WO2013030177A1

WO2013030177A1 - Abuse resistant tablet comprising oxycodone and paracetamol

Info

Publication number: WO2013030177A1
Application number: PCT/EP2012/066656
Authority: WO
Inventors: Céline MALYS; Jean-Baptiste ROCHAIS
Original assignee: Sanofi
Priority date: 2011-08-29
Filing date: 2012-08-28
Publication date: 2013-03-07
Also published as: FR2979242A1

Abstract

The invention relates to a tablet formulation based on paracetamoland oxycodone. The invention also relates to a process for preparing said tablet and to the use thereof.

Description

ABUSE RESISTANT TABLET COMPRISING OXYCODONE AND PARACETAMOL

Field of the invention

The invention relates to a tablet formulation based on paracetamol and oxycodone. The invention also relates to a process for preparing said tablet and to the use thereof.

Technological background and technical problem

In the treatment of pain, certain analgesics used, such as oxycodone, are also known as narcotics or psychotropic agents which may, in the context of diverted use or misuse, become the subject of drug dependency or abuse. Drug dependency is characterized by the obsessive desire to obtain and to self- administer a substance. Abuse of such substances is defined as excessive and deliberate, permanent or intermittent use having detrimental consequences on the physical or mental health.

In the context of a therapeutic treatment, these analgesics, and in particular oxycodone, are generally formulated in an oral-use composition, such as a tablet. The analgesics present in the pharmaceutical composition may be extracted chemically under the action of water or other liquids, and may thus be the subject of a diverted use, especially by being administered thereafter generally parenterally in an unauthorized, unsupervised, illegal and dangerous manner.

Tablets based on paracetamol and oxycodone exist on the market, in particular the tablets sold under the name Percocet® by the company Endo Pharmaceuticals. The oxycodone present in these tablets may thus be the subject of diverted use and may thus be used, especially after grinding the tablet, dissolving and/or filtering, followed by an extraction of the oxycodone, by drug addicts by administering it by injection, inhalation or orally in solution form. The person thus wishing to divert the use of oxycodone generally seeks to separate the oxycodone from the paracetamol, the latter being hepatotoxic. Thus, the Applicant has succeeded in developing a novel formulation of tablets based on these two active agents, which can reduce the risk of abusive and/or diverted use of oxycodone, while at the same time affording the patient a quality of treatment against pain in accordance with his needs and/or comparable to the treatment using the conventional formulations.

The Applicant proposes a novel formulation of tablets comprising paracetamol and oxycodone which renders difficult or even impossible separation of the oxycodone from the rest of the tablet and in particular from the paracetamol, thus discouraging the diverted use of oxycodone.

The present invention also describes a tablet based on paracetamol and oxycodone which has dissolution and/or pharmacokinetic and/or pharmacological properties comparable to the conventional formulations. Summary of the invention

More specifically, a subject of the present invention is a tablet, characterized in that it comprises at least one active layer comprising paracetamol and oxycodone, and at least one gelling layer comprising hydroxypropylmethylcellulose.

As specified above, the tablet according to the invention renders difficult, or even impossible, the separation of the oxycodone for a diverted use, irrespective of the methods commonly employed for separating oxycodone from the rest of the tablet, and in particular from paracetamol, for instance hot or cold extraction with water or any other suitable extraction liquid.

The tablet according to the invention has the advantage of having a release and activity of the active principles that are not impaired by the formulation. In the context of the present invention, the pharmaceutical tablet is advantageously an immediate-release tablet. For reasons of simplicity, unless otherwise indicated, in the description, the term "oxycodone" includes oxycodone or a salt thereof. The preferred oxycodone salt is oxycodone hydrochloride. Detailed description of the invention

The tablets according to the present invention are of a size suitable for standard oral administration. Thus, tablets with a weight of less than 1200 mg and preferably less than 800 mg are preferred. For example, its weight may be between 500 and 1200 mg and advantageously between 600 and 700 mg.

The novel composition according to the invention thus makes it possible, for assays of active principles that are identical to those of the existing tablets, to have tablets of acceptable sizes for oral administration, despite the addition of constituents that solve the problems indicated above.

The term "active layer" means a layer comprising the therapeutic agents, namely at least paracetamol and oxycodone. Thus, the active layer is prepared especially by mixing paracetamol and oxycodone, and optionally other components, as illustrated, for example, in example 1 .

The amount of oxycodone may vary, for example, between 2 and 80 mg (inclusive), and preferably between 2 and 20 mg, and may especially be 2.5; 2.6; 2.7; 2.8.; 3; 3.5; 5; 7.5 or 10 mg. The amount of oxycodone is preferably 2.5 mg in the tablet.

The amount of paracetamol may range, for example, between 250 and 650 mg (inclusive), and may especially be 250; 300; 325; 350; 500 or 600 mg. The amount of paracetamol is preferably 325 mg in the tablet. The term "gelling layer" means a layer giving the gelling nature to the tablet. Thus, the tablet according to the invention forms a gel under the action of an aqueous medium, such as water or an aqueous solution of an organic acid (for example citric acid or acetic acid) or of a base (for example a sodium bicarbonate or sodium tetraborate solution), or an aqueous-alcoholic solution (for example based on a C1 -C4 alcohol, such as isopropanol or ethanol).

The hydroxypropylnnethylcellulose present in the gelling layer preferably has a viscosity of between 15 000 and 200 000 cp, and advantageously between 75 000 and 140 000 cp (inclusive). The term "cp" means centipoises, which is the standard unit of viscosity. The viscosity of hydroxypropylnnethylcellulose is the apparent viscosity measured according to monograph No.0348 relating to the analysis of hypromellose in the European pharmacop/ea (version 7.0).

The amount of hydroxypropylnnethylcellulose depends on the characteristics of the tablet, and in particular on the agents and constituents present in the tablet and, of course, on the desired gelling effect. According to one particular embodiment of the invention, the amount of hydroxypropylnnethylcellulose is between 30% and 50% by weight relative to the weight of the gelling layer. More particularly, the amount of hydroxypropylnnethylcellulose is 40% by weight relative to the weight of the gelling layer.

The weight ratio of the active layer relative to the gelling layer preferably ranges from 45/55 to 70/30; it may be, for example, 50/50 or 60/40. Advantageously, it is between 55/45 and 65/35; preferably, the ratio is 60/40.

The tablet according to the invention may also comprise standard excipients for tablets, including, but in a nonlimiting manner, diluents such as lactose, starches, celluloses, calcium hydrogen phosphate, binders and/or lubricants, optionally glidants agents and optionally disintegrants, such as starch, modified starch, celluloses and/or modified celluloses.

The tablet may also comprise components that can modify the release characteristics of the active agents. The tablet according to the invention has slow release or immediate release of the active agents, preferably immediate release. Preferably, the tablet according to the invention also comprises, relative to the total weight of the tablet:

- at least one diluent, preferably in a proportion of from 10% to 25% by weight, and/or

- at least one binder, preferably in a proportion of from 1 % to 5% by weight, and/or

- at least one lubricant, preferably in a proportion of from 0.1 % to 3% by weight, and/or

- at least one glidant, preferably in a proportion of from 0.01 % to 1 % by weight, and/or

- at least one disintegrant, preferably in a proportion of from 2% to 10% by weight.

Preferably, the diluent is present in the gelling layer and advantageously in a proportion of between 15% and 20% by weight relative to the total weight of the tablet according to the invention.

As specified above, diluents may be chosen from lactose, starches, celluloses, calcium hydrogen phosphate and a mixture thereof. According to one particularly preferred embodiment of the present invention, the diluent is microcrystalline cellulose.

Preferably, the binder is present in the active layer and advantageously in a proportion of between 1 .5% and 4.0% by weight relative to the total weight of the tablet according to the invention.

The binder is advantageously a hydrophilic agent chosen from hydrophilic polymers or hot-melt agents such as cellulose derivatives (hydroxypropylcellulose), povidone (polyvinylpyrrolidone), sucrose, gums, starches, gelatin, macrogols (polyethylene glycols) or a mixture thereof. According to a particularly preferred embodiment of the present invention, the binder is polyvinylpyrrolidone (for example Povidone K25 or Povidone K30) and/or pregelatinized starch. Preferably, the active layer does not comprise any hydroxypropylmethyl cellulose or more generally any gelling agent. The lubricant may be present in the gelling layer, in the active layer or, preferably, in both layers. Advantageously, the amount of lubricant in the tablet is between 0.7% and 3% by weight relative to the total weight of the tablet according to the invention, and in particular in a proportion of from 0.3% to 1 .2% by weight in the gelling layer and in a proportion of from 0.4% to 1 .8% by weight in the active layer.

The lubricant is preferably chosen from talc, magnesium stearate, stearic acid, glyceryl monostearate, polyoxyethylene glycols with a molecular weight of from 400 to 7 000 000, hydrogenated castor oil, glyceryl behenate, mono-, bi- or trisubstituted glycerides, sodium stearyl fumarate, sold under the name Pruv® by the company JRS Pharma, and a mixture thereof.

According to one particularly preferred embodiment of the present invention, the lubricant is magnesium stearate, talc or a mixture thereof.

The disintegrant may be present in the gelling layer, in the active layer or, preferably, in both layers. Advantageously, the amount of disintegrant in the tablet is between 2% and 10% by weight relative to the total weight of the tablet according to the invention, and in particular in a proportion of from 1 % to 5% by weight in the gelling layer and/or in a proportion of from 1 % to 5% by weight in the active layer.

The disintegrant is chosen in particular from the group consisting of croscarmellose sodium, modified starch and derivatives thereof, crospovidone, sodium carboxymethyl starch, and mixtures thereof.

Glidants may also be present in the gelling layer, in the active layer or in both layers, preferably in the gelling layer. Advantageously, the amount of glidants in the tablet is between 0.05% and 0.20% by weight relative to the total weight of the tablet according to the invention, and in particular in a proportion of from 0.05% to 0.20% by weight in the gelling layer. The agents may be chosen especially from colloidal silica or any other silica or silicate, for example the product sold by Degussa under the trade name Aerosil ®, or a mixture thereof.

Even more particularly, the tablet according to the invention is characterized in that it comprises:

- at least one diluent, which is a microcrystalline cellulose, and/or

- at least one binder chosen from the group consisting of povidone (K25 and/or K30), pregelatinized starch, and a mixture thereof, and/or

- at least one disintegrant chosen from croscarmellose sodium, crospovidone, sodium carboxymethyl starch, and a mixture thereof, and/or

- at least one lubricant, which is magnesium stearate and/or talc, and/or

- at least one glidant, which is silica.

Finally, according to a most particularly preferred embodiment, the tablet according to the invention is characterized in that it comprises, relative to the total weight of the tablet:

- in the active phase: from 0.4% to 2% by weight of oxycodone, from 50% to 60% by weight of paracetamol, from 1 % to 2% by weight of povidone, from 0.5% to 2% of pregelatinized starch, from 1 % to 1 .5% of sodium carboxymethyl starch, from 1 % to 1 .5% of talc, from 0.1 % to 0.15% of magnesium stearate, and

- in the gelling phase: from 12% to 20% of hydroxypropylmethylcellulose, from 15% to 20% by weight of microcrystalline cellulose, from 3% to 5% by weight of croscarmellose sodium, from 0.1 % to 0.2% of silica and from 0.3% to 0.5% of magnesium stearate.

Preferably, the active layer and the gelling layer are of identical color and appearance, such that separation between these layers is not readily visible by a possible user wishing to divert its use. The tablet comprising at least the two layers advantageously comprises at least one colorant, in at least one of the layers, or in both layers, for example iron oxide (in particular yellow iron oxide) or quinoline yellow, etc. It may also be advantageous for the tablet to comprise, in at least one of the layers, or in both layers, preferably in the gelling layer, at least one nasal irritant, including organic or inorganic acids, salts, ketones, sulfates, bisulfates, persulfates, glycerophosphates, borates, titanates, amino acids or peptides, or a mixture thereof. Mention may be made in particular of sodium lauryl sulfate, poloxamers, sorbitan monoesters, glyceryl monooleates, or a mixture thereof. Preferably, sodium lauryl sulfate is used.

A coating (or film coating) may be applied to the pre-tableted part consisting of the layers described above. A coated tablet may be particularly advantageous for dissimulating the various layers of the tablet and/or for protecting it against moisture. According to one particular embodiment, the tablet according to the invention has a coating. A coated two-layer tablet is particularly preferred.

When the composition has been subjected to the tableting process, the tablet resulting therefrom may also be subjected in particular to a coating operation, especially by film coating according to operating conditions that are well known to those skilled in the art. Thus, in particular, the tablet according to the invention is characterized in that it is covered with a film coating. More particularly, this film coating may comprise at least one component chosen from the group consisting of hypromellose, polyvinyl alcohol, polyethylene glycols, acrylic polymers, titanium dioxide, talc, colorants, and mixtures thereof. It is possible, for example, to use a mixture of lactose monohydrate, hydroxypropylmethylcellulose (in particular of low viscosity, for example of 15 cp), titanium dioxide, polyethylene glycol (for example PEG 3350), and iron oxide (for example yellow iron oxide). Mention may be made, for example, of Opadry II yellow (ref. 32F32349) or white (ref. 32F38977), sold by the company COLORCON. Unless otherwise specified, the proportions indicated (expressed as a percentage, ratio, amount, etc.) by weight relative to the total weight of the tablet are understood as being relative to the total weight of the tablet without counting a possible coating or covering thereof, especially a film coating.

A tablet according to the invention that is particularly preferred is an optionally coated two-layer tablet. However, the tablet according to the invention may comprise more than two layers, namely three layers. According to another aspect of the invention, a process is proposed for preparing a tablet according to the invention, which comprises the separate preparation of the active layer and of the gelling layer, followed by the assembly of the two layers in a device suitable for manufacturing tablets, optionally followed by the application of a coating using a standard process for coating the tablet thus formed.

A tablet with a "sandwich" arrangement (layers one on the other) may be prepared according to a standard tableting process, in which the first layer is tableted using a suitable composition in powder form and one or more layers are tableted on the first layer or the subsequent layers to form a two-layer or multilayer tablet.

The tablet according to the invention may be in various forms, in particular a cylindrical, oblong, elliptical, lenticular, spheroidal, ovoidal or other form.

The tablet according to the present invention may be obtained by any standard tableting technique known to those skilled in the art by mixing powders and/or granulation, for example using rotary presses. Thus, the components of the tablet according to the invention are mixed together either as a solution or in the form of powders and/or granules, in order then to be optionally dried and then tableted. The mixtures necessary for tableting may be obtained by dry granulation or direct mixing of the constituents. According to another aspect of the invention, a method is proposed for treating a patient requiring a treatment against pain, in particular occasional, transient or chronic pain, this method comprising the oral administration to said patient of the tablet according to the invention.

The invention also relates to the tablet according to the invention for oral use in a method for treating pain, in particular occasional, transient or chronic pain. Finally, the invention relates to the tablet according to the invention for use in a therapeutic treatment method, in particular for treating pain, and more specifically occasional, transient or chronic pain, which is directed toward avoiding the diverted use of the oxycodone present in the tablet. The examples that follow illustrate the present invention without, however, limiting its scope. Unless otherwise indicated, the percentages indicated are weight percentages.

Examples

Example 1

Process for manufacturing a film-coated two-layer tablet

Preparation of the active layer

Oxycodone and yellow iron oxide are predispersed with part of the mixture consisting of the other components of the active layer, including paracetamol. This dispersion is then mixed with the rest of the mixture. The mixture obtained is calibrated on a calibrator of oscillating or rotary type.

The mixture is then lubricated with talc and magnesium stearate using an overturning mixer.

Preparation of the gelling layer The constituents of the gelling layer are screened on a manual or vibrating screen, and then mixed. The mixture is then lubricated with magnesium stearate using an overturning mixer. The two layers thus prepared are tableted on a two-layer rotary press.

Film coating of the tablet thus obtained is performed in a perforated paddle turbomixer. Example 2

A tablet is prepared according to the process of example 1 . Its composition is detailed in Table 1 below. Table 1

Talc lubricant 8.40 1 .39

Magnesium stearate lubricant 0.80 0.13

Yellow iron oxide colorant 0.70 0.12

Oxycodone hydrochloride active agent No. 2 2.70 0.45

Total active layer 361.50 60.00

Total tablet (without coating) 602.50 100.00

Opadry II yellow 32F32349 (composed of lactose

monohydrate, HPMC 15 cp, titanium dioxide, PEG 27.1 1 4.31 3350 and yellow iron oxide)

Purified water qs qs

Total coated tablet 629.61 100.00

For comparative purposes, the hypromellose 100 000 cp was replaced with pregelatinized potato starch, which is another ingredient that can be used as a gelling agent. However, the tablet then obtained, once ground and placed in contact with water, gives insufficient gelling to limit the injection.

Dissolutions (medium 0.1 N HCI - 900 ml) of the paracetamol of the tablet of Table 1 and of the tablet Percocet ® were performed and are similar. Example 3

- Anti-diversion test (by hot injection) with the tablet described in Table 1 :

Materials:

1 ml syringe with 0.35 mm needle (Steribox)

Crucible (Stericup)

Filter (Sterifiltre) or OCB Cigarette filter

Extraction liquid: water/4% acetic acid/5% citric acid

Procedure (according to the practice of drug addicts)

Grinding of the tablets

Transfer into the Stericup

Addition of 2 ml of extraction liquid

Mixing

Heating by flame Addition of the filter

Hot filling of the syringe through the filter

Quantification of the active principle

Result: the gelling layer greatly limits the recovery of the oxycodone: only 14% by weight of the oxycodone present is recovered.

- Test of cold extraction with the tablet described in Table 1 :

Test on ten tablets ground in 20 ml of ice-cold water (about 1 °C) (the drug addict's aim is to obtain a drinkable solution, having taken care beforehand to separate the paracetamol from the oxycodone in order to reduce the hepatotoxic risk) with stirring using a glass rod. The assay of the paracetamol and of the oxycodone was performed by the HPLC method described in the USP.

Test without gelling layer:

Recovery: 8% of paracetamol - 67% of oxycodone

Test with gelling layer: no filtration possible

If the volume of water is increased in order to be able to pass through a filter (for example such as a coffee filter) (about 200 ml), then 46% paracetamol and 34% oxycodone are recovered.

- With a small volume of water, good extraction of the paracetamol but impossible to filter with the gelling layer

- With a large volume of water, filtration possible but not recovery of all of the oxycodone and excessive recovery of the paracetamol

The gelling layer thus prevents the practice of cold extraction of the paracetamol.

Claims

1. A tablet, characterized in that it comprises at least one active layer comprising paracetamol and oxycodone, and at least one gelling layer comprising hydroxypropylmethylcellulose.

2. The tablet as claimed in claim 1 , characterized in that it is an immediate- release tablet.

3. The tablet as claimed in claim 1 or 2, characterized in that it comprises between 2 and 20 mg of oxycodone.

4. The tablet as claimed in any one of the preceding claims, characterized in that it comprises between 250 and 650 mg of paracetamol.

5. The tablet as claimed in any one of the preceding claims, characterized in that the hydroxypropylmethylcellulose has a viscosity of between 15 000 and 200 000 cp.

6. The tablet as claimed in any one of the preceding claims, characterized in that its weight is between 500 and 1200 mg and advantageously between

600 and 700 mg.

7. The tablet as claimed in any one of the preceding claims, characterized in that the amount of hydroxypropylmethylcellulose is between 30% and 50% by weight relative to the weight of the gelling layer.

8. The tablet as claimed in any one of the preceding claims, characterized in that the weight ratio of the active layer relative to the gelling layer ranges between 45/55 and 70/30, and the ratio is preferably 60/40.

9. The tablet as claimed in any one of the preceding claims, characterized in that it also comprises, relative to the total weight of the tablet, at least one diluent, preferably in a proportion of from 10% to 25% by weight, at least one binder, preferably in a proportion of from 1 % to 5% by weight, at least one lubricant, preferably in a proportion of from 0.1 % to 3% by weight, optionally at least one glidant, preferably in a proportion of from 0.01 % to 1 %, and/or optionally at least one disintegrant, preferably in a proportion of from 2% to 10% by weight.

10. The tablet as claimed in any one of the preceding claims, characterized in that it comprises at least one diluent present in the gelling layer and advantageously in a proportion of between 15% and 20% by weight relative to the total weight of the tablet.

11. The tablet as claimed in any one of the preceding claims, characterized in that it comprises at least one binder present in the active layer and advantageously in a proportion of between 1 .5% and 4% by weight relative to the total weight of the tablet.

12. The tablet as claimed in any one of the preceding claims, characterized in that it comprises at least one lubricant present in the gelling layer, in the active layer or, preferably, in both layers, and advantageously the amount of lubricant in the tablet is between 0.7% and 3% by weight relative to the total weight of the tablet.

13. The tablet as claimed in any one of the preceding claims, characterized in that it comprises at least one diluent, which is microcrystalline cellulose.

14. The tablet as claimed in any one of the preceding claims, characterized in that it comprises at least one disintegrant present in the gelling layer, in the active layer or, preferably, in both layers, and advantageously the amount of disintegrant in the tablet is between 2% and 10% by weight relative to the total weight of the tablet.

15. The tablet as claimed in any one of the preceding claims, characterized in that it comprises:

- at least one diluent, which is a microcrystalline cellulose, and/or

- at least one binder chosen from povidone, pregelatinized starch, and a mixture thereof, and/or

- at least one lubricant, which is magnesium stearate and/or talc, and/or

- at least one glidant, which is silica.

16. The tablet as claimed in any one of the preceding claims, characterized in that it comprises, relative to the total weight of the tablet:

- in the active phase: from 0.4% to 2% by weight of oxycodone, from 50% to 60% by weight of paracetamol, from 1 % to 2% by weight of povidone, from 0.5% to 2% of pregelatinized starch, from 1 % to 1 .5% of sodium carboxymethyl starch, from 1 % to 1 .5% of talc, from 0.1 % to 0.15% of magnesium stearate;

- in the gelling phase: from 12% to 20% of hydroxypropylmethylcellulose, from 15% to 20% by weight of microcrystalline cellulose, from 3% to 5% by weight of croscarmellose sodium, from 0.1 % to 0.2% of silica, and from

0.3% to 0.5% of magnesium stearate.

17. The tablet as claimed in any one of the preceding claims, characterized in that it comprises at least one colorant, in at least one of the layers or in both layers.

18. The tablet as claimed in any one of the preceding claims, characterized in that it comprises in at least one of the layers, or in both layers, preferably in the gelling layer, at least one nasal irritant, such as sodium lauryl sulfate.

19. The tablet as claimed in any one of the preceding claims, characterized in that the tablet has a coating.

20. The tablet as claimed in any one of the preceding claims for oral use in a method for treating pain, in particular occasional, transient or chronic pain.