Many drugs, which could be efficiently administered by nebulizer for both topical dosing to the respiratory tract and systemic dosing by inhalation as an alternative to injection, are stable for the short time needed for nebulization in pharmacologically acceptable diluents but require storage for physical and/or chemical shelf life stability as dry powders or in vehicles that cannot be safely nebulized in the volumes needed for effective operation of presently practical nebulizers. Also, many drugs that could be efficiently co-administered in the same bolus of diluent do not have good shelf life stability if stored as ready-to-administer unit doses. Also, with regard to co-administration of two or more drugs in combination, individual patient needs and changing patient needs over time often require different doses of different ingredients. It is impractical to manufacture all possible combinations that might be required or to expect individual patients to stock all combinations that they may need at different times. For economy in manufacturing as well as to minimize administration errors, it is desirable to simplify and standardize to the greatest practical extent the way patients and care-givers administer drugs. For drugs for which the most practical means of administration is by nebulization, it is desirable to have a single technology that is efficient and economical for drugs stored in small volumes of liquids that require dilution for nebulization, and for drugs stored as freeze-dried solids that require dissolution for nebulization. For drugs which may at times be needed in combination and for which the optimal dose of different components of the mix may vary at different times, it is desirable to have a single, simple, user-friendly and efficient way for patients to take whatever dose of whichever components they need when they need it.
Recently developed microporous membrane nebulizers offer greater portability and greater control, precision and uniformity of aerosol particle size than previously available jet nebulizers. They also have different parameters for optimal drug packaging. Jet nebulizers have a functional dead space (volume of fill remaining in the device when effective nebulization stops) in the range of 0.5 to 1 ml, mandating dilution of medication fill volumes to approximately 2.5 ml or more, or the “washing through” of remaining medication by additional diluent, for effective, reproducible dosing. In contrast, microporous membrane nebulizers have zero functional dead space. For maximum user convenience and speed of dosing, medications intended for nebulization with microporous membrane devices should be dosed in volumes that would barely fill the functional dead space and not nebulize at all with the older generation of jet nebulizers.
New dosing technologies make it possible to achieve reproducible systemic dosing of many systemically acting drugs by inhalation, as a patient-preferred alternative to repeated injections. Many new products of genetic and molecular engineering fall into this class. To achieve acceptable shelf-life stability, many of these drugs require either storage in the freeze-dried state for reconstitution immediately prior to administration, or storage in small volumes of liquid vehicle, which are not themselves pharmaceutically acceptable for nebulizer administration but which can be made pharmaceutically acceptable by mixing with larger volumes of appropriate diluents, immediately prior to administration. In some circumstances, these medications may be more effective or better tolerated by patients if co-administered with other drugs. Optimal prescribing in many such cases requires sufficient dose individualization and/or variation over time to render the manufacture of all commonly used fixed dose combinations impractical.
There is thus a need for a flexible yet standardizable packaging and delivery system to meet these medication needs and fully exploit their therapeutic potential.
A number of two chamber ampule and vial systems have been developed to address such needs. One such system is described in U.S. Pat. No. 6,247,617. Limitations of this system include the following. For drugs that require non-physiologic storage conditions for shelf-life stability, it is desirable to store unit doses at the highest possible concentration in the smallest possible volumes of non-physiologic vehicle, to minimize the amount of non-physiologic material administered on nebulization. For drug volumes of less than approximately 50 microliters, a significant and variable fraction of the packaged drug dose may be left on the walls of a drug chamber like that of U.S. Pat. No. 6,247,617 that is not rinsed or “washed out” into the full nebulizer mix. Thus, dosing can become irregular and unpredictable. Further, while ampule and vial systems have been developed in which there is “washing out” of the entire drug storage chamber with the resulting nebulizer mix, such systems do not address stability and shelf-life issues and dose variation issues. In addition, such systems have the drawbacks of relatively cumbersome and costly filling processes for the separate chambers, and the requirement that the first chamber to be filled must then tolerate whatever conditions are created in the process by which the second chamber is filled.
The present invention provides ampule designs suitable for the packaging of small volumes of drug solution or suspension or solid phase drugs for dissolution. The ampule comprises an integrated mixing chamber and an aperture designed to facilitate accurate pouring in of diluent or diluent already mixed with other drugs. The same aperture, in some embodiments modified by cutting off a portion to create a narrow outflow slit, is configured to facilitate accurate pouring out of the drug-diluent mix after mixing, into either the intake reservoir of a nebulization device or into another ampule of the present invention for mixing with another drug. In one embodiment, the ampule comprises an upper cone that flips down into a lower cone that serves as a funnel for pouring in of diluent into the integrated mixing chamber and flips up to create a narrow exit orifice for pouring out of drug mixed with diluent from the integrated mixing chamber. In other embodiments, an upper cone serves as a sterile closure during storage and a separate pouring spout may be provided. In different embodiments the ampule is designed to accommodate liquid drug concentrate volumes as small as 2 to 10 microliters or one or more small, breakable inner ampules containing either dry drug in a solid phase or a liquid dosage form for which ampule adherence properties are such that without the separate inner ampule there would be a risk of drug loss by adherence to the walls of the outer ampule. The ampule is designed to be scalable to accommodate any reasonable target fill volume or mixing volume for unit dose nebulizer administration.
The present invention provides single, disposable ampules for storage and dilution of small volumes of drug in either liquid vehicle or in solid phase for suspension or dissolution in diluent at the time of nebulization.
By small liquid volume, as used herein, it is meant a liquid volume sufficiently small that its physical and chemical properties will not alter the nebulization characteristics of the diluent, and that the mass of any non-physiologic constituents will be below the threshold of toxicity. Such volumes will generally be in the range of 2 to 100 μl.
By small solid volume, as used herein, it is meant a volume of solid phase drug small enough for easy and efficient dissolution or suspension in a volume of diluent sufficient for efficient administration in the device intended for nebulization, without adversely affecting the nebulization properties of the resulting solution or suspension. With presently available nebulization devices, practical upper limits for a small solid volume for most clinical applications will be of the order of magnitude of 1 mg. However, as understood by those skilled in the art, the practical upper limit for nebulization does not determine the effective dose of a drug. Instead, the relationship between the desired treatment dose and the practical upper dose limit for this technique will determine the appropriateness of this delivery system for each drug. As the practical upper limit is also limited by the number of minutes one wishes to ask a user to spend inhaling each dose, if a particular treatment is critical and there are no practical alternatives, it may become practical to use larger volumes of liquid or solid drugs requiring larger volumes of diluent and correspondingly longer nebulization times.
The practical ability to increase dose by increasing nebulized volume and treatment time may not apply to drugs stored for shelf life stability in non-physiologic liquid storage vehicles, as increasing dose of these formulations will result in increased dose of excipients along with increased doses of drug, raising issues of possible excipient toxicity.
Various ampule designs of the present invention are exemplified by
As shown in these figures, all ampule designs of the present invention comprise a lower chamber, referred to as the medication mixing chamber 2 with side walls 2w, an open top 2t, and a sealed bottom 2b. As shown by
All ampules of the present invention further comprise an intake aperture designed to facilitate the precise and accurate pouring in of diluents and an outflow aperture designed to facilitate the precise and accurate pouring out of the diluent-drug mix after mixing. The intake and exit apertures may or may not be one and the same. Intake apertures will generally but not necessarily have the shape of a cone or polygonal cross-section pyramid. The outflow aperture in different embodiments may be the same as the intake aperture or may be a pouring spout incorporated in an intake cone, the narrow opening in an upper cone, or a slit cut out of an upper cone.
In the illustrated embodiments the intake aperture comprises a lower cone or pyramid 3 positioned at the top 2t of the medication mixing chamber 2. The lower cone 3 comprises a narrower bottom 3b contiguous with the top 2t of the medication mixing chamber 2 and a wider open top 3t.
All ampules of the present invention further comprise an upper cone or pyramid 4, either closed at its own apex or topped by a closed cap 8. The upper cone or pyramid 4 is attached at its lower and widest circumference to the upper and widest circumference of the lower cone or pyramid 3.
In various embodiments of this invention, the drug packaged in the ampule is delivered to the medication mixing chamber prior to opening the ampule (to add diluent which may or may not already contain other drugs) either by tapping the bottom of the unopened ampule against a hard surface to tap down any drug adherent to the upper parts of the ampule, by positioning the ampule so that a brittle inner drug-containing ampule falls to the bottom of the mixing chamber, or packaging the drug in an inner ampule 13 that is already anchored to the bottom of the medication mixing chamber.
In embodiments of the ampule of the present invention depicted in
Alternatively, in embodiments of the ampule of the present invention depicted in
Each ampule embodiment further comprises either a base 1 or rack 10 to support the ampule in an upright position. For ampule designs in which the bottom of the medication mixing chamber 2 must be sufficiently tough and flexible to enable pinching the outer ampule to break open a brittle inner ampule and shatter it sufficiently to allow effective mixing of its contents with the surrounding diluent, a base cannot be directly attached to the bottom of the ampule as such an attachment would reduce the flexibility needed for pinching. These embodiments provide for either a rack from which the ampule can be removed to pinch the medication mixing chamber and break the inner ampule (see
For manufacturing of ampule designs of
All embodiments of the invention in which an inner ampule is tethered to the bottom of the main ampule of the invention are molded in a horizontal position, so that the tether can be anchored to the bottom when the two pieces of the main ampule are sealed together after filling. In these embodiments the join line extends around the ampule from top to bottom in a plane perpendicular to the plane of the tear line, which runs circumferentially around the ampule between the cones.
If storage stability requires a specific atmosphere, such as dry nitrogen, the plastic used for the ampule must be impermeable to both the gases one wants to keep in and those one wants to keep out, and the ampules must be sealed in the required atmosphere.
Embodiments as depicted in
For manufacturing and filling operations in which filled and sealed ampules are transferred or transported while still in position in the outer part of the molds in which the upper parts were made, it may be most practical to flip
Ampules of the present invention may contain a single ingredient or fixed dose combination of ingredients, either freeze-dried in the mixing chamber or dissolved or suspended in volumes of liquid vehicle as small as 2 to 10 microliters. Drug may also be stored in a separate inner ampule, to be broken after diluent is added to the outer ampule, when there is a risk of loss by adherence to surfaces of the ampule in the absence of this precaution. This may occur for drugs in the form of fine powders and for drugs in small volumes of liquid vehicles with surface tension and boundary layer properties that favor the unrecognized adherence of small volumes of drug powder or drug in vehicle to the inside of the ampule, in the absence of a separate, inner ampule. Such small inner vials may be brittle so that the vial is broken by pinching the flexible sides of the outer ampule over the brittle inner ampule. In this embodiment, the brittle inner vial preferably further comprises a flexible outer mesh coating to keep the broken pieces together and prevent their being poured out with the drug mix when the ampule is emptied. Broken inner ampule pieces can also be prevented from pouring out of the drug mix via a baffle 15 such as depicted in
Cleanliness rather than sterility is all that is needed for this step for the overwhelming majority of patients taking inhaled medications, as only liquids need to be kept sterile up to the time of nebulization and hard, dry surfaces including those of the nebulizers used to administer these medications need only be kept clean.
Drug formulations packaged directly in the medication mixing chamber of the ampules of this invention will generally be freeze-dried drugs requiring mixing and dissolution for nebulization, or small volumes of drug in solution or suspension in a liquid vehicle that may or may not be pharmaceutically acceptable for nebulization as it is, but that can be made pharmaceutically acceptable for nebulization by mixing with a larger volume of an appropriately formulated diluent. The diluent may already contain other drugs at the time that it is added. If there is a risk of loss of the intended drug content by unrecognized or hard-to-control adherence to the inside of the ampule, which will most commonly be the case for drugs in the form of fine powders, the drug may be packaged in a separate inner ampule, for which several embodiments have been shown (
It is anticipated that the drug packaged in the ampule will generally be mixed with the diluent or mix of diluent and other drugs that has been poured into the mixing chamber by gently swirling the ampule. It is possible that certain combinations of drug and diluent may require alternate mixing procedures.
Various means for filling the ampules of the present invention are depicted in
When the fill of the embodiment of the ampule illustrated in
Further, it is possible using the ampules of the present invention to package two or more drugs separately via means of sealed inner ampules in the same ampule, to be mixed within the same ampule upon addition of diluent. One drug may be placed directly in the outer ampule in a small volume of liquid, and one or more drugs may be packaged in inner ampules of the types previously described, which are placed or tethered in the outer ampule prior to sealing.
This patent application claims the benefit of priority from U.S. Provisional Application Ser. No. 60/577,872, filed Jun. 8, 2004, the teachings of which are herein incorporated by reference in their entirety.
Filing Document | Filing Date | Country | Kind | 371c Date |
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PCT/US05/20026 | 6/8/2005 | WO | 12/5/2006 |
Number | Date | Country | |
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60577872 | Jun 2004 | US |