WO2014160167A1

WO2014160167A1 - Implantable drug delivery compositions comprising aromatic polyurethanes and methods of treatment thereof

Info

Publication number: WO2014160167A1
Application number: PCT/US2014/025953
Authority: WO
Inventors: Alexander Schwarz
Original assignee: Endo Pharmaceuticals Solutions Inc.
Priority date: 2013-03-14
Filing date: 2014-03-13
Publication date: 2014-10-02

Abstract

A drug delivery composition comprises a drug elution rate-controlling excipient comprising an aromatic polyurethane defining a reservoir. The reservoir contains at least one discrete solid dosage form comprising at least one active pharmaceutical ingredient (API) and optionally, a sorption enhancer. The drug delivery composition is in an implantable dosage form. A method of treating or preventing one or more diseases or conditions in a subject comprises implanting the drug delivery composition into a subject to systemically deliver a therapeutically effective amount of the API to the subject for a period of time of at least one month at a pseudo-zero order elution rate.

Description

IMPLANTABLE DRUG DELIVERY COMPOSITIONS COMPRISING AROMATIC POLYURETHANES AND METHODS OF TREATMENT THEREOF

This application is related to and claims the benefit of U .S. Provisional Application No. 61/784,218, entitled "IMPLANTABLE DRUG DELIVERY COMPOSITIONS COMPRISING AROMATIC POLYURETHANES AND METHODS OF TREATMENT THEREOF" filed on March 14, 2013, the contents of which are incorporated by reference.

FIELD OF THE INVENTION

The invention relates to reservoir-based drug delivery compositions that are implantable into a subject in order to deliver therapeutically effective amounts of a drug, for example, at a pseudo-zero order rate, for extended periods of time (e.g. , at least one month, one year, etc.) . In particu lar, the invention relates to reservoir- based drug delivery compositions comprising aromatic polyurethanes.

BACKGROUND OF THE INVENTION

Drug compositions come in many different forms and may be administered to a patient via several different routes, such as oral, parenteral, topical, intravenous, su bcutaneous, intranasal, etc. Depending on the active and the treatment desired, different routes of administration may be preferable.

Some diseases and conditions may be long lasting, requ iring treatment for many weeks, months, or even years. Typically, a patient taking a traditional oral dosage form (e.g., tablets or capsu les) may be required to take the oral dose at least once per day for the duration of the treatment. For example, a patient may need to take an oral dose twice a day for a year or longer. One of the problems with treatments that requ ire continuous dosage over a long period of time is that often the patient may not be compliant in taking the medications. In other words, the patient may forget, believe the treatment is u nnecessary, or g row tired of having to take many pills over an extremely long period of time. Accordingly, treatments are necessary which can alleviate these compliance issues, but still provide effective and efficient treatment to the patient.

As one example, compliance with breast cancer medications has been an issue. Breast cancer is the leading life-threatening cancer affecting women, and 200,000 new cases of breast cancer are diagnosed each year. Typical treatment is interventional (e.g. , chemotherapy/radiation/surgery) followed by adjunctive therapy (e.g. , used with or after the primary treatment), where appropriate. After interventional therapy, almost all (e.g. , about 95%) hormone receptor positive, post-menopausal patients are prescribed an aromatase inhibitor to suppress estrogen and prevent recurrence. Studies have docu mented low compliance, low adherence, and low persistence, for example, with patients prescribed a five-year aromatase inhibitor therapy. As another example, compliance with schizophrenia medications has also been an issue. Schizophrenia is a complex mental disorder, which affects both men and women equally. Although there is no cure for schizophrenia, the treatment success rate with antipsychotic medications and psycho-social therapies can be high. However, an estimated 40% of all relapses suffered by schizophrenic patients are due to

noncompliance in taking their prescribed medicine. Patient relapse from noncompliance may also result in the return of more severe and dangerous psychotic symptoms, and persistent noncompliance can worsen the prognosis and make the patient less likely to respond to medication.

Additional examples of diseases or conditions that typically have treatment regimens lasting several years include Parkinson's disease, spasticity, and osteoporosis. Parkinson's disease is a progressive neurodegenerative disorder that is characterized by a patient's selective loss of dopaminergic neurons, which results in motor impairments, such as bradykinesia (i.e., slowness of movement), tremors, muscular rigidity, and postural instability. Spasticity is an involuntary tension, stiffening or contractions of muscles, which typically results from an injury to a part of the central nervous system (e.g., brain or spinal cord) that controls voluntary movements and results in increased activity or excitability in muscles. Spasticity is most often related to cerebral palsy, multiple sclerosis (MS), physical trauma (e.g., a brain or spinal cord injury), a blockage or bleeding in the brain (e.g., a stroke), or an infection (e.g., meningitis or encephalitis). Osteoporosis is a condition in which the bones become weak and break easily, particularly in post-menopausal women.

Accordingly, there has remained a need for effective dosage forms that provide therapeutically effective amounts of a drug over a long period of time, particularly where compliance is an issue, long-term treatment is needed, and/or a steady dose (e.g. , zero order) is desired.

SUMMARY OF THE INVENTION

Aspects of the present invention include reservoir-based drug delivery

compositions comprising aromatic polyurethanes, which may be implanted into a subject in order to deliver a therapeutically effective amount of a drug to the subject for long periods of time (e.g. , at least one month, at least three months, at least six months, at least one year, etc.). The therapeutically effective amount of the drug may be delivered at a pseudo-zero order rate. Accordingly, the present invention is directed to drug compositions, methods of treatment, methods of delivering the drug, subcutaneous delivery systems, and kits regarding the same.

According to an embodiment of the present invention, a drug delivery

composition comprises a drug elution rate-controlling excipient comprising a thermoplastic polymer defining a reservoir, wherein the thermoplastic polymer comprises an aromatic polyurethane. The reservoir contains at least one discrete solid dosage form comprising at least one active pharmaceutical ingredient (API), and the drug delivery composition is in an implantable dosage form.

According to another embodiment of the present invention, a method of delivering a therapeutically effective amount of an API from an implantable drug delivery composition comprises implanting a reservoir- based drug delivery composition into a subject to systemically deliver a therapeutically effective amount of the API to the subject at a pseudo-zero order rate for a period of time of at least one month. The drug delivery composition comprises at least one discrete solid dosage form, which comprises the API, surrounded by an excipient comprising an aromatic polyurethane.

According to another embodiment of the present invention, a method of treating or preventing one or more diseases or conditions in a subject comprises implanting a reservoir- based drug delivery composition into a subject to systemically deliver a therapeutically effective amount of an API to the subject for a period of time of at least one month at a pseudo-zero order elution rate, wherein the drug delivery composition comprises at least one discrete solid dosage form comprising the API surrounded by an excipient comprising at least one aromatic polyurethane.

According to another embodiment of the present invention, a subcutaneous delivery system comprises a thermoplastic reservoir implant comprising at least one discrete solid dosage form surrounded by a polymeric rate-controlling excipient, the at least one discrete solid dosage form comprising at least one active pharmaceutical ingredient (API), and the polymeric rate-controlling excipient comprising an aromatic polyurethane. The subcutaneous delivery system provides for release of the API at an elution rate suitable to provide a therapeutically effective amount of the API to a subject at a pseudo-zero order rate for a period of time of at least one month.

According to another embodiment of the present invention, a kit for

subcutaneously placing a drug delivery composition comprises a reservoir-based drug delivery composition comprising a rate-controlling excipient defining a reservoir containing at least one discrete solid dosage form, wherein the rate-controlling excipient comprises anaromatic polyurethane; and an implanter for inserting the reservoir-based drug delivery composition beneath the skin. BRIEF DESCRIPTION OF THE DRAWINGS

The invention may be further understood by reference to the drawings in which : Figure 1 depicts the role of the excipient in a reservoir-based drug delivery composition according to one aspect of the present invention;

Figure 2 depicts the cylindrical shape of a reservoir-based drug delivery composition according to one embodiment of the present invention;

Figure 3 depicts the difference between a drug reservoir and a matrix-based implant;

Figure 4 is a graph showing the elution rate (micro g/day) of risperidone from aromatic and aliphatic polyurethane implants, according to embodiments of the present invention described in Example 2; and

Figure 5 is a graph showing the elution rate (micro g/day) of paliperidone from aromatic and aliphatic polyurethane implants, according to embodiments of the present invention described in Example 3.

DETAILED DESCRIPTION OF THE INVENTION

Aspects of the present invention include reservoir-based drug delivery

compositions comprising aromatic polyurethanes which may be implanted into a subject in order to deliver a therapeutically effective amount of a drug to the subject for a long period of time (e.g., at least one month, at least three months, at least six months, at least one year, etc.). Additional aspects of the present invention include methods of treatment, methods of delivering the drug, subcutaneous delivery systems, and kits regarding the same.

As discussed in more detail below, although it was previously believed that only aliphatic polyurethanes could be used in subcutaneous implants (e.g., polyurethanes comprising aliphatic and/or cycloaliphatic isocyanates, such as 4,4'-diisocyanato dicyclohexylmethane (HMDI)), the applicant has now discovered that aromatic polyurethanes (e.g., polyurethanes comprising aromatic diisocyanates, such as methylene diphenyl diisocyanate (MDI)) can be used to safely and effectively control the release of APIs from subcutaneous implants (e.g., at pseudo-zero order elution rates).

As used herein, the term "therapeutically effective amount" refers to those amounts that, when administered to a particular subject in view of the nature and severity of that subject's disease or condition, will have a desired therapeutic effect, e.g. , an amount which will cure, prevent, inhibit, or at least partially arrest, delay the onset of or partially prevent a target disease or condition or one or more symptoms thereof.

The terms "active pharmaceutical ingredient," "API," "drug," or "active" may be used herein interchangeably to refer to the pharmaceutically active compound(s) in the drug delivery composition. This is in contrast to other ingredients in the drug delivery composition, such as excipients, which are substantially or completely pharmaceutically inert. A suitable API in accordance with the present invention is one where there is or likely may be patient compliance issues for treating a certain disease or condition, where long-term treatment is needed, and/or where a steady dose (e.g., zero order) is desired.

The term "pharmaceutically acceptable," as used herein, means approved by a regulatory agency, e.g. of the U.S. Federal or a state government or listed in the U.S. Pharmacopeia or other generally recognized pharmacopeia for use in animals, and more particularly in humans.

The terms "subject" and "patient", are used interchangeably herein and refer to a mammalian individual, such as a human being.

Each compound used herein may be discussed interchangeably with respect to its chemical formula, chemical name, abbreviation, etc. For example, PTMO may be used interchangeably with poly(tetramethylene oxide). Additionally, each polymer described herein, unless designated otherwise, includes homopolymers, copolymers, terpolymers, and the like.

As used herein and in the claims, the terms "comprising" and "including" are inclusive or open-ended and do not exclude additional unrecited elements, compositional components, or method steps. Accordingly, the terms "comprising" and "including" encompass the more restrictive terms "consisting essentially of" and "consisting of." Unless specified otherwise, all values provided herein include up to and including the endpoints given, and the values of the constituents or components of the compositions are expressed in weight percent of each ingredient in the composition.

Reservoir-Based Drug Delivery Composition

The drug delivery composition is a reservoir-based drug delivery composition. As used herein, the "reservoir-based composition" is intended to encompass a composition having a substantially or completely closed, surrounded, or encased hollow space or reservoir, where the hollow space or reservoir is filled, at least partially, with at least one discrete solid dosage form.

In one embodiment of the present invention, a drug delivery composition comprises a drug elution rate-controlling excipient comprising a thermoplastic polymer defining a reservoir, wherein the polymer comprises an aromatic polyurethane and the reservoir contains at least one discrete solid dosage form comprising at least one API. The elastomeric polymer defining the reservoir is formed separate from the at least one discrete solid dosage form (i.e., the elastomeric polymer defining the reservoir and the at least one discrete solid dosage form are not two "layers" that are bonded to each other; rather, the elastomeric polymer defining the reservoir is separately formed and the at least one discrete solid dosage form is placed into contact with the elastomeric polymer when it is loaded into the reservoir) .

A reservoir-based composition, as used herein, is in contradistinction to a matrix- based composition . As depicted in Figu re 3, a drug reservoir includes a reservoir portion 120 and a rate controlling portion (excipient 110) whereas a matrix-based implant only consists of the matrix material 130 with the drug incorporated therein . In other words, in a reservoir system, the drug is contained within or is surrou nded by some type of rate-controlling material (e.g. , a wall, membrane, or casing) . In a matrix system, the drug is combined within some type of matrix, often polymeric, which often erodes or degrades in order to release the active to the su bject. A matrix system will typically not contain a separate rate-controlling layer because it relies on the chemical composition of the matrix itself to control the rate of drug release.

Thus, there are some major distinctions between the two types of systems. The reservoir-based system allows for a much higher drug loading (e.g. , on the order of 98% maximum) whereas a matrix-based system contains a much smaller amount (e.g. , on the order of 25% maximu m). Although a higher drug loading may be beneficial, it can also be dangerous because of the increased risk of drug overdose or dumping into the subject if the su rrounding material were to break or rupture. Additionally, the reservoir- based composition of the present invention allows for a zero-order or pseudo-zero order rate of release of the active. A matrix-based system, on the contrary, typically provides for a first order rate of release when used over long periods of time. A first order rate may be characterized by a high initial rate of release that decays or diminishes quickly over time.

As used herein, the term "pseudo-zero order" or "pseudo-zero order rate" refers to a zero-order, near-zero order, substantially zero order, or controlled or sustained release of an API. A zero order release profile may be characterized by release of a constant amount of the API per unit time. A pseudo-zero order release profile may be characterized by approximating a zero-order release by release of a relatively constant amou nt of the API per u nit time (e.g. , within 40%, 30%, 20%, or 10% of the average value). Under a pseudo-zero order rate, the composition may initially release an amount of the API that produces the desired therapeutic effect, and g radually and continually release other amou nts of the API to maintain the level of therapeutic effect over an extended period of time (e.g. , at least one month, six months, or one year) . In order to maintain a near-constant level of API in the body, the API may be released from the composition at a rate that will replace the amou nt of API being metabolized and/or excreted from the body. It will be appreciated by one of ordinary skill in the art that there may be some initial period of time before steady state is reached (e.g. , a ramp up before the target range is reached), which still complies with the definition of "pseudo- zero order. "

Without wishing to be bound to a particular theory, it is believed that a concentration gradient occurs where the concentration of API within the reservoir is "infinite" (e.g., the reservoir acts an infinite supply, but the concentration is practically limited by the amount of active for the given duration of release) and the concentration outside the drug delivery composition is zero (e.g. , the subject acts as an infinite sink where the active is constantly being taken away from the composition by the subject's body, such as circulatory, lymphatic systems, etc.) . Additionally, the excipient 110 (e.g. , the wall through which the active passes) becomes fu lly saturated with the active ingredient at steady state. Accordingly, this gradient allows the "infinite" supply of API to be adsorbed into the excipient, dissolve in and diffuse through the polymer wall, and then be desorbed for release into the subject. The selection of the excipient 110 may help to provide the pseudo-zero order release of the drug . Without wishing to be limited, it is believed that the release of the drug is not dependent on the desorption from the excipient.

Dosage Form(s)

The drug delivery composition comprises at least one dosage form comprising at least one API. In one embodiment of the present invention, the drug delivery

composition comprises at least one discrete solid dosage form comprising at least one API surrou nded by an excipient comprising an aromatic polyurethane.

As used herein, the term "discrete solid dosage form" is intended to encompass any dosage form that is in the form of a solid . The solid dosage form may include any cohesive solid form (e.g. , compressed formulations, pellets, tablets, etc.) . The solid dosage form may include a solid body or mass comprising the API, which may be prepared in any suitable manner known to one of ordinary skill in the art (e.g. , compressed, pelleted, extruded) .

The solid dosage forms are "discrete" in that there are one or more dosage forms contained within the reservoir. In other words, the discrete solid dosage form includes one or more solid formulations which are separate and distinct from the polymeric rate- controlling excipient. In an exemplary embodiment, the discrete solid dosage form(s) do not fill the entire reservoir or cavity (e.g. , the solid dosage forms are su bstantially spherical and the reservoir is substantially cylindrical) . For example, the solid dosage form need not be co-extruded with the surrounding excipient such that the solid dosage form fills the entire cavity.

The discrete solid dosage forms may be of any su itable shape and of any su itable quantity. In one embodiment of the present invention, the discrete solid dosage forms are su bstantially spherical in shape. The discrete solid dosage form(s) may be "substantially spherical" in that the solid dosage forms are spherical or nearly spherical in that the length of the longest radius is approximately equal to the shortest radius of the dosage form. For example, the shape of the dosage form may not deviate from a

5 perfect sphere by more than about 10%. In another embodiment, the discrete solid dosage forms comprise more than one pellet (e.g., 2-9 pellets) . The nu mber of discrete solid dosage forms may be proportional to the elution rate. In other words, a higher number of dosage forms may result in a higher average elution rate than a smaller number of dosage forms. Thus, it may be preferable to include more discrete solid lo dosage forms to give a higher elution rate (e.g. , 7-9 pellets) .

The discrete solid dosage form may comprise one or more active pharmaceutical ingredients. A suitable API in accordance with the present invention is one where compliance is at issue, where long term treatment is needed, and/or where a steady dose (e.g. , zero order) is required, for example, to minimize side effects. The amount of i s API is not particularly limited, but may be preferably on the order of about 75-100 wt% of the solid dosage form, about 75-97 wt% of the solid dosage form, or about 85-95 wt% of the solid dosage form (e.g. , about 88 wt%) .

The discrete solid dosage form may also comprise a sorption enhancer. As used herein, the term "sorption enhancer" is intended to encompass compou nds which

20 improve release of the API from the drug delivery composition. Without wishing to be bou nd to a particu lar theory, the sorption enhancers may improve release of the API from the d rug delivery composition by drawing water or other fluids into the reservoir from the subject, disintegrating or breaking apart the discrete solid dosage form(s), and/or allowing the API to come into contact or remain in contact the inner walls of the

25 excipient. Such a mechanism may be depicted, for example, in Figure 1. Figure 1

represents the rate-controlling excipient 110. The API, located in the reservoir on the left side of the diagram, is sorbed 112 from the reservoir to the excipient. The API then crosses through the excipient 110. The API is then desorbed 114 from the excipient into the subject.

30 Any suitable sorption enhancer(s) may be selected by one of ordinary skill in the art. Particularly su itable sorption enhancer(s) may include "polymeric sorption enhancers," for example, negatively-charged polymers, such as croscarmellose sodium, sodiu m carboxymethyl starch, sodium starch glycolate, sodium acrylic acid derivatives, chondroitin sulfate, poly-glutamic acid, poly-aspartic acid, and combinations thereof. In

35 an exemplary embodiment, the sorption enhancer is croscarmellose sodium . The

amount of the sorption enhancer is not particularly limited, but may be present on the order of about 0-25 wt% of the solid dosage form, about 1-25 wt% of the solid dosage form, about 2-20 wt% of the solid dosage form, about 2- 12 wt% of the solid dosage form, about 5- 10 wt% of the solid dosage form (e.g., about 5 wt% or about 10 wt% of the solid dosage form) .

According to alternative embodiments, suitable sorption enhancers may include one or more "sugar-based sorption enhancers" as described in more detail below, or may include one or more "non-polymeric sorption enhancers" as described in more detail below. In one embodiment, a suitable sorption enhancer can comprise a combination of two or more polymeric, non-polymeric and/or sugar-based sorption enhancers.

The amount of sorption enhancer may be proportional to the elution rate. In other words, a higher weight percent of sorption enhancer in the drug composition may result in a higher average elution rate than a smaller weight percentage. Thus, it may be preferable according to particular embodiments to include a higher weight percent of sorption enhancer to give a higher elution rate (e.g. , 8-25 wt%).

The discrete solid dosage form may also comprise other ingredients as long as they do not adversely impact the elution rate. Other suitable ingredients may include, for example, lubricants, excipients, preservatives, etc. A lubricant may be used in the pelleting or tableting process to form the discrete solid dosage form(s), as would be well known by one of ordinary skill in the art. Suitable lu bricants may include, but are not limited to, magnesium stearate, calcium stearate, zinc stearate, stearic acid,

polyethylene g lycol, and the like. The amou nt of any additional ingredients is not particularly limited, but is preferably on the order of less than about 5 wt% of the solid dosage form, and most preferably less than about 3 wt% of the solid dosage form, particularly preferably about 2% or less of the solid dosage form.

In one embodiment of the present invention, the at least one discrete solid dosage form comprises : 75- 100 wt% API based on the total weight of the at least one discrete solid dosage form; 0-25 wt% of at least one sorption enhancer based on the total weight of the at least one discrete solid dosage form ; and 0-5 wt% lubricant based on the total weight of the at least one discrete solid dosage form. In another

embodiment of the present invention, the at least one discrete solid dosage form comprises : 75-97 wt% API based on the total weight of the at least one discrete solid dosage form ; 1-25 wt% of at least one sorption enhancer based on the total weight of the at least one discrete solid dosage form ; and 0-5 wt% lubricant based on the total weight of the at least one discrete solid dosage form. For example, 85-95 wt% API based on the total weight of the at least one discrete solid dosage form ; 5-20 wt% of croscarmellose sodium based on the total weight of the at least one discrete solid dosage form; and 0-5 wt% stearic acid based on the total weight of the at least one discrete solid dosage form . Excipient

The discrete solid dosage form(s) is/are surrounded by a polymeric excipient. In other words, the discrete solid dosage form(s) is/are substantially or completely surrounded, encased, or enclosed by the excipient. According to embodiments of the present invention, the polymeric excipient is an aromatic polyurethane.

In the present invention, there are no holes or pores in the excipient to allow egress of the API or ingress of bodily fluids, unlike an osmotic system, which requires a hole to allow release of the API. Moreover, there is no (or negligible) build up of pressure within a drug delivery composition in accordance with the present invention, unlike an osmotic system, which requires pressure to force the API out of the device.

In one embodiment of the present invention, the excipient is substantially or completely non-porous. "Substantially nonporous" may refer to a material which has a porosity or void percentage less than about 10%, about 5%, or about 1%, for example. In particular, the excipient is substantially non-porous in that there are no physical pores or macropores, which would allow for egress of the API from the drug delivery composition. In another embodiment, the excipient is practically insoluble in water. Solubility is the concentration of a solute when the solvent has dissolved all the solute that it can at a given temperature (e.g. , the concentration of solute in a saturated solution at equilibrium). As used herein, the term "practically insoluble in water" is consistent with the definition in The United States Pharmacopeia - National Formulary (USP-NF) definition, which provides for more than 10,000 parts solvent to one part solute (e.g. , one gram of the excipient in greater than 10,000 ml_ of water).

Without wishing to be bound to a particular theory, it is believed that a concentration gradient across the excipient (e.g., wall, membrane, layer) allows for continuous release of the API. As depicted in Figure 1, sorption 112 of the API occurs from the reservoir onto the rate-controlling excipient 110. The API then dissolves into and fully saturates the excipient 110, diffuses through it, and the API is then desorbed 114 from the excipient into the subject. Accordingly, this gradient allows the "infinite" supply of API to be adsorbed onto the excipient, diffuse through it and desorbed into the subject, which, based on the excipient selected, may help to provide the pseudo-zero order release of the drug. Thus, the excipient may also be called a drug elution rate- controlling or rate-controlling excipient herein . The "rate-controlling excipient" is intended to encompass materials which control the elution rate of the API. In other words, a polymeric excipient, that when encasing the drug delivery composition, provides a different rate of release, namely, a controlled rate of release (e.g. , pseudo- zero order) as compared to the release of an API from an identical composition without a rate-controlling excipient. The excipient defines the shape of the reservoir. The reservoir may be of any suitable size and shape. In an exemplary embodiment, the excipient is substantially cylindrically shaped. As used herein, the terms "cylindrical" or "cylindrically shaped" may be used interchangeably to mean at least substantially having the shape of a cylinder. As used herein, the term "cylinder" includes and refers to, but is not limited to : circular cylinders, having a circular cross-section ; elliptical cylinders, having an elliptical cross-section ; generalized cylinders, having any shape in cross-section ; oblique cylinders, in which the end su rfaces are not parallel to one another and/or are not normal to the axis of the cylinder; and conical and frusto-conical analogs thereof. In accordance with one aspect of the invention, a hollow tu be may include a substantially consistent cross-sectional area and two substantially equally-sized circular ends. The cylindrical shape defines the shape of the excipient defining the reservoir (e.g. , the outer portion of the drug delivery composition) . An embodiment of the cylindrically shaped excipient is depicted, for example, in Figure 2. Preferably, the dimensions of the cylindrical hollow tu be shou ld be as precise as possible (e.g. , a consistent shape and dimension along the length of the tube, in particular, a consistent circular cross-section) . The reservoir may be of any suitable size depending on the active and location of delivery. For example, the composition may range in size from about 2mm to about 4mm in diameter (e.g. , about 2.7 mm in diameter) and about 6mm to about 50mm in length, for example about 45 mm in length .

Aromatic Polyurethanes

The polymeric excipient comprises a thermoplastic, aromatic polyurethane. The excipient allows for delivery of a therapeutically effective amou nt of the API to the su bject, for example, at a pseudo-zero order rate, for the intended period of time that the implant resides in a patient. Although it was previously believed that only aliphatic polyu rethanes could be used in subcutaneous implants (e.g ., polyurethanes comprising aliphatic and/or cycloaliphatic isocyanates, such as 4,4'-diisocyanato

dicyclohexylmethane (HMDI)), the applicant has now discovered that aromatic polyurethanes (e.g . , polyurethanes comprising aromatic diisocyanates, such as methylene diphenyl diisocyanate (MDI)) can be used to safely and effectively control the release of APIs from su bcutaneous implants (e.g ., at pseudo-zero order elution rates) .

According to an embodiment of the present invention, a drug delivery

composition comprises a polymeric excipient (e.g ., a drug elution rate-controlling excipient comprising a thermoplastic polymer) defining a reservoir. The polymeric excipient comprises or consists of an aromatic polyurethane (e.g ., the polyurethane comprises aromatic diisocyanates) . The reservoir contains at least one discrete solid dosage form comprising at least one active pharmaceutical ingredient (API), and the drug delivery composition is in an implantable dosage form . Non-limiting examples of suitable aromatic diisocyanates include methylene diphenyl diisocyanate (MDI), toluene diisocyanate (TDI), p-phenylene diisocyanate (PPDI), naphthalene diisocyanate (NDI), and combinations thereof. According to preferred embodiments, the polymeric excipient contains no aliphatic or cycloaliphatic isocyanates (i. e. , the isocyanates are all aromatic) .

The polymer may be formed by any suitable means or techniques known to one of ordinary skill in the art. For example, the polymer may be formed from monomers, polymer precursors, pre-polymers, polymers, etc. Polymer precursors may include monomeric as well as oligomeric su bstances capable of being reacted or cu red to form polymers. The polymers may be synthesized using any su itable constituents.

Polyu rethanes may be formed, for example, from polyols (e.g. , comprising two or more hydroxyl or alcohol fu nctional grou ps, -OH), isocyanates (e.g. , comprising an isocyanate grou p, -N=C=0), and, optional chain extenders, catalysts, and other additives.

Su itable polyols may include, for example, polyether polyols, polycarbonate- based polyols, and the like, which may include diols, triols, etc. Polyether polyols may include, for example, polyalkylene glycols (e.g. , polyethylene glycols, polypropylene glycols, polybutylene glycols), poly(ethylene oxide) polyols (e.g. , polyoxyethylene diols and triols), polyoxypropylene diols and triols, and the like. Alternative polyols may include, for example, 1,4-butanediol, 1,6-hexanediol, 1, 12-dodecanediol, and the like. Suitable chain extenders may include, for example, ethylene glycol, 1,4-butanediol ( 1,4- BDO or BDO), 1,6-hexanediol, cyclohexane dimethanol, and hydroquinone bis(2- hydroxyethyl) ether ( HQEE) .

For example, the polyol segment or segments may be represented by one or more of the following formulas :

0-(CH₂-CH₂-C 2-C ₂)_x-0- (Formula 1)

-[0-(CH₂)_n]_x-0- (Formula 2)

0-[(CH₂)₆-C0₃]_n (Formula 3)

The polyols may also include mixtu res of one or more types of polyol segments.

According to one embodiment, the aromatic polyurethane comprises

poly(tetramethylene oxide) (PTMO) and an aromatic diisocyanate. The PTMO preferably has a molecu lar weight between about 500 daltons to about 5,000 daltons (e.g., between about 1,500 daltons to about 3,500 daltons, or between about 2,000 daltons to about 3,000 daltons) . In one embodiment of the present invention, for example, the polymer is an aromatic polyurethane comprising poly(tetramethylene oxide) (PTMO) and polymerized methylene diphenyl diisocyanate (MDI) and 1,4-butanediol.

The polymers may be processed using any su itable techniques, such as extrusion, injection molding, compression molding, spin-casting . For example, the polymer may be extruded or injection molded to produce hollow tubes having two open ends (see e.g. , Figure 2). The hollow tube can be loaded with the discrete solid dosage form(s). The open ends are sealed to form the reservoir-based drug delivery composition. A first open end may be sealed before filling the tube with the discrete solid dosage form(s), and the second open end may be sealed after the tube is filled with all of the discrete solid dosage form(s). The tube may be sealed using any suitable means or techniques known in the art. For example, the ends may be plugged, filled with additional polymers, heat sealed, or the like. The tubes should be permanently sealed such that the discrete solid dosage form(s) may not be removed. Also, the ends should be suitably sealed such that there are no holes or openings that would allow egress of the active once implanted.

The wall thickness of the excipient may be selected to provide for the desired elution rate. The wall thickness may be inversely proportional to elution rate. Thus, a larger wall thickness may result in a lower elution rate. The excipient may form a wall having an average thickness of about 0.05 to about 0.5 mm, or about 0.1 mm to about 0.3 mm (e.g. , about 0.1 mm, about 0.2 mm, or about 0.3 mm).

In one embodiment of the present invention, the drug delivery composition does not require erosion or degradation of the excipient in vivo in order to release the API in a therapeutically effective amount. Alternatively, the excipient is not substantially erodible and/or not substantially degradable in vivo for the intended life of the implantable composition. As used herein, "erosion" or "erodible" are used interchangeably to mean capable of being degraded, disassembled, and/or digested, e.g. , by action of a biological environment. A compound that is "not substantially erodible" is not substantially degraded, disassembled, and/or digested over time (e.g. , for the life of the implant). Alternatively, the material may be "not substantially erodible" or "does not require erosion" in vivo in order to provide for release of the API. In other words, the compound may erode over time, but the API is not substantially released due to erosion of the material. With respect to "degradation" or "degradable," these are intended to mean capable of partially or completely dissolving or decomposing, e.g. , in living tissue, such as human tissue. Degradable compounds can be degraded by any mechanism, such as hydrolysis, catalysis, and enzymatic action. Accordingly, a compound that is "not substantially degradable" does not substantially dissolve or decompose over time (e.g. , for the life of the implant) in vivo. Alternatively, the material may be "not substantially degradable" or "not requiring degradation" in order to provide for release of the API. In other words, the compound may degrade over time, but the API is not substantially released due to degradation of the material. Polymer Selection

Without wishing to be bound to a particu lar theory, it is believed that by selecting specific polymers with certain contents or ratios of hard to soft segments, certain desired elution rates may be achieved .

According to particular embodiments, the polymeric excipient comprises at least one polymer having soft and hard segments. As used herein, the term "segment" may refer to any portion of the polymer including a monomer unit, or a block of the polymer, or a sequence of the polymer, etc. "Soft segments" may include a soft phase of the polymer, which is amorphous with a glass transition temperature below the use temperature (e.g. , ru bbery) . "Hard segments" may include a hard phase of the polymer that is crystalline at the use temperature or amorphous with a glass transition temperatu re above the use temperature (e.g. , glassy) . The use temperature may include a range of temperatu res including room temperature (about 20-25 ° C) and body temperature (about 37 ° C) . Without wishing to be bound to a particular theory, the soft segment may provide for the greatest impact on sorption onto the excipient and the hard segment may impact diffusion across or through the excipient. See e.g. , Figu re 1 showing sorption 112 of the API from the reservoir into the excipient 110 and desorption 114 of the API from the excipient into the subject. Any suitable aromatic polyurethane comprising hard and soft segments may be selected by one of ordinary skill in the art, as long as the polymer allows for delivery of a therapeutically effective amount of the API to the subject at a pseudo-zero order rate for the intended period of time of the implant.

Su itable hard and soft segments of the aromatic polyurethane may be selected by one of ordinary skill in the art. It will be appreciated by one of ordinary skill in the art that although certain types of polymers are described herein, the hard and soft segments may be derived from monomers, polymers, portions of polymers, etc. In other words, the polymers listed may be changed or modified during polymerization, but those polymers or portions of those polymers in polymerized form constitute the hard and soft segments of the final polymer.

Examples of suitable soft segments include, but are not limited to, those derived from (poly)ethers, (poly)carbonates, (poly)silicones, or the like. For example, the soft segments may be derived from alkylene oxide polymers selected from the grou p consisting of poly(tetramethylene oxide) (PTMO), polyethylene glycol (PEG),

poly(propylene oxide) (PPO), poly(hexamethylene oxide), and combinations thereof. The soft segment may also be derived from polycarbonate soft segments (obtainable from Lubrizol) or silicone soft segments (obtainable from Aortech) .

According to preferred embodiments, the hard segments comprise aromatic diisocyanates. Examples of suitable aromatic diisocyanates include, but are not limited to, methylene diphenyl diisocyanate (MDI), toluene diisocyanate (TDI), p-phenylene diisocyanate (PPDI), naphthalene diisocyanate (NDI).

The polymer may be formed by any suitable means or techniques known to one of ordinary skill in the art. For example, the polymer may be formed from monomers, polymer precursors, pre-polymers, polymers, etc. Polymer precursors may include monomeric as well as oligomeric substances capable of being reacted or cured to form polymers. The polymers may be synthesized using any suitable constituents.

The soft segments may be derived from polyols including polyether polyols, polycarbonate-based polyols, and the like. For example, soft segments may be derived from polyether polyols, such as polyalkylene glycols (e.g. , polyethylene glycols, polypropylene glycols, polybutylene glycols), poly(ethylene oxide) polyols (e.g., polyoxyethylene diols and triols), polyoxypropylene diols and triols, and the like. Soft segments may be derived from polyols, such as 1,4-butanediol, 1,6-hexanediol, 1, 12- dodecanediol, and the like. The soft segment derived from the polyols may be represented by the following formulas or mixtures thereof, for example:

0-(CH₂-CH2-CH2-CH₂)_x-0- (Formula 1)

-[0-(CH₂)_n]_x-0- (Formula 2)

0-[(CH₂)₆-C0₃]_n (Formula 3)

According to particular embodiments, the soft segments comprise PTMO having an average molecular weight between about 500 daltons to about 5,000 daltons (e.g., between about 1,500 daltons to about 3,500 daltons, or between about 2,000 daltons to about 3,000 daltons).

The hard segments are preferably derived from aromatic diisocyanates, such as methylene diphenyl diisocyanate (MDI), toluene diisocyanate (TDI), p-phenylene diisocyanate (PPDI), or naphthalene diisocyanate (NDI) . For example, the polymer may be an aromatic polyurethane comprising poly(tetramethylene oxide) as the soft segment and polymerized methylene diphenyl diisocyanate (MDI) and 1,4-butanediol as the hard segment.

The relative content of the soft and hard segments may provide an elution rate within a target range of average daily elution rate for the active pharmaceutical ingredient. The relative content of the soft and hard segments refers to the amount or content of soft segments to hard segments in the polymer. The relative content may also be defined as a ratio of soft segment to hard segments (e.g. , at least about 2 : 1 or at least about 4: 1 of soft to hard segments). For example, the soft content may be 50% or more, 60% or more, 70% or more, or 80% or more relative to the hard content.

The ratio of soft to hard segments may vary depending on the desired elution rate. Without wishing to be bound to a particular theory, it is believed that the soft segments may contribute to the sorption of the API into the excipient and/or the hard segment may contribute to the rate of diffusion (e.g. , how fast the active diffuses through the excipient). The rate of diffusion through the excipient probably does not matter much, however, once the implant reaches steady state (e.g. , a constant or near constant elution rate) . Thus, it may be desirable to have a higher ratio of soft segments relative to hard segments (e.g. , at least about 2 : 1, at least about 3 : 1, or at least about 4 : 1) . The relative content of the soft and hard segments may also be considered directly proportional on the molecular weights of both the soft and hard segments. In other words, for a given ratio, a higher molecular weight polymer for the soft segment results in a higher relative content of soft segments to hard segments.

The molecu lar weights of each of the soft and hard segments may be selected depending on the specific soft and hard seg ments selected. In particular, the size (e.g. , molecu lar weight) of the soft segment may impact the elution rate. For example, the soft block (e.g. , polyether) molecular weights may range from about 500- 12,000 daltons (daltons may be used interchangeably with g/mol for molecular weight) . For the case of PTMO as the soft segment, the molecu lar weights may range from about 500 daltons to about 5,000 daltons (e.g ., about 1 ,500 daltons to about 3,500 daltons, or about 2,000 daltons to about 3,000 daltons) . In some cases, a higher molecular weight may be preferred (e.g. , about 2000-3000 daltons) in order to elevate elution, as compared to less than about 1000 daltons. For the case of PPO as the soft segment, the molecu lar weight may range from about 2000-12,0000 daltons, and again a higher molecular weight may be preferred to elevate elution rates. Without wishing to be bound to a particular theory, it is believed that by increasing the molecular weight of soft segments in the polymer, the content of hard segments is reduced providing for better dissolution and diffusion of the API through the excipient.

The Shore D hardness or Shore hardness of the polymer segments may also have an impact on the elution rates. In some cases, the Shore hardness may be inversely proportional to the elution rate (e.g. , a higher Shore hardness results in a lower elution rate) .

In one embodiment of the present invention, the excipient is su bstantially or completely non-porous, in that the polymer has a porosity or void percentage less than about 10%, about 5%, or about 1%, for example. In particu lar, the excipient is su bstantially non-porous in that there are no physical pores or macropores which would allow for egress of the API from the drug delivery composition . In another embodiment, the excipient is practically insoluble in water, which equates to one gram in > 10,000 rml_ of water. In another embodiment of the present invention, the drug delivery

composition does not require erosion or degradation of the excipient in vivo in order to release the API in a therapeutically effective amount. Alternatively, the excipient is not substantially erodible and/or not substantially degradable in vivo for the intended life of the implantable composition (e.g. , the API is not released due to erosion or degradation of the material in vivo).

The rate-controlling aromatic polyurethane excipient may comprise a

substantially non-porous polymer comprising soft and hard segments selected based on the relative content of soft and hard segments of the polymer to obtain an elution rate within a target range of average daily elution rate for the active pharmaceutical ingredient. A therapeutically effective amount of the API is delivered to the subject at a pseudo-zero order rate within a target range between a maximum and minimum value of a desired average daily elution rate for the active pharmaceutical ingredient. Pseudo- zero order refers to a zero-order, near-zero order, substantially zero order, or controlled or sustained release of the API. The composition may initially release an amount of the API that produces the desired therapeutic effect, and gradually and continually release other amounts of the API to maintain the level of therapeutic effect over the intended duration of treatment (e.g. , about one year).

As previously noted, the excipient defines the shape of the reservoir, which may be of any suitable size and shape. In an exemplary embodiment, the excipient is substantially cylindrically shaped. An embodiment of a cylindrically shaped excipient is depicted, for example, in Figure 2. The reservoir may be of any suitable size depending on the active and location of delivery, e.g. , a ratio of about 1 : 1.5 to 1 : 5 diameter to length.

The wall thickness of the excipient may also be selected to provide for the desired elution rate. The wall thickness may be inversely proportional to elution rate. Thus, a larger wall thickness may result in a lower elution rate. The excipient may form a wall having an average thickness of about 0.05 to about 0.5 mm, or about 0.1 mm to about 0.3 mm (e.g. , about 0.1 mm, about 0.2 mm, or about 0.3 mm).

According to one aspect of the present invention, a method of delivering a therapeutically effective amount of an active pharmaceutical ingredient from an implantable drug delivery composition comprises implanting a reservoir-based drug delivery composition into a subject to systemically deliver a therapeutically effective amount of an active pharmaceutical ingredient to the subject at a pseudo-zero order rate for a period of time of at least one month. The drug delivery composition comprises at least one discrete solid dosage form surrounded by an excipient comprising an aromatic polyurethane, and the at least one discrete solid dosage form comprises the active pharmaceutical ingredient or a pharmaceutically acceptable salt thereof. According to particular embodiments, the polymer comprises a substantially non-porous, thermoplastic polymer comprising soft and hard segments, and the relative content of the soft and hard segments preferably provide an elution rate within a target range between a maximum and minimum value of a desired average daily elution rate for the active pharmaceutical ingredient.

Implantation

The drug delivery composition may be implanted into the subject in any suitable area of the subject using any suitable means and techniques known to one of ordinary skill in the art. For example, the composition may be implanted su bcutaneously, e.g. , at the back of the upper arm or the upper back (e.g. in the scapu lar region) . As used herein, the terms "su bcutaneous" or "subcutaneously" or "subcutaneous delivery" means directly depositing in or underneath the skin, a su bcutaneous fat layer, or

intramuscularly. The d rug delivery composition may be delivered subcutaneously using any suitable equipment or techniques. In one embodiment, the drug delivery

composition is placed subcutaneously in the subject's arm . Alternative sites of subcutaneous administration may also be used as long as a pharmaceutically acceptable amou nt of the API wou ld be released into the subject in accordance with the present invention . Preferably, the drug delivery composition should not migrate significantly from the site of implantation . Methods for i mplanting or otherwise positioning the compositions into the body are well known in the art. Removal and/or replacement may also be accomplished using suitable tools and methods known in the art.

Once implanted, the reservoir- based drug delivery composition may systemically deliver a therapeutically effective amount of the API to the subject at a pseudo-zero order rate for a long duration (e.g. , a period of time of at least one month) . As used herein, the term "systemic" or "systemically" refers to the introduction of the API into the circulatory, vascu lar and/or lymphatic system (e.g. , the entire body) . This is in contrast to a localized treatment where the treatment wou ld only be provided to a specific, limited, localized area within the body. Thus, the API is systemically delivered to the subject by implanting the drug delivery composition su bcutaneously into the subject.

According to embodiments of the present invention in which the reservoir-based drug delivery composition comprises lidocaine as the API, the lidocaine may be delivered locally to a specific, limited, or localized area within the body. For example, the drug delivery composition may be subcutaneously implanted in or near an area of the su bject's body where there is localized pain or itch, or in or near the bladder of subjects suffering from interstitial cystitis or overactive bladder. The drug delivery composition may deliver lidocaine locally to the site of pain, itch, interstitial cystitis, or overactive bladder, while also delivering lidocaine systemically. A therapeutically effective amount of the API is delivered to the subject at a pseudo-zero order rate. Pseudo-zero order refers to a zero-order, near-zero order, substantially zero order, or controlled or sustained release of the API. A pseudo-zero order release profile may be characterized by approximating a zero-order release by

5 release of a relatively constant amount of the API per u nit time (e.g. , within about 30% of the average value) . Thus, the composition may initially release an amount of the API that produces the desired therapeutic effect, and gradually and continually release other amounts of the API to maintain the level of therapeutic effect over the intended duration (e.g. , about one year) . In order to maintain a near-constant level of API in the body, lo the API may be released from the composition at a rate that will replace the amou nt of API being metabolized and/or excreted from the body.

Without wishing to be bound to a particular theory, it is believed that the reservoir-based d rug composition works by releasing the API through the excipient membrane or wall . In other words, the active diffuses across the excipient, e.g., as i s depicted in Figu re 1. Thus, sorption 112 of the active occurs from the reservoir onto the rate-controlling excipient 110. The active fully saturates the excipient 110 at steady state, and the active diffuses through the excipient and is then desorbed 114 from the excipient into the su bject at a pseudo-zero order rate.

The therapeutically effective amount of the active may be delivered to the subject

20 at a target range between a maximum value and a minimum value of average daily

elution rate for the API. As used herein, the term "elution rate" refers to a rate of API delivery, which in one embodiment is based on the oral dose rate multiplied by the fractional oral bioavailability, which may be depicted as follows:

Oral Dose X Fractional Oral Bioavailability % = Target Elution Rate (mg/day)

25 The elution rate may be an average rate, e.g. , based on the mean average for a given period of time, such as a day (i .e., average daily elution rate) . Thus, a daily elution rate or average daily elution rate may be expressed as target daily oral dosage multiplied by oral bioavailability. For example, a desired daily dose of 1 mg/day for a drug that has 85% oral bioavailability would expect delivery of about 850 micrograms per day.

₃o The maximu m and minimum values refer to a maximu m average daily elution rate and a minimum average daily elution rate, respectively. The minimu m value required for a pharmaceutically effective dose may be correlated to or determined from a trough value for an oral dosage version of the API (e.g. , based on the blood/plasma concentrations for oral formulations) . Similarly, maximu m value may be correlated to or

35 determined from the peak value for an oral dosage version of the API (e.g. , the

maximu m blood/plasma concentration when an oral dosage is first administered or a pharmaceutically toxic amou nt) . In other words, the target range is a range between maximum and minimum average daily elution rates, respectively, which may be determined based on blood/plasma concentrations for equivalent oral dosage forms containing the same active.

The drug delivery composition is long lasting. In other words, the API is delivered

5 to the subject (e.g. , at a pseudo-zero order rate) for an extended period of time. For example, the API is delivered to the su bject for at least about one month (about one month or greater), at least about three months (about three months or greater), at least about six months (about six months or greater), at least about one year (about one year or greater), at least about two years (about two years or greater) or any period of time lo within those ranges.

Prior to implantation, the drug delivery composition may undergo any suitable processing, such as sterilization (such as by gamma radiation), heat treatment, molding, and the like. Additionally, the drug delivery composition may be conditioned or primed by techniques known in the art. For example, the drug delivery composition may be i s place in a medium (e.g. , an aqueous medium, such as saline) . The mediu m, priming temperature, and time period of priming can be controlled to optimize release of the active upon implantation .

Subcutaneous Delivery Systems and Kits

In one aspect of the present invention, a subcutaneous delivery system comprises

20 a reservoir implant comprising at least one discrete solid dosage form surrou nded by a polymeric rate-controlling excipient comprising an aromatic polyu rethane. The at least one discrete solid dosage form comprises at least one API. The subcutaneous delivery system provides for release of the API at an elution rate suitable to provide a

therapeutically effective amount of the API to a subject at a pseudo-zero order rate for a

25 period of time of at least one month . In another aspect of the present invention, a kit for subcutaneously placing a drug delivery composition comprises a reservoir-based drug delivery composition comprising a polymeric rate-controlling excipient comprising an aromatic polyurethane defining a reservoir containing at least one discrete solid dosage form comprising at least one API; and an implanter for inserting the reservoir- based

30 drug delivery composition beneath the skin .

As discussed above, the drug delivery composition may be implanted into the subject in any su itable area of the su bject using any su itable means and techniques known to one of ordinary skill in the art. For example, the composition may be implanted subcutaneously, e.g. , at the back of the u pper arm, by directly depositing in

35 or underneath the skin, a subcutaneous fat layer, or intramuscularly.

The d rug delivery composition may be delivered su bcutaneously using any suitable equipment or techniques, e.g. , an implanter known to one ordinary skill in the art. The kits may comprise the drug delivery composition pre-loaded into the implanter or the drug delivery composition may be loaded by the doctor or other user. The implanter may be an implantation device, such as a syringe, cannula, trocar or catheter, that may be inserted into an incision made at the delivery site of the subject. Suitable implantation devices and implantation methods include the trocar and methods disclosed in US 7,214,206 and US 7,510,549, the disclosures of which are herein incorporated by reference in their entirety, for all purposes. Other suitable methods for implanting or otherwise positioning the compositions into the body, e.g. , by a doctor, are well known in the art. Removal and/or replacement may also be accomplished using suitable tools and methods known in the art. Kits may also comprise other equipment well known in the art, such as scalpels, clamps, suturing tools, hydration fluid, and the like.

Methods of Treatment

Embodiments of the present invention include methods of treating or preventing one or more diseases or conditions comprising implanting a reservoir-based drug delivery composition into a subject to deliver a therapeutically effective amount of an API to the subject for long periods of time {e.g. , at least one month, at least three months, at least six months, at least one year, etc.). Suitable active pharmaceutical ingredients in accordance with the present invention may include active pharmaceutical ingredients in oral dosage forms where compliance is at issue, where long term treatment is needed, and/or where a steady dose (e.g. , zero order) is required, for example, to minimize side effects. In other words, suitable APIs may be selected for the treatment of diseases and conditions that are long-lasting (e.g. , requiring treatment for many weeks, months or even years). Diseases and conditions may include, but are not limited to, estrogen related disorders (e.g. , breast cancer, short stature in children or adolescents), psychotic disorders (e.g. , schizophrenia, Bipolar disorder), benign prostatic hyperplasia, overactive bladder, Parkinson's disease, smoking cessation, Alzheimer's, Sickle cell anemia, pulmonary arterial hypertension, autoimmune diseases (e.g., multiple sclerosis, Crohn's disease, Lupus), spasticity, osteoporosis, restless legs syndrome, pain, itch, interstitial cystitis, overactive bladder, and the like. The methods of treatment described herein may treat, delay onset, or inhibit recurrence of the disease or condition. A pharmaceutically effective or therapeutic amount of API should be administered sufficient to affect or produce the desired therapy.

Treatment of Estrogen-Related Disorders

Treatment of an estrogen-related disorder or estrogen-receptor disorder may include treatment of any estrogen-related or estrogen-receptor disorders, diseases, or conditions known to one of ordinary skill in the art, such as breast cancer,

endometriosis, uterine fibroids (also called leiomyomas), short stature in children or adolescents and the like. Estrogen-related disorders may include high estrogen levels or normal estrogen levels that need to be reduced . It is intended that a pharmaceutically effective amount of an API would be administered via the drug delivery composition, which will inhibit, or at least partially arrest or partially prevent or suppress estrogen. For example, treatment may include treatment that can suppress or delay the recurrence of breast cancer. For the treatment of estrogen-related disorders, the active may include aromatase inhibitors, such as anastrozole, letrozole, exemestane, etc.

For the case of aromatase inhibitors as the API, releasing an amou nt of aromatase inhibitor effective to inhibit or slow onset or recurrence of an estrogen-related disorder, such as breast cancer (e.g. , lower estrogen levels), is desired . A doctor would be able to determine the efficacy of the treatment (i.e., know the aromatase inhibitor was working to treat breast cancer) using techniques known to one of ordinary skill in the art. For example, one method for assessing the effectiveness of aromatase inhibitor(s) in the treatment of an estrogen-related disorder, such as breast cancer, comprises measu ring mean serum concentrations of estradiol in a su bject over time.

In another embodiment of the present invention, the estrogen-related disorder is short stature in children or adolescents. Estrogens have been found to be important for bone maturation, growth plate fusion, and cessation of longitudinal growth in children and adolescents. For the treatment of short stature, the active may include aromatase inhibitors, such as anastrozole, letrozole, etc. According to preferred embodiments, treating short stature in a child or adolescent (e.g., a male child or adolescent) with an aromatase inhibitor is effective in increasing the predicted adult height of the subject. A su bject's predicted adu lt height can be determined by examining the subject's bone age according to known methods. Following treatment with the aromatase inhibitor, the bone age of the su bject may be examined again to determine if the predicted adult height had increased, which would indicate that the aromatase inhibitor had been effective in increasing the subject's projected adult height. Another method may comprise monitoring the subject's bone age acceleration before, during, and after treatment with an aromatase inhibitor.

According to an embodiment of the present invention, a method for treating an estrogen-related disorder (e.g ., breast cancer, endometriosis, uterine fibroids, short statu re in children, etc. ) comprises implanting a reservoir-based drug delivery composition into a subject to systemically deliver a therapeutically effective amount of an aromatase inhibitor (e.g . , anastrozole, letrozole, etc.) to the subject for a period of time of at least one month (e.g ., at a pseudo-zero order elution rate), wherein the drug delivery composition comprises at least one discrete solid dosage form comprising the aromatase inhibitor or a pharmaceutically acceptable salt thereof surrounded by an excipient comprising an aromatic polyurethane.

Treatment of the Symptoms of a Psychotic Disorder

The treatment of the symptoms of a psychotic disorder (such as schizophrenia, bipolar disorder, or autism) can require long lasting treatment, often on the order of many years, even for the life of the patient. Compliance with antipsychotic medications has also been an ongoing issue. The treatment of a psychotic disorder in accordance with the present invention may be directed to men or women. By "treatment," it is intended that a pharmaceutically effective amount of risperidone would be administered via the drug delivery composition, which will cure, prevent, inhibit, or at least partially arrest or partially prevent or suppress the symptoms of the psychotic disorder. The treatment is particularly effective in that once the implant is administered to the patient, the patient will continue to receive a therapeutically effective dose for the intended duration of the implant (e.g. , one year). This is in contrast to the oral dosage form, which requires compliance by the patient and continued oral administration consistently over the same duration of time.

As used herein, the terms "psychotic disorder" or "psychosis" may be used interchangeably to refer to a disorder in which psychosis is a recognized symptom. The symptoms of psychosis may include, but are not limited to, hallucinations, delusions, paranoia, mania, depression, emotional changes, personality changes, behavioral changes, and lack of awareness of mental changes. The term "antipsychotic" refers to drugs used to treat psychosis. Common conditions for which antipsychotics are prescribed include schizophrenia, mania, and delusional disorders. Antipsychotics also act as mood stabilizers making them suitable for the treatment of bipolar disorder (even when no symptoms of psychosis are present).

The psychotic disorder may include, for example, schizophrenia, bipolar disorder, autism, or any variations thereof. Schizophrenia may include various types including paranoid subtype, disorganized subtype, catatonic subtype, undifferentiated subtype, or residual subtype. For example, the paranoid subtype (also known as paranoid schizophrenia) may include the presence of auditory hallucinations or prominent delusional thoughts about persecution or conspiracy. Bipolar disorder may include different versions including bipolar disorder I, bipolar disorder II, cyclothymic disorder, bipolar disorder not otherwise specified (NOS), or bipolar disorder with rapid cycling. For example, bipolar disorder I may be characterized by at least one manic episode or mixed episode (symptoms of both mania and depression occurring simultaneously), and one or more depressive episodes, that lasts for at least 7 days. Autism includes developmental disorders that appear in the first 3 years of life and affects the brain's normal

development of social and commu nication skills.

For the case of risperidone, releasing an amou nt of risperidone effective to inhibit, stabilize or slow onset or recurrence of psychotic conditions, such as schizophrenia, or symptoms thereof is desired . A doctor would be able to determine the efficacy of the treatment (i .e., know the risperidone was working to treat the psychotic disorder) using techniques known to one of ordinary skill in the art. For example, after a subject has begu n a regimen of risperidone, a clinician may use a rating scale which assesses the psychiatric symptoms of schizophrenia, for example, in order to determine whether there has been an improvement in those symptoms over time. The Brief Psychiatric Rating Scale (BPRS) is a mu lti-item inventory of general psychopathoiogy which may be used to evaluate the effects of risperidone treatment, for example, in a schizophrenia patient. The BPRS psychosis cluster (conceptual disorganization, hallucinatory behavior, suspiciousness, and unusual thought content) is considered a particularly useful subset for assessing schizophrenic patients. Another traditional assessment, the Clinical Global Impression (CGI), reflects the impression of a skilled observer that is fu lly familiar with the manifestations of the psychotic disorder (e.g., schizophrenia), about the overall clinical state of the patient. In addition, the Positive and Negative Syndrome Scale (PANSS) and the Scale for Assessing Negative Symptoms (SANS) may be employed. Improvement in a subject's symptoms, as measu red by a clinician according to any of the aforementioned assessments, or other assessments used in the art to evaluate the symptoms of a psychotic disorder, can be used to indicate whether the amount of risperidone being used is effective.

In one embodiment of the present invention, a method of treating the symptoms of a psychotic disorder comprises implanting a reservoir-based drug delivery composition into a subject to systemically deliver a therapeutically effective amou nt of risperidone or a pharmaceutically acceptable salt thereof to the subject for a period of time of at least one month (e.g ., at a pseudo-zero order elution rate) . The drug delivery composition comprises at least one discrete solid dosage form comprising risperidone or a

pharmaceutically acceptable salt thereof su rrou nded by an excipient comprising an aromatic polyu rethane.

Treatment of Parkinson's Disease

Monoamine oxidase B (MAO-B) inhibitors, such as rasagiline, provide an alternative first-line treatment for the symptoms of Parkinson's disease, or serve as an adju nctive treatment in addition to other drugs, such as levodopa. One mechanism of action of rasagiline is believed to be its MAO-B inhibitory activity, which causes an increase in extracellular levels of dopamine in the brain . Treatment of one or more of the symptoms of Parkinson's disease according to embodiments of the present invention include treatment of one or more symptoms known to one of ordinary skill in the art. Symptoms of Parkinson's disease may include, but are not limited to, motor impairments such as bradykinesia (i.e., slowness of movement), problems with balance, muscular rigidity, postural instability, and/or tremors. Symptoms of Parkinson's disease may also include, but are not limited to, non-motor symptoms, such as bladder and bowel dysfunction, postural hypotension, anxiety, apathy, dementia, depression, psychosis, pain, and/or sleep disturbances.

The treatment of one or more of the symptoms of Parkinson's disease can require long-lasting treatment, often on the order of many years. The treatment of symptom(s) of Parkinson's disease in accordance with the present invention is directed to early or advanced Parkinson's disease, and to monotherapy (i.e., as a subject's only

dopaminergic medication) or adjunctive therapy (i.e., used in addition to (with or after) treatment with one or more other dopaminergic medications, typically levodopa).

By "treatment," it is intended that a pharmaceutically effective amount of rasagiline would be administered via the drug delivery composition, which will inhibit, or at least partially arrest or partially prevent or suppress one or more symptoms of Parkinson's disease. For example, treatment may include treatment that can suppress one or more motor impairments, such as bradykinesia, muscular rigidity, postural instability, and/or tremors. The treatment is particularly effective in that once the implant is administered to the patient, the patient will continue to receive a

therapeutically effective dose for the intended duration of the implant (e.g. , one month, three months, six months, one year, 18 months, two years, 30 months, or more).

The methods of treatment described herein may treat, delay onset, suppress, or inhibit one or more symptoms of Parkinson's disease. A pharmaceutically effective or therapeutic amount of rasagiline should be administered sufficient to effect or produce the desired therapy. For example, releasing an amount of rasagiline effective to inhibit or suppress one or more symptoms of Parkinson's disease (e.g., bradykinesia, tremors, muscular rigidity, and/or postural instability) is desired. A doctor would be able to determine the efficacy of the treatment (i.e., know the rasagiline was working to treat symptoms of Parkinson's disease) using techniques known to one of ordinary skill in the art. For example, after a subject has begun a regimen of rasagiline, a clinician may use a rating scale which assesses the symptoms of Parkinson's disease in order to determine whether there has been an improvement in those symptoms over time. One measure of effectiveness is the Unified Parkinson's Disease Rating Scale (UPDRS). Improvement in a subject's symptoms, as measured by a clinician according to the aforementioned assessment, or other assessments used in the art to evaluate the symptoms of Parkinson's disease, can be used to indicate whether the amount of rasagiiine being used is effective.

According to one aspect of the present invention, a method of treating one or more symptoms of Parkinson's disease comprises implanting a reservoir-based drug 5 delivery composition into a subject to systemically deliver a therapeutically effective amount of rasagiiine to the subject for a period of time of at least one month (e.g., at a pseudo-zero order elution rate). For example, rasagiiine may be administered to treat depression in a subject with Parkinson's disease. The drug delivery composition comprises at least one discrete solid dosage form comprising rasagiiine or a

t o pharmaceutically acceptable salt thereof (e.g., rasagiiine hemitartrate) surrounded by an excipient comprising an aromatic polyurethane.

Treatment of Spasticity

Spasticity is an involuntary tension, stiffening or contractions of muscles, which typically results from an injury to a part of the central nervous system (e.g., brain or

15 spinal cord) that controls voluntary movements and results in increased activity or

excitability in muscles. Spasticity is most often related to cerebral palsy, multiple sclerosis (MS), physical trauma (e.g ., a brain or spinal cord injury), a blockage or bleeding in the brain (e.g., a stroke), or an infection (e.g., meningitis or encephalitis). Symptoms of spasticity, e.g., the involuntary tension, stiffening or contractions of

20 muscles, may range from slight muscle stiffness to permanent shortening of the muscle (contracture). Additional symptoms of spasticity may include, but are not limited to, increased muscle tone, overactive reflexes, involuntary movements that may include spasms (brisk and/or sustained involuntary muscle contractions) or clonus (a series of fast involuntary contractions), pain, decreased functional abilities and delayed motor

25 development, abnormal posture, and contractures (permanent contractions of the

muscle and tendon due to severe persistent stiffness and spasms). Spasticity may be constantly present or event-triggered, and may result in pain that impacts daily life activities.

Tizanidine is an imidazoline central a₂-adrenoceptor agonist that is effective at 30 managing spasticity. Tizanidine is in a class of medications called skeletal muscle

relaxants, and works by slowing action in the brain and nervous system to allow muscles to relax. Treatment of one or more of the symptoms of spasticity according to embodiments of the present invention include treatment of one or more symptoms known to one of ordinary skill in the art, such as those discussed above.

35 By "treatment," it is intended that a pharmaceutically effective amount of

tizanidine would be administered via the drug delivery composition, which will inhibit, or at least partially arrest or partially prevent or suppress one or more symptoms of spasticity. For example, treatment may include treatment that can suppress involuntary tension, stiffening and/or contractions of muscles. The treatment is particularly effective in that once the implant is administered to the patient, the patient will continue to receive a therapeutically effective dose for the intended duration of the implant (e.g. , one month, three months, six months, one year, 18 months, two years, 30 months, or more) .

The methods of treatment described herein may treat, delay onset, suppress, or inhibit one or more symptoms of spasticity. A pharmaceutically effective or therapeutic amou nt of tizanidine should be administered sufficient to effect or produce the desired therapy. For example, releasing an amount of tizanidine effective to inhibit or suppress one or more symptoms of spasticity (e.g . , involuntary tension, stiffening or contraction of muscles) is desired . A doctor wou ld be able to determine the efficacy of the treatment (i.e., know the tizanidine was working to treat symptoms of spasticity) using techniques known to one of ordinary skill in the art. For example, after a subject has begu n a regimen of tizanidine, a clinician may conduct a clinical examination to assess strength and reflexes, using rating scales such as the Ashworth Scale or Modified Ashworth Scale (which provide an objective score of muscle tone based on range of motion) . Alternatively, the clinician may make functional measu rements using assessments such as the Fugl-Meyer Assessment, which provides an objective score based on motor functioning, balance, sensation and joint functioning . Improvement in a su bject's symptoms, as measured by a clinician according to the aforementioned assessments, or other assessments used in the art to evaluate the symptoms of spasticity, can be used to indicate whether the amount of tizanidine being used is effective.

According to one aspect of the present invention, a method of treating one or more symptoms of spasticity comprises implanting a reservoir-based drug delivery composition into a subject to systemically deliver a therapeutically effective amount of tizanidine to the subject for a period of time of at least one month (e.g., at a pseudo- zero order elution rate) . The drug delivery composition comprises at least one discrete solid dosage form comprising tizanidine (e.g . , tizanidine free base) surrounded by an excipient comprising an aromatic polyurethane.

Treatment and Prevention of Osteoporosis and Invasive Breast Cancer

According to embodiments of the present invention, the treatment or prevention of an estrogen-related disorder may include the treatment or prevention of osteoporosis (e.g. , in a post-menopausal woman), or decreasing the risk of invasive breast cancer (e.g. , in a post-menopausal woman, such as a post-menopausal woman with

osteoporosis or a post-menopausal woman with a high risk of developing invasive breast cancer). The binding of raloxifene to estrogen receptors results in the activation of certain estrogenic pathways and the blockade of others. Thus, raloxifene is an estrogen agonist/antagonist.

Raloxifene is currently indicated for the prevention and treatment of osteoporosis in post-menopausal women. Osteoporosis is a condition in which the bones become thin and weak and break easily. By "treatment," it is intended that a pharmaceutically effective amount of raloxifene would be administered via a drug delivery composition of the present invention, which will reverse or stop the progression of osteoporosis, or which will inhibit, or at least partially arrest or partially prevent or suppress the progression of osteoporosis. By "prevention," it is intended that a pharmaceutically effective amount of raloxifene would be administered via a drug delivery composition of the present invention, which will prevent, inhibit, or at least partially arrest or partially prevent or suppress the development of osteoporosis in a subject that has not yet developed or shown signs of osteoporosis.

A doctor would be able to determine the efficacy of the treatment (i.e., know the raloxifene was working to produce the desired therapy) using techniques known to one of ordinary skill in the art. For example, after a subject has begun a regimen of raloxifene to treat osteoporosis, a clinician may conduct a clinical examination to assess reductions in the subject's serum or urine levels of bone turnover markers (e.g., bone- specific alkaline phosphatase, osteocalcin, or collagen breakdown products), decreases in bone resorption based on radiocalcium kinetics studies, increases in bone mineral density (BMD), and/or decreases in the incidence of fractures. A clinician may alternatively use conventional radiography to assess bone density. Improvement in a subject's symptoms, as measured by a clinician according to the aforementioned assessments, or other assessments used in the art to evaluate osteoporosis, can be used to indicate whether the amount of raloxifene being used is effective.

Raloxifene is also indicated for decreasing the risk of developing invasive breast cancer (i.e. , breast cancer that has spread outside of the milk ducts or lobules into surrounding breast tissue) in post-menopausal women who are at a high risk of developing invasive breast cancer, or in post-menopausal women who have

osteoporosis. A patient may have a high risk of breast cancer if she has had at least one abnormal breast biopsy {e.g., a biopsy showing lobular carcinoma in situ or atypical hyperplasia), one or more first-degree relatives (e.g. , a mother, sister, or daughter) with breast cancer, or a 5-year predicted risk of breast cancer > 1.66% (based on the modified Gail model).

According to an embodiment of the present invention, a method for treating or preventing an estrogen-related disorder in a subject comprises decreasing the risk of breast cancer (e.g. , invasive breast cancer) from developing in the subject. In particular embodiments, the subject is a post-menopausal woman, such as a post-menopausal woman with osteoporosis or a post-menopausal woman with a high risk of developing invasive breast cancer. By "decreasing the risk" of invasive breast cancer from developing in a subject, it is intended that a pharmaceutically effective amou nt of raloxifene would be administered via a drug delivery composition of the present invention, which will prevent, inhibit, or at least partially arrest or partially prevent or su ppress the development of invasive breast cancer in a subject that has not developed invasive breast cancer.

According to one aspect of the present invention, a method for treating or preventing osteoporosis, and/or decreasing the risk of invasive breast cancer, comprises implanting a reservoir-based drug delivery composition into a subject (e.g. , a postmenopausal woman) to systemically deliver a therapeutically effective amount of raloxifene to the subject for a period of time of at least one month (e.g ., at a pseudo- zero order elution rate) . The drug delivery composition comprises at least one discrete solid dosage form comprising raloxifene (e.g ., raloxifene free base) surrou nded by an excipient comprising an aromatic polyurethane.

Treatment of Neu rological Disorders

According to embodiments of the present invention, a method for treating one or more symptoms of a neurological disorder in a su bject comprises treating one or more symptoms of Parkinson's disease in the subject {e.g. , idiopathic Parkinson's disease) . In another embodiment, a method for treating one or more symptoms of a neurological disorder in a subject comprises treating one or more symptoms of RLS in the su bject (e.g. , moderate-to-severe primary restless legs syndrome) . Pramipexole is currently indicated for treating the signs and symptoms of Parkinson's disease (e.g. , idiopathic Parkinson's disease) . The mechanism of action of pramipexole as a treatment for Parkinson's disease is believed to be related to its ability to stimulate dopamine receptors in the striatum. Pramipexole is also indicated for treating restless legs syndrome (RLS) (e.g. , moderate-to-severe primary restless legs syndrome). RLS is a neurological disorder that affects the legs (and sometimes arms or other parts of the body) and causes an uncontrollable urge to move them, especially at night and when sitting or lying down, and is usually accompanied by uncomfortable and sometimes painful sensations in the legs.

A doctor would be able to determine the efficacy of the treatment (i .e., know the pramipexole was working to treat symptoms of Parkinson's disease or RLS) using techniques known to one of ordinary skill in the art. One measure of effectiveness is the Unified Parkinson's Disease Rating Scale (UPDRS). As another example, after a subject has begun a regimen of pramipexole, a clinician may use the International RLS Rating Scale (IRLS Scale), which assesses the symptoms of RLS in order to determine whether there has been an improvement in symptoms over time.

According to one aspect of the present invention, a method for treating one or more symptoms of Parkinson's disease or restless legs syndrome comprises implanting a reservoir- based drug delivery composition into a subject to systemically deliver a therapeutically effective amount of pramipexole to the subject for a period of time of at least one month (e.g., at a pseudo-zero order elution rate). The drug delivery

composition comprises at least one discrete solid dosage form comprising pramipexole (e.g., pramipexole free base) surrounded by an excipient comprising an aromatic polyurethane.

Treatment of Pain, Itch, Interstitial Cystitis and Overactive Bladder

The methods, compositions, and kits of the invention can also be used to treat pain, itch, interstitial cystitis and/or overactive bladder resulting from a number of conditions. Lidocaine is a synthetic amide that is well-known for its sedative, analgesic, and cardiac depressant properties. The term "pain" as used herein includes all types of pain. In one embodiment, the pain may be acute or chronic. In another embodiment, the pain may be nociceptive, dysfunctional, idiopathic, neuropathic, somatic, visceral, inflammatory, and/or procedural. The term "itch" refers to all types of itching and stinging sensations that may be localized or generalized, and may be acute, intermittent or persistent. The itch may be idiopathic, allergic, metabolic, infectious, drug-induced, or due to specific disease states due to liver or kidney disease, or cancer.

By "treatment," it is intended that a pharmaceutically effective amount of lidocaine would be administered via a drug delivery composition of the present invention, which will partially or fully suppress, arrest, inhibit, or prevent pain, itch, interstitial cystitis and/or overactive bladder. In one embodiment, the pain, itch, interstitial cystitis or overactive bladder may be eliminated permanently or for a short period of time. In another embodiment, the severity of the pain, itch, interstitial cystitis or overactive bladder may be lessened permanently, or for a short period of time.

According to one aspect of the present invention, a method for treating pain, itch, interstitial cystitis and/or overactive bladder comprises implanting a reservoir-based drug delivery composition into a subject to systemically or locally deliver a

therapeutically effective amount of lidocaine to the subject for a period of time of at least one month (e.g., at a pseudo-zero order elution rate). The drug delivery composition comprises at least one discrete solid dosage form comprising lidocaine (e.g., lidocaine free base) surrounded by an excipient comprising an aromatic polyurethane.

Active Pharmaceutical Ingredients As discussed above, suitable active pharmaceutical ingredients in accordance with the present invention may include active pharmaceutical ingredients in oral dosage forms where compliance is at issue, where long term treatment is needed, and/or where a steady dose (e.g. , zero order) is required, for example, to minimize side effects. In other words, suitable APIs may be selected for the treatment of diseases and conditions that are long-lasting (e.g. , requiring treatment for many weeks, months or even years) . For example, the active pharmaceutical ingredient may be selected from the group consisting of anastrozole, exemestane, dutasteride, oxybutynin, letrozole, selegiline, tolterodine, tizanidine, varenicline, rivastigmine, rasagiline, asenapine, paliperidone, aripiprazole, rotigotine, folic acid, vardenafil, fingolimod, laquinimod, risperidone, nicergoline, guanfacine, raloxifene, pramipexole, lidocaine, histrelin, and

pharmaceutically acceptable salts thereof (e.g. , HCI, tartrate, mesylate, maleate, palmitate, and the like) . According to particular embodiments, the API has a molecular weight that is less than or equal to about 8,000 g/mol, less than or equal to about 4,000 g/mol, less than or equal to about 2,000 g/mol, or less than or equal to about 1 ,000 g/mol . In one embodiment of the present invention, the selected API is hydrophobic.

For the treatment of estrogen-related disorders, the active may include aromatase inhibitors, such as anastrozole, letrozole, exemestane, etc. For the treatment of psychotic disorders including schizophrenia, the active may include risperidone, asenapine (e.g. , asenapine maleate), paliperidone, etc. For the treatment of Bipolar disorder, the active may include risperidone, aripiprazole, etc. For the treatment of benign prostatic hyperplasia, the active may include dutasteride, etc. For the treatment of overactive bladder, the active may include oxybutynin (e.g. , oxybutynin HCI or oxybutynin free base), tolterodine (e.g. , tolterodine tartrate), etc. For the treatment of Parkinson's disease, the active may include monoamine oxidase B inhibitors, such as selegiline (e.g. , selegiline HCI), rasagiline (e.g., rasagiline hemitartrate) , rotigotine, pramipexole (e.g., pramipexole free base), etc. For the treatment of spasticity, the active may include tizanidine (e.g. , tizanidine free base), etc. For smoking cessation, the active may include varenicline (e.g ., varenicline free base), etc. For the treatment of Alzheimer's, the active may include rivastigmine (e.g. , rivastigmine tartrate), etc. For the treatment of sickle cell anemia, the active may include folic acid, etc. For the treatment of pu lmonary arterial hypertension, the active may include vardenafil, etc. For the treatment of autoimmune diseases including multiple sclerosis, Crohn's disease, or Lupus, the active may include fingolimod (e.g. , fingolimod free base), laquinimod, etc. For the treatment or prevention of osteoporosis or invasive breast cancer, the active may include raloxifene (e.g., raloxifene free base) . For the treatment of pain, itch, interstitial cystitis, or overactive bladder the active may include lidocaine (e.g. , lidocaine free base), etc. For the treatment of hormone-related diseases or conditions, such as prostate cancer in men, uterine fibroids in women, or central precocious puberty in children, the active may include histrelin (e.g., histrelin acetate), etc. For the treatment of depression, the active may include selegiline, etc.

Sorption Enhancer(s) and the Discrete Dosage Form

In another aspect of the present invention, the at least one discrete solid dosage form, within the reservoir, may also comprise at least one sorption enhancer in an amount effective to modulate the average daily elution rate of the active pharmaceutical ingredient to provide for release of the active pharmaceutical ingredient at pseudo-zero order within the target range at the therapeutically effective amount for a period of time of at least one month. As used herein, the terms "modulate" or "modulation" may be used to describe a change in the activity of the drug delivery composition. This may equate to a change in elution rate {e.g. , an increase or a decrease in a given elution rate or range) .

Sorption enhancers may include compounds which improve the release of the API from the drug delivery composition. Without wishing to be bound to a particular theory, the sorption enhancers may improve release of the API from the drug delivery composition by drawing water or other fluids into the reservoir from the subject, disintegrating or breaking apart the discrete solid dosage form(s), and/or allowing the API to come into contact or remain in contact the inner walls of the excipient. Such a mechanism may be depicted, for example, in Figure 1.

Any suitable sorption enhancer(s) may be selected by one of ordinary skill in the art. Particularly suitable sorption enhancer(s) may include, for example, negatively- charged polymers, such as croscarmellose sodium, sodium carboxymethyl starch, sodium starch glycolate, sodium acrylic acid derivatives (e.g., sodium polyacrylate), cross-linked polyacrylic acid (e.g., CARBOPOL^®), chondroitin sulfate, poly-glutamic acid, poly-aspartic acid, sodium carboxymethyl cellulose, neutral polymers, such as polyethylene glycol, polyethylene oxide, polyvinylpyrrolidone, and combinations thereof. In an exemplary embodiment, the sorption enhancer is croscarmellose sodium.

According to alternative embodiments, suitable sorption enhancers may include one or more "sugar-based sorption enhancers." Sugar-based sorption enhancers include monosaccharides (e.g., glucose, fructose, galactose, glucosamine, galactosamine, etc.), disaccharides (e.g ., sucrose, lactose, maltose, etc.), and sugar alcohols (preferably formed from monosaccharides or disaccharides, e.g., sorbitol, mannitol, etc.). The sugar-based sorption enhancers may have an acyclic or cyclic structure, and may optionally have one or more modifying groups attached thereto (e.g., carbonyl groups, methyl groups, acyl groups, etc.). According to particular embodiments, sugar-based sorption enhancers may also include oligosaccharides (i.e., sugars having from three to ten monosaccharide units bonded together) .

According to particular embodiments, the sugar-based sorption enhancers are selected from the group consisting of monosaccharides, disaccharides, oligosaccharides, sugar alcohols, and combinations thereof. For example, the one or more sugar-based sorption enhancers may be selected from the group consisting of monosaccharides, disaccharides, sugar alcohols formed from monosaccharides or disaccharides, and combinations thereof. According to one embodiment, the one or more sugar-based sorption enhancers are selected from the group consisting of glucosamine, sucrose, lactose, sorbitol, and combinations thereof. For example, the one or more sugar-based sorption enhancers may comprise or consist of glucosamine.

According to alternative embodiments, suitable sorption enhancers may include one or more "non-polymeric sorption enhancers." Non-polymeric sorption enhancers include non-polymeric acids, bases, and salts. According to particular embodiments, non-polymeric sorption enhancers include amino acids and salts thereof (e.g., arginine and salts thereof, glutamic acid and salts thereof, such as glutamic acid monosodium salt, etc.); citric acid and salts thereof (e.g., sodium citrate) ; salts of tartaric acid, gluconic acid, acetic acid, ascorbic acid, and/or boric acid; and/or polyamino carboxylic acids and salts thereof (e.g., ethylenediaminetetraacetic acid (EDTA)). According to one embodiment, the one or more non-polymeric sorption enhancers are selected from the group consisting of glutamic acid monosodium salt, sodium gluconate,

ethylenediaminetetraacetic acid (EDTA), potassium sulfate, citric acid, sodium acetate, sodium ascorbate, sodium borate, sodium citrate, arginine, tromethamine, sodium bitartrate, and combinations thereof.

According to a particular embodiment, the one or more non-polymeric sorption enhancers comprise or consist of one or more polyamino carboxylic acids or salts thereof, such as ethylenediaminetetraacetic acid (EDTA). According to another embodiment, the one or more non-polymeric sorption enhancers comprise or consist of one or more salts of ascorbic acid, such as sodium ascorbate.

The average molecular weights of the non-polymeric sorption enhancers used in embodiments of the present invention are not particularly limited, but are preferably less than about 400 g/mol, or less than about 300 g/mol. According to particular

embodiments, the average molecular weights of the non-polymeric sorption enhancers range from about 50 g/mol to about 400 g/mol, from about 70 g/mol to about 350 g/mol, or from about 100 g/mol to about 300 g/mol.

The amount of the sorption enhancer is not particularly limited, but may be on the order of about 0-25 of the solid dosage form, about 1-25 wt% of the solid dosage form, about 2-20 wt% of the solid dosage form, about 2- 12 wt% of the solid dosage form, about 5- 10 wt% of the solid dosage form (e.g. , about 5 wt% or about 10 wt% of the solid dosage form).

The selection of the specific sorption enhancer may have an impact on the elution rate. For example, a higher weight percent of sorption enhancer in the composition may result in a higher average elution rate than a smaller weight percentage. Thus, it may be preferable to include a higher weight percent of sorption enhancer to give a higher elution rate (e.g. , about 8-25 wt% or about 10-20 wt%) .

embodiment of the present invention, the at least one discrete solid dosage form comprises: 75-97 wt% API based on the total weight of the at least one discrete solid dosage form ; 1-25 wt% of at least one sorption enhancer based on the total weight of the at least one discrete solid dosage form ; and 0-5 wt% lu bricant based on the total weight of the at least one discrete solid dosage form. For example, 85-95 wt% (e.g. , about 88 wt%) API based on the total weight of the at least one discrete solid dosage form ; 5-20 wt% (e.g. , about 10 wt%) of at least one sorption enhancer (e.g. , croscarmellose sodium) based on the total weight of the at least one discrete solid dosage form ; and 0-5 wt% (e.g. , 2%) lubricant (e.g. , stearic acid) based on the total weight of the at least one discrete solid dosage form. In another example, the at least one discrete solid dosage form comprises about 89.25% API, about 10% of at least one sorption enhancer (e.g. , croscarmellose sodium), and about 0.75% lubricant (e.g. , magnesium stearate) . Preferably, each component of the drug delivery composition is provided in an amount effective for the treatment of the disease or condition being treated .

The therapeutically effective amount of the API may be delivered to the su bject at a target range of average daily elution rate for the API. The target elution rate (mg/day) is based on the oral dose rate multiplied by the fractional oral bioavailability. The elution rate may be an average rate, e.g. , based on the mean average for a given period of time, such as a day (i .e. , average daily elution rate). The average daily elution rate of the active pharmaceutical ingredient may vary in direct proportion to the amount of sorption enhancer in the drug delivery composition (e.g. , more sorption enhancer may provide for a higher average daily elution rate) . According to another aspect of the present invention, two or more sorption enhancers which produce different average daily elution rates in a given implant if used alone can be combined to achieve a single desired elution rate. For example, a polymeric, non-polymeric or sugar-based sorption enhancer which produces a first average daily elution rate in a given implant when used alone can be combined with a polymeric, non-polymeric or sugar-based sorption enhancer which produces a second average daily elution rate in a given implant when used alone (wherein the second average daily elution rate is less than the first average daily elution rate) to produce an average daily elution rate that is intermediate between the first and second average daily elution rates.

The number and shape of the discrete dosage form(s) may be optimized to provide for the desired elution rates. For example, the discrete solid dosage forms may be of suitable shape to not fill the entire cavity of the reservoir. In one embodiment, the at least one discrete dosage form is substantially spherical in shape in that the solid dosage forms are spherical or nearly spherical. For example, the shape of the dosage form may not deviate from a perfect sphere by more than about 10%. The number of discrete dosage forms may be selected to provide a given elution rate. The discrete solid dosage forms may comprise more than one pellet (e.g. , 2-9 pellets). The number of discrete solid dosage forms may be directly proportional or related to the elution rate. In other words, a higher number of dosage forms may result in a higher average elution rate than a smaller number of dosage forms. Thus, it may be preferable to include more discrete solid dosage forms to give a higher elution rate (e.g. , 7-9 pellets).

Drug Delivery Compositions, Subcutaneous Delivery Systems, and Kits

As previously noted, the drug delivery composition is long lasting, and the API may be delivered to the subject at a pseudo-zero order rate for an extended period of time (e.g. , at least about one month (about one month or greater), at least about three months (about three months or greater), at least about six months (about six months or greater), at least about one year (about one year or greater), or any period of time within those ranges).

According to one embodiment of the present invention, a subcutaneous delivery system for releasing an active pharmaceutical ingredient at a pseudo-zero order comprises a reservoir implant comprising a rate-controlling aromatic polyurethane excipient defining a reservoir. The reservoir contains at least one discrete solid dosage form comprising the active pharmaceutical ingredient or a pharmaceutically acceptable salt thereof and an effective amount of at least one sorption enhancer to modulate the elution rate of the active pharmaceutical ingredient for release of a therapeutically effective amount of the active pharmaceutical ingredient within the target range at pseudo-zero order for a period of time of at least one month . The amount of sorption enhancer may be directly proportional to the average daily elution rate.

The drug delivery composition may be implanted into the subject in any suitable area of the subject using any suitable means and techniques known to one of ordinary skill in the art. For example, the composition may be implanted subcutaneously, e.g. , at the back of the u pper arm or in the u pper back (e.g. , scapu lar region), by directly depositing in or underneath the skin, a subcutaneous fat layer, or intramuscularly.

According to another embodiment of the present invention, a kit for

subcutaneously placing a drug delivery composition includes a reservoir-based drug delivery composition comprising a rate-controlling aromatic polyurethane excipient defining a reservoir containing at least one discrete solid dosage form and an implanter for inserting the reservoir-based drug delivery composition beneath the skin, and optionally instructions for implantation and explantation of the drug delivery

composition . The rate-controlling excipient comprises soft and hard segments and the relative content of soft and hard segments of the polymer are selected to obtain an elution rate within a target range of average daily elution rate for the active

pharmaceutical ingredient. The at least one discrete solid dosage form comprises an active pharmaceutical ingredient or a pharmaceutically acceptable salt thereof and at least one sorption enhancer in an amount effective to modu late the elution rate of the active pharmaceutical ingredient to provide for release of the active pharmaceutical ingredient at pseudo-zero order within the target range at the therapeutically effective amount for a period of time of at least one month, and the amount of sorption enhancer may be directly proportional to the average daily elution rate.

The drug delivery composition may be delivered subcutaneously using any suitable equipment or techniques, e.g. , an implanter known to one ordinary skill in the art. The kits may comprise the drug delivery composition pre-loaded into the implanter or the drug delivery composition may be loaded by the doctor or other user. The implanter may be an implantation device, such as a syringe, cannula, trocar or catheter, that may be inserted into an incision made at the delivery site of the su bject. Suitable implantation devices and implantation methods include the trocar and methods disclosed in US 7,214,206 and US 7,510,549, the disclosures of which are herein incorporated by reference in their entirety, for all purposes. Other su itable methods for implanting or otherwise positioning the compositions into the body, e.g. , by a doctor, are well known in the art. Removal and/or replacement may also be accomplished using suitable tools and methods known in the art. Kits may also comprise other equipment well known in the art, such as scalpels, clamps, sutu ring tools, hydration fluid, and the like. EXAMPLES

Embodiments of the present invention may be further understood by reference to the Examples provided below.

Example 1: Manufacturing of Drug Implants

Tubing was received in continuous length rolls and was cut to an appropriate starting length using a single-edged razor blade (or suitably sized scalpel). One end of each tubing section was thermally sealed imparting a semi-spherical closure on the tip of the tubing section.

The API and an sorption enhancer, e.g. croscarmellose sodium, were premixed in a Turbula blender. Stearic acid was added as a lubricant and the mixture was again mixed in a Turbula blender. The standard drug blend was 88% API, 10% sorption enhancer, and 2% stearic acid.

The drug blend was compacted using a single punch tablet press. Drug pellets were manually placed inside each sealed section of tubing. The open section of each pellet-containing tubing section was then sealed into a semi-spherical seal. Sterilization was accomplished by gamma irradiation of the implants.

Example 2: Risperidone Implants Comprising Aromatic Polvurethane

Drug containing pellets were manufactured as described in Example 1. Nine pellets of the risperidone blend were placed into various polyurethane tubings of 4 mm diameter and 0.2 mm wall thickness for a total of about 480 mg risperidone per implant. The aromatic polyurethane tubing comprised poly(tetramethylene oxide) (PTMO) as the soft segment and polymerized methylene diphenyl diisocyanate (MDI) and 1,4- butanediol as the hard segment. The aliphatic polyurethane tubing comprised poly(tetramethylene oxide) (PTMO) as the soft segment and polymerized 4,4'- diisocyanato dicyclohexylmethane (HMDI) and 1,4-butanediol as the hard segment. The total length of each implant was about 55 mm. The implants were sterilized by gamma irradiation and placed in an elution bath consisting of 200 mL saline at 37 °C. Weekly exchanges of the elution media were analyzed by HPLC for 17 weeks. The release graph is shown in Figure 4. As can be seen in Figure 4, risperidone was released from both the "aromatic" and "aliphatic" polyurethane tubings at pseudo-zero order for multiple weeks. The aromatic hard segment/soft segment PTMO with a molecular weight of about 2,000 daltons provided substantially equivalent release rates as the compositionaily equivalent aliphatic tubing (aliphatic hard segment/soft segment PTMO with a molecular weight of about 2,000 daltons). A higher molecular weight PTMO soft segment (about 2,900 daltons) released risperidone at a higher daily rate.

Example 3: Paiiperidone Implants Comprising Aromatic Polvurethane Drug containing pellets were manufactured as described in Example 1. Nine pellets of the paliperidone blend were placed into various polyurethane tubings of 4 mm diameter and 0.2 mm wall thickness for a total of about 400 mg paliperidone per implant. The aromatic polyurethane tubing comprised poly(tetramethylene oxide) (PTMO) as the soft segment and polymerized methylene diphenyl diisocyanate (MDI) and 1,4-butanediol as the hard segment. The aliphatic polyurethane tubing comprised poly(tetramethylene oxide) (PTMO) as the soft segment and polymerized 4,4'- diisocyanato dicyclohexylmethane (HMDI) and 1,4-butanediol as the hard segment. The total length of each implant was about 55 mm. The implants were sterilized by gamma irradiation and placed in an elution bath consisting of 200 imL saline at 37 °C. Weekly exchanges of the elution media were analyzed by HPLC for 9 weeks. The release graph is shown in Figure 5. As can be seen in Figure 5, paliperidone was released from both the "aromatic" and "aliphatic" polyurethane tubings at pseudo-zero order for multiple weeks. The soft segment PTMO with a molecular weight of about 2,900 daltons provided higher release rates than the compositionally equivalent soft segment tubing with PTMO having a molecular weight of about 2,000 daltons.

Although the invention is illustrated and described herein with reference to specific embodiments, the invention is not intended to be limited to the details shown. Rather, various modifications may be made in the details within the scope and range of equivalents of the claims and without departing from the invention.

Claims

What is claimed is:

1) A drug delivery composition comprising :

a drug elution rate-controlling excipient comprising a thermoplastic polymer defining a reservoir, wherein :

the thermoplastic polymer comprises an aromatic polyurethane, the reservoir contains at least one discrete solid dosage form comprising at least one active pharmaceutical ingredient (API), and

the drug delivery composition is in an implantable dosage form.

2) The drug delivery composition according to claim 1, wherein the aromatic polyurethane comprises aromatic diisocyanates.

3) The drug delivery composition according to claim 2, wherein the aromatic diisocyanates are selected from the group consisting of methylene diphenyl diisocyanate (MDI), toluene diisocyanate (TDI), p-phenylene diisocyanate (PPDI), naphthalene diisocyanate (NDI), and combinations thereof.

4) The drug delivery composition according to claim 1, wherein the aromatic polyurethane comprises poly(tetramethylene oxide) (PTMO) and polymerized methylene diphenyl diisocyanate (MDI) and 1,4-butanediol.

5) The drug delivery composition according to claim 4, wherein the PTMO has an average molecular weight between about 500 daltons to about 5,000 daltons.

6) The drug delivery composition according to claim 4, wherein the PTMO has an average molecular weight between about 1,500 daltons to about 3,500 daltons.

7) The drug delivery composition according to claim 4, wherein the PTMO has an average molecular weight between about 2,000 daltons to about 3,000 daltons.

8) The drug delivery composition according to claim 1, wherein the aromatic polyurethane comprises soft segments and hard segments.

9) The drug delivery composition according to claim 8, wherein the hard segments comprise aromatic diisocyanates.

10) The drug delivery composition according to claim 9, wherein the aromatic diisocyanates are selected from the group consisting of methylene diphenyl diisocyanate (MDI), toluene diisocyanate (TDI), p-phenylene diisocyanate (PPDI), naphthalene diisocyanate (NDI), and combinations thereof.

11) The drug delivery composition according to claim 8, wherein the soft segments are derived from polyethers, polycarbonates, or polysilicones.

12) The drug delivery composition according to claim 8, wherein the soft segments are selected from the group consisting of poly(tetramethylene oxide) (PTMO), polyethylene glycol (PEG), poly(propylene oxide) (PPO), poly(hexamethylene oxide), and combinations thereof. 13) The drug delivery composition according to claim 8, wherein the soft segments have an average molecular weight between about 500 Daltons to about 5,000 Daltons.

14) The drug delivery composition according to claim 13, wherein the soft 5 segments comprise poly(tetramethylene oxide) (PTMO).

15) The drug delivery composition according to claim 1, wherein the at least one API is selected from the group consisting of anastrozole, exemestane, dutasteride, oxybutynin, letrozole, selegiline, tolterodine, tizanidine, varenicline, rivastigmine, rasagiline, asenapine, paliperidone, aripiprazole, rotigotine, folic acid, vardenafil, lo fingolimod, laquinimod, risperidone, nicergoline, guanfacine, raloxifene, pramipexole, lidocaine, histrelin, and pharmaceutically acceptable salts thereof.

16) The drug delivery composition according to claim 1, wherein the at least one discrete solid dosage form comprises at least one sorption enhancer.

17) The drug delivery composition according to claim 16, wherein the at least i s one sorption enhancer is selected from the group consisting of croscarmellose sodium, sodium carboxymethyl starch, sodium starch glycolate, sodium acrylic acid derivatives, cross-linked polyacrylic acid, chondroitin sulfate, poly-glutamic acid, poly-aspartic acid, sodium carboxymethyl cellulose, polyethylene glycol, polyethylene oxide,

polyvinylpyrrolidone, and combinations thereof.

2o 18) The drug delivery composition according to claim 16, wherein the at least one sorption enhancer comprises one or more sugar-based sorption enhancers.

19) The drug delivery composition according to claim 16, wherein the at least one sorption enhancer comprises one or more non-polymeric sorption enhancers.

20) The drug delivery composition according to claim 1, wherein the at least 25 one discrete solid dosage form comprises:

75-100 wt% API based on the total weight of the at least one discrete solid dosage form;

0- 25 wt% of at least one sorption enhancer based on the total weight of the at least one discrete solid dosage form; and

30 0-5 wt% lubricant based on the total weight of the at least one discrete solid dosage form.

21) The drug delivery composition according to claim 1, wherein the at least one discrete solid dosage form comprises:

75-97 wt% API based on the total weight of the at least one discrete solid dosage

35 form;

1- 25 wt% of at least one sorption enhancer based on the total weight of the at least one discrete solid dosage form; and 0-5 wt% lubricant based on the total weight of the at least one discrete solid dosage form.

22) The drug delivery composition according to claim 1, wherein the API has a molecular weight that is less than or equal to about 8,000 g/mol.

23) A method of delivering a therapeutically effective amount of an active pharmaceutical ingredient (API) from an implantable drug delivery composition comprising :

implanting a reservoir-based drug delivery composition into a subject to systemically deliver a therapeutically effective amount of the API to the subject at a pseudo-zero order rate for a period of time of at least one month,

wherein the drug delivery composition comprises at least one discrete solid dosage form surrounded by an excipient comprising an aromatic polyurethane, the at least one discrete solid dosage form comprising the API.

24) The method according to claim 23, wherein the API is selected from the group consisting of anastrozole, exemestane, dutasteride, oxybutynin, letrozole, selegiline, tolterodine, tizanidine, varenicline, rivastigmine, rasagiline, asenapine, paliperidone, aripiprazole, rotigotine, folic acid, vardenafil, fingolimod, laquinimod, risperidone, nicergoline, guanfacine, raloxifene, pramipexole, lidocaine, histrelin, and pharmaceutically acceptable salts thereof.

25) The method according to claim 23, wherein the aromatic polyurethane comprises aromatic diisocyanates.

26) The method according to claim 25, wherein the aromatic diisocyanates are selected from the group consisting of methylene diphenyl diisocyanate (MDI), toluene diisocyanate (TDI), p-phenylene diisocyanate (PPDI), naphthalene diisocyanate (IMDI), and combinations thereof.

27) The method according to claim 23, wherein the aromatic polyurethane comprises poly(tetramethylene oxide) (PTMO) and polymerized methylene diphenyl diisocyanate (MDI) and 1,4-butanediol.

28) The method according to claim 27, wherein the PTMO has an average molecular weight between about 500 daltons to about 5,000 daltons.

29) The method according to claim 23, wherein the aromatic polyurethane comprises soft segments and hard segments, wherein the hard segments comprise aromatic diisocyanates.

30) The method according to claim 29, wherein the aromatic diisocyanates are selected from the group consisting of methylene diphenyl diisocyanate (MDI), toluene diisocyanate (TDI), p-phenylene diisocyanate (PPDI), naphthalene diisocyanate (NDI), and combinations thereof. 31) The method according to claim 29, wherein the soft segments are derived from polyethers, polycarbonates, or polysilicones.

32) The method according to claim 29, wherein the soft segments have an average molecular weight between about 500 Daltons to about 5,000 Daltons.

33) The method according to claim 32, wherein the soft segments comprise poly(tetramethylene oxide) (PTMO).

34) The method according to claim 23, wherein the at least one discrete solid dosage form comprises at least one sorption enhancer,

35) The method according to claim 34, wherein the at least one sorption enhancer is selected from the group consisting of croscarmellose sodium, sodium carboxymethyl starch, sodium starch glycolate, sodium acrylic acid derivatives, cross- linked polyacrylic acid, chondroitin sulfate, poly-glutamic acid, poly-aspartic acid, sodium carboxymethyl cellulose, polyethylene glycol, polyethylene oxide, polyvinylpyrrolidone, and combinations thereof,

36) The drug delivery composition according to claim 34, wherein the at least one sorption enhancer comprises one or more sugar-based sorption enhancers.

37) The drug delivery composition according to claim 34, wherein the at least one sorption enhancer comprises one or more non-polymeric sorption enhancers.

38) The method according to claim 23, wherein the at least one discrete solid dosage form comprises:

75-97 wt% API based on the total weight of the at least one discrete solid dosage form;

1-25 wt% of at least one sorption enhancer based on the total weight of the at least one discrete solid dosage form; and

0- 5 wt% lubricant based on the total weight of the at least one discrete solid dosage form.

39) The method according to claim 23, wherein the API has a molecular weight that is less than or equal to about 8,000 g/mol.

40) A method of treating or preventing a disease or condition in a subject comprising :

implanting a reservoir-based drug delivery composition into a subject to systemically deliver an API to the subject for a period of time of at least one month at a pseudo-zero order elution rate,

wherein the drug delivery composition comprises at least one discrete solid dosage form comprising the API surrounded by an excipient comprising at least one aromatic polyurethane, wherein the drug delivery composition is therapeutically effective to treat or prevent the disease or condition.

41) The method according to claim 40, wherein the disease or condition is an estrogen-related disorder and the API is an aromatase inhibitor.

42) The method according to claim 41, wherein the aromatase inhibitor is anastrozole, letrozole, exemestane, or a pharmaceutically acceptable salt thereof.

43) The method according to claim 42, wherein the estrogen-related disorder is breast cancer, endometriosis, uterine fibroids, or short stature in children.

44) The method according to claim 40, wherein the disease or condition is a psychotic disorder and the API is risperidone or a pharmaceutically acceptable salt thereof.

45) The method according to claim 44, wherein the psychotic disorder is schizophrenia, bipolar disorder, or autism.

46) The method according to claim 40, wherein the disease or condition is Parkinson's disease and the API is rasagiline or a pharmaceutically acceptable salt thereof.

47) The method according to claim 40, wherein the disease or condition is depression in a subject with Parkinson's disease and the API is rasagiline or a

pharmaceutically acceptable salt thereof.

48) The method according to claim 40, wherein the disease or condition is spasticity and the API is tizanidine or a pharmaceutically acceptable salt thereof.

49) The method according to claim 40, wherein the disease or condition is osteoporosis or invasive breast cancer in a post-menopausal woman, and the API is raloxifene or a pharmaceutically acceptable salt thereof.

50) The method according to claim 40, wherein the disease or condition is

Parkinson's disease and the API is pramipexole or a pharmaceutically acceptable salt thereof.

51) The method according to claim 40, wherein the disease or condition is restless legs syndrome and the API is pramipexole or a pharmaceutically acceptable salt thereof.

52) The method according to claim 40, wherein the disease or condition is pain, itch, interstitial cystitis, or overactive bladder, and the API is lidocaine or a pharmaceutically acceptable salt thereof.

53) The method according to claim 40, wherein the disease or condition is prostate cancer, uterine fibroids, or central precocious puberty, and the API is histrelin or a pharmaceutically acceptable salt thereof. 54) The method according to claim 40, wherein the disease or condition is depression, and the API is selegiline or a pharmaceutically acceptable salt thereof.

55) The method according to claim 40, wherein the aromatic polyurethane comprises aromatic diisocyanates.

56) The method according to claim 55, wherein the aromatic diisocyanates are selected from the group consisting of methylene diphenyl diisocyanate (MDI), toluene diisocyanate (TDI), p-phenylene diisocyanate (PPDI), naphthalene diisocyanate (NDI), and combinations thereof.

57) The method according to claim 40, wherein the aromatic polyurethane comprises poly(tetramethylene oxide) (PT O) and polymerized methylene diphenyl diisocyanate (MDI) and 1,4-butanediol.

58) The method according to claim 57, wherein the PTMO has an average molecular weight between about 500 daltons to about 5,000 daltons.

59) The method according to claim 40, wherein the aromatic polyurethane comprises soft segments and hard segments, wherein the hard segments comprise aromatic diisocyanates.

60) The method according to claim 59, wherein the aromatic diisocyanates are selected from the group consisting of methylene diphenyl diisocyanate (MDI), toluene diisocyanate (TDI), p-phenylene diisocyanate (PPDI), naphthalene diisocyanate (NDI), and combinations thereof.

61) The method according to claim 59, wherein the soft segments are derived from polyethers, polycarbonates, or poiysilicones.

62) The method according to claim 61, wherein the soft segments have an average molecular weight between about 500 Daltons to about 5,000 Daltons.

63) The method according to claim 59, wherein the soft segments comprise poly(tetramethylene oxide) (PTMO).

64) The method according to claim 40, wherein the at least one discrete solid dosage form comprises at least one sorption enhancer.

65) The method according to claim 64, wherein the at least one sorption enhancer is selected from the group consisting of croscarmellose sodium, sodium carboxymethyl starch, sodium starch giycolate, sodium acrylic acid derivatives, cross- linked polyacrylic acid, chondroitin sulfate, poly-glutamic acid, poly-aspartic acid, sodium carboxymethyl cellulose, polyethylene glycol, polyethylene oxide, polyvinylpyrrolidone, and combinations thereof.

66) The method according to claim 64, wherein the at least one sorption enhancer comprises one or more sugar-based sorption enhancers. 67) The method according to claim 64, wherein the at least one sorption enhancer comprises one or more non-polymeric sorption enhancers.

68) The method according to claim 40, wherein the at least one discrete solid dosage form comprises:

5 75-97 wt% API based on the total weight of the at least one discrete solid dosage form;

0-5 wt% lubricant based on the total weight of the at least one discrete solido dosage form,

69) The method according to claim 40, wherein the API has a molecular weight that is less than or equal to about 8,000 g/mol.

70) The method according to claim 40, wherein the API is selected from the group consisting of anastrozole, exemestane, dutasteride, oxybutynin, letrozole,s selegiline, tolterodine, tizanidine, varenicline, rivastigmine, rasagiline, asenapine,

paliperidone, aripiprazole, rotigotine, folic acid, vardenafil, fingolimod, laquinimod, risperidone, nicergoline, guanfacine, raloxifene, pramipexole, Iidocaine, histrelin, and pharmaceutically acceptable salts thereof.

71) A subcutaneous delivery system comprising :

o a thermoplastic reservoir implant comprising at least one discrete solid dosage form surrounded by a polymeric rate-controlling excipient comprising an aromatic polyurethane,

the at least one discrete solid dosage form comprising at least one active pharmaceutical ingredient (API),

5 wherein the subcutaneous delivery system provides for release of the API at an elution rate suitable to provide a therapeutically effective amount of the API to a subject at a pseudo-zero order rate for a period of time of at least one month.

72) The subcutaneous delivery system according to claim 71, wherein the aromatic polyurethane comprises aromatic diisocyanates.

o 73) The subcutaneous delivery system according to claim 72, wherein the aromatic diisocyanates are selected from the group consisting of methylene diphenyl diisocyanate (MDI), toluene diisocyanate (TDI), p-phenylene diisocyanate (PPDI), naphthalene diisocyanate (NDI), and combinations thereof.

74) The subcutaneous delivery system according to claim 71, wherein the5 aromatic polyurethane comprises poly(tetramethylene oxide) (PTMO) and polymerized methylene diphenyl diisocyanate (MDI) and 1,4-butanediol. 75) The subcutaneous delivery system according to claim 74, wherein the PTMO has an average molecular weight between about 500 daltons to about 5,000 daltons.

76) The subcutaneous delivery system according to claim 71, wherein the aromatic polyurethane comprises soft segments and hard segments, wherein the hard segments comprise aromatic diisocyanates.

77) The subcutaneous delivery system according to claim 76, wherein the aromatic diisocyanates are selected from the group consisting of methylene diphenyl diisocyanate ( DI), toluene diisocyanate (TDI), p-phenylene diisocyanate (PPDI), naphthalene diisocyanate (NDI), and combinations thereof.

78) The subcutaneous delivery system according to claim 76, wherein the soft segments are derived from polyethers, polycarbonates, or polysilicones.

79) The subcutaneous delivery system according to claim 76, wherein the soft segments have an average molecular weight between about 500 Daltons to about 5,000 Daltons.

80) The subcutaneous delivery system according to claim 76, wherein the soft segments comprise poly(tetramethylene oxide) (PTMO).

81) The subcutaneous delivery system according to claim 71, wherein the at least one discrete solid dosage form comprises at least one sorption enhancer.

82) The subcutaneous delivery system according to claim 81, wherein the at least one sorption enhancer is selected from the group consisting of croscarmellose sodium, sodium carboxymethyl starch, sodium starch glycolate, sodium acrylic acid derivatives, cross-linked polyacrylic acid, chondroitin sulfate, poly-glutamic acid, poly- aspartic acid, sodium carboxymethyl cellulose, polyethylene glycol, polyethylene oxide, polyvinylpyrrolidone, and combinations thereof.

83) The subcutaneous delivery system according to claim 81, wherein the at least one sorption enhancer comprises one or more sugar-based sorption enhancers.

84) The subcutaneous delivery system according to claim 81, wherein the at least one sorption enhancer comprises one or more non-polymeric sorption enhancers.

85) The subcutaneous delivery system according to claim 71, wherein the at least one discrete solid dosage form comprises:

0-5 wt% lubricant based on the total weight of the at least one discrete solid dosage form. 86) The subcutaneous delivery system according to claim 71, wherein the API has a molecular weight that is less than or equal to about 8,000 g/mol.

87) The subcutaneous delivery system according to claim 71, wherein the API is selected from the group consisting of anastrozole, exemestane, dutasteride, oxybutynin, letrozole, selegiline, tolterodine, tizanidine, varenicline, rivastigmine, rasagiline, asenapine, paliperidone, aripiprazole, rotigotine, folic acid, vardenafil, fingolimod, laquinimod, risperidone, nicergoline, guanfacine, raloxifene, pramipexole, lidocaine, histrelin, and pharmaceutically acceptable salts thereof.

88) A kit for subcutaneously placing a drug delivery composition comprising : a reservoir-based drug delivery composition comprising a rate-controlling excipient defining a reservoir containing at least one discrete solid dosage form comprising an API,

wherein the rate-controlling excipient comprises an aromatic polyurethane; and an implanter for inserting the reservoir-based drug delivery composition beneath the skin.

89) The kit according to claim 88, wherein the aromatic polyurethane comprises aromatic diisocyanates.

90) The kit according to claim 89, wherein the aromatic diisocyanates are selected from the group consisting of methylene diphenyl diisocyanate (MDI), toluene diisocyanate (TDI), p-phenylene diisocyanate (PPDI), naphthalene diisocyanate (NDI), and combinations thereof.

91) The kit according to claim 88, wherein the aromatic polyurethane comprises poly(tetramethylene oxide) (PTMO) and polymerized methylene diphenyl diisocyanate (MDI) and 1,4-butanediol.

92) The kit according to claim 91, wherein the PTMO has an average molecular weight between about 500 daltons to about 5,000 daltons.

93) The kit according to claim 88, wherein the aromatic polyurethane comprises soft segments and hard segments, wherein the hard segments comprise aromatic diisocyanates.

94) The kit according to claim 93, wherein the aromatic diisocyanates are selected from the group consisting of methylene diphenyl diisocyanate (MDI), toluene diisocyanate (TDI), p-phenylene diisocyanate (PPDI), naphthalene diisocyanate (NDI), and combinations thereof.

95) The kit according to claim 93, wherein the soft segments are derived from polyethers, polycarbonates, or polysilicones.

96) The kit according to claim 93, wherein the soft segments have an average molecular weight between about 500 Daltons to about 5,000 Daltons. 97) The kit according to claim 93, wherein the soft segments comprise poly(tetramethylene oxide) (PTMO).

98) The kit according to claim 88, wherein the at least one discrete solid dosage form comprises at least one sorption enhancer.

99) The kit according to claim 98, wherein the at least one sorption enhancer is selected from the group consisting of croscarmellose sodium, sodium carboxymethyl starch, sodium starch glycolate, sodium acrylic acid derivatives, cross-linked polyacrylic acid, chondroitin sulfate, poly-glutamic acid, poly-aspartic acid, sodium carboxymethyl cellulose, polyethylene glycol, polyethylene oxide, polyvinylpyrrolidone, and

combinations thereof.

100) The kit according to claim 98, wherein the at least one sorption enhancer comprises one or more sugar-based sorption enhancers.

101) The kit according to claim 98, wherein the at least one sorption enhancer comprises one or more non-polymeric sorption enhancers.

102) The kit according to claim 88, wherein the at least one discrete solid dosage form comprises:

0-5 wt% lubricant based on the total weight of the at least one discrete solid dosage form.

103) The kit according to claim 88, wherein the API has a molecular weight that is less than or equal to about 8,000 g/mol.

104) The kit according to claim 88, wherein the API is selected from the group consisting of anastrozole, exemestane, dutasteride, oxybutynin, letrozole, selegiline, tolterodine, tizanidine, varenicline, rivastigmine, rasagiline, asenapine, paliperidone, aripiprazole, rotigotine, folic acid, vardenafil, fingolimod, laquinimod, risperidone, nicergoline, guanfacine, raloxifene, pramipexole, lidocaine, histrelin, and

pharmaceutically acceptable salts thereof.

105) The drug delivery composition according to claim 16, wherein the at least one sorption enhancer comprises a combination of two or more sorption enhancers selected from the group consisting of polymeric sorption enhancers, non-polymeric sorption enhancers, and sugar-based sorption enhancers.

106) The drug delivery composition according to claim 105, wherein the sorption enhancers comprise a combination of a first sorption enhancer, which produces a first average daily elution rate in the drug delivery composition, and a second sorption enhancer, which produces a second average daily elution rate in the drug delivery composition, wherein the second average daily elution rate is less than the first average daily elution rate, and wherein the combination of the first and second sorption enhancers produces an average daily elution rate that is intermediate between the first and second average daily elution rates.

107) The method according to claim 34, wherein the at least one sorption enhancer comprises a combination of two or more sorption enhancers selected from the group consisting of polymeric sorption enhancers, non-polymeric sorption enhancers, and sugar-based sorption enhancers.

108) The method according to claim 107, wherein the sorption enhancers comprise a combination of a first sorption enhancer, which produces a first average daily elution rate in the drug delivery composition, and a second sorption enhancer, which produces a second average daily elution rate in the drug delivery composition, wherein the second average daily elution rate is less than the first average daily elution rate, and wherein the combination of the first and second sorption enhancers produces an average daily elution rate that is intermediate between the first and second average daily elution rates.

109) The method according to claim 64, wherein the at least one sorption enhancer comprises a combination of two or more sorption enhancers selected from the group consisting of polymeric sorption enhancers, non-polymeric sorption enhancers, and sugar-based sorption enhancers.

110) The method according to claim 109, wherein the sorption enhancers comprise a combination of a first sorption enhancer, which produces a first average daily elution rate in the drug delivery composition, and a second sorption enhancer, which produces a second average daily elution rate in the drug delivery composition, wherein the second average daily elution rate is less than the first average daily elution rate, and wherein the combination of the first and second sorption enhancers produces an average daily elution rate that is intermediate between the first and second average daily elution rates.

111) The subcutaneous delivery system according to claim 81, wherein the at least one sorption enhancer comprises a combination of two or more sorption enhancers selected from the group consisting of polymeric sorption enhancers, non-polymeric sorption enhancers, and sugar-based sorption enhancers.

112) The subcutaneous delivery system according to claim 111, wherein the sorption enhancers comprise a combination of a first sorption enhancer, which produces a first average daily elution rate in the drug delivery composition, and a second sorption enhancer, which produces a second average daily elution rate in the drug delivery composition, wherein the second average daily elution rate is less than the first average daily elution rate, and wherein the combination of the first and second sorption enhancers produces an average daily elution rate that is intermediate between the first and second average daily elution rates.

113) The kit according to claim 98, wherein the at least one sorption enhancer comprises a combination of two or more sorption enhancers selected from the group consisting of polymeric sorption enhancers, non-polymeric sorption enhancers, and sugar-based sorption enhancers.

114) The kit according to claim 113, wherein the sorption enhancers comprise a combination of a first sorption enhancer, which produces a first average daily elution rate in the drug delivery composition, and a second sorption enhancer, which produces a second average daily elution rate in the drug delivery composition, wherein the second average daily elution rate is less than the first average daily elution rate, and wherein the combination of the first and second sorption enhancers produces an average daily elution rate that is intermediate between the first and second average daily elution rates.