Extended dosage forms of stavudine are provided comprising beadlets formed by extrusion-spheronization and coated with a seal coating. The beadlets are also coated with a modified release coating such that a hard gelatin capsule containing such beadlets will provide blood levels of stavudine over approximately 24 hours. The beadlets are prepared from a dry blend of stavudine, a spheronizing agent, a suitable diluent and a stabilizing amount of magnesium stearate. The magnesium stearate, in contrast to other similar pharmaceutical adjuncts, has been found to stabilize stavudine against degradation due to hydrolysis in the presence of the limited amount of water necessary for the extrusion-spheronization process. Also included in the scope of the invention are hard gelatin capsules containing, in addition to the stavudine beadlets, similar beadlets containing other therapeutic agents utilized to treat retroviral infections.

SUMMARY OF THE INVENTION

Stable beadlets containing stavudine prepared by conventional extrusion/spheronization techniques are provided. The beadlets are suitable for preparing extended release dosage forms capable of providing 24 hour blood levels of stavudine with a single dose. The beadlet formulation in accordance with the present invention is novel in that there is included in the dry blend an amount of magnesium stearate sufficient to stabilize stavudine against hydrolysis during subsequent processing to form the beadlets. Hydrolysis of stavudine in the formulation manifests itself both in loss of potency and as a discoloration of the beadlets formed therefrom, i.e. beadlets formed in accordance with the invention stay white whereas those prepared with other similar conventional adjuncts become yellow to brown in color. The beadlets are first seal-coated and then coated with a modified release coating of a polymeric barrier material, such as ethylcellulose, and a suitable plasticizer therefor that provides for the release of stavudine over time, so that they will provide blood levels of stavudine over approximately 24 hours. An appropriate amount of such beadlets is filled into conventional hard gelatin capsules. Similar beadlets of other compounds active against retroviruses may be included in the capsules as well, thereby providing for an extended combination therapy over approximately 24 hours.

DETAILED DESCRIPTION OF THE INVENTION

Studies of various conventional extended release dosage forms have shown that a beadlet formulation appears to be most suitable for stavudine. One of the primary reasons for this is that, as stated above, it is common for AIDS medications to be given in combinations in order to obtain the maximum antiretroviral effect. Utilizing beadlets, it is possible to compound two or more medications individually into beadlets, which are then filled into conventional hard gelatin capsules. Such separate compounding avoids any potential compounding problems that might be encountered with trying to combine such medications into the same formulation. Another reason favoring beadlets is that it has been found that stavudine is generally absorbed throughout the GIT as described above. Therefore, it would be ideally suited for extended release in a form, such as beadlets, that would slowly pass through the system. In addition, of the recognized forms of sustained or extended release, beadlets have been shown to possess a more reproducible GI transit time than larger dosage forms, such as tablets.

A significant advantage of an extended release dosage form of stavudine is that a single daily dosage tends to increase patient compliance since fewer doses are missed. This is particularly important with regard to AIDS medication since it is a primary objective of the therapy to keep the virus at low or undetectable levels. A further advantage of extended release dosage forms of medicaments such as stavudine is a reduction in the side effects resulting from the elevated blood levels that can result from ingesting individual dosages too close together. An additional advantage of the beadlets of the present invention over other extended forms of sustained release is that there is a lower incidence of dose dumping as might result, for example, from inadvertently chewing a matrix tablet. Finally, since many AIDS patients often experience GI upset or diarrhea, beadlets are a preferable dosage form since they pass more slowly through the small intestine and colon and thus produce more consistent blood levels. It is reported, for example, in the Int. J. Pharm. Vol. 140 (AUG. 30), pages 229 235 (1996) that pellets have a longer residual time in the colon in comparison to tablets.

Those of ordinary skill in the art will recognize that there are several techniques for forming beadlets containing a medicament that can be coated to produce extended release. Drug coating or layering onto sugar seeds, and direct formulation by rotary granulation are two such conventional techniques. However, both of these methods would entail substantial contact with water, which would result in degradation of a medicament, such as stavudine, that hydrolyzes comparatively quickly in contact with moisture and heat. Other methodologies utilizing non-aqueous solvents might be utilized, but would be significantly disadvantaged due to safety and environmental issues. The extrusion and spheronization technique would therefore appear to be the method of choice since it permits the manufacture of beadlets containing a high loading of medicament in a relatively short time with, most important for stavudine, minimum contact with water.

Extrusion spheronization is a well-known technique for forming beadlets of medicament. The process, in essence, comprises forming a mixture of an art-recognized spheronizing agent and other suitable dry excipients with the medicament, wet granulating the mixture with a limited amount of water to form a wetted mass of powder that is extruded through a conventional extruder equipped with a suitable screen to form discrete extrudates. The extrudates are then transferred to a spheronizer wherein they are cut and shaped into discrete spherical beadlets, which are thereafter dried. Spheronizers are commercial equipment well known to those of ordinary skill in the art. The resulting spheroids may vary in both size and degree of sphericity depending on a number of factors such as the amount of water in the wetted powder, the configuration of the plates in the spheronizer, both the speed and duration of operation of the spheronizer, and the like. Typically, spheroids produced by this process are 0.5 to 1.5 millimeters at their largest dimension. Such spheroids are ideally suited for coating to form an extended release dosage form by virtue of their size and shape. For the same reason, they are also readily filled into conventional empty gelatin capsules. It will be appreciated that, with a moisture sensitive medicament such as stavudine, the steps of extrusion and spheronizing would be carried out in rapid succession to minimize contact with water.

While there are a number of spheronizing agents known to those of ordinary skill in the art utilized as being useful in the manufacture of beadlets by the extrusion/spheronization technique, the most common is microcrystalline cellulose. Other agents useful in extrusion/spheronization techniques include sodium carboxymethylcellulose and corn starch, however, the quality of beadlets prepared therefrom is not as good as those obtained utilizing microcrystalline cellulose. The spheronizing agent functions to provide plasticity to the formulation that fosters the formation of spherical beadlets and also to supply the binding properties that give the beadlets strength and integrity. Microcrystalline cellulose is typically utilized as the single excipient in spheronizing techniques or it may commonly be combined with a suitable diluent, typically lactose, more preferably Lactose Hydrous NF. Microcrystalline cellulose is commercially available from a number of sources and in a variety of grades and physical characteristics or specifications. For example, a variety of grades and types of microcrystalline cellulose are available under the trademark Avicel from FMC Corporation. Typically, microcrystalline cellulose, with or without a diluent such as lactose, is utilized to formulate the granulation for spheronization without any other conventional additives, such as conventional tabletting lubricants, flowing agents and the like. In fact, the manufacturer's descriptive literature on Avicel states that it is an advantage of the product that it can be used without such conventional agents. A description of the use of microcrystalline cellulose in extrusion and spheronization as well as a composition containing microcrystalline cellulose and a hydrocolloid may be found in U.S. Pat. No. 5,725,886, assigned to FMC Corporation.

Even the use of extrusion and spheronization techniques with a minimum contact with water has not proved ideal for formulation of extended dosage forms of stavudine due to its tendency to hydrolyze in the presence of moisture. However, it has been found in accordance with the present invention, that stavudine can be compounded into a granulation suitable for extrusion and spheronization without undergoing any material degradation by the inclusion in the formulation of magnesium stearate. This result is considered unexpected for two reasons. First, because of the properties of the excipients utilized to form such granulations, specifically microcrystalline cellulose, and the nature of the techniques itself, one of ordinary skill in the art would not be motivated to consider including a conventional tabletting lubricant in the formulation. Second, magnesium stearate is effective in stabilizing stavudine in the granulation whereas other similar conventional tabletting lubricants/processing aids, such as talc and colloidal amorphous silicon, do not produce the stabilizing effect. In general, an amount of magnesium stearate between about 0.5 and 3.0 percent by weight, preferably between about 1.4 and 1.7 percent by weight, based on the weight of stavudine present, is sufficient to provide the stabilizing effect realized in accordance with the present invention. Magnesium stearate possesses an added unexpected advantage in that it protects the beadlets from turning yellow to brown, i.e. beadlets prepared from a formulation containing magnesium stearate are noticeably whiter than those prepared from formulations without it or with other conventional tabletting lubricants.

In general, stavudine comprises from about 33 to about 67 percent by weight of the beadlets formed by extrusion and spheronization in accordance with the present invention. The process is advantageous in that it enables a high loading of medicament into the beadlets. The finished dosage forms will contain stavudine in various dosages depending of its projected therapeutic regimen. Generally, beadlets containing dosages of stavudine of 37.5 mg., 50 mg., 75 mg. and 100 mg., respectively, would be contemplated in a single hard gelatin capsule. The requisite amount of stavudine is combined with microcrystalline cellulose, a suitable diluent such as lactose, preferably Lactose Hydrous NF, and a stabilizing amount of magnesium stearate, thoroughly mixed and wet granulated with a minimum amount of water to achieve the requisite granulation. The diluent is required to obtain a reasonable weight for the beadlets so that they can be filled into conventional gelatin capsules utilizing conventional filling apparatus. It will be understood by those of ordinary skill in the art of pharmaceutical compounding that other similar ingredients may be substituted for the preferred lactose in the formulations. Such other diluents include, for example, dicalcium phosphate, mannitol and cornstarch. The granulation is formed in a conventional blender and is thereafter extruded utilizing a Nica, Luwa or other conventional extrusion equipment to form an extrudate which is then processed in conventional spheronizing equipment such as Caleva, Nica, Luwa, or other type, to convert the extrudate into beadlets of the desired particle size range. The beadlets contemplated in accordance with the present invention would be, for example, from about 0.7 to about 1 mm in diameter.

The beadlets thus-formed may be dried by tray drying in a suitable oven or by fluidized bed drying. The finished beadlets are coated with a seal coating utilizing conventional film-formers such as hydroxypropyl methylcellulose (HPMC), hydroxypropyl cellulose (HPC) and the like, in combination with an antiadherent agent to retard the tendency of the beadlets to agglomerate during the coating operation. While talc is preferred, microcrystalline cellulose and magnesium stearate may also serve as antiadherent agents. In general, the weight ratio of film-former to antiadherent agent in the coating composition will be from about 4:1 to 2:1. The seal coating aids in rounding the beadlets and insulates stavudine in the beadlets from contact with the modified release coating. The beadlets are then coated with a barrier or modified release coating to achieve extended dissolution and absorption over a period such that they will provide blood levels of stavudine over a 24 hour period. Typically, the modified release coating constitutes from about four to about six percent by weight of the finished beadlets. The modified release coating comprises a polymeric barrier material and a suitable plasticizer therefor. The polymeric barrier material may be a suitable polymethacrylate but is preferably a commercially available aqueous latex dispersion of ethylcellulose. Suitable commercial preparations of ethylcellulose include , e.g. Surelease available from Colorcon, which is available in combination with a plasticizer and Aquacoat.RTM. available from FMC Corporation, which is typically mixed with a suitable plasticizer. Preferred plasticizers include a mixture of acetylated monoglycerides, dibutyl sebacate, triethylcitrate and the like. An appropriate amount of the modified release coated beadlets is then filled into the appropriate size hard gelatin capsules. Generally, the coated beadlets will be comprised of from about 50 to about 67 percent by weight, preferably about 55 percent by weight, of stavudine.

A further advantage of the beadlets of the present invention is that they can be combined in hard gelatin capsules as described with other medicaments useful in the treatment of retroviral infections so that blood levels of the combination over a period of 24 hours can be achieved with a single dose. Such combination therapy is considered a treatment of choice in the treatment of AIDS. Such therapeutics agents include, for example, didanosine (2', 3'-dioxyinosine), [3S-(3R*,8R*,9R*,12R*)]-3,12-Bis(1,1-dimethylethyl)-8-hydroxy-4,11-dioxo-- 9-(phenylmethyl)-6{[4-(2-pyridinyl)phenyl]methyl }-2,3,6,10,13-pentaazaretetradecanedioic acid dimethyl ester, indinavir, lodenosine and others as are or will hereafter become available for the treatment of retroviral infections. Such agents would be utilized in combinations of two or three as therapeutically appropriate and might be combinable in appropriate sized hard gelatin capsules. It is within the purview of the present invention to combine such antiretrovirals dosage-wise such that a two capsule dose taken once a day would be required to combine effective dosages of the combination. The ability to formulate stable beadlets of stavudine in accordance with the present invention enables such combination therapy possible to that effective blood levels of the combination over 24 hours can be realized with a single dosage.
 

Claim 1 of 34 Claims

1. Extruded-spheronized beadlets comprising stavudine, a spheronizing agent, and a quantity of magnesium stearate sufficient to stabilize stavudine against degradation during the extrusion-spheronization process.
 

____________________________________________
If you want to learn more about this patent, please go directly to the U.S. Patent and Trademark Office Web site to access the full patent.