Drug – bio-affecting and body treating compositions – Preparations characterized by special physical form – Tablets – lozenges – or pills
Reexamination Certificate
2002-05-03
2004-06-01
Page, Thurman K. (Department: 1615)
Drug, bio-affecting and body treating compositions
Preparations characterized by special physical form
Tablets, lozenges, or pills
C424S400000, C424S451000, C424S464000, C424S468000, C424S474000, C424S475000, C424S480000, C424S484000, C424S489000, C424S490000, C514S964000
Reexamination Certificate
active
06743445
ABSTRACT:
The present invention relates to controlled, usually delayed release formulations, especially compositions that are suitable for delivering an active ingredient to the colon.
Compositions comprising amylose have been used in the preparation of dosage forms that can be used to deliver an active ingredient to the colon. The preparation of such dosage forms is described in U.S. Pat. No. 5,294,448 and involves contacting an active ingredient with a solution or dispersion of amylose formed from an aqueous amylose-butanol complex at a temperature in excess of 60° C. to form a film and drying that film. Temperatures in excess of 60° C. are considered to be essential in order to maintain or melt respectively the amylose in the solution or dispersion that comprises the film-forming composition. When the compositions are cooled the amylose in the films formed therefrom is in the glassy state.
Glassy amylose is one of the amorphous forms of amylose, the other being rubbery amylose. The rate of cooling and drying of the amylose film is considered to be important in the preparation of amylose films. If the rate of cooling is too low, crystalline regions of amylose are formed. If the quantity of water within the film exceeds a certain amount, the amylose may be formed in the rubbery form. Both crystalline and rubbery amylose are not digestible in the Gastro-Intestinal (GI) tract and are not considered to be suitable for the preparation of formulations for use in the delivery of an active material to the colon. In contrast glassy amylose has been found to be resistant to attack by the &agr;-amylases present in the small intestine but is degraded by the microflora present in the colon. These properties mean that it is particularly suitable for the preparation of dosage forms that can be used to deliver an active ingredient to the colon.
However, coats or films comprising purely glassy amylose have been found to swell in an aqueous environment and these swollen films are unable to retain their structural integrity when subject to mechanical stresses such as those experienced by the dosage form on its passage through the GI tract. Films or coats comprising amylose only are therefore unsuitable for the preparation of dosage forms for use in colonic delivery.
In order to overcome the disadvantages associated with films comprising amylose only, mixed compositions comprising amylose and a film-forming polymer have been prepared. See for example U.S. Pat. No. 5,294,488. The presence of a film-forming polymer prevents or limits the degree to which the amylose swells and confers some structural integrity on the film during its passage through the GI tract. Further ingredients such as water-soluble plasticisers may be added to the composition to assist in the formation of the final film or coat.
As with the preparation of “amylose only” films, the preparation of films from the mixed film-forming composition required that the composition be contacted with the active ingredient at a temperature in excess of 60° C. As before, this was in order to ensure that the amylose present in the composition was either completely solvated or in a melted form prior to the coating step. Upon drying the film, the amylose is preferably present in the glassy state. Coats or films comprising rubbery amylose may be formed but require the presence of porosity enhances in order to facilitate release of active material.
The formation of dosage forms in accordance with the method described in U.S. Pat. No. 5,294,448 has been found to be completely satisfactory for the preparation of dosage forms in which the active material is not temperature sensitive, but cannot be used for active materials that are thermolabile at temperatures above 60° C. There is, therefore, a need for a method of coating, active materials for the preparation of dosage forms in which the active material is thermolabile above 60° C. The present invention addresses, at least in part, that problem.
The present inventors have surprisingly found that a film-forming composition can be prepared which can be used to coat active materials at temperatures of less than 60° C. Surprisingly the structural integrity of the films formed is substantially retained during their passage through the GI tract. By retention of structural integrity, it should be understood that the coat or film does not substantially swell and is retained by the active material on its passage through the GI tract. However, parts of the film may be lost, weakened or degraded at certain points in the GI tract as will be described herein below. These films are also unexpectedly resistant to digestion in both the stomach and the small intestine, but are degraded by the microflora present in the colon.
A first aspect of the invention provides a method of coating an active material or a formulation containing an active material comprising the steps of contacting an active material or formulation containing it at a temperature of less than 60° C. with a film-forming composition comprising an aqueous dispersion of an amylose-alcohol complex, an insoluble film-forming polymer and a plasticiser, coating being carried out at a temperature of less than 60° C. The coating step may suitably be carried out at a temperature of between 5 and 50° C., preferably between 20 and 40° C., more preferably between 30 and 40° C. and especially between 35 and 37° C. As indicated above, coatings formed according to the first aspect of the invention are surprisingly able to retain their structural integrity during their passage through the GI tract. They are substantially resistant to digestion in both the stomach and the small intestine but are degraded by the microflora present in the colon.
By the term “film-forming” it is to be understood that the composition is able to form a coat or a film upon contact with the active material (or a formulation containing the active material) that solidifies upon drying. The structural integrity of the film is substantially retained during its passage through the GI tract. The film or coat is also able to substantially resist digestion in the stomach and small intestine but is degraded by the microflora of the colon.
It is also believed that the films or coatings formed using the method of the present invention comprise substantially homogeneous mixtures of amylose and an insoluble cellulosic or acrylic polymer. The term homogeneous includes films comprising distinct regions of amylose randomly dispersed in an insoluble cellulosic polymer matrix as well as films in which the dispersion is such that the regions of amylose are indistinguishable from an insoluble cellulosic polymer matrix material for example.
The term “active material” applies to any material which is or may be sensitive to temperatures above low ambient, for example 20 to 40° C., but also includes materials that are not degraded at temperatures outside this range. The active material could, for example, be a foodstuff or a pharmaceutical. It particularly includes any compound or composition useful in human or veterinary medicine, in therapy or diagnosis.
Preferred active materials include therapeutically active ingredients that find application in treating diseases of the colon or diseases the therapeutic management of which is best effected via the colon. Such diseases include, but are not limited to, cancer of the colon, irritable bowel syndrome (IBS) and Crohn's disease.
It will be appreciated that the active material may be mixed with other carrier materials suitable to a particular use. Thus, particularly for therapeutic use, the active material will often be mixed with one or more of a bulking agent and a lubricant, for example lactose and magnesium stearate, respectively. Dosages of active materials for therapeutic use will be as disclosed in the literature, for example in the ABPI data sheet compendium, or may sometimes be less owing to the more efficient delivery of the material. The active in material may be used together with one or more additional active materials.
The invention also includes a the co
Leong Chuei Wuei
Newton John Michael
BTG International Limited
Evans Charesse
Nixon & Vanderhye
Page Thurman K.
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