HK1235707A1 - Highly concentrated drug particles, formulations, suspensious and uses thereof - Google Patents

Description

Highly concentrated pharmaceutical particles, formulations, suspensions and uses thereof

The application is a divisional application of Chinese patent application No. 200980140859.X (PCT/US2009/005629), 2009, 10 months and 14 days, entitled "highly concentrated drug particles, formulations, suspensions and uses thereof".

Cross Reference to Related Applications

This application claims the benefit of U.S. provisional application serial No.61/196,277 filed on 15/10/2008 and U.S. provisional application serial No.61/204,714 filed on 9/1/2009, which is currently pending, and which applications are incorporated herein by reference in their entirety.

Technical Field

The present invention relates to organic chemistry, pharmaceutical chemistry, and protein chemistry for pharmaceutical research and development. Aspects of the present invention provide highly concentrated pharmaceutical particle formulations (particle formulations), suspension formulations comprising such particle formulations, devices comprising such suspension formulations, and their use in treating diseases or disorders.

Background

Drugs, including proteins, peptides and polypeptides, tend to degrade in aqueous solution over time, i.e., they are typically unstable in aqueous solution. Due to this chemical instability, drugs in solution are generally not suitable for long-term storage or for delivery devices providing extended release of the drug. In addition, drugs with short in vivo half-lives are particularly difficult to formulate in a storable and deliverable form. Pharmaceutical formulations continue to suffer from important drawbacks, namely limiting their use, particularly in terms of their method of delivery (e.g. subcutaneous or intravenous injection) and ability to be administered at a sufficient therapeutic dose. Improvements in drug formulation and delivery are needed to improve patient compliance and extend the availability of drugs.

Vehicles in which the drug is insoluble, but capable of being suspended therein, have been shown to improve chemical stability (e.g., U.S. patent nos. 5,972,370 and 5,904,935). In addition, it is beneficial to suspend a beneficial active agent in a vehicle when the active agent exhibits low solubility in the desired vehicle. However, suspensions have poor physical stability due to sedimentation, chemical instability, and aggregation of the suspended beneficial agent. Another problem is the ability to achieve the necessary drug concentration in the carrier, for example to provide prolonged delivery. The problem of using non-aqueous carriers tends to be exacerbated by the increased concentration of the drug.

Several approaches have been taken to achieve prolonged drug delivery at a controlled rate. For example, Brodbeck et al have described depot gel compositions that can be injected into a desired site and provide sustained release of the drug (U.S. Pat. Nos.6,673,767: 6,468,961: 6,331,311; and 6,130,200).

Implantable infusion pumps for drug delivery via intravenous, intra-arterial, intrathecal, intraperitoneal and epidural routes are also described. Such pumps are typically inserted surgically subcutaneously into the lower abdominal tissue pocket for controlled delivery of the drug. A number of systems for insulin delivery, controlling pain, and chemotherapy delivery have been described (e.g., Health Services/Technology Association text (HSTAT), External and Implantable Infusion Pumps, by Ann a. graham, c.r.n.a., m.p.h., Thomas v. holohan, m.d., Health Technology Review, No.7, Agency for Health care Policy, and Research Office of Health Technology Assessment,1 month 1994).

Another means of prolonged drug delivery uses osmotic delivery devices. Such devices may be implanted in a subject to release the drug in a controlled manner for a predetermined administration period. Generally, these devices operate by absorbing fluid from the external environment and releasing an amount of medication corresponding to the inhaled fluid. An example of such an osmotic delivery system is(ALZA Corporation, Mountain View, CA).The device is a titanium implant delivery system, the use of which(ALZA Corporation, Mountain View, CA) technology to control symptoms associated with advanced (stage 4) prostate cancer by delivering leuprolide acetate. Use ofDevice treatment reduces the amount of testosterone produced and circulating in the subject and provides continuous treatment for 12 months.

For extended delivery, a period of up to one year of administration is desirable. Long-term storage of such drugs at physiological temperatures presents a number of challenges. One such challenge is that settling of the drug in the liquid formulation may occur, which may lead to non-uniformity of the drug in the drug suspension. Another challenge is the ability to obtain a suspension formulation that is reliably pumped from the delivery device for extended delivery. A third challenge is the ability of high doses of drugs to be delivered over time when constrained by the typically small volume available in implantable delivery devices that store the drugs. For example, the implant reservoirs typically range from about 25 ul to about 250 ul.

The above-described devices and formulations have been used to deliver drugs to subjects. Although these devices have been used for human and veterinary purposes, there remains a need for such formulations, drug delivery devices and methods: they can be delivered at the desired therapeutic concentration for an extended period of time and provide drug stability over an extended period of time. The highly concentrated pharmaceutical granule formulation of the present invention provides a solution to many of the challenges and problems outlined above. The present invention provides desirable improvements in, for example, drug formulation and delivery that improve longer term, compliance, available drug types, and drug stability.

Summary of The Invention

The present invention relates generally to highly concentrated drug particle formulations and suspension formulations comprising highly concentrated drug particle formulations and a suspending vehicle (suspension vehicle) and devices comprising such formulations, methods of making such formulations and devices, and methods of use thereof.

In one aspect, the present invention relates to highly concentrated pharmaceutical granule formulations. In one embodiment, the invention includes a granular formulation comprising from about 25 wt% to about 80 wt% of a drug and from about 75 wt% to about 20 wt% of one or more other ingredients, wherein the ratio of drug to other ingredients is from about 1:1 to about 5: 1. In another embodiment, the drug is present in an amount of about 40% to about 75% by weight and the one or more other ingredients are present in an amount of about 60% to about 25% by weight.

The granular formulation of the present invention may include other ingredients in addition to the pharmaceutical ingredient. Examples of one or more other ingredients include, but are not limited to, antioxidants, carbohydrates, and buffers. In one embodiment, the ratio of drug to antioxidant to carbohydrate to buffer is about 2-20:1-5:1-5: 1-10. Examples of antioxidants include, but are not limited to, cysteine, methionine, tryptophan, and mixtures thereof. Examples of buffering agents include, but are not limited to, citrate, histidine, succinate, and mixtures thereof. Examples of carbohydrates include, but are not limited to, disaccharides such as lactose, sucrose, trehalose, cellobiose, and mixtures thereof.

In one embodiment, the particle formulation is a spray-dried particle formulation.

The drug included in the particle formulation of the present invention may be, for example, a protein or a small molecule. Some embodiments of the invention encompass the use of peptide hormones, such as incretin mimetics (e.g., glucagon-like proteins (e.g., GLP-1) and analogs and derivatives thereof; exenatide (e.g., Exendin-4) and analogs and derivatives thereof); PYY (also known as peptide YY, tyrosyl tyrosine peptide (peptide tyrosine-tyrosine)) and analogues and derivatives thereof; oxyntomodulin and its analogs and derivatives); gastroinhibitory peptides (GIP) and analogs and derivatives thereof; and leptin, and analogs and derivatives thereof. Other embodiments include the use of interferon proteins (e.g., alpha interferon, beta interferon, gamma interferon, lambda interferon, omega interferon, tau interferon, consensus interferon, variant interferon, and mixtures thereof, and analogs or derivatives thereof, such as pegylated forms). Other examples of useful proteins include recombinant antibodies, antibody fragments, humanized antibodies, single chain antibodies, monoclonal antibodies, avimers, human growth hormone, epidermal growth factor, fibroblast growth factor, platelet-derived growth factor, transforming growth factor, nerve growth factor, and cytokines.

In one embodiment, the particles of the particle formulation are particles of about 2 microns to about 10 microns. Typically, for example, particles formed by spray drying have a defined size range represented by a curve centered on the average. In one embodiment, the curve is a bell curve and the average particle size is from about 2 microns to about 10 microns.

In a second aspect, the present invention is directed to a suspension formulation comprising a highly concentrated pharmaceutical granule formulation and a suspension vehicle. In one embodiment, a suspension formulation comprises a highly concentrated pharmaceutical granule formulation of the present invention and a non-aqueous, single-phase suspension vehicle. The suspending vehicle typically comprises one or more polymers and one or more solvents. The suspension vehicle exhibits viscous fluid characteristics and the particulate formulation is uniformly dispersed within the vehicle.

In one embodiment, the polymer of the suspension vehicle comprises a polymer comprising a pyrrolidone, such as polyvinylpyrrolidone.

The solvent used to suspend the carrier can be, for example, lauryl lactate, lauryl alcohol, benzyl benzoate, and mixtures thereof.

In some embodiments, the suspending vehicle consists essentially of one or more polymers and one or more solvents. For example, the solvent may consist essentially of benzyl benzoate. For example, the polymer may consist essentially of polyvinylpyrrolidone. In one embodiment, the suspension vehicle consists essentially of benzyl benzoate and a polymer comprising polyvinylpyrrolidone.

The ratio of polymer to solvent in the suspension vehicle can vary, for example, the suspension vehicle can comprise from about 40 wt% to about 80 wt% polymer and from about 20 wt% to about 60 wt% solvent. Preferred embodiments of the suspending vehicle include vehicles formed from a polymer and a solvent combined in the following proportions: about 25 wt% solvent and about 75 wt% polymer; about 50 wt% solvent and about 50 wt% polymer; and about 75 wt% solvent and about 25 wt% polymer.

The suspending vehicle typically has a viscosity of from about 5,000 to about 30,000 poise, preferably from about 8,000 to about 25,000 poise, more preferably from about 10,000 to about 20,000 poise at 33 ℃. In one embodiment, the suspending vehicle has a viscosity of about 15,000 poise ± about 3,000 poise at 33 ℃.

In a third aspect, the present invention is directed to an osmotic delivery device (osmotic delivery device) comprising a suspension formulation comprising a highly concentrated pharmaceutical particle formulation of the present invention and a suspension vehicle.

In one embodiment, the size of the osmotic delivery device may be reduced and still provide delivery of a desired therapeutic amount of drug over a desired period of time when added to a suspension formulation comprising a highly concentrated drug particle formulation of the present invention.

In a fourth aspect, the present invention relates to a method of treating a disease or condition in a subject in need of such treatment using a suspension formulation comprising a highly concentrated pharmaceutical granule formulation of the present invention and a suspension vehicle. The method typically comprises delivering the suspension formulation from one or more osmotic delivery devices to a subject at a substantially uniform rate for a period of time ranging from about 1 month to about 1 year.

In a fifth aspect, the present invention is directed to a method of making an osmotic delivery device comprising adding a highly concentrated drug particle formulation of the present invention and a suspension vehicle to a reservoir of the osmotic delivery device.

The present invention also includes methods of making the suspension formulations, granule formulations, suspension vehicles, and devices of the present invention as described herein.

These and other embodiments of the invention will be apparent to those skilled in the art from consideration of the present disclosure.

Brief Description of Drawings

Figure 1 provides data from an in vitro release rate assay of suspension formulation 1 (as described in example 2). The graph shows the release rate per day (shown as a straight line through the data points) at 37 ℃ at an approximate release rate of 50 ug/day for 100 days. In the figure, the vertical axis is the amount of drug released (ug/day) and the horizontal axis is the time in days.

Figure 2 provides data from an in vitro release rate analysis of suspension formulation 2 (as described in example 2). The graph shows the release rate per day (shown as a straight line through the data points) at 37 ℃ at an approximate release rate of 75 ug/day for 110 days. In this figure, the vertical axis is the release rate of the drug (ug/day) and the horizontal axis is the time in days.

Figure 3 provides data from an in vitro release rate analysis of suspension formulation 3 (as described in example 2). The graph shows the release rate per day (shown as a straight line through the data points) at 37 ℃ at an approximate release rate of 80 ug/day for 100 days. In the figure, the vertical axis is the amount of drug released (ug/day) and the horizontal axis is the time in days.

Figure 4 provides data from an in vitro release rate analysis of 4 omega interferon particle suspension formulations. The graph shows the release rate per day (shown as a straight line through the data points) at 37 ℃ at approximate release rates of 10, 25, 30, and 50 ug/day for 100 days. In this figure, the vertical axis is the release rate of the drug (ug/day) and the horizontal axis is time in days, 10 ug/day data is shown as squares, 25 ug/day data is shown as diamonds, 30 ug/day data is shown as triangles, and 50 ug/day data is shown as circles. Error bars are shown for each measurement.

Figure 5 provides data from an in vitro release rate analysis of 5 exenatide particle suspension formulations. The graph shows the release rate per day (shown as a straight line through the data points) at 37 ℃ at approximate release rates of 5, 10, 20,40, and 75 ug/day for up to 110 days. In this figure, the vertical axis is the release rate of the drug (ug/day) and the horizontal axis is time in days, 5 ug/day data is shown as diamonds, 10 ug/day data is shown as open squares, 20 ug/day data is shown as triangles, 40 ug/day data is shown as circles, and 75 ug/day is shown as solid squares. Error bars are shown for each measurement.

Fig. 6A provides an illustration (not to scale) of an implantable osmotic drug delivery device 10 showing the basic components of the device. In fig. 6A, the receptacle 12 comprises an inner wall and an outer wall, wherein the inner wall defines a cavity. A semi-permeable membrane 18 is at least partially inserted into the first end of the reservoir and an osmotic engine (osmotic engine) is contained within a first chamber 20 defined by a first surface of the semi-permeable membrane 18 and a first surface of the piston 14. The pharmaceutical suspension formulation is contained within a second chamber 16 defined by a second surface of the piston 14 and a first surface of a diffusion moderator 22. The diffusion moderator is at least partially inserted into the second end of the reservoir. The diffusion moderator contains delivery orifices 24. In this embodiment, a flow path (flowpath)26 is formed between the threaded diffusion reducer 22 and threads 28 formed on the inner surface of the vessel 12. Fig. 6B provides an illustration of an implantable osmotic drug delivery device having a length of about 45mm and a diameter dimension of about 3.8 mm. In fig. 6B, an optional laser marking tape 60 is shown and an optional outer directional groove 62 is shown. Also shown are the reservoir 12, semi-permeable membrane 18 and diffusion moderator 22. Fig. 6C provides an illustration of an implantable osmotic drug delivery device having a reduced length relative to the implantable osmotic drug delivery device of fig. 6B, wherein the device has dimensions of about 30mm in length and about 3.8mm in diameter. In fig. 6C, an optional laser identification band 60 is shown and an optional outer directional groove 62 is shown. Also shown are the reservoir 12, semi-permeable membrane 18 and diffusion moderator 22.

Detailed Description

All patents, publications, and patent applications cited in this specification are herein incorporated by reference as if each individual patent, publication, or patent application were specifically and individually indicated to be incorporated by reference and set forth in its entirety herein for all purposes.

1.0.0 definition

It is to be understood that the terminology used herein is for the purpose of describing particular embodiments only, and is not intended to be limiting. As used in this specification and the appended claims, the singular forms "a", "an", and "the" include plural referents unless the context clearly dictates otherwise. Thus, for example, reference to "a solvent" includes one or more such solvents, and reference to "a protein" includes one or more proteins, protein mixtures, and the like.

Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention pertains. Although other methods and materials similar or equivalent to those described herein can be used in the practice of the present invention, the preferred materials and methods are described herein.

In describing and claiming the present invention, the following terminology will be used in accordance with the definitions set out below.

The terms "drug," "therapeutic agent," and "beneficial agent" are used interchangeably to refer to any therapeutically active substance that is delivered to a subject to produce a desired beneficial effect. In one embodiment of the invention, the drug is a protein, such as an interferon or an incretin mimetic. In another embodiment of the invention, the drug is a small molecule, such as a hormone, e.g., an androgen or an estrogen. The devices and methods of the invention are well suited for the delivery of proteins, small molecules, and combinations thereof.

The terms "peptide," "polypeptide," and "protein" are used interchangeably herein and generally refer to a molecule comprising a chain of two or more amino acids (e.g., most commonly L-amino acids, but also including, for example, D-amino acids, modified amino acids, amino acid analogs, and/or amino acid mimetics). Peptides may also include other groups that modify the amino acid chain, such as functional groups added by post-translational modification. Examples of post-translational modifications include, but are not limited to, acetylation, alkylation (including methylation), biotinylation, glutamylation, glycylation, glycosylation, prenylation, lipidation, phosphopantetheinylation, phosphorylation, selenization, C-terminal amidation. The term protein also includes proteins comprising amino-terminal and/or carboxy-terminal modifications. Modifications of the terminal amino group include, but are not limited to, deamination, N-lower alkyl, N-di-lower alkyl, and N-acyl modifications. Modifications of the terminal carboxyl group include, but are not limited to, amide, lower alkyl amide, dialkyl amide, and lower alkyl ester modifications (e.g., where lower alkyl is C₁-C₄Alkyl groups). The term protein also includes amino acid modifications between the amino terminus and the carboxy terminus, such as, but not limited to those described above. In one embodiment, the protein may be modified by the addition of small molecules.

The terminal amino acid at one end of the peptide chain typically has a free amino group (i.e., the amino terminus). The terminal amino acid at the other end of the chain typically has a free carboxyl group (i.e., carboxyl terminus). Typically, the amino acids that form a protein are numbered in such an order that they begin at the amino terminus and increase in the direction of the carboxy terminus of the protein.

The phrase "amino acid residue" as used herein refers to an amino acid that is incorporated into a protein through an amide bond or an amide bond mimetic.

The phrase "incretin mimetic" as used herein includes, but is not limited to, glucagon-like peptide 1(GLP-1) and derivatives and analogs thereof, and exenatide and derivatives and analogs thereof. Incretin mimetics are also referred to as "insulinotropic peptides".

The term "insulinotropic" as used herein means the ability of a compound, such as a protein (e.g., insulinotropic hormone), to stimulate or affect insulin production and/or activity. Such compounds typically stimulate insulin secretion or biosynthesis in a subject.

The term "interferon" as used herein includes, but is not limited to, three main types of human interferons: type I interferons (e.g., alpha interferons (including alpha-2 a and alpha-2 b), beta interferons (including beta-1 a and beta 1-b), omega interferons, tau interferon, and variants thereof); type II interferons (e.g., gamma interferon and variants thereof); and type III interferons (e.g., lambda interferon and variants thereof). In addition, the term means various consensus interferon alpha (e.g., U.S. patent nos. 4,695,623, 4,897,471, 5,372,808, 5,541,293, and 6,013,253).

The term "carrier" as used herein refers to a medium for carrying a drug. The vehicle of the present invention typically comprises ingredients such as a polymer and a solvent. The suspension vehicle of the present invention typically comprises solvents and polymers for preparing a suspension formulation that also comprises a highly concentrated pharmaceutical granule formulation.

The phrase "phase separated" as used herein refers to the formation of multiple phases (e.g., a liquid phase or a gel phase) in the suspending vehicle, for example, when the suspending vehicle is contacted with an aqueous environment. In some embodiments of the invention, the suspending vehicle is formulated so as to exhibit phase separation upon contact with an aqueous environment having less than about 10% water.

The phrase "single phase" as used herein refers to a solid, semi-solid, or liquid homogeneous system that is both physically and chemically homogeneous throughout.

The term "disperse" as used herein refers to the dispersion, suspension or otherwise distribution of a compound, such as a highly concentrated pharmaceutical granule formulation, in a suspension vehicle. Typically, highly concentrated drug particle formulations of the present invention are uniformly suspended in a non-aqueous suspension vehicle in which the drug particles are substantially insoluble. The substantially insoluble material generally retains its original physical form over the life of the dosage form containing the suspension. For example, the solid particles of the highly concentrated pharmaceutical granule formulation of the present invention are generally maintained as particles in a non-aqueous suspending vehicle.

The phrase "chemically stable" as used herein refers to the formation of a formulation that forms degradation products in no more than an acceptable percentage over a period of time by chemical means such as deamidation (typically by hydrolysis), aggregation, or oxidation.

The phrase "physically stable" as used herein refers to formulations that form an aggregate (e.g., dimers and other higher molecular weight products) in no more than an acceptable percentage. In addition, a physically stable formulation does not change its physical state, for example, when going from a liquid to a solid, or from an amorphous form to a crystalline form.

The term "viscosity" as used herein generally refers to a value determined by the ratio of shear stress to shear rate (see, e.g., Considine, D.M. & Considine, g.d., Encyclopedia of Chemistry, 4 th edition, vannonstand, Reinhold, NY,1984) substantially as follows:

F/A. mu. V/L (equation 1)

Where F/a is the shear stress (force per unit area),

μ ═ proportionality constant (viscosity), and

V/L-flow rate per layer thickness (shear rate).

From this relationship, the ratio of shear stress to shear rate defines the viscosity. Shear stress and shear rate measurements are typically made using parallel plate rheometry conducted under selected conditions (e.g., a temperature of about 37 ℃). Other methods of measuring viscosity include measuring kinematic viscosity using a viscometer, such as a Cannon-Fenske viscometer, an Ubbelohde viscometer for Cannon-Fenske opaque solutions, or an Ostwald viscometer. In general, the suspension vehicles of the present invention have a viscosity sufficient to prevent settling of the microparticle formulation suspended therein during storage and for use in methods of delivery, for example, in implantable drug delivery devices.

The term "non-aqueous" as used herein means that the total moisture content, e.g., the total moisture content of a suspension formulation, is generally less than or equal to about 10 wt%, preferably less than or equal to about 7 wt%, more preferably less than or equal to about 5 wt%, and more preferably less than about 4 wt%.

The term "subject" as used herein refers to any member of the subfamily chordata, including without limitation humans and other primates, including non-human primates such as macaque and other monkey species, and chimpanzees and other ape species; farm animals such as cattle, sheep, pigs, goats, and horses; domestic mammals such as dogs and cats; test animals include rodents such as mice, rats and guinea pigs; birds, including domestic, wild and game birds such as chicken, turkey and other gallinaceous birds, ducks, geese and the like. The term does not denote a particular age. Thus, both adult and neonatal individuals are encompassed.

The term "osmotic delivery device" as used herein typically refers to a device for delivering one or more beneficial active agents (e.g., an incretin mimetic) to a subject, wherein the device comprises, for example, a reservoir (e.g., made of a titanium alloy) having a lumen containing a suspension formulation (e.g., comprising an incretin mimetic) and an osmotic agent component. A piston assembly located in the internal chamber separates the suspension formulation from the osmotic agent component. A semipermeable membrane located at a first end of the reservoir is adjacent the osmotic agent formulation, and a flow modulator located at a second end of the reservoir, which defines a delivery orifice through which the suspension formulation exits the device, is adjacent the suspension formulation. Typically, the osmotic drug delivery device is implanted in the subject, for example subcutaneously (e.g., on the medial, lateral or dorsal side of the upper arm; or in the abdominal region). A typical osmotic delivery device is(ALZA Corporation, Mountain View, CA) delivery device.

The term "continuous delivery" as used herein typically means a substantially continuous release of drug from an osmotic delivery device. For example,the drug delivery device releases the drug at a predetermined rate based on osmotic principles. Enter intoThe extracellular fluid of the device passes through the semipermeable membrane directly into the osmotic engine, which expands to drive the piston at a slow and consistent drive rate (rate gradient). The piston motion causes the release of the pharmaceutical formulation through the diffusion moderator orifice. Thus, drug release from an osmotic delivery device is continuous at a slow, controlled, consistent rate.

The term "substantially steady-state delivery" as used herein typically means that the drug is delivered at or near a target level over a defined period of time, wherein the amount of drug delivered from the osmotic engine is substantially zero order delivery.

2.0.0 general overview of the invention

Before describing the present invention in detail, it is to be understood that this invention is not limited to particular types of drug delivery, particular types of drug delivery devices, particular sources of drugs, particular solvents, particular polymers, etc., and the use of such particular situations can be selected in accordance with the teachings of the present specification. It is also to be understood that the terminology used herein is for the purpose of describing particular embodiments only, and is not intended to be limiting.

The transitional phrases "comprising," "consisting essentially of …," and "consisting of …" define the scope of the invention to exclude from the claims other components or steps (if any) that are not described. The term "comprising" as a synonym for "comprising", "containing" or "characterized in" is open-ended and does not exclude other, unrecited elements or method steps. The transitional term "consisting essentially of …" limits the scope of the claims to specific materials or steps and those materials or steps that do not materially affect the basic and novel characteristics of the invention. The transformative phrase "consisting of …" does not include any elements, steps, or components not specified by the claims. The open claims phrase "comprising" is typically used to describe the formulation and device components and process steps of the present invention (e.g., granular formulation comprising, suspension vehicle comprising, drug delivery device comprising, or process of making comprising). Such description expressly includes further defined embodiments of the invention that may be described using the transformative phrase "consisting essentially of …" (e.g., a particle formulation consisting essentially of …; a suspension formulation consisting essentially of …; a suspension vehicle consisting essentially of …; a drug delivery device consisting essentially of …; or a manufacturing process consisting essentially of …), and even further defined embodiments of the invention may be described using the transformative phrase "consisting essentially of …" (e.g., a particle formulation consisting of …; a suspension formulation consisting of …; a suspension vehicle consisting of …; a drug delivery device consisting of …; or a manufacturing process consisting of …).

In one aspect, the present invention relates to highly concentrated pharmaceutical granule formulations comprising from about 25 wt% to about 75 wt% of a drug and one or more other ingredients (e.g., stabilizers), based on the total weight of the granule formulation. Typically, the ratio of drug to the total amount of one or more other ingredients is from about 1:3 (drug: other ingredients) to 5:1 (drug: other ingredients), for example, a ratio of 1.4:1:1:2 (drug: antioxidant: carbohydrate: buffer, where antioxidant, carbohydrate, and buffer are stabilizers) or 15:1:1:1 (drug: antioxidant: carbohydrate: buffer, where antioxidant, carbohydrate, and buffer are stabilizers). In one embodiment, the granule formulation comprises about 40-50 wt% drug and 60-50 wt% other ingredients (e.g., stabilizers), wherein the ratio of drug to other ingredients is about 1-2: 1.

The drug in the highly concentrated drug particle formulations of the present invention is typically a protein or a small molecule. The one or more stabilizing agents are typically selected from carbohydrates, antioxidants, amino acids, and buffers.

In one embodiment of the invention, the drug is a protein. Examples of proteins useful in the practice of the present invention are discussed further below and include, but are not limited to, the following: interferons such as alpha interferon, beta interferon, gamma interferon, lambda interferon, omega interferon, tau interferon, consensus interferon, variant interferons, and mixtures thereof. Other proteins include, but are not limited to, incretin mimetics such as glucagon-like peptide-1 (GLP-1), GLP-1 derivatives (such as GLP-1(7-36) amide) or GLP-1 analogs, exenatide derivatives or exenatide analogs. Other examples of useful proteins include recombinant antibodies, antibody fragments, humanized antibodies, single chain antibodies, monoclonal antibodies, avimers, human growth hormone, epidermal growth factor, fibroblast growth factor, platelet-derived growth factor, transforming growth factor, nerve growth factor, and cytokines.

In another embodiment of the invention, the drug is a small molecule. Examples of types of small molecules useful in the practice of the present invention are discussed further below and include, but are not limited to, anti-angiogenesis inhibitors (e.g., tyrosinase inhibitors), microtubule inhibitors, DNA repair inhibitors, and polyamine inhibitors. Examples of specific small molecules for use in the practice of the present invention are discussed further below and include, but are not limited to, the following: testosterone, dehydroepiandrosterone, androstenedione, androstenediol, androsterone, dihydrotestosterone, estrogen, progesterone, prednisolone, pregnenolone, estradiol, estriol, and estrone.

The highly concentrated pharmaceutical granule formulations of the present invention typically include one or more of the following additional ingredients (e.g., stabilizers); one or more carbohydrates (e.g., lactose, sucrose, trehalose, raffinose, cellobiose, and mixtures thereof); one or more antioxidants (e.g., methionine, ascorbic acid, sodium thiosulfate, ethylenediaminetetraacetic acid (EDTA), citric acid, butylated hydroxytoluene, and mixtures thereof); and one or more buffering agents (e.g., citrate, histidine, succinate, and mixtures thereof).

In a preferred embodiment, the highly concentrated drug particle formulation comprises a drug, a disaccharide (e.g., sucrose), an antioxidant (e.g., methionine), and a buffer (e.g., citrate). The drug typically comprises from about 20% to about 80% by weight of the drug, preferably from about 25% to about 75% by weight, more preferably from about 25% to about 50% by weight of the highly concentrated drug particle formulation. The ratio of drug to stabilizer is typically about 5:1, preferably about 3:1, more preferably about 2:1. Highly concentrated pharmaceutical granule formulations are preferably granule formulations prepared by spray drying and have a low water content, preferably less than or equal to about 10 wt%, more preferably less than or equal to about 5 wt%. In another embodiment, the particulate formulation may be lyophilized.

In a second aspect, the present invention is directed to a suspension formulation comprising a highly concentrated pharmaceutical granule formulation and a suspension vehicle. The suspension vehicle is typically a non-aqueous, single-phase suspension vehicle comprising one or more polymers and one or more solvents. The suspension vehicle exhibits viscous fluid characteristics. The granular formulation is homogeneous and uniformly dispersed in the carrier.

The suspending vehicle of the present invention comprises one or more solvents and one or more polymers. The solvent is preferably selected from the group consisting of lauryl lactate, lauryl alcohol, benzyl benzoate and mixtures thereof. More preferably, the solvent is lauryl lactate or benzyl benzoate. The polymer preferably comprises pyrrolidones, for example in some embodiments the polymer is polyvinylpyrrolidone (e.g., polyvinylpyrrolidone K-17, which typically has an average molecular weight of about 7,900-10,800). In one embodiment of the invention, the carrier consists essentially of benzyl benzoate and polyvinylpyrrolidone.

Suspension formulations typically have a low total water content, for example less than or equal to about 10 wt%, and in preferred embodiments, less than or equal to about 5 wt%.

In another aspect, the present invention relates to an implantable drug delivery device comprising the suspension formulation of the present invention. In a preferred embodiment, the delivery device is an osmotic delivery device. In one embodiment, the present invention relates to the use of an osmotic delivery device having an overall length of from about 35mm to about 20mm in length, preferably from about 30mm to about 25mm in length, more preferably from about 28mm to 33mm in length and from about 8mm to about 3mm in diameter, preferably from about 3.8 to 4mm in diameter. In some embodiments, osmotic delivery devices having these dimensions are loaded with a suspension formulation comprising a highly concentrated drug particle formulation of the present invention. In one embodiment, the osmotic delivery device has a length of about 30mm and a diameter of about 3.8 mm.

The invention also includes methods of preparing the highly concentrated pharmaceutical granule formulations and/or suspension formulations of the invention and osmotic drug delivery devices loaded with the suspension formulations of the invention. In one embodiment, the invention includes a method of manufacturing an osmotic delivery device comprising loading a suspension formulation into a reservoir of the osmotic delivery device.

In another aspect, the invention relates to a method of treating a disease or condition in a subject in need of such treatment, for example, by delivering a drug from an osmotic delivery device to the subject at a substantially uniform rate for a period of about 1 month to about 1 year. In one embodiment, the invention relates to a method of treating diabetes (e.g., type 2 diabetes or gestational diabetes) in a subject in need of such treatment, comprising delivering at a substantially uniform rate a highly concentrated pharmaceutical particle formulation of the invention, e.g., comprising an incretin mimetic, from an osmotic delivery device. Typically, the suspension formulation is delivered for a period of about 1 month to about 1 year, preferably about 3 months to about 1 year. The method may further comprise subcutaneously inserting an osmotic delivery device loaded with a suspension formulation of the present invention into a subject. Such osmotic delivery devices may also be used in therapeutic methods involving, for example, the treatment of type 2 diabetes.

In another embodiment, the invention relates to the treatment of interferon response disorders by administering a highly concentrated pharmaceutical granule formulation comprising one or more interferons. Examples of interferon response disorders include, but are not limited to, viral infections (e.g., hepatitis c virus infection), autoimmune diseases (e.g., multiple sclerosis), and some cancers.

In another aspect, the invention relates to a drug being delivered from a delivery device, such as an osmotic delivery device, for an extended period of up to about 400 ug/day for up to about 90 days, for an extended period of up to about 200 ug/day for up to about 180 days, or for an extended period of up to about 100 ug/day for up to 1 year.

3.0.0 formulations and compositions

3.1.0 highly concentrated pharmaceutical granule formulation

In one aspect, the present invention provides highly concentrated pharmaceutical granule formulations for pharmaceutical applications. The granule formulation typically contains from about 20 wt% to about 75 wt% of the drug and includes one or more other ingredients (e.g., stabilizers). Examples of other ingredients that are stabilizing ingredients include, but are not limited to, carbohydrates, antioxidants, amino acids, buffers, inorganic compounds, and surfactants.

3.1.1 typical drugs

The highly concentrated drug particle formulation may comprise one or more drugs. The drug may be any physiologically or pharmacologically active substance, particularly those known for delivery to the human or animal body, such as drugs, vitamins, nutrients, and the like. The highly concentrated pharmaceutical granule formulation of the present invention is typically a pharmaceutical formulation and may be packaged, for example, in dry form or in a suspension formulation.

Drugs that can be delivered by osmotic delivery systems include, but are not limited to, drugs that can act on the peripheral nerve, adrenergic receptors, cholinergic receptors, skeletal muscle, cardiovascular system, smooth muscle, blood circulation system, synoptic sites, neuroeffector junction endocrine and hormonal systems, immune system, reproductive system, skeletal system's own active substance system, digestive and excretory systems, histamine system, or central nervous system. In addition, drugs that can be delivered by the osmotic delivery system of the present invention include, but are not limited to, drugs for the treatment of infectious diseases, chronic pain, diabetes, autoimmune diseases, endocrine disorders, metabolic disorders, cancer, and rheumatoid arthritis.

In general, suitable drugs for highly concentrated drug particle formulations include, but are not limited to: peptides, proteins, polypeptides (e.g., enzymes, hormones, cytokines), polynucleotides, nucleoproteins, polysaccharides, glycoproteins, lipoproteins, steroids, analgesics, local anesthetics, antibiotics, anti-inflammatory corticosteroids, ophthalmic drugs, other small molecules for pharmaceutical applications (e.g., ribavirin), or synthetic analogs of these species and mixtures thereof.

In one embodiment, preferred drugs include macromolecules. Such macromolecules include, but are not limited to, pharmaceutically active peptides, proteins, polypeptides, genes, gene products, other gene therapy agents, or other small molecules. In preferred embodiments, the macromolecule is a peptide, polypeptide, or protein. A number of peptides, proteins or polypeptides useful in the practice of the present invention are described herein. In addition to the peptides, proteins or polypeptides described, modifications of such peptides, proteins or polypeptides are well known to those skilled in the art and may be used in the practice of the invention in light of the teachings provided herein. Such modifications include, but are not limited to, amino acid analogs, amino acid mimetics, analogous proteins, or derived proteins. In addition, the medicaments disclosed herein may be formulated alone or in combination (e.g., as a mixture).

Examples of proteins that can be formulated into highly concentrated pharmaceutical granule formulations of the present invention include, but are not limited to, the following: a growth hormone; a somatostatin; growth hormone (somatropin), somatotropin analogs; growth regulator-C; somatotropin + amino acids; somatotropin + protein; a follicle stimulating hormone; luteinizing hormone; luteinizing Hormone Releasing Hormone (LHRH); LHRH analogs such as leuprolide, nafarelin, and goserelin; LHRH agonists or antagonists; growth hormone releasing factor; a calcitonin; colchicine; gonadotropin-releasing hormone; gonadotropins, such as chorionic gonadotropin; oxytocin; octreotide; a vasopressin; corticotropin; an epidermal growth factor; fibroblast growth factor; platelet-derived growth factor; transforming a growth factor; a nerve growth factor; prolactin; the icosapeptide corticotropin; lypressin polypeptides such as thyrotropin-releasing hormone; thyroid stimulating hormone; a secretin; a pancreatin; enkephalin; glucagon; endocrine material (endocrine agent) secreted in the body and distributed through the blood stream, and the like.

Other proteins that can be formulated into highly concentrated drug particle formulations include, but are not limited to, the following: alpha-antitrypsin; factor VII: factor IX and other coagulation factors; insulin; a peptide hormone; corticotropin (adrenocorticotropic hormone), thyroid stimulating hormone, and other pituitary hormones; erythropoietin; growth factors such as granulocyte colony stimulating factor, granulocyte macrophage colony stimulating factor, insulin-like growth factor 1; tissue-type plasminogen activator; CD 4; 1-deamino-8-d-arginine vasopressin; interleukin-1 receptor antagonists; tumor necrosis factor, tumor necrosis factor receptor; a tumor suppressor protein; pancreatin; lactase; cytokines include lymphokines, chemokines, or interleukins such as interleukin-1, interleukin-2; a cytotoxic protein; superoxide dismutase; and endocrine material secreted by the animal and distributed through the bloodstream.

In some embodiments, the drug may be one or more proteins. Examples of one or more proteins include, but are not limited to, the following: one or more proteins selected from the group consisting of recombinant antibodies, antibody fragments, humanized antibodies, single chain antibodies, monoclonal antibodies, and avimers; one or more proteins selected from the group consisting of human growth hormone, epidermal growth factor, fibroblast growth factor, platelet-derived growth factor, transforming growth factor and nerve growth factor; or one or more cytokines.

Some embodiments of the invention comprise the use of: peptide hormones, such as incretin mimetics (e.g., glucagon-like proteins (e.g., GLP-1) and analogs and derivatives thereof; exenatide (e.g., Exendin-4) and analogs and derivatives thereof); PYY (also known as peptide YY, tyrosyl tyrosine peptide) and analogs and derivatives thereof; oxyntomodulin and its analogs and derivatives); gastroinhibitory peptides (GIP) and analogs and derivatives thereof; and leptin, and analogs and derivatives thereof. Other embodiments include The use of interferon proteins (e.g., interferon-alpha, interferon-beta, interferon-gamma, interferon-lambda, interferon-omega, interferon-tau, consensus interferon, variant Interferons, and mixtures thereof, and analogs or derivatives thereof such as pegylated forms; see, e.g., The Interferons: Characterisation and Application, Anthony Meager, Ed., Wiley-VCH (1/5 2006)).

GLP-1 (including the three forms of this peptide, GLP-1(1-37), GLP-1(7-37), and GLP-1(7-36) amide and GLP-1 analogs) has been shown to stimulate insulin secretion (i.e., insulinotropic), which induces glucose uptake in cells and results in a decrease in serum glucose levels (see, e.g., Mojsov, S., int.J.peptide Protein Research,40:333-343 (1992)).

A large number of GLP-1 derivatives and analogs that exhibit insulinotropic effects are known in the art (see, e.g., U.S. Pat. Nos. 5,118,666; 5,120,712; 5,512,549; 5,545,618; 5,574,008; 5,574,008; 5,614,492; 5,958,909; 6,191,102; 6,268,343; 6,329,336; 6,451,974; 6,458,924; 6,514,500; 6,593,295; 6,703,359; 6,706,689; 6,720,407; 6,821,949; 6,849,708; 6,849,714; 6,887,470; 6,887,849; 6,903,186; 7,022,674; 7,041,646; 7,084,243; 7,101,843; 7,138,486; 7,141,547; 7,144,863; and 7,199,217). Examples of GLP-1 derivatives and analogs include, but are not limited to(Glaxogroup Limited, Greenford, Middlesex, UK) (albicide) drug, tasoglutide drug (Hoffmann-La Roche Inc.), and(Novo Nordisk A/SLTD, Bagsvaerd, DK) (liraglutide) medicaments. Thus, for convenience of reference herein, a family of GLP-1 derivatives and analogs having insulinotropic activity are collectively referred to as "GLP-1".

Exendin-3 and Exendin-4 are well known in the art (Eng, J. et al J.biol.chem.,265:20259-62 (1990): Eng., J. et al J.biol.chem.,267:7402-05 (1992)). The use of exendin-3 and exendin-4 in the treatment of type 2 diabetes and the prevention of hyperglycemia has been proposed (see, e.g., U.S. Pat. No. 5,424,286). A number of exendin-4 derivatives and analogues (including, for example, exendin-4 agonists) are well known in the art (see, for example, U.S. Pat. nos. 5,424,286; 6,268,343; 6,329,336; 6,506,724; 6,514,500; 6,528,486; 6,593,295; 6,703,359; 6,706,689; 6,767,887; 6,821,949; 6,849,714; 6,858,576; 6,872,700; 6,887,470; 6,887,849; 6,924,264; 6,956,026; 6,989,366; 7,022,674; 7,041,646; 7,115,569; 7,138,375; 7,141,547; 7,153,825; and 7,157,555). An example of a derivative or analog of a toxin-specific Excretion peptide is the peptide Lisina (Sanofi-Aventis). Exenatide is a synthetic form of exendin-4 (Kolterman o.g. et al, j.clin.endocrinol.meta.88 (7):3082-9 (2003)). Thus, for ease of reference herein, the exenatide, exendin-4 (e.g., exendin-4 or exendin-4-amide), exendin-4 derivatives and exendin-4 analog families are collectively referred to as "exenatide".

PYY is a 36 amino acid residue peptide amide. PYY inhibits intestinal motility and blood flow (Laburthey, M., trends Endocrinol Metab.1(3):168-74(1990), mediates intestinal secretion (Cox, H.M. et al, Br J Pharmacol 101(2):247-52 (1990): Playford, R.J. et al, Lancet 335(8705):1555-7(1990)) and stimulates net absorption (MacFayden, R.J. et al, Neuropeptides 7(3):219-27(1986)) the sequence of PYY and its analogs and derivatives are well known in the art (e.g., U.S. Pat. Nos. 5,574,010 and 5,552,520).

Oxyntomodulin is a naturally occurring 37 amino acid peptide hormone found in the colon that suppresses appetite and contributes to weight loss (Wynne K et al, Int J Obes (Lond)30(12):1729-36 (2006)). The sequences of oxyntomodulin and analogs and derivatives thereof are well known in the art (e.g., U.S. patent publication Nos. 2005-0070469 and 2006-0094652).

GIP is an insulinotropic peptide hormone (efondic, s. et al, Horm Metab res.36:742-6(2004)) and is secreted by the duodenal and jejunal mucosa in response to absorbed fats and carbohydrates that stimulate insulin secretion by the pancreas. GIP circulates as a biologically active 42-amino acid protein. GIP is known as gastroinhibitory peptide and glucose-dependent insulinotropic peptide. GIP is a 42-amino acid gastrointestinal regulatory peptide that stimulates insulin secretion from pancreatic beta cells in the presence of glucose (Tseng, C. et al, PNAS 90: 1992-Bush 1996 (1993)). The sequence of GIP and its analogs and derivatives are well known in the art (e.g., Meier J.J., Diabetes Metab Res Rev.21(2):91-117 (2005): Edfendic S., Horm MetabRes.36(11-12):742-6 (2004)).

Leptin is a 16 kilodalton protein hormone which plays a key role in regulating energy intake and energy expenditure, including appetite and metabolism (Brennan et al, Nat Clin practice Endocrinol Metab 2(6):318-27 (2006)). Leptin proteins (encoded by the obesity (Ob) gene), analogs and derivatives have been proposed as modulators for controlling body weight and obesity in animals, including mammals and humans. The sequences of leptin and its analogs and derivatives are well known in the art (e.g., U.S. Pat. Nos.6,734,106: 6,777,388; 7,307,142; and 7,112,659; PCT International publication No. WO 96/05309).

The highly concentrated pharmaceutical granule formulation of the present invention is typical of the use of incretin mimetics and interferons (example 1). These examples are not intended to be limiting.

In another embodiment, preferred drugs include modified proteins, including, but not limited to, hybrid proteins (e.g., an in-frame fusion of the coding sequences of two or more proteins or two or more chemically conjugated proteins), small molecules that bind to proteins (e.g., targeting molecules that bind to therapeutic proteins, therapeutic small molecules that bind to targeting proteins, or a combination of targeting moieties, therapeutic small molecules, targeting proteins, and therapeutic proteins). Examples of hybrid proteins include, but are not limited to, exenatide/PYY, oxyntomodulin/PYY, monoclonal antibodies/cytotoxic proteins, albumin fusion proteins (e.g., GLP-1/albumin), and exenatide/oxyntomodulin/PYY. Examples of small molecules that bind proteins include, but are not limited to, monoclonal antibodies/cytotoxic drugs (e.g., vinblastine, vincristine, doxorubicin, colchicine, actinomycin D, etoposide, taxol, puromycin, and gramicidin D).

Examples of drugs that may be used in the practice of the present invention include, but are not limited to, hypnotics and sedatives such as sodium pentobarbital, phenobarbital, secobarbital, thiopental, amides and ureas exemplified by diethylisovaleramide and α -bromo-isovalerylurea, carbamates or disulfirane, heterocyclic hypnotics such as dioxopiperidines and glutaramides, antidepressants such as isocarboxazid, nialamide, phenelzine, imipramine, tranylcypromine, pargyline, tranquilizers such as chlorpromazine, promazine, fluphenazine, reserpine, despin, meprobamate, benzodiazepines such as chlorazinone, anticonvulsants such as promethione, phenytoin, phenbutamide, ethosuximine, intramuscular and anti-parkinsonian drugs such as memantin, meclodocaine, diphenhydramine, diphenon, diphenoxylate, phenidione, doxorazine, and diphenoxylate, such as doxorazine, doxoraline, doxorazine, such as doxorazine, and an, doxorazine, and an, such as doxorabicinamide, and an₁、PGE₂、PGF_lα、PGF_2αPGA; antibacterial agents such as penicillin, tetracycline, oxytetracycline, chlortetracycline, chloramphenicol, sulfonamides, tetracycline, bacitracin, chlortetracycline, erythromycin, isoniazid, rifampin, ethambutol, pyrazinamide, rifabutin, rifapentine, cycloserine, ethionamide, streptomycin, amikacin/kanamycin, capreomycin, p-aminosalicylic acid, levoOfloxacin, moxifloxacin and gatifloxacin, antimalarials such as 4-aminoquinolines, 8-aminoquinolines, pyrimethamine, chloroquine, sulfadoxine-pyrimethamine, mefloquine, atovaquone-proguanil, quinine, doxycycline, artemisinin (sesquiterpene lactone) and derivatives, leishmania resistant drugs (such as meglumine antimonate, sodium antimonate, amphotericin, miltefosine and paromomycin), trypanosomiasis resistant drugs (such as benznidazole and nifurtimox), amebic resistant drugs (such as metronidazole, tinidazole and diniconazole), antiprotozoal drugs (such as efluoro-ornithine, furazolidone, melarsinol, metronidazole, ornidazole, paromomycin sulfate, pentamidine, pyrimethamine and tinidazole), hormonal drugs such as prednisolone, cortisone, hydrocortisone, triamcinolone, tretinomycin, urocorticotropin, norgestrinone, isovalerolactone, isovaleramide, isovalerolactone, doxycycline, doxyc,Rimantadine, zanamivir, abacavir, didanosine, emtricitabine, lamivudine, stavudine, zalcitabine, zidovudine, tenofovir, efavirenz, delavirdine, nevirapine, loviramine, amprenavir, atazanavir, darunavir, furinavir, indinavir, lopinavir, nelfinavir, ritonavir, saquinavir, tipranavir, enfuvirtide, adefovir, fomivirsen, imiquimod, inosine, podophyllotoxin, ribavirin, viramidine, fusion blockers (e.g., gp-41 inhibitor (T-20), CCR-5 inhibitors) that specifically target viral surface proteins or viral receptors; anti-motion sickness drugs such as scopolamine, dimenhydrinate); idoxuridine, hydrocortisone, physostigmine, fosetyl-choline and iodide; and other beneficial agents.

In one embodiment of the invention, steroids are incorporated into the highly concentrated pharmaceutical granule formulation of the invention (e.g., testosterone, dehydroepiandrosterone, androstenedione, androstenediol, androsterone, dihydrotestosterone, estrogen, progesterone, prednisolone, pregnenolone, estradiol, estriol, estrone, and mixtures thereof).

Various forms of the above-described drugs may be used in the highly concentrated drug particle formulations of the present invention, including, but not limited to, the following: uncharged molecules; a molecular complex component; and pharmacologically acceptable salts such as hydrochloride, hydrobromide, sulfate, laurate, palmitate, phosphate, nitrate, borate, acetate, maleate, tartrate, oleate or salicylate. For acidic drugs, salts of metals, amines or organic cations, such as quaternary ammonium salts, may be used. In addition, simple derivatives of the drugs, such as esters, ethers, amides, and the like, which have solubility characteristics suitable for the purposes of the present invention, may also be used.

In another embodiment, a combination of small molecules may be incorporated into the highly concentrated drug particle formulations of the present invention. One or more such small molecules may each be incorporated into one or more highly concentrated drug particle formulations of the present invention and used alone or in combination. As another example, two or more small molecules may be conjugated and the combined small molecules may be formulated into highly concentrated drug particle formulations of the present invention (e.g., folate-conjugated vinca alkaloids: Reddy et al, Cancer Res.67(9):4434-4442 (2007)).

The highly concentrated pharmaceutical granule formulation of the present invention may be included in different dosage forms for drug delivery, such as solutions, dispersions, pastes, creams, particles, granules, tablets, emulsions, suspensions, powders, and the like. In addition to one or more drugs, the pharmaceutical formulation may optionally include pharmaceutically acceptable carriers and/or other ingredients such as antioxidants, stabilizers, buffers, and permeation enhancers. In a preferred embodiment, the highly concentrated drug particle formulation of the present invention is used to form a suspension formulation suitable for use in an osmotic delivery device.

The above drugs and others known to those skilled in the art are useful in methods of treatment for a variety of diseases and conditions, including, but not limited to, the following: chronic pain, hemophilia and other hematologic diseases, endocrine disorders, growth disorders, metabolic diseases, rheumatic diseases, diabetes (including type 2 diabetes), leukemia, hepatitis, renal failure, infectious diseases (including bacterial infections, viral infections (e.g., infections caused by human immunodeficiency virus, hepatitis c, hepatitis b, yellow fever, west nile, dengue fever, marburg, ebola, etc.) and parasitic infections), genetic diseases (e.g., cerebroside lipase deficiency and adenosine deaminase deficiency), hypertension, septic shock, autoimmune diseases (e.g., graves 'disease, systemic lupus erythematosus, multiple sclerosis and rheumatoid arthritis), shock and wasting diseases, cystic fibrosis, lactose intolerance, crohn's disease, inflammatory bowel disease, cancer (including colon and rectal), breast cancer, pancreatic cancer, renal failure, inflammatory bowel disease, leukemia, lung cancer, bladder cancer, kidney cancer, non-hodgkin's lymphoma, pancreatic cancer, thyroid cancer, endometrial cancer, prostate cancer, and other cancers. In addition, some of the above agents are useful in the treatment of infectious diseases requiring long-term treatment, including, but not limited to, tuberculosis, malaria, leishmaniasis, trypanosomiasis (african trypanosomiasis and south american trypanosomiasis), and parasitic worms.

The amount of drug in the highly concentrated drug particle formulation is that amount necessary to deliver a therapeutically effective amount of the active agent to achieve the desired therapeutic effect at the delivery site. In fact, it may vary depending on variables such as the particular active agent, site of delivery, severity of the disease, and desired therapeutic effect. Beneficial agents and dosage unit amounts thereof are well known in The art and are described in The Pharmacological Basis of Therapeutics, 1 st edition, (2005) of Goodman & Gilman: remington's Pharmaceutical Sciences, 18 th edition, (1995), mack publishing co.; and Martin's Physical Pharmacy and Pharmaceutical Sciences, version 1.00 (2005), Lippincott Williams & Wilkins. Typically, for osmotic drug delivery systems, the volume of the chamber containing the drug formulation is from about 100ul to about 1000ul, more preferably from about 140ul to about 200 ul. In one embodiment, the volume of the chamber containing the pharmaceutical formulation is about 150 ul.

The highly concentrated pharmaceutical particle formulation of the present invention is preferably chemically and physically stable at the delivery temperature for at least about 1 month, at least about 1.5 months, preferably at least about 3 months, preferably at least about 6 months, more preferably at least about 9 months, more preferably at least about 12 months. The delivery temperature is typically the body temperature of a normal human body, e.g. about 37 ℃ or slightly higher, e.g. about 40 ℃. Furthermore, the highly concentrated drug particle formulations of the present invention are preferably chemically and physically stable for at least about 3 months, preferably at least about 6 months, more preferably at least about 12 months at storage temperatures. Examples of storage temperatures include refrigeration temperatures, such as about 5 ℃; or room temperature, e.g., about 25 ℃.

Highly concentrated drug particle formulations may be considered to be chemically stable provided that less than about 25%, preferably less than about 20%, more preferably less than about 15%, more preferably less than about 10% and more preferably less than about 5% of drug particle breakdown products are formed after about 3 months, preferably after about 6 months, preferably after about 12 months and preferably after about 24 months at the delivery temperature.

Highly concentrated drug particle formulations may be considered to be physically stable, provided that less than about 10%, preferably less than about 5%, more preferably less than about 3%, more preferably less than about 1% drug aggregates are formed after about 3 months, preferably after about 6 months, at the delivery temperature and after about 6 months, preferably after about 12 months, at the storage temperature.

Example 3A provides representative data relating to the stability of highly concentrated drug particle formulations of the present invention.

When the drug in the highly concentrated drug particle formulation is a protein, the protein solution is maintained in a frozen condition and lyophilized or spray dried to a solid state. The Tg (glass transition temperature) may be a factor considered to result in a stable protein composition. While not wishing to be bound by any particular theory, the theory of forming high Tg amorphous solids to stabilize peptides, polypeptides, or proteins has been used in the pharmaceutical industry. Generally, if an amorphous solid has a higher Tg, e.g. 100 ℃, the protein has no mobility when stored at room temperature or even at 40 ℃, since the storage temperature is below Tg. Using molecular information calculations it has been demonstrated that if the glass transition temperature is above the storage temperature of 50 ℃, there is zero mobility of the molecules. Zero mobility of the molecule correlates with better stability. The Tg is also dependent on the moisture level in the product formulation. Generally, the more moisture, the lower the Tg in the composition.

Thus, in some aspects of the invention, excipients with higher Tg's may be included in protein formulations to improve stability, for example, sucrose (Tg 75 ℃) and trehalose (Tg 110 ℃). Preferably, the granule formulation may be formed using, for example, spray drying, lyophilization, dehydration, freeze drying, grinding, granulation, ultrasonic droplet generation (drop crystallization), crystallization, precipitation, or other available techniques in the art for forming granules from a mixture of ingredients. The particles are preferably substantially uniform in shape and size.

Typical spray drying methods may include, for example, subjecting a composition comprising a small molecule or protein, such as an incretin mimetic (e.g., exenatide: example 1); and a spray solution of stabilizing excipient is loaded into the sample chamber. The sample chamber is typically maintained at a desired temperature, for example, a refrigerated temperature to room temperature. Refrigeration generally promotes drug stability. The solution, emulsion or suspension is introduced into a spray dryer where the fluid is atomized into droplets. The droplets may be formed by using a rotary atomizer, a pressure atomizing nozzle, a pneumatic atomizing nozzle, or a sonic nozzle. The droplet mist is immediately contacted with a drying gas in a drying chamber. The drying gas removes the solvent from the droplets and carries the particles into a collection chamber. Factors that may affect yield during spray drying include, but are not limited to, charge localized on the particles (which may promote adhesion of the particles to the spray dryer) and aerodynamics of the particles (which may make it difficult to collect the particles). In general, the yield of the spray-drying process depends in part on the particle formulation.

In one embodiment of the invention, the particles are sized such that they can be delivered through an implantable osmotic drug delivery device. Consistent particle shape and size typically help provide consistent and uniform release rates from such drug delivery devices; however, particle formulations with abnormal particle size distribution characteristics may also be used. For example, in a typical implantable osmotic delivery device having a delivery orifice, the particle size is less than about 30%, more preferably less than about 20%, more preferably less than about 10% of the delivery orifice diameter. In one embodiment of a particle formulation for use in an osmotic drug delivery system, where the delivery orifice of the implant is about 0.5mm in diameter, the particle size may be, for example, from less than about 150 microns to about 50 microns. In one embodiment of a particle formulation for use in an osmotic drug delivery system, where the delivery orifice of the implant is about 0.1mm in diameter, the particle size may be, for example, from less than about 30 microns to about 10 microns. In one embodiment, the orifice is about 0.25mm (250 microns) and the particle size is about 2 microns to about 5 microns.

Typically, the particles of the particle formulations of the present invention do not sediment at the delivery temperature for less than about 3 months, preferably do not sediment for less than about 6 months, more preferably do not sediment for less than about 12 months, more preferably do not sediment for less than about 24 months, and most preferably do not sediment for less than about 36 months at the delivery temperature when incorporated into a suspension vehicle. The suspending vehicle typically has a viscosity of from about 5,000 to about 30,000 poise, preferably from about 8,000 to about 25,000 poise, more preferably from about 10,000 to about 20,000 poise. In one embodiment, the suspending vehicle has a viscosity of about 15,000 poise ± about 3,000 poise. In general, smaller particles tend to have a lower settling rate in the viscous suspension vehicle than larger particles. Thus, micron to nanometer sized particles are typically desirable. Based on simulation modeling studies, in viscous suspension formulations, it is desirable that particles from about 2 microns to about 10 microns of the present invention do not settle at room temperature for at least 20 years. In one embodiment of the particle formulation of the present invention for use in an implantable osmotic drug delivery device, the particles are included in a size of less than about 50 microns, more preferably less than about 10 microns, and more preferably from about 2 to about 7 microns.

In one embodiment, the highly concentrated pharmaceutical granule formulation of the present invention comprises one or more drugs as described above and one or more other ingredients (e.g., one or more stabilizers). The stabilizer may be, for example, a carbohydrate, an antioxidant, an amino acid, a buffer, an inorganic compound, or a surfactant. The amount of stabilizer and buffer in a granular formulation can be determined experimentally based on the activity of the stabilizer and buffer and the desired formulation characteristics. Typically, the amount of carbohydrate in the formulation is determined by focusing on aggregation. Generally, the carbohydrate level should not be too high to avoid promoting crystal growth in the presence of water due to excess carbohydrate not being bound to the drug. Typically, the amount of antioxidant in the formulation is determined by focusing on oxidation, while the amount of amino acids in the formulation is determined by focusing on oxidation and/or the formability of the granules during spray drying. Typically, the amount of buffer in the formulation is determined by concerns about pre-processing, concerns about stability and formability of the particles during spray drying. Buffers may be required to stabilize the drug during processing, such as solution preparation and spray drying, in solubilizing all excipients.

Examples of carbohydrates that may be included in the granular formulation include, but are not limited to, monosaccharides (e.g., fructose, maltose, galactose, glucose, D-mannose, and sorbose), disaccharides (e.g., lactose, sucrose, trehalose, and cellobiose), polysaccharides (e.g., raffinose, melezitose, maltodextrin, dextran, and starch), and sugar alcohols (non-cyclic polyols; e.g., mannitol, xylitol, maltitol, lactitol, xylitol sorbitol, pyranosyl sorbitol, and inositol). Preferred carbohydrates include disaccharides and/or non-reducing sugars, such as sucrose, trehalose and raffinose.

Examples of antioxidants that may be included in the particulate formulation include, but are not limited to, methionine, ascorbic acid, sodium thiosulfate, catalase, platinum, ethylenediaminetetraacetic acid (EDTA), citric acid, cysteines, thioglycerol, thioglycolic acid, thiosorbitol, butylated hydroxyanisole, butylated hydroxytoluene, and propyl gallate. In addition, readily oxidizable amino acids can be used as antioxidants, such as cysteine, methionine and tryptophan. The preferred antioxidant is methionine.

Examples of amino acids that may be included in the granule formulation include, but are not limited to, arginine, methionine, glycine, histidine, alanine, L-leucine, glutamic acid, iso-leucine, L-threonine, 2-aniline, valine, norvaline, juglandose, phenylalanine, tryptophan (trytophan), serine, asparagine, cysteine, tyrosine, lysine and norleucine. Preferred amino acids include those that are readily oxidized, e.g., cysteine, methionine, and tryptophan.

Examples of buffering agents that may be included in the particle formulation include, but are not limited to, citrate, histidine, succinate, phosphate, maleate, tris, acetate, carbohydrate, and gly-gly. Preferred buffers include citrate, histidine, succinate and tris.

Can include mineralization in granular formulationsExamples of compounds include, but are not limited to, NaCl, Na₂SO₄、NaHCO₃、KCl、KH₂PO₄、CaCl₂And MgCl₂。

In addition, the granule formulation may include other excipients such as surfactants and salts. Examples of surfactants include, but are not limited to, polysorbate 20, polysorbate 80,(BASF Corporation, MountOlive, NJ) F68 and Sodium Dodecyl Sulfate (SDS). Examples of salts include, but are not limited to, sodium chloride, calcium chloride, and magnesium chloride.

All ingredients included in the granular formulation are typically pharmaceutically acceptable for use in mammals, particularly humans.

Table 1 below provides examples of particle formulation composition ranges for particles comprising protein (the range values are approximate, e.g., in the column for "range," protein is present in an amount of about 25 wt% to about 80 wt%). Although preferred embodiments include proteins, carbohydrates, antioxidants, and/or amino acids and buffers, some embodiments, for example, may include only proteins and carbohydrates; proteins and antioxidants; protein and buffer; proteins, carbohydrates and antioxidants; protein, carbohydrate, and buffer; proteins, antioxidants and buffers; wherein the wt% range of protein is specified in table 1 and the remaining wt% consists of selected other ingredients. Thus, in some embodiments, a granular formulation may comprise, while in other embodiments, consist essentially of, selected ingredients. Furthermore, as described above, the granular formulation of the present invention may comprise other excipients and/or stabilizers. A preferred embodiment of the invention consists essentially of protein, with approximate wt% ranges provided in table 1, plus selected stabilizers (e.g. carbohydrates and/or antioxidants and/or amino acids and/or buffers and combinations thereof) to bring the total wt% essentially to 100%. Small molecules may also be formulated as described herein. Typically, the range of wt% of small molecules selected is the same as the range provided for proteins in table 1.

TABLE 1

Some preferred levels of particle loading in suspension formulations are below about 40%, below about 30%, below about 20%, and below about 10%, with lower levels of particle loading in suspension formulations typically being greater than about 0.1%, greater than about 1%, and preferably greater than about 5%. Several exemplary embodiments of the highly concentrated drug particle formulations of the present invention are illustrated in example 1, wherein the drug is a protein.

Table 2 below provides examples of compositional ranges for particulate formulations comprising particles of an incretin mimetic, such as glucagon-like peptide-1 (GLP-1), a GLP-1 derivative (such as GLP-1(7-36) amide), or a GLP-1 analog, exenatide, an exenatide derivative, or an exenatide analog. The description of the specific embodiments described in table 1 also applies to the formulations described in table 2.

TABLE 2

Within the weight percent range of the components of the granule formulation, some preferred ratios of the components are as follows: the ratio of drug to one or more other ingredients (e.g., stabilizers) is 1:4, 1:3, 1:2, 1:1, 2:1, 2.5:1, 5:1, 10:1, 16:1, and 20:1, preferably about 1:4 to 10:1 (i.e., about 1 to 10:4-1), or preferably about 1:3 to 5:1 (i.e., 1 to 5: 3-1). The invention also includes ranges corresponding to ratios of all of these drugs to other ingredients (e.g., stabilizers), such as about 1:1 to 2:1 (i.e., 1 to 2:1), about 1:4 to about 20:1 (i.e., about 1 to 20:4-1), about 1:4 to about 16:1 (i.e., about 1 to 16:4-1), about 1:3 to about 10:1 (i.e., about 1 to 10:3-1), about 1:2 to about 20:1 (i.e., about 1 to 20:2-1), and the like.

Accordingly, the present invention includes, in one aspect, a granular formulation comprising from about 25 wt% to about 80 wt%, preferably from about 40 wt% to about 75 wt%, of a drug; and about 75% wt% to about 20% wt%, preferably about 60% wt% to about 25% wt% of one or more other ingredients, such as a stabilizer selected from the group consisting of antioxidants, carbohydrates, and buffers, wherein the ratio of drug to antioxidant to carbohydrate to buffer is about 2-20:1-5:1-5:1-10, preferably about 5-10:1-2.5:1-2.5: 1-5. Typically, the granular formulations of the present invention comprise less than about 10 wt%, preferably less than about 5 wt% residual moisture.

Examples of the present granule formulations include, but are not limited to, protein drugs, methionine antioxidants, sucrose carbohydrates and citrate buffers, wherein the protein comprises about 40 wt% to about 70 wt% of the granule formulation and the ratio of protein to other ingredients is about 1:2 to 3:1 (i.e., about 1-3: 2-1). Specific proteins exemplified below include interferons and incretin mimetics (example 1).

In summary, the selected drug or combination of drugs is formulated in a dry powder in a solid state that maintains the maximum chemical and biological stability of the drug. The particle formulation provides long term storage stability at elevated temperatures and thus allows for the delivery of a stable and biologically effective drug to a subject over an extended period of time. In one embodiment, the peptides, polypeptides or proteins in the highly concentrated pharmaceutical granule formulation of the present invention can be stably transported and/or stored without refrigeration or freezing. Peptides, polypeptides, or proteins cannot be stably transported and/or stored without the stability provided by the highly concentrated pharmaceutical granule formulations of the present invention, which may otherwise require refrigeration or freezing conditions for transport and storage. For example, highly concentrated pharmaceutical granule formulations are placed in sterile vials or ampoules. In use, the granular formulation of the present invention can be rapidly re-dissolved with, for example, water for injection into a highly concentrated solution of water, and then administered to a subject by bolus injection.

For example, the particle size distribution (0.1 microns to 20 microns) of the dried particle powder can be adequately controlled by spray drying or freeze drying processes for preparing granular formulations. The process parameters for forming the dry powder are optimized to produce particles having the desired particle size distribution, density, and surface area.

Selected excipients and buffers in highly concentrated pharmaceutical granule formulations may provide, for example, the following functions: density improvement of the dry powder; protecting the chemical stability of the drug; maintaining the physical stability of the drug (e.g., high glass transition temperature and avoidance of phase-to-phase transition); producing a homogeneous dispersion in suspension; improving hydrophobicity and/or hydrophilicity to control solubility of the dry powder in a selected solvent; and controlling the pH and maintaining the pH (for solubility and stability) of the product during processing.

3.2.0 vehicle formulations and suspension formulations

In one aspect of the invention, the suspension vehicle provides a stable environment in which the highly concentrated drug particle formulation is dispersed. Highly concentrated pharmaceutical granule formulations are chemically and physically stable in the suspending vehicle (as described above). The suspension vehicle typically comprises one or more polymers and one or more solvents that form a solution of sufficient viscosity to uniformly suspend the drug-containing particles. The suspending vehicle may contain other ingredients including, but not limited to, surfactants, antioxidants, and/or other compounds that are soluble in the vehicle.

The viscosity of the suspension vehicle is typically sufficient to prevent sedimentation of the highly concentrated drug particle formulation during storage and use in a delivery method, such as in an implantable drug delivery device. The suspension vehicle is biodegradable, i.e., the suspension vehicle is broken down or destroyed in response to a biological environment over a period of time, while the highly concentrated drug particles dissolve in the biological environment and the active pharmaceutical ingredient in the particles is absorbed.

The solvent in which the polymer is dissolved can affect the properties of the suspension formulation, such as the behavior of a highly concentrated drug particle formulation during storage. The solvent and polymer combination may be selected such that the resulting suspended carrier exhibits phase separation upon contact with an aqueous environment. In some embodiments of the invention, the solvent and polymer combination may be selected such that the resulting suspension vehicle exhibits phase separation when contacted with an aqueous environment having less than about 10% water.

The solvent may be an acceptable solvent that is immiscible with water. The solvent may also be selected so that the polymer is dissolved in the solvent at a high concentration, for example, a polymer concentration greater than about 30%. Examples of solvents useful in the practice of the present invention include, but are not limited to, lauryl alcohol, benzyl benzoate, benzyl alcohol, lauryl lactate, decyl alcohol (also known as decyl alcohol), ethylhexyl lactate, and long chain (C)₈To C₂₄) Fatty alcohols, esters or mixtures thereof. The solvent used to suspend the carrier may be "dry," i.e., it has a low moisture content. Preferred solvents for suspending the carrier formulation include lauryl lactate, lauryl alcohol, benzyl benzoate and mixtures thereof.

Examples of polymers for use in the suspending vehicle formulations of the present invention include, but are not limited to, polyesters (e.g., polylactic acid or polylactic polyglycolic acid), pyrrolidone-containing polymers (e.g., polyvinylpyrrolidone (PVP) having a molecular weight ranging from about 2,000 to about 1,000,000), esters or ethers of unsaturated alcohols (e.g., vinyl acetate), polyoxyethylene polyoxypropylene block copolymers, or mixtures thereof. In one embodiment, the polymer is PVP having a molecular weight of 2,000 to 1,000,000. In a preferred embodiment, the polymer is polyvinylpyrrolidone K-17 (typically having an average molecular weight of about 7,900-10,800). Polyvinylpyrrolidone is characterized by its K-value (e.g., K-17), which is the viscosity index. The polymer used for the suspension vehicle may comprise one or more different polymers, or may comprise different grades of a single polymer. The polymer used for the suspending vehicle may also be dry or have a low moisture content.

In general, the suspending vehicle of the present invention may vary in the composition based on the desired characteristic properties. In one embodiment, the suspension vehicle may comprise from about 40 wt% to about 80 wt% polymer and from about 20 wt% to about 60 wt% solvent. Preferred embodiments of the suspending vehicle include vehicles formed by combining a polymer and a solvent in the following ratios: about 25 wt% solvent and about 75 wt% polymer; about 50 wt% solvent and about 50 wt% polymer; about 75 wt% solvent and about 25 wt% polymer. Thus, in some embodiments, the suspension vehicle may comprise, while in other embodiments, consist essentially of, selected ingredients.

The suspension vehicle may exhibit newtonian behavior. The suspending vehicle is typically formulated to provide a viscosity that maintains uniform dispersion of the particulate formulation for a predetermined period of time. This facilitates the preparation of a suspension formulation suitable for providing controlled delivery of a drug contained in a highly concentrated drug particle formulation. The viscosity of the suspending vehicle may vary depending on the desired application, the size and type of the particulate formulation, and the addition of the particulate formulation to the suspending vehicle. The viscosity of the suspending vehicle can be varied by varying the type and relative amount of solvent or polymer used.

The suspending vehicle may have a viscosity ranging from about 100 poise to about 1,000,000 poise, preferably from about 1,000 poise to about 100,000 poise. In a preferred embodiment, the suspending vehicle typically has a viscosity of from about 5,000 to about 30,000 poise, preferably from about 8,000 to about 25,000 poise, more preferably from about 10,000 to about 20,000 poise at 33 ℃. In one embodiment, the suspending vehicle has a viscosity of about 15,000 poise ± about 3,000 poise at 33 ℃. A parallel plate rheometer can be used at 10^-4The viscosity was measured at 33 ℃ at a shear rate per second.

The suspension vehicle may exhibit phase separation upon contact with an aqueous environment; typically, however, the suspending vehicle exhibits substantially no phase separation with changes in temperature. For example, the suspending vehicle typically does not exhibit phase separation over a temperature range of about 0 ℃ to about 70 ℃ and under temperature cycling (e.g., cycling from 4 ℃ to 37 ℃ to 4 ℃).

The suspension vehicle can be prepared by combining the polymer and solvent under dry conditions, for example, in a drying oven. The polymer and solvent can be combined at an elevated temperature, e.g., about 40 ℃ to about 70 ℃, and allowed to liquefy and form a single phase. The ingredients may be mixed under vacuum to remove air bubbles generated in the dried ingredients. The ingredients may be combined using a conventional mixer such as a twin screw blade or similar mixer (set at a speed of about 40 rpm). However, higher speed mixing of the components may also be used. Once a liquid solution of the ingredients is obtained, the suspension vehicle can be allowed to cool to room temperature. Differential Scanning Calorimetry (DSC) can be used to verify that the suspension vehicle is a single phase. In addition, the components of the carrier (e.g., solvent and/or polymer) can be treated to substantially reduce or substantially remove peroxides (e.g., by treatment with methionine; see, e.g., U.S. patent application publication No. 2007-0027105).

The highly concentrated drug particle formulation is added to a suspension vehicle to form a suspension formulation. In some embodiments, a suspension formulation may comprise, while in other embodiments, consist essentially of, a highly concentrated drug particle formulation and a suspension vehicle.

The suspension formulation may be prepared by dispersing the particle formulation in the suspension vehicle. The suspension vehicle may be heated and the particulate formulation added to the suspension vehicle under dry conditions. The ingredients may be mixed under vacuum at elevated temperatures, e.g., from about 40 ℃ to about 70 ℃. The ingredients may be mixed at a sufficient speed (e.g., about 40rpm to about 120rpm) and for a sufficient amount of time (e.g., about 15 minutes) to provide a uniform dispersion of the particle formulation in the suspending vehicle. The mixer may be a twin screw blade or other suitable mixer. The resulting mixture may be removed from the mixer, sealed in a dry container to prevent water contamination of the suspension formulation, and allowed to cool to room temperature prior to further use, e.g., loading into an implantable drug delivery device, unit dose container, or multi-dose container.

The suspension formulations typically have a total moisture content of less than about 10 wt%, preferably less than about 5 wt% and more preferably less than about 4 wt%.

The suspension formulations of the present invention are illustrated with reference to an incretin mimetic and interferon (example 2). In addition, the stability of the drug particle formulation suspended in biocompatible, single-phase and non-aqueous vehicles is described in example 3B. These examples are not intended to be limiting.

In summary, the components of the suspension vehicle provide biocompatibility. The components of the suspension vehicle provide suitable chemical-physical properties to form a stable suspension of highly concentrated drug particle formulations. These properties include, but are not limited to, the following: the viscosity of the suspension; the purity of the carrier; residual moisture of the carrier; the density of the support; compatibility with dry powders; compatibility with implantable devices; the molecular weight of the polymer; stability of the carrier; as well as the hydrophobicity and hydrophilicity of the carrier. These properties can be exploited and controlled, for example, by varying the carrier composition and manipulating the ratios of ingredients used in the suspension carrier.

4.0.0 delivery of suspension formulations

The suspension formulations described herein may be used in implantable drug delivery devices to provide sustained delivery of the compound over an extended period of time (e.g., weeks, months, or up to about 1 year), for example, at least about 1 month, at least about 1.5 months, preferably at least about 3 months, preferably at least about 6 months, more preferably at least about 9 months, more preferably at least about 12 months. Such implantable drug delivery devices are typically capable of delivering the compound at a desired flow rate over a desired period of time. The suspension formulation is loaded into the implantable drug delivery device by conventional techniques.

The suspension formulation may be delivered, for example, using osmotic, mechanical, electromechanical, or chemically driven drug delivery devices. The highly concentrated drug particle formulation is delivered at a flow rate that delivers a therapeutically effective drug to a subject in need of drug therapy.

The medicament may be administered for a period ranging from more than about 1 week to about 1 year or more, preferably from about 1 month to about 1 year or more, more preferably from about 3 months to about 1 year or moreAnd (4) delivering. The implantable drug delivery device may include a reservoir having at least one aperture through which the drug is delivered. The suspension formulation may be stored in the reservoir. In one embodiment, the implantable drug delivery device is an osmotic drug delivery device, wherein delivery of the drug is osmotically driven. Some osmotic drug delivery devices and their components have been described, for exampleDrug delivery devices or the like (see, e.g., U.S. Pat. Nos. 5,609,885, 5,728,396, 5,985,305, 5,997,527, 6,113,938, 6,132,420, 6,156,331, 6,217,906, 6,261,584, 6,270,787, 6,287,295, 6,375,978, 6,395,292, 6,508,808, 6,544,252, 6,635,268, 6,682,522, 6,923,800, 6,939,556, 6,976,981, 6,997,922, 7,014,636, 7,207,982, 7,112,335, 7,163,688, U.S. patent publication Nos.2005-0175701, 2007-0281024, and 2008-0091176).

Drug delivery devices typically consist of a cylindrical reservoir containing an osmotic power source (engine), a piston, and a drug formulation. The reservoir is terminated at one end by a rate controlling semi-permeable membrane and the other end by a diffusion regulator through which the drug formulation is released from the drug reservoir. The piston separates the drug formulation from the osmotic power source and utilizes a seal to prevent water in the osmotic power source compartment from entering the drug reservoir. The diffusion moderator is designed to interface with the drug formulation to prevent body fluids from entering the drug reservoir through the aperture.

The device releases the drug at a predetermined rate based on the osmotic principle. Entry of extracellular fluidDevices, i.e. direct access to salt kinetics through semi-permeable membranesA source, the salt power source diffusing to drive the piston at a slow and smooth delivery rate. Movement of the piston forces the drug formulation to be released through the orifice or exit port at a predetermined shear rate. In one embodiment of the present invention, the substrate is,the reservoir of the device is loaded with a suspension formulation of the present invention comprising a highly concentrated drug particle formulation, wherein the device is capable of delivering the suspension formulation to a subject at a predetermined therapeutically effective delivery rate over an extended period of time (e.g., about 1, about 3, about 6, or about 12 months).

Implantable devices such asThe device provides the following benefits of beneficial high concentration active granule formulation administration: the pharmacokinetic true 0-order release of beneficial agents; long release time (e.g., up to about 12 months); patient compliance and reliable delivery and administration of active agents.

Other implantable drug delivery devices may be used in the practice of the present invention and may include regulator-type implantable pumps that provide constant, adjustable, or programmable flow of the compound, such as those available from Codman & Shurtleff, Inc.

The amount of highly concentrated drug particle formulation used in the delivery device of the present invention is that amount necessary to deliver a therapeutically effective amount of the active agent to achieve the desired therapeutic effect. In practice, this will depend on such variables as the particular active agent, site of delivery, severity of the disease and the desired therapeutic effect. Examples of approximate release rates for typical highly concentrated drug particle formulations of the present invention are provided in example 4, including the release rate of exenatide (fig. 2,3 and 5) and the release rate of omega interferon (fig. 1 and 4).

The data provided in fig. 4 and 5 illustrate another aspect of the invention in which highly concentrated drug particles of the invention can be used in a method of controlling the rate of drug release by varying the weight percentage of particles loaded into a suspension formulation, the concentration of drug in the particle formulation, or both. This method is useful for preparing osmotic drug delivery devices capable of delivering a specific concentration of drug over time, where a series of stock particle formulations covering drug concentration/particle range can be used individually or in combination to provide a selected concentration of drug over time within a particle loading concentration range. This can provide for effectiveness in the manufacturing process to prepare different dosing regimens or even to provide for dedicated individual dosing, e.g. according to body weight. Thus, different dosage levels can be provided as desired.

Typically, for osmotic drug delivery devices, the beneficial agent compartment containing the beneficial agent has a volume of from about 100ul to about 1000ul, more preferably from about 120ul to about 500ul, and more preferably from about 150ul to about 200 ul.

Typically, the osmotic drug delivery device is implanted into a subject, for example subcutaneously. The device may be inserted subcutaneously into one or both arms (e.g., on the medial, lateral, or dorsal side of the upper arm) or into the abdomen. The preferred location on the abdomen is the extended area under the skin of the abdomen, under the ribs and on the waistline. To provide multiple locations for inserting one or more osmotic drug delivery devices in the abdomen, the abdominal wall may be divided into the following 4 quadrants: the upper right quadrant extends 5-8 cm below the right lateral rib and about 5-8 cm to the right of the midline, the lower right quadrant extends 5-8 cm above the waist line and 5-8 cm to the right of the midline, the upper left quadrant extends 5-8 cm below the left lateral rib and about 5-8 cm to the left of the midline, and the lower left quadrant extends 5-8 cm above the waist line and 5-8 cm to the left of the midline. This provides a variety of useful locations for implantation of one or more devices at one or more times.

The suspension formulations of the present invention containing highly concentrated drug particle formulations may also be delivered from drug delivery devices that are not implantable or implanted, e.g., external pumps such as peristaltic pumps for subcutaneous delivery in a hospital setting.

The suspension formulations of the present invention may also be used in infusion pumps, for example(DURECT Corporation, Cupertino CA) osmotic pump, which is a micro infusion pump for continuous administration to test animals (e.g., mice and rats).

The suspension formulations of the present invention may also be used in the form of an injection to provide a high concentration bolus dose of the drug.

By osmotic delivery devices, e.g.Some of the advantages and benefits of the suspension formulations of the present invention delivered by the device include, but are not limited to, the following. Increased therapeutic compliance may produce better results, and this increased compliance may be achieved using implantable osmotic drug delivery devices. The therapeutic effect may be improved due to implantable osmotic devices such asThe device can provide continuous and consistent drug delivery 24 hours per day. In addition, unlike other sustained release preparations and depot injections, when used, the injection is administeredWhen the device is administered, for example, if a safety issue arises for a particular subject, the administration of the drug can be immediately discontinued by removing the device.

The invention also includes methods of making formulations of the invention, including the granular formulations, suspension vehicles, and suspension formulations described above. The invention also includes methods of manufacturing an osmotic delivery device comprising, for example, loading a selected suspension formulation into a reservoir of the osmotic delivery device.

5.0.0 suspension formulation applications

The suspension formulations described herein provide a promising alternative to many therapies requiring daily administration of selected drugs. For example, suspension formulations of the present invention comprising highly concentrated incretin mimetic particle formulations are useful for the treatment of diabetes (e.g., diabetes and gestational diabetes) and diabetes-related disorders (e.g., diabetic cardiomyopathy, insulin resistance, diabetic neuropathy, diabetic nephropathy, diabetic retinopathy, cataracts, hyperglycemia, hypercholesterolemia, hypertension, hyperinsulinemia, hyperlipidemia, atherosclerosis, and tissue ischemia, particularly myocardial ischemia), as well as hyperglycemia (e.g., associated with medical treatment with increased risk of hyperglycemia, including beta-blockers, thiazide diuretics, corticosteroids, nicotinic acid, pentamidine, protease inhibitors, L-asparaginase, and certain antipsychotics), reduction of food intake (e.g., treatment of obesity), Control appetite or weight loss), stroke, hypolipidemic, acute coronary syndrome, hibernating myocardium, regulating gastrointestinal motility, and increasing urinary flow.

In addition, the suspension formulations of the present invention may be potential modulators of appetite in subjects treated with the formulations.

As another example, highly concentrated pharmaceutical particle formulations comprising interferon may be used to treat interferon-responsive diseases, such as viral infections, immune disorders, and cancer. Treatment of such interferon-responsive diseases is typically carried out over an extended period of time. For example, omega interferon may be used to treat viral infections such as flavivirus infections (e.g., hepatitis C, yellow fever and West Nile: Buckwold, V.E., et al, anti Research 73:118-125 (2007)). Non-compliance with dosing regimens has historically been a problem with such long-term treatments. When provided, for example, in an osmotic delivery device, the suspension formulations of the present invention provide the ideal alternative to daily injection.

In one embodiment, the suspension formulation is administered using an osmotic delivery device as described above. The release rate of the suspension formulations of the present invention provide osmotic drug delivery systems that deliver drug consistently and consistently at delivery rates selected over an extended period of time. An example of the delivery rate achieved using a suspension formulation of the present invention is provided in example 4. The release rate data shows that the drug was consistently and consistently delivered at an approximate delivery rate of 50 ug/day for interferon (figure 1), 75 ug/day for exenatide (figure 2), and 80 ug/day for exenatide (figure 3).

The exit (exit) shear rate of the suspension formulation from the osmotic delivery device is determined such that the target daily delivery rate of the drug is suitably achieved by substantially continuously and consistently delivering the suspension formulation from the osmotic delivery device. Examples of outlet shear rates include, but are not limited to, about 1 to about 1x 10^-7Reciprocal seconds, preferably about 4x 10^-2To about 6x 10^-4Reciprocal seconds, more preferably 5x 10^-3To 1x 10^-3The last few seconds.

6.0.0 osmotic drug delivery device

For example, highly concentrated drug particle formulations of the present invention can be delivered using an osmotic delivery system. In one embodiment, the present invention relates to the use of osmotic drug delivery devices having a reduced size relative to currently used osmotic drug delivery devices. Figure 6B shows a schematic representation of an osmotic delivery system having dimensions of about 45mm in length and about 3.8mm in diameter. Osmotic Delivery devices of this size have been used to deliver, for example, omega interferon particle suspension formulations and exenatide (exintede) particle suspension formulations ("Continuous Delivery of Stabilized Proteins and Peptides at Consistent rates for at least one free thread Three from the sameDevice, "2008 American Association of Pharmaceutical Sciences, Annual Meeting and Exposion, Poster No. T3150, Nov.18,2008, Yang, B. et al: "A Phase 1b Study of ITCA 650 ContinuousSubcutaneous Delivery of Exenatide viaDevice powers Fating and Postprandial Plasma Glucose, "American Diabetes Association 69th scientific sessions, June 5-9,2009, Luskey, K.et al; and "A Phase Ib Study of ITCA 650: Continuous Subcutaneous Delivery of Exenatide viaDevice LowersFating and Postprandial Plasma Glucose, "European Association for the student Diabetes 45th Annual Meeting, 9.29.10.3.2009, Luskey, K. The highly concentrated drug particle formulations of the present invention facilitate the use of osmotic drug delivery devices of even smaller size while still providing the ability to continuously provide long-term controlled amounts of drug delivery over time. For example, figure 6C shows a schematic representation of an osmotic delivery system having dimensions of about 30mm in length and about 3.8mm in diameter. By increasing the concentration of drug in the drug particle formulation, the amount of drug particle suspension formulation loaded into the osmotic delivery device may be reduced, the flow rate of the drug particle suspension formulation may be reduced and the size of the osmotic delivery device may be reduced while maintaining the ability to provide continuous long-term delivery of a predetermined amount of drug over time.

Embodiments of implantable osmotic drug delivery devices typically include the following components (see fig. 6A): an impermeable reservoir; an inner wall defining a cavity; a semipermeable membrane disposed over the first end of the reservoir; a first chamber capable of containing an osmotic agent; a piston; a second chamber capable of containing a pharmaceutical suspension formulation; and a diffusion moderator and an orifice at the second end of the reservoir. The first chamber is defined by a first surface of the semi-permeable membrane and a first surface adjacent the piston. The second chamber is defined by the second surface of the piston and the first surface of the diffusion reducer.

FIG. 6A depicts a diagram for practicing the present inventionExamples of drug delivery systems. In fig. 6A, an osmotic drug delivery device 10 is shown that includes a reservoir 12. The piston assembly 14 is located within and divides the reservoir chamberInto two chambers. In this example, chamber 16 contains a beneficial agent formulation and chamber 20 contains an osmotic agent formulation. A semipermeable membrane 18 is positioned distal to the reservoir, adjacent to a chamber 20 containing the osmotic agent formulation. A diffusion moderator 22 is located on the distal end of the reservoir 12 and fits snugly, the reservoir 12 being adjacent to the chamber 16 containing the suspension formulation containing the drug. The diffusion reducer 22 includes a delivery orifice 24. The diffusion reducer 22 may be any suitable flow device (flow device) having a delivery orifice. In this embodiment, a flow passage 26 is formed between the threaded diffusion moderator 22 and threads 28 formed on the interior surface of the reservoir 12. In alternative embodiments, the diffusion moderator may: for example, (i) is press-fit (or friction-fit) through the opening and contacts the smooth interior surface of the reservoir; or (ii) comprises two sheets having an outer shell constructed and arranged for positioning over the opening, an inner core inserted over the outer shell, and a fluid passageway having a spiral shape defined between the outer shell and the inner core (e.g., U.S. patent publication No. 2007-0281024).

Fluid is drawn into the chamber 20 through the semi-permeable membrane 18. The beneficial agent formulation is dispensed from the chamber 16 through a delivery orifice 24 in the diffusion reducer 22. The piston assembly 14 engages and seals against the interior wall of the reservoir 12, thereby isolating the osmotic agent formulation in the chamber 20 from fluid imbibed from the beneficial agent formulation in the chamber 16 through the semipermeable membrane 18. At steady state, the suspension formulation is expelled through the delivery orifice 24 in the diffusion moderator 22 at a rate equivalent to the rate at which external fluids are drawn into the chamber 20 through the semi-permeable membrane 18. Namely, it isDrug delivery devices release drug at a predetermined rate based on the osmotic principle. Extracellular fluid enters directly through a semi-permeable membraneAn osmotic power source of the drug delivery device that is expandable to drive the piston at a slow and consistent delivery rate. The piston motion forces the drug formulation to be released through the diffusion reducer orifice, resulting in substantially steady state drug delivery.

The semi-permeable membrane 18 may be in the form of a plunger (plug) that resiliently engages in sealing association with the interior surface of the reservoir 12. In fig. 6A, a device having protrusions frictionally engaging the semipermeable membrane 18 with the interior surface of the reservoir 12 is shown.

Embodiments of osmotic drug delivery devices having reduced size typically contain similar components as described with respect to fig. 6A. Osmotic drug delivery devices currently in use typically have the dimensions shown in fig. 6B, i.e., a length of about 45mm and a diameter of about 3.8 mm. An osmotic drug delivery device having a reduced size relative to currently used devices is shown in fig. 6C, which has dimensions of about 30mm in length and about 3.8mm in diameter. Marker bands (e.g., the laser marker bands shown in fig. 6B and 6C) are optional and may be used, for example, to mark devices with different doses or different drug suspensions to differentiate the devices and may also be used to assist in determining the desired insertion direction for implantation. External grooves (e.g., as shown in fig. 6B and 6C) are also optional and are typically used to aid in identifying the semi-permeable membrane end of the device and determining the desired direction of insertion of the device for implantation.

The reduced size osmotic drug delivery device reservoirs of the present invention are typically constructed of materials that are impermeable to the environment of use (e.g., body fluids) and to the osmotic agent and drug suspension formulation. Preferred materials for the reservoir include, but are not limited to, titanium and titanium alloys. Typical sizes of reservoirs for use in the devices of the present invention include osmotic drug delivery devices having an overall length of: from about 35mm to about 20mm in length, preferably from about 30mm to about 25mm in length, more preferably from about 28mm to 33mm in length and from about 8mm to about 3mm in diameter, preferably from about 3.8 to 4mm in diameter. In one embodiment, the osmotic delivery device has a length of about 30mm and a diameter of about 3.8 mm.

Typical embodiments of osmotic drug delivery device components and materials for their preparation can be found, for example, in the following documents: U.S. Pat. Nos. 5,728,396, 6,113,938, 6,132,420, 6,270,787, 6,375,978, 6,544,252, 6,508,808, 5,997,527, 6,524,305, 6,287,295, 7,163,688, 7,074,423, 7,014,636, 6,939,556, 7,207,982, 7,241,457, 7,407,499 and U.S. patent publication Nos.2005-0010196, 2005-0101943, 2005-0175701, 2007-0281024, 2008-0091176. Such components may be sized to provide an osmotic drug delivery device having a reduced size according to the teachings of the present specification.

In one embodiment, an osmotic drug delivery device that maintains substantially the same reservoir diameter between larger and smaller provides the following advantages: one size of component (e.g., semi-permeable membrane, piston, and diffusion moderator) can be made for both devices without reservoirs and the components can be used interchangeably between the two devices. Similarly, devices having a range of reservoir lengths can be provided, with the remaining components being used interchangeably to prepare multiple devices having different reservoirs of different lengths and thus different volumes and drug loading capacities.

7.0.0 some of the advantages of the highly concentrated pharmaceutical granule formulation of the present invention

Highly concentrated particles with active drug are used to prepare osmotic drug delivery devices that can deliver high doses of drug while keeping the overall size of the device small enough to facilitate implantation and remain acceptable to the patient. Highly concentrated drug particle formulations are particularly useful when high doses of the selected drug are required in order to effectively treat a disease or condition. Indeed, highly concentrated drug particle formulations expand the utility and application of osmotic drug delivery devices, making the devices useful for drugs with low potency, requiring dosages that are typically considered too high for such devices; such as proteins such as GLP-1, exenatide, PYY, oxyntomodulin, GIP, interferons (e.g., alpha interferon, beta interferon, gamma interferon, tau interferon, consensus alpha interferon, and variant interferons), antibodies, or small molecules such as testosterone or other steroids. Highly concentrated particles also facilitate the preparation of high dose osmotic drug delivery devices required for dose range studies for animal toxicology studies and human initial dose discovery studies.

Highly concentrated drug particles are also used to prepare osmotic drug delivery devices that can deliver therapeutic doses of drug for extended periods of time. They are particularly useful in the treatment of chronic diseases and disorders such as diabetes and obesity, where almost annually no device replacement is required. Example 5 shows that highly concentrated particles are used to prepare implantable osmotic drug delivery devices that can deliver drug doses at desired delivery rates.

In contrast, suspension formulations comprising a particle formulation containing a relatively low concentration of active drug (less than about 20%) require high particle loading to achieve high daily drug doses. Higher daily doses require higher weight percentages of particles and can lead to difficulties in the formulation being reasonably pumped through the device diffusion moderator, for example, such high particle loadings can lead to physical blockage of the outlet passage or device failure where the internal device pressure is sufficient to cause drainage from the semi-permeable membrane. While one possible solution may be to increase the diameter of the outlet channel and/or decrease the length of the outlet channel, this strategy can allow moisture from the bodily fluids to enter the drug formulation chamber through the diffusion moderator and cause drug instability or physical instability of the suspension and possibly device failure.

The higher concentration of drug in the particles serves to maintain particle loading of about 30% or less, 20% or less, or preferably 10% or less of the particles by weight of the total suspension formulation. Thus, advantages of the highly concentrated drug particle formulations of the present invention include the ability to provide higher concentrations of drug while maintaining lower particle loading in suspension formulations due to higher drug concentrations.

Highly concentrated drug particle formulations with higher concentrations of active drug may also have advantages in terms of production methods and overall yields. The production of particles typically starts with an aqueous solution of the drug, followed by a drying step, such as spray drying or lyophilization. In particular, proteins are unstable in aqueous solutions, and therefore it is important to minimize the period of time that the drug is exposed to water. The high concentration of the drug in solution means that a relatively low amount of water must be removed during the drying process and thus the drying process is fast. A faster drying process is particularly important for the preparation of drug particles containing drug molecules that are unstable to high temperatures and/or upon exposure to moisture.

Other benefits are that the particle size formed by the faster drying process is smaller than that formed using lower concentrations. Providing smaller particles further reduces the likelihood of clogging the diffusion moderator outlet channel and facilitates the application of smaller channel diameters and/or lengths for the reliability and performance of osmotic specific drug delivery device/formulation combinations, if desired.

Another advantage of the suspension formulation of the present invention comprising a highly concentrated drug particle formulation is the ability to deliver the drug using an osmotic drug delivery device of reduced size, while maintaining the ability to provide long-term, sustained delivery of the desired drug concentration. In one embodiment, the present invention relates to an osmotic drug delivery device having an overall length of from about 35mm to about 20mm in length, preferably from about 30mm to about 25mm in length, more preferably from about 28mm to 33mm in length and from about 8mm to about 3mm in diameter, preferably from about 3.8 to 4mm in diameter. An osmotic delivery device may be loaded with a suspension formulation of the present invention comprising a highly concentrated drug particle formulation. The advantages of using the osmotic delivery device of the present invention having a reduced size (as compared to current osmotic delivery devices, e.g., having the dimensions shown in fig. 6B) include, but are not limited to, (i) improved ease of implantation and removal; (ii) the number of possible implantation sites is large (e.g. on the underside of the arms and the whole abdominal area); and (iii) a reduction in the psychological impact on the patient in terms of implantation/removal of foreign bodies.

Furthermore, the ability to use a suspension formulation comprising the highly concentrated drug particle formulation of the present invention in a variety of different sized osmotic delivery devices allows for (the size of the device) and combines with the drug concentration in the suspension formulation to provide a device of a wide dosage form, drug concentration, and delivery duration size. For example, suspension formulations having the same drug concentration may be used in devices that deliver drug to different volumes by filling the reservoirs for at least about 1 month, at least about 1.5 months, preferably at least about 3 months, preferably at least about 6 months, more preferably at least about 9 months, and more preferably at least about 12 months.

Advantages of the highly concentrated pharmaceutical granule formulation of the present invention include improved drug stability, which allows for wide geographical distribution, e.g. no refrigeration required; and improving drug utilization by having poor solubility while being stable in highly concentrated drug granule formulations. Other advantages of suspension formulations comprising the highly concentrated drug particle formulations of the present invention include the ability to deliver more drug in a smaller volume, less non-drug ingredients of the suspension formulation, improved patient compliance with extended term therapy, and reduced potential drug side effects (e.g., nausea and/or vomiting) due to consistent drug delivery, no peak or trough drug concentrations.

Other objects will be apparent to those skilled in the art upon review of the following description and claims.

Experiment of

The following examples are put forth so as to provide those of ordinary skill in the art with a complete disclosure and description of how the devices, methods, and formulations of the present invention are made and used, and are not intended to limit the scope of what the inventors regard as their invention. Attempts have been made to ensure accuracy with respect to numbers used (e.g., amounts, temperature, etc.), but some experimental error and deviation should be accounted for. Unless otherwise indicated, parts are parts by weight, molecular weight is weight average molecular weight, temperature is in degrees celsius, and pressure is at or near atmospheric.

The compositions produced according to the invention meet the specifications for purity and content required for pharmaceutical products.

Example 1

Highly concentrated pharmaceutical granule formulation

This example describes the preparation of spray-dried granular formulations having a high concentration of active pharmaceutical ingredient (i.e., drug). The formulations of the present invention extend the drug loading in spray-dried powder formulations.

A. Preparation 1-omega interferon

Frozen batches of omega interferon solution 5g/L were thawed at 2-8 ℃ and added to 22mM sodium citrate buffer pH 5.9. The solution was dialyzed against sodium citrate to form a final solution with 14mg/ml omega interferon. The solution was then formulated with sucrose and methionine and spray dried using a Niro SD Micro spray dryer equipped with a 0.5L collection vessel. The pump feed was 400g/h, the sparger gas was 2.3kg/h, the sparger gas was at ambient temperature, the process gas outlet temperature was 140 ℃ and the process gas was 30 kg/h. The dry powder contained 35% omega interferon with 3.0% residual moisture. The ratio of the components in the granular preparation is as follows: 2:1:2:1 (omega interferon: methionine: sucrose: citrate buffer).

B. Preparation 2-exenatide

An exenatide solution is prepared as follows: 2.5g of exenatide is dissolved in a sodium citrate buffer solution with pH 5.8-6.0. The solution was dialyzed against a formulation solution comprising sodium citrate buffer, sucrose and methionine. The formulated solution was then spray dried using Buchi290 with a 0.7mm nozzle, an exit temperature of 85 deg.C, an atomization pressure of 100Psi, a solids content of 2% and a flow rate of 2.8 ml/min. The dry powder contained 44.82% exenatide with 3.8% residual moisture and a density of 0.2329 g/ml. The ratio of the components in the granular preparation is 5:1:1:3.5 (exenatide: methionine: sucrose: citrate buffer).

The drug concentration in the granular formulation was 44.82 wt%.

C. Preparation 3-Exenatide

An exenatide solution is prepared as follows: 13.7g of exenatide was dissolved in 50mM sodium citrate buffer pH 6.0. The solution was dialyzed against a formulation solution comprising sodium citrate buffer, sucrose and methionine. The formulated solution was then spray dried using a Niro SD Micro spray dryer fitted with a 0.5L collection vessel. The pump feed was 400g/h, the sparger gas was 2.3kg/h, the sparger gas was at ambient temperature, the process gas outlet temperature was 140 ℃ and the process gas was 30 kg/h. The dry powder contained 41.24% exenatide with 4.13% residual moisture. The ratio of the components in the granular preparation is as follows: 5:1:1:3.4 (exenatide: methionine: sucrose: citrate buffer).

The drug concentration in the granular formulation was 41.24 wt%.

D. Preparation of 4-omega interferon

Frozen batches of omega interferon solution containing omega interferon at a concentration of 5mg/mL were thawed at 2-8 ℃ and then dialyzed against sodium citrate solution at ph6.0 to form a solution with 14mg/mL omega interferon. The solution was then formulated with sucrose and methionine. The formulated solution was then spray dried using Buchi290 with a 0.7mm nozzle, an exit temperature of 80 ℃, an atomization pressure of 100Psi, a solids content of 2% and a flow rate of 2.8 ml/min. The dry powder contained 69% omega interferon with 4% residual moisture. The ratio of the components in the granular preparation is as follows: 6.8:1:1:1 (omega interferon: methionine: sucrose: citrate buffer).

The concentration of the drug in the granular preparation was 69 wt% (weight percent).

The formulations described in examples 1A-1D are summarized in table 3. In table 3, the weight percent of drug (wt% s) was determined directly using HPLC methods, while the wt% s of the other ingredients were based on calculations from the formulation and calibrated based on 0 wt% moisture. Thus, the weight percentages of the listed components add up to substantially 100%.

TABLE 3

Sodium citrate/citric acid form the citrate buffer of the granule formulation.

E. Preparation 5- -PYY

PYY solution was prepared as follows: 1g PYY was dissolved in 25mM sodium citrate buffer pH 5.0. The solution was dialyzed against a formulation solution comprising sodium citrate buffer, sucrose and methionine. The formulated solution was then spray dried using a Buchi290Micro spray dryer with a 0.7mm nozzle, an outlet temperature of 100 ℃, an atomization pressure of 100Psi, a solids content of 2% and a flow rate of 2.8 ml/min. The dry powder contained 27.6% PYY. The ratio of the components in the granular preparation is as follows: 1.8:1.0:2.2:1.5(PYY: methionine: sucrose: citrate buffer).

The concentration of PYY in the granular formulation was 27.6 wt%. In table 4, PYY weight percent (wt% s) was determined directly using HPLC methods, while the wt% s of the other ingredients were based on calculations from the formulation and calibrated based on 0 wt% moisture. Thus, the weight percentages of the listed components add up to substantially 100%.

TABLE 4

Composition (I)	Target granule formulation 5 (wt%)	Approximate solidification
			Sodium citrate	16.0	1.0
Citric acid	6.8	0.4
			Methionine	15.5	1.0
PYY	27.6	1.8
			Sucrose	34.1	2.2
Total of	100.0

Sodium citrate/citric acid form the citrate buffer of the granule formulation.

F. Preparation 6-oxyntomodulin

An oxyntomodulin solution was prepared as follows: 1g of oxyntomodulin was dissolved in 25mM sodium citrate buffer pH 4.0. The solution was dialyzed against a formulation solution comprising sodium citrate buffer, sucrose and methionine. The formulated solution was then spray dried using a Buchi290Micro spray dryer with a 0.7mm nozzle, an outlet temperature of 100 ℃, an atomization pressure of 100Psi, a solids content of 2% and a flow rate of 2.8 ml/min. The dry powder contained 43.3% oxyntomodulin. The ratio of the components in the granular preparation is as follows: 4.1:1.8:1:2.6 (oxyntomodulin: methionine: sucrose: citrate buffer).

The concentration of oxyntomodulin in the granule formulation was 43.3 wt%. In table 5, the weight percent oxyntomodulin (wt% s) was determined directly using the HPLC method, while the wt% s of the other ingredients were based on calculations from the formulation and calibrated based on 0 wt% moisture. Thus, the weight percentages of the listed components add up to substantially 100%.

TABLE 5

Composition (I)	Target granular formulation 6	Approximate solid ratio
			Sodium citrate	16.0	1.0
Citric acid	6.8	0.4
			Methionine	15.5	1.0
PYY	27.6	1.8
			Sucrose	34.1	2.2
Total of	100.0

Sodium citrate/citric acid form the citrate buffer of the granule formulation.

The data provided in example 1 demonstrates that the granular formulation of the present invention is capable of producing highly concentrated drug granules.

Example 2

Suspension formulation

This example describes the preparation of a suspension formulation comprising a suspension vehicle of the present invention and a particle formulation.

A. Suspension formulation 1-omega interferon

The granular formulation was prepared as described in example 1, formulation 1.

The suspending vehicle was formed by dissolving the polymer polyvinylpyrrolidone in the solvent benzyl benzoate at a weight ratio of about 50: 50. The viscosity of the vehicle was approximately 12,000-18,000 poise when measured at 33 ℃. The particles comprising 35% omega interferon were dispersed in the vehicle at a concentration of 8.13 wt% particles relative to the total weight of the suspension formulation.

B. Suspension formulation 2

The granular formulation was prepared as described in example 1, formulation 2.

The suspending vehicle was formed by dissolving the polymer polyvinylpyrrolidone in the solvent benzyl benzoate at a weight ratio of about 50: 50. The viscosity of the vehicle was approximately 12,000-18,000 poise when measured at 33 ℃. The granules comprising 44.82% exenatide were dispersed in the vehicle at a concentration of 11.2 wt% granules relative to the total weight of the suspension formulation.

C. Suspension formulation 3

The granular formulation was prepared as described in example 1, formulation 3.

The suspending vehicle was formed by dissolving the polymer polyvinylpyrrolidone in the solvent benzyl benzoate at a weight ratio of about 50: 50. The viscosity of the vehicle was approximately 12,000-18,000 poise when measured at 33 ℃. The granules comprising 41.24% exenatide are dispersed in the vehicle at a concentration of 12 wt% granules relative to the total weight of the suspension formulation.

The granular formulations 1-3 described in example 1 were dispersed in the vehicle at the concentrations (in weight%) shown in table 6.

TABLE 6

Ingredient suspension formulation 1 suspension formulation 2 suspension formulation 3

Granular formulation

Polymer (polyvinylpyrrolidone)

Solvent (benzyl benzoate)

D. Other suspension formulations

The granular formulation was prepared as described in example 1. The exenatide granule formulation is as described in example 1, formulation 3.

The suspending vehicle was formed by dissolving the polymer polyvinylpyrrolidone in the solvent benzyl benzoate at a weight ratio of about 50: 50. The viscosity of the vehicle was approximately 12,000-18,000 poise when measured at 33 ℃. The particles as described in example 1 were dispersed in the carrier at the concentrations shown in table 7. The particle concentration is given relative to the total weight of the suspension formulation.

The granular formulations 3, 5 and/or 6 described in example 1 were dispersed in the vehicle at the concentrations (in weight%) shown in table 7.

TABLE 7

Composition (I)

Granular formulation

Polymer (polyvinylpyrrolidone)

Solvent (benzyl benzoate)

Oxyntomodulin; exenatide, Exenatide (particle ratio)

The data provided in example 2 shows that the highly concentrated pharmaceutical granule formulation of the present invention is capable of producing a suspension formulation for pharmaceutical applications.

Example 3

Drug stability in granular and suspension formulations

A. Stability of granular formulation

A study was conducted to evaluate the stability of the granular formulation as a spray-dried powder. Samples were analyzed by Size Exclusion Chromatography (SEC) and reverse phase high performance liquid chromatography (RP-HPLC). The results are shown in Table 8.

TABLE 8

Drug loading impurity-aggregate purity in granulate of granular formulation

Not determined

Purity data based on SEC and RP-HPLC show excellent stability of highly concentrated pharmaceutical granule formulations of the present invention.

B. Stability of suspension formulation

Studies were conducted to evaluate the stability of drug particle formulations suspended in biocompatible, single-phase and non-aqueous vehicles. For analytical testing, omega interferon or exenatide is extracted from the suspension with an extraction solvent and the sample is analyzed using Size Exclusion Chromatography (SEC), reverse phase high performance liquid chromatography (RP-HPLC) and bioassay.

The extraction solvent dissolves the suspension vehicle and precipitates the drug. The drug pellet was washed several times, dried, and then redissolved with water for analysis. Omega interferon monomers and aggregated forms were separated by SEC method using TSK-Gel Super SW2000 column and detected with UV detector at 220 nm. The purity and identity (identity) of omega interferon was determined by RP-HPLC with a Zorbax 300SB-C8RP-HPLC column at acidic pH and with UV detection at 220 nm.

The exenatide monomeric and aggregated forms were separated by SEC method using TSK-Gel Super SW2000 column and detected with UV detector at 220 nm. The purity and identity of exenatide was determined by RP-HPLC with a Higgins CLIPEUS-C8 column, at acidic pH and with UV detection at 210 nm.

The suspension formulations had the target particle loadings as shown in table 8. Delivery of implantable osmotic drugs (e.g. to a delivery deviceDelivery device) the reservoir was filled to the suspension volume shown in table 9 and stored at 25 ℃ and 40 ℃. Several samples were taken and analyzed at the initial and subsequent time points as shown in table 9. The monomer level was determined by SEC and the purity level by RP-HPLC. The analysis results are shown in table 9.

TABLE 9

Suspension formulation storage temperature storage time (month) monomer aggregates purity as determined by RP-HPLC

Not determined

Analysis of low degradation product levels (where the monomeric form predominates) and purity as shown by the ratio of monomeric to aggregated form shows that suspension formulations comprising the highly concentrated pharmaceutical granule formulation of the present invention provide excellent stability and pharmaceutical purity.

Example 4

Release rate

A study was conducted to evaluate the release rate of a suspension formulation according to an embodiment of the present invention using an implantable osmotic drug delivery device. For each study, the implantable osmotic delivery device drug reservoir was filled with 160ul of one of the suspension formulations described in example 2. The membrane end of the osmotic pump was placed in a stoppered glass vial filled with 3ml of Phosphate Buffered Saline (PBS), and the diffusion moderator end of the osmotic pump was placed in a glass vial filled with 2.5-3 ml of release rate medium (citrate buffer containing 0.14M NaCl and 0.2% sodium azide at pH 6.0).

Each system was placed into a capped tube with the diffusion moderator side down and partially immersed in a 37 ℃ water bath. At specific time points, the glass vial on the end of the diffusion moderator was replaced with a fresh glass vial filled with 2.5-3 ml of release rate medium (citrate buffer containing 0.14M NaCl and 0.2% sodium azide at pH 6.0). Samples were taken from the diffusion reducer end of the osmotic pump and analyzed using RP-HPLC.

The in vitro release rate results obtained by RP-HPLC analysis are shown in FIG. 1, FIG. 2 and FIG. 3. Figure 1 provides data for suspension formulation 1. The data shows an approximate release rate of 50 ug/day at 37 ℃ to a daily release rate of 100 days. Figure 2 provides data for suspension formulation 2. The graph shows an approximate release rate of 75 ug/day to a daily release rate of 110 days at 37 ℃. Figure 3 provides data for suspension formulation 3. The graph shows an approximate release rate of 80 ug/day to a daily release rate of 100 days at 37 ℃. The substantially steady-state delivery of the drug at the predetermined release rate is shown by the horizontal line of data points.

The release rate data shows that the system delivers drug consistently and uniformly, approaching the approximate rate of 50 ug/day omega interferon for suspension formulation 1; for suspension formulation 2, approximate rate of approximately 75 ug/day exenatide; for suspension formulation 3, the approximate rate of 80 ug/day exenatide was approached.

The release rates of other suspension formulations over a range of drug delivery concentrations were also determined. The results of their in vitro release rates by RP-HPLC analysis are shown in FIGS. 4 and 5. Figure 4 provides in vitro release data for omega interferon from an implantable osmotic drug delivery device. Omega interferon particles and suspension formulations were prepared substantially as described above. The release rate is controlled by varying the particle loading in the suspension formulation or the drug concentration in the particles of the particle formulation, or both. The data show release rates per day at 37 ℃, 100 days with approximate release rates of 10, 25, 30, and 50 ug/day. A substantially steady-state delivery of drug at a predetermined release rate is illustrated by a horizontal line of data points.

Figure 5 provides data for in vitro release of exenatide from an implantable osmotic drug delivery device. Exenatide granules and suspension formulations are prepared substantially as described above. The release rate is controlled by varying the particle loading in the suspension formulation or the drug concentration in the particles of the particle formulation, or both. The data show daily release rates over 110 days at 37 ℃, with approximate release rates of 5, 10, 20,40, and 75 ug/day. The substantially steady-state delivery of the drug at the predetermined release rate is shown by the horizontal line of data points.

The release rate data shown in fig. 4 and 5 further demonstrate that the osmotic drug delivery system uses the particle and suspension formulations of the present invention to deliver drug consistently, consistently and consistently at near preselected delivery rates.

Taken together, these data show that suspension formulations comprising highly concentrated drug particle formulations of the present invention provide consistent and consistent drug delivery at preselected delivery rates.

Example 5

Drug delivery rate, amount and lifetime

The data provided in table 10 shows that highly concentrated particles are used to prepare implantable osmotic drug delivery devices that can deliver drug doses at a specified delivery rate for an extended period of time.

Watch 10

Total dose delivery over device life for suspension delivery period

As will be apparent to those skilled in the art, various modifications and variations can be made to the above-described embodiments without departing from the spirit and scope of the invention. Such modifications and variations are intended to be within the scope of the present invention.

The invention relates to the following technical scheme:

1. a granular formulation comprising from about 25 wt% to about 80 wt% of a drug; and about 75 wt% to about 20 wt% of one or more other ingredients, wherein the ratio of drug to other ingredients is about 1:1 to about 5: 1.

2. The granular formulation of item 1, wherein the drug comprises about 40 wt% to about 75 wt% and the one or more other ingredients comprise about 60 wt% to about 25 wt%.

3. The particle formulation of item 1 or item 2, wherein the one or more additional ingredients are selected from the group consisting of antioxidants, carbohydrates, and buffers.

4. The granular formulation of any one of the preceding claims, wherein the one or more additional ingredients comprise an antioxidant and the antioxidant is selected from cysteine, methionine and tryptophan.

5. The granular formulation of item 4, wherein the antioxidant is methionine.

6. The particle formulation of any one of the above, wherein the one or more additional ingredients comprise a buffer and the buffer is selected from the group consisting of citrate, histidine, succinate, and mixtures thereof.

7. The particle formulation of item 6, wherein the buffering agent is citrate.

8. The granule formulation of any one of the above, wherein the one or more additional ingredients comprise a carbohydrate and the carbohydrate is a disaccharide.

9. The granule formulation of item 8, wherein the disaccharide is selected from the group consisting of lactose, sucrose, trehalose, cellobiose, and mixtures thereof.

10. The granule formulation of item 9, wherein the disaccharide is sucrose.

11. The particle formulation of any one of the above, wherein the one or more additional ingredients comprise an antioxidant, a carbohydrate, and a buffer and the ratio of drug to antioxidant to carbohydrate to buffer is about 2-20:1-5:1-5: 1-10.

12. The granular formulation of any one of the preceding claims, wherein the granular formulation is a spray-dried granular formulation.

13. The granule formulation of any one of the above, wherein the drug is a protein.

14. The granule formulation of item 13, wherein the protein is an interferon.

15. The particle formulation of item 14, wherein the interferon is selected from the group consisting of consensus interferon, alpha interferon, beta interferon, gamma interferon, tau interferon, omega interferon, and mixtures thereof.

16. The particle formulation of item 13, wherein the protein is an incretin mimetic.

17. The particle formulation of item 16, wherein the incretin mimetic is glucagon-like peptide-1 (GLP-1), a derivative of GLP-1, or an analog of GLP-1.

18. The particle formulation of item 17, wherein the incretin mimetic is GLP-1(7-36) amide.

19. The particle formulation of item 16, wherein the incretin mimetic is exenatide, an exenatide derivative or an exenatide analog.

20. The particle formulation of item 19, wherein the incretin mimetic is exenatide.

21. The granule formulation of item 13, wherein the protein is selected from the group consisting of exenatide, PYY, GLP-1(7-36) amide, oxyntomodulin, GIP, and leptin.

22. The particle formulation of item 13, wherein the protein is selected from the group consisting of recombinant antibodies, antibody fragments, humanized antibodies, single chain antibodies, monoclonal antibodies, and avimers.

23. The granule formulation of item 13, wherein the protein is selected from the group consisting of human growth hormone, epidermal growth factor, fibroblast growth factor, platelet-derived growth factor, transforming growth factor, and nerve growth factor.

24. The particle formulation of item 13, wherein the protein is a cytokine.

25. The particle formulation of any of the above, wherein the particles of the particle formulation are particles of about 2 microns to about 10 microns.

26. A suspension formulation comprising the granule formulation of any one of the above; and a non-aqueous, single-phase suspension vehicle comprising one or more polymers and one or more solvents; wherein the suspension carrier exhibits viscous fluid characteristics; and the granular preparation is uniformly dispersed in the carrier.

27. The suspension formulation of item 26, wherein the one or more polymers are pyrrolidone-containing polymers.

28. The suspension formulation of item 27, wherein the one or more polymers is polyvinylpyrrolidone.

29. The suspension formulation of any of claims 26-28, wherein the one or more solvents are selected from the group consisting of lauryl lactate, lauryl alcohol, benzyl benzoate, and mixtures thereof.

30. The suspension formulation of item 26, wherein the suspension vehicle consists essentially of one or more polymers and one or more solvents.

31. The suspension formulation of item 30, wherein the one or more solvents consist essentially of benzyl benzoate.

32. The suspension formulation of item 30 or item 31, wherein the one or more polymers consists essentially of polyvinylpyrrolidone.

33. The suspension formulation of item 30, wherein the suspension vehicle consists essentially of benzyl benzoate and a polymer comprising pyrrolidones.

34. The suspension formulation of any of items 26-33, wherein the suspension vehicle is about 50% solvent and about 50% polymer.

35. The suspension formulation of any of claims 26-34, wherein the suspension vehicle has a viscosity of about 15,000 poise ± about 3,000 poise.

36. An osmotic drug delivery device comprising the suspension formulation of any of claims 26-35.

37. The osmotic delivery device of item 36, wherein the osmotic delivery device comprises a reservoir having dimensions of about 35mm to about 20mm in length and about 8mm to about 3mm in diameter.

38. The osmotic delivery device of item 37, wherein the reservoir has a dimension of from about 30mm to about 25mm in length and from about 4mm to about 3.8mm in diameter.

39. A method of making an osmotic delivery device comprising adding the suspension formulation of any of items 26-35 to a reservoir of the osmotic delivery device.

40. The method of item 39, wherein the osmotic delivery device comprises a reservoir having dimensions of about 35mm to about 20mm in length and about 8mm to about 3mm in diameter.

41. The method of item 40, wherein the receptacle has dimensions of about 30mm to about 25mm in length and about 4mm to about 3.8mm in diameter.

42. A pharmaceutical formulation comprising the granular formulation of any one of items 1-25.

43. A pharmaceutical formulation comprising the suspension formulation of any one of claims 26-35.

Claims (35)

1. An osmotic delivery device for the extended delivery of exenatide, comprising:

a pharmaceutical suspension formulation having chemical and physical stability of at least 6 months at 40 ℃, said formulation comprising,

a granular formulation comprising 25 wt% to 80 wt% exenatide; and 75 wt% to 20 wt% of one or more other ingredients, wherein the one or more other ingredients comprise an antioxidant, a carbohydrate, and a buffer; and

a non-aqueous, single-phase suspending vehicle comprising one or more polymers and one or more solvents;

wherein the suspension vehicle has a viscosity of about 8,000 to about 25,000 poise at 33 ℃ and the particulate formulation is uniformly dispersed in the suspension vehicle; and is

Wherein the osmotic drug delivery device releases exenatide at a sustained release in vitro release rate of at most 80 μ g/day for at least 100 days at 37 ℃.

2. The osmotic delivery device of claim 1, wherein said osmotic delivery device comprises:

an impermeable reservoir comprising inner and outer surfaces and first and second open ends,

a semi-permeable membrane sealingly associated with the first open end of the reservoir,

an osmotic engine within the reservoir, the osmotic engine abutting the semi-permeable membrane,

a piston adjacent to the osmotic engine, wherein the piston forms a movable seal with the interior surface of the reservoir, the piston dividing the reservoir into a first chamber and a second chamber, the first chamber containing the osmotic engine and the second chamber containing the particulate formulation and the suspending vehicle, and

a diffusion moderator defining a delivery orifice inserted into the second open end of the reservoir, wherein the diffusion moderator is adjacent to the suspension formulation.

3. An osmotic drug delivery device according to claim 1 or claim 2, wherein said reservoir comprises titanium or a titanium alloy.

4. An osmotic delivery device according to any of claims 1 to 3, wherein said reservoir has dimensions of 35 mm-20 mm in length and 8mm-3mm in diameter.

5. An osmotic delivery device according to any of claims 1 to 4, wherein said reservoir has dimensions of 30 mm-25 mm in length and 4mm-3.8mm in diameter.

6. An osmotic drug delivery device according to any of claims 1 to 5, wherein the drug is present in an amount of about 40% to about 75% by weight and the one or more other ingredients are present in an amount of about 60% to about 25% by weight.

7. An osmotic delivery device according to any of claims 1 to 6, wherein said antioxidant is selected from the group consisting of cysteine, methionine and tryptophan.

8. The osmotic delivery device of claim 7, wherein said antioxidant is methionine.

9. An osmotic drug delivery device according to any of claims 1 to 8, wherein the buffering agent is selected from the group consisting of citrate, histidine, succinate and mixtures thereof.

10. The osmotic delivery device of claim 9, wherein said buffer is citrate.

11. The osmotic delivery device of any of claims 1 to 10, wherein the carbohydrate is a disaccharide.

12. The osmotic delivery device of claim 11, wherein said disaccharide is selected from the group consisting of lactose, sucrose, trehalose, cellobiose, and mixtures thereof.

13. The osmotic delivery device of claim 12, wherein said disaccharide is sucrose.

14. An osmotic drug delivery device according to any of claims 1 to 13, wherein said antioxidant is methionine, said carbohydrate is sucrose, and said buffer is citrate.

15. The osmotic delivery device of any of claims 1 to 14, wherein the particles of the particle formulation are about 2 microns to about 10 microns.

16. An osmotic drug delivery device according to any of claims 1 to 15, wherein the one or more polymers are polymers comprising pyrrolidones.

17. An osmotic drug delivery device according to any of claims 1 to 16, wherein the one or more solvents are selected from the group consisting of lauryl lactate, lauryl alcohol, benzyl benzoate and mixtures thereof.

18. An osmotic drug delivery device according to any of claims 1 to 17, wherein the suspension vehicle comprises benzyl benzoate and polyvinylpyrrolidone.

19. An osmotic drug delivery device according to any of claims 1 to 18, wherein the suspending vehicle is about 50% solvent and about 50% polymer.

20. The osmotic delivery device of any of claims 1 to 19, wherein the suspension vehicle has a viscosity of about 15,000 poise ± about 3,000 poise.

21. An osmotic drug delivery device according to any of claims 1 to 20, wherein the particulate formulation is a spray-dried particulate formulation or is prepared by a process comprising lyophilization.

22. An osmotic drug delivery device according to any of claims 1 to 21, wherein said sustained release in vitro release rate is at least 20 μ g/day, at least 30 μ g/day, at least 40 μ g/day, at least 50 μ g/day, at least 60 μ g/day, or at least 80 μ g/day.

23. An osmotic drug delivery device according to any of claims 1 to 21, wherein said sustained release in vitro release rate is at least 20 μ g/day.

24. An osmotic drug delivery device according to any of claims 1 to 21, wherein said sustained release in vitro release rate is at least 30 μ g/day.

25. An osmotic drug delivery device according to any of claims 1 to 21, wherein said sustained release in vitro release rate is at least 40 μ g/day.

26. An osmotic drug delivery device according to any of claims 1 to 21, wherein said sustained release in vitro release rate is at least 50 μ g/day.

27. An osmotic drug delivery device according to any of claims 1 to 21, wherein said sustained release in vitro release rate is at least 60 μ g/day.

28. An osmotic drug delivery device according to any of claims 1 to 21, wherein said sustained release in vitro release rate is at least 80 μ g/day.

29. An osmotic drug delivery device according to any of claims 1 to 28, wherein said osmotic drug delivery device releases exenatide at a sustained release in vitro release rate of at most 100 μ g/day to 1 year at 37 ℃.

30. An osmotic delivery device according to any of claims 1 to 28, wherein said osmotic delivery device releases exenatide at a sustained release in vitro release rate of at most 100 μ g/day for at least 3 months to 1 year.

31. A method of treating type 2 diabetes in a subject in need thereof, the method comprising: subcutaneously inserting into a subject an osmotic delivery device comprising a drug suspension formulation comprising,

a granular formulation comprising 25 wt% to 80 wt% exenatide; and 75 wt% to 20 wt% of one or more other ingredients, wherein the one or more other ingredients comprise an antioxidant, a carbohydrate, and a buffer; less than 0.5% of exenatide aggregates are stored at 25-40 ℃ for up to 6 months; and

a non-aqueous, single-phase suspending vehicle comprising one or more polymers and one or more solvents;

wherein the suspension vehicle has a viscosity of about 8,000 to about 25,000 poise at 33 ℃ and the particulate formulation is uniformly dispersed in the suspension vehicle; and is

The osmotic drug delivery device releases exenatide with a sustained release in vitro release rate of at most 80 μ g/day for at least 100 days at 37 ℃.

32. The method of claim 31, wherein the method comprises delivering the suspension formulation at a substantially uniform rate for a period of about 1 month to about 1 year.

33. The method of claim 31 or claim 32, wherein the method comprises delivering the suspension formulation at a substantially uniform rate for a period of about 3 months to about 1 year.

34. The method of any one of claim 31 or claim 33, wherein the exenatide is delivered at most 400 μ g/day up to about 90 days, at most 200 μ g/day up to about 180 days, or at most 100 μ g/day up to about 1 year.

35. The method of any one of claim 31 or claim 33, wherein the exenatide is delivered at most 100 μ g/day to about 1 year.