Stock material or miscellaneous articles – Coated or structually defined flake – particle – cell – strand,... – Particulate matter
Reexamination Certificate
1998-07-17
2002-05-21
Nutter, Nathan M. (Department: 1711)
Stock material or miscellaneous articles
Coated or structually defined flake, particle, cell, strand,...
Particulate matter
C427S213300, C427S213310, C427S213350, C264S004100, C264S004300, C264S004600
Reexamination Certificate
active
06391452
ABSTRACT:
BACKGROUND
1. Field of Invention
The present invention relates to compositions for delivery of drugs intended to reside in the nose. The invention also pertains to methods of making such nasal drug delivery compositions and to improved methods of removing solvents from pharmaceutical preparations.
2. Background
A number of intranasal preparations are known which are specifically designed to deliver drugs across the nasal mucosal membranes to effect systemic drug administration. However, there remains a need for intranasal preparations specifically designed to retain the drugs for extended periods of time in the nose without crossing the mucosal membranes.
Cortesi, R., Esposito, E., Menegatti, E., Gambri, R., and Nastruzzi, C., “Gelatin Microspheres as a New Approach for the Controlled Delivery of Synthetic Nucleotides and PCR-Generated DNA Fragments”, Int. J. Pharm. 105:181-6 (1994), disclose a gelatin solution emulsified in isopropyl palmitate as the oil phase (without surfactant). Gel beads are formed by cooling the emulsion, and these are then washed with acetone and collected on a sintered glass disk. The mean volume particle diameter is 22 &mgr;m, with a range of 5-42 &mgr;m. As particles below 10 &mgr;m tend to deposit in the lungs, this range of particle size is not suitable for administration of pharmaceuticals intended for retention in the nose.
Illum et al. , PCT/GB95/01735 describe a drug delivery composition for nasal administration comprising ICAM-1 and bioadhesive compositions comprising chitosan, a liquid polymeric material, or a variety of water-swellable microspheres, including gelatin. Ilium discloses the concept of emulsifying a warm aqueous solution of gelatin and ICAM-1 in a vegetable oil containing a surfactant, followed by thermal gelation, hardening with acetone, harvesting the ICAM/gelatin microspheres, and drying.
However, the processes taught by Ilium for the production of gelatin microspheres and the resulting product are not desirable for commercial scale pharmaceutical use. The process requires large amounts of oil and acetone. The resulting product has been found to contain mainly aggregates of small primary particles. These aggregates tend to deaggregate during handling, resulting in mixtures of fragments and non-aggregated particles with about 3.5% by volume of particles with volume diameters below 10 &mgr;m. Particles below 10 &mgr;m volume diameter are not suitable for administration of drugs intended for nasal retention, as they tend to enter the lower airway and lungs, which is not desirable from either a safety or commercial standpoint.
Accordingly, it is desirable to provide a pharmaceutical preparation for delivery of drugs to the nose that maintains biological activity and physical integrity, exhibits extended intranasal residence time, and allows sustained release of active ingredient in the nasal cavity. The desired characteristics for an intranasal formulation include:
(1) a pharmaceutically acceptable formulation with respect to process consistency, scalability, and GRAS (generally regarded as safe) components;
(2) sustained release of active drug over time;
(3) high quality and activity of released drug;
(4) restricted particle size range of volume diameter 10-100 &mgr;m, preferably 20-80 &mgr;m, to minimize concerns about lung delivery;
(5) lack of irritation to the mucociliary apparatus;
(6) convenient and reproducible administration into the nasal cavity;
(7) dry powder based;
(8) stability over time without refrigeration; and
(9) residual solvent levels at or below pharmaceutically acceptable levels.
Criteria for a commercially suitable process for producing such a product include minimal solvent consumption and demonstrated scalability to at least 300 g.
One problem commonly found in pharmaceutical compositions in which the production process involves solvents is unacceptably high levels of residual solvent in the final product, so that the product does not meet safety and regulatory requirements. Traditional methods of removing solvents are frequently unsatisfactory. For example, evaporation under vacuum at room temperature may be inadequate and at elevated temperatures may cause degradation of the active ingredient. The alternative technique, extraction by supercritical fluid, is not always effective when applied to dry powders. Thus, there is a need for an improved method of removing residual solvents from pharmaceutical formulations.
The present invention provides these and other advantages.
SUMMARY OF INVENTION
The present invention provides an improved process for production of pharmaceutical gelatin-based microsphere compositions comprising one or more drugs to be delivered to and retained in the nose, and the drug-containing microspheres produced by this process. The invention also concerns improved methods of removing solvents from dry powder pharmaceutical compositions.
In general, the process for making the microsphere/drug composition comprises the following steps:
a) preparing a low-salt or salt-free aqueous solution of gelatin and the drug to be delivered at a temperature above the gelation temperature of the gelatin;
b) preparing a solution of a suitable oil and a suitable surfactant;
c) emulsifying a mixture of the solution of step (a) and the solution of step (b) to generate a water-in-oil emulsion wherein the volume ratio of (a):(b) is between 1:2 and 1:10;
d) continuing emulsification until the target droplet size is achieved;
e) thereafter reducing the temperature of said emulsion to below the gelation temperature of the gelatin at a controlled rapid rate to achieve gelation before droplet coalescence, thus allowing the formation of gelatin microspheres associated with drug at the desired particle size;
the emulsion in steps (c, d) and (e) above being mixed at the maximum rate consistent with a low-vortex or vortex-free circulation pattern;
f) separating the drug-containing microspheres from the oil/surfactant phase; and
g) dehydrating the drug-containing microspheres to produce a dry powder.
The invention also comprises an improved method for removing residual solvent from pharmaceutical matrices such as dry powders by contacting said matrices with a humidified stream of a suitable gas under conditions which permit residual solvent to be entrained in the gas, and then drawing off the gas. This can be done in discreet batches or as part of a continuous flow process.
The resulting product is a free-flowing powder comprising gelatin microspheres associated with drug, with a volume particle diameter of between 40-60 &mgr;m and wherein a preponderance of the microspheres exist as unaggregated individual particles, rather than as aggregates of smaller particles.
The invention further comprises an intranasal drug delivery system comprising the above gelatin microspheres in association with a drug to be delivered to and retained in the nose.
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Franz, J., D
Antonsen Kris P.
Caudle Margaret
Concessio Neville M.
Nayar Rajiv
Shearer Michael A.
Bayer Corporation
Nutter Nathan M.
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