Drug – bio-affecting and body treating compositions – Enzyme or coenzyme containing
Reexamination Certificate
1999-08-25
2004-03-23
Lovering, Richard D. (Department: 1712)
Drug, bio-affecting and body treating compositions
Enzyme or coenzyme containing
C424S009500, C424S009600, C424S046000, C424S094300, C424S094400, C424S491000, C424S499000, C514S965000
Reexamination Certificate
active
06709650
ABSTRACT:
FIELD OF THE INVENTION
This invention relates to spray-dried microparticles and their use as therapeutic vehicles. In particular, the invention relates to means for delivery of diagnostic and therapeutic agents and biotechnology products, including therapeutics based upon rDNA technology.
BACKGROUND OF THE INVENTION
The most commonly used route of administration of therapeutic agents, oral or gastrointestinal, is largely inapplicable to peptides and proteins derived from the rDNA industry. The susceptibility of normally blood-borne peptides and proteins to the acidic/proteolytic environment of the gut, largely precludes this route for administration. The logical means of administration is intravenous, but this presents problems of poor patient compliance during chronic administration and very often rapid first-pass clearance by the liver, resulting in short IV lifetimes.
Recently, the potential for delivery by mucosal transfer has been explored. Whilst nasal delivery has been extensively explored, the potential delivery of peptides via the pulmonary airways is largely unexplored.
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 &mgr;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 metered 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.
Concurrently, there is a move toward 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. 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. In general, biotechnology products are available in low quantity and, furthermore, are susceptible to the methods currently employed to dry and micronise prior to mixing with excipient. Further, it is particularly difficult to provide blends of drug and excipient which are sufficiently free-flowing that they flow and dose reproducibly in the modern multiple dose inhalers such as the Turbohaler (Astra) and Diskhaler (Glaxo). Studies have revealed that, contrary to expectation, spray-dried (spherical) salbutamol microparticles showed greater forces of cohesion and adhesion than similarly-sized particles of micronised drug. Electron micrographs of the spray-dried material revealed the particles to possess pitted, rough surfaces.
Haghpanah et al reported, at the 1994 British Pharmaceutical Conference, that albumin microparticles incorporating salbutamol, had been produced by spray-drying and were of a suitable size for respiratory drug delivery, i.e. 1-5 &mgr;m. The aim was to encapsulate salbutamol, for slow release. It does not appear that the product is of substantially uniformly spherical or smooth microparticles that have satisfactory flow properties, for multi-dose dry powder inhalers.
Diagnostic agents comprising hollow microcapsules have been used to enhance ultrasound imaging. For example, EP-A-458745 (Sintetica) discloses a process of preparing air- or gas-filled microballoons by interfacial polymerisation of synthetic polymers such as polylactides and polyglycolides. WO-A-91/12823 (Delta) discloses a similar process using albumin. Wheatley et al (1990) Biomaterials 11:713-717, disclose ionotropic gelation of alginate to form microbubbles of over 30 &mgr;m diameter. WO-A-91/09629 discloses liposomes for use as ultrasound contrast agents.
Przyborowski et al, Eur. J. Nucl. Med. 7:71-72 (1982), disclose the preparation of human serum albumin (HSA) microspheres by spray-drying, for radiolabelling, and their subsequent use in scintigraphic imaging of the lung. The microspheres were not said to be hollow and, in our repetition of the work, predominantly poorly formed solid microspheres are produced. Unless the particles are hollow, they are unsuitable for echocardiography. Furthermore, the 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 et al refer to two earlier disclosures of methods of obtaining albumin particles for lung scintigraphy. Aldrich & Johnston (1974) Int. J. Appl. Rad. Isot. 25:15-18, disclose the use of a spinning disc to generate 3-70 &mgr;m diameter particles which are then denatured in hot oil. The oil is removed and the particles labelled with radioisotopes. Raju et al (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 &mgr;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. The conditions that are given in Example 1 (ethanol as solvent, 2-5% w/v solute) mean that there is no control of surface morphology, and 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.
Conte et al (1994) Eur. J. Pharm. Biopharm. 40(4):203-208, disclose spray-drying from aqueous solution, with a maximum solute concentration of 1.5%. High drug content is required, in order to obtain the most nearly spherical particles. This entails shrunken and wrinkled particle morphology. Further, after suspension in butanol, to facilitate Coulter analysis, sonication is apparently necessary, implying that the particles are not fully dry.
It is an object behind the present invention to provide a therapeutic delivery vehicle and a compositio
Heath David
Johnson Richard A.
Senior Peter J.
Sutton Andrew D.
Elam Drug Delivery Limited
Lovering Richard D.
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