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    • 专利摘要:
    process of preparing an excipient for pharmaceutical compositions in powder for inhalation, carrier particles for a pharmaceutical formulation of dry powder, pharmaceutical composition in the form of dry powder for inhalation and dry powder inhaler. The present invention relates to a process for preparing carrier particles for use in formulations of dry powders for inhalation. the present invention also includes carrier particles obtainable by said process and pharmaceutical powder formulations involving them.
    公开号:BR112012024059B1
    申请号:R112012024059-5
    申请日:2011-03-11
    公开日:2021-06-01
    发明作者:Rossella Musa；Daniela Cocconi；Alain Chamayou；Laurence Galet
    申请人:Chiesi Farmaceutici S.P.A.；
    IPC主号:
    专利说明:

    FIELD OF THE INVENTION
    [001]. The present invention involves a process for preparing carrier particles for use in formulations of dry powders for inhalation and carrier particles therefrom. BACKGROUND OF THE INVENTION
    [002]. Dry powder inhalation drug therapy (DPI) has been used for several years to treat respiratory conditions such as asthma, chronic obstructive pulmonary disease (COPD) and allergic rhinitis.
    [003]. Compared to oral drug administration, only relatively small doses are required for effective therapy, as first-pass metabolism is significantly reduced. These small doses reduce the body's exposure to the drug and minimize side effects. Systemic adverse effects are also reduced, as topical pulmonary administration takes the drug directly to the site of action. Lower dosage regimens can also lead to considerable cost savings, especially when costly therapeutic agents are involved.
    [004]. Dry powders are typically formulated by mixing the drug in micronized form with coarse carrier particles, resulting in an ordered mixture where the micronized active particles adhere to the surface of the carrier particles, remaining so while in the inhaler device.
    [005]. The excipient makes the micronized powder less cohesive and improves its flow, making it easier to handle the powder during the manufacturing process (draining, filling, etc.).
    [006]. During inhalation, drug particles separate from the surface of carrier particles and enter the lower part of the lungs, while larger carrier particles settle mainly in the oropharyngeal cavity.
    [007]. Redispersion of drug particles from the surface of the carrier is considered the critical factor that most determines drug availability to the lungs. This will depend on the mechanical stability of the powder mixture and the way in which it is influenced by the adhesion characteristics between the drug and the carrier and the external forces required to break the non-covalent bonds formed between the adhered particles. Very strong bonds between the adhered particles can actually prevent the micronized drug particles from separating from the surface of the carrier particles. Different approaches aimed at modulating adhesion have been proposed in the art to promote the release of drug particles from carrier particles and, thus, increase the respirable fraction. For example, the use of additives with lubricating or non-stick properties has been suggested as a solution to the technical problem.
    [008]. One additive that has been shown to be particularly useful is magnesium stearate.
    [009]. The benefit of using magnesium stearate in dry powders is shown in US 6,528,096. Specifically, it shows that said additive can be used to alter the surface properties of carrier particles and thereby improve the properties of dry powder formulations. This reference reports an “advantageous relationship” between carrier particles with a surface coated with magnesium stearate and the fine particle fraction (respirable fraction) of the emitted dose. A critical condition for the functioning of this present invention is the need to ensure the coating of magnesium stearate on more than 15% of the surface of the carrier particles. In the Examples, coating percentages of up to 38% were obtained.
    [0010]. However, it would be highly advantageous to develop a process capable of giving higher percentages of surface coating, as this would make it possible to improve the formulation performances using a smaller amount of additive.
    [0011]. The problem is solved by the process of the present invention. BRIEF DESCRIPTION OF THE INVENTION
    [0012]. In a first aspect, the present invention is directed to a process for the preparation of an excipient for pharmaceutical compositions in powder for inhalation, and the process consists of subjecting lactose particles with a mass diameter in the range of 30-1000 micrometers to the coating to dried with 0.11.3% magnesium stearate by weight of the filler, to obtain a surface coating of the lactose particles with the mentioned magnesium stearate, such that the coated particles have more than 60% coating surface, the dry coating step being carried out in a high shear mixer granulator based on frictional behavior, at a rotation speed equal to or greater than 500 rpm, preferably equal to or greater than 1000 rpm; but equal to or less than 2500 rpm, preferably less than 2000 rpm.
    [0013]. Preferably, the high shear mixer granulator mentioned is the CYCLOMIXTM equipment.
    [0014]. In a second aspect, the present invention is directed to carrier particles for formulations of dry powders for inhalation, such carrier particles including lactose particles with a mass diameter in the range of 30-1000 micrometers, coated with 0.1-1. 3% magnesium stearate by weight of the carrier such that the coated particles have more than 60% surface coating. These carrier particles are obtained by a process that comprises the step of dry coating in a high-shear mixing granulator, based on the friction behavior between the aforementioned lactose particles and magnesium stearate, at a rotation speed equal to or greater at 500 rpm, preferably equal to or greater than 1000 rpm; but equal to or less than 2500 rpm, preferably less than 2000 rpm.
    [0015]. In a third aspect, the present invention is directed to carrier particles for dry powder formulations for inhalation, such carrier particles including lactose particles with a mass diameter in the range of 301000 micrometers, coated with 0.1-1.3% of magnesium stearate by weight of the carrier, such that the coated particles have more than 60% surface coating.
    [0016]. In a fourth aspect, the present invention concerns a pharmaceutical composition in the form of a dry powder for inhalation containing the carrier particles of the present invention and one or more active ingredients.
    [0017]. In a fifth aspect, the present invention relates to a dry powder inhaler loaded with the aforementioned dry powder pharmaceutical composition.
    [0018]. In a sixth aspect, the present invention concerns a process for preparing the aforementioned pharmaceutical composition including a step of mixing the carrier particles of the present invention with one or more active ingredients.
    [0019]. In a further aspect, the present invention is also directed to a kit containing a dry powder pharmaceutical formulation according to the present invention and a dry powder inhaler. DEFINITIONS
    [0020]. Unless otherwise specified, the terms “active ingredient”, “active ingredient”, “active” and “active substance”, “active compound” and “therapeutic agent” are used interchangeably.
    [0021]. The term "high shear mixer granulator based on frictional behavior" refers to an apparatus equipped with mixing elements in the form of paddles, where the particles are accelerated by the paddles and intensely mixed by friction against the wall of the vessel/reactor.
    [0022]. The term "dry coating" refers to a mechanical process whereby a first substance (ie, magnesium stearate) physically interacts (ie, the coating) with a second substance (ie, the carrier) under dry conditions; for example, without solvents, binding agents/binders or water.
    [0023]. The term "surface coating" refers to the covering of the surface of carrier particles by forming a film/film of magnesium stearate around these particles, as shown in the schematic in Figure 1. The film thickness is estimated as a value approximately less than 10 nm by X-ray photoelectron spectroscopy (XPS) [X-ray photoelectron spectroscopy].
    [0024]. Percent surface coating indicates the degree to which magnesium stearate coats the surface of all carrier particles.
    [0025]. Taking all of the above information into consideration, it is clear to technicians [experts] on the subject that film coating according to the present invention affects at least 60% of the total surface of carrier particles.
    [0026]. The term “hygroscopic” refers to an active compound that never completely dries out in contact with air with a moisture content >0% relative humidity, but which always contains a certain amount of absorptively bound water (H. Sucker, P. Fuchs and P. Speiser: Pharmaceutical Technology, Georg Thieme Verlag, Stuttgart, New York, 2nd edition 1991, page 85).
    [0027]. The term "hydrophilic" refers to an active compound that can easily attract/associate with water. For example, formoterol is a typical hydrophilic active ingredient.
    [0028]. Generally speaking, the particle size of particles is quantified by determining a characteristic equivalent sphere diameter, known as volume diameter, by laser diffraction.
    [0029]. Particle size can also be quantified by determining mass diameter by means of known suitable instruments and techniques, such as sieving.
    [0030]. The volume diameter (DV) is related to the mass diameter (DM) by the density of the particles (assuming the size is independent of the density of the particles).
    [0031]. In the present document, the particle size range is expressed in terms of mass diameter. Otherwise, the particle size distribution is expressed in terms of: i) volume median diameter (DMV), which corresponds to the 50% diameter by weight or volume, respectively, of the particles; for example, d(v0.5), and ii) volume diameter (DV) in micrometers of 10% and 90% of the particles, respectively; for example, d(v0,1) and d(v0,9).
    [0032]. The term "good flow/flow properties" refers to a formulation which is easily handled during the manufacturing process and which is capable of ensuring accurate and reproducible administration of the effective therapeutic dose.
    [0033]. The flow/flow characteristics can be evaluated by determining the Carr index; a Carr index of less than 25 is usually considered an indicator of good flow characteristics.
    [0034]. The term "good homogeneity" refers to a formulation in which, after mixing, the uniformity of the active ingredient content expressed as relative standard deviation (RPD) is less than 5%, preferably equal to or less than 2.5%.
    [0035]. The term "physically stable in the device before use" refers to a formulation in which the active particles do not separate and/or detach considerably from the surface of the carrier particles either during the manufacture of the dry powder or in the delivery device before the use. The separation tendency can be evaluated according to Staniforth et al. J. Pharm. Pharmacol. 34, 700-706, 1982, being considered acceptable when the distribution of the active ingredient in the powder formulation after the test expressed as relative standard deviation (RPD) does not change significantly in relation to the formulation before the test.
    [0036]. The term “respirable fraction” refers to an index of the percentage of particles of the active ingredient that would deeply reach the lungs in a patient. The respirable fraction, also called fine particle fraction (FPF), is commonly evaluated in vitro in suitable equipment, usually the Multistage Cascade Impactor or Multi Stage Liquid Impinger (MLSI), according to procedures described in common Pharmacopoeias. It is calculated by the ratio between the breathable dose and the administered (emitted) dose. The administered dose is calculated from the accumulated deposition in the equipment, while the respirable dose (dose of fine particles) is calculated from the deposition in Stages 3 (S3) to the filter (AF [ost-filter]) corresponding to particles < 4 .7 micrometers.
    [0037]. A respirable fraction greater than 30% represents an index of good inhalation performance.
    [0038]. The term "therapeutic amount" means the amount of active ingredient which, administered to the lungs via a dry powder formulation, as described herein, determines the desired biological effect.
    [0039]. By "single dose" is meant the amount of active ingredient administered at one time per inhalation by triggering the inhaler.
    [0040]. By triggering is meant the release of active ingredient from the device through a single activation (for example, mechanical or respiratory). BRIEF DESCRIPTION OF THE FIGURES
    [0041]. Figure 1: Schematic of the film/film formation process around a single carrier particle.
    [0042]. Figure 2: SEM photographs at different magnifications of: lactose particles + 0.5% magnesium stearate at 1500 rpm for 5 min (left); lactose particles + 0.5% magnesium stearate at 1500 rpm for 10 min (center); lactose particles + 0.5% magnesium stearate at 1500 rpm for 15 min (right).
    [0043]. Figure 3: Water adsorption in increasing percentage of relative humidity. DETAILED DESCRIPTION OF THE INVENTION
    [0044]. The present invention is directed to a process of preparing an excipient for pharmaceutical compositions in powder for inhalation, the process consisting in subjecting lactose particles to dry coating with magnesium stearate to determine the surface coating of the lactose particles, where the mentioned dry coating is carried out in a high shear mixing granulator based on frictional behavior.
    [0045]. It is verified that, when using this type of equipment where the particles are subjected to frictional forces, the occurrence of breakage of the carrier particles is less likely than in other equipment, such as those based on impact forces.
    [0046]. Magnesium stearate is an additive with lubricating properties, which is mainly used to increase the breathable fraction of the active ingredient.
    [0047]. Any type of commercially available pharmaceutical grade magnesium stearate can be used, regardless of its origin.
    [0048]. The amount of magnesium stearate must be between 0.1 and 1.3% by weight of the loader, so that the relevant formulation maintains its homogeneity during conditions equivalent to those that may occur during commercial processing.
    [0049]. Favorably, the mentioned amount should be comprised between 0.15 and 1.0% by weight (w/w).
    [0050]. Within these limits, the amount of magnesium stearate will depend on both the dry powder inhaler and the active ingredient employed in the powder formulation. The technician [expert] will take into account the physical and chemical properties of the active ingredient and the type of inhaler; for example, with a single dose or multiple doses, in order to select the appropriate amount.
    [0051]. In an embodiment of the present invention, the amount of magnesium stearate can be comprised between 0.15 and 0.5%; more preferably between 0.2 and 0.4% w/w or between 0.1 and 0.3%. In other embodiments, the amount can be between 0.3 and 0.5% w/w or between 0.4 and 1.0% w/w; more preferably between 0.5 and 0.8% by weight of the magazine. In further embodiments, it may be comprised between 0.65 and 1.25%, preferably between 0.7 and 1.1% w/w. In a specific representation, the amount of magnesium stearate is 0.1%.
    [0052]. In other representations, the amount of magnesium stearate will depend on the particle size and thus the surface area of the carrier particles.
    [0053]. For example, with carrier particles with a large surface area, such as those with a small particle size (eg 60-90 micrometers), the amount of magnesium stearate will preferably be between 0.65 and 1.25%, while, with carrier particles with a smaller surface area, such as those with a larger particle size (eg 90-150 micrometers), the amount will preferably be between 0.1 and 0.3%.
    [0054]. Lactose particles can be represented by any type of crystalline lactose or mixtures thereof. Advantageously, the lactose particles are α-lactose or beta-lactose or solvates thereof. Preferably, the carrier particles are α-lactose monohydrate particles.
    [0055]. All lactose particles have a mass diameter in the range of 30-1000 micrometers. Particles with a mass diameter of between 50 and 500 can be used advantageously. In a preferred embodiment, the mass diameter is comprised between 60 and 200 micrometers. In specific representations, particles with a mass diameter comprised between 60 and 90 micrometers or 90 and 150 micrometers can be used. In other embodiments, the mass diameter is comprised between 150 and 400 micrometers or between 210 and 355 micrometers.
    [0056]. The size of carrier particles is an important factor in the efficiency of the inhaler. The desired particle size can be obtained by sieving.
    [0057]. In a particularly preferred representation, the particle size distribution meets the following parameters: d(v0.1) comprised between 85 and 100 micrometers, d(v0.5) comprised between 125 and 135 micrometers and d(v0.9) comprised between 180 and 190 micrometers.
    [0058]. The lactose particles are subjected to dry coating with magnesium stearate particles until the degree of surface coating is greater than 60%; favorably equal to or greater than 70%, more favorably greater than or equal to 80%, preferably greater than or equal to 85%, more preferably greater than or equal to 90%, and even more preferably greater than or equal to 95%. Under specific conditions, a 100% surface coating can be obtained.
    [0059]. The degree of surface coating of lactose particles by magnesium stearate can be determined by first measuring the contact angle with water and then applying the equation known in the literature as Cassie and Baxter, cited on page 338 by Colombo I et al Il Farmaco 1984, 39(10), 328341, and described below.COSÜmixture = fMgSt COSÜMgst + flactore COSOlactose where: fMgSt and flactore are the surface area fractions of magnesium stearate and dα-lactose; water contact angle of magnesium stearate;^lactose is the water contact angle of α-lactosesemixtureThe experimental contact angle values.
    [0060]. Measuring the contact angle between a liquid and a solid surface is commonly used in the art to determine the wettability of solids. This approach is based on the ability of a liquid to spontaneously spread over the surface of a solid to achieve thermodynamic equilibrium.
    [0061]. For the purpose of the present invention, the contact angle can be determined with methods essentially based on goniometric determinations, which involve direct observation of the angle formed between the solid substrate and the liquid under test. Therefore, it is simple to perform, and the only limitation is linked to a possible bias arising from intra-operator variability. However, it should be emphasized that this obstacle can be overcome through the adoption of a fully automated procedure, such as computer-assisted image analysis.
    [0062]. A particularly useful approach is the sessile or static drop method, as referenced on page 332 of Colombo et al (ibidem), which is performed by depositing a drop of liquid on the surface of the powder in the form of a disk obtained by compaction (method of the compacted powder disc).
    [0063]. Typically, the procedure is carried out as follows:
    [0064]. The compacted disc is prepared by adding the sample to the disc from a press and applying a compression force of 5 kN for 3 minutes. Then, the compacted disc is placed on a plate of a surface wettability tester and a drop of water of about 10 µL is formed on the surface of the disc.
    [0065]. The tester available from Lorentzen & Wettre GmbH represents an example of a suitable surface wettability tester.
    [0066]. The photographs are taken with a video camera and the values of the contact angles with the water are provided by a computer that assists in image analysis.
    [0067]. If a fully automated procedure is not available, the base (b) and height (h) of the drop are measured on the display using a mobile reading scale, followed by the water contact angles (WCA) are calculated by applying the following formula:WCA = [arctg 2h/b]x2x180/π
    [0068]. Typically, values are calculated as the average of three different measurements taken at room temperature. Accuracy is generally approximately ± 5°.
    [0069]. The degree of surface coating of lactose particles by magnesium stearate can also be determined by X-ray photoelectronic spectroscopy (XPS), a well-known tool for determining the degree as well as uniformity of distribution of certain elements on the surface of other substances. . In the XPS instrument, photons of a specific energy are used to excite the electronic states of atoms below the surface of the sample. Electrons ejected from the surface have the energy filtered by a hemispherical analyzer (HSA) before the intensity for a defined energy is registered by a detector. Once core-shell electrons in solid-state atoms are quantified, the resulting energy spectra exhibit resonance peaks characteristic of the electronic structure for atoms on the sample surface.
    [0070]. Typically, XPS determinations are performed on an Axis-Ultra instrument available from Kratos Analytical (Manchester, UK [UK]) using monochromatic Al Kα radiation (1486.6 eV) operated at an emission current of 15 mA and anode potential 10 kV (150 W). A low energy electron flood gun is used to compensate for the electrification of insulators. Total spectral scans [survey scans], from which the quantification of detected elements are obtained, are acquired with an analyzer pass energy of 160 eV and a step size of 1 eV. High resolution spectra of the C 1s, O 1s, Mg 2s, N 1s and Cl 2p regions are acquired with a pass energy of 40 eV and a step size of 0.1 eV. The area examined is approximately 700 μm x 300 μm for full spectra profiles and a spot diameter of 110 μm for high resolution spectra.
    [0071]. In the context of the present invention, by XPS, it is possible to calculate both the degree of coating and the depth of the magnesium stearate film around the lactose particles. The degree of coating with magnesium stearate (MgSt) is estimated using the following equation: % coating MgSt = (% Mgsample/%Mg ref) x 100whereMgsample is the amount of Mg in the analyzed mixture;Mg ref is the amount of mg in the commercially available MgSt reference sample.
    [0072]. Values are typically calculated as the average of two different determinations. Typically, an accuracy of 10% is assumed for routinely performed XPS experiments.
    [0073]. XPS determinations can be obtained with commercially available instruments such as the Axis-Ultra instrument from Kratos Analytical (Manchester, UK [UK]), typically using monochromatic Al Kα radiation, in accordance with known procedures.
    [0074]. Within the limits of experimental error, a good consistency has been found between the degree of coating obtained by the XPS determinations and the estimates obtained by theoretical calculations based on the Cassie and Baxter equation.
    [0075]. Another analytical technique that can be used favorably to determine the degree of coating is scanning electron microscopy (SEM) [scanning electron microscopy (SEM)].
    [0076]. This analysis can also rely on an EDX[Electron Dispersive X-ray analyzer] type analyzer, which can produce a selective image for certain types of atoms; for example, magnesium atoms. In this way, it is possible to obtain a clear set of data on the distribution of magnesium stearate on the surface of carrier particles.
    [0077]. SEM can alternatively be combined with Raman or IR spectroscopy [in infrared] to determine the degree of coating, according to known procedures.
    [0078]. The equipment in which the process of the present invention is to be carried out consists of a friction-based high-shear mixer granulator, operated at a rotation speed equal to or greater than 500 rpm, but equal to or less than 2500 rpm; preferably between 500 and 2000 rpm and more preferably between 1000 and 1500 rpm.
    [0079]. In fact, if the carrier particles have a mass diameter equal to or greater than 90 micrometers, at a rotation speed of 2000 rpm, the lactose particles begin to rupture and, thus, a significant reduction in size of the particles is observed.
    [0080]. The CYCLOMIXTM equipment (Hosokawa Micron Group Ltd) represents a typical high shear mixing granulator that can be employed to carry out the process of the present invention.
    [0081]. The aforementioned equipment features a conical stationary container equipped with mixing elements in the form of paddles, which rotate close to the inner wall of the container.
    [0082]. The powder is loaded into the conical mixing vessel from the top; and the degree of filling can vary between 30 and 100%. Together, the rotation of the paddles and the conical shape of the container force the powder from the base into the upper region of the container. Upon reaching the top, the powder flows in a downward movement towards the center of the container. This flow pattern results in a fast macromix. During upward movement, the powder particles are accelerated by the paddles and intensely mixed by friction with the container. These effects are sufficient to reduce strength, break, displace, flatten and wrap the magnesium stearate particles around the carrier particles to form a coating.
    [0083]. The product temperature remained constant during all experiments. However, the temperature can be accurately and reliably controlled.
    [0084]. When the process is carried out within the stipulated limits in terms of rotation speed, the particle size of the lactose particles remains essentially the same and a high degree of coverage is obtained.
    [0085]. However, when lactose particles substantially free from fine lactose particles are desired, the rotation speed should preferably be kept at a level equal to or less than 1500, i.e. between 1000 and 1500 rpm; while, at a higher rotational speed, it would be possible to produce in situ a small percentage of fine carrier particles, as reported, for example, in publication 00/53158.
    [0086]. Typically, a fraction of no more than 10% of fine particles can be produced with a DMM of less than 20 micrometers, preferably less than 10 micrometers.
    [0087]. In any case, it would be preferable to obtain magnesium stearate coated lactose carrier particles free of fine lactose particles.
    [0088]. Processing time depends on the type of carrier particles and the batch size and must be adjusted by the person skilled in the art.
    [0089]. Equipment with a capacity of up to 500 liters are currently available on the market.
    [0090]. Typically the processing time comprises between 1 and 30 minutes, is preferably kept between 2 and 20 minutes and more preferably between 5 and 15 minutes.
    [0091]. In some representations, the processing time is 10 minutes.
    [0092]. Processing time can also affect the degree of coating and should be adjusted by the skilled person depending on the amount of magnesium stearate employed and the degree of coating desired.
    [0093]. Carrier particles obtained by the process of the present invention exhibit good flow/flow properties, as they have a Carr index well below the value of 25, which is normally considered the differentiation value for free-flowing powders.
    [0094]. Carr's index is calculated by applying the following formula: Carr's index = [(ds - dv)/ds] x 100 where:dv is the gross bulk density; eds is the packed bulk density.
    [0095]. Densities were calculated according to the method described below.
    [0096]. Powder mixtures (approximately 70 g) were poured into a graduated glass beaker and the unseated apparent volume V0 was read; the bulk density before settlement (gross bulk density, dv) was calculated by dividing the sample weight by the volume V0. After 1250 taps with the device described, the apparent volume after settlement (V1250) was read and the apparent density after settlement (compacted bulk density, ds) was calculated.
    [0097]. Since the flow properties of the loader are good, consequently the flow properties of the corresponding pharmaceutical formulations in the form of dry powders are good.
    [0098]. Pharmaceutical formulations containing the carrier of the present invention also show adequate aerosol performance in terms of respirable fraction and significantly superior to the aerosol performance of formulations containing a carrier prepared in accordance with US 6,528,096.
    [0099]. Furthermore, the percentage of respirable MgSt particles delivered by the carrier of the present invention is significantly less than the percentage delivered by the prior art carrier. This indicates that said additive adheres more strongly to the surface of carrier particles, presents a much lower release of the carrier of the present invention during inhalation and, therefore, is less available for systemic absorption.
    [00100]. The formulations containing the charger of the present invention also showed physical stability in the device prior to use.
    [00101]. Finally, due to their increased hydrophobic properties, the carrier particles of the present invention tend to adsorb less water, as demonstrated by the dynamic vapor sorption experiments, making them particularly useful for the preparation of dry powder formulations containing hydrophobic and active ingredients /or hydrophilic.
    [00102]. Accordingly, the present invention is directed to a pharmaceutical composition in the form of a dry powder for inhalation containing the carrier particles of the present invention and one or more active ingredients.
    [00103]. The active ingredient can be virtually any pharmaceutically active compound amenable to administration by inhalation in dry powders.
    [00104]. As an example, they can be selected from short-acting and long-acting beta2-agonists such as terbutaline, reproterol, salbutamol, salmeterol, formoterol, carmoterol, milveterol, indacaterol, olodaterol, fenoterol, clenbuterol, bambooterol, broxaterol, epinephrine, isoprenaline or hexoprenaline or salts and/or solvates thereof; short- and long-acting anticholinergics, such as tiotropium, ipratropium, oxitropium, oxybutynin, aclinide, trospium, glycopyrronium, or the compounds known under the codes GSK 573719 and GSK 1160274, in the form of salts and/or solvates thereof; Bifunctional Muscarinic Antagonist (MABA) compounds for inhalation, such as GSK 961081; short-acting and long-acting corticosteroids such as butixocart, rofleponide, flunisolide, budesonide, ciclesonide, mometasone and its ester, ie, furoate, fluticasone and its ester, ie, propionate and furoate, beclomethasone and its ester, ie propionate , loteprednol or triamcinolone acetonide and solvates thereof; leukotriene antagonists such as andolast, iralukast, pranlukast, imitrodast, seratrodast, zileuton, zafirlukast or montelukast; phosphodiesterase inhibitors such as filaminast, piclamilast or roflumilast; a PAF Inhibitor such as apafant, rorapafant or israpafant; analgesics such as morphine, fentanyl, pentazocine, buprenorphine, pethidine, tilidine or methadone; potency agents such as sildenafil, alprostadil or phentolamine; or a pharmaceutically acceptable derivative or salt of any of the aforementioned compounds or classes of compounds. Since these compounds have chiral centers, they can be used in optically pure form, or they can be presented as diastereomeric mixtures or racemic mixtures.
    [00105]. The dry powder formulations of the present invention may also employ high molecular weight proteins, peptides, oligopeptides, polypeptides, polyamino acids, nucleic acid, polynucleotides, oligonucleotides, and polysaccharides.
    [00106]. Examples of macromolecules that can be used in the present invention are: albumins (preferably, human serum insulin; albumin); BSA; IG G; IgM; insulin; GCSF; GMCSF; LHRH; VEGF; hGH; lysozyme; alpha-lactoglobulin; basic fibroblast growth factor basic fibroblast growth factor; (bFGF); asparaginase; urokinase-VEGF; chymotrypsin; trypsin; streptokinase; interferon; carbonic anhydrase; ovalbumin; glucagon; ACTH; oxytocin; phosphorylase b; alkaline phosphatase-secretin; vasopressin; levothyroxine; fatase; betagalactosidase; parathyroid hormone, calcitonin; fibrinogen; polyamino acids (for example; DNAse, alpha1-antitrypsin; polylysine, polyarginine); angiogenesis inhibitors or pro-immunoglobulins (eg, antibodies); somatostatin and analogues; casein; collagen; gelatine; soy protein; and cytokines (for example; interferon, interleukin); immunoglobulins; physiologically active proteins, such as peptide hormones, cytokines, growth factors, factors acting on the cardiovascular system, factors acting on the central and peripheral nervous system, factors acting on humoral electrolytes and hemal substances, factors acting on bones and skeleton, factors acting on the gastrointestinal system, factors acting on the immune system, factors acting on the respiratory system, factors acting on the genitals, and enzymes; Hormones and hormone modulators, including insulin, proinsulin, insulin C-peptide, growth hormone, parathyroid hormone, luteinizing hormone-releasing hormone (LH-RH), adrenocorticotropic hormone (ACTH), amylin, oxytocin, luteinizing hormone, (D-Tryp6)- LHRH, nafarelin acetate, leuprolide acetate, follicle-stimulating hormone, glucagon, prostaglandins, estradiols, testosterone, and other factors acting on the genital organs and their derivatives, analogues and congeners. As analogues of the mentioned LH-RH, known substances described, for example, in US 4,008,209, US 4,086,219, US 4,124,577 US 4,317,815 and US 5,110,904 can be mentioned; Hematopoietic or thrombopoietic factors include, among others, erythropoietin, granulocyte colony stimulating factor (G-CSF), granulocyte macrophage colony stimulating factor (GM-CSF) and macrophage colony stimulating factor (M-CSF), preparation of leukocyte proliferation factor, thrombopoietin, platelet proliferation stimulating factor, megakaryocyte proliferation (stimulating) factor, and factor VIII; Enzymes and enzyme cofactors, including pancrease, L-asparaginase, hyaluronidase, chymotrypsin, trypsin, streptokinase, urokinase, pancreatin, collagenase, trypsinogen, chymotrypsinogen, plasminogen, streptokinase, adenylcyclase, and superoxide dismutase (SOD); Vaccines include Hepatitis B, MMR (measles, mumps and rubella), and Polio vaccines; Growth factors include nerve growth factors (NGF, NGF-2/NT-3), epidermal growth factor (EGF), fibroblast growth factor (FGF), insulin-like growth factor (IGF), transforming factor growth factor (TGF), platelet-derived growth factor (PDGF), and hepatocyte growth factor (HGF); Factors acting on the cardiovascular system, including factors that control blood pressure, arteriosclerosis, etc., such as endothelins, endothelin inhibitors, endothelin antagonists, endothelin-producing enzyme inhibitors vasopressin, renin, angiotensin I, angiotensin II, angiotensin III , angiotensin I inhibitors, angiotensin II receptor antagonists, atrial natriuretic peptide (ANP), and antiarrhythmic peptide; Factors acting on the central and peripheral nervous system, including opioid peptides (eg; enkephalins, endorphins), neurotrophic factor (NTF), calcitonin gene-related peptide (CGRP), thyrotrophin releasing hormone (TRH), salts and derivatives, and neurotensin; Factors acting on the gastrointestinal system, including secretin and gastrin; Factors acting on humoral electrolytes and hemal substances, including factors that control hemagglutination, plasma cholesterol level, or metal ion concentrations, such as calcitonin, apoprotein E, and hirudin. Laminin and intercellular adhesion molecule 1 (ICAM 1) represent examples of cell adhesion factors; Factors acting on the kidneys and urinary tract, including substances that regulate renal function, such as brain natriuretic peptide (BNP), and urotensin; Factors that act on the sense organs, including factors that control the sensitivity of various organs, such as substance P; Chemotherapeutic agents such as paclitaxel, mitomycin C and doxorubicin; Factors acting on the immune system, including factors that control inflammation and malignant neoplasms, and factors that attack infection-causing microorganisms, such as chemotactic peptides; and naturally occurring, chemically synthesized or recombinant peptides or proteins that can act as antigens, such as cedar pollen [cedar pollen] and ragweed pollen [ragweed pollen], and these isolated substances or together with/linked to haptens, or together with an adjuvant.
    [00107]. Formulations containing a beta2-agonist, an anticholinergic or an inhalation corticosteroid, alone or in any combination thereof, constitute specific embodiments of the present invention.
    [00108]. These actives can be present in the form of a specific salt and/or solvate thereof, such as beta2-agonists; for example, formoterol fumarate dihydrate, salbutamol sulphate, salmeterol xinafoate, milveterol hydrochloride and indacaterol maleate; anticholinergics; for example, as glycopyrronium bromide in the form of enantiomer (3R,2R') or racemic mixture (3S,2R') and (3R,2S'), tiotropium bromide, oxitropium bromide, ipratropium bromide, oxybutynin chloride, aclinide bromide or trospium chloride.
    [00109]. In turn, inhaled corticosteroids may be present in a specific form of their ester and/or solvate; for example, beclomethasone dipropionate or its monohydrate form, fluticasone propionate, fluticasone furoate or mometasone furoate.
    [00110]. In a specific embodiment, formulations containing the dihydrate form of formoterol fumarate and its combinations with inhalation corticosteroids and/or anticholinergics are preferred.
    [00111]. In another specific representation, a salt of vilanterol or indacaterol and combinations thereof with inhaled corticosteroids and/or anticholinergics represent the preference.
    [00112]. In order for the active substance to be inhalable, that is, to be able to reach the deep part of the lungs, such as the respiratory and terminal bronchioles and the alveolar ducts and sacs, it must be in particulate form with an average particle diameter (determined as the mass average diameter) of at most about 10 micrometers; for example 1 to 10 micrometers and preferably 1 to 6 micrometers. These microfine particles can be obtained in a manner known per se; for example, by micronization, controlled precipitation from selected solvents, spray drying, supercritical fluids or in accordance with the processes described in WO 2004/073827, WO 2008/155570, WO 2008/114052 and WO 2010 /007447.
    [00113]. The therapeutically effective amount of active substance can vary within wide limits depending on the nature of the active substance, the type and severity of the condition being treated and the condition of the patient in need of treatment.
    [00114]. Typically, the active substance particles are added to the carrier particles of the present invention by means of mixing. The particles can be blended using a tumbling blender (e.g., a Turbula mixer) according to procedures known in the art.
    [00115]. In particular, the mixer rotation speed and mixing time must be adjusted by the person skilled in the art to obtain a good uniformity of distribution of the active ingredient in the formulation.
    [00116]. An excellent uniformity of distribution of the active ingredient is obtained when it has a particle size distribution where not more than 10% of the particles have a volume diameter [d(v,0.1)] less than 0.8 micrometer, preferably , less than 0.9 micrometer and more preferably less than 1 micrometer, and not more than 50% of the particles have a volume diameter [d(v, 0.5)] less than 1.7 micrometer, preferably less at 1.9 micrometers and more preferably less than 2 micrometers.
    [00117]. The dry powder inhalation formulation containing the carrier particles of the present invention can be used with any dry powder inhaler.
    [00118]. Dry powder inhalers can be essentially divided into: i) single dose (unit dose) inhalers, for the administration of single subdivided doses of the active compound; ii) multi-dose metered-dose inhalers or reservoir-type inhalers pre-loaded with quantities of active principles sufficient for longer treatment cycles.
    [00119]. Dry powder formulations may be presented in unit dosage form. Dry powder compositions for topical pulmonary administration by inhalation may, for example, be presented in capsules and cartridges of, for example, gelatin, or blisters of, for example, aluminum foil, for use in an inhaler or insufflator.
    [00120]. The dry powder inhalation formulation according to the present invention is particularly suitable for multi-dose dry powder inhalers containing a reservoir from which individual therapeutic dosages can be delivered on demand by actuation of the device.
    [00121]. A preferred multi-dose device is the inhaler described in publication WO 2004/012801.
    [00122]. Other multi-dose devices that can be used are, for example, the DISKUSTM from GlaxoSmithKline, the TURBOHALERTM from AstraZeneca, the TWISTHALERTM from Schering and the CLICKHALERTM from Innovata.
    [00123]. As examples of commercially available single-dose devices may be mentioned the ROTOHALERTM by GlaxoSmithKline and the HANDIHALERTM by Boehringer Ingelheim.
    [00124]. The following examples illustrate the present invention in detail.EXAMPLESExample 1 - Preparation of the loader - Study of processing conditions
    [00125]. Commercially available α-lactose monohydrate was sieved to obtain a sample with particles ranging in diameter from 90 to 150 μm.
    [00126]. Approximately 450 g of the aforementioned α-lactose monohydrate, mixed with 0.5% w/w magnesium stearate, was placed in the stationary conical container of the 1 liter laboratory model CYCLOMIXTM equipment (Hosokawa Micron Ltd).
    [00127]. The process was carried out by varying the different parameters (speed of rotation, processing time).
    [00128]. α-lactose monohydrate and a mixture of α-lactose monohydrate and 0.5% magnesium stearate processed at 2000 rpm for 15 minutes were also processed for comparative purposes.
    [00129]. The particles obtained were collected and submitted to physical-chemical technological characterization.
    [00130]. In particular, the following characteristics were determined: i) crystallinity by X-ray diffractometry (XRD) [X-ray diffractometry] of powder; ii) magnesium stearate in the powder by determinations of differential exploratory calorimetry-thermogravimetric analysis (ATG-DSC) [ thermogravimetric-differential scanning calorimetry] and by Fourier-Transformed-Infra-Red analysis [Fourier-Transformed-Infra-Red analysis].iii) surface aspect by scanning electron microscopy (SEM);iv) size distribution; of particles (DTP) by laser diffraction with a Malvern equipment; v) angle of contact with water by the sessile drop method, where the powder is presented in the form of a disk obtained by compaction (compacted powder disk method), of according to the procedure reported above in the description; vi) adsorption of water at an increasing percentage of relative humidity by dynamic vapor sorption (DVS) experiments. vii) flow properties o) by the Carr index.
    [00131]. The list of experiments performed is shown in Table 1.


    [00132]. The XRD analysis performed on the sample obtained under the most stressful conditions (1500 rpm for 15 minutes) among the conditions tested indicates that α-lactose remains crystalline.
    [00133]. The marker band at 2850 cm-1 in the FT-IR spectrum also confirms the presence of magnesium stearate in the samples.
    [00134]. Representative photographs of SEM are shown in Figure 2.
    [00135]. From the images, it can be seen that the treatment of carrier particles mixed with 0.5% w/w of magnesium stearate at 1500 rpm for 5, 10 and 15 minutes does not considerably change the size of the particles.
    [00136]. The same was observed for a rotation speed of 1000 rpm (data not shown).
    [00137]. In contrast, at 2000 rpm, the lactose particles begin to break down, and a reduction in particle size is observed, along with the production of a significant amount of fine particles.
    [00138]. The findings are confirmed by the results of the DTP analysis presented in Table 2. The results are expressed as the mean of three determinations.
    [00139]. In Table 2, the water contact angle values and the corresponding degree of surface coating calculated from the Cassie and Baxter equation are also presented.
    [00140]. This equation was applied to the experimental values of the penultimate column of Table 2 using the reference values for magnesium stearate alone and α-lactose monohydrate alone.
    [00141]. The variability in terms of S.D. of the experimental values is always less than ± 10%, typically ± 5%.
    [00142]. The results show that the degree of surface coating is always above 85%.
    [00143]. In addition, from the DVS experiments, it can be seen that the increased hydrophobic character of carrier particles coated with magnesium stearate compared to those with lactose makes them less likely to adsorb water from ambient moisture (see Figure 3).

    [00144]. Density values and corresponding Carr index for 5, 10 and 15 minutes are shown in Table 3.

    [00145]. All samples exhibit good flow properties as they have a Carr index of 5-8, which is well below the value of 25, which is the generally considered differentiation value.Example 3 - Preparation of other carrier particles
    [00146]. Carrier particles according to the present invention are prepared as described in Example 1, but mixing α-lactose monohydrate with 0.3% w/w magnesium stearate at 1000 rpm, and with 0.5% w/w stearate of magnesium at 500 rpm, at different mixing times. The particle size distribution, the flow/flow and the contact angle with water of the obtained samples were determined.
    [00147]. The results of the determination of the contact angles with water are presented in Table 4.
    Example 4 - Inhalable dry powder DPB formulations containing the carrier of the invention
    [00148]. Carrier particles were prepared as described in Examples 1 and 3, at a rotation speed of 1000 rpm for 15 minutes.
    [00149]. Micronized beclomethasone dipropionate is obtained by conventional jet mill micronization.
    [00150]. A powder formulation according to the present invention is prepared with the composition shown in Table 5.

    [00151]. The final formulation is loaded into the multi-dose dry powder inhaler described in publication WO 2004/012801.
    [00152]. Other powder formulations according to the present invention are prepared with the compositions shown in Tables 6 and 7


    [00153]. The aerosol performances of the presented formulations were evaluated using a Multi Stage Liquid Impinger (MSLI), in accordance with the procedure described in the European Pharmacopoeia [European Pharmacopoeia] 2nd edition, 1995, part V.5.9.1, pages 15-17.
    [00154]. The results in terms of delivered dose (DA), fine particle mass (MPF), fine particle fraction (FPF) and mass median aerodynamic diameter (MAMM) are shown in Table 8 (mean of three determinations ± SD)

    [00155]. The FPF, which is an index of the respirable fraction, was excellent, indicating that the formulations containing the carrier particles of the present invention are capable of determining good aerosol performance.
    [00156]. The formulations presented also resulted in a significantly higher FPF compared to analogous formulations containing a charger prepared by mixing α-lactose monohydrate and magnesium stearate in a Turbula mixer at 32 rpm for 120 minutes, in accordance with US document 6,528,096.Example 5 - Inhalable dry powder formulation containing formoterol fumarate the carrier of the invention
    [00157]. The loader was prepared as described in Example 1, at a rotation speed of 1000 rpm for 10 minutes.
    [00158]. Micronized formoterol fumarate dihydrate was obtained by conventional jet mill micronization.
    [00159]. The powder formulation according to the present invention was prepared with the composition shown in Table 9.
    [00160]. The final formulation was loaded into the multi-dose dry powder inhaler described in publication WO 2004/012801.

    [00161]. The aerosol performances of the presented formulations were evaluated using a Multi Stage Liquid Impinger (MSLI) in accordance with the procedure described in the European Pharmacopoeia [European Pharmacopoeia] 2nd edition, 1995, part V.5.9.1, pages 15-17.
    [00162]. The results in terms of delivered dose (DA), fine particle mass (MPF), fine particle fraction (FPF) and mass median aerodynamic diameter (MAMM) are shown in Table 10 (mean of three determinations ± SD).

    [00163]. The FPF proved to be satisfactory.
    [00164]. The presented formulation also resulted in a significantly higher FPF compared to an analogous formulation containing a charger prepared by mixing α-lactose monohydrate and magnesium stearate in a Turbula mixer at 32 rpm for 120 minutes, in accordance with the document US 6,528,096.Example 6 - Inhalable dry powder containing formoterol fumarate + DPB formulation and the carrier of the invention
    [00165]. The charger is prepared as described in Example 1, at a rotation speed of 1000 rpm for 15 minutes.
    [00166]. Micronized beclomethasone dipropionate and formoterol fumarate dihydrate were obtained by conventional milling.
    [00167]. A powder formulation according to the present invention is prepared with the composition shown in Table 11.
    [00168]. The final formulation is loaded into the multi-dose dry powder inhaler described in publication WO 2004/012801.
    Example 7 - Inhalable dry powder formulation containing glycopyrronium bromide and the carrier of the invention
    [00169]. The loader is prepared as described in Example 1, at a rotation speed of 1000 rpm for 15 minutes.
    [00170]. Micronized glycopyrronium bromide in the form of a racemic mixture (3S,2R’) and (3R,2S’) is obtained as described in WO 2010/007447.
    [00171]. A powder formulation according to the present invention is prepared with the composition shown in Table 12.
    [00172]. The final formulation is loaded into the multi-dose dry powder inhaler described in publication WO 2004/012801.
    Example 8 - Determination of the respirable fraction of magnesium stearate
    [00173]. The favorable properties of the loader of the present invention are illustrated by the experiment below, where the release of fine Mg particles from a formulation of the same was investigated.
    [00174]. Samples of carrier particles according to the present invention, as described in Example 1, prepared by mixing α-lactose monohydrate with 0.1%, 0.3% w/w or 0.5% w/w stearate of magnesium in a CYCLOMIX™ apparatus at 1000 rpm for 10 minutes, were loaded into the multi-dose dry powder inhaler described in publication WO 2004/012801.
    [00175]. For comparison purposes, a test blank as well as carrier particles prepared by mixing α-lactose monohydrate with 0.3% w/w or 0.5% w/w magnesium stearate in a Turbula mixer a 32 rpm for 120 minutes, in accordance with US 6,528,096, were also prepared.
    [00176]. Micronized beclomethasone dipropionate (DPB) was added as shown in Example 4.
    [00177]. The respirable fraction of magnesium stearate was evaluated using a Twin Stage Impinger apparatus (TSI, Copley Instruments Ltd, UK [UK]), in accordance with the procedure described in FU IX, 4th Supplement, 1996, and applying an air flow of 60 L/min.
    [00178]. The limit value of the aerodynamic diameter (AED) for deposition in the lower separation chamber is 6.4 micrometers. Particles with larger DAE are deposited in Stage 1, while particles with smaller DAE are deposited in Stage 2.
    [00179]. Ten doses of 15-18 mg were administered for each experiment.
    [00180]. After aerosolization, the TSI apparatus was disassembled and the quantities of particles deposited in the two separate chambers were collected with a mixture of water:acetonitrile:HCl (2N) 40:40:20 v/v/v and brought to a volume of 50 mL .
    [00181]. The samples were calcined in a microwave oven and the amount of Mg was determined by flame atomic absorption spectroscopy using a Perkin-Elmer Analyst 800 instrument, in accordance with conventional procedures recognized in the art.
    [00182]. The limit of detection (LOD) was 0.062 mg/ml.
    [00183]. The respirable fraction (FPF) of magnesium stearate was calculated by the ratio between the respirable dose and the administered (emitted) dose. The administered dose is calculated from the accumulated deposition in the device, while the respirable dose is calculated from the deposition in Stages 2 corresponding to particles with an AED < 6.4 micrometers.
    [00184]. The results are shown in Table 13 (mean ± SD).

    [00185]. As can be seen, the percentage of respirable MgSt particles delivered by the carrier of the present invention is significantly less than the percentage delivered by a comparative carrier.
    [00186]. This indicates that said additive is much less released from the carrier of the present invention during inhalation, as it adheres more strongly to the surface of carrier particles and thus becomes less available for systemic absorption.
    权利要求:
    Claims (12)
    [0001]
    1. PROCESS FOR PREPARING AN EXCIPIENT FOR POWDERED PHARMACEUTICAL COMPOSITIONS FOR INHALATION, characterized in that it consists of subjecting lactose particles with a mass diameter in the range of 90 micrometers to 400 micrometers to dry coating with 0.1% to 1.0% of magnesium stearate by weight of the excipient to obtain a surface coating of the lactose particles with the mentioned magnesium stearate in such a way that the coated particles have more than 60% surface coating, the coating step being Dry is performed in a high shear mixing granulator based on frictional behavior at a rotation speed equal to or greater than 1000 rpm, but equal to or less than 1500 rpm.
    [0002]
    2. Process according to claim 1, characterized in that the dry coating step is carried out for a period between 2 minutes and 20 minutes.
    [0003]
    3. PROCESS, according to claim 2, characterized in that the period is between 5 minutes and 15 minutes.
    [0004]
    4. Process, according to one of claims 1 to 3, characterized in that the coated particles have at least 80% surface coating.
    [0005]
    5. Process according to claim 4, characterized in that the coated particles have more than 90% surface coating.
    [0006]
    6. CARRIER PARTICLES FOR A DRY POWDERED PHARMACEUTICAL FORMULATION, characterized by including lactose particles with a mass diameter in the range of 90 micrometers to 400 micrometers, coated with 0.1% to 1.0% magnesium stearate by weight of the carrier , such that the coated particles have more than 60% surface coating, and these carrier particles are obtained by a process that comprises dry coating in a high shear mixing granulator, based on the friction behavior to a rotation speed equal to or greater than 1000 rpm, but equal to or less than 1500 rpm.
    [0007]
    7. PHARMACEUTICAL COMPOSITION IN THE FORM OF DRY POWDER FOR INHALATION characterized by containing the carrier particles as defined by claim 6 and one or more active ingredients.
    [0008]
    8. PHARMACEUTICAL COMPOSITION, according to claim 7, characterized in that the active ingredient is represented by a beta2-agonist selected from the group consisting of salmeterol, formoterol, carmoterol milveterol, and indacaterol or a salt and/or solvate thereof.
    [0009]
    9. PHARMACEUTICAL COMPOSITION according to claim 7, characterized in that the active ingredient is represented by an anticholinergic selected from the group consisting of tiotropium and glycopyrronium.
    [0010]
    10. PHARMACEUTICAL COMPOSITION according to claim 7, characterized in that the active ingredient is represented by a corticosteroid selected from the group consisting of beclomethasone dipropionate, fluticasone propionate, fluticasone furoate, budesonide or mometasone furoate.
    [0011]
    11. PHARMACEUTICAL COMPOSITION according to claim 7, characterized in that the active ingredient is represented by a phosphodiesterase inhibitor.
    [0012]
    12. DRY POWDER INHALER characterized in that it is loaded with the pharmaceutical composition as defined by one of claims 7 to 11.
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    同族专利:
    公开号 | 公开日
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    PL2552424T3|2018-10-31|
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    US20150202159A1|2015-07-23|
    UA110106C2|2015-11-25|
    CN104257610A|2015-01-07|
    JP6162181B2|2017-07-12|
    JP2013523670A|2013-06-17|
    EP2552424B1|2018-05-09|
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    法律状态:
    2018-01-23| B07D| Technical examination (opinion) related to article 229 of industrial property law [chapter 7.4 patent gazette]|
    2018-04-10| B06F| Objections, documents and/or translations needed after an examination request according [chapter 6.6 patent gazette]|
    2019-01-29| B07E| Notice of approval relating to section 229 industrial property law [chapter 7.5 patent gazette]|Free format text: NOTIFICACAO DE ANUENCIA RELACIONADA COM O ART 229 DA LPI |
    2019-04-09| B06T| Formal requirements before examination [chapter 6.20 patent gazette]|
    2021-04-06| B09A| Decision: intention to grant [chapter 9.1 patent gazette]|
    2021-06-01| B16A| Patent or certificate of addition of invention granted|Free format text: PRAZO DE VALIDADE: 20 (VINTE) ANOS CONTADOS A PARTIR DE 11/03/2011, OBSERVADAS AS CONDICOES LEGAIS. PATENTE CONCEDIDA CONFORME ADI 5.529/DF |
    优先权:
    申请号 | 申请日 | 专利标题
    EP10158951|2010-04-01|
    EP10158951.3|2010-04-01|
    PCT/EP2011/053695|WO2011120779A1|2010-04-01|2011-03-11|Process for preparing carrier particles for dry powders for inhalation|
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