Classifications

• • 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
  • 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
  • A61K9/141—Intimate drug-carrier mixtures characterised by the carrier, e.g. ordered mixtures, adsorbates, solid solutions, eutectica, co-dried, co-solubilised, co-kneaded, co-milled, co-ground products, co-precipitates, co-evaporates, co-extrudates, co-melts; Drug nanoparticles with adsorbed surface modifiers
  • A61K9/145—Intimate drug-carrier mixtures characterised by the carrier, e.g. ordered mixtures, adsorbates, solid solutions, eutectica, co-dried, co-solubilised, co-kneaded, co-milled, co-ground products, co-precipitates, co-evaporates, co-extrudates, co-melts; Drug nanoparticles with adsorbed surface modifiers with organic compounds

Definitions

• the field of the invention is dry powder pharmaceutical formulations.
• Dry powder inhalers are widely used to treat pulmonary diseases, such as asthma, as well as other diseases and conditions.
• pulmonary diseases such as asthma
• Various dry powder inhaler designs have been proposed and used.
• a dose of dry powder is released from a container, such as a blister disk, gelatin capsule, etc., or a dose is metered out from bulk storage.
• the dry powder is formulated either as a pure active pharmaceutical, or an active pharmaceutical and an excipient carrier.
• the patient's inspiratory effort is required to remove and disperse the powder into inhalable primary particles.
• dispersion of particles of from about 1- 5 or 1-10 microns is believed to be necessary for good pulmonary deposition, i.e., to allow the active drug particles to be inhaled deep into the lungs, where they are better absorbed by the body.
• One known approach to resolving this problem is to reduce or eliminate the unstable amorphous phase, by conditioning or by exposing the powder containing the amorphous phase to controlled humidity, prior to packaging.
• This conditioning process intends to effectively reduce Tg to ambient conditions, changing the immobile amorphous glassy state, to a mobile amorphous rubbery state.
• the mobile amorphous state readily converts to a more physically stable crystalline state.
• the powder is then ready for packaging for use in a dry powder inhaler.
• the intended result of using conditioned powder is to have the powder become more physically stable, upon exposure to elevated relative humidity, when the package is opened.
• the objective of the conditioning is to convert amorphous phase to a crystalline phase, without producing a significant change in the particle size distribution of the powder.
• Figure 1 shows an example of micronized albuterol sulfate, before and after conditioning. As shown in Fig. 1, no significant change in particle size distribution is observable after conditioning.
• Fig. 2 is a graph of respirable dose ( fine particle fraction ) for micronized albuterol sulfate, blended with ⁇ -lactose monohydrate, versus storage time in months.
• the powder formulation conditioned as is well known in the field, shows a significant decrease in respirable dose, over time.
• the respirable dose for the conditioned formulation is almost as rapid as for the unconditioned formulation. This will result in a decrease in the dose received by a patient, when the formulation is stored unpackaged (i. e. , in an opened package ) at common environmental conditions (for example, 25°C and 75% RH ) over time.
• the hydrophilic pharmaceutical compound is processed to remove particles having a diameter of less than about 3 microns.
• the hydrophilic excipient is also processed to remove excipient particles having a diameter of less than about 10 microns.
• the processed pharmaceutical compound and processed excipient are mixed or blended.
• the mixture is then ripened by exposing it to a ripening environment.
• the ripening environment preferably has relatively high humidity and temperature. During ripening, remaining fine particles tend to fuse to other particles, stabilizing the formulation.
• the processed hydrophilic pharmaceutical compound, and the processed excipient may be separately ripened, before they are blended together.
• the hydrophilic excipient is processed to remove particles having a diameter of less than about 10 microns.
• the processed excipient is blended with the hydrophobic pharmaceutical compound, and the blend is then ripened, by exposure to a high humidity and high temperature environment.
• the hydrophilic excipient may be separately ripened before blending.
• the formulations are more physically stable than prior formulations.
• the respirable dose provided by the formulation remains relatively constant over time, even with exposure to high humidity conditions. Consequently, patients using unsealed dry powder inhalers and pharmaceutical powder containers, can continue to receive a consistent and proper dose of inhaled pharmaceutical formulation, even though the inhaler and container may have been unsealed and exposed to humidity in the environment for several weeks or months.
• Fig. 1 is a graph showing the particle size distribution of micronized albuterol sulfate before and after conditioning to remove the amorphous phase, as is known in the art, without changing the particle size distribution.
• Fig. 2 is a graph of data for micronized albuterol sulfate formulations in lactose, showing respirable dose per actuation, over time, for albuterol sulfate, conditioned as is known in the art, and also for unconditioned micronized albuterol sulfate.
• Fig. 3 is a graph for an albuterol sulfate in lactose formulation, where the formulation was processed according to the invention, to reduce the level of hydrophylic fine albuterol sulfate particles in the formulation, and without similarly processing the lactose, versus an equivalent control formulation, in which neither the albuterol sulfate or the lactose was so processed.
• Fig. 4 is a graph showing processing of lactose to remove fine particles, by controlled sieving.
• Fig. 5 is a graph showing reduction of fine particles of lactose, by exposure to a high humidity ripening process.
• Fig. 6 is a graph showing reduction of fine particles of albuterol sulfate by controlled milling.
• Fig. 7 is a graph of physical stability, similar to Fig. 3 but for a micronized beclamethasone dipropianate in lactose formulation, where the lactose fine particles were removed by sieving, and the active drug-lactose formulation was exposed to a high humidity ripening environment.
• Small particles in a powder are inherently likely to remain highly energetic, even after the amorphous to crystalline phase transition is complete, due to their high surface to volume ratio. These particles are likely to interact with each other, and with other larger particles, which they are in contact with, in an effort to reduce their surface energy, and therefore shift the powder to a more stable state. Such a phenomenon is commonly observed during crystallization from solutions, and is known as Ostwald ripening, or the Kelvin effect. In general, large particles grow in size, at the expense of smaller particles, which fuse or are absorbed into the larger particles.
• respirable fine particle dose or fraction means particles having an aerodynamic diameter of less than about 6 microns.
• hydrophilic substances whether an excipient or carrier, or an active pharmaceutical
• the most energetic hydrophilic fines are preferably removed.
• active pharmaceutical powders used in an inhaled formulation, particles of less than 3 microns in diameter, and preferably less than 1 micron in diameter, are removed, to increase stability.
• the intent has been to maximize the amount of fine particles, to achieve high efficiency, i.e., good dispersal of the powder, with the available inspiratory force of the patient. Consequently, in the past, the presence of fines (active pharmaceutical particles of less than about 1 micron in diameter) in the formulation, was considered advantageous, as it improved efficiency. Removing fines, as in the step described above, reduces efficiency, and is contrary to the principles of most prior dry powder inhaler formulations.
• hydrophilic excipient particles which have previously undergone particle size reduction (by, for example, milling, spray drying, grinding, controlled crystallization, etc.) will also undergo ripening, where the smaller particles tend to fuse to each other, and to larger particles, thus reducing the particle count and shifting size distribution toward larger particles. Consequently, it is advantageous to remove the hydrophilic excipient fines as well.
• the function of the excipient is to act as a carrier and/or bulking agent. Particles below about 10 microns do not significantly contribute to this purpose. Consequently, sub- 10 micron particles are preferably removed. Removing them improves the physical stability of the excipient, without degrading the functions performed by the excipient. Even powders which have not been size reduced may have a significant amount of fines present, due to particle attrition during packaging and handling.
• Fig. 3 graphs the improved stability of albuterol sulfate, via the methods of the invention.
• the target preferred minimum particle size cutoff for the excipient particles may vary with the formulation and application, but typically will be less than 50 microns, and preferably will be less than 20 microns, and more preferably less than 10 microns.
• the minimum particle diameter cutoff size for an active pharmaceutical may vary depending on the properties of the pharmaceutical and the specific application. Typically, for an active pharmaceutical, the minimum desirable particle size cutoff is 4, 3, 2, and more preferably one micron in diameter. For many inhaled pharmaceuticals, intended for delivery into the deep lung, the preferred particle size is from 1-10 microns in diameter, or 1-5 microns in diameter.
• the fine hydrophilic particles, excipient or active pharmaceutical can be removed using various known techniques, including controlled milling, sieving, air classification, controlled crystallization or controlled ripening under high humidity.
• Fig. 4 shows reduction in sub 10 micron lactose particles, by controlled sieving.
• Fig. 6 shows reduction in sub one micron albuterol sulfate particles, by controlled milling.
• Fig. 5 shows reduction in sub 10 micron lactose particles by exposure to high humidity.
• the initial active bulk powder In formulations intended for inhalation, containing pure active pharmaceutical powder, and no excipient, the initial active bulk powder must undergo particle size reduction, so that the particles are in the preferred respirable range of diameters, typically about 1-10 microns. This size reduction by milling, spray drying, grinding, etc., is thought to create the amorphous areas on the particles, as described above, tending to make these particles unstable.
• Active hydrophilic pharmaceuticals are accordingly preferably processed to remove the fine particles (typically, less than 3 micron in diameter). The processed hydrophilic pharmaceutical may then also, optionally, be ripened, by exposing it to high humidity before packaging. This results in a more stable neat dry powder.
• the active hydrophilic pharmaceutical is to be prepared in a formulation including a hydrophilic excipient, such as lactose
• the pharmaceutical and excipient are initially separately processed to remove the active pharmaceutical fine particles (less than 3 microns), and the excipient is also separately processed to remove the excipient fine particles ( typically less than 10 microns in diameter).
• the processed active pharmaceutical and the processed excipient may then be separately ripened, by separately exposing them to high humidity. After this separate ripening, the pharmaceutical and excipient are blended, with the blend then preferably further ripened by exposing it to high humidity.
• the processed pharmaceutical and the processed excipient may be blended (without separate ripening), with the blend then ripened by exposure to high humidity.
• the ripening preferably is performed by placing the powder in an air environment at 15-60°C, and a relative humidity of 50-99%, and more preferably in an environment at
• the formulation is preferably packaged directly, with no further processing or drying steps.
• Hydrophobic, or non-polar active pharmaceutical compositions have been found to be much less subject to the physical instability characteristic of hydrophilic compositions.
• the excipient is preferably processed and ripened, as described above.
• Fig. 7 shows data for the hydrophobic pharmaceutical beclomethasone dipropianate and lactose. As shown, by processing the formulation to remove fines, stability is improved.
• the amount of fines removed may vary, with fewer fines providing better stability.
• At least 80%, or 90%, or more preferably, 99%, of the active fines of less than 1 micron in diameter, and of the excipient fines of less than 10 microns in diameter, are removed, before packaging.

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• Health & Medical Sciences (AREA)
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• Bioinformatics & Cheminformatics (AREA)
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• 2001
  • 2001-03-27 EP EP01922711A patent/EP1274400A1/de not_active Withdrawn
  • 2001-03-27 CA CA002404645A patent/CA2404645A1/en not_active Abandoned
  • 2001-03-27 JP JP2001574078A patent/JP2004515260A/ja active Pending
  • 2001-03-27 AU AU2001249479A patent/AU2001249479A1/en not_active Abandoned
  • 2001-03-27 WO PCT/US2001/009711 patent/WO2001076560A1/en not_active Application Discontinuation

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