Drug – bio-affecting and body treating compositions – Preparations characterized by special physical form – Tablets – lozenges – or pills
Reexamination Certificate
1996-08-19
2004-09-07
Webman, Edward J. (Department: 1617)
Drug, bio-affecting and body treating compositions
Preparations characterized by special physical form
Tablets, lozenges, or pills
C424S473000
Reexamination Certificate
active
06787156
ABSTRACT:
FIELD OF THE INVENTION
The present invention relates to a composition for controlled delivery of an active substance into an aqueous medium.
BACKGROUND OF THE INVENTION
It is known to obtain sustained release of an active substance, e.g. a pharmaceutically active powder, by embedding it in a matrix of an insoluble substance from which the active substance will gradually diffuse. Sustained release of an active substance contained in a tablet core may also be achieved by applying to the core a semi-permeable coating through which water and dissolved active substance may diffuse or an insoluble coating provided with a hole through which the active substance is released. Gradual release of an active substance may furthermore be obtained by microencapsulating particles of an active substance in one or more layers of film which may be of different types, e.g. of a type which mediates diffusion of the active substance or release thereof in the intestines.
These conventional ways of providing sustained release of an active substance have certain drawbacks, in that it is difficult to maintain a constant concentration of the active substance, for example a constant concentration of a pharmaceutically active substance in plasma for the entire period when the dosage form is present in the body. In particular, this may be the problem with drugs which have a brief half-life in the body. Furthermore, the penetration of water through diffusion coatings may cause hydrolysis of active substances which are unstable in an aqueous environment.
WO 89/09066 discloses a composition for controlled delivery of an active substance into an aqueous phase by erosion at a substantially constant rate of a surface or surfaces of the composition, the composition containing a) a matrix of a crystalline polyethylene glycol polymer with a molecular weight of at least 20,000 daltons, b) at least one non-ionic emulsifier dispersed in the polyethylene glycol matrix in an amount of 2-50% by weight of the crystalline polymer and the non-ionic emulsifier, the non-ionic emulsifier having at least one domain which is compatible with the polyethylene glycol polymer and being selected from fatty acid esters and fatty alcohol ethers, and c) at least one active substance substantially homogeneously dispersed in the polyethylene glycol matrix and/or located in geometrically well-defined zones within the composition, the non-ionic emulsifier and/or the active substance reducing the water affinity of domains between grains and in cracks in the crystalline polymer matrix and in the crystalline polymer matrix itself, thereby substantially eliminating water diffusion in the interface between the polymer crystals, so that the erosion is predominantly effected by the dissolving action of an aqueous medium on a surface or surfaces of the composition exposed to the medium.
Other controlled release compositions based on this principle are disclosed in WO 91/04015, which relates to compositions that provide a regulated non-initial burst release of an active substance at a predetermined time.
The present invention is a further development based on the inventions disclosed in WO 89/09066 and WO 91/04015. In particular, the present invention provides a novel coating based on certain cellulose derivatives, the coating being particularly suitable for controlled release compositions with a matrix containing an active substance, e.g. a matrix such as that disclosed WO 89/09066.
SUMMARY OF THE INVENTION
The present invention thus relates to a composition for controlled delivery of at least one active substance into an aqueous medium by erosion at a preprogrammed rate of at least one surface of the composition, comprising
i) a matrix comprising the active substance, the matrix being erodible in the aqueous medium in which the composition is to be used, and
ii) a coating having at least one opening exposing at least one surface of said matrix, the coating comprising
a) a first cellulose derivative which has thermoplastic properties and which is substantially insoluble in the aqueous medium in which the composition is to be used,
and at least one of
b) a second cellulose derivative which is soluble or dispersible in water,
c) a plasticizer, and
d) a filler,
said coating being a coating which crumbles and/or erodes upon exposure to the aqueous medium, in particular a body fluid, at a rate which is equal to or slower than the rate at which the matrix erodes in the aqueous medium, allowing exposure of said surface of the matrix to the aqueous medium to be controlled.
The combination of the matrix and the active substance must be substantially impenetrable to fluids of the aqueous phase, for example body fluids present where the composition of the invention is introduced into the body (e.g. in the gastrointestinal tract, including the rectum, in the vagina or subcutaneously) or into a body cavity via a catheter (e.g. the urinary bladder, the gall bladder, the uterus, a central nervous system cavity, infectious/malignant/post-operative cavities, etc.), in order to avoid degradation of the active substance residing in the matrix due to the action of water in the case of an active substance which is susceptible to hydrolysis. The inclusion of the active substance in a matrix into which water diffusion is substantially eliminated will thus impart stability to the composition, so that the active substance will remain active even when the composition has been exposed to body fluids or other fluids for a period of time. As the fluids can only act on the surface of a matrix of this type, the active substance embedded therein is only exposed to the fluids in question when it is released or immediately prior to its release from the matrix. A matrix of a type which is substantially impenetrable to water will therefore ensure the stability of the active substance in the matrix until the time when the active substance is actually released, and will also ensure that release of the active substance takes place at a controlled and reproducible rate, since the release proceeds gradually from the surface or surfaces of the matrix exposed to the fluids in question.
Due to the controlled release of the active substance from the composition of the invention, it is possible to obtain a substantially constant rate of release or a controlled pulsatile release of the active substance over a specific period of time. Adherence to a strict dosage regimen, e.g. requiring administration of a drug at set intervals up to several times a day, may therefore be dispensed with. Furthermore, it is possible to include two or more different active substances in the composition of the invention, adapted to be released at different concentrations and/or intervals, thus making it easier for patients to follow a prescribed regimen.
An additional advantage of the composition of the invention is that it may be produced by relatively simple and inexpensive methods, e.g. by extrusion, as will be explained in more detail below. Furthermore, the composition allows for the incorporation of high concentrations of the active substance relative to the composition's size. This is obviously a great advantage, notably when the composition is to be used for the delivery of a pharmaceutically active substance, since it allows for the delivery of the required amount of the active substance without the composition being unnecessarily large. Compositions of the invention in which the matrix contains a surface active agent may furthermore be used for the delivery of sparingly soluble or non-soluble pharmaceutical powders which can otherwise be difficult to administer, since such substances are compatible with the lipophilic domains of the surface active agent.
DETAILED DISCLOSURE OF THE INVENTION
A suitable matrix for use in the compositions of the invention is one of the type described in WO 89/09066 or WO 91/04015, to which reference is made and which are incorporated herein by reference, i.e. a matrix containing a crystalline polyethylene glycol polymer with a molecular weight of at least 20,000 daltons
BM Research A/S
Burrous Beth A.
Foley & Lardner
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