EA038558B1 - Water soluble pharmaceutical film with enhanced stability - Google Patents

Abstract

The invention comprises an oral thin film that is instantly wettable, rapid dissolving, non-sticky, non-tacky and non-curving, the said film capable of carrying an active ingredient for oral delivery being a moisture stabilized film that remains non-sticky and non-curving when exposed to 705% RH (relative humidity) at 25°C for at least 2 min up to 2 h in open conditions without packaging.; and a process/method of making them. The active ingredient may comprise, without limitation, an active pharmaceutical, nutraceutical or cosmaceutical ingredient. The processes/method comprising (a) drying a casted film in two or more stages, (b) drying of the film after casting is done alternately both the sides, (c) coating the dried film with synthetic water insoluble moisture resistant/moisture repellant hydrophobic polymers that does not melt at high temperature, (d) adding a synthetic water insoluble moisture resistant/moisture repellant hydrophobic polymer that does not melt at high temperature to the solution to be casted as a film.

Description

The technical field to which the invention relates

The invention relates to dosage forms of the orally disintegrating stable film type for the delivery of active pharmaceutical substances, nutraceuticals, diagnostic agents and food additives.

Background to the invention

Oral thin film is a dosage form used for the delivery of various pharmaceutical active substances, nutraceuticals, diagnostics and nutritional supplements.

The literature contains information on oral soluble films intended for use in various fields, including, in particular, for changing the delivery profile of certain pharmaceutical substances by changing the rate of their dissolution or absorption, or bypassing metabolic processes, which makes it possible to increase the bioavailability of a drug. Several illustrative examples of oral thin films are disclosed in US patent No. 6709671, in US patent application No. 2008053466, US patent No. 4900552 and US patent No. 5166233.

However, commercially available oral thin films, when exposed to moisture in the ambient air, are prone to bending for a short period during normal oral use. The curled edges of oral thin films create difficulties when dispensing from a multi-dose container. These folded edges also make it difficult to stack such films in single-dose or multi-dose packages. These folded edges can lead to the delivery of more than one dosage form, which can cause serious adverse effects when the dose is delivered. Bending these thin films negatively affects their appearance and raises doubts about the stability of the films. Therefore, it is important that the films retain their flatness during casting, packaging and throughout their entire shelf life and do not deform during use due to the effect on them of various conditions of the ambient air. Moreover, films made using prior art methods have the disadvantage that the films adhere to each other or to the surface of the package due to their smooth surface and hygroscopic properties. This limits their acceptability for further processing, such as cutting, stacking, packaging, filing and handling of the film, and can also lead to microbial contamination, decreased drug potency and dosing errors.

In addition, prior art films contemplate the use of hydrophilic polymers and water in the film casting process. As a result of these factors, moisture-sensitive active pharmaceutical ingredients are unstable during the known casting process of said films and during storage.

Thus, there is a need to solve the long-standing problem of adhesion, bending of oral thin films and instability of moisture-sensitive active pharmaceutical ingredients.

GB927963 discloses a method of preventing adhesion and making non-sticking water-soluble films from polyvinyl alcohol derivatives by making a film from a composition comprising a water-soluble polyvinyl alcohol derivative and not more than 30% by weight of an aliphatic dicarboxylic acid based on a polyvinyl alcohol derivative, whereby the solubility of said acid is less than 3.0% at 20 ° C and more than 0.3% at 100 ° C. GB927963 also claims a non-stick film made from a water-soluble polyvinyl alcohol derivative in combination with an aliphatic dicarboxylic acid in an amount of less than 30% by weight, said acid having a water solubility of less than 3.0% at 20 ° C and more than 0.3% at 100 ° C. This method is limited to films made, in particular, from derivatives of polyvinyl alcohol, and to which an aliphatic dicarboxylic acid has been added, and this method does not encompass within its scope other water-soluble polymers and other additives that would result in a water-soluble non-tack and non-flexing film.

US Pat. No. 3,316,190 discloses the provision of a cold water soluble polyvinyl alcohol film that is non-stick at high humidity, including either surfactant alone or in combination with a water-soluble starch as defined in one of the basic element groups below. : (a) 0.2 to 20% by weight of a surfactant having an HLB number in the range of 8 to 20, based on the weight of the polyvinyl alcohol, (b) 2 to 50% by weight of water-soluble starch, based on the weight of the polyvinyl alcohol, and 0.2 to 20% by weight of a surfactant having an HLB in the range of 8 to 20% based on the weight of the polyvinyl alcohol, (c) 2 to 50% by weight of water-soluble starch based on the weight of the polyvinyl alcohol and from 0.2 to 20% by weight of an anionic surfactant having an HLB number in the range of 8 to 20%, based on the weight of the polyvinyl alcohol, (d) 2 to 50% by weight of a water-soluble starch based on e the weight of polyvinyl alcohol and 0.2 to 20% by weight of a nonionic surfactant having an HLB number in the range of 8 to 20%, based on the weight of a polyvinyl alcohol selected from the group consisting of fatty acid ethylene oxide adducts, fatty alcohols and

- 1038558 alkylphenols. Dialkyl sulfosuccinate was used as anionic surfactant; and examples of the implementation of technological processes for the production of films were given. This patent also describes a method of making non-stick films, limited to the production of polyvinyl alcohol as a film-forming polymer and either only one surfactant or a combination of surfactant and water-soluble starch.

WO 2007030754 discloses films having one of the following groups of essential features / elements of an edible film: (1) at least one non-tacky substance selected from the group consisting of lubricants, release agents, glidants, and combinations thereof, (2) an edible water-soluble polymer component, comprising at least one polymer selected from the group consisting of hydroxypropyl cellulose, hydroxypropyl methyl cellulose, polyethylene oxide, and a combination thereof, and a non-tacky substance comprising vitamin E-TPGS (tocopheryl polyethylene glycol succinate) present in amounts ranging from about 0.01% to about 20% by weight by weight of the film, (3) an edible water-soluble polymer component comprising polyethylene oxide in combination with a polymer selected from the group consisting of hydroxypropyl cellulose, hydroxypropyl methyl cellulose, and a combination thereof; and vitamin E-tocopheryl polyethylene glycol succinate, present in amounts sufficient to impart non-sticky and therapeutic properties, said film being non-sagging, (4) an edible, water-soluble polymer comprising polyethylene oxide, hydroxypropyl cellulose and polydextrose, wherein polyethylene oxide and polypropyl cellulose are present in a ratio being approximately 45:45:10; and at least one non-tacky substance, (5) an edible water-soluble polymer and a coating on at least one surface of the non-sag film, the coating comprising at least one non-tacky substance, (6) a multilayer film for delivering an active substance, comprising: (a ) at least one first film layer comprising: (i) an edible water-soluble polymer; and (ii) a non-sticky substance; and (b) a second film layer comprising: (i) an edible water-soluble polymer; and (ii) an active ingredient selected from the group consisting of cosmetic substances, pharmaceutical substances, vitamins, bioactive substances, and a combination thereof, wherein the first film layer is substantially in contact with the second film layer.

WO 2007030754 also discloses a method of making a non-sag film having a substantially uniform distribution of components, including the following main features: at least one non-tacky substance for forming a matrix with a uniform distribution of the components; creating a surface with top and bottom sides; (d) feeding the film to the upper side of the specified surface; and (e) drying the film by applying heat to the underside of the surface.

In US patent US 8765167, issued on the basis of the above application WO 2007030754, a narrow formula of the invention is given, while the patent claims an oral film for delivering the required amount of active ingredient, including a swallowable water-soluble polymer matrix, and the films are characterized by a generally uniform distribution of the required amount of active a component in a polymer matrix, which is measured mainly in equal metered individual unit doses, which vary within no more than 10% of the required amount of active component, the film is non-sagging, and the active component is generally evenly distributed, while the film is formed using a controlled drying process ensuring the rapid formation of a viscoelastic matrix for inclusion in the structure of the matrix and fixing the active component in place and maintaining its basically uniform distribution; the film is non-sagging and the active ingredient is substantially evenly distributed.

In addition to these elements, which are common to all claims, below are some highlighted basic elements in the claims. In one embodiment of the invention (claim 1), the non-sticky substance included in the group is limited to include stearates; stearic acid; vegetable oil; waxes; a mixture of magnesium stearate and sodium lauryl sulfate; boric acid; surfactants; sodium benzoate; sodium acetate; sodium chloride; DL-leucine; polyethylene glycol; sodium oleic acid; sodium lauryl sulfate; magnesium lauryl sulfate; talc; corn starch; silicon dioxide of amorphous modification; siloid; metal stearates, vitamin E, vitamin E-tocopheryl polyethylene glycol succinate, silicon dioxide, and combinations thereof. In another embodiment (claim 13), the polymers comprise at least one polymer selected from the group consisting of hydroxypropyl cellulose, hydroxypropyl methyl cellulose, hydroxyethyl cellulose, carboxymethyl cellulose, polyethylene oxide, and combinations thereof, and the non-sticky substance is limited to a selection from the group consisting of vitamin E, vitamin E-tocopheryl polyethylene glycol succinate and sodium benzoate, the non-tacky substance being present in amounts ranging from about 0.01% to about 20% by weight of the film. Also, in an embodiment of the invention (claim 14), the main elements include a swallowable water-soluble polymer matrix containing polyethylene oxide in combination with a polymer selected from

- 2,038558 groups including hydroxypropyl cellulose, hydroxypropyl methyl cellulose, hydroxyethyl cellulose, carboxymethyl cellulose and combinations thereof; and a non-tacky substance selected from the group consisting of vitamin E, vitamin E-tocopheryl polyethylene glycol succinate and sodium benzoate, the non-tacky substance being present in an amount sufficient to provide non-tacky and therapeutic properties. In another embodiment of the invention, the basic elements include: a water-soluble polymer matrix containing polyethylene oxide and a polymer selected from the group consisting of hydroxypropyl cellulose, hydroxyethyl cellulose, carboxymethyl cellulose and polydextrose, wherein polyethylene oxide, a polymer selected from the group consisting of hydroxypropyl cellulose, hydroxymethylcellulose, carboxyl cellulose , are present in a ratio of approximately 45:45:10 by weight; at least one non-sticky substance selected from the group consisting of stearates, stearic acid; vegetable oil; waxes; a mixture of magnesium stearate and sodium lauryl sulfate; boric acid; surfactants; sodium benzoate; sodium acetate; sodium chloride; DL-leucine; polyethylene glycol; sodium oleic acid; sodium lauryl sulfate; magnesium lauryl sulfate; talc; corn starch; amorphous silicon dioxide; siloid; metal stearates, vitamin E, vitamin E-tocopheryl polyethylene glycol succinate, silicon dioxide, and combinations thereof. In a further embodiment of the invention, the basic elements include at least one non-tacky substance selected from the group consisting of stearates, stearic acid; vegetable oil; waxes; a mixture of magnesium stearate and sodium lauryl sulfate; boric acid; surfactants; sodium benzoate; sodium acetate; sodium chloride; DL-leucine; polyethylene glycol; sodium oleic acid; sodium lauryl sulfate; magnesium lauryl sulfate; talc; corn starch; silicon dioxide of amorphous modification; siloid; metal stearates, vitamin E, vitamin Etocopherylpolyethylene glycol succinate, silicon dioxide, and combinations thereof. In yet another embodiment of the claims, a multilayer film is disclosed comprising: (a) at least one first film layer comprising (i) a swallowable water-soluble polymer matrix; and (ii) at least one non-sticky substance selected from the group consisting of stearates, stearic acid; vegetable oil; waxes; a mixture of magnesium stearate and sodium lauryl sulfate; boric acid; surfactants; sodium benzoate; sodium acetate; sodium chloride; DL-leucine; polyethylene glycol; sodium oleic acid; sodium lauryl sulfate; magnesium lauryl sulfate; talc; corn starch; amorphous silicon dioxide; siloid; metal stearates, vitamin E, vitamin Etocopheryl polyethylene glycol succinate, silicon dioxide, and combinations thereof; and (b) a second film layer containing (i) a swallowable water-soluble polymer matrix; and (ii) a substantially uniformly distributed required amount of active component in the structure of the polymer matrix, wherein the active component is selected from the group consisting of cosmetic substances, pharmaceutical substances, vitamins, bioactive substances, and combinations thereof, wherein the first layer of the film is mainly in contact with the second a layer of film; in this case, the film is formed by carrying out a controlled drying process, due to which a viscoelastic matrix is quickly formed for inclusion in the matrix structure and fixing the active component in place and maintaining its basically uniform distribution. In yet another embodiment of the invention, the following main features of a method for producing a non-sag film are disclosed, including: creating a surface having a top and a bottom side; feeding the film to the upper side of the surface; and drying the film by applying heat to the underside of the surface. In another embodiment, in addition to the water-soluble polymers, the use of at least one non-tacky substance is provided, including sodium benzoate, an active ingredient selected from the group consisting of an opiate, an opioid derivative, an analgesic, and combinations thereof; the film is formed by a controlled drying process to maintain a substantially uniform distribution. In addition, the following basic elements are disclosed: a multilayer film comprising (a) a first film layer containing (i) a swallowable, water-soluble or water-swellable polymer matrix; and (b) at least a second film layer comprising (i) a swallowable, water-soluble or water-swellable polymer matrix comprising a water-soluble or swellable polymer, wherein the first and / or second layers also include: the amount required is substantially uniform a distributed active component, wherein the component is selected from the group consisting of a non-sticky substance, a sweetener, a flavoring agent, an acidifier, an oxide filler, propylene glycol, vitamin E acetate, polyacrylic acid, a preservative, a buffering agent, a coloring agent, and combinations thereof; and wherein the first film layer is substantially in contact with the second film layer; the film is formed by performing a controlled drying process to maintain an overall uniform distribution of the component.

In the context of the above patent, vitamin E is an oily liquid. The specified vitamin contained in the film, at a concentration exceeding a certain level, gives the film an oily appearance and reduces its aesthetic appeal. Moreover, it is necessary to add acceptable plasticizers to all film compositions, which in many cases may be liquids. When vitamin E is added in combination with liquid plasticizers, films are oily to the touch. This means that the use of vitamin E and other liquid

- 3,038558 non-stick film auxiliaries restricts the use of other liquid or oily adjuvants with other functions, such as plasticizers, flavors, surfactants, emulsifiers, sweeteners, etc.

However, when using vegetable oils and waxes, including stearic acid, the film becomes unpleasant, although the film is intended for oral administration by dissolving in the mouth. Waxes, which have a liquid consistency at a higher ambient temperature, change the appearance of the film, imparting a waxiness to it. Vegetable oils pose problems due to their oxidation and rancidity, which, in turn, leads to the need to include antioxidants in the composition. In addition, some of the excipients referred to as non-sticky substances are classified as lubricants, however, when used in films, they impart tackiness to them due to their oily and waxy properties and include substances such as stearic acid, vitamin E, oils and waxes. Similarly, among the aforementioned excipients, some are moisture-absorbing in nature, such as polyethylene glycols, boric acid, etc. Films made using these moisture-absorbing auxiliaries will be susceptible to weathering and will not be stable for a sufficiently long period of time.

In addition, the above application does not provide a detailed description of the controlled heating process. In the process of casting such films, the casting of films in all cases is carried out on the substrate material, which is a tape made of PVC or similar materials, stainless steel and a number of other metals. In this case, the heat is supplied from the bottom side, the heat is first transferred to the substrate material, which, in turn, transfers it to the film. Drying of the film depends on the substrate material.

There is a need to make non-adherent films by methods other than those hitherto used to allow for a wider variety of methods to create non-adherent films, and different methods may be required depending on the different properties of the actives added to the film.

In addition, although the films are non-sticky, prior art methods do not eliminate the problem of bending of the films during production.

Thus, the object of the present invention is to provide an orally disintegrating dosage form in the form of a stable film for the delivery of active pharmaceutical substances, nutraceuticals, nutritional supplements, diagnostics and cosmeceuticals through the use of new alternative methods.

Another object of the present invention is to solve the problem of bending of the film from the edges when exposed to atmospheric conditions characterized by a constant change in humidity and temperature. The known technical solutions provide only for ensuring the stability of the films, and they completely lack information regarding the solution to the problem of bending of the films. However, the films available on the market are not without this disadvantage.

It is another object of the present invention to provide fast wettability, adequate tensile strength and fast disintegration, while creating, using new methods, stable films that are non-bendable, non-sticky or non-tacky.

Another object of the present invention is to provide a manufacturing technology and methodology for the production of non-bendable and non-stick films.

For purposes of describing the present invention, the term “stable film” means and includes a non-bending film and a non-stick or non-tacky film.

Summary of the invention

The present invention provides for an oral thin film that is fast-wetting, fast-dissolving, non-sticking, non-sticky and non-bending, while said film is capable of carrying the active ingredient for oral delivery, while the film is hydrolytically stabilized, retaining its non-sticking and non-bending properties under exposure to 70 ± 5% relative humidity at 25 ° C for at least 2 minutes to 2 hours unpacked open.

The present invention also provides processes / methods for making an oral thin film that is fast-wetting, fast dissolving, non-sticking, non-tacky and non-bending.

In one embodiment of the present invention, a process (method) for making an instant oral water-soluble film for oral delivery of an active ingredient includes the steps of casting a film containing a water-soluble polymer (s), optional additives; and drying the film by applying heat; the drying of the film after casting is carried out by increasing the drying temperature in two or more stages. In one example of the implementation of the specified technological process / method in the first stage, the drying temperature is maintained in the range from 45 to 60 ° C, and drying is carried out until the moisture content in the film is in the range from 50 to 20% , in the second step, the drying temperature is maintained in the range from 60 to 110 ° C, and drying is carried out until the moisture content in the film is in the range from 30 to 10%, and in the third step, the drying temperature is maintained in the range from 80 ° C to 130 ° C, and drying is carried out until the moisture content of the film is in the range from 10 to 2% at the end of the drying process. The process in accordance with this exemplary embodiment of the invention also includes admixing additives that include the active ingredient and excipients. The active ingredient may include, in particular, an active pharmaceutical, nutraceutical or cosmeceutical ingredient.

In another embodiment, the present invention includes a process (method) for making an instant, oral water-soluble film for oral delivery of an active ingredient, the process comprising the steps of casting a film comprising water-soluble polymer (s), optional additives; and drying the film by applying heat, wherein the drying of the film after casting is carried out alternately on both sides, in which: (a) in the first stage, drying is carried out on the upper side of the cast film at a temperature of 70 to 120 ° C until the moisture content in the film will not be in the range of 50 to 20%, (b) the produced film is then removed from the substrate and dried in a second step on the other side at 70-120 ° C until the moisture content of the film is in the range from 20 to 2%. It is preferable that the first drying step is carried out in the range of 35 to 25%, and the second drying step is carried out in the range of 10 to 2%, and that the film contains the active ingredient. The specified technological process (method) may include the following steps: (a) casting a solution containing a rapidly water-soluble polymer in the form of a film on a substrate, (b) drying the cast film at 100 ° C to a semi-dry state to a moisture content in the range from 20 to 50%, (c) coating the semi-dried film with a moisture-resistant or water-repellent solution, (d) drying at 80 ° C, (e) removing the double-layer film from the substrate, (f) flipping the removed two-layer film and casting with a moisture-resistant or water-repellent solution, and (g) drying at 80 ° C. The thickness of the thin film of the moisture resistant or water-repellent polymer can be in the range of 1-5 µm, the thickness of the entire single-layer or multilayer film can be in the range of 40 to 150 µm, and the moisture content of the entire film can be in the range of 10 to 2%.

In yet another embodiment, the present invention includes a process (method) for making an instant oral water-soluble film for oral delivery of an active ingredient, comprising the steps of casting a film containing a water-soluble polymer (s), optional additives; and drying the film by applying heat, coating the dried film with synthetic water-insoluble moisture-resistant / water-repellent hydrophobic polymers that do not melt at high temperatures, the thickness of the coating is such that it prevents moisture from absorbing moisture from the humid ambient air, but the film quickly dissolves on contact with water.

In yet another embodiment, the present invention provides a process / method for making an instant oral water-soluble film for oral delivery of an active ingredient and includes the steps of casting a film containing a water-soluble polymer (s), optional synthetic water-insoluble moisture-resistant / water-repellent additives and one or more synthetic water-insoluble moisture-resistant / water-repellent hydrophobic polymers that do not melt at high temperatures, while the polymer is added in a range that provides fast wettability and fast solubility upon contact of the film with water. The concentration of the synthetic water-insoluble moisture-resistant / water-repellent hydrophobic polymer used in the film ranges from 1.5 to 7.5% of dry weight of dry film. It is preferred that the water-insoluble polymer is a polymethacrylate. The specified technological process (method) may also include the addition of one or more moisture-absorbing substances in addition to the water-insoluble polymer to make the film.

DETAILED DESCRIPTION OF THE INVENTION Brief Description of the Drawings and Items

FIG. 1 is a diagram of the machine used to produce stabilized film: (1) indicates the casting / dispersing of the solution, (2) the roll, (3) the first stage of drying, (4) the cast film, (5) the backup roll, (6 ) - the second stage of drying.

FIG. 2 is a diagram of the machine used to produce the water repellent / moisture resistant film: (1) indicates the casting / dispersion of the solution, (2) the roll, (3) the casting of the film, (4) the heating device, (5) the moisture resistant polymer solution, (6) - heating device, (7) - overturning of the film, (8) - moisture resistant polymer solution, (9) - heating device, (10) - dried film.

FIG. 3: (1) - multi-dose container, (2) - films stacked in a multi-dose container, and (3) - dispensing of one film from a stack, in which the film is exposed to humid ambient air during its use and is difficult to dispense if films

- 5 038558 are sticky and / or curved.

The present invention provides a method of producing a fast-wetting, non-sticking and non-bending oral thin film by using processes that increase the hydrolytic stabilization of an oral thin film when exposed to humid ambient air at a relative humidity of 70 ± 5% or less, wherein hydrolytic stabilization is defined as maintaining the flatness of the thin film during casting, packaging and storage such that the oral thin film remains non-sticky and non-bending when exposed to 70 ± 5% relative humidity at 25 ° C for at least 2 minutes to 2 hours open without packaging.

The invention also provides for a fast-wetting, orally dissolving, non-sticking and non-bending oral thin film capable of carrying an active ingredient for oral delivery, as well as a method for making such a film.

In a first embodiment of the processes used to improve the hydrolytic stabilization of an oral thin film, the cast film is dried with a gradual increase in temperature. In an illustrative embodiment of the present invention, the temperature is increased in three steps. In the first step, the temperature is maintained in the range of 45 to 60 ° C, and drying is carried out until the moisture content of the film is in the range of 50 to 20%; in the second step, the drying temperature is maintained in the range of 60 to 110 ° C, and drying is carried out until the moisture content of the film is in the range of 30 to 10%; and in the third step, the drying temperature is maintained in the range of 80 to 130 ° C, and drying is carried out until the moisture content of the film is in the range of 10 to 2% at the end of the drying process (Example 1).

In a second embodiment of the present invention, hydrolytic stabilization of the oral thin film is achieved by drying the cast film alternately on both sides in two steps. In the first step, drying is carried out on the top side of the cast film at a temperature of 100 ° C until the moisture content of the film is in the range of 50 to 20%, more preferably in the range of 35 to 25%. The produced film is then removed from the support and dried on the other side at a temperature of 100 ° C until the moisture content of the film is in the range of 20 to 2%, more preferably in the range of 10 to 2%. FIG. 1 is a schematic diagram of a machine used to make a stabilized film (example 2).

The first and second embodiments of the present invention described above are improved methods for drying cast films over prior art methods. In accordance with the methods of the prior art, the cast films are dried on one side by applying heat, which leads to the migration of all water-soluble components on one side together with water molecules, and this is one of the reasons for the appearance of film defects such as bending of edges, adhesion etc., or to obtain a film with a uniform distribution of components, it is necessary to carry out rapid heating, but this does not lead to obtaining a non-bending film, since heating / drying is uneven on two surfaces. In the present invention (a) heating applied only on one side is performed in more than two stages, which allows moisture to redistribute for a sufficient period of time, to reach equilibrium over the entire cross section of the film, and then drying is carried out in a further step; or (b) drying is carried out in two stages, in the first stage on one side to a certain temperature, and then the film is inverted and further drying is carried out at a higher temperature on the other side; These two approaches provide a film in which not only a uniform distribution of molecules occurs, but also the production of a uniformly dried non-bending film.

FIG. 2 is a schematic diagram of a machine used to produce a water repellent / moisture resistant film.

In accordance with a third illustrative embodiment of the present invention, hydrolytic stabilization of an oral thin film made from water-soluble polymers is provided by coating them with water-insoluble moisture-resistant / water-repellent hydrophobic polymers that do not melt at high temperatures and change the ability of the films to absorb moisture and increase their resistance to changing conditions of ambient humidity in order to eliminate adhesion and bending of the film during storage and use, while the thickness of the coating is such as to prevent the absorption of moisture from the humid ambient air, but at the same time ensure the rapid dissolution of the film on contact with water. The moisture resistant / water repellent polymers are used as a thin layer on an already cast oral thin film, coating or enveloping the film on both sides using a thin layer of moisture resistant / water repelling substances. This ensures that the film is wrapped and protected from moisture. The film produced remains flat and flexible. The preferred range for the thickness of the coated layer is from 5 to 1 µm. In the specified embodiment of the present iso

- Casting 6 038558 at the first stage, the mortar is cast and dried at 100 ° C, the moisture content in the semi-dried film is in the range from 20 to 5%. Then, the produced film is coated with a solution / cast with a solution of a moisture resistant / water-repellent polymer and dried at 80 ° C. The resulting bilayer film is removed from the substrate; overturned and further casting the moisture-proof / water-repellent solution and dried at 80 ° C. The resulting three-layer / layered film contains moisture in the range of 10 to 2%. The present invention is illustrated by examples 3, 3.1 and 3.2.

The moisture resistant / water repellent polymers used as a thin layer on an already cast oral thin film can be polyacrylates.

In accordance with a fourth illustrative embodiment of the present invention, hydrolytic stabilization is achieved by adding to a water-soluble polymer containing a solution prepared for casting a film, a synthetic water-insoluble hydrophobic polymer that does not melt even under extreme temperature conditions in the range from 55 ° C to 60 ° C. , while the synthetic polymer is added within a range that will not negatively affect the solubility properties of the film, provide rapid wettability and rapid solubility when the film is in contact with water, and, in addition, impart anti-bending, bending and blocking properties to the films. Such water-insoluble polymers include, in particular, acrylic / methacrylic acid copolymers including pH dependent polymers such as acrylic acid / methacrylic acid copolymers, pH independent polymers including acrylic / methacrylic copolymers and carbomeric polymers. The presence of a hydrophobic / water-insoluble polymer at a concentration ranging from 1.5 to 7.5% in known film compositions will impart anti-bending and anti-stick properties to the films (Example 4).

According to a fifth exemplary embodiment of the methods for enhancing the hydrolytic stabilization of an oral thin film, moisture absorbers in combination with hydrophobic polymers in the range of 1 to 10% may be added.

Other ingredients such as emulsifiers, preservatives, buffering agents, antioxidants, plasticizers, super leavening agents, absorbents, sweeteners, flavor enhancers, flavors, coloring agents, water-insoluble polymers, pH modifiers, buffering agents, surfactants and stabilizers can also be added in the manufacture of oral thin film.

The film-forming polymer that can be used in the manufacture of the films of the present invention includes one or more or a combination of hydrocolloids, natural or semi-synthetic, including but not limited to hydroxypropyl methylcellulose, hydroxyethyl cellulose, carboxymethyl cellulose, pullulan, polyvinyl alcohol, soluble polyethylene copolymers, polyethylene grafted polymers , guar gum, xanthan gum, locust bean gum, carrageenan, tragacanth gum, pectin, carboxymethyl guar gum, and carboxymethyl locust bean gum. Polyoxyethylene polymers are selected based on viscosity and molecular weight.

Preferred ranges in which the various ingredients are used are indicated below as a percentage of the dry weight of the finished film and include, in particular: actives 0.01-80%, emulsifying agent (s) 0.1-10%, preservative (s) - 0.01-10%, buffer (s) - 0.0110%, antioxidant (s) - 0.001-10%, plasticizer (s) - 0.5-40%, super baking powder ( i) - 0.01-5%, absorbent (s) - 0.01-10%, flavor (s) - 0.001-10%, coloring matter (s) - 0.001-5%, water-insoluble (f) / hydrophobic polymer (s) - 1.5-7.5%, modifier (s) - pH 0.01-10%, buffer (s) - 0.01-5%, stabilizer ( s) - 0.01-5% and water-soluble polymer (s) - 25-85%.

The moisture resistant polymers used in the present invention include, in particular, polymethacrylate (s). The polymethacrylate used may be selected from the group including, inter alia: poly (butyl methacrylate, (2-dimethylaminoethyl) methacrylate, methyl methacrylate), poly (ethyl acrylate, methyl methacrylate), poly (methacrylic acid, methyl methacrylate), polymethacrylic acid, ethyl (poly acrylate), methacrylic acid, methyl methacrylate), poly (methyl acrylate, methyl methacrylate, methacrylic acid), poly (ethyl acrylate, methyl methacrylate, trimethylammonioethyl methacrylate chloride) poly (ethyl acrylate, methyl methacrylate, trimethylammonioethyl methacrylate chloride) ethyl cellulose derivatives

The thickness of single-layer or multilayer films can vary over a wide range from 40 microns to 150 microns, more preferably from about 50 microns to about 120 microns, and the moisture content should preferably be in the range from 10 to 2%.

The above list is illustrative only and not limiting in any way; the illustrated ingredients may be substituted with alternative materials having equivalent function and properties that will be apparent to those skilled in the art.

The active compound / ingredient can be, for example, medicinal, nutraceutical, nutritional, cosmeceutical, coloring and diagnostic agent.

- 7 038558

The present invention is particularly suitable for pharmaceutical, nutraceutical and nutritional supplements that have the ability to absorb moisture or that degrade upon exposure to moisture.

In addition to the above examples of implementation of the present invention, there can be several other examples of the implementation of the present invention, providing the achievement of hydrolytic stabilization, including examples that are obvious variants or equivalents of the above examples, all of which do not depart from the scope of the present invention disclosed in this description ... The following non-limiting examples are provided for illustrative purposes only and do not limit the scope of the means used for hydrolytic stabilization, nor the conditions used for hydrolytic stabilization.

Example 1. Drying of a cast film from a solution with a gradual increase in temperature

Excipient name Quantity (in%) Maltodextrin 15.6 Polyvinyl alcohol 1.8 Sorbic acid 0.2 Sucralose 0,4 Polysorbate 80 2 Water 80

Maltodextrin, polyvinyl alcohol, bronopol, sucralose and polysorbate 80 were added in the sequence shown in table. 1 to 400 ml of water. The resulting solution was then stirred at room temperature until a homogeneous solution was formed. It was then applied to a tape of backing material using known film casting equipment. The backing material can be Teflon coated PVC tape, PVC tape or stainless steel tape. The wet film thickness was adjusted until a dry thickness in the range of 20 µm to 50 µm was achieved. The resulting film was then dried in a first heating chamber at 60 ° C, the film was then recooled to room temperature and then re-dried at 90 ° C in a second drying chamber, the resulting film was cooled again to room temperature, and this procedure was repeated to dry the film in a third heating chamber at 120 ° C. The produced film was then removed from the support and cut into pieces to the desired size and shape. The resulting films had a uniform appearance and quickly dissolved.

Hydrolytic stability test: These films were then placed in leaky multi-dose containers, exposed to 70 ± 5%, 50 ± 5% and 30 ± 5% relative humidity at 25 ± 2 ° C, and their stability was monitored for 15, 30 and 45 minutes unpacked and unpacked. The films were stable for at least 10, 12 and 15 minutes, respectively, in the unpackaged state and in the multi-dose container into which the films were placed after they had been exposed to ambient humidity several times, for a total of 45 minutes. in the process of handling them and in the process of application.

Example 1.1. Drying a cast film containing a pharmaceutical substance with a gradual increase in temperature

Ingredient name Quantity (in%) Phenylephrine 1.17 Maltodextrin 14.68 Polyvinyl alcohol 1.69 Sorbic acid 0.188 Sucralose 0.37 Polysorbate 80 1.88 Water 80

Phenylephrine, maltodextrin, polyvinyl alcohol, bronopol, sucralose and polysorbate 80 were added in the sequence shown in table. 1 to 400 ml of water. The resulting solution was then stirred at room temperature until a homogeneous solution was formed. It was then applied to a tape of backing material using known film casting equipment. The backing material can be Teflon coated PVC tape, PVC tape or stainless steel tape. The wet film thickness was adjusted until a dry thickness in the range of 20 µm to 50 µm was achieved. The resulting film was then dried in a first heating chamber at 60 ° C, the film was then recooled to room temperature and then re-dried at 90 ° C in a second drying chamber, the resulting film was cooled again to room temperature, and this procedure was repeated to dry the film in a third heating chamber at 120 ° C. The produced 8,038,558 film was then removed from the support and cut into pieces to the desired size and shape. The resulting films had a uniform appearance and quickly dissolved. These films were then placed in a multi-dose container, exposed to 70 ± 5%, 50 ± 5% and 30 ± 5% relative humidity at a temperature of 25 ± 2 ° C and their stability was monitored for 15, 30 and 45 min in unpackaged and packed. The films were stable for at least 10, 12 and 15 minutes, respectively, in the unpackaged state and in the multi-dose container into which the films were placed after they had been exposed to ambient humidity several times, for a total of 45 minutes. in the process of handling them and in the process of application.

Example 1.2. Formulation of a stable film containing a pharmaceutically active substance, dried with a gradual increase in temperature

Ingredient name Percentage Phenylephrine 2.5 Hydroxypropyl methylcellulose 5 c / s twenty Polyethylene glycol 4000 eight Bronopol 0.1 Twin 80 0.5 Sucralose 0.1 Water 68.8

Hydroxypropyl methylcellulose was dissolved in a predetermined amount of water, and polyethylene glycol 4000 was added to the hydroxypropyl methylcellulose solution. The rest of the ingredients, including phenylephrine, were added to the polymer solution. The resulting solution was then stirred at room temperature until a homogeneous solution was formed. It was then applied to the tape of the backing material using a known coating machine. The backing material can be Teflon coated PVC tape, PVC tape or stainless steel tape. The wet film thickness was adjusted until a dry thickness in the range of 20 to 50 µm was achieved. The resulting film was then dried in a first heating chamber at 60 ° C, the film was then recooled to room temperature and then re-dried at 90 ° C in a second drying chamber, the resulting film was cooled again to room temperature, and this procedure was repeated to dry the film in a third heating chamber. chamber at 120 ° C. The produced film was then removed from the support and cut into pieces to the desired size and shape. These films were then placed in a multi-dose container, exposed to various humidity conditions as described in Example 1, and their stability was monitored for 15, 30 and 45 minutes unpackaged and packaged. The films were stable for at least 10, 12 and 15 minutes, respectively, in the unpackaged state and in the multi-dose container into which the films were placed after they had been exposed to ambient humidity several times, for a total of 45 minutes. in the process of handling them and in the process of application.

Example 2. Drying of a film in two stages

Excipient name Quantity (in%) Pullulan 14.54 Polyvinyl alcohol 1.79 Bronopol 0.20 Sucralose 0.40 Polysorbate 80 1.99 Polyethylene glycol 1.40 Water 79.68

Pullulan, polyvinyl alcohol, bronopol, sucralose and polysorbate 80, talc and titanium dioxide were added to 400 ml of water as described in example 1. The resulting solution was then stirred at room temperature until a homogeneous solution was formed. The resulting solution was then applied to a tape of support material using known film casting equipment. The backing material can be Teflon coated PVC tape, PVC tape or stainless steel tape. The wet film thickness was adjusted until a dry thickness in the range of 20 to 50 µm was achieved. At the first stage, drying was carried out from above at 100 ° C. The produced film was then removed from the support and dried on the other side at a temperature of 100 ° C. The films thus obtained were subjected to the test described in Example 1, and all films were found to retain their flatness for a period of at least about 10 minutes in the unpacked state, and for the entire observation period at their location in the package.

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Example 2.1

Ingredient name Quantity (in%) Simethicone 5.8 Neusilin 2,3 Pullulan 8.47 Polyvinyl alcohol 1.04 Bronopol 0.11 Sucralose 0.23 Polysorbate 80 1.15 Polyethylene glycol 0.81 Water 80

Simethicone and neusilin were thoroughly mixed and added to a solution of pullulan, polyvinyl alcohol, bronopol, sucralose, and polysorbate 80 in a certain amount of water. The resulting solution was then stirred at room temperature until a homogeneous solution was formed. The resulting solution was then applied to a tape of support material using known film casting equipment. The backing material can be Teflon coated PVC tape, PVC tape or stainless steel tape. The wet film thickness was adjusted until a dry thickness in the range of 20 µm to 80 µm was achieved. At the first stage, drying was carried out from above at 100 ° C. The produced film was then removed from the support and dried on the other side at a temperature of 100 ° C. The produced films were then removed from the support and cut into pieces to the desired size and shape.

The films thus obtained were subjected to the test described in Example 1, and all films were found to retain their flatness for a period of at least about 10 minutes in the unpacked state, and for the entire observation period at their location in the package.

Example 2.2. Drying of a film containing a pharmaceutical substance in two stages

Ingredient name Percentage Simethicone twenty Neusilin eight Hydroxypropyl methylcellulose 5 c / s twenty Polyvinyl alcohol 5 Polyethylene glycol 3.5 Twin 80 1.45 Sucralose 0.05 Water 42

Simethicone and neusilin were thoroughly mixed and added to a solution of hydroxypropyl methylcellulose, polyvinyl alcohol, polyethylene glycol, sucralose, and Tween 80 in a certain amount of water. The resulting solution was then stirred at room temperature until a homogeneous solution was formed. The resulting solution was then applied to a tape of support material using known film casting equipment. The backing material can be Teflon coated PVC tape, PVC tape or stainless steel tape. The wet film thickness was adjusted until a dry thickness in the range of 20 to 80 µm was achieved. At the first stage, drying was carried out from above at 100 ° C. The produced film was then removed from the support and dried on the other side at a temperature of 100 ° C. The produced films were then removed from the support and cut into pieces to the desired size and shape.

The films thus obtained were subjected to the test described in Example 1, and all films were found to retain their flatness for a period of at least about 12 minutes in the unpacked state and for the entire observation period at their location in the package.

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Example 3. Method of Making Non-Sticky Oral Thin Films Coated with a Coating or Outer Layer

Excipient name Quantity (in%) Solution A Pullulan 13.44 Polyvinyl alcohol 1.99 Bronopol 0.20 Sucralose 0.40 Polysorbate 80 1.99 Water 67.00 Solution B Copolymer of methacrylic acid 2,3 Ethanol 12.68

Solution A: pullulan, polyvinyl alcohol, bronopol, sucralose, and polysorbate 80 were added to water.

Solution B: Methacrylic acid copolymer was dissolved in ethanol.

Solution A was thoroughly mixed at room temperature until a homogeneous solution was formed. The wet film thickness was adjusted until a dry thickness in the range of 20 to 50 µm was achieved. Drying was carried out at 100 ° C. Then, solution B was applied to a moisture-resistant / water-repellent polymer solution and dried at 80 ° C. The resulting bilayer film was removed from the substrate; turned over and further casting was carried out together with a moisture-proof / water-repellent solution and dried at 80 ° C. The moisture content of the obtained three-layer / layered film was in the range of 10 to 2%.

The films thus obtained were subjected to the test described in Example 1, and all films were found to retain their flatness for a period of at least about 10 minutes in the unpacked state and during the entire observation period when they were packaged.

Example 3.1. A method of making stable films with coating on both sides of the films

Ingredient name Percentage Donepezil 1.16 Pullulan 12.56 Polyvinyl alcohol 1.86 Bronopol 0.189 Polysorbate 80 0.37 Sucralose 1.86 Water 82

Solution A: Donepezil, pullulan, polyvinyl alcohol, bronopol, sucralose and polysorbate 80 were added to water.

Solution B: As described in example 3.

Solution A was thoroughly mixed at room temperature until a homogeneous solution was formed. The wet film thickness was adjusted until a dry thickness in the range of 20 to 50 µm was achieved. Drying was carried out at 100 ° C. Then, solution B was applied to a moisture-resistant / water-repellent polymer solution and dried at 80 ° C. The resulting two-layer film was removed from the substrate, turned over, and further casting was carried out with a moisture-proof / water-repellent solution and dried at 80 ° C. The moisture content of the obtained three-layer / layered film was in the range of 10 to 2%.

The films thus obtained were subjected to the test described in Example 1, and all films were found to retain their flatness for a period of at least about 10 minutes in the unpacked state and during the entire observation period when they were packaged.

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Example 4. Coating of moisture resistant polymer particles of moisture sensitive ingredient

Ingredient name Quantity (in%) Montelukast sodium 2 Copolymer of methacrylate acid 2 Pullulan 14.54 Polyvinyl alcohol 1.79 Glycerol 4.20 Sucralose 0.40 Polysorbate 80 1.99 Talc 0.20 Titanium dioxide 0.20 Water 72.68

Particles of montelukast sodium were coated with methacrylate copolymer using a fluidized bed coater. Pullulan, polyvinyl alcohol, bronopol, sucralose and polysorbate 80, talc and titanium dioxide were added to 400 ml of water in the sequence shown in example 1. The resulting solution was then stirred at room temperature until a homogeneous solution was formed. The resulting solution was then applied to a tape of support material using known film casting equipment. The backing material can be Teflon coated PVC tape, PVC tape or stainless steel tape. The thickness of the coating was adjusted until a thickness in the range of 20 to 50 µm was achieved. The resulting film was then dried in a heating chamber at 120 ° C. The produced film was then removed from the support and cut into pieces to the desired size and shape.

The films thus obtained were subjected to the test described in Example 1, and all films were found to retain their flatness for a period of at least about 10 minutes in the unpacked state and during the entire observation period when they were packaged.

Example 5. Composition of stable films using hydrophobic polymers

Ingredient name Percentage Ondansetron 4.4 Copolymer of methacrylate acid 3.3 Hydroxypropyl methylcellulose 22.2 Polyvinyl alcohol 2.77 Glycerol 5.55 Sucralose 0.55 Polysorbate 80 1.11 Water 60

A polymer solution was prepared by adding hydroxypropyl methylcellulose to a predetermined amount of water, and then the remaining ingredients were added to the resulting solution. The solution was stirred to obtain a uniform dispersion and cast onto a substrate to obtain a dry film thickness ranging from 50 to 100 µm. The film was dried at 70 ° C until a moisture content in the range of 4 to 10% was reached. The produced film was then removed from the support and cut into pieces to the desired size and shape.

The films thus obtained were subjected to the test described in Example 1, and all films were found to retain their flatness for a period of at least about 10 minutes in the unpacked state and during the entire observation period when they were packaged.

Example 6

Ingredient name Quantity (in%) Ondansetron 3.69 Copolymer of methacrylate acid 2.77 Hydroxypropyl methylcellulose 18.66 Polyvinyl alcohol 2.32 Glycerol 4.66 Sucralose 0.46 Polysorbate 80 0.93 Talc 3.69 Titanium dioxide 2.77 Water 60

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A polymer solution was prepared by adding hydroxypropyl methylcellulose to a predetermined amount of water, and then the remaining ingredients were added to the resulting solution. The solution was stirred to obtain a uniform dispersion and cast onto a substrate to obtain a dry film thickness ranging from 50 to 100 µm. The film was dried until a moisture content in the range of 4 to 10% was reached. The produced film was then removed from the support and cut into pieces to the desired size and shape.

The films thus obtained were subjected to the test described in Example 1, and all films were found to retain their flatness for a period of at least about 15 minutes in the unpacked state and during the entire observation period when they were packaged.

Claims (14)

CLAIM 1. A method of making a rapidly dissolving oral water-soluble film for oral delivery of an active ingredient, comprising the steps of casting a film containing a water-soluble polymer (s) and additives; and drying the film by applying heat; in which the drying of the film after casting is carried out by increasing the drying temperature in two or more stages, while the method makes it possible to obtain a hydrolytically stabilized film that retains its non-stick and non-bending properties when exposed to 70 ± 5% relative humidity at 25 ° C, according to at least for a period of time from 2 minutes to 2 hours unpacked open. 2. The method according to claim 1, wherein the drying is carried out in three stages, wherein: a) in the first stage, the drying temperature is maintained in the range from 45 to 60 ° C and drying is carried out until the moisture content of the film is in the range from 50 to 20%; b) in the second step, the drying temperature is maintained in the range from 60 to 110 ° C and drying is carried out until the moisture content of the film is in the range from 30 to 10%; and c) in the third step, the drying temperature is maintained in the range from 80 to 130 ° C and drying is carried out until the moisture content of the film is in the range from 10 to 2% at the end of the drying process; and d) additives include an active ingredient and excipients. 3. The method according to claim 1, including the steps of casting a film containing water-soluble polymer (s) and additives; and drying the film by applying heat; in which drying of the film after casting is carried out alternately on both sides in two stages, in which: (a) in the first stage, drying is carried out on the upper side of the cast film at a temperature of 70 to 120 ° C until the moisture content of the film is be in the range of 50 to 20%, and (b) in a second step, the produced film is then removed from the substrate and dried on the other side at a temperature of 70 to 120 ° C until the moisture content of the film is in the range of 20 to 2%; the method allows obtaining a hydrolytically stabilized film that retains its non-stick and non-bending properties when exposed to 70 ± 5% relative humidity at 25 ° C, at least for a period of time from 2 minutes to 2 hours in the open state without packing. 4. The method according to claim 3, wherein: a) the first stage of drying is carried out until the moisture content of the film is in the range from 35 to 20%, or b) the second stage of drying is carried out until the moisture content in the film is in the range of 10 to 2%, c) additives include an active ingredient and excipients. 5. The method according to claim 1, wherein: a) the thickness of a thin film of a moisture-resistant or water-repellent polymer is in the range from 1 to 5 microns, b) the thickness of the entire single or multi-layer film is between 40 and 150 μm, and c) the moisture content of the entire film is between 10% and 2%, and d) additives include an active ingredient and excipients. 6. A method of making a rapidly dissolving oral water-soluble film for oral delivery of an active ingredient, comprising the steps of casting a film containing a water-soluble polymer (s), optional synthetic water-insoluble moisture-resistant / water-repellent additives and one or more synthetic water-insoluble moisture-resistant / water-repellent, which are non-hydrophobic polymers the temperature at which the aforementioned synthetic water-insoluble moisture-resistant / water-repellent hydrophobic polymers are added in a range that provides fast wettability and fast solubility upon contact of the film with water; drying the film after application; the method allows obtaining a hydrolytically stabilized film that retains its non-stick and non-bending properties when exposed to 70 ± 5% relative humidity at 25 ° C, at least for a period of time from 2 minutes to 2 hours in the open state without packing. - 13 038558 7. The method of claim 6, wherein the concentration of the synthetic water-insoluble moisture-resistant / water-repellent hydrophobic polymer used in the film is in the range of 1.5 to 7.5% on a dry weight basis. 8. The method of claim 7, wherein the synthetic water-insoluble moisture-resistant / water-repellent hydrophobic polymer consists of one or more compounds selected from the group consisting of poly (butyl methacrylate, (2-dimethylaminoethyl) methacrylate, methyl methacrylate), poly (ethyl acrylate , methyl methacrylate), poly (methacrylic acid, methyl methacrylate), poly (methacrylic acid, ethyl acrylate), poly (methacrylic acid, methyl methacrylate), poly (methyl acrylate, methyl methacrylate, methacrylic acid), poly (ethyl acrylate, methyl methacrylate, trimethyl cellulose ammonium nitrate) and shellac. 9. A method according to claim 5, 6 or 7, wherein the water-insoluble polymer is polymethacrylate. 10. The method of claim 8, further comprising adding one or more moisture-absorbing agents to make the film. 11. The method according to claim 6, further comprising the following steps: a) casting a solution containing a water-soluble polymer in the form of a film on a substrate, b) drying the cast film at 100 ° C to a semi-dry state to a moisture content in the range of 20 to 50%, c) applying a moisture-resistant or water-repellent solution to the semi-dried film, and d) drying at 80 ° C, e) removing the double layer film from the substrate, f) flipping the removed two-layer film and casting with a moisture-proof or water-repellent solution, and g) drying at 80 ° C. 12. Oral thin film, including at least water-soluble polymers and additives, wherein said film is rapidly wetting, rapidly dissolving, non-sticking, non-sticky and non-bending, while the film is able to carry the active ingredient for oral delivery, while the film is moisture stabilized, maintains its non-sticking and non-bending properties when exposed to 70 ± 5% relative humidity at 25 ° C for at least 2 minutes to 2 hours when unpacked unpacked. 13. The method of claim 1, wherein the active ingredient is an active pharmaceutical, nutraceutical or cosmeceutical ingredient. 14. The method of claim 6, wherein the active ingredient is an active pharmaceutical, nutraceutical or cosmeceutical ingredient.