WO2003059390A1 - Film mucoadhesif oral - Google Patents

Film mucoadhesif oral Download PDF

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Publication number
WO2003059390A1
WO2003059390A1 PCT/KR2003/000084 KR0300084W WO03059390A1 WO 2003059390 A1 WO2003059390 A1 WO 2003059390A1 KR 0300084 W KR0300084 W KR 0300084W WO 03059390 A1 WO03059390 A1 WO 03059390A1
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WIPO (PCT)
Prior art keywords
weight
adhesive layer
water
poloxamer
film
Prior art date
Application number
PCT/KR2003/000084
Other languages
English (en)
Inventor
Yong-Ho Chung
Jei-Man Ryu
Jae-Hee Jung
Yu-Eun Kim
Chong-Su Cho
Hoo-Kyun Choi
Myung-Kwan Chun
Jae-Soon Ahn
Tae-Hee Kim
Original Assignee
Dong Wha Pharm. Ind. Co., Ltd.
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Publication date
Application filed by Dong Wha Pharm. Ind. Co., Ltd. filed Critical Dong Wha Pharm. Ind. Co., Ltd.
Priority to AU2003206143A priority Critical patent/AU2003206143A1/en
Publication of WO2003059390A1 publication Critical patent/WO2003059390A1/fr

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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
    • A61K9/0012—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
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
    • A61K47/10—Alcohols; Phenols; Salts thereof, e.g. glycerol; Polyethylene glycols [PEG]; Poloxamers; PEG/POE alkyl ethers
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
    • A61K47/32—Macromolecular compounds obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. carbomers, poly(meth)acrylates, or polyvinyl pyrrolidone
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
    • A61K47/36—Polysaccharides; Derivatives thereof, e.g. gums, starch, alginate, dextrin, hyaluronic acid, chitosan, inulin, agar or pectin
    • A61K47/38—Cellulose; Derivatives thereof

Definitions

  • the present invention relates to a new oral mucoadhesive film, which consists of two layers of an adhesive layer containing a drug, a polyacrylic acid polymer, a cellulose derivative, poloxamer and a plasticizer and a protective layer containing a water-insoluble and water-impermeable polymer and a plasticizer, and a method of preparing the same.
  • Gels one of drug administration preparations using oral mucous membrane, are usually used in treating ulcerative stomatitis, herpes simplex, etc.
  • mucoadhesive polymers used in conventional oral mucoadhesive films are quickly swelled or dissolved when contacted with water so that they remain on the oral mucous membrane only for a short time, which prevents sustained release of drugs. Further, with the swelling of polymers, the diffusion of drugs varies and then its delivery rate cannot be estimated.
  • polyacrylic acid and cellulose derivatives have excellent mucoadhesiveness (J. Pharm. Sci., 89(7), 850-866, 2000).
  • the polymers cannot maintain their form in oral cavity for a long time due to the high swelling or solubility in saliva (U.S. Patent Nos. 4,292,299 and 4,740,365, and European Patent No. 654,261).
  • the shape maintenance time of preparations is only less than 1 hour and the preparations are changed to gel form after being attached, so that drugs in the preparations cannot be delivered effectively.
  • the polymer has too high solubility in water to be used in the preparations which need to be attached for a long time.
  • Oral mucoadhesive preparations need to be convenient for use, to give minimum feeling of foreign substances after being attached so as to enhance the compliance of patients, to maintain the adhesiveness without changing their forms for a certain period of time in order to deliver drugs effectively, and to have ease and effectiveness of preparing.
  • a method of preparing a mucoadhesive preparation containing three or four layers of adhesive layer, impermeable layer, drug reservoir layer and controlled release layer comprises making each layer to be dried to a fixed weight, binding each layer with one another, and then completely drying the combined layers (U.S. Patent Nos. 5,196,202 and 4,900,552).
  • the preparing processes are complicated and have low effectiveness due to the difficulty in adjusting dry weight and binding these layers.
  • the hydration speed differs in each layer, which results in twist and curling of the preparation and also loss of drugs.
  • the film also has the defect that it has the thickness of about 800 ⁇ m, which is thicker than those of conventional oral mucoadhesive films, and gives the feeling of foreign substances when attached.
  • the film having a protective layer containing water-insoluble materials such as ethyl cellulose (EC), hydroxypropyl cellulose phthalate (HPC-P) and cellulose acetate phthalate (CA-P) (U.S. Patent No. 4,876,092)
  • EC ethyl cellulose
  • HPC-P hydroxypropyl cellulose phthalate
  • CA-P cellulose acetate phthalate
  • the type of mucoadhesive polymers used in protective layer and adhesive layer and the affinity between the layers should be considered preferentially for maintaining the form of preparations.
  • a method to add a plasticizer such as polyalcohols in an adhesive layer and a protective layer for increasing the affinity between the two layers has a defect that it is difficult to maintain the preparations for a long time due to the high solubility and swelling of the mucoadhesive polymers used in the adhesive layer (Korean Laid-open Publication No. 2000-31828).
  • a method to add a water-insoluble carbonated titanium and talc in an adhesive layer for maintaining the form of preparations This method also has a defect that the affinity between layers decreases due to the low flexibility of the adhesive layer, thereby resulting in the separation of layers (Korean Laid-open Publication No. 1997-9794).
  • the present inventors have been able to prepare a new oral mucoadhesive film on the base of the revelation that when polyacrylic acid polymers and cellulose derivatives, which cannot maintain the adhesiveness for a long time due to the swelling and solubility in saliva despite of the excellent mucoadhesiveness, are added with poloxamer, the swelling and solubility in saliva can be adjusted.
  • the present invention relates to an oral mucoadhesive film for an effective drug delivery through oral mucous membrane, which has a long lasting adhesiveness and a good flexibility, does not give a feeling of foreign substances to users, and is prepared with ease and efficiency, and a method of preparing the same.
  • an oral mucoadhesive film which contains an adhesive layer consisting essentially of a polyacrylic acid polymer, poloxamer, a cellulose derivative, a drug which can be absorbed through mucous membrane and a plasticizer, and a protective layer consisting essentially of a water-insoluble and water-impermeable polymer and a plasticizer, wherein each of the polyacrylic acid polymer and the cellulose derivative is in an amount of 5 to 80 % by weight and the poloxamer is in an amount of 5 to 70 % by weight, based on the weight of the polymers in the adhesive layer, and a mixture of the polymers is in an amount of 5 to 20 % by weight, the drug is in an amount of 0.05 to 20 % by weight, and the plasticizer in the adhesive layer is in an amount of 0.1 to 10 % by weight, based on the weight of the adhesive layer; the water-insoluble and water-impermeable polymer is in an amount of 5 to
  • the oral mucoadhesive film of the present invention consists of an adhesive layer containing a drug and a protective layer.
  • the protective layer consists of a water-insoluble and water-impermeable polymer such as ethyl cellulose (EC), polyurethane (PU), polyethylene (PE), and polyester, and a plasticizer.
  • the adhesive layer consists of a cellulose derivative such as hydroxypropyl cellulose (HPC), hydroxymethyl cellulose (HMC), hydroxyethyl cellulose (HEC), hydroxypropylethyl cellulose (HPEC) and hydroxypropylmethyl cellulose (HPMC), a polyacrylic acid polymer such as carbomer and polycarbophil, poloxamer and a plasticizer.
  • the adhesive layer is a drug-containing layer and can adhere to oral mucous membrane to deliver the drug, and the protective layer prevents the drug-containing adhesive layer from being lost or detached from the mucous membrane due to rapid swelling .
  • polyacrylic acid polymers contained in the adhesive layer are carbomer, polycarbophil, and mixtures thereof.
  • Polycarbophil is a cross-linked acrylic acid polymer with divinyl glycol and carbomer is polymerized by allyl sucrose or allyl pentaerythritol.
  • carbomer are carbopol series 980, 934, 940, 941, 934P, 97 IP, 974P, 981, 1342, 1382, 2984 and 5984EP sold on the market by the trade name "Carbopol” and Noveon series AA-1, CA-1 and CA-2 sold on the market by the trade name "Noveon", preferably carbopol 934P and carbopol 97 IP.
  • Cellulose derivatives have an excellent film-forming ability and are used as a binder and film-coating agent for tablets.
  • cellulose derivatives are hydroxypropyl cellulose, hydroxymethyl cellulose, hydroxyethyl cellulose, hydroxypropylethyl cellulose and hydroxypropylmethyl cellulose, preferably hydroxypropylethyl cellulose and hydroxypropylmethyl cellulose.
  • Poloxamer a copolymer of polyethylene glycol and polypropylene glycol, used as an emulsifier and a supplementary solubilizer, is characterized by a variety of gel formation according to the type, concentration and mixing ratio. Examples are poloxamer series 124, 188, 338 and 407, preferably poloxamer 188 and poloxamer 407.
  • plasticizer used in the adhesive layer examples include castor oil and polyethylene glycol (PEG), preferably polyethylene glycol.
  • Drugs which are added in the adhesive layer include all drugs that can be absorbed through mucous membranes.
  • the drugs are those for oral diseases such as triamcinolone acetonide and glycyrrhetinic acid; anti-inflammatory agents such as ketoprofen and piroxicam; anti-histamines such as diphenhydramine and chlorpheniramine; hormones such as estradiol and testosterone; antihypertensive agents such as clonidine and propranolol; bronchodilators such as theophylline and terbutaline; and anesthetics such as lidocaine and dibucaine.
  • oral diseases such as triamcinolone acetonide and glycyrrhetinic acid
  • anti-inflammatory agents such as ketoprofen and piroxicam
  • anti-histamines such as diphenhydramine and chlorpheniramine
  • hormones such as estradiol and testosterone
  • antihypertensive agents such as
  • drugs as have high bioavailability enough to be administered in a small amount, as are easily metabolized when administered orally, and as have a gastro-intestinal adverse effect.
  • water-insoluble and water-impermeable polymers examples include polyester, polyurethane, polyethylene and ethyl cellulose, preferably polyurethane and ethyl cellulose.
  • Ethyl cellulose is used as a water-insoluble coating agent for tablets or granules for the purpose of controlled release, masking of taste, and improvement of stability, etc.
  • plasticizer used in the protective layer are triethyl citrate (TEC), castor oil and polyethylene glycol (PEG), preferably polyethylene glycol and triethyl citrate.
  • TEC triethyl citrate
  • PEG polyethylene glycol
  • the film according to the present invention consists of two layers of an adhesive layer and a protective layer, as illustrated in Fig. 1.
  • films are manufactured by preparing a solution mixed with cross-linked polyacrylic acid polymer and cellulose derivative, which have an excellent mucoadhesiveness. Even though the film prepared from the solution is homogeneous, it has high swelling and solubility in saliva to decrease the delivery of drugs through mucous membranes, and also it has too high viscosity for large-scale production of the high concentrated solution. Further, it has low flexibility to give a feeling of foreign substances when attached to mucous membranes.
  • the present inventors have prepared a film by adding poloxamer into the polymer solution to prepare an adhesive layer, in which the solution can be prepared at a low temperature, the viscosity of the mixed solution is so low as to make it easy to prepare the film, and the film has low swelling and solubility in saliva, thereby enabling the film to be attached to mucous membranes for a long time.
  • An adhesive layer is required to have a mucoadhesiveness as well as an ability to control the release of drug into mucous membranes.
  • a proper combination of the above-mentioned polymers is important for the requirements.
  • Each of the polyacrylic acid polymer and cellulose derivative is added in an amount of 5 to 80 % by weight, preferably 20 to 50 % by weight, based on the weight of the polymers in the adhesive layer. If the amount of each polymer is less than 5 % by weight, it is impossible to prepare the film with constant thickness because of low viscosity of polymer solution, thereby also decreasing the adhesiveness of film. While if the amount of each polymer is more than 80 % by weight, it is difficult to prepare the polymer solution.
  • Poloxamer is added in an amount of 5 to 70 % by weight, preferably 20 to 50 % by weight, based on the weight of the polymers in the adhesive layer. If the amount is less than 5 % by weight, the solubility and swelling of film increase so that it is difficult to maintain the form of film. Further, in case the poloxamer is added in an amount of more than 70 % by weight, it is difficult to prepare the polymer solution of high concentration.
  • the mixed solution of the above three polymers is prepared so that the concentration of the polymers is 5 to 20 % based on the weight of the adhesive layer, in which the preferred weight ratios of poloxamer/cross-linked polyacrylic acid and poloxamer/hydroxypropylmethyl cellulose range from 1: 1 to 1: 1.5, respectively. Within the above range of concentration, it is easy to adjust the film thickness and drying time at the time of preparing the film.
  • Drugs are added in an amount of 0.05 to 20 % by weight based on the weight of the adhesive layer. If the drug is added in an amount of more than 20 % by weight, it has an adverse effect on the viscosity of the solution of adhesive layer and makes the preparing of film difficult.
  • the water-insoluble and water-impermeable polymer is added in an amount of 5 to 50 % by weight, preferably 10 to 30 % by weight, based on the weight of the protective layer. If the amount is less than 5 % by weight, the fluidity of solution containing the polymer is too high to make film. Further, in case the polymer is added in an amount of more than 50 % by weight, it is difficult to prepare film having a constant thickness.
  • a proper plasticizer for each layer is selected in consideration of the mucoadhesiveness of adhesive layer and the affinity between the two layers.
  • the plasticizer used in the adhesive layer of the present film are castor oil and polyethylene glycol (PEG).
  • the plasticizer used in the protective layer of the present film are triethyl citrate (TEC), castor oil and polyethylene glycol (PEG).
  • the film having polyethylene glycol added in the adhesive layer and triethyl citrate added in the protective layer which has the most superior mucoadhesiveness, flexibility and high affinity between layers to provide a long residence time of the preparation in oral cavity.
  • the amount of plasticizer added in the adhesive layer or protective layer is the amount of plasticizer added.
  • 0.1 to 10 % by weight preferably 2 to 8 % by weight, based on the respective weight of the adhesive layer or protective layer. If the amount is more than 10 % by weight, it affects adversely the film formation and drying process of adhesive layer and protective layer and makes it difficult to prepare the film.
  • 5 to 80 % by weight of a polyacrylic acid polymer, 5 to 70 % by weight of poloxamer and 5 to 80 % by weight of a cellulose derivative, based on the total weight of the polymers in the adhesive layer, are dissolved in a mixed solvent of water and ethanol to make a solution in which the concentration of the polymers is 5 to 20 % by weight based on the total weight of the adhesive layer.
  • 0.05 to 20 % by weight of a drug and 0.1 to 10 % by weight of a plasticizer for adhesive layer, based on the total weight of the adhesive layer, are added to the solution in turn to make a homogeneous coating solution for adhesive layer.
  • a water-insoluble and water-permeable polymer and 0.1 to 10 % by weight of a plasticizer for protective layer are dissolved in ethanol to make a homogeneous coating solution.
  • the coating solution for adhesive layer is coated on a release liner with a coater (Laboratory Drawdown Coater LC-100, Chem Instruments) and then dried to make an adhesive layer.
  • the coating solution for protective layer is also coated on the adhesive layer with a coater and then dried to make an oral mucoadhesive film consisting of an adhesive layer and a protective layer.
  • the oral mucoadhesive film of the present invention has a thickness ranging from 30 to 500 ⁇ m, preferably from 50 to 300 ⁇ m, when being dried, in which each thickness of an adhesive layer and a protective layer is 20 to 300 ⁇ m and 10 to 200 ⁇ m, respectively.
  • the film with the thickness of less than 30 ⁇ m has difficulty in maintaining the form of film and adversely affects favorable release of drug.
  • the film with the thickness of more than 500 ⁇ m gives a feeling of foreign substances to users.
  • the oral mucoadhesive film of the present invention may be prepared with the addition of the conventional lubricants, disintegrating agents, coloring agents, etc. according to the type of preparations. Brief Description of the Drawings
  • Fig. 1 is a schematic cross-sectional view of the oral mucoadhesive film consisting of an adhesive layer containing a drug and a protective layer.
  • Fig. 2 is a graph showing the dissolution rate of drug in Examples 1 and 2, Comparative Example 1 and Aftach tablet.
  • Fig. 3 is a graph showing the change of concentration of drug in the surface of tongue when the films of Example 1 and Control group 2 are attached to the tongue of rat.
  • Fig. 4 is a graph showing the change of concentration of drug absorbed into the tissue of tongue when the films of Example 1 and Control group 2 are attached to the tongue of rat.
  • Each of the solutions for adhesive layer and protective layer was prepared according to the compositions shown in the following Tables 1 and 2.
  • a polyacrylic acid polymer, poloxamer and a cellulose derivative were dissolved in a mixed solvent of water and ethanol to make a homogeneous solution, to which a drug and a plasticizer for adhesive layer were added and dissolved to obtain a homogeneous coating solution for adhesive layer.
  • a water-insoluble and water-impermeable polymer and a plasticizer for protective layer were dissolved in ethanol to make a homogeneous coating solution.
  • the solution for adhesive layer was coated on a release liner with a coater (Laboratory Drawdown Coater LC-100, Chem Instruments) and dried to obtain an adhesive layer.
  • the solution for protective layer was also coated on the adhesive layer with a coater and then dried to prepare an oral mucoadhesive film consisting of an adhesive layer and a protective layer and containing 25 ⁇ g of triamcinolone acetonide per one sheet of film.
  • the film has the thickness of 60 to 100 ⁇ m.
  • TAA Triamcinolone acetonide
  • CP940 Carbopol 940
  • CP974P Carbopol 974P
  • HPMC Hydroxypropylmethyl cellulose
  • PEG Polyethylene glycol EtOH: Ethanol
  • Triethyl citrate PU Polyurethane CO: Castor oil
  • Attach tablet (Dong Wha Pharm. Ind. Co., Ltd.), an oral mucoadhesive film which contains triamcinolone acetonide, hydroxypropyl cellulose and carboxyvinyl polymer in an adhesive layer and hydroxypropyl cellulose and calcium carboxymethyl cellulose in a protective layer, was selected as control group 1.
  • Innert plaster Sudo Pharm. Ind. Co., Ltd.
  • an oral mucoadhesive film which contains triamcinolone acetonide as a main component, was selected as control group 2.
  • Table 5 shows the adhesiveness and mechanical strength of each film.
  • the adhesiveness of film As the concentration of mucoadhesive polymers in adhesive layer increases from 8 to 10 %, the adhesiveness of film also increases. When the concentration increases over 10 %, however, the adhesiveness shows a little increase. Even in case of similar concentration of polymers, the films prepared from the compositions consisting of three polymers of poloxamer, carbopol and hydroxypropylmethyl cellulose (Examples 10, 1, 5 and 6) show more increased adhesiveness than those prepared from the composition consisting of one or two polymers (Comparative Examples 10, 2, 4 and 5).
  • the films prepared from the composition containing polyethylene glycol in adhesive layer and triethyl citrate in protective layer as a plasticizer show superior adhesiveness to those prepared from the composition containing castor oil and triethyl citrate in adhesive layer and protective layer (Comparative Examples 13, 18 and 22). Meanwhile, the composition containing triethyl citrate in adhesive layer may not be used to prepare a film (Comparative Example 17).
  • the films containing polyethylene glycol in adhesive layer and triethyl citrate in protective layer as a plasticizer show the most superior affinity between layers.
  • Such result is considered to be caused by the fact that polyethylene glycol is similar to poloxamer contained in adhesive layer in structure, and triethyl citrate to ethyl cellulose contained in protective layer.
  • Water content of film is calculated by the following formula:
  • Control group 1 Attach tablet
  • Control group 2 Innert plaster
  • FT-IR M. Series, Midac Corporation, USA
  • DMTA glass transition temperature
  • the IR peak derived from the hydrogen bond of poloxamer and carboxyl group of carbopol shifts from 1110 to 1 107 cm "1 and the Tg shown in the mixture of carbopol and hydroxypropylmethyl cellulose decreases from 190 to 170 °C.
  • Rectal mucous membrane of rabbit was attached to both vials of the apparatus for measurement of bioadhesiveness, and then films were attached therebetween.
  • the counterweight was weighed as bioadhesiveness when the vial was dropped (H. G. Choi, J. H. Jung, J. M. Ryu, S. J. Yoon, Y. K. Oh and C. K. Kim, Development of in situ-gelling and mucoadhesive acetaminophen liquid suppository, Int. J. Pharm., 165, 33-44, 1998).
  • Table 8 shows the bioadhesiveness measured as above.
  • PEG polyethylene glycol TEC: triethyl citrate CO: castor oil
  • the films prepared in Examples and Comparative Examples were cut and attached to glass wall of dissolution test vessel at a height of 5, 7.5 and 10 cm each. Detachment of each sample was observed in 900 ml of phosphate buffer (pH 6.8) at 37+ 0.5 °C with the rotation of paddle at 100 ⁇ m by applying method 2 of dissolution test. The attached time of control group was measured in the same manner. Table 9 shows the film thickness and attached time measured as above.
  • the films containing polyethylene glycol and triethyl citrate as a plasticizer show long attached time above 24 hours when they contain all three type of polymers in adhesive layer (Examples 1 and 9), which is longer than that of the films containing single or two polymers in adhesive layer (Comparative Examples 1 , 2 and 5).
  • the attached time varies from 6.0 to 24 hours in accordance with the type of plasticizer, which corresponds to the results from the adhesive force and bioadhesiveness.
  • Experiment 6 drug dissolution test
  • Dissolution solvent was mixture of phosphate buffer (pH 6.8) and ethanol (3:2, v/v). Sample solution was collected at regular intervals and the amount of released drug was analyzed by HPLC.
  • Fig. 2 is a graph showing the dissolution rate of drug in Examples 1 and 2, Comparative Example 1 and Aftach tablet.
  • each film was attached to the inside of lower lip of applicant and time required to be detached was measured. Further, feeling of use was evaluated when applied to oral mucous membrane and indicated by the following four stages:
  • Table 10 shows the attached time and feeling of use as measured above.
  • Control group 2 1.5 2.7
  • the film of Example 3 shows the longest adhesion time of 4.2 hours, and those of Examples 1 and 8 show the adhesion time of 3.8 and 3.0 hours, respectively, all of them show over 3 hours.
  • control group 1 (Aftach tablet) shows 3.2 hours of attached time
  • control group 2 Innert plaster
  • control group 3 Sematitis patch Taisho A
  • the films according to the present invention have superior initial adhesion to oral mucous membrane, show no swelling or detachment of polymers, and leave no remnants on oral mucous membrane during their adhesion and after being detached.
  • the films of control groups 1 and 2 show increase of swelling in polymers within several minutes after their adhesion to oral mucous membrane, which gives a notable feeling of foreign substances to users.
  • the film of control group 2 has a good initial adhesion, but the polymer layer in the film swells to be detached from the protective film, which augments the feeling of foreign substances and displeasure and also gives a bitter taste. Further, a portion of the detached polymer layer remains in oral cavity to make some problems.
  • Experiment 8 animal experiment (in vivo) Each oral mucoadhesive film of Example 1 and control group 2 was attached to the tongue of rats, and then each amount of drug remained in the surface of tongue and that absorbed into the tissue of tongue was assayed.
  • SPF male wister rats (Charles River, Japan, weigh 260 to 350 g) were used and five rats were placed in a group. After being anesthetized, each rat was provided with the films, and then was left freely. After a certain period of time, each tissue of tongue was removed and then analyzed. Each of the amount of drug remained in the surface of tongue and that absorbed into the tissue of tongue was determined by HPLC and LC/MS. As shown in Fig.
  • the film of Example 1 is superior to that of control group 2 in the maintenance of drug in the surface of tongue. Further, according to Fig. 4, the film of Example 1 shows a slowly increase of drug absorbed into the tissue of tongue with the lapse of time, and produces a superior result to that of Control group 2 in 2 hours.
  • the oral mucoadhesive film of the present invention is superior in physicochemical aspects such as adhesiveness, mechanical strength and attached time as well as bioadhesiveness. Further, the film shows sustained-release of drugs and gives long attached time and little feeling of foreign substances when attached to users. Moreover, the preparing process of the present invention is convenient for adjusting the film thickness and drying time.

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Abstract

L'invention concerne un nouveau film mucoadhésif oral contenant des polymères mucoadhésifs. Le film, comportant deux couches d'une couche adhésive renfermant des médicaments et une couche protectrice ayant fonction de protection et de support, colle aux muqueuses orales, les médicaments pouvant ainsi être absorbés de façon régulière par les muqueuses orales.
PCT/KR2003/000084 2002-01-16 2003-01-15 Film mucoadhesif oral WO2003059390A1 (fr)

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AU2003206143A AU2003206143A1 (en) 2002-01-16 2003-01-15 Oral mucoadhesive film

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KR1020020002577A KR100843001B1 (ko) 2002-01-16 2002-01-16 구강점막 부착형 필름제제
KR10-2002-0002577 2002-01-16

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CN102970974A (zh) * 2010-05-06 2013-03-13 卢福研究公司 用于治疗皮炎和牛皮癣的去炎松缩酮制剂
US8741333B2 (en) 2004-06-07 2014-06-03 Nuvo Research Inc. Compositions and methods for treating dermatitis or psoriasis
US8741332B2 (en) 2004-06-07 2014-06-03 Nuvo Research Inc. Compositions and methods for dermally treating neuropathic pain
US8907153B2 (en) 2004-06-07 2014-12-09 Nuvo Research Inc. Adhesive peel-forming formulations for dermal delivery of drugs and methods of using the same
US20150104493A1 (en) * 2012-10-22 2015-04-16 Robert W. McDonald, III Dissolvable Strip for Treatment of Oral Thermal Burns
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US11000473B2 (en) * 2016-08-08 2021-05-11 Pharmedica Ltd. Adhesive oral dissolved films in managing oral care
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WO2019018338A1 (fr) * 2017-07-17 2019-01-24 Northriver Pharm, LLC Composition nasale comprenant un polymère mucoadhésif
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