WO2011018246A2

WO2011018246A2 - Controlled release paliperidone composition

Info

Publication number: WO2011018246A2
Application number: PCT/EP2010/005211
Authority: WO
Inventors: Korinde Annemarie Jansen
Original assignee: Synthon B.V.
Priority date: 2009-08-13
Filing date: 2010-08-11
Publication date: 2011-02-17
Also published as: WO2011018246A3

Abstract

The present invention relates to A controlled-release pharmaceutical tablet, comprising: (a) an inner hydrogel tablet core comprising paliperidone or a pharmaceutically acceptable salt thereof and a pH-independently gelling polymer; and (b) an outer hydrogel layer surrounding said inner tablet core comprising a pH-independently gelling polymer; wherein said outer layer does not contain paliperidone or a pharmaceutically acceptable salt thereof, to a method of making such tablets and for use in medicine.

Description

CONTROLLED RELEASE PALIPERIDONE COMPOSITION

[0001] The present invention relates to a tablet containing the pharmaceutically active agent paliperidone, which tablet provides a modified and/or extended release.

Background of the Invention

[0002] Paliperidone, or 9-hydroxyrisperidone (chemically: (±)-3-(2-(4-(6-fluoro-l,2- benzisoxazol-3-yl)-l-piperidinyl)ethyl)-6,7,8,9-tetrahydro-9-hydroxy-2-methyl-4H-pyrido[l,2- a]pyrimidin-4-one), of the formula (I)

is a major human metabolite of the known antipsychotic drug risperidone and is itself an antipsychotic. Paliperidone has been disclosed in US5158952 (EP0368388). Subsequently an amorphous and several crystalline forms of paliperidone were disclosed in WO2008/021342.

[0003] Paliperidone has been approved for short-term treatment of acute

schizophrenia and for long-term or maintenance treatment of schizophrenia. It is marketed as an extended release tablet under the brand name INVEGA® (Ortho-McNeil-Janssen

Pharmaceuticals, Inc.). The tablets are based on an osmotic delivery technology, wherein osmotic pressure is used to deliver paliperidone at a controlled rate. The package insert for the U.S. INVEGA® tablet, describes the tablet as a "delivery system, which resembles a capsule- shaped tablet in appearance, [which] consists of an osmotically active trilayer core surrounded by a subcoat and semipermeable membrane. The trilayer core is composed of two drug layers containing the drug and excipients, and a push layer containing osmotically active components. There are two precision laser-drilled orifices on the drug-layer dome of the tablet. Each tablet strength has a different colored water-dispersible overcoat and print markings. In an aqueous environment, such as the gastrointestinal tract, the water-dispersible color overcoat erodes quickly. Water then enters the tablet through the semipermeable membrane that controls the rate at which water enters the tablet core, which, in turn, determines the rate of drug delivery. The hydrophilic polymers of the core hydrate and swell, creating a gel containing paliperidone that is then pushed out through the tablet orifices. The biologically inert components of the tablet remain intact during gastrointestinal transit and are eliminated in the stool as a tablet shell, along with insoluble core components."

[0004] WO2004/010981 (EPl 539115 and US2004/0092534) describes an osmotic dosage form for controlled delivery of paliperidone. The dosage form delivers paliperidone for more than about 22 hours and exhibits a substantially ascending rate of release with 90% delivery occurring at about 20 hours.

[0005] WO2006/017537 (EP 1802286) proposes a sustained dosage form having an ascending zero order release pattern. The dosage form structure comprises a delay layer comprising a polymeric matrix and a microencapsulated drug; and a second layer comprising a polymeric matrix and non-microencapsulated drug matrix. The delay layer is substantially free of non-microencapsulated drug and the second layer is located adjacent to the delay layer.

Example 3 describes a paliperidone tablet containing an inner core surrounded by an inner layer and an outer layer end caps. Microencapsulated paliperidone is contained in the inner core and inner layer but not in the outer layer. The trilayer arrangement is achieved by compressing the inner layer and outer layer material simultaneously onto the compressed inner core; e.g.

sometimes referred to in the art as compression coating or press coating.

[0006] WO2006/085856 relates to dosing benzisoxazole derivatives such as paliperidone in order to achieve certain blood plasma parameters. In general, for a single dose "D" the following two criteria are desired: (a) a mean dose proportional maximum plasma concentration of 0.5 ng/mL/mg < C_max/D < 8 ng/mL/mg and (b) a mean dose proportional area under a plasma concentration-time curve of 30 ng.hr/mL/mg < AUC_inf/D < 300 ng.hr/mL/mg, or, exhibiting the time of the peak plasma concentration T_max > 9 hours. A variety of osmotic dosage forms are described for achieving the desired blood plasma criterion, though the application indicates it is not limited to osmotic dosage forms.

[0007] WO2007/044234 and WO2007/081736 relate to osmotic dosage forms having both controlled release and fast release aspects. Both patent applications exemplify

paliperidone-containing osmotic dosage forms.

[0008] WO2009/025859 discloses a paliperidone sustained release composition having a first and second component. The first component comprises a delay layer comprising a polymer and the second component comprises non-coated paliperidone. The first and second components are adjacent to each other and in particular can be arranged as an "inlay" tablet. The inlay tablet comprises an inlay core containing non-coated paliperidone and at least one water swelling polymer. Partially surrounding the inlay core is an outer layer that contains a water insoluble pharmaceutical excipient. Preferably the tablet has a relative bioavailability of 1.5 to 3.0 times the bioavailability of the commercial fNVEGA® tablet. [0009] As the osmotic system employed in the commercial INVEGA® tablet is somewhat complicated to manufacture, it would be desirable to find a simpler system to provide controlled release of paliperidone, preferably a system that is able to be bioequivalent to INVEGA®.

SUMMARY OF THE INVENTION

[0010] The present invention relates to the discovery of a tablet-in-tablet design for controlled release. A first aspect of the invention relates to a controlled-release pharmaceutical tablet, comprising:

(a) an inner hydrogel tablet core comprising paliperidone or a

pharmaceutically acceptable salt thereof and a pH-independently gelling polymer; and

(b) an outer hydrogel layer surrounding said inner tablet core comprising a pH-independently gelling polymer;

wherein said outer layer does not contain paliperidone or a pharmaceutically acceptable salt thereof. The paliperidone is typically contained in small amounts such as 1-15 mg. The pH- independently gelling polymer in the inner tablet core and outer layer are each independently selected from each other. Often these polymers are selected from the group consisting of polyethylene oxide, hydroxypropyl methylcellulose, hydroxypropyl cellulose, and combinations thereof. Preferably the pH-independently gelling polymer comprises, or consists of, polyethylene oxide. The mass ratio of the core tablet to the outer layer is often within the range of 1 :3 to 1 :8; in some embodiments preferably within the range of 1 :4 to 1 :6. The tablet generally exhibits release over an extended period of time and preferably releases less than 100% of the paliperidone in 20 hours in a dissolution test as described hereinafter. In some embodiments, the release profile is substantially S-shaped.

[0011] Another aspect of the invention relates to a process for making the above tablet, which comprises compression coating an excipient composition, which comprises a pH- independently gellable polymer, around a hydrogel tablet, which comprises paliperidone or a pharmaceutically acceptable salt thereof and a pH-independently gellable polymer, to form an outer hydrogel layer surrounding said hydrogel tablet.

[0012] A further aspect of the invention relates to the use of the dosage form specified above for making a medicament for the treatment of paliperidone-treatable diseases, e.g., schizophrenia. For example, schizophrenia can be treated by administering a tablet of the invention to a patient in need thereof.

Detailed Description of the Invention

[0013] The present invention relates to a controlled release pharmaceutical tablet that combines two controlled release structures or mechanisms: a hydrogel matrix containing the drug surrounded by an extra, non-drug-containing hydrogel barrier layer. The outer hydrogel layer does not contain the active ingredient to any appreciable extent prior to the start of release and the concomitant migration of the drug out of the matrix core and then through the outer hydrogel layer. This design is especially useful in controlling and/or tailoring the desired release of the drug, especially providing relatively low doses of paliperidone over a prolonged period.

[0014] The inner tablet core comprises the whole dose of paliperidone. For convenience and in absence of an indication to the contrary, the word "paliperidone" is used herein to refer to paliperidone per se (i.e., paliperidone base) as well as its pharmaceutically acceptable salts. Generally the amount of paliperidone is from 1 to 15 mg, and frequently 6 mg, (expressed in terms of the weight of the paliperidone base in the case of a salt thereof). The relative amount of the paliperidone in the tablet core is generally from 3 to 25 % and typically 10% +/- 3%, i.e., about 10%, of the total mass of the inner tablet core.

[0015] The inner tablet core is a hydrogel tablet. As is well understood in the art, a hydrogel tablet gels upon sufficient contact with water, e.g., hydration, to provide a gel matrix which delays and/or controls the release of the drug contained therein. This type of release is in contrast to other matrix-based systems such as an insoluble inert matrix or an insoluble erodible matrix. In the present invention, the hydrogel inner tablet core contains a pH-independently gelling polymer; i.e., at least one polymer that is capable, upon hydration, of gelling substantially independently of the pH of the water. The pH-independently gelling polymer provides or at least contributes to the subsequent formation of a hydrogel matrix. Such polymers are known in the art and include polyethylene oxides, hydroxypropyl methylcelluloses, hydroxypropyl celluloses, and combinations thereof. Preferably the pH-independently gelling polymer is a

polyoxyethylene oxide, especially a high-molecular-weight polyethylene oxide having a molecular weight of at least 900,000, preferably higher than 1,000,000, and typically between 1 and 10 million. One advantage of polyethylene oxide over other gelling polymers is a relatively fast hydration rate, i.e., the dosage form is equilibrated in the body environment quite quickly. Additionally this polymer can be compressed into a tablet. The amount of the pH-independently gelling polymer, especially polyethylene oxide, is not particularly limited but generally is from 20 to 60 %, more typically 20 to 40%, of the total mass of the inner tablet core. For clarity, the recited amounts refer to the total content in the inner tablet core of pH-independently gelling polymers in the event that two or more are used. [0016] The inner tablet core can and typically does contain additional excipients such as a binder, diluent, lubricant, etc., provided that such additional excipients do not remove the hydrogel nature of the inner tablet core. Usually the inner tablet core contains at least one compressible matrix-forming binder/filler excipient, which preferably is a hydrophilic compound that may be water soluble or water insoluble. Typical binder/fillers to be used include

microcrystalline cellulose(s) ("MCC"), silicified MCC, polyvinylpyrrolidone, starch, hydroxypropyl cellulose, etc., and combinations thereof. A binder/filler generally constitutes from 10 to 70%, more typically 25 to 65% of the weight of the inner tablet core.

[0017] The dissolution curve in a dissolution test in an apparatus Type I at a suitable speed and using a suitable buffer has preferably has a substantially S-shaped. Such a S-shaped curve is characterized in that the release rate is relatively slow in the first time period of release (which corresponds to the time in which paliperidone penetrates from the inner portion of the tablet to the surface). Subsequently, the release is relatively high for a significant portion of the release profile (which corresponds to the release of paliperidone from the surface), eventually the release rate slows (as the concentration of paliperidone in the tablet diminishes). This results in a substantially "S"-shaped dissolution curve.

[0018] The composition of the tablet core may also comprise:

a) Soluble filler: This is used to facilitate the solubility of the drug substance in the matrix, if necessary, and support the diffusion of drug substance via the matrix network, if needed.

b) Buffering agent: In order to modify the solubility of paliperidone in the intestinal tract, different types of organic or inorganic acids and/or bases may be used. Typically tartaric acid or fumaric acid is used as the acid; magnesium oxide is used as the base. c) Glidant: For better flow of powders during tabletting, it is useful to use appropriate glidant(s), for instance colloidal silicon dioxide.

d) Lubricant: To avoid adherence of powders to punches, it is common to use a suitable lubricant. Examples include magnesium stearate and sodium stearyl fumarate.

e) Colorant; an example is iron oxide.

[0019] Unlike the elaborate osmotic delivery system, osmotic agents such as sodium chloride or sodium acetate are not required in the inner tablet core and preferably sodium chloride and sodium acetate are not included in the tablet of the invention.

[0020] The inner tablet core is compression coated to form a surrounding outer hydrogel layer, which also contains at least one pH-independently-gelling polymer as described above. The pH-independently gelling polymer in the outer layer may be the same as or different from the pH-independently gelling polymer used in the inner tablet core. Generally it is desirable to use the same kind of polymer in both the core and outer layer, though the specific grade may vary. As with the inner tablet core, the preferred pH-independently gelling polymer for use in the outer hydrogel layer is a polyethylene oxide, especially a high molecular weight polyethylene oxide, preferably molecular weight higher than 1,000,000, and typically from 1 to 10 million. The relative amount of the pH-independently gelling polymer(s), especially polyethylene oxide, is generally from 20 to 60 %, more typically 20 to 40%, of the total mass of the outer layer.

[0021] The outer layer may further contain additional excipients as described above for the inner tablet core, such as a binder, filler, lubricant, etc. Advantageously, the excipient(s) are selected in such a way that it increases the elastic properties and allows for adhesion of the outer layer to the inner tablet core via compression coating. Usually at least one binder/filler such as described above for the inner tablet core is present in the outer layer. Typically the binder/filler is MCC, especially commercially available PH 102. Additionally, a water soluble filler may be used, which is preferably copovidone. The layer coat can also contain a colorant, glidant and/or lubricant as described above for the tablet core.

[0022] Unlike the inner tablet core, however, the outer hydrogel layer does not contain paliperidone. It should be understood that this exclusion of the paliperidone does not prohibit trace or otherwise accidental amounts of paliperidone from being present in the outer layer. Rather, the point is that no significant amount of paliperidone (i.e., no more than 1% of total dose, typically no more than 0.1 %) is present in the outer layer.

[0023] The tablets of the invention are capable of releasing low doses (e.g., 1-15 mg) of paliperidone over a prolonged period. The release pattern or dissolution curve is determined in part by the viscosity of the gel layer after hydration, which viscosity depends on the amount, kind, and molecular mass of the pH-independently gelling polymer. In addition to the excipients selected, the mass ratio of the inner core:outer layer has an influence on the release rate. In general, the mass ratio of inner core to outer layer is at least 1 :2, respectively, typically in the range from 1 :3 to 1 :8, and in some embodiments preferably from 1 :4 to 1 :6.

[0024] From a practical perspective the total mass of the inner tablet core is generally within the range of 40 to 100 mg, more typically 50 to 70 mg. The mass of the coating layer is generally within the range of 150 to 480 mg, more typically 240 to 360 mg, including about 280, 300, 320, or 340 mg. The inner tablet core and the overall compression coated tablet are normally the same shape, preferably round including flat round or a convex round tablet shape. The core tablet usually has a diameter of 7 millimeters or less, usually 6 millimeters or less. The coated tablet preferably has a diameter of about 1 1 millimeters or less, typically 9 to 10.5 millimeters and in some embodiments preferably about 10 miilimeters.

[0025] In some aspects, the tablet-in-tablet dosage form of the present invention is additionally coated by an enteric coating layer to delay the release of paliperidone in the stomach. Such coating layer may be made, e.g., from polyacrylate polymers, such as sold under brand name Eudragit.

[0026] In a preferred embodiment of the invention, the inner tablet core and outer coating layer have the following compositions:

Tablet Core

5 to 20% of paliperidone base;

20 to 40% of a polyethylene oxide of a molecular mass higher than 1,000,000;

40 to 60% of a filler/binder;

0 to 20% of other excipients

Coating Layer

20 to 40% of a polyethylene oxide of a molecular mass higher than 1 ,000,000

50 to 80% of a filler/binder;

0 to 10% of other excipients.

[0027] In this preferred embodiment, the mass ratio of the inner tablet core to the outer coating layer is preferably within the range from 1 :3 to 1 :8, more preferably from 1 :4 to 1 :6.

[0028] The tablet of the invention can provide release of paliperidone for more than 18, and preferably more than 20 hours, as measured in an in vitro dissolution test. The dissolution testing is carried out in 500 ml of phosphate buffer at pH 6.8 in a Type I apparatus at 100 rpm paddle speed. Typically, the preferred tablet of the present invention exhibits the following dissolution profile expressed in terms of the percentage amount of paliperidone released at various durations:

Less than 25% in 6 hours;

Less than 55% in 12 hours, preferably 25-50%; and

Less than 100% in 20 hours, preferably 85-98%.

Less preferred embodiments will meet only one or two of the release requirements for the three time points listed. Additionally, preferred tablets of the invention are able to provide a substantially S-shaped dissolution curve. Such a curve is characterized by that the release rate is relatively slow in the first time period of release (which corresponds to the time in which paliperidone penetrates from the inner portion of the tablet to the surface) , then it is relatively high for a significant portion of the release profile ( which corresponds to free release of paliperidone from the surface), before the release rate slows ( as the concentration of paliperidone in the tablet diminishes) ; thereby forming an "S" shaped curve. It is desirable that the S-shaped dissolution curve be relatively long and not a step-function. For example, the time from release of 20% of the paliperidone to the time of release of 80% of the paliperidone is desirably at least 5 hours, more preferably at least 6 hours, and in some embodiments at least 8 hours such as 8 to 14 hours.

[0029] Likewise some embodiments of the present invention preferably have a dissolution curve similar to that of the INVEGA® and more preferably are considered bioequivalent in vivo to INVEGA®.

[0030] The tablets of the invention can be made by conventional tablet-in-tablet or compression coating techniques. The inner tablet core is first made via any convenient tabletting technique such as direct compression or wet granulation, though direct compression is preferred for simplicity when the excipient selection so permits. A tablet blend, which contains the ingredients of the inner core tablet including paliperidone and at least one pH-independently gelling polymer, etc., is compressed in a tablet punch to form a tablet; e.g., a round tablet of diameter 6 mm. This tablet forms the inner tablet core of the final "tablet-in-tablet." Then a second, larger tablet punch, e.g., round diameter 10 mm, is partially charged with a portion of an excipient composition corresponding to the outer coating layer and containing at least one pH- independently gelling polymer and optionally other excipients as described above. The previously produced inner tablet core is placed and centered in the partially charged punch, additional excipient composition is added and the whole material compressed to form a compression coating layer around the tablet core; e.g., a tablet-in-tablet. Tablet presses allowing such a technique are known as alternate tablet presses or "tablet-in tablet" presses and are known in the art.

[0031] The tablets of the invention may be finally coated by a thin film coating to prevent undesired action of the external environment during handling and storage and/or to enhance handling and cosmetic properties. Typically any such coating serves only "cosmetic" purposes such as taste masking, surface improvement, etc. Suitable film-coating materials are sold under the commercial brand name Opadry® . The amount of film coat typically does not exceed 3% of the total mass. Nonetheless, the tablets usually do not contain any kind of surface coating.

[0032] The tablets of the invention can exhibit physical parameters (hardness, friability) comparable with those of conventional tablets. [0033] The tablets of the present invention can be used in a method for treating schizophrenia and other diseases treatable by paliperidone and/or for making medicaments for treating the same. Such methods comprise administering an effective amount of the tablets to the patient in need thereof. The tablets may be administered in dosage amounts and regimens corresponding to those known and recommended in the art.

[0034] The invention will be further illustrated by way of the following non-limiting examples.

Example 1

Two batches of tablet-in-tablets of the following composition were made:

Process: [0035] Paliperidone, microcrystalline cellulose and iron oxide were mixed for 10 minutes in a free fall mixer at 22 rpm. The blend was forced sieved over a 300 micron sieve. Magnesium oxide was sieved over a 500 micron sieve. The remaining excipients except magnesium stearate were added to the preblend and it was mixed for 15 minutes. Magnesium stearate was sieved over an 800 micron sieve and added to the blend. The blend was mixed for another 5 minutes. Tablets were compressed into a tablet mass of 60 mg with a 6 mm punch.

[0036] The outer shell was made as follows: All excipients except magnesium stearate were mixed for 20 minutes in a free fall mixer at 22 rpm. Magnesium stearate was sieved through an 800 micron sieve and mixed with the blend for 5 minutes. Tablets were compressed on a Killian tablet-in-tablet press, with a total tablet mass of 300 mg and a diameter of 10 mm.

Example 2

The tablets were made by a similar process as described in example 1. The tablets were then coated with an enteric coating as given in the table below.

Example 3

Tablets were made by a similar process as described in example 1 , but using a different total tablet mass.

[0037] Each of the patents and patent applications mentioned above are incorporated herein by reference. The invention having been described it will be obvious that the same may be varied in many ways and all such modifications are contemplated as being within the scope of the invention as defined by the following claims.

Claims

1. A controlled-release pharmaceutical tablet, comprising:

(a) an inner hydrogel tablet core comprising paliperidone or a pharmaceutically acceptable salt thereof and a pH-independently gelling polymer; and

(b) an outer hydrogel layer surrounding said inner tablet core comprising a pH- independently gelling polymer;

wherein said outer layer does not contain paliperidone or a pharmaceutically acceptable salt thereof.

2. The tablet according to claim 1, wherein said paliperidone is present as paliperidone base and in an amount between 1-15 mg.

3. The tablet according to claims 1 and 2, wherein said pH-independently gelling polymer in said inner tablet core and in said outer layer are each independently selected from the group consisting of polyethylene oxide, hydroxypropyl methylcellulose, hydroxypropyl cellulose, and combinations thereof.

4. The tablet according to claim 3, wherein said pH-independently gelling polymer in said inner tablet core comprises polyethylene oxide, preferably having a MW of 1 million to 10 million.

5. The tablet according to claims 3 and 4, wherein said pH-independently gelling polymer in said outer layer comprises polyethylene oxide, preferably having a MW of 1 million to 10 million.

6. The tablet according to claims 1-5, wherein said inner tablet core and/or said outer layer further comprises a binder/filler selected from the group comprising microcrystalline cellulose, silicified microcrystalline cellulose, polyvinylpyrrolidone, starch,

hydroxypropyl cellulose, and combinations thereof.

7. The tablet according to claims 1-6, wherein said inner tablet core comprises:

5 to 20% of paliperidone base;

20 to 40% of a polyethylene oxide of a molecular mass higher than 1,000,000; 40 to 60% of a filler/binder; and

0 to 20% of other excipients;

and wherein said outer layer comprises:

20 to 40% of a polyethylene oxide of a molecular mass higher than 1,000,000; 50 to 80% of a filler/binder; and

0 to 10% of other excipients.

8. The tablet according to claims 1-7, wherein the mass ratio of said inner tablet core to said outer layer is within the range of 1 :3 to 1:8, preferably 1 :4 to 1 :6.

9. The tablet according to claims 1-8, wherein said tablet exhibits a substantially S-shaped dissolution curve in a dissolution test in 500 ml phosphate buffer pH 6.8 in Apparatus Type I at 100 rpm.

10. The tablet according to claim 9, wherein in said dissolution test, the time from the release of 20% of said paliperidone to 80% of said paliperidone is at least 6 hours.

11. The tablet according to claims 1-10, wherein said tablet exhibits less than 100% release of said paliperidone at 20 hours in a dissolution test in 500 ml phosphate buffer pH 6.8 in Apparatus Type I at 100 rpm.

12. The tablet according to claim 11, wherein said tablet exhibits less than 25% release in 6 hours; 25-50% release in 12 hours; and 85-98% release in 20 hours.

13. A process for making the tablet according to claim 1-12, which comprises compression coating an excipient composition, which comprises a pH-independently gelling polymer, around a hydrogel tablet, which comprises pal iperi done or a pharmaceutically acceptable salt thereof and a pH-independently gelling polymer, to form an outer hydrogel layer surrounding said hydrogel tablet.

14. The process according to claim 13, wherein the weight of said excipient composition is 3 to 8 times the weight of said hydrogel tablet.

15. The process according to claims 13 or 14, wherein said pH-independently gelling

polymer in the hydrogel tablet and/or the outer hydrogel layer are each independently selected from the group comprising polyethylene oxide, hydroxypropyl methylcellulose, hydroxypropyl cellulose, and combinations thereof; and preferably are polyethylene oxide.

16. The tablet according to claims 1-12 or obtained by the process of claims 13-15, for use in medicine, as in treating paliperidone-treatable diseases, such as schizophrenia.