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EP1778188A1 - Poudres sechees par pulverisation contenant au moins un derive de saccharose a liaison o en 1,4 et procedes de realisation associes - Google Patents

Poudres sechees par pulverisation contenant au moins un derive de saccharose a liaison o en 1,4 et procedes de realisation associes

Info

Publication number
EP1778188A1
EP1778188A1 EP05738129A EP05738129A EP1778188A1 EP 1778188 A1 EP1778188 A1 EP 1778188A1 EP 05738129 A EP05738129 A EP 05738129A EP 05738129 A EP05738129 A EP 05738129A EP 1778188 A1 EP1778188 A1 EP 1778188A1
Authority
EP
European Patent Office
Prior art keywords
spray
sucrose
powder
solution
dried powder
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Withdrawn
Application number
EP05738129A
Other languages
German (de)
English (en)
Inventor
Richard Fuhrherr
Stefan Bassarab
Karoline Bechtold-Peters
Wolfgang Friess
Patrick Garidel
Torsten Schultz-Fademrecht
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Boehringer Ingelheim Pharma GmbH and Co KG
Boehringer Ingelheim Pharmaceuticals Inc
Original Assignee
Boehringer Ingelheim Pharma GmbH and Co KG
Boehringer Ingelheim Pharmaceuticals Inc
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Boehringer Ingelheim Pharma GmbH and Co KG, Boehringer Ingelheim Pharmaceuticals Inc filed Critical Boehringer Ingelheim Pharma GmbH and Co KG
Publication of EP1778188A1 publication Critical patent/EP1778188A1/fr
Withdrawn legal-status Critical Current

Links

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
    • A61K9/14—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
    • 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
    • A61K39/00—Medicinal preparations containing antigens or antibodies
    • A61K39/395—Antibodies; Immunoglobulins; Immune serum, e.g. antilymphocytic serum
    • 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

Definitions

  • the invention relates to the use of novel oligosaccharides / oligosaccharide mixtures for the production and stabilization of pharmaceutical compositions, predominantly powders, which contain an active pharmaceutical ingredient.
  • the powders are preferably produced by spray drying or freeze drying.
  • the present invention relates in particular to corresponding antibody-containing powders and to processes for their preparation.
  • Active substances / active substance preparations formulated in aqueous solutions are sometimes subject to instabilities, which can lead to reduced effectiveness or bioactivity and increased toxicity or intolerance. This applies both to classic pharmaceuticals and to active substances containing peptides or proteins.
  • the stability of active pharmaceutical ingredients can be positively influenced by changing the structure (internal) or by adding suitable auxiliary substances (external).
  • auxiliaries can roughly be divided into the following classes: sugars and polyols, amino acids, amines, salts, polymers and surfactants.
  • Sugar and polyols are often used as non-specific stabilizers.
  • the stabilizing effect of biological agents is primarily attributed to "preferential exclusion" (Xie and Timasheff, 1997, Biophysical Chemistry, 64 (1-3), 25-43; Xie and Timasheff, 1997, Protein Science, 6 (1), 211-221; Timasheff, 1998, Advances in protein chemistry, 51, 355-432).
  • reducing sugars are mostly avoided with biological active substances.
  • Sucrose and trehalose are preferred as non-reducing sugars.
  • excipients examples include glucose, sorbitol, glycerol (Boctor and Mehta, 1992, Journal of Pharmacy and Pharmacology, 44 (7), 600-3; Timasheff, 1993, Annual review of biophysics and biomolecular structure, 22, 67-97; Chang et al., 1993, Pharmaceutical Research, 10 (10), 1478-83) and Mannitol (Hermann et al., 1996, Pharmaceutical Biotechnology, 9 (Formulation, Characterization, and Stability of Protein Drugs), 303-328; Chan et al., 1996, Pharmaceutical Research, 13 (5), 756-761). It is also known that a wide variety of polymers have a stabilizing effect on active pharmaceutical ingredients, predominantly on proteins, such as antibodies.
  • HSA Human serum albumin
  • HP-ß-CD hydroxypropyl- ⁇ -cyclodextrin
  • PVP polymer having hydroxypropyl- ⁇ -cyclodextrin
  • HES hydroxyethyl starch
  • amino acids can also be used for stabilization, alone or in combination with other auxiliaries.
  • auxiliaries Preferably be any suitable auxiliaries.
  • Amino acids used in protein stabilization For example, the addition of histidine, glycine, sodium aspartate (Na-Asp), glutamate and inhibits
  • Lysine hydrochloride (Lys-HCl) the aggregation of rhKGF in 10 mM
  • propylene glycol improves the structural stability of rhCNTF (Dix et al., 1995, Pharmaceutical Research (Supplement), 12, S97). Lysine and arginine increase the thermostability of IL-1 R (increase in Tm), whereas glycine and alanine have a destabilizing effect (Remmele et al., 1998, Pharmaceutical Research, 15 (2), 200-
  • the stability of active pharmaceutical ingredients can be increased by various drying processes. However, drying usually also takes place in the presence of auxiliaries which maintain the stability of the active ingredients and are said to improve the properties of the dry powder. A crucial factor in stabilization by drying is the immobilization of the active ingredient in an amorphous matrix.
  • the amorphous state has a high viscosity with low molecular mobility and low reactivity.
  • Advantageous auxiliaries must therefore be able to form an amorphous matrix with the highest possible glass transition temperature in which the active ingredient is embedded.
  • the choice of excipients therefore depends in particular on their stabilization capabilities.
  • factors such as the pharmaceutical acceptance of the excipient and its influence on particle formation, dispersibility and flow properties also play a decisive role, especially when it comes to spray drying processes.
  • Spray drying is a particularly suitable method for increasing the chemical and physical stability of peptide- / protein-like pharmaceutical active ingredients (Maa et al., 1998, Pharmaceutical Research, 15 (5), 768-775). Spray drying is increasingly being used particularly in the field of pulmonary therapy (US Pat. No. 5,626,874; US Pat. No. 5,972,388; Broadhead et al., 1994, J. Pharm. Pharr ⁇ acol., 46 (6), 458-467), since inhalation is also used in the treatment of systemic diseases is now an alternative (WO 99/07340).
  • the average particle size of the powders is in the range of 1-10 ⁇ m, preferably 1-7.5 ⁇ m, so that the particles can get into deeper sections of the lungs and thus into the bloodstream.
  • DE-A-17922 07 describes, by way of example, the production of corresponding spray drying particles.
  • auxiliary substances are sugars and their alcohols (eg trehalose, lactose, sucrose or mannitol) as well as various polymers (Maa et al., 1997, Pharm. Development and Technology, 2 (3), 213-223; Maa et al., 1998, supra; dissertation Adler, 1998, University of Er Weg; Costantino, et al., 1998, J. Pharm. Sei., 87 (11), 1406-1411).
  • the predominantly used auxiliary substances have various disadvantages.
  • the addition of trehalose and mannitol for example, worsens the flow properties of spray drying formulations (C. Bosquillon et al., 2001 Journal of Controlled Release, 70 (3), 329-339).
  • Mannitol also tends to recrystallize at a content of more than 20 percent by weight (Costantino et al., 1998, supra), whereby the stabilizing effects decrease dramatically. Lactose, a commonly used adjuvant, improves the flow properties of spray drying formulations (C. Bosquillon et al., 2001, supra), but is particularly problematic when formulating active substances containing peptides / proteins, because lactose due to its reducing properties destabilizing Maillard reactions can interact with peptides / proteins.
  • Protein agregates are characterized by a reduced or lack of biological activity and an increased antigenicity.
  • Lactosucrose and multiple sugars (oligosaccharides) called coupling sugars with the main components maltosyl sucrose and glucosyl sucrose are used in the food sector. They are used as fillers and dispersants in addition to sweeteners such as aspartame, as moderately sweet components in chewing gum, to stabilize against the crystallization of trehalose syrups or as so-called NDOs (non-digestible oligosaccharides).
  • An object of the invention was to provide new auxiliaries for the production of pharmaceutical preparations.
  • the corresponding preparations should include characterized by good long-term stability.
  • Another object of the present invention was to provide new auxiliaries for the production of dried pharmaceutical preparations.
  • the corresponding powder-like pharmaceutical preparations should be characterized by good long-term stability and, if possible, by ability to be shaken.
  • Another object of the present invention was to provide new auxiliaries for the preparation of pharmaceutical formulations containing peptide / protein, in particular for those which are produced by spray drying.
  • the corresponding peptide / protein-containing pharmaceutical preparations should in turn be distinguished by good long-term stability and, if possible, by ability to be shaken.
  • Another object of the present invention was to provide new auxiliaries for the formulation of therapeutic antibodies or antibody derivatives, in particular for those which result from spray drying.
  • the corresponding antibody-containing pharmaceutical preparations should in turn be distinguished by good long-term stability and, if possible, by ability to be shaken.
  • Another object of the present invention was to provide corresponding pharmaceutical preparations for inhalation application, be it in the form of a dry powder, a propellant aerosol or a propellant-free inhalation solution.
  • the present invention relates to spray-dried powders containing a pharmaceutical active ingredient and one or more 1,4 O-linked sucrose derivatives selected from the compounds: 1,4 O-linked D-gal sucrose (lactosucrose), 1,4 O-linked D -Glu-sucrose (glucosyl-sucrose), or 1, 4 O-linked Glu-Glu-sucrose (maltosyl-sucrose).
  • Preferred powders contain lactosucrose or a combination of glucosyl and maltosyl sucrose as sucrose derivatives, with lactosucrose being particularly preferred.
  • lactosucrose also means molecules with the following structural formula:
  • Glucosyl sucrose in the sense of the present invention is also understood to mean molecules with the following structural formula:
  • maltosyl sucrose also means molecules with the following structural formula:
  • the corresponding powders contain, in addition to the 1,4-linked sucrose derivative, one or more mono-, di- and / or polysaccharides, the additional use of mono- and / or di-saccharides in the Powder production is preferred.
  • powders from a combination of glucosyl and maltosyl sucrose have also proven to be according to the invention, preferably in combination with further mono-, di- and / or polysaccharides.
  • the active pharmaceutical ingredient is preferably a biological macromolecule, which can be a polypeptide or a protein, for example a growth factor, enzyme or antibody.
  • a biological macromolecule which can be a polypeptide or a protein, for example a growth factor, enzyme or antibody.
  • spray-dried powders with (a) a proportion of 25 to 99.99% (w / w), preferably 80 to 90% (w / w), of at least one 1,4-linked sucrose derivative or an a sugar mixture which contains at least one 1,4O-linked sucrose derivative, and (b) with a biological macromolecule as a pharmaceutical active ingredient, preferably in a concentration between 0.01 and 75% (w / w), in each case based on the Dry mass of the powder, the sum of the percentages by weight of sugar / sugar mixture and biological macromolecule not exceeding 100% (w / w).
  • the spray-dried powders according to the invention can contain further auxiliaries, such as amino acids, peptides, proteins or also other sugars .
  • Particularly advantageous are powders which, in addition to the 1,4O-linked sucrose derivative or a sugar mixture which contains at least one 1,4O-linked sucrose derivative and the pharmaceutical active ingredient, have at least one amino acid, a peptide, preferably a dipeptide or contain tri-peptide and / or a salt.
  • the present invention relates to spray-dried powders which, based on their dry matter (a), are at least between 25 and 90% (w / w) a 1,4 O-linked sucrose derivative or a sugar mixture containing at least one 1,4 O-linked sucrose derivative, (b) between 1 and 39.99% (w / w) of at least one amino acid and / or at least one peptide as a further auxiliary and (c) contain at least 0.01% (w / w) of an active pharmaceutical ingredient.
  • the further auxiliary is preferably the amino acid isoleucine or a di- or tri-peptide with at least one isoleucine residue.
  • the present invention relates to spray-dried powders which, in relation to their dry mass, contain a proportion of (a) approximately 60 to 80% (w / w) of at least one 1,4-linked sucrose derivative or a sugar mixture containing at least one , 4 O-linked sucrose derivative, (b) about 10 to 19.99% (w / w) of an amino acid, preferably isoleucine and (c) about 0.01 to 30% (w / w) of an active pharmaceutical ingredient, preferably of a peptide / protein, for example an antibody.
  • the present invention relates to spray-dried powders which, with respect to their dry weight (a), contain approximately 60 to 90% (w / w) of at least one 1,4O-linked sucrose derivative or a sugar mixture containing at least one 1 4 contains O-linked sucrose derivative, (b) about 1 to 19.99% (w / w) of an isoleucine-containing tri-peptide, preferably tri-isoleucine and (c) about 0.01 to 39% (w / w w) an active pharmaceutical ingredient, preferably a peptide / protein, for example an antibody.
  • the corresponding powders in particular after admixing an amino acid, preferably isoleucine, or a pptide, preferably isoleucine-containing tri-peptides, have very good flow properties and are distinguished by a very high proportion of inhalable particles.
  • the corresponding powders also have very good process and storage stability.
  • the present invention relates to spray-dried powders which a) one or more 1,4O-linked sucrose derivatives) or a sugar mixture containing at least one 1,4O-linked sucrose derivative and b) at least one pharmaceutical Contain active ingredient, the spray-dried powder above a glass transition temperature of greater than 40 ° C, preferably greater than 45 ° C, more preferably greater than 50 ° C, even further preferably greater than 55 ° C and particularly preferably greater than 60 ° C.
  • the corresponding powders according to the invention usually have a maximum glass transition temperature of approximately 96 to 110 ° C. In individual cases, however, the value can be even higher.
  • the proportion of the auxiliary added, in particular the proportion of 1,4-linked sucrose derivative or the proportion of the derivative mixture in the powder is primarily responsible for the corresponding glass transition temperature.
  • the present invention relates to pharmaceutical compositions for inhalation applications which contain or consist of, or are produced from, the powders according to the invention described here.
  • preferred pharmaceutical compositions are the powders according to the invention
  • the spray-dried powders according to the invention used to produce the pharmaceutical composition are distinguished by a high proportion of inhalable particles with a medium aerodynamic
  • MMAD Particle diameter
  • the invention further provides methods for producing the corresponding spray-dried powder according to the invention, characterized in that a solution or suspension which a) contains or contains at least one or more 1,4O-linked sucrose derivative (s) Sugar mixture and b) contains at least one active pharmaceutical ingredient, is produced and this is sprayed under suitable conditions.
  • the temperature for the spraying process is preferably between 50 and 200 ° C (inflow temperature) and 30 and 150 ° C (outflow temperature). Description of the pictures
  • 40 corresponds to a real volume flow of ⁇ 0.67 m 3 / h, 50 to a real volume flow of ⁇ 1.05 m 3 / h and 60 to a real volume flow of ⁇ 1.74 m 3 / h.
  • the atomization rate was 40, corresponding to a real volume flow of -0.67 m 3 / h.
  • Figure 1 shows the aggregate content after freeze-drying, pulverization, open storage for one week at 75% relative humidity and 40 ° C (forced storage stability) and reconstitution.
  • Aqueous solutions with a) 4.5% LS55P and 0.5% IgG, b) 4.5% Coupling Sugar and 0.5% IgG, freeze-dried, c) 5.0% IgG Portion and d) 4.5% mannitol portion and 0.5% IgG portion.
  • Both the LS55P and the Coupling Sugar-containing powders are characterized by a low proportion of aggregates.
  • Figure 2 shows the aggregate content after freeze drying, pulverization, equilibration, four weeks of dry storage at 40 ° C (equilibrated storage stability) and reconstitution.
  • Both the LS55P and the Coupling Sugar-containing powders are characterized by a low proportion of aggregates.
  • Figure 3 shows the aggregate content after freeze-drying, pulverization, vacuum drying, four weeks of dry storage at 40 ° C (vacuum-dried storage stability) and reconstitution.
  • Both the LS55P and the Coupling Sugar-containing powders are characterized by a low proportion of aggregates.
  • Figure 4 shows the aggregate content after spray drying, open storage for one week at 75% relative humidity and 40 ° C (forced storage stability) and reconstitution.
  • Aqueous solutions with a) 9% LS55P and 1% IgG, b) 9% Coupling Sugar and 1% IgG, c) 9% Coupling Sugar S and 1% IgG were spray dried.
  • Both the LS55P and the Coupling Sugar and Coupling Sugar S containing powders are characterized by a low proportion of aggregates.
  • Figure 5 shows the aggregate content after spray drying, open storage for one week at 75% relative humidity and 40 ° C (forced storage stability) and reconstitution.
  • Aqueous solutions with a) 8% LS55P, 1% isoleucine and 1% IgG, b) 8% coupling sugar, 1% isoleucine and 1% IgG, c) 8% were spray dried.
  • Both the LS55P and the Coupling Sugar and Coupling Sugar S containing powders are characterized by a low proportion of aggregates.
  • Figure 6 shows the aggregate content after spray drying, open storage for one week at 75% relative humidity and 40 ° C (forced storage stability) and reconstitution.
  • Aqueous solutions containing a) 3% LS55P, 6% citrulline and 1% IgG, b) 3% coupling sugar, 6% and 1% IgG, c) 3% coupling sugar were spray dried S portion, 6% citrulline portion and 1% IgG portion, d) 3% trehalose portion, 6% citrulline portion and 1% IgG portion, and e) 10% IgG portion.
  • Both the LS55P and the Coupling Sugar and Coupling Sugar S containing powders are characterized by a low proportion of aggregates.
  • Figure 7 shows the aggregate content after spray drying, open storage for one week at 75% relative humidity and 40 ° C (forced storage stability) and reconstitution.
  • Aqueous solutions were spray-dried with a) 9.9% LS55P content 0.1% IgG content, b) 9% LS55P content 1% IgG content, c) 6% LS55P content 4% IgG content, d) 4% LS55P portion 6% IgG portion, e) 2.5% LS55P portion 7.5% IgG portion, f) 1% LS55P portion 9% IgG portion g) 0.5% LS55P portion 9 , 5% IgG portion and h) 10% IgG portion.
  • the powders containing LS55P are characterized by a low proportion of aggregates.
  • Figure 8 shows the aggregate content after spray drying, open storage for one week at 75% relative humidity and 40 ° C (forced storage stability) and reconstitution.
  • Aqueous solutions with a) 9.9% Coupling Sugar content 0.1% IgG content, b) 9% Coupling Sugar content 1% IgG content, c) 6% Coupling Sugar content 4% IgG content were spray dried , d) 4% Coupling Sugar portion 6% IgG portion, e) 2.5% Coupling Sugar portion 7.5% IgG portion, f) 1% Coupling Sugar portion 9% IgG portion and g) 10 % IgG content.
  • Coupling sugar-containing powders are characterized by a low proportion of aggregates.
  • Figure 9 shows the aggregate content after spray drying, open storage for one week at 75% relative humidity and 40 ° C (forced storage stability) and reconstitution.
  • Aqueous solutions with a) 3.00% LS55P and 0.33% IgG, b) 2.9166% LS55P, 0.0833% tri-isoleucine and 0.33% IgG were spray-dried , c) 2.833% LS55P portion, 0.166% tri-isoleucine portion and 0.33% IgG portion and d) 2.66% LS55P portion, 0.33% tri-isoleucine portion. and 0.33% IgG content.
  • the powders containing LS55P are characterized by a low proportion of aggregates.
  • FIG. 10 shows the aggregate content, spray drying and open storage for one week at 75% relative humidity and 40 ° C (forced storage stability) and reconstitution.
  • Aqueous solutions with a) 3.00% LS90P and 0.33% IgG, b) 2.9166% LS90P, 0.0833% tri-isoleucine and 0.33% IgG were spray-dried , c) 2.833% LS90P component, 0.166% tri-isoleucine component and 0.33% IgG component and d) 2.66% LS90P component, 0.33% tri-isoleucine component. and 0.33% IgG content.
  • the powders containing LS90P are characterized by a low proportion of aggregates.
  • Figure 11 shows the aggregate content, spray drying and open storage for one week at 75% relative humidity and 40 ° C (forced storage stability) and reconstitution.
  • Aqueous solutions with a) 2.66% LS90P content, 0.33% tri-isoleucine content were spray-dried. and 0.33% IgG, b) 2.66% LS55P, 0.33% tri-isoleucine.
  • the powder containing LS90P and LS55P is characterized by a low proportion of aggregates. Especially when compared to the raffinose and hydroxyethyl starch (HES) listed in the prior art.
  • Figure 12 shows the aggregate content after spray drying, vacuum drying, four weeks' dry storage at 40 ° C (vacuum-dried storage stability) and reconstitution.
  • Aqueous solutions with a) 9% coupling sugar and 1% IgG, b) 8% coupling sugar, 1% (w /) isoleucine and 1% IgG, c) 3% coupling were spray dried Sugar content, 6% citrulline content and 1% IgG content and d) 10% IgG content
  • the powder containing coupling sugar is characterized by a low content of aggregates.
  • Figure 13 shows the aggregate content after spray drying, vacuum drying, four weeks' dry storage at 40 ° C (vacuum-dried storage stability) and reconstitution.
  • the powders containing LS55P are characterized by a low proportion of aggregates.
  • Figure 14a + b shows the aggregate content after spray drying, vacuum drying, three months' dry storage at 2-8 ° C, 25 ° C and 40 ° C (1 or 3 months stability) and reconstitution.
  • Aqueous solutions with a) 3.00% LS90P and 0.33% IgG and, b) 2.66% LS55P, 0.33% isoleucine and 0.33% IgG were spray dried.
  • Both the LS55P and the powder containing LS90P are characterized by a particularly low aggregate content after three months of storage.
  • Figure 15a + b shows the aggregate content after spray drying, open three-month storage at 29% relative humidity and 43% relative humidity at 25 ° C (open 1 or 3 months stability) and reconstitution.
  • Aqueous solutions were spray-dried with a) 2.9166% LS90P content, 0.0833% tri-isoleucine content and 0.33% IgG content at an AAF of 40, b) 2.833% LS90P content, 0.166% tri Isoleucine content and 0.33% IgG content with an AAF of 40, c) 2.66% LS90P content, 0.33% tri-isoleucine content and 0.33% IgG content with an AAF of 40, d) 1.60% LS90P content, 0.20% tri-isoleucine content and 0.33% IgG content with an AAF of 40, e) 2.66% LS90P content, 0.33% tri-isoleucine Portion and 0.33% IgG portion with an AAF of 50, f) 2.66% LS90
  • Figure 16 shows the fine particle fraction (FPF) with a cut-off diameter of less than 5 ⁇ m for various powders.
  • the powders were prepared by spray drying aqueous solutions which contained LS55P and IgGI or LS55P, isoleucine and IgGI. The solutions were prepared and sprayed as described in EXAMPLES. Powder containing isoleucine has an FPF of -35% while isoleucine-free powder has only one of FPF -16%.
  • Figure 17 shows the fine particle fraction (FPF) with a cut-off diameter of less than 5 ⁇ m for various powders.
  • the powders were produced by spray drying aqueous solutions which contained LS90P and IgGI or LS90P, isoleucine and IgGI. The solutions were prepared and sprayed as described in EXAMPLES. Powder containing isoleucine has an FPF of -28% while isoleucine-free powder has only one of FPF -23%.
  • Figure 18 shows the fine particle fraction (FPF) with a cut-off diameter smaller than 5 // m of various powders.
  • the powders were prepared by spray drying aqueous solutions which contained LS55P and IgGI or LS55P, tri-isoleucine and IgGI. The solutions were prepared and sprayed as described in EXAMPLES. Tri-isoleucine-containing powders have an FPF greater than 50% or 58%, while tri-isoleucine-free powders only have an FPF of -16%.
  • Figure 19 shows the Mass Mean Aerodynamic Diameter (MMAD) and Mass Mean Diameter (MMD) of different powders.
  • the powders were prepared by spray drying aqueous solutions which contained LS55P and IgGI or LS55P, tri-isoleucine and IgGI. The solutions were prepared and sprayed as described in EXAMPLES. All powders have an MMAD of less than 5 ⁇ m and an MMD of less than 3.5 ⁇ m.
  • the diagram shows the influence of the tri-isoleucine content on the at constant total solids concentrations and spray parameters MMAD and MMD. A 10% tri-isoleucine content based on the total solids content of the formulation significantly reduces the MMAD.
  • Figure 20 shows the fine particle fraction (FPF) with a cut-off diameter of less than 5 ⁇ of different powders.
  • the powders were prepared by spray drying aqueous solutions which contained LS90P and IgGI or LS90P, tri-isoleucine and IgGI. The solutions were prepared and sprayed as described in EXAMPLES. Tri-isoleucine containing powders have an FPF of -40% to -59% while tri-isoleucine free powders only have an FPF of -24%.
  • Figure 21 shows the Mass Mean Diameter (MMD) and Mass Mean Aerodynamic Diameter (MMAD) of different powders.
  • the powders were prepared by spray drying aqueous solutions which contained LS90P and IgGI or LS90P, tri-isoleucine and IgGI. The solutions were prepared and sprayed as described in EXAMPLES. All powders have an MMAD of less than 6.5 ⁇ m and an MMD of less than 5 m.
  • the diagram shows the influence of the tri-isoleucine content with constant total solids concentrations and spray parameters on the MMAD and MMD.
  • a 10% tri-isoleucine content based on the total solids content of the formulation significantly reduces the MMAD compared to 2.5% and 5% tri-isoleucine content.
  • a lower solids content (e.g. TS: 2%) and a higher spray pressure (AAF 50 or 60) significantly reduce the MMAD and MMD.
  • Figure 22 shows the residual monomer content after spray drying, forced storage and reconstitution.
  • Aqueous solutions were sprayed with a) 3.33% (w / w) lysozyme content, b) 0.33% (w / w) lysozyme and 3.0% LS90P content, c) 0.33% (w / w) Lysozyme, 0.33% (w / w) isoleucine and 2.66% (w / w) LS90P and d) 0.33% (w / w) lysozyme, 0.33% ( w / w) tri-isoleucine and 2.66% (w / w) LS90P content.
  • the powder containing LS90P is characterized by a high residual monomer content.
  • Figure 23 shows the aggregate content after spray drying, vacuum drying, three months' dry storage at 2-8 ° C, 25 ° C and 40 ° C (3 months stability) and Reconstitution.
  • Aqueous solutions were sprayed with a) 3.33% (w / w) calcitonin, b) 0.166% (w / w) calcitonin and 3.166% LS90P, c) 0.166% (w / w) calcitonin, 0.33% (w / w) isoleucine and 2.833% (w / w) LS90P content and e) 0.166% (w / w) calcitonin, 0.33% (w / w) tri-isoleucine and 2.833 % (w / w) LS90P share.
  • the powder containing LS90P is characterized by a low aggregate content.
  • Figure 24 shows an inhaler for the inhalation application of dry powder preparations.
  • 1, 4 O-linked sucrose derivative or a sugar mixture containing at least one 1, 4 O-linked sucrose derivative means i) a 1, 4 O-linked sucrose derivative, preferably with one of those specified in this patent Formula, ii) a mixture of these, preferably a mixture of maltosyl and glucosyl sucrose, iii) a mixture of at least one 1,4-linked sucrose derivative with one of the above-mentioned formula and further sugars, preferably a mixture of lactosucrose, Lactose and sucrose, or from glucosyl and / or maltosyl sucrose, sucrose, fructose and glucose, iv) a mixture of at least 55% (w / w) lactosucrose, maximum 25% (w / w) lactose and maximum 10% ( w / w) sucrose v) a mixture of at least 88% (w / w) lactosucrose, a maximum of 10% (w / w
  • powder formulation or "dry powder formulation” means powder formulations which usually have less than about 10% (w / w) residual moisture, preferably less than 7% (w / w) residual moisture, particularly preferably less than 5% ( w / w) residual moisture and even more preferably less than 3% (w / w) residual moisture.
  • the residual moisture essentially depends on the type and proportion of the active pharmaceutical ingredient in the powder formulation.
  • amorphous means that the powdered formulation contains less than 10% crystalline components, preferably less than 7%, more preferably less than 5%, in particular less than 4, 3, 2 or 1%.
  • inhalable means that the powders are suitable for pulmonary application. Inhalable powders can be dispersed and inhaled with the aid of an inhalation device, so that the particles reach the lungs and, if necessary, have a systemic effect via the alveoli.
  • MMD mass median diameter
  • Mass median diameter is a measurement for the average particle size distribution, since the powders of the invention are generally polydisperse. The results are expressed as the diameter of the volume total distribution at 50% total volume.
  • the MMD values can be determined, for example, using laser diffractometry (cf. chapter: EXAMPLES, method), whereby of course any other conventional method can also be used (eg electron microscopy, centrifugal sedimentation).
  • MMAD mass median aerodynamic diameter
  • fine particle fraction describes the inhalable part of a powder consisting of particles with a particle size of 5 5 ⁇ m MMAD.
  • the FPF is more than 20%, preferably more than 30%, particularly preferably more than 40% , even more preferably more than 50%, even more preferably more than 55%.
  • cut-off diamenter used in this context indicates which particles are taken into account when determining the FPF.
  • An FPF of 30% with a cut-off diameter of 5 ⁇ m (FPF 5 ) means that at least 30% of all particles in the powder have an average aerodynamic particle diameter of less than 5 m.
  • spray solution means aqueous solutions or suspensions in which the active pharmaceutical ingredient is dissolved / suspended together with at least one auxiliary.
  • time of flight is the designation for a standard measurement method as described in more detail in the chapter EXAMPLES. In the case of a time of flight measurement, the MMAD and FPF are determined simultaneously (see also: chapter EXAMPLES, method).
  • pharmaceutically acceptable excipients “carrier material” or “matrices” refers to excipients that may optionally be included in the formulation within the scope of the invention. The excipients can, for example, be applied pulmonally without any significant adverse toxicological effects on the test subjects or to have the subject's lung.
  • salts from inorganic acids such as chloride, sulfate, phosphate, diphosphate, bromide and nitrate salts.
  • salts from organic acids such as malate, maleate, Fumarate, tartrate, succinate, ethyl succinate, citrate, acetate, lactate, methanesulfonate, benzoate, ascorbate, para-toluenesulfonate, palmoate, salicylate and stearate, as well as estolate, gluceptate and lactobionate salts.
  • pharmaceutically acceptable cations includes, but is not limited to, lithium, sodium, potassium, calcium, aluminum and ammonium (including substituted ammonium).
  • polysaccharide or “oligosaccharide” means multiple sugar from at least three sugar residues.
  • a “pharmaceutical active substance” is to be understood as a substance, a medicament, a composition or a combination thereof, which has a pharmacological, mostly positive, effect on an organism, an organ and / or a cell, if the active substance with the organism , Organ or cell is brought in. Introduced into a patient, the effect can be local or systemic.
  • biological macromolecule means peptides, proteins, fats, fatty acids, or also nucleic acids.
  • peptide or “polypeptide” means polymers of amino acids consisting of two to one hundred amino acid residues.
  • the term peptide or polypeptide is used as a pseudonym and encompasses both homopeptides 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” is composed of three peptide-linked amino acids.
  • protein used here means polymers of amino acids with more than 100 amino acid residues.
  • analogs denotes peptides / proteins in which single or more amino acids have been substituted, eliminated (for example fragments), added (for example derivatives with a C- or N-terminal extension) or otherwise modified by the native (wild-type) sequence it is also possible to derivatize the native protein, for example by sugar, polyethylene glycol, etc.
  • Analogs have a bioactivity of at least 10, 20, 30 or 40%, preferably at least 50, 60 or 70% and particularly preferably at least 80, 90, 95 100% or more than 100% bioactivity of the native, non-synthetic protein.
  • 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 to the carboxyl group, any other arrangement in the molecule is also conceivable.
  • the amino acid can also contain other functional groups, such as amino , Carboxamide, carboxyl, imidazole, thio groups and other groups, using amino acids of natural or synthetic origin, racemic or optically active (D- or L-) including various stereoisomeric ratios.
  • isoleucine includes both D- Isoleucine, L-isoleucine, racemic isoleucine and different ratios of the two enantiomers.
  • pure or pure protein formulation means spray-dried powder consisting of one or more proteins and optionally a suitable buffer (typically from 0 to 15% (w / w) based on the weight of the dry powder).
  • the powder generally contains no other auxiliary substances, ie the content of any further auxiliary substances is less than 1% (w / w) based on the weight of the dry powder.
  • a "surface-active" substance is able to lower the surface tension of the solution in which it is dissolved.
  • the surface activity is measured, for example, by the tensiometer method according to Lecomte du Noüy (Bauer, Frömming,
  • the present invention relates to spray-dried powders containing a pharmaceutical active ingredient and one or more 1,4 O-linked sucrose derivatives) selected from the compounds: 1,4 O linked D-gal sucrose (lactosucrose), 1,4 O-linked D-Glu-sucrose (glucosyl sucrose), or 1, 4 O-linked Glu-Glu-sucrose (maltosyl sucrose).
  • the corresponding powders contain, in addition to the 1,4-linked sucrose derivative, one or more mono-, di- and / or polysaccharides, the additional use of mono- and / or di-saccharides in the Powder production is preferred.
  • the invention consequently also includes corresponding powders with lactosucrose, lactose and sucrose, the proportion of lactosucrose in relation to the total sugar content in the powder being ⁇ 40% (w / w), preferably ⁇ 55% (w / w), and also> 88 % (w / w) is.
  • powders of the invention in addition to the pharmaceutical active include a as Nyuka- oligo ® LS55P, or shortly LS55P, called sugar mixture Company Hayashibara Shoji, Inc., Japan, at least 55% lactosucrose, maximum 25% (w / w) Lactose and a maximum of 10% (w / w) sucrose.
  • powders of the invention in addition to the pharmaceutical active include a as Nyuka Oligo ® LS90P, or shortly LS90P, called sugar mixture Company Hayashibara Shoji, Inc., Japan, at least 88% (w / w) lactosucrose and a maximum of 10% (w / w) contains lactose and sucrose.
  • powders from a combination of glucosyl and maltosyl sucrose have also proven to be according to the invention, preferably again in combination with other mono-, di- and / or polysaccharides.
  • the present invention also includes corresponding powders which contain a mixture of glucosyl and maltosyl sucrose, sucrose, glucose and / or fructose, the proportion of glucosyl and maltosyl sucrose preferably being 25% of the total sugar content in the powder. (w / w) or more. According to a further preferred embodiment, the respective proportion of glucosyl and maltosyl sucrose is at least 18% (w / w) of the total sugar proportion of the powder.
  • the spray-dried powders according to the invention contain, in addition to the pharmaceutical active ingredient, a sugar mixture from the company Hayashibara Shoji, Inc., Japan called Coupling Sugar®, each containing at least 18% (w / w) glucosyl and maltosyl sucrose, between 11 and Contains 15% (w / w) sucrose and between 5 and 9% (w / w) glucose and fructose.
  • the present invention also relates to those spray-dried powders which, in addition to the pharmaceutical active ingredient, contain a sugar mixture from the company Hayashibara Shoji, Inc., Japan, which is referred to as Coupling Sugar S® and which contain at least 25% (w / w) glucosyl and / or maltosyl Sucrose, contains between 48 and 56% (w / w) sucrose and no more than 10% (w / w) glucose and fructose.
  • a sugar mixture from the company Hayashibara Shoji, Inc., Japan which is referred to as Coupling Sugar S® and which contain at least 25% (w / w) glucosyl and / or maltosyl Sucrose, contains between 48 and 56% (w / w) sucrose and no more than 10% (w / w) glucose and fructose.
  • Spray-dried powders whose proportion of 1,4-linked sucrose derivative or of a sugar mixture containing at least one 1,4-linked sucrose derivative, with respect to the dry mass of the powder, between 25 and 99, have proven to be particularly advantageous.
  • the proportion of 1,4 O-linked sucrose derivative or of a sugar mixture containing at least one 1,4 O-linked sucrose derivative should be chosen so that the spray-dried powder is at least partially amorphous, preferably completely amorphous.
  • the proportion of 1, 4 O-linked sucrose derivative or in a sugar mixture containing at least one 1, 4 O-linked sucrose derivative can also be reduced below 60% (w / w).
  • further stabilizing auxiliaries are preferably added to the powders in a suitable amount. Examples of other stabilizing auxiliaries can be found elsewhere in this patent.
  • the proportion of active pharmaceutical ingredient in the dry mass of the powders according to the invention is generally between 0.01 and 75% (w / w), preferably between 0.33 and 50% (w / w), more preferably between 0.33 and 45 % (w / w), more preferably between 0.33 and 40% (w / w).
  • the proportion of the active pharmaceutical ingredient in the solids content of the powder according to the invention is between 0.33 and 35% (w / w), preferably between 0.33 and 30% (w / w), more preferably between 0.33 and 25% (w / w) and even more preferably between 0.33 and 10% (w / w).
  • the proportion is thus, for example, 0.01, 0.02, 0.03 ...
  • powders with a ratio of 1,4 O-linked sucrose derivative or a sugar mixture containing at least one 1,4 O-linked sucrose derivative to active ingredient of, for example, 25/75, 26/74, 27/73, 28 / 72, 29/71, 30/70, 31/69, 32/68, 33/67, 34/66, 35/65, 36/64, 37/63, 38/62, 39/61, 40/60, 41/59, 42/58, 43/57, 44/56, 45/55, 46/54, 47/53, 48/52, 49/51, 50/50, 51/49, 52/48, 53 / 47, 54/46, 55/45, 56/44, 57/43, 58/42, 59/41, 60/40, 61/39, 62/38, 63/37, 64/36, 65/35, 66/34, 67/33, 68/32, 69/31, 70/30, 71/29, 72/28,
  • the proportion of the 1,4O-linked sucrose derivative or the sugar mixture containing at least one 1,4O-linked sucrose derivative, the proportion of active pharmaceutical ingredient, or both Shares are reduced accordingly, the proportion of the 1,4 O-linked sucrose derivative or the sugar mixture containing at least one 1,4 O-linked sucrose derivative, based on the dry mass of the powder, preferably one of the values between 80 and 90% (w / w).
  • antibiotics include antibiotics, anti-viral active ingredients, anepileptics, pain relievers (analgesics), anti-inflammatory active ingredients or bronchodilators.
  • antibiotics include antibiotics, anti-viral active ingredients, anepileptics, pain relievers (analgesics), anti-inflammatory active ingredients or bronchodilators.
  • active ingredients that target the peripheral nervous system, adrenergic receptors, cholinergic receptors, skeletal muscles, the cardiovascular system, smooth muscles, the blood circulating system, synaptic sites, neuroeffectoral junctions, the endocrine system, the immune system, etc. reproductive system, the skeletal system, the autacoid systems, the alimentary and excretory systems, the histamine system and the central nervous system.
  • Suitable active substances also include, for example, hypnotics and sedatives, psychic energizers, tranquilizers, anti-convulsants, muscle relaxants, anti-parkinsonian substances, pain relievers, anti-inflammatory substances, muscle contractants, anti-microbial substances, hormonal substances, such as contraceptives, sympathomimetics, diuretics, Active substances regulating fat metabolism, anti-androgenic substances, antiparasitic, neoplastic, antineoplastic and hypoglycemic.
  • the term pharmaceutical active ingredient also includes, for example, active ingredients that target the respiratory system, for example against one of the following Diseases have an effect: asthma, chronic obstructive pulmonary diseases (COPD), emphysemic chronic bronchitis, bronchopulmonary dysplasia (BPD), neonatal respiratory distress syndrome (RDS), bronchiolitis, Krupp, post-extubation stridor, pulmonary fibrosis, pneumonia or cystic fibrosis ,
  • COPD chronic obstructive pulmonary diseases
  • BPD emphysemic chronic bronchitis
  • BPD bronchopulmonary dysplasia
  • RDS neonatal respiratory distress syndrome
  • bronchiolitis Krupp, post-extubation stridor, pulmonary fibrosis, pneumonia or cystic fibrosis ,
  • bronchodilators include, among other beta agonists, anticholinergics or methylxanthines.
  • anti-inflammatory agents are steroids, cromolyn, nedokromil and leukotriene inhibitors.
  • steroids include beclomethasone, betamethasone, biclomethasone, dexamethasone, triamcinolone, budesonide, butixocort, ciclesonide, flutikasone, flunisolide, lcomethasone, mometasone, tixocortol, and loteprednol.
  • Other examples are budesonide, fluticasone propionate, beclomethasone dipropionate, fometerol and triamcinolone acetonide.
  • anti-microbial active ingredients are erythromycin, oleandomycin, troleandomycin, roxithromycin, clarithromycin, davercin, azithromycin, flurithromycin, dirithromycin, josamycin, spiromycin, midecamycin, leucomycin, miocamycin, andolitomycin, andokitamycin, andokitamycin, Fluoroquinolones, for example, ciprofloxacin, ofloxacin, levofloxacin, trovafloxacin, alatrofloxacin, Moxifioxicin, norfloxacin, Eoxacin, grepafloxacin, gatifloxacin, lomefloxacin, sparfloxacin, temafloxacin, pefloxacin, amifloxacin, fleroxacin, tosufloxacin, prulifloxacin, Irloxacin, Pazufloxacin, clinafloxacin and
  • the pharmaceutical active ingredient is a biological macromolecule. According to the definition given above, this includes, for example, peptides, proteins, fats, fatty acids or nucleic acids.
  • Biopharmaceutical proteins / polypeptides include e.g. Antibodies, enzymes, growth factors e.g. Steroids, cytokines, lymphokines, adhesion molecules, receptors and their derivatives or fragments are, however, not restricted to these. In general, all polypeptides that act as agonists or antagonists and / or can find therapeutic or diagnostic use are significant.
  • Suitable peptides or proteins in the sense of the invention are, for example, 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.
  • IL interleukins
  • IFN interferon
  • TNF tumor necrosis factor
  • antibodies and fragments thereof are monocional, polyclonal, multispecific and single-chain (single chain) antibodies and fragments thereof, such as 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, Antibody Fusion Proteins, Wiley-Liss Inc.).
  • the antibodies can be of human or non-human origin.
  • IgA, IgD, IgE, IgG and IgM are also suitable.
  • various surface antigens such as CD4, CD20 or CD44, various cytokines, for example IL2, IL4 or IL5.
  • Other examples are antibodies against certain immunoglobulin classes (eg anti-IgE antibodies) or against viral proteins (eg anti-RSV, anti-CMV antibodies, etc.).
  • Fab fragments consist of the variable regions of both chains, which are held together by the adjacent constant regions.
  • Other antibody fragments are F (ab ') 2 fragments, which can be produced by proteolytic digestion with pepsin.
  • Such antibody fragments are also referred to as a single-chain Fv fragment (scFv). Examples of scFv antibodies are known and described, see for example Huston et al., 1988, Proc. Natl. Acad. Be. USA, 16, 5879ff.
  • scFv derivatives such as slide, tri and pentabodies.
  • a person skilled in the art refers to a bivalent homodimeric scFv derivative as “diabody”.
  • the shortening of the peptide linker in the scFv molecule to 5-10 amino acids results in the formation of homodimers by superposition of VH / VL chains.
  • the diabodies can additionally be stabilized by introduced disulfide bridges Examples of diabodies can be found in the literature, for example in Perisic et al., 1994 (Structure, 2, 1217ff).
  • the person skilled in the art refers to a bivalent, homodimeric scFv derivative as “minibody”.
  • fusion protein which contains the CH3 region of an immunoglobulin, preferably IgG, particularly preferably IgGI, as the dimerization region. This connects the scFv fragments via a hinge region, also from IgG, and a linker region.
  • IgG immunoglobulin
  • IgGI immunoglobulin-like region
  • the fragments which the person skilled in the art calls mini-antibodies and which have a bi-, tri-or tetravalent structure are also derivatives of scFv fragments.
  • the multimerization is achieved via di-, tri- or tetrameric “coiled coil” structures (Pack, P. et al., 1993, Biotechnology, 11, 1271ff; Lovejoy, B. et al., 1993, Science, 259, 1288ff; Pack, P. et al., 1995, J. Mol. Biol., 246, 28ff).
  • a particularly preferred embodiment of the invention comprises a protein from the class of antibodies, more precisely type 1 immunoglobulin G. It is a humanized monoclonal antibody with 95% human and 5% murine antibody sequences. The antibody has a molecular weight of approx. 148 kilodaltons (kDa), consisting of two light and two heavy chains and a total of four disulfide bridges.
  • kDa kilodaltons
  • Spray-dried powders which contain a peptide or protein or a combination of peptide / peptide, peptide / protein or protein / protein as an active ingredient are particularly advantageous.
  • the corresponding biological macromolecules can make up between 0.01 and 75% (w / w), preferably between 0.01 and 50% (w / w) of the dry mass of the powder.
  • the proportion is therefore, for example, 0.01, 0.02, 0.03 ... 0.08, 0.09, 0.1, 0.2, 0.3 ... 0.8, 0.9 etc. ; 1, 2, 3, ... 8, 9, 10 etc .; 11, 12, 13, ... 18, 19, 20 etc .; 21, 22, 23, ... 28, 29, 30 etc .; 31, 32, 33, ...
  • Powders preferably spray-dried powders, having a ratio of 1,4 O-linked sucrose derivative or a sugar mixture containing at least one 1,4 O-linked sucrose derivative to peptide / protein of 25/75, 26 are particularly advantageous and according to the invention / 74, 27/73, 28/72, 29/71, 30/70, 31/69, 32/68, 33/67, 34/66, 35/65, 36/64, 37/63, 38/62 , 39/61, 40/60, 41/59, 42/58, 43/57, 44/56, 45/55, 46/54, 47/53, 48/52, 49/51, 50/50, 51 / 49, 52/48, 53/47, 54/46, 55/45, 56/44, 57/43, 58/42, 59/41, 60/40, 61/39, 62/38, 63/37 , 64/36, 65/35, 66/34, 67/33, 68/32, 69/31, 70
  • the proportion of 1,4O-linked sucrose derivative or the sugar mixture containing at least one 1,4O-linked sucrose derivative, the proportion of active pharmaceutical ingredient, or both portions are reduced accordingly, the proportion of 1,4 O-linked sucrose derivative or the sugar mixture containing at least one 1,4 O-linked sucrose derivative, preferably having a value between 80 and 90% (w / w).
  • the proportion is preferably between 0.1 and 10% (w / w), more preferably between 0.2 to 5% (w / w) of the total weight of the powder. Accordingly, powders are preferred, their proportion of cytokines 0.2, 0.3, 0.4 ... 0.8, 0.9, etc .; 1, 2, 3, ... etc; 4.1, 4.2, 4.3, ... 4.8, 4.9 etc .; 4.91, 4.92, 4.93, ... 4.98, 4.99% (w / w).
  • the active pharmaceutical ingredient is one or more antibodies or a derivative thereof (preferred embodiment)
  • the active ingredient content in the solids content of the powder is between 0.01 and 75% (w / w), preferably between 0.1 and 50 % (w / w), more preferably between 0.33 and 50% (w / w), for example 0.1, 0.2, 0.3, 0.33, ... 0.66, 0.7, 0.8, 0.9 etc .; 1, 2, 3, ... 8, 9, 10 Etc; 11, 12, 13, ... 18, 19, 20 etc .; 21, 22, 23, ... 28, 29, 30 etc .; 31, 32, 33, ... 38, 39, 40 etc .; 41, 42, 43, ... 48, 49, etc; 49.1, 49.2, 49.3, ... 49.8, 49.9 etc .; 49.91, 49.92, 49.93, ... 49.98, 49.99, 50% (w / w).
  • the antibody content of the solid content of the powder is between 10 and 50% (w / w), more preferably between 10 and 30% (w / w), even more preferably between 10 and 20% (w / w).
  • Particularly advantageous and according to the invention are powders, preferably spray-dried powders, with a ratio of 1,4 O-linked sucrose derivative or a sugar mixture containing at least one 1,4 O-linked sucrose derivative to antibodies of 50/50, 51/49 , 52/48, 53/47, 54/46, 55/45, 56/44, 57/43, 58/42, 59/41, 60/40, 61/39, 62/38, 63/37, 64 / 36, 65/35, 66/34, 67/33, 68/32, 69/31, 70/30, 71/29, 72/28, 73/27, 74/26, 75/25, 76/24 , 77/23, 78/22, 79/21, 80/20
  • the present invention relates to spray-dried powder, characterized in that the dry mass of the spray-dried powder is at least 25% (w / w), preferably between 50 and 99.99% (w / w), particularly preferably between 60 and 90% ( w / w) sugar containing at least one 1,4-0 linked sucrose derivative and up to 75% (w / w) of a pharmaceutical active ingredient, the proportion of lactosucrose, maltosyl sucrose and / or glucosyl sucrose at least 20 % (w / w) in relation to the dry mass of the powder and the sum of the weight percent is a maximum of 100% (w / w).
  • a person skilled in the art is able to prepare corresponding powders.
  • a person skilled in the art knows that, based on the total solids content of a solution to be sprayed, a maximum of 10% (w / w) of an active pharmaceutical ingredient can be added if the proportion of 1, 4 O-linked sucrose derivative or a sugar mixture containing at least 1, 4 O-linked sucrose derivative should be 90% (w / w).
  • the powders according to the invention can also contain other auxiliaries, such as amino acids, peptides, non-biological or biological polymers, and / or contain one or more sugars.
  • Further auxiliaries known in the prior art are, for example, lipids, fatty acids, fatty acid esters, steroids (eg cholesterol) or chelating agents (eg EDTA) and various cations (see above).
  • Auxiliaries with a high glass transition temperature for example greater than 40 ° C., preferably greater than 45 ° C., or greater than 55 ° C. are particularly preferred.
  • a list of suitable excipients can be found, for example, in Kippe (Eds.), "Handbook of Pharmaceutical Excipients" 3rd Ed., 2000.
  • Suitable protein-containing adjuvants are, for example, albumin (human or recombinant origin), gelatin, casein, hemoglobin and the like.
  • the sugars are preferably a mono-, di-, oligo- or polysaccharide or a combination thereof. Examples of simple sugar are fructose, maltose, galactose, glucose, D-mannose, sorbose and the like.
  • Suitable double sugars for the purposes of the invention are, for example, lactose, sucrose, trehalose, cellobiose, and the like.
  • raffinose, melezitose, dextrin, starch and the like are particularly suitable.
  • mannitol As sugar alcohols, mannitol, xylitol, maltitol, galactitol, arabinitol, adonitol, lactitol, sorbitol (glucitol), pyranosylsorbitol, inositol, myoinositol and the like can be considered as auxiliary substances.
  • Those amino acids are preferably used which act as a buffer (for example glycine or histidine) and / or as a dispersing agent.
  • the last groups mainly include hydrophobic amino acids such as leucine, valine, isoleucine, tryptophan, alanine, methionine, phenylalanine, tyrosine, histidine or proline.
  • isoleucine in addition to the 1,4O-linked sucrose derivative or a sugar mixture containing at least one 1,4O-linked sucrose derivative has proven to be advantageous, preferably in a concentration of 1 to 19.99% (w / w), particularly preferably from 5 to 19.99% (w / w), even more preferably from 10 to 19.99% (w / w).
  • the proportion of can also be increased to values up to 40% (w / w), provided that The proportion of the 1,4 O-linked sucrose derivative or a sugar mixture containing at least one 1,4 O-linked sucrose derivative or the proportion of active pharmaceutical ingredient is reduced accordingly, so that the solids content of the powder is at most 100% (w / w ) results.
  • di-, tri-, oligo-, or polypeptides as a further auxiliary which contain one or more of these predominantly hydrophobic amino acid residues is also particularly advantageous.
  • Particularly preferred are peptides with up to 20 amino acids, more preferably with up to 15 amino acids, even more preferably with up to 12 amino acids, even more preferably with up to 11 amino acids, even more preferably with up to 10 amino acids, even more preferably with up up to 9 amino acids even more preferably with up to 8 amino acids, even more preferably with up to 7 amino acids, even more preferably with up to 7, 6, 5, 4 or 3 amino acids.
  • the peptides used for stabilization do not correspond to the active pharmaceutical ingredient at the same time.
  • tri-peptides include, for example, one or more of the following tri-peptides: Leu-Leu-Gly, Leu-Leu-Ala, Leu-Leu-Val, Leu-Leu-Leu, Leu-Leu-Met, Leu-Leu -Pro, Leu-Leu-Phe, Leu-Leu-Trp, Leu-Leu-Ser, Leu-Leu-Thr, Leu-Leu-Cys, Leu-Leu-Tyr, Leu-Leu-Asp, Leu-Leu-Glu , Leu-Leu-Lys, Leu-Leu-Arg, Leu-Leu-His, Leu-Gly-Leu, Leu-Ala-Leu, Leu-Val-Leu, Leu-Met-Leu, Leu-Pro-Leu, Leu - Phe-Leu, Leu-Trp-Leu, Leu-Ser-Leu, Leu-Thr
  • tri-peptides of the general formulas: III-X-X; X-Ile-X; XX-Ile proven, where X can be one of the following amino acids: alanine, glycine, arginine, histidine, glutamic acid, glutamine, asparagine, aspartic acid, cysteine, leucine, lysine, isoleucine (Ile), valine, tryptophan, methionine, phenylalanine, proline , Serine, threonine, tyrosine, L-aspartyl-L-phenylalanine methyl ester ( aspartame), trimethylammonioacetate.
  • X can be one of the following amino acids: alanine, glycine, arginine, histidine, glutamic acid, glutamine, asparagine, aspartic acid, cysteine, leucine, lysine, isoleucine (Ile), valine, tryptophan
  • Corresponding tri-peptides of the formula (Ile) 2 -X are particularly preferred, for example Ile-Ile-X, Ile-X-Ile, or X-Ile-Ile, where X in turn can be one of the amino acids listed above.
  • Suitable polymers include, for example, the polyvinylpyrrolidones already mentioned above as auxiliaries, derivatized celluloses, such as Hydroxymethyl, hydroxyethyl or hydroxypropyl ethyl cellulose, polymeric sugars such as e.g. Fiscoll, särke such as Hydroxyethyl or hydroxypropyl starch, dextrins such as e.g. Cyclodextrins (2-hydroxypropyl-ß-cyclodextrin, sulfobutyl ether-ß-cyclodextrin), polyethylenes, glycols and / or pectins.
  • derivatized celluloses such as Hydroxymethyl, hydroxyethyl or hydroxypropyl ethyl cellulose
  • polymeric sugars such as e.g. Fiscoll, särke such as Hydroxyethyl or hydroxypropyl starch
  • dextrins such as e.g
  • the salts are, for example, inorganic salts such as chlorides, sulfates, phosphates, di-phosphates, hydrobromides and / or nitrate salts.
  • the powders according to the invention can also contain organic salts, such as e.g.
  • Lactates methanesulfonates, benzoates, ascorbates, paratoluenesulfonates, palmoates,
  • Salicylates can be stearates, estolates, gluceptates or lactobionate salts.
  • corresponding salts can be pharmaceutically acceptable cations, such as
  • the present invention relates to spray-dried powders which, in addition to the 1,4O-linked sucrose derivative or a sugar mixture containing at least one 1,4O-linked sucrose derivative and the active pharmaceutical ingredient, contain a pharmaceutically acceptable salt.
  • the present invention thus also relates to spray-dried powders which, in addition to the 1,4-linked sucrose derivative or a sugar mixture containing at least one 1,4-linked sucrose derivative, and the pharmaceutical Active ingredient contain one or more pharmaceutically acceptable excipients and / or one or more salts.
  • the present invention relates to spray-dried powders which, in addition to the 1,4O-linked sucrose derivative or a sugar mixture containing at least one 1,4O-linked sucrose derivative, and the pharmaceutical active ingredient comprise one or more amino acid (s) , preferably an amino acid, as a further auxiliary.
  • the pharmaceutical active ingredient comprise one or more amino acid (s) , preferably an amino acid, as a further auxiliary.
  • the present invention also relates to those powders which, in terms of their dry matter a), have at least 25% (w / w), preferably between 50 and 90% (w / w), particularly preferably between 60 and 90% (w / w) a 1,4O-linked sucrose derivative or a sugar mixture containing at least one 1,4O-linked sucrose derivative, b) between 1 and 19.99% (w / w) amino acids and c) between 0.01 and 74% (w / w) of an active pharmaceutical ingredient, preferably a biological macromolecule, the sum of the weight fractions being at most 100% (w / w).
  • the proportion of the 1,4 O-linked sucrose derivative or a sugar mixture containing at least one 1,4 O-linked sucrose derivative is at least 60% (w / w), preferably between 60 and 90% (w / w) in relation to the dry mass of the powder.
  • the proportion of amino acids is preferably between 1 and 19.99% (w / w) and the proportion of the active pharmaceutical ingredient between 0.01 and 39% (w / w).
  • the present invention also relates to powders which contain, for example, 80% (w / w) of a 1,4O-linked sucrose derivative or a sugar mixture containing at least one 1,4O-linked sucrose derivative / 19% (w / w) amino acid / 1% (w / w) active pharmaceutical ingredient (80/19/1) or for example (80/18/2); (80/17/3); (80/16/4); (80/15/5); (80/14/6); (80/13/7) (80/12/8); (80/11/9); (80/10/10); (70/20/10); (70/19/11); (70/18/12); (70/17/13) (70/16/14) (70/15/15); (70/14/16); (70/13/17); (70/12/18); (70/11/19); (70/10/20) (60/20/20) (60/19/21); (60/18/22); (60/17/23); (60/16/24); (60/15/25); (60/14/26) (60/13/27) (60/12/1) or for example (80/18/2
  • the active ingredient content is reduced to a constant amino acid content of 20% (w / w) to 0.01% (w / w), for example to 9.99, ... 9.9, 9.8, 9.7 ... 9.3, 9.2, 9.1 ... 9, 8 7, 6, 5, 4, 3, 2, 1, ... 0.9, 08, 0.7, ... 0.66, ... 0.6, 0.5, 0.4, 0.3, 0.2, 0.1, 0.09, 0.08, 0.07, 0.06, 0.05 , 0.04, 0.03 0.02, 0.01% (w / w), the proportion of 1, 4 O-linked sucrose derivative or the sugar mixture containing at least one 1,4 O-linked sucrose Derivative, for example
  • the proportion of the 1,4O-linked sucrose derivative or the sugar mixture containing at least one 1,4O-linked sucrose derivative, amino acids / peptides and / or pharmaceutical active ingredient can be adjusted / reduced accordingly , so that the weight percentages of the individual components add up to a maximum of 100% (w / w).
  • the amino acid added is isoleucine
  • the proportion of isoleucine is preferably 5 to 19.99% (w / w), more preferably 10 to 19.99% (w / w) of the total solids content of the powder.
  • the sum of the weight percentages of the individual components amounts to a maximum of 100% (w / w).
  • Powders with the following composition are also according to the invention: 80% (w / w) of 1,4 O-linked sucrose derivative or a sugar mixture containing at least one 1,4 O-linked sucrose derivative / 10% (w / w) amino acid or Peptide / 10% (w / w) active pharmaceutical ingredient (80/10/10); (79/11/10); (78/12/10); (77/13/10); (76/14/10); (75/15/10); (74/16/10); (73/17/10); (72/18/10); (71/19/10); (70/20/10), the proportion of the active pharmaceutical ingredient also from 10 to 0.01% (w / w), for example to 9.99, ... 9.9, 9.8, 9.7 .. . 9.3, 9.2, 9.1 ...
  • powders with the following composition are also according to the invention: 80% (w / w) of 1,4 O-linked sucrose derivative or a sugar mixture containing at least one 1,4 O-linked sucrose derivative, / 19% (w / w) Isoleucine / 1% (w / w) active pharmaceutical ingredient (80/19/1); (80/18/2); (80/17/3); (80/16/4); (80/15/5) (80/14/6); (80/13/7); (80/12/8); (80/11/9); (80/10/10); (70/19/11); (70/18/12); (70/17/13) (70/16/14); (70/15/15); (70/14/16); (70/13/17); (70/12/18); (70/11/19); (70/10/20) (60/19/21); (60/18/22); (60/17/23
  • 1,4 O-linked sucrose derivative or a sugar mixture containing at least one 1,4 O-linked sucrose derivative, isoleucine and / or pharmaceutical active ingredient must be adjusted accordingly, so that the weight percentages of the individual components in total add up to a maximum of 100% (w / w).
  • Another embodiment of the present invention relates to the use of at least one 1,4 O-linked sucrose derivative or a sugar mixture containing at least one 1,4 O-linked sucrose derivative, and peptides, preferably tri-peptides, for stabilizing powders contain a pharmaceutical active ingredient, preferably in the form of a peptide, protein, or a mixture of these.
  • peptides preferably tri-peptides
  • the peptides are those which contain at least one isoleucine, preferably two isoleucines, or, in a particularly advantageous embodiment, consist of three isoleucines.
  • powders are considered according to the invention with a) a proportion of at least one 1,4O-linked sucrose derivative or a sugar mixture containing at least one 1,4O-linked sucrose derivative of at least 25% (w / w) , preferably from 60 to 99% (w / w), particularly preferably from 80 to 90% (w / w), b) a proportion of 1 to 19.99% (w / w) of a peptide, preferably a tri-peptide , particularly preferably tri-isoleucine and c) 0.01 to at most 74% (w / w) of an active pharmaceutical ingredient, preferably a peptide / protein.
  • the sum of the individual solids is a maximum of 100% (w / w).
  • Powders with the following composition are also according to the invention: 89% (w / w) of at least one 1,4 O-linked sucrose derivative or a sugar mixture containing at least one 1,4 O-linked sucrose derivative, / 1% (w / w ) Peptide, preferably in the form of a tri-peptide, even more preferably an isoleucine-containing tri-peptide, particularly preferably tri-isoleucine / 10% (w / w) active pharmaceutical ingredient (89/1/10) (88/2/10 ); (87/3/10); (86/4/10); (85/5/10); (84/6/10); (83/7/10); (82/8/10); (81/9/10) (80/10/10); (79/11/10); (78/12/10); (77/13/10); (76/14/10); (75/15/10); (74/16/10) (73/17/10); (72/18/10) or (71/19/10), the proportion of the active pharmaceutical ingredient also from 10 to 0.01% (w / w), for example to 9.99, ...
  • powders with the following composition are therefore also: 80% (w / w) of at least one 1,4-O-linked sucrose Derivative or a sugar mixture containing at least one 1,4 O-linked sucrose derivative / 19% (w / w) of a peptide, preferably a tri-peptide, particularly preferably tri-isoleucine / 1% (w / w) pharmaceutical active ingredient (80/19/1) (80/18/2); (80/17/3); (80/16/4); (80/15/5); (80/14/6); (80/13/7); (80/12/8); (80/11/9) (80/10/10); (70/19/11); (70/18/12); (70/17/13); (70/16/14); (70/15/15); (70/14/16) (70/13/17); (70/12/18); (70/11/19); (70/10/20); (60/20/20); (60/19/21); (60/18/22) (60/17/23); (60/16/24); (60/15/25); (60/14/
  • 39% (w / w) can be increased so that the sum of the parts by weight in relation to the dry mass of the powder results in a maximum of 100% (w / w).
  • the proportion of the peptide which is not intended as a therapeutic agent
  • the tri-peptides is reduced from 10 to 1 (w / w)
  • the proportion of the 1,4-linked sucrose can also be reduced.
  • Derivative or a sugar mixture containing at least one 1,4 O-linked sucrose derivative can be increased in the powder. With a constant active ingredient content of 10% (w / w), for example, powders with a content of 1,4 O-linked sucrose derivative or a sugar mixture containing at least one 1,4 O-linked sucrose derivative, of 80.1% 80.2, 80.3
  • the powders can additionally contain surface-active substances such as Tween 20, 40, 60, 80, Brij 35, Pluronic F 88 and Pluronic F 127. These are preferably used in a concentration of 0.01-0.1% (w / w).
  • a spray-dried powder is particularly preferred that contains at least one 1,4-linked sucrose derivative or a sugar mixture containing at least one 1,4-linked sucrose derivative and additionally contains Tween 20, preferably in a concentration of 0.01-0.1% (w / w), as a surface-active substance.
  • the particles in the powders according to the invention have an MMD and / or MMAD between 1 and 10 ⁇ m, preferably between 1 and 5 ⁇ m.
  • the present invention relates to spray-dried powders with a composition described here, which are characterized by a glass transition temperature of greater than 40 ° C.
  • the corresponding powders according to the invention usually have a maximum glass transition temperature of approximately 96 to 110 ° C. In individual cases, however, the value can be even higher.
  • the present invention also relates to pharmaceutical compositions which contain at least one of the spray-dried powders according to the invention described here.
  • the present invention also provides methods for producing one of the spray-dried powder described in more detail above.
  • the method is characterized in that a solution / suspension to be sprayed containing a pharmaceutical active ingredient and at least one 1,4O-linked sucrose derivative or a sugar mixture containing at least one 1,4O-linked sucrose derivative, below a temperature of 200/120 ° C (inlet inlet temperature) is preferably sprayed at below 186/96 ° C, preferably between 186/96 ° C and 60/40 ° C, for example at 180-150 / 95-80 ° C.
  • the process according to the invention is described in more detail in the "EXAMPLES" section using a few examples.
  • the powders according to the invention can be produced in which the active pharmaceutical ingredient, preferably a biological macromolecule, in the form of a peptide or protein, in an aqueous solution, depending on the Solubility conditions of the respective active ingredient.
  • Buffered solutions with a pH of 3-11, preferably of 3.5-9 are mostly used.
  • An aqueous solution with a pH of 4-7.8 is particularly advantageous for the manufacture of inhalable powders.
  • the pH of the solution should be below the pI of the peptide / protein.
  • the aqueous solution can optionally contain additional water-soluble organic solvents, such as acetone, alcohols or the like.
  • Such mixed solvent systems normally contain between 10-20% (v / v) of a water-soluble organic solvent.
  • the solids content in the solution to be sprayed is usually between 0.01-20% (w / w), preferably between 0.05-10% (w / w), particularly preferably between 0.1-5% (w / w).
  • spray-dried powders were started from an aqueous solution with a solids content of 10% (w / w), 3.33% (w / w) or 2.00% (w / w), and freeze-dried powders from an aqueous solution with a solids content of 10% (w / w).
  • the auxiliary or a mixture of suitable auxiliary substances is usually in a second container in ultrapure water or a suitable buffer solution with a pH of 3 to 11, preferably 3.5 to 9 and particularly preferably 4.0 to 7.8 dissolved and mixed in a second step with the active ingredient solution.
  • the solution / suspension is then adjusted to the desired solids content with ultrapure water or a suitable buffer solution with a pH of 3 to 11, preferably 3.5 to 9 and particularly preferably 4.0 to 7.8.
  • the present invention relates to a method for producing a spray-dried powder, characterized in that a) a pharmaceutical active ingredient is dissolved / suspended in an aqueous solution / suspension; b) one or more 1, 4 O-linked sucrose derivatives selected from the compounds lactosucrose, glucosyl sucrose, or maltosyl sucrose or a sugar mixture containing at least one of these 1,4 O-linked sucrose derivatives is dissolved / suspended in an aqueous solution / suspension; c) if the active substance and 1,4 O-linked sucrose derivative or the sugar mixture containing at least one 1,4 O-linked sucrose derivative is dissolved / suspended in different solutions / suspensions, these are mixed; d) the solution / suspension containing one or more 1, 4 O-linked sucrose derivative (s) and the active pharmaceutical ingredient below a temperature of 200/120 ° C (inflow / outflow temperature), preferably between 60/40 and 186 / 96 ° C is sprayed.
  • the 1, 4 O-linked sucrose derivative can also be part of a sugar mixture which contains at least one 1, 4 O-linked sucrose derivative.
  • suitable sugar mixtures are described in more detail, for example, under "Definitions”.
  • the sugar mixtures can additionally contain one or more mono-, di- and / or polysaccharides, the additional use of Monosaccharides and / or di-saccharides are preferred in powder production.
  • sugar mixtures can be used with lactosucrose, lactose and sucrose, the proportion of lactosucrose in relation to the total proportion of sugar being ⁇ 40% (w / w) , preferably> 55% (w / w), particularly preferably> 88% (w / w) or more
  • the sugar mixture is preferably a sugar mixture from the Hayashibara company designated as Nyuka-Oligo® LS55P, or LS55P for short Shoji, Inc., Japan, which contains at least 55% lactosucrose, a maximum of 25% (w / w) lactose and a maximum of 10% (w / w) sucrose
  • the sugar mixture is a sugar mixture from the company Hayashibara Shoji, Inc., Japan called Nyuka-Oligo® LS90P, or LS90P for short, which contains at least 88% lactosucrose and a maximum of 10% (w / w) lactose and sucrose
  • Sugar mixtures from a combination of glucosyl and maltosyl sucrose can also be used, preferably again in combination with other mono-, di- and / or Polysaccharides. Accordingly, corresponding sugar mixtures of glucosyl and maltosyl sucrose, sucrose, glucose and / or fructose are also suitable for the purposes of the present invention, the proportion of glucosyl and maltosyl sucrose preferably being 25% (w / w) in relation to the total sugar content. or more. According to a further embodiment, the respective proportion of glucosyl and maltosyl sucrose is at least 18% (w / w) of the total sugar proportion.
  • the sugar mixture used is a sugar mixture called Coupling Sugar® from Hayashibara Shoji, Inc., Japan, which contains at least 18% (w / w) glucosyl and maltosyl sucrose, between 11 and Contains 15% (w / w) sucrose and between 5 and 9% (w / w) glucose and fructose.
  • Coupling Sugar S® a sugar mixture from the company Hayashibara Shoji, Inc., Japan, referred to as Coupling Sugar S®, which contains at least 25% (w / w) glucosyl and / or maltosyl sucrose, between 48 and 56%, is also suitable for the purposes of the present invention.
  • (w / w) contains sucrose and not more than 10% (w / w) glucose and fructose.
  • the excipient content of the 1,4 O-linked sucrose derivative or a sugar mixture containing at least one 1,4 O-linked sucrose derivative in the solution / suspension to be sprayed is between 25% and 99.99% (w / w ), preferably between 60% and 99% (w / w), more preferably between 60 and 90% (w / w), particularly preferably between 80 and 90% (w / w) in relation to the solids content of the spray solution.
  • the active substance concentration is normally between 0.01 and 75% (w / w), preferably between 0.01 and 40% (w / w), particularly preferably between 0.01 and 30% (w / w) in relation to the solids content the solution or suspension to be sprayed.
  • the person skilled in the art is able, starting from the powder compositions according to the invention described above, to prepare solutions / suspensions to be sprayed which, after spraying, lead to the corresponding powder compositions.
  • the present invention also relates to processes for producing a spray-dried powder, as described above, characterized in that the solids content of the solution / suspension to be sprayed is between 25 and 99.99%. (w / w), preferably between 60 and 90% (w / w) of at least one 1,4 O-linked sucrose derivative or a sugar mixture containing at least one 1,4 O-linked sucrose derivative.
  • the present invention relates to a corresponding method, characterized in that the solids content of the solution / suspension to be sprayed has a pharmaceutical active ingredient between 0.01 and 75% (w / w), preferably between 0.01 and 30% (w / w), particularly preferably between 0.33 and 30% (w / w).
  • a spray solution / suspension with a solids content of a) is at least 25% (w / w), for example between 25 to 99.99% (w / w), of at least one 1,4-linked sucrose Derivative or a sugar mixture containing at least one 1,4-linked sucrose derivative and b) at least 0.01% (w / w), preferably 0.01 to 75% (w / w) of an active pharmaceutical ingredient, preferably one biological macromolecule, produced and sprayed, the sum of the percentages by weight not exceeding 100% (w / w), based on the solids content of the spray solution.
  • a spray solution / suspension with a solids content a) of at least one 1,4 O-linked sucrose derivative or a sugar mixture containing at least one 1,4 O-linked sucrose derivative of at least 60% (w / w ), preferably between 60 to 90% (w / w), and b) 0.01 to 40% (w / w) of an active pharmaceutical ingredient, preferably a biological macromolecule, produced and sprayed, the sum of the percentages by weight of the solution or suspension is a maximum of 100% (w / w), based on the solids content of the spray solution.
  • the solution / suspension to be sprayed additionally contains, in a further embodiment, one or more pharmaceutically acceptable auxiliaries and / or one or more salts.
  • the auxiliaries are preferably amino acids, peptides or their salts, sugars, polyols, salts of organic acids and / or polymers.
  • the spray solution preferably contains one or more amino acids and / or peptides or proteins as further auxiliaries.
  • the present invention also relates to a method for producing spray-dried powders, characterized in that the solution / suspension to be sprayed with respect to its solids content a) at least 25% (w / w), preferably at least 60% (w / w) at least a 1,4 O-linked sucrose derivative or a sugar mixture containing at least one 1,4 O-linked sucrose derivative, b) between 1 and 39.99% (w / w) of at least one amino acid and / or at least one peptide and c) contains at least 0.01% (w / w) of an active pharmaceutical ingredient.
  • auxiliaries including pharmaceutically acceptable salts, peptides and amino acids
  • suitable auxiliaries including pharmaceutically acceptable salts, peptides and amino acids
  • the spray solution contains, in addition to at least one 1,4 O-linked sucrose derivative or a sugar mixture containing at least one 1,4 O-linked sucrose derivative, one or more amino acids as a further auxiliary. Spray solutions are considered advantageous
  • a person skilled in the art is able to produce corresponding powders and to adjust the proportions by weight so that the sum of the solids amounts to a maximum of 100% (w / w). If the proportion (based on the total solids content) of pharmaceutical active ingredient is, for example, 10% (w / w) and the proportion of at least one 1,4O-linked sucrose derivative or a sugar mixture containing at least one 1,4O-linked sucrose -Derivat, 80% (w / w) the expert knows that he can add a maximum of 10% (w / w) of amino acids to the spray solution / suspension.
  • the spray solution contains, in addition to at least one 1,4 O-linked sucrose derivative or a sugar mixture containing at least one 1,4 O-linked sucrose derivative, isoleucine as a further auxiliary.
  • Spray solutions / suspensions with a solids content a) of at least 25% (w / w), preferably 60 to 90% (w / w) of at least one 1,4-linked sucrose derivative or a sugar mixture containing at least one 1 are considered advantageous.
  • 4 O-linked sucrose derivative, b) 1 to 19.99% (w / w) isoleucine, c) and at least 0.01% (w / w) of an active pharmaceutical ingredient, preferably a peptide / protein, such as, for example Antibody.
  • the proportion of the active pharmaceutical ingredient is preferably 0.01 to a maximum of 74% (w / w), preferably 0.01 to 39% (w / w) depending on the concentration of the 1,4-linked sucrose derivative or the sugar mixture containing at least one 1,4-O-linked sucrose derivative, the sum of the solids content being at most 100%.
  • a person skilled in the art is able to produce corresponding powders and to adjust the proportions by weight so that the sum of the solids amounts to a maximum of 100% (w / w).
  • the proportion (based on the total solids content) of pharmaceutical active ingredient is, for example, 10% (w / w) and the proportion of the 1,4O-linked sucrose derivative or a sugar mixture containing at least one 1,4O-linked sucrose derivative 80% (w / w) the skilled worker knows that he can add a maximum of 10% (w / w) of isoleucine to the spray solution / suspension.
  • the solution to be sprayed contains, in addition to at least one 1,4-linked sucrose derivative or a sugar mixture containing at least one 1,4-linked sucrose derivative, one or more tri-peptides, preferably tri containing isoleucine Peptides, particularly preferably tri- Isoleucine.
  • Solutions or suspensions to be sprayed are considered advantageous if their solids content a) contains at least 25% (w / w), preferably 60 to 90% (w / w) of at least one 1,4 O-linked sucrose derivative or a sugar mixture containing at least one 1, 4 O-linked sucrose derivative, b) 1 to 19.99% (w / w) of a tri-peptide, preferably tri-isoleucine, and c) at least 0.01% (w / w) of an active pharmaceutical ingredient, preferably a peptide / protein, such as an antibody, the sum of the solid components being at most 100% (w / w).
  • the proportion of the active pharmaceutical ingredient is preferably 0.01 to a maximum of 74% (w / w), preferably 0.01 to 39% (w / w), depending on the concentration of the 1,4-linked sucrose derivative or the sugar mixture containing at least one 1,4 O-linked sucrose derivative, the sum of the solid fractions being at most 100%.
  • a person skilled in the art is able to produce corresponding powders and to coordinate the weight fractions so that the sum of the solid fractions results in a maximum of 100% (w / w).
  • the proportion (based on the total solids content) of pharmaceutical active ingredient is, for example, 10% (w / w) and the proportion of at least one 1,4-linked sucrose derivative or a sugar mixture containing at least one 1,4-linked sucrose Derivative 80% (w / w), the person skilled in the art knows that he can add a maximum of 10% (w / w) of tri-peptide, preferably tri-isoleucine, to the solution or suspension to be sprayed.
  • the optimal excipient and protein content for each protein or peptide is determined experimentally.
  • Preferred formulations of the invention may also contain at least one further excipient in order to improve powder properties such as dispersibility and flowability while maintaining a superior aggregate inhibition.
  • the spraying takes place in conventional spray dryers, for example in devices from Niro A / S (Soeborg, DK), Büchi Labortechnik GmbH (Flawil, CH) or the like.
  • the optimal conditions for spray drying depend on the respective formulation and can be determined experimentally. Air is typically used as the gas, but inert gases such as nitrogen or argon are also suitable.
  • the spray drying temperature which means inlet and outlet temperatures (ouf / ef temperature)
  • the temperature sensitivity of the active ingredient used is determined by the temperature sensitivity of the active ingredient used, depending on the stabilizers used.
  • a / n / ef temperature of 50-200 ° C is common, while the outlet temperature is usually 30-150 ° C.
  • an / n / ef temperature of approximately 170-185 ° C. and an ouf / ef temperature of 80-100 ° C. were used.
  • an / n / ef temperature of up to 200 ° C., preferably 60-185 ° C.
  • Spraying is typically at a pressure of about 20-150 psi, preferably at about 30 or 40-100 psi, for example at about 30, 40, 50, 60, 70, 80, 90 or 100 psi.
  • the "liquid feed rate” is normally between 0.1 and 100 ml / min, preferably between 0.1 and 30 ml / min, for example approx. 3 ml / min.
  • an aspirator flow rate of 20-40 m 3 / h, preferably 30-40 m 3 / h such as 38.3 m 3 / h and atomization flow rates of 0.3-2.5 m 3 / h, preferably of approximately 0.67 m 3 / h, 1.05 m 3 / h and 1.74 m 3 / h have been found to be particularly suitable.
  • the spray-dried active substance formulations preferably the protein powder formulations
  • the aim is to obtain a more uniform residual water content of the formulations, preferably less than 2% (w / w), and thus to improve both the active ingredient stability and powder properties such as the glass transition temperature, flowability and dispersibility.
  • the conditions of the post-drying process must be selected so that the Aggregate formation of the active substance was not significantly increased. This applies in particular to the use of biological macromolecules, such as the use of peptides / proteins.
  • the spray-dried active ingredient powder formulations are preferably produced, processed and stored under dry conditions (at low relative atmospheric humidity).
  • the post-drying process enables the powder to be further reduced in moisture despite the relatively high residual water content after spray drying.
  • the auxiliaries which are the subject of the invention stabilize the proteins in the preferred formulations, even under non-optimal process and storage conditions.
  • the dry protein powder formulations produced within the scope of this invention have a residual water content of below 15% (w / w), usually below 10% (w / w), and preferably below 6% (w / w).
  • the spray-dried protein powder formulations more preferably have a residual water content of less than 5% (w / w), particularly preferably less than 3% (w / w) and most preferably between 0.2 and 2.0% (w / w)
  • Formulations with a low residual moisture generally show improved stability during packaging and storage.
  • the dry protein powder formulations of the invention are primarily hygroscopic, i.e. they tend to absorb moisture from your surroundings. To avoid this, such powders are usually stored in containers such as blister packs in the absence of atmospheric moisture. Surprisingly, it was found in selected formulations of the powders according to the invention that the powders remain stable both in terms of protein stability and inhaulability even when stored for one month under 43% relative air humidity.
  • the stabilizing effects of the auxiliaries described here are able to protect the protein from the extreme stresses during spray drying and storage.
  • spray-dried pure protein formulations form aggregates to a large extent.
  • Process-related factors such as heat, shear stress and denaturation at the air-water interfaces cause aggregation (up to approx. 3.7 or 6.6% aggregates) during spray drying and subsequent drying (up to approx. 4.0 or 5.8% aggregates).
  • the absence of the stabilizing hydration shell of the proteins leads to massive aggregate formation (from approximately 11.8 to approximately 18.9% aggregates).
  • the preferred spray-dried formulations of the invention are able to reduce the formation of aggregates both after spray-drying and to keep them at a very low level under different storage conditions.
  • Spray drying and subsequent vacuum drying form only about 0.5 to about 1.8% aggregates in the preferred formulations, in contrast to up to about 4.0% aggregates in pure protein formulations.
  • the preferred formulations aggregates from approx. 1.0 to approx. 13.1%
  • pure protein formulations approximately 18.2 to 18.9% aggregates
  • an analog reference formulation with trehalose as auxiliary This advantage is particularly evident when comparing the formulation listed in Example 4.
  • the powder formulations containing LS55P and Coupling Sugar are characterized by low aggregate contents (approx. 1.4 to 3.2% aggregates), especially in comparison to pure protein powders (approx. 11.8% aggregates).
  • the powder formulations containing LS55P and Coupling Sugar are characterized by low aggregate contents (approx. 1.1 to 2.1% aggregates), especially in comparison to pure protein powders (approx. 13.2% aggregates).
  • LS55P (80%), isoleucine (10%) and IgGI (10%) formulations with a fine particle fraction of approx. 35% show after vacuum drying with subsequent filling under nitrogen after three months' storage under dry conditions at 2 to 8 ° C, 25 ° C and 40 ° C aggregate contents below 1.9%.
  • LS55P (80%), tri-isoleucine (10%) and IgGI (10%) formulations with an MMAD of approx. 3.9 ⁇ m and a fine particle fraction of 58.3% after spray drying show after vacuum drying with subsequent filling under nitrogen after three months Storage under dry conditions at 2 to 8 ° C and 25 ° C aggregate contents below 1.9% and in dry storage conditions at 40 ° C (3 months stability) they show aggregate contents below 2.6%.
  • LS90P (90%) and IgGI (10%) formulations with an MMAD of approx. 3.8 ⁇ m, an MMD of approx. 2.8 ⁇ m and a fine particle fraction of approx. 24% after spray drying show vacuum drying with subsequent filling under nitrogen after storage for one or three months under dry conditions at 2 to 8 ° C, 25 ° C and 40 ° C (1 or 3 months stability) aggregate contents below 1, 2 or 2.2%.
  • LS90P (80%), isoleucine (10%) and IgGI (10%) formulations with a fine particle fraction of approx. 28% show after vacuum drying with subsequent filling under nitrogen after one or three months storage under dry conditions at 2 to 8 ° C, 25 ° C and 40 ° C (1 or 3 months stability) aggregate contents below 0.9 or 1.1%.
  • LS90P (80%), tri-isoleucine (10%) and IgGI (10%) formulations with an MMAD of approx.4.8 ⁇ m and a fine particle fraction of 53.2% after spray drying show after vacuum drying with subsequent filling under nitrogen after one month or three months storage under dry conditions at 2 to 8 ° C, 25 ° C and 40 ° C (1 or 3 months stability) aggregate contents below 1.0 or 2.3%. Furthermore, variations of the above-mentioned LS90P (80%), tri-isoleucine (10%) and IgGI (10%) formulations after one month or three months open storage at approx. 43% relative air humidity and 25 ° C (open 1 or .. 3 months stability) still low aggregate contents between approx. 0.5% and 0.7 or 0.8%.
  • the MMADs are between approx. 3.9 and 3.3 ⁇ m and the FPFs between approx. 55.6 and 58.9%.
  • the formulations mentioned above continue to show small MMADs (approx. 4.1 to 3.5 ⁇ m) and a high fine particle fraction (approx. 62.3 to 67.3% ).
  • powders can be produced which preferably have an average particle size (MMD) of less than 20 ⁇ m, preferably less than 10 ⁇ m.
  • these particles according to the invention have an average particle size of less than 7.5 ⁇ m, preferably less than 5 ⁇ m.
  • Particles with an average particle size of less than 4 ⁇ m and more preferably less than 3.5 ⁇ m are particularly preferred.
  • particles with an average particle diameter of 0.1-5 ⁇ m, preferably 0.2-4 m can also be produced.
  • non-respirable particles e.g. Lactose, with a particle size of at least 40 / m, preferably between 40 and 200 microns, mixed. The proportion is preferably at least 15%, more preferably at least 20%, even more preferably at least 30%, even more preferably at least 40% and particularly preferably at least 50 or 60%.
  • the sharkability essentially depends on the mean aerodynamic particle diameter (MMAD).
  • the particles according to the invention preferably have an MMAD of less than 10 ⁇ m and more preferably less than 7.5 ⁇ m. Powders consisting of particles with an MMAD of less than 5.5 ⁇ m, preferably less than 5 ⁇ m, even more preferably less than 4.5 ⁇ m, are particularly advantageous.
  • the powders described in the examples can be used with the appropriate particle sizes Produce a combination of the optimal spray drying condition and the choice and concentration of auxiliary substances according to the invention.
  • inhalable powders with an FPF of greater than 28%, preferably greater than 40, more preferred greater than 50 and even more preferred greater than 55% could be produced (see EXAMPLES).
  • the powders according to the invention are furthermore distinguished by a glass transition temperature of at least 40 ° C., preferably of at least 50 ° C., more preferably of at least 55 ° C., even more preferably of at least 60 ° C.
  • Particularly preferred powders have a glass transition temperature of at least 65 ° C.
  • the glass transition temperature of the powders according to the invention is 40 to 110 ° C.
  • the present invention also relates to powders, preferably spray-dried powders, containing an active pharmaceutical ingredient and LS90P, LS55P, coupling sugar or coupling sugar S, the glass transition temperature being 40 ° C. and higher, preferably between 45 and 60 ° C. or higher.
  • the glass transition temperature is 55 ° C and more, preferably between 55 and 60 ° C or higher.
  • the powders according to the invention are suitable for the manufacture of a medicament, preferably for the manufacture of an inhaled medicament.
  • powder can also be freeze-dried with an attached
  • Lyophilsate can of course also be used in a suitable mill Cutting mill, ball mill, pin mill, mortar mill, air jet mill or other suitable processes can be pulverized (see Bauer, Frömming, 5%, weight, and other suitable processes).
  • the dry protein powder formulations made in accordance with this invention have a residual water content of less than 15% (w / w), usually less than 10% (w / w), and preferably less than 5% (w / w).
  • the spray-dried protein powder formulations more preferably have a residual water content of less than 3% (w / w), particularly preferably less than 2% (w / w) and most preferably between 0.2 and 1.5% (w / w)
  • Formulations with a low residual moisture generally show improved stability during packaging and storage.
  • the dry protein powder formulations of the invention are primarily hygroscopic, i.e. they tend to absorb moisture from your surroundings. To avoid this, such powders are usually stored in containers such as blister packs in the absence of atmospheric moisture.
  • the stabilizing effects of the auxiliaries described here are able to protect the protein from the extreme stresses during freeze drying and storage.
  • freeze-dried pure protein formulations form aggregates to a large extent.
  • Process-related factors such as stress during freezing, concentration, pH shift and denaturation at the air-water interfaces cause aggregation (up to approx. 2.1% aggregates) during freeze-drying.
  • aggregation up to approx. 2.1% aggregates
  • the preferred freeze-dried formulations of the invention are able to reduce the formation of aggregates both after freeze-drying and to keep them at a very low level under different storage conditions.
  • the freeze-dried and powdered lysophilsates are characterized by particularly challenging storage conditions (40 ° C, 75% relative humidity), the forced storage stability, due to the clear superiority of the preferred formulations (aggregates from approx. 1.2 to approx. 1.5%) compared to pure protein formulations from (approx. 14.5% aggregates) and an analog reference formulation with mannitol (approx. 34.0% aggregates ) as an excipient.
  • the powder formulations containing LS55P and Coupling Sugar are characterized by low aggregate contents (approx. 2.6 and 4.6% aggregates), especially in Relation to pure protein powders (approx. 15.3% aggregates) as well as an analog reference formulation with mannitol (approx. 11.6% aggregates).
  • the powder formulations containing LS55P and Coupling Sugar are characterized by low aggregate contents (approx. 1.2 and 1.5% aggregates), especially in Relation to pure protein powders (approx. 14.5% aggregates) and an analog reference formulation with mannitol (approx. 6.2% aggregates) as an excipient.
  • the powders according to the invention are furthermore distinguished by a glass transition temperature of at least 40 ° C., preferably of at least 50 ° C., more preferably of at least 55 ° C.
  • the glass transition temperature of the powders according to the invention is 40 to 110 ° C., but can also exceed this value in individual cases.
  • the present invention also relates to powder, preferably freeze-dried and powdered powder containing a pharmaceutical active ingredient and LS90P, LS55P, coupling sugar or coupling sugar S, the glass transition temperature being 40 ° C. and higher, preferably between 45 and 60 ° C. or higher.
  • the glass transition temperature is 55 ° C and more, preferably between 55 and 60 ° C or up to 110 ° C.
  • the powder preparations according to the invention can be applied directly as dry powder via so-called dry powder inhalers, or after suspension or reconstitution in the form of aerosols via so-called nebulizers.
  • the inhalable powders according to the invention can be applied using inhalers known from the prior art.
  • Inhalation powders according to the invention can be applied, for example, by means of inhalers, which are applied a single dose from a supply by means of a measuring chamber, as described in US Pat. No. 4,570,630A, or via other apparatus, as described in DE 36 25 685 A ,
  • the inhalable powders according to the invention are preferably filled into capsules (so-called inhalettes) which are used in inhalers, as described, for example, in WO 94/28958.
  • suitable inhalers can be found, among others. in US 5,458,135; US 5,785,049 or WO 01/00263. Further suitable inhalers are known from WO 97/41031; US 3,906,950 and US 4,013,075 are known. Further dispersion inhalers for dry powder preparations are described in EP 129 985; EP 472 598; EP 467 172 and US 5,522,385.
  • the inhalable powders according to the invention can be administered, for example, by means of the inhaler known under the name Turbohaler® (AstraZeneca LP) or with inhalers as disclosed for example in EP 237507 A.
  • Turbohaler® AstraZeneca LP
  • inhalers as disclosed for example in EP 237507 A.
  • suitable inhalers are the Rotahaler® or the Discus® (both from GlaxoSmithKline Corp.), the Spiros TM Inhaler (Dura Pharmaceuticals) and the Spinhaler® (Fiscon).
  • FIG. 24 An inhaler which is particularly preferred for use of the pharmaceutical combination according to the invention in inhalets can be seen in FIG. 24.
  • This inhaler for inhaling powdered pharmaceuticals from capsules is characterized by a housing 1, containing two windows 2, a deck 3, in which there are air inlet openings and which is provided with a sieve 5 fastened via a sieve housing 4, one with a deck 3 connected inhalation chamber 6, on which a pusher 9 provided with two ground needles 7 and movable against a spring 8 is provided, as well as a mouthpiece 12 which can be folded via an axis 10 and is connected to the housing 1, the deck 3 and a cap 11, as well as air passage holes 13 for setting the flow resistance.
  • inhalable powders according to the invention are to be filled into capsules (inhalettes) in the sense of the preferred use mentioned above, fill quantities of 1 to 30 mg per capsule are appropriate.
  • the powders according to the invention can also be applied as inhalation aerosols containing propellant gas or propellant gas-free.
  • the powders according to the invention are suspended in pressure-liquefiable solvents or solvent mixtures or reconstituted in an aqueous solution. Suitable suspensions or solutions are known in the prior art. Reconstitution in physiological solutions with a pH of 3-11, preferably 4-9, is advantageous, for example. Reconstitution in an aqueous solution with a pH of 5.5-7.8 is particularly advantageous.
  • suspensions or solutions containing propellant gas for the reconstitution of the powders according to the invention can also contain other auxiliaries in the form of
  • Stabilizers emulsifiers, surface-active substances, water-soluble organic solvents.
  • Corresponding substances are known to the person skilled in the art, and are exemplified in (Bauer, Textbook of Pharmaceutical
  • propellant gases which can be used to produce the inhalation aerosols according to the invention are also known from the prior art.
  • Suitable propellants are selected from the group consisting of hydrocarbons such as n-propane, n-butane or isobutane and halogenated hydrocarbons such as preferably chlorinated and fluorinated derivatives of methane, ethane, propane, butane, cyclopropane or cyclobutane.
  • the above-mentioned propellant gases can be used alone or in mixtures thereof.
  • Particularly preferred propellants are halogenated alkane derivatives selected from TG11, TG 12, TG 134a (1, 1, 1, 2-tetrafluoroethane), TG227 (1, 1, 1, 2,3,3,3-heptafluoropropane) and mixtures thereof, wherein the propellant gases TG 134a, TG227 and mixtures thereof are preferred.
  • the inhalation aerosols containing propellant gas according to the invention can contain up to 5% (w / w) of active ingredient. Aerosols according to the invention contain, for example, 0.002-5% (w / w), 0.01-3% (w / w), 0.015-2% (w / w), 0.1-2% (w / w), 0, 5-2% (w / w) or 0.5-1% (w / w) of the active pharmaceutical ingredient. Content aerosols with a corresponding concentration of active substance can be adjusted by targeted reconstitution of the powders according to the invention in a corresponding amount of solvent.
  • MDIs metered dose inhalers.
  • examples include the Ventolin® (Ventolin Pharmacy) or the inhalers described in US 5,32,094 or US 5,672,581.
  • a further aspect of the present invention relates to medicaments in the form of propellant-containing aerosols as described above in connection with one or more inhalers suitable for the administration of these aerosols.
  • the present invention further relates to inhalers, thereby characterized in that they contain propellant-containing aerosols according to the invention described above.
  • the present invention further relates to cartridges which can be used with a suitable valve in a suitable inhaler and which contain one of the above-mentioned inhalation aerosols containing propellant gas according to the invention.
  • Suitable cartridges and methods for filling these cartridges with the inhalation aerosols containing propellant gas according to the invention are known from the prior art.
  • the powders according to the invention can also be reconstituted in propellant-free inhalation solutions or suspensions.
  • Corresponding propellant-free inhalation solutions contain, for example, aqueous or alcoholic, preferably ethanolic, optionally ethanolic in a mixture with aqueous solvents.
  • aqueous / ethanolic solvent mixtures the relative proportion of ethanol to water is not limited, but the maximum limit is preferably up to 70% (v / v), in particular up to 60% (v / v) ethanol.
  • the remaining volume percentages are filled up with water.
  • Co-solvents and / or further auxiliaries, as described above, can be added to the propellant-free inhalation solutions according to the invention.
  • co-solvents can be used which contain hydroxyl groups or other polar groups, such as alcohols - especially isopropyl alcohol, glycols - especially propylene glycol, polyethylene glycol, polypropylene glycol, glycol ether, glycerol, polyoxyethylene alcohols and polyoxyethylene fatty acid esters.
  • auxiliaries and additives are understood to mean any pharmacologically acceptable substance which is not an active substance but can be formulated together with the active substance (s) in the pharmacologically suitable solvent in order to improve the qualitative properties of the active substance formulation.
  • These substances preferably have no or no significant or at least no undesirable pharmacological effect in the context of the desired therapy.
  • the auxiliaries and additives include, in addition to the above-mentioned, for example surface-active substances, such as, for example, soy lecithin, oleic acid, sorbitan esters, such as polysorbates, polyvinylpyrrolidone, other stabilizers, Complexing agents, antioxidants and / or preservatives which ensure or extend the period of use of the finished pharmaceutical formulation, flavorings, vitamins and / or other additives known in the prior art.
  • the additives also include pharmacologically acceptable salts such as sodium chloride as isotonic agents.
  • the preferred auxiliary substances include antioxidants, such as, for example, ascorbic acid, unless already used for adjusting the pH, vitamin A, vitamin E, tocopherols and similar vitamins or provitamins occurring in the human organism.
  • Preservatives can be used to protect the formulation from contamination with germs. Suitable preservatives are those known from the prior art, in particular cetylpyridinium chloride, benzalkonium chloride or benzoic acid or benzoates such as sodium benzoate in the concentration known from the prior art.
  • the above-mentioned preservatives are preferably contained in concentrations of up to 50 mg / 100 ml, particularly preferably between 5 and 20 mg / 100 ml. Accordingly, the present invention also includes propellant-free inhalation aerosols which are produced by reconstituting the powders according to the invention.
  • those inhalers are particularly suitable which can nebulize a small amount of a liquid formulation in the therapeutically necessary dosage into an aerosol suitable for therapeutic inhalation within a few seconds.
  • those nebulizers are preferred in which an amount of less than 100 ⁇ L, preferably less than 50 ⁇ L, particularly preferably between 10 and 30 ⁇ L of active ingredient solution, preferably with a stroke to an aerosol with an average particle size of less than 20 ⁇ m, preferably less than 10 ⁇ m, can be atomized so that the inhalable portion of the aerosol already corresponds to the therapeutically effective amount.
  • Such a device for propellant-free administration of a metered amount of a liquid medicament for inhalation use is described, for example, in international patent application WO 91/14468 and in WO 97/12687 (there described in detail in particular in FIGS. 6a and 6b).
  • express reference is made to the corresponding FIGS. 6a and 6b of WO 97/12687 including the associated description parts.
  • the nebulizers described there are also known under the name Respimat® (Boehringer Ingelheim Pharma). Due to its cylinder-like shape and a handy size of less than 9 to 15 cm in length and 2 to 4 cm in width, this device can be carried by the patient at any time.
  • the nebulizer sprays a defined volume of the drug formulation using high pressures through small nozzles, so that inhalable aerosols are created.
  • the preferred atomizer consists of an upper housing part, a pump housing, a nozzle, a locking mechanism, a spring housing, a spring and a storage container, characterized by - a pump housing which is fastened in the upper housing part and which has a nozzle body at one end with the Carries the nozzle or nozzle arrangement,
  • a spring housing with the spring located therein, which is rotatably mounted on the upper housing part by means of a rotary bearing,
  • the hollow piston with valve body corresponds to a device disclosed in WO 97/12687. It projects partially into the cylinder of the pump housing and is arranged axially displaceably in the cylinder. In the context of the present invention, reference is made in particular to FIGS. 1-4 - in particular to FIG. 3 - and the associated parts of the description.
  • the hollow piston with valve body exerts a pressure of 5 to 60 MPa (approximately 50 to 600 bar), preferably 10 to 60 MPa (approximately 100 to 600) on its high pressure side at the time the spring is triggered bar) on the fluid, the measured active ingredient solution. Volumes of 10 to 50 microliters are preferred, volumes of 10 to 20 microliters are particularly preferred, and a volume of 15 microliters per stroke is very particularly preferred.
  • the valve body is preferably attached to the end of the hollow piston which faces the nozzle body.
  • the nozzle in the nozzle body is preferably microstructured, i.e. made by microtechnology.
  • Microstructured nozzle bodies are disclosed, for example, in WO 94/07607; reference is hereby made to this document, in particular to FIG. 1 disclosed there and its description.
  • the nozzle body is e.g. from two firmly connected plates made of glass and / or silicon, of which at least one plate has one or more microstructured channels which connect the nozzle inlet side to the nozzle outlet side.
  • On the nozzle outlet side there is at least one round or non-round opening of 2-10 ⁇ m deep and 5-15 ⁇ m wide, the depth preferably being 4.5 to 6.5 micrometers and the length 7-9 micrometers.
  • the jet directions of the nozzles in the nozzle body can run parallel to one another or they are inclined towards one another in the direction of the nozzle opening.
  • the jet directions can be inclined at an angle of 20-160 degrees, an angle of 60-150 degrees is preferred, particularly preferably 80-100 °.
  • the nozzle openings are preferably arranged at a distance of 10-200 ⁇ m, more preferably at a distance of 10-100 ⁇ m, particularly preferably 30-70 ⁇ m. 50 ⁇ m are most preferred.
  • the jet directions meet in the vicinity of the nozzle openings.
  • the liquid pharmaceutical preparation hits the nozzle body with an inlet pressure of up to 600 bar, preferably 200 to 300 bar, and is injected through the nozzle openings atomized an inhalable aerosol.
  • the preferred particle or droplet sizes of the aerosol are up to 20 ⁇ m, preferably 3-10 // m.
  • the locking mechanism contains a spring, preferably a cylindrical helical compression spring, as a store for the mechanical energy.
  • the spring acts on the output flange as a jumping piece, the movement of which is determined by the position of a locking element.
  • the path of the output flange is precisely limited by an upper and a lower stop.
  • the spring is preferably via a force-transmitting gear, e.g. a screw-type thrust gear, tensioned by an external torque generated when the upper housing part is turned against the spring housing in the lower housing part.
  • the upper part of the housing and the output flange contain a single or multi-speed wedge gear.
  • the locking member with engaging locking surfaces is arranged in a ring around the output flange.
  • the ring is arranged in a plane perpendicular to the atomizer axis. After tensioning the spring, the locking surfaces of the locking member slide into the path of the output flange and prevent the spring from relaxing.
  • the locking element is triggered by a button.
  • the trigger button is connected or coupled to the locking member.
  • the release button is moved parallel to the ring plane, and preferably into the atomizer; the deformable ring is deformed in the plane of the ring. Structural details of the locking mechanism are described in WO 97/20590.
  • the lower part of the housing is pushed in the axial direction over the spring housing and covers the bearing, the drive of the spindle and the reservoir for the fluid.
  • the upper housing part When the atomizer is actuated, the upper housing part is rotated against the lower housing part, the lower housing part taking the spring housing with it.
  • the spring is compressed and tensioned via the screw-type thrust gear, and the locking mechanism engages automatically.
  • the angle of rotation is preferably an integer fraction of 360 degrees, for example 180 degrees.
  • the driven part in the upper part of the housing is shifted by a predetermined distance, the hollow piston is withdrawn within the cylinder in the pump housing, as a result of which a portion of the fluid is sucked out of the reservoir into the high-pressure space in front of the nozzle.
  • the storage container contains the aqueous aerosol preparation according to the invention.
  • the atomization process is initiated by gently pressing the trigger button.
  • the barrage clears the way for the stripping section.
  • the tensioned spring pushes the piston into the cylinder of the pump housing.
  • the components of the atomizer are made of a material that is suitable for their function.
  • the housing of the atomizer and - as far as the function allows - other parts are preferably made of plastic, e.g. manufactured by injection molding. Physiologically harmless materials are used for medical purposes.
  • FIGS. 6 a / b of WO 97/12687 A corresponding nebulizer (Respimat®) is described in FIGS. 6 a / b of WO 97/12687, including the associated description, to which reference is again made at this point. This is particularly suitable for the application of the propellant-free inhalation aerosols according to the invention.
  • Figure 6a shows the W097 / 12687 shows a longitudinal section through the atomizer with the spring tensioned
  • Figure 6b of the W097 / 12687 shows a longitudinal section through the atomizer with the spring released:
  • the upper housing part (51) contains this Pump housing (52), at the end of which the holder (53) for the atomizing nozzle is attached.
  • the nozzle body (54) and a filter (55) are located in the holder.
  • the hollow piston (57) fastened in the output flange (56) of the locking tension mechanism partially projects into the cylinder of the pump housing.
  • the hollow piston carries the valve body (58) at its end.
  • the hollow piston is sealed by means of the seal (59).
  • the stop (60) Inside the upper part of the housing is the stop (60), against which the output flange rests when the spring is relaxed.
  • the stop (61) is located on the output flange, against which the output flange rests when the spring is tensioned.
  • the locking member (62) slides between the stop (61) and a support (63) in the upper part of the housing.
  • the release button (64) is connected to the locking member.
  • the upper housing part ends in the mouthpiece (65) and is closed with the clip-on protective cap (66).
  • the spring housing (67) with compression spring (68) is rotatably mounted on the upper part of the housing by means of the snap lugs (69) and rotary bearings.
  • the lower housing part (70) is pushed over the spring housing.
  • the exchangeable storage container (71) for the fluid (72) to be atomized is located within the spring housing.
  • the storage container is closed with the stopper (73) through which the hollow piston protrudes into the storage container and with its end is immersed in the fluid (supply of active substance solution).
  • the spindle (74) for the mechanical counter is mounted in the outer surface of the spring housing.
  • the drive pinion (75) is located at the end of the spindle which faces the upper housing part.
  • the rider (76) sits on the spindle.
  • the mass applied should be at least 97%, preferably at least 98%, of all actuations of the inhaler (hub) of a defined amount with a tolerance range of at most 25%, preferably 20% Amount. Between 5 and 30 mg of formulation are preferably applied as a defined mass per stroke, particularly preferably between 5 and 20 mg.
  • a further aspect of the present invention relates to medicaments in the form of propellant-free inhalation solutions or suspensions as described above in connection with a device suitable for the administration of these formulations, preferably in connection with the Respimat®.
  • the present invention preferably aims at propellant-free inhalation solutions or suspensions containing one of the powders according to the invention in connection with the device known under the name Respimat®.
  • the present invention relates to the above-mentioned devices for inhalation, preferably the Respimat®, characterized in that they contain propellant-free inhalation solutions or suspensions according to the invention described above.
  • the propellant-free inhalation solutions or suspensions according to the invention can, in addition to the solutions and suspensions intended for application in the Respimat®, also be present as concentrates or sterile, ready-to-use inhalation solutions or suspensions.
  • Ready-to-use formulations can be generated from the concentrates, for example, by adding isotonic saline solutions.
  • Sterile, ready-to-use formulations can be applied using energy-operated stand-up or portable nebulisers that generate inhalable aerosols using ultrasound or compressed air according to the Venturi principle or other principles.
  • a further aspect of the present invention relates to medicaments in the form of propellant-free inhalable solutions or suspensions as described above, which are present as concentrates or sterile ready-to-use formulations, in connection with a device suitable for administering these solutions, characterized in that this device is an energy-operated standing or portable nebulizer that is inhalable Aerosols generated using ultrasound or compressed air according to the Venturi principle or other principles.
  • nebulizers for the inhalation application of reconstituted aerosols are the AERx TM (Aradigm), the Ultravent® (Mallinkrodt) and the Aconll® (Maquest Medical Products).
  • the antibody is derived from a murine antibody in which the complementarily determining regions of the murine antibody have been transferred to a human immunoglobulin scaffold.
  • a chimeric antibody with 95% human and 5% murine content was formed.
  • the antibody is expressed from murine myeloma cell lines. The cells are removed with the aid of tangential flow microflitration and the cell-free solution is purified by various chromatography methods. Other steps include nuclease treatment, low pH treatment and nanofiltration.
  • the antibody-containing bulk solution contains histidine 25 mM and glycine 1.6 mM as a buffer and was concentrated to about 100 mg / ml for the preparation of the solution for spray drying by means of diafiltration.
  • the bulk for the preparation of the solution to be sprayed had 0.4 to 0.8% aggregates.
  • the finished medicinal product can be stored for at least 2 years at 2-8 ° C.
  • Nyuka-Oligo® LS55P, Nyuka-Oligo® LS90P, Coupling Sugar® and Coupling Sugar S® were purchased from Hayashibara Shoji, Inc., Japan.
  • Sucrose, lactose, mannitol, raffinose, hydroxyethyl starch and L-isoleucine were purchased from Sigma-Aldrich Chemie GmbH, Germany. Trehalose comes from Georg Breuer GmbH, Germany. Tri-isoleucine was purchased from Iris Biotech GmbH, Germany. Chicken egg white lysozyme (lysozyme), 135500 U / mg, was obtained from SERVA Electrophoresis GmbH, Germany. Synthetic salmon calcitonin (Calcitonin) was purchased from Biotrend Chemicals GmbH, Germany.
  • the spray drying was carried out with the help of a Büchi Mini Spray Dryer B-290 from Büchi Labortechnik GmbH. Spray drying the formulations were carried out in principle according to the description in "Spray Drying Handbook", 5th Edition., K. Masters, John Wiley and Sons, Inc., NY, NY (1991):
  • the spray dryer consists of a heating system, a filter, an aspirator, one A drying tower, a cyclone, temperature sensors for measuring the inlet and outlet temperatures and a collecting vessel are built up.
  • the solution to be sprayed is pumped into a two-substance nozzle, where compressed air is used to atomize the solution into small drops Drying takes place in the spray tower by means of heated air which is sucked through the spray tower using the aspirator.
  • the product is collected in the collecting vessel after passing through the cyclone. Two different cyclones were used:
  • the solids content in the sprayed solutions was 10% (w / v) 3.33% and 2.00% in 50 to 600 ml.
  • Freeze drying was carried out using a Christ LPC-16 / NT Epsilon 2-12 D freeze dryer from Martin Christ Gefriertrocknungsanlagen GmbH.
  • the freeze dryer consists of the drying chamber, a condenser to separate the sublimed solvent, a pump to create the vacuum and the electrical equipment. Drying is controlled by the shelf temperature and the vacuum in the drying chamber.
  • the solids content of the freeze-drying solution was 5% (w / v).
  • the solution was portioned into 2R vials of 0.5 ml each and positioned in the freeze-dryer with common freeze-drying stoppers. First, the solutions were frozen at -40 ° C in 30 minutes. Second, the main drying was carried out at 0.11 mbar in three steps.
  • X-ray diffractometry wide-angle X-ray diffractometry (WAXS): In order to determine the crystallinity of the dried samples, the samples were examined with a Seifert, X-ray diffractometer XRD 3000 TT (from Seifert, Ahrensburg, DE) in a room heated to 22 ° C.
  • the X-ray tube Cu anode, Cu-K ⁇ radiation with ⁇ 0.15418 mm (primary filter Ni) was operated with an anode voltage of 40 kV and a current of 30 mA.
  • the powder diffractograms were recorded with the ScanX-Rayflex application, version 3.07 device XRD 3000 (scan), or the Rayflex version 2.1, 1996 (analysis) on the detector SO 1000 V.
  • Size exclusion chromatography SEC-HPLC was carried out to quantify IgGI protein aggregates in the reconstituted powders.
  • the SEC-HPLC was carried out with an HP1090 from Agilent.
  • a TSK3000SWXL column 300 x 7.8mm) from Tosoh Biosep (Tosoh Bioscience, Stuttgart, Germany) was used for the separation.
  • a buffer of 0.1 M di-sodium hydrogenphosphate dihydrate and 0.1 M sodium sulfate was dewatered as the eluent and was adjusted to pH 6.8 with 85% ortho-phosphoric acid.
  • the amount of sample applied was 25 l at a protein concentration of 2-10 mg / ml.
  • the protein was detected using a diode array detector from Agilent at 280 nm. HP-Chemstation software from Agilent was used to evaluate the chromatograms.
  • the amount of sample applied was 25 l at a protein concentration of 2-10 mg / ml.
  • the protein was detected using an Agilent UV detector at 280 nm.
  • the Agilent Chemstation software from Agilent was used to evaluate the chromatograms.
  • the remaining soluble monomer is quantified using the following method.
  • a calibration line was created with lysozyme standard solutions with concentrations of 2.5 mg / ml, 5.0 mg / ml and 10 mg / ml.
  • the AUC of the monomer peaks was considered in relation to the corresponding lysozyme concentrations in the investigated standard solution.
  • the residual monomer content of the various lysozyme formulations examined was calculated using the calibration curve. The higher the residual monomer content of a formulation, the better the protein stability.
  • the mass median diameter or the mean particle sizes of the particles were determined with the aid of the Sympatech Helos from Sympatech GmbH (Clausthal-Zellerfeld, DE).
  • the measuring principle is based on laser diffraction, a helium-neon laser is used. 1-3 mg of powder are dispersed with an air pressure of 2bar and passed through a parallel laser beam in front of the Fourier lens (50mm). The particle size distribution is evaluated using a Fraunhofer model. Two measurements were carried out for each powder.
  • Mass median aerodynamic diameter (MMAD) and fine particle fraction (FPF) For the measurements, 12-18 mg powder was filled into hard gelatin capsules (size 3) and placed in the HandiHaler (powder inhaler from Boehringer Ingelheim). The HandiHaler was connected to the USP EP / throat of the impactor inlet of the measuring device with an adapter and the powder was applied at 39.0l / min with a suction time of 6.15sec. The air flow rate was controlled via an external control wall. At least three capsules were measured for each powder.
  • MMAD mass median aerodynamic diameter
  • FPF fine particle fraction
  • the aerodynamic particle size (MMAD) is determined simultaneously via a flight time determination and the fine particle fraction (FPF) via a single-stage impactor (effective cut off diameter at 39L / min: 5 , 0 / ym).
  • the powder After application via the EP / USP Throat or Sample Induction Port, the powder reaches a thin capillary where 0.2% of the powder is taken for time of flight measurement under isokinetic conditions. After passing through the capillary, the time of flight measurement is carried out using 2 laser beams, which, like a light barrier, record the flight times for a defined distance.
  • the result is a number distribution, which is then converted to a mass distribution and thus to the mass median aerodynamic diameter (MMAD).
  • MMAD mass median aerodynamic diameter
  • the remaining 99.8% of the powder population that passed the capillary are separated using the single-stage impactor.
  • the fraction larger than 5.0 ⁇ m separates in the impactor due to the inertia on a baffle plate.
  • the fine particle fraction (FPF) follows the air flow and is finally separated on a depth filter.
  • the determination of the fine particle fraction was carried out gravimetrically.
  • the fine particle fraction is calculated from the proportion of the powder deposited on the filter in relation to the total amount of powder used, ie powder weighed in per capsule.
  • the residual water content in the dried products was determined by means of coulometric titration (Metrohm 737 KF Coulometer with 703 titration level, Germany). For the determination, powder was dissolved or dispersed in methanol (Hydranal-Methanol dry, VWR / Merck Eurolab). The measurement solution (Hydranal-Coulomat solution, VWR / Merck Eurolab) of the Metrohm Coulometer was conditioned at the start of the measurements, i.e. the measuring solution was balanced to a zero water content. The sample was injected into the titration cell and measured.
  • Stability determination The powder or proteins contained in the powder were examined for various stabilities after spray drying. For IgGI and calcitonin, the percentage of protein aggregates was taken as a measure of the stability of the formulations. In the case of lysozyme, the percentage of the residual monomer content was assessed as a measure of the stability of the formulations.
  • the innovative adjuvants described in the invention were partially compared with pure protein formulations, analog trehalose formulations, analog raffinose formulations, analog sucrose formulations, analog sucrose-lactose formulations or analog hydroxyethyl starch formulations. The analysis for the examination for aggregates was carried out with a validated size exclusion chromatography (SEC-HPLC) with UV detection (DAD).
  • the pretreated powders were first reconstituted in ultrapure water (pH 6 to 8).
  • Forced storage stability Selected formulations were examined for their stability in open glass vials after one week's open storage at approx. 40 ° C and approx. 75% relative atmospheric humidity (40 ° C, 75% rh).
  • Example 1 Spray drying an IgGI 10% (w / v) formulation Pure IgGI with a concentration of approx. 109 mg / ml, formulated in a glycine histidine buffer pH 6 (see materials), was diluted with demineralized water (pH approx. 7.5) to a content of 100 mg / ml and in the absence of other auxiliaries as described above using the cyclone I spray-dried with an atomization flow rate of about 0.67 m 3 / h. The volume of the solution was 50 ml. The content of aggregates was examined as described above.
  • IgGI with a concentration of approx. 102.8 mg / ml, formulated in a glycine histidine buffer pH 6 (see materials), was diluted with demineralized water (pH approx. 7.5) to a content of 33 mg / ml and in the absence of other auxiliaries as described above using the cyclone I spray-dried with an atomization flow rate of about 0.67 m 3 / h.
  • the volume of the solution was 150 ml.
  • the aggregate content was examined as described above.
  • the MMD of the powder was determined as described above.
  • the MMD of the powder after spray drying was 2.8 ⁇ m.
  • the MMAD and FPF of the powder were determined as described above.
  • the MMAD of the powder after spray drying was 3.8 ⁇ m and the fine particle fraction was 23.6% based on the weight of powder in the capsule.
  • the solution thus obtained contains about 6% (w / v) auxiliary or matrix and 4% (w / v)
  • the aggregate content was examined as described above.
  • LS55P 2.0 g was dissolved in about 15 ml of demineralized water (pH about 7.5). Next, approximately 29.18 ml of pure IgGI with a concentration of approximately 102.8 mg / ml, formulated in a glycine histidine buffer pH 6 (see materials), were added and mixed with demineralized water (pH approximately 7.5). diluted to a volume of 50 ml.
  • the solution thus obtained contains about 4% (w / v) auxiliary or matrix and 6% (w / v)
  • the solution thus obtained contains about 0.5% (w / v) excipient or matrix and 9.5% (w / v) protein and was, as described above, using Cyclone I with an atomization flow rate of about 0.67 m 3 / h spray dried.
  • the aggregate content was examined as described above. The following aggregate contents resulted for the storage stability.
  • the MMD of the powder was 2.9 ⁇ m.
  • the MMAD and FPF of the powder were determined as described above. • The MMAD was 4.3 ⁇ m and the fine particle fraction was 15.9% based on the weight of powder in the capsule.
  • demineralized water 40 ml of demineralized water (pH approx. 7.5) dissolved. Next, about 0.518 ml of pure IgGI with a concentration of about 96.55 mg / ml, formulated in a glycine histidine buffer pH 6 (see materials), was added and with demineralized water
  • the solution thus obtained contains about 6% (w / v) excipient or matrix and 4% (w / v) protein and was spray-dried as described above using the cyclone I with an atomization flow rate of about 0.67 m 3 / h , The aggregate content was examined as described above. The following aggregate contents resulted for the storage stability.
  • the solution thus obtained contains about 4% (w / v) excipient or matrix and 6% (w / v) protein and was spray-dried as described above using the cyclone I with an atomization flow rate of about 0.67 m 3 / h , The aggregate content was examined as described above. The following aggregate contents resulted for the storage stability. • After one week's open storage at 75% relative humidity and 40 ° C (forced storage stability), the solution made up of the reconstituted powder had around 9.9% aggregates.
  • the solution thus obtained contains about 9% (w / v) excipient or matrix and 1% (w / v) protein and was spray-dried as described above using the cyclone I with an atomization flow rate of about 0.67 m 3 / h , The aggregate content was examined as described above. The following aggregate contents resulted for the storage stability.
  • Example 2 Spray drying a trehalose 8% (w / v) L-isoleucine 1% (w / v) IgGI 1% (w / v) formulation 4.0 g of trehalose and 0.5 g of L-isoleucine were dissolved in about 40 ml of demineralized water (pH about 7.5) in an ultrasonic bath.
  • the MMAD of the powder after spray drying was 7.3 ⁇ m and the fine particle fraction was 28.1% based on the weight of powder in the capsule.
  • the solution thus obtained contains about 9% (w / v) excipient or matrix and 1% (w / v) protein and was spray-dried as described above using the cyclone I with an atomization flow rate of about 0.67 m 3 / h , The aggregate content was examined as described above.
  • the solution thus obtained contains about 3% (w / v) excipient or matrix and 0.33% (w / v) protein and was, as described above, using the cyclone II with an atomization flow rate of about 0.67 m 3 / h spray dried.
  • the aggregate content was examined as described above. • After one week's open storage at 75% relative air humidity and 40 ° C (forced storage stability), the solution made up of the reconstituted powder only had around 5.9% aggregates.
  • the MMAD and FPF of the powder were determined as described above. • The MMAD was 4.9 ⁇ m and the fine particle fraction was 34.7% based on the weight of powder in the capsule.
  • the solution thus obtained contains about 9% (w / v) excipient or matrix and 1% (w / v) protein and was spray-dried as described above using the cyclone I with an atomization flow rate of about 0.67 m 3 / h , The aggregate content was examined as described above.
  • Example 3 Spray drying a trehalose 3% (w / v) L-citrulline 6% (w / v) IgGI 1% (w / v) formulation 1.50 g of trehalose and 3.00 g of L-citrulline were dissolved in about 40 ml of demineralized water (pH about 7.5) in an ultrasonic bath. Next, about 4.6 ml of pure IgGI with a concentration of about 109 mg / ml, formulated in a glycine histidine buffer pH 6 (see materials), were added and the mixture was adjusted with demineralized water (pH about 7.5) Diluted volume of 50 ml.
  • the solution thus obtained contains about 9% (w / v) excipient or matrix and 1% (w / v) protein and was spray-dried as described above using the cyclone I with an atomization flow rate of about 0.67 m 3 / h ,
  • the aggregate content was examined as described above. • After one week's open storage at 75% relative air humidity and 40 ° C (forced storage stability), the solution made up of the reconstituted powder had around 5.9% aggregates.
  • the solution thus obtained contains about 9% (w / v) excipient or matrix and 1% (w / v) protein and was spray-dried as described above using the cyclone I with an atomization flow rate of about 0.67 m 3 / h , The aggregate content was examined as described above.
  • the solution thus obtained contains about 9% (w / v) excipient or matrix and 1% (w / v) protein and was spray-dried as described above using the cyclone I with an atomization flow rate of about 0.67 m 3 / h , The aggregate content was examined as described above.
  • the solution thus obtained contains about 9% (w / v) excipient or matrix and 1% (w / v) protein and was spray-dried as described above using the cyclone I with an atomization flow rate of about 0.67 m 3 / h , The aggregate content was examined as described above.
  • the solution thus obtained contains about 3% (w / v) excipient or matrix and 0.33% (w / v) protein and was, as described above, using the cyclone II with an atomization flow rate of about 0.67 m 3 / h spray dried.
  • the aggregate content was examined as described above.
  • the aggregate content was examined as described above. • After one week's open storage at 75% relative air humidity and 40 ° C (forced storage stability), the solution made up of the reconstituted powder had around 12.6% aggregates.
  • the solution thus obtained contains about 3% (w / v) auxiliary or matrix and 0.33% (w / v) protein and was, as above, using the cyclone II with an atomization flow rate of about 0.67 m 3 / h spray dried.
  • the aggregate content was examined as described above.
  • sucrose 2.00% (w / v) lactose 0.66% (wv) tri-isoleucine 0.33% (w / v) lgG1 0.33% (w / v) formulation 6.0 g of sucrose, 2.0 g of lactose and 1 g of tri-isoleucine were dissolved in about 280 ml of demineralized water (pH about 7.5) in an ultrasonic bath.
  • the solution thus obtained contains about 3% (w / v) excipient or matrix and 0.33% (w / v) protein and was, as described above, using the cyclone II with an atomization flow rate of about 0.67 m 3 / h spray dried.
  • the aggregate content was examined as described above. • After one week's open storage at 75% relative air humidity and 40 ° C (forced storage stability), the solution made up of the reconstituted powder had around 8.8% aggregates.
  • the MMD of the powder was 4.7 ⁇ m after spray drying.
  • the MMAD and FPF of the powder were determined as described above.
  • the MMAD of the powder after spray drying was 4.8 ⁇ m and the fine particle fraction was 53.2% based on the weight of powder in the capsule.
  • the solution thus obtained contains about 3.00% (w / v) excipient or matrix and 0.33% (w / v) protein and was, as described above, using the cyclone II with an atomization flow rate of about 1.05 m 3 / h spray dried.
  • the aggregate content was examined as described above. The following aggregate contents resulted for the storage stability.
  • the MMAD and FPF of the powder were determined as described above.
  • the MMAD of the powder after spray drying was 3.6 ⁇ m and the fine particle fraction was 58.0% based on the weight of powder in the capsule.
  • the MMD of the powder was 2.6 ⁇ m after spray drying.
  • the MMAD and FPF of the powder were determined as described above.
  • the MMAD of the powder after spray drying was 3.3 ⁇ and the fine particle fraction was 58.9% based on the weight of powder in the capsule.
  • the MMD of the powder was 3.2 ⁇ m after spray drying.
  • the MMAD and FPF of the powder were determined as described above.
  • the MMAD of the powder after spray drying was 3.9 ⁇ m and the fine particle fraction was 55.6% based on the weight of powder in the capsule.
  • the MMD of the powder was 4.8 ⁇ m after spray drying.
  • the MMAD and FPF of the powder were determined as described above. • The MMAD of the powder after spray drying was 5.2 ⁇ m and the fine particle fraction was 45.7% based on the weight of powder in the capsule.
  • the MMD of the powder was determined as described above. • The MMD of the powder was 4.2 ⁇ m after spray drying.
  • the MMAD and FPF of the powder were determined as described above.
  • the solution thus obtained contains about 3% (w / v) excipient or matrix and 0.33% (w / v) protein and was, as described above, using the cyclone II with an atomization flow rate of about 0.67 m 3 / h spray dried.
  • the aggregate content was examined as described above.
  • the MMD of the powder was determined as described above. • After spray drying, the MMD of the powder was 3.4 ⁇ m.
  • the MMAD and FPF of the powder were determined as described above.
  • the MMAD was 3.9 ⁇ m and the fine particle fraction based on the weight of powder in the capsule was 58.3%.
  • the MMAD was 3.8 ⁇ m and the fine particle fraction based on the weight of powder in the capsule was 59.6%.
  • the solution thus obtained contains about 3% (w / v) excipient or matrix and 0.33% (w / v) protein and was, as described above, using the cyclone II with an atomization flow rate of about 0.67 m 3 / h spray dried.
  • the aggregate content was examined as described above. • After one week's open storage at 75% relative air humidity and 40 ° C (forced storage stability), the solution prepared from the reconstituted powder had around 3.4% aggregates.
  • the MMD of the powder was determined as described above.
  • the MMD of the powder was 2.9 ⁇ .
  • the MMAD and FPF of the powder were determined as described above.
  • the MMAD was 4.4 ⁇ m and the fine particle fraction was 58.6% based on the weight of powder in the capsule.
  • the solution thus obtained contains about 3% (w / v) excipient or matrix and 0.33% (w / v) protein and was, as described above, using the cyclone II with an atomization flow rate of about 0.67 m 3 / h spray dried.
  • the aggregate content was examined as described above.
  • the MMD of the powder was 2.9 ⁇ .
  • the MMAD and FPF of the powder were determined as described above.
  • the MMAD was 4.4 ⁇ and the fine particle fraction was 58.6% based on the weight of powder in the capsule.
  • Example 5 Production of further powders according to the invention Spray drying of a lysozyme 3.33% (w / v) formulation 5 g of lysozyme is dissolved in about 140 ml of demineralized water (pH about 7.5) and diluted to a volume of 150 ml with demineralized water (pH about 7.5). The solution thus obtained is spray dried as described above using Cyclone II.
  • the residual monomer content was examined as described above. After forced storage, the solution from the reconstituted powder had a residual monomer content of 35.3%.
  • the MMD of the powder was determined as described above.
  • the MMD of the powder was 3.2 ⁇ m.
  • the MMAD and FPF of the powder were determined as described above.
  • the MMAD was 4.0 ⁇ m and the fine particle fraction was 70.4% based on the weight of powder in the capsule.
  • the residual monomer content was examined as described above. After forced storage, the solution from the reconstituted powder had a residual monomer content of 47.9%.
  • the MMD of the powder was determined as described above.
  • the MMD of the powder was 3.9 ⁇ m.
  • the MMAD and FPF of the powder were determined as described above.
  • the MMAD was 4.1 ⁇ m and the fine particle fraction was 29.0% based on the weight of powder in the capsule.
  • the residual monomer content was examined as described above. After forced storage, the solution from the reconstituted powder had a residual monomer content of 47.9%.
  • the MMD of the powder was determined as described above.
  • the MMD of the powder was 2.7 ⁇ m.
  • the MMAD and FPF of the powder were determined as described above.
  • the MMAD was 3.6 ⁇ m and the fine particle fraction was 58.6% based on the weight of powder in the capsule.
  • the MMAD and FPF of the powder were determined as described above.
  • the MMAD was 3.9 ⁇ m and the fine particle fraction was 59.0% based on the weight of powder in the capsule.
  • the MMD of the powder was determined as described above.
  • the MMD of the powder was 2.6 ⁇ m.
  • the MMAD and FPF of the powder were determined as described above.
  • the MMAD was 4.3 ⁇ m and the fine particle fraction was 47.3% based on the weight of powder in the capsule.
  • the MMD of the powder was determined as described above.
  • the MMD of the powder was 2.5 ⁇ m.
  • the MMAD and FPF of the powder were determined as described above.
  • the MMAD was 3.5 ⁇ m and the fine particle fraction was 60.4% based on the weight of powder in the capsule.
  • Example 6 Freeze-drying an IgGI 5% (w / v) formulation
  • IgGI with a concentration of approx. 109 mg / ml, formulated in a glycine histidine buffer pH 6 (see materials), was diluted with demineralized water (pH approx. 7.5) to a content of 50 mg / ml and in the absence of other auxiliaries freeze-dried.
  • the volume of the solution was 50 ml and was distributed to commercially available 2R vials before freeze-drying.
  • the lyophilisate was lyophilized in the 2R vials using a spatula and further treated as described above.
  • the aggregate content was examined as described above.
  • the solution thus obtained contains about 4.5% (w / v) auxiliary or matrix and 0.5% (w / v)
  • Protein was distributed to commercially available 2R vials and freeze-dried as described above.
  • the lyophilisate was lyophilized in the 2R vials using a spatula and further treated as described above.
  • the aggregate content was examined as described above.

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Abstract

L'invention concerne des poudres séchées par pulvérisation et des procédés pour les réaliser. Les poudres de la présente invention contiennent un agent pharmaceutique et un ou plusieurs dérivés de saccharose à liaison O en 1,4, sélectionnés parmi les composés suivants: saccharose D-Gal à liaison O en 1,4 (lactosucrose), saccharose D-Glu à liaison O en 1,4 (glucosyle sucrose), saccharose Glu-Glu à liaison O en 1,4 (maltosyle sucrose). Des compositions préférées comportent du glucosyle sucrose et du maltosyle sucrose.
EP05738129A 2004-05-10 2005-05-04 Poudres sechees par pulverisation contenant au moins un derive de saccharose a liaison o en 1,4 et procedes de realisation associes Withdrawn EP1778188A1 (fr)

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DE102004022926A DE102004022926A1 (de) 2004-05-10 2004-05-10 Sprühgetrocknete Pulver enthaltend zumindest ein 1,4 O-verknüpftes Saccharose-Derivat und Verfahren zu deren Herstellung
PCT/EP2005/004806 WO2005112892A1 (fr) 2004-05-10 2005-05-04 Poudres sechees par pulverisation contenant au moins un derive de saccharose a liaison o en 1,4 et procedes de realisation associes

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CN101304970A (zh) * 2005-12-21 2008-11-12 卫材R&D管理有限公司 1，2-二氢吡啶化合物的无定形物
EP2077132A1 (fr) 2008-01-02 2009-07-08 Boehringer Ingelheim Pharma GmbH & Co. KG Dispositif distributeur, dispositif de stockage et procédé pour la distribution d'une formulation
WO2010060875A1 (fr) * 2008-11-27 2010-06-03 Boehringer Ingelheim International Gmbh Nouveaux médicaments sous forme de poudre cristalline à inhaler
WO2010112358A2 (fr) 2009-03-31 2010-10-07 Boehringer Ingelheim International Gmbh Procédé de revêtement d'une surface d'un composant
EP3508239B1 (fr) 2009-05-18 2020-12-23 Boehringer Ingelheim International GmbH Adaptateur, dispositif d'inhalation et pulvérisateur
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EP2694220B1 (fr) 2011-04-01 2020-05-06 Boehringer Ingelheim International GmbH Appareil médical pourvu d'un récipient
US9827384B2 (en) 2011-05-23 2017-11-28 Boehringer Ingelheim International Gmbh Nebulizer
WO2013152894A1 (fr) 2012-04-13 2013-10-17 Boehringer Ingelheim International Gmbh Pulvérisateur comprenant des moyens de détrompage
US10192396B2 (en) 2013-02-14 2019-01-29 Cfph, Llc Games using financial indicators as random number generators
ES2836977T3 (es) 2013-08-09 2021-06-28 Boehringer Ingelheim Int Nebulizador
JP6643231B2 (ja) 2013-08-09 2020-02-12 ベーリンガー インゲルハイム インターナショナル ゲゼルシャフト ミット ベシュレンクテル ハフツング ネブライザ
EP3139979B1 (fr) 2014-05-07 2023-07-05 Boehringer Ingelheim International GmbH Unité, nébuliseur et procédé
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