WO2005115333A2 - A biomolecule-containing formulation of increased stability - Google Patents
A biomolecule-containing formulation of increased stability Download PDFInfo
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- WO2005115333A2 WO2005115333A2 PCT/US2005/017914 US2005017914W WO2005115333A2 WO 2005115333 A2 WO2005115333 A2 WO 2005115333A2 US 2005017914 W US2005017914 W US 2005017914W WO 2005115333 A2 WO2005115333 A2 WO 2005115333A2
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- dry particle
- interferon
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- particle formulation
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/10—Dispersions; Emulsions
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/0012—Galenical forms characterised by the site of application
- A61K9/0019—Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner
- A61K9/0024—Solid, semi-solid or solidifying implants, which are implanted or injected in body tissue
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/70—Carbohydrates; Sugars; Derivatives thereof
- A61K31/7024—Esters of saccharides
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K38/00—Medicinal preparations containing peptides
- A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
- A61K38/17—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
- A61K38/19—Cytokines; Lymphokines; Interferons
- A61K38/21—Interferons [IFN]
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
- A61K47/16—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing nitrogen, e.g. nitro-, nitroso-, azo-compounds, nitriles, cyanates
- A61K47/18—Amines; Amides; Ureas; Quaternary ammonium compounds; Amino acids; Oligopeptides having up to five amino acids
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
- A61K47/32—Macromolecular compounds obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. carbomers, poly(meth)acrylates, or polyvinyl pyrrolidone
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
- A61K9/16—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
- A61K9/1605—Excipients; Inactive ingredients
- A61K9/1617—Organic compounds, e.g. phospholipids, fats
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
- A61K9/16—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
- A61K9/1605—Excipients; Inactive ingredients
- A61K9/1617—Organic compounds, e.g. phospholipids, fats
- A61K9/1623—Sugars or sugar alcohols, e.g. lactose; Derivatives thereof; Homeopathic globules
Definitions
- the invention relates generally to formulations deliverable via sustained release systems, such as implantable drug delivery devices and depot injections.
- 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 - ⁇ receptor and are produced by leukocytes, fibroblasts, or lymphoblasts in response to virus or interferon inducers.
- Interferon Type I includes interferon alpha (IFN- ⁇ ), interferon beta (IFN- / 3), and interferon omega (IFN- ⁇ ), but IFN- ⁇ has limited homology to human IFN- ⁇ (about 60%) and human LFN- ⁇ (about 29%). Interferons classified as Type II are produced by T- lymphocytes. Interferon Type II includes interferon gamma (IFN- ⁇ ). Interferons are used for treatment of viral hepatitis, multiple sclerosis, and certain cancers. IFN- ⁇ in particular has been indicated for treatment of Hepatitis B & C populations. The injectable form of IFN- ⁇ is currently in Phase II clinical studies. This injectable form is solution- based and is not formulated for sustained delivery.
- sustained delivery of IFN- ⁇ can improve the therapeutic effect of IFN- ⁇ 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 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.
- Interferon is a biomolecule, specifically a protein.
- 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.
- 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 can be reduced to dry particle protein formulations using drying techniques such as freeze-drying (or lyophilization), spray- drying, and dessication.
- Such dry particle protein formulations can exhibit significantly increased stability over time at ambient and even elevated temperature.
- the suspension vehicle has a high viscosity, e.g., 1 kP or more, so that the particles are substantially uniformly dispersed in the suspension for a desired duration.
- the suspension formulation should be stable at storage and delivery conditions for the desired duration and maintain its flowability for the operational life of the implantable drug delivery device.
- Non-aqueous suspension vehicles for delivering beneficial agents via implantable drug delivery devices have been described in literature.
- U.S. Patent No. 5,904,935 (Eckenhoff et al.) teaches non-aqueous suspension vehicles that include waxes having a softening temperature at or less than body temperature, hydrogenated vegetable oils, silicon oil, medium chain fatty acid monoglycerides, and polyols.
- the viscosity of these suspension vehicles can be increased to a desired level using thickening agents such as hydrogels, such as cellulose ethers, e.g., hydroxypropyl cellulose and povidone.
- 6,264,990 discloses non-aqueous, anhydrous, aprotic, hydrophobic, non-polar suspension vehicles with low reactivity.
- examples of such vehicles include perfluorodecalin, methoxyflurane, and perfiuorotributylamine.
- Polymeric materials such as polyvinylpyrrolidone (PVP), may also be used as suspension vehicles.
- U.S. Patent Publication No. US-2004-0224903-A1 discloses suspension vehicles made of single-phase, viscous, flowable compositions that are substantially formed of hydrophobic, non-polymeric materials.
- Non-polymeric materials used in forming these suspension vehicles include, but are not limited to, hydrophobic saccharide materials, organogels, or lipid materials that behave as single-phase vehicles.
- exemplary saccharide materials that may be used in formulating a suspension vehicle include, but are not limited to, substituted sucrose esters that exist as fluids at ambient or physiological temperatures, such as sucrose acetate isobutyrate (SAEB).
- SAEB sucrose acetate isobutyrate
- Non-polymeric materials allow the formulation of protein suspensions that are not only stable at ambient and physiological temperatures but are also capable of maintaining substantially uniform dispersion of protein particles.
- Hydrophobic vehicles such as SAIB, particularly when used without added excipients, can behave like a depot in the presence of a hydrophilic medium. This means that the protein suspended in the vehicle would not be instantaneously released from the vehicle in the presence of the hydrophilic medium.
- the depot effect of the suspension vehicle is typically desirable.
- control of release by the suspension vehicle is cumulative to the control of release by the delivery device. This additional control of release by the suspension vehicle may or may not be desirable depending upon the application.
- the invention relates to a suspension formulation for therapeutic use which comprises a non-aqueous, hydrophobic vehicle exhibiting viscous fluid characteristics, a dry particle formulation comprising a biomolecule dispersed in the vehicle, and a surfactant incorporated in at least one of the hydrophobic vehicle and dry particle formulation.
- the invention in another aspect, relates to a dry particle formulation comprising an interferon, a buffer, a surfactant, and one or more stabilizers selected from the group consisting of a carbohydrate, an antioxidant, and an amino acid.
- the invention relates to an implantable delivery device which comprises a suspension formulation comprising a non-aqueous, hydrophobic vehicle exhibiting viscous fluid characteristics, a dry particle formulation comprising an interferon dispersed in the vehicle, and a surfactant incorporated in at least one of the vehicle and dry particle formulation.
- the implantable delivery device further includes a reservoir containing the suspension formulation in an amount sufficient to provide continuous delivery of the interferon in a therapeutically effective dose in an environment of use over at least one month.
- the invention in another aspect, relates to a method of enhancing release of interferon omega in a hydrophilic release rate medium which comprises suspending a dry particle formulation of interferon omega in a non-polymeric, hydrophobic vehicle and incorporating a surfactant in at least one of the dry particle formulation and the hydrophobic vehicle.
- FIG. 1 shows a scanning electron microscope (SEM) image of spray dried
- IFN- ⁇ particles according to one embodiment of the invention.
- FIG. 2 shows SEM image of IFN- ⁇ particles spray dried with Pluronic F68.
- FIG. 3 shows fraction of IFN- ⁇ recovered from aqueous phase over time at 37°C.
- FIG. 4 shows total IFN- ⁇ recovered from aqueous and solid phases over time at 37°C.
- the invention will now be described in detail with reference to a few preferred embodiments, as illustrated in accompanying drawings.
- 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 formulations including biomolecules that are deliverable via sustained delivery systems, in particular implantable drug delivery devices and possibly depot injections.
- Biomolecules considered herein are those that may provide a therapeutic benefit to an animal or human subject and exhibit increased stability when formulated in a non-aqueous suspension. Biomolecules considered herein are generally degradable in water but generally stable as dry particles at ambient and physiological temperatures. Examples of biomolecules include, but are not limited to, peptides, polypeptides, proteins, amino acids, nucleotides, polymers of amino acid residues or nucleotide residues, hormones, viruses, antibodies that are naturally derived, synthetically produced, or recombinantly produced, conjugated proteins, such as lipoproteins and post translationally modified forms, e.g., glycosylated proteins, and proteins having D-amino acids, modified, derivatized or non-naturally occurring amino acids in the D- or L- configuration and/or peptomimetic units as part of their structure.
- biomolecules that may provide a therapeutic effect include, but are not limited to, baclofen, GDNF, neurotrophic factors, conatonkin G, Ziconotide, clonidine, axokine, anitsense oligonucleotides, adrenocorticotropic hormone, angiotensin I and II, atrial natriuretic peptide, bombesin, bradykinin, calcitonin, cerebellin, dynorphin N, alpha and beta endorphin, endothelin, enkephalin, epidermal growth factor, fertirelin, follicular gonadotropin releasing peptide, galanin, glucagon, gonadorelin, gonadotropin, goserelin, growth hormone releasing peptide, histrelin, insulin, interferons, leuprolide, LHRH, motilin, nafarerlin, neurotensin, oxyto
- interferons Of particular interest in this invention are interferons.
- the interferons may be recombinant molecules that can activate the Interferon Type I receptor (a- ⁇ 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.
- Embodiments of the invention provide dry particle formulations including biomolecules. Dry particle formulations of the invention have a low moisture content, typically less than 5 wt%.
- a dry particle formulation includes an interferon as described above.
- the dry particle interferon formulation also includes stabilizers. In one embodiment, the stabilizers include a carbohydrate, an antioxidant and/or amino acid.
- the dry particle interferon formulation also includes a buffer.
- the amounts of stabilizers and buffer in the dry particle formulation can be determined experimentally based on the activities of the stabilizers and buffers and the desired characteristics of the formulation.
- 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.
- the amount of antioxidant in the formulation is determined by oxidation concerns.
- the amount of amino acid in the formulation is determined by oxidation concerns and/or formability of particles during spray drying.
- the amount of buffer in the formulation is determined by pre-processing concerns, aggregation concerns, and formability of particles during spray drying.
- the buffer may stabilize interferon during processing, e.g., spray drying, when all excipients are solubilized. In general, too much buffer can produce a buffer system in the presence of water, which can then lead to crystallization.
- Preferred carbohydrates include non-reducing sugars, e.g., sucrose, trehalose, mannitol, and dextrans.
- antioxidants examples 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, propyl gallate.
- amino acids examples 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.
- buffers examples 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 dry particle formulation may include other excipients selected from, for example, surfactants, bulking agents, and salts.
- surfactants include, but are not limited to, Polysorbate 20, Polysorbate 80, Tween 20, Tween 80, Pluronic F68, and sodium docecyl sulfate (SDS).
- bulking agents include, but are not limited to, mannitol and glycine.
- salts include, but are not limited to, sodium chloride, calcium chloride, and magnesium chloride. Possible advantages of incorporating a surfactant into the dry particle formulation will be further discussed in this disclosure.
- a dry particle interferon formulation includes 1:2:1 :1.5-2.5 interferon: carbohydrate: antioxidant and/or amino acid: buffer.
- a dry particle interferon formulation is 1 :2:1:1.5-2.5 IFN- ⁇ : sucrose: methionine: citrate.
- a dry particle interferon formulation includes 1:2:1 :1.5-2.5:0.06 interferon: carbohydrate: antioxidant and/or amino acid: buffer: surfactant.
- Dry particle formulations may be prepared by spray drying, lyophilization, 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.
- atomized gas typically, air, nitrogen, or inert gas
- the mist of droplets are immediately brought into contact with a drying gas in a drying chamber.
- Suspension formulations according to embodiments of the invention are prepared by incorporating dry particle formulations according to embodiments of the invention into non-aqueous, hydrophobic vehicles.
- the non- aqueous, hydrophobic vehicles may be any combination of solvent, liquid or non-liquid polymer, liquid or non- liquid non-polymer, and surfactant.
- a non-aqueous, hydrophobic vehicle used in a suspension formulation of the invention is biodegradable, i.e., it disintegrates or breaks down over a period of time in response to a biological environment. This breakdown may take place by one or more physical or chemical processes, such as by enzymatic action, oxidation, reduction, hydrolysis (e.g., proteolysis), displacement, or dissolution by solubilization, emulsion or micelle formation.
- the components of the vehicle are selected such that the vehicle has a viscosity in a range from 1 kP to 1,000 kP, preferably 5 kP to 250 kP, more preferably 5 kP to 30 kP.
- the components of the vehicle are chosen such that the vehicle does not react with the biomolecule.
- the components of the vehicle may be chosen such that the vehicle has little or no solubility for the selected biomolecule and particle excipients, thereby maintaining the selected biomolecule and excipients as dry particles, thereby achieving stability of the selected biomolecule.
- a suspension formulation is made by suspending a dry particle formulation according to an embodiment of the invention in a non-aqueous, single-phase, hydrophobic vehicle including a non-polymer.
- non-polymeric materials suitable for use include, but are not limited to, hydrophobic saccharide materials, organogels, or lipid materials that behave as single-phase vehicles, e.g., lipid gels such as dioleoyl phisphatidylcholine (DOPC).
- lipid gels such as dioleoyl phisphatidylcholine (DOPC).
- lipid gels such as dioleoyl phisphatidylcholine (DOPC).
- lipid gels such as dioleoyl phisphatidylcholine (DOPC).
- lipid gels such as dioleoyl phisphatidylcholine (DOPC).
- lipid gels such as dioleoyl
- SAIB a liquid non-polymer
- SAIB a liquid non-polymer
- solvents for creating lipid gel vehicle include, but are not limited to, n-methyl propanol, cottonseed oil, sesame oil, soybean oil, vitamin E, castor oil, Polysorbate 80, and N dimethylacetamide.
- the non-aqueous, single-phase, hydrophobic vehicle described above may also include excipients such as surfactants, preservatives, and stabilizers.
- Surfactants may be included in the vehicle to facilitate release of the biomolecule from the vehicle once the formulation is delivered to an environment of use or to help maintain stability of the biomolecule when the biomolecule is suspended in the vehicle. Where included, surfactants will typically account for less than 20 wt%, preferably less than 10 wt%, more preferably less than 5 wt% of the vehicle. Generally, preservatives are included in the vehicle only in amounts sufficient to achieve the desired preservative effect.
- surfactants examples include, but are not limited to, Tweens, Pluronics, Span 20, Span 40, Span 60, Span 80, glyceryl caprylate, glyceryl laurate, PEG- 8 caprylic capric glycerides, polyglyceryl-6 oleate, dioctyly sodium, sulfo succinate, and Vitamin E TPGS.
- Preservatives that may be used in the vehicle include, for example, antioxidants and antimicrobial agents. Examples of potentially useful antioxidants include, but are not limited to, tocopherol (vitamin E), ascorbic acid, ascorbyl palmitate, butylated hydroxyanisole, butylated hydroxytoulene, and propyl gallate.
- a suspension formulation according to an embodiment of the invention includes a dry particle interferon formulation, as described above, suspended in a non-aqueous, hydrophobic vehicle. Varying amounts of the dry particle interferon formulation may be loaded into the vehicle to provide a formulation that allows dosing of the interferon at a desired rate over a chosen time period.
- the suspension formulation may include 0.1 to 40 wt%, preferably 0.1 to 20 wt%, of an interferon.
- the suspension formulation may include greater than 60 wt%, preferably greater than 80 wt%, of the suspension vehicle.
- Suspension formulations may be formulated for delivery from an implantable drug delivery device or for use as a depot injection.
- the implantable drug delivery device may be embodied by any such device capable of delivering a flowable formulation at a controlled rate over a sustained period after implantation within a subject.
- a suitable implantable drug delivery device is an osmotic pump implant, such as available under the trade name DUROS® implant. Non-osmotic pump implants may also be used.
- the suspension formulation may be formulated for delivery at flow rates up to 5 ml/day, depending on the biomolecule to be delivered and the implantable drug delivery device used to deliver the suspension formulation.
- the formulation is preferably formulated for delivery of between 0.5 and 5 ⁇ L/day, with flow rates of about 1.5 ⁇ L/day and 1.0 ⁇ L/day being particularly preferred.
- a suspension formulation according to an embodiment of the invention is formulated to deliver interferon from an implanted device in a range from 1 ng/day to 600 ⁇ g/day over one month, preferably over three months, more preferably over one year.
- non-aqueous, hydrophobic vehicles can behave like a depot when released into a hydrophilic medium.
- This depot effect may or may not be desirable depending on the application.
- the inventors have found that addition of a small amount of surfactant directly into dry particle formulations of the invention and/or into hydrophobic vehicles incorporating the dry particle formulations of the invention can enhance stability of the biomolecules in the dry particle formulations as the dry particle formulations are released from the hydrophobic vehicles into the hydrophilic media.
- the inventors believe that addition of the small amount of surfactant directly into the dry particle formulations or suspension vehicles of the invention may have modified the interfacial behavior of the biomolecules in the dry particle formulations, leading to reduction in denaturation and aggregation of the biomolecules as the biomolecules transition from a hydrophobic vehicle into a hydrophilic medium.
- the surfactants may have helped to form particles having more hydrophobic excipients on the outside and more hydrophilic excipients on the inside. This biomolecular distribution may have played an important role in biomolecule stability during release from the hydrophobic vehicle into the hydrophilic medium.
- Surfactants that may be incorporated in dry particle formulations and/or suspension vehicles according to embodiments of the invention may be ionic or nonionic.
- surfactants include, but are not limited to, Polysorbate 20, Polysorbate 80, Tweens, Pluronic F68, sodium docecyl sulfate (SDS), Span 20, Span 40, Span 60, Span 80, Vitamin E TPGS, glyceryl caprylate, glyceryl laurate, PEG-8 caprylic capric glycerides, polyglyceryl-6 oleate, Pluronics, and dioctyly sodium sulfosuccinate.
- Table 2 shows surfactant loading for dry particle formulations and suspension vehicles according to some embodiments of the invention.
- SAIB hydrophobic vehicle
- hydrophilic release rate medium phosphate buffer solution
- SAIB is a high viscosity, hydrophobic liquid with limited water solubility. It has a viscosity of approximately 3.2 kP at 37°C.
- SAIB is produced by the controlled esterification of natural sugar (sucrose) with acetic and isobutyric anhydrides. The materials used for the study are listed in Table 3 below.
- Solid particles of omega-interferon were obtained by spray drying LFN- ⁇ with sucrose and methionine from 25 mM citrate solution with a solution concentration containing 3.3, 6.6, 3.3 and 7.1 mg/mL of IFN- ⁇ , sucrose, methionine and citrate, respectively to give a final composition of 1:2:1:2.15 (IFN- ⁇ : sucrose: methionine: citrate).
- the SEM image of the particles is shown in FIG. 1.
- the average particle size is 6.51 ⁇ m.
- EXAMPLE 2 Solid particles of IFN- ⁇ with 1% Pluronic F68 surfactant was obtained by spray drying IFN- ⁇ with sucrose and methionine and Pluronic F68 (Polyethylene oxide- PolyPropylene oxide copolymer) from 25 mM citrate solution with a solution concentration containing 3.3, 6.6, 3.3 7.1 and 0.2 mg/mL of IFN- ⁇ , sucrose, methionine, citrate, and Pluronic F68, respectively to give a final composition of 1:2:1 :2.15:0.06 (IFN- ⁇ : sucrose: methionine: citrate: Pluronic F68).
- IFN- ⁇ sucrose: methionine: citrate: Pluronic F68
- Stability samples of IFN- ⁇ /SAIB suspension in PBS were obtained by weighing approximately 8 mg of IFN- ⁇ /SAIB suspension into a 5 mL Vacutainer ® glass tube and adding 2 mL of PBS to the tube. The samples were stored at 37°C for stability testing. At each stability time point, the sample was taken out from the stability chamber. The liquid was decanted into a HPLC (High Performance Liquid Chromatrogram) vial and was analyzed directly by fast RP-HPLC (Reverse Phase High Performance Liquid Chromatography) method.
- HPLC High Performance Liquid Chromatrogram
Abstract
Description
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Priority Applications (10)
Application Number | Priority Date | Filing Date | Title |
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BRPI0511593-0A BRPI0511593A (en) | 2004-05-25 | 2005-05-23 | stable formulations during the transition from hydrophobic vehicle to hydrophilic |
NZ551258A NZ551258A (en) | 2004-05-25 | 2005-05-23 | A biomolecule-containing formulation of increased stability |
AU2005247439A AU2005247439B2 (en) | 2004-05-25 | 2005-05-23 | A biomolecule-containing formulation of increased stability |
JP2007515217A JP2008500345A (en) | 2004-05-25 | 2005-05-23 | Biomolecule-containing preparations with increased stability |
DE602005008053T DE602005008053D1 (en) | 2004-05-25 | 2005-05-23 | A SUSPENSION FORMULATION OF INCREASED STABILITY CONTAINING BIOMOLECULES - RELEASED BY AN IMPLANTABLE AID |
CA002568714A CA2568714A1 (en) | 2004-05-25 | 2005-05-23 | A biomolecule-containing formulation of increased stability |
EP05753131A EP1755650B8 (en) | 2004-05-25 | 2005-05-23 | A biomolecule-containing suspension formulation of increased stability deliverable via an implantable delivery device |
MXPA06013755A MXPA06013755A (en) | 2004-05-25 | 2005-05-23 | Formulations stable during transition from hydrophobic vehicle to hydrophilic medium. |
IL179279A IL179279A (en) | 2004-05-25 | 2006-11-14 | Biomolecule-containing formulation of increased stability |
NO20066029A NO20066029L (en) | 2004-05-25 | 2006-12-27 | Formulations that are stable through transition from hydrophobic vehicle to hydrophilic medium |
Applications Claiming Priority (4)
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US57466204P | 2004-05-25 | 2004-05-25 | |
US60/574,662 | 2004-05-25 | ||
US65022605P | 2005-02-03 | 2005-02-03 | |
US60/650,226 | 2005-02-03 |
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WO2005115333A2 true WO2005115333A2 (en) | 2005-12-08 |
WO2005115333A3 WO2005115333A3 (en) | 2006-05-18 |
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PCT/US2005/017914 WO2005115333A2 (en) | 2004-05-25 | 2005-05-23 | A biomolecule-containing formulation of increased stability |
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US (2) | US20050266087A1 (en) |
EP (1) | EP1755650B8 (en) |
JP (1) | JP2008500345A (en) |
KR (1) | KR20070046791A (en) |
AR (1) | AR049118A1 (en) |
AT (1) | ATE400291T1 (en) |
AU (1) | AU2005247439B2 (en) |
BR (1) | BRPI0511593A (en) |
CA (1) | CA2568714A1 (en) |
DE (1) | DE602005008053D1 (en) |
ES (1) | ES2309768T3 (en) |
IL (1) | IL179279A (en) |
MX (1) | MXPA06013755A (en) |
NZ (1) | NZ551258A (en) |
PE (1) | PE20060456A1 (en) |
TW (1) | TW200611712A (en) |
WO (1) | WO2005115333A2 (en) |
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WO2005115333A3 (en) | 2006-05-18 |
CA2568714A1 (en) | 2005-12-08 |
BRPI0511593A (en) | 2008-01-02 |
MXPA06013755A (en) | 2007-02-08 |
PE20060456A1 (en) | 2006-06-02 |
IL179279A0 (en) | 2007-03-08 |
US20080112994A1 (en) | 2008-05-15 |
EP1755650B1 (en) | 2008-07-09 |
EP1755650B8 (en) | 2008-10-15 |
ATE400291T1 (en) | 2008-07-15 |
DE602005008053D1 (en) | 2008-08-21 |
AU2005247439B2 (en) | 2010-02-11 |
ES2309768T3 (en) | 2008-12-16 |
NZ551258A (en) | 2009-07-31 |
IL179279A (en) | 2010-06-30 |
AU2005247439A1 (en) | 2005-12-08 |
AR049118A1 (en) | 2006-06-28 |
TW200611712A (en) | 2006-04-16 |
JP2008500345A (en) | 2008-01-10 |
EP1755650A2 (en) | 2007-02-28 |
KR20070046791A (en) | 2007-05-03 |
US20050266087A1 (en) | 2005-12-01 |
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