Solid state active pharmaceutical compositions for transdermal drug delivery

Abstract

Transdermal drug delivery systems and methods of fabricating such systems for the delivery of an active pharmaceutical ingredient (API) are provided. The active pharmaceutical ingredient shall have an unfavorable water solubility of less than about 10 milligrams per milliliter, an unfavorable melting point greater than about 120°C, and a log P value ranging from about -2 to about 8. More particularly, the present disclosure is directed to improving the permeation of such compounds through the skin by forming a solid-state particulate including the drug (API) and polyvinylpyrrolidone that is complexed, solvated, processed, micronized and incorporated into an adhesive layer to maintain a solid-state suspension of glass-like particulates.

Description

[0001] SOLID STATE ACTIVE PHARMACEUTICAL COMPOSITIONS FOR TRANSDERMAL DRUG DELIVERY

[0002] Related Applications

[0003] The present application claims priority to U.S. Provisional Patent Application No. 63 / 617.832. filed on January 5, 2024. the entire contents of which are incorporated herein by reference.

[0004] Technical Field

[0005] The present disclosure is directed to transdermal drug delivery systems for active pharmaceutical ingredients (APIs) exhibiting high melting points and low water solubility to improve the permeation of such APIs through the skin.

[0006] Background of the Invention

[0007] The Food and Drug Administration (FDA) has established a system known as the Biopharmaceuticals Classification System (BCS), which is used to classify drug substances based on their permeability and solubility. Drug substances in category I have high permeability and high solubility, drug substances in category II have high permeability and low solubility, drug substances in category III have low permeability and high solubility, and drug substances in category IV have low permeability and low solubility. Transdermal delivery' of solubilized APIs is well-known to those skilled in the art. Specifically, those APIs in most solubilized platforms are in the Class I or Class III categories of the FDA’s BCS, such as nicotine, scopolamine, and methylphenidate, which have relatively low melting points and high-water solubility. Meanwhile, many APIs in development or recently launched in the past few years have been assigned to BCS categories II and IV, which exhibit low solubility as defined by the FDA. Of commercially viable APIs made into transdermal drug delivery systems, applicable APIs might include buprenorphine, clonidine, estradiol, ethinyl estradiol, and norelgestromin, which would fit into the BCS category II, which includes drugs that exhibit low solubility but high permeability. Additionally, these drugs have relatively high melting points. These are incorporated into their respective commercially viable products in a solubilized state. Meanwhile. BCS category IV drugs exhibit low solubility and low permeability. To clarify the meaning of low solubility in the present application (sparingly soluble to practically insoluble in water). Table 1 below can be used for reference: Table 1: Derivation of USP / NF solubility chart to illustrate concentration types

[0008] Such low solubility APIs can have a solubility of less than about 10 mg / g or 10 mg / mL.

[0009] Particular APIs include lenalidomide with a water solubility of less than about 1 mg / mL and melting point of 265°C to 270°C and other immunomodulatory (IMiDs) compounds with similar physicochemical characteristics, 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, as well as other steroids or hormones with similar physicochemical characteristics, olanzapine with a water solubility of less than about 0.1 mg / mL and a melting point of 195°C, as well as other antipsychotics / tricyclics with similar physicochemical characteristics, 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 characteristics. As such, there is a need to develop transdermal drug delivery systems that address the availability of these drugs by modifying how the drug is solubilized and / or suspended in a formulation and to allow for these compounds to permeate at an appreciable rate above and beyond the permeation rates associated with certain APIs in a solubilized state, so that they can be effectively delivered through the skin. The transdermal delivery of these types of compounds is expected to overcome deficiencies in other routes of administration, such as, oral or IV bolus administration, where such deficiencies include but are not limited to toxicity or the peaks (above therapeutic values) and valleys (sub-therapeutic values) of pharmacokinetic profiles after administration.

[0010] Transdennal deliver}’ of APIs is well-known for compounds that exhibit very low water solubility, such as, estradiol, testosterone, buprenorphine, fentanyl, and granisetron in a solubilized drug-in-adhesive platform. These drug-in-adhesive platforms include commercially available and marketed API products, such as Vivelle Dot® for estradiol (water solubility less than 1 mg / mL and melting point of 173°C to 180°C), Testoderm® for testosterone (water solubility less than 1 mg / mL and melting point of 153°C to 155°C), BuTrans® for buprenorphine (water solubility less than 1 mg / mL and melting point of 219°C), generic Fentanyl Transdermal Systems for fentanyl (water solubility of about 0.2 mg / mL and melting point of 181°C to 183°C), and Sancuso®) for granisetron (water solubility' less than 0.1 mg / mL and melting point of 226°C). These commercial transdermal delivery systems incorporate the drug in a solubilized drug-in-adhesive matrix and maintain its solubility throughout the shelf life and intended application period. It has been shown that known APIs with solubility within these matrices are maintained at or close to the saturation solubility of the matrix to obtain maximal permeation from the transdermal system (e.g., maintain a constant concentration gradient to achieve sustainable delivery). It is known that transdermal drug delivery systems are typically available in a solubilized drug-in-adhesive formulation in their simplest formulations. With APIs exhibiting challenging solubility and permeability requirements such as those referenced above, modifications to the formulations are needed to maintain the API in solution, alternative pathways to solubility must be provided for upon application, and / or specific permeability enhancers are required to try to increase the permeability of the drug molecules, all of which can complicate the path towards a commercial product with additional costs, testing, and approval requirements. In consideration of the aforementioned problems, a need exists for a transdermal drug delivery system where the permeation of low water solubility APIs is improved.

[0011] Summary of the Invention

[0012] In accordance with one embodiment of the present disclosure, a transdermal drug delivery' system is disclosed. The transdermal drug delivery system includes a drug-in-adhesive layer that includes a solid-state particulate complex including an active pharmaceutical ingredient having a water solubility of less than about 10 milligrams per milliliter and a melting point greater than about 120°C and a soluble polymer; an adhesive polymer; and a surfactant. Further, a 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 adhesive blend with excipients and process solvents, the API and / or complex is suspended and does not significantly change or solubilize upon process completion.

[0013] In one embodiment, the active pharmaceutical ingredient has a log P value ranging from about -2 to about 8.

[0014] In another embodiment, the active pharmaceutical ingredient can be an immunomodulatory (IMiD) agent, a steroid, a hormone, an antipsychotic, a tricyclic antidepressant, or a Bruton’s tyrosine kinase inhibitor.

[0015] In still another embodiment, the soluble polymer can include polyvinylpyrrolidone.

[0016] In yet another embodiment, the solid-state particulate complex can have a particle size of less than about 300 micrometers.

[0017] In one more embodiment, the adhesive polymer can include an acrylate copolymer, an ethylene-vinyl acetate copolymer, a vinyl acetate -aery lie copolymer, a rubber co-polymer, a poly isobutylene polymer, a silicone polymer, or a combination thereof.

[0018] In an additional embodiment, the surfactant can include a nonionic surfactant. For instance, the nonionic surfactant can include steareth-2. oleth-2. ceteth-3, oleth-3, Cl 2-13 pareth-3, oleth-5. C12-13 pareth-4, laureth-4, laureth-9, ceteareth-6, oleth-10. oleth-20, steareth-10, a poloxamer, a polyethylene glycol, or a combination thereof. In another embodiment, the transdermal drug delivery system can include an insoluble excipient. Further, the insoluble excipient can include crosslinked polyvinylpyrrolidone.

[0019] In still another embodiment, the transdermal drug delivery system can include an occlusive backing layer, wherein the occlusive backing layer forms an exterior facing-surface of the transdermal drug delivery system; and a release liner, wherein the release liner is positioned adjacent a skin contacting surface of the drug-in-adhesive layer.

[0020] In accordance with another embodiment of the present disclosure, a method of forming a solid-state particulate complex comprising an active pharmaceutical ingredient and a soluble polymer for transdermal delivery systems is provided. The method includes combining the active pharmaceutical ingredient and the soluble polymer in a process solvent system to solubilize both the active pharmaceutical ingredient and the soluble polymer; evaporating the process solvent system to form a film; and micronizing the film to form the solid-state particulate complex. Further, the solid- state particulate complex exhibits no evidence of birefringence or crystallinity and has a particle size of less than about 300 micrometers.

[0021] In one embodiment, a 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 can have a water solubility of less than about 10 milligrams per milliliter, a melting point greater than about 120°C, and a log P value ranging from about -2 to about 8.

[0023] In still another embodiment, the active pharmaceutical ingredient can be an immunomodulatory (IMiD) agent, a steroid, a hormone, an antipsychotic, a tricyclic antidepressant, or a Bruton’s tyrosine kinase inhibitor.

[0024] In yet another embodiment, tire soluble polymer can include polyvinylpyrrolidone.

[0025] In accordance with one more embodiment of the present disclosure, a method of fonning a drug-in-adhesive 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-state particulate complex, wherein the solid-state particulate complex has a particle size of less than about 300 micrometers; and adding the solid-state particulate complex to a second process solvent system, an adhesive polymer, and a surfactant to form a drug-in-adhesive layer formulation.

[0026] In one embodiment, a 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 can have a water solubility of less than about 10 milligrams per milliliter, a melting point greater than about 120°C, and a log P value ranging from about -2 to about 8. In still another embodiment, the active pharmacal ingredient can be an immunomodulatory agent, a steroid, a hormone, an antipsychotic, a tricyclic antidepressant, or a Bruton’s tyrosine kinase inhibitor.

[0028] In yet another embodiment, the adhesive polymer can include an acrylate copolymer, an ethylene-vinyl acetate copolymer, a vinyl acetate -aery lie copolymer, a rubber co-polymer. a poly isobutylene polymer, a silicone polymer, or a combination thereof.

[0029] In still another embodiment, the surfactant can include a nonionic surfactant. Further, the nonionic surfactant can include steareth-2, oleth-2, ceteth-3, oleth-3, C12-13 pareth-3, oleth-5, Cl 2- 13 pareth-4, laureth-4, laureth-9, ceteareth-6, oleth-10, oleth-20, steareth-10, a poloxamer. a polyethylene glycol, or a combination thereof.

[0030] In one more embodiment, the method can include adding an insoluble excipient to the drugin-adhesive layer formulation. Further, the insoluble excipient can include crosslinked polyvinylpyrrolidone.

[0031] In an additional embodiment, the method can include coating the drug-in-adhesive layer formulation onto one of a backing layer or a release liner.

[0032] In a further embodiment, the method can also then include evaporating the second process solvent system to form a dried drug-in-adhesive layer formulation.

[0033] In an additional embodiment, the method can also include applying the other of the backing layer or the release liner onto an exposed surface of the dried drug-in-adhesive layer formulation to form a laminate.

[0034] In one more embodiment, the method can include converting the laminate to a specified patch size via die cutting; and including an inherent overlay system with the laminate in a flat heat- sealed pouch.

[0035] Other features and aspects of the present disclosure are set forth in greater detail below.

[0036] Brief Description of the Drawings

[0037] A full and enabling disclosure of the present disclosure, including the best mode thereof to one skilled in the art, is set forth more particularly in the remainder of the specification, including reference to the accompanying figure, in which:

[0038] Fig. 1 is a cross-sectional view of a transdermal drug delivery system according to one embodiment of the present disclosure, where the transdermal drug delivery system includes a micronized solid state API glassy particulate incorporated as a drug-in-adhesive matrix;

[0039] Fig. 2 is a flow chart illustrating a method of making the transdermal drug delivery system of Fig. 1 in which the micronized solid state API glassy solid-state particulates (SSP) with soluble polyvinylpyrrolidone are made and then subsequently added herein to the drug-in-adhesive matrix;

[0040] Fig. 3 is a graph comparing the average flux (micrograms / square centimeter / hour) of dexamethasone through Strat-M® (synthetic membrane) for various transdermal drug delivery system formulations to compare a formulation where the dexamethasone is in the form of a precipitated molecular solid suspension or in the form of a suspended micronized powder;

[0041] Fig. 4 is a graph describing the cumulative permeation (micrograms / square centimeter) of dexamethasone through Strat-M® (synthetic membrane) for various transdermal drug delivery system formulations to compare a formulation where the dexamethasone is in the form of a precipitated molecular solid suspension or in the form of a suspended micronized powder;

[0042] Fig. 5 is a graph describing the average flux (micrograms / square centimeter / hour) of dexamethasone through Strat-M® (synthetic membrane) for various transdermal drug delivery system formulations including the first use of solid-state particles with varying ratios of polyvinylpyrrolidone to dexamethasone to form the transdermal drug-in-adhesive matrix;

[0043] Fig. 6 is a graph describing the cumulative permeation of dexamethasone (micrograms / square centimeter) through Strat-M® (synthetic membrane) for various transdermal drug delivery system formulations including the first use of solid-state particles with varying ratios of polyvinylpyrrolidone to dexamethasone to form the transdermal drug-in-adhesive matrix;

[0044] Fig. 7 is another graph describing the average flux (micrograms / square centimeter / hour) of dexamethasone through Strat-M® (synthetic membrane) for various transdermal drug delivery system formulations to compare formulations where polyvinylpyrrolidone and dexamethasone were used to form a solid state micronized particulate to when the polyvinylpyrrolidone and dexamethasone or dexamethasone alone were added separately as raw materials in the solid-state;

[0045] Fig. 8 is another graph describing the cumulative permeation (micrograms / square centimeter) of dexamethasone through Strat-M® (synthetic membrane) for various transdermal drug delivery system formulations to compare formulations where polyvinylpyrrolidone and dexamethasone were used to form a solid-state micronized particulate to when the polyvinylpyrrolidone and dexamethasone or dexamethasone alone were added separately as raw materials;

[0046] Fig. 9 is a graph describing the average flux (micrograms / square centimeter / hour) of lenalidomide through Strat-M® (synthetic membrane) for various transdermal drug delivery system formulations to compare a formulation where the lenalidomide is in the form of a precipitated molecular solid suspension or in the form of a solid-state micronized particulate with polyvinylpyrrolidone; and

[0047] Fig. 10 is a graph describing the cumulative permeation (micrograms / square centimeter) of lenalidomide through Strat-M® (synthetic membrane) for various transdermal drug delivery system formulations to compare a formulation where the lenalidomide is in the form of a precipitated molecular solid suspension or in the form of a solid-state micronized particulate with poly viny Ipy rrolidone ;

[0048] Fig. 11 is a graph describing the average flux (micrograms / square centimeter / hour) of olanzapine through Strat-M® (synthetic membrane) for various transdermal drug delivery system formulations to compare a formulation where the olanzapine is in the form of a precipitated molecular solid suspension or in the form of a solid-state micronized particulate with polyvinylpyrrolidone: and

[0049] Fig. 12 is a graph describing the cumulative permeation (micrograms / square centimeter) of olanzapine through Strat-M® (synthetic membrane) for various transdermal drug delivery system fonnulations to compare a formulation where the olanzapine is in the form of a precipitated molecular solid suspension or in the form of a solid-state micronized particulate with poly viny Ipy rrolidone .

[0050] Repeat use of reference characters in the present specification and drawing is intended to represent the same or analogous features or elements of the present disclosure.

[0051] Detailed Description of Representative Embodiments

[0052] It is to be understood by one of ordinary skill in the art that the present discussion is a description of exemplary embodiments only and is not intended as limiting the broader aspects of the present disclosure.

[0053] Definitions

[0054] As used herein, the terms "about," “approximately,” or “generally,” when used to modify a value, indicates that the value can be raised or lowered by 5% and remain within the disclosed embodiment. Further, when a plurality of ranges is provided, any combination of a minimum value and a maximum value described in the plurality of ranges are contemplated by the present disclosure. For example, if ranges of “from about 20% to about 80%” and “from about 30% to about 70%” are described, a range of “from about 20% to about 70%” or a range of “from about 30% to about 80%” are also contemplated by the present disclosure.

[0055] As used herein, the term “disperse” means to cause to break up. to cause to become spread widely, and / or to cause to evaporate or vanish.

[0056] As used herein, the term “dispersion” means a system in which distributed particles of one material are dispersed in a continuous phase of another material. The two phases may be in the same or different states of matter. The term can also or alternatively mean a system consisting of a dispersed substance and the medium in which it is dispersed.

[0057] As used herein, the term “molecular dispersion” means a true solution of a solute phase in a solvent. The dispersed phase (solute) is in the form of separate molecules homogeneously distributed throughout the dispersion medium (solvent). The molecule size is less than 1 nm.

[0058] As used herein, the term “molecular solid suspension” means the term “molecular solid suspension” shall refer specifically to a solid, such as an API. dissolved by 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 to serve as a carrier of the first solid. The solid excipient carrier is not soluble in the first or second solvent, however, freely disperses or suspends, dependent on particle size of substrate, in one or both solvents in combination. The solid excipient carrier may or may not be micronized. Solid excipient carriers, such as Parteck SLC (silicon dioxide) or Kollidon CL-M (crospovidone) have found suitability in preparation of these Molecular Solid Suspensions. For the current invention, the particle size of about no more than about 180 micrometers (pm) (Mesh #80) particle size (D90) to ensure processability of the final formulation as a transdermal delivery system. The solubilized solid in the first process solvent is in most cases an API and is added to the dispersed or suspended solid carrier, in most cases a pharmaceutically acceptable excipient, in a second process solvent (and not the first process solvent). Additionally, excipients which are amenable to production of a homogeneous dispersion are added to modify availability and permeation of API from the platform. Thus, the medium is a homogeneous blend of excipients, adhesive, polymer, or solvent such that the resulting formulation is a suspension of dispersed particles within said medium. By solvent evaporation, a viscous liquid remains, such as a pressure sensitive adhesive, which incorporates the medium and uniformly suspended particles or co-particles of API, carrier excipient, and other excipients, if needed. The API and or particle excipients may be amorphous, amorphous-like, partially amorphous, crystalline, or combinations thereof to produce a suitable formulation. The formulary of combinations of drug concentrations, significantly above solubilized saturation point, drive availability of drug to solubilize in water-based solution, and more specifically the increase in available drug is now more permeable due to enhanced concentration gradient and innate reservoir of the molecular solid suspension. As known to those skilled in the art, a molecular dispersion is a true solution and a dispersion ty pically results in a physical mixture of a solid material dispersed in a liquid, such as a molecular dispersion, colloid or suspension.

[0059] As used herein, the term “solid state particulate” (SSP) or suspension means a solid active pharmaceutical ingredient (API) or solid API combined with a substrate (APFsubstrate) that is incorporated into a combination of a suitable system. It should be understood that the solid-state API or APFsubstrate is not formed in situ. Rather, the API or the APFsubstrate complex is added into a system, such as a transdermal delivery system (TDS), in the form of a solid particulate that does not change during the formulation, blending, coating, or finished drug manufacturing process to form a solid state suspension as part of a drug-in-adhesive layer. The API may be present as a micronized drug which does not solubilize to a significant level within the drug-in-adhesive system. The APFsubstrate, on the other hand, is formed by first dissolving the API and then dissolving the polymer together in a suitable solvent system at a preferred ratio of API:Substrate:solvent system. The resulting molecular dispersion or true solution is then evaporated off to remove volatile organic solvents, leaving behind a glass-like drug containing substrate where no presence of drug crystallinity is found, where it should be understood that the terms "glass-like" and "glassy" are sometimes used synonymously with amorphous solid; however, these terms refer specifically to amorphous materials that undergo a glass transition and are not synonymous with the term “amorphous.” In these API: substrate complexes, it lias been found within the present disclosure to not maximize the drug loading for availability / permeability for transdermal delivery' of the API through skin but rather to actually maximize the minimum effective level of the API within the solid particulate to achieve maximum availability. This is in direct contradiction to that which is taught within the industry to achieve maximum effective concentrations to achieve the highest amount of API within such polymeric systems. Typically, the goal of creating such solid-state particulates is claimed for improvement of oral delivery of drugs to maximize drug loading, minimize particle size, and ensure the amorphous nature of the solid excipient carrier, which may or may not be micronized. Polymers of pertinent use are soluble in solvents which are also useful to solubilize the API but is not necessarily required to be the same as long as the polymer and solvent system is miscible with the solvent of choice to dissolve the API and the polymeric substrate. Preferably, water-soluble polymers, such as Plasdone (povidone / polyvinylpyrrolidone) or Kollidon 30 or 30LP and Kollidon 90 (soluble povidone / polyvinylpyrrolidone) have found suitability in preparation of these solid-state suspensions. Further, Kollidon 12 and Kollidon 12PF were found not amenable to forming a glass-like particle which is capable of being micronized, possibly due to their low molecular weight. It is believed other molecular weights, such as Kollidon 25, 45, 60. 120 would be suitable such that a viable means of production of the API: substrate was amenable to the creation of a glass-like particulate which is micronizable. For the present disclosure, it is believed that a particle size of about no more than about 250 pm would ensure processability’ of the final formulation as a transdermal delivery sy stem. The API and or API: substrate as a micronized particulate is a glass or glass-like material, which is a form of an amorphous material. However, it should be understood that not all amorphous particles are a glass or glass-like material, where it has been found that the glassy presence of the particulate is particularly necessary to achieve maximum efficiency to produce a suitable formulation.

[0060] As known to those skilled in the art, a molecular dispersion is a true solution and a dispersion typically results in a physical mixture of a solid material dispersed in a liquid, such as a molecular dispersion, colloid, or suspension. The system of the present disclosure is a culmination of the utility found by incorporating solid state materials with specific physicochemical characteristics into a transdermal system and producing a more suitable environment for the API to be available for deliver}' and indeed perpetuate permeation of API from the delivery system to the subject or patient. It is well-known that most skilled in the art were instructed or trained to believe that a solubilized drug within a transdermal patch is a requirement to allow transdermal drug delivery to be achieved and maximized. The present disclosure thus goes against common belief, understanding, acceptance, and instruction, which challenges the concept that solid particulates in an appropriate formulation can not only exceed a solubilized transdermal drug delivery approach, but can also maximize the efficiency and achieve high levels of permeation from a transdermal delivery system above and beyond that achievable from a solubilized drug transdermal delivery system approach. As used herein, the term “suspension” means a coarse dispersion which is a heterogeneous dispersed system in which the dispersed phase particles are larger than 1000 nm (1 pm). Coarse dispersions are characterized by relatively fast sedimentation of the dispersed phase caused by gravity or other forces. The dispersed phase of coarse dispersions may be easily separated from the continuous phase by filtration. The particles may be visible to the naked eye, and the mixture is only classified as a suspension when and while the particles have not settled. In chemistry, a suspension is a heterogeneous mixture of a fluid that contains solid particles sufficiently large for sedimentation. The particles may be visible to the naked eye, usually must be larger than one micrometer, and will eventually settle, although the mixture is only classified as a suspension when and while the particles have not settled.

[0061] As used herein, the term “partition coefficient (P)” or “distribution coefficient (D)” means the ratio of concentrations of a compound in a mixture of two immiscible solvents at equilibrium. This ratio is therefore a comparison of the solubilities of the solute in these two liquids. The partition coefficient generally refers to the concentration ratio of un-ionized species of compound, whereas the distribution coefficient refers to the concentration ratio of all species of the compound (ionized plus un-ionized). In the chemical and pharmaceutical sciences, both phases usually are solvents. Most commonly, one of the solvents is water, while the second is hydrophobic, such as 1 -octanol. Hence the partition coefficient measures how hydrophilic ("water-loving") or hydrophobic ("water-fearing") a chemical substance is. Partition coefficients are useful in estimating the distribution of drugs within the body. Hydrophobic drugs with high octanol-water partition coefficients are mainly distributed to hydrophobic areas such as lipid bilayers of cells. Conversely, hydrophilic drugs (low octanol / water partition coefficients) are found primarily in aqueous regions such as blood serum. The partition coefficient, abbreviated P, is defined as a particular ratio of the concentrations of a solute between the two solvents (a biphase of liquid phases), specifically for un-ionized solutes, and the logarithm of the ratio is thus log P. When one of the solvents is water and the other is a non-polar solvent, then the log P value is a measure of lipophilicity or hydrophobicity. The defined precedent is for the lipophilic and hydrophilic phase types to always be in the numerator and denominator respectively; for example, in a biphasic system of n-octanol (hereafter simply "octanol") and water. Formula I below demonstrate this relationship:

[0062] Detailed Description

[0063] Generally speaking, solid state suspensions are formed by suspending an API within a suitable substrate, such as a pressure sensitive adhesive or a polymer carrier, with or without additional excipients and / or solvents, while maintaining the solid state particulates within the system in a maimer such that the solid state particulates are dispersed homogeneously and consistently to create a suspension of suitable particles within the polymer / adhesive system. The solid-state suspensions contemplated by the present disclosure are undissolved and can be micronized to a particle size such that an API or an API: substrate complex is amenable to incorporation into a transdermal delivery system. The present disclosure contemplates a system where a uniform suspension of particulates is added to a formulation where the API is not solubilized to a significant level which would result in change the solid state particulate nature of the API or the APksubstrate complex in the process solvent, adhesive, or excipients of the system.

[0064] In other words, the API can be formulated within the polymer / adhesive / excipient system to maintain a homogeneous and non-settling solid particulate suspension where the micronized drug remains intact as a solid particulate and the particles are suspended during the production process to prepare a finished dosage form as a drug-in-adhesive layer between a backing layer and a release liner. The formation of a solid-state suspension in which the solute is not solubilized by the medium with the intent of forming a solid-state suspension is contemplated. Thus, a molecular dispersion or true solution is not present within the carrier. Rather, what is present is a suspension of solid-state drug particulates. A drug-in-adhesive layer with suitable excipients that does not solubilize the API nor interfere with the dispersive aspects of the API within the system but contributes to the enhancement of availability’ and thus permeability of said API can thus be formed.

[0065] One embodiment of the present disclosure is presented where the API is first incorporated into a solubilized carrier. Specifically, in one embodiment, the present disclosure requires that the API be solubilized by a polymer / solvent composition, after which the solvent is evaporated, and the dried material is in the form of an APksubstrate complex, which can be micronized. For instance, the API / solubilized carrier solution can be dried by solvent evaporation, leaving a glass-like film. The glass film or glass-like material can then be broken up and micronized to form solid state, glasslike particles to form an APksubstrate complex where there is no evidence of API crystallinity. These solid state, glass-like particles are then added to an adhesive layer of a transdermal delivery system without solubilizing the API, nor the polymer carrying the solubilized API. Thus, a solid- state particulate in the form of a micronized powder can be dispersed and suspended within the adhesive layer that includes a suspended, solid-state particulates that are uniformly and homogeneously distributed within the adhesive layer. The formation of glass-like particles results in a significant increase in the water-solubility’ of the API in the presence of the transdermal system by application and occlusive nature of same.

[0066] In one particular embodiment, the present disclosure contemplates an APksubstrate complex as a micronizable glass-like particulate for ultimate incorporation into a drug product. Also contemplated is a micronized API solid state particulate alone. In any event, the solid state particulates, either as the API alone or as the complex that includes the API and the substrate, can be micronized such that the particulates have a D100 value of less than about 300 micrometers, meaning that 100% of the micronized solid state particulates have a particle size of less than about 300 micrometers. Further, in some embodiments, the solid-state particulates can have a D100 value of less than about 150 micrometers. In other embodiments, the solid-state particulates can have a D90 value ranging from about 0.1 micrometers to about 75 micrometers, meaning that at least 90% of the particulates have a particle size between about 0.1 micrometers and about 75 micrometers.

[0067] The present disclosure also contemplates that the API and substrate complex is formed as the result of a combination of a solubilized API and a solubilized polymer in a suitable solvent system, where the evaporation of solvent system leaves behind a glass-like solid without the presence of crystalline API. In other words, the API is free of crystals. In other words, the API is solubilized by the solidified polymer or carrier substrate without the need for additional volatile process solvents and after drying, the APksubstrate complex is in the form of a hard, glass or glass-like material and amenable to particle reduction processes to reduce its particles size upon application of friction and pressure to achieve 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 are present in a precipitated or insoluble state to form a true solution in the solvent system prior to evaporation or drying. In one embodiment, the substrate can be a soluble polymer. For instance, the substrate can be a film-forming polymer, such as polyvinylpyrrolidone, also known as povidone. Further, the API can have a melting point that is greater than about 120°C and can have a log P value that is relative to that of the substrate, such as a log P value ranging from about -2 to about 8.

[0068] It should also be understood that additional additives may be incorporated into the API:substrate complex to impart additional characteristics such as antioxidants, preservatives, solid- state solubility agents, agents to adjust the melting point, agents to adjust the log P value, agents to adjust the dispersibility or reduce the solubility of the APFsubstrate within the drug-in-adhesive complex, or any other additives known by one of skill in the art so result in a dried material that is glass-like and amenable to particle size reduction.

[0069] The resulting solid state particulate composition, which can include the API or a complex of the API and a substrate, can be incorporated into a transdermal delivery system in the form of a drug- in-adhesive transdermal delivery system without exhibiting significant solubility of the API. the APLsubstrate complex, or the substrate itself, when the solid state particulate API or API :substrate complex is suspended within the drug-in-adhesive layer of the transdermal delivery system.

[0070] The transdermal delivery system can include an insoluble excipient for maintaining dispersion / suspension characteristics. Further, the insoluble excipient can also act as a sponge for other liquid excipients to reduce cold flow / migration. The system can also include at least one permeation enhancer which does not dissolve the solid-state particulate API or the API: substrate complex to a significant extent.

[0071] Additionally, the system can include process solvents for blending purposes, where the process solvents do not change the characteristics of the solid-state particulate API or API: substrate complex except for suspending the particulates within the substrate, where such solvents are removed during the curing process.

[0072] Further, the system can include at least one backing layer, at least one release liner layer, and an inherent overlay system may be incorporated to ensure adhesion of die system. Additionally, it should be understood that in some embodiments, a multilaminate structure could be presented as a viable embodiment of the above in a consolidated system.

[0073] By incorporating the solid state particulate composition of the present disclosure into a transdermal delivery system reduces the ability of the API and or excipients of low molecular weight to migrate away from the active area of the transdermal delivery system (e.g., patch) and remain available for delivery from the transdermal delivery system rather than transferring to packaging, an overlay layer, or other material not associated with the transdermal delivery system application. Without intending to be limited by any particular theory, the present inventors have found that the solid state particulate composition of the present disclosure also above reduces the ability of the API. any excipients, and / or the adhesive to be subject to cold flow, which is the movement of the adhesive and spreading of the drug product away from the active area of the transdermal deliver}' system. Moreover, the compositions of the present disclosure reduce tire potential for the API to degrade in the presence of oxygen, moisture, and / or excipients by complexing the API within the solid-state particulate, where die API is well-protected from external or environmental impact.

[0074] In general, it has been found that solid state suspensions and specifically those made in the form of a solid-state suspension are surprisingly unique and allow key advantages over the solubilized and / or molecular solid suspension platforms of similar composition to obtain maximum performance for permeation and sustainability of the delivery profile without losing concentration gradient. Typically, and known to those skilled in the art, solid drugs incorporated into transdermal systems are less available for solubilizing in skin or media, and as a result are less penneable than the formulated solubilized drug platforms. The limitation of these systems is drug loading to achieve theoretical delivery possible to obtain therapeutic blood levels of said drug, where continuing to increase drug loading either causes crystallization events or overwhelms the semi-permeable membrane (i.e.. skin), ultimately reducing the overall delivery of the drug from a saturated solubilized system. Those molecules with intennediate 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 that are sparingly soluble or greater than about 30 mg / mL which exhibit low melting points, less than about 120°C, are less amenable to a solid state particulate suspension; however, it is possible to load into the system these molecules and potentially make them more amenable to availability and thus permeability. Liquid APIs, at about ambient or room temperature, are typically incorporated within a liquid system at or above their saturation level to optimize availability and permeability which may not add significant value, although, the scientific basis is justified for improvement. It was found that it is possible through the present disclosure to exceed saturation of the API in a solid state within a transdermal drug -in-adhesive passive delivery system, which is surprising considering that the API is in a solid state, where it would not be expected by one of skill in the art that the API in its solid-state would be readily available for solubilization and subsequent permeation through membranes, such as human skin, which is not the typical behavior of solid-state particulates of API incorporated into a transdermal drug-in-adhesive or matrix systems.

[0075] The type of saturation is not super saturated wherein the API is still solubilized at a level above saturation, but the API is present in an over saturated level purposefully to be well above the ability of the matrix to solubilize to a significant extent the amount of API contained within the system and forces particulates to form. These particulates may be nanoparticulate or micronized drug with a less than about 300 micrometer particle size, such as a less than about 150 micrometer particle size (DI 00), or may be present as an API and substrate complex as a nanoparticulate or micronized solid-state particulate composition which does not change from its glass-like particulate nature while in presence of the other components of the transdermal delivery system’s drug-inadhesive layer. In one embodiment, the particle size can range from about 0.1 micrometers to about 150 micrometers, or any range therebetween. The solid state particulate API and substrate complex of the current invention is a glass-like particulate which is capable undergoing a reduction in its particle size by mechanical, precipitation, or other means to a particle size of less than about 300 micrometers, such as less than about 150 micrometers (D100) and such that the micronizing process does not impart excessive heat to cause melting or thermal change to the formed particulates. The micronized form of the API can be accomplished after dissolving both the API and a polymeric substrate into a suitable solvent system, followed by evaporation of the organic volatile solvents to less than ICH Q3C residual solvent levels. The resulting true solution (followed by evaporation of solvents) is produced as a sub-saturation for the purpose of maximal availability and permeability of the API for transdermal delivery. Each API and substrate complex can have an optimal level to maximize drug delivery from a transdermal patch. In contrast, most research alludes to maximizing the API to substrate ratio in such a manner to achieve the highest concentration of drug possible to form spray -dried, melt-extruded, spheronized particulates, and such methods are typically referred for oral pharmaceutical drug product development. It should be understood that the glass or glasslike particulates contemplated by the present disclosure are amorphous in nature, although not all amorphous materials are glass-like. Thus, to achieve the solid-state particulate API or API and substrate complex of the current invention, a glass or glass-like particulate is necessary to be achieved for purposes of drug-loading within the glass-like particulate. Surprisingly, these glass or glass-like particles are water soluble. It has been found that a polymer such as soluble polyvinylpyrrolidone (povidone) is uniquely amenable to such API and substrate complexes. Other polymers are contemplated which have similar organic solubility' to PVP and are also water soluble. These API:substrate complexes impart a significant improvement in the water solubility' of the API, and that the resulting particulate is a glass and that a glass is an amorphous material without the presence of crystalline entities amenable to particle size reduction. Other possible soluble polymers that can be used include celluloses (hydroxypropyl methylcellulose (HPMC) and derivatives, ethylcellulose (EC), acry lics), or any other soluble polymer that can be film fonning, amenable to particle size reduction, organic solvent soluble and water soluble.

[0076] Such amorphicity is accomplished by controlling the weight ratio of the substrate to API, where it has been found that a ratio of 1 : 1 when forming the complex using a process solvent that is evaporated would produce an amorphous structure that is undesirable because it is not glass-like in nature. On the other hand, to produce an amorphous and glass-like particulate, the weight ratio of the substrate to the API used to form the complex can range about 1.25 : 1 to about 20: 1 ; such as from about 1.5: 1 to about 15: 1; such as from about 2:1 to about 10: 1, such as from about 4: 1 to about 8: 1, or any ranges therebetween.

[0077] The present disclosure contemplates a method of preparation of a solid particulate API and substrate complex. For instance, the method involves solubilizing an API in a polymer to form a molecular dispersion (true solution) with molecularly dispersed active pharmaceutical ingredient(s) within said system and evaporation of said process solvents from said system to leave a uniform, homogeneous, crystal-free glass or glass-like structure which is amenable to particle size reduction and micronization. It should be understood that the API is undersaturated in the resulting complex of the API and the polymer. In some embodiments, the API can be present in the solid state particulate complex in an amount ranging from about 2 wt.% to about 30 wt.%, such as from about 4 wt.% to about 20 wt.%, such as from about 5 wt.% to about 7.5 wt.%, and any ranges therebetween, while the polymer can be present in an amount ranging from about 70 wt.% to about 98 wt.%, such as from about 80 wt.% to about 96 wt.%, such as from about 92.5 wt.% to about 95 wt.%, and any ranges therebetween. It should be understood that depending on the particular API, the weight ratio of the polymer to the API can vary when forming the complex. For instance, if the API is lenalidomide, the weight ratio of the polymer to the API can range from about 2.5:1 to about 20: 1; if the API is dexamethasone, the weight ratio of the polymer to the API can range from about 4: 1 to about 8: 1, and if the API is olanzapine, the weight ratio of the polymer to the API can range from about 4:1 to about 10: 1. In any event, a 1 : 1 ratio of polymer to API was not successful in the formation of a clear, glass-like material that could be micronized into a solid state particulate complex of the API and the polymer.

[0078] Further, the solvents that can be used to incorporate the API into the polymer to form the solid state particulate complex can include ethyl acetate, isopropanol, a polar aprotic solvent such as n-methyl-2-pyrrolidone (NMP), or a combination thereof, where the solvents are ultimately evaporated to form a transparent-glass like film that can be micronized to form the complex to use as a component of a transdermal delivery system. Further, the solvent can be present (prior to its evaporation), at a concentration ranging from about 10 wt.% to about 25 wt.% based on the total weight of the API, polymer, solvent, and any other excipients that may be present. Once the solid state particulate API and polymer complex is micronized, it can be added to various other components to form a transdermal delivery system, although it is to be understood that the particulate complex can also be incorporated into other dosage forms to prepare uniform dosage forms such as creams, gels, ointments, plasters, balms, salves, and / or pastes so long as there is a substrate created to support the suspension of the solid state particulate, whether it be the API or the API and polymer complex. When used in a transdermal deliver,' system, the transdermal delivery system can include a drug-in-adhesive layer that includes the solid state particulate API and polymer complex, an insoluble micronized solid material, such as cross-linked polyvinylpyrrolidone (crospovidone), a permeation enhancer, an adhesive polymer, other excipients, etc., as discussed in more detail below. The aforementioned components are combined to form a stable solid state particulate API and polymer in a uniform dispersion in the drug-in-adhesive layer, where the API in solid particulate form is not dissolved or disrupted upon the application of heat or the passage of time with no chemical or physical separation. This is in stark contrast to other systems, which have shown to fail, where it is obvious under polarized light microscopy that birefringence occurs in formulations, meaning that the API is separated from the glass-like particulate. On the other hand, the compositions and formulations of the present disclosure result in a solid-state particulate API which remains unchanged without birefringence after formation of the transdermal system.

[0079] Solid State Particulate API in a Transdermal Delivery System

[0080] As mentioned above, in some embodiments, the present disclosure is directed to a solid- state particulate API or API and polymer complex formed as described above, as well as a transdermal drug delivery system for the delivery' of said API through the skin. The transdermal drug delivery system includes a drug-in-adhesive layer that includes the solid-state particulate API or solid-state particulate API and polymer complex, an insoluble excipient, a permeation enhancer, and a pressure sensitive adhesive. The transdermal drug delivery system may also include other excipients as discussed below. Further, a method of forming the solid-state particulate API and then incorporating it into a drug-in-adhesive layer is contemplated.

[0081] More specifically, the present disclosure results in significantly improved performance characteristics for new and existing commercially available APIs having certain water solubility and melting temperature ranges. Permeation has shown to have improved benefits utilizing the solid-state particulate API or API and polymer complex contemplated herein to promote an increase in rate of API delivery as well as sustainability of the API delivery profile over up to about 7 days.

[0082] Stability of the API in a solubilized system is sometimes not trivial to overcome and the API may degrade to an unacceptable level over the shelf-life of the product and or the concentration gradient is lost due to patch efficiency and solubility issues after application. Thus, the solid state particulate API composition or formulation of the current invention maintains the API in a solid state which improves the ability of the API to remain stable during shelf-life storage and protects against environmental conditions such as oxidation or hydrolysis during storage as solid APIs are typically more stable than their solubilized solutions of the same API. Surprisingly, the solid-state particulate API of the current invention makes the API more readily available for permeation and facilitates the maintenance of a constant concentration gradient by incorporating the API into the drug-in-adhesive matrix in a uniform and consistent manner.

[0083] Relevant to the present disclosure, transdermal delivery of an API with a negative Log P is outside the scope of Lipinski’s Rule of 5, where this famous "rule of 5" has been highly influential in API development, but only about 50% of orally administered new chemical entities obey it. The rule is important to keep in mind during API discovery when a pharmacologically active lead structure is optimized stepwise to increase the activity and selectivity of the compound as well as to ensure API-like physicochemical properties are maintained as described by Lipinski's rule. Candidate APIs that conform to the “rule of 5” tend to have lower attrition rates during clinical trials and hence have an increased chance of reaching the market. The rule of 5 is not a set of 5 rules, however each rule is divisible by 5. A negative Log P implies the molecule should exhibit higher water solubility (hydrophilicity) as compared to being soluble in the organic phase (lipophilicity). Some molecules close to Log P of 0 to -1.5 exhibit unexpected solubilities and may not be properly determined by Log P alone as it pertains to hydrophilicity / lipophilicity.

[0084] Table 2: Lipinski’s Rule of 5

[0085] Modifications to the rules throughout the years include the Ghose filter, Veber’s rules, and other notable changes, such as, Log P from -0.4 to + 5.6; molar refractivity from 40 to 130; molecular weight from 180 to 480; and # of atoms from 20 to 70 which includes donor and acceptors in totality rather than independently accounting for them as a rule #1 or #2. Rotatable bonds less than 10 and polar surface area no greater than 140 A2have been found to have good oral bioavailability. These rules have been found to correlate to transdermal delivery of APIs as well to show viability of delivery.

[0086] Table 3: Ghose Filter and Veber’s Rule Sets Of particular interest, the present inventors have found that the APIs contemplated by the present disclosure may be outside the scope of Lipinski’s rule of 5, Ghose filter, or Veber’s rule on 1 or more key attributes, which would indicate that successful transdermal delivery is not viable; yet, the methods and formulations of the present disclosure show that transdermal delivery with increased penneation through the skin can be achieved.

[0087] Interestingly enough, melting point and water solubility are left out of these general rules of thumb as it comes to the development of APIs for drug delivery. The present inventors recognized APIs which exhibit characteristics for low water solubility (less than about 10 mg / mL) and have relatively high melting points (greater than about 120°C) are preferable to the current invention as solid-state particulate APIs are obtained. However, depending on other properties, API molecules that exhibit higher water solubility than 10 mg / mL may be amenable to formation of these solid-state particulate APIs, such that melting points are greater than about 120°C.

[0088] Transdermal delivery systems (TDS) described herein include transdermal formulations which may be in form of a liquid or semi-solid form of a desired degree of viscosity, for example, a suspension, nano suspension, micro suspension, dispersion, emulsion, micro emulsion, nano emulsion, gel. ointment, cream, paste, lotion, mousse, adhesive, patch, plaster or balm.

[0089] The transdermal formulation may form part of a transdermal delivery system that includes the transdermal formulation. Exemplary transdermal delivery systems include, without limitation, topical or transdermal formulations, systems, patches, or matrices in a bi-layered, multilayered, or monolithic system, with or without adhesive, with or without overlay, as a drug-in-adhesive, reservoir, microreservoir, hydrogel, mucoadhesive, adhesive, and / or tape as a system, patch, plaster, or combinations thereof for topical or transdermal use.

[0090] The solid-state particulate API. the solid state particulate API and substrate complex, or a combination thereof, may be used to be incorporated into or used to produce a microneedle, microblade, micro protrusion, dissolvable microneedle, absorbable microneedle, as a system, patch, plaster, or combinations thereof for topical or transdermal use.

[0091] In further embodiments, the formulations provided herein provide for stable solid-state fonnulations of the API within the transdermal formulations wherein the solid-state properties provide protection of the drug from a degradation profile of a solubilized drug in a similar composition. For example, the formulations are shelf stable and maintain at least 90% of their activity over a predetermined period, when stored under standard ambient conditions. In still further embodiments, the formulations are shelf stable for at least 3 months, 6 months. 9 months, one (1) year, two (2) years, or longer.

[0092] In another embodiment and depending on the API being delivered, the average flux rate of the API included in the transdermal drug delivery systems of the present disclosure can be at least 1 pg / cm2 / hr continuously throughout a period of 1, 2, 3, 4. 5. 6, 7, or more days. In some embodiments, the average flux rate of the API included in the transdermal drug delivery systems of the present disclosure can be at least 2 pg / cn / hr continuously throughout a period of 1. 2, 3, 4, 5, 6, 7, or more days, or the average flux rate of the API included in the transdennal drug delivery systems of the present disclosure can be at least 3 pg / cnv / hr continuously throughout a period of 1, 2, 3, 4, 5. 6, 7, or more days. In still other embodiments, the average flux rate of the API included in the transdermal drug delivery systems of the present disclosure can be at least 4 pg / cm2 / hr continuously throughout a period of 1, 2, 3, 4, 5. 6, 7, or more days. In yet other embodiments, the average flux rate of the API included in the transdennal drug delivery systems of the present disclosure can be at least 5 pg / cm2 / hr continuously throughout a period of 1, 2, 3, 4, 5, 6, 7, or more days. In still other embodiments, the average flux rate of the API included in the transdermal drug delivery’ systems of the present disclosure can be at least 6 p.g / cm2 / hr, 7 pg / cnr / hr. 8 |ig / cm2 / hr. or even 10 pg / cm2 / hr continuously throughout a period of 1, 2, 3, 4. 5. 6, 7, or more days.

[0093] Referring to Fig. 1 and according to one particular embodiment, the transdermal drug delivery system 100 includes a drag-in-adhesive layer 110 containing a solid-state particulate API and / or API and polymer complex 112. The drug-in-adhesive layer 110 is disposed between a backing layer 120 and a release liner 130. The backing layer 120 has an exterior surface 140 that is exposed to the ambient environment when the transdermal drag delivery system 100 is in use. Meanwhile, the release liner 130 is positioned on a skin-contacting surface 150 of the drag-inadhesive layer 110, where the release liner 130 is removable so that the drag-in-adhesive layer 110 can be positioned directly on the skin during use of the transdermal drug delivery system 100. As a result of the specific combination of components used to form drag-in-adhesive layer, such as the solid state particulate API and / or API and polymer complex 112, particular process solvents, insoluble excipient, and permeation enhancers, as well as the specific weight percentages and ratios of such components utilized, the present inventors have found that the transdermal drug delivery' system 100 can include solid state particulate API drag-in-adhesive matrix layer that fonns a skin-contacting surface, which facilitates the delivery of the API in a controlled manner at elevated levels. As shown in Fig. 1. the drag-in-adhesive layer 110 can be in the form of a single layer so that the active pharmaceutical ingredient in solid state particulate form 112 is uniformly dispersed throughout the adhesive component of the system 100.

[0094] The various components of the transdermal drug delivery system 100 are discussed in detail below.

[0095] I. Solid State Particulate Drag-in-adhesive Laver a. Active Pharmaceutical Ingredient

[0096] The API component of the drug-in-adhesive layer of the transdermal drag delivery system of the present disclosure can be any drug or active pharmaceutical ingredient (API) that has a low water solubility and high melting point, as APIs having such properties have been found to exhibit increased permeation and stability utilizing the transdermal delivery systems of the present disclosure. For instance, the API can 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 Further, the API can have a melting point of greater than 120°C, such as a melting point ranging 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 ranges therebetween. Moreover, the API can have a log P value ranging 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 ranges therebetween.

[0097] In one embodiment, the API can be an immunomodulatory agent. For instance, the immunomodulatory agent can include all pharmaceutically acceptable forms of an immunomodulatory imide compound, such as thalidomide, including analogs of thalidomide including lenalidomide, pomalidomide, and iberdomide including, for example, free base, salts, polymorphs, solvates, solutions, isomers, amorphous, crystalline, co crystalline, solid solution, prodrugs, analogs, derivatives, and metabolites and combinations thereof. The compound may be in the form of a pharmaceutically acceptable salt, such as an acid addition salt or a base salt, or a solvate thereof, including a hydrate thereof. Suitable acid addition salts are formed from acids which form non-toxic salts and examples are the hydrochloride, hydrobromide, hydroiodide, sulphate, bisulphate, nitrate, phosphate, hydrogen phosphate, acetate, maleate, fumarate, lactate, tartrate, citrate, gluconate, succinate, saccharate, benzoate, methane sulphonate, ethane sulphonate, benzenesulphonate, p- toluenesulphonate and pamoate salts.

[0098] In another embodiment, 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 drat are produced in the adrenal cortex of vertebrates, as well as the synthetic analogues of these hormones. Two main classes of corticosteroids, glucocorticoids and mineralocorticoids, are involved in a wide range of physiological processes, including stress response, immune response, and regulation of inflammation, carbohydrate metabolism, protein catabolism, blood electrolyte levels, and behavior. Synthetic pharmaceutical drugs with corticosteroid-like effects are used in a variety of conditions, ranging from hematological neoplasms to brain tumors or skin diseases. Dexamethasone and its derivatives are almost pure glucocorticoids, while prednisone and its derivatives have some mineralocorticoid action in addition to the glucocorticoid effect. Fludrocortisone is a synthetic mineralocorticoid. Hydrocortisone is typically used for replacement therapy, e.g., for adrenal insufficiency and congenital adrenal hyperplasia. Other corticoids include budesonide. and deflazacort. In another embodiment, the API can be an androgenic steroid such as testosterone, methyltestosterone, oxymetholone. or fluoxymesterone. In still another embodiment, the API can be an estrogen such as a conjugated estrogen, an esterified estrogen, estropipate, 17-B estradiol, 17-B estradiol valerate, equilin, mestranol, estrone, estriol, ethinyl estradiol, or diethylstilbestrol. In yet another embodiment, the API can be a progestin or progestogen such as progesterone, 19-norprogesterone, norethinedrone and its derivatives, melengestrol, chlormadinone, ethisterone, medryoxyprogesterone and its derivatives, hydroxyprogesterone and its derivatives, ethynodiol diacetate, norethynodrel, 17-a hydrosxyproge sterone, dydrogesterone, dimethisterone, ethinylestrenol, norgestrel, norelgestromin, norgestimate, drospirenone, etonogestrel, levonorgestrel, desogestrel, demegestone. promegestone, or megestrol acetate. Also contemplated are 5 -alpha-reductase inhibitors which can include dutasteride and finasteride.

[0099] Also contemplated are anti-inflammatory agents, such as, hydrocortisone, cortisone, dexamethasone, dexamethasone acetate, triamcinolone, and other derivatives, fluocinolone. triamcinolone, medrysone. prednisolone, flurandrenolide, prednisone, halcinonide, methylprednisolone, fludrocortisone, corticosterone, paramethasone, betamethasone and derivatives.

[0100] In yet another embodiment, the API can be an antipsychotic or tricyclic antidepressant. For instance, the API can be olanzapine (2-methyl-10-(4-methyl-l-piperazinyl)-4H-thieno-[2,3- b][l,5]benzo-diazepine), which is an antipsychotic medication used to treat schizophrenia and bipolar disorder. It is usually classed with atypical antipsychotics, a newer generation of antipsychotics. It has been approved by the FDA in tablet form under the brand name Zyprexa® for treatment of schizophrenia and bipolar mania. Olanzapine has also been investigated for use as an antiemetic at oral doses of 10 mg and 5 mg a day, generally in combination with one or more further agents, e.g., to treat nausea and vomiting after administration of the chemotherapeutic cisplatin. Other antipsychotic APIs contemplated by the present disclosure include thiopropazate, chlorpromazine, triflupromazein, mesoridazine, piperacetazine, thioridazine, acetophenazine, fluphenazine. perphenazine, trifluoperazine, chlorprathixene, thiothixene, haloperidol, bromperidol, loxapine, molindone, aripiprazole, lurasidone, quetiapine, cariprazine, brexpiprazole, olanzapine, ziprasidone, asenapine, risperidone, paliperidone, lumateperone, iloperidone, pimavanserin, and clozapine.

[0101] In still another embodiment, the API can be a Bruton’s tyrosine kinase (BTK) inhibitor. BTK inhibitors are a type of drug that works to treat cancers caused by defective B cells, such as chronic lymphocy tic leukemia, B-cell lymphomas, and Waldenstrom macroglobulinemia. For example, the API can be ibrutinib, acalabrutinib, pirtobrutinib, zanubrutinib, evobrutinib, tirabrutinib, and orelabrutinib.

[0102] Regardless of the particular API utilized, the amount of the API contained in the drug-inadhesive layer can range from about 1 wt.% to about 40 wt.%. such as from about 2 wt.% to about 30 wt.%, such as from about 3 wt.% to about 25 wt.%, such as from about 3.5 wt.% to about 20 wt.%, such as from about 4 wt.% to about 15 wt.%, such as from about 4.5 wt.% to about 8 wt.%, or any ranges therebetween, based on the dry weight of the drug-in-adhesive layer. b. Soluble Polymer

[0103] The soluble polymer that can be used to form the solid-state particulate API and soluble polymer complex can include polyvinylpyrrolidone (PVP or povidone), such as uncrosslinked PVP. Suitable soluble grades of PVP as provided by BASF can includes Kollidon® grades 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 copolymers thereof by different vendors, such as Plasdone®. Other soluble polymers that can be used include celluloses such as ethylcellulose (Ethocel® or Aquaion®). Preferably, polymers, such as Plasdone® (povidone / polyvinylpyrrolidone) or Kollidon® K-30 or K-30 LP and Kollidon® K-90 (soluble povidone / polyvinylpyrrolidone) have found suitability in preparation of these solid-state suspensions. Further. Kollidon® K-12 (molecular weight range 2,000-3,000; pH 4.63), and Kollidon® K-12 PF were found not amenable to forming a glass-like particle which is capable of being micronized. possibly due to their low molecular weight. It is believed other molecular weights, such as Kollidon® K-25. K-45. K-60. or K-120 (molecular weight of 3,000,000) would be suitable such that a viable means of production of the APEsubstrate was amenable to the creation of a glass-like particulate which is micronizable. Thus, in some embodiments, when the soluble polymer is polyvinylpyrrolidone, the polyvinylpyrrolidone can have a molecular weight that is greater than 3,000, such as from about 7.000 to about 3.000.000 in Daltons.

[0104] Regardless of the particular soluble polymer utilized, the amount of the soluble polymer contained in the drug-in-adhesive layer can range from about 1.5 wt.% to about 50 wt.%, such as from about 2 wt. to about 47.5 wt.%, such as from about 3 wt.% to about 45 wt.%, such as from about 4.5 wt.% to about 40 wt.%, or any ranges therebetween, based on the dry weight of the drugin-adhesive layer.

[0105] Moreover, the ratio of the soluble polymer to the API in the final drug-in-adhesive layer can range from about 1.25: 1 to about 20: 1, such as from about 1.5:1 to about 15: 1, such as from about 2:1 to about 10:1, such as from about 4: 1 to about 8: 1, or any ranges therebetween. c. Process Solvent for API and API 'Soluble Polymer Solid Particulate Formation

[0106] A first process solvent can be used to dissolve or solubilize the API and the soluble polymer for forming a glass-like film upon evaporation of the solvent, which can then be micronized to form the solid-state particulate API or API and polymer complex. In one embodiment, the first process solvent can include one or more polar aprotic solvents to maximize solubility and thus concentration of drug in first solvent system.

[0107] A polar aprotic solvent is a solvent that lacks an acidic proton and is polar. Such solvents lack hydroxyl and amine groups. These solvents do not serve as proton donors in hydrogen bonding, although they can be proton acceptors. Specific examples contemplated by the present disclosure can include Pharmasolve® a brand name of n-methyl-2-pyrrolidone (NMP), 2-pyrollidone (2-pyrol®). dioxane, propylene carbonate, dimethyl sulfoxide (DMSO), dimethyl isosorbide, dimethylacetamide, ethyl acetate, or a combination thereof, although it is to be understood that other polar aprotic solvents are also contemplated by the present disclosure, including, but not limited to, isopropanol, ethyl acetate, acetone, acetonitrile, dichloromethane, dimethylformamide. DMPU. and tetrahydrofuran.

[0108] Regardless of the particular polar aprotic solvent or combination of polar aprotic solvents utilized, the total amount of polar aprotic solvent contained in the micronized solid-state particulate containing the API can be detectable in an amount less than ICH Q3C Impurities: Guideline for Residual Solvents. For NMP, this equates to levels of less than about 530 parts per million, or less than about 0.053 wt.%, such as less than about 390 parts per millions, or less than about 0.039 wt.%. based on the dry weight of the solid state particulate, where the NMP is to be considered a process solvent. However, it is to be understood that such solvents are introduced in larger wt.% levels to form the glass-like film that is then micronized to form the solid-state particulate API or API and polymer complex prior to any evaporation or drying. d. Insoluble Excipient

[0109] The drug-in-adhesive layer of the transdermal drug delivery system of the present disclosure can also include an insoluble excipient to act as a substrate for forming the drug-inadhesive layer. In one embodiment, the insoluble excipient can be a micronized crosslinked polyvinylpyrrolidone (PVP). such as a crosslinked homopolymer of N-vinyl-2-pyrrolidone. In one particular embodiment, the crosslinked PVP is in the form of a water-insoluble powder. Such cross-linked PVPs are commercially available under the name Kollidon®. available from BASF. A specific example of a cross-linked PVP that is contemplated for use in the present disclosure is Kollidon® CL-M. Other cross-linked PVPs that can be used include Kollidon® CL-SF and CL-F, as well as Ashland Polyplasdone®. Other insoluble excipients that are contemplated include cellulosic derivatives, such as ethyl cellulose, croscarmellose, carboxymethylcellulose, or starches, as well as cross-linked acry lic polymers, such as Carbopol, minerals or clays, such as silica, Polargel®, bentonite, kaolin, or silicates.

[0110] Further, the insoluble excipient can be micronized, although this is not required, and can have an average particle size ranging from about 1 micrometer to about 40 micrometers, such as from about 2 micrometers to about 30 micrometers, such as from about 3 micrometers to about 10 micrometers. In addition, in one particular embodiment, greater than 90% of the particles utilized can have a particle size less than about 15 micrometers. The particle size of the cross-linked PVP contemplated for use in the drug-in-adhesive matrix layer of the present disclosure is thus smaller than typical cross-linked PVPs, which can have particle sizes up to 150 micrometers. Without intending to be limited by any particular theory, the present inventors have found that utilizing an insoluble cross-linked PVP can result in the formation of a stable polymer blend that is used to form the drug-in-adhesive layer, where the solid state particulate API or API and polymer complex described above is maintained in a uniform suspension with minimal sedimentation as the insoluble excipient can assist in maintaining homogeneity of suspended particles in a substantially liquid composition. This, in turn, enables the formation of a homogeneous dispersion of the solid- state particulate API in the drug-in-adhesive layer so that the transdermal drug delivery system can deliver the API in a controlled manner through the skin.

[0111] The amount of the insoluble excipient contained in the drug-in-adhesive layer can range from about 1 wt.% to about 15 wt.%. such as from about 2 wt.% to about 10 wt.%, such as from about 3 wt.% to about 9 wt.%, such as from about 4 wt.% to about 8 wt.%, or any ranges there betw een based on the dry weight of the drug-in-adhesive layer. e. Process Solvent for Drug-in-Adhesive Layer Formation

[0112] A second process solvent system can be used to form the drug-in-adhesive layer. Airy suitable solvent can be used so long as the second process solvent system does not dissolve or significantly disrupt the solid-state particulate API or API: substrate. The APkpolymer complex is not capable of being dissolved therein since the solid-state particulates must remain insoluble and be ultimately suspended homogeneously within the resulting drug-in-adhesive transdermal delivery system.

[0113] In one embodiment, the second process solvent system is typically different from the first process solvent, where the drug or API is not necessarily soluble to a significant extent in the second solvent system. Solvents contemplated for preparation of the blend of the drug-in-adhesive matrix may include volatile solvents such as. esters, alkanes, silicones, cyclics. which may include but not limited to heptane, hexane, pentane, ethyl acetate, propyl acetate, butyl acetate, cyclohexane, volatile silicone fluids, and toluene. In certain cases, polar aprotics or alcohols may be used, but not in the presence of polyvinylpyrrolidone: API particulate complexes due to solubility’ of PVP in presence of alcohol or polar aprotic solvents, such as but not limited to NMP, DMSO, ethanol, or isopropanol.

[0114] Regardless of the particular solvent or combination solvents utilized, the total amount of volatile solvent contained in the resulting drug-in-adhesive layer can be detectable in the transdermal drug delivery’ system in an amount less than ICH Q3C Impurities: Guideline for Residual Solvents. For most Class 3 solvents, to be considered a process solvent, the solvent is ty pically present in an amount of less than 5000 parts per million or less than 0.5 wt.% based on the dry weight of the drugin-adhesive layer. However, it is to be understood that such solvents are introduced in larger wt.% levels to form the excipient formulation and prior to any evaporation or drying. It is intended that any volatile process solvent will meet the requirements of ICH Q3C guidance document, if so incorporated into the system. f. Adhesive Polymer

[0115] The drug-in-adhesive layer of the transdermal drug delivery system of the present disclosure also includes one or more suitable pressure sensitive adhesives (PSA). Adhesive polymers may be made from various materials which include plastics, polymers, pressure sensitive adhesives, selfadhering systems, or may require additional excipients to obtain pressure sensitive properties. Basic adhesive systems are selected from polyacrylics, silicones, polyisobutylenes, rubbers, and combinations thereof either by physical blending or copolymerization is disclosed. These materials may be obtained from solvent-borne, water-borne, physical mixtures, extruded, co-extruded, hot melt, or otherwise formed as polymerized or unpolymerized materials.

[0116] In one embodiment, the PSA can be an acry lic polymer. Useful acrylic polymers include various homopolymers, copolymers, terpolymers and the like of acry lic acids and derivatives thereof as a cross-linked, cross-linkable, uncross-linked, uncross-linkable, grafted, block, cured and noncuring pressure sensitive adhesives (PSAs). These acrylic polymers include copolymers of alkyl acrylates or methacrylates. Polyacrylates include aery lie acid, methacrylic acid, and derivatives thereof without limitation, methyl acylate, methyl methacrylate, ethyl acrylate, ethyl methacrylate, n- butyl acrylate, n-butyl methacrylate, hexyl acrylate, 2-ethylbutyl acry late, isooctyl acrylate, 2- ethylhexyl acrylate, 2-ethylhexyl methacrylate, decyl acrylate, decylmethacrylate, dodecyl acrylate, dodecyl methacrylate, tridecyl acrylate, tridecyl methacrylate, vinyl acetate, 2-hydroxyethyl acry late, glycidyl methacrylate, or octylacrylarnide. The acry lic polymer may be functional species with levels of hydroxyl or carboxyl moieties or combinations thereof, non-functional species without functional moieties. non-reactive species with moieties which are less reactive than hydroxyl or carboxyl moieties, such as methyl or ethyl or propyl or butyl capped acrylamides. Exemplary acrylics include Plastoid B® by Evonik or acrylic PSAs by Henkel Corporation include, without limitation, one or more of: Duro-Tak® 87-900 A, 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® 87-235 A, Duro-Tak 387-2353 / 87-2353, Gelva® GMS 9073, Duro-Tak® 87-2852. 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 the disclosure herewith incorporates known and unknown naming conventions comprising the monomers disclosed.

[0117] In one particular embodiment, the present inventors have found that the use of a PSA that includes an aery late copolymer without having -COOH or -OH functional groups or moieties contribute to the improved permeation of the API contained in the drug-in-adhesive layer. Further, it has also been found that an acry late copoly mer having a solids content ranging from about 30% to about 55%, such as from about 35% to about 50%, such as from about 36% to about 45% also contributes to the improved solubility' and penneation of the immunomodulatory agent. Additionally, an acry late copolymer having a viscosity' of less than about 6500 centipoise, such as from about 2000 centipoise to about 5000 centipoise, such as from about 2500 centipoise to about 4500 centipoise may also contribute to the improved solubility and permeation of the API, where the viscosity impacts the loading capacity of the components in polymer blend used to form the drug-inadhesive matrix layer. Further, an acrylate copolymer that includes vinyl acetate may also be beneficial.

[0118] Particular examples include Duro-Tak® 87-9301 (non-reactive amine, 36.5% solids), Duro- Tak® 387-2516 / 87-2516 (vinyl acetate; -OH functional groups; 41.5% solids; viscosity of 4350 centipoise). Duro-Tak® 387-2052 / 87-2052 (vinyl acetate; -COOH functional groups. 47.5% solids; viscosity of 2750 centipoise), or Duro-Tak® 87-4098 (vinyl acetate; 38.5% solids content; viscosity of 6500 centipoise).

[0119] In still another embodiment, the PSA can include silicone. Suitable silicone adhesives include pressure sensitive adhesives made from silicone polymer and resin. The polymer to resin ratio can be varied to achieve different levels of tack. Specific examples of useful silicone adhesive which are commercially available include the standard DuPont® Liveo® BIO-PSA series (7-4400. 7- 4500, and 7-4600 series) and the amine compatible (end capped) DuPont® Liveo® BIO-PSA series (7-4100, 7-4200, and 7-4300 series) manufactured by DuPont. Preferred adhesives include LIVEO® versions of the 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. Soft elastomeric silicone 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).

[0120] In still another embodiment, the PSA can include poly isobutylene. Suitable polyisobutylene adhesives are those which are pressure sensitive and have suitable tack. Polyisobutylene can comprise a mixture of high and medium molecular weight polyisobutylenes, polybutenes, and mineral oils. Specifically, high molecular weight polyisobutylenes are those with a molecular weight of at least about 425.000. Medium molecular weight polyisobutylenes are those with a molecular weight of at least 40.000 but less than about 425,000. Low molecular weight polyisobutylenes are those with a molecular weight of at least 100 but less than about 40,000. Specific examples of useful polyisobutylene adhesives which are commercially available include Oppanol® High Molecular WeightN grades 50. 50SF. 80, 100 and 150, and Oppanol® Medium Molecular Weight B grades 10N, 10SFN, 11SFN, 12SFN, 12N. 13SFN. 14SFN, 15SFN, and 15N manufactured by BASF. Specific examples of polybutenes are commercially available from Soltex as polybutenes of various molecular weights and by Ineos as Indopol and Panalane with various molecular weights. A specific example of a useful poly isobutylene formulated adhesive which is commercially available includes Henkel Duro-Tak® 87-6908.

[0121] Other pressure sensitive adhesives obtained from rubber block copolymers, such as Styrene- Isoprene-Styrene (SIS) or Styrene-Butadiene-Styrene (SBS) based adhesives are also contemplated by the present disclosure.

[0122] Regardless of the particular PSA utilized, the pressure sensitive adhesive can be present in an amount ranging from about 1 wt.% to about 80 wt.%, such as from about 20 wt.% to about 75 wt.%, such as from about 25 wt.% to about 70 wt.%, or any ranges therebetween, based on the dry weight of the drug-in-adhesive layer.

[0123] In addition, it should be understood that other polymers can be utilized as adhesive polymers in combination with a plasticizer. For instance, other polymers that can be utilized that can include an ethylene-vinyl acetate copolymer, such as Celanese® EVAs, a polyvinylpyrrolidone, such as BASF’s Kollidons™ or Ashland’s Plasdones®. a cellulose, such as Ashland’s Aquaion™, Benecel™ or Klucel™ or a combination thereof. g. Skin Permeation and Solubility Enhancers

[0124] The drug-in-adhesive layer of the transdermal drug delivery system of the present disclosure can also include one or more suitable surfactants (e.g., non-ionic surfactants), plasticizers, humectants, or a combination thereof that can serve as a skin permeation enhancer to improve the permeation of the API through the skin during use of the transdermal drag delivery system.

[0125] In some embodiments, the skin permeation enhancer can include one or more of the following: sulfoxides, and similar chemicals such as but not limited to dimethyl sulfoxide, dimethylacetamide, dimethylformamide, dimethyl sulfoxide, dimethyl isosorbide; azone, pyrrolidone such as but not limited to N-methyl-2 -pyrrolidone, 2-pyrrolidone, N-(2-hydroxyethyl)-2-pyrrolidone (HEP), n-octyl pyrrolidone (NOP). N-ethyl-pyrrolidone (NEP); esters, fatty acid esters such as but not limited to propylene glycol monolaurate, butyl ethanoate, ethyl ethanoate, isopropyl myristate, isopropyl palmitate, ethyl oleate, oleyl oleate, methyl ethanoate, decyl oleate, propylene glycol monocaprate, propylene glycol monolaurate, diethylene glycol monoethyl ether, glycerol monooleate, glycerol monolaurate, lauryl laurate, lauryl lactate, and others; fatty acids (C8 to C26 fatty acids), such as but not limited to capric acid, caprylic acid, lauric acid, oleic acid, myristic acid, linoleic acid, stearic acid, palmitic acid, stearic acid, arachidic acid, behenic acid, lignoceric acid, cerotic acid, myristoleic acid, palmitoleic acid, sapienic acid, elaidic acid, vaccenic acid, lenoelaidic acid, alpha-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-butyl alcohol, tert-amyl alcohol, 3-methyl-3-pentanol. heptanol, octanol, perlargonic alcohol, decanol, undecyl alcohol, tridecyl alcohol, pentadecyl alcohol, cetyl alcohol, palmitoleyl alcohol, heptadecyl alcohol, stearyl alcohol, oleyl alcohol, Lauryl alcohol, myristy l alcohol, nonadecyl alcohol, arachidyl alcohol, heneicosyl alcohol, behenyl alcohol, erucyl alcohol, lignoceryl alcohol, ceryl alcohol, hepacosanol, montanyl alcohol, nonacosanol, myricyl alcohol, dotriacontanol, geddyl alcohol and others.; and glycols such as but not limited to , nathanol, dodecanol, propylene glycol, dipropylene glycol, tripropylene glycol, polyethylene glycol (MW 200 to 20000), glycerol and others ethers alcohol 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, esters of fatty alcohols, essential oils, hydramol, surfactant type enhancers such as but not limited to a nonionic surfactant, such as a nonionic surfactant of a fatty alcohol, one of its derivatives, or a combination thereof. For instance, polyoxyethylene or alcohol ethoxylate surfactants based on laury l alcohol, oleyl alcohol, or cetyl alcohol such as Brij L. LT, C, CS, O or S, such as but not limited to S2, LT3, 02. 03. 05. LT4, L4, CS6, 010, S10, CS12. L9. S20, 020. S721. CS20, CS25, LT23, or L23, where 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 Pareth-3 or C12-C12 Pareth-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. Meanwhile, the number after each series of letters or letter refers to the number of moles of EO present, referring to the level of ethoxylation. Specifically, non-ionic surfactants having HLB values of less than about 12, such as HLB values less than about 10. such as HLB values between about 5 and about 10, were found to be highly advantageous, including, but not limited to 03, 05, L4, S2, LT3, LT4, C2, and / or CS6. Meanwhile, non-ionic surfactants having HLB values above 12, such as 010 and 020 with HLB values of 12.4 and 15.5, respectively, were found to not be as advantageous in the particular formulations of the present disclosure in terms of improvement of the permeation of the API. Additionally, surfactants such as sodium laury l sulfate, tween, polysorbate; terpene, terpenoids and all penetration or permeation enhancers referred in the book “Percutaneous Penetration Enhancers"’ (Eric W. Smith, Howard I. Maibach, 2005. Nov, CRC press) are contemplated by the present disclosure.

[0126] For example, nonionic surfactants that can be utilized include oleths that include one or more polyethylene glycol ethers of oleyl alcohol and laureths that include one or more polyethylene glycol ethers lauryl alcohol. For instance, the skin permeation enhancer can be polyethylene glycol dodecyl ether (Brij L4 or laureth-4). Without intending to be limited by any particular theory, is believed that the nonionic surfactant contributes to an increase in flux and the ability' of the system to overcome a barrier of drop in flux 24-hours post application to the skin.

[0127] Other non-ionic surfactants that are contemplated are ABA-type co-polymers of poly (ethylene oxide) (PEO=A) and poly (propylene oxide) (PPO=B), which can be referred to as poloxamers (e.g., P181 (HLB of 29), P188 (HLB > 24), P338 (HLB > 24), P407 (HLB of 18-23), or a combination thereof, commercially' available as Kolliphor®, Pluronic®, or Lutrol®), or any other suitable surfactant having an HLB value of greater than about 18, such as from about 18 to about 32, such as from about 18 to about 30, which can act as a solubility enhancer when used in combination with a nonionic surfactant having an HLB of less than about 12.

[0128] Regardless of the particular skin permeation enhancer utilized, the skin penneation enhancer can be contained in a polymer blend used to form die drug-in-adhesive layer and can be present in an amount ranging from about 1 wt.% to about 40 wt.%, such as from about 7.5 wt.% to about 35 wt.%, such as from about 10 wt.% to about 30 wt.%, or any ranges therebetween, based on the dry weight of the drug-in-adhesive layer of the transdermal drug delivery system. In one particular embodiment, the skin penneation enhancer can include from about 2.5 wt.% to about 30 wt.%, such as from about 5 wt.% to about 22.5 wt.%, such as from about 7.5 wt.% to about 25 wt.% of a non-ionic surfactant, where it has been found that the use of such skin permeation enhancers can result in a transdermal drug delivery system that exhibits significantly improved onset and sustained delivery of the API. h. Other Excipients

[0129] The drug-in-adhesive layer can also include gelling agents and / or thickening and / or suspending agents and / or polymers and / or adhesive polymers and / or pressure sensitive adhesive polymers known to those skilled in the art either alone or in combinations thereof without any limitation to following like natural polymers, polysaccharides and its derivatives such as but not limited to (agar, alginic acid and derivatives, cassia tora, collagen, gelatin, gellum gum, guar gum, pectin, potassium, or sodium carrageenan, tragacanth, xantham, gum copal, chitosan, resin etc.), semisynthetic polymers and its derivatives such as without any limitation to cellulose and its derivatives (methylcellulose, ethyl cellulose, carboxymethyl cellulose, hydroxypropyl cellulose, hydroxylpropylmethyl cellulose, hydroxypropyl methylcellulose acetate succinate etc.), synthetic polymers and its derivatives such as without any limitation 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), silicon dioxide, polyvinyl alcohol, acrylic polymers (Eudragit), acrylic acid esters, polyacrylate copolymers, polyacrylamide, polyvinyl pyrrolidone homopolymer and polyvinyl pyrrolidone copolymers such as but not limited to (PVP, Kollidon 30, poloxamer), isobutylene, ethyl vinyl acetate copolymers, natural rubber, synthetic rubber, hot melt adhesives, styrene-butadiene copolymers, bentonite, all water and / or organic solvent swellable polymers, etc. In exemplary embodiments, formulations of the disclosure may comprise gelling agents and / or thickening and / or suspending agents and / or polymers and / or adhesive polymers and / or pressure sensitive adhesive polymers.

[0130] The drug-in-adhesive layer can also include plasticizers known to those skilled in the art either alone or in combination thereof without any limitation to following like glycerol and its esters, phosphate esters, glycol derivatives, sugar alcohols, sebacic acid esters, citric acid esters, tartaric acid esters, adipate, phthalic acid esters, triacetin, oleic acid esters and all the plasticizers which can be used in transdermal drug delivery system referred in the book “Handbook of Plasticizers” (George Wypych, 2004, Chem Tec Publishing).

[0131] The drug-in-adhesive layer can further include solubilizers, additional surfactants, emulsifying agents, dispersing agents and similar compounds or chemicals known to those skilled in the art either alone or in combination thereof without any limitation to following like polysorbate 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, propy lene gly col monocapry late ty pe I, propy lene glycol monocapry late type II, propylene glycol dicapr late, medium chain trigly cerides, propylene glycol monolaurate type II, linoleoyl polyoxy 1-6 glycerides, oleoyl-polyoxy 1-6-glycerides, lauryl poly oxy l-6-gylccridcs. polyglyceryl-3-dioleate. diethylene glycol monoethyl ether, propylene glycol monolaurate type I, polyglyceryl-3-dioleate, caprylocaproylpolyoxyl-8 glycerides, cyclodextrins and others.

[0132] The drug-in-adhesive layer can further include excipients or chemicals known to those skilled in the art either alone or in combination thereof without any limitation to following like cholecaciferol, vitamin D3, Vitamin B12. cyanocobalamin, Vitamin E. tocopherol, tocopherol acetate, tocopherol polyethylene glycol succinate (TPGS). polyethylene glycol (PEG), hyaluronic acid, alpha-hydroxy acids or derivatives thereof, BHA, BHT, panthenol, propyl gallate, ascorbyl palmitate, sugars, sugar alcohols, amino acids, polyols, phytantriol, pantothenic acid, urea, and other antioxidants or protectants and or atypical humectants.

[0133] II. Backing Laver

[0134] Referring again to Fig. 1, in addition to the drug-in-adhesive layer 110, the transdermal drug delivery system 100 of the present disclosure can include a backing layer 120 that forms the exterior surface 140 of the transdermal drug delivery system 100. The backing layer 120 can be occlusive in nature and can protect the polymer layer (and any other layers present) from the environment and prevents loss of the drug and / or release of other components to the environment during use.

[0135] Materials suitable for use as backing layers are well-known known in the art and can comprise films of polyester, polyethylene, polypropylene, vinyl acetate resins, ethylene / vinyl acetate copolymers, ethylene / vinyl alcohol copolymers, polyvinyl chloride, polyurethane, cotton, cellulose(s), and the like, in part or in multi-laminate or co-extruded forms, which may include metal foils, aluminum vapor coated plastics, non-woven fabric, cloth and commercially available laminates. A typical backing material has a thickness in the range of 2 to 1000 micrometers. For example, 3M's Scotchpak® 1012 or 9732 (a polyester film with an ethylene vinyl acetate copolymer heat seal layer), 9723 (a laminate of polyethylene and polyester), 9754 (a polyester film backing laminate), or CoTran® 9720 (a polyethylene film), Japan Vilene’s polyester films such as EH-1212, or non-woven polyesters, such as EW2080S, EW-9100, EW-9050, EW-2500N, etc., are useful in the transdermal drug delivery systems described herein, as are Dow® backing layer films, such as Dow® BLF 2050 (a multi-layer backing comprising ethylene vinyl acetate layers and an internal SARAN® layer as well as Kuraray’s ethylene-vinyl alcohol based films, such as, EF-F, EF-E, EF-XL, VM-XL. and HF- ME.

[0136] III. Release Liner

[0137] Referring still to Fig. 1, in addition to the drug-in-adhesive layer 110 and the backing layer 120, the transdermal drug delivery system 100 of the present disclosure can also include a release liner 130 disposed on the skin-contacting surface 150 of the transdermal drug delivery system that can protect the drug-in-adhesive layer 110 of the transdermal drug delivery system 100 until it is ready to be applied to a patient’s skin. Once the transdermal drug delivery sy stem 100 is to be applied to a patient’s skin at its skin-contacting surface 150, the release liner 130 can be removed and discarded. Materials suitable for use as release liners are well-known known in the art, such as polymers or fluids of silicone or fluorosilicone or fluorocarbon coated or casted or cured onto a substrate, such as polyester, polyethylene (LDPE or HDPE), styrene, polyvinylchloride (PVC) films, which may include but not limited to commercially available products from Dow Coming Corporation designated Bio-Release® liner and Syl-off® 7610, Loparex's PET release liner which are silicone-coated polyester films. Japan Vilene’s silicone coated polyester release liners. Saint Gobain’s 4130, 4140, 7819, 7748, 7754, 8005, 8310, 6113, 6113A, 7015, 6024, 8312, 8312N, or 9011 liner, and 3M's 1020, 1022. 9741. 9744. 9748. 9749. and 9755 Scotchpak® liners, which are fluoropolymer-coated polyester films.

[0138] IV. Overlay System

[0139] In addition to the drug-in-adhesive layer 110. the backing layer 120, and the release liner 130, the transdermal drug delivery system 100 of the present disclosure can also include an optional or inherent overlay system 160 to ensure the transdermal drug delivery system is adhered and secured to the patent’s skin during the entire intended wear period. The overlay system 160 can be an occlusive or non-occlusive material made from cloth, fabric, paper, foam, or plastics, and incorporates an adhesive layer for skin contact and adherence. Materials suitable for use as overlay systems are well-known known in the art and include but not limited to the commercially available products of medical tapes, such as 3M's Cotran® 1523, 2480, 2484, 2476P, 9693, 9695, 9699, 9865, 9907T, or 9952. Overlay systems may be customized in a manner to ensure compatibility with the drug-in-adhesive system to mitigate migration or cold flow and ensure adequate interlaminar adhesion to the drug-in-adhesive system and overall, for proper adhesion to patient during the intended wear period. In most cases, the drug-in-adhesive layer is formulated in a manner which inhibits the ability of the drug-in-adhesive layer to act solely alone to adhere to the patient for the intended wear period. In this case, the present inventors have found that the overlay system can serve to adhere the system to the patient, reduces potential for cold flow, and ensure patch is almost 100% adhered to the patient during the wear period which ensures ability for the TDS to deliver consistently and therapeutically.

[0140] V. Method of Making the Transdermal Drug Delivery System

[0141] Generally, the drug-in-adhesive layer of the present disclosure is made by combining the components in a specific order, resulting in the ability to form a transdermal drug delivery system with a solid state particulate API or API and polymer complex homogeneously distributed within the drug-in-adhesive layer that exhibits improved permeation of the API through the skin. Referring to Fig. 2, one method 200 of making a formulation for a transdermal drug delivery system of the present disclosure is shown. First, in step 201, which is a blending step, the API can be added to a first process solvent to form a solution, where the API is solubilized or dissolved in the solvent to form a true solution. Further, in step 202, which is also a blending step and can be omitted entirely or can occur before or in conjunction with step 201, the soluble polymer can be added to the solution containing the first process solvent and the API, where the polymer is also solubilized or dissolved in the solvent. Next, in step 203, which is a drying step, the solution is heated or dried so that the first process solvent is evaporated, leaving a glass-like, clear film containing tire API or the API and die soluble polymer. Next, in step 204, the film is micronized to form solid state particulates of the API or the API and polymer, which can be referred to as a micronization step. Then, hr step 205, which is a blending step, the particulates are combined w ith other components such as an adhesive polymer, non-ionic surfactant, second process solvent, an insoluble excipient, etc. Thereafter, in step 206, the aforementioned components are blended or mixed to homogenize and form suspension. Then, in step 207, the resulting drug-in-adhesive layer can be coated on to a release liner or backing layer on one surface, after which any organic solvents present can be allowed to evaporate in step 608. Then, the opposing surface of the drug-in-adhesive layer can be applied to (e.g., laminated to) a backing layer or release liner in step 209. Thereafter, individual transdermal drug delivery systems can be die-cut from a large sheet of the formed transdermal drug delivery system, either with or without an inherent overlay system that ensures adhesion to a patient, where it is understood that inherent overlay systems are not drug-bearing and can be non-woven / non-occhisive or occlusive in nature to form the finished drug product contained in a flat heat-sealed pouch.

[0142] The present disclosure may be better understood by reference to the following examples. EXAMPLES OVERVIEW

[0143] Efforts were pursued to understand the viability of solid state active pharmaceutical ingredients as a viable alternative to a solubilized API platform for drug-in-adhesive transdermal delivery systems.

[0144] For in vitro permeation testing, the prepared transdermal formulations in the following examples were subjected to a flux (in vitro permeation) test as follows with Strat-M® synthetic membrane. The Strat-M® synthetic membrane is utilized as instructed by the Millipore-Sigma instruction guide on its use. The patches are die cut to a 5 / 16” diameter (~0.5 cm2) and affixed to the skin with use of an overlay to secure patch to skin. Receiver media is either standard saline (0.9% NaCl in DI water) or a fixed concentration (l%-5%) of povidone in DI Water. Sample volume is 5 mL. Franz cell volume is 5 mL. Sampling intervals are over the intended wear period from 0 to up to 168 hours. Sample time points are typically at 8, 24, 48. 72, 96, 120, 144 and 168 hours. Actual patch size is 0.5 cm2with an effective flux area of about 0.6 cm2. Aliquots taken are analyzed by HPLC method for each independent API. Typically, 3-5 replicates per formulation are performed to ensure adequate statistical significance is obtained for each study.

[0145] EXAMPLE 1

[0146] In Example 1, lenalidomide was utilized 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 incorporated into a solid-state particulate complex in a drug-inadhesive formulation.

[0147] EXAMPLE 2

[0148] In Example 2, the feasibility of utilizing silicone dioxide instead of polyvinyl pyrrolidone was considered as a substrate with dexamethasone as the API. It was found that although the silicon dioxide was claimed to be an amorphous carrier of the drug, the resulting solution of dexamethasone, silicon dioxide and organic solvent (DMSO) did not dissolve both dexamethasone and silicon dioxide. Particulates of silicon dioxide appeared gel-like, but solid particulate presence was observed. The resulting blend was dried under heat in a convection oven. A powder was obtained and considered to provide an amorphous nature of die API. However, the addition of such a level of silicon dioxide in an adhesive would be detrimental to the quality of adhesive characteristics, such that loading 5% drug would add no less than 5% silicon dioxide to a formulation and would be more if the concentration of the API to silicon dioxide is less than a 1 : 1 ratio. For example, a 10% API in silicon dioxide formulation would add 45% silicon dioxide to an adhesive formulation when loading 5% drug into the drug-in-adhesive. Based on this circumstance and prior knowledge of presence of silicon dioxide in transdermal adhesives, it was considered that a polymer would be preferred to silicon dioxide as the API substrate for forming a solid-state particulate complex. EXAMPLE 3

[0149] In Example 3. it was found that specific ratio combinations of dexamethasone in Kollidon 30 (soluble polyvinylpyrrolidone) were suitable with standard process solvents (ethyl acetate and isopropanol). Solutions containing polymer to API ratios of 8:1. 6.7:1. 5:1. 4:1 and up to a 1:1 were produced to assess the solubility of dexamethasone in the solutions. It was found that a 5:1 ratio or 20% by weight of dexamethasone (DEX) to povidone (PVP) would dissolve the drug in solution, while the 4:1 ratio or 25% by weight DEX to PVP was slightly soluble with evidence of haziness and undissolved dexamethasone. The 1 : 1 ratio or 50% by weight DEX to PVP resulted in an insoluble suspension of DEX in solubilized PVP. The resulting mixtures were then dried and assessed for crystallinity of the dried films. Surprisingly, it was found that Kollidon 30 kept the dexamethasone solubilized within the dried film without the presence of the organic solvents required to solubilize both DEX and PVP. Without the process solvents, neither DEX nor PVP would solubilize in the presence of each other. The resulting films were crystal free for 12.5% DEX (8:1), 15% DEX (6.7:1), and 20% DEX (5:1). Both 25% DEX (4:1) and certainly 50% DEX (1:1) exhibited crystals as micro dispersions of DEX throughout the dried DEX:PVP films. All films were brittle and capable of particle size reduction processes by physical / mechanical means. The 8:1 to 5:1 were clear, slightly yellowish in color, and transparent. All films were micronized and sieved to less than 150 micrometer particle size for processing.

[0150] EXAMPLE 4

[0151] Example 4 outlines the development of a stable solid state suspension of Dexamethasone: PVP particulates in a drug-in-adhesive preparation, which is used as a comparative example and was produced to prepare an oversaturated drug-in-adhesive system to allow for enhancement of concentration gradient, to maintain performance characteristics, such as permeability, chemical stability for example protection from hydrolysis or oxidation, and physical stability such as reduction of or even prevention of drug migration and adhesive cold flow. As a drug-in-adhesive was the primary focus for the formulation strategy, this added to the potential delivery challenges and potential stability issues. Solid-state compositions have improved stability', reduced cold-flow, and reduced migration of low molecular weight entities away from the active area of the transdermal system. Table 4 outlines the various components of the formulations for in situ formation of a molecular solid suspension utilizing an insoluble excipient (crospovidone) rather than the soluble polymer contemplated by the present disclosure. Table 4: Dexamethasone in Dissolved State Added to form Molecular Solid Suspension In Situ

[0152] Referring to Figs. 3-4, Fig. 3 presents die corresponding average flux and Fig. 4 presents the corresponding cumulative permeation of the resulting molecular solid suspensions with an API and insoluble excipient to illustrate the development of a viable dexamethasone formulation for comparison to the concepts described in the present disclosure. The API, dexamethasone, is either added to the system in a dissolved state to form the molecular solid suspensions as a suspended particulate formed in situ or added as a micronized powder raw material as obtained from the vendor without further processing to change the state or makeup of the raw material, dexamethasone. As can be seen, both the molecular solid suspension (11-171-3) and suspended raw material dexamethasone (11-171-4) observed similar delivery profile as well as delivery rates from the same composition of drug-in-adhesive, although the addition of the drug is performed in distinctly different manners. The result of these differences is not significant.

[0153] EXAMPLE 5

[0154] Next, in Example 5, Tables 5 A and 5B present one embodiment of the present disclosure directed to the preparation of a solid-state particulate of dexamethasone and soluble povidone in a micronized glass-like particulate as evidenced by lack of birefringence under polarized light microscopy. The preparation of DEX:PVP in specified ratios has surprisingly shown improved performance in the opposite manner for which povidone is known and taught in prior art. Maximizing PVP is not optimal and in the current invention, maximizing PVP to ensure solubility7of the API in water is found most surprising.

[0155] Table 5A: Dexamethasone:Polyvinylpyrrolidone as Solid-State Particulates (% Dry Weight) Table 5B: Dexamethasone:Polyvinylpyrrolidone as Solid-State Particulates in TPS

[0156] Meanwhile, Table 6 presents the comparison formulations to evaluate utility of the Solid- State Particulates as prepared above in Table 5A. Table 6 is a physical mixture without dissolution of tire drug and polymer to form a premade solid-state particulate which was micronized and incorporated into a drug-in-adhesive formulation; instead, Table 6 includes physical mixtures of solid raw materials added and suspended within the drug-in-adhesive system.

[0157] Table 6: Dexamethasone and Polyvinylpyrrolidone Added Individually as Raw Materials

[0158] Referring to Figs. 5-6, Fig. 5 presents the corresponding average flux and Fig. 6 presents the cumulative penneation for various samples where the amount of PVP was increased, thus increasing the PVP to API ratio for purposes of the preparation of the solid state particulate, where an increase in the PVP present enhances the perfonnance characteristics of the transdermal delivery system, such as permeation rates, as shown.

[0159] Next, referring to Figs. 7-8, Fig. 7 presents the corresponding average flux and Fig. 8 presents the cumulative permeation of increasing the differences observed in an optimized solid-state particulate as compared to simply an amorphous 1: 1 ratio of DEX:PVP or physical mixtures and suspensions. These graphs support the claim that an optimized ratio of DEX:PVP to form a transparent, clear, glass or glass-like film which is hard and brittle capable of mechanical or physical means to reduce particle size and obtain a micronized glass or glass-like particulate for incorporation into a transdermal delivery system results in superior performance in terms of flux when compared to other formulations with the same drug loading, where all formulations comprise 5% dexamethasone in various states.

[0160] EXAMPLE 6

[0161] Next, in Example 6, efforts were pursued to understand solubility of the various APIs in various organic solvents and excipients typically used in pharmaceutical API products, and specifically, in transdermal and topical formulations. The key aspect of the solvent system is to solubilize the API in presence of the soluble polymer and form a true solution. These solvents should be volatile in nature at elevated temperatures during the curing process to achieve ICH residual solvent limits of said residual solvent after processing. The solvent system should be designed such that solubilized drug is obtained in a concentration of about 10 wt.% to about 50 wt.% of the solvent system.

[0162] The formulation strategy was to prepare a monolayer or monolithic drug-in-adhesive layer coated between a backing layer and a disposable release liner. Surprisingly, it was found that the incorporation of solid state particulate API and or API: substrate complex into a transdermal patch as a suspension of solid state particulates within the drug-in-adhesive to produce a consistent and uniform polymer blend and resulting laminate after evaporation of process solvents including the process solvent of the solubilized API which resulted in a molecular dispersion of the API during particulate formation. The API forms a particulate with the other excipients suspended uniformly within the polymer blend with the solvent system during the blending process to produce a homogeneous wet suspension, and the solid-state API particulate forms in situ in the blend prior to coating and evaporation of the solvent system.

[0163] A solubilized grade of povidone, such as Kollidon 25, 30, or 90, was incorporated into a solution of specified process solvents, such as ethyl acetate:isopropanol in a 3: 1 to 1:3 ratio to dissolve the povidone into solution at about a 10 wt.% to 50 wt.% solution of povidone to solvent. Furthermore, the API, such as dexamethasone, lenalidomide, dexamethasone acetate, ibrutinib, or olanzapine, was added to the mixture and solubilized within the polymer / solvent solution. The drug concentration was about 5 wt.% to about 50 wt.% within the polymer / solvent solution and the dry weight ratio of the polymer to the API was about 2: 1 to about 10: 1, or about 4: 1 to about 8: 1. The solvent was dried off of the polymer / API solution to leave a glass or glass-like film which is hard and brittle and amenable to particle size to obtain a micronization of the polymer:API complex, where there was no evidence of crystallization of the API within the film or the particulate. Achieving a micronized particle was necessary to allow for incorporation and processing of a drug-in-adhesive drug product to allow coating and eventual solvent evaporation. The API / polymer complex should remain unchanged in the presence of the drug-in-adhesive system such that the APEpolymer complex retains its glass or glass-like particulate within the system without evidence of crystallization of the API within the system by presence of birefringence under polarized light microscopy. A micronized grade of insoluble excipient, such as crospovidone, a cross-linked povidone, was incorporated into the drug-in-adhesive layer formulation to support the solid-state suspension, with the understanding that other insoluble substrates may be viable such that they disperse within matrix and allow for affinity of crystalline and or molecular dispersion of the API.

[0164] It should be noted that the use of an insoluble povidone, such as crospovidone, and soluble povidone, such as Kollidon 30, in either a dissolved or suspended undissolved state is considered to be a unique combination of crospovidone and povidone. At the very least, the present disclosure contemplates using both in an undissolved state, while others claim the use of insoluble povidone (crospovidone) alone or soluble povidone alone as a crystal inhibitor, thickener, or stabilizing or dispersing polymer. It should be understood in the present disclosure that the API is not molecularly dispersed (dissolved) within the transdermal system and instead is maintained in a solid-state particulate form.

[0165] A transdermal delivery' system (TDS) for administration of an API can be formed that includes an active substance area comprising a pharmaceutical composition of at least one (1) solid state API or APksubstrate micronized glass or glass-like particulate of less than about 150 pm, and where substrate is a material which forms a brittle, hard film amenable to particle size reduction, such as Kollidon 30 soluble povidone, optionally an insoluble excipient to act as a dispersing and thickening agent, at least one (1) excipient to act as permeation enhancer or plasticizer that does not, however, act on the API nor APksubstrate until activated by application to skin and the hydration of the patch under occlusion; at least one (1) polymer to act as adhesive backbone, such as acry lic pressure sensitive adhesive, polyisobutylene, silicone PSAs, or combinations thereof. The cured adhesive composition can be coated between an impermeable backing layer and a release liner and maintains the glass or glass-like particulate of the APksubstrate within the matrix without detriment. The composition may incorporate an overlay adhesive system.

[0166] One aspect of the solid state particulate APksubstrate complex that has been determined in this example is that the fonned film can include from about 1 wt.% to about 50 wt.% of the API and from about 50 wt.% to about 99 wt.% of the substrate (e.g., soluble polymer) that is capable of dissolving the API and forming a brittle, hard film amenable to micronization under physical or mechanical means. The exact range for the API and soluble polymer has been found to depend on the characteristics of the API, such as solubility in water, solubility in organics. Log P, solubility parameters, and other modalities of comparison have been contemplated. To produce reasonable loaded solid-state particles, the API should be loaded such that the amount of soluble polymer (e.g., polyvinylpyrrolidone) added to the drug-in-adhesive system is less than about 50 wt.%; otherwise, the drug-in-adhesive system will become a solid fdm as compared to an adhesive or adhesive like material which exhibits difficulty' in adhering to a substrate, such as skin. Table 7 summarizes the concentration of API and substrate in various solid state particulate complexes that were formed.

[0167] Table 7: APLSubstrate % Loading for Solid-State Particulates

[0168] For these APIs, it was found that an amount between about 10 wt.% and about 25% wt.% was preferred. The presence of the API within die substrate, such as PVP, is undersaturated, where the solubility of the API is well below the saturation point within the solid polymer and resulting in a solid-state particulate complex. Therefore, the API is maintained in a solid state that is without the presence of crystallinity and can be described as noncrystalline. The limit to incorporation into a drug-in-adhesive matrix is the amount of drug: substrate (PVP. in most cases) that can be incorporated into the system. To not be limited by the current scope of the work performed, the empirical evidence suggests that formulations with up to about 5 wt.% drug loading and 45 wt.% PVP by dry weight when added to the drug-in-adhesive matrix, which starts with a 10 wt.% drug loading into solid state particle to form the solid state particulate complex are possible and have been made and tested successfully.

[0169] EXAMPLE 7

[0170] Next, in Example 7, Tables 8 A and 8B present another embodiment of the present disclosure directed to the preparation of a solid-state particulate of lenalidomide and soluble povidone in a micronized glass-like particulate as evidenced by lack of birefringence under polarized light microscopy. Table 8B: Lenalidomide:Polyvinylpyrrolidone as Solid-State Particulates in TPS

[0171] Referring to Figs. 9-10, Fig. 9 presents the corresponding average flux and Fig. 10 presents the cumulative permeation of the difference observed in an optimized solid-state particulate as compared to the previously developed molecular solid suspension (LLD-TDS-009 control) supporting the claim that an optimized ratio of LLD:PVP to form a transparent, clear, glass or glasslike fdm which is hard and brittle capable of mechanical or physical means to reduce particle size and obtain a micronized glass or glass-like particulate for incorporation into a transdermal delivery system is at least equivalent to the performance when compared to the developed molecular solid suspension (LLD-TDS-009) formulation as well as the same drug loading with increasing ratio of PVP:API from about 4:1 to about 10: 1, where all formulations included 5 wt.% lenalidomide. It should be noted that the LLD-TDS-009 control utilized 8 wt.% lenalidomide. Thus, the solid-state particulate API and polymer complex of the present disclosure is superior in efficiency where the drug delivered is equivalent to the control (LLD-TDS-009) despite there being 37.5 wt.% less drug loaded into the formulation of the present disclosure.

[0172] EXAMPLE 8

[0173] Next, in Example 8, Tables 9A and 9B present another embodiment of the present disclosure directed to the preparation of a solid-state particulate of olanzapine and soluble povidone in a micronized glass-like particulate as evidenced by lack of birefringence under polarized light microscopy.

[0174] Table 9A: Olanzapine:Polyvinylpyrrolidone as Solid-State Particulates (% Dry Weight) Table 9B: Olanzapine:Polyvinylpyrrolidone as Solid-State Particulates vs. Molecular Solid

[0175] Suspension in TPS

[0176] Referring to Figs. 11-12. Fig. 11 presents the corresponding average flux and Fig. 12 presents the cumulative permeation of an early non-optimized solid-state particulate as compared to the control, which is a developed clinical formula for Olanzapine TDS as OLA 151 Lot # 2B019. The drug in this formula is loaded as a solubilized drug-in-adhesive platform at 8 wt.% with a 15 mg / cm2coat weight. Comparatively, the other formulations include 5 wt.% drug loading in a solid state particulate complex suspension with only about a 13 mg / cm2coat weight and the APLPVP particulates form a transparent, clear, glass or glass-like film which is hard and brittle capable of mechanical or physical means to reduce particle size and obtain a micronized glass or glass-like particulate for incorporation into a transdermal delivery system. It is obvious that the currently nonoptimized solid state particulate suspensions are superior in performance for the initial 24 hours, and when compared to overall duration on this Strat-M membrane there is a significant depletion (-100% at 72 hours), while the control formulation only exhibits about 84% depletion at 72 hours. This is in direct relation to offloading of the drug on the membrane and overall drug loading of the lower 5 wt.% formulations. Thus, proof of concept is shown here in. however, a final formulation still requires further optimization to maintain an improved concentration gradient.

[0177] These and other modifications and variations of the present disclosure may be practiced by those of ordinary skill in the art, without departing from the spirit and scope of the present disclosure. In addition, it should be understood that aspects of the various embodiments may be interchanged both in whole or in part. Furthermore, those of ordinary skill in the art will appreciate that the foregoing description is by way of example only, and is not intended to limit the invention so further described in such appended claims.

Claims

WHAT IS CLAIMED IS:

1. A transdermal drug delivery system comprising: a drug-in-adhesive layer, the drug-in-adhesive layer comprising: a solid-state particulate complex including an active pharmaceutical ingredient having a water solubility of less than about 10 milligrams per milliliter and a melting point greater than about 120°C and a soluble polymer; an adhesive polymer; and a surfactant. wherein a 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 log P value ranging from 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, 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-state particulate complex has a particle size of less than about 300 micrometers.

6. The transdermal drug deliver}' system of claim 1, wherein the adhesive polymer comprises an acrylate copolymer, an ethylene-vinyl acetate copolymer, a vinyl acetate- acrylic copolymer, a rubber co-polymer, a polyisobutylene polymer, a silicone polymer, or a combination 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 steareth-2, oleth-2, ceteth-3. oleth-3, C12-13 pareth-3, oleth-5, C12-13 pareth-4, laureth-4. laureth-9. ceteareth-6. oleth-10, oleth-20, steareth-10, a poloxamer, a polyethylene glycol, or a combination thereof.

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

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

11. The transdermal drug deliver}’ system of claim 1. further comprising: an occlusive backing layer, wherein the occlusive backing layer forms an exterior facingsurface of the transdermal drug delivery system; and a release liner, wherein the release liner is positioned adjacent a skin contacting surface of the drug-in-adhesive layer.

12. A method of forming a solid-state particulate complex comprising an active pharmaceutical ingredient and a soluble polymer for transdermal delivery systems, the method comprising: combining the active pharmaceutical ingredient and the soluble polymer in a process solvent system to solubilize both the active pharmaceutical ingredient and the soluble polymer; evaporating the process solvent system to form a film; and micronizing the film to form the solid-state particulate complex, wherein the solid-state particulate complex exhibits no evidence of birefringence or crystallinity and has a particle size of less than about 300 micrometers.

13. The method of claim 12, wherein a 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 milligrams per milliliter, a melting point greater than about 120°C, and a log P value ranging from 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, 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 of forming a drug-in-adhesive layer for a transdermal drug delivery' system, the method comprising: 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 fonn a solid-state particulate complex, wherein the solid-state particulate complex has a particle size of less than about 300 micrometers; and adding the solid-state particulate complex to a second process solvent system, an adhesive polymer, and a surfactant to form a drug-in-adhesive layer formulation.

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

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

20. The method of claim 17, wherein the active pharmaceutical ingredient is an immunomodulatory agent, a steroid, a hormone, an antipsychotic, a tricyclic antidepressant, or a Bruton’s tyrosine kinase inhibitor.

21. The method of claim 17, wherein the adhesive polymer comprises an acrylate copolymer, an ethylene-vinyl acetate copolymer, a vinyl acetate-acrylic copolymer, arubber co-polymer, a polyisobutylene polymer, a silicone polymer, or a combination thereof.

22. The method of claim 17. wherein the surfactant comprises a nonionic surfactant, wherein the nonionic surfactant comprises steareth-2, oleth-2, ceteth-3, oleth-3, C12-13 pareth-3, oleth-5, C12-13 pareth-4, laureth-4, laureth-9, ceteareth-6, oleth-10, oleth-20, steareth-10. a poloxamer, a polyethylene glycol, or a combination thereof.

23. The method of claim 17. further comprising adding an insoluble excipient to the drugin-adhesive layer formulation.

24. The method of claim 23, wherein the insoluble excipient comprises crosslinked polyvinylpyrrolidone .

25. The method of claim 17, further comprising coating the drug-in-adhesive 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 dried drug-in-adhesive layer formulation.

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

28. The method of claim 27, further comprising: converting the laminate to a specified patch size via die cutting; and including an inherent overlay system with the laminate in a flat heat-sealed pouch.

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