EP1100467A1

EP1100467A1 - Method for making coated gabapentine or pregabaline particles

Info

Publication number: EP1100467A1
Application number: EP99932956A
Authority: EP
Inventors: Etienne Bruna; Edouard Gendrot; Charles Chauveau; Alain-Gilles Demichelis
Original assignee: Ethypharm SAS
Current assignee: Ethypharm SAS
Priority date: 1998-08-03
Filing date: 1999-07-23
Publication date: 2001-05-23
Also published as: CN1321083A; FR2781793B1; WO2000007568A1; AU742701B2; NZ509980A; AU4916099A; FR2781793A1; AR021746A1; US6488964B2; PE20001030A1; CA2338173A1; US20020012679A1; ZA200100943B; JP2002522375A

Abstract

The invention concerns a method for making coated particles of η-aminobutyric acid analogue whereof the lactam content by weight relative to the weight of η-aminobutyric acid analogue is less than 0.5 %. The invention is characterised in that it consists in spraying a coating solution comprising at least a polymer in an organic solvent on said η-aminobutyric acid analogue particles.

Description

PROCESS FOR THE MANUFACTURE OF COATED GABAPENTINE OR PREGABALINE PARTICLES

The invention relates to a process for manufacturing coated γ-aminobutyric acid (GABA) analog particles containing less than 0.5% lactam by weight relative to the weight of GABA analog.

The invention also relates to the coated particles capable of being obtained by said process, as well as any dosage form using said coated particles.

In the following description and in the claims, the invention is more particularly described in relation to the analogs of γ-aminobutyric acid chosen from the group comprising gabapentin and pregabalin. However, as already said, the process applies to any analogue of γ-aminobutyric acid capable of producing lactam molecules as a degradation product.

Gabapentin, also known as 1-aminomethylcyclohexane acetic acid, is an analogue of γ-aminobutyric acid (GABA). It has anti-convulsant properties and is used in the treatment of epilepsy. This well-known molecule is described in particular in documents US-A-4024175 and

US-A-4087544.

From a pharmacokinetic point of view, it is essential that the plasma concentration of gabapentin reaches its peak in 2 to 3 hours.

This is one of the reasons why gabapentin is currently marketed in France in the form of capsules filled with a powder mixture consisting of gabapentin, hydrated lactose, corn starch and talc. The capsules are dosed at 100 mg, 300 mg or 400 mg of active principle and are marketed under the brand NEURONTIN® by PARKE-DAVIS.

Even if the capsules make it possible to obtain a satisfactory plasma concentration of gabapentin, they nevertheless remain unsuitable for pediatric use. To resolve this problem, an attempt has been made to present gabapentin in the form of an aqueous solution.

However, the document PHARMACEUTICAL RESEARCH, Volume 9, Number 5, from 1992 demonstrates:

_ on the one hand, that gabapentin is capable of being degraded in aqueous solution to give, by intramolecular cyclization, a degradation product of the lactam type, the rate of which must not exceed 0.5% by weight relative to the weight of the principle active for any dosage form regardless of the dosage; _ and secondly, that gabapentin has a sufficiently bitter taste that it is essential to mask its taste.

To solve the problem of masking the taste, document EP-A-0 458 751 has proposed to present gabapentin in the form of particles coated with a first hydrophilic layer of a polymer insoluble in water and with a second layer hydrophobic. Even if a satisfactory taste masking effect is obtained, the coating process of the first layer requires the presence of water, so that one can expect an intramolecular cyclization of gabapentin leading to the formation of lactam. within the finished product.

Pregabalin is also an analogue of γ-aminobutyric acid known as an anti-epileptic and more particularly described in document WO 98/58641 for its application as an anti-inflammatory agent. The Applicant has found that pregabalin exhibits a phenomenon identical to that of gabapentin with regard to its degradation in aqueous solution of lactam molecules. In addition, like gabapentin, pregabalin must reach a maximum plasma concentration in 2 to 3 hours. Finally, this molecule also has a bitter taste making it difficult to use as such within a pharmaceutical formulation.

The first problem which the invention proposes to solve is to provide a galenic form of GABA analog, the lactam content of which is less than 0.5% by weight relative to the weight of GABA analog. The second problem which the invention proposes to solve is to provide a galenic form of GABA analog, capable of being able to be used in pediatrics.

A third problem which the invention proposes to solve is to provide a galenic form of GABA analog in which the bitter taste of said analog is masked while leading to a maximum plasma concentration in 2 to 3 hours.

To do this, the invention provides a process for manufacturing coated particles of γ-aminobutyric acid analog, the lactam content by weight relative to the weight of GABA analog 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 onto said particles of γ-aminobutyric acid analog.

In a first embodiment, the analogue of γ-aminobutyric acid is gabapentin.

In another embodiment of the invention, the analogue of γ-aminobutyric acid is pregabalin.

It has in fact been found that, quite surprisingly, the fact of coating the gabapentin or pregabalin particles with a polymer dissolved in an organic solvent, makes it possible to obtain a level of lactam in the coated particle of less than 0, 5% by weight relative to the weight of gabapentin or pregabalin. In addition, the coating of polymer also makes it possible to mask the taste of the analogue of γ-aminobutyric acid without delaying its release, thus making it possible to obtain usual plasma concentrations.

To obtain the masking of the taste while allowing the rapid release of the gabapentin, the polymer represents between 60 and 80% by weight of the gabapentin.

For a proportion of polymer less than 60%, a sufficient taste masking is not obtained. Conversely, for a proportion of polymer greater than 80%, the taste of gabapentin is perfectly masked, but the active ingredient may not be released quickly enough.

Advantageously, the gabapentin particles are coated in an amount of 70% by weight of polymer.

Similarly, concerning pregabalin, to obtain the masking of the taste while allowing the rapid release of the molecule, the polymer represents between 15 and 30% by weight of pregabalin.

For a proportion of polymer less than 15%, a sufficient taste masking is not obtained. Conversely, for a proportion of polymer greater than 35%, the taste of gabapentin is perfectly masked, but the active principle may not be released quickly enough.

Advantageously, the pregabalin particles are coated in an amount of 20% by weight of polymer.

Furthermore, the various methods of manufacturing gabapentin or pregabalin lead to the production of particles whose size can vary between 2 micrometers and a few millimeters.

If the size of the particles of analog of active principle is too small, that is to say of the order of 50 micrometers, the spraying of the solution leads to an irregular coating of the particles.

To solve this problem, we seek to increase the size of the particles by spraying on said particles a solution of a water-soluble binding agent in an organic solvent by the technique known as the fluidized air bed also called "spray coating", then sieving and calibrating the agglomerated particles obtained.

The actual coating of gabapentin or pregabalin is carried out on agglomerated particles or not, whose size is between 100 and 400 micrometers, preferably around 250 micrometers by the same technique called the fluidized bed. The coated gabapentin or pregabalin particle obtained is in the form of agglomerated or non-agglomerated 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, isopropanol, alone or as a mixture.

According to an advantageous embodiment, the polymer is dissolved in a solvent comprising 50 parts of acetone and 50 parts of ethanol per 100 parts by mass / mass.

Likewise, when a preliminary stage of uniformization of the size of the gabapentin or pregabalin particles is carried out, the binding agent is dissolved in an organic solvent identical or different from that used during spraying.

Furthermore, to obtain a polymeric coating allowing both to rapidly release the analogue of γ-aminobutyric acid, but also to mask the taste of the active molecule, the polymer is chosen from the group comprising polymethacrylate, copolymers aminoethylmethacrylate, cellulosic polymers, alone or as a mixture.

Advantageously, the polymethacrylate is an EUDRAGIT, in particular the EUDRAGIT E® marketed by the company ROHM.

Among the cellulose polymers, it is possible to choose ethyl cellulose, hydroxypropyl methyl cellulose, hydroxypropyl cellulose, cellulose acetophthalate, alone or as a mixture. Furthermore, it may be necessary to combine plasticizing agents with said polymer such as ethyl phthalate.

To optimize the masking of the taste of the active principle, the coating solution can also contain a sweetening agent chosen from the group comprising aspartame, potassium acesulfam, sodium saccharinate, monoammonium glycyrrhizinate, sugars and derivatives , as well as polyols and derivatives, alone or as a mixture. In practice, the sweetening agent represents between 1 and 6% by weight of the analogue of γ-aminobutyric acid.

Furthermore, to avoid the phenomena of electrostatism during coating and thereby lead to better control of the process, the solution also comprises an antistatic agent chosen from the group comprising colloidal silica, precipitated silica and talc.

In practice, the antistatic agent represents between 2 and 8% by weight of the analogue of γ-aminobutyric acid, advantageously between 5 and 6% by weight.

According to another characteristic of the process of the invention, the spraying of both the polymer in solution and the binder in solution is carried out as already said by the fluidized bed technique.

At laboratory scale, the spraying air inlet temperature must be minimum and more particularly between 35 and 45 ° C, advantageously 40 ° C.

On an industrial scale, the atomizing air inlet temperature is higher and is more particularly between 40 and 80 ° C., advantageously 60 ° C.

Anyway, and in both cases, the temperature of the particles agglomerated or not during the coating must be minimum and advantageously between 20 and 30 ° C.

The particles coated with gabapentin or pregabalin obtained can be used in any suitable dosage form, it being understood that the lactam content of said dosage form is less than 0.5% by weight relative to the weight of GABA analog .

In a first embodiment, the coated particles are used as such in the form of a sachet. According to an advantageous embodiment of the invention, the coated particles can be subjected to a compression step after having previously dry-mixed said coated particles with the usual compression excipients.

The excipients used for the manufacture of these tablets are known to those skilled in the art and are chosen in particular from the group comprising diluents, lubricants, flavoring agents, sweetening agents, alone or as a mixture.

The tablets capable of being obtained according to the process of the invention can advantageously be of two types.

The first type corresponds to multiparticulate tablets with rapid disintegration without supply of water, in less than 60 seconds in the oral cavity, also called FLASHTAB®, trademark registered by the Applicant and more particularly described in document EP-A-548 356. .

In this case, the excipients added during the compression step also comprise at least one disintegrating agent capable of allowing the active principle to disintegrate quickly.

Advantageously, the disintegrating agent is chosen from the group comprising sodium carboxymethylcellulose, crosslinked PVP (also called crospovidone) and carboxymethyl starch.

Furthermore, the polymer intended for coating the gabapentin or pregabalin particles must be chosen so that it is insoluble at neutral pH, corresponding to the salivary pH (therefore masking the taste) and that it is soluble or permeable. at a pH between 1 and 4 corresponding to the gastric pH.

In addition, the hardness of the tablet is between 30 and 70 N, advantageously 50 N.

The second type of tablet corresponds to so-called "fast dispersible" tablets, that is to say rapidly hydrodispersible tablets capable of disintegrate in a very short time <1 minute, preferably <15 seconds, in a minimum volume of water which will depend on the mass of the tablet.

The latter dosage form can therefore be advantageously used in pediatrics.

In this case, the excipients added during compression will further comprise not only a disintegrating agent but also a maintenance agent in suspension of the coated particles or swelling agent.

Likewise, the hardness of the tablet obtained is between 30 and 100 N, advantageously 70 N.

The invention and the advantages which result therefrom will emerge more clearly from the following exemplary embodiments.

All the examples being carried out on a laboratory scale, the various parameters are adjusted accordingly.

In the following three examples, the lactam level is measured by quantitative determination carried out by HPLC with respect to an external lactam standard.

EXAMPLE 1 1 - Manufacture of coated gabapentin particles

a) Manufacture of agglomerated particles

Gabapentin particles are first agglomerated from the following mixture:

PVP = polyvinyl providone marketed by BASF In accordance with the process of the invention, the size of the particles of active principle is standardized by spraying on the gabapentin particles the binding agent in solution in ethanol, by the spray coating technique.

The fluidizing air temperature is adjusted to 40 ° C., the temperature of the particles during manufacture being 21 ° C.

We then proceed to sieving, then calibrating the agglomerated particles obtained to obtain a majority of particles of size between 250 and 350 microns.

h) Coating of agglomerated particles

The agglomerated particles thus formed are then coated according to the same process by spraying with a solution comprising: I Ludragit E lOO 280 mg

Ethanol QSP 1,027 mg Acetone QSP 1,027 mg

Colloidal silica 42 mg

1: Aerosil R972 marketed by DEGUSSA

c) Percentage of lactam produced at the end of the manufacture of the coated particles

The percentage of lactam by weight relative to the weight of gabapentin present in the coated particles varies between 0.07 and 0.1% from one batch to another. 2 - Manufacture of rapidly hydrodispersible gabapentin tablets

Once the gabapentin particles have been coated, said particles are mixed with the powder mixture comprising

1: Pearlitol: marketed by ROQUETTE

2: Avicel CE 15: marketed by FMC

3: Kollidon CL marketed by BASF

The tablets are produced on a rotary press equipped with the 18 mm diameter punch. The pressure exerted is 16 KNewton +/- 2.

The hardness of the tablets obtained is around 70 Newtons.

a) Dissolution tests

Tests were carried out for dissolving the tablets obtained in an acid medium (0.06 N of HCl) under standard conditions (apparatus 2, and paddle speed 50 rotations per minute).

The tests were carried out under storage conditions of the tablets at 25 ° C. and 60% relative humidity. The results are shown in the table below.

As shown in the table above, 96% of the tablet is dissolved in 5 minutes, which proves the ability of the polymer to rapidly release the active ingredient.

b) Percentage of lactam contained in the rapidly water-dispersible tablet

We also measured the percentage of lactam present in the tablet at the end of manufacture (T ₀ ), after 42 days, 3 and 6 months of storage. The results are shown in the table below (percentage of lactam by weight relative to the weight of gabapentin)

It is found that the tablet is stable vis-à-vis the degradation product for six months under accelerated storage conditions. As already said, this type of tablet has the advantage of being able to be used in pediatrics.

EXAMPLE 2

1 / Manufacture of coated gabapentin particles

a) The same manufacturing process as that described in Example 1 is followed, starting with a mass of gabapentin equal to 300 mg, the other constituents being used in proportion.

b) The percentage of lactam dosed in the particles coated at the end of the process varies between 0.07 and 0.10% by weight relative to the weight of gabapentin from one batch to another.

2 / Manufacture of the rapidly hydrodispersible tablet

Next, quick-dispersing gabapentin tablets 300 mg are made by mixing the coated particles obtained and the following powder mixture:

The production of the tablets is carried out on a rotary tablet equipped with a 16 mm diameter punch. The pressure exerted is 12 KN +/- 2. The hardness of the tablet obtained is around 55 N. a) Dissolution test

As before, the percentages of dissolution of gabapentin in an acid medium were then calculated. The results are shown in the table below.

b) Percentage of lactam

The percentage of lactam present in the tablet obtained according to the invention was also measured. The results are shown in the table below (by weight relative to the weight of gabapentin).

EXAMPLE 3

1 / Manufacture of coated pregabalin particles

In this step, coated pregabalin particles are prepared, the composition of which is as follows:

The coated particles are produced according to the process of the invention in a fluidized bed by spraying with a solution comprising Eudragit, potassium acesulfame and talc in 96% ethanol.

This fluidized bed technique is carried out in an apparatus of the GLATT / GPGC 1 type, the temperature of the product being between 20 and 25 ° C.

The percentage of lactam measured on the particles coated with pregabalin is:

2 / Manufacture of the fast disintegrating multiparticulate tablet

Once the pregabalin particles have been coated, said particles are mixed with a powder mixture comprising:

The hardness of the tablets obtained is 40 N.

a) Dissolution test The percentages of dissolution of pregabalin in an acid medium were calculated under the same conditions as for Examples 1 and 2. The results are shown in the table below.

b) Percentage of lactam

The percentage of lactam calculated on the tablets is shown in the table below.

The advantages of the invention appear clearly from the description. It should be noted in particular that the invention makes it possible to simultaneously solve the three problems, namely:

• propose a galenic form of analog of GABA whose percentage of toxic lactam is less than 0.5%;

• mask the bitter taste of analogs of γ-aminobutyric acid;

• and obtain a maximum plasma concentration of the active molecule in 2 to 3 hours after ingestion.

The coated particles also have the advantage, in addition to their conventional manufacturing process, of being able to be incorporated in particular into tablets of the FLASHTAB® or fast hydrodispersibility type, tablets which are not swallowed directly, but after having been disintegrated in contact with the saliva in the mouth in the first case, or in contact with water in the second case.

It is therefore no longer necessary in this case to ingest solid forms, which may prove to be inadequate, in particular in children and the elderly, and complicated in the case of the treatment of a person suffering from epilepsy.

As already stated, the invention is not limited to a process for the manufacture of particles coated with gabapentin or pregabalin, but relates to any analogue of γ-aminobutyric acid capable of degrading into lactam molecules in aqueous solution.

Claims

1 / Process for the manufacture of coated particles of γ-aminobutyric acid analog whose lactam content by weight relative to the weight of γ-aminobutyric acid analog is less than 0.5%, characterized in that a coating solution comprising at least one polymer in at least one organic solvent is sprayed onto said particles of analog of γ-aminobutyric acid.

2 / A method according to claim 1, characterized in that the analog of γ-aminobutyric acid is gabapentin.

3 / A method according to claim 1, characterized in that the analog of γ-aminobutyric acid is pregabalin.

4 / A method according to claim 2, characterized in that the polymer represents between 60 and 80% by weight of gabapentin.

5 / A method according to claim 3, characterized in that the polymer represents between 15 and 30% by weight of pregabalin.

6 / A method according to one of claims 1 to 5, characterized in that the particles of analog of γ-aminobutyric acid are previously uniform in size, by spraying onto said particles a solution of a water-soluble binding agent in an organic solvent, then sieving and sizing of the agglomerated particles obtained.

Il Method according to one of claims 1 to 6, characterized in that the spraying of the coating solution is carried out in a fluidized bed.

8 / A method according to one of claims 1 to 7, characterized in that the organic solvent is chosen from the group comprising acetone, ethanol, isopropanol, alone or as a mixture. 9 / A method according to claim 8, characterized in that the organic solvent comprises 50 parts of acetone and 50 parts of ethanol per 100 parts by mass / mass.

10 / A method according to claim 6, characterized in that the binding agent is dissolved in ethanol.

11 / A method according to one of claims 1 to 10, characterized in that the polymer is chosen from the group comprising polymethacrylate, amino ethylmethacrylate copolymers, cellulose polymers, alone or as a mixture.

12 / A method according to one of claims 1 to 11, characterized in that the coating solution also contains a sweetening agent selected from the group comprising aspartame, potassium acesulfam, monoammonium glycyrrhizinate, saccharin sodium, sugars and derivatives, polyols and derivatives, alone or as a mixture.

13 / A method according to one of claims 1 to 12, characterized in that the coating solution further contains an antistatic agent selected from the group comprising colloidal silica, precipitated silica and talc.

14 / A method according to one of claims 1 to 13, characterized in that the coated particles obtained are dry mixed with compression excipients before subjecting them to a compression step to obtain tablets.

15 / A method according to claim 14, characterized in that the compression excipients are chosen from the group comprising diluents, lubricants, flavoring agents, sweetening agents, alone or as a mixture.

16 / A method according to claim 15, characterized in that the compression excipients further comprise at least one disintegrating agent selected from the group comprising sodium carboxymethylcellulose, crospovidone and carboxymethyl starch. 111 Method according to claim 16, characterized in that the compression excipients further comprise an agent for keeping the coated particles in suspension.

18 / coated particles capable of being obtained by the method according to one of claims 1 to 13.

19 / Tablet capable of being obtained by the method according to one of claims 1 to 15.

20 / Multiparticulate tablet for oral administration without the use of water, the disintegration speed of which causes disintegration in less than 60 seconds in the oral cavity capable of being obtained by the method according to one of claims 1 to 16.

21 / Multiparticulate tablet with rapid hydrodispersibility capable of forming a stable suspension in a small volume of water, capable of being obtained by the process according to one of claims 1 to 17.