U.S. patent application number 10/091062 was filed with the patent office on 2003-04-10 for compositions and methods for mucosal delivery.
This patent application is currently assigned to Lavipharm Laboratories Inc.. Invention is credited to Buranachokpaisan, Thitiwan, Chen, Li-Lan H., Osborne, James, Pfister, William R., Renn, Donald W., Tan, Hock Seng, Tao, Li.
Application Number | 20030068378 10/091062 |
Document ID | / |
Family ID | 26814665 |
Filed Date | 2003-04-10 |
United States Patent
Application |
20030068378 |
Kind Code |
A1 |
Chen, Li-Lan H. ; et
al. |
April 10, 2003 |
Compositions and methods for mucosal delivery
Abstract
Mucosal surface-coat-forming film dosage units containing a
water-soluble hydrocolloid, an effective dose of a sexual
dysfunction active agent and a mucosal adhesion enhancer, wherein
the mucosal adhesion enhancer is a starch graft copolymer.
Inventors: |
Chen, Li-Lan H.; (Edison,
NJ) ; Pfister, William R.; (Robbinsville, NJ)
; Renn, Donald W.; (Glen Cove, ME) ;
Buranachokpaisan, Thitiwan; (Morristown, NJ) ;
Osborne, James; (Princeton Junction, NJ) ; Tan, Hock
Seng; (East Brunswick, NJ) ; Tao, Li; (Edison,
NJ) |
Correspondence
Address: |
ALLEN BLOOM
C/O DECHERT
PRINCETON PIKE CORPORATION CENTER
P.O. BOX 5218
PRINCETON
NJ
08543-5218
US
|
Assignee: |
Lavipharm Laboratories Inc.
East Windsor
NJ
|
Family ID: |
26814665 |
Appl. No.: |
10/091062 |
Filed: |
March 5, 2002 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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10091062 |
Mar 5, 2002 |
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09619899 |
Jul 19, 2000 |
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09619899 |
Jul 19, 2000 |
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09434878 |
Nov 5, 1999 |
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60116823 |
Jan 21, 1999 |
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Current U.S.
Class: |
424/486 |
Current CPC
Class: |
A61P 15/10 20180101;
A61K 9/0007 20130101; A61K 9/0031 20130101; A61K 9/0034 20130101;
A61K 9/0056 20130101; A61P 31/12 20180101; A61K 9/7007 20130101;
A61P 15/18 20180101; A61P 1/02 20180101; A61P 31/04 20180101; A61P
31/10 20180101; A61K 9/0043 20130101; A61K 9/006 20130101; A61K
31/505 20130101; A61P 43/00 20180101; A61K 31/495 20130101; A61K
9/7015 20130101; A61K 9/145 20130101; A61K 9/1623 20130101 |
Class at
Publication: |
424/486 |
International
Class: |
A61K 009/14 |
Claims
What is claimed:
1. A dosage unit comprising a mucosal surface-coat-forming film,
wherein the mucosal surface-coat-forming film comprises a
water-soluble hydrocolloid, an effective dose of a sexual
dysfunction active agent and a mucosal adhesion enhancer, wherein
the mucosal adhesion enhancer is a starch graft copolymer.
2. The dosage unit of claim 1, wherein the mucosal adhesion
enhancer is a copolymer of starch and acrylic acid.
3. The dosage unit of claim 1, wherein the film exhibits a dry tack
value of less than 3.5 g.
4. The dosage unit of claim 1, wherein the film exhibits a dry tack
value of less than 2.0 g.
5. The dosage unit of claim 1, wherein the film exhibits a wet tack
value of greater than 35 g.
6. The dosage unit of claim 1, wherein the water-soluble
hydrocolloid exhibits a gelation temperature that is greater than
70.degree. C. for a 2% polymer solution.
7. The dosage unit of claim 1, wherein the water-soluble
hydrocolloid exhibits a hydration rate in 24 hours of 5-20% at 75%
humidity at room temperature.
8. The dosage unit of claim 1, wherein the water-soluble
hydrocolloid is a polymer selected from the group consisting of a
natural, semi-natural and synthetic biopolymer.
9. The dosage unit of claim 8, wherein the water-soluble
hydrocolloid is selected from the group consisting of a
polysaccharade and a polypeptide.
10. The dosage unit of claim 8, wherein the water-soluble
hydrocolloid comprises a hydroxypropylmethylcellulose polymer.
11. The dosage unit of claim 10, wherein the
hydroxypropylmethylcellulose polymer has a molecular weight of less
than 200,000 Daltons.
12. The dosage unit of claim 1, wherein the film further comprises
at least one of an emulsifier, a plasticizer, a taste modifying
agent, a water soluble inert filler, a preservative, a coloring
agent, a stabilizer and a buffering agent.
13. The dosage unit of claim 1, wherein the film further comprises
an emulsifier present at a concentration in the range of 0.1 to 10
wt % of the dosage unit.
14. The dosage unit of claim 1, wherein the film further comprises
a taste modifying agent comprising at least one of a sweetening
agent, a flavoring agent and a taste masking agent.
15. The dosage unit of claim 1, wherein the film further comprises
a water soluble inert filler present at a concentration in the
range of 0.5 to 50 wt % of the dosage unit.
16. The dosage unit of claim 1, wherein the film further comprises
a preservative present at a concentration in the range of 0.01 to
10 wt % of the dosage unit.
17. The dosage unit of claim 1, wherein the active agent is present
at a concentration in the range of 0.01 to 75 wt % of the dosage
unit.
19. The dosage unit of claim 1, wherein the sexual dysfunction
active agent is sildenafil citrate.
20. The dosage unit of claim 1, wherein the film has a dry film
thickness in the range of 1 to 20 mil.
21. The dosage unit of claim 20, wherein the film has a dry film
thickness of less than 10 mils.
22. The dosage unit of claim 1, wherein the film exhibits a tensile
strength greater than 1500 psi.
23. The dosage unit of claim 1, wherein the film exhibits a %
elongation of less than 20%.
24. The dosage unit of claim 1, wherein the film exhibits a modulus
in the range of 35,000 to 300,000 psi.
24. The dosage unit of claim 1, wherein the film exhibits a
dissolution time in the range of 10 to 600 seconds upon application
to an oral mucosal surface.
25. The dosage unit of claim 1, wherein the film exhibits a
dissolution time in the range of 1 to 300 seconds upon application
to an oral mucosal surface.
26. The dosage unit of claim 24, wherein the film exhibits a
tensile strength greater than 1,500 psi, a % elongation of less
than 20% and a disintegration time in the range from 1 to 300
seconds upon application to an oral mucosal surface.
27. The dosage unit of claim 1, wherein the active agent is
encapsulated within a polymer, wherein the polymer is chemically or
physically distinct from the hydrocolloid.
28. The dosage unit of claim 1, wherein the dosage unit comprises
at least two active agents.
29. The dosage unit of claim 1, wherein the mucosal adhesion
enhancer is present at a concentration of up to 50%.
30. A dosage unit comprising a mucosal surface-coat-forming film,
wherein the mucosal surface-coat-forming film comprises a
water-soluble hydrocolloid, an effective dose of a sexual
dysfunction active agent and a mucosal adhesion enhancer; wherein
the active agent is encapsulated within a polymer which is
chemically or physically distinct from the hydrocolloid; wherein
the mucosal adhesion enhancer is a starch graft copolymer; wherein
the film exhibits a dry tack value of less than 3.5 g, a wet tack
of greater than 35 g, a gelation temperature that is greater than
70.degree. C. for a 2% polymer solution, a dry film thickness of
not more than 20 mil, a water content of 0.5 to 10%, a tensile
strength greater than 1500 psi, a modulus in the range of 35,000 to
300,000 psi, a % elongation of less than 20%, a tear propagation
resistance of 0.001 to 1 N, and a dissolution time on not more than
600 seconds upon application to an oral mucosal surface.
31. The dosage unit of claim 30, wherein the mucosal adhesion
enhancer is a copolymer of starch and acrylic acid.
32. The dosage unit of claim 30, wherein the film exhibits a dry
tack value of less than 2.0 g.
33. The dosage unit of claim 30, wherein the water-soluble
hydrocolloid exhibits a hydration rate in 24 hours of 5-20% at 75%
humidity at room temperature.
34. The dosage unit of claim 30, wherein the water-soluble
hydrocolloid is a polymer selected from the group consisting of a
natural, semi-natural and synthetic biopolymer.
35. The dosage unit of claim 34, wherein the water-soluble
hydrocolloid is selected from the group consisting of a
polysaccharade and a polypeptide.
36. The dosage unit of claim 34, wherein the water-soluble
hydrocolloid comprises a hydroxypropylmethylcellulose polymer.
37. The dosage unit of claim 36, wherein the
hydroxypropylmethylcellulose polymer has a molecular weight of less
than 200,000 Daltons.
38. The dosage unit of claim 30, wherein the film further comprises
at least one of an emulsifier, a plasticizer, a taste modifying
agent, a water soluble inert filler, a preservative, a coloring
agent, a stabilizer and a buffering agent.
39. The dosage unit of claim 30, wherein the film further comprises
an emulsifier present at a concentration in the range of 0.1 to 10
wt % of the dosage unit.
40. The dosage unit of claim 30, wherein the film further comprises
a taste modifying agent comprising at least one of a sweetening
agent, a flavoring agent and a taste masking agent.
41. The dosage unit of claim 30, wherein the film further comprises
a water soluble inert filler present at a concentration in the
range of 0.5 to 50 wt % of the dosage unit.
42. The dosage unit of claim 30, wherein the film further comprises
a preservative present at a concentration in the range of 0.01 to
10 wt % of the dosage unit.
43. The dosage unit of claim 30, wherein the active agent is
present at a concentration in the range of 0.01 to 75 wt % of the
dosage unit.
44. The dosage unit of claim 30, wherein the sexual dysfunction
active agent is sildenafil citrate.
45. The dosage unit of claim 30, wherein the film has a dry film
thickness in the range of 1 to 20 mil.
46. The dosage unit of claim 45, wherein the film has a dry film
thickness of less than 10 mils.
47. The dosage unit of claim 30, wherein the film exhibits a
dissolution time in the range of 10 to 600 seconds upon application
to an oral mucosal surface.
48. The dosage unit of claim 30, wherein the film further exhibits
a dissintegration time in the range of 1 to 300 seconds upon
application to an oral mucosal surface.
49. The dosage unit of claim 30, wherein the active agent is
encapsulated within a polymer, wherein the polymer is chemically or
physically distinct from the hydrocolloid.
50. The dosage unit of claim 30, wherein the dosage unit comprises
at least two active agents.
51. The dosage unit of claim 30, wherein the mucosal adhesion
enhancer is present at a concentration of up to 50%.
Description
[0001] This Application is a continuation of U.S. patent
application Ser. No. 09/619,899, filed Jul. 19, 2000, which
application is a continuation-in-part of U.S. patent application
Ser. No. 09/434,878, filed Nov. 5, 1999, which claims priority to
U.S. Provisional Application Ser. No. 60/116,823, filed Jan. 21,
1999. The disclosures of each of the noted applications are
incorporated herein by reference as if set forth herein in their
entireties.
[0002] The present invention is directed to a device and method for
administering sexual dysfunction active agents in a dissolving film
configuration.
[0003] Many pharmaceutical dosage forms are administrated orally in
the form of solid shaped articles such as tablets, pills, caplets
and capsules that retain their shape under moderate pressure.
Generally these dosage forms are designed to be swallowed whole or
chewed to deliver the medication with adequate amounts of liquid.
Some patients, particularly pediatric and geriatric patients, have
difficulty swallowing or chewing solid dosage forms. Certain
patients such as children or animals resist taking medication, and
may try to hide a solid pill in order to spit it out later. In
addition, many pediatric and geriatric patients are unwilling to
take a solid dosage form because the active agent is difficult to
swallow or is retained in the pharynx or gullet even when liquids
are consumed with the dosage unit. Furthermore, the availability of
liquids at the time of administering medications may be limited for
certain patients and may be restricted for certain diseases and/or
treatments. Chewable tablets provide some advantages over the
conventional tablets. However, they are not suitable for children
wearing braces and the taste of the medication may be unpleasant
and difficult to mask in a chewable tablet. At the same time, water
may be still required for the administration of chewable
tablets.
[0004] In addition, the standard oral dosage forms, such as
tablets, pills, caplets, and capsules, are designed for short
residence time in the mouth. Absorption of the agent from these
dosage forms occurs in the gastrointestinal (GI) tract, after the
agent has separated from the dosage form and dissolved in the
gastric fluids. For some active agents, it is desirable to achieve
absorption through the oral mucosal tissues in order to accelerate
onset of the therapeutic effect.
[0005] Many active agents are poorly absorbed, even after they are
dispersed in the stomach, because of low solubility or slow
dissolution rate in the gastric fluids. Tablets may be formulated
so as to be quick dissolving. These tablets are commonly placed on
the tongue and disintegrate rapidly in the oral cavity. However,
these dosage units are not fixed to a mucosal surface and may move
around in the mouth. Consequently, they do not overcome a risk
associated with choking or gagging that occurs with subjects having
limited control of their swallowing reflexes. However, once placed
in the mouth, these tablets dissolve rapidly in the saliva to
provide a liquid formulation which is then swallowed. Quick
dissolving tablets may be formed from a particulate support matrix
containing the therapeutic agent, where the particulate support
matrix is a protein (U.S. Pat. Nos. 5,807,576, 5,635,210,
5,595,761). Alternatively, the tablet maybe formed from a laminate
with several layers and an outer coating (JP 100535518). Tablets
have also been manufactured from shearform matrices which are
substantially amorphous sugar formed when crystalline sugar is
subjected to heat and shear (WO 95/07194; WO 95/35293). Other
methods of forming quick dissolving tablets include wet granulation
methods (EP 0627 218) and dry granulation methods (EP 0124027A1)
and by freeze-drying techniques (EP 0084705A2). Generally, quick
dissolving tablets are formed using complex multi-step
manufacturing processes. In addition, these tablets may have poor
mechanical strength, are fragile and friable and have insufficient
holding capacity for active ingredients (U.S. Pat. No. 5,720,974)
and may be difficult to store and handle.
[0006] Therapeutic compounds are sometimes provided as powders or
granules which may be difficult to swallow and cause unpleasant
sensations in the mouth. Furthermore, many quick dissolving tablets
contain particulates (>25 microns) which leave a "gritty" and
unpleasant taste in the mouth. In the elderly, powders may cause
choking and discomfort associated with trapping of granules in
dentures. Powders and granules are generally packaged in a sealed
pouch which requires tearing before use. This causes problems for
geriatric patients and those suffering from arthritis in the
fingers as well as for children. Consequently, problems of spillage
of the contents arise in this group of patients. Furthermore, these
oral preparations should be taken with water which for certain
patients are inconvenient and may cause reduced patient
compliance.
[0007] Liquid, syrups or suspensions are an alternative to solid
dosage forms and are considered desirable for pediatric and
geriatric patients who have problems in swallowing tablets.
However, these dosage forms are often difficult to measure
accurately and administer easily. Liquid formulations deteriorate
rapidly upon exposure to heat or atmosphere and consequently have a
relatively short shelf life. Furthermore, liquid formulations
require a relatively large volume and-are bulky to store.
[0008] In addition to solid and liquid dosage forms, rapidly
dissolving buccal/oral delivery systems have been developed. These
systems are commonly freeze dried preparations which are more
expensive to manufacture as compared to tablets (U.S. Pat. No.
5,648,093). Furthermore, freeze dried preparations are brittle and
fragile when handled and must be kept in dry conditions to avoid
disintegration. The instability of freeze-dried preparations has
been reduced somewhat by the addition of mannitol (U.S. Pat. No.
4,946,684). WO 9820862 reports a film that is formed according to a
method that does not utilize freeze drying and avoids problems
described in the art such as rigidity of the films, delayed
softening and poor solubility in the mouth (U.S. Pat. No.
4,876,092; EP 0200508; EPO 381194; CA-PS 1-26331; DE 2449865.5; DE
3630603; EP 0452446 and EP 0219762). However, the film described in
WO 9820862 relies on the use of at least two different non-ionic
surfactants to achieve immediate wettability.
[0009] It is desirable that a dosage unit should provide a
non-invasive, effective and economic means to deliver an active
agent to the target site. Where the target site is the plasma,
additional issues arise concerning the rate of delivery of the
active agent to that site as measured by bioavailability. For many
types of active agent, fast onset of the therapeutic effect is
desirable. Traditional oral dosages, such as tablets, are limited
in onset time by the rate of absorption in the gastrointestinal
tract. Formulations have been developed which, when applied in the
mouth, lead to faster onset that the traditional oral dosages
because they target the oral mucosa. These formulations include
dosage units containing 75%-90% polyethylene glycol that melt at
body temperature, in the mouth.( U.S. Pat. Nos. 5,004,601 and
5,135,752) Other formulations include liquid forms, lozenges or
tablets that are administered sublingually or by a sweetened matrix
on a stick. (U.S. Pat. No. 5,770,606, Streisand et al. and Zhang et
al., Christie et al., Sasaki et al.). Whereas the above references
address the delivery route, they do not address the problems of
bioavailability that arise from poor solubility or low dissolution
rate.
[0010] A delivery device that addresses the above limitations would
represent a desirable improvement on existing delivery systems.
SUMMARY OF THE INVENTION
[0011] A novel dosage unit-and its method of manufacture and use is
provided. In an embodiment, the dosage unit includes a
water-soluble hydrocolloid, mucosal surface-coatforming film, such
film including an effective dose of an active agent.
[0012] In an embodiment of the invention, the hydrocolloid includes
a polymer selected from the group consisting of a natural,
semi-natural and synthetic biopolymer being exemplified by a
polysaccharide and a polypeptide. In addition to the hydrocolloid,
the film may further include one or more of an emulsifier, a
plasticizer, a taste modifying agent, a water soluble inert filler,
a preservative, a buffering agent, a coloring agent, a permeation
enhancer, and a stabilizer. The film may further include an active
agent selected from the group consisting of a therapeutic agent, a
dietary supplement and a hygiene aid. Embodiments of the invention
utilize effective amounts of sildenafil citrate, nicotine,
hydromorphone, oxybutynine or estradiol as active agents in the
dosage unit. The active agent may be encapsulated within a second
polymer having dissolution properties that are different from those
of the hydrocolloid. More than one active agent may be included in
the film. In an embodiment of the invention, the emulsifier may
have a concentration of 0.1-10%w. The water inert filler may
include a concentration range of 0.5-50% and the preservative may
include a concentration range of 0.01-10%. A mucosal adhesion
enhancer such as starch graft copolymer may be included in the
dosage unit.
[0013] In embodiments of the invention, the dosage unit may further
include any of the following features: a dry film thickness in the
range of 1-20 mil, more particularly less than 10 mils, a dry tack
value of less than 3.5 g, more particular less than 2 g, a wet tack
value of greater than 35 g, a tensile strength greater than
1500psi, a modulus in the range of 35,000-300,000 psi, a tear
propagation resistance in the range 0.0001N-1N, a disintegration
time in a range from 1-300 seconds, a dissolution time in a range
from 10-600 seconds, and a percentage elongation less than 20%.
[0014] In embodiments of the invention, methods are provided for
making a dosage unit, that include in one embodiment, dissolving a
hydrocolloid in a solvent so as to form a substantially homogeneous
preparation; adding to the hydrocolloid preparation, an active
agent and at least one reagent selected from the group consisting
of an emulsifier, a plasticizer, a taste modifier, a water soluble
inert filler, a coloring agent, a preservative, a permeation
enhancer, a stabilizer and a buffering agent to form a coatable
mixture; and forming a mucosal surface-coat forming film from the
mixture for packaging as a dosage unit. The method may further
include the step of coating the mixture onto a backing film. In a
further embodiment, the reagents including: a hydrocolloid, an
active agent, and at least one reagent selected from the group
consisting of an emulsifier, a plasticizer, a taste modifier, a
water soluble inert filler, a coloring agent, a preservative, a
permeation enhancer, a stabilizer, and a buffering agent, may be
combined in any order in a vessel having a heating source and a
mechanical mixing device, the combined ingredients being mixed
during and after the addition of the ingredients to the vessel, an
effective amount of heat being applied for melting a substantial
portion of the mixture. The mixture may then be formed into a film
in a dry extrusion process.
[0015] In an embodiment of the invention, a method is provided for
administering an active agent to a subject, that includes obtaining
a water-soluble hydrocolloid, mucosal surface-coat forming film,
such film including an effective dose of an active agent; and
placing the film on a mucosal surface coat forming film in the
subject; so as to release the active agent.
[0016] In a further embodiment of the invention, a dosage unit is
provided that includes a water soluble hydrocolloid and an
effective dose of sildenafil citrate in a muco sal-surface
contacting film. More particularly, an effective dose of sildenafil
citrate is formed into a solid dispersion with xylitol for treating
erectile dysfunction. The sildenafil/xylitol dispersion may be
mixed with at least one reagent selected from the group consisting
of an emulsifier, a plasticizer, a taste modifier, a coloring
agent, a preservative, a permeation enhancer, a stabilizer and a
buffering agent. The solid dispersion of sildenafil and xylitol may
arise at a ratio of 9 parts sildenafil to one part xylitol.
According to embodiments of the invention directed to a dosage unit
and method of making a dosage unit suitable for erectile
dysfunction, the water solubility of sildenafil in the solid
dispersion is at least 20 mg/ml, more particularly about 50 mg/ml.
More particularly, the film may be capable of completely
dissolution at the oral mucosal surface within 10-600 seconds.
BRIEF DESCRIPTION OF THE FIGURES
[0017] There are shown in the drawings certain exemplary
embodiments of the present invention as presently preferred. It
should be understood that the present invention is not limited to
the embodiments disclosed as examples, and is capable of variation
within the spirit and scope of the appended claims.
[0018] FIG. 1 shows possible application sites in the oral cavity
for the inventive dosage unit. (1) is the upper lip; (2) is the
gingiva; (3) is the hard palate; (4) is the cheek; (5) is the
lingual; (6) is the sublingual; (7) is the lower lip;
[0019] FIG. 2 illustrates one manufacturing process for the dosage
unit. (8) is the mixing and degassing tank; (9) is the coating slot
with thickness controller; (10) is the polyester backing belt; (11)
is the drying oven with aeration controller; (12) is the intraoral
film; (13) is the die cutting and (14) is the intraoral unit
dose;
[0020] FIG. 3 shows examples of packaging and dispensing devices
for the intraoral delivery system. (15) is a heat sealed single
pouch; (16) is a multi-unit blister card; (17) is a multi-unit
dispensing pack, 17(a) the container snap and 17(b) the lid
closure; (18) is a multiunit roll-type dispenser cylinder; (19) is
a perforated film strip; and (20) is a single dose film;
[0021] FIG. 4 demonstrates the disintegration and dissolution time
of the intraoral delivery system as a function of
thickness.--.circle-solid.-- is disintegration time and --
.smallcircle.-- is dissolving time;
[0022] FIG. 5 shows the release profiles of -- .tangle-soliddn.---
nicotine, -- .gradient.-- oxybutynin, --.circle-solid.--
hydromorphone and --.smallcircle.- estradiol; and,
[0023] FIG. 6 shows the pharmacokinetics in six subjects after
administration of a dissolving film sildenafil formulation and
after administration of the commercial tablet containing the same
dosage of sildenafil. Sildenafil film --.tangle-soliddn.-- Viagra
--.gradient.--.
DETAILED DESCRIPTION OF INVENTION
[0024] Delivery of active agents in solid form via the mouth causes
problems to patients who may choke on the dosage unit. This effect
is caused at least in part by the mobility of the dosage unit
within the mouth. We have developed a new class of dosage units
which are not mobile in the mouth because on contact with the moist
mucosal surface, the film becomes a coating that adheres to the
mucosal surface and then disintegrates and dissolves over a time
frame controlled in the design of the dosage. The dosage unit, in
an embodiment of the invention, is in the form of a flexible,
non-tacky, dry conveniently packaged film. Once removed from the
package and placed on a mucosal surface, the mucosal surface-coat
forming film hydrates substantially immediately to form a coating
on the moist surface of the mucous membrane and then disintegrates
and dissolves to release the active agent from the film.
[0025] The dosage unit may release the active agent over a period
of time that is determined by a number of different factors. These
factors include the dimensions of the film, the concentration of
the active agent, the solubility of the agent at the mucosal
surface and how the agent is dispersed throughout the film. The
thickness of the film is a factor in determining the rate of
dissolution. A thick film will dissolve more slowly than an
otherwise similar thin film. A thick film may be desirable for its
holding capacity for active agents that are required in high
dosages. Although the surface area of a film can be adjusted up to
about 5 square centimeters, increased thickness may also be
desirable for purposes of achieving effective active agent dosages.
The active agent can form a solid dispersion with a water soluble
inert filler for purposes of increasing the solubility of the agent
when released from the film thereby enhancing bioavailability of
the active agent. This is exemplified here by sildenafil which is
incorporated in a film with a water soluble inert filler, for
example, xylitol, which has been found here to enhance the
bioavailability of this agent. Solubilizing agents that are well
known in the art may be included in the film. The extent of uptake
of the active agent from the dosage unit at the mucosal surface can
be controlled by the dissolution rate of the film. A dissolving
film will release the active agent and this in turn will cause the
active agent to be swallowed and taken up in the GI tract. In
contrast, slow release of the active agent at the mucosal surface
will give rise to increased uptake by the mucosal surface. A
further parameter governing the release of an active agent at the
mucosal surface is the manner in which the agent is dispersed in
the film. For example, the agent may be dispersed as colloidal
particles or microencapsulated within the film or alternatively may
be mixed throughout the film as a reagent during casting.
[0026] The dosage unit of the invention may be used as a vehicle
for delivering a wide range of active agents. For example, the
active agent may be a small molecule, a protein, a nucleic acid
including antisense molecules or other biological or synthetic
molecules.
[0027] The term "mucosal surface-coat-forming" as applied to a film
as used in this description and in the following claims unless
specified otherwise, means a film that coats the mucosal surface on
contact, and may not thereafter be manually recovered or moved from
the contact site; and subsequently disintegrates and dissolves so
as to release the active agent. It should be noted that for
purposes of the description of the invention and the claims,
"mucosal surface" refers to any moist surface of the body. This
includes the surfaces identified in FIG. 1. It further includes a
wound surface where lymph fluid bathes the tissue surface.
[0028] Embodiments of the present invention include a process,
composition and method of use for a quick dissolving film for local
and systemic delivery of pharmaceutical agents to a mucosal surface
in a subject. In the following text, specific reference may be made
to the oral cavity by way of example. However, it is not intended
to limit the scope of the invention to the oral cavity. The dosage
unit of the invention may be applied to any mucosal surface as
deemed appropriate for the systemic or local delivery of an active
agent including vaginal, rectal, and ocular surfaces. For purposes
of oral delivery, the films may be applied on lingual, sub-lingual,
buccal, gingival, and palatal surfaces (FIG. 1).
[0029] For vaginal delivery of such agents as contraceptive agents
including nonoxynol or anti-infectives including antifungal agents,
antibacterial agents and anti-viral agents, or fragrant or hygiene
agents; the film should be non-sticky when removed from the
packaging but should have mucoadhesive properties when applied in
the vagina. Although films containing active agents for use in the
vagina have been used, they appear to have some significant
drawbacks most particularly the lack of adhesive properties at the
mucosal surface. This makes these films impractical to administer.
(U.S. Pat. Nos. 5,380,529; 5,595,980 and 5,529,782).
[0030] Embodiments of the invention provide improved dosage forms
to deliver active agents that are appropriate for all age groups
and that physician, parents, patients and family members can
administer easily. These dosage forms are economical to prepare and
have an extended shelf life. They are easy to handle and non-tacky
before administration so as to avoid disintegration prior to use
and are conveniently packaged for shelf life, ease of storage and
distribution. The dosage form may be administered to the subject by
placing the film on a mucous surface, at which time the film
becomes a mucoadhesive coating, characterized by the property that
it can no longer exist in an independent form and is subsequently
dispersed in solution.
[0031] Embodiments of the invention provide a delivery system for
active agents and other active agents that will dissolve and
completely release their contents on a moist mucosal surface for
example in the oral cavity. The release of the active agent occurs
without mastication or the need for intake of water. With
particular reference to the oral cavity, an embodiment of the
invention provides active agents that remain in the oral cavity for
treatment or modification of the oral environment; for example, for
periodontal disease treatment or breath-odor control. Furthermore,
embodiments of the invention further provide improvements that
include: improved organoleptic properties (smell and taste), and
texture and feel of dosage forms intended to be placed in the oral
cavity; a dosage form which "melts" in the mouth and leaves a
smooth pleasant after feel following dissolution; and a prolonged
retention of the active agent in the mouth following dissolution of
the quick dissolving dosage form to extend the residence time of
the active agent cleared from the mouth by the production of saliva
and subsequent swallowing. Depending on the optimal program for a
specific application of the invention, the disintegration time and
the dissolution time can be controlled within a prescribed range by
adjustment of the formulation and the thickness of the film. In
some cases, it is desirable for release of the active agent to
occur after dissolution of the film. For these applications, the
active agent may be encapsulated in a material with dissolution
properties that are different from those of the hydrocolloid.
Encapsulation of the active agent also may be utilized to achieve
masking of taste for active agents that are bitter. In some cases,
two or more different active agents may be included in the film. An
example where multiple active agents frequently are administered is
cold medications, which often contain several active agents.
[0032] "Coating solution" is defined here and in the claims as a
viscous and homogeneous mixture of hydrocolloids, active agents and
other additives in a solvent. The coating solution is treated
according to the method of the invention to form a film.
[0033] "Subject" is defined here and in the claims as a human or
animal species.
[0034] "Thickness" is defined here and in the claims by
measurements in mil (a mil=one thousandth of an inch) determined
when a film is placed between two microscopic slides.
[0035] "Permeation enhancer" as defined here and in the claims is a
natural or synthetic molecule which facilitates the absorption of
an active agent through a mucosal surface.
[0036] "Enzyme inhibitor" as defined here and in the claims is a
natural or synthetic molecule which inhibits enzymatic metabolism
of an active agent in the saliva or in a mucosal tissue.
[0037] "Water Content" is defined here and in the claims as %
residual water content per unit dose as measured according to the
Karl Fisher method and expressed as percent of the dry weight of
the film.
[0038] "The hydration rate" is defined here and in the claims as
the speed of absorbing water at 25.degree. C. and 75% relative
humidity in 24 hours.
[0039] "Percentage of swelling" is defined here as a percentage of
the initial volume that is increased before dissolving. In an
embodiment of the invention, the percentage of swelling is less
than 10% in 60 seconds.
[0040] Taste modifying agents include flavoring agents, sweetening
agents and taste masking agents and are exemplified by: the
essential oils or water soluble extracts of menthol, wintergreen,
peppermint, sweet mint, spearmint, vanillin, cherry, chocolate,
cinnamon, clove, lemon, orange, raspberry, rose, spice, violet,
herbal, fruit, strawberry, grape, pineapple, peach, kiwi, papaya,
mango, coconut, apple, coffee, plum, watermelon, nuts, durean,
green tea, grapefruit, banana, butter, camomile, sugar, dextrose,
lactose, mannitol, sucrose, xylitol, malitol, acesulfame potassium,
talin, glycyrrhizin, sucralose, aspartame, saccharin, sodium
saccharin, sodium cyclamate and honey.
[0041] Emulsifying agents include solubilizers and wetting agents
and are exemplified by polyvinyl alcohol, sorbitan esters,
cyclodextrins, benzyl benzoate, glyceryl monostearate,
polyoxyethylene alkyl ethers, polyoxyethylene stearates, poloxamer,
polyoxyethylene castor oil derivatives, hydrogenated vegetable
oils, bile salts, polysorbates and ethanol. Plasticizers may
include glycerin, sorbitol, propylene glycol, polyethylene glycol,
triacetin, triethyl citrate (TEC), acetyl triethyl citrate (ATEC)
and other citrate esters.
[0042] Active agents (for human and veterinary applications)
include therapeutic agents, nutritional supplements and hygiene
aids. The therapeutic agents are exemplified by analgesics,
a-adrenergic receptor blockers, anti-Alzheimer's disease
medication, antianginal, antianxiety, antiarrythmics,
antiarthritics, antibiotics, anticoagulants/thrombolytics- ,
anticonvulsants/anti-Parkinson medication, anti-depressants,
anti-diabetics, anti-diarrheal, anti-epileptics, anti-fungal,
anti-gout, anti-heartworm medication for dogs, anti-histamines,
anti-hypertensives, anti-inflammatories, anti-infectives,
antimigraines, anti-nasuants/antiemetics,
anti-neoplastics/anti-tumor active agents, anti-pruitics,
anti-psychotics, anti-pyretics, anti-spasmodics, anti-virals,
bronchial dilators/anti-asthmatics, calcium antagonists, cardiac
agents, cardiotonics, central nervous system actives,
contraceptives, coronary vasodilators, cough/cold remedies, dietary
supplements, including vitamins and minerals, diuretics, fertility
active agents, flea control agents for animals (Ivermectin), HZ
receptor antagonists, herbal actives, hormones, hypoglycemics,
hypolipidemics, muscle relaxants, ovulation stimulators, peptide
active agents, polypeptide active agents, proteins such as insulin,
calcitonin, LHRH and the like. Sedatives and hypnotics, sexual
dysfunction active agents, sleep aids, smoking cessation aids,
steroids and steroidals, tranquilizers, laxatives, ophthalmic
preparations, nutritional supplements, breath fresheners, breath
deodorants, saliva substitutes, antigingivitis agents, anti-cavity
agents, anti-plaque agents, diagnostic indicators, and local
anesthetics. Also included are active agents for treatment of
osteoporosis, hormone replacement, treatment of periodontal
disease, antiseptics, corticosteroids, non steroidal anti
inflammatory agents, antiviral agents and vaccines.
[0043] Water soluble inert fillers include mannitol, xylitol,
sucrose, lactose, maltodextrin, dextran, dextrin, modified
starches, dextrose, sorbitol, and dextrates. The water soluble
inert fillers may be used in embodiments of the invention as inert
carriers to form a high water soluble dispersion with active
agents.
[0044] Buffering agents include acidulants and alkalizing agents
exemplified by citric acid, fumaric acid, lactic acid, tartaric
acid, malic acid, as well as sodium citrate, sodium bicarbonate and
carbonate, sodium or potassium phosphate and magnesium oxide.
[0045] Coloring agents may include FD & C coloring agents,
natural coloring agents, and natural juice concentrates, pigments
such as titanium oxide, silicon dioxide and zinc oxide.
[0046] Stabilizers as used here and in the claims, include
anti-oxidants, chelating agents, and enzyme inhibitors as
exemplified by ascorbic acid, vitamin E, butylated hyroxyanisole
(BHA), butylated hydroxytoluene (BHT), propyl gallate, dilauryl
thiodipropionate, thiodipropionic acid, gum guaiac, citric acid,
edetic acid and its salts and glutathione.
[0047] Preservatives which here include anti-microbial agents and
non-organic compounds are exemplified by sodium benzoate, parabens
and derivatives, sorbic acid and its salts, propionic acids and its
salts, sulfur dioxide and sulfites, acetic acid and acetates,
nitrites and nitrates.
[0048] The mechanical properties of the film is determined by
tensile strength modulus, percent elongation (ASTM D882, standard
test method for tensile properties of thin plastic sheet) and tear
propagation resistance (ASTM D1938, standard test method for tear
propagation resistance of plastic film and thin sheet by single
tear method). The mechanical properties are measured here using
standard protocols as described in Annual Book of ASTM Standards,
American National Standards Institute, N.Y 1995.
[0049] The "tensile strength" (psi) is the property of film that
requires a load to cause load deformation failure of film.
[0050] The "% elongation" is measured when the film snaps as
sufficient force is applied so as to exceed the elastic limit.
[0051] The "release study" is the percentage of active agents
released from the film as a function of time in a suitable
dissolution vessel and medium under specified conditions of
temperature and pH.
[0052] "Dry tack" is quantitative values for tackiness (grams) of
dry film by Texture Analyzers (Model TA.XT2i with 6 mm diameter
stainless steel cylinder probe) from Texture Technologies Corp. The
tackiness after the addition of 10 ml of water on the same surface
area is defined as the wet tack (gram) to simulate the adhesion of
film upon the contact with a moist mucosal surface. In an
embodiment of the invention, the dry tack ranges from 0.2-3.5
grams, with a preferred range of 0.4-2.0 grams and the wet tack is
in the range of 35-150 grams with a preferred range of 40-100
grams.
[0053] "Tear propagation resistance" is defined here and in the
claims as the average force (N) necessary to propagate, a tear
across a film or sheet under a specified rate of extension as
defined in ASTM D1938 and is interpreted from the load time chart.
In a preferred embodiment of the invention, the tear resistance
ranges from 0.0001N-1N with a preferred range of 0.01-1N.
[0054] "Disintegration time" is defined here and in the claims as
the time (second) at which a film breaks when brought into contact
with water or saliva. In an embodiment of the invention, the
disintegration time ranges from 1-300 seconds.
[0055] "Dissolving time" is defined here and in the claims as the
time (seconds or minutes) at which not less than 80% of the tested
film is dissolved in an aqueous media or saliva. In an embodiment
of the invention, the dissolution time ranges from 10-600
seconds.
[0056] "Modulus" is a measurement of stiffness of a film.
[0057] A factor that plays a significant role in determining the
properties of mucosal surface-coat-forming composition is the
viscosity of the hydrocolloid. The viscosity of the hydrocolloid
depends on its molecular size, derivation, hydrophobicity and
hydrophilicity and the presence of other additives in the
formulation. A comparison of films formed from the hydrocolloid,
hydroxymethylcellulose, having different viscosity values is shown
in Table 9a and 9b.
[0058] In embodiments of the invention, a hydrocolloid
concentration in the range of 5-99% of the dry weight of the films
is provided, more particularly greater than 10%. These films have
dry tack and wet tack properties that improve ease of handling and
use. The low dry tack properties of the film provide for a
physically attractive and easily handled film that is neither
fragile nor sticky and can be easily removed from packaging and
placed on a mucosal surface. The wet tack properties of the film
provide the advantage of stickiness of the moistened film such that
when the film is placed on the mucosa, it remains attached at that
site until it dissolves. In contrast, if the wet tack is too low,
the film can move in the mouth and may be swallowed before
dissolving and possibly give rise to choking. Furthermore, the low
moisture content and low dry tack of the film enhances the
shelf-life of the film and the flexibility of the dosage forms.
These properties render the films suitable for easy making,
packaging, handling and application.
[0059] In an embodiment of the invention, a water soluble polymer
(2% polymer solution) is selected having a gelation temperature
greater than 70.degree. C. The hydration rate of a hydrocolloid
having these features is rapid with a percentage moisture
absorption of polymers in the range of 5-20% at 75% humidity at
room temperature. The hydration rate is selected according to the
desired wettability of the film thereby obviating the need for
surfactants. The wet tack of the hydrated film ranges from 35-150
grams more particularly 40-100 grams. The percentage swelling may
be less than 10% within 60 seconds. The film is cast so as to have
a thickness of 1-20 mil . The water content of the film ranges from
0.5-10% with a preferred range of 1-5%. In embodiments of the
invention, the film may be formed using a mixture of two or more
types of the same hydrocolloid that differ only in molecular
weights and/or different degrees of substitution. The time of
dissolution of the film is in the range of 10-600 seconds, (see
FIG. 4), the time of disintegration of the film may be 1-300
seconds. The active agent in the film may be encapsulated in a
polymer having different chemical or physical properties from the
hydrocolloid of the film and having dissolution properties
different from those of the hydrocolloid. Examples of the films
formed according to the invention having properties that fall into
the above ranges are provided in Table 1,3,6 and 7. The ease of
handling is characterized by the dry tack of the film and the
flexibility is reflected by the tensile strength, modulus, %
elongation and tear resistance of the film. For example, the dry
tack is in the range of 0.2-3.5 grams more particularly 0.4-2.0
grams. The tensile strength may be in the range of 1500-10,000 psi,
more particularly 2000-8000, more particularly greater than 2000
psi, the modulus is in the range of 35,000-300,000 and the %
elongation is less than 20% more particularly 1-10% for a film
having a thickness of 2 mil. In embodiments of the invention, the
hydrocolloid may be a water soluble non-gelling (at room
temperature) natural polysaccharide or derivatives including pectin
and derivatives, guar gum arabic, tragacanth gum, xanthan gum,
gellan sodium salt, propyleneglycol alginate, starches (amylose,
amylopectin), modified starches, hydroxyethyl starch, pullulan,
carboxymethyl starch, gum ghatti, okra gum, karaya gum, dextrans,
dextrins and maltodextrins, konjac, acemannan from aloe, locust
bean gum, tara gum, quince seed gum, fenugreek seed gum,
scleroglucan, gum arabic, psyllium seed gum, tamarind gum, oat gum,
quince seed gum, carrageenans, scleraglucan, succinoglucan, larch
arabinogalactan, flaxseed gum, chondroitin sulfates, hyaluronic
acid, curdlan, chitosan, deacetylated konjac, and rhizobium
gum.
[0060] In embodiments of the invention, the hydrocolloid may be a
water soluble non-gelling polypeptide or protein exemplified by
gelatins, albumins, milk proteins, soy protein, and whey proteins.
The hydrocolloid may further be selected from a group of synthetic
hydrocolloids exemplified by any of the following:
polyethylene-imine, hydroxyethyl cellulose, sodium carboxymethyl
cellulose, carboxymethyl cellulose, hydroxypropyl cellulose,
hydroxypropyl methyl cellulose, methyl cellulose, ethyl cellulose,
polyacrylic acids, low molecular weight polyacrylamides and their
sodium salts (carbomers), polyvinylpyrrolidone, polyethylene
glycols, polyethylene oxides, polyvinyl alcohols, pluronics,
tetronics, and other block co-polymers, carboxyvinyl polymers, and
colloidal silicon dioxide. A preferred embodiment of the invention
utilizes a hydroxypropyl methyl cellulose having a methoxy content
of about 19-30% and hydroxypropyl content of 7-12% and a molecular
weight of approximately 50,000-250,000 daltons (Table 9).
[0061] In addition to hydrocolloids and the active agents, the
films may contain any or all of the following ingredients:
emulsifying agents, solubilizing agents, wetting agents, taste
modifying agents, plasticizers, active agents, water soluble inert
fillers, preservatives, buffering agents, coloring agents, and
stabilizers. In a preferred embodiment, the percentage dry weight
concentration of at least single ingredients incorporated in a film
in each of the following categories is as follows: emulsifying
agent (0.1%-10%), plasticizer (0.5-20%), active agents (0.01-75%),
taste modifying agents (0.1-10%), coloring agents (0.01-5%), water
soluble inert fillers (0.5-50%), preservatives (0.01-10%),
buffering agents (0.1-10%) and stabilizers (0.01-5%.
[0062] Methods for manufacturing the dosage unit of the invention
include the solvent casting methods as shown in FIG. 2 or
alternatively extrusion methods as exemplified in Example 11. The
extrusion method involves blending ingredients to form a film using
mechanical force and moderate heat. Significantly, the above
processes do not rely on a freeze drying step. Nor do the above
processes rely on extremes of heat or cold during manufacture.
[0063] In an embodiment of the invention, the solvent casting
method includes a natural or synthetic hydrocolloid that is
completely dissolved or dispersed in water or in a water alcoholic
solution under mixing to form a homogenous formulation. In addition
to the active agent and the hydrocolloid, any of the ingredients
listed above may be added and dispersed or dissolved uniformly in
the hydrocolloid solution. The active ingredients and flavoring
agents can be incorporated before or after film forming. This
homogeneous mixture (coating solution) with a solid content of
5-50% and a viscosity of 500-15000 cps was degassed (8) and coated
on the non-siliconized side of a polyester film (10) at 5-50 mil
wet film thickness (9), more preferably 5-20mil wet film thickness
and dried under aeration at a temperature between 40-100.degree. C.
so as to avoid destabilizing the agents contained within the
formulation (11). The manufacturing process for forming the dosage
unit is illustrated in FIG. 2. The dry film formed by this process
is a glossy, stand alone, self supporting, non-tacky and flexible
film (12). The dry film is then cut into a suitable shape (13) and
surface area for active agent delivery at the preferred site. For
example, the cast film can be die-cut into different shapes and
sizes using a rotary die. The film may be cut into a size that
contains for example, a single dosage unit. For example, a dosage
unit may include a film size with surface area of 5cm.sup.2 that
contains a dosage of active agent in the range of 20-250 mg (14).
The size of the film may be varied according to the dosage
required. The dosage contained in each square centimeter is
selected according to the active agent. Films are then packaged
into a single pouch package, multi-unit blister card or multiple
unit dispensers (FIG. 3).
[0064] In contrast to the above method, the dry extrusion method
does not rely on placing the hydrocolloid in a solvent. Instead,
the ingredients of the dosage unit are mixed together in dry form
and heated. The heated blend is then forced through an extrusion
die to form a film of selected thickness. The film can then be cut
and packaged.
[0065] The dry extrusion method has a number of advantages. First,
it is an economical process. Second, because there is no drying
oven, extrusion of the film is faster than solvent coating. Third,
the dry extrusion avoids the step of removing residual solvent.
Some residual solvent is generally present in the solvent coating
process and can affect the safety or stability of the film. Where a
film requires an organic solvent rather than water, removal of the
solvent from the film may be required by environmental regulations.
The extrusion process avoids any need for recovering solvent and
avoids residual solvent in the film.
[0066] The dosage unit may be prepared for use by selecting a film
that is capable of delivering an effective dose and administering
the film to the patient by placing it on a mucosal surface such as
the oral mucosa (FIG. 1) where it dissolves in the body fluid for
example, saliva (0.5-10 minutes) and is swallowed in liquid form.
FIG. 4 graphically represents the rate of disintegration and
dissolution for different thickness films. FIG. 5 shows the release
profile of four active agents from films according to Examples 5-8.
The fraction of the dose absorbed through the mucosal tissue can be
facilitated by the use of a permeation enhancer into the film.
[0067] The overall bioavailability of the active agent which is
absorbed both locally at the mucous membrane and systemically
within the gastrointestinal system is improved compared to the same
dose of the active agent given in a conventional oral tablet or
capsule dosage form. This is exemplified in FIG. 6 and Table 11
which show the improved bioavailability of Sildenafil film over
Viagra. The oral retention characteristics, mouth feel properties,
flavor and taste of the film can be modified based on the
hydrocolloid and other excipients used to prepare the films and the
medications.
[0068] The invention is illustrated but not meant to be limited to
the examples provided below. According to Examples 1-8, the
hydrocolloid was dissolved in water under agitated mixing to form a
uniform and viscous solution. Additional ingredients were then
added sequentially to the viscous solution such as peppermint,
aspartame, propyl glycol, benzoic acid and citric acid under
agitated mixing until they were uniformly dispersed or dissolved in
the hydrocolloid. The resultant mixture was degassed in a vacuum
chamber until trapped air bubbles were removed.
[0069] The viscosity, pH and specific gravity were measured. The
formulation was then coated on the non-siliconized side of a
polyester film at a wet thickness of 10 mil and dried in a hot air
circulating oven at 50.degree. C. for 9 minutes. A glossy,
substantially transparent, stand alone, self-supporting, non-tacky
and flexible film was obtained after drying. The dry film was cut
into different shapes for measurement of dry tack, wet tack,
tensile strength modulus, elongation, tear resistance, residual
water content, disintegration and dissolution. The dosage form was
25-250 mg in various shapes, sizes, and thickness.
[0070] Example 9 shows how the properties of dosage units vary when
different hydroxymethylcellulose polymers are utilized. Example 10
shows how mucoadhesion can be increased up to at least 84% using an
enhancer exemplified by starch graft copolymer.
[0071] In vivo studies of the dosage unit show that it is well
tolerated by patients (Example 12) and shows enhanced
bioavailability (Example 13)
EXAMPLES
[0072] Examples 1-3
Quick dissolving Films, Compositions and Associated Properties
[0073] The films were prepared as follows: a homogeneous mixture of
ingredients was prepared in a coating solution in the amounts
indicated in Table 1. The amounts are given as percentage weight of
coating solution. The mixture was degassed in a vacuum chamber and
coated on the non-siliconized side of a polyester film and dried in
a hot air circulating oven to form a self supporting non-tacky and
flexible film. The film was then cut into dosage units ready for
packaging.
1TABLE 1 Formulation of quick dissolving films using several
different hydrocolloids. Composition: coating solution % Ex. 1 Ex.
2 Ex. 3 Pullalan (P-20) w % 17.5 Methocel E5 w % 21.06 POLYOX WSR
N-10 w % 1.8 PVA (Vinol 125) w % 1.5 Cellulose gum w % 8.1
Propylene glycol w % 1.0 2.5 Aspartame w % 0.8 0.475 0.46
Peppermint w % 1.0 1.0 0.6 Citric acid w % 0.7 0.8 Cremphor EL40 w
% 1.0 1.0 Benzoic acid w % 0.013 0.1 0.01 FD&C blue #1 w % qs.
FD&C yellow #5 w % qs. Ethanol w % 10.6 Water w % 74.42 67.025
85.6
[0074]
2TABLE 2 Properties of the film formed from the coating solution of
Table 1. Properties of dry film Ex. 1 Ex. 2 Ex. 3 Thickness (mil)
2.1 2.5 2.6 Water content % 1.7 8.5 8.0 Dry tack (g) 0.67 0.55 0.60
Wet tack (g) 60.16 86.64 72.27 Tensile strength (psi) 5242 2381
2036 % Elongation (sec) 2.9 4 2.9 Modulus (psi) 266834 272502 44566
Tear resistance (N) 0.02 0.16 0.01 Disintegration (sec) 12 20 12
Dissolving time (sec) 41 60 39
[0075]
3TABLE 3 Dry weight percentages for components of Example 1
according to Tables 1 and 2 Ingredients Percentage (w/w) Methocel
E5 82.35 Propylene glycol 3.91 Aspartame 3.13 Citric acid 2.74
Peppermint oil 3.91 PEG-40 Hydrogenated castor oil 3.91 Benzoic
acid 0.5 FD&C blue #1 qs. FD&C yellow #5 qs.
[0076]
4TABLE 4 Mean values for parameters according to Example 1 in Table
1. Properties Value + SD (n) Weight (g/dosage film) 0.028 0.001 (4)
Thickness (mil) 2.1 0.12 (3) PH 3.07 (1) Density (g/cm2) 1.0485
0.009 (3) % Water content 1.7 0.24 (2) Dry tack (g) 0.674 0.110 (6)
Wet tack (g) 60.169 11.680 (6) tensile strength (psi) 5242 379 (5)
% Elongation 2.9 0.4 (5) Modulus (psi) 266834 7910 (5)
Tear-propagation resistance (N) 0.02 0.00 (4) Disintegration time
(sec) 12 1 (3) Dissolving time (sec) 41 5 (3)
Examples 4-8
Hydropropylmethylcellulose based Quick Dissolving Intraoral Film
Containing Therapeutic Agents
[0077] The films were prepared according to Examples 1-3.
Therapeutic agents were added to the homogeneous mixture (coating
solution) prior to forming the film.
5TABLE 5 Composition (coating solution) Ex. 4 Ex. 5 Ex. 6 Ex. 7 Ex.
8 Nicotine 1.4 Hydromorphone 2.92 Oxybutynin 3.71 Estradiol 1.49
Peppermint 1.0 1.0 1.0 1.0 1.0 Methocel E5 (HPMC) 21.06 21.06 21.06
21.06 21.06 Propylene glycol 1.0 1.0 1.01 1.0 1.0 Aspartame 0.8 0.8
0.8 0.8 0.8 Citric acid 0.7 0.7 0.7 0.7 0.7 Cremphor EL40 1.0 1.0
1.0 1.0 1.0 Benzoic acid 0.013 0.013 0.013 0.013 0.013 FD&C
blue #1 qs. FD&C yellow #5 qs. Water 74.43 73.03 71.51 70.72
72.94
[0078]
6TABLE 6 Properties of the film formed according to the formulation
in Table 5 Properties Ex. 4 Ex. 5 Ex. 6 Ex. 7 Ex. 8 Thickness (mil)
3.0 2.9 2.9 3.2 2.7 Density (g/cm3) 1.18 1.19 1.13 1.20 1.16 Water
content % 1.8 2.93 2.42 2.32 2.31 Dry tack (g) 0.67 0.608 0.619
1.215 0.671 Wet tack (g) 49.08 54.81 84.34 88.85 39.91 Tensile
strength (psi) 4393 3373 4138 3549 3688 % Elongation (sec) 8.3 8.3
7.6 8.1 7.5 Modulus (psi) 45969 48168 42110 41745 53334 Tear
resistance (N) 0.03 0.02 0.01 0.03 0.01 Disintegration (sec) 43.0
34.3 27.3 36.0 55.7 Dissolving time (sec) 73.7 64.3 58.0 65.7
111.3
[0079]
7TABLE 7 Composition of the Sildenafil film (% wet base)
Composition Percentage Sildenafil citrate 28.93 Xylitol 3.21
Methocel E15 4.59 Propylene Glycol 3.67 Aspartame 0.46 Benzoic acid
0.0045 Peppermint oil 0.46 Sodium EDTA 0.0045 Polyoxamer L-44 2.3
Water 55 Polypro 5000 0.92
[0080]
8TABLE 8 Properties of the film formed according to the formulation
in Table 7 Properties Ex. 9 Thickness 3.2 .+-. 0.1 Density
(g/cm.sup.3) 1.230 Dry tack (g) 1.21 .+-. 0.19 Wet tack (g) 23.79
.+-. 3.45 Tensile strength (psi) 421 .+-. 49 % Elongation 4.0 .+-.
0.7 Modulus (psi) 31822 .+-. 6137 Tear resistance (N) 0.04 .+-. 00
Disintegration (sec) 8.3 .+-. 1.5 Dissolution (sec) 23.7 .+-.
1.5
[0081] Table 9: A comparison of properties of dosage units using
different hydroxypropyl-methylcellulose polymers
[0082] The properties of a dosage unit according to the invention
may be modified by varying individual components. For example, the
dissolution of the film may be prolonged by using
hydroxypropylmethylcellulose (BPMC) with higher molecular weight as
shown below in Table 9.
9TABLE 9a Properties of selected commercial
hydroxypropylmethylcellulose polymers. Methocel Type (Dow
Pharmaceuticals) Property E3 E5 K3 E15 A15 E50 F50 % Methoxyl 29 29
22 29 30 29 28 % Hydroxypropyl 8.5 8.5 8.1 8.5 0 8.5 5.0 Viscosity
2% (cps) 2-4 4-6 2-4 12-18 12-18 40-60 40-60 * Each value is the
mean S .+-. D, n = 6
[0083]
10TABLE 9b Properties of films prepared according to Example 1,
using different hydroxypropyl- methylcellulose polymers Property E3
E5 K3 E15 A15 E50 F50 Dry tack (g) 0.61 .+-. 0.08 0.67 .+-. 0.110
0.82 .+-. 0.12 0.66 .+-. 0.09 0.52 .+-. 0.09 0.68 .+-. 0.14 0.52
.+-. 0.12 Wet tack (g) 93.4 .+-. 8.95 60.169 .+-. 11.6 60.2 .+-.
8.77 65.4 .+-. 17.8 18.4 .+-. 3.0 79.1 .+-. 17.1 64.1 .+-. 11.2
Tensile strength 1921 .+-. 442 5242 .+-. 379 2043 .+-. 268 4316
.+-. 384 3351 .+-. 165 3725 .+-. 123 3905 .+-. 590 (psi) %
Elongation 4.2 .+-. 1.2 2.9 .+-. 0.4 3.8 .+-. 0.8 16.9 .+-. 4.3
11.1 .+-. 2.4 11.4 .+-. 2.4 15.0 .+-. 3.4 Modulus (psi) 44368 .+-.
864 266834 .+-. 79 41737 .+-. 816 46889 .+-. 416 35914 .+-. 964
41651 .+-. 282 43644 .+-. 942 Tear resistance (N) 0.040.01 .+-.
0.02 .+-. 0 0.05 .+-. 0.01 0.09 .+-. 0.03 0.12 .+-. 0.02 0.05 .+-.
0.01 0.08 .+-. 0.01 Disintegration (sec) 17.0 .+-. 4.4 12 .+-. 1
15.3 .+-. 1.5 21.9 .+-. 1.6 161.0 .+-. 15.9 33.2 .+-. 5.1 24.1 .+-.
1.3 Dissolution (sec) 35.7 .+-. 2.1 41 .+-. 5 31.0 .+-. 1.0 51.6
.+-. 1.3 >600 71.6 .+-. 3.3 62.1 .+-. 2.8
Example 10
Enhancement of Mucoadhesion
[0084] The enhancement of mucoadhesion was similarly applicable to
films of varying thickness. The following formulations were
prepared:
11TABLE 10 Composition/Test results Example 1 Example 10a Example
10b Composition of example 1 100% 99.9% 95% Starch graft
copolymer.cndot. 0 0.1% 0 5% Mean Mucoadhesion 17.5 26.6 32.3
measurement (g).cndot..cndot. Standard deviation 7.8 4.7 4.0
Increase in mucoadhesion % base value 525 84.6% .cndot.Starch graft
copolymers were prepared by polymerization in water using 1:3
Amioca corn starch: acrylic acid (supplied by NSCC) and are
described in further detail in U.S. Pat. No. 4,690,996 and Block
and Graft Copolymerization, vol 1, R.J. Ceresa, ed. John Wiley and
Sons 1973 both references herein incorporated by reference.
.cndot..cndot.Mucoadhesion was tested using a tensile instrument
(e.g. Texture Analyzer) which measures force of detachment of the
invention product from a simulated mucosal tissue material. The
mucosal-like material is prepared from a mixture of 3.25% gellan
gum and 1.6% mucin in water. The product to be tested was brought
into contact with the simulated mucosal surface for 5 second and
detached. The force of detachment was measured as the value of
mucoadhesion in # grams force (g or gf). Test conditions used are
follows: speed of application = 3 mm/s, speed of detachment = 2
mm/s, force applied before detachment = 150 g, contact time = 5 s,
contact surface = 122.7 mm.sup.2
Example 11
Preparation of Film Using Dry Extrusion Techniques
[0085] 77.8 g Plyetheylene Oxide (Polyox.RTM. WSR N-10) was mixed
using mechanical force and additional ingredients were added during
the mixing as follows: 5.5 g Estradiol, 3.7 g Peppermint, 3.7 g
Propylene Glycol, 3.0 g Aspartame, 2.6 g Citric Acid, 3.7g Cremphor
EL 40 and 0.05 g Benzoic acid. The temperature was maintained at
about 70.degree. C.
[0086] The blend was allowed to mix at 70.degree. C. until uniform.
It was then forced through an extrusion die to form a film 5 mils
in thickness. The film was then cut into dosage forms ready for
packaging.
Example 12
HUMAN CLINICAL ACUTE IRRITATION STUDY
[0087] An initial clinical irritation study of placebo samples
formulated according to Example 1 was conducted. Six HPMC-based
films were applied by each of 12 subjects within one hour. The site
of application and the oral mucosae were evaluated for any acute
irritation prior to each application, immediately after each
application, one hour and 24 hours after last application. The
following indications: erythema, edema, bullae, maceration and
discharge were scored on a scale of 0-4. There was no measurable
irritation for any of the sites examined and for any of the
indications during each application, or one hour and 24 hours after
the last application.
[0088] Each subject was asked to assess the mouth feel, product
taste, sensation and dissolution time for each application. All
subjects described films gave them very smooth mouth feel and
indicated the taste of freshness the film delivered into the oral
cavity for each application. All subjects felt the dissolution time
of the film was very short (<2 min).
[0089] The majority of the subjects states a preference for the
film compared with tablets or capsules. All of the subjects
indicated that they preferred the film to solutions or syrups.
Example 13
Human Pharmacokinetics Study Showing Increased Bioavailability of
an Active Agent Delivered by a Dosage Unit in the Form of a
Film
[0090] A dissolving film suitable for administration via the oral
mucosa and containing the active agent, sildenafil citrate,
formulated according to Table 7. The properties of the dosage unit
are described in Table 8.
[0091] A two way crossover study was conducted comparing intraoral
sildenafil, applied sublingually, with a commercial table
(Viagra.RTM. at the same dosage. The average plasma levels and the
pharmacokinetics analysis are displayed in FIG. 6 and Table 11.
FIG. 6 and Table 11 show that the bioavailability of the equivalent
dosage from the dissolving film is about 25% higher than the
bioavailability of the table.
12TABLE 11 A comparison of pharmacokinetic parameters of Sildanedil
film and Viagra film Sildanefil (S) Statistical Parameters film
Viagra (V) film Ratio S/V power AUC*(99-t) 365.5 293.1 1.247 0.86
AUC (infinity) 378 310.4 1.218 .088 Cmax 109.9 106.8 1.029 0.15
Tmax 1 1 1 0.08 Ke 0.354 0.285 1.245 0.32 t 1.992.56 0.775 0.775
0.23 *Area under the curve
[0092] The present invention having been disclosed in connection
with the foregoing embodiments, additional embodiments will now be
apparent to persons skilled in the art. The present invention is
not intended to be limited to the embodiments specifically
mentioned, and accordingly reference should be made to the appended
claims rather than the foregoing discussion, to assess the spirit
and scope of the present invention in which exclusive rights are
claimed.
* * * * *