Drug – bio-affecting and body treating compositions – Preparations characterized by special physical form – Particulate form
Reexamination Certificate
1996-11-22
2001-04-10
Zitomer, Fred (Department: 1713)
Drug, bio-affecting and body treating compositions
Preparations characterized by special physical form
Particulate form
C424S490000, C424S493000, C424S494000, C424S495000, C424S497000
Reexamination Certificate
active
06214386
ABSTRACT:
FIELD OF THE INVENTION
The present invention concerns a pharmaceutical composition suitable for preparing an extemporaneous suspension, that promptly releases active agents or ingredients (drugs). These compositions and the extemporaneous suspensions prepared with them are suitable for oral administration.
BACKGROUND OF THE INVENTION
Suspensions are heterogeneous systems in which the continuous phase (external phase) is liquid or semisolid, while the dispersed phase (internal phase) consists of solid particles that are insoluble in the medium used. Pharmaceutical suspensions can be prepared during the industrial production phase (ready-to-use suspensions), or prepared by the patient at the time of use (extemporaneous suspensions).
Suspensions are one of the most versatile of the pharmaceutical forms that can be used for administration. Suspensions are suitable for internal or external delivery of active agents, such as oral, injectable, and dermatologic uses.
The use of suspensions for the administration of active ingredients has been known for some time, and ready-to-use oral suspensions are usually preferred in everyday practice. This preference is due to the fact that the patient must simply agitate the bottle prior to use, because the continuous liquid phase is already present in the bottle. Extemporaneous suspensions, however, require the patient to first redisperse the powdered drug in a solution such as water.
Examples of “ready-to-use” suspensions on the market include BACTRIM®, a syrup with antibacterial action, and MAALOX®, a suspension with antacid action used to treat epigastric pain.
U.S. Pat. No. 4,764,375 discloses crystals of soluble active agents that are incorporated into melted waxes, and the formation of extemporaneous suspensions with or without the addition of surfactants. Further, waxes have been used to coat tablets, principally to mix with powders, or for granulation in the melted state. In addition, waxes have been used to form wax matrices of tablets or granulated materials, for the purpose of obtaining controlled-release formulations,
Pharm. Acta Helv.,
56 4/5, 111 (1981).
European Patent application 608,850 (EP 608,850) discloses formation of microgranulated materials having characteristics such that they can easily be suspended in aqueous solutions after film-coating. However, the disclosed preparation of these suspensions in quantity, with standard, consistent and repeatable, characteristics, is typically influenced by a large number of variables, for example the density of the internal and external phases; the ratio of the phase volumes; the viscosity of the external phase; and the dimensions, degree of aggregation, and shape of the particles. The variability of these parameters can cause difficulties during resuspension, even after agitation at the time of use. In some cases the resuspension difficulties can lead to a nonhomogeneous distribution of the active agent.
In addition, currently available suspensions can have certain limitations which make them poorly suitable for use. This can occur, for example, when a problem exists with the instability of the vehicle or palatability of the suspended form, such as when an active agents with unpleasant organoleptic characteristics are used, or when mutually incompatible active agents are combined in the same formulation.
Reduction or elimination of these drawbacks often involves taking additional measures such as masking the organoleptic characteristics of active agent, or isolating it from the ingestion medium. This is frequently accomplished by microencapsulation. However, this often requires the employment of solvents and in a process that is costly.
Another drawback of masking by microencapsulation is the delaying action that the encapsulating substances can exert at the time of release of the active agent. In some cases this delaying effect has been used specifically to modulate the release of the drug according to a predetermined profile. For example, U.S. Pat. No. 5,296,236 discloses microgranular controlled-release suspensions for oral use which have the peculiarity of gradually releasing various types of active agents over time, thus adapting them to the various desired therapeutic conditions.
A delay in the release of the active agent is not always desirable or necessary for the administration of certain active agents such as, for example, analgesics, antipyretics, antitussives, and the like.
Another advantage of suspensions is their particular ease of swallowing especially when compared to solid pharmaceutical forms. This is a typical characteristic of liquids. This is particularly important in pediatrics, for the elderly, and patients suffering from motor coordination impairment, such as stroke victims, who can have difficulties swallowing tablets.
The need for a solution to this problem is epitomized by the continuing search for devices making it easy to crush a tablet to produce a powder that can be dispersed in water. For example, International Patent Applications WO 95/6427 and WO 95/6428 have recently described devices, a syringe and superimposed cups, capable of crushing tablets and the subsequent resuspension of the resultant powder in water. These devices have obvious limitations, for example, in the presence of poorly palatable active agents. In addition, the excipients of the tablets are not normally those most suitable for promoting suspension of the crushed tablet.
Thus there is a particular need for drugs that are readily available in suspended form, and, when necessary, for the ability to mask the taste of these drugs. Many active agents possess palatability problems. It is well known, for example, that acetaminophen, a very common analgesic and antipyretic, has a bitter and metallic taste that makes it difficult to administer by means of liquid formulations, particularly to children. Other examples include of Naproxen ((+)6-Methoxy-&agr;-methyl-2-naphthaleneacetic acid), a well-known anti-inflammatory known to depart an intense burning sensation in the mouth; diltiazem, a cardiovascular drug having a strongly bitter taste; and moguisteine a bitter-tasting antitussive with anesthetic properties. Some drugs such as diltiazem are unstable in aqueous solution. Thus, it is advantageous to have available an extemporaneous suspension that has good stability as well as a pleasant taste.
There is also a need for formulations that control the hygroscopicity of certain substances. For example, it is known from the literature that potassium bicarbonate can be used to prevent osteoporosis and hypertension,
New Engl. J. Med.
330, 1251, 1776 (1994), and U.S. Pat. No. 5,171,583. However, this salt has tolerability and hygroscopicity problems. Thus, the ability to provide a pharmaceutical form which can overcome these drawbacks without delaying the release of the active agent constitutes a suitable solution to the problem.
An object of the present invention is to provide pharmaceutical formulations for use in a liquid suspension for oral use which, allows prompt release of the active agent, and avoids the aforementioned problems that are encountered with common ready-to-use suspensions. The present compositions are simple and inexpensive to prepare and their preparation readily lends itself to scale-up on a commercial scale.
SUMMARY OF THE INVENTION
The present invention provides a composition for prompt-release of an active agent, and a liquid suspension comprising the composition and a liquid carrier. The composition comprises an active agent in microgranule form. The microgranules containing the active agent are coated with a film coating mixture containing at least one lipid material and an optional hydrophilic additive. The coating envelopes the microgranules but does not impart a controlled release property to the composition, and affords prompt release thereof once ingested.
The inventors have found that film-coating with lipid (including wax) materials, applied in the melted state and optionally in the presence of hydrophilic additives, as wetting agents, provide formulat
Golzi Roberto
Santus Giancarlo
Darby & Darby
Recordati S.A.
Zitomer Fred
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