Drug – bio-affecting and body treating compositions – Preparations characterized by special physical form – Particulate form
Reexamination Certificate
2000-10-13
2002-03-26
Spear, James M. (Department: 1615)
Drug, bio-affecting and body treating compositions
Preparations characterized by special physical form
Particulate form
Reexamination Certificate
active
06361798
ABSTRACT:
BACKGROUND OF THE INVENTION
Microcapsules and Microspheres formed from various natural and synthetic polymers and resins have become popular delivery vehicles for various active agents such as drugs, diagnostic reagents and the like. Degradable microcapsules and microspheres are of particular interest for use in so called “depot” formulations, where delivery of the active agent over an extended period of time is desired. Despite the growing number of uses of microcapsules and microspheres, there remains a need for an economic, safe and reliable method for their manufacture and formulation that avoids the most significant wastes and expenses associated with existing methods, while simultaneously enabling the ability to aseptically formulate the products in a simple and efficient manner.
Processes for preparing microcapsules and microspheres typically involve the formation of at least one dispersed phase in a continuous phase. The dispersed phase typically includes the active agent. In the case of microspheres, the dispersed phase will also typically include polymer so that, upon solidification in the continuous phase, the dispersed phase becomes a microsphere. Microcapsules are similarly formed using multiple phases. In a typical practice, a water-oil-water (w/o/w) emulsion is formed, and the polymer caused to precipitate out of one phase onto the surface of a dispersed phase to form a capsule wall thereon upon solidification of the polymer. Once the capsules or spheres are produced, they must then be formulated into a finished dosage form.
Most microsphere processes result in a suspension of particles in a suspending liquid that is not the suspending liquid desired for the final dosage form. Current techniques for processing and formulating microspheres and microcapsules into the final dosage form typically involve dead end filtration and powder filling processes. Although the powder processes can be made aseptic, they tend to have the drawbacks of using large volumes of flammable solvents, capital intensive equipment trains are generally required for a fixed scale and they take a comparatively long time to produce a finished batch. Likewise, the time and capital expense associated with powder filling processes can put one at a significant competitive disadvantage.
There is a need for a process that can efficiently, economically and aseptically process and formulate microcapsules and microspheres into final dosage forms.
DISCLOSURE OF THE INVENTION
The present invention is directed to a method and apparatus for processing and formulating active agent containing polymer bodies, and more particularly microspheres and microcapsules. The method and apparatus according to the invention are ideal for formulating microcapsules and microspheres suitable for carrying drugs, diagnostic reagents, or various other active agents into final dosage form. The inventive method provides a simple, economic, efficient and aseptic means of formulating a product wherein the sterile field need not be compromised throughout the entire production cycle. As used herein, terms such as “sterile” and “aseptic” are taken to mean sterile or aseptic enough to meet current USP standards. The apparatus according to the invention is relatively inexpensive and easily broken down and sterilized, thereby significantly reducing capital expenditures associated with aseptic powder processes. Moreover, product batches can be produced with shorter cycle times than current processes for producing microcapsules and microspheres. A 500 gram bacth of leuprolide containing microspheres can be prepared and processed into final dosage vials on the order of three days.
The method and apparatus of the invention are most preferably employed to formulate microspheres produced in accordance with the process disclosed in co-pending application Ser. No. 08/800,924, filed Feb. 13, 1997 U.S. Pat. No. 5,945,126, incorporated herein by reference. Preferably, the active agent is a drug or diagnostic agent and the microspheres are intended for the delivery of such drug or diagnostic agent to a patient in need thereof. The preferred drugs may be peptide drugs, proteinaceous drugs, steroidal drugs, non-steroidal drugs, simple compounds and so on. A representative list of suitable drugs and other active agents may be found in U.S. Pat. Nos. 5,407,609, 4,767,628, 3,773,919 and 3,755,558, all incorporated herein by reference. Of particular interest are LH-RH agonists such as leuprolide, triptorelin, goserelin, nafarelin, historelin and buserelin, LH-RH antagonists, somatostatin and its analogs such as octreotide, human, salmon and eel calcitonin, growth hormones, growth hormone releasing hormones, growth hormone releasing peptide, parathyroid hormones and related peptides, interferon, erythropoietin, GM-CSF, G-CSF, thymosin, antitrypsin, enterostatin, and chemotherapy drugs, antibiotics and analgesics for regional administration. An especially preferred drug for use in the instant invention is leuprolide.
The advantages of the invention are accomplished by maintaining and processing the microspheres or microcapsules as a suspension. While significant advantages can be achieved by processing the product as a suspension, there is also a significant potential for product losses if adequate precautions are not taken to maintain the suspension and ensure proper product flow throughout the process.
Generally speaking, the formulating process of the invention involves the concentration, washing and. formulating of agent containing polymer bodies, i.e., microspheres or microcapsules, that are maintained in a suspension of a continuous phase. Typically, the continuous phase containing the polymer bodies is initially water, or water containing residual impurities from the process used to make the microspheres or microcapsules, such as surfactants, residual solvent and the like. In order to formulate the polymer bodies into a final product it is necessary to process the polymer bodies into an appropriate sterile concentration of polymer bodies in a suitable pharmaceutically acceptable diluent or carrier, i.e., formulating medium. The present process accomplishes this aseptically by processing the polymer bodies as a suspension using a filter capable of removing the continuous phase without deleteriously effecting the suspension of polymer bodies. The continuous phase which, as noted, can initially be water, but subsequently during the process can be other suspending media, including water for injection and formulating medium, is then cycled back to a process vessel as a suspension for further processing in subsequent phases. Advantageously, a hollow fiber filter provides an ideal means of accomplishing the concentration of the polymer bodies, and the replacement of the continuous phase with other continuous phases such as water and/or formulating medium.
In practicing the inventive method of formulating according to the invention, a suspension of agent containing polymer bodies in a continuous phase is provided in a process vessel. In a preferred embodiment the apparatus will employ only a single processing vessel, which serves to formulate the microspheres and microcapsules in accordance with the method described herein. However, configurations can be devised in which the process vessel performs multiple functions. For example, it can also serve as a solvent removal vessel as a preliminary step to the practice of the inventive method. Similarly, multiple process vessels can be employed in series, each functioning to perform one or more phases of the formulating process, such as a concentrating phase, a washing phase and a formulating phase, respectively.
Since one of the advantages of the invention is derived from the simplicity and limited capital costs of the apparatus used, it is generally preferred that a minimum number of vessels be employed. However, on larger scale processes, where significant volumes are to be processed, it may be necessary to employ two process vessels and hollow fiber filters in series to minimize losses. Thus, in another pre
Murtagh James
Thanoo Bagavathikanun Chithambara
Oakwood Laboratories L.L.C.
Spear James M.
Watts Hoffmann Fisher & Heinke
LandOfFree
Method and apparatus for formulating microspheres and... does not yet have a rating. At this time, there are no reviews or comments for this patent.
If you have personal experience with Method and apparatus for formulating microspheres and..., we encourage you to share that experience with our LandOfFree.com community. Your opinion is very important and Method and apparatus for formulating microspheres and... will most certainly appreciate the feedback.
Profile ID: LFUS-PAI-O-2826945