Classifications

• • B—PERFORMING OPERATIONS; TRANSPORTING
  • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
  • B01J—CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
  • B01J2/00—Processes or devices for granulating materials, e.g. fertilisers in general; Rendering particulate materials free flowing in general, e.g. making them hydrophobic
  • B01J2/02—Processes or devices for granulating materials, e.g. fertilisers in general; Rendering particulate materials free flowing in general, e.g. making them hydrophobic by dividing the liquid material into drops, e.g. by spraying, and solidifying the drops
  • B01J2/04—Processes or devices for granulating materials, e.g. fertilisers in general; Rendering particulate materials free flowing in general, e.g. making them hydrophobic by dividing the liquid material into drops, e.g. by spraying, and solidifying the drops in a gaseous medium

Definitions

• This invention relates to a particle engineering technique based on continuous spray freezing and drying.
• porous micro and nano particles can be designed in order to be applied for various purposes.
• the word "comprising” in the claims is used in its inclusive sense and does not exclude other elements being present.
• the use of the indefinite article "a” in a claim before an element does not exclude more than one of the element being present.
• the efficacy of particles can be significantly influenced by their physical properties such as particle size distribution and morphology. Dissolution rate of Insoluble materials could be increased via formation of micro and nanoparticulates.
• particle engineering is essential for development of inhalation aerosols, injectable suspensions, controlled release dosage forms, and other specialized modes of drug delivery.
• Production of "Engineered Particles" is often difficult by currently available micronisation techniques. High energy milling techniques such as air jet milling are far from ideal since products of these methods are often cohesive, high electrostatic charged, and difficult to process downstream.
• Other alternative methods for preparation of engineered particles are spray drying, supercritical processing, solvent evaporation, and emulsion coacervation techniques.
• Spray-freeze drying is a relatively new method for particle engineering in which, a solution containing dissolved material is sprayed into a cold phase to form frozen and solid particles. After that this particles will be dried using lyophilization technique.
• the powders produced by SFD differ from those obtained by other methods. SFD powders show a larger median particle size, as the droplet shrinkage during drying is low. The size of the droplets could be controlled by choosing an appropriate spraying condition. A high specific surface area may indicate a highly porous inner structure, which leads to low density of the particles.
• U.S. Pat. No. 2003/0202978 Al [ I ] describes a process for producing pharmaceutical compositions by SFD technique which are suitable for transdermal particle delivery from a needleless syringe system. In the U.S.
• Pat. No. 2005/0160615 Al [2] a method of manufacturing heat-sensitive pharmaceutical powders is described. The method includes atomization of a drug containing solution or suspension into a cold gas phase or liquid nitrogen.
• WO 2006/051067 Al [3] describes a process for preparing formulations of lipophilic active substances by SFD. The lipophilic ingredient had been incorporated in sugar based formulations.
• WO 2008/048115 A2 [4] relates to an apparatus included a chamber which was kept at a pressure below the triple-point pressure of the aqueous portion of the raw material.
• U. S. Pat. No. 6862890 B2 [5] describes a system and method for the production of microparticles and nanoparticles of materials that can be dissolved.
• the apparatus contains a mixer immersed in the cryogenic liquid.
• This invention relates to spray freeze drying techniques and, more particularly, to novel, improved methods and apparatus for carrying out spray freeze drying in continuous form.
• This invention relates to an economical SFD method of improved cooling, atomization and collection compartments.
• the materials to be dried is frozen by a supercooled air flow, separated from air flow by a cyclone separator and introduced into a lyophilizer to be dried.
• the disclosed spray freeze drying apparatus comprise a process for production of micro and nanoparticles by atomization of solutions into a supercooled air flow and collection of produced particles by a cyclone separator and finally freeze drying the frozen particles under vacuum conditions. It is a feature of this preferred process that solution or suspension of interest is atomized by nebulizer or modified nozzles into a current of supercooled air flow.
• a number of paralleled pipes (Cupper or Aluminum or any other kinds of conductive materials) are immersed in liquid nitrogen to construct a supercooled pathway [1] for establishment of a supercooled air flow.
• An efficient vacuum pump [2] located at the end of circuit sucks air and consequently the air enters through the inlet and passes through the supercooled pipes and after that enters the cyclone separator [3] to produce cyclonic current.
• the cyclone separator is immersed in liquid nitrogen [4] to keep the strenght of supercooled circuit.
• the solution or suspension containing particle forming material or any other ingredient is atomized or nebulized [5] into the supercooled air flow before entrance into the cyclone [6] and from the freezing compartment the frozen particles are conducted to the cyclone separator and the frozen particles are separated from the air in the cyclone. Then the frozen product is removed from the separation compartment and transferred to a lyophilizer to be dried.
• FIG. 1 is a schematic illustration of the spray freeze drying system constructed in accord with the principles of the present invention.
• FIG. 2 is an electron micrograph of mannitol particles produced by the preferred process of this invention. DETAILED DESCRIPTION OF PREFERRED EMBODIMENTS OF THE
• Spray freeze drying is a process conceptually similar to spray drying, in that a solution or suspension is introduced via a nozzle, spinning disk or an equivalent device into a cold fluid to atomize the solution to form fine droplets. Spraying the formulation into the supercooled air flow causes the atomized droplets to form frozen particles. The particles are collected, and then the solvent is removed, generally through sublimation (lyophilization) in a vacuum. This produces a fine dry powder having particles of a specified size and characteristics.
• the powder forming ingredient could be one or more pharmaceutical, nutraceutical, food or other substances that are functional in powder form.
• the present invention also could be constructive for heat-sensitive materials, such as proteins, peptides, nucleic acids, lipids and lipid complexes, vaccines, carbohydrates and polymers. The method always produces a powder from any dissolved or suitably suspended in water or any other solvents. Also, lyoprotectants and cryoprotectants may be added to aid in preventing degradation of substances during the process.
• Suitable excipients include, but are not limited to, proteins such as gelatin, immunoglobulins, human and bovine serum albumin, carbohydrates including monosaccharides, disaccharides and polysaccharides, cyclodextrins, amino acids such as monosodium glutamate, glycine, alanine, arginine or histidine.
• proteins such as gelatin, immunoglobulins, human and bovine serum albumin
• preferred ingredients are mannitol, trehalose, sorbitol, sucrose, and lactose.
• the excipients could be used in amounts ranging from about 1 to 95 wt %, with from about 1 to 50 wt % preferred, from about 10 to 40 wt % being especially preferred, and from about 10 to 20% being particularly preferred.
• the compositions do not contain substantial amounts of excipients, i.e. they are substantially free of excipients.
• the composition contains less than about 10%, with less than about 5%, and preferably less than about 2-3% by weight any components other than the main component.
• the pre-spray freeze dry formulation is atomized into a supercooled air flow. Generally, temperatures ranging from about -80° to -30° C are used. The air flow may be replaced with nitrogen or any other inert gas.
• the atomization conditions are generally controlled to produce liquid droplets having an average diameter of from about 5 to about 30 ⁇ , with droplets of average size 10 ⁇ being preferred. Air jet and ultrasonic nozzles and nebulizers are applicable in this field. In one embodiment of the invention, two parallel nozzles or four fluid nozzles could be applied to enter two separate solutions into the supercooled air flow. Once the frozen droplets are produced, they should be collected and dried. Application of the cyclone separator lets to collect the product in a continuous way. After that, elimination of the water or any other solvents could be done in a variety of ways, as is known in the art for lyophilization.
• the particles are lyophilized for a period of time sufficient to remove the majority of the water or any other solvents in the particles.
• the actual period of time will depend on the temperature, the strength of the vacuum, the size of the sample, etc.
• the particles are lyophilized to dryness of about 1 to 10% remaining water, and from about 1 to about 5% being preferred.
• the dried powder may be further formulated in other ways, for example, in the preparation of sustained release compositions or may be used in formulations prepared for administration via ophthalmic, subcutaneous or any other routes of administration.
• the powder compositions of the invention may be reconstituted for injection.
• the powders of the invention show good stability, and thus in some embodiments they can be reconstituted into liquid form using diluents such as physiological saline, buffers, salts, etc.
• diluents such as physiological saline, buffers, salts, etc.
• spray freeze dried particles produced by this method can have morphology desirable for respiratory administration of medicaments using respiratory delivery devices.
• Dried particles were characterized based on morphology and particle size distribution.
• example 1 The process of example 1 is repeated in the presence of salmeterole xinafoate or Budesonide as active ingredient in the proportion of 0.1%.
• Example 5 The process of example 3 is repeated except that raloxifene hydrochloride was applied as active ingredient.
• Example 5
• example 5 The process of example 5 is repeated using two separate solutions. A solution of Budesonide and a solution of PLGA were nebulized individually at same time into the supercooled flow.

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• Chemical & Material Sciences (AREA)
• Organic Chemistry (AREA)
• Chemical Kinetics & Catalysis (AREA)
• Medicinal Preparation (AREA)

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Citations (7)

• 2012
  • 2012-03-21 WO PCT/EP2012/054964 patent/WO2013139384A1/fr not_active Ceased

Patent Citations (7)

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