MX2008007839A - Water-soluble films comprising low-viscosity alginates - Google Patents

Abstract

A film comprising as a film-forming agent an alginate salt of monovalent cation or a mixture of alginate salts containing at least one alginate salt of monovalent cation, the film-forming agent being such that a 10%aqueous solution thereof at a temperature of 20°C has a viscosity of 100-1000 mPas, as measured at a shear rate of 20 rpm by use of a Brookfield viscometer with a spindle No. 2. A method of preparing the film. The film is useful for delivery of active ingredients to a mammal.

Description

WATER SOLUBLE FILMS COMPRISING LOW VISCOSITY ALGINATES FIELD OF THE INVENTION The present invention relates to a polymeric film comprising an alginate polymer as well as a method for preparing such a film. Further, the invention relates to a composition in the form of an alginate film, comprising at least one biologically active substance, such as a therapeutically active substance, and with a method for the preparation of such a composition. Finally, the invention relates to the use of a polymeric film comprising an alginate polymer for preparing a medicament, as well as to the use of a pharmaceutical film composition based on a polymer film comprising an alginate polymer for therapy. BACKGROUND OF THE INVENTION Alginate, the salt of alginic acid, is a linear polysaccharide produced naturally by brown seaweeds (Phaeophyceae, mainly Laminaria). It is typically composed of 100-3000 monomer residues bonded together in a flexible chain. These residues are of two types, that is residues of D-mannuronic acid (M) linked by β- (1? 4) bonds and L-guluronic acid (G) linked by a- (l? 4) bonds respectively. The residues are epimers (residues of D-mannuronic acid that are enzymatically converted to Ref. No.: 193807 residues of L-guluronic acid after polymerization) and only differ in C5. However, in the polymer chain they give rise to very different conformations; any of the two D-mannuronic acid residues are diequatorially linked to 4Ci while the bond connecting either of the two guluronic acid residues is a diaxial-1C4 bond / as illustrated in Formula I, below. Formula I The waste is organized in blocks of waste that alternate identically or strictly (for example MMMMMM .... GGGGGG .... OR GMGMGMGM ....). Different monovalent and polyvalent cations, for example Na +, K +, NH +, g2 + and Ca2 +, are present as counterions to the negatively charged groups of the alginates. Depending on factors such as average polymer chain length, polymer composition and the cations present in the flow characteristics of alginates vary widely, from free circulation (low viscosity) to anti-drip (high viscosity).

The alginates find applications in various fields, for example in food and pharmaceutical products where they are applied, for example, as agents, thickeners, stabilizers and gelling agents. Its use in pharmaceutical compositions is mentioned in a number of patents and patent applications. Thus, US Patent No. 6,923,988 assigned by Lipocine, Inc. describes a solid pharmaceutical composition for improved delivery of active ingredients. It is mentioned that the pharmaceutical composition may comprise alginate as a disintegrant. US Patent No. 6,923,981 assigned to Warner-Lambert Company describes the rapid dissolution of orally consumable films for oral hygiene. A list of film-forming agents is given and even when sodium alginate is mentioned therein, pullulan is indicated to be preferred and no example of an alginate film is given. U.S. Patent No. 6, 656, 493 and 6, 740, 332, both assigned to Wm. Wrigley Jr. Company describes edible film formulations for oral hygiene. Film formulations contain at least three types of film-forming agents, viz. a maltodextrin, a hydrocolloid and a filler. The purpose of the hydrocolloid is to provide esters and reduce brittleness and alginates are mentioned as examples of a hydrocolloid.

U.S. Patent Application No. 20050013847, assigned to FMC Corporation, relates to delivery systems comprising a homogeneous, heat shrinkable gel film, wherein the gel film comprises: a film forming amount of a water soluble thermoreversible alginate and optionally at least one of a plasticizer, a second film former, a thickening agent, and an agent that controls the pH; and an active substance. The second film former should be optional but all the examples show films comprising at least two film formers. The exemplified process for preparing the gel film comprises heating the alginate-containing mixture to an elevated temperature to form a homogeneous molten composition. The active substance is added either before or after the formation of the molten composition and the molten composition containing the active substance then it is cooled and further processed. It is mentioned that to modify the dissolution profile of the dosage forms the films may contain aggregate components that can create solid dosage forms having immediate, enteric or delayed release capabilities. U.S. Patent No. 6,709,671, assigned to LTS Lohmann Therapie-Systeme AG discloses a monolayer film formed of a mucoadhesive composition which comprises at least one water soluble polymer; a surfactant alone or in combination with at least one member selected from the group consisting of a polyalcohol and a plasticizer, or a polyalcohol and a plasticizer; and at least one cosmetic or pharmaceutical ingredient, for application inside the mouth. There are many ways to deliver active pharmaceutical ingredients (drugs) to the body (collectively called formulations) depending on the type of drug and the disorder to be treated. For example, oral formulations such as tablets, capsules and pills; drug solutions in prefilled bottles and syringes for injection; topical formulations such as patches and ointments as well as nasal sprays. There are also other ways of delivering drugs, such as implanted pumps and formulations in depot delayed release that must be placed in the body. The selected formulation will typically have a marked influence on the therapeutic result of the drug, its side effects and the ease with which the patient can use the medication. The most widely used drug formulation is the tablet that will be swallowed for the release of the drug in the intestine. The tablets consist of a drug that is mechanically compressed together with a number of additional substances that provide the structure and supply properties of the tablet. The tablets need to be swallowed with a liquid such as water and some patients, for example children and elderly patients, may have difficulty swallowing them. A problem associated with oral tablets is that many drugs can be degraded during passage through the acidic environment of the stomach. When the drug has entered the intestine, the drug is transported into the bloodstream via the portal vein within the liver where a large portion of the active pharmaceutical ingredients is typically metabolized to inactive chemicals by enzymes that normally take care of foreign substances in the liver. food, viz. the so-called first-pass metabolism. These factors result in a significant delay before a positive therapeutic effect can be observed, leading to a risk of gastrointestinal side effects increased by the need to administer considerably higher amounts of drug than would be necessary by, for example, direct injection of a drug solution inside a vein. Although injections provide a rapid pharmacological effect and reduce the risk of side effects, injections should usually be performed by medically qualified personnel in a medical center or hospital, thus limiting the convenience of this form of administration.

Nasal sprays may produce a rapid onset of action but are generally limited to local treatment of the respiratory tract. Other forms of formulations such as reservoirs, patches or infusion devices are generally applied to address conditions where a sustained level of drug is required for longer periods. SUMMARY OF THE INVENTION It is a general object of the present invention to provide a film that is adhesive to a wet surface of the body of a mammal and has a rapid dissolution profile in contact with the humid surface. It is another general object of the invention to provide a film that is easy to prepare and does not require the presence of additives, such as surfactants and disintegrants, in order to obtain the beneficial properties indicated above. It is still a further object of the invention to provide a film formulation containing a biologically active substance, which can be a therapeutic or non-therapeutic substance, the film formulation can be used to deliver the biologically active substance to a mammal by the application of the film formulation to a wet surface, such as a mucous membrane, of the mammal.

It is still a further object of the invention to provide a pharmaceutical film composition which is easy and convenient for self-administration, which has a reduced dose of the active ingredient and thus less potential side effects and which can produce the desired pharmaceutical effect of a fast and reliable way. It is another object of the present invention to provide a pharmaceutical film composition comprising one or more active ingredients that allow the first pass metabolism of the active ingredients to be avoided. It is another object of the present invention to provide a pharmaceutical film composition that allows the rapid onset of the pharmacological action of one or more active ingredients.

It is another object of the invention to provide a pharmaceutical film composition that allows the administration of active ingredients that are susceptible to destruction or deterioration in the gastrointestinal tract. It is still a further object of the invention to provide a pharmaceutical or non-pharmaceutical film composition that allows easy and appropriate administration of active ingredients systemically and / or locally to a mammalian subject. It is still a further object of the invention to provide a pharmaceutical or non-pharmaceutical film composition that adheres firmly to the mucosa of the mouth of a mammalian subject before it has dissolved, decreasing the risk to lose it, from the mouth of the subject, either voluntarily or involuntarily. It is another object of the invention to provide a pharmaceutical or non-pharmaceutical film formulation comprising active ingredients that are susceptible to deterioration at elevated temperatures, such as temperatures substantially higher than room temperature. It is a further object of the invention to provide a pharmaceutical or non-pharmaceutical film formulation capable of containing at least one active ingredient at a high level. It is an object of the present invention to provide a method for preparing a film that can be used in a pharmaceutical or non-pharmaceutical film composition according to the invention. The present invention is based on the surprising finding that by using an alginate composition as defined herein, as an independent film-forming agent, a film that is adhesive to a moist surface of the body of a mammal and that has A rapid dissolution profile in contact with the wet surface can be obtained. Very advantageously, the film of the invention is bioadhesive, which means that when applied to a wet surface, such as a mucosa or a cornea, it adheres thereto, preferably in seconds.

In addition, in contact with a wet surface, such as a mucosa, the film of the invention is capable of dissolving within a period of time of less than a few minutes, for example in less than 2 minutes. Thus, according to one aspect of the invention there is provided a film comprising as a film-forming agent a monovalent cation alginate salt or a mixture of alginate salts containing at least one monovalent cation alginate salt, the agent Film former is such that a 10% aqueous solution thereof at a temperature of 20 ° C has a viscosity of 100-1000 mPas, as measured at a shear rate of 20 rpm by the use of a viscometer of Brookfield with a spindle No. 2. In one embodiment of the invention the film comprises at least one biologically active substance. According to another aspect of the invention, there is provided the use of a composition for preparing a film, the composition comprises one or more active ingredients and, as a film-forming agent, a monovalent cation alginate salt or a mixture of salts of monovalent cation alginate, characterized in that the film-forming agent is such that a 10% aqueous solution thereof at a temperature of 20 ° C has a viscosity of 100-1000 mPas.

By using the film-forming composition of the invention, a film formulation can be prepared, comprising a film capable of containing a high amount of one or more active ingredients, and having very desirable characteristics, according to what is mentioned herein. previously. Thus, in accordance with one aspect of the invention, there is provided a film formulation comprising a biologically active ingredient, the film formulation is capable of adhering firmly to a moist surface of the body of a mammal and has a rapid dissolution profile in contact with the wet surface. In one embodiment, the film composition is a pharmaceutical composition; in another embodiment the film composition is a non-pharmaceutical composition. According to another aspect there is provided a method for preparing a film by preparing a composition comprising, as a film-forming agent, a monovalent cation alginate salt or a mixture of alginate salts containing at least one salt of monovalent cation alginate, the film-forming agent is such that a 10% aqueous solution thereof at a temperature of 20 ° C has a viscosity of 100-1000 mPas, as measured at a shear rate of 20 rpm by using a Brookfield viscometer with a No. 2 spindle, distributing the composition over a solid surface, and allowing the composition to dry on the surface. Generally, once the alginate salt composition of the invention has dissolved, the viscosity of the alginate solution varies only slightly with time. For example, the viscosity was measured, as indicated hereinabove, in 10 minutes of the alginate solution. In one embodiment of the method of the invention, at least one biologically active substance is added to the film-forming composition. In accordance with yet another aspect, the use of the film of the invention for preparing a medicament is provided. In accordance with yet another aspect the invention provides a method of medical treatment of a mammal in need of such treatment by administering to the mammal a pharmaceutical film composition according to the invention. Objects, aspects and still further embodiments of the invention will be apparent from the following description and the appended claims. DETAILED DESCRIPTION OF THE INVENTION In accordance with one embodiment of the invention, an alginate film is provided, based on a film forming composition comprising an alginate composition. The alginate composition to be used according to the present invention comprises at least one salt of alginic acid and one or more monovalent cations, preferably selected from the sodium, potassium and ammonium ions. More preferably the alginate composition of the invention comprises sodium alginate. The alginate composition of the invention has a dynamic viscosity, as measured in a 10% aqueous solution thereof at a temperature of 20 ° C with a Brookfield LVF viscometer (from Brookfield Engineering Laboratories, Inc.), using a No. 2 spindle at a shear rate of 20 rpm, 100-1000 mPas, or 200-800 mPas, for example 300-700 mPas. It should be noted that for the purposes of the present invention, and unless otherwise indicated, any% value is based on the weight of the components. In other words for example 100 g of a 10% aqueous solution of an alginate containing 10 g of alginate and 90 g of the other components, including water. The alginate composition of the invention preferably has an average content of guluronate (G) from 50 to 85%, preferably from 60 to 80%, most preferably from 65 to 75% by weight, an average mannuronate (M) content from 15 to 50%, preferably from 20 to 40%, most preferably from 25 to 35% by weight, and an average molecular weight in the range from 30,000 g / mol to 90,000 g / mol, for example from 35,000 g / mol to 85,000 g / mol mol, such as from 40,000 g / mol to 70,000 g / mol or from 40,000 g / mol to 50,000 g / mol. An exemplary alginate composition for use in accordance with the present invention is Protanal® LFR 5/60, sold by FMC BioPolymer. Protanal® LFR 5/60 is a low molecular weight sodium alginate (low viscosity) extracted from the stem of Laminaria hyperborea. As an example of an alginate that can be mixed with the alginate of the monovalent cation in order to modify the viscosity of the alginate composition, mention can be made of Protanal® LF 10/60. This is a sodium alginate, sold by FMC BioPolymer, which has a% G / M ratio of 65-75 / 25-35, a viscosity of 20-70, as measured in a 1% aqueous solution of the same at a temperature of 20 ° C and at a shear rate of 20 rpm by using a Brookfield viscometer with a spindle No. 2. An increase in the average molecular weight of the alginate polymer composition will result in an increase in the viscosity of the composition. The higher the viscosity, the lower the resulting release ratio in alginate matrix systems. It is contemplated that the viscosity of the alginate composition can be adjusted by mixing any number of alginates having differing viscosities. This should be done if a mixture of alginates is used, then not all alginates, taken separately, need to have a viscosity within the specified ranges. However, to be useful for the purposes of the invention the alginate mixture resulting from the combination of more than one alginate species must be such as to have a viscosity value within the range indicated above. In fact, very advantageously the alginate-based film-forming composition of the invention will result in a film having suitable dissolution properties in contact with a wet surface, such as a mucous membrane or a cornea. The dissolution characteristics of the film strongly influence the release of any active ingredient incorporated in the film to the body of the subject being treated. By means of the film of the invention which dissolves rapidly it is possible to supply, in a short period of time, in this case essentially the dissolution time of the film, in this case preferably less than 2 minutes, an amount of active ingredient within the body of the subject that is treated. This will give a very advantageous concentration against - the time profile of the ingredient active within the body of the subject, allowing a high maximum level of concentration to be obtained in a relatively low total dose of the active ingredient, compared to other forms of administration. The film-forming composition of the invention may additionally comprise any suitable excipient, such as one or more fillers or plasticizers. The plasticizer, when present, can be selected from for example polyethylene glycols, glycerol and sorbitol. A preferred plasticizer is sorbitol together with a small part of glycerol. An appropriate amount of plasticizer is for example from 10 to 85 g, or from 30 to 70 g, for example from 50 to 60 g of plasticizer per 100 g of alginate. The filler, when present, may be for example microcrystalline cellulose. An appropriate amount of filler can be 0-20%, for example 5-10% by weight of the total pharmaceutical composition. However, it should be understood that it is a very advantageous feature of the invention that, apart from the alginate composition, no or very low level of other agents, such as fillers and plasticizers, are required which influence the physical characteristics of the movie. This feature allows a high level of active ingredient to be included in the composition of the film of the invention. He Active ingredient, when present in a high amount can by itself contribute to the advantageous properties of the film, such as appropriate surface properties.

The mechanical properties of the film of the invention are very satisfactory, in particular the film is flexible, viz. this allows it to bend and fold without breaking, and has a very good tensile strength. By using the alginate-based film-forming composition as defined herein above a formulation according to the invention can be prepared, in the form of a film containing one or more biologically active ingredients. The terms "biologically active ingredient", "active ingredient", "active substance" and "biologically active substance", are used alternatively herein and means that they include any substance having a desired biological activity or effect when administered to a mammalian subject of according to the invention. The active ingredient / substance can be for example a therapeutically active ingredient. It can also be a biologically active ingredient that is not generally considered as a pharmacist, for example a naturopathic preparation. As an example of a non-pharmaceutical active ingredient there may be mentioned a stimulant or a nutraceutical, the latter generally defined as a substance that can be considered a food or part of a food and provides medical or health benefits, including the prevention and treatment of the disease. Other biologically active substances may have a therapeutic use and a non-therapeutic use. The term "wet surface" as used herein preferably refers to a surface having a moisture preferably similar to that of a normally hydrated mucosa or cornea of a mammalian subject, but also to a somewhat less moist surface such as the one inside the ear. The film formulation according to the invention preferably has a thickness of 0.1 to 2 mm, for example 0.2 to 1 mm, from 0.2 to 0.6 mm, for example 0.5 mm. The dosage unit may be of any suitable surface area, taking into consideration the concentration of the active ingredient within the film and the appropriate dosage to be administered. As an example, a dosage unit having a surface area of from 1 cm 2 to 10 cm 2 can be selected when the film is to be applied inside the buccal cavity, while a smaller surface area, such as from 0.04 cm 2 to 1 cm 2 can be applied. be preferable when the film should be applied on the eye. It will be in the person's knowledge experienced in the art adapting the size and shape of the film dosing unit taking into consideration such parameters as the loading of the active ingredients within the film, the dosage required, the administration site to the body of the mammalian subject etc. Also, it should be considered that the film dosing unit can have any suitable shape for adapting the administration site of the active ingredient, for example it can be rectangular, circular, oblong, oval etc. The film formulation of the invention may comprise up to 85% by weight of the total formulation, of one or more active ingredients, for example up to 70% by weight, or up to 60% by weight, such as more than 20% by weight, or more than 30% by weight, for example more than 40% by weight. However, it should be understood that it is also contemplated that the film formulation of the invention may contain a very low level of active ingredient, if so desired for some reason, for example if the active ingredient is to be supplied in a very low dosage. . Thus, if preferred, the film formulation can contain the active ingredient at a very low level, for example as low as 0.000001% by weight. The active ingredients can be selected from all currently known active substances and, in the future - from those currently unknown.

Thus, according to one aspect, the invention provides a unit dosage form in the form of a film having a selected surface area and thickness and containing an active ingredient in a defined concentration.

The active ingredient, which leaves the dissolved film formulation of the invention to diffuse through the interface will reach the underlying tissue and blood circulation, to allow not only local but also systemic administration while essentially avoiding first-pass metabolism and gastrointestinal digestion. In addition to the active ingredients the film formulation of the invention can comprise any pharmaceutically or physiologically acceptable additive (eg non-toxic at the aggregate level), such as one or more flavoring agents (taste maskers) and / or coloring agents. Examples of flavoring agents are sorbitol, peppermint, orange flavoring, cherry flavoring, and cranberry extract. Examples of coloring agents are titanium dioxide and color for green or red food. The pH of the film influences the rate of dissolution of the film. Generally, a film having a pH from 6 to 9, for example from 8 to 9, has an optimum dissolution rate in contact with a wet surface. The dissolution time of a film according to the invention additionally is proportional to the thickness of the film and the concentration of any particle in the film. The person skilled in the art, taking into consideration the desired time of dissolution for a given application, will be able to select an appropriate film thickness simply by preparing the films of a range of different thicknesses and testing the films for the dissolution time. The active substance can be dissolved in the film solution, and / or can be undissolved and be present therein for example as an emulsion or suspension. For example, the active substance may be present as a suspension of particles. In this case, as indicated above, the dissolution time will be somewhat larger due to the presence of particulate material in the film. The person skilled in the art will be able to determine the thickness and unit dosage surface required and taking into consideration the level of particulate material and desired dissolution time, if necessary by performing simple tests. In one embodiment of the invention, the film of the invention is supplied with the printed text material or printed images, such as a brand name, a trademark, a dosage indication, a symbol etc.

In one embodiment of the invention, the formulation of the film is a pharmaceutical film composition. The "pharmaceutical film composition", or "pharmaceutical film formulation" etc., as used herein, means including a composition according to the invention in the form of a film, which comprises any of the biologically active ingredients. according to what is defined here above, viz. any substance that has a desired biological activity or effect when administered to a mammalian subject, and the substance is useful in therapy. The present invention also relates to the use of the pharmaceutical film composition of the invention for therapy, especially for nicotine therapy and analgetic therapy. The very advantageous properties of the pharmaceutical formulation of the invention in the treatment of the disorders according to the aforementioned, as well as in the treatment of a number of other diseases that will be readily self-evident for those skilled in the art, They will be obvious under the light of the description. It should be noted that the pharmaceutical film composition according to the invention can be administered orally, nasally, rectally, intravaginally, topically, via wounds, the ears and the eyes of a patient. When administered via the eyes of a patient, the pharmaceutical film composition is preferably applied in the lower part of the eye directly to the cornea. When the film is used as a means of administering an active ingredient to the eye, this may be in replacement of for example eye drops or ointments, with obvious advantages. In fact, eye drops can be difficult to administer to obtain a homogenous and accurate dosage. Also, ointments or other semi-liquid formulations are often provided in packings, such as tubes or bottles, of fairly short shelf life after opening due to, for example, spoilage bacteria, so that in many cases the packaging must be discarded even when it is not empty yet. The formulation of the invention, on the other hand, is easy to apply in an accurate and controlled dosage and can be provided in individual dosage packages, for example in bubble containers, in sealed envelopes or in any other appropriate form, as will be obvious for the person experienced in the art. The film of the invention can be used for the delivery of a variety of substances to the body and for a range of different purposes.

Since the properties of the film are to adhere and dissolve quickly and completely in contact with the wet tissue, thereby releasing the substance in solution, the most obvious application will be to supply substances locally. Examples of local disorders are microbial infections in the upper respiratory tract and genital tract, local inflammations in muscles or joints, skin disorders such as psoriasis, wound healing or for local pain management. However, the compounds released from the film can also be absorbed by the surrounding tissue and further distributed to the rest of the body via the bloodstream. This concept of fast and efficient supply to the bloodstream with few side effects has been shown for many substances by rectally administering substances. However, the use of rectal formulations is not widely used possibly due to the inconvenience of administration and due to the tradition of using tablets for oral administration. The films can also be used to deliver certain substances to the body that are slowly absorbed by the mucosa by, for example, releasing the substance into the oral cavity which will be swallowed for a slow supply to the intestine.

To illustrate how film-based delivery can be used for various disorders, some examples are given below: The film can be used to treat disorders in the stomach, where the substances are supplied from the "serum side" instead of the side gastric or by absorption of the intestine and after the passage of the liver. Typical stomach disorders favorable for film delivery would be acid-related symptoms such as gastritis, ulcers, reflux or infections caused by Pylori Helicobacter. The types of substances that can be used include antimicrobial agents, histamine 2 receptor antagonists, and proton pump inhibitors. Because the film can supply substances without the need to swallow water as with compressed tablets the invention is very useful for any medication wherein the disorder of the patients makes them unable to swallow and / or keep the medication in the body. The typical disorders are stroke, migraine, acute heart conditions and patients with obstructed digestion channel, dizziness, nausea and other situations where water is not available or can be swallowed. Many different types of substances can be used, among these substances that act in the CNS such as serotonin receptor antagonists, prescription-free seasickness tablets and various anti-inflammatory substances. Another disorder wherein the technology of the film described in this application can be used is obesity. In fact, obese patients can be treated surgically (having parts of their stomach or bowel removed) to reduce the absorption of substances from the intestine. The provision of medication by film preparations having their effects on the nervous system would be unaffected by the patents of gastrointestinal operation history. An example of a type of substance that can be supplied in a film formulation according to the invention is sibutramine. An interesting group of substances comprises peptides and proteins. The substances of this group can not be easily received via the mouth and in the intestine since they will be digested by the enzymes (proteases and peptidases) present in the stomach and intestine. However, peptides and certain proteins can be absorbed through the mucosal tissue after being released from the film since, in contrast to the intestine; there is little peptidase activity in the mouth. Since the film melts in the mouth, does not have any sugar additive and does not have to be swallowed, it will be very appropriate for oral diabetes therapy. Examples of classes of appropriate substances are the sulfoneurides, biguanid derivatives. The patients who are very suitable candidates for the supply of film substances are the elderly people and the children. Both groups of patients are typically receiving more medication than the average and frequently can not self-medicate properly. Older people often receive medication for sleep and for disorders typically associated with the aging process such as dementia, Parkinson's disease, Alzheimer's disease, anxiety, depression and deficiencies of vitamins, nutrients and cofactors. Substance classes for this patient cohort include drugs that act on the CNS, antimicrobial agents, and low molecular weight cofactors. In one embodiment of the invention, there is provided a method for preparing a film comprising, as a film-forming agent, a monovalent cation alginate salt or a mixture of alginate salts containing at least one monovalent cation alginate salt. , the film-forming agent is such that a 10% aqueous solution of the film at a temperature of 20 ° C has a viscosity of 100-1000 mPas, as measured at a shear rate of 20 rpm by use of a Brookfield viscometer with a No. 2 spindle, by preparing a solution of the film forming agent, distributing the solution on a solid surface, and allowing the solution to dry on the surface. To distribute a solution or composition on a solid surface the solution or composition can simply be poured on and / or spread uniformly on the surface, for example by the use of a suction vane or similar equipment. A film formulation according to the present invention, which contains at least one active ingredient, can be prepared for example by dissolving the active ingredients in an appropriate solvent; optionally adjusting the pH of the solution of active ingredients around pH neutral or alkaline, - optionally adding plasticizer and microcrystalline cellulose, as well as any other appropriate physiologically and / or pharmaceutically acceptable additive; adding an alginate salt composition that is such that a 10% aqueous solution thereof at a temperature of 2 0 ° C has a viscosity of 100-1000 mPas as measured at a shear rate of 20 rpm per medium of a Brookfield viscometer with a No. 2 spindle; and processing the solution to get a movie. A suitable solvent for dissolving the active ingredients may be for example water or an alcohol, for example methanol, ethanol, n-propanol, isopropanol, or t-butanol. Depending on the solubility and stability of the active ingredients, the solution thereof can be adjusted to a pH of 6-10, for example 8-10, or 8-9. To this end, any agent that adjusts the pH that is compatible with the intended use and with the other ingredients of the composition can be used, for example an appropriate buffer system, aqueous sodium hydroxide, aqueous potassium hydroxide, sodium bicarbonate etc. . In one embodiment of a method for preparing a film formulation according to the invention comprising at least one active ingredient, the active ingredients and the alginates are simply dissolved together in an appropriate solvent or mixture of solvents and the solution is then processed to a movie and it is allowed to dry. In another embodiment, the active ingredient is added to the alginate solution to give an emulsion or suspension of active ingredient in the alginate solution. In a further embodiment, the film-forming composition of the invention can comprise both dissolved and undissolved active ingredients. As an example, a film-forming composition of the invention may comprise a combination of the active ingredient dissolved in the alginate solution and the active ingredient suspended in the solution. After distributing the film-forming composition, optionally comprising any ingredient active, on the solid surface, it is allowed to dry the composition on the surface. The dry film formulation according to the invention preferably contains a homogeneous distribution of solubilized or suspended active ingredients. This contributes to the very advantageous supply of the active ingredient through the wet surface to which the film adheres. Thus, when it adheres to a moist surface of the body, such as a mucosa or a cornea, the film will quickly dissolve and in the dissolution of the film a concentration gradient of the active ingredient will be quickly established at the interface of the film. and of the wet surface, giving rise to a diffusion of active ingredient through this interface. The active ingredient will thus penetrate the body, leaving the film while the latter dissolves. In one embodiment, the active ingredient is applied to the film of the invention after forming the film, the film may or may not comprise (other) active ingredient. Thus, an active ingredient can be applied for example as an aerosol spray on a dry or wet film. An active ingredient can also be applied as a powder on the film. Also, a flavoring agent can be applied in the same way. The processing of the solution to obtain a dry film may comprise the steps of distributing the solution over a stand and allow the wet film to dry. Drying is preferably carried out at room temperature, for example 17-25 ° C, and under a normal atmosphere for a period of for example 10 hours. The drying can also be carried out under a dry atmosphere or under a lower than atmospheric pressure. In case the active ingredients are not susceptible to thermal degradation, the drying can be accelerated by increasing the temperature, for example at 35 ° C. The film thus obtained can then be formed to the appropriate size and shape, for example by perforation or cutting. Optionally, before processing the solution in a film, any air bubble can be removed for example by moderate heating or by using a vacuum. The formulation of the film according to the present invention presents, for example, the following advantages: the production of the films is reproducible; - no plasticizer or filler is required; - the film can be folded and rolled up without any risk of sticking, cracking or breaking; - the film has a very good surface tension resistance (breakage); - a relatively large amount of active ingredients can be included in the film; - there is no need for heat treatment in the preparation process; the active ingredients are rapidly metabolized without any collapse in the stomach, allowing a reduced dose and less negative side effects, in this way, the film can be administered without any consideration to the ingestion of food; - when applied in the mouth, there is a low risk of spitting the film out, since the films adhere to the mucous membranes in the mouth; - no residue in the mouth after oral or buccal administration; - the text or numbers can be easily printed on the film; - the film can be classified in millimeters and cut in the desired length and shape (eg circular, oval, square, rectangular, etc.); - the dose can be easily adapted individually to each patient; - there is no need to cover it with sugar, or any other cover, making production simpler and less expensive; and the film is free of lactose (which can cause allergic reactions) and gelatin. The specific examples below should be interpreted as merely illustrative, and not limitative of the rest of the description in any way at all. Without further elaboration, it is believed that a person skilled in the art can, based on the description herein, utilize the present invention to its fullest extent. All publications cited herein are hereby incorporated by reference in their entirety. The term "comprising / comprising" means "including / including but not limited to". Thus, other ingredients can be included. EXAMPLES EXAMPLE 1 A film formulation according to the invention was prepared by using the following ingredients: - 12 g of sodium alginate corresponding to Protanal® LFR 5/60 having a viscosity of 300 - 700 mPas as aqueous solution 10% and that has a temperature of 20 ° C; - 80 g of distilled water - 3 g of sorbitol - 2 g of glycerol - 2 g of cranberry extract - 1 drop of color for green food - sodium hydroxide 5 g of paracetamol (as an active pharmaceutical ingredient).

The active pharmaceutical ingredient was mixed with water and the pH adjusted to about 8 - 8.5 by the addition of aqueous NaOH. The plasticizing, flavoring and coloring agents were added. The Protanal® LFR 5/60 was then added to the aforementioned aqueous solution at room temperature in small portions and mixed until a homogeneous solution was obtained. The solution was applied to a 900 cm2 glass plate as a support by means of a suction blade for the application of the wet film. The thickness was adjusted up to 0.8-1 mm. The film was dried for approximately 12 hours at room temperature at atmospheric pressure, giving approximately a 30% loss of film thickness.

The surface area of the film as prepared was 900 cm2. From this film, dosage units of the appropriate size can be obtained. As an example, a 6 cm2 film dosing unit contains approximately 33 mg of paracetamol. When placed inside the mouth, against the palate, the film dosing unit adhered to it practically immediately and dissolved in 1.5 minutes without leaving any residue. EXAMPLE 2 Proceeding generally as in EXAMPLE 1 a film formulation according to the invention was prepared by using the following ingredients: - 12 g of sodium alginate corresponding to Protanal® LFR 5/60 having a viscosity of 300 - 700 mPas as a 10% aqueous solution and having a temperature of 20 ° C; - 80 g of distilled water - 3 g of sorbitol - 2 g of glycerol - 2 g of cranberry extract - 1 drop of green food color - sodium hydroxide - 12 g of paracetamol (as an active pharmaceutical ingredient). A 6 cm2 film dosing unit contains approximately 80 mg of paracetamol. EXAMPLE 3 A film formulation according to the invention was prepared by using the following ingredients: - 12 g of sodium alginate corresponding to Protanal® LFR 5/60 having a viscosity of 300 - 700 mPas as an aqueous solution 10% and that has a temperature of 20 ° C; - 80 g of distilled water - 3 g of sorbitol - 2 g of glycerol - 2 g of cranberry extract - 1 drop of color for green foods - 6 g of ibuprofen (as an active pharmaceutical ingredient) dissolved in ethanol. Ibuprofen was dissolved in a small volume of ethanol and the solution was mixed with water, resulting in the precipitation of ibuprofen crystals. The plasticizing, flavoring and coloring agents were added. The Protanal® LFR 5/60 was then added, at room temperature in small portions and mixed until a homogenous milky white suspension of ibuprofen crystals was obtained. The suspension was applied to a 900 cm2 glass plate as a support by means of a suction blade for the application of the wet film. The thickness was adjusted up to 0.8-1 mm. The film was dried for approximately 12 hours at room temperature at atmospheric pressure, giving approximately a 30% loss of film thickness.

The surface area of the film as prepared was 900 cm2. From this film, dosage units of the appropriate size can be obtained. As an example, a 6 cm2 film dosing unit contains approximately 40 mg of ibuprofen. When placed inside the mouth, against the palate, the film dosing unit adhered to it practically immediately and dissolved in 1.5 minutes without leaving any residue.

EXAMPLE 4 By proceeding generally as in EXAMPLE 1, but using aqueous bicarbonate buffer to regulate the pH of the film-forming composition, a film formulation according to the invention was prepared by using the following ingredients: - 12 g of sodium alginate corresponding to Protanal® LFR 5/60 having a viscosity of 300 - 700 mPas as a 10% aqueous solution and having a temperature of 20 ° C; - 80 g of distilled water - 3 g of sorbitol - 2 g of glycerol - 2 g of cranberry extract - 1 drop of green food color - sodium bicarbonate 5 g of acetylsalicylic acid (as an active pharmaceutical ingredient). A 6 cm2 film dosage unit contains approximately 33 mg of acetylsalicylic acid. EXAMPLE 5 Proceeding generally as in EXAMPLE 1 a film formulation according to the invention was prepared by using the following ingredients: - 12 g of sodium alginate corresponding to Protanal® LFR 5/60 having a viscosity of 300 - 700 mPas as a 10% aqueous solution and having a temperature of 20 ° C; - 80 g of distilled water - 2 g of cranberry extract - 1 drop of color for green food - sodium hydroxide - 12 g of paracetamol (as an active pharmaceutical ingredient). A 6 cm2 film dosing unit contains approximately 80 mg of paracetamol. The film prepared without the plasticizer is more brittle but dissolves very quickly, in contact with a wet surface. EXAMPLE 6 A film formulation according to the invention was prepared by using the following ingredients: - 11 g of sodium alginate corresponding to Protanal® LFR 5/60 having a viscosity of 300 - 700 mPas as an aqueous solution to 10% and that has a temperature of 20 ° C; - 80 g of a buffer solution of aqueous potassium phosphate pH 8.5, 0.1 M. - 2 g of glycerol - 3 g of sorbitol . 5 g of nicotine birtrate (as a biologically active substance). The active ingredient was mixed with the intermediate buffer solution. Glycerol and sorbitol were added. The Protanal® LFR 5/60 was then added to the aqueous solution prepared in this way at room temperature in small portions and mixed until a homogeneous solution was obtained. The solution was applied to a 1200 cm2 glass plate as a support by means of a suction blade for the application of the wet film. The thickness was adjusted to approximately 0.3 mm. The film was dried for approximately 12 hours at room temperature at atmospheric pressure, giving approximately a loss of 30% of the thickness of the film. From this film, which has a dry film thickness of approximately 0.2 mm, 3 cm2 dosage units were cut. When placed inside the mouth, against the palate, the dosing unit of the film adhered to it practically immediately and dissolved in 1.5 minutes without leaving any residue. EXAMPLE 7 By using the same film-forming composition and process as in EXAMPLE 6, it was prepared a nicotine bitartrate film having a wet film thickness of about 0.15 MI, and a dry film thickness of about 0.1 mm. Dosing units of 3 cm2, when placed inside the mouth, dissolved within 45 seconds without leaving any residue. EXAMPLE 8 By proceeding generally as in EXAMPLE 1 a film formulation according to the invention was prepared by using the following ingredients: - 11 g of sodium alginate corresponding to Protanal® LFR 5/60 having a viscosity of 300 - 700 mPas as a 10% aqueous solution and having a temperature of 20 ° C; - 80 g of distilled water - 3 g of sorbitol - 2 g of glycerol - sodium hydroxide 6 g of paracetamol (as an active pharmaceutical ingredient). The films of different thicknesses of dry film were prepared and tested for dissolution time in contact with the wet surface on the palate of the mouth. The results are reported in table 1, below. Table 1: Time of dissolution as a function of the thickness of the dry film of a film of the invention The same films were also prepared with the addition of peppermint oil as a flavoring agent. The flavoring agent efficiently masked the paracetamol flavor without appreciably influencing the dissolution time of the film. In general, the administration of the active ingredient by means of a film formulation according to the invention is surprisingly more efficient than by the use of for example an oral formulation. As an example, a unit dosage of a film of an active ingredient as exemplified herein above shows a therapeutic effect required when it is delivered for example to an adult human subject while containing an amount of active ingredient corresponding only to a fraction of which is usually administered by the oral route to obtain the same level of therapeutic effect, such as analgesia.

EXAMPLE 9 The films obtained by the use of an alginate having a viscosity according to the invention were compared with the films obtained by the use of alginates that are not according to the invention. The following ingredients were used: - 11 g of alginate A, or C (as defined in Table 1 below) - 3 g of glycerol - 4 g of sorbitol - 80 g of distilled water An aqueous solution of glycerol and sorbitol was prepared and the alginate was added under gentle stirring by turning the blades at the bottom of the mixing vessel. The solution was mixed until homogeneous, so additional water was added, if required. The solution was applied to a 900 cm2 glass plate as a support by means of a suction blade for the application of the wet film. The thickness of the film was adjusted to 1 mm. The film was dried for approximately 12 hours at room temperature at atmospheric pressure. The characteristics of the films obtained by the use of alginate A, B and C, respectively, are presented in table 2.

Table 2 * Measured in a 1% solution at a shear rate of 20 rpm by means of a Brookfield viscometer with a No spindle. 2. ** That corresponds to a viscosity of 300-700 mPas as a 10% aqueous solution. *** Which corresponds to a viscosity of more than 1000 mPas as a 10% aqueous solution. EXAMPLE 10 Five compounds of different therapeutic uses and of different chemical natures were selected to study if they could be included in the dosage form of film and with contained supply properties (the structural integrity of the film, adheres firmly to the mucus, dissolves rapidly under wet conditions, releases the substance when dissolved.) Substance 1: Paracetamol (N-Acetyl-p-aminophenol or '-Hydroxyacetanilid) pKa 9.5, Mw 151.2 only slightly soluble in water Substance 2: Acetylsalicylic acid; 2 -Acetoxibensoesira pKa 3.5, Mw 180.16 1 g / 100 g of water Substance 3: Ibuprofen; p-Isobutylhydratropic acid pKa 4.8, Mw 206.29 slightly soluble in water Substance 4: Nicotine; (S) - (l-Methyl-2-pyrrolidinyl) pyridine 3 pKa 8.5, Mw 162.23 liquid miscible with water substance 5: Lidocaine; Diethylaminoacet-2, 6-xylidide pKa 7.9, Mw 234.34 The hydrochloride salt dissolves in water As can be seen by the chemical formulas, these compounds differ in size, pKa, water solubility, type of ring systems, presence of basic groups (amine groups) and acidic (carboxylic) groups (the whole substance is shown as completely protonated ) etc. Paracetamol, nicotine and lidocaine have high values of pKa, 7.9-9.5. Ibuprofen and acetylsalicylic acid have low pKa values, 3.5-4.8. The pKa values show that the first three substances are basic while the last two compounds are acidic. Paracetamol and ibuprofen are reported to be only slightly soluble in water and the basic and acidic substances must have a low or high pH. Despite the great variability in the physical properties reflected in the different properties of Solubility of these substances are all possible to be successfully formulated into a film formulation according to the invention with each positive property retained, indicating that the film formulations of the invention are useful essentially independent of the pKa value of the active substance to be incorporated. in the same. Generally, thus the substances having values between approximately 1 and 14, for example between 2 and 12, or between 3 and 10, for example between 3.5 and 9.5, will be feasible to formulate with the film technology of the invention. It is noted that in relation to this date, the best method known to the applicant to carry out the aforementioned invention, is that which is clear from the present description of the invention.

Claims (32)

1. CLAIMS Having described the invention as above, the content of the following claims is claimed as property: 1. A bioadhesive film characterized in that it comprises, as a film-forming agent, a monovalent cation alginate salt or a mixture of alginate salts which contain at least one monovalent cation alginate salt, the film forming agent has a guluronate content of 50 to 85% by weight, an average manure content of 15 to 50% by weight, an average molecular weight of 30,000 g / mole up to 90,000 g / mol and that is such that a 10% aqueous solution thereof at a temperature of 20 ° C has a viscosity of 10-1000mPas, as measured at a shear rate of 20 rpm by the use of a Brookfield viscometer with a spindle No.
2. 2. A film according to claim 1, characterized in that the monovalent cation is selected from Na +, K + and NH4 +.
3. 3. A film according to claim 1 or 2, characterized in that the monovalent cation alginate salt comprises from 25 to 35% by weight of β-D manurate.
4. 4. A film according to any of claims 1-3, characterized in that the monovalent cation alginate salt comprises from 65 to 75% by weight of a-D guluronate.
5. 5. A film according to any of claims 1-4, characterized in that it comprises a plasticizer.
6. 6. A film according to any of claims 1-5, characterized in that it comprises a filler.
7. 7. A film according to any of claims 1-6, characterized in that it has a thickness of 0.1 to 2 mm.
8. 8. A film according to any of claims 1-7, characterized in that the film, in contact with a wet surface, dissolves in a period of less than 2 minutes.
9. 9. A film according to any of claims 1-8, characterized in that it comprises at least one biologically active substance.
10. 10. A film according to any of claims 1-9, characterized in that it comprises at least one therapeutically active substance.
11. 11. A film according to any of claims 1-10, characterized in that it comprises at least less a biologically active substance and / or a therapeutically active substance selected from antimicrobial agents, histamine 2 receptor antagonists, proton pump inhibitors, serotonin receptor antagonists, anti-inflammatory substances, agents acting in the CNS, peptides , proteins, nicotine, nicotine analogs and analgesics.
12. 12. A film according to any of claims 1-11, characterized in that the composition comprises a biologically and / or pharmaceutically active substance at a concentration from 0.000001% by weight up to 85% by weight of the total weight of the composition.
13. 13. A film according to claim 12, characterized in that the concentration is from 30% by weight to 80% by weight of the total weight of the composition.
14. 14. A film according to claim 13, characterized in that the concentration is from 50% by weight to 70% by weight of the total weight of the composition.
15. 15. A film according to any of claims 1-14, characterized in that it comprises at least one pharmaceutically and / or physiologically acceptable additive.
16. 16. A dosage unit characterized in that it comprises a film according to any of claims 10-15.
17. 17. A method for manufacturing a bioadhesive film by preparing a composition characterized in that it comprises, as a film-forming agent, a monovalent cation alginate salt or a mixture of alginate salts containing at least one monovalent cation alginate salt, the film forming agent has a guluronate content of 50 to 85% by weight, an average manure content of 15 to 50% by weight, an average molecular weight of 30,000 g / mol to 90,000 g / mol and which is that a 10% aqueous solution thereof at a temperature of 20 ° C has a viscosity of 10-1000 mPas, as measured at a shear rate of 20 rpm by using a Brookfield viscometer with a spindle No .2, by distributing the composition on a solid surface.
18. 18. A method according to claim 17, characterized in that the monovalent cation is selected from Na +, K + and NH +.
19. 19. A method according to claim 17 or 18, characterized in that the monovalent cation alginate salt comprises from 25 to 35% by weight of β-D manuronate.
20. 20. A method according to any of claims 17-19, characterized in that the monovalent cation alginate salt comprises from 65 to 75% by weight of a-D guluronate.
21. 21. A method according to any of claims 17-20, characterized in that the composition comprises a plasticizer.
22. 22. A method according to any of claims 17-21, characterized in that the composition comprises a filler.
23. 23. A method according to any of claims 17-22, characterized in that the composition comprises at least one biologically active substance.
24. 24. A method according to any of claims 17-23, characterized in that the composition comprises at least one therapeutically active substance.
25. 25. A method according to any of claims 17-24, characterized in that the composition comprises at least one pharmaceutically and / or physiologically active additive.
26. 26. A method according to any of claims 17-25, characterized in that the composition comprises at least one biologically active substance selected from microbial agents, antagonists of histamine receptors 2, proton pump inhibitors, antagonists. of the serotonin receptor, anti-inflammatory substances, agents that act on the CNS, peptides, proteins, nicotine, nicotine analogs and analgesics.
27. 27. A method according to any of claims 17-26, characterized in that the composition comprises a biologically and / or therapeutically active substance at a concentration from 0.000001% by weight up to 85% by weight of the total weight of the composition.
28. 28. A method according to claim 27, characterized in that the concentration is from 30% by weight to 80% by weight of the total weight of the composition.
29. 29. A method according to claim 28, characterized in that the concentration is from 50% by weight to 70% by weight of the total weight of the composition.
30. 30. A method according to any of claims 17-29, characterized in that it comprises preparing film dosing units.
31. 31. A method of therapeutic treatment of a mammal characterized in that it comprises administering to the mammal a film according to any of claims 9-15.
32. 32. The use of a composition for preparing a bioadhesive film, the composition comprises, as a film-forming agent, a monovalent cation alginate salt or a mixture of alginate salts containing at least one monovalent cation alginate salt. , the film forming agent has a guluronate content from 50 to 85% by weight, an average manure content from 15 to 50% by weight, an average molecular weight of 30,000 g / mol to 90,000 g / mol and that is such that a 10% aqueous solution thereof at a temperature of 20 ° C has a viscosity of 10-lOOOmPas, as measured at a shear rate of 20 rpm by using a Brookfield viscometer with a No. 2 spindle.