Drug – bio-affecting and body treating compositions – Preparations characterized by special physical form – Capsules
Reexamination Certificate
1998-09-21
2001-05-08
Page, Thurman K. (Department: 1615)
Drug, bio-affecting and body treating compositions
Preparations characterized by special physical form
Capsules
C424S451000, C034S329000, C034S337000, C034S341000
Reexamination Certificate
active
06228394
ABSTRACT:
1. FIELD OF THE INVENTION
This invention is directed at methods for extracting undesirable materials present in capsules, which capsules are used to store and maintain powdered pharmaceutical formulations. In particular, the subject invention pertains to a method of treating capsules used to hold such powdered formulations to reduce the amount of undesirable materials such as molding lubricant or impurities that may be present in such capsules. Molding lubricant can cause retention of the powdered formulation, and result in inconsistent dosing of active drug. This invention also relates to a method for removing undesirable material from drug powder or from the material forming the capsule. Undesirable material in the capsules can be either moisture or impurities that, over a period of time, can come in contact with the capsule contents. Finally, the invention also relates to capsules treated according to the above method.
2. DESCRIPTION OF RELATED ART
Capsules are frequently used as a storage means for finely divided, pharmaceutical powders comprising active drug that is to be delivered to a patient via inhalation. For example, to avoid the use of propellant gases some of which (chloro-fluoro-carbons or CFCs) have been implicated with environmental damage (depletion of the ozone layer in the atmosphere), dry powder comprising the drug is placed in a capsule to be used with a dry powder inhaler (DPI). Generally, such devices cut or pierce the capsules comprising the dry powder prior to administration, and then the powder is inhaled by the patient.
The capsules usually consist of two (2) halves that are generally supplied by the capsule manufacturer in an assembled (closed) but not locked state. During capsule filling, the two halves are separated, filled with the pharmaceutical powder formulation comprising the active drug, and then closed and locked. Locked capsules are then inserted into the DPI.
Often, the capsule is a hard, gelatin capsule. Hard cellulose and plastic capsules suitable for storing pharmaceutical powders are also used. Such capsules are available from Capsugel (Belgium), Su-Heung (South Korea) and Elanco (U.S.A.), among other manufacturers.
Where the active drug in the powdered pharmaceutical formulation is to be delivered to the upper respiratory tract (i.e., intranasally), the particles of active drug should be about 20 to about 100 &mgr;m in size. Where administration of the active drug is to be to the lower respiratory tract (i.e., intrapulmonary ) the particles of active drug are preferably less than about 5 &mgr;m in size.
Such sizes present handling problems (i.e., filling the capsules during manufacture), so the active drug is usually mixed with a coarse carrier. The carrier is typically glucose, lactose or mannitol. Additionally, many drugs used in inhalation therapy are given in small doses, i.e., less than about 250 micrograms, so the carrier can also serve as a bulking agent for such drugs. See, for example, U.S. Pat. No. 5,254,335. Moreover, the carrier can also be used to improve the aerodynamic flow of the formulation, and possibly to allow for the dispersion of the particles during inhalation.
Ipratropium bromide (I.B.) is an active drug that is typically administered via inhalation and marketed by Boehringer Ingelheim Pharmaceuticals, Inc. under the brand name ATROVENT®. It presents problems for use in DPIs since the amount of I.B. to be administered is very low (<50 micrograms). Accordingly, I.B. must be blended with a bulking agent such as lactose or glucose for administration via DPIs.
During manufacture of gelatin capsules the internal surfaces of such capsules become coated with mould release lubricants. This is because the manufacturing process for such capsules involves dipping mould pins into molten, capsule forming material, removing the pins from the bath of capsule forming material, and then allowing the capsule-forming material to harden on the pins. The hard capsule shells are then removed from the pins. In order to remove the capsule shells without damage, it is necessary to lubricate the mould pins. It is this lubricant which can coat the inside surface of the capsule. And it is this lubricant which can cause active drug retention in the capsule by the pharmaceutical formulation “sticking” to the walls of the capsule rather than being inhaled.
The problem of drug retention in capsules is compounded by the fact that the amount of lubricant in capsules varies not only from lot to lot but also within each lot from capsule to capsule. The lack of reproducibility in the fraction of drug that reaches the lungs, i.e. the inhalable fraction, may thus be due not only to the presence of lubricant, but also to the relatively large variance in the amount of lubricant in the capsules. None of these factors has proven easy to control during capsule manufacturing.
Additionally, as can well be imagined, the level of ambient humidity in addition to the moisture levels of the powdered pharmaceutical formulation, or capsules, can also affect consistency in dosing of active drug. Such can lead to retention of powdered formulation on the walls and surfaces of the capsules.
Lubricants have been shown to be responsible for most of the powder retention in hard gelatin capsules. Brown, S. (Boehringer Ingelheim Pharmaceuticals, Inc., Unpublished Results, 1994) and later Clark, A. R. and Gonda, I., (U.S. Pat. No. 5,641,510) have addressed this problem by extracting the lubricant material from the capsules using organic liquid solvents. Brown clearly demonstrated that washing the lubricant out of the capsules with an organic solvent leads to a marked reduction of retention. However, use of such solvents can introduce new impurities and solvent contamination, and do not allow for processing of the capsules in their closed state. Another possible solution is to limit the amount of oil that the capsule manufacturer use, so as to minimize adhesion of the powder to the internal surface of the capsule. This has proved not to be practical.
Accordingly, it is an object of the present invention to develop a method for reducing rentention of dry, powdered pharmaceutical formulation in capsules.
It is another object of the present invention to reduce the variation in amount of active drug provided in a dose from a DPI.
It is another object of the present invention to remove moisture or impurities from capsules and also powdered active drug formulations. Other objects and advantages of the present invention will become apparent to one of ordinary skill in the art.
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 solve
Horhota Stephen T.
Saim Said
Boehringer Ingelheim Pharmaceuticals Inc.
Devlin Mary-Ellen M.
Page Thurman K.
Raymond Robert P.
Seidleck Brian K.
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