Process for producing wet ribavirin pellets

Details Process for producing wet ribavirin pellets Process for producing wet ribavirin pellets

2001-03-19

2004-04-13

Wilson, James O. (Department: 1623)

Drug, bio-affecting and body treating compositions

Preparations characterized by special physical form

Capsules

C514S043000

Reexamination Certificate

active

06720000

ABSTRACT:

BACKGROUND OF THE INVENTION
1. Field of the Invention
The present invention relates to a process for making oral pharmaceutical dosages of ribavirin. More specifically, the drug ribavirin is a synthetic nucleoside analog with broad spectrum antiviral activity. Ribavirin is one of a combination of drugs being administered to patients with Hepatitis C and other viral infections.
Ribavirin is currently manufactured, among other methods, using a process commonly called dry compaction. Dry compaction utilizes high pressure to form a ribbon of ribavirin that is subsequently reduced to a free flowing powder by milling. The undesirable side effects of manufacturing ribavirin by dry compaction include the creation of excessive dust, a potential health hazard, as well as the risk that high pressure, which can produce high heat, could produce polymorphic forms. Different polymorphs or combinations of polymorphs are undesirable because they can sometimes change the manner in which the active drug moiety is absorbed.
The present invention describes a method for manufacturing ribavirin using a wet granulation process. This process forms a free flowing ribavirin by mixing ribavirin with a wetting agent and various excipients to form a granulation that can be extruded and spheronized, producing a pellet. This process is not only an alternative method for producing ribavirin, but also offers several advantages over the dry compaction process. One advantage of wet granulation is that significantly less dust is produced, which is important from a health and safety standpoint. Another advantage of the present invention is that wet granulation allows for greater control of dissolution rates. In addition, this wet granulation method results in the ribavirin having better flow characteristics, enabling faster encapsulation and lower weight variations. Finally, because there is little heat or excessive pressure, the wet granulation method lowers the risk of creating polymorphs and, therefore, allows for greater uniformity of the crystalline structure.
2. Description of the Prior Art
It is well known in the art that a raw drug often is unsuitable for medicinal purposes because the raw drug has undesirable dissolution profiles and cannot be efficiently encapsulated because of poor flow qualities. For efficient encapsulation, proper flow is vital to producing a uniform, quality pharmaceutical product for a variety of reasons, including that these factors can affect how much active drug is absorbed and when it is absorbed into the human body.
Excipients are often added to raw drugs in order to create a mixture having improved flow, compaction, or disintegration characteristics. These excipients can add various qualities either to the end product or to some stage of the manufacturing process. Common excipients include disintegrants, lubricants, fillers, binders and wetting agents. Disintegrants absorb water quickly when the dosage form reaches the alimentary canal. Lubricants help with mold release and flow. Fillers provide bulk and, along with binders and wetting agents, add adhesion to the mixture. However, some formulas produce a finished dosage form that is too large or results in disintegration rates which could be slower or faster than is optimal.
The following three methods are commonly used to mix excipients with raw drugs to produce pharmaceutical capsules: (1) direct blend, (2) dry compaction, and (3) wet granulation. In the direct blend process, drugs and selected excipients are added to a blender and mixed in the dry state to produce a uniform distribution of the active drug. This direct blend method requires an active drug with acceptable flow characteristics. In the dry compaction process, drugs and selected excipients are mixed and then compacted into a ribbon and milled to a uniform particle size. This operation often generates heat. The result is a free flowing powder that can be encapsulated. Finally, in the wet granulation process, the drugs are mixed either in their liquid form or with a wetting agent to produce a wet mass that can be further processed to produce a free flowing material, which in turn can be encapsulated.
Heretofore, there have been no references in the prior art that demonstrate the successful use of the wet granulation process to manufacture ribavirin capsules. Rather ribavirin is presently made using a dry compaction process as shown in U.S. Pat. Nos. 6,051,252, 5,916,594 and 5,914,128. Each of U.S. Pat. Nos. 6,051,252, 5,916,594 and 5,914,128 describes a method of producing dosages of ribavirin using high pressures which could generate high temperatures. Specifically, U.S. Pat. Nos. 6,051,252 and 5,914,128 both describe the use of compressing forces that range from 50 to 75 kilonewtons of force.
Although the most common pharmaceutical dosage of ribavirin is 200 mg, other dosages could be manufactured.
SUMMARY OF THE INVENTION
It is, therefore, an object of the present invention to provide an alternative method for preparing pharmaceutical dosages of ribavirin which reduces the amount of ribavirin dust that is produced during the manufacturing process, allows for greater control of dissolution rates, and increases flow rates. This goal is accomplished through a wet granulation process that combines ribavirin with specific disintegrants, binders, fillers, and wetting agents in sufficient quantities to form an extrudable mass.
One preferred embodiment of the invention teaches that the extrudable mass is mixed to form a uniform mixture of active drug and excipients, which mixture is subsequently formed into pellets by extrusion and spheronization.
More specifically, the present invention is a process for producing ribavirin pellets, comprising the steps of mixing ribavirin with at least one excipient into a uniform mixture; forming said uniform mixture into a granulated mass by adding a wetting agent to said uniform mixture; shaping said granulated mass into flowable particles; and drying said flowable particles, resulting in dried flowable particles.
These objects, as well as other objects and advantages of the present invention, will become apparent from the following description, in reference to the illustrations and charts appended hereto.


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