Classifications

• • 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
  • A61K47/20—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing sulfur, e.g. dimethyl sulfoxide [DMSO], docusate, sodium lauryl sulfate or aminosulfonic 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
  • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
  • A61K47/26—Carbohydrates, e.g. sugar alcohols, amino sugars, nucleic acids, mono-, di- or oligo-saccharides; Derivatives thereof, e.g. polysorbates, sorbitan fatty acid esters or glycyrrhizin
• • 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]
• • 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
  • A61K47/02—Inorganic compounds
• • 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
• • 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
  • A61K9/0002—Galenical forms characterised by the drug release technique; Application systems commanded by energy
  • A61K9/0004—Osmotic delivery systems; Sustained release driven by osmosis, thermal energy or gas
• • 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
  • A61K9/00—Medicinal preparations characterised by special physical form
  • A61K9/10—Dispersions; Emulsions
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P35/00—Antineoplastic agents
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
  • C07H1/00—Processes for the preparation of sugar derivatives
  • C07H1/06—Separation; Purification
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
  • C07H13/00—Compounds containing saccharide radicals esterified by carbonic acid or derivatives thereof, or by organic acids, e.g. phosphonic acids
  • C07H13/02—Compounds containing saccharide radicals esterified by carbonic acid or derivatives thereof, or by organic acids, e.g. phosphonic acids by carboxylic acids
  • C07H13/04—Compounds containing saccharide radicals esterified by carbonic acid or derivatives thereof, or by organic acids, e.g. phosphonic acids by carboxylic acids having the esterifying carboxyl radicals attached to acyclic carbon atoms

Definitions

• the present invention relates to methods for reducing peroxide levels in non- polymeric preparations and to compositions used in and prepared by such methods.
• SAIB Sucrose acetate isobutyrate
• SAIB is a hydrophobic liquid with limited water solubility. It is soluble in a large number of biocompatible solvents. SAIB has an unusual property - it undergoes a dramatic change in viscosity with small additions of heat or with the addition of solvents. It is a very viscous liquid, having a viscosity of approximately 3200 poise at 37° C. SAIB is produced by the controlled esterification of natural sugar (sucrose) with acetic and isobutyi ⁇ c anhydrides. SAEB metabolizes to sucrose, acetic acid and isobutyric acid.
• SAIB is orally non-toxic and is currently used to stabilize emulsions in the food industry.
• SAIB is commonly found in the beverage industry, where it is used as a weighting agent to help stabilize the final beverage formula.
• SAD3 has been reported to be useful as a gelling system-type drug excipient that allows for sustained or controlled release of drugs.
• SAIB can be applied via injection or an aerosol spray.
• SAEB is compatible with cellulose esters and other polymers that can affect the rate of delivery of the substance, hi one example, SAIB is the main ingredient for the SABER drug delivery system, which also consists of a pharmaceutically acceptable solvent.
• Drug delivery systems including SAEB delivery systems, are still confronted by various issues of drug instability, as such systems are considered for longer and longer drug delivery durations.
• Drug instability can occur via a number of factors, including denaturation, precipitation, oxidation, aggregation, and others, hi particular, a number of excipients used to facilitate delivery and release of drugs have peroxides or are susceptible to the formation of peroxides, which may lead to oxidation of active ingredient in the formulation, hi the example of SAEB, the presence of peroxides is deleterious to a drug incorporated in an SAEB drug formulation as the drug is likely to undergo oxidative degradation.
• the peroxide levels must be reduced.
• An aspect of the present invention comprises methods of treating sucrose acetate isobutyrate (SAIB) formulations to be used as drug delivery vehicles comprising adding to the formulations an amount of bisulfite salt effective to substantially remove peroxides, the bisulfite salt comprising sodium metabisulfite, potassium metabisulfite, sodium bisulfite, or potassium bisulfite, or a mixture thereof.
• SAIB sucrose acetate isobutyrate
• drug delivery vehicles adapted to provide prolonged stability of a drug that is to be delivered in vivo comprising sucrose acetate isobutyrate having substantially reduced levels of peroxide, the drug delivery vehicle being treated with an amount of bisulfite salt effective to substantially reduce levels of peroxide in said drug delivery vehicle, the bisulfite salt comprising sodium metabisulfite, potassium metabisulfite, sodium bisulfite, or potassium bisulfite, or a combination thereof.
• Figure 1 illustrates a bar graph of the results of Study I - Stability of omega- interferon in untreated SAIB.
• Figure 2 illustrates a bar graph of the results of Study Ha - Stability of omega- interferon in alumina treated SAIB.
• Figure 3 illustrates a bar graph of the results of Study lib - Stability of omega- interferon in alumina treated SAIB.
• Figure 4 illustrates a bar graph of the results of Study III - Stability of omega- interferon in untreated SAIB.
• Figure 5 illustrates a bar graph of the results of Study VIb - Stability of omega- iuterferon in untreated SAIB.
• Figure 6 illustrates a bar graph of the results of Study Via - Stability of omega- interferon in sodium metabisulfite treated SAIB.
• Figure 7 illustrates a bar graph that provides comparisons of oxidation of omega-IFN in sodium metabisulfite treated and untreated SAIB.
• Figure 8 illustrates an osmotically pump-driven implantable device, Duros® being an example, that facilitates in vivo delivery of an active agent in an SAIB vehicle.
• sucrose acetate isobutyrate formulations that are to be used as drug delivery vehicles comprising adding an amount of a bisulfite salt effective for substantially removing peroxide from the formulations, the bisulfite salt comprising sodium metabisulfite, potassium metabisulfite, sodium bisulfite, or potassium bisulfite, or a combination thereof.
• the bisulfite salt is sodium metabisulfite.
• a ratio ranging from about 1:1 to about 1:4 (weight: volume) SAIB:aqueous solution of bisulfite salt (“aqueous bisulfite salt”) can be used.
• the bisulfite salt is a metabisulfite salt
• the bisulfite salt is preferably sodium metabisulfite.
• the ratio of the aqueous bisulfite salt to SAIB is 1:1.
• a volume of sodium metabisulfite solution can be made up to 1 liter, and an approximate proportion of 1 : 1 of S AIB :aqueous sodium metabisulfite was used.
• the aqueous bisulfite salt in SAIB can be from about 0.1 % weight to volume of water (w/v) to about 50 % w/v; preferably, from about 0.5 % w/v to about 30 % w/v.
• the aqueous bisulfite salt is preferably from about 1 % w/v to about 15 % w/v. In some embodiments, the aqueous bisulfite salt is about 5 % w/v solution in water.
• the method removes peroxide to a level that is at least less than 50 % of the levels before the method, or starting levels, and, preferably, less than 20 % of the starting levels. In some embodiments, peroxide is removed to less than 10 % of the starting levels. While in some embodiments, the method removes peroxide to a level that is less than 5 % of the starting levels. Furthermore, the method can remove peroxide so that the resulting SAIB formulation contains peroxide in amounts less than 20 ppm, and, preferably, less than 10 ppm. In some embodiments, the method removes peroxide to result in an SAIB formulation containing less than 5 ppm.
• the resulting SAIB formulation from this method can serve as a drug delivery vehicle for use with a medical delivery device, including a drag eluting stent, a catheter, or other drug delivery implants.
• the SAIB formulation can be loaded into an osmotically pump-driven implantable device of the type disclosed in U.S. Patent No. 6,395,292, for example.
• the osmotically pump-driven implantable device is a Duros® device (Alza Corporation, Mountain View, California), hi other embodiments, the SAIB formulation can serve as a drug depot for drug delivery.
• the step of adding the bisulfite salt comprises mixing a solution of the bisulfite salt with the sucrose acetate isobutyrate formulation.
• the SATB formulation can be further comprised of a cosolvent, which can be selected from a number of solvents including pharmaceutically acceptable solvents, e.g., hexane, ethyl acetate, ethanol, benzyl benzoate, N-methyl pyrrolidone, and iso-propyl alcohol, among others.
• the cosolvent is hexane or ethyl acetate
• the methods further comprise vacuum treating the formulation to remove the cosolvent.
• some embodiments comprise the additional step of removing bisulfite salt from the formulation.
• This removal step comprises washing the formulation with water to remove the bisulfite salt
• a further step of drying the formulation over magnesium sulfate can be utilized to remove the water.
• calcium chloride anhydrous, calcium sulfate anhydrous, activated silica gel, phosphorous pentoxide, or drying under vacuum, or a combination thereof can be used to also remove the water
• glycerin can be used to wash the bisulfite-added formulation to remove the bisulfite salt. Afterwards, residual glycerin can be removed by washing with water and then drying to remove water.
• the methods of substantially removing peroxide from a sucrose acetate isobutyrate formulation comprising the steps of adding the aqueous bisulfite salt, washing the formulation, and drying the formulation are repeated at least once. The steps can be repeated to further reduce the levels of peroxide in the SAEB formulation.
• the present invention includes a drug delivery vehicle comprising SAD3 that provides for prolonged stability of a drug that is to be delivered by maintaining substantially reduced levels of peroxide, the drug delivery vehicle being treated with sodium metabisulfite.
• the prolonged stability comprises reduced oxidation, deamidation, or aggregation, e.g., dinierization, of the drug over extended periods of time in which drug is within environment of delivery vehicle.
• the prolonged stability is reduced oxidation.
• the extended periods of time can be periods from about one week to a few months, and up to about a year.
• the prolonged stability is evidenced by significant improvements in oxidation, deamidation, or aggregation levels of the drug when the delivery vehicle has been treated with a bisulfite salt versus untreated delivery vehicle, hi some preferred embodiments, the prolonged stability is characterized as about 50 % less oxidation, about 33 % less deamidation, or about 75 % less dimerization as compared to untreated delivery vehicles.
• the drug can be selected from any known and desired biomolecular material that can act as therapeutics and other therapeutic active agents that are susceptible to oxidative degradation.
• biomolecular material refers to peptides, polypeptides, proteins, nucleic acids, viruses, antibodies, small molecules susceptible to oxidation, and any other naturally derived, synthetically produced, or recombinantly produced active agent that includes nucleic or amino acid.
• drags can be selected from among the following: a steroid, NSAIDS, peptides, proteins such as growth factors or hormones, anti-tumor agents, antibiotics, analgesics, local anesthetics, antiviral agents, antipsychotics, anticoagulants, oligonucleotides for gene therapy, active small molecules, and others.
• the term "removing” and all variations thereof, refer to decreasing by any measurable degree the level of peroxide present in a drag formulation.
• the term “substantially removing” is used herein to describe a dramatic decrease in the level of peroxide present in a drag formulation, such as SAIB formulation. The dramatic decrease is at least 50 % of original levels (levels before treatment) and in some instances is 10 % of original levels. In preferred aspects of the present invention, the "substantial removal” describes a decrease to less than 5 % of original levels.
• drag delivery vehicle or “delivery vehicle” refers to a formulation that is biocompatible and used to carry a drag without reacting with the same drug. Also, the vehicle does not alter or minimally alters the activity of the drag. Furthermore, the vehicle allows for the transport of the drug in vivo and eventual delivery of the drug to a biological site for therapeutic effect.
• Prolonged stability is used to refer to the stabilizing effect of the drug delivery vehicles of the present invention on the carried drug. Prolonged stability can be evidenced by significant improvements in oxidation, deamidation, or aggregation of the drug over extended periods of time.
• Each of the experiments involved protein particles consisting of omega- interferon, which were suspended in SATB at a particle loading of either 4 % or 10 % by weight.
• the suspensions were prepared in a dry box under nitrogen at 45°'C. The suspension was mixed for 15 minutes while maintaining the temperature. Suspension mixing was performed by hand. Aliquots from the prepared suspensions were transferred to clear crimp-top glass vials and sealed under nitrogen. Each aliquot contained at least six milligrams of protein to allow for stability testing in triplicate. These samples were stored in an oven at 40° C. Samples were withdrawn at regular intervals (as indicated in Table 1) and analyzed for omega-interferon content and purity was assessed using reverse phase HPLC and size exclusion chromatography.
• Size exclusion chromatography was used to monitor the omega- interferon content and purity in the formulations. The percentages of monomer and dimer in the formulation were quantified using SEC. The stability of omega-interferon was judged by using a stability indicating chromatographic technique based on reverse phase HPLC (rp-HPLC). This technique was used to monitor the oxidation, deamidation and formation of an unknown species of omega-interferon in the formulations. The peroxide content of the vehicle was determined using EP 2002, 2.5.5 (Method A with auto titration). See Extra Pharmacopoeia. 2002 Ed. Content and purity assay of omega-interferon by size exclusion chromatography (SEC).
• SEC Size exclusion chromatography
• Study Ha Treatment of SAB3 (lot #TD1030507) with neutral alumina by heating and stability in this treated SAIB for 4 weeks • Study lib: Treatment of SAIB (lot #TD1030507) with neutral alumina in presence of ethanol and stability in this treated SAIB for 4 weeks
• Study in Stability in untreated SAIB (lot #TD2032663) for 2 weeks .
• Study IV Treatment of SAIB (lot #TD2032663) with basic alumina by heating .
• Study V Treatment of SAIB (lot #TD2032663) with 10 % aqueous methionine solution by heating .
• Study Via Treatment of SAIB (lot #TD2032663) with 5 % aqueous solution of sodium metabisulfite and stability in treated S AIB for 8 weeks .
• Study VIb Stability in untreated SAIB (lot #TD2032663) for 8 weeks Table 1. Details about stability studies of omega-interferon in SAIB
• SAIB was heated to 75° C.
• Alumina (15 % w/w) was added to the heated SAIB.
• the mixture was stirred for 40 minutes and filtered though a 5.0 ⁇ m filter at 75° C.
• the treated SAEB was then collected, sampled for peroxide testing, and used for preparation of suspension for stability testing.
• SAEB was mixed with 15% absolute ethanol to reduce the viscosity.
• Basic alumina (15 % w/w) was added to the SAEB containing ethanol. The resulting mixture was stirred for 1 hour and filtered though a 0.2 ⁇ m filter. The filtered SAEB was placed overnight under vacuum at 60° C to remove the ethanol. This treated SAEB was then collected, sampled for peroxide testing, and used for preparation of suspension for stability testing.
• SAIB was heated to 90° C.
• Basic alumina (15 % w/w) was added to the heated SAIB.
• Two different grades of alumina were used - Basic Super I and Basic Standard Activity I.
• the resulting mixture was stirred for 40 minutes.
• the mixture was then centrifuged at 4000 rpm while temperature was maintained at 75° C. After centrifugation, the supernatant was collected and sampled for peroxide analysis.
• SAIB was vigorously agitated with 4 parts of 10 % aqueous solution of methionine at 80° C for 45 minutes using a magnetic stirrer. (Evaporated water was replenished as necessary) Afterwards, the methionine solution was decanted. SAEB was then washed with 4 parts of water by agitating for 15 minutes at 70° - 80° C. This washing step was carried out three times. SAIB was placed overnight in vacuum oven at 70° C to remove residual water, and, afterwards, was sampled for peroxide analysis.
• SAIB was dissolved in two parts of hexane. The resulting solution was treated with a 5 % aqueous solution of sodium metabisulfite by vigorous shaking. The aqueous layer was removed and the SAIB layer was washed with water. The SAIB layer was dried with MgSO 4 . Hexane was removed from SAD3 by evaporation under vacuum at 50° C. The treated SAD3 was sampled for peroxide analysis and used for preparation of suspension for stability testing.
• the omega content in the suspension was 1.00 % and not 1.66% because the particles contained 11.45% omega and the loading of particles in suspension was at 10%
• the omega content in the suspension was 1.17 % and not 1.66% because the particles contained 11.45% omega and the loading of particles in suspension was at 10%. ** standard deviation in parenthesis
• FIG. 8 illustrates an osmotically pump-driven implantable device for delivering an SAIB formulation acting as a drug delivery vehicle, active agent within.
• an osmotically pump-driven implantable device 10 shown comprising an impermeable reservoir 12.
• the reservoir 12 is divided into two chambers by a piston 16.
• the first chamber 18 is adapted to contain an SAIB formulation 19 containing an active agent 20 and the second chamber 21 is adapted to contain a fluid-imbibing agent.
• a back-diffusion regulating outlet 22 is inserted into the open end of the first chamber 18 and a semipermeable membrane 24 encloses the open end of the second chamber 21.
• the piston 16 is driven towards the open end of the first chamber 18 by the osmotic pressure generated by the fluid-imbibing agent in the second chamber 21.
• the pressure created by the piston 16 can force the contents of the first chamber 18 out the opening, i.e., the SAIB formulation 19 comprising active agents 20.
• the release rate of the active agent can be governed by the osmotic pumping rate.

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