Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Heterocyclic carbon compounds containing a hetero ring...
Reexamination Certificate
2002-03-21
2003-07-29
Henley, III, Raymond (Department: 1614)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Heterocyclic carbon compounds containing a hetero ring...
C424S499000
Reexamination Certificate
active
06599897
ABSTRACT:
The present invention relates to a novel pharmaceutical formulation comprising 11-[4-[2-(2-hydroxyethoxy)ethyl]-1-piperazinyl]dibenzo[b,f][1,4]thiazepine or a pharmaceutically acceptable salt thereof (hereinafter referred to as the “agent”), processes for its preparation, and its use. In particular the present invention relates to a formulation which is easily suspended or dissolved in aqueous media.
The “agent” can be used to treat diseases of the central nervous system such as psychoses. A particular example of the “agent” is quetiapine fumarate (sold under the trade name Seroquel®). Quetiapine fumarate has been marketed for a number of years for the treatment of schizophrenia and related disease conditions. A considerable body of literature describes how to use quetiapine fumarate. Specific references for the preparation and use of the “agent” are European Patent Application EP 240,228 and 282,236, U.S. Pat. No. 4,879,288 and International Patent Application WO 97/45124.
Quetiapine fumarate is marketed as a tablet. Although doctors, nurses and other carers try to ensure that the patient takes the tablet(s), in psychotic patients there is frequently a problem with non-compliance. For example, the patient may “cheek” the tablet resulting in a missed dosage. Compliance problems would be reduced if the “agent” could be administered in the form of an oral solution or suspension. An oral solution or suspension has the additional advantage of being easier to swallow and hence a better method of administration for those patients who have problems swallowing tablets.
To avoid problems with the “agent” deteriorating, the formulation of the present invention is provided as low moisture content granules which are readily dissolved or suspended in aqueous media prior to administration. The granules are also free flowing which enables uniform filling and emptying of sachets so that an accurate dose of the therapeutic product can be administered.
Various low moisture content formulations of the “agent” were prepared but found to be unsuitable, because either the granules were too hard and therefore not easily dispersed, or were not free flowing and compacted upon standing or vibration.
Eventually we found a granule formulation of the “agent” which was free flowing and yet also surprisingly easily dissolved or suspended in aqueous media. Thus, the present invention provides a granule formulation of the “agent” which is free flowing and easily dissolved or suspended in aqueous media. For example, it should be suitable for administration within the time scale of the person administering the dose. Typically, it should be suitable for administration in less than 15 minutes, preferably less than 5 minutes and more preferably in less than 2 minutes.
In particular, the present invention provides a granule formulation comprising 11-[4-[2-(2-hydroxyethoxy)ethyl]-1-piperazinyl]dibenzo[b,f][1,4]thiazepine or a pharmaceutically acceptable salt thereof and a freely or very water-soluble binder, wherein the granules have a bulk density range of 0.15 g/ml to 0.60 g/ml and a tap density range of 0.20 g/ml to 0.70 g/ml and 80% of the granules are in the size range of 75 to 850 microns.
The preparation, physical properties and beneficial pharmacological properties of the “agent” are described in published European Patents EP 240,228 and 282,236 as well as in U.S. Pat. No. 4,879,288, the entire contents of which are herein incorporated by reference.
Preferably the “agent” is 11-[4-[2-(2-hydroxyethoxy)ethyl]-1-piperazinyl]dibenzo[b,f][1,4]thiazepine or a highly water-soluble pharmaceutically acceptable salt thereof. More preferably the “agent” is 11-[4-[2-(2-hydroxyethoxy)ethyl]-1-piperazinyl]dibenzo[b,f][1,4]thiazepine or a dihydrochloride, maleate, citrate or a fumarate salt thereof. Most preferably the “agent” is quetiapine fumarate (Seroquel).
A freely or very water-soluble binder is a binder which dissolves in less than 10 parts of water per 1 part of binder by weight and comprises maltodextrin, mannitol, xylitol, pre-gelatin starch, sucrose or poly[1-(2-oxo-1-pyrrolidinyl)ethylene] (povidone). Preferably the binder dissolves in less than 1 part of water per 1 part of binder.
Preferably the very water-soluble binder is maltodextrin.
Preferably, the present invention provides a granule formulation comprising Seroquel® and maltodextrin, wherein the granules have a bulk density range of 0.15 g/cc to 0.60 g/cc and a tap density range of 0.20 g/cc to 0.7 g/cc and 80% of the granules are in the size range of 75 to 850 microns.
Bulk density is the density of a free flowing powder. Tap density is the density of the powder after it has been vibrated or tapped on a surface several times. Bulk density is determined by pouring a volume of 100 ml of powder into a graduated cylinder and measuring the weight of the powder. Tap density is determined by placing the same cylinder, containing the 100 ml of powder used to measure the bulk density, on a piece of equipment that raises and drops the cylinder 200 times (the amplitude of the raising and lowering in this standard test is 0.5 inches). The new volume of the powder is measured and since the weight of the powder is already known the tap density can be calculated.
Preferably the granules have a bulk density range of 0.261 g/ml to 0.400 g/ml; in particular 0.261 g/ml to 0.368 g/ml.
Preferably the granules have a tap density range of 0.342 g/ml to 0.500 g/ml; in particular 0.342 g/ml to 0.464 g/ml.
Granules with the desired bulk density, tap density and size range characteristics can be formed by using a fluid bed process. The fluid bed process involves fluidising the components of the formulation on a bed of air, adding water and then drying. Components of the formulation could alternatively be added as a solution or suspension with the water.
Accordingly, in another aspect, the present invention provides a process for preparing a formulation as defined above which comprises:
i) fluidising one or more components on a bed of air in a fluid bed;
ii) adding, to the fluid bed, water optionally containing one or more components;
iii) drying.
Preferably the “agent” and the freely or very water-soluble binder and any other components are fluidised on the bed of air.
The fluid bed process is well known in the art, for example see Schaefer T., Worts O., Control of Fluidized Bed Granulation I. Effect of spray angle, nozzle height and starting materials on granule size and size distribution, Arch. Pharm. Chemi Sci. Ed. 5, 1977, 51-60; Schaefer T., Worts O., Control of Fluidized Bed Granulation II. Estimation of Droplet Size of Atomized Binder Solutions, Arch. Pharm. Chemi Sci. Ed. 5, 1977, 178-193; Schaefer T., Worts O., Control of Fluidized Bed Granulation III. Effects of Inlet Air Temperature and Liquid Flow Rate on Granule Size and Size Distribution. Control of Moisture Content on Granules in the Drying Phase, Arch. Pharm. Chemi Sci. Ed. 6, 1978, 1-13; Schaefer T., Worts O., Control of Fluidized Bed Granulation IV. Effects of Binder Solution and Atomization on Granule size and size distribution, Arch. Pharm. Chemi Sci. Ed. 6, 1978, 14-25; Schaefer T., Worts O., Control of Fluidized Bed Granulation V. Factors Affecting Granule Growth, Arch. Pharm. Chemi Sci. Ed. 6, 1978, 69-82; Kawai S., Granulation and Drying of Powdery or Liquid Materials by Fluidized Bed Technology, Drying technology, 11(4), 1993, 719-731; and Kokubo H., Sunada H., Effect of Process Variable on the Properties and Binder Distribution of Granules Prepared in a Fluidized Bed, Chem. Pharm. Bull. 45(6), 1997, 1069-1072.
The size and density of the granules can be affected by altering conditions such as temperature, atomnisation air pressure, process air volume and water addition spray rate used in the fluid bed process. A key parameter affecting the characteristics of the granules is the moisture level in the granules; this moisture level result
AstraZeneca AB
Gilbert George A.
Henley III Raymond
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