Multilayer pharmaceutical product for release in the colon

Details Multilayer pharmaceutical product for release in the colon Multilayer pharmaceutical product for release in the colon

2001-11-19

2003-10-14

Spear, James M. (Department: 1615)

Drug, bio-affecting and body treating compositions

Preparations characterized by special physical form

Tablets, lozenges, or pills

C424S463000, C424S474000, C424S439000, C424S451000, C424S464000, C424S462000, C424S497000

Reexamination Certificate

active

06632454

ABSTRACT:

The invention relates to a multilayer drug form composed of a core with an active pharmaceutical ingredient, of an inner polymer coating and of an outer polymer coating.
PRIOR ART
(Meth)acrylate copolymers which comprise monomers with quaternary ammonium groups, e.g. trimethylammoniumethyl methacrylate chloride, and their use for release-slowing medicament coatings have been known for a long time (for example from EP-A-181 515 or from DE 1 617 751). Processing takes place in organic solution or as aqueous dispersion, for example by spraying onto medicament cores or else without solvent in the presence of flow aids by application in the melt (see EP-A-0 727 205).
EP-A 629 398 describes pharmaceutical formulations which have a core with an active ingredient and an organic acid, where the core has a two-layer covering. The inner covering in this case is formed by a release-slowing (meth)acrylate copolymer with quaternary ammonium groups (EUDRAGIT® RS), while the outer covering has an enteric coating, for example a copolymer of the type EUDRAGIT® L30D-55 (ethyl acrylate/methacrylic acid, 50:50). The release characteristics achieved can be described by a rapid release of active ingredient after a time lag at elevated pH.
EP 0 704 207 A2 describes thermoplastic materials for drug coverings soluble in intestinal juice. These comprise copolymers of 16 to 40% by weight acrylic or methacrylic acid, 30 to 80% by weight methyl acrylate and 0 to 40% by weight of other alkyl esters of acrylic acid and/or methacrylic acid.
EP 0 704 208 A2 describes coating agents and binders for drug coverings soluble in intestinal juice. These comprise copolymers of 10 to 25% by weight methacrylic acid, 40 to 70% by weight methyl acrylate and 20 to 40% by weight methyl methacrylate. The description mentions not only monolayer coatings but also multilayer coating systems. These may consist of a core which comprises, for example, a basic or a water-sensitive active ingredient, have a sealing layer of another coating material such as cellulose ether, cellulose ester or a cationic polymethacrylate, for example of the EUDRAGIT® type, inter alia including EUDRAGIT® RS and RL, and are then additionally provided with the abovementioned covering soluble in intestinal juice.
PROBLEM AND SOLUTION
The intention was to provide a drug form which releases virtually no active ingredient in the stomach and enables uniform and long-lasting release of active ingredient in the intestine, in particular shortly before or only in the colonic region. The nature of the release of active ingredient is intended in particular to comply with the requirement that in the USP release test two hours at pH 1.2 and a subsequent change in the buffer to pH 7.0, the release of the active ingredient present is less than 5% in the period up to 2.0 hours after the start of the test and 30 to 80% at the time eight hours after the start of the test.
The problem is solved by the use of a multilayer drug form which is essentially composed of
a) a core with an active pharmaceutical ingredient
b) an inner coating of a copolymer or of a mixture of copolymers composed of 85 to 98% by weight free-radical polymerized C1- to C4-alkyl esters of acrylic or methacrylic acid and 15 to 2% by weight (methy)acrylate monomers with a quaternary ammonium group in the alkyl radical and
c) an outer coating of a copolymer composed of 80 to 95% by weight free-radical polymerized C
1
- to C
4
-alkyl esters of acrylic or methacrylic acid and 5 to 25% by weight (meth)acrylate monomers with an anionic group in the alkyl radical,
for producing a drug form for which, in the USP release test two hours at pH 1.2 and a subsequent change in the buffer to pH 7.0, the release of the active ingredient present is less than 5% in the period up to 2.0 hours after the start of the test and 30 to 80% at the time eight hours after the start of the test.
It has been found, surprisingly, that the active ingredient release profile of the inner coating after dissolution of the outer, enteric coating differs from an active ingredient release profile obtained when inner coating is employed without outer coating. On use of the structure known in principle from EP 0 704 208 A2 and EP-A 629 398, an unexpectedly slow, very constant active ingredient release is obtained.
On carrying out the USP release test two hours at pH 1.2 and a subsequent change in the buffer to pH 7.5 the release of the active ingredient present at the time six hours after the start of the test is only 30 to 80%. This is particularly advantageous in the therapy of disorders in which local increases in the pH may occur in parts of the colon, but it is also intended in these cases to avoid active ingredient release which is too fast, or it is intended to achieve delayed active ingredient release.
In addition, unexpectedly, active ingredient release takes place substantially independently of the thickness of the outer coating.
Evidently there is an interaction with the inner coating layer during dissolution of the outer coating layer. The previously undisclosed release profile increases the possibilities for the skilled worker in the formulation of novel drug forms. In particular, the release characteristics are advantageous for some active ingredient substances which are intended to be released in the intestine, in particular shortly before or only in the colonic region, as constantly as possible. The evidently only extremely slight effect of the thickness of the outer coating layer on the release profile increases the safety of use in relation to manufacturing tolerances.
MODE OF OPERATION OF THE INVENTION
The invention describes the use of a multilayer drug form for which, in the USP release test for two hours at pH 1.2 and a subsequent change in the buffer to pH 7.0, the release of the active ingredient present is less than 5% in the period up to 2.0 hours after the start of the test and 30 to 80%, in particular 40 to 70%, at the time eight hours after the start of the test.
The USP release test (according to USP XXIV, method B, modified test for enteric coated products) is known to the skilled worker. The test conditions are, in particular: paddle method, 100 revolutions per minute, 37° C.; pH 1.2 with 0.1 N HCl, pH 7.0 by addition of 0.2 M phosphate buffer and adjustment with 2 N NaOH.
The multilayer drug form to be used consists essentially of a core with an active ingredient, of an inner and of an outer coating. It is possible in the usual way for excipients in use in pharmacy to be present, but they are not critical for the invention.
Core with an Active Pharmaceutical Ingredient
Cores
Carriers or cores for the coatings are tablets, granules, pellets, crystals of regular or irregular shape. The size of granules, pellets or crystals is ordinarily between 0.01 and 2.5 mm, and that of tablets between 2.5 and 30.0 mm. The carriers normally contain 1 to 95% active ingredient and, where appropriate, further pharmaceutical excipients. The usual production processes are direct compression, compression of dry, moist or sintered granules, extrusion and subsequent rounding off, wet or dry granulation or direct pelleting (e.g. on plates) or by binding of powders (powder layering) on active ingredient-free beads (nonpareils) or active ingredient-containing particles.
Beside the active ingredient, the cores may contain further pharmaceutical excipients: binders such as lactose, cellulose and derivatives thereof, polyvinylpyrrolidone (PVP), humectants, disintegration promoters, lubricants, disintegrants, starch and derivatives thereof, sugar solubilizers or others.
The cores can be provided in the usual way with an active pharmaceutical ingredient by applying the appropriate active ingredient for example as active ingredient powder to carrier particles (nonpareils) by means of an aqueous binder. The active ingredient cores (pellets) can be obtained after drying and screening in the required size fraction (e.g. 0.7 to 1 mm). This process is referred to inter alia as powder layering.
Active Pharmaceutical Ingredients
The active pharmaceut

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