EP1673066A2 - Aqueous aerosol preparation - Google PatentsAqueous aerosol preparation
- Publication number
- EP1673066A2 EP1673066A2 EP20040790427 EP04790427A EP1673066A2 EP 1673066 A2 EP1673066 A2 EP 1673066A2 EP 20040790427 EP20040790427 EP 20040790427 EP 04790427 A EP04790427 A EP 04790427A EP 1673066 A2 EP1673066 A2 EP 1673066A2
- European Patent Office
- Prior art keywords
- active ingredient
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL, OR TOILET PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/10—Dispersions; Emulsions
- A61K9/107—Emulsions ; Emulsion preconcentrates; Micelles
- A61K9/1075—Microemulsions or submicron emulsions; Preconcentrates or solids thereof; Micelles, e.g. made of phospholipids or block copolymers
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL, OR TOILET 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
- A61K9/0078—Sprays or powders for inhalation; Aerolised or nebulised preparations generated by other means than thermal energy for inhalation via a nebulizer such as a jet nebulizer, ultrasonic nebulizer, e.g. in the form of aqueous drug solutions or dispersions
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL, OR TOILET PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/10—Dispersions; Emulsions
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL, OR TOILET PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
- A61K9/19—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles lyophilised, i.e. freeze-dried, solutions or dispersions
Aqueous aerosol formulation
Field of the Invention
The invention relates to aqueous preparations for application as an aerosol. The preparations contains active ingredient and can be used pharmaceutically or to promote wellness. More particularly, the invention relates to sterile aqueous preparations for inhalation with a nebulizer system such. B. intended a pump, jet, ultrasonic, vibrating membrane nebulizer or other aerosol generating system for aqueous formulations. It further relates to the nasal or pulmonary administration of physicochemically, organoleptically or physiologically problematic substances. In further aspects, the invention provides methods for preparing such formulations and their uses concerns.
Background of the Invention
The treatment of pulmonary disorders by aerosol allows targeted
Drug therapy, as the active ingredient can be brought directly to the pharmacological target site by means of inhalation devices [D. Koehler and W. Fleischer: Theory and Practice of inhalation therapy, Arcis Verlag GmbH, Munich, 2000, ISBN 3-89075-140-7]. The requirement is that the inhaled droplets or particles reach the target tissue and be deposited there. The smaller the diameter of the aerosol particles, the greater the probability that active agents reach the peripheral lung regions. Depending on the type and extent of the deposition can be by inhalation diseases such. As asthma, chronic obstructive pulmonary disease (COPD) or treat emphysema quasi topically, but also agents such. transfer means mainly alveolar as insulin absorption into the bloodstream. For application of active substances predominantly propellant-driven metered dose inhalers, dry powder inhalers and liquid nebuliser are used today. Fashion scope of the deposition at the destination will depend on the droplet or particle size, the anatomy of the respiratory tract of humans or animals and the breathing pattern. For the deposition of aerosols in the lungs of rodents such. B. rats due to the smaller geometry of the airways is required much smaller droplets than z. As for horses. For lung deposition in adults, the aerosol droplets or particles should have an aerodynamic diameter less than 5 - 6 microns have, for infants less than 2 - 3 microns. Furthermore, infants breathe through the nose, which is why the administration of active agents by inhalation nebulizer systems should be used with nasal mask. This restriction is also true for other species such as rodent. The influences on the aerosol generation and deposition are mainly influenced by three factors, which are as follows divided:
(1) the biologically-physiological factors, which are characterized by:
- the type of breathing maneuvers such as respiratory rate, river for swimming, speed, and volume,
- the anatomy of the respiratory tract, particularly the Glottisregion
- the age and health or disease state of the patient
(2) the droplet or particle spectrum, which in turn is influenced by:
- the nature and structure of the inhaler - the time between generation and inhalation (drying properties)
- the modification of the droplet or Partikeispektrums by the inhalation flow
- the stability or integrity of the aerosol cloud generated
(3) the active ingredient or the active compound preparation, whose properties are affected by: - the particle size
- the dosage form (. Eg solution, suspension, emulsion, liposome dispersion)
- the shape and surface properties of the drug particles and the carrier particles (smooth spheres or folded porous structures) in the case of powder aerosols
- hygroscopicity (influences the growth of the particles) - the interface properties, such as wettability and spreadability
- evaporative and evaporative emissions performance of the carrier medium, the advantages and disadvantages of different inhalers and different ways to compensate the system-related disadvantages have been discussed by M. Keller [Development and Trends in Pulmonary Drug Delivery, Chimica Oggi, Chemistry today, No. 11/12, 1998].
The question of where aerosol particles are deposited in the bronchial tree, is the subject of numerous studies for years. These are complemented by ever-improving
Calculation models of lung deposition. The regional deposition patterns in mouth breathing has a high variability through the breathing maneuvers and the different anatomy of the bronchial tree. The frequently mentioned in the literature respirable size range 0.5 to 6 microns into account neither the overlapping deposition nor the quantitative or relative deposition rates.
At breathing through the mouth in a healthy adult is about 40 - 60% of the particles in the range of 2.5 - 4.5 microns preferably deposited in the alveolar region. A bronchial deposition in the order of about 5-28% have particle 2-8 .mu.m, in parallel to the oropharyngeal deposition increases. The deposition in the oropharynx is for particles of 6 microns been 25 - 45%, and increases to 60-80%. for particles of 10 microns diameter. From this derives that for optimal qualitative and quantitative alveolar deposition in adult, particle sizes of 1, 5 - 3 microns are advantageous if the oropharyngeal and bronchial deposition is to be as low as possible. The bronchial deposition of about 18 - 28% for particles in the size range 6-9 micrometers is relatively low and is always accompanied by a corresponding higher oropharyngeal deposition associated. depending on the
Move disease state, the geometry of the bronchial tree and the age of patients above orders of magnitude, especially in children and babies to smaller particle sizes. In infants less than 1 year is assumed that only droplets and particles with an aerodynamic diameter of less than 2 - 3 microns enter to any significant extent into the deeper regions of the lungs.
is also known for the treatment of sinusitis, that only the smallest aerosol droplets passing through the small ostio in the nasal cavity, with a pulsed aerosol that more active agent can be deposited at the target site than in a continuous nebulization.
The deposition of the aerosol particles in the respiratory tract is essentially determined by the following four parameters: - particle size,
- the particle velocity,
- the geometry of the airways, and
- the inhalation technique and the breathing maneuvers
According to the Stokes' law may be deduced that the flow velocity and density of the aerosol particles are of importance, for which reason used as a measure for the deposition behavior in the respiratory tract of the aerodynamic and not the geometric particle diameter. Various studies it is known that for pulmonary therapy only droplet or particle sizes having an aerodynamic diameter of about 0.6 to 6 microns are suitable. Particles having an aerodynamic
Diameter greater than about 6 microns impaktieren the upper respiratory tract, such smaller than 0.6 micron are exhaled after inhalation. This means that z. B. powder with very low density and an aerodynamic diameter of about 3 microns a geometric diameter of z. B. can have 10 microns larger. By contrast, in aqueous systems having a density of about 1 mg / cm 3 of the geometric and aerodynamic diameters approximately equal.
Composition and form of aerosols are very varied. Aerosols are depending on the composition of short or long service life; their droplet or particle size is subject to changes that are affected by the physicochemical characteristics of the formulation components. Small aqueous droplets evaporate quickly core to a solid depending on humidity, so that the concentration of dissolved substance (s) is in complete evaporation of 100%. The resulting diameter (d 2) from the original diameter (d corresponds to the cube root of the concentration ratio before (c- and after (c 2) shrinkage (density of 1 g / cm 3 for the solute required) according to the formula: d 2 = d 3!> £ & ι / c 2). Thus leads z. B. the drying of surf aerosols by the wind (at a seawater droplets c ^ = 3.6%) of 20 microns to a salt particles with a diameter of approximately 6.7 microns, making it become respirable. This effect is exploited z. B. liquid Vemeblern to shrink by drying effects (eg. B. heating by PARI Therm) or admixing dry air the particle size.
Conversely, particles can grow in a humid environment, and this growth is particularly dependent on the hygroscopicity of the active and / or auxiliary. For example, a dry Natriumchioridpartikel of 0.5 microns requires about 1 second for complete growth, with a 5 micron particles, this takes about 10 seconds which is a proof that the speed with respect to the Partikeiwachstum is also dependent on size. Solid particles from Pulververneblern and MDIs, up to 4 - 5 times increase of its original size, as in the bronchial tree, a humidity of 95 - 100% prevails. (D. Koehler and W. Fleischer: Theory and Practice of inhalation therapy, Arcis Verlag GmbH, Munich, 2000, ISBN 3-89075-140-7).
For toxicological studies frequently rodents and dogs are used. Rodent breathe similar to infants through the nose, which is why the aerosol should be administered using nasal mask in this case, in order to obtain a high lung deposition.
For the treatment of some lung diseases such. B. Asthma are mainly corticosteroids, beta-agonists and anticholinergic agents, which are brought by means of metered dose inhalers, powder inhalers and nozzle or Ultraschallvemeblem directly to the site of action. The pulmonary administration of corticosteroids for the treatment of asthma has been found over oral therapy therefore be particularly advantageous because it can inhibit effectively marked reduction of adverse side effects, the underlying inflammatory process with much smaller drug doses. Agents, such as beclomethasone dipropionate (BDP), budesonide (BUD), and fluticasone propionate (FP) are mainly used as pump sprays for treatment of allergic diseases in the nasal region, while for metered dose inhalers (MDI), dry powder inhalers (DPI), and jet nebulizer used.
For the treatment of children under 5 years no Pulvervemebler are usually because the children are not able to generate the respiratory currents that allow reproducible deagglomerated powder in respirable particles and deposited with sufficient dosing in the lungs can , Metered dose inhalers have the disadvantage that the aerosol at a rate of up to 100 km / h can be released upon actuation of the valve. Due to lack of coordination between triggering of the spray and inhalation impacted more than 90% of the active ingredient in the throat, which may lead to undesirable side effects (hoarseness, voice change, thrush etc.). Furthermore, a cold stimulus can be caused by the evaporation of the propellant gas, which can lead to a closure of the epiglottis or an asthma attack at hyperreagiblen patients, which is why the inhalation of steroids always with intent chambers, so called spacers with about 250 - was 750 ml volume done , For the application of steroids in young children who can not perform mouth breathing, there is for nose breathing -Special Space versions (z. B. Babyhaler ®). but the use of MDIs and spacers is very complex because agents during the inhalation process sediment, adsorb to the spacer walls or charge electrostatically. This can lead to insufficient metering accuracy and irreproducible drug therapy. This is the reason why the nebulization of aqueous preparations by means of nozzles, membrane or Ultraschallvemeblem for pulmonary administration of active ingredients in children and young children to metered dose inhalers and powder inhalers is advantageous if sufficiently small droplets or particles are generated.
Ideal conditions for a therapy by means of nebulization of aqueous formulation is sufficiently soluble in water or isotonic saline and stable drug in which do not change the chemical-physical characteristics in the course of manufacture and storage. If the solubility of the drug, however, too low to produce an aqueous solution of sufficient concentration, the nebulization can be drawn in the form of a suspension into consideration. Breathing simulator means, different nebulization efficiencies are detected for the selected pharmaceutical form (suspension or solution) (deposited dose in the nebuliser remaining drug content etc.). The respirable, so respirable fraction of the generated aerosol can be calculated that by means of laser diffraction or Impaktormessung the percentage of drug-containing droplets having a geometric or aerodynamic diameter of less than 5 or 3 microns, it is determined [N. Luangkhot et. al .; Characterization of salbutamol solution Compared To budesonide suspensions Consisting of submicron and micrometer particles in the PARI LC STAR and a new PARI Electronic Nebuliser (eFlowT). Drug delivery to the Lungs XI, 11 & 12. 12. 2000, p.14 - 17]. In said study it is reported that budesonide-containing suspensions in which the particle size of the suspended drug is significantly smaller than 1 micron, in contrast to a micro-suspension can obscure similar efficiency as a salbutamol sulfate solution. This finding is confirmed by Keller et al. [Nebulizer nano suspension. Important device and formulation interactions, Resp. Drug Delivery VIII, 2002, p. 197-206]. In addition, it is stated that micro suspensions should not be nebulized with an ultrasonic nebulizer. In the case of nebulization of a budesonide suspension (Pulmicort ®) could be detected by ultracentrifugation that approximately 4.6% of the budesonide dissolved in Pulmicort ® molecularly or solubilized form and that only this fraction can be aerosolized by an ultrasonic nebulizer. The currently commercially for nebulisation aqueous corticosteroid preparations are micro-suspensions of beclomethasone dipropionate (Clenil ®), budesonide (Pulmicort ®) and Fiuticason propionate (Flixotide ®), ie, the micronized active ingredient (about 90% of the suspended drug particles are less 5 microns) is finely dispersed and stabilized in water before. The smaller the particle size of the active substance now and the lower the density difference of the active ingredient and the dispersing medium, the longer the active ingredient remains in suspension, that is, the slower is usually sedimentation. the sedimented particles or agglomerates must before use by shaking the packaging material again be finely dispersed to ensure that as little active ingredient remains in the container and the nebulizer can be filled with the declared dose. For this and for better wetting of the lipophilic active surface with water, a surfactant or wetting agent is added usually, this is due to inhalation-safe, however, to avoid unwanted side effects. As an example, Pulmicort ® is to be used, which is three concentrations of 0.5 mg and 1 mg budesonide per 2 ml in the trade. Budesonide is suspended before in saline, buffered with citric acid and sodium citrate, and as a wetting agent polysorbate 80 (= Tween ® 80). The average particle size of 3 tested Pulmicort ® batches was larger than specified (about 2.8 to 3.2 microns) and scattered from 3.7 to 4.4 microns. The different findings may be due to the method of measurement (laser diffraction), but also due to particle growth or particle agglomeration. In a publication by Vaghi et al. [In vitro comparison of Pumicort RESPULES with Clenil ® via aerosol in combination with threee nebulisers, ERS Annual Congress Stockholm, Sept. 14-18, 2002], electron micrographs of Pulmicort ® and Clenil ® were shown from which it appears that the particles are in Clenil ® needle-like and mostly larger than 10 microns, while the Pulmicort ® particles are more rounded and have in the range of about 1 - 6 move microns in diameter. The disadvantage is further that the aerosol characteristics of such micro suspensions may change during nebulization. This can be such. B. derived from the increase in the budesonide concentration in the residual non-nebulized Pulmicort ® suspension. This effect can be explained by the fact inter alia that larger particles can not be transported by aerosol droplets, which have a smaller diameter and, therefore, remain in the nebulizer as a residue. In membrane, the coarse particles are retained by the sieving effect of the aerosol generating membrane. This is not to advocate an economic perspective.
In in vitro studies using a Baby Cast SAINT Model (Sophia Anatomical Infant Nose Throat) has been found that it was possible to demonstrate the use of Pulmicort ® and a jet nebulizer only about 1% of the declared amount of active ingredient as the lung dose. This finding coincides z. T. with clinical findings of pediatricians who report inadequate efficacy of Pulmicort ® Vernebler in infants and explain this by saying that too little active ingredient can be transported into the lungs because both the particles and droplets for toddlers are too big.
A little easier to handle the treatment of the nasal mucosa appears. It is usually possible, already with simple devices for aerosol generation such. B. mechanical sprayers to wet the mucous membrane with an active ingredient preparation. But here provide poorly soluble drugs a challenge. The efficacy of the drug suspensions used in practice in relation to the used amount of active ingredient rather low and unreliable, presumably due to the particularly slow dissolution of the drug in the small liquid volumes on the nasal mucosa available is available to return.
however, is particularly difficult therapy of the mucosa in the less ventilated cavities of the upper respiratory tract already easy to handle drugs, and even more so with poorly soluble active ingredients. In general, only a very small proportion of the dose of a suspended drug in aerosolized form reaches this target tissue.
State of the art
there are a number of proposals on how to solubilize water-insoluble active compounds or can solve in the literature. It was in particular attempts to particulate systems with particle sizes in the nanometer range.
In the publication DE 101 45 361 A1 methods for making nanoparticle systems and a process for preparing a sterile submicron suspension will be described. Although such submicron suspensions of the above reasons, an advance over conventional micro suspensions with particle diameters of approximately 1 - representing 6 microns, they nevertheless have certain disadvantages because even in the presence of a stabilizing surfactant particle growth due to "Ostwald Ripening" during the storage can not be entirely suppressed. Under certain storage conditions, dissolved particles may precipitate and somewhat favor as seed crystals, the particle growth. can not be kept constant three years, classified as critical - but after the particle size of the therapeutic efficiency is of fundamental importance, products whose particle size during common pharmaceutical storage times of 2 are.
In the publication WO 00/27376 nanoparticulate aqueous preparations of active compound for the production of aerosols are described, wherein said drug particle sizes of less than 1000 nm, preferably less than 50 nm. These preparations are prepared oberflächenmodifizeirender means using, which adsorb on the surface of the drug particles. As such means E TPGS is proposed among other vitamin.
In the document RU 1280217 a propylene glycol-containing mixture is described as a solubilizer for the preparation of budesonide-containing aqueous preparations. These
However, preparations have a high viscosity and are hyperosmolar, which is why a non-irritating inhalation treatment is not given, especially since the excipients used so far can not be considered safe inhalation-. The use of propylene glycol leads already at a concentration of about 1% to hyperosmolar solutions that cause a cough after inhalation. Furthermore, they have high viscosities, which is why formulations that were prepared using this adjuvant for inhalation therapy are inappropriate and certainly can not be used with a vibrating membrane because of their physical properties.
In summary, it can be stated that the problem of administration of poorly soluble drugs through nasal or pulmonary administered aerosols could not be solved satisfactorily so far. In particular, the pulmonary administration of such substances to pediatric patients is still extremely problematic in the prior art.
Other types of drugs whose administration by inhalation is not yet satisfactory, such substances represent, which are felt due to their organoleptic properties, particularly their poor taste, or because of their irritate the mucous membranes or coughing or bronchoconstriction inducing properties of the patient to be unpleasant, which can be an obstacle to the adequate compliance with a prescribed therapy and for therapeutic success. Description of the Invention
It is therefore an object of the invention to provide improved formulations for the application as an aerosol, which does not have the disadvantages of the previously known preparations. In particular, it is an object of the invention to enable the inhaled administration of such drugs, which could be administered by inhalation or only in an unsatisfactory manner due to their low water solubility, their bad taste or its mucous membrane irritant properties. A further object is to provide methods for producing such preparations.
The solution of the priority object is achieved according to the invention by a composition according to claim 1. Preferred embodiments of the invention are specified in the subclaims.
It has been found that a combination of a nonionic surfactant and a phospholipid can mediate in aqueous inhalation preparations especially in connection with physiologically or physicochemically problematic substances in an unexpected from a knowledge of the operation of the individual surfactants extent desirable pharmaceutical properties, which run in more detail below become.
The inventive preparations is aqueous preparations. This generic term refers to liquid compositions in which the liquid carrier or solvent consists predominantly of water, and containing in addition to the carrier, at least one further substance, which serves as active or excipient. The liquid state means that it is either a liquid single-phase system or a multi-phase system with liquid phase coherent. The formulations of the invention, therefore, include aqueous solutions, colloidal solutions, suspensions and emulsions. Even if the liquid vehicle consists mainly of water, it may be one or more at least partially water-miscible liquids include, for example, in some cases proportions. Ethanol, glycerol, propylene glycol or polyethylene glycol. According to the invention, however, formulations which are substantially free of such non-aqueous liquids.
In the context of the present invention, the term sterility in conventional pharmaceutical sense, to understand. It is understood as freedom from germs capable of reproduction, and is demonstrated by appropriate tests, as they are binding specified in the applicable pharmacopoeia. According to the current state of science in general contamination rate (Sterility Assurance Level) of 10 -6 as acceptable for sterile preparations is considered, that in a million units could be a unit may be contaminated. In practice, however, the contamination rate is likely to be rather larger. So you go for. B. thereof that, for aseptically manufactured preparations, the contamination rate is expected to be at about 10 "3. Since the one hand, the extent of sterility tests for quality control of lots according to Pharmacopoeia is limited and itself contaminations may be caused as artefacts other hand, in carrying out the tests, it is difficult to demand sterility in an absolute sense as a property or evidence concerning a given subject. Therefore, the sterility of a preparation should especially be understood that the preparation in question meets the requirements of the applicable pharmacopoeia with regard to sterility.
To be suitable for inhalation, preparations must be present as an aerosol or, can be converted into an aerosol according to the invention as provided in situ. Aerosols are commonly referred to as dispersions of liquid or solid particles (= particles) in a gas - usually in air - to define. Aqueous preparations which can be converted for use in aerosols, have - unlike, for. As organic solutions or suspensions in pressure-liquefied propellant gases - are aerosolized in particular nebulizers.
The preparations of the invention are now characterized in that they contain an active agent and a combination of a nonionic surfactant and a phospholipid.
An active substance shall be understood as a substance or mixture of substances here, which can be used for therapeutic, diagnostic, prophylactic or otherwise relevant to the well-being purposes. The active agent may be a chemically defined ( "small") molecule, or a naturally derived peptide, protein or polysaccharide. If the active substance is not a surfactant and preferably not to any other substance which is also commonly used as a pharmaceutical excipient and their effect primarily based on their physicochemical properties.
Surfactants are amphiphilic, to be understood above or surface-active substances. Such compounds have at least one more hydrophilic and at least one more hydrophobic or lipophilic molecule region. They accumulate in phase boundaries and lower the interfacial tension. Surfactants are employed to, among other things, to stabilize multi-phase systems. Nonionic surfactants are those surfactants which in aqueous media at substantially neutral pH values (for. Example, between pH 4 and 10) have no real ionic charge, but at best partial charges. Phospholipids are defined as amphiphilic lipids which contain phosphorus. also known as phosphatides, they play in nature in particular as a bilayer-forming constituents of biological membranes play an important role. Widespread and frequently used also for pharmaceutical purposes such phospholipids are chemically derived from phosphatidic are. In this there is a (usually double) acylated glycerol-3-phosphate in which the fatty acid residues of different lengths can be. The descendants of phosphatidic are for. For example, the phosphocholines or phosphatidylcholines, in which the phosphate group is additionally esterified with choline, furthermore phosphatidyl ethanolamines, phosphatidylinositols, etc. Lecithins are natural mixtures of various phospholipids which have a high proportion of phosphatidyl cholines in the rule.
Suitable nonionic surfactants are in particular those which are to be considered for inhalation as harmless. These mainly include tyloxapol, polysorbate, in particular polysorbate 80, and Vitamin E TPGS. The presently most preferred by the inventors nonionic surfactant is tyloxapol.
Suitable phospholipids are also those that are, due to their physiological properties for administration by inhalation. These include primarily Phospholipidmi- mixtures which are extracted in the form of lecithin from natural sources such as soybeans or egg yolk, preferably in hydrogenated form and / or freed from lysolecithins, as well as purified, enriched or partially synthetically prepared phospholipids, preferably with saturated fatty acid residues. Especially preferred purified, enriched or partially synthetically prepared medium- to long-chain zwitterionic phospholipids which are largely free of unsaturations in the acyl chains and free from lysolecithins and peroxides. Of the phospholipid lecithin is particularly preferred. Examples for enriched or pure compounds are dimyristoyl phosphatidyl choline (DMPC),
Distearoylphosphatidylcholine (DSPC) and dipalmitoylphosphatidylcholine (DPPC). Of these, DMPC is currently the most preferred. Alternatively, phospholipids with Oleylresten phosphatidylglycerols and without choline residue for some embodiments and applications of the invention are suitable.
That the combination of tyloxapol with a phospholipid is pharmaceutically and physiologically acceptable in itself, is inter alia, from the fact that it is contained in the inhalation product Exosurf Neonatal ®. The product is used for the substitution of lung surfactant in acute neonatal respiratory distress syndrome (RDS). Unlike in the inventive preparations Exosurf Neonatal ® contains surfactants other than itself has no other active ingredient in the traditional sense.
In one of the preferred embodiments, the preparation tyloxapol as non-ionic surfactant and lecithin as phospholipid, and in a further preferred embodiment tyloxapol as non-ionic surfactant and DMPC as phospholipid contains.
In some cases it may be advantageous, in addition to the nonionic surfactant and the phospholipid to use another surfactant. It may be a further nonionic surfactant to act another Phopsholipid or an ionic surfactant having no phosphorus. however, it is preferably a nonionic surfactant. Particularly useful are the nonionic surfactants mentioned above.
The invention used according to the invention and surfactant used according to the phospholipid can perform different functions. However, one of the remarkable effects of the combination is their ability to solubilize poorly soluble active agents in colloidal, namely better than by a single one of the surfactants - is possible (see also Example 1) - also with a correspondingly increased concentration within the physiologically yet to be accepted limits.
The use of the surfactant in formulations for inhalation colloidal solubilization of poorly soluble drugs is an important embodiment of the invention. In a preferred embodiment, the preparation is therefore a single-phase system, that is as an aqueous solution. With "single phase" and "solution" are also particularly colloidal solutions meant in which the solutes or some of them not molecularly, but there are in colloidal. Without the inventors to want to limit the validity of certain theories is to assume that form in many cases by the surfactants of the preparations micelles or mixed micelles according to the invention, in which slightly soluble active ingredients can be solubilized. The position of the molecules that are solubilized in such micelles or mixed micelles depends on the structure of these molecules and the surfactants used. For example, it is assumed that especially non-polar molecules, especially in the interior of the colloidal structures are located, while polar substances tend to locate at the surface.
The colloidal systems than can present the single-phase preparations, that contain particles which are located in the middle in the colloidal size range, i.e. below about 1 micron in accordance with generally customary definition, or between 1 and about 500 nm, as described by is defined other sources (H. Stricker, Physikalische Pharmazie, 3rd edition, p 440). So you're using a light microscope virtually untraceable, and not lead to a pronounced turbidity of the solution, but at best a opalescence. Preferably, the single-phase colloidal preparations of the invention contain association colloids having a mean particle size of below 500 nm (as measured by photon correlation spectroscopy). Particularly preferred are colloids with average
Particle size to about 200 nm, and in further preferred embodiments colloids with average particle sizes up to about 100 nm and to about 50 nm are included.
In addition to the micelles, mixed micelles and other colloidal structures in the lower size range, it is also possible that the surfactants form colloids with double membrane structures can exist in which also sparingly soluble active ingredients solubilized. Such colloids occur mainly as liposomes. A process for the preparation and characterization of liposomes and liposome preparations are known in the art per se. Among the known liposomes An average particle size to about 200 nm are those preferred in the invention which have a predominantly colloidal size, that is, whose average particle size is below about 1 micron, more preferably at most about 500 nm or even at most approximately 200 nm. Allowed usually the sterile filtration through a filter having a pore size of 0.22 microns.
Depending on which structures formed and which further pharmaceutical effects are to be achieved, the weight ratio between the nonionic surfactant and the phospholipid must be determined or optimized taking into account the selection of the surfactants. According to the invention preferably has a weight ratio of about 5: 1 to about 1: 2. A particularly good solubilization is usually achieved with ratios of about 3: 1 to 1, 5: 1, that is with a slight excess of the nonionic surfactant, such as about 2: 1 . This is true especially then be selected if the DMPC also preferred as the nonionic surfactant, the preferred and tyloxapol as a phospholipid (or DPPC or DSPC). In particular, sparingly soluble corticosteroids such as budesonide can thereby solubilize surprisingly good.
In preparation, the total content should be limited to surfactant especially for physiological reasons to a maximum value of about 3 wt .-%, when a pulmonary application is provided. In a nasal application of higher amounts of surfactant may be considered such. , Up to about 10 wt .-%. To avoid irritation of mucous membranes, it would be advantageous to restrict the surfactant even possibly no more than about 5 wt .-%. Preferably, however, the preparation in the case of pulmonary application provision contains a surfactant from about 0.01 to 3.0 wt .-%. Particularly preferred are concentrations of from about 0.1 to 2.0 wt .-%. However, the optimum amount of surfactants also depends on the active substance, ie its physicochemical properties and its content into the preparation, as well as the choice of surfactants and the intended effects and
Product characteristics. Is, for example, especially the solubilization of a sparingly soluble active ingredient such as budesonide intended and will be selected in combination with DMPC or lecithin the preferred surfactants tyloxapol, the especially preferred total surfactant is about 1 to 2 wt .-%, in particular about 1.5 wt. -%. If, however, especially to improve the organoleptic properties of the formulation desired, u. U. a significantly lower surfactant sufficient and therefore be pharmaceutically advantageous z. As a content of not more than about 1.0 wt .-%, and better yet not more than about 0.5 wt .-%.
As already mentioned, of course, also the active ingredient content consideration must find. Very low-dose active compounds can tend to solubilize at lower surfactant levels both also mask the taste. In addition, lower amounts of surfactant are sufficient to mitigate the irritate the mucous membranes, coughing and bronchospasm inducing properties of drugs. A preferred weight ratio between surfactant content (ie total content of surfactant and phospholipid) and active ingredient content is at least about 1: 1, more preferably at least about 5: 1. For the solubilization of certain sparingly soluble active compounds can even ratios greater than 10: 1 is required. Thus, in a preferred embodiment for the solubilization of the sparingly soluble active ingredient budesonide a ratio of about 50: select 1: 1 to 100th However, significantly lower surfactant-drug ratios can usually be sufficient, if desired any colloidal solubilization of the active ingredient or is required and the surfactant is mainly used for masking undesirable organoleptic or physiological properties of the active substance or to improve the spreading of the aerosol in the respiratory tract.
In the selection of surfactants, the surfactant and the ratio thereof to the active ingredient content, the effect on the physicochemical properties of the preparation must be kept in mind, of course, important for the nebulization to an inhalation aerosol administrable. Chief among these are the surface tension and the dynamic viscosity.
The surface tension should be set in particular for the pulmonary application so that it is about 25 to 80 mN / m, preferably about 30 to 75 mN / m. It should be noted that in the lowest part of this interval a particularly good spreading of the preparation is to be expected in the respiratory tract, but that the quality of the aerosol and the efficiency of nebulization may suffer. On the other hand, it can be in the use of surfactants, which is necessary for the colloidal solubilization of a sparingly soluble active ingredient, difficult to avoid that the surface tension is quite far reduced below that of water or physiological buffer solution. Sun can be found in each case a compromise has to be adjusted depending on the drug and intended use. Specifically, for the solubilization of poorly soluble active agents have a surface tension in the range of about 30 to 50 mN / m is particularly preferred.
The dynamic viscosity also has a significant influence on the
Particle size distribution of produced during nebulization and aerosol to the Verneblungseffizienz. You should be adjusted to about 3 mPas ranging from about. 1 Particularly preferred is a dynamic viscosity in the range of about 1, 0 to about 2.5 mPas.
As mentioned previously, aqueous preparations according to the invention for the application are to be applied as an aerosol, in situ - that is, immediately in the application - is generated by a suitable device. Common types of nebulizers with which such formulations can be aerosolized, have already been presented above. For some time jet nebulizer be used in therapy, more recently, ultrasonic nebulizer. Recently, efficient nebulizer were developed, named the operating principle based on their piezoelectric, electro-hydrodynamic and / or on a vibrating membrane or with pores (z. B. eFlow ™, eFlow Baby ™, Aeroneb ™, Aero Box ™ or AERx ™) are. The different mechanisms of aerosol generation lead to differences in the Verneblungsqualität for certain preparations.
The formulations of the present invention are in particular the requirements of the nebulization by working with vibrating porous membranes nebulizer (vibrating membrane) turned off. A particularly preferred nebulizer, the preparation should be for its use, the eFlow ™ Pari GmbH. This nebuliser and the devices of a similar type are particularly suitable for modern aerosol therapy: they are small and obscure relatively large volumes of liquid within a short time usually executed in high quality aerosols. Of course, these nebulizers have limitations or application problems such. As when it comes to the nebulization suspensions of poorly soluble active ingredients. Characterized that it comes through the pores of a vibrating membrane in the aerosol generation to an extrusion of the inhalation liquid, larger solid particles of an aerosolization either completely excluded (when their diameter is at least about as large as the pore diameter) or lead - at particle sizes in the lower micrometer range - at least to a more or less pronounced sieve effect. This results in a reduced active ingredient content in actually delivered by the nebulizer and available for inhalation. For the administration of poorly soluble active agents with such nebulizers, the present invention is particularly advantageous: Thus, these active compounds can rather than be microsuspension now formulated as a colloidal solution and inhales what the sieving effect virtually eliminated through the pores of the membrane or at least significantly reduces.
In another embodiment of the invention is the preparation for the treatment of the oral or nasal mucosa such. As determined in allergic rhinitis, vasomotor rhinitis, nasal polyps, or inflammatory diseases of the oral mucosa. For this application, in principle, very simple devices can will used to generate the aerosol, eg. B. mechanical sprayers, as they are often used for oral or nasal spray. Alternatives include jet, ultrasonic or piezoelectric
used vibrating membrane, which are necessary in the case of nasal administration to adapt accordingly.
In another embodiment, the preparation for the treatment of mucous membrane of the incidental, pine or sinus is determined. These mucous membranes of the aerosol therapy are generally accessible. However, the efficient application of an aerosol is difficult and with the ordinary nebulizers hardly feasible due to low ventilation of these cavities. The simple nasal inhalation of an aerosolized preparation of active compound performs these namely in the proximity of the sinuses, however, the aerosol stream passes predominantly the openings (ostia) to the sinuses, without a substantial proportion of the aerosol enters the Nebenhöh-Ien. On the other hand, just the face and sinuses are very often the place of inflammatory processes that can be treated with budesonide.
Recently, however, specially adapted jet nebulisers are available with which the sinuses can be reached much better than previously. This nebulizer one hand, have a nose piece for directing the aerosol current into the nose. If only one nostril is used for inhalation of the aerosol, the other must be closed by a suitable device. Furthermore, these nebulisers are characterized in that they can ausstömen an aerosol with pulsating pressure. The pulsating pressure meantime ensure an intensified ventilation of the sinuses so that a simultaneously inhaled aerosol can better distribute into these cavities. Examples of appropriate Verneblervorrichtungen are disclosed in DE 102 39 321 B3. In one of the preferred embodiments, the preparation of the invention for the manufacture of a medicament for the application is used with the aid of one of the devices described therein for the treatment of upper respiratory tract infections, in particular with a device of the type PARI Sinus.
In the sense of a compatible aerosol, the preparation should be adjusted to a physiologic tonicity or osmolality possible. So desirable is an osmolality of physiological fluids, that does not deviate too much from that of about 290 mOsmol / kg. But here compromises between the physico-chemical or pharmaceutical needs on the one hand and the physiological needs on the other have to be made in individual cases again. In general, an osmolality is in
Range of about 200 to 550 mOsmol / kg, and especially in the range of about 230 to about 350 mOsmol preferable / kg for the inventive preparations.
If the required or desired osmolality is not reached by the drug contained in the preparation and the surfactants, it may be adjusted by the addition of one or more suitable osmotically active excipients to the desired value. Such excipients are mainly harmless mineral salts that react broadly neutral (unless, except where such aids are to adjust the pH simultaneously or buffer) such. For example, sodium, calcium or magnesium chlorides, sulfates or phosphates. One of the particularly preferred excipients is sodium chloride. Other preferred excipients for this purpose are magnesium and calcium sulfate and chloride. It is known from these calcium and magnesium salts that they may have a positive or supportive effect in the inhalation of drug solutions, possibly because they themselves counteract the local irritation caused by the application and have a bronchodilatory effect, which currently in the clinical literature is postulated (for example R. Hughes et al, Lancet 2003; 361 (9375):... 2114-7). Especially magnesium sulfate has excellent pulmonary compatibility.
As an alternative to the neutral mineral salts, physiologically acceptable organic excipients can be used as isotonizing agent. Particularly suitable are water-soluble substances with a relatively low molecular weight, z. As having a molecular weight of less than 300, or even better less than 200, and with a correspondingly high osmotic activity. Examples of such excipients are sugars and sugar alcohols, in particular trehalose, mannitol, sorbitol and isomalt.
In the sense of a compatible aerosol, the preparation according to the invention should be set to a euhydrischen pH. The term includes euhydrisch already that, in turn, can exist a tension between pharmaceutical and physiological requirements, so that a compromise must be found, the z. B. still be guaranteed sufficient in economic terms stability of the formulation during storage, on the other hand largely tolerated. Preferably, the pH is in the slightly acidic to neutral range, ie between pH values from about pH 4 to pH 8. It must be noted that variations may be more easily tolerated for weakly acidic medium than shifts of the pH value in the alkaline range inside. Particularly preferred is a pH ranging from about 4.5 to about 7.5.
To adjust and possibly buffering the pH again physiologically largely acceptable acids, bases and salts in question. Suitable excipients for lowering the pH value or as acidic components of a buffer system are strong mineral acids, particularly sulfuric acid and hydrochloric acid. Furthermore come moderately strong inorganic or organic acids and acid salts in question, eg. However, phosphoric acid, citric acid, tartaric acid, succinic acid, fumaric acid, methionine, acidic hydrogen phosphates with sodium or potassium, lactic acid, glucuronic acid, etc. Most preferred are sulfuric acid and hydrochloric acid. For raising the pH value or as basic components of a buffer system are particularly suitable mineral bases such as sodium hydroxide or other alkali and alkaline earth metal hydroxides and oxides such as in particular magnesium hydroxide and calcium hydroxide, ammonium hydroxide and basic ammonium salts such as ammonium acetate, as well as basic amino acids such as lysine , carbonates such as sodium or magnesium carbonate, sodium hydrogen carbonate, citrates such as sodium citrate, etc.
In a preferred embodiment, the preparation according to the invention contains a buffer system of two components, and one of the particularly preferred buffer systems contains citric acid and sodium citrate.
Not primarily for physiological, but from pharmaceutical considerations, the chemical stabilization of the preparation may be indicated by other additives. This depends mainly on the type of active ingredient present. Among the most common degradation reactions of chemically defined substances in aqueous formulations are especially hydrolysis reactions which are limited primarily by an optimal pH adjustment and oxidation reactions. Examples of active agents that are oxidatively vulnerable are those which olefinische-, aldehyde, primary or secondary hydroxyl, ether, thioether, enediol, keto or amino groups. Therefore, in such oxidation-sensitive active ingredients, the addition of an antioxidant or synergistic with an antioxidant excipient may be advisable or necessary. Antioxidants are natural or synthetic substances, which can prevent or interrupt the oxidation of the active ingredients. These are primarily adjuvants which are themselves oxidized and act as reducing agent such as tocopherol, reduced glutathione, catalase Peroxidbismutase. Synergistic substances are. For example those which may not occur directly as reactants in oxidation processes, but by an indirect mechanism such as the complexation of metal ions which act catalytically in the oxidation, which counteract oxidation, as shown (for example, EDTA derivatives, EDTA: Ethylenediaminetetraacetic acid ) the case is. Further suitable antioxidants are ascorbic acid, sodium ascorbate and other salts and esters of ascorbic acid (for. Example ascorbyl palmitate), fumaric acid and its salts, malic acid and its salts, butyl hydroxy anisole, propyl gallate, as well as sulphites such as sodium metabisulfite. Besides EDTA and its salts also optionally act citric acid and citrates, malic acid and its salts and maltol (3-hydroxy-2-methyl-4H-pyran-4-one) as a chelating agent.
In one of the preferred embodiments, the composition comprises at least one antioxidant. In another embodiment, it contains both an antioxidant and a chelating agent. Particularly preferred is the combination of a vitamin E derivative, in particular Vitamin E acetate, with an EDTA derivative, in particular sodium edetate. Is This combination has proven to be particularly advantageous for obtaining a high chemical stability and durability of the preparation of certain drugs. Especially in combination with the active ingredient budesonide this adjuvant combination is preferred.
As mentioned above, the inventive combination of a nonionic surfactant and a phospholipid has a markedly high ability to solubilize poorly soluble active agents in colloidal. It is likely that this form micelles or mixed micelles with lipophilic core and a hydrophilic outer region. A particular advantage of colloidal solutions such as these is that they as preparations for inhalation better (ie without high
Drug losses in nebulizer) can be aerosolized and that aerosols of finer droplet size can be produced than z. As in the case of micro suspensions is the case.
An aerosol with a low mean particle size or with a large proportion of droplets in the lower micrometer range is particularly important if an inhalation into the deeper regions of the respiratory tract, that is intended to get into the fine branches of the bronchioles or even in the alveoli. It is also particularly important and advantageous when it comes to children's concerns in those patients in which the corresponding anatomical structures are formed significantly smaller than in adults. In one of the preferred embodiments, the preparation is therefore intended for use on children, making infants, toddlers, children and adolescents are meant. In particular, the provision for use on infants and young children is preferred.
A further advantage of the micellar and mischmizellaren solutions is that they can be filtered through a membrane filter having a pore size of 0.22 microns to remove any existing germs (sterile filtration). This method of sterilization is always particularly important when a heat or radiation sterilization of chemical or physicochemical considerations does not seem possible or not favorable.
The recoverable by the inventive surfactant advantage of colloidal solutions to micro suspensions such. As Pulmicort ® suspension for inhalation is thus obvious. Accordingly, the active ingredient is a poorly soluble in water active agent in a particularly preferred embodiment. Among sparingly water-soluble active ingredients such substances are to be understood that in aqueous media at room temperature and substantially neutral pH, such. B. to pH 10, in particular at pH 5 to 8 are sparingly soluble in pH. 4 Sparingly soluble in this context means that the solubility of an active substance is so small that at least 30 parts water to the solution of a part of active ingredient are necessary. This corresponds to substances called "practically insoluble" the terms commonly used "sparingly soluble", "slightly soluble", "very slightly soluble" and "insoluble" are attributable. Under poorly soluble active agents also poorly soluble active derivatives or salts of active ingredients are to be understood, of which certainly more soluble salts or derivatives exist. Especially advantageous is the invention in the formulation of active ingredients which have a saturation solubility in water at room temperature of not more than about 0.1 wt .-%. Furthermore, agents of the categories "very slightly soluble", "practically insoluble" and "insoluble" are particularly preferred.
In a further preferred embodiment, there is a sparingly soluble active substance which, from the group of corticoids, betamimetics, anticholinergics, anesthetics
Immunomodulators and anti-infectives including antibiotics, antivirals and antifungals is selected. A particularly preferred poorly soluble active ingredient is budesonide.
The content of the sparingly soluble active ingredient is usually not more than about 2 wt .-%, preferably in the range of about 0.01 to 1, 0 wt .-%. In the case of budesonide is a colloidal solution having an active ingredient content of about 0.15 to 0.35 mg / ml particularly preferred, and especially with a content of about 0.2 mg / ml. In this embodiment, a physiologically well-tolerated preparation is provided which, in contrast to the previously known budesonide preparations for inhalation with modern nebulizers, even from those who work with a porous, vibrating membrane quickly clouded, efficiently and without any major drug losses may, at such fine, high-quality aerosols, which are also suitable for pediatric use.
About the advantages described for the formulation of poorly soluble active agents addition, the inventive preparations, however, offer additional benefits and
Applications. Thus, the inventors have found by experiments subjects that preparations with a combination of a nonionic surfactant and a phospholipid, surprisingly, able to mask the taste of active ingredients in ski real inhalation. A pronounced bad taste is in the inhalation of aerosols extremely unpleasant and disturbing, and it can lead to noncompliance and treatment failure. The bad taste is perceived by the patient on the part of the aerosol, which is reflected in inhalation of the mouth and throat. Although can be achieved by optimizing the particle size of the aerosol that a minimum proportion of the preparation is reflected there - this goes also lost for therapy, unless the lining of the mouth, throat or nasal cavity, the tissue to be treated - it is difficult to achieve with today's means that this share is so far reduced that the bad taste of a drug is therefore no longer perceived. In this respect, a mask the taste, which is mediated by the combination of excipients in the preparation, particularly advantageous.
Accordingly, the preparation of the invention in a further preferred embodiment contains a bad tasting active ingredient. A bad taste can have different forms, all of which are included here, for example. B. sour, hot, metallic, biting, evil, corrupt, anesthetic, etc. The agent with bad taste can - in contrast to other embodiments of the invention - be any water solubility. Preferably, the active substance belongs to the group of corticoids, betamimetics, anticholinergics, anesthetics, and anti-infectives. A preferred drug in this context is the antibiotic tobramycin including its salts and other derivatives.
A bad Wirkstoffgesehmaek sometimes goes -jedoch not necessarily - associated with mucosal irritation caused by the substance. In this case occur at different levels, which can lead to cough, coughing, bronchoconstriction and bronchospasm in the case of inhalation of a slight irritation of the pharynx and / or the airways. The -durchgeführten by the inventors inhalation experiments with such substances indicate surprisingly suggests that these adverse effects can be mitigated by the inventive design of the preparation or concealed. In a further embodiment of the invention, the composition therefore contains a mucosa irritating or cough or bronchoconstriction-inducing agent. This ingredient can be any water-solubility. such active substances derived from the group of corticoids, betamimetics, anticholinergics, anesthetics and anti-infective agents are preferred in this connection again.
An especially preferred active ingredient is the antibiotic tobramycin including its salts and derivatives. From this drug is known to cough and
, Can trigger bronchoconstriction, when applied in the form of the previously known preparations.
Further preferred active ingredients which are partially attributable to the already defined criteria of preference for the information contained in the formulation agents are selected from the group consisting of corticosteroids, beta-sympathomimetics, anticholinergics, anesthetics, immunomodulators, antiinfectives, angiotensin converting enzyme (ACE) inhibitors, cytostatics, insbedondere budesonide, ciclesonide, fluticasone, mometasone, beclomethasone, flunisolide; Formoterol, salmeterol, levalbuterol; Thiotropium, oxitropium, ipratropium; Lidocaine, prilocaine, mepivacaine, bupivacaine, articaine, cyclosporine, tacrolimus, sirolimus, rapamycin, azathioprine; Ciprofloxacin, Moxifloxacin, azithromycin, clarithromycin, erythromycin, metronidazole, ketoconazole, itraconazole, voriconazole, Clotrimazoi, bifonazole, fluconazole, amphotericin B, natamycin, nystatin, amikacin, acyclovir, famciclovir, valaciclovir, didanosine, saquinavir, ritonavir, lamivudine, stavudine, zidovudine , Ribivarin, captopril, lisinopril, perindopril, trandolapril, cilazapril, carmustine, lomustine, taxol, etopside, cisplatin; Acetylcysteine, N-acetyl cysteine, reduced glutathione, TNF-alpha-antibodies including the pharmaceutically acceptable derivatives of these substances such. For example, the salts, conjugates, enantiomers, racemates, epimers, diastereomers, or a complex of these agents.
In a further embodiment, the composition comprises at least one further active ingredient. This can be advantageous for example in the treatment of asthma, if more than one active ingredient has to be inhaled for therapeutic reasons and the patient the application with the least possible amount of time to be made possible. Important combinations of active substances in this connection are such. B. (a) a beta-mimetic and a parasympatholytic, (b) a beta-mimetic and a corticoid, and (c) a parasympatholytic and a corticoid. Other combinations offer with mast cell stabilizers such as cromolyn or nedocromil in including their therapeutically usable salts. Combinations of antibiotics and bronchodilators and mucolytic can be useful. In principle, useful is the addition of physiologically acceptable and well tolerated antioxidants such. As tocopherols, catalase, Peroxidbismutase as these radical oxygen, which is responsible many inflammatory processes intercept or reduce.
In addition to therapeutic agents and such agents may be selected which are to serve primarily diagnostic, prophylactic or welfare-enhancing purposes. Accordingly, a composition of the invention for therapeutic, diagnostic and prophylactic applications may be determined. Particularly preferably, the determination for therapeutic application.
Regardless of whether therapeutic, diagnostic, or prophylactic effect is intended, the active ingredient can be administered in the form of the preparation according to the invention to its effect locally (eg. As in the nose, throat or the bronchial tubes) at or near the to unfold lining of the respiratory tract, or it can be achieved a system Siche effect after absorption into the bloodstream. A more local effect is, however, are in the treatment of respiratory diseases of the upper and lower respiratory tract in the foreground.
Particularly advantageous is the use of the preparation of the invention for preparing medicaments which are employed for the prophylaxis or treatment of bronchial or pulmonary diseases or symptoms, z. B. of bronchial asthma or chronic obstructive bronchitis. In this case, the preparation is preferably intended for inhalation with a jet, ultrasonic or piezoelectric vibrating membrane, z. As with a PARI eFlow ™ or - in the case of pediatric use - a eFlow Baby ™.
Likewise, the preparation of the invention for preparing medicaments can be used which are to be used for the prophylaxis or treatment of diseases or symptoms of the mucous membrane of the frontal, pine or sinuses, z. Example of acute and chronic sinusitis or polyp. For this use, it is advantageous if the application of the preparation using a Düsenvemeblers such. As the PARI Sinus happens, which is specially adapted for this application. Such suitable nebuliser the one hand have a nose piece for directing the Aerosoistroms in the nose. If only one nostril is used for inhalation of the aerosol, the other must be closed by a suitable device. Furthermore, these nebulisers are characterized in that they can ausstömen an aerosol with pulsating pressure. The pulsating pressure waves provide an intensified ventilation of the sinuses so that a simultaneously inhaled aerosol can better distribute into these cavities. Examples of appropriate Verneblervorrichtungen are disclosed in DE 102 39 321 B3.
Alternatively, the use of the preparation of the invention for preparing medicaments which are intended for the prophylaxis or treatment of diseases or symptoms of the mucous membrane of the mouth and / or nasal cavity, z. B. stomatitis, aphthous ulcers, allergic rhinitis, vasomotor rhinitis, chronic rhinitis, or polyps. In this case, the application can be carried out by a device with a mechanical atomizer, as it is frequently used in a nasal or oral spray, or by a possibly adapted jet, ultrasonic or Schwingmembranverneblers.
The production of the preparation is done by a combination of known process steps which select in each case in the light of the specific requirements of the active substance and the desired product properties and be adjusted if necessary. In addition to general pharmaceutical requirements that apply to all pharmaceutical preparations, the special requirements for preparations for inhalation should be considered. The preparations must therefore be sterile free of viable None of what needs to be assured by careful selection and execution of the process steps. Additional requirements may arise from specific application requirements. If z. B. is determined, the preparation for inhalation using a nebulizer of the type of operating with porous vibrating membranes a device that requires the preparation process, inter alia, to ensure that the size of the active ingredient particles - if present - in fact be below the threshold above which an undesired sieving effect occurs.
If it is, the composition is an aqueous solution, which, for the forth above sense, colloidal, ie for. B. micellar or mischmizellare solutions are to be understood, and if it no heat sterilization in the final is possible due to the physical or chemical thermal instability of the preparation or of individual components, the sterile filtration provides as sterilization procedures. Even if it is in the preparation of an aqueous suspension such as a micro-suspension, a final sterilization can be critical, as they significantly alter the particle size distribution of the suspension particles and thereby influence important properties of the preparation can. In the case of solutions and colloidal solutions of the preferred manufacturing method may include the steps of:
(A) providing the intended ingredients;
(B) preparing an aqueous liquid composition from the ingredients provided;
Preparation (c) sterile filtration in step (a) above; and
(D) filling in step (b) sterile-filtered preparation in sterile containers under aseptic conditions.
In a variant of the preparation, the ingredients in step (a) are provided in sterile condition in order to limit the output bioburden of the formulation. Can not be provided all the starting materials in a sterile condition, should be pre-sterilized least ones where this is possible without quality deterioration.
The aqueous preparation of the intended ingredients or starting materials of step (b) can take place in several partial steps. For instance can. B. be carried out first preparing an aqueous solution (optionally colloidal solution) of the nonionic surfactant and the phospholipid as well as possibly further adjuvants. To form a homogeneous colloidal solution, it may be advantageous for this purpose to apply a process step at a relatively high energy input, z. B. a homogenization under high pressure (high pressure homogenization), sonication or heating to about 45 ° C to about 50-70 ° C or even to even higher temperatures. To reduce the bacterial load and to increase the effectiveness of subsequent germ reduction measures should be possibly worked with sterilized or low-germ raw materials and possible under aseptic conditions. Furthermore, it might be appropriate to subject these colloidal adjuvant solution prepared in a first partial step of the method step (b) a heat sterilization process.
the active ingredient in the thus prepared colloidal solution would then dissolve in a further sub-step, possibly again under aseptic conditions. This is preferably done without any use of crushing method in which solid drug particles are mechanically divided. Rather, it is preferred that an energy input at this stage - if necessary - is carried out by heat or possibly by sonication. In many cases, however, the incorporation of active ingredients by stirring alone, even the colloidal dispersion of poorly soluble drugs into micelles or mixed micelles into it succeeds.
In an indirectly or directly following process step, the previously prepared, sterile active substance-containing solution or colloidal solution, that is through a filter - z. B. a membrane filter - having a pore size of about 0.22 um filtered, if necessary with application of pressure to remove the germs and particles contained in the solution. Suitable sterile filtration processes are known in principle in different variants, together with the equipment usable for this purpose in the art.
In another, indirectly or directly following process step, the previously sterile-filtered solution or colloidal solution under aseptic conditions in the
Primary packaging, that is filled into the final containers, which are then sealed. Also for this process step, the appropriate versions and devices are known per se.
In the primary packaging, it may be glass containers (z. B. vials) with closure devices made of elastomers and metal safety caps, alternatively, plastic or blister IALS primary packaging systems. A single primary packaging may each contain a single dose or a multiple thereof. In all cases, however, where heat sterilization of the preparation is possible and will not cause a significant loss of quality, a method is preferable, which includes the final sterilization of the preparation, instead of the sterile filtration by a pharmacopeia compliant heat sterilization process after its filling in the primary packaging.
Suitable primary packaging made of plastic are, for. B. polypropylene or polyethylene vials (PP / PE vials) and cycloolefin copolymer blister (COC blister). Sealed plastic containers such as PP or PE vials can be advantageous beipsielsweise with the blow-fill-seal process forms in an integrated process, filled and sealed. The containers thus prepared are insbereonder suitable for liquid products with a volume from about 0.2 ml. Particularly patient-friendly, they can be formed with a closure which is removable by twisting or kinking. The resulting opening through which the liquid content is removed, can be designed so that they fit on a luer connection or luer lock connector. Thus, the opening may be round and have a diameter which substantially corresponds to the outer diameter of a male luer connector. In this way, an ordinary syringe luer connector could be connected positively with the container to accommodate, for example, the contents of the container and to transfer in a nebulizer or the contents of the container to mix with the contents of the syringe and then to a nebuliser to give. Ais a further alternative, it can be provided that the plastic container is such that it is substantially fitting manner after removal of the closure element with a provided for the supply of liquid connector of a correspondingly adapted nebulizer, whereby a direct filling of the preparation allows the reservoir of the inhaler is.
Plastic containers of this kind are also advantageous continue because they can be easily provided with embossing. This makes it possible to dispense with paper labels on the one hand, which is desirable to prevent migration of constituents of the adhesive, the paper or the printing ink through the container wall in the preparation. On the other hand important information can be made available by such an embossing visually impaired patients. The embossing can contain various information, such. For example, a batch number, an expiration date, a product, instructions for use, or one or more volume or dosage markings. In particular for pediatric patients, where often a flexible dosage by age or body size is desirable, a plurality of volume markings can be used to facilitate removal of the desired dose, without further aids, increasing the risk of medication error can be reduced.
To increase the Lagerungsstabilitat it may be advantageous to subject the preparations of freeze-drying described above, according to the invention to store them in the solid state. The required for nebulization liquid form can it be restored by mixing with sterile water just before Anendung. Therefore, a solid composition is provided according to the invention, which is obtainable by freeze-drying of the formulations of the invention described above. The methods of freeze drying are known in the art as such.
The following examples serve to illustrate the invention; however, they are not meant to be exclusive design variants. Example 1: Solubilization of budesonide with tyloxapol and DMPC
buffered, aqueous solutions of tyloxapol, DMPC and tyloxapol were prepared in a mixture with DMPC. In these, the saturated solubility of budesonide was measured by added an excess of budesonide and treated the respective approach with heat and ultrasound, and was then allowed to stand for equilibration. The equilibrated mixtures were filtered through a membrane filter with a pore size of 0.22 .mu.m and the Budesonidgehalt determined in the filtrate. In Tab. 1 Selected results from these experiments are shown. The saturation concentration of budesonide in DMPC solution could not be increased, moreover, by further increasing the DMPC content.
Tyloxapol [wt .-%] DMPC [wt .-%] Budesonide [.mu.g / ml] 0 1 20 1 5 0 204 1 0.5 268
Example 2: Preparation of a sterile colloidal solution of budesonide
Budesonide is an example of a poorly water soluble drug which may be formulated by the inventive combination of surfactants advantageously as a colloidal aqueous solution.
The starting materials referred to in Table 2 were provided in the amounts indicated. In the water for injection, the starting materials specified except budesonide was first dissolved by stirring with a magnetic stirrer or dispersed. Subsequently, the batch with a high-pressure homogenizer for 10 minutes at 1500 bar was homogenized. As a result opalescent colloidal solution having a pH of about 4.5.
In this solution provided 200 mg of budesonide previously been given. This mixture was heated to about 60-70 ° C and this was sonicated for about 30 min. Subsequently, the mixture was cooled with stirring using a magnetic stirrer at room temperature. Evaporated water was replaced by a corresponding quantity of water for injections. In this way, an opalescent colloidal solution. This was then manually sterilized under a laminar flow box with sterile equipment through a membrane filter with a pore size of 0.22 .mu.m, and filled into provided, sterile vials made of glass. The vials were aseptically sealed, stored at various temperature conditions and checked decomposition products and physical parameters related to different time intervals.
The characterization of the charged preparation gave a Budesonidgehalt of 202.34 g / ml, a surface tension of 38.8 mN / m, a dynamic viscosity of 1, 07 mPas, an osmolality of 0.282 Osmol / kg and a pH of 4, 25 at 21.8 ° C. The measured by photon correlation spectroscopy at a 90 ° angle mean size of the colloidal particles was 13.1 nm (expressed as z-average) and indicates micellar structures.
The advantages of such a colloidal solution of the active substance budesonide are particularly evident when compared with the commercial product Pulmicort ® suspension having a mean particle size of about 4 microns. The colloidal solution is solution-typical behavior in contrast to the suspension and can obscure much better. The benefits and advantages of the colloidal budesonide solution according to the invention are particularly evident in the treatment of asthma and chronic obstructive bronchitis in children and infants.
Figure 1 shows for the colloidal budesonide solution (here as "Bude Flow ™") in-vitro using a respiratory replica of a 9 month old baby (Sophia Anatomical Infant Nose Throat = SAINT-Model) significantly improved lung deposition and lower unwanted nasal or oropharyngeal deposition than the Pulmcort ® suspension ( "Pulmicort"), as can be seen from the percentage ratio of the lung dose for "guest deposition". In these studies, two different nebulizers namely the jet nebulizer PARI LC PLUS ® and the piezoelectric nebuliser PARI eFlow ™ baby were used. the drug doses used for the nebulization are further indicated in the legend. Percentage deposition details are given in Table 3. In vivo studies with radiolabeled budesonide confirm the better deposition of the colloidal budesonide solution according to the invention in comparison to the suspension.
The colloidal solution may also be in the form of preservative-free nasal sprays or other application devices such as a compressor working with a pulsating jet nebulizer such. be as the PARI SINUS ™, used and used therapeutically for nasal treatment of paranasal and / or Stirnhöhlentzündungen or allergic rhinitis.
Example 3: Preparation of a budesonide formulation for nasal application of 3.75 g tyloxapol were weighed into a 1000 ml beaker. For this purpose 486.0 g of water were added for injections and (stirred 20 ° C) until complete dissolution of the tyloxapol stirred at room temperature. To the resulting solution were added 4.23 g of sodium chloride, 0.2 g of citric acid and 0.25 g sodium citrate. After dissolution of all components of the pH of the solution was adjusted to 4.3 by addition of sodium citrate. 7.5 g Lipoid PC 14:14 (dimyristoylphosphatidylcholine) were added to the solution and using an Ultra-Turrax at 11000 U / min homogenised (5 minutes). The formulation was homogenized at 1500 bar for 20 minutes followed by Hoehdruckhomogenisation (Microfluidies M100EH). The resultant solution exhibited slight opalescence which is after 12 hours almost disappeared on the magnetic stirrer.
After addition of 400 .mu.g / ml budesonide, the formulation was once again homogenized (Ultra Turrax followed by Hoehdruckhomogenisation), after another 12 hours of standing time on the magnetic stirrer, the now slightly opalescent preparation through a 0,22μm membrane filter was sterile filtered under aseptic conditions and (in Pumpzerstäuberflaschen 100 .mu.l / hub) bottled.
The final budesonide-containing formulation exhibited the following physico-chemical characteristics: pH value of 4.3 at 22.7 ° C, a dynamic viscosity of 1, 16 mPas, a surface tension of 40.6 mN / m and an osmolality of 0.262 osmol / kg.
Example 4: Preparation of a sterile solution of tobramycin
Tobramycin is an example of an active agent with bad taste, which can cause coughing and bronchoconstriction.
There was prepared an opalescent colloidal solution of 0.45 g of DMPC, 0.91 g tyloxapol, 0.225 g of sodium chloride in 89.59 g of water for injections accordingly provided amounts. This was done as in Example 2, that is, the mixture was first homogenized under high pressure without the active ingredient at 1500 bar. In this solution 5.41 g of 96% sulfuric acid were added and 10.88 g of tobramycin. It first came to precipitate. The mixture was then stirred for 24 h at room temperature with a magnetic stirrer, thereby forming a clear again, optionally colloidal solution sterile and transferred as described in Example 2. FIG. _ The characterization of the charged preparation gave a pH of 6.23 at 21, 8 ° C, a dynamic viscosity of 2.07 mPas, a surface tension of 36.5 mN / m and an osmolality of 0.229 Osmol / kg.
Example 5: Preparation of a sterile solution of lidocaine in a solution of the ingredients shown in Table 2 (without budesonide) were incorporated 0.55% (w / v) lidocaine base. After a sterile filtration, the colloidal solution was in single-dose containers pre-sterilized (0.5 to 3 ml) of glass and fills polypropylene. In inhalation studies showed that the unwanted in this connection local anesthetic effect of lidocaine was reduced. Example 6: Preparation of a sterile solution of cyclosporin
This example describes the possibility to solubilize the water insoluble immunomodulator cyclosporine according to the invention.
The starting materials referred to in Table 4 were provided in the amounts indicated. Cyclosporine is first suspended in propylene glycol or dissolved. This mixture is mixed with aqueous buffer solution containing the amounts of tyloxapol, DMPC and NaCl listed in Table 4, and made up with water for injections ad 100 ml. is filled 3 ml single dose containers of glass or polypropylene - by Hoehdruckhomogenisation, as described above, a colloidal solution after sterile filtration through a 0.22 micron filter into presterilized 0.5 is formed. The Cyclosporingehalt of the resulting formulation is 570 ug / ml.
The determined by photon correlation spectroscopy average particle size (z-average) of this colloidal dispersion is 9.7 nm.
Example 7: Preparation of combination products
Combinations of steroids, such. B. budesonide with water-insoluble or water-soluble substances from the group of betamimetics (such. As salbutamol, formoterol) and / or anticholinergics (such. As ipratropium, Thiotropium) are therapeutically preferable because of a synergistic effect and improved patient compliance. colloidal budesonide solution produced in a accordance with Example 2 (200 ug / ml) in a first approach, formoterol (20 μ / ml) and in a second approach, ipratropium bromide incorporated (100 ug / ml). The resulting colloidal solutions were sterile filtered and into presterilized 0.5 - bottled 5 ml single dose containers of glass or polypropylene.
Example 8 Preparation of a freeze-dried combination product with vitamin E and reduced glutathione Aeetat
Antioxidants such. B. reduced glutathione and tocopherols (vitamin E derivatives) can inflammatory processes induced by free radical oxygen reduced. The following example illustrates the possibility to solubilize the water-insoluble tocopherol acetate with the water soluble, but storage unstable in a dissolved state glutathione by means of the surfactant combination according to the invention and to stabilize by a subsequent freeze-drying process. , 2 g tyloxapol, 2 g of DMPC, and 20 mg of tocopherol acetate are mixed in 200 ml water for injection and prehomogenized with an Ultra-Turrax. The dispersion is in a high-pressure homogenizer at 1500 bar about 15 minutes homogenized. In 50 ml of the resulting colloidal solution 2.5 g of reduced glutathione are dissolved rapidly under stirring and adjusted to a pH value of pH 6 by addition of lysine monohydrate. The resulting colloidal glutathione vitamin E Aeetat solution is immediately sterile filtered into glass vials and then freeze-dried. The osmolality of the resulting solution was 0.342 osmol / kg.
After addition of water for injection to the lyophilized under shaking dissolves completely within 10 seconds.
Priority Applications (2)
|Application Number||Priority Date||Filing Date||Title|
|DE2003147994 DE10347994A1 (en)||2003-10-15||2003-10-15||Aqueous aerosol formulation|
|PCT/EP2004/011571 WO2005037246A2 (en)||2003-10-15||2004-10-14||Aqueous aerosol preparation|
|Publication Number||Publication Date|
|EP1673066A2 true EP1673066A2 (en)||2006-06-28|
Family Applications (1)
|Application Number||Title||Priority Date||Filing Date|
|EP20040790427 Withdrawn EP1673066A2 (en)||2003-10-15||2004-10-14||Aqueous aerosol preparation|
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|EP (1)||EP1673066A2 (en)|
|AU (1)||AU2004281531A1 (en)|
|BR (1)||BRPI0415470A (en)|
|CA (1)||CA2542666A1 (en)|
|DE (1)||DE10347994A1 (en)|
|MX (1)||MXPA06004132A (en)|
|NZ (1)||NZ546824A (en)|
|RU (1)||RU2363449C2 (en)|
|WO (1)||WO2005037246A2 (en)|
Families Citing this family (87)
|Publication number||Priority date||Publication date||Assignee||Title|
|US5823179A (en)||1996-02-13||1998-10-20||1263152 Ontario Inc.||Nebulizer apparatus and method|
|US20030199425A1 (en) *||1997-06-27||2003-10-23||Desai Neil P.||Compositions and methods for treatment of hyperplasia|
|TW465235B (en)||1998-09-17||2001-11-21||United Video Properties Inc||Electronic program guide with digital storage|
|ES2165768B1 (en)||1999-07-14||2003-04-01||Almirall Prodesfarma Sa||New quinuclidine derivatives and pharmaceutical compositions containing them.|
|CA2826724C (en)||2000-04-11||2016-02-02||Trudell Medical International||Aerosol delivery apparatus with positive expiratory pressure capacity|
|US20030205226A1 (en)||2002-05-02||2003-11-06||Pre Holding, Inc.||Aerosol medication inhalation system|
|US6904908B2 (en)||2002-05-21||2005-06-14||Trudell Medical International||Visual indicator for an aerosol medication delivery apparatus and system|
|US8545463B2 (en)||2003-05-20||2013-10-01||Optimyst Systems Inc.||Ophthalmic fluid reservoir assembly for use with an ophthalmic fluid delivery device|
|AT501766T (en)||2003-05-20||2011-04-15||James F Collins||An ophthalmic drug delivery system|
|US20050026948A1 (en) *||2003-07-29||2005-02-03||Boehringer Ingelheim International Gmbh||Medicaments for inhalation comprising an anticholinergic and a betamimetic|
|DE10347994A1 (en)||2003-10-15||2005-06-16||Pari GmbH Spezialisten für effektive Inhalation||Aqueous aerosol formulation|
|PE09412005A1 (en) *||2003-12-16||2005-11-08||Nycomed Gmbh||Aqueous suspensions of ciclesonide for aerosolisation|
|US20070020299A1 (en) *||2003-12-31||2007-01-25||Pipkin James D||Inhalant formulation containing sulfoalkyl ether cyclodextrin and corticosteroid|
|US20070020196A1 (en) *||2003-12-31||2007-01-25||Pipkin James D||Inhalant formulation containing sulfoalkyl ether cyclodextrin and corticosteroid prepared from a unit dose suspension|
|US7878978B2 (en)||2004-03-18||2011-02-01||University Of Pittsburgh- Of The Commonwealth System Of Higher Education||Use of relaxin to increase arterial compliance|
|ES2257152B1 (en) *||2004-05-31||2007-07-01||Laboratorios Almirall S.A.||Antimuscarinics and combinations comprising beta-adrenergic agents agonists.|
|GB2419094A (en) *||2004-10-12||2006-04-19||Sandoz Ag||Pharmaceutical composition of unpleasnt tasing active substances|
|GB0501956D0 (en) *||2005-01-31||2005-03-09||Arrow Internat||Nebulizer formulation|
|US20090220587A1 (en) *||2005-02-01||2009-09-03||United State Army||Liposomal drug delivery constructs targeted by lipid-conjugated peptide ligands|
|US7741431B2 (en) *||2005-02-01||2010-06-22||The United States Of America As Represented By The Secretary Of The Army||Liposomes containing novel targeting and/or fusogenic peptides, preparations containing them and therapeutic use thereof|
|GB0507577D0 (en)||2005-04-14||2005-05-18||Novartis Ag||Organic compounds|
|EP1712220A1 (en) *||2005-04-15||2006-10-18||PARI GmbH Spezialisten für effektive Inhalation||Pharmaceutical aerosol composition|
|GB0510463D0 (en) *||2005-05-23||2005-06-29||Britania Pharmaceuticals Ltd||Improvements in or relating to organic materials|
|CA2615173C (en)||2005-07-14||2012-01-03||Lipothera, Inc.||Sustained release enhanced lipolytic formulation for regional adipose tissue treatment|
|BRPI0616642A2 (en) *||2005-09-29||2011-06-28||Nektar Therapeutics||antibiotic formulations, unit doses, kits and methods|
|US20070293460A1 (en) *||2005-10-31||2007-12-20||Richie's Pharmacy And Medical Supply, Incorporated||Delivery of a combination therapy for asthma and chronic obstructive pulmonary disease|
|DE102006051512A1 (en) *||2005-12-06||2007-06-14||Pari GmbH Spezialisten für effektive Inhalation||Pharmaceutical drug compounds with cyclosporin|
|US20070178050A1 (en) *||2005-12-20||2007-08-02||Verus Pharmaceuticals, Inc.||Methods and systems for the delivery of corticosteroids having an increased lung depositon|
|US20070197486A1 (en) *||2005-12-20||2007-08-23||Verus Pharmaceuticals, Inc.||Methods and systems for the delivery of corticosteroids|
|US20070185066A1 (en) *||2005-12-20||2007-08-09||Verus Pharmaceuticals, Inc.||Systems and methods for the delivery of corticosteroids|
|US20070249572A1 (en) *||2005-12-20||2007-10-25||Verus Pharmaceuticals, Inc.||Systems and methods for the delivery of corticosteroids|
|US20070160542A1 (en) *||2005-12-20||2007-07-12||Verus Pharmaceuticals, Inc.||Methods and systems for the delivery of corticosteroids having an enhanced pharmacokinetic profile|
|US20070178051A1 (en) *||2006-01-27||2007-08-02||Elan Pharma International, Ltd.||Sterilized nanoparticulate glucocorticosteroid formulations|
|EP1820493A3 (en) *||2006-02-10||2008-05-07||PARI Pharma GmbH||Aerosols for sinunasal drug delivery|
|US20070202051A1 (en) *||2006-02-10||2007-08-30||Pari Gmbh||Aerosols for sinunasal drug delivery|
|US20070191327A1 (en) *||2006-02-15||2007-08-16||Verus Pharmaceuticals, Inc.||Sterilization of corticosteroids with reduced mass loss|
|GB0604141D0 (en) *||2006-03-01||2006-04-12||Arrow Int Ltd||Nebulizer formulation|
|US7959943B2 (en)||2006-05-10||2011-06-14||Medtronics Xomed, Inc.||Solvating system and sealant for medical use in the middle or inner ear|
|US7976873B2 (en)||2006-05-10||2011-07-12||Medtronic Xomed, Inc.||Extracellular polysaccharide solvating system for treatment of bacterial ear conditions|
|US20070264296A1 (en)||2006-05-10||2007-11-15||Myntti Matthew F||Biofilm extracellular polysachharide solvating system|
|US7993675B2 (en)||2006-05-10||2011-08-09||Medtronic Xomed, Inc.||Solvating system and sealant for medical use in the sinuses and nasal passages|
|US20080031957A1 (en) *||2006-05-15||2008-02-07||Deluca Hector F||Pulmonary delivery of 1alpha,25-dihydroxyvitamin D3 and co-administration of parathyroid hormone or calcitonin|
|GB2443287B (en) *||2006-10-17||2009-05-27||Lipothera Inc||Methods, compositions and formulations for the treatment of thyroid eye disease|
|US8088095B2 (en)||2007-02-08||2012-01-03||Medtronic Xomed, Inc.||Polymeric sealant for medical use|
|KR100868295B1 (en)||2007-02-15||2008-11-11||풍림무약주식회사||Solid dispersion containing leflunomide and preparation method thereof|
|HUE039497T2 (en)||2007-03-07||2019-01-28||Abraxis Bioscience Llc||Nanoparticle comprising rapamycin and albumin as anticancer agent|
|WO2008131170A1 (en) *||2007-04-18||2008-10-30||Particle Sciences, Inc,||Aerosol dispersions of particles with active pharmaceutical ingredients|
|EP3326630A3 (en) *||2007-05-03||2018-08-29||Abraxis BioScience, LLC||Methods and compositions for treating pulmonary hypertension|
|US9119783B2 (en)||2007-05-07||2015-09-01||Insmed Incorporated||Method of treating pulmonary disorders with liposomal amikacin formulations|
|AR066901A1 (en) *||2007-05-18||2009-09-23||Alcon Mfg Ltd||fodfolipidicas elcuidado compositions and contact lens preservation of pharmaceutical compositions|
|EP2155188B1 (en)||2007-06-01||2013-10-09||Abraxis BioScience, LLC||Methods and compositions for treating recurrent cancer|
|US20090053149A1 (en) *||2007-08-24||2009-02-26||University Of Pittsburgh-Of The Commonwealth System Of Higher Education||Surfactant-based antimicrobial solution for inhalation|
|EP2030644A1 (en) *||2007-08-31||2009-03-04||PARI Pharma GmbH||Aerosols for sinunasal drug delivery|
|AU2008296195A1 (en) *||2007-09-07||2009-03-12||Epigenesis Pharmaceuticals, Llc||(DHEAS) inhalation compositions|
|WO2009052625A1 (en) *||2007-10-25||2009-04-30||Merck Frosst Canada Ltd.||Novel crystalline salts of montelukast|
|JP2011507968A (en) *||2007-12-27||2011-03-10||エイヤーズ ファーマシューティカルズ、インク．||Aerosolized nitrite and nitric oxide donating compounds and the use thereof|
|WO2009102976A2 (en) *||2008-02-15||2009-08-20||Timothy Sean Immel||Aerosol therapy device with high frequency delivery|
|EP2100598A1 (en)||2008-03-13||2009-09-16||Laboratorios Almirall, S.A.||Inhalation composition containing aclidinium for treatment of asthma and chronic obstructive pulmonary disease|
|EP2100599A1 (en)||2008-03-13||2009-09-16||Laboratorios Almirall, S.A.||Inhalation composition containing aclidinium for treatment of asthma and chronic obstructive pulmonary disease|
|WO2009137611A2 (en) *||2008-05-06||2009-11-12||Board Of Regents, The University Of Texas System||Treatment of pulmonary fungal infection with voriconazole via inhalation|
|CA2727432C (en)||2008-06-12||2016-10-11||Medtronic Xomed, Inc.||Method for treating chronic wounds with an extracellular polymeric substance solvating system|
|WO2009156706A1 (en) *||2008-06-27||2009-12-30||University Of Strathclyde||Pulmonary drug delivery with vesicles comprising non-ionic surfactants|
|TW201010727A (en) *||2008-09-03||2010-03-16||Alcon Res Ltd||Pharmaceutical composition having relatively low ionic strength|
|US8551454B2 (en) *||2009-03-13||2013-10-08||Luitpold Pharmaceuticals, Inc.||Device for intranasal administration|
|US9132084B2 (en)||2009-05-27||2015-09-15||Neothetics, Inc.||Methods for administration and formulations for the treatment of regional adipose tissue|
|WO2011088413A2 (en) *||2010-01-15||2011-07-21||Lithera, Inc.||Lyophilized cake formulations|
|US20110208153A1 (en) *||2010-02-24||2011-08-25||John Alvey||Formulations and methods for nutrient delivery|
|EP2366408B1 (en) *||2010-03-01||2012-07-18||Laboratorios SALVAT, S.A.||Aqueous clear solutions of fluocinolone acetonide for treatment of otic inflammation|
|BR112013001030A2 (en)||2010-07-15||2016-05-24||Corinthian Ophthalmic Inc||drop generating device|
|AU2011278924B2 (en)||2010-07-15||2015-06-18||Eyenovia, Inc.||Ophthalmic drug delivery|
|US10154923B2 (en)||2010-07-15||2018-12-18||Eyenovia, Inc.||Drop generating device|
|EA201390121A8 (en)||2010-07-15||2014-02-28||Коринтиан Офтэлмик, Инк.||Method and system for performing remote monitoring and treatment|
|EP2646012A4 (en)||2010-11-24||2014-12-10||Neothetics Inc||Selective, lipophilic, and long-acting beta agonist monotherapeutic formulations and methods for the cosmetic treatment of adiposity and contour bulging|
|FR2971713A1 (en) *||2011-02-18||2012-08-24||De La Mer Laboratoire||aqueous ionic solution sea water container and at least one immiscible originally comprises a seawater.|
|US20120237550A1 (en) *||2011-03-16||2012-09-20||Siemens Healthcare Diagnostics Inc.||Maintaining Antibody-Binding Activity Of Immunosuppressant Drug Conjugates|
|EP2510928A1 (en)||2011-04-15||2012-10-17||Almirall, S.A.||Aclidinium for use in improving the quality of sleep in respiratory patients|
|CN102872017B (en) *||2011-07-13||2015-02-04||中国科学院上海药物研究所||Use of 6-(4-difluoromethoxy)-3methoxyphenyl)pyridazine-3(2H)-one in preparation of antitumor drugs|
|NZ700983A (en)||2012-05-21||2016-10-28||Insmed Inc||Systems for treating pulmonary infections|
|WO2014085526A1 (en)||2012-11-29||2014-06-05||Insmed Incorporated||Stabilized vancomycin formulations|
|AU2014209141B2 (en)||2013-01-24||2018-05-10||Palvella Therapeutics, Inc.||Compositions for transdermal delivery of mTOR inhibitors|
|EP2886121A1 (en) *||2013-12-23||2015-06-24||Dr. Falk Pharma Gmbh||Aqueous suspension containing budesonide for the treatment of inflammatory changes to the oesophagus|
|CN106456595A (en) *||2014-02-10||2017-02-22||帕塔拉制药有限责任公司||Mast cell stabilizers treatment for systemic disorders|
|WO2015175939A1 (en)||2014-05-15||2015-11-19||Insmed Incorporated||Methods for treating pulmonary non-tuberculous mycobacterial infections|
|KR101669556B1 (en) *||2014-07-02||2016-10-28||한미약품 주식회사||Liquid Formulation of Montelukast or Pharmaceutically Acceptable Salt Thereof for Oral Administration|
|EP3177271A4 (en) *||2014-08-08||2018-02-28||Shenzhen Hightide Biopharmaceutical Ltd.||Liquid formulation compositions, medicament delivery devices, and methods of preparation and use thereof|
|WO2017027387A1 (en)||2015-08-07||2017-02-16||Patara Pharma, LLC||Methods for the treatment of mast cell related disorders with mast cell stabilizers|
|RU2684563C2 (en) *||2017-08-14||2019-04-09||Федеральное государственное бюджетное образовательное учреждение высшего образования "Тихоокеанский государственный медицинский университет" Министерства здравоохранения Российской Федерации||Method of medical therapeutic treatment of rhinitis, formed in patients receiving nasal decongestants|
Family Cites Families (32)
|Publication number||Priority date||Publication date||Assignee||Title|
|LU76682A1 (en) *||1977-02-01||1977-06-27|
|US4150071A (en) *||1977-08-26||1979-04-17||Respiratory Care, Inc.||Nebulizer|
|US5192528A (en) *||1985-05-22||1993-03-09||Liposome Technology, Inc.||Corticosteroid inhalation treatment method|
|US5006343A (en) *||1988-12-29||1991-04-09||Benson Bradley J||Pulmonary administration of pharmaceutically active substances|
|US5364632A (en) *||1989-04-05||1994-11-15||Yissum Research Development Company Of The Hebrew University Of Jerusalem||Medicinal emulsions|
|DE4203306A1 (en)||1992-02-06||1993-08-12||Ig Spruehtechnik Gmbh||Asthma or pulmonary aerosol preparations with lecithin|
|US5336507A (en) *||1992-12-11||1994-08-09||Sterling Winthrop Inc.||Use of charged phospholipids to reduce nanoparticle aggregation|
|DE4322111C2 (en)||1993-07-02||2001-05-10||Pari Gmbh||inhalation nebulizer|
|GB9410222D0 (en)||1994-05-21||1994-07-06||Glaxo Wellcome Australia Ltd||Medicaments|
|WO1996013254A1 (en) *||1994-10-26||1996-05-09||Glaxo Wellcome House||Pharmaceutical composition comprising atovaquone|
|IT1277832B1 (en)||1995-03-02||1997-11-12||Giuseppina Magni||Packaging nebulizzabili substances|
|WO1997029738A1 (en) *||1996-02-16||1997-08-21||The Administrators Of The Tulane Educational Fund||Methods and compositions for treating eustachian tube dysfunction by inhalation|
|US5660858A (en)||1996-04-03||1997-08-26||Research Triangle Pharmaceuticals||Cyclosporin emulsions|
|US5891465A (en) *||1996-05-14||1999-04-06||Biozone Laboratories, Inc.||Delivery of biologically active material in a liposomal formulation for administration into the mouth|
|US6465016B2 (en) *||1996-08-22||2002-10-15||Research Triangle Pharmaceuticals||Cyclosporiine particles|
|US6458373B1 (en) *||1997-01-07||2002-10-01||Sonus Pharmaceuticals, Inc.||Emulsion vehicle for poorly soluble drugs|
|US6086376A (en) *||1998-01-30||2000-07-11||Rtp Pharma Inc.||Dry aerosol suspension of phospholipid-stabilized drug microparticles in a hydrofluoroalkane propellant|
|US6241969B1 (en) *||1998-06-26||2001-06-05||Elan Corporation Plc||Aqueous compositions containing corticosteroids for nasal and pulmonary delivery|
|WO2000027376A2 (en)||1998-10-26||2000-05-18||Michael Schedler||Use of thiol compounds, oxidoreductases and/or hydrolases for the treatment of tinnitus, especially chronic tinnitus|
|RU2180217C2 (en)||2000-03-21||2002-03-10||Закрытое акционерное общество "Пульмомед"||Stable budesonide-containing aqueous solution with anti-inflammatory effect|
|GB0009612D0 (en)||2000-04-18||2000-06-07||Glaxo Group Ltd||Therapeutic formulations|
|GB0009605D0 (en)||2000-04-18||2000-06-07||Glaxo Group Ltd||Medicaments|
|GB0009591D0 (en)||2000-04-18||2000-06-07||Glaxo Group Ltd||Medical combinations|
|US6787532B2 (en) *||2000-08-05||2004-09-07||Smithkline Beecham Corporation||Formulation containing anti-inflammatory androstane derivatives|
|US20020137764A1 (en) *||2000-10-31||2002-09-26||Karin Drechsel||Inhalable formulation of a solution containing a tiotropium salt|
|US20030055026A1 (en) *||2001-04-17||2003-03-20||Dey L.P.||Formoterol/steroid bronchodilating compositions and methods of use thereof|
|DE10145361A1 (en)||2001-09-14||2003-04-03||Pari Gmbh||Sterile liquid composition for pulmonary administration in aerosol form comprises a sparingly water-soluble drug in the form of suspended particles of defined size|
|JP2005508220A (en)||2001-10-24||2005-03-31||パーリ・ゲーエムベーハー||Pharmaceutical compositions prepared equipment|
|US20030129242A1 (en) *||2002-01-04||2003-07-10||Bosch H. William||Sterile filtered nanoparticulate formulations of budesonide and beclomethasone having tyloxapol as a surface stabilizer|
|DE10239321B3 (en)||2002-08-27||2004-04-08||Pari GmbH Spezialisten für effektive Inhalation||Aerosol therapy device|
|AU2003260754B2 (en)||2002-08-29||2009-12-03||Cipla Limited||Pharmaceutical products and compositions comprising specific anticholinergic agents, beta-2 agonists and corticosteroids|
|DE10347994A1 (en)||2003-10-15||2005-06-16||Pari GmbH Spezialisten für effektive Inhalation||Aqueous aerosol formulation|
- 2003-10-15 DE DE2003147994 patent/DE10347994A1/en not_active Withdrawn
- 2004-10-14 AU AU2004281531A patent/AU2004281531A1/en not_active Abandoned
- 2004-10-14 MX MXPA06004132A patent/MXPA06004132A/en unknown
- 2004-10-14 EP EP20040790427 patent/EP1673066A2/en not_active Withdrawn
- 2004-10-14 BR BRPI0415470 patent/BRPI0415470A/en not_active IP Right Cessation
- 2004-10-14 NZ NZ54682404A patent/NZ546824A/en unknown
- 2004-10-14 WO PCT/EP2004/011571 patent/WO2005037246A2/en active Application Filing
- 2004-10-14 CA CA 2542666 patent/CA2542666A1/en not_active Abandoned
- 2004-10-14 RU RU2006114451/15A patent/RU2363449C2/en not_active IP Right Cessation
- 2005-04-14 US US11/106,999 patent/US7758886B2/en active Active
Non-Patent Citations (1)
|See references of WO2005037246A2 *|
Also Published As
|Publication number||Publication date|
|Courrier et al.||Pulmonary drug delivery systems: recent developments and prospects|
|ES2525087T3 (en)||phospholipid based powders drug delivery|
|CA2408464C (en)||Stable metal ion-lipid powdered pharmaceutical compositions for drug delivery and methods of use|
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