Drug – bio-affecting and body treating compositions – Preparations characterized by special physical form – Tablets – lozenges – or pills
Reexamination Certificate
2000-04-18
2004-04-27
Dodson, Shelley A. (Department: 1616)
Drug, bio-affecting and body treating compositions
Preparations characterized by special physical form
Tablets, lozenges, or pills
C424S480000, C424S484000, C424S485000, C424S488000, C424S489000, C424S494000
Reexamination Certificate
active
06726928
ABSTRACT:
FIELD OF THE INVENTION
The present invention relates to a process for preparing solid pharmaceutical dosage forms and, in particular, to a process for preparing a solid, oral, rapidly disintegrating dosage form of a pharmaceutically active substance which has an unpleasant taste.
BACKGROUND OF THE INVENTION
Many pharmaceutically active substances are presented for oral administration in the form of conventional oral dosage forms, including tablets, pills or capsules. The tablet, pill or capsule generally has to be swallowed with water so that the pharmaceutically active substance can be absorbed via the gastrointestinal tract. For some patients, swallowing the tablet, pill or capsule is difficult or impossible and this is particularly the case for pediatric patients and geriatric patients. A similar difficulty is often encountered when trying to administer tablets to non-human animals which may be uncooperative in taking tablets, pills or capsules.
Oral solid pharmaceutical dosage forms which rapidly disintegrate in the mouth and methods for their preparation have been proposed in GB-A-1548022 and GB-A-2111423. The solid dosage forms, as disclosed in these references, comprise an open matrix network carrying the pharmaceutically active substance, the open matrix comprising a water-soluble or water-dispersible carrier material which is inert towards the pharmaceutically active substance. The solid dosage forms are prepared by the sublimation or removal of solvent from a solution or suspension comprising the pharmaceutically active substance and the carrier material. Sublimation or removal of solvent is preferably carried out by freeze drying.
U.S. Pat. No. 5,382,437 to Ecanow discloses a readily dissolved carrier composition suitable for use in administration of drugs and foodstuffs. The composition comprises a skeletal structure produced by contacting a gel and a rigidifying material for the gel with liquified ammonia at low temperature until the mass solidifies. As the mass is slowly warmed to ambient temperature under vacuum, the solid ammonia sublimes from the solid state to the gas state to provide a porous drug or foodstuff delivery system.
Other methods for the preparation of oral solid pharmaceutical dosage forms which rapidly disintegrate in the mouth are disclosed in U.S. Pat. Nos. 4,855,326; 5,039,018; 5,120,549; 5,330,763; PCT/JP93/01631; PCT/US93/125661 and WO 98/57648, which are incorporated herein by reference.
The solid dosage forms which are produced by these various methods rapidly disintegrate on being placed in the mouth of the patient, thereby delivering the desired dose of the pharmaceutically active substance.
Although the solid dosage forms as described above overcome the problems of swallowing tablets, pills or capsules, the patient will taste the pharmaceutically active substrate as the dosage form disintegrates. For some pharmaceutically active substances, the taste, if slightly unpleasant, can be rendered acceptable by the use of sweetening agents, flavoring agents and the like, which mask the taste. Yet, in some pharmaceutically active substances, the unpalatable taste will still exist, despite the use of sweetening agents and flavoring agents. In those instances in which over-flavoring techniques alone will not suffice, the insolubilization techniques of the present invention can result in palatable formulations.
SUMMARY OF THE INVENTION
Through the efforts of the present inventors, a new method for the preparation of a solid, oral, rapidly disintegrating dosage form of a pharmaceutically active substance which has an unacceptable taste has been developed, which does not wholly depend upon trying to mask the unacceptable taste by the use of sweetening agents, flavoring agents and the like. In general, the present invention uses the less soluble form to the drug to reduce or eliminate the use of sweetening agents, flavor and the like.
In a first aspect, the present invention provides a process for the preparation of a solid, oral, rapidly disintegrating dosage form of a pharmaceutically active substance which has an unacceptable taste. The process comprises forming a solution or a suspension in a solvent of a form of the pharmaceutically active substance which is less soluble in water than the form with the unacceptable taste, together with a water-soluble or water-dispersible carrier material, forming discrete units of the solution or suspension. The solvent is then removed from the discrete units under conditions whereby a network of the carrier material carrying a unit dosage of the less soluble form of the pharmaceutically active substance is formed.
In another aspect, the invention provides a rapidly disintegrating dosage form of a pharmaceutically active substance when prepared by the process of the invention.
The present invention also includes within its scope, a solid, oral, rapidly disintegrating dosage form of a pharmaceutically active substance which has been rendered more palatable by the process as described above.
The present invention is also directed to a solid, oral, rapidly disintegrating dosage form comprising loperamide free base as the pharmaceutically active substance in a network of a carrier material selected from the group consisting of water-soluble and water-dispersible carrier materials.
Further, the invention discloses a solid, oral, rapidly disintegrating dosage form comprising domperidone free base as the pharmaceutically active substance in a network of a carrier material selected from the group consisting of water-soluble and water-dispersible carrier materials.
DETAILED DESCRIPTION OF THE INVENTION
As used herein and in the claims, the term “rapidly disintegrating” means that the solid dosage form will disintegrate in water at 37° C. in 60 seconds or less, preferably 5 to 10 seconds or less, when tested by the following procedure which is analogous to the Disintegration Test for Tablets, B.P. 1973 and which is further described in British Patent No. 1548022.
Disintegration Test—Apparatus
A glass or suitable tube 80 to 100 mm long, with an internal diameter of about 38 mm and an external diameter of 30 to 31 mm and fitted at the lower end so as to form a basket, with a disc or rustproof wire gauze complying with the requirements for a No. 1.70 sieve (B.P. 1983, page A136).
A glass cylinder with a flat base and an internal diameter of about 45 mm containing water and not less than 15 cm deep at a temperature between 36° C. and 38° C.
The basket is suspended centrally in the cylinder in such a way that it can be raised and lowered repeatedly in a uniform manner so that at the highest position, the gauze just breaks the surface of the water and at the lowest position, the upper rim of the basket just remains clear of the water.
Method
Place one shaped article (the rapidly disintegrating dosage form) in the basket and raise and lower it in such a manner that the complete up and down movement is repeated at a rate equivalent to thirty times a minute. The shaped articles are considered disintegrated when no particle remains above the gauze which would not readily pass through it.
On oral administration of the solid dosage form of the invention to a patient, the pharmaceutical dosage form rapidly disintegrates in the mouth. The rapidly disintegrating dosage form of the present invention enables poorly tasting pharmaceutically active substances to be presented in a palatable form without changing the bioavailability of the pharmaceutically active substance relative to an existing solid dosage form (i.e., pills and tablets) containing the more soluble compound. The pharmaceutically active substance is presented as a less soluble form rendering less of the drug to be tasted as the solid dosage form dissolves disintegrates in the saliva.
The pharmaceutically active substance with the unacceptable taste may be presented in less soluble form prior to formation of the solution or suspension. Alternatively, the pharmaceutically active form may be converted into the less soluble form during the process of the invention, for exampl
Kearney Patrick
Thompson Andrew R.
Yarwood Richard J.
Dodson Shelley A.
Nickey Donald O.
R.P. Scherer Technologies, Inc.
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