Drug – bio-affecting and body treating compositions – Preparations characterized by special physical form – Particulate form
Patent
1995-01-12
1998-09-15
Page, Thurman K.
Drug, bio-affecting and body treating compositions
Preparations characterized by special physical form
Particulate form
424464, 424468, 424461, A61K 914
Patent
active
058075836
DESCRIPTION:
BRIEF SUMMARY
This application is a 371 of PCT/SE93/0025 filed Mar. 16,1993.
TECHNICAL FIELD OF THE INVENTION
The present invention relates to the manufacture of pellets having defined and sustained release characteristics and their multiple unit dose formulations.
The term "pellets" will forthcomingly refer to spherical or spheroidal particles having diameters ranging from 0.2-2.5 mm.
By "multiple unit dose formulation" is contemplated an oral dose formulation that at the appropriate location in the gastrointestinal tract, usually the stomach or intestines makes available a high number of similar units (e.g. pellets or granules).
DESCRIPTION OF THE PRIOR ART
In the field of pharmaceutical development, it is generally agreed that the oral administration of a multiple unit dose formulation possessing a sustained release of the drug substance is beneficial compared to conventional tablet formulations having similar release properties. The benefits of multiple unit dose formulations are primarily that the transport and distribution of the free units in the various segments of the gastrointestinal tract are more uniform and reproducible than single unit dosage forms.
With respect to tablets one has successfully obtained the desired release properties by coating the tablets with wax-like substances or mixes thereof, or by embedding the drug substance in a matrix of binder of different degree of hydrophilicity/hydrophobicity, if necessary together with auxiliary substances like fillers, buffering substances etc.
With respect to granulation/pelletization of powdery drugs the more common techniques are: solution or suspension that contains an active substance, binder and water. The amount of active substance in the pellets/granules will normally be </=30% (w/w). The product will have a spherical/spheroidal form when the starting material has such a form. appropriate plastifying binder (e.g. 10-50% microcrystalline cellulose or methyl cellulose), followed by rounding the extrudate on a rotating disc. like suitable polymers. The geometric shape of the ultimate pellets/granules is determined by the geometric shape of the crystals. substance.
In order to optimize and control the sustained release properties, the granules should preferably be spherical (pellets) and have a uniform size. Niro Atomizer has introduced a novel method for preparing pellets (U.S. Pat No. 5,030,400 that is hereby incorporated by reference). By their process, pellets are prepared in a high shear mixer by spraying an aqueous binder solution onto finely divided solid material during continued mixing. A controlled growth of the pellets is achieved by carefully controlling the liquid saturation of the moist granules during the process. The process requires a high energy input.
It has recently been demonstrated that pelletization can be achieved in high shear mixers from powdery mixtures containing active substances and wax-like hydrophilic melting binders (i.e. polyethylene glycols) (PCT application PCT/SE91/00690 (now U.S. Pat. No. 5,476,677) and T. Schaefer et al, Drug Development and Industrial Pharmacy 16 (1990) 1249-77)). Polyethylene glycol liquefies during the process due to the development of heat caused by the agitation. This latter process is usually classified as melt granulation or thermoplastic granulation. Pellets within the size range given above and with a narrow size distribution and a high content of active drug substance have been achieved.
Processes for the manufacture of sustained release formulations (granules/pellets as well as tablets) using wax-like binders are well-known (U.S. Pat. No. 4,013,784 and U.S. Pat. No. 4,132,753 granules; U.S. Pat. No. 4,935,246 coating of granules; Ghali et al, Drug Dev Ind Pharm 15(9) (1989) 1311-1328 extrusion and spheronization).
DIFFICULTIES ASSOCIATED WITH MANUFACTURE OF DELAYED RELEASE GRANULES
A major problem related to the manufacture of granules and pellets is to control their release properties. Granules/pellets present an extremely large surface and a high release rate potential compa
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patent: 5030400 (1991-07-01), Danielsen et al.
patent: 5358560 (1994-10-01), Hitch et al.
Schaefer et al, Drug Development and Industrial Pahrmacy, 16(8), pp. 1249-1277 (1990).
Ghali et al, Drug Development and Industrial Pharmacy, 15(9), pp. 1311-1328 (1989).
Kristensen Arne
Kristensen Henning
Schaefer Torben
Thomsen, deceased Lars Juul
Benston, Jr. William E.
Page Thurman K.
Pharmacia AB
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