WO2021110732A1 - Procédé de production de particules lyophilisées par pulvérisation, et particules ainsi produites - Google Patents

Procédé de production de particules lyophilisées par pulvérisation, et particules ainsi produites Download PDF

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Publication number
WO2021110732A1
WO2021110732A1 PCT/EP2020/084241 EP2020084241W WO2021110732A1 WO 2021110732 A1 WO2021110732 A1 WO 2021110732A1 EP 2020084241 W EP2020084241 W EP 2020084241W WO 2021110732 A1 WO2021110732 A1 WO 2021110732A1
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Prior art keywords
particles
freeze
spray
solution
range
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PCT/EP2020/084241
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German (de)
English (en)
Inventor
Alf Lamprecht
Mohamed Ehab ALI
Daris Grizic
Dominic LUCAS
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Rheinische Friedrich-Wilhelms-Universität Bonn
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Priority to DE112020006012.8T priority Critical patent/DE112020006012A5/de
Publication of WO2021110732A1 publication Critical patent/WO2021110732A1/fr

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    • 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
    • A61K9/1623—Sugars or sugar alcohols, e.g. lactose; Derivatives thereof; Homeopathic globules
    • 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
    • A61K31/045—Hydroxy compounds, e.g. alcohols; Salts thereof, e.g. alcoholates
    • A61K31/05—Phenols
    • 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
    • A61K31/16—Amides, e.g. hydroxamic acids
    • A61K31/165—Amides, e.g. hydroxamic acids having aromatic rings, e.g. colchicine, atenolol, progabide
    • 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
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/21—Esters, e.g. nitroglycerine, selenocyanates
    • A61K31/215—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids
    • A61K31/216—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids of acids having aromatic rings, e.g. benactizyne, clofibrate
    • 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
    • A61K31/33—Heterocyclic compounds
    • A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
    • A61K31/35—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having six-membered rings with one oxygen as the only ring hetero atom
    • A61K31/352—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having six-membered rings with one oxygen as the only ring hetero atom condensed with carbocyclic rings, e.g. methantheline 
    • 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
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/415—1,2-Diazoles
    • 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
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/4164—1,3-Diazoles
    • A61K31/4174—Arylalkylimidazoles, e.g. oxymetazolin, naphazoline, miconazole
    • 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
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
    • A61K31/5375—1,4-Oxazines, e.g. morpholine
    • A61K31/5377—1,4-Oxazines, e.g. morpholine not condensed and containing further heterocyclic rings, e.g. timolol
    • 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
    • A61K31/60—Salicylic acid; Derivatives thereof
    • A61K31/612—Salicylic acid; Derivatives thereof having the hydroxy group in position 2 esterified, e.g. salicylsulfuric acid
    • A61K31/616—Salicylic acid; Derivatives thereof having the hydroxy group in position 2 esterified, e.g. salicylsulfuric acid by carboxylic acids, e.g. acetylsalicylic acid
    • 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
    • A61K31/63—Compounds containing para-N-benzenesulfonyl-N-groups, e.g. sulfanilamide, p-nitrobenzenesulfonyl hydrazide
    • A61K31/635—Compounds containing para-N-benzenesulfonyl-N-groups, e.g. sulfanilamide, p-nitrobenzenesulfonyl hydrazide having a heterocyclic ring, e.g. sulfadiazine
    • 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
    • A61K9/14—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
    • A61K9/1629—Organic macromolecular compounds
    • A61K9/1635—Organic macromolecular compounds obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyvinyl pyrrolidone, poly(meth)acrylates
    • 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
    • A61K9/1629—Organic macromolecular compounds
    • A61K9/1652—Polysaccharides, e.g. alginate, cellulose derivatives; Cyclodextrin
    • 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
    • F—MECHANICAL ENGINEERING; LIGHTING; HEATING; WEAPONS; BLASTING
    • F26—DRYING
    • F26B—DRYING SOLID MATERIALS OR OBJECTS BY REMOVING LIQUID THEREFROM
    • F26B5/00—Drying solid materials or objects by processes not involving the application of heat
    • F26B5/04—Drying solid materials or objects by processes not involving the application of heat by evaporation or sublimation of moisture under reduced pressure, e.g. in a vacuum
    • F26B5/06—Drying solid materials or objects by processes not involving the application of heat by evaporation or sublimation of moisture under reduced pressure, e.g. in a vacuum the process involving freezing
    • F26B5/065—Drying solid materials or objects by processes not involving the application of heat by evaporation or sublimation of moisture under reduced pressure, e.g. in a vacuum the process involving freezing the product to be freeze-dried being sprayed, dispersed or pulverised

Definitions

  • the present invention relates to a method for producing spray-freeze-dried particles.
  • the spray freeze drying process combines the advantageous properties of the spray drying and freeze drying drying processes established in the pharmaceutical industry. The combination of both processes, the processes with each other. Thermolabile substances are gently dried due to the low temperatures, while porous, spherical microparticles with good flow properties can be produced at the same time.
  • WO 2013 / 041542A1 describes the spray-freeze-drying of proteins, polypeptides, oligopeptides, peptides DNA, RNA using at least one cryoprotectant and at least one stabilizer from aqueous solution.
  • Ali and Lamprecht also describe in the International Journal of Pharmaceutics 516, 170, 177, 2017, spray-freeze drying as an alternative technique for the lyophilization of polymeric and lipid-based nanoparticles.
  • the present invention was based on the object of providing a method which, in particular, allows the production of particles with improved release properties.
  • a method for producing spray-freeze-dried pharmaceutical particles comprising the following steps, a) providing a solution comprising at least one pharmaceutical active ingredient and a solvent, b) spraying the solution into a cold environment, whereby solidified droplets are obtained, and c) removing the solvent by atmospheric sublimation or vacuum freeze-drying, whereby spherical spray-freeze-dried particles are obtained, wherein in step a) the solvent is selected from tert-butanol, dimethyl sulfoxide, water and mixtures thereof and the solution has a solids content Range from> 1.5% to ⁇ 60%, based on the total volume of the solution (m / V), and in step b) droplets with a mean diameter in the range from> 30 pm to ⁇ 700 pm are generated and the droplets are sprayed into an environment with a temperature in the range from> -100 ° C. to ⁇ 20 ° C. pm.
  • the method enables the production of porous, spherical, completely or partially amorphous particles.
  • the spray-freeze-dried particles have a high sphericity and good flowability, which makes processing of the particles easier.
  • lipophilic active ingredients and auxiliaries which are insoluble or poorly soluble in water or aqueous solution can be used and sprayed.
  • the solids content of the sprayed solution and the droplet size have a significant influence on the resulting flowability of the spray-freeze-dried particles obtained.
  • Another advantage is that the method offers the possibility of producing particles or amorphous solid dispersions for thermolabile active ingredients. This is not possible, for example, by melt extrusion due to the temperature and also only possible to a limited extent by spray drying.
  • the production of spray-freeze-dried particles or sphero-polyophilisates basically comprises the process steps of creating droplets, freezing the droplets and drying them.
  • a solution containing an active ingredient and usually one or more auxiliaries is frozen by spraying in a very cold environment and then dried by means of sublimation in a vacuum or under atmospheric pressure.
  • a suitable spray head for example a drop generator
  • a liquid jet is generated which, for example, experiences a uniform tear-off of the drops due to a piezoelectric pulse.
  • the set jet of droplets can be directed into a spray tower, which is cooled from the outside, for example by a cold nitrogen flow. As a result, the drops freeze through very quickly.
  • the particles frozen in this way are dried in a subsequent drying step.
  • the particles frozen in this way can then be collected and are atmospherically or by means of vacuum Freeze drying lyophilized.
  • the frozen droplets settle on a drying sieve due to the exit speed from the nozzle and the force of gravity, after which the drying process is initiated.
  • the frozen droplets release the solvent into the gas flow by sublimation. After the solvent has been removed, a framework consisting of the solid components of the solution used remains.
  • a continuously operating spray-freeze-drying process is preferred. Unless otherwise described, the spray freeze-drying process is preferably carried out in accordance with the teaching of WO 2013/041542 A1 and the device and process parameters described there. Further parameters used in detail in the context of the present invention are set out in the examples.
  • the properties of the spray-freeze-dried particles produced in this way can in particular be adjusted via the composition of the sprayed starting solution.
  • the solids concentration of the starting solution can have an influence on the shape and porosity of the particles.
  • the spray settings usually show a somewhat smaller influence on particle formation.
  • the freezing temperature influences the particle morphology and a temperature in the range from> -100 ° C to ⁇ -50 ° C has proven to be advantageous for a quick and gentle freezing step in aqueous solutions.
  • solvents such as tert-butanol, which solidify at higher temperatures, a correspondingly higher freezing temperature is possible and a range from> - 100 ° C to ⁇ -20 ° C is preferred.
  • a higher freezing temperature is also possible and a range from> -100 ° C to ⁇ 0 ° C is preferred.
  • the spray-freeze drying method uses cold air for the freezing step.
  • a temperature range can be set by external cooling with liquid nitrogen.
  • the temperature can be in the range from> -60 ° C or> -50 ° C to ⁇ -20 ° C.
  • a preferred temperature in each case, which is low enough to ensure the stability of the active ingredient by rapid freezing, can be the A person skilled in the art can determine by means of simple experiments, whereby he provides, in particular as a function of the drop speed, that the drops are frozen before they hit the collecting container.
  • the average diameter of the spray-freeze-dried particles can be adjusted in particular through the specifications of the spray nozzle.
  • the mean diameter of the drops in step b) is in the range from 50 ⁇ m to bis 500 ⁇ m, preferably in the range from 150 ⁇ m to 400 ⁇ m, preferably in the range from 200 ⁇ m to 400 ⁇ m.
  • droplet diameters in this range achieved particles with preferred particle diameters D50 (volumetric) in the range from von 30 ⁇ m to 500 ⁇ m, preferably in the range from 50 ⁇ m to 300 ⁇ m.
  • D50 volumemetric
  • a person skilled in the art will adapt corresponding openings of the spray nozzles. Replacing the orifice of a drop jet nozzle with a double diameter model can double the diameter of the drop when the stimulation rate is changed to double, which can result in a drop size difference of about 10%.
  • the solution can in principle comprise customary auxiliaries for spray freeze drying, for example selected from the group comprising mannitol, sucrose, lactose, trehalose, hydroxypropylmethyl cellulose (HPMC), hydroxypropylmethyl cellulose acetate succinate (HPMC-AS), low-viscosity hydroxypropyl cellulose (PVPyrrol), (PVPyrrol) ), Maltodextrin, dextran, anionic copolymers of methacrylic acid and methyl methacrylate (e.g. Eudragit E), and / or surfactants such as polyethylene glycol and its copolymers (e.g.
  • polyvinyl caprolactam-polyvinyl acetate-polyethylene glycol graft copolymer available under the brand Soluplus®
  • polyoxyethylene (20 ) sorbitan monooleate polysorbate 80
  • polyoxyethylene (20) sorbitan monolaurate polysorbate 20
  • the spraying of a solution in contrast to the spraying of a suspension, has proven to be essential for achieving the advantageous properties of the particles exposed.
  • the interaction of the droplet size, the solids content of the sprayed solution and the freezing temperature have proven to be advantageous influencing variables for the flowability of the particles obtained.
  • the solids content of the solution plays an essential role here.
  • the solids content is in the range from> 1.5% to ⁇ 60%, based on the total volume of the solution (m / V).
  • the solids content can relate to the active ingredient or, in the event that the solution comprises at least one auxiliary substance in addition to the active substance, to the active substance and auxiliary substance. At higher solids contents, compact particles result which are no longer sufficiently compact. Lower solids contents lead to particles with insufficient mechanical stability.
  • concentration data are given in the form of the mass fraction in the solvent with the percentage value% (m / V).
  • Tert-butanol, dimethyl sulfoxide, water and mixtures thereof are preferred as solvents for spray freeze drying.
  • tert-butanol can advantageously be used.
  • Dimethyl sulfoxide can also advantageously be used.
  • These solvents can also be used to spray-freeze-dry lipophilic active ingredients and auxiliaries such as celecoxib, fenofibrate, chloramphenicol and clotrimazole that are insoluble or poorly soluble in water or aqueous solution. If tert-butanol is used, higher drying temperatures can also be used.
  • water is preferred as the solvent for the production of spray-freeze-dried particles containing an active protein such as lysozyme.
  • the solution comprises at least one auxiliary, preferably a stabilizer.
  • the solids content, for example of active ingredient and excipient, of the solution is in the range from> 1.5% to ⁇ 50%, preferably in the range from> 3% to ⁇ 25%, based on the total volume of the solution (m / V).
  • the solids content of the solution is preferably in the range of> 3% or> 5% to ⁇ 10%, ⁇ 15% or ⁇ 25%, based on the total volume of the solution (m / V). Solids contents of 10% (m / V) resulted in particles with good flow behavior.
  • the solids content can be 1% to 1.5% (m / V), for the production of particles for tableting in the range of 20% to 40% (m / V).
  • the solution can have at least one stabilizer as an auxiliary.
  • the solution can also contain an anti-freeze agent.
  • the auxiliary used is a stabilizer, in particular polyvinylpyrrolidone (PVP), and optionally an anti-freeze agent.
  • the antifreeze agent is preferably selected from the group comprising mannitol and sucrose.
  • the term “stabilizer” denotes a pharmaceutically acceptable excipient which gives the spray-freeze-dried particles or sphero-polyophilizates mechanical strength.
  • the stabilizer can be selected from among hydroxypropylmethyl cellulose (HPMC),
  • HPMC-AS Hydroxypropylmethylcellulose acetate succinate
  • HPC-SSL low-viscosity hydroxypropylcellulose
  • PVP polyvinylpyrrolidone
  • maltodextrin dextran and / or anionic copolymers of methacrylic acid and methyl methacrylate (e.g. Eudragit E).
  • a preferred stabilizer is polyvinylpyrrolidone (PVP).
  • PVP polyvinylpyrrolidone
  • an amount of stabilizer such as PVP in the solution based on the total volume of the (m / V), from 0.75% up to 30%, for example from 0.75%, 1.5%, 5% or 7, 5%, resulting spray-dried particles with good mechanical properties.
  • anti-freeze refers to pharmaceutically acceptable excipients, as they are commonly used in formulations that are subjected to freeze-drying in order to reduce the formation of ice crystals in the freezing droplet and to improve the subsequent reconstitution of the active ingredient solution.
  • antifreeze agents can be, for example, alcohols, preferably polyalcohols such as mannitol, sorbitol and the like.
  • the anti-freeze agent can also be a sugar, for example selected from sucrose and trehalose.
  • a preferred alcohol as an anti-freeze agent is mannitol.
  • a preferred sugar as an anti-freeze agent is sucrose.
  • a particularly preferred anti-freeze agent is mannitol.
  • stabilizer and anti-freeze agent it may be preferred to use stabilizer and anti-freeze agent.
  • the use of stabilizers and anti-freeze agents in a spray-freeze-drying process can enable the production of lyophilizate powders, the particles of which have good mechanical stability and good flow behavior. If the stabilizer and antifreeze agent are used, the stabilizer and antifreeze agents can be used in independent proportions. Spray-freeze-dried particles with very good sphericity and flowability were obtained using 0.75%, 5% and 7.5%, based on the total volume of the solution (m / V), of mannitol and polyvinylpyrrolidone. Higher proportions of antifreeze agents such as mannitol can also be used to stabilize such as polyvinylpyrrolidone. It may be preferred to use higher proportions of polyvinylpyrrolidone than of mannitol if this has a positive effect on the solubility or the stability of the active ingredient.
  • the solution can have a light-absorbing compound.
  • the solution can also contain a compound with an antioxidant effect. It may be preferred to use light absorbents and / or antioxidants.
  • the use of light absorbents in a spray-freeze-drying process can protect a pharmaceutical active substance from light damage during the manufacture of the particles as well as during their storage.
  • An antioxidant can also be an active pharmaceutical ingredient Protect from oxidation during the manufacture of the particles and during their storage.
  • Light absorbents can be selected from the group comprising benzophenones such as oxybenzone or azobenzone, salicylates such as homomenthyl salicylate (homosalate) or octyl salicylate, cinnamic acid esters such as octinoxate and / or octocrilene.
  • Antioxidants can be selected from the group comprising ascorbyl palmitate, ascorbic acid, BHT, BHA, tocopherol, da-tocopherol-polyethylene glycol-1000-succinate (TPGS), propylgalat and / or sodium metabisulphite.
  • the advantageous properties of the particles are based essentially on the fact that a solution is sprayed in contrast to a suspension.
  • a suspension is a coarsely dispersed dispersion and tends to sedimentation and phase separation, which would make the solids content of the sprayed droplets and the morphology of the particles heterogeneous.
  • the term “solution” includes “colloidal solutions”.
  • a “colloidal solution” is a solution in which particles with a diameter of less than 1 ⁇ m are finely distributed in the solvent, so that the properties of the colloidal solution can behave like a real solution. So nanoparticles of a poorly soluble pharmaceutical substance in solvents can be selected from tert. -Butanol, dimethyl sulfoxide, water and their mixtures form a colloidal solution that can be sprayed with the same advantageous properties of the particles as a real chemical solution.
  • a solution comprising at least one pharmaceutical active ingredient and a solvent, prior to the spraying of which is preceded by a step of producing a colloidal solution, optionally including a nanonization of the pharmaceutical active ingredient.
  • Nanonization refers to the reduction of the particle size down to the nanometer range, i.e. the conversion into a nanoparticulate composition by means of a comminution process, for example by means of a grinding process.
  • nanonization of the active ingredient aprepitant which is only sparingly soluble in an aqueous environment, is preferred.
  • the method accordingly comprises, that a colloidal solution is provided, wherein the provision of the solution is optionally preceded by a nanonization of the at least one pharmaceutical active ingredient.
  • the method comprises that the provision of the solution is preceded by an extraction of the at least one pharmaceutical active substance from an active substance source such as an active substance plant.
  • active ingredient plant is understood to mean a plant from which a pharmaceutically active ingredient can be obtained. This can be done in particular by extracting the usable components such as leaves, flowers, fruits, bark, seeds or roots of the plant. It is preferred that an extraction in solvents selected from tert. -Butanol, dimethyl sulfoxide, water and mixtures thereof takes place. The extracts can then directly provide a sprayable solution.
  • a solution of a mixture of the pharmaceutical active ingredients cannabidiol (CBD) and tetrahydrocannabinol (THC) can be produced from the plant drug cannabis flos by extraction in tert-butanol.
  • CBD cannabidiol
  • THC tetrahydrocannabinol
  • the pharmaceutical active ingredient can be selected from the group comprising synthetic or natural compounds, in particular so-called small molecules, proteins, peptides, DNA, RNA, polysaccharides such as heparin, antibodies, insulin, or the like.
  • tert-butanol as a solvent
  • lipophilic active ingredients are selected from the group comprising celecoxib, fenofibrate, chloramphenicol and clotrimazole.
  • the particles are preferably dried by means of vacuum freeze-drying.
  • the frozen particles can be transferred to a customary freeze dryer and lyophilized using conventional drying times, for example from 24 to 48 hours and / or using a vacuum of 0.1 mbar to 1 mbar.
  • the proportion of active ingredient in the solution can be up to its maximum solubility in the solvent, in particular in the range from> 2.5% to ⁇ 10%, based on the total volume of the solution (m / V) .
  • the proportion of stabilizer such as PVP in the solution can also be in the range from> 2.5% to ⁇ 10%, in particular in the range from> 5% to ⁇ 7.5%, based on the total volume of the solution (m / V) , lie.
  • Preferred protein active ingredients are selected from the group comprising lysozyme. Protein active ingredients are preferably sprayed using water as the solvent. Furthermore, protein active ingredients are preferably dried by means of atmospheric sublimation. Spraying from aqueous solution and atmospheric drying have proven to be advantageous for the spray-freeze-drying of protein active ingredients.
  • the frozen particles can be dried with a drying gas such as nitrogen or dry air, preferably in a temperature range from -20 to -5 ° C.
  • a drying gas such as nitrogen or dry air, preferably in a temperature range from -20 to -5 ° C.
  • the drying step can be carried out continuously, for example by drying on a conveyor sieve or a sieve disk.
  • the proportion of active ingredient in the solution can be in the range from> 0.5% to ⁇ 5%, based on the total volume of the solution (m / V).
  • the proportion of stabilizer such as mannitol in the solution can be in the range from> 2.5% to ⁇ 10%, in particular in the range from> 5% to ⁇ 7.5%, based on the total volume of the solution (m / V), lie.
  • the process allows the production of spray-freeze-dried particles with good sphericity, which can be referred to as sphero polyophilizates.
  • Another object of the invention relates to spray-freeze-dried particles, in particular produced by the method described above, the particles having a pharmaceutical active ingredient and at least one auxiliary, characterized in that the particles have a sphericity in the range from> 0.75 to ⁇ 1 and a powder sample of the particles has an angle of repose of ⁇ 40 °.
  • the particles are preferably comprising tert by means of spray freeze drying from a solution. -Butanol, dimethyl sulfoxide, water or mixtures thereof prepared as described above.
  • the particles show excellent flow properties, as a result of which a significant improvement in the handling of the lyophilizate powder can be provided during storage, such as in particular during administration.
  • the particles are usually used in powder form for administration or reconstituted in solution immediately before administration, and good flow properties are essential for such administration.
  • Flowable powders are also preferred for the production of lyophilizates to be administered parenterally, since their flowability simplifies their filling or storage as so-called “bulk” goods is possible.
  • the sphericity or roundness which represents a dimensionless parameter of the particles, can be determined using image analysis methods, for example using a particle size measuring device such as a Camsizer X2 (Retsch Technology, Haan).
  • a particle size measuring device such as a Camsizer X2 (Retsch Technology, Haan).
  • images of individual particles are recorded and evaluated over the whole.
  • the spray- Freeze-dried particles have a sphericity in the range from 0.8 to 0.99, preferably in the range from 0.9 to 0.99 or in the range from 0.93 to 0.98.
  • the angle of repose also known as the angle of repose, is determined by pouring the powder sample loosely into a cone of repose. In the context of the invention, the angle of repose was measured according to the specifications of the European Pharmacopoeia (PhEur 2.9.36) using a funnel whose opening was 1.0 cm wide. A smaller angle of repose corresponds to a better flowability of the particles in the powder sample.
  • a powder sample of the spray-freeze-dried particles has an angle of repose of ⁇ 35 ° or ⁇ 30 °.
  • the angle of repose can be in the range from> 30 ° to ⁇ 35 °. Particles with such angles of repose show excellent flowability.
  • the spray-freeze-dried particles have a particle diameter D50 (volumetric) in the range from 30 ⁇ m to 500 ⁇ m, preferably in the range from 50 ⁇ m to 300 ⁇ m.
  • the particles can also advantageously have a particle diameter D50 in the range of> 150 ⁇ m,> 200 ⁇ m or> 250 to ⁇ 300 ⁇ m, ⁇ 350 ⁇ m or ⁇ 400 ⁇ m. Particles with a particle diameter D50 in these areas exhibited very good flow properties and are accordingly suitable for nasal, oral, sublingual and buccal administration.
  • the spray-freeze-dried particles comprise an active ingredient selected from the group comprising celecoxib, fenofibrate, chloramphenicol and clotrimazole. In further preferred embodiments, the spray-freeze-dried particles comprise an active ingredient selected from the group comprising aprepitant, levodopa (L-dopa) and acetylsalicylic acid. In more preferred In embodiments, the spray-freeze-dried particles comprise an active ingredient mixture.
  • the spray-freeze-dried particles comprise an active ingredient mixture of cannabidiol (CBD) and tetrahydrocannabinol (THC).
  • CBD cannabidiol
  • THC tetrahydrocannabinol
  • Another subject matter is a pharmaceutical preparation or a medicament comprising spray-freeze-dried particles according to the invention, in particular spray-freeze-dried particles produced by the method described above.
  • spray-freeze-dried particles in particular spray-freeze-dried particles produced by the method described above.
  • FIG. 2 the release profile of a physical mixture of celecoxib
  • FIG. 4 in FIG. 4a the droplet diameter of spray-freeze-dried particles for different solids concentrations and nozzle diameters, in FIG. 4b) the respective slope angles.
  • FIG. 5 shows the flow of spray-freeze-dried particles plotted against the
  • FIG. 6 shows the flow rate of spray-freeze-dried particles plotted against the
  • FIG. 7 in FIGS. 7 a), b) and c) scanning electron microscope images of spray-freeze-dried particles, magnified 200 times.
  • FIG. 9 shows a scanning electron microscope image of a spray-freeze-dried particle, magnified 200 times.
  • FIG. 10 shows a scanning electron microscope image of a spray-freeze-dried particle, magnified 200 times.
  • FIG. 11 the stability of lysozyme in spray-freeze-dried lysozyme particles for vacuum freeze-drying (SFD) and for atmospheric sublimation
  • FIG. 12 is a scanning electron microscope image of spray-freeze-dried particles, magnified 200 times.
  • FIG. 13 is a scanning electron microscope image of a spray-freeze-dried particle, magnified 200 times.
  • Fenofibrate, chloramphenicol, clotrimazole and celecoxib were obtained in pharmaceutical grade.
  • Polyvinylpyrollidone (PVP, Kollidon® 25) was obtained from BASF, Ludwigshafen, Germany.
  • D (-) - mannitol [Ph. Eur.] Was obtained from VWR International, Amsterdam, Netherlands.
  • Tert-butanol [Ph. Eur.] was obtained from Sigma.
  • Ultrapure water was made with a MilliQ, Millipore Corp., Billerica, MA, USA. Methods:
  • the spray freeze drying process used involved three steps: droplet generation, freezing and freeze drying.
  • a monodisperse drop generator (MTG-01-02, FMP Technologies GmbH, Erlangen, Germany) with a nozzle diameter of 100 ⁇ m (if not stated otherwise) on the spray tower was used to generate the drops.
  • the freezing process was carried out by spraying solutions in cold air (-60 ° C to -100 ° C) in a cooled stainless steel spray tower, which was surrounded by a jacket cooled with liquid nitrogen.
  • the solutions of active ingredient and excipient (s) were sprayed into the spray tower by means of the nozzle mentioned above.
  • the particles were then dried in the same tower.
  • the drying gas used was nitrogen or dry air, preferably in a temperature range from -20 to -5 ° C. for aqueous solutions, the drying gas being passed through a loose pile of ice particles until the sphero polyophilizates were dry.
  • the dryness was measured by means of the residual content in the exhaust air and the process was stopped at approx. 20 ppm.
  • this drying step can be carried out continuously, by drying on a conveyor sieve or a sieve disc.
  • freeze-drying To remove the solvent by means of vacuum freeze-drying, the particles were alternatively collected in a vessel at the lower end of the spray tower for the subsequent freeze-drying.
  • the frozen particles were for 48 hours in an Alpha 1-4 LSC Plus freeze dryer (Martin Christ, Germany) at a vacuum of 0.1 mbar and a condenser temperature of -52 ° C lyophilized. In the following, both processes are referred to as freeze-drying.
  • a Hitachi SU3500 SEM (Hitachi Ltd., Tokyo, Japan) was used to view the surface morphology of the spray-freeze dried samples.
  • the samples were attached to an aluminum plate with double-sided adhesive tape and coated with gold using a Polaron SC7640 sputter coater (Quorum Technologies Ltd., Newhaven, UK) in an argon atmosphere.
  • the calibration was carried out with indium as the standard.
  • Non-hermetically sealed aluminum crucibles were filled with 5-10 mg sample and analyzed. After an equilibration time of 2 minutes at 25 ° C., the samples were heated to 110 ° C. in the case of fenofibrate and 170 ° C. for celecoxib, chloramphenicol and clotrimazole at 5 K / min. This was followed by a cooling step back to 25 ° C.
  • the evaluation of the melting peaks was carried out in the first heating cycle.
  • the STARcsw 13.0 program was used to evaluate the results.
  • the X-ray powder diffractometry was carried out using an X'Pert Philips (X'Pert Philips Analytical B.V., Almelo, Netherlands) device. The following configuration was used: Transmission-Reflection-Spinner, scanned angular range from 4 ° 28 to 45 ° 28, generator input 40 mA and 45 kV. The data were collected using the PANalytical X'Pert HighScore Plus program, version 2.2. c edited.
  • Example 1 Production of spray-freeze-dried pharmaceutical particles comprising fenofibrate, chloramphenicol, clotrimazole and celecoxib
  • the active ingredients fenofibrate, chloramphenicol, clotrimazole and celecoxib were each dissolved in tert-butanol at a concentration of 5% (w / v) and the solutions were mixed with a concentration of 5% polyvinylpyrrolidone (PVP, Kollidon® 25).
  • the solutions were sprayed into the spray tower as described above using a nozzle diameter of 100 ⁇ m by means of a nozzle in cold air ( ⁇ 100 ° C.) and then freeze-dried.
  • the melting point of the spray-freeze-dried particles and the pure active ingredients fenofibrate, chloramphenicol, clotrimazole and celecoxib as well as PVP was determined by means of differential calorimetry (DSC). As expected, the pure active ingredients showed a sharp melting point, while PVP showed no detectable melting point. In the case of the spray-freeze-dried particles, the particles with chloramphenicol, clotrimazole and celecoxib showed no detectable melting point, which indicates the presence of amorphous particles. The particles containing fenofibrate showed a weak but significant melting point, which suggests a partially crystalline structure. The structure of the particles was further investigated by means of X-ray powder diffractometry.
  • FIG. 1 shows in FIGS. La), b), c) and d) the specific reflexes of the pure substances fenofibrate (FENO), chloramphenicol (CHLORO), clotrimazole and celecoxib in their crystalline pure form, the amorphous signal from PVP, as well below the signals of the spray-freeze-dried particles.
  • the particles with chloramphenicol, clotrimazole and celecoxib only show signals that indicate the presence of amorphous particles during the diffractogram of the particles containing fenofibrate shows reflections of a partially crystalline fenofibrate structure.
  • the release determination was carried out using a custom-made release apparatus.
  • the release vessels were completely filled with a volume of 20.0 ml of the celecoxib particles produced according to Example 1.
  • the spray lyophilized samples were added directly to the medium.
  • An Agilent Cary 8454 UV-Vis spectroscope (Agilent Technologies, Santa Clara, CA, USA) at a wavelength of 255 nm (Celecoxib) was used to quantify the sample.
  • a physical mixture of 50% by weight celecoxib and 50% by weight polyvinylpyrrolidone was investigated. At different times in the range from 5 to 360 minutes, a 1.0 ml sample was taken, replaced by 1.0 ml fresh phosphate buffer and the sample was examined UV-metrically for the active ingredient content.
  • FIG. 2 shows the release profile of the physical mixture of celecoxib and polyvinylpyrrolidone and the spray-freeze-dried particles.
  • the spray-freeze-dried particles showed a release that was up to 450% greater than that of the physical mixture. Without being tied to a specific theory, it is assumed that this is based on the one hand on the highly porous structure of the spray-freeze-dried particles and on the other hand on the amorphous structure of the sprayed celecoxib.
  • the PVP stabilized the supersaturation of the solution only slightly; after reaching the maximum, the content of dissolved celecoxib fell due to precipitation.
  • Example 3 Investigation of different solids contents with varying nozzle size Solutions with different solids concentrations of polyvinylpyrrolidone (PVP, Kollidon® 25) and mannitol were each prepared in water and as described above using nozzle diameters of 20 ⁇ m, 50 mm or 100 m in a nozzle in cold air (- 100 ° C) sprayed into the spray tower and then freeze-dried.
  • PVP polyvinylpyrrolidone
  • mannitol mannitol
  • the angle of repose or repose angle measurement was carried out according to the recommended procedure described in the European Pharmacopoeia (Ph. Eur. 2.9.36) for determining the angle of repose.
  • the evaluation was carried out using a photograph of the sample after it had been trickled onto a flat surface through a funnel.
  • the fixed funnel was filled slowly and from the upper edge of the funnel in order to minimize the impact of the particles on the top of the sample.
  • the position of the camera was chosen so that the lens was always in a plane with the smooth surface.
  • the evaluation was carried out using an image processing program. Lines were drawn along the slope of the hill to determine the height from their intersection, as well as the base to determine the diameter of the conical base.
  • the mean droplet diameter and the width of the particle size distribution were also determined.
  • the volumetric D50 value was determined from the sum of all individual particle measurements, and the span representing the polydispersity was determined using the standard calculation used in the Camsizer X2.
  • the following table 1 summarizes the compositions used, nozzle openings, as well as the specific slope angles, sphericity, droplet diameter and width of the particle size distribution (SPAN):
  • FIGS. 3a), b) and c) show scanning electron microscope images of the particles of samples 4, 5 and 10 magnified 200 times. As can be seen from FIG. 3, the particles exhibited a spherical shape and good porosity.
  • FIG. 4a shows the droplet diameter of Examples 1 to 15 for various solids concentrations and nozzle diameters
  • FIG. 4b shows the respective slope angles.
  • FIG. 4 in particular particles produced from solutions with a solids content of 5% to 15% (m / V) and an average droplet diameter of more than 150 ⁇ m have a good angle of repose.
  • the flowability of the 15 samples was measured on an ERWEKA granulate flow tester with a funnel opening of 10 mm. The samples were each weighed to 0.250 g on an analytical balance and measured. Samples which did not flow were marked with "#na”. The measurement was carried out according to the specifications of the European Pharmacopoeia (PhEur 2.9.16) with a funnel with an opening 1.0 cm wide.
  • FIG. 5 shows the flow of the samples plotted against the solids content determined with a funnel opening of 10 mm. The results are reported in seconds per 0.250 g sample. As can be seen from FIG. 5, in particular particles produced from solutions with a solids content of 5% (m / V) and more showed good flow behavior, even with small nozzle diameters or particle sizes. In addition, they had good mechanical stability.
  • FIG. 6 shows the flow of the samples plotted against the solids content determined with a funnel opening of 6 mm. The results are reported in seconds per 0.250 g sample. As can be seen from FIG. 6, the measurement with a smaller funnel opening confirmed the good flow behavior of the particles produced from solutions with a solids content of 5% (m / V) and more.
  • Example 4 Determination of the maximum solids content Solutions with different solids concentrations of polyvinylpyrrolidone (PVP, Kollidon® 25), mannitol, sucrose or mixtures thereof were each prepared in water and, as described above, using a nozzle diameter of 100 ⁇ m by means of a nozzle in cold air (-100 ° C) in the Spray tower sprayed and then freeze-dried.
  • PVP polyvinylpyrrolidone
  • mannitol mannitol
  • sucrose sucrose
  • the slope angle was determined as described in Example 3.1 using the method described in the European Pharmacopoeia (Ph. Eur. 2.9.36), and the sphericity was determined using the Camsizer X2 particle size measuring device (Retsch Technology, Haan). The mean droplet diameter and the width of the particle size distribution (SPAN) were also determined as described under Example 3.1.
  • FIGS. 7a), b) and c) show scanning electron microscope images of the particles from samples 16, 17, 18 and 19 magnified 200 times.
  • the particles samples 16, 17 and 19 showed a good spherical shape.
  • the particle of sample 17 with a solids content of 60% (w / v) showed good sphericity and an already quite compact surface. While the angle of repose of the sample with a higher proportion of stabilizer compared to antifreeze could not be determined, the Sample with 20% (w / v) stabilizer and antifreeze agent each have a good angle of repose and moderately good sphericity.
  • Example 5 Determination of different active ingredient and auxiliary substance concentrations in tert-butanol
  • Figures 8a), b), c), d) and e) each show scanning electron microscope images of the particles of samples 20, 21, 22, 23 and 24 magnified 200 times. As can be seen from Table 3 and FIG. 8, samples 20 to 24 showed good sphericity, angle of repose and good porosity of the particles.
  • Example 6 Use of hydroxypropyl cellulose as a stabilizer
  • Ligur 9 shows the scanning electron microscope image of a spray-freeze-dried particle of sample 25 magnified 200 times. As can be seen from Table 4 and Ligurium 9, sample 25 showed a good angle of repose, sufficient sphericity and good porosity of the particles. This shows that hydroxypropyl cellulose can also be used as a stabilizer in tert-butanol with good results.
  • a solution of 5% (w / V) PVP and 5% (w / V) Celecoxib was prepared in tert-butanol and as described above using a nozzle diameter of 200 ⁇ m by means of a nozzle in cold air (- 100 ° C) in the spray tower. After settling in a cooled vessel at the lower end of the spray tower, the frozen particles were collected on a sieve with a mesh size of 20 ⁇ m and dried by means of atmospheric sublimation. The frozen particles were left in the same tower for 60 hours and lyophilized with nitrogen at a gas flow of 601 min 1 and a temperature of 15 ° C. Angle of repose, sphericity, mean droplet diameter and width of the particle size distribution (SPAN) were determined as described in Example 3.1.
  • FIG. 10 shows the scanning electron microscope image of a particle of sample 26 dried by atmospheric sublimation, magnified 200 times.
  • the sample 26 showed a good angle of repose, sufficient sphericity and good porosity of the particles. This shows that good results were also achieved with atmospheric sublimation, which are comparable to sublimation using vacuum.
  • Example 8 Spray-freeze-drying of a protein by means of atmospheric sublimation and vacuum-freeze-drying
  • a solution of 5% (w / v) mannitol, 2.5% (w / v) Kollidon® 12 PF and 1% (w / v) lysozyme was prepared in water and as described above using a nozzle diameter of 200 ⁇ m by means a nozzle in cold air (- 100 ° C) in the spray tower sprayed. After settling in a cooled vessel at the lower end of the spray tower, the frozen particles were collected on a sieve with a mesh size of 20 ⁇ m and dried by means of atmospheric sublimation. The frozen particles were left in the tower for 24 hours and lyophilized with nitrogen at a gas flow of 60 L min-1 and a temperature of -10 ° C.
  • the solution was sprayed under identical conditions and to remove the solvent by means of vacuum freeze drying, the frozen particles were collected in a vessel at the lower end of the spray tower and transferred to an Alpha 1-4 LSC Plus freeze dryer (Martin Christ, Germany) and lyophilized for 24 hours at a vacuum of 0.1 mbar.
  • FIG. 11 shows the yield of spray-freeze-dried lysozyme particles for vacuum freeze-drying (SFD) and for atmospheric sublimation (aSFD).
  • SFD vacuum freeze-drying
  • ASFD atmospheric sublimation
  • a solution of 2.5% (w / v) mannitol, 2.5% (w / v) Kollidon® 25 and 0.3% (w / v) L-dopa was prepared in water and using a as described above A nozzle diameter of 100 ⁇ m was sprayed into the spray tower by means of a nozzle in cold air (-100 ° C.). After settling in a cooled vessel at the lower end of the spray tower, the frozen particles were collected on a sieve with a mesh size of 20 ⁇ m.
  • the frozen particles were collected in a vessel at the lower end of the spray tower, transferred to an Alpha 1-4 LSC Plus freeze dryer (Martin Christ, Germany) and placed under a vacuum of 0.1 mbar for 24 hours lyophilized.
  • L-dopa particles showed good sphericity and angle of repose.
  • Spray-freeze-dried pharmaceutical L-Dopa particles can release the active ingredient in the throat via the mucous membranes, which is of great advantage in particular for Parkison patients who suffer from swallowing problems.
  • Example 10 Spray-freeze-drying of acetylsalicylic acid (ASA) in tert-butanol Acetylsalicylic acid (ASA) was at room temperature with gentle stirring in tert. -Butanol dissolved at a concentration of 150 mg / ml. The spray tower was precooled to a temperature of -125 ° C. with liquid nitrogen. The ASA solution was sprayed through a nozzle (150 kPa, 30 kHz, nozzle diameter: 200 ⁇ m) into the precooled tower. The frozen particles were collected on a glass container and, after the spraying process was complete, transferred to a freeze dryer and dried. Freeze-drying took place under reduced pressure (0.01 bar) for 24 hours.
  • ASA acetylsalicylic acid
  • ASA tert-butanol
  • the particles obtained showed that active ingredients which are readily soluble in water, such as acetylsalicylic acid, can be spray-freeze-dried in high concentration even without auxiliaries.
  • Example 11 Spray-freeze-drying from a colloidal solution of nanoparticles
  • a colloidal solution of nanoparticles of the poorly soluble neurokinin-1 receptor antagonist aprepitant (Emend®, MSD) was produced.
  • an aqueous suspension of 2.0 g of aprepitant and 8 ml of water, which contained 0.12 g of hydroxypropylmethylcellulose and 0.12 g of sodium lauryl sulfate was ground in a vibrating mill (Retsch MM400) for 4 hours at 30 Hz.
  • the colloidal nano solution obtained contained particles with a particle size of 202 ⁇ 5 nm (Z-average, measured with PCS, Horiba SZ-100) and, after grinding, was used directly for the production of freeze-dried particles. To this end, trehalose was added as an anti-freeze agent.
  • the colloidal spray solution had a final composition of trehalose: aprepitant in a mixing ratio of 1: 1 and a solids content of 5, 10 or 20% (w / v) and was as described above using a nozzle diameter of 100 ⁇ m by means of a nozzle in cold air (- 100 ° C) sprayed into the spray tower. After settling in a cooled vessel at the lower end of the spray tower, the frozen particles were collected on a sieve with a mesh size of 20 ⁇ m.
  • the frozen particles were collected in a vessel at the lower end of the spray tower, transferred to an Alpha 1-4 LSC Plus freeze dryer (Martin Christ, Germany) and lyophilized for 24 hours at a vacuum of 0.1 mbar.
  • FIG. 12 shows the scanning electron microscope image of the spray-freeze-dried particles of sample Ap-2, magnified 200 times. As can be seen from Table 7 and FIG. 12, the particles showed a good angle of repose and a good sphericity. This shows that spray-freeze-dried pharmaceutical particles can also be produced from a colloidal solution of particles with a size in the nanometer range.
  • Example 12 Spray-freeze-drying from a solution of an active ingredient mixture
  • an extract of cannabidiol (CBD) and tetrahydrocannabinol (THC) was produced from the plant drug cannabis flos. Extraction was here in tert-butanol.
  • the plant drug cannabis flos was first heated in accordance with the general recommendations at 120 ° C for 30 minutes in a preheated oven in an amber glass container with a lid. After cooling, the plant drug was comminuted in a chopper and tert-butanol, in a ratio of 1 ml of tert-butanol to 0.1 g of plant drug, was added as an extraction solvent.
  • the suspension was treated in the closed amber glass for two cycles, one each lasting 30 minutes, in the ultrasonic bath, with a 30-minute break between the two cycles by one Avoid increasing the temperature of the suspension due to the energy of the ultrasound.
  • the plant material was separated off by centrifugation (4500 rpm); followed by a filtration to remove the finest particles (membrane filter 0.2 ⁇ m pore size).
  • Table 8 Parameters of the CBD / THC particles with 7% (m / V) Kollidon® 25 and 3% (m / V) extract:
  • FIG. 13 shows the scanning electron microscope image of a spray-freeze-dried particle of the sample CBD / THC-2, magnified 200 times.
  • the particles of the active substance mixture showed good sphericity and angle of repose. This shows that mixtures of active ingredients can also be produced from a solution in tert-butanol with good sphericity and flowability.

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Abstract

L'invention concerne un procédé de production de particules pharmaceutiques lyophilisées par pulvérisation, comprenant les étapes suivantes : a) fournir une solution comprenant au moins un principe actif pharmaceutique et un solvant, b) pulvériser la solution dans un environnement froid, par lequel des gouttelettes solidifiées sont obtenues, et c) éliminer le solvant par sublimation atmosphérique ou lyophilisation sous vide, par lequel des particules sphériques lyophilisées par pulvérisation sont obtenues. Dans l'étape a), le solvant est choisi parmi le tert-butanol, le diméthylsulfoxyde, l'eau et des mélanges de ceux-ci, et la solution a une teneur en matières solides se situant dans la plage allant de ≥ 1,5 % à ≤ 60 %, par rapport au volume total de la solution (m/V). A l'étape b), des gouttes ayant un diamètre moyen se situant dans la plage allant de ≥ 30 µm à ≤ 700 µm sont produites. Les gouttes sont pulvérisées dans un environnement ayant une température se situant dans la plage allant de ≥ -100 °C à ≤ 20° C.
PCT/EP2020/084241 2019-12-05 2020-12-02 Procédé de production de particules lyophilisées par pulvérisation, et particules ainsi produites WO2021110732A1 (fr)

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