Classifications

• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K38/00—Medicinal preparations containing peptides
  • A61K38/04—Peptides having up to 20 amino acids in a fully defined sequence; Derivatives thereof
  • A61K38/14—Peptides containing saccharide radicals; Derivatives thereof, e.g. bleomycin, phleomycin, muramylpeptides or vancomycin
• • 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
  • A61K9/007—Pulmonary tract; Aromatherapy
  • A61K9/0073—Sprays or powders for inhalation; Aerolised or nebulised preparations generated by other means than thermal energy
  • A61K9/0075—Sprays or powders for inhalation; Aerolised or nebulised preparations generated by other means than thermal energy for inhalation via a dry powder inhaler [DPI], e.g. comprising micronized drug mixed with lactose carrier particles
• • 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
  • A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
  • A61K31/19—Carboxylic acids, e.g. valproic acid
  • A61K31/195—Carboxylic acids, e.g. valproic acid having an amino group
  • A61K31/197—Carboxylic acids, e.g. valproic acid having an amino group the amino and the carboxyl groups being attached to the same acyclic carbon chain, e.g. gamma-aminobutyric acid [GABA], beta-alanine, epsilon-aminocaproic acid or pantothenic acid
  • A61K31/198—Alpha-amino acids, e.g. alanine or edetic acid [EDTA]
• • 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
  • A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
  • A61K9/4808—Preparations in capsules, e.g. of gelatin, of chocolate characterised by the form of the capsule or the structure of the filling; Capsules containing small tablets; Capsules with outer layer for immediate drug release
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P11/00—Drugs for disorders of the respiratory system
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
  • A61P31/04—Antibacterial agents
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K2121/00—Preparations for use in therapy
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K2300/00—Mixtures or combinations of active ingredients, wherein at least one active ingredient is fully defined in groups A61K31/00 - A61K41/00

Definitions

• Vancomycin is a glycopeptide antibiotic used in the prophylaxis and treatment of infections caused by Gram-positive bacteria. Vancomycin is the international nonproprietary name (INN) corresponding to the compound with the following formula:
• vancomycin acts by inhibiting proper cell wall synthesis in Gram-positive bacteria. More specifically, it is believed that vancomycin prevents incorporation of N-acetylmuramic acid (NAM) and N-acetylglucosamine (NAG) glycan subunits into the peptidoglycan matrix; which forms the major structural component of Gram-positive cell walls.
• NAM N-acetylmuramic acid
• NAG N-acetylglucosamine
• Vancomycin has been administered intravenously for systemic therapy, as well as orally in the treatment of pseudomembranous colitis. Vancomycin has also been used off-label in a nebulized aerosol form for the treatment of various infections of the upper and lower respiratory tract.
• Vancomycin has also been used off-label in a nebulized aerosol form for the treatment of various infections of the upper and lower respiratory tract.
• the use of an approved drug in an off-label manner may put a patient at risk as the safety and efficacy have not been studied and/or the appropriate dose may not be given.
• delivery by nebulization can take up to 20 minutes, which is a significant burden to
• the present disclosure generally relates to dry powder compositions and methods for administering and preparing such compositions.
• the present disclosure provides a composition comprising vancomycin or a pharmaceutically acceptable salt thereof, wherein the composition is a dry powder.
• the present disclosure also provides a method comprising administering a dry powder composition comprising vancomycin or a pharmaceutically acceptable salt thereof to a subject via pulmonary administration.
• the present disclosure provides a method comprising spray drying an aqueous composition comprising vancomycin or a pharmaceutically acceptable salt thereof and a hydrophobic amino acid so as to form a dry powder composition.
• Figure 1 is a graph depicting the aerodynamic particle size distribution of a dry powder vancomycin composition (Lot SAO 10) as measured using the Andersen Cascade Impactor and Monodose RSOl Model 7 inhaler.
• Figure 2 is a graph depicting the effect of leucine content on the delivery efficiency of dry powder vancomycin compositions (Lots SA002, SA006, SA007, SA008 and SA009) as measured using the fast screening impactor and Monodose RSOl Model 7 inhaler.
• Emitted dose (%) is the amount of drug in the dry powder that exits the inhaler as a percentage of the initial amount of drug in the dry powder present in the capsule.
• Fine particle fraction (%) is the amount of drug in the dry powder having an aerodynamic size less than 5 ⁇ as a percentage of the emitted dose.
• Delivery efficiency (%) is the amount of drug in the dry powder having an aerodynamic diameter less than 5 ⁇ as a percentage of the initial amount of drug in the capsule.
• Figure 3 is an image of lab-scale dry powder vancomycin particles (Lot SAO 10) obtained using a scanning electron microscope.
• Figure 4 is a graph depicting the aerodynamic particle size distribution of a dry powder vancomycin composition (Lot SAO 10) stored at 25°C and 60% relative humidity (RH) for a period up to 6 months as measured using the Andersen Cascade Impactor and Monodose RS01 Model 7 inhaler.
• Figure 5 is a graph depicting the emitted dose content uniformity under 3 different stability conditions for a period up to 6 months of 10 consecutive actuations through a Monodose RS01 Model 7 inhaler compared to FDA draft guidance specification limits of ⁇ 20% (Lot SAOIO).
• Figure 6 is a graph depicting the aerodynamic particle size distribution of a dry powder vancomycin composition of the present disclosure (Lot G- 1 1-26-1) as measured from three Monodose RS01 Model 7 inhalers tested at 100 L/min for 2.4 s (equivalent to 4 L) using a Next Generation Impactor.
• Figure 7 is a graph depicting the emitted dose content uniformity across ten Monodose RS01 Model 7 inhalers tested at 100 L/min for 2.4 s (equivalent to 4 L) for lot G-l 1-26-1.
• the ⁇ 20% and ⁇ 25% represent the FDA draft guidance limits.
• Figure 8 is a graph depicting the effect of trehalose concentration on the chemical stability of a dry powder vancomycin composition of the present disclosure at 50°C for 4 weeks.
• Figure 9 is a graph depicting a comparison of two lots of dry powder vancomycin compositions containing 10% leucine.
• Figure 10 is an image of pilot-scale dry powder vancomycin particles (Lot 19SA01.HQ00005) obtained using a scanning electron microscope.
• Figure 1 1 is a graph depicting plasma concentrations as a function of time (semi-log) after a single dose administration of a vancomycin dry powder composition (Lot G-l 1-026-1) or intravenous administration of vancomycin (inhaled vancomycin dose 16 mg, circle; inhaled vancomycin dose 32 mg, triangle; inhaled vancomycin dose 80 mg, square; Intravenous infusion 250 mg over 60 min, circle with line).
• a composition of the present disclosure generally relates to dry powder vancomycin compositions and methods for administering and preparing such compositions.
• a composition of the present disclosure may be administered to a subject via pulmonary administration in an amount effective to treat and/or prevent a bacterial infection in the subject.
• Administration of an effective amount of a composition of the present disclosure may be particularly useful in treating a gram-positive bacterial infection in a subject suffering from pneumonia, cystic fibrosis, bronchiectasis, or other chronic lung disease with a bacterial infection of the subject's airway and/or lung.
• a composition of the present disclosure is a dry powder comprising vancomycin or a pharmaceutically acceptable salt thereof.
• vancomycin includes analogues and derivatives of vancomycin.
• dry means that the composition has a moisture content such that the particles are readily dispersible in an inhalation device to form an aerosol. In some embodiments, this moisture content may be below about 10% by weight water, below about 7% by weight water, below about 5% by weight water or below about 3% by weight water.
• a dry powder composition of the present disclosure may have a tap density greater than about 0.4 g/cm , greater than about 0.45 g/cm or greater than about 0.5 g/cm .
• vancomycin may be predominately used in the descriptions contained in this disclosure, it should be understood that the present disclosure may be practiced with any other glycopeptide antibiotics (e.g. vancomycin, teicoplanin, telavancin, bleomycin, ramoplanin, and decaplanin), and derivatives and analogues thereof, among other things, to treat certain gram positive infections.
• a dry powder composition of the present disclosure comprises vancomycin, or a pharmaceutically acceptable salt thereof, present in an amount of about 90% by weight of the composition, the powder having a tap density of greater than about 0.4 g/cm , and further comprises leucine in an amount of about 10% by weight of the composition.
• a dry powder composition of the present disclosure may comprise particles having an average particle size of less than or equal to about 10 microns ( ⁇ ) in diameter as defined by the mass median aerodynamic diameter (MMAD) (measured using cascade impaction). In some embodiments, at least 95% of the particles have a MMAD of less than about 10 ⁇ . In some embodiments, the diameter may be less than or equal to about 7 ⁇ .
• the diameter may be less than or equal to about 5 ⁇ . In certain specific embodiments, the diameter may be between about 0.5 ⁇ and about 5 ⁇ ⁇ in diameter, particularly about 1 ⁇ to about 3 ⁇ . Dry powder compositions of the present disclosure comprising particles having an average particle size of less than or equal to about 10 ⁇ in diameter may be particularly useful for delivery via an oral inhalation device.
• a dry powder composition of the present disclosure may comprise particles having an average particle size of greater than or equal to about 10 ⁇ in diameter as defined by MMAD (measured using cascade impaction). In some embodiments, at least 95% of the particles have a MMAD of greater than about 10 ⁇ . In certain specific embodiments, the particle size may be between about 10 ⁇ and about 50 ⁇ in diameter, particularly about 20 ⁇ to about 40 ⁇ . Dry powder compositions of the present disclosure comprising particles having an average particle size of greater than or equal to about 10 ⁇ in diameter may be particularly useful for nasal delivery.
• the particles may be hollow. In some embodiments, the particles may be porous. In some embodiments, the particles may have a spheroidal shape distribution, which may be relatively uniform. In some embodiments, the vancomycin potency as measured by microbial activity is effectively unchanged when compared to the unformulated drug (i.e. within 5% of the drug).
• Vancomycin or a pharmaceutically acceptable salt thereof suitable for use in the present disclosure is generally available through various commercial vendors.
• suitable pharmaceutically acceptable salts of vancomycin include, but are not limited to, vancomycin hydrochloride, vancomycin sulfate, etc.
• a composition of the present disclosure may further comprise one or more additives.
• a suitable additive includes a hydrophobic amino acid.
• hydrophobic amino acids may include, but are not limited to, tryptophan, tyrosine, leucine, trileucine and phenylalanine.
• the hydrophobic amino acid additive remains on the surface of the particles and protects them from moisture and light, thereby increasing the stability of the formulation.
• a suitable additive includes a carbohydrate bulking agent.
• Such carbohydrate bulking agents may include, but are not limited to, lactose, mannitol, trehalose, raffinose, and maltodextrins.
• the carbohydrate bulking agent may also improve the chemical stability of vancomycin or a pharmaceutically acceptable salt thereof.
• Other additives known to those of ordinary skill in the art may also be included.
• additives suitable for use in the compositions of the present disclosure may be included in an amount of about 50% or less by weight of the composition, 30% or less by weight of the composition, or 10% or less by weight of the composition. In other embodiments, additives suitable for use in the compositions of the present disclosure may be included in an amount of from about 10% to about 30% by weight of the composition. In other embodiments, additives suitable for use in the compositions of the present disclosure may be included in an amount of from about 10% to about 20% by weight of the composition.
• compositions of the present disclosure may further comprise pharmaceutically acceptable auxiliary substances or adjuvants, including, without limitation, pH adjusting and buffering agents and/or tonicity adjusting agents, such as, for example, sodium acetate, sodium lactate, sodium chloride, potassium chloride, calcium chloride, etc. Leucine has the dual benefit of also modifying the pH.
• compositions of the present disclosure may contain pharmaceutically acceptable carriers and excipients including microspheres, microcapsules, nanoparticles or the like.
• the dry powder composition may be reconstituted and the resulting reconstituted powder may have a pH greater than 3.0, preferably greater than 3.5 and most preferably greater than 4.0.
• a dry powder vancomycin composition may be particularly useful in alleviating symptoms and/or treating subjects suffering from conditions including, but not limited to pneumonia and cystic fibrosis with gram-positive bacterial infections, and/or colonization of the airways- and/or lung parenchyma by bacteria or other pathogens susceptible to vancomycin or its derivatives.
• Other conditions may include, but are not limited to, bronchitis, bronchiectasis, diffuse panbronchiolitis, bronchiolitis, bronchiolitis obliterans, bronchiolitis obliterans organizing pneumonia (BOOP), pneumonia of any cause, including but not limited to community acquired pneumonia, nosocomial pneumonia and ventilator associated pneumonia (VAP).
• gram-positive bacterial infections may include, but are not limited to, bacterial infections by Streptococcus pneumoniae, and Staphylococcus aureus, including methicillin-resistant Staphylococcus aureus.
• the effective amount needed to treat a particular condition or disease state will depend on the pathogen, individual, the condition, length of treatment, the regularity of treatment, the type of vancomycin used, and other factors, but can be readily determined by one of ordinary skill.
• the patient can achieve a desired dosage by inhaling an appropriate amount of the composition.
• a dry powder composition of the present disclosure may be delivered to a subject by any means so long as the solid particles of the dry powder composition are capable of being inhaled by a subject so that the particles reach the lungs to permit penetration into the upper and lower airways.
• a dry powder composition of the present disclosure may be delivered to a subject by placing the dry powder within a suitable dosage receptacle in a sufficient amount.
• suitable dosage receptacles include those used in reservoir devices (e.g., devices that contain more than one dose in which the device itself meters the dose) or factory- metered dose devices (e.g., devices in which each dose is contained in either a single unit or multiple units).
• a suitable reservoir device may have a dosage receptacle that fits within a suitable inhalation device to allow for the aerosolization of the dry powder composition by dispersion into a gas stream to form an aerosol and then delivering the aerosol so produced from a mouthpiece attached for subsequent inhalation by a subject in need of treatment.
• a dosage receptacle includes any container enclosing the composition known in the art such as gelatin, hydroxypropyl methyl cellulose or plastic capsules with a removable portion or body that can be cut or pierced that allows dispersal of the dry powder composition (e.g., via a gas stream directed into the container and via centrifugal force).
• Such containers are exemplified by those shown in U.S. Pat.
• Suitable containers also include those used in conjunction with GlaxoSmithKIine's Ventolin Rotahaler brand powder inhaler or Fisons' Spinhaler brand powder inhaler.
• Another suitable unit-dose container which provides a superior moisture barrier is formed from an aluminum foil plastic laminate. The powder composition is filled by weight or by volume into the depression in the formable foil and hermetically sealed with a covering foil-plastic laminate. Such a container for use with a powder inhalation device is described in U.S. Pat. No.
• a dry powder composition of the present disclosure may be delivered to a subject via a tracheal tube.
• compositions of the present disclosure may be prepared by spray drying an aqueous mixture of vancomycin or a salt thereof and a pharmaceutically acceptable carrier under conditions sufficient to provide a respirable dry powder composition.
• the dry powder composition is substantially amorphous.
• spray drying is a process in which a homogeneous aqueous mixture of vancomycin or a salt thereof and the carrier is introduced via a nozzle (e.g., a two fluid nozzle), spinning disc or an equivalent device into a hot gas stream to atomize the solution thereby forming fine droplets which subsequently mix into a hot gas stream.
• the aqueous mixture may be a solution, suspension, slurry, or the like, but should be homogeneous to ensure uniform distribution of the components in the mixture and ultimately the powdered composition.
• the aqueous mixture is a solution.
• the aqueous mixture may have a solids content of at least 1 % by weight water.
• the aqueous mixture may have a solids content of at least 2% by weight water. In other embodiments, the aqueous mixture may have a solids content of at least 4% by weight water.
• the solvent generally water, rapidly evaporates from the droplets producing a fine dry powder having particles 1 to 5 ⁇ in diameter.
• the spray drying is done under conditions that result in a substantially amorphous powder of homogeneous constitution having a particle size that is respirable, a low moisture content and characteristics that allow for ready aerosolization.
• the particle size of the resulting powder is such that more than about 95% of the mass is in particles having a diameter of about 10 ⁇ or less.
• dry powder compositions may be prepared by other processes such as lyophilization and jet milling as disclosed in WO 91/16038, the disclosure of which is hereby incorporated by reference.
• a number of formulation and processing strategies may be useful to improve, among other things, the storage and stability properties of the dry powder vancomycin compositions of the present disclosure.
• the vancomycin used may be chosen to be of a higher purity.
• steps may be taken to avoid oxidation of vancomycin.
• processing and packaging of the composition may be performed under nitrogen.
• the processing and packaging may be performed to minimize exposure to direct light. Such steps may reduce light-mediated degradation of vancomycin.
• steps may be taken to reduce the amount of moisture in the composition.
• Such steps may be useful to avoid hydrolysis, deamidation, and oxidation of vancomycin.
• a carbohydrate bulking agent may be added to the composition, which also may improve chemical stability.
• compositions of the present disclosure have many advantageous properties
• one particularly advantageous property is that the compositions may have a pharmacokinetic profile that is favorable for antibacterial efficacy of a time dependent bactericidal antibiotic, such as vancomycin, in that it may provide a prolonged high concentration of vancomycin in the lung, and thereby increase the time during which the mimmum inhibitory concentrations of target pathogens are exceeded.
• the median amount of time necessary for the blood plasma levels of a subject to reach their maximum concentration of vancomycin may be greater than or equal to about 30 minutes, greater than or equal to about one hour, or less than or equal to about six hours. In some embodiments, T max may be between about one hour and three hours. Similarly, in certain embodiments, the median amount of time necessary for blood plasma levels of a subject to decrease to one half of the total maximum concentration of vancomycin (t] /2 ) may be greater than six hours. In some embodiments, t ⁇ a may be about eight hours.
• the dry powder composition may provide a mean maximum blood plasma concentration of vancomycin within the range of about 50% to about 150% of about 620 ng/mL, a mean AUCo-24h value within the range of about 50% to about 150% of about 6,250 nghr/mL, and a median T max value within the range of about 0.75 hours to 3 hours, as measured following a single pulmonary administration.
• a mean maximum blood plasma concentration of vancomycin within the range of about 50% to about 150% of about 620 ng/mL
• a mean AUCo-24h value within the range of about 50% to about 150% of about 6,250 nghr/mL
• a median T max value within the range of about 0.75 hours to 3 hours
• the present disclosure also provides compositions wherein the vancomycin or the pharmaceutically acceptable salt thereof is present in the dry powder composition in an amount of about n x 80 mg and wherein the dry powder composition provides: a mean maximum blood plasma concentration of vancomycin (Cmax) within the range of about 50% to about 150% of about n x 620 ng/mL; an mean AUC 0-24 value within the range of about 50% to about 150% of about n x 6,250 nghr/mL; and a median Tma value in the range of about 0.5 hours to about 6 hours, wherein the maximum blood plasma concentration of vancomycin, the AUCo -24h value, and the T max value are measured following a single pulmonary administration of the dry powder composition; wherein n represents a factor to be multiplied and may be a value from 0.01 to 10.
• Cmax mean maximum blood plasma concentration of vancomycin
• the dry powder vancomycin compositions of the present disclosure may provide a delivery efficiency of 40% or more. In other embodiments, the dry powder vancomycin compositions of the present disclosure may provide a delivery efficiency of 60% or more. Delivery efficiency (%) is the amount of the dry powder having an aerodynamic diameter less than 5 ⁇ as a percentage of the initial amount of dry powder in the capsule.
• Delivery efficiency is the emitted dose (%) (i.e., the amount of the dry powder that exits the inhaler as a percentage of the initial amount of the dry powder present in the capsule) multiplied by the fine particle fraction (%) (i.e., respirable amount or the amount of the dry powder having a mass median aerodynamic diameter (MMAD) of 5 ⁇ or less as a percentage of the emitted dose).
• emitted dose i.e., the amount of the dry powder that exits the inhaler as a percentage of the initial amount of the dry powder present in the capsule
• the fine particle fraction i.e., respirable amount or the amount of the dry powder having a mass median aerodynamic diameter (MMAD) of 5 ⁇ or less as a percentage of the emitted dose
• the dry powder vancomycin compositions of the present disclosure may provide an absolute bioavailability of 40% or more. Absolute bioavailability is calculated as AUCo-inf of vancomycin after the vancomycin composition administration divided by AUCo-inf of vancomycin after intravenous administration and adjusted for dose.
• Dry powder vancomycin compositions were produced on a Buchi lab scale spray dryer at high yield (75-95%) and at two different batch sizes (1 g and 20 g) with no loss in purity. These powders exhibited very high delivery efficiencies and consistency across lots.
• the full aerodynamic particle size distribution for the 20 g batch is depicted in Figure 1 showing that the vast majority of the particle size distribution is less than 5 ⁇ and that a significant proportion (approx. 59%) is within the ultra-fine particle fraction (3 ⁇ ) predictive of deep lung delivery.
• the delivery efficiency of dry powder vancomycin compositions may be improved through the addition of small amounts of leucine (Figure 2).
• the addition of leucine to vancomycin powders significantly reduces the water content of the powder and the mass median aerodynamic diameter.
• the addition of leucine results in powders with more physiologically acceptable pH values. See Table 1 below for the effect of leucine concentration on powder water content, particle size and reconstituted pH.
• An example batch formula is included in Table 2.
• the target mass of leucine is weighed into a beaker.
• the required mass of de-ionized water is added and mixed using a magnetic stir bar. Vancomycin hydrochloride is then added and the solution is stirred for 1.0-1.5 hours until visibly clear.
• the feedstock solution is prepared immediately before being spray dried.
• the solution concentration is approximately 4% w/w total dissolved solids.
• a benchtop spray drying system (Buchi model 191) with high efficiency cyclone is used to generate and collect the powder.
• the powder is more conveniently recovered from the process stream across 4 cyclone powder collection events.
• the equilibrium drying condition is established using de-ionized water.
• the nozzle input is switched to feedstock solution.
• the solution is fed to the dryer until a quarter of the solution has been utilized and then the nozzle is switched back to water for approximately 5 minutes to clear the system.
• the dryer is then shutdown momentarily to allow for collector change-out, restarted immediately and lined-out on water prior to resuming feed solution.
• the filled collector is rapidly capped on removal to minimize exposure to room humidity.
• Each collector is then transferred into individual glass sample vials within a low humidity dry glove box and the complete set of vials packaged into an aluminum pouch with desiccant and heat-sealed.
• Figure 3 depicts a scanning electron microscope (SEM) image of a vancomycin-leucine powder formulation from Lot SAO 10.
• dry powder vancomycin compositions of the present disclosure may be prepared using spray drying methods. Such methods have proven to be very efficient and exhibit excellent batch to batch consistency.
• Table 3 below shows yield, primary particle size and water content data for batch sizes ranging from 25 g to 100 g, which were prepared using spray drying methods.
• X 10 , X 50 and X 90 are the mass diameter of particles to which 10%, 50% and 90% of the distribution is smaller, respectively.
• ND Not determined.
• Figure 7 shows that the emitted dose content uniformity for Lot G-l 1 -26-1 meets the FDA's draft guidance specifications for aerosol dose content uniformity (i.e., no more than 1 out of 10 actuations should be outside ⁇ 20% of the label claim with no actuation outside ⁇ 25% of the label claim).
• a carbohydrate bulking agent was included in a vancomycin-leucine formulation.
• the chemical stability of this formulation was studied at 50°C for 4 weeks.
• Figure 8 shows that the addition of a carbohydrate bulking agent (e.g., trehalose) can improve the chemical stability of dry-powder vancomycin compositions of the present disclosure.
• a carbohydrate bulking agent e.g., trehalose
• the powder production process has been successfully scaled-up from lab to pilot-scale equipment.
• the process can produce up to 1 ,000 g of powder per day at high yield (75%) and with no loss in purity.
• Figure 10 depicts a SEM image of particles from a 1 ,000 g lot (Lot 19SA01.HQ00005) manufactured on a Niro Mobile Minor "2000" spray dryer.
• Table 5 shows powder testing data from two scaled-up lots.
• Table 6 shows the corresponding final product test results for Lot 19SA01.HQ00002. TABLE 5
• AUC 0-t refers to the area under the plasma concentration-time curve to the last measurable time point (24 h) calculated by the linear trapezoidal rule.
• AUCo-inf refers to the area under the concentration- time curve to infinity.
• C max refers to the maximum blood plasma concentration of vancomycin
• T max refers to the amount of time necessary to reach maximum blood plasma levels of vancomycin
• ti/ 2 refers to the elimination half-life associated with the terminal slope (K e i) of the semilogarithmic drug concentration-time curve, calculated as 0.693/K e i-
• T max value was more than one hour with all doses, suggesting a slow absorption of vancomycin from the lungs. There was a slight trend towards a shorter T max with increasing doses (16 mg: 2 h (range 1-3 h); 32 mg: 1.5 h (range 1-3 h); 80 mg: 1.25 h (range 1- 2 h).
• the observed T max values were considerably higher than expected based on previously published results with inhaled antibiotic powder (TOBI Podhaler prescribing information, T max of 1 h with all tested doses ranging from 28 mg to 112 mg).
• the C max of vancomycin was very closely dose proportional between 16 mg and 80 mg (R > 0.95).
• This pharmacokinetic profile is very favorable for antibacterial efficacy of a time dependent (and concentration-independent at concentrations exceeding approximately 1 ⁇ g/ml) bactericidal antibiotic, such as vancomycin, in that it provides a more prolonged high concentration of vancomycin in the lung, and thereby increases the time during which the minimum inhibitory concentrations of target pathogens are exceeded.

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• 2012
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  • 2012-05-21 KR KR1020137033895A patent/KR101763195B1/ko active IP Right Grant
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  • 2012-05-21 AU AU2012254999A patent/AU2012254999B2/en not_active Ceased
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