EP2299990A1 - Nouvelles particules à principe actif incorporé pour inhalation - Google Patents

Nouvelles particules à principe actif incorporé pour inhalation

Info

Publication number
EP2299990A1
EP2299990A1 EP09761699A EP09761699A EP2299990A1 EP 2299990 A1 EP2299990 A1 EP 2299990A1 EP 09761699 A EP09761699 A EP 09761699A EP 09761699 A EP09761699 A EP 09761699A EP 2299990 A1 EP2299990 A1 EP 2299990A1
Authority
EP
European Patent Office
Prior art keywords
lactide
polymer
amino
molecular mass
mass
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Withdrawn
Application number
EP09761699A
Other languages
German (de)
English (en)
Inventor
Michael Krueger
Marc Egen
Elke Jahr
Regis Cartier
Anja Enderle
Thierry Bouyssou
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Boehringer Ingelheim International GmbH
Original Assignee
Boehringer Ingelheim International GmbH
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Boehringer Ingelheim International GmbH filed Critical Boehringer Ingelheim International GmbH
Priority to EP09761699A priority Critical patent/EP2299990A1/fr
Publication of EP2299990A1 publication Critical patent/EP2299990A1/fr
Withdrawn legal-status Critical Current

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Classifications

    • 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
    • A61K31/56—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids
    • A61K31/57—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids substituted in position 17 beta by a chain of two carbon atoms, e.g. pregnane or progesterone
    • A61K31/573—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids substituted in position 17 beta by a chain of two carbon atoms, e.g. pregnane or progesterone substituted in position 21, e.g. cortisone, dexamethasone, prednisone or aldosterone
    • 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
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
    • A61K9/16—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
    • A61K9/1605—Excipients; Inactive ingredients
    • A61K9/1629—Organic macromolecular compounds
    • A61K9/1641—Organic macromolecular compounds obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyethylene glycol, poloxamers
    • A61K9/1647—Polyesters, e.g. poly(lactide-co-glycolide)

Definitions

  • the invention relates to methods for the preparation of sustained-release medicaments and to medicaments obtainable by means of these methods for inhalative use.
  • the invention relates to poly (lactide-co-glycolide) -based
  • Dry powder formulations which have a delayed release of active ingredient.
  • the invention also relates to the use of these medicaments for the treatment of respiratory diseases, in particular for the treatment of COPD (chronic obstructive pulmonary disease) and asthma.
  • COPD chronic obstructive pulmonary disease
  • Diffusion barrier can form or impede the distribution of the drug.
  • Active ingredients are usually made accessible by oral administration. Unless this route is due to specific properties of the active ingredient or special
  • inhalation powders which are filled, for example, into suitable capsules (inhalettes), are applied by means of powder inhalers in the lungs.
  • other systems in which the amount of powder to be applied is pre-dosed (eg blister), as well as multi-dose powder systems known.
  • inhalative application may also be effected by administration of suitable powdered inhalation aerosols, which are suspended, for example, in HFA134a, HFA227 or their mixture as propellant gas.
  • suitable powdered inhalation aerosols which are suspended, for example, in HFA134a, HFA227 or their mixture as propellant gas.
  • the microparticles of the pure active substance are usually applied by the respiratory tract to the lung surface, for example in the alveoli, by means of the inhalation process. These particles sediment on the surface and are absorbed by active and passive transport processes in the body directly after the dissolution process.
  • a critical factor in such multi-component systems is a uniform distribution of the drug in the powder mixture.
  • respirable particles inhalable fraction
  • the average particle size of these respirable particles is in the range of a few micrometers, typically between 0.1 and 10 .mu.m, preferably below 6 .mu.m.
  • Such particles are usually produced by micronization (air jet milling).
  • powder preparations consisting of co-spray-dried ⁇ -galactosidase with trehalose [J. Broadhead, S.K. Edmond Rouan, CT.
  • Powder preparations consisting of a spray micronisate, which by co-spray drying of at least two active substances and one or more physiologically acceptable excipients [WO 01/13885]; Powder preparations consisting of spray-dried rhDNase, optionally co-spray-dried with salts, and either directly or in the form of a mixture with a physiologically acceptable excipient, e.g. Lactose, mannitol or sodium chloride were provided for inhalation applications [H. K. Chan, A. Clark, I Gonda, M. Mumenthaler, C.
  • Lactose which is converted by a subsequent recrystallization of the primary amorphous excipient in crystalline ⁇ -lactose monohydrate [H. -K. Chan, I. Gonda, J. Pharm. Sci., 87 (5), (1998) 647-654].
  • the object of the invention is that a controlled release of the active ingredient is made possible by means of the inhalable powder according to the invention. It is therefore the task of
  • Dissolution rate (retardation) in comparison to particles of the pure active substance.
  • a specific object of the invention is to provide inhalation powders having a retardation characterized in that a maximum of 60% of the
  • Release behavior show that particles in a diffusion cell according to Franz show a delayed dissolution behavior.
  • inhalable powders which have a delayed dissolution rate in comparison to the pure active substance particles and to processes for their preparation.
  • Another aspect of the invention is to provide retarded inhalable powders containing a biodegradable, chemically modified polymer and methods for their preparation.
  • retarded inhalable powders which consist exclusively of a low molecular weight active substance and a biodegradable polymer and to processes for their preparation.
  • Inhalable powders according to the invention contain microparticles in which one or more active substances are incorporated in an auxiliary substance matrix of a biodegradable polymer.
  • the active ingredient or a physiologically acceptable salt thereof
  • the active ingredient is physically stably incorporated as a solid in a solid matrix of an excipient (biodegradable polymer).
  • the active ingredient can be incorporated into the solid matrix in such a way that it has a delayed release.
  • this is to be understood as meaning that the dissolution behavior of the inhalable particles in a release medium, determined in a diffusion cell according to Franz, is delayed in comparison to inhalable particles of the pure active substance.
  • the inhalable microparticles contain an active substance and, according to the definition of the present invention, represent inhalable, active ingredient-containing microparticles (active substance particles).
  • the inhalable fraction represents the amount of inhalable active ingredient particles (particles ⁇ 5 ⁇ m), as described on the basis of Pharm. Eur. 2.9.18 (European Pharmacopoeia, 6th edition 2008, Apparatus D - Andersen Cascade Impactor) or USP30-NF25 ⁇ 601> is determinable.
  • the inhalable fraction is also referred to in the context of the present invention as FPD (Fine Particle Dose).
  • the inhalable particles of the inhalable powders according to the invention achieve the abovementioned objects if the active substance or several active substances is / are incorporated in an auxiliary substance matrix of a biodegradable polymer.
  • a biodegradable polymer is meant a polymer which is decomposed by the organism. In particular, it is understood that during the residence time of the polymer in the human body no cell change and no toxic effect in vivo results.
  • the object is achieved if the active substance or several active substances is / are incorporated in an auxiliary substance matrix from a biodegradable polymer and the excipient (biodegradable polymer) is selected from the group consisting of PLGA (which is understood to mean co-polymers of the type poly). (lactide-co Glycolide)), PEG-modified (poly (lactide-co-glycolide)) based polymers, and PEG-modified (poly-lactides).
  • PLGA which is understood to mean co-polymers of the type poly.
  • the group consisting of PEG-modified PLGA and PEG-modified poly-lactides comprises block co-polymers which are selected from the substance class of the PEG [lactide co-glycolides] and the substance class of the PEGs. [poly-lactide].
  • Block copolymers according to the invention are characterized in that they contain at least one hydrophilic and one hydrophobic block.
  • the chemical compounds of the PLGAs do not represent block co-polymers, but correspond to simple co-polymers.
  • block copolymers polymers consisting of longer sequences or blocks of each monomer (e.g., block A corresponds to aaaaaaaaaaaaaaa ...; block B corresponds to bbbbbbbb ).
  • block A corresponds to aaaaaaaaaaaaaaa ...
  • block B corresponds to bbbbbbbbb .
  • Each lower case letter stands for one
  • Monomer unit Depending on the number of blocks one also speaks of diblock, triblock copolymers.
  • a diblock structure (A-B) or triblock structure (A-B-A) is to be understood as meaning that the polymer is made up of different units which repeat regularly at the molecular level and consist of two or three blocks.
  • the block A consists of successive monomer units aaaaaaaa ... of a first polymer and the block B of successive monomer units bbbbbbbbb ... of the second polymer.
  • polymers from the class of block co-polymers can be selected for the production of the inhalable powders according to the invention. These include at least one water-soluble block (block B) and at least one non-water-soluble block (block A).
  • block B PEG (polyethylene glycol) is used to a particular degree.
  • non-water-soluble block A a polyester compound is chosen in particular.
  • the polyester block the polymer class of the poly (lactide-co-glycolides) is used.
  • the monomer units a of block A in the case of the (i) PEG- [lactide-co-glycolides] both lactide units a 1 and glycolide units a 2 , wherein the monomer units "lactide unit a 1 " and “glycolide unit a 2 " either statistically randomly distributed within the block or even occur alternately or alternately in the course of the block or in the case of
  • the lactide units can represent D-lactide as well as L-lactide.
  • a specific embodiment of the invention is the use of block co-polymers which have a di-B lock structure.
  • inhalable powders which are characterized in that a maximum of 60% of the active ingredient in a maximum of 30 minutes, and a maximum of 80% of the active ingredient is released in a maximum of 10 hours, wherein the inhalable powder contains microparticles, in which one or more active ingredients in an excipient matrix of a biodegradable polymer is incorporated.
  • the inhalable powders containing microparticles in which one or more active substances are incorporated in an excipient matrix of a biodegradable polymer are characterized in a further embodiment in that a maximum of 90% of the active ingredient has dissolved after 10 hours, preferably at most 90% of the active ingredient is solved after 12 hours.
  • the solution behavior of the inhalable fraction of the inhalable powder according to the invention serves as a measure of the retardation of the active ingredient.
  • This solution behavior can be determined using a Franz diffusion cell (see Figure 1).
  • a lower compartment is filled with a freely selectable release medium (preferably PBS buffer) and the membrane (here o filter membrane) placed on the surface of the medium, whereby air bubbles are no longer present between the release medium and the membrane.
  • the upper part of the cell closes the system and forms an air compartment.
  • the lower compartment is with hoses to a pump connected, which direct the medium to a device for measuring data acquisition, for example, a UV detector or a fluorescence detector. With such detectors, an active ingredient can be detected quantitatively.
  • the release medium is mixed with a stirring system, such as a magnetic stirrer, to better distribute an active substance contained in the release medium within the chamber.
  • the inhalable fraction of the inhalable powders according to the invention is deposited in finely distributed form on a filter membrane 1 in a Franz diffusion cell.
  • a first compartment 2 for receiving a liquid release medium is arranged free of air bubbles, which continuously, as indicated by the terminals 3 and the flow arrow D, implemented and a means for measuring data acquisition, such as a UV or fluorescence detector supplied.
  • a second compartment 4 Above the membrane 1 is formed as a second compartment 4, an air chamber and the entire diffusion cell 5 (Franz cell) is surrounded by a heat insulation 6 and can be controlled by a hotplate 7 in the desired manner.
  • a magnetic stirrer 8 is used for mixing the release medium.
  • the inhalable fraction of the inhalable powders according to the invention may preferably be deposited on a cellulose membrane.
  • the deposition of the inhalable fraction can be effected by placing this filter on the filter plate of the Andersen cascade impactor.
  • the application is then carried out in accordance with Pharm. Eur. 2.9.18 (European Pharmacopoeia, 6th edition 2008, Apparatus D - Andersen Cascade Impactor), with only the deposition plates are inserted into the cascade impactor, not for the deposition of particles from 0 microns to 5 microns, so that all particles smaller than 5 microns are deposited on the filter.
  • a filter is used, which is made of regenerated cellulose.
  • FaIIA active compounds which have a water solubility of more than 0.01 g per 100 ml
  • case B organic solvent which is completely miscible with water
  • case C organic solvent, preferably dichloromethane of more than 0.01 g per 100 ml
  • the object of the present invention is achieved by the use of active ingredients having a water solubility of more than 0.01 g per 100 ml if inhalation powders containing microparticles are embedded in a polymer, the biodegradable polymer being a Substance selected from the substance classes of PEG [lactide co-glycolides] or PEG- [poly-lactides] represents. Such substances are available under the name Resomer® (Boehringer Ingelheim Pharma GmbH & Co. KG, Germany). In particular, polymers of these two classes of substances are suitable if they have the properties (a), (b), (c), (d) and (e):
  • a lactide content of 95-100%, preferably 100% (mass% based on the molecular mass and 100% based on the molecular mass of the polymer block A of the co-polymer) and the lactide content of the components L -Lactide and D-lactide may contain and the D-lactide to L-lactide maximally in the ratio of n: 4 and n is a number less than or equal to 1, possibly the lactide portion consists exclusively of L-lactide.
  • the object of the invention is fulfilled when using active ingredients having a water solubility of more than 0.01 g per 100 ml when inhalation powders containing microparticles are embedded in a polymer, the biodegradable polymer a substance selected from the substance classes of the PEG [lactide co-glycolides] or the PEG [poly-lactides] represents.
  • active ingredients having a water solubility of more than 0.01 g per 100 ml when inhalation powders containing microparticles are embedded in a polymer
  • the biodegradable polymer a substance selected from the substance classes of the PEG [lactide co-glycolides] or the PEG [poly-lactides] represents.
  • Such substances are called Resomer®
  • polymers of these two classes of substances are suitable if they have the properties (f), (g), (h), (i) and (j):
  • the lactide portion may contain the components L-lactide and D-lactide and the D-lactide to L-lactide maximally in the ratio n: A is present and n is a number less than or equal to 1, optionally the lactide portion consists exclusively of L-lactide.
  • the object of the invention is fulfilled when using active ingredients which have a solubility of more than 0.01 g per 100 ml in an organic solvent which is completely miscible with water, if inhalation powders containing microparticles embedded in a polymer, wherein the biodegradable polymer is a substance selected from the class of PEG- [lactide-co-glycolides].
  • active ingredients which have a solubility of more than 0.01 g per 100 ml in an organic solvent which is completely miscible with water, if inhalation powders containing microparticles embedded in a polymer, wherein the biodegradable polymer is a substance selected from the class of PEG- [lactide-co-glycolides].
  • Such substances are known as Resomer® (Boehringer Ingelheim Pharma GmbH & Co. KG,
  • polymers of this class of substances are suitable if they have the properties (k), (1), (m), (n) and (o): (k) a PEG content of 10 - 15% (mass) % related to
  • the object according to the invention is fulfilled when using active substances which have a solubility in an organic solvent, preferably dichloromethane, of more than 0.01 g per 100 ml, when inhalable powders containing microparticles are transformed into a polymer be embedded, wherein the biodegradable polymer is a substance from the class of PEG- [lactide co-glycolides].
  • active substances which have a solubility in an organic solvent, preferably dichloromethane, of more than 0.01 g per 100 ml, when inhalable powders containing microparticles are transformed into a polymer be embedded, wherein the biodegradable polymer is a substance from the class of PEG- [lactide co-glycolides].
  • Such substances are available under the name Resomer® (Boehringer Ingelheim Pharma GmbH & Co. KG, Germany).
  • polymers are suitable if they have the properties (p), (q), (r), (s) and (t):
  • (t) a lactide content of 50-85% (mass% based on molecular mass and 100% based on the molecular mass of polymer block A of the co-polymer) and thereby the lactide content of the components L-lactide and D.
  • -Laktid may contain and the D-lactide to L-lactide maximally in the ratio n: 4 and n is a number less than or equal to 1, optionally, the lactide portion consists exclusively of L-lactide.
  • the object of the invention is embedded in a polymer when using active substances which have a solubility in an organic solvent, preferably dichloromethane, of more than 0.01 g per 100 ml, when inhalable powders containing microparticles are embedded wherein the biodegradable polymer is a substance of the class of PLGA and the
  • Polymer PLGA has a modified end group, wherein the end group of the polymer is selected from the group consisting of -COOH or a terminal alkyl group.
  • a terminal alkyl group is understood as meaning an end group of the structure - (CH 2 ) n -CH 3 , where n may be a number selected from 8, 9, 10, 11, 12, 13, 14, 15.
  • n 11.
  • polymer blends of these polymers with the end groups consisting of -COOH or a terminal alkyl group can be used as embedding material.
  • Another specific embodiment is additionally characterized in that a maximum of 80% of the active ingredient is released in a maximum of 18 hours.
  • Inhalable powders are characterized in that these inhalable powders contain microparticles embedded in a polymer, the biodegradable polymer being a substance of the class PLGA and the polymer PLGA having a modified end group, the end group of the polymer corresponding to the structure -COOH.
  • Another specific embodiment is further characterized in that more than 80% of the active ingredient is released in a maximum of 18 hours.
  • the invention relates to methods by means of which the objects according to the invention are achieved.
  • the invention includes corresponding part Hers process for the production of inhalable powder according to the invention.
  • Such powders can be used both directly as powder inhalants (multi-dose systems, pre-metered multi-dose and single-dose systems) and as components blended with other (e.g., coarse) excipient.
  • the production process can be controlled so that the particles are present in a suitable particle size, usually between 0.1 and 10 .mu.m, and these particles have such surface properties that they are easily fluidizable or dispersible.
  • a formulation based on this preparation method allows the active ingredient or a physiologically acceptable salt thereof to be administered to the patient by inhalation in a therapeutically relevant dose as a delayed-release drug.
  • the particles of the inhalable powders according to the invention which are prepared by the process according to the invention are characterized by a high physical stability. In particular, they are suitable when used as Pulverinhalativum a high fines content during the application, technically determined, for example by means of cascade impactor measurement arises.
  • the proportion of particles by this method that are less than 5 ⁇ m (aerodynamic) is greater than 15%; preferably more than 30%, particularly preferably more than 50% achieved.
  • Characterized are powder thus produced by a particle size, for example, as measured by laser diffraction, by an average particle size X 50 in the range of 1 .mu.m to 10 .mu.m, preferably from 1 .mu.m to 6 .mu.m.
  • the term "average particle size X 50" as used herein refers to the 50% value from the volume distribution measured by a laser diffractometer according to the dry dispersion method.
  • the manufacturing method of the microparticles or the inhalable powder according to the invention is characterized in that a solution or emulsion of the active ingredient or a physiologically acceptable salt thereof with an excipient selected from the group consisting of PLGA (which is understood to mean co-polymers of the type poly (lactide co-
  • Glycolide PEG-modified (poly (lactide-co-glycolide)) based polymers and PEG-modified (poly-lactides) are suitably dissolved or emulsion-processed, sprayed and dried in a spray tower.
  • a suitable separation method for example cyclone or fine particle filter
  • the microparticles produced in this way are characterized by special values in terms of particle size.
  • an inlet temperature of the drying gas of 3O 0 C to 35O 0 C preferably from 4O 0 C to 25O 0 C and particularly preferably from 45 0 C to 15O 0 C and - a starting temperature of the drying gas from 3O 0 C to 12O 0 C and
  • drying of the spray thus obtained by means of a drying gas using the following parameters: an inlet temperature of the drying gas from 30 0 C to 35O 0 C, preferably from 40 0 C to 25O 0 C and particularly preferably from 145 0 C to 15O 0 C. and a starting temperature of the drying gas of 3O 0 C to 12O 0 C and (iv) separating the dried solid particles from the drying gas stream in the usual way.
  • Spray mist with a droplet size with the characteristic value X 50 between 7 ⁇ m and 25 ⁇ m is present, 20
  • drying of the spray thus obtained by means of a drying gas using the following parameters: an inlet temperature of the drying gas from 30 0 C to 35O 0 C, preferably from 40 0 C to 25O 0 C and particularly preferably from 145 0 C to 25 15 0 C and a starting temperature of the drying gas from 3O 0 C to 12O 0 C and
  • the inhalable powders thus obtained can be used for the preparation of a medicament. Preference is given to the production of a medicament for the treatment of respiratory diseases, in particular for the treatment of COPD and / or asthma. Likewise, the invention relates to the use of the inhalable powders thus obtained for the manufacture of a medicament for inhalation use to a particular extent for the preparation of a medicament for inhalation use, which enables a delayed release of the active ingredient.
  • chemical compounds (active substances) listed below can be used alone or in combination as a drug-relevant constituent of the inhalable powders according to the invention.
  • W is a pharmacologically active agent and (for example) selected from the group consisting of betamimetics, anticholinergics, corticosteroids, PDE4 inhibitors, LTD4 antagonists, EGFR inhibitors, dopamine agonists, HIV antihistamines, PAF- Antagonists and PI3 kinase inhibitors.
  • a pharmacologically active agent selected from the group consisting of betamimetics, anticholinergics, corticosteroids, PDE4 inhibitors, LTD4 antagonists, EGFR inhibitors, dopamine agonists, HIV antihistamines, PAF- Antagonists and PI3 kinase inhibitors.
  • two- or three-fold combinations of W can be combined and used for application in the device according to the invention. Exemplary combinations of W would be:
  • W represents a betamimetics combined with an anticholinergic, corticosteroids, PDE4 inhibitors, EGFR inhibitors or LTD4 antagonists,
  • W represents an anticholinergic agent combined with a betamimetics, corticosteroids, PDE4 inhibitors, EGFR inhibitors or LTD4 antagonists
  • W represents a corticosteroid combined with a PDE4 inhibitor
  • W represents a PDE4 Inhibitors combined with an EGFR inhibitor or LTD4 antagonist
  • W represents an EGFR inhibitor combined with a LTD4 antagonist.
  • Preferred betamimetics for this purpose are compounds selected from the group consisting of albuterol, arformoterol, bambuterol, bitolterol, broxaterol, carbuterol, clenbuterol, fenoterol, formoterol, hexoprenaline, ibuterol, isoetharines, isoprenaline, levosalbutamol, mabuterol, meluadrine, metaproterenol , Orciprenaline, Pirbuterol, Procaterol, Reproterol, Rimiterol, Ritodrine, Salmefamol, Salmeterol, Soterenol, Sulphone terol, Terbutaline, Tiaramide, Tolubuterol, Zinterol, CHF-1035, HOKU-81, KUL-1248 and 3- (4- ⁇ 6- [2-Hydroxy-2- (4-hydroxy-3-hydroxymethyl-phenyl) -ethyl-amino]
  • the acid addition salts of the betamimetics are preferably selected from the group consisting of hydrochloride, hydrobromide, hydroiodide, hydrosulfate, hydrophosphate, hydromethanesulfonate, hydronitrate, hydromaleate, hydroacetate, hydrocitrate, hydrofumarate, hydrotartrate, hydroxalate, hydrosuccinate, hydrobenzoate and hydro- toluenesulfonate.
  • anticholinergic compounds are preferably used here, which are selected from the group consisting of tiotropium salts, preferably the
  • the cations are the pharmacologically active ingredients.
  • the aforementioned salts may preferably contain chloride, bromide, iodide, sulfate, phosphate, methanesulfonate, nitrate, maleate, acetate, citrate, fumarate, tartrate, oxalate, succinate , Benzoate or p-toluenesulfonate, with chloride, bromide, iodide, sulfate, methanesulfonate or p-toluenesulfonate being preferred as counterions.
  • the chlorides, bromides, iodides and methanesulfonates are particularly preferred.
  • anticholinergics are selected from the salts of the formula AC-I
  • X ⁇ is a single negatively charged anion, preferably an anion selected from the group consisting of fluoride, chloride, bromide, iodide, sulfate, phosphate, methanesulfonate, nitrate, maleate, acetate, citrate, fumarate, tartrate, oxalate, succinate, benzoate and p-Toluenesulfonate, preferably a singly negatively charged anion, more preferably an anion selected from the group consisting of fluoride, chloride, bromide, methanesulfonate and p-toluenesulfonate, most preferably bromide, optionally in the form of their racemates, enantiomers or hydrates.
  • anion selected from the group consisting of fluoride, chloride, bromide, iodide, sulfate, phosphate, methanesulfonate, nitrate, maleate, acetate,
  • the compound of the formula AC-2 may also be present in the form of the free base AC-2-base.
  • Preferred corticosteroids are compounds selected from the group consisting of beclomethasone, betamethasone, budesonide, butixocort, ciclesonide, deflazacort, dexamethasone, etiprednol, flunisolide, fluticasone, loteprednol, mometasone, prednisolone, prednisone, rofleponide, triamcinolone, RPR - 106541, NS-126, ST-26 and
  • Examples of possible salts and derivatives of steroids may be: alkali metal salts, such as, for example, sodium or potassium salts, sulphobenzoates, phosphates, isonicotinates, acetates, dichloroacetates, propionates,
  • Preferred PDE4 inhibitors are compounds selected from the group consisting of enprofylline, theophylline, roflumilast, ariflo (cilomilast), tofimilast, pumafentrin, lirimilast, arofylline, atizoram, D-4418, bay 198004, BY343, CP-325,366, D-4396 (Sch-351591), AWD-12-281 (GW-842470), NCS-613, CDP-840, D-4418, PD-168787, T-440, T-2585, V- 11294A, Cl-1018, CDC-801, CDC-3052, D-22888, YM-58997, Z-15370 and
  • the acid addition salts of the PDE4 inhibitors are selected from the group consisting of hydrochloride, hydrobromide, hydroiodide, hydrosulfate, hydrophosphate, hydromethanesulfonate, hydronitrate, hydromaleate, hydroacetate, hydrocitrate, hydrofumarate, hydrotartrate, hydroxalate, hydrosuccinate, hydrobenzoate and hydro-p-hydroxybenzene. toluenesulfonate.
  • Preferred LTD4 antagonists here are compounds selected from the group consisting of montelukast, pranlukast, zafirlukast, MCC-847 (ZD-3523), MN-001, MEN-91507 (LM-1507), VUF-5078 , VUF-K-8707, L-
  • these acid addition salts are selected from the group consisting of hydrochloride, hydrobromide, hydroiodide, hydrosulfate, hydrophosphate, hydromethanesulfonate, hydronitrate, hydromaleate, hydroacetate, hydrocitrate, hydrofumarate,
  • Hydrotartrate, hydrooxalate, hydrosuccinate, hydrobenzoate and hydro-p-toluenesulfonate examples of salts or derivatives which the LTD4 antagonists are able to form are understood as meaning alkali salts, such as, for example, sodium or potassium salts, alkaline earth salts, sulfobenzoates, phosphates, isonicotinates, acetates, propionates, dihydrogen phosphates, palmitates, pivalates or furoates.
  • alkali salts such as, for example, sodium or potassium salts, alkaline earth salts, sulfobenzoates, phosphates, isonicotinates, acetates, propionates, dihydrogen phosphates, palmitates, pivalates or furoates.
  • the EGFR inhibitors used are preferably compounds selected from the group consisting of cetuximab, trastuzumab, ABX-EGF, Mab ICR-62 and - 4 - [(3-chloro-4-fluorophenyl) amino] -6- ⁇ [4- (morpholin-4-yl) -1-oxo-2-buten-1-yl] amino ⁇ -7-cyclopropylmethoxyquinazoline
  • these acid addition salts are selected from the group consisting of hydrochloride, hydrobromide, hydroiodide, hydrosulfate, hydrophosphate, hydromethanesulfonate, hydronitrate, hydromaleate, hydroacetate, hydrocitrate, hydrofumarate, hydrotartrate, hydroxalate, hydrosuccinate, hydrobenzoate and hydro-p-toluenesulfonate.
  • Preferred dopamine agonists are compounds selected from the group consisting of bromocriptine, cabergoline, alpha-dihydroergocryptine, lisuride, pergolide, pramipexole, roxindole, ropinirole, talipexole,
  • these acid addition salts are selected from the group consisting of hydrochloride, hydrobromide, hydroiodide, hydrosulfate, hydrophosphate, hydromethanesulfonate, hydronitrate, hydromaleate,
  • Hl antihistamines here preferably compounds are used, which are selected from the group consisting of epinastine, cetirizine, azelastine, fexofenadine, levocabastine, loratadine, mizolastine, ketotifen, emedastine, dimetindene, clemastine, bamipine, Cexchlorpheniramin, pheniramine, doxylamine, chlorphenoxamine , Dimenhydrinate, diphenhydramine, promethazine, ebastine, desloratidine and meclocine, optionally in the form of their racemates, enantiomers, diastereomers and optionally in the form of their pharmacologically acceptable acid addition salts, solvates or hydrates.
  • these acid addition salts are selected from the group consisting of hydrochloride, hydrobromide, hydroiodide, hydrosulfate, hydrophosphate, hydromethanesulfonate, hydronitrate, hydromaleate, hydroacetate, hydrocitrate, hydrofumarate, hydrotartrate, hydroxalate, hydrosuccinate, hydrobenzoate and hydro-p-toluenesulfonate.
  • substance formulations As pharmaceutically active substances, substance formulations or
  • Substance mixtures are used for all inhalable compounds, e.g. also inhalable macromolecules, as disclosed in EP 1 003 478.
  • substances, substance formulations or substance mixtures are used for the treatment of respiratory diseases, which are used in the inhalation area.
  • the compound may be derived from the group of derivatives of ergot alkaloids, triptans, CGRP inhibitors, phosphodiesterase V inhibitors, optionally in the form of their racemates, enantiomers or diastereomers, optionally in the form of their pharmacologically acceptable acid addition salts, their solvates and / or or hydrates.
  • Measuring instrument laser diffraction s-spectrometer (HELOS), Sympatec (particle size determination by means of fraunhof diffraction)
  • Dispersing unit Dry disperser RODOS with suction funnel, Sympatec
  • 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 feed Approx. 200 mg of the test substance are weighed on a map sheet.
  • the powder is then placed 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 supply of the sample is as continuous as possible.
  • the amount of product must not be too large so that adequate dispersion is achieved.
  • Measuring method To determine the droplet size, the spray cone (spray) of the nozzle is analyzed directly in the laser measuring zone with respect to the droplet size distribution. The median value X 50 is the drop size below which 50% of the drop quantity lies. H 2 O is used as a test solution to determine suitable nozzle parameters.
  • Measuring instrument Laser diffraction spectrometer (HELOS) 5 from Sympatec
  • Dispersing unit RODOS / dispersing pressure: 3 bar
  • Measurement conditions Measurement conditions / measurement parameters Procedure: Measurement procedure as specified by the equipment manufacturer. The meter calculates the hydrodynamic diameter (Dh) of a suspension and gives the size distribution (volume-related determination mode). The measurement results listed below correspond to the respective main peaks of the determined size distributions (for the purposes of this invention, the droplet size of the main peak corresponds to the hydrodynamic
  • Dry powder formulations obtained by preparing w / o (water in DCM) emulsions which were spray dried.
  • the emulsions are prepared by means of an ultrasound apparatus (Sonics & Materilas Inc., type Vibra Cell, equipped with a 3 mm tip).
  • the tip is immersed 0.5 2 cm in the solution and the ultrasonic apparatus at 30% operated.
  • the inhalable fraction of the inhalable powders according to the invention was investigated in a dissolution model (diffusion cell according to Franz) with respect to controlled release of the salbutamol or budesonide.
  • a dissolution model diffusion cell according to Franz
  • the cascade impactor stages 0 and 1 has been discriminated particles> 5 micrometers.
  • Table 4 Process parameters for the inhalable powders discussed in Examples 1-5.
  • Example 1 (Production method according to case A):
  • inhalable embedding particles were prepared by spray-drying together with various triblock copolymers (identification code SR 2.8, SR 11, SR 14, SR 1.3).
  • the release behavior (37 0 C, release medium PBS buffer (phosphate-buffered-solution)) of the active ingredient in the inhalable fraction of the inhalable powder according to the invention is shown.
  • the triblock copolymers used were LGP t 8546; LP t 52; LGP t 5046 and LRP 17046 are used. All particles showed retardation over 24 hours.
  • Example 2 (Production method according to case A):
  • inhalable embedding particles were prepared by spray-drying together with various diblock-co-polymers
  • the release behavior is 37 0 C, release medium PBS buffer
  • the pattern with the identification code SRME was prepared by adding additional ethanol to the W / O emulsion (water / dichloromethane) until
  • release behavior 37 0 C, release medium PBS buffer (phosphate-buffered-solution)) of the active ingredient in the inhalable fraction of the inhalable powder according to the invention is shown.
  • release behavior 37 0 C release medium PBS buffer (phosphate-buffered-solution)) of the active ingredient in the inhalable fraction of the inhalable powder according to the invention is shown.
  • release behavior 37 0 C release medium PBS buffer (phosphate buffered solution)) of the active ingredient in the inhalable fraction of the inhalable powder according to the invention is shown.
  • Example 6 (Production method according to case B):
  • Embedding particles were prepared according to the "Case B" preparation method with a composition as indicated in Table 5. The composition of these embedding particles is listed in Table 5.
  • the release behavior is 37 ° C, release medium PBS buffer (phosphate buffered solution) of the active ingredient in the inhalable fraction of the inhalable powder according to the invention.
  • Embedding particles were prepared according to the manufacturing method "Case B” with a composition as indicated in Table 5. The composition of these embedding particles is listed in Table 5. In Figure 8 this is Release behavior 37 ° C., release medium PBS buffer (phosphate-buffered solution) of the active ingredient in the inhalable fraction of the inhalable powder according to the invention.
  • the polymer RG503H corresponds to a PLGA polymer having an end group -COOH and the polymer RG503S corresponds to a PLGA polymer having an end group of an alkyl radical.
  • Table 5 Compositions of the microparticles of Examples 1, 2, 6 and 7 (% - data correspond to mass per volume (w / v) in grams per declared volume).
  • the current Nos. 1-4 correspond to Example 1
  • the current Nos. 5-7 correspond to Example 2
  • the current Nos. 8-10 correspond to Example 6
  • the consecutive Nos. 11-15 correspond to Example 7.

Abstract

L'invention porte sur la préparation de poudres à inhaler présentant une libération différée du principe actif, ainsi que sur des procédés pour les préparer, et sur des médicaments préparés au moyen desdites poudres à inhaler.
EP09761699A 2008-06-09 2009-06-08 Nouvelles particules à principe actif incorporé pour inhalation Withdrawn EP2299990A1 (fr)

Priority Applications (1)

Application Number Priority Date Filing Date Title
EP09761699A EP2299990A1 (fr) 2008-06-09 2009-06-08 Nouvelles particules à principe actif incorporé pour inhalation

Applications Claiming Priority (3)

Application Number Priority Date Filing Date Title
EP08104316 2008-06-09
PCT/EP2009/057059 WO2009150136A1 (fr) 2008-06-09 2009-06-08 Nouvelles particules à principe actif incorporé pour inhalation
EP09761699A EP2299990A1 (fr) 2008-06-09 2009-06-08 Nouvelles particules à principe actif incorporé pour inhalation

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EP2299990A1 true EP2299990A1 (fr) 2011-03-30

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EP (1) EP2299990A1 (fr)
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WO (1) WO2009150136A1 (fr)

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UA111162C2 (uk) 2010-08-04 2016-04-11 Флекшен Терап'Ютікс, Інк. Ін'єкційна композиція ацетоніду триамцинолону для лікування болю
CA2843139C (fr) * 2011-08-04 2019-09-24 Flexion Therapeutics, Inc. Corticosteroides destines a traiter une douleur articulaire
IL310250A (en) 2016-05-05 2024-03-01 Liquidia Tech Inc Terfostinil in dry powder form for the treatment of pulmonary hypertension
CN109985585A (zh) * 2019-05-13 2019-07-09 苏州岸谷纳米技术有限公司 一种生物降解高分子微球的快速制备方法
CN114272228B (zh) * 2022-01-04 2023-08-22 丽珠医药集团股份有限公司 噻托溴铵吸入微球及其制备方法和吸入式制剂

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PT954282E (pt) * 1997-01-16 2005-06-30 Massachusetts Inst Technology Preparacao de particulas para inalacao
EP0975334B1 (fr) * 1997-04-17 2003-10-22 Amgen Inc., Microparticules biodegradables pour administration soutenue d'agents therapeutiques
DE19813174A1 (de) * 1998-03-25 1999-05-27 Schering Ag Mikropartikel aus Polymeren und mindestens einer gerüstbildenden Komponente und ihre Herstellung und Verwendung in der Ultraschalldiagnostik und zur ultraschallinduzierten Wirkstofffreisetzung
KR100321854B1 (ko) * 1998-12-30 2002-08-28 동국제약 주식회사 루테이나이징 호르몬 릴리싱 호르몬 동족체를 함유하는 장기 서방출성 미립구 및 그의 제조방법
WO2002005785A1 (fr) * 2000-07-18 2002-01-24 Aeropharm Technology Incorporated Aerosols therapeutiques a liberation modulee
EP1556018A1 (fr) * 2002-09-30 2005-07-27 Acusphere, Inc. Liberation reguliere de microparticules poreuses a inhaler
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JP5552118B2 (ja) 2014-07-16
US20110311630A1 (en) 2011-12-22
WO2009150136A1 (fr) 2009-12-17
JP2011522859A (ja) 2011-08-04
CA2727309A1 (fr) 2009-12-17

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