Note: Descriptions are shown in the official language in which they were submitted.
CA 02296654 2000-O1-18
WO 99/04764 PCT/US98/15096
Tannic Acid-Polymer Compositions for Controlled Release of
Pharmaceutical Agents, Particularly in the Oral Cavity
Background of the Invention
Field of the Invention
The field of the invention is controlled or sustained release compositions
for the release of one or more pharmaceuticals or other agents. Essential
components in the compositions of the present invention include one or more
polymers and tannic acid or tannin. Release of the desired agent can be
adjusted
to a predetermined period of time and for ~ predetermined concentration. The
site
of action of the agent is topical, local or systemic. Polymers are cellulosic
or
protemaceous.
Related Art
Controlled-release products are well known in the pharmaceutical field and
are used to maintain a desired level of medicament over a desired period of
time
while increasing patient compliance by reducing the number of administrations
necessary to achieve the desired level.
Compositions Comprising Polymers and Tannic Acid or Tannin
Calderon et al., J. Agr. Food Chem. 16:479 (1968), compared tannic acid
and quebracho tannin coprecipitation with gelatin to form gelatin/tannin
precipitates. Calderon disclosed that proteins as different as egg albumin and
gelatin readily combine with tannins to form precipitates. Calderon addressed
the
problem of the formation of precipitates between proteins and tannins in
natural
beverages such as fi~uit juice, wines and beer, and further explored the
possibility
that adding a protein, such as gelatin, to the hazy solution could entrap haze
CA 02296654 2000-O1-18
WO 99/04764 PCT/US98/15096
-2-
particles and decrease tannin in the beverage. Calderon was not directed to
any
use for the precipitates, and did not further characterize them.
U.S. PatentNo. 3,255,018 discloses an adhesive chewing gum containing
a tannic acid and gelatin complex. This complex is added to make the gum base
non-adhesive to the teeth.
U.S. Patent No. 3,679,792 discloses a chewing gum composition having
anti-caries activity. The chewing gum contains a gelatin-tannic acid adduct
used
as an adhesive to counteract the tendency of chewing gum compositions to
adhere
to teeth, and particularly to certain types of dentures and artificial teeth.
U.S. Patent No. 4,274,410 discloses an infra-vaginal contraceptive and
drug-release sponge. The document discloses a collagen slurry and a tanning
agent to cross-link the collagen.
U.S. Patent No. 5,223,029 discloses a hardening material for medical and
dental use. Essential components include tri-calcium phosphate or tetra-
calcium
phosphate and a hardening adjuster that may comprise tannin and collagen. The
document suggests using decomposed gelatin (water-soluble gelatin or gelatin
21,
products of Nitta Gelatin Inc.). Collagen can be used by preparing a solution
independent of the tannin solution, by dissolving it in the tannin solution,
or by
using it in its powdered state. No use, other than a hardener, and no physical
characteristics of the tannin-collagen combination is given. Further, the
document
discloses the use of the complex for the slow release of tannic acid for the
formation of a cement and not as a flexible adhesive. Further, there is no
suggestion that this complex should be used for drug release or is suitable
for this
purpose.
Rodu et al., J. Oral Pathol. 17:324 ( 1988), evaluated the in vitro virucidal
activity of soluble components of a topical film-forming medication,
ZilactinTM.
ZilactinTM is a hydroxypropylcellulose-based film-forming medication. Other
active ingredients include tannic acid, salicylic acid and boric acid, which
are
disclosed as necessary for the unique adherent film-forming properties of the
medication.
CA 02296654 2000-O1-18
WO 99/04764 PCT/US98/15096
-3-
Rodu et al., J. Oral Pathol. 17:564 (1988), discloses a bioadhesive agent,
ZilactinTM, as a mucosal bioadhesive that is based on hydroxypropylcellulose
and
is complexed with three organic acids. ZilactinTM is reported to form an
adherent
and soluble film resulting in significant pain relief and protection of ulcers
from
irritants for several hours. The medication was made, among other embodiments,
with a combination of hydroxypropylcellulose and tannic acid dissolved in SD40
alcohol for comparison testing with the parent compound ZilactinTM. The
physical
properties of this binary complex were not investigated, and no use for this
complex for releasing drugs was disclosed or suggested.
U. S. Patent No. 5,081,157 discloses a film-forming composition for topical
application of medicaments to body tissues. The film-forming composition
includes hydroxypropylcellulose for treating skin mucosal tissue and other
moist
tissue by forming an adherent film. An esterification agent is an essential
component of the film. A weak carboxylic acid such as tannic acid is suggested
as the specific esterification agent component. The cellulosic compound is
reacted
with the weak carboxylic acid to form the film.
Gamiz Gracia, et al., J. Pharm. Biomed. Anal. 15:447 (1997) discloses a
flow injection analysis method to determine albumin tannate in tablets.
Albumin
tannate is a compound of tannic acid (tannin) with albumin (50%), used for its
astringent properties in the treatment of diarrhea. This document discloses
albumin tannate as a drug and not as a drug carrier. No physical properties of
this
compound are reported.
U. S. PatentNo. 4,524,824 discloses a dental cement in which a tannic acid
derivative, consisting of a tannic acid-protein combination, is reported.
Suggested
proteins include albumin and gelatin. Precipitates are formed between the
tannic
acid and the protein. The precipitates are used for the slow release of tannic
acid
for the formation of a cement and not to form a flexible adhesive. Moreover,
there is no disclosure or suggestion to use such a complex to release a drug.
None
of the physical characteristics of the complex is provided.
*rB
CA 02296654 2000-O1-18
WO 99/04764 ~ PCTIUS98/15096
-4-
WO 93/ 10827 discloses coating guidewires using a protein-based coating
that has been pretreated by the addition of weak organic acids, for example
tannic
acid. Suggested proteins include gelatin, collagen and albumin. No physical
characteristics are provided for the coating. Furthermore, there is no
disclosure
or suggestion to release a pharmaceutical from the coating.
Oral Delivery Systems
Oral controlled-release delivery systems should ideally be adaptable so that
release rates and profiles can be matched to physiological and
chronotherapeutic
requirements. The art describes free forms, such as sublingual tablets,
troches,
and buccals. In addition to non-attached oral sustained or controlled release
forms, other forms are designed to adhere to the oral mucosa and deliver an
active
pharmaceutical agent either directly into the oral mucosa, or into the saliva.
Ointments and other sticky adhering compositions also have been used. The
active ingredient in all these forms can act locally or systemically.
U.S. Patent No. 4,829,056 describes a buccal tablet consisting of
etorphine, at least one monosaccharide, disaccharide or mixture thereof, and a
mixture of xanthan gum and locust bean gum in a weight ratio of 3:1 to 1:1,
wherein the total weight of the mono- and/or disaccharides relative to the
combined weight of xanthan and locust bean gums is in the ratio of 20:1 to
3:1.
The buccai tablet is intended to be placed between the gingival surface of the
jaw
and the buccal mucosa where it gels to produce a soft hydrated tablet which
may
be retained in position so as to provide release of etorphine for up to two
hours.
The buccal tablet is said to provide improved bioavailability.
U.S. Patent No. 4,948,580 describes a bioadhesive composition which may
be employed as an oral drug delivery system and includes a freeze-dried
polymer
mixture formed of the copolymer poly(methyl vinyl ether/maleic anhydride) and
gelatin dispersed in an ointment base. This composition is said to be useful
to
CA 02296654 2000-O1-18
WO 99/04764 ~ PCT/US9$/15096
-5-
deliver active ingredients such as steroids, antifungal agents, and
antibacterial
agents, to the oral mucosa.
U.S. Patent No. 4,597,959 describes a cosmetic breath -freshener
composition in wafer form which is said to have slow release properties. The
composition includes a multiplicity of microencapsulated liquid droplets of
flavoring material contained in an adhesive base.
U.S. Patent No. 5,077,051 describes bioadhesive microcapsules which
comprise xanthan gum, locust bean gum, a bulking agent and an active agent.
The
microcapsules are said to be useful for delivering buffering agents to the
oral
cavity for anticarious purposes. The microcapsules are prepared by preparing a
hot aqueous solution or suspension of the active agent; adding xanthan gum,
locust bean gum and a bulking agent to form a viscous solution; and then (a)
cooling and then drying the viscous solution to obtain a solid material which
is
then formed into microcapsules, or (b) spray-drying the viscous solution to
form
the microcapsules.
U.S. Patent No. 4,915,948 describes a tablet which is said to have
improved adhesion to mucous membranes. The tablet includes a water soluble
biopolymer selected from xanthan gum, a pectin and mixtures thereof, and a
solid
polyol having a solubility at room temperature in water greater than about
20g/100g solution.
U.S. Patent Nos. 4,994,276, 5,128,143, and 5,135,757, describe a
controlled release excipient comprised of synergistic heterodisperse
polysaccharides (e.g., a heteropolysaccharide, such as xanthan gum in
combination
with a polysaccharide gum capable of cross-linking with the
heteropolysaccharide,
such as locust bean gum) that is capable of processing into oral solid dosage
forms
using either direct compression, following addition of drug and lubricant
powder,
conventional wet granulation, or a combination of the two. Release of the
medicament from the formulations is reported to proceed according to zero-
order
or first-order mechanisms.
CA 02296654 2000-O1-18
WO 99/04764 ~ PCT/US98/15096
-6-
U. S. Patent No. 4,059,686 describes a pharmaceutical preparation for oral
cavity administration characterized by being a mixture of a pharmacologically
active agent, a pharmaceutical carrier, and sodium polyacrylate in
conventional
dosage form. It adheres strongly to a local site and dissolves gradually over
a
prolonged period of time, releasing appropriate amounts of the active agent.
The
preparation is designed to adhere to mucosal membranes.
U.S. Patent No. 4,876,092 describes a sheet-shaped adhesive preparation
comprising an adhesive layer containing, as essential components, a
carboxyvinyl
polymer, a water-insoluble methacrylic copolymer, a polyhydric alcohol, and a
pharmaceutically active agent, and a water-impermeable and water-insoluble
carrier layer containing, as essential components, a pharmaceutically active,
water-
insoluble, film-forming high molecular weight compound and a plasticizes,
which
can adhere within the oral cavity over a period of time and release an active
agent.
The preparation is designed to be adhered to the mucous membrane.
U.S. Patent No. 3,972,995 describes a dosage form for buccal
administration of a drug, and which is directly applicable to the interior
surfaces
of the mouth. The dosage form is comprised of a support member which is water-
insoluble, waterproof and flexible, a moisture-activated adhesive precursor
applied
to one surface of the support member, and an active ingredient applied to the
central portion of the support member, either directly or dispersed in a
matrix.
The dosage form is applied directly to the interior surface of the mouth.
Contact
with saliva activates the adhesive and causes the support member to adhere to
the
interior surface of the mouth, thereby exposing the active ingredient to a
limited
area of the oral mucosa while isolating the active ingredient from the
remainder
of the oral environment.
U.S. Patent No. 5,330,761 describes a controlled release bioadhesive tablet
which includes a locally active agent, a heterodisperse gum matrix, and a
pharmaceutically acceptable diluent. The final product adheres to mucous
membranes and releases the locally active agent over a desired period of time.
CA 02296654 2000-O1-18
WO 99/04764 PCT/US98/15096
_7_
Nagai, T., et al. (J. Cont. Rel. 6:353 (1987)) describes a sustained-release
tablet capable of sticking tightly to human gingiva and not the cheek mucosa.
Further described is a self administered plaster with a water-impermeable
backing
layer (film).
S U.S. Patent No. 4,772,470 discloses an oral bandage comprising a soft
adhesive film comprising a mixture of polycarboxylic acid and/or a
polycarboxylic
acid anhydride and a vinyl acetate polymer in a compatible state, and an oral
preparation comprising such an oral bandage having incorporated therein a
topical
drug. The oral bandage or preparation is reported to exhibit strong adhesion
of
long duration when applied to the oral mucosa or teeth. This patent purports
to
teach a composition for topical administration of pharmaceutically active
agents.
It is drawn primarily to the use of anesthetic compositions, but may comprise
other agents as well. The composition comprises the active agent in a
pharmaceutically acceptable solvent, and in an admixture also includes a
bioadhesive.
U.S. Patent No. 4,900,554 describes an adhesive device for application to
body tissue having an adhesive layer and a backing layer positioned over one
side
of the adhesive layer. The adhesive layer includes one or more acrylic acid
polymers having adhesive properties upon dissolution or swelling in water and
at
least one water-insoluble cellulose derivative. The backing layer is water-
insoluble
or sparingly water-soluble. This patent discloses a composition comprising the
active agent in an admixture that also includes a bioadhesive. Further, it
includes
a backing layer so that the adhesive does not adhere to adjacent areas.
U.S. Patent No. 5,446,070 relates to compositions and methods for topical
administration of pharmaceutically active compounds and specifically to
anesthetic
compounds for topical administration. The invention is a flexible bioadhesive
composition for topical administration. The invention is a flexible
bioadhesive
composition for topical application comprising a pharmaceutically active
agent,
a solvent and a plasticizer, in admixture with a polysaccharide bioadhesive
carrier,
wherein the composition is substantially free of water, substantially water-
CA 02296654 2000-O1-18
WO 99/04764 PCT/US98/15096
_g_
insoluble, and wherein the pharmaceutically active agent is present in a non-
crystallized form. The patent discloses that an exceptionally high loading of
anesthetic agents can be added to a Garner without loss of the adhesive
properties,
so that more rapid delivery of an anesthetic agent to a tissue without
substantial
crystallization of the agent can occur. The document discloses the use of the
composition for topical administration to hard tissue such as teeth.
European Patent Application 223 245 discloses a curable composition
containing methacrylate monomers and a polymerization initiator for
application
to teeth and having the property of in situ polymerization to form a hardened
filler.
The document discloses the use of such filler in combination with an active
agent,
thereby releasing the active agent from the hardened filler.
Furthermore, each of the above-cited references further discuss sustained-
release compositions, many of which can be used to release a pharmaceutically
active agent in the oral cavity.
Several problems are associated with controlled-release or
sustained-release formulations in the oral cavity.
A major problem is providing prolonged release at effective
concentrations. For example, fungal infections beginning in the mouth and then
entering other parts of the body are life-threatening to immuno-compromised
patients. It is thus desirable to release antifungal agents on an ongoing
basis.
However, it is very difficult to achieve.
Buccal tablets and sublingual tablets are pharmaceutical preparations
primarily intended for systemic effect. These tablets are placed between the
cheek
and gingival or under the tongue and allowed to dissolve slowly. The drugs
absorbed through the oral mucous membrane enter directly, not through the
portal
circulation but through the systemic circulation. An advantage of these
tablets is
in the efficient absorption of the drug, because the drug is not decomposed by
the
liver. However, if the disintegration and dissolution of the tablet are too
rapid, the
object of this method of administration is not achieved.
CA 02296654 2000-O1-18
WO 99/04764 ~ PCT/US98/15096
-9-
A problem with these sustained-release devices involves the area of
comfort. Patients often reject these oral sustained-release devices because
they
have a "foreign" feeling. As a result, these devices are often dislodged by
the
patient.
Recently, a tablet for stomatitis has been developed which is applicable
directly to the affected region. But this preparation is also hard and has a
certain
thickness, and persons using it are aware of its presence. Accordingly, the
tablet
may be dislodged with the tongue and swallowed during eating and drinking.
Therefore, it is difficult to retain within the oral cavity for a long time.
Moreover, the known preparations are usually composed of components
which are soluble or disintegrable within the mouth. Thus, the
pharmaceutically
active agents contained in the preparations are mostly swallowed without being
absorbed through the mucous membrane in the oral cavity. Thus, these
preparations are not completely satisfactory as a sustained- or controlled-
release
I 5 preparation for the oral cavity.
In order to retard disintegration of the above said preparations, the
following trials have been made without successful results as a preparation
for oral
cavity administration:
1. to add larger amounts of a binder, without employing a disintegrant,
such as starch;
2. to add a large amount of hydrophobic lubricant, such as magnesium
stearate;
3. to coat the tablet with a water-repellent substance such as wax or
paraffin.
Ointments are not satisfactory for oral cavity administration because of
insufficient adhesion and rather high solubility.
Mucosal patches, which demonstrate good adhesion for extended periods
of time, cause adverse reactions like mucosal itching and irritation at the
patch
sites or even necrosis in severe cases. (Contact-Dermatitis 25(4):230-6
(1991);
Maturitas 13(2):151-4 {1991).) In addition to health complications, the side
CA 02296654 2000-O1-18
WO 99/04764 ~ PCT/US98/15096
-10-
effects profile of a product can lead to added therapeutic costs by requiring
treatment by physicians or visits to emergency rooms.
Another problem is localized release to teeth. That is, the application of
agents that are designed to be delivered to teeth, for example, tooth
whiteners and
desensitizing agents, are for the most part wasted because delivery is to the
whole
oral cavity and not local to the tooth.
Another problem is the difficulty of application of sustained release devices
for the oral cavity.
A particular problem involves the difficulty of obtaining prolonged release
of highly soluble drugs when the delivery system is in an aqueous environment
such as the oral cavity. Hydrogel systems release the drug too quickly.
Erosive
systems, for example systems using the polymer EudragitTM, also result in
release
that is undesirably rapid.
Accordingly, there is a need for an oral controlled-release pharmaceutical
delivery device with the following characteristics. Release can be sustained
at
desired concentrations for a desired period of time, and particularly for
highly
soluble drugs when the delivery system is in an aqueous environment such as
the
oral cavity. Necrosis is avoided. Release can be localized to teeth.
Application
is easy and uncomplicated. Patient comfort is provided. The device does not
impart a "foreign" feeling to the oral cavity. The device facilitates buccai
absorption, resulting in rapid systemic delivery of the released agent. The
device
can also provide localized treatment of the oral mucosa.
Summary of the Invention
The invention is broadly directed to a liquid composition comprising a
polymer and tannic acid or tannin, which composition either dries to form a
solid
composition capable of controlled release of a pharmaceutical, or forms a
precipitate that is capable of being dried to form a solid composition capable
of
controlled release of a pharmaceutical.
CA 02296654 2000-O1-18
WO 99/04764 - PCT/US98/15096
-11-
In highly preferred embodiments, the invention is directed to a liquid
composition comprising a polymer and tannic acid or tannin, where the liquid
composition dries to form an adhesive solid composition capable of .controlled
release of a pharmaceutical or forms a precipitate that can dry to form an
adhesive
solid composition capable of controlled release of a pharmaceutical.
The invention further encompasses liquid compositions comprising a
polymer and tannic acid or tannin and a pharmaceutical, where the liquid
composition dries to form a solid composition capable of controlled release of
the
pharmaceutical agent or forms a precipitate that is capable of being dried to
form
a solid composition capable of controlled release of the pharmaceutical.
In highly preferred embodiments, the invention is directed to a liquid
composition comprising a polymer and tannic acid or tannin and a
pharmaceutical,
where the liquid composition dries to form an adhesive solid composition
capable
of controlled release of the pharmaceutical, or forms a precipitate that dries
to
form an adhesive solid composition capable of controlled release of the
pharmaceutical.
The invention further encompasses a liquid composition comprising a
polymer and tannic acid or tannin and a pharmaceutical, wherein the
pharmaceutical agent is entrapped in liposomes or microcapsules, microspheres,
nanocapsules or nanospheres and where the liquid composition dries to form a
solid composition capable of controlled release of the pharmaceutical agent or
forms a precipitate that is capable of being dried to form a solid composition
capable of controlled release of the pharmaceutical.
In highly preferred embodiments, the invention is directed to a liquid
composition comprising a polymer and tannic acid or tannin and a
pharmaceutical
wherein the pharmaceutical agent is entrapped in Iiposomes or microcapsules,
microspheres, nanocapsules or nanospheres and where the liquid composition
dries to form an adhesive solid composition capable of controlled release of
the
pharmaceutical agent or forms a precipitate that is capable of being dried to
form
an adhesive solid composition capable of controlled release ofthe
pharmaceutical.
CA 02296654 2000-O1-18
WO 99/04764 - PCT/US98/15096
-12-
The invention naturally encompasses solid compositions comprising a
polymer, tannic acid or tannin, and a pharmaceutical, where the solid
composition
is capable of controlled release of the pharmaceutical. -_
In preferred embodiments, the invention is directed to a solid adhesive
composition comprising a polymer, tannic acid or tannin, and a pharmaceutical,
where the solid composition is capable of controlled release of the
pharmaceutical.
In preferred embodiments, the polymer is a protein. Preferred proteins
include, but are not limited to, gelatin, hydrolyzed gelatin, albumin and
collagen.
In alternative embodiments, the polymer is a cellulosic polymer. Preferred
polymers include, but are not limited to, hydroxyethylcellulose,
hydroxypropylcellulose, and hydroxypropylmethylcellulose.
The invention is also directed to methods of making each of the
compositions disclosed herein.
The invention is also directed to the use of the solid compositions in the
treatment of various conditions, or in uses where controlled release of an
agent is
desirable.
In preferred embodiments, the invention is directed to a composition for
sustained release of a pharmaceutical in the oral cavity.
In a highly preferred form, the invention is in the form of a pharmaceutical
oral patch that can be attached to the surface of a tooth or other hard dental
structure where it can release an agent for topical, systemic, or local
treatment.
Brief Description of the Figures
Figure 1: In vitro release of nicotine from patches containing nicotine
entrapped in liposomes compared to patches containing nicotine not entrapped
in
liposomes. Figure 1 shows the average release of nicotine from Patches # 285-
23A
(I, II), 285-23B (III, IV), 285-28(V) containing centrifuged liposomes Type
MLV, and comparison to nicotine release from non-liposomal nicotine Patches #
CA 02296654 2000-O1-18
WO 99/04764 - PCTIUS98/15096
-13-
49A00 (VI,VIII). The filled circle is I-II; the filled square is III-IV; the
open
triangle is V, and the filled triangle is VI-VIII.
Figure 2: In vivo release of nicotine from patches containing nicotine
entrapped in liposomes compared to patches containing nicotine not entrapped
in
liposomes. Figure 2 shows release of nicotine from patch # 285-28 containing
centrifuged liposomes Type MLV compared to nicotine release from non-
liposomal Patch #158-64. The solid circle is #285-28 and the solid box is #158-
64.
Figure 3: In vitro release of flurbiprofen from patch.
Detailed Description of the Preferred Embodiments
The invention is broadly directed to a liquid composition comprising a
polymer and tannic acid or tannin, which composition either dries to form a
solid
composition capable of controlled release of a pharmaceutical, or forms a
precipitate that is capable of being dried to form a solid composition capable
of
controlled release of a pharmaceutical.
In preferred embodiments, the polymer is a protein. Preferred proteins
include, but are not limited to, gelatin, hydrolyzed gelatin, albumin and
collagen.
In alternative embodiments, the polymer is a cellulosic polymer. Preferred
polymers include, but are not limited to, hydroxyethylcellulose,
hydroxypropylcellulose, and hydroxypropylmethylcellulose.
In preferred embodiments of the invention, the liquid composition
comprises a mixture of the polymer and tannic acid or tannin.
The minimal essential components of the liquid composition can be a
polymer and tannic acid or tannin. It is understood, however, that the liquid
composition may contain more than one polymer. Thus, the composition can
encompass more than one protein, more than one cellulosic polymer, and
combinations of the two.
CA 02296654 2000-O1-18
WO 99/04764 PCT/US98/15096
-14-
Thus, the composition can consist essentially of any of the proteins or
cellulosic polymers disclosed herein, as well as other appropriate proteins
and
cellulosic polymers, and tannic acid or tannin.
Optional components include plasticizers, such as glycerol, polyethylene
glycols, and citrate esters, glycerol being a particularly preferred
plasticizes when
the polymer is a hydrolyzed gelatin.
However, glycerol may also be used as a plasticizes with other proteins
described herein or in general embodiments in which a protein is used in
combination with tannic acid or tannin.
Emulsifiers may also be added, optionally.
In highly preferred embodiments, the invention is directed to a liquid
composition comprising a polymer and tannic acid or tannin, where the liquid
composition dries to form an adhesive solid composition capable of controlled
release of a pharmaceutical or forms a precipitate that can dry to form an
adhesive
solid composition capable of controlled release of a pharmaceutical.
In preferred embodiments, the polymer is a protein. Preferred proteins
include, but are not limited to, gelatin, hydrolyzed gelatin, collagen and
albumin.
In alternative embodiments, the polymer is a cellulosic polymer. Preferred
cellulosic polymers include, but are not limited to, hydroxyethylcellulose,
hydroxypropylcellulose, and hydroxypropylmethylcellulose.
In preferred embodiments, the liquid composition comprises a mixture of
the polymer and tannic acid or tannin.
The minimal essential components in the liquid composition can be the
polymer and tannic acid or tannin. It is understood, however, that the liquid
composition may contain more than one polymer. Thus, the composition
encompasses more than one protein, more than one cellulosic polymer, and
combinations of the two.
Thus, the composition can consist essentially of any of the proteins or
cellulosic polymers disclosed herein, as well as other appropriate proteins
and
cellulosic polymers, and tannic acid or tannin.
CA 02296654 2000-O1-18
WO 99/04764 PCT/US98/15096
-15-
Other components are optionally included. These include plasticizers, such
as glycerol, polyethylene glycols and citrate esters, with glycerol being the
particularly preferred plasticizer when the polymer is a hydrolyzed gelatin.
Emulsifiers may also be added optionally.
S The invention further encompasses liquid compositions comprising a
polymer and tannic acid and tannin and a pharmaceutical, where the liquid
composition dries to form a solid composition capable of controlled release of
the
pharmaceutical or forms a precipitate that is capable of being dried to form a
solid
composition capable of controlled release of the pharmaceutical.
In preferred embodiments, the polymer is a protein. Preferred proteins
include, but are not limited to, gelatin, hydrolyzed gelatin, collagen and
albumin.
In alternative embodiments, the polymer is a cellulosic polymer and tannic
acid or tannin and a pharmaceutical. Preferred cellulosic polymers include,
but are
not limited to, hydroxyethylcellulose, hydroxypropylcellulose, and
hydroxypropylmethylcellulose.
In preferred embodiments, the liquid composition comprises a mixture of
the polymer, tannic acid or tannin, and a pharmaceutical.
The minimal essential components of the liquid composition can be,
therefore, a polymer, tannic acid or tannin, and the pharmaceutical. However,
it
is to be understood that more than one polymer or type of polymer can be
included. That is, more than one protein, more than one cellulosic polymer,
and
combinations of the two, are encompassed.
Thus, the composition can consist essentially of any of the proteins or
cellulosic polymers disclosed herein, as well as other appropriate proteins
and
cellulosic polymers, and tannic acid or tannin, and the pharmaceutical.
Optional agents include plasticizers such as glycerol, polyethylene glycols
and citrate esters, glycerol being the particularly preferred plasticizer when
the
polymer is a protein, and particularly hydrolyzed gelatin.
Emulsifiers may also be added optionally.
CA 02296654 2000-O1-18
WO 99/04764 PCTlUS98/15096
-16-
In highly preferred embodiments, the invention is directed to a liquid
composition comprising a polymer and tannic acid or tannin and a
pharmaceutical,
where the liquid composition dries to form an adhesive solid composition
capable
of controlled release of the pharmaceutical, or forms a precipitate that dries
to
form an adhesive solid composition capable of controlled release of the
pharmaceutical.
In preferred embodiments, the polymer is a protein. Preferred proteins
include, but are not limited to, gelatin, hydrolyzed gelatin, collagen and
albumin.
Alternatively, the polymer is a cellulosic polymer. Preferred cellulosic
polymers include, but are not limited to, hydroxyethylcellulose,
hydroxypropylcellulose, and hydroxypropylmethylcellulose.
In preferred embodiments, the liquid composition comprises a mixture of
the polymer and tannic acid or tannin and the pharmaceutical.
The minimal essential components for forming the adhesive solid
composition can be the polymer, tannic acid or tannin, and a pharmaceutical.
It
is understood, however, that the liquid composition may contain more than one
polymer or type of polymer. Thus, the composition encompasses mixtures of
various proteins, cellulosic polymers, and combinations of the two.
Thus, the composition can consist essentially of any of the proteins or
cellulosic polymers disclosed herein, as well as other appropriate proteins
and
cellulosic polymers, and tannic acid or tannin, and the pharmaceutical.
Optional components include plasticizers such as glycerol, polyethylene
glycols and citrate esters, glycerol being the particularly preferred
plasticizer when
the polymer is hydrolyzed gelatin.
Emulsifiers may also be added optionally.
The invention further encompasses liquid compositions comprising a
polymer and tannic acid or tannin and a pharmaceutical, wherein the
pharmaceutical agent is entrapped in liposomes or microcapsules, microspheres,
nanocapsules or nanospheres and where the liquid composition dries to form a
solid composition capable of controlled release of the pharmaceutical agent or
CA 02296654 2000-O1-18
WO 99/04764 PCT/US98/15096
-17-
forms a precipitate that is capable of being dried to form a solid composition
capable of controlled release of the pharmaceutical.
Also for this aspect of the invention in which the pharmaceutical agent is
entrapped in liposomes or microcapsules, microspheres, nanocapsules or
nanospheres, in preferred embodiments, the polymer is a protein. Preferred
proteins include, but are not limited to, gelatin, hydrolyzed gelatin,
collagen, and
albumin.
The liposome may be a multilamellar vesicle or unilamellar vesicle.
Liposomes comprise phospholipids and/or sphingolipids and optionally lipids
such
as cholesterol and phosphatidic acid and antioxidants. Preferred phospholipids
are
soybean lecithin, egg lecithin, soybean phosphatidylcholine, egg
phosphatidylcholine, synthetic phosphatidylcholine, phosphatidylserine,
phosphatidylinositol, phosphatidylglycerol, phosphatidylethanolamine, alone or
in
mixtures. A preferred sphingolipid is sphingomyelin. Highly preferred
liposomes
comprise phosphatidylcholine, phosphatidylethanolamine, cholesterol and an
antioxidant.
The microcapsule, microsphere, nanocapsule or nanosphere comprises
polymers and optionally plasticizers and emulsifiers. The preferred polymers
comprising these microcapsules, microspheres, nanocapsules or nanospheres are
polyalkyl methacrylate such as polymethylmethacrylate, polyalkylcyanoacrylates
such as polymethylcyanomethacrylate, polyesters such as polylactic acid and
polylactic/glycolic acid copolymers, cellulose derivatives such as
ethylcellulose and
cellulose acetate and proteins such as albumin, gelatin, and hydrolyzed
gelatin, and
polysaccharides such as sodium alginate, pectin, chitosan, guar gum, and
xanthan
gum.
In alternate embodiments of the liquid composition of the invention the
polymer is a cellulosic polymer. Preferred cellulosic polymers include, but
are not
limited to, hydroxyethylcellulose, hydroxypropylcellulose, and
hydroxypropylmethylcellulose.
CA 02296654 2000-O1-18
WO 99/04764 - PCT/US98/15096
-18-
In preferred such embodiments, the liquid composition comprises a
mixture of the polymer, tannic acid or tannin, and a pharmaceutical entrapped
in
liposomes or microcapsules, microspheres, nanocapsules or nanospheres.
The minimal essential components of the liquid composition can be,
therefore, a polymer, tannic acid or tannin, and the pharmaceutical entrapped
in
a liposome or microcapsule, microsphere, nanocapsule or nanosphere. However,
it is to be understood that more than one polymer or type of polymer can be
included. That is, more than one protein, more than one cellulosic polymer,
and
combinations of the two, are encompassed. It is further understood that more
than one type of liposome or microcapsule, microsphere, nanocapsule or
nanosphere or combination of any of them, are also encompassed.
Thus the composition can consist essentially of any of the proteins or
cellulosic polymers disclosed herein, as well as other appropriate proteins
and
cellulosic polymers, and tannic acid or tannin, and the pharmaceutical
entrapped
1 S in any of the liposomes or microcapsules, microspheres, nanocapsules or
nanospheres, or combination of liposomes or microcapsules, microspheres,
nanocapsules or nanospheres as disclosed herein.
Optional agents include plasticizers such as glycerol, polyethylene glycols,
and citrate esters, glycerol being the particularly preferred plasticizer when
the
polymer is a protein, and particularly hydrolyzed gelatin.
Emulsifiers may also be added optionally.
In highly preferred embodiments, also for this additional aspect of the
invention in which the pharmaceutical agent is entrapped in liposomes or
microcapsules, microspheres, nanocapsules or nanospheres, the invention is
directed to liquid compositions comprising a polymer and tannic acid or tannin
and
a pharmaceutical wherein the pharmaceutical agent is entrapped in liposomes or
microcapsules, microspheres, nanocapsules or nanospheres and where the liquid
composition dries to form an adhesive solid composition capable of controlled
release of the pharmaceutical agent or forms a precipitate that is capable of
being
*rB
CA 02296654 2000-O1-18
WO 99/04764 PCT/US98I15096
-19-
dried to form an adhesive solid composition capable of controlled release of
the
pharmaceutical.
In preferred embodiments, the polymer is a protein. Preferred proteins
include, but are not limited to, gelatin, hydrolyzed gelatin, collagen, and
albumin.
The liposomes may be a multilamellar vesicle or a unilamellar vesicle.
Liposomes comprise phospholipids and/or sphingolipids and optionally lipids
such
as cholesterol and phosphatidic acid and antioxidants. Preferred phospholipids
are
soybean lecithin, egg lecithin, soybean phosphatidylcholine, egg
phosphatidylcholine, synthetic phosphatidylcholine, phosphatidylserine,
phosphatidylinositol, phosphatidylglycerol, phosphatidylethanolamine, alone or
in
mixtures. A preferred sphingolipid is sphingomyelin. Highly preferred
liposomes
comprise phosphatidylcholine, phosphatidylethanolamine, cholesterol and an
antioxidant.
The microcapsule, microsphere, nanocapsule or nanosphere comprises
polymers and optionally plasticizers and emulsifiers. The preferred polymers
comprising these or microcapsules, microspheres, nanocapsules or nanospheres
are polyalkyl methacrylate such as polymethylmethacrylate,
polyalkylcyanoacrylates such as polymethylcyanomethacrylate, polyesters such
as
polylactic acid and polylactic/glycolic acid copolymers, cellulose derivatives
such
as ethylcellulose and cellulose acetate and proteins such as albumin, gelatin,
and
hydrolyzed gelatin, and polysaccharides such as sodium alginate, pectin,
chitosan,
guar gum, and xanthan gum.
In alternate embodiments of the liquid composition of the invention the
polymer is a cellulosic polymer. Preferred cellulosic polymers include, but
are not
limited to, hydroxyethylcellulose, hydroxypropylcellulose, and
hydroxypropylmethylcellulose.
In such preferred embodiments, the liquid composition comprises a
mixture of the polymer, tannic acid or tannin, and a pharmaceutical entrapped
in
liposomes or microcapsules, microspheres, nanocapsules or nanospheres.
CA 02296654 2000-O1-18
WO 99/04764 - PCT/US98/15096
-20-
The minimal essential components of the liquid composition can be,
therefore, a polymer, tannic acid or tannin, and the pharmaceutical entrapped
in
a liposome or microcapsule, microsphere, nanocapsule or nanosphere. -However,
it is to be understood that more than one polymer or type of polymer can be
included. That is, more than one protein, more than one cellulosic polymer,
and
combinations of any of them, are encompassed. It is further understood that
more
than one type of liposome or microcapsule, microsphere, nanocapsule or
nanosphere or combination of the two, are also encompassed.
Thus the composition can consist essentially of any of the proteins or
cellulosic polymers disclosed herein, as well as other appropriate proteins
and
cellulosic polymers, and tannic acid or tannin, and the pharmaceutical
entrapped
in any of the liposomes or microcapsules, microspheres, nanocapsules or
nanospheres, or combination of liposomes or microcapsules, microspheres,
nanocapsules or nanospheres as disclosed herein.
Optional agents include plasticizers such as glycerol, polyethylene glycols,
and citrate esters, glycerol being the particularly preferred plasticizer when
the
polymer is a protein, and particularly hydrolyzed gelatin.
Emulsifiers may also be added optionally.
The invention naturally encompasses solid compositions comprising a
polymer, tannic acid or tannin, and a pharmaceutical, where the solid
composition
is capable of controlled release of the pharmaceutical.
In preferred embodiments, the polymer is a protein. Preferred proteins
include, but are not limited to, gelatin, hydrolyzed gelatin, albumin and
collagen.
Alternatively, the polymer is a cellulosic polymer. Preferred polymers
include, but are not limited to, hydroxyethylcellulose,
hydroxypropylcellulose, and
hydroxypropylmethylcellulose.
Since the liquid composition can comprise a mixture of the polymer, tannic
acid or tannin and the pharmaceutical, the solid composition accordingly
comprises a mixture of a polymer, tannic acid or tannin, and a pharmaceutical.
CA 02296654 2000-O1-18
WO 99!04764 PCT/US98115096
-21-
Thus, the pharmaceutical is dispersed or embedded in the dried matrix of
the polymer-tannic acid/tannin.
The minimal essential components in the solid composition can include the
polymer, tannic acid or tannin, and a pharmaceutical. It is understood,
however,
that the solid composition may contain more than one suitable polymer. Thus,
the
composition encompasses more than one protein, more than one cellulosic
polymer, and combinations of the two.
Thus, the solid composition can consist essentially of any of the proteins
or cellulosic polymers disclosed herein, as well as other appropriate proteins
and
cellulosic polymers, and tannic acid or tannin and the pharmaceutical.
When appropriate, the solid composition of this invention may be coated
with a suitable pharmaceutical coating.
In preferred embodiments, the invention is directed to a solid adhesive
composition comprising a polymer, tannic acid or tannin, and a pharmaceutical,
where the solid composition is capable of controlled release of the
pharmaceutical.
In preferred embodiments, the polymer is a protein. Preferred proteins
include, but are not limited to, gelatin, hydrolyzed gelatin, albumin and
collagen.
Alternatively, the polymer is a cellulosic polymer. Preferred cellulosic
polymers include, but are not limited to, hydroxyethylcellulose,
hydroxypropylcellulose, and hydroxypropylmethylcellulose.
The solid adhesive composition comprises a mixture of a polymer, tannic
acid or tannin and a pharmaceutical.
Thus, the pharmaceutical is dispersed or embedded in the dried adhesive
matrix of the polymer-tannic acid/tannin.
The minimal essential components in the solid adhesive composition can
be the polymer, tannic acid or tannin, and the pharmaceutical. It is
understood,
however, that the solid composition may contain more than one polymer. Thus,
the composition encompasses more than one protein, more than one cellulosic
polymer, and combinations of the two.
CA 02296654 2000-O1-18
WO 99/04764 PCT/US98/15096
-22-
Accordingly, the composition can consist essentially of any of the proteins
or cellulosic polymers disclosed herein, combinations thereof, as well as
other
appropriate polymers, and tannic acid or tannin, and a pharmaceutical.
The solid compositions described herein encompass biodegradable
formulations.
Although the above description relates specifically to the release of
pharmaceuticals, it is to be understood that other agents can be released from
the
solid compositions described herein. Examples of such agents include, but are
not
limited to, cosmetics, vitamins, minerals, flavorants, colorants, toxins such
as
pesticides, odorants, and the like.
For controlling the release of a pharmaceutical or other agent from the
solid compositions disclosed herein, the agent can be entrapped in the
polymeraannic acid matrix. The extent of such entrapment, and thereby the
extent
of sustained release, is controlled by the choice of polymer.
The solvents used to prepare the polymer-tannic complex can be useful as
release-adjusting agents, since they can strongly affect the release rate, as
shown
in the examples herein.
An outer polymer matrix as shown in the examples herein, is a form of
release-adjusting agent because it contributes to controlling the release of
the
drug. It can be formulated with or without its own release-adjusting agents,
to
retard release from the inner matrix by varying amounts.
Release of the pharmaceutical can also be controlled by the addition of pH-
adjusting agents, release-adjusting agents, solubility-adjusting agents, and
combinations thereof, to the solution or suspension of the polymer being added
to the dried precipitate.
The invention is also directed to methods of making each of the
compositions disclosed herein.
In its broadest embodiment, the polymer and tannic acid or tannin are
mixed in a solvent, and the mixture is then dried to form the solid
composition.
CA 02296654 2000-O1-18
WO 99/04764 PCT/US98115096
-23-
Alternatively, the polymer may be first dissolved in a solvent and the tannic
acid
or tannin separately dissolved in a solvent prior to mixing.
The polymer may or may not form a precipitate when mixed with the
tannic acid or tannin. In embodiments in which the tannic acid or tannin forms
a
precipitate with the polymer, the composition is made as follows:
(1) the polymer is dissolved in a solvent,
(2) tannic acid or tannin is added in a solvent,
{3) a precipitate is allowed to form,
(4) the precipitate is dried to form the solid composition.
A pharmaceuticals) can be added to the polymer solution or the tannic
acid solution. When added to a polymer solution which will form a precipitate,
the pharmaceutical is then mixed in the precipitate that is formed, so that
when the
precipitate is dried the pharmaceutical is embedded or dispersed in the solid
composition formed from the precipitate.
In alternative embodiments, however, the solid composition can be formed
as in steps 1-4 and then one or more pharmaceuticals can be added to this
precipitate that is further processed for controlled release of the
pharmaceuticals j
from the dried precipitate. The drug can be added to the dried precipitate in
solution and then subsequently dried or can be mixed in powdered form with the
precipitate. This can then be pressed or otherwise formed together according
to
methods well known in the art.
Preferred solvents for the polymer include, but are not limited to, water,
ethanol, and mixtures of water and ethanol, isopropanol, mixtures of water and
isopropanol, n-propanol, and mixtures of water and n-propanol.
Preferred solvents for the tannic acid or tannin include, but are not limited
to, water, ethanol, and mixtures of water and ethanol, isopropanol, mixtures
of
water and isopropanol, n-propanol, and mixtures of water and n-propanol.
When the polymer is a protein, preferred solvents include, but are not
limited to, water, ethanol, and mixtures of water and ethanol, isopropanol,
CA 02296654 2000-O1-18
WO 99/04764 - PCT/US98/15096
-24-
mixtures of water and isopropanol, n-propanol, and mixtures of water and n-
propanol.
When the polymer is a cellulosic polymer, preferred solvents include, but
are not limited to, water, ethanol, and mixtures of water and ethanol,
isopropanol,
mixtures of water and isopropanol, n-propanol, and mixtures of water and
n-propanol.
When the polymer and tannic acid are dissolved in the same solvent,
preferred solvents include, but are not limited to, water, ethanol, and
mixtures of
water and ethanol, isopropanol, mixtures of water and isopropanol, n-propanol,
and mixtures of water and n-propanol.
In alternative embodiments, the dried precipitate disclosed above is ground
into a powder, and the powder is then mixed with a further polymer in a
solvent,
and this mixture is then dried to form the final solid composition. This
second
polymer thus forms an outer matrix over the complex.
Preferred polymers for mixing with the polymer-tannic acid/tannin
precipitate include any polymer that physically binds the powder together,
allowing the powder to adhere to the tooth as a mass. The polymer needs to be
flexible, and therefore, a plasticizer is essential. The polymer should be
degradable
and/or allow saliva to diffuse through it to allow for drug release from the
powder.
The polymer should be either soluble or dispersible in a solvent in which the
powder is insoluble, so that the powder will not re-dissolve when the polymer
is
added.
This second polymer can optionally be formulated with release-adjusting
agents, pH-adjusting agents, emulsifiers, and solubility-adjusting agents.
The preferred second polymer is a polyacrylate polymer, and particularly
a EudragitTM polymer.
Preferred polymers that can be used as a second polymer when the first
polymer is a protein or a cellulosic polymer include, but are not limited to,
EudragitTM L-100, EudragitTM L 30D-55, EudragitTM S-100, EudragitTM NE-100,
EudragitTM NE-30, EudragitTM RL, EudragitTM RS, hydroxypropylcellulose,
hydroxyethylcellulose, hydroxypropylmethylcellulose, pectin, calcium
pectinate,
*rB
CA 02296654 2000-O1-18
WO 99/04764 ~ PCT/US98/15096
-25-
alginic acid, calcium alginate, cellulose acetate phthalate, carbopol, guar
gum, gum
tragacanth, gum acacia, other vegetable gums, and chitosan.
The second polymer serves as a matrix for the tannic-polymer-complex
powder (precipitate). It binds the powder together for ease of application and
control of dosage. That is, a premeasured amount of the pharmaceutical agents)
can be applied in one single application, rather than in repeated applications
(as in
a varnish coated onto teeth, for example).
It further can help control the rate of releasing the drug by controlling or
attenuating the ability of the saliva to interact with the precipitate. The
degradation of the polymer and permeability with saliva allow for the release
of
the powder into the saliva and thereby for the release of the pharmaceutical.
In preferred embodiments, the composition is made as follows: ( 1 ) protein
and a pharmaceutical are dissolved in a solvent comprising ethanol and water;
(2) tannic acid or tannin is added in a solvent comprising ethanol and water;
(3) a
precipitate is allowed to form; (4) the precipitate is dried to form the solid
composition.
In highly preferred embodiments, the first four steps above are performed
but the following additional steps are then performed: (S) the dried
precipitate is
ground into a powder; (6) the powder is mixed with a EudragitTM polymer and a
plasticizer in a solvent comprising ethanol and water or as a latex suspension
in
water; (7) the mixture is dried.
In highly-preferred embodiments of the invention, the protein is hydrolyzed
gelatin and the second polymer is EudragitTM L-100.
Preferred pharmaceuticals include, but are not limited to, nicotine, nicotine
salts, nicotine polymer complexes, lidocaine, piroxicam, flurbiprofen,
dihydroergotamine mesylate, ergotamine tartarate, sumaptriptan succinate,
isosorbide dinitrate, isosorbide mononitrate, nifedipine, ondansetron
hydrochloride, and peptide drugs. Highly or significantly water-soluble
pharmaceuticals are particularly suited for release from embodiments in which
a
CA 02296654 2000-O1-18
WO 99/04764 PCT/US98/15096
-26-
protein-tannic acid/tannin precipitate has been formed. Embodiments including
a second polymer are particularly suitable for releasing such pharmaceuticals.
In certain embodiments of the invention, the same or a-_ different
pharmaceutical can be added in the second polymer solution and be released
therefrom (when solidified).
The invention is also directed to the use of the solid compositions in the
treatment of various conditions. The compositions can also be used as a powder
or microcapsule in a capsule for oral delivery to the gastrointestinal tract,
compressed into tablets alone or with typical excipients for oral delivery to
the
gastrointestinal tract, as a lozenge for local delivery to the oral cavity or
for
delivery to the gastrointestinal tract, a suppository for rectal delivery, a
vaginal
tablet or suppository, or as an ointment for topical use.
Accordingly, depending on the use of the compositions, the physical form
of the composition can be adjusted. For example, the compositions may be used
as a film, nanoparticle, microparticle or bead. The compositions could also be
used as a powder or microcapsules in a capsule, compressed into tablets alone
or
with typical excipients, as a lozenge, suppository, vaginal tablet or
suppository,
or as an ointment. When appropriate, the composition of this invention may be
coated with a suitable pharmaceutical coating.
In preferred embodiments, the invention is directed to a composition for
sustained release of a pharmaceutical in the oral cavity. In a highly
preferred form,
the invention is in the form of a pharmaceutical oral patch that can be
attached to
the surface of a tooth, denture, or other hard dental structure.
The method provides for buccal absorption of an active agent resulting in
rapid systemic delivery of desired amounts of agent for a desired period of
time.
The method also provides for the delivery of an active agent confined to
a tooth area and avoiding release elsewhere in the oral cavity.
The method also allows for localized treatment of affected sites in the oral
cavity or throat area.
CA 02296654 2000-O1-18
WO 99/04764 PCT/US98/15096
_27_
The invention also provides a patient with the compositions described
herein by adhesively adhering the solid, sustained-release composition to the
hard
surface of the patient's mouth, for example, teeth or dentures
As a pharmaceutical oral patch, the solid composition can be modified into
any shape and size, depending on the purposes of drug release. Thus, if large
amounts of a drug are to be released, in addition to increasing the
concentration
of drug, in the sustained-release composition, the solid form can be larger in
size
and/or greater in thickness.
The important consideration for shape and size is that the patch does not
confer unusual sensation to the patient when applied, and can effectively
release
the desired pharmaceutically active agent at the desired levels and for the
desired
duration of time. For example, for the rapid release of a small amount of
drug, a
thin layer, in which the drug is dispersed, may be required.
The following considerations are important in choosing the site of
application: (1) the salivary flow around the site; (2) the accessibility for
application; (3) the comfort of the patient.
Patch components are suitable to remain in the oral cavity for prolonged
periods of time. In a preferred embodiment, the patch remains in the oral
cavity
between 6 to 8 hours. However, other embodiments can last for various desired
periods of time.
The invention is also directed to a method for making the sustained-release
compositions so that the rate of release can be adjusted in the final, solid
form.
The invention is also directed to methods for using the compositions of the
present invention to release appropriate pharmaceutical agents in the oral
cavity.
Potentially, any pharmaceutically active agent can be released, although, as
mentioned, the preferred agents are those that are soluble or very soluble in
water.
In addition, potentially any condition can be treated by means of the
release of a pharmaceutical from the patch. These are described in more detail
below.
Preferred sites of application include but are not limited to the upper teeth.
CA 02296654 2000-O1-18
WO 99!04764 PCT/US98/15096
-28-
The sites of action for the pharmaceutically active agents include the oral
mucosa of the mouth, throat, and esophagus per se, systemic delivery via the
oral
mucosa, or localized delivery to one or more teeth.
The amount of active agent included in the final, controlled release product
S can be determined by one skilled in the art without undue experimentation,
and is
generally from about 0.1% to about 35% by weight of the final product. The
particular amount of the active agent included will, of course, depend upon
the
particular agent and its intended use.
The present invention can include other locally active agents, such as
flavorants and sweeteners. The flavoring agents may be natural or synthetic.
The
flavoring agent is a common flavorant including wintergreen, peppermint,
spearmint, menthol, fruit flavors, vanilla, cinnamon, various spices, or
others
known in the art. Generally any flavoring or food additive, such as those
described in Chemical Used in Food Processing, Pub. No. 1274, National
Academy of Sciences, pages 63-258, can be used. The amount of flavoring
employed is normally a matter of preference subject to such factors as flavor
type,
individual flavor, and strength desired. Generally, the final product includes
from
about 0.1 % to about 5% weight flavorant.
Sweeteners useful in the present invention include sucrose and aspartame.
In general, sweeteners (when present) are included in an amount from about
0.001 % to about 5.0% by weight of the final product.
Effective amounts of coloring agents (e.g., titanium dioxide, F.D. & C.,
and D. & C. dyes; see the Kirk-Othmer Encyclopedia of Chemical Technology,
vol. 5, pp. 857-884); softeners, stabilizers, binders, odor-controlling
agents, and
preservatives can also be contained in the patch, as long as they do not
impair
adhesiveness or impede pharmacological effects.
The term "therapeutically effective amount" is intended to mean the
amount of pharmaceutically active agent sufficient to produce the desired
effect
when released from the dental patch described herein. These amounts are known
in the art or may be determined by methods known in the art. The amounts
CA 02296654 2000-O1-18
WO 99/04764 PCT/US98/15096
-29-
depend upon the agents chosen and whether the site of action is the tooth per
se,
the oral mucosa (and the region of the oral mucosa), or systemic.
The upper limit on the amount of drug in the composition is determined
by the properties of the polymeric matrix and the chemical interaction of the
drug
with the polymeric matrix.
The amount of active agent in the composition necessary to provide the
desired amounts and concentration in the oral cavity can be determined by
known
methods. Thus, the concentration and the quantity of the agent per unit area
of
the patch (i.e., per square or cubic millimeter) can be varied independently
in order
to achieve a desired effect. Higher concentrations of agent contained in a
dosage
form of decreased thickness will result in an agent with fast onset and short
duration. High concentrations of an agent contained in a dosage form of
increased
thickness (higher milligrams of agent per square or cubic millimeter) will
result in
potent effect with fast onset and long duration. Low concentrations of the
agent
in a dosage form of decreased thickness will result in mild effect with longer
onset
and short duration. Low concentrations of the agent contained in a dosage form
of increased thickness will have mild effect with longer onset and longer
duration.
As shown in the above explanation, the ability to coat thin or thick, enables
the
practitioner of the invention to vary the dosage of the system as needed for
particular anatomical sites of interest and according to the specific drug.
The term
"onset" is intended to mean the time needed to reach the desired concentration
level of the pharmaceutical agent. It is used according to its normal and art-
recognized meaning.
The term "duration" as used herein, means the period of time during which
the desired concentration of pharmaceutical agent is delivered. This term is
used
according to its normal and art-recognized meaning.
The term "adhesive" as used herein, means an adhesive which attaches, and
preferably strongly attaches, the release layer to teeth or other hard
structures in
the mouth such as dentures. To qualify as an adhesive, the substance must be
capable of maintaining adhesion in the moist or wet environments of the oral
CA 02296654 2000-O1-18
WO 99/04764 PCT/US98/15096
-30-
cavity. It can also be "self adhesive" in that it attaches to the site of
interest
without the need to reinforce its attachment by way of another adhesive. Thus,
the term "adhesive" is used according to its normal and art-recognized
meaning.
Adhesion can only be quantified with reference to a specific type of test or
S usage. It is not in itself a basic physical property, such as the surface
free energy
or the film thickness, whose measurement can be accomplished by a variety of
methods. "Adhesion performance" must therefore be defined and measured in the
context of the application of interest. Whether a given adhesive is effective
for the
oral cavity can be determined by a peel test in artificial saliva.
1 U The strength of adherence can be measured by standard tests for measuring
the force, for example in dynes per square centimeter, as disclosed in U.S.
Patent
No. 4,615,697.
The term "subject" or "patient" is intended to include all mammals,
preferably humans.
15 The term "patch", as used herein, is intended to mean a three-dimensional
solid composition that can be adhered to teeth, or other hard structures in
the
mouth, such as dentures, which can contain a pharmaceutically active agent,
and
which can release the pharmaceutically active agent in effective amounts, for
a
desired period of time, from its site of attachment within the oral cavity.
20 By "pharmaceutically active agent" is intended any chemical or biochemical
that can be released from the dental patch to prevent, cure, or ameliorate an
undesirable physiological condition (see below). The term "drug" is used
interchangeably herein. These terms are used according to their normal and art-
recognized meanings.
25 Although any agent can be used, depending on the purpose of therapy, the
following are exemplary:
1. anti-inflammatory, analgesic agents: content 0.1-5%
2. steroidal anti-inflammatory agents: content 0.002-0.5%
3. antihistamines:0.l-2%
30 4. local anesthetics: 0.05-2%
CA 02296654 2000-O1-18
WO 99/04764 PCT/US98/15096
-31-
5. bacteriocides and disinfectants: 0.01-10%
6. vasoconstrictors: 0.01-1
7. hemostatics:0.05-1%
8. chemotherapeutics:0.05-1%
9. antibiotics:0.001-10%
10. cosmetics
11. tooth desensitizing agents: 0.1-10%
12. antifungals:0.1-10%
13. vasodilators:0.1-10%
14. antihypertensives:0.1-10%
15. antiemetics:0.1-10%
16. antimigraine:0.1-10%
17. antiarrhythmics:0.1-10%
18. antiasthmatics:0.1-10%
19. antidepressants:0.1-10%
20. vaccines:0.1-1%
21. peptides:0.1-1%
22. hormones:0.1-1%
23. anti-proton pumps or H receptor blockers: 0.1-10%
24. smoking cessation aids: 1-S%
Examples of anti-inflammatory, analgesic agents include acetaminophen,
methyl saiicylate, monoglycol salicylate, aspirin, mefenamic acid, flufenamic
acid,
indomethacin, diclofenac, alclofenac, diclofenac sodium, ibuprofen,
flurbiprofen,
fentizac, bufexamac, piroxicam, phenylbutazone, oxyphenbutazone, clofezone,
pentazocine, mepirizole, and tiaramide hydrochloride.
Examples of steroidal anti-inflammatory agents include hydrocortisone,
predonisolone, dexamethasone, triamcinolone acetonide, fluocinolone acetonide,
hydrocortisone acetate, predonisolone acetate, methylpredonisolone,
dexamethasone acetate, betamethasone, betamethasone valerate, flumetasone,
flourometholone, beclomethasone dipropionate, and budesonide.
CA 02296654 2000-O1-18
WO 99104764 PCT/US98/15096
-32-
Examples of antihistamines include diphenhydramine hydrochloride,
diphenhydramine salicylate, diphenhydramine, chlorpheniramine hydrochloride,
chlorpheniramine maleate, isothipendyl hydrochloride, tripelennamine
hydrochloride, promethazine hydrochloride, and methdilazine hydrochloride.
Examples of local anesthetics include dibucaine hydrochloride, dibucaine,
lidocaine hydrochloride, lidocaine, benzocaine, p-buthylaminobenzoic acid 2-
(diethylamino) ethyl ester hydrochloride, procaine hydrochloride, tetracaine
hydrochloride, chloroprocaine hydrochloride, oxyprocaine hydrochloride,
mepivacaine, cocaine hydrochloride, and piperocaine hydrochloride.
Examples of bacteriocides and disinfectants include thimerosol, phenol,
thymol, benzalkonium chloride, benzethonium chloride, chlorhexidine, providone
iodide, cetylpyridinium chloride, eugenol, and trimethylammonium bromide.
Examples of vasoconstrictors include naphazoline nitrate, tetrahydrozoline
hydrochloride, oxymetazoline hydrochloride, phenylephrine hydrochloride, and
tramazoline hydrochloride.
Examples of hemostatics include thrombin, phytonadione, protamine
sulfate, aminocaproic acid, tranexamic acid, carbazochrome, carbaxochrome
sodium sulfonate, rutin, and hesperidin.
Examples of chemotherapeutic drugs include vinblastine, cis-platin,
5-fluorouracil (SFU), methotrexate (MTX), 6 mercaptopurine (6MP), 1-~3-D-
arabinofuranosylcytosine (ara-C), mechlorethamine, chlorambucil, melphalan
oxazaphosphorines, carboplatin, JM40, spiroplatin, tetraplatin, JM216, and
taxol.
Examples of antibiotics include penicillin, meticillin, oxacillin, cefalotin,
cefaloridin, erythromycin, lincomycin, tetracycline, chlortetracycline,
oxytetracycline, metacycline, chloramphenicol, kanamycin, streptomycin,
gentamicin, bacitracin, and cycloserine.
Examples of antifungal drugs include amphotericin, clotrimazole,
econazole nitrate, fluconazole, grisofulvin, itraconazole, ketoconazole,
miconazole, nystatin, terbinafine hydrochloride, undecenoic acid, and zinc
undeconoate.
CA 02296654 2000-O1-18
WO 99/04764 ~ PCT/US98/15096
-33-
Examples of vasodilator drugs include buflomedil hydrochloride,
bucheneine hydrochloride, naftidrofury oxalate, oxpentifylline, glyceryl
trinitrate,
isosorbide dinitrate, isosorbide mononitrate and pentaerythritol tetranitxate.
Examples of antihypertensive drugs include amlodipine, benazepril
hydrochloride, captopril, clonidine hydrochloride, diazoxide, diltiazem,
hydrochloride, enalapril maleate, enalaprilat, felodipine, isradipine,
nicardipine
hydrochloride, nifedipine, atenolol, metoprolol tartarate, oxpenolol
hydrochloride,
propranolol hydrochloride and verapamil hydrochloride.
Examples of antiarrhythmic drugs include quinidine, quinidine salts,
procainamide hydrochloride, lidocaine, and mexiletine hydrochloride.
Examples of antiemetic drugs include metoclopramide hydrochloride,
nabilone, and ondansetron hydrochloride.
Examples of proton pump inhibitors or H receptor Mockers include
omeprazole, ranitidine and cimetidine.
Examples of antimigraine drugs include dihydroergotamine mesylate,
ergotamine tartarate, sumatriptan succinate and other triptan drugs.
Examples of peptide or protein drugs include insulin, buserelin acetate,
goserlin acetate, leuprorelin acetate, calcitonin, cyclosporin, gonadorelin,
somastatin, vasopressin, oxytocin, interferon, and human growth hormone.
Examples of antidepressant drugs include fluoxetine hydrochloride,
imipramine, maprotiline hydrochloride, and phenelzine sulfate.
Examples of antiasthmatics include salbutamol and terbutaline sulfate.
Examples of smoking cessation aids include nicotine, nicotine salts,
nicotine polymer complexes, and cotinine.
Examples of cosmetics include breath fresheners and tooth whiteners.
When release of the agent is localized to the teeth, preferred agents include
tooth-whitening agents, such as carbamide peroxide, and tooth-desensitizing
agents, such as potassium nitrate and strontium chloride.
The conditions amenable to treatment with the patch described herein
include, but are not limited to oral infections, lesions, low or high blood
pressure,
*rB
CA 02296654 2000-O1-18
WO 99/04764 ~ PCT/US98/15096
-34-
Helicobacter infections, pain, cough, migraine, vomiting, nausea,
inflammation,
sleep apnea, snoring, gerd and reflux disease. Preferred conditions include
yeast
infections, periodontal diseases, snoring, oral ulcers or other lesions.
The invention will now be illustrated in greater detail with reference to the
following examples, but it should be understood that these are not intended to
limit the present invention.
Examples
Example 1
Prolonged Sustained Release of Highly Soluble Drugs
Materials and Methods
Hydrolyzed gelatin was purchased from Croda.
Tannic acid USP was purchased from Merck.
Nicotine was purchased from The Nicobrand Company.
Pilocarpine was purchased from Laob.
Preparation of Formulations
Hydrolyzed gelatin and the drug (nicotine or pilocarpine) were dissolved
in a mixture of ethanol and water (or water atone). A solution of tannic acid
in
water and ethanol (or water alone) was added. The precipitate that formed was
air-dried to constant weight and ground to a powder.
CA 02296654 2000-O1-18
WO 99/04764 PCT/US98115096
-35-
In Vitro Release Experiments
The powder (0.5 gm) was inserted into dialysis bags which werestirred in
100 ml phosphate buffer (O.O1M, pH 7.4) at room temperature. Samples of 0.5
ml were taken for analysis.
Results
Formulations of nicotine and pilocarpine, both highly soluble drugs, were
prepared. These formulations, used to illustrate the controlled release of
highly
soluble drugs, are given in Tables 1-2.
Table 1: Liquid Formulation
245-49 (nicotine)
Ingredient Weight
Hydrolyzed gelatin 10
1N HCl 6
Nicotine I
Ethanol 40
Water 33
Tannic acid 10
Table 2: Liquid Formulation
245-43C (pilocarpine)
Ingredient Weight
Pilocarpine 0.3
Hydrolyzed gelatin 9
Tannic acid 9
Water 81.7
CA 02296654 2000-O1-18
WO 99/04764 - PCT/US98/15096
-36-
The in vitro release of the active ingredients from the powders obtained
from these formulations was tested. The results are summarized in Tables 3-4.
Table 3: In ease of NicotineFormulation
Vitro Rel from 245-49
Time (hr) % Cum Rel % Cum Rel
0.25 I .99 3.50
0.5 3.19 5.45
1 5.18 7.39
2 8.76 10.50
3 12.35 16.34
4 17.93 23.35
5 21.91 26.85
6 25.10 30.74
7 27.09 35.80
Table 4: In Vitro
Release of Pilocarpine
from Formulation
245-43C
Time (hr) % Cum Rel
0.25 2.77
0.5 5.03
1 7.28
2 14.22
3 19.77
4 25.32
5 31.56
6 37.46
7 42.66
8 47.86
CA 02296654 2000-O1-18
WO 99/04764 ~ PCT/US98115096
-37-
The results show that one can control the release of highly soluble drugs
with these formulations. The release can take place over many hours with less
than half the drug having been released in eight hours.
Example 2
Control Over the Rate of Drug Release in Prolonged
Controlled Release of a Highly Soluble Drug: I
Materials and Methods
Hydrolyzed gelatin was purchased from Croda.
Tannic acid USP was purchased from Merck.
Sodium salicylate was purchased from Merck.
Preparation of Formulation
The powder of gelatin-tannic acid was formulated with the highly soluble
drug sodium salicylate and prepared using two different ratios of ethanol and
water. in formulation 245-66A the weight proportion of the solvent was 3:1
{ethanol : water) and in formulation 245-68A it was 1:1.
Results
The formulations used are described in Tables 5-6.
CA 02296654 2000-O1-18
WO 99/04764 - PCT/US98/15096
-38-
Table 5: Liquid
Formulation 245-66A
Ingredient Weight
Hydrolyzed gelatin 10
Sodium Salicylate I
Water 19
Ethanol 60
Tannic acid l0
Table 6: Liquid Formulation
245-68A
Ingredient Weight
Hydrolyzed gelatin 10
Sodium Salicylate 1
Water 39.5
Tannic acid 10
Ethanol 39.5
1 S In vitro release studies were carried out on the powders obtained from
these formulations as in Example 1.
The results of the in vitro release studies are summarized in Tables 7
and 8.
CA 02296654 2000-O1-18
WO 99!04764 PCT/US98/15096
-39-
Table 7: In
Vitro Release
of Sodium
Salicyiate
from
Formulation
245-66A
Time (hr) % Cumulative % Cumulative
Release ._
Release
0.25 I 5 24
0.5 21 34
1 29 45
2 40 57
3 45 66
4 52 70
5 59 78
6 68 83
7 74 86
Table 8: In
Vitro Release
of Sodium
Salicylate
from
Formulation
245-68A
Time (hr) % Cumulative % Cumulative
Release Reiease
0.25 9 14
0.5 15 20
1 22 29
2 32 39
3 39 47
4 44 52
5 49 56
6 52 60
7 55 64
One can see that a high proportion of water in the solvent mixture
decreases the release rate of the active ingredient while a higher ethanol
content
CA 02296654 2000-O1-18
WO 99/04764 - PCT/US98/15096
-40-
increases the release rate. In both cases one has prolonged release of the
highly
soluble substance, sodium salicylate, from the matrix.
Example 3
Control Over the Rate of Drug Release in Prolonged
Controlled Release of a Highly Soluble Drug: ll
Materials
Hydrolyzed gelatin was purchased from Croda.
Tannic acid USP was purchased from Merck.
Nicotine was purchased from The Nicobrand Company.
Preparation of Formulation
The powder of gelatin-tannic acid was formulated with the highly soluble
drug nicotine and prepared using two different ratios of ethanol and water. In
formulation 245-70 the weight proportion of the solvent was 3:1
(ethanol:water)
and in formulation 245-49 it was 1:1.
Results
The formulations are given in Tables 9 and 10.
CA 02296654 2000-O1-18
WO 99/04764 ~ PCT/US98/15096
-41-
Table 9: Liquid
Formulation
245-70
Ingredient Weight
Hydrolyzed gelatin10
1N HCl 5
Nicotine 1
Water 17
Ethanol 57
Tannic acid 10
Table 10: Liquid
Formulation
245-49
Ingredient Weight
Hydrolyzed gelatin10
1 N HCI 6
Nicotine 1
Water 34
Ethanol 39
Tannic acid 10
In vitro release studies were carried out on the powders obtained from
these formulations as in Example 1.
The release pattern of nicotine from formulations 245-70 and 241-49 is
illustrated in Tables 11 and 12.
CA 02296654 2000-O1-18
WO 99/04764 - PCT/US98/15096
-42-
Table 11: Release of Nicotine mulation 245-70
from for
Time (hr) % Cumulative % Cumulative
Release Release
0.25 15 12
0.5 20 17
1 28 25
2 38 35
3 43 42
4 45 46
5 46 52
6 49 55
7 49 56
Table 12: ReleaseNicotine from ation 245-49
of formul
Time (hr) % Cumulative % Cumulative
Release Release
0.25 4.5 4
0.5 6 S
1 7 7
2 11 10
3 13 11
4 15 14
5 17 16
6 19 18
7 20 19
As it was shown for sodium salicylate, the effect of the solvent mixture
was achieved with nicotine also. Increased amounts of water in the solvent
mixture during the preparation of the formulation results in slower release.
CA 02296654 2000-O1-18
WO 99/04764 ~ PCTIi1S98/15096
-43-
Example 4
Prolonged Sustained Release of Nicotine
from a Pharmaceutical Oral Patch
Materials
Hydrolyzed gelatin was purchased from Croda.
Tannic acid USP was purchased from Merck.
Eudragit L-100, Eudragit 30D-SS and triethyl citrate NF were purchased
from Rhom Pharma.
Nicotine was purchased from The Nicobrand Company.
Preparation of Formulations
The patch was formed by mixing the powder formed from Formulation
245-70 (Table 9) with an ethanolic solution of Eudragit L-100 and a
plasticizer.
The mixture was transferred to plastic molds and dried to form an adhesive
pharmaceutical oral patch.
In Vitro Release
The dry patches (300 mg) were stirred in 100 ml buffer (phosphate,
0.01 M, pH 7.4) at room temperature. Samples of the solution (0.5 ml) were
analyzed.
Results
In vitro release experiments were carried out. The results are summarized
in Table 13.
CA 02296654 2000-O1-18
WO 99/04764 - PCT/US98115096
-44-
Table 13: In
Vitro Release
of Nicotine
from a
Pharmaceutical
Oral Patch
Time (hr) % Cumulative % Cumulative
Release _
Release
0.25 2 3.5
0.5 3.2 5.5
1 5.2 7.4
2 8.8 10.5
3 12.4 16.3
4 17.9 23.4
5 21.9 26.9
6 25.1 30.7
7 27.1 35.8
Example S
Prolonged Sustained Release of Pilocarpine
from a Pharmaceutical Oral Patcl:
Materials
Hydrolyzed gelatin was purchased from Croda.
Tannic acid USP was purchased from Merck.
Eudragit L-100, Eudragit 30D-SS and triethyl citrate NF were purchased
from Rhom Pharma.
Pilocarpine was purchased from Laob.
CA 02296654 2000-O1-18
WO 99/04764 - PCT/US98/15096
-45-
Preparation of Formulations
The patch was formed by mixing the powder formed from Formulation
245-43C (Table 2) with a water suspension of Eudragit L 30D-55.
The mixture was transferred to plastic molds and dried to form a
S pharmaceutical oral patch.
In Vitro Release
The dry patches (300 mg) were stirred in 100 ml buffer (phosphate,
0.01 M, pH 7.4) at room temperature. Samples (0.5 ml) of the solution were
analyzed.
Results
In vitro release experiments were carried out. The results are summarized
in Table 14.
Table 14: In
Vitro Release
of Pilocarpine
from a
Pharmaceutical
Oral Patch
~ Time (hr) % Cumulative % Cumulative
Release Release
0.25 7.9 4.3
0.5 11.6 6.2
1 16.1 8.5
2 21 12
3 27 15.1
4 31.1 17.8
5 32.6 21.6
The results show that one can control the release of soluble drugs from a
pharmaceutical oral patch for several hours.
CA 02296654 2000-O1-18
WO 99/04764 - PCT/US98/15096
-46
Example 6
In Vitro Release of Nicotine from an _
Adhesive Pharmaceutical Oral Patch
Materials
Hydrolyzed gelatin was purchased from Croda.
Tannic acid USP was purchased from Merck.
Eudragit L-100 and Triethyl Citrate NF were purchased from Rhom
Pharma.
Nicotine was purchased from The Nicobrand Company.
Preparation of Formulations
The patch was formed by mixing the powder formed from liquid
Formulation 158-72 (Table 15), with an ethanolic solution of Eudragit L-100
and
a plasticizer.
The mixture was transferred to plastic molds and dried to form an adhesive
pharmaceutical oral patch.
Table 15: Liquid
Formulation 158-72
Ingredient Weight
Hydrolyzed gelatin28
37% HCI 0.5
Nicotine t
Water 47.5
Ethanol 3
Tannic acid 20
CA 02296654 2000-O1-18
WO 99/04764 - PCT/US98/15096
-47-
In Vivo Release Experiment
The pharmaceutical oral patch (190 mg), containing 2 mg nicotine, was
attached to the buccal side of an upper molar tooth by means of self adhesion.
Saliva samples were expectorated at given time intervals and tested for
nicotine content.
Results
One volunteer wore the pharmaceutical oral patch for a period of four
hours. The patch conformed to the contour of the tooth and was comfortable to
wear. Saliva samples were collected and analyzed by chromatography. The
results are listed in Table 16.
Table 16: In Vivo
Release of Nicotine
from a
Pharmaceutical Oral
Patch
Time (min) Concentration
(ppm)
0 0.3
15 13.4
30 25.1
60 23.8
90 51.6
120 20.1
180 26.3
240 18.1
The results indicate that clinically significant concentrations of nicotine as
an example of soluble drug, can be maintained in the oral cavity for several
hours.
The pharmaceutical oral patch self adhered to the tooth for the entire period
of the
experiment.
CA 02296654 2000-O1-18
WO 99/04764 - PCT/C1S98l15096
-48
Example 7
In Vivo Release of Nicotine from a Second
Adhesive Pharmaceutical Oral Patch
Materials
Hydrolyzed gelatin was purchased from Croda.
Tannic acid USP was purchased from Merck.
Eudragit 30D-55 and Triethyl Citrate NF were purchased from Rhom
Pharma.
Nicotine was purchased from The Nicobrand Company.
Preparation of Formulations
The patch was formed by mixing the powder formed from liquid
Formulation 41 B001 SL (Table 17) with an aqueous suspension of Eudragit L
30D-55 and a plasticizer.
The mixture was transferred to plastic molds and dried to form an adhesive
pharmaceutical oral patch.
Table 17: Liquid
Formulation 41BOO1SL
Ingredient Weight
Hydrolyzed gelatin27.5
37% HCl I
Nicotine I .6
Water 46.5
Ethanol 3.2
Tannic acid 20.1
*rB
CA 02296654 2000-O1-18
WO 99/04764 ~ PCT/US98/15096
-49-
In Vivo Release Experiment
The pharmaceutical oral patch (115 mg), containing 2 mg nicotine, was
attached to the buccal side of an upper molar tooth by means of self adhesion.
Saliva samples were expectorated at given time intervals and tested for
nicotine content.
Results
One volunteer wore the pharmaceutical oral patch for a period of four
hours. The patch conformed to the contour of the tooth and was comfortable to
wear. Saliva samples were collected and analyzed by chromatography. The
results are listed in Table 18.
Table 18: In Vivo
Release of Nicotine
from a
Pharmaceutical Oral
Patch
Time (min) Concentration (ppm)
0 0.3
30 2.7
60 5.6
120 11.3
180 28.6
240 0.7
The results indicate that clinically significant concentrations of nicotine
can
be maintained in the oral cavity for several hours. The pharmaceutical oral
patch
self adhered to the tooth for the entire period of the experiment.
CA 02296654 2000-O1-18
WO 99/04764 PCT/US98/15096
-50
Example 8
Release of Liposome Encapsulated Nicotine from
Pharmaceutical Oral Patches
Nicotine was entrapped in liposomes of both the multilamellar vesicle
(MLV) and small unilamellar vesicle (SUV) type. The formulations used for the
formation of the Iiposomes are given in Table 19.
Table 19: Ingredients of MLV and SUV Liposomes:
Type Materials weight(g)mole%
NlCOtine Egg Phosphatidylcholine1 60.9
(PC)
99% Synthetic
Liposomes 0.1 6.6
MLV
Phosphatidylethanolamine
(PE) 99% 0 32
275 5
Cholestero195% . .
NiCOtine Soybean Phosphatidyicholine1,2 62.8
(PC)
Liposomes Synthetic 0.12 6.8
SUV
Phosphatidylethanolamine
(PE) 99% 0 4
3 30
Cholestero195% . .
The phospholipids and lipids were dissolved in 25 ml chloroform:methanol
(2:1 ) in a round bottom flask of 100-1000 ml. The lipid solution was dried
for 2
hours to form a lipid film onto the sides of the flask, using a rotary
evaporator
apparatus. The lipids were hydrated by addition of 10-20 ml H20 or PBS
(phosphate buffered saline) solution (0.01 M, pH 7.4), followed by vortexing
and
shaking in a 37°C water bath, for 2-4 hours to form MLV liposomes. The
liposomes were characterized by standard chemical and electron microscope
techniques.
MLV Nicotine Liposomes:
Nicotine (0.2 ml), a volatile and water soluble drug, was dissolved in an
aqueous medium and added to the lipid film at the hydration step.
SUV Nicotine Liposomes:
CA 02296654 2000-O1-18
WO 99/04764 ~ PCT/US98/15096
-51-
Nicotine (0.2 ml), in an aqueous medium was added to placebo liposomes
(MLV) followed by 1 hour sonication to form nicotine liposomes of type SUV.
The percent entrapment of the nicotine was determined for each type of
liposome and is shown in Table 20.
Table 20: Efficiency of Nicotine Encapsulation in Liposomes:
Type of liposomes % of encapsulation
SUV 36
MLV 15
One can see that nicotine encapsulation in the liposomes was as expected
for a water soluble drug. More drug was encapsulated in the SUV than in the
MLV due to the higher percent internal aqueous volume in this form of
liposome.
The liposomes were stored at 4°C (closed tightly).
Pharmaceutical oral patches were made using nicotine trapped in MLV
liposomes with and without an outer polymer matrix. The other ingredients of
the
patches are given in Table 21.
Table 21: Non Active Ingredients of Patches:
Materials Batch# Batch# Batch# Batch# Batch#
285-23A285-23B285-28 49A004 158-64
~'gt w'gt ~'gt ~'gt H'gt
(g) fig) fig) (g) (g)
H20 3.3 3.3 3.1 33 33
BycoE 2.6 2.6 3.1 26 26
H20 1.1 1.1 1.3 11 11
Ethanol 0.3 0.3 - 3 3
Tannic Acid 1.9 1.9 1.7 19 19
MatrIX(Elldr.L-30D+Glycerin)'~' - -
lVlatCIX (Eudr.L-100+Ethanol)- 'f' - + +
CA 02296654 2000-O1-18
WO 99/04764 PCT/US98/15096
-52-
Patches of Batches# 285-23A, 285-23B:
2g of MLV liposomes containing entrapped nicotine were suspended in
water. BycoE~'~"'' was added and finally a solution of tannic acid in ethanol-
water
was added. The precipitate was dried at 50 ° C, ground to a powder and
mixed
with a polymer matrix based on EudragitT"" (approx. 1:1 ). Polypropylene molds
were filled with the mixture (190mg/well) and dried at 35°C. These
patches
contain ~2 mg nicotine each and are formed with an outer polymer matrix.
Patches of Batch# 285-28:
Solution of tannic acid in water was added dropwise into solution of Byco
1 O ET"'. 0.45g of the tannic acid-Byco preparation were mixed with 0.63g of
MLV
liposomes containing entrapped nicotine. Polypropylene molds were filled with
the mixture (280mg/well) and dried at 35 °C in the oven. These patches
contain
~2 mg nicotine each and are formed without an outer polymer matrix.
Patches without liposomes # 49A004 and 158-64:
Nicotine neutralized with HCl was dissolved in water. Byco ETM was added
and finally a solution of tannic acid in ethanol-water was added. The
precipitate
was dried at 50°C, ground to a powder and mixed with a polymer matrix
based
on EudragitT"" (approx. 1:1 ). Polypropylene molds were filled with the
mixture
(190mg/well) and dried at 35 °C. These patches contain ~2 mg nicotine
each and
are formed with an outer polymer matrix.
Release Assays:
In vitro: Patches containing liposomes were introduced into dialysis tubes
with a molecular weight cutoff of 50,000 and stirred in bulk solutions of 50-
100
ml phosphate buffered saline (PBS) (O.O1M, pH 7.4). 0.2m1 samples were
collected at times 0-7h. The nicotine was determined by a validated HPLC
method.
CA 02296654 2000-O1-18
WO 99/04764 PCT/US98/15096
-53-
In vivo: The pharmaceutical oral patch was attached to an upper back
tooth. Saliva samples were collected at times 0-180 min. The nicotine was
determined by a validated HPLC method.
Results in Vitro:
The average results of release of nicotine from the in vitro pharmaceutical
oral patches are summarized in Figure 1.
The release of drug from liposomal patches #285-28 (V) was slower than
from the non liposomal nicotine patches #49A004 (VI-VIII). The release of
nicotine from both of these types of patches was characterized by a single
rate
constant. In contrast, the release profile of nicotine from liposomal patches
#285-
23A (I and II) and #285-23B (III and IV), was characterized by a two phase
release of the drug and was also slower than the non-liposomal formulation.
Results in Vivo:
The release experiment of nicotine in vivo was performed, using patch
#285-28 containing centrifuged nicotine liposomes type MLV and compared to
non-liposomal nicotine patch #158-64. The results are shown in Figure 2.
One sees that salivary concentrations of nicotine were higher for the
formulation without liposomes. The profiles of release were similar.
Example 9
Release of Liposome Encapsulated Flurbiprofen
from Pharmaceutical Oral Patches
Flurbiprofen was entrapped in multilamellar vesicle type liposomes as
follows:
Soybean phosphatidylcholine ( 14 gm) was dissolved in 100 ml ethanol in a
1000 ml round bottom flask along with 2.3 gm flurbiprofen. The lipid solution
CA 02296654 2000-O1-18
WO 99/04764 PCT/US98/15096
-54-
was dried for 1.5 hours to form a lipid film with flurbiprofen dispersed
therein.
onto the sides of the flask, using a rotary evaporator apparatus. The lipids
were
hydrated by addition of 140 ml HzO, followed by rotation for 2 hours-and slow
stirring for 1 hour to form MLV liposomes. The liposomes were characterized by
standard chemical and electron microscope techniques. The non-encapsulated
flurbiprofen was removed by dialysis. The liposomes were obtained by
centrifugation at 10°C for 1 hour at 17500 rpm.
Patches of Batch# 285- 62:
Tannic acid (1.7 gm) in 1.3 gm water was added dropwise to a solution of
3.1 gm hydrolyzed gelatin (BycoETM) in water. The tannic acid - hydrolyzed
gelatin preparation was mixed with 9.6 gm of MLV liposomes containing
entrapped flurbiprofen. Polypropylene molds were filled with the mixture (200
mg/well) and the patches were dried in an oven at 30°C.
Release Assays:
In vitro: Patches containing liposomes were stirred in bulk solutions of
100 ml PBS (0.01 M, pH 7.4). 0.2m1 samples were collected at times 0-7h. The
flurbiprofen was determined by a validated HPLC method.
Results in Vitro:
The average results of the in vitro release of flurbiprofen from the
pharmaceutical oral patches are summarized in Figure 3 and Table 22. One can
see clear sustained release of the flurbiprofen from the patches.
Table 22: Cumulative Release of Flurbiprofen
Time % cumulative release
0 0
15 7.53
30 10.94
60 ~ 15.37
CA 02296654 2000-O1-18
WO 99/04764 PCT/US98/15096
-SS-
120 21.12
180 27.19
240 30.81
300 33.66
360 37.44
