Drug – bio-affecting and body treating compositions – Preparations characterized by special physical form – Tablets – lozenges – or pills
Reexamination Certificate
2001-06-25
2003-03-18
Dees, Jose′ G. (Department: 1616)
Drug, bio-affecting and body treating compositions
Preparations characterized by special physical form
Tablets, lozenges, or pills
C424S468000, C424S441000, C424S473000, C514S025000, C514S449000
Reexamination Certificate
active
06534087
ABSTRACT:
BACKGROUND OF THE INVENTION
1. Field
The present invention relates to a method for preparing compositions, preferably pharmaceutical compositions, in form of expanded, mechanically stable, lamellar, porous, sponge-like or foam structures out of solutions and dispersions and to dosage forms obtainable by the above method.
2. Description
Pharmaceutical technology formulation work is mostly determined by physico-chemical properties of the pure active drug substance (particle size and shape, flowability, compressibility, polymorphism, wettability, melting point, stability, shelf-life etc.) or other important additives. Many dosage forms are known to the pharmaceutical market, the most important being tablets and capsules. The stabilization of highly sensitive drugs that are supposed to be used or applied orally or parenterally after rehydration, such as dry solutions or dispersions (e.g. suspensions, emulsions) are of major interest.
Downstreaming the pure drug substance into the final market formulation normally comprises several fundamental operations such as milling, seizing, wet or dry granulation, slugging, encapsulation etc. Today, many of these processes are designed to manufacture large amounts of material, e.g. high-speed tabletting. Mechanical energy, produced by impact, pressure or shear stress, can be detrimental to the material. Very often this leads to melting, decomposition or inactivation of the drug substance. Deposits or incrustations caused in this manner may interrupt the process or even destroy the machines.
To facilitate the manufacturing process of dosage form, drug substance has normally to be mixed, blended or granulated with different pharmaceutical excipients, such as lubricants, filler, binder, flowing or dispersing agents etc. These additives can influence the properties of the final composition but can only partially protect against mechanical energy and can even induce stability problems by themselves.
The final composition as well as the corresponding dosage form is also supposed to have very specific properties before, during or after application. For bulk materials (powders, granules, pellets, tablets etc.) high stability and compatibility are desired during storage. Dry suspensions must show exquisite dispersibility in liquids; tablets have to disintegrate either very fast or very slowly after being swallowed. A sufficient wettability of drug particles in gastric or intestinal fluids is a prerequisite for good solubility and absorption. As they are dosed by volume, pharmaceutical powders or granules need sufficient bulk density for tabletting or encapsulation. Depending on dose, these important galenical properties can be negatively impacted by a drug substance or excipient with unsuitable physico-chemical properties (e.g. low melting point; low solubility etc.).
In summary, manner in which a pharmaceutically active compound or pharmaceutically suitable excipient(s) is incorporated into a galenical composition or formulation can be a critical factor that has to be controlled. This manner is essential to:
mask undesirable properties;
stabilize, inertize and protect the critical, incorporated compound;
obtain optimal flowability and density for downstream work; and
get the necessary dispersibility and release characteristics during or after application.
Several techniques for improving these properties are known in the art. However, they very often are not able to overcome all problems and can even induce new problems. For example:
fluid bed coating is not suitable for substances having low melting points or fine and light particles having very high surface area and cylindrical or pin shape;
powders out of (co)precipitation processes (e.g. spray-drying) retain significant amounts of reactive material located to the particle surface;
freeze-drying is very expensive and not suitable for substances that are sensitive to freeze-thaw cycles; and
spray-congealing, melt-embedding or melt-extrusion are only feasible for temperature resistant materials.
International Patent Application WO 96/40077 (Quadrant Holdings Cambridge Limited) discloses a method for the preparation of thin, foamed glass matrices. This method comprising the steps of (a) preparing an initial mixture comprising at least one glass matrix-forming material and at least one solvent including a solvent for the glass matrix-forming material, (b) evaporating bulk solvent from the mixture to obtain a syrup, (c) exposing the syrup to a pressure and temperature sufficient to cause boiling of the syrup, and (d) optionally removing the residual moisture.
International Patent Application WO 98/02240 (Universal Preservation Technologies) discloses a method of preserving sensitive biological dispersions, suspensions, emulsions and solutions by forming stable foams from fluid materials to be dehydrated, as an aid both to the drying of one or more biologically active substrates in the fluid and as an aid in preparing an easily divisible dried product suitable for further commercial use. The stable foams are formed by partially removing the water to form a viscous liquid and by further subjecting the reduced liquid to vacuum, to cause it to boil during further drying at temperatures substantially lower than 100° C. In other words, reduced pressure is applied to viscous solutions or suspensions of biologically active materials to cause the solutions or suspensions to foam during boiling, and using the foaming process further solvent removal causes the ultimate production of a stable open-cell or closed-cell foam.
However, both references disclose boiling as necessary step to prepare compositions. In addition, the mixtures, solutions, emulsions or dispersions have initially to be concentrated by evaporating bulk solvent to obtain the necessary syrup for further use (low vacuum; <30/<24 Torr). Then, after having obtained a syrup of sufficient viscosity, “foaming” (expansion of structure) is carried out at temperature and pressure conditions that cause the syrup to boil.
Sinnamon et al. [
J. Dairy Sci.,
40: 1036-1045 (1957)] discloses the properties of a new dry whole milk, dried under high vacuum and low temperatures in the form of an expanded sponge-like structure. The obtained product disperses easily in cold water and has a natural flavor when reconstituted in the fresh state. However, this method was devised to improve dispersibility and flavor of food products such as dried milk. As a disadvantageous prerequisite, an initial concentration step (up to 50% w/w solids) is necessary for the following foaming process, too. Only when nitrogen will be bubbled through said concentrated milk, the requested “puffed” foam structure is achievable.
Schroeder [Ph. D. thesis entitled “Entwicklung von kompakten Darreichungsformen aus sprühgetrockneten Milcherzeugnissen zur spontanen Rekonstitution” (1999)] discloses mainly the development of a technology which provides densification of dairy or non-dairy food products without changing the instant properties of the originally spray dried powders during reconstitution. However, the described method for vacuum drying of wetted powders took place under conditions (50° C./37.5 Torr) which caused the incorporated water to boil while the requested foam structure was created.
The long felt problem in the art is to provide a processes and compositions that minimize the mentioned disadvantages.
SUMMARY OF THE INVENTION
The subject invention provides a method for preparing a pharmaceutical composition. This method comprises (a) preparing a solution or a homogeneous dispersion, (b) expanding the solution or homogeneous dispersion by exposing it to a change in pressure under conditions such that the solution or homogeneous dispersion does not boil, and (c) stabilizing the expanded solution or homogeneous dispersion to form the pharmaceutical composition. In this method, the solution or a homogeneous dispersion contains a liquid and a compound selected from the group consisting of one or more pharmaceutically active compounds, one or more pharmaceutical
Busson Patrick
Schroeder Marco
Dees Jose′ G.
DeWitty Robert M
Hoffmann-La Roche Inc.
Johnston George W.
Parise John P.
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