Drug – bio-affecting and body treating compositions – Preparations characterized by special physical form – Particulate form
Reexamination Certificate
1998-10-22
2001-05-15
Page, Thurman K. (Department: 1615)
Drug, bio-affecting and body treating compositions
Preparations characterized by special physical form
Particulate form
C514S781000, C514S785000
Reexamination Certificate
active
06231890
ABSTRACT:
TECHNICAL FIELD
This invention relates to a composition wherein a sparingly water-soluble acidic drug (and an inorganic powder) is/are suspended in the form of fine particles, and a process for the preparation thereof.
BACKGROUND ART
As the liquid preparations of a sparingly water-soluble acidic drug such as a non-steroidal analgesic or anti-inflammatory drug, suspending syrups are disclosed in JP-A-1-258618 and JP-A-2-286615. These syrups, however, have the problem in stability of their suspended particles with lapse of time. More specifically, these publications report that the commercially available suspending liquid preparations preferably have a particle size of 30-250 &mgr;m and that particles with a less size undesirably float and those with a larger size precipitate. However, a suspended substance within the disclosed range of particle size precipitates tightly at the bottom of a vessel and thus it should be redispersed by vigorous shaking just before oral administration. However, this redispersion is extremely difficult and even redispersed, there have arisen the problems of an unpleasant rough feeling in the mouth and agglomeration of the drug in the stomach, thus not exerting sufficient effects.
In order to solve the above problems, there may be proposed a means of pulverizing a drug. However, it has been difficult in the processes using conventional apparatuses such as a homogenizer or the like to set up the conditions such as high concentration and viscosity of the drug or stabilizer, a low-temperature control or the like, and the pulverization to the required particle size was difficult to achieve.
Moreover, many of surface active agents or thickeners may dissolve ibuprofen or the like and selection of these suspension-stabilizing components is significant not only for stability of suspended particles but also for irritating property.
Furthermore, many of sparingly water-soluble acidic drugs may melt at or around a sterilization temperature and there have been presented the problems such as diminished ingestiveness due to change in drug properties by a high-temperature sterilization during the preparation.
DISCLOSURE OF THE INVENTION
An object of this invention is to provide a suspension of a sparingly water-soluble acidic drug in which the acidic drug is stable over a prolonged period of time and highly dissolvable and which further can be subjected to a high-temperature sterilization, has a diminished irritative property to the oropharyngeal mucous membrane and is easy to take.
Another object of this invention is to provide a process for simply and easily producing the suspension having superior properties as stated above.
We made our earnest studies to improve dissolution and stability of sparingly water-soluble acidic drugs, especially non-steroidal anti-inflammatory or analgesic agents. As a result, it has been found that in a suspension of a sparingly water-soluble acidic drug having average particle size of 1-15 &mgr;m, a polyglycerol fatty acid ester, a water-soluble polyhydric alcohol and water, the acidic drug is stable over a prolonged period of time and highly dissolvable. It has also been found that a high-temperature sterilization can be applied and irritation to the oropharyngeal mucous membrane can be diminished by incorporating into said suspension an inorganic powder having average particle size of 1-15 &mgr;m.
More particularly, this invention relates to a suspension of a sparingly water-soluble acidic drug whose average particle size is 1-15 &mgr;m, a polyglycerol fatty acid ester, a water-soluble polyhydric alcohol and water, and a suspension of a sparingly water-soluble acidic drug whose average particle size is 1-15 &mgr;m, an inorganic powder whose average particle size is 1-15 &mgr;m, a polyglycerol fatty acid ester, a water-soluble polyhydric alcohol and water. It is further concerned with a process for the preparation of a suspension of a sparingly water-soluble acidic drug whose average particle size is 1-15 &mgr;m, which comprises pulverizing and dispersing a sparingly water-soluble acidic drug, a polyglycerol fatty acid ester, a water-soluble polyhydric alcohol and water by means of a pulverizer comprising a main shaft adapted to rotate in a casing and a plurality of layshafts adapted to revolve in relationship interlocked with the rotation of the main shaft, each of the layshafts being fitted with a multiplicity of annular grinding media.
The sparingly water-soluble acidic drug as used herein is meant to indicate the drug which shows crystallizability at a melting point of around 40-120° C., is sparingly soluble in water in a lower pH range and has an acidic group or a salt thereof, for example, a carboxyl group, a thiocarboxyl group, a dithiocarboxyl group, a sulfo group, a sulfino group, etc. One such drug may be ibuprofen. It is essential that this sparingly water-soluble acidic drug has an average particle size of 1-15 &mgr;m. If it is less than this range, irritation by the sparingly water-soluble drug will be enhanced when administered, while, if more than this range, ingestiveness or precipitation stability of suspended particles will become inferior.
An essential surface active agent is a polyglycerol fatty acid ester. Polyoxyethylene sorbitan monooleate surface active agents (Polysolvate 80 and the like) or polyoxyethylene hydrogenated castor oil surface active agents (HCO 60 and the like) are not desirable, because they may increase solubility of ibuprofen or floatings may be generated with lapse of time.
Preferable polyglycerol fatty acid esters may be those in which a polymerization degree of glycerol is 3 or more, the fatty acid has 12-22 carbon atoms, the number of fatty acids bound by ester linkage is 1-7 and the final HLB is not less than 4.
Of these polyglycerol fatty acid esters, preferable ones are decaglycerol monostearate, decaglycerol distearate, heptaglycerol monostearate, decaglycerol heptabehenoate and the like, and they may be used alone or in combination with two or more thereof.
An amount of the polyglycerol fatty acid ester to be incorporated is 0.001-1.0% by weight, preferably 0.002-0.5% by weight, in terms of the final preparation. If it is less than 0.001% by weight, dispersion of suspended particles will be insufficient, while, if more than 1.0% by weight, a solubility of the drug may be increased and irritative property may be strengthened.
As the water-soluble polyhydric alcohol, there may be mentioned, for example, glycerol, ethylene glycol, propylene glycol, 1,3-butylene glycol, diglycerol, polyglycerol, diethylene glycol, polyethylene glycol, dipropylene glycol, polypropylene glycol, sorbitan, sorbitol, mannitol, xylitol, erythritol, trehalose and the like.
Of these water-soluble polyhydric alcohols, preferables are, for example, glycerol, diglycerol and polyglycerol.
An amount of the water-soluble polyhydric alcohol to be incorporated is 0.01-20% by weight, preferably 0.1-10% by weight. If it is less than 0.1%, dispersibility and re-dispersibility of the suspension may be decreased, while, if more than 20%, its viscosity may be increased, which leads to an unpleasant rough feeling in the mouth.
The inorganic powder as used herein is meant to be an inorganic compound containing one or more components selected from the group consisting of magnesium, aluminum, titanium and silicic acids.
As the inorganic compounds, there may be mentioned, for example, magnesium oxide, magnesium hydroxide, aluminum magnesium hydroxide, aluminum magnesium metasilicate, magnesium carbonate, magnesium chloride, magnesium sulfate, aluminum oxide, aluminum hydroxide gel, titanium oxide, light anhydrous silicic acid and the like, and they may be used alone or in combination with two or more thereof.
Particularly preferable inorganic compounds are titanium oxide, aluminum magnesium hydroxide, aluminum hydroxide gel and light anhydrous silicic acid alone or in the form of a mixture of two or more thereof.
The said sparingly water-soluble acidic drug may produce an unacceptably highly irritating action on the oropharyngeal
Hasegawa Kazuo
Naito Mayumi
Nakajima Toshiaki
Nakano Hiroshi
Okudaira Ichiro
Lorusso & Loud
Page Thurman K.
Pulliam Amy E.
Taisho Pharmaceutical Co. Ltd.
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