Mucoadhesive composition and a process for the preparation thereof

The present invention relates to a composition applicable to the oral cavity for releasing active substances in the oral cavity and is a modification of and improvement on the invention described and claimed in Israel Patent 129,819.

In Israel Patent 129,819 there is described and claimed a composition applicable to the oral cavity comprising a film or sheet being adhesive to mucosa (mucoadhesive) with instant wettability, said film or sheet comprising a homogeneous mixture consisting of at least one water-soluble polymer, a mixture of nonionic surfactants, at least one polyalcohol, at least one cosmetically or pharmaceutically active agent, and optionally at least one flavor, characterized in that the mixture of nonionic surfactants consists of two components, the first component being a polyoxyethylene sorbitan fatty acid ester of a a-hydro-Q-hydroxypoly(oxyethylene)-poly(oxypropylene)poly(oxyethylene) block copolymer, and the second component being a polyoxyethylene alkyl ether or a polyoxyethylene castor oil derivative, wherein the ratio between the first and second component of the binary surfactant mixture is maintained between 1:10 and 1:1.

la

In order that the invention may be better understood and appreciated, description from Israel Specification No. 129,819 is included herein, it being understood that this is for background purposes only, the subject matter of Israel Specification No. 129,819 specifically disclaimed and not forming a part of the present invention.

Mucoadhesive dosage forms for application to the oral cavity which are designed to deliver therapeutic and/or cosmetic agents to the oral mucosa are known in the art. US patent 5,047,244 describes a mucoadhesive carrier allowing the controlled release of a therapeutic agent via the mucosal tissue comprising an anhydrous but hydratable polymer matrix and amorphous fumed silica. An optional waterinsoluble film can be added to provide a non-adhering surface. In WO 91/06270, the same authors disclose a trilaminate film suitable for prolonged delivery of an active ingredient in the oral cavity.

In a similar way, US patent 4,876,092 discloses a sheet-shaped adhesive preparation comprising an adhesive layer containing certain water-soluble and water-insoluble polymers and a water-insoluble carrier which can adhere to the oral mucosa thereby releasing an active agent to the oral cavity. All the devices so far cited are not completely water soluble and will stay in the oral cavity even after the therapeutic goal has been achieved leaving the patient with a certain discomfort in the mouth resulting mainly from the support layer which leaves an insoluble residue in the mouth.

A number of attempts have been made to reduce the adverse feeling in the oral cavity caused by the rigidity and inflexibility of the support layer by introducing soft film supports. EP 0 200 508 Bl and EP 0 381 194 Bl disclose the use of.polyethylene films, polyvinyl acetate, ethylene-vinyl acetate copolymers, metal foils, laminates of cloth or paper and a plastic film, and similar materials as soft film supports, whereby synthetic resins like polyethylene, vinyl acetate homopolymers, and ethylene-vinyl acetate are the preferred materials. In a similar way, CA 1 263 312 discloses the use of polyolefines such as polyethylene, polypropylene, polyesters, PVC, and non-woven fabrics as soft support materials.

However, these devices still leave the patient with a considerable amount of residue from the water-insoluble support film thereby still causing a feeling of discomfort. The obvious solution to overcome this problem was to develop mucoadhesive films which completely disintegrate, or even completely dissolve in the saliva. Fuchs and Hilmann (DE 24 49 865.5) prepared homogeneous, water-soluble films intended for buccal administration of hormones. They proposed the use of water-soluble cellulose-derivatives, like hydroxyethyl cellulose, hydroxypropyl cellulose, or methyl hydroxypropyl cellulose, as film forming agents.

Both DE 36 30 603 and EP 0 219 762 disclose the use of swellable polymers such as gelatine or corn starch as film forming agents, which upon application to the oral cavity slowly disintegrate, thereby releasing an active ingredient incorporated in the film. The same polymers can also be used to prepare films which are intended for dental cleansing, as described in EP 0 452 446 Bl.

These preparations still create an adverse feeling in the mouth which is mainly caused by their initial rigidity and delayed softening. Thus, there has still been a demand for a composition for use in the oral cavity which meets the requirement of providing a pleasant feeling in the mouth.

The present invention discloses methods and compositions that are capable of avoiding an adverse feeling by providing the film which is intended for application to the oral mucosa with instant wettability, while achieving adequate tensile strength in the free film to allow for easy coating, converting, and packaging of a consumer-friendly product.

The present invention contemplates a rapidly dissolving film which.can be adhered to the oral cavity thereby releasing a pharmaceutically or cosmetically active agent, said film comprising water-soluble polymers, one or more polyalcohols, and one or more pharmaceutically or cosmetically active ingredients and nicotine bitartrate. Optionally, the formulation may contain a combination of certain plasticizers or surfactants, colorants, sweetening agents, flavors, flavor enhancers, or other excipients commonly used to modify the taste of formulations intended for application to the oral cavity. The resulting film is characterized by an instant wettability which causes the film to soften immediately after application to the mucosal tissue thus preventing the patient from experiencing any prolonged adverse feeling in the mouth, and a tensile strength suitable for normal coating, cutting, slitting, and packaging operations.

3a

More specifically, according to the present invention, there is now provided a composition applicable to the oral cavity, for releasing active substances in the oral cavity, wherein the composition comprises as essential components at least one water-soluble or water-dispersible polymer, and the active substance, nicotine bitartrate, and wherein said composition exhibits instant wettability which causes the composition to soften immediately after application to the oral mucosa, followed by rapid dissolution or disintegration of the composition.

Preferably the composition is a film which is orally applicable, the thickness of said film being preferably between 5 and 200 pm, more preferably less than 70 pm.

In preferred embodiments of the present invention said polymer(s) is/are selected from the group consisting of: water-soluble cellulose derivatives, in particular hydroxypropylmethyl cellulose, hydroxyethyl cellulose, hydroxypropyl cellulose; and polyvinyl pyrrolidone, carboxymethyl cellulose, polyvinyl alcohol, sodium alginate, polyethylene glycol; and natural gums, in particular xanthane gum, tragacantha, guar gum, acacia gum, arabic gum; water-dispersible polyacrylates, in particular polyacrylic acid, methylmethacrylate copolymer, carboxyvinyl copolymers; and mixtures of the aforementioned polymers.

Preferably said composition comprises as essential components polyvinyl pyrrolidone and hydroxypropylmethyl cellulose.

In preferred embodiments the concentration of the water-soluble polymer lies between 20 and 75%, preferably between 50 and 75%.

Said composition further, preferably, comprises at least one polyalcohol, wherein said polyalcohol is preferably selected from the group consisting of glycerol, polyethylene glycol, propylene glycol, and glycerol monoesters with fatty acids.

3b

Preferably the proportion of the polyalcohol amounts to 0.1 to 5 %-wt. of the dry composition.

The composition preferably further comprises at least one surfactant, the total concentration of surfactant(s) being in the range of 0.1 to 5 %-wt.

In preferred embodiments of the present invention said composition further comprises a mixture of nonionic surfactants, said mixture consisting of two components, the first component being a polyoxyethylene sorbitan fatty acid ester or a a-hydro-CL1-hydroxypoly(oxyethylene)poly(oxypropylene)poly(oxyethylene) block copolymer, and the second component being a polyoxyethylene alkyl ether or a polyoxyethylene castor oil derivative, wherein the ratio between the first and second component of the binary surfactant mixture is maintained between 1:10 and 1:1 preferably between 1:5 and 1:3.

Preferably the amount of active substance incorporated into the composition is between 0.01 and 20 %-wt.

The compositions of the present invention preferably further comprise one or more ingredients selected from the group of flavors, flavor enhancers and fragrances, preferably from the group consisting of menthol, lemon mint flavor, peppermint flavor, herb mint flavor, aspartame and caramel.

Also preferred are compositions further comprising a cosmetically active ingredient that is selected from the group consisting of breath freshening compounds, flavors used for oral hygiene, fragrances used for oral hygiene, active agents used for oral cleansing, and active agents used for dental cleansing.

In another aspect of the present invention there is provided a process for the manufacture of an orally applicable film applicable for releasing active substances in the oral cavity, said process comprising the steps of:

3c (a) dissolving or dispersing, while stirring, at least one polymer selected from the group of water-soluble or water-dispersible polymers, to form a solution or dispersion;

(b) adding the active substance, nicotine bitartrate;

(c) coating this solution or dispersion onto a carrier material which has a surface tension which prevents the solution or dispersion from being soaked into the carrier material;

(d) drying the solution or dispersion to form said film;

(e) peeling the film off the carrier material; and (f) cutting the film into pieces of suitable size.

Preferably in said process said polymer(s) is/are selected from the group consisting of: water-soluble cellulose derivatives, in particular hydroxypropylmethyl cellulose, hydroxyethyl cellulose, hydroxypropyl cellulose; and polyvinyl pyrrolidone, carboxymethyl cellulose, polyvinyl alcohol, sodium alginate, polyethylene glycol; and natural gums, in particular xanthane gum, tragacantha, guar gum, acacia gum, arabic gum; water-dispersible polyacrylates, in particular polyacrylic acid, methylmethacrylate copolymer, carboxyvinyl copolymers; and mixtures of the aforementioned polymers.

Preferably said solution or dispersion further contains one or more ingredients selected from the group of flavors, flavor enhancers, fragrances, breath freshening compounds, flavors used for oral hygiene, fragrances used for oral hygiene, active agents used for oral cleansing, and active agents used for dental cleansing.

The mucoadhesive film of the present invention contains as essential components a water-soluble polymer or a combination of water-soluble polymers/ one or more plasticizers or surfactants, one or more polyalcohols, and a pharmaceutically or cosmetically active ingredient.

The polymers used for the mucoadhesive film include polymers .which are hydrophilic and/or water-dispersible. Preferred polymers are water-soluble cellulose-derivatives. Hydroxypropylmethyl cellulose, hydroxyethyl cellulose, or hydroxypropyl cellulose, either alone, or mixtures thereof, are particularly preferred. Other optional polymers, without limiting the invention, include polyvinyl pyrrolidone, carboxymethyl cellulose, polyvinyl alcohol, sodium alginate, polyethylene glycol, natural gums like xanthane gum, tragacantha, guar gum, acacia gum, arabic gum, waterdispersible polyacrylates like polyacrylic acid, .

methylmethacrylate copolymer, carboxyvinyl copolymers. The concentration of the water-soluble polymer in the final film can vary between 20 and 75 % (w/w), preferably between 50 and 75 % (w/w).

The surfactants used for the mucoadhesive film may be one or more nonionic surfactants. When a combination of surfactants is used, the first component may be a polyoxyethylene sorbitan fatty acid ester or a cc-hydro-Q-hydroxypoly (oxyethylene)poly (oxypropylene)poly(oxyethylene) block copolymer, while the second component may be a polyoxyethylene alkyl ether or a polyoxyethylene castor oil derivative. Preferably, the HLB value of the polyoxyethylene sorbitan fatty acid ester should be between 10 and 20, whereby a range of 13 to 17 is particularly preferred. The ahydro-Q-hydroxypoly(oxyethylene)poly(oxypropylene) poly(oxyethylene) block copolymer should contain at least 35 oxypropylene-units, preferably not less than 50 oxypropyleneunits.

The polyoxyethylene alkyl ether should have an HLB value between 10 and 20, whereby an HLB value of not less than 15 is preferred. The polyoxyethylene castor oil derivative has to have an HLB value of 14-16.

In order to achieve the desired instant wettability, the ratio between the first and second component of the binary surfactant mixture should be kept within 1:10 and 1:1, more preferably between 1:5 and 1:3.

The total concentration of surfactants in the final film depends on the properties of the other ingredients, but usually has to stay between 0.1 and 5 % (w/w).

The polyalcohol is used to achieve the desired level of softness of the film. Examples of polyalcohols include glycerol, polyethylene glycol, propylene glycol, glycerol monoesters with fatty acids or other pharmaceutically used polyalcohols. The concentration of the polyalcohol in the dry film usually ranges between 0.1 and 5 % (w/w).

The film is well suited for the delivery of a wide range of pharmaceutically active ingredients via the mucous membranes of a patient, particularly the buccal mucosa. Therapeutic agents which exhibit absorption problems due to solubility limitations, degradation in the gastro-intestinal tract, or extensive metabolism, are particularly well suited. Without limiting the invention, examples of the therapeutic agents include hypnotics, sedatives, antiepileptics, awakening agents, psychoneurotropic agents, neuromuscular blocking agents, antispasmodic agents, antihistaminics, antiallergics, cardiotonics, antiarrhythmics, diuretics, hypotensives, vasopressors, antitussive expectorants, thyroid hormones, sexual hormones, antidiabetics, antitumor agents, antibiotics and chemotherapeutics, and narcotics.

The amount of drug to be incorporated into the film depends on the kind of drug and is usually between 0.01 and 20 % (w/w), but it can be higher if necessary to achieve the desired effect.

Cosmetically active agents may include breath freshening compounds like menthol, other flavors or fragrances commonly used for oral hygiene, and/or actives used for dental and/or oral cleansing like quarternary ammonium bases. The effect of flavors may be enhanced using flavor enhancers like tartaric acid, citric acid, vanillin, or the like. Colorants which may optionally be mixed in the film must be safe in terms of toxicity and should be accepted by the Food And Drug Administration for use in cosmetics.

The mucoadhesive film according to the present invention can. be prepared as follows: The polyalcohol, surfactants, plasticizers, and possible other ingredients except the water-soluble or water-dispersible polymer(s) are dissolved in a sufficient amount of a solvent which is compatible with them. Examples of compatible solvents include water, alcohols or mixtures thereof. After a clear solution has been formed, the water-dispersible polymer or mixture of water-dispersible polymers is slowly added with stirring, and heat if necessary, until a clear and homogeneous solution has been formed, followed by the addition of active ingredients and flavors. The solution is coated onto a suitable carrier

ד material and dried to form a film. The carrier material must have a surface tension which allows the polymer solution to spread evenly across the intended coating width without soaking in to form a destructive bond between the two. Examples of suitable materials include non-siliconized polyethylene terephthalate film, non-siliconized kraft paper, polyethylene-impregnated kraft paper, or non-siliconized polyethylene film.

The coating of the solution onto the carrier material can be performed using any conventional coating equipment. A more preferred coating technique would involve a knife-over-roll coating head.

The thickness of the resulting film depends on the concentration of solids in the coating solution and on the gap of the coating head and can vary between 5 and 200 pm. Drying of the film is carried out in a high-temperature airbath using a drying oven, drying tunnel, vacuum drier, or any other suitable drying equipment, which does not adversely affect the active ingredient(s) or flavor of the film. In order to reliably avoid an adverse feeling in the mouth, a dry film thickness of 70 pm should not be exceeded.

For better ease of use, the dry film can be cut into pieces of suitable size and shape and packed into a suitable container.

The invention will now be explained more specifically with reference to the following example, which is given for illustration of this invention and is not intended to be limiting thereof.

EXAMPLE

82.7 g Kollidon 30 (a polyvinylpyrrolidone; supplied by BASF) are dissolved in a solution of 360 ml water and 1330 ml ethanol at ambient temperature with stirring. Then, 110.25 g hydroxypropylmethyl cellulose are added at 55-60 °C and stirred vigorously until the solution is clear and homogeneous. After the mixture has been allowed to cool, 39.4 g flavor are added, followed by adding a mixture of 20.69 g nicotine bitartrate and 15.75 g caramel liquid in 60 ml water, with stirring. The thusobtained liquid is then coated onto a suitable carrier material, for example non-siliconized, polyethylene-coated kraft paper, using conventional coating/drying equipment. Coating gap and web speed have to be adjusted in such a way that a dry film thickness between 20 and 50 pm is obtained. The drying temperature depends on the length of the drying oven and the web speed, and has to be adjusted in such a way that the solvents are removed completely, or at least almost completely, from the film. The resulting film is peeled off the carrier web and cut into pieces of suitable shape and size, so as to deliver a nicotine dose between 1-2 mg per piece.

It will be evident to those skilled in the art that the invention is not limited to the details of the foregoing illustrative examples and that the present invention may be embodied in other specific forms without departing from the essential attributes thereof, and it is therefore desired that the present embodiments and examples be considered in all respects as illustrative and not restrictive, reference being made to the appended claims, rather than to the foregoing description, and all changes which come within the meaning and range of equivalency of the claims are therefore intended to be embraced therein.