WO2020165010A1 - Procédé de préparation de microparticules poreuses - Google Patents

Procédé de préparation de microparticules poreuses Download PDF

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WO2020165010A1
WO2020165010A1 PCT/EP2020/052934 EP2020052934W WO2020165010A1 WO 2020165010 A1 WO2020165010 A1 WO 2020165010A1 EP 2020052934 W EP2020052934 W EP 2020052934W WO 2020165010 A1 WO2020165010 A1 WO 2020165010A1
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microparticles
porous
pulmonary
emulsion
active agent
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PCT/EP2020/052934
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English (en)
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Moritz Beck-Broichsitter
Shirui MAO
Xiaofei Zhang
Jiaqi Li
Lan Zhang
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Bayer Aktiengesellschaft
Shenyang Pharmaceutical University
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Publication of WO2020165010A1 publication Critical patent/WO2020165010A1/fr

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/007—Pulmonary tract; Aromatherapy
    • A61K9/0073—Sprays or powders for inhalation; Aerolised or nebulised preparations generated by other means than thermal energy
    • A61K9/0075—Sprays or powders for inhalation; Aerolised or nebulised preparations generated by other means than thermal energy for inhalation via a dry powder inhaler [DPI], e.g. comprising micronized drug mixed with lactose carrier particles
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
    • A61K31/35—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having six-membered rings with one oxygen as the only ring hetero atom
    • A61K31/351—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having six-membered rings with one oxygen as the only ring hetero atom not condensed with another ring
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/4965—Non-condensed pyrazines
    • A61K31/497—Non-condensed pyrazines containing further heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
    • A61K47/32—Macromolecular compounds obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. carbomers, poly(meth)acrylates, or polyvinyl pyrrolidone
    • 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
    • A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
    • A61K9/50—Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals
    • A61K9/5005—Wall or coating material
    • A61K9/5021—Organic macromolecular compounds
    • A61K9/5026—Organic macromolecular compounds obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyvinyl pyrrolidone, poly(meth)acrylates
    • 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
    • A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
    • A61K9/50—Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals
    • A61K9/5005—Wall or coating material
    • A61K9/5021—Organic macromolecular compounds
    • A61K9/5031—Organic macromolecular compounds obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyethylene glycol, poly(lactide-co-glycolide)
    • 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
    • A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
    • A61K9/50—Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals
    • A61K9/5089—Processes
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00—Drugs for disorders of the respiratory system

Definitions

  • the invention relates to the preparation of porous microparticles for inhalation formulations for pul monary drug delivery as well as the microparticles and the dry powder formulations produced hereof.
  • the invention relates to a premix membrane emulsification based process using polyvinylpyrroli done as a porogenic agent for the preparation of porous microparticles for inhalation formulations for pulmonary drug delivery as well as the microparticles and the pharmaceutical compositions proucked hereof.
  • Respiratory drug delivery has drawn great attention in recent years since this route can be utilized for both local and systemic treatments. It is extremely suitable for the local treatment of lung dis eases such as asthma, fibrosis, cystic fibrosis, pulmonary arterial hypertension, chronic obstructive pulmonary disease (COPD), lung cancers and lung metastases, with the advantages of a targeted local lung action, very thin diffusion path to the blood stream and rich vasculature, rapid onset of therapeutic action, relatively low metabolic activity and fewer systemic side effects than oral therapy. Also a systemic delivery of drugs via the lung and particularly the alveolar regions is an attractive therapeutic concept due to the enormous absorption surface area and also extensive vasculariza tion as well as the aforementioned relatively low metabolic activity.
  • COPD chronic obstructive pulmonary disease
  • the key features of the formulation such as the size and geometry of the particles, will have signif icant impact on the likelihood of being deposited in the targeted regions of the lung.
  • Lung deposition is furthermore influenced by flow and aerolization properties, the mode of inhalation and the inha lation device.
  • Inhalation dosage technology has therefore primarily focused on two parallel devel opment pathways: Fabrication of novel inhaler devices with enhanced efficiency and/or improve ment of the existing inhalation formulations via advanced particle engineering strategies.
  • An im portant determinant of aerosol deposition is the aerodynamic particle size, often expressed as the mass median aerodynamic diameter (MMAD) of a group of particles, where particles with an MMAD in the range of 1-5 pm inhaled at slow flow are more likely to deposit in the more distal parts of the lung, while those in the range of 5-10 pm will deposit proximally in the oral pharynx and tracheo bronchial tree, and those larger than 10 pm will likely deposit in the mouth.
  • Other desirable product characteristics constitute a high fine particle fraction (FPF), and emitted dose (ED), high dose consistency and uniformity and, ideally, independence of the type of device and inhalation flow rate.
  • the particles should have a relatively narrow parti cle size distribution (PSD) and should be readily aerosolizable at relatively low aerodynamic disper sion forces. Additionally, the requirement of physical and chemical stability implies that storage must not have a significant effect on the drug's physical form (e.g., crystallinity, polymorphism), PSD and/or the dose content uniformity.
  • PSD parti cle size distribution
  • Phagocytosis mechanism is size-dependent, with particles 1-5 pm in size being optimum for uptake by macrophages. Unfavorably this is overlapping the optimum range of MMAD for efficient pulmo nary drug delivery. It has been found that large porous microparticles with high geometric diameters (10-20 pm) and low bulk densities (-0.4 g/cm 3 ) show reduced clearance while keeping a favorable MMAD for deep lung deposition [Edwards D.A., Hames J., Caponetti G., Hrkach J., Abdelaziz B.- J., Eskew M.L., Mintzes J., Deaver D., Lotan N., Langer R., Science 276, 1868-1871 (1997)].
  • porosity of the particles is not only desired to decrease the density of the particles and to control the particle aerodynamics, but may also be beneficial for a controlled and constant release of the drug by diffusion through the pores.
  • Porosity increases the particle surface which is in imme diate contact with the release medium.
  • a high level of internal porosity generates a larger inner surface, which can potentially increase the uptake of the release medium into the particles and contribute to drug pore-diffusion.
  • a precise formulation of the pharmaceutically active compounds is essential to ensure that the micro particles will be deposited to the appropriate part of the lung and deliver the correct amount of pharmaceutically active agent over the appropriate period of time.
  • a careful control over pore for mation during particle synthesis and similarly over the so induced porous structure of the microparti cles is important to achieve the desired aerodynamic properties together with a favorable kinetic drug release behavior.
  • the development of an appropriate carrier system with adequate aerodynamic properties and evasion of macrophage uptake, that will allow particles to be respirable, yet confer sustained release of drug once deposited in the lung, is therefore a difficult technical problem for the person skilled in the art.
  • the full optimization of such a delivery system with optimal particle properties, such as efficient drug encapsulation, suitable aerodynamics and a predictable, sustained release of the drug is therefore highly challenging for the pharmaceutical technologist.
  • LPFs Large porous particles based on biocompatible and biodegradable poly (lactide-co-gly- colide) acid (PLGA), already being used for implantable or injectable depot systems, were sug gested as potential sustained-release carriers for pulmonary drug delivery.
  • sustained serum insulin levels for 4 days were observed following pulmonary delivery in rats. [Ed wards D.A., Abdelaziz B.-J., Langer R., J. Appl. Physiol. 85, 379-385 (1998)].
  • inhalable PLGA-LPPs were macromolecular drugs, to achieve either a systemic effect or a local treatment of chronic lung diseases (e.g., COPD, cystic fibrosis).
  • COPD chronic lung diseases
  • cystic fibrosis typically large soluble therapeutic agents such as peptides and proteins, where the encapsulation within a polymer carrier also serves to prevent degradation of the sensitive mac romolecules both on storage and in vivo and deliver the native macromolecule in a sustained man ner.
  • microparticles have mostly been produced via double emulsion (w o/w e ) extraction meth ods, which means that the water-soluble drug is first dissolved in an aqueous phase, which is then emulsified with the PLGA polymer solution, prior to further emulsifying with an aqueous solution containing emulsifier [e.g. polyvinyl alcohol (PVA) etc.].
  • w o/w e double emulsion
  • emulsifier e.g. polyvinyl alcohol (PVA) etc.
  • Budesonide-loaded large porous PLGA microparticles have been obtained via a double-emulsion solvent evaporation and using ammonium bicarbonate as a porogen, which decomposes into ammonia and carbon dioxide during emulsification.
  • the produced particles showed a sustained release of budesonide in vitro for 24 h and also an improved therapeutic efficacy in a murine asthma model [Oh Y.J., Lee J., Seo J.Y., Rhim T., Kim S.-H., Yoon H.J., Lee K.Y., J. Control. Release, 150, 56-62 (2011)].
  • Doxorubicin-loaded highly porous PLGA-based LPPs for the treatment of metastatic lung cancer. These were found to be deposited in the lungs of mice and remain in situ for up to 14 days, also tumor growth in the treated mice was significantly reduced [Kim I., Byeon H.J., Kim T.H., Lee E.S., Oh K.T., Shin B.S., Lee K.C., Youn Y.S, Biomaterials, 33, 5574-5583 (2012)].
  • a drawback of the use of gas-forming agents however lies in the fact that particle size and pore size are usually coupled and therefore cannot be varied independently.
  • PLGA particles prepared by the single-emulsification method have been reported as being naturally less porous as those made by double emulsification [Edwards D.A., Hames J., Caponetti G., Hrkach J., Abdelaziz B.-J., Eskew M.L., Mintzes J., Deaver D., Lotan N., Langer R., Science, 276, 1868-1871 (1997)]. Still less reports on the introduction of porosity and the use of porogenic agents for the manufacture of porous microspheres by a single emulsion method are available.
  • Extractable porogens such as poloxamers and fatty acid salts
  • a single emulsion protocol for the preparation of porous PLGA microparticles, where the porous structure of the particles is generated by the time difference between PLGA droplet hardening and in situ extraction of the water-soluble porogens from the oil-phase into the water phase.
  • respirable pharmaceutical formulations which reach the targeted lung regions either to achieve a systemic pharmacological effect or for a local treatment of a lung disease, while being adjustable to release the pharmaceutically active agent in/af ter a predefined time period, e.g. in a sustained manner.
  • sus tained-release formulations for pulmonary administration comprising drug loaded porous microparti cles.
  • the present invention therefore aims at developing a simple and efficient one-pot process for the preparation of porous microparticles encapsulating pharmaceutically active agents, especially small molecule drugs with a low solubility in water and/or organic solvents, where the resulting micropar ticles are suitable for pulmonary drug delivery and where the process does not have the disad vantages mentioned for the processes of the prior art.
  • the objective was in particular to develop a process, which is flexible in adjusting the aerodynamic properties of the resulting microparticles as well as controlling the in vitro and in vivo release rates of the encapsulated drug.
  • Another objective of the invention was to provide a sustained-release pharmaceutical composition comprising porous microparticles.
  • Another objective of the invention was to provide a sustained-release pharmaceuti cal composition comprising porous microparticles with reduced burst release.
  • the invention pertains to a process for the preparation of porous microparticles for pulmonary drug delivery comprising a matrix material and a pharmaceutically active agent, the process comprising the steps
  • a first phase (a) comprising a pharmaceutically active agent, a matrix material, a porogenic agent and a volatile solvent, is emulsified with
  • step (ii) the secondary o/w emulsion (B) resulting from step (ii) is emulsified with
  • step (v) optionally drying the porous microparticles resulting from step (v),
  • step (i) is polyvinylpyrrolidone and/or a polyvi nylpyrrolidone derivative and that the porous membrane in step (iii) is a glass membrane.
  • the invention further pertains to porous microparticles for pulmonary drug delivery comprising a matrix material and a pharmaceutically active agent, obtainable by the process according to the invention.
  • the invention further pertains to a pharmaceutical composition for pulmonary drug delivery com prising porous microparticles comprising a matrix material and a pharmaceutically active agent, obtainable by the process according to the invention.
  • the invention further pertains to a use of the pharmaceutical composition according to the invention for use in the treatment and/or prevention of diseases, preferably pulmonary diseases or conditions of the lungs and/or airways.
  • the process according to the invention is a simple and efficient one-pot single-emulsion based method for the preparation of porous microparticles for pulmonary drug delivery.
  • the method is es- pecially suitable for the encapsulation of hydrophobic small molecule drugs and achieves good en capsulation efficiency of the pharmaceutically active agents.
  • a further advantage of the process ac cording to the invention is that the process can be conducted in one step without the need to subse quently load the microparticles with the pharmaceutically active agent or to separate the porogenic agent in an extra step. It is not necessary to wash out possible residues of the porogenic agent, due to the good biocompatibility of the polyvinylpyrrolidone employed.
  • the porosity and the physicochem ical properties of the microparticles can favorably be adjusted by the amount of polyvinylpyrrolidone employed.
  • the microparticles have favorable properties, such as an ideal MMAD that allows for lung deposition, large geometric diameter which prevents the particle from macrophage uptake and slows down mucociliary clearance, sufficient drug loading capacity, exhibition of sustained drug release, reduction of burst release as well as reproducible particle morphology.
  • a further advantage of the porous microparticles produced according to the invention is that these may be administered in form of a pulmonary sustained-release formulation, where the release rate may be controlled via the matrix type as well as the porogen type and amount used during the preparation process.
  • the invention is illustrated in detail hereinafter. Various embodiments can be combined here with one another as desired, unless the opposite is apparent to the person skilled in the art from the context.
  • polyvinylpyrrolidone and/or a polyvinylpyrrolidone derivative is em ployed as an extractable porogenic agent within the single emulsion based process according to the invention. It may be referred to herein generally as“porogen”,“porogenic agent”,“pore forming agent” or the like.
  • Polyvinylpyrrolidones are commercially available hydro philic polymers suitable for use in solid pharmaceutical preparations. They are polydisperse mac- romolecular molecules, with a chemical name of 1-ethenyl-2-pyrrolidinone polymers and 1 -vinyl-2- pyrrolidinone polymers. Povidone polymers are produced commercially as a series of products hav ing mean molecular weights ranging from about 2000-3000 (e.g. PVP K-12) to about 3000000 (e.g. K-120) daltons.
  • PVP polypeptide-binders
  • solubilisation enhancers binders
  • film formers solubilisation enhancers
  • taste masking agents e.g., acetyl-N-phenyl-N-phenyl-N-phenyl-N-phenyl-N-phenyl-N-phenyl-N-phenyl-N-phenyl-N-phenyl-N-phenyl-N
  • Polyvinylpyrrolidones have been incorporated in tablets and microspheres to enhance or extend the release of the pharmaceuticals.
  • EP 2361616 A1 and Verma R.K., Kaushal A.M., Garg S., Int. J. Pharm., 263, 9-24 (2003) disclose coated solid dosage forms, preferably tablets, where the coating may comprise PVP as a hydrophilic pore former. In contact with water PVP will dissolve and thus generate water-filled channels, which will support dissolving of the tablet and result in faster drug release.
  • Povidone K-30 has been used as a channeling agent in injectable microspheres of poly (lactic acid) for long-acting control led-release parenteral administration.
  • Povidone polymers are prepared by, for example, Reppe's process, comprising: (a) obtaining 1 ,4- butanediol from acetylene and formaldehyde by the Reppe butadiene synthesis; (b) dehydrogenat- ing the 1 ,4-butanediol over copper at 200° C to form g-butyrolactone; and (c) reacting g-butyrolac- tone with ammonia to yield pyrrolidone. Subsequent treatment with acetylene gives the vinyl pyrrol- idone monomer. Polymerization is carried out by heating in the presence of water and ammonia.
  • the manufacturing process for povidone polymers produces polymers containing molecules of un equal chain length, and thus different molecular weights.
  • the molecular weights of the molecules vary about a mean or average for each particular commercially available grade. Because it is difficult to determine the polymer's molecular weight directly, the most widely used method of classifying various molecular weight grades is by K-values, based on viscosity measurements.
  • the K-values of various grades of povidone polymers represent a function of the average molecular weight, and are derived from viscosity measurements and calculated according to Fikentscher's formula.
  • the weight-average of the molecular weight, M w is determined by methods that measure the weights of the individual molecules, such as by light scattering. If in doubt, the data on the K value from the European Pharmacopeia (Ph. Eur.) are used.
  • Table 1 provides molecular weight data for several commercially available povidone polymers, all of which are soluble.
  • Mv is the viscosity-average molecular weight
  • M n is the number-average molecular weight
  • M is the weight-average molecular weight.
  • M and M n were determined by light-scattering and ultra-centrifugation, and Mv was determined by viscosity measurements.
  • the polyvinylpyrrolidone (derivative) employed in the sense of the present invention preferably has a good solubility in water. In this case, the polyvinylpyrrolidone (derivative) is normally linear and not crosslinked.
  • polyvinylpyrrolidones also have a very good solubility in various solvents, which extends from extremely hydrophilic solvents, such as water (> 100mg/ml), to more hydropho bic liquids, such as butanol or methylene chloride (> 100mg/ml).
  • the polyvinylpyrrolidone (derivative) employed normally has a K value of at least 12.
  • the polyvi nylpyrrolidone (derivative) which is used in the process according to the invention normally has a K value of from 12 to 120, preferably from 12 to 40, particularly preferably from 12 to 17.
  • polyvinylpyrrolidone with a K value of 12 is used.
  • the polyvinylpyrrolidone (derivative) is normally used as porogenic agent in an amount of e.g. 1% up to about 200%, by weight (w/w) relative to the matrix material employed in the process according to the invention.
  • the polyvinylpyrrolidone (derivative) is used in a ratio of from 1% to 100%, preferably of from 1% to 30%, more preferably of from 5% to 20%, particularly preferably of from 10% to 15% by weight (w/w), relative to the matrix material.
  • porogenic agents such as those listed before, may be used in addition to polyvinylpyrrolidone (derivatives) and combined with the process according to the invention. These will be chosen to show good compatibility with the single emulsion process according to the present invention. In a preferred embodiment of the process according to the invention no additional porogenic agents are used. Preferably polyvinylpyrrolidone is used as the sole porogenic agent.
  • polyvinylpyrrolidone can favorably be used as a porogenic agent in a single emulsion-solvent evaporation process.
  • the novel method can be conducted as a one-pot, one-step process under efficient encapsulation of the active agent.
  • the polyvinylpyrrolidone (de rivative) can be used as an extractable porogenic agent during the inventive single emulsion pro cess, where the extraction of the porogenic agent from the formed drug-loaded microparticles takes place simultaneously to particle formation/hardening. Still, significant drug loss through mass ex change does not take place, so that good encapsulation efficiency for the active agents is achieved.
  • microparticles have favorable aerodynamic properties for pul monary administration and also show good porosity with a regular pore distribution, which may be controlled by the amount and ratio of the porogenic agent employed.
  • any remaining polyvinylpyrrolidone from the microparticles may be done by an additional washing step, preferably with water.
  • an additional washing step preferably with water.
  • remaining residues of the polyvinylpyrroli done are not removed, e.g. by extraction, from the porous microparticles before these are furnished for pulmonary administration.
  • the porous microparticles comprising the pharmaceutically active agent are not further purified subsequent to their preparation and before administration in form of a pharmaceutical composition.
  • The“pharmaceutically active agent” is a therapeutic, diagnostic, or prophylactic agent. It may be referred to herein generally as a“drug”,“active agent” or“pharmaceutically active ingredient (API)”. As used herein, the terms further include any physiologically or pharmacologically active substance that produces a localized or systemic effect in a patient.
  • Suitable pharmaceutically active agents are in principle all pharmaceutically active chemical com pounds, which show compatibility with the employed single emulsion process according to the in vention.
  • the identity of the active agent may therefore be limited by its solubility or partition coeffi cient between the organic and aqueous emulsion phases. If the solubility in the aqueous phase is too high some of the drug may be lost during emulsification and/or particle hardening resulting in a lower efficiency for drug encapsulation.
  • the logP value represents a measure for the lipophilicity of a chemical entity (e.g. an active phar maceutical ingredient), where P (partition coefficient) is the ratio of the concentration of a chemical entity (measured at a pH value where the chemical entity is in an unionized form) in a mixture of two inmiscible phases at equilibrium, usually between octanol and water (herein mentioned logP values refer to octanol/water partition coefficients).
  • logP can be experimentally determined using high performance liquid chromatography (HPLC) by correlating the chemical entity ' s retention time with similar compounds with known log P values [Valko K, J. Chromatogr. A, 28, 299-310 (2004)].
  • HPLC high performance liquid chromatography
  • the active agent preferably has a logP oct/wat value of from -1.0 to +7.
  • the pharmaceutically active agent is a (hydro- phobic) small molecule compound with low aqueous solubility.
  • low aqueous solubility means that the drug has a solubility of less than 1 mg/ml_, and preferably less than 0.1 g/mL, in aqueous media at 15-25°C and physiologically neutral pH (about 5.0-8.0), e.g. a very slightly soluble (0.1 mg/ml-1 mg/ml) or practically insoluble ( ⁇ 0.1 mg/ml) drug (according to the solubility definitions in Pharm. Eur. 8-5, Chapter 1.4, Solubility).
  • the pharmaceutically active agent exhibits sufficient solubility (>10mg/ml, preferably >30mg/ml, preferably >100mg/ml) in a water-immiscible organic phase, preferably an organic solvent of class 2 or class 3 (according to The International Conference on Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use (ICH) guideline Q3C; www.ich.org) or a mixture thereof, preferably in a water-immisci ble organic class 2 or 3 solvent chosen from the list of the following solvents: dichloromethane, cyclohexane, hexane, methylbutylketone, N-methylpyrrolidone, tert.- butylmethylether, ethylacetate, diethylether, heptane, pentane or mixtures thereof, especially preferably in dichloromethane and N- methylpyrrolidone or a mixture thereof.
  • compositions A variety of pharmaceutically active agents may be employed in the process according to the in vention and in the pharmaceutical compositions.
  • suitable pharmaceu tically active agents include the following categories and examples of pharmaceutically active agents and alternative forms of these pharmaceutically active agents such as alternative salt forms, free acid forms, free base forms, and hydrates:
  • organic nitrates and NO-donors for example sodium nitroprusside, nitroglycerin, isosorbide mo nonitrate, isosorbide dinitrate, molsidomine or SIN-1 , and inhalational NO;
  • cGMP cyclic guanosine monophosphate
  • cAMP cyclic adenosine monophosphate
  • PDE phosphodiesterases
  • PDE 4 inhibitors such as roflumilast or revamilast
  • PDE 5 inhibitors such as sildenafil, vardenafil, tadalafil, udenafil, dasantafil, avanafil, mirodenafil or lodenafil;
  • prostacyclin analogs and IP receptor agonists for example and preferably iloprost, beraprost, treprostinil, epoprostenol or NS-304;
  • endothelin receptor antagonists for example and preferably bosentan, darusentan, ambrisentan or sitaxsentan;
  • HNE human neutrophile elastase
  • sivelestat sivelestat
  • DX-890 Reltran
  • Rho kinase inhibitors for example and preferably fasudil, Y-27632, SLx-2119, BF-66851 , BF- 66852, BF-66853, KI-23095 or BA-1049;
  • anti-obstructive agents as used, for example, for the therapy of chronic-obstructive pulmonary disease (COPD) or bronchial asthma, for example and preferably inhalatively or systemically administered beta-receptor mimetics (e.g. bedoradrine) or inhalatively administered anti-musca- rinergic substances;
  • COPD chronic-obstructive pulmonary disease
  • bronchial asthma for example and preferably inhalatively or systemically administered beta-receptor mimetics (e.g. bedoradrine) or inhalatively administered anti-musca- rinergic substances;
  • antiinflammatory and/or immunosuppressive agents as used, for example for the therapy of chronic-obstructive pulmonary disease (COPD), of bronchial asthma or pulmonary fibrosis, for example and preferably systemically or inhalatively administered corticosteroides, flutiform, pirfenidone, acetylcysteine, budesonide, azathioprine or BIBF-1120;
  • COPD chronic-obstructive pulmonary disease
  • chemotherapeutics as used, for example, for the therapy of neoplasias of the lung or other organs;
  • active compounds used for the systemic and/or inhalative treatment of pulmonary disorders for example for cystic fibrosis (alpha-1 -antitrypsin, aztreonam, ivacaftor, lumacaftor, ataluren, amika cin, levofloxacin), chronic obstructive pulmonary diseases (COPD) (LAS40464, PT003, SUN-101), acute respiratory distress syndrome (ARDS) and acute lung injury (ALI) (interferon-beta- 1a, traumakines), obstructive sleep apnoe (VI-0521), bronchiectasis (mannitol, ciprofloxacin), Bronchi olitis obliterans (cyclosporine, aztreonam) and sepsis (pagibaximab, Voluven, ART-123);
  • cystic fibrosis alpha-1 -antitrypsin, aztreonam, ivacaf
  • antithrombotic agents for example and preferably from the group of platelet aggregation inhibi tors, anticoagulants or profibrinolytic substances;
  • active compounds for lowering blood pressure for example and preferably from the group of cal cium antagonists, angiotensin All antagonists, ACE inhibitors, endothelin antagonists, renin inhib itors, alpha-blockers, beta-blockers, mineralocorticoid receptor antagonists and diuretics; and/or
  • active compounds that alter fat metabolism, for example and preferably from the group of thyroid receptor agonists, cholesterol synthesis inhibitors such as for example and preferably HMG- CoA-reductase or squalene synthesis inhibitors, ACAT inhibitors, CETP inhibitors, MTP inhibi tors, PPAR-alpha, PPAR-gamma and/or PPAR-delta agonists, cholesterol absorption inhibitors, lipase inhibitors, polymeric bile acid adsorbers, bile acid reabsorption inhibitors and lipoprotein(a) antagonists.
  • cholesterol synthesis inhibitors such as for example and preferably HMG- CoA-reductase or squalene synthesis inhibitors, ACAT inhibitors, CETP inhibitors, MTP inhibi tors, PPAR-alpha, PPAR-gamma and/or PPAR-delta agonists, cholesterol absorption inhibitors, lipase inhibitors, polymeric bile acid adsorbers, bile acid rea
  • Antithrombotic agents are preferably to be understood as compounds from the group of platelet aggregation inhibitors, anticoagulants or profibrinolytic substances.
  • an active compound is a platelet aggregation inhibitor, for example and preferably aspirin, clopidogrel, ticlopidine or dipyridamole.
  • an active compound is a thrombin inhibitor, for example and preferably ximelagatran, melagatran, dabigatran, bivalirudin or Clexane.
  • an active compound is a GPIIb/llla antagonist, for example and preferably tirofiban or abciximab.
  • an active compound is a factor Xa inhibitor, for example and preferably rivaroxaban, apixaban, fidexaban, razaxaban, fondaparinux, idraparinux, DU-176b, PMD-3112, YM-150, KFA-1982, EMD-503982, MCM-17, MLN-1021 , DX 9065a, DPC 906, JTV 803, SSR-126512 or SSR-128428.
  • factor Xa inhibitor for example and preferably rivaroxaban, apixaban, fidexaban, razaxaban, fondaparinux, idraparinux, DU-176b, PMD-3112, YM-150, KFA-1982, EMD-503982, MCM-17, MLN-1021 , DX 9065a, DPC 906, JTV 803, SSR-126512 or SSR-128428.
  • an active compound is heparin or a low molecular weight (LMW) heparin derivative.
  • LMW low molecular weight
  • an active compound is a vitamin K antagonist, for example and preferably coumarin.
  • the agents for lowering blood pressure are preferably to be understood as compounds from the group of calcium antagonists, angiotensin All antagonists, ACE inhibitors, endothelin antagonists, renin in hibitors, alpha-blockers, beta-blockers, mineralocorticoid-receptor antagonists and diuretics.
  • an active compound is a calcium antagonist, for example and preferably nifedipine, amlodipine, verapamil or diltiazem.
  • an active compound is an alpha- 1 -receptor blocker, for example and preferably prazosin.
  • an active compound is a beta-blocker, for example and pref erably propranolol, atenolol, timolol, pindolol, alprenolol, oxprenolol, penbutolol, bupranolol, metipranolol, nadolol, mepindolol, carazolol, sotalol, metoprolol, betaxolol, celiprolol, bisoprolol, car- teolol, esmolol, labetalol, carvedilol, adaprolol, landiolol, nebivolol, epanolol or bucindolol.
  • a beta-blocker for example and pref erably propranolol, atenolol, timolol, pindolol, alpren
  • an active compound is an angiotensin All antagonist, for example and preferably losartan, candesartan, valsartan, telmisartan or embursatan or a dual angiotensin All antagonist/neprilysin-inhibitor, by way of example and with preference LCZ696 (valsartan/sacubitril).
  • an active compound is an ACE inhibitor, for example and preferably enalapril, captopril, lisinopril, ramipril, delapril, fosinopril, quinopril, perindopril or tran- dopril.
  • an active compound is an endothelin antagonist, for example and preferably bosentan, darusentan, ambrisentan or sitaxsentan.
  • an active compound is a renin inhibitor, for example and preferably aliskiren, SPP-600 or SPP-800.
  • an active compound is a mineralocorticoid-receptor antagonist, for example and preferably spironolactone, eplerenone and finerenone (BAY 94-8862).
  • an active compound is a diuretic, for example and preferably furosemide, bumetanide, Torsemide, bendroflumethiazide, chlorthiazide, hydrochlorthiazide, hydro flumethiazide, methyclothiazide, polythiazide, trichlormethiazide, chlorthalidone, indapamide, metolazone, quinethazone, acetazolamide, dichlorphenamide, methazolamide, glycerol, isosorbide, mannitol, amiloride or triamterene.
  • a diuretic for example and preferably furosemide, bumetanide, Torsemide, bendroflumethiazide, chlorthiazide, hydrochlorthiazide, hydro flumethiazide, methyclothiazide, polythiazide, trichlormethiazide, chlorthalidone, indapamide, metolazone
  • Agents altering fat metabolism are preferably to be understood as compounds from the group of CETP inhibitors, thyroid receptor agonists, cholesterol synthesis inhibitors such as HMG-CoA- reductase or squalene synthesis inhibitors, the ACAT inhibitors, MTP inhibitors, PPAR-alpha, PPAR-gamma and/or PPAR-delta agonists, cholesterol-absorption inhibitors, polymeric bile acid adsorbers, bile acid reabsorption inhibitors, lipase inhibitors and the lipoprotein(a) antagonists.
  • CETP inhibitors such as HMG-CoA- reductase or squalene synthesis inhibitors
  • ACAT inhibitors such as HMG-CoA- reductase or squalene synthesis inhibitors
  • MTP inhibitors PPAR-alpha, PPAR-gamma and/or PPAR-delta agonists
  • cholesterol-absorption inhibitors polymeric bile acid adsorbers
  • an active compound is a CETP inhibitor, for example and preferably torcetrapib, (CP-5294/4), JJT-705 or CETP-vaccine (Avant).
  • an active compound is a thyroid receptor agonist, for example and preferably D-thyroxin, 3,5,3'-triiodothyronin (T3), CGS 23425 or axitirome (CGS 26214).
  • an active compound is an HMG-CoA-reductase inhibitor from the class of statins, for example and preferably lovastatin, simvastatin, pravastatin, fluvastatin, atorvastatin, rosuvastatin or pitavastatin.
  • statins for example and preferably lovastatin, simvastatin, pravastatin, fluvastatin, atorvastatin, rosuvastatin or pitavastatin.
  • an active compound is a squalene synthesis inhibitor, for example and preferably BMS-188494 or TAK-475.
  • an active compound is an ACAT inhibitor, for example and preferably avasimibe, melinamide, pactimibe, eflucimibe or SMP-797.
  • an active compound is an MTP inhibitor, for example and preferably implitapide, BMS-201038, R-103757 or JTT-130.
  • an active compound is a PPAR-gamma agonist, for example and preferably pioglitazone or rosiglitazone.
  • an active compound is a PPAR-delta agonist, for example and preferably GW 501516 or BAY 68-5042.
  • an active compound is a cholesterol-absorption inhibitor, for example and preferably ezetimibe, tiqueside or pamaqueside.
  • an active compound is a lipase inhibitor, for example and preferably orlistat.
  • an active compound is a polymeric bile acid adsorber, for example and preferably cholestyramine, colestipol, colesolvam, CholestaGel or colestimide.
  • ASBT IBAT
  • an active compound is a lipoprotein(a) antagonist, for example and preferably gemcabene calcium (CI-1027) or nicotinic acid.
  • the pharmaceutical composition comprises one or more additional therapeutic agents selected from the group consisting of cGMP elevating agents e.g. sGC stimulators and activators, PDE inhibitors, IP receptor agonists, endo- thelin receptor antagonists, HNE inhibitors, signal transduction cascade inhibitors, antithrombotic agents and vasodilators.
  • cGMP elevating agents e.g. sGC stimulators and activators, PDE inhibitors, IP receptor agonists, endo- thelin receptor antagonists, HNE inhibitors, signal transduction cascade inhibitors, antithrombotic agents and vasodilators.
  • sGC stimulators for example and preferably BAY 41-2272 (3-(4-Amino-5-cyclopropyl- pyrimidin-2-yl)-1-(2-fluorobenzyl)-1 H-pyrazolo[3,4-b]pyridine of formula (I).
  • BAY 41-2272 has been encapsulated in non-porous, dipalmitoylphosphatidylcholine/albumin/lactose (DAL)-based microparticles. These were obtained via a spray-drying method and were tested for in halation in an awake lamb model of acute pulmonary hypertension [Evgenov O.V., Kohane D.S, Bloch K.D., Stasch J.-P., Volpato G.P., Bellas E., Evgenov N.V., Buys E.S., Gnoth M.J., Graveline A. R., Liu R., Hess D.R., Langer R., Zapol W.M., Am. J. Respir. Crit. Care Med., 176, 1138-1145 (2007)].
  • the pulmonary vasodilation that occurred after inhaling DAL-cinaciguat microparticles was dose depend ent and lasted for more than 60 mins.
  • Suitable matrix materials are those, which are compatible with the employed single emulsion method. In general these are matrix materials, which exhibit sufficient solubility (> 10mg/ml, prefer- ably > 30mg/ml, more preferably > 100mg/ml) in the organic solvent / solvent mixture that is being used for the preparation procedure.
  • the matrix material is a biocompatible, preferably biodegradable, polymer.
  • biocompatible describes a material which may be inserted, e.g. by inhalation, into a living subject without causing an adverse response. For example, it does not cause inflammation or acute rejection by the immune system that cannot be adequately controlled. It will be recognized that “biocompatible” is a relative term, and some degree of immune response is to be expected even for substances that are highly compatible with living tissue.
  • biodegradable describes a poly meric matrix material which degrades in a physiological environment to form monomers and/or other non-polymeric moieties that can be reused by cells or disposed of without significant toxic effect.
  • Deg radation may be biological, for example, by enzymatic activity or cellular machinery, or may be chemical (e.g. hydrolysis). Degradation of a polymer may occur at varying rates, with a half-life in the order of days, weeks, months, or years, depending on the polymer or copolymer used.
  • the biocompatible and/or biodegradable polymer can be a poly(lactide), a poly(glycolide), a poly- (lactide-co-glycolide) (PLGA), a poly(caprolactone), a poly(orthoester), a poly(phosphazene), a po- ly(hydroxybutyrate) or a copolymer containing a poly(hydroxybutarate), a poly(lactide-co-caprolac- tone), a polycarbonate, a polyesteramide, a polyanhydride, a poly(dioxanone), a poly(alkylene alkylate), a copolymer of polyethylene glycol and a polyorthoester, a biodegradable polyurethane, a poly(amino acid), a polyamide, a polyesteramide, a polyetherester, a polyacetal, a polycyanoacrylate, a poly(oxyethylene)/poly(oxypropylene)
  • the biocompatible or biodegradable polymer can comprise any lactide residue, including all racemic and stereospecific forms of lactide, including, but not limited to, L-lactide, D- lactide, and D, L-lactide, or a mixture thereof.
  • Useful polymers comprising lactide include, but are not limited to poly(L-lactide), poly(D-lactide), and poly(DL-lactide); and poly(lactide-co-glycolide), including poly(L-lactide-co-glycolide), poly(D-lactide-co-glycolide), and poly(DL-lactide-co-glycolide); or copolymers, terpolymers, combinations, or blends thereof.
  • Lactide/ glycolide polymers can be conveniently made by melt polymerization through ring opening of lactide and glycolide monomers. Additionally, racemic DL-lactide, L-lactide, and D-lactide polymers are commercially available. In addition to copolymers comprising glycolide and DL-lactide or L-lactide, copolymers of L-lactide and DL-lactide are commercially available. Homopolymers of lactide or glycolide are also commercially available. When the biodegradable and/or biocompatible polymer is poly(lactide-co-glycolide), poly(lactide), or poly(glycolide), the amount of lactide and glycolide in the polymer can vary.
  • the biodegradable polymer contains 0 to 100 mole %, 40 to 100 mole %, 50 to 100 mole %, 60 to 100 mole %, 70 to 100 mole %, or 80 to 100 mole % lactide and from 0 to 100 mole %, 0 to 60 mole %, 0 to 50 mole %, 0 to 40 mole %, 0 to 30 mole%, or 0 to 20 mole% glycolide, preferably 40 to 60 mole% lactide and 40 to 60 mole% glycolide, preferably 48 to 52 mole % lactide and 48 to 52 mole % glycolide, wherein the amount of lactide and glycolide is 100 mole%.
  • the biodegradable polymer can be poly(lactide), 95:5 poly(lactide-co-glycolide) 85:15 poly(lactide-co-glycolide), 75:25 poly(lactide-co-glycolide), 65:35 poly(lactide-co-glycolide), 52:48 poly(lactide-co-glycolide), 48:52 poly(lactide-co-glycolide), or 50:50 poly(lactide-co-glycolide), where the ratios are mole ratios.
  • the inherent viscosity is from 0.05 to 1.0 dl_/g, preferably from 0.1 to 0.5 dl_/g, more preferably from 0.16 to 0.44 dL/g.
  • the biodegradable polymer may either be an end-capped polymer (terminal carboxy-groups are esterified) or comprise mainly free terminal carboxy groups (acid).
  • the biodegradable polymer comprises mainly free terminal carboxy groups.
  • the matrix mate rial is poly(lactide-co-glycolide) acid (PLGA).
  • the biodegradeable and/or biocompatible polymer can also be a poly(caprolactone) or a poly(lactide-co-caprolactone).
  • the polymer can be a poly(lactide- caprolactone), which, in various aspects, can be 95:5 poly(lactide-co-caprolactone), 85:15 poly(lac- tide-co-caprolactone), 75:25 poly(lactide-co-caprolactone), 65:35 poly(lactide-co-caprolactone), or 50:50 poly(lactide-co-caprolactone), where the ratios are mole ratios.
  • Table 2 provides molecular weight data for several commercially available PLGA polymers, which may be typically and preferably employed as matrix material in the inventive process.
  • PLGA 503H as matrix polymer.
  • any combination of the aforementioned biodegradable polymers can be used, including, but not limited to, copolymers thereof, mixtures thereof, or blends thereof.
  • any suitable polymer, copolymer, mixture, or blend, that comprises the disclosed residue is also considered disclosed.
  • the process for the preparation of the porous microparticles according to the invention corresponds to analogous premix membrane emulsification combined with O/W single emulsification-solvent evaporation methods (PME-ESE method) as described previously in the state of the art [T.V.P. Doan, J.C. Olivier, Int. J. Pharm. 2009, 382, 61-66; T.V.P. Doan, W. Couet, J.C. Olivier, Int. J. Pharm. 2011 , 414, 112-117.].
  • a premix membrane emulsification / O/W single emulsification-solvent evaporation process in gen eral constitutes of three fundamental steps: (1) The emulsification of a polymer solution comprising the pharmaceutically active agent, followed by (2) membrane emulsification and (3) particle hardening through solvent evaporation and polymer precipitation.
  • the process according to the invention comprises the following steps:
  • a first phase (a) comprising a pharmaceutically active agent, a matrix material, a porogenic agent and a volatile solvent, is emulsified with
  • step (ii) passing the primary o/w emulsion (A) resulting from step (i) through a porous membrane to form a secondary o/w emulsion (B),
  • step (ii) the secondary o/w emulsion (B) resulting from step (ii) is emulsified with
  • step (v) optionally drying the porous microparticles resulting from step (v),
  • step (i) is polyvinylpyrrolidone and/or a polyvi nylpyrrolidone derivative and that the porous membrane in step (iii) is a glass membrane.
  • the first phase (a) (“organic phase", “oil phase”) comprises the matrix material, the pharmaceuti cally active agent and the porogenic agent dissolved or dispersed in a suitable volume of a solvent and can be provided using any suitable means (e.g. stirring, mixing means).
  • suitable solvents are those, which show good compatibility with the employed single emulsion method.
  • a solvent can be selected based on its biocompatibility as well as the solubility or dispersability of the matrix material, the porogenic agent and/or the pharmaceutically active agent. For example, the ease with which the matrix material is dissolved in the solvent and the lack of detrimental effects of the solvent on the pharmaceutically active agent to be delivered are factors to consider in selecting the solvent.
  • the solvent can be selected based on its immiscibility with the aqueous phase.
  • Organic solvents will typically be used to dissolve hydrophobic and some hydrophilic matrix materials.
  • a wide variety of organic solvents can be used.
  • the organic solvent / solvent mix is volatile, which means it has a low enough boiling point that the solvent can be removed under atmospheric pressure or under vacuum.
  • Preferred solvents are acceptable for administration to humans in a trace amount (e.g. ⁇ 50 mg / day / human).
  • the solvent or solvent mix is a water-immiscible solvent or solvent mix, preferably an organic solvent of class 2 and class 3 (according to The International Conference on Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use (ICH) guideline Q3C; www.ich.org) or a mixture thereof, more preferably a water-immiscible organic class 2 or 3 solvent from the list of the following solvents: dichloromethane, cyclohexane, hexane, methylbutylketone, N- methylpyrrolidone, tert.-butylmethylether, ethylacetate, diethylether, heptane, pentane or mixtures thereof, particularly preferably dichloromethane and N-methylpyrrolidone or a mixture thereof.
  • solvents preferably dichloromethane and N-methylpyrrolidone or a mixture thereof.
  • the matrix material can be present in the first phase in any desired weight %.
  • the matrix material can be present in the first phase in about 0.1 % to about 60% weight to volume (w/v), including without limitation, about 5%, 10%, 15%, 20%, 30%, 40%, or 50% weight to volume (w/v).
  • the matrix material is dissolved in the solvent to form a matrix material solution having a concentration of between 0.1 and 60% weight to volume (w/v), more preferably between 5% and 30% weight to volume (w/v).
  • the matrix ma terial is used in an amount of 15 to 25% weight to volume (w/v).
  • the pharmaceutically active ingredient can be present in the first phase in about 0.01 % to about 90% relative to the sum of amounts of matrix and API, weight to weight (w/w), including without limitation, about 0.1 %, 0.5%, 1 %, 5%, 10%, 15%, 20%, 30%, 40%, 50%, 60%, 70%, or 80% relative to the sum of amounts of matrix and API (w/w).
  • the pharmaceutically active agent is used in an amount of 1 to 10% relative to the sum of amounts of matrix and API (w/w).
  • the porogenic agent can be present in the first phase in about 1 % up to about 200%, by weight (w/w) relative to the matrix employed in the process according to the invention, including without limitation, about 5%, 10%, 15%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 100%, 120%, and 150%.
  • the porogenic agent is used in a ratio of from 1 % to 100%, preferably of from 1 % to 30%, more preferably of from 5% to 30%, more preferably of from 5% to 20%, by weight (w/w), and particularly preferably of from 10% to 15%, by weight (w/w) relative to the matrix material.
  • the first phase can further comprise additives such as cosolvents, surfactants, emulsifiers, blends of two or more polymers, or a combination thereof, among other additives.
  • additives such as cosolvents, surfactants, emulsifiers, blends of two or more polymers, or a combination thereof, among other additives.
  • the second phase is in form of an aqueous phase.
  • water can be mixed with another water-miscible solvent, which at the same time must not be miscible with the organic solvent used for the preparation of the first phase.
  • methanol may be added to the second phase, in case n-heptane or cyclohexane is used for the preparation of the first phase.
  • the second phase can contain other excipients, such as buffers, salts, sugars, surfactants, emulsifiers, and/or viscosity-modifying agents, or combinations thereof.
  • the aqueous phase further comprises an emulsifying agent.
  • the emulsifying agent may serve to form stable microdroplets with an inner organic solvent phase and an outer aqueous phase, from which during the further pro cess steps (e.g. by stirring and subsequent solvent evaporation) formation of solid porous microparticle of reproducible morphology, size, and aerodynamic diameter occurs.
  • Non-limiting examples of emulsifying agents include those from the group of anionic emulsifiers (e.g. sodium lauryl sulfate), cationic emulsifiers (e.g. cetyl pyridinium chloride), amphoteric emulsifiers (e.g. lecithin), and non-ionogenic emulsifiers (e.g. macrogol stearate, macrogol sorbitan oleate, pol- yvinylalcohol).
  • anionic emulsifiers e.g. sodium lauryl sulfate
  • cationic emulsifiers e.g. cetyl pyridinium chloride
  • amphoteric emulsifiers e.g. lecithin
  • non-ionogenic emulsifiers e.g. macrogol stearate, macrogol sorbitan oleate, pol- yvinylalcohol.
  • the aqueous phase further comprises polyvinyl alcohol (PVA) as emulsifying agent in a concentration of from 0.05% to 5%, preferably from 0.1 % to 3%, more preferably from 0.1 to 0.5%, by weight (w/v) in the aqueous phase, particularly preferably at a concentration of 0.5% by weight (w/v) in the aqueous phase.
  • PVA polyvinyl alcohol
  • the various PVA types available differ in their degree of hydrolysis; completely (>98 mole-%) hydrolysed, medium (90.5-96.5 mole-%) hydrolysed, par tially ( ⁇ 8-89 mole-%) hydrolysed); and degree of polymerization (usually -500-2500 monomers) the latter being reflected in different viscosities.
  • the emulsifier is PVA 205.
  • the emulsifier is PVA 217.
  • the first phase (a) and the second phase (b) may be used in any ratio, which provides a stable emulsion after emulsification.
  • the ratios typically employed in the inventive process range between 1/5 and 1/100 by volume (v/v) [phase (a)/phase (b)].
  • the ratio between phase (a) and phase (b) is in the range from 3/25 (v/v) to 3/100 (v/v).
  • the first phase (a) and the second phase (b) are subjected to an emulsification treatment to prepare the o/w emulsion.
  • the emulsification treatment may be carried out using any suitable means known in the art such as mechanical stirring, high speed shearing, ultrasonic emulsifying, high pressure homogenizing or microfluidizer, preferably mechanical stirring, high speed shearing. It has been found advantageous to control the stirring speed during the ho mogenization step to adjust the microparticle size. In general, smaller microparticle sizes are achieved by applying a higher homogenization speed (VH). Typically, the homogenization speed (VH) for the emulsification is in the range of from 1000 to 20000 rpm.
  • the emulsification treatment is preferably carried out under such conditions as to produce an O/W emulsion in which most of the oil droplets contained therein have an average diameter of about 0.5 to 50 pm.
  • the total time for the homogenization step is in the range of 20-60 seconds.
  • This time frame includes the injection of phase (a) into phase (b), which typically is being performed within 1- 20 seconds, preferably within 5-15 seconds, partic ularly preferably within 10 seconds.
  • the total homogenization time is 20- 30 seconds, preferably 30 seconds of which during the first 10 seconds phase (a) is injected into phase (b).
  • one or more additives selected from surfactants and water-soluble polymers which contribute to the stabilization of the O/W emulsion may be added to the mixed system.
  • Usable surfactants include those from the group of anionic emulsifiers (e.g. sodium lauryl sulfate, sodium stearate), cationic emulsifiers (e.g. cetyl pyridinium chloride), amphoteric emulsifiers (e.g.
  • non-ionogenic emulsifiers e.g. macrogol stearate, macrogol sorbitan oleate, pol- yvinylalcohol polyvinyl pyrrolidone, carboxymethylcellulose, hydroxypropylcellulose, gelatin and the like.
  • emulsifiers e.g. macrogol stearate, macrogol sorbitan oleate, pol- yvinylalcohol polyvinyl pyrrolidone, carboxymethylcellulose, hydroxypropylcellulose, gelatin and the like.
  • additives may be used at such a concentration as to give a 0.01 to 10% (w/w) aqueous solution.
  • the primary o/w emulsion resulting from the emulsification treatment of step (i) is passed through a porous membrane, wherein a secondary o/w emulsion is formed.
  • an SPG Silicon nitride membrane, nickel membrane and/or stainless steel membrane
  • an SPG membrane is used.
  • the particle size of the primary o/w emulsion can be controlled by the SPG membrane pore size [Liu R., Ma G.H., Wan Y.H., Su Z.G., Colloids and Surfaces B: Biointer faces 45, 144-53 (2005); Zhou Q.Z., Ma G.H., Su Z.G., J. Membr. Sci 326, 694-700 (2009)].
  • the pore wall of the SPG mem brane will squeeze the droplets and eventually affect the surface morphology of the microparticles.
  • the secondary emulsion obtained after step (ii) is emulsified with a second aqueous phase (c).
  • the aqueous phase (c) employed in step (iii) has an identical composition as the first aqueous phase employed in step (i).
  • the second phase can contain other excipients as listed above under step (i).
  • the aqueous phase fur ther comprises an emulsifying agent as described above.
  • the emulsifying agent is typically used in a concentration of from 0.05% to 5% by weight (w/v) in the aqueous phase.
  • the aqueous phase further comprises polyvinyl alcohol (PVA) as emulsifying agent in a concentration of from 0.05% to 5%, preferably from 0.1 % to 3%, more preferably from 0.1 to 0.5%, by weight (w/v) in the aqueous phase, particularly preferably at a concentration of 0.5% by weight (w/v) in the aqueous phase.
  • PVA polyvinyl alcohol
  • the emulsifier is PVA 205.
  • the emulsifier is PVA 217.
  • the secondary emulsion (B) and the aqueous phase (c) may be used in any ratio, which provides a stable emulsion after emulsification.
  • the ratios typically employed in the inventive process range between 1/2 and 1/10 by volume (v/v) [secondary emulsion (B) /phase (c)].
  • the ratio between secondary emulsion (B) and phase (c) is in the range from 50/150 (v/v) to 50/300 (v/v).
  • one or more additives selected from surfactants and water-soluble polymers which contribute to the stabilization of the O/W emulsion may be added to the mixed system.
  • Usable surfactants include those from the group of anionic emulsifiers (e.g. sodium lauryl sulfate, sodium stearate), cationic emulsifiers (e.g. cetyl pyridinium chloride), amphoteric emulsifiers (e.g. lecithin), and non-ionogenic emulsifiers (e.g.
  • macrogol stearate macrogol sorbitan oleate, pol- yvinylalcohol polyvinyl pyrrolidone, carboxymethylcellulose, hydroxypropylcellulose, gelatin and the like.
  • additives may be used at such a concentration as to give a 0.01 to 10% (w/w) aqueous solution.
  • the emulsion resulting from the emulsification treatment of step (iii) may optionally be stirred for a further time period, typically to support the microparticle formation or to achieve a higher efficiency for the extraction of the porogenic agent.
  • an optional stirring step may also be combined with step (iv) of the inventive process and thereby serve to remove the volatile solvents via evaporation.
  • Solvent evaporation may further be supported by application of a reduced pressure. The time period for the stirring and stirring speed may then favorably be chosen to achieve the desired degree of evaporation of the solvent.
  • the emulsion resulting from step (iii) is typically stirred for a time period of 1 to 10 hours, preferably of 2 to 7 hours while applying a stirring speed (vs) of typically 300 to 2000 rpm, preferably 500 to 1000 rpm. In a typical procedure the emulsion is stirred for about 4 h while applying a speed of about 800 rpm.
  • the porous microparticles are typically separated from the remaining phase via centrifugation, filtration or sedimentation.
  • the microparticles are separated by centrifugation, typically with a centrifugation speed of 1000 rpm to 5000 rpm, for a time period of 5 to 15 minutes. In a typical procedure a centrifugation speed of 3000 rpm for a time period of 5 minutes is applied.
  • the resulting microparticle pellet may then be typically washed with distilled water, e.g. to remove the residues of e.g. emulsifier adsorbed on microspheres surface during the preparation process. Typically this may be performed by addition of water, followed by mixing and centrifugation (1000 rpm to 5000 rpm, preferably of 4000 rpm for a time period of 5-15 minutes, preferably of 10 minutes, and thereafter decanting of water).
  • the collected microparticles are subjected to lyophilisation in order to completely dry the microparticles. Drying the particles may be particularly advantageous to reduce aggregation and improve flowability and good dispersibility of the resulting microparticle powder.
  • porous microparticle is used herein to refer generally to a variety of structures having sizes from about 10 nm to 2000 pm (2 mm) and includes microcapsules, microspheres, nanoparti cles, nanocapsules, nanospheres as well as in general particles, that are less than about 2000 pm (2 mm).
  • the microparticles may or may not be spherical in shape.
  • the porous microparticles are spherical in shape.
  • the term“porous microparticles” refers to particles that are interspersed with pores of various sizes and numbers. In a preferred embodi ment of the invention the pores pervade the entire volume of the microparticles.
  • the aerodynamic behavior as well as the drug release rate of the porous microparticles and the pharmaceutical preparations according to the invention may be controlled and adjusted by control ling microparticle composition and thereby microparticle geometric size, and/or microparticle poros ity.
  • the porosity and the release rate of the microparticles is in turn dependent on the ratio and type of the polyvinylpyrrolidone and/or polyvinylpyrrolidone derivative employed as a porogenic agent within the inventive process.
  • Porosity is the ratio of the volume of voids contained in the microparticles (V v ) to the total volume of the microparticles (V t ):
  • the absolute density is a measurement of the density of the solid material present in the micropar ticles, and is equal to the mass of the microparticles (which is assumed to equal the mass of solid material, as the mass of voids is assumed to be negligible) divided by the volume of the solid ma terial (i.e., excludes the volume of voids contained in the microparticles and the volume between the microparticles).
  • Absolute density can be measured using techniques such as helium pyc- nometry.
  • the envelope density is equal to the mass of the microparticles divided by the volume occupied by the microparticles (i.e., equals the sum of the volume of the solid material and the volume of voids contained in the microparticles and excludes the volume between the microparti cles).
  • Envelope density can be measured using techniques such as mercury porosimetry or using a GeoPycTM instrument (Micromeritics, Norcross, Georgia). However, such methods are limited to geometric particle sizes larger than desirable for pulmonary applications.
  • the envelope density can be estimated from the tap density (p t ) of the microparticles.
  • the tap density (p t ) is a measurement of the packing density and is equal to the mass of micropar ticles divided by the sum of the volume of solid material in the microparticles, the volume of voids within the microparticles, and the volume between the packed microparticles of the material. Tap density can be measured using a GeoPycTM instrument or techniques such as those described in the British Pharmacopoeia and ASTM standard test methods for tap density. It is known in the art that the envelope density can be estimated from the tap density for essentially spherical micropar ticles by accounting for the volume between the microparticles:
  • the porosity can be expressed as follows:
  • size refers to the number average particle size, unless otherwise specified.
  • D size average particle size
  • n, number of particles of a given diameter (D,).
  • geometric size As used herein, the terms “geometric size,” “geometric diameter,” “volume average size,” “volume average diameter”,“volume mean diameter” or “D g " refers to the volume weighted diameter average.
  • D represents diameter
  • v represents the relative amount of particles with diameter D, in relation to all particles.
  • volume median refers to the median diameter value of the volume- weighted distribution.
  • the median is the diameter for which 50% of the total are smaller and 50% are larger, and corresponds to a cumulative fraction of 50%.
  • Geometric particle size analysis can be performed on a Coulter counter, by light scattering, by light microscopy, scanning electron microscopy, or transmission electron microscopy, laser diffraction methods, or time-of-flight methods, as known in the art.
  • aerodynamic diameter refers to the equivalent diameter of a sphere with density of 1 g/mL, were it to fall under gravity with the same velocity as the particle analyzed.
  • the aerodynamic diameter (D a , MMAD) of a microparticle is related to the volumetric median diameter (D V,5O ) and the tap density (p e ) by the following:
  • Porosity affects tap density (EQ. 8) which in turn affects aerodynamic diameter.
  • porosity can be used to affect both where the microparticles go in the lung and the rate at which the microparticles release the pharmaceutically active agent in the lung.
  • Gravitational settling (sedimentation), inertial impaction, Brownian diffusion, interception and electrostatic precipitation affect particle deposition in the lungs. Gravitational settling and inertial impaction are dependent on d a and are the most important factors for deposition of particles with aerodynamic diameters between 1 pm and 10 pm.
  • Aerodynamic diameters can be determined on the dry powder using an Aerosizer (TSI), which is a time of flight technique, or by cascade impaction, or liquid impinger techniques.
  • TSI Aerosizer
  • Fine Particle Fraction or“respirable dose” refer to a dose of drug that has an aerodynamic size such that particles or droplets comprising the drug are in the aerodynamic size range that would be expected to reach the lung upon inhalation.
  • Fine particle fraction / respirable dose can be measured using a next generation cascade impactor (NGI), a liquid impinge, or time of flight methods (as described by United States Pharmacopeia [USP34_NF29 Chapter ⁇ 601 > Aerosols, Nasal Sprays, Metered-Dose Inhalers, and Dry Powder Inhalers Monograph, The United States Pharmacopoeia and The National Formulary: The Official Compendia of Standards. The United States Pharmacopeial Convention, Inc., Rockville, MD., USA. 2011. Apparatus 6] and European Pharmacopoeia [Ph. Eur. Section 2.9.18, Preparations for inhalation: Aerodynamic assessment of fine particles, European Pharmacopoeia: 7th Ed., Council of Europe, 67075, France. 2010]
  • NTI next generation cascade impactor
  • the porous microparticles preferably have an experimentally determined aerodynamic diameter (MMAD) of between 1 pm and 7 pm.
  • the porous microparticles obtainable via the process according to the invention typically have an MMAD of from 1 to 7 pm.
  • the porous microparticles have a volume average diameter (D V,5O ) from about 7 pm to 30 pm.
  • the porous microparticles have a volume average diameter (D v, so), from about 9 pm to 20 pm.
  • the geometric particle size of the porous microparticles obtainable via the process according to the invention preferably is greater than 5 pm, preferably with an MMAD value between 2 pm to 5 pm, and a geometric particle size of greater than 7 pm, more preferably with an MMAD value between 2 pm to 4 pm, and a geometric particle size of between 8 pm to 15 pm.
  • the porous microparticles comprise the pharmaceutically active agent encapsu lated, microencapsulated, or otherwise contained within the microparticles.
  • the micro particles can comprise 0.01 % to about 90% API relative to the sum of amounts of matrix and API, weight to weight (w/w) , including without limitation, about 0.1 %, 0.5%, 1 %, 5%, 10%, 15%, 20%, 30%, 40%, 50%, 60%, 70%, or 80% relative to the sum of amounts of matrix and API (w/w), includ ing any range between the disclosed percentages.
  • the pharmaceutically active agent is used in an amount of 5 to 10% relative to the sum of amounts of matrix and API (w/w).
  • microparticles with a non-uniform pore distribu tion are obtained, which exhibit a gradient morphology with higher internal porosity in the particle core than external porosity on the particle surface.
  • part of the pore channels on the surface of the forming particles are closed while passing the membrane, potentially due to friction between the droplets and the membrane walls.
  • the slope of the internal porosity equation is larger than the external one, indicating that the higher the PVP concentration, the greater the difference between the inner and outer porosity, the stronger the friction between the droplets and the pore walls, the more the number of closed pore channels.
  • the invention pertains to microparticles with a non-uniform pore distribution.
  • Such microparticles with a non-uniform pore distribution with decreasing porosity along the particle radius show advantageous properties, such as an improved release profile with diminished burst release of the pharmaceutically active agent within the first release period.
  • sustained release indicates that, for example, after 4 hours, less than 60% of the active agent or active agent fraction has been released. Alternatively, it may indicate that, after 12 hours, less than 85% of the active agent or active agent fraction has been released.
  • the porous microparticles release the pharmaceutically active agent in a sustained manner. Under experimental conditions described in the methods section, preferably, less than 60% of encapsulated API is released within 4 hours, and less than 75% of API is released within 8 hours after start of the dissolution experiment.
  • a therapeutically effective amount of the pharmaceutically active agent is released from the porous microparticles in the lungs for at least 2 hours, preferably for at least 4 hours, most preferably for at least 12 hours, for at least particularly preferable 24 hours.
  • microparticle porosity and thus density an iterative process can be used to define where the microparticles go in the lung and the duration over which the microparticles release the pharma ceutically active agent: 1) the matrix material, the pharmaceutically active agent content, and the microparticle geometric size are selected to determine the time and amount of initial pharmaceuti cally active agent release; 2) the porosity of the microparticles is selected to adjust the amount of initial pharmaceutically active agent release, and to ensure that significant release of the pharma ceutically active agent occurs beyond the initial release and that the majority of the pharmaceutically active agent release occurs within a given time period; and then 3) the geometric particle size and the porosity are adjusted to achieve a certain aerodynamic diameter which enables the particles to be deposited by inhalation to the region of interest in the lung.
  • the term "initial release” refers to the amount of pharmaceutically active agent re leased shortly after the microparticles become wetted.
  • the initial release upon wetting of the micro particles may result from pharmaceutically active agent which is not fully encapsulated and/or phar maceutically active agent which is located close to the exterior surface of the microparticle.
  • the amount of pharmaceutically active agent released in the first hour is used as a measure of the initial release.
  • the micropaticles exhibit a burst re lease of the pharmaceutically active agent of less than 35% after 1 hour.
  • the pharmaceutical composition according to the invention can be administered as the sole phar maceutical composition or in combination with one or more other pharmaceutical compositions or active agents where the combination causes no unacceptable adverse effects.
  • “Combination” means for the purposes of the invention not only a dosage form which contains all the active agents (so-called fixed combinations), and combination packs containing the active agents separate from one another, but also active agents which are administered simultaneously or sequen tially, as long as they are employed for the prophylaxis or treatment of the same disease.
  • “Fixed dose combination” refers to a pharmaceutical product that contains two or more active ingredients that are formulated together in a single dosage form available in certain fixed doses.
  • excipients include, but are not limited to: coloring agents, taste masking agents, salts, hygroscopic agents, antioxidants, and chemical stabilizers. Further, various excipients may be incorporated in, or added to, the particulate matrix to provide structure and form to the particulate compositions.
  • the pharmaceutical composition comprises the porous microparticles and optionally one or more pharmaceutically acceptable excipients.
  • porous micro particles can be formulated so as to be suitable for aerosolization or for dry powder inhalation, preferably for dry powder inhalation.
  • the formulated porous microparticle size can be varied ac cording to the size deemed to be optimal for pulmonary delivery.
  • Suitable inhalers comprise dry powder inhalers (DPIs). Same such inhalers include unit dose inhal ers, where the dry powder is stored in a capsule or blister, and the patient loads one or more of the capsules or blisters into the device prior to use. Other multi-dose dry powder inhalers include those where the dose is pre-packaged in foil-foil blisters, for example in a cartridge, strip or wheel. Other multi-dose dry powder inhalers include those where the bulk powder is packaged in a reservoir in the device.
  • DPIs dry powder inhalers
  • the term "emitted dose” or "ED" refers to an indication of the delivery of dry powder from a suitable inhaler device after a firing or dispersion event from a powder unit or reservoir.
  • ED is defined as the ratio of the dose delivered by an inhaler device (described in detail below) to the nominal dose (i.e., the mass of powder per unit dose placed into a suitable inhaler device prior to firing).
  • the ED is an experimentally-determined amount, and is typically determined using an in vitro device set up which mimics patient dosing.
  • a nominal dose of dry powder (as defined above) is placed into a suitable dry powder inhaler, which is then actuated, dispersing the powder.
  • the resulting aerosol cloud is then drawn by vacuum from the device, where it is cap tured on a tared filter attached to the device mouthpiece.
  • the amount of powder that reaches the filter constitutes the delivered dose.
  • the porous microparticles according to the invention can be combined (e.g. blended) with one or more pharmaceutically ac ceptable bulking agents and administered as a dry powder blend formulation.
  • the bulking agent can, for example, comprise particles which have a volume average size between 10 and 500 pm.
  • pharmaceutically acceptable bulking agents include sugars such as mannitol, sucrose, lactose, fructose and trehalose and amino acids.
  • Amino acids that can be used include glycine, arginine, histidine, threonine, asparagine, aspartic acid, serine, glutamate, proline, cysteine, methi onine, valine, leucine, isoleucine, tryptophan, phenylalanine, tyrosine, lysine, alanine, and gluta mine.
  • the bulking agents are selected from the group consisting of lactose, mannitol, sorbitol, trehalose, xylitol, and combinations thereof.
  • Fine particle fraction is the ratio of mass of particles in the formulation with aerodynamic diameter (D a ) less or equal to ⁇ 5 pm, to the total mass of delivered particles.
  • the microparticles according to the invention exhibit a fine particle fraction large than 15%, preferably of from 20% to 70%, most preferably of from 20% to 50%.
  • the present invention also relates to a use of the pharmaceutical composition for pulmonary drug delivery, preferably via inhalation, to treat or prevent disorders, preferably pulmonary diseases or conditions of the lungs and/or airways, wherein the pharmaceutical composition comprises the po rous microparticles comprising a pharmaceutically effective amount of a pharmaceutically active agent according to the invention.
  • the present invention also relates to a method for treating or preventing a preferably pulmonary disease or condition of the lungs and/or airways, comprising pulmonary administration of the pharmaceutical composition, preferably via inhalation, wherein the composition comprises the porous microparticles comprising a pharmaceutically effective amount of an active agent according to the present invention.
  • pulmonary diseases or conditions of the lungs and/or airways according to the inven tion include but are not limited to chronic pulmonary diseases, lung cancer, cystic fibrosis, idiopathic pulmonary fibrosis, asthma, bronchitis, pneumonia, pleurisy, emphysema, pulmonary fibrosis, dia betes, interstitial lung disease, sarcoidosis, chronic obstructive pulmonary disease (COPD), asthma, infant respiratory distress syndrome, adult respiratory distress syndrome, pulmonary actinomycosis, pulmonary alveolar proteinosis, pulmonary anthrax, pulmonary arteriovenous malformation, pulmo nary edema, pulmonary embolus, pulmonary histiocytosis X (eosinophilic granuloma), pulmonary nocardiosis, pulmonary tuberculosis, pulmonary veno-occlusive disease, rheumatoid lung disease, and others.
  • COPD chronic obstructive pulmonary disease
  • the present invention also relates to the use of any pharmaceutical composition described herein in the manufacture of a medicament for the treatment of treating diseases or conditions of a patient or subject, such as diseases or conditions of the lungs and/or airways.
  • the present invention also provides any dry powder formulation herein comprising respirable porous microparticles for use in the treatment of diseases or conditions of a patient or subject, such as diseases or conditions of the lungs and/or airways.
  • the present invention also relates to a use of the pharmaceutical composition according to the invention to treat or prevent disorders, preferably pulmonary hypertension, chronic obstructive pulmonary disease (COPD), pulmonary fibrosis and lung cancer.
  • disorders preferably pulmonary hypertension, chronic obstructive pulmonary disease (COPD), pulmonary fibrosis and lung cancer.
  • COPD chronic obstructive pulmonary disease
  • the term“pulmonary hypertension” encompasses both primary and secondary subforms thereof, as defined below by the Dana Point classification according to their respective aetiology [see D. Montani and G. Simonneau, in: A.J. Peacock et al. (Eds.), Pulmonary Circulation. Diseases and their treatment, 3 rd edition, Hodder Arnold Publ., 2011 , pp. 197-206; M.M. Hoeper et al., J. Am. Coll. Cardiol.
  • PAH pulmonary arterial hypertension
  • APAH pulmonary arterial hypertension
  • Group 2 of the Dana Point classification comprises PH patients having a causative left heart disorder, such as ventricular, atrial or valvular disorders.
  • Group 3 comprises forms of pulmonary hypertension associated with a lung disorder, for example with chronic obstructive lung disease (COPD), interstitial lung disease (ILD), pulmonary fibrosis (IPF), and/or hypoxaemia (e.g. sleep apnoe syndrome, alveolar hypoventilation, chronic high-altitude sickness, hereditary deformities).
  • COPD chronic obstructive lung disease
  • ILD interstitial lung disease
  • IPF pulmonary fibrosis
  • hypoxaemia e.g. sleep apnoe syndrome, alveolar hypoventilation, chronic high-altitude sickness, hereditary deformities.
  • Group 4 includes PH patients having chronic thrombotic and/or embolic disorders, for example in the case of thromboembolic obstruction of proximal and distal pulmonary arteries (CTEPH) or non-thrombotic embolisms (e.g. as a result of tumour disorders, parasites, foreign bodies).
  • CTEPH proximal and distal pulmonary arteries
  • non-thrombotic embolisms e.g. as a result of tumour disorders, parasites, foreign bodies.
  • Less common forms of pulmonary hypertension such as in patients suffering from sarcoidosis, histiocytosis X or lymphangiomatosis, are summarized in group 5.
  • FIG. 1A In vitro release profiles of BAY 41-2272 loaded LPPs prepared with different amounts of polyvinylpyrrolidone.
  • FIG. 2B Enlargement of Figure 2A (data points of the first 4 hours).
  • FIG. 4 Surface morphology of BAY 41-2272 loaded LPPs prepared with different amounts of polyvinylpyrrolidone.
  • API active pharmaceutical ingredient pharmaceutically active agent
  • Polyvinyl alcohol PVA 205 and 217, partially hydrolyzed, Kuraray Co., Ltd., Japan
  • Polyvinylpyrrolidone PVP K12, K17, K30; International Specialty Products
  • PLGA Resomer® RG 502, 502H, 503H, Evonik, Essen, Germany
  • Lactose Lactohale ® LH 200, LH300; DFE pharma, The Netherlands
  • Phosphate acid HPLC grade; Tianjin Guangfu Chemical Institute, China
  • BAY 41-2272 was detected at a wavelength of 220 nm.
  • the drug retention time of BAY 41-2272 was about 17 min.
  • BAY 41-2272 content was quantified by using a standard control method. Pre- cision of the system was determined with each sample set run, by six times injection of one BAY 41-2272 standard, coefficient of variation of peak areas resulting from these six injections was below 2%.
  • %DL Drug loading
  • %EE encapsulation efficiency
  • %DL amount of API (weight) / amount of API+excipient (weight) * 100 [%]
  • Encapsulation efficiency (%EE) measured drug loading / theoretical drug loading * 100 [%]
  • Encapsulation efficiency (EE) of BAY 41-2272-loaded PLGA microparticles was measured according to the following procedures: 10.0 mg of BAY 41-2272-loaded microparticles were dissolved in 1.5 mL DCM and vortexed for 10 min to ensure complete dissolving of microparticles. Then the solution was diluted to 50.0 mL with methanol to precipitate the PLGA and dissolve BAY 41-2272. 4 mL of the mixture was centrifuged at 10000 rpm for 5 min and 5.0 pL of the supernatant was collected for HPLC analysis as described in the methods.
  • Geometric particle size and size distribution of the microparticles was determined using a laser particle size analyzer (BT-9300S, Bettersize Instruments Ltd., China). The samples were dispersed in 0.5% (w/v) PVA solution for measurement. The geometric diameter of samples was represented by volumetric median diameter (D v, so). The size distribution was considered as satisfactory (i.e., narrow size distribution) for span values below or equal to 1. Span was defined according to the following equation (EQ. 9):
  • Theoretical mass mean aerodynamic diameters (MMAD t ) of the particles were calculated from measured tapped density values (p t ) of the particles.
  • p t measured tapped density values
  • MMAD t The theoretical mass mean aerodynamic diameter (MMAD t ) of the microparticles was calculated according to the following equation (EQ. 11):
  • Cross-sectional morphology of microparticles was obtained by embedding the microparticles in an aqueous solution containing 30% gelatin and 5% glycerin. External morphology of micronized BAY 41-2272-lactohale powder blend and microparticles and internal morphology of microparticles were observed using field emission scanning electron microscopes (FESEM) (Inspect F50, FEI Co., Ltd., USA; JSM-7800F, JEOL Ltd., Japan). A small amount of sample was sprinkled to double-sided adhesive tape attached to a copper stub and was sputter-coated with gold under vacuum. Photographs were taken at varied magnifications with an accelerating voltage of 2-10 kV.
  • FESEM field emission scanning electron microscopes
  • the FESEM images of the microparticles were analyzed using Image J software (developed at the U.S. National Institutes of Health; http://rsb.info.nih.gov/nih-image/download.html).
  • Theoretical porosity was employed to describe the external and internal morphology of the microparticles.
  • Theoretical external and internal porosity were defined as the area of total pores divided by the area of surfaces and cross-sections of the microparticles, respectively. At least five representative microparticles were used for the calculation.
  • Total intrusion volume (mL/g) and total pore area (m 2 /g) were defined as the difference between cumulative intrusion (mL/g) and cumulative pore area (m 2 /g) measured at 170 psia and 60000 psia, respectively.
  • Skeletal density (g/mL) and experimental porosity (%) were calculated according to the following equations (EQ. 12) and (EQ. 13): Skeletal density ( (EQ. 12)
  • NTI Next Generation Impactor
  • the in vitro aerosolization performance of the microparticles from a dry powder inhaler (DPI, Cyclohaler ® , Teva Pharmaceutical Industries Ltd., Netherlands) using No. 3 HPMC capsules (Capsugel ® , Suzhou, China) was characterized using a NEXT GENERATION IMPACTORTM (NGI, Copley Scientific Ltd., UK) with a stainless steel induction port (i.e. USP throat) and pre-separator attachments.
  • the impactor was equipped with a critical flow controller (Copley TPK 2000), a flow meter (Copley DFM 2000) and a vacuum pump (Copley HCP5, all Copley Scientific, UK).
  • the NGI impactor plates Prior to the measurement, to decrease particle re-entrainment, the NGI impactor plates were coated with a thin film of ethanolic 10% TWEEN ® 20 (w/v) solution and left in a fuming hood for 60 min to evaporate the ethanol.
  • HPMC capsules size 3, Capsugel ® , Suzhou, China
  • the cut-off particle aerodynamic diameters of each stage of the impactor were: pre-separator (10.0 pm), stage 1 (6.12 pm), stage 2 (3.42 pm), stage 3 (2.18 pm), stage 4 (1.31 pm), stage 5 (0.72 pm), stage 6 (0.40 pm), and stage 7 (0.24 pm).
  • the NGI was equipped with a micro orifice collector (MOC; Dso, 0.07 pm), which acts as a final filter.
  • the MOC used was configured to collect 80% of particles of > 70 nm in size.
  • individal components devices, capsules, throat, pre-separator and all impactor plates containing microparticles
  • dichloromethane washed with dichloromethane and the solvent fractions were collected into separate volumetric flasks (50.0 ⁇ 0.05ml_), diluted to the final volume with methanol and analyzed by HPLC as described in the methods.
  • the experimental mass median aerodynamic diameter (MMAD e ) and the geometric standard deviation (GSD) were obtained by a linear fit of the cumulative percent less than the particle size range by weight plotted on a probability scale as a function of the logarithm of the effective cut-off diameter (see USP general chapter 601).
  • the fine particle fraction is considered the fraction of particles that is available for lung deposition.
  • FPF is the ratio of mass of particles in the formulation with aerodynamic diameter (Da) less or equal to ⁇ 5 pm, to the total mass of delivered particles.
  • Da aerodynamic diameter
  • FPF was determined by calculating the mass of particles in stages 1 to 5 (0.72 pm to 6.12 pm) from the sum of API amounts in stages 1-5 and drug loading, and dividing the mass of particles in stages 1 to 5 by the total mass of delivered particles (EQ. 14).
  • GSD values were calculated according to below equation (EQ. 15). These values can be similarly obtained from the bundled software of the Next Generation Cascade Impactor (NGI, Copley Scientific Inc.).
  • M stage 1 th r ough 5 is the sum of mass of API (thus the sum of mass of aerolized particles, assuming content uniformity) found in each of the NGI collector stages 1 , 2, 3, 4, and 5.
  • M total is the sum of mass of API (thus the sum of aerolized particles, assuming content uniformity) found in all parts of the NGI (capsule, inhaler, adapter, induction port, pre-separator, all collector stages).
  • DSC Differential scanning calorimetry
  • Thermodynamic analysis of BAY 41-2272 can be performed with differential scanning calorimetry (DSC-1 , Mettler-Toledo, GieBen, Germany). Samples of the microparticles (approximately 5 mg ) are placed in hermetically sealed aluminum pans. The samples are scanned at a heating rate of 10 °C /min from 25 °C to 260 °C under nitrogen atmosphere. Respective thermic events (e.g. glass transition points of polymer, and/or melting points of APIs) are recorded, respectively. The melting temperature was determined from the endothermic peak of the DSC curve recorded.
  • DSC-1 differential scanning calorimetry
  • XRPD pat terns can be measured using an X-ray diffractometer (Xpert PRO, PANalytical B.V., the Nether lands) with Cu-K c radiation generated at 40mA and 40 kV. Samples are scanned in a 2Q range of 2.5°-50° with a step size of 0.05° and a counting time of 0.2 s per step.
  • Morphological examination of microparticles can be performed using a scanning electron micro scope (SEM) (Hitachi S-3400N, Hitachi Ltd., Japan or Quanta 600, FEI, Hillsboro, USA). A few milligrams ( ⁇ 5 mg) of microparticles are sprinkled onto double-sided adhesive tape attached to an aluminum stub and are then sputter-coated with a thin layer of gold under vacuum. Photographs are taken at varied magnifications (see respective Figures 4 and 5) with an accelerating voltage of 4-5 kV to investigate surface characteristics and morphologies of the microparticles.
  • SEM scanning electron micro scope
  • the drug e.g. for BAY 41-2272 23.7-50.0 mg corresponding to 65.8-138.7 mmol; 5-10%, w/w, Drug/(Drug+PLGA)
  • the organic phase was first injected into 50 mL of aqueous phase containing 0.5% (w/v) PVA 205 (4 °C) as an emulsifier.
  • a high-speed homogenizer (Ultra Turrax TP 25, Janke & Kunkel KG.IKA-Werk, Ger many) was used for the emulsification operated at a homogenization speed (VH) of 8000 rpm for 30 s.
  • the primary emulsion was then poured into the premix reservoir of an outernal pressure membrane emulsification device (MG-20, SPG Technology Co., Ltd., Japan) and the secondary emulsion with smaller and relatively uniform size was achieved by extruding the primary emulsion through a 10 pm SPG membrane (SPG Technology Co., Ltd., Japan) for three times with a N2 pressure. Then the emulsion was transferred into 0.5% (w/v) PVA 205 aqueous phase (220 ml_) to form a final o/w emul sion. The final emulsion was stirred at 800 rpm for 4 h at room temperature (using a water bath at 25 °C) to evaporate the volatiles.
  • the final emulsion was gradually solidified to form microparticles.
  • the solidified microparticles were subsequently collected by centrifugation (3000 rpm, 5 min), washed three times with distilled water and lyophilized (LGJ-10D, Four-Ring Science Instru ment Plant Beijing, China) for 24 h (0.0001 atm; -40°C for 16 h, -20°C for 7 h, 20°C for 1 h) to obtain dry microparticles.
  • the drug e.g. for BAY 41-227223.7 mg corresponding to 65.8 mmol; 5%, w/w, Drug / (Drug + PLGA)
  • 67.5 mg porogenic agent PVP (15%, w/w, PVP/PLGA) were dissolved in 3.0 mL DCM and the mixture was vortexed (VORTEX 3, Janke & Kunkel KG.IKA-Werk, Germany) for 15 min to ensure complete mixing.
  • the organic phase was then injected into 270 mL aqueous phase containing 0.5% (w/v) PVA 205 (4 °C) as an emulsifier under high speed homogenization (Ultra Turrax TP 25, Janke & Kunkel KG.IKA-Werk, Germany) at 15000 rpm for 30 s to obtain O/W emulsion. Then, the emulsion was stirred at 800 rpm/min for 4 h at room temperature (using a water bath at 25 °C) to evaporate the DCM. In this process, the emulsion was gradually solidified to form microparticles.
  • the solidified microparticles were subsequently collected by centrifugation (3000 rpm, 5 min), washed three times with distilled water and lyophilized (0.0001 atm, -40 °C for 16 h, -20 °C for 7 h, 20°C for 1 h) for 24 h (LGJ-10D, Four-Ring Science Instrument Plant Beijing, China) to obtain dry microparticles.
  • porous micro particles containing BAY 41-2272 were prepared under the given process conditions.
  • the particle characteristics were determined as described in the methods section.
  • the experiments under the given process conditions and the test results are shown in Table 3.
  • R Reference example. For all experiments ⁇ 23.7 mg (65.8 mmol) of BAY 41-2272 was used. For all experiments an 0.5% (w/v) aqueous PVA 205 solution (50+220 ml_) was used (O/W ratio of final emulsion 3:270).
  • Reference example 1 -R was prepared by the described method without the use of any porogenic agent; reference example 6-R was prepared by the described single emulsion method without the use of a mem- brane emulsification.
  • Table 3 shows that good drug encapsulation efficiencies and favorable particle properties, such as low MMAD values were achieved by the described method.
  • PME premix membrane emulsification
  • ESE single emulsification-solvent evaporation
  • Fig. 1 is a graph where the data of the theoretical internal and external porosity are linearly fitted, respectively. Fig. 1 shows a larger slope of the theoretical internal porosity compared to the external internal porosity. This means that the difference between the theoretical internal and external po rosity increases as the increment of PVP concentration.
  • This example illustrates embodiments of the porous microparticles encapsulating an API, which are obtained via a process according to the invention, and thereof derived pharmaceutical compositions for pulmonary drug delivery.
  • Specific embodiments have a sustained release profile, where the API is released over a specified time period.
  • the resulting microparticles prepared under the conditions described above were tested with regard to their in vitro release behavior under non-sink conditions as described in the methods section (method E)).
  • the release rate of the encapsulated API may be evaluated in vitro to identify those formulations having a desired release rate in a given amount of time.
  • the level of porosity for the respective polymer type can be used to adjust the amount of pharmaceutical agent released after a certain period of time, and particles having a desired release profile can be further analyzed in vivo.
  • Fig. 2 is a graph of percent of API released in vitro at the indicated time points from the optimised formulations.
  • Fig. 2 shows the in vitro release rate of the optimised microparticle formulations comprising BAY 41- 2272 as API, which were prepared as described in example I-3, experiments 2 to 5 and reference experiments 1-R and 6-R.
  • the in vitro release rate can be used to evaluate the desired level of sus tained release in vivo.
  • Microparticles which were obtained by the former ESE method (6-R) without the use of a membrane show a less favorable release profile with a high burst release within the first hour. Dense microparticles which do not have a sufficient degree of porosity show significantly slower release (reference Ex.
  • the PVP concentration in the prep aration according to the invention affects mainly the initial drug burst but not the release behavior at later stages.
  • the burst release of low-level PVP formulations (below 20% PVP/PLGA, experiments 2 and 3) is below 30%, equivalent to the burst release of dense microparticles (24.4 ⁇ 1.1%).
  • 20% PVP/PLGA formulation has the external porosity of about 4% and the burst release of more than 50% within 1 h, which are similar to the results of Ex. 6-R.
  • the difference in external porosity of particles prepared by the two methods is the main reason for the different burstrelease.
  • PME method could adjust the number of pores on the surface of particles and further control the release behavior.
  • Table 6 shows the in vitro burst release amount within 1 h of BAY 41-2272 loaded LPPs prepared with different polyvinylpyrrolidone ratio.
  • microparticles prepared under the conditions described above were tested with regard to their in vitro aerosolization performance from a dry powder inhaler (Cyclohaler ® , Teva Pharmaceutical Industries Ltd., Netherlands ) using No. 3 HPMC capsules (Capsugel ® , Su- zhou, China) as described in the methods.
  • the content of drug loaded LPP powder on each stage was detected by HPLC and the aerosol performance parameters, FPF%, MMAD e and GSD values, were calculated by the NGI software.
  • Fig. 3 is a depiction of the in vitro aerodynamic diameter distribution and the deposition of the optimised particle formulations comprising BAY 41-2272 as API, which were prepared as described in example I-3, experiments 2 and 3 as well as the reference experiments 1-R and 6-R, in the NGI model compared with a conventional lactose-based powder blend.
  • porous microparticles according to the invention exhibit fine particle fractions that are in the range of commonly used and marketed dry powder inhaler formulations [which is in the range of ⁇ 20% - 30%, Muralidharan P, Hayes D. Mansour H.M., Expert Opin. Drug Deliv. 12, 947-962 (2014)] in which the API is applied to the patient in pure form or blended with solid excipients such as e.g. lactose or mannitol. 6-R presented lower FPF value due to the large MMAD value.
  • Figure 3 shows the percentages of particles mass in each of the cut-off plates of the NGI.
  • a typical pattern for solid API formulations when emitted from a dry powder inhaler can be observed with the majority of particles ending up in the preseparator (-35-55% of particle mass), followed by the mass of particles in the induction port ( ⁇ 10-25% of particle mass).
  • the fine particle fraction (sum of stages 1-5), as also shown in Table 7, is about 25%.
  • This example illustrates embodiments of the porous microparticles containing an API, which are obtained via a process according to the invention, and which are suitable to be administered in the form of pharmaceutical compositions for pulmonary drug delivery.
  • Thermodynamic calorimetry (DSC) as well as X-ray powder diffraction (X-RPD) can be used to evaluate the physical form and the encapsulation state of the pharmaceutically active agent.
  • FIGs. 4 and 5 show SEM photographs (recorded as specified in the methods section) of the external (series 1) and internal (series 2, 3) morphology of porous microparticles comprising BAY 41-2272 as API, which were obtained by the single emulsion method according to the invention as described (Fig. 4 (b)-(e): example I-3, experiments 2 to 5) as well as reference examples 1-R (Fig. 4 (a)) and 6-R (Fig. 5).
  • the external and internal morphology (Fig. 4 (a-e)) were analyzed using Image J software to calcu late the porosity of the microparticles. The results are shown in Table 5.
  • the internal and external porosity of the formulations increased with increasing PVP concentration.
  • the internal porosity was greater than the external porosity because the SPG pore walls had an effect on the surface pores of LPPs.
  • the linear fit between the porosity data and PVP con centration is shown in Figure 1 , R 2 was greater than 0.9.
  • the slope of the internal porosity equation was larger than that of the external one, indicating that the higher the PVP concentration, the greater the difference between the inner and outer porosity, the stronger the friction between the droplets and the pore walls, the more the number of closed pore channels.
  • This example illustrates embodiments of the porous microparticles encapsulating an API, which are obtained via a process according to the invention, and thereof derived pharmaceutical compositions for pulmonary drug delivery.
  • a specific embodiment shows a sustained therapeutic efficacy for pulmonary drug delivery in an in vivo inhalation model.
  • a specific embodiment shows a sustained anti hypertensive efficacy in a pulmonary arterial hypertension animal model.
  • Porous microparticles which were identified from the in vitro release experiments to have the desired release profile, can be further assessed in a selected in vivo animal model of pulmonary drug delivery.

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Abstract

La présente invention concerne un procédé à base d'émulsification de membrane de premix, qui utilise de la polyvinylpyrrolidone en tant qu'agent porogène pour la préparation de microparticules poreuses pour des formulations à inhaler destinées à l'administration de médicaments pulmonaires, ainsi que les microparticules et les compositions pharmaceutiques produites ici.
PCT/EP2020/052934 2019-02-13 2020-02-06 Procédé de préparation de microparticules poreuses WO2020165010A1 (fr)

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