Solid active pharmaceutical compositions for transdermal drug delivery

Abstract

Transdermal drug delivery systems for delivering active pharmaceutical ingredients (APIs) and methods for manufacturing such systems are provided. The active pharmaceutical ingredient should have an unfavorable water solubility of less than about 10 mg / mL, an unfavorable melting point above about 120°C, and a log P value ranging from about -2 to about 8. More specifically, this disclosure relates to improving the permeability of such compounds through the skin by forming solid particles comprising the drug (API) and polyvinylpyrrolidone, said solid particles being compounded, solvated, treated, micronized, and added to an adhesive layer to maintain a solid suspension of glassy particles.

Description

[0001] Related applications

[0002] This application claims priority to U.S. Provisional Patent Application No. 63 / 617,832, filed January 5, 2024, the entire contents of which are incorporated herein by reference. Technical Field

[0003] This disclosure relates to transdermal drug delivery systems for active pharmaceutical ingredients (APIs) exhibiting high melting points and low water solubility, in order to improve the permeability of such APIs through the skin. Background of the Invention

[0005] The U.S. Food and Drug Administration (FDA) has established a system called the Biologics Classification System (BCS), which classifies drugs based on their permeability and solubility. Class I drugs have high permeability and high solubility, Class II drugs have high permeability and low solubility, Class III drugs have low permeability and high solubility, and Class IV drugs have low permeability and low solubility. Transdermal delivery solubilized APIs are well known to those skilled in the art. Specifically, most APIs in solubilized platforms fall into Class I or III of the FDA's BCS, such as nicotine, scopolamine, and methylphenidate, which have relatively low melting points and high water solubility. Meanwhile, many APIs developed in the past few years or recently introduced have been classified into BCS Classes II and IV, which, according to the FDA definition, exhibit low solubility. Among commercially viable APIs used in transdermal drug delivery systems, applicable APIs may include buprenorphine, clonidine, estradiol, ethinylestradiol, and phenytoin, which would fall under BCS Class II, which includes drugs exhibiting low solubility but high permeability. Furthermore, these drugs have relatively high melting points. These drugs are added to their respective commercially viable products in a solubilized state. Meanwhile, BCS Class IV drugs exhibit low solubility and low permeability. To clarify the meaning of low solubility (slightly soluble in water to almost insoluble in water) in this application, Table 1 below can be used as a reference:

[0006] Table 1: Derivation of USP / NF solubility diagrams by concentration type

[0007]

[0008] Such low-solubility APIs can have solubilities of less than about 10 mg / g or 10 mg / mL. Specific APIs include lenalidomide with a water solubility of less than about 1 mg / mL and a melting point of 265°C to 270°C, and other immunomodulatory (IMiD) compounds with similar physicochemical properties; dexamethasone with a water solubility of less than about 1 mg / mL and a melting point of 260°C to 264°C, dexamethasone acetate with a water solubility of less than about 1 mg / mL and a melting point of 238°C to 240°C, and other steroids or hormones with similar physicochemical properties; olanzapine with a water solubility of less than about 0.1 mg / mL and a melting point of 195°C, and other antipsychotics / tricyclic drugs with similar physicochemical properties; and ibrutinib with a water solubility of less than about 0.1 mg / mL and a melting point of 149°C to 158°C, and other Bruton's tyrosine kinase (BTK) inhibitors with similar physicochemical properties. Therefore, there is a need to develop transdermal drug delivery systems that address the availability of these drugs. These systems alter the way drugs are solubilized and / or suspended in the formulation, enabling these compounds to permeate at rates significantly higher than and exceeding the permeation rates associated with certain APIs in their solubilized state, thus allowing for efficient delivery across the skin. Transdermal delivery of these types of compounds holds promise for overcoming the limitations of other routes of administration, such as oral or intravenous bolus administration, which include, but are not limited to, toxicity or peak (above therapeutic value) and trough (below therapeutic level) values ​​in post-dose pharmacokinetic profiles.

[0009] For compounds exhibiting very low water solubility in solubilized binder-dispersed drug delivery platforms, such as estradiol, testosterone, buprenorphine, fentanyl, and granisetron, transdermal delivery of APIs is well-known. These binder-dispersed drug delivery platforms include commercially available and marketed API products such as Vivelle Dot® for estradiol (water solubility less than 1 mg / mL and melting point 173°C to 180°C); Testoderm® for testosterone (water solubility less than 1 mg / mL and melting point 153°C to 155°C); BuTrans® for buprenorphine (water solubility less than 1 mg / mL and melting point 219°C); the Universal Fentanyl Transdermal System for fentanyl (water solubility of approximately 0.2 mg / mL and melting point 181°C to 183°C); and Sancuso® for granisetron (water solubility less than 0.1 mg / mL and melting point 226°C). These commercial transdermal delivery systems incorporate drugs into a solubilized, binder-dispersed drug matrix, maintaining their solubility throughout their shelf life and intended application period. It has been shown that known APIs must maintain or approach the matrix's saturation solubility in these matrices to achieve maximum permeation from the transdermal system (e.g., maintaining a constant concentration gradient for sustainable delivery). Known transdermal drug delivery systems are typically offered in their simplest formulation as a solubilized, binder-dispersed drug formulation. For APIs exhibiting challenging solubility and permeability requirements, such as those mentioned above, formulation improvements are needed to maintain the API in solution, alternative dissolution pathways must be provided at application, and / or specific permeability enhancers are required to attempt to increase the permeability of the drug molecule. All of these can complicate the path to commercial products, incurring additional costs, testing, and approval requirements. Given these issues, there is a need for a transdermal drug delivery system in which the permeability of APIs with low water solubility is improved. Invention Overview

[0011] According to one embodiment of this disclosure, a transdermal drug delivery system is disclosed. The transdermal drug delivery system includes a binder-dispersed drug layer comprising a solid particulate complex, a binder polymer, and a surfactant. The solid particulate complex comprises an active pharmaceutical ingredient having a water solubility of less than about 10 mg / mL and a melting point above about 120°C, and a soluble polymer. Furthermore, the weight ratio of the soluble polymer to the active pharmaceutical ingredient ranges from about 1.25:1 to about 20:1. It should be understood that when added to the binder blend along with excipients and process solvents, the API and / or complex are suspended and do not significantly change or solubilize upon completion of the process.

[0012] In one embodiment, the active pharmaceutical ingredient has a log P value of about -2 to about 8.

[0013] In another embodiment, the active pharmaceutical ingredient may be an immunomodulatory (IMiD) agent, a steroid, a hormone, an antipsychotic drug, a tricyclic antidepressant, or a Bruton's tyrosine kinase inhibitor.

[0014] In yet another embodiment, the soluble polymer may include polyvinylpyrrolidone.

[0015] In yet another embodiment, the solid particulate composite may have a particle size of less than about 300 micrometers.

[0016] In another embodiment, the adhesive polymer may include acrylate copolymers, ethylene-vinyl acetate copolymers, vinyl acetate-acrylic acid copolymers, rubber copolymers, polyisobutylene polymers, siloxane polymers, or combinations thereof.

[0017] In another embodiment, the surfactant may include a nonionic surfactant. For example, the nonionic surfactant may include stearyl alcohol polyether-2, oleyl alcohol polyether-2, cetyl alcohol polyether-3, oleyl alcohol polyether-3, C12-13 alkanol polyether-3, oleyl alcohol polyether-5, C12-13 alkanol polyether-4, lauryl alcohol polyether-4, lauryl alcohol polyether-9, cetearyl alcohol polyether-6, oleyl alcohol polyether-10, oleyl alcohol polyether-20, stearyl alcohol polyether-10, poloxamer, polyethylene glycol, or combinations thereof.

[0018] In another embodiment, the transdermal drug delivery system may include insoluble excipients. Further, the insoluble excipients may include cross-linked polyvinylpyrrolidone.

[0019] In yet another embodiment, the transdermal drug delivery system may include an occlusive backing layer and a release liner, wherein the occlusive backing layer forms the outer surface of the transdermal drug delivery system, and wherein the release liner is disposed adjacent to the skin-contacting surface of the adhesive-dispersible drug layer.

[0020] According to another embodiment of this disclosure, a method is provided for forming a solid particulate complex comprising an active pharmaceutical ingredient and a soluble polymer for a transdermal delivery system. The method includes combining the active pharmaceutical ingredient and the soluble polymer in a process solvent system to degrade both the active pharmaceutical ingredient and the soluble polymer; evaporating the process solvent system to form a membrane; and micronizing the membrane to form the solid particulate complex. Furthermore, the solid particulate complex does not exhibit birefringence or crystallinity and has a particle size of less than about 300 micrometers.

[0021] In one embodiment, the weight ratio of the soluble polymer to the active pharmaceutical ingredient can range from about 1.25:1 to about 20:1.

[0022] In another embodiment, the active pharmaceutical ingredient may have a water solubility of less than about 10 mg per milliliter, a melting point above about 120°C, and a log P value of about -2 to about 8.

[0023] In yet another implementation, the active pharmaceutical ingredient may be an immunomodulatory (IMiD) agent, a steroid, a hormone, an antipsychotic drug, a tricyclic antidepressant, or a Bruton's tyrosine kinase inhibitor.

[0024] In yet another embodiment, the soluble polymer may include polyvinylpyrrolidone.

[0025] According to one or more embodiments of this disclosure, a method for forming a binder-dispersed drug layer for a transdermal drug delivery system is provided. The method includes combining an active pharmaceutical ingredient and a soluble polymer in a first process solvent system to solubilize the active pharmaceutical ingredient and the soluble polymer; evaporating the first process solvent system to form a film; micronizing the film to form a solid particulate complex, wherein the solid particulate complex has a particle size of less than about 300 micrometers; and adding the solid particulate complex to a second process solvent system, a binder polymer, and a surfactant to form a binder-dispersed drug layer formulation.

[0026] In one embodiment, the weight ratio of the soluble polymer to the active pharmaceutical ingredient can range from about 1.25:1 to about 20:1.

[0027] In another embodiment, the active pharmaceutical ingredient may have a water solubility of less than about 10 mg per milliliter, a melting point above about 120°C, and a log P value of about -2 to about 8.

[0028] In yet another implementation, the active pharmaceutical ingredient may be an immunomodulator, steroid, hormone, antipsychotic, tricyclic antidepressant, or Bruton's tyrosine kinase inhibitor.

[0029] In another embodiment, the adhesive polymer may include acrylate copolymers, ethylene-vinyl acetate copolymers, vinyl acetate-acrylic acid copolymers, rubber copolymers, polyisobutylene polymers, siloxane polymers, or combinations thereof.

[0030] In yet another embodiment, the surfactant may include a nonionic surfactant. Further, the nonionic surfactant may include stearyl alcohol polyether-2, oleyl alcohol polyether-2, cetyl alcohol polyether-3, oleyl alcohol polyether-3, C12-13 alkanol polyether-3, oleyl alcohol polyether-5, C12-13 alkanol polyether-4, lauryl alcohol polyether-4, lauryl alcohol polyether-9, cetearyl alcohol polyether-6, oleyl alcohol polyether-10, oleyl alcohol polyether-20, stearyl alcohol polyether-10, poloxamer, polyethylene glycol, or combinations thereof.

[0031] In yet another embodiment, the method may include adding an insoluble excipient to a binder-dispersible pharmaceutical layer formulation. Furthermore, the insoluble excipient may include cross-linked polyvinylpyrrolidone.

[0032] In another embodiment, the method may include coating an adhesive-dispersible drug layer formulation onto one of a backing layer or a release liner.

[0033] In another embodiment, the method may further include subsequently evaporating a second process solvent system to form a dry binder-dispersed drug layer formulation.

[0034] In another embodiment, the method may further include applying another of the backing layer or release liner to the exposed surface of the dried adhesive-dispersed pharmaceutical layer formulation to form a laminate.

[0035] In another embodiment, the method may include: die-cutting the laminate to a specified patch size; and housing the inherent coverage system together with the laminate in a flat heat-sealable bag.

[0036] Other features and aspects of this disclosure are described in more detail below. Brief description of the attached diagram

[0038] The complete and implementable disclosure, including its best mode of practice for those skilled in the art, is set forth in more detail in the remainder of the specification, including reference to the accompanying drawings, wherein:

[0039] Figure 1 This is a cross-sectional view of a transdermal drug delivery system according to one embodiment of the present disclosure, wherein the transdermal drug delivery system includes micronized solid API glassy particles incorporated as a binder-dispersed drug matrix.

[0040] Figure 2 This describes the preparation Figure 1 A flowchart of a method for a transdermal drug delivery system, wherein micronized solid API glassy solid particles (SSP) containing soluble polyvinylpyrrolidone are prepared and then subsequently added to a binder-dispersed drug matrix;

[0041] Figure 3 This is a graph comparing the average flux (µg / cm² / h) of dexamethasone per Strat-M® (synthetic membrane) of various transdermal drug delivery system formulations, comparing formulations in which dexamethasone is in the form of a precipitated molecular solid suspension or a suspended micronized powder form.

[0042] Figure 4 It is a graph describing the cumulative permeation (µg / cm²) of dexamethasone through Strat-M® (synthetic membrane) in various transdermal drug delivery system formulations, comparing formulations in which dexamethasone is in the form of a precipitated molecular solid suspension or a suspended micronized powder form;

[0043] Figure 5 This is a graph depicting the average flux (µg / cm² / h) of dexamethasone through Strat-M® (synthetic membrane) for various transdermal drug delivery system formulations, which for the first time utilize solid particles with different polyvinylpyrrolidone to dexamethasone ratios to form a transdermal binder-dispersed drug matrix.

[0044] Figure 6 It is a graph describing the cumulative permeation (µg / cm²) of dexamethasone through Strat-M® (synthetic membrane) in various transdermal drug delivery system formulations, which for the first time use solid particles with different polyvinylpyrrolidone to dexamethasone ratios to form a transdermal binder-dispersed drug matrix.

[0045] Figure 7 This is another graph describing the average flux (µg / cm² / h) of dexamethasone through Strat-M® (synthetic membrane) in various transdermal drug delivery system formulations, which compares formulations that use polyvinylpyrrolidone and dexamethasone to form solid micronized particles with formulations in which polyvinylpyrrolidone and dexamethasone or dexamethasone alone are added as solid raw materials.

[0046] Figure 8 This is another graph describing the cumulative permeation (µg / cm²) of dexamethasone through Strat-M® (synthetic membrane) in various transdermal drug delivery system formulations, comparing formulations that use polyvinylpyrrolidone and dexamethasone to form solid micronized particles with formulations in which polyvinylpyrrolidone and dexamethasone or dexamethasone alone are added as raw materials.

[0047] Figure 9It is a graph describing the average flux (µg / cm² / h) of lenalidomide through Strat-M® (synthetic membrane) for various transdermal drug delivery system formulations, comparing formulations in which lenalidomide is in the form of a precipitated molecular solid suspension or in the form of solid micronized particles of polyvinylpyrrolidone.

[0048] Figure 10 It is a graph describing the cumulative permeation (µg / cm²) of lenalidomide through Strat-M® (synthetic membrane) in various transdermal drug delivery system formulations, comparing formulations in which lenalidomide is in the form of a precipitated molecular solid suspension or in the form of solid micronized particles of polyvinylpyrrolidone.

[0049] Figure 11 It is a graph describing the average flux (µg / cm² / h) of olanzapine through Strat-M® (synthetic membrane) for various transdermal drug delivery system formulations, comparing formulations in which olanzapine is in the form of a precipitated molecular solid suspension or in the form of solid micronized particles of polyvinylpyrrolidone.

[0050] Figure 12 This is a graph depicting the cumulative permeation (µg / cm²) of olanzapine through Strat-M® (synthetic membrane) in various transdermal drug delivery system formulations, comparing formulations in which olanzapine is in the form of a precipitated molecular solid suspension or in the form of solid micronized particles of polyvinylpyrrolidone.

[0051] Reference numerals used repeatedly in this specification and drawings are intended to indicate the same or similar features or elements of this disclosure.

[0052] Detailed description of representative implementation schemes

[0053] Those skilled in the art will understand that the present discussion is merely a description of exemplary embodiments and is not intended to limit the broader aspects of this disclosure.

[0054] definition

[0055] As used herein, the terms “about,” “approximately,” or “generally,” when used to modify numerical values, indicate that the value may fluctuate by 5% or more while remaining within the range of the disclosed embodiments. Furthermore, when multiple ranges are provided, this disclosure covers any combination of the minimum and maximum values ​​described within the multiple ranges. For example, if ranges of “about 20% to about 80%” and “about 30% to about 70%” are described, this disclosure also covers a range of “about 20% to about 70%” or a range of “about 30% to about 80%.”

[0056] As used in this article, the term "dispersion" means causing breakage, causing widespread diffusion, and / or causing evaporation or dissipation.

[0057] As used herein, the term "dispersion" refers to a system in which discrete particles of one material are dispersed in a continuous phase of another material. These two phases may be in the same or different states of matter. The term may also, or alternatively, refer to a system consisting of the dispersed material and the medium in which it is dispersed.

[0058] As used herein, the term "molecular dispersion" refers to a real solution of the solute phase in a solvent. The dispersed phase (solute) is in the form of individual molecules that are uniformly distributed throughout the dispersion medium (solvent). The molecular size is less than 1 nm.

[0059] As used herein, the term "molecular solid suspension" means that the term "molecular solid suspension" specifically refers to a solid, such as an API, which is dissolved in a suitable first solvent as a true solution (molecular dispersion), however, it is incorporated into a combination of a suitable second solvent and a suitable solid excipient, which serves as a carrier for the first solid. The solid excipient carrier is insoluble in either the first or second solvent, but is freely dispersed or suspended in one solvent or a combination of two solvents, depending on the particle size of the substrate. The solid excipient carrier may or may not be micronized. Solid excipient carriers such as Parteck SLC (silica) or Kollidon CL-M (crosslinked polyvinylpyrrolidone) have been found suitable for preparing these molecular solid suspensions. For the purposes of this invention, to ensure the processability of the final formulation as a transdermal delivery system, the particle size is approximately no more than about 180 micrometers (μm) (80-mesh sieve) particle size (D90). The solid solubilized in the first process solvent is, in most cases, an API, which is then added to a dispersed or suspended solid carrier (in most cases, a pharmaceutically acceptable excipient) in a second process solvent (rather than the first process solvent). Additionally, excipients suitable for producing homogeneous dispersions are added to alter the availability and permeability of the API in the platform. Thus, the medium is a homogeneous blend of excipients, binders, polymers, or solvents, such that the resulting formulation is a suspension of dispersed particles in said medium. Upon solvent evaporation, a viscous liquid, such as a pressure-sensitive adhesive, is left, containing the medium along with homogeneously suspended API, carrier excipients, and other excipients (if desired) in particles or co-particles. The API and / or particulate excipients can be amorphous, quasi-amorphous, partially amorphous, crystalline, or combinations thereof to produce a suitable formulation. Formulation with drug concentrations significantly above the solubility saturation point facilitates the solubility of the drug in aqueous solutions, and more specifically, the increased availability of the drug is now more permeable due to the enhanced concentration gradient and the inherent reservoir of the molecular solid suspension. As is known to those skilled in the art, molecular dispersions are true solutions, and dispersions generally result in physical mixtures of solid materials dispersed in a liquid, such as molecular dispersions, colloids, or suspensions.

[0060] As used herein, the term "solid particle" (SSP) or suspension refers to a solid active pharmaceutical ingredient (API) or a combination of a solid API and a substrate (API:substrate) incorporated into a suitable system. It should be understood that the solid API or API:substrate is not formed in situ. Rather, the API or API:substrate complex is added to a system, such as a transdermal delivery system (TDS), in the form of solid particles that remain unchanged during formulation, blending, coating, or finished drug manufacturing, thereby forming a solid suspension as part of a binder-dispersed drug layer. The API may exist as a micronized drug that does not significantly solubilize within the binder-dispersed drug system. Alternatively, the API:substrate is formed by first dissolving the API and then dissolving the polymer together in a suitable solvent system at a preferred API:substrate:solvent ratio. The resulting molecular dispersion or true solution is then evaporated to remove the volatile organic solvent, leaving a substrate containing the glassy drug, in which no drug crystals are found. It should be understood that the terms “glass-like” and “glassy” are sometimes used synonymously with amorphous solids; however, these terms specifically refer to amorphous materials undergoing a glass transition and are not synonymous with the term “amorphous”.

[0061] As has been found in this disclosure, in these API:substrate complexes, the goal is not to maximize drug loading for the availability / permeability of the API through the skin for transdermal delivery, but rather to maximize the minimum effective level of the API within the solid particles to achieve maximum availability. This directly contradicts the industry-guided approach of achieving maximum effective concentration to achieve the highest API amount in such polymer systems. Typically, the purpose of producing such solid particles is to improve oral delivery of drugs by maximizing drug loading, minimizing particle size, and ensuring the amorphous nature of the solid excipient carrier, which may or may not be micronized. Polymers for relevant applications are soluble in a variety of solvents that can also be used to solubilize the API, but are not necessarily required to be identical, provided that the polymer and solvent system are miscible with the solvent selected to dissolve the API and the polymer substrate. Preferably, water-soluble polymers, such as Plasdone (povidone / polyvinylpyrrolidone) or Kollidon 30 or 30LP and Kollidon 90 (soluble povidone / polyvinylpyrrolidone), have been found suitable for preparing these solid suspensions. Furthermore, Kollidon 12 and Kollidon 12PF were found to be unsuitable for forming glassy particles that can be micronized, likely due to their low molecular weight. Other molecular weights, such as Kollidon 25, 45, 60, and 120, are believed to be suitable, making feasible production methods for the API:substrate suitable for producing micronized glassy particles. For the purposes of this disclosure, a particle size not exceeding about 250 μm is believed to ensure the processability of the final formulation as a transdermal delivery system. The micronized particulate form of the API and / or API:substrate is a glassy or glassy material, which is an amorphous material. However, it should be understood that not all amorphous particles are glassy or glassy materials, where the presence of glassy particles has been found to be particularly necessary for achieving the production of suitable formulations with maximum efficiency.

[0062] As is known to those skilled in the art, molecular dispersions are true solutions and dispersions generally result in physical mixtures in which solid materials are dispersed in a liquid, such as molecular dispersions, colloids, or suspensions. By incorporating solid materials with specific physicochemical properties into transdermal systems and creating an environment more suitable for API delivery and ensuring sustained penetration of the API from the delivery system into the subject or patient, the systems of this disclosure are found to be highly effective. It is generally known that most people skilled in the art are taught or trained to believe that solubilized drugs within transdermal patches are a necessary condition for enabling and maximizing transdermal drug delivery. Therefore, this disclosure contradicts common views, understandings, acceptances, and teachings by challenging the notion that solid particles in suitable formulations can not only surpass solubilized transdermal drug delivery methods but also maximize efficiency and achieve high levels of penetration from transdermal delivery systems that are higher than and exceed those achievable with solubilized transdermal drug delivery systems.

[0063] As used herein, the term "suspension" refers to a coarse dispersion, which is a heterogeneous dispersion system in which the dispersed phase particles are larger than 1000 nm (1 μm). Coarse dispersions are characterized by the relatively rapid settling of the dispersed phase due to gravity or other forces. The dispersed phase of a coarse dispersion can be easily separated from the continuous phase by filtration. The particles can be visible to the naked eye, and the mixture is classified as a suspension only before the particles have settled. Chemically, a suspension is a heterogeneous mixture of fluids containing solid particles large enough to settle. The particles can be visible to the naked eye, typically must be larger than one micrometer and eventually settle, but the mixture is classified as a suspension only before the particles have settled.

[0064] As used herein, the terms “partition coefficient (P)” or “distribution coefficient (D)” refer to the ratio of the concentrations of a compound in a mixture of two immiscible solvents at equilibrium. Therefore, this ratio is a comparison of the solubility of the solute in both liquids. The partition coefficient typically refers to the ratio of the concentrations of the unionized form of a compound, while the distribution coefficient refers to the ratio of the concentrations of all forms of the compound (ionized plus unionized). In chemistry and pharmacy, both phases are typically solvents. One of the most common solvents is water, while another is hydrophobic, such as 1-octanol. Therefore, the partition coefficient measures how hydrophilic (“hydrophilic”) or hydrophobic (“hydrophobic”) a chemical substance is. The distribution coefficient is used to estimate the distribution of drugs in the body. Hydrophobic drugs with a high octanol-water partition coefficient are primarily distributed to hydrophobic regions such as the lipid bilayer of cells. Conversely, hydrophilic drugs (low octanol / water partition coefficient) are primarily found in aqueous regions such as serum. The partition coefficient, abbreviated as P, is defined as the specific ratio of solute concentrations between two solvents (in a two-phase liquid system), particularly for unionized solutes, and the logarithm of this ratio is thus log P. When one solvent is water and the other is a nonpolar solvent, the log P value is a measure of lipophilicity or hydrophobicity. The convention is that the lipophilic and hydrophilic phase types are always represented in the numerator and denominator, respectively; for example, in a two-phase system of n-octanol (hereinafter referred to as "octanol") and water. Equation I illustrates this relationship:

[0065]

[0066] Detailed Explanation

[0067] Generally, solid suspensions are formed by suspending an API in a suitable substrate, such as a pressure-sensitive adhesive or polymer carrier, with or without additional excipients and / or solvents, while maintaining the solid particles within the system in a manner that ensures uniform and consistent dispersion, thereby creating a suitable particle suspension within a polymer / adhesive system. The solid suspensions covered in this disclosure are undissolved and can be micronized to a specific particle size, making the API or API:substrate complex suitable for inclusion in a transdermal delivery system. This disclosure covers a system in which a homogeneous particle suspension is added to a formulation in which the API is not significantly solubilized, a significant level that would alter the solid particle properties of the API or API:substrate complex in the system's process solvent, binder, or excipients.

[0068] In other words, APIs can be formulated within a polymer / binder / excipient system to maintain a homogeneous and non-settling solid particle suspension, wherein the micronized drug remains as intact solid particles, and these particles remain suspended during production, to prepare a finished dosage form serving as a binder-dispersed drug layer between a backing layer and a release liner. This encompasses the formation of a solid suspension in which the solute is not solubilized by the medium, with the aim of forming a solid suspension. Therefore, there is no molecular dispersion or true solution within the carrier. Instead, a suspension of solid drug particles exists. Thus, a binder-dispersed drug layer containing suitable excipients can be formed, which neither solubilizes the API nor interferes with the dispersibility of the API within the system, but contributes to improving the usability of the API and thus its permeability.

[0069] One embodiment of this disclosure is presented, in which the API is first added to a solubilized carrier. Specifically, in one embodiment, this disclosure requires the API to be solubilized by a polymer / solvent composition, followed by solvent evaporation, resulting in a dried material in the form of an API:substrate composite that can be micronized. For example, the API / solidated carrier solution can be dried by solvent evaporation, leaving a glassy film. The glassy film or glassy material can then be broken down and micronized to form solid glassy particles, thereby forming an API:substrate composite in which there are no signs of API crystallization. These solid, glassy particles are then added to the adhesive layer of a transdermal delivery system without solubilizing the API or the polymer carrying the solubilized API. Thus, the micronized powdered solid particles can be dispersed and suspended within the adhesive layer, which contains uniformly and evenly distributed suspended solid particles. The formation of glassy particles results in a significant increase in the water solubility of the API in the presence of the transdermal system, through its application and occlusion properties.

[0070] In one specific embodiment, this disclosure covers an API: a substrate complex, which is used as micronizable glassy particles for final incorporation into a pharmaceutical product. It also covers a separate micronized API solid particle. In any case, the solid particles, whether a single API or a complex comprising an API and a substrate, can be micronized such that the particles have a D100 value of less than about 300 micrometers, meaning that 100% of the micronized solid particles have a particle size of less than about 300 micrometers. Furthermore, in some embodiments, the solid particle complex may have a D100 value of less than about 150 micrometers. In other embodiments, the solid particles may have a D90 value of from about 0.1 micrometers to about 75 micrometers, meaning that at least 90% of the particles have a particle size of from about 0.1 micrometers to about 75 micrometers.

[0071] This disclosure also covers composites of API and substrate formed as a result of combining a solubilized API and a solubilized polymer in a suitable solvent system, wherein evaporation of the solvent system leaves a glassy solid in which no crystallized API is present. In other words, the API is crystal-free. In other words, the API is solubilized by a cured polymer or carrier substrate without the need for additional volatile process solvents, and after drying, the API:substrate composite is in the form of a hard glass or glassy material and is suitable for particle size reduction treatment to reduce its particle size when friction and pressure are applied, thereby achieving micronization of the resulting solid material. It should be understood that both the API and the substrate are soluble in the same solvent system, and neither the API nor the substrate exists in a precipitated or insoluble state prior to evaporation or drying, thus forming a true solution in the solvent system. In one embodiment, the substrate may be a soluble polymer. For example, the substrate may be a film-forming polymer, such as polyvinylpyrrolidone, also known as polyvinyl ketone. Furthermore, the API may have a melting point above about 120°C and may have a log P value related to the log P value of the substrate, such as a log P value ranging from about -2 to about 8.

[0072] It should also be understood that additional additives may be added to the API:substrate complex to impart additional properties, such as antioxidants, preservatives, solid solubilizers, agents that adjust the melting point, agents that adjust the log P value, agents that adjust the dispersibility or reduce the solubility of the API:substrate in a binder-dispersed drug complex, or any other additives known to those skilled in the art that thereby produce a glassy, ​​dry material suitable for reducing particle size.

[0073] The resulting solid particle composition can be added to a transdermal delivery system in the form of a binder-dispersed drug transdermal delivery system, the composition of which may contain an API or an API-substrate complex, and when the solid particle API or API:substrate complex is suspended in the binder-dispersed drug layer of the transdermal delivery system, it does not exhibit significant dissolution of the API, API:substrate complex or the substrate itself.

[0074] Transdermal delivery systems may contain insoluble excipients to maintain dispersion / suspension properties. Furthermore, insoluble excipients can act as a "sponge" for other liquid excipients to reduce cold flow / migration. The system may also contain at least one penetration enhancer that does not significantly dissolve solid particulate APIs or API:matrix compounds.

[0075] Additionally, the system may include a process solvent for blending purposes, wherein the process solvent does not alter the properties of the solid particle API or API:substrate composite, except to suspend the particles in the substrate, wherein such solvent is removed during the curing process.

[0076] Furthermore, the system may include at least one backing layer, at least one release liner layer, and may incorporate an inherent covering system to ensure system adhesion. Additionally, it should be understood that in some embodiments, a multi-layered structure may be provided as a feasible implementation of the above-described features within the combined system.

[0077] By incorporating the solid particulate compositions of this disclosure into transdermal delivery systems, the ability of APIs and / or low molecular weight excipients to migrate away from the active region of the transdermal delivery system (e.g., a patch) is reduced, and they remain usable for delivery from the transdermal delivery system, rather than being transferred to packaging, overlays, or other materials unrelated to transdermal delivery. Without intending to be bound by any particular theory, the inventors of this invention have discovered that the solid particulate compositions of this disclosure also reduce the ability of APIs, any excipients, and / or binders to undergo cold flow, i.e., the movement of the binder and the diffusion of the pharmaceutical product away from the active region of the transdermal delivery system. Furthermore, the compositions of this disclosure reduce the likelihood of API degradation in the presence of oxygen, moisture, and / or excipients by incorporating the API within the solid particles, in which the API is well protected from external or environmental influences.

[0078] In general, solid suspensions, particularly those prepared in solid suspension form, have been found to be unexpectedly unique and offer key advantages over solubilized and / or molecular solid suspension platforms of similar composition to achieve optimal performance in terms of permeability and delivery profile sustainability without sacrificing concentration gradients. It is generally known to those skilled in the art that solid drug products incorporated into transdermal systems are less readily solubilized in the skin or media, and therefore have weaker permeability than formulation-based solubilized drug platforms. The limitation of these systems is achieving the theoretically possible delivery volume to reach therapeutic blood levels of the drug, where further increases in drug load either lead to crystallization events or overburden the semipermeable membrane (i.e., the skin), ultimately reducing the total drug delivery from saturated solubilized systems. Molecules with moderate to high water solubility, such as those listed in the United States Pharmacopeia (USP) as soluble to very soluble or greater than about 100 mg / mL, and some molecules with low solubility or greater than about 30 mg / mL and low melting points (below about 120°C), are less suitable for preparation as solid particulate suspensions. However, these molecules can be loaded into the system, potentially making them more readily available and therefore more permeable. Liquid APIs are typically added to liquid systems at or above their saturation levels at approximately ambient temperature or room temperature to optimize usability and permeability. This may not add significant value, but the scientific basis for the improvement is reasonably explained.

[0079] It has been found that the present disclosure makes it possible to oversaturate APIs in a solid state in a transdermal adhesive-dispersed drug delivery system. This is surprising, given that the API is in a solid state, where a person skilled in the art would not expect that a solid API would be readily used for solubilization and subsequent permeation through a membrane, such as human skin. This is not typical behavior of solid API particles incorporated into a transdermal adhesive-dispersed drug or matrix system.

[0080] The saturated type is not supersaturation, where the API is still solubilized at a level above saturation. Rather, the API is intentionally present at a supersaturated level, thus having a significantly higher capacity than the amount of API contained in the matrix solubilization system, and forcing particle formation. These particles can be nanoparticles or micronized drugs with a particle size of less than about 300 micrometers, such as less than about 150 micrometers (D100), or can exist as a composite of API and substrate in the form of nanoparticles or micronized solid particle compositions that do not alter their glassy particle properties when other components of the binder-dispersed drug layer in the transdermal delivery system are present. In one embodiment, the particle size can be in the range of about 0.1 micrometers to about 150 micrometers, or any range therebetween. The solid particle API and substrate composite of the present invention is a glassy particle whose particle size can be reduced to less than about 300 micrometers, such as less than about 150 micrometers (D100), by mechanical, precipitation, or other means, and such that the micronization process does not impart excessive heat that would cause the formed particles to melt or thermally change. The micronization of the API can be accomplished by dissolving both the API and the polymer substrate in a suitable solvent system, followed by evaporation of the volatile organic solvent to below ICH Q3C residual solvent levels. The resulting true solution (followed by solvent evaporation) is produced in a subsaturated state to maximize the availability and permeability of the API for transdermal delivery. Each API-substrate complex can be optimally positioned to maximize drug delivery from the transdermal patch. In contrast, most studies mention maximizing the API-to-substrate ratio to achieve the highest possible drug concentration, resulting in spray-dried, melt-extruded, spherical particles, and such methods are generally recommended for oral drug product development. It should be understood that the glass or glassy particles covered by this disclosure are inherently amorphous, although not all amorphous materials are glassy. Therefore, to obtain the solid particulate API or API-substrate complex of the present invention, glass or glassy particles must be obtained for loading the drug within the glassy particles. Surprisingly, these glass or glassy particles are water-soluble. Polymers such as soluble polyvinylpyrrolidone (PVP) have been found to be uniquely suitable for such API-substrate composites. Other polymers with similar organic solubility to PVP and also water-soluble are also included. These API:substrate composites achieve a significant improvement in the water solubility of the API, and the resulting particles are glassy, ​​and glass is an amorphous material, lacking crystalline entities suitable for particle size reduction. Other possible soluble polymers that can be used include cellulose (hydroxypropyl methylcellulose (HPMC) and its derivatives, ethyl cellulose (EC), acrylic acid) or any other film-forming polymer suitable for particle size reduction, soluble in organic solvents, and soluble in water.

[0081] Such amorphous properties are achieved by controlling the weight ratio of the substrate to the API. It has been found that when forming the composite using an evaporated process solvent, a 1:1 ratio will produce an undesirable amorphous structure because it is not inherently glassy. On the other hand, in order to produce amorphous and glassy particles, the weight ratio of the substrate to the API used to form the composite can range from about 1.25:1 to about 20:1; such as about 1.5:1 to about 15:1; such as about 2:1 to about 10:1; such as about 4:1 to about 8:1, or any range therebetween.

[0082] This disclosure covers a method for preparing a composite of a solid particulate API and a substrate. For example, the method includes solubilizing the API in a polymer to form a molecular dispersion (true solution), wherein (multiple) active pharmaceutical ingredients are dispersed at the molecular level within the system, and evaporating the process solvent from the system to leave a uniform, homogeneous, amorphous glass or glassy structure suitable for particle size reduction and micronization. It should be understood that the API is undersaturated in the resulting API-polymer composite. In some embodiments, the amount of API present in the solid particulate composite can range from about 2 wt% to about 30 wt%, such as about 4 wt% to about 20 wt%, such as about 5 wt% to about 7.5 wt%, and any range therebetween, while the amount of polymer present can range from about 70 wt% to about 98 wt%, such as about 80 wt% to about 96 wt%, such as about 92.5 wt% to about 95 wt%, and any range therebetween. It should be understood that, depending on the specific API, the weight ratio of polymer to API when forming the composite can vary. For example, if the API is lenalidomide, the polymer-to-API weight ratio can range from about 2.5:1 to about 20:1; if the API is dexamethasone, the polymer-to-API weight ratio can range from about 4:1 to about 8:1; and if the API is olanzapine, the polymer-to-API weight ratio can range from about 4:1 to about 10:1. However, a 1:1 polymer-to-API ratio has not successfully formed a transparent, glassy material that can be micronized into solid particulate composites of API and polymer.

[0083] Furthermore, solvents that can be used to incorporate the API into the polymer to form a solid particulate complex may include ethyl acetate, isopropanol, polar aprotic solvents such as N-methyl-2-pyrrolidone (NMP), or combinations thereof, wherein the solvent is ultimately evaporated to form a transparent glassy film, which may be micronized to form a complex for use as a component of a transdermal delivery system. Additionally, based on the total weight of the API, polymer, solvent, and any other excipients that may be present, the solvent (before its evaporation) may be present at a concentration of about 10% to about 25% by weight.

[0084] Once the solid-particle API and polymer complex is micronized, it can be added to various other components to form a transdermal delivery system. However, it should be understood that the particle complex can also be added to other dosage forms to prepare homogeneous dosage forms, such as creams, gels, ointments, plasters, balms, salves, and / or pastes, as long as a substrate is present to support the suspension of the solid particles (whether API or API and polymer complex). When used in a transdermal delivery system, the transdermal delivery system may include a binder-dispersed drug layer comprising the solid-particle API and polymer complex, insoluble micronized solid materials such as cross-linked polyvinylpyrrolidone (cross-linked povidone), penetration enhancers, binder polymers, other excipients, etc., as discussed in more detail below. The above components are combined to form a stable solid-particle API and polymer in a homogeneous dispersion within the binder-dispersed drug layer, wherein the API in solid-particle form is not dissolved or destroyed upon application of heat or over time, and there is no chemical or physical separation. This contrasts sharply with other systems that have shown failure, where birefringence was clearly visible in the formulation under polarized light microscopy, indicating separation of the API from the glassy particles. In contrast, the compositions and formulations of this disclosure produce solid particulate APIs that remain unchanged after forming the transdermal system, without birefringence.

[0085] Solid particle APIs in transdermal delivery systems

[0086] As described above, in some embodiments, this disclosure relates to solid particulate APIs or API-polymer complexes formed as described above, and transdermal drug delivery systems for delivering said APIs through the skin. The transdermal drug delivery system includes a binder-dispersed drug layer comprising the solid particulate API or a solid particulate API-polymer complex, insoluble excipients, a penetration enhancer, and a pressure-sensitive binder. The transdermal drug delivery system may also include other excipients discussed below. Furthermore, methods for forming solid particulate APIs and then incorporating them into a binder-dispersed drug layer are covered.

[0087] More specifically, this disclosure enables novel and existing commercially available APIs with specific water solubility and melting temperature ranges to exhibit significantly improved performance characteristics. Improved permeability has been demonstrated when utilizing the solid particulate APIs or API-polymer composites covered herein, thereby facilitating increased API delivery rates and the sustainability of API delivery profiles over up to approximately 7 days.

[0088] The stability of APIs in solubilized systems is sometimes difficult to address, and APIs may degrade to unacceptable levels during the product's shelf life, and / or cause loss of concentration gradients after application due to patch efficiency and solubility issues. Therefore, the molecular solid-particle API compositions or formulations of the present invention maintain the API in a solid state, which improves the API's ability to remain stable during shelf-life storage and protects against the effects of environmental conditions during storage, such as oxidation or hydrolysis, since solid APIs are generally more stable than their solubilized solutions. Unexpectedly, the solid-particle APIs of the present invention make the API easier to use for penetration, and by incorporating the API in a uniform and consistent manner into a binder-dispersed drug matrix, it helps maintain a constant concentration gradient.

[0089] In connection with this disclosure, transdermal delivery of APIs with negative Log P exceeds the scope of Lipinski's Rule of 5, a well-known rule that has a significant impact on API development, yet only about 50% of new oral-dose chemical entities comply with it. It is important to keep this rule in mind during API discovery as pharmacologically active lead structures are progressively optimized to improve the activity and selectivity of compounds, and to ensure that the physicochemical properties of the API-like structure are maintained as described by Lipinski's Rule. Candidate APIs that meet the Rule of 5 often have a lower rejection rate during clinical trials, thus increasing their chances of market entry. The Rule of 5 does not refer to a set of five rules, but rather that each rule is divisible by 5. Negative Log P means that the molecule should exhibit higher water solubility (hydrophilicity) compared to its solubility in organic phases (lipophilicity). Some molecules with Log P values ​​close to 0 to -1.5 exhibit unexpected solubility, and this may not be adequately determined by Log P alone, as it involves hydrophilicity / lipophilicity.

[0090] Table 2: Ribinsky's Five Rules

[0091]

[0092] Modifications to the rules over the years have included Ghose sieving, Veber's rule, and other notable revisions such as Log P values ​​from -0.4 to +5.6; molar refractive indices from 40 to 130; molecular weights from 180 to 480; and atomic numbers from 20 to 70, which include the sum of donor and acceptor, rather than considering them independently as in rules #1 or #2. Rotatable bonds less than 10 and A bonds not exceeding 140 have been found. 2 The polar surface area of ​​these components contributes to good oral bioavailability. These rules have also been found to relate to transdermal delivery of APIs, demonstrating the feasibility of such delivery.

[0093] Table 3: Ghose Filtering and Veber Rule Set

[0094]

[0095] Of particular interest is that the inventors have discovered that the APIs covered by this disclosure may exceed the scope of the Ribinski Five Rules, Ghose screening, or Veber Rules in one or more key properties, which would indicate that successful transdermal delivery is not feasible; however, the methods and formulations of this disclosure show that transdermal delivery with enhanced permeability through the skin can be achieved.

[0096] Interestingly, melting point and water solubility are excluded from these general rules of thumb when discussing the development of APIs for drug delivery. The inventors recognize that APIs exhibiting low water solubility (less than about 10 mg / mL) and a relatively high melting point (above about 120°C) are preferred for this invention because they result in solid particulate APIs. However, depending on other properties, API molecules exhibiting water solubility above 10 mg / mL may be suitable for forming these solid particulate APIs, provided the melting point is above about 120°C.

[0097] The transdermal delivery systems (TDS) described herein include transdermal formulations that can be in liquid or semi-solid form of desired viscosity, such as suspensions, nanosuspensions, microsuspensions, dispersions, emulsions, microemulsions, nanoemulsions, gels, ointments, creams, pastes, lotions, mousses, adhesives, patches, plasters, or ointments.

[0098] Transdermal formulations can form part of a transdermal delivery system that includes the transdermal formulation. Exemplary transdermal delivery systems include, but are not limited to: bilayer, multilayer, or monolithic topical or transdermal formulations, systems, patches, or matrices, with or without an adhesive, with or without a covering layer, as an adhesive-dispersed drug, reservoir, microreservoir, hydrogel, mucosal adhesive, adhesive and / or tape, as a system, patch, plaster, or combination thereof for topical or transdermal use.

[0099] Solid particulate APIs, solid particulate APIs and substrates, or combinations thereof, may be incorporated into or used in the production of microneedles, microblades, microprotrusions, soluble microneedles, absorbable microneedles, as systems, patches, plasters, or combinations thereof for topical or transdermal use.

[0100] In further embodiments, the formulations provided herein provide a stable solid formulation of the API within a transdermal formulation, wherein the solid nature provides protection against degradation characteristics of the drug in similar compositions that would affect the solubilized drug. For example, the formulation has storage stability, retaining at least 90% of its activity for a predetermined period of time when stored under standard environmental conditions. In still other embodiments, the formulation has storage stability for at least 3 months, 6 months, 9 months, one (1) year, two (2) years, or longer.

[0101] In another embodiment, and depending on the API being delivered, the average flux rate of the API contained in the transdermal drug delivery system of this disclosure can be consistently at least 1 μg / cm³ over a period of 1, 2, 3, 4, 5, 6, 7 or more days. 2 / hr. In some embodiments, the average flux rate of the API included in the transdermal drug delivery system of this disclosure can be consistently at least 2 μg / cm³ over a period of 1, 2, 3, 4, 5, 6, 7 or more days. 2 / hr, or the average throughput rate of the API included in the transdermal drug delivery system of this disclosure can be consistently at least 3 μg / cm³ over the entire time period of 1, 2, 3, 4, 5, 6, 7 or more days. 2 / hr. In other embodiments, the average flux rate of the API included in the transdermal drug delivery system of this disclosure can be consistently at least 4 μg / cm³ over a period of 1, 2, 3, 4, 5, 6, 7 or more days. 2 / hr. In some further embodiments, the average flux rate of the API included in the transdermal drug delivery system of this disclosure can be consistently at least 5 μg / cm³ over a period of 1, 2, 3, 4, 5, 6, 7 or more days. 2 / hr. In other embodiments, the average flux rate of the API included in the transdermal drug delivery system of this disclosure can be consistently at least 6 μg / cm³ over a period of 1, 2, 3, 4, 5, 6, 7 or more days. 2 / hr, 7 μg / cm 2 / hr, 8 μg / cm 2 / hr or even 10 μg / cm 2 / hr.

[0102] Reference Figure 1According to one embodiment, the transdermal drug delivery system 100 includes a binder-dispersed drug layer 110 containing solid particulate APIs and / or APIs and polymer complexes 112. The binder-dispersed drug layer 110 is disposed between a backing layer 120 and a release liner 130. When the transdermal drug delivery system 100 is used, the backing layer 120 has an outer surface 140 exposed to the surrounding environment. Simultaneously, the release liner 130 is located on the skin-contacting surface 150 of the binder-dispersed drug layer 110, wherein the release liner 130 is removable, allowing the binder-dispersed drug layer 110 to be directly applied to the skin during use of the transdermal drug delivery system 100. Due to the specific combination of components used to form the binder-dispersed drug layer, such as solid particulate API and / or API and polymer complex 112, specific process solvents, insoluble excipients and penetration enhancers, and the specific weight percentages and ratios of such components used, the inventors have discovered that a transdermal drug delivery system 100 can include a solid particulate API binder-dispersed drug matrix layer forming a surface that contacts the skin, which facilitates the controlled delivery of API at elevated levels. Figure 1 As shown, the binder-dispersed drug layer 110 can be in the form of a single layer, such that the active drug component 112 in the form of solid particles is uniformly dispersed in the binder component of the entire system 100.

[0103] The various components of the transdermal drug delivery system 100 are discussed in detail below.

[0104] I. Solid particulate binder for dispersible drug layers

[0105] a. Active pharmaceutical ingredients

[0106] The API component of the binder-dispersible drug delivery system of this disclosure can be any drug or active pharmaceutical ingredient (API) having low water solubility and a high melting point, as APIs with such properties have been found to exhibit increased permeability and stability when using the transdermal delivery system of this disclosure. For example, the API may have a water solubility of less than about 10 mg / mL, such as less than about 5 mg / mL, such as less than about 1.5 mg / mL, such as less than about 1.25 mg / mL, such as less than about 1 mg / mL. Furthermore, the API may have a melting point above 120°C, such as from about 140°C to about 285°C, such as from about 145°C to about 280°C, such as from about 150°C to about 275°C, or any range between these ranges. Additionally, the API may have a log P value of from about -2 to about 8, such as from about -1.75 to about 6, such as from about -1.5 to about 4, such as from about -0.5 to about 3, or any range between these ranges.

[0107] In one implementation, the API can be an immunomodulator. For example, immunomodulators can include immunomodulatory imide compounds such as thalidomide, including analogs of thalidomide, and all pharmaceutically acceptable forms including lenalidomide, pomalidomide, and iberlidomide, including, for example, free bases, salts, polymorphs, solvates, solutions, isomers, amorphous forms, crystals, cocrystals, solid solutions, prodrugs, analogs, derivatives, and metabolites, and combinations thereof. The compound can be in the form of a pharmaceutically acceptable salt, such as an acid addition salt or a base salt, or a solvate thereof, including its hydrate. Suitable acid addition salts are formed from acids that form non-toxic salts and examples include hydrochlorides, hydrobromides, hydroiodates, sulfates, hydrogen sulfates, nitrates, phosphates, hydrogen phosphates, acetates, maleates, fumarates, lactates, tartrates, citrates, gluconates, succinates, glycosides, benzoates, methanesulfonates, ethanesulfonates, benzenesulfonates, p-toluenesulfonates, and dihydroxynaphthylates.

[0108] In another implementation, the API can be a hormone, such as a steroid. For example, the API can be a corticosteroid, such as dexamethasone or dexamethasone acetate. Corticosteroids are a class of steroid hormones produced in the adrenal cortex of vertebrates, and synthetic analogues of these hormones. Two main classes of corticosteroids—glucocorticoids and mineralocorticoids—are involved in a wide range of physiological processes, including stress responses, immune responses, and the regulation of inflammation, carbohydrate metabolism, protein catabolism, blood electrolyte levels, and behavior. Synthetic drugs with corticosteroid-like effects are used for a variety of conditions, from hematologic malignancies to brain tumors or skin diseases. Dexamethasone and its derivatives are almost purely glucocorticoids, while prednisone and its derivatives have some mineralocorticoid effects in addition to glucocorticoid effects. Fludrocortisone is a synthetic mineralocorticoid. Fludrocortisone is commonly used in replacement therapy, for example, for adrenal insufficiency and congenital adrenal hyperplasia. Other corticosteroids include budesonide and deficotinide. In another embodiment, the API can be an androgenic steroid, such as testosterone, methyltestosterone, oxymethylene, or fluoromethyltestosterone. In yet another embodiment, the API can be an estrogen, such as conjugated estrogen, esterified estrogen, piperazine estradiol sulfate, 17-β estradiol, 17-β estradiol valerate, estradiol valerate, mestriol, estrone, estriol, ethinylestradiol, or diethylstilbestrol. In another implementation, the API can be a progestin or progestogen, such as progesterone, 19-norprogesterone, norethindrone and its derivatives, melenprogesterone, chlormedroxyprogesterone, ethinylprogesterone, medroxyprogesterone and its derivatives, hydroxyprogesterone and its derivatives, diacetylnorethindrone, isethindrone, 17-α-hydroxyprogesterone, dydrogesterone, dimethinestrone, ethinylestradiol, norethindrone, norgestrel, norgestrel, drospirenone, etoposide, levonorgestrel, desogestrel, dimegestrol, prmegestrol, or megestrol acetate. It also covers 5-α-reductase inhibitors, which may include dutasteride and finasteride.

[0109] It also covers anti-inflammatory agents such as hydrocortisone, cortisone, dexamethasone, dexamethasone acetate, triamcinolone and other derivatives, fluocinolone, triamcinolone, methylhydroxysone, prednisolone, fluocinolone acetonide, prednisolone, halcinonide, methylprednisolone, fluocinolone acetonide, corticosteroids, peramisone, betamethasone and their derivatives.

[0110] In another implementation, the API can be an antipsychotic or a tricyclic antidepressant. For example, the API could be olanzapine (2-methyl-10-(4-methyl-1-piperazinyl)-4H-thieno-[2,3-b][1,5]benzo-diazepine), an antipsychotic used to treat schizophrenia and bipolar disorder. It is generally classified as an atypical antipsychotic, a new generation of antipsychotics. Its tablet form has been approved by the FDA under the brand name Zyprexa® for the treatment of schizophrenia and bipolar mania. The use of olanzapine as an antiemetic, in oral doses of 10 mg and 5 mg daily, is also being investigated, typically in combination with one or more other medications, for example, to treat nausea and vomiting following administration of the chemotherapy drug cisplatin. Other antipsychotic drug APIs covered in this disclosure include thiopropirazine, chlorpromazine, trifluprozine, mesoridazine, piperazine, thioridazine, acetaminophen, fluphenazine, perphenazine, trifluoperazine, cloprothixone, tevothixone, haloperidol, bromoperidol, loxapine, morinone, aripiprazole, lurasidone, quetiapine, cariprazine, ipilpirazine, olanzapine, ziprasidone, asenapine, risperidone, paliperidone, rumepiride, ipraridone, pimovaserin, and clozapine.

[0111] In yet another implementation, the API can be a Bruton's tyrosine kinase (BTK) inhibitor. BTK inhibitors are a class of drugs used to treat cancers caused by defective B cells, such as chronic lymphocytic leukemia, B-cell lymphoma, and Waldenström macroglobulinemia. For example, the API can be ibrutinib, acalabrutinib, pitotuchutinib, zanubrutinib, évorabutinib, teirabrutinib, and orelabrutinib.

[0112] Regardless of the specific API used, the amount of API contained in the binder-dispersed drug layer may be from about 1% to about 40% by weight, such as from about 2% to about 30% by weight, such as from about 3% to about 25% by weight, such as from about 3.5% to about 20% by weight, such as from about 4% to about 15% by weight, such as from about 4.5% to about 8% by weight, or any range between these ranges, based on the dry weight of the binder-dispersed drug layer.

[0113] b. Soluble polymers

[0114] Soluble polymers that can be used to form complexes of solid particulate APIs and soluble polymers may include polyvinylpyrrolidone (PVP or povidone), such as uncrosslinked PVP. Suitable soluble grades of PVP supplied by BASF may include the Kollidon® series K-17 (molecular weight 7,000-11,000; pH 4.64), K-25 (molecular weight 28,000-34,000; pH 4.00), K-30 (molecular weight 44,000-54,000; pH 4.10), and K-90 (molecular weight 1,000,000-1,500,000; pH 5.68). Other functional polymers may include Kollidon® VA64 (molecular weight range 45,000-70,000, pH 4.51) or other povidones and their copolymers supplied by different suppliers, such as Plasdone®. Other soluble polymers that may be used include cellulose, such as ethyl cellulose (Ethocel® or Aqualon®). Preferably, polymers such as Plasdone® (povidone / polyvinylpyrrolidone) or Kollidon® K-30 or K-30 LP and Kollidon® K-90 (soluble povidone / polyvinylpyrrolidone) have been found suitable for preparing these solid suspensions. Furthermore, Kollidon® K-12 (molecular weight range 2000-3000; pH 4.63) and Kollidon® K-12 PF have been found unsuitable for forming glassy particles that can be micronized, likely due to their low molecular weight. Other molecular weights, such as Kollidon® K-25, K-45, K-60 or K-120 (molecular weight 3,000,000), are believed to be suitable, making feasible production methods for the API: substrate suitable for producing micronizable glassy particles. Therefore, in some embodiments, when the soluble polymer is polyvinylpyrrolidone, polyvinylpyrrolidone can have a molecular weight greater than 3,000, such as about 7,000 to about 3,000,000 Daltons.

[0115] Regardless of the specific soluble polymer used, the amount of soluble polymer contained in the binder-dispersed drug layer, based on the dry weight of the binder-dispersed drug layer, can range from about 1.5% by weight to about 50% by weight, such as about 2% by weight to about 47.5% by weight, such as about 3% by weight to about 25% by weight, such as about 4.5% by weight to about 40% by weight, or any range between these ranges.

[0116] Furthermore, the ratio of the soluble polymer to the API in the final binder-dispersed drug layer can range from about 1.25:1 to about 20:1, such as about 1.5:1 to about 15:1, such as about 2:1 to about 10:1, such as about 4:1 to about 8:1, or any range between these ranges.

[0117] c. Process solvents used for the formation of API and API / soluble polymer solid particles

[0118] The first process solvent can be used to dissolve or solubilize the API and the soluble polymer to form a glassy film after solvent evaporation, which can then be micronized to form solid particulate API or a complex of the API and the polymer. In one embodiment, the first process solvent may include one or more polar aprotic solvents to maximize the solubility of the drug in the first solvent system and thus maximize its concentration.

[0119] Polar aprotic solvents are solvents that lack acid protons and are polar. Such solvents lack both hydroxyl and amino groups. These solvents do not act as proton donors in hydrogen bonding, but they can act as proton acceptors. Specific examples covered by this disclosure may include N-methyl-2-pyrrolidone (NMP), 2-pyrrolidone (2-pyrol®), dioxane, propylene carbonate, dimethyl sulfoxide (DMSO), dimethyl isosorbide, dimethylacetamide, ethyl acetate, or combinations thereof, all under the trademark Pharmasolve®. However, it should be understood that this disclosure also covers other polar aprotic solvents, including but not limited to isopropanol, ethyl acetate, acetone, acetonitrile, dichloromethane, dimethylformamide, DMPU, and tetrahydrofuran.

[0120] Regardless of the specific polar aprotic solvent or combination of polar aprotic solvents used, the total amount of polar aprotic solvent contained in the micronized solid particles containing API can be detectable and is less than the ICH Q3C Impurities: Residual Solvents Guideline. For NMP, this is equivalent to less than about 530 ppm, or less than about 0.053% by weight, based on the dry weight of the solid particles, such as less than about 390 ppm, or less than about 0.039% by weight, where NMP is considered a process solvent. However, it should be understood that such solvents are introduced in larger weight percentages prior to any evaporation or drying to form a glassy film, which is then micronized to form solid particles of API or API and polymer complexes.

[0121] d. Insoluble excipients

[0122] The binder-dispersed drug layer of the transdermal drug delivery system of this disclosure may also include an insoluble excipient as a substrate for forming the binder-dispersed drug layer. In one embodiment, the insoluble excipient may be micronized cross-linked polyvinylpyrrolidone (PVP), such as a cross-linked homopolymer of N-vinyl-2-pyrrolidone. In a specific embodiment, the cross-linked PVP is in the form of a water-insoluble powder. Such cross-linked PVPs are commercially available under the name Kollidon® and are supplied by BASF. A specific example of the cross-linked PVP covered for use in this disclosure is Kollidon® CL-M. Other cross-linked PVPs that may be used include Kollidon® CL-SF and CL-F, as well as Ashland Polyplasdone®. Other insoluble excipients covered include cellulose derivatives such as ethyl cellulose, cross-linked carboxymethyl cellulose, carboxymethyl cellulose, or starch, and cross-linked acrylic polymers such as carbomer, minerals or clays such as silica, Polargel®, bentonite, kaolin, or silicates.

[0123] Furthermore, the insoluble excipients can be micronized, but this is not required, and their average particle size can range from about 1 micrometer to about 40 micrometers, such as about 2 micrometers to about 30 micrometers, such as about 3 micrometers to about 10 micrometers. Additionally, in one specific embodiment, more than 90% of the particles used may have a particle size of less than about 15 micrometers. Therefore, the cross-linked PVPs used in the binder-dispersed drug matrix layers covered in this disclosure have a smaller particle size than typical cross-linked PVPs, which can have particle sizes up to 150 micrometers. Without wishing to be limited by any particular theory, the inventors have discovered that stable polymer blends can be formed using insoluble cross-linked PVPs to form binder-dispersed drug layers, wherein the aforementioned solid particle APIs or API-polymer complexes remain in a homogeneous suspension with minimal sedimentation because the insoluble excipients help maintain the homogeneity of the suspended particles in a substantially liquid composition. This, in turn, enables the formation of a homogeneous dispersion of solid particle APIs in the binder-dispersed drug layer, allowing transdermal drug delivery systems to deliver APIs through the skin in a controlled manner.

[0124] Based on the dry weight of the binder-dispersed drug layer, the amount of insoluble excipients contained in the binder-dispersed drug layer can range from about 1% to about 15% by weight, such as about 2% to about 10% by weight, such as about 3% to about 9% by weight, such as about 4% to about 8% by weight, or any range between these ranges.

[0125] e. Process solvents used to form binder-dispersed drug layers

[0126] The second process solvent system can be used to form a binder-dispersed drug layer. Any suitable solvent can be used as long as the second process solvent system does not dissolve or significantly damage the solid particle API or API:substrate. The API:polymer complex cannot be dissolved in it because the solid particles must remain insoluble and ultimately be uniformly suspended within the resulting binder-dispersed transdermal drug delivery system.

[0127] In one embodiment, the second process solvent system is typically different from the first process solvent, wherein the drug or API does not necessarily need to be significantly soluble in the second solvent system. The solvents covered for preparing blends of binder-dispersible drug matrices may include volatile solvents such as esters, alkanes, polysiloxanes, cyclic compounds, which may include, but are not limited to, heptane, hexane, pentane, ethyl acetate, propyl acetate, butyl acetate, cyclohexane, volatile polysiloxane fluids, and toluene. In some cases, polar aprotic solvents or alcohols may be used, but only in the absence of polyvinylpyrrolidone:API particle complexes, because PVP is soluble in alcohols or polar aprotic solvents such as, but not limited to, NMP, DMSO, ethanol, or isopropanol.

[0128] Regardless of the specific solvent or combination of solvents used, the total amount of volatile solvents contained in the resulting binder-dispersed drug layer in a transdermal drug delivery system can be detectable and is less than the amount specified in the ICH Q3C Guideline on Impurities: Residual Solvents. For most Class 3 solvents considered process solvents, the solvent is typically present in amounts less than 5000 ppm or less than 0.5% by weight, based on the dry weight of the binder-dispersed drug layer. However, it should be understood that such solvents are introduced at larger weight levels to form excipient formulations prior to any evaporation or drying. The intention is that if any volatile process solvent is added to the system, the solvent will comply with the requirements of the ICH Q3C Guideline document.

[0129] f. Adhesive polymer

[0130] The adhesive-dispersed drug layer of the transdermal drug delivery system disclosed herein further comprises one or more suitable pressure-sensitive adhesives (PSAs). The adhesive polymer can be made of a variety of materials, including plastics, polymers, pressure-sensitive adhesives, self-adhesive systems, or other excipients that may be needed to obtain pressure-sensitive properties. Basic adhesive systems selected from polyacrylic acid, polysiloxanes, polyisobutylene, rubber, and combinations thereof are disclosed, obtained through physical blending or copolymerization. These materials can be obtained from solvent-based, aqueous, physical mixtures, extrudates, co-extrudates, hot melts, or otherwise formed as polymeric or unpolymerized materials.

[0131] In one embodiment, the PSA can be an acrylic polymer. Useful acrylic polymers include various homopolymers, copolymers, terpolymers, etc., of acrylic acid and its derivatives, which are crosslinked, crosslinkable, non-crosslinkable, non-crosslinkable, grafted, block, cured, and non-cured pressure-sensitive adhesives (PSAs). These acrylic polymers include copolymers of alkyl acrylates or alkyl methacrylates. Polyacrylates include acrylic acid, methacrylic acid, and their derivatives, but are not limited to methyl acrylate, methyl methacrylate, ethyl acrylate, ethyl methacrylate, n-butyl acrylate, n-butyl methacrylate, hexyl acrylate, 2-ethylbutyl acrylate, isooctyl acrylate, 2-ethylhexyl acrylate, 2-ethylhexyl methacrylate, decyl acrylate, decyl methacrylate, dodecyl acrylate, dodecyl methacrylate, tridecyl acrylate, tridecyl methacrylate, vinyl acetate, 2-hydroxyethyl acrylate, glycidyl methacrylate, or octylacrylamide. Acrylic polymers can be functional substances having a certain amount of hydroxyl or carboxyl moieties or combinations thereof, non-functional substances without functional moieties, or non-reactive substances with acrylamides that are less reactive than hydroxyl or carboxyl moieties, such as methyl, ethyl, propyl, or butyl-terminated acrylamides. Exemplary acrylic materials include Evonik's Plastoid B® or Henkel Corporation's PSA acrylic acid, including but not limited to one or more of the following: Duro-Tak® 87-900A, Duro-Tak 87-9301, Duro-Tak® 87-4098, Duro-Tak® 387-2510 / 87-2510, Duro-Tak® 387-2287 / 87-2287, Duro-Tak® 87-4287, Duro-Tak® 387-2516 / 87-2516, Duro-Tak® 87-2074, Duro-Tak® 87-235A, Duro-Tak 387-2353 / 87-2353, Gelva® GMS 9073, Duro-Tak® 87-2852, Duro-Tak® Duro-Tak® 387-2051 / 87-2051, Duro-Tak® 387-2052 / 87-2052, Duro-Tak® 387-2054 / 87-2054, Duro-Tak® 87-2194, or Duro-Tak® 87-2196. It should also be understood that this disclosure incorporates known and unknown naming conventions for the disclosed monomers.

[0132] In one specific embodiment, the inventors have found that using PSA comprising acrylate copolymers that do not have -COOH or -OH functional groups or portions helps improve the permeability of APIs contained in binder-dispersed drug layers. Furthermore, it has been found that acrylate copolymers with solid content ranging from about 30% to about 55%, such as about 35% to about 50%, and such as about 36% to about 45%, also help improve the solubility and permeability of immunomodulators. Additionally, acrylate copolymers with viscosities less than about 6500 centipoise, such as about 2000 centipoise to about 5000 centipoise, and such as about 2500 centipoise to about 4500 centipoise, can also help improve the solubility and permeability of APIs, wherein viscosity affects the loading capacity of components in polymer blends used to form binder-dispersed drug matrix layers. Furthermore, acrylate copolymers comprising vinyl acetate may also be beneficial.

[0133] Specific examples include Duro-Tak® 87-9301 (non-reactive amine, 36.5% solids), Duro-Tak® 387-2516 / 87-2516 (vinyl acetate; -OH functional group; 41.5% solids; viscosity 4350 centipoise), Duro-Tak® 387-2052 / 87-2052 (vinyl acetate; -COOH functional group, 47.5% solids; viscosity 2750 centipoise), or Duro-Tak® 87-4098 (vinyl acetate; 38.5% solids; viscosity 6500 centipoise).

[0134] In another embodiment, the PSA may comprise a polysiloxane. Suitable polysiloxane adhesives include pressure-sensitive adhesives prepared from a siloxane polymer and a resin. The polymer-to-resin ratio can be varied to achieve different levels of tack. Specific examples of commercially available and useful polysiloxane adhesives include the standard DuPont® Liveo® BIO-PSA® series (7-4400, 7-4500, and 7-4600 series) manufactured by DuPont and the amine-compatible (terminated) DuPont® Liveo® BIO-PSA® series (7-4100, 7-4200, and 7-4300 series). Preferred adhesives include well-known BIO-PSA® 7-4101, 7-4102, 7-4201, 7-4202, 7-4301, 7-4302, 7-4401, 7-4402, 7-4501, 7-4502, 7-4601, and 7-4602 in LIVEO® specifications. Soft elastomer polysiloxane adhesives include DuPont® Liveo® soft skin adhesives, such as MG7-9700 kit (A&B), MG7-9800 kit (A&B), MG7-9850 kit (A&B), and MG7-9900 kit (A&B).

[0135] In another embodiment, the PSA may include polyisobutylene. Suitable polyisobutylene adhesives are pressure-sensitive and have suitable tack. The polyisobutylene may include high-molecular-weight and medium-molecular-weight polyisobutylene, polybutene, and mineral oil mixtures. Specifically, high-molecular-weight polyisobutylene is that which has a molecular weight of at least about 425,000. Medium-molecular-weight polyisobutylene is that which has a molecular weight of at least 40,000 but less than about 425,000. Low-molecular-weight polyisobutylene is that which has a molecular weight of at least 100 but less than about 40,000. Specific examples of commercially available and useful polyisobutylene adhesives include Oppanol® high-molecular-weight N-grade 50, 50SF, 80, 100, and 150 manufactured by BASF, and Oppanol® medium-molecular-weight B-grade 10N, 10SFN, 11SFN, 12SFN, 12N, 13SFN, 14SFN, 15SFN, and 15N. Specific examples of polybutene are available commercially from Soltex as polybutene of various molecular weights, and from Ineos as Indopol and Panalane of various molecular weights. Specific examples of commercially available, useful adhesives formulated with polyisobutylene include Henkel Duro-Tak® 87-6908.

[0136] This disclosure also covers other pressure-sensitive adhesives obtained from rubber block copolymers, such as styrene-isoprene-styrene (SIS) or styrene-butadiene-styrene (SBS) based adhesives.

[0137] Regardless of the specific PSA used, the pressure-sensitive adhesive may be present in amounts ranging from about 1% to about 80% by weight, such as about 20% to about 75% by weight, such as about 25% to about 70% by weight, or any range between these ranges, based on the dry weight of the adhesive-dispersed drug layer.

[0138] Furthermore, it should be understood that other polymers can be combined with plasticizers as adhesive polymers. For example, other polymers that can be used may include ethylene-vinyl acetate copolymers, such as Celanese® EVA; polyvinylpyrrolidone, such as BASF's Kollidons™ or Ashland's Plasdones®; cellulose, such as Ashland's Aqualon™, Benecel™, or Klucel™, or combinations thereof.

[0139] g. Skin penetration and solubility enhancer

[0140] The adhesive-dispersed drug layer of the transdermal drug delivery system disclosed herein may also contain one or more suitable surfactants (e.g., nonionic surfactants), plasticizers, wetting agents, or combinations thereof, which may act as skin permeability enhancers to improve the permeability of APIs through the skin during use of the transdermal drug delivery system.

[0141] In some embodiments, the skin penetration enhancer may include one or more of the following: sulfoxides and similar chemicals, such as, but not limited to, dimethyl sulfoxide, dimethylacetamide, dimethylformamide, dimethyl sulfoxide, and dimethyl isosorbide; azones and pyrrolidones, such as, but not limited to, N-methyl-2-pyrrolidone, 2-pyrrolidone, N-(2-hydroxyethyl)-2-pyrrolidone (HEP), N-octylpyrrolidone (NOP), and N-ethylpyrrolidone (NEP); esters and fatty acid esters, such as, but not limited to, propylene glycol monolaurate, butyl acetate, ethyl acetate, and nutmeg. Isopropyl palmitate, ethyl oleate, oleic acid ester, methyl acetate, decyl oleate, propylene glycol monodecanoate, propylene glycol monolaurate, diethylene glycol monoethyl ether, glyceryl monooleate, glyceryl monolaurate, lauryl laurate, lauryl lactate, and others; fatty acids (C8-C26 fatty acids), such as, but not limited to, caprylic acid, caprylic acid, lauric acid, oleic acid, myristic acid, linoleic acid, stearic acid, palmitic acid, stearic acid, arachidic acid, behenic acid, ceric acid, ceric acid, myristoleic acid, palmitoleic acid, hexadecenoic acid, trans oleic acid, isoleic acid, trans linoleic acid (lenoelaidic acid) (acids), α-linolenic acid, arachidonic acid, eicosapentaenoic acid, erucic acid, docosahexaenoic acid and others; fatty alcohols (C4 to C24 fatty alcohols), such as but not limited to tert-butanol, tert-pentanol, 3-methyl-3-pentanol, heptanol, octanol, nonanol, decanol, undecaneol, tridecaneol, pentadecaneol, cetyl alcohol, palm oil alcohol, heptadecanol, octadecaneol, oleyl alcohol, lauryl alcohol, myristyl alcohol, nonadecaneol, eicosanol, docosanol, mustard alcohol, creosyl alcohol, wax alcohol, heptadecanol, octadecaneol, nonadecaneol, triadecaneol, triadecanol, tritetradecaneol, tritetradecaneol and others. He; and glycols, such as but not limited to nathanol, dodecyl alcohol, propylene glycol, dipropylene glycol, tripropylene glycol, polyethylene glycol (molecular weight 200 to 20000), glycerol and other ether alcohols, such as but not limited to diethylene glycol monoethyl ether; urea, triglycerides such as but not limited to medium-chain triglycerides (MCT), triacetin, triolein; polyoxyethylene fatty alcohol ethers, triethyl citrate, polyoxyethylene fatty acid esters, fatty alcohol esters, essential oils, hydramol, surfactant enhancers, such as but not limited to nonionic surfactants, such as nonionic surfactants of fatty alcohols, their derivatives or combinations thereof.For example, polyoxyethylene or alcohol ethoxylated surfactants based on lauryl alcohol, oleyl alcohol, or cetyl alcohol, such as the Brij L, LT, C, CS, O, or S series, such as, but not limited to, S2, LT3, O2, O3, O5, LT4, L4, CS6, O10, S10, CS12, L9, S20, O20, S721, CS20, CS25, LT23, or L23, wherein the lauryl alcohol (L) series has a C12 alkyl chain, the synthetic lauryl alcohol (LT) series has a C12-13 alkyl chain (e.g., C12-13 alkanol polyether-3 or C12-C12 alkanol polyether-4), the cetyl alcohol (C) series has a C16 alkyl chain, the cetearyl alcohol (CS) series has a C16-18 alkyl chain, the stearyl alcohol (S) series has a C18 alkyl chain, and the oleyl alcohol (O) series has a C18:1 alkyl chain. Furthermore, each series of letters or the numbers following them indicates the molar number of EO present, representing the ethoxylation level. Specifically, nonionic surfactants with HLB values ​​less than about 12, such as HLB values ​​less than about 10, and HLB values ​​from about 5 to about 10, are found to be highly advantageous, including but not limited to O3, O5, L4, S2, LT3, LT4, C2, and / or CS6. Meanwhile, nonionic surfactants with HLB values ​​higher than 12, such as O10 and O20 with HLB values ​​of 12.4 and 15.5 respectively, are not advantageous in the specific formulations of this disclosure in terms of improving API permeability. Additionally, this disclosure covers surfactants such as sodium dodecyl sulfate, Tween, polysorbates; terpenes, terpenoids, and all penetration or permeation enhancers mentioned in "Percutaneous Penetration Enhancers" (Eric W. Smith, Howard I. Maibach, 2005. Nov, CRC press).

[0142] For example, nonionic surfactants that can be used include oleyl alcohol polyethers containing one or more oleyl alcohols and lauryl alcohol polyethers containing one or more lauryl alcohols. For example, skin penetration enhancers can be polyethylene glycol dodecyl ethers (Brij L4 or lauryl alcohol polyether-4). Without being limited to any particular theory, nonionic surfactants are believed to contribute to increased flux and the system's ability to overcome flux decline barriers 24 hours after application to the skin.

[0143] Other nonionic surfactants covered are ABA-type copolymers of poly(ethylene oxide) (PEO=A) and poly(propylene oxide) (PPO=B), which may be called poloxamers (e.g., P181 (HLB 29), P188 (HLB>24), P338 (HLB>24), P407 (HLB 18-23) or combinations thereof, commercially available as Kolliphor®, Pluronic®, or Lutrol®), or any other suitable surfactant having an HLB value greater than about 18, such as about 18 to about 32, such as about 18 to about 30, which can act as a solubility enhancer when used in combination with a nonionic surfactant having an HLB value less than about 12.

[0144] Regardless of the specific skin penetration enhancer used, the skin penetration enhancer contained in the polymer blend used to form the binder-dispersed drug layer of the transdermal drug delivery system can be present in amounts ranging from about 1% to about 40% by weight, such as from about 7.5% to about 35% by weight, such as from about 10% to about 30% by weight, or any range between these ranges, based on the dry weight of the binder-dispersed drug layer. In one specific embodiment, the skin penetration enhancer may include about 2.5% to about 30% by weight, such as from about 5% to about 22.5% by weight, such as from about 7.5% to about 25% by weight of a nonionic surfactant, wherein the use of such a skin penetration enhancer has been found to result in transdermal drug delivery systems exhibiting significantly improved API onset and sustained delivery.

[0145] h. Other auxiliary materials

[0146] The adhesive-dispersible drug layer may also contain gelling agents and / or thickeners and / or suspending agents and / or polymers and / or adhesive polymers and / or pressure-sensitive adhesive polymers known to those skilled in the art, which may be used alone or in combination, and are not limited to the following: natural polymers, polysaccharides and their derivatives such as, but not limited to, agar, alginic acid and its derivatives, cassia gum, collagen, gelatin, gellan gum, guar gum, pectin, potassium or sodium carrageenan, tragacanth gum, xanthan gum, copal gum, chitosan, resins, etc.; semi-synthetic polymers and their derivatives such as, but not limited to, cellulose and its derivatives (methylcellulose, ethylcellulose, carboxymethylcellulose, hydroxypropylcellulose, hydroxypropyl methylcellulose, hydroxypropyl methylcellulose acetate succinate, etc.); and synthetic polymers and their derivatives such as, but not limited to, carboxyvinyl polymers or carbomers (Carbopol 940, Carbopol 934, Carbopol 971p). NF), polyethylene and its copolymers, clays such as, but not limited to, silicates, bentonite, silica, polyvinyl alcohol, acrylic polymers (Eudragit), acrylates, polyacrylate copolymers, polyacrylamide, polyvinylpyrrolidone homopolymers and polyvinylpyrrolidone copolymers such as, but not limited to, PVP, Kollidon 30, poloxamer, isobutylene, ethylene vinyl acetate copolymers, natural rubber, synthetic rubber, hot melt adhesives, styrene-butadiene copolymers, bentonite, all water-soluble and / or organic solvent-swellable polymers, etc. In one exemplary embodiment, the formulations of this disclosure may comprise gelling agents and / or thickeners and / or suspending agents and / or polymers and / or adhesive polymers and / or pressure-sensitive adhesive polymers.

[0147] The adhesive-dispersible drug layer may also contain plasticizers known to those skilled in the art, which may be used alone or in combination, and are not limited to, glycerol and its esters, phosphate esters, glycol derivatives, sugar alcohols, sebacic acid esters, citrate esters, tartrate esters, adipate esters, phthalates, triacetin, oleate esters, and all plasticizers that can be used in transdermal drug delivery systems as mentioned in the Handbook of Plastics (George Wypych, 2004, Chem Tec Publishing).

[0148] The adhesive-dispersible pharmaceutical layer may further comprise solubilizers, additional surfactants, emulsifiers, dispersants, and similar compounds or chemicals known to those skilled in the art, used alone or in combination, including but not limited to, polysorbates such as, but not limited to, polysorbate 20, polysorbate 40, polysorbate 60, polysorbate 80, etc.; span, such as, but not limited to, span 80, span 20, etc.; surfactants such as anionic, cationic, nonionic, and amphoteric, propylene glycol monocaprylate type I, propylene glycol monocaprylate type II, propylene glycol dicaprylate, medium-chain triglycerides, propylene glycol monolaurate type II, linoleyl polyoxyethylene-6-glycerol, oleyl polyoxyethylene-6-glycerol, lauryl polyoxyethylene-6-glycerol, polyglycerol-3-dioleate, diethylene glycol monoethyl ether, propylene glycol monolaurate type I, polyglycerol-3-dioleate, capryloyl hexanoyl polyoxyethylene-8-glycerol, cyclodextrins, and others.

[0149] The binder-dispersible drug layer may further contain excipients or chemicals known to those skilled in the art, which may be used alone or in combination, and are not limited to, cholecaciferol, vitamin D3, vitamin B12, cyanocobalamin, vitamin E, tocopherol, tocopheryl acetate, tocopherol polyethylene glycol succinate (TPGS), polyethylene glycol (PEG), hyaluronic acid, α-hydroxy acids or their derivatives, BHA, BHT, panthenol, propyl gallate, ascorbyl palmitate, sugars, sugar alcohols, amino acids, polyols, phytanetriol, pantothenic acid, urea, and other antioxidants or protectants and / or atypical wetting agents.

[0150] II. Backing layer

[0151] Refer again Figure 1In addition to the adhesive-dispersed drug layer 110, the transdermal drug delivery system 100 of this disclosure may include a backing layer 120 forming the outer surface 140 of the transdermal drug delivery system 100. The backing layer 120 may be inherently closed and may protect the polymer layer (and any other layers present) from environmental influences and prevent drug loss and / or release of other components into the environment during use. Suitable materials for use as the backing layer are well known in the art and may include films of polyester, polyethylene, polypropylene, vinyl acetate resin, ethylene / vinyl acetate copolymer, ethylene / vinyl alcohol copolymer, polyvinyl chloride, polyurethane, cotton, (various) cellulose, etc., in partial or multilayer laminated or co-extruded form, and may include metal foil, aluminum vapor-coated plastics, nonwoven fabrics, cloths, and commercially available laminates. Typical backing materials range in thickness from 2 to 1000 micrometers. For example, 3M's Scotchpak® 1012 or 9732 (polyester film with a heat-sealed ethylene vinyl acetate copolymer layer), 9723 (a laminate of polyethylene and polyester), 9754 (a polyester film backing laminate), or CoTran® 9720 (polyethylene film), Japan Vilene's polyester films such as EH-1212, or nonwoven polyesters such as EW2080S, EW-9100, EW-9050, EW-2500N, etc., can be used in the transdermal drug delivery system described herein. Dow® backing films such as Dow® BLF 2050 (a multilayer backing consisting of an ethylene vinyl acetate layer and an inner SARAN® layer), and Kuraray's ethylene-vinyl alcohol based films such as EF-F, EF-E, EF-XL, VM-XL, and HF-ME are also available.

[0152] III. Release liner

[0153] Still refer to Figure 1In addition to the adhesive-dispersible drug layer 110 and the backing layer 120, the transdermal drug delivery system 100 of this disclosure also includes a release liner 130 disposed on the skin-contacting surface 150 of the transdermal drug delivery system, which protects the adhesive-dispersible drug layer 110 of the transdermal drug delivery system 100 until it is ready to be applied to the patient's skin. Once the transdermal drug delivery system 100 is applied to the patient's skin with its skin-contacting surface 150, the release liner 130 can be removed and discarded. Materials suitable for use as release liner are well known in the art, such as polymers or fluids of polysiloxanes or fluoropolysiloxanes or fluorocarbons coated, cast, or cured onto a substrate, such as polyester, polyethylene (LDPE or HDPE), styrene, and polyvinyl chloride (PVC) films, which may include, but are not limited to, commercially available products from Dow Corning Corporation, designated as Bio-Release® liners and Syl-off® 7610, Loparex's PET release liners, which are polyester films coated with polysiloxanes, Japan Vilene's polyester release liners coated with polysiloxanes, and Saint Gobain's 4130, 4140, 7819, 7748, 7754, 8005, 8310, 6113, 6113A, 7015, 6024, 8312, 8312N, or 9011 gaskets, and 3M's 1020, 1022, 9741, 9744, 9748, 9749, and 9755 Scotchpak® gaskets, are polyester films coated with fluoropolymers.

[0154] IV. Coverage system

[0155] In addition to the adhesive-dispersible drug layer 110, backing layer 120, and release liner 130, the transdermal drug delivery system 100 of this disclosure may also include an optional or inherent covering system 160 to ensure adhesion and fixation of the transdermal drug delivery system to the patient's skin throughout the intended wear period. The covering system 160 may be an enclosed or non-enclosed material made of cloth, fabric, paper, foam, or plastic, combined with an adhesive layer for skin contact and adhesion. Suitable materials for use as a covering system are known in the art and include, but are not limited to, commercially available medical tape products such as 3M's Cotran® 1523, 2480, 2484, 2476P, 9693, 9695, 9699, 9865, 9907T, or 9952. The covering system may be tailored in a manner that ensures compatibility with the adhesive-dispersible drug system, mitigates migration or cold flow, and ensures sufficient interlayer adhesion to the adhesive-dispersible drug system and, overall, proper adhesion to the patient during the intended wear period. In most cases, the formulation of adhesive-dispersed drug layers inhibits their ability to act alone to adhere to the patient during the intended wear period. In such cases, the inventors have discovered that the covering system can serve to adhere the system to the patient, reduce the likelihood of cold flow, and ensure near 100% adhesion of the patch to the patient during wear, thus ensuring consistent and therapeutic delivery of TDS.

[0156] V. Methods for preparing transdermal drug delivery systems

[0157] Generally, the binder-dispersed drug layer of this disclosure is prepared by combining components in a specific order, enabling the formation of a transdermal drug delivery system in which solid particulate APIs or API-polymer complexes are uniformly distributed within the binder-dispersed drug layer, exhibiting improved API permeability through the skin. (See also...) Figure 2This invention discloses a method 200 for preparing a formulation for use in a transdermal drug delivery system according to the present disclosure. First, in step 201, a blending step, an API is added to a first process solvent to form a solution, wherein the API is solubilized or dissolved in the solvent to form a true solution. Next, in step 202, also a blending step and which may be omitted entirely or performed before or with step 201, a soluble polymer is added to the solution containing the first process solvent and the API, wherein the polymer is also solubilized or dissolved in the solvent. Next, in step 203, a drying step, the solution is heated or dried to evaporate the first process solvent, leaving a clear, glassy membrane containing the API or the API and a soluble polymer. Next, in step 204, the membrane is micronized to form solid particles of the API or the API and the polymer; this may be referred to as a micronization step. Then, in step 205, a blending step, the particles are combined with other components, such as binder polymers, nonionic surfactants, a second process solvent, insoluble excipients, etc. Subsequently, in step 206, the above components are blended or mixed to homogenize and form a suspension. Then, in step 207, the resulting adhesive-dispersed drug layer can be coated onto one surface of a release liner or backing layer, after which any organic solvents present can be evaporated in step 608. Then, in step 209, the opposing surfaces of the adhesive-dispersed drug layer can be applied to (e.g., laminated to) the backing layer or release liner. Subsequently, individual transdermal drug delivery systems, with or without an inherent covering system that ensures adhesion to the patient, can be die-cut from a large sheet of molded transdermal drug delivery system, wherein the inherent covering system does not carry the drug and may be nonwoven / non-occlusive or occlusive in nature, to form a finished drug product contained in a flat, heat-sealed bag.

[0158] The present disclosure can be better understood by referring to the following embodiments.

[0159] Implementation Examples Overview

[0160] A feasibility study was conducted to understand solid active pharmaceutical ingredients as a viable alternative to solubilized API platforms used in binder-dispersed transdermal drug delivery systems.

[0161] For in vitro permeability testing, the transdermal formulations prepared in the following examples were subjected to flux (in vitro permeability) testing using a Strat-M® synthetic membrane as follows. The Strat-M® synthetic membrane was used according to Millipore-Sigma's instructions for use. The patch was die-cut to a diameter of 5 / 16 inch (~0.5 cm). 2The patch is applied to the skin using a cover layer to ensure it is firmly attached. The receiving medium is standard physiological saline (0.9% NaCl in DI solution) or a fixed concentration (1%-5%) of povidone in DI solution. The sample volume is 5 mL, and the Franz cell volume is 5 mL. Sampling intervals are within the expected wear period, from 0 hours to a maximum of 168 hours. Sampling time points are typically 8 hours, 24 hours, 48 ​​hours, 72 hours, 96 hours, 120 hours, 144 hours, and 168 hours. The actual patch size is 0.5 cm. 2 The effective flux area is approximately 0.6 cm². 2 The aliquots of each individual API obtained were analyzed by HPLC. Typically, each formulation was repeated 3-5 times to ensure sufficient statistical significance for each study.

[0162] Example 1

[0163] In Example 1, lenalidomide was used as the API, and an amorphous form of lenalidomide:polyvinylpyrrolidone in a 1:1 ratio from Dr. Reddy's Laboratory was formulated. The resulting micronized powder was added to a solid particulate complex in a binder-dispersed pharmaceutical formulation.

[0164] Example 2

[0165] In Example 2, dexamethasone was used as the API, and the feasibility of using silica instead of polyvinylpyrrolidone as the substrate was considered. It was found that although silica is claimed to be an amorphous carrier for the drug, the resulting solution of dexamethasone, silica, and an organic solvent (DMSO) could not dissolve either dexamethasone or silica. The silica particles were gel-like, but solid particles were observed. The resulting blend was dried in a convection oven. A powder was obtained, and this powder was considered to impart amorphous properties to the API. However, adding this amount of silica to the binder would be detrimental to the binder's properties, to the point that a 5% drug loading would require at least 5% silica to be added to the formulation, and even more silica would be added if the API to silica concentration ratio was less than 1:1. For example, when a 5% drug was loaded into a binder-dispersed drug, a 10% API silica formulation would require 45% silica to be added to the binder formulation. Based on this situation and previous knowledge about the presence of silica in transdermal adhesives, it is considered that polymers are preferred as API matrices for forming solid particulate complexes compared to silica.

[0166] Example 3

[0167] In Example 3, it was found that specific ratios of dexamethasone to Kollidon 30 (soluble polyvinylpyrrolidone) were suitable for use with standard process solvents (ethyl acetate and isopropanol). Solutions containing the polymer and API at ratios of 8:1, 6.7:1, 5:1, 4:1, and up to 1:1 were prepared to evaluate the solubility of dexamethasone in solution. A 5:1 ratio, or 20% by weight of dexamethasone (DEX) to povidone (PVP), was found to dissolve the drug in solution, while a 4:1 ratio, or 25% by weight of DEX to PVP, was slightly soluble, showing signs of turbidity and undissolved dexamethasone. A 1:1 ratio, or 50% by weight of DEX to PVP, resulted in an insoluble suspension of DEX in the solubilized PVP. The resulting mixtures were then dried, and the crystallinity of the dried film was evaluated. Surprisingly, Kollidon 30 was found to maintain the solubility of dexamethasone within the dried membrane, without the presence of the organic solvents required for solubilizing both DEX and PVP. In the absence of process solvents, DEX and PVP did not solubilize each other in their presence. Membranes with 12.5% ​​DEX (8:1), 15% DEX (6.7:1), and 20% DEX (5:1) were crystal-free. Crystals as microdispersions of DEX were present throughout the dried DEX:PVP membrane at 25% DEX (4:1), as were those at 50% DEX (1:1). All membranes were brittle and capable of particle size reduction by physical / mechanical means. The 8:1 to 5:1 ratios were clear, slightly yellowish, and transparent. All membranes were micronized and sieved to a particle size of less than 150 micrometers for processing.

[0168] Example 4

[0169] Example 4 outlines the development of a stable solid suspension of dexamethasone:PVP particles in binder-dispersed pharmaceutical formulations, used as a comparative example, and produced to prepare supersaturated binder-dispersed pharmaceutical systems to achieve enhanced concentration gradients, thereby maintaining performance properties such as permeability, chemical stability (e.g., protection against hydrolysis or oxidation), and physical stability such as reduced or even prevented drug migration and binder cold flow. Since binder-dispersed pharmaceuticals are a primary focus of formulation strategies, this increases potential delivery challenges and potential stability issues. The solid composition exhibits improved stability, reduced cold flow, and a reduction in low molecular weight entities migrating away from the active sites of the transdermal system. Table 4 summarizes various components of formulations that utilize insoluble excipients (crosslinked povidone) instead of the soluble polymers covered by this disclosure to form molecular solid suspensions in situ.

[0170] Table 4: In-situ formation of molecular solid suspensions when dexamethasone in its dissolved state is added.

[0171]

[0172] refer to Figure 3-4 , Figure 3 The corresponding average flux of the resulting molecular solid suspension containing API and insoluble excipients is presented. Figure 4 The corresponding cumulative permeation amounts of the resulting molecular solid suspensions containing API and insoluble excipients are presented to illustrate the development of a feasible dexamethasone formulation for comparison with the concepts described in this disclosure. API, dexamethasone, is added to the system either in a dissolved state to form a molecular solid suspension, as in-situ formed suspended particles, or as a micronized powder raw material obtained from a supplier, without further processing to alter the state or composition of the raw material dexamethasone. It can be seen that, despite the drastically different methods of drug addition, both the molecular solid suspension (11-171-3) and the suspended raw material dexamethasone (11-171-4) exhibit similar delivery profiles and delivery rates from the same binder-dispersed pharmaceutical composition. These differences are not statistically significant.

[0173] Example 5

[0174] Next, in Example 5, Tables 5A and 5B present an embodiment of this disclosure relating to the preparation of solid particles of dexamethasone and soluble povidone, which are micronized glassy particles, as evidenced by the lack of birefringence under polarized light microscopy. The preparation of DEX:PVP at a specific ratio surprisingly showed improved performance, contrary to the methods known and taught in the prior art for povidone. Maximizing PVP is not optimal; in this invention, maximizing PVP to ensure the solubility of the API in water was found to be most surprising.

[0175] Table 5A: Dexamethasone: Polyvinylpyrrolidone as solid particles (% dry weight)

[0176]

[0177] Table 5B: Dexamethasone: Polyvinylpyrrolidone as solid particles in TDS

[0178]

[0179] Table 6 also presents comparative formulations evaluating the efficacy of solid particles prepared as described in Table 5A above. Table 6 presents physical mixtures, rather than dissolving the drug and polymer to form pre-prepared solid particles, micronizing them, and adding them to a binder-dispersed pharmaceutical formulation; instead, Table 6 includes physical mixtures of solid raw materials added and suspended in a binder-dispersed pharmaceutical system.

[0180] Table 6: Dexamethasone and polyvinylpyrrolidone added separately as raw materials

[0181]

[0182] refer to Figure 5-6 , Figure 5 The corresponding average throughput for various samples is presented. Figure 6 The cumulative permeation amounts of various samples are presented, with an increase in the amount of PVP. Therefore, the ratio of PVP to API was increased for the purpose of preparing solid particles. The increased presence of PVP enhances the performance characteristics of the transdermal delivery system, such as the permeation rate, as shown.

[0183] Next, refer to Figure 7-8 , Figure 7 The corresponding average flux was presented. Figure 8 The cumulative permeation was shown, with increased differences observed in optimized solid particles compared to simply amorphous 1:1 ratios of DEX:PVP or physical mixtures and suspensions. These figures support the claim that optimizing the DEX:PVP ratio to form transparent, clear glass or glassy, ​​rigid, and brittle membranes, which can reduce particle size mechanically or physically, yields micronized glass or glassy particles for inclusion in transdermal delivery systems; achieving superior flux performance compared to other formulations with equivalent drug loading, all containing 5% dexamethasone in different states.

[0184] Example 6

[0185] Next, in Example 6, studies were conducted to understand the solubility of various APIs in a variety of organic solvents and excipients commonly used in pharmaceutical API products, and particularly in transdermal and topical formulations. A key aspect of the solvent system is the solubilization of the API in the presence of a soluble polymer to form a true solution. These solvents should be inherently volatile at elevated temperatures during the curing process to meet the ICH residual solvent limit for the residual solvent after processing. The solvent system should be designed such that the solubilized drug is obtained at a concentration of about 10% to about 50% by weight of the solvent system.

[0186] The formulation strategy involves preparing a single-layer or monolithic adhesive-dispersed drug layer coated between a backing layer and a disposable release liner. Unexpectedly, incorporating solid-particle APIs and / or API:substrate complexes as a suspension of solid particles in an adhesive-dispersed drug within the transdermal patch yields a consistent and homogeneous polymer blend and the resulting laminate after evaporation of the process solvent, which includes a process solvent for solubilizing the API molecular dispersion obtained during particle formation. During blending, the API forms particles with other excipients, which are uniformly suspended in the polymer blend containing the solvent system to produce a homogeneous wet suspension, and the solid API particles are formed in situ within the blend prior to coating and solvent system evaporation.

[0187] Solubilizing grade povidone, such as Kollidon 25, 30, or 90, is added to a solution of a specified process solvent, such as an ethyl acetate:isopropanol ratio of 3:1 to 1:3, thereby dissolving the povidone in the solution at a concentration of about 10% to 50% by weight relative to the solvent. Additionally, an API, such as dexamethasone, lenalidomide, dexamethasone acetate, ibrutinib, or olanzapine, is added to the mixture and solubilized in the polymer / solvent solution. The drug concentration in the polymer / solvent solution is about 5% to about 50% by weight, and the dry weight ratio of the polymer to the API is about 2:1 to about 10:1, or about 4:1 to about 8:1. The solvent in the polymer / API solution is dried to remove it, leaving a glassy or glassy film that is rigid yet brittle and suitable for particle size reduction to achieve micronization of the polymer:API complex, wherein there is no evidence of API crystallization in the film or particles. Obtaining micronized particles is necessary for the addition and processing of binder-dispersed pharmaceutical products to achieve coating and final solvent evaporation. API / polymer complexes should remain unchanged in the presence of binder-dispersed drug systems, so that the API:polymer complex maintains its glassy or glassy particles within the system. There is no evidence of such crystallization of API within the system, i.e., birefringence under polarized light microscopy.

[0188] Adding micronized, insoluble excipients such as cross-linked povidone (cross-linked povidone) to binder-dispersed drug layer formulations to maintain a solid suspension is also feasible, provided that other insoluble substrates are dispersed in the matrix and achieve affinity for the crystallization and / or molecular dispersion of the API.

[0189] It should be noted that the use of insoluble povidones such as crospovidone, and soluble povidones such as Kollidon 30, either in a dissolved state or in a suspended, undissolved state, are considered unique combinations of crospovidone and povidone. This disclosure covers at least the use of both in an undissolved state, while other studies advocate the use of insoluble povidone (crospovidone) alone or soluble povidone alone as a crystallization inhibitor, thickener, or stabilizing or dispersing polymer. It should be understood that in this disclosure, the API is not dispersed (dissolved) in the transdermal system in molecular form, but rather remains in solid particulate form.

[0190] A transdermal delivery system (TDS) for administering an API can be formed, the system comprising an active substance region containing a pharmaceutical composition containing at least one (1) a solid API smaller than about 150 µm or API:substrate micronized glass / glassy particles smaller than about 150 µm, wherein the substrate is a material suitable for forming a brittle, rigid film with reduced particle size, such as soluble povidone Kollidon 30; optionally, an insoluble excipient as a dispersant and thickener; at least one (1) an excipient as a penetration enhancer or plasticizer, but said excipient only acts on the API or API:substrate when activated by application to the skin and hydration of the patch under occluded conditions; and at least one (1) a polymer as an adhesive backbone, such as acrylic pressure-sensitive adhesive, polyisobutylene, silicone PSA, or combinations thereof. The cured adhesive composition can be applied between an impermeable backing layer and a release liner, retaining the glassy and glassy particles of the API:substrate in the matrix without damage. The composition can be incorporated into a covering adhesive system.

[0191] The solid particle API-substrate composite identified in this embodiment is characterized by a film formed comprising approximately 1% to approximately 50% by weight of API and approximately 50% to approximately 99% by weight of a substrate (e.g., a soluble polymer), the substrate being capable of dissolving the API and forming a fragile, rigid film suitable for micronization by physical or mechanical methods. The exact range of API and soluble polymer has been found to depend on the properties of the active pharmaceutical ingredient, such as solubility in water, solubility in organic solvents, Log P, solubility parameters, and other comparative methods have been considered. To produce reasonably loaded solid particles, the API should be loaded such that the amount of soluble polymer (e.g., polyvinylpyrrolidone) added to the binder-dispersed drug system is less than approximately 50% by weight; otherwise, the binder-dispersed drug system will become a solid film rather than an adhesive or adhesive-like material, exhibiting poor adhesion to substrates such as skin. Table 7 summarizes the concentrations of API and substrate in the various solid particle composites formed.

[0192] Table 7: API of solid particles: loading % of substrate

[0193]

[0194] For these APIs, an amount of approximately 10% to approximately 25% by weight is found to be preferred. APIs present within substrates such as PVP are undersaturated, meaning the solubility of the API is much lower than the saturation point within the solid polymer, resulting in a solid-particle complex. Therefore, the API remains a solid without crystallization and can be described as amorphous. A limitation of adding a binder-dispersible drug matrix is ​​the amount of drug that can be added to the system: the amount of substrate (in most cases, PVP). Without being limited by the scope of current work, empirical evidence suggests that formulations with drug loadings up to approximately 5% by weight and 45% by weight of PVP on a dry weight basis are possible when a binder-dispersible drug matrix is ​​added, and have been successfully prepared and tested, with the formulations initially added to solid particles at a drug loading of 10% by weight to form a solid-particle complex.

[0195] Example 7

[0196] Next, in Example 7, Tables 8A and 8B present another embodiment of the present disclosure, which relates to the preparation of solid particles of lenalidomide and soluble povidone in the form of micronized glassy particles, as demonstrated by the lack of birefringence under a polarized light microscope.

[0197] Table 8A: Lenalidomide: Polyvinylpyrrolidone as solid particles (% dry weight)

[0198]

[0199] Table 8B: Lenalidomide: Polyvinylpyrrolidone as solid particles in TDS

[0200]

[0201] refer to Figure 9-10 , Figure 9 The corresponding average flux is shown. Figure 10The cumulative permeation is shown, and the difference observed in the optimized solid particles compared to the previously developed molecular solid suspension (LLD-TDS-009 control) supports the claim that optimizing the LLD:PVP ratio to form a transparent, clear, glassy or glassy, ​​rigid and brittle membrane, which can reduce particle size mechanically or physically, yields micronized glassy or glassy particles for inclusion in transdermal delivery systems. These particles are at least equivalent in performance to the developed molecular solid suspension (LLD-TDS-009) formulation and to a PVP:API ratio increased from about 4:1 to about 10:1 at the same drug loading, wherein all formulations contain 5% by weight lenalidomide. It should be noted that the LLD-TDS-009 control uses 8% by weight lenalidomide. Therefore, the solid particle API and polymer complex of this disclosure is superior in efficiency, with drug delivery equivalent to the control (LLD-TDS-009), but with a 37.5% by weight reduction in drug loaded into the formulation of this disclosure.

[0202] Example 8

[0203] Next, in Example 8, Tables 9A and 9B present another embodiment of the present disclosure, which relates to the preparation of solid particles of olanzapine and soluble povidone, which are micronized glassy particles, as evidenced by the lack of birefringence under a polarized light microscope.

[0204] Table 9A: Olanzapine: Polyvinylpyrrolidone as solid particles (% dry weight)

[0205]

[0206] Table 9B: Comparison of Olanzapine and Polyvinylpyrrolidone as Solid Parts and as Molecular Solid Suspension in TDS

[0207]

[0208] refer to Figure 11-12 , Figure 11 Presents the corresponding average flux of early, unoptimized solid particles compared to the control. Figure 12 The cumulative penetration of early-stage, unoptimized solid particles is presented compared to a control, OLA 151 Lot # 2B019, a clinical formulation of the developed olanzapine TDS. In this formulation, the drug is loaded in a solubilized binder-dispersed drug platform at a loading of 8% by weight and a coating weight of 15 mg / cm³. 2 In contrast, other formulations contain 5% by weight of drug in the form of a solid particulate complex suspension, with a coating weight of only about 13 mg / cm³. 2Furthermore, the API:PVP particles form a transparent, clear, glassy or glassy, ​​hard, and brittle membrane. This membrane can be mechanically or physically reduced in size to obtain micronized glassy or glassy particles suitable for inclusion in transdermal delivery systems. Clearly, the unoptimized solid particle suspension exhibits excellent performance in the first 24 hours, with significant attenuation (~100% at 72 hours) compared to the total duration on the Strat-M membrane, while the control formulation shows only about 84% at 72 hours. This is directly related to drug deloading on the membrane and the relatively low (5% by weight) total drug loading of the formulation. Therefore, this paper presents a validation of the concept, but the final formulation still requires further optimization to maintain the improved concentration gradient.

[0209] These and other modifications and variations to this disclosure can be made by those skilled in the art without departing from the spirit and scope thereof. Furthermore, it should be understood that aspects of the various embodiments can be interchanged, in whole or in part. Moreover, those skilled in the art will understand that the foregoing description is merely exemplary and is not intended to limit the invention thereto, as the invention is further described in the appended claims.

Claims

1. A transdermal drug delivery system comprising: A binder-dispersed drug layer, the binder-dispersed drug layer comprising: Solid particulate complex comprising an active pharmaceutical ingredient having a water solubility of less than about 10 mg per milliliter and a melting point above about 120°C and a soluble polymer; Adhesive polymers; and Surfactants, The weight ratio of the soluble polymer to the active pharmaceutical ingredient ranges from about 1.25:1 to about 20:

1.

2. The transdermal drug delivery system of claim 1, wherein the active pharmaceutical ingredient has a logP value of about -2 to about 8.

3. The transdermal drug delivery system of claim 1, wherein the active pharmaceutical ingredient is an immunomodulatory (IMiD) agent, a steroid, a hormone, an antipsychotic drug, a tricyclic antidepressant, or a Bruton's tyrosine kinase inhibitor.

4. The transdermal drug delivery system of claim 1, wherein the soluble polymer comprises polyvinylpyrrolidone.

5. The transdermal drug delivery system of claim 1, wherein the solid particle complex has a particle size of less than about 300 micrometers.

6. The transdermal drug delivery system of claim 1, wherein the adhesive polymer comprises acrylate copolymers, ethylene-vinyl acetate copolymers, acetate-acrylic acid copolymers, rubber copolymers, polyisobutylene polymers, siloxane polymers, or combinations thereof.

7. The transdermal drug delivery system of claim 1, wherein the surfactant comprises a nonionic surfactant.

8. The transdermal drug delivery system of claim 7, wherein the nonionic surfactant comprises stearyl alcohol polyether-2, oleyl alcohol polyether-2, cetyl alcohol polyether-3, oleyl alcohol polyether-3, C12-13 alkanol polyether-3, oleyl alcohol polyether-5, C12-13 alkanol polyether-4, lauryl alcohol polyether-4, lauryl alcohol polyether-9, cetearyl alcohol polyether-6, oleyl alcohol polyether-10, oleyl alcohol polyether-20, stearyl alcohol polyether-10, poloxamer, polyethylene glycol, or combinations thereof.

9. The transdermal drug delivery system of claim 1, further comprising insoluble excipients.

10. The transdermal drug delivery system of claim 9, wherein the insoluble excipient comprises cross-linked polyvinylpyrrolidone.

11. The transdermal drug delivery system of claim 1, further comprising: An occlusive backing layer and a release liner, wherein the occlusive backing layer forms the outer surface of the transdermal drug delivery system, and wherein the release liner is disposed adjacent to the skin-contacting surface of the adhesive-dispersible drug layer.

12. A method for forming a solid particulate complex comprising an active pharmaceutical ingredient and a soluble polymer for use in a transdermal delivery system, the method comprising: The active pharmaceutical ingredient and the soluble polymer are combined in a process solvent system to solubilize both the active pharmaceutical ingredient and the soluble polymer. The process solvent system is evaporated to form a film; and The film is micronized to form the solid particle composite, wherein the solid particle composite does not exhibit any signs of birefringence or crystallinity and has a particle size of less than about 300 micrometers.

13. The method of claim 12, wherein the weight ratio of the soluble polymer to the active pharmaceutical ingredient ranges from about 1.25:1 to about 20:

1.

14. The method of claim 12, wherein the active pharmaceutical ingredient has a water solubility of less than about 10 mg per milliliter, a melting point above about 120°C, and a log P value of about -2 to about 8.

15. The method of claim 12, wherein the active pharmaceutical ingredient is an immunomodulatory (IMiD) agent, a steroid, a hormone, an antipsychotic drug, a tricyclic antidepressant, or a Bruton's tyrosine kinase inhibitor.

16. The method of claim 12, wherein the soluble polymer comprises polyvinylpyrrolidone.

17. A method for forming a binder-dispersed drug layer for a transdermal drug delivery system, the method comprising: The active pharmaceutical ingredient and the soluble polymer are combined in the solvent system of the first process to solubilize both the active pharmaceutical ingredient and the soluble polymer. The solvent system of the first process is evaporated to form a film; The membrane is micronized to form a solid particle composite, wherein the solid particle composite has a particle size of less than about 300 micrometers; and The solid particulate complex is added to a second process solvent system, a binder polymer, and a surfactant to form a binder-dispersed drug layer formulation.

18. The method of claim 17, wherein the weight ratio of the soluble polymer to the active pharmaceutical ingredient ranges from about 1.25:1 to about 20:

1.

19. The method of claim 17, wherein the active pharmaceutical ingredient has a water solubility of less than about 10 mg per milliliter, a melting point above about 120°C, and a log P value of about -2 to about 8.

20. The method of claim 17, wherein the active pharmaceutical ingredient is an immunomodulator, steroid, hormone, antipsychotic drug, tricyclic antidepressant, or Bruton's tyrosine kinase inhibitor.

21. The method of claim 17, wherein the adhesive polymer comprises acrylate copolymers, ethylene-vinyl acetate copolymers, acetate-acrylic acid copolymers, rubber copolymers, polyisobutylene polymers, siloxane polymers, or combinations thereof.

22. The method of claim 17, wherein, The surfactant includes nonionic surfactants, wherein the nonionic surfactants include stearyl alcohol polyether-2, oleyl alcohol polyether-2, cetyl alcohol polyether-3, oleyl alcohol polyether-3, C12-13 alkanol polyether-3, oleyl alcohol polyether-5, C12-13 alkanol polyether-4, lauryl alcohol polyether-4, lauryl alcohol polyether-9, cetearyl alcohol polyether-6, oleyl alcohol polyether-10, oleyl alcohol polyether-20, stearyl alcohol polyether-10, poloxamer, polyethylene glycol, or combinations thereof.

23. The method of claim 17, further comprising adding an insoluble excipient to the binder-dispersible pharmaceutical layer formulation.

24. The method of claim 23, wherein the insoluble excipient comprises cross-linked polyvinylpyrrolidone.

25. The method of claim 17, further comprising coating the adhesive-dispersible pharmaceutical layer formulation onto one of a backing layer or a release liner.

26. The method of claim 25, further comprising evaporating the second process solvent system to form a dry binder-dispersed pharmaceutical layer formulation.

27. The method of claim 26, further comprising applying another of the backing layer or the release liner to an exposed surface of the dried adhesive-dispersed pharmaceutical layer formulation to form a laminate.

28. The method of claim 27, further comprising: The laminate is transformed into a specified patch size by die-cutting; and The inherent covering system is housed together with the laminate within a flat, heat-sealed bag.

Images