Drug – bio-affecting and body treating compositions – Preparations characterized by special physical form – Implant or insert
Reexamination Certificate
1999-01-06
2001-06-12
Page, Thurman K. (Department: 1615)
Drug, bio-affecting and body treating compositions
Preparations characterized by special physical form
Implant or insert
C424S423000, C424S486000, C424S489000
Reexamination Certificate
active
06245346
ABSTRACT:
The present invention relates to pharmaceutical compositions containing biodegradable polymers for the controlled release of water-insoluble active principles.
Pharmaceutical compositions for controlled release containing biodegradable polymers are extremely useful for the distribution of medical and pharmaceutical products and find a great variety of applications in which they offer numerous advantages in relation to formulations of standard medicines.
Simple administration of a formulation for controlled release assures slow release of the active principle in the course of a sustained period.
One of the first applications of this type of formulation for controlled release is in the domain of drug abuse. The treatment of patients who are addicted to the use of drugs is made delicate and difficult insofar as, with standard formulations, it is not always easy to obtain the co-operation of the patient. Thus, with standard formulations, there is always the risk that the patient refuses to follow the necessary treatment at the desired moment. With formulations for controlled release, a single dose assures on the other hand effective treatment for a certain length of time, longer than what it is possible to obtain with a single dose.
The formulations for controlled release are equally particularly useful in applications such as cancer therapy where long term treatments are often necessary.
Another important application of these formulations is in the field of hormone therapy for example in connection with contraceptives where continuous release of the active principle at a relatively constant concentration is necessary for a certain length of time.
Pharmaceutical compositions for controlled release can thus be proposed in a variety of galenical formulations. Thus there are implant formulations, as well as formulations which allow oral or parenteral administration. Oral formulations are normally presented in the form of tablets or capsules which can be easily swallowed or ingested.
Parenteral formulations can be presented notably in the form of microgranules, microspheres or microcapsules.
According to the aim and the circumstances of the desired form of therapy, implants can sometimes be preferred to parenteral formulations. This preference exists notably in a case where it is desired to have a certain flexibility in relation to the therapy protocol. In relation to parenteral formulations, implants present the advantage of being able to be removed surgically, if it should be necessary for any reason, to stop the treatment before the complete release of the active principle has taken place.
The pharmaceutical compositions according to the present invention can be presented notably in the form of implants, microgranules and/or microspheres.
The discovery of polymers which are easily biodegradable has considerably advanced the technology of the field of pharmaceutical compositions for controlled release. It is of course advantageous to be able to introduce a pharmaceutical composition containing polymer into the human or animal body knowing that the polymer is going to degrade in the course of a certain lapse of time, thus permitting slow release of the active principle without letting any foreign matter remain in the patient's body.
As far as biodegradable polymers are concerned the copolymers and homopolymers of polylactide and polyglycolide are particularly preferred in the formulations for controlled release because they are easily degradable, decomposing into inoffensive products such carbon dioxide and water, and not leaving any residue in the time after the release of the active principle.
The U.S. Pat. No. 3,773,919 describes polymer formulations of medicines containing polylactides. It is mentioned there that the invention presents a particular interest for medicines which require prolonged administration or sustained slow release, for example for certain medicines for regulating fertility or the hormones used in hormone substitution therapy.
It is advisable to notice that implants, such as microgranules, can be prepared according to a “dry process” which avoids the use of solvents for the prior dissolution of the active principles and/or of the polymers. This avoids the drawback of processes such as microencapsulation, where the problem is always encountered of traces of residual solvent which can compromise the use of the compositions for therapeutic purposes. The Applicant Company has perfected this “dry process” for the preparation of microgranules and implants. This process has been described in the Swiss patent 679 207 of which the Applicant Company is the owner. Microgranules coming from this process permit regular release of the active substance over a period of approximately one month.
However, there still exists a need for pharmaceutical compositions which permit sustained release of water-insoluble active principles over a more significant length of time such as two or even three or four months.
Now, in a way that has been totally surprising and unexpected, the Applicant Company has been able to perfect a new type of pharmaceutical composition which permits controlled release of water-insoluble active principles over a period longer than one month, and in particular of two to three months, or even longer.
The pharmaceutical compositions according to the present invention are characterised by the fact that they include a homopolymer of lactic acid with a low molecular weight.
The polymer can be a homopolymer of D,L-lactic acid or of L-lactic acid. The Applicant Company has discovered that the use of this polymer makes it possible to obtain slow and regular release of an active principle during two to three months, or even longer.
This result is even more surprising in that the polymer used in the present case is a polymer which has a low molecular weight. In fact, one might think that the lower the molecular weight of the polymer, the more significant would be its speed of degradation. The Applicant Company discovered, however, that this was not so for the homopolymers of D,L-lactic acid and of L-lactic acid.
In practice, the molecular weight of the homopolymer of L-lactic acid is advantageously chosen to be between approximately 1,000 and 30,000, preferably between approximately 3,000 and 15,000, and being even more preferably about 4,000.
The molecular weight of the homopolymer of D,L-lactic acid is advantageously chosen to be between approximately 1,000 and 30,000, preferably between approximately 2,000 and 20,000 and even more preferably between approximately 2,000 and 6,000.
The percentage of polymer in the pharmaceutical composition according to the invention is between 98 and 70%, preferably between 95 and 75% and even more preferably between 85 and 75%.
The use of this type of polymer thus makes it possible to obtain slow and progressive release of the active principles which have been made water-insoluble.
According to the invention, “water-insoluble active principles” are understood to be active principles which can themselves be soluble in an aqueous solution but which are rendered insoluble by being transformed into an insoluble salt of the active principle.
In the context of the present invention, “water-insoluble” is understood to mean a solubility in water which does not exceed 100 &mgr;g/ml (definition by the USP, United States Pharmacopoea) in conditions of ambient temperature and slow agitation.
The active principle made water-insoluble according to the present invention can be chosen amongst proteins, polypeptides, hormones. In particular, the active principle can be chosen amongst the acceptable pharmaceutical salts of oxytocin, vasopressin, ACTH, calcitonin, LH-RH or its analogues, the epidermal growth factor, prolactin, inhibin, interferon, somatostatin, or its analogues such as vapreotide pamoate, insulin, glucagon, the atrial natriuretic factor, endorphin, a peptic inhibitor of renin, growth hormone releasing factor, the peptide T as well as their synthetic analogues.
The pharmaceutically acceptable insoluble salts of the active princip
Gurny Robert
Heimgartner Frederic
Orsolini Piero
Rothen-Weinhold Alexandra
Debio Recherche Pharmaceutique S.A.
Evans Charesse L.
Page Thurman K.
Piper Marbury Rudnick & Wolfe
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