U.S. patent number RE33,093 [Application Number 07/272,354] was granted by the patent office on 1989-10-17 for bioadhesive extruded film for intra-oral drug delivery and process.
This patent grant is currently assigned to Johnson & Johnson Consumer Products, Inc.. Invention is credited to Martin M. Perl, Howard Rubin, Michael T. Schiraldi.
United States Patent |
RE33,093 |
Schiraldi , et al. |
October 17, 1989 |
**Please see images for:
( Certificate of Correction ) ** |
Bioadhesive extruded film for intra-oral drug delivery and
process
Abstract
A bioadhesive extruded single or multi-layered thin film,
especially useful in intra-oral controlled-releasing delivery,
having a water soluble or swellable polymer matrix bioadhesive
layer which can adhere to a wet mucous surface and which
bioadhesive layer consists essentially of .[.40-95.].
.Iadd.20-92.Iaddend.% by weight of a hydroxypropyl cellulose 5-60%
of a homopolymer of ethylene oxide, 0-10% of a water-insoluble
polymer such as ethyl cellulose, propyl cellulose, polyethylene and
polypropylene, and 2-10% of a plasticizer, said film having
incorporated therein a medicament, e.g. anesthetics, analgesics,
anticaries agents, anti-inflammatories, antihistamines,
antibiotics, antibacterials, fungistats, etc.
Inventors: |
Schiraldi; Michael T. (East
Brunswick, NJ), Perl; Martin M. (Brooklyn, NY), Rubin;
Howard (Rockaway, NJ) |
Assignee: |
Johnson & Johnson Consumer
Products, Inc. (New Brunswick, NJ)
|
Family
ID: |
26955461 |
Appl.
No.: |
07/272,354 |
Filed: |
November 16, 1988 |
Related U.S. Patent Documents
|
|
|
|
|
|
|
Application
Number |
Filing Date |
Patent Number |
Issue Date |
|
Reissue of: |
874904 |
Jun 16, 1986 |
04713243 |
Dec 15, 1987 |
|
|
Current U.S.
Class: |
424/676; 424/435;
424/449 |
Current CPC
Class: |
A61K
9/006 (20130101) |
Current International
Class: |
A61K
9/00 (20060101); A01N 059/10 (); A61K 033/16 () |
Field of
Search: |
;424/151,449,435 |
References Cited
[Referenced By]
U.S. Patent Documents
|
|
|
4292299 |
September 1981 |
Suzuki et al. |
4421738 |
December 1983 |
Yamigawa et al. |
4517173 |
May 1985 |
Kizawa et al. |
|
Primary Examiner: Schofer; Joseph L.
Assistant Examiner: Kulkosky; Peter F.
Claims
What is claimed is:
1. A pharmaceutically acceptable controlled-releasing
medicament-containing extruded single or multi-layered thin film,
capable of adhering to a wet mucous surface, comprising a water
soluble or swellable polymer matrix bioadhesive layer which can
adhere to a wet mucous surface and which bioadhesive layer consists
essentially of .[.40-95.]..Iadd.20-93.Iaddend.% by weight of a
hydroxypropyl cellulose having a molecular weight above 100,000,
5-60% of a homopolymer of ethylene oxide having a molecular weight
from 3,000,000 to 5,000,000, 0-10% of a water-insoluble polymer
selected from the group consisting of ethyl cellulose, propyl
cellulose, polyethylene and polypropylene, and 2-10% of a
plasticizer, said film having incorporated therein a
pharmaceutically effective amount of said medicament.
2. The extruded film of claim 1, made in a form which is so thin
and flexible when wet as to be unobtrusive to the patient when
properly positioned and placed in the patients mouth.
3. The extruded film of claim 2 having a thickness no greater than
0.25 millimeters.
4. The extruded film of claim 1, in single layer form, which also
contains up to 10% by weight of a non-soluble polymer selected from
the group consisting of ethyl cellulose, polyethylene,
polypropylene and carboxymethyl cellulose free acid.
5. The extruded film of claim 1, in multi-layer laminated form,
which is addition to the bioadhesive layer also contains a
reservoir layer in which at least a major portion of the medicament
is contained.
6. The extruded multi-layer film of claim 5 in which the reservoir
layer consists essentially of a polymer matrix comprised of both a
water soluble or swellable polymer and a non-water soluble polymer
selected from the group consisting of ethyl cellulose, propyl
cellulose, polyethylene and polypropylene, and also hydroxypropyl
cellulose.
7. The extruded film of claim 1 in multi-layer laminated form,
which in addition to the bioadhesive layer also contains an outer
protective-barrier membrane layer.
8. The extruded multi-layer film of claim 7 in which the outer
protective-barrier membrane layer is thinner than the bioadhesive
layer, and said outer protective barrier layer consists essentially
of a polymer matrix of a major proportion of a non-water-soluble
polymer selected from the group consisting of ethyl cellulose,
propyl cellulose, polyethylene and polypropylene, and a minor
proportion of hydroxypropyl cellulose.
9. The extruded multi-layer film of claim 1 in the form of a triple
layered laminate containing sodium fluoride for anticaries
protection having the following composition:
Description
BACKGROUND OF THE INVENTION
1. Field of the Invention
The present invention relates to a controlled-releasing
medicament-containing preparation for intra-oral use, and is more
especially concerned with such a preparation (and the process of
using it) in the form of a very thin extruded thermoplastic film
(which can be in single layer or laminated multi-layer form) having
at least one bioadhesive layer containing
.[.40-95.]..Iadd.20-93.Iaddend.% of a thermoplastic cellulose ether
and 5-60% of a homopolymer of ethylene oxide which can adhere to
the mucosa of the oral cavity. The extruded film drug delivery
system of the present invention, which has incorporated therein the
medicament to be dispensed, is so thin and flexible when wet as to
be unobtrusive to the patient after it has been properly positioned
and placed in the mouth.
2. Description of the Prior Art
Several systems have previously been described which pertain to the
delivery of drugs into the oral cavity. These include:
1. Treatment of periodontal disease with tetracycline,
chlorhexidine or metronidazole loaded into hollow cellulose acetate
fibers. These fibers are packed in the periodontal pockets and
provide controlled release of the drug to the infected area.
2. Cast films containing ethyl cellulose/propylene glycol with
chlorhexidine or metronidazole for treatment of periodontal
disease.
3. An orthodontic appliance with a hydroxyethyl methacrylate/methyl
methacrylate copolymer (HEMA/MMA) matrix. Sodium fluoride is
incorporated into the HEMA/MMA matrix to provide sustained fluoride
release and enhanced anticaries activity. HEMA/MMA with fluoride
may also be attached to the tooth in the form of a wafer-like
tablet.
4. Silicone/ethyl cellulose/polyethylene glycol films containing
sodium fluoride are applied as coatings on orthodontic bands or in
chewing gum. Controlled release of fluoride and anticaries activity
is claimed. The above systems are discussed in the "The Compendium
of Continuing Education" Vol VI, No. 1, January 1985 p. 27-36
review article "Controlled Drug Delivery: A New Means of Treatment
of Dental Disease", by J. Max Goodson, D.D.S., Ph.D. of the Forsyth
Dental Center. Other systems, described in GB patent application
No. 2,042,888 and U.S. Pat. Nos. 4,292,299/4,226,848 (Teijin Ltd.,
Japan), use combinations of cellulosic and polyacrylate polymers.
The preferred materials are hydroxypropyl cellulose ("Klucel") and
a copolymer of acrylic acid ("Carbopol") that is administered in
the form of thin tablets (discs), granules or powder. Other
polymers that might be added are vinyl copolymers, polysaccharides,
gelatin and collagen. U.S. Pat. No. 4,517,173 (Nippon Soda Co. Ltd,
Japan) uses various celluloses in a multi-layered non-extruded cast
film preparation.
Examples of prior art products currently on the market include
ointments such as ORABASE* with Benzocaine (Squibb), Kenalog*
(Triamcinolone Acetonide) in ORABASE* (Squibb) and Mycostatin*
(Nystatin) ointment (Squibb).
The prior art products and delivery systems described above are
useful but have the following disadvantages:
Tablets, appliances, hollow fibers are "bulky" in the mouth, are
difficult to keep in place and inconvenient to apply.
Ethyl cellulose and/or silicone films do not adhere to mucosal
tissue.
Ointments (i.e., ORABASE*) have an unpleasant feel and do not last
very long.
Except for ORABASE*, all the foregoing systems require professional
application to the tooth or periodontal pockets.
The bioadhesive film of the present invention alleviates many of
the above problems. It may be applied easily by the consumer. It
has very little or no mouthfeel, it has good adhesion to the
mucosal tissues, and provides controlled release of the
medicament.
OBJECT OF THE INVENTION
It is an object of this invention to provide an extruded film that
is an effective and convenient intra-oral drug delivery system and
method for applying and delivering controlled dosages of
therapeutic agents into the oral cavity. This technology may also
be extended for controlled drug delivery in skin care,
gynecological applications, wound care and like uses.
SUMMARY OF THE INVENTION
The invention involves a pharmaceutically acceptable
controlled-releasing medicament-containing extruded single or
multi-layered thin film, capable of adhering to a wet mucous
surface, comprising a water soluble or swellable polymer matrix
bioadhesive layer which can adhere to a wet mucous surface and
which bioadhesive layer consists essentially of
.[.40-95.Iadd.20-93.Iaddend.% by weight of hydroxypropyl cellulose
5-60% of a homopolymer of ethylene oxide, 0-10% of a
water-insoluble polymer selected from the group consisting of ethyl
cellulose, propyl cellulose, polyethylene and polypropylene, and
2-10% of a plasticizer, said film having incorporated therein a
pharmaceutically effective amount of said medicament.
The present invention is directed to an extruded single or
multi-layered laminated thin (1-10 mils or 0.025-0.25 mm) film,
composed of selected water soluble and/or insoluble polymers.
Various therapeutic agents are incorporated into the film during
manufacture which are useful for treatment of oral disorders (i.e.,
denture discomfort, caries, periodontal disease, aphthous ulcers,
etc.).
The extruded film of the present invention must have at least one
bioadhesive layer, but may also have a reservoir layer and/or an
outer protective barrier membrane layer. The therapeutic agent may
be incorporated into any or all of the layers. When properly
formulated and fabricated, these films will adhere to wet mucosal
surfaces, provide a protective barrier for injured tissue and
deliver controlled/sustained dosages of medication to the infected
areas. The film may be designed for localized drug delivery (i.e.,
the periodontal pocket, an aphthous lesion), or may allow diffusion
of the drug into the oral cavity.
An example of a non-localized system would be the delivery of
sodium fluoride for caries prevention. A single or laminated film
with good adhesion to the tooth or mucosal tissue may be employed
in which the fluoride release rates may be controlled by varying
film solubilities and/or concentration of fluoride in a
multi-layered film.
An example of a localized application of medication would be in the
treatment of aphthous lesions. A laminated two layer film with
benzocaine incorporated into the adhesive layer would directly
contact the injured mucosa. The outer layer would consist of
non-soluble/non-adhesive polymers that provide durability,
protection and directs the delivery of benzocaine toward the
lesion.
The film forming polymers that are useful in this invention are
selected from pharmaceutical grade materials, or those that are
considered generally regarded as safe (GRAS) as food additives.
They include, hydroxypropyl cellulose, and polyethylene oxide
homopolymers. Small amounts of other polymers, e.g., polyvinyl
ether-maleic acid copolymers and the like may be used in small
amounts as well, replacing a small portion of the other polymers.
The above materials are either water soluble of swellable and are
most useful in the bioadhesive layer of the film. Various
non-soluble polymers may also be incorporated for modification of
the film's permeability properties, such as ethyl cellulose, propyl
cellulose, polyethylene, polypropylene and carboxymethylcellulose
(free acid). By varying the ratios of the above polymers both the
solubility and the adhesive properties of each layer of film may be
controlled. Therefore, depending on the desired delivery rate, the
type of disorder to be treated, the area to be treated and the
medication being administered it is possible to custom design the
film by selecting and blending various polymers. The final film
product may also be fabricated into flexible tapes of varied
thickness and width, "spots" of different sizes and shapes or other
pre-shaped forms.
The medicaments and pharmaceutical agents set forth in the prior
art discussed above may generally be delivered by the drug delivery
system of the present invention. Usable medicaments are those which
are capable of withstanding the heats and pressures generated in
the extrusion process involved in making the film of the present
invention. Preferred medicaments include:
Anesthetics/Analgesics-benzocaine, dyclonine HCl, phenol, aspirin,
phenacetin, acetaminophen, potassium nitrate, etc.
Anticaries Agents-sodium fluoride, sodium monofluorophosphate,
stannous fluoride, etc.
Anti-inflammatories-hydrocortisone acetate, triamcinolone
acetonide, dipotassium, glycyrrhizinate, etc.
Antihistamines-chlorpheniramine maleate, ephedrine HCL,
diphenhydramine HCL, etc.
Antibiotics-i.e., tetracycline, doxycycline hyclate, meclocycline,
minocycline, etc.
Antibacterials-chlorhexidine, cetyl pyridinium chloride,
benzethonium chloride, dequalinium chloride, silver sulfadiazene,
phenol, thymol, hexedine, hexetidine, alexidine, etc.
Fungistats-nystatin, miconazole, ketoconazole, etc.
The above are illustrative examples of therapeutic agents that are
used to treat oral disorders. The present invention is not to be
limited to these specific materials especially where it is intended
to deliver drug outside of the oral cavity e.g. to skin where other
drugs may be desirable.
The film of the present invention has the advantage of being an
extruded film, rather than a cast film. When a multi-layered film
is involved, the different layers can be coextruded and then
laminated together, or else each layer can be separately extruded
one on the other, and then laminated together, so that the final
multi-layered film is still very thin. The films of the present
invention can be made in thicknesses of only 1-10 mils or
0.025-0.25 mm. The films are so thin that when placed in the mouth
after they become wet they soon become unobtrusive, and hardly
noticeable by most patients.
The film must always have a bioadhesive layer, which enables it to
adhere to wet mucosal surfaces. The bioadhesive layer has
.[.40-95.Iadd.20-93.Iaddend.% of hydroxypropyl cellulose, 5-60% of
a homopolymer of ethylene oxide and 2-10% of a glycol plasticizer
(all percents are % by weight).
The Hydroxypropyl cellulose (HPC), useful for purposes of the
present invention is commercially available from Hercules, Inc.
(Wilmington, DE) under the tradename KLUCEL*. Preferred grades
include Klucel MF, with a molecular weight around 600,000 and
having a viscosity of 4,000-6,000 cps (Brookfield) in 2 percent
water solutions, or Klucel HF, having a molecular weight around
1,000,000 and viscosity of 1500-2500 cps in 1 percent water
solution. In general, any HPC having a Molecular Weight above about
100,000 is useful for purposes of this invention.
The homopolymer of ethylene oxide useful for purposes of the
present invention has a relatively high molecular weight, i.e.,
above 100,000 and preferably above 3,000,000. Such polymers are
commercially available from various sources. The Union Carbide
Corporation material, "Polyox WSR-301", which has a molecular
weight of approximately 4,000,000-5,000,000 is most preferred for
purposes of the present invention.
The "plasticizer" useful for purposes of the present invention are
selected from glycols such as propylene glycol and polyethylene
glycol; polyhydric alcohols such as glycerin and sorbitol; glycerol
esters such as glycerol triacetate; fatty acid triglycerides such
as NEOBEE* M-5 and MYVEROLS*; mineral oil; vegetable oils such as
castor oil, etc.
For the uses for the present invention contemplated here, the
plasticizer should be non-toxic. The purpose of the plasticizer is
to improve polymer melt processing by reducing the polymer melt
viscosity and to impart flexibility to the final product.
The preferred plasticizer for use in the present invention is
either propylene glycol or polyethylene glycol (such as is
available from Union Carbide Corporation as their series of
Carbowaxes which runs from 200 to 600 molecular weight, of which we
prefer to use Carbowax 400, which has a molecular weight of 400,
average.
In addition to the polymers and plasticizer which are required
ingredients of the films of the present invention, minor amounts of
other non-essential but customary ingredients will often be used if
desired, e.g., antioxidants, preservatives, flavors, colorants.
DETAILED DESCRIPTION
The following examples will serve to illustrate the present
invention in greater detail. The units shown in the examples are
parts by weight. The thickness of the layers is expressed in either
mils (0.001 inches) or millimeters. For easy conversion, 4 mils is
approximately equal to 0.1 mm.
EXAMPLE 1
Triple Layered Laminate Containing Sodium Fluoride for Anticaries
Protection
This three layered film laminate is comprised of a "bioadhesive"
layer, a sodium fluoride "reservoir" layer and, an "outer
protective barrier membrane" layer, in which the composition and
thickness of each layer are as shown below:
______________________________________ Outer Protective Bio- % w/w
Barrier adhesive Reservoir Membrane Layer Layer Layer (4 mils) (1
mil) (1 mil) Ingredients (0.1 mm) (0.025 mm) (0.025 mm)
______________________________________ Polyethylene oxide 60.0 --
-- homopolymer (Unison Carbide-Polyox* WSR-301) Hydroxypropyl
Cellulose 30.0 20.0 24.0 (Hercules, Inc.-Klucel* MF) Polyethylene
(Allied 5.0 -- -- Chemical-6A) (Low Density) Propylene Glycol,
U.S.P. 3.0 -- -- Polyethylene Glycol 2.0 -- -- 400 (Union Carbide)
Ethyl Cellulose (Hercules, -- 59.0 69.6 Inc.-N100F) Caprylic/Capric
-- 5.0 6.0 Triglyceride(PVO Incorporated-Neobee M-5) Sodium
Fluoride, U.S.P. -- 16.0 0.4 100.0 100.0 100.0
______________________________________
The process used to make the above laminate was:
a. Powder Blending-Each layer is made separately and all
ingredients used therein except propylene glycol and Neobee M-5
(liquid plasticizers) are placed in a Patterson Kelley (PK)
V-blender equipped with liquid addition capabilities. The
ingredients which are all powders are blended for approximately
10-15 minutes while the liquid plasticizer is slowly added to the
mix. Three separate powder blends are made, one for each layer.
b. Extrusion Process-A standard Johnson 2-1/2 inch vinyl/polyolefin
extruder equipped with a single three stage screw was used to
extrude the "powder blend". The temperature conditions for the
water soluble powders are however quite different from those used
for vinyls and polyolefins. The temperature (.degree.C.) profile
for the "reservoir" and "membrane layers" of the triple laminate
was as follows:
______________________________________ Barrel Zone 1 100 Barrel
Zone 2 125 Barrel Zone 3 135 Barrel Zone 4 145 Barrel Zone 5 160
Barrel Zone 6 170 Adapter 180 Die Zone 1 180 Die Zone 2 180 Die
Zone 3 180 ______________________________________
The films which had a width of 18 inches, were extruded at
approximately 20 feet/minute through a flat lipped die. The
temperature profile for the "bioadhesive layer" was:
______________________________________ Barrel Zone 1 125 Barrel
Zone 2 140 Barrel Zone 3 165 Barrel Zone 4 170 Barrel Zone 5 185
Barrel Zone 6 185 Adapter 185 Die Zone 1 185 Die Zone 2 185 Die
Zone 3 185 ______________________________________
Each layer is extruded separately with the first layer extruded as
a "free film". Successive layers are extruded onto each other and
laminated by passing them through heated stainless steel
rollers.
Test Results:
In vitro fluoride ion release studies were conducted on samples of
the above described triple laminate film measuring 0.5
cm.times.1.25 cm (0.625 cm.sup.2) according to the following
procedures:
The test sample is adhered to a glass slide by prewetting the film
and placing the bioadhesive layer on the glass surface. The slide
is then immersed in a beaker containing 100 ml of distilled water
with continuous stirring. Five milliliter aliquots are withdrawn
from the solution, at prescribed time intervals, and analyzed for
fluoride content with an Orion Ionanalyzer equipped with a fluoride
specific electrode. Release rates are then calculated from the
data.
The results obtained indicated fluoride release rates in the order
of 0.05-0.2 mgs/cm.sup.2 /hr for 24 hours. This falls within the
desired range for maintaining constant low levels of fluoride in
the mouth and enhanced anticaries activity. Release rates may be
tailored to desired use levels by modification of the film
composition and construction.
EXAMPLE 2
Single Layer Adhesive Film Containing Hydrocortisone Acetate (0.5%)
As An Anti-Inflammatory Agent
The composition of the film, which was 0.1 mm. thick, was as
follows:
______________________________________ Ingredients % w/w
______________________________________ Ethylene Oxide Homopolymer
59.4 (Polyox* WSR-301) Hydroxypropyl Cellulose 30.0 (Klucel* MF)
Polyethylene (AC-6A) 5.0 Propylene Glycol 3.0 Polyethylene Glycol
400 2.0 Butylated Hydroxy Toluene (BHT) 0.1 FCC (preservative)
Hydrocortisone Acetate 0.5 100.0
______________________________________
The powder blending process and extruder conditions used were the
same as those described in Example I for the "bioadhesive layer" of
the sodium fluoride trilaminate. In vitro tests were performed on
the above film and demonstrated a prolonged drug release
pattern.
EXAMPLE 3
Single Layer Adhesive Film Containing Triamcinolone Acetonide
(0.1%) As An Anti-Inflammatory
The composition of the film, which was 0.1 mm. thick, was as
follows:
______________________________________ Ingredients % w/w
______________________________________ Ethylene Oxide Homopolymer
59.9 (Polyox WSR-301) Hydroxypropyl Cellulose 29.9 (Klucel MF)
Polyethylene (AC-6A) 5.0 Propylene Glycol 3.0 Polyethylene Glycol
400 2.0 BHT 0.1 Triamcinolone Acetonide 0.1 100.0
______________________________________
The powder blending process and extruder conditions used to make
the film of this Example 3 were the same as those of the
"bioadhesive layer" of Example I.
Other desired active medicament ingredients may be incorporated
into the adhesive films of any of Examples 1-3 in place of the
particular medicament used in said examples. These include
Benzocaine (analgesic), Potassium nitrate (analgesic), Silver
sulfadiazene (antimicrobial),
Chlorhexidine (antimicrobial), miconazole nitrate (antifungal),
Benzethonium chloride (antimicrobial), Tetracycline (antibiotic)
and other similar therapeutic compounds.
EXAMPLE 4
Analgesic Films with Potassium Nitrate
This example shows 5 variations of the film having different
solubilities, resulting in different release rates.
______________________________________ % w/w Ingredients 1 2 3 4 5
______________________________________ Polyethylene oxide 23.75
57.00 55.00 55.00 57.00 homopolymer (Polyox* WSR-301) Hydroxypropyl
Cell- 68.30 -- -- -- -- ulose, N.F. (Klucel* HF) Hydroxypropyl
Cell- -- 28.40 29.90 22.40 22.40 ulose, N.F. (Klucel* MF) Ethyl
Cellulose -- 4.75 5.00 12.50 12.50 Polyethylene Glycol 400 1.90
1.90 2.00 2.00 2.00 Polyethylene Glycol 8000 0.95 -- -- -- --
Propylene Glycol, U.S.P. -- 2.85 3.00 3.00 3.00 BHT, F.C.C. 0.10
0.10 0.10 0.10 0.10 Potassium Nitrate, F.C.C. 5.00 5.00 5.00 5.00
3.00 ______________________________________
The above ingredients are blended in a Patterson-Kelly powder
blender equipped with liquid addition capabilities. The resulting
powder blend is then extruded into film on a Killion or Johnson
vinyl extruder using processing procedures similar to those of the
bioadhesive layer of Example I.
example 5
Anesthetic Films with Benzocaine (Laminate)
This is an example of a two-layer laminate. The processing
conditions used were similar to those of the bioadhesive layer and
outer protective barrier membrane layer of Example I.
______________________________________ A. Inner medicated
bioadhesive layer Polyoxyethylene Homopolymer 57.00 (Polyox*
WSR-301) Hydroxypropyl Cellulose, N.F. 28.40 (Klucel* MF)
Polyethylene (AC-6A) 4.75 Propylene Glycol, U.S.P. 2.85
Polyethylene Glycol 400 1.90 BHT, F.C.C. 0.10 Benzocaine, U.S.P.
5.00 100.00 B. Outer protective/barrier layer Hydroxypropyl
Cellulose 78.00 (Klucel* MF) Ethyl Cellulose 20.00 Polyethylene
Glycol 400 2.00 100.00 ______________________________________
Part A was extruded on a Johnson extruder followed by subsequent
extrusion and lamination of Part B to A.
Samples were applied to oral lesions, and provided profound
anesthetic effects (lasting several hours) within minutes of
application.
The identical two-layer laminate may also be made by coextruding
the inner medicated bioadhesive layer (Part A) and the outer
protective barrier layer (Part B) through separate die slots within
a coextruder and laminating the two layers together.
EXAMPLE 6
Anesthetic Films with Phenol and Dyclonine HCl
Four variations of a single layer bioadhesive film were made as
shown below:
______________________________________ Ingredients 1 2 3 4
______________________________________ Polyethylene oxide homo-
59.10 54.00 59.70 58.20 polymer (Polyox* WSR-301) Hydroxypropyl
Cellulose 29.45 26.91 29.75 29.00 (Klucel HF) Ethyl Cellulose 4.93
4.50 4.98 4.85 Propylene Glycol, U.S.P. 2.96 2.70 2.99 2.91
Polyethylene Glycol 400 1.97 1.80 1.99 1.94 BHT, F.C.C. 0.09 0.09
0.09 0.10 Phenol, U.S.P. 1.50 -- -- -- Dyclonine HCl -- 10.00 0.50
3.00 ______________________________________
Following the procedures for the bioadhesive layer of Example I,
the powders were blended in P-K blender equipped with liquid
addition capabilities. Resulting powders were extruded on a Killion
laboratory-sized extruder.
EXAMPLE 7
Silver Sulfadiazene Films-Antimicrobial
Three different single-layered bioadhesive films containing 1.0%
0.5% and 0.5% respectively of silver sulfadiazene (SSD) were
prepared on a heated Carver laboratory press (designed to simulate
extruded conditions) as shown below.
______________________________________ % w/w Ingredients A B
______________________________________ Polyethylene oxide
homopolymer 60.00 60.00 (Polyox* WSR-301) Hydroxypropyl Cellulose
28.9 29.4 (Klucel* HF) Polyethylene (AC-6A) 5.0 5.0 Propylene
Glycol, U.S.P. 3.0 3.0 Polyethylene Glycol 400 2.0 2.0 BHT, F.C.C.
0.1 0.1 Silver Sulfadiazine 1.0 0.5 100.0 100.0
______________________________________
Effects on wound repair and activity against Staphylococcus aureus
were evaluated in the guinea pig model. Full-thickness excisions
were inoculated with 3.8.times.10.sup.5 organisms, (Staph. aureus)
and wound surface microbiology samples taken 10 minutes and 24
hours after treatment. Test films were placed on the wound and
covered with BIOCLUSIVE* Transparent Dressings secured with elastic
tape. Wound contraction was measured over an eight-day period using
OPTOMAX* Computer-Assisted Image Analysis. The three films tested
were the following:
A. 1.0% Silver Sulfadiazene, 125.degree. C./2 minutes/4 tons
B. 0.5% Silver Sulfadiazene, 125.degree. C./2 minutes/4 tons
C. 0.5% Silver Sulfadiazene, 150.degree. C./3 minutes/4 tons
SILVADENE Cream and an untreated occluded control. The results
indicated that:
1. SILVADENE* treated wounds significantly inhibited full-thickness
wound contraction.
2. Film A, B and C inhibited wound contraction relative to that of
BIOCLUSIVE* dressed wounds.
3. The three SSD films each permitted substantially faster wound
contraction than that of wounds treated daily with SILVADENE*
cream.
4. All films were very active against S. Aureus 24 hours after
inoculation.
The films may be scaled up by using an extruder. This example
demonstrates the feasibility of such a film to perform its intended
purpose. Use of a press for larger samples would result in a
non-uniform and lower-quality film than an extruded film.
Based on the above findings, the films were very effective
antibacterial agents, while mildly inhibiting wound contraction.
They offer clinicians a convenient and more effective delivery
system for antimicrobials which can be place in wounds beneath any
dressing or can be laminated to any acceptable dressing face.
* * * * *