Organic compounds

Details Organic compounds Organic compounds

2001-05-17

2002-08-13

Page, Thurman K. (Department: 1615)

Drug, bio-affecting and body treating compositions

Preparations characterized by special physical form

Tablets, lozenges, or pills

C424S465000, C424S474000, C424S464000, C424S480000

Reexamination Certificate

active

06432447

ABSTRACT:

This invention is concerned with formulations for sustained release of fluvastatin.
Fluvastatin is a member of a class of drugs commonly referred to as HMG CoA reductase inhibitors (sometimes called “statins”). The statins are used to reduce blood cholesterol levels in patients in need of such treatment. The site of action of the statins is the liver. Conventional rapid release forms of statins, e.g. which release the statin within about 2 hours have mild side effects associated with systemic delivery of the statin. The statins appear to enter systemic circulation because of the relatively high concentration of statin entering the liver in a relatively short space of time tends to flood the liver such that some of the statin is not metabolised on the first pass.
Sustained release formulations have been suggested as a means of preventing or amelioratiing the side effects associated with systemic entry of the statins-lovastatin, simvastatin and pravastatin (see EP 0 375 156).
Several methods of providing sustained release formulations have been proposed in the art. One such means is to use certain excipients in a matrix which modify the release of an active agent dispersed within said matrix. Hydroxypropyl methyl cellulose (HPMC) polymers have been suggested as release-modifying excipients, either alone or in combination with other materials, in sustained release formulations for use with a wide variety of active agents including the HMG CoA reductase inhibitors, see for example U.S. Pat. No. 4,369,172, U.S. Pat. No. 4,357,469, U.S. Pat. No. 4,226,849 and U.S. Pat. No. 4,389,393. It is thought that formulations containing HPMC polymers prolong drug release by forming a gelatinous matrix upon exposure to the aqueous medium of the stomach which prevents or delays ingress of the aqueous medium of the stomach into the dosage form and thereby preventing its rapid disintegration. The gel matrix is thought to form as a result of hydration of the HPMC polymer. However, the applicant could not find any suggestion that hydration of the HPMC occurred during storage of oral dosage forms containing HPMC Furthermore, whether hydration occurs during storage or not, none of the aforementioned documents refer to any instability problems associated with the use of HPMC and in particular colour instability.
The applicant was therefore surprised to find that dosage forms comprising HPMC polymers formed gel-like domains upon storage, which domains, still more surprisingly were highly coloured. Whereas this discolouration left the dosage forms with an unsightly, uneven mottled appearance, it was of no consequence for the safety and efficacy of the dosage forms. Nevertheless, the mottled appearance may by disturbing to patients and lead to poor patient compliance.
There is a need, therefore to provide dosage forms of fluvastatin for sustained release which are colour-stable upon prolonged periods of storage.
In accordance with the present invention there is provided oral dosage forms comprising a mixture of fluvastatin, HPMC polymers and optionally other pharmaceutical excipients which are colour-stable upon prolonged periods of storage.
As used hereinbove, “colour-stable” used in connection with oral dosage forms is taken to mean said dosage form in which the mottled discolouration hereinabove described is either substantially prevented or is present at levels not detectable by visual inspection, i.e. the mottled disclouration is either so faint as to be not apparent or it is capable of being masked by one or more excipients, e.g. colouring agents.
The presence of the gel-like domains may be detected by visual appearance alone. However, it may also be detected using known analytical techniques, for example microcalorimetry. Microcalorimetry may detect any heat flow, e.g. an exotherm as a result of excipient interactions, e.g. an exotherm associated with the hydration of HPMC. It is a characteristic of oral dosage forms of the invention that they display a significant heat flow, i.e. a heat flow of greater than 5 micro Watts, e.g. up to 59 micro Watts, more particularly 19 to 59 micro Watts over a relatively long period of time, e.g. a period of 48 hours, when subjected to a stress test at 40 degrees centigrade and 75% relative humidity. The stress test may be carried out on an isothermal microcalorimeter (CSC Corporation, Provo. Utah) set to 40 degrees centigrade. The oral dosage form may be subjected to an environment of 75% relative humidity by, e.g. by preparing minihydrostats using a sodium chloride solution inside 250 microlitre polypropylene vial inserts.
As stated hereinabove, colour-stability may be achieved by substantially preventing or modulating the formation of HPMC gels. One means of achieving the object of colour stability may be to reduce the ambient moisture levels surrounding the oral dosage forms during storage. Applicant has found that oral dosage forms stored under conditions such that the relative humidity does not exceed 75%, more preferably no more than 60%, e.g. 40 to 60% at a temperature of between 25 and 40 degrees centigrade, display a markedly reduced tendency towards discolouration. The type of packaging employed may also reduce discolouration. Whereas conventional blister packaging may be employed, e.g. Triplex TPX blisters, it is preferred to use high density polyethylene (HDPE) bottles. Oral dosage forms as hereinabove described packaged in HDPE bottles may exhibit substantially no discolouration associated with the formation of HPMC gels. Oral dosage forms as hereinabove described packaged in HDPE bottles form another aspect of the present invention.
Oral dosage forms according to the invention may be formulated in any conventional form, e.g. powders, capsules or tablets. Preferred oral dosage forms may be in the form of tablets.
Oral dosage forms hereinabove described may be formed of a granulated mass comprising fluvastatin, HPMC and optionally other excipients commonly used in oral dosage forms, e.g. tablets. Surprisingly the applicant has found that the finer is the mean particle size of the granulated mass the less intense is the observed mottled disclouration. The applicant believes that the increased colour stability observed as the mean particle size is decreased may be due to the ability of the finer granules to form a tighter compact when compressed, thereby reducing the incidence and size of any voids in the compacted mass. As the HPMC gels are thought to form in these voids, the smaller their number and/or size, the less tendency there is for gels to form.
Preferred oral dosage forms are tablets which are formed of granulates having a mean granulate particle size of less than about 200 microns, e.g. less than 125 microns, more particularly 100 to 125 microns. However, the contribution to the art is the recognition of a correlation between granulate size and the incidence and nature of the disclouration. It follows that the skilled artisan will understand that for different excipient mixtures, e.g. amounts of HPMC polymer, the incidence and nature of discolouration may vary within this preferred range, and in fact discolouration may be absent or visually insignificant outside of the aforementioned ranges. However, with no more than routine experimentation, the skilled person will be able to determine a suitable granulate size for a given excipient mixture. Granulates as hereinabove described and oral dosage forms, e.g. tablets made therefrom are further aspects of the present invention.
The reduction of moisture levels surrounding the oral dosage forms upon storage and the use of fine granulates as hereinabove described may be used alone or in combination to achieve the objects of the present invention.
As is clear from the definition provided above, an oral dosage form may be “colour-stable” notwithstanding that it may contain significant amounts of HPMC gel such that the mottled discolouration would be quite apparent were it not for the presence of a colouring agent masking said discolouration.
Accordingly the invention provides in another of its aspect

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