Patent Application
20110311630
The invention relates to processes for preparing delayed-release medicaments and medicaments for administration by inhalation that may be produced by these processes. The invention relates in particular to poly-[lactide-co-glycolide]-based dry powder formulations which have a delayed release of active substance. The invention also relates to the use of these medicaments for the treatment of respiratory complaints, particularly for the treatment of COPD (chronic obstructive pulmonary disease) and asthma.
To achieve a reproducible and constant release of active substance it may be necessary to delay the release of active substance using special formulation techniques. In inhalative applications in particular in which the active substance after being administered by inhalation is present in finely divided form on the surface of the lungs for absorption, a rapid absorption of active substance is observed. This is reflected in a pharmacokinetic behaviour that corresponds to that observed after intravenous administration. From the field of the oral formulations it is known (R. H. Müller and G. E. Hildebrand: “Pharmazeutische Technologie: Moderne Arzneiformen”, Wissenschaftliche Verlagsgesellschaft mbH Stuttgart, 1997, ISBN 3-8047-1504-4), that the use of particular adjuvants may form an additional diffusion barrier to the process of the release of active substance or may interfere with the distribution of the active substance. This may occur as a result of
Active substances are usually provided by oral administration. If this route is not suitable or not desirable on account of special properties of the active substance or particular demands made of the administration, various other possible methods of administering substances are known in the art.
In the form of powders for inhalation, inhalable powders packed for example into suitable capsules (inhalettes) are delivered to the lungs by means of powder inhalers. Other systems are also known in which the quantity of powder to be administered is pre-dosed (e.g. blisters), and multi-dose powder systems are also known. Alternatively, the medicaments may be administered by inhalation of suitable powdered inhalable aerosols which are suspended for example in HFA134a, HFA227 or mixtures thereof, as propellant gas.
During powder inhalation, the microparticles of the pure active substance are conventionally administered through the airways to the surface of the lungs, e.g. in the alveoli, by the inhalation process. These particles are deposited on the surface and are absorbed into the body directly after the dissolving process by active and passive transporting processes.
Inhalation systems are known in the literature in which the active substance is present in the form of solid particles, either as a micronised suspension in a suitable solvent system as carrier, or in the form of a dry powder.
Usually, powder inhalants, e.g. in the form of capsules for inhalation, are prepared on the basis of the general teaching, as described in DE-A-179 22 07.
A critical factor in multi-substance systems of this kind is the uniform distribution of the medicament in the powder mixture.
Another significant aspect with powder inhalants is that during the inhalative administration of the active substance only particles of a specific aerodynamic size reach the target organ, the lungs. The mean particle size of these lung-bound particles (inhalable fraction) is in the region of a few microns, typically between 0.1 and 10 μm, preferably below 6 μm. Particles of this kind are usually produced by micronisation (air jet milling).
It is known from the literature that particles in the region of a few microns may be prepared by spray-drying. Conventionally, formulations that can be handled industrially and which are sufficiently dispersible for medicinal administration (inhalation) are prepared from spray-dried particles of this kind using the process mentioned above (DE-A-179 22 07), [Y.-F. Maa, P.-A. Ngyuyen, J. D. Andya, N. Dasovich, T. D. Sweeny, S. J. Shire, C. C. Hsu, Pharmaceutical Research, 15, No. 5 (1998), 768-775; M. T. Vidgrén, P. A. Vidgrén, T. P. Paronen, Int. J. Pharmaceutics, 35 (1987), 139-144; R. W. Niven, F. D. Lott, A. Y. Ip, J. M. Cribbs, Pharmaceutical Research, 11, No. 8 (1994), 1101-1109].
The spray-drying of pure active substances for inhalation purposes (powder inhalation) is also described in the prior art [e.g.: EP 0 072 046 A1; WO 2000 000176 A1; U.S. Pat. No. 6,019,968; A. Chawla, K. M. G. Taylor, J. M. Newton, M. C. R. Johnson, Int. J. Pharm, 108 (3), (1994), 233-240].
Besides these examples, the pharmaceutical companies in particular make use of other manufacturing techniques based on spray-drying methods that describe special formulations for inhalable powders. The following may be mentioned as examples of these:
Powdered preparations consisting of co-spray-dried β-galactosidase with trehalose [J. Broadhead, S. K. Edmond Rouan, C. T. Rhodes, Pharm Acta Helvetiae, 70 (1995), 125-131], which may be mixed for example with other physiologically acceptable excipients; powdered preparations consisting of a spray micronisate which is obtained by co-spray-drying at least two active substances and one or more physiologically acceptable adjuvants [WO 01/13885]; powdered preparations consisting of spray-dried rhDNase, optionally co-spray-dried with salts, and prepared either directly or in the form of a mixture with a physiologically acceptable adjuvant e.g. lactose, mannitol or sodium chloride for inhalative administration [H. K. Chan, A. Clark, I Gonda, M. Mumenthaler, C. Hsu, Pharm Research, 14 (1997), 431-437]; spray-dried IGF1 preparations for inhalative administration [WO 9955362]; co-spray micronisates from active substances and physiologically acceptable adjuvants [WO 9952506] for inhalative administration; powdered preparations containing co-spray micronisates of SLPI protein in physiologically acceptable carrier materials [WO 9917800]; co-spray-dried interferon with a carrier material [WO 9531479]; co-spray micronisates comprising an active substance and cellulose derivatives [WO 9325198]; co-spray micronisates, consisting of RhDNase and a physiologically acceptable adjuvant, e.g. lactose, the initially amorphous adjuvant being converted into crystalline α-lactose monohydrate by subsequent recrystallisation [H.-K. Chan, I. Gonda, J. Pharm. Sci., 87 (5), (1998) 647-654].
Conventional manufacturing technologies for preparing embedding particles for administration by inhalation are based on the use of physiologically acceptable adjuvants. In the prior art the adjuvants that are used in powdered inhalants serve primarily to ensure that a uniform mixture and hence dilution of the active substance can be achieved using the adjuvants.
The aim of the invention is to enable a controlled release of the active substance to take place using the inhalable powder according to the invention. The invention therefore sets out to provide inhalable powders which have a time-delayed solution rate (delayed release) compared with particles of the pure active substance.
By delayed release is meant here that particles according to the invention have release characteristics such that particles display delayed dissolution characteristics in a Franz-type diffusion cell. As a consequence, a slower and at the same time long-lasting release of a pharmaceutical active substance from the inhalable powder according to the invention is observed, preferably from particles that have an aerodynamic size of less than 5 μm.
It is thus an aim of the invention to provide inhalable powders which have a delayed dissolution rate compared with the pure active substance particles as well as processes for preparing them. The invention sets out particularly to provide the above-mentioned inhalable powders for low molecular active substances, as well as for water-soluble active substances.
In another aspect the invention relates to the preparation of delayed-release inhalable powders which contain a biodegradable chemically modified polymer and processes for the preparation thereof.
Moreover the invention relates to the preparation of delayed-release inhalable powders which consist exclusively of a low molecular active substance and a biodegradable polymer and processes for the preparation thereof.
The invention also sets out to provide medicaments which contain inhalable powders according to the invention.
During the preparation of an inhalable powder for pulmonary (or nasal) inhalation the active substance (or a physiologically acceptable salt thereof) is incorporated in physically stable form as a solid in a solid matrix of an adjuvant.
By a corresponding choice of adjuvants, using the formulation technique according to the invention the active substance may be incorporated in the solid matrix such that it has a delayed release. By this is meant, according to the invention, that the solution characteristics of the inhalable particles in a release medium are delayed by comparison with inhalable particles of the pure active substance, determined in a Franz diffusion cell.
The inhalable fraction represents the amount of inhalable active substance particles (particles<5 μm) that can be determined on the basis of the Pharm. Eur. 2.9.18 (European Pharmacopoeia, 6th edition 2008, Apparatus D—Andersen Cascade Impactor) or USP30-NF25<601>. The inhalable fraction is also referred to within the scope of the present invention as the FPD (Fine Particle Dose).
Surprisingly it has been found that the inhalable particles of the inhalable powders according to the invention solve the problems stated above if the active substance or several active substances is or are incorporated in an adjuvant matrix and the adjuvant is selected from among the block copolymers which contain at least one hydrophilic and one hydrophobic block. In particular, the problem is solved if the active substance or several active substances is or are incorporated in an adjuvant matrix and the adjuvant is selected from among the PEG-modified (poly-[lactide-co-glycolide]) based polymers (hereinafter referred to as PEG-modified PLGA). These substances may be obtained for example under the name Resomer® (Boehringer Ingelheim Pharma GmbH & Co. KG, Germany). Substances from this category are particularly suitable if they
Of particular importance are the PEG-[lactide-co-glycolides] listed in Table 1 as embedding materials for inhalable powders according to the invention.
According to the invention the inhalable powders (based on the inhalable fraction (particles with an aerodynamic particle size of less than 5 μm)) are characterised in that at most 90% of the active substance has gone into solution after 10 hours, preferably at most 90% of the active substance has dissolved after 12 hours.
In another embodiment, inhalable powders according to the invention (based on the inhalable fraction (particles with an aerodynamic particle size of less than 5 μm)) are characterised in that 40% to 80% of the active substance, preferably 50% to 80% of the active substance, more preferably 60% to 80% of the active substance and still more preferably 70% to 80% of the active substance goes into solution within less than 200 minutes.
Also, in another embodiment, inhalable powders, based on their inhalable fraction, are characterised in that 40% to 80% of the active substance, preferably 50% to 80% of the active substance, more preferably 60% to 80% of the active substance and still more preferably 70% to 80% of the active substance goes into solution within less than 120 minutes.
Also, in another embodiment, inhalable powders, based on their inhalable fraction, are characterised in that 40% to 80% of the active substance, preferably 50% to 80% of the active substance, more preferably 60% to 80% of the active substance and still more preferably 70% to 80% of the active substance goes into solution within less than 60 minutes.
The solution characteristics of the inhalable fraction of the inhalable powder according to the invention serve as a measurement of the delayed release of the active substance.
These solution characteristics may be determined using a Franz diffusion cell (cf.
In this embodiment the lower compartment is connected to a pump by tubes that carry the medium to a device for measurement data acquisition, for example a UV detector or a fluorescence detector. An active substance can be quantitatively detected using detectors of this kind.
Finally, the release medium is mixed with a stirrer system such as a magnetic stirrer in order to distribute an active substance taken up in the release medium more evenly inside the chamber.
[numerical data in the next section refer to
Preferably the inhalable fraction of the inhalable powders according to the invention may be deposited on a cellulose membrane. The depositing of the inhalable fraction may be preferably carried out by placing this filter on the filter plate of the Andersen Cascade Impactor. Delivery is then carried out in accordance with Pharm. Eur. 2.9.18 (European Pharmacopoeia, 6th edition 2008, Apparatus D—Andersen Cascade Impactor), while only the deposition plates that are not used for the deposition of particles from 0 to 5 μm in size are placed in the cascade impactor, so that all the particles smaller than 5 μm are deposited on the filter.
The invention further relates to processes by which the problems according to the invention are solved. The invention comprises corresponding manufacturing methods for producing inhalable powders according to the invention. Such powders may be used both directly as powdered inhalants (multi-dose systems, pre-metered multi-dose systems and single dose systems) and also as components which are mixed with other (e.g. coarse-grained) adjuvants.
In order to produce such particles, the manufacturing method may be controlled so as to obtain the particles in a suitable particle size, usually between 0.1 and 10 μm, and so that the particles have surface qualities that make them easy to swirl and disperse.
In all, a formulation based on this manufacturing method enables the active substance or a physiologically acceptable salt thereof to be administered to the patient by inhalation in a therapeutically useful dose as a delayed-release medicament.
The particles of the inhalable powders according to the invention which are prepared by the process according to the invention are characterised by high physical stability. They are particularly suitable if a high fine content is delivered when they are used as powdered inhalants, determined technically, e.g. by measurement with a cascade impactor. Typically the proportion of the particles produced by this method that are smaller than 5 μm (aerodynamically) is greater than 15%; in some cases, fine contents of more than 30%, or more than 50%, are obtained.
Powders thus produced are characterised by a particle size, e.g. measured by laser diffraction, by a mean particle size X50 in the range from 1 μm to 10 μm, preferably from 1 μm to 6 μm. By the mean particle size X50 in the sense used here is meant the 50% value from the volume distribution, measured with a laser diffractometer by the dry dispersion method.
The manufacturing method for the microparticles or inhalable powders according to the invention is characterised in that a solution or emulsion of the active substance or a physiologically acceptable salt thereof is suitably dissolved or processed to form an emulsion with an adjuvant selected from among the PEG-modified (poly-[lactide-co-glycolide]) based polymers (PEG-modified PLGA), which is then sprayed and dried in a spraying tower. The particles/the powder may be obtained by a suitable deposition process (e.g. cyclone or fine particle filter). The microparticles thus prepared are characterised by special values in terms of their particle size.
For active substances that have a water solubility of more than 0.01 g per 100 mL, it has proved appropriate, when preparing microparticles in the form of embedding particles of the inhalable powders according to the invention, to use a process that comprises the following steps:
For active substances which have a solubility of more than 0.01 g per 100 mL in an organic solvent which is completely water-miscible, it has proved suitable, when preparing microparticles in the form of embedding particles of the inhalable powders according to the invention, to use a process that comprises the following steps:
For active substances which have a solubility of more than 0.01 g per 100 mL in an organic solvent, preferably dichloromethane, it has proved suitable, when preparing microparticles in the form of embedding particles of the inhalable powders according to the invention, to use a process that comprises the following steps:
The particle sizes were determined within the scope of the present invention by laser diffraction (Fraunhofer diffraction). By the mean particle size X50 in the sense used here is meant the 50% value from the volume distribution. More detailed information on this can be found in the experimental descriptions of the invention.
According to the invention the inhalable powders thus obtained may be used for preparing a medicament. They are preferably used to prepare a medicament for treating respiratory complaints, particularly for treating COPD and/or asthma. The invention also relates to the use of the inhaler powders thus obtained for preparing a medicament for use by inhalation, particularly for preparing a medicament for inhalation which allows a delayed release of the active substance.
The chemical compounds listed hereinafter (active substances) may be used on their own or in combination as the medicament-relevant component of the inhalable powders according to the invention.
In the compounds mentioned below, W is a pharmacologically active substance and is selected (for example) from among the betamimetics, anticholinergics, corticosteroids, PDE4-inhibitors, LTD4-antagonists, EGFR-inhibitors, dopamine agonists, H1-antihistamines, PAF-antagonists and PI3-kinase inhibitors. Moreover, double or triple combinations of W may be combined and used in the device according to the invention. Combinations of W might be, for example:
The compounds used as betamimetics are preferably compounds selected from among albuterol, arformoterol, bambuterol, bitolterol, broxaterol, carbuterol, clenbuterol, fenoterol, formoterol, hexoprenaline, ibuterol, isoetharine, isoprenaline, levosalbutamol, mabuterol, meluadrine, metaproterenol, orciprenaline, pirbuterol, procaterol, reproterol, rimiterol, ritodrine, salmefamol, salmeterol, soterenol, sulphonterol, terbutaline, tiaramide, tolubuterol, zinterol, CHF-1035, HOKU-81, KUL-1248 and
The anticholinergics used are preferably compounds selected from among the tiotropium salts, preferably the bromide salt, oxitropium salts, preferably the bromide salt, flutropium salts, preferably the bromide salt, ipratropium salts, preferably the bromide salt, glycopyrronium salts, preferably the bromide salt, trospium salts, preferably the chloride salt, tolterodine. In the above-mentioned salts the cations are the pharmacologically active constituents. As anions the above-mentioned salts may preferably contain the chloride, bromide, iodide, sulphate, phosphate, methanesulphonate, nitrate, maleate, acetate, citrate, fumarate, tartrate, oxalate, succinate, benzoate or p-toluenesulphonate, while chloride, bromide, iodide, sulphate, methanesulphonate or p-toluenesulphonate are preferred as counter-ions. Of all the salts the chlorides, bromides, iodides and methanesulphonates are particularly preferred.
Other preferred anticholinergics are selected from among the salts of formula AC-1
wherein X− denotes an anion with a single negative charge, preferably an anion selected from among the fluoride, chloride, bromide, iodide, sulphate, phosphate, methanesulphonate, nitrate, maleate, acetate, citrate, fumarate, tartrate, oxalate, succinate, benzoate and p-toluenesulphonate, preferably an anion with a single negative charge, particularly preferably an anion selected from among the fluoride, chloride, bromide, methanesulphonate and p-toluenesulphonate, particularly preferably bromide, optionally in the form of the racemates, enantiomers or hydrates thereof. Of particular importance are those pharmaceutical combinations which contain the enantiomers of formula AC-1-ene
wherein X− may have the above-mentioned meanings. Other preferred anticholinergics are selected from the salts of formula AC-2
wherein R denotes either methyl or ethyl and wherein X− may have the above-mentioned meanings. In an alternative embodiment the compound of formula AC-2 may also be present in the form of the free base AC-2-base.
Other specified compounds are:
The above-mentioned compounds may also be used as salts within the scope of the present invention, wherein instead of the methobromide the salts metho-X are used, wherein X may have the meanings given hereinbefore for X−.
As corticosteroids it is preferable to use compounds selected from among beclomethasone, betamethasone, budesonide, butixocort, ciclesonide, deflazacort, dexamethasone, etiprednol, flunisolide, fluticasone, loteprednol, mometasone, prednisolone, prednisone, rofleponide, triamcinolone, RPR-106541, NS-126, ST-26 and
PDE4-inhibitors which may be used are preferably compounds selected from among enprofyllin, theophyllin, roflumilast, ariflo (cilomilast), tofimilast, pumafentrin, lirimilast, arofyllin, atizoram, D-4418, Bay-198004, BY343, CP-325.366, D-4396 (Sch-351591), AWD-12-281 (GW-842470), NCS-613, CDP-840, D-4418, PD-168787, T-440, T-2585, V-11294A, CI-1018, CDC-801, CDC-3052, D-22888, YM-58997, Z-15370 and
The LTD4-antagonists used are preferably compounds selected from among montelukast, pranlukast, zafirlukast, MCC-847 (ZD-3523), MN-001, MEN-91507 (LM-1507), VUF-5078, VUF-K-8707, L-733321 and
EGFR-inhibitors which may be used are preferably compounds selected from among cetuximab, trastuzumab, ABX-EGF, Mab ICR-62 and
The dopamine agonists used are preferably compounds selected from among bromocriptine, cabergoline, alpha-dihydroergocryptine, lisuride, pergolide, pramipexole, roxindole, ropinirole, talipexole, terguride and viozan, optionally in the form of the racemates, enantiomers, diastereomers thereof and optionally in the form of the pharmacologically acceptable acid addition salts, solvates or hydrates thereof. According to the invention these acid addition salts are preferably selected from among the hydrochloride, hydrobromide, hydriodide, hydrosulphate, hydrophosphate, hydromethanesulphonate, hydronitrate, hydromaleate, hydroacetate, hydrocitrate, hydrofumarate, hydrotartrate, hydrooxalate, hydrosuccinate, hydrobenzoate and hydro-p-toluenesulphonate.
H1-Antihistamines which may be used are preferably compounds selected from among epinastine, cetirizine, azelastine, fexofenadine, levocabastine, loratadine, mizolastine, ketotifen, emedastine, dimetindene, clemastine, bamipine, cexchlorpheniramine, pheniramine, doxylamine, chlorphenoxamine, dimenhydrinate, diphenhydramine, promethazine, ebastine, desloratidine and meclozine, optionally in the form of the racemates, enantiomers, diastereomers thereof and optionally in the form of the pharmacologically acceptable acid addition salts, solvates or hydrates thereof. According to the invention these acid addition salts are preferably selected from among the hydrochloride, hydrobromide, hydriodide, hydrosulphate, hydrophosphate, hydromethanesulphonate, hydronitrate, hydromaleate, hydroacetate, hydrocitrate, hydrofumarate, hydrotartrate, hydroxalate, hydrosuccinate, hydrobenzoate and hydro-p-toluenesulphonate.
The pharmaceutically effective substances, formulations or mixtures of substances used may be any inhalable compounds, including also for example inhalable macromolecules, as disclosed in EP 1 003 478. Preferably, substances, formulations or mixtures of substances for treating respiratory complaints which are administered by inhalation are used.
In addition, the compound may come from the group of ergot alkaloid derivatives, the triptans, the CGRP-inhibitors, the phosphodiesterase-V inhibitors, optionally in the form of the racemates, enantiomers or diastereomers thereof, optionally in the form of the pharmacologically acceptable acid addition salts, the solvates and/or hydrates thereof.
Examples of ergot alkaloid derivatives are dihydroergotamine and ergotamine.
a) Determining Particle Size by Laser Diffraction (Average Particle Size x50):
The apparatus are operated in accordance with the manufacturers operating instructions.
About 200 mg of the test substance are weighed onto a piece of card.
Using another piece of card all the larger lumps are broken up. The powder is then sprinkled finely over the front half of the vibrating channel (starting about 1 cm from the front edge). After the start of the measurement the frequency of the vibrating channel is varied so that the sample is fed as continuously as possible. However, the quantity of product must not be too great, so as to ensure that adequate dispersion is achieved.
a) Dry Powder Formulations which Contain a Water-Soluble Active Substance
These are produced using a spray dryer made by Büchi, of the B-290 mini-spray dryer type. The dry powder formulations listed in Table 2 were obtained by preparing w/o (water in DCM) emulsions which were spray-dried. The emulsions were prepared using an ultrasound apparatus (made by Sonics & Materilas Inc., Vibra Cell type, fitted with a 3 mm tip). To prepare the emulsion the tip is dipped 0.5-2 cm into the solution and the ultrasound apparatus is operated at 30%.
b) Dry Powder Formulations which Contain a Non-Water-Soluble Active Substance
The dry powder formulations listed in Table 3 are obtained by spray-drying solutions of the polymer and of the active substance budesonide.
The inhalable fraction of the inhalable powders according to the invention was investigated in a dissolution model (Franz-type diffusion cell) with regard to the controlled release of salbutamol or budesonide. (In order to consider the particle fraction that would be deposited in the lungs in human application from a HandiHaler®, particles>5 μm were differentiated by using stages 0 and 1 of the cascade impactor).
The inhalable powders discussed in Examples 1 to 5 that follow, distinguishable by their respective identification codes, were obtained by the spray-drying method. The respective process parameters are listed in Table 4.
Embedding particles (identification code SR 2.8; SR 11; SR 14; SR 1.3) were prepared by spray-drying from the active substance salbutamol together with different triblock copolymers.
Embedding particles (identification code SR 12.0; SR 13.0; SR 6.1) were prepared by spray-drying from the active substance salbutamol together with different diblock copolymers.
Embedding particles were prepared by spray-drying from the active substance salbutamol together with the triblock copolymer. In the sample with the identification code SBR 2.0 the spray-drying was carried out from a homogeneous solution of the active substance and of the polymer (embedding material: triblock copolymer LGP t 8546) in acetone. The sample with the identification code SR 2.8, on the other hand, was prepared by producing a W/O emulsion, with the active substance dissolved in the aqueous phase and using dichloromethane (containing triblock copolymer LGP t 8546 dissolved therein as embedding material) as the organic phase.
The sample with the identification code SRME was prepared by adding further ethanol to the W/O emulsion (water/dichloromethane) until the emulsion clarified. Measurements using dynamic light scattering with an apparatus made by Malvern, of the Zetasizer nano ZS type, showed that for microemulsions characteristic double peaks were observed at 12 nm and 300 nm, which remained stable for at least 45 minutes.
Other inhalable embedding particles (identification code SBR 3.0; SR 6.1) were prepared by spray-drying from the active substance salbutamol together with the diblock copolymer RGP d 5055.
Other inhalable embedding particles (identification code BR 3.0, BR 4.0; BR 2.0; BR 1.2) were prepared by spray-drying from the active substance budesonide together with the triblock copolymers LP t 52; LRP t 7046 and LGP t 8546.
| Number | Date | Country | Kind |
|---|---|---|---|
| 08104316.8 | Jun 2008 | EP | regional |
| Filing Document | Filing Date | Country | Kind | 371c Date |
|---|---|---|---|---|
| PCT/EP2009/057059 | 6/8/2009 | WO | 00 | 7/26/2011 |
