DESC:FIELD OF THE INVENTION

The present invention relates to a pharmaceutical composition comprising Apremilast with at least one rate-controlling polymer, wherein the use of rate-controlling polymer in an immediate release composition substantially controls the drug release characteristics. Further, the invention relates to a process for the preparation of an immediate release composition of Apremilast.

BACKGROUND OF THE INVENTION

Apremilast is a phosphodiesterase-4 (PDE4) inhibitor, and it is chemically known as N-[2-[(1S)-1-(3-ethoxy-4-methoxyphenyl)-2-(methylsulfonyl)ethyl]-2,3-dihydro 1,3-dioxo-1H-isoindol-4-yl]acetamide. Its empirical formula is C22H24N2O7S and the molecular weight is 460.5. The chemical structure of apremilast is shown in formula below:

The U.S. Patent No. 6,020,358 and the U.S. Patent No. 7,427,638 discloses Apremilast and its stereomerically pure (+) isomer. The U.S. Patent No. 7,893,101 discloses the crystal form B of apremilast, while the U.S. Patent No. 9,468,605 describes an immediate release dosage form comprising apremilast with lactose, carboxymethyl cellulose, fumed silica and magnesium stearate.

Currently, Apremilast tablet is available under the brand name of OTEZLA®, for the treatment of adult patients with active psoriatic arthritis, and for treatment of patients with moderate to severe plaque psoriasis.

The aqueous solubility of crystalline form is lower than its amorphous form, which may result into differences in their bioavailability. Therefore, it is desirable to have an amorphous form of Apremilast, which provides drug release characteristics similar to the reference drug product, and also comply with high purity needs of regulatory agencies. However, the development of an ideal immediate release composition comprising an amorphous form of apremilast is rendered more difficult by the fact that amorphous form dissolves rapidly. Therefore, there exists a need for an immediate release composition comprising an amorphous form of Apremilast with at least one rate-controlling polymer such that it substantially controls the drug release characteristics, and thereby it provides similar dissolution profile to the reference drug product.

OBJECTS OF THE INVENTION

The primary object of the invention is to provide a pharmaceutical composition comprising an amorphous form of Apremilast with at least one rate-controlling polymer.

Another object of the invention is to provide an immediate release composition comprising an amorphous form of Apremilast with at least one rate-controlling polymer, at least one diluent/filler, at least one disintegrant, and at least one lubricant, wherein the rate-controlling polymer in the immediate release composition substantially controls the drug release characteristics.

Another object of the invention is to provide an immediate release composition comprising an amorphous form of Apremilast with ethyl cellulose as a rate-controlling polymer.

Another object of the invention is to provide a process for the preparation of an immediate release composition of amorphous apremilast.

SUMMARY OF THE INVENTION

In a first embodiment, the invention relates to a pharmaceutical composition comprising an amorphous form of Apremilast with at least one rate-controlling polymer, at least one diluent/filler, at least one disintegrant, and lubricant, wherein the rate-controlling polymer in the immediate release composition substantially controls the drug release characteristics.

In a preferred embodiment, the invention relates to an immediate release composition comprising an amorphous form of Apremilast with ethyl cellulose as a rate-controlling polymer, mannitol and microcrystalline cellulose as diluents/fillers, croscarmellose sodium as disintegrant, magnesium stearate as lubricant and a suitable film coat.

In another embodiment, the invention relates to a process for the preparation of an immediate release composition of amorphous apremilast by wet granulation method.

DETAILED DESCRIPTION

The present invention relates to a pharmaceutical composition comprising an amorphous form of Apremilast with at least one rate-controlling polymer.
Further, the present invention is to provide an immediate release pharmaceutical composition of amorphous Apremilast, wherein the said composition in the form of tablets.

In one embodiment, the present invention relates to an immediate release composition comprising an amorphous form of Apremilast with at least one rate-controlling polymer, at least one diluent/filler, at least one disintegrant, at least one lubricant, and optionally film coating.

The term “Immediate release” for the purpose of the invention, means the pharmaceutical composition that disintegrates rapidly and gets dissolved to release the drug immediately after oral administration. The immediate release tablet of the present invention provides similar dissolution profile to the reference drug product, commercially available as OTEZLA® (Apremilast; Oral tablets).

The term “Amorphous form” for the purpose of the invention, means no crystalline form can be detected within the limits of a powder X-ray diffractometer. In a preferred embodiment, Apremilast is used as a pure amorphous form in the pharmaceutical composition, in an amount from 5 mg to 500 mg. Preferably, the amount of Apremilast in the composition is selected from 10 mg, 20 mg and 30 mg.

Not bound to any theory, the term "rate-controlling polymer" for the purpose of the invention, means a pharmaceutically acceptable excipient that substantially controls the drug release characteristics from the pharmaceutical composition. The rate-controlling polymer, as used hereinbefore, refers to an excipient that provides the release of the amorphous Apremilast from its pharmaceutical composition at a controlled rate such that the immediate release composition of the present invention provides similar dissolution profile to the reference drug product OTEZLA® (Apremilast; Oral tablets).

The rate-controlling polymer(s) may be added as intra-granular and/or extra-granular portion with one or more pharmaceutically acceptable excipients. The commonly used rate-controlling polymer that are used in the art, includes ethyl cellulose, hypromellose (or hydroxy propyl methylcellulose), Hydroxy propyl cellulose, and other suitable polymers known in the art. Preferably, the rate-controlling polymer is ethyl cellulose dispersion. The Aquacoat ECD 30% dispersion is commercially available, as a dispersion of ethyl cellulose (EC 10 cps), cetyl alcohol and sodium lauryl sulphate (SLS).

The inventors of the present invention tried to use the commonly used rate-controlling agents in the pharmaceutical composition containing amorphous form of apremilast, such that it is bioequivalent with the reference drug product. However, it was found that only Ethyl Cellulose can be used as rate-controlling polymer to obtain desired finished dosage form of amorphous form of Apremilast.

In addition to the above-mentioned ingredients, the immediate release pharmaceutical composition of the present invention may also comprise one or more pharmaceutically acceptable excipients such as diluents, binders, disintegrants and lubricants or mixtures thereof. It is known to a person skilled in the art that the excipients can perform more than one function in the pharmaceutical composition.

The pharmaceutically acceptable excipients include inactive ingredients to obtain the immediate release pharmaceutical compositions. Preferably, the “inactive ingredients” of the present invention includes, non-limiting examples, such as mannitol, microcrystalline cellulose, triethyl citrate, croscarmellose sodium, magnesium stearate and other suitable inactive ingredients.

Solvents may be used in present invention include all the solvents well known in the art or their mixtures thereof are selected from the group comprising isopropyl alcohol, methylene chloride, purified water, or mixture thereof.

The term “film coat” for the purpose of the invention, means a thin polymer-based coat applied to a solid dosage form such as a tablet, so as to provide aesthetic look and moisture barrier. In a preferred embodiment of the present invention, the film coating is Opadry Amb II®.

The film coating comprises a water-soluble film forming polymer with plasticizers, colorants, opacifiers and coating solvents. Preferably the film coating composition comprises polyvinyl alcohol, titanium dioxide, talc, iron oxide yellow, iron oxide black, iron oxide red, Glycerol esters of fatty acids and SLS.

In another embodiment, the present invention relates to an immediate release pharmaceutical composition comprising: (i) a tablet core comprising an amorphous form of Apremilast, ethyl cellulose, at least one diluent, at least one disintegrant, at least one lubricant, and (ii) a film coating.

In another embodiment, the present invention relates to an immediate release pharmaceutical composition comprising: (i) a tablet core comprising an amorphous form of Apremilast, ethyl cellulose, mannitol, microcrystalline cellulose, croscarmellose sodium, magnesium stearate, and (ii) a film coating comprising a water-soluble film forming polymer.

In yet another embodiment of the present invention is to provide a process for the preparation of immediate release pharmaceutical composition of amorphous Apremilast in the form of tablets.

In yet another embodiment the present invention may be prepared by a conventional process known in the art, such as wet granulation, direct compression and dry granulation. Preferably the method for preparation of the said pharmaceutical composition is wet granulation.

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.

EXAMPLES:

The following examples are illustrative of the present invention, and the examples should not be considered as limiting the scope of this invention in any way, as these examples and other equivalents thereof will become apparent to those versed in the art, in the light of the present disclosure.

EXAMPLE-1: Pharmaceutical Composition of Apremilast tablet.

Each film coated tablet contains:
Apremilast ……… 30mg
Colour: Titanium Dioxide, Iron oxide red, Iron oxide yellow & Iron oxide black
Excipients: Q.s.
Sr. No. Ingredients mg/unit % w/w
Intra-granular Part
1 Apremilast 30.000 9.615
2 Mannitol (Pearlitol 160 C) 122.000 39.103
3 Microcrystalline cellulose (Avicel PH 101) 95.500 30.609
Granulation
4 Ethyl Cellulose Dispersion (Aquacoat ECD 30 %) Ethyl Cellulose 10 cps 26.300 8.429
Cetyl Alcohol 2.400 0.769
Sodium Lauryl Sulphate 1.300 0.417
5 Triethyl citrate (TEC) 4.500 1.400
Extra-granular Part
6 Croscarmellose sodium 15.000 4.808
7 Magnesium Stearate 3.000 0.962
Core Tablet weight 300.000
Film Coating
8 Opadry Amb II® Polyvinyl Alcohol 4.440 1.423
Titanium Dioxide 2.594 0.831
Talc 3.720 1.192
Iron Oxide Yellow 0.197 0.063
Iron Oxide Black 0.061 0.020
Iron Oxide Red 0.148 0.047
GMCC TYPE 1 (NF, PhEur) / Glycerol Esters of Fatty Acids JSFA 0.480 0.154
SLS 0.360 0.115
9 Purified water q.s. q.s.
Film Coated Tablets 312.000 100.000

Manufacturing Process:
1. Co-sift Apremilast, Microcrystalline Cellulose and Mannitol through # 30.
2. Take Ethyl Cellulose Dispersion in a beaker and add Triethyl citrate slowly into it and mix it for 30 minutes using stirrer.
3. Dry mix blend of step 1 for 10 minutes in RMG and granulated with solution of step 2.
4. Dry the granules of step 3 in Rapid Fluid Bed Dryer till desired LOD is achieved. Pass the dried granules through # 20.
5. Sift Croscarmellose sodium through # 30.
6. Blend the material of step 4 and 5 for 10 minutes at 15 RPM.
7. Sift Magnesium stearate through # 30 and mix it for 2 minutes at 15 RPM.
8. Compress Tablets of 300.00 mg on a Tablet Press.
9. Take Opadry Amb II in a beaker with purified water and mix it for 30 minutes using stirrer to make 20 % w/w solution.
10. Coat the tablets of step 8 using coating solution of step 9 in an Autocoater with 4 % Weight gain.
11. Pack the coated tablets in PVC – Alu Blister and HDPE Bottle (60’s count).

EXAMPLE-2: Dissolution profile of tablets with Amorphous Apremilast with different polymers.

Time Points (minutes) Reference product (Otezla®) Test Products with different polymers
With Ethyl Cellulose With Hypromellose With Hydroxy-propyl cellulose
5 63 (62-65) 62 (60-64) 94 (93-95) 73 (69-79)
10 77 (77-78) 74 (73-74) 98 (98-99) 87 (85-91)
15 82 (81-82) 79 (78-80) 100 (100 -100) 94 (92-97)
20 84 (83-85) 83 (82-83) 100 (100 -100) 97 (96-99)
30 86 (85-87) 86 (85-87) 100 (100-101) 100 (99-101)
45 89 (88-90) 90 (89-91) 101 (100-101) 102 (101-103)

The dissolution test is performed with the media of pH 6.8 Phosphate Buffer with 0.3 % SLS; Volume 900 ml; and Paddle apparatus at 75 rpm.

In above Example, the dissolution test was performed with the rate-controlling polymers such as ethyl cellulose, hypromellose and hydroxy-propyl cellulose respectively. However, the results from the dissolution profile of Apremilast tablets made with different rate-controlling polymers indicates that only ethyl cellulose polymer substantially controls the drug release characteristics of Amorphous Apremilast tablet to comply with the dissolution profile to Otezla® tablet.

EXAMPLE-3: Dissolution Profile of Batches with Crystalline and Amorphous Apremilast.

Dissolution Profile: Media – pH 6.8 Phosphate Buffer with 0.3% SLS, Apparatus – Paddle, Vol. – 900 mL, RPM – 75
Time Points (min.) Otezla® (Apremilast Tablets; 30 mg)
(Reference product) Apremilast Tablets; 30 mg
Test Batch-I Apremilast Tablets;
30 mg
Test Batch-II
Polymorph Crystalline Crystalline Amorphous
5 63 (62-65) 53 (49 - 55) 62 (60-64)
10 77 (77-78) 78 (76-81) 74 (73-74)
15 82 (81-82) 89 (88-91) 79 (78-80)
20 84 (83-85) 93 (92-95) 83 (82-83)
30 86 (85-87) 96 (95-98) 86 (85-87)
45 89 (88-90) 96 (96-99) 90 (89-91)
Note: Results are in Mean (Minimum – Maximum)

The dissolution profile of tablets with Amorphous Apremilast containing rate-controlling polymer (i.e. Test Batch-II) complies with the dissolution profile of the reference product (Otezla®; crystalline form). However, the dissolution profile of test tablets with Crystalline Apremilast (i.e. Test Batch-I) was relatively slow compared to the dissolution profile of the reference product.

EXAMPLE-4: Pharmaceutical Composition of Apremilast tablet.

Apremilast Tablets 30 mg
Each film coated tablet contains:
Apremilast ………30mg
Colour:- Titanium Dioxide, Iron oxide red, Iron oxide yellow & Iron oxide black
Excipients: - Q.s
Sr. No. Ingredients mg/unit % w/w
Intra-granular Part
1 Apremilast 30.000 9.615
2 Mannitol (Pearlitol 160 C) 129.000 41.346
3 Microcrystalline cellulose (Avicel PH 102) 102.00 32.692
4 Ethyl Cellulose 7 cps 15.00 4.808
Granulation
5 Ethyl Cellulose 7 cps 15.00 4.808
6 Isopropyl Alcohol q.s. --
7 Methylene Chloride q.s. --
Extra-granular Part
8 Croscarmellose sodium 6.000 1.923
9 Magnesium Stearate 3.000 0.962
Core Tablet weight 300.000 --
Film Coating
10 Opadry Amb II® Polyvinyl Alcohol 4.440 1.423
Titanium Dioxide 2.594 0.831
Talc 3.720 1.192
Iron Oxide Yellow 0.197 0.063
Iron Oxide Black 0.061 0.020
Iron Oxide Red 0.148 0.047
GMCC TYPE 1 (NF, PhEur)/GLYCEROL ESTERS OF FATTY ACIDS JSFA 0.480 0.154
SLS 0.360 0.115
9 Purified water q.s. q.s.
Film Coated Tablets 312.000 100.000

Manufacturing Process:
1. Co-sift Apremilast, Microcrystalline Cellulose, Mannitol and Ethyl Cellulose 7cps through # 30.
2. Take Ethyl Cellulose 7cps in a beaker, and add into mixture of IPA and DCM till a clear solution is made using stirrer.
3. Dry mix blend of step 1 for 10 minutes in RMG and granulated with solution of step 2.
4. Dry the granules of step 3 in Rapid Fluid Bed Dryer till desired LOD is achieved. Pass the dried granules through # 20.
5. Mill oversized granules through 1.5 mm screen in Multi-mill. Again sift the milled material through # 20 and mill oversized granules from screen 1.0 mm in Multi-mill.
6. Sift Croscarmellose sodium through # 30.
7. Blend the material of step 4 and 5 for 10 minutes at 15 RPM.
8. Sift Magnesium stearate through # 30 and mix it for 2 minutes at 15 RPM.
9. Compress Tablets of 300.00 mg on a Tablet Press.
10. Take Opadry Amb II in a beaker with P. water and mix it for 30 minutes using stirrer to make 20 % w/w solution.
11. Coat the tablets of step 8 using coating solution of step 9 in an Auto-coater with 4 % Weight gain.

EXAMPLE-5: Dissolution Profile comparison of RLD (Crystalline) Vs Test (Amorphous – Ethyl Cellulose Non-Aqueous Granulation)

Dissolution Profile : Media – pH 6.8 Phosphate Buffer with 0.3% SLS, Apparatus – Paddle, Vol. – 900 mL, RPM – 75
Time Points (min) Otezla® (Apremilast Tablets 30 mg) - RLD Apremilast Tablets 30 mg - Test Product
Remarks Crystalline Amorphous (containing EC, Non-aqueous granulation)
15 79 (78-80) 78 (77-78)
30 87 (86-88) 84 (84-85)
45 91 (89-91) 87 (87-88)
60 92 (91-93) 89 (89-89)
Note: Results are in Mean (Minimum – Maximum)

The dissolution profile of tablets with Amorphous Apremilast containing rate-controlling polymer (i.e. Test product) complies with the dissolution profile of the reference product (i.e. Otezla® tablets).

EXAMPLE-6: Stability Data for Apremilast Tablets 30 mg.

Parameters Specifications Initial 1M (40/75) 2M (40/75) 3M (40/75) 3M
(25/60)
Average weight 312.0 ± 5 % 315 314.7 314.3 314.7 314.9
LOD NMT 5.0% 2.78% 1.50% 3.2 2.72 2.27
Hardness 90N - 160N 129
(109-141) 136
(132-138) 131
(90-148) 137
(131-143) 130
(124-137)
Dissolution NLT 70% (Q) in 60 mins 89
(89-90) ND 88
(87-89) 88
(88-88) 87
(86-88)
% Assay 90 -110.0% 99.4 99.2 101.1 100.6 99.8
Related substances (By HPLC)
Acetamido Sulfone impurity NMT 0.30 % ND ND 0.066 ND ND
Amino Sulfone impurity NMT 0.30 % ND ND ND ND ND
Apremilast stage- II NMT 0.30 % ND ND BQL BQL ND
5-Acetyl of Apremilast NMT 0.30 % ND ND ND ND ND
Desmethyl Apremilast NMT 0.30 % ND ND ND ND ND
Maximum unknown impurity NMT 0.20 % 0.064 0.059 0.068 0.063 0.063
Total impurity NMT 2.0 % 0.15 0.137 0.153 0.145 0.142

From the above dissolution data, it can be concluded that use of rate-controlling polymer in an immediate release composition comprising amorphous Apremilast substantially controls the drug release characteristics and would be useful in achieving bioequivalence with regards to the reference drug product. ,CLAIMS:We claim:
1. An immediate release pharmaceutical composition of Apremilast comprising amorphous form of Apremilast with at least one rate-controlling polymer, and optionally a film coating.

2. The immediate release pharmaceutical composition according to claim 1, wherein the said rate-controlling polymer comprises ethyl cellulose.

3. The immediate release pharmaceutical composition according to claim 1, wherein the said film coating comprises a water-soluble film forming polymer.

4. The immediate release pharmaceutical composition according to claim 1, wherein the said composition is in the form of tablet.

5. The immediate release pharmaceutical composition according to claim 4, wherein the dissolution profile of the said tablet is similar with the dissolution profile of marketed Otezla® tablet.

6. The immediate release tablet composition according to claim 1, wherein the composition comprises Apremilast in an amount from 10 mg to 200 mg.

7. A process for preparation of an immediate release pharmaceutical composition of Apremilast comprising steps of:
a) preparing granules using amorphous Apremilast, ethyl cellulose and other suitable excipients,
b) drying and milling the granules obtained in step a)
c) blending the granules obtained in step b) with suitable excipients,
d) compressing the resulting granules into tablet, and
e) optionally, providing a film coat onto the tablets obtained in step d).

8. The process according to claim 7, wherein the said composition is prepared by wet granulation method.

9. The immediate release pharmaceutical composition of Apremilast, wherein the composition comprises: (i) a tablet core comprising an amorphous form of Apremilast, ethyl cellulose, at least one diluent, at least one disintegrant, at least one lubricant, and (ii) a film coating.

10. The immediate release pharmaceutical composition according to claim 9, wherein the said composition comprises: (i) a tablet core comprising an amorphous form of Apremilast, ethyl cellulose, mannitol, microcrystalline cellulose, croscarmellose sodium, magnesium stearate, and (ii) a film coating comprising a water-soluble film forming polymer.