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
• • 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
  • A61K38/18—Growth factors; Growth regulators
• • 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
  • A61K38/22—Hormones
  • A61K38/28—Insulins
• • 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
  • A61K9/1682—Processes
  • A61K9/1694—Processes resulting in granules or microspheres of the matrix type containing more than 5% of excipient

Definitions

• the invention relates to a process for the controlled crystallization of powder, in particular spray-dried powder. Furthermore, the invention relates to a method for improving, maintaining or reducing the flowability (FPF) of a powder, in particular while maintaining the stability of the substance, a method for improving the aerodynamic properties of a powder and a method for better fillability of a powder, in particular a spray-dried powder ,
• FPF flowability
• the roughness of the particle surface can be increased.
• the increase in roughness can be increased, for example, by coating the particles with nanoscale particles.
• Conventional methods for applying nanoparticles to powders are, for example, mechanical methods such as, for example, coating in a jet mill or in a hybridizer (Nara company).
• free-fall mixers are also used (M. Eber, 2004, Dissertation Uni Er Weg, title: Efficacy and Performance of Nanoscale Flow control agents). When mixing spray-dried material with carrier systems, sieves or free-fall mixers are usually used.
• the powder properties can also be optimized by hydropobization of the particle surface.
• hydrophobic substances can be added directly to the spray solution. Both by the atomization of the spray solution in the smallest droplets and the evaporation of the droplet in the drying tower of the spray dryer due to a lower solubility of the excipient compared to the active ingredient and other excipients, the hydrophobic substances accumulate on the surface. It is also possible to coat the spray-dried particles in a separate process step with a hydrophobic film.
• amorphous powders are hygroscopic and tend to form powder agglomerates. Both effects are intrinsically undesirable and increase the requirements for storage of the powders and application in, for example, pulmonary application.
• the state of the art for solving this problem is the follow-up of further process steps.
• the literature describes the coating of spray-dried particles with so-called film formers or else the mixing of spray-dried particles with other auxiliaries, for example with nanoscale particles but also with significantly coarser particles in the size of about 50-100 ⁇ m.
• the present invention relates to a process for increasing, maintaining or reducing the flowability (FPF) of a powder, a process for improving the aerodynamic properties of a powder and a process for reducing the electrostatics of a powder containing an active ingredient, in particular a protein, and at least one Excipient characterized in that
• the present invention preferably relates to processes according to the invention in which the exposure period is chosen so that the adjuvant crystallizes before the active ingredient.
• the present powder is a spray-dried powder.
• Annealing creates a thermodynamically stable particle surface, thereby reducing the level of unwanted temperature and humidity induced changes in the powder during storage In the case of the powder it is uncritical, as it results from the composition of the spray drop, and no segregation is possible with purely spray-dried powders or unknown.
• annealing in addition to the storage stability and the flow and dispersancy of the powder can be optimized. Due to the thermodynamic stabilization of the particle surface, storage can take place even at higher humidities. This improves product safety in particular for the patient. By creating a nano-scale surface roughness improves the flowability and aerodynamics. This, in turn, translates into better fillability / processability and inhalability.
• Areas of application of the present invention can be found e.g. in the development of powdered dosage forms of medicaments e.g. for inhalation.
• Annealing creates a thermodynamically stable particle surface. This reduces the level of unwanted temperature and humidity induced changes in the powders during storage.
• the homogeneity of the active substance in the powder is uncritical insofar as it results from the composition of the spray drop. Discharge processes are not possible or unknown in purely spray-dried powders
• Crystallization inhibitors such as HSA can improve the particle properties of powders. Crystallization inhibitors assist in the formation of an amorphous matrix in the interior of the particle core where the readily water-soluble components, e.g. Sugar as well as the protein are located.
• the invention does not result from the prior art.
• WO03 / 037303 is not relevant because this method is a
• WO0030614 describes a process in which amorphous fractions are crystallized.
• the powder is subjected to a supercritical or subcritical gas.
• the gas additionally contains water or an organic solvent.
• the supercritical or Subcritical gas penetrates into the particle and causes a crystallization of amorphous parts due to the solvent vapor.
• WO0030614 is not relevant since the publication only describes supercritical processes. However, the present application in its preferred embodiment excludes supercritical processes.
• the annealing of spray dried particles also inherently involves controlled crystallization of surfaces while maintaining the amorphous contents within the particle (zoning). By an amorphous environment, the protein can be stabilized. This essential procedural step is not part of the patent application WO0030614.
• WO9505805 describes a process for complete crystallization of the substances used, i. WO9505805 also describes no zoning.
• WO9505805 only carriers and micronized chemical substances are mentioned, but no proteins and the active ingredient and other substances are mechanically mixed, i. the active substance is applied to a carrier, whereas in the present invention the protein is embedded in a hydrophilic matrix and thereby stabilized.
• DE102004048390 describes amorphous, spray-dried lactose mixed with the carrier alpha-lactose monohydrate. Subsequently, the mixture is conditioned with moisture to crystallize the spray dried portion.
• the patents US556293, US5709884, US5874063 also describe Processes in which powders are conditioned with solvent vapor.
• the vapor may consist of both water and an organic solvent such as ethanol.
• the patent US5562923 describes a method in which mechanically micronized particles are mixed with solvent vapor consisting of a low-chain alcohol or ketone or ethyl acetate.
• the patent US556293 is not relevant because proteins are not part of the US patent.
• mechanically micronized powder is conditioned. Spray dried powders are also not part of US5562923.
• the patent US570984 is not relevant because proteins are not part of the US patent.
• only powder mixtures consisting of different substances or particles prepared separately are conditioned and not spray-dried powder.
• the patent US5874063 is not relevant because proteins are not part of the US patent.
• the goal of this process is the nearly complete reduction of amorphous content to crystalline particles.
• the particle When annealing spray-dried powder, the particle is essentially amorphous. That is, the crystallinity is less than 50%. After annealing, amorphous portions are still required for protein stabilization. This fact clearly distinguishes the present application / invention from the US patent US5874063.
• Harjunen et al. (Drug Development and Industrial Pharmacy, Vol 28, No. 8, 2002, Page 949-955) showed that by varying the mixing ratio of water and ethanol in a lactose-containing spray solution it is possible to produce particles with amorphous contents between 0% and 100%. However, these methods are not comparable to a controlled crystallization of surfaces. For example, as described by Harjunen et al. described the lactose at 15% by weight in ethanol as a crystalline suspension. Spray drying is used here for solid / liquid separation and not for the generation of new particles.
• DVS Dynamic Vapor Sorption
• FIGURE 2 With the present measurement, a decrease of the mass can be detected both at 50% RH and at 60% RH. This decrease results from the collapse of the surface due to crystallization of the powder. Due to the collapse, there is a sudden supersaturation of condensed water vapor on the surface. From this follows an evaporation of this water and, accordingly, a mass reduction.
• FIGURE 2
• FIGURE 3 Atomic force measurements Images (AFM) of a spray-dried powder containing 80% phenylalanine, 10% LS90P and 10% IgGI when stored below 50% RH
• Sample preparation The powder was applied to the AFM sample disc using a spatula.
• An adhesive (STKY dot) made the adhesive bond between the sample holder and the lowest powder layer.
• the overlying powder layers adhered by the particle adhesion. Loose particles were blown off with the help of a dry stream of nitrogen.
• TappingMode Scan rate 1-2 Hz
• Tip frequency 250-300 kHz
• Atomic force measurements Images of a spray-dried powder containing 80% phenylalanine, 10% LS90P and 10% IgGI when stored below 60% RH
• the fine particle fraction was determined using an Impactor Inlet (TSI) in combination with the Aerodynamic Particle Sizer (APS, TSI).
• TSI Impactor Inlet
• APS Aerodynamic Particle Sizer
• the separation limit of the impactor nozzle was 5.0 ⁇ m.
• the APS was used to determine the aerodynamic particle size and the particle size distribution using a time-of-flight determination.
• the powder was split after passing through the Sample Induction Port. A proportion of 0.2% was sucked under isokinetic conditions into a small capillary and fed to the time of flight measurement unit. The remaining portion was used for the determination of the fine particle fraction.
• the powder was filled into capsules of size 3 and applied with an inhaler (HandiHaler®, Boehringer Ingelheim).
• the flow rate for applying the powder was adjusted so that a pressure drop of 4 kPa prevailed over the HandiHaler.
• the air volume was 4 liters according to the PharmEur.
• the measurements were made by coating the impactor plate with a high-viscosity Brij solution.
• the applied mass results from the differential weighing of the capsule before and after application by the inhaler (HandiHaler®, Boehringer Ingelheim).
• Powder 1 spray dried powder consisting of 60% phenylalanine, 30% LS90P and 10% IgGI
• Powder 2 spray dried powder consisting of 60% phenylalanine, 30% LS90P and 10% lysozyme
• Powder 3 spray dried powder consisting of 60% phenylalanine, 30% LS90P and 10% calcitonin
• Heating the powder determined When heating an amorphous powder, the constituents of the particle after passing through the
• Powder may cause melting or decomposition of the powder.
• the crucible is closed by cold welding.
• the measurements were carried out with a non-perforated crucible.
• Furnace gas Nitrogen / 40ml_ / min
• Flush gas Nitrogen / 150ml_ / min
• Powder 1 Spray Dried Powder: 60% Phenylalanine / 40% LS90P Powder 2: Spray Dried Powder: 60% Phenylalanine / 30% LS90P / 10% IgGI Powder 3: Spray Dried Powder: 60% Phenylalanine / 30% LS90P / 9% IgGI / 1% HSA powder 4: freeze-dried powder: 100% LS90P
• Powder refers to a very fine, comminuted substance.
• Spray-dried powders means a powder made by spray-drying.
• Particles refers to a particle of a substance In the present invention, by particles are meant the particles in the powders according to the invention The terms particles and powder are used interchangeably in the present invention.With a powder are also its constituents, the particles, Particles also indicate the total amount of particles the powder.
• mixtures means mixtures which are generated from a true solution of all components or have been suspended from a solution in which one or more of the components has been suspended
• meaning of this invention also means those mixtures which have arisen by a physical mixing process of solid particles of these components or which have arisen by applying a solution or suspension of these components to one or more solid components.
• composition means liquid, semi-solid or solid mixtures of at least two starting materials.
• composition means a composition for application in the patient.
• pharmaceutically acceptable excipients refers to excipients which may optionally be included in the formulation within the scope of the invention
• the excipients may be administered pulmonally, for example, without having significant adverse toxicological effects on the subject or the volunteer lung.
• salts of inorganic acids such as
• Chloride sulfate, phosphate, diphosphate, bromide and nitrate salts.
• salts of organic acids such as malate, maleate, fumarate, tartrate, succinate,
• active substances substances that cause an effect or a reaction in an organism.
• an active ingredient is used for therapeutic purposes in humans or on the animal body, it is referred to as a drug or medicament.
• a "protein active substance” or “protein active ingredient” is understood as meaning an active ingredient which is structurally present as a protein or structurally represents a protein, polypeptide or peptide.
• active ingredients are insulin, insulin-like growth factor, human growth hormone (hGH) and other growth factors,
• Tissue plasminogen activator tPA
• EPO erythropoietin
• cytokines for example, interleukins (IL) such as IL-1, IL-2, IL-3, IL-4, IL-5, IL-6, IL-7, IL-8, IL-9, IL-10, IL-11, IL-12, IL-13, IL-14, IL-15, IL-16, IL-17, IL-18, interferon (IFN) -alpha, beta, gamma , omega or tau, tumor necrosis factor (TNF) such as TNF-alpha, beta or gamma, TRAIL, G-CSF, GM-CSF, M-CSF, MCP-1 and VEGF.
• IFN interferon
• TNF tumor necrosis factor
• antibodies monoclonal, polyclonal, multispecific and single chain antibodies and fragments thereof, e.g. Fab, Fab ', F (ab') 2, Fc and Fc 'fragments, light (L) and heavy (H) immunoglobulin chains and their constant, variable or hypervariable regions and Fv and Fd fragments (Chamov et al., 1999).
• the antibodies may be of human or non-human origin. Humanized and chimeric antibodies are also considered. Likewise, this relates to conjugated proteins and antibodies which are associated, for example, with a radioactive substance or a chemically-defined drug.
• fragment antigen-binding Fab
• fragment antigen-binding Fab
• fragment antigen-binding Fab
• They can be produced, for example, by treatment with a protease, for example papain, from conventional antibodies or else by DNA cloning.
• Other antibody fragments are F (ab ') 2 fragments produced by proteolytic digestion with pepsin can be.
• the variable region of the heavy and light chain are often linked together by means of a short peptide fragment of about 10 to 30 amino acids, particularly preferably 15 amino acids. In this way, a single polypeptide chain is formed in which VH and VL are linked by a peptide linker.
• Such antibody fragments are also referred to as a single-chain Fv fragment (scFv). Examples of scFv antibodies are known and described, see e.g. Huston et al. (1988).
• diabody a person skilled in the art refers to a bivalent homodimeric scFv
• the diabodies can additionally be introduced by introducing disulfide bridges be stabilized. Examples of diabodies can be found in the literature, eg in Perisic et al. (1994).
• minibody refers to a divalent, homodimeric scFv derivative which consists of a fusion protein which contains the CH3 region of an immunoglobulin, preferably IgG, particularly preferably IgGI, as a dimerization region which links the scFv fragments via a hinge Region, also of IgG, and a linker region
• IgG immunoglobulin
• IgGI immunoglobulin receptor 1
• trimers The person skilled in the art refers to a trivalent homotrimeric scFv derivative by "tri-body” (Kortt et al., 1997) .
• trimers The direct fusion of VH-VL without the use of a linker sequence leads to the formation of trimers.
• fragments designated by the skilled person as mini-antibodies which have a bi-, tri- or tetravalent structure, are likewise derivatives of scFv fragments. Multimerization is achieved via di-, tri- or tetrameric coiled-coil structures (Pack et al., 1993 and 1995, Lovejoy et al., 1993).
• adjuvants substances which are added to a formulation, in the present invention, a powder, in particular a spray-dried powder.
• adjuvants usually have no effect themselves, in particular no pharmaceutical effect, and serve to formulate the actual ingredient , eg of an active ingredient, or to optimize it with respect to a particular aspect (eg storage stability).
• a pharmaceutical "excipient” means a part of a drug or a pharmaceutical composition, and among other things, ensures that the drug is delivered to the site of action and released there.Advantages have three basic tasks: carrier function, control of drug release and stability enhancement also the production of drug forms, which thereby change in duration or speed of action.
• amino acid means compounds which contain at least one amino and at least one carboxyl group Although the amino group is usually in the ⁇ -position relative to the carboxyl group, any other arrangement in the molecule is conceivable.
• the amino acid may also contain other functional groups, such as amino Amino acids of natural or synthetic origin, racemic or optically active (D- or L-) including various stereoisomeric ratios are used, for example, the term isoleucine includes both D Isoleucine, L-isoleucine, racemic isoleucine and various ratios of the two enantiomers.
• peptide polypeptide or protein
• polymers of amino acids consisting of more than two amino acid residues Further, by the term “peptide”, “polypeptide” or “protein” are polymers of amino acids consisting of more than 10 Meant amino acid residues.
• the term peptide, polypeptide or protein is used as a pseudonym and includes both homo- and heteropeptides, ie polymers of amino acids consisting of identical or different amino acid residues.
• a "di-peptide” is thus composed of two peptide-linked amino acids, a "tri-peptide” of three peptide-linked amino acids.
• protein refers to polymers of amino acids having more than 20 and more preferably more than 100 amino acid residues.
• small protein refers to proteins below 5OkD and below 3OkD and between 5-5OkD respectively.
• small protein further refers to polymers of amino acid residues of less than 500 amino acid residues or of fewer than 300 amino acid residues or of polymers of 50, respectively -500 amino acid residues.
• Preferred small proteins are, for example, growth factors such as human growth hormone / factor, insulin, calcitonin or the like.
• protein stability means monomer content above 90%, preferably above 95%.
• oligosaccharide or “polysaccharide” means multiple sugars which are composed of at least three monomeric sugar molecules.
• % (w / w) means the percentage, by weight, of an active ingredient or an excipient in the spray-dried powder, whereby the stated proportion is based on the dry substance of the powder ,
• amorphous means that the powdered formulation contains less than 10% crystalline fractions, preferably less than 7%, more preferably less than 5%, especially less than 4, 3, 2, or 1%.
• inhalable means that the powders are suitable for pulmonary administration.
• MMD mass median diameter
• Mass median diameter or “MMD” is a measure of the average
• the results are expressed as the diameter of the volume sum distribution at 50% throughput.
• the MMD values can be determined by way of example by means of laser diffractometry, whereby, of course any other common method can be used (eg electron microscopy, centrifugal sedimentation).
• MMAD median aerodynamic diameter
• fine particle fraction describes the inhalable part of a powder consisting of particles with a particle size of ⁇ 5 ⁇ m MMAD
• the FPF is more than 20%, preferably more than
• (FPF 5 ) means that at least 30% of all particles in the powder have an average aerodynamic particle diameter of less than 5 ⁇ m.
• relative FPF describes the FPF relative to a starting or starting value, for example, the relative FPF after storage refers to the FPF before storage.
• time of flight is the term used for a standard measurement method as described in more detail in the EXAMPLES chapter: In a time of flight measurement, the MMAD is determined by determining the time of flight of a particle for a defined measurement
• the MMAD correlates with the flight time. It means that Particles with a large MMAD require a longer time to fly than correspondingly smaller particles (see also: EXAMPLES, Method).
• applied mass indicates the amount of powder applied using an inhaler, in which case the application is determined by means of a capsule, for example, by weighing the capsule before and after application before and after application.
• Annealing involves the controlled exposure of an amorphous powder to moisture, or to a water-containing or solvent-containing gas with a defined relative humidity at a defined temperature over a defined exposure period as well
• the controlled crystallization of the particles by moisture The tempering is intended to modify the surface structure so that crystallization occurs mainly on the surface, and the core of the particle remains amorphous This is usually one or more excipients, and the positive effect of tempering is the improvement in physicochemical properties g crystallization on the particle surface, the substance or the active ingredient or in particular the protein is further stabilized by an amorphous environment in the core of the particle. Crystallization of the entire particle, however, is to be avoided.
• the tempering takes place preferably at relative humidities greater than 30%. Ideally, however, at 50-60% relative humidity.
• the exposure time depends on the crystallization rate of the excipient.
• crystal means a substance whose smallest constituents, such as ions, molecules and atoms are composed of crystal structures, and substances and compound compounds are "crystalline” if "crystallinity" or “crystallization” is detected by suitable methods.
• suitable analytical methods are X-ray diffraction, solution calorimetry and methods for determining hygroscopicity (for example with a DVS, Porotec).
• X-ray diffraction an X-ray beam is diffracted at a crystal lattice. From the arrangement of the diffraction spectrum, the crystal structure can be determined. A quantitative statement of the crystallinity or crystallization results from the intensities of the reflection peaks.
• Quantification of crystallinity is also possible with solution calorimetry and hygroscopicity determination.
• solution calorimetry the different heat tones of amorphous and crystalline modification forms of a solid are used for the quantification.
• determining the hygroscopicity one exploits the property that the amorphous modification is less hygroscopic than the crystalline modification.
• analytical methods a calibration line with samples of known crystallinity must be recorded before quantification of the crystallinity.
• relative humidity means the capacity of air or nitrogen or the like for a vapor
• the vapor may consist of water or another organic solvent
• the relative humidity refers to the ratio of the actual obtained to the maximum possible mass Steam in air or nitrogen or similar.
• vapor means the gaseous state of matter of a substance into which it comes by boiling or by sublimation consist of both water and an organic solvent.
• organic solvents pharmaceutically acceptable substances are preferred, such as ethanol or isopropanol.
• the following organic solvents can be used, such as glucofurol, ethyl lactate, N-methyl-2-pyrollidone, dimethyl sulfoxide, ethylene glycol or lower-chain saturated hydrocarbons, for example pentane, hexane, heptane.
• the application is not limited to these examples.
• room temperature means a temperature of about 20-25 0 C (+ I- 10%).
• ambient temperature refers to a temperature of 25 ° C.
• the term "monomer content” and “monomer” refers to the percentage of proteins consisting of a single subunit of the protein. Limitations of the monomer content are fragments consisting of fragments of the monomer and di- or oligomers consisting of several subunits. The monomer content mentioned in the patent is determined by exclusion chromatography.
• aggregates means the proportion of di- and oligomers of proteins that consist of a single subunit in the native state.
• the present invention relates to the modification of surfaces of powders, in particular spray-dried powders, by controlled exposure to Powder with humidity / temperature. This creates crystals on the surface. Inside, the powder particles remain largely amorphous. This process is referred to hereafter as annealing.
• the essence of the invention aims at optimizing flowability and improving the aerodynamic and electrostatic properties of the powders.
• the present invention relates to a process for increasing, maintaining or reducing the flowability (FPF) of a powder comprising an active substance, in particular a protein, and at least one excipient, characterized in that
• the present invention particularly preferably relates to a method according to the invention in which the amorphous powder contains both the active ingredient and the excipient. That is, said amorphous powder is a mixture of active ingredient and excipient. Both components are controlled in a controlled manner in this mixture to give moisture, i. annealed.
• the present invention relates to a process for increasing, maintaining or reducing the flowability (FPF) of a powder, characterized in that an amorphous powder containing an active ingredient, preferably a protein active ingredient, and at least one excipient
• the present invention relates to a process for increasing, maintaining or reducing the flowability (FPF) of a powder, characterized in that an amorphous powder containing a protein and at least one adjuvant (i) over a defined exposure period
• the present invention preferably relates to a method according to the invention in which the exposure period is chosen so that the excipient crystallizes before the active ingredient.
• the present invention preferably relates to a process according to the invention wherein the adjuvant predominantly crystallizes on the surface of the powder particle, i. at least 10% or at least 50% or 50-100%, preferably more than 85% or more than 90%, and the active ingredient is predominantly in the interior of the powder particle in an amorphous state.
• the present invention further preferably relates to a method according to the invention, wherein the crystallinity of the powder particles is less than / below 50%.
• the use of crystallization inhibitors such as HSA is preferred.
• the powder contains at least 0.1% (w / w) HSA, at least 0.5% (w / w) HSA, at least 1% (w / w) HSA, at least 5% (w / w) HSA, at least 10% (w / w). w) HSA, at least 15% (w / w) HSA.
• the powder contains between 0.1% (w / w) - 60% (w / w) HSA, 0.5% (w / w) - 60% (w / w) HSA, 1% (w / w) - 60% (w / w) HSA, 10% (w / w) - 60% (w / w) HSA, 0.1% (w / w) - 40% (w / w) HSA, 0.5% (w / w) - 40 % (w / w) HSA, 1% (w / w) - 40% (w / w) HSA, 10% (w / w) - 40% (w / w) HSA, 0.1% (w / w) - 20% (w / w) HSA, 0.5% (w / w) - 20% (w / w) HSA, 1% (w / w) - 20% (w / w) HSA, 10% (w / w)
• the present invention furthermore preferably relates to a process according to the invention in which the relative humidity of the water-containing or solvent-containing gas is greater than 30% (w / w), preferably between 30-90%, 50-80% and particularly preferably between 50-60% ( w / w).
• the present invention further preferably relates to an inventive
• a preferred adjuvant herein is phenylalanine.
• a particularly preferred embodiment is therefore a process according to the invention in which at least 10% (w / w) phenylalanine is used as an auxiliary. Furthermore, phenylalanine contents of at least 30% (w / w) and at least 40%
• the method according to the invention is carried out while maintaining the stability of the substance.
• the stability of the substance is maintained or improved, in particular the storage stability and in particular under increased humidity conditions.
• the stability of the substance is maintained or improved, in particular the storage stability and especially at elevated relative humidity.
• the storage takes place for example over 3 months or 6 months.
• the temperature is less than 60 ° C.
• the present powder is a spray-dried powder.
• the invention relates to powders comprising a protein or a protein active ingredient and phenylalanine as adjuvant and optionally a sugar, the powder being characterized in that it contains at least 10% (w / w), at least 30%, at least 40%.
• (w / w) contains phenylalanine, preferably 10% (w / w), and more preferably 30% (w / w).
• further substances in particular further auxiliaries, may also be contained in the powder.
• this specific embodiment of the present invention also relates to a pharmaceutical composition which contains a powder consisting of a protein or a protein active ingredient and phenylalanine as adjuvant and optionally a sugar, the powder being at least 10% (w / w), at least 30%, at least 40% (w / w) of phenylalanine, preferably 10% (w / w) and most preferably 30% (w / w).
• a preferred embodiment of the process according to the invention is a process for increasing the FPF, the FPF in particular being increased by at least 6%, preferably by 7%, 8%, 9%, 10%, 11%, 12%,
• the invention further relates to a method for improving the aerodynamic properties of a powder containing an active ingredient, in particular a protein, and at least one excipient, characterized in that - an amorphous powder
• the present invention preferably relates to a method according to the invention for improving the aerodynamic properties of a powder in which the exposure period is selected so that the adjuvant crystallizes before the active ingredient.
• the use of crystallization inhibitors such as HSA is furthermore preferred.
• the powder contains at least 0.1% (w / w) HSA, at least 0.5% (w / w) HSA, at least 1% (w / w) HSA, at least 5% (w / w) HSA, at least 10% (w / w). w) HSA, at least 15% (w / w) HSA.
• the powder contains between 0.1% (w / w) - 60% (w / w) HSA, 0.5% (w / w) - 60% (w / w) HSA, 1% (w / w) - 60% (w / w) HSA, 10% (w / w) - 60% (w / w) HSA, 0.1% (w / w) - 40% (w / w) HSA, 0.5% (w / w) - 40 % (w / w) HSA, 1% (w / w) - 40% (w / w) HSA, 10% (w / w) - 40% (w / w) HSA, 0.1% (w / w) - 20% (w / w) HSA, 0.5% (w / w) - 20% (w / w) HSA, 1% (w / w) - 20% (w / w) HSA, 10% (w / w)
• the present invention furthermore preferably relates to a method according to the invention for improving the aerodynamic properties of a powder in which the relative humidity of the water-containing gas is greater than 30% (w / w), preferably between 30-90%, 50-80% and especially preferably between 50-60% (w / w).
• the temperature is preferably less than 60 0 C.
• the invention further relates to a method for reducing the electrostatics of a powder containing an active ingredient, in particular a protein, and at least one excipient, characterized in that - an amorphous powder
• the present invention preferably relates to a method according to the invention for reducing the electrostatics of a powder in which the exposure period is selected so that the adjuvant crystallizes in front of the active ingredient.
• the present invention furthermore preferably relates to a method according to the invention for reducing the electrostatics of a powder in which the relative humidity of the water-containing or solvent-containing gas is greater than 30% (w / w), preferably between 30-90%, 50-80% and particularly preferably between 50-60% (w / w).
• the temperature is preferably less than 60 ° C.
• the invention relates to powders comprising a crystallization inhibitor such as HSA.
• the powder contains at least 0.1% (w / w) HSA, at least 0.5% (w / w) HSA, at least 1% (w / w) HSA, at least 5% (w / w) HSA, at least 10% (w / w). w) HSA, at least 15% (w / w) HSA.
• the powder contains between 0.1% (w / w) - 60% (w / w) HSA, 0.5% (w / w) - 60% (w / w) HSA, 1% (w / w) - 60% (w / w) HSA, 10% (w / w) - 60% (w / w) HSA, 0.1% (w / w) - 40% (w / w) HSA, 0.5% (w / w) - 40 % (w / w) HSA, 1% (w / w) - 40% (w / w) HSA, 10% (w / w) - 40% (w / w) HSA, 0.1% (w / w) - 20% (w / w) HSA, 0.5% (w / w) - 20% (w / w) HSA, 1% (w / w) - 20% (w / w) HSA, 10% (w / w)
• the invention relates to a method for filling powders, characterized in that the powders have been treated according to the described methods.
• the present method relates to volumetric and mass-dependent filling, e.g. with a jack, a filling roller or a free fall dispenser.
• the improved fillability by means of an additional tempering step is characterized in that the resulting improvement in the flowability and a reduction in the electrostatic charging of the powders reduces the filling times and improves the filling precision.
• the exposure time is at least 1 hour or more, at least 4 hours or more, at least 8 hours or more, at least 12 hours or more, at least 20 hours or more, preferably 20 hours, and most preferably 20 hours and more more preferably in a range between 1 hour to 72 hours and between 4 to 48 hours.
• the temperature during the exposure period of less than 60 0 C, in particular between -10 is 0, C to 60 ° C, preferably between 4 ° C to 40 0 C and particularly preferably between 16 ° C and 35 ° C.
• the active ingredient in the method according to the invention is a protein such as insulin, insulin-like growth factor, human growth hormone (hGH) and other growth factors, tissue plasminogen activator (tPA), erythropoietin (EPO), cytokines, for example interleukins (IL) such as IL-1, IL-2, IL-3, IL-4, IL-5, IL-6, IL-7, IL-8, IL-9, IL-10, IL-11, IL-12, IL -13, IL-14, IL-15, IL-16, IL-17, IL-18, interferon (IFN) -alpha, beta, gamma, omega or tau, Tumor Necrosis Factor (TNF) such as TNF-alpha, beta or gamma, TRAIL, G-CSF, GM-CSF, M-CSF, MCP-1 and VEGF.
• TNF Tumor Necrosis Factor
• antibodies are monoclonal, polyclonal, multispecific and single chain antibodies and fragments thereof, e.g. Fab, Fab ', F (ab') 2, Fc and Fc 'fragments, light (L) and heavy (H) immunoglobulin chains and their constant, variable or hypervariable regions as well as Fv and Fd fragments (Chamov et al., 1999).
• the antibodies may be of human or non-human origin. Humanized and chimeric antibodies are also considered.
• the invention further relates to powders having increased, maintained or reduced reduced flowability (FPF) or improved aerodynamic or electrostatic properties preparable by the inventive method.
• FPF reduced flowability
• the invention relates to powders having increased flowability or increased nanorail, which can be produced by one of the illustrated processes according to the invention.
• the powder contains a substance 1 and at least one further substance 2, wherein substance 2 crystallizes in front of substance 1.
• the present invention thus furthermore relates to a process for increasing, maintaining or reducing the flowability (FPF) of a powder comprising a substance 1, in particular a protein, and at least one substance 2, characterized in that
• a preferred embodiment of the present invention relates to methods which preclude further coating with further particles, e.g. Exclusion of a coating with Mg stearate or phospholipids.
• a further preferred embodiment of the present invention relates to methods which preclude mixing with particles such as the smallest leucine particles or generally with nanoscale particles but also with significantly larger carriers.
• a specific embodiment of the method thus relates to methods to the exclusion of mixing with other particles.
• a preferred embodiment of the present invention relates to a process that conditions amorphous or semi-crystalline powders without the use of supercritical or subcritical media.
• the present invention excludes supercritical processes or the application of supercritical or subcritical media.
• the present invention thus further relates to a method for increasing, Preservation or reduced reduction of the flowability (FPF) of a powder or for improving the aerodynamic or electrostatic properties of a powder containing an active ingredient, in particular a protein, and at least one excipient, characterized in that - an amorphous powder
• optimization of the aerodynamic behavior by annealing is not limited to antibodies, but is also possible with other classes of proteins such as enzymes (e.g., lysozyme) and hormones (e.g., calcitonin).
• enzymes e.g., lysozyme
• hormones e.g., calcitonin
• the disaccharide sucrose or the polymer PVP can be used as an adjuvant.
• the applicability is not limited to these 3 substances, but may also be, for example, a polyol, an amino acid, a mono-, oligo- or polysaccharides or a protein stabilizing polymer.
• the inventive powder is optimized by a controlled exposure to moisture in terms of aerodynamic behavior or fluidity while maintaining protein stability.
• the optimization of the powder properties is accompanied by a surface crystallization of the particle surface.
• Particularly noteworthy is the addition of hydrophobic or poorly soluble substances in the spray solution, said substance after Drying under the influence of moisture can be crystallized well and controllably.
• the phenylalanine shows this property, in particular at a Phenylalaninanteil in the powder of at least 10% (w / w), at least 30% (w / w) or at least 40% (w / w), wherein at least 10% (w / w). w) are preferred.
• This amino acid accumulates on the droplet surface due to hydrophobicity in the spray drop. Due to the lower solubility compared to antibodies and the commonly used sugars or polyols, such as Sachcharose, mannitol, the evaporation of the droplet first forms a solid layer mainly consisting of phenylalanine. Due to its hydrophobicity and low solubility, the phenylalanine in the dried particle is enriched in the particle surface. There is at least partial separation between a phenylalanine-rich phase at the particle surface and a phenylalanine-poor phase in the core of the particle. At the core of the particle, on the other hand, the active substance and optionally other readily soluble excipients are enriched.
• the particle surface can be crystallized by the layer structure of the particle without damaging the protein in the nucleus.
• the powder components used are not homogeneously distributed in the particle, but can accumulate depending on the physicochemical properties of the components in certain areas or layers of the particle.
• the crystallizable components accumulate on the outer particle layers.
• a spray solution having a composition in powder with 60% phenylalanine / 30% LS90P / 10% IgGI showed the lowest surface tension. The reduction of the surface tension is due to the addition of the phenylalanine. Following these results, the phenylalanine accumulates on the droplet surface.
• a powder is obtained by phase separation of the two adjuvants LS90P and phenylalanine in spray-drying and in which the phenylalanine forms the outer layer in the particle and, accordingly, the LS90P forms the inner layer in the particle.
• a spray solution was prepared consisting of phenylalanine, LS90P and IgGI in an 80/10/10 ratio.
• the solids content of the spray solution was 3.83% (w / v).
• the solution was dried under the following conditions: Spray dryer: SD-Micro (Niro)
• Atomizing gas rate 4kg / h
• Drying gas rate 28kg / h
• the spray-dried powder was exposed to various humidities in the DVS.
• the powder was exposed to controlled humidity and determined morphological changes in relation to the exposure time in the moisture. For this purpose, the powder was first dried down and then exposed to the target moisture. The powder was scanned at regular intervals. The Target moistures were 50% RH and 60% RH.
• the AFM images ( Figures 3 and 4) showed that crystallization can be induced in the particles as a function of the air humidity, thereby increasing the surface roughness. It also turned out that the powder absorbs water very quickly. At 50% and 60%, respectively, water has been absorbed within about 1 hour, so that recrystallization effects began.
• the phenylalanine was brought into solution with heating (80 ° C.). After cooling the solution to room temperature, the protein and sugar were added.
• Spray Dryer SD-Micro (Niro)
• the produced powders were annealed at 50% relative humidity for 20 hours.
• the annealing process improved the aerodynamic behavior of the tested powders.
• the fine particle fraction increased by the annealing.
• the protein was stabilized via the annealing process, so that no moisture-induced damage is present.
• the monomer content after annealing is approximately unchanged.
• the improvement in the aerodynamics of phenylalanine can probably be attributed to 2 effects.
• the phenylalanine-containing powder formed by the influence of moisture on the particle surface small crystals. These act as a spacer.
• the crystalline surfaces are far less hygroscopic, so that less capillary forces occur through water vapor condensation.
• This example is intended to show how the tempering effect behaves depending on the proportion of the excipient to be crystallized.
• phenylalanine was used as the crystallizable component and its proportion reduced from 50% to 5% in the spray-dried powder.
• the compositions of the powders are shown in Table 5 and the spraying conditions in Table 6.
• the powders were tempered for 20 hours at 50% relative humidity and room temperature.
• Table 7 shows the monomer contents of the powders before and after annealing. It has been shown that the annealing does not induce any damage to the IgGI antibody since, after annealing, the monomer contents do not become significantly lower.
• the aerodynamic behavior could be improved up to 10% phenylalanine content (see Table 8). Both the fine particle fraction and the discharged mass could be increased by the tempering of the powders 1-5. At 5% phenylalanine content breaks both the Fine particle fraction as well as the discharged mass. With too small amounts of crystallizable substances, the tempering effect can not form accordingly.
• various proteins were spray-dried with the excipients LS90P and phenylalanine and then tempered. It should be shown that the tempering effect is not limited to a protein class to optimize the powder properties, but that annealing can be used independently of the protein.
• the compositions of the powders are listed in Table 9 and the spray conditions in Table 10.
• Figure 5 shows the fine particle fraction and the applied masses of the powders produced before and after annealing.
• the fine particle fractions of the prepared powders 1-3 are similarly high both before and after annealing.
• the applied masses show no significant differences depending on the protein used. That is, the optimization of the aerodynamic behavior by annealing is not limited to IgGI antibodies but, as shown in this example, is also possible with enzymes (e.g., lysozyme) and hormones (e.g., calcitonin).
• SPRAY DRYING POWDER Fundamental to tempering is a layered build up of powders. This means that the powder components used are not homogeneously distributed in the particle, but can accumulate depending on the physicochemical properties of the components in certain areas or layers of the particle.
• the crystallizable components accumulate on the outer particle layers. In this example, it should be checked whether a layer formation in the particle or a phase separation of the auxiliaries has taken place.
• the glass transition temperatures were determined calorimetrically (DSC) using a spray-dried powder consisting of 60% phenylalanine, 30% LS90P and 10% IgGI. The spray conditions are shown in Table 11 and the parameters of the DSC method in Table 12. The DSC measurements were carried out with a non-perforated crucible. The results refer to the mean of 6 individual measurements. Evaluated were the onset and the center of the Glass transition temperature.
• the solution 4 corresponds to a spray solution of the composition in the powder with 60% phenylalanine / 30% LS90P / 10% IgGL which is typical for this patent specification
• the LS90P has no higher surface activity than water, so that the sugar does not accumulate on the surface after atomization of the spray solution.
• the spray solution 4 shows the lowest surface tension. The reduction in surface tension is due to the addition of phenylalanine. Following these results, the phenylalanine enriches on the droplet surface.
• a powder is obtained by phase separation of the two adjuvants LS90P and phenylalanine in spray-drying and in which the phenylalanine forms the outer layer and, accordingly, the LS90P forms the inner layer in the particle.
• the aim of the freeze-drying of an aqueous LS90P solution was the production of X-ray amorphous powder.
• an aqueous solution with a low solids content (5 g / 100 ml) was prepared and freeze-dried as described in Table 16.
• Figure 6 shows the recrystallization enthalpies of the LS90P after heating the powders in a DSC instrument (DSC821 / Mettler Toledo). It can be seen that the enthalpy of crystallization, based on the mass fraction, is greatly increased by the addition of 1% HSA. Thus, the crystallization enthalpy of the LS90P before annealing increases from 6.80J / g to 24.3J / g and after annealing from 4.8J / g to 26.0J / g. That is, the addition of 1% HSA increases the amorphicity of the LS90P.
• tempering can improve the FPF.
• protein integrity (monomer content) can also be improved by annealing as mentioned in this example (see Table 20).
• the monomer content is significantly higher in powder 1 after annealing in particular.
• EXAMPLE 8 SPRAY DRYING OF OTHER POWDERS CONTAINING IGG1 / PHENYLALANINE AND ANOTHER AUXILIARY
• Storage condition 1 25 ° C / 60% r.F.
• Storage condition 2 25 ° C / 75% r.F.
• Table 23 shows the fine particle fractions of the powders produced before and after annealing. Powders 1 and 2 showed no significant improvement in aerodynamic properties. An important reason for this observation is that the aerodynamic properties were very good right after production. Substituting the MMAD with the fine particle fraction, which is defined as the mass fraction of particles smaller than 5.0 ⁇ m, it becomes clear that the optimization potential is limited by annealing by the high MMAD. It is also important in tempering that no particle comminution takes place with this process.
• Table 24 lists the monomer contents. By tempering the particles, the powder could be stabilized. That is, the surface was crystallized. This crystalline layer acts as a moisture barrier and can thereby protect the amorphous core.
• Excipients for protein stabilization are not limited to one substance class. As shown, in addition to LS90P, for example, the disaccharide sucrose or the polymer PVP can be used. The applicability is not limited to these 3 substances, but may also be, for example, a polyol, an amino acid, a mono-, oligo- or polysaccharides or protein stabilizing polymers. The functionality and thus the selection of the further excipient lies in the stabilization of the protein by the further excipient.

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