Definitions

• troche For treatment of health problems in the mouth or throat, people have for centuries held in their mouths a composition containing herbal or other medication for topical application.
• the oldest name for such a composition derived from Latin and previously from Greek, is "troche”.
• a modern form of troche is the cough drop, so named because it was formed by "dropping" hot, viscous, sugar-based candy onto a sheet or into a mold where it cools to form the troche.
• Another modern form of troche is the throat "lozenge”, so named because it was in the shape of a diamond (like on playing cards), which is the meaning of the word "lozenge”.
• the structural characteristics of these types of troches are determined by their primary structural ingredients which are typically corn syrup or sugars, including sugar alcohols.
• An oral patch typically includes one or more flexible layers that do not dissolve entirely such as invented by Anthony et al. and disclosed in US patent 5,713,852.
• Another example of an oral patch is the Denti Patch which has one or more non- soluble thermo-plastic layers and lidocaine, offered for sale by Noven Pharmaceuticals, Inc.
• the word "patch" does not include preparations that move about the mouth rather than resting in one place, such as cough drops, throat lozenges, or other troches.
• an oral patch as used herein and other forms of oral medicinal topical preparations such as troches are that an oral patch is designed to (1) release medication into the mouth over a relatively long period of time, such as 30 minutes or more, (2) be at least mildly adherent so that it can be placed in a preferred location and not be dislodged by gravity or gentle movement, and (3) remain in the mouth as a single item that will not spread to be in a plurality of locations in the mouth at one time.
• the invention is an adherent oral patch including a hydrophilic polymer that is liquid at human mouth temperatures.
• the oral patch is made of two primary components.
• the first component is a porous molecular network formed as a unitary solid structure that remains a solid at human mouth temperatures, in contrast to being crumbly or a paste.
• the network is preferably hydrophilic so that, even when applied to a wet mucosal surface in the mouth, it will tend to adhere by absorbing moisture from the mucosal surface.
• the network slowly dissolves in saliva so that the patch merely dissipates over time and the patch never has to be removed from the mouth.
• the second component is a hydrophilic polymer that is liquid at human mouth temperatures.
• the polymer is distributed throughout the pores of the network. Because the polymer is hydrophilic and liquid at human mouth temperatures, it will adhere very well to wet surfaces inside the mouth and is quite soft which provides a soothing feeling to any sensitive tissue such as canker sores.
• the second component is preferably partially hydrolyzed collagen such as gelatin from animal protein.
• the oral patch will adhere to teeth, gums, cheek, lips, or tongue without the user first drying saliva from the tissue. If the patient merely places the oral patch in his or her mouth and presses it in the desired location for 10 to 40 seconds, it will adhere to the tissues that it has been touching without movement, even though those tissues are wet.
• a desired medication is also located within the pores of the network along with the hydrophilic polymer.
• the network component may be comprised of a thermo gel having a melting temperature higher than human mouth temperatures.
• the thermo gel is elasto-plastic, such as formed by a mixture of the hydrogels konjac gum and xanthan gum dissolved in hot water and then cooled to form an elasto- plastic gel.
• the network may be comprised of a complex carbohydrate, such as cellulose, pectin, maltodextrin, or starch from potato, rice, corn, or wheat.
• the network may be comprised of a hydrogel with a melting temperature higher than temperatures in the human mouth formed of amino acids, such as peptides.
• the hydrophilic polymer gels to a solid at room temperatures.
• the oral patch to be removed from the mouth and placed on a smooth surface, such as a plastic bag. Because the hydrophilic polymer then gels, the oral patch again becomes handleable with the fingers to return it to the mouth without being too sticky to handle or leaving a residue on the fingers or on the plastic bag.
• the hydrophilic polymer is protein gelatin (collagen) rendered from animal tissue, which solidifies at just below mouth temperatures and remains a solid even at clothes pocket temperatures so it will not melt in a pocket.
• the invention is a method for manufacturing an adherent oral patch.
• ingredients for forming the porous network, molecules of the hydrophilic polymer, molecules of the medication, and water are mixed together.
• the mixture is heated to dissolve all ingredients, either before the ingredients are added together or after they are added together, and the mixture is then cooled, thereby causing the ingredients for forming a network to form the porous network as a unitary solid structure having the medication and the hydrophilic polymer within its pores.
• the hot mixture may be deposited into a mold of a suitable shape to form the preferred unitary solid structure.
• the mold may be formed in powdered starch, as is well known in the candy making industry for forming gumdrops.
• the mold may be formed of a rigid material such as metal or plastic. If the mold is thin plastic or aluminum, it may also serve as packaging for delivery of the oral patch to the consumer.
• Figure 1a shows a side view of a soft, adherent, soluble oral patch.
• Figure 1 b shows a top view of the same oral patch.
• Figure 2 shows, in representational form, the structure of the solid, porous network, including the pores.
• Figure 1 shows a preferred shape for the oral patch. It is made with slowly dissolving hydrocolloids so that that it typically lasts in the mouth for at least one to six hours.
• the patch can be formed in the shape of a tablet or a lozenge or a wafer or any other desired shape.
• a preferred shape is a thin lentil as shown in Figure 1a.
• Figure 2 shows, in representational form, the structure of the solid, porous network, including the pores.
• a requirement for the network is that it remains a solid, rather than melting, at human mouth temperatures. So that the oral patch will slowly erode, the network should be made of a material with a low to moderate rate of disintegration in warm saliva. If the network does not erode fast enough, medication will be drawn out of the network faster than the network erodes and, although a portion of the oral patch remains in the mouth, it will no longer be releasing medication.
• the hydrophilic polymer that, along with water and medication, fills pores of the network helps to slow the loss of medication from within pores of the network. Being a polymer, its molecules are long and they tend to be entangled by the network.
• molecules of the medication may be weakly chemically bound, such as by cross-linking, to molecules of the hydrophilic polymer or the network or both.
• the strands of linguini are like the long molecules of a polymer that is liquid at mouth temperatures. Their length keeps them from easily falling out of the fish net bag. Many different compositions can be used to form the network.
• the network is comprised of a thermo gel having a melting temperature higher than human mouth temperatures. This allows the entire mixture to be a liquid at temperatures far above human mouth temperatures and allows the network to be formed by cooling the mixture such that the thermo gel forms the desired network by a gelation process. The temperature at which the gel forms can be lower than human mouth temperatures, provided the temperature at which it melts again is higher than human mouth temperatures.
• Readily available materials that form such a gel include agar, in various forms, carrageenan, in most of its forms, particularly kappa carrageenan, konjac gum, locust bean gum, and xanthan gum. All of these materials form a thermo gel that is sufficiently elastic or plastic or a combination thereof for the network to feel soft in the human mouth if it is adequately hydrated. If water is dried out of the network, it will become hard and will produce an unattractive feel when placed in contact with sensitive tissues, such as canker sores. To prevent the network from drying out, it may be packaged with a hermetic seal or a non- evaporating plasticizer, such as glycerol (glycerin) may be added. However, the more glycerol is added the less adherent the oral patch will be.
• glycerol glycerin
• Synthetic hydrogels may be used for either the network that does not melt at mouth temperatures or the adherent, liquid polymer.
• Protein-based hydrogels are usually prepared using proteins extracted from natural sources, but they may be synthesized, such as with diblock copolvpeptide amphiphiles, as taught by Nowak, et. al, "Rapidly Recovering Hydrogel Scaffolds From Self-Assembling Diblock Copolypeptide Amphiphiles". Nowak, A. P.; Breedveld, V.; Pakstis, L.; Ozbas, B.; Pine, D. J.; Pochan, D.; Deming, T. J. Nature , 2002, 417, 424-428.
• Synthetic hydrogels may also be made from polysaccharides and synthetic block copolymers which form thermoreversible gels and allow the solubilisation of hydrophobic medications for controlled release, as taught by Williams, PA, at the Centre for Water Soluble Polymers, North East Wales Institute, Plas Coch, Mold Road, Wrexham, Wales.
• the network may be formed with a complex carbohydrate, such as cellulose, pectin, starch, maltodextrin or other polysaccharides. Forming of hydrated network structures out of such materials is well known in the candy making industry for making gummy candies. Or the network may be formed with a combination of a true hydrogel and a complex carbohydrate.
• the most crucial ingredient for the adherent oral patch is a hydrophilic polymer that is liquid at human mouth temperatures located within pores of the network.
• Collagen molecules such as gelatin rendered from animal protein, such as from pork or cattle skin or from fish, serve very well as this ingredient. Collagen molecules tend to adhere very well to the tissues of the mouth lining which, themselves, are collagen molecules. The collagen molecules may be partially hydrolyzed, making them shorter and lower in molecular weight, in the form of commercially available gelatin.
• Hydrated hydrolyzed collagen assists with wound healing in human skin.
• the inventor has found that, when applied in the mouth via an oral patch, it reduces pain and assists with healing of wounds and other lesions in the mouth.
• Oral patches made according to this invention with no other active ingredient were tested for short term pain reduction in aphthous ulcers with success equal to commercially available topical treatments having no anesthetic. Tests for speeding of healing of oral wounds showed small but significant improvement.
• bloom strength refers to the strength of the gel that is formed.
• Gelatin with a higher bloom strength (made with longer collagen molecules) is preferred for the adherent oral patch because it also has a higher viscosity in liquid form.
• the high viscosity in liquid form prevents the gelatin molecules from escaping the network substantially faster than the network erodes, and the high viscosity better retains the medication for slow release.
• the adherent oral patch is suitable for use with all of the medications mentioned in U. S. Patent 6,139,861 issued to Friedman, including steroids, such as a glucocorticoid steroids, and non-steroidal anti-inflammatory drugs such as naproxen sodium, ibuprofen, acetaminophen, and ketoprofen.
• the medication may also be an antimicobial, such as an anti-fungal for treatment of Candida organisms (thrush), such as nystatin, clotrimazole, miconazole, or fluconazole.
• the medication may be intended for treatment of canker sores (aphthous ulcers), including pharmaceutical antibiotics such as tetracycline, penicillin, or amoxicillin, or other canker sore treatment medications such as amlexanox or licorice root (glycyrrhiza) extract in any of its forms, including deglycyrrhizinated (DGL) or enzymatically modified with glucuronidase enzyme.
• canker sores an aphthous ulcers
• pharmaceutical antibiotics such as tetracycline, penicillin, or amoxicillin
• other canker sore treatment medications such as amlexanox or licorice root (glycyrrhiza) extract in any of its forms, including deglycyrrhizinated (DGL) or enzymatically modified with glucuronidase enzyme.
• the oral patches may be manufactured by processes well known in the candy making industry. The process is to form a well-hydrated mixture at temperatures above the activation temperature and below the boiling temperature of water so that water does not boil off and yet the hydrogels are fully activated for gelling when the product is cooled.
• the network can be formed of a combination of a true hydrogel such as xanthan gum with locust bean gum or with konjac gum and a complex carbohydrate such as cellulose or pectin or starch.
• an effective ratio by weight is 56% water, 16% gelatin, 11 % licorice extract, 10% cellulose, 4.8% glycerol, and 2.2% gums such as kappa carrageenan or xanthan gum plus locust bean gum or konjac gum heated to between 130 and 200 degrees F.
• the water may be increased up to 75%, increasing the amount of subsequent drying required.
• the hot mixture is poured or squirted into molds.
• the molds be may open top molds, including a flat sheet, or closed molds. Open top molds may be formed by pressing a plug into powdered starch such as cornstarch or may be formed in a tray for packaging the products such as thermo formed PVC or PET or a cold press laminate of aluminum and PVC with a thin layer of polyamide for strength. Closed molds may be used such as in an injection-molding machine. The molds may be plastic lined, in which case the plastic becomes a part of the final packaging. A suitable size for each oral patch is 0.8 grams poured into the mold.
• the starch absorbs some of the excess water and the oral patches are further dried in a drying room before being removed from the starch, packaged in a hermetic seal, and sterilized with gamma radiation or heat and pressure in a retort.
• the oral patches are deposited in molds formed in a tray, the tray is stored in a drying room until the oral patches lose a suitable amount of moisture.
• a suitable method of drying in trays is to expose them without convection to room temperature and humidity for 3 days or, with convection, for 24 hours. In the drying process, the oral patches lose about 47% of their weight, so an oral patch that started at 0.8 grams poured into the mold becomes 0.42 grams.
• the trays are then sealed with a film or foil lid that is adhered by conventional heat-sealing techniques and the entire package is sterilized with gamma radiation or heat and pressure in a retort.
• the oral patches be medium dry to dry. With this starting dryness, the oral patches are more adherent and have more integrity so they can be removed for talking or eating and then replaced.
• the only drawback to this dryness is that the oral patch becomes hard when it dries, giving the oral patch a less soothing feel. It is also less conforming and therefore does not stick well to hard surfaces such as guns and teeth.
• the oral patch When the oral patch is placed in contact with delicate tissue, such as a large canker sore, most users prefer that the oral patch be moist and soft.
• the packaging film is a barrier to germs, this allows the oral patches to remain sterile and not grow mold even when they are moist.
• Effective films are cellophane, polystyrene, poybutadiene, polyamide, Tyvek (matted polyethylene threads) and expanded films such as Goretex. Polyamide with a thickness of .7 mil to 1.0 mil is effective. Allowing such a package to sit for a day or two with a few drops of water on the package is sufficient to hydrate the oral patch inside. Conversely, allowing the package to sit on a shelf in a dry room for one to three days is sufficient to dry out the oral patch.

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• 2003
  • 2003-10-29 JP JP2004551629A patent/JP2006505614A/ja not_active Withdrawn
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  • 2003-10-29 CA CA002505126A patent/CA2505126A1/en not_active Abandoned
  • 2003-10-29 CN CN 200380108321 patent/CN1735393A/zh active Pending
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