JP2009507854A - Uniform film for fast-dissolving formulations incorporating anti-blocking agents - Google Patents

Abstract

  The present invention relates to water-soluble films incorporating anti-blocking agents and methods for their preparation. An anti-blocking agent may improve the flow characteristics of the composition, thereby reducing film adhesion problems to the user's mouth or to other units of film. In particular, the present invention relates to an edible water-soluble form in the form of a film composition comprising a water-soluble polymer, an active ingredient comprising a cosmetic agent, a pharmaceutical product, a vitamin, a physiologically active substance and a combination thereof, and at least one anti-tacking agent. It relates to a delivery system.

Description

  The present invention relates to fast-dissolving films incorporating anti-blocking agents and methods for their preparation. The film may also contain active ingredients that are evenly distributed throughout the film.

  Active ingredients such as drugs or pharmaceuticals may be prepared in tablet form to allow accurate and consistent dosing. However, the preparation and dispensing of this form of drug tends to be inaccurate, with the high percentage of adjuvant that must be added to obtain a manageable size, the larger drug form requires additional storage space. It has a number of disadvantages, including dispensing, including counting the number of tablets. Furthermore, many people estimated to be on the order of 28% of the population have difficulty swallowing tablets. While the tablet may be broken or broken into smaller pieces as a means to overcome dysphagia, it is not a suitable solution for many tablet or pill forms. For example, crushing or destroying the tablet or pill form, alone or with food, for ease of consumption, may also destroy the controlled release characteristics.

As an alternative to tablets and pills, films may be used to deliver active ingredients such as drugs, pharmaceuticals and the like. However, in the past, methods of manufacturing films and drug delivery systems comprising them have suffered from a number of undesirable properties that make it impossible to use them in practice.
Films incorporating pharmaceutically active ingredients are disclosed in expired Fuchs et al. US Pat. 4, 136, 145 ("Fuchs"). These films may be formed into sheets, dried, and then cut into individual doses. The Fuchs disclosure claims the production of a uniform film comprising a combination of water soluble polymers, surfactants, fragrances, sweeteners, plasticizers and drugs. Allegedly flexible films are disclosed to be useful for oral, topical or enteral applications. Examples of specific applications disclosed by Fuchs include application of the film to the mucosal areas of the body including the mouth area, rectal area, vaginal area, nasal area and ear area.

  However, testing of films produced according to the method disclosed in Fuchs reveals that the films suffer from particle agglomeration or agglomeration, ie self-aggregation that makes them essentially non-uniform. The cause of this result is the Fuchs process parameter, which is not disclosed, but the process parameter is likely to involve the use of relatively long drying times, thereby causing intermolecular attraction, convection (convection) force), promote airflow, etc. to form the agglomerates.

  Aggregate formation causes the film components and any actives present to be distributed in an irregular manner as well. When high doses are involved, slight dimensional changes of the film result in large differences in the amount of active ingredient per film. If the film contains a low dose of active ingredient, it is possible that a portion of the film substantially lacks any active ingredient. Since film sheets are usually cut into unit doses, some doses may therefore lack or contain insufficient amounts of recommended therapeutic active ingredients. The inability to achieve high accuracy with respect to the amount of active ingredient in the cut film can be detrimental to the patient. For this reason, formulations formed by methods such as Fuchs are subject to government agencies or regulatory authorities such as the US Federal Drug Administration (“FDA”) with respect to active ingredient variability in the formulation. It may happen that the strict criteria are not met. Currently, the formulation should not change more than 10% in the amount of active ingredient present, as required by various world regulatory authorities. When applied to a film-based formulation unit, this effectively dictates that there is uniformity in the film.

  The problem of self-aggregation resulting in film non-uniformity is described in Schmidt US Pat. 4,849,246 ("Schmidt"). Schmidt specifically points out that the method disclosed by Fuchs does not provide a uniform film, and the creation of a non-uniform film inevitably requires accurate dosing, which is particularly important in the pharmaceutical field as discussed above. I was aware of the obstacles. Shcmidt abandoned the idea that a monolayer film as described by Fuchs might provide an accurate formulation, and instead tried to solve this problem by forming a multilayer film. Moreover, his method is a multi-step method that adds cost and complexity and is impractical for commercial applications.

  Another US patent directly addressed the problems of self-aggregation and non-uniformity inherent in conventional film forming techniques. In one attempt to overcome inhomogeneities, Horstmann et al., US Pat. No. 5,629,003 and Zerbe et al., US Pat. No. 5,948,430, include additional components, ie, gel formers and polyvalents, respectively. An effort was made to incorporate alcohol to increase the viscosity of the film, followed by drying to reduce aggregation of the components in the film. These methods have the disadvantage of requiring additional components, which translates into additional costs and manufacturing steps. In addition, both methods involve conventional time-consuming drying such as a high temperature air bath using a drying oven, a drying tunnel, a vacuum drier or other such drying device. Adopt use of method. Long drying times help promote the aggregation of active ingredients and other adjuvants despite the use of viscosity modifiers. The method also risks exposing the active ingredient, i.e. drugs, vitamin C or other ingredients, to prolonged exposure to moisture and high temperatures, which may make the active ingredient ineffective or harmful. It could even be.

  In addition to the concerns associated with the degradation of active ingredients during prolonged exposure to moisture, the conventional drying methods themselves cannot provide a uniform film. The length of heat exposure during conventional processing, often referred to as “thermal history” and the method in which heat is applied, has a direct impact on the formation and morphology of the resulting film product. Achieving uniformity by conventional drying methods is particularly difficult when a relatively thick film suitable for incorporation of the drug active ingredient is desired. It is more difficult to achieve a thicker uniform film because the surface of the film and the inner part of the film do not experience the same external conditions simultaneously during drying. Thus, observing a relatively thick film produced from the conventional processing reveals a non-uniform structure caused by convective and intermolecular forces, and a moisture content greater than 10% to maintain flexibility. Is required. The amount of free moisture can interfere with the drug over time and result in potential problems, resulting in end product inconsistencies.

  Conventional drying methods generally involve the use of forced hot air using a drying oven, tunnel dryer or the like. Difficulties in achieving a uniform film are directly related to the rheological properties and the process of moisture evaporation in the film-forming composition. When the surface of a water-soluble polymer solution comes into contact with high-temperature airflow, for example, when the film-forming composition passes through a hot air oven, the surface water quickly evaporates to form a polymer film or skin on the surface To do. This seals the remainder of the water-soluble film-forming composition directly under the surface to form a barrier, but the remaining water evaporates through the barrier to achieve a dry film on itself. Must be forced. If the temperature outside the film continues to rise, the water pressure will rise below the surface of the film, causing the surface of the film to stretch, eventually tearing the film surface and allowing water vapor to escape. To do. As soon as the water vapor escapes, the polymer film surface reforms and the process is repeated until the film is completely dried. The result of repeated destruction and reformation of the surface of the film is observed as a “ripple effect”, which results in a film that is not flat and thus non-uniform. Frequently, depending on the polymer, the surface is very tightly sealed, making it difficult to remove residual water, resulting in very long drying times, higher temperatures and higher energy costs.

  Other factors such as mixing technology also affect the production of pharmaceutical films suitable for commercialization and regulatory approval. Air can be entrapped in the composition during the mixing process or after the film manufacturing process, but this can occur in the film product as it evaporates the moisture during the drying stage. It can leave a void. The film frequently collapses around the cavity, resulting in a non-planar film surface and a non-uniform final film product. Uniformity is still affected even if the cavities in the film caused by bubbles do not collapse. This situation also provides a non-uniform film in which the non-uniformly distributed space occupies the area that would otherwise have been occupied by the film composition. None of the above-mentioned patents handle or suggest solutions to problems caused by air introduced into the film.

  In addition, the film goes through a great number of processing steps after, for example, primary packaging in canisters and secondary packaging, for example in pouches or blister packs. The processing step presents an important challenge for the development of good quality films that possess optimal film surface properties such as low coefficient of friction or high slip coefficient. Throughout this process, it is important to maintain film integrity from initial manufacture to packaging. Accordingly, it is preferable to prevent or reduce problems that compromise the integrity of the film (eg, films that become soft, sticky, adhere, dry, or brittle over time).

  More specifically, commercial film products such as candy films and breath films typically include canisters (24 to 32 per canister) that include 16 or more film units (also referred to as strips). Until the film strip). The number of film strips per canister will vary based on the product type, active ingredient dose and packaging configuration, among other considerations. However, when packaging multiple film strips in a canister, the problem often arises that the strips stick together.

  Adhesion between film strips is a common problem with edible film products and can occur due to various causes. For example, in some cases, adhesion between film strips may be caused by components used in the film product. Ingredients such as perfumes, plasticizers, and active ingredients in the film can sometimes soften the film and have a detrimental effect on film quality. For example, in a film having a high acidulent content, the acid can exert an effect of imparting excessive plasticity to the film. The effect can be enhanced by the hygroscopicity of some acids or other components in the film.

  In some cases, adhesion between film strips can be caused by changes in film properties due to temperature and / or humidity changes. Some films can become tacky over time when exposed to sub-optimal temperature and / or humidity conditions. This problem can be amplified for products that have a very narrow optimal temperature and / or humidity range for storage.

  Overall, films that exhibit tackiness or become tacky over time may present a great many problems. First, the conversion from a master roll to a daughter roll and further conversion to a film strip is substantially more difficult when the film is sticky. Furthermore, the sticky film strips tend to adhere to each other during packaging, for example when stacked in a canister. As a result, it becomes difficult for the user to remove a single film from the film packaging at a time. Overall, this adhesion in packaging reduces not only the ease of use for individual consumers, but also the beauty of the filmstrip.

  Thus, it relates to a composition that allows films to slide smoothly together, thereby providing, among other benefits, ease of conversion, maximum storage stability and ease of consumer use. There is a need. Furthermore, there is a need for a method of preparing such a film that maintains a uniform distribution of the components therein, thereby inhibiting undesired aggregation in the final film product and promoting uniformity.

(Summary of Invention)
In one aspect of the present invention,
Edible water-soluble polymer;
At least one anti-tacking agent selected from the group consisting of a lubricant, an antiadherant, a glidant and combinations thereof; and a cosmetic agent, pharmaceutical, vitamin, physiological Provided is an edible film for delivery of an active ingredient comprising an active ingredient selected from the group consisting of a bioactive agent and combinations thereof and is self-supporting.

In another aspect of the invention,
An edible film for delivery of an active ingredient comprising:
An edible water soluble polymer component comprising at least one polymer selected from the group consisting of hydroxypropylcellulose, hydroxypropylmethylcellulose, polyethylene oxide and combinations thereof;
An active ingredient selected from the group consisting of beauty agents, pharmaceuticals, vitamins, bioactive substances and combinations thereof; and an adhesive comprising vitamin E TPGS present in an amount of about 0.01% to about 20% by weight of the film The film is provided comprising an inhibitor.

In another aspect of the invention,
An edible water-soluble polymer comprising polyethylene oxide together with a polymer selected from the group consisting of hydroxypropylcellulose, hydroxypropylmethylcellulose and combinations thereof; and sufficient to provide anti-tack and therapeutic properties Vitamin E TPGS present in various amounts
An edible film for delivery of an active ingredient comprising, wherein the film is self-supporting.

In some embodiments,
An edible water-soluble polymer comprising polyethylene oxide and hydroxypropylcellulose;
Polydextrose;
An active ingredient selected from the group consisting of cosmetics, pharmaceuticals, vitamins, bioactive substances and combinations thereof; and an edible film for delivery of an active ingredient comprising at least one anti-sticking agent, wherein the polyethylene oxide, hydroxy The film is provided wherein propylcellulose and polydextrose are present in a ratio of about 45:45:10.

In other aspects,
(A) a self-supporting film having at least one surface comprising the following components:
(I) an edible water-soluble polymer; and (ii) an active ingredient selected from the group consisting of beauty agents, pharmaceuticals, vitamins, bioactive substances and combinations thereof; and (b) the at least one of the self-supporting films. An edible film for delivery of an active ingredient comprising a coating on a surface comprising at least one anti-tacking agent.

Some embodiments are:
(A) at least one first film layer comprising:
(I) an edible water-soluble polymer; and (ii) an anti-tacking agent; and (b) a second film layer comprising the following components:
Provided is a multilayer film for delivery of an active ingredient comprising (i) an edible water-soluble polymer; and (ii) an active ingredient selected from the group consisting of cosmetics, pharmaceuticals, vitamins, bioactive substances and combinations thereof. The first film layer is substantially in contact with the second film layer.

The present invention is also a method for producing a self-supporting film having a substantially uniform component distribution comprising:
Mixing an edible water-soluble polymer, a solvent, an active ingredient selected from the group consisting of cosmetics, pharmaceuticals, vitamins, physiologically active substances and combinations thereof, and at least one anti-adhesive agent to obtain a uniform ingredient distribution Forming a matrix having;
Forming a self-supporting film from the matrix;
Providing a surface having a top side and a bottom side;
Providing the method comprising: feeding the film onto the top surface of the surface; and drying the film by applying heat to the bottom surface of the surface.

(Detailed description of the invention)
For the purposes of the present invention, the term non-self aggregating uniform heterogneity is the ability of a film of the present invention to be formed from one or more components in addition to a polar solvent. When the film is formed by conventional drying methods such as a high temperature air bath using a drying oven, a drying tunnel, a vacuum drier or other such drying device Means the ability to substantially reduce (ie, less or no) the occurrence of agglomeration or agglomeration of components in the film as commonly experienced in The term heterogneity, as used herein, includes not only films that incorporate a combination of ingredients such as a polymer and an active ingredient, but also films that incorporate a single ingredient such as a polymer. Uniform heterogeneity includes the substantial absence of agglomeration or agglomeration, as is common with conventional future methods and heat drying methods used to form films.

Furthermore, the film of the present invention has a substantially uniform thickness, which is also not provided by the use of conventional drying methods used for drying water-based polymer systems. The lack of uniform thickness adversely affects the uniformity of component distribution throughout the area of a given film.
The film products of the present invention are made with a suitably selected combination of polymer and polar solvent and may optionally contain active ingredients and other fillers known in the art. These films provide a non-self-aggregating uniform heterogeneity of the components in the film by utilizing the chosen casting or deposition method and controlled drying process. . Examples of controlled drying processes include Magoon ("" incorporated herein by reference, as well as hot air impingement across the bottom substrate and bottom heating plate. Magoon ”) US Pat. Examples include, but are not limited to, the use of the devices disclosed in US Pat. Other drying techniques for obtaining the films of the present invention are controlled radiative drying such as infrared radiation and radio frequency radiation (ie, microwaves) in the absence of uncontrolled airflow. It is.

  The purpose of the drying process is to provide a method for drying a film that avoids the troublesome problems such as the famous “rip” effect associated with conventional drying methods that initially dry the top surface of the film to trap moisture therein. Is to provide. In conventional oven drying methods, the moisture trapped therein is then evaporated, so that the top surface is changed by being split and then reshaped. These troublesome problems are avoided by the present invention, and further, the film lowers first by drying the bottom surface of the film or preventing film formation (skin) on the top surface of the film, and then the film becomes deep. However, a uniform film is provided by drying the depth. This can be achieved by applying heat to the bottom surface of the film with virtually no top airflow, or alternatively, again with controlled microwaves, again with virtually no top airflow. And may be achieved by evaporating the water or other polar solvent in the film. Alternatively, drying may be accomplished by using a balanced fluid flow, such as a balanced air flow, where the lower end airflow and state airflow are controlled to produce a uniform film. Provided. In such cases, the airflow directed at the top of the film should not create a condition that causes movement of particles present in the wet film due to the force generated by the airflow. Furthermore, the air flow directed to the lower edge of the film should preferably be controlled so that the film does not lift due to the force of the air. Uncontrolled airflow either above or below the film can cause non-uniformity in the final film product. The humidity level in the area surrounding the top surface may also be appropriately adjusted to prevent premature closure or skinning of the polymer surface.

This method of drying the film provides various benefits. Among these are faster drying times and a more uniform surface of the film, as well as a uniform distribution of components for any given area in the film. Further, the faster drying time allows viscosity to be quickly formed in the film, further promotes uniform distribution of the components in the final film product, and reduces aggregation of the components in the final film product. Make it possible. Preferably, the film drying occurs within about 10 minutes or less, or more preferably within about 5 minutes.
The present invention results in exceptionally uniform film products when care is taken to reduce aggregation of the components of the composition. The film is produced by avoiding and removing the introduction of excess air in the mixing process, selecting the polymer and solvent to provide a controllable viscosity, and drying the film thoroughly and rapidly.

  The product and manufacturing method of the present invention provide a film that relies on the interaction between the various steps of manufacturing the film and substantially reduces the self-aggregation of the components in the film. Specifically, these steps include a special method used to form the film, which prepares the composition mixture to prevent bubble encapsulation, the viscosity of the film-forming composition and the film Is to control the method of drying. More specifically, if the active ingredient is not soluble in the polar solvent chosen, the higher viscosity of the ingredients in the mixture is particularly advantageous to prevent the active ingredient from sinking. However, the viscosity interferes with selected casting methods, preferably including reverse roll coating, due to its ability to provide a substantially consistent thickness film. Or it should not be too high to prevent.

In addition to the viscosity of the film or film-forming component or film-forming matrix, there are other considerations considered by the present invention to achieve the desired film uniformity. For example, a stable suspension is realized, which prevents sedimentation of solids (eg, drug particles) in non-colloidal applications. One approach provided by the present invention is to increase the viscosity (μ) of the liquid phase by balancing the density of the microparticles (ρ _p ) and the density of the liquid phase (ρ ₁ ). For isolated particles, Stokes' law relates the terminal settlement velocity (V _o ) of a rigid spherical body of radius (r) in a viscous fluid as follows:
V ₀ = (2 gr ^r ) (ρ _p −ρ ₁ ) / 9 μ
However, at high particle concentrations, the local particle concentration affects the local viscosity and density. Suspension viscosity is a strong function of solids volume fraction, and particle-particle and particle-liquid interactions further hinder the settlement rate.

Stokian analysis has shown that the incorporation of a third phase, eg, dispersed air or nitrogen, promotes suspension stability. Furthermore, increasing the number of particles results in a disturbed settlement effect based on the solid volume fraction. In a low concentration particle suspension, the sedimentation velocity v can be expressed as:
v / V ₀ = 1 / (1 + κφ)
In the formula, κ is a constant, and φ is the volume fraction of the dispersed phase. Suspending more particles in the liquid phase results in a reduction in speed. Particle geometry is also an important factor because the size of the particles affects the particle-particle flow interaction.

Similarly, the viscosity of the suspension depends on the volume fraction of the dispersed solid. For low concentration suspensions of non-interactive spherical particles, the formula for suspension viscosity can be expressed as:
μ / μ ₀ = 1 + 2.5Φ
Where μ ₀ is the viscosity of the continuous phase and Φ is the solid volume fraction. At higher volume fractions, the viscosity of the suspension can be expressed as:
μ / μ ₀ = 1 + 2.5φ + C ₁ φ ² + C ₂ φ ³ +
In the formula, C is a constant.

  The viscosity of the liquid phase is critical and is preferably changed by customizing the liquid composition into a viscoelastic non-Newtonian fluid with a low yield stress value. It is equivalent to preparing a stationary high viscosity continuous phase. Viscoelastic or highly structured fluid phase formation provides additional resistance to particle settling. Moreover, flocculation or agglomeration can be controlled by minimizing particle-particle interactions. The net effect would be the protection of a homogeneous dispersed phase.

The addition of hydrocolloids to the aqueous phase of the suspension can increase viscosity and cause viscoelasticity, depending on the type of hydrocolloid, its concentration and the particle composition, geometry, size and volume fraction. Stability can be given. The particle size distribution of the dispersed phase needs to be controlled by selecting the smallest practical particle size in the high viscosity medium, ie <500 μm. The presence of a low yield stress or low shear rate elastic can also result in permanent stability, regardless of the apparent viscosity. The critical particle size can be calculated from the yield stress value. In the case of isolated spherical particles, the maximum shear stress developed when sinking throughout a medium of a given viscosity is
τ _max = 3Vμ / 2r
Can be given as. For pseudoplastic fluids, the viscosity in this shear stress regime may be successfully the zero shear rate viscosity at the Newtonian plateau.

  As with a stable suspension, maintaining this stability at the wet film stage until sufficient drying occurs to maintain uniformity and the particles and matrix are confined to a solid form is also film casting. It is an important feature for the production of pre-mix compositions that are fed into film casting machinery film. For viscoelastic fluid systems, the rheology that results in a stable suspension for a long time, eg, 24 hours, must be balanced with the requirements for high speed film casting operations. A preferred property for the film is shear thinning or pseudoplastic, whereby the viscosity decreases with increasing shear rate. Time-dependent shear effects such as thixotropy are also advantageous. Structural recovery and shear thinning behavior are important properties, as is the ability of a self-level film as the film is formed.

The rheological requirements for the compositions and films of the present invention are very strict. This is due to the need to produce a stable suspension of particles (e.g., 30-60% by weight) in a viscoelastic fluid matrix having acceptable viscosity values over a wide shear rate range. . During mixing, during pumping and during film casting, shear rates in the range of 10 to 10 ⁵ sec ⁻¹ may be experienced, and pseudoplasticity is a preferred embodiment.
In film casting or coating, rheology is also a critical factor with respect to the ability to form films with favorable uniformity. Shear viscosity, extensional viscosity, viscoelasticity and structural recovery affect film quality. As an illustrative example, the leveling of a shear thinning pseudoplastic fluid is derived as follows:
α ^{(n−1 / n)} = α ₀ ^{(n−1 / n)} − ((n−1) / (2n−1)) (τ / K) ^{1 / n} (2π / λ) ^{(3 + n) / n} h ^{(2n + 1) /} nt
Where α is the amplitude of the surface wave, α ₀ is the initial amplitude, λ is the wavelength of the surface roughness, and both “n” and “K” are both the viscosity power law index ). In this example, the leveling behavior is associated with a viscosity that increases as n decreases and decreases as K increases.

  Preferably, the film or film-forming composition of the present invention has a very rapid structural recovery, i.e., when the film is formed during processing, the film does not collapse and its structure and composition uniformity. Does not become discontinuous. Such extremely rapid structural recovery delays particle settling and sedimentation. Furthermore, the film or film-forming composition of the present invention is preferably a shear thinning pseudoplastic fluid. Such fluids considering properties such as viscosity and elasticity promote thin film formation and uniformity.

  Thus, the homogeneity in the mixture of components depends on a large number of variables. As described herein, the viscosity of the components, the mixing technique, and the rheological properties of the resulting mixable composition and wet casted film are important aspects of the invention. Furthermore, control of particle size and particle shape is a further consideration. Preferably, the particle size is 150 microns or less, for example 100 microns or less. Such particles may also be spherical, substantially spherical, or non-spherical, such as irregularly shaped particles or elliptical particles. Ellipsoidal particles or ovals are preferred because they tend to sink to a lesser extent than spherical particles and have the ability to maintain uniformity in the film-forming matrix.

  Many techniques may be employed in the mixing stage to prevent air bubble entrapment in the final film. An antifoam or surface tension reducing agent is employed to provide a composition mixture that is substantially free of bubble formation in the final product. Furthermore, preferably the mixing speed is controlled to prevent cavitation of the mixture in a manner that pulls air into the mixture. Ultimately, bubble reduction can be further achieved by allowing the mixture to remain for a sufficient amount of time to allow the bubbles to escape prior to drying the film. Preferably, the method of the present invention initially forms a masterbatch of film-forming ingredients without active ingredients such as drug particles or volatile substances such as flavor oils. The active ingredient is added to a smaller mixture of the masterbatch just prior to casting. Thus, it can be allowed to leave the masterbatch premix for longer periods of time without concern for drug or other ingredient instability. In forming a matrix containing the film forming polymer and polar solvent in addition to any additives and active ingredients, this may be done in a number of steps. For example, all of the components may be added together or a premix may be prepared. The benefit of the premix is that all ingredients except the active ingredient may be pre-mixed and the active ingredient may be added just prior to film formation. This is particularly important with respect to active ingredients that can be degraded by prolonged exposure to water, air or other polar solvents.

  FIG. 6 shows an apparatus 20 suitable for premix preparation, addition of active ingredients and subsequent film formation. A premix or masterbatch 22 containing film forming polymer, polar solvent, and any other additives except the drug active ingredient is added to a masterbatch feed tank 24. Premix or masterbatch 22 like components are preferably formed in a mixer (not shown) prior to adding them to the masterbatch feed tank 24. Next, a predetermined amount of master batch is passed through the first metering pump 26 and the control valve 28 to either the first mixer 30 or the second mixer 30 ′ or the first mixer 30 and the second mixer 30 ′. Supply controllably to both. However, the present invention is not limited to the use of the two mixers 30, 30 ', and any number of mixers may be used appropriately. Furthermore, the present invention is not limited to any particular arrangement of mixers 30, 30 ′, such as a parallel arrangement as depicted in FIG. 6, and other arrangements or arrangements of mixers, such as parallel and serial series or combinations. It may be used appropriately. The required amount of other ingredients, such as drugs or fragrances, is added to the preferred mixer through each opening 32, 32 'of the mixer 30, 30'. Preferably, the residence time of the premix or masterbatch 22 is minimized in the mixer 30, 30 '. Although complete dispersion of the drug in the premix or masterbatch 22 is preferred, excessive residence time can result in leaching or dissolving of the drug (especially in the case of soluble drugs). Accordingly, the mixer 30, 30 'is often smaller, i.e., has a longer residence time, compared to the primary mixer (not shown) used in forming the premix or masterbatch 22. short. After the drug has been mixed with the masterbatch premix for a time sufficient to provide a uniform matrix, a quantity of the uniform matrix is then transferred to the pan 36 via the second metering pumps 34, 34 '. To supply. A metering roller 38 determines the thickness of the film 42 and applies the film to the application roller. The film 42 is finally formed into a substrate 44 and is carried away by the support roller 46.

  Appropriate viscosity uniformity in the mixture and in a stable suspension of particles, as well as casting means, are important to promote uniformity in the initial steps of forming the composition and film. The method of drying the wet film is also important. Although these variables and characteristics initially support uniformity, a controlled and rapid drying process ensures that uniformity is maintained until the film is dry.

  The wet film is then preferably exposed (exposed (at the top) of the film 48 using controlled bottom drying or controlled microwave drying as described herein. exposed)) Dry with no external airflow or heat on the surface. Controlled bottom drying or controlled microwave drying allows the release from the film without the disadvantages of the prior art. Conventional convection air drying from the top is not employed because it begins to dry at the top layer of the top edge of the film, resulting in a vapor-like fluid evaporating This is because it forms a barrier to heat flow, such as fluid flow and heat energy for drying. Such a dried upper end portion acts as a barrier to further water vapor release when drying the portion downward, which results in a non-uniform film. As already mentioned, some upper air flow can be used to assist in drying the film of the present invention, but it must not cause conditions that cause particle motion or ripple effects in the film. . When top air is employed, it balances the bottom air drying to avoid non-uniformity and prevent film lift-up on the carrier belt. It is done. If the bottom air flow serves as the main drying source and the top air flow is the minor drying source, the balance top air flow and the bottom air flow may be suitable. The benefit of some top airflow is that it moves the escape of water vapor from the film, thus contributing to the overall drying process. However, the use of either top airflow or top drying must be balanced by a number of factors including, but not limited to, the rheological properties of the composition and the mechanical aspects of the processing. Any top fluid flow, such as air, must also not defeat the inherent viscosity of the film-forming composition. In other words, the upper end airflow cannot break or distort or physically disturb the surface of the composition. Furthermore, the airflow rate is preferably below the yield value of the film, i.e. below any level of force that can move the liquid in the film-forming composition. For thin or low viscosity compositions, a low air flow rate must be used. For thick or highly viscous compositions, higher airflow rates may be used. In addition, the air flow rate is a preferred low to avoid any lifting or other movement of the film formed from the composition.

  Further, the films of the present invention may contain temperature sensitive particles such as perfumes that may be volatile, or drugs that may have a low decomposition temperature. In such cases, the drying temperature may be lowered when increasing the drying time in order to properly dry the uniform film of the present invention. Furthermore, bottom drying also tends to result in lower internal film temperatures compared to top drying. In bottom-end drying, the evaporated water vapor carries heat away more easily from the film compared to top-end drying, which lowers the internal film temperature. Such lower internal film temperatures often result in reduced drug degradation and reduced loss of certain volatile materials such as perfumes.

Further, the particles or microparticles may be added to the film-forming composition or matrix after the composition or matrix has been formed into a film. For example, the particles may be added to the film 42 prior to drying the film 42. An instrument that controllably measures particles for the film and controlsably places the particles on the film surface through appropriate techniques, for example, slightly or softly touching the surface of the film May be placed on the film surface through the use of a doctor blade (not shown). Other suitable techniques include, but are not limited to, the use of additional rollers to place the particles on the film surface, spraying the particles onto the film surface, and the like. The particles may be placed on either or both of the opposing film surfaces, i.e., the top film surface and / or the bottom film surface. Preferably, the particles are safely placed on the film, such as embedded in the film. Further, such particles are preferably not fully encased or fully embedded in the film, for example as if the particles are partially embedded or partially encapsulated. , Exposed to the film surface.
The particles can be any useful organoleptic agent, cosmetic agent, pharmaceutical agent, or combinations thereof. Preferably, the medicament is a taste-masked medicament or a controlled release medicament. Useful sensory organ stimulants include fragrances and sweeteners. Useful cosmetic agents include breath freshening or decongestants such as menthol containing menthol crystals.

  Although the method of the present invention is not limited to any particular apparatus for the preferred drying described above, one particular useful drying apparatus 50 is depicted in FIG. The drying device 50 is a nozzle arrangement for directing a high-temperature fluid such as hot air to the lower end of the film 42 arranged on the substrate 44, although not limited thereto. Hot air enters the drying device inlet end 52 and moves vertically upward toward the air deflector 56, as depicted by the vector 54. The air deflector 56 redirects the air movement to minimize the upward force on the film 42. As air moves past the air deflector 56 and through the chamber portions 58 and 58 'of the drying device 50, the air is tangent as depicted by vectors 60 and 60', as depicted in FIG. Oriented in the direction. Since the hot air flow is substantially tangential to the film 42, film lift when dried is thereby minimized. Although the air deflector 56 is depicted as a roller, other devices and geometries for deflecting air or hot fluid may be used as appropriate. Further, the outlet ends 62 and 62 'of the drying device 50 project downward. Such downward overhangs provide a downward force or downward velocity vector, as indicated by vectors 64 and 64 ', which tends to provide a traction or drag effect of film 42, which can help lift film 42. prevent. Lifting of the film 42 can not only result in film or other non-uniformity, but can also result in uncontrolled processing of the film 42, which can cause the film 42 and / or substrate 44 to move away from the processing apparatus. Because it lifts up.

Film thickness monitoring and control also contributes to the production of uniform films by providing uniform thickness films. The thickness of the film may be monitored with a measuring instrument such as a beta ray thickness meter. In order to communicate via a feedback loop to control and adjust the opening of the coating apparatus, the instrument is connected to other instruments at the end of the drying apparatus, i.e. drying oven or tunnel dryer. This may result in uniform film thickness control.
Such film products are generally formed by combining appropriately selected polymers and polar solvents, as well as any active ingredient or filler as desired. Preferably, the solvent content in the combination is at least about 30% by weight, based on the weight of the entire combination. The matrix formed by this combination is preferably formed into a film by roll coating and then preferably dried by a rapid and controlled drying process to ensure film uniformity, more specifically non-self. Maintain uniform heterogeneity of cohesiveness. The resulting film preferably contains less than about 10% by weight solvent, more preferably less than about 8% by weight solvent, even more preferably less than about 6% by weight solvent, and most preferably less than about 2% solvent. Including. The solvent may be water or a polar organic solvent that may be, but is not limited to, ethanol, isopropanol, acetone, methylene chloride, or any combination thereof.

  The parameters discussed above, such as, but not limited to, rheological properties, viscosity, mixing method, molding method and drying method also contribute to the selection of materials for the various components of the present invention. Influence. In addition, such considerations with the selection of appropriate materials provide the compositions of the present invention, which include no more than 10% of pharmaceutically active ingredients and / or cosmetic active ingredients per unit area. Included are pharmaceutical preparations and / or cosmetic preparations or film products with little variation. In other words, the homogeneity of the present invention is determined by the presence of variation of no more than 10% by weight of the pharmaceutically active ingredient and / or cosmetic active ingredient throughout the matrix. Preferably, the variation is less than 5% by weight, less than 2% by weight, less than 1% by weight, or less than 0.5% by weight.

(Film-forming polymer)
The polymer is a water-soluble polymer, a water-swellable polymer, a water-insoluble polymer, or a combination of one or more of a water-soluble polymer, a water-swellable polymer, or a water-insoluble polymer. Also good. The polymer includes cellulose or a cellulose derivative. Specific examples of useful water-soluble polymers include polyethylene oxide (PEO), pullulan, hydroxypropylmethylcellulose, hydroxyethylcellulose, hydroxypropylcellulose, polyvinylpyrrolidone, carboxymethylcellulose, polyvinyl alcohol, sodium aginate, polyethylene glycol , Xanthan gum, gum tragacanth, guar gum, acacia gum, gum arabic, polyacrylic acid, methyl methacrylate copolymer, carboxyvinyl copolymer, starch, gelatin, and combinations thereof, but are not limited thereto. In some embodiments, a combination of cellulosic polymers such as PEO and hydroxypropylcellulose is employed. Specific examples of water insoluble polymers include, but are not limited to, ethyl cellulose, hydroxypropyl ethyl cellulose, cellulose acetate phthalate, hydroxypropyl methylcellulose phthalate, and combinations thereof.

  As used herein, the phrase “water-soluble polymer” and variants thereof are at least partially soluble in water, preferably completely or mostly soluble in water. Or a polymer that absorbs water. A polymer that absorbs water is often referred to as a water-swellable polymer. Useful materials with the present invention may be water soluble or water swellable at room temperature and other temperatures, such as temperatures above room temperature. Further, the material may be water soluble or water swellable at pressures below atmospheric pressure. Preferably, the water soluble polymer is water soluble or water swellable with a water uptake of at least 20% by weight. Water swellable polymers having a water uptake of 25% by weight or more are also useful. The film or formulation of the present invention formed from such a water soluble polymer is preferably sufficiently water soluble and becomes soluble upon contact with body fluids.

  Other polymers for incorporation into the films of the present invention include biodegradable polymers, copolymers, block polymers and combinations thereof. Among the known useful polymers or polymers that meet the above criteria, polyglycolic acid (PGA), polylactic acid (PLA), polydioxanoes, polyoxalates, poly (α-esters), polyanhydrides , Polyacetates, polycaprolactones, poly (orthoesters), polyamino acids, polyaminocarbonates, polyurethanes, polycarbonates, polyamides, poly (alkyl cyanoacrylates), and copolymers thereof. Further useful polymers include L-lactic acid and D-lactic acid stereopolymers, copolymers of bis (carboxyphenoxy) propanoic acid and sebacic acid, copolymers of sebacic acid, copolymers of caprolactone, poly (lactic acid) / poly (glycolic acid) / Polyethylene glycol copolymer, polyurethane and poly (lactic acid) copolymer, polyurethane and poly (lactic acid) copolymer, α-amino acid copolymer, α-amino acid and caproic acid copolymer, α-benzyl glutamate and polyethylene glycol copolymer, succinate And poly (glycol) copolymers, polyphosphazenes, polyhydroxy-alkanoates, and mixtures thereof. Two-component and three-component systems are contemplated.

Other specific polymers that are useful include those marketed under the registered trademarks of Medisorb and Biodel. Medisorb materials are marketed by Wilmington and Delaware DuPont companies and are collectively identified as “lactide / glycolide” including “hydroxyacetic acid and hydroxypolymer and propanoic acid, 2-hydroxy-polymer” . Four such polymers include lactide / glycolide 100 L, believed to be 100% lactide having a melting point in the range of 338 ° F. to 347 ° F. (170 ° C. to 175 ° C.); 437 ° F. to 455 Lactide / Glycolide 100 L believed to be 100% lactide having a melting point in the range of ° F (225 ° C to 235 ° C); melting point in the range of 338 ° F to 347 ° F (170 ° C to 175 ° C) Lactide / glycolide 85/15, which is believed to be 85% lactide and 15% glycolide having a 50% lactide and 50% lactide having a melting point in the range of 338 ° F. to 347 ° F. (170 ° C. to 175 ° C.) % Lactide / glycolide 50/50 which is considered to be a copolymer of% glycolide.
Biodel materials represent a family of different polyanhydrides that are chemically different.

A variety of different polymers may be used, but it is preferred to select a polymer to provide the desired viscosity of the mixture prior to drying. For example, if the active ingredient or other ingredients are not soluble in the chosen solvent, polymers that provide greater viscosity are preferred to help maintain uniformity. On the other hand, if the component is soluble in the solvent, a polymer that provides a lower viscosity may be preferred.
The polymer plays an important role in affecting the viscosity of the film. Viscosity is a property of a liquid that controls the stability of the active ingredient in an emulsion, colloid or suspension. Generally, the viscosity of the matrix varies from about 400 cps to about 100,000 cps, preferably from about 800 cps to 60,000 cps, and most preferably from about 1,000 cps to about 40,000 cps. Preferably, the viscosity of the film-forming matrix increases rapidly when the drying process begins.

  The viscosity may be adjusted according to the other components in the matrix based on the active ingredient selected. For example, if the component is not soluble in the selected solvent, an appropriate viscosity may be selected to prevent settling of the component that adversely affects the resulting film uniformity. The viscosity may be adjusted by various means. In order to increase the viscosity of the film matrix, higher molecular weight polymers may be selected or cross-linking agents such as calcium, sodium and potassium salts may be added. The viscosity may also be adjusted by adjusting the temperature or by adding a viscosity increasing component. Ingredients that increase viscosity or stabilize emulsion / suspension may include carrageenan, hydroxypropyl methylcellulose, locust bean gum, guar gum, xanthan gum, dextran, gum arabic, gellan gum and combinations thereof. Nonlimiting examples include higher molecular weight polymers, polysaccharides and gum alginate. When used alone, certain polymers that normally require a plasticizer to achieve a flexible film can be combined without a plasticizer and still be able to achieve a flexible film. Observed. For example, when used in combination, HPMC and HPC provide a flexible and durable film with the appropriate plasticity and elasticity for manufacturing and storage. No additional plasticizers or polyhydric alcohols are required for flexibility.

(Release control film)
The term “controlled release” means the release of the active ingredient at a preselected rate or at a preferred rate. This speed varies depending on the application. Preferred rates include not only delayed release, sustained release or sequential release, but also fast release or immediate release. Consider combinations of release patterns, such as an initial spiked release of the active ingredient followed by a lower level of sustained release. Pulsed drug release is also contemplated.
The polymer selected for the film of the present invention may also be selected to allow controlled disintegration of the active ingredient. This may be accomplished by providing a substantially water insoluble film that incorporates the active ingredient released from the film over time. This may be accomplished by incorporating a variety of different soluble or insoluble polymers, and may also include a combination of biodegradable polymers. Alternatively, the coated controlled release active ingredient particles may be incorporated into a readily soluble film matrix to achieve controlled release characteristics of the active ingredient within the digestive system upon consumption.
Films that provide controlled release of the active ingredient are particularly useful for buccal, gingival, sublingual and vaginal applications. The films of the present invention are particularly useful where mucous membranes or mucus are present, due to their ability to easily wet and adhere to these areas.

  The convenience of administering a single dose of medication that releases the active ingredient in a controlled manner over an extended period of time, as opposed to regular single doses, has long been recognized in the pharmaceutical industry. It has been. The benefits to patients and clinicians in having consistent and uniform blood levels of medication over time are similarly recognized. The benefits of various sustained release formulations are well known. However, the preparation of a film that provides controlled release of the active ingredient has several benefits, not just those well known for controlled release tablets. For example, a thin film is not swallowed like a tablet, so it is difficult to inadvertently aspirate and provides increased patient compliance. Furthermore, some embodiments of the films of the present invention are designed to adhere to the buccal cavity and tongue where they dissolve controllably. In addition, thin films may not be crushed in the form of controlled release tablets, which is a problem that leads to misuse of drugs such as oxycontin.

The active ingredient employed in the present invention may be incorporated into the film composition of the present invention in a controlled release formulation. For example, the drug particles may be coated with a polymer such as ethyl cellulose or polymethacrylate, commercially available under the trade names such as Aquacoat ECD and Eudragit E-100, respectively. Drug solutions may be absorbed onto such polymeric materials and incorporated into the film compositions of the present invention. In addition to sweeteners and / or flavors, other ingredients such as fats and waxes may be employed in such controlled release compositions.
A co-pending PCT application of the title “Uniform Films For Rapid Dissolve Dosage Form Incorporating Taste-Masking Compositions,” the entire contents of which are incorporated herein by reference (US provisional application No. express delivery of the same invention name) Express Mail Lavbel No .: based on EU552991605 US, filed on Sep. 27, 2003, agent arrangement No. 1199-15P), incorporating the active ingredient into the film composition Prior to, taste-masked may be masked.

(Active ingredient)
When introducing an active ingredient into the film, the amount of active ingredient per unit area is determined by the uniform distribution of the film. For example, when the film is cut into individual formulations, the amount of active ingredient in the formulation can be known with considerable accuracy. This is achieved because the amount of active ingredient in a given area is substantially equal to the amount of active ingredient in the same size area in other parts of the film. The accuracy in the formulation is particularly advantageous when the active ingredient is a medicine, ie a drug.
The active ingredients that may be incorporated into the film of the present invention include pharmaceutical active ingredients, cosmetic active ingredients, drugs, medicines, ragweed pollens, spores, microorganisms including bacteria, seeds Antigens or allergens such as, mouthwash ingredients such as chlorate or chlorite, flavorings, fragrances, enzymes, preservatives, sweeteners, colorants, spices, vitamins and combinations thereof However, it is not limited to these.

  A wide variety of medicaments, bioactive substances and pharmaceutical compositions may be included in the formulations of the present invention. Examples of useful drugs include ACE inhibitors, antianginal agents, antiarrhythmic agents, anti-cholesterolemic, analgesics, anesthetics, anticonvulsants, antidepressants, antidiabetics , Anti-diarrhea preparation, antidote, antihistamine, antihypertensive, anti-inflammatory, anti-lipid agent, antidepressant, anti-nauseant, anti-stroke agent (anti -stroke agent), antithyroid agent, antitumor agent, antiviral agent, alkaloid, amino acid preparation, antitussive agent, anti-uricemic drug, antiviral agent, anabolic preparation (anabolic) preparation), systemic and non-systemic antiinfectives, anti-neoplastic, antiparkinsonian, antirheumatic, appetite enhancer, biological response modifier, blood regulator (blood modifier), bone metabolism regulator, cardiovascular agent, medium Central nervous system stimulate, cholinesterase inhibitor, contraceptive, decongestant, dietary supplement, dopamine receptor agonist, endometriosis management agent, enzyme, erection Erectile dysfunction therapy, pregnancy-promoting drugs, gastrointestinal drugs, homeopathic remedy, hormones, management agents for hypercalcemia and hypocalcemia, immunomodulators, Immunosuppressant, migraine preparation, motion sickness treatment, muscle relaxant, obesity management agent, osteoporosis preparation, labor inducer, parasympathetic blockade, parasympathetic Neurostimulants, prostaglandins, psychootherapeutic agents, respiratory agents, analgesics, Smoking cessation aid (such as bromocriptine and nicotine), sympathetic blockade, tremor preparation, urinary tract agent, vasodilator, laxative, antacid Agent, ion exchange resin, antipyretic, appetite suppressant, expectorant, anxiolytic, anti-ulcer, anti-inflammatory, coronary dilator, cerebral dilator, peripheral vasodilator, psychotropic, stimulant (Stimulant), antihypertensive, vasoconstrictor, migraine treatment, antibiotic, tranquilizer, antipsychotic, antitumor, anticoagulant, antithrombotic, hypnotic, antiemetic, anti Anti-nauseant, anticonvulsant, neuromuscular, hyperglycemic and hypo-glycemic agents, thyroid and anti-thyroid preparations, diuresis Drugs, antispasmodics, terine relaxants, anti-obesity drugs, Blood cell formation agent (erythropoietic drug), anti-asthmatics, cough suppressants, mucolytics, DNA and genetic modifying drugs (genetic modifying drug), and combinations thereof.

Examples of medicating active ingredients contemplated for use in the present invention include antacids, H ₂ antagonists, and analgesics. For example, an antacid formulation can be prepared using a component of calcium carbonate alone or in combination with magnesium hydroxide and / or aluminum hydroxide. Furthermore, antacids can be used in combination with H ₂ antagonists.
Analgesics include opiates and opiate derivatives such as oxycodone (available as Oxycontin®), ibuprofen, aspirin, acetaminophen, and combinations thereof, and caffeine as needed. May be included.

  Other preferred drugs for other preferred active ingredients for use in the present invention include antidiarrheals such as immodium AD, antihistamines, antitussives, decongestants, vitamins, and breath fresheners (breath) freshener). Suitable vitamins contemplated for use in the present invention may be any conventionally known vitamin, such as, but not limited to, vitamins A, B, C and E. Common drugs used alone or in combination for cold, pain, fever, cough, congestion, runny nose and allergies such as acetaminophen, chlorpheniramine maleate, dextromethorphan, pseudoephedrine hydrochloride (pseudoephedrine HCl) And diphenhydramine may be included in the film composition of the present invention.

Anxiolytics such as alprazolam (available as Xanax®); antipsychotics such as clozapine (available as Clozaril®) and haloperidol (available as Haldol®); diclofenac ( Non-steroidal anti-inflammatory drugs such as Voltaren® and Etodolac (available as Lodine®); Loratadine (available as Claritin®), Astemizole (Hismanal®) Antihistamines such as nabumetone (available as Relafen®) and clemastine (available as Tavist®); granisetron hydrochloride (available as Kytril®) and nabilone (Cesamet (Available as (registered trademark)); Bentolin (registered trademark), Bronchodilators such as acid albuterol (available as Proventil®); fluoxetine hydrochloride (available as Prozac®), sertraline hydrochloride (available as Zoloft®) and paroxetine hydrochloride (Paxil ( Antidepressants such as Imigra®; enalaprilates (available as Vasotec®), captopril (available as Capoten®) And anti-Alzheimer's drugs such as nicergoline, an ACE inhibitor such as lisinopril (available as Zestril®); and nifedipine (available as Procardia® and Adalat®) and verapamil hydrochloride (Calan Ca ^H antagonists such as (available as (registered trademark)) are also included in the present invention. Contemplated for use.

Erectile dysfunction therapy includes drugs that promote blood flow to the penis and drugs that provide autonomic activity, such as drugs that increase parasympathetic (cholinergic) activity and sympathy Examples include, but are not limited to, drugs that reduce neuronal (adrenergic) activity. Non-limiting useful drugs include sildenafil such as Viagra®, tadalafil such as Cialis®, vardenafil, apomorphine such as Uprima®, yohimbine hydrochloride such as Aphrodyne® And alprostadil, such as Caverject®.
Well-known H ₂ antagonists contemplated for use in the present invention include cimetidine, ranitidine hydrochloride, famotidine, nizatidine, ebrotidine, mifetidine, roxatidine, pisatidine and aceroxatidine.

  Active antacid components include, but are not limited to: aluminum hydroxide, aminoacetic acid aluminum hydroxide, aminoacetic acid, aluminum phosphate, sodium dihydroxyaluminum carbonate, bicarbonate, bismuth aluminate, bismuth carbonate , Bismuth subcarbonate, bismuth subgallate, bismuth subnitrate, bismuth subsilysilate, calcium carbonate, calcium phosphate, citrate ion (acid or salt), aminoacetic acid, hydrate magnesium aluminate sulfate (hydrate magnesium) aluminate sulfate, magaldrate, magnesium aluminate, magnesium carbonate, magnesium glycinate, magnesium hydroxide, magnesium oxide, magnesium trisilicate, milk solids, aluminum Monobasic or dibasic calcium phosphate (aluminum mono- or dibasic calcium phosphate), tricalcium phosphate, potassium bicarbonate, sodium tartrate, sodium bicarbonate, magnesium aluminosilicate, tartaric acid and salts.

The pharmaceutically active agent employed in the present invention may contain allergens or antigens, such as grass, tree or ragweed plant pollen; extremely removed from the skin and hair of animals with cats and other fur. Small scale animal scales; insects such as dust mites, bees, and wasps; and drugs such as penicillin, but are not limited to these.
Botanicals, herbals and minerals may also be added to the film. Examples of botanicals include, but are not limited to, roots; bark; leaves; stems; flowers; fruits; tobacco; sunflower seeds; snuffs;
Antioxidants may also be added to the film to prevent degradation of active ingredients, particularly photosensitive active ingredients.

The physiologically active substance employed in the present invention may be beneficial bacteria. More specifically, it is a kind of bacteria that is usually present on the surface of the tongue and in the back of the throat. Such bacteria help food digestion by breaking down proteins found in food. Accordingly, it may be preferable to incorporate these bacteria into the oral film product of the present invention.
It may also be preferable to include active ingredients for treating malodors of breath and related oral care conditions, such as active ingredients effective to control microorganisms. Since malodor of breath can be caused by the presence of anaerobic bacteria that produce volatile sulfur compounds in the oral cavity, ingredients that suppress such microorganisms may be preferred. Examples of such components include antibacterial agents such as triclosan, chlorine dioxide, chlorate, chlorite, among others. The use of chlorite, particularly sodium chlorite, in oral care compositions such as mouthrinse and toothpaste is described in US Pat. Nos. 6,251,372, 6,132,702,6. , 077,502, and US Publication No. 2003/0129144, all of which are incorporated herein by reference. Such ingredients are incorporated in an amount effective to treat malodors and related oral conditions.

For cosmetic active agents, use in breath freshening compounds such as menthol, other perfumes or fragrances, especially in tooth cleansing and oral cleansing such as quaternary ammonium bases Similar to the active ingredient to be used, those used for oral hygiene may be included. The effect of the perfume may be improved using a perfume enhancer such as tartaric acid, citric acid, vanillin and the like.
In addition, coloring additives can be used in preparing the film. Such coloring additives include foods, drugs and cosmetic colors (FD & C), drugs and cosmetic colors (D & C), or external drugs and cosmetic colors (Ext) D & C). These pigments are dyes, their corresponding lakes, and certain natural and derived colorants. Lakes are dyes adsorbed on aluminum hydroxide.
Other examples of colorants include known azo dyes, organic or inorganic pigments, or naturally occurring colorants. Inorganic pigments such as iron or titanium oxides are preferred and are added at concentrations ranging from about 0.001 to about 10%, preferably from about 0.5 to about 3%, based on the weight of all components.

The perfume may be selected from natural and synthetic flavoring liquids. Illustrative lists of such include volatile oils, synthetic perfume oils, perfume aromatics, oils, liquids, oleoresin or plants, leaves, flowers, fruits, stems and combinations thereof Is included. A non-limiting list of representative examples includes citrus oils such as mint oil, cocoa, lemon, orange, grape, lime and grapefruit, as well as apple, pear, peach, grape, strawberry, raspberry, cherry, plum Included are fruit essences, which may be pineapples, apricots or other fruit flavors.
A film containing flavoring may be added to provide a beverage or soup with a warm or cold taste. These flavors include, but are not limited to, tea leaf flavors and soup flavors such as beef and chicken.
Other useful flavors include aldehydes and esters such as benzaldehyde (cherry, almond), citral (ie alpha citral (lemon, lime)), neral (ie beta citral (lemon, lime)), decanal ( Orange, lemon), aldehyde C-8 (citrus fruit), aldehyde C-9 (citrus fruit), aldehyde C-12 (citrus fruit), tolyl aldehyde (cherry, almond), 2,6-dimethyloctanol (Green fruit), 2-dodecenal (citrus, mandarin), combinations thereof and the like.

Sweeteners may be selected from the following non-limiting list: glucose (corn syrup), dextrose, invert sugar, fructose, and combinations thereof; various salts thereof such as saccharin and sodium salts; dipeptides such as aspartame Sweeteners; dihydrochalcone compounds, glycyrrhizin; Stevia Rebaudiana (stevioside); chloro derivatives of sucrose such as sucralose; sugar alcohols such as sorbitol, mannitol, xylitol and the like. Hydrogenated starch hydrolysates and synthetic sweeteners 3,6-dihydro-6-methyl-1-1-1,2,3-oxathiazin-4-one-2,2-dioxide, especially its potassium salt (acesulfame Natural strong sweeteners such as K), sodium and calcium salts, and Lo Han Kuo are also contemplated. Other sweeteners may also be used.
In combining the active ingredient with the polymer in the solvent, the type of matrix formed depends on the solubility of the active ingredient and the polymer. If the active ingredient and / or polymer is soluble in the chosen solvent, this can form a solution. However, if the component is not soluble, the matrix can be classified as an emulsion, colloid, or suspension.

(dose)
The film product of the present invention is capable of containing a wide range of amounts of active ingredients. The film is capable of providing an accurate dose (determined by the size of the film and the concentration of the active ingredient in the original polymer / water combination), regardless of whether the required volume is high or very low. is there. Thus, depending on the type of active ingredient or pharmaceutical composition incorporated into the film, the amount of active ingredient may be as high as about 300 mg, preferably up to about 150 mg, or as low as the microgram range. Or any amount between them.
The film products and methods of the present invention are highly suitable for high dose low dose drugs. This is achieved through a high degree of uniformity of the film. Therefore, low dose drugs, particularly more potent racemic mixtures of active ingredients, are preferred.

(Anti-adhesive composition)
It is useful to add anti-blocking agents such as lubricants, anti-adhesive agents and glidants to the film composition of the present invention. Anti-tacking agents reduce the flow characteristic of the material, for example, reducing sticking to the die during the extrusion process and sticking to the root of the mouth during administration of the formulation. Help by reducing.
During film consumption, particles tend to adhere to the palate. This is undesirable for films containing bitter drugs such as, for example, dextromethorphan, because the attached particles elude the drug and increase the amount of bitterness perceived by the user Because. The addition of an anti-blocking agent to the film reduces adhesion to the palate, thereby effectively reducing the bitterness that can be perceived by the user during consumption.

An anti-blocking agent can also provide a reduced coefficient of friction between films, thereby reducing film formulation unit problems, i.e., the mutual adhesion of strips. More specifically, in many types of film packages, the strips are stacked together. The incorporation of an anti-blocking agent allows the individual strips to slide smoothly relative to each other as each unit is removed from the packaging.
Examples suitable for use as an anti-blocking agent include stearates such as magnesium stearate, calcium stearate, and sodium stearate; stearic acid; sterotex; talc; waxy substance (wax); Stearowet; boric acid; sodium benzoate; sodium acetate; sodium chloride; DL-leucine; carbowax 4000; carbowax 6000; sodium oleate; sodium lauryl sulfate; Magnesium; and combinations thereof include, but are not limited to:

Examples of suitable anti-adhesive agents include, but are not limited to, talc; corn starch; Cab-O-Sil; syloid; DL-leucine; sodium lauryl sulfate; metal stearate; . Examples of suitable glidants include, but are not limited to, talc; corn starch; Cab-O-Sil; syloid; aerosol; and combinations thereof.
Some embodiments of the present invention include fat and / or wax as an anti-sticking agent.
Vitamin E is another suitable anti-blocking agent for use in some embodiments of the present invention. Vitamin E may serve as both an anti-sticking agent and an active ingredient in the film. Preferably, vitamin E TPGS (d-α tocopheryl polyethylene glycol 1000 succinate) is employed. Vitamin E TPGS is a water-soluble form of vitamin E derived from natural sources. Compared to other forms, Vitamin E TPGS is easily absorbed. Furthermore, Vitamin E TPGS gives virtually no taste to the film. Vitamin E TPGS may be employed in solution, for example in a 10% aqueous solution or a 20% aqueous solution. Vitamin E TPGS is particularly useful in reducing the viscosity of the film and the tendency to adhere to the user's palate. Vitamin E may be present in an amount from about 0.01% to about 20% by weight of the composition.

The anti-blocking agent is generally present in an amount from about 0.01% to about 20% by weight of the film composition. More specifically, the anti-blocking agent is about 0.01% to about 10% by weight of the film composition, and more specifically about 0.25% to about 5% of the film composition. It may be present in an amount of mass%.
Combinations of antiblocking agents can also be employed. For example, in some embodiments of the invention, a combination of stearate and silica, such as magnesium stearate, may be used. SIPERNAT 500LS (commercially available from Degussa), a silica product with an average particle size of 4.5 μm, is suitable for use in the present invention. The combination of magnesium stearate and silica can provide improved glidant properties, i.e., help the film strips slide smoothly against each other during packaging. Thus, in some embodiments, the magnesium stearate may be present in an amount from about 0.1% to about 2.5% by weight of the film composition and silica is about 0.0% of the film composition. It may be present in an amount of 1% to about 1.5% by weight. Such a combination of anti-blocking agents may be useful in various films containing various perfumes and / or active ingredients.

  In some embodiments, an anti-blocking agent may be included in the film composition itself. For example, a monolayer or multilayer film containing an anti-tacking agent may be formed. For example, a multilayer film may include two, three, or more film layers that are substantially in contact with each other. In some embodiments, the film layers may be laminated together. The antiblocking agent may be present in one or more layers of the multilayer film. For example, some embodiments may include a bilayer film in which an anti-blocking agent is present in one of the two film layers. Some embodiments may include a three-layer film in which the anti-blocking agent is present in each outer layer and not the inner or intermediate layer of the three-layer film. Accordingly, various different combinations of layers may be formed.

  Alternatively, in some embodiments, an anti-blocking agent may be included in the composition used to coat the outer surface of the film. For example, an anti-tacking agent may be applied to the film in the form of a wet or dry coating, such as a sugared coating or a sugar-free coating. The film may be coated with the anti-blocking agent by any conventional method such as, but not limited to, dip coating, spray coating, dusting, or fluidized bed. One or more film surfaces may be coated. In some embodiments, the anti-stick coating may be applied to a substrate, such as a backing for the film, rather than directly to the film itself. When removing the film from the support, the anti-stick coating may adhere to the film.

(Defoaming composition and de-foaming composition)
An antifoam component and / or a defoamer component may also be used with the film of the present invention. These components assist in the removal of air, such as trapped air, from the film forming composition. As mentioned above, such trapped air can result in a non-uniform film. Simethicone is one particularly useful antifoam and / or defoamer. However, the present invention is not so limited and other antifoams and / or defoamers may be used as appropriate.
Simethicone is generally used in the medical field as a treatment for gas or colic in infants. Simethicone is a mixture of fully methylated linear siloxane polymer and silicon dioxide containing repeating units of polydimethylsiloxane stabilized with trimethylsiloxy endblocking units. Simethicone typically contains 90.5% to 99% polymethylsiloxane and 4% to 7% silicon dioxide. The mixture is a gray translucent viscous fluid that is insoluble in water.

  When dispersed in water, simethicone spreads across the surface to form a thin film with low surface tension. In this way, simethicone reduces the surface tension of bubbles located in a solution, such as foam bubbles, causing their collapse. This action of simethicone mimics the dual action of oil and alcohol in water. For example, in an oily solution, any trapped bubbles will rise to the surface and disperse more quickly and easily because the oily liquid has a lighter density compared to the aqueous solution. Because. On the other hand, alcohol / water mixtures are known not only to reduce the surface tension of water, but also to reduce water density. Therefore, any bubbles trapped inside the mixture solution are also easily dispersed. Simethicone solution provides both of these benefits. Simethicone not only reduces the surface tension of the aqueous solution, but also reduces the interfacial energy of any bubbles trapped inside the aqueous solution. As a result of this unusual functionality, simethicone can be used not only for external processes that require the removal of bubbles from the product, but also for physiological processes (anti-gasses in the stomach). gas)) with excellent defoaming properties that can be used for.

In order to prevent the formation of bubbles in the film of the present invention, the mixing step can be performed under vacuum. However, as soon as the mixing step is complete and the film solution has returned to normal atmospheric conditions, air is reintroduced into or brought into contact with the mixture. In many cases, very small bubbles are again trapped inside the polymer viscous solution. Incorporation of simethicone into the film-forming composition either substantially reduces or eliminates bubble formation.
Simethicone is about 0.01 wt% to about 5.0 wt%, more preferably about 0.05 wt% to about 2.5 wt%, most preferably about 0.1 wt% to about 1.0 wt%. May be added to the film-forming mixture as an antifoaming agent.

(Optional ingredient)
Various other ingredients and fillers may also be added to the films of the present invention. These include surfactants; plasticizers that assist in compatibilizing the components in the mixture; polyhydric alcohols; silicone-containing compounds that promote smoother film surfaces by releasing oxygen from the film Defoaming agents such as: and thermosetting gels such as, but not limited to, pectin, carrageenan, and gelatin to help maintain the dispersion of the components.
Various additives that can be incorporated into the compositions of the present invention may provide a variety of different actions. Examples of additive classes include excipients, lubricants, buffers, stabilizers, foaming agents, pigments, colorants, fillers, bulking agents, sweetening agents, flavoring agents ( flavoring agent, fragrance, release modifier, adjuvant, plasticizer, flow accelerator, mold release agent, polyhydric alcohol, granulating agent, diluent, binder, buffering agent (Buffer), absorbent, glidant, adhesive, anti-adhesive, acidulant, softener, resin, demulcent, solvent, surfactant, emulsifier, elastomer and mixtures thereof It is done. These additives may be added together with the active ingredient.

  Examples of useful additives include gelatin, vegetable protein (such as sunflower protein, soy protein, cottonseed protein, peanut protein, grape seed protein), whey protein, whey protein isolate isolate), blood protein, egg protein, acrylated protein, water soluble polysaccharides (such as alginate), carrageenan, guar gum, agar-agar, xanthan gum, gellan gum, gum arabic and related gums ( Gucci gum (gum ghatti), Karaya gum, gum tragancanth (gum tragancanth), pectin, water-soluble derivatives of cellulose: alkylcellulose, hydroxyalkylcellulose and hydroxyalkylalkylcellulose (methylcellulose, hydroxymethi) Cellulose, hydroxyethylcellulose, hydroxypropylcellulose, hydroxyethylmethylcellulose, hydroxypropylmethylcellulose, hydroxybutylmethylcellulose and the like, cellulose esters and hydroxyalkylcellulose esters (such as cellulose acetate phthalate (CAP), hydroxypropylmethylcellulose (HPMC) Carboxyalkylcellulose (such as carboxymethylcellulose), carboxyalkylalkylcellulose, carboxyalkylcellulose esters and their alkali metal salts; polyacrylic acid and polyacrylic acid esters, polymethacrylic acid and polymethacrylic acid esters, polyvinylacetate Tartar, polyvinyl alcohol, polyvinyl acetate Water-soluble synthetic polymers such as phthalate (PVAP), polyvinylpyrrolidone (PVP), PVY / vinyl acetate copolymer, and polycrotonic acid; phthalated gelatin, gelatin succinate, cross-linked gelatin, shellac, Water-soluble chemical derivatives of starch, cation-modified acrylates and methacrylates (eg tertiary or quaternary amino groups (such as diethylaminoethyl groups optionally quaternized)); and others Similar polymers of are also suitable.

Such extenders are optionally in the range of up to about 80%, preferably in the range of about 3% to about 50%, more preferably 3%, preferably based on the weight of all components. Any preferred amount within the range of -20% may be added.
Further examples of additives include polyalkylene oxides (such as polyethylene glycol, polypropylene glycol, polyethylene propylene glycol), low molecular weight organic plasticizers (glycerol, glycerol monoacetate, diacetate or triacetate, triacetin, polysorbate, cetyl alcohol, Such as propylene glycol, sorbitol, sodium diethylsulfosuccinate, triethyl citrate, tributyl citrate, etc.), and about 0.5% to about 30% based on the weight of the polymer It is added at a concentration in the range, preferably about 0.5% to about 20%.

In order to improve the flow properties of the starch material, compounds such as animal or vegetable oils, preferably their hydrogenated forms, especially those that are solid at room temperature, may be further added. These fats preferably have a melting point of 50 ° C. or higher. C ₁₂ - fatty acids, C ₁₄ - fatty acids, C ₁₆ - fatty acids, C ₁₈ - fatty acids, C ₂₀ - fatty acids, and C ₂₂ - triglycerides of fatty acids are preferred. These fats can be added alone without the addition of extenders or plasticizers, and can be advantageously added alone or with monoglycerides and / or diglycerides or phospholipids, in particular lecithin. The monoglycerides and diglycerides are preferably derived from the above-mentioned types of fat, namely C ₁₂ -fatty acids, C ₁₄ -fatty acids, C ₁₆ -fatty acids, C ₁₈ -fatty acids, C ₂₀ -fatty acids, and C ₂₂ -fatty acid triglycerides.

The total amount of fat, monoglyceride, diglyceride and / or lecithin used is up to about 5% by weight of the total composition, preferably in the range of about 0.5% to about 2%.
It is further useful to add silicon dioxide, calcium silicate, or titanium dioxide at a concentration of about 0.02% to about 1% by weight of the total composition. These compounds act as texturizing agents.
These additives are used in amounts sufficient to achieve their intended purpose. In general, a combination of some of these additives can be used to alter the overall release characteristics of the active ingredient and to modify the release, i.e. delay or accelerate the release.

  Lecithin is one surface active agent for use in the present invention. Lecithin can be included in the feedstock in an amount of about 0.25% to about 2.00% by weight. Other surfactants, i.e. surfactants, include cetyl alcohol, sodium lauryl sulfate, Spans (R) and Tween (R), which are commercially available from ICI Americas, Inc. It is not limited to. Also useful are ethoxylated oils, which may be ethoxylated castor oil, such as Cremophor® EL, commercially available from BASF. Carbowax® is yet another modifier that is very useful in the present invention. A preferred hydrophilic-lipophilic balance (“HLB”) may be achieved using a combination of Tween® or surfactant. However, the present invention does not require the use of surfactants, and the films or film-forming compositions of the present invention are essentially free of surfactants while still providing the preferred uniformity characteristics of the present invention. It does not have to be.

It may be more useful to add polydextrose to the film of the present invention. Polydextrose acts as a filler and solubility enhancer, ie polydextrose increases the dissolution time of the film in the oral cavity.
Having identified additional modifiers that enhance the methods and products of the present invention, Applicants have identified all such additional modifiers as claimed in the claimed invention. It is intended to be included within the scope.
Other components include binders that contribute to the ease of forming the film and general quality. Non-limiting examples of binders include starch, pregelatinize starch, gelatin, polyvinyl pyrrolidone, methyl cellulose, sodium carboxymethyl cellulose, ethyl cellulose, polyacrylamide, polyvinyl oxoazolidone, and polyvinyl alcohol.

(Formation of film)
The film of the present invention must be formed into a sheet prior to drying. After mixing the preferred ingredients including the polymer, water, and the active ingredient or other preferred ingredients to form a multi-component matrix, the combination can be extruded, coated, spreading, casting ) Or the other component matrix is formed into a sheet or film by any method known in the art, such as drawing. If a multilayered film is preferred, this may be accomplished by coextruding more than one combination of components that may be the same composition or different compositions. Multilayered films may also be achieved by coating, spreading, or casting the combination onto an already formed film layer.

A variety of different film forming techniques may be used, but it is preferred to choose a method that provides a flexible film, such as reverse roll coating. The flexibility of the film allows it to be rolled and transported for storage or before being cut into individual formulations. Preferably, the films are also self-supporting, or in other words, can maintain their integrity and structure without a separate support. The film of the present invention may select materials that are edible or ingestible.
Coating or casting methods are particularly useful for the purposes of forming the films of the present invention. Specific examples include reverse roll coating, gravure coating, dipping or dip coating, metering rod or Meyer bar coating (especially when a multilayer film is preferred. Examples include meyer bar coating, slot die or extrusion coating, gap or knife over roll coating, air knife coating, curtain coating, or combinations thereof.

Roll coating, or more specifically reverse roll coating, is particularly preferred when forming the films of the present invention. This method provides excellent control and uniformity of the resulting film, which is preferred in the present invention. In this method, the coating material is measured onto the applicator roller by a precise setting of the gap between the top measuring roller and the application roller below it. The coating is carried from the application roller to the substrate as it passes around the support roller adjacent to the application roller. Three roll processes and four roll processes are common.
The gravure coating process relies on engraved roller running in the coating bath, which fills the engraved dot or line of the roller with the coating material. . Excess coating on the roller is wiped off by a doctor blade, which is then deposited on the substrate as it passes between the engraved roller and the pressure roller. .
Offset gravure is common when the coating is deposited on an intermediate roller before being transferred to the substrate.

In a simple dip coating or dip coating process, the substrate is dipped into the coating bath, which usually allows the coating to return into the bath as the substrate floats. It has a low viscosity.
In the metering rod coating process, excess coating is deposited onto the substrate as it passes over a bath roller. A wire-wound metering rod, sometimes known as a Meyer Bar, allows the preferred amount of coating to remain on the substrate. The amount is determined by the diameter of the wire used on the bar.
In the slot die process, the coating is squeezed through the slot onto the substrate by gravity or under pressure. If the coating is 100% solids, the process is referred to as “extrusion”, where the line speed is often much faster than the extrusion rate. This allows the coating to be much thinner than the slot width.

Gap or knife over roll coating depends on the coating applied to the substrate, which in turn reduces the “gap” between the “knife” and the support roller. pass. As the coating and substrate pass through, the excess is scraped off.
Air knife coating is where the coating is applied to a substrate and the excess is blown away from the air knife by a powerful jet. This method is useful for aqueous coatings.
In the curtain coating process, a bathtub with a slot in the base allows a continuous curtain of coating to enter the gap between the two conveyors. The object to be coated passes along the conveyor at a controlled speed and thus receives the coating on its upper end surface.

(Dry film)
The drying step is also a contributing factor in maintaining the uniformity of the film composition. A controlled drying process reduces the tendency of the components in the film to agglomerate or agglomerate in the absence of a viscosity increasing composition or a composition whose viscosity is controlled, for example by the choice of polymer. It is particularly important when it can have. An alternative method of forming a film with an accurate dose that does not require the controlled drying process is to cast the film over a given well. In this way, the ingredients can agglomerate but this does not result in the transfer of the active ingredient to the adjacent formulation as each well can define the formulation unit itself.

When a controlled drying process or a rapid drying process is preferred, this may be via various methods. Various methods, including those that require heating, may be used. The liquid carrier is removed from the film in such a manner that the uniformity obtained in the wet film, or more specifically, non-self-aggregating uniform heterogeneity is maintained.
Preferably, the film is dried from the lower end of the film to the upper end of the film. Preferably during the initial setting period of the film during which a solid viscoelastic structure is formed, there is substantially no air flow beyond the top of the film. This occurs within the first few minutes of the drying process, for example in the range of about 0.5 minutes to 4.0 minutes. By controlling the drying in such a manner, destruction and re-formation of the upper end direction of the film due to the conventional drying method are prevented. This is accomplished by forming the film and placing the film on the top surface of the surface having a top surface and a bottom surface. Next, heat is first applied to the top surface of the film to provide the energy necessary to evaporate or otherwise remove the liquid carrier. Films dried in this manner dry more quickly and uniformly than air-dried films or those dried by conventional drying means. In contrast to air-dried films that initially dry at the top and edges, films that are dried by the application of heat to the bottom edge dry simultaneously at the center as well as at the edges. This also prevents the settling of components that occurs in films dried by conventional means.
The temperature for drying the film is about 100 ° C. or less, preferably about 90 ° C. or less, and most preferably about 80 ° C. or less.

Other methods of controlling the drying process that may be used alone or in combination with other controlled methods as disclosed above include controlling the humidity in the drying apparatus where the film dries and For example, modifying. In this manner, premature drying of the top surface of the film is avoided.
Furthermore, the length of drying time can be appropriately controlled, i.e. the balance between the thermal sensitivity and volatility of the components, in particular fragrances and drugs. The amount of energy, temperature, length and speed of the conveyor can be balanced to adapt to the active ingredient and minimize loss, degradation or inefficiency in the final film.
A specific example of a suitable drying method is disclosed by Magoon. Magoon is specifically directed to the method of drying the pulp. However, we have adapted this process for the preparation of thin films.

Magoon's method and apparatus is based on the interesting properties of water. Water transfers energy both in and around its surroundings by conduction and convection, but water only radiates energy in and to the water. Thus, Magonon's device includes a surface on which the pulp is placed and is transparent to infrared radiation. The lower end of the surface is in contact with the temperature-controlled water bath. The water bath temperature is preferably controlled at a temperature slightly below the boiling temperature of water. This causes a “refractance window” when the wet pulp is placed on the surface of the device. This means that infrared energy can only radiate through the surface up to the area on the surface occupied by the pulp and only until the pulp is dry. Magoon's equipment provides the film of the present invention with an effective drying time that reduces the fact of aggregation of the film's components.
The film may initially have a thickness of about 500 μm to about 1,500 μm, or about 20 mils to about 60 mils, and when dried, about 3 μm to about 250 μm, or It may have a thickness of about 0.1 mil to 10 mil. Preferably, the dried film has a thickness of about 2 mils to about 8 mils, more preferably about 3 mils to about 6 mils.

(Use of thin film)
The thin films of the present invention are suitable for many applications. The high degree of uniformity of the components of the film makes them very suitable especially for incorporating pharmaceuticals. In addition, the polymer used in the construction of the film may be selected to take into account the range of disintegration times for the film. Variation and extension of the time at which the film disintegrates can achieve control of the rate at which the active ingredient is released, which can allow for a sustained release delivery system. In addition, the film can be applied to various body surfaces, especially wound surfaces either on mucosa (such as oral mucosa, anal mucosa, vaginal mucosa, ocular mucosa), on the skin surface or in the body such as during surgery. And any of them including similar surfaces may be used to administer the active ingredients.

  The film may be used for oral administration of the active ingredient. This is accomplished by preparing the films as described above and introducing them into the oral cavity of the mammal. This film may be prepared and applied to the second layer or support layer and removed therefrom prior to use, ie, introduction into the oral cavity. An adhesive may be used to adhere to any support material or backing material that is known in the art and preferably not water soluble. When an adhesive is used, it is preferably a food adhesive that is ingestible and does not change the properties of the active ingredient. The mucoadhesive composition is particularly useful. The film compositions often serve as mucoadhesives themselves.

The film may be applied to the sublingual or tongue of a mammal. When this is preferred, a specific film form that matches the form of the tongue may be preferred. Accordingly, the film may be cut into a form in which the side of the film that matches the back of the tongue is longer than the side that matches the front of the tongue. Specifically, the preferred form may be a triangle or a trapezoid. Preferably, the film adheres to the oral cavity and prevents the film from being removed from the oral cavity, allowing more active ingredient to be introduced into the oral cavity as the film dissolves.
Other uses for the film of the present invention take advantage of the tendency of the film to dissolve quickly when introduced into a liquid. The active ingredient may be introduced into the liquid by preparing the film according to the invention, allowing it to be introduced into the liquid, and allowing it to dissolve. This may be used either to prepare a liquid formulation of the active ingredient or to add flavor to the beverage.

  The films of the present invention are preferably packaged in a hermetically sealed outdoor and moisture resistant package to protect the active ingredient from exposure to oxidation, hydrolysis, volatilization and interaction with the surrounding environment. Referring to FIG. 1, each packaged pharmaceutical dosage unit 10 includes a film 12 individually wrapped in a pouch or between foil and / or plastic laminate sheets 14. As depicted in FIG. 2, the pouches 10, 10 ′ can be joined together at a tearable or perforated joint 16. The pouches 10, 10 'may be packaged in rolls as depicted in FIG. 5, or stacked as shown in FIG. 3 and sold in a dispenser 18 as shown in FIG. The dispenser may contain a complete supply of medications that are primarily prescribed for the intended treatment, but due to the thinness of the films and packages, tablets, capsules and liquids Smaller and easier to use than conventional bottles used for Furthermore, the films of the present invention dissolve as soon as they come into contact with saliva or mucosal areas, eliminating the need to wash the formulation with water.

Preferably, a set of such unit formulations, eg, 10-90 days supply, are packaged together according to a predetermined regimen or treatment, depending on the particular treatment. The individual films can be packaged on a backing and released for use.
The features and advantages of the present invention are more fully shown by the following examples, which are provided for purposes of illustration and are not to be construed as limiting the invention in any way.

(Example 1-2 :)
Water-soluble thin film compositions were prepared using the amounts listed in Table 1. In particular, Vitamin E was incorporated into Composition 1 as an antiblocking agent along with various other ingredients. Composition 2 contained the same ingredients as composition 1, but lacked vitamin E.

The above ingredients for each composition were mixed by blending until a uniform mixture was obtained and then cast into a film. In particular, the solution was cast on release paper (available from Griff Paper & Film) using a K control coater with a 350 micron smooth bar. The film was then dried at about 80 ° C. for about 10 minutes. Composition 1 was dried to a moisture level of about 2.68% and Composition 2 was dried to a moisture level of about 3.35%.
The dried film was verified for various properties, including an elution test that measures how long it takes for the film to dissolve in the mouth and a bending test that measures the flexibility of the film. In addition, the panel observed the tendency of the film to show stickiness in the mouth and the tendency to adhere to the user's palate.
To verify the dissolution rate, an approximately 20 mm × 100 mm film piece with an attached weight of 2.85 g was lowered into a 32.5 ° C. water bath to a depth of approximately 50 mm. The time required for the film to dissolve and separate into two pieces was measured (in seconds).

  The film was also subjected to a bending test, that is, a 180 ° C. bending test. The dried film is placed in a humidity analyzer (Mettler Toledo humidity analyzer HR73) to obtain moisture content and any remaining in the film after drying at 80 ° C. according to the present invention. The solvent (eg water) was also removed. The film was then creased to about 180 ° and observed for breakage. Films that broke during creasing were considered failures. If the film did not break during crease, a 200 g weight was dropped onto the creased film from a height of approximately 8.5 mm. A broken film was considered a failure, and an unbroken one was considered a pass. However, it should be noted that this flexibility test is an extreme test. Films that fail this test are still considered feasible within the scope of the present invention. More specifically, there may be some applications that do not require such strong flexibility characteristics.

  Both compositions 1 and 2 films showed sufficient strength and excellent tear resistance, passed the 180 ° bend test both before and after placement in the humidity analyzer, moderate to fast Dissolved on the tongue at a speed. Composition 1 containing vitamin E showed no stickiness in the mouth and no tendency to adhere to the user's palate. In contrast, composition 2 did not contain vitamin E. Composition 2 showed a tendency to stick and adhere to the palate.

(Example 3-243 :)
A water-soluble thin film was prepared incorporating the amount of silica and magnesium stearate described in Table 2 as an anti-tack agent. More specifically, various combinations of silica and magnesium stearate were incorporated into a variety of different film compositions as shown in the table below.

In addition to silica and magnesium stearate, each of the films listed above contains various components, among them polymers and perfumes. The remaining ingredients are provided below for the contents of each film used in Table 2.
The film identified as “SOURS” in Table 2 above includes the following ingredients listed in Table 3.

  The film identified as “benzocaine / menthol” in Table 2 above includes the following ingredients listed in Table 4.

  The film identified as “Energy / Health Supplement” in Table 2 above includes the following ingredients listed in Table 5.

  The film identified as “oral analgesic” in Table 2 above includes the following ingredients listed in Table 6.

  The film identified as “melatonin” in Table 2 above includes the following ingredients listed in Table 7.

  The film identified as “chlorine dioxide” in Table 2 above includes the following ingredients listed in Table 8.

  The film identified as “Comprehensive Vitamin” in Table 2 above includes the following ingredients listed in Table 9.

  The film identified as “Zinc / Elderberry” in Table 2 above includes the following ingredients listed in Table 10.

  Films identified as “Vitamin B Group” in Table 2 above include the following ingredients listed in Table 11.

  The film identified as “Immune Booster” in Table 2 above includes the following ingredients listed in Table 12.

  The film identified as “COLD & COUGH” in Table 2 above includes the following ingredients listed in Table 13.

  The film identified as “stress relief” in Table 2 above includes the following ingredients listed in Table 14.

  The film identified as “cinnamint” in Table 2 above includes the following ingredients listed in Table 15.

  The film identified as “dextromethorphan hydrobromide” in Table 2 above includes the following ingredients listed in Table 16.

The films prepared in these examples showed improved glidant properties, particularly the ability to slip smoothly from one another without sticking together.
(Examples 244-300)
A water-soluble thin film was prepared incorporating the amount of silica and magnesium stearate described in Table 17 as an antiblocking agent. More specifically, various combinations of silica and magnesium stearate were incorporated into a variety of different film compositions as shown in the table below.

In addition to silica and magnesium stearate, the remaining components included in the films listed in Table 17 are provided in connection with Table 2 above. The contents of the films used in Table 2 and Table 17 are the same.
The films prepared in these examples showed improved glidant properties, particularly the ability to slip smoothly from one another without sticking together.
While having described what is presently believed to be a preferred embodiment of the present invention, those skilled in the art will clearly understand that changes and modifications may be made thereto without departing from the spirit of the invention. It is intended to include all such changes and modifications as fall within the true scope of the invention.

FIG. 1 shows a side view of a package containing a unit dosage film of the present invention. FIG. 2 shows a top view of two adjacent linked packages containing individual unit formulations of the present invention separated by a tearable perforation. FIG. 3 shows a side view of the adjacent connected packages of FIG. 2 arranged in a stacked configuration. FIG. 4 shows a perspective view of a dispenser for dispensing packaged unit dosage forms, where the dispensers include packaged unit dosage forms in a stacked configuration. FIG. 5 is a schematic view of a roll of linked unit dose packages of the present invention. FIG. 6 is a schematic diagram of an apparatus suitable for preparing a pre-mix, adding active ingredients, and subsequently forming the film. FIG. 7 is a schematic view of an apparatus suitable for drying the film of the present invention.

Claims (26)

Edible water-soluble polymer;
At least one anti-tacking agent selected from the group consisting of lubricants, anti-adhesion agents, glidants and combinations thereof; and selected from the group consisting of beauty agents, pharmaceuticals, vitamins, bioactive substances and combinations thereof An edible film for delivery of an active ingredient comprising the active ingredient, wherein the film is self-supporting.   The film of claim 1, wherein the anti-sticking agent comprises vitamin E TPGS.   The film of claim 1, wherein the anti-blocking agent comprises magnesium stearate.   The film according to claim 3, wherein the anti-sticking agent further comprises silica.   The film of claim 1, wherein the anti-tacking agent is present in an amount from about 0.01% to about 20% by weight of the delivery system. The anti-sticking agent is
Magnesium stearate present in an amount of about 0.1% to about 2.5% by weight of the delivery system; and silica present in an amount of about 0.1% to about 1.5% by weight of the delivery system. The film of claim 1, comprising:   The film of claim 1, wherein the water soluble polymer comprises polyethylene oxide and cellulose polymer.   The film of claim 7, wherein the cellulose polymer comprises hydroxypropyl cellulose.   The film of claim 7, wherein the cellulose polymer comprises hydroxypropylmethylcellulose.   The film of claim 1, wherein the active ingredient comprises dextromethorphan.   The film of claim 1 further comprising polydextrose.   The film according to claim 1, which is applied to the oral cavity of a mammal.   14. The film of claim 13, which adheres to a mammalian tongue. An edible film for delivery of an active ingredient comprising:
An edible water-soluble polymer component comprising at least one polymer selected from the group consisting of hydroxypropylcellulose, hydroxypropylmethylcellulose, polyethylene oxide and combinations thereof;
An active ingredient selected from the group consisting of beauty agents, pharmaceuticals, vitamins, bioactive substances and combinations thereof; and an adhesive comprising vitamin E TPGS present in an amount of about 0.01% to about 20% by weight of the film The film comprising an inhibitor. An edible water-soluble polymer comprising polyethylene oxide together with a polymer selected from the group consisting of hydroxypropylcellulose, hydroxypropylmethylcellulose, and combinations thereof; and present in an amount sufficient to provide anti-stick and therapeutic properties Vitamin E TPGS
An edible film for delivery of an active ingredient, comprising: An edible water-soluble polymer comprising polyethylene oxide and hydroxypropylcellulose;
Polydextrose;
An active ingredient selected from the group consisting of cosmetics, pharmaceuticals, vitamins, bioactive substances and combinations thereof; and an edible film for delivery of an active ingredient comprising at least one anti-sticking agent, wherein the polyethylene oxide, hydroxy The film, wherein propylcellulose and polydextrose are present in a ratio of about 45:45:10. (A) a self-supporting film having at least one surface comprising the following components:
(I) an edible water-soluble polymer; and (ii) an active ingredient selected from the group consisting of beauty agents, pharmaceuticals, vitamins, bioactive substances and combinations thereof; and (b) the at least one of the self-supporting films. An edible film for delivery of an active ingredient comprising a coating on a surface and comprising at least one anti-tacking agent. (A) at least one first film layer comprising:
(I) an edible water-soluble polymer; and (ii) an anti-tacking agent; and (b) a second film layer comprising the following components:
(I) an edible water-soluble polymer; and (ii) a multilayer film for delivery of an active ingredient comprising an active ingredient selected from the group consisting of cosmetics, pharmaceuticals, vitamins, bioactive substances and combinations thereof, The film, wherein the first film layer is substantially in contact with the second film layer.   The multilayer film of claim 18, wherein the first film layer is laminated to the second film layer. A method for producing a self-supporting film having a substantially uniform component distribution comprising:
(A) A uniform mixture of an edible water-soluble polymer, a solvent, an active ingredient selected from the group consisting of beauty agents, pharmaceuticals, vitamins, bioactive substances and combinations thereof, and at least one anti-adhesive agent Forming a matrix having a component distribution;
(B) forming a self-supporting film from the matrix;
(C) providing a surface having a top surface and a bottom surface;
(D) feeding the film onto the top surface of the surface; and (e) drying the film by applying heat to the bottom surface of the surface.   21. The method of claim 20, wherein the anti-sticking agent comprises vitamin E TPGS.   21. The method of claim 20, wherein the antiblocking agent comprises magnesium stearate and silica.   21. The method of claim 20, wherein the matrix further comprises polydextrose.   21. The method of claim 20, wherein the film is ingestible.   21. The method of claim 20, wherein the film is flexible when dried.   21. The method of claim 20, wherein (e) comprises applying a hot air stream to the bottom surface of the surface with substantially no top airflow.

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