Drug – bio-affecting and body treating compositions – Preparations characterized by special physical form – Particulate form
Reexamination Certificate
2001-01-16
2003-05-27
Page, Thurman K. (Department: 1615)
Drug, bio-affecting and body treating compositions
Preparations characterized by special physical form
Particulate form
C424S480000, C424S482000, C424S490000, C424S494000, C427S402000, C427S407100
Reexamination Certificate
active
06569462
ABSTRACT:
BACKGROUND OF THE INVENTION
Layering processes involve loading solid inert cores with drugs and/or excipients. Inert cores, placed in a suitable vessel such as a coating pan or a fluid bed, may be layered according to different methods. Some methods consist of spraying onto the cores a solution/suspension containing both drug and binding agent. Others are based on layering the drug directly in powdery form where drug loading occurs by gravity and adhesion is ensured by a liquid binder sprayed onto the cores. Some examples concerning different layering processes are described in the following patents: WO 95/14460, WO 96/01621.
The layering process is particularly suitable for production of small drug loaded units, multiples of which are placed into capsules for patient delivery. In the case of spherical inert cores such as non pareils, the layering techniques from solution/suspensions, produce homogeneous drug loaded particles, which retain an approximately spherical shape. They are therefore particularly suitable for successively film coating to build up the particle with the aim of providing a desired drug release profile. These spraying methods based on liquid applications are very time consuming due to the relative low concentration of the active substance in the liquid vehicle and the need to evaporate large amounts of solvent. In addition they are subject to process and product variables. Also it is preferable that liquid layering methods are based on aqueous systems; nevertheless organic solvents are often used for those active substances having poor aqueous solubility. A process using organic solvent has disadvantages of high costs, environmental pollution and explosion hazard. Drug state transitions can also occur either during or after the liquid spraying phase. As a result, crystalline drugs once loaded on inert cores, may assume a different crystalline state or even a metastable amorphous state, both altering the drug release profile on storage.
Known powder layering techniques based on drug loading by gravity overcome some of the above-mentioned drawbacks. However limiting factors accompany the use of powder layering such as non-uniform distribution of the drug onto the seeds, and high dust formation during the process which lowers the yields and requires the process to be run discontinuously with intermediate drying. This is necessary to avoid sticking or agglomeration of individual cores. but is very time consuming if an adequately deep layer is to be loaded onto the cores. A typical industrial process may take in the order of 24 hours.
The non-uniform drug distribution gives rise to single loaded units with irregular shape and rough surface and causes an increment of the products surface specific area (SSA). An increase of the SSA means a higher spray volume must be applied to get the desired average thickness. Poor reliability from batch to batch is also associated with such a layering system. Moreover, when coating is based on weight gain, the poor batch reproducibility gives rise to finished products with a variable average film thickness and therefore the resulting units will each have different release profiles. Where a final sealing coating is required, the volume of sealant is increased due to high surface area of the units.
Additionally, known powder layering techniques produce a rather considerable dust formation which tends to be suspended on the air stream during the process. This dust problem is also responsible for cross-contamination and safety hazards for the operators, as well as loss of active substance through the exhaust of the ventilation system.
Another disadvantage of powder layering is that the poor reliability requires time-consuming procedures to get satisfactory results in matter of process validation. This is necessary to meet requirements of medicine control agencies.
There is need therefore for a process for applying a drug or excipient layer to a unit or seed particle with improved layering times over solution/suspension coating techniques.
There is also a need for a process to prepare spherical dosage forms with improved regularity of shape.
Furthermore there is a need for a process for preparing multiple units dosage forms with consistent properties and improved reliability of the units.
The present invention provides a process for applying a layer to a pharmaceutical unit, such as a seed unit or tablet, which comprises:
(a) spraying the unit with dry particles of drug and/or excipient,
(b) applying to the unit a binder comprising solvent, and
(c) drying.
Steps (a) and (b) can be initiated, and/or terminated, sequentially in either order or simultaneously. Generally once the process has started steps (a) and (b) are run simultaneously for sufficient time to load the desired amount of drug onto the pellet. During simultaneous loading (ie steps (a) and (b) running for a period together) it is possible to reach an equilibrium where solvent evaporates or dries at a rate substantially equal to the rate of binder application.
Conveniently the binder is applied before the powder application starts, for example about 20 seconds or less before, eg about 10 seconds before, and is terminated preferably after the powder spraying has stopped to ensure all drug has been applied and to minimise loss. Drying may continue until substantially all solvent is removed.
Powder atomisation ensures a homogeneous drug loading and an enhanced sphericity.
In one aspect of this invention when coating the unit with particles of drug and/or excipient; the unit and the particles are at different electrical potentials such that electrostatic attraction occurs between them;
Optionally, the dry particles may be electrically charged with respect to the unit.
Accordingly this invention also provides a process for applying a layer to a pharmaceutical unit (eg seed or tablet) which comprises:
(a) spraying the unit with dry particles of drug and/or excipient, the unit and the particles being at different electrical potentials such that electrostatic attraction occurs between them;
(b) applying to the unit a binder, and
(c) drying.
As above steps (a) and (b) can be carried out, and/or initiated, sequentially in either order or simultaneously.
Spraying in the manner described herein permits layering to substantially the whole surface of the unit in a single operation.
Electrostatic attraction can minimise dust formation, and thus there is reduced loss of active substance through the exhaust of the ventilation system. Furthermore, the particles are strongly attracted to the seed units, and consequently the volume of particles carried off during evaporation of the binder is reduced. However an electric charge is unsuitable in cases where an organic solvent is used for the binder, and accordingly, in such cases the invention can be used without applying a charge.
The present invention is particularly suitable for the production of pharmaceutical units with high drug loading. Such a method ensures high reliability while improving the productivity in comparison with known powder layering processes. It finds broad applicability on drug loading of inert cores such as non pareils seeds or granules on the manufacturing of multiparticulate dosage forms. Layering of monolithic dosage forms such as tablets is however possible, eg tablets up to about 20 mm in length. Drug particles are sprayed through a nozzle connected with an air flow inlet. Particles are thus atomized onto inert seeds loaded on conventional equipments such as for instance coating pans beds. This system ensures uniform layering, and improved process productivity in comparison with known powder layering techniques based on gravity loading when processing the same quantity of components in the same coating bowl.
Preferably the powder and binder are applied from different directions, or in the same direction but along separate axes. This can avoid over wetting and thus sticking or aggolmeration. As a result process time can be reduced significantly being strictly dependent on spraying rates of powder and binder.
The
Cornelli Livio Maria
La Grasta Giovanni
Marconi Marco Giuseppe Raffaele
Eurand International S.p.A.
Oh Simon J.
Page Thurman K.
Thompson Hine LLP
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