EP0783298A1 - Spray-dried microparticles as therapeutic vehicles - Google Patents

Spray-dried microparticles as therapeutic vehicles

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Publication number
EP0783298A1
EP0783298A1 EP95932122A EP95932122A EP0783298A1 EP 0783298 A1 EP0783298 A1 EP 0783298A1 EP 95932122 A EP95932122 A EP 95932122A EP 95932122 A EP95932122 A EP 95932122A EP 0783298 A1 EP0783298 A1 EP 0783298A1
Authority
EP
European Patent Office
Prior art keywords
microparticles
microparticles according
water
soluble material
microcapsules
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.)
Ceased
Application number
EP95932122A
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German (de)
English (en)
French (fr)
Inventor
Andrew Derek Sutton
Richard Alan Johnson
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Quadrant Healthcare UK Ltd
Original Assignee
Andaris Ltd
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Filing date
Publication date
Application filed by Andaris Ltd filed Critical Andaris Ltd
Priority to EP95932122A priority Critical patent/EP0783298A1/en
Publication of EP0783298A1 publication Critical patent/EP0783298A1/en
Ceased legal-status Critical Current

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Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
    • A61K9/16—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/007—Pulmonary tract; Aromatherapy
    • A61K9/0073—Sprays or powders for inhalation; Aerolised or nebulised preparations generated by other means than thermal energy
    • A61K9/0075—Sprays or powders for inhalation; Aerolised or nebulised preparations generated by other means than thermal energy for inhalation via a dry powder inhaler [DPI], e.g. comprising micronized drug mixed with lactose carrier particles
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K49/00—Preparations for testing in vivo
    • A61K49/22—Echographic preparations; Ultrasound imaging preparations ; Optoacoustic imaging preparations
    • A61K49/222—Echographic preparations; Ultrasound imaging preparations ; Optoacoustic imaging preparations characterised by a special physical form, e.g. emulsions, liposomes
    • A61K49/223—Microbubbles, hollow microspheres, free gas bubbles, gas microspheres
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
    • A61K9/16—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
    • A61K9/1682—Processes
    • A61K9/1688—Processes resulting in pure drug agglomerate optionally containing up to 5% of excipient
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
    • A61K9/16—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
    • A61K9/1682—Processes
    • A61K9/1694—Processes resulting in granules or microspheres of the matrix type containing more than 5% of excipient
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
    • A61K9/50—Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
    • A61K9/50—Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals
    • A61K9/5089—Processes
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00—Drugs for disorders of the respiratory system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/24—Antidepressants
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/26—Psychostimulants, e.g. nicotine, cocaine

Definitions

  • This invention relates to spray-dried microparticles and their use as therapeutic vehicles.
  • the invention relates to means for delivery of diagnostic and therapeutic agents and biotechnology products, including therapeutics based upon rDNA technology.
  • Alveolar cells in their own right, provide an effective barrier. However, even passage of material to the alveolar region represents a significant impediment to this method of administration. There is an optimal size of particle which will access the lowest regions of the pulmonary airways, i.e. an aerodynamic diameter of ⁇ 5 ⁇ m. Particles above this size will be caught by impaction in the upper airways, such that in standard commercial suspension preparations, only 10-30% of particles, from what are normally polydispersed suspensions, reach the lowest airways.
  • Current methods of aerosolising drugs for inhalation include nebulisation, metered dose inhalers and dry powder systems. Nebulisation of aqueous solutions requires large volumes of drugs and involves the use of bulky and non ⁇ portable devices.
  • the most common method of administration to the lung is by the use of volatile propellant-based devices, commonly termed etered dose inhalers.
  • the basic design is a solution of propellant, commonly CFC 11, 12 or 114, containing either dissolved drug or a suspension of the drug in a pressurised canister. Dosing is achieved by depressing an actuator which releases a propellant aerosol of drug suspension or solution which is carried on the airways. During its passage to the lung, the propellant evaporates to yield microscopic precipitates from solution or free particles from suspension. The dosing is fairly reproducible and cheap, but there is growing environmental pressure to reduce the use of CFCs. Furthermore, the use of CFC solvents remains largely incompatible with many of the modern biotechnology drugs, because of their susceptibility to denaturation and low stability.
  • dry powder devices which consist of dry powders of drugs usually admixed with an excipient, such as lactose or glucose, which facilitates the aerosolisation and dispersion of the drug particles.
  • excipient such as lactose or glucose
  • the energy for disaggregation is often supplied by the breath or inspiration of air through the device.
  • Drugs are currently micronised, to reduce particle size. This approach is not applicable for biotechnology products.
  • biotechnology products are available in low quantity and, furthermore, are susceptible to the methods currently employed to dry and icronise prior to mixing with excipient.
  • spray-dried (spherical) salbutamol microparticles showed greater forces of cohesion and adhesion than similarly-sized particles of micronised drug.
  • EP- A-458745 discloses a process of preparing air- or gas-filled microballoons by interfacial polymerisation of synthetic polymers such as polylactides and polyglycolides.
  • WO-A-9112823 discloses a similar process using albumin. Wheatley et al. (1990) Biomaterials
  • WO-A-9109629 discloses liposomes for use as ultrasound contrast agents.
  • HSA human serum albumin
  • microspheres were prepared in a one-step process which we have found to be unsuitable for preparing microcapsules suitable for echocardiography; it was necessary in the prior process to remove undenatured albumin from the microspheres, and a wide size range of microspheres was apparently obtained, as a further sieving step was necessary.
  • Przyborowski e_t a refer to two earlier disclosures of methods of obtaining albumin particles for lung scintigraphy.
  • Raju et &1 (1978) Isotopenpraxis 14(2):57-61 used the same spinning disc technique but denatured the albumin by simply heating the particles. In neither case were hollow microcapsules mentioned, and the particles prepared were not suitable for echocardiography.
  • EP-A-0606486 (Teijin) describes the production of powders in which an active agent is incorporated into small particles, with carriers comprised of cellulose or cellulose derivatives. The intention is to prevent drug particles from adhering to the gelatin capsules used in a unit dose dry powder inhaler.
  • Page 12 of this publication refers to the spray-drying of "medicament and base", to obtain particles of which 80% or more were 0.5-10 ⁇ m in size. No directions are given as to what conditions should be used, in order to obtain such a product.
  • EP-A-0611567 (Teijin) is more specifically concerned with the production of powders for inhalation, by spray- drying.
  • the carrier is a cellulose, chosen for its resistance to humidity.
  • Example 1 ethanol as solvent, 2-5% w/v solute
  • Example 4 reports a poor lower airway respirable fraction (12%), indicating poor dispersion properties.
  • Spherical particles are apparently obtained at high drug content, indicating that particle morphology is governed by the respective drug and carrier contents.
  • microparticles and also microcapsules and microspheres
  • the wall-forming material is substantially unaffected by spray-drying.
  • highly uniform microparticles, microspheres or microcapsules of heat-sensitive materials such as enzymes, peptides and proteins, e.g. HSA, and other polymers, may be prepared and formulated as dry powders, for therapeutic or diagnostic use.
  • a process for preparing microcapsules of the invention comprises atomising a solution (or dispersion) of a wall-forming material.
  • a therapeutic or diagnostic agent may be atomised therewith, or coupled to the microcapsules thus produced.
  • the material may be an active agent itself.
  • Unfixed capsules of this invention composed of non- denatured HSA or other spray-dryable material, possess highly smooth surfaces and may be processed with relatively low levels of excipients to produce free-flowing powders ideal for dry powder inhalers.
  • the process of spray-drying in its current form, gives rise to relatively little denaturation and conversion to polymers in the production of the free- flowing powder.
  • the size of the microcapsule suspension can be such that 90% of the mass lies within the desired size, e.g. the respirable region of 1-5 ⁇ m. In essence therefore we have defined how to produce microparticles which are: predominantly 1-5 ⁇ m in size; smooth and spherical; gas-containing; and composed of undamaged protein molecules and which may be stored and shipped prior to other processing steps.
  • DPI's dry powder inhalers
  • HSA HSA
  • a potential carrier molecule which may: protect labile molecules; enhance uptake of peptides across the lung; bind low molecular weight drug through natural binding affinities; and be covalently modified to carry drugs across cellular barriers to the systemic circulation and beyond.
  • microparticles comprising low molecular weight active with lactose; active alone: peptides with HSA and modified polymeric carriers with active.
  • active alone: peptides with HSA and modified polymeric carriers with active.
  • the process of the invention can be controlled in order to obtain microspheres with desired characteristics.
  • the pressure at which the protein solution is supplied to the spray nozzle may be varied, for example from 1.0-10.0 x 10 Pa, preferably 2-8 x 10 s Pa, and most preferably about 7.5 x 10 Pa.
  • Other parameters may be varied as disclosed below.
  • novel microspheres may be obtained.
  • a further aspect of the invention provides hollow microspheres in which more than 30%, preferably more than 40%, 50%, or 60%, of the microspheres have a diameter within a 2 ⁇ m range and at least 90%, preferably at least 95% or 99%, have a diameter within the range 1.0-8.0 ⁇ m.
  • the interquartile range may be 2 ⁇ m, with a median diameter of 3.5, 4.0, 4.5, 5.0, 5.5, 6.0 or 6.5 ⁇ m.
  • at least 30%, 40%, 50% or 60% of the microspheres may have diameters within the range 1.5-3.5 ⁇ m, 2.0-4.0 ⁇ m, 3.0-5.0 ⁇ m, 4.0-6.0 ⁇ m, 5.0-7.0 ⁇ m or 6.0- 8.0 ⁇ m.
  • a said percentage of the microspheres have diameters within a 1.0 ⁇ m range, such as 1.5-2.5 ⁇ m, 2.0-3.0 ⁇ m, 3.0-4.0 ⁇ m, 4.0-5.0 ⁇ m, 5.0-6.0 ⁇ m, 6.0-7.0 ⁇ m or 7.0-8.0 ⁇ m.
  • a further aspect of the invention provides hollow microspheres with proteinaceous walls in which at least 90%, preferably at least 95% or 99%, of the microspheres have a diameter in the range 1.0-8.0 ⁇ m; at least 90%, preferably at least 95% or 99%, of the microspheres have a wall thickness of 40-500 nm, preferably 100-500 nm.
  • the wall-forming material and process conditions should be so chosen that the product is sufficiently non- toxic and non-immunogenic in the conditions of use, which will clearly depend on the dose administered and duration of treatment.
  • the wall-forming material may be a starch derivative, a synthetic polymer such as tert-butyloxy- carbonylmethyl polygluta ate (US-A-4888398) or a polysaccharide such as polydextrose.
  • the wall-forming material can be selected from most hydrophilic, biodegradable physiologically compatible polymers, as described in more detail in WO-A- 9218164.
  • the wall-forming material is proteinaceous.
  • it may be collagen, gelatin or (serum) albumin, in each case preferably of human origin (i.e. derived from humans or corresponding in structure to the human protein) .
  • human serum albumin HSA
  • it is human serum albumin (HSA) derived from blood donations or, ideally, from the fermentation of microorganisms (including cell lines) which have been transformed or transfected to express HSA. Further detail is given in WO-A-9218164.
  • the protein solution or dispersion is preferably 0.1 to 50% w/v, more preferably about 5.0-25.0% protein, particularly when the protein is albumin. About 20% is optimal. Mixtures of wall-forming materials may be used, in which case the percentages in the last two sentences refer to the total content of wall-forming material.
  • the preparation to be sprayed may contain substances other than the wall-forming material and solvent or carrier liquid. Again, reference may be made to WO-A-9218164.
  • the protein solution or dispersion (preferably solution) , referred to hereinafter as the "protein preparation" is atomised and spray-dried by any suitable technique which results in discrete microspheres or microcapsules of 1 to 10 ⁇ m diameter. These figures refer to at least 90% of the population of microcapsules, the diameter being measured with a Coulter Master Sizer II.
  • microcapsules means hollow particles enclosing a space, which space is filled with a gas or vapour but not with any solid materials. Honeycombed particles resembling the confectionery sold in the UK as Maltesers® are not formed.
  • the atomising comprising forming an aerosol of the protein preparation by, for example, forcing the preparation through at least one orifice under pressure into, or by using a centrifugal atomiser in a chamber of warm air or other inert gas.
  • the chamber should be big enough for the largest ejected drops not to strike the walls before drying.
  • the gas or vapour in the chamber is clean (i.e. preferably sterile and pyrogen-free) and non- toxic when administered into the bloodstream in the amounts concomitant with administration of the microcapsules in use.
  • the rate of evaporation of the liquid from the protein preparation should be sufficiently high to form hollow microcapsules but not so high as to burst the microcapsules.
  • the rate of evaporation may be controlled by varying the gas flow rate, concentration of protein in the protein preparation, nature of liquid carrier, feed rate of the solution and, more importantly, the temperature of the gas encountered by the aerosol.
  • an inlet gas temperature of at least about 100°C, preferably at least 110°C, is generally sufficient to ensure hollowness and the temperature may be as high as 250 ⁇ C without the capsules bursting.
  • the outlet temperature may be monitored to ensure an adequate temperature in the chamber.
  • An outlet temperature of 40-150°C has been found to be suitable. Controlling the flow rate has been found to be useful in controlling the other parameters such as the number of intact hollow particles.
  • the microcapsules comprise typically 96-98% monomeric HSA.
  • microparticles of the invention preferably have a maximum interquartile range of 3 ⁇ m, more preferably 2 ⁇ m, and most preferably 1.5 ⁇ m, with respect to their mass median particle size.
  • the mass median particle diameter is determined by Coulter counter with a conversion to a volume-size distribution. This is achieved by spray-drying in which there is a combination of low feed stock flow rate with high levels of atomisation and drying air. The effect is to produce microcapsules of very defined size and tight size distribution.
  • A Constant related to nozzle design
  • B Constant related to liquid viscosity
  • a and b Constants related to nozzle design
  • the droplet size is most affected by the relative velocity at the nozzle and concurrently the mass ratio of air to liquid.
  • the air to liquid ratio is in the range of 0.1-10 and at these ratios it appears that the average droplet size is 15-20 ⁇ m.
  • an air to liquid ratio ranging from 20-1000:1. The effect is to produce particles at the high ratios which are exceedingly small by comparative standards, with very narrow size distributions.
  • microparticles produced at the lower ratios of air to liquid, slightly larger particles are produced, but they still nevertheless have tight size distributions which are superior to microparticles produced by emulsion techniques.
  • the microparticles may comprise at least 50, more preferably 70 or 80, and most preferably 90, % by weight HSA or other carrier material.
  • the microparticles may be formulated with a conventional excipient such as lactose or glucose.
  • the microparticles may comprise therapeutic agent and carrier, or a compound which alone is therapeutically- active.
  • the amount of the active principle will be chosen having regard to its nature and activity, to the mode of administration and other factors known to those skilled in the art.
  • the number of particles administered may be such as to deliver 100 mg/day ⁇ -1 anti- trypsin, or 0.1 mg/day of an active material such as beclomethasone.
  • the active principle may be, for example, a diagnostic substance or a classical pharmaceutical entity which may or may not bind, covalently or otherwise, to the carrier material.
  • the therapeutic agent may be a proteinaceous material such as insulin, parathyroid hormone, calcitonin or similar bioactive peptide, albuterol, salicylate, naproxen, augmentin or a cytotoxic agent.
  • a marker such as lysine-fluorescein may be included.
  • Microparticles of the invention may comprise an antagonist or receptor-binding component in addition to the therapeutic or diagnostic agent.
  • a sugar or other molecule may be included in the molecular vehicle, with a view to directing administration of the vehicle- bound drug to a given receptor at or beyond the alveoli.
  • HSA is used herein as an illustrative example of water-soluble carrier materials for use in the invention.
  • Other materials that can be used include simple and complex carbohydrates, simple or complex amino- or polyamino-acids, fatty acid or fatty acid esters, or natural or recombinant human proteins or fragments or short forms thereof.
  • the invention allows for the nature of the dry microcapsules to be manipulated, in order to optimise the flow or vehicle properties, by changing and reducing the forces of cohesion and adhesion within the microcapsule preparation.
  • the microcapsules may be made predominantly positive or negative by the use of highly-charged monomeric or polymeric materials, e.g. lysine or poly-lysine and glutamate or poly-glutamate in systems without HSA or heterogeneous systems including HSA and active principles.
  • a further embodiment of the invention is the co-spray- drying of the active principle with HSA in order to facilitate stabilisation of the active principle during formulation, packing and, most importantly, during residence on the alveolar lining.
  • HSA co-spray- drying of the active principle with HSA
  • protease inhibitors can be used to protect peptide drugs, there may well be contra-indications to this approach.
  • HSA both as excipient and vehicle, it can offer a large excess of alternative substrate on which the locally-active proteases may act.
  • a further advantage is that, since HSA has been shown to cross the alveolar barrier, by receptor- or non-receptor-mediated transcytotic mechanisms, it may be used as a vehicle to facilitate the passage of an active principle across the epithelial lining.
  • active principle may be covalently linked to HSA via cleavable linkages prior to spray-drying.
  • This embodiment represents a method of carrying active principles all the way from device to bloodstream, and possibly to targets within the body.
  • the formation of particles with optimal aerodynamic size means that the "physical" vehicle delivers the active principle to the site of absorption. Once deposited upon the alveoli, the "molecular” vehicle then protects and facilitates passage into the bloodstream and, once in the bloodstream, can further enhance circulatory half-life and even direct the active principle to certain sites within the body on the basis of receptor-mediated events.
  • a suitable linker technology is described in WO-A- 9317713 (Rijksuniversiteit Groningen) .
  • Esterase-sensitive polyhydroxy acid linkers are described. Such technology, used in the derivatisation of HSA prior to spray-drying, enables the production of a covalent carrier system for delivery of drugs to the systemic vasculature. This utilises the potential of HSA to cross the alveoli to carry drugs over a prolonged period whilst protecting potentially unstable entities.
  • the active principle used in this invention may be imbibed into or otherwise associated with the microparticles after their formation, it is preferably formulated with the HSA.
  • the microparticles may be at least partly coated with a hydrophobic or water-insoluble material such as a fatty acid, in order to delay their rate of dissolution and to protect against hydroscopic growth.
  • Example 1 The spray dryer used in the Examples, available from A/S Niro Atomizer, Soeborg, Denmark, under the trade name "Mobile Minor”, is described in detail in WO-A-9218164.
  • Example 1 The spray dryer used in the Examples, available from A/S Niro Atomizer, Soeborg, Denmark, under the trade name "Mobile Minor”, is described in detail in WO-A-9218164.
  • the peristaltic pump speed was maintained at a rate of approximately 10 ml/minute such that with an inlet air temperature of 220°C the outlet air temperature was maintained at 95°C.
  • Compressed air was supplied to the two fluid atomising nozzle at 2.0-6.0 Bar (2.0-6.0 x 10 Pa). In this range microcapsules with a mean size of 4.25-6.2 ⁇ m are obtained.
  • microparticles were produced with a particle size of 4.7 ⁇ m. These soluble microparticles were smooth and spherical with less than 1% of the particles over a particle size of 6 ⁇ m. The microparticles were dissolved in aqueous medium and the molecular weight of the HSA determined by gel filtration chromatography. The resultant chromatograms for the HSA before and after spray-drying HSA are essentially the same.
  • Alpha-l antitrypsin derived from human serum was spray-dried under conditions similar to Example 1 with an inlet temperature of 150°C and an outlet temperature of 80°C. In all other respects the conditions for drying were the same as Example 1.
  • the soluble microparticles produced had a mean size of 4.5 ⁇ m.
  • the microparticles were dissolved in aqueous medium and analysed for retention of protein structure and normal trypsin inhibitory activity, then compared to the original freeze dried starting material. Analysis by gel permeation and reverse phase chromatography and capillary electrophoresis, revealed that there were no significant structural changes after spray- drying. Analysis of the inhibitory activity (Table 2) showed that within the experimental error, full retention of inhibitory activity had been achieved.
  • microcapsules composed of alcohol dehydrogenase (ADH) and lactose were prepared (ADH 0.1% w/w; Lactose 99.9% w/w) .
  • ADH alcohol dehydrogenase
  • lactose 99.9% w/w
  • Table 3 The microcapsules were smooth and spherical and contained air as evidenced by their appearance in diphenylxylene (DPX) under light microscopy.
  • Example 4 A series of experiments was performed under the conditions described in Example 1, to examine the influence of liquid feed rate on the yield of intact spherical particles. We find that, using the ability of gas- containing microparticles to reflect ultrasound, we are able to determine optimal condition for maximising the yield of intact smooth spherical microcapsules.
  • the microparticles formed after spray-drying are heat-fixed, to render them insoluble, and then suspended in water to make the echo measurements.
  • increasing the liquid feed rate decreases the number of intact microparticles formed during the initial spray-drying (Table 4) .
  • the mean particle size and overall pressure stability, i.e. thickness of the shell do not change but the total echogenicity does, as the liquid flow rate is increased from 4 to 16 ml/min. We find that slower rates of evaporation (at higher liquid flow rates) lead to fewer intact spherical particles being formed.
  • the assay was conducted by resuspending the heat-fixed microparticles at a concentration of 1x10 ml in 350 ml of water. This solution is stirred slowly in a 500 ml beaker above which is mounted an 3.5 MHz ultrasound probe attached to a Sonus 1000 medical imaging machine. The grey scale images obtained are captured by an image analyser and compared against a water blank to yield video density units of echo reflectance.
  • the assay can also be adapted to examine the pressure resistance, by assessing the echo- reflectance before and after exposure of the sample to cyclical bursts of pressure applied to the stock solution of particles. This analysis distinguishes incomplete particles which entrain air upon reconstitution, from fully spherical particles which "encapsulate" air within the shell.
  • Example 5 The dose response for fixed albumin particles of Example 1 is c. 5, 9, 13, 20, 22 and 24 VDU's (backscatter intensity) at respective microcapsule concentrations of 0.25, 0.5, 1, 2, 3 and 4 x 10 per ml.
  • Example 5 The dose response for fixed albumin particles of Example 1 is c. 5, 9, 13, 20, 22 and 24 VDU's (backscatter intensity) at respective microcapsule concentrations of 0.25, 0.5, 1, 2, 3 and 4 x 10 per ml.
  • Example 5 The dose response for fixed albumin particles of Example 1 is c. 5, 9, 13, 20, 22 and 24 VDU's (backscatter intensity) at respective microcapsule concentrations of 0.25, 0.5, 1, 2, 3 and 4 x 10 per ml.
  • a range of materials has been used to manufacture smooth spherical soluble microparticles.
  • the range of microparticles produced includes inert materials such as HSA, lactose, mannitol, sodium alginate; active materials alone such as ⁇ l-antitrypsin; and mixtures of active and inert carrier such as lactose/alcohol dehydrogenase, lactose/budesonide, HSA/salbutamol.
  • inert materials such as HSA, lactose, mannitol, sodium alginate
  • active materials alone such as ⁇ l-antitrypsin
  • mixtures of active and inert carrier such as lactose/alcohol dehydrogenase, lactose/budesonide, HSA/salbutamol.
  • the particles are suspended in propanol and then visualised by microscopy. Those particles which contain gas appear to have an intense white core surrounded by an intact black rim whilst broken or miss-formed particles appear as ghosts. Microscopic evaluation of the following microparticles exemplifies the range of materials and actives which can be dried to produce smooth spherical particles:
  • Example 7 Lactose and Budesonide were spray-dried under the conditions described in the table below (Table 6) .
  • the resultant dry powder was blended with excipient grade lactose in a V type blender in the proportions outlined in Table 7.
  • the blends were then loaded into gelatin capsules and discharged from a Rotahaler into a twin stage impinger run at 60 1/min.
  • the respirable fraction was calculated as the percentage deposited into the lower chamber. Table 7
  • respirable fractions obtained are considerably superior to micronised product currently used in this device which are usually in the range of 10-20% maximum.
  • Example 7 The Budesonide/Lactose formulations detailed in Example 7 were tested in an experimental gravity fed multi- dose DPI. The parameters examined were the variation of emitted dose over 30 shots and the respirable fraction in a four-stage impinger device. The results are shown below (Table 8) .
  • microcapsules may be coated with fatty acids such as palmitic or behenic acids.
  • the soluble microcapsules of Example 1 were coated by suspending a mixture of soluble HSA microcapsules and glucose (50% w/w) in an ethanolic solution containing 10% palmitic or behenic acid. The solution was evaporated and the resultant cake milled by passage through a Fritsch mill.
  • coated microcapsules very quickly lost all air and thus the potential to reflect ultrasound. However, coated microcapsules retained their structure for a longer period and hence showed a prolonged signal over several minutes.
  • HSA only HSA/Palmitic HSA/Behenic Coated Coated
  • Soluble mannitol microcapsules were prepared as set out in Example 1 (15% aqueous mannitol spray-drying feedstock) and coated with palmitic acid and behenic acid as described in Example 8. A sample of each was suspended in water and the echogenicity measured. Ten minutes after the initial analysis, the echogenicity of the suspended samples was repeated (Table 10) . Table 10 Echogenicity of Coated Mannitol Microcapsules
  • Example 10 Soluble microcapsules with a model active (Lysine- Fluoroscein) contained within the matrix were prepared to allow the production of a free-flowing dry powder form of the "active" compound. On dissolution of the microcapsules, the active compound was released in its native form.
  • a model active Lisine- Fluoroscein
  • FITC fluorescein isothiocyanate
  • the FITC-lysine adduct was mixed with 143 ml of 25% ethanol containing 100 mg/ml HSA to give the spray-drying feedstock.
  • the spray-drying conditions used to form the microcapsules are detailed in Table 11 below. In the absence of ethanol we have found that only a small percentage of the particles are smooth and spherical.
  • the spray-drying process produced 17.21 g of microcapsules that did not dissolve when a sample was resuspended in ethanol. Moreover, no release of the FITC- lysine adduct was observed. However, when 10 ml water was added to the ethanol-suspended microcapsules, the microcapsules dissolved and the FITC-lysine was released. Analysis of the adduct using TLC before incorporation into the microcapsules and after release from the microcapsules on dissolution showed the model compound was unchanged. Table 11
  • the soluble microcapsules were sized in a non-aqueous system of ammonium thiocyanate and propan-2-ol using a Multisizer II (Coulter Electronics) .
  • the microcapsules had a mean size of 3.28 ⁇ 0.6 ⁇ m and with 90% of the mass within 2-5 ⁇ m.
  • the microcapsules were mixed with glucose (50% w/w microcapsules : 50% w/w glucose) , and milled by the passage of the mixture through a Fritsch mill three times. When a sample of the powder was added to water, the FITC-lysine was released intact when compared with its original form as determined by TLC analysis.
  • Example 11 shows the feasibility of making an amino acid or peptide formulation which could be used for respiratory formulations, which incorporates HSA within the formulation.
  • Example 11 500 mg beclomethasone was dissolved in ethanol and added to 50 ml HSA feedstock (10% w/v) and spray-dried using the conditions outlined in Example 10.
  • the microcapsules hence formed were sized in the non-aqueous system as detailed in Example 10.
  • the microcapsules had a mean size of 3.13 ⁇ 0.71 ⁇ m, 90% of which were between 2 and 5 ⁇ m.
  • the beclomethasone was extracted from the microcapsules by the precipitation of the HSA in 10% TCA, and the supernatant was extracted into ethanol.
  • Example 12 Whereas in Examples 10 and 11 at least, any binding of the active compounds was an effect of the intrinsic nature of albumin, this Example gives a product following initial cross-linking of the active compound, prior to spray- drying.
  • the soluble microcapsules thus made were sampled, characterised and analysed for drug content.
  • the microcapsules had a mean size of 3.2 ⁇ 0.6 ⁇ m with 90% by mass between 2-5 ⁇ m.
  • the analysis of the drug content of the microcapsules showed that the microcapsules did not release drug; even after dissolution, drug was still bound to the HSA.
  • Proteinase K digestion of the albumin released the bound drug which was shown to be linked to only a limited number of amino-acids and small peptides. It has been shown previously that the activity of doxorubicin bound to polymeric carriers proves beneficial in tumours, showing the multidrug-resistant phenotype.
  • Naproxen microcapsules were prepared as detailed in Examples 10 and 12 using a ratio of 1 to 5, drug to HSA.
  • the soluble microcapsules retained the active compound of a non-aqueous solvent. Moreover, on dissolution of the microcapsules in aqueous solution, the active compound was still bound to the albumin, as shown by HPLC analysis at 262 nm, as before. The naproxen was released from the albumin on digestion with proteinase K and esterases.
  • Examples 8 to 13 an assessment of their behaviour in a dry powder inhaler was made. The dosing reproducibility of each formulation was assessed in conjunction with the aerolisation of the sample by microscopic evaluation.
  • DPI dry powder inhaler
  • Example 10 A comparison of the dosing and deposition of fixed insoluble microcapsules and soluble microcapsules as produced in Example 10 was made in the lung of rabbits.
  • Anaethestised New Zealand white rabbits were dosed either with soluble microcapsules or fixed microcapsules.
  • the dosing was carried out using a computer controlled nebuliser (Mumed Ltd. , UK) .
  • the soluble microcapsules were suspended in CFC 11 and the fixed particles were suspended in water. After dosing, the lungs of the rabbits were removed and an assessment of the deposition of the capsules made.
  • the fixed capsules were found intact in the alveoli tissue of the lung. This showed that the microcapsules were of the appropriate size for dispersion through the lungs. In comparison, no evidence of the presence of intact soluble microcapsules was found, the capsules having dissolved in the fluids of the lung. However, the presence of FITC-lysine adduct was observed in some of the alveoli tissue when studied using fluorescent microscopy. In addition, the presence of the adduct was also found the blood and urine of the animals, as opposed to that of the fixed capsules which showed no presence in either.

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EP95932122A 1994-09-29 1995-09-26 Spray-dried microparticles as therapeutic vehicles Ceased EP0783298A1 (en)

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RU2147226C1 (ru) 2000-04-10
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NO971438L (no) 1997-03-26
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NO971438D0 (no) 1997-03-26

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