Drug – bio-affecting and body treating compositions – Preparations characterized by special physical form – Particulate form
Reexamination Certificate
1998-09-02
2002-08-27
Page, Thurman K. (Department: 1615)
Drug, bio-affecting and body treating compositions
Preparations characterized by special physical form
Particulate form
C424S499000, C424S500000, C424S501000, C424S502000, C424S464000, C424S465000, C514S951000
Reexamination Certificate
active
06440462
ABSTRACT:
This invention relates to agglomerates of &bgr;-lactam antibiotics, including e.g. penicillin V potassium, amoxicillin trihydrate, cephalexin monohydrate, which are suitable for direct tablet formation.
The most important and most frequently used form for orally administrable &bgr;-lactam antibiotics and mixtures, containing &bgr;-lactam antibiotics beside a second pharmaceutically active agent and optionally beside auxiliaries, is a tablet or a film tablet. For the production of a tablet or a film tablet, there are at the moment two processes known, namely granulation and direct tablet formation.
During granulation, generally very fine-grained, powdered, cohesive, non free-flowing and non-compressible pharmaceutically active agents are granulated in a multi-stage process to form coarser, free-flowing and compressible granules. In such a process, the pharmaceutically active agents are mixed in a first step with a binding agent, compacted whilst moist or dry and subsequently granulated in a second step through a sieve. The binding agent may, e.g. be dissolved in the moistening liquid used for moistening and granulating the powder. In a moist granulation process, drying of the granules is carried out including subsequent sieving to the final grain size. In a dry granulation process, after granulation it is generally necessary to separate the particles which are too coarse or too fine, and to recycle these particles, the coarse grain particles being pulverized again and the fine particles being compacted again. The granulates obtained may be mixed with auxiliaries which are preferably pharmaceutically acceptable required for tablet formation and compressed into tablets.
Granulation is generally very time and energy consuming and expensive, and may be thus extremely uneconomical. The described production processes for a tablet requires a considerable amount of apparatus and a high amount of validation work, and owing to the large number of production steps there are many sources of error.
Direct tablet formation is a much easier process; the pharmaceutically active agents being easily mixed with auxiliaries (carriers, binding agents, lubricants etc.) and the mixture is pressed into tablets. However, until now, despite the clear economic advantages over granulation, direct tablet formation could only be used to a limited extent, since it may generally only be carried out with, e.g. the following provisos: The pharmaceutically active agents has to be sufficiently free-flowing and compressible per se, and the proportion of pharmaceutically active agents per tablet must be a maximum of 100 mg or 25%. With such provisos good free-flow capability and good compressibility may only be obtained by addition of high amounts of special auxiliaries (e.g. Tablettose®, Ludipress® etc.).
In the case of &bgr;-lactam antibiotic tablets, the proportion of the &bgr;-lactam antibiotic per tablet may be up to 80% and more (e.g. 1 g and more), and &bgr;-lactam antibiotics are generally not sufficiently free-flowing and compressible per se. For example, especially penicillin V potassium, phenoxymethylpenicillin potassium, amoxicillin trihydrate and cephalexin monohydrate are generally obtained during production in an average volume-based grain size of 10 &mgr;m to 30 &mgr;m with the following grain size distribution:
4 &mgr;m to 80 &mgr;m
80%
>125 &mgr;m
1% to 5%
and having a bulk density of 0.15 g/ml to 0.45 g/ml.
These characteristics make it generally impossible to use the direct tablet formation process for &bgr;-lactam antibiotics.
Mixtures containing &bgr;-lactam antibiotics, for example a combination of amoxycillin trihydrate (&bgr;-lactam antibiotic) as, e.g. an anti-bacterially active compound with a second pharmaceutically active agent, e.g. a potassium salt of clavulanic acid (potassium clavulanate) as, e.g. a &bgr;-lactamase inhibitor are of enormous interest for the treatment of infections caused by gram-positive and gram-negative bacteria, which have become resistant to amoxycillin as a result of &bgr;-lactamase formation. Combinations of amoxicillin trihydrate/potassium clavulanate/auxiliaries are on the market under the trade name Augmentin®. The most important pharmaceutical form for the oral administration thereof is a tablet or a film tablet. Up to now, the preparation of Augmentin® tablets or film tablets has been particularly difficult because of the following problems in addition to the problems with tablet formation in case of &bgr;-lactam antibiotics as described above:
A potassium clavulanate may be extremely moisture sensitive and may degrade quickly in the presence of water
A mixture of two pharmaceutically active agents in a defined ratio has to be produced which may include the danger of disintegration of the two components during production because, e.g. of inhomogeneous contents of a pharmaceutically active agent in a tablet or a film tablet
The total proportion of the two pharmaceutically active agents per tablet may be up to 80% and more and the ability of the active ingredients to be compressed into a tablet or a film tablet may be determined almost exclusively by the physical properties of the active ingredients, i.e. deformation behaviour under pressure.
Thus, when producing a tablet or a film tablet with a combination of amoxicillin trihydrate and potassium clavulanate in a first step granulation has generally to be carried out, in order to ensure that a compressable mixture with satisfactory free-flow capability and compressibility is obtained; and to prevent disintegration of the active ingredients. However, owing to the extreme sensitivity of potassium clavulanate towards moisture, moist granulation with aqueous-alcoholic mixtures or binding agent solutions; or with pure water; which is at present the usual way for the production of &bgr;-lactam antibiotic tablets or film tablets, cannot be effected; because during moistening and subsequent granulation of the amoxycillin trihydrate/potassium clavulanate/auxiliaries powder, as well as during the subsequent drying of the granules, potassium clavulanate may be degraded due to the water present to an unacceptable extent.
In practice, up to now for the production of tablets or film tablets containing amoxycillin trihydrate and potassium clavulanate with sufficient uniformity there are in general only two alternative granulation processe, both of which may be complicated, and extremely uneconomical and unecological, namely:
Moist Granulation With Water-free Organic Solvents
The active ingredients amoxycillin trihydrate and potassium clavulanate are mixed in a first step with a binding agent, the mixture is moistened with a water-free, organic solvent, granulated and dried. The binding agent may also be added dissolved in the solvent. The granulates obtained may be sieved to the final grain size and mixed with tablet forming auxiliaries (binding agents, disintegrants etc.) before being compressed into tablets. Such a process is uneconomical and unecological, since the solvent has to be recycled; special equipment is necessary, solvent losses arise, etc.
Dry Granulation (Compactation, Briquette Formation)
The active ingredients amoxycillin trihydrate and potassium clavulanate may generally be mixed with a binding agent and compacted in dry form. Compactation may take place by compressing the pharmaceutically active agent/binding agent-mixture either on a roller compactor to form so-called “shells” or on a tablet press having large stamps to form so-called “briquettes”. Both the shells and the briquettes obtained are pulverized or broken in a mill or a sieve, in order to obtain an appropriate granulate. After granulation it is generally necessary to separate the particles which are too coarse or too fine, and to recycle these particles, the coarse grain particles being pulverized again and the fine particles being compacted again (briquette formation). The granulates thus obtained may be mixed with auxiliaries required for tablet formation (lubricants, disintegrants etc.) which are preferably pharmaceutically acceptable
Raneburger Johannes
Zeisl Erich
Biochemie Gesellschaft m.b.H.
Page Thurman K.
Pfeiffer Hesna J.
Sheikh Humera N.
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