Buccal delivery system for therapeutic agents

A unidirectional buccal delivery system for the delivery of therapeutic agents over an extended period of time. The delivery system includes a matrix for releasing the drug into the oral cavity at a sustained rate and a means for securing the matrix to the palate or other adequate regions in the oral cavity.

This application is a continuation of Provisional application Ser. No. 
60/003,600 filed Sep. 12, 1995. 
BRIEF DESCRIPTION OF THE INVENTION 
The present invention is directed to a unidirectional buccal delivery 
system for the delivery of therapeutic agents at a sustained rate over an 
extended period of time. 
DETAILED DESCRIPTION OF THE INVENTION 
In accordance with the present invention, a unidirectional buccal delivery 
system for therapeutic agents is provided. 
The term "unidirectional" as used herein is intended to mean that greater 
than 50%, preferably greater than 80% and most preferably greater than 95% 
of the drug is released into the buccal cavity and is not absorbed through 
the mucosa. 
The unidirectional delivery system includes a matrix which contains the 
therapeutic agent for release into the oral cavity. The matrix releases 
the therapeutic agent at a sustained rate into the oral cavity. The term 
"sustained rate" as used herein means release of the drug for an extended 
period of time ranging from about 12 hours to about 7 days. 
Preferably the matrix is any hydrophobic or hydrophilic polymeric material. 
When hydrophilic polymers are used, they should be crosslinked to allow 
swelling of the matrix, but not dissolution into the oral cavity. The 
matrix polymer is chosen based on the molecular weight, hydrophobicity or 
hydrophilicity of the drug and the desired release rate. Thus, for the 
delivery of a protein, a suitable polymer would be a lightly crosslinked 
hydrogel which would allow for water absorption and swelling permitting 
the large hydrophilic protein to be released in the oral cavity. In 
general, hydrophobic polymers would be chosen to release hydrophobic drugs 
and hydrophilic polymers to release hydrophilic drugs. The degree of the 
polymer hydrophobicity/hydrophilicity will dictate the rate of release and 
the duration of activity. 
Polymers useful with this invention include, but are not limited to, 
polyolefins and their copolymers such as ethylene vinyl acetate, ethylene 
acrylic acid, ethylene methyl acrylate, plasticized vinyls, polyurethanes, 
nylons, thermoplastic elastomers such as Hytrel.TM. and hydrogels. The 
polymers of choice may or may not be completely crystalline, but 
preferably have a minimum of 20% amorphous regions. The glass transition 
temperature of the amorphous regions or amorphous polymers should be less 
than the body temperature, i.e., less than 35.degree. C. 
Suitable matrices for use with the present invention include those 
disclosed in U.S. Pat. Nos. 4,538,603 and 4,551,490, incorporated by 
reference herein. A preferred matrix is an ethylene-vinyl acetate 
copolymer. 
The delivery system also includes a means for securing the matrix to the 
palate or other adequate regions in the oral cavity such as the oral 
mucosa or tooth. The means for securing the matrix to the oral mucosa may 
be a thin film/patch that adheres to the palate or other adequate regions 
in the oral cavity. The securing means also serves as a barrier to prevent 
penetration of the drug into the mucosa from the matrix, thereby achieving 
unidirectional delivery of the drug into the oral cavity. 
Preferably the securing means is a pressure sensitive adhesive. The 
pressure sensitive adhesives for securing the matrix to the desired region 
in the oral cavity must be able to adhere to a moist surface. A preferred 
pressure sensitive adhesive for use as described herein are the 
Hydrocolloid pressure sensitive adhesives. Hydrocolloid adhesives are 
composed of hydrophobic rubbers into which hydrocolloid powders are 
dispersed (J. L. Chen and G. N. Cyr, Adhesion in Biological Systems, R. S. 
Manly, ed. p. 163 Academic Press, NY, 1970; incorporated by reference 
herein). Hydrocolloid adhesives contain from 40 to 60% hydrocolloid 
powders with the remaining being hydrophobic rubbers. Hydrocolloid powders 
are materials that exhibit very high water absorption such as gelatin, 
pectin, polyacrylic acid, sodium carboxymethyl-cellulose, polyethylene 
oxide, karaya gum, methylcellulose, alginates, hydroxyethyl cellulose and 
polyvinyl pyrrolidone. Suitable hydrophobic rubbers include, but are not 
limited to polyisobutylene, butyl rubber, kraton, EPDM (ethylene proplyene 
diene modified rubber) polyisoprene and hot melt acrylics. Several such 
systems are described in U.S. Pat. Nos. 3,972,328 and 4,551,490 
(incorporated by reference herein). 
Non-hydrocolloid adhesives which are substantially hydrophilic to rapidly 
absorb the moisture from the buccal membrane and provide a dry surface for 
adhesion to take place may also be used. An example of a non-hydrocolloid 
adhesive suitable for use as described herein are hydrogels such as those 
described in U.S. Ser. No. 08/220,530, (filing date: Mar. 30, 1994) and 
urethane pressure sensitive adhesives described in EP Patent 597636 
(incorporated by reference herein). 
A preferred means for securing the matrix is an orahesive polymer system 
such as described in U.S. Pat. No. 3,972,328. 
The delivery system of the present invention may optionally contain a 
barrier membrane. The barrier membrane, when present is located between 
the matrix for releasing the therapeutic agent and the means for securing 
the matrix to a region of the oral cavity. The barrier membrane prevents 
the drug from diffusing from the matrix into the means for securing the 
matrix. A suitable barrier membrane should be able to adhere to both the 
matrix and the means for securing and will be able to maintain and/or 
promote the unidirectional drug delivery into the oral cavity. Suitable 
barrier membranes for use as described herein are crystalline polymers 
such as polyesters and or metalized films such as metalized polyethylene 
or polypropylene. Preferred barrier membranes are coated with very thin 
tie-layers of polymers which have good adhesion to many polymeric 
substrates. Such tie-layers include ethylene acrylic acid, ethylene butyl 
acrylate and ethylene vinyl acetate. 
The delivery system may optionally contain a control membrane which is 
adjacent to the matrix and at the opposite surface from the means for 
securing. The control membrane is used for better control of the drug 
release as in the case when the release of the therapeutic agent from the 
matrix has to be accurately controlled. For example, for very potent drugs 
or drugs with a narrow therapeutic window. To exert control on drug 
release, the permeation of the drug through the control membrane has to be 
slower that through the matrix. Examples of suitable materials for the 
control membrane are the ethylene vinyl acetate and ethylene methyl 
acrylate family of copolymers such as those described in U.S. Pat. No. 
4,758,434 (incorporated by reference herein) because as the ethylene 
content of the copolymer is increased, diffusion through the membrane 
decreases. Thus a particular ratio of ethylene to vinyl acetate can be 
utilized that would provide the desired control for almost any 
application. An example of a commercially available ethylene-vinyl acetate 
copolymer is Vynathene EY904-00/25 from Quantum Chemical Corp., having 51% 
vinyl acetate content. 
Examples of therapeutic agents for use with the present invention are those 
which have a specific regional absorption i.e., those therapeutic agents 
which are absorbed from a small section of the gastrointestinal tract or 
therapeutic agents which have short half-lives. The term "short half-life" 
or "short half-lives" as used herein refers to half-lives less than 6 
(six) hours and preferable less than 3 (three) hours. 
An example of a therapeutic agent having a narrow absorption window are 
angiotensin converting enzyme (ACE) inhibitors such as Captopril 
(1-(2s)-3-mercapto-2-methyl-1-oxopropyl!-L-proline), which is absorbed in 
the duodenum. Captopril is widely used for the treatment of hypertension, 
heart failure and other cardiovascular conditions. Captopril is generally 
available in the form of tablets which, as indicated in the Physicians' 
Desk Reference (PDR) 49th Edition, 1995, page 710, is administered in a 
dose of from 25 to 150 mg, two or three times daily. Captopril is 
disclosed in U.S. Pat. No. 4,105,776 to Ondetti et al., the disclosure of 
which is incorporated by reference herein. 
An example of a therapeutic agent useful with this invention, having a 
short half-life is levodopa. Levodopa is known to be useful in the 
treatment of Parkinson disease, especially in conjunction with carbidopa. 
Levodopa in combination with carbidopa is generally available in the form 
of tablets which, as indicated in the Physicians' Desk reference (PDR) 
49th Edition, 1995, pages 959 and 961, are administered in a total of from 
200 mg to 1000 mg, in 2 to 4 divided doses daily.

The following examples and preparations describe the manner and process of 
making and using the preferred embodiments of the invention and are 
illustrative rather than limiting. It should be understood that there may 
be other embodiments which fall within the spirit and scope of the 
invention as defined by the claims appended hereto. 
EXAMPLE 1 
A. Matrix Preparation 
The matrix for the captopril was an ethylene-vinyl acetate copolymer, 
Vynathene EY904-00/25 from Quantum Chemical Corp., having 51% vinyl 
acetate content. 
The matrix was prepared by dissolving the ethylenevinyl acetate copolymer 
in toluene and adding a solution of captopril (100 mg) in methylene 
chloride. Large volumes of solvent were needed to keep the polymer and 
drug dissolved due to the hydrophobic nature of the ethylene-vinyl acetate 
and the hydrophilic nature of captopril. The resulting solution was 16% 
solids. 
A film was prepared by casting the solution in release liner and then 
carefully removing the solvent in a vacuum oven at room temperature for 
several hours and gradually raising the temperature with a final drying at 
80.degree. C. for two (2) hours. The resulting film was unevenly opaque 
with some crystallization of captopril on the surface. The film was heat 
laminated to a Mylar/ethylene-vinyl acetate copolymer backing film at 
120.degree. C. for several seconds. Circular disks 3 cm in diameter were 
punched out and attached to Orahesive with transfer adhesive. 
The disk is 3 cm in diameter and approximately 30 mils in thickness. To 
keep the delivery system a size suitable for use as described, 20 mils 
thickness was allowed for the captopril matrix. Using these constraints in 
thickness and area a drug loading of 29% by weight was needed to put 100 
mg in the matrix.