WO2016079246A1 - Bioadhesive films - Google Patents

Abstract

The present invention relates to a film comprising i) a film-forming hydrophilic polymer that is soluble in a solvent, ii) a bioadhesive substance that is slightly soluble in said solvent, iii) optionally, a drug substance.

Description

Bioadhesive films Field of the invention

The present invention relates to bioadhesive films especially suitable for application to the oral cavity. The bioadhesive films comprise a film-forming polymer, a bioadhesive substance and optionally, a drug substance. The formulation principle ensures the presence of the bioadhesive substance in the film in the form of solid material, which enables in situ swelling of the bioadhesive substance upon contact with eg saliva in the oral cavity. The film may be provided with one or more further layers, eg a backing lay- er that is insoluble in water or saliva and/or a layer that may influence the release of the drug substance from the final composition.

Moreover, the films are suitable for local application to internal wet surfaces such as vocal cord, vagina or the bowel eg for treatment of inflammatory bowel disease. Nota- bly, the invention relates to films for application to the oral cavity to deliver a drug substance to the oral mucosa.

Background of the invention

One or the major problems relating to treatment of diseased in the skin or mucosa is to deliver a correct amount of the drug substance to the diseased skin or mucosa. Compositions for use in the treatment of diseases in the skin or mucosa are very often in the form of a creme, an ointment or a gel, which is applied by the patient by spreading a variable amount of the composition on a diseased area of variable size, and the composition is spread on the area in a layer of variable thickness.

Accordingly, it is normally very difficult to obtain reliable results regarding eg relationship between dose and effect, inter- and intraindividual variations etc.

Transdermal systems like plasters are normally used for drug substances that must penetrate the skin, i.e. they are not intended for use in the treatment of diseases of the skin or mucosa, where the drug substances should act locally on or within the skin or mucosa. US 4,765,983 relates to an adhesive medical tape for use in stomatitis. The tape comprises a support layer consisting of an intestine soluble polymer and at least one medicament-containing layer consisting essentially of a water-soluble polymer containing a steroid, an anti-inflammatory substance, an antibiotic, a local anaesthetic or a protein. The variability of dosage makes it very difficult to control treatment of a skin or mucosa disease and to make a correct decision regarding continuing or discontinuing treatment as it eg may be difficult to judge the benefit/risk profile for the treatment. If eg systemic side effects are observed then it is difficult to know whether the side-effects are due to over-dosing (the patient applies a too large dose by eg spreading the composition over a too large area, or the patient spreads the composition in a too thick layer) or whether the side-effects can only be avoided by termination of the treatment. Under-dosing may also be a problem in the topical therapy, especially when creams, ointments, lotions or other liquid or semi-liquid compositions are used. In general, 30% of patient undergoing topical treatment is subject to under-dosing.

In order to have a pharmaceutical composition approved by the regulatory health authorities, substantial documentation relating to the therapeutic effect, indication, side effects, toxic effects, dosages etc. is required. To this end it would be advantageous if effects relating to variability in dosages could be avoided or substantial reduced, i.e. if it is possible to ensure that the dose applied is controlled and not subject to the judgement of the patient applying the composition (eg area, thickness, frequency etc.). In this manner a more reliable benefit/risk profile could be obtained.

Moreover, in order to be effective the compositions for use in the treatment of diseases in the mucosa must stay on the diseased site for a specific period of time. Often compositions like eg films are not intended to be used in the treatment of diseased in the oral cavity, but are used to obtain a relatively fast absorption into the systemic circulation. Films normally disintegrate relatively fast, which either makes them unsuitable for use or they may be applied many times daily. Another problem relates to administration to the oral cavity or other mucosa located in a humid environment such as vagina, ocular mucosa etc. Many diseases are located to the oral cavity and require local treatment (eg oral lichen planus). Such treatment is often by use of solutions, cremes, pastes, or ointments, where it is administered by spreading the composition on the diseased area with a finger. In addition to the disadvantages mentioned above, saliva produced by the salivary glands together with movements of the tongue tend to remove the composition from the administration site and will reduce the effect of the treatment. Thus, there is a need for developing compositions for treatment of a disease located to the skin or mucosa, wherein the compositions are designed in such a manner that a specific dose easily can be applied to the diseased area. Notably, the composition may stay on the application site for a prolonged period of time. Detailed description of the invention

The present inventors have found a method by which it is possible to obtain improved adhesion to eg the oral mucosa. The idea behind the invention is to make use of different physico-chemical properties of a film-forming substance and a bioadhesive substance, respectively. The invention provides a film with a relatively large content of bio- adhesive substance in order to obtain a strong bioadhesive effect. The bioadhesive effect is often obtained by use of substances that swell upon contact with water and which have binding properties eg like binding agents used in tablet technology. Such substances are also used today in formulation of films, but during manufacture, the bioadhesive substance is dissolved in aqueous medium, which means that the bioad- hesive substance swells. Although the material during manufacture is dried the initial swelling has occurred and the film-forming substance and the bioadhesive substance are part of the network in the film. Moreover, the concentration of the bioadhesive substance in such a film has an upper limitation in order to avoid any negative influence on the ability of the film-forming substance to form a film and to manufacture the film However, in contrast to known films, the bioadhesive substance contained in a film of the present invention has not been swelled during the processing. Accordingly, the concentration of the bioadhesive substance in the film has, if any, only minor impact on the film-forming agent's ability to form a film, and the bioadhesive properties of the bio- adhesive substance have not been affected in any way, as the bioadhesive substance has not been pre-swelled during manufacturing of the film. Due to the content on the outer surface (facing the mucosa) of undissolved bioadhesive substance, the outer surface will expand upon contact with water or saliva and due to the uneven structure the grip on the mucosa will be improved. This larger and uneven surface area together with a suitable high concentration of bioadhesive substance in the film enables a stronger bioadhesive effect.

The present invention provides a film comprising

i) a film-forming substance that is soluble in a solvent,

ii) a bioadhesive substance that is slightly soluble in said solvent,

iii) optionally, a drug substance.

The film is intended for medical use and for application to the skin or mucosa, notably the oral mucosa.

As mentioned above, an important feature of the present invention is to use a combination of a film-forming substance and a bioadhesive substance, where the two substances have different solubilities in specific solvents. Thus, the film-forming substance must be soluble in a solvent, whereas the bioadhesive substance should not dissolve or at least only a small amount of the bioadhesive substance should dissolve.

The solvent may be C1 -C3 alkanol such as methanol, ethanol, propanol or isopropanol, or mixtures thereof. The solvent or solvent mixture may also contain at the most 20% v/v of an aqueous medium such as water.

In some cases, the solvent is ethanol or ethanol-water mixtures. Ethanol may contain up to 20% v/v water, normally about 3-10% v/v. The solvent or solvent mixture (in the following commonly denoted "solvent") used in the preparation of the film. Thus, to cast the film the ingredients are contained in the solvent; the film-forming agent is dissolved in the solvent and the bioadhesive substance is in undissolved form or at least 90% w/w of the bioadhesive substance is in undissolved form. The ingredients are dissolved/dispersed in the same type of solvent, but may be applied in the casting process as one, two or three different mixtures.

The solubilities of the film-forming substance and the bioadhesive substance in the solvent used are important in order to obtain the desired properties of a film of the inven- tion. Thus, the film-forming substance must have a solubility in a first solvent of 3 g/100 ml or more at 25 °C or 10 g/100 ml or more at 25 °C, and the bioadhesive substance must have a solubility in said first solvent of 0.5 g/100 ml or less at 25 °C or 0.1 g/100 ml or less at 25 °C. Due to the difference in solubility, the bioadhesive substance is attached to the film as small particles. A small amount of the bioadhesive substance may be dissolved in the solvent and may therefore be an integral part of the film, but in order to achieve maximal bioadhesive effect, it is contemplated that the bioadhesive substance is attached to/included in the film.

Dependent on the properties of the drug substance it may be an integral part of the film or may be attached to the film. Thus, if the drug substance is soluble in the solvent used and capable of forming film, then it may be an integral part of the film. If these conditions not are present the drug substance may be attached to the film (eg in a sep- arate layer) or it may be present in adherent to the film.

In the present context the term "integral part of the film" means that the drug substance together with the film-forming hydrophilic polymer form the film. As mentioned herein, a hydrophobic film may be applied on top of the hydrophilic film in order to ensure that the drug substance after application to the mucosa penetrates the mucosa and does not significantly leaches out to eg the oral cavity (if the film is applied on the oral mucosa) The film-forming polymer is a hydrophilic polymer, which is the basic ingredient in the film and is the ingredient that has the ability to form a film. In order to avoid any confusion with other ingredients present in a film the term "film-forming hydrophilic polymer" is used in the following. The film-forming hydrophilic polymer is suitably a polymer that is soluble in or forms a gel in a C1-C3 alkanol such as methanol, ethanol, propanol or isopropanol, notably ethanol, propanol or isopropanol. The casting process requires that the polymer, which is the main component of the film, is in dissolved form to allow a casting process resulting in a homogeneous film (with respect to thickness, dose distribution, properties etc.).

Suitable film-forming hydrophilic polymers are polyvinylpyrrolidone (PVP), acrylates and acrylic copolymers (eg Eudragit®), and mixtures thereof. Other polymers like eg ethylcellulose (EC), hydroxypropylcellulose (HPC), or mixtures thereof may also be used. Ethylcellulose (EC), hydroxypropylcellulose (HPC), or mixtures thereof may es- pecially be used in combination with polyvinylpyrrolidone (PVP) and/or acrylates in- cludeing acrylic copolymers (eg Eudragit®) In the examples especially PVP and acrylic copolymers have been used.

Polyvinylpyrrolidone can be used in a grade having an approximate molecular weight of from 2,500 Da to 3,000,000 Da (eg Povidone with K-values of from 12 to 120). PVP can be purchased as Kollidon®:

In the low MW-range suitable grades are contemplated to have a MW of from about 25,000 to about 120,000 Da, notably from about 70,000 to about 100,000 Da. In the examples herein Kolllidon® 90F has mainly be used and accordingly, a preferred PVP has a Mw of from about 900,000 - about 3,000,000, notably from about 1 ,000 to about 1 ,500,000. Ethylcellulose is sold under the trademark ETHOCEL™ (Dow Chemical Company) and is available in many different grades. Dow Chemical Company produces ethylcellulose in two ethoxyl types (denoted Standard and Medium). Dependent on its ethoxyl content ethylcellulose may have different softening point and melting point temperatures. Ethyl- cellulose is also produced in a number of different viscosities. In the table below is given a listing of available ethylcelluloses.

ETHOCEL polymers

In plasticized form it has excellent thermoplasticity and is useful for compositions made by molding, extrusion or lamination. Ethylcellulose is also an excellent film- former and is used in coating of eg tablets. The above-mentioned ethylcellulose qualities have an ethoxyl content of at least 45.0% and, accordingly they are soluble in eth- anol and practically insoluble in water. Acrylates and acrylic acid derivative include polymethacrylates, methacrylate copolymers, acrylic copolymers and methacrylate polymers. Preferred acrylates are those sold under the trademark EUDRAGIT®, which are soluble in ethanol, or acry- lates/octaacrylamide copolymer (sold under the name DERMACRYL 79). These in- elude EUDRAGIT®E 12,5 (amino methacrylate copolymer), EUDRAGIT® E100 (amino methacrylate copolymer; basic butylated methacrylate copolymer), EUDRAGIT®E PO ((amino methacrylate copolymer), EUDRAGIT®L 100-55, EUDRAGIT®L 100 (meth- acrylic acid - methyl methacrylate copolymer 1 :1 ), EUDRAGIT®S 100 (methacrylic acid-methyl methacrylate copolymer 1 :2), EUDRAGIT®RL 100, EUDRAGIT®RL 100 (ammonio methacrylate copolymer type A), EUDRAGIT®RL PO, EUDRAGIT®RS 100 (ammonio methacrylate copolymer type B), EUDRAGIT®RS PO. EUDRAGIT®E is a cationic polymer based on dimethylaminoethyl methacrylate and other neutral methacrylic acid esters: EUDRAGIT®L and S are methacrylic acid copolymers and are cationic copolymerization products of methacrylic acid and methyl methacrylate. EU- DRAGIT®RL or RS is ammonio methacrylate copolymers synthesized from acrylic acid and methacrylic acid.

EUDRAGIT® E 100 is soluble up to pH 5.5 and E 12.5 is soluble above pH 5. EUDRAGIT® L30 D-55, L-100-55 (methacrylic acid - ethyl acrylate copolymer 1 :1 ), L 100, L 12,5, are normally used in enteric formulations, but may be used in order to delay release of the drug substance from film of the invention. EUDRAGIT® L30 D-55, and L-100-55 dissolve at a pH about 5.5 and the grades L 100 and L 12,5 dissolve at pH 6 or above.

As the pH in saliva normally is about 5-6 these polymers are of interest for films for mucosal use such as eg oral, dermal or vaginal use. If sustained or prolonged release is desired polymers being soluble at lower of higher pH may be more suitable for use. EUDRAGIT® products are also available for sustained-release formulations and such grades may be of interest to incorporate in films of the invention either alone or together with another hydrophilic polymer. Relevant grades belong to the RL, RS, NE and NM series such as RL 100, RL PO, RL 30D, and RL 12,5, RS 100, RS PO, RS 30D, and RS 12,5, NE 30D and NE 40D, and NM 30D. EUDRAGIT® RL 100 / EUDRAGIT® RS 100

Solid substances. EUDRAGIT® RL 100 (Type A) and EUDRAGIT® RS 100 (Type B) are described in the monographs quoted above. EUDRAGIT® RL PO / EUDRAGIT® RS PO

Solid substances obtained from EUDRAGIT® RL 100 or EUDRAGIT® RS 100. EUDRAGIT® RL PO (Type A) and EUDRAGIT® RS PO (Type B) are described in the monographs quoted above. Chemical structure

EUDRAGIT® RL 100 / RL PO and EUDRAGIT® RS 100 / RS PO are copolymers of ethyl acrylate, methyl methacrylate and a low content of a methacrylic acid ester with quaternary ammonium groups (tnmethylammonioethyl methacrylate chloride). The ammonium groups are present as salts and make the polymers permeable. The molar ratio of ethyl acrylate, methyl methacrylate and tnmethylammonioethyl methacrylate is approx. 1 :2:0.2 in EUDRAGIT® RL and approx. 1 :2:0.1 in EUDRAGIT® RS.

The monomers are randomly distributed along the copolymer chain. Based on SEC method the weight average molar mass (Mw) of EUDRAGIT® RL 100, EUDRAGIT® RL PO, EUDRAGIT® RS 100 and EUDRAGIT® RS PO is approximately 32,000 g/mol.

Characters

EUDRAGIT® RL 100 and EUDRAGIT® RS 100: colourless, clear to cloudy granules with a faint amine like odour.

EUDRAGIT® RL PO and EUDRAGIT® RS PO: white powder with a faint amine-like odour. Solubility

1 g of the substances dissolves in 7 g aqueous methanol, ethanol and isopropyl alcohol (containing approx. 3 % water), as well as in acetone, ethyl acetate and methylene chloride to give clear to cloudy solutions.

The substances are practically insoluble in petroleum ether, 1 N sodium hydroxide and water.

Assay

Ph. Eur.:

EUDRAGIT® RL 100 and RL PO: 8.9 - 12.3 % ammonio methacrylate units on DS. EUDRAGIT® RS 100 and RS PO: 4.5 - 7.0 % ammonio methacrylate units on DS. The test is performed according to the Ph. Eur. monograph. Viscosity / Apparent viscosity

1 - 15 mPa ^* s

The viscosity of the Test solution is determined by means of a Brookfield viscometer (UL adapter / 30 rpm / 20 °C).

The test is performed according to Ph. Eur. 2.2.10 or USP <912> method II.

EUDRAGIT L 100-55

Solid substance. The product contains 0.7% Sodium Laurilsulfate Ph. Eur. / NF and 2.3% Polysorbate 80 Ph. Eur. / NF on solid substance. EUDRAGIT® L 100-55 is described in the monographs quoted above.

EUDRAGIT® L 100-55 is the dry substance obtained from EUDRAGIT® L 30 D-55.

Chemical structure

EUDRAGIT® L 100-55 contains an anionic copolymer based on methacrylic acid and ethyl acrylate. The ratio of the free carboxyl groups to the ester groups is approx. 1 :1 .

C2H5

n

The monomers are randomly distributed along the copolymer chain. Based on SEC method the weight average molar mass (Mw) of EUDRAGIT® L 100-55 is approx. 320,000 g/mol.

Characters

White powder with a faint characteristic odour. Solubility

1 g of EUDRAGIT® L 100-55 dissolves in 7 g methanol, ethanol, isopropyl alcohol and acetone, as well as in 1 N sodium hydroxide to give clear to cloudy solutions.

EUDRAGIT® L 100-55 is practically insoluble in ethyl acetate, methylene chloride, pe- troleum ether and water.

Viscosity / Apparent viscosity

100 - 200 mPa ^* s

The viscosity of the Test solution is determined by means of a Brookfield viscometer (Spindle 1 / 30 rpm / 20 °C).

The test is performed according to Ph. Eur. 2.2.10 or USP <912> method I.

Hydroxypropylcellulose is a non-ionic water-soluble cellulose ether. It combines organic solvent solubiltiy, thermoplasticity and surface activity and that thickening and stabiliz- ing properties. The films are flexible and non-tacky at high humidity. Hydroxypropylcellulose is sold under the name KLUCEL™. In the present context, the preferred film-forming hydrophilic polymers are selected from PVP, hydroxypropylcellulose (HPC), acrylates and acrylic acid derivatives, and mixtures thereof. The concentration of the film-forming hydrophilic polymer(s) in the films according to the invention is normally from about 40% to about 92% w/w notably from about 50 to about 85% w/w or from about 60% to 75% w/w.

A film of the invention also contains a bioadhesive substance. In order to ensure an easy manufacture of the film and to obtain the desired bioadhesive properties in situ after application to the mucosa, it is important that the bioadhesive in itself does not contribute significantly to the viscosity of a solution containing the film-forming polymer.

In the present context, the term "bioadhesive" or "bioadhesion" indicates attachment to a specified biological location such as to the surface of the skin, a lip or a mucosal surface. A bioadhesive substance imparts bioadhesiveness to the drug-containing film of the invention or, in certain cases it may be included in a composition of the invention eg as a separate layer, which - after application - is the inner layer facing the skin or mucosa, i.e. the layer that is in contact with the skin or mucosa.

The bioadhesive substance for use in the present context can be selected from dex- tran, polyethylene oxides, alginate, tragacanth, carrageenan, pectin, methylcellulose, hydroxypropylmethylcellulose (HPMC), carboxymethylcellulose and alkali salts thereof, polymers of acrylic acids (PAA derivatives), chitosan, lectins, thiolated polymers, poly- ox WSRA, PAA-co-PEG (PEG is polyethylene glycol), and mixtures thereof.

In general it is expected that the adhesive effect of polymers increases with increasing molecular weight. Thus, in general adhesive polymers having relatively high molecular weight are preferred.

Polyethylene oxide can be used in grade having an approximate molecular weight of from 100,000 to 4,000,000. Preferred grades have an average molecular weight of from about 700,000 to about 4,000,000. Polyethylene oxide is sold under the name POLYOX™ (Dow Chemical Company) with molecular weights ranging from 100,000 to 7,000,000 Da. Dextran can be used in grade having an approximate molecular weight of from 400,000 Da to about 2,000,000 Da. Preferred dextrans have a molecular weight of from about 500,000 to about 1 ,000,000 notably from about 700,000 to about 800,000 or from about 1 ,000,000 to about 2,000,000 Da.

Cellulose derivatives include hydroxypropylmethylcellulose, methylcellulose and car- boxymethylcellulose. Methylcellulose is sold under the name METHOCEL™ (Dow Chemical Company) and is available in a wide range of viscosity grades (from less than 3 to over 100,000 mPA^*s).

HPMC is sold in various qualities depending on the viscosity. HPMC is sold under the names Metocel® and Klucel®. A suitable HPMC has an average molecular weight from about 80,000 to about 140,000.

Carboxymethylcellulose is available in a broad selection of grades. The viscosity ranges from 10 to 100,000 mPa^*s. It is also available as its sodium salt with a broad range of substitution levels. Dow Chemical Company sells sodium carboxymethylcellulose under the name WALOCEL™.

Polyvinylalcohol can be used in grade having an approximately molecular weight of from 20,000 Da to 200,000 Da.

Preferred bioadhesive substances are polyethylene oxides, dextrans, or combinations thereof.

The inclusion of a bioadhesive substance in the film according to the invention makes is possible to obtain a final formulation that is bioadhesive and can remain on the skin or mucosal surface for a prolonged period of time without falling off.

The amount of the bioadhesive substance in the film per surface area is important in order to ensure a suitable bioadhesion. The concentration of the bioadhesive substance in the film is from about 5% to about 60% w/w, notably from about 8% to about 50% or from about 10% to about 40% w/w.

The present inventors have found that the weight ratio between the bioadhesive sub- stance and the film-forming polymer in the film should be in a range of from 0.2 to 10. It may depend on the particular film-forming polymer and the particular bioadhesive substance used, but the above mentioned range is normally applicable. The ratio will to a certain degree depend on the bioadhesive substance chosen so that the higher bioadhesive potential, the bioadhesive substance has, the lower ratio is required and vice versa. The numbers given are, however, regarded as general guidance.

The present inventors have found that the weight ratio between the bioadhesive substance and the hydrophilic polymer in the film should be in a range of from 0.1 to 10 such as from 0.2 to 10. It may depend on the particular hydrophilic polymer and the particular bioadhesive substance used, but the above mentioned range is normally applicable. The ratio will to a certain degree depend on the bioadhesive substance chosen so that the higher bioadhesive potential, the bioadhesive substance has, the lower ratio is required and vice versa. The numbers given are, however, regarded as general guidance. In the examples herein further examples are given. In particular suitable re- suits have been obtained when the weight ratio between the bioadhesive substance and the hydrophilic polymer is from 0.1 to 4 or from 0.1 to 2.

A film according to the invention may also contain a drug substance. The drug substance is selected from drug substances, which are indicated for treatment of a disease of the skin, lip, or mucosa, or in the case, where the films are included in compositions for application on an internal surface as described here, the drug substance may be any drug substance that is indicated for the specific treatment. In the present context, the drug substance may be selected from drug substances, which are indicated for treatment of a disease in the oral cavity such as a drug substance that is indicated for local treatment of a disease in the oral cavity. Drug substances of particular interest are mentioned herein. The drug substance may be present in dissolved, undissolved or partly dissolved form dependent on the drug solubility in the film-forming polymer and bioadhesive substance used. A film according to the invention may also contain one or more pharmaceutically acceptable excipients including those mentioned herein. Besides the excipients mentioned herein below, the film may contain a plasticizer. The plasticizer imparts a certain plasticity to the film, it facilitates the manufacturing process and/or it improve the flexi- bility and processability of the film-forming polymer(s). Examples of suitable plasticizers are citric acid esters like acetyl triethyl citrate, tributyl citrate or triethylcitrate, castor oil, diacetylated monoglycerides, dibutyl sebacate, diethyl phthalate, sorbitol, glycerol or glycerol derivatives like triacetin or tributyrin, a cellulose derivative like cellulose nitrate, glycols like polyethylene glycols notably polyethylene glycols with a molecular weight from about 100 to about 1500, polyethylene glycol monomethyl ether, propylene glycol, or mixtures thereof.

Wetting agents may also be included in the film to increase the wetting of the drug substance in the film and thereby increase the release rate of the drug substance from the film. Suitable wetting agents are eg polysorbates such as Tween 20 or 80.

A plasticizer may affect the release rate of the drug substance. Accordingly, a plasticizer may also be regarded as a release rate modifier. Normally, a change in concentration of plasticizer will affect the release rate. Normally and if present the concentration of a plasticizer in the film is in a range of from 0 to about 10% w/w such as from about 0.5 to about 5% w/w.

The film may also contain a solubility improving agent in order to adjust or manipulated the release rate of the drug substance from the film. If present, the drug substance is dissolved in the solubility-improving agent and, optionally in one or more volatile solvents, notably a C1-C3 alkanol, before fed into the apparatus making the film. In this manner it is ensured that the solubility improving agent containing drug substance is located within the film. Suitable solubility improving agents include a polyoxyethylene fatty alkyl ester, an isopropyl ester of a straight or branched CS-CM fatty acid, a propyl- ene glycol mono- or diester of a CS-CM alkanol or alkenol, a straight or branched C8-C24 alkanol or alkenol, a C6-C22 acylglyceride, N-alkylpyrrolidone or N-alkylpiperidone, and a mineral oil such a paraffin.

The polyoxyethylene fatty alkyl ester is suitably selected from the group consisting of polyoxyethylene-15-stearyl ether, polyoxyethylene-1 1 -stearyl ether, polyoxyethylene- 14-butyl ether, polyoxyethylene-10-cetyl ether, and polyoxyethylene-3-myristyl ether. The isopropyl ester of a straight or branched CS-CM fatty acid is isopropyl myristate, isopropyl palmitate, isopropyl isostearate, isopropyl linolate or isopropyl monooleate. The propylene glycol mono- or diester of a CS-CM alkanol or alkenol is propylene glycol monolaurate, propylene glycol monocaprylate or propylene glycol dipelargonate.

The straight or branched C8-C24 alkanol or alkenol may be capryl, lauryl, cetyl, stearyl, oleyl, linoyl or myristyl alcohol or 2-octyldodecanol.

The C6-C22 acylglyceride is a vegetable oil eg sesame oil, sunflower oil, palm kernel oil, corn oil, safflower oil, olive oil, avocado oil, jojoba oil, grape kernel oil, canola oil, wheat germ oil, almond oil, cottonseed oil, peanut oil, walnut oil or soybean oil, a highly purified vegetable oil eg medium chain triglycerides (caprylic/capric triglycerides), long chain triglycerides, castor oil, caprylic monoglyceride, caprylic/capric mono- and diglyc- erides or caprylic/capric mono-, di- or triglycerides.

N-alkylpyrrolidone is typically N-methylpyrrolidone and N-alkylpiperidone is typically N- methylpiperidone.

The solubility-improving agent may also be a fatty acid such as a medium, long or very long chain fatty acid including oleic acid and linoleic acid.

The thickness of the film may be varied depending on the intended use. In order to en- sure a suitable strength of the film, the thickness normally is in a range of from micrometer to about 5 mm. The thickness is like the thickness of paper.

The thickness of the film is the same throughout the length and width of the film. In the present context the term "same" means that the difference in thickness over a length of 1 m and a width of 1 m is at the most 15%.

The thickness of the film or the amount of film per square meter may have influence on the bioadhesion. Thus, a decrease in the amount of film per square meter will result in a poorer bioadhesion and vice versa. The bioadhesive substance and the drug substance are homogeneously distributed in the film, which means that each the concentration of the substances carried by the film (bioadhesive substance, drug substance and optionally the substances/additives mentioned herein) is the same per surface area, wherein the surface area is measured as length x width of a given part of the film. The hydrophilic film may be provided with a lipophilic film layer to reduce the water-solubility of the hydrophilic film.

A film contains an amount of the bioadhesive substance and the drug substance and, if other additives or ingredients have been employed, such a substance will also be part of the film.

The release of the drug substance from the film may be immediate release or modified release dependent on the specific drug substance and the intended use. The release rate may be adjusted eg to obtain a slower release by

i) use of film-forming polymer(s) with an increased average molecular weight, ii) use of film-forming polymer(s) normally intended for use in sustained release compositions or enteric coated compositions,

iii) use of a mixture of film-forming polymers, wherein at least one of the polymers is insoluble in water or saliva

iv) increasing the concentration of bioadhesive substance to obtain a more compact film upon application to eg the oral cavity, where the bioadhesive substance swells, v) cross-linking of the film-forming polymer (in the film),

iii) increasing the thickness,

iv) applying a further layer eg of hydrophobic material on the film, which hydrophobic layer is intended to be applied closest to the oral mucosa and thus retarding the release of drug substance from the film.

A suitable hydrophobic material that can be used as a backing layer is

poly(caprolactone).

Analogous, the release rate may be adjusted eg to obtain a faster release by i) use of film-forming polymer(s) with an decreased average molecular weight, ii) decrease the amount of bioadhesive substance to decrease the compactness of the swelled film,

iii) increasing concentration of solubility-improving substance

iv) increase porosity of the film, v) decreasing the thickness of the film.

The films according to the invention can be used in medicine, notably for the treatment of a disease located to the skin or mucosa.

In a specific aspect, the films according to the invention are for use in the treatment of diseases of the oral cavity, notably for local treatment of the oral mucosa.

The invention also relates to pharmaceutical compositions comprising the hydrophilic film, to methods for obtaining the film and to use of the film and the pharmaceutical composition in medicine.

The use of films in medicine offer one or more of the following advantages:

i) It is possible to improve the therapeutic effect e.g. designing the compositions as a controlled release composition. In this manner the drug substance is released from the composition over a prolonged period of time and peak concentration of the drug substance at the applied site is avoided; such peak concentrations are very often responsible for un-desired effects such as irritation.

ii) The film is dry, i.e. there is no or only small amounts of water present in the composition. Moreover, the semi-solid compositions that normally are used for treatment of a disease in the skin or mucosa may contain excipients like vegetable oils, waxes, surfactants that may be subject to degradation. Degradation is normally faster if the com- position contains a liquid solvent; thus, from a stability perspective, it is an advantage to develop compositions without or with only a minor amount of a solvent present. Accordingly, long shelf-lives are envisaged of the films and compositions of the invention.

iii) The method by which the films are obtained makes it possible to obtain films with a content of more than one drug substance. The different drug substances may be added to the casting or spraying process by injecting or spraying one composition containing all drug substances dissolved or dispersed in a solvent in the desired concentrations through one valve, or by using different valves to different drug substance (or a mixture of these two illustrative examples). Another possibility is to provide one layer of film containing one drug substance and then on top of this layer provide another layer of film containing a second drug substance. Thus, combination products with two or more drug substances can easily be obtained. iv) The drug substance will be homogeneous distributed in the film; thus, a correct dosing is secured and can be expressed e.g. as amount drug substance per surface area. v) The film and compositions are highly skin or mucosa friendly vi) The films /compositions are easy to apply. Normally, the composition contains three layers: a release-liner layer, a layer containing the hydrophilic polymer and the drug substance, and, optionally, a backing layer. The release liner layer serves as a protective layer for the drug-containing layer and is to be removed before application. The backing layer can be regarded as a coating that protects the composition from being removed from the application site (eg in the oral cavity by movements of the tongue or presence of saliva) or as an occlusive layer that drives the release of the active substance to the skin or mucosa. vii) In contrast to compositions normally used to treat diseases of the skin or mucosa, the film and compositions of the invention do not smell. viii) The film and compositions of the invention do not contain any or any substantial amount of alcohol or surfactants. The presence of such substances in topical or mucosal compositions often leads to irritation of the skin or mucosa. ix) The films and compositions of the invention do not contain any preservatives. However, it is contemplates that methods like solvent casting or spraying are suitable methods to prepare a film of the invention. However, other methods may also be suitable to prepare a film. Such methods are intended to be part of the present invention in relation to preparation of the films according to the invention.

Such films are suitable for use in pharmaceutical compositions for application on the skin or mucosa for the treatment of diseases located to such areas. In the present context the term "mucosa" includes mucosa in the oral cavity, in the vagina, in the rectum, in the eye, in the ear as well as the lips. The films are also useful in compositions for application on internal surfaces such as e.g. organs (eg the liver, spleen, heart etc), tissues such as vocal cord, mucosa such as the gastrointestinal mucosa etc. Due to the nature of the films, the compositions of the invention can be provided for immediate release of the drug substance or for controlled release of the drug substance by varying the ingredients employed in the composition or in the films. The films typically become invisible after application, which makes it possible to apply the compositions on any part of the skin or mucosa such as in the face. It is also possible to apply eg cosmetics on the applied composition. This enables good patient compliance as the treatment does not leave any visible signs. Pharmaceutical compositions

As mentioned herein, the present invention also provides pharmaceutical compositions comprising the films described herein.

The pharmaceutical compositions are intended for use on the skin or on a mucosal sur- face, notably a mucosal surface of the oral cavity. A composition of the invention is typically a mono- or multiple layered composition, wherein one or more of the layers are in the form of a film as described herein. The film or composition of the invention may have a round, elongated or polygonal shape. The composition or the invention is a dosage form, which also could be denoted sheet, layered composition, membrane, patch.

In a simple form the composition only contains one layer, namely the film as describe above. Such a composition is suitable for use on the skin or on the mucosa. After application the composition stays on the application site due to its bioadhesive character. The composition may also contain more than one layer such as two or three or more layers. If the composition for example contains two layers, each layer may be a film layer containing a drug substance, where the drug substance in the two layers may be the same or different; only one of the layers may be a film according to the present in- vention. The layers may also have different compositions with respect to nature and content of film-forming polymers and/or bioadhesive substances in order to facilitate a different release pattern of the drug substance from the two different layers. Another example is that the composition contains one or more film layer(s) containing a drug substance and another therapeutically inert layer, which functions as a backing layer to protect the film layer(s) from moisture or saliva or to function as an occlusive layer, which may drive the penetration of the drug substance into the skin or mucosa. In case, where such a composition is applied to the oral mucosa, a backing layer protects the drug-layer from being washed away from the application site, which would result in swallowing of the composition, whereby the desired local therapeutic effect is reduced or eliminated.

Alternatively, the composition may contain a layer, wherein a specific area is made up of one type of films and another specific area is made up of another type of films. Another example is a composition containing three layers: one hydrophobic film layer that is intended to come into contact with the application site and on top of this layer a film layer according to the invention and on top of this layer a backing layer as mentioned above. Many variations are possible provided that one layer corresponds to a film according to the present invention. All variations are within the scope of the present invention.

In some cases it may be desired to have one or more layers without any content of a drug substance between the layer(s) of film according to the invention and/or a backing layer. Such layers may have the same composition as the film layer containing the drug substance, but without any content of drug substance, or the composition may be dif- ferent eg containing a film-forming hydrophobic polymer or a mixture of a hydrophobic and film-forming hydrophilic polymer. It is envisaged that such a layer may be used to adjust the release of the drug substance from the composition. Thus, such a composition is of particular interest in the case where a controlled release composition is desired. In this manner, it is contemplated that an improved ratio between side effects and clinical effect can be obtained, i.e. it is possible to reduce the unwanted effects and at the same time achieve a therapeutically effective response.

The backing layer is typically either co-casted with the drug-containing layer or it is provided as a coating layer on top of a drug-containing layer. Typically, the backing layer is water-impermeable to enable an occlusive effect and/or a protective effect against eg saliva. Suitable materials for backing layer include ethylcellulose as mentioned herein before, carbothane or polysoftane. Moreover, materials such as

actylates/octylacrylamide copolymer (sold under the name DERMACRL® 79), amino methacrylate copolymer (EUDRAGIT®) as mentioned herein before, dimethylami- noethyl methacrylate, methacrylate, methyl methacrylate (e.g. EUDRAGIT ®E 100) and other acrylates may be used or added as film-forming agents. Plasticizers like those mentioned herein before (e.g. tributyl citrate) can also be added.

The backing layer, if present, normally has a thickness in the same order of magnitude as the composition. The backing layer, if present, normally make up about 5-60% w/w of the composition. The backing layer may make up 10-60% w/w of the composition. In some cases, it may be up to 30-60% w/w of the composition.

A composition of the invention may be provided with a release liner layer. This layer is not part of the composition and is an inert layer, which must be removed before application on the skin or mucosa. The release liner layer only serves a practical purpose as it may be difficult to handle and to pack films or layers of films without protecting the composition from the environment. Thus, if the composition only contains one layer, i.e. the film according to the invention, it may be provided with a release liner layer both on the two outermost surfaces.

The films and/or the compositions containing the film may also contain one or more pharmaceutically acceptable excipients, some of which have already been disclosed herein and they can also be added to a composition of the invention so that they are part of the composition, i.e. they may or may not be contained inside the film.

Such excipients (which also may be used in the preparation of the film according to the invention) include taste-masking agents such as aromas or sweetening agents; pH adjusting agents such as buffer substances like citrates, acetate, or phosphate; release modifiers; pore-forming agent, stabilizing agents; anti-oxidants; pigments; skin conditioning agents including urea, glycerol etc, anti-irritative agents such as glycerol, menthol, eucalyptol or nicotinamide; anti-nucleating agents such as glycerol,; penetration enhancers such as azone, N-methylpyrrolidone, propylene glycol etc.

The release of the drug substance from the composition may be immediate or modified dependent on the particular drug substance employed and the intended use. The release rate may be adjusted as described herein before, and/or it may be adjusted by use of specific pharmaceutically acceptable excipient.

A faster release may be obtained by use of penetration enhancer and/or by inclusion of a plasticizer. A composition of the invention suitable for use on the skin or mucosa is typically composed of

i) from about 75-100% w/w of a film according to the invention

ii) from about 0-25% w/w of one or more pharmaceutically acceptable excipients (as described herein), A composition of the invention suitable for use on the skin or mucosa is typically composed of

i) from about 50-70% w/w of the film according to the invention

ii) from about 0-10% w/w of one or more pharmaceutically acceptable excipients (as described herein), and

iii) from about 30 to 50 % w/w of a backing layer.

Method for preparing films according to the invention

The present invention also provides methods for preparing films.

A first method comprising

i) dissolving the hydrophilic polymer in a solvent,

ii) suspending the bioadhesive substance in the resulting solution from step i) iii) optionally, adding a drug substance to the resulting dispersion from step ii) iv) casting or spraying the resulting mixture from step ii) or iii),

wherein said hydrophilic polymer is soluble in said solvent, and said bioadhesive substance is slightly soluble or less in said solvent,

to obtain films, wherein at least 90% w/w of the bioadhesive substance is present in solid form.

An alternative method for preparing films according to the invention comprises the steps of

i) dissolving the hydrophilic polymer in a solvent to obtain a first solution,

ii) optionally, dissolving or suspending a drug substance in said first solution to obtain a first mixture,

iii) suspending the bioadhesive substance in said solvent to obtain a second dispersion,

iiv) dual-casting or dual-spraying the first mixture and the second dispersion, wherein said hydrophilic polymer is soluble in said solvent, and said bioadhesive sub- stance is slightly soluble in said solvent,

to obtain films, wherein at least 90% w/w of the bioadhesive substance is present in solid form.

In the above-mentioned methods, the first and second hydrophilic film-forming poly- mers may be dissolved in the same step i). Alternatively, they may be dissolved separately and either admixed before casting or spraying via different nozzles. As mentioned herein before a suitable solvent is one or more volatile solvents, notably a C1-C3 alkanol such as ethanol or ethanol-water mixtures. Water may be present up to about 20% v/v notably from about 3 to about 10% v/v. In those cases where the film- forming hydrophilic polymer and the bioadhesive substance are casted or sprayed together or by dual-casting or dual-spraying, i.e. from two separate syringes, water may be used in concentrations up to about 60% v/v, notably up to about 50% v/v or up to about 40% v/v. In cases the solvent for the film-forming hydrophilic polymer is not the same as the solvent used for the bioadhesive substance must be a solvent in which the bioadhesive substance is only slightly soluble or less than slightly soluble. A suitable solvent in which the bioadhesive substance is not soluble is notably ethanol or ethanol- water mixtures with a water content up to about 20% v/v, notable from about 3 to about 10% v/v.

The concentration of the film-forming hydrophilic polymer in the solvent is typically in a range of from about 2 to about 40% w/w, notably from about 3 to about 30% w/w.

The concentration of the bioadhesive substance in first solvent or in the dispersion is typically from about 1 to about 20% w/w notably from about 1 to about 15% w/w.

The methods mentioned above may include a final step of coating an outer surface of the film with a hydrophobic polymer. The coating may be in form of spraying, film casting, etc.

The present invention also relates to a kit as described in the claims.

Use in medicine

The films and the compositions according to the invention are suitable for use cine. As mentioned above, the film and compositions according to the invention are primarily intended for local administration to a diseased site on the skin or on a mucosa. However, it is envisaged that a person skilled in the art and based on the present disclosure will be able to utilize the concept of present invention to obtain compositions that ena- ble delivery to the systemic circulation after administration to the skin or mucosa or compositions that enable delivery of the drug substance to a body cavity such as the oral cavity. However, the object of the present invention is to provide films and compositions that stay on the diseased tissue to obtain a local effect. Drug substances suitable for use in connection with the present invention may be drug substances that are small molecules or it may be peptides, proteins, biologies including mono- or polyclonal antibodies.

Skin diseases

Examples of skin diseases are actinic keratosis, skin cancers (basal cell carcinoma, Bowen's disease, squamous cell carcinoma, and malignant melanomas), genital warts, acne, dermatitis, psoriasis, rosacea, ichtyoisis, eczema, atopic dermatitis, puritus, pustolis palmophantatis, pain, infections, viral diseases such as herpes. Today some of these skin diseases (actinic keratosis, skin cancers (basal cell carcinoma, Bowen's disease, squamous cell carcinoma, and malignant melanomas), genital warts) may be treated with imiquimod, which is a prescription medication that acts as an immune response modifier. It has also been suggest to be used in the treatment of vulvar intraepithelial neoplasia, vaginal intraepithelial neoplasia, and common warts. However, there are several adverse effects of the treatment such as blisteres, bloody dry eschar, pain and general discomfort. Moreover, many of the patients cannot tolerate the treatment.

Another treatment of actinic keratosis is ingenol.

A gel containing ingenol mebutate is on the market today in two different strengths for use on either the face and scalp (0.015%) or the trunk and extremities (0.05%), respectively. Clinical studies have shown has ingenol mebutate gel applied topically for 2 to 3 days is effective for field treatment of actinic keratosis. Ingenol mebutate is sold under the name Picato®. The substance is an ester of the diterpene ingenol and angelic acid. Ingenol mebutate is practically not absorbed through the skin. However, application of the gel very often leads to irritations of the application site. This includes redness, scaling, crusting, pain, and sometimes infection. Other side-effects include eye irritation such as periorbital edema, headache and nasophyryngitis.

Due to the common side-effect of irritation of the application site there is a need for de- veloping a composition containing ingenol mebutate or another ingenol derivative which upon application to the skin is less irritative than the known composition. Moreover, a composition of the invention containing eg ingenol mebutate or imiquimod and being in the form of a sheet with a well-defined area (i.e. it contains the desired dose of the drug substance) may have improved long term and less recurrence due to correct dosing at every application.

A composition suitable for use typically comprises a film based on PVP, acrylates or ethylcellulose and additionally contains a bioadhesive substance and a drug substance. It may further comprise one of more of a plasticizer, an anti-irritative agent or other suitable pharmaceutically acceptable excipients. When imiquimod is the drug substance, it may be present in the film as a dispersion or a solution, where e.g. oleic acid is used as a solvent. A typical example of a film-forming polymer is an acrylate or an ammonium acrylate. The plasticizer may be tributyl citrate and the anti-irritative agent may be glycerol.

Other drug substances used in the treatment of skin diseases and suitable for use in accordance with the present invention are vitamin D derivatives or analogues, corticosteroids, phosphodiesterase 4 inhibitors , ingenol derivatives, retinol such as adaplene, JAK inhibitors, NK-1 receptor antagonists, calcineurin inhibitors such as tacrolimus or picrolimus, keratolytic agents such as salicylic acid or lactic acid, antibiotics such as fu- cidic acid, bactoban, or clindamycin, non-steriodal antiinflammatory agents such as diclofenac, naproxene, ibuprofen, ketoprofen, anti-neoplastic agents such as 5-fluoracil, local anesthetics such as lidocain, xylocaine, prilocain etc. Diseases of mucosa, notably the lips and oral cavity Diseases of the oral cavity that can be treated with the films or compositions of the invention include:

Inflammatory conditions such as oral lichen planus and mouth ulcers. Such conditions are normally treated with corticosteroids. The corticosteroid may be selected from the group consisting of amcinonide, betamethasone, budenoside, clobetasol, clobetasone, cortisone, desonide, desoxycortisone, desoximethasone, dexamethasone, diflucorto- lon, diflorasone, flucortisone, flumethasone, flunisolide, fluocinonide, fluocinolon, fluo- rometholone, fluprednisolone, flurandrenolide, fluticasone, halcinonide, halobetasol, hydrocortisone, meprednisone, methylprednisone, mometasone, paramethasone, prednicarbate, prednisone, prednisolone and triamcinolone or a pharmaceutically acceptable ester or acetonide thereof. The corticosteroid may preferably be selected from betamethasone, budenoside, clobetasol, clobetasone, desoximethasone, diflucortolon, diflorasone, fluocinonide, fluocinolon, halcinonide, halobetasol, hydrocortisone, mo- metasone and triamcinolone or a pharmaceutically acceptable ester thereof. The corticosteroid ester may for instance be betamethasone acetate, betamethasone dipropio- nate, betamethasone valerate, elobetasol propionate, dexamethasone acetate, flumethasone pivalate, fluticasone propionate, hydrocortisone acetate, hydrocortisone butyrate or mometasone furoate. The acetonide may be selected from fluocinolone ac- etonide or triamcinolone acetonide. The corticosteroid is preferably betamethasone di- propionate or betamethasone valerate.

Pain conditions (treatment with analgesics such as NSAIDs - ibuprofen, ketoprofen, di- clofenc etc.).

Fungal diseases (treatment with metronidazole, ketoconazole etc.).

Viral diseases such as herpes simplex (treatment with acyclovir). Various dysplasia conditions (treatment with 5-fluoruracil, diclofenac, retinoids, ingenol mebutate) .

In the following is given a more specific description of the clinical applications for treatment of oral diseases.

Use as simple wound dressings (with or without incorporated drugs) (a) Oral Ulceration

The oral mucosa is frequently traumatised during mastication and as the result thermal, chemical and physical injury. This usually leads to ulceration of the oral mucosa. The ulcerated area is painful, very sensitive to touch, hot foods and drinks, alcohol and strong or spicy flavours. This can be very uncomfortable and make eating, drinking and speech difficult. In addition, around 25% of the population experience recurrent episodes of oral ulceration (known as aphthous ulceration) at some point during their lives. They experience one or several mouth ulcers at a time that develop spontaneously, last a few days to a few weeks and then heal by themselves. These crops of ulcers re- cur frequently.

As with a wound to the skin, there is a natural instinct to cover such wounds in the mouth. Unfortunately, the equivalent of a Band-Aid does not yet exist for the mouth. Thin and flexible film compositions that adhere to the oral mucosa and provide a de- gree of protection to the wound from the spicy foods, strong flavours etc that pass through the mouth as well as providing a degree of protection from bacterial contamination and physical trauma would speed wound healing and provide relief from the discomfort associated with oral ulcers. Ideally, these compositions should resorb slowly over a few days so that removal is not necessary. Healing of protected wounds in the mouth is generally very fast.

In some cases it is relevant to use films without any content of drug substance and, thus, the present invention also relates to such films (as described in detail herein, but without any content of drug substance), to compositions comprising the film and to the use of the films and compositions in medicine, i.e. not only to the above-mentioned appliance.

(b) Wound dressing following surgery

Surgical procedures in the mouth, particularly extractions, are more common than any other form of surgical procedure. Currently, following a simple tooth extraction, the open socket is left unprotected to form a blood clot and heal by itself. Fortunately, healing in the mouth is very effective, None-the-less, post extraction haemorrhage is common - often due the blood clot being dislodged, infection of the tooth socket - leading to delay in wound healing or the very painful condition of 'dry socket', is also common. Patients also dislike the sensation of an open socket in the mouth and the associated taste of blood. Covering the extraction socket with an adhesive film composition eg in the form of a dressing, would help to keep the forming blood clot in place and so reduce post-extraction haemorrhage and improve wound healing. It would also reduce infection and the entry of food debris into the socket again facilitating wound healing and reducing wound infection. As well as physically covering the open socket providing comfort and reassurance to the patient. Such compositions would require good adhesion, need to have good strength, low permeability and ideally to stay in place for the first 24 hours while the blood clot stabilises.

As well as extractions many other surgical procedures are performed in the mouth, in- eluding, biopsies, gingival surgery, surgical extractions, implant surgery, orthodontic surgery etc. All leave open wounds or areas of suturing where suitable wound dressings would help reduce wound infection and secondary haemorrhage as well as providing physical protection and comfort for the patient. (c) Active wound dressings

Although physical protection alone would have considerable benefit, the incorporation of drugs and other active agents in some wound dressings would have particular value in specific situations:

(i) Antiseptics. As secondary infection is a common issue with oral

wounds, the incorporation and slow release of a well-tolerated antiseptic agent such as chlorhexidine gluconate or cetylpyridinium chloride (used in antiseptic mouthwashes) could be of value in situation where secondary infection is a particular issue.

(ii) Analgesics. Most oral ulcers are associated with pain and inflammation so the incorporation and slow release of a well-established topical analgesic/anti-inflammatory agent such as benzydamine hydrochloride could provide pain relief and a soothing effect as well as physical coverage.

(iii) Haemostatic. Post extraction haemorrhage is a common problem of concern to dentists and patients. Where haemorrhage is difficult to con- trol with simple measures such as direct pressure. In such situations, dentists and oral surgeons often use tranexamic acid - which inhibits fibrinolysis. However, because it comes in a tablet form it is difficult to apply locally to the tooth socket and so its main effect is systemic. Release of tranexamic acid from a socket covering composition eg in the form of a sheet or patch would physically prevent/reduce haemorrhage as well as preventing fibrinolysis locally in the socket whilst minimising the likelihood of any systemic effect. The composition would amplify the local effect of transexamic acid by preventing its loss from the socket.

Actinic Keratosis and Oral Leukoplakia

Actinic Keratosis (Solar Keratosis) is UV light induced premalignant lesion of the lip that has a significant risk of developing into a lip cancer. Such lesions are often surgically excised or treated with cryotherapy but recently the application of Imiquimod (Aldara), diclofenac (Solaraze) and Fluorouracil (Efudix) creams has been shown to be of benefit in treating some cases of actinic keratosis. However, better methods of retaining, local- ising and slowly releasing the active agents are needed than is achieved with the creams. Thus there is an interest in incorporating these drugs into film or layered compositions that can cover the area of actinic keratosis and slowly release the active agent for improved treatment. Oral leukoplakia is a potentially malignant lesion of the oral mucosa that has a significant risk of converting to oral cancer. Oral leukoplakias are more common than actinic keratosis and occur more frequently in smokers. Their potential for malignant change is usually assessed by taking a biopsy of the lesion. A histopathologist then grades the degree of dysplasia in the lesion. Those lesions exhibiting moderate or severe dyspla- sia are considered at high risk of progressing to cancer. Current treatment of oral dys- plastic lesion involves risk reduction e.g. stopping smoking and if the lesion is considered at high risk then surgical excision. Since oral leukoplakias can be extensive and it is difficult to access regions of the mouth, surgical treatment can be difficult and may be mutilating and unpleasant for the patient often leaving residual morbidity. Moreover, surgical removal may not reduce the risk of an oral cancer developing. Attempts have been made to use Imiquimod (Aldara), diclofenac (Solaraze) and Fluorouracil (Efudix) creams to treat oral leukoplakias. However, the presence of saliva make application and retention of the creams difficult and the large size of many oral leukoplakias and the risk of swallowing the drug compound the difficulties as well as significantly increas- ing the risk of systemic side effects from the drugs. Localised, slow release delivery via a bioadhesive composition of the invention, directly to the lesion would solve many of these problems particularly if the composition has an impermeable backing to ensure unidirectional delivery of the drug into the lesion and not into the oral cavity where it could be swallowed.

'Cold Sores' Between 40% and 70% of the population (depending on geographic area and socioeconomic group) are latently infected with the herpes simplex type 1 virus. Of these, 20-40% experience periods of reactivation of the virus, which most commonly presents as cold sores. In many individuals, cold sores are a common and reoccurring problem. Most often they are present as a crop of vesicles (small blisters) at the junction of the lip and the surrounding skin. These then rupture to form small ulcers that exude fluid and then crust over before healing spontaneously over 7 to 10 days. They cause considerable, pain, discomfort and embarrassment. If treated with topical antiviral agents such as acyclovir (Zovirax) or Penciclovir (Vectavir) cream at the earliest stages of le- sion development the duration and severity of episodes can be reduced. However, the cream needs to be applied very frequently (respectively 5 x daily and 2 hourly) to be effective and does nothing to provide coverage to prevent secondary infection or hide the appearance of the lesions. Small skin adhesive film compositions delivering slow release acyclovir or a similar antiviral agent, would be more effect and would also provide coverage to hide the lesions and prevent secondary infection.

Less commonly, cold sores form small, localised crops of blisters and ulcers on the lining mucosa of the mouth, most often the roof of the mouth. Again these are very painful but much more difficult to apply an anti-viral cream to. With appropriate formulation in accordance with the present invention, a composition of the invention can used to treat cold sores on the lips could also be used to treat lesions within the mouth

Treatment of Immunologically Mediated Oral Mucosal Disease

There are several common immunological mediated oral mucosal diseases that result in extensive areas of oral mucosal erosion (thinning) and ulceration. Wherever there is thinning or ulceration of the oral mucosa it is painful, very sensitive to touch, hot foods and drinks, alcohol and strong or spicy flavours. This can be extremely uncomfortable and make eating, drinking and speech difficult. As previously discussed, simple coverage of such areas can provide considerable relief. However, these conditions are either recurrent - such as recurrent aphthous stomatitis, or chronic. Therefore, suppression of the underlying disease process is essential if lesion improvement is to occur with long- term improvements for the patient.

Many of these conditions are susceptible to immunomodulatory drugs such as steroids, cyclosporine and mycophenelate mofetil. Generally steroids are the first line of therapy but there are virtually none formulated for topical drug delivery to lesions in the mouth, particularly as creams and ointments will not adhere to the oral mucosa and therefore easily swallowed and have virtually no duration of action where needed. As a result, steroid tablets (prednisolone and betamethasone valerate) are dissolved in water to make mouthwashes or steroid inhalers are directed at affected areas of oral mucosa. However, the contact time of drugs delivered in this way to oral lesions is extremely short and so high doses, high potency steroids and frequent application is required to compensate for this. In turn this increases the risk of both oral and systemic side effects. Indeed, for more severe and difficult to treat lesions it is often necessary to resort to the use of systemic steroids to treat a localised disease. Even then, many patients area resistant to treatment and it is often necessary to turn to more potent or steroid sparing alternative immunomodulatory drugs such as azathioprine, cyclosporine and mycophenelate mofetil. Again there are no topical oral preparations of these drugs so they frequently have to be used systemically. Because the oral lesions are superficial and easily accessible modern biological agents such as antibodies and kinase inhibitors that often have to be given parenterally (by injection) could be applied directly to the lesion and have an effect if they were available in a suitable delivery system. Thus bioadhesive compositions in accordance with the present invention providing unidirectional drug delivery into the lesion would provide much needed and effective treatment of a wide range of oral mucosal diseases. In terms of the most widely applicable drug to incorporate into a sheet a steroid preparation would be the best starting place. Hydrocortisone has the benefit of no significant absorption from the gut. In gen- eral it is of too low potency to be effective for oral mucosal diseases but with longer retention times and slow release it may well prove effective when delivered from a unidirectional patch. Stronger steroid preparations however, are widely used including tri- macinolone acetonide - that has a proven track record as a topically delivered medium potency steroid (used to be available as triamcinolone in OROBASE® for topical deliv- ery to oral lesions - but is no longer available). Otherwise betamethasone or fluocino- lone have increasing potency and are widely used for treating oral mucosal disease currently. While steroids and other immunomodulatory drugs suppress the underlying disease process they are not effective at providing immediate symptomatic pain relief. Therefore a combined steroid and topical analgesic/antiinflammatory (benzidamine hy- drochloride) drug delivery membrane could be of particular value. Specific oral mucosal diseases suitable to being treated with a composition in accordance with the present invention include:

(i) Recurrent aphtous stomatitis - as previously described

(ii) Oral lichen planus (OLP) - This condition affects 1.5 - 2% of the population. Unlike the skin form of lichen planus, Oral lichen planus once established lasts for many years, causes far more painful lesions and is much more resistant to treatment. Patients get widespread erosions and ulceration that affects mainly the buccal mucosa (inside the cheeks), the sides of the tongue and the gums that are often painful and extremely sensitive to foods etc.

(iii) Pemphigoid - this is a group of blistering conditions that can affect the skin and mucous membranes. It is caused by auto-antibodies damaging the junction between the epithelium and the underlying connective tissue so that the epithelium splits from the underlying tissue. The oral mucosa is invariably affected producing large blisters that break down to form extensive areas of oral ulceration. The gums are widely affected but ulcers can also develop on the roof of the mouth tongue and inside the cheeks. It is somewhat less common the OLP.

(iv) Pemphigus - this is another blistering condition affecting the skin and mucous membranes. It is slightly different to pemphigus in that autoantibodies damage the junctions that bond epithelial cells to each other. Again the oral mucosa is invariably affected. Although it is slightly less common than pemphigus it is generally more severe and difficult to treat often necessitating the use of systemic steroids and immunomodulatory drugs. However, the use of muco-adhesive membranes that uni- directionally deliver potent steroids in a slow release fashion would likely preclude the necessity to deliver these drugs systemically.

Delivery of local anaesthetics

Local anaesthetics are used widely eg within dentistry. In order to deliver sufficient local anaesthesia for tooth extraction it is usually necessary to give it by nerve block injection or local infiltration injection. Because the injection itself is painful it is not uncommon to first apply topical local anaesthetic gel to the oral mucosa at the intended site of injection. This is frequently done for children and apprehensive patients. Unfor- tunately, the gel often makes poor contact with the mucosa so that local anaesthetic penetration is poor and most of the gel becomes dissipated in the mouth. This causes unpleasant numbness around the mouth and also has a very bitter and unpleasant taste. As a result the procedure is often of limited effect. Topical delivery of local anaesthetic via a uni-directional , bioadhesive composition (eg a drug delivery patch) would result in better localisation and penetration of the local anaesthetic, and thus bet- ter efficacy, as well as limiting the adverse effects of widespread numbness and bad taste. The composition would only need a short attachment time or if sterile could be left in place and the injection given through the composition.

An effective bioadhesive, local anaesthetic composition eg in the form of a drug deliv- ery patch, could potentially provide sufficient analgesia for many types of routine dentistry on upper teeth -where infiltration local anaesthesia is usually given, or where procedures are relatively minor.

Local anaesthetic is also extensively used in the mouth for soft tissue surgery including gingival surgery, biopsies etc. Again infiltration anaesthesia is usually given in these situations and it is likely that efficient local anaesthesia could be obtained in these situations, because bone penetration of the local anaesthetic agent is not required, simply by using a uni-directional, bioadhesive local anaesthetic drug composition. The most obvious local anaesthetic to use in this situation would be lignocaine (lido- caine) hydrochloride although articaine would be a possible alternative. The incorporation of adrenaline as occurs in many local anaesthetic injection solutions may be beneficial in causing local vasoconstriction and thereby enhancing and prolonging the effect of the local anaesthetic agent.

Treatment of oral mucositis

Radiotherapy and chemotherapy for cancers are associated with serious side effects. One of the worst is the oral mucositis that occurs. This results in extensive sloughing and ulceration of the oral mucosa. The resulting pain and discomfort often makes eat- ing and drinking impossible and requires the use of narcotic analgesics. Frequently, the cancer treatment has to be abandoned or reduced because of the severity and distress caused by oral mucositis. Currently there is no effective preventative or curative measures. However, the use of bioadhesive wound dressings in accordance with the present invention as discussed above would be helpful in their own right but the inclu- sion of a local analgesic e.g. benzidamine hydrochloride could be even more effective at alleviating pain. Benzidamine hydrochloride mouthwashes do provide symptomatic relief but their effect is very short lived. This could be extended and enhance by a composition of the invention, which provides uni-directional delivery to the affected mucosa from the composition eg in the form of a drug delivery patch. Also recent research has shown that the use of an adrenaline mouthwash before radio- or chemotherapy treatment sessions can help prevent oral mucositis. This appears to be because the vasoconstriction induced in the subepithelial blood vessels by the adrenaline reduces the toxic bystander effects of the treatment on the oral mucosa. Unfortunately, the short contact time with the mucosa that occurs with mouthwash delivery and indiscriminate application to all mucosal sites means that drug delivery is inefficient and systemic side effects of the adrenaline more likely. More direct, prolonged and sustained release of adrenaline into susceptible oral mucosal sites using a composition in accordance with the present invention eg a uni-directional, bioadhesive drug delivery patch or membrane delivery system would be far more efficient and effective.

Delivery of drugs into the oral cavity

Instead of using film or layered compositions (eg in the form of membranes or patches) to deliver drugs uni-directionally into the oral mucosa to which they are attached as a wound dressing, it is also possible to design composition that adhere to the oral muco- sa but deliver drugs into the oral cavity. These can be used to treat more widespread problems in the mouth e.g. oral candidiasis or to slowly deliver drugs to the throat, oesophagus and upper Gl tract.

The main advantage of such systems is the ability of the composition (eg in the form of a membrane or a patch) to act as a drug reservoir and slowly but continuously release the drug into the mouth.

(i) Oral candidiasis. This is a common fungal infection of the mouth. It is particularly common in those who wear dentures, those who smoke or have a high sugar intake, those with diabetes or are immunocompromised and those who are taking antibiotics or immunosuppressant treatments including steroids. There are several antifungal drugs that would be effective and safe for treating oral fungal infections (although several are no longer available as oral preparations). However, they all need frequent application because they are rapidly lost from the oral cavity due to swallowing. The main advantage of a composition in accordance with the present invention (eg in the form of a membrane or a patch delivery system) would be the possibility of providing a slow and continual release of drug into the oral cavity. The drugs likely to be most effective and safe would be nystatin and amphotericin. Although the az- ole antifungals are very effective the risk of systemic absorption and the potential to interact with other drugs means they are likely to have a worse safety profile,

(ii) Drugs can also be delivered to the throat e.g. antiseptics, analgesics and local anaesthetics for treating sore throats colds etc. or to the oesophagus and stomach e.g. antacids, proton pump inhibitors etc or even systemically via the Gl tract. The main advantage being the possibility for slow and continuous drug delivery.

Systemic delivery of drugs across the oral mucosa

Although the films and compositions according to the invention primarily are intended for local treatment of the skin or mucosa, it is contemplated that films or compositions made in accordance with the present invention but comprising a drug substance that is intended for delivery into the systemic circulation may be suitable for application to the oral mucosa, but for systemic administration through the oral mucosa. The oral mucosa is readily accessible is more permeable than skin and better supplied with blood vessels. It also has the advantage that drugs delivered across the oral mucosa and into the circulation avoid the problem of first pass metabolism in the liver. This means that drugs that need rapid administration, including some emergency drugs, and some drugs that would otherwise need to be delivered by injection or would be inactivated in the liver can be more effectively administered across the oral mucosa. Adhesive drug delivery compositions that uni-directionally deliver such drugs across the oral mucosa can be very effective. They can be used to deliver emergency drugs in the unconscious patients or where injections not possible e.g. where suitably trained staff are not available.

(i) Emergency drug administration: Drugs commonly delivered across the oral mucosa include:

a. Glyceryl trinitrate - This is usually given in the form of a sublingual (under the tongue) spray or quickly dissolving tablet to treat episodes of angina (chest pains). However, the speed of delivery is such that it often causes very severe headache due to the over quick dilatation of cerebral as well as cardiac blood vessels and may need to be re- peated several times. Transmucosal delivery of glyceryl trinitrate in a more controlled fashion from a bioadhesive composition eg in the form of a membrane or a patch could produce a smoother and longer duration of dosage and avoid such problems.

b. Aspirin - is often delivered across the oral mucosa in heart attack and stroke patients, particularly when unconscious, in order to reduce thrombosis and worsening of the condition. This usually achieved by placing a soluble aspirin tablet in the buccal sulcus (between the gums and the inside of the cheek) and allowing it to dissolve. However, much of the drug is lost into the oral cavity rather than accurately delivered across the oral mucosa. Again a more controlled, more directed and longer duration of trans-mucosal delivery could be achieved using the formulation principle in accordance with the present invention, eg in the form of a a bioadhesive drug delivery patch.

c. Midazolam - is very effective at halting epileptic fits, particularly when they are prolonged or recurring. Although normally given by intravenous injection, this can be very difficult in a fitting patient. So more recently it has been recommended that midazolam solution is simply placed between the cheek and the gums or under the tongue as it rapidly crosses the oral mucosa to enter the circulation and abort fitting. Delivery by this route is uncertain with much of the drug being lost or swallowed. Again a more controlled, more directed and longer duration of trans-mucosal delivery could be achieved using a composition in accordance with the present invention eg as a bioadhesive drug delivery patch.

Delivery of narcotic analgesics. Narcotic (opioid) analgesics are widely used for the treatment of severe and intractable pain particularly cancer related pain and for management of post-operative and trauma related pain (including battlefield injuries). The main problem is that most opioid analgesics need to be given by injection with frequent repeat doses by injection because they are rapidly metabolised in the liver. Some opioid analgesics are now available in patch form for transdermal delivery or sprays for trans nasal delivery but trans mucosal delivery via bioadhesive oral compositions, eg patches, offers considerable advantages. Including, slower, more controlled and more sustained drug delivery. More effective drug penetration into the circulation than with skin patches as well as the avoidance of first pass metabolism in the liver. Drugs likely to provide good candidates for this approach include: morphine, pethidine, buprenorphine and fentanyl.

The invention is described in the following non-limiting examples. Legends to figures

Figure 1 shows a test apparatus suitable for bioadhesiveness testing

Figure 2 shows an apparatus for testing buccal penetration

Figure 3 shows images of the film applicator used in the examples

Figure 4 shows the results of the preparation of films using dextran as bioadhesive substance

Figure 5 shows the results of the preparation of films using PEO as bioadhesive sub- stance

Figure 6 shows the results of the preparation of films containing a drug substance and dextran as bioadhesive substance

Figure 7 shows the results of the preparation of films containing a drug substance and PEO as bioadhesive substance

Figure 8 shows the result of the preparation of a two-layered film composition made of a film containing clobetasol propionate on a hydrophobic film and using PEO as bioadhesive substance

Figure 9 shows the result of the preparation of a two-layered film composition made of a film containing clobetasol propionate on a hydrophobic film and using dextran as bio- adhesive substance

Figure 10 illustrates a method for in vitro testing

Figure 11 shows the results of in vitro release testing of films

Materials

The following materials are used in the experiments reported in the Examples below.

• Polyvidone 90.000 (Kollidone 90K) is obtained from BASF, Germany

• Klucel LF is obtained from Hercules Incorporated, US

• Eudragit E, is obtained from Evonik Industries

· Eudragit RS, Evonik Industries

• Dermacryl 79, is obtained from AkzoNobel • Tributyl citrate, Ethanol, Sodium acetate, Hydrochloric acid & Betamethasone dipropionate are obtained from Sigma-Aldrich

• Dextran, Molecular weight 500,000, 750,000, 1 ,000,000 are obtained from Pharmacosmos Denmark

· Polyethylene oxide (Polyox) 400,000, 2,000,000, 4,000,000 are obtained from The Dow Chemical Company

• Medium chain triglyceride, Henry Lamotte Oils GmbH

• Imiquimod is obtained from APIChem Technology Co., Ltd.

• Carbothane is obtained from Lubrizol Corporation US

In Example 16 and onwards, the following materials are used:

• Polyvinylpyrrolidone with Mw 1 ,000,000 - 1 ,500,000 (PVP). BASF, Germany.

• Eudragit RS100 (RS100). Evonik Industries, Germany.

• Polycaprolactone with Mw 80,000 (PCL). Sigma Aldrich, UK.

· Dextrans with Mw 500,000 (DEX5). Pharmacosmos, Denmark.

• Polyethylene oxide with Mw 400,000 (PE04) and Mw 2,000,000 (PEO20).

Sigma Aldrich, UK

• Clobetasol propionate analytical standard. Sigma Aldrich, UK.

• Solvent for PVP and RS100: 97 vol% ethanol (Sigma Aldrich, UK) in distilled water.

• Solvent for PCL: 90/10 vol/vol blend of dichloromethane/dimethylformamide (Fisher Scientific, UK).

• Baking paper or tin foil as the substrate used to produce the films.

Methods

Analysis of Betamethasone dipropionate by HPLC:

Column: Sunfire C18; 3.5 μιη or 5 μιη; 150x4.6 mm ID or equivalent

Mobile Phase: Acetonitrile/0.01 M (NH4)2HP04 pH 6.4, 70:30 (v/v).

Flow rate: 0.8 ml/min

Detection Wavelength: 240 nm

Analysis of Imiquimod by HPLC:

Column: Phenomenex Cie column or equivalent

Mobile phase: 40:60 Acetonitril to water containing 1 % trifluoroacetic acid Flow rate: 1 ml/min

Detection wavelength

Examples

Example 1

Preparation of a film using dextran as bioadhesive substance

1 ) The content of the different dextrans varied between 2.5, 5.0 and 7.5% by weight of the ethanolic dispersion or between 25 to 75% by weight of the film-forming polymer.

To prepare the dispersions, dextran was suspended in ethanol by stirring and ultra sound followed by slowly addition of the film-forming polymer while slowly stirring. The resulting suspension was stirred overnight to complete the dissolution of the film- forming polymer.

The suspension was then formed into mono-layered film using a conventional coating technique. Example 2

Preparation of a film using polyethylene oxide as bioadhesive substance Film-forming Bioadhesive substance Solvent polymer Polyethylene Polyethylene Polyethylene Ethanol oxide oxide oxide

400.000 2.000.000 4.000.000

Polyvidone X X X X X

90.000 10%

Klucel LF 5% X X X

Eudragit E X X X

15%

Eudragit RS X X X X X

15%

Dermacryl 79 X X X

10%

The content of the different molecular weight of polyethylene oxide varied between 2.5, 5.0 and 7.5% by weight of the dispersion or between 25 to 75% by weight of the film- forming polymer.

To prepare the film polyethylene oxide was suspended in ethanol by stirring and ultra sound followed by slowly addition of the film-forming polymer while slowly stirring. The resulting suspension was stirred overnight to complete the dissolution of the film- forming polymer.

The suspension was then formed into mono-layered film using a conventional coating technique.

Example 3

Preparation of a film containing the drug substance imiquimod

Two different methods were used:

1.5 g of imiquimod was suspended by stirring in 20 g ethanol to which 80 g of a 10% PVP 90K (film-forming polymer) in ethanol was added and stirred slowly for 2 hours.

2.5 g imiquimod was suspended by stirring in 20 g 0.1 M acetate buffer pH 4.0 for 2 hours, whereby imiquimod partly dissolves. Then 80 g of a 10% PVP 90.000 in ethanol was added and stirred slowly for 2 hours. After dissolution of the film-forming polymer, the bioadhesive substance was added to obtain a suspension. The suspension was then formed into mono-layered film using a conventional coating technique.

The following bioadhesive substances have been used in both methods:

Dextran 500,000 Da

Dextran 750,000 Da

Dextran 2,000,000 Da

Polyethylene oxide 400,000 Da

Polyethylene oxide 2,000,000 Da

Polyethylene oxide 4,000,000 Da

The bioadhesive substances were added in proportion to the film-forming polymer so that the weight ratio between the bioadhesive substance and the film-forming polymer was in the range of from 0.1-5. Specific weight ratios obtained were: 0.2, 0.25, 0.3, 0.4, 0.6, 0.7, 0.75, 0.8, 1 , 1.2, 1.25, 1 .3, 1.5, 1.6, 1.7, 2, 2.4, 2.7, 3, and 4.

Example 4

Preparation of a film containing the drug substance imiquimod

Two different methods were used:

1.5 g of imiquimod was suspended by stirring in 20 g ethanol to which 80 g of a film- forming polymer in ethanol was added and stirred slowly for 2 hours.

2.5 g imiquimod was suspended by stirring in 20 g 0.1 M acetate buffer pH 4.0 for 2 hours, whereby imiquimod partly dissolves. Then 80 g of a film-forming polymer in ethanol was added and stirred slowly for 2 hours. The following film-forming polymers were used in both methods:

Eudragit® E as a 15% solution in ethanol

Eudragit® RS as a 15% solution in ethanol

Dermacryl 79 as a 10% solution in ethanol The following bioadhesive substances have been used in both methods:

Dextran 500,000 Da Dextran 750,000 Da

Dextran 2,000,000 Da

Polyethylene oxide 400,000 Da

Polyethylene oxide 2,000,000 Da

Polyethylene oxide 4,000,000 Da

The bioadhesive substances were added in proportion to the film-forming polymer so that the weight ratio between the bioadhesive substance and the film-forming polymer was in the range of from 0.1-2. Specific weight ratios obtained were: 0.2, 0.25, 0.3, 0.4, 0.6, 0.7, 0.75, 0.8, 1 , 1.2, 1.25, 1 .3, 1.5, 1.6, 1.7, and 2.

After dissolution of the film-forming polymer, the bioadhesive substance was added to obtain a suspension. The suspension was then formed into mono-layered film using a conventional coating technique.

Example 5

Preparation of two-layered composition comprising a film containing imiquimod layered on a hydrophobic film The films described in Example 3 and 4 were prepared, but casted on a hydrophobic film containing poly(caprolactone) to obtain a two-layered composition.

Example 6

Preparation of film containing the drug substance betamethasone diproprionate and dextran as bioadhesive substance

Composition I II III IV

Ingredients

(mg)

Polyvidone 100 100 100 100

90.000

Dextran 75 75 75 75

750.000

Tributyl citrate 0 50 100 0

Medium chain 0 0 0 75

triglyceride Betamethasone 5 5 5 5

dipropionate

(BDP)

Ethanol 1000 1000 1000 1000

BDP, tributyl citrate and/or medium chain triglyceride were dissolved in ethanol. Then dextran with a molecular weight of approximately 750.000 was added by stirring and ultra sound, and finally Polyvidone 90.000 was added during slowly stirring.

The resulting suspension was stirred overnight to complete the dissolution of the film- forming polymer. The suspension was then formed into mono-layered film using a conventional coating technique. Example 7

Preparation of a film containing the drug substance betamethasone diproprio- nate and polyethylene oxide as bioadhesive substance

BDP, tributyl citrate and/or medium chain glyceride were dissolved in ethanol. Then polyethylene oxide with a molecular weight of approximately 750.000 was added by stirring and ultra sound, and finally Eudragit RS was added during slowly stirring. The resulting suspension was stirred overnight to complete the dissolution of the film- forming polymer. The suspension was then formed into mono-layered film using a conventional coating technique.

Example 8

Preparation of a film the drug substance imiquimod and dextran as bioadhesive substance

Composition I II III Iv V VI VII VIII

Ingredients

mg

Imiquimod 25 25 25 25 25 25 25 25

Acetate buffer 200 200 200 200 200 200 200 200

0.22 M pH

4.65

Acetic acid, A few A few A few A few A few A few A few A few glacial drops drops drops drops drops drops drops drops to disto to to to to to to solve disdisdisdisdisdisdisimiqui solve solve solve solve solve solve solve mod imiqui imiqui imiqui imiqui imiqui imiqui imiqui mod mod mod mod mod mod mod

Denatured 1000 1000 1000 1000 1000 1000 1000 1000 ethanol

Luvitec 90K 100 100 100 100 100 100 100 100

(Polyvinylpyr- rolidon

90.000)

Eudragit RS 0 0 0 0 450 450 450 450

100

Dextran T750 75 75 75 75 75 75 75 75

(750.000)

Tributyl citrate 0 50 100 50 0 150 300 150

≥ 97% Captex 300 0 0 0 50 0 0 0 50

(Medium

chain triglyceride) imiquimod is suspended in acetate buffer to obtain a suspension, wherein imiquimod is partly dissolved. Tributyl citrate and/or medium chain triglyceride were dissolved in eth- anol. The imiquimod suspension obtained is added. Then dextran with a molecular weight of approximately 750.000 was added by stirring and ultra sound, and finally Eu- dragit RS was added during slowly stirring.

The resulting suspension was stirred overnight to complete the dissolution of the film- forming polymer. The suspension was then formed into mono-layered film using a con- ventional coating technique.

Example 9

Preparation of a two-layered composition containing a drug-containing layer and a backing layer

Four compositions were made two of which were without any coating, one was with I- coating and the fourth was with Ill-coating. The II- and Ill-coatings were sprayed on the films.

Example 10

In vivo adhesion testing of compositions The films exemplified in the examples herein were tested for bioadhesion by placing 1 cm x 1 cm sheet on the middle of the tongue. The subject tested the film was asked to evaluate the bioadhesiveness on a scale from 0 to 5, where 5 is strong bioadherence and 0 is no bioadherence.

Example 11

In vitro adhesion testing of films

The bioadhesive forces of the films are were determined by means of a bioadhesive measuring device shown in Figure 1. Buccal mucosa was cut into strips/pieces and washed with tyroide solution. At time of testing a section of buccal mucosa (c) was secured keeping the mucosal side out, on the upper glass vial (B) using rubber band and aluminium cap. The diameter of each exposed mucosal membrane was 1 cm. The vial with the sheep buccal mucosa (C) was stored at 37°C for 10 min. Then one vial with section of buccal mucosa (C) and another vial were fixed on height adjustable pan (E). To a lower vial the film (D) was placed with the help of bilayered adhesive tape, adhesive side facing downward. The height of the lower vial was adjusted so that the film could adhere to the pig buccal mucosa on the upper vial. A constant force was applied on the upper vial for 2 min, after which it was removed and the upper vial was then connected to the balance. Then the weight on right side pan was slowly added in an in- crement of 0.5 g till the two vials just separated from each other. The total weight (g) required to detach two vials was taken as a measure of bioadhesive strength. From this bioadhesive strength, the force of adhesive was calculated.

Other suitable methods may also be used such as the in vitro and in vivo methods de- scribed by Kockish et al. in Journal of Controlled Release, 77 (2001 ) 1-6, which is incorporated by reference in its entirety.

Example 12

In vitro release testing of compositions

The purpose of the study is to explore the effect of polymer and bioadhesive polymer, plasticizer and oily release- enhancing agent on the in vitro release of betamethasone dipropionate, BDP, from compositions described herein

Membrane:

Dow Corning® 7-4107 Silicone Elastomer Membrane, 75μηη. Diffusion cell system:

Modified dialysis cells.

Receptor compartment: 3.75 ml. The actual volume of each cell is registered by weighing of the assembled cell before and after filling of the receptor compartment. Diameter: 1.55 cm, corresponding to an available diffusion area of 1 .89 cm².

Sheets of silicone membrane are cut to size (circles, 0 = 22mm). The membrane is placed between the two compartments of the dialysis cells with the glossy side facing the donor compartment.

The film or composition is applied directly onto the membrane by pressing the actuator. The receptor compartment is filled with preheated and degassed receptor medium (the actual volume of each cell is registered by weighing) and possible air bubbles removed. The sampling arm is sealed with a plastic bung and parafilm to prevent evaporation of the receptor medium. Uniform mixing of the receptor phase is obtained with a magnetic bar placed in the receptor compartment. The diffusion cells are placed in a heating cab- inet set at 37°C to maintain a temperature of 32°C at the membrane surface. The stirring bed is set.

Receptor medium:

10% w/w methyl-13 -cyclodextrin in 0.05M acetate buffer pH 4.0. The receptor medium is degassed in an ultrasound water bath for minimum 20 minutes prior to the start of the experiment and before 24h and 48h sampling. It was ensured that sink conditions were present at all times during the study period; i.e. that the concentration of the drug compounds in the recipient phase was below 10% of the solubility of the drug substances in the medium.

Exposure and sampling times:

Samples of 1500μΙ (the actual volume is weighed and registered) are withdrawn from each cell at regular time intervals. After each sampling the receptor compartment is refilled (the exact same volume as withdrawn) with preheated fresh receptor medium. The withdrawn samples are stored in brown sealed HPLC vials at 2-8°C and protected from light until quantification by HPLC analysis at the end of the experiment. Sampling time points: 0, 1 , 6, 24, 30, 48, 54, 72 h.

Study design:

Each formulation is tested in 3 replicates (n = 3). Example 13

In vitro skin penetration studies

To investigate the skin penetration and permeation of imiquimod from compositions according to the examples herein a skin diffusion experiment is conducted. Full thickness skin from pig ears was used in the study. The skin was cleaned and kept frozen at - 18°C before use. On the day prior to the experiment the skin was placed in a refrigerator (5 ±3°C) for slow defrosting.

Static Franz-type diffusion cells with an available diffusion area of 3.14 cm² and recep- tor volumes ranging from 8.6 to 1 1.1 ml are used in substantially the manner described by T.J. Franz, "The finite dose technique as a valid in vitro model for the study of percutaneous absorption in man", in Current Problems in Dermatology, 1978, J.W.H. Mall (Ed.), Karger, Basel, pp. 58-68. The specific volume is measured and registered for each cell. A magnetic bar is placed in the receptor compartment of each cell. After mounting the skin, physiological saline (35°C) is filled into each receptor chamber for hydration of the skin. The cells aree placed in a thermally controlled water bath, which is placed on a magnetic stirrer set at 300 rpm. The circulating water in the water baths is kept at 35±1 °C resulting in a temperature of about 32°C on the skin surface. After 30 min the saline is replaced by the receptor medium, consisting of 1 part acetate buffer (100mM, pH 4.0) and 1 part saline.

The in vitro skin permeation of each test composition containing imiquimod is tested in 3 replicates (i.e. n=6). Each test composition is applied on the skin membrane at 0 hours using a pipette. The skin penetration experiment is allowed to proceed for 24 hours. Samples are then collected from the receptor compartments for up to 72 hours.

The concentration of imiquimod in the samples is determined by HPLC.

Example 14

In vitro penetration in buccal tissue culture

The apparatus used is shown in Figure 2.

A bethamethasone dipropionate containing film is applied directly onto the membrane by pressing the actuator. The cells are kept at 37 C in a heating cabinet. The receptor compartment is filled with preheated receptor medium. The actual volume of each cell is registered by weighing. The receptor medium consists of 10 w/w methyl-13 cy- dodekstrin in 0.05M acetate buffer pH 4.0. At different time intervals for up to 48 hours samples of receiver fluid is removed and replaced by fresh preheated receptor medium. Withdrawn samples are stored in brown sealed HPLC vials at 2 -8 °donor medium and protected from light until quantification by HPLC analysis at the end of the experi- ment. Each experiment is run in triplicate.

Example 15

In vitro skin irritation studies in human cell culture

In vitro skin irritation studies in human cell culture is tested in accordance to OECD's Test Guidelines "OECD Guidelines for the testing of chemicals - In Vitro Skin Irritation: Reconstructed Human Epidermis Test Method. 439, adopted 26 July 2013.

Example 16

Film fabrication

In order to produce the films, polymeric dispersions were prepared by adding the different components to the solvent and then stirring overnight on a magnetic stirrer. The film-forming hydrophilic polymer(s) was/were soluble in the solvent, whereas the bio- adhesive substance has a lower solubility and is mainly present as solid material. Later, films were produced using a stainless steel one-sided film applicator (500 μηη clearance gap; Ascott Analytical Equipment, UK) (see Figure 3).

To prepare the films, a volume (i.e. 2-3 mL) of the solutions was poured on a substrate (i.e. baking paper, tin foil). Then, the applicator was moved on the substrate at a con- stant speed over the poured solution in order to create a uniform wet film. Afterwards, the films were left to dry at room temperature and, finally, were removed for storage.

Example 17

Preparation of a film using dextrans as bioadhesive substance

Aim : To demonstrate the fabrication of bioadhesive films containing dextran particles as bioadhesive substance.

A series of dispersions were prepared, and films were produced following the method previously described. Dex 500,000 could easily be substituted with Dex 2,000,000 and give suitable results (films)

The results are shown in Figure 4. It is seen that an increase in concentration of Dex5 from 10 wt% to 20 wt% (in solution) lead to a more ruptured surface. Example 18

Preparation of a film using dextrans as bioadhesive substance

Aim : To demonstrate the fabrication of bioadhesive films containing polyethylene oxide particles as bioadhesive substance. A series of dispersions were prepared, and films were produced following the method previously described. PEO with a molecular weight of 400,000 was used, but could easily be substituted with PEO 2,000,000 and form films.

10 t% 5 wt% 5 wt% 80.00wt% Ye

10 wt% 5 wt% 10 wt% 75.00 wt% Yes 10 wt% 5 wt% 2© wt<¾ 65.00 wt% Yes 10 wt% 10 wt% 5 wt% 75.00 wt% Yes 10 wt% 10 wt% 10 wt% 70 OO t¾ Yes 10 wt% 10 wt% 20 wt% 60.00 wt% Yes 10 wt% 15 wt% 5 wt% 70.00 wt% Yes 10 wt% 15 wt% 10 wt% 65.00 wt% Yes 10 wt% 15 wt% 20 wt% 55.00 wt% Yes

The results are shown in Figure 5.

The results show that an increase in PEO of from 10 wt% to 20 wt% results in a more ruptured surface.

Example 19

Preparation of a film containing a drug substance and a bioadhesive substance

To demonstrate the fabrication of bioadhesive films containing the drug dobetasol propionate, and dextran or polyethylene oxide particles as bioadhesive substances.

A series of dispersions were prepared, and films were produced following the method previously described.

The results are shown in Figures 6 and 7. From the figures it is seen that roughness decreases when the concentration of Eudragit ® RS 100 increases irrespectively of whether dextran or polyethylene oxide is used as a bioadhesive substance.

Thus, in conclusion:

It was observed on electronic microscopy images that surface roughness of the films decreased as the proportion of Eudragit RS100 increased in the composition.

It does not appear that the addition of the drug affected the appearance of the films, at least at the concentration level used in this study. It is likely that greater amounts of drug will have some effect on the fabrication of the films. Example 20

Preparation of a two-layered composition made of a film containing clobetasol propionate on a hydrophobic film

Aim : To demonstrate the fabrication of two-layered bioadhesive films, made of a layer containing the drug clobetasol propionate and a hydrophobic and non adhesive back- ing layer.

Method of fabrication:

First, a layer of PCL was produced on tin foil using the film applicator.

Once the PCL was partially dry, a layer of the drug containing solution was produced on top.

All films were then left to dry for a prolonged amount of time (1 hour minimum) at room temperature. Compositions: Same as in example 19

Observations:

A strong attachment between both layers was achieved (see Figures 8 and 9).

Example 21

In vivo adhesion testing of compositions

Aim : To demonstrate the bioadhesive properties of the films in vivo A series of two-layered compositions of the films were prepared following the methods described previously.

Method of analysis: • Samples of dimensions 1.5 x 1 cm were cut from each film composition and were tested on the tongue of a volunteer.

The volunteer then was asked to evaluate the strength of the adhesion from 0 to 5, where 0 indicates that there is no adhesion and 5 indicates a strong adhesion of the film.

Results:

Observations:

· Stiffness of PCL backing layer affects flexibility of patch and its adaptation to mouth movements.

Bioadhesive layer is thin (<0.5 mm). It is expected that a thicker layer will increase adhesive properties. Conclusion: Addition of bioadhesive substances, especially polyethylene oxide, increases in vivo adhesion.

Example 22

In vitro testing of adhesive properties of films

Aim : To demonstrate the bioadhesive properties of the films in vitro. A series of two-layered compositions of the films were prepared following the methods described previously.

Method of study:

Samples of dimensions 1.5 x 1 cm were cut from each film composition and were applied to a Petri dish that had been previously wetted with 1 ml. of water.

Samples were applied by pressing on the surface of the PCL backing layer with a finger for a minimum time of 5 seconds.

The samples were then covered with artificial saliva (Volume = 3-5 ml_), and the petri dishes were placed on a rocker tray set at a speed of 50 rpm.

The dishes were continuously observed in order to determine the time at which the backing layer detached from the plastic.

Study terminated after 1 hour,

(see Figure 10)

Results:

Number Composition Time (Minutes) (PVP:RS100:PEO/DEX) Plate 1 Plate 2

1 10:0:0 >70 >70

2 10:10:0 >70 >70

3 10:0:10 (PEO) >70 >70

4 10:10:10 (PEO) >70 >70

5 10:0:10 (DEX) >70 70

6 10:10:10 (DEX) >70 >70

Observations:

• After 40 minutes, first indications of detachment were observed although most of the sample surface was still attached to plastic.

· After 60 minutes, all samples were still attached.

After 70 minutes, only one sample detached (i.e. 10 wt% PVP + 10 wt% DEX5)

Conclusions: All film compositions exhibited significant adhesive properties in vitro, exceeding 1 hour of adhesion time.

Example 23

In vitro drug release testing of films

Aim : To demonstrate the release of the drug clobetasol propionate contained within a film

Compositions: Same as in example 19. Composition of Green's cell culture medium - Dulbecco's Modified Eagle's Medium : Ham's F12 medium in a 3:1 (v/v) ratio supplemented with 10 % (v/v) FCS

- 0.1 μΜ cholera toxin

- 10 ng/ml of epidermal growth factor (EGF)

- 0.4 μg/ml hydrocortisone

- 0.18 mM adenine

- 5 μg/ml insulin

- 5 μg/ml transferrin

- 2 mM glutamine

- 0.2 μΜ triiodothyronine

- 0.625 μg/ml amphotericin B

- 100 lU/ml penicillin

- 100 μg/ml streptomycin Method of analysis:

• Samples of dimensions 1.2 x 1.2 cm were cut from each film composition and were placed in vials containing 5 mL of Green's cell culture medium.

• All vials were incubated at 37°C for 30, 60 and 120 minutes.

• At those time points, 1 .5 mL of cell culture media were removed from each vial · The concentration of clobetasol propionate released from the films was measured using high-performance liquid chromatography (HPLC).

Observations:

• As expected, increasing RS100 concentration reduced material solubility. · Films containing polyethylene oxide tended to break down faster than those containing dextran. This may be related to particle size of the bioadhesive substance.

See Figure 1 1. Conclusions: The drug clobetasol propionate was successfully incorporated into the films and was released after immersion in cell culture media. The addition of RS100 may result in slowed release.

Claims

Claims

1. A film comprising

i) a film-forming hydrophilic polymer that is soluble in a solvent,

ii) a bioadhesive substance that is slightly soluble in said solvent,

iii) optionally, a drug substance.

2. A film according to claim 1 , wherein the film-forming hydrophilic polymer has a solubility in said solvent of 3 g/100 ml or more at 25 °C or 10 g/100 ml or more at 25 °C.

3. A film according to claim 1 or 2, wherein the bioadhesive substance has a solubility in said solvent of 0.5 g/100 ml or less at 25 °C or 0.1 g/100 ml or less at 25 °C.

4. A film according to any of the preceding claims, wherein the bioadhesive substance is at the most very slightly soluble in said solvent.

5. A film according to any of the preceding claims, wherein at least 90% w/w of the bioadhesive substance is present in solid form in the film.

6. A film according to any of the preceding claims, wherein at least 95% w/w or 99% w/w of the bioadhesive substance is present in solid form in the film.

7. A film according to any of the preceding claims, wherein said solvent is ethanol or ethanol-water mixtures.

8. A film according to claim 7, wherein said ethanol-water mixtures contain 20% v/v water or less or 10% v/v water or less.

9. A film according to claim 7 or 8, wherein said ethanol-water mixtures contain 5% v/v water or less such as 3% v/v water of less.

10. A film according to any of the preceding claims, wherein the film-forming hydrophilic polymer is selected from polyvinylpyrrolidone (PVP), ethylcellulose, hydroxypropylcellu- lose, acrylates and acrylic copolymers (Eudragit®), and mixtures thereof.

1 1. A film according to any of the preceding claims, wherein the film-forming agent is PVP or Eudragit® or mixtures thereof.

12. A film according to any of the preceding claims, wherein the bioadhesive substance is selected from dextrans, polyethylene oxides (PEOs), alginate, tragacanth, carragee- nan, pectin, gelatin, guar, xanthan, gellan, methylcellulose, hydroxypropylmethylcellu- lose (HPMC), polyvinylalcohol (PVA), polymers of acrylic acids (PAA derivatives), chi- tosan, lectins, thiolated polymers, polyoxo WSRA, PAA-co-PEG (PEG is polyethylene glycol), and mixtures thereof.

13. A film according to any of the preceding claims, wherein the bioadhesive substance is dextran having an average molecular weight of from 400,000 Da to 2,000,000 Da.

14. A film according to any of claims 1-10, wherein the bioadhesive substance is poly- ethylene oxide having an average molecular weight of from 100,000 Da to 4,000,000

Da.

15. A film according to any of the preceding claims, wherein the weight ratio between the bioadhesive substance and the film-forming hydrophilic polymer in the film is in a range of from 0.1 to 10.

16. A film according to any of the preceding claims, wherein a drug substance is present in the film.

17. A film according to any of the preceding claims, wherein a drug substance is present and is selected from drug substances, which are indicated for treatment of a disease of the skin or mucosa.

18. A film according to any of the preceding claims, wherein a drug substance is pre- sent and is selected from drug substances, which are indicated for treatment of a disease in the oral cavity.

19. A film according to claim 18, wherein the drug substance is selected from drug substances, which are indicated for local treatment of a disease in the oral cavity.

20. A film according to any of the preceding claims, wherein the water content is at the most about 5% w/w.

21. A film according to any of the preceding claims for use in medicine.

22. A film according to any of the preceding claims, wherein a drug substance is present, and the film is for use in the treatment of diseases of the oral cavity.

23. A composition comprising a film as defined in any of claims 1-22.

24. A composition according to claim 23, wherein the concentration of the film in the composition is from 70 to 100% w/w.

25. A composition according to claim 23 or 24 in the form of a layered composition.

26. A film according to any one of claims 1-22 or a composition according to any one of claims 22-25, wherein an outer surface of said film or composition is provided with a coating.

27. A composition according to claim 26, wherein the coating is water-impermeable.

28. A composition according to claim 26 or 27, wherein the coating comprises carbo- thane.

29. A composition as defined in any of claims 22-28 for use in medicine.

30. A composition as defined in any of claims 22-29 for use in the treatment of diseases of the oral cavity.

31. A kit comprising

i) a film or a composition as defined in any of claim 1 -30, and

ii) an applicator for applying the composition in the oral cavity.

32. A method for preparing a film according to any of claims 1 -22, the method comprising

i) dissolving the film-forming polymer in a solvent, ii) suspending the bioadhesive substance in the resulting solution from step i), iii) if relevant, adding the drug substance to the resulting dispersion from step ii), iv) casting or spraying the resulting mixture from step ii) or step iii) on a suitable surface, and

v) drying the material to obtain a film,

wherein said film-forming substance is soluble in said solvent, and said bioadhesive substance is slightly soluble in said solvent,

to obtain a film, wherein at least 90% w/w of the bioadhesive substance is present in solid form.

33. A method for preparing a film according to any of claims 1 -22, the method comprising

i) adding the film-forming polymer, the bioadhesive substance and, if relevant, the drug substance to a solvent,

ii) casting or spraying the resulting mixture from step i) on a suitable surface, and iii) drying the material to obtain a film,

wherein said film-forming substance is soluble in said first solvent, and said bioadhesive substance is slightly soluble in said solvent,

to obtain a film, wherein at least 90% w/w of the bioadhesive substance is present in solid form.