Drug – bio-affecting and body treating compositions – Preparations characterized by special physical form – Tablets – lozenges – or pills
Reexamination Certificate
1998-12-15
2003-10-21
Page, Thurman K. (Department: 1615)
Drug, bio-affecting and body treating compositions
Preparations characterized by special physical form
Tablets, lozenges, or pills
C424S451000, C424S452000, C424S464000, C424S489000
Reexamination Certificate
active
06635278
ABSTRACT:
BACKGROUND OF THE INVENTION
The invention relates to pharmaceutical formulations for human or veterinary use that contain the nucleotide analog 9-[2-[[bis[(pivaloyloxy)methyl]phosphono]methoxy]ethyl]adenine (adefovir dipivoxil or hereafter “AD”). The present invention also relates to methods to prepare the formulations.
AD is the bis-pivaloyloxymethyl ester of the parent compound 9-[2-(phosphonomethoxy)ethyl]adenine (“PMEA”), which has antiviral activity in animals and in humans. AD and PMEA have been described, e.g., U.S. Pat. Nos. 4,724,233 and 4,808,716, EP 481 214, Benzaria et al., “Nucleosides and Nucleotides” 14(3-5):563-565, 1995, Holy et al., “Collect. Czech. Chem. Commun.” 54:2190-2201, 1989, Holy et al., “Collect. Czech. Chem. Commun.” 52:2801-2809, 1987, Rosenberg et al., “Collect. Czech. Chem. Commun.” 53:2753-2777, 1988, Starrett et al., “Antiviral Res.” 19:267-273, 1992 and Starrett et al., “J. Med. Chem.” 37:1857-1864, 1994. Heating of solid AD resulted in a decomposition process initiated by hydrolysis (Lee et al., Amer. Assoc. Pharm. Sci., Western Regional Meeting, poster Nos. F-1 and F-2, Apr. 24-25, 1997).
Prior AD formulations have not contained alkaline excipients. Typical AD formulations contain pregelatinized starch, croscarmellose sodium, lactose monohydrate, talc and magnesium stearate. Such compositions are typically packaged with up to 5 g of silica gel as a desiccant. The desiccant is needed to allow storage of AD of at least 2 years at room temperature.
OBJECTS OF THE INVENTION
The invention compositions or methods accomplish one or more of the following objects.
A principal object of the invention is to provide AD formulations having improved stability, whereby the amount or presence of stabilizing means such as silica gel or activated carbon is reduced or eliminated and the formulations can be stored at room temperature.
Another object is to provide compositions used as intermediates to prepare the AD formulations.
Other objects are to provide methods to make the AD formulations.
SUMMARY OF THE INVENTION
In accordance with the objects, the invention provides formulations comprising AD and an alkaline excipient with or without L-carnitine-L-tartrate.
Embodiments include intermediate compositions containing AD and AD formulations in the form of unit dosages, such as tablets or capsules typically comprising about 2-50% AD and about 0.001-10% alkaline excipient.
Other embodiments include a product produced by the process of contacting a mixture comprising AD and an alkaline excipient.
Other embodiments include a method comprising mixing AD with an alkaline excipient to obtain a mixture.
Other embodiments include methods to make a formulation comprising AD and an alkaline excipient by wet granulation or by direct compression.
Other embodiments include a product made by the process of preparing a formulation comprising AD and an alkaline excipient by wet granulation or by direct compression.
DETAILED DESCRIPTION OF THE INVENTION
Formulations such as tablets comprising AD and an alkaline excipient were found to have a significantly improved stability when stored at room temperature (about 15-25° C. as used herein) in closed containers compared to control formulations lacking an alkaline excipient. Without being bound to any theory, it appears that the alkaline excipient stabilizes AD by adjusting the local pH or by reducing the rate of AD degradation product formation. The pivaloyloxymethyl moieties in AD, esters of PMEA, are typically susceptible to acid- and base-catalyzed hydrolysis. Aqueous AD solutions have their maximum stability at a low pH, about 3-5, but AD tablets containing acidic excipients, such as citric acid, actually compromised the stability of AD compared to control formulations lacking acidic excipients. Thus the stabilizing effect of alkaline excipients on AD was not reasonably predictable.
The invention formulations permit storage at room temperature with a reduced or eliminated requirement for packaging aids such as silica gel or activated carbon. The formulations also allow the use of AD preparations that are about 97% pure AD while retaining sufficient stability to retain a shelf-life of at least 2 years at room temperature. As used here, “shelf-life” means the storage time at room temperature that one can hold a formulation while the purity of the AD remains at ≧ about 92% purity.
AD is a nucleotide analog having antiviral activity against HIV, HBV, CMV, and several other viruses. It has the following structure.
Anhydrous crystalline AD is preferred in invention compositions over previously described amorphous AD, see, Starrett et al., “J. Med. Chem.” 19:1857-1864, 1994. U.S. application 08/900,745 describes crystalline forms of AD.
When one prepares invention compositions using anhydrous crystalline AD, a portion of the AD may comprise the crystalline dihydrate of AD (AD.2H
2
O) or amorphous AD. The portion of the crystalline dihydrate of AD or amorphous AD will typically be less than about 20% of the AD that is present. These forms may arise during processing of intermediate compositions and formulations. For example, some invention compositions comprising L-carnitine-L-tartrate may generate some AD.tartrate during processing or storage. AD used in invention compositions may comprise other crystalline salts such as AD.½H
2
SO
4
, AD.HBr, AD.HCl, AD.HNO
3
, AD.CH
3
SO
3
H, AD.C
2
H
5
SO
3
H, AD.&bgr;-naphthalene sulfonic acid, AD.&agr;-naphthalene sulfonic acid, AD.(S)-camphor sulfonic acid, AD.fumaric acid, AD.succinic acid, AD.maleic acid, AD.ascorbic acid or AD.nicotinic acid.
Anhydrous AD crystals generally have a median size by light scattering of about 25-150 &mgr;m, usually about 30-80 &mgr;m. Individual anhydrous AD crystal preparations usually comprise crystals that have a length range of about 1-200 &mgr;m and have a typical maximum dimension for individual crystals in a preparation of about 60-200 &mgr;m. In some preparations, about 1-10% of the crystals will have a maximum dimension of greater than 250 &mgr;m. Anhydrous AD crystals typically have tablet, plate, needle, and/or irregular habits. Aggregates of anhydrous crystals also occur with a typical diameter range of about 25-150 &mgr;m. Anhydrous AD crystals are usually used to prepare invention compositions. However, during wet granulation and other processing steps needed to prepare formulations, a portion of the crystals may convert to an amorphous form or absorb water to form AD.2H
2
O crystals. Anhydrous AD crystals have an endothermic transition as measured by differential scanning calorimetry at about 102° C. (usually 102±1° C.).
AD.2H
2
O crystals typically have a median size of about 15-85 &mgr;m by light scattering, ordinarily about 25-80 &mgr;m. Individual AD.2H
2
O crystal preparations usually contain crystals that have a length range of about 1-300 &mgr;m. Anhydrous AD crystals have an endothermic transition as measured by differential scanning calorimetry at about 73° C. (usually 73±1° C.).
As used herein “excipient” means a component or an ingredient that is acceptable in the sense of being compatible with the other components of the formulation and not deleterious to a patient or animal to which the formulation is to be administered.
“Alkaline excipient,” as used herein, is an excipient with a pK
a
of the conjugated acid of at least about 4.0 and that has a K
sp
of about 1×10
−3
to about 1×10
−15
, usually about 1×10
−4
to about 1×10
−11
. Alkaline excipients are usually an alkaline carbonate or an alkaline hydroxide. Alkaline carbonates include calcium carbonate, magnesium carbonate, zinc carbonate, manganese carbonate, aluminum carbonate, ferrous carbonate or cobalt carbonate. Alkaline hydroxides include magnesium hydroxide, calcium hydroxide, aluminum hydroxide or iron hydroxide.
As used herein and unless otherwise stated or implied by context, the terms “excipient” or “alkaline excipient” or a specific type of excipie
Dahl Terrence C.
Yuan Lung-Chi J.
Gilead Sciences, Inc.
Hensley Max D.
Page Thurman K.
Tran S.
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