Drug – bio-affecting and body treating compositions – Preparations characterized by special physical form – Particulate form
Reexamination Certificate
2001-10-30
2004-02-10
Page, Thurman K. (Department: 1615)
Drug, bio-affecting and body treating compositions
Preparations characterized by special physical form
Particulate form
C424S491000, C424S493000, C424S496000, C424S489000, C424S484000, C424S485000, C424S488000, C424S500000, C424S501000, C424S502000
Reexamination Certificate
active
06689388
ABSTRACT:
FIELD OF THE INVENTION
This invention relates to sustained-release powders made from high viscosity liquids.
BACKGROUND OF THE INVENTION
Many high viscosity fluids have useful utilitarian properties, but need to be converted into a powder so that they can then be employed in various applications. A powder, preferably a free flowing powder, can be weighed more precisely, and can be used in various machinery without clogging the apparatus or plugging various portals. In the pharmaceutical industry, many therapeutic agents are high viscosity fluids, and would need to be converted to a powder to enable a proper dosage form such as a tablet or a capsule. Many food ingredients, nutrients, cosmetics, and feed stuffs are also produced as high viscosity fluids, especially those substances that are in an oil base.
Further, once a high viscosity fluid is converted into a powder, it can then be further processed into a stabilized, sustained-release form. The benefits of producing sustained-release formulations of drugs or other therapeutic agents is now widely recognized in the medical literature and is utilized in many commercial products. It is important to distinguish between solid monolithic dosage forms such as tablets, and powders, and particles that are loosely packed into capsules. A sustained-release powder consists of microparticles that are microencapsulated using a manufacturing process that enables them to be ingested, as, for example a powdered drink-mix which can be added to a liquid and still retain its sustained-release and taste masking properties, or encapsulated in two piece hard shell gelatin capsules. Certain polymer-based microencapsuled powders may behave differently when subjected to the high pressures required to form tablets, and may fracture in the process. In addition, sustained-release tablet formulations may employ other techniques that emanate from their large size, surface area and the swelling properties of hydrocolloids. These are designated monolithic dosage forms, because their sustained-release properties arise from their size. In this case, diffusion and solubility issues become important for sustained-release. It is the rate of diffusion through a thick barrier that produces the sustained-release.
One example of sustained-release dosage forms are multi-particle formulations that when ingested in capsule form, rapidly disintegrate into a large number of subunits. This is fine for drugs that are effective at relatively low doses, or dose levels that can fit into a capsule that is a reasonable size. The amount of drug that can fit into a two piece hard shell capsule that is easy for most people to swallow is at most about 800 mg. based on bulk density of the compound. But when large doses are required, such as for example with nutraceuticals, amino acids, or botanical substances, it is desirable to take them in a powder dosage form that can be mixed with a liquid and consumed.
There are many different ways to microencapsulate drugs that can result in sustained-release properties for the drugs. Many of these methods can be found in M. H. Goucho,
Microcapsules and Microencapsulation Techniques,
1976, hereby incorporated by reference, M. H. Goucho,
Microcapsules and other Capsules,
1979, also incorporated by reference; and
Aqueous Polymeric Coatings For Pharmaceutical Dosage Forms,
1989, (publ. Marcel Dekker, Inc.), further incorporated by reference. Most of the methods of producing sustained-release microparticles can be classified into either physical or chemical systems. Physical methods would include such techniques as pan coating, gravity-flow, centrifuge, and the Wurster Process. The Wurster Process employs a high velocity air stream that is directed through a cylindrical fluidized bed in which the particles are suspended in the air. A coating is sprayed onto the suspended particles, and the particles flow out the top of the cylinder and descend back to the fluidized layer. The flow of air dries the coating, so that successive layers can be applied repeatedly by further spraying. Variables that control the process include the number of cycles, temperature, pressure, and humidity, and can be used to provide the desired coating composition and thickness.
Chemical methods of microencapsulation are usually coacervation or phase separation. This technique involves dissolving a membrane forming polymer in a suitable solvent or vehicle and the drug to be dissolved is suspended in this solution and kept under agitation. The coating precipitates onto a droplet of the drug, similar to crystallization.
Fluidized bed granulation or coating is one of the most common techniques used at the present time for small particle sustained-release. Fluidized bed equipment is available as “top spray”, “bottom spray”, and “tangential-spray”. The core drug is first preheated in the vessel to about 30° C. with hot air, placing the particles in suspension. The floating particles are then sprayed with a polymer to provide a coating, while drying at the same time. Inlet temperature, spray rate, and air throughput must be adjusted to provide optimum end product. Furthermore, the finished particles must be subjected to a post-drying period at around 40° C., where any residual moisture can be driven off. In some case, this last drying period may be up to 24 hours.
Many of the polymers that are used to provide sustained-release properties to powders in the fluidized bed process require solvents such as acetone, isopropyl alcohol, chlorinated solvents, alkanes, methyl ethyl ketone, cyclohexane, toluene, carbon tetrachloride, chloroform, and the like. Evaporation of the solvents becomes an environmental concern, and in many states, it is illegal to release these emissions into the atmosphere. Aqueous or water based polymers are limited mainly to ethyl cellulose and methacrylic acid esters such as poly methacrylate dispersions. In addition, 10-20% of a suitable plasticizer such as triethyl citrate must be added to the polymer. For example, U.S. Pat. No. 5,603,957 uses a solvent-based polymer system to deliver aspirin over a 24-hour period. Preferred solvents are acetone/alkanol mixtures, or cyclohexane, toluene, or carbon tetrachloride. Castor oil, a low melting point oil, is also included in the polymer solvent mix.
Typical aqueous ethyl cellulose polymers currently in wide use include; Surelease®, Colorcon, West Point, Pa., and Aquacoat®, FMC Corporation, Philadelphia, Pa. In the Aquacoat® brochure available on their web site, it is recommended that for sustained-release applications, at least a two hour curing time at 60° C. be conducted to insure reproducible release profiles. This should be done in a tray dryer. Subjecting drugs and other therapeutic compounds such as botanical extracts to 60° C. temperatures for 2 hours or more is likely to result in a loss of potency or degradation of active principles, and is especially problematic for substances with low melting points. Botanical extracts, in particular, have many volatile compounds that can be destroyed if kept at high temperatures for long periods.
Another polymer in common use for sustained-release applications is Eudragit®, Huls America, Somerset N.J. This is a neutral methacrylic acid ester with a small proportion of trimethylammonioethyl methacrylate chloride. This polymer is also applied using the fluid bed process, or can be used in a standard wet granulation procedure.
Wet granulation involves mixing the drug or therapeutic agent with water in a conventional high-speed mixer until a pasty mass, and then dried in an oven over 24 hours at 60° C. Wet granulations have the additional draw back in that they can effect the potency of botanical extracts by causing instability, or transformation. In addition, when dried at 60° C., many sensitive active principles are lost.
Spray drying high viscosity fluids on a maltodextrin carrier is the preferred method for converting wet substances to dry powders. This method is less than ideal in that the yields are usually very low, and the high viscosity fluid or paste must usua
Di Nola-Baron Liliana
Lipoprotein Technologies, Inc.
Page Thurman K.
Thorpe North & Western LLP
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