Drug – bio-affecting and body treating compositions – Preparations characterized by special physical form – Implant or insert
Reexamination Certificate
2000-02-23
2001-11-20
Dees, Jose′ G. (Department: 1616)
Drug, bio-affecting and body treating compositions
Preparations characterized by special physical form
Implant or insert
C424S422000, C424S423000, C424S424000, C424S464000, C424S465000, C424S468000, C424S474000, C424S475000, C424S482000, C424S484000, C424S486000, C514S002600, C514S009100, C514S011400, C514S806000
Reexamination Certificate
active
06319512
ABSTRACT:
The present invention relates to an implant for the controlled release of pharmaceutically active principles. It also relates to a process for the production of such an implant.
Controlled release formulations of medicinal products are extremely useful for the administration of medical and pharmaceutical products and have a wide variety of applications in which they offer numerous advantages in comparison with standard formulations of medicinal products.
A single administration of a controlled release formulation ensures the slow release of the active principle over a prolonged period.
One of the prime applications of this type of controlled release formulation lies in the field of drug addiction. The treatment of patients who are addicted to the use of drugs is rendered awkward and difficult in so far as, with standard formulations, it is not always easy to obtain the patient's cooperation. Thus, with standard formulations, there is always the risk that the patient will refuse to follow the necessary treatment at the desired time. With controlled release formulations, a single administration, on the other hand, ensures an effective treatment for a certain period, superior to that which can be obtained from a single dose.
Controlled release formulations of medicinal products are also particularly useful in applications such as anti-cancer therapy where long term treatments are often required.
Another important application for these formulations lies in the field of hormone therapy, for example, relating to contraceptives where the continuous release of the active principle in a relatively constant concentration is required over a certain period.
Controlled release formulations of medicinal products may be proposed in a variety of pharmaceutical forms. Thus, there exist formulations of implants and formulations permitting oral or parenteral administration.
Oral formulations are normally in the form of tablets or capsules which may easily be swallowed or ingested.
Parenteral formulations often have a spherical structure. They suffer from the constraint of size because they have to be able to be introduced into the patient's body by injection using a needle of a reasonable diameter. Said formulations are often produced using granulation or microencapsulation processes.
Implants may take several forms. They are thus often moulded in the form of films then treated to give different shapes, such as cylindrical rods, spherical particles and others.
Depending on the purpose and the circumstances of the desired form of therapy, implants may sometimes be preferred to carenteral formulations. This preference exists particularly if a certain flexibility is desired with respect to the treatment protocol. Compared with parenteral formulations, implants have the advantage of being able to be removed surgically if it should prove necessary to stop the treatment before the complete release of the active principle has taken place.
A phenomenon often observed with controlled release formulations of medicinal products is that of the “burst effect”, that is, a very large initial release of the active principle. In certain cases, this effect may be desirable. On the other hand, there are cases where it may prove to be dangerous. This is the case particularly as regards hormone therapies which use active principles having very troublesome or even toxic side-effects in high concentrations. In such cases, it is imperative to be able to ensure slow and uniform release in small quantities of the active principle.
The patent application EP 0 659 406 in the names of DOW CORNING ASIA Ltd. and SUMITOMO PHARMACEUTICALS COMPANY Ltd. provides a possible solution to the problem described above. This application describes a cylindrical rod of controlled release formulation comprising an internal layer which does not disintegrate and an external layer which is impermeable to water. In the examples of this application, one may read that this formulation is prepared by immersing the internal layer in a solution containing the substance which constitutes the external layer or coating. This method known as “dipping” or immersion is also described in the U.S. Pat. No.4,894,231 in the name of BIOMEASURE, Inc. In this patent, the external layer is also a substance which is impermeable to water which acts as a “barrier”, thus also preventing an excessively large initial release of the active principle.
This patent, apart from the dipping method, also describes the coating of the internal layer with an external layer by spraying.
All the implants or other controlled release formulations of medicinal products produced by the methods described above suffer, however, from several shortcomings.
The formation of the external layer by methods such as dipping or spraying makes it very difficult or cumbersome to obtain a layer with a smooth and uniform surface. These methods also have the disadvantage of not permitting reliable control of the thickness of the layer. It would be very desirable, however, to be able to obtain, by a simple method, implants comprising a smooth and uniform external layer, with a chosen thickness, which would also make it possible to control more effectively or even limit the “burst effect”.
The methods known as dipping have an additional disadvantage. In fact, these methods require the use of organic solvents such as acetone, chloroform or methylene chloride. It is necessary, therefore, to remove said solvents in order to be able to introduce the implants or other formulations into the body of the patient to be treated.
The applicant company, after considerable work and research, has managed to respond to the existing need for an implant for he controlled release of pharmaceutically active principles for which the “burst effect” is appreciably controlled whilst avoiding the disadvantages of the formulations described in the prior art.
The invention provides, therefore, an implant for the controlled release of at least one pharmaceutically active principle, said implant comprising a core which contains at least one active principle and a sheath which surrounds said core, and is wherein said sheath is composed of at least one polymeric film applied around said core.
According to a preferred embodiment of the invention, the sheath is composed of at least two polymeric films, one surrounding part of the core and the other surrounding the remaining part.
The sheath consists of at least one polymeric film applied around the core. Thus, it is possible to have a sheath consisting of:
at least two identical or different polymeric films which are each applied around a part of the core as indicated above,
or at least two identical or different superposed polymeric films applied around the core.
Of course, the sheath may also consist of the two polymeric films juxtaposed in order to surround the whole of the core onto which is applied at least one other polymeric film.
The implant according to the invention has the advantage of having a perfectly smooth and uniform sheath, the thickness of which may be chosen, which permits great flexibility in terms of the choice of the release profile, thus offering the possibility of a more precise regulation of the “burst effect” and thus of the initial rate of release of the pharmaceutically active principle. This thickness may be controlled as a function of the thickness of the polymeric film chosen and the number of superposed polymeric films applied around the core.
Advantageously, the core is composed of a biodegradable polymer mixed with at least one pharmaceutically active principle.
The sheath may also be composed of a biodegradable polymer, this possibly being the same polymer as that forming the core, or another polymer.
The polymer of the sheath may optionally be mixed beforehand with one or more pharmaceutically active principles. Said active principles may optionally be the same as those which are combined with the polymer forming the core.
The biodegradable polymers used in the implant according to the invention may be chosen from the group comprising:
Gurny Robert
Heimgartner Frederic
Orsolini Piero
Rothen-Weinhold Alexandra
Choi Frank
Debio Recherche Pharmaceutique SA
Dees Jose′ G.
Piper Marbury Rudnick & Wolfe
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