WO2003059390A1

WO2003059390A1 - Oral mucoadhesive film

Info

Publication number: WO2003059390A1
Application number: PCT/KR2003/000084
Authority: WO
Inventors: 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
Current assignee: Dong Wha Pharm Co Ltd
Priority date: 2002-01-16
Filing date: 2003-01-15
Publication date: 2003-07-24
Anticipated expiration: 2004-07-16
Also published as: KR100843001B1; KR20030062139A; AU2003206143A1

Abstract

The present invention relates to a new oral mucoadhesive film containing mucoadhesive polymers. The film, consisting of two layers of an adhesive layer containing drugs and a protective layer functioning as a protector and supporter, adheres to oral mucous membranes so that the drugs may be absorbed steadily through the oral mucous membranes.

Description

ORAL MUCOADHESIVE FILM

Technical Field

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.

Background Art

Contrary to skin, most of mucous membranes placed in gastrointestinal tract and oral cavity, etc. easily absorb active substances of large molecular weight such as peptides so that they are of great value for essential administration route of such active substances. Especially, drugs absorbed through oral mucous membrane or gum are not influenced by gastrointestinal effect and hepatic first- pass metabolism, and therefore, they are effectively used in oral diseases as well as other diseases requiring systemic effect.

Gels, one of drug administration preparations using oral mucous membrane, are usually used in treating ulcerative stomatitis, herpes simplex, etc.

However, gels are easily mixed with saliva and swell to lose the gel form quickly so that the amount of drugs absorbed in oral mucous membrane is less than that swallowed per os. Tablets, even though having the advantage of elongated time of maintaining the form, give a feeling of foreign substances to users due to their bulkiness and thickness as well as have the possibility to be swallowed with food during a mealtime. On the other hand, films are suitable to be oral mucoadhesive preparations since they are easy to use with little feeling of foreign substances, maintain the adhesiveness during the attached time for drug administration, and provide protection to the treatment time. In order to administrate drug through oral mucous membrane, the form of preparation containing the drug should be maintained within a certain period of time. Most of 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.

Among the polymers, polyacrylic acid and cellulose derivatives have excellent mucoadhesiveness (J. Pharm. Sci., 89(7), 850-866, 2000). However, 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). In the preparations having an adhesive layer containing sodium carboxymethyl cellulose, polyacrylic acid and hydroxyethyl cellulose (U.S. Patent No. 6,159,498), 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. Further, in case of the preparations containing hydroxypropylmethyl cellulose (U.S. Patent No. 5,948,430), the polymer has too high solubility in water to be used in the preparations which need to be attached for a long time. Considering the above, the introduction of new mucoadhesive polymers which maintain their forms and adhesiveness during the release of drugs is required in the development of oral mucoadhesive preparations. 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.

There is disclosed a method of preparing a mucoadhesive preparation containing three or four layers of adhesive layer, impermeable layer, drug reservoir layer and controlled release layer. The method 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). However, 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. Further, the film also has the defect that it has the thickness of about 800 μm, which is thicker than those of conventional oral mucoadhesive films, and gives the feeling of foreign substances when attached.

In case of a single layer film, the residence time of the preparation is affected as the mucoadhesive layer is exposed to water in oral cavity, which limits the use of the film only to delivery of rapid-acting drugs (U.S. Patent No. 5,948,430). Also disclosed is a film consisting of two layers of a protective layer and an adhesive layer, which lengthens the residence time of the preparation and increases the efficiency of drug absorption in mucous membrane, thereby somewhat solving the problem of single- or multiple-layered films. However, the double-layered film consisting of an adhesive layer containing vinyl acetate, polyacrylic acid, etc. and a protective layer containing polyethylene, aluminum, etc. (U.S. Patent No. 5,137,729) has some defects that the two layers are separated each other and that a feeling of foreign substances is given to users when attached. Further, 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) has decreased affinity between protective layer and adhesive layer, and also has different rate of hydration by saliva after being attached, which results in the possibility of separation of the two layer. Accordingly, 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.

Disclosed is 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. However, this method 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). Further disclosed is 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).

Considering the above-mentioned problems of oral mucoadhesive films, 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.

Disclosure of the Invention

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.

In accordance with one aspect of the present invention, it is provided 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 50 % by weight and the plasticizer in the protective layer is in an amount of 0.1 to 10 % by weight, based on the weight of the protective layer; and the film has a thickness ranging from 30 to 500 μm.

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. Further, 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 .

Examples of 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. Examples of 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. Examples of 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.

Examples of the plasticizer used in the adhesive layer are 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. Examples of 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.

Preferably used are such 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.

Examples of the water-insoluble and water-impermeable polymers are 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.

Examples of the plasticizer used in the protective layer are triethyl citrate (TEC), castor oil and polyethylene glycol (PEG), preferably polyethylene glycol and triethyl citrate.

The film according to the present invention consists of two layers of an adhesive layer and a protective layer, as illustrated in Fig. 1.

In the preparing process of an adhesive layer with excellent film-forming ability and mucoadhesiveness, 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.

Considering the above problems, 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.

The result of measuring the change of water contents in films prepared by adding poloxamer shows that the water contents decrease in films with an increase of poloxamer in the composition, thereby increasing the shape maintenance time in an aqueous solution (see Experiment 2). It is suggested that poloxamer and carbopol or hydroxypropylmethyl cellulose form a hydrogen bond, thereby forming a dense third-dimensional network structure.

The formation of hydrogen bond due to the addition of poloxamer can be confirmed by infrared spectrophotometer (IR), and the change of film flexibility can be identified by dynamic mechanical thermal analyzer (DMTA). It is confirmed that the characteristic peaks of poloxamer due to hydrogen bonds in IR change to short wave number with an increase of poloxamer in the composition. It is considered that the decrease of glass transition temperature, which shows the movement of molecules, compared to that of the mixture of hydroxypropylmethyl cellulose and carbopol, indicates the increase of film flexibility (see Experiment 3).

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. In the protective layer which protects the adhesive layer from saliva, 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.

In order to maintain the form of oral mucoadhesive film consisting of a mucoadhesive layer and a water-insoluble and water-impermeable protective layer until an active substance is released, coherence between the two layers is required for a long time.

According to the present invention, a proper plasticizer for each layer is selected in consideration of the mucoadhesiveness of adhesive layer and the affinity between the two layers. Examples of the plasticizer used in the adhesive layer of the present film are castor oil and polyethylene glycol (PEG). Examples of the plasticizer used in the protective layer of the present film are triethyl citrate (TEC), castor oil and polyethylene glycol (PEG).

When triethyl citrate is used in the adhesive layer, it is impossible to form a film. Castor oil and polyethylene glycol added in the adhesive layer have a good effect on the film formation and flexibility. In the adhesive layer, polyethylene glycol is better to be added than castor oil for a good adhesiveness.

Most preferred is 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

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.

The method of preparing the mucoadhesive film of the present invention are described as follows:

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.

Separately, 5 to 50 % by weight of a water-insoluble and water-permeable polymer and 0.1 to 10 % by weight of a plasticizer for protective layer, based on the total weight of the protective layer, are dissolved in ethanol to make a homogeneous coating solution. After being defoamed, 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.

After being defoamed, 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 μm, preferably from 50 to 300 μm, when being dried, in which each thickness of an adhesive layer and a protective layer is 20 to 300 μm and 10 to 200 μm, respectively. The film with the thickness of less than 30 μm has difficulty in maintaining the form of film and adversely affects favorable release of drug.

Further, the film with the thickness of more than 500 μm 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

The above and other objects, features and other advantages of the present invention will be more clearly understood from the following detailed description taken in conjunction with the accompanying drawings, in which:

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.

Best Mode for Carrying Out the Invention

Hereinafter, the present invention will be described in detail, in conjunction with various examples. These examples are provided only for illustrative purposes, and the present invention is not to be construed as being limited to these examples.

Examples 1 to 19

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.

Separately, a water-insoluble and water-impermeable polymer and a plasticizer for protective layer were dissolved in ethanol to make a homogeneous coating solution.

After being defoamed, 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. After removing bubbles, 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 μg of triamcinolone acetonide per one sheet of film. The film has the thickness of 60 to 100 μm.

Comparative Examples 1 to 12

The procedures of Examples were repeated using the following composition as shown in Table 3 to obtain a film consisting of an adhesive layer and a protective layer.

Comparative Examples 13 to 22

The procedures of Examples 1 to 10 were repeated except the type of plasticizer as shown in the following composition of Table 4 to obtain a film consisting of an adhesive layer and a protective layer.

In Tables 1 to 4, the abbreviations have the following meanings:

AL: Adhesive layer

PL: Protective layer

C.E.: Comparative Examples

Comp.: Component

TAA: Triamcinolone acetonide

P407: Poloxamer 407

PI 88: Poloxamer 188

CP971P: Carbopol 971P

CP934P: Carbopol 934P

CP940: Carbopol 940 CP974P: Carbopol 974P HPMC: Hydroxypropylmethyl cellulose PEG: Polyethylene glycol EtOH: Ethanol EC: Ethyl cellulose

TEC: Triethyl citrate PU: Polyurethane CO: Castor oil

Control group 1

Among the products on the market, 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.

Control group 2

Among the products on the market, 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.

Control group 3

Among the products on the market, Stomatitis patch Taisho A (Japan Taisho Pharm. Ind. Co., Ltd.), an oral mucoadhesive film which contains extract of Lithospermi Radix and enoxolone as main components, was selected as control group 3.

Experiment 1 : measurement of adhesiveness and mechanical strength

Each of the film samples prepared in Examples and Comparative Examples was attached to a polypropylene plate, and then the strength required to detach each film from the polypropylene plate was measured using Instron (AGS-

5000D, Shimadzu). Table 5 shows the adhesiveness and mechanical strength of each film.

Table 5

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). Further, the films prepared from the composition containing polyethylene glycol in adhesive layer and triethyl citrate in protective layer as a plasticizer (Examples 10, 1, 5 and 6) 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).

As a result, 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.

Mechanical strength shows no great change in proportion to the concentration of polymers in adhesive layer. Further, it is impossible to measure mechanical strength of other films except those containing polyethylene glycol and triethyl citrate in adhesive layer and protective layer, respectively, as a plasticizer (Examples 10, 1, 5 and 6), Experiment 2: measurement of water content and shape maintenance time of film

Water content and shape maintenance time of each film were measured in phosphate buffer (pH 6.8). Table 6 shows the results.

Water content of film is calculated by the following formula:

Water content (% by weight)=[(the weight of swollen film-the weight of dried film)/the weight of swollen filmjxlOO

As the proportion of poloxamer increases in composition, water content decreases but shape maintenance time of film increases.

Table 6

Control group 1 : Attach tablet Control group 2: Innert plaster

Experiment 3: infrared spectrophotometer (IR) and dynamic mechanical thermal analyzer (DMTA)

FT-IR (M. Series, Midac Corporation, USA) was used for IR of films and DMTA was used to measure glass transition temperature (Tg) in the temperature ranging from room temperature to 300 °C at the rate of 5 °C/min. Table 7 shows the results.

As the proportion of poloxamer increases in composition, 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.

Table 7

Films Wave number (cm^"1) Tg (°C) Poloxamer (%)

Comparative Example 8 1110 190 -

Experiment 4: measurement of bioadhesiveness

Rectal mucous membrane of rabbit was attached to both vials of the apparatus for measurement of bioadhesiveness, and then films were attached therebetween. Putting counterweights in turn on the opposite site, 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.

Table 8

PEG: polyethylene glycol TEC: triethyl citrate CO: castor oil

As shown in Examples of Table 8, when polyethylene glycol and triethyl citrate are added in adhesive layer and protective layer, respectively, as a plasticizer, the bioadhesiveness increases from 6.27 to 11.02 according to the increase of the concentration of polymer contained in adhesive layer. Meanwhile, the film containing polyethylene glycol and castor oil as a plasticizer (Comparative Example 14), that containing castor oil and triethyl citrate (Comparative Example 13), those containing castor oil and polyethylene glycol (comparative Examples 15 and 19), and that containing castor oil and castor oil (Comparative Example 16) show lower adhesiveness than those containing polyethylene glycol and triethyl citrate in adhesive layer and protective layer, respectively. Further, these films show no great change in adhesiveness to living body according to the increase of polymers.

Experiment 5: measurement of attached time

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 φm 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.

Table 9

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

Each oral mucoadhesive film was attached to cellulose membrane and then dissolution test was carried out using diffusion cell. 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.

Comparing the drug dissolution of the film of the present invention with that of control group 1 shows that the films of the present invention has more favorable drug dissolution than those on the market. Fig. 2 is a graph showing the dissolution rate of drug in Examples 1 and 2, Comparative Example 1 and Aftach tablet.

Experiment 7: evaluation of adhesiveness to oral mucous membrane

In order to evaluate the adhesiveness to actual oral mucous membrane, 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:

1 : little feeling;

2: a little feeling of foreign substances; 3: discomfort resulting from feeling of foreign substances; and

4: others (feeling of irritation, pain, etc.)

Table 10 shows the attached time and feeling of use as measured above.

Table 10

Films Adhesion time (hr) Feeling of use

Example 1 3.8 1.4

Example 3 4.2 1.7

Example 8 3.0 1.8

Comparative Example 1 1.2 1.5

Comparative Example 13 1.7 1.6

Comparative Example 22 1.4 1.9

Control group 1 3.2 2.8

Control group 2 1.5 2.7

Control group 3 3.5 2.1

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. The film containing carbopol only as a mucoadhesive polymer (Comparative Example 1) and that containing castor oil and triethyl citrate as a plasticizer for adhesive layer and protective layer, respectively (Comparative Example 13), have the adhesion time ranging from 1.2 to 1.7 hours, which are shorter than those of the above Examples. Further, control group 1 (Aftach tablet) shows 3.2 hours of attached time, control group 2 (Innert plaster) shows 1.5 hours and control group 3 (Stomatitis patch Taisho A) shows 3.5 hours.

While the control groups give a feeling of foreign substances when attached to oral mucous membrane, the films prepared in Examples and

Comparative Examples give no feeling of foreign substances.

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. Meanwhile, 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. Especially, 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. 3, 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. Industrial Applicability

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.

Claims

What is Claimed is:

1. 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 50 % by weight and the plasticizer in the protective layer is in an amount of 0.1 to 10 % by weight, based on the weight of the protective layer; and the film has a thickness ranging from 30 to 500 μm.

2. The oral mucoadhesive film according to claim 1, wherein the polyacrylic acid polymer is one or more selected from the group consisting of carbopol series 980, 934, 940, 941, 934P, 971P, 974P, 981, 1342, 1382, 2984 and 5984EP, and Noveon series AA-1, CA-1 and CA-2; the poloxamer is one or more selected from the group consisting of poloxamer series 124, 188, 338 and 407; the cellulose derivative is one or more selected from the group consisting of hydroxypropyl cellulose, hydroxymethyl cellulose, hydroxyethyl cellulose, hydroxypropylethyl cellulose and hydroxypropylmethyl cellulose; the drug is one or more selected from the group consisting of medicines for oral diseases, anti-inflammatory agents, anti-histamines, hormones, antihypertensive agents, bronchodilators and anesthetics; the plasticizer in the adhesive layer is polyethylene glycol; the water-insoluble and water-impermeable polymer is one or more selected from the group consisting of polyester, polyurethane, polyethylene and ethyl cellulose; and the plasticizer in the protective layer is triethyl citrate.

3. The oral mucoadhesive film according to claim 2, wherein the polyacrylic acid polymer is one or more selected from the group consisting of carbopol series 934P and 97 IP; the poloxamer is one or more selected from the group consisting of poloxamer series 188 and 407; the cellulose derivative is one or more selected from the group consisting of hydroxypropylethyl cellulose and hydroxypropylmethyl cellulose; the drug is medicines for oral diseases; and the water-insoluble and water-impermeable polymer is one or more selected from the group consisting of polyurethane and ethyl cellulose.

4. The oral mucoadhesive film according to one of claims 1 to 3, wherein the weight ratios of poloxamer/polyacrylic acid polymer and poloxamer/cellulose derivative range from 1: 1 to 1: 1.5, respectively; the water-insoluble and water- impermeable polymer is in an amount of 10 to 30 % by weight based on the weight of the protective layer; and the film has a thickness ranging from 50 to 300 μm.

5. A method of preparing an oral mucoadhesive film containing an adhesive layer and a protective layer, which comprises:

(1) dissolving 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, 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, and then adding 0.05 to 20 % by weight of a drug and 0.1 to 10 % by weight of a plasticizer for the adhesive layer, based on the total weight of the adhesive layer, to the solution to make a homogeneous coating solution for the adhesive layer; (2) dissolving 5 to 50 % by weight of a water-insoluble and water- impermeable polymer and 0.1 to 10 % by weight of a plasticizer for the protective layer, based on the total weight of the protective layer, in ethanol to make a homogeneous coating solution for the protective layer;

(3) defoaming the coating solution for the adhesive layer prepared by (1), coating the solution on a release liner with a coater, and then drying the coated layer to make the adhesive layer; and (4) defoaming the coating solution for the protective layer prepared by (2), coating the solution on the adhesive layer prepared by (3) with a coater, and then drying the coated layer to make the oral mucoadhesive film.

6. The method according to claim 5, wherein the weight ratios of poloxamer/polyacrylic acid polymer and poloxamer/cellulose derivative range of from 1 : 1 to 1 : 1.5, respectively; the water-insoluble and water-impermeable polymer is added in an amount of 10 to 30 % by weight based on the weight of the protective layer; and the film has a thickness ranging from 50 to 300 μm.