U.S. patent application number 14/022999 was filed with the patent office on 2014-04-17 for mucoadhesive drug delivery devices and methods of making and using thereof.
The applicant listed for this patent is GEL-DEL TECHNOLOGIES, INC.. Invention is credited to Eric P. Berg, David B. Masters.
Application Number | 20140107227 14/022999 |
Document ID | / |
Family ID | 34676802 |
Filed Date | 2014-04-17 |
United States Patent
Application |
20140107227 |
Kind Code |
A1 |
Masters; David B. ; et
al. |
April 17, 2014 |
MUCOADHESIVE DRUG DELIVERY DEVICES AND METHODS OF MAKING AND USING
THEREOF
Abstract
The present invention relates to mucoadhesive drug delivery
devices and their methods of preparation and use. More specifically
the present invention relates to mucoadhesive drug delivery devices
comprising one or more biocompatible purified proteins combined
with one or more biocompatible solvents and one or more
mucoadhesive agents. The mucoadhesive drug delivery devices may
also include one or more pharmacologically active agents. The drug
delivery devices of the present invention adhere to mucosal tissue,
thereby providing a vehicle for delivery of the pharmacologically
active agent(s) through such tissue.
Inventors: |
Masters; David B.;
(Minneapolis, MN) ; Berg; Eric P.; (Plymouth,
MN) |
|
Applicant: |
Name |
City |
State |
Country |
Type |
GEL-DEL TECHNOLOGIES, INC. |
ST. PAUL |
MN |
US |
|
|
Family ID: |
34676802 |
Appl. No.: |
14/022999 |
Filed: |
September 10, 2013 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
|
|
11007053 |
Dec 8, 2004 |
8529939 |
|
|
14022999 |
|
|
|
|
60527962 |
Dec 8, 2003 |
|
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Current U.S.
Class: |
514/775 ;
514/773; 514/776 |
Current CPC
Class: |
A61K 9/006 20130101;
A61K 47/42 20130101; A61K 38/38 20130101; A61K 31/557 20130101;
A61K 38/39 20130101; A61K 9/19 20130101; A61K 47/10 20130101; A61K
38/363 20130101; A61K 38/57 20130101 |
Class at
Publication: |
514/775 ;
514/773; 514/776 |
International
Class: |
A61K 47/42 20060101
A61K047/42 |
Claims
1. A mucoadhesive device, comprising: a solidified cohesive mass or
cohesive body formed from at least one free-form protein, the
solidified cohesive mass or cohesive body including at least one
pharmacologically active agent and at least one mucoadhesion
enhancement agent, wherein the solidified cohesive mass or cohesive
body is formed into a delivery vehicle such that the at least one
free-form protein and the at least one mucoadhesion enhancement
agent is capable of adhering the delivery vehicle to mucosal tissue
for delivering the at least one pharmacologically active agent to
the patient.
2. The mucoadhesive device of claim 1, wherein the cohesive body is
compressed to form the delivery vehicle.
3. The mucoadhesive device of claim 1, wherein the delivery vehicle
comprises a plurality of mucoadhesive particles.
4. The mucoadhesive device of claim 3, wherein the plurality of
mucoadhesive particles are combined with one or more carriers to
define a particle formulation, wherein the muchoadhesive particles
attach to the mucosal tissue.
5. The mucoadhesive device of claim 1, further comprising a
migration-vulnerable drug delivery device including a secondary
pharmacologically active agent, wherein the migration-vulnerable
drug delivery device is maintained at a desired treatment site due
to the adherence of the at least one mucoadhesion enhancement agent
to the mucosal tissue.
6. The mucoadhesive device of claim 1, wherein the delivery vehicle
further comprises at least one biocompatible solvent,
7. The mucoadhesive device of claim 1, wherein the at least one
pharmacologically active agent is homogenously distributed through
the delivery vehicle.
8. The mucoadhesive device of claim 1, wherein the at least one
free-form protein, the at least one pharmacologically active agent
and the at least one mucoadhesion enhancement agent are
homogenously distributed within the delivery vehicle.
9. The mucoadhesive device of claim 1, wherein the at least one
free-form protein has available binding sites.
10. The mucoadhesive device of claim 1, wherein the at least one
free-form protein is present in amount of about 15% to 85% by
weight of the delivery vehicle.
11. The mucoadhesive device of claim 1, wherein the at least one
mucoadhesion enhancement agent is present in amount of about 0.15%
to 35% by weight of the delivery vehicle.
12. The mucoadhesive device of claim 1, wherein the at least one
pharmacologically active agent is present in amount of about
0.00001% to 95% by weight of the delivery vehicle.
13. The mucoadhesive device of claim 1, wherein the delivery
vehicle further comprises at least one biocompatible solvent.
14. The mucoadhesive device of claim 13, wherein the at least one
biocompatible solvent is present in an amount of about 5% to 60% by
weight of the delivery vehicle.
Description
RELATED APPLICATIONS
[0001] This application is a continuation of application Ser. No.
11/007,053 filed Dec. 8, 2004, which claims the benefit of U.S.
Provisional Application No. 60/527,962 filed Dec. 8, 2003 both of
which are hereby fully incorporated herein by reference.
FIELD OF THE INVENTION
[0002] The present invention relates to mucoadhesive drug delivery
devices and their methods of preparation and use. More specifically
the present invention relates to mucoadhesive drug delivery devices
comprising one or more biocompatible purified proteins combined
with one or more biocompatible solvents and one or more
mucoadhesive agents. The mucoadhesive drug delivery devices may
also include one or more pharmacologically active agents. The drug
delivery devices of the present invention adhere to mucosal tissue,
thereby providing a vehicle for delivery of the pharmacologically
active agent(s) through such tissue.
BACKGROUND OF THE INVENTION
[0003] The localized and systemic delivery of pharmacologically
active agents for treatment of body tissues, diseases, and wounds
requires that for proper absorption of the particular
pharmaceutical component, the drug delivery device be maintained at
the site of administration for an effective period of time. Given
the tendency of natural bodily fluids to clear applied
pharmaceutical components from the site of administration, the
administration of drugs to wet mucosal tissues located in body
sites, such as buccal, sublingual, palate, nasal, vaginal, anal,
urethral, stomach, intestinal or pulmonary areas, have been
problematic. For example, in the mouth, saliva, natural replacement
of the mucosal tissue, eating, drinking, and speaking movements are
some of the problems that have limited the effectiveness and
residence time of pharmaceutical carriers.
[0004] Various benefits can be obtained through delivery of
pharmacologically active agents through the mucosal tissue. For
example, mucosal drug delivery is generally noninvasive, thereby
avoiding the uncomfortable aspects of intravenous, intramuscular,
or subcutaneous delivery means. Furthermore, mucosal drug delivery
device attachment protects the pharmacologically active agents from
clearance from the drug absorption site, thereby increasing the
bioavailability of the drug.
[0005] Many theories have been proposed to describe mucoadhesion,
namely electronic theory, adsorption theory, wetting theory,
diffusion theory and fracture theory. Mucoadhesion is believed to
occur in three stages: wetting, interpenetration and mechanical
interlocking between mucin and the mucoadhesive substance.
According to electronic theory, mucoadhesion occurs from the
formation of an electric double layer at the mucoadhesive interface
by the transfer of electrons between the mucoadhesive substance and
the mucin glycoprotein network. Adsorption theory states that
mucoadhesive systems adhere to tissue through secondary molecular
interactions such as van der Waals forces and hydrogen bonding.
Intimate molecular contact is a prerequisite for the development of
strong adhesive bonds, whereby wetting equilibrium and the dynamic
behavior of the bioadhesive substance with the mucus is critical.
The interfacial energetics is responsible for the contact of the
two surfaces and the adhesive strength. Further, diffusion theory
states that interpenetration of the bioadhesive substance and mucus
may lead to sustained mucoadhesion and by mechanical interlocking
between mucin and mucoadhesives. It is noted that additional
explanations for mucoadhesion may also exist.
[0006] Bioadhesive carriers are known in the art and include gels,
pastes, tablets, and films. These products, however, may lack one
or several of the preferred characteristics for an efficient and
commercially acceptable pharmaceutical delivery device. Some
characteristics which are preferred by users of bioadhesive
carriers include controlled water-erodability, ease of handling and
application to the delivery/treatment site, and ease of comfort,
with minimal foreign body sensation. Other preferred
characteristics for an effective and user-friendly product for
administration to mucosal surfaces include the use of
pharmaceutically approved components or materials; instantaneous
adhesion to mucosal surface upon application; and increased
residence time for the protection of the affected tissue or the
delivery of the pharmaceutical component for enhanced
absorption.
[0007] Bioadhesive gels which are used for application to mucosal
tissues and especially the oral cavity are known in the art. For
example, U.S. Pat. No. 5,192,802 describes a bioadhesive teething
gel made from a blend of sodium carboxymethyl cellulose and xantham
gum. The gel may also have potential use in the treatment of canker
sores, fever blisters, and hemorrhoids. However, this type of
pharmaceutical carrier has a very limited residence time, given
that body fluids such as saliva quickly wash it away from the
treatment site. Bioadhesive gels are also described in U.S. Pat.
Nos. 5,314,915; 5,298,258; and 5,642,749. The gels described in
those patents use an aqueous or oily medium and different types of
bioadhesive and gelling agents.
[0008] Denture adhesive pastes are another type of bioadhesive
product known in the art. However, these preparations are used
primarily for their adhesive properties, to adhere dentures to the
gums, rather than for the protection of tissue or for the topical
delivery of pharmaceuticals, although drugs such as local
anesthetics may be used in the paste for the relief of sore gums.
U.S. Pat. Nos. 4,894,232 and 4,518,721 describe denture adhesive
pastes. The '721 patent describes a combination of sodium
carboxymethyl cellulose and polyethylene oxide in polyethylene
glycol.
[0009] Pastes have also been used as film protectants and as drug
delivery systems. One such example having film forming and adhesive
properties is the product commercialized under the name
Orabase.RTM., which is a thick gel or paste for the relief of mouth
sores. Ingredients include guar gum, sodium carboxymethyl
cellulose, tragacanth gum, and pectin. Even though it does provide
numbing to the area of application, the film forming behavior and
bioadhesion do not last. Thus, this product has a limited residence
time.
[0010] Bioadhesive tablets are described in U.S. Pat. No.
4,915,948. The water-soluble bioadhesive material used in this
device is a xanthan gum or a pectin combined with an adhesion
enhancing material such as a polyol. Although residence time is
improved with the use of bioadhesive tablets, they are not user
friendly, especially when used in the oral cavity, given the
unpleasant feelings associated with their solidity, bulkiness, and
slow dissolution time. Bioadhesive tablets are also described in
U.S. Pat. Nos. 4,226,848; 4,292,299; and 4,250,163, and are single
layer or bilayer devices having an average thickness of 0.2 to 2.5
mm. The bioadhesive tablets described in these patents utilize a
non-adhesive component such as cellulose ether, a bioadhesive
component such as polyacrylic acid, sodium carboxymethyl cellulose,
or polyvinylpyrrolidone, and a binder for tableting purposes. The
cellulose derivatives may or may not be water-soluble. The claimed
cellulosic materials in the '299 patent are methyl cellulose,
hydroxypropyl cellulose, and hydroxypropylmethyl cellulose.
[0011] The use of bandages or bioadhesive laminated films, which
are thin and flexible and therefore have a decreased foreign body
sensation, is described in U.S. Pat. Nos. 3,996,934 and 4,286,592.
These products are used to deliver drugs through the skin or
mucous. The laminated films usually include an adhesive layer, a
reservoir layer, and a backing layer. Bioadhesive devices designed
to release drug through the skin at a given rate and over a period
of time are usually not water soluble, and are not dissolved or
washed away by bodily fluids.
[0012] In addition to film systems for the delivery of drug through
the skin, film delivery systems for use on mucosal surfaces are
also known. These types of systems, which are water-insoluble and
usually in the form of laminated, extruded or composite films, are
described in U.S. Pat. Nos. 4,517,173; 4,572,832; 4,713,243;
4,900,554; and 5,137,729. The '173 patent describes and claims a
membrane-adhering film consisting of at least three layers,
including a pharmaceutical layer, a poor water soluble layer, and
an intermediate layer. The pharmaceutical layer includes the drug
and a cellulose derivative selected from hydroxypropyl cellulose,
methyl cellulose, and hydroxypropyl methyl cellulose. The poor
water soluble layer is made by the combination of one or more
cellulose derivatives with a poor water soluble fatty acid, and the
intermediate layer is made of cellulose derivatives. The '832
patent relates to a soft gelatin film for buccal delivery, made by
the combined use of a water soluble protein, a fatty acid ester or
carboxyvinyl polymer, and a polyhydric alcohol such as cellulose
and polysaccharides, and also teaches the use of coloring or
flavoring agents. The '243 patent describes a single or
multi-layered bioadhesive thin film made from 40-95% water soluble
hydroxypropyl cellulose, 5-60% water-insoluble ethylene oxide,
0-10% water-insoluble ethyl cellulose, propyl cellulose,
polyethylene, or polypropylene, and a medicament. The films are
three-layered laminates and include a bioadhesive layer, a
reservoir layer, and a non water-soluble outer protective layer.
The '729 patent teaches a soft adhesive film applicable to the oral
mucosa containing a systemic drug and comprising a mixture of a
vinyl acetate non water-soluble homopolymer, an acrylic acid
polymer, and a cellulose derivative. Finally, the '554 patent
describes a device for use in the oral cavity having an adhesive
layer including a mixture of an acrylic acid polymer, a
water-insoluble cellulose derivative, a pharmaceutical preparation,
and a water-insoluble or sparingly soluble backing layer. The
adhesive layer contains the pharmaceutical, and upon application to
the mucosal surface, delivers the drug. The '554 patent also states
that "it is impossible to achieve an adhesive device for
application to body tissue without all three components, that is,
acrylic acid polymer, water insoluble cellulose derivative and a
water insoluble or sparingly soluble backing layer."
SUMMARY OF THE INVENTION
[0013] The present invention is generally a mucoadhesive drug
delivery device, comprising one or more biocompatible purified
proteins, combined with one or more pharmacologically active
agents, one or more mucoadhesive agents and one or more
biocompatible solvents. The mucoadhesive devices may further
include other additives, such as drug release/diffusion controlling
agents and/or optional mucous tissue penetration enhancers.
[0014] In one embodiment of the present invention it has been found
that mucoadhesive devices including ovalbumin have produced
excellent mucoadhesive results. Such embodiment generally comprise
ovalbumin combined with one or more mucoadhesive agents (e.g.
glycerol), one or more pharmacologically active agents and water.
These embodiments have been shown to provide excellent adhesion
(e.g. strength and contact duration) and have provided excellent
transmucosal delivery of the pharmacologically active agents.
[0015] The mucoadhesive delivery systems of the present invention
are intended to incorporate drugs that may be delivered locally or
systemically. For example, in one embodiment of the present
invention a mucoadhesive device may deliver an anesthetic and/or
analgesic agent to alleviate the pain associated with many oral
mucosal wounds or lesions. The dynamic nature of oral mucosal and
its wide range of variable health and tissue characteristics make
this a challenging endeavor for the medical and dental
community.
[0016] The mucoadhesive devices of the present invention provide a
new drug delivery biomaterial that is formulated into a
mucoadhesive, protein engineered device for transmucosal drug
applications. The mucoadhesive devices of the present invention
including drugs such as demopressin have been found to provide a
controlled systemic release through the oral mucosa. Furthermore,
it has been determined that the delivery of pain relief
medicaments, such as capsaicin, may be locally administered to the
mucosal tissue to alleviate pain caused by wounds and/or
lesions.
[0017] The mucosa is characterized by an outermost layer of
stratified squamous epithelium. Below this layer lies a basement
membrane (lamina propria) followed by the submucosa as the
innermost layer. The oral epithelium is similar to stratified
squamous epithelia found in the rest of the body (e.g., skin) in
that it has a mitotically active basal cell layer, advancing
through a number of differentiating intermediate layers to the
superficial layers, where cells are shed from the surface of the
epithelium. The epithelium of the buccal mucosa is about 40-50 cell
layers thick, while that of the sublingual mucosa is somewhat
thinner. The turnover rate for the buccal epithelium is estimated
to be at 5-6 days, which is representative of the entire oral
mucosa. The mucosae of tissues subject to mechanical stress, that
is the gingiva and hard palate, are keratinized. The mucosa of the
soft palate, the sublingual, and the buccal regions are not
keratinized. The keratinized epithelia contain neutral lipids like
ceramides and acylceramides that serve as a physical barrier, to
make the tissue impermeable to water and microorganisms. In
contrast, the non-keratinized epithelia, such as the floor of the
mouth and the buccal epithelia, do not contain acylceramides and
only trace amounts of ceramide. The non-keratinized epithelia have
been found to be considerably more permeable to water than
keratinized epithelia, thereby enhancing drug absorption.
[0018] The oral mucosa in general is somewhat leaky. It is
estimated that the water permeability of the oral mucosa is 4-4000
times greater than that of the skin. This wide range in
permeability is due to the relative thickness and degree of
keratinization of the mucosal tissues. Among the intra-oral sites,
the sublingual mucosa (i.e., the tissues lining the inner cheek)
are intermediate in permeability. Although there are many factors
that affect permeability of drugs through these barriers, including
basement membrane, the outer epithelium is considered to be the
primary barrier to mucosal penetration.
[0019] The cells of oral epithelia are surrounded by mucus, which
is comprised mainly of proteins and carbohydrates. This mucus
matrix may play a role in cell-cell adhesion, and acts as a barrier
and as a lubricant to allow cells to move relative to one another.
The mucus matrix may also assist in the bioadhesion of mucoadhesive
drug delivery systems. At physiologic pH the mucus network carries
a negative charge, due to sialic acid and sulfate residues, and
forms a strongly cohesive gel structure that binds to the
epithelial cell surface. The mucus comes from the salivary glands
and is secreted as part of the saliva. This water rich environment
is the chief reason that hydrophilic polymeric matrices are
suitable as vehicles for oral the transmucosal mucoadhesive systems
of the present invention. The transmucosal mucoadhesive device of
the present invention is generally hydrophilic and will breakdown
in water when warmed by contact with the mouth in a customized time
frame.
[0020] Additionally, in some embodiments of the present invention,
local and systemic drug delivery through the mucosal tissue has a
number of potential applications, including the treatment of
bacterial, viral and fungal infections, pain and inflammation,
apthous stomatitis, toothaches, periodontal disease and
pain/inflammation caused by dental procedures. In one example, the
buccal mucosa has an expanse of smooth muscle and its mucosa is
relatively immobile compared to sublingual space. Therefore, it can
be used to retain transmucosal drug delivery systems.
Alternatively, the sublingual area and roof of the mouth are also
considered suitable tissue areas for attachment of the mucadhesive
devices of the present invention.
[0021] However, it is again noted that the delivery devices of the
present invention are suitable for administration to any of the
mucosal tissues of the body.
BRIEF DESCRIPTION OF THE FIGURES
[0022] The above mentioned and other advantages of the present
invention, and the manner of attaining them, will become more
apparent and the invention itself will be better understood by
reference to the following description of the embodiments of the
invention taken in conjunction with the accompanying drawing,
wherein:
[0023] FIG. 1 depicts embodiments of mucoadhesive drug delivery
devices of the present invention in wafer and particulate form;
[0024] FIG. 2 depicts a scanning electron microscope (SEM) image of
one embodiment of the mucoadhesive particles of the present
invention at 400.times. magnification;
[0025] FIG. 3 depicts a scanning electron microscope (SEM) image of
one embodiment of the mucoadhesive particles of the present
invention at 10,000.times. magnification;
[0026] FIG. 4 depicts a scanning electron microscope (SEM) image of
the albumin starting material used in one embodiment of the
mucoadhesive particles of the present invention at 400.times.
magnification;
[0027] FIG. 5 depicts a scanning electron microscope (SEM) image of
the albumin starting material used in one embodiment of the
mucoadhesive particles of the present invention at 10,000.times.
magnification.
DETAILED DESCRIPTION OF THE INVENTION
[0028] Many embodiments of the mucoadhesive drug delivery devices
of the present invention possess some general physiochemical
features such as predominantly anionic hydrophilicity with numerous
hydrogen bond-forming groups, suitable surface property for wetting
mucus/mucosal tissue surfaces and sufficient flexibility to
penetrate the mucus network or tissue crevices. Based on the
previously mentioned mucoadhesion theories, it may be concluded
that the most efficient mucoadhesive drug delivery devices have
physicochemical properties that are closely related to those of the
mucus substrate. Therefore, the utilization of mucoadhesive
proteins, biocompatible solvents and mucoadhesive agents as found
in the devices of the present invention provide optimum properties
that closely mimic the mucus substrate.
[0029] The mucoadhesive devices generally include one or more
purified mucoadhesive biocompatible proteins combined with one or
more biocompatible solvents, and one or more mucoadhesive agents.
In various embodiments of the present invention the mucoadhesive
drug delivery devices also include one or more pharmacologically
active agents. It is noted that additional additive materials, such
as biocompatible polymers like polyanhydride, polylactic acid,
polyurethane and the like, and/or other therapeutic entities may be
included in the mucoadhesive devices to provide various beneficial
features such as noninvasive characteristics, drug release control,
patient compliance, ease of use and/or enhanced biocompatibility
and drug bioavailability. Generally, the mucoadhesive devices of
the present invention include a homogenous distribution of the
protein, solvent, mucoadhesive agents and other additives, as well
as the homogenous distribution of the pharmacologically active
agents.
[0030] The purified mucoadhesive proteins may be natural proteins
or they may be synthetic or genetically engineered or any
combination thereof. In many embodiments of the present invention,
the devices include water-absorbing, mucoadhesive proteins. Such
water absorbing proteins have an additional affinity to adhere to
mucosal tissue thereby providing sufficient time to deliver any
pharmacologically active agent included in the device. This differs
from other protein devices, such as gelatins, since gelatins
require a substantial amount of water, thereby making them more
lubricious and reducing their mucoadhesive potential.
[0031] Additionally, the proteins of the present invention are
generally purified and in a free-form state. Normally, free-form
proteins are comprised of protein molecules that are not
substantially crosslinked to other protein molecules, unlike
tissues or gelatins. Normally, tissue or gelatin is already in a
crosslinked matrix form and is thereby limited in forming new
intermolecular or intramolecular bonds. Therefore, the purified
free-form protein molecules when added to solvent have the capacity
to freely associate or intermingle with each other and other
molecules or particles, such as solvents, mucoadhesive agents or
pharmacologically active agents to form a homogeneous structure.
Therefore, the resulting mucoadhesive devices of the present
invention include a homogenous distribution of the purified
proteins, pharmacologically active agents, mucoadhesive agents,
biocompatible solvents and other ingredients. Generally, a
homogeneous distribution pertains to the uniform stochiometric
intermingling of all types of molecules making up the matrix of the
mucoadhesive devices. Additionally, the binding sites of the
purified free-form proteins for the attraction and retention of
solvent, drug, protein or other molecules are generally available
for binding whereas proteins derived from tissues and gelatins have
generally lost some or most of their binding capability.
[0032] As previously suggested, the mucoadhesive protein utilized
may either be naturally occurring, synthetic or genetically
engineered and in various embodiments of the present invention are
soluble in an aqueous environment. A preferred embodiment of the
present invention includes soluble naturally occurring purified
protein. Examples of mucoadhesive proteins that may be used in the
mucoadhesive drug delivery devices of the present invention
include, but are not limited to proteins derived from animal (e.g.
mammal, fish, birds . . . ) tissues such as elastin and collagen,
or fluids such as serum albumin, fibrinogen and thrombin; animal
byproduct proteins, such as egg white proteins (e.g. ovalbumin,
plakalbumin . . . ), milk proteins (e.g. casein, lactalbumin,
lactoglobulin . . . ); prealbumin, glutamine oligopeptide, keratin,
fibronectin, silk, silk fibroin, actin, myosin, fibrinogen,
thrombin, aprotinin, antithrombin III and any other biocompatible
natural protein. Additionally, plant proteins, such as whey protein
(e.g. betalactoglobulin and alphlactalbumin), rice protein, grape
vine protein, grape leaf protein, maize protein, olive protein,
canola protein, soy protein, cottonseed protein, cotton leaf
protein, seaweed protein, wheat protein (e.g. agglutinen) tobacco
proteins (e.g. tobacco leaf, root and stem proteins such as F1 and
F2 protein), and chickpea protein.
[0033] Preferred mucoadhesive proteins found to have enhanced
mucoadhesive properties when included in the mucoadhesive devices
of the present invention are egg white proteins such as ovalbumin,
and plant proteins such as soy proteins, whey protein (e.g.
betalactoglobulin and alphlactalbumin), rice protein, grape vine
protein, grape leaf protein, maize protein, olive protein, canola
protein, cottonseed protein, cotton leaf protein, seaweed protein,
wheat protein such as agglutinin, tobacco proteins (leaf, root,
stem) such as F1 and F2 protein, chickpea protein and fish protein.
One type of protein that has produced exemplary results in
embodiments of the present invention has been egg albumen (e.g.
ovalbumin). Examples of other proteins that are commercially
available and may be utilized in some embodiments of the present
invention include Type I soluble collagen, soluble elastin, and
soluble albumin manufactured by Kensey Nash Corporation, 55 East
Uwchlan Avenue, Exton, Pa. 19341, Sigma-Aldrich Corporation, St.
Louis, Mo., USA or Elastin Products Company, Inc., P.O. Box 568,
Owensville, Mo., USA 65066. It is noted that combinations of
natural proteins may be utilized to optimize desirable
characteristics of the resulting mucoadhesive delivery devices,
such as mucoadhesive enhancement, strength, degradability, drug
resorption, etc.
[0034] As previously suggested the proteins of the present
invention are generally purified proteins. The purity of each
natural protein component mixed in the coatable composition phase
(the coatable composition will be described further below) during
production of particles include 20% or less other proteins or
impurities, preferably 10% or less other proteins or impurities,
more preferably 3% or less other proteins or impurities and if
available ideally 1% or less other proteins or impurities.
[0035] Other proteins that may be utilized in the mucoadhesive
devices of the present invention, such as synthetic proteins, are
generally prepared by chemical synthesis utilizing techniques known
in the art. Also, individual proteins may be chemically combined
with one or more other proteins of the same or different type to
produce a dimer, trimer or other multimer or fragmented to produce
protein fragments or parts. A simple advantage of having a larger
protein molecule is that it will make interconnections with other
protein molecules to create a stronger delivery device that is less
susceptible to dissolving when implanted, injected, attached or
administered upon the mucous membrane and provides additional
protein structural and biochemical characteristics.
[0036] Additional, protein molecules can also be chemically
combined to any other chemical so that the chemical does not
release from the mucoadhesive proteins. In this way, the chemical
entity can provide surface modifications to the mucoadhesive device
or structural contributions to the device to produce specific
characteristics. The surface modifications can enhance and/or
facilitate mucosal attachment depending on the chemical substance.
The structural modifications can be used to facilitate or impede
dissolution, enzymatic degradation or dissolution of the
mucoadhesive delivery device.
[0037] Synthetic mucoadhesive proteins may be cross-linked, linked,
bonded, chemically and/or physically linked to pharmacological
active agents, enzymatically, chemically or thermally cleaved and
utilized alone or in combination with other proteins partial
proteins (e.g. peptides), lipids, carbohydrates and/or drugs, to
form the mucoadhesive proteins. Examples of such synthetic
mucoadhesive proteins include, but are not limited to
heparin-protein, chondroitin-protein, GAGs-collagen,
heparin-collagen, collagen-elastin-heparin, collagen-albumin,
collagen-albumin-heparin, albumin-polyethylene glycol,
collagen-albumin-elastin-heparin, collagen-hyaluronic acid,
collagen-chondroitin-heparin, collagen-chondroitin,
albumin-lethecin, albumin-cellulose, albumin-casein, albumin-soy
protein, albumin-wheat protein, albumin-retinol and the like.
[0038] Finally, genetically engineered proteins may be utilized in
the mucoadhesive devices of the present invention. A specific
example of a particularly preferred genetically engineered protein
for use in the devices of the present invention is human collagen
produced by FibroGen, Inc., 225 Gateway Blvd., South San Francisco,
Calif. 94080. Other examples of particularly preferred genetically
engineered proteins for use in the mucoadhesive devices of the
present invention are commercially available under the nomenclature
"ELP", "SLP", "CLP", "SLPL", "SLPF" and "SELP" from Protein Polymer
Technologies, Inc. San Diego, Calif. ELP's, SLP's, CLP's, SLPL's,
SLPF's and SELP's are families of genetically engineered protein
polymers consisting of silklike blocks, elastinlike blocks,
collagenlike blocks, lamininlike blocks, fibronectinlike blocks and
the combination of silklike and elastinlike blocks, respectively.
The ELP's, SLP's, CLP's, SLPL's, SLPF's and SELP's are produced in
various block lengths and compositional ratios. Generally, blocks
include groups of repeating amino acids making up a peptide
sequence that occurs in a protein. Genetically engineered proteins
are qualitatively distinguished from sequential polypeptides found
in nature in that the length of their block repeats can be greater
(up to several hundred amino acids versus less than ten for
sequential polypeptides) and the sequence of their block repeats
can be almost infinitely complex. Table A depicts examples of
genetically engineered blocks. Table A and a further description of
genetically engineered blocks may be found in Franco A. Ferrari and
Joseph Cappello, Biosynthesis of Protein Polymers, in:
Protein-Based Materials, (eds., Kevin McGrath and David Kaplan),
Chapter 2, pp. 37-60, Birkhauser, Boston (1997).
TABLE-US-00001 TABLE A Protein polymer sequences Polymer Name
Monomer Amino Acid Sequence SLP 3 [(GAGAGS).sub.9 GAAGY)] SLP 4
(GAGAGS).sub.n SLP F [(GAGAGS).sub.9 GAA VTGRGDSPAS AAGY].sub.n SLP
L3.0 [(GAGAGS).sub.9 GAA PGASIKVAVSAGPS AGY].sub.n SLP L3.1
[(GAGAGS).sub.9 GAA PGASIKVAVSGPS AGY].sub.n SLP F9 [(GAGAGS).sub.9
RYVVLPRPVCFEK AAGY].sub.n ELP I [(VPGVG)].sub.n SELP 0
[(GVGVP).sub.8 (GAGAGS).sub.2].sub.n SELP 1 [GAA (VPGVG).sub.4
VAAGY (GAGAGS.sub.9].sub.n SELP 2 [(GAGAGS).sub.6 GAAGY
(GAGAGS).sub.5 (GVGVP).sub.8].sub.n SELP 3 [(GVGVP).sub.8
(GAGAGS).sub.8].sub.n SELP 4 [(GVGVP).sub.12 (GAGAGS).sub.8].sub.n
SELP 5 [(GVGVP).sub.16 (GAGAGS).sub.8].sub.n SELP 6 [(GVGVP).sub.32
(GAGAGS).sub.8].sub.n SELP 7 [(GVGVP).sub.8 (GAGAGS).sub.6].sub.n
SELP 8 [(GVGVP).sub.8 (GAGAGS).sub.4].sub.n KLP 1.2
[(AKLKLAEAKLELAE).sub.4].sub.n CLP 1 [GAP(GPP).sub.4].sub.n CLP 2
{[GAP(GPP).sub.4].sub.2 GPAGPVGSP}.sub.n CLP-CB
{[GAP(GPP).sub.4].sub.2 (GLPGPKGDRGDAGPKGADGSPGPA) GPAGPVGSP}.sub.n
CLP 3 (GAPGAPGSQGAPGLQ).sub.n Repetitive amino acid sequences of
selected protein polymers. SLP = silk like protein; SLPF = SLP
containing the RGD sequence from fibronectin; SLPL 3/0 and SLPL 3/1
= SLP containing two difference sequences from laminin protein; ELP
= elastin like protein; SELP = silk elastin like protein; CLP =
collagen like protein; CLP-CB = CLP containing a cell binding
domain from human collagen; KLP = keratin like protein
[0039] The nature of the elastinlike blocks, and their length and
position within the monomers influences the water solubility of the
SELP polymers. For example, decreasing the length and/or content of
the silklike block domains, while maintaining the length of the
elastinlike block domains, increases the water solubility of the
polymers. For a more detailed discussion of the production of
SLP's, ELP's, CLP's, SLPF's and SELP's as well as their properties
and characteristics see, for example, in J. Cappello et al.,
Biotechnol. Prog., 6, 198 (1990), the full disclosure of which is
incorporated by reference herein. One preferred SELP, SELP7, has an
elastin:silk ratio of 1.33, and has 45% silklike protein material
and is believed to have weight average molecular weight of
80,338.
[0040] Generally, the amount of purified protein found in
embodiments of the mucoadhesive devices of the present invention
may vary between from about 15% to about 85%, preferably from about
20% to 80% by weight, and most preferably from about 50% to 70% by
weight based upon the weight of the final particles. As used
herein, unless stated otherwise, all percentages are percentages
based upon the total mass of the composition or devices being
described, e.g., 100% is total.
[0041] The mucoadhesive delivery devices utilized in various
embodiments of the present invention also include one or more
biocompatible solvents. By using a biocompatible solvent, the risk
of adverse tissue reactions to the solvent is minimized.
Additionally, the use of a biocompatible solvent reduces the
potential structural and/or pharmacological degradation of the
pharmacologically active agent that some such pharmacologically
active agents undergo when exposed to organic solvents. Suitable
biocompatible solvents for use in the method of the present
invention include, but are not limited to, water; saline; dimethyl
sulfoxide (DMSO); biocompatible alcohols, such as methanol and
ethanol; various acids, such as formic acid; oils, such as olive
oil, peanut oil and the like; and combinations of these and the
like. Preferably, the biocompatible solvent comprises water.
Generally, the amount of biocompatible solvent suitable to wet and
or dissolve the protein components for use in the method of the
present invention will range from about 50% to about 10000%,
preferably from about 100% to about 5000% and more preferably from
about 200% to about 1000% by weight, based upon the weight and/or
amount of the protein.
[0042] As used herein, unless stated otherwise, all percentages are
percentages based upon the weight of the identified final form.
[0043] Additionally, a mucoadhesive agent, such as humectants, may
be utilized in the devices of the present invention to make the
matrix more water absorbing thereby enhancing mucoadhesion.
Generally, the mucoadhesive agents possess humectant properties
being that they are substances that promote the retention of
moisture. Examples of mucoadhesive agents include but are not
limited to glycerin, pectin, polyethylene glycol, sorbitol,
maltitol, mannitol, hydrogenated glucose syrups, xylitol,
polydextrose, glyceryl triacetate, propylene glycol, propylene
glycol alginate, sodium alginate, castor oil and some
polysaccharides such as glycogen. Generally, the amount of
mucoadhesive agents used in the method of the present invention
will range from about 0.1% to about 35%, preferably from about 5%
to about 30% and more preferably from about 10% to about 25% by
weight, based upon the weight of the mucoadhesive device.
[0044] In addition, the mucoadhesive drug delivery devices of the
present invention may include one or more pharmacologically active
agents. As used herein, "pharmacologically active agent" generally
refers to a pharmacologically active agent having a direct or
indirect beneficial therapeutic effect upon introduction into a
host. Pharmacologically active agents further includes
neutraceuticals. The phrase "pharmacologically active agent" is
also meant to indicate prodrug forms thereof. A "prodrug form" of a
pharmacologically active agent means a structurally related
compound or derivative of the pharmacologically active agent which,
when administered to a host is converted into the desired
pharmacologically active agent. A prodrug form may have little or
none of the desired pharmacological activity exhibited by the
pharmacologically active agent to which it is converted.
Representative examples of pharmacologically active agents that may
be suitable for use in the mucoadhesive devices of the present
invention include, but are not limited to, (grouped by therapeutic
class):
[0045] Antidiarrheals such as diphenoxylate, loperamide and
hyoscyamine;
[0046] Antihypertensives such as hydralazine, minoxidil, captopril,
enalapril, clonidine, prazosin, debrisoquine, diazoxide,
guanethidine, methyldopa, reserpine, trimethaphan;
[0047] Calcium channel blockers such as diltiazem, felodipine,
amlodipine, nitrendipine, nifedipine and verapamil;
[0048] Antiarrhyrthmics such as amiodarone, flecainide,
disopyramide, procainamide, mexiletene and quinidine,
[0049] Antiangina agents such as glyceryl trinitrate, erythrityl
tetranitrate, pentaerythritol tetranitrate, mannitol hexanitrate,
perhexilene, isosorbide dinitrate and nicorandil;
[0050] Beta-adrenergic blocking agents such as alprenolol,
atenolol, bupranolol, carteolol, labetalol, metoprolol, nadolol,
nadoxolol, oxprenolol, pindolol, propranolol, sotalol, timolol and
timolol maleate;
[0051] Cardiotonic glycosides such as digoxin and other cardiac
glycosides and theophylline derivatives;
[0052] Adrenergic stimulants such as adrenaline, ephedrine,
fenoterol, isoprenaline, orciprenaline, rimeterol, salbutamol,
salmeterol, terbutaline, dobutamine, phenylephrine,
phenylpropanolamine, pseudoephedrine and dopamine;
[0053] Vasodilators such as cyclandelate, isoxsuprine, papaverine,
dipyrimadole, isosorbide dinitrate, phentolamine, nicotinyl
alcohol, co-dergocrine, nicotinic acid, glycerl trinitrate,
pentaerythritol tetranitrate and xanthinol;
[0054] Antiproliferative agents such as paclitaxel, estradiol,
actinomycin D, sirolimus, tacrolimus, everolimus and
dexamethasone;
[0055] Antimigraine preparations such as ergotanmine,
dihydroergotamine, methysergide, pizotifen and sumatriptan;
[0056] Anticoagulants and thrombolytic agents such as warfarin,
dicoumarol, low molecular weight heparins such as enoxaparin,
streptokinase and its active derivatives;
[0057] Hemostatic agents such as aprotinin, tranexamic acid and
protamine;
[0058] Analgesics and antipyretics including the opioid analgesics
such as buprenorphine, dextromoramide, dextropropoxyphene,
fentanyl, alfentanil, sufentanil, hydromorphone, methadone,
morphine, oxycodone, papaveretum, pentazocine, pethidine,
phenopefidine, codeine dihydrocodeine; acetylsalicylic acid
(aspirin), paracetamol, and phenazone;
[0059] Immunosuppressants, antiproliferatives and cytostatic agents
such as rapamycin (sirolimus) and its analogs (everolimus and
tacrolimus);
[0060] Neurotoxins such as capsaicin, botulinum toxin (botox);
[0061] Hypnotics and sedatives such as the barbiturates
amylobarbitone, butobarbitone and pentobarbitone and other
hypnotics and sedatives such as chloral hydrate, chlormethiazole,
hydroxyzine and meprobamate;
[0062] Antianxiety agents such as the benzodiazepines alprazolam,
bromazepam, chlordiazepoxide, clobazam, chlorazepate, diazepam,
flunitrazepam, flurazepam, lorazepam, nitrazepam, oxazepam,
temazepam and triazolam;
[0063] Neuroleptic and antipsychotic drugs such as the
phenothiazines, chlorpromazine, fluphenazine, pericyazine,
perphenazine, promazine, thiopropazate, thioridazine,
trifluoperazine; and butyrophenone, droperidol and haloperidol; and
other antipsychotic drugs such as pimozide, thiothixene and
lithium;
[0064] Antidepressants such as the tricyclic antidepressants
amitryptyline, clomipramine, desipramine, dothiepin, doxepin,
imipramine, nortriptyline, opipramol, protriptyline and
trimipramine and the tetracyclic antidepressants such as mianserin
and the monoamine oxidase inhibitors such as isocarboxazid,
phenelizine, tranylcypromine and moclobemide and selective
serotonin re-uptake inhibitors such as fluoxetine, paroxetine,
citalopram, fluvoxamine and sertraline;
[0065] CNS stimulants such as caffeine and 3-(2-aminobutyl)
indole;
[0066] Anti-alzheimer's agents such as tacrine;
[0067] Anti-Parkinson's agents such as amantadine, benserazide,
carbidopa, levodopa, benztropine, biperiden, benzhexol,
procyclidine and dopamine-2 agonists such as
S(-)-2-(N-propyl-N-2-thienylethylamino)-5-hydroxytetral-in
(N-0923),
[0068] Anticonvulsants such as phenytoin, valproic acid, primidone,
phenobarbitone, methylphenobarbitone and carbamazepine,
ethosuximide, methsuximide, phensuximide, sulthiame and
clonazepam,
[0069] Antiemetics and antinauseants such as the phenothiazines
prochloperazine, thiethylperazine and 5HT-3 receptor antagonists
such as ondansetron and granisetron, as well as dimenhydrinate,
diphenhydramine, metoclopramide, domperidone, hyoscine, hyoscine
hydrobromide, hyoscine hydrochloride, clebopride and brompride;
[0070] Non-steroidal anti-inflammatory agents including their
racemic mixtures or individual enantiomers where applicable,
preferably which can be formulated in combination with dermal
and/or mucosal penetration enhancers, such as ibuprofen,
flurbiprofen, ketoprofen, aclofenac, diclofenac, aloxiprin,
aproxen, aspirin, diflunisal, fenoprofen, indomethacin, mefenamic
acid, naproxen, phenylbutazone, piroxicam, salicylamide, salicylic
acid, sulindac, desoxysulindac, tenoxicam, tramadol, ketoralac,
flufenisal, salsalate, triethanolamine salicylate, aminopyrine,
antipyrine, oxyphenbutazone, apazone, cintazone, flufenamic acid,
clonixerl, clonixin, meclofenamic acid, flunixin, coichicine,
demecolcine, allopurinol, oxypurinol, benzydamine hydrochloride,
dimefadane, indoxole, intrazole, mimbane hydrochloride, paranylene
hydrochloride, tetrydamine, benzindopyrine hydrochloride,
fluprofen, ibufenac, naproxol, fenbufen, cinchophen, diflumidone
sodium, fenamole, flutiazin, metazamide, letimide hydrochloride,
nexeridine hydrochloride, octazamide, molinazole, neocinchophen,
nimazole, proxazole citrate, tesicam, tesimide, tolmetin, and
triflumidate;
[0071] Antirheumatoid agents such as penicillamine,
aurothioglucose, sodium aurothiomalate, methotrexate and
auranofin;
[0072] Muscle relaxants such as baclofen, diazepam, cyclobenzaprine
hydrochloride, dantrolene, methocarbamol, orphenadrine and
quinine;
[0073] Agents used in gout and hyperuricaemia such as allopurinol,
colchicine, probenecid and sulphinpyrazone;
[0074] Oestrogens such as oestradiol, oestriol, oestrone,
ethinyloestradiol, mestranol, stilboestrol, dienoestrol,
epioestriol, estropipate and zeranol;
[0075] Progesterone and other progestagens such as allyloestrenol,
dydrgesterone, lynoestrenol, norgestrel, norethyndrel,
norethisterone, norethisterone acetate, gestodene, levonorgestrel,
medroxyprogesterone and megestrol;
[0076] Antiandrogens such as cyproterone acetate and danazol;
[0077] Antioestrogens such as tamoxifen and epitiostanol and the
aromatase inhibitors, exemestane and 4-hydroxy-androstenedione and
its derivatives;
[0078] Androgens and anabolic agents such as testosterone,
methyltestosterone, clostebol acetate, drostanolone, furazabol,
nandrolone oxandrolone, stanozolol, trenbolone acetate,
dihydro-testosterone, 17-(.alpha.-methyl-19-noriestosterone and
fluoxymesterone;
[0079] 5-alpha reductase inhibitors such as finasteride,
turosteride, LY-191704 and MK-306;
[0080] Corticosteroids such as betamethasone, betamethasone
valerate, cortisone, dexamethasone, dexamethasone 21-phosphate,
fludrocortisone, flumethasone, fluocinonide, fluocinonide desonide,
fluocinolone, fluocinolone acetonide, fluocortolone, halcinonide,
halopredone, hydrocortisone, hydrocortisone 17-valerate,
hydrocortisone 17-butyrate, hydrocortisone 21-acetate,
methylprednisolone, prednisolone, prednisolone 21-phosphate,
prednisone, triamcinolone, triamcinolone acetonide;
[0081] Glycosylated proteins, proteoglycans, glycosaminoglycans
such as chondroitin sulfate; chitin, acetyl-glucosamine, hyaluronic
acid;
[0082] Complex carbohydrates such as glucans;
[0083] Further examples of steroidal anti-inflammatory agents such
as cortodoxone, fludroracetonide, fludrocortisone, difluorsone
diacetate, flurandrenolone acetonide, medrysone, amcinafel,
amcinafide, betamethasone and its other esters, chloroprednisone,
clorcortelone, descinolone, desonide, dichlorisone, difluprednate,
flucloronide, flumethasone, flunisolide, flucortolone,
fluoromethalone, fluperolone, fluprednisolone, meprednisone,
methylmeprednisolone, paramethasone, cortisone acetate,
hydrocortisone cyclopentylpropionate, cortodoxone, flucetonide,
fludrocortisone acetate, flurandrenolone, aincinafal, amcinafide,
betamethasone, betamethasone benzoate, chloroprednisone acetate,
clocortolone acetate, descinolone acetonide, desoximetasone,
dichlorisone acetate, difluprednate, flucloronide, flumethasone
pivalate, flunisolide acetate, fluperolone acetate, fluprednisolone
valerate, paramethasone acetate, prednisolamate, prednival,
triamcinolone hexacetonide, cortivazol, formocortal and
nivazol;
[0084] Pituitary hormones and their active derivatives or analogs
such as corticotrophin, thyrotropin, follicle stimulating hormone
(FSH), luteinising hormone (LH) and gonadotrophin releasing hormone
(GnRH);
[0085] Hypoglycemic agents such as insulin, chlorpropamide,
glibenclamide, gliclazide, glipizide, tolazamide, tolbutamide and
metformin;
[0086] Thyroid hormones such as calcitonin, thyroxine and
liothyronine and antithyroid agents such as carbimazole and
propylthiouracil;
[0087] Other miscellaneous hormone agents such as octreotide;
[0088] Pituitary inhibitors such as bromocriptine;
[0089] Ovulation inducers such as clomiphene;
[0090] Diuretics such as the thiazides, related diuretics and loop
diuretics, bendrofluazide, chlorothiazide, chlorthalidone,
dopamine, cyclopenthiazide, hydrochlorothiazide, indapamide,
mefruside, methycholthiazide, metolazone, quinethazone, bumetanide,
ethacrynic acid and frusemide and potasium sparing diuretics,
spironolactone, amiloride and triamterene;
[0091] Antidiuretics such as desmopressin, lypressin and
vasopressin including their active derivatives or analogs;
[0092] Obstetric drugs including agents acting on the uterus such
as ergometrine, oxytocin and gemeprost;
[0093] Prostaglandins such as alprostadil (PGE1), prostacyclin
(PGI2), dinoprost (prostaglandin F2-alpha) and misoprostol;
[0094] Antimicrobials including the cephalosporins such as
cephalexin, cefoxytin and cephalothin;
[0095] Penicillins such as amoxycillin, amoxycillin with clavulanic
acid, ampicillin, bacampicillin, benzathine penicillin,
benzylpenicillin, carbenicillin, cloxacillin, methicillin,
phenethicillin, phenoxymethylpenicillin, flucloxacillin,
meziocillin, piperacillin, ticarcillin and azlocillin;
[0096] Tetracyclines such as minocycline, chlortetracycline,
tetracycline, demeclocycline, doxycycline, methacycline and
oxytetracycline and other tetracycline-type antibiotics;
[0097] Amnioglycoides such as amikacin, gentamicin, kanamycin,
neomycin, netilmicin and tobramycin;
[0098] Antifungals such as amorolfine, isoconazole, clotrimazole,
econazole, miconazole, nystatin, terbinafine, bifonazole,
amphotericin, griseofulvin, ketoconazole, fluconazole and
flucytosine, salicylic acid, fezatione, ticlatone, tolnaftate,
triacetin, zinc, pyrithione and sodium pyrithione;
[0099] Quinolones such as nalidixic acid, cinoxacin, ciprofloxacin,
enoxacin and norfloxacin;
[0100] Sulphonamides such as phthalysulphthiazole, sulfadoxine,
sulphadiazine, sulphamethizole and sulphamethoxazole;
[0101] Sulphones such as dapsone;
[0102] Other miscellaneous antibiotics such as chloramphenicol,
clindamycin, erythromycin, erythromycin ethyl carbonate,
erythromycin estolate, erythromycin glucepate, erythromycin
ethylsuccinate, erythromycin lactobionate, roxithromycin,
lincomycin, natamycin, nitrofurantoin, spectinomycin, vancomycin,
aztreonam, colistin IV, metronidazole, tinidazole, fusidic acid,
trimethoprim, and 2-thiopyridine N-oxide; halogen compounds,
particularly iodine and iodine compounds such as iodine-PVP complex
and diiodohydroxyquin, hexachlorophene; chlorhexidine; chloroamine
compounds;
[0103] and benzoylperoxide;
[0104] Antituberculosis drugs such as ethambutol, isoniazid,
pyrazinamide, rifampicin and clofazimine;
[0105] Antimalarials such as primaquine, pyrimethamine,
chloroquine, hydroxychloroquine, quinine, mefloquine and
halofantrine;
[0106] Antiviral agents such as acyclovir and acyclovir prodrugs,
famcyclovir, zidovudine, didanosine, stavudine, lamivudine,
zalcitabine, saquinavir, indinavir, ritonavir, n-docosanol,
tromantadine and idoxuridine;
[0107] Anthelmintics such as mebendazole, thiabendazole,
niclosamide, praziquantel, pyrantel embonate and
diethylcarbamazine;
[0108] Cytotoxic agents such as plicamycin, cyclophosphamide,
dacarbazine, fluorouracil and its prodrugs (described, for example,
in International Journal of Pharmaceutics, 111, 223-233 (1994)),
methotrexate, procarbazine, 6-mercaptopurine and mucophenolic
acid;
[0109] Anorectic and weight reducing agents including
dexfenflurarnine, fenfluramine, diethylpropion, mazindol and
phentermine;
[0110] Agents used in hypercalcaemia such as calcitriol,
dihydrotachysterol and their active derivatives or analogs;
[0111] Antitussives such as ethylmorphine, dextromethorphan and
pholcodine;
[0112] Expectorants such as carbolcysteine, bromihexine, emetine,
quanifesin, ipecacuanha and saponins;
[0113] Decongestants such as phenylephrine, phenylpropanolamine and
pseudoephedrine;
[0114] Bronchospasm relaxants such as ephedrine, fenoterol,
orciprenaline, rimiterol, salbutamol, sodium cromoglycate,
cromoglycic acid and its prodrugs (described, for example, in
International Journal of Pharmaceutics 7, 63-75 (1980)),
terbutaline, ipratropium bromide, salmeterol and theophylline and
theophylline derivatives;
[0115] Antihistamines such as meclozine, cyclizine, chlorcyclizine,
hydroxyzine, brompheniramine, chlorpheniramine, clemastine,
cyproheptadine, dexchlorpheniramine, diphenhydramine,
diphenylamine, doxylamine, mebhydrolin, pheniramine, tripolidine,
azatadine, diphenylpyraline, methdilazine, terfenadine, astemizole,
loratidine and cetirizine;
[0116] Local anaesthetics such as benzocaine, bupivacaine,
amethocaine, lignocaine, lidocaine, cocaine, cinchocaine,
dibucaine, mepivacaine, prilocaine, etidocaine, veratridine
(specific c-fiber blocker) and procaine;
[0117] Stratum corneum lipids, such as ceramides, cholesterol and
free fatty acids, for improved skin barrier repair [Man, et al. J.
Invest. Dermatol., 106(5), 1096, (1996)];
[0118] Neuromuscular blocking agents such as suxamethonium,
alcuronium, pancuronium, atracurium, gallamine, tubocurarine and
vecuronium;
[0119] Smoking cessation agents such as nicotine, bupropion and
ibogaine;
[0120] Insecticides and other pesticides which are suitable for
local application;
[0121] Dermatological agents, such as vitamins A, C, B1, B2, B6, B
12, B 12.alpha., and E, vitamin E acetate and vitamin E
sorbate;
[0122] Allergens for desensitisation such as house, dust or mite
allergens;
[0123] Nutritional agents and neutraceuticals, such as vitamins,
essential amino acids and fats;
[0124] Macromolecular pharmacologically active agents such as
proteins, enzymes, peptides, polysaccharides (such as cellulose,
amylose, dextran, chitin), nucleic acids, cells, tissues, and the
like;
[0125] Bone mending biochemicals such as calcium carbonate, calcium
phosphate, hydroxyapetite or bone morphogenic protein (BMP);
[0126] Angiogenic growth factors such as Vascular Endothelial
Growth Factor (VEGF) and epidermal growth factor (EFG), cytokines
interleukins, fibroblasts and cytotaxic chemicals; and
[0127] Keratolytics such as the alpha-hydroxy acids, glycolic acid
and salicylic acid; and
[0128] DNA, RNA or other oligonucleotides.
[0129] Additionally, the mucoadhesive drug delivery devices of the
present invention are particularly advantageous for the
encapsulation, incorporation and/or scaffolding of macromolecular
pharmacologically active agents such as proteins, enzymes,
peptides, polysaccharides, nucleic acids, cells, tissues, and the
like. Immobilization of macromolecular pharmacologically active
agents into or onto a device can be difficult due to the ease with
which some of these macromolecular agents denature when exposed to
organic solvents, constituents present in bodily fluids or to
temperatures appreciably higher than room temperature. However,
since the method of the present invention utilizes biocompatible
solvents such as water, saline, DMSO or ethanol the risk of the
denaturation of these types of materials is reduced. Furthermore,
due to the size of these macromolecular pharmacologically active
agents, these agents may be encapsulated within the devices of the
present invention and thereby are protected from constituents of
bodily fluids that would otherwise denature them. Thus, the devices
of the present invention allow these macromolecular agents to exert
their therapeutic effects, while yet protecting them from
denaturation or other structural degradation.
[0130] Examples of proteins and/or polypeptides which can be
incorporated into the mucoadhesive devices of the present invention
include, but are not limited to, hemoglobin, vasporessin, oxytocin,
endorphin, lutein, lutenizing hormone, estrogen, testosterone,
adrenocorticocotrophic hormone, epidermal growth factor, prolactin,
luliberin or luteinising hormone releasing factor, human growth
factor, and the like; enzymes such as adenosine deaminase,
superoxide dismutase, xanthine oxidase, and the like; enzyme
systems; blood clotting factors; clot inhibitors or clot dissolving
agents such as streptokinase and tissue plasminogen activator;
antigens for immunization; hormones (e.g. steroid, polypeptide . .
. ); polysaccharides such as heparin; oligonucleotides; bacteria
and other microbial microorganisms including viruses; monoclonal
antibodies, such as herceptin and rituximab; vitamins; cofactors;
growth factors; retroviruses for gene therapy, combinations of
these and the like.
[0131] An efficacious amount of the aforementioned
pharmacologically active agent(s) can easily be determined by those
of ordinary skill in the art taking into consideration such
parameters as the particular pharmacologically active agent chosen,
the size and weight of the patient, the desired therapeutic effect,
the pharmacokinetics of the chosen pharmacologically active agent,
and the like, as well as by reference to well known resources such
as Physicians' Desk Reference.RTM.: PDR--57 ed (2003)--Medical
Economics 1974. In consideration of these parameters, it has been
found that a wide range exists in the amount of the
pharmacologically active agent(s) capable of being incorporated
into and subsequently released from or alternatively allowed to
exert the agent's therapeutic effects from within the mucoadhesive
drug delivery devices. More specifically, the amount of
pharmacologically active agent that may be incorporated into and
then either released from or active from within the mucoadhesive
devices may range from about 0.00001% to about 95%, more
preferably, from about 0.001% to about 80%, most preferably from
about 0.1% to 60%, based on the weight of the mucoadhesive devices.
It is important to note that the pharmacologically active agents
are generally homogenously distributed throughout the mucoadhesive
devices thereby allowing for a controlled release of these
agents.
[0132] Finally, one or more additive materials may be added to the
mucoadhesive drug delivery devices to manipulate the material
properties and thereby add additional structure or modify the
release of pharmacologically active agents. That is, while a
mucoadhesive device that includes a relatively fast-degrading
protein material without a particular additive material will
readily degrade thereby releasing drug relatively quickly upon
insertion or implantation, a mucoadhesive device that includes a
particular polymeric material, such as polyanhydride, will degrade
slowly, as well as release the pharmacologically active agent(s)
over a longer period of time. For example, insoluble purified
proteins that are commercially available and may be utilized in
some embodiments of the present invention include Type I insoluble
collagen and insoluble elastin, manufactured by Kensey Nash
Corporation, 55 East Uwchlan Avenue, Exton, Pa. 19341,
Sigma-Aldrich Corporation, St. Louis, Mo., USA or Elastin Products
Company, Inc., P.O. Box 568, Owensville, Mo., USA 65066. Other
examples of biodegradable and/or biocompatible additive materials
suitable for use in the mucoadhesive drug delivery devices of the
present invention include, but are not limited to polyurethanes,
vinyl homopolymers and copolymers, acrylate homopolymers and
copolymers, polyethers, cellulosics, epoxies, polyesters, acrylics,
nylons, silicones, polyanhydride, poly(ethylene terephthalate),
polyacetal, poly(ethylene oxide)/poly(butylene terephthalate)
copolymer, polycarbonate, poly(tetrafluoroethylene) (PTFE),
polycaprolactone, polyethylene oxide, poly(vinyl chloride),
polylactic acid, polyglycolic acid, polypropylene oxide,
poly(akylene)glycol, polyoxyethylene, sebacic acid, polyvinyl
alcohol (PVA), 2-hydroxyethyl methacrylate (HEMA), polymethyl
methacrylate, 1,3-bis(carboxyphenoxy)propane, lipids,
phosphatidylcholine, triglycerides, polyhydroxybutyrate (PHB),
polyhydroxyvalerate (PHV), poly(ethylene oxide) (PEO), poly ortho
esters, poly (amino acids), polycynoacrylates, polyphophazenes,
polysulfone, polyamine, poly (amido amines), fibrin, graphite,
flexible fluoropolymer, isobutyl-based, isopropyl styrene, vinyl
pyrrolidone, cellulose acetate dibutyrate, guar gum, xanthan gum,
sodium carboxymethyl cellulose, tragacanth gum, silicone rubber,
copolymers of these, and the like. Other materials that may be
incorporated into the coatable composition to provide enhanced
features include, but are not limited to, ceramics, bioceramics,
glasses bioglasses, glass-ceramics, resin cement, resin fill; more
specifically, glass ionomer, hydroxyapatite, calcium sulfate,
Al.sub.2O.sub.3, tricalcium phosphate, calcium phosphate salts,
sugars, starches, carbohydrates, salts, polysaccharides, and
carbon. Additional other materials that may be incorporated into
the coatable composition include alloys such as, cobalt-based,
galvanic-based, stainless steel-based, titanium-based, zirconium
oxide, zirconia, silica, aluminum-based, vanadium-based,
molybdenum-based, nickel-based, iron-based, or zinc-based (zinc
phosphate, zinc polycarboxylate).
[0133] Other additives may be utilized, for example, to facilitate
the processing of the mucoadhesive devices, to stabilize the
pharmacologically active agents, to facilitate the activity of the
pharmacologically active agents, to enhance the permeation of the
pharmacologically active agents into the mucosal tissue or to alter
the release characteristics of the biocompatible protein particles.
For example, when the pharmacologically active agent is to be an
enzyme, such as xanthine oxidase or superoxide dismutase, the
protein matrix device may further comprise an amount of an enzyme
substrate, such as xanthine, to facilitate the action of the
enzyme. Another example may be the inclusion of permeation
enhancers in the mucoadhesive devices to assist in facilitating the
absorption of the pharmacologically active agents into the mucosal
tissue. Examples of permeation enhancers (e.g. membrane permeation
enhancers) include, but are not limited to, reagents such as
ascorbic acid, citric acid, glutamine and Lauroylcarnitine.
[0134] Additionally, hydrophobic substances such as lipids can be
incorporated into the biocompatible protein particles to extend the
duration of drug release, while hydrophilic, polar additives, such
as salts and amino acids, can be added to facilitate, i.e., shorten
the duration of, drug release. Exemplary hydrophobic substances
include lipids, e.g., tristeafin, ethyl stearate,
phosphotidycholine, polyethylene glycol (PEG); fatty acids, e.g.,
sebacic acid erucic acid; combinations of these and the like. A
particularly preferred hydrophobic additive useful to extend the
release of the pharmacologically active agents comprises a
combination of a dimer of erucic acid and sebacic acid, wherein the
ratio of the dimer of erucic acid to sebacic acid is 1:4. Exemplary
hydrophilic additives useful to shorten the release duration of the
pharmacologically active agent include but are not limited to,
salts, such as sodium chloride; and amino acids, such as glutamine
and glycine. If additives are to be incorporated into the coatable
composition, they will preferably be included in an amount so that
the desired result of the additive is exhibited.
[0135] One method of producing the mucoadhesive devices of the
present invention is by providing one or more selected mucoadhesive
proteins, adding other materials (pharmacologically active agents,
additives, mucoadhesive agents, etc.) and solvents (water) to form
a coatable composition. Once prepared, the coatable composition may
be coated onto any suitable surface from which it may be released
after drying by any suitable method. Examples of suitable coating
techniques include spin coating, gravure coating, flow coating,
spray coating, coating with a brush or roller, screen printing,
knife coating, curtain coating, slide curtain coating, extrusion,
squeegee coating, and the like. The coated film (preferably having
a substantially planar body having opposed major surfaces) is
desirably thin enough so as to be capable of drying within a
reasonable amount of time and also thin enough so that the film can
be formed into a cohesive body comprising a substantially
homogeneous dispersion of the components of the coatable
composition. For example, a thinner film will tend to form a more
homogeneous cohesive body when the film is formed into the shape of
a cylinder. A typical coated film of the coatable composition have
a thickness in the range of from about 0.01 millimeters to about 20
millimeters, more preferably from about 0.05 millimeters to about 5
millimeters.
[0136] Initially, when the film is first coated, it is likely to be
non-cohesive, fluidly-flowable, and/or non self-supporting. Thus,
the coated film is preferably dried sufficiently so that it becomes
cohesive, i.e., the film preferably sticks to itself rather than
other materials. The film may simply be allowed to dry at room
temperature, or alternatively, may be dried under vacuum under
conditions of mild heating or conditions of mild cooling. Heating
the coatable composition is generally not utilized. However, when
utilizing heat to dry the film, care should be taken to avoid
denaturation or structural degradation of the pharmacologically
active agent incorporated therein. Also, care should be taken to
not irreversibly denature the proteins of the coatable composition
or cohesive body during preparation through various actions on the
composition that will disrupt the secondary and/or tertiary
structure of the protein(s) such as application of excessive heat
or strong alkaline or acid solution, which may cause
coagulation/gelation. See table 1 for example of lost mucoadhesive
characteristics of heated protein materials. Such coagulation or
gelation will excessively inhibit the mucoadhesive function of the
device. It is noted that the cohesive body may be prepared without
the film step if the proper amounts of protein, solvent and other
components are known to achieve the necessary characteristics of
the cohesive body.
[0137] The specific solvent content at which the film becomes
cohesive unto itself will depend on the individual components
incorporated into the coatable composition. A cohesive body is
achieved when the components of the composition are in the proper
amounts so that the resulting composition is tacky or cohesive to
itself more than to other materials or surface that it contacts.
Generally, films that have too high of a solvent content will not
be cohesive. Films that have too low of a solvent content will tend
to crack, shatter, or otherwise break apart upon efforts to form
them into a cohesive body. With these considerations in mind, the
solvent content of a partially dried film will preferably be from
about 8% to about 80%, more preferably from about 12% to about 50%
and most preferably from about 15% to about 45%.
[0138] Additionally, embodiments of the present invention may
include the addition of reagents to properly pH the resulting
mucoadhesive devices and thereby enhance the biocompatible and/or
mucoadhesive characteristics of the device with the host tissue of
which it is to be administered. When preparing the coatable
composition and/or cohesive body, the pH steps of the mixture of
biocompatable materials, such as purified proteins, mucoadesive
agents, pharmacologically active agents and other additives, and
the biocompatable solvent(s), occur during the preparation of the
coatable composition or may occur after the cohesive body is
formed. For example, the pH steps can be started with the addition
of biocompatable solvent to the protein or to the mixture of
protein material and optional biocompatible materials, or the pH
steps can be started after mixing the material(s) and solvent(s)
together before the cohesive body is formed. In various embodiments
of the present invention, the pH steps can include the addition of
drops of 0.05N to 4.0N acid or base to the solvent wetted material
until the desired pH is reached as indicated by a pH meter, pH
paper or any pH indicator. More preferably, the addition of drops
of 0.1N-0.5 N acid or base are used. Although any acid or base may
be used, the preferable acids and bases are HCl and NaOH,
respectively. If known amounts of biocompatable material are used
it may be possible to add acid or base to adjust the pH when the
biocompatable material is first wetted, thereby allowing wetting
and pH adjustments to occur in one step. Alternatively, the pH
steps may be performed after the cohesive body is formed by
applying the acid or base after the cohesive body is formed.
[0139] Furthermore, the cohesive body and/or mucoadhesive device
may be set up with pores that allow fluid flow through the
particles, enhancing movement of the pharmacologically active
agents through the particles and/or enhancing the mucoadhesion of
the mucoadhesive device. Pores may be created in the cohesive body
or mucoadhesive device by incorporating a substance in the cohesive
body during its preparation that may be removed or dissolved out of
the matrix before administration of the device or shortly after
administration. Porosity may be produced in such devices by the
utilization of materials such as, but not limited to, salts such as
NaCl, amino acids such as glutamine, microorganisms, enzymes, added
gases (e.g. air, nitrogen, carbon dioxide . . . ), other gases
caused by chemical reactions (e.g. hydrogen from hydrogen peroxide
. . . ) copolymers or other materials, which will be leeched out of
the mucoadhesive device to create pores.
[0140] Once the film is capable of forming a cohesive body, such a
cohesive body may be formed by any of a number of methods. For
example, the film may be rolled, folded, accordion-pleated,
crumpled, or otherwise shaped such that the resulting cohesive body
has a surface area that is less than that of the coated film. For
example the film can be shaped into a cylinder, a cube, a sphere or
the like. Preferably, the cohesive body is formed by rolling the
coated film to form a cylinder. As previously suggested, the
cohesive body may be prepared without the film step if the proper
amounts of protein, mucoadhesive agent, solvent and other
components are known and properly mixed to achieve the necessary
characteristics of the cohesive body.
[0141] Once so formed, the cohesive body or coatable composition
may be solidified prior to forming the mucoadhesive device. Such
solidfication occurs due to a reduction of solvent (e.g. water),
which generally comprises a reduction in the bulk solvent, thereby
predominantly leaving ordered solvent, such as water. For example,
ordered water is normally known as water molecules that are is
direct interaction with the other components of the device (e.g.
protein, drug . . . ) and is not the pooling of water molecules or
formation of water molecule pockets within the cohesive body or
coatable composition. Many gelatins and other compositions known in
the art include much bulk solvent or bulk water. The interaction
between solvent molecules and other molecules are enhanced during
the reduction of solvent, which is mainly due to intermolecular and
intramolecular forces (i.e., ionic, dipole-dipole such as hydrogen
bonding, London dispersion, hydrophobic, etc.) formed between
solvent molecules, the protein molecules and the drug molecules
that are strengthened upon the reduction of solvent.
[0142] The cohesive body may be solidified into a compressed matrix
or spread matrix form. A compressed matrix is formed by removing
bulk water from the cohesive body by compression. Alternatively, a
spread matrix form is generally solidifying the coatable
composition or cohesive body utilizing one or more of solidifying
techniques without applying compression to the cohesive body. It is
noted that a combination of these techniques may also be utilized.
Alternatives to solidify the cohesive body other than compression
may be to apply heat, freeze drying, freezing to freeze fracture
(e.g. liquid nitrogen, dry ice or conventional freezing) or other
drying techniques to solidify the coatable composition or cohesive
body before processing the coatable composition or cohesive body
into mucoadhesive particles (an explanation of methods to make
particles is described below).
[0143] In preparation of the mucoadhesive devices of the present
invention, the cohesive body or the particles made from the
solidified coatable composition or cohesive body, as will be
described below, may be compressed to form a larger mucoadhesive
device, such as a wafer, sphere, or cylinder.
[0144] Any manually or automatically operable mechanical,
pneumatic, hydraulic, or electrical molding device capable of
subjecting the cohesive body to pressure is suitable for use in the
method of the present invention. In the production of various
embodiments of the present invention, a molding device may be
utilized that is capable of applying a pressure of from about 100
pounds per square inch (psi) to about 100,000 psi for a time period
of from about 0.2 seconds to about 48 hours. Preferably, the
molding device used in the method of the present invention will be
capable of applying a pressure of from about 1000 psi to about
30,000 psi for a time period of from about 0.5 second to about 60
minutes. More preferably, the molding device used in the method of
the present invention will be capable of applying a pressure of
from about 3,000 psi to about 25,000 psi for a time period of from
about 1 second to about ten minutes.
[0145] Compression molding devices suitable for use in the practice
of the method of the present invention are generally known.
Suitable devices may be manufactured by a number of vendors
according to provided specifications, such as desirable pressure,
desired materials for formulation, desired pressure source, desired
size of the moldable and resulting molded device, and the like. For
example, Gami Engineering, located in Mississauga, Ontario
manufactures compression molding devices to specifications provided
by the customer. Additionally, many compression molding devices are
commercially available. See U.S. Pat. No. 6,342,250 and U.S.
application Ser. No. 09/796,170, which are incorporated by
reference herein, for a description of one type of compression
molding device that may be utilized in the process of the present
invention.
[0146] As previously suggested, the compression molding devices
utilized in the process of the present invention are generally
capable of applying from about 100 psi to about 100,000 psi for a
time period of from about 0.2 seconds to about 48 hours, preferably
capable of applying from about 1000 psi to about 30,000 psi for a
time period of from about 0.5 second to about 60 minutes, and more
preferably, capable of applying a pressure of from about 3000 psi
to about 25,000 psi for a time period of from about 1 second to
about 10 minutes.
[0147] The resulting mucoadhesive devices preferably have as little
solvent as possible while still being cohesive and possessing the
desired features relevant to the device's function, e.g.,
preferably a solvent content of from about 5% to about 60%, more
preferably a solvent content of from about 10% to about 50% and
most preferably 15% to 40%. It is found that when a material
utilized in the production of the particles of the present
invention includes one or more pharmacologically active agent, the
partial drying of the film to form a cohesive body and subsequent
compressing of the cohesive body, forces more solvent out of the
body, thereby producing a resulting material that has a
significantly higher concentration of pharmacologically active
agents relative to other components of the material. As a result of
the substantially uniform dispersion of a greater concentration of
pharmacologically active agents, a sustained, controlled release of
the pharmacologically active agent is achieved, while reducing the
initial high concentration effects that can be associated with
other devices that include pharmacologically active agents.
[0148] The mucoadhesive drug delivery devices of present invention
may be formed into any shape and size, such as a cylinder, a tube,
a wafer or any other shape that may optimize the delivery of the
incorporated pharmacologically active agent.
[0149] As previously suggested, mucoadhesive devices may
alternatively be derived from a solidified cohesive mass produced
by solidifying the coatable composition or cohesive body by
applying heat, crosslinking, freeze fracturing techniques such as
liquid nitrogen freeze fracturing or dry ice freeze drying, vacuum
or other similar drying techniques to eliminate excess solvent from
the coatable composition or cohesive body rather than by removing
the excess solvent through compression. These alternative
techniques remove enough solvent from the cohesive body to provide
a solidified cohesive mass that is of the proper composition and
structure for the production of distinct particles. However, it is
important not to eliminate too much solvent wherein the interaction
of solvent and protein is lost. Embodiments of the resulting
solidified cohesive mass following heating, or any of the
alternative techniques identified above, usually have as little
solvent as possible while still being cohesive and possessing the
desired features relevant to the device's function, e.g.,
preferably a solvent content of from about 5% to about 60%, more
preferably a solvent content of from about 10% to about 50% and
most preferably 15% to 40%. As previously mentioned, the proteins,
solvent and the pharmacologically active agents will interact by
binding through intermolecular and intramolecular forces (i.e.,
ionic, dipole-dipole such as hydrogen bonding, London dispersion,
hydrophobic, etc.) that are enhanced during the steps of
solidifying the coatable composition or cohesive body.
[0150] One example of a method to solidify the coatable composition
or cohesive body to make particles is by heating the cohesive body
and then processing the resulting solidified cohesive body into
mucoadhesive particles. In such a method the coatable composition
or cohesive body may be dried under mild heat. In such embodiments,
the coatable composition or cohesive body is heated under vacuum.
It is important to note that heat should be applied so as to remove
solvent and not denature or gel the cohesive body. Such gelation
will inhibit the mucoadhesive qualities of the device. Generally,
the heating process may be conducted under mild heat for
approximately 10 seconds to 48 hours, preferably 1-24 hours and
most preferably 2-6 hours per gram of coatable composition or
cohesive body material. Embodiments of the resulting solidified
coatable composition or cohesive body following heating, or any of
the alternative techniques identified above, usually have as little
solvent as possible while still being cohesive and possessing the
desired features relevant to the device's function, e.g.,
preferably a solvent content of from about 5% to about 60%, more
preferably a solvent content of from about 10% to about 50% and
most preferably 15% to 40%. Once the coatable composition or
cohesive body is solidified it may be processed further into
particles by utilizing any particle processing technique, such as
grinding or homogenizing (a description of particle processing
techniques is explained below).
[0151] It is found that when a solidified coatable composition or
cohesive body utilized in the production of the mucoadhesive
devices of the present invention includes one or more
pharmacologically active agents, the partial drying of the film to
form a cohesive body and subsequent solidification of the cohesive
body or the solidfication of the coatable composition, forces more
solvent out of the body, thereby producing a resulting material
that has a significantly higher concentration of pharmacologically
active agents. As a result of the substantially uniform dispersion
of a greater concentration of pharmacologically active agents, a
sustained, controlled release of the pharmacologically active agent
is achieved, while reducing the initial high concentration effects
that can be associated with other devices that include
pharmacologically active agents.
[0152] As previously suggested, particles may be derived from a
solidified cohesive mass produced by solidifying the coatable
composition or cohesive body by applying heat, freeze fracturing
techniques such as liquid nitrogen freeze fracturing or dry ice
freeze drying, vacuum or other similar drying techniques to
eliminate excess solvent from the coatable composition or cohesive
body rather than compressing it. It is noted that particles may
also be prepared from a compressed matrix as described in the
present application.
[0153] Before the solidified cohesive mass is processed into
particles or after particles are produced, the cohesive body or
solidified cohesive mass may also be crosslinked to provide
additional beneficial characteristics. The optional step of
crosslinking the mass may be performed by any means known in the
art such as exposure to chemical crosslinking agents like
glutaraldehyde, p-Azidobenzolyl Hydazide, N-5-Azido
2-nitrobenzoyloxysuccinimide, N-Succinimidyl
6-[4'azido-2'nitro-phenylamino]hexanoate and
4-[p-Azidosalicylamido]butylamine, applying dehydrothermal means,
ultraviolet light, or other radiation sources like ultrasound,
microwave or gamma radiation.
[0154] Particles utilized to prepare the mucoadhesive devices of
the present invention are generally prepared by further processing
the compressed matrix or solidified cohesive mass. FIG. 1 depicts
embodiments of the mucoadhesive particles utilized to prepare
device embodiments of the present invention. Examples of producing
the particles utilized in products of the present invention include
the crushing, cutting, homogenizing, pulverizing or grinding of the
compressed matrix or solidified cohesive mass. In various
embodiments of the present invention particles may be formed by
freezing the compressed matrix or cohesive mass in liquid nitrogen
and pulverizing the frozen mass, by utilizing other freeze/solid
fracture or particle forming techniques or by partially heating the
cohesive body until substantially rigid, but still retaining some
solvent content and processing the resulting mass into
particles.
[0155] In two embodiments of the present invention the particles
are prepared utilizing a mill grinder or a homogenizer. Types of
mill grinders and homogenizers that may be utilized include, but
are not limited to ball mills, grinder stations, polytron
homogeneizers and the like. One example of a polytron homogenizer
that may be utilized in processing particles of the present
invention may be a Polytron PT1200E purchased from the Kinematica
corporation of Switzerland. An example of a ball mill that may be
utilized in processing particles of the present invention may be a
ball mill/roller mill purchased from U.S. Stoneware, Inc. and
distributed by ER Advanced Ceramincs of Palestine, Ohio.
[0156] In another embodiment of the present invention, particles
are prepared by reducing the solvent content of the coatable
composition by spray drying the composition using a spray drying
apparatus. The basic idea of spray drying is the production of
highly dispersed particles of the present mucoadhesive material
that includes all of its components from a solution or a suspension
by evaporating the solvent. In this process the solution/suspension
is sprayed into a hot air stream. The formed droplets have a large
surface area in comparison to their volume. Since the heat transfer
from the hot air to the liquid phase is proportional to the surface
area, the temperature of the small droplets is raising much faster
than it would do in one large drop of the same volume. This fact is
important for the evaporation process: The higher the droplet
temperature the faster the evaporation of the bulk solvent. The
removal of a substantial amount of the bulk solvent produces a
plurality of mucoadhesive particles that include a homogenous
distribution of protein, mucoadhesive agent, solvent and
pharmacologically active agent. An example of a spray drying device
that may be utilized to prepare such particles includes, but is not
limited to, the Buchig.RTM. Spray Dryer B-290, manufactured by
Brinkmann Instruments, Inc., One Cantiague Road, P.O. Box 1019
Westbury, N.Y. 11590-0207. Other spray drying devices that may be
utilized in the present invention may be acquired from Niro Inc.,
9165 Rumsey Road, Columbia, Md. 21045.
[0157] Generally, the particles may vary in size but are normally
equal to or less than 2 mm. In many embodiments of the present
invention the particles are approximately 10 nm-1.75 mm, preferably
500 nm-1.5 mm and more preferably 1-1000 .mu.m. The particles can
be made to disassociate at very slow or fast rates in aqueous
solutions. Another characteristic of the particles produced from
the cohesive mass is that they no longer aggregate when in the
particulate state. It is also noted that generally, many particle
embodiments of the present invention are substantially soluble
thereby allowing them to dissolve and degrade over time.
[0158] Embodiments of the resulting particles of the present
invention utilizing any of the alternative techniques identified
above, usually have as little solvent as possible while still being
cohesive and possessing the desired features relevant to the
particle's function, e.g., preferably a solvent content of from
about 5% to about 60%, more preferably a solvent content of from
about 10% to about 50% and most preferably 15% to 30%.
[0159] FIG. 2 depicts a scanning electron microscope (SEM) image of
one embodiment of the mucoadhesive particles of the present
invention. As depicted in FIG. 2, the particles appear to possess
an ordered structure of protein, solvent, mucoadhesive agent and
drug due to the interaction of these components derived during
fabrication. Furthermore, as depicted in FIG. 3, a closer view of
the same particles of FIG. 2, the surface of this embodiment of the
particles of the present invention has a rough texture and is
somewhat porous. Conversely, as depicted in FIGS. 4 and 5,
particles of the starting albumin material is relatively amorphous,
has a smooth texture and is not porous.
[0160] After the particles are formed using the various methods
described above, they may be characterized for their basic
structure. First the particles may be segregated using a series of
pharmaceutical drug sieves. Additional characterization of the
particles will consist of verification of the shape and size of the
particles using light and electron microscopy.
[0161] Also, the particles may be administered as a mucoadhesive
device that adheres to mucosal tissue of the body (e.g. the buccal
cavity, sublingual region, gums, gingival, palate region, the
vaginal wall or the anal wall) for absorption of the
pharmacologically active agent(s) through the mucosal tissue. In
one embodiment of the present invention, a particle loaded saline
solution or gasous particle spray may be administered as a nasal
spray, mouth spray, vaginal spray or spray to any other part of the
body that includes mucosal tissue. The spray is generally utilized
to deliver the particles of the present invention that thereby
deliver one or more pharmacologically active agents and is usually
separated from any other liquid carrier (e.g. saline) until just
prior to administration. It is noted that any biocompatible
solution may be utilized rather than saline to deliver the
particles of the present invention. This type of particulate
solution or gasous spray may be administered by any means known in
the art, such as a nasal spray bottle or an inhaler.
[0162] Alternatively, a mucoadhesive drug delivery device may be
formed utilizing the particles. For example, particles of the
present invention may be compressed into a drug delivery device in
the form of a cylinder, wafer or any other suitable shape or
design. For example, FIG. 1 depicts embodiments of the present
invention formed in wafer and particulate form. The compression may
be performed by any device known in the art, such as a conventional
pill press or any of the compression devices disclosed above. Such
a drug delivery device has been found to have mucoadhesive
characteristics that make it optimal for sublingual, palate,
vaginal, anal, gingival, or buccal drug delivery.
[0163] In one embodiment of the present invention, a coatable
composition is prepared comprising one or more natural proteins,
such as egg white proteins (e.g. ovalbumin), one or more
biocompatible solvents such as water, one or more mucoadhesive
agents such as glycerol and one or more pharmacologically active
agents, such as fentanyl, capsaicin, ibuprofen, acetaminophen,
desmopressen, vitamins (e.g. vitamins A, C, B1, B2, B6, B12,
B12.alpha., E, vitamin E acetate, vitamin E sorbate, K, lutein,
lucopene, PABA, choline, inositol, folic, biotin, omega 3) and/or
minerals (e.g. iron, selenium, calcium, copper, boron, chromium,
magnesium, potassium and zinc) may be produced into a mucoadhesive
drug delivery device. The solvent (e.g. water) is reduced from the
coatable composition and it is next formed into a cohesive body or
is solidified into a solidified cohesive mass and processed into
particles. The cohesive body or particles next may be compressed
into a mucoadhesive device (e.g. wafter, tablet, sphere . . . ) and
adhered to the inside of the mouth, nose, vaginal cavity or anal
cavity by simply applying the device to the mucosal tissue. For
example, administration of such a device can be done by simply
pressing the device to the mucosal tissue, such as the buccal
cavity tissue, sublingual tissue, palate tissue, vaginal cavity or
nasal cavity. Alternatively, the particles may be simply
administered to the mucosal tissue by spraying particles into or
onto such tissue (e.g. a nasal spray). The device will generally
deliver the drug through the mucosal tissue without losing the drug
orally or by flushing out with bodily fluids.
[0164] As previously suggested, embodiments of the mucoadhesive
devices of the present invention may include mucoadhesive particles
that may be combined with one or more excipients, carriers or
adjuvants to form a particle formulation or composition. The
excipients, carriers or adjuvants preserve the singularity of each
particle in each individual dose, inhibit aggregation of particles
and allow for the quick or slow dispersion of the particles once
administered. For example, the rapid dispersion of the particles
allows the particles to attach throughout the buccal cavity or
other mucosal sites, such as lung, nasal, sublingual, intestinal,
ocular, uterine, fallopian, pulmonary, stomach, vaginal, gingival,
and/or rectal sites. Alternatively, the particles may be combined
with an excipient, carrier or adjuvant formulation that slows the
release of the particles thereby localizing them for a desired
period of time or for fast release of particles to allow dispersed
mucosal attachment.
[0165] Formulations or compositions suitable for use in the
practice of the present invention include mucoadhesive devices
(e.g. particles, sheets, wafers . . . ) formed into capsules, gels,
cachets, tablets, effervescent or non-effervescent powders or
tablets, powders or granules; as a solution or suspension in
aqueous or non-aqueous liquid; or as an oil-in-water liquid
emulsion or a water-in-oil emulsion. The compounds of the present
invention may also be presented as a bolus, electuary, or
paste.
[0166] Generally, formulations are prepared by uniformly mixing the
particles with liquid carriers or finely divided solid carriers or
both, and then if necessary shaping the product. A pharmaceutical
carrier is selected on the basis of the chosen route of
administration and standard pharmaceutical practice. Each carrier
must be "acceptable" in the sense of being compatible with the
other ingredients of the formulation and not injurious to the
subject. This carrier can be a solid or liquid and the type is
generally chosen based on the type of administration being used.
Examples of suitable solid carriers include lactose, sucrose,
gelatin, agar and bulk powders. Examples of suitable liquid
carriers include water, pharmaceutically acceptable fats and oils,
alcohols or other organic solvents, including esters, emulsions,
syrups or elixirs, suspensions, solutions and/or suspensions, and
solution and or suspensions reconstituted from non-effervescent
granules and effervescent preparations reconstituted from
effervescent granules. Such liquid carriers may contain, for
example, suitable solvents, preservatives, emulsifying agents,
suspending agents, diluents, sweeteners, thickeners, and melting
agents. Preferred carriers are edible oils, for example, corn or
canola oils. Polyethylene glycols, e.g., PEG, are also preferred
carriers.
[0167] The formulations for mucosal administration may comprise a
non-toxic, pharmaceutically acceptable, inert carrier such as
lactose, starch, sucrose, glucose, fructose, dextrose, methyl
cellulose, magnesium stearate, carrageenan, dicalcium phosphate,
calcium sulfate, mannitol, sorbitol, cyclodextrin, cyclodextrin
derivatives, or the like.
[0168] Capsules or tablets can be easily formulated and can be made
easy to administer to the buccal cavity or other mucosal sites.
Tablets may contain other suitable carriers, binders, lubricants,
diluents, disintegrating agents, coloring agents, flavoring agents,
flow-inducing agents, or melting agents. A tablet may be made by
compression or molding the mucoadhesive particles, cohesive body or
cohesive mass of the present invention, optionally with one or more
additional materials (e.g. carriers, binders, lubricants, diluents,
disintegrating agents, coloring agents . . . ). As previously
suggested, compressed tables may be prepared by compressing the
particles, cohesive body or cohesive mass in a free flowing form
(e.g., powder, granules) optionally mixed with a binder (e.g.,
gelatin, hydroxypropylmethylcellulose, povodone, carbocol,
polyvinylalcohol), lubricant, inert diluent, preservative,
disintegrant (e.g., sodium starch glycolate, cross-linked
carboxymethyl cellulose) surface-active or dispersing agent.
Suitable binders include starch, gelatin, natural sugars such as
glucose or beta-lactose, corn sweeteners, natural and synthetic
gums such as acacia, tragacanth, or sodium alginate,
carboxymethylcellulose, polyethylene glycol, waxes, or the like.
Lubricants used in these dosage forms include sodium oleate, sodium
stearate, magnesium stearate, sodium benzoate, sodium acetate,
sodium chloride, or the like. Disintegrators include, for example,
starch, methyl cellulose, agar, bentonite, xanthan gum, or the
like. In one example, molded tablets may be made by molding in a
suitable machine a mixture of the mucoadhesive particles of the
present invention moistened with an inert liquid diluent (e.g.
solvent, such as water, mucoadhesive agent such as glycerol . . .
).
[0169] The tablets may optionally be coated or scored and may be
formulated so as to provide slow- or controlled-release of the
active ingredient. The coatings may be utilized to retain the
particles while passing through the oral tract and into the
stomach. Tablets may also optionally be provided with an enteric
coating to provide release in parts of the gut other than the
stomach. Additionally, the tablets may be coated on one side to act
as a dissolution barrier when the opposite side is attached to the
mucosal tissue.
[0170] Exemplary pharmaceutically acceptable carriers and
excipients that may be used to formulate oral dosage forms of the
present invention are described in U.S. Pat. No. 3,903,297 to
Robert, issued Sep. 2, 1975, or the Handbook of Pharmaceutical
Excipients, by Arthur H. Kibbe (Editor), Ainley Wade and Paul J.
Weller, Amer. Pharmaceutical Assoc.; 3rd edition (Jan. 15, 2000),
both of which are incorporated by reference herein in their
entirety. Techniques and compositions for making dosage forms
useful in the present invention are described in the following
references: 7 Modem Pharmaceutics, Chapters 9 and 10 (Banker &
Rhodes, Editors, 1979); Lieberman et al., Pharmaceutical Dosage
Forms: Tablets (1981); and Ansel, Introduction to Pharmaceutical
Dosage Forms 2nd Edition (1976).
[0171] In addition to the mucoadhesive proteins and the
biocompatible solvent(s), the particles or devices made from the
particles of the present invention advantageously may themselves
incorporate other drug delivery devices that would otherwise
typically migrate away from the desired delivery site and/or are
potentially undesirably reactive with surrounding bodily fluids or
tissues. Such migration is undesirable in that the therapeutic
effect of the pharmacological agents encapsulated therein may occur
away from the desired site, thus eliminating the advantage of
localized delivery or enhanced absorption. When a drug delivery
device incorporating a migration-vulnerable and/or reactive drug
delivery device (hereinafter referred to as a "two-stage drug
delivery device") is subsequently implanted, attached and/or
administered, the migration-vulnerable and/or reactive drug
delivery device(s) is/are held in place and protected by the
two-stage mucoadhesive device. Then, as the material of the
migration-vulnerable drug delivery devices degrade or dissolve,
thereby releasing the pharmacologically active agents incorporated
therein, the pharmacologically active agents diffuse through and/or
release from the mucoadhesive device of the two-stage drug delivery
device. Furthermore, the mucoadhesive device reduces, if not
prevents, the potential for undesirable reaction with bodily fluids
or tissues that may otherwise occur upon implantation, application
or administration of a reactive drug delivery device. Examples of
such drug delivery devices subject to migration for the delivery
site include, but are not limited to, particles, vesicles, e.g.,
liposomes, lipospheres and microspheres.
[0172] Vesicles are made up of microparticles or colloidal carriers
composed of lipids, carbohydrates or synthetic polymer matrices and
are commonly used in liquid drug delivery devices. Vesicles, for
example, have been used to deliver anesthetics using formulations
with polylactic acid, lecithin, iophendylate and phosphotidyl
choline and cholesterol. For a discussion of the characteristics
and efficiency of drug delivery from vesicles, see, e.g., Wakiyama
et al., Chem., Pharm. Bull., 30, 3719 (1982) and Haynes et al.,
Anesthiol, 74, 105 (1991), the entire disclosures of which are
incorporated by reference herein.
[0173] Liposomes, the most widely studied type of vesicle, can be
formulated to include a wide variety of compositions and structures
that are potentially non-toxic, biodegradable and non-immunogenic.
Furthermore, studies are in progress to create liposomes that
release more drug in response to changes in their environment,
including the presence of enzymes or polycations or changes in pH.
For a review of the properties and characteristics of liposomes
see, e.g., Langer, Science, 249, 1527 (1990); and Langer, Ann.
Biomed. Eng., 23, 101 (1995), the entire disclosures of which are
incorporated by reference herein.
[0174] Lipospheres are an aqueous microdispersion of water
insoluble, spherical microparticles (from about 0.2 to about 100 um
in diameter), each consisting of a solid core of hydrophobic
triglycerides and drug particles that are embedded with
phospholipids on the surface. Lipospheres are disclosed in U.S.
Pat. No. 5,188,837, issued to Domb, the disclosure of which is
incorporated herein by reference.
[0175] Microspheres typically comprise a biodegradable polymer
matrix incorporating a drug. Microspheres can be formed by a wide
variety of techniques known to those of skill in the art. Examples
of microsphere forming techniques include, but are not limited to,
(a) phase separation by emulsification and subsequent organic
solvent evaporation (including complex emulsion methods such as oil
in water emulsions, water in oil emulsions and water-oil-water
emulsions); (b) coacervation-phase separation; (c) melt dispersion;
(d) interfacial deposition; (e) in situ polymerization; (f) spray
drying and spray congealing; (g) air suspension coating; and (h)
pan and spray coating. These methods, as well as properties and
characteristics of microspheres are disclosed in, e.g., U.S. Pat.
No. 4,652,441; U.S. Pat. No. 5,100,669; U.S. Pat. No. 4,526,938; WO
93/24150; EPA 0258780 A2; U.S. Pat. No. 4,438,253; and U.S. Pat.
No. 5,330,768, the entire disclosures of which are incorporated by
reference herein.
[0176] Inasmuch as the migration-vulnerable and/or reactive
particles or devices made of such particles will desirably further
encapsulate a pharmacologically active agent, the amount of these
devices to be utilized in the two-stage drug delivery device may be
determined by the dosage of the pharmacologically active agent, as
determined as described hereinabove. The amount of
migration-vulnerable and/or reactive drug delivery devices to be
included in the particles or device made of such particles of the
present invention desirably ranges from about 10 to about 1
billion, more preferably ranges from about 10,000 to about 500
million, and most preferably ranges from about 1 million to about
200 million.
[0177] Other embodiments of the mucoadhesive drug delivery devices
of the present invention may include a plurality of layers. For
example, a multi-layered drug delivery device may comprise
alternating layers of mucoadhesive material that have drug release
additives, which inhibit and/or enhance the release of drugs. These
layers may be arranged to manage the directional flow of drugs to a
desired site. Alternatively, alternating layers may include
different amounts of the same pharmacologically active agents or
the alternating layers may include different pharmacologically
active agents that are laminated together to form the mucoadhesive
drug delivery device.
[0178] The previous description has disclosed and suggested various
embodiments related to the preparation and administration of the
mucoadhesive devices of the present invention. As previously
mentioned, the devices of the present invention provide optimum
tissue residency time for delivery of the pharmacologically active
agents, but furthermore dissolve/degrade and disappear upon
delivery of the such agents. The disappearance of such devices
without inconvenience, discomfort or adverse reaction is an
important feature of the present devices. For example, the
preparation of such devices with soluble proteins that are common
in food products provide beneficial dissolving and/or degradation
of the devices once they have delivered their active agents.
Generally, the mucoadhesive devices will remain adhered to the
mucosal tissue for approximately 2 min. to 16 hours per 125
mg/cm.sup.2, preferable about 5 min. to 2 hours per 125 mg/cm.sup.2
and more preferably from about 10 min. to 1 hour per 125
mg/cm.sup.2. In a few embodiments of the present invention devices
comprising ovalbumin, glycerol, water and a drug adhered
comfortably and was unmovable from the buccal surface with the
tongue. These embodiments melted away without notice in
approximately 3 minutes for the fast dissolve formulation and in
approximately 15 to 30 minutes for the slow dissolve formulations.
In another example such wafers have been found to immediately
attach to a wetted finger and stay attached after submersion into
37.degree. C. saline while it melts away completely without
detaching. This has demonstrated the ability for a wafer of the
mucoadhesive material to have adequate strength to stay attached
and hold together for a desired time when placed in an aqueous
environment.
[0179] Furthermore, it has been found that in many embodiments of
the present invention, the mucoadhesive devices and particles have
mucoadhesive tensile strengths (corrected for technique and
preparation (an example of which is found in tables 1-3)) that are
approximately greater than 0.01 N/cm.sup.2, optionally greater than
0.05 N/cm.sup.2 or optionally greater than 0.15 N/cm.sup.2 or
optionally greater than 0.30 N/cm.sup.2.
Example I
Mucoadhesive Composition
[0180] Powdered egg albumin (Alfachem) (50 gs) is added to a
stirred (magnetic stirrer) solution of glycerol (15 gs) in saline
(0.9%) (187.5 mls) in a 500 ml beaker. After all the albumin has
been added, and mostly dispersed, the solution is shaken at the
slow settting for 30 minutes on a platform shaker (Eberbach).
(Note: an active drug may be added to the glycerol/saline solution
before the albumin is added.) The resulting solution/dispersion was
divided into two-250 ml beakers up to the 125 ml mark
(approximately one-half full). The two beakers were covered with
foil and placed in a freezer at -20.degree. C. overnight. The
frozen solutions were next placed onto a freeze-drier platform
previously held at -30.degree. C. and left to equilibrate for one
hour. Cooling of the platform was then discontinued when a vacuum
of 200 millitor was obtained. The condenser was then turned off.
Full vacuum was then continued for 48 hours or until the platform
temperature reached ambient (25.degree. C. on the temperature
dial). The resulting freeze-dried solid was then removed and ground
for one hour using a ceramic ball mill (2 cm.times.2 cm media) and
roller mill set at 35 rpm. The final milled product was passed
through a 150 .mu. sieve to yield 40 gs of a slightly yellow, fine
mucoadhesive particles. (It is noted that portions of the particles
were compressed into uniform wafers (approximately 6 mm in
diameter, 50, 100 and 150 mg) using a pneumatic press. Such wafers
produced buccal residence time when tested in vivo of 3 min., 10
min. and 20 min. respectively).
Example II
In Vitro Bioadhesion Tests on Mucosal Tissue
[0181] Mucoadhesive devices including ovalbumin, glycerol and water
(no drug) were made into particles utilizing the methods described
above. 150 mg of the particles were compressed into 1 cm diameter
wafers at 1375 psi for 3 min (MAD1, MAD 2 and MAD3). The wafers
were then tested for mucoadhesive attachment by adhering them to
the bottom of a glass beaker with double sided Scotch.RTM., 3M tape
and pressing the bottom of the beaker to fresh wetted mucosal
membrane from pig intestine that was cleaned for usage in sausage
casing. The bottom of the beaker was pressed to the mucosal
membrane for 30 seconds at approximately 10 psi. The beaker was
then placed on a Satorius electronic balance and the membrane
pulled slowly in an upward motion at a 45.degree. angle away from
the wafer and beaker until completely detached. The measurement
taken was the detachment force, which is the difference between the
starting weight of the beaker, wafer and membrane and the lowest
weight registered on the scale during the removal of the membrane.
Similar measurements were also taken of mucoadhesive wafers heated
at 120.degree. C., sodium alginate powder compressed into wafers at
1375 psi for 3 min, 1 cm wetted collagen gel wafers and the glass
beaker as control for pig intestine adhesion. The following table
(Table 1) discloses the mucoahesive results of an average of three
wafers of each type:
TABLE-US-00002 TABLE 1 Results from Mucoadhesive Devices (MAD)
(tensile stress (N/cm.sup.2) Sodium Collagen Glass Contact
MAD.sup.a Heated MAD Alginate Gel Beaker Time(s) (N/cm.sup.2)
(N/cm.sup.2) (N/cm.sup.2) (N/cm.sup.2) (N/cm.sup.2) 30 0.38 0.03
0.08 <0.01 <0.01 .sup.a(average, n = 3)
Example III
In Vitro Bioadhesion Tests on Mucosal Tissue
[0182] Mucoadhesive devices including ovalbumin, glycerol and water
were made into wafers and were tested for mucoadhesive attachment
to fresh mucosal membrane from pig intestine by Christer Nystrom,
Ph.D., of the University of Uppsala, Uppsala, Sweden. A TA-HDi
texture analyser (Stable Micro Systems, Haslemere, UK) with a 5 kg
load cell was used. The pig intestine was cut into approximately 2
cm.sup.2 pieces and placed in a tissue holder. The mucoadhesive
devices were attached to the upper probe using double-sided tape
(Scotch, 3M). After spreading 3 ml of buffer [Krebs-Ringer
Bicarbonate] with a pipette onto mucosa, the studied material was
brought into contact with mucosa under a force of 0.5 N over 30
seconds. The probe was then raised at a constant speed of 0.1 mm/s
and the detachment force was recorded as a function of
displacement. The detachment force was measured at a sampling rate
of 25 measurements/second throughout the measuring cycle and the
maximum force was determined using computer software. The tensile
stress (N/cm2) was obtained by dividing detachment force by area of
the mucoadhesive wafer or probe. The work of adhesion was
calculated from the area under the curve of tensile stress versus
probe displacement.
[0183] The tensile stress and the work of adhesion for the tested
mucoahesive devices and the probe are presented in Table 2. In
table 3 results for materials used in a previous study are shown
(Bredenberg, S. Nystrom, C, (2002), In vitro evaluation of
bioadhesion in particulate systems and possible improvement using
interactive mixtures, J. Pharm Pharmacol). In this study, taking
into account all data generated for tablets, powders and mixtures,
there seemed to be a maximum tensile stress of approximately 1.5
N/cm2. This value of 1.5 N/cm2 reflected the intrinsic strength of
the mucus layer since that would be the strongest part of the
system in this study. Lower tensile stress values would then
reflect a weakening of the bioadhesive joint.
[0184] For dry powders and tablets, dehydration of mucosa is a
possible mechanism for bioadhesion. This mechanism is caused by
water movement from mucosa to the dry powder, resulting in adhesion
between the two surfaces. Another mechanism is adhesion forces due
to surface tension created between the mucosa and material.
Attraction forces due to surface energy effects have also been
identified as a possible bioadhesive mechanism. Since the metal
probe used as a control had rather high tensile stress and work,
probably due to surface tension and/or attraction forces, powders
of mannitol is a better control reference since it has no
bioadhesive properties (Table 3). Compared to mannitol, the
mucoadhesive devices had significant bioadhesive properties and
could be compared to interactive mixtures of mannitol+Ac-Di-Sol and
Emcompress (DCP)+Ac-Di-Sol.RTM. (DCP=Dicalcium Phosphate;
Ac-Di-Sol.RTM.=ADS=a modified cellulose gum) (Table 3). These
results indicate that the mucoadhesive devices are comparable to
the interactive mixtures (especially DCP+Ac-Di-Sol.RTM.) used in
the study by Bredenberg and Nystrom (2002), but slightly less to
tablets of sodium alginate, a well-known strong bioadhesive
material. However, even though highly bioadhesive, sodium alginate
also dissolves very rapidly in an aqueous environment, thereby
rendering it relatively ineffective as a mucoadhesive drug delivery
device.
TABLE-US-00003 TABLE 2 Results from Mucoadhesive Devices (MAD)
(tensile stress (N/cm2) and tensile work (mJ/cm2) Contact MAD 1 MAD
2 MAD 3 Probe.sup.a MAD 1 MAD 2 MAD 3 Probe.sup.a Time (s)
(N/cm.sup.2) (N/cm.sup.2) (N/cm.sup.2) (N/cm.sup.2) (mJ/cm.sup.2)
(mJ/cm.sup.2) (mJ/cm.sup.2) (mJ/cm.sup.2) 30 0.736 0.633 0.933
0.407 0.058 0.052 0.075 0.032 .sup.a(average, n = 3)
TABLE-US-00004 TABLE 3 Results from a previous study (tensile
stress (N/cm.sup.2) and tensile work (mJ/cm.sup.2) Mixture.sup.a
Mixture.sup.a Sodium Mixture.sup.a Mixture.sup.a Sodium Mannitol +
DCP + Alginate Mannitol + CDP + Alginate Contact Mannitol.sup.a ADS
ADS Tablets Mannitol.sup.a ADS ADS Tablet. Time(s) (N/cm.sup.2)
(N/cm.sup.2) (N/cm.sup.2) (N/cm.sup.2) (mJ/cm.sup.2) (mJ/cm.sup.2)
(mJ/cm.sup.2) (mJ/cm.sup.2) 30 0.017 0.284 0.845 1.44 0.015 0.032
0.102 .182 .sup.a(average, n = 5)
[0185] The results of Table 1 and Tables 2 and 3 differ for the
absolute tensile stress measurements due to the difference between
cleaned (Table 1) and fresh, untouched (Table 2 and 3) pig
intestine and due to pig intestine detachment angle techniques
(Table 1 45.degree. and Table 2 and 3 0.degree.). Therefore, the
values are best compared after being corrected by subtracting the
probe or the beaker glass tensile stress, which is a correction for
the mucoadhesive property variation due to different pig intestine
batches and handling and also a correction for the detachment
angle.
[0186] While the invention has been described in conjunction with
specific embodiments thereof, it is evident that many alternatives,
modifications, and variations will be apparent to those skilled in
the art in light of the foregoing description. Accordingly, it is
intended to embrace all such alternatives, modifications, and
variations, which fall within the spirit and broad scope of the
invention.
Sequence CWU 1
1
21159PRTArtificialsynthetic construct similar to silk protein 1Gly
Ala Gly Ala Gly Ser Gly Ala Gly Ala Gly Ser Gly Ala Gly Ala1 5 10
15Gly Ser Gly Ala Gly Ala Gly Ser Gly Ala Gly Ala Gly Ser Gly Ala
20 25 30Gly Ala Gly Ser Gly Ala Gly Ala Gly Ser Gly Ala Gly Ala Gly
Ser 35 40 45Gly Ala Gly Ala Gly Ser Gly Ala Ala Gly Tyr 50
5526PRTArtificialseq. repeated indefinitely, synthetic construct
similar to silk protein 2Gly Ala Gly Ala Gly Ser1
5371PRTArtificialseq. repeated indefinitely, synthetic construct
similar to silk protein containing RGD sequence from fibronectin.
3Gly Ala Gly Ala Gly Ser Gly Ala Gly Ala Gly Ser Gly Ala Gly Ala1 5
10 15Gly Ser Gly Ala Gly Ala Gly Ser Gly Ala Gly Ala Gly Ser Gly
Ala 20 25 30Gly Ala Gly Ser Gly Ala Gly Ala Gly Ser Gly Ala Gly Ala
Gly Ser 35 40 45Gly Ala Gly Ala Gly Ser Gly Ala Ala Val Thr Gly Arg
Gly Asp Ser 50 55 60Pro Ala Ser Ala Ala Gly Tyr65
70474PRTArtificialseq. repeated indefinitely, synthetic construct
similar to silk protein containing sequence from laminin protein.
4Gly Ala Gly Ala Gly Ser Gly Ala Gly Ala Gly Ser Gly Ala Gly Ala1 5
10 15Gly Ser Gly Ala Gly Ala Gly Ser Gly Ala Gly Ala Gly Ser Gly
Ala 20 25 30Gly Ala Gly Ser Gly Ala Gly Ala Gly Ser Gly Ala Gly Ala
Gly Ser 35 40 45Gly Ala Gly Ala Gly Ser Gly Ala Ala Pro Gly Ala Ser
Ile Lys Val 50 55 60Ala Val Ser Ala Gly Pro Ser Ala Gly Tyr65
70573PRTArtificialseq. repeated indefinitely, synthetic construct
similar to silk protein containing a different sequence from
laminin protein. 5Gly Ala Gly Ala Gly Ser Gly Ala Gly Ala Gly Ser
Gly Ala Gly Ala1 5 10 15Gly Ser Gly Ala Gly Ala Gly Ser Gly Ala Gly
Ala Gly Ser Gly Ala 20 25 30Gly Ala Gly Ser Gly Ala Gly Ala Gly Ser
Gly Ala Gly Ala Gly Ser 35 40 45Gly Ala Gly Ala Gly Ser Gly Ala Ala
Pro Gly Ala Ser Ile Lys Val 50 55 60Ala Val Ser Gly Pro Ser Ala Gly
Tyr65 70671PRTArtificialseq. repeated indefinitely, synthetic
construct similar to silk protein containing the RGD sequence from
fibronectin. 6Gly Ala Gly Ala Gly Ser Gly Ala Gly Ala Gly Ser Gly
Ala Gly Ala1 5 10 15Gly Ser Gly Ala Gly Ala Gly Ser Gly Ala Gly Ala
Gly Ser Gly Ala 20 25 30Gly Ala Gly Ser Gly Ala Gly Ala Gly Ser Gly
Ala Gly Ala Gly Ser 35 40 45Gly Ala Gly Ala Gly Ser Arg Tyr Val Val
Leu Pro Arg Pro Val Cys 50 55 60Phe Glu Lys Ala Ala Gly Tyr65
70720PRTArtificialseq. repeated indefinitely, synthetic construct
similar to elastin protein. 7Val Pro Gly Val Gly Val Pro Gly Val
Gly Val Pro Gly Val Gly Val1 5 10 15Pro Gly Val Gly
20852PRTArtificialseq. repeated indefinitely, synthetic construct
similar to silk and elastin proteins. 8Gly Val Gly Val Pro Gly Val
Gly Val Pro Gly Val Gly Val Pro Gly1 5 10 15Val Gly Val Pro Gly Val
Gly Val Pro Gly Val Gly Val Pro Gly Val 20 25 30Gly Val Pro Gly Val
Gly Val Pro Gly Ala Gly Ala Gly Ser Gly Ala 35 40 45Gly Ala Gly Ser
50982PRTArtificialseq. repeated indefinitely, synthetic construct
similar to silk and elastin proteins. 9Gly Ala Ala Val Pro Gly Val
Gly Val Pro Gly Val Gly Val Pro Gly1 5 10 15Val Gly Val Pro Gly Val
Gly Val Ala Ala Gly Tyr Gly Ala Gly Ala 20 25 30Gly Ser Gly Ala Gly
Ala Gly Ser Gly Ala Gly Ala Gly Ser Gly Ala 35 40 45Gly Ala Gly Ser
Gly Ala Gly Ala Gly Ser Gly Ala Gly Ala Gly Ser 50 55 60Gly Ala Gly
Ala Gly Ser Gly Ala Gly Ala Gly Ser Gly Ala Gly Ala65 70 75 80Gly
Ser10111PRTArtificialseq. repeated indefinitely, synthetic
construct similar to silk and elastin proteins. 10Gly Ala Gly Ala
Gly Ser Gly Ala Gly Ala Gly Ser Gly Ala Gly Ala1 5 10 15Gly Ser Gly
Ala Gly Ala Gly Ser Gly Ala Gly Ala Gly Ser Gly Ala 20 25 30Gly Ala
Gly Ser Gly Ala Ala Gly Tyr Gly Ala Gly Ala Gly Ser Gly 35 40 45Ala
Gly Ala Gly Ser Gly Ala Gly Ala Gly Ser Gly Ala Gly Ala Gly 50 55
60Ser Gly Ala Gly Ala Gly Ser Gly Val Gly Val Pro Gly Val Gly Val65
70 75 80Pro Gly Val Gly Val Pro Gly Val Gly Val Pro Gly Val Gly Val
Pro 85 90 95Gly Val Gly Val Pro Gly Val Gly Val Pro Gly Val Gly Val
Pro 100 105 1101188PRTArtificialseq. repeated indefinitely,
synthetic construct similar to silk and elastin proteins. 11Gly Val
Gly Val Pro Gly Val Gly Val Pro Gly Val Gly Val Pro Gly1 5 10 15Val
Gly Val Pro Gly Val Gly Val Pro Gly Val Gly Val Pro Gly Val 20 25
30Gly Val Pro Gly Val Gly Val Pro Gly Ala Gly Ala Gly Ser Gly Ala
35 40 45Gly Ala Gly Ser Gly Ala Gly Ala Gly Ser Gly Ala Gly Ala Gly
Ser 50 55 60Gly Ala Gly Ala Gly Ser Gly Ala Gly Ala Gly Ser Gly Ala
Gly Ala65 70 75 80Gly Ser Gly Ala Gly Ala Gly Ser
8512108PRTArtificialseq. repeated indefinitely, synthetic construct
similar to silk and elastin proteins. 12Gly Val Gly Val Pro Gly Val
Gly Val Pro Gly Val Gly Val Pro Gly1 5 10 15Val Gly Val Pro Gly Val
Gly Val Pro Gly Val Gly Val Pro Gly Val 20 25 30Gly Val Pro Gly Val
Gly Val Pro Gly Val Gly Val Pro Gly Val Gly 35 40 45Val Pro Gly Val
Gly Val Pro Gly Val Gly Val Pro Gly Ala Gly Ala 50 55 60Gly Ser Gly
Ala Gly Ala Gly Ser Gly Ala Gly Ala Gly Ser Gly Ala65 70 75 80Gly
Ala Gly Ser Gly Ala Gly Ala Gly Ser Gly Ala Gly Ala Gly Ser 85 90
95Gly Ala Gly Ala Gly Ser Gly Ala Gly Ala Gly Ser 100
10513128PRTArtificialseq. repeated indefinitely, synthetic
construct similar to silk and elastin proteins. 13Gly Val Gly Val
Pro Gly Val Gly Val Pro Gly Val Gly Val Pro Gly1 5 10 15Val Gly Val
Pro Gly Val Gly Val Pro Gly Val Gly Val Pro Gly Val 20 25 30Gly Val
Pro Gly Val Gly Val Pro Gly Val Gly Val Pro Gly Val Gly 35 40 45Val
Pro Gly Val Gly Val Pro Gly Val Gly Val Pro Gly Val Gly Val 50 55
60Pro Gly Val Gly Val Pro Gly Val Gly Val Pro Gly Val Gly Val Pro65
70 75 80Gly Ala Gly Ala Gly Ser Gly Ala Gly Ala Gly Ser Gly Ala Gly
Ala 85 90 95Gly Ser Gly Ala Gly Ala Gly Ser Gly Ala Gly Ala Gly Ser
Gly Ala 100 105 110Gly Ala Gly Ser Gly Ala Gly Ala Gly Ser Gly Ala
Gly Ala Gly Ser 115 120 12514208PRTArtificialseq. repeated
indefinitely, synthetic construct similar to silk and elastin
proteins. 14Gly Val Gly Val Pro Gly Val Gly Val Pro Gly Val Gly Val
Pro Gly1 5 10 15Val Gly Val Pro Gly Val Gly Val Pro Gly Val Gly Val
Pro Gly Val 20 25 30Gly Val Pro Gly Val Gly Val Pro Gly Val Gly Val
Pro Gly Val Gly 35 40 45Val Pro Gly Val Gly Val Pro Gly Val Gly Val
Pro Gly Val Gly Val 50 55 60Pro Gly Val Gly Val Pro Gly Val Gly Val
Pro Gly Val Gly Val Pro65 70 75 80Gly Val Gly Val Pro Gly Val Gly
Val Pro Gly Val Gly Val Pro Gly 85 90 95Val Gly Val Pro Gly Val Gly
Val Pro Gly Val Gly Val Pro Gly Val 100 105 110Gly Val Pro Gly Val
Gly Val Pro Gly Val Gly Val Pro Gly Val Gly 115 120 125Val Pro Gly
Val Gly Val Pro Gly Val Gly Val Pro Gly Val Gly Val 130 135 140Pro
Gly Val Gly Val Pro Gly Val Gly Val Pro Gly Val Gly Val Pro145 150
155 160Gly Ala Gly Ala Gly Ser Gly Ala Gly Ala Gly Ser Gly Ala Gly
Ala 165 170 175Gly Ser Gly Ala Gly Ala Gly Ser Gly Ala Gly Ala Gly
Ser Gly Ala 180 185 190Gly Ala Gly Ser Gly Ala Gly Ala Gly Ser Gly
Ala Gly Ala Gly Ser 195 200 2051576PRTArtificialseq. repeated
indefinitely, synthetic construct similar to silk and elastin
proteins. 15Gly Val Gly Val Pro Gly Val Gly Val Pro Gly Val Gly Val
Pro Gly1 5 10 15Val Gly Val Pro Gly Val Gly Val Pro Gly Val Gly Val
Pro Gly Val 20 25 30Gly Val Pro Gly Val Gly Val Pro Gly Ala Gly Ala
Gly Ser Gly Ala 35 40 45Gly Ala Gly Ser Gly Ala Gly Ala Gly Ser Gly
Ala Gly Ala Gly Ser 50 55 60Gly Ala Gly Ala Gly Ser Gly Ala Gly Ala
Gly Ser65 70 751664PRTArtificialseq. repeated indefinitely,
synthetic construct similar to silk and elastin proteins. 16Gly Val
Gly Val Pro Gly Val Gly Val Pro Gly Val Gly Val Pro Gly1 5 10 15Val
Gly Val Pro Gly Val Gly Val Pro Gly Val Gly Val Pro Gly Val 20 25
30Gly Val Pro Gly Val Gly Val Pro Gly Ala Gly Ala Gly Ser Gly Ala
35 40 45Gly Ala Gly Ser Gly Ala Gly Ala Gly Ser Gly Ala Gly Ala Gly
Ser 50 55 601756PRTArtificialseq. repeated indefinitely, synthetic
construct similar to keratin protein. 17Ala Lys Leu Lys Leu Ala Glu
Ala Lys Leu Glu Leu Ala Glu Ala Lys1 5 10 15Leu Lys Leu Ala Glu Ala
Lys Leu Glu Leu Ala Glu Ala Lys Leu Lys 20 25 30Leu Ala Glu Ala Lys
Leu Glu Leu Ala Glu Ala Lys Leu Lys Leu Ala 35 40 45Glu Ala Lys Leu
Glu Leu Ala Glu 50 551815PRTArtificialseq. repeated indefinitely,
synthetic construct similar to collagen protein. 18Gly Ala Pro Gly
Pro Pro Gly Pro Pro Gly Pro Pro Gly Pro Pro1 5 10
151939PRTArtificialseq. repeated indefinitely, synthetic construct
similar to collagen protein. 19Gly Ala Pro Gly Pro Pro Gly Pro Pro
Gly Pro Pro Gly Pro Pro Gly1 5 10 15Ala Pro Gly Pro Pro Gly Pro Pro
Gly Pro Pro Gly Pro Pro Gly Pro 20 25 30Ala Gly Pro Val Gly Ser Pro
352063PRTArtificialseq. repeated indefinitely, synthetic construct
similar to collagen protein with a cell binding domain from human
collagen. 20Gly Ala Pro Gly Pro Pro Gly Pro Pro Gly Pro Pro Gly Pro
Pro Gly1 5 10 15Ala Pro Gly Pro Pro Gly Pro Pro Gly Pro Pro Gly Pro
Pro Gly Leu 20 25 30Pro Gly Pro Lys Gly Asp Arg Gly Asp Ala Gly Pro
Lys Gly Ala Asp 35 40 45Gly Ser Pro Gly Pro Ala Gly Pro Ala Gly Pro
Val Gly Ser Pro 50 55 602115PRTArtificialseq. repeated
indefinitely, synthetic construct similar to collagen protein.
21Gly Ala Pro Gly Ala Pro Gly Ser Gln Gly Ala Pro Gly Leu Gln1 5 10
15
* * * * *