a sachet
pack including a plurality of unit doses of a medicament enclosed
between a first strip and a second strip. The device includes a
first member, a second member, an actuator, and a mouthpiece. The
actuator pulls the first strip against the first member and the
second strip against the second member to release a unit dose of
the medicament from the sachet pack. The mouthpiece is positioned
relative to the sachet pack, the first member, and the second
member, to deliver the unit dose of the medicament to an oral
cavity of a patient.
[0018] In accordance with a third embodiment of the present
invention, a delivery device is provided which includes a sachet
pack including a plurality of unit doses of a medicament enclosed
between a first strip and a second strip. The device further
includes a first roller, a second roller, an actuator, and a
mouthpiece. The first roller is spaced apart forward from the
second roller, the first strip is wrapped around the first roller,
and the second strip is wrapped around the second roller. The
actuator, upon actuation by a patient, pulls the first strip around
the first roller and pulls the second strip around the second
roller to release a unit dose of the medicament from the sachet
pack. The mouthpiece is positioned relative to the sachet pack, the
first roller, and the second roller, to deliver the unit dose of
the medicament to an oral cavity of the patient.
[0019] In accordance with a fourth embodiment of the present
invention, a delivery device is provided which includes a sachet
pack including a plurality of unit doses of a medicament enclosed
between a first strip and a second strip. The device further
includes a first roller, a second roller, an actuator, and a
mouthpiece. The first roller is spaced apart forward from a second
roller, the first strip is wrapped around the first roller, and the
second strip is wrapped around the second roller. Upon actuation by
a patient, the actuator causes a predetermined rotation of the
first and second rollers, the predetermined rotation being selected
such that repeated actuation of the actuator will cause successive
ones of the plurality of the unit doses to be released from the
sachet pack. The mouthpiece is positioned relative to the sachet
pack, the first roller, and the second roller, to deliver the unit
dose of the medicament to an oral cavity of the patient.
[0020] In accordance with a fifth embodiment of the present
invention, a delivery device is provided which includes a sachet
pack including a plurality of unit doses of a medicament enclosed
between a first strip and a second strip. The device further
includes a first roller, a second roller, an actuator, and a
mouthpiece. The first roller is spaced apart forward from and above
the second roller, the first strip is wrapped around the first
roller, and the second strip is wrapped around the second roller.
Upon actuation by a patient, the actuator pulls the first strip
around the first roller and pulls the second strip around the
second roller to release a unit dose of the medicament from the
sachet pack. The mouthpiece surrounds the first and second rollers
and has a top surface, a bottom surface, and a pair of lateral
surfaces. The bottom surface has an opening formed therein, and the
released medicament passes through the opening.
[0021] In accordance with further aspects of the present invention,
the mouthpiece of the fifth embodiment may be utilized in the
first, second, third, or fourth embodiments. Preferably, the
opening of the mouthpiece has a forward edge, a rear edge, and a
pair of lateral edges, and the forward edge contacts the first
strip and the rear edge contacts the second strip. Most preferably,
the first strip separates from the second strip at a separation
point, and the separation point is midway between the forward and
rear edges.
[0022] In accordance with other aspects of the present invention,
the actuator of the second, third, fourth, and fifth embodiments
may include an actuator input, a drive, a first pair of index
rollers, and a second pair of index rollers. This actuator may also
form a part of the sachet advance mechanism of the first
embodiment. The first pair of index rollers define a first nip
therebetween, and the first strip passes through the first nip. The
second pair of index rollers defines a second nip therebetween, and
the second strip passes though the second nip. The drive is coupled
to the actuator input, the first pair of index rollers and the
second pair of index rollers. Upon actuation of the actuator input
by a patient, the drive causes rotation of the first and second
pairs of index rollers, which in turn, pull the a portion of the
first and second strips through the first and second nips,
respectively. In certain preferred embodiments, the drive may
comprise a gear which engages one of the first pair of index
rollers and one of the second pair of index rollers, and which gear
is coupled to the actuator input such that actuation of the
actuator input causes a predetermined rotation of the gear.
[0023] In accordance with still other aspects of the present
invention, the actuator of the second, third, fourth, and fifth
embodiments may include an actuator input coupled to a carriage,
and the carriage is coupled to the first and second strips. This
actuator may also form a part of the sachet advance mechanism of
the first embodiment. With this actuator, actuation of the actuator
input causes a movement of the carriage away from the first and
second members (in the case of the second embodiment) or from the
first and second rollers (in the case of the third fourth and fifth
embodiments). Preferably, actuation of the actuator input causes a
movement of the carriage from an first position to a second
position and then to the first position, the first position being
closer to the first and second members than the second position (in
the case of the second embodiment) and closer to the first and
second rollers than the second position (in the case of the third
fourth and fifth embodiments). Most preferably, the carriage may
include a first draw roller and a second draw roller. The first and
second draw rollers are rotationally fixed when the carriage moves
from the first position to the second position. However, the first
draw roller rotates to wrap the first strip thereabout when the
carriage moves from the second position to the first position, and
the second draw roller rotates to wrap the second strip thereabout
when the carriage moves from the second position to the first
position.
[0024] In accordance with other aspects of the present invention,
the actuator of the second, third, fourth, and fifth embodiments
may include a stored energy component, a stored energy initiator,
an actuation trigger, and a draw component. The stored energy
component may also form part of the sachet advance mechanism of the
first embodiment. The stored energy initiator is coupled to the
stored energy component, and when actuated, stores energy in the
stored energy component. In contrast, the actuation trigger, when
actuated, releases the energy from the stored energy component. The
draw component is coupled to the stored energy component and the
draw component pulls the first strip against the first member and
the second strip against the second member when the energy is
released from the stored energy component. The draw component can
be implemented in a variety of ways. For example, the draw
component may be comprised of the drive and first and second pairs
of index rollers described above, or of the carriage and first and
second draw rollers as described above. Most preferably, the stored
energy component includes a gear and a torsion element, and the
gear of the stored energy component is engaged with the gear of the
drive (described above). The torsion element, which may, for
example, be a torsion spring, is coupled between the stored energy
initiator and the gear of the stored energy initiator.
[0025] Preferably, the medicament contained in the sachet packs
described above comprise drug particles greater than 10 microns 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. 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. However, the medicament may
alternately be in the form of a semi solid or a liquid.
[0026] The term "drug" or "medicament" 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.
[0027] The term "particle size" refers to the diameter of the
particle.
[0028] The term "deposition" means the deposit of the unit dose at
the intended point of absorption and/or action. For example,
gastro-intestinal 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.
[0029] 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.
[0030] 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.
[0031] The term "deliver" is meant to cover all ex vivo and in vivo
delivery, i.e., dispensing and administering, respectively.
[0032] 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.
[0033] 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 via the devices described herein. 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
[0034] FIG. 1 shows a partial cross-section through a drug delivery
device including a sachet advance mechanism.
[0035] FIG. 2 shows a perspective view of a drug delivery device in
accordance with an embodiment of the present invention.
[0036] FIG. 3 is an exploded perspective view of the drug delivery
device of FIG. 2.
[0037] FIG. 4(a) is a perspective view of the sachet drive assembly
of the drug delivery device of FIG. 1.
[0038] FIG. 4(b) is an exploded perspective view of one embodiment
of the sachet drive mechanism.
[0039] FIG. 5 is a simplified view of the lead rollers of the
chassis and the various gears and rollers of the sachet drive
mechanism of FIGS. 4(a, b).
[0040] FIG. 6 is an exploded perspective view of a drug delivery
device in accordance with another embodiment of the present
invention, including a stored energy component.
[0041] FIG. 7 is a perspective view of the chassis of the drug
delivery device of FIG. 6.
[0042] FIG. 8 is an exploded perspective view of the chassis of
FIG. 7.
[0043] FIG. 9 is a simplified side view of the chassis of FIG. 7,
including a stored energy component.
[0044] 10(a) is a perspective view of the drug delivery device of
FIG. 6 in a closed position.
[0045] FIGS. 10(b) and 10(c) are perspective views of the drug
delivery device of FIG. 6 as it is being opened and prepared for
use by a patient.
[0046] FIG. 10(d) is a perspective view of the drug delivery device
of FIG. 6 when it is open and ready for use by a patient.
[0047] FIG. 11(a) is a perspective view of a drug delivery device
according to another embodiment of the present invention in a
closed position.
[0048] FIGS. 11(b) is a perspective view of the drug delivery
device of FIG. 11(a) with its cover open.
[0049] FIG. 11(c) is a perspective view of the drug delivery device
of FIG. 11(b) when it is ready for use by a patient.
[0050] FIG. 11(d) is a partial cross-section through a side of the
device of FIG. 11(a), showing a stored energy component.
[0051] FIG. 11(e) shows a side view of a moveable component of FIG.
11(a).
[0052] FIG. 11(f) shows a top view of the moveable component
engaged with an exemplary stored energy initiator.
[0053] FIGS. 12(a-d) show a cross-section through a side of a drug
delivery device according to another embodiment of the present
invention.
[0054] FIG. 12(e) shows a side view of the drug delivery device of
FIG. 12(a-d).
[0055] FIG. 13 shows a cross-section through a side of the drug
delivery device according to the embodiment of FIG. 12(a-e) with a
"scraping" type mouthpiece.
[0056] FIG. 14 shows a perspective view of a "scraping" type
mouthpiece in accordance with an embodiment of the present
invention.
[0057] FIG. 15(a) shows a sachet pack in further detail
[0058] FIGS. 15(b,c) illustrate the composition of two prior art
sachet packs that can be used in conjunction with the various
embodiments of the present invention.
[0059] FIGS. 16(a) to FIGS. 16(c) show variations on a drug
dispenser according to an embodiment of the present invention where
a lever actuates the sachet driving mechanism.
[0060] FIG. 17 shows an illustrative sachet advance mechanism and
sachet pack that can be used in conjunction with the devices of
FIGS. 16(a) through 16(c).
[0061] FIG. 18 shows an illustrative pulley, belt, and clutch
arrangement for connecting the lever and gear of the device of FIG.
16(b).
[0062] FIG. 19 shows a clutch arrangement for connecting the lever
and gear connection of the devices of FIGS. 16(a) and (c).
[0063] FIGS. 20(a-c) show a preferred acutation mechanism for the
embodiment of FIG. 17.
DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS
[0064] Drug delivery devices in accordance with the present
invention are designed to store multiple doses of a medicament, and
to deliver a unit dose of the medicament into the oral cavity of a
patient for gastrointestinal (e.g., gastric, intestinal, and/or
colonic) absorption or action; esophageal absorption or action;
and/or absorption or action in the oral cavity (e.g., sublingual,
lingual, or buccal). This is to be distinguished from prior art
insufflation delivery devices which are designed to deliver
medicament into the lungs (e.g., pulmonary deposition) or into the
nasal passages.
[0065] FIG. 1 shows a partial cross-section through a drug delivery
device including a sachet advance mechanism 25 including an
actuator input 14, a mouthpiece 5, and a sachet pack 170. The
sachet pack 170 includes a plurality of unit doses of a medicament
enclosed between a first strip and a second strip. Upon actuation
by a user via the actuator input 14, the sachet advance mechanism
25, which is engaged with the sachet pack 170, separates the first
strip from the second strip to release one of the plurality of the
unit doses from the sachet pack. The mouthpiece 5 includes an
opening (not shown), and each released unit dose passes through the
opening. The sachet advance mechanism may be constructed in a
variety of ways. For example, the sachet advance mechanism may be
constructed using known techniques using gears, cams, levers,
linkages, pulleys, pistons, augers, slides, torsion elements, and
the like. Although the actuator input 14 is shown located on the
top of the device, it may alternatively be located on one of the
sides to provide a more ergonomic design (e.g., so that the button
is located at a convenient location for the user's thumb when in
use).
[0066] FIG. 2 shows a perspective view of a drug delivery device
1000 in accordance with a first embodiment of the present
invention, and FIG. 3 shows an exploded perspective view of FIG. 2.
Further details of the device 1000 are shown in FIGS. 4(a,b).
Referring to FIG. 3, a drug delivery device 1000 includes a housing
100 comprised of a first body portion 1 and a second body portion
2. The sachet pack 170 described above is shown in further detail
in FIG. 4(b). The sachet pack 170 is comprised of a plurality of
individual sachets 17, and is stored within the housing 100. The
sachet pack 170 is a continuous sheet which is comprised of a pair
of strips 1701, 1702 which are adhered to each other and which
enclose a medicament.
[0067] The device 1000 includes a chassis 3 having a pair of lead
rollers 7.1, 7.2 (collectively, lead rollers 7), wherein roller 7.1
is offset forward and above with respect to roller 7.2 as shown in
FIG. 3. A sachet drive mechanism 20, which is partially enclosed
within a hollow interior of chassis 3, is operable to sequentially
feed each sachet 17 from sachet pack 170 through lead rollers 7.
Sachet drive mechanism 20 is driven by actuator 14. Chassis 3,
sachet drive mechanism 20, sachet pack 170, and actuator 14 are
enclosed within the housing 100 as shown in FIGS. 2 and 3. However,
a portion of actuator 14 (e.g., button 14.1) is accessible through
an opening in the housing 100 in order to allow a patient to
operate the actuator 14. In this regard, button 14.1 may be flush
with the outer surface of housing 100, may be recessed with respect
to the outer surface of the housing 100, or may extend beyond the
outer surface of the housing 100.
[0068] A mouthpiece 4 is secured to the housing 100. As a sachet
passes through rollers 7.1, 7.2 under the control of the sachet
drive mechanism 20, the opposing adhered strips 1701, 1702
separate, releasing the medicament. The mouthpiece 4 includes an
opening 4.1 for delivering the medicament. A cover 5 is removably
secured to the mouthpiece 4 and/or housing 100 via, for example, a
friction fit. FIG. 3 shows a perspective view of the device 1000,
with the cover 5 secured to the mouthpiece 4/housing 100.
[0069] FIG. 4(a) shows a perspective view of the sachet drive
mechanism 20, and FIG. 4(b) is an exploded view of FIG. 4(a). FIG.
5, in turn, illustrates the interaction between drive mechanism 20
and rollers 7. Using the coordinates (left, right, upper, lower)
shown in FIGS. 4 and 5 for purposes of illustration, upper and
lower index rollers 12.1 and 11.1 are rotatably secured to an upper
right portion of the chassis of mechanism 20, upper and lower index
rollers 12.2 and 11.2 are rotatably secured to a lower right
portion of chassis 29, a waste roller 8.1 is rotatably secured to
an upper left portion of chassis 29, and a waste roller 8.2 is
rotatably secured to a lower left portion of chassis 29.
[0070] Referring to FIG. 4(a,b) (collectively, "FIG. 4"), sachet
pack 170 is comprises a continuous sheet which includes a plurality
of individual sachets 17. Preferably, the sachet pack 170 includes
at least two, and up to 90, or more individual sachets 17. Each
individual sachet 17, in turn, may contain, for example, between
about 50 mg and 1 g of a powder/particulate medicament or about 0.5
ml to about 5 ml of a liquid or semi-solid medicament. In the
embodiment shown in FIG. 4, each individual sachet 17 is separated
by each adjacent sachet by a fold 1700 so that the sachets 17 can
be folded one on top of the other as illustrated in FIGS. 3 and 4.
In certain embodiments, the folds 1700 may be perforated.
[0071] As noted above, the continuous sheet which comprises the
sachet pack is, in fact, itself comprised of a pair of opposing
strips 1701, 1702 which are adhered to each other and which enclose
a medicament. As shown in FIG. 4, in the preferred embodiment, the
medicament is not distributed throughout the continuous sheet.
Rather, the medicament is isolated in medicament containing regions
171 on each individual sachet. Preferably, only one medicament
containing region 171 is provided on each individual sachet, and
each medicament containing region 171 includes a unit dose of
medicament.
[0072] Referring to FIG. 5, the continuous sachet sheet is fed in a
direction 21 towards rollers 7 in chassis 3. After the continuous
sheet passes through roller 7.2, strip 1702 is wrapped around
roller 7.2 and is fed into a nip formed between rollers 12.2 and
11.2, and strip 1701 is wrapped around roller 7.1 and is fed into a
nip formed between rollers 12.1 and 11.1. After exiting the nip
formed between rollers 12.1, 11.1, strip 1701 is wrapped around
waste roller 8.1, and after exiting the nip formed between rollers
12.2, 11.2, strip 1702 is wrapped around waste roller 8.2.
Preferably, roller 8.1 and 8.2 are biased in a counterclockwise
direction so that strips 1701, 1702 are wound around respective
rollers 8.1, 8.2 as they exit from the aforementioned nips.
[0073] Referring to FIG. 4, rollers 12.1 and 12.2 include driven
gears 120.1 and 120.2 which, in turn, are engaged with outer teeth
9.1 of drive gear 9. Drive gear 9 is rotatably secured to axle 91
for rotation about axis 90. A gear lock 16 pivotably secured to
carriage 29 and is biased (e.g., via a spring) for movement in
clockwise direction. Gear lock 16 is engaged with gear 9 to prevent
gear 9 from rotating in a counter-clockwise direction. In certain
embodiments, waste rollers 8.1, 8.2 may be driven by gear 9, rather
than being biased (e.g., via a spring). In other embodiments, the
waste rollers 8.1, 8.2 may be omitted entirely.
[0074] Referring again to FIG. 3, actuator 14 is shown as a lever
pivotably secured to housing 100 via axes 14.3. When button 14.1 on
actuator is pressed inward towards the device 1000, protrusion 14.2
engages the inner teeth 9.2 of gear 9, causing gear 9 to rotate in
a clockwise direction. One full stroke of the actuator 14 rotates
the gear 9 by a fixed amount. The gear ratios between the gears 9,
11.1, and 11.2 are selected such that one individual sachet 17 is
opened each time the actuator 14 is pressed. Although a simple gear
arrangement is shown, it should be appreciated that additional or
alternative elements, such as gears, linkages, belts, chains,
pulleys, sprockets, and the like may be incorporated into the
design in order to adjust the force that needs to be applied to the
actuator button 14.1 by the patient in order to cause a full stroke
of the actuator.
[0075] In FIGS. 2-5, rollers 11.1. 11.2, 12.1, and 12.2 are
illustrated as extended gears in order to provide a particularly
firm grip on the sachets 17. It should be appreciated, however,
that other roller profiles can alternatively be used. For example,
by applying an appropriate nip pressure, a roller with a smooth
profile can be used.
[0076] Preferably, the device 1000 is a disposable delivery device
which is sold with the sachet pack 170 loaded and ready for use.
When the device 1000 is assembled, strips 1701 and 1702 are wrapped
around rollers 7.1, 7.2, passed through rollers 11.1, 12.1, 11.2,
12.2, with the end of strip 1701 secured to waste roller 8.1 and
the end of strip 1702 secured to waste roller 8.2, and with an
individual sachet 17 positioned relative to the rollers 7.1, 7.2
such that actuation of the actuator 14 will cause the medicament
contained in the individual sachet 17 to be dispensed. Preferably,
the sachet pack 170 is manufactured with a lead section which does
not include any medicament containing regions 171, but rather, is
intended to facilitate loading of the sachet pack into the
device.
[0077] A second embodiment of the present invention (device 1000')
is illustrated in FIGS. 6-10, with similar components bearing
similar reference numerals to FIGS. 1-5.
[0078] Referring to FIGS. 10(a)-10(d), in use, a patient moves
cover 5' first in a direction 21 (FIGS. 6 and 10(b)), and then in a
direction 22 (FIGS. 6 and 10(c)) to expose the mouthpiece 4.
Preferably, the cover 5' can be secured on the rear of the housing
100' as shown in FIG. 10(d). As the cover 5' moves in the direction
22 (clockwise from the perspective in FIG. 6 and counterclockwise
from the perspective in FIG. 10(b)), lever 5.1 turns cover hinge
9.21 clockwise (from the perspective of FIG. 6), thereby tensioning
torsion spring 9.22, which, in turn, applies a clockwise force to
gear 9.23.
[0079] As shown in FIGS. 6 and 9, actuator 14' includes an index
button 14.1' which extends through opening 102 in housing 100'.
Actuator 14' further includes an arm 14.2 having a protrusion 14.3.
Arm 14.2 extends between gear 9.1 and housing part 2'. Index gear
9.1 includes four stops 9.11 through 9.14. Actuator 14' is biased
so that, when no force is applied to button 14.1', the actuator 14'
is in the position shown in FIG. 9, with the protrusion 14.3
engaged against one of the four stops 9.11 though 9.14. When button
14.1' is pressed, protrusion 14.3 moves in a direction 23, becomes
disengaged from the stop (in this case stop 9.12), and the index
gear 9.1 moves counterclockwise 90 degrees under the force of the
cover hinge gear 9.2, thereby driving gears 120.1, 120.2, and 80
and releasing the medicament from the next sachet 17 in the sachet
pack 170.
[0080] Rotation of the gear 9.1 can be controlled to release
medicament from only one sachet 17 in a number of ways. For
example, the tension in the torsion spring 9.22 and the size of the
gear 9.23 relative to gear 9.1 can be selected so that the
clockwise force applied to gear 9.23 is sufficient only to rotate
gear 9.1 90 degrees. Alternatively, actuator 14' could be
configured to allow protrusion 14.3 to move in the direction 23
only momentarily, regardless of whether or not the user continued
to press button 14.1'. Preferably, both of these techniques are
used.
[0081] It should be noted while the use of four stops (9.11 to
9.14) to generate a 90 degree rotation of gear 9.1 is advantageous,
it is by no means required. For example, two stops could be used to
generate a 180 degree rotation of gear 9.1, six stops could be used
to generate a 60 degree rotation, eight stops could be used to
generate a 45 degree rotation, and so on. The desired rotation is a
function of the size of the sachet 17 and the relative sizes of the
various gears 9.1, 120.1, 120.2, and 80.
[0082] If the index button 14.1' is not pressed, the tension in the
torsion spring 9.22 will be released when the cover 5' is returned
to its original position over the mouthpiece as shown in FIG.
10(a).
[0083] An alternative embodiment which utilizes a cover hinge gear
9.2 and index gear 9.1 is shown in FIGS. 11(a-f). In accordance
with this embodiment, the torsion spring 9.22 is tensioned not by
the removal of cover 5", but by moving actuator 500 laterally from
the position shown in FIG. 11(b) to the position shown in FIG.
11(c). Moreover, in accordance with the embodiment of FIG. 11(a-c),
this lateral movement of actuator 500 also causes mouthpiece 4' to
move from its retracted position (as shown in FIGS. 11(a,b)) to its
extended position (as shown in FIG. 11(c)).
[0084] A simple mechanism for accomplishing this functionality is
shown in FIGS. 11(d ,e, f), with similar components bearing similar
reference numerals to FIG. 9. It should be appreciated, however,
than alternative mechanisms may also be used. Referring to FIG.
11(e, f), the chassis 3 (including, e.g, gears 9.1, 12.1, 11.1,
12.2., 11.2 et al), gear 9.2, and mouthpiece 4' together comprise a
movable component 400 that is mounted within housing 100 for
lateral movement in directions 209 and 210. Actuator 500 is coupled
to rack 501, which, in turn, is engaged with gear 502. Gear 502, in
turn, is connected to torsion spring 6 so that a counterclockwise
movement of gear 502 tensions torsion spring 6, and a clockwise
movement of gear 502 releases the tension in torsion spring 6.
Therefore, when actuator 500 is moved in direction 210, torsion
spring 6 is tensioned, such that actuation of button 14 will cause
a next sachet 17 is the sachet pack 170 to be opened as described
above with regard to FIG. 9.
[0085] Actuator 500 is also engaged with slot 504 on movable
component 400. When actuator 500 is in its rearward position (as
shown in FIGS. 11(a, b)), its shaft 503 rests against rear end
504.2 of slot 504. As actuator moves in direction 210, torsion
spring 6 is tensioned by rack 501 and gear 502 (as described above)
until shaft 504 contacts front end 504.1 of slot 504. After shaft
504 contacts front end 504.1, movable component 400 moves in the
direction 210 under the direction of actuator 500 and shaft 503,
until mouthpiece 4 reaches the extended position shown in FIG.
11(c). At this point, the device is ready for use by the
patient.
[0086] By moving actuator 500 in the direction 209, any tension in
torsion spring 6 is released, and after contacting rear end 504.2,
movable component 400 moves in the direction 209 until the
mouthpiece 4 reaches the retracted position shown in FIG. 11(a,b
).
[0087] While the mechanisms discussed above are preferred, it
should be appreciated that alternative devices for delivering a
medicament from a sachet can alternatively be used. For example,
referring to FIGS. 12(a-e), an alternative design is shown, with
similar components bearing similar reference numerals to FIGS. 1-9.
In this embodiment, an actuator 14" is biased in the position shown
in FIG. 12(e), and is movable in a direction 24 to dispense the
medicament from a next sachet 17 in a sachet pack. Actuator 14" is
coupled to a carriage 3". Carriage 3" includes, as draw rollers,
waste rollers 8.1" and 8.2". Waste rollers 8.1" and 8.2" are biased
for rotation in a clockwise direction from the perspective of FIG.
12(a). The continuous sachet sheet is fed in a direction 21. Strip
1702 is wrapped around roller 7.2 and is then wrapped around waste
roller 8.2 whereas strip 1701 is wrapped around roller 7.1 and is
then wrapped around waste roller 8.1.
[0088] When actuator 14" is in the position shown in FIG. 12(e),
carriage 3" is in the position shown in FIGS. 12(a). As actuator
14' moves in the direction 24, carriage 3" and waste rollers 8.1"
and 8.2" also move in the direction 24, pulling strips 1701 and
1702 around rollers 7.1 and 7.2, respectively, and releasing
medicament from the next sachet 17 in the sachet pack as shown in
FIG. 12(c). When the actuator 14" is released, it will move in the
direction 25, until it returns to its initial position as shown in
FIG. 12(d). Since the waste rollers 8.1" and 8.2" are biased for
clockwise rotation, they will collect the "spent" portion of strips
1201 and 1202 as they move in the direction 25.
[0089] A wide variety of mouthpiece designs can be used in
accordance with the various embodiments of the present invention.
Preferably, however, the mouth piece is of the "scraping" type
design shown in FIGS. 1-11, and 13. Referring to FIG. 14, the
mouthpiece 4 covers the rollers 7, and the opening 4.1 in the
mouthpiece has a length 4.1 1 and a width 4.12. The length 4.1 1 is
at least equal to, and preferably greater than, the width 171.1
(FIG. 15a) of the medicament containing region 171 of the sachet.
Moreover, the "peel point" or "separation point".pi.of the sachet
(i.e., the point at which the sheet 1701 separates from sheet 1702)
is approximately at the midpoint of the width 4.12 of the opening
4.1, as illustrated in FIG. 13. Lengthwise edges 4.21 and 4.22 are
in adjacent to strips 1701 and 1702 respectively, to prevent powder
that remains on the strips after the sachet has been opened from
entering the interior of the device. In this regard, the edges 4.21
and 4.22 are sufficiently close to (and, in some embodiments, in
contact with) the strips 1701, 1702 respectively to remove the
medicament from the strips as they pass.
[0090] When a dose of medicament is administered, a sachet 17 will
be advanced and opened via rollers 7, and the majority of the
medicament contained in the sachet 17 will be deposited on the
tongue of the patient. Some powder, however, may be retained on the
edges of the slot 4.1, as the combination of saliva and
condensation may cause some adherence of the medicament. This
medicament, however, can be removed by the patient using the tongue
or lips. Any medicament remaining on the mouthpiece can be clearly
seen by the patient, and the mouthpiece can then be reinserted into
the mouth of the patient for removal of the medicament.
[0091] As noted above, sachets are widely used in the art as
packaging for pharmaceutical products. Two exemplary prior art
sachet designs are illustrated in FIG. 15(a,b).
[0092] Referring to FIG. 15(a, b), each strip 1701, 1702 in one
prior art sachet design is comprised of an exterior paper layer
8000 adhered to an aluminum foil layer 8002 via polythene adhesive
8001. Below the aluminum foil layer 8002 is an corner layer 8003
and a wax laquer layer 8004. The wax laquer layer 8004 of strip
1701 faces the wax laquer layer 8004 of strip 1702, and the paper
layers 8000 of strips 1701 and 1702 form the exterior surface of
the sachet 17. The medicament is isolated in a medicament
containing region 171 in each sachet 17, as described above. The
sachet 17 is heat sealed by applying heat and pressure to the
non-medicament containing regions 172 of the sachet, causing the
wax laquer 8004 (which is a heat sensitive adhesive) of strip 1701
to adhere to the wax laquer 8004 of strip 1702.
[0093] Referring to FIG. 15(c), each strip 1701, 1702 in another
prior art sachet design is comprised of an exterior polyester layer
8000' adhered to an aluminum foil layer 8002 via an adhesive 8001'.
Below the aluminum foil layer 8002 is an adhesive layer 8003' and a
polythene layer 8004'. (Polythene layer 8004' can be polypropylene,
polyethyline, etc.) The polythene layer 8004' of strip 1701 faces
the polythene layer 8004' of strip 1701, and the polyester layers
8000' of strips 1701 and 1702 form the exterior surface of the
sachet 17. The medicament is isolated in a medicament containing
region 171 in each sachet 17, as described above. The sachet 17 is
heat sealed by applying heat to the non-medicament containing
regions 172 of the sachet, causing the polythene 8004' (which is a
heat sensitive adhesive) of strip 1701 to adhere to the polythene
8004' of strip 1702.
[0094] It should be appreciated that the exemplary sachet designs
of FIGS. 15(b) and 15(c) are merely two examples of the many
existing sachet designs known in the art, and that any sachet which
is capable of being peeled apart in the manner set forth above is
suitable for use in conjunction with the present invention.
Particularly preferred materials include peelable flexible strips
which include aluminum and polypropylene.
[0095] Moreover, although the embodiments described above utilize a
sachet pack including sachets that are folded over one another
prior to use, alternative arrangements may also be employed. For
example, the sachet pack could be stored in the device as a roll.
In such an embodiment, the individual sachets need not be separated
from each other via folds.
[0096] Unlike many devices, the delivery devices described herein
can be used without regard to the angle of administration. In other
words, the dose is effectively delivered out of the device
regardless of whether the patient head is bent forward, bent back,
or is upright. In many devices, the medicament must be `metered`
accurately from a hopper to the mouthpiece. For this reason, such
devices are often sensitive to the angle that the device is held.
In other words, with such devices, it may not be possible to
consistently deliver an accurate dose, unless the device is held,
for example, in an upright position. With the embodiments of the
present invention described above, the medicament is released from
a sachet at a location sufficiently close to the mouthpiece such
that the medicament is delivered out of the mouthpiece via the
force of gravity. Moreover, in the preferred embodiments of the
present invention, the medicament is released from the sachet while
it is directly above the opening in the mouthpiece, thereby
ensuring that the medicament will be delivered to the mouth of the
patient via the force of gravity (assuming, of course, that the
device is positioned so that the opening in the mouthpiece is at
angle to horizontal of less than 90 degrees).
[0097] FIGS. 16(a) to FIG. 16(c) show devices 1000'" according to
alternative embodiments of the present invention, wherein the
actuator 14 is a lever 2010. In each figure, lever 2010 is
depressed in the direction of arrow 2002 to drive a sachet advance
mechanism 25 (not shown). FIG. 16(a) shows the lever 2010 with its
free end at the rear of the device 1000'" where the fingers 2006 of
a human hand 2004 depress the lever 2010. FIG. 16(b) shows the free
end of the lever 2010 at the front of the device 1000'", and FIG.
16(c) shows the lever 2010 with the free end at the rear of the
device 1000'" with a dispensing portion 2004 angled downward for an
improved ergonomic design. In each case, the device is acutated by
the user squeezing the lever 2010 towards the housing of the device
as shown.
[0098] Using a lever to actuate the sachet advance mechanism 25 of
the device is advantageous to geriatric patients with weakened hand
muscles from the onset of arthritis and other conditions associated
with old age that weaken motor function. The lever provides added
leverage to reduce the amount of force needed to drive the sachet
advance mechanism.
[0099] FIG. 17 shows an illustrative sachet advance mechanism 25
for the embodiments of FIGS. 16(a)-16(c), with similar components
bearing similar reference numerals as FIGS. 1-15. Referring to FIG.
17, the the continuous sachet sheet is fed towards rollers 7.1,
7.2. After the continuous sheet passes through roller 7.2, strip
1702 is wrapped around roller 7.2 and is fed into a nip formed
between rollers 12.2 and 11.2, and strip 1701 is wrapped around
roller 7.1 and is fed into a nip formed between rollers 12.1 and
11.1. After exiting the nip formed between rollers 12.1, 11.1,
strip 1701 is wrapped around waste roller 8.1, and after exiting
the nip formed between rollers 12.2, 11.2, strip 1702 is wrapped
around waste roller 8.2. Gear 9 is engaged with gears 120.1, 120.2,
80.1, and 80.2 which drive rollers 11.1, 11.2, 8.1 and 8.2
respectively.
[0100] FIG. 18 shows the device 1000'" of FIG. 16(b) with the free
end of the lever 2010 at the front of the device 1000'". The other
end of the lever 2010 is coupled to a clutch 220 that turns in one
direction to drive the gear 9 via belt 200 and pulleys 2012. When
pressure is applied to the lever 2010, the clutch 220 is turned,
driving the belt 200 to turn the main gear 9. Although a belt and
pulley arrangement is shown, it should be understood that the
pulley and belt could be replaced with a sprocket and chain,
respectively. Alternatively, the pulley and belt could be repaced
with a linkage arrangement or a gear arrangement. For ease of
illustration, only the gear 9 of the sachet advance mechanism of
FIG. 17 is shown in FIG. 18. Preferably, the clutch 220 and pulleys
2012 are sized so that each full depression of the lever 2010 turns
the gear 9 by an amount sufficient to cause a unit dose of
medicament to be delivered through mouthpiece 4. Preferably, the
mouthpiece 4 is of the type discussed above with regard to FIGS. 6,
10, 11, 13, and 14.
[0101] FIG. 19 shows the drug dispenser of FIGS. 16(a) and 16(c)
where the free end of the lever 2010 is at the rear of the device
1000'". The lever 2010 is connected directly to the main gear 9 via
a one-way clutch 220 that causes the gear 9 to turn in one
direction upon depressing the lever 2010, thereby turning the gears
of the sachet drive mechanism as previously discussed.
[0102] FIGS. 20(a-c) show a particularly preferred acutation
mechanism for the embodiment of FIG. 17. In this embodiment, the
main gear 9 includes a plurality of receptacles 9.9 (in this case,
three) which are configured to receive end 204 of a drive arm 201.
Drive arm 201 includes a first member 201.1 and a second member
201.2 interconnected via a free linkage 203. The free end of second
member 201.2 is secured to the housing via a fixed point linkage
202. The free end 204 of the first member 201.1 of the drive arm
201 is configured to engage the receptables 9.9 as described
above.
[0103] In operation, a user lifts the lever 2010. Preferably, an
overcentre spring (not shown) normally holds the lever 2010 down,
so that a small amount of force is required to lift the lever, and
thereafter, the lever 2010 will rise to the upward position shown
in FIGS. 16(a-c). The user can push the lever 2010 up and down
freely. However, when the lever is pushed completely down it will
be held down by the overcentre spring. The lever 2010 is coupled to
free linkage 203 so that when the lever 2010 rises to the position
shown in FIGS. 16(a-c), the drive arm 201 is in the position shown
in FIGS. 20(a) and 20(c), and when the lever is pushed completely
down, the drive arm is in the position shown in FIG. 20(b). 101041
A safety button 2030 (shown only in FIG. 16(a) for ease of
illustration) may also provided to prevent accidental actuation of
the device of FIGS. 16(a-c). Referring to FIG. 20(a), when the
lever 2010 is in its upward position (as shown FIGS. 16a-c), and
the button 2030 is pressed, end 204 of drive arm 201 becomes
engaged with adjacent receptacle 9.9. Thereafter, if the linkage
203 of the drive arm 201 moves in the direction 26 under the
impetus of lever 2010, the drive arm 201 will follow path 29 to the
position shown in FIG. 20(b), thereby rotating gear 9 by
approximately 120 degrees, and opening one of the sachets 17. When
the drive arm 201 reaches the position shown in FIG. 20(b), end 204
becomes disengaged from the receptacle 9.9, so that when the
linkage 203 of the drive arm 201 subsequently moves upward in the
direction 27 under the impetus of lever 2010, the drive arm 201
follows the path 28 shown in dotted lines as shown in FIG. 20(c),
without causing further rotation of the drive gear 9. If the button
2030 were to be subsequently pressed, end 204 of drive arm 201
would become engaged with the now adjacent receptable 9.9.
[0104] In this regard, the path 28 could be defined, for example,
by a slot on an interior surface of the housing which engages an
outwardly facing protrusion on the end 204 of drive arm 201. In
such an embodiment, the end 204 could also include an inwardly
facing protrusion which is engagable with the receptable 9.9. The
safety button 2030, when pressed, could move the end 204 towards
the gear 9.9, thereby bringing the end 204 into engagement with the
receptable, and thereby preventing the end 204 from engaging the
slot as it moves in the direction 29. As one of ordinary skill in
the art will appreciate, however, alternative techniques could also
be used to implement the drive arm movement illustrated in FIGS.
20(a-c).
[0105] It should be noted that although the safety button 2030 is
illustrated in connection with the embodiment of FIG. 16(a-c), this
feature can also be incorporated into the other embodiments of the
present invention which are described herein. In this regard, a
safety button 2030 could be provided in any of the embodiments
described above, to prevent accidental actuation of the device
(e.g., by dropping the device), or actuation by a child.
[0106] For example, the saftey button 2030 could be interconnected
between actuator 14 of FIG. 1 and gear 9 to prevent actuation of
actuator 14 from causing the device to release medicament, absent
prior actuation of the safety button. Similarly, in the device of
FIG. 6, the saftey button 2030 could be interconnected between
actuator 14' and gear 9.1, between gear 9.2 and gear 9.3, between
lever 5.1 and gear 9.2, or between cover hinge 9.21 and torsion
spring 9.22, to prevent actuation of acuator 14 from causing the
device to release medicament, absent prior actuation of the safety
button. In the embodiment of FIG. 11, for example, the saftey
button 2030 could be interconnected between actuator 14' and gear
9.1, between gear 9.2 and gear 9.3, between actuator 500 and gear
9.2, or between cover hinge 9.21 and torsion spring 9.22, to
prevent actuation of acuator 14' from causing the device to release
medicament, absent prior actuation of the safety button. In the
embodiment of FIG. 12, for example, the safety button 2030 could be
interconnected between actuator 14" and rollers 8.1" and 8.2". In
the embodiment of FIG. 18, the safety button 2030 could, for
example, be interconnected between the lever 2010 and the clutch
220 or gear 9, and in the embodiment of FIG. 19, the safety button
2030 could, for example, be interconnected between the lever 2010
and the clutch 220. Other arrangements will also be apparent to
those skilled in the art.
[0107] In certain embodiments of the present invention, a dose
counter 36 (for ease illustration, shown only in FIG. 10) may be
disposed within the housing.
[0108] The dose counter 36 may be coupled to actuator 14, 14', 14"
of FIGS. 1-20, to the sachet advance mechanism 25 of FIG. 1, to the
sachet drive mechanism 20 of FIGS. 3-5, to the chassis 3' and
associated components of FIGS. 6-11, or to the chassis 3" and
associated components of FIGS. 12-13, to count the number of unit
doses that have been dispensed by the drug delivery device over
time. Such a dose counter 36 may be of a mechanical or electrical
design, as is known in the art.
[0109] In a particularly preferred embodiment, however, the dose
counter 36 may simply comprise a transparent window in the housing
which is disposed in the path of one of the strips 1701, 1702,
downstream of the separation point of the first and second strips
(e.g., downstream of the rollers 7). In such an embodiment, the
dose count could simply be imprinted on the interior surface of one
of the strips 1701, 1702. As an example, the number 2 could be
imprinted on the interior surface of strip 1701 of a first sachet
17 in the sachet pack 170, with subsequent sachets sequentially
numbered, so that when the second sachet 17 in the sachet pack 170
is the next dose to be delivered, the number 2 will be visible
through the dose counter 36. The number 1, in turn, could be
imprinted on the interior surface 1701 of lead section of the
sachet pack 170 so that, prior to its first use, the number 1 is
visible through the dose counter 36.
[0110] As noted above, the drug delivery devices in accordance with
the various embodiments of the present invention are designed to
store multiple doses of a medicament, and to deliver a unit dose of
the medicament into the oral cavity of a patient for
gastrointestinal (e.g., gastric, intestinal, and/or colonic)
absorption or action; esophageal absorption or action; and/or
absorption or action in the oral cavity (e.g., sublingual, lingual,
or buccal). The medicament may be in the form of a solid,
semi-solid, or liquid.
[0111] Exemplary medicaments which can be delivered into the oral
cavity of a patient in accordance with the various embodiments of
the present invention are described in WO 01/64182, entitled
"Improvements In or Relating to the Delivery of Oral Drugs",
published Sep. 9, 2001, and U.S. Provisional Application Ser. No.
60/317,522, filed Sep. 5, 2001, entitled "Functional Powders for
Oral Delivery", the entire disclosures of each of which are hereby
incorporated by reference.
[0112] Preferably, when the medicament is a solid, the medicament
comprises drug particles greater than 10 microns 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. 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.
[0113] 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.
[0114] 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.
[0115] 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.
[0116] 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.
[0117] 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.
[0118] 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.
[0119] 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.
[0120] 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.
[0121] 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.
[0122] 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.
[0123] 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.
[0124] 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 gastro-intestinal tract. Coating the drug with excipient can
also be done in order to mask the bitter taste of certain drugs.
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. The excipient can also be used in a mixture with
the drug 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.
[0125] 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.
[0126] 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.
[0127] 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.
[0128] 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.
[0129] Representative biodegradable polymers include, polylactides,
polyglycolides, poly(ethylene terephthalate), polyhydroxy-butyrate,
polyhydroxy-valerate and polyurethane.
[0130] Representative acrylates and methacrylates are polyacrylic
and methacrylic polymers such as those sold under the Trademarks
Eudragit. Amberlite and Carbopol.
[0131] 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-diarrheal 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.
[0132] 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, flurbiprofen, 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, phentermine 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.
[0133] 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, acetaminophen, 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.
[0134] The devices in accordance with embodiments of the present
invention are particularly useful for delivering fast melt
formulations, such as those described in U.S. patent application
Ser. No. 10/___,___, filed Mar. 7, 2003, entitled "FAST MELT
MULTIPARTICULATE FORMUALTIONS FOR ORAL DELIVERY," (Attorney Docked
No. 478.1023US) the entire disclosure of which is hereby
incorporated by reference. A fast melt formulation, as defined
herein, is a formulation which dissolves or disperses in a
patient's mouth within 1 minute after administration without the
coadministration of a fluid. Preferably, the formulation dissolves
or disperses in a patient's mouth within 30 seconds, or 15 seconds
after administration without the coadministration of a fluid. In
this regard, the term "disperses" means that the administered
formulation becomes hydrated in the mouth and the particles of the
formulation become suspended is saliva, such that the
multiparticulate formulation is wetted and easily swallowed.
[0135] The effect of humidity can have a negative impact of the
flowability of particles (e.g., due to cohesiveness). This can be a
particular problem with respect to fast melt formulations which are
designed to absorb water. Accordingly, the mulitple dose sachet
delivery devices in accordance with embodiments of the present
invention are particularly useful for the delivery of fast melt
formulations, becauase the unit doses are premetered prior to
actuation of the device. This reduces the contamination of the unit
doses as compared to having the formulation in a multiple dose
reservoir. Moreover, providing the premetered unit doses in sachets
(which are sealed) minimizes the effect of humidity and moisture on
the formulation.
[0136] In certain embodiments, the fast melt formulation is a drug
formulation for gastrointestinal deposition comprising a
non-compressed free flowing plurality of particles comprising an
active agent and a water-soluble excipient, the particles having a
mean diameter of greater than 10 .mu.m to about 1 mm, the particles
comprising at least about 50% drug and the formulation dissolving
or dispersing in a patient's mouth within 1 minute after
administration without the coadministration of a fluid.
[0137] In other embodiments, the devices described herein are used
to treat a patient with an active agent for gastrointestinal
deposition by administering a fast melt formulation comprising a
non-compressed free flowing plurality of particles comprising an
active agent and a water-soluble excipient, the particles having a
mean diameter of greater than 10 .mu.m to about 1 mm, and the
formulation dissolving or dispersing in a patient's mouth within 1
minute after administration without the coadministration of a
fluid.
[0138] The water-soluble excipient of the fast melt formulation can
be a sugar alcohol including, but not limited to sorbitol,
mannitol, maltitol, reduced starch saccharide, xylitol, reduced
paratinose, erythritol, and combination thereof. Other suitable
water-soluble excipients include gelatin, partially hydrolyzed
gelatin, hydrolyzed dextran, dextrin, alginate and mixtures
thereof.
[0139] The fast melt formulations preferably include a salivary
stimulant including, but not limited to citric acid, tartaric acid,
malic acid, fumaric acid, adipic acid, succinic acid, acid
anhydrides thereof, acid salts thereof and combinations thereof.
The salivary stimulant can also be an effervescent agent, such as
wherein the effervescence is the result of a reaction of a soluble
acid source and an alkali metal carbonate or carbonate source. The
carbonate sources can be selected from the group consisting of dry
solid carbonate and bicarbonate salts such as sodium bicarbonate,
sodium carbonate, potassium bicarbonate and potassium carbonate,
magnesium carbonate and sodium sesquicarbonate, sodium glycine
carbonate, L-lysine carbonate, arginine carbonate and amorphous
calcium carbonate.
[0140] The fast melt formulations preferably comprise a sweetener
such as a water-soluble artificial sweetener, including but not
limited to soluble saccharin salts, such as sodium or calcium
saccharin salts, cyclamate salts, acesulfam-K, the free acid form
of saccharin and mixtures thereof. The sweetener can also comprise
a dipeptide based sweetener such as L-aspartyl L-phenylalanine
methyl ester. The fast melt formulations can also comprise further
pharmaceutical excipients such as polyvinyl alcohol,
polyvinylpyrrolidine, acacia or a combination thereof.
[0141] The dissolution or dispersion of the fast melt formulation
can be improved with the use of a surfactant, such as sodium lauryl
sulphate (Texapon K 12), various polysorbates known under the trade
name Tween, ethers of polyhydroxy ethylene fatty acids known under
the trade name Brij, esters of polyhydroxy ethylene fatty acids
known under the trade name Myrj, sodium desoxycholate, glycerol
polyethylene glycol ricinoleate (Cremophor EL),
polyoxyethylene-polyoxypropylene polymers known under the trade
name Pluronic, and various polyalkoxy alkylene sterol ethers.
[0142] The fast melt formulations can also comprise starches, e.g.,
corn starch, or modified starches, e.g., sodium starch glycolate or
mixtures thereof, in any proportions. Starches can provide
increased salivation due to the porous nature of the starch.
Increased salivation favors rapid dissolution or dispersion of the
formulation upon oral administration.
[0143] When a starch is present in the formulation, the formulation
can further comprise a starch degrading enzyme will have a
synergistic effect with the starch with respect to dissolution or
dispersion. The enzymes upon being contacted with an aqueous
solution will initiate conversion of the starch to mono and
polysaccharides which quickly dissolve in the aqueous environment
and further contribute to improving the taste of the
multiparticulate formulation and increasing salivation. The enzymes
can be chosen for their degradation effect on the starch and also
for their stability over time, i.e. during the shelf-life of the
fast melt multiparticulate formulation. Advantageously, the enzyme
will be chosen from the group of starch degrading enzymes
comprising alpha-amylase, beta-amylase, amyloglucosidase,
debranching enzymes and glucose-fructose isomerase. In certain
embodiments, the enzymes can be an equal mixture of
amyloglucosidase and a-amylase.
[0144] In certain embodiments, the fast melt formulations for
gastrointestinal deposition are prepared by a process comprising
melt granulating the water soluble excipient and the active agent
to form a homogenous mixture. In an alternate embodiment, the
process comprises melt coating the water-soluble excipient onto the
active agent which can be optionally pregranulated with a
pharmaceutically acceptable excipient. In such processes, the
water-soluble excipient is a water-soluble alcohol such as
xylitol.
[0145] The melt granulation and melt coating processes are
particularly preferred as it is not necessary to use an aqueous
fluid as a processing aid. This results in a process which can be
used for a wide variety of active agents, including those agents
which would be susceptible to degradation upon contact with water.
Accordingly, such processes provide advantages over many prior art
processes for making fast melt systems which rely on water as a
processing aid. These prior art processes would not be suitable for
water liable drugs as such processes would result in degradation of
the drug during the manufacturing process and during storage due to
residual moisture in the final product.
[0146] Any of the active agents described above can also be used in
accordance with fast melt formulations. However, particularly
preferred agents for fast melt formulations include antibiotics
such as clarithromycin, amoxicillin erythromycin, ampicillin,
penicillin, cephalosporins, e.g., cephalexin, pharmaceutically
acceptable salts thereof and derivatives thereof. Other preferred
agents are acetaminophen and NSAIDS such as ibuprofen,
indomethacin, aspirin, diclofenac and pharmaceutically acceptable
salts thereof.
[0147] The size of the unit dose of the fast melt formulations 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
[0148] In the preceding specification, the invention has been
described with reference to specific exemplary embodiments and
examples thereof. It will, however, be evident that various
modifications and changes may be made thereto without departing
from the broader spirit and scope of the invention as set forth in
the claims that follow. The specification and drawings are
accordingly to be regarded in an illustrative manner rather than a
restrictive sense.
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