An implantable device includes a reservoir containing a suspension of an interferon in an amount sufficient to provide continuous delivery of the interferon at a therapeutically effective rate of 1 ng/day to 600 .mu.g/day to maintain and achieve therapeutic blood or plasma levels of the interferon throughout a substantial period of the administration period.

Description of the Invention

BACKGROUND OF THE INVENTION

The invention relates to delivery of interferon at controlled rates over extended periods of time.

Interferons are a group of glycoprotein cytokines produced by cells in response to various stimuli, such as exposure to virus, bacterium, parasite, or other antigen. Interferons have antiviral, immunomodulatory, and antiproliferative activities. Interferons are classified as Type I or Type II. Interferons classified as Type I bind to a common receptor called the Interferon Type I or .alpha.-.beta. receptor and are produced by leukocytes, fibroblasts, or lymphoblasts in response to virus or interferon inducers. Interferon Type I includes interferon alpha (IFN-.alpha.), interferon beta (IFN-.beta.), and interferon omega (IFN-.omega.), but IFN-.omega. has limited homology to human IFN-.alpha. (about 60%) and human IFN-.beta. (about 29%). Interferons classified as Type II are produced by T-lymphocytes. Interferon Type II includes interferon gamma (IFN-.gamma.). Interferons are used for treatment of viral hepatitis, multiple sclerosis, and certain cancers. IFN-.omega. in particular has been indicated for treatment of Hepatitis B & C populations. The injectable form of IFN-.omega. is currently in Phase II clinical studies for Hepatitis C. This injectable form is solution-based and is not formulated for sustained delivery.

There is interest in delivering interferons to patients in a controlled manner over a prolonged period without intervention. For instance, sustained delivery of IFN-.omega. can improve the therapeutic effect of IFN-.omega. by reduction or elimination of peak plasma-level related effects of multiple bolus injections, thereby potentially minimizing systemic side effects such as fatigue and flu-like symptoms. Sustained delivery of a beneficial agent without intervention can be provided by implantable drug delivery devices, e.g., osmotic, mechanical, or electromechanical pump implants, and depot injections. Implantable drug delivery devices are attractive for a number of reasons. For example, implantable drug delivery devices can be designed to provide therapeutic doses of the drug over periods of weeks, months, or even a year. Depot injections typically provide therapeutic doses over periods of weeks. Implantable drug delivery devices once inserted in the patient are not easily tampered with by the patient. Thus, patient compliance is generally assured.

Sustained delivery of an interferon requires the interferon to be contained within a formulation that is substantially stable at elevated temperature, e.g., 37.degree. C. or higher, over the operational life of the implantable delivery drug device. Interferon is a biomolecular material, specifically a protein. Generally speaking, protein formulations that are stable at elevated temperature for a long duration, e.g., weeks, months, or a year, are difficult to design. Proteins are naturally active in aqueous environments. Therefore, it would be convenient to formulate proteins as aqueous solutions. Unfortunately, proteins are typically only marginally stable in aqueous formulations for a long duration. One reason for this is that proteins can degrade via a number of mechanisms, such as deamidation (usually by hydrolysis), oxidation, disulfide interchange, and racemization, and water is a reactant in many of these degradation pathways. Water also acts as a plasticizer and facilitates denaturation and/or aggregation of protein molecules.

Aqueous protein formulations may be reduced to particles using techniques such as freeze-drying or lyophilization, spray-drying, and desiccation. Such particle protein formulations may exhibit increased stability over time at ambient and even elevated temperature. However, there is the challenge of delivering particle formulations from an implantable drug delivery device at a controlled flow rate. It has been suggested to suspend particle protein formulations in non-aqueous, flowable vehicles to allow their delivery from an implantable drug delivery device. A suitable vehicle typically has a high viscosity, e.g., 1 kP or more, so that the particles can be uniformly dispersed in the suspension for a desired duration.

From the foregoing, there continues to be a need for a formulation of interferon that is stable at storage and delivery conditions for a desired duration and deliverable via an implantable drug delivery device.

SUMMARY OF THE INVENTION

In one aspect, the invention relates to a suspension formulation of interferon which comprises a non-aqueous, single-phase vehicle including at least one polymer and at least one solvent, the vehicle exhibiting viscous fluid characteristics, and an interferon contained in a particle formulation dispersed in the vehicle. The particle formulation includes a stabilizing component comprising one or more stabilizers selected from the group consisting of carbohydrates, antioxidants, and amino acids. The suspension formulation is characterized in that less than 10% of the interferon degrades over 3 months under an accelerated storage condition.

In another aspect, the invention relates to a method of treating an interferon-responsive disorder which comprises administering to a subject the suspension formulation described above.

DETAILED DESCRIPTION OF THE INVENTION

The invention will now be described in detail with reference to a few preferred embodiments, as illustrated in accompanying drawings. In the following description, numerous specific details are set forth in order to provide a thorough understanding of the invention. However, it will be apparent to one skilled in the art that the invention may be practiced without some or all of these specific details. In other instances, well-known features and/or process steps have not been described in detail in order to not unnecessarily obscure the invention. The features and advantages of the invention may be better understood with reference to the drawings and discussions that follow.

The invention provides particle formulations of interferon that can be used to prepare suspension formulations of interferon that are deliverable via sustained delivery systems, e.g., implantable drug delivery devices and depot injections. Interferons that may be included in particle formulations of the invention may be recombinant molecules that can activate the Interferon Type I receptor (.alpha.-.beta. receptor) or Interferon Type II receptor. These recombinant molecules may or may not contain sequence homology to native human Type I or Type II interferons. Interferons according to embodiments of the invention may be selected from the group consisting of proteins having the biological activity of recombinant human interferon, interferon analogs, interferon isoforms, interferon mimetics, interferon fragments, hybrid interferon proteins, fusion protein oligomers and multimers of the above, homologues of the above, glycosylation pattern variants of the above, muteins of the above, and interferon molecules containing the minor modifications enumerated above. Interferons according to the invention shall not be limited by method of synthesis or manufacture and shall include those synthesized or manufactured by recombinant (whether produced from cDNA or genomic DNA), synthetic, transgenic, and gene-activated methods. Specific examples of interferons include, but are not limited to, IFN-.alpha., IFN-.beta., IFN-.omega., and IFN-.gamma..

Particle formulations of the invention are preferably chemically and physically stable for at least 1 month, more preferably at least 3 months, most preferably at least 6 months, at delivery temperature. The delivery temperature could be normal body temperature, e.g., 37.degree. C., or slightly higher than normal body temperature, e.g., 40.degree. C. Particle formulations of the invention are preferably chemically and physically stable for at least 3 months, more preferably at least 6 months, most preferably at least 12 months, at storage temperature. The storage temperature could be refrigeration temperature, e.g., around 5.degree. C., or room temperature, e.g., around 25.degree. C. The term "chemically stable" means that an acceptable percentage of degradation products produced by chemical pathways such as deamidation (usually by hydrolysis) or oxidation is formed. For example, a formulation may be considered chemically stable if less than 35%, preferably no more than about 20%, breakdown products are formed after 3 months, preferably after 6 months, at delivery temperature and after 6 months, preferably after 12 months, at storage temperature. The term "physically stable" means that an acceptable percentage of aggregates (e.g., dimers and other higher molecular weight products) is formed. For example, a formulation may be considered physically stable if less than 10%, preferably no more than 3%, more preferably less than 1%, aggregates are formed after 3 months, preferably after 6 months, at delivery temperature and 6 months, preferably 12 months, at storage temperature.

Preferably, particle formulations of the invention are formable into particles using processes such as spray drying, lyophilization, desiccation, freeze-drying, milling, granulation, ultrasonic drop creation, crystallization, and precipitation. Preferably, the particles are uniform in shape and size to ensure consistent and uniform rate of release from the delivery device. Preferably, the particles are sized such that they can be delivered via an implantable drug delivery device. For example, in a typical osmotic pump implant having a delivery orifice, the size of the particles should be no greater than 30%, preferably no greater than 20%, more preferably no greater than 10%, of the diameter of the delivery orifice. It is also desirable that the particles when incorporated in a suspension vehicle do not settle within 3 months at delivery temperature. Generally speaking, smaller particles tend to have a lower settling rate in viscous suspension vehicles than larger particles. Therefore, micron- to nano-sized particles are typically desirable. For an osmotic pump implant having a delivery orifice diameter in a range from 0.1 to 0.5 mm, for example, particle sizes are preferably less than 50 .mu.m, more preferably less than 10 .mu.m, most preferably in a range from 3 to 7 .mu.m.

The invention provides particle formulations of interferons possessing many or all of the characteristics described above. For example, particle formulations according to embodiments of the invention are chemically and physically stable at 40.degree. C. for at least 6 months and at 5.degree. C. and 25.degree. C. for at least 12 months. We have found that particle formulations according to embodiments of the invention can be prepared by spray drying with high yield, e.g., greater than 50%, with average particle size typically less than 50 .mu.m and moisture content typically below 5% by weight. Particle formulations according to embodiments of the invention may also be prepared by other suitable processes available in the art for forming particles from a mixture of components, such as lyophilization, freeze-drying, milling, granulation, ultrasonic drop creation, crystallization, precipitation, and dessication. Particle formulations according to embodiments of the invention preferably have a low moisture content, typically less than 5% by weight.

In one embodiment, a particle formulation includes an interferon as described above, one or more stabilizers, and optionally a buffer. The stabilizers may be carbohydrate, antioxidant and/or amino acid. The amounts of stabilizers and buffer in the particle formulation can be determined experimentally based on the activities of the stabilizers and buffers and the desired characteristics of the formulation. Carbohydrate, antioxidant, amino acid, and buffer levels are generally all of concern in creating a particle formulation according to the invention. Typically, the amount of carbohydrate in the formulation is determined by aggregation concerns. In general, the carbohydrate level should not be too high so as to avoid promoting crystal growth in the presence of water due to excess carbohydrate unbound to interferon. Typically, the amount of antioxidant in the formulation is determined by oxidation concerns, while the amount of amino acid in the formulation is determined by oxidation concerns and/or formability of particles during spray drying. Typically, the amount of buffer in the formulation is determined by pre-processing concerns, stability concerns, and formability of particles during spray drying. Buffer may be required to stabilize interferon during processing, e.g., solution preparation and spray drying, when all excipients are solubilized. However, care should be exercised in determining the amount of buffer. Too much buffer can produce a buffer system in the presence of water, which can then lead to crystallization.

Examples of carbohydrates that may be included in the particle formulation include, but are not limited to, monosaccharides, such as fructose, maltose, galactose, glucose, D-mannose, and sorbose, disaccharides, such as lactose, sucrose, trehalose, cellobiose, polysaccharides, such as raffinose, melezitose, maltodextrins, dextrans, and starches, and alditols (acyclic polyols), such as mannitol, xylitol, maltitol, lactitol, xylitol sorbitol, pyranosyl sorbitol, and myoinsitol. Preferred carbohydrates include non-reducing sugars, such as sucrose, trehalose, mannitol, and dextrans.

Examples of antioxidants that may be included in the particle formulation include, but are not limited to, methionine, ascorbic acid, sodium thiosulfate, catalase, platinum, ethylenediaminetetraacetic acid (EDTA), citric acid, cysteins, thioglycerol, thioglycolic acid, thiosorbitol, butylated hydroxanisol, butylated hydroxyltoluene, and propyl gallate.

Examples of amino acids that may be included in the particle formulation include, but are not limited to, arginine, methionine, glycine, histidine, alanine, L-leucine, glutamic acid, Iso-leucine, L-threonine, 2-phenylamine, valine, norvaline, praline, phenylalanine, trytophan, serine, asparagines, cysteine, tyrosine, lysine, and norleucine. Preferred amino acids include those that readily oxidize, e.g., cysteine, methionine, and trytophan.

Examples of buffers 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.

The particle formulation may include other excipients, such as surfactants, bulking agents, and salts. Examples of surfactants include, but are not limited to, Polysorbate 20, Polysorbate 80, PLURONIC.RTM. F68, and sodium docecyl sulfate (SDS). Examples of bulking agents include, but are not limited to, mannitol and glycine. Examples of salts include, but are not limited to, sodium chloride, calcium chloride, and magnesium chloride.

Table 1 (see Original Patent) shows examples of particle formulation composition ranges of the invention.

One particularly useful example of particle interferon formulations includes 1:2:1:1.5-2.5 interferon:carbohydrate:antioxidant and/or amino acid:buffer. The term "antioxidant and/or amino acid" refers to antioxidant alone or amino acid alone or a combination of antioxidant and amino acid. In another example, particle interferon of formulations 1:2:1:1.5-2.5 IFN-.omega.:sucrose:methionine:citrate were prepared.

As stated earlier, particle formulations of the invention may be prepared by known techniques such as spray drying, lyophilization, desiccation, or other technique available in the art for forming particles from a mixture of components. A typical spray dry process may include loading a spray solution containing a protein and stabilizing excipients into a sample chamber, which may be maintained at refrigeration to room temperature. Refrigeration generally promotes stability of the protein. A feed pump then sprays the spray solution into a nozzle atomizer. At the same time, atomized gas (typically, air, nitrogen, or inert gas) is directed at the outlet of the nozzle atomizer to form a mist of droplets from the spray solution. The mist of droplets are immediately brought into contact with a drying gas in a drying chamber. The drying gas removes solvent from the droplets and carries the particles into a collection chamber. In spray drying, factors that can affect yield include, but are not limited to, localized charges on particles, which could promote adhesion of the particles to the spray dryer, and aerodynamics of the particles, which could make it difficult to collect the particles. In general, yield of the spray dry process depends in part on the particle formulation. As will be demonstrated below, particle formulations of the invention can be effectively spray dried.

In one embodiment, spray dried particles were formed from spray solutions containing IFN-.omega., sucrose (carbohydrate), methionine (amino acid), and citrate (buffer). In a preferred embodiment, IFN-.omega., sucrose, methionine, and citrate are present in the solution in a ratio of 1:2:1:1.5-2.5 (IFN-.omega.:sucrose:methionine:citrate). FIG. 1 (see Original Patent) shows a SEM image for spray dried particles formed from a spray solution having IFN-.omega.:sucrose:methionine:citrate in a ratio of 1:2:1:2.15. The average particle size is 4-5 .mu.m. The particles have buckled or raisin-like morphology. FIG. 2 (see Original Patent) shows particle size distributions of four different spray dry runs for a spray solution having IFN-.omega.:sucrose:methionine:citrate in a ratio of 1:2:1:2.15. FIG. 2 shows that IFN-.omega. formulations of the invention can be reproducibly spray dried with tight particle size distribution profiles.

Table 2 (see Original Patent) shows yield data for various spray-dried formulations of the invention. The results show that yield greater than 60% is achievable with IFN-.omega. particle formulations of the invention. In Table 2, "batch size" is starting solid material (g) in spray dry solution and "yield" is percent solid material captured after spray drying.
 

Claim 1 of 33 Claims

1. An implantable device comprising: a reservoir containing a suspension formulation comprising a non-aqueous, single-phase vehicle consisting essentially of about 20% to 60% (w/w) benzyl benzoate and about 40% to 80% (w/w) polyvinylpyrrolidone, the vehicle exhibiting viscous fluid characteristics; and a particle formulation dispersed in the vehicle, the particle formulation comprising an interferon, a carbohydrate, methionine, and a buffer.

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