Dispensing method for producing dissolvable unit dose membrane structures

Abstract

To provide a method for forming a dissolvable unit dose film construct having a desired disintegration profile.SOLUTION: The present invention further comprises: providing a muco-adhesive composition comprising a muco-adhesive polymer matrix comprising a water-soluble polymer, a water-dispersible polymer, a water-swellable polymer, or combinations thereof, and a liquid carrier, and drying the composition to form a muco-adhesive film substrate; forming a composition for active layer comprising a polymer matrix for the active layer composition comprising a water-soluble polymer, a water-dispersible polymer, a water-swellable polymer or a combination thereof, an active ingredient, and a liquid carrier; depositing the composition for the active layer on the muco-adhesive substrate as a plurality of individual volumes; and removing the liquid carrier from the plurality of deposited individual volumes to form a plurality of dissolvable film active layers on the muco-adhesive substrate.SELECTED DRAWING: Figure 8

Description

[Technical Field]

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS

[0001] This application claims the benefit of and priority to U.S. Provisional Patent Application No. 62 / 692003, filed July 29, 2018, entitled "Dispensing Method for Producing Dissolvable Unit Dose Film Constructs," and U.S. Provisional Patent Application No. 62 / 691327, filed July 28, 2018, entitled "Dispensing Method for Producing Dissolvable Unit Dose Film Constructs," each of which is incorporated herein by reference in its entirety.

[0002] FIELD OF THE INVENTION This application is directed to the field of thin films, and more particularly to methods for making dissolvable unit dose membrane structures for use in drug delivery. [Background technology]

[0003]

[0003] Fast-dissolving drug delivery systems were first developed in the late 1970s as an alternative to tablets, capsules, and syrups for pediatric, elderly, and other patients who had difficulty swallowing traditional oral solid dosage forms. In response to this need, a variety of orally disintegrating tablet (ODT) formats were commercialized. Most ODT products were formulated to dissolve in less than one minute upon exposure to saliva, forming a solution that could be more easily swallowed.

[0004] More recently, dissolving oral thin films (OTFs) have emerged in the form of breath strips in the confectionery and oral care markets. These products have become widely accepted by consumers for delivering vitamins and personal care products, and later, other active ingredients, including pharmaceuticals.

[0005]

[0005] Pharmaceutical companies and consumers alike have adopted OTFs as a practical and acceptable alternative to traditional pharmaceutical forms, such as liquids, tablets, and capsules. OTFs provide fast, accurate dosing in a convenient, portable, safe, and effective manner, without the need for water or measuring devices. OTFs are typically the size of a postage stamp and disintegrate on the patient's tongue within a matter of seconds for rapid release of one or more active pharmaceutical ingredients (APIs). More broadly, the use of thin films has evolved to include a variety of products manufactured and used for a wide range of transmucosal drug delivery within the oral cavity and across other mucosal interfaces.

[0006]

[0006] Despite the trend toward thin film drug delivery, many drawbacks and disadvantages still exist with such products, and there are various unmet market needs in the field. Summary of the Invention [Problem to be solved by the invention]

[0007] Exemplary embodiments are directed to membranes and their manufacture for oral and transmucosal drug delivery that address currently existing but unmet needs, including but not limited to dissolvable oral thin films and dissolvable transmucosal thin films. More particularly, exemplary embodiments are directed to dissolvable unit dose membrane structures. [Means for solving the problem]

[0008]

[0008] In an exemplary embodiment, the dissolvable unit-dose membrane structure is manufactured by the steps of: providing a mucoadhesive composition comprising a mucoadhesive polymer matrix, the mucoadhesive polymer matrix comprising a water-soluble polymer, a water-dispersible polymer, a water-swellable polymer, or a combination thereof, and a liquid carrier. The method includes the steps of: drying the mucoadhesive composition to remove at least a portion of the liquid carrier, thereby forming a mucoadhesive membrane substrate; forming an active layer composition, the composition comprising a polymer matrix, the active layer composition comprising a water-soluble polymer, a water-dispersible polymer, a water-swellable polymer, or a combination thereof, an active ingredient, and a liquid carrier; and drying the active layer composition at a shear rate of 1 s -1 The method further comprises depositing the active layer composition onto the mucoadhesive substrate as a plurality of individual volumes, and removing the liquid carrier from the deposited plurality of individual volumes to form a plurality of dissolvable film active layers on the mucoadhesive substrate.

[0009]

[0009] In another exemplary embodiment, a method for forming a dissolvable unit-dose membrane structure includes providing a mucoadhesive composition comprising a mucoadhesive polymer matrix. The mucoadhesive polymer matrix comprises a water-soluble polymer, a water-dispersible polymer, a water-swellable polymer, or a combination thereof, and a liquid carrier. The method includes the steps of: drying the mucoadhesive composition to remove at least a portion of the liquid carrier, thereby forming a mucoadhesive membrane substrate; forming a composition for an active layer, the composition having a solids content of at least 5% by weight and a shear rate of 1 s -1The method further comprises the steps of: having a viscosity at 200 cps to 300 cps; the active layer composition comprises a water-soluble polymer, a water-dispersible polymer, a water-swellable polymer, or a combination thereof, an active ingredient, and a liquid carrier; dispensing the active layer composition onto the mucoadhesive substrate as a plurality of individual volumes, each having a volume of between 0.1 μL and 50 μL, using a spraying system having a piezoelectric or pneumatically actuated valve; removing the liquid carrier from the deposited plurality of individual volumes to form a plurality of dissolvable membrane active layers on the mucoadhesive substrate; and cutting the mucoadhesive membrane substrate to separate at least a portion of the plurality of dissolvable membrane active layers, thereby forming individual unit doses.

[0010] In some exemplary embodiments, the active layer composition is deposited onto the mucoadhesive substrate in multiple individual volumes ranging from 0.1 μL to 5,000 μL, e.g., multiple individual volumes ranging from 0.1 μL to 50 μL; the active layer composition deposited onto the mucoadhesive substrate is subjected to a shear rate of 1 s -1 Viscosity between 25 cps and 5,000 cps at, for example, a shear rate of 1 s -1 and / or the active layer composition has a solids content of at least 5% by weight when deposited.

[0011] In some embodiments, active layers, such as two layers containing the same active ingredient or two layers containing different active ingredients, are applied to opposite sides of the mucoadhesive substrate. [Brief explanation of the drawings]

[0012] [Figure 1]

[0012] FIG. 1 illustrates an exemplary system for producing a dissolvable unit dose membrane structure according to one embodiment of the present disclosure. [Figure 2]

[0013] FIG. 1 illustrates a dissolvable unit dose membrane structure with a window frame effect according to one embodiment of the present disclosure. [Figure 3]

[0014] FIG. 1 illustrates dissolvable unit dose membrane structures with dissolvable active layers of different sizes, according to one embodiment of the present disclosure. [Figure 4]

[0015] FIG. 4a shows a dissolvable unit dose membrane structure having a first dissolvable active layer on a first side of a mucoadhesive substrate according to one embodiment of the present disclosure.

[0016] FIG. 4b shows a dissolvable unit dose membrane structure having a second dissolvable active layer on a second side of the mucoadhesive substrate according to one embodiment of the present disclosure. [Figure 5]

[0017] FIG. 1 shows a dissolvable unit dose membrane structure having multiple distinct active layers on a mucoadhesive substrate according to one embodiment of the present disclosure. [Figure 6]

[0018] 1 is a graph of cumulative vardenafil concentration plotted against time according to an example comparison. [Figure 7]

[0019] 1 is a graph of cumulative buprenorphine concentration plotted against time according to an example comparison. [Figure 8]

[0020] 1 is a graph of cumulative buprenorphine concentration plotted against time according to an example comparison. [Figure 9]

[0021] FIG. 1 is a schematic showing deposition onto a mucoadhesive substrate using a volumetric flow through a thin tip. [Figure 10]

[0022] FIG. 1 is a schematic diagram illustrating deposition onto a mucoadhesive substrate using a jetting system. DETAILED DESCRIPTION OF THE INVENTION

[0013]

[0023] Wherever possible, the same reference numbers will be used throughout the drawings to refer to the same parts.

[0024] A method for producing a dissolvable unit dose membrane structure for use in drug delivery is provided. Embodiments of the present disclosure, compared to methods that do not include one or more of the features disclosed herein, include the ability to incorporate multiple active ingredients into a single dissolvable unit dose membrane structure by separately depositing the active ingredients at separate locations on a common carrier matrix, even if the active ingredients are otherwise incompatible with each other, the ability to deposit high concentrations of active ingredients into a single dissolvable unit dose membrane structure by separately depositing the active ingredients at separate locations on a common carrier matrix, even if the active ingredients are otherwise incompatible with the dissolvable membrane carrier, or a combination thereof.

[0014]

[0025] 1-5, in one embodiment, a method for forming a dissolvable unit-dose membrane structure 10 includes providing a mucoadhesive composition comprising a polymer matrix, the polymer matrix comprising a water-soluble polymer, a water-dispersible polymer, a water-swellable polymer, or a combination thereof, and a liquid carrier. The mucoadhesive composition is dried to remove at least a portion of the liquid carrier, thereby forming a dissolvable mucoadhesive substrate 20.

[0015]

[0026] A soluble composition is formed on the substrate 20, including a polymer matrix, an active ingredient, and a liquid carrier, to provide a soluble active layer 12. Like the substrate 20, the polymer matrix for the soluble active layer 12 is a film-forming matrix, and is a biologically compatible, liquid-based, film-forming matrix including a water-soluble polymer, a water-dispersible polymer, a water-swellable polymer, or a combination thereof. The polymer for the composition forming the active layer 12 may be the same or different from that used to form the mucoadhesive substrate 20. The soluble composition for forming the active layer 12 is deposited on the mucoadhesive substrate 20 as a plurality of individual dosage units, and at least a portion of the liquid carrier is removed to form a plurality of soluble active layers 12.

[0016]

[0027] In some embodiments, the mucoadhesive composition of substrate 20 can also include an active ingredient. The active ingredient of the mucoadhesive composition can be the same as the active ingredient of the dissolvable composition forming active layer 12, or can be compositionally different from the active ingredient of that layer.

[0017]

[0028] In one embodiment, the mucoadhesive substrate 20 is formed as a continuous web onto which multiple active layers 12 are applied and then cut into individual units 10 for subsequent packaging. In another embodiment, the mucoadhesive substrate 20 is formed as a continuous web that is cut into individual units 10 before applying the active layer 12 to the mucoadhesive substrate 20. In yet another embodiment, the mucoadhesive composition is formed to directly provide the mucoadhesive substrate 20 as individual units, such as by stenciling a thixotropic paste onto a carrier.

[0018]

[0029] Known methods of dissolvable film manufacturing involve casting a liquid formulation as a continuous film, sheet, or web in the form of a wide, long roll onto a continuous substrate (e.g., paper or polyester liner, which may or may not have a release coating) to form what is sometimes referred to as a master roll. This manufacturing process includes drying the liquid formulation to remove the solvent (aqueous and / or non-aqueous) and produce a thin film on the substrate. The master roll thus formed is then converted into smaller unit doses by a combination of roll slitting and die cutting into individual unit doses, which are then transferred from the manufacturing substrate to the product's original packaging.

[0019]

[0030] Unlike conventional methods of forming dissolvable thin films as cast sheets that are subsequently cut into smaller unit doses, the dissolvable unit dose film structures 10 of the present invention can be manufactured by depositing the active liquid formulation directly onto a continuous polymeric film matrix or onto discrete film units, in either case forming individual single unit dose films. Among other advantages, the use of individually formed doses can limit the variability of the active ingredient between each dissolvable unit dose film structure 10 that can occur across the web as a result of coating thickness variations in conventional master roll formation. This can help ensure the deposition of relatively more precise and consistent volumes of formulation and active ingredient, directly forming smaller scale single unit doses.

[0020]

[0031] In certain embodiments, depositing the active ingredient in unit dosage form onto the membrane is accomplished by direct dispensing, as described in more detail herein.

[0032] In general, a method for depositing a dissolvable composition comprising an active ingredient in a unit dose form onto a mucoadhesive substrate 20 can employ dispensing a small volume, such as at least 0.1 μL up to about 5,000 μL, and in some embodiments up to about 500 μL, e.g., up to about 100 μL, up to about 50 μL, of the dissolvable composition used to form the active layer 12, directly onto the surface of the mucoadhesive substrate 20. In some embodiments, the dispensed amount is between 0.1 μL and about 10 μL, e.g., about 0.1 μL, 0.5 μL, 1 μL, 2 μL, 3 μL, 4 μL, 5 μL, or any other amount, up to about 10 μL, 20 μL, 30 μL, 40 μL, 50 μL, 100 μL, or even up to about 500 μL, or even up to 5,000 μL, as well as any and all ranges or subranges therein. In some embodiments, the entire volume is dispensed in a single step, although if the total volume is greater than 10 μL, it may be desirable to sequentially dispense multiple smaller volumes adjacent and / or on top of each other to form active layer 12. In some embodiments, reducing the amount of each dispensed volume to achieve the same unit dose in more dispense operations overall increases the accuracy and repeatability of the unit dose amount compared to fewer dispense operations with larger volumes. Without being bound by theory, it is believed that the multiple dispense operations may average out random variations in each dispensed volume.

[0021]

[0033] In contrast, conventional inkjet printing, as used in conventional printing techniques, dispenses droplet volumes on the order of 2-20 pL, and therefore requires extremely low viscosities to produce such small droplet sizes. The use of such conventional techniques in film formation as described herein is impractical for commercial production and may further limit the amount of active ingredients and other solid content that can be used. Compositions applied according to exemplary embodiments are typically high viscosity blends having solids contents of 5% by weight or more, e.g., 10% by weight or more solids, e.g., 20% by weight or more solids. For example, the solid content is 15% by weight or more.

[0022]

[0034] The soluble composition containing the active ingredient can be dispensed from the dispenser head by a force that moves the liquid from a reservoir in the dispenser head or a reservoir connected to the dispenser head to the surface of the substrate. This can be advantageously accomplished by spraying through a dispenser head positioned above the substrate. The substrate can be a continuous polymeric film sheet, a single unit polymeric film, or other material that serves as both the surface on which the soluble composition containing the active ingredient is deposited and the surface that forms part of the final soluble unit dose film structure 10, eliminating the need for a transfer sheet. The dispenser head is typically, but not necessarily, needle-tipped.

[0023]

[0035] Jetting devices are described in U.S. Pat. No. 9,789,511 to Aguilar et al., the entirety of which is incorporated by reference as if fully set forth herein. Generally, a "jetting device" is a device that expels, or "jetted," droplets of material from a dispenser nozzle to land on a substrate, where the droplets leave the dispenser nozzle before contacting the substrate. Thus, in the jetting process, the dispensed droplets "fly" between the dispenser and the substrate and do not contact either the dispenser or the substrate for at least a portion of the distance between the dispenser and the substrate. U.S. Pat. No. 9,789,511, column 1, lines 12-21. Jetting devices and jetting processes are further described in U.S. Pat. No. 8,257,779 to Abernathy et al., the entirety of which is incorporated by reference as if fully set forth herein.

[0024]

[0036] The soluble composition containing the active ingredient can also be dispensed by a jetting system using a piezoelectric or pneumatically actuated valve. Piezoelectric systems involve applying an electrical charge to an expanding and contracting piezoelectric material to control the flow of the soluble composition containing the active ingredient, while pneumatic systems use air pressure to control the valve. This non-contact dispensing is defined by the ability to dispense the soluble composition containing the active ingredient without requiring a dispenser head to move in the Z-axis and contact the substrate, thereby enabling a faster and more accurate process. Frequencies of 1 to 3,000 Hz are a typical, though not required, operating range for valves used in deposition processes. Piezoelectrically actuated valves are described in U.S. Patent No. 10,022,744 to MacIndoe et al., the entire contents of which are incorporated by reference as if fully set forth herein.

[0025]

[0037] The shape of the deposit of the dissolvable composition containing the active ingredient formed by direct dispensing can be any type. In some embodiments, the shape can be round, which occurs when the formulation is released from a cylindrical tip when the surface energy of the substrate surface is uniform. In other embodiments, square, rectangular, or more complex polygonal shapes can be adopted. This can be achieved by providing a dispenser head in which the formulation is released from the head and trapped between the head and the target surface to create the desired shape. In this way, the liquid fills the gap (typically about 1 mm in height) between the substrate and the dispenser head. Therefore, if the contour of the surface of the dispensing head closest to the substrate is rectangular, a rectangular deposit will be formed.

[0026]

[0038] Alternatively, a single unit dose can be formed by repeated dispensing cycles of smaller amounts from one or more dispensing units. Each dispenser head can be attached to a robotic arm that controls the location where the dissolving composition containing the active ingredient is deposited onto the substrate. Alternatively, the platform on which the substrate is placed can be equipped with a motor to move the substrate as the formulation is dispensed from the fixed dispenser head. These configurations allow the size and shape of the dose to be changed as needed.

[0027]

[0039] The modular design of the microdeposition jetting system allows for easy customization of the equipment to meet deposition requirements. The dispensing nozzles and liquid reservoirs can be interchanged with those of different sizes or configurations. This modular design also allows for easier cleaning, decontamination, and maintenance of the equipment, as the actuator is separate from the parts that come into contact with the active ingredient.

[0028]

[0040] It is understood that other methods can be employed to dispense soluble compositions of various geometries. For example, the surface energy of the substrate can be adjusted to provide better wetting by the dispensed formulation. In one embodiment, corona or plasma treatment using a mask with openings of the desired geometry results in a clearly defined region on the substrate surface with increased surface energy, which promotes fluid migration over the treated area. In another embodiment, the surface energy of the dispensed formulation can be modified or adjusted to achieve desired flow characteristics during and after dispensing. In yet another embodiment, a dam or frame of the desired geometry is provided on the substrate surface, and the soluble composition is then dispensed from a dispensing head into the defined area to produce a deposit with a specific geometry and uniformity.

[0029]

[0041] The jetting system also has the capability to dispense small, repeatable deposit volumes in the nanoliter range, with multiple dots dispensed to achieve larger deposit volumes. In some embodiments, the practical limit on the maximum overall dispense volume for the continuous production of individual dissolvable unit-dose membrane structures 10 is approximately 0.5 mL.

[0030]

[0042] It is understood that the flow characteristics of the dispensed formulation can affect the ability to consistently obtain uniform film distribution. The fluid viscosity of the formulation used to form the active layer 12 and any other layers dispensed onto the mucoadhesive substrate 20 is determined by the shear rate of 1 s -1 Viscosities range from 25 to 100,000 cps, with higher viscosities being better achieved by varying nozzle geometry and heating the fluid, and lower viscosities being preferred for room temperature jetting techniques. The specific viscosity of the active formulation within this range can vary depending on a variety of factors, depending on the characteristics of the resulting deposit, including how the formulation is desired to behave after being dispensed onto the substrate, which itself may correlate to the specific profile achieved. For example, the ability of the formulation to prevent spreading beyond its intended range can be affected by the viscosity of the formulation and its surface tension, as well as the surface energy of the substrate. Generally, the viscosity of the composition applied to form the active layer 12 is controlled by a shear rate of 1 s. -1 , between 25 cps and 5,000 cps, for example, shear rate 1 s -1 and about 30 cps, about 40 cps, about 50 cps, about 75 cps, about 100 cps, about 200 cps, about 300 cps, about 400 cps, about 500 cps, about 600 cps, about 700 cps, about 800 cps, about 900 cps, about 1,000 cps, about 2,000 cps, about 3,000 cps, or about 4,000 cps, and any and all ranges or subranges therein, e.g., at a shear rate of 1 s -1 In some embodiments, the viscosity of the composition applied to form the active layer 12 is between 500 cps and 800 cps at a shear rate of 1 sec. -1 It is understood that the level may be as low as 1 cps.

[0031]

[0043] PCT / US2016 / 046217, assigned to the Purdue Research Foundation (Purdue), describes methods and systems for depositing an active ingredient onto a substrate. The active ingredient is delivered as a fluid to a fluid dispensing device for generation of one or more droplets for deposition on the substrate, e.g., for generation of microdoses. Purdue describes various methods and apparatus for dispensing a fluid containing an active ingredient onto a substrate, but does not disclose the critical process controls required for repeatable, reproducible deposition of a liquid that meets pharmaceutical specifications, such as content uniformity, or provide guidance for developing such process controls. In paragraph

[0045] , Purdue acknowledges that droplet dynamics are affected by surface tension and viscosity, teaches that viscosity is preferably less than about 20 mPas, and utilizes a positive displacement pump to assist droplet ejection.

[0032]

[0044] The viscosity of the formulation can increase or decrease with temperature, which can affect the quality of the deposit. Heating the formulation in a holding container before dispensing or dispensing through a heated nozzle can usually reduce the liquid viscosity and improve the deposit quality. The temperature of the formulation should not be heated above the decomposition temperature of the active ingredient, or the temperature should be low enough to avoid boiling the solvent of the formulation. In one embodiment, the formulation can be heated as it exits the nozzle, which can reduce the duration of heating applied to the formulation.

[0033]

[0045] Figure 1 shows an exemplary system for performing direct dispensing, in which a depositor 100 equipped with a dispenser head of the type described herein dispenses a dissolvable composition containing an active ingredient directly onto a mucoadhesive substrate 20 to form a dissolvable unit-dose film structure 10. For example, Figures 9 and 10 schematically illustrate the use of a dispenser head having a fine tip for volumetric dispensing by a piezoelectric actuator and a dispenser head having a controllable valve for spraying onto the mucoadhesive substrate, respectively. The mucoadhesive substrate 20 can emerge from the depositor 100 along a conveyor 200.

[0034]

[0046] Once the dissolvable composition has been deposited onto the mucoadhesive substrate 20 or other surface on which it is to be deposited, the solvent (e.g., water) can be removed by a thermal drying process, leaving the dissolvable unit-dose film structure 10 in a self-supporting, subsequently applicable form. Any suitable drying process can be used, including forced ambient air, chilled air, and inert gas. Exemplary methods include, but are not limited to, gas-forced air drying, in which hot air is blown down on the deposit at high velocity to minimize boundary layers and facilitate mass transfer, drying in a box oven, IR drying, and combinations thereof. Alternatively, nitrogen or argon gas can be blown down on the deposit. In some embodiments, the combination of a small volume and the use of highly volatile pharmaceutically acceptable solvents (e.g., ethanol, acetone, etc.) results in short drying times, which can also be useful when applying active layers to opposing sides of the mucoadhesive substrate 20, for example, as illustrated in Figures 4a and 4b, allowing for rapid flipping after the initial deposition to form multiple active layers on the substrate.

[0035]

[0047] In one embodiment, individual thin film unit doses are directly dispensed in an array onto a stationary but continuous web of polymer film as substrate 20, as depicted in FIG. 1. Following deposition of that array by direct dispensing, the web is advanced a predetermined distance, and another array is formed thereon by direct dispensing onto the web at a different location. While the second array is being deposited, a vacuum encapsulation fixture is lowered over the first array, using the polymer film as the bottom of an enclosure to which a vacuum is applied. Some heat can also be applied, if necessary or desired. After the second array is deposited and the first array is dried, the vacuum is released, and the encapsulation fixture is raised or removed. The web is advanced, and the process proceeds in a step-and-repeat fashion, with the second array being subjected to vacuum drying by the encapsulation fixture while a third array is directly dispensed.

[0036]

[0048] It is understood that the polymeric membrane can be held in place during the encapsulation process to reinforce the polymeric membrane against collapse when a vacuum is applied. For example, application of a vacuum can be performed on the opposite lower surface of the membrane (i.e., opposite the surface on which the active formulation is deposited). The resulting suction can be achieved, for example, using an array of holes in a flat metal plate to hold the membrane firmly in place prior to positioning the vacuum fixture and applying the vacuum.

[0037]

[0049] In addition to improving the production of thin films, the use of direct dispensing to deposit discrete amounts of active formulation can also provide the ability to achieve improved film structure thereby formed.

[0050] Some conventional drug delivery membranes employ a two-layer design, in which the first layer contains a formulation containing an active ingredient, and the second layer functions as an inert backing layer or a layer containing a different active ingredient or the same active ingredient at a different concentration. The second or backing layer may be the same formulation as the first layer, or a different formulation, except that it does not contain the same active ingredient at the same active ingredient concentration as the first layer. The backing layer can function, for example, as a barrier to the flow of the active ingredient into the oral cavity and gastrointestinal tract. A significant drawback of conventional membranes and the associated wide-web manufacturing process is the requirement that the first and second layers be of equal area. The layers are formed over the web, with one layer coated over the other in a second, separate casting or lamination step. In addition to requiring equal areas for the first and second layers, this process also results in a master roll that requires slitting into narrower widths, along with removing the beginning and end of the roll, to obtain a defect-free slit roll with a uniform coating thickness. These same considerations apply to situations requiring more than two layers.

[0038]

[0051] Embodiments of the present invention employing unit-dose deposition by direct dispensing can overcome these drawbacks by providing a two-layer membrane that includes a smaller area of ​​active layer directly dispensed within a larger area defined by a backing layer. This can be used to create the window frame effect shown in Figure 2, in which the dissolvable unit-dose membrane structure 10 is a multi-layer membrane that includes a mucoadhesive substrate 20 and a smaller first dissolvable active layer 12. The mucoadhesive substrate 20 thus provides a peripheral seal around the first dissolvable active layer 12 when the dissolvable unit-dose membrane structure 10 is applied to the mucosa. This prevents leakage of the active ingredient from the periphery of the first dissolvable active layer 12 into the oral cavity, further enhancing the likelihood of delivering all of the drug or other active ingredient via the desired mucosal route.

[0039]

[0052] Additionally, the use of a window frame can be used to effectively seal the first dissolvable active layer 12, thereby masking any unpleasant taste from the active ingredient. The mucoadhesive substrate 20 can prevent leakage of the drug from the first dissolvable active layer 12 into the oral cavity, where a noticeable taste may result.

[0040]

[0053] A further advantage of embodiments of the present invention compared to conventional two-layer membranes is that dispensing the first dissolvable active layer 12 directly onto the mucoadhesive substrate 20 in discrete unit doses increases dose accuracy and uniformity among dissolvable unit-dose membrane structures 10 because a consistent, precise volume of dissolvable composition is applied regardless of the area or thickness of the backing layer. Temperature control of the dispensed fluid and the temperature control of the jetting system actuator can provide repeatability of the dispensed dose. Conversely, in conventional wide-web membrane manufacturing, deposition thickness characterization is typically performed by examining the deposition weight per unit area (i.e., "coat weight" sampling). Although process parameters are typically adjusted at the front end of the coating operation and subsequently maintained after the desired target is achieved, the accuracy of the active layer coat weight is affected by variations in the thickness of the underlying backing layer. For example, dimpling or thinning of the backing layer will result in localized areas of greater active layer thickness. This concern can be overcome in some embodiments of the present invention because the thickness of each dissolvable active layer is controlled by the thickness of the backing layer. This is because the active layer 12 can be individually measured and dispensed as a consistent volume, regardless of any variations in the mucoadhesive substrate 20 to which it is applied. It is further understood that, using exemplary embodiments, separate active layers can be deposited onto a backing layer that is a continuous web, although this may result in reintroducing certain trimming and other conversion steps in manufacturing. However, for units manufactured by depositing an active ingredient-containing formulation onto an inert backing layer, loss of the active ingredient is expected to be much less, since the trimmed material does not contain the expensive active ingredient.

[0041]

[0054] Referring to FIG. 3 , in certain embodiments, various dose strengths can be achieved by forming smaller or larger first dissolvable active layers 12 on the mucoadhesive substrate 20. Thus, the same size mucoadhesive substrate 20 can be used to deliver the same size film across multiple dose strengths. Similarly, the same size first dissolvable active layer 12 can be used with different sized mucoadhesive substrates, which can be varied to suit the ability of a particular user class to handle the dissolvable unit dose film structure 10, which may be independent of the amount of active ingredient being delivered (i.e., larger films may be desired for pediatric or elderly patients). This can also be of particular benefit for low doses and / or certain potencies of drugs, which, when used alone without a backing layer, may require a resulting film that is too small to handle.

[0042]

[0055] As shown in Figure 3, two types of dissolvable unit dose film structures 10 can be formed using uniformly sized mucoadhesive substrates 20. In a first dissolvable unit dose film structure 10, for example, for use with a pediatric-sized dose of active ingredient, a small dissolvable active layer 12a is deposited on the mucoadhesive substrate 20, which provides a dissolvable unit dose film structure 10 large enough to be easily handled due to the size of the mucoadhesive substrate 20. For an adult-sized dose, the same mucoadhesive substrate 20 can be used with a larger dissolvable active layer 12b deposited thereon to deliver a larger amount of active ingredient with the same size dissolvable unit dose film structure 10. Because the area of ​​the first dissolvable active layer 12 can be adjusted by the deposition volume, the same active formulation can be used for both pediatric and adult doses.

[0043]

[0056] An additional advantage realized by the exemplary embodiment, in which the same size mucoadhesive substrate 20 is used for different sized small and large dissolvable active layers 12a, 12b, is the standardization of overall membrane size across multiple dosage strengths. As a result, device equipment and packaging can also be standardized with the same overall membrane size, defined by the area of ​​the mucoadhesive substrate 20.

[0044]

[0057] It will be appreciated that in some embodiments, it may be desirable to incorporate additional components into the active layer formulation used to produce small and large dissolvable active layers 12a and 12b of different dosage strengths to more easily distinguish them, particularly since the overall size of doses containing small and large dissolvable active layers 12a and 12b may be visually similar. Distinction can be achieved, for example, by using different colors for the active layers of different strengths. Colorants can also be used to distinguish dissolvable unit dose membrane structures 10 containing different active ingredients, even if the dose size or strength is the same. Colorants also provide visual recognition to a vision system, which measures the surface area of ​​the dispensed product and applies pass / fail criteria based on software algorithms associated with the vision system camera.

[0045]

[0058] In some cases, two active ingredients must be delivered to the recipient simultaneously. This can be accomplished by combining two different active ingredients in an active layer formulation. However, such combinations may not be possible in many situations, such as when the active ingredients are incompatible (e.g., they react or decompose when in contact with each other). Alternatively, two different pH buffers may be required because each active ingredient requires a different buffer system to affect solubility or improve bioavailability. However, it is not possible to incorporate two different buffers into the same formulation to produce two different pH values.

[0046]

[0059] As shown in Figures 4a and 4b, a dissolvable unit dose film structure 10 can be formed with a first dissolvable active layer 12 (Figure 4a) formed on a first side 2 of a mucoadhesive substrate 20, and a second dissolvable active layer 14 (Figure 4b) formed on a second side 4 of the mucoadhesive substrate 20. The first dissolvable active layer 12 and the second dissolvable active layer 14 can comprise the same composition or different compositions, the same active ingredient or different active ingredients, the same size / dosage or different sizes / dosages, or various combinations thereof.

[0047]

[0060] In this embodiment, after the first active layer 12 is applied to the substrate 20, the substrate can be inverted to apply the second active layer 14 as a second soluble composition comprising a polymer matrix, where the polymer matrix comprises a water-soluble polymer, a water-dispersible polymer, a water-swellable polymer, or a combination thereof, and the second soluble composition further comprises an active ingredient and a liquid carrier. The second soluble composition is deposited on the mucoadhesive substrate 20 as a plurality of individual dosage units on the side of the mucoadhesive substrate 20 opposite the first soluble composition (second side 4, opposite first side 2). The individual dosage units are dried to remove at least a portion of the liquid carrier from the second soluble composition, forming the second soluble active layer 14. The active ingredient of the second soluble composition can be the same as the active ingredient of the first soluble composition, or the active ingredient of the second soluble composition can be compositionally different from the active ingredient of the first soluble composition.

[0048]

[0061] 5, a method of forming a dissolvable unit dose film structure 10 includes depositing a second dissolvable composition onto a mucoadhesive substrate 20 as a plurality of individual dosage units spatially separated from the first dissolvable composition. At least a portion of the liquid carrier is removed from the second dissolvable composition to form a second dissolvable active layer 16 on the same side of the mucoadhesive substrate 20 as the first dissolvable active layer 12.

[0049]

[0062] In a further embodiment, a method for forming a dissolvable unit-dose membrane structure 10 includes forming a third dissolvable composition comprising a polymer matrix, where the polymer matrix comprises a water-soluble polymer, a water-dispersible polymer, a water-swellable polymer, or a combination thereof, and the third dissolvable composition further comprises an active ingredient and a liquid carrier. The third dissolvable composition is deposited on the mucoadhesive substrate 20 as multiple individual volumes spatially separated from the first and second dissolvable compositions. The individual dosage units are dried to remove at least a portion of the liquid carrier from the third dissolvable composition, forming a third dissolvable active layer. The active ingredient of the third dissolvable composition may be the same as the active ingredient of the first dissolvable composition, the second dissolvable composition, or both, or the active ingredient of the third dissolvable composition may be compositionally distinct from the active ingredients of the first dissolvable composition, the second dissolvable composition, or both, forming a third, compositionally distinct, dissolvable active layer 18. Any suitable number of additional dissolvable compositions can be similarly formed and deposited to yield any suitable number of additional dissolvable active layers.

[0050]

[0063] In another embodiment, a method of forming a dissolvable unit dose membrane structure 10 includes providing a mucoadhesive composition comprising a polymer matrix, the polymer matrix comprising a water-soluble polymer, a water-dispersible polymer, a water-swellable polymer, or a combination thereof, and a liquid carrier. The mucoadhesive composition is dried to form a liquid carrier. At least a portion of the carrier is removed to form the mucoadhesive substrate 20. A first dissolvable composition is formed, comprising a polymer matrix, where the polymer matrix comprises a water-soluble polymer, a water-dispersible polymer, a water-swellable polymer, or a combination thereof, an active ingredient, and a liquid carrier. The first dissolvable composition is deposited onto the mucoadhesive substrate 20 as a plurality of individual dosage units, and the plurality of individual dosage units are maintained without further active drying, such that the plurality of individual dosage units constitute a plurality of first dissolvable active layers 12. The mucoadhesive composition can further comprise an active ingredient. The active ingredient of the mucoadhesive composition can be the same as the active ingredient of the first dissolvable composition or can be compositionally different from the active ingredient of the first dissolvable composition.

[0051]

[0064] Any suitable combination of mucoadhesive substrate 20 and any suitable number of dissolvable active layers deposited on first side 2 or second side 4 can be formed by appropriate combination of the foregoing embodiments, including any suitable number of active ingredients in any suitable combination and distribution in the mucoadhesive substrate 20 and the dissolvable active layers.

[0052]

[0065] The mucoadhesive substrate 20 may be formed as a continuous web of film, and subsequently, after formation of the dissolvable unit dose film structure 10, the mucoadhesive substrate 20 may be separated into smaller individual films.

[0053]

[0066] The dissolvable composition can be broadly characterized as a biologically compatible, liquid-based, film-forming polymer matrix, optionally containing an active ingredient, which, upon drying, forms an erodible, disintegrable, and / or dissolvable film, including, but not limited to, the dissolvable compositions described in U.S. Patent No. 7,470,397 to Meathrel et al., which is incorporated by reference in its entirety as if fully set forth herein. It is understood that the resulting film has a combination of sufficient solids content to provide film strength to aid handling and a balanced solids content to provide disintegration at a predetermined rate. The dissolvable composition can be further broadly characterized as a biologically compatible, liquid-based, film-forming polymer matrix containing a high concentration of the active ingredient, which, upon drying, forms an active ingredient-containing layer.

[0054]

[0067] Any suitable polymer can be used as the polymer matrix. It will be understood that the polymer or polymers selected for any particular embodiment will depend on a variety of factors, including the active ingredient or ingredients to be incorporated or deposited, the desired disintegration rate (which can be adjusted with or without the use of surfactants), and the rheology of the liquid formulation used to form the mucoadhesive substrate 20 or dissolvable active layer, as well as other factors known to those skilled in the art of manufacturing conventional thin film structures.

[0055]

[0068] The one or more polymers may be water-soluble, water-dispersible, water-swellable, water-insoluble, or a combination thereof, and may include cellulose or a cellulose derivative. While the use of water-swellable and water-insoluble polymers is contemplated, the formulation will include a sufficient amount of water-soluble and / or water-dispersible polymer to ensure eventual disintegration of the membrane that is subsequently formed.

[0056]

[0069] Exemplary polymers include, but are not limited to, water soluble hydroxypropyl methylcellulose, hydroxyethyl cellulose, hydroxypropyl cellulose, polyvinylpyrrolidone, carboxymethyl cellulose, sodium carboxymethyl cellulose, methyl cellulose, polyvinyl alcohol, sodium alginate, polyethylene glycol, polyethylene oxide, chitosan, xanthan gum, tragacanth, guar gum, acacia gum, gum arabic, carrageenan, pullulan, polyacrylic acid, methyl methacrylate copolymer, carboxyvinyl copolymer. and various copolymers, or combinations of the above, as well as other known water-soluble polymers, especially cellulose derivatives and / or gums. Other polymers that can be used include, but are not limited to, ethyl cellulose, hydroxypropyl ethyl cellulose, cellulose acetate phthalate, hydroxypropyl methyl cellulose phthalate, copolymers thereof, and combinations thereof.

[0057]

[0070] In some embodiments, the polymer matrix can contain a surfactant to adjust the dissolution rate. In other embodiments, the dissolution rate can be adjusted by using a combination of a high molecular weight polymer and a low molecular weight polymer, with or without the use of a surfactant. For example, when the water-soluble component contains a combination of a low molecular weight polymer (e.g., less than about 5 kDa to 60 kDa) and a high molecular weight polymer (e.g., greater than 60 kDa to about 150 kDa, up to about 900 kDa, or more), particularly advantageous properties of film strength and disintegration profile (i.e., the rate at which the film disintegrates upon contact with the oral cavity or other mucous membrane) can be obtained.

[0058]

[0071] Various other polymers can be selected by those skilled in the art after receiving the teachings of this specification, and preferably contain a sufficient amount of high molecular weight components to provide adequate film strength and a sufficient amount of low molecular weight components to facilitate the desired film characteristic of disintegration profile.In addition, a water-soluble polymer can be selected as the film matrix-forming component, including other components that aid film strength and disintegration, such as surfactants, fillers, and plasticizers.It is understood that other components useful for film processing, such as rheology modifiers, can be used.Any suitable modifier can be used, including acrylic polymer potassium salt, for example, acrylic acid polymer cross-linked with divinyl glycol (commercially available as NOVEON by Lubrizol).The selection of any particular combination of inactive formulation ingredients may depend to some extent on its interaction with one or more active ingredients and its effect on the properties of one or more active ingredients.

[0059]

[0072] The water-soluble low-molecular-weight component does not have to be a water-soluble polymer. Instead, the low-molecular-weight component may be other low-molecular-weight molecules, monomers, oligomers, or combinations thereof (e.g., xylitol, glycerol, polyethylene glycol, propylene glycol). The low-molecular-weight component is present in an amount that helps promote disintegration but provides adequate film strength for processing and distribution. Various concentrations of the low-molecular-weight component can be used.

[0060]

[0073] The amounts of high and low molecular weight components can be adjusted to obtain the desired disintegration profile, which can range from a few seconds to a few minutes, or even a few hours. If slower disintegration is desired, the concentration of the high molecular weight component can be increased relative to the concentration of the low molecular weight component. If faster disintegration is desired, the concentration of the low molecular weight component can be increased relative to the concentration of the high molecular weight component. Furthermore, the thickness of the dissolvable unit dose membrane structure 10 can be adjusted to obtain the desired disintegration profile. For longer disintegration times, the thickness is increased. Adequate membrane strength should be maintained to allow for membrane handling.

[0061]

[0074] Other ingredients that can be incorporated in addition to any active ingredient can include, but are not limited to, plasticizers, sweeteners, thickeners, buffers, stabilizers, flavorings, and / or other additives, and are preferably, but not necessarily, water-soluble.The types and amounts of these ingredients are known to those skilled in the art of formulating conventional dissolvable thin films.However, because exemplary embodiments employ the deposition of individual, separate unit doses, the formulation may contain less total solids or non-volatiles than those used in conventional methods, but a significantly smaller volume is deposited, and as a result, any drying time required may be reduced. It is understood that, if the formulation is a liquid formulation employed to form individual unit dose membranes, it will require less drying time. Thus, while referred to herein as a liquid formulation employed to form individual unit dose membranes, the term is understood to encompass any moist, non-solid, flowable material. In some embodiments, a buffering agent is incorporated into the formulation for the mucoadhesive substrate 20, but not into the formulation(s) for the one or more active layers. In other embodiments, a buffering agent is incorporated into the formulation(s) for the one or more active layers, but not into the formulation for the mucoadhesive substrate 20. In yet other embodiments, a buffering agent is employed in the formulation for both the mucoadhesive substrate 20 and the active layer(s), but not in others. In some embodiments, neotame and / or sucralose can be used as sweeteners. It is further understood that in some embodiments, additives in the composition for the active layer can also be used to separate ingredients from ingredients present in the substrate. For example, sweeteners or other ingredients used to form the active layer that are incompatible with the active ingredient (e.g., that may cause precipitation of the active) can instead be incorporated into the composition used to form the mucoadhesive substrate 20.

[0062]

[0075] The dissolvable unit dose membrane structure 10 can contain one or more active ingredients, typically, but not necessarily, pharmaceutical formulations. A wide variety of active ingredients can be incorporated into or applied to the polymer matrix. The active ingredient can be deposited before or after membrane formation and can be incorporated in any form, such as a solution, emulsion, suspension, or dispersion. The specific form may depend on the particular combination of active ingredient and polymer used. That is, the active ingredient-containing liquid formulation deposited on the membrane can be in the form of a solution in which all ingredients, including any drug substance, are completely dissolved and soluble in the bulk liquid; an emulsion, as typically used for aqueous formulations containing oil-soluble ingredients, such as flavorings; or a suspension or dispersion, in which insoluble active ingredients or other excipients can be added to the bulk liquid formulation while achieving uniformity of distribution in the subsequently deposited layer and the formed dissolvable unit dose membrane structure 10.

[0063]

[0076] Active ingredients include, but are not limited to, ACE inhibitors, antianginals, antiarrhythmics, antiasthmatics, anticholesterols, tranquilizers, analgesics, anesthetics, anticonvulsants, antidepressants, antidiabetic drugs, antidiarrheal preparations, detoxifiers, antihistamines, antihypertensives, anti-inflammatory drugs, antilipids, antimanic drugs, antiemetics, antistroke drugs, antithyroid preparations, antineoplastics, antivirals, acne medications, alkaloids, amino acid preparations, cough suppressants, antiuricemics, antivirals, anabolic preparations, steroid ... Systemic and non-systemic anti-infectives, anti-neoplastics, anti-Parkinson's drugs, anti-rheumatics, appetite stimulants, biological response modifiers, blood modifiers, bone metabolism regulators, cardiovascular agents, central nervous system stimulants, cholinesterase inhibitors, contraceptives, decongestants, dietary supplements, dopamine receptor agonists, drugs for managing endometriosis, enzymes, drugs for treating erectile dysfunction, fertility drugs, gastrointestinal agents, homeopathic remedies, hormones, hypercalcemia and hypocalcemia Drugs for the management of vasodilators, immunomodulators, immunosuppressants, migraine preparations, motion sickness medications, muscle relaxants, drugs for the management of obesity, osteoporosis preparations, labor-inducing drugs, parasympatholytics, parasympathomimetics, prostaglandins, psychiatric drugs, respiratory drugs, sedatives, smoking cessation aids, sympatholytics, tremor preparations, urinary tract drugs, vasodilators, laxatives, antacids, ion exchange resins, antipyretics, appetite suppressants, expectorants, anxiolytics, antiulcer drugs, anti-inflammatory substances, coronary artery dilators, cerebral dilators, peripheral These include peripheral vasodilators, psychotropic drugs, stimulants, antihypertensives, vasoconstrictors, antimigraine drugs, antibiotics, tranquilizers, antipsychotics, antineoplastics, anticoagulants, antithrombotic drugs, hypnotics, antiemetics, antivomiting drugs, anticonvulsants, neuromuscular agents, hyperglycemic and hypoglycemic agents, thyroid and antithyroid drugs, diuretics, anticonvulsants, uterine relaxants, antiobesity drugs, erythropoiesis drugs, antiasthmatic drugs, cough suppressants, mucolytic drugs, DNA and gene modifiers, and combinations thereof. The type and amount of active ingredient used are known to those skilled in the art of formulating conventional dissolvable thin films.

[0064]

[0077] In some embodiments, the active ingredient comprises buprenorphine. When a sweetener is used in a composition comprising buprenorphine.

[0078] Embodiments are further described and illustrated by reference to the following examples, which are offered by way of illustration and not by way of limitation. [Example]

[0065] Example 1

[0079] The ingredients were combined and mixed together by vortexing in a suitable mixer to form a homogeneous fluid as described in Table 1.

[0066] [Table 1]

[0067] Example 2

[0080] 154 μL of the formulation of Example 1 was microdeposited onto a 22 mm×22 mm die-cut membrane composed of sodium carboxymethylcellulose and phosphate buffer, equivalent to 23 mg of apomorphine HCl 0.5 hydrate for each unit dose membrane.

[0068] Example 3

[0081] The ingredients were blended together with an overhead mixer to form the solutions described in Table 2.

[0069] [Table 2]

[0070]

[0082] Monolithic membranes were prepared by applying the liquid of Example 3 to a polyester substrate and drying the wet membrane in a laboratory convection oven at 70° C. for 40 minutes. Dry membrane weight is 422.4 mm 2 measured at 70 mg per dose, and vardenafil free base at 0.024 mg / mm 2 The unit was 23.6 mm for use in diffusivity studies. 2 Each tablet was die-cut into 0.56 mg of vardenafil base.

[0071] Example 4

[0083] The ingredients were blended together in an overhead mixer to form the solutions described in Table 3.

[0072] [Table 3]

[0073]

[0084] A membrane was prepared by applying the liquid of Example 4 to a polyester substrate and drying the wet membrane in a laboratory convection oven at 70°C for 50 minutes. The dry membrane weight was 422.4 mm 2 It was measured at 55 mg per dose.

[0074] Example 5

[0085] The ingredients were blended together in an overhead mixer to form the solutions described in Table 4.

[0075] [Table 4]

[0076]

[0086] 22 μL of the solution from Example 5 was microdeposited with a positive displacement pipette onto the dried film from Example 4. The dispensed liquid was dried in a laboratory convection oven at 70° C. for 30 minutes. The surface area of ​​the dried microdeposit was 12.56 mm 2 and contained 0.559 mg of vardenafil free base. All units were 52.65 mm 2 die-cut and activated Sediment 12.56mm 2 It included:

[0077] Example 6

[0087] 23.6 mm in Example 3 2 The permeability of the unit of Example 5 is 52.65 mm 2Diffusivity studies were performed comparing permeability in units of 100 μL. ORL-200 24-well plates (MatTek Corp., Ashland, MA) containing oral cell tissue cultures were utilized as diffusion membranes. Tissues were equilibrated in a CO2 5% chamber set at 37°C and 95% relative humidity. 300 μL of Dulbecco's phosphate-buffered saline (DPBS) receiving medium was added to each well in the 24-well plate and placed in the CO2 chamber overnight. The following morning, tissue inserts were removed from the ORL-200-ASY assay medium, and transepithelial electrical resistance (TEER) was measured for each tissue insert to confirm viability after overnight equilibration. The tissues were then placed in 24-well plates containing 300 μL of pre-equilibrated DPBS receiving medium. Before applying the membrane of each example to the donor side of the tissue insert, each insert was pre-wetted with 25 μL of DPBS, followed by wetting an additional 25 μL of DPBS onto the top surface of each prototype. The 24-well plate containing each tissue insert was returned to the incubator for a specific time frame and then removed from the incubator after a certain period of time. The tissue insert was transferred to a new 24-well plate containing 300 μL of receiving medium and returned to the incubator for an additional specific period of time. 300 μL of receiving medium from each well of the 24-well plate was transferred to an HPLC vial and analyzed by UPLC. This experimental procedure was repeated at all time points (i.e., 5, 15, 30, 45, 60, and 120 minutes). Cumulative vardenafil concentrations are plotted against time as shown in Figure 6. Cumulative vardenafil concentrations (ng / cm 2 As detailed in the table of active surface area (watts / hour), microdeposited Prototype Example 5 outperformed monolithic Prototype Example 3 when normalized to active surface area.

[0078] [Table 5]

[0079] Example 7

[0088] The ingredients were blended together in an overhead mixer to form the solutions described in Table 5.

[0080] [Table 6]

[0081]

[0089] A monolithic membrane was prepared by applying the liquid of Example 7 to a polyester substrate and drying the wet membrane in a laboratory convection oven at 40° C. for 30 minutes, followed by drying at 70° C. for 15 minutes. The dry membrane weight was 281.6 mm 2 50 mg per 1000 mg of buprenorphine HCl, 0.031 mg / mm 2 The unit was 26.4 mm for use in studies on diffusion. 2 Each tablet was die-cut into 0.81 mg of buprenorphine HCl.

[0082] Example 8

[0090] The ingredients were blended together in an overhead mixer to form the solutions described in Table 6.

[0083] [Table 7]

[0084]

[0091] The viscosity of the resulting solution from Example 8 was measured using a Brookfield DV-2T LV viscometer at 25°C with a spindle SC4-27 and a shear rate of 1.02 s -1 The viscosity obtained was 602 cps. 24 μL of the solution of Example 8 was measured using a volumetric Microdeposits were made by pipette onto the dried film of Example 4. The dispensed liquid was dried in a laboratory convection oven at 70°C for 30 minutes. The surface area of ​​the dried microdeposit was 12.56 mm 2 and contained 0.813 mg of buprenorphine HCl. All units are 52.65 mm 2 Die cut to 12.56mm active stack 2 It included:

[0085] Example 9

[0092] 26.4 mm in Example 72 The permeability of the unit of Example 8 is 52.65 mm 2 Diffusivity studies were performed in comparison to permeability in units of 1000 mg / mL. The permeability procedure in Example 6 was followed. Cumulative buprenorphine concentrations are plotted against time as shown in Figure 7. Cumulative buprenorphine concentrations (ng / cm 2 As detailed in the table of (per hour), when normalized to surface area, microdeposited Prototype Example 8 outperformed monolithic Prototype Example 7.

[0086] [Table 8]

[0087] Example 10

[0093] The ingredients were blended together in an overhead mixer to form the solutions described in Table 7.

[0088] [Table 9]

[0089]

[0094] A membrane was prepared by applying the liquid of Example 10 to a polyester substrate and drying the wet membrane in a laboratory convection oven at 70°C for 50 minutes. The dry membrane weight was 422.4 mm 2 It was measured at 55 mg per dose.

[0090] Example 11

[0095] 24 μL of the solution from Example 8 was microdeposited with a positive displacement pipette onto the dried film from Example 10. The dispensed liquid was dried in a laboratory convection oven at 70°C for 30 minutes. The surface area of ​​the dried microdeposit was 12.56 mm 2 and contained 0.813 mg of buprenorphine HCl. All units are 52.65 mm 2 Die cut to 12.56mm active deposit 2 It included:

[0091] Example 12

[0096] 52.65 mm in Example 11 2 The permeability of the unit of Example 8 is 52.65 mm 2 Diffusivity studies were performed compared to permeability in units of 1000 mg / mL. The permeability procedure in Example 6 was followed. Cumulative buprenorphine concentrations are plotted against time as shown in Figure 8. Cumulative buprenorphine concentrations (ng / cm 2 As detailed in the Table of % saturation / hour, when normalized to surface area, microdeposited prototype Example 11 outperformed microdeposited prototype Example 8, and Example 12, in which the substrate membrane contained a buffer, provided an additional advantage in terms of drug diffusion.

[0092] [Table 10]

[0093]

[0097] The above description is merely illustrative of preferred embodiments that achieve the objects, features, and advantages of the present invention, and is not intended to limit the present invention to the illustrated embodiments. Example 13

[0098] The ingredients were blended together in an overhead mixer to form the solutions described in Table 8.

[0094] [Table 11]

[0095]

[0099] A membrane was prepared by applying the liquid of Example 13 to a polyester substrate and drying the wet membrane in a laboratory convection oven at 70°C for 50 minutes. The dry membrane weight was 422.4 mm 2 It was measured at 55 mg per dose.

[0096] Example 14

[0100] The ingredients are blended together in an overhead mixer to form a solution as described in Table 9. did.

[0097] [Table 12]

[0098] Example 15

[0101] 6 μL of the solution from Example 14 was pipetted onto the dried membrane from Example 13 with a positive displacement pipette. The dispensed liquid was dried in a laboratory convection oven at 70°C for 20 minutes. The surface area of ​​the dried microdeposit was 7.0 mm. 2 and contained 0.182 mg of buprenorphine HCl. All units are 52.65 mm 2 Die cut to 7.0mm active deposit 2 It included:

[0099] Example 16

[0102] The ingredients are blended together in an overhead mixer to form the solution described in Table 10. Successful.

[0100] [Table 13]

[0101] Example 17

[0103] 28 μL of the solution from Example 16 was pipetted onto the dried membrane from Example 13. The dispensed liquid was dried in a laboratory convection oven at 70°C for 40 minutes. The surface area of ​​the dried micro-sediment was 19.6 mm 2 and contained 2.15 mg of buprenorphine HCl. All units are 52.65 mm 2 Die cut to 19.6mm active stack 2 It included:

[0102] Example 18

[0104] 52.65 mm in Example 15 2 The permeability of the unit was 52.65 m in Example 17. m 2Diffusivity studies were performed in comparison to permeability in units of 1000 mg / mL. The permeability procedure in Example 6 was followed. Cumulative buprenorphine concentrations (ng / cm 2 / hr) table, the cumulative buprenorphine concentration in Example 17 is higher compared to Example 15.

[0103] [Table 14]

[0104] Example 19

[0105] The ingredients are blended together in an overhead mixer to form the solution described in Table 11. Successful.

[0105] [Table 15]

[0106] The liquid of Example 19 was applied to a polyester substrate and the wet film was placed in a laboratory convection oven. The membrane was prepared by drying in a pan at 70°C for 20 minutes. The dry membrane weight was 10 cm 2 It was measured at 53 mg per dose.

[0107] Example 20 The ingredients are blended together in an overhead mixer to form the solution described in Table 12. Successful.

[0108] [Table 16]

[0109] The viscosity of the solution obtained from Example 20 was measured using a Brookfield DV-2T LV viscometer, spindle SC4-27, shear rate 1.02 s at 25°C -1 The viscosity was measured using a meter and found to be 2,289 cps.

[0110] Example 21

[0109] 22 μL of the solution from Example 20 was pipetted onto the dried membrane from Example 19. The dispensed liquid was dried in a laboratory convection oven at 70°C for 20 minutes. The surface area of ​​the dried microdeposit was 20.0 mm 2 and contained 2.8 mg of apomorphine HCl. All units are 52.65 mm 2 Die cut to 20.0mm active deposit 2 It included.

[0111] Example 22

[0110] 11 μL of the solution from Example 20 was pipetted onto the dried membrane from Example 19. The dispensed liquid was dried in a laboratory convection oven at 70 °C for 20 min. The surface area of ​​the dried microdeposit was 12.6 mm 2 and contained 1.4 mg of apomorphine HCl. All units are 52.65 mm 2 Die cut to 12.6mm active deposit 2 It included.

[0112] Example 23

[0111] 52.65 mm of Example 21 2 The permeability of the unit of Example 22 was 52.65 m m 2 Diffusivity studies were performed in comparison to permeability in units of 1000 mg / mL. The permeability procedure in Example 6 was followed. Cumulative apomorphine concentrations (ng / cm 2 As shown in the table ( / hr), the cumulative apomorphine concentration in Example 21 is higher compared to Example 22.

[0113] [Table 17]

[0114] While the present invention has been described with reference to preferred embodiments, it is understood that modifications may be made without departing from the scope of the present invention. It will be understood by those skilled in the art that various modifications may be made and equivalents may be substituted for elements of the present invention without departing from the essential scope thereof. In addition, many changes may be made to adapt a particular situation or material to the teachings of the present invention without departing from the essential scope thereof. Therefore, it is intended that the invention not be limited to the particular embodiment disclosed as the best mode contemplated for carrying out this invention, but that the invention will include all embodiments falling within the scope of the appended claims.

Claims

1. 1. A method of forming a dissolvable unit dose membrane structure, comprising: providing a mucoadhesive composition comprising a mucoadhesive polymer matrix, the mucoadhesive polymer matrix comprising: a first water-soluble polymer, a first water-dispersible polymer, a first water-swellable polymer, or a combination thereof; and a first liquid carrier; drying the mucoadhesive composition to remove at least a portion of the first liquid carrier, thereby forming a mucoadhesive film substrate; forming a composition for a first active layer, the composition comprising a first polymer matrix, the first polymer matrix comprising: a second water-soluble polymer, a second water-dispersible polymer, a second water-swellable polymer, or a combination thereof; a first active ingredient; and a second liquid carrier, the composition for the first active layer being heated at a shear rate of 1 s －１ is between 1 cps and 300 cps. depositing a composition for the first active layer onto the mucoadhesive substrate in a volume ranging between 0.1 μL and 5,000 μL; and removing at least a portion of the second liquid carrier from the deposited first active layer composition to form a first dissolvable membrane active layer on the mucoadhesive substrate; A method comprising:

2. The method of claim 1 , wherein the composition for the first active layer, as deposited, has a solids content of at least 5% by weight.

3. The method of claim 1 , wherein the mucoadhesive polymer matrix further comprises a second active ingredient.

4. 4. The method of claim 3, wherein the second active ingredient is compositionally different from the first active ingredient.

5. forming a composition for a second active layer, the composition for the second active layer comprising: a second polymer matrix, the polymer matrix comprising a third water-soluble polymer, a third water-dispersible polymer, a third water-swellable polymer, or a combination thereof; a second active ingredient; and a third liquid carrier; depositing a second active layer composition onto the mucoadhesive substrate; and removing at least a portion of the third liquid carrier from the deposited second active layer composition to form a second dissolvable film active layer overlying the mucoadhesive substrate. The method of claim 1 further comprising:

6. 6. The method of claim 5, wherein the second dissolvable membrane active layer is formed on the same side of the mucoadhesive membrane backing as the first dissolvable membrane active layer.

7. 7. The method of claim 6, wherein the second dissolvable membrane active layer is spatially separated from the first dissolvable membrane active layer on the mucoadhesive membrane substrate.

8. 6. The method of claim 5, wherein a second dissolvable membrane active layer is formed on the opposite side of the mucoadhesive membrane backing from the first dissolvable membrane active layer.

9. 6. The method of claim 5, wherein the second active ingredient is compositionally different from the first active ingredient.

10. forming a composition for a third active layer, the composition for the third active layer comprising: a third polymer matrix, the polymer matrix comprising a fourth water-soluble polymer, a fourth water-dispersible polymer, a fourth water-swellable polymer, or a combination thereof; a third active ingredient; and a fourth liquid carrier; depositing a composition for a third active layer onto the mucoadhesive substrate; and removing at least a portion of the fourth liquid carrier from the deposited third active layer composition to form a third dissolvable membrane active layer overlying the mucoadhesive membrane substrate. The method of claim 5 further comprising:

11. 10. The method of claim 1, wherein the polymer matrix of the mucoadhesive membrane substrate and the first dissolvable membrane active layer comprises at least one common water-soluble polymer, at least one water-dispersible polymer, at least one water-swellable polymer, or a combination thereof.

12. 10. The method of claim 1, wherein the mucoadhesive composition is a thixotropic paste.

13. 10. The method of claim 1, wherein the mucoadhesive membrane substrate is formed as a continuous web of membrane and then separated into smaller individual membranes after forming the first dissolvable membrane active layer on the mucoadhesive membrane substrate.

14. The method of claim 1 , wherein the step of depositing the composition for the first active layer comprises depositing using a jetting system.

15. The method of claim 1 , wherein depositing the composition for the first active layer comprises depositing by a piezoelectric or pneumatically actuated valve.

16. 10. The method of claim 1, further comprising cutting the mucoadhesive membrane substrate to form individual unit doses.

17. 10. The method of claim 1, wherein the active ingredient comprises at least one of buprenorphine or apomorphine.

Images