DESC:FIELD OF THE INVENTION

The present invention relates to a bilayer pharmaceutical composition comprising a first layer of sustained-release bupropion or its pharmaceutically acceptable salts and a second layer of sustained-release naltrexone or its pharmaceutically acceptable salts with pharmaceutically acceptable excipients for the treatment of obesity-related conditions. It further provides the methods for preparing the said pharmaceutical compositions.

BACKGROUND OF THE INVENTION

Obesity is generally referred as a disorder characterized by the excess accumulation of fat in the body resulting in an increased body weight and body fat percentage. Obesity has been recognized as one of the leading causes of disease and is emerging as a global problem. Obesity is a chronic disease associated with high morbidity and mortality, caused by adipose tissue accumulation due to disrupted regulation of energy balance or hyper nutrition. There are currently 250 million obese people in the world, and it is estimated that about 300 million people worldwide will be obese by the year 2025.

The BMI (Body Mass Index) value has been used as a standard measurement of obesity and over-weight. There has been reported that the BMI values over 25 and 30 indicate over- weight and obesity respectively in case of western people and the BMI value above 23 indicates over-weight and the precaution of adult disease.

There have been several methods to treat obesity, for example, diet therapy or exercise therapy, however, those methods often result in failure because of genetic factor such as personal differences in respect to appetite, favor to high-fat food and metabolism of fat formation. Therefore, there exists a need for therapy to promote reducing body weight other than classical approach methods.

The drugs for the treatment of obesity include, not limiting examples, such as Orlistat, Lorcaserin, Sibutramine, Rimonabant, Metformin, Exenatide, Pramlintide, combination of Phentermine/Topiramate, combination of Naltrexone/Bupropion, combination of Bupropion/Zonisamide, GT389-255 (Investigational drug), Diethylpropion, Liraglutide, Methamphetamine, Phendimetrazine, Benzphetamine. Such drugs can be administered by oral or parenteral route of administration by a person with ordinary skill in the art.

Bupropion is a weak norepinephrine-dopamine reuptake inhibitor (NDRI) and may act as a releasing agent of dopamine and norepinephrine. The IUPAC name of Bupropion is (±)-2-(tert-Butylamino)-1-(3-chlorophenyl) propan-1-one. The chemical structure of Bupropion is shown in formula below:

Naltrexone is an opioid receptor antagonist used primarily in the management of alcohol dependence and opioid dependence. The IUPAC name of Naltrexone is 17-(cyclopropylmethyl)-4,5a-epoxy- 3,14-dihydroxymorphinan-6-one. The chemical name of Naltrexone is shown in formula below:

Currently, the combination of Bupropion/Naltrexone is available as an extended-release tablet (CONTRAVE®) marketed by Orexigen Therapeutics. CONTRAVE® is a round, bi-convex, film coated, extended release trilayer tablet. Each trilayer tablet comprises two drug layers, containing the drug and excipients, separated by rapidly dissolving inert layer. Each trilayer tablet contains 8 mg of naltrexone hydrochloride and 90 mg of bupropion hydrochloride.

The composition and the use of CONTRAVE® tablet is disclosed in U.S. Patent numbers 7375111, 7462626, 8088786, 8318788, 8722085, 8815889, and 8916195. However, the CONTRAVE® is a complex trilayer tablet wherein the middle layer essentially needs to dissolve rapidly within a time period of 30 minutes to separate the upper and lower drug layers. The said compositions may cause problems of reproducibility and uncertainty regarding predictability of disintegration and dissolution. Further, there exists a need to develop a simple composition from economical point of view with a lesser number of unit operations for the bulk production. Hence, there exists a strong need for the development of a simple and stable pharmaceutical composition to overcome the problems of the prior art.

OBJECTS OF THE INVENTION

The primary object of the invention is to provide a bilayer pharmaceutical composition comprising a first layer of sustained-release bupropion or its pharmaceutically acceptable salts and a second layer of sustained-release naltrexone or its pharmaceutically acceptable salts with suitable pharmaceutically acceptable excipients.

Another object of the invention is to provide a process for the preparation of a bilayer pharmaceutical composition comprising a first layer of sustained-release bupropion or its pharmaceutically acceptable salts and a second layer of sustained-release naltrexone or its pharmaceutically acceptable salts with suitable pharmaceutically acceptable excipients.

SUMMARY OF THE INVENTION

In a first embodiment, the invention relates to a bilayer pharmaceutical composition comprising a first layer of sustained-release bupropion or its pharmaceutically acceptable salts and a second layer of sustained-release naltrexone or its pharmaceutically acceptable salts, with suitable pharmaceutically acceptable excipients.

In a preferred embodiment, the invention relates to a bilayer tablet comprising a first matrix layer of sustained-release bupropion or its pharmaceutically acceptable salts and a second matrix layer of sustained-release naltrexone or its pharmaceutically acceptable salts, with suitable pharmaceutically acceptable excipients.

In a preferred embodiment, the invention relates to a bilayer tablet comprising a first matrix layer of sustained-release bupropion or its pharmaceutically acceptable salts and a second layer of sustained-release pellets of naltrexone or its pharmaceutically acceptable salts, with suitable pharmaceutically acceptable excipients.

In another embodiment, the invention relates to a process for the preparation of a bilayer pharmaceutical composition comprising bupropion or its pharmaceutically acceptable salts and naltrexone or its pharmaceutically acceptable salts, with suitable pharmaceutically acceptable excipients. The said pharmaceutical composition can be prepared by direct compression, dry granulation, wet granulation or pelletization method.

DETAILED DESCRIPTION

The present invention relates to a bilayer pharmaceutical composition comprising a first layer of sustained-release bupropion or its pharmaceutically acceptable salts and a second layer of sustained-release naltrexone or its pharmaceutically acceptable salts with suitable pharmaceutically acceptable excipients.

The term "sustained-release" refers to a pharmaceutical composition such that its dissolution profile is extended over a longer period of time than that of an immediate release composition.

In a preferred embodiment, the sustained-release composition can be obtained with suitable pharmaceutically acceptable excipients, by either matrix layer or multiple-unit pellet system (MUPS).

The term "matrix layer" refers to an active drug layer comprising at least one drug with at least one rate-controlling agent such that it produces sustained-release drug matrix layer, which can be incorporated into a bilayer pharmaceutical composition of the present invention.

The term "multiple-unit pellet system (MUPS)" refers to an agglomerate of pellets comprising at least one drug with suitable pharmaceutically acceptable excipients such that it produces sustained-release drug pellets, which can be incorporated into a bilayer pharmaceutical composition of the present invention.

In a preferred embodiment, the bilayer pharmaceutical composition comprises a first layer comprising between about 50 mg and about 200 mg of sustained-release bupropion or its pharmaceutically acceptable salts and a second layer comprising between about 2 mg and about 35 mg of sustained-release naltrexone or its pharmaceutically acceptable salts with suitable pharmaceutically acceptable excipients.

The suitable pharmaceutically acceptable excipients that can be incorporated into sustained-release pharmaceutical compositions include diluents, binders, rate-controlling agents, stabilizers, wetting agents, lubricants, glidants and coating excipients. Preferably the non-limiting examples, includes L-Cysteine HCl, Microcrystalline Cellulose (MCC), silicified microcrystalline cellulose, PROSOLVE SMCC 90 (i.e. Silicified microcrystalline cellulose composed of 98% microcrystalline cellulose and 2% colloidal silicon dioxide), Lactose Monohydrate, Hypromellose (HPMC), Hydroxypropyl Cellulose (HPC), Ethyl cellulose, Crospovidone, croscarmellose sodium, sodium starch glycolate (SSG), mannitol, glyceryl behenate, Dibasic calcium phosphate dihydrate, Magnesium stearate, Colloidal Silicon Dioxide, Edetate Disodium, Polyethylene glycol (PEG), hydrogenated vegetable oil, or other conventional tablet excipients thereof.

The rate-controlling agents incorporated into any of the drug layers of the sustained-release pharmaceutical composition, are within the concentration of 1-50 %W/W. Preferably, the “rate-controlling agents” of the present invention includes, non-limiting examples, such as Hypromellose (HPMC), Hydroxypropyl Cellulose (HPC), Ethyl cellulose or mixtures thereof.

In another embodiment, the invention relates to a bilayer pharmaceutical composition, wherein the first layer comprises between about 50 mg and about 200 mg of sustained-release bupropion or its pharmaceutically acceptable salts, a second layer comprises between about 2 mg and about 35 mg of sustained-release naltrexone or its pharmaceutically acceptable salts, wherein the naltrexone dissolution profile in a dissolution test of USP Apparatus 2 Paddle Method at 50 rpm in a dissolution medium of water is:
a) between 40 to 80% of naltrexone released in one hour;
b) between 60 to 90% of naltrexone released in two hours.
c) at least 99% % of naltrexone released in 8 hours.

In another embodiment, the invention relates to the stability of the bilayer pharmaceutical compositions, wherein the impurity profile is within the prescribed limits. The Examples 5 and 6 describes the impurities of Bupropion Layer and Naltrexone Layer with their measured limit.

In another embodiment, the invention relates to a method of treating overweight or obesity, comprising a bilayer pharmaceutical composition, wherein about 180 mg of said sustained-release formulation of bupropion or a pharmaceutically acceptable salt thereof is administered twice daily, and about 16 mg of said sustained-release formulation of naltrexone or a pharmaceutically acceptable salt thereof is administered twice daily.

In another embodiment, the invention relates to a process for the preparation of a bilayer pharmaceutical composition comprising bupropion or its pharmaceutically acceptable salts and naltrexone or its pharmaceutically acceptable salts with suitable pharmaceutically acceptable excipients. The said pharmaceutical composition can be prepared by direct compression, dry granulation, wet granulation or pelletization method.

In order to further illustrate the present invention, the following examples are provided for the purpose of clarity of understanding. However, it is not intended in any way to limit the scope of present invention and it is readily apparent to those of ordinary skill in the art in light of the teachings of this invention that certain changes and modifications may be made thereto without departing from the scope of the invention.

Example 1: Bilayer tablet (Bupropion Hydrochloride SR layer + Naltrexone Hydrochloride SR layer)

Ingredients Qty (mg/tablet) %W/W
Drug Layer - I
Bupropion hydrochloride 90.0 5 – 40
L-Cysteine HCl 4.0 0.2 – 20
Microcrystalline Cellulose (MCC) 190.0 5 – 75
Hydroxypropyl Cellulose (HPC) / Hypromellose 77.0 1 – 50
Magnesium stearate 6.0 0.2 – 10
Total wt. (1st layer) in mg 367.0
Drug Layer – II
Naltrexone hydrochloride 8.0 0.5 – 10
Microcrystalline Cellulose (MCC) 92.0 3 – 50
Hypromellose K4M (HPMC K4M) 60.0 3 – 30
Hydroxypropyl Cellulose (HPC) 17.0 3 – 50
Edetate Disodium 4.0 0.1 – 5
Colloidal Silicon Dioxide 14.0 0.1 – 5
Lactose Monohydrate 92.0 3 – 50
Magnesium stearate 6.0 0.2 – 10
Total wt. (2nd layer) in mg 293.0
Total wt. (1st + 2nd layer) in mg 660.0
Film Coating
Opadry-II Blue in mg 20.0
Total wt. of coated tablets in mg 680.0

Manufacturing Process:
(i) Weigh all the ingredients required for the preparation of drug layer-I,
(ii) Sift all ingredients of drug layer -I through 30# sieve and load in granulator,
(iii) Granulate the blend of the sifted ingredients for an appropriate time,
(iv) Dry the granules appropriately till LOD less than 1.5%,
(v) Sift the dried granules from 20# sieve and add lubricant to the dry granules,
(vi) Weigh all the ingredients required for the preparation of drug layer-II,
(vii) Sift all ingredients of drug layer -II through 40# sieve and blend for 5 minutes in a blender.
(viii) Granulate the blend of the sifted ingredients for an appropriate time,
(ix) Dry the granules appropriately till LOD less than 1.5%,
(x) Sift the dried granules from 20# sieve and add lubricant to the dry granules,
(xi) The blend of both drug layers is compressed to prepare a bilayer tablet.
(xii) Optionally film coat the compressed tablets.

Example 2: Bilayer tablet (Bupropion HCl sustained-release matrix layer + Naltrexone HCl sustained-release MUPS layer)

Ingredient Qty (mg/tablet) %W/W
Drug Layer - I
Bupropion hydrochloride 90.0 5 – 40
L-Cysteine HCl 4.0 1 – 20
Microcrystalline Cellulose (MCC) 190.0 5 – 50
Hydroxypropyl Cellulose (HPC)/Hypromellose 77.0 1 – 50
Magnesium stearate 6.0 0.5 – 10
Total wt. (1st layer) in mg 367.0
Drug Layer – II: MUPS containing Naltrexone HCl SR pellets
Drug Layering (Naltrexone core pellets)
Naltrexone hydrochloride 8.0 0.5 – 10
Celphere/Sugar Spheres 72.0 1 – 50
Hypromellose 8.0 3 – 30
Edetate Disodium 4.0 0.1 – 5
SR Coating over Naltrexone Pellets
Drug Layered pellets of Naltrexone in mg 92.0 15 – 55
Ethyl cellulose 8.0 0.1 – 20
Hypromellose 8.0 0.1 – 20
Lubrication
SR Coated pellets of Naltrexone in mg 108 20 – 55
Prosolve SMCC 90 (Lubrication) 125.0 1 – 50
PEG (Lubrication) 20.0 3 – 50
Hydrogenated Vegetable Oil (Lubrication) 20.0 0.2 – 10
Colloidal Silicon Dioxide (Lubrication) 14.0 3 – 50
Magnesium stearate(Lubrication) 6.0 0.5 – 10
Total wt. (2nd layer) in mg 293.0
Total wt. (1st + 2nd layer) in mg 660.0
Film Coating
Opadry-II Blue in mg 20.0
Total weight in mg 680.0

Manufacturing Process:
(i) Weigh all the ingredients required for the preparation of drug layer-I,
(ii) Sift all ingredients of drug layer-I through 30# sieve and load in granulator,
(iii) Granulate the blend of the sifted ingredients for an appropriate time,
(iv) Dry the granules appropriately till LOD less than 1.5%,
(v) Sift the dried granules from 20# sieve and add lubricant to the dry granules,
(vi) Weigh all the ingredients required for the preparation of drug layer-II,
(vii) Load inert spheres in Fluidized bed equipment,
(viii) Prepare drug layering solution and spray it on the inert spheres,
(ix) Prepare SR coating solution and spray it on the drug loaded spheres,
(x) Dry the spheres appropriately till LOD less than 1.5%,
(xi) Sift the lubricants through 30# sieve and mix with dried spheres,
(xii) Blend of both the layers is compressed to prepare a bilayer tablet,
(xiii) Optionally film coat the compressed tablets.

Example 3: Bilayer tablet (Bupropion Hydrochloride SR layer + Naltrexone Hydrochloride SR layer)

Batch ASBNET1014 (Coated Tablets)
Sr. No. Ingredients mg/tab
Layer 1 - Bupropion Hydrochloride
1 Bupropion HCl 90
2 MCC 112 211
3 HPC 20
4 Cysteine HCl monohydrate 8
5 HPC 15
6 Purified Water q.s.
7 HPC 25
8 Magnesium stearate 6
Part 1 Avg. wt 375
Layer 2 - Naltrexone Hydrochloride
1 Naltrexone hydrochloride 8
2 Silicified MCC 236.5
3 Hypromellose K4M (HPMC K4M) 30
4 Edetate Disodium 6
5 Magnesium stearate 4
6 FD&C blue #2 (Aluminium Lake) 0.5
Part 2 Avg. Wt 285
Total 660
Film Coating
1 Opadry-II Blue in mg 26
2 Total weight in mg 686

The manufacturing Process for Example 3 is same as that described for Example 1.

Example 4: Dissolution Profile of Bilayer tablet (as described in Example 3).

Method Paddle-Sinker; 50 RPM
(1st Sample) Paddle-Sinker; 50 RPM
(2nd Sample)
Bupropion Part Naltrexone Part Bupropion Part Naltrexone Part
Time (Hr) % Drug Release RSD % Drug Release RSD % Drug Release RSD % Drug Release RSD
0.5 24 11.32 41 22.41 25 8.17 53 17.89
1 37 11.54 61 18.54 39 9.46 75 12.67
2 57 11.23 81 12.72 59 9.44 90 4.6
3 73 9.88 91 8.81 75 7.57 96 3.13
4 84 8.19 95 5.82 86 6.04 98 3.76
6 97 4.18 100 2.97 96 2.87 99 3.88
8 101 1.08 101 2.69 99 0.79 98 3.82
12 98 1.75 98 3.08 98 0.88 99 1.84

The naltrexone dissolution profile in a dissolution test of USP Apparatus 2 Paddle Method at 50 rpm in a dissolution medium of water is:
a) between 40 to 80% of naltrexone released in one hour;
b) between 60 to 90% of naltrexone released in two hours; and
c) at least 99% % of naltrexone released in 8 hours.

The sustained-release formulation of naltrexone or a pharmaceutically acceptable salt thereof provides an in-vitro release rate of naltrexone in the dissolution test of at least 99% in 8 hours.

Example 5: Stability Data of Bilayer tablet.

B. No ASBNET1014 (Bilayer) – 1st Sample
Related Substance Initial 1M ACC 2M ACC 3M ACC 3M CRT
Bupropion HCL Part
Compound F (RRT 1.84) 0.186 1.205 1.863 2.386 0.377
Compound C (RRT 1.91) ND 0.013 0.037 0.076 ND
Single Maximum Impurity 0.044 0.117 0.239 1.664 0.055
Total Impurity (3.3%) 0.373 1.95 3.382 5.368 0.681
Naltrexone HCL Part
Impurity J (RRT 1.96) 0.14 0.581 ND ND ND
Impurity D 0.122 0.071 1.008 0.148 0.167
Single Maximum Impurity 0.344 0.799 0.066 0.193 0.836
Total Impurity 0.741 1.564 1.074 3.976 1.529

*Compound F: (1-(3-chlorophenyl)-1-hydroxy-2-propanone) - Limit is 2.5%
*Compound C: (1-(3-chlorophenyl)-2-hydroxy-1-propanone) - Limit is 0.5%
*Impurity J: 17-(Cyclopropylmethyl)-4,5-a-epoxy-14-hydroxy-3-methoxy
morphinan-6-one.
*Impurity D: 2,2' Bisnaltrexone
*RRT: Relative Retention Time
*CRT: Controlled Room Temperature

The stability data indicated that the bilayer tablets remained stable since the impurity profile is within the prescribed limits.

Example 6: Stability Data of Bilayer tablet.

B. No ASBNET1014 (Bilayer) – 2nd Sample
Related Substance Initial 1M ACC 2M ACC 3M ACC 3M CRT
Bupropion HCL Part
Compound F (RRT 1.84) 0.186 1.351 1.921 2.455 0.422
Compound C (RRT 1.91) ND 0.015 0.041 0.075 ND
Single Maximum Impurity 0.044 0.133 0.247 0.137 0.095
Total Impurity (3.3%) 0.373 2.178 3.357 5.281 0.914
Naltrexone HCL Part
Impurity J (RRT 1.96) 0.14 0.649 ND ND ND
Impurity D 0.122 0.087 0.874 0.164 0.143
Single Maximum Impurity 0.344 0.78 ND 1.912 1.008
Total Impurity 0.741 1.639 0.874 4.154 1.871

*Compound F: (1-(3-chlorophenyl)-1-hydroxy-2-propanone) - Limit is 2.5%
*Compound C: (1-(3-chlorophenyl)-2-hydroxy-1-propanone) - Limit is 0.5%
*Impurity J: 17-(Cyclopropylmethyl)-4,5-a-epoxy-14-hydroxy-3-methoxy
morphinan-6-one.
*Impurity D: 2,2' Bisnaltrexone
*RRT: Relative Retention Time
*CRT: Controlled Room Temperature

The stability data indicated that the bilayer tablets remained stable since the impurity profile is within the prescribed limits. ,CLAIMS:1. A bilayer pharmaceutical composition comprising a first layer of sustained-release bupropion or its pharmaceutically acceptable salts and a second layer of sustained-release naltrexone or its pharmaceutically acceptable salts, with suitable pharmaceutically acceptable excipients.

2. A bilayer tablet comprising a first matrix layer of sustained-release bupropion or its pharmaceutically acceptable salts and a second matrix layer of sustained-release naltrexone or its pharmaceutically acceptable salts, with suitable pharmaceutically acceptable excipients.

3. A bilayer tablet comprising a first matrix layer of sustained-release bupropion or its pharmaceutically acceptable salts and a second layer of sustained-release pellets of naltrexone or its pharmaceutically acceptable salts, with suitable pharmaceutically acceptable excipients.

4. The bilayer pharmaceutical composition according to claim 1, wherein the sustained-release composition is obtained with suitable pharmaceutically acceptable excipients, in the form of matrix layer or multiple-unit pellet system (MUPS).

5. The bilayer pharmaceutical composition according to claim 1, wherein the first layer comprises between about 50 mg and about 200 mg of sustained-release bupropion or its pharmaceutically acceptable salts and a second layer comprises between about 2 mg and about 35 mg of sustained-release naltrexone or its pharmaceutically acceptable salts.

6. The bilayer pharmaceutical composition according to claim 1, wherein the first layer comprises between about 50 mg and about 200 mg of sustained-release bupropion or its pharmaceutically acceptable salts and a second layer comprises between about 2 mg and about 35 mg of sustained-release naltrexone or its pharmaceutically acceptable salts, wherein the rate-controlling agent is contained in the said composition at a concentration of 1- 50 % W/W.

7. The bilayer pharmaceutical composition according to claim 1, wherein the first layer comprises between about 50 mg and about 200 mg of sustained-release bupropion or its pharmaceutically acceptable salts and a second layer comprises between about 2 mg and about 35 mg of sustained-release naltrexone or its pharmaceutically acceptable salts, wherein the naltrexone dissolution profile in a dissolution test of USP Apparatus 2 Paddle Method at 50 rpm in a dissolution medium of water is:
a) between 40 to 80% of naltrexone released in one hour;
b) between 60 to 90% of naltrexone released in two hours.
c) at least 99% % of naltrexone released in 8 hours.

8. The bilayer pharmaceutical composition according to claim 1, wherein the first layer comprises between about 50 mg and about 200 mg of sustained-release bupropion or its pharmaceutically acceptable salts and a second layer comprises between about 2 mg and about 35 mg of sustained-release naltrexone or its pharmaceutically acceptable salts, wherein the sustained-release formulation of naltrexone or a pharmaceutically acceptable salt thereof provides an in-vitro release rate of naltrexone in the dissolution test of at least 99% in 8 hours.

9. A method of treating overweight or obesity, comprising a bilayer pharmaceutical composition, wherein about 180 mg of said sustained-release formulation of bupropion or a pharmaceutically acceptable salt thereof is administered twice daily, and about 16 mg of said sustained-release formulation of naltrexone or a pharmaceutically acceptable salt thereof is administered twice daily.

10. The bilayer pharmaceutical composition according to claim 1, wherein the pharmaceutical composition is prepared by granulation or pelletization method.