Drug – bio-affecting and body treating compositions – Preparations characterized by special physical form – Capsules
Reexamination Certificate
2001-11-16
2003-08-19
Page, Thurman K. (Department: 1615)
Drug, bio-affecting and body treating compositions
Preparations characterized by special physical form
Capsules
C424S458000, C424S461000, C424S462000, C424S493000, C424S494000, C424S497000, C424S490000
Reexamination Certificate
active
06607747
ABSTRACT:
BACKGROUND OF THE INVENTION
2′, 3′-dideoxyinosine, which is also known as didanosine or ddI, is an acid labile drug which will degrade in the stomach. Didanosine has the following structural formula.
Didanosine is known to be effective in the treatment of patients with the HIV virus by inhibiting HIV replication. Furthermore, ddI has become widely used as a component of the therapeutic cocktails for treating AIDS.
Didanosine is generally available in a variety of oral dosages, including Chewable/Dispersible Buffered Tablets in strengths of 25, 50, 100 or 150 mg of didanosine. Each tablet is buffered with calcium carbonate and magnesium hydroxide. Didanosine tablets also contain aspartame, sorbitol, microcrystalline cellulose, Polyplasdone®, mandarin-orange flavor, and magnesium stearate. Didanosine Buffered Powder for Oral Solution is supplied for oral administration in single-dose packets containing 100, 167 or 250 mg of didanosine. Packets of each product strength also contain a citrate-phosphate buffer (composed of dibasic sodium phosphate, sodium citrate, and citric acid) and sucrose. A didanosine Pediatric Powder for Oral Solution is also available and which is supplied for oral administration in 4- or 8-ounce glass bottles containing 2 or 4 grams of didanosine respectively, and is to be mixed with commercial antacid before oral ingestion.
With particular emphasis on the tablets, whether ingested alone or as part of a combination (“cocktail”) therapy regimen, the current chewable/dispersible buffered tablets are not conducive from a patient ease of use standpoint. Whereas the other products which are a part of the AIDS therapeutic cocktail are capsules or tablets and easily swallowed, the ddI Chewable/Dispersible Buffered Tablets must be thoroughly chewed or uniformly dispersed in water before administration.
Because ddI degrades rapidly at acidic pH, ddI, in its chewable/dispersible form and its buffered powder for oral solution form, contains buffering agents and is administered with antacids in the pediatric powder form. However, the presence of the large quantities of antacid components in the formulation can lead to significant GI imbalance as noted by severe diarrhea. Many patients also complain about chewing the large ddI tablets (a single dose is two tablets of 2.1 g each), the taste of the ddI or the time required to disperse the tablets and the volume of fluid (4 oz) required for the dose. As the current adult dose is 200 mg ddI, twice a day, or a single dose of 400 mg ddI daily, a high ddI load formulation without antacid or buffers is necessary to avoid the discomforting side effects and difficulty of administering the current ddI compositions.
SUMMARY OF THE INVENTION
The present invention relates to a spheronized beadlet comprising about 80% to about 100% by weight of an acid labile medicament, about 0% to about 10% by weight of a disintegrant, and about 0% to about 10% by weight of a binder selected from the group consisting of sodium carboxymethylcellulose, hydroxypropylmethylcellulose, potassium alginate, sodium alginate and partially pregelatinized corn starch. The present invention also relates to a high drug load pharmaceutical composition comprising said acid labile spheronized beadlet and an enteric coating disposed thereon. The present invention further relates to processes for making said spheronized beadlet and high drug load pharmaceutical composition.
The beadlets and pharmaceutical composition of the present invention are useful for administering a high loading of acid labile medicament is a small total amount of pharmaceutical composition.
DETAILED DESCRIPTION
In the present invention, a spheronized beadlet is provided wherein the beadlet contains (a) a high loading, about 80-100% by weight, of an acid labile medicament such as ddI, pravastatin, erythromycin, digoxin, pancreatin, 2′,3′-dideoxyadenosine, 2′,3′-dideoxycytosine and the like, (b) optionally one or more binders, and (c) optionally a disintegrant. Preferably, the acid labile medicament is ddI.
Binders, suitable for the present invention, are those which are non-acidic and, when utilized in small proportions, support formation of beadlets during spheronization. A suitable binder should also be non-acidic, and preferably alkaline, so as to minimize degradation of the acid labile medicament during spheronization. Typically, suitable binders include one or more binders wherein the amount of binder present in the core is an amount within the range of from about 0% to about 10% by weight, and preferably, about 1% by weight of the beadlet. In the present invention, sodium carboxymethylcellulose is the preferred binder. Examples of other binders, which are suitable for use in the present invention, include partially pregelatinized corn starch (Starch 1500; Colorcon, Ltd.), hydroxypropyl methylcellulose (HPMC) (Shin-Etsu Chemical Co., Ltd.), potassium alginate and sodium alginate.
The spheronized beadlet of the present invention may also include one or more disintegrants in an amount within the range from about 1% to about 4% by weight of the beadlet. Examples of suitable disintegrants include sodium starch glycolate (EXPLOTAB®; Edward Mendell Co.), cross-linked sodium carboxymethylcellulose (Ac-Di-Sol; FMC Corp), corn starch, and cross-linked polyvinylpyrrolidone. Sodium starch glycolate is the preferred disintegrant.
In the process of the present invention of high (80-100%) potency beadlets, containing acid labile medicaments, such as ddI, are formed using an aqueous extrusion/spheronization methodology. No specialized equipment is required as conventional extrusion and spheronization equipment was found to be adequate for beadlet formation. Use of a non-acidic, and preferably alkaline binder, such as sodium carboxymethylcellulose, and dusting during spheronization with a dry blend mixture, comprising the medicament, the optional binder, and the optional disintegrant, provide assurance of the chemical stability of the medicament and maximize the drug load. The process of the present invention also resulted in a high (>90%) yield of beads of narrow particle size cut.
The beadlets of the present invention may be prepared as follows. A granulation solvent, such as is typically suitable for spheronization of an acid labile medicament, is mixed with (a) an acid labile medicament, (b) optionally a binder, and (c) optionally a disintegrant, to form a wet mass. The preferred granulation solvent is water. The relative proportions of the components in the wet mass are typically about 80-100 parts by weight acid labile medicament, about 0 to about 10 parts binder, about 0 to about 10 parts disintegrant, and about 20 to about 36 parts granulation solvent. Preferably, the relative proportions of the components of the wet mass containing ddI are about 95 parts ddI, 1 part sodium carboxymethylcellulose, 4 parts sodium starch glycolate and about 25 parts water.
The wet mass is then extruded, for example by employing a Nica or other type extruder, to form an extrudate. The extrudate is subsequently spheronized using a spheronizer such as Caleva, Nica or other type, to form beadlets. During spheronization, a dry mixture containing the same proportions of acid labile medicament, optional binder and optional disintegrant, as are present in the wet mass, is dusted onto the extrudate and onto the forming beadlets to absorb granulation solvent at the surface of the extrudate and beadlets and, thus, reduce the surface tackiness of the beadlets, thereby forming non-agglomerating beadlets.
In one embodiment, the dry mixture is prepared and then separated into two parts. of these parts, a first part, containing about 4% to about 15% of the dry mixture, is set aside for use in dusting during spheronization, while the second part is mixed with the granulation solvent to form the wet mass which is subsequently extruded and spheronized.
Normally, drug beads are formed, through spheronization, by first preparing a wet mass which is extruded into threads or noodles. These threads o
Ullah Ismat
Wiley Gary J
Bristol--Myers Squibb Company
McNeil Scott Alexander
Page Thurman K.
Rodney Burton
Sheikh Humera N.
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