Patent Application
20070202182
In order for a drug to achieve its desired result, it typically has to be delivered to a biological site of interest. Most drugs in use today are solid ingestibles. For these drugs to be absorbed into the bloodstream and transported to a biological site of interest, they usually have to first be dissolved and then permeate the intestinal walls. The preparation of small particles can increase the dissolution rate and potentially the bioavailability of a selected drug candidate. Solubility may be modified by physically grinding a drug to yield micron size and smaller particles. However, this mechanical approach can cause chemical or physical degradation of the drug, by shearing and heat stress.
Recent advances in drug formulation have enabled drugs to be rendered in nanoparticle-size. For instance, the patent application “Nanoparticle formation of pharmaceutical ingredients,” filed on Jan. 13, 2006, and assigned Ser. No. 11/332,131 [attorney docket 200504581-1], describes multiple approaches for forming nanoparticles of drugs. However, most pharmaceutical processing equipment is geared towards micron-sized particles. Therefore, such existing equipment may then not be able to be used on nanoparticles of drugs, slowing the adoption of nanoparticle-sized drug formulations. For these and other reasons, there is a need for the present invention.
The drawings referenced herein form a part of the specification. Features shown in the drawing are meant as illustrative of only some embodiments of the invention, and not of all embodiments of the invention, unless otherwise explicitly indicated.
In the following detailed description of exemplary embodiments of the invention, reference is made to the accompanying drawings that form a part hereof, and in which is shown by way of illustration specific exemplary embodiments in which the invention may be practiced. These embodiments are described in sufficient detail to enable those skilled in the art to practice the invention. Other embodiments may be utilized, and logical, mechanical, and other changes may be made without departing from the spirit or scope of the present invention. The following detailed description is, therefore, not to be taken in a limiting sense, and the scope of the present invention is defined only by the appended claims.
First, a slurry is prepared (102), in which nanoparticles of a pharmaceutical ingredient have been formed within a solvent. In one embodiment, one or more of the approaches described in the patent application “Nanoparticle formation of pharmaceutical ingredients,” filed on Jan. 13, 2006, and assigned Ser. No. 11/332,131 [attorney docket 200504581-1], may be employed to prepare this slurry. The solvent may be a single solvent, or a multiple solvent, such as a binary solvent.
For instance, the solvent may be a binary solvent, such as ethanol:chloroform having a proportion of 80% ethanol to 20% chloroform by volume (i.e., 80% of the volume of the solvent is ethanol, and 20% of the volume is chloroform). Other solvent combinations have also been proven to result in nanoparticle formation. These include 80% ethanol by volume and 20% water by volume; 80% methanol by volume and 20% water by volume; and, 80% acetone by volume and 20% water by volume. It is noted that the terminology “solvent” as used herein is inclusive of the plural “solvents,” when, for instance, a binary solvent, or another type of multiple solvent, like a ternary solvent, is used.
Referring back to
Next, a solid formulation of the nanoparticles is prepared from the slurry (106). This solid formulation includes at least micron-sized particles formed at least from the nanoparticles of the pharmaceutical ingredient. The micron-sized particles are thus at least one micron in size, whereas the nanoparticles are less than one micron in size, and may be only nanometers in size. Different techniques and approaches for preparing such a solid formulation of the nanoparticles, resulting in micron-sized particles, are described in detail later in the detailed description.
It is noted that electrostatic collection is not employed in preparing the solid formulation of the nanoparticles from the slurry, in at least some embodiments of the invention. Electrostatic collection can be a complex procedure, and not having to employ such electrostatic collection, such as by instead using one of the techniques described in detail later in the detailed description, simplifies the solid formulation preparation.
Finally, one or more techniques may be utilized to form ready-to-dispense elements, such as pills, of the pharmaceutical ingredient from the micron-sized particles of the solid formulation of the nanoparticles of the pharmaceutical ingredient (108). Such techniques can include spray-drying, fluidized bed coating, dry and wet milling, dry blending, and compaction, among other types of techniques. These techniques are employable within the context of micron-sized particles, and rely upon the containment of stray particles using high efficiency particulate air (HEPA) filtering systems, which can screen only micron-sized particles, and not, for instance, nanoparticles.
Therefore, embodiments of the invention are advantageous, because they allow for pharmaceutical ingredients to have increased bioavailability, as a result of the nanoparticles, but provide for ready-to-dispense elements to be formed, as a result of the micron-sized particles formed from the nanoparticles. That is, embodiments of the invention allow for the utilization of industry-standard pharmaceutical processing equipment, which is optimized for micron-sized particles, in relation to nanoparticles of pharmaceutical ingredients. As a result, embodiments of the invention facilitate the adoption of nanoparticles into drug formulations, since existing pharmaceutical processing equipment can be employed in relation to such nanoparticles.
Spray-drying of the nanoparticles within the solvent of the slurry can be accomplished within part 304 as follows. First, the slurry is introduced into a spray-drying apparatus (306). Next, the nanoparticles are mixed into a drying gas, to disperse the slurry into micron-sized droplets (308). The temperature and relative humidity of the flow of the drying gas may be appropriately controlled to result in dispersal of the slurry into micron-sized droplets. The drying gas may be compressed air, nitrogen, carbon dioxide, or another type of drying gas that has little or no chemical reactivity with the material being dried.
The solvent is evaporated from the micron-sized droplets of the slurry (310), resulting in agglomerates of the nanoparticles forming as the at least micron-sized particles of the solid formulation. The introduction, mixing, and evaporation of parts 306, 308, and 310 thus results in the concentration or aggregation of the nanoparticles of the slurry into larger, micron-sized agglomerates that retain the high surface area-to-volume ratio of the nanoparticles. However, the nanoparticle agglomerates (i.e., the micron-sized particles) have a sufficiently high density. As a result, the micron-sized particles can be collected (312), using existing equipment, such as a cyclone-collecting apparatus.
The resulting of the mixing of the nanoparticles of the slurry 200 into the drying gas 404 is the dispersion of the slurry 200 into micron-sized droplets 410A, 410B, . . . , 410N, collectively referred to as the droplets 410. The solvent from these droplets 410 evaporates, resulting in the formation of agglomerates 412A, 412B, . . . , 412N, collectively referred to as the agglomerates 412, of the nanoparticles. These agglomerates 412 are the at least micron-sized particles of the solid formulation of the pharmaceutical ingredient.
The drying gas 404, and the evaporated solvent, are exhausted from the cyclone-collecting apparatus 414, as indicated by the arrow 416. However, the micron-sized particles themselves are collected within the cyclone-collecting apparatus 414, as indicated by the arrow 418. The collected micron-sized particles can be subjected to various techniques to form ready-to-dispense elements of the pharmaceutical ingredient, as has been described in relation to part 108 of the method 100 of
It is noted that the slurry 200 can include a residual dissolved portion of the pharmaceutical ingredient that has not been formed into nanoparticles, as has been described. In this case, the evaporation of the solvent in part 310 of
Fluidize-bed coating of the excipient particles with the nanoparticles formed within the slurry can be accomplished within part 504 as follows. First, an excipient powder, which includes the excipient particles, is fluidized (506). For instance, the excipient powder may be introduced into a fluidized bed-coating apparatus. Next, the slurry is delivered to the fluidized excipient particles (508), resulting in coating of the excipient particles with the nanoparticles formed within the slurry, to form the micron-sized particles. Thus, an atomizing-spraying apparatus may be used to deliver the slurry, including the nanoparticles formed therewithin, to the excipient particles of the powder.
The slurry may be top-sprayed onto the excipient particles, bottom- or fountain-sprayed onto the excipient particles, or tangential- or side-sprayed onto the excipient particles. The excipient particles may be a water-insoluble material or a water-soluble material. For instance, the excipient particles may be cellulose acetate, a polyacrylic-based excipient, fumed silica, talc, titanium dioxide, zinc oxide, cornstarch, hydroxypropyl methylcellulose (HPMC), or another type of excipient particle. In another embodiment, the excipient particles themselves may be of the same or different pharmaceutical ingredient as the nanoparticles that have been formed within the slurry. That is, the excipient parts may have the same or different chemical composition as that of the pharmaceutical ingredient of the nanoparticles in such an embodiment. Furthermore, the excipient particles may themselves be at least micron-sized, such that the micron-sized particles of the solid formulation of the pharmaceutical ingredient result from coating the nanoparticles of the pharmaceutical ingredient onto these excipient particles.
Thereafter, the excipient particles, as have been coated with the nanoparticles of the pharmaceutical ingredient, are dried (510). For instance, a drying gas may be introduced into the fluidized bed-coating apparatus to dry the excipient particles as coated. The fluidize bed-coating process of part 504 may be repeated as desired (512), to achieve the needed, desired, or appropriate coating of the excipient particles with the nanoparticles of the pharmaceutical ingredient. Thus, the excipient powder fluidized in part 506 is that which has had its excipient particles already coated with nanoparticles, more of the slurry with more of the nanoparticles is introduced in part 508, and then the excipient particles as twice (or more) coated with the nanoparticles are dried in part 510.
During the fluidized-bed coating process in part 504, the flow rates of the slurry and of a fluidizing gas used to fluidize the excipient powder can be controlled to affect the thickness of nanoparticle coating on the excipient particles. Furthermore, the temperature of the fluidizing gas, or of a separate drying gas if a different gas is used for drying, may be controlled to optimize drying of the excipient particles after coating with nanoparticles. Examples of fluidizing gases include compressed air, nitrogen, carbon dioxide, as well as other types of fluidizing gases. Thus, the fluidizing gas can serve as the drying gas to dry the nanoparticle-coated excipient particles, or a different drying gas can be employed. Examples of drying gases that are separate from the fluidizing gas include compressed air, nitrogen, carbon dioxide, as well as other types of drying gases.
Next, the slurry 200 is delivered to the excipient powder 604, as has been fluidized as the excipient particles 614, via the atomizing-spraying apparatus 616, as indicated by the arrow 618. The atomizing-spraying apparatus 616 atomizes the slurry 200, and sprays the slurry 200 onto the excipient particles 614. The result is the pharmaceutical ingredient nanoparticle-coated excipient particles 620A, 620B, . . . , 620N, collectively referred to as the nanoparticle-coated excipient particles 620. That is, the atomized slurry 200 coats the particles 614, such that the nanoparticles coat the particles 614, to result in the nanoparticle-coated particles 620. These nanoparticle-coated particles 620 are at least micron-sized particles, where the excipient particles 614 themselves are at least micron-sized.
It is noted that the atomizing-spraying apparatus 616 as depicted in the example of
In one embodiment, coating the tablets with the nanoparticles formed within the slurry can be accomplished within part 702 as follows. First, the tablets are tumbled within a drum apparatus (704). Next, the slurry is delivered to the tablets being tumbled (706), resulting in coating of the tablets with the nanoparticles formed within the slurry, to form the micron-sized particles. The slurry may be delivered via utilization of an atomizing-spraying apparatus. Thereafter, the tablets, as have been coated with the nanoparticles of the pharmaceutical ingredient, are dried (708). For instance, a drying gas may be introduced into the drum apparatus to dry the tablets as coated.
The coating process of part 702 may be repeated as desired (710), to achieve the needed, desired, or appropriate coating of the tablets with the nanoparticles of the pharmaceutical ingredient. Thus, the tablets tumbled in part 704 are that which have already been coated with nanoparticles. Likewise, more of the slurry with more of the nanoparticles is introduced in part 706, and then the tablets as twice (or more) coated with the nanoparticles are dried in part 708.
During the coating process in part 702, the flow rates of the slurry and of a drying gas can be controlled to affect the thickness of the nanoparticle coating on the tablets. Furthermore, the temperature of the drying gas may be controlled to optimize drying of the tablets after coating with nanoparticles. Examples of drying gases include compressed air, nitrogen, carbon dioxide, as well as other types of drying gases.
The result is the pharmaceutical ingredient nanoparticle-coated tablets 810A, 810B, . . . , 810N, collectively referred to as the nanoparticle-coated tablets 810. That is, the atomized slurry 200 coats the tablets 804, such that the nanoparticles coat the tablets 804, to result in the nanoparticle-coated tablets 810. The nanoparticle-coated tablets 810 are the at least micron-sized particles. Further, a drying gas 812 is introduced into the drum apparatus 802, as indicated by the arrow 814, to dry the coated tablets 810. The at least micron-sized particles, as the coated tablets 810, can then be subjected to various techniques to form ready-to-dispense elements of the pharmaceutical ingredient, as has been described in relation to part 108 of the method 100 of
It is noted, therefore, that although specific embodiments have been illustrated and described herein, it will be appreciated by those of ordinary skill in the art that any arrangement calculated to achieve the same purpose may be substituted for the specific embodiments shown. This application is intended to cover any adaptations or variations of the disclosed embodiments of the present invention. It is thus manifestly intended that this invention be limited only by the claims and equivalents thereof.
