Drug – bio-affecting and body treating compositions – Designated organic nonactive ingredient containing other... – Solid synthetic organic polymer
Reexamination Certificate
2000-03-01
2003-03-18
Page, Thurman K. (Department: 1615)
Drug, bio-affecting and body treating compositions
Designated organic nonactive ingredient containing other...
Solid synthetic organic polymer
C424S400000, C424S489000, C424S490000, C424S493000, C424S495000
Reexamination Certificate
active
06534549
ABSTRACT:
The present invention relates to controlled, usually delayed release formulations, where the release characteristics are controlled by a polymer.
BACKGROUND OF THE INVENTION
In U.S. Pat. No. 3,499,962 and GB 1,072,795 colloidal amylose solutions, prepared under conditions of high pressure and temperature, were used to coat or encapsulate particles used, for example, in nutritional, pharmaceutical, cosmetic and agricultural applications. Encapsulation of active materials at lower temperatures and pressures required the presence of a salt such as an aqueous alkali metal hydroxide. These conditions are not conductive to the encapsulation of sensitive or reactive particles that are unstable when subjected to heat, light or conditions substantially different to those encountered in certain physiological environments.
The ability of faecal micro-organisms present in the colon to degrade amylose has been disclosed by Cairns et al, J.Cer.Sci.,12,203-206,(1990). The preparation and use of formulations containing amylose is described in U.S. Pat. Nos. 5,294,448 and 5,108,758. The preparation of amylose solutions has been discussed by Ring et al., Macromolecules, 1985, 18,182 where an aqueous dispersion of amylose in complexed form was heated with a C
1-5
alcohol to between 70° C. and 90° C. Amylose solutions prepared using similar techniques were used in the formulation of those compositions described in U.S. Pat. Nos. 5,294,448 and 5,108,758, EP-A-0502032 and GB-A-2220350.
SUMMARY OF THE INVENTION
The present invention provides a method for producing a controlled release composition comprising an active ingredient and a film formed from a film-forming composition comprising a mixture of a substantially water-insoluble film-forming polymer and amylose, the method comprising contacting the active ingredient with a solution of the film-forming composition in a solvent system comprising (1) water and (2) a water-miscible organic solvent which on its own is capable of dissolving the film-forming polymer and removing the water and organic solvent, wherein the weight ratio of amylose to film-forming polymer is in the range 1:2 to 3:2 and the solvent system contains at least 50% w/w organic solvent.
The temperature used in the process generally need be no higher than 60° C. and may often be ambient. Preferably the temperature is in the range 20 to 40° C.
The controlled release composition formed according to the method of the present invention finds particular application in the delivery of an active material to the colon. The composition has been found to be substantially resistant to the conditions present in the stomach and the small intestine but is susceptible to attack by the micro-organisms of the colon.
The present invention should generally be accompanied by solvent recovery. Thus during the step in which the solvent is removed by evaporation, the vapour, which generally comprises a mixture of water vapour and solvent vapour, should be recovered, condensed and the solvent preferably recycled in the process. The condensed solvent mixture may be separated to render the solvent substantially free of water, or a mixture of water and solvent of known solvent concentration may be reused in the process.
Suitable condenser equipment for solvent removal and recovery from an active ingredient coating station is known and is available, for instance from the manufacturers Glatt.
The organic solvent which is used in the invention is selected for its miscibility with water. It is preferably sufficiently water-miscible such that a homogeneous blend containing 10 to 90% of an organic solvent at room temperature and pressure can be formed. The solvent should also be selected for its ability to solubilise the film-forming polymer and the amylose. Thus those components should be soluble in the organic solvent (in the absence of water) at a concentration of at least 5 or 6%, preferably at least10%, at a temperature of 40° C.
Suitable solvents are C
2-10
-alkanols, ethers, alcohol ethers and esters of mono or higher base carboxylic acids, generally with mono alkanols, which are liquid at room temperature and miscible with water in the stated amounts. Suitable esters are, for instance, esters of lactic acid, such as ethyl lactate. Preferably the solvent is a C
2-4
alkanol, and is most preferably selected from ethanol and propanol.
The relative amounts of solvent and water required for use in the solvent system of the present invention have been found to depend upon the nature of both the organic solvent used and the water-insoluble polymer. The organic solvent comprises at least 50% by weight (w/w) of the solvent system, preferably between 60 and 90% of the solvent system. By way of example, when ethyl cellulose is used as the insoluble polymer, the organic solvent system used in the preparation of the film-forming composition preferably contains at least 60% by weight organic solvent when propanol is used and at least 70% by weight organic solvent when ethanol is used.
The film-forming compositions of choice used in the method of the present invention are those which give rise to films in which the amylose is present in the glassy state. Films comprising glassy amylose have been found to be resistant to degradation by both the stomach and the amylase enzymes of the small intestine, but have been found to be susceptible to attack by the micro-organisms present in the colon.
Glassy amylose is one of the two forms of predominantly amorphous amylose, the other being a rubbery form.
Amylose exists in its glassy state below the glass transition temperature (Tg). Rising through this temperature, there is a sharp increase in the heat capacity of the amylose of 0.5±0.15 Jg
−1
K
−1
(joules per gram per degree Kelvin). This heat capacity increment allows the Tg to be identified and can be measured by differential scanning calorimetry. Examples of procedures for obtaining Tg values and earlier literature references to such procedures are given in Orford et al, Int.J.Biol.Macromol., 1989,11,91.
The particular Tg of a given preparation of amylose depends upon its purity and other properties. Thus, for example, the theoretical Tg for pure, dry amylose may be predicted to be 210° C. but the presence of water depresses this figure: with 10% w/w of water the Tg is 80° C. and at 20% w/w of water it is 7° C. It has been found that &agr;-amylolytic enzymes such as those present in the small intestine do not readily degrade glassy amylose and this effect is still apparent at up to 20° C. above the Tg. Such materials have been found to be sufficiently insoluble in aqueous media over the pH range 1-9 at 37° C. to be resistant to degradation in the stomach or intestine. They are, however, degraded by faecal micro-organisms present in the colon.
The ability of glassy amylose to provide the required delayed release characteristics is not lost immediately the glassy amylose passes through the Tg and films containing amylose which has been produced in the glassy condition at temperatures less than the Tg may therefore then be utilized at the Tg or at temperatures slightly higher than the Tg as well as at temperatures less than the Tg, whilst still retaining its glassy properties. However, the glassy amylose present in the films formed from the film-forming compositions used according to the method of the present invention preferably has a Tg of no more than 20° C. below the temperature at which use of the composition is envisaged, i.e. at body temperature of about 37° C., i.e. more than or equal to 17° C., and is preferably more than or equal to about 30° C. or, more preferably, more than or equal to about 40° C. The Tg can be predetermined by controlling the amount of water in it. This can be achieved by varying the concentration of the amylose in the film-forming composition.
The ultimate test of the suitability of a particular sample of amylose in a film formed under any given conditions is of course its ability to resist hydrolytic degradation under aqueous conditions, particularly at a pH of 1-9 and a temp
Newton John Michael
Siew Lee Fung
BTG International Limited
Fubara Blessing
Page Thurman K.
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