Drug – bio-affecting and body treating compositions – Preparations characterized by special physical form – Particulate form
Reexamination Certificate
2001-02-05
2002-12-03
Page, Thurman K. (Department: 1615)
Drug, bio-affecting and body treating compositions
Preparations characterized by special physical form
Particulate form
C424S489000, C424S464000, C424S465000, C424S494000, C514S561000
Reexamination Certificate
active
06488964
ABSTRACT:
CROSS REFERENCE TO RELATED APPLICATIONS
This application is a continuation of PCT application PCT/FR99/01811, filed Jul. 23, 1999, and published in French as WO 00/07568 on Feb. 17, 2000. PCT/FR99/01811 claimed the priority of French application FR98/10091, filed Aug. 3, 1998. The entire disclosures of both are incorporated herein by reference.
FIELD OF THE INVENTION
The invention relates to a process for manufacturing coated particles of &ggr;-aminobutyric acid (GABA) analogue containing less than 0.5% of lactam by weight relative to the weight of GABA analogue.
The invention also relates to the coated particles which can be obtained by the said process, as well as to any pharmaceutical form using the said coated particles.
BACKGROUND
In the description hereinbelow and in the claims, the invention is described more particularly in relation to the &ggr;-aminobutyric acid analogues chosen from the group comprising gabapentin and pregabalin. However, as already stated, the process applies to any &ggr;-aminobutyric acid analogue which can produce lactam molecules as degradation product.
Gabapentin, also known as 1-aminomethylcyclohexaneacetic acid, is a &ggr;-aminobutyric acid (GABA) analogue. It has anti-convulsant properties and is used in the treatment of epilepsy. This well-known molecule is described in particular in documents U.S. Pat. No. 4,024,175 and U.S. Pat. No. 4,087,544.
From the point of view of pharmacokinetics, it is essential for the concentration of gabapentin in the plasma to reach its peak in 2 to 3 hours.
This is one of the reasons why gabapentin is currently sold in France in the form of gel-capsules filled with a mixture of powder consisting of gabapentin, hydrated lactose, corn starch and talc. The gel-capsules contain 100 mg, 300 mg or 400 mg doses of active principle and are sold under the trade name NEURONTIN® by Parke-Davis.
Although gel-capsules allow the satisfactory concentration of gabapentin in the plasma to be obtained, they are, however, unsuitable for pediatric use.
To solve this problem, attempts have been made to present gabapentin in the form of an aqueous solution.
However, the document Pharmaceutical Research, Volume 9, Number 5, 1992, demonstrates:
on the one hand, that gabapentin is liable to be degraded in aqueous solution to give, by intramolecular cyclization, a lactam-type degradation product, the content of which should not exceed 0.5% by weight relative to the weight of the active principle for any pharmaceutical form, irrespective of the dosage;
and, on the other hand, that gabapentin has a sufficiently bitter taste for it to be essential to mask its taste.
To solve the problem of masking the taste, document EP-A-0,458,751 proposed presenting gabapentin in the form of particles coated with a hydrophilic first layer of a water-insoluble polymer and a hydrophobic second layer. Even though satisfactory masking of the taste is obtained, the process of coating the first layer requires the presence of water, such that an intramolecular cyclization of gabapentin can be expected, leading to the formation of lactam inside the finished product itself.
Pregabalin is also a &ggr;-aminobutyric acid analogue which is known as an anti-epileptic agent and is more particularly described in document WO 98/58641 for its application as an anti-inflammatory agent. The Applicant has observed that pregabalin displayed a phenomenon identical to that of gabapentin as regards its degradation in aqueous solution into lactam molecules. In addition, just like gabapentin, pregabalin must reach a maximum concentration in the plasma in 2 to 3 hours. Finally, this molecule also has a bitter taste, making it difficult to use in its native form in a pharmaceutical formulation.
SUMMARY OF THE INVENTION
The first problem which the invention proposes to solve is to provide a pharmaceutical form of a GABA analogue, whose lactam content is less than 0.5% by weight relative to the weight of GABA analogue.
The second problem which the invention proposes to solve is to provide a pharmaceutical form of a GABA analogue which can be used in paediatrics.
The third problem which the invention proposes to solve is to provide a pharmaceutical form of a GABA analogue in which the bitter taste of the said analogue is masked, while at the same time giving a maximum concentration in the plasma in 2 to 3 hours.
To do this, the invention proposes a process for manufacturing coated particles of a &ggr;-aminobutyric acid analogue whose lactam content by weight relative to the weight of GABA analogue is less than 0.5%.
This process is characterized in that a coating solution comprising at least one polymer in at least one organic solvent is sprayed on to the said particles of &ggr;-aminobutyric acid analogue.
In a first embodiment, the &ggr;-aminobutyric acid analogue is gabapentin.
In another embodiment of the invention, the &ggr;-aminobutyric acid analogue is pregabalin.
It has been found, entirely surprisingly, that the fact of coating the gabapentin or the pregabalin particles with a polymer dissolved in an organic solvent makes it possible to obtain a lactam content in the coated particle of less than 0.5% by weight relative to the weight of gabapentin or of pregabalin. In addition, the polymer coating also makes it possible to mask the taste of the &ggr;-aminobutyric acid analogue without, however, delaying its release, thus making it possible to obtain usual concentrations in the plasma.
DETAILED DESCRIPTION OF THE INVENTION
To obtain the masking of the taste while at the same time allowing the rapid release of the gabapentin, the polymer represents between 60 and 80% by weight of the gabapentin.
For a polymer proportion of less than 60%, sufficient masking of the taste is not obtained. Conversely, for a polymer proportion of greater than 80%, the gabapentin taste is entirely masked, but the active principle may not be released quickly enough.
Advantageously, the gabapentin particles are coated to a proportion of 70% by weight of polymer.
Similarly, as regards pregabalin, to obtain masking of the taste while at the same time allowing rapid release of the molecule, the polymer represents between 15 and 30% by weight of the pregabalin.
For a polymer proportion of less than 15%, sufficient masking of the taste is not obtained. Conversely, for a polymer proportion of greater than 35%, the gabapentin taste is entirely masked, but the active principle may not be released quickly enough.
Advantageously, the pregabalin particles are coated to a proportion of 20% by weight of polymer.
Moreover, the various processes for manufacturing gabapentin or pregabalin give particles which can range between 2 micrometers and a few millimeters in size.
If the size of the particles of active principle analogue is too small, i.e. about 50 micrometers, spraying of the solution leads to non-uniform coating of the particles.
To solve this problem, it is sought to increase the size of the particles by spraying a solution of a water-soluble binder in an organic solvent on to the said particles by the so-called fluidized air bed technique, also known as “spray coating”, after which the aggregated particles obtained are screened and calibrated.
The actual coating of the gabapentin or pregabalin is carried out on the aggregated or non-aggregated particles, the size of which is between 100 and 400 micrometers, preferably in the region of 250 micrometers, by the same so-called fluidized bed technique.
The coated gabapentin or pregabalin particle obtained is in the form of a coated, aggregated or non-aggregated particle, the size of which is between 100 and 450 micrometers, with a median of about 250 micrometers.
To dissolve the polymer, the organic solvent is chosen from the group comprising acetone, ethanol and isopropanol, alone or as a mixture.
According to one advantageous embodiment, the polymer is dissolved in a solvent comprising 50 parts of acetone and 50 parts of ethanol per 100 parts on a mass/mass basis.
Similarly, when a step of pre-uniforming of the size of the gabapentin or pregabalin particles is c
Bruna Etienne
Chauveau Charles
Demichelis Alain-Gilles
Gendrot Edouard
Heslin Rothenberg Farley & & Mesiti P.C.
Page Thurman K.
Pulliam Amy E
Societe Laboratoires des Products Ethiques - Ethypharm
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