JP2006505614A - Dissolvable oral patch containing collagen and reticulated active ingredients - Google Patents

Abstract

An adhesive oral patch for oral drug administration comprising a hydrophilic polymer that is liquid at oral temperature is disclosed. Preferably, the hydrophilic polymer solidifies in a gel state just below the mouth temperature, and preferably collagen such as animal gelatin. Mouth patches are porous networks that are solid at mouth temperature and slowly dissolve in saliva. In some embodiments, the network is an elastic plastic and in some cases is hydrophilic. The hydrophilic polymer is accommodated in the pores of the network together with the drug. The intraoral patch is formed by mixing and hydrating the components, heating to an activation temperature not lower than the boiling point of water, and cooling to gel. The heated mixture can be molded in a mold such as a flat sheet, and the mold itself can be used as a package. The package is provided with an antibacterial moisture permeable film, and the mouth patch can be dried or moistened without generating mold.

Description

  The present invention relates to an adhesive intraoral patch comprising a hydrophilic polymer that is liquid at intraoral temperature. This intraoral patch consists of two main members.

  This application is a continuation of 10 / 236,289 filed on Sep. 4, 2002 and claims US 60/34477 filed on Dec. 28, 2001, filed on Nov. 5, 2002. Claims 287843 priority.

  For the treatment of oral or throat medical conditions, compositions containing herbs and topical therapeutic agents have been retained in the mouth for centuries. The name of such a composition has been called “troche” from Latin and Greek. The current troche form is the cough drop form. The name stems from “dropping” high-viscosity sugar base candy on a sheet or mold and allowing it to cool to form a troche. Another form of troche is the “diamond drop” for throat, which is due to the diamond shape of the playing card (diamond). The structural characteristics of these forms of lozenges are determined by the major components that are typically sugars such as corn syrup and sugar alcohol. These lozenges hardly adhere to teeth and hardly adhere to gums, cheeks and lips.

  Adhesive oral patches have been developed to provide a higher concentration of the drug than a troche at a specific location in the mouth. A typical intraoral patch is one that is invented by Anthony et al. And includes a flexible layer that does not completely dissolve as disclosed in US Pat. No. 5,713,852. Another example of an oral patch is a DentiPatch, which has a non-dissolvable thermoplastic layer and a ride caine and is sold by Noven Pharmaceuticals, Inc. The term “patch” as used herein is a concept that does not include troches such as cough drops and throat drops that move without being fixed in the mouth. Also, powders, liquids, pastes, mucus gels, tablets, troches and the like that disintegrate in the mouth are not included.

  The biggest difference between the oral patch used here and other forms of oral medicines such as lozenges is that the oral patch (1) releases the drug in the mouth over 30 minutes, and (2) at least some adhesiveness It can be fixed at a suitable location, does not easily shift, and (3) is designed to stay in the mouth without collapsing.

  There are a variety of uses for drugs including therapeutics that can be administered locally in the mouth. In many forms of treatment, it is advantageous to keep the drug in one place in the mouth, and it is desirable not to move it during conversation. US Pat. No. 6,139,861 granted to Mark Friedman reports a method for adhering a slow-dissolving therapeutic agent to one location in the mouth. These methods include two forms of adhesive dissolving patches that Friedman calls "mucoadhesive disintegrating tablets". These tablets are formed of polymeric carboxymethylcellulose, hydroxymethylcellulose, polyacrylic acid and carbopol 934. None of them dissolve at the mouth temperature.

  The present invention relates to an adhesive intraoral patch comprising a hydrophilic polymer that is liquid at intraoral temperature. This intraoral patch consists of two main members.

  The first member is a porous molecular network formed as a single solid structure that maintains a solid state at the mouth temperature without collapsing or becoming a paste. Preferably, the network is hydrophilic and has adhesive force by absorbing moisture from the mucosal surface even when in contact with the wet mucosal surface in the mouth. Preferably, the network is one that dissolves slowly in saliva, disperses in the mouth over time, and does not require peeling of the patch.

  The second member is a hydrophilic polymer that is liquid at the mouth temperature. This polymer is administered through the pores of the network. Since this polymer is hydrophilic and liquid at the mouth temperature, it adsorbs well to the wet surface of the mouth and gives a gentle feel to rough tissues such as mouth ulcers. Preferably, this second member is partially hydrolyzed collagen such as gelatin derived from animal protein.

  Even if the user does not wipe the saliva from the tissue, the oral patch will adsorb to the teeth, gums, cheeks, lips, or tongue. If the patient places the intraoral patch into the mouth and presses it for 10 to 40 seconds to the desired location, the intraoral patch will adhere to the tissue even if the tissue is wet. This is much easier than wiping the tissue with a towel or the like and gluing the mouth patch. When the mouth patch is used on the lips or under the tongue, the mouth patch can be easily peeled off for conversation and can be easily replaced without using a towel or a mirror.

  The desired drug can also be provided in the network pores with the hydrophilic polymer.

  The network component can include a thermogel having a melting temperature higher than the mouth temperature. Preferably, the thermogel is an elastic plastic such as that formed from a mixture of hydrogel konjac gum and xanthan gum that is dissolved in hot water and cooled to form an elastic plastic gel. Alternatively, the network can include complex carbohydrates such as cellulose, pectin, maltodextrin, or starches such as potato, rice, onion, wheat. Further, the network can be composed of a hydrogel having a higher melting temperature than the mouth temperature provided by amino acids such as peptides.

  In the preferred embodiment, the hydrophilic polymers solidify at room temperature. Thereby, the mouth patch can be taken out of the mouth and placed on a smooth surface such as a plastic bag. Since this hydrophilic polymer is gelled, the patch in the mouth can be returned to the mouth with the finger without leaving a part of the patch in the finger. In one embodiment, the hydrophilic polymer is protein gelatin (collagen) from animal tissue that solidifies just below the mouth temperature and is solid at the pocket temperature and not dissolved in the pocket.

  In another aspect, the present invention provides a method for manufacturing an adhesive intraoral patch. In this method, the component forming the porous network, the hydrophilic polymer molecule, the drug molecule and water are mixed. This mixture is heated to a temperature that dissolves all the components before or after the components are mixed, and then cooled to form a porous network, solids with drug and hydrophilic polymer in the pores. A porous network that is a structure is provided. Prior to cooling, the heated mixture can be placed in a suitably shaped mold to provide a solid structure of the preferred shape. The mold can be prepared with powder starch as practiced by a steel company. Alternatively, the mold can be molded from a rigid material such as metal or plastic. If the mold is thin plastic or aluminum, it can also be used as a package product for oral patches provided to users.

  FIG. 1 shows a preferred shape of the intraoral patch. It is provided in a hydrocolloid that slowly dissolves so that the effect lasts at least 1 to 6 hours. The intraoral patch can be provided in tablet, drop, wafer or other shapes. The preferred shape is a thin lens shape as shown in FIG.

  FIG. 2 shows a typical shape of a solid porous network including pores. In order to carry out the present invention, it is necessary that the network does not dissolve at the mouth temperature. The reticulate is made of a substance with a slow degradation rate in saliva so that the intraoral patch slowly collapses. If the network does not degrade quickly, the drug will dissolve out of the network faster than the network collapses. Part of the mouth patch will remain in the mouth. The hydrophilic polymer that fills the pores of the network together with moisture and the drug slows the dissolution of the drug. Because it is a polymer, its molecules will be long and entangled in the network. The polymer molecules, together with the network structure, will entangle the drug molecules. In order to promote the entangled state, the drug molecule can be chemically weakly bonded to the hydrophilic polymer or the network molecule by cross-linking or the like.

  By analogy, imagine a fishnet bag filled with Ringwinial Fred to understand that a porous network filled with a polymer that is liquid at the mouth temperature becomes very sticky without breaking down. I want. In the case of chilled Ringwini Alfred, the Alfred sauce is solidified and the entire structure is not very sticky. Imagine being heated in a micro oven. Alfredo sauce dissolves and is sticky. The fishnet bag itself is not sticky. However, the hole is large enough, and the ringwini bundle with the sauce hangs out of the hole. If warm, if the entire structure is thrown towards the wall, it will probably adsorb to the wall. The bag itself remains integral. Ringwini bundles are similar to long molecules of polymer that are liquid at mouth temperature. Their length prevents Ringwini from falling out of the fishnet bag.

  Many different compositions are available for constructing the network. In order to facilitate the production, it is convenient to provide the network with a thermogel having a melting temperature equal to or higher than the mouth temperature. Thus, the whole mixture can be liquefied at a temperature substantially exceeding the mouth temperature, the mixture can be cooled, and the desired network can be formed in the thermogel by gelatinization. If the melting temperature is higher than the mouth temperature, the gel solidification temperature can be made lower than the mouth temperature.

  Easily available materials for forming such gels are various forms of agar, most forms of carrageenan, especially kappa carrageenan, konjac gum, locust bean gum, xanthan gum and the like. All of these materials form a thermogel that is sufficiently elastic or plastic to feel soft in the mouth when it absorbs moisture. The reticulated body hardens when dry and gives discomfort when in contact with sensitive skin in the mouth. To prevent the net from drying, the product can be packaged in an airtight seal or a non-volatile plasticizer such as glycerol (glycerin) can be added. However, if the amount of glycerin is high, the adhesiveness of the oral patch will be impaired.

  Synthetic hydrogels can be used for reticulates that do not dissolve at the mouth temperature or for adhesive liquid polymers. In general, protein-based hydrogels are made with proteins from natural sources, but it is also possible to synthesize such compounds as Diblock Copolypeptide Amphiphiles. Nowak et al. “Rapidly recovered hydrogel scaffolds with self-assembled diblock copolypeptide amphiphiles” Nowak, A.P .; Breedveld, V; Paxtis, L; Ozabas, B; Pine, DJ; Pochang, D See Deming, TJ Nature, 2002, 417, 424-428. The use of synthetic materials allows for control of the copolymer chain length and composition. Synthetic hydrogels can also be made from synthetic block copolymers that form thermoreversible gels with polysaccharides, solubilizing hydrophobic drugs to allow controlled release. See the books of Williams (PA, Water-soluble Polymer Center, Northeast Wales Institute, Pluscock, Mold Road, Rexham, Wales).

  Instead of forming a network with an intrinsic hydrogel, the network can be formed with complex carbohydrates such as cellulose, pectin, starch, maltodextrin, and other polysaccharides. The formation of hydrated networks from such materials is known in the confectionery industry. Alternatively, the network can be formed from a combination of intrinsic hydrogel and complex carbohydrates.

  The most important component of the adhesive mouth patch is a hydrophilic polymer that is liquid at the mouth temperature provided in the pores of the network. Collagen molecules such as gelatin derived from animal protein such as pork, cowhide or fish are very effective as this component. Collagen molecules are very adherent to the oral tissues that are themselves collagen. Collagen molecules can be partially hydrolyzed, the molecules can be shortened, the molecular weight can be reduced to a commercially available gelatin form.

  Hydrated hydrolyzed collagen aids skin wound healing. The inventor has discovered that when applied in the form of a mouth patch, the patch relieves pain and helps heal wounds in the mouth. The effect of reducing the short-term pain sensation in the mouth ulcer of the mouth patch of the present invention containing no other active ingredient was as effective as the general treatment not containing an anesthetic agent. Tests to improve the healing rate of oral wounds showed significant improvements.

  Commercial gelatin is graded according to “bloom strength” which represents the strength of the gel formed. Gels with high bloom strength (long gelatin molecules) are suitable for adhesive intraoral patches. This is because at the same time it is liquid and has high viscosity. The high viscosity in liquid form prevents gelatin molecules from escaping from the network faster than the network collapses, reducing the drug release rate. The maximum bloom strength of the commercial product is 250, which is suitable for the present invention.

  The adhesive intraoral patch is suitable for use with all drugs taught in Friedman US Pat. No. 6,139,861. They include steroids such as glucocorticoid steroids and non-steroidal anti-inflammatory drugs such as naproxensodium, ibuprofen, acetaminophen, ketoprofen. The drug may be a fungicide such as an antibacterial agent for the treatment of Candida (slush) such as nystatin, clotrimazole, miconazole, fluconazole. The drug is a therapeutic agent for oral ulcer and may contain antibiotics such as tetracycline, penicillin, amoxicillin. Moreover, other ulcer therapeutic agents, such as an amlexanox and a licorice root (Glyciliza) extract, may be included, and what was deglycerized (DGL) or enzymatically modified with the glucuronidase enzyme may be included.

  Once the network is formed from the hydrogel described above, the intraoral patch can be produced by methods well known in the confectionery industry. This process forms a fully hydrated mixture at a temperature above the activation temperature and below the boiling point of water, fully activating the hydrogel without boiling the water and gelling on cooling. In this process, the network can be formed from a combination of an intrinsic hydrogel such as xanthan gum and locust rubber or konjac rubber, or a complex carbohydrate such as cellulose, pectin or starch. In pharmaceutical licorice root extract, the effective weight ratio is 56% water, 16% gelatin, 11% licorice extract, 10% cellulose, 4.8% glycerol, 2.2% gum It is. The rubber is kappa carrageenan, xanthan gum, locust bean gum or konjac gum, and is heated to 130 to 200 degrees Fahrenheit. The water can be increased up to 75%, after which the required amount of dryness is increased.

  A hot mixture is poured into the mold. The mold may be an open top or closed mold containing a flat sheet. The upper open type can be formed by pushing the plug into a powder starch such as corn starch. Alternatively, it may be formed in a product packaging tray such as thermoformed PVC or PET, or a cold press laminate of aluminum and PVC with a thin polyamide reinforcement layer. The closed mold can be used as in an injection molding machine. The mold may be plastic-backed. In that case, the plastic becomes part of the final package. A suitable size for each mouth patch is 0.8 g injected into the mold.

  If the oral patch is stored in a powder starch, the starch will absorb some of the excess moisture and the oral patch will be further dried before being removed from the starch, packaged in a hermetic seal and gamma sterilized in the retort. Or sterilized by heating and pressure.

  If the oral patch is placed in a mold in the tray, the tray is stored in the drying room until the moisture in the oral patch is in a suitable state.

  A suitable method of drying in the tray is exposure to room temperature and room humidity for 3 days in no convection or 24 hours in convection. Drying reduces the weight of the mouth patch by about 47%, so that the mouth patch, originally 0.8 g, is 0.42 g. The tray is sealed with a film bonded by conventional heat sealing techniques, and the entire package is sterilized by gamma radiation in the retort or sterilized by heat and pressure.

  In most applications, most users prefer the mouth patch to be semi-dry rather than fully dry. With this starting dryness, the mouth patch is more adhesive and has higher shape stability and can be taken out of the mouth during conversations and meals and exchanged. The only drawback of this dryness is that the intraoral patch hardens when dry and the comfort is reduced. Shape flexibility is also slightly impaired, and adhesion to hard parts such as gums and teeth is poor. When the oral patch is brought into contact with a delicate tissue such as an ulcer, it is desired that the patch is somewhat moist and soft. Therefore, it is desirable to wrap the film with a film capable of applying moisture without removing the intraoral patch from the package. If the wrapping film is bacterial protective, the oral patch is stored in a sterile condition and the mold does not grow even if it contains moisture. Effective films are expanded films such as cellophane, polybutadiene, polyamide, Tyvek (polyethylene yarn) and Gore-Tex. Polyamides having a thickness of 0.7 mil to 1.0 mil are effective. If you drop a few drops of water on such a package and leave it for a day or two, the humidity of the mouth patch will just improve. On the other hand, if the package is placed in a drying room for 1 to 3 days, it will dry moderately.

  The embodiments of the present invention have been described above. These modifications are possible within the scope of the present invention.

FIG. 1a is a side view of a flexible adhesive-dissolving intraoral patch. FIG. 1b is a plan view thereof. FIG. 2 shows a typical shape of a solid porous network structure including pores.

Claims (45)

An adhesive oral patch that administers a drug to the mouth over time,
(a) a porous network formed as a solid structure that is solid at the mouth temperature and having a slow decomposition rate in saliva;
(b) drug molecules housed in the pores of the network,
(c) a hydrophilic polymer molecule that is liquid at the mouth temperature and contained in the pores of the network,
An intraoral patch characterized by comprising. The intraoral patch according to claim 1, wherein the net-like body is hydrophilic. The mouth patch according to claim 1, wherein the reticulate body contains a thermogel having a melting temperature higher than the mouth temperature. The intraoral patch according to claim 3, wherein the thermogel is an elastic plastic. The intraoral patch according to claim 4, wherein the thermogel is a mixture of konjac gum and xanthan gum which is dissolved in hot water and cooled to form an elastic plastic gel. The intraoral patch according to claim 2, wherein the reticulate body contains at least one hydrogel selected from konjac gum, xanthan gum, locust bean gum, agar and carrageen. The intraoral patch according to claim 1, wherein the reticulate contains complex carbohydrates. The intraoral patch according to claim 7, wherein the network is cellulose. The oral patch according to claim 7, wherein the reticulate contains at least one complex carbohydrate selected from pectin, potato starch, rice starch, corn starch, wheat starch and maltodextrin. The intraoral patch according to claim 1, wherein the reticulate contains an amino acid. The oral patch according to claim 10, wherein the amino acid is a peptide hydrogel. The intraoral patch according to claim 1, wherein the hydrophilic polymer forms a thermoreversible gel that is gel-like at room temperature and liquid at the mouth temperature. The oral patch according to claim 12, wherein the hydrophilic polymer is gelatin derived from animal tissue. The oral patch according to claim 1, wherein the hydrophilic polymer contains a protein. The intraoral patch according to claim 14, wherein the hydrophilic polymer is collagen. The oral patch according to claim 1, wherein the drug is a steroid. The oral patch according to claim 16, wherein the steroid is a glucocorticoid steroid. The oral patch according to claim 1, wherein the drug is a non-steroidal anti-inflammatory drug. The oral patch according to claim 1, wherein the drug is an antibiotic. The oral patch according to claim 19, wherein the drug is an antibacterial agent. The oral patch according to claim 1, wherein the drug is a licorice root extract. The oral patch according to claim 21, wherein the drug is an enzymatically modified licorice root extract. The intraoral patch according to claim 1, which is contained in a packaging material containing an antibacterial moisture permeable film. A method of manufacturing an adhesive oral patch for administering a topical drug in the mouth over time, comprising:
(a) A drug, a component for forming a hydrophilic porous network that is solid at mouth temperature and slowly decomposes in saliva, a molecule of a hydrophilic polymer that is liquid at mouth temperature, and water. Mixing the containing mixture;
(b) heating the mixture;
(c) cooling the mixture, causing the component to form a network, and forming the hydrophilic porous network as a solid structure containing the drug and the hydrophilic polymer in the pores;
The manufacturing method characterized by comprising. 25. A method according to claim 24, wherein the network is formed of gelatin obtained in the cooling step. The manufacturing method according to claim 24, wherein the hydrophilic polymer forms a thermoreversible gel which is in a gel state at room temperature and is a viscous liquid at the mouth temperature in the cooling step. The production method according to claim 24, wherein the hydrophilic polymer contains a protein. 28. The method according to claim 27, wherein the hydrophilic polymer is gelatin derived from animal tissue. The manufacturing method according to claim 24, wherein the high temperature mixture is poured into a mold between the heating step and the cooling step, and the cooling step is performed in that state. 30. A method according to claim 29, wherein the mold is formed of powder starch. 30. A method according to claim 29, wherein the mold is a flat and rigid plastic sheet. 26. The method of claim 25, further comprising the step of wrapping the oral patch with a packaging material comprising an antimicrobial moisture permeable film. A moisture-regulated packaging mouth patch,
(a) An intraoral patch comprising an intraoral patch packaged with a packaging material including an antibacterial moisture-permeable film. 34. An intraoral patch according to claim 33, wherein the film is an antibacterial moisture permeable film and is selected from cellophane, polystyrene, polybutadiene, polyamide, Tyvek and Gore-Tex expanded film. 34. The intraoral patch of claim 33, wherein the film is polyamide. It is a drop to provide collagen to the lesion in the mouth,
(a) a porous network formed as a solid structure;
(b) collagen molecules housed in the pores of the network,
A drop characterized by comprising. 37. A drop according to claim 36, wherein the collagen is partially hydrolyzed. 37. The drop according to claim 36, wherein the collagen is derived from an animal protein. 37. A drop according to claim 36, wherein the network is hydrophilic. 37. The drop of claim 36, wherein the network comprises a thermogel having a melting temperature that is higher than the mouth temperature. 37. The drop according to claim 36, wherein the network comprises at least one hydrogel selected from konjac gum, xanthan gum, locust bean gum, agar and carrageenan. 40. The drop of claim 36, wherein the network comprises complex carbohydrates. 37. The drop of claim 36, wherein the thermogel is a mixture of konjac gum and xanthan gum that is dissolved in hot water and cooled to form an elastic plastic gel. 37. A drop according to claim 36, wherein the network comprises cellulose. 37. A drop according to claim 36, wherein the network contains amino acids.

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