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
• • 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
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/13—Amines
  • A61K31/135—Amines having aromatic rings, e.g. ketamine, nortriptyline
  • A61K31/137—Arylalkylamines, e.g. amphetamine, epinephrine, salbutamol, ephedrine or methadone
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
  • A61K31/205—Amine addition salts of organic acids; Inner quaternary ammonium salts, e.g. betaine, carnitine
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/33—Heterocyclic compounds
  • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
  • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
  • A61K31/439—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom the ring forming part of a bridged ring system, e.g. quinuclidine
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/33—Heterocyclic compounds
  • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
  • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
  • A61K31/46—8-Azabicyclo [3.2.1] octane; Derivatives thereof, e.g. atropine, cocaine
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P11/00—Drugs for disorders of the respiratory system
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P11/00—Drugs for disorders of the respiratory system
  • A61P11/06—Antiasthmatics

Definitions

• Tiotropium bromide is known from European patent application EP 418 716 AI and has the following chemical structure:
• Tiotropium is the free ammonium cation.
• the beta imetic salmeterol is also known from the prior art. It is used, for example, in the therapy of asthma.
• WO 00/69468 discloses pharmaceutical combinations of long-acting betamimetics 25 with long-acting anticholinergics, which are characterized by a synergistic effect of the two pharmaceutical components.
• One of the specific drug combinations disclosed in WO 00/69468 is the combination of tiotropium bromide with salmeterol xinafoate.
• the active ingredients salmeterol and tiotropium are administered by inhalation. Suitable inhalable powders can be used.
• the correct preparation of the above-mentioned compositions which can be used for the inhalative administration of a medicinal substance, is based on various parameters which are connected with the nature of the medicinal substance itself. Without limitation, examples of these parameters are the stability of action of the starting material under various environmental conditions, the stability during the course of the preparation of the pharmaceutical formulation and the stability in the final compositions of the drug.
• the active pharmaceutical ingredient used in the preparation of the aforementioned pharmaceutical compositions should be as pure as possible and its stability in long-term storage must be ensured under various environmental conditions. This is imperative in order to prevent drug compositions from being used which, in addition to the actual active ingredient, contain, for example, degradation products thereof. In such a case, the content of active substance found in capsules could be lower than specified.
• Active pharmaceutical ingredient must be avoided as far as possible, a high stability of the active ingredient compared to the grinding process is an essential necessity. Only a sufficiently high stability of the active ingredient during the grinding process allows the production of a homogeneous drug formulation in which the defined amount of active ingredient is always reproducible is included. Another problem that can arise during the grinding process for producing the desired pharmaceutical formulation is the energy supply resulting from this process and the stress on the surface of the crystals. Under certain circumstances, this can lead to polymorphic changes, to a conversion to the amorphous shape or to a change in the crystal lattice. Since the same crystalline morphology of the active ingredient must always be guaranteed for the pharmaceutical quality of a pharmaceutical formulation, increased demands must also be made on the stability and properties of the crystalline active ingredient against this background.
• a further object of the present invention is to provide a pharmaceutical formulation comprising a tiotropium salt and salmeterol xinafoate, which is characterized by the highest possible stability of the two active ingredients in the formulation.
• the active ingredients tiotropium and salmeterol are particularly effective.
• active substances which have a particularly high effectiveness, only small amounts of the active substance are required per individual dose in order to achieve the therapeutically desired effect.
• the auxiliary its grain size is of particular importance. The finer the auxiliary, the poorer its flow properties are.
• the particle size of the auxiliary is of great importance for the emptying behavior of capsules in an inhaler during use. It has also shown that the grain size of the excipient has a strong influence on the inhalable active ingredient content of the inhalable powder.
• the inhalable or inhalable active ingredient fraction is understood to mean the particles of the inhalation powder that are transported deep into the branches of the lungs when inhaled with the air we breathe. The particle size required for this is between 1 and 10 / m, preferably less than 6 ⁇ m.
• an inhalation powder containing a tiotropium salt and salmeterol xinafoate, which is characterized by a high degree of homogeneity and uniformity of dispersibility.
• the present invention further aims at Provision of an inhalation powder which allows the application of the inhalable active ingredient with the least possible variability.
• the emptying behavior from the powder reservoir plays an important role, although not exclusively, but especially when applying inhalation powders using powder-containing capsules. If the powder formulation is only released to a small extent from the powder reservoir due to poor or poor emptying behavior, significant amounts of the active ingredient-containing inhalation powder remain in the powder reservoir (e.g. the capsule) and cannot be used therapeutically by the patient. The consequence of this is that the dosage of the active ingredient in the powder mixture must be increased so that the amount of active ingredient applied is sufficiently high to achieve the therapeutically desired effect.
• tiotropium salts 1 are understood to mean salts which are formed by the pharmacologically active cation Tiotropium T.
• an explicit reference to the cation tiotropium can be recognized by using the designation T.
• the inhalable powders according to the invention contain tiotropium T and salmeterol xinafoate 2, which is characterized by a melting point of about 124 ° C., in a mixture with a physiologically acceptable auxiliary.
• the above melting point was obtained via DSC (Differential Scanning Calorimetry) using a Mettler DSC 820 and evaluated with the Mettler software package STAR. The data were collected at a heating rate of 10 K / min.
• X-ray powder diagram data can be found in the experimental part of the present invention.
• the X-ray powder diagram of the salmeterol xinafoate which is preferably used according to the invention is shown in FIG. 1.
• the salmeterol xinafoate 2 used in the inhalable powders according to the invention particularly preferably has a tamped volume> 0.134 g / cm, preferably of> 0.14 g / cm, particularly preferably of> 0.145 g / cm.
• the tamped volume is determined according to the test method of European Pharmacopoeia 4 (2002): "apparent density after settling” / "density of settled product", identical to "tapped density”, measured in grams per milliliter) or as "Carr packed bulk density”"determined according to the ASTM standard (D6393-99, Standard Test Method for Bulk Solids Characterization by Carr Indices), measured in grams per cm 3 .
• the ramming volume is a measure of the volume that solid, crushed materials take up after compression of the same under defined conditions.
• the salmeterol xinafoate 2 described above is preferably contained in an amount of 0.002 to 15%.
• Inhalation powders containing 0.01 to 10% 2 are preferred according to the invention.
• Particularly preferred inhalation powders contain 2 in an amount of 0.05 to 5%, preferably 0.1 to 3%, particularly preferably 0.125 to 2%, further preferably 0.25 to 2%.
• the inhalable powders according to the invention also preferably contain 0.001 to 5% tiotropium.
• Inhalation powders containing 0.01 to 3% tiotropium V_ are preferred according to the invention.
• Particularly preferred inhalation powders contain Tiotropium Y_ in an amount of 0.02 to 2.5%, preferably 0.03 to 2.5%, particularly preferably 0.04 to
• Tiotropium Y_ means the free ammonium cation. If the term 1 is used in the context of the present invention, this is to be understood as a reference to tiotropium in combination with a corresponding counterion.
• the preferred counterion (anion) is chloride, bromide, iodide, methanesulfonate or para-toluenesulfonate. Of these anions, bromide is preferred.
• the present invention preferably relates to inhalable powders which contain between 0.0012 to 6%, preferably 0.012 to 3.6%, tiotropium bromide 1.
• inhalable powders which contain about 0.024 to 3%, preferably about 0.036 to 3%, particularly preferably about 0.048 to 2.4% tiotropium bromide 1.
• the tiotropium bromide preferably contained in the inhalable powders according to the invention can include solvent molecules during the crystallization.
• the hydrates of tiotropium bromide are preferably used to produce the inhalable powders containing tiotropium according to the invention.
• the crystalline tiotropium bromide monohydrate known from WO 02/30928 is particularly preferably used. This crystalline tiotropium bromide monohydrate is characterized by an endothermic maximum at 230 ⁇ 5 ° C. which occurs in the thermal analysis by means of DSC at a heating rate of lOK / min.
• the present invention preferably relates to inhalable powders which contain between 0.00125 to 6.25%, preferably 0.0125 to 3.75%, crystalline tiotropium bromide monohydrate.
• inhalable powders which contain about 0.025 to 3.125%, preferably about 0.0375 to 3.125%, particularly preferably about 0.05 to 2.5% tiotropium bromide monohydrate.
• the medicinal products according to the invention containing the combinations of 1 and 2 are usually used in such a way that the tiotropium V_ and salmeterol xinafoate 2 together in doses of 5 to 5000 ⁇ g, preferably 10 to 2000 ⁇ g, particularly preferably 15 to 100 ⁇ g, further preferably 20 to 500 ⁇ g , according to the invention preferably from 25 to 250 ⁇ g, preferably from 30 to 125 ⁇ g, particularly preferably 40 to 70 ⁇ g per single dose.
• the combinations according to the invention from 1 and 2 may contain such an amount of tiotropium V_ and salmeterol xinyfoat 2 that, for example, 4.5 ⁇ g V_ and 25 ⁇ g 2, 4.5 ⁇ g V and 30 ⁇ g 2 per single dose.
• the amounts of active ingredients V and 2 applied per single dose above correspond approximately to the subsequent amounts of 1 and 2: 5 applied per single dose , 4 ⁇ g 1 and 25 ⁇ g 2, 5.4 ⁇ g 1 and 30 ⁇ g 2, 5.4 ⁇ g 1 and 35 ⁇ g 2, 5.4 ⁇ g 1 and40 ⁇ g 2, 5.4 ⁇ g 1 and 50 ⁇ g 2, 5.4 ⁇ g 1 and 60 ⁇ g 2, 5.4 ⁇ g 1 and70 ⁇ g 2, 5.4 ⁇ g 1 and 80 ⁇ g 2, 5.4 ⁇ g 1 and 90 ⁇ g 2, 5.4 ⁇ g 1 and lOO ⁇ g 2, 5.4 ⁇ g 1 and 10 ⁇ g 2, 12 ⁇ g 1 and 25 ⁇ g 2, 12 ⁇ g 1 and 30 ⁇ g 2, 12 ⁇ g 1 and 35 ⁇ g 2, 12 ⁇ g 1 and 40 ⁇ g 2, 12 ⁇ g 1 and 50 ⁇ g 2, 12 ⁇ g 1 and 60 ⁇ g 2, 12 ⁇ g 1 and 70 ⁇ g 2, 12 ⁇ g 1 and 80 ⁇ g 2, 12 ⁇ g 1 and 90 ⁇ g 2,
• the amounts of active ingredients 1 and 2 applied per single dose above correspond approximately to the subsequent amounts of tiotropium bromide monohydrate 1 and 2 applied per single dose : 5.6 ⁇ g 1 and 25 ⁇ g 2, 5.6 ⁇ g 1 and 30 ⁇ g 2, 5.6 ⁇ g 1 and 35 ⁇ g 2, 5.6 ⁇ g 1 and 40 ⁇ g 2, 5.6 ⁇ g 1 and 50 ⁇ g 2, 5.6 ⁇ g 1 and 60 ⁇ g 2, 5 , 6 ⁇ g 1 and 70 ⁇ g 2, 5.6 ⁇ g 1 and 80 ⁇ g 2, 5.6 ⁇ g 1 and 90 ⁇ g 2, 5.6 ⁇ g 1 and lOO ⁇ g 2, 5.6 ⁇ g 1 and 1 lO ⁇ g 2, 12.5 ⁇ g 1 and 25 ⁇ g 2, 12, 5 ⁇ g 1 and 30 ⁇ g 2, 12.5 ⁇ g 1 and 35 ⁇ g 2, 12.5 ⁇ g 1 and 40 ⁇ g 2, 12.5 ⁇ g 1 and 50 ⁇ g 2, 12.5 ⁇ g 1
• auxiliaries which are used to represent the inhalable powder used in the pharmaceuticals according to the invention
• Monosacchari.de e.g. glucose or arabinose
• disaccharides e.g. lactose, sucrose, maltose, trehalose
• oligo- and polysaccharides e.g. dextrans
• polyalcohols e.g. sorbitol, mannitol, xylitol
• salts e.g. sodium chloride, calcium carbonate.
• Mono- or disaccharides are preferably used, the use of lactose or glucose being particularly, but not exclusively in the form of their hydrates, is preferred.
• Lactose is used as an auxiliary, particularly preferably lactose monohydrate, as particularly preferred in the sense of the invention.
• Auxiliaries which have an average particle size of 10 to 50 ⁇ m are particularly preferably used.
• the mean particle size in the sense used here is understood to mean the 50% value from the volume distribution, measured with a laser diffractometer using the dry dispersion method.
• the excipient is characterized by an average particle size of 12 to 35 ⁇ m, particularly preferably 13 to 30 ⁇ m.
• the 10% fine fraction in the sense used here means the 10% value from the volume distribution measured with a laser diffractometer.
• the 10% fine fraction value stands for the particle size below which 10% of the particle quantity lies (based on volume distribution).
• inhalation powders in which the 10% fine fraction is approximately 1 to 4 ⁇ m, preferably approximately 1.5 to 3 ⁇ m, are particularly preferred.
• Inhalation powders in which the excipient has a specific surface area between 0.2 and 1.5 m 2 / g, preferably between 0.3 and 1.0 m / g, are also preferred according to the invention.
• Auxiliaries of high crystallinity are preferably used for the powder formulations according to the invention. This crystallinity can be assessed on the basis of the enthalpy (enthalpy of solution) released when the auxiliary is dissolved.
• enthalpy enthalpy of solution
• the inhalable powders according to the invention are characterized by a high degree of homogeneity in the sense of the individual dosage accuracy. This is in a range of ⁇ 8%, preferably ⁇ 6%, particularly preferably ⁇ 4%.
• excipient mixtures which consist of a mixture of coarser excipient with an average particle size of 17 to 50 ⁇ m, preferably from 20 to 40 ⁇ m, particularly preferably 25 to 35 ⁇ m and finer excipient with an average particle size from 1 to 8 ⁇ m, preferably from 2 to 7 ⁇ m, particularly preferably 3 to 6 ⁇ m.
• the mean particle size is understood to mean the 50% value from the volume distribution measured by means of laser diffraction using the dry dispersion method. If the above-mentioned excipient mixtures are used, the 10% fine fraction of the coarser excipient component is about 2 to 5 ⁇ m, preferably about 3 to 4 ⁇ m, and that of the finer excipient component is about 0.5 to 1.5 ⁇ m.
• Inhalable powders are preferred in which the proportion of finer excipient in the total formulation is 2 to 10%, preferably 3 to 7%, particularly preferably 4 to 6%.
• auxiliary mixture in the context of the present invention, it is always to be understood here as a mixture which was obtained by mixing previously clearly defined components.
• an auxiliary mixture of coarser and finer auxiliary components is to be understood as meaning only those mixtures which are obtained by mixing a coarser auxiliary component with a finer auxiliary component.
• the coarser and finer excipient components can consist of the chemically identical or chemically different substances already mentioned above as excipients, preference being given to inhalation powders in which the coarser excipient component and the finer auxiliary component consist of the same chemical compound. If, for example, lactose monohydrate is used as the auxiliary, lactose monohydrate is preferably also used if an auxiliary fraction with the above-mentioned smaller average particle size is specifically added.
• the procedure according to the invention is preferably as follows.
• the free base of salmeterol known from the prior art is taken up together with l-hydroxy-2-naphthoic acid in a solvent mixture consisting of an alcohol and an ether.
• At least 1 mol of 1-hydroxy-2-naphthoic acid preferably 1 to 1.1 mol of 1-hydroxy-, is used per mole of salmeterol used.
• 2-naphthoic acid particularly preferably 1 mol of 1-hydroxy-2-naphthoic acid.
• Suitable low-chain alcohols according to the invention preferably ethanol, n-propanol or isopropanol, particularly preferably ethanol, are suitable as alcohol.
• diethyl ether, methyl ethyl ether, tetrahydrofuran, dioxane or tert-butyl methyl ether are particularly preferably used according to the invention, the tert-butyl methyl ether being particularly preferred according to the invention.
• the ratio of alcohol to ether (volume ratio) according to the invention is preferably in a range from about 1: 2 to 2: 1, particularly preferably in a range from about 1: 1.5 to 1.5: 1.
• the ratio of alcohol to ether is particularly preferred 1: 1.
• the total amount of solvent used is naturally determined by the size of the batch. About 5 to 20 liters, particularly preferably about 7 to 15 liters, of solvent are preferably used per mole of salmeterol base used. It is particularly preferred to use about 9 to 12 liters of solvent per mole of salmeterol used, it being possible for the two components alcohol and ether to be present in the aforementioned volume ratios in said solvent.
• the suspension obtained is heated to a temperature of> 40 ° C., preferably to a temperature of> 50 ° C., particularly preferably to a temperature of about 55-56 ° C., and stirred in the process. The heating is carried out until a clear solution is obtained.
• the solution is then filtered and the filter is optionally rinsed with a small amount (about 1 to 1.5 liters per mole of salmeterol used) of the above-mentioned solvent.
• the filtrate obtained is then cooled to a temperature of about 30 to 40 ° C., preferably about 35-38 ° C. and stirred at this temperature until the crystallization of the salmeterol xinafoate begins.
• the addition of salmeterol xinafoate seed crystals can be helpful here.
• the suspension is cooled further with stirring, preferably to a temperature of about -10 ° C to about 10 ° C, particularly preferably to a temperature of about 0 ° C to about 5 ° C.
• the crystallization is complete and the product obtained is separated off using a suitable filter and, if appropriate, washed with alcohol and / or ether.
• the salmeterol xinafoate obtained in this way corresponds to the above-mentioned specification by which the inhalable powders according to the invention are characterized.
• another aspect of the present invention relates to inhalation powder containing, in addition to Tiotropium V_ salmeterol xinafoate 2, which can be obtained according to the process described above.
• the inhalable powders are prepared from the excipient and the active ingredient using methods known in the art.
• the inhalable powders according to the invention are accordingly obtainable, for example, according to the procedure described below.
• the active ingredient 1 used has an average particle size of 0.5 to 10 ⁇ m, preferably 1 to 6 ⁇ m, particularly preferably 2 to 5 ⁇ m.
• 1 and the auxiliary are preferably added via a sieve or a sieve granulator with a mesh width of 0.1 to 2 mm, particularly preferably 0.3 to 1 mm, most preferably 0.3 to 0.6 mm.
• the auxiliary is preferably introduced and then the active ingredient is introduced into the mixing container. This is preferably done
• auxiliary substance mixture consisting of coarser auxiliary substance with an average particle size of 17 to 50 ⁇ m, particularly preferably from 20 to 35 ⁇ m and finer auxiliary substance with an average particle size of 1 to 8 ⁇ m, preferably from 2 to 7 ⁇ m, particularly preferably 3 to 6 ⁇ m, is used as the auxiliary substance
• the auxiliary substance mixture is first prepared by alternately layering the two auxiliary substance components in layers and then mixing them.
• the addition of the salmeterol xinafoate 2 takes place in an analogous manner an average particle size of 0.5 to 10 ⁇ m, preferably 1 to 6 ⁇ m, particularly preferably 2 to 5 ⁇ m.
• 2 and the powder mixture containing component 1 are preferably added via a sieve or a sieve granulator with a mesh size of 0.1 to 2 mm, particularly preferably 0.3 to 1 mm, most preferably 0.3 to 0.6 mm.
• the powder mixture containing component 1 is preferably introduced and then 2 is introduced into the mixing container. In this mixing process, the two components are preferably added in portions. Alternating, layer-by-layer sieving of the two components is particularly preferred.
• the mixing process of the powder mixture containing the component 1 with the active ingredient 2 can already take place during the addition of the two components. However, it is preferred to mix only after the two components have been sieved in layers.
• the inhalable powder according to the invention can also be obtained by first presenting, in analogy to the procedure described above, a powder mixture consisting of auxiliary and 2, to which component 1 is then added in accordance with the procedure described above.
• the inhalable powder according to the invention can also be obtained by initially introducing an auxiliary portion, then adding the first portion 1 or the first portion 2, then sieving in an auxiliary portion again and finally the first portion of the second Active ingredient component 1 or 2 is added.
• This addition sequence of the components auxiliary, 1 and 2 is then repeated until all of the components have been added in the desired amount.
• the alternating, layer-by-layer sieving of the 3 components is also particularly preferred here.
• the mixing process can take place while the 3 components are being added. Preferably, however, the three components are mixed only after the layered sieving.
• micronizing Corresponding micronizing processes are known from the prior art.
• the procedure below has proven particularly useful for micronizing this crystalline active ingredient modification 1.
• Common mills can be used to carry out the process.
• the micronization is preferably carried out with exclusion of moisture, particularly preferably using an appropriate inert gas, such as nitrogen.
• an appropriate inert gas such as nitrogen.
• the use of air jet mills has proven to be particularly preferred, in which the grinding material is comminuted by the particles colliding with one another and the particles colliding with the walls of the grinding container.
• nitrogen is preferably used as the grinding gas.
• the ground material is conveyed by means of the grinding gas under specific pressures (grinding pressure).
• the grinding pressure is usually set to a value between approximately 2 and approximately 8 bar, preferably between approximately 3 and approximately 7 bar, particularly preferably between approximately 3.5 and approximately 6.5 bar.
• the ground material is introduced into the air jet mill by means of the feed gas under specific pressures (feed pressure).
• feed pressure a feed pressure between approximately 2 and approximately 8 bar, preferably between approximately 3 and approximately 7 bar, particularly preferably between approximately 3.5 and approximately 6 bar, has proven successful.
• An inert gas, particularly preferably nitrogen, is also preferably used as the feed gas.
• the grinding stock (crystalline tiotropium bromide monohydrate 1) can be fed in at a conveying rate of approximately 5-35 g / min, preferably approximately 10-30 g / min.
• the following device has proven to be a possible embodiment of an air jet mill: 2-inch microniser with grinding ring 0.8 mm bore, from Sturtevant Inc., 348 Circuit Street, Hanover, MA 02239 , UNITED STATES.
• the grinding process is preferably carried out with the following grinding parameters: grinding pressure: about 4.5 - 6.5 bar; Feed pressure: approx. 4.5 - 6.5 bar: supply of the regrind: approx. 17 - 21 g / min.
• the ground material thus obtained is then processed under the specific conditions specified below.
• the micronisate is exposed to a relative humidity of at least 40% at a temperature of 15-40 ° C., preferably 20-35 ° C., particularly preferably at 25-30 ° C. water vapor.
• the humidity is preferably up a value of 50-95% RH, preferably 60-90% RH, particularly preferably 70-80% RH.
• Relative humidity is understood here as the quotient of the partial pressure of water vapor and the vapor pressure of water at the temperature in question.
• the micronizate obtainable from the grinding process described above is preferably exposed to the above-mentioned room conditions at least over a period of 6 hours. However, the micronizate is preferably exposed to the above-mentioned room conditions for about 12 to about 48 hours, preferably about 18 to about 36 hours, particularly preferably about 20 to about 28 hours.
• the inventive micronizate of tiotropium bromide 1 obtainable according to the above procedure has an average particle size of between 1.0 ⁇ m and 3.5 ⁇ m, preferably between 1.1 ⁇ m and 3.3 ⁇ m, particularly preferably between 1.2 ⁇ m and 3.0 ⁇ m Q ( 5.8) of greater than 60%, preferably greater than 70%, particularly preferred greater than 80%.
• the characteristic value Q denotes (5. 8), the amount of particles of the particles in the volume distribution of the particles is below 5.8 microns based.
• the particle sizes were determined in the context of the present invention by means of laser diffraction (Fraunhofer diffraction). More detailed information can be found in the experimental descriptions of the invention.
• tiotropium micronizate which is preferably used according to the invention and was produced according to the above process are specific surface values in the range between 2 m 2 / g and 5 m 2 / g, particularly values between 2.5 m / g and 4.5 m / g and particularly outstandingly between 3.0 m 2 / g and 4.0 m 2 / g.
• a particularly preferred aspect of the present invention relates to the inhalable powders according to the invention, which are characterized as containing component 1 of the tiotropium bromide monohydrate micronizate described above.
• the procedure below has proven particularly useful.
• Common mills can be used to carry out the process.
• the micronization is preferably carried out with exclusion of moisture, particularly preferably using an appropriate inert gas, such as nitrogen.
• an appropriate inert gas such as nitrogen.
• the use of air jet mills has proven to be particularly preferred, in which the grinding material is comminuted by the particles colliding with one another and the particles colliding with the walls of the grinding container.
• nitrogen is preferably used as the grinding gas.
• the ground material is conveyed by means of the grinding gas under specific pressures (grinding pressure).
• the grinding pressure is usually set to a value between approximately 2 and approximately 12 bar, preferably between approximately 5 and approximately 10 bar, particularly preferably between approximately 5 and approximately 8.5 bar.
• the ground material is introduced into the air jet mill by means of the feed gas under specific pressures (feed pressure).
• feed pressure a feed pressure between approximately 2 and approximately 12 bar, preferably between approximately 5.5 and approximately 10.5 bar, particularly preferably between approximately 5.5 and approximately 9 bar, has proven successful.
• An inert gas, particularly preferably nitrogen, is also preferably used as the feed gas.
• the grinding stock (crystalline salmeterol xinafoate) can be fed in at a conveying rate of approximately 5-100 g / min, preferably approximately 10-60 g / min.
• a particularly preferred aspect of the present invention relates to the inhalable powders according to the invention, which are characterized by a content of salmeterol xinafoate micronisate 2, which was obtained according to the micronization process described above.
• the present invention further relates to the use of the inhalable powder according to the invention for the manufacture of a medicament for the treatment of respiratory diseases, in particular for the treatment of COPD and / or asthma.
• the inhalable powders according to the invention can be administered, for example, by means of inhalers which dose a single dose from a supply by means of a measuring chamber (e.g. according to US 4570630A) or via other apparatus (e.g. according to DE 36 25 685 A).
• the inhalable powders according to the invention are preferably filled into capsules (for so-called inhalers), which are used in inhalers as described, for example, in WO 94/28958.
• the capsules containing the inhalable powder according to the invention are particularly preferably administered with an inhaler as shown in FIG.
• This inhaler 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, an inhalation chamber 6 connected to deck 3, one of which has two Ground needles 7 provided, against a spring 8 movable pusher 9 is provided, a mouthpiece 12 connected to the housing 1, the deck 3 and a cap 11 via an axis 10 and air passage holes 13 for adjusting the flow resistance.
• the present invention further relates to the use of the inhalable powder according to the invention for the manufacture of a medicament for the treatment of
• Respiratory diseases in particular for the treatment of COPD and / or asthma, characterized in that the inhaler described above and shown in FIG. 2 is used.
• Capsules whose material is selected from the group of synthetic plastics, particularly preferably selected from the group consisting of polyethylene, polycarbonate, polyester, polypropylene and polyethylene terephthalate, are particularly preferably used for the application of the inhalable powder according to the invention by means of capsules containing powder.
• Polyethylene, polycarbonate or polyethylene terephthalate are particularly preferred as synthetic plastic materials. If polyethylene is used as one of the capsule materials particularly preferred according to the invention, polyethylene with a density of between 900 and 1000 kg / m 3 , preferably from 940 to 980 kg / m 3 , particularly preferably from about 960 to 970 kg / m 3 (high density polyethylene) for use.
• the synthetic plastics in the sense of the invention can be processed in many ways by means of the manufacturing process known in the prior art.
• the injection molding processing of the plastics is preferred. Injection molding is particularly preferred, without the use of mold release agents. This manufacturing process is well defined and characterized by a particularly good reproducibility.
• capsules mentioned above which contain the aforementioned inhalation powder according to the invention.
• These capsules can contain about 1 to 20 mg, preferably about 3 to 15, particularly preferably about 4 to 12 mg of inhalation powder.
• Formulations preferred according to the invention contain 4 to 6 mg inhalation powder.
• Inhalation capsules which contain the formulations according to the invention in an amount of 8 to 12 mg, particularly preferably 9 to 11 mg, are of equal importance according to the invention.
• the present invention relates to an inhalation kit consisting of one or more of the capsules described above, characterized by a content of inhalable powder according to the invention, in conjunction with the inhaler according to FIG. 2.
• the present invention further relates to the use of the capsules mentioned above, characterized by a content of inhalable powder according to the invention, for the manufacture of a medicament for the treatment of respiratory diseases, in particular for the treatment of COPD and / or asthma.
• Filled capsules containing the inhalable powders according to the invention are produced by methods known in the art by filling the empty capsules with the inhaled powders according to the invention.
• lactose monohydrate is used as auxiliary. This can be obtained, for example, from Borculo Domo Ingredients, Borculo / NL under the product name Lactochem Extra Fine Powder. The specifications for particle size and specific surface area according to the invention are met by this lactose quality. Furthermore, this lactose has the above-mentioned solution enthalpy values preferred for lactose according to the invention.
• the following examples used lactose batches that had the following specifications: a): average particle size: 17.9 ⁇ m; 10% fine fraction: 2.3 ⁇ m; specific surface area: 0.61 m 2 / g; or b) average particle size: 18.5 ⁇ m; 10% fine fraction: 2.2 ⁇ m; specific surface area: 0.83 2 / g; c) average particle size: 21.6 ⁇ m; 10% fine fraction: 2.5 ⁇ m; specific surface area: 0.59 m 2 / g; d) average particle size: 16.0 ⁇ m; 10% fine fraction: 2.0 ⁇ m; specific surface area: 0.79 m 2 / g
• lactose monohydrate (200M) is used as the coarser auxiliary. This can be obtained, for example, from DMV International, 5460 Veghel NL under the product name Pharmatose 200M. This lactose is characterized by an average particle size of approximately 30 to 35 ⁇ m. Lactose batches 200M used, for example, had a medium one
• lactose monohydrate with an average particle size of 3-4 ⁇ m is used as the finer excipient. This can be obtained by customary processes (micronization) from commercially available lactose monohydrate, for example the lactose 200M mentioned above. Micronized lactose batches used had, for example, an average particle size of 3.7 ⁇ m with a 10% fine fraction of 1.1 ⁇ m or also an average particle size of 3.2 ⁇ m with a 10% fine fraction of 1.0 ⁇ m.
• the crystalline salmeterol xinafoate thus obtained has a tamped volume of 0.27 g / cm 3 .
• the salmeterol xinafoate obtainable according to the above procedure is blown with an air jet mill of the type MC JETMLLL 50 from Jetpharma; Via Sotto Bisio 42 a / c, 6828-Balixa, Switzerland, micronized.
• the following grinding parameters are set, for example: grinding pressure 7.5 bar, feed pressure 8.0 bar. Feed (of the crystalline salmeterol xinafoate) or flow rate) 40 g / min.
• the micronized salmeterol xinafoate thus obtained has a tamped volume of 0.19 g / cm 3 .
• the crystalline tiotropium bromide monohydrate obtainable according to WO 02/30928 is blown with an air jet mill of the type 2-inch Microniser with a grinding ring 0.8 mm bore,
• nitrogen as the grinding gas is, for example, the following
• the ground material obtained is then spread out on tray plates in a layer thickness of approximately 1 cm and subjected to the following climatic conditions for 24-24.5 hours: temperature: 25-30 ° C .; Relative humidity: 70-80%.
• the devices were operated in accordance with the manufacturer's operating instructions.
• Measuring device Laser diffraction spectrometer (HELOS), Sympatec (particle size determination by means of Fraunhofer diffraction) Dispersing unit: Dry disperser RODOS with
• Focal length 100 mm (measuring range: 0.9 - 175 ⁇ m)
• Measuring time / waiting time approx. 15 s (in the case of 200 mg)
• Sample preparation / product supply Approximately 200 mg of the test substance are weighed out on a card sheet.
• the powder is then on the front half of the vibrating trough (from about 1 cm from the front
• the frequency of the vibrating trough is varied so that the
• the sample is fed as continuously as possible. However, the amount of product must not be too large so that sufficient dispersion is achieved.
• the devices were operated in accordance with the manufacturer's operating instructions.
• Measuring device laser diffraction spectrometer (HELOS),
• Dispersing unit RODOS dry disperser with suction funnel,
• Focal length 200 mm (measuring range: 1.8 - 350 ⁇ m)
• Measuring time / waiting time approx. 10 s (in the case of 200 mg)
• test substance Approximately 200 mg of the test substance are weighed out on a card sheet. With another map sheet all larger agglomerates are crushed. The powder is transferred to the vibrating trough. A distance of 1.2 to 1.4 mm is set between the vibrating channel and the funnel. After starting the measurement, the Amplitude setting of the vibrating trough increased as continuously as possible to 100% towards the end of the measurement.
• the specific surface is determined by exposing the powder sample to a nitrogen / helium atmosphere at different pressures. By cooling the sample, the nitrogen molecules condense on the surface of the particles. The amount of condensed nitrogen is determined by the change in the thermal conductivity of the nitrogen / helium mixture and the surface of the sample is determined by the area requirement of nitrogen. The specific surface is calculated using this value and the sample weight.
• Measuring device Monosorb, Quantachrome
• Adsorbate 30% nitrogen in helium
• Measuring cell with capillary tube, W. Pabisch GmbH & Co.KG.
• the measured values are displayed by the device in [m 2 ] and are usually converted in [cm 2 / g] to the sample weight (dry mass):
• Reaction cell 100 ml thermistor resistance: 30.0 k ⁇ (at 25 ° C) stirrer speed: 500 rpm Thermostat: Thermostat of the 2277 Thermal Activity Monitor TAM, Fa.
• Measuring ampoules Crushing ampoules 1 ml, Thermometric. Seal: silicone stopper and beeswax, Thermometric
• the electrical calibration takes place during the measurement, once before and once after the ampoule break. The calibration after the ampoule break is used for evaluation.
• Heating power 500 mW
• the empty inhalation capsules can be filled manually or by machine with inhalation powder containing tiotropium.
• the following devices can be used.
• MG2 S.r.l 1-40065 Pian di Macina di Pianoro (BO), Italy
• the sieved components are then mixed (mixing: 900 revolutions).
• the final mixture is passed twice over a hand sieve and then mixed in each case (mixing: 900 revolutions).
• the sieved components are then mixed (mixing: 900 revolutions).
• the final mixture is passed twice over a rotary sieve and then mixed in each case (mixing: 900 revolutions).
• Inhalation powders can be obtained in accordance with or in analogy to the procedure described in Example 1, which lead, for example, to the following inhalation capsules after filling the corresponding plastic capsules:
• Tiotropium bromide monohydrate 0.0113 mg salmeterol xinafoate 0.0726 mg
• Lactose monohydrate 5.41-61 mg
• Tiotropium bromide monohydrate 0.0225 mg salmeterol xinafoate 0.1450 mg
• Tiotropium bromide monohydrate 0.0225 mg salmeterol xinafoate 0.2180 mg
• Lactose monohydrate 10.7595 mg polvethylene capsules: 100.0 mg
• Tiotropium bromide monohydrate 0.0056 mg salmeterol xinafoate 0.0726 mg
• Tiotropium bromide monohydrate 0.0056 mg salmeterol xinafoate 0.1090 mg
• Tiotropium bromide monohydrate 0.0125 mg salmeterol xinafoate 0.0435 mg
• Tiotropium bromide monohydrate 0.0125 mg salmeterol xinafoate 0.0508 mg
• Lactose monohydrate 9.9367 mg polvethylene capsules: 100.0 mg
• Tiotropium bromide monohydrate 0.0225 mg salmeterol xinafoate 0.0435 mg
• Tiotropium bromide monohydrate 0.0063 mg salmeterol xinafoate 0.0435 mg
• auxiliary material About 20-23 g of auxiliary material are placed in a suitable mixing container via a hand sieve with a mesh size of 0.315 mm. Then one after the other
• Tiotropium bromide monohydrate 1 in portions of approx. 90-110 mg, auxiliary in portions of approx. 20-23 g and salmeterol xinafoate 2 in portions of approx. 650-670 mg are sieved in layers. This procedure is repeated 6 times. Finally, a final portion of adjuvant of about 20-23 g is added. The sieved components (6 layers 1 and 2 as well as 13 layers of excipient) are then mixed (mixing: 900 revolutions). The final mixture is passed twice over a hand sieve and then mixed in each case (mixing: 900 revolutions).
• Inhalation powders can be obtained in accordance with or in analogy to the procedure described in Example 13, which lead, for example, to the following inhalation capsules after filling the corresponding plastic capsules:
• Example 14 Tiotropium bromide monohydrate: 0.0113 mg
• Lactose monohydrate 5.3437 mg polvethylene capsules: 100.0 mg
• Tiotropium bromide monohydrate 0.0225 mg salmeterol xinafoate 0.2180 mg
• Example 19 Tiotropium bromide monohydrate: 0.0056 mg
• Lactose monohydrate 9.9512 mg polvethylene capsules: 100.0 mg
• Tiotropium bromide monohydrate 0.0125 mg salmeterol xinafoate 0.0508 mg
• Example 24 Tiotropium bromide monohydrate: 0.0063 mg
• the auxiliary mixture thus obtained is then subjected to the procedure of Example 13 to produce the final mixture.
• the sieved components (6 layers 1 and 2 and 13 layers of excipient mixture) are then mixed (mixing: 900 revolutions).
• the final mixture is passed twice over a hand sieve and then mixed in each case (mixing: 900 revolutions).
• lactose monohydrate (3-4 ⁇ m) stands for micronized lactose and the term lactose monohydrate for coarser lactose:
• Example 26 Tiotropium bromide monohydrate: 0.0113 mg
• Lactose monohydrate 5.0575 mg polvethylene capsules: 100.0 mg
• Tiotropium bromide monohydrate 0.0225 mg salmeterol xinafoate 0.2180 mg
• Example 31 Tiotropium bromide monohydrate: 0.0056 mg
• Lactose monohydrate 5.1104 mg
• Tiotropium bromide monohydrate 0.0125 mg salmeterol xinafoate 0.0435 mg
• Tiotropium bromide monohydrate 0.0125 mg salmeterol xinafoate 0.0508 mg
• Example 36 Tiotropium bromide monohydrate: 0.0063 mg Salmeterol xinafoate 0.0435 mg

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