CA1297408C - Bioadhesive extruded film for intra-oral drug delivery and process - Google Patents
Bioadhesive extruded film for intra-oral drug delivery and processInfo
- Publication number
- CA1297408C CA1297408C CA000539509A CA539509A CA1297408C CA 1297408 C CA1297408 C CA 1297408C CA 000539509 A CA000539509 A CA 000539509A CA 539509 A CA539509 A CA 539509A CA 1297408 C CA1297408 C CA 1297408C
- Authority
- CA
- Canada
- Prior art keywords
- layer
- film
- extruded
- bioadhesive
- cellulose
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Expired - Lifetime
Links
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/20—Pills, tablets, discs, rods
- A61K9/2072—Pills, tablets, discs, rods characterised by shape, structure or size; Tablets with holes, special break lines or identification marks; Partially coated tablets; Disintegrating flat shaped forms
- A61K9/2086—Layered tablets, e.g. bilayer tablets; Tablets of the type inert core-active coat
- A61K9/209—Layered tablets, e.g. bilayer tablets; Tablets of the type inert core-active coat containing drug in at least two layers or in the core and in at least one outer layer
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/0012—Galenical forms characterised by the site of application
- A61K9/0053—Mouth and digestive tract, i.e. intraoral and peroral administration
- A61K9/006—Oral mucosa, e.g. mucoadhesive forms, sublingual droplets; Buccal patches or films; Buccal sprays
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/02—Drugs for disorders of the nervous system for peripheral neuropathies
Abstract
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% 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.
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% 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.
Description
7~
DRUG DELIVE~R~Y AND PROCESS
S BACKGROUND OF THE INVENTION
Field of the Invention The present invention relates to a c:on~rolled-releasing medicament-containing preparation for intra-oral use, and i8 more especially concerned with s~ch a preparation (and the process of using it) in the form of a very thin extruded thermoplastic fi}m (which can be in single layer ; or la~inated multi-layer form) having at least one bioadhesive layer containing gO-95~ of a thermoplastic aellulose ether and 5-60% of a homopolymer of ethylene oxide which can adhere to the mUcosa o~ the oral ~a~ity.
The extruded film drug delivery system of the present invention, which has incorporated thersin the medicament to be dispensed, is so thin and flexible when wet as to be unobtrusive to the patient ater it has been properly positioned and placed in the mouth.
Descri~tion of the Prior Art Several sys~ems have previously been described which pertain to the delivery of drugs in~o the oral cavity.
These include:
1. Treatment of periodontal disease with tetracycline, chlorhexidine or metronidazole loaded into hollo~
cellulose acetate fibers. These fibers are packed in the periodontal pockets and pro~ide controlled release of the drug to the infected area.
;'` ~
~ J~ 1191 ,.
79~08 2. Cast films containing ethyl cellulose/propylene glycol with chlorhexidine or metronidazole for treatment of periodontal disease.
DRUG DELIVE~R~Y AND PROCESS
S BACKGROUND OF THE INVENTION
Field of the Invention The present invention relates to a c:on~rolled-releasing medicament-containing preparation for intra-oral use, and i8 more especially concerned with s~ch a preparation (and the process of using it) in the form of a very thin extruded thermoplastic fi}m (which can be in single layer ; or la~inated multi-layer form) having at least one bioadhesive layer containing gO-95~ of a thermoplastic aellulose ether and 5-60% of a homopolymer of ethylene oxide which can adhere to the mUcosa o~ the oral ~a~ity.
The extruded film drug delivery system of the present invention, which has incorporated thersin the medicament to be dispensed, is so thin and flexible when wet as to be unobtrusive to the patient ater it has been properly positioned and placed in the mouth.
Descri~tion of the Prior Art Several sys~ems have previously been described which pertain to the delivery of drugs in~o the oral cavity.
These include:
1. Treatment of periodontal disease with tetracycline, chlorhexidine or metronidazole loaded into hollo~
cellulose acetate fibers. These fibers are packed in the periodontal pockets and pro~ide controlled release of the drug to the infected area.
;'` ~
~ J~ 1191 ,.
79~08 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/M~A with fluoride may also be attached to the tooth in the form of a waSer-like tablet.
matrix. Sodium fluoride is incorporated into the HEMA/MMA matrix to provide sustained fluoride release and enhanced anticaries activity. HEMA/M~A with fluoride may also be attached to the tooth in the form of a waSer-like tablet.
4. Silicone/ethyl cellulo~e~polyQthylene glycol Pilms containing sodium fluoride ~re applied as coa~ings on orthodontic bands or in chewing gum. Controlled release of 1uoride and anticaries activity is claimed.
The above systems are discussed in the "The Compendium o~
Continuing Educatio~ Vol VI~ No. 1, Jan.1985 p. 27-36 review article ~'Con~rolled Drug Delivery: A New Means of Treatment of Dental Disease~', by J. Max Goodson, D.D.S., Ph.D. of the Forsyth Dental Cent,er. Other systems, described . in GB patent 2,04~,888 issued 5ept3~r 28, 1983 and U.S~
Patents 4,292,299/4,226,848 (Teijin Ltd., Japan), use combina~ions of cellulosic and polyacrylate polymers. The pre~erred materials are hydroxypropyl cellulose ~"Kluce~") and a copolymer of acrylic acid ("Carbopo~"~ that is administered in the form of thin tablets ~discs), gran~les or powder. Other polymer that might be added are vinyl copolymers, polysaccharides, gelatin and collagen. U.S.
patent 4,S17,173 (Nippon Soda Co. Ltd, Japan) uses various celluloses in a multi-layered non-extruded cast film preparation.
* Trade Mbrk J&J llgl 7~
Examples of prior ar~ products currently on the market include ointments such as O~ABASE~ with Benzocaine (Squibb), Kenalog* (Triamcinolone Acetonide) in ORABASE*
(Squibb) and Mycosta~in* (Nystatin~ oin~ment (Squibb).
The prior art products and delivery syste~s described above are useful but have ~he following disadvantages:
Tablees, appliances, hollow fibers are "bulky" in the mouth, are di~ficult 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.
Excepe for ORABASE~, all the foregoing systems require professional application to ~he too~h or periodontal pockets.
The bioadhesive film of the present invention alleviates many of the above problems. It may be applied easily by the consu~er. It has veey little or no mouthfeel, it has good adhesion to the mucosal tissues, and provides controlled release of the medicament.
Obiect 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 J~J 1191 ~Z~7~
controlled drug delivery in skin care, gynecological applications, wound care and like uses.
Summary Qf the Inv_ntion 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~ by weight of hydroxypropyl cellulose 5-60~ of a homopolymer o~ ethylene oxide, 0-lOlt of a water-insoluble polymer selected from the group consisting of ethyl cellulose, propyl cellulose, polyethylene and polypropylene, and 2-10% o~ 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 (l-10 mils or O.OZ5-0.25 mm~
film, composed of selected water soluble and/or insoluble polymers. Various therapeu~ic agents are incorporated into the film during ma~ufacture which are useful for treatment of oral disorders (i.e., denture discomfort, caries, periodontal disease, aphehous ulcers, etc.).
The extruded fil~ of the present invention must have at leas~ one bioadhesive layer, but may also have a reservoir layer and/or an outer protective barrier me~brane layer.
The therapeutic agent may be incorporated into any or all of the layers. When properly formulated and fabricated, these ~ilms will adhere to wet mucosal surfaces, provide a protective barrier f or injured tissue and deliver controlledtsustained dosages of medication to the infected J&J 1191 7~
areas. The film may be designed for localized drug delivery (i.e., the periodontal pocke~, an aphthous lesion), or may allow diffusion of the ~rug into the oral cavity.
An example of a non-localized ystem 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 i~ ~hich the fluoride release ra~es may be controlled by varying film solubilities andJor concentration of fluoride in a multi-layered film.
An example of a localized application oS medication would be in the treatment of aphthous lesions. A laminated two layer film with benzocaine incorporated into the adhesive layer would direct}y contact the injured mucosa. The outer layer would consist o~ 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 thi~
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 or swellable and are most useful i~ the bioadhesive layer of the film. Various non-soluble polymers may also be incorporated for modifica~ion of the film's permeability properties, such as ethyl cellulose, propyl cellulose, polyethylene, polypropylene and carboxymethylcellulose (free acid). By varying the ratios J~J 11~1 7~
of the above polymers both the solubility and the adhesive propertie of each layer of film may be controlled.
Therefore, depending on the de~ired 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 druq delivery system of the present invention. Usable medicaments are those which are capable of withstanding the heats and pressures generated in the extru6ion process involved in making the film oflthe present invention.
Preferred medicaments include:
Anesthetis/Analqesics - benzocaine, dyclonine HCl, phenol, aspirin, phenacetin, acetaminophen, potassium nitrate, etc.
Anticaries Aqents - sodium fluoride, sodium monofluoro-phosphate, stannous fluoride, etc.
Anti-inflammatories - hydrocortisone acetate, ~riamcinolone acetonide, dipotassium, glycyrrhizinate, etc.
Antihistamines - chlorpheniramine maleate, ephedrine HCL, diphenhydramine HCL, etc.
.
Antib]otic - i.e., tetracycline, doxycycline ~; hyclate, meclocycline, minocycline, etc.
J~J 1191 2~
A~tibac~erials - chlorhexidine, cetyl pyridinium chloride, benze~honium chloride, dequalinium chloride, silver sulfadiazene, phenol~ ~hymol, hexedine, hexetidine, alexidine, etc.
Funqistats - nys~aein, miconazole, ketoconazole,~etc.
The above are illustrative examples of therapeutic agents that are used to treat oral disorders. The pre ent invention is not to be limited to these specific materials especially where it is inte~ded to daliver 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 stil} very thin. The ~ilms of the present invention can be made in thicknesses of only 1-10 mils or 0.025-O.Z5 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 i~ to adhere to wet mucosal surfaces. The bioadhe~ive layer has 40-55% of hydroxypropyl cellulose, S-60% of a homopolymer of ethylene oxide and 2-10% of a glycol plasticizer (all percents are % by weight).
The ~ydLoxypropyl cellulose (HPC), useful for purposes of the present inven~ion is commercially available from Hercules, Inc. (Wilmington, DE) under the tradename J&J 1191 KLUCEL~. Preferred grades include Kl~cel MF, with a molecular weigh~ around 600,000 and having a YiSCosity of 4,000-6,000 cps (Brookfield~ in 2 percent water solutions, or Klucel HF, having a molecular weight around 1,000 and viscosity of 1500-2500 cps in 1 percen~ 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 use~ul 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 ~ateeial, "Polyox WSR-30l", 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 prQpylene ~; 20 glycol and polyethylene glycol; polyhydric alcohols such as glycerin and sorbitol: glycerol es~ers 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-~oxic. The purpose of the plasticizer is to improve polymer melt processing by reducing the polymer melt viscosity and to impart flexibility ~o the final product.
The preferred plasticizer ~or use in the present invention is either propylene qlycol or polyethylene glycol (sueh as is a~ailable from Union Carbide Corporation as their series of Carbowaxes which runs from 200 to 600 ~olecular J~J 1191 '~ rr~e~ tc weight, of which we prefer to use Carbowax ~OO, which has a molecular weight o~ 400, average.
In addition ~o the polymers and plasticizer which are required i~gredients of the films of the present invention, minor a~ounts of other non-essential bu~
customaLy ingredients will often be used if desired, e.g.
antioxidants, preserva~ivas, 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 thickn~s Oe the layers is expressed in either mils (.OOl inches) or millimeters. For easy conversion, 4 mils is approximately equal to O.l mm.
FLUORIDE FOR ANTICARIES PROTECTION:-This three layered film laminate is comprised of a "bioadhesive~ layer, a sodium ~luoride ~reservoir" layer and, an "outer protective barrier membrane" layer, in which the composition and thickness of each layer are as ~hown below:
~r~le~rK
J~J 1191 Outer Protective % w/w Barrier BioadhesiveReservoir Membrane Layer Layer Layer (4 ~ils) tl ~il) (1 ~il) Inqredients ~0.1 mm2 (0.025_m~) (0.025 m~) Polyethylene Oxiae 60.0 homopolymer ~Union Carbide-Polyox* WSR-301) Hydroxypropyl Celluloæe 30.0 20.0 24.0 (Hercules, Inc.-~lucel~ MF) Polyethylene (Allied Chemical-6A) (Lo~ Density) 5~0 ;
Propylene Glycol, U.S.P. 3.0 Polyethylene Glycol 2.0 400 (Union Carbide) Ethyl Cellulose ~Hercules, 25 I~c.-NlOOF) - 59.0 69.6 CapryliclCapric - 5.0 6.0 Triglyceride (PVO Incorporated-Neobee M-5) Sodium Fluoride, U.S.P. =_ 16.0 0.4 100.0 lVO.O 100.0 The process used to make the above la~inate was :
J~J 1191 ~337~
a) Powder_Blendinq - Each layer is made separately and all ingredie~s used therein except propylene glycol and Neobee M-5 (liquid plasticizers) are placed in a Patterson ~elley (PK) V-blender lequipped with liquid addition capabilitias. The ingrledients which are all powders are blended for approximately 10-lS minutes ; while the liguid plasticizer is slowly added to the mix. Three separate powder blends are made. one for each layer.
b) Ex~rusion Pr_ces6 - A standard Johnson 2-1/2 inch vinyl~polyolefin extruder equipped with a single three ~tage screw was used to extrude the "powder blend".
The temperature aonditions for the water soluble powders are however quite different from those used for vinyl6 and polyolefins. The temperature (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 lB0 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:
J~J 1191 .~
7~
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 iayer is extruded separately with the first layer extruded as a "~ree film". Successive layers are extruded onto each other and laminated by pas6ing them through heated stainless steel rollers.
Test Results:
, In vi~ro fluoride ion release studies were conducted on samples of the above described triple laminate film measuring 0.5 cm x 1.25cm tO.625 cm2) 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 con~inuous stirring. Pive milliliter aliquots are withdrawn from the solution, at prescribed time intervals. and analyzed for fluoride content with an Orion Ionanlyzer equipped with a fluoride specific electrode. Release ra~es are then calcula~ed from the data.
The results obtained indicated fluoride release rates in ~he order of 0.05-0.2 mgs~cm~/hr for 24 hours. This J~J 1191 ~alls within the desirable range for maintaining constan~
low levels of fluoride in the mouth and enhanced anticaries activity. Release rates may be tailored to desired use le~els by modification of ~he film composition and construction.
EXAMPLE ? - SINGLE LAYER ADHESIVE FILM CONTAINING
HYD~OCORTISONE ACETATE (0.5%) AS AN ANTI-INFL~MMATORY
AGENT:
The co~position of the ~ilm, which was 0.1 mm. thick, was as follows:
Inqredients %_w~w, Ethylene Oxide Homopoly~er 59.4 (Polyox* WSR-301) Hydroxypropyl Cellulose 30.0 20 (Klucel* MF) Polyethylene (AC-6A) 5.0 Propylene Glycol 3~0 Polyethylene Glycol 400 2.0 ;~ Butylated ~ydroxy Toluene (BHT) FCC (preservative) 0.1 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 J~J lL91 . ~Z~7~
~bioadhesive layer" of the sodium fluoride ~rilaminate.
In vitro tests were performed on the above ilm and demonstrated a prolonged drug release pattern.
EXA~PL~ 3 - SINGLE LAY2R ADHESIVE FILM CONTAINING
TRIAMCINOLON2 ACETONI~E (0.1%) AS AN ANTI-INFLAM~ATORY:
The composition of the film, which was 0.1 mm. thick, was as follows:
Inqredient & %_W/W
Ethylene Oxide Homopolymer 59.9 (Polyox WSR-301) Hydroxypropyl Cellulose 29.9 (~lucel ~F) Polyethylene (AC-6A) 5.0 Propylene Glycol 3.0 Polyethylene Glycol 400 2.0 25 BHT 0.1 ~ri~mcinolone Acetonide 0.1 }00 . O
The powder blending process and extruder conditions used to ~ake the film of this Examele 3 were the same as those of ~he "bioadhesive layer" of Example I.
Other desired active medicament ingredients may be incorporated into the adhesive films of any of Examples J~J 1191 1-3 in place of the particular medic,3ment used in said examples. These include ~en~ocaine (analgesic~, Potassium ni~rate ~analgesic), Silver sulfadiazene (antimicrobial), S Chlorhexidine (antimicrobial), miconazole nitrate ~antifungal~, Benzethonium chloride (antimicrobial), Tetracycline (antibiotic) and other similar therapeutic compounds.
EXAMPLE 4 - AN~LGESIC FILMS WITH POTASSIUM NITRATE
This Qxample shows 5 variations of the film having different solubilities, resulting in di~ferent release rates.
: . 20 : 30 J~J 1191 . ~ .,. . , ~ ~
% w/w Inqredients 1 2 3 4 5 5 Polyethylene oxide 23.75 57.0055.00 55.00 57.00 homopolymer (Polyox*
WS~-301) Hydroxypropyl Cell- 68.30 - - - _ ulose, N.F. (~lucel~
HF) Hydroxypropyl Cell- - 28.4029.90 22.40 22.~0 ulose, N.~. (Klucel~
M~) ~thyl Cellulose - 4.75 5.00 12.50 12.50 Polyethylene Glycol1.90 1.90 2.00 2.00 2.00 gOO
Polyethylene Glycol0.95 - - - -Propylene Glycol, - 2.85 3.00 3.00 3.00 25 U.S.P.
BHT, F.C.C. 0.10 0.10 0.100.10 0.10 Potassium Nitrate, 5.00 5.00 5.00 5.00 ~.00 30 F.C.C.
The above ingredients are blended in a Pa~terson-Kelly powder blender equipped with liquid addition capabilities.
The resulting powder blend is then extruded into film on a Killion or Johnson vinyl ex~ruder using proces~ing J~J 1191 ~2~79~
procedures si~ilar to those of the bioadhesive layer of Example I.
X~MPLE 5 - ANESTHETIC FILMS ~ITH BENZOCAINE (LAMINATE) This is an example of a t~o-layer laminate. The processing conditions used were similar to those o~ 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 gO01. 90 BHT, F.C.C. 0.10 Benzocaine, U.S.P. 5.00 100 . 00 J~J 1191 B. Outer pro~ective/barrier_layer Hydroxypropyl Cellulose 78.00 tKlucel* MF) Ethyl Cellulose 20.00 Polyethylene Glycol 400 2.00 1~0 . 00 : Par~ A was extruded on a Johnson extruder followed by subsequent extrusion and lamination of Part B to A.
Samples were ap~lied to oral lesions, and provided pro~ound lS anesthet1c e~ects ~}asting several hours) within minutes of application.
The identical t~o-layer laminate may also be made by coexeruding the inner medicated bioadhesive layer (Part A) and the outer protective barrier layer (Part B~ through separate die slots within a coextruder and lami~ating ~he `~ two layers toge~her.
,~ .
EXAMPLE 6 - ANESTHETIC FILMS WITH PH~NOL AND DYCLONIN~ HCl Four variations of a single layer bioadhesive film were made as shown below:
Inqredients l 2 3 4 Polyethylene oxide ho~o- 59.lO 54.0059.70 58.20 polymer (Polyox* W5R-30l) Hydroxypropyl Cellulose 29.45 26.~l29.75 29.00 (Klucel HF) ~5 Ethyl Cellulose 4.93 4.50 4.98 4.85 J~J ll9l ~2~
Propylene Glycol, U.S.P. 2.96 2.70 2.99 2.91 Polyethylene Glycol 4Q0 1.97 1.80 1.99 1.94 BHT, F.C.C. 0.090.09 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, ths powders were blended in P-K blender equipped with liquid addition capabilities. Resulting powders were extruded on a Killion laboratory-sized extruder.
~hree different single-layered bioadhesive films containing 1.0% 0.5~ and 0.5% respectively of silver sulfadiazene (SSD) were prepared on a heated Car~er laboratory press (designed to simulate extruded condieions) as shown below.
J~ 1191 7~
~ w~w Inqredients A
5 Polyethylene oxide homopolymer60.0060.00 (Polyox* WSR-301) ~ydroxypropyl Cellulose 2~.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 20 Silver Sulfadiazine 1.0 0.5 100.O 100.O
:, Effects on wound repair and activity against Stale~y~ococcus aureus were evaluated in the guinea pig model. Full-thickness excisions were inoculated with 3. n : x 105 organisms, (Staph. aureus) and wound surface microbiology samples taken 10 minutes and 24 hours after ~rea~ment. Test films were placed on the wound and covered wi~h BIOCLUSIVE* Transparent Dressings secured with elastic tape. Wound contraction was measured over an eight-day period using OP~OMAX~ Computer-Assisted Image Analysis. The three films tested were the following:
A. 1.0% Silver Sulfadiazene, 125C/2 minutes/~ tons J~J 1191 7~
B. 0.5% Silver Sulfadiazene, 125C~2 minutes/4 tons C. 0.5% Silver Sulfadiazene. 150C/3 minutes/4 tons SILVADEN~ Cream and an untreated occluded control. The results indicated that:
1. SILVADENE~ treated wounds significan~ly 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 ~ilms each permi~ted substantially lS faster wound contraction than that of wounds treated daily with SILVADENE~ cream.
. All ~ilms 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 ineended purpose. Use of a press for larger sample~ would result in a non-uniform and lower-quality film than an extrude~ film.
Based on the above findings, the films were very effective antibacterial agents, while mildly inhibiting wound con~raction. They offer clinicians a convenient and more effective delivery system for antimicrobials which can be place in wounds beneath any dressing or can be la~inated to any acceptable dressing face.
J~J 1191
The above systems are discussed in the "The Compendium o~
Continuing Educatio~ Vol VI~ No. 1, Jan.1985 p. 27-36 review article ~'Con~rolled Drug Delivery: A New Means of Treatment of Dental Disease~', by J. Max Goodson, D.D.S., Ph.D. of the Forsyth Dental Cent,er. Other systems, described . in GB patent 2,04~,888 issued 5ept3~r 28, 1983 and U.S~
Patents 4,292,299/4,226,848 (Teijin Ltd., Japan), use combina~ions of cellulosic and polyacrylate polymers. The pre~erred materials are hydroxypropyl cellulose ~"Kluce~") and a copolymer of acrylic acid ("Carbopo~"~ that is administered in the form of thin tablets ~discs), gran~les or powder. Other polymer that might be added are vinyl copolymers, polysaccharides, gelatin and collagen. U.S.
patent 4,S17,173 (Nippon Soda Co. Ltd, Japan) uses various celluloses in a multi-layered non-extruded cast film preparation.
* Trade Mbrk J&J llgl 7~
Examples of prior ar~ products currently on the market include ointments such as O~ABASE~ with Benzocaine (Squibb), Kenalog* (Triamcinolone Acetonide) in ORABASE*
(Squibb) and Mycosta~in* (Nystatin~ oin~ment (Squibb).
The prior art products and delivery syste~s described above are useful but have ~he following disadvantages:
Tablees, appliances, hollow fibers are "bulky" in the mouth, are di~ficult 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.
Excepe for ORABASE~, all the foregoing systems require professional application to ~he too~h or periodontal pockets.
The bioadhesive film of the present invention alleviates many of the above problems. It may be applied easily by the consu~er. It has veey little or no mouthfeel, it has good adhesion to the mucosal tissues, and provides controlled release of the medicament.
Obiect 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 J~J 1191 ~Z~7~
controlled drug delivery in skin care, gynecological applications, wound care and like uses.
Summary Qf the Inv_ntion 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~ by weight of hydroxypropyl cellulose 5-60~ of a homopolymer o~ ethylene oxide, 0-lOlt of a water-insoluble polymer selected from the group consisting of ethyl cellulose, propyl cellulose, polyethylene and polypropylene, and 2-10% o~ 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 (l-10 mils or O.OZ5-0.25 mm~
film, composed of selected water soluble and/or insoluble polymers. Various therapeu~ic agents are incorporated into the film during ma~ufacture which are useful for treatment of oral disorders (i.e., denture discomfort, caries, periodontal disease, aphehous ulcers, etc.).
The extruded fil~ of the present invention must have at leas~ one bioadhesive layer, but may also have a reservoir layer and/or an outer protective barrier me~brane layer.
The therapeutic agent may be incorporated into any or all of the layers. When properly formulated and fabricated, these ~ilms will adhere to wet mucosal surfaces, provide a protective barrier f or injured tissue and deliver controlledtsustained dosages of medication to the infected J&J 1191 7~
areas. The film may be designed for localized drug delivery (i.e., the periodontal pocke~, an aphthous lesion), or may allow diffusion of the ~rug into the oral cavity.
An example of a non-localized ystem 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 i~ ~hich the fluoride release ra~es may be controlled by varying film solubilities andJor concentration of fluoride in a multi-layered film.
An example of a localized application oS medication would be in the treatment of aphthous lesions. A laminated two layer film with benzocaine incorporated into the adhesive layer would direct}y contact the injured mucosa. The outer layer would consist o~ 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 thi~
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 or swellable and are most useful i~ the bioadhesive layer of the film. Various non-soluble polymers may also be incorporated for modifica~ion of the film's permeability properties, such as ethyl cellulose, propyl cellulose, polyethylene, polypropylene and carboxymethylcellulose (free acid). By varying the ratios J~J 11~1 7~
of the above polymers both the solubility and the adhesive propertie of each layer of film may be controlled.
Therefore, depending on the de~ired 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 druq delivery system of the present invention. Usable medicaments are those which are capable of withstanding the heats and pressures generated in the extru6ion process involved in making the film oflthe present invention.
Preferred medicaments include:
Anesthetis/Analqesics - benzocaine, dyclonine HCl, phenol, aspirin, phenacetin, acetaminophen, potassium nitrate, etc.
Anticaries Aqents - sodium fluoride, sodium monofluoro-phosphate, stannous fluoride, etc.
Anti-inflammatories - hydrocortisone acetate, ~riamcinolone acetonide, dipotassium, glycyrrhizinate, etc.
Antihistamines - chlorpheniramine maleate, ephedrine HCL, diphenhydramine HCL, etc.
.
Antib]otic - i.e., tetracycline, doxycycline ~; hyclate, meclocycline, minocycline, etc.
J~J 1191 2~
A~tibac~erials - chlorhexidine, cetyl pyridinium chloride, benze~honium chloride, dequalinium chloride, silver sulfadiazene, phenol~ ~hymol, hexedine, hexetidine, alexidine, etc.
Funqistats - nys~aein, miconazole, ketoconazole,~etc.
The above are illustrative examples of therapeutic agents that are used to treat oral disorders. The pre ent invention is not to be limited to these specific materials especially where it is inte~ded to daliver 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 stil} very thin. The ~ilms of the present invention can be made in thicknesses of only 1-10 mils or 0.025-O.Z5 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 i~ to adhere to wet mucosal surfaces. The bioadhe~ive layer has 40-55% of hydroxypropyl cellulose, S-60% of a homopolymer of ethylene oxide and 2-10% of a glycol plasticizer (all percents are % by weight).
The ~ydLoxypropyl cellulose (HPC), useful for purposes of the present inven~ion is commercially available from Hercules, Inc. (Wilmington, DE) under the tradename J&J 1191 KLUCEL~. Preferred grades include Kl~cel MF, with a molecular weigh~ around 600,000 and having a YiSCosity of 4,000-6,000 cps (Brookfield~ in 2 percent water solutions, or Klucel HF, having a molecular weight around 1,000 and viscosity of 1500-2500 cps in 1 percen~ 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 use~ul 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 ~ateeial, "Polyox WSR-30l", 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 prQpylene ~; 20 glycol and polyethylene glycol; polyhydric alcohols such as glycerin and sorbitol: glycerol es~ers 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-~oxic. The purpose of the plasticizer is to improve polymer melt processing by reducing the polymer melt viscosity and to impart flexibility ~o the final product.
The preferred plasticizer ~or use in the present invention is either propylene qlycol or polyethylene glycol (sueh as is a~ailable from Union Carbide Corporation as their series of Carbowaxes which runs from 200 to 600 ~olecular J~J 1191 '~ rr~e~ tc weight, of which we prefer to use Carbowax ~OO, which has a molecular weight o~ 400, average.
In addition ~o the polymers and plasticizer which are required i~gredients of the films of the present invention, minor a~ounts of other non-essential bu~
customaLy ingredients will often be used if desired, e.g.
antioxidants, preserva~ivas, 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 thickn~s Oe the layers is expressed in either mils (.OOl inches) or millimeters. For easy conversion, 4 mils is approximately equal to O.l mm.
FLUORIDE FOR ANTICARIES PROTECTION:-This three layered film laminate is comprised of a "bioadhesive~ layer, a sodium ~luoride ~reservoir" layer and, an "outer protective barrier membrane" layer, in which the composition and thickness of each layer are as ~hown below:
~r~le~rK
J~J 1191 Outer Protective % w/w Barrier BioadhesiveReservoir Membrane Layer Layer Layer (4 ~ils) tl ~il) (1 ~il) Inqredients ~0.1 mm2 (0.025_m~) (0.025 m~) Polyethylene Oxiae 60.0 homopolymer ~Union Carbide-Polyox* WSR-301) Hydroxypropyl Celluloæe 30.0 20.0 24.0 (Hercules, Inc.-~lucel~ MF) Polyethylene (Allied Chemical-6A) (Lo~ Density) 5~0 ;
Propylene Glycol, U.S.P. 3.0 Polyethylene Glycol 2.0 400 (Union Carbide) Ethyl Cellulose ~Hercules, 25 I~c.-NlOOF) - 59.0 69.6 CapryliclCapric - 5.0 6.0 Triglyceride (PVO Incorporated-Neobee M-5) Sodium Fluoride, U.S.P. =_ 16.0 0.4 100.0 lVO.O 100.0 The process used to make the above la~inate was :
J~J 1191 ~337~
a) Powder_Blendinq - Each layer is made separately and all ingredie~s used therein except propylene glycol and Neobee M-5 (liquid plasticizers) are placed in a Patterson ~elley (PK) V-blender lequipped with liquid addition capabilitias. The ingrledients which are all powders are blended for approximately 10-lS minutes ; while the liguid plasticizer is slowly added to the mix. Three separate powder blends are made. one for each layer.
b) Ex~rusion Pr_ces6 - A standard Johnson 2-1/2 inch vinyl~polyolefin extruder equipped with a single three ~tage screw was used to extrude the "powder blend".
The temperature aonditions for the water soluble powders are however quite different from those used for vinyl6 and polyolefins. The temperature (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 lB0 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:
J~J 1191 .~
7~
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 iayer is extruded separately with the first layer extruded as a "~ree film". Successive layers are extruded onto each other and laminated by pas6ing them through heated stainless steel rollers.
Test Results:
, In vi~ro fluoride ion release studies were conducted on samples of the above described triple laminate film measuring 0.5 cm x 1.25cm tO.625 cm2) 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 con~inuous stirring. Pive milliliter aliquots are withdrawn from the solution, at prescribed time intervals. and analyzed for fluoride content with an Orion Ionanlyzer equipped with a fluoride specific electrode. Release ra~es are then calcula~ed from the data.
The results obtained indicated fluoride release rates in ~he order of 0.05-0.2 mgs~cm~/hr for 24 hours. This J~J 1191 ~alls within the desirable range for maintaining constan~
low levels of fluoride in the mouth and enhanced anticaries activity. Release rates may be tailored to desired use le~els by modification of ~he film composition and construction.
EXAMPLE ? - SINGLE LAYER ADHESIVE FILM CONTAINING
HYD~OCORTISONE ACETATE (0.5%) AS AN ANTI-INFL~MMATORY
AGENT:
The co~position of the ~ilm, which was 0.1 mm. thick, was as follows:
Inqredients %_w~w, Ethylene Oxide Homopoly~er 59.4 (Polyox* WSR-301) Hydroxypropyl Cellulose 30.0 20 (Klucel* MF) Polyethylene (AC-6A) 5.0 Propylene Glycol 3~0 Polyethylene Glycol 400 2.0 ;~ Butylated ~ydroxy Toluene (BHT) FCC (preservative) 0.1 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 J~J lL91 . ~Z~7~
~bioadhesive layer" of the sodium fluoride ~rilaminate.
In vitro tests were performed on the above ilm and demonstrated a prolonged drug release pattern.
EXA~PL~ 3 - SINGLE LAY2R ADHESIVE FILM CONTAINING
TRIAMCINOLON2 ACETONI~E (0.1%) AS AN ANTI-INFLAM~ATORY:
The composition of the film, which was 0.1 mm. thick, was as follows:
Inqredient & %_W/W
Ethylene Oxide Homopolymer 59.9 (Polyox WSR-301) Hydroxypropyl Cellulose 29.9 (~lucel ~F) Polyethylene (AC-6A) 5.0 Propylene Glycol 3.0 Polyethylene Glycol 400 2.0 25 BHT 0.1 ~ri~mcinolone Acetonide 0.1 }00 . O
The powder blending process and extruder conditions used to ~ake the film of this Examele 3 were the same as those of ~he "bioadhesive layer" of Example I.
Other desired active medicament ingredients may be incorporated into the adhesive films of any of Examples J~J 1191 1-3 in place of the particular medic,3ment used in said examples. These include ~en~ocaine (analgesic~, Potassium ni~rate ~analgesic), Silver sulfadiazene (antimicrobial), S Chlorhexidine (antimicrobial), miconazole nitrate ~antifungal~, Benzethonium chloride (antimicrobial), Tetracycline (antibiotic) and other similar therapeutic compounds.
EXAMPLE 4 - AN~LGESIC FILMS WITH POTASSIUM NITRATE
This Qxample shows 5 variations of the film having different solubilities, resulting in di~ferent release rates.
: . 20 : 30 J~J 1191 . ~ .,. . , ~ ~
% w/w Inqredients 1 2 3 4 5 5 Polyethylene oxide 23.75 57.0055.00 55.00 57.00 homopolymer (Polyox*
WS~-301) Hydroxypropyl Cell- 68.30 - - - _ ulose, N.F. (~lucel~
HF) Hydroxypropyl Cell- - 28.4029.90 22.40 22.~0 ulose, N.~. (Klucel~
M~) ~thyl Cellulose - 4.75 5.00 12.50 12.50 Polyethylene Glycol1.90 1.90 2.00 2.00 2.00 gOO
Polyethylene Glycol0.95 - - - -Propylene Glycol, - 2.85 3.00 3.00 3.00 25 U.S.P.
BHT, F.C.C. 0.10 0.10 0.100.10 0.10 Potassium Nitrate, 5.00 5.00 5.00 5.00 ~.00 30 F.C.C.
The above ingredients are blended in a Pa~terson-Kelly powder blender equipped with liquid addition capabilities.
The resulting powder blend is then extruded into film on a Killion or Johnson vinyl ex~ruder using proces~ing J~J 1191 ~2~79~
procedures si~ilar to those of the bioadhesive layer of Example I.
X~MPLE 5 - ANESTHETIC FILMS ~ITH BENZOCAINE (LAMINATE) This is an example of a t~o-layer laminate. The processing conditions used were similar to those o~ 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 gO01. 90 BHT, F.C.C. 0.10 Benzocaine, U.S.P. 5.00 100 . 00 J~J 1191 B. Outer pro~ective/barrier_layer Hydroxypropyl Cellulose 78.00 tKlucel* MF) Ethyl Cellulose 20.00 Polyethylene Glycol 400 2.00 1~0 . 00 : Par~ A was extruded on a Johnson extruder followed by subsequent extrusion and lamination of Part B to A.
Samples were ap~lied to oral lesions, and provided pro~ound lS anesthet1c e~ects ~}asting several hours) within minutes of application.
The identical t~o-layer laminate may also be made by coexeruding the inner medicated bioadhesive layer (Part A) and the outer protective barrier layer (Part B~ through separate die slots within a coextruder and lami~ating ~he `~ two layers toge~her.
,~ .
EXAMPLE 6 - ANESTHETIC FILMS WITH PH~NOL AND DYCLONIN~ HCl Four variations of a single layer bioadhesive film were made as shown below:
Inqredients l 2 3 4 Polyethylene oxide ho~o- 59.lO 54.0059.70 58.20 polymer (Polyox* W5R-30l) Hydroxypropyl Cellulose 29.45 26.~l29.75 29.00 (Klucel HF) ~5 Ethyl Cellulose 4.93 4.50 4.98 4.85 J~J ll9l ~2~
Propylene Glycol, U.S.P. 2.96 2.70 2.99 2.91 Polyethylene Glycol 4Q0 1.97 1.80 1.99 1.94 BHT, F.C.C. 0.090.09 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, ths powders were blended in P-K blender equipped with liquid addition capabilities. Resulting powders were extruded on a Killion laboratory-sized extruder.
~hree different single-layered bioadhesive films containing 1.0% 0.5~ and 0.5% respectively of silver sulfadiazene (SSD) were prepared on a heated Car~er laboratory press (designed to simulate extruded condieions) as shown below.
J~ 1191 7~
~ w~w Inqredients A
5 Polyethylene oxide homopolymer60.0060.00 (Polyox* WSR-301) ~ydroxypropyl Cellulose 2~.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 20 Silver Sulfadiazine 1.0 0.5 100.O 100.O
:, Effects on wound repair and activity against Stale~y~ococcus aureus were evaluated in the guinea pig model. Full-thickness excisions were inoculated with 3. n : x 105 organisms, (Staph. aureus) and wound surface microbiology samples taken 10 minutes and 24 hours after ~rea~ment. Test films were placed on the wound and covered wi~h BIOCLUSIVE* Transparent Dressings secured with elastic tape. Wound contraction was measured over an eight-day period using OP~OMAX~ Computer-Assisted Image Analysis. The three films tested were the following:
A. 1.0% Silver Sulfadiazene, 125C/2 minutes/~ tons J~J 1191 7~
B. 0.5% Silver Sulfadiazene, 125C~2 minutes/4 tons C. 0.5% Silver Sulfadiazene. 150C/3 minutes/4 tons SILVADEN~ Cream and an untreated occluded control. The results indicated that:
1. SILVADENE~ treated wounds significan~ly 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 ~ilms each permi~ted substantially lS faster wound contraction than that of wounds treated daily with SILVADENE~ cream.
. All ~ilms 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 ineended purpose. Use of a press for larger sample~ would result in a non-uniform and lower-quality film than an extrude~ film.
Based on the above findings, the films were very effective antibacterial agents, while mildly inhibiting wound con~raction. They offer clinicians a convenient and more effective delivery system for antimicrobials which can be place in wounds beneath any dressing or can be la~inated to any acceptable dressing face.
J~J 1191
Claims (14)
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%
by weight of a 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.
by weight of a 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.
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 3 wherein, in the bioadhesive layer the hydroxypropyl cellulose has a molecular weight above 100,000 and the homopolymer of ethylene oxide has a molecular weight from 3,000,000 to
5,000,000.
5. The extruded film of Claim 4, 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.
J&J 1191
5. The extruded film of Claim 4, 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.
J&J 1191
6. The extruded film of Claim 4, in multi-layer laminated form, which in addition to the bioadhesive layer also contains a reservoir layer in which at least a major portion of the medicament is contained.
7. The extruded multi-layer film of Claim 6 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.
8. The extruded film of Claim 4 in multi-layer laminated form, which in addition to the bioadhesive layer also contains an outer protective-barrier membrane layer.
9. The extruded multi-layer film of Claim 8 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.
10, 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:
J&J 1191
J&J 1191
11.The process of preparing the extruded multi-layer laminate film of Claim 10 comprising:
(a) separately blending the ingredients for each of the three layers into a uniform powder mixture.
J&J 1191 (b) separately and serially extruding each uniform powder mixture through an extruder die, with the bioadhesive layer being extruded first as a free film, the reservoir layer being extruded onto it, and the outer protective barrier layer being extruded onto the reservoir layer, and (c) laminating the three layers together
(a) separately blending the ingredients for each of the three layers into a uniform powder mixture.
J&J 1191 (b) separately and serially extruding each uniform powder mixture through an extruder die, with the bioadhesive layer being extruded first as a free film, the reservoir layer being extruded onto it, and the outer protective barrier layer being extruded onto the reservoir layer, and (c) laminating the three layers together
12. The extruded multi-layer film of claim 1 in the form of a two-layered laminate or a coextrudedlaminate containing Benzocaine as an anesthetic having the following composition:
13. The process of preparing the extruded multi-layer laminate film of claim 12 comprising:
a) Separately blending the ingredients for each of the two layers into a uniform powder mixture.
b) Separately and serially extruding each uniform powder J&J 1191 mixture through an extruder die, with the bioadhesive layer being extruded first as a free film, the outer protective barrier layer being extruded onto the bioadhesive layer. and c) Laminating the two layers together.
a) Separately blending the ingredients for each of the two layers into a uniform powder mixture.
b) Separately and serially extruding each uniform powder J&J 1191 mixture through an extruder die, with the bioadhesive layer being extruded first as a free film, the outer protective barrier layer being extruded onto the bioadhesive layer. and c) Laminating the two layers together.
14. The process of preparing the extruded multi-layer laminate film of claim 12 comprising:
a) Separately blending the ingredients for each of the two layers into a uniform powder mixture.
b) Co-extruding the bioadhesive layer and the other protective barrier layer through separate die slots within a coextruder, and laminating the two layers together.
J&J 1191
a) Separately blending the ingredients for each of the two layers into a uniform powder mixture.
b) Co-extruding the bioadhesive layer and the other protective barrier layer through separate die slots within a coextruder, and laminating the two layers together.
J&J 1191
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US06/874,904 US4713243A (en) | 1986-06-16 | 1986-06-16 | Bioadhesive extruded film for intra-oral drug delivery and process |
US874,904 | 1992-04-28 |
Publications (1)
Publication Number | Publication Date |
---|---|
CA1297408C true CA1297408C (en) | 1992-03-17 |
Family
ID=25364834
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
CA000539509A Expired - Lifetime CA1297408C (en) | 1986-06-16 | 1987-06-12 | Bioadhesive extruded film for intra-oral drug delivery and process |
Country Status (13)
Country | Link |
---|---|
US (1) | US4713243A (en) |
EP (1) | EP0250187B1 (en) |
JP (2) | JP2540332B2 (en) |
KR (1) | KR940011243B1 (en) |
AT (1) | ATE95058T1 (en) |
AU (1) | AU7415587A (en) |
CA (1) | CA1297408C (en) |
DE (1) | DE3787573T2 (en) |
GR (1) | GR870935B (en) |
IE (1) | IE61785B1 (en) |
NZ (1) | NZ220573A (en) |
PH (1) | PH24845A (en) |
ZA (1) | ZA874294B (en) |
Families Citing this family (312)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
JPS62169723A (en) * | 1986-01-22 | 1987-07-25 | Teisan Seiyaku Kk | Sustained release preparation |
JPS62223112A (en) * | 1986-03-25 | 1987-10-01 | Rooto Seiyaku Kk | Remedy for periodontosis |
JPH0759496B2 (en) * | 1986-03-25 | 1995-06-28 | ロ−ト製薬株式会社 | Periodontal disease treatment agent |
US5196202A (en) * | 1986-09-01 | 1993-03-23 | Teikoku Seiyaku Kabushiki Kaisha | Sustained release dosage form |
US5213615A (en) * | 1986-10-11 | 1993-05-25 | Ivoclar Ag | Dental material and method for the control of caries and paradentitis |
GB8712518D0 (en) * | 1987-05-28 | 1987-07-01 | Univ Belfast | Unit-dose film composition |
US4808410A (en) * | 1987-12-16 | 1989-02-28 | Richardson-Vicks Inc. | Pharmaceutical compositions containing dyclonine HC1 and phenol |
US4906475A (en) | 1988-02-16 | 1990-03-06 | Paco Pharmaceutical Services | Estradiol transdermal delivery system |
US5234957A (en) * | 1991-02-27 | 1993-08-10 | Noven Pharmaceuticals, Inc. | Compositions and methods for topical administration of pharmaceutically active agents |
US5446070A (en) * | 1991-02-27 | 1995-08-29 | Nover Pharmaceuticals, Inc. | Compositions and methods for topical administration of pharmaceutically active agents |
US5719197A (en) * | 1988-03-04 | 1998-02-17 | Noven Pharmaceuticals, Inc. | Compositions and methods for topical administration of pharmaceutically active agents |
GB8810951D0 (en) * | 1988-05-09 | 1988-06-15 | Innovata Biomed Ltd | Buccal local anaesthetic |
IT1217628B (en) * | 1988-05-18 | 1990-03-30 | Neo Abello Spa | PHARMACEUTICAL FORM AND SUPPORT FOR THE ADMINISTRATION OF HELLERGENIC EXTRACTS |
US5085866A (en) * | 1988-12-02 | 1992-02-04 | Southern Research Institute | Method of producing zero-order controlled-released devices |
US4992276A (en) * | 1988-12-14 | 1991-02-12 | Warner-Lambert Company | Antiseptic compositions containing hexahydro-5-pyrimidinamine compounds and thymol and methods for preparing same |
DK254289D0 (en) * | 1989-05-25 | 1989-05-25 | Dumex Ltd As | MEASURES FOR TREATING Fungal INFECTIONS |
US5021053A (en) * | 1989-07-14 | 1991-06-04 | Alza Corporation | Oral osmotic device with hydrogel driving member |
US5776493A (en) * | 1989-07-14 | 1998-07-07 | Alza Corporation | Oral osmotic device for delivery of nystatin with hydrogel driving member |
US5198220A (en) * | 1989-11-17 | 1993-03-30 | The Procter & Gamble Company | Sustained release compositions for treating periodontal disease |
US5290271A (en) * | 1990-05-14 | 1994-03-01 | Jernberg Gary R | Surgical implant and method for controlled release of chemotherapeutic agents |
US5059123A (en) * | 1990-05-14 | 1991-10-22 | Jernberg Gary R | Periodontal barrier and method for aiding periodontal tissue regeneration |
US5197882A (en) * | 1990-05-14 | 1993-03-30 | Gary R. Jernberg | Periodontal barrier and method for aiding periodontal tissue regeneration agents |
US5634943A (en) * | 1990-07-12 | 1997-06-03 | University Of Miami | Injectable polyethylene oxide gel implant and method for production |
US5147654A (en) * | 1990-07-23 | 1992-09-15 | Alza Corporation | Oral osmotic device for delivering nicotine |
US5332576A (en) * | 1991-02-27 | 1994-07-26 | Noven Pharmaceuticals, Inc. | Compositions and methods for topical administration of pharmaceutically active agents |
IL97930A (en) * | 1991-04-23 | 1996-06-18 | Perio Prod Ltd | Sustained-release toothbleaching preparations containing a peroxy agent |
IT1250421B (en) * | 1991-05-30 | 1995-04-07 | Recordati Chem Pharm | CONTROLLED RELEASE PHARMACEUTICAL COMPOSITION WITH BIO-ADHESIVE PROPERTIES. |
BR9206408A (en) * | 1991-08-23 | 1994-11-22 | Gillette Canada | Oral brush, extended release matrix, process for releasing an antimicrobial agent from an oral brush and for releasing an antimicrobial agent in an animal's mouth and an oral wear indicator brush |
US5340581A (en) | 1991-08-23 | 1994-08-23 | Gillette Canada, Inc. | Sustained-release matrices for dental application |
US5906834A (en) * | 1992-06-15 | 1999-05-25 | The Gillette Company | Color changing matrix as wear indicator |
US5571533A (en) * | 1992-02-07 | 1996-11-05 | Recordati, S.A., Chemical And Pharmaceutical Company | Controlled-release mucoadhesive pharmaceutical composition for the oral administration of furosemide |
US5248310A (en) * | 1992-03-27 | 1993-09-28 | Alza Corporation | Oral osmotic device with hydrogel driving member |
US5512299A (en) * | 1992-03-30 | 1996-04-30 | Alza Corporation | Method of treating oral inflammatory disease |
US5242910A (en) * | 1992-10-13 | 1993-09-07 | The Procter & Gamble Company | Sustained release compositions for treating periodontal disease |
AU679937B2 (en) * | 1992-11-18 | 1997-07-17 | Johnson & Johnson Consumer Products, Inc. | Extrudable compositions for topical or transdermal drug delivery |
US5573776A (en) * | 1992-12-02 | 1996-11-12 | Alza Corporation | Oral osmotic device with hydrogel driving member |
US6015844A (en) * | 1993-03-22 | 2000-01-18 | Johnson & Johnson Medical, Inc. | Composite surgical material |
US5447725A (en) * | 1993-06-11 | 1995-09-05 | The Procter & Gamble Company | Methods for aiding periodontal tissue regeneration |
US5489437A (en) * | 1993-08-17 | 1996-02-06 | Applied Extrusion Technologies, Inc. | Hydrogel products and methods of producing same |
CA2169729C (en) * | 1993-08-19 | 2001-04-03 | James E. Biegajski | Water-soluble pressure-sensitive mucoadhesive |
US5578315A (en) * | 1993-12-01 | 1996-11-26 | Rutgers, The State University Of New Jersey | Mucosal adhesive device for long-acting delivery of pharmaceutical combinations in oral cavity |
US5458879A (en) * | 1994-03-03 | 1995-10-17 | The Procter & Gamble Company | Oral vehicle compositions |
WO1996000072A1 (en) * | 1994-06-23 | 1996-01-04 | The Procter & Gamble Company | Treatment of nicotine craving and/or smoking withdrawal symptoms with a transdermal or transmucosal composition containing nicotine and caffeine or xanthine |
US5614578A (en) * | 1994-10-28 | 1997-03-25 | Alza Corporation | Injection-molded dosage form |
WO1996025910A1 (en) * | 1995-02-23 | 1996-08-29 | Cygnus, Inc. | Water-soluble pressure-sensitive mucoadhesive |
US5713852A (en) * | 1995-06-07 | 1998-02-03 | Alza Corporation | Oral dosage and method for treating painful conditions of the oral cavity |
CA2184316A1 (en) * | 1995-09-12 | 1997-03-13 | Wei-Chi Liao | Buccal delivery system for therapeutic agents |
US20050152950A1 (en) * | 1995-11-13 | 2005-07-14 | Saffran Bruce N. | Method and apparatus for macromolecular delivery using a coated membrane |
US5906814A (en) * | 1995-12-07 | 1999-05-25 | The Andrew Jergens Company | Topical film-forming compositions |
JP2791317B2 (en) * | 1995-12-26 | 1998-08-27 | 株式会社三和化学研究所 | Multilayer film preparation |
ATE427124T1 (en) * | 1996-06-26 | 2009-04-15 | Univ Texas | HOT-MELTED EXTRUDABLE PHARMACEUTICAL FORMULATION |
US6500777B1 (en) | 1996-06-28 | 2002-12-31 | Ethicon, Inc. | Bioresorbable oxidized cellulose composite material for prevention of postsurgical adhesions |
US5993787A (en) * | 1996-09-13 | 1999-11-30 | Johnson & Johnson Consumer Products, Inc. | Composition base for topical therapeutic and cosmetic preparations |
SE9603667D0 (en) * | 1996-10-08 | 1996-10-08 | Astra Ab | Pharmaceutical compositions |
US5800832A (en) * | 1996-10-18 | 1998-09-01 | Virotex Corporation | Bioerodable film for delivery of pharmaceutical compounds to mucosal surfaces |
AU769500B2 (en) * | 1996-10-18 | 2004-01-29 | Arius Two, Inc. | Pharmaceutical carrier device suitable for delivery of pharmaceutical compounds to mucosal surfaces |
US5955097A (en) | 1996-10-18 | 1999-09-21 | Virotex Corporation | Pharmaceutical preparation applicable to mucosal surfaces and body tissues |
EP1342548B1 (en) * | 1996-10-28 | 2015-12-23 | General Mills, Inc. | Embedding and encapsulation of controlled release particles and encapsulated product |
DE19646392A1 (en) * | 1996-11-11 | 1998-05-14 | Lohmann Therapie Syst Lts | Preparation for use in the oral cavity with a layer containing pressure-sensitive adhesive, pharmaceuticals or cosmetics for dosed delivery |
US6096328A (en) * | 1997-06-06 | 2000-08-01 | The Procter & Gamble Company | Delivery system for an oral care substance using a strip of material having low flexural stiffness |
US6045811A (en) * | 1997-06-06 | 2000-04-04 | The Procter & Gamble Company | Delivery system for an oral care substance using a permanently deformable strip of material |
US6582708B1 (en) | 2000-06-28 | 2003-06-24 | The Procter & Gamble Company | Tooth whitening substance |
US5879691A (en) * | 1997-06-06 | 1999-03-09 | The Procter & Gamble Company | Delivery system for a tooth whitener using a strip of material having low flexural stiffness |
US20020018754A1 (en) | 1999-03-15 | 2002-02-14 | Paul Albert Sagel | Shapes for tooth whitening strips |
US5894017A (en) * | 1997-06-06 | 1999-04-13 | The Procter & Gamble Company | Delivery system for an oral care substance using a strip of material having low flexural stiffness |
US6136297A (en) * | 1997-06-06 | 2000-10-24 | The Procter & Gamble Company | Delivery system for an oral care substance using a strip of material having low flexural stiffness |
US5989569A (en) * | 1997-06-06 | 1999-11-23 | The Procter & Gamble Company | Delivery system for a tooth whitener using a permanently deformable strip of material |
US20040096422A1 (en) * | 1997-06-17 | 2004-05-20 | Schwartz Herbert E. | Compositions of polyacids and polyethers and methods for their use in reducing pain |
US7192984B2 (en) * | 1997-06-17 | 2007-03-20 | Fziomed, Inc. | Compositions of polyacids and polyethers and methods for their use as dermal fillers |
US20050074495A1 (en) * | 1997-06-17 | 2005-04-07 | Fziomed, Inc. | Compositions of polyacids and methods for their use in reducing adhesions |
US6869938B1 (en) | 1997-06-17 | 2005-03-22 | Fziomed, Inc. | Compositions of polyacids and polyethers and methods for their use in reducing adhesions |
US5906997A (en) * | 1997-06-17 | 1999-05-25 | Fzio Med, Inc. | Bioresorbable compositions of carboxypolysaccharide polyether intermacromolecular complexes and methods for their use in reducing surgical adhesions |
US6123957A (en) * | 1997-07-16 | 2000-09-26 | Jernberg; Gary R. | Delivery of agents and method for regeneration of periodontal tissues |
US6153210A (en) * | 1997-08-14 | 2000-11-28 | Periodontix, Inc. | Use of locally delivered metal ions for treatment of periodontal disease |
US20050048102A1 (en) * | 1997-10-16 | 2005-03-03 | Virotex Corporation | Pharmaceutical carrier device suitable for delivery of pharmaceutical compounds to mucosal surfaces |
US6072100A (en) * | 1998-01-28 | 2000-06-06 | Johnson & Johnson Consumer Products, Inc. | Extrudable compositions for topical or transdermal drug delivery |
US5981499A (en) * | 1998-02-20 | 1999-11-09 | Atlantic Biomed Corporation | Lesion-directed antibiotics in dry dosage forms for the treatment of shallow ulcers of the oral mucosa |
US6103266A (en) * | 1998-04-22 | 2000-08-15 | Tapolsky; Gilles H. | Pharmaceutical gel preparation applicable to mucosal surfaces and body tissues |
ES2237104T3 (en) * | 1998-04-29 | 2005-07-16 | Virotex Corporation | CARRIER DEVICE FOR PHARMACEUTICAL PRODUCTS SUITABLE FOR THE CONTRIBUTION OF PHARMACEUTICAL COMPOUNDS TO MUCOUS SURFACES. |
US20050147690A1 (en) * | 1998-09-25 | 2005-07-07 | Masters David B. | Biocompatible protein particles, particle devices and methods thereof |
US7662409B2 (en) | 1998-09-25 | 2010-02-16 | Gel-Del Technologies, Inc. | Protein matrix materials, devices and methods of making and using thereof |
DE19856101A1 (en) * | 1998-12-04 | 2000-06-08 | Labtec Gmbh | Patch for local administration of drugs in the oral cavity includes a drug-containing matrix comprising a water-insoluble cellulose ether and a water-soluble cellulose ether in a defined ratio |
WO2000045798A1 (en) * | 1999-02-02 | 2000-08-10 | Ortho-Mcneil Pharmaceutical, Inc. | Method of manufacture for transdermal matrices |
US6319510B1 (en) | 1999-04-20 | 2001-11-20 | Alayne Yates | Gum pad for delivery of medication to mucosal tissues |
DE60016927T2 (en) | 1999-07-02 | 2005-12-22 | The Procter & Gamble Company, Cincinnati | COMPOSITIONS CONTAINING ORGANOSILOXAN RESINS FOR THE RELEASE OF MOIST MAINTENANCE MATERIALS AND FOR EXTENDING THE RELEASE |
DE19954421A1 (en) * | 1999-11-12 | 2001-05-31 | Lohmann Therapie Syst Lts | Film-like preparation for the biphase release of pharmacologically active or other substances |
US6432415B1 (en) | 1999-12-17 | 2002-08-13 | Axrix Laboratories, Inc. | Pharmaceutical gel and aerosol formulations and methods to administer the same to skin and mucosal surfaces |
US6566345B2 (en) | 2000-04-28 | 2003-05-20 | Fziomed, Inc. | Polyacid/polyalkylene oxide foams and gels and methods for their delivery |
WO2001068124A2 (en) | 2000-03-15 | 2001-09-20 | The Brigham And Women's Hospital, Inc. | Suppression of vascular disorders by mucosal administration of heat shock protein peptides |
US7785572B2 (en) * | 2000-03-17 | 2010-08-31 | Lg Household And Health Care Ltd. | Method and device for teeth whitening using a dry type adhesive |
US6689344B2 (en) | 2000-03-17 | 2004-02-10 | Lg Household & Healthcare Ltd. | Patches for teeth whitening |
ATE421894T1 (en) | 2000-03-17 | 2009-02-15 | Lg Household & Health Care Ltd | PLASTER FOR WHITENING TEETH |
US8652446B2 (en) | 2000-03-17 | 2014-02-18 | Lg Household & Healthcare Ltd. | Apparatus and method for whitening teeth |
US7067116B1 (en) * | 2000-03-23 | 2006-06-27 | Warner-Lambert Company Llc | Fast dissolving orally consumable solid film containing a taste masking agent and pharmaceutically active agent at weight ratio of 1:3 to 3:1 |
JP2003531682A (en) * | 2000-04-28 | 2003-10-28 | フジオメッド インコーポレイテッド | Hemostatic compositions of polyacids and polyalkylene oxides and methods of using the same |
WO2002000182A2 (en) | 2000-06-28 | 2002-01-03 | The Procter & Gamble Company | Structures and compositions increasing the stability of peroxide actives |
USRE44145E1 (en) | 2000-07-07 | 2013-04-09 | A.V. Topchiev Institute Of Petrochemical Synthesis | Preparation of hydrophilic pressure sensitive adhesives having optimized adhesive properties |
AU7323001A (en) | 2000-07-07 | 2002-01-21 | Av Topchiev Inst Petrochemical | Preparation of hydrophilic pressure sensitive adhesives having optimized adhesive properties |
DE10038571A1 (en) * | 2000-08-03 | 2002-02-14 | Knoll Ag | Compositions and dosage forms for use in the oral cavity in the treatment of mycoses |
US6756051B1 (en) * | 2000-11-15 | 2004-06-29 | Li-Lan H. Chen | Bioadhesive, closed-cell foam film, sustained release, delivery devices and methods of making and using same |
US6500408B2 (en) | 2001-01-27 | 2002-12-31 | Jc Technologies, Inc. | Enamel-safe tooth bleach and method for use |
US8980334B2 (en) | 2001-02-28 | 2015-03-17 | Axiomedic Ltd. | Double-layered absorbable solid compositions for the topical treatment of oral mucosal disorders |
EP2324821A1 (en) * | 2001-02-28 | 2011-05-25 | Axiomedic Ltd. | Oral care compositions |
US6514483B2 (en) * | 2001-03-12 | 2003-02-04 | Colgate Palmolive Company | Strip for whitening tooth surfaces |
US6503486B2 (en) * | 2001-03-12 | 2003-01-07 | Colgate Palmolive Company | Strip for whitening tooth surfaces |
US6419906B1 (en) * | 2001-03-12 | 2002-07-16 | Colgate Palmolive Company | Strip for whitening tooth surfaces |
JP4116447B2 (en) | 2001-05-01 | 2008-07-09 | エイ.ブイ.トップチーブ インスティテュート オブ ペトロケミカル シンセシス | Hydrogel composition |
US8206738B2 (en) | 2001-05-01 | 2012-06-26 | Corium International, Inc. | Hydrogel compositions with an erodible backing member |
US8541021B2 (en) * | 2001-05-01 | 2013-09-24 | A.V. Topchiev Institute Of Petrochemical Synthesis | Hydrogel compositions demonstrating phase separation on contact with aqueous media |
DE60239528D1 (en) | 2001-05-01 | 2011-05-05 | Corium International Redwood City | TWO-PHASE, WATER-ABSORBING BIOADHESIVE COMPOSITION |
US20050113510A1 (en) | 2001-05-01 | 2005-05-26 | Feldstein Mikhail M. | Method of preparing polymeric adhesive compositions utilizing the mechanism of interaction between the polymer components |
US20050215727A1 (en) | 2001-05-01 | 2005-09-29 | Corium | Water-absorbent adhesive compositions and associated methods of manufacture and use |
US8840918B2 (en) | 2001-05-01 | 2014-09-23 | A. V. Topchiev Institute of Petrochemical Synthesis, Russian Academy of Sciences | Hydrogel compositions for tooth whitening |
US6660292B2 (en) | 2001-06-19 | 2003-12-09 | Hf Flavoring Technology Llp | Rapidly disintegrating flavored film for precooked foods |
US6946142B2 (en) | 2001-06-23 | 2005-09-20 | Lg Household & Healthcare Ltd. | Multi-layer patches for teeth whitening |
US20030118653A1 (en) * | 2001-07-06 | 2003-06-26 | Lavipharm Laboratories Inc. | Quick dissolving oral mucosal drug delivery device with moisture barrier coating |
US6585997B2 (en) * | 2001-08-16 | 2003-07-01 | Access Pharmaceuticals, Inc. | Mucoadhesive erodible drug delivery device for controlled administration of pharmaceuticals and other active compounds |
US20060073174A1 (en) * | 2001-08-16 | 2006-04-06 | Access Pharmaceuticals, Inc. | Adherent and erodible film to treat a moist surface of a body tissue |
US6419903B1 (en) * | 2001-08-20 | 2002-07-16 | Colgate Palmolive Company | Breath freshening film |
US20030083286A1 (en) * | 2001-08-22 | 2003-05-01 | Ching-Leou Teng | Bioadhesive compositions and methods for enhanced intestinal drug absorption |
US20030124196A1 (en) * | 2001-08-22 | 2003-07-03 | Susan Weinbach | Pulsatile release compositions and methods for enhanced intestinal drug absorption |
US8900497B2 (en) | 2001-10-12 | 2014-12-02 | Monosol Rx, Llc | Process for making a film having a substantially uniform distribution of components |
US20070281003A1 (en) | 2001-10-12 | 2007-12-06 | Fuisz Richard C | Polymer-Based Films and Drug Delivery Systems Made Therefrom |
US8603514B2 (en) | 2002-04-11 | 2013-12-10 | Monosol Rx, Llc | Uniform films for rapid dissolve dosage form incorporating taste-masking compositions |
US8663687B2 (en) | 2001-10-12 | 2014-03-04 | Monosol Rx, Llc | Film compositions for delivery of actives |
US7357891B2 (en) | 2001-10-12 | 2008-04-15 | Monosol Rx, Llc | Process for making an ingestible film |
US7666337B2 (en) | 2002-04-11 | 2010-02-23 | Monosol Rx, Llc | Polyethylene oxide-based films and drug delivery systems made therefrom |
US20110033542A1 (en) | 2009-08-07 | 2011-02-10 | Monosol Rx, Llc | Sublingual and buccal film compositions |
US20190328679A1 (en) | 2001-10-12 | 2019-10-31 | Aquestive Therapeutics, Inc. | Uniform films for rapid-dissolve dosage form incorporating anti-tacking compositions |
US8765167B2 (en) | 2001-10-12 | 2014-07-01 | Monosol Rx, Llc | Uniform films for rapid-dissolve dosage form incorporating anti-tacking compositions |
US7425292B2 (en) | 2001-10-12 | 2008-09-16 | Monosol Rx, Llc | Thin film with non-self-aggregating uniform heterogeneity and drug delivery systems made therefrom |
US7910641B2 (en) | 2001-10-12 | 2011-03-22 | Monosol Rx, Llc | PH modulated films for delivery of actives |
US10285910B2 (en) | 2001-10-12 | 2019-05-14 | Aquestive Therapeutics, Inc. | Sublingual and buccal film compositions |
US8900498B2 (en) | 2001-10-12 | 2014-12-02 | Monosol Rx, Llc | Process for manufacturing a resulting multi-layer pharmaceutical film |
US11207805B2 (en) | 2001-10-12 | 2021-12-28 | Aquestive Therapeutics, Inc. | Process for manufacturing a resulting pharmaceutical film |
KR20030045473A (en) * | 2001-12-04 | 2003-06-11 | 대신제약주식회사 | Pharmaceutical composition having adherent property to mucous membrane |
US20030224090A1 (en) * | 2002-02-11 | 2003-12-04 | Edizone, Lc | Snacks of orally soluble edible films |
GB0205868D0 (en) * | 2002-03-13 | 2002-04-24 | Univ Nottingham | Polymer composite with internally distributed deposition matter |
US8017150B2 (en) | 2002-04-11 | 2011-09-13 | Monosol Rx, Llc | Polyethylene oxide-based films and drug delivery systems made therefrom |
EP1528894B1 (en) | 2002-04-29 | 2015-06-03 | Gel-Del Technologies, Inc. | Biomatrix structural containment and fixation systems |
US6949240B2 (en) | 2002-05-23 | 2005-09-27 | The Procter & Gamble Company | Tooth whitening products |
US7776314B2 (en) | 2002-06-17 | 2010-08-17 | Grunenthal Gmbh | Abuse-proofed dosage system |
US8956160B2 (en) * | 2002-07-02 | 2015-02-17 | Ranir, Llc | Device and method for delivering an oral care agent |
US6921529B2 (en) | 2002-07-29 | 2005-07-26 | Joseph C. Maley | Treatment modality and method for fungal nail infection |
US20040120991A1 (en) * | 2002-09-07 | 2004-06-24 | Mars Incorporated | Edible films having distinct regions |
US20050100515A1 (en) * | 2002-09-11 | 2005-05-12 | The Procter & Gamble Company | Tooth whitening products |
US8524200B2 (en) | 2002-09-11 | 2013-09-03 | The Procter & Gamble Company | Tooth whitening products |
US20040120903A1 (en) * | 2002-09-11 | 2004-06-24 | The Procter & Gamble Company | Tooth whitening strips |
US6916463B2 (en) * | 2002-09-24 | 2005-07-12 | The Procter & Gamble Company | Oral products having an aesthetic layer |
DE10252726B4 (en) * | 2002-11-13 | 2008-05-08 | Lts Lohmann Therapie-Systeme Ag | Multilayer transmucosal therapeutic system |
SE0302947D0 (en) | 2003-01-24 | 2003-11-07 | Magle Ab | A composition material for transmucosal delivery |
EA012306B1 (en) * | 2003-01-24 | 2009-08-28 | Магле Холдинг Аб | A composition material for transmucosal delivery |
US7041311B2 (en) * | 2003-02-28 | 2006-05-09 | International Flavors & Fragrances Inc. | Preparation for saliva flow |
WO2004096125A2 (en) * | 2003-04-14 | 2004-11-11 | Shire Laboratories, Inc. | Pharmaceutical compositions releasing their active agents from a buccal or sublingual location to overcome an absorption window problem |
WO2004103328A1 (en) * | 2003-04-30 | 2004-12-02 | Icure Pharmaceutical Corporation | Patch for tooth whitening |
US7276246B2 (en) * | 2003-05-09 | 2007-10-02 | Cephalon, Inc. | Dissolvable backing layer for use with a transmucosal delivery device |
US7306812B2 (en) * | 2003-05-09 | 2007-12-11 | Cephalon, Inc. | Dissolvable backing layer for use with a transmucosal delivery device |
CA2544776C (en) * | 2003-05-28 | 2014-04-15 | Monosolrx Llc | Polyethylene oxide-based films and drug delivery systems made therefrom |
US20050118261A1 (en) * | 2003-06-12 | 2005-06-02 | Oien Hal J. | Compositions and methods of administering doxepin to mucosal tissue |
US8465537B2 (en) * | 2003-06-17 | 2013-06-18 | Gel-Del Technologies, Inc. | Encapsulated or coated stent systems |
US7472655B2 (en) * | 2003-07-01 | 2009-01-06 | Lu Hao Leng | Table top |
DE102004032051A1 (en) | 2004-07-01 | 2006-01-19 | Grünenthal GmbH | Process for the preparation of a secured against misuse, solid dosage form |
DE102005005446A1 (en) | 2005-02-04 | 2006-08-10 | Grünenthal GmbH | Break-resistant dosage forms with sustained release |
DE10361596A1 (en) | 2003-12-24 | 2005-09-29 | Grünenthal GmbH | Process for producing an anti-abuse dosage form |
US8075872B2 (en) | 2003-08-06 | 2011-12-13 | Gruenenthal Gmbh | Abuse-proofed dosage form |
DE10336400A1 (en) | 2003-08-06 | 2005-03-24 | Grünenthal GmbH | Anti-abuse dosage form |
US20070048228A1 (en) | 2003-08-06 | 2007-03-01 | Elisabeth Arkenau-Maric | Abuse-proofed dosage form |
US20050036958A1 (en) * | 2003-08-13 | 2005-02-17 | Jianxun Feng | Dental bleaching |
WO2005016321A1 (en) * | 2003-08-15 | 2005-02-24 | Qlt Usa, Inc. | Adhesive bioerodible transmucosal drug delivery system |
US20050036957A1 (en) | 2003-08-15 | 2005-02-17 | Michael Prencipe | Tooth whitening dental tray and method of use |
US20050069502A1 (en) * | 2003-08-15 | 2005-03-31 | Chopra Suman K. | Hydrophobic polymer carrier based liquid tooth whitening composition |
US20050038181A1 (en) * | 2003-08-15 | 2005-02-17 | Colgate-Palmolive Company | Silicone polymer based liquid tooth whitening composition |
US8815215B2 (en) * | 2003-08-15 | 2014-08-26 | Colgate-Palmolive Company | Hydrophobic tooth whitening system and methods of use |
EP1660013A4 (en) | 2003-08-26 | 2011-07-20 | Gel Del Technologies Inc | Protein biomaterials and biocoacervates and methods of making and using thereof |
US7666396B2 (en) * | 2003-09-11 | 2010-02-23 | Kimberly-Clark Worldwide, Inc. | Single-use moisturizing product |
WO2005046663A1 (en) | 2003-11-04 | 2005-05-26 | Shire Laboratories, Inc. | Compositions of quaternary ammonium containing bioavailability enhancers |
ATE493981T1 (en) * | 2003-11-04 | 2011-01-15 | Supernus Pharmaceuticals Inc | ONCE DAILY DOSAGE FORMS OF TROSPIUM |
AU2004289248B2 (en) | 2003-11-07 | 2012-05-03 | U.S. Smokeless Tobacco Company Llc | Tobacco compositions |
US8627828B2 (en) | 2003-11-07 | 2014-01-14 | U.S. Smokeless Tobacco Company Llc | Tobacco compositions |
KR100462465B1 (en) * | 2003-11-20 | 2004-12-23 | 정천수 | A charging battery case having uni-jack, and a jack plug for the case |
EP1691746B1 (en) * | 2003-12-08 | 2015-05-27 | Gel-Del Technologies, Inc. | Mucoadhesive drug delivery devices and methods of making and using thereof |
WO2005061033A1 (en) * | 2003-12-15 | 2005-07-07 | Alexza Pharmaceuticals, Inc. | Treatment of breakthrough pain by drug aerosol inhalation |
JP4128521B2 (en) * | 2003-12-19 | 2008-07-30 | 信越化学工業株式会社 | Gel sheet and method for producing the same |
CA2554649C (en) | 2004-01-30 | 2015-10-27 | Corium International, Inc. | Rapidly dissolving film for delivery of an active agent |
US20070269519A1 (en) * | 2004-03-03 | 2007-11-22 | Constantine Georgiades | Whitening products |
WO2005090461A2 (en) * | 2004-03-19 | 2005-09-29 | The Tapemark Company | Thermoplastic films and methods for making |
US20050208108A1 (en) * | 2004-03-19 | 2005-09-22 | Jannusch Leonard C | Thermoplastic films and methods for making |
EP2468266A3 (en) * | 2004-04-22 | 2012-10-24 | AcuCort AB | Pharmaceutical compositions for acute glucocorticoid therapy |
DE602005015506D1 (en) * | 2004-04-28 | 2009-09-03 | Shinetsu Chemical Co | Film preparation and process for its production |
PT1765292T (en) | 2004-06-12 | 2017-12-29 | Collegium Pharmaceutical Inc | Abuse-deterrent drug formulations |
DE102004032049A1 (en) | 2004-07-01 | 2006-01-19 | Grünenthal GmbH | Anti-abuse, oral dosage form |
JP5270158B2 (en) | 2004-08-05 | 2013-08-21 | コリウム インターナショナル, インコーポレイテッド | Adhesive composition |
US8899976B2 (en) | 2004-09-24 | 2014-12-02 | Align Technology, Inc. | Release agent receptacle |
US20060099550A1 (en) * | 2004-11-10 | 2006-05-11 | Ranir/Dcp Corporation | Device and method for delivering an oral care agent |
US7766658B2 (en) | 2004-11-30 | 2010-08-03 | Align Technology, Inc. | Systems and methods for intra-oral diagnosis |
US20060115785A1 (en) | 2004-11-30 | 2006-06-01 | Chunhua Li | Systems and methods for intra-oral drug delivery |
US7947508B2 (en) | 2004-11-30 | 2011-05-24 | Align Technology, Inc. | Systems and methods for intra-oral diagnosis |
US8691772B2 (en) | 2005-01-04 | 2014-04-08 | Yeda Research And Development Co. Ltd. | HSP60, HSP60 peptides and T cell vaccines for immunomodulation |
DE102005005449A1 (en) | 2005-02-04 | 2006-08-10 | Grünenthal GmbH | Process for producing an anti-abuse dosage form |
KR100741654B1 (en) * | 2005-02-07 | 2007-07-23 | 한웅코텍 주식회사 | oil gel soft sheet appling to skin |
US9050393B2 (en) | 2005-02-08 | 2015-06-09 | Bruce N. Saffran | Medical devices and methods for modulation of physiology using device-based surface chemistry |
ES2490595T3 (en) | 2005-02-17 | 2014-09-04 | Abbott Laboratories | Transmucosal administration of drug compositions to treat and prevent disorders in animals |
DE102005011029A1 (en) * | 2005-03-08 | 2006-09-14 | Maria Clementine Martin Klosterfrau Vertriebsgesellschaft Mbh | Composition for peroral application with controlled release of active substances |
WO2006107390A2 (en) | 2005-04-04 | 2006-10-12 | Kronos Advanced Technologies, Inc. | An electrostatic fluid accelerator for and method of controlling a fluid flow |
US20060275369A1 (en) * | 2005-06-01 | 2006-12-07 | Cao Group, Inc. | Orally Therapeutic Plastics and Devices Formed Therefrom |
US8263047B2 (en) * | 2005-09-29 | 2012-09-11 | Wickenhauser Alan J | Topical anesthetic for dental procedures |
US8623334B1 (en) | 2005-09-29 | 2014-01-07 | Alan J. Wickenhauser | Topical anesthetic |
WO2008134071A1 (en) * | 2007-04-26 | 2008-11-06 | Theraquest Biosciences, Inc. | Multimodal abuse resistant extended release formulations |
US20100210732A1 (en) * | 2005-11-02 | 2010-08-19 | Najib Babul | Methods of Preventing the Serotonin Syndrome and Compositions for Use Therefor |
US20090082466A1 (en) * | 2006-01-27 | 2009-03-26 | Najib Babul | Abuse Resistant and Extended Release Formulations and Method of Use Thereof |
US8329744B2 (en) * | 2005-11-02 | 2012-12-11 | Relmada Therapeutics, Inc. | Methods of preventing the serotonin syndrome and compositions for use thereof |
JP5657206B2 (en) * | 2005-12-21 | 2015-01-21 | コルゲート・パーモリブ・カンパニーColgate−Palmolive Company | Cleaning and / or gloss compositions and methods of use thereof |
WO2007078874A2 (en) * | 2005-12-30 | 2007-07-12 | Cogentus Pharmaceuticals, Inc. | Oral pharmaceutical formulations containing non-steroidal anti-inflammatory drugs and acid inhibitors |
AU2007207503A1 (en) * | 2006-01-20 | 2007-07-26 | Monosol Rx, Llc | Film bandage for mucosal administration of actives |
MX2008012264A (en) * | 2006-03-24 | 2009-02-20 | Auxilium Int Holdings Inc | Stabilized compositions containing alkaline labile drugs. |
US8465759B2 (en) | 2006-03-24 | 2013-06-18 | Auxilium Us Holdings, Llc | Process for the preparation of a hot-melt extruded laminate |
EP2007362B1 (en) | 2006-04-04 | 2018-09-05 | KG Acquisition LLC | Oral dosage forms including an antiplatelet agent and an acid inhibitor |
GB0613552D0 (en) * | 2006-07-07 | 2006-08-16 | Univ Heriot Watt | Resorbable insert |
US9682256B2 (en) | 2006-07-14 | 2017-06-20 | Colgate-Palmolive Company | Methods of making compositions comprising films |
AU2007275034A1 (en) * | 2006-07-21 | 2008-01-24 | Lab International Srl | Hydrophilic abuse deterrent delivery system |
PL2054031T3 (en) | 2006-07-21 | 2016-09-30 | Transmucosal delivery devices with enhanced uptake | |
SA07280459B1 (en) | 2006-08-25 | 2011-07-20 | بيورديو فارما إل. بي. | Tamper Resistant Oral Pharmaceutical Dosage Forms Comprising an Opioid Analgesic |
WO2008028047A2 (en) * | 2006-08-30 | 2008-03-06 | Lab International Srl | Bioadhesive film drug delivery system |
CN101516331A (en) | 2006-09-20 | 2009-08-26 | 莫诺索尔克斯有限公司 | Edible water-soluble film containing a foam reducing flavoring agent |
RU2453143C2 (en) * | 2006-10-31 | 2012-06-20 | Вм. Ригли, Дж. Компани | Method for production of structure providing for flavouring agent release and such structure |
US7731604B2 (en) * | 2006-10-31 | 2010-06-08 | Taylor Made Golf Company, Inc. | Golf club iron head |
CA2678500A1 (en) * | 2007-02-15 | 2008-08-21 | Derma-Young Ltd. | Compositions and methods for enhancing transmucosal delivery |
DE102007011485A1 (en) * | 2007-03-07 | 2008-09-11 | Grünenthal GmbH | Dosage form with more difficult abuse |
US20090098192A1 (en) * | 2007-10-11 | 2009-04-16 | Fuisz Richard C | Extrudable and Extruded Compositions for Delivery of Bioactive Agents, Method of Making Same and Method of Using Same |
US9125434B2 (en) | 2007-10-11 | 2015-09-08 | Philip Morris Products S.A. | Smokeless tobacco product, smokeless tobacco product in the form of a sheet, extrudable tobacco composition, method for manufacturing a smokeless tobacco product, method for delivering super bioavailable nicotine contained in tobacco to a user, and packaged smokeless tobacco product sheet |
EA021392B1 (en) * | 2007-10-11 | 2015-06-30 | Филип Моррис Продактс С.А. | Smokeless tobacco product |
AU2014202358B2 (en) * | 2007-10-11 | 2016-06-16 | Philip Morris Products S.A. | Method for making a dosage |
US11890371B2 (en) | 2007-12-26 | 2024-02-06 | Petvivo Holdings, Inc. | Biocompatible protein-based particles and methods thereof |
RU2493830C2 (en) | 2008-01-25 | 2013-09-27 | Грюненталь Гмбх | Drug form |
CA2720108C (en) | 2008-03-11 | 2016-06-07 | Depomed, Inc. | Gastric retentive extended-release dosage forms comprising combinations of a non-opioid analgesic and an opioid analgesic |
US8372432B2 (en) | 2008-03-11 | 2013-02-12 | Depomed, Inc. | Gastric retentive extended-release dosage forms comprising combinations of a non-opioid analgesic and an opioid analgesic |
DE102008014533A1 (en) * | 2008-03-15 | 2009-09-17 | Lts Lohmann Therapie-Systeme Ag | Gingival wafer |
AU2009243681B2 (en) | 2008-05-09 | 2013-12-19 | Grunenthal Gmbh | Process for the preparation of an intermediate powder formulation and a final solid dosage form under usage of a spray congealing step |
US8172569B2 (en) | 2008-06-12 | 2012-05-08 | Align Technology, Inc. | Dental appliance |
EP2306981A1 (en) * | 2008-06-19 | 2011-04-13 | University Of The Witwatersrand, Johannesburg | A transmucosal delivery system |
AU2009271271A1 (en) * | 2008-06-23 | 2010-01-21 | Biodelivery Sciences International, Inc. | Multidirectional mucosal delivery devices and methods of use |
GB0812742D0 (en) * | 2008-07-11 | 2008-08-20 | Critical Pharmaceuticals Ltd | Process |
US10016534B2 (en) | 2008-11-17 | 2018-07-10 | Gel-Del Technologies, Inc. | Protein biomaterial and biocoacervate vessel graft systems and methods of making and using thereof |
WO2010083035A2 (en) | 2009-01-14 | 2010-07-22 | Corium International, Inc. | Transdermal administration of tamsulosin |
EA021886B1 (en) | 2009-03-04 | 2015-09-30 | Редженера Фарма Лтд. | Isolated fraction of mastic gum |
WO2010100651A2 (en) | 2009-03-04 | 2010-09-10 | Regenera Pharma Ltd. | Compositions of polymeric myrcene |
US9017718B2 (en) * | 2009-05-21 | 2015-04-28 | Bionex Pharmaceuticals Llc | Dual and single layer dosage forms |
PL2456427T3 (en) | 2009-07-22 | 2015-07-31 | Gruenenthal Gmbh | Hot-melt extruded controlled release dosage form |
EP2997965B1 (en) | 2009-07-22 | 2019-01-02 | Grünenthal GmbH | Tamper-resistant dosage form for oxidation-sensitive opioids |
US8475832B2 (en) | 2009-08-07 | 2013-07-02 | Rb Pharmaceuticals Limited | Sublingual and buccal film compositions |
US8701671B2 (en) | 2011-02-04 | 2014-04-22 | Joseph E. Kovarik | Non-surgical method and system for reducing snoring |
US9549842B2 (en) | 2011-02-04 | 2017-01-24 | Joseph E. Kovarik | Buccal bioadhesive strip and method of treating snoring and sleep apnea |
BR112012012945A2 (en) | 2009-11-25 | 2020-12-29 | Arisgen Sa | MUCOSAL RELEASE COMPOSITION, ITS PRODUCTION METHOD, PRE-FORMED PEPTIDE COMPLEX, KIT AND USE OF AN ACTIVE PEPTIDE AGENT |
US10610528B2 (en) | 2009-12-08 | 2020-04-07 | Intelgenx Corp. | Solid oral film dosage forms and methods for making same |
US20110136815A1 (en) | 2009-12-08 | 2011-06-09 | Horst Zerbe | Solid oral film dosage forms and methods for making same |
US10668060B2 (en) | 2009-12-10 | 2020-06-02 | Collegium Pharmaceutical, Inc. | Tamper-resistant pharmaceutical compositions of opioids and other drugs |
US8597681B2 (en) | 2009-12-22 | 2013-12-03 | Mallinckrodt Llc | Methods of producing stabilized solid dosage pharmaceutical compositions containing morphinans |
US9198861B2 (en) | 2009-12-22 | 2015-12-01 | Mallinckrodt Llc | Methods of producing stabilized solid dosage pharmaceutical compositions containing morphinans |
ES2606227T3 (en) | 2010-02-03 | 2017-03-23 | Grünenthal GmbH | Preparation of a pharmaceutical powder composition by an extruder |
WO2011119287A1 (en) * | 2010-03-26 | 2011-09-29 | Dow Global Technologies Llc | Melt-extruded film |
US9572773B2 (en) | 2010-04-26 | 2017-02-21 | Novartis A.G. | Layered drug delivery device |
US20110290694A1 (en) * | 2010-05-27 | 2011-12-01 | Monosol Rx, Llc | Oral film dosage form having indicia thereon |
DE102010029942A1 (en) * | 2010-06-10 | 2011-12-15 | Robert Bosch Gmbh | injection needle |
EP2579844B1 (en) | 2010-06-10 | 2016-02-24 | Midatech Ltd. | Nanoparticle film delivery systems |
TWI516286B (en) | 2010-09-02 | 2016-01-11 | 歌林達股份有限公司 | Tamper resistant dosage form comprising an anionic polymer |
MX2013002377A (en) | 2010-09-02 | 2013-04-29 | Gruenenthal Gmbh | Tamper resistant dosage form comprising inorganic salt. |
KR101910781B1 (en) | 2010-09-07 | 2018-10-22 | 레제네라 파마 리미티드 | Compositions Comprising Acidic Extracts Of Mastic Gum |
US9149959B2 (en) | 2010-10-22 | 2015-10-06 | Monosol Rx, Llc | Manufacturing of small film strips |
BR112013011054B1 (en) | 2010-11-08 | 2017-09-26 | Colgate-Palmolive Company | Composites, compositions comprising them and method of producing a composite |
CA2819995A1 (en) | 2010-12-13 | 2012-06-21 | Colgate-Palmolive Company | Oral flavored compositions comprising polymer matrix films and hydrophobic/lipophilic additives and alcohol-free method for producing thereof |
US20130280184A1 (en) | 2010-12-13 | 2013-10-24 | Colgate-Palmolive Company | Oral Compositions and Method for Producing Thereof |
BR112013014675A2 (en) | 2010-12-13 | 2016-08-02 | Colgate Palmolive Co | oral compositions and methods for producing same |
US10130684B2 (en) | 2011-02-03 | 2018-11-20 | Pharmedica Ltd. | Oral dissolving films for insulin administration, for treating diabetes |
US11844720B2 (en) | 2011-02-04 | 2023-12-19 | Seed Health, Inc. | Method and system to reduce the likelihood of dental caries and halitosis |
US8658631B1 (en) | 2011-05-17 | 2014-02-25 | Mallinckrodt Llc | Combination composition comprising oxycodone and acetaminophen for rapid onset and extended duration of analgesia |
US8858963B1 (en) | 2011-05-17 | 2014-10-14 | Mallinckrodt Llc | Tamper resistant composition comprising hydrocodone and acetaminophen for rapid onset and extended duration of analgesia |
US8741885B1 (en) | 2011-05-17 | 2014-06-03 | Mallinckrodt Llc | Gastric retentive extended release pharmaceutical compositions |
BR112014001091A2 (en) | 2011-07-29 | 2017-02-14 | Gruenenthal Gmbh | tamper resistant tablet that provides immediate release of the drug |
LT2736495T (en) | 2011-07-29 | 2017-11-10 | Grünenthal GmbH | Tamper-resistant tablet providing immediate drug release |
EP2744572B1 (en) | 2011-08-18 | 2017-12-13 | BioDelivery Sciences International, Inc. | Abuse-resistant mucoadhesive devices for delivery of buprenorphine |
US20140017299A1 (en) * | 2011-08-18 | 2014-01-16 | Monosol Rx, Llc | Steroid hormone delivery systems and methods of preparing the same |
US9901539B2 (en) | 2011-12-21 | 2018-02-27 | Biodelivery Sciences International, Inc. | Transmucosal drug delivery devices for use in chronic pain relief |
BR112014019988A8 (en) | 2012-02-28 | 2017-07-11 | Gruenenthal Gmbh | BREAK-RESISTANT DOSAGE FORM COMPRISING A PHARMACOLOGICALLY ACTIVE COMPOUND AND AN ANIONIC POLYMER |
AR090695A1 (en) | 2012-04-18 | 2014-12-03 | Gruenenthal Gmbh | PHARMACEUTICAL DOSAGE FORM RESISTANT TO ADULTERATION AND RESISTANT TO IMMEDIATE RELEASE OF DOSE |
US10064945B2 (en) | 2012-05-11 | 2018-09-04 | Gruenenthal Gmbh | Thermoformed, tamper-resistant pharmaceutical dosage form containing zinc |
PL2908798T3 (en) | 2012-10-17 | 2019-02-28 | Procter & Gamble | Strip for the delivery of an oral care active and methods for applying oral care actives |
JP6466417B2 (en) | 2013-05-29 | 2019-02-06 | グリュネンタール・ゲゼルシャフト・ミト・ベシュレンクテル・ハフツング | A tamper-resistant dosage form with a bimodal release profile |
CA2907950A1 (en) | 2013-05-29 | 2014-12-04 | Grunenthal Gmbh | Tamper-resistant dosage form containing one or more particles |
MX368846B (en) | 2013-07-12 | 2019-10-18 | Gruenenthal Gmbh | Tamper-resistant dosage form containing ethylene-vinyl acetate polymer. |
CN105531305A (en) * | 2013-09-30 | 2016-04-27 | 金伯利-克拉克环球有限公司 | Thermoplastic article with thermal active agent |
CA2931553C (en) | 2013-11-26 | 2022-01-18 | Grunenthal Gmbh | Preparation of a powdery pharmaceutical composition by means of cryo-milling |
US11833177B2 (en) | 2013-12-20 | 2023-12-05 | Seed Health, Inc. | Probiotic to enhance an individual's skin microbiome |
US11839632B2 (en) | 2013-12-20 | 2023-12-12 | Seed Health, Inc. | Topical application of CRISPR-modified bacteria to treat acne vulgaris |
US11826388B2 (en) | 2013-12-20 | 2023-11-28 | Seed Health, Inc. | Topical application of Lactobacillus crispatus to ameliorate barrier damage and inflammation |
EP2889030A1 (en) | 2013-12-30 | 2015-07-01 | Uluru Inc. | Controlling the erosion rates of mucoadhesive devices that deliver actives and other compounds and providing increased and variable therapeutic blood levels |
CA2947786A1 (en) | 2014-05-12 | 2015-11-19 | Grunenthal Gmbh | Tamper resistant immediate release capsule formulation comprising tapentadol |
EP3148512A1 (en) | 2014-05-26 | 2017-04-05 | Grünenthal GmbH | Multiparticles safeguarded against ethanolic dose-dumping |
EP3285745A1 (en) | 2015-04-24 | 2018-02-28 | Grünenthal GmbH | Tamper-resistant dosage form with immediate release and resistance against solvent extraction |
EP3302349B1 (en) | 2015-06-05 | 2019-11-20 | Unilever PLC | Oral care device |
JP2018526414A (en) | 2015-09-10 | 2018-09-13 | グリュネンタール・ゲゼルシャフト・ミト・ベシュレンクテル・ハフツング | Protection against oral overdose with abuse-inhibiting immediate release formulations |
WO2017085262A1 (en) * | 2015-11-19 | 2017-05-26 | Dermtreat Aps | A pharmaceutical film composition having improved residence time on the application site |
DE102016000541A1 (en) | 2016-01-14 | 2017-07-20 | Hofmann & Sommer GmbH und Co.KG | Cellulose fiber-based carrier matrices (smartFilms) for the application of ingredients and their preparation |
KR20230137362A (en) | 2016-05-05 | 2023-10-04 | 어퀘스티브 테라퓨틱스, 아이엔씨. | Enhanced delivery epinephrine compositions |
US11273131B2 (en) | 2016-05-05 | 2022-03-15 | Aquestive Therapeutics, Inc. | Pharmaceutical compositions with enhanced permeation |
US9737530B1 (en) | 2016-06-23 | 2017-08-22 | Collegium Pharmaceutical, Inc. | Process of making stable abuse-deterrent oral formulations |
EP3634507A4 (en) * | 2017-06-07 | 2021-03-24 | EGY-Nano Pharma, LP | Oral prolonged drug delivery platforms |
US11672757B2 (en) | 2017-06-28 | 2023-06-13 | University Of Pittsburgh-Of The Commonwealth System Of Higher Education | Hot melt extrusion for pharmaceutical vaginal film products |
DE102017127434A1 (en) * | 2017-11-21 | 2019-05-23 | Lts Lohmann Therapie-Systeme Ag | Pocket-shaped oral-release films with high drug loading |
JP7243301B2 (en) * | 2018-03-15 | 2023-03-22 | 大正製薬株式会社 | oral composition |
GB2575625A (en) | 2018-06-22 | 2020-01-22 | Church & Dwight Co Inc | Oral care compositions comprising benzocaine and mucoadhesive thin films formed therefrom |
US10758329B1 (en) | 2019-08-20 | 2020-09-01 | Raymond L. Wright, III | Hydrating mouth guard |
CN111249328B (en) * | 2020-03-13 | 2021-06-25 | 河南护理职业学院 | Compound oral ulcer film and preparation method thereof |
Family Cites Families (9)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
JPS5562012A (en) * | 1978-11-06 | 1980-05-10 | Teijin Ltd | Slow-releasing preparation |
GB2042888B (en) * | 1979-03-05 | 1983-09-28 | Teijin Ltd | Preparation for administration to the mucosa of the oral or nasal cavity |
JPS5620513A (en) * | 1979-07-31 | 1981-02-26 | Eisai Co Ltd | Sugar-coated tablet containing fat-soluble drug |
JPS5758615A (en) * | 1980-09-26 | 1982-04-08 | Nippon Soda Co Ltd | Film agnent and its preparation |
JPS5890507A (en) * | 1981-11-24 | 1983-05-30 | Nippon Soda Co Ltd | Manufacture of film preparation adhesive to mucous membrane |
JPS59222406A (en) * | 1983-06-01 | 1984-12-14 | Teijin Ltd | Pharmaceutical preparation for remedying periodontosis and its preparation |
JPS605159A (en) * | 1983-06-24 | 1985-01-11 | ライオン株式会社 | Production of medical band |
WO1985003878A1 (en) * | 1984-03-01 | 1985-09-12 | Sandoz Ag | Pharmaceutical compositions |
JPS62223114A (en) * | 1986-03-25 | 1987-10-01 | Rooto Seiyaku Kk | Slowly-releasing remedy for periodontosis |
-
1986
- 1986-06-16 US US06/874,904 patent/US4713243A/en not_active Ceased
-
1987
- 1987-06-04 NZ NZ220573A patent/NZ220573A/en unknown
- 1987-06-12 CA CA000539509A patent/CA1297408C/en not_active Expired - Lifetime
- 1987-06-12 AU AU74155/87A patent/AU7415587A/en not_active Abandoned
- 1987-06-15 AT AT87305280T patent/ATE95058T1/en not_active IP Right Cessation
- 1987-06-15 DE DE87305280T patent/DE3787573T2/en not_active Expired - Lifetime
- 1987-06-15 IE IE158387A patent/IE61785B1/en not_active IP Right Cessation
- 1987-06-15 PH PH35405A patent/PH24845A/en unknown
- 1987-06-15 GR GR870935A patent/GR870935B/en unknown
- 1987-06-15 JP JP62147181A patent/JP2540332B2/en not_active Expired - Lifetime
- 1987-06-15 EP EP87305280A patent/EP0250187B1/en not_active Expired - Lifetime
- 1987-06-16 KR KR1019870006074A patent/KR940011243B1/en not_active IP Right Cessation
- 1987-06-16 ZA ZA874294A patent/ZA874294B/en unknown
-
1996
- 1996-01-25 JP JP8011326A patent/JP2706064B2/en not_active Expired - Lifetime
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ATE95058T1 (en) | 1993-10-15 |
EP0250187A3 (en) | 1988-06-01 |
NZ220573A (en) | 1989-11-28 |
EP0250187B1 (en) | 1993-09-29 |
KR880000087A (en) | 1988-03-23 |
ZA874294B (en) | 1989-01-25 |
PH24845A (en) | 1990-10-30 |
EP0250187A2 (en) | 1987-12-23 |
IE871583L (en) | 1987-12-16 |
JP2706064B2 (en) | 1998-01-28 |
DE3787573D1 (en) | 1993-11-04 |
AU7415587A (en) | 1987-12-17 |
JPH08253414A (en) | 1996-10-01 |
GR870935B (en) | 1987-10-19 |
IE61785B1 (en) | 1994-11-30 |
US4713243A (en) | 1987-12-15 |
JP2540332B2 (en) | 1996-10-02 |
JPS6319152A (en) | 1988-01-26 |
KR940011243B1 (en) | 1994-12-03 |
DE3787573T2 (en) | 1994-02-10 |
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