Title:  Supercritical fluid extraction of mould lubricant from hard shell capsules

United States Patent:  6,228,394

Assignee:  Boehringer Ingelheim Pharmaceuticals, Inc. (Ridgefield, CT)

Filed:  September 21, 1998

Hard shelled capsules and dry, powdered pharmaceutical formulations are treated with supercritical fluids to remove impurities such as mold lubricants and moisture.

SUMMARY OF THE INVENTION

The current invention addresses the problems of retention of powdered formulation in the capsules in a simple and non-intrusive way. It provides a new and novel means for minimizing the amount of powder retained in the capsules following inhalation, thereby increasing the amount of active drug reaching the lungs of the patient, while improving its reproducibility. This invention also provides a means for controlling the moisture level of the capsules.

Use of supercritical fluids (SCFs) to extract lubricant material from capsules provides great flexibility in processing. The amount and nature of the unextracted fraction of the lubricant material left in the capsules can be affected by either changing the extraction time, pressure, temperature, and/or flow rate of the pure SCF, or by adding small amounts of an organic solvent to the pure SCF to increase or decrease the solvent strength of the SCF mixture. Contrary to extraction with liquid solvents, the present methods also allows for extraction of capsules in either their open, closed or locked state with no apparent physical change. The ability to extract closed capsules is important since capsules are provided by the capsule manufacturer in their closed state, and are fed into the capsule filling machine in a closed state, and it would therefore be preferable to be able to extract them in this state without causing them to open.

It has been unexpectedly discovered that SCFs can be used in lieu of organic solvents, aqueous solvents, or solid substances to treat the capsules so as to achieve a lower retention of drug and carrier in the capsule following inhalation, and concomitantly achieve higher and more consistent drug delivery from DPIs. SCFs are found to selectively extract the fraction of the lubricant material that is responsible for most of the drug retention from either open, closed or locked capsules. In addition, it has been discovered that SCFs can also be used to remove trace impurities and moisture from capsules, drug and carrier particles in order to achieve more consistent surface properties, with no observed damage to either the capsule or the formulation. It has been found that selective extraction of lubricant material has a surprisingly positive effect on drug retention in the capsule and fine particle mass (particles <5.8 .mu.m) in a cascade impactor used to determine the aerodynamic particle size distribution of the powder and thereby approximate the amount of drug that will reach the lungs of the patient. It is found that extraction with SCFs provides a means to remove most of the adhesive fraction from the lubricant material, leaving nearly-solid to completely solid residue on the internal surface of the capsules. This novel method thus provides a means for removing the components of the lubricant material which are in large part responsible for drug retention in the capsule, and for making the surface of the capsules more uniform and more consistent by leaving an essentially solid residue on the internal surface of the capsules. The same technique is found to provide a means for reducing the moisture content of the capsules to a level that is similar to the desired level just prior to packaging of the DPI.

Claim 1 of 21 Claims

What is claimed is:

1. A method for removing supercritical fluid soluble material from the interior of a body or a cap or both of a hard shell capsule which comprises the steps of exposing the body or the cap or both of the hard shell capsule to a supercritical fluid which supercritical fluid has a critical temperature less than about 200^oC. and a critical pressure of less than about 10,000 psi to transfer the supercritical fluid soluble material to the supercritical fluid and removing the supercritical fluid and the supercritical fluid soluble material from the body or the cap or both of the hard shell capsule.

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