WO2007112287A2

WO2007112287A2 - Hme transdermal compositions containing testosterone

Info

Publication number: WO2007112287A2
Application number: PCT/US2007/064716
Authority: WO
Inventors: Michael M. Crowley; Justin M. Keen; John J. Koleng; Randall Mack; Terri Sebree; Theodore M. Smith; Feng Zhang
Original assignee: AUXILIUM PHARMACEUTICALS Inc
Current assignee: AUXILIUM PHARMACEUTICALS Inc
Priority date: 2006-03-24
Filing date: 2007-03-22
Publication date: 2007-10-04
Anticipated expiration: 2008-09-24
Also published as: WO2007112287A3

Abstract

A bioadhesive laminate comprising testosterone and methods for its preparation are provided. The laminate comprises a hot-melt extruded (HME) drug reservoir layer comprising testosterone and an inert backing layer. The drug reservoir layer comprises a thermoplastic bioadhesive composition containing testosterone and the inert backing layer. The laminate is adapted for transdermal administration. When administered buccally to a subject, the laminate provides therapeutically effective plasma levels of testosterone such that the Cmax of testosterone is less than about 1000 ng/dL and the Tmax falls within the period of about two to fifteen hours. In a particular embodiment, the laminate provides therapeutic plasma levels of testosterone in the range of about 300 to 1000 ng/dL throughout a period of about one to twenty four hours after buccal administration to a subject. The laminate provides an in vitro controlled release of testosterone for a period of about four to thirty hours after exposure to an aqueous assay medium.

Description

HME TRANSDERMAL COMPOSITIONS CONTAINING TESTOSTERONE

BY:

Michael M. Crowley, Justin Keen, John J. Koleng, Randall Mack, Terry Sebree,

Ted Smith and Feng Zhang,

FIELD OF THE INVENTION

The present invention concerns a hot-melt extruded (HME) composition comprising testosterone. In particular, the invention concerns a multi-layered laminate comprising an inert backing layer and a drug reservoir layer comprising testosterone. The invention also concerns a process for preparing the same and a method of use thereof in the treatment of a disease or disorder associated with testosterone deficiency.

BACKGROUND OF THE INVENTION

Administration of testosterone is well known in the art for the treatment of testosterone deficiency related disorders such as hypogonadism, Peyronie's disease, priapism, impotence, erectile dysfunction, reduced libido, loss of muscle mass, and others associated with testosterone deficiency. There is growing awareness of the occurrence of these disorders in the human population.

Testosterone can be administered transdermally, transmucosally or in a body cavity using a dosage form such as a patch, implant, film, gel, cream, ointment, or suppository. ANDRODERM® (Watson Labs) and TESTODERM® (Alza Corp.) are exemplary extended release transdermal films containing testosterone.

STRIANT® (Columbia Laboratories) is an extended release mucoadhesive buccal tablet containing testosterone, anhydrous lactose NF, carbomer 934P, hypromellose USP, magnesium stearate NF, lactose monohydrate NF, polycarbophil USP, colloidal silicon dioxide NF, starch NF and talc USP.

Testosterone is prone to degradation in alkaline conditions. Its major degradants include 6-beta-hydroxytestosterone, 4-Androsten-16-alpha-ol-3, 17-dione,

Androstenedione, and Epi-testosterone. Consequently, any formulation containing testosterone must provide sufficient stability under processing, handling and storage conditions to ensure an acceptable product shelf-life.

A number of patents disclose transdermal or buccal dosage forms containing testosterone and include cast and extruded films, including U.S. Patent No. 6,585,997 (U.S. Pregrant Patent Application Publication No. 20030044446) to Moro et al. (Access Pharmaceuticals); U.S. Patent No. 6,562,369 to Luo et al. (Dermatrends Inc.); U.S. Patent No. 6,555,131 to Wolff et al. (Schwarz Pharma AG); U.S. Patents No. 6,010,715, No. 5,679,373, No. 5,662,926, and No. 5,676,969 to Wick et al. (Bertek Inc.); and PCT International Patent Application Publication No. WO 00/19975.

Many researchers have utilized hot-melt extrusion techniques to produce pharmaceutical preparations in various forms, including films. Aitken-Nichol et al. (Aitken-Nichol, C, F. Zhang, and J.W. McGinity, Hot Melt Extrusion of Acrylic Films. Pharmaceutical Research, 1996. 13(5): p. 804-808) used hot-melt extrusion methods to produce acrylic polymer films containing the active lidocaine HCl. Grabowski et al. (Grabowski, S., et al., Solid active extrusion compound preparations containing low- substituted hydroxypropylcellulose. 1999: US5939099 WO9625151 DE19504832 EP0809488) produced solid pharmaceutical preparations of actives in low- substituted hydroxypropyl cellulose using hot-melt extrusion techniques. Repka and McGinity (Repka, M.A. and J.W. McGinity, Hot-melt extruded films for transmucosal & transdermal durg delivery applications. Drug Delivery Technology, 2004. 4(7): p. 40, 42, 44-47) used hot-melt extrusion processes to produce bioadhesive films for topical and mucosal adhesion applications for controlled drug delivery to various mucosal sites (Repka, M.A., S. L. Repka, and J.W. McGinity, Bioadhesive hot-melt extruded film for topical and mucosal adhesion applications and drug delivery and process for preparation thereof April 23, 2002: US Patent # 6,375,963).

Various different drugs have been included in HME compositions. Achieving chemical stability of a drug included within the matrix of the HME composition and a therapeutic release profile can be difficult when comparing different combinations of matrix-forming material, drugs, excipients and processing conditions.

Various different thermoplastic materials have been used as the matrix-forming material in HME compositions. These materials are generally, but not necessarily, polymeric. One of the more desired polymers for this use has been poly(ethylene oxide) (PEO), because PEO-based HME compositions are bioadhesive and adhere to mucosal tissue.

U.S. Patent No. 6,488,961 to McGinity et al. (The University of Texas) discloses hot-melt extruded non-film formulations comprising high molecular weight PEO and a plasticizer (PEG). U.S. Patent No. 6,375,963 to Repka et al. discloses a bioadhesive hot- melt extruded film composition comprising a water swellable or water soluble thermoplastic polymer (such as HPC or PEO) and a bioadhesive polymer (such as polycarbophil, carbopol, a co-polymer of methyl vinyl ether and maleic acid or anhydride, one or more acrylic polymers, one or more polyacrylic acids, copolymers of these polymers, a water soluble salt of a co-polymer of methyl vinyl ether and maleic acid or anhydride, a combination thereof and their salts. In some embodiments, the film contains an organic acid, a superdisintegrant, a super- absorbent and/or an antioxidant. This patent discloses a multi-layered film and generally discloses coextrusion of the layers with an optional adhesive between the layers of the film. U.S. Pat. No. RE 33,093 (No. 4,713,243) to Schiraldi et al. describes a bioadhesive hot-melt extruded film for intra-oral drug delivery and the processing thereof. U.S. Patent No. 6,072,100 to Mooney et al. discloses an extruded composition containing a thermoplastic water-soluble polymer selected from the group consisting of hydroxypropyl cellulose and polyethylene oxide; a water-soluble polymer derived from acrylic acid; medicament; and plasticizer.

However, none of these references describe a buccal film for delivery of testosterone which provides good to excellent product stability and a good to excellent release profile over a period of 12 or 24 hours. Given the importance of testosterone therapy and the advantages of buccal administration of testosterone over other modes of administration, there is an ongoing need for new and improved buccal formulations containing testosterone.

SUMMARY OF THE INVENTION

The present invention is based upon the discovery that the selection of suitable polymer components in the reservoir layer permits superior release profiles thereby providing plasma concentrations for testosterone from 300 to 1000 ng/dl or from 300 to 1500 ng/dl that can be maintained for extended periods, such at least 12 hours or longer. Thus, the present invention provides a new transdermal bioadhesive laminate containing testosterone as the active agent. The laminate is used to treat disorders associated with testosterone deficiency. The laminate consists of at least two different layers: 1) an optionally-inert flexible backing layer; 2) a drug reservoir layer; and 3) an optional release liner layer. In one aspect, the laminate is a bioadhesive multi-layered laminate adapted for transdermal delivery of testosterone, the laminate consisting essentially of: a) an inert flexible non-bioadhesive backing layer comprising a hydrophobic polymer; b) a flexible hot-melt extruded bioadhesive reservoir layer comprising at least one water swellable or water soluble thermoplastic polymer, testosterone, optionally at least one bioadhesive polymer, optionally an antioxidant, and optionally one or more other pharmaceutical excipients; and optionally c) an adhesive interposed the backing layer and the reservoir layer for maintaining the two layers together; wherein a unit dose of the film provides a blood plasma concentration of testosterone in the range of about 300-1000 ng/dl or 300- 1500 ng/dl for a period of at least 6 hours, such as at least 8 hours or at least 12 hours after mucosal buccal application to a subject. In some embodiments, the unit dose of the film provides a blood plasma concentration of testosterone in the range of about 300-1000 ng/dl or 300-1500 ng/dl for a period of about 30 hours, such as about 24 hours after mucosal buccal application to a subject. The unit dose of film can be administered once daily and is maintained in contact with the buccal mucosa for at least 6 hours, such as at least 8 hours or at least 12 hours or for 24 hours. Some embodiments of the invention include a unit dose that provides an in vivo monomodal or bimodal testosterone plasma concentration profile following transdermal administration.

In some embodiments of the laminate, the unit dose provides a circadian rhythm type of plasma profile for testosterone. Circadian rhythm type plasma profile is defined as a unit dose that provides a substantially similar release profile over each 24 hour period. In some embodiments, the circadian rhythm profile is characterized by two phases, an elevated phase wherein the concentration of testosterone is maintained at above about 500 ng/dl and a reduced phase wherein the concentration of testosterone is maintained at below about 500 ng/dl. In such an embodiment, the elevated phase can be maintained for between about 8 and 15 hours, such as about 12 hours, wherein the remainder of the release profile, about 16 to 9 hours respectively, is maintained in the reduced phase in a 24-hour period.

Additionally or alternatively, the unit dose results in a testosterone Cmax less than about 1500 ng/dl, about 1100 ng/dL or about 1000 ng/dL or less following administration, such as about 900 ng/dl or less. Additionally or alternatively, the testosterone Cmax can occur within 15 hours, such as within 12 hours, after administration of a unit dose of the laminate. The inventors have discovered that a drug reservoir layer that comprises at least two different thermoplastic polymers can result in substantially improved release profiles. In general, the backing layer comprises about 10 to about 60% wt. of the laminate, and/or the reservoir layer comprises about 40 to about 90% wt. of the laminate. Further, a unit dose of the laminate can comprises 0.1 to 20 mg of testosterone, such as between 1 and 30% by weight of the reservoir layer, such as between 10 and 20% by weight (e.g. about 15% by weight). The thermoplastic polymer can be selected from the group including but not limited to HPC, PEO, an acrylic polymer, a cellulosic polymer or a combination thereof; the hydrophobic polymer can be selected from the group including but not limited to ethyl cellulose, carnauba wax, beeswax, cellulose acetate, poly(hydroxypropyl glutamate), Eudragit RS, Eudragit RL, Eudragit E, poly(3-hydroxybutyrate-co-3- hydroxy valerate), poly(isobutylcyanoacrylate), Polyvinyl acetate phthalate, poly(isohexylcyanoacrylate), poly(orthoesters) and a combination thereof; and/or the bioadhesive polymer can be selected from the group including but not limited to carbomer, polycarbophil, PEO, a co-polymer of methyl vinyl ether and maleic acid or anhydride, chitosan, starch, a cellulosic polymer, or a combination thereof. Prior to inclusion in the reservoir layer, the testosterone API can have an average particle size of less than 250μ and, upon inclusion, the testosterone can be homogeneously dispersed throughout the reservoir layer. Homogeneously dispersed is defined to mean distributed and mixed uniformly in structure or composition throughout the matrix.

In some embodiments, the testosterone has been solubilized in the reservoir layer during hot-melt extrusion thereof. The backing layer can be solvent cast onto the reservoir layer; and/or an adhesive can be present and maintain the backing layer adjacent the reservoir layer. Good results have been achieved by employing two or three different grades of PEO in the reservoir layer and, optionally, an acidic component.

The unit dose form can be cut into a predetermined form with dimensions that provide an effective dose being delivered, good adhesion and comfort during delivery. In one embodiment, the unit dose has an average and exposed surface area between 32 and 250 mm², such as 32 - 137 mm² for 5 mg doses, 40 - 55 mm² for 7.5 mg doses, 130 - 145 mm² for 10 mg doses, 99 - 121 mm² for 12.5 mg doses, 91 - 142 mm² for 15 mg doses and 107 - 241 mm² for 20 mg doses. The unit dose has a surface area to dose ratio of 5 to 35 mm² / mg testosterone based upon the exposed reservoir surface, such as 6 - 33 mm² for 5 mg doses, 6 - 8 mm / mg for 7.5 mg doses, 13 - 15 mm / mg for 10 mg doses, 8 - 10 mm²/ mg for 12.5 mg doses, 6 - 10 mm²/ mg for 15 mg doses and 7 - 12 mm²/ mg for 20 mg doses.

Depending upon the formulation used for the laminate, it can be adapted to provide a predetermined approximate testosterone plasma concentration profile following transdermal administration to a subject. In some embodiments, the laminate provides a biphasic plasma profile having a first elevated phase above 500 ng/dL for the period of 0.5 to 4 hours after administration and a subsequent reduced phase of 500 ng/dL or below for a period of 20 to 23.5 hours, respectively, after administration in a 24-hour period. Such a laminate can be suitable for up to 6 times daily administration. In some embodiments, the laminate provides a biphasic plasma profile having a first elevated phase above 500 ng/dL for the period of 0.5 to 12 hours after administration and a subsequent reduced phase of 500 ng/dL or below for the period of 12 to 23.5 hours, respectively, after administration in a 24-hour period. Such a laminate can be suitable for up to twice daily administration. In some embodiments, the laminate provides a biphasic plasma profile having a first elevated phase above 500 ng/dL for the period of 1 to 15 hours after administration and a subsequent reduced phase of 500 ng/dL or below for the period of 9 to 23 hours, respectively, after administration in a 24-hour period. Such a laminate can be suitable for up to twice daily administration. In some embodiments, the laminate provides a biphasic plasma profile having a first elevated phase above 500 ng/dL for the period of 2 to 12 hours after administration and a subsequent reduced phase of 500 ng/dL or below for the period of 12 to 22 hours, respectively, after administration in a 24-hour period. Such a laminate can be suitable for up to twice daily administration. In some embodiments, the laminate provides a biphasic plasma profile having a first elevated phase above 500 ng/dL for the period of 1 to 15 hours after administration and a subsequent reduced phase of 500 ng/dL or below for the period of 9 to 23 hours, respectively, after administration in a 24-hour period. Such a laminate can be suitable for up to twice daily administration. In some embodiments, the laminate provides a biphasic plasma profile having a first elevated phase above 350 ng/dL for the period of 0.5 to 12 hours after administration and a subsequent reduced phase of 350 ng/dL or below for the period of 12 to 23.5 hours, respectively, after administration in a 24-hour period. Such a laminate can be suitable for up to twice daily administration.

Other embodiments of the invention include those wherein: 1) the thermoplastic matrix-forming material is selected from the group consisting of polyethylene oxide (PEO); polypropylene oxide (PPO); polyvinylpyrrolidone (PVP); polyvinylpyrrolidone- co-vinylacetate (PVP-VA); PLA, PLGA, acrylate and methacrylate copolymers; polyethylene; polycaprolactone; polyethylene-co-polypropylene; alkylcelluloses such as methylcellulose; hydroxyalkylcelluloses such as hydroxymethylcellulose, hydroxyethylcellulose, hydroxypropylcellulose, and hydroxybutylcellulose; hydroxyalkyl alkylcelluloses such as hydroxyethyl methylcellulose and hydroxypropyl methylcellulose; starches, pectins; polysaccharides such as tragacanth, gum arabic, guar gum, sucrose sterate, xanthan gum, lipids, waxes, mono-, di-, and tri-glycerides, cetyl alchohol, steryl alcohol, parafilm waxes and others, hydrogenated vegetable and castor oil, glycerol monostearte, polyols including xylitol, manitol, and sorbitol, alpha-hydroxyl acids including citric and tartaric acid, adipic acid maleic acid malic acid, citric acid, enteric polymers such as CAP, HPMC AS, shellac, and a combination thereof. The laminate can be formulated for transdermal, transmucosal, skin, buccal, urethral, rectal, nasal, vaginal, ophthalmic, or otic drug delivery, or as an implantable drug delivery device. The present laminate provides an in vivo testosterone blood level in the therapeutic range using a lower dose than currently commercially available testosterone products.

The pharmaceutical composition is formulated such that drug therein may or may not be dissolved during extrusion.

Any fine particle of drug made by any fine particle production technology can be incorporated into the claimed pharmaceutical composition. Drug-containing particles are dispersed within the matrix via melt processing.

The HME composition can be used to treat one or more disorders associated with testosterone deficiency, e.g. hypogonadism, Peyronie's disease, priapism, impotence, erectile dysfunction, reduced libido, loss of muscle mass, etc. The method of use includes the transdermal, in particular buccal, administration of a bioadhesive hot-melt extruded composition comprising testosterone in controlled release form. During use, the bioadhesive layer absorbs moisture to initiate dermal adhesion and begins to release testosterone in a controlled manner. Another aspect of the invention provides a process for the manufacture of a bioadhesive multi-layered laminate adapted for transdermal delivery of testosterone, the process comprising the steps of: providing an inert composition comprising a hydrophobic polymer; providing a drug composition comprising testosterone dispersed within a thermoplastic bioadhesive composition; hot-melt extruding the inert composition to form a backing layer; hot-melt extruding the drug composition to form a drug reservoir layer; and laminating the backing layer and drug reservoir layer together thereby forming the multi-layered laminate .

In the embodiment of the invention where both the backing layer and the reservoir layer are hot-melt extruded, the layers can be extruded individually (sequentially or simultaneously) or they can be coextruded simultaneously. The lamination step can be conducted by: 1) applying an adhesive to one or both of the layers and subsequently pressing the layers together; 2) applying pressure and/optionally additional heat to the layers while pressing them together; and/or 3) applying a solvent to the interlaminar surface of one or both layers and pressing the layers together. If the reservoir and backing layers of the laminate are coextruded or extruded and subsequently laminated, the layers can comprise at least one polymer in common; however, the layers will retain their individual characteristics of hydrophobicity and hydrophilicity. The reservoir and backing layers optionally possess approximately the same melt flow index (melt flow rate, melt flow rate, melt index, meaning that their melt flow indices will fall within individual predefined ranges and that those ranges overlap at least to some predefined extent.

Still another aspect of the invention provides a process for the manufacture of a bioadhesive bi-layered laminate adapted for transdermal delivery of testosterone, the process comprising the steps of: providing a drug composition comprising testosterone dispersed within a thermoplastic bioadhesive composition; hot-melt extruding the drug composition to form a drug reservoir layer; providing an inert composition comprising a hydrophobic polymer in a solvent; and solvent casting the inert composition onto the reservoir layer to form an inert backing layer and thereby form the bi-layered laminate. Some embodiments of the process, wherein the reservoir layer is hot-melt extruded and the backing layer is prepared by solvent evaporation (solvent casting), include those wherein: 1) the solvent for casting is an organic solvent, an aqueous organic solvent or an aqueous solvent; 2) the solvent for casting is selected from the group consisting of alcohols, ketones, and or water; 3) the reservoir layer is hot-melt extruded as otherwise described herein; 4) the reservoir layer comprises ingredients as otherwise described herein; 5) the step of solvent casting comprises the steps of: pouring the inert composition onto the reservoir layer and removing solvent from the poured composition to form the inert backing layer; 6) the solvent is removed from the inert composition by drying at atmospheric or less than atmospheric pressure optionally while heating; 7) further comprising the step of cutting the laminate into unit doses and packaging the unit doses into single dose packaging or multi-dose packaging.

It has also been found that greater degradation also occurs when the time of exposure of the alkaline labile drug, such as testosterone (Ts), to heat is increased. Thus, another aspect of the invention requires minimizing the heat exposure of testosterone so as to minimize the formation of its degradants during processing. This is done by selecting the appropriate processing conditions to minimize extrusion temperature and duration of extrusion time and to decrease the matrix viscosity.

The composition of the invention is a multi-layered laminate that can be in the shape of a sheet, rod, tablet, pill, capsule, tube, strand, geometric form, non-geometric form or cylinder. A laminate will comprise at least two layers: a bioadhesive drug reservoir layer and a backing layer. In one embodiment, the backing layer of the laminate also includes an acidic component, so as to minimize any interfacial degradation that might occur at the interface of the reservoir layer and the backing layer. The invention can include combinations of two or more embodiments disclosed herein.

BRIEF DESCRIPTION OF THE FIGURES

The following figures form part of the present description and describe exemplary embodiments of the claimed invention. The skilled artisan will be able, in light of these figures and the description herein, to practice the invention without undue experimentation . FIG. 1 depicts a cross- sectional front elevation of an exemplary embodiment of a mono-layered hot-melt extruded composition according to the invention.

FIG. 2 depicts a cross- sectional front elevation of an exemplary embodiment of a bi-layered hot-melt extruded composition according to the invention. FIGS. 3A-3B depict cross-sectional front elevations of exemplary embodiments of a tri-layered hot-melt extruded composition according to the invention.

FIG. 4 depicts in vitro release profiles for the formulations of Example 14.

FIG. 5 depicts in vivo release profiles for the formulations of Example 14.

FIG. 6 depicts in vitro release profiles for the formulations of Example 15. FIG. 7 depicts in vivo release profiles for the formulations of Example 15.

FIG. 8 depicts in vitro release profiles for the formulations of Example 16.

FIG. 9 depicts in vivo release profiles for the formulations of Example 16.

FIG. 10 depicts in vitro release profiles for the formulations of Example 17.

FIG. 11 depicts in vivo release profiles for the formulations of Example 17. FIG. 12 depicts in vitro release profiles for the formulations of Example 18.

FIG. 13 depicts in vivo release profiles for the formulations of Example 18.

FIGS. 14a and 14b depict release profiles for various different extended release HME compositions made according to Example 19.

FIG. 15a depicts the testosterone mean plasma concentration after several days of dosing (day 3 of 13) for human subjects to which an extended release dosage form of the invention has been administered.

FIG. 15b depicts the testosterone mean plasma concentration after single day dosing for human subjects to which an extended release dosage form of the invention has been administered. DETAILED DESCRIPTION OF THE INVENTION

The invention provides a bi-layered laminate comprising: a HME layer comprising testosterone dispersed within a controlled release thermoplastic bioadhesive matrix; and an optionally-inert backing layer, whereby a unit dose of the laminate provides a therapeutically effective amount of testosterone. By "optionally-inert backing layer" is meant that the backing layer is optionally inert. Therefore, the backing layer can be inert and exclude active agent or it can be therapeutic and include active agent. The laminate is used to treat a disorder associated with testosterone deficiency. The treatment requires transdermal administration of the laminate in a manner such that testosterone is absorbed. First pass metabolism, as occurs when administering a drug perorally, of testosterone be avoided with transdermal administration.

As used herein, the term "transdermal administration" is taken to mean application of the laminate to a dermal or mucosal surface of the body in a subject, whereby the bioadhesive nature of the laminate, in particular the reservoir layer, causes it to removably adhere to the surface. Accordingly, transdermal encompasses the term transmucosal. As used herein, the term "transmucosal administration" is taken to mean application of the laminate to a mucosal surface of the body in a subject, whereby the bioadhesive nature of the laminate, in particular the reservoir layer, causes it to removably adhere to the surface. Dermal and mucosal modes of administration include skin, buccal, sublingual, subdermal, urethral, rectal, nasal, vaginal, ophthalmic, or otic administration, or as an implantable drug delivery device.

The term "hot-melt extrusion" or "hot-melt extruded" is used herein to describe a process whereby a blended composition is heated and/or compressed to a molten (or softened) state and subsequently forced through an orifice where the extruded product (extrudate) is formed into its final shape in which it solidifies upon cooling. The blended composition is conveyed through one or more heating zones typically by a screw mechanism. The screw or screws are rotated by a variable speed motor inside a cylindrical barrel where only a small gap exists between the outside diameter of the screw and the inside diameter of the barrel. In this conformation, high shear is created at the barrel wall and between the screw fights by which the various components of the powder blend are well mixed and disaggregated. As used herein, the term "extrudate" refers to a HME composition. Coextrusion is a process whereby two or more material feed streams, at least one of which is molten, are brought together and placed in contact with one another prior to exiting through an extrusion die. In one process, both material feed streams are molten prior when they are placed in contact with one another. In an alternate process, one material feed stream is molten and the second material feed stream is a preformed solid or semi-solid extrudate onto which the first material is placed prior to extrusion through a die. Coextrusion can be achieved using different types of dies: a dual manifold (or multi- manifold) die or a feed block die assembly. The term "coextrusion" is taken to mean an extrusion process in which at least two different melt compositions are extruded substantially simultaneously through a dual confining orifice to form respective first and second layers of a laminate, whereby the sum total cross-sectional area of the two layers corresponds substantially to the cross-sectional area of the exit orifice in the extrusion die. The term "lamination" is taken to mean an extrusion process in which at least two different layers are hot-melt extruded and combined after exiting the extrusion orifice and then bonded by a set of opposing rollers. The lamination can be conducted with heat, pressure, adhesive and/or solvent.

The term "hot-melt extrudable" is taken to mean that a material or composition can be hot-melt-extruded with no significant thermal degradation, e.g. less than 5% wt. or less than 10% wt. degradation. The term "thermally processable" is taken to mean a material or composition that softens or melts at the extrusion processing temperature with no significant thermal degradation.

FIG. 1 depicts a conceptual cross-sectional front elevation of an exemplary monolithic hot-melt extruded composition (1) comprising a drug reservoir (2) according to the invention. The extrudate prepared as detailed herein provides testosterone dispersed within a thermoplastic bioadhesive matrix comprising a thermoplastic polymer, bioadhesive polymer, and water soluble and/or erodible polymer. The thermoplastic polymer is considered a thermal binder, a pressure softenable binder, or a combination thereof. Exemplary thermal binders include: polyethylene oxide; polypropylene oxide; polyvinylpyrrolidone; polyvinylpyrrolidone-co-vinylacetate; acrylate and methacrylate copolymers; polyethylene; polycaprolactone; polyethylene-co-polypropylene; alkylcelluloses such as methylcellulose; hydroxyalkylcelluloses such as hydroxymethylcellulose, hydroxyethylcellulose, hydroxypropylcellulose, and hydroxybutylcellulose; hydroxyalkyl alkylcelluloses such as hydroxyethyl methylcellulose and hydroxypropyl methylcellulose; starches, pectins; PLA and PLGA, polyesters (shellac), wax such as carnauba wax, beeswax; polysaccharides such as cellulose, tragacanth, gum arabic, guar gum, and xanthan gum.

A specific embodiment of the binder is poly(ethylene oxide) (PEO), which can be purchased commercially from companies such as the Dow Chemical Company and Sumitomo Seika, which market PEO exemplary grades with an average molecular weight from about 100,000 to about 8,000,000. Some of the grades of PEO that are suitable for use in this invention are described in the tables below, which differentiate the grades according to their approximate molecular weights and solution viscosity.

In general, any PEO material described herein or any known PEO having the characteristics of a PEO material as described herein can be used. In one embodiment, the term "PEO Grade 1" is taken to mean a polyethylene oxide with a solution viscosity in the range of 12 - 8800 mPa»s at 25⁰C in a 5% solution or approximate molecular weight range from 100,000 - 600,000. Examples of Grade 1 PEOs are listed in the table above and include POLYOX WSR N-IO, WSR N-80, WSR N-750, WSR N-3000, WSR N-205 or equivalents thereof.

In one embodiment, the term "PEO Grade 2" is taken to mean a polyethylene oxide with a solution viscosity in the range of 8800 mPa»s at 25⁰C in a 5% solution to 4000 mPa»s at 25⁰C in a 2% solution or approximate molecular weight range from 900,000 - 2,000,000. Examples of Grade 2 PEOs are listed in the table above and include POLYOX WSR N-1105, WSR N-12K, WSR N-60, or equivalents thereof.

In one embodiment, the term "PEO Grade 3" is taken to mean a polyethylene oxide with a solution viscosity in the range of 1650 - 15,000 mPa»s at 25⁰C in a 1% solution or approximate molecular weight range from 4,000,000 - 8,000,000. Examples of Grade 1 PEOs are listed in the table above and include POLYOX WSR 301, WSR Coagulant, WSR 303, WSR 308, or equivalents thereof.

PEO Grade 1, PEO Grade 2 and/or PEO Grade 3 can occur in the drug reservoir layer, the inert backing layer or both layers. In the embodiment wherein a particular grade of PEO occurs in the reservoir layer and the inert backing layer, that grade of PEO is independently selected at each occurrence from its respective definition. In other words, if PEO Grade 1 occurs in the reservoir layer and the backing layer, then it will be selected at each occurrence from the above- specified group for PEO Grade 1. Likewise for PEO Grade 2 and PEO Grade 3.

When three grades of PEO are included in the same layer, PEO Grade 3 has a higher viscosity than PEO Grade 2, which has a higher viscosity than PEO Grade 1. When two grades of PEO are included in the same formulation, there are several possible combinations: a) PEO Grade 3 + PEO Grade 2, wherein PEO Grade 3 has a higher viscosity than PEO Grade 2; b) PEO Grade 3 + PEO Grade 1, wherein PEO Grade 3 has a higher viscosity than PEO Grade 1; and c) PEO Grade 2 + PEO Grade 1, wherein PEO Grade 2 has a higher viscosity than PEO Grade 1. When three different grades of PEO are present, the amount of each ranges between 0 to 99.5% wt. of the layer. In specific embodiments of such a composition, the amount of PEO Grade 1 can be between 5 and 50% by wt. of the layer, such as 5%, 10%, 26.85%, 27.9%, 23.67%, 32.9%, 36.01%, 34%, 38.16%, 33.86% of the layer; the amount of PEO Grade 2 can be between 5 and 50% by wt. of the layer, such as 5%, 22.18%, 21.16%, 26.16%, 20.36%, 28.64%, 27%, 30.35%, 14.96%, 15.91%, 18.36%, 18.86%, 19.36%, 7.5% of the layer; and the amount of PEO Grade 3 can be between 5 and 50% by wt. of the layer, such as 13.79%, 16.29%, 16.79%, 17.44%, 19.1%, 18%, 20.24%, 29.93%, 31.83%, 36.5%, 45% wt. of the layer.

The total amount of PEO present ranges from about 10 to about 70% wt. of the reservoir layer and 0 to about 60% of the backing layer.

When any type or class of material is present in both the reservoir and the backing layer, it will be independently selected at each occurrence from the list of suitable materials described herein or known to the artisan in the field of pharmaceutics. For example, if PEO is present in both the reservoir layer and the backing layer, the grade or grades of PEO used in reservoir layer will be selected at each occurrence independently of the grade or grades of PEO used in the backing layer.

Suitable thermal binders that may or may not require a plasticizer include, for example, Eudragit™ RS PO, Eudragit™ SlOO, Kollidon SR (polyvinyl acetate)-co- poly(vinylpyrrolidone) copolymer), Ethocel™ (ethylcellulose), HPC

(hydroxypropylcellulose), cellulose acetate butyrate, poly(vinylpyrrolidone) (PVP), poly(ethylene glycol) (PEG), poly(ethylene oxide) (PEO), polyvinyl alcohol) (PVA), hydroxypropyl methylcellulose (HPMC), ethylcellulose (EC), hydroxyethylcellulose (HEC), sodium carboxymethyl-cellulose (CMC), dimethylaminoethyl methacrylate - methacrylic acid ester copolymer, ethylacrylate - methylmethacrylate copolymer (GA-MMA), C-5 or 60 SH-50 (Shin-Etsu Chemical Corp.), cellulose acetate phthalate (CAP), cellulose acetate trimelletate (CAT), polyesters (shellac), waxes (carnauba wax, beeswax), poly(vinyl acetate) phthalate (PVAP), hydroxypropylmethylcellulose phthalate (HPMCP), poly(methacrylate ethylacrylate) (1:1) copolymer (MA-EA), poly(methacrylate methylmethacrylate) (1:1) copolymer (MA-MMA), poly(methacrylate methylmethacrylate) (1:2) copolymer, Eudragit LlOO (MA-EA, 1:1), Eudragit L-100-55 (MA-EA, 1:1), hydroxypropylmethylcellulose acetate succinate (HPMCAS), Coateric (PVAP), , polycaprolactone, starches, pectins; polysaccharides such as cellulose, tragacanth, gum arabic, guar gum, sugars and xanthan gum.

Some of the above-noted binders are bioadhesive alkaline thermoplastic polymers. PEO can be used as the matrix-forming thermoplastic. In one embodiment, the PEO is wet granulated with an acidic component and optionally one or more other excipients to form an excipient mixture. The excipient mixture is then mixed with testosterone and other excipients that can be included in the formulation and then extruded. Therefore, the invention also provides a method of preparing a therapeutic stabilized bioadhesive hot-melt extruded composition comprising testosterone, PEO, and an acidic component, the process comprising the steps of: mixing the acidic component with the PEO to form an excipient mixture, and then blending the excipient mixture with the testosterone. The mixing step can be a wet granulation step.

PEO is considered a bioadhesive polymer, since it adheres to a biological surface (e.g. skin, mucosa). However, a reservoir layer made with PEO as the major thermoplastic matrix-forming polymer is not bioadhesive per se in the absence of water. PEO requires activation with moisture in order to adhere to the surface. During use, a PEO-based reservoir layer is moistened either with water present at the site of administration (for example water from saliva or a mucosal surface) or with other water. For this reason, PEO is termed a moisture-activated bioadhesive polymer. In one embodiment, PEO is neutralized or moderately acidified with an acidic component. The polymer is neutralized by wet granulating it with the other materials, such as poloxamer, to be included in the matrix, and the acidic component, such as citric acid and/or CARBOPOL®. Wet granulation is conducted with water (or buffer) or an aqueous alcohol solution. After this excipient mixture has been prepared, it is optionally dried and then blended with the testosterone followed by hot-melt extrusion of the entire mixture.

When wet granulation is employed to prepare the excipient mixture, an aqueous medium is used. Exemplary aqueous medium includes water, buffer, or water (or buffer) containing organic solvent. In one embodiment, the organic solvent is water miscible. Suitable water miscible solvents include methanol, ethanol, propanol, iso-propanol, benzyl alcohol, cyclomethicone, glycerin, propylene glycol, low molecular weight polyethylene glycol, simethicone, and others known to those of ordinary skill in the art.

The acidic component can be mixed with the PEO as a liquid or solid. For example, the acidic component may be dissolved, suspended or wet with the aqueous medium used for wet granulation. Alternatively, the acidic component can be added in solid form.

In one embodiment, the acidic component will dissolve during the wet granulation step. In another embodiment, it will not. For example, when the acidic component is an acidic polymer, it may or may not dissolve during wet granulation. The acidic component can at least become hydrated (or wet) with the aqueous medium.

Other polymeric materials that can be included in the matrix include cellulosic polymers including HPMC, HPC, HEC, methylcellulose; polyvinyl alcohol, polyvinylpyrrolidone, polyvinylpyrrolidone-co-vinyl acetate and other polymers approved for pharmaceutical use known to those of ordinary skill in the art.

The bioadhesive thermoplastic matrix can further comprise other materials, in particular other polymers such as KLUCEL (hydroxypropylcellulose), CARBOPOL, POLYCARBOPHIL, GANTREZ, poloxamer, and combinations thereof. The product literature for CARBOPOL® indicates that aqueous solutions containing it have a pH in the range of 2.5-4.0, meaning it is an acidic polymer, and it is a bioadhesive polymer. GANTREZ® is a copolymer of methyl vinyl ether and maleic anhydride, and its solution pH will depend upon the form in which it is provided. GANTREZ® MS is a mixed calcium and sodium salt of the polymer having a solution pH between 5.5-7.0. GANTREZ® is a bioadhesive polymer but not a thermoplastic polymer. The product literature for POLYCARBOPHIL®, high molecular weight, cross-linked, acrylic acid- based polymers, indicates that aqueous solutions containing it have a pH less than 4.0, meaning it is an acidic polymer, and it is a bioadhesive polymer, poloxamer 407 is a block copolymer of ethylene glycol and propylene glycol and according to the product literature it has a solution pH of 6.0-7.4. Poloxamer is not considered a bioadhesive polymer.

An extrudate composed of PEO and poloxamer can form a homogeneous polymer matrix when melt extruded at 100⁰C. Compositions further comprising HPMC, PVA, or SLS can be made.

A single polymer or a combination of polymers can serve to give the matrix its thermoplastic and bioadhesive properties. Accordingly, the thermoplastic bioadhesive matrix of the invention can include a combination of materials, some of which may or may not be water soluble and/or erodible, bioadhesive, or thermoplastic. It is only important that the matrix retain its bioadhesive thermoplastic nature prior to hot-melt extrusion and retain its bioadhesive nature after hot-melt extrusion. The matrix can contain one or more bioadhesive polymers, and/or one or more thermoplastic polymers. In one embodiment, the thermoplastic polymer is also the bioadhesive polymer. The hot-melt extrusion equipment is typically a single or twin-screw apparatus, but can be composed of more than two screw elements. A typical hot- melt extrusion apparatus contains a mixing/conveying zone, a heating/melting zone, and a pumping zone in succession up to the orifice. In the mixing/conveying zone, the powder blends are mixed and aggregates are reduced to primary particles by the shear force between the screw elements and the barrel. In the heating/melting zone, the temperature is at or above the melting point or glass transition temperature of the thermal binder or binders in the blend such that the conveying solids become molten as they pass through the zone. A thermal binder in this context describes an inert excipient, typically a polymer that is sufficiently solid at ambient temperature, but becomes molten, softened or semi-liquid when exposed to elevated heat or pressure. The thermal binder acts as the matrix in which the active or actives and other functional ingredients are dispersed, or the adhesive with which they are bound such that a continuous composite is formed at the outlet orifice. Once in a molten state, the homogenized blend is pumped to the orifice through another heating zone that maintains the molten state of the blend. At the orifice, the molten blend can be formed into strands, cylinders or films. The extrudate that exits is then solidified typically by an air- cooling process. The extrudate can be a single layer or it can be a coextruded laminate or a laminate comprising individually extruded layers that are subsequently laminated to form a bi-layered, tri-layered or other multi-layered laminate. Once solidified, the extrudate may then be further processed to form pellets, spheres, fine powder, tablets, and the like. An example of a single screw apparatus similar to the description above is the Randcastle Taskmaster, model 1 inch, 36:1.

Temperature can be an important process variable to consider for the hot- melt extrusion. The composition can be HME at any temperature desired provided it does not result in excessive degradation of the composition or any of it components.

Other process variables such as feed rate and screw speed are optimized to provide adequate shear and mixing. The effect of feed rate and screw speed on such dependent variables as the level of shear and mixing inside the extruder depends heavily on the design of the equipment and namely the screw elements. Generally, increasing the screw speed will increase the shear forces between the screw element and the barrel wall, thereby allowing for more rigorous mixing and a greater extent of particle disagregation. Decreasing the feed rate (non-flood feeding) will generally allow for more complete mixing and particle disagregation due a reduction in the amount of material within the extruder. Reducing the amount of material will in turn also increase the shear forces the material is subjected to due to a decrease in the effective channel depth.

The order or ways in which the components of a formulation are fed to the extruder should be considered. One method is to pre-blend all formulation components before being fed to the extruder. This can be done by any traditional mixing or blending technique. Alternatively, formulation components may be fed individually if done simultaneously, and given that there is adequate mixing of the formulation components in the mixing/conveying zone of the extruder. For example, the drug is mixed with the excipient composition after formation of the excipient composition. The blend is then hot- melt extruded. Furthermore, components other than the base polymers may also be fed downstream of the initial feed port to reduce their residence time in the extruder given that there is adequate mixing of the formulation components before and in the last mixing zone. For example, an excipient blend may be fed at the initial feed port and a heat sensitive component may be fed prior to the last zone to minimize the time of heat exposure. Additionally, a solid non-melting component that significantly increases the melt viscosity may be fed downstream to reduce the amount of energy required to rotate the extruder screw.

Another suitable process employs a preformed excipient mixture, which can be prepared by a variety of different methods. One particular method is wet or dry granulation. In one embodiment, the excipient mixture is prepared by wet granulating the bioadhesive thermoplastic polymer and one or more other excipients, in the presence of an aqueous medium. The excipient mixture is optionally dried after wet granulation. Then, the dry or wet excipient mixture is mixed with drug, and optionally one or more other excipients, to form a blend that is then hot- melt extruded. The aqueous medium can be added in portions or in a bolus. The aqueous medium can be water, buffer or an aqueous alcohol solution. The preformed excipient mixture can also be formed by hot-melt extruding a physical mixture of the bioadhesive thermoplastic polymer, an acidic component and, optionally, one or more other excipients to form an extrudate that is then ground, milled, pelletized, beaded or pulverized to form the excipient mixture. Subsequently, the preformed excipient mixture is mixed with the testosterone, and optionally one or more other excipients, and hot- melt extruded to form the drug reservoir layer. The HME composition of the invention is made according to a process as described herein. Exemplary formulations and processes for their preparation are detailed in the examples below.

General methods for hot-melt extrusion of the monolithic matrix of FIG. 1 are detailed herein and in Example 1.

Wet granulation technique (water addition rate, acidification time and water content) may have an impact upon testosterone stability. The rate of water addition can be changed by using "BOLUS" loading versus "SERIAL" addition (sequential addition of portions).

The total quantity of water in the excipients may have an impact upon testosterone stability in the formulation. A reduction in major impurities may be observed using higher water loading, for example 7.5% water instead of 5% water. Even so, a water loading of up to 98% can be used provided the extruder is equipped to handle the increased amounts of steam formed using feed mixtures having high water content.

Instead of water or buffer alone, the aqueous medium for wet granulation can be a hydroalcoholic granulation solution. The ratio of water to water miscible solvent (in particular alcohol) in the granulation solution can range from 5:95 to 95:5.

Formulations providing an extended release of drug can be made. A bi-layered laminate was made according to Example 14 and its in vitro (FIG. 4) and in vivo (FIG. 5) performance of unit doses was evaluated. The bi-layered laminate of Example 14 comprises a hot-melt extruded drug reservoir layer and a solvent cast inert backing layer.

The weight of a unit dose (SR4) from Example 14 averaged 109.5 mg. For a unit dose of laminate, the average length was 20.77 mm, the average width was 11.61 mm and the average thickness was 0.42 mm thus providing an average surface area of 241 mm² for the exposed reservoir surface and a surface area to dose ratio of 12.1 mm / mg testosterone based upon the exposed reservoir surface. As used herein, the term "exposed reservoir surface" means that surface of the reservoir layer that is adapted for contact to a subject during transdermal administration. The weight of a unit dose (SR12) in Example 14 averaged 107.9 mg. Its average length was 11.74 mm, average width was 9.70 mm and average thickness was 0.87 mm thus providing an average surface area of 114 mm² for the exposed reservoir surface and a surface area to dose ratio of 5.7 mm² / mg testosterone based upon the exposed reservoir surface. The laminate provides an extended release of testosterone, wherein the total amount of time during which testosterone is released can be varied according to the composition of the reservoir layer.

FIG. 4 depicts the in vitro release profile for the laminates SR4 and SR12, which release testosterone over a total approximate 4-hour or 12-hr period, respectively, after initial exposure to an aqueous environment. In other words, the SR4 laminate releases testosterone substantially continuously over an extended period of about four hours once the laminate has been placed in the aqueous assay medium. The SR12 laminate releases testosterone substantially continuously over an extended period of about twelve hours once the laminate has been placed in the aqueous assay medium. The in vivo performance of the SR4 and SR 12 formulations was evaluated by administration of each laminate to the buccal mucosa of different subjects. The in vivo study was a single center, 3-period crossover study in 12 otherwise healthy hypogonadal males. Each subject received a single dose of 2 testosterone buccal film formulations and a single dose of a commercially available testosterone gel (TESTIM™). Each dose was separated from the others by at least 7 days to wash out. Pharmacokinetic data is presented in the following tables and depicted in FIG. 5.

AUC(o-₂₄) Pharmacokinetic Summary (Baseline Adjusted, ng h/dL)

AUC o-₂₄ Treatment Com arisons & 95% Confidence Intervals (Baseline Ad usted)

Cmax Pharmacokinetic Summary (Baseline Adjusted, ng/dL)

Cmax Treatment Com arisons & 95% Confidence Intervals (Baseline Ad usted)

Tmax Pharmacokinetic Summary (Baseline Adjusted, hr)

Due to the higher testosterone dose and the extremely high bioavailability of testosterone when using the formulation of the invention as compared to the TESTIM™ gel, peak plasma levels of testosterone exceeded 2000 ng/dL. In order to account for this, the unit dose size of testosterone (or concentration of testosterone in a unit dose) can be decreased, and the molecular weight of the PEO modified as needed to provide the release profile as desired.

The observed Cmax for unit doses of the SR4 and SR12 laminates exceeded the observed Cmax for a unit dose (100 mg) of the TESTIM™ gel. This is because of the higher dose of testosterone in the laminates and the higher bioavailability of testosterone when delivered with the laminate as compared to the gel. The higher dose of TESTIM™ gel was used due to the lower bioavailability (approximately 10%) of the gel. Based upon the known bioavailability of the TESTIM™ gel and the observed AUCo-24 for the laminates of the invention, the laminates provided approximately the same AUCo-24 as did the gel. The SR4 dose provided an AUC that was 111% of that provided by the gel and the SR12 dose provided an AUC that was 132% of that provided by the gel. Therefore, the laminates provided approximately 70 - 85% bioavailability, which is about 5 - 8 times the bioavailability observed with the gel. Bi-layered laminates were made according to Example 15, and its in vitro (FIG. 6) and in vivo (FIG. 7) performance were evaluated as described herein. The bi-layered laminates of Example 15 comprise a hot-melt extruded drug reservoir layer and a solvent cast inert backing layer. The laminates provide an extended release of testosterone, wherein the total amount of time during which testosterone is released can be varied according to the composition of the reservoir layer. FIG. 6 depicts the in vitro release profile for the laminates Formulas A, B, C, and D, which release testosterone over a total about 12-hr to 18-hr period after initial exposure to an aqueous environment. In other words, the laminates release testosterone substantially continuously over an extended period of about twelve to eighteen hours once the laminate has been placed in the aqueous assay medium. Key differences between the SR4 and SR12 laminates are: the SR4 laminate includes only one bioadhesive thermoplastic polymer (Polyethylene Oxide) and one bioadhesive polymer (Polycarbophil); and the SR 12 laminate includes two different grades of bioadhesive thermoplastic polymer (Polyethylene Oxide) and one bioadhesive polymer. Moreover, the Formulations A-D comprise a different backing layer than do the SR4 and SR 12 formulations. The backing layer for formulations SR4 & SR 12 was applied by solvent casting. The backing layer for formulations A-D was prepared by melt extrusion and applied to the drug reservoir using an adhesive. The dimensions and surface area of the doses differed. The weight of Formulation A doses averaged 186 mg, the average length was 15.15 mm, the average width was 9.65 mm and the average thickness was 1.23 mm thus providing an average surface area of 146 mm² for the exposed reservoir surface and a surface area to dose ratio of 7.3 mm² / mg testosterone based upon the exposed reservoir surface. The weight of Formulation B doses averaged 214 mg, the average length was 16.62 mm, the average width was 10.16 mm and the average thickness was 1.27 mm providing an average surface area of 169 mm² for the exposed reservoir surface and a surface area to dose ratio of 8.45 mm² / mg testosterone based upon the exposed reservoir surface. The weight of Formulation C doses averaged 171 mg, the average length was 14.98 mm, the average width was 9.78 mm and the average thickness was 1.22 mm providing an average surface area of 146 mm² for the exposed reservoir surface and a surface area to dose ratio of 7.30 mm² / mg testosterone based upon the exposed reservoir surface. The weight of Formulation D doses averaged 173 mg, the average length was 15.67 mm, the average width was 9.80 mm and the average thickness was 1.13 mm providing an average surface area of 154 mm² for the exposed reservoir surface and a surface area to dose ratio of 10.3 mm / mg testosterone based upon the exposed reservoir surface.

The in vivo performance of the Formulations A-D was evaluated by administration of each laminate to the buccal mucosa of different subjects. An in vivo study was a single center, 4 way crossover study in 12 otherwise healthy hypogonadal males. Each subject received a single unit dose of 4 testosterone buccal film formulations (A, B, C, & D). Each dose was separated from the others by at least 72 hours to wash out. Pharmacokinetic data is presented in the following tables.

AUC o-₂₄ Pharmacokinetic Summar (Baseline Ad usted, n h/dL)

AUC(o-24) Treatment Comparisons & 95% Confidence Intervals (Baseline Adjusted)

Comparison Ratio 95% Confidence Interval

A vs B 99.1% (81.2%, 120.9%)

A vs C 98.0% (80.3%, 119.6%)

A vs D 92.4% (75.7%, 112.7%)

B vs C 98.9% (81.1%, 120.7%)

B vs D 93.2% (76.4%, 113.7%)

C vs D 94.2% (77.2%, 115.0%)

Cmax Pharmacokinetic Summar (Baseline Ad usted, n /dL)

Cmax Treatment Comparisons & 95% Confidence Intervals (Baseline Adjusted)

Comparison Ratio 95% Confidence Interval

A vs B 109.5% (89.9%, 133.4%)

A vs C 97.3% (79.8%, 118.5%)

A vs D 106.8% (87.7%, 130.1%)

B vs C 88.8% (72.9%, 108.2%)

B vs D 97.6% (80.1%, 118.8%)

C vs D 109.8% (90.2%, 133.8%) When compared to the SR4 and SR12 laminates, the Formulations A-D provided substantially the same AUCo-₂₄ albeit with a substantially lower Cmax and an extended Tmax. Key differences between the Formulations A-D versus the SR4 and SR12 laminates are: Formulations A-D comprise two to three different grades of PEO (Polyethylene Oxide); they exclude polycarbophil; and Formulations A-D are processed at much higher temperatures. The dose for all formulations was 20 mg, except for formulation D, which was 15 mg. The dimensions, surface area and thickness varied as described above.

Formulations A, B and D provided a bimodal (biphasic) plasma concentration profile for testosterone. In these particular formulations, the plasma concentration of testosterone peaked twice: 1) Formulation A exhibited a first plasma concentration peak of 1200-1300 ng/dL at 2-4 hours after administration and a second plasma concentration peak of 600-800 ng/dL at 8-12 hours after administration; 2) Formulation C exhibited a first plasma concentration peak of 1200-1300 ng/dL at 3-5 hours after administration and a second plasma concentration peak of 600-800 ng/dL at 6-10 hours after administration; and 3) Formulation D exhibited a first plasma concentration peak of 800-1000 ng/dL at 2- 6 hours after administration and a second plasma concentration peak of 1000-1100 ng/dL at 8-12 hours after administration. On the other hand, Formulation B provided a mono- modal (monophasic) plasma concentration profile having a peak plasma concentration 900-1100 ng of testosterone/dL at about 4-8 hours after administration.

The laminate Formulations E-J were prepared according to Example 16 and the in vitro (FIG. 8) and in vivo (FIG. 9) performance thereof were evaluated as described herein. The bi-layered laminates of Example 16 comprise a hot-melt extruded drug reservoir layer and a solvent cast inert backing layer. The laminates provide an extended release of testosterone, wherein the total amount of time during which testosterone is released can be varied according to the composition of the reservoir layer. FIG. 8 depicts the in vitro release profile for the laminates Formulas E-J, which release testosterone over a total about 12-hr to 24-hr period after initial exposure to an aqueous environment. The Formulations E-J differ amongst themselves in the amount of each grade of PEO included, the testosterone dose and the film dimensions (length, width, surface area, and thickness) as described below.

The weight of Formulation E (10 mg Testosterone dose) doses averaged 156 mg, the average length was 22.42 mm, the average width was 6.46 mm and the average thickness was 1.12 mm thus providing an average surface area of 145 mm² for the exposed reservoir surface and a surface area to dose ratio of 14.5 mm² / mg testosterone based upon the exposed reservoir surface. The weight of Formulation F (10 mg Testosterone dose) doses averaged 157 mg, the average length was 21.51 mm, the average width was 6.31 mm and the average thickness was 1.16 mm thus providing an average surface area of 133 mm² for the exposed reservoir surface and a surface area to dose ratio of 13.3 mm² / mg testosterone based upon the exposed reservoir surface. The weight of Formulation G (5 mg Testosterone dose) doses averaged 164 mg, the average length was 21.47 mm, the average width was 6.36 mm and the average thickness was 1.21 mm thus providing an average surface area of 137 mm² for the exposed reservoir surface and a surface area to dose ratio of 32.8 mm² / mg testosterone based upon the exposed reservoir surface. The weight of Formulation H (15 mg Testosterone dose) doses averaged 168 mg, the average length was 21.90 mm, the average width was 6.48 mm and the average thickness was 1.20 mm thus providing an average surface area of 142 mm² for the exposed reservoir surface and a surface area to dose ratio of 9.5 mm / mg testosterone based upon the exposed reservoir surface. Formulation I was cut from the same bulk film mass as Formulation H, but to a smaller size to provide a 12.5 mg Testosterone dose. The weight of Formulation I doses averaged 141 mg, the average length was 19.29 mm, the average width was 6.29 mm and the average thickness was 1.20 mm providing an average surface area of 121 mm² for the exposed reservoir surface and a surface area to dose ratio of 9.7 mm² / mg testosterone based upon the exposed reservoir surface. The weight of Formulation J (10 mg Testosterone dose) doses averaged 158 mg, the average length was 22.41 mm, the average width was 6.48 mm and the average thickness was 1.13 mm providing an average surface area of 145 mm for the exposed reservoir surface and a surface area to dose ratio of 14.5 mm / mg testosterone based upon the exposed reservoir surface.

The Formulations E-J differ from Formulations A-D in the amount of each grade of PEO included and in the presence of Carbopol in each of Formulations E-J. Moreover, Formulations E-J are extruded at higher temperatures than Formulations A-D. Also, the Formulations E-J comprise a different backing layer than do the SR4 and SR12 formulations and the Formulations A-D. The backing film was modified using Eudragit RS PO in place of Eudragit E PO to reduce permeability and provide an improved barrier. This backing film was applied to the drug reservoir using an adhesive. In other words, each laminate releases testosterone substantially continuously over an extended period of about 24 hours once the laminate has been placed in the aqueous assay medium. The in vivo performance of the Formulations E-J was evaluated by administration of each laminate to the buccal mucosa of different subjects. The in vivo study was a single center study in 12 otherwise healthy hypogonadal males. Each subject received a single dose of 4 out of 6 testosterone buccal film formulations (E, F, G, H, I & J). Each dose was separated from the others by at least 72 hours to wash out. Pharmacokinetic data is presented in the following tables.

AUC o-₂₄ Pharmacokinetic Summar (Baseline Ad usted, n h/dL)

AUC(o-24) Treatment Comparisons & 95% Confidence Intervals (Baseline Adjusted)

Comparison Ratio 95% Confidence Interval

E vs F 95.3% (76.8%, 118.1%)

G vs F 64.3% (51.8%, 79.7%)

H vs F 127.6% (104.6%, 155.7%)

I vs F 114.3% (92.2%, 141.7%)

J vs F 127.4% (102.8%, 158.0%)

Cmax Pharmacokinetic Summary (Baseline Adjusted, ng/dL)

Cmax Treatment Comparisons & 95% Confidence Intervals (Baseline Adjusted)

Comparison Ratio 95% Confidence Interval

E vs F 106.7% (78.9%, 144.3%)

G vs F 77.7% (57.4%, 105.0%)

H vs F 129.2% (97.7%, 170.9%)

I vs F 128.2% (94.8%, 173.4%)

J vs F 157.7% (116.6%, 213.3%)

Tmax Pharmacokinetic Summar (Baseline Ad usted, hr)

The Formulations E-J each provide a Cmax of less than 900 ng/dL with a Tmax at about 4 to 8 hours after buccal administration. These formulations also provide a testosterone plasma level between about 300 and about 900 ng/dL throughout the period of about 1 to 15 hours, or about 1 to 12 hours, after buccal administration to a subject.

Each of Formulation E-J provided a bimodal plasma concentration profile for testosterone. In these particular formulations, the plasma concentration of testosterone peaked twice: 1) Formulation E exhibited a first plasma concentration peak of 700-900 ng/dL at 2-6 hours after administration and a second plasma concentration peak of 700- 900 ng/dL at 6-10 hours after administration; 2) Formulation F exhibited a first plasma concentration peak of 600-800 ng/dL at 2-5 hours after administration and a second plasma concentration peak of 500-700 ng/dL at 8-12 hours after administration; 3) Formulation G exhibited a first plasma concentration peak of 600-800 ng/dL at 2-6 hours after administration and a second plasma concentration peak of 500-700 ng/dL at 6-10 hours after administration; 4) Formulation H exhibited a first plasma concentration peak of 800-1000 ng/dL at 2-4 hours after administration and a second plasma concentration peak of 800-1000 ng/dL at 6-11 hours after administration; 5) Formulation I exhibited a first plasma concentration peak of 900-1000 ng/dL at 2-6 hours after administration and a second plasma concentration peak of 700-900 ng/dL at 6-11 hours after administration; and 6) Formulation J exhibited a first plasma concentration peak of 900-1100 ng/dL at 2-6 hours after administration and a second plasma concentration peak of 900-1100 ng/dL at 6-10 hours after administration.

The laminate Formulation K was prepared according to Example 17 and its in vitro (FIG. 10) and in vivo (FIG. 11) performance were evaluated as described herein. The bi- layered laminate comprises a hot-melt extruded drug reservoir layer and a solvent cast inert backing layer. The laminate provides an extended release of testosterone. FIG. 10 depicts the in vitro release profile for the laminate Formula K, which releases testosterone over a total about 12-hr to 24-hr period after initial exposure to an aqueous environment. The Formulation K differs from Formulations SR4 and SR 12 in the amount of each grade of PEO included and in the presence of Carbopol (5% wt.) as opposed to the presence of polycarbophil (2% wt., Formulation SR4 and SR12). Moreover, Formulation K is extruded at higher temperatures than Formulations SR4 and SR12. Also, Formulation K comprises a different backing layer than do the SR4 and SR 12 formulations and the A-D formulations, but the same backing layer used in Formulations E-J. The Formulation K differs from Formulations A-D in the amount of each grade of

PEO included and in the presence of Carbopol (5% wt.) as opposed to its absence (Formulation A-D). Formulation K differs from Formulations E-J in the amount of each grade of PEO included, the amount of Carbopol (5% wt.) present, the amount of testosterone present. The dimensions of K differed from SR4, SR12 and Formulations A- J. The weight of Formulation K (12.5mg Testosterone dose) doses averaged 155 mg, the average length was 21.03 mm, the average width was 6.29 mm and the average thickness was 1.17 mm providing an average surface area of 132 mm² for the exposed reservoir surface and a surface area to dose ratio of 10.6 mm² / mg testosterone based upon the exposed reservoir surface. In other words, each laminate releases testosterone substantially continuously over an extended period of about 1 - 24 hours once the laminate has been placed in the aqueous assay medium.

The in vivo performance of the Formulation K was evaluated by administration of the laminate to the buccal mucosa of different subjects. Each subject received a dose of Formulation K for seven consecutive days. Pharmacokinetic data is presented in the following tables. AUC o-24 Pharmacokinetic Summar (Baseline Ad usted, n h/dL)

The Formulation K provides a Cmax of less than 900 ng/dL with a Tmax at about 3 to 9 hours after buccal administration. These formulations also provide a testosterone plasma level between about 300 and about 900 ng/dL throughout the period of about 0.5 to 15 hours, or about 1 to 12 hours, after buccal administration to a subject.

The laminate Formulations L-P were prepared according to Example 18 and their in vitro (FIG. 12) and in vivo (FIG. 13) performance were evaluated as described herein. The bi-layered laminates comprise a hot-melt extruded drug reservoir layer and a hot-melt extruded inert backing layer. The laminate provides an extended release of testosterone. FIG. 12 depicts the in vitro release profile for the laminate Formulations L-P, which release testosterone over a total about 18-hr to 24-hr period after initial exposure to an aqueous environment. The Formulations L-P differ from Formulations SR4 and SR 12 in the amount of each grade of PEO included, the presence of poloxamer in the Formulations L-P, and in the presence of Carbopol (5% wt.) in the Formulations L-P as opposed to the presence of polycarbophil (2% wt., Formulation SR4 and SR12). Moreover, Formulations L-P are extruded at higher temperatures than Formulations SR4 and SR12. Also, Formulations L-P comprise a different backing layer than do the SR4 and SR 12 formulations.

The Formulations L-P differ from Formulations A-D in the amount of each grade of PEO included, the presence of poloxamer in the Formulations L-P as opposed to its absence in Formulations A-D, and in the presence of Carbopol (5% wt.) as opposed to its absence (Formulation A-D). Also, Formulations L-P comprise a different backing layer than do the Formulations A-D. Formulations L-P were prepared using a coextrusion method in which the drug reservoir and the backing layer were prepared simultaneously in a dual manifold die fusing the two layers together.

Formulations L - P also had different dimensions as described below. The weight of Formulation L (12.5mg Testosterone dose) doses averaged 155 mg, the average length was 18.17 mm, the average width was 6.29 mm and the average thickness was 1.21 mm thus providing an average surface area of 114 mm² for the exposed reservoir surface and a surface area to dose ratio of 9.1 mm / mg testosterone based upon the exposed reservoir surface. The weight of Formulation M (12.5 mg Testosterone dose) doses averaged 135 mg, the average length was 15.76 mm, the average width was 6.28 mm and the average thickness was 1.19 mm thus providing an average surface area of 99 mm² for the exposed reservoir surface and a surface area to dose ratio of 7.9 mm² / mg testosterone based upon the exposed reservoir surface. The weight of Formulation N (15 mg Testosterone dose) doses averaged 130 mg, the average length was 14.58 mm, the average width was 6.28 mm and the average thickness was 1.22 mm thus providing an average surface area of 91.5 mm² for the exposed reservoir surface and a surface area to dose ratio of 6.1 mm² / mg testosterone based upon the exposed reservoir surface. The weight of Formulation P (15 mg Testosterone dose) doses averaged 145 mg, the average length was 15.1 mm, the average width was 6.28 mm and the average thickness was 1.35 mm thus providing an average surface area of 95 mm² for the exposed reservoir surface and a surface area to dose ratio of 6.3 mm² / mg testosterone based upon the exposed reservoir surface.

In other words, each laminate releases testosterone substantially continuously over an extended period of about 24 hours once the laminate has been placed in the aqueous assay medium.

The in vivo performance of the Formulations L-P was evaluated by administration of the laminate to the buccal mucosa of different subjects. Subjects received a dose of Formulations L-P for seven consecutive days. Pharmacokinetic data is presented in the following tables. Da 1 AUC o-24 Pharmacokinetic Summar (^ng VdL)

Day 7 Baseline Adjusted AUC(o-₂₄) Treatment Comparisons & 95% Confidence Intervals

Da 1 Cmax (^ng/dL) Pharmacokinetic Summar

Da 1 Baseline Ad usted C_max (^ng/_dL) Pharmacokinetic Summar

Day 7 C_max ( /diO Pharmacokinetic Summary

Day 7 Baseline Adjusted C_max ( ^g/_dL) Pharmacokinetic Summary

Day 7 Baseline Ad usted C_maχ Treatment Com arisons & 95% Confidence Intervals

Da 7 T_max (hr) Pharmacokinetic Summar

The Formulations M & N provide a Cmax of less than 900 ng/dL with a Tmax at about 3 to 12 hours after buccal administration. These formulations also provide a testosterone plasma level between about 300 and about 900 ng/dL throughout the period of about 0.5 to 15 hours, or about 1 to 12 hours, after buccal administration to a subject. These formulations also provide a testosterone plasma level between about 600 and about 900 ng/dL throughout the period of about 2 to 14-15 hours after buccal administration to a subject. The Formulations L & P provide a Cmax of greater about 900 ng/dL to about 1200 ng/dL with a Tmax at about 7-9 hours after buccal administration. These formulations also provide a testosterone plasma level between about 300-1200 ng/dL throughout the period of about 1 to 12 hours after buccal administration to a subject.

Two formulations were prepared using differing Carbopol loads in which the target film thickness was 1.50 mm. These formulations were prepared by the hydroalcoholic wet granulation technique in which the Vitamin E and Vitamin E Succinate were emulsified with the Poloxamer. The in vitro dissolution profiles are presented in FIGS. 14a and 14b. The formulations differed in the amount of CARBOPOL polymer present: 12.5% (FIG. 14a); 15% (FIG. 14b). It can be concluded that increasing the dose thickness and the Carbopol content in the formulation retards the in vitro dissolution rate. The thickness of the reservoir layer can range from about 0.01 to about 20 mm or otherwise be manufactured in any size adapted for a particular purpose.

The laminate of the invention provides a reproducible plasma profile during single to multiple day administration. FIG. 15A depicts the mean plasma concentration for testosterone third day of administration of a thirteen day cycle in human subjects to which an extended release dosage form of the invention has been administered. The laminate was administered twice daily. FIG. 15B depicts the mean plasma concentration for testosterone during the first day administration of an eleven day administration cycle in human subjects to which an extended release dosage form of the invention has been administered. The laminate was administered twice daily.

In the embodiments of FIGS. 15A and 15B, the overall daily plasma concentration profile was bimodal due to the twice daily administration of the laminate. In other words, the individual laminate provided a monomodal plasma profile when administered a single time (once daily) and provided a bimodal (biphasic) plasma profile when administered twice daily.

POLYOX (PEO) polymers contain residual calcium salts from the catalyst during synthesis. An acidic component or acidifying agent can be added to the PEO polymer to neutralize these alkaline materials prior to or during hot-melt extrusion. In one example, the acidic component was added in liquid form to the granulation mass or the granulation liquid medium. The total acidic component is present in an amount to sufficient to neutralize alkaline species present in the matrix. In other words, the total molar concentration of acidic component (or of total acidic groups) exceeds the molar concentration of total alkaline groups present in the composition. An acidic component can have 1, 2 or more moles of acidic groups per mole of acidic component.

Optionally, no wet granulation is required. In this embodiment, all materials to be added to a formulation are blended and then hot-melt extruded. This process, however, is only suitable when water soluble acidic components are used, as non-water soluble acidic components, such as CARBOPOL®, do not stabilize the film as well in this type of process. This because CARBOPOL® requires water for hydration in order to exert its acidic property. One way to overcome this disadvantage is to wet the non-water soluble acidic component prior to granulation with the bioadhesive alkaline thermoplastic polymer and extending the granulation time sufficiently to permit interaction of the non-water soluble acidic component with the bioadhesive alkaline thermoplastic polymer to form a neutral or moderately acidic excipient mixture.

As used herein, the term "acidic component" or "acidifying agent" means one or more acidic polymers (e.g. Carbopol®, Polycarbophil, polyacrylic acid), one or more inorganic acids (e.g. a mineral acid, (phosphoric acid, boric acid, hydrochloric acid, nitric acid, sulfuric acid, hydrobromic acid), one or more organic acids (non-polymeric carboxylic acid such as acetic acid, citric acid, tartaric acid, fumaric acid, succinic acid, amino acid, alpha-hydroxyl acid, ascorbic or adipic acid), or a combination thereof. An acidic component also includes the salt form or buffer of an acid, wherein the salt has solution pH of less than 7 or less than 6 when dissolved in water. The above-listed acidic components are merely illustrative and non-limiting. Any acidic component having a pKa of less than 7 or less than 6 would be suitable for use in the present invention. Specific embodiments include those wherein the acidic component is selected from the group consisting of: hydrochloric acid, phosphoric acid, citric acid and a combination thereof. An acidic component can be a combination of an acidic polymer and an organic acid, an acidic polymer and an inorganic acid, or an inorganic acid and an organic acid. An acidic component may also be a combination or two or more acidic polymers, two or more inorganic acids, or two or more organic acids. Exemplary formulations containing an acidic component in the reservoir layer are detailed below.

The solid dosage formulations of the invention can assume any shape or form known in the art of pharmaceutical sciences. The dosage form can be a sphere, tablet, bar, plate, paraboloid of revolution, ellipsoid of revolution or other one known to those of ordinary skill in the art. The solid dosage form can also include surface markings, cuttings, grooves, letters and/or numerals for the purposes of decoration, identification and/or other purposes.

The matrix and/or the additional functional excipients may be formulated as to provide a predetermined approximate release profile under predetermined conditions. The drug can be released according to a sustained, controlled, slow, pulsatile or extended drug release profile.

The pharmaceutical composition may deliver one or more active agents in an extended release manner, and mechanisms employed for such delivery can include active agent release that is pH-independent; diffusion or dissolution controlled; erosion controlled; pseudo-zero order (approximates zero-order release), zero-order, pseudo-first order (approximates first-order release), or first-order; or slow, or sustained release or otherwise controlled release. The in vitro release profile for the active agent can also be sigmoidal in shape, wherein the release profile comprises an initial slow release rate, followed by a middle faster release rate and a final slow release rate of active agent.

As used herein, the term "extended release" profile assumes the definition as widely recognized in the art of pharmaceutical sciences. An extended release dosage form will release drug at substantially constant rate over an extended period of time or a substantially constant amount of drug will be released incrementally over an extended period of time. An extended release tablet generally effects at least a two-fold reduction in dosing frequency as compared to the drug presented in a conventional dosage form (e.g., a solution or rapid releasing conventional solid dosage forms).

By "controlled release" is meant a release of an active agent to an environment over a period of about eight hours up to about 12 hours, 16 hours, 18 hours, 20 hours, a day, or more than a day. By "sustained release" is meant an extended release of an active agent to maintain a constant drug level in the blood or target tissue of a subject to which the device is administered. The term "controlled release", as regards to drug release, includes the terms "extended release", "prolonged release", "sustained release", or "slow release", as these terms are used in the pharmaceutical sciences. A controlled release can begin within a few minutes after administration or after expiration of a delay period (lag time) after administration.

A slow release dosage form is one that provides a slow rate of release of drug so that drug is released slowly and approximately continuously over a period of 3 hr, 6 hr, 12 hr, 18 hr, a day, 2 or more days, a week, or 2 or more weeks, for example. A pseudo-first order release profile is one that approximates a first order release profile. A first order release profile characterizes the release profile of a dosage form that releases a constant percentage of an initial drug charge per unit time.

A pseudo-zero order release profile is one that approximates a zero-order release profile. A zero-order release profile characterizes the release profile of a dosage form that releases a constant amount of drug per unit time.

FIG. 2 depicts a conceptual cross-sectional front elevation of an exemplary bi- layered hot-melt extruded composition (3) (a laminate) comprising a drug reservoir layer (2) and a backing layer (4). The drug reservoir is a bioadhesive layer comprising testosterone, and a bioadhesive thermoplastic polymer. The backing layer is non- bioadhesive and more hydrophobic than the reservoir layer.

The hydrophobic composition of the backing layer generally comprises a hydrophobic non-bioadhesive matrix. The backing layer can be hot-melt extruded or it can be cast onto the drug reservoir layer as described herein or using methods known to those in the art. Suitable materials that can be used in preparing a thermoplastic matrix of the backing layer include, by way of example and without limitation, EUDRAGIT, ethylcellulose, polyethylene, cellulose acetate butyrate, cellulose acetate phthalate, wax, polyvinyl alcohol, polyvinyl acetate phthalate, polyester, shellac, other materials recognized in the chemical arts as having similar physical properties, or a combination thereof. The backing layer can be extruded as described herein or it can be a prefabricated layer that is subsequently laminated to the reservoir layer. In one embodiment, the backing layer is impermeable to aqueous medium and drug. Non-limiting exemplary materials suitable for this type of backing layer include ethylcellulose, EUDRAGIT RS, wax, other materials recognized in the chemical arts as having similar physical properties, or a combination thereof. In another embodiment, it is semipermeable, meaning it is impermeable to drug and permeable to aqueous medium. Non-limiting exemplary materials suitable for this type of backing layer include PEO and ethylcellulose, PEO and EUDRAGIT RS, cellulose acetate and its derivatives, other materials recognized in the chemical arts as having similar physical properties, or a combination thereof. In still another embodiment, it is permeable to aqueous medium and drug. Non-limiting exemplary materials suitable for this type of backing layer include PEO and EUGRAGIT E, other materials recognized in the chemical arts as having similar physical properties, or a combination thereof.

Exemplary backing layers were made according to the examples below. In one embodiment, the hydrophobic composition of the backing layer is extruded separately from the hydrophilic composition of the reservoir layer. In another embodiment, the hydrophobic composition of the backing layer is coextruded with the hydrophilic composition of the reservoir layer. In one embodiment, the backing layer and reservoir layers are extruded individually (albeit simultaneously or sequentially) and thereafter heat- laminated, solvent-laminated, or adhesive-laminated together during manufacture. In another embodiment, one layer is extruded onto the other layer which has been preformed, such as by extrusion or casting. In another embodiment, the backing layer and the reservoir layer are extruded separately and subsequently heat-laminated, solvent-laminated or adhesive-laminated together.

The step of heat-catalyzed lamination is conducted by passing the backing layer and reservoir layer in contact with each other simultaneously through a laminator that applies pressure and optionally heat to the opposing layers. If the layers are sufficiently hot prior to lamination, they need not be heated again when placed in the laminator. If the layers are not sufficiently hot prior to lamination to permit suitable lamination, then they are heated just prior to and/or during lamination. The heat source can be located within or external to the laminator. The layers will generally be heated to about 100-170 °C or at least about 60 °C prior to and/or during lamination. The temperature for lamination will be below the temperature at which a layer degrades.

Solvent lamination can be achieved without heat by applying a fine mist of water or other suitable solvent or plasticizer two one or both of the opposing layers immediately prior to combining under pressure. This solvent lamination process is suitable when the reservoir layer and the backing layer each comprise a solvent-activated or plasticizer- activated adhesive material such as PEO.

The laminator can be a set of opposing rollers driven by one or two motors. The laminator will apply pressure to both layers during the lamination step. The contact pressure will generally be at least 40 pounds per linear inch or in the range of about 40 - 600 pounds per linear inch. The laminator rollers will be sufficiently rigid to withstand the forces exerted. The rollers may be hollow and internally baffled to allow for the use of a heat transfer fluid. The rollers may be comprised of a multiple metals and/or alloys providing suitable hardness and may contain suitable coatings to provide adequate release of the heated polymer. Suitable coatings for the rollers include, for example, Teflon®, Titanium Nitride, Chrome, and other material(s) used in the polymer industry for coating of heat laminator s.

When the reservoir layer is adhesive-laminated to the backing layer, the adhesive is a material known in the field of polymers as suitable to adhering the two layers together. The specific adhesive will vary according to the chemical composition, chemical properties, and physical properties of the reservoir layer and the backing layer. A non- limiting exemplary adhesive comprises KLUCEL and EUDRAGIT ElOO. For example, a bioadhesive reservoir layer comprising a hydrophilic HME matrix can be adhered to a non-bioadhesive backing layer comprising a hydrophobic HME matrix by applying an adhesive material at the interface between the two layers and subsequently pressing the two layers together. Weight or pressure can be applied to the layers optionally followed by drying to remove solvent, if present, from the adhesive.

Studies to investigate the pH (when placed in solution) of the backing layer were conducted to eliminate the potential for drug degradation at the interface between the backing layer and the reservoir layer in a laminate composition. Such degradation may occur during heat-catalyzed lamination or during storage of the laminate. The pH of the backing layer (made according to the example below) was determined to be 9.0 after dispersing 2 grams in 10OmL of purified water. The pH of the suspension was determined after aliquots of citric acid monohydrate were added. Addition of 10 mg of citric acid reduced the suspension pH to 4.6 and addition of 50 mg reduced the suspension pH to 3.4. A backing film formulation was prepared containing 1.0% citric acid. The citric acid monohydrate was dissolved in water (5% based on solids) and wet granulated with the PoIyOx polymers. The remaining materials were blended under high shear followed by granulation with dibutyl sebacate. The results indicate decreased degradation of testosterone in the reservoir layer when the backing layer included an acidic component in an amount sufficient to render the solution pH of the backing film less than about 7.

A solvent cast backing layer is made by first preparing a casting composition comprising a solvent and at least a hydrophobic polymer. The casting composition is then poured directly onto a reservoir layer, and the solvent is removed from the casting composition. After a sufficient amount of solvent has been removed, the backing layer will have been formed. A solvent cast backing layer adheres directly to the reservoir layer. Solids forming part of the casting composition can be completely or partially dissolved in the solvent. The solvent is removed via a drying step that can be conducted according to any conventional method known in the pharmaceutical sciences for removing a solvent from a composition. For example, the solvent can be removed by tray drying, vacuum drying, heat drying, air drying or a combination thereof. The use of heat and vacuum is optional. Although it is not necessary to completely remove all of the solvent from the backing layer, any organic solvent present therein can be present at a level of less than about 2-3% wt. of the backing layer and any water present therein be present at a less of less than about 1 - 8 % wt of the backing layer.

The ratio of the thickness of the reservoir layer to the thickness of the backing layer can be varied as needed depending upon the performance desired for the laminate. In one embodiment, the ratio ranges from about 0.05 to about 1.5

When the backing layer and reservoir layer are laminated together by heat- catalyzed lamination, they can have at least one polymer in common. For example, if the reservoir layer contains PEO, then the backing layer could contain PEO.

Generally, the reservoir layer and the backing layer possess melt flow indices that are not too dissimilar if the layers are to be laminated by heat-catalyzed lamination in the absence of an adhesive between the layers. This means their melt flow indices will fall within individual predefined ranges and that those ranges overlap at least to some predefined extent. For example, the melt flow index of the reservoir layer can be within no more than 75% or within no more than 50% of the melt flow index of the backing layer. As used herein, the term melt flow index is taken to mean the amount, in grams, of a resin which can be forced through a plastometer or rheometer (as defined in ASTM D 1238) in ten minutes at a given temperature and force. FIGS. 3A-3B depict conceptual cross-sectional front elevations of exemplary tri- layered laminates. The laminate of FIG. 3 A is a hot- melt extruded composition (5) comprising a drug reservoir layer (2), a backing layer (4) and a release liner layer (6). The drug reservoir layer and backing layer are as described herein. The release liner layer temporarily adheres to the bioadhesive layer during storage of the HME composition, and it is removable by hand before administration of the HME composition to a subject. The release layer may or may not be coextruded with the other two layers. The laminate (7) of FIG. 3B comprises a hot-melt extruded drug reservoir layer (8) coated with a hot-melt extruded or solvent cast backing layer (8). The release liner layer (10) is removably affixed to the reservoir layer and/or backing layer. The laminate (7) is hemispherical or semi-cylindrical in shape. In one embodiment, all surfaces of the reservoir layer, except those intended to be in transdermal contact (for transdermal drug delivery), are covered with a backing layer. In another embodiment, the surface of the reservoir layer that is coated with a backing layer opposes the surface of the reservoir layer that is intended for transdermal contact. Any release layer that can temporarily adhere to the reservoir layer will be suitable for use according to the invention. Exemplary non-limiting suitable release layers obtainable from commercial sources include DOW SARANEX™, BLF, 3M CoTran and SCOTCHPAK, Delstar Stratex and Delnet.

The release layer is attached to the face of the reservoir layer that is opposite the backing layer such that the release layer and backing layer oppose one another. In other words, the reservoir layer is between the release layer and the backing layer. The contact surface area of the release layer can be the same size as or bigger than the corresponding contact surface of the reservoir layer.

The laminate may also contain various functional excipients, such as: hydrophilic polymer, antioxidant, super-disintegrant, surfactant including amphiphillic molecules, wetting agent, stabilizing agent, retardant, thermal lubricant, colorant, solubilizer, chelating agent, similar functional excipient, or combination thereof, and plasticizers including citrate esters, polyethylene glycols, PG, triacetin, diethylphthalate, castor oil, and others known to those or ordinary skill in the art. The laminate may also include an acidifying agent, adsorbent, alkalizing agent, buffering agent, colorant, flavorant, sweetening agent, diluent, opaquant, complexing agent, fragrance, preservative or a combination thereof. As used herein, the term "adsorbent" is intended to mean an agent capable of holding other molecules onto its surface by physical or chemical (chemisorption) means. Such compounds include, by way of example and without limitation, powdered and activated charcoal and other materials known to one of ordinary skill in the art.

A buffering agent is used to resist change in pH upon dilution or addition of acid or alkali. Such compounds include, by way of example and without limitation, potassium metaphosphate, potassium phosphate, monobasic sodium acetate and sodium citrate anhydrous and dihydrate, salts of inorganic or organic acids, salts of inorganic or organic bases, and others known to those of ordinary skill in the art.

As used herein, the term "alkalizing agent" is intended to mean a compound used to provide alkaline medium for product stability. Such compounds include, by way of example and without limitation, ammonia solution, ammonium carbonate, diethanolamine, monoethanolamine, potassium hydroxide, sodium borate, sodium carbonate, sodium bicarbonate, sodium hydroxide, triethanolamine, and trolamine and others known to those of ordinary skill in the art. As used herein, the term "colorant" is intended to mean a compound used to impart color to solid (e.g., tablets) pharmaceutical preparations. Such compounds include, by way of example and without limitation, FD&C Red No. 3, FD&C Red No. 20, FD&C Yellow No. 6, FD&C Blue No. 2, D&C Green No. 5, D&C Orange No. 5, D&C Red No. 8, caramel, and ferric oxide, red, other F.D. & C. dyes and natural coloring agents such as grape skin extract, beet red powder, beta-carotene, annato, carmine, turmeric, paprika, and other materials known to one of ordinary skill in the art. The amount of coloring agent used will vary as desired.

Exemplary chelating agents include EDTA, polycarboxylic acids, polyamines, derivatives thereof, and others known to those of ordinary skill in the art. Exemplary hydrophilic polymers which can be a primary or secondary polymeric carrier that can be included in the composition include poly(vinyl alcohol) (PVA), polyethylene-polypropylene glycol (e.g. poloxamer), carbomer, polycarbophil, or chitosan. The "hydrophilic polymers" of the present invention include one or more of hydroxypropyl methylcellulose, carboxymethylcellulose, hydroxypropyl cellulose, hydroxyethyl cellulose, methylcellulose, natural gums such as gum guar, gum acacia, gum tragacanth, or gum xanthan and povidone. "Hydrophilic polymers" also include polyethylene oxide, sodium carboxymethycellulose, hydroxyethyl methyl cellulose, hydroxymethyl cellulose, carboxypolymethylene, polyethylene glycol, alginic acid, gelatin, polyvinyl alcohol, polyvinylpyrrolidones, polyacrylamides, polymethacrylamides, polyphosphazines, polyoxazolidines, poly(hydroxyalkylcarboxylic acids), carrageenate alginates, carbomer, ammonium alginate, sodium alginate, or mixtures thereof.

Exemplary hydrophobic polymers include alkylcelluloses, ethyl cellulose, Eudragit RS, waxes, polyesters, combinations thereof, and others known to those of ordinary skill in the art.

Thermal lubricants include glyceryl monosterarate, vitamin E succinate, glycerol monooleate, combinations thereof, and others known to those of ordinary skill in the art.

Solubilizers include cyclodextrins, povidone, combinations thereof, and others known to those of ordinary skill in the art.

As used herein, the term "antioxidant" is intended to mean an agent that inhibits oxidation and thus is used to prevent the deterioration of preparations by oxidation due to the presence of oxygen free radicals or free metals in the composition. Such compounds include, by way of example and without limitation, ascorbic acid, ascorbyl palmitate, butylated hydroxyanisole, butylated hydroxytoluene, hypophophorous acid, monothioglycerol, sodium ascorbate, sodium formaldehyde sulfoxylate and sodium metabisulfite and others known to those of ordinary skill in the art. Other suitable antioxidants include, for example, vitamin C, BHT, BHA, sodium bisulfite, vitamin E and its derivatives, propyl gallate or a sulfite derivative. As used herein, the term "disintegrant" is intended to mean a compound used in solid dosage forms to promote the disruption of a solid mass (layer) into smaller particles that are more readily dispersed or dissolved. Exemplary disintegrants include, by way of example and without limitation, starches such as corn starch, potato starch, pre-gelatinized and modified starches thereof, sweeteners, clays, bentonite, microcrystalline cellulose (e.g., Avicel™), carboxymethylcellulose calcium, croscarmellose sodium, alginic acid, sodium alginate, cellulose polyacrilin potassium (e.g., Amberlite™), alginates, sodium starch glycolate, gums, agar, guar, locust bean, karaya, pectin, tragacanth, crospovidone and other materials known to one of ordinary skill in the art. A superdisintegrant is a rapidly acting disintegrant. Exemplary superdisintegrants include crospovidone and low substituted HPC.

Suitable surfactants include Polysorbate 80, sorbitan monooleate, sodium lauryl sulfate or others. Soaps and synthetic detergents may be employed as surfactants. Suitable soaps include fatty acid alkali metal, ammonium, and triethanolamine salts.

Suitable detergents include cationic detergents, for example, dimethyl dialkyl ammonium halides, alkyl pyridinium halides, and alkylamine acetates; anionic detergents, for example, alkyl, aryl and olefin sulfonates, alkyl, olefin, ether and monoglyceride sulfates, and sulfosuccinates; nonionic detergents, for example, fatty amine oxides, fatty acid alkanolamides, and pory(oxyethylene)-b/øcfc-pory(oxypropylene) copolymers; and amphoteric detergents, for example, alkyl β-aminopropionates and 2-alkylimidazoline quaternary ammonium salts; and mixtures thereof.

Wetting agent is an agent that decreases the surface tension of a liquid. Wetting agents would include alcohols, glycerin, proteins, peptides water miscible solvents such as glycols, hydrophilic polymers Polysorbate 80, sorbitan monooleate, sodium lauryl sulfate, fatty acid alkali metal, ammonium, and triethanolamine salts, dimethyl dialkyl ammonium halides, alkyl pyridinium halides, and alkylamine acetates; anionic detergents, for example, alkyl, aryl and olefin sulfonates, alkyl, olefin, ether and monoglyceride sulfates, and sulfosuccinates; nonionic detergents, for example, fatty amine oxides, fatty acid alkanolamides, and poly(oxyethylene)-b/øcfc-poly(oxypropylene) copolymers; and amphoteric detergents, for example, alkyl β-aminopropionates and 2-alkylimidazoline quaternary ammonium salts; and mixtures thereof.

Retardants are agents that are insoluble or slightly soluble polymers with a Tg above 45⁰C, or above 5O⁰C before being plasticized by other agents in the formulation including other polymers and other excipients needed for processing. The excipients include waxes, acrylics, cellulosics, lipids, proteins, glycols, and the like.

A desiccant can be used to aid in storing a formulation according to the invention.

Suitable desiccants include sodium sulfate, calcium sulfate, magnesium sulfate, sodium hydroxide, sodium bicarbonate, clay, vermiculite, paper, activated alumina, zeolite, calcium chloride, molecular sieve, or anhydrous chemicals. In some cases a desiccant is needed if the matrix materials or the drug are hygroscopic since moisture may affect the stability of the HME composition and/or drug therein. As used herein, the term "opaquant" is intended to mean a compound used to render a composition opaque. May be used alone or in combination with a colorant. Such compounds include, by way of example and without limitation, titanium dioxide and other materials known to one of ordinary skill in the art. Some of the materials listed herein may be too brittle or may have Tg values that are generally too high rendering them too difficult to extrude. The glass transition temperature is reduced upon the addition of a plasticizer. As used herein, the glass transition temperature is taken to mean the temperature at which a solid material softens or melts (or the glass transition temperature (Tg) is the temperature at which a polymer changes during the heat cycle from a brittle substance (glass) to a rubbery mass). Such materials can be combined with one or more plasticizers to render them thermoformable. Plasticizers, such as low molecular weight PEG, generally broaden the average molecular weight of a polymer in which they are included thereby lowering its glass transition temperature or softening point. Plasticizers also generally reduce the viscosity of a polymer. It is possible the plasticizer will impart some particularly advantageous physical properties to the film of the invention.

Plasticizers useful in the invention can include, by way of example and without limitation, low molecular weight polymers, oligomers, copolymers, oils, small organic molecules, low molecular weight polyols having aliphatic hydroxyls, ester-type plasticizers, glycol ethers, poly(propylene glycol), multi-block polymers, single block polymers, low molecular weight poly(ethylene glycol), citrate ester-type plasticizers, triacetin, propylene glycol and glycerin. Such plasticizers can also include ethylene glycol, 1,2-butylene glycol, 2,3-butylene glycol, styrene glycol, diethylene glycol, Methylene glycol, tetraethylene glycol and other poly(ethylene glycol) compounds, monopropylene glycol monoisopropyl ether, propylene glycol monoethyl ether, ethylene glycol monoethyl ether, diethylene glycol monoethyl ether, sorbitol lactate, ethyl lactate, butyl lactate, ethyl glycolate, dibutyl sebacate, acetyltributylcitrate, triethyl citrate, acetyl triethyl citrate, tributyl citrate and allyl glycolate. All such plasticizers are commercially available from sources such as Aldrich or Sigma Chemical Co. It is also contemplated and within the scope of the invention, that a combination of plasticizers may be used in the present formulation. The PEG based plasticizers are available commercially or can be made by a variety of methods, such as disclosed in Poly(ethylene glycol) Chemistry: Biotechnical and Biomedical Applications (J. M. Harris, Ed.; Plenum Press, NY) the disclosure of which is hereby incorporated by reference.

Preservatives include compounds used to prevent the growth of microorganisms.

Suitable preservatives include, by way of example and without limitation, benzalkonium chloride, benzethonium chloride, benzyl alcohol, cetylpyridinium chloride, chlorobutanol, phenol, phenylethyl alcohol, phenylmercuric nitrate and thimerosal and others known to those of ordinary skill in the art.

As used herein, the term "flavorant" is intended to mean a compound used to impart a pleasant flavor and often odor to a pharmaceutical preparation. Exemplary flavoring agents or flavorants include synthetic flavor oils and flavoring aromatics and/or natural oils, extracts from plants, leaves, flowers, fruits and so forth and combinations thereof. These may also include cinnamon oil, oil of wintergreen, peppermint oils, clove oil, bay oil, anise oil, eucalyptus, thyme oil, cedar leave oil, oil of nutmeg, oil of sage, oil of bitter almonds and cassia oil. Other useful flavors include vanilla, citrus oil, including lemon, orange, grape, lime and grapefruit, and fruit essences, including apple, pear, peach, strawberry, raspberry, cherry, plum, pineapple, apricot and so forth. Flavors that have been found to be particularly useful include commercially available orange, grape, cherry and bubble gum flavors and mixtures thereof. The amount of flavoring may depend on a number of factors, including the organoleptic effect desired. Flavors will be present in any amount as desired by those of ordinary skill in the art. Particular flavors are the grape and cherry flavors and citrus flavors such as orange.

It should be understood, that compounds used in the art of pharmaceutical formulation generally serve a variety of functions or purposes. Thus, if a compound named herein is mentioned only once or is used to define more than one term herein, its purpose or function should not be construed as being limited solely to that named purpose(s) or function(s).

The hot-melt extruded composition of the invention will include at least an effective amount of testosterone. By the term "effective amount", it is understood that, with respect to, for example, pharmaceuticals, a therapeutically effective amount is contemplated. A therapeutically effective amount is the amount or quantity of drug that is sufficient to elicit the required or desired therapeutic response, or in other words, the amount that is sufficient to elicit an appreciable biological response when administered to a patient. Where possible, any of the materials employed herein can be present in its free acid, free base or pharmaceutically acceptable salt form. As used herein, "pharmaceutically acceptable salts" refer to derivatives of the disclosed compounds wherein the compound is modified by making acid or base salts thereof. Examples of pharmaceutically acceptable salts include, but are not limited to, mineral or organic acid salts of the drug. The pharmaceutically acceptable salts include the conventional non-toxic salts, for example, from non-toxic inorganic or organic acids. For example, such conventional non-toxic salts include those derived from inorganic acids such as hydrochloric, hydrobromic, sulfuric, sulfonic, sulfamic, phosphoric, nitric and the like; and the salts prepared from organic acids such as amino acids, acetic, propionic, succinic, glycolic, stearic, lactic, malic, tartaric, citric, ascorbic, pamoic, maleic, hydroxymaleic, phenylacetic, glutamic, benzoic, salicylic, sulfanilic, 2-acetoxybenzoic, fumaric, toluenesulfonic, methane sulfonic, ethane disulfonic, oxalic, isethionic, and other known to those of ordinary skill in the pharmaceutical sciences. Lists of suitable salts are found in texts such as Remington's Pharmaceutical Sciences, 18th Ed. (Alfonso R. Gennaro, ed.; Mack Publishing Company, Easton, PA, 1990); Remington: the Science and Practice of Pharmacy 19^th Ed.( Lippincott, Williams & Wilkins, 1995); Handbook of Pharmaceutical Excipients, 3^rd Ed. (Arthur H. Kibbe, ed.; Amer. Pharmaceutical Assoc, 1999); the Pharmaceutical Codex: Principles and Practice of Pharmaceutics 12 Ed. (Walter Lund ed.; Pharmaceutical Press, London, 1994); The United States Pharmacopeia: The National Formulary (United States Pharmacopeial Convention); and Goodman and Gilman's: the Pharmacological Basis of Therapeutics (Louis S. Goodman and Lee E. Limbird, eds.; McGraw Hill, 1992), the disclosures of which are hereby incorporated by reference.

The phrase "pharmaceutically acceptable" is employed herein to refer to those compounds, materials, compositions, and/or dosage forms which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of human beings and animals without excessive toxicity, irritation, allergic response, or other problem or complication, commensurate with a reasonable benefit/risk ratio.

As used herein, the term testosterone means all available forms of the compound including crystalline, semi-crystalline, amorphous, hydrate, anhydrous, diastereomeric, and enantiomeric forms. The term "testosterone" also includes derivatives thereof, such as the C17-esters thereof. Testosterone (17β-hydroxyandrost-4-en-3-one) is commercially available from several commercial sources including: Pharmacia & Upjohn (Kalamazoo, MI, 49001); and Diosynth B.V. (a Division of Akzo Nobel) (The Netherlands).

Testosterone and any other materials included in the laminate can be present in any particle size suitable for hot-melt extrusion. Fine particle sizes and larger particle sizes can be used. It can be added as a liquid, solid, emulsion, or any other suitable form.

There are several methods well known in the pharmaceutical literature for producing fine drug particles in the micro or nanometer size range. These methods can be divided into three primary categories: (1) mechanical micronization (2) solution based phase separation and (3) rapid freezing techniques. Drug particles made according to any of these techniques will be suitable for use in the present pharmaceutical composition.

Such processes include mechanical milling by ball mill, jet mill, or other similar grinding process; solution based phase separation techniques such as spray drying, emulsification/evaporation, emulsification/solvent extraction, complex coacervation, gas antisolvent precipitation (GAS), precipitation with a compressed antisolvent (PCA), aerosol solvent extraction system (ASES), evaporative precipitation into aqueous solution (EPAS), supercritical antisolvent (SAS), solution-enhanced dispersion by supercritical fluids (SEDS), rapid expansion from supercritical to aqueous solutions (RESAS), pressure induced phase separation (PIPS); or freezing techniques such as spray freezing into liquid (SFL) and ultra rapid freezing (URF). Detailed descriptions of these methods are included in references cited herein, the entire disclosures of which are hereby incorporated by reference.

Mechanical micronization is most commonly done by milling techniques that can produce particles in the range of 1 to 20 microns. The most common processes utilized for this type of mechanical particle size reduction are ball and jet milling. There are many solution based phase separation processes documented in the pharmaceutical literature for producing micro and nano-sized drug particles. Some of the more commonly known processes are spray drying, emulsification/evaporation, emulsification/solvent extraction, and complex coacervation. Some of the lesser-known processes are, for the sake of brevity, listed below along with their respective illustrating references: a) gas antisolvent precipitation (GAS) - WO9003782, EP0437451, DK59091; b) precipitation with a compressed antisolvent (PCA) - US 5,874,029; c) aerosol solvent extraction system (ASES); d) evaporative precipitation into aqueous solution (EPAS) - US patent application 20040067251; e) supercritical antisolvent (SAS); f) solution- enhanced dispersion by supercritical fluids (SEDS); and g) rapid expansion from supercritical to aqueous solutions (RESAS).

Freezing techniques for producing micro or nano-sized drug particles are listed below along with their respective illustrating references: a) spray freezing into liquid (SFL) - WO02060411, USPTO App. No. 2003054042, and No. 2003024424; and b) ultra rapid freezing (URF).

Drug-containing particles may or may not undergo substantial aggregation or agglomeration during hot-melt extrusion and/or will be disaggregated to essentially primary particles during hot-melt extrusion due to the intense mixing and agitation that occurs during the process. In some cases, the extrudate may need to be processed more than one time through the extruder in order to provide the desired degree of disaggregation. As used herein, the term "disaggregate", as used in reference to the drug- containing particles, means to reduce a loosely bound agglomerate to essentially its primary constituent particles. As used herein, the term "to agglomerate" or "agglomeration", as used in reference to the drug-containing particles means individual particles form a larger particle.

An alkaline labile compound is one that degrades under alkaline conditions during processing and / or storage. Alkaline is defined as a pH of greater than 7.0. For example, when a material being tested is dissolved or dispersed in water, the liquid (water) will have a pH of greater than 7.0. An alkaline polymer is a polymer that forms a solution having a pH greater than 7.0 when the polymer is placed, dissolved and/or dispersed in water.

As used herein, the terms "therapeutic compound", "therapeutic agent", "active agent" and "drug" are used interchangeably, unless otherwise specified. The process of the invention can be used to prepare composition and dosage forms comprising essentially any one or more active agents. Active agents include physiological substances or pharmacological active substances that produce a systemic or localized effect or effects on animals and human beings.

The laminate of the invention can include one or more other drugs known to be useful for coadministration with testosterone. Representative steroidal drugs are prednisone, prednisolone, cortisone, Cortisol and triamcinolone; androgenic steroids such as methyltesterone, testosterone, and fluoxmesterone; estrogenic steroids such as 17β- estradiol, α-estradiol, estriol, α-estradiol 3 benzoate, and 17-ethynylestradiol-3-methyl ether; progestational steriods such as progesterone, 19-nor-pregn-4-ene-3,20-dione, 17- hydroxy-19-nor-17-α-pregn-5(10)-ene-20-yn-3-one, 17α-ethynyl-17-hydroxy-5(10)- estren-3-one, and 9β, 10α-pregna-4,6-diene-3,20-dione.

Representative estrogen antagonist-agonist drugs are clomiphene citrate and raloxifene HCl.

The active agents (drugs) listed herein should not be considered exhaustive and is merely exemplary of the many embodiments considered within the scope of the invention. Many other active agents can be administered with the formulation of the present invention. Suitable drugs are selected from the list of drugs included herein as well as from any other drugs accepted by the U.S.F.D.A. or other similarly recognized authority in Canada (Health Canada), Mexico (Mexico Department of Health), Europe (European Medicines Agency (EMEA)), South America (in particular in Argentina (Administraciόn Nacional de Medicamentos, Alimentos y Tecnologia Medica (ANMAT) and Brazil (Ministerio da Saύde)), Australia (Department of Health and Ageing), Africa (in particular in South Africa (Department of Health) and Zimbawe (Ministry of Health and and Child Welfare), ) or Asia (in particular Japan (Ministry of Health, Labour and Welfare), Taiwan (Executive Yuans Department of Health), and China (Ministry of Health People's Republic of China)) as being suitable for administration to humans or animals. Some embodiments of the invention include those wherein the active substance is pharmacologically or biologically active or wherein the environment of use is the GI tract of a mammal.

The amount of therapeutic compound incorporated in each dosage form will be at least one or more unit doses and can be selected according to known principles of pharmacy. An effective amount of therapeutic compound is specifically contemplated. By the term "effective amount", it is understood that, with respect to, for example, pharmaceuticals, a pharmaceutically effective amount is contemplated. A pharmaceutically effective amount is the amount or quantity of a drug or pharmaceutically active substance which is sufficient to elicit the required or desired therapeutic response, or in other words, the amount which is sufficient to elicit an appreciable biological response when administered to a patient. The appreciable biological response may occur as a result of administration of single or multiple unit doses of an active substance. A unit dose of the laminate will comprise about 0.1 - 30 mg of testosterone. The term "unit dose" is used herein to mean a dosage form containing a quantity of the therapeutic compound, said quantity being such that one or more predetermined units may be provided as a single therapeutic administration.

The physical dimensions of a unit dose of the laminate will vary according to the physical dimensions of the individual reservoir and backing layers as well as according to the concentration and amount of testosterone present in the reservoir layer. In general, and in particular for transmucosal administration, the laminate may be shaped as square, rectangle or oval, and the surface area of the contact surface of the reservoir layer in a unit dose will be within the range of about 0.1 - 3 cm². The thickness (height) of the laminate will be less than or equal to about 2.0 mm.

The total amount of testosterone in a unit dose will be within the range of about 0.1 - 20 mg or 0.1 - 30 mg. Therefore, the concentration of testosterone in the reservoir layer will be within the range of about 6 - 33 mm²/mg.

A dosage form according to the invention that comprises two or more active agents can include subtherapeutic amounts of one or more of those active agents such that an improved, additive or synergistic clinical benefit is provided by the dosage form. By "subtherapeutic amount" is meant an amount less than that typically recognized as being therapeutic on its own in a subject to which the dosage form is administered. Therefore, a dosage form can comprise a subtherapeutic amount of a first drug and a therapeutic amount of a second drug. Alternatively, a dosage form can comprise a subtherapeutic amount of a first drug and a subtherapeutic amount of a second drug.

The laminate is administered transdermally by placing a unit dose size of the laminate in contact with a dermal surface, such as the skin or a mucosal surfaces. There should be sufficient amount of moisture on the dermal surface to wet the contact surface of the laminate thereby initiating bioadhesion of the laminate onto the dermal surface. When administered buccally, the laminate can be administered such that the bioadhesive contact surface is in direct contact with the mucosa anywhere within the buccal cavity. For example, the mucosa can be from the gum, inner cheek, inner lip, or sublingual mucosal surfaces. The optionally-inert backing layer (meaning it might or might not be inert) may be non-bioadhesive thus eliminating undesirable adhesion to opposing mucosal surfaces. For example, a laminate placed on the distal surface of the gum will not simultaneously also adhere to the inner cheek or inner labial surfaces. The backing layer may be substantially impermeable to diffusion of testosterone, meaning that less than 10% or less than 5% of the charge of testosterone in the reservoir layer is released through the backing layer.

In view of the above description and the examples below, one of ordinary skill in the art will be able to practice the invention as claimed without undue experimentation. The foregoing will be better understood with reference to the following examples that detail certain procedures for the preparation of formulations according to the present invention. All references made to these examples are for the purposes of illustration. The following examples should not be considered exhaustive, but merely illustrative of only a few of the many embodiments contemplated by the present invention. The exemplary formulations of the reservoir layer, as described herein, can be used in combination with any of the exemplary formulations of the backing layer to form a laminate. Likewise, the exemplary formulations of the reservoir layer, as described herein, can be used in combination with any exemplary release liner layer described herein. EXAMPLE 1

Preparation of a bi-layered laminate by hot-melt extrusion and solvent casting.

A drug reservoir layer is made by mixing its ingredients to obtain a uniform mixture and hot-melt extruding the mixture through a die to form a hot-melt extruded extrudate, e.g. film. A backing layer is cast onto the reservoir layer by dissolving at least partially the ingredients of the backing layer and casting the mixture onto a surface of the hot-melt extruded film. The solvent is then removed to form the bi-layered laminate.

The ingredients of the reservoir layer comprise a bioadhesive thermoplastic water soluble and/or water erodible composition and testosterone. One or more bioadhesive polymers are included in the reservoir layer. One or more other thermoplastic polymers are included in the reservoir layer. One or more water soluble and/or erodible polymers are included in the reservoir layer. One or more antioxidants are included in the reservoir layer. One or more plasticizers are optionally included in the reservoir layer. One or more acidic components are optionally included in the reservoir layer. One or more hydrophobic polymers are optionally included in the reservoir layer. One or more thermal lubricants are optionally included in the reservoir layer. One or more other excipients are optionally included in the reservoir layer. Suitable ranges for the amounts of each ingredient are detailed below. Raw Material % w/w

Testosterone 1 - 30

Alkaline Thermoplastic Bioadhesive Polymer 10 - 99

Optional Antioxidant 0 - 10

Optional Acidic Component 0 - 40

Optional Hydrophilic polymer 0 - 75

Optional Hydrophobic polymer 0 - 75

Optional water soluble and/or erodible polymer 0 - 50

Optional bioadhesive polymer 0 - 50

Optional Thermoplastic Polymer 0 - 60

Optional Plasticizer 0 - 20

Optional thermal lubricant 0 - 20

Optional Opaquant 0 - 5

The ingredients of the backing layer comprise a hydrophobic film-forming polymer. One or more thermoplastic polymers are optionally included in the backing layer. One or more plasticizers are optionally included in the backing layer. One or more other hydrophobic polymers are optionally included in the backing layer. One or more hydrophilic polymers are optionally included in the backing layer. One or more opaquants are included in the backing layer. One or more other excipients are optionally included in the backing layer. An alcohol or other organic solvent or combination of organic solvents is used to dissolve (either partially or completely) the other ingredients of the backing layer prior to casting the solution onto the extruded reservoir layer. Suitable ranges for the amounts of each ingredient are detailed below. Raw Material % w/w

Hydrophobic film-forming polymer 10 - 90

Optional other hydrophobic Polymer 0 - 50

Optional Hydrophilic polymer 0 - 80

Optional Plasticizer 0 - 20

Optional Opaquant 0 - 10

EXAMPLE 2

Preparation of a bi-layered laminate by hot-melt extrusion of both layers.

The ingredients of the drug reservoir layer are hot-melt extruded as described herein. The ingredients of the backing layer are hot-melt extruded in a manner substantially similar to the procedure used for the reservoir layer. The two layers are then laminated to one another by heat lamination and/or adhesive lamination. In adhesive lamination, an adhesive is placed onto the surface of at least one of the two layers, then the layers are pressed together to form the laminate. In heat lamination, the two layers are pressed together while heated. Alternatively, the reservoir composition and the backing composition are coextruded through a dual manifold die, thereby forming a laminate in situ. In a dual manifold die, the molten or softened reservoir composition is brought into contact with the molten or softened backing composition prior to solidification of both layers, meaning that one layer might or might not solidify prior to the compositions being brought into contact with one another.

The ingredients for the hot-melt extruded drug reservoir layer are as detailed herein.

The hot-melt extruded backing layer comprises at least one thermoplastic polymer and at least one hydrophobic polymer. One or more other thermoplastic polymers are optionally included in the backing layer. One or more plasticizers are optionally included in the backing layer. One or more other hydrophobic polymers are optionally included in the backing layer. One or more hydrophilic polymers are optionally included in the backing layer. One or more opaquants are included in the backing layer. One or more thermal lubricants are optionally included in the backing layer. One or more antioxidants are optionally included in the backing layer. One or more other excipients are optionally included in the backing layer. Suitable ranges for the amounts of each ingredient are detailed below. Raw Material % w/w

Thermoplastic Polymer 30 - 90

Hydrophobic polymer 25 - 85

Optional Hydrophilic polymer 0 - 50

Optional Thermoplastic Polymer 0 - 50

Optional Acidic Component 0 - 40

Optional Plasticizer 0 - 20

Optional Antioxidant 0 - 10

Optional thermal lubricant 0 - 20

Optional Opaquant 0 - 5

EXAMPLE 3 Preparation of an excipient mixture suitable for hot-melt extrusion.

Method A. Wet granulation with water. A bioadhesive alkaline thermoplastic polymer is wet granulated with water, and an acidic component under high shear until the ingredients are uniformly mixed. One or more other bioadhesive polymers are optionally included in the granulation. One or more other thermoplastic polymers are optionally included in the granulation. One or more other alkaline polymers are optionally included in the granulation. One or more antioxidants are included in the granulation. One or more plasticizers are optionally included in the granulation. One or more excipients are optionally included in the granulation. After granulation, the granulate is optionally dried.

Method B. Wet granulation with buffer. The process of Method A is followed except that a buffer rather than water is used as the liquid medium used for granulation.

Method C. Wet granulation with aqueous organic solvent.

The process of Method A or Method B is followed except that a water miscible organic solvent is included in the liquid medium used for granulation. The liquid medium can comprise a major portion of water (or buffer) or organic solvent. The liquid medium generally contains at least 5% water (or buffer).

Method D. Wet granulation with a mineral acid.

The process of Method A or Method B is followed except that a mineral acid is used as the liquid granulation medium. Method E. Hydroalcoholic wet granulation with a mineral acid.

The process of Method A or Method B is followed except that a water miscible organic solvent is included in the mineral acid liquid medium for granulation. The liquid medium can comprise a major portion of water, mineral acid or organic solvent. The liquid granulation medium generally contains at least 5% water. Method F. Wet granulation with a mineral acid in the presence of an alkaline labile drug.

The process of Method A or Method B is followed except that a mineral acid is used as the liquid granulation medium and the acid labile drug is present during the granulation step. Method G. Hydroalcoholic wet granulation with a mineral acid in the presence of an alkaline labile drug

The process of Method A or Method B is followed except that a water miscible organic solvent is included in the mineral acid liquid medium for granulation and the acid labile drug is present during the granulation step. The liquid medium can comprise a major portion of water, mineral acid or organic solvent. The liquid granulation medium generally contains at least 5% water.

Method H. Dry granulation A bioadhesive alkaline thermoplastic polymer and an acidic component are dry granulated until the ingredients were uniformly mixed. One or more other bioadhesive polymers are optionally included in the granulation. One or more other thermoplastic polymers are optionally included in the granulation. One or more other alkaline polymers are optionally included in the granulation. One or more antioxidants are included in the granulation. One or more plasticizers are optionally included in the granulation. One or more excipients are optionally included in the granulation.

EXAMPLE 4

The following process was used to prepare a hot-melt extruded composition according to the invention. The following ingredients in the amounts indicated were used in preparing hot-melt extruded control and sample compositions containing testosterone (Ts) as the active agent. Method A.

An excipient mixture was prepared according to Example 3, Methods A, B, D and or F, was mixed with testosterone and blended under high shear to form a uniform blend. The blend is hot-melt extruded using an extruder equipped with a film (sheet) die. Method B.

Method A was followed with the following exceptions. A Randcastle Taskmaster hot-melt extruder equipped with a 6-inch flat die (feedblock die or multi-manifold die) was operated at 60 - 90 RPM, 6 - 9 Drive Amps with an Extrusion Temperature from about 65 - 135⁰C to prepare the composition. All powders were blended in a v-shell blender prior to extrusion. Temperature zones were set as follows: zone 1: 65°C, zone 2:

120⁰C, zone 3: 125°C, zone 4: 135°C, die temperature 135°C. The powder blend was placed in a feed hopper that is located at the head of a horizontal screw such that the material is starve fed by a mass flow controller operated at 1.5 kg/hr. The residence time of the material in the extruder was approximately three to five minutes. The extrudate was cut into approximately one-foot sections after exiting the die and placed on an aluminum sheets and allowed to cool at ambient conditions. In one embodiment, the granulated wet mass was placed in the feed hopper.

EXAMPLE 5

Method A.

The combined processes of Examples 3 and 4 are used to prepare a hot-melt extruded composition according to the invention. The following ingredients in the amounts indicated were used in preparing hot-melt extruded control and sample compositions containing testosterone (Ts) as the active agent.

Raw Material % w/w

Testosterone, USP 15.00

PoIyOx WSR N80 26.85

PoIyOx WSR N12K 20.36

PoIyOx WSR 301 16.79

Carbopol 974P 10.00

Vitamin E Succinate 5.00

Titanium Dioxide 1.00

Poloxamer 407 5.00

Testosterone and any other ingredients were added to the wet granulated excipient mixture prepared according to Example 3, methods A, B, E, F and or G. The blend was hot-melt extruded as a monolayer film using an extruder having a barrel temperature of 135°C. The moisture content of the blend prior to extrusion was 3.1%. The HME composition is then analyzed by HPLC according to Example 6 to determine the amount of degradants present.

Method B. Use of two acidic components (acidic organic acid, acidic polymer) and an antioxidant.

The procedure of Example 3, method G was followed except that citric acid was added as a secondary acidifier and butylated hydroxytoluene was added as an antioxidant in place of Vitamin E succinate. As above, the excipient mixture was prepared by wet granulating the PoIyOx and Poloxamer with 5% water under high shear. Carbopol was added and blended until uniform. Raw Material % w/w

Testosterone, USP 15.00

PoIyOx WSR N80 26.85

PoIyOx WSR N12K 20.36

PoIyOx WSR 301 16.79

Carbopol 974P 10.00

Citric Acid Monohydrate 1.00

Butylated Hydroxytoluene 4.00

Titanium Dioxide 1.00

Poloxamer 407 5.00

Method C. Use of two acidic components (acidic organic acid, acidic polymer) without an antioxidant.

The procedure of Example 3, methods E, F and or G was followed except that citric acid was added as a secondary acidifier. As above, the lot was prepared by wet granulating the PoIyOx and Poloxamer with 5% water under high shear. Carbopol was added and blended until uniform.

Raw Material % w/w

Testosterone, USP 15.00

PoIyOx WSR N80 26.85

PoIyOx WSR N12K 20.36

PoIyOx WSR 301 16.79

Carbopol 974P 10.00

Citric Acid Monohydrate 5.00

Titanium Dioxide 1.00

Poloxamer 407 5.00

Method D. This method was similar to that of Examples 3 and 4, with the following exceptions.

Raw Material % w/w

Testosterone, USP 15.00

PoIyOx WSR N80 26.85

PoIyOx WSR N12K 20.36

PoIyOx WSR 301 16.79

Carbopol 974P 10.00

Butylated Hydroxytoluene 4.00

Titanium Dioxide 1.00

Poloxamer 407 6.00 Method E.

This method was similar to that of Examples 3 and 4, with the following exceptions.

Raw Material % w/w

Testosterone, USP 15.00

PoIyOx WSR N80 26.85

PoIyOx WSR N12K 18.86

PoIyOx WSR 301 16.79

Carbopol 974P 10.00

Butylated Hydroxytoluene 4.00

Titanium Dioxide 1.00

Poloxamer 407 7.50

Method F.

Raw Material % w/w

Testosterone, USP 15.00

PoIyOx WSR N80 26.85

PoIyOx WSR N12K 19.36

PoIyOx WSR 301 16.79

Carbopol 974P 10.00

Butylated Hydroxytoluene 2.00

Titanium Dioxide 1.00

Poloxamer 407 9.00

Method G.

This method was similar to that of Examples 3 and 4, with the following exceptions. In this example, the liquid medium was added as a bolus or in sequential portions to the granulation ingredients. Raw Material % w/w

Testosterone, USP 15.00

PoIyOx WSR N80 26.85

PoIyOx WSR N12K 19.36

PoIyOx WSR 301 16.79

Carbopol 974P 10.00

Vitamin E 2.00

Titanium Dioxide 1.00

Poloxamer 407 9.00

Method H

The same procedure or Method G was followed except that water and alcohol (ethanol) (50:50) was used as the liquid medium for granulation. EXAMPLE 6

Determination of drug stability.

Twenty doses were sampled from a HME composition at the beginning, middle and end of the extrusion run a formulation. Composites of 10 doses were analyzed in duplicate for impurities by HPLC at each time point. The weight percent for each degradant was determined. Specific degradants analyzed include: 6B-Hydroxy- testosterone, 4-Androsten-16-alpha-ol-3,17-dione, Epi- Testosterone and unidentified degradants. The HPLC method employed will vary according to the drug included in the

HME composition. Such methods are found in HPLC in the Pharmaceutical Industry

(edited by Godwin W. Fong, Stanley K. Lam, New York : M. Dekker, 1991) or HPLC Methods for Pharmaceutical Analysis (by George Lunn and Norman R. Schmuff. New

York : John Wiley & Sons, 1997).

Determination of drug release.

Samples from the beginning, middle and end of a lot of extruded laminate

(reservoir layer containing testosterone and backing layer excluding drug) were sampled and dissolution studies were conducted in 1,000 mL of Simulated Saliva Fluid (0.1% sodium lauryl sulfate at pH 6.75) at 100 rpm using the paddles. Samples were withdrawal at 1, 2, 4, 6, 8, 12 and 24 hours and assayed for testosterone content by HPLC.

EXAMPLE 7

Preparation of a backing film. Method A. An exemplary backing film was prepared by hot-melt extrusion of a hydrophobic composition containing the following ingredients in the specified amounts.

Raw Material % w/w

PoIyOx WSR N80 10.00

PoIyOx WSR 205 7.50

PoIyOx WSR 301 36.50

Eudragit RS PO 35.00

Ethyl Cellulose Std 100 6.25

FD&C Red 40 Lake 0.15

Titanium Dioxide 0.60

Citric Acid, monohydrate 1.00

Dibutyl Sebacate 3.00

The backing layer formulation was modified to minimize degradation of testosterone at the interface between the backing layer and the reservoir layer. The backing layer formulation included citric acid and the blend was wet granulated with water to acidify the polymers. These blends were extruded as a bilayer film at a 3:1 drug layer to backing layer ratio and overall target thickness of 1.20 mm using the Randcastle coextrusion line at 135°C maximum processing temperatures. The moisture content of the blend prior to extrusion was 2.4%.

EXAMPLE 8

Preparation of a bi-layered laminate by coextrusion.

An exemplary bi-layered laminate comprising a backing layer and a reservoir layer was prepared by hot-melt coextrusion of a hydrophobic composition (as described in Example 7) and a hydrophilic composition, respectively, containing the following ingredients in the specified amounts.

Reservoir Layer (Hydrophilic composition)

Compound % w/w

Lot 1 Lot 2

Testosterone, USP 15 .00 15 .00

PoIyOx WSR N80 26 .85 26 .85

PoIyOx WSR N12K 18 .36 18 .36

PoIyOx WSR 301 16 .29 13 .79

Carbopol 974P 12 .50 15 .00

Vitamin E Succinate 3 .00 3 .00

Vitamin E 2 .00 2 .00

Titanium Dioxide 1 .00 1 .00

Poloxamer F127 5 .00 5 .00

Total 100. 00 100. 00

The films were coextruded with the acidified backing film formulation as described above. The drug layer thickness was 1.10 mm and the backing film thickness was 0.40 mm. Doses were cut to provide a 15 mg Testosterone dose.

EXAMPLE 9

Preparation of a bi-layered laminate by coextrusion.

A clinical formulation was modified to achieve a slower dissolution profile. The testosterone concentration was lowered from 15% to 8.18% and the carbopol concentration was increased from 10% to 15%. The batch was prepared using Disoynth sourced testosterone by wet granulation acidification with 5%, 50 mM hydrochloric acid and 5% ethanol. The granulation was coextruded with the acidified backing film. These blends were coextruded to form a bi-layered laminate having a 2.75:1 drug layer to backing layer weight ratio and overall target thickness of 1.50 mm using the Randcastle coextrusion line at 135°C maximum processing temperature. The moisture content of the blend prior to extrusion was 2.0%.

EXAMPLE 10

Preparation of a bi-layered laminate by coextrusion. The methods of Examples 7 and 8 followed to prepare a bi-layered laminate comprising the following ingredients in the specified amounts. Reservoir layer

Raw Material % w/w

Testosterone, USP 8.18

PoIyOx WSR N80 26.85

PoIyOx WSR N12K 22.18

PoIyOx WSR 301 16.79

Carbopol 974P 15.00

Vitamin E Succinate 5.00

Titanium Dioxide 1.00

Poloxamer 407 5.00

Backing layer

Raw Material % w/w

PoIyOx WSR N80 10.00

PoIyOx WSR 205 7.50

PoIyOx WSR 301 36.50

Eudragit RS PO 35.00

Ethyl Cellulose Std 100 6.25

FD&C Red 40 Lake 0.15

Titanium Dioxide 0.60

Citric Acid, monohydrate 1.00

Dibutyl Sebacate 3.00

EXAMPLE 11

Preparation of a bi-layered laminate by coextrusion.

The methods of Examples 7 and 8 were followed to prepare a bi-layered laminate comprising the following ingredients in the specified amounts.

Reservoir layer

Raw Material % w/w

Testosterone, USP 8.18

PoIyOx WSR N80 23.67

PoIyOx WSR N12K 20.36

PoIyOx WSR 301 16.79

Carbopol 974P 15.00

Glyceryl Monooleate 5.00

Vitamin E Succinate 5.00

Titanium Dioxide 1.00

Poloxamer 407 5.00

The melt viscosity of the formulation was significantly increased as compared to another formulation containing less Carbopol. Processing conditions were modified to avoid over pressurizing the extruder. The screw speed was increased by 22% and the feed rate was decreased by 46% to achieve acceptable pressure at the adapter. EXAMPLE 12 Exemplary method for hot-melt extrusion of a reservoir layer. A Randcastle Taskmaster hot-melt extruder equipped with a 6-inch flat die was operated at 60 - 90 RPM, 6 - 9 Drive Amps with an Extrusion Temperatures from 65 - 135⁰C to prepare the composition. All powders were blended in a v-shell blender prior to extrusion. Temperature zones were set as follows: zone 1: 65°C, zone 2: 120⁰C, zone 3: 125°C, zone 4: 135°C die temperature 135°C. The powder blend was placed in a hopper that is located at the head of a horizontal screw such that the material is starve fed by a mass flow controller operated at 1.5 kg/hr. The residence time of the material in the extruder was approximately three to five minutes. The extrudate was cut into approximately one foot sections after exiting the die and placed on an aluminum sheets and allowed to cool at ambient conditions.

EXAMPLE 13

Exemplary method for hot-melt extrusion of a backing layer.

A Randcastle Taskmaster hot-melt extruder equipped with a 6-inch flat die was operated at 60 - 90 RPM, 6 - 9 Drive Amps with an Extrusion Temperatures from 65 - 135⁰C to prepare the composition. All powders were blended in a v-shell blender prior to extrusion. Temperature zones were set as follows: zone 1: 65°C, zone 2: 120⁰C, zone 3:

130⁰C, zone 4: 130⁰C, adapter: 135°C, transfer tube: 135°C, die temperature 140⁰C. The powder blend was placed in a hopper that is located at the head of a horizontal screw such that the material is starve fed by a mass flow controller operated at 0.5 kg/hr. The residence time of the material in the extruder was approximately five minutes. The extrudate was cut into approximately one-foot sections after exiting the die and placed on an aluminum sheets and allowed to cool at ambient conditions.

EXAMPLE 14

Preparation of a bi-layered laminate by hot-melt extrusion and solvent casting.

The general methods of Examples 1 and 2 were followed in order to prepare a laminate. Powdered compositions were made according to Tables 1 and 2 by dry blending the ingredients to form a drug-containing mixture, which was then hot-melt extruded into films according to the conditions in Table 3. The resultant films were cut into sections and an alcoholic solution (50% ethanol) of the backing film formulation (Table 4) was cast onto the testosterone-containing film sections. The solvent was removed by heat and evaporation from the backing film to provide a bi-layered laminate exhibiting a unidirectional drug release in vivo and in vitro. The resultant bilayered laminate was cut into unit doses each containing about 20 mg of testosterone. The weight of SR4 doses averaged 109.5 mg, the average length was 20.77 mm, the average width was 11.61 mm and the average thickness was 0.42 mm providing an average surface area of 241 mm² for the exposed reservoir surface and a surface area to dose ratio of 12.1 mm / mg testosterone based upon the exposed reservoir surface. The weight of SR12 doses averaged 107.9 mg, the average length was 11.74 mm, the average width was 9.70 mm and the average thickness was 0.87 mm providing an average surface area of 114 mm² for the exposed reservoir surface and a surface area to dose ratio of 5.7 mm² / mg testosterone based upon the exposed reservoir surface. The doses were then evaluated in vitro (Figure 4) and in vivo (Figure 5) to determine their release properties.

The doses were tested in vitro using simulated saliva fluid (0.10% sodium lauryl sulfate adjusted to pH 6.75 ± 0.05 with phosphoric acid) at 37.0 ± 0.5⁰C using the Paddle Method (100 rpm) with Ointment Disks covered with a 17 mesh Teflon screen. The paddle height was adjusted 2.5 cm above the top of the ointment disks. Samples (3 mL) were withdrawn and the media replaced from each vessel at 1, 2, 4, 6, 8 and 12 hours and filtered through a 10 μm polyethylene free-flow dissolution filter into a labeled test tube. The resultant samples were analyzed for testosterone content by a gradient HPLC method using a Prodigy™ ODS-2, 5 μm, 150A, 4.6 x 250 mm column at 243 nm wavelength of detection. Mobile phase A was 55/45 Methanol/Water, v/v and Mobile Phase B was 100% Methanol. The flow rate was 1.0 niL/min, the column temperature was 4O⁰C, the injection volume was 25 μL and the run time was 25 minutes.

Table 1. Testosterone Bioadhesive Film Formulation SR4

Table 2: Testosterone Bioadhesive Film Formulation SR12

Table 3: Hot-melt Processing Parameters

Table 4: Low Permeability Backing Film Formulation

EXAMPLE 15 Preparation of a bi-layered laminate by hot-melt extrusion and solvent casting.

The powdered ingredients in Table 5 were dry blended and then hot-melt extruded into films according to the conditions in Table 6. The resultant films were cut into sections and an alcoholic solution of the poorly permeable backing film formulation (Table 7) was cast onto the testosterone-containing films to provide laminates having a unidirectional drug release. The resultant bilayered films were cut into doses. The weight of Formulation A doses averaged 186 mg, the average length was 15.15 mm, the average width was 9.65 mm and the average thickness was 1.23 mm providing an average surface area of 146 mm for the exposed reservoir surface and a surface area to dose ratio of 7.3 mm / mg testosterone based upon the exposed reservoir surface. The weight of Formulation B doses averaged 214 mg, the average length was 16.62 mm, the average width was 10.16 mm and the average thickness was 1.27 mm providing an average surface area of 169 mm² for the exposed reservoir surface and a surface area to dose ratio of 8.45 mm / mg testosterone based upon the exposed reservoir surface. The weight of Formulation C doses averaged 171 mg, the average length was 14.98 mm, the average width was 9.78 mm and the average thickness was 1.22 mm providing an average surface area of 146 mm² for the exposed reservoir surface and a surface area to dose ratio of 7.30 mm² / mg testosterone based upon the exposed reservoir surface. The weight of Formulation D doses averaged 173 mg, the average length was 15.67 mm, the average width was 9.80 mm and the average thickness was 1.13 mm providing an average surface area of 154 mm² for the exposed reservoir surface and a surface area to dose ratio of 10.3 mm / mg testosterone based upon the exposed reservoir surface.

The testosterone release profile for a unit dose of each of the formulations was evaluated in vitro (FIG. 6) and in vivo (FIG. 7).

Table 5: Testosterone Bioadhesive Film Formulations A, B, C & D

Formulation (%w/w)

Component

A B C D

PoIyOx WSR N80 43.20 45.50 43.00 34.00

PoIyOx WSR N12K 30.80 32.50 21.00 27.00

PoIyOx WSR 301 10.00 18.00

Testosterone, USP 20.00 16.00 20.00 15.00

Vitamin E Succinate 5.00 5.00 5.00 5.00

Titanium Dioxide 1.00 1.00 1.00 1.00

Testosterone Dose (mg) 20 20 20 15

Table 6: Hot-melt Processing Parameters

Table 7: Low Permeability Backing Film Formulation

EXAMPLE 16 Preparation of a bi-layered laminate by hot-melt extrusion and solvent casting.

The powdered ingredients in Table 8 were dry blended and then hot-melt extruded into films according to the conditions in Table 9. The resultant films were cut into sections and an alcoholic solution of the poorly permeable backing film formulation (Table 10) was cast onto the testosterone-containing film to provide unidirectional drug release. The resultant bilayered films were cut into unit doses. The weight of Formulation E (10 mg Testosterone dose) doses averaged 156 mg, the average length was 22.42 mm, the average width was 6.46 mm and the average thickness was 1.12 mm providing an average surface area of 145 mm² for the exposed reservoir surface and a surface area to dose ratio of 14.5 mm / mg testosterone based upon the exposed reservoir surface. The weight of Formulation F (IO mg Testosterone dose) doses averaged 157 mg, the average length was 21.51 mm, the average width was 6.31 mm and the average thickness was 1.16 mm providing an average surface area of 133 mm² for the exposed reservoir surface and a surface area to dose ratio of 13.3 mm² / mg testosterone based upon the exposed reservoir surface. The weight of Formulation G (5 mg Testosterone dose) doses averaged 164 mg, the average length was 21.47 mm, the average width was 6.36 mm and the average thickness was 1.21 mm providing an average surface area of 137 mm² for the exposed reservoir surface and a surface area to dose ratio of 32.8 mm² / mg testosterone based upon the exposed reservoir surface. The weight of Formulation H (15 mg Testosterone dose) doses averaged 168 mg, the average length was 21.90 mm, the average width was 6.48 mm and the average thickness was 1.20 mm providing an average surface area of 142 mm² for the exposed reservoir surface and a surface area to dose ratio of 9.5 mm² / mg testosterone based upon the exposed reservoir surface. Formulation I was cut from the same bulk film mass as Formulation H, but to a smaller size to provide a 12.5 mg Testosterone dose. The weight of Formulation I doses averaged 141 mg, the average length was 19.29 mm, the average width was 6.29 mm and the average thickness was 1.20 mm providing an average surface area of 121 mm for the exposed reservoir surface and a surface area to dose ratio of 9.7 mm² / mg testosterone based upon the exposed reservoir surface. The weight of Formulation J (10 mg Testosterone dose) doses averaged 158 mg, the average length was 22.41 mm, the average width was 6.48 mm and the average thickness was 1.13 mm providing an average surface area of 145 mm² for the exposed reservoir surface and a surface area to dose ratio of 14.5 mm / mg testosterone based upon the exposed reservoir surface.

The testosterone release profile for a unit dose of each of the formulations was evaluated in vitro (FIG. 8) and in vivo (FIG. 9). Table 8: ^" Testosterone Bioadhesive Film Formulations E - J

Table 9: Hot-melt Processing Parameters

Table 10: Low Permeabilit Backin Film Formulati o n

EXAMPLE 17 Preparation of a bi-layered laminate by hot-melt extrusion and solvent casting.

The powdered ingredients in Table 11 were dry blended and then hot-melt extruded into films according to the conditions in Table 12. The resultant films were cut into sections and an alcoholic solution of the poorly permeable backing film formulation (Table 13) was cast onto the testosterone-containing film to provide bi-layered laminates exhibiting unidirectional drug release. The resultant bi-layered laminates were cut into unit doses. The weight of Formulation K (12.5mg Testosterone dose) doses averaged 155 mg, the average length was 21.03 mm, the average width was 6.29 mm and the average thickness was 1.17 mm providing an average surface area of 132 mm² for the exposed reservoir surface and a surface area to dose ratio of 10.6 mm² / mg testosterone based upon the exposed reservoir surface. The release profiles in vitro (FIG. 10) and in vivo (FIG. 11) are depicted.

Testosterone Bioadhesive Film Formulation K

Hot-melt Processing Parameters

Low Permeability Backing Film Formulation

EXAMPLE 18 Preparation of a bi-layered laminate by hot-melt coextrusion.

The powdered ingredients in Tables 14 and 15 were blended to form their respective compositions and then hot-melt coextruded into a bilayered laminate according to the conditions in Table 16. The resultant bilayered laminates were cut into unit doses exhibiting unidirectional drug release. The resultant bi-layered laminates were cut into unit doses. The weight of Formulation L (12.5mg Testosterone dose) doses averaged 155 mg, the average length was 18.17 mm, the average width was 6.29 mm and the average thickness was 1.21 mm providing an average surface area of 114 mm² for the exposed reservoir surface and a surface area to dose ratio of 9.1 mm² / mg testosterone based upon the exposed reservoir surface. The weight of Formulation M (12.5 mg Testosterone dose) doses averaged 135 mg, the average length was 15.76 mm, the average width was 6.28 mm and the average thickness was 1.19 mm providing an average surface area of 99 mm for the exposed reservoir surface and a surface area to dose ratio of 7.9 mm / mg testosterone based upon the exposed reservoir surface. The weight of Formulation N (15 mg Testosterone dose) doses averaged 130 mg, the average length was 14.58 mm, the average width was 6.28 mm and the average thickness was 1.22 mm providing an average surface area of 91.5 mm² for the exposed reservoir surface and a surface area to dose ratio of 6.1 mm² / mg testosterone based upon the exposed reservoir surface. The weight of Formulation P (15 mg Testosterone dose) doses averaged 145 mg, the average length was 15.1 mm, the average width was 6.28 mm and the average thickness was 1.35 mm providing an average surface area of 95 mm for the exposed reservoir surface and a surface area to dose ratio of 6.3 mm² / mg testosterone based upon the exposed reservoir surface. The release profiles in vitro (FIG. 12) and in vivo (FIG. 13) are depicted.

Table 14: Testosterone Bioadhesive Film Formulations L - P.

Table 15: Poorl Permeable Backin Film Formulation

Table 16: Hot-melt Processing Parameters

The compositions were hot-melt coextruded through a dual manifold flat (sheet type) die.

EXAMPLE 19

Exemplary formulations for an acid-stabilized composition in a reservoir layer of the invention.

In vitro release profiles for some exemplary laminates made according to this example are depicted in FIGS.14a and 14b.

Method A.

Raw Material % w/w

Testosterone 5-20

Thermoplastic Bioadhesive Polymer 40-85

Acidic Component 0.001 -10

Optional Antioxidant 0-10

Optional Hydrophilic polymer 0-75

Optional Hydrophobic polymer 0-75

Optional Bioadhesive polymer 0-50

Optional Thermoplastic Polymer 0-60

Optional Plasticizer 0-20

Optional thermal lubricant 0-10

Optional Opaquant 0-5 Method B. Raw Material % w/w

Testosterone 5-20

PEO 5.00-75.0

Acidic Component 0.01 -15.00

Antioxidant 0.10-25.00

Optional Hydrophilic polymer 0.00 - 50.00

Optional Hydrophobic polymer 0.00 - 60.00

Optional bioadhesive polymer 0.001 - 10.00

Optional Thermoplastic Polymer 0.00 - 25.00

Optional Plasticizer 0.00 - 10.00

Optional thermal lubricant 0.00 - 20.00

Optional Opaquant 0.00 - 5.00

Method C. Raw Material % w/w

Testosterone 5-20

PEO 5.00-75.0

Polymeric Acidic Component 0.25 - 35.00

Optional Non-polymeric acidic component 0.00 - 15.00

Antioxidant 0.10-25.00

Hydrophilic polymer 2.00 - 10.00

Optional Hydrophobic polymer 0.00 - 50.00

Optional bioadhesive polymer 0.00 - 60.00

Optional Thermoplastic Polymer 0.00 - 20.00

Optional Plasticizer 0.00 - 10.00

Optional Opaquant 0.00 - 20.00

0.00-5.00 Method D. Raw Material % w/w

Testosterone 5-20

PEO Grade 1 5.00-50.00

PEO Grade 2 5.00-50.00

PEO Grade 3 5.00-50.00

Polymeric Acidic Component 0.25 - 35.00

Antioxidant 0.10-25.00

Hydrophilic polymer 5.00-10.00

Optional Non-polymeric Acidic Component 0.00 - 75.00

Optional Hydrophobic polymer 0.00 - 50.00

Optional bioadhesive polymer 0.00 - 60.00

Optional Thermoplastic Polymer 0.00 - 20.00

Optional Thermal Lubricant 0.00 - 20.00

Optional Plasticizer 0.00 - 10.00 Optional Opaquant 0.00-5.00 Method E. Raw Material % w/w

Testosterone 5 - 20

PEO Grade 1 5.00 - 50.00

PEO Grade 2 5.00 - 50.00

PEO Grade 3 5.00 - 50.00

CARBOPOL 0.25 - 25.00

POLOXAMER 2.00 - 10.00

Antioxidant 0.10 - 20.00

Opaquant 0.25 - 5.00

Optional Non-polymeric Acidic Component 0.00 - 50.00

Optional Hydrophobic polymer 0.00 - 60.00

Optional Bioadhesive Polymer 0.00 - 20.00

Optional Thermoplastic Polymer 0.00 - 20.00

Optional Thermal Lubricant 0.00 - 10.00

Optional Plasticizer 0.00 - 15.00

In one embodiment of the invention, the alkaline thermoplastic bioadhesive polymer is selected from the group consisting of PEO and Hydroxypropyl Cellulose.

In one embodiment of the invention, the Grade 1, Grade 2 and Grade 3 of PEO is independently selected at each occurrence from the group consisting of POLYOX WSR 301, POLYOX WSR N80, POLYOX WSR N12K, POLYOX WSR N-IO, POLYOX WSR N-750, POLYOX WSR N-3000, POLYOX WSR 3333, POLYOX WSR 205, POLYOX WSR 1105, POLYOX WSR N60K, POLYOX WSR Coagulant, POLYOX WSR 303, and POLYOX WSR 308.

In one embodiment of the invention, the hydrophilic polymer is selected from the group consisting of poloxamer (polyethylene-polypropylene glycol), polyethylene oxide, poly(vinyl alcohol) (PVA), carbomer, polycarbophil, chitosan, hydroxypropyl methylcellulose, carboxymethylcellulose, sodium carboxymethylcellulose, hydroxypropyl cellulose, hydroxyethyl cellulose, hydroxyethyl methyl cellulose, hydroxymethyl cellulose, methylcellulose, povidone (polyvinylpyrrolidones), carboxypolymethylene, polyethylene glycol, alginic acid, polyacrylamides, polymethacrylamides, polyphosphazines, polyoxazolidines, poly(hydroxyalkylcarboxylic acids), carrageenate alginates, carbomer, ammonium alginate, sodium alginate, or mixtures thereof, natural gums such as gum guar, gum acacia, gum tragacanth, or gum xanthan, and gelatin. In one embodiment of the invention, the hydrophobic polymer is selected from the group consisting of GANTREZ, EUDRAGIT RS, alkylcelluloses, ethylcellulose, waxes, polyesters, combinations thereof and others known to those of ordinary skill in the art.

In one embodiment of the invention, the bioadhesive polymer is selected from the group consisting of Polyethylene Oxide, Carbomer, Polycarbophil, Copolymer of Methyl

Vinyl Ether and Maleic Acid or Anhydride, Sodium Carboxymethylcellulose, one or more acrylic polymers, one or more polyacrylic acids, copolymers of these polymers, a combination thereof and others known to those of ordinary skill in the art.

In one embodiment of the invention, the thermoplastic polymer is selected from the group consisting of polyethylene oxide; polypropylene oxide; polyvinylpyrrolidone; polyvinylpyrrolidone-co-vinylacetate; PLA, PLGA, acrylate and methacrylate copolymers; polyethylene; polycaprolactone; polyethylene-co-polypropylene; alkylcelluloses such as methylcellulose; hydroxyalkylcelluloses such as hydroxymethylcellulose, hydroxyethylcellulose, hydroxypropylcellulose, and hydroxybutylcellulose; hydroxyalkyl alkylcelluloses such as hydroxyethyl methylcellulose and hydroxypropyl methylcellulose; starches, pectins; polysaccharides such as tragacanth, gum arabic, guar gum, sucrose sterate, xanthan gum, lipids, waxes, mono, di, and tri glycerides, cetyl alchohol, steryl alcohol, parafilm waxes and the like, hydrogenated vegetable and castor oil, glycerol monostearte, polyols including xylitol, manitol, and Sorbitol, alpha hydroxyl acids including citric and tartaric acid edipic acid meleaic acid malic acid, citric acid, enteric polymers such as CAP, HPMC AS, shellac, and a combination thereof to those of ordinary skill in the art.

In one embodiment of the invention, the polymeric acidic component is selected from the group consisting of CARBOPOL, Polycarbophil, Polyvinyl Acetate Phthalate, Polyacrylic Acid, Polymethacrylates, Gantrez (copolymers of methyl vinyl ether and maleic anhydride), PLA, PLGA, Chitosan, Cellulose Acetate Phthalate, Shellac, HPMCAS, Polysaccharides, Alginic Acid, Hyaluronic Acid, Xanthan gum, a combination thereof and others known to those of ordinary skill in the art. Lists of acidic polymers are found in texts such as Remington's Pharmaceutical Sciences, 18th Ed. (Alfonso R. Gennaro, ed.; Mack Publishing Company, Easton, PA, 1990); Remington: the Science and Practice of Pharmacy 19^th Ed.( Lippincott, Williams & Wilkins, 1995); Handbook of Pharmaceutical Excipients, 3^rd Ed. (Arthur H. Kibbe, ed.; Amer. Pharmaceutical Assoc, 1999); the Pharmaceutical Codex: Principles and Practice of Pharmaceutics 12^th Ed. (Walter Lund ed.; Pharmaceutical Press, London, 1994); The United States Pharmacopeia: The National Formulary (United States Pharmacopeial Convention); and Goodman and Gilman's: the Pharmacological Basis of Therapeutics (Louis S. Goodman and Lee E. Limbird, eds.; McGraw Hill, 1992), the disclosures of which are hereby incorporated by reference.

In one embodiment of the invention, the non-polymeric acidic component is selected from the group consisting of hydrochloric acid, phosphoric acid, nitric acid, boric acid, sulfuric acid, hydrobromic acid, alpha hydroxyl acids including citric, tartaric acid, adipic acid, maleic acid, malic acid, succinic acid, acetic acid, fumaric acid, amino acids, a combination thereof and others known to those of ordinary skill in the art.

In one embodiment of the invention, the plasticizer is selected from the group consisting of glycols such as propylene glycol and polyethylene glycol; polyhydric alcohols such as glycerin and sorbitol; glycerol esters such as glycerol triacetate; fatty acid triglycerides; mineral oil; diethyl phthalate, tributyl citrate, triethyl citrate, dibutyl sebacate, vegetable oils such as castor oil, a combination thereof and others known to those of ordinary skill in the art.

In one embodiment of the invention, the antioxidant is selected from the group consisting of Vitamin E, Vitamin E succinate, Vitamin E TPGS, ascorbic acid, ascorbyl palmitate, butylated hydroxyanisole, butylated hydroxytoluene, hypophophorous acid, monothioglycerol, propyl gallate, sodium bisulfite, sodium ascorbate, sodium formaldehyde sulfoxylate and sodium metabisulfite a combination thereof and others known to those of ordinary skill in the art.

In one embodiment of the invention, the opaquant is selected from the group consisting of titanium dioxide, talc, and calcium carbonate, In one embodiment of the invention, the thermal lubricant is selected from the group consisting of fatty esters such as glyceryl monooleate, glyceryl monostearate; waxes such as carnauba wax and beeswax; vitamin E succinate, a combination thereof and others known to those of ordinary skill in the art.

EXAMPLE 20 Exemplary formulations for a hot-melt extruded backing layer in a laminate of the invention.

Method A. Raw Material % w/w

Thermoplastic Polymer __ __

Hydrophobic polymer 5.00 - 10.00

Optional Hydrophilic polymer 0.00 - 50.00

Optional Thermoplastic Polymer 0.00 - 75.00

Optional Acidic Component 0.00 - 10.00

Optional Plasticizer 0.00 - 20.00

Optional Antioxidant 0.00 - 15.00

Optional thermal lubricant 0.00 - 20.00 Optional Opaquant 0.00 - 5.00

Method B.

Raw Material % w/w

PEO 5.00 - 75.00

Hydrophobic polymer 5.00 - 55.00

Optional Hydrophilic polymer 0.00 - 50.00

Optional Thermoplastic Polymer 0.00 - 75.00

Optional Acidic Component 0.00 - 10.00

Optional Plasticizer 0.00 - 20.00

Optional Antioxidant 0.00 - 15.00

Optional thermal lubricant 0.00 - 20.00 Optional Opaquant 0.00 - 5.00

Method C. Raw Material % w/w

PEO Grade 1 5.00 - 50.00

PEO Grade 2 5.00 - 50.00

PEO Grade 3 5.00 - 50.00

Hydrophobic polymer 5.00 - 55.00

Optional Hydrophilic polymer 0.00 - 50.00

Optional Thermoplastic Polymer 0.00 - 75.00

Optional Acidic Component 0.00 - 10.00

Optional Plasticizer 0.00 - 20.00

Optional Antioxidant 0.00 - 15.00

Optional thermal lubricant 0.00 - 20.00 Optional Opaquant 0.00 - 5.00 Method D. Raw Material % w/w

PEO Grade 1 5.00 - 50.00

PEO Grade 2 5.00 - 50.00

PEO Grade 3 5.00 - 50.00

Polyacrylate polymer 10.00 - 85.00

Ethyl Cellulose 1.00 - 45.00

Optional Thermoplastic Polymer 0.00 - 75.00

Optional Acidic Component 0.00 - 10.00

Optional Plasticizer 0.00 - 20.00

Optional Antioxidant 0.00 - 15.00

Optional thermal lubricant 0.00 - 20.00

Optional Opaquant 0.00 - 5.00

EXAMPLE 21

General procedure for preparing a laminate comprising a HME reservoir layer comprising PEO, testosterone and an acidic component.

Method A.

The process for preparing a stabilized bioadhesive hot-melt extruded laminate comprising: a bioadhesive hydrophilic reservoir layer comprising testosterone, PEO and an acidic component; and a hydrophobic low permeability backing layer, comprises the steps of: wet granulating at least one PEO polymer, an antioxidant, at least one bioadhesive polymer, at least one acidic component, optionally one or more hydrophobic polymers, optionally one or more hydrophilic polymers, and optionally one or more other excipients to form an excipient mixture having a solution pH (when dissolved in water) of less than 7; mixing the excipient mixture with testosterone to form a bioadhesive thermoplastic hydrophilic first composition; providing a thermoplastic hydrophobic second composition comprising at least one hydrophobic polymer, a plasticizer, optionally one or more hydrophilic polymers, and optionally at least one acidic component, wherein the second composition excludes a drug; coextruding the first composition and the second composition to form a bioadhesive hydrophilic reservoir layer and a hydrophobic low permeability backing layer, respectively; and laminating the reservoir layer and backing layer to form a bioadhesive bi-layered hot-melt coextruded laminate.

Method B.

The process for the preparing a stabilized bioadhesive hot- melt extruded composition comprising testosterone, at least one PEO polymer, and an acidic component, comprises the steps of: wet granulating at least one thermoplastic PEO polymer, an antioxidant, at least one bioadhesive polymer, at least one acidic component, optionally one or more hydrophobic polymers, optionally one or more hydrophilic polymers, and optionally one or more other excipients to form an excipient mixture having a solution pH (when dissolved in water) of less than 7; mixing the excipient mixture with testosterone to form a bioadhesive thermoplastic hydrophilic composition; and hot-melt extruding the hydrophilic composition to form the bioadhesive hot-melt extruded composition.

Some embodiments of the process of Methods A and B include those wherein: 1) the excipient mixture is dried prior to conducting step b); 2) the first composition is dried prior to step d); 3) the wet granulation is conducted with water; 4) the wet granulation is conducted with aqueous alcohol; 5) the thermoplastic polymer is PEO; 6) the acidic component is an acidic polymer; 7) the acidic component is a simple organic acid; 8) another hydrophilic polymer is present in the excipient mixture; 8) a hydrophobic polymer is present in the excipient mixture; 9) the bioadhesive polymer is also the acidic component; 10) the acidic component is a simple organic acid and the bioadhesive polymer; 11) the wet granulation step is conducted by first wet granulating poloxamer, an antioxidant, PEO and an organic acid and then adding a bioadhesive polymer; 12) the wet granulation step is conducted by first mixing an aqueous solution of simple organic acid and hydrophilic polymer with an alcohol solution of antioxidant and then adding in PEO and then adding in a bioadhesive polymer; 13) the first composition comprises two or more thermoplastic and water swellable, water soluble or water erodible polymers; 14) the second composition comprises two or more different hydrophobic polymers; 15) the acidic component is an inorganic acid; 16) the laminating step is heat-catalyzed lamination; 17) the laminating step is placement of an adhesive between the reservoir layer and the backing layer followed by pressing of the two layers together; 18) one or more hydrophilic polymers comprises one or more bioadhesive polymers, one or more thermoplastic polymers, or a combination thereof; and/or 19) the first composition comprises two or more PEO polymers.

The above is a detailed description of particular embodiments of the invention. It will be appreciated that, although specific embodiments of the invention have been described herein for purposes of illustration, various modifications may be made without departing from the spirit and scope of the invention. Accordingly, the invention is not limited except as by the appended claims. All of the embodiments disclosed and claimed herein can be made and executed without undue experimentation in light of the present disclosure.

Claims

What is claimed is:

1) A controlled release bioadhesive multi-layered laminate adapted for transdermal delivery of testosterone comprising: a) a backing layer; and b) a hot-melt extruded bioadhesive reservoir layer comprising at least one water swellable or water soluble thermoplastic polymer, testosterone, at least one bioadhesive polymer, optionally an antioxidant, and optionally, one or more other pharmaceutical excipients; c) wherein a unit dose of the laminate provides a blood plasma concentration of testosterone in the range of 300 to 1000 ng/dl throughout a period of at least 8 hours after initial transdermal application to a subject.

2) The laminate of claim 1, wherein the period is at least 12 hours.

3) The laminate of claim 1, wherein the transdermal application is buccal application. 4) The laminate of claim 1, wherein the backing layer is inert.

5) The laminate of claim 1, wherein the thermoplastic polymer is also the bioadhesive polymer.

6) The laminate of claim 1, wherein the thermoplastic polymer is polyethylene oxide.

7) The laminate of claim 6, wherein the thermoplastic polymer is a combination of at least two different grades of polyethylene oxide.

8) The laminate of claim 6, wherein the thermoplastic polymer is a combination of at three different grades of polyethylene oxide.

9) The laminate of claim 1 further comprising an adhesive interposed the backing layer and the reservoir layer for maintaining the layers together. 10) The laminate of claim 1, wherein the layers have been laminated together with heat and pressure.

11) The laminate of claim 1, wherein the backing layer has been solvent cast onto the reservoir layer.

12) The laminate of claim 1, wherein the laminate provides a circadian rhythm plasma profile for testosterone when administered once daily. 13) The laminate of claim 12, wherein the plasma profile is biphasic having a first elevated phase above 500 ng/dL for a period of 8 to 15 hours and a subsequent reduced phase of 500 ng/dL or below for a period of 16 to 9 hours, respectively, in a 24-hour period.

14) The laminate of claim 12, wherein the plasma profile is biphasic having a first elevated phase above 500 ng/dL for a period of 0.5 to 4 hours and a subsequent reduced phase of 500 ng/dL or below for a period of 20 to 23.5 hours, respectively, in a 24-hour period.

15) The laminate of claim 12, wherein the plasma profile is biphasic having a first elevated phase above 500 ng/dL for a period of 0.5 to 12 hours and a subsequent reduced phase of 500 ng/dL or below for a period of 12 to 23.5 hours, respectively, in a 24-hour period.

16) The laminate of claim 12, wherein the plasma profile is biphasic having a first elevated phase above 500 ng/dL for a period of 1 to 15 hours and a subsequent reduced phase of 500 ng/dL or below for a period of 9 to 23 hours, respectively, in a 24-hour period. 17) The laminate of claim 12, wherein the plasma profile is biphasic having a first elevated phase above 500 ng/dL for a period of 2 to 12 hours and a subsequent reduced phase of 500 ng/dL or below for a period of 12 to 22 hours, respectively, in a 24-hour period.

18) The laminate of claim 12, wherein the plasma profile is biphasic having a first elevated phase above 500 ng/dL for a period of 1 to 15 hours and a subsequent reduced phase of 500 ng/dL or below for a period of 9 to 23 hours, respectively, in a 24-hour period.

19) The laminate of claim 12, wherein the plasma profile is biphasic having a first elevated phase above 350 ng/dL for a period of 0.5 to 12 hours and a subsequent reduced phase of 350 ng/dL or below for a period of 12 to 23.5 hours, respectively, in a 24-hour period. 20) The laminate of claim 1, wherein the reservoir layer comprises 40 to 90% wt. of the laminate.

21) The laminate of claim 20, wherein the backing layer comprises 10 to 60% wt. of the laminate.

22) The laminate of claim 1, wherein the backing layer is substantially non-bioadhesive and comprises a hydrophobic polymer.

23) The laminate of claim 22, wherein the thermoplastic polymer is selected from the group consisting of HPC, PEO, an acrylic polymer, a cellulosic polymer or a combination thereof; the hydrophobic polymer is selected from the group consisting of ethyl cellulose, carnauba wax, beeswax, cellulose acetate, poly(hydroxypropyl glutamate), Eudragit RS, Eudragit RL, Eudragit E, poly(3-hydroxybutyrate-co-3- hydroxy valerate), poly(isobutylcyanoacrylate), Polyvinyl acetate phthalate, poly(isohexylcyanoacrylate), poly(orthoesters) and a combination thereof; and/or the bioadhesive polymer is selected from the group consisting of carbomer, polycarbophil,

PEO, a co-polymer of methyl vinyl ether and maleic acid or anhydride, chitosan, starch, a cellulosic polymer, or a combination thereof.

24) A unit dose comprising the laminate of claim 1, wherein the reservoir layer comprises

0.1 to 20 mg of testosterone. 25) The unit dose of claim 24, wherein the reservoir layer comprises 40 to 90% wt. of the laminate.

26) The unit dose of claim 25, wherein the backing layer comprises 10 to 60% wt. of the laminate.

27) The unit dose of claim 24, wherein the reservoir layer has an average and exposed surface area between 90 and 250 mm².

28) The unit dose of claim 24, wherein the unit dose has a surface area to dose ratio of 5 to 35 mm / mg testosterone based upon the exposed surface of the layer.

29) A bioadhesive laminate comprising a controlled release bioadhesive hot-melt extruded drug reservoir layer, and a substantially non-bioadhesive inert backing layer, wherein: a) the drug reservoir layer comprises 0.1 to 20 mg of testosterone, and at least two different grades of PEO; b) the backing layer comprises a hydrophobic polymer; and c) a unit dose of the laminate provides a blood plasma concentration of testosterone in the range of 300 to 1000 ng/dl throughout a period of at least 8 hours after initial transdermal application to a subject.

30) The laminate of claim 29, wherein the reservoir layer has an average and exposed surface area between 90 and 250 mm².

31) The laminate of claim 30, wherein the laminate has a surface area to dose ratio of 5 to 35 mm² / mg testosterone based upon the exposed reservoir surface. 32) The laminate of claim 29, wherein the reservoir layer comprises 40 to 90% wt. of the laminate.

33) The laminate of claim 32, wherein the backing layer comprises 10 to 60% wt. of the laminate. 34) The laminate of claim 29, wherein: a) the reservoir layer further comprises a hydrophilic polymer and a bioadhesive polymer; and b) the backing layer further comprises PEO. 35) The laminate of claim 34, wherein the reservoir layer further comprises an acidic component.

36) The laminate of claim 34, wherein the reservoir layer further comprises an opaquant.

37) The laminate of claim 34, wherein the reservoir layer further comprises an antioxidant.

38) The laminate of claim 34, wherein the backing layer is a solvent cast layer or a hot- melt extruded layer.

39) The laminate of claim 29 further comprising a release liner layer.

40) A bioadhesive laminate comprising a controlled release bioadhesive hot-melt extruded drug reservoir layer, and a substantially non-bioadhesive inert backing layer, wherein: a) the drug reservoir layer comprises 0.1 to 20 mg of testosterone, at least three different grades of PEO, a hydrophilic polymer, a bioadhesive polymer, and an acidic component; b) the backing layer comprises a hydrophobic polymer and PEO; c) a unit dose of the laminate provides a blood plasma concentration of testosterone in the range of 300 to 1000 ng/dl throughout a period of at least 8 hours after initial transdermal application to a subject; and d) each grade of PEO, hydrophobic polymer, hydrophilic polymer, and acidic component are independently selected at each occurrence.

41) The laminate of claim 40, wherein the reservoir layer further comprises an opaquant.

42) The laminate of claim 40, wherein the reservoir layer further comprises an antioxidant. 43) The laminate of claim 40, wherein the backing layer is a solvent cast layer or a hot- melt extruded layer.

44) The laminate of claim 40, wherein the backing layer comprises a hydrophobic polymer, and at least three different grades of PEO, wherein each grade of PEO, hydrophobic polymer, hydrophilic polymer, thermoplastic polymer, and acidic component are independently selected at each occurrence.

45) A method of treating one or more disorders associated with testosterone deficiency, the method comprising the step of transdermally administering to a subject at least one unit dose of a bioadhesive laminate according to claim 1, claim 29 or claim 40, wherein the bioadhesive layer absorbs moisture to initiate dermal adhesion and begin release of testosterone in a controlled manner.

46) A unit dose multi-layered laminate comprising: a) a backing layer; and b) a controlled release bioadhesive reservoir layer comprising 0.1 to 20 mg of testosterone and a moisture-activated bioadhesive polymer, wherein c) the reservoir layer has an average and exposed surface area of 90 to 250 mm ; d) the reservoir layer has a surface area to dose ratio of 5 to 35 mm / mg testosterone based upon the exposed surface of the layer; and e) the unit dose provides a blood plasma concentration of testosterone in the range of

300 to 1000 ng/dl throughout a period of at least 8 hours after initial transdermal application to a subject.

47) The unit dose of claim 46, wherein the unit dose provides a circadian rhythm plasma profile for testosterone when administered once daily. 48) The unit dose of claim 47, wherein the plasma profile is biphasic having a first elevated phase above 500 ng/dL for a period of 8 to 15 hours and a subsequent reduced phase of 500 ng/dL or below for a period of 16 to 9 hours, respectively, in a 24-hour period.

49) The unit dose of claim 47, wherein the reservoir layer comprises 40 to 90% wt. of the laminate.

50) The unit dose of claim 49, wherein the backing layer comprises 10 to 60% wt. of the laminate.

51) The unit dose of claim 47, wherein the reservoir layer is a hot-melt extruded layer.

52) The unit dose of claim 51 further comprising an adhesive interposed the backing layer and the reservoir layer for maintaining the layers together.

53) The unit dose of claim 51, wherein the layers have been laminated together with heat and pressure.

54) The unit dose of claim 51, wherein the backing layer has been solvent cast onto the reservoir layer. 55) A unit dose multi-layered laminate comprising: a) a backing layer; and b) a controlled release bioadhesive reservoir layer comprising 5 to 20 mg of testosterone and a moisture-activated bioadhesive polymer, wherein c) the reservoir layer has an average and exposed surface area of 32 to 250 mm ; d) the reservoir layer has a surface area to dose ratio of 5 to 35 mm / mg testosterone based upon the exposed surface of the layer; and e) the unit dose provides a blood plasma concentration of testosterone in the range of 300 to 1000 ng/dl throughout a period of at least 8 hours after initial transdermal application to a subject.

56) The unit dose of claim 55, wherein the reservoir layer comprises 5 mg of testosterone; the reservoir layer has an average and exposed surface area of 32 to 137 mm²; and the reservoir layer has a surface area to dose ratio of 6 to 33 mm / mg testosterone. 57) The unit dose of claim 55, wherein the reservoir layer comprises 7.5 mg of testosterone; the reservoir layer has an average and exposed surface area of 40 to 55 mm²; and the reservoir layer has a surface area to dose ratio of 6 to 8 mm² / mg testosterone.

58) The unit dose of claim 55, wherein the reservoir layer comprises 10 mg of testosterone; the reservoir layer has an average and exposed surface area of 130 to 145 mm²; and the reservoir layer has a surface area to dose ratio of 13 to 15 mm² / mg testosterone.

59) The unit dose of claim 55, wherein the reservoir layer comprises 12.5 mg of testosterone; the reservoir layer has an average and exposed surface area of 99 to 121 mm²; and the reservoir layer has a surface area to dose ratio of 8 to 10 mm² / mg testosterone.

60) The unit dose of claim 55, wherein the reservoir layer comprises 15 mg of testosterone; the reservoir layer has an average and exposed surface area of 91 to 142 mm²; and the reservoir layer has a surface area to dose ratio of 6 to 10 mm² / mg testosterone.

61) The unit dose of claim 55, wherein the reservoir layer comprises 20 mg of testosterone; the reservoir layer has an average and exposed surface area of 107 to 241 mm²; and the reservoir layer has a surface area to dose ratio of 7 to 12 mm² / mg testosterone. 62) A process for the manufacture of a bioadhesive multi-layered laminate adapted for transdermal delivery of testosterone, the process comprising the steps of: a) providing an inert composition comprising a hydrophobic polymer; b) providing a drug composition comprising testosterone dispersed within a thermoplastic bioadhesive composition; c) hot-melt extruding the inert composition to form a backing layer; d) hot-melt extruding the drug composition to form a drug reservoir layer; and e) laminating the backing layer and drug reservoir layer together thereby forming the multi-layered laminate.

63) A process for the manufacture of a bioadhesive bi-layered laminate adapted for transdermal delivery of testosterone, the process comprising the steps of: a) providing a drug composition comprising testosterone dispersed within a thermoplastic bioadhesive composition; b) hot-melt extruding the drug composition to form a drug reservoir layer; c) providing an inert composition comprising a hydrophobic polymer in a solvent; and d) solvent casting the inert composition onto the reservoir layer to form an inert backing layer and thereby form the bi-layered laminate.