AU3421099A - Particulate active agent support for pulmonary application - Google Patents

Particulate active agent support for pulmonary application Download PDF

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Publication number
AU3421099A
AU3421099A AU34210/99A AU3421099A AU3421099A AU 3421099 A AU3421099 A AU 3421099A AU 34210/99 A AU34210/99 A AU 34210/99A AU 3421099 A AU3421099 A AU 3421099A AU 3421099 A AU3421099 A AU 3421099A
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AU
Australia
Prior art keywords
particulate
water
pulmonary administration
excipient
particulate excipient
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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.)
Abandoned
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AU34210/99A
Inventor
Holger Bengs
Jurgen Grande
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Siemens Axiva GmbH and Co KG
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Aventis Research and Technologies GmbH and Co KG
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Priority to DE19816085 priority Critical
Priority to DE19816085 priority
Application filed by Aventis Research and Technologies GmbH and Co KG filed Critical Aventis Research and Technologies GmbH and Co KG
Priority to PCT/EP1999/002385 priority patent/WO1999052506A1/en
Publication of AU3421099A publication Critical patent/AU3421099A/en
Application status is Abandoned legal-status Critical

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    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL, OR TOILET PURPOSES
    • A61K9/00Medicinal preparations characterised by special physical form
    • A61K9/0012Galenical forms characterised by the site of application
    • A61K9/007Pulmonary tract; Aromatherapy
    • A61K9/0073Sprays or powders for inhalation; Aerolised or nebulised preparations generated by other means than thermal energy
    • A61K9/0075Sprays 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
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL, OR TOILET PURPOSES
    • A61K9/00Medicinal preparations characterised by special physical form
    • A61K9/14Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
    • A61K9/16Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
    • A61K9/1605Excipients; Inactive ingredients
    • A61K9/1629Organic macromolecular compounds
    • A61K9/1652Polysaccharides, e.g. alginate, cellulose derivatives; Cyclodextrin

Description

WO 99/52506 PCT/EP99102385 Description PARTICULATE EXCIPIENTS FOR PULMONARY ADMINISTRATION 5 The invention relates to a dry-formulable particulate excipient which is prepared from linear water-insoluble polysaccharides, processes for its preparation and its use. 10 In modern pharmaceutical technology, formulations are desirable whose use form can be administered sparingly and bring a specific influence to bear on the biodistribution, bioavailability or absorption of a medicament. Above all, particulate systems, so-called microparticles, which generally 15 have a particle size in the range of less than 100 pm, have proven of high quality as administration forms or "drug delivery systems" and serve for making available active compounds, in particular pharmaceuticals, in the biological organism. In this context, microparticles in a size range from 1 to 100 pm have especially proven suitable for parenteral use, e.g. 20 subcutaneous injection, in which a long-term release of the active compound can take place for weeks. Significantly smaller microparticles in the range of less than 0.5 pm are being intensively investigated in order to overcome the blood-brain barrier. 25 Therapeutic substances need an administration form which fulfills the physiological conditions (e.g. therapeutic proteins and many others which, for example, are orally administered, can denature in the stomach or undergo enzymatic digestion, and are therefore usually only administered as an injection or in a different invasive manner). 30 In particular, a specific form of noninvasive administration, the pulmonary administration form, offers, in the context of inhalation therapy, the possibility of absorbing therapeutic substances via the lungs with preservation of the therapeutic, diagnostic or prophylactic properties 35 (Patton, Chemtech 1997, 27 (12), 34-38) and makes possible systemic and local treatment and thus leads to a higher patient compliance. For this, it is necessary to make available particulate systems in a size and quality such that they are able to penetrate into bronchi and alveoli, where on account of 2 sensitive membranes an effective absorption of active compound into the blood stream of the organism takes place. Previous to this, the pulmonary administration form already on the market and based on propellant-driven metered aerosols was especially known, 5 which is employed almost totally for the therapy of asthmatic disorders. A disadvantage, however, is the use of ozone-damaging propellants. At present, great efforts are also being undertaken to transfer the administration of pharmaceuticals via the lungs to other active compounds with other indication areas. At the focal point of interest at present are 10 powder inhalation systems, so-called "dry powder inhalers" based on a pharmaceutical dry formulation. This is described in WO 96/32149, and for this the excipient used for the active compound is human serum albumin including additive; Langer et al. in Science 276, 1997, 1868 describe the use of microparticles of polylactic acid, which are loaded to 10-20% with 15 insulin and achieve comparable results to correspondingly subcutaneously injected microparticles (Abstract Controlled Release Society Conference, Sweden 1997). The size of the particles is in the range between 8 and 20 pm. 20 In WO 97/35562, active compound-loaded microparticles for pulmonary administration are described which are prepared from aqueous solution and disadvantageously can only absorb water-soluble active compounds. A further publication WO 97/44013 discloses porous particles of polylactic co-glycolic acid, which have a diameter of 5 to 30 pm. 25 In WO 96/32116, microparticles of the order of size of 0.5 to 50 pm are described, which consist of nucleic acids or viral vectors and can be obtained from a suspension by means of hydrophilic oligomeric polysaccharides with drying, in particular spray drying. WO 96/32152 describes particles consisting of the active compound 30 a-1-antitrypsin of size 1-50 gm, diluents also being allowed. The publication WO 97/36574 describes hollow particles having a smooth surface; the size is 0.5-7.0 pm. In the publications WO 97/36574, WO 96/36314, WO 96/00127 and 35 WO 96/32096, further particulate systems are described, which consist of partly synthetic polymers or of the active compound as such, of very different size.

3 In the prior art, it is problematic that the depot action of the particles is relatively limited. In addition, these are water-soluble products mostly arising from a chemical synthesis which restricts their biocompatibility (solvent residues, foreign material etc.). Likewise, inhomogeneous particles 5 which are uneven in size, surface area and composition are obtained, which restricts the bioavailability, in particular in pulmonary administration, e.g. loss due to deposits outside the target site and adverse effect on the dispersibility. In addition, problems result in the prior art with respect to the loading ability of the carrier. 10 It is therefore the object of the invention to develop a dry-formulable excipient of a special quality for the applicators available on the market and which gets around these disadvantages. In particular, the possibility should be provided here of establishing a particle technology which is able to 15 achieve a depot effect in the lung. It is therefore likewise the object of the invention to prepare dispersible particulate excipients. An object is likewise the provision of a process which is as simple and advantageous as possible for the preparation of dry formulations which can preferably be used in the context of pulmonary administration. In this regard, the 20 optimization of the excipient in size, surface area and morphology with respect to use for inhalation is likewise an object. The object is achieved in that particulate excipients for pulmonary administration are made available which contain at least one linear water insoluble polysaccharide and whose mean size is less than 10 pm. 25 By means of the measures according to the invention additional advantages are achieved: * Easier loading ability of the excipient with active compound due to the good suspensibility in various media (e.g. dispersion process, spray 30 drying); * Acceptability and high biocompatibility of the excipient used due to naturally occurring structures and due to the use of naturally identical products; * The avoidance of an addition of surface-active compounds in the 35 preparation of the active compound formulation; " The aerodynamic diameter, which has a positive effect for the flight behavior. This is achieved on account of the porous surface nature in comparison with a smooth sphere and is assisted by the tendency 4 accompanying the surface roughness for cluster and/or agglomerate formation. Within the meaning of the invention, particulate excipient designates 5 particles of a mean size of less than 10 pm, in particular of 1 to 10 pm, preferably 2 to 6 pm and particularly preferably 1 to 3 pm, which as an essential constituent contain at least one linear water-insoluble polysaccharide. Linear water-insoluble polysaccharides within the meaning of the present 10 invention are polysaccharides, preferably polyglucans, in particular poly(1,4-alpha-D-glucan), which consist of monosaccharides, disaccharides, further oligomers thereof or derivatives. These are always linked to one another in the same manner. Each base unit defined in this way has exactly two linkages, each one to another 15 monomer. Excluded therefrom are the two base units, which form the beginning and the end of the polysaccharide. These base units have only one linkage to a further monomer. In the case of three or more linkages (covalent bonds) of a monomer to another group, preferably a further saccharide unit, branching is referred to. At least three glycosidic bonds 20 then start from each saccharide unit in the polymer backbone. According to the invention, branchings do not occur or only occur to such a small extent that in general they are no longer accessible to the conventional analytical methods in the existing very small branching proportions. For example, this is the case if, based on the totality of all 25 hydroxyl groups present to 100 hydroxyl groups which are not needed for the synthesis of the linear polysaccharide, at most 5 hydroxyl groups are occupied by linkages to other saccharide units. The degree of branching here is maximal (100%) if the free hydroxyl groups (or other functional groups occurring) have further glycosidic (or 30 other) bonds to further saccharides in any saccharide unit. The degree of branching is minimal (0%) if apart from the hydroxyl groups which cause the linearity of the polymer no further hydroxyl groups on the saccharides are modified by chemical reaction. Examples of preferred water-insoluble linear polysaccharides are linear 35 poly-D-glucans, the nature of the linkage being insignificant as long as linearity within the meaning of the invention is present. Examples are poly(1,4-alpha-D-glucan) and poly(1,3-beta-D-glucan), poly(1,4-alpha-D glucan being particularly preferred.

5 If the base unit has three or more linkages, this is referred to as branching. The so-called degree of branching results here from the number of hydroxyl groups per 100 base units which are not involved in the synthesis of the linear polymer backbone and which form branchings. 5 According to the invention, the linear water-insoluble polysaccharides have a degree of branching of less than 8%, i.e. they have less than 8 branchings to 100 base units. Preferably, the degree of branching is less than 4% and in particular at most 1.5%. 10 If the water-insoluble linear polysaccharide is a polyglucan, e.g. poly(1,4 alpha-D-glucan), the degree of branching in the 6-position is less than 4%, preferably at most 2% and in particular at most 0.5%, and the degree of branching in the other positions not involved in the linear linkage, e.g. the 15 2- or 3-position in the case of the preferred poly(1,4-alpha-D-glucan), is preferably in each case at most 2% and in particular at most 1%. Particularly preferred are polysaccharides, in particular poly-alpha-D glucans, which have no branchings, or whose degree of branching is so 20 minimal that it is no longer detectable using conventional methods. According to the invention, the prefixes "alpha", "beta" or "D" on their own relate to the linkages which form the polymer backbone and not to the branchings. 25 "Water insolubility" in the sense of the present invention means that no detectable solubility of the compound exists under normal conditions (room temperature of 25 0 C and an air pressure of 101325 pascals or based on values differing at most 20% therefrom). 30 In the case of the polysaccharides used according to the invention, in particular of the polyglucans such as poly(1,4-alpha-D-glucan), this means that at least 98% of the amount employed, preferably an amount of greater than 99.5%, is insoluble in water. The term insolubility here can also be 35 explained with the aid of the following observation. If 1 g of the linear polysaccharide to be investigated is heated to 130 0 C in 1 I of deionized water under a pressure of I bar, the resulting solution only remains stable briefly, for a few minutes. On cooling under normal conditions, the substance reprecipitates. After further cooling and separation using the 6 centrifuge with inclusion of experimental losses, at least 66% of the amount employed can be recovered in this way. In the context of this invention, linear, water-insoluble polysaccharides are preferably used which can be obtained with the aid of generally defined 5 biotechnological or genetic engineering methods. A particularly advantageous embodiment of the invention described here is the preparation in a biotechnological process, in particular in a biocatalytic process or in an enzymatic process. Linear polysaccharides prepared by biocatalysis (also: biotransformation) in 10 the context of this invention means that the linear polysaccharide is prepared by catalytic reaction of monomeric base units such as oligomeric saccharides, e.g. of mono- and/or disaccharides, by using a so-called biocatalyst, customarily an enzyme, under suitable conditions. Preferably, poly(1,4-alpha-D-glucan) in particular is prepared by means of 15 polysaccharide synthases and/or starch synthases and/or glycosyl transferases and/or alpha-1,4-glucan transferases and/or glycogen synthases and/or amylosucrases and/or phosphorylases. Linear polysaccharides from fermentation in the usage of the invention are linear polysaccharides which can be obtained by enzymatic processes 20 using organisms occurring in nature, such as fungi, algae or microorganisms or using organisms not occurring in nature, which can be obtained by modification of natural organisms, such as fungi, algae or microorganisms, by means of genetic engineering methods of general definition. Moreover, linear polysaccharides for the preparation of the 25 delayed-release tablet [sic] described in the present invention can be obtained from nonlinear polysaccharides which contain branchings by treating them with an enzyme and linear polymers thereof can be obtained with cleavage (e.g. by means of enzymes, such as amylase, iso-amylase, gluconohydrolase, pullulanase, inter alia) and removal of the branchings. 30 The obtainment and purification of linear water-insoluble polysaccharides by means of biotechnological and genetic engineering methods from plants cannot be excluded and is expressly also included. The particulate excipients can be prepared in particular by the microparticle technique which is the subject of the patent application (German Patent 35 Office, ref.: 197 37 481.6). In addition to the dry formulation, inhalations based on dispersions and suspensions of the excipient are conceivable, which are expressly also CORRECTED SHEET (RULE 91)

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7 included here. A particularly suitable and preferred embodiment, however, is to be seen as inhalation based on the dry formulation. In this connection, this is a dispersible dry powder which can be administered to the airways by means of dry powder inhalers. 5 It is essential to the invention that microparticles are made available in the dry formulation as described in the patent application (German Patent Office, ref.: 197 37 481.6). In this connection, these are monoparticles (Figure 1 and 2) which have a particularly suitable aerodynamic diameter which has an advantageous effect on an inhalation (e.g. decreased 10 deposition on walls). The clusters and/or aggregates and/or agglomerates formed from the monoparticles exhibit particularly advantageous aerodynamic diameters for the purposes of the invention. Likewise, an improved active compound distribution and lung penetration (also: respiratory depth) is achieved on account of the mixing of these particles 15 taking into account the anatomical conditions of the lungs (see Examples on Andersen Impactor). For the definition of the aerodynamic diameter mentioned, the invention makes use of the definition on the basis of the specification WO 97/36574, [lacuna] being determined by the multiplication of the geometric diameter, 20 which determines the spatial extent of a spherical structure (e.g. a spherical particle) by the distance from surface to surface through the center point of the spherical structure, with the root of the particle density. A cluster and/or an aggregate and/or agglomerate is to be understood as meaning an accumulation of monoparticles which result due to the build-up 25 of noncovalent forces. A cap-like and/or raspberry-like and/or spherical structure, for example, acts particularly advantageously here, as shown in Figure 3 and Figure 4. Noncovalent forces can be, for example, bipolar interactions, van-der-Waals forces, hydrogen bridges or alternatively steric interactions, the latter as generally defined also being designated as the 30 key-lock principle. The molecular weights MW of the linear polysaccharides used according to the invention can vary within a wide range from 103 g/mol to 107 g/mol, preferably molecular weights MW [lacuna] used in the range from 104 g/mol to 105 g/mol, in particular 5 x 103 g/mol to 5 x 104 g/mol. For the linear 35 polysaccharide poly(1,4-alpha-D-glucan) preferably used, corresponding ranges of the molecular weights are used. CORRECTED SHEET (RULE 91)

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8 "Biocompatible" within the meaning of this invention means that the polysaccharides employed may be subject to complete biological degrada tion and very substantially no concentration takes place in the body. 5 Biological degradation is regarded here as any process occurring in vivo which leads to degradation or destruction of the polymer In particular, hydrolytic or enzymatic processes likewise fall in this area. For the biocompatibility of the polysaccharides and its degradation products (metabolites), even the naturally identical character of the polysaccharides 10 employed is not in the end of great importance. Therefore the polysaccharides in question are particularly suitable for therapeutic, diagnostic or prophylactic use. In addition, the term "pharmaceutically acceptable" within the meaning of this invention adds that a carrier for an active compound, an auxiliary or 15 even a so-called excipient can be absorbed by a living being without significant side effects resulting for the organism. In the particular case of pulmonary administration, this means that the auxiliary can be absorbed by the lungs and is degraded, dissolved and further transported by the endogenous mechanisms or else deposits occur which also do not lead to 20 disadvantageous effects for the living being due to accumulation. "Controlled release of active compound" is understood as meaning that the active compounds is released after a specific time and/or period of time in a dose which is advantageous for the biological organism with acceptance of a statistical deviation corresponding to the circumstances. 25 This definition also includes extremes. On the one hand, the spontaneous release of all active compounds present in the formulation within a period of time approximating to the value zero. On the other hand, the minimal necessary amount/dose for the attainment of a therapeutic effect over a 30 long, even infinite period of time, at least a period of time which is necessary to release all active compounds present in the formulation. For the dry formulation present here, therefore, reference is synonymously made to a depot formulation or formulation having delayed release. "Dry formulation" and/or "powder" within the meaning of this invention 35 means a composition which consists of fine solid particles of the respective pharmaceutical composition. These particles are free-flowing and dispersible in their entirety.

9 In the particular case of use by inhalation, dry formulation and/or powder additionally means that they are used in an apparatus for the inhalation of a dry powder such that a therapeutic effect is discernible. In this connection, the term "utilizable for the pulmonary transport of active compounds" or 5 "inhalable", "breathable" or "respirable" is also used. In this connection, in the context of this invention "dry" is understood as meaning a water content of less than 25%, a water content of less than 15% being preferred. A water content of 5% to 10% is particularly 10 preferred. "Therapeutic effect" within the meaning of this invention means that a therapeutically effective amount of an active compound reaches the desired target site, displays its action there, and causes a physiological reaction. The palliative and/or curative effect is included. 15 "Dispersibility" within the meaning of this invention means that the dry formulation obtained by external mechanical forces can be atomized or fluidized such that this state is so stable for a determined short period of time (solid in gaseous or solid in liquid) that a continuing process can be initiated which gives a greater benefit. In the context of this invention 20 pulmonary use, i.e. active compound absorption via the lungs, serves as an outstanding example, but other active compound transport phenomena are also not excluded. For pulmonary administration, the generally accessible inhalers found on the market, in particular so-called "dry powder inhalers" can be employed 25 and equipment already described in patents and publications can be used (manufacturer: 3M Manufacturing Minnesota Mining, Inc., Inhale Therapeutic Systems, Inc., Dura Pharmaceuticals, Aerogen and Aradigm Corporation, WO 94/16756, WO 96/30068, WO 96/13292, WO 96/33759, WO 96/13290, WO 96/32978, WO 94/08552, WO 96/09085, WO 95/28192). 30 The active compounds which can be administered to the airways as a pharmaceutical composition by means of the excipient described are subject to no restrictions whatsoever. In particular, the pharmaceutical composition is efficacious for syndromes which are either genetically caused or else have been acquired in the 35 course of life. The release of the active compound can either take place systemically or locally. A palliative or curative effect can be demanded.

10 The active compounds employed with the present invention can be either water-soluble or water-insoluble. The active substances or active com pounds employed in the pharmaceutical sector can either be therapeutically or diagnostically active, but also prophylactically active. 5 The active compounds employed can apply to all sorts of indications. Those to be mentioned are, for example: asthma, cystic fibrosis, general lung diseases, diabetes (hypoglycemic reaction), cancer, mucoviscidosis, renal anemia, hemophilia, stimulation of ovulation, neutropenias, Gaucher's disease, hypernephroma, hair cell 10 leukemia, carcinoma, multiple sclerosis, chronic granulomatosis, myocardial infarct, thromboses, pituitary hyposomia, treatment of heparin associated thrombocytopenia (HAT) type 11, vaccinations, prevention of hepatitis B, stimulation of growth of cellular elements, bronchitis, chronic airway disorders, lung diseases and chest infections. 15 The particulate excipients are subject to no restrictions whatsoever with respect to the stability of the active compounds. The naturally identical polysaccharides used are chemically inert substances, so that even sensitive active compounds, such as peptides and proteins can be administered. In this context, peptides and proteins are particularly of 20 interest which are constructed of the twenty natural amino acids. The partial replacement of natural amino acids by amino acids which do not occur naturally, however, has no effect on the utility of the invention described here (e.g. cetrorelix). Furthermore, the administration of oligonucleotides or viral vectors is also possible. 25 In the case of the proteins and peptides, compounds derived from nature can be employed or even those which can be prepared, in particular, by biotechnological and/or genetic engineering process steps and are generally to be incorporated under the designation of recombinant active compounds. In particular, therapeutics or vaccines are distinguished here, 30 as are human DNAse (dornase alpha), erythropoietin alpha (epoetin alpha), erythropoietin beta (epoetin beta), factor VII (eptacog alpha), factor Vill, follitropin alpha, follitropin beta, G-CSF, glycosylated (lenograstim), G-CSF (filgrastim), GM-CSF (molgramostim), glucagon, glucocerebrosidase (alglucerase), IL-2 (aldesleukin), interferon alpha-2a, interferon alpha-2b, 35 interferon beta-1b, interferon gamma-1b, insulin (human insulin, lispro), t-PA (alteplase), r-PA (reteplase), human growth hormone (HGH, somatropin), hirudin, hepatitis B-antigen, hepatitis A/B combination 11 vaccine, MPIF-1 (myeloid progenitor inhibitor factor-1), KGF-2 (keratinocyte growth factor). All in all, active compounds from the following group and classes of these 5 active compounds can also be advantageously used, especially in pulmonary administration, with the technology presented here: calcitonin, felbamate, AZT, DDI, GCSF, lamotrigin, gonadotropin releasing factor (hormone) (GNRH, GHRH and GHRH analogs), luteinizing hormone releasing hormone (LHRH) and LHRH analogs (both antagonists and 10 agonists, e.g. leuprolide acetate, leuprolide, lupron or lupron depot, buserelin, ramorelix, cetrorelix), TRH (thyreotropin releasing hormone), adenosine deaminase, argatroban, a1-antitrypsin, albuterol, amiloride, terbutalin, isoproterenol, metaprotaranol, pirbuterol, fluticasone propionate, budesonied, beclomethasone dipropionate, cromoglycic acid, disodium 15 cromoglycate, nedocromil, sultanol, beclomethasone, bambuterol, mometasone, triacetonide, isoproterenol, cromolyn, salmeterol, salmeterol xinotate, formotorol, triamcinolone acetonide, flunisolide, fluticasone, salbutamol, budesonide, fenoterol, ipratropium bromide, tachykinin, tradykinin, furosemide, disodium cromoglycate, nafarelin, cromolyn sodium, 20 albuterol sulfate, metaproterenol sulfate, somatostatin, oxytocin, desmopressin, ACTH analogs, secretin glucagon, codeine, morphine, disodium cromoglycate, diltiazem, cromoglycate, ketotifen, cephalosporin, pentamidine, fluticasone, tipredan, noscapine, isoetharine, amiloride, ipratropium, oxitropium, cortisone, prednisolone, aminophyline, 25 theophyline, methapyrilene. Analgesics, anginal preparations, antiallergics, antihistamines, antiinflammatories, bronchodilators, bronchospasmolytics, diuretics, anticholinergics, antiadhesion molecules, cytokine modulators, biologically active endonucleases, recombinant human DNases, neurotransmitters, 30 leukotrine inhibitors, vasoactive intestinal peptide, endothelin antagonists, analeptics, analgesics, local anesthetics, anesthetics, antiepileptics, anticonvulsants, antiparkinson agents, antiemetics, compounds regulating or stimulating the hormone system, compounds regulating or stimulating the cardiovascular system, compounds regulating or stimulating the 35 respiratory tract system, vitamins, trace elements, antioxidants, cytostatics, antimetabolites, antiinfectives, immunomodulators, immunosuppressants, antibiotics, proteins, peptides, hormones, growth hormones, growth factors, xanthines, vaccines, steroids, b2 mimetics.

13 Example 2 Characterization of the poly(1,4-a-D-glucan) synthesized with amylo 5 sucrase from Example 1 by means of gel permeation chromatography 2 mg of the poly(1,4-a-D-glucan) from Example 1 are dissolved in dimethyl sulfoxide (DMSO, p. a. from Riedel-de-Haen) at room temperature and filtered (2 mm filter). One part of the solution is injected into a gel 10 permeation chromatography column. DMSO is used as an eluent. The signal intensity is measured by means of an RI detector and evaluated against pullulan standards (Polymer Standard Systems). The flow rate is 1.0 ml per minute. The result of a measurement is indicated below: numerical average of the 15 molecular weight (Mn) of 3200 g/mol and a weight average of the molecular weight (MW) of 9300 g/mol. This corresponds to a dispersity of 2.8. Example 3 20 Preparation of microparticles of poly(1,4-a-D-glucan) 400 g of poly(1,4-a-D-glucan) are dissolved in 2 I of dimethyl sulfoxide (DMSO, p.a. from Riedel-de-Haen) at 40*C in the course of [lacuna]. The solution is then stirred at room temperature for one hour. The solution is 25 added to 20 I of double-distilled water with stirring through a dropping funnel over a period of time of 2 h. The mixture is stored at 6*C for 40 h. A fine suspension is formed. The particles are separated off by first decanting off the supernatant. The sediment is slurried and centrifuged in small portions (ultracentrifuge RC5C: 5 minutes each at 5000 revolutions per 30 minute). The solid residue is slurried with double-distilled water and centrifuged again a total of three times. The solids are collected and the suspension of about 1000 ml is freeze-dried (Christ Delta 1-24 KD). 283 g of white solid are isolated (Example 3a: yield 71%). The collected supernatants are kept at a temperature of 18*C overnight. Working up is 35 carried out as described. A further 55 g of the white solid are isolated (Example 3b: yield 14%). The total yield is 85%. CORRECTED SHEET (RULE 91)

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14 Example 4 Desulfurization of the microparticles from Example 3 5 To remove dimethyl sulfoxide remaining in the particles, the procedure is as follows. 100 g of the amylose particles from Example 9 are added to 1000 ml of deionized water. The mixture is left by itself for 24 h with slight swirling. The particles are removed as described in Example 9 10 (ultracentrifuge RC5C: 15 minutes each, 3000 rpm. After freeze-drying, a final weight of 98.3 g results (98% yield). Sulfur determination by elemental analysis gives the following values (test method combustion and IR detection): sulfur content of the particles from Example 2: 6% +/- 0.1% 15 sulfur content of the particles from Example 3: < 0.01% Example 5 Investigations of the microparticles from Example 3 by means of electron 20 microscopy To characterize the particles, scanning electron micrographs (SEMs) (Camscan S-4) are carried out. The figures (Figure 1 and Figure 2) show plots of the particles which illustrate that they are spherical, very uniform 25 particles with respect to shape, size and surface roughness. The figures (Figure 3 and Figure 4) show plots of the clusters and/or agglomerates formed. Example 6 30 Investigations of the size distributions of the particles from Example 3 To characterize the size distributions of the particles from Examples 1 and 9, investigations with a Mastersizer were carried out (Malvem Instruments). 35 The investigation was carried out in the Fraunhofer mode (evaluation: multimodal, number) with a density of 1.080 g/cm3 and volume concentration in the range from 0.012% to 0.014%. CORRECTED SHEET (RULE 91)

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15 Table 1: Characterization of the particle diameters of the microparticles from Example 3 5 Example Diameter Particle distribution No. dn* dw*2 dw / d (10%)*4 d (50%)*5 d (90%)*6 (mm) (mm) dn* 3 (mm) (mm) (mm) 3a 1.664 4.184 2.541 0.873 1.504 2.624 3b 0.945 2.345 2.481 0.587 0.871 1.399 *1 * dn: Number average of the diameter *dw: Weight average of the diameter dw / dn: Dispersity of the particle diameters 10 4 d(10%): 10% of all particles have a smaller diameter than the value indicated d(50%): 50% of all particles have a smaller diameter than the value indicated *6 d(90%): 90% of all particles have a smaller diameter than the value 15 indicated Example 7 Determination of the flight distance of microparticles of poly(1,4-ai-D 20 glucan) An Andersen impactor (Andersen Samplers Inc., 4215 Wendell Drive, Atlanta, GA, USA and cf. Pharmacopoeia Europaeum, Stuttgart, Deutsche CORRECTED SHEET (RULE 91)

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16 Apothekerverlag 1997, Chap. 2.9.18; here: appliance D) consists of a cascade of plates separated from one another, which are successively equipped with smaller holes (pores). Depending on the aerodynamic particle size, deposition takes place on the individual plates. 5 Table 2: Characteristics of the Andersen impactor Filter stage Hole diameter Hole diameter Number of holes [inch] [F.mI*1 0 0.1004 2550 96 1 0.0743 1887 96 2 0.0360 914 400 3 0.0280 711 400 4 0.0210 533 400 5 0.0135 342 400 6 0.0100 254 400 7 0.0100 254 201 The data in "mm" were obtained by conversion of the manufacturer's 10 data in "inches". The Andersen impactor experiments proceed as follows: 100 mg of the substance (in this case: three different samples of microparticles and agglomerates (clusters) of poly(1,4-a-D-glucan); prepared according to 15 Ex. 3 and 4) are added to the mixture opening of the impactor and sucked into the filter cascade using the pump belonging to the equipment (pump output: 35 I/min.). After one minute, the apparatus is stopped and the mass of the individual filters (or impact plates) is determined. The masses of microparticles are plotted in the following figure. In this case, the good flow 20 behavior with minimal pump output is especially clear, which is reflected in the high mass on higher impact plates (filters). The residue remaining at the starting point can be minimized by keeping the particles in suspension by mechanical vibration at the mixture opening of the impactor (cf. Sample 2). The behavior of various samples of poly(1,4-a-D-glucan) in 25 the Anderson impactor is shown in Figure 5. REPLACEMENT SHEET (RULE 26) 17 Example 8 Determination of the flight distance of powders of further polysaccharides, [lacuna] conventional inhalers and microparticles of synthetic polymers 5 (comparison examples) The comparison examples with other, partly water-soluble polysaccharides, material from conventional inhalers and microparticles of synthetic, but biodegradable polymers (comparison examples) were carried out 10 analogously to Example 8. The polysaccharides are a potato starch of the type Toffena (SUdstarke) and a rice starch of the type Remygel (REMY) with particle sizes up to 100 mm and around 4 mm. The inhalers are the Aerolizer (Inhaler 1, Ciba Geigy) and the Atemur Diskus (Inhaler 2, cascan). The microparticles of polylactide-co-glycolide (PLGA) were 15 prepared by means of spray drying (material PLGA 65:35-d, I of Medisorb) and have approx. diameters between 2 and 15 mm. The behavior of other, partly water-soluble polysaccharides in the Andersen impactor (comparison examples) is shown in Figure 6. 20 The behavior of material from conventional inhalers and microparticles from synthetic, biodegradable polymers in the Andersen impactor (comparison examples) is shown in Figure 7. 25 Example 9 Determination of the flight distance of microparticles of various geometries of poly(1,4-a-D-glucan) and agglomerates thereof 30 The flight or deposition behavior of microparticles of various size and surface roughness is investigated in a curved tube. The experiments form the basis for estimation of an optical morphology of particles and agglomerates for administration in a dry powder inhaler. The model is based on the following assumptions: passage through which air flows 35 d = 20 mm; air density rfi = 1.2 kg/m 3 ; air viscosity h = 1.81 x 10-5 Pa s; flow rate vfi = 5 m/s; radius of curvature R = 20 (200) mm; angle of CORRECTED SHEET (RULE 91)

ISA/EP

18 curvature a = 450; particle diameter x = 1 - 5 mm; solid density rs = 1550 kg/m 3 ; form factor Y = 1 and differing. First, the behavior of spherical and nonspherical particles is compared with one another. For nonspherical particles, a structure for the description of 5 the geometry is prespecified. The settling rates in the gravitational field in air and the radial deflection of such a particle when flowing through a bend in a tube are sought. With the aid of the calculated deflection, it can be estimated how many particles touch the wall and remain adhered, i.e. are deposited, when flowing through the bend in the tube. 10 The deviation of the particle form from the sphere can be described with the aid of the form factor T. It is defined as the ratio of the surface of a sphere with equal volume to the actual surface of the particle. For spheres, T = 1, for nonspherical particles T is < 1. The smaller the form factor, all the more a particle follows the air flow and all the less it is deposited by wall 15 adhesion in tube curves. The aerodynamic diameter behaves reciprocally to the form factor. A value of T = 0.8 is, for example, comparable with a decrease in the solid density from 1550 kg/m 3 to 1400 kg/M 3 . In a first observation, a smooth sphere was compared with a sphere with a rough surface. The roughness was approximated by relatively small 20 spherical sections (spherical caps) which were mounted on a base sphere. The sections were on the one hand directed outward (raspberry structure) and on the other hand inward (crater landscape). For outwardly directed sections, the form factor turned out to be T = 0.958 and for inwardly directed sections to be T = 0.946. Furthermore, agglomerates of particles 25 were observed. The observed agglomerates (bodies) ideally form the following arrangements in the arrangement of a very tight spherical packing (for tetrahedrons see also Figure 2). The bodies are modeled from agglomerates of individual spheres and have the following structure: a) a tetrahedron constructed from spheres having 4 layers. The edges are 30 formed of 4 spheres in each case. All in all, the tetrahedron consists of 20 individual spheres; b) bodies formed from 3 spherical layers having 3, 7 and again 3 individual spheres (small double cone); c) bodies formed from 5 layers having a sphere number of 1, 3, 7, 3 and 1 per layer (large double cone). 35 The table summarizes the results of the calculations. For comparability, only the deviation from the spherical form is considered as a parameter in the case of a prespecified volume-equivalent particle diameter of 5 pm. It is CORRECTED SHEET (RULE 91)

ISA/EP

19 to be noted that the diameter of the individual spheres for the abovementioned geometries is correspondingly lower. The settling rate decreases with increasing deviation from the spherical form. Accordingly, the degree of deposition when flowing through a bend in the tube also 5 decreases. In comparison with the sphere having the diameter of 5 pm, the degree of deposition is reduced to 66% for the particle forms constructed from agglomerates. The results of these model experiments confirm the advantageousness of the present invention with respect to the surface roughness, and also the agglomerates, which are organized in the sense of 10 a very tight spherical packing. In particular, it is seen that with a decreasing form factor T, i.e. toward zero, the aerodynamic diameter improves. The better the aerodynamic diameter, the deeper the lung penetration (respiratory depth). 15 Table 2: Results of the calculation for the particle forms described above Form Agglomerate Settling rate in Radial Degree of factor density the gravitational deflection deposition T [kg/m 3 ] field [mm] [%] [m/s] Sphere 1 1550 0.001165 0.466 2.33 Sphere 0.946 1550 0.001134 0.453 2.26 (caps on the inside) Sphere 0.958 1550 0.001141 0.456 2.28 (caps on the outside) Agglomerate 0.49 1430 0.000753 0.301 1.50 Tetrahedron Agglomerate 0.56 1390 0.000782 0.313 1.56 double cone 3 planes Agglomerate 0.52 1405 0.000762 0.305 1.52 double cone 5 planes CORRECTED SHEET (RULE 91)

ISA/EP

20 Example 10 Loading of the particles with active compound by means of a suspension process 5 The microparticles, or agglomerates, of poly(1,4-a-D-glucan) (preparation in Examples 3 and 4) are loaded with active compound by means of a suspension process. 250 mg of buserelin are dissolved in 10 ml of distilled water. 100 mg of particles are added. The suspension is stirred for 3 h. The 10 suspension is centrifuged. The centrifugate is washed with water. The particulate solid is separated off by centrifuge (3000 rpm) and the centrifugate is freeze-dried. By dissolution of an exact amount of the particles in a water-dimethyl sulfoxide and spectroscopic measurement in a UV-Vis spectrometer, the loading with buserelin can be calculated to be 15 3.28% by means of a calibration curve, based on the total mass of the particles. By means of the modification of the solvent for the active compound, e.g. alcohols, the solubility and thus the loading of the particles with active compound can be influenced. (* 5-Oxo-L-prolyl-L-histidyl-L-tryptophyl-L-seryl-L-tyrosyl-O-tert-butyl-D 20 seryl-L-leucyl-L-arginyl-N-ethyl-L-prolinamide) Example 11 Loading of the particles with active compound by means of spray drying 25 The microparticles are suspended in distilled water, or a mixture of water and a readily volatile component such as acetone or ethanol. To do this, 10 g of the solid are suspended in 1000 ml of the solvent. 0.5 g of theophylline was dissolved in the solvent beforehand. The spray drier (mini 30 spray drier 191 from BOchi) is operated as follows: Atomization air flow 700 liters per hour, inlet temperature 200*C, nozzle cooling switched on, nozzle diameter 0.5 mm, aspirator 70%, pump 10%. The spectroscopic investigation of the loading (description see example above) shows a degree of loading of 4.8%. This value agrees with the 35 theoretically achievable value of 5.0% within the limits of error. Example 12 CORRECTED SHEET (RULE 91)

ISA/EP

21 Determination of the solubility of polysaccharides 100 mg of poly(1,4-a-D-glucan) are added to 5 ml of double-distilled water. The reaction vessel is slowly heated with stirring (magnetic stirrer). It is 5 heated in a step program with intervals of twenty degrees and observed with the eye. No changes are to be observed at temperatures of 40*C, 60*C, 80*C and 100 0 C. According to these observations, the compound can be assigned the characteristic "water-insoluble". 10 Example 13 Determination of the solubility of polysaccharides and classification according to the German Pharmacopeia (GP) 15 564 mg of poly(1,4-a-D-glucan) are heated in about 0.5 I of double-distilled water in an autoclave at 1.3 bar and 130*C for 1.5 hours (Certoclav apparatus). The weight of the reaction vessel has been measured before hand. The pressure in the apparatus is then released and it is cooled to room temperature. The contents are weighed. They correspond to 20 501.74 g. After a further 24 hours, the mixture is centrifuged and the supernatant is decanted. The solid residue is dried and weighed: 468 mg. A dissolved fraction of 96 mg is calculated therefrom. Based on the solvent employed, it is calculated therefrom that for 1 mg of poly(1,4-a-D-glucan) 5226 mg of water are necessary. According to the classification in the 25 German Pharmacopeia, the classification results therefrom that this substance is "very poorly soluble", since between 1000 and 10,000 parts of solvent are necessary in order to bring 1 part of the substance into solution. Of the 7 classes for the classification of solubility (from "very readily soluble" (Class 1) to "virtually insoluble" (Class 7), this is Class Number 6. 30 Example 14 Determination of the solubility of polysaccharides and classification according to the German Pharmacopeia (GP) 35 CORRECTED SHEET (RULE 91)

ISA/EP

22 The experiment is carried out as in Example 13. The only difference is a cooling process which is inserted after the autoclave treatment and cooling to room temperature. The substance mixture is stored at 5 0 C for 3 hours. 5 526 mg of poly(1,4--D-glucan) are weighed into about 480 ml of double distilled water. After the heat treatment, a final weight of 468.09 g results. The dried sediment amounts to 488 mg. 38 mg of the poly(1,4-a-D-glucan) have therefore dissolved. This corresponds to a ratio of 1 mg of substance to 12,318 parts of solvent. The substance is therefore to be assigned to 10 Class Number 7 as specified in the GP according to this treatment method and accordingly to be classified as virtually insoluble, because more than 10,000 parts of solvent are needed for one part of substance. Example 15 15 Preparation of microparticles from an autoclaved poly(1-4-alpha-D-glucan) suspension 3.5 g of poly(1-4-alpha-D-glucan) powder are washed three times with 20 water at 60*C. It is then suspended in 200 ml of deionized water. The suspension is placed in a laboratory autoclave (Pressure Vessels; type 452 HCT 316; from Parr Instruments Deutschland GmbH). The chamber is flushed with nitrogen so that a pressure of 1.5 bar is reached. The autoclave is heated to 130 0 C with stirring. The autoclaving time at this 25 temperature is 30 min. A pressure of about 5 bar is generated. After cooling of the autoclave, the suspension is removed and immediately sprayed into a spray dryer. During this the suspension is continuously stirred with the aid of a magnetic stirrer. The spray dryer (Mini Spray Dryer 191, from Buchi, Switzerland) is 30 operated as follows: atomizing nitrogen stream 700 liters per hour, inlet temperature 220 0 C, nozzle cooling switched on, nozzle diameter 0.5 mm, aspirator 70%, pump 70%. The spray-dried material is removed from the collecting vessel of the cyclone and stored in the dry. The size of more than 90% of the 35 microparticles is in the range below 10 pm (analysis of electron micrographs). CORRECTED SHEET (RULE 91)

ISA/EP

23 Example 16 Preparation of microparticles from poly(1,4-alpha-D-glucan) 5 The possibility of producing polyglucan resulting directly from biotransformation for preparing respirable particles is investigated. This is done by preparing a 20% strength suspension by suspending 500 g of poly(1,4-alpha-D-glucan) from Example 1 in 2.5 I of water. The suspension is spray dried. This is done by operating the spray dryer (Mini Spray Dryer 10 B-191 from Buchi) as follows: atomizing air stream 650 liters per hour, inlet temperature 140 0 C, no nozzle cooling, nozzle diameter 0.7 mm, aspirator 70%, pump 30%. 197.5 g of white solid are taken from the product collecting vessel. The yield is 40%. A proportion of more than 90% of the particles have their diameter in the range 1-10 urm. 15 The utilizability as excipient for administration as dry powder in the administration of an active substance by inhalation is determined using the Andersen impactor apparatus described in Example 7. The results show in Figure 8 the respirability in principle of the particles obtained by spray 20 drying (see also Figures 5-7 relating to Examples 7 and 8). Example 17 Characterization of the flowability of microparticles and powders of poly 25 (1,4-alpha-D-glucan) in accordance with List et al., Arzneiformenlehre, WVG, Stuttgart, 1985; section 2.10.1. 100 g of powder from Ex. 3 and 4 and Ex. 1 are packed into a flow funnel (flowability tester from Engelsmann, Ludwigshafen) keeping the outflow 30 orifice closed during this. The outflow orifice is opened and the powder is mixed with the agitating bow by actuating a crank while it is running out. After resting for a period of 2 minutes, the diameter and height of the powder cone are measured and the angle of repose is determined there from. If the bulk volume is too high, only 50 g of powder are employed 35 instead of 100 g. CORRECTED SHEET (RULE 91)

ISA/EP

24 Table: the following applies: tan a = h/r according to List (supra, page 53 et seq.) Dry binder Height of cone Radius of cone Angle of repose Unit h in cm r in cm a in Microparticles from 6.4 8.50 37.0 Ex. 3, 4 Powder from Ex. 1 3.6 6.25 29.9 Powder from Ex. 1 4.1 6.75 31.3 5 Powders with an angle of repose 30' are particularly suitable. Corres ponding reference measurements with materials known to flow well, such as EMDEX@, Avicel@, Toffena@, reveal angles of repose around 30* (cf. Bauer, Fr6ming, F0hrer, Pharmazeutische Technologie, Stuttgart, 1989, p. 345). 10 Example 18: Loading of microparticles prepared from an autoclaved poly(1-4-alpha D-glucan) suspension 15 3.5 g of poly(1-4-alpha-D-glucan) powder are washed three times with water at 600C. It is then suspended in 200 ml of deionized water. The suspension is placed in a laboratory autoclave (Pressure Vessels; type 452 HCT 316; from Parr Instruments Deutschland GmbH). The chamber is 20 flushed with nitrogen so that a pressure of 1.5 bar is reached. The autoclave is heated to 1300C with stirring. The autoclaving time at this temperature is 30 min. A pressure of about 5 bar is generated. After cooling of the autoclave, the suspension is removed, 175 mg of theophylline (corresponding to a 5% loading) are dissolved therein, and the 25 active substance-containing suspension is immediately sprayed into a spray dryer. During this the suspension is continuously stirred with the aid of a magnetic stirrer. The spray dryer (Mini Sprohtrockner 191, from B~chi, Switzerland) is operated as follows: atomizing nitrogen stream 700 liters per hour, inlet 30 temperature 220 0 C, nozzle cooling switched on, nozzle diameter 0.5 mm, aspirator 70%, pump 70%. CORRECTED SHEET (RULE 91)

ISA/EP

25 The spray-dried material (yield at least 25% based on the amount of solid used in the autoclave) is removed from the collecting vessel of the cyclone and stored in the dry. The size of more than 90% of the microparticles is in the range below 10 pm (analysis of electron micrographs). 5 The loading of the microparticles with theophylline is checked by photometry. This is done by dissolving 50 mg of the sample in 100 ml of dimethyl sulfoxide at 60 0 C and measuring at 271 nm (Lambda 20 Photometer, Perkin Elmer). The degree of loading is at least 95%. 20 mg of the active substance-loaded microparticles are packed into the 10 metering chamber of a commercially available dry powder inhaler (Aerolizer@ from Ciba-Geigy), and the flight distance is measured with the Andersen impactor as described in Example 7. CORRECTED SHEET (RULE 91)

ISA/EP

C4' E -a C cc co ca, CL E6 cas a.)N <. co-) . 0 0 E u -a (N co a: LO N 0N -bM D W ~ NU CuC N, 06 6 o 6 ai >aNc Cu - U)) co Co W; ON No~ 00 CD CD a 0 Cl)l 0* Eu 00 Cu (: (Q) N 0o 1- 0 0LO (0J -C U - 0 C' 0 a) a Cu Q) a) a) m 0 C 5 6 N mC C1 (D (D C) (D CO r- CO M, M M a, .E0 C 0 M V,~ a, M * 0) 0 V) C%40)

-

F V- co o C ) - o-rN= z o1 w DCj r r> c ~ ( ) U ca

F

-e 0 0)0 CD) M~ M M 0> (, ro L 6 c4 C6 j .- 6 6 6 6 C4 *~ ~ (N U)t a, U) (O - ) 0 m cc6 0 a) D1 ICL T

Claims (18)

1. A particulate excipient for pulmonary administration, which contains at 5 least one linear water-insoluble polysaccharide and which is of a mean size of less than 10 pm.
2. The particulate excipient as claimed in claim 1, wherein this forms agglomerates and/or clusters which are smaller than 60 pm. 10
3. The particulate excipient as claimed in claims I and 2, wherein this is present in a mixture and enables effective active substance distribution and penetration thereof into the lung. 15
4. The particulate excipient for pulmonary administration as claimed in one of the preceding claims, consisting entirely or partially of at least one water-insoluble linear polysaccharide, which has been prepared in a biotechnological process. 20
5. The particulate excipient for pulmonary administration as claimed in one of the preceding claims, consisting entirely or partially of at least one water-insoluble linear polysaccharide, which has been prepared by a biocatalytic process. 25
6. The particulate excipient for pulmonary administration as claimed in one of the preceding claims, consisting entirely or partially of at least one water-insoluble linear polysaccharide, which has been prepared by an enzymatic process. 30
7. The particulate excipient for pulmonary administration as claimed in one of claims 1 to 6, wherein the linear water-insoluble polysaccharide is poly(1,4-a-D-glucan).
8. The particulate excipient for pulmonary administration as claimed in 35 one of claims 1 to 7, which is biocompatible and/or pharmaceutically acceptable. CORRECTED SHEET (RULE 91) ISA/EP 29
9. The use of the particulate excipient for pulmonary administration as claimed in one of claims 1 to 8 for the controlled release of active compound into the aveoles. 5
10. The particulate excipient as claimed in one of claims 1 to 8, which additionally contains one or more active compounds.
11. The use of particulate excipients as claimed in one of claims 1 to 9 for the preparation of pharmaceutical compositions. 10
12. The use of particulate excipients as claimed in one of claims 1 to 9 for the preparation of pharmaceutical compositions which achieve a therapeutic effect. 15
13. The use of the particulate excipient as claimed in one of claims 1 to 9 as a pulmonary administration form.
14. The use of the particulate excipient as claimed in one of claims 1 to 9 or 16 to 17 for pulmonary administration by means of a dry 20 formulation.
15. The use of the particulate excipient as claimed in one of claims 1 to 9 or 14 as a pulmonary administration form, by means of inhalation with the aid of a "dry powder inhaler". 25
16. A dispersible dry formulation and/or powder, which contains of the particulate excipient as claimed in one of claims 1 to 9.
17. The dispersible dry formulation and/or powder as claimed in claim 11, 30 which has a water content of less than 25%, preferably a water content of less than 15% and particularly preferably a water content of 5-10%.
18. A pharmaceutical composition, comprising linear water-insoluble 35 polysaccharides as claimed in one of claims 1 to 9 in addition to customary excipients, auxiliaries and/or additives.
AU34210/99A 1998-04-09 1999-04-08 Particulate active agent support for pulmonary application Abandoned AU3421099A (en)

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