pH-sensitive polymers be selected from, but not limited to methacrylic acid and methyl methacrylate copolymers, dimethylaminoethyl methacrylate and butyl methacrylate and methyl methacrylate copolymers, methyl acrylate and methacrylic acid and octyl acrylate copolymers, styrene and acrylic acid copolymers, butyl acrylate and styrene and acrylic acid copolymers, and ethylacrylate-methacrylic acid copolymers; cellulose acetate phthalate; cellulose acetate succinates; hydroxyalkyl cellulose phthalates such as hydroxypropylmethyl cellulose phthalate; hydroxyalkyl cellulose acetate succinates such as hydroxypropylmethyl cellulose acetate succinate; vinyl acetate phthalates; vinyl acetate succinate; cellulose acetate trimelliate; polyvinyl derivatives such as polyvinyl acetate phthalate, polyvinyl alcohol phthalate, polyvinyl butylate phthalate, and polyvinyl acetoacetal phthalate; zein; shellac; and mixtures thereof.

The pulsed release caffeine formulation wherein the release retarding agent is present in the range of 1-50% w/w of composition. The pulsed release caffeine formulation wherein the release retarding agent is present in the range of 1-40% w/w of composition. The pulsed release caffeine formulation wherein the release retarding agent is present in the range of 1-30% w/w of composition. The pulsed release caffeine formulation wherein the release retarding agent is present in the range of 1-20% w/w. The pulsed release caffeine formulation wherein the release retarding agent is present in the range of 1-10% w/w.

According to one embodiment, the release retarding agent used in the core or coating of the particulate system, or in the combination, so that both core and coating contain the release retarding agent. Further core and coating of the particulate system contain same or different release retarding agent.

According to one more embodiment of this invention, caffeine pulsed release formulations comprised of at least one food grade excipient selected from the group of, but not limited to binder, diluent/filler, pore former, antioxidant, solvent, inert core, disintegrants, coating agents, film former, glidant, lubricant, oil vehicle and the combinations thereof. These excipients used for preparation of particulate systems as well as for converting particulate systems and the combinations thereof in final formulations.

As per one more embodiment, diluents/fillers selected from, but not limited to microcrystalline cellulose, polyvinylpyrrolidone, carrageenan, chitosan, pectinic acid, modified starches, coprocessed microcrystalline cellulose, glycerides, sodium alginate, beta-cyclodextrin and the combination thereof. The pulsed release caffeine formulation wherein the diluents/fillers is present in the range of 1-20% w/w of composition. The pulsed release caffeine formulation wherein the diluents/fillers is present in the range of 1-15% w/w of composition. The pulsed release caffeine formulation wherein the diluents/fillers is present in the range of 1-10% w/w of composition. The pulsed release caffeine formulation wherein the diluents/fillers is present in the range of 1-5% w/w. The pulsed release caffeine formulation wherein the diluents/fillers is present in the range of 1-5% w/w.

As per one embodiment, pore forming agents selected from, but not limited to sodium alginate, cellulose polymers, polyethylene glycols, sugar, starches, maltodextrin and the combinations thereof. The pulsed release caffeine formulation wherein the pore forming agents is present in the range of 1-20% w/w of composition. The pulsed release caffeine formulation wherein the pore forming agents is present in the range of 1-15% w/w of composition. The pulsed release caffeine formulation wherein the pore forming agents is present in the range of 1-10% w/w of composition. The pulsed release caffeine formulation wherein the pore forming agents is present in the range of 1-5% w/w. The pulsed release caffeine formulation wherein the pore forming agents is present in the range of 1-5% w/w.

According to one important embodiment, the invention describe herein also relates to the process for preparation of the particulate systems and caffeine pulsed release formulations. As per the process, caffeine combined with release retarding agents and at least one or more food grade excipients to prepare the particulate system of the caffeine. The process for preparation of the particulate system selected from, but not limited to wet granulation, dry granulation, melt granulation, hot melt extrusion, extrusion spheronization, coating of the inert core with active and the combinations thereof, without any limitation. The techniques and the equipment's, which are known in formulation industry and are viable, which are selected from, but not limited to rapid mixer granulator, planetary mixer, top spray granulation, fluid bed processor, pan coating can be used for the preparation of particulate systems.

Further, the particulate systems coated with release retarding agent and at least one food grade excipient to achieve desired release profile.

The particle size of the particulate system is in the range of 100 to 1500 micron, preferably in the range of 300 to 750 micron.

The process of caffeine formulation of particulate system comprising:

- (a) loading of caffeine and food grade excipient in a granulator;
- (b) adding an aqueous shellac solution to rapid mixer granulator containing caffeine and food grade excipient;
- (c) wet mass obtained from step (b), pass through extruder machine with 0.5-0.7 mm radial screen;
- (d) load extrudes on 2.0 mm pitch spheronizer plate having speed of 1500 to 1800 rpm for 20-30 sec to get the spherical granules;
- (e) unload the spherical granules of step (d) from spheronizer and dry in tray drier for 1.5 to 2.5 h at temp. 60±5° C.; and
- (f) coat granules obtained from step (e), with coating solution of release retarding agent to obtain coated granules.

As per one embodiment of present invention, the particulate systems formulated in finished dosage forms selected from the group of, but not limited to tablets, capsules, caplets, soft gel capsules, oil suspensions, powder mixtures, granules and the like, without any limitation. The formulations also formed by combining plurality of the particulate systems in different ratios and then processing into tablets, capsules, caplets, soft gel capsules, oil suspensions, powder mixtures, granules and the like, without any limitation.

According to one important embodiment, caffeine pulsed release formulations tested for release profile of caffeine in variety of dissolution media, corresponding to physiological pH conditions, in suitable dissolution apparatus. Caffeine formulations described herein release specific percentage of caffeine at various physiological pH conditions over entire GIT. The formulations release not more than 30% of the caffeine within 2 hours in pH 1.2, not more than 60% of the caffeine within 4 hours in pH 5.5 and about 100% of caffeine is released at pH 7.2 in 8 hours. Caffeine formulations as described herein exhibit lag time of caffeine released for initial 2 hours, but certain amount of caffeine is released in 4 hours, so that desired levels of caffeine are reached, and these levels are sustained through additional drug release till 6 to 8 hours at alkaline pH. Thus, the formulations as described herein release the caffeine in pulses over entire GIT and can be administered to subjects for getting continuous action of the active for period of 8 hours. In certain cases, the formulation also has continuous release of caffeine over 2 to 8 hours interval, wherein the caffeine gets released in multiple pulses over entire GIT.

EXAMPLES

The present invention is now illustrated by means of non-limiting examples.

Example 1: Particulate System I (First) and Process of Preparation

TABLE NO. 01

Composition of Example 1

Sr.No.
Ingredients
% W/W

1
Caffeine 99% extract powder
64.67

2
Shellac
3.22

3
MCC 101
5

4
Methacrylic acid-Ethyl acrylate copolymer (1:1)
27.11

5
Purified Water q.s
QS

A) Procedure:

Preparation of Caffeine Granules

Natural caffeine extract powder and microcrystalline cellulose (MCC 101) powders were weighed and loaded in rapid mixing granulator. Prepare shellac solution with purified water in another container. Added this solution gradually in rapid mixing granulator at impeller speed of 200 rpm and chopper speed of 300 rpm. After complete addition of aqueous shellac solution, stop mixing and unload the wet mass from the rapid mixing granulator. Pass wet mass through extruder machine with 0.5-0.7 mm radial screen attached. Maintain screw speed at 60 rpm to produce uniform extrude. Collect all the extrudes in tray for further spheronization process. The extrudes of 0.4 kg are loaded on 2.0 mm pitch Spheronizer plate and spheronization was started at the speed of 1600 rpm for 25 sec to get the spherical granules. Granules were unloaded from spheronizer and dried in tray drier using oven for 2 hrs at temp. 60±5° C.

Coating of Caffeine Granules: Dilute Methacrylic acid-Ethyl acrylate copolymer (1:1) to make a dispersion of 25% with purified water. Caffeine granules are loaded in fluidised bed coater (Pam Glatt 125C) and coated with 25% aqueous Methacrylic acid-Ethyl acrylate copolymer (1:1) dispersion using below process parameters: Inlet temperature at 30° C., Outlet temperature at 28° C., Product temperature at 27° C., Flow rate at 4 RPM. Atomization Air Pressure at 1.5 bar.

B) Dissolution Profile:

Dissolution study of pulsed release caffeine formulation was performed using a USP II paddle apparatus

- a. Dissolution medium: 0.1N HCL, 0.25% SLS in pH 5.5 Phosphate Buffer

Media
Time points in Hour

0.1N HCL
2

pH 5.5 Phosphate Buffer
4

- b. Dissolution medium volume: 900 ml at each stage
- c. Type: USP Type II Paddle
- d. RPM: 75
- e. Temperature: 37° C.+/−0.5° C.
- f. Time: 4 Hrs.
- g. Sampling Interval: As per above table.

Analysis using HPLC at Wavelength 272 nm.

TABLE 02

Dissolution data of caffeine formulation of Example 1

Media
Time (Hrs)
% Caffeine Release

0.1N HCl
1
9.6 ± 2

2
17.1 ± 2

pH 5.5 Phosphate
3
96.40 ± 2

Buffer
4
100.00 ± 2

(Note:

variation of ±2 is subjected to condition)

Example 2: Particulate System II Second and Process of Preparation

TABLE 03

Composition of example 2

Sr. No.
Ingredients
% W/W

1
Caffeine 99% extract powder
64.67

2
Shellac
3.22

3
MCC
5

4
Shellac
27.11

5
Brilliant Blue FCF
2.5

6
Purified water q.s
QS

A) Procedure

Preparation of Caffeine Granules: Natural Caffeine Extract powder and Microcrystalline cellulose MCC 101 powders were weighed and loaded in rapid mixer granulator. Prepare shellac solution with purified water in another container. Added this solution gradually in Rapid mixing granulator at impeller speed of 200 rpm and chopper speed of 300 rpm. After complete addition of solution, mixing was stopped, and wet mass was unloaded from the rapid mixer granulator. Wet mass was passed through extruder machine with 0.5-0.7 mm radial screen attached. Screw speed was maintained at 60 rpm to produce uniform extrude. All the extrudes were collected in tray for further spheronization process. The extrudes of 0.4 kg are loaded on 2.0 mm pitch Spheronizer plate and spheronization was started at the speed of 1600 rpm for 25 sec to get the spherical granules. Granules were unloaded from spheronizer and dried in tray drier using oven for 2 hrs at temp. 60*5° C.

Enteric Coating of Caffeine Granules: Caffeine granules were loaded in fluid bed coater (Pam Glatt 125C) and coated with 25% aqueous shellac dispersion using below process parameters: Inlet temperature at 38° C., Outlet temperature at 37° C., Product temperature at 35° C., Flow rate at 4 RPM, Atomization Air Pressure at 1.8 bar Color Coating of Caffeine Granules: Enteric coated Caffeine granules were loaded in fluid bed coater (Pam Glatt 125C) and coated with Brilliant Blue FCF solution using below process parameters: Inlet temperature at 45° C., Outlet temperature at 43° C., Product temperature at 41° C., Flow rate at 4 RPM, Atomization Air Pressure at 2.2 bar

B) Dissolution Profile:

- a. Dissolution medium: 0.1 N HCL, 0.25% SLS in pH 5.5 Phosphate Buffer, 0.25% SLS in pH 7.2 Phosphate Buffer

Media
Time points in hr.

0.1N HCL
2

pH 5.5 Phosphate Buffer
4

pH 7.2 Phosphate Buffer
6

- b. Dissolution medium volume: 900 ml at each stage
- c. Type: USP Type II Paddle
- d. RPM: 75
- e. Temperature: 37° C.+/−0.5° C.
- f. Time: 6 Hrs.
- g. Sampling Interval: As per above table.

Analysis using HPLC at Wavelength 272 nm.

TABLE NO 04

Dissolution data of caffeine formulation of Example 2

Media
Time (Hrs)
% Caffeine Release

0.1N HCl
1
6.1 ± 2

2
9.3 ± 2

pH 5.5 Phosphate Buffer
3
12.5 ± 2

4
15.2 ± 2

pH 7.2 Phosphate Buffer
5
99.60 ± 2

6
100.0

(Note:

variation of ±2 is subjected to condition)

Example 3: Particulate System III (Third) and Process of Preparation

TABLE NO 05

Composition of example 3

Sr.No.
Ingredients
% W/W

1
Caffeine 99% extract powder
64.67

2
Shellac
12.87

3
MCC 101
5

4
Stearic Acid
17.46

5
Water q.s.
QS

A) Procedure

Preparation of Caffeine Granules by Extrusion & Spheronization (E&S):

Natural caffeine extract powder and microcrystalline cellulose (MCC 101) powders were weighed and loaded in rapid mixing granulator. Prepare shellac solution with purified water in another container. Added this solution gradually in rapid mixing granulator at impeller speed of 200 rpm and chopper speed of 300 rpm. After complete addition of solution, mixing was stopped, and wet mass was unloaded from the rapid mixer granulator. Wet mass was passed through extruder machine with 0.5-0.7 mm radial screen attached. Screw speed was maintained at 60 rpm to produce uniform extrude. All the extrudes were collected in tray for further spheronization process. The extrudes of 0.4 kg of loaded on 2.0 mm pitch Spheronizer plate and spheronization was started at the speed of 1600 rpm for 25 sec to get the spherical granules. Granules were unloaded from spheronizer and dried in tray drier using oven for 2 hrs at temp. 60±5° C.

Hot Melt Coating of Caffeine Granules: Caffeine granules were loaded in fluid bed coater (Pam Glatt 125C) and coated with Stearic acid in molten state heated at 130-140° C. temp. using below process parameters: Inlet temperature at 32° C., Outlet temperature at 31° C., Oil Bath temperature at 130-140° C., Atomization Air temperature at 140° C., Product temperature at 28-32° C., Flow rate at 4 RPM, Atomization Air Pressure at 2.2 bar

- A) Dissolution Profile
- a) Dissolution medium: 0.1N HCL, 5.5 Phosphate Buffer, 7.2 Phosphate Buffer

Media
Time points in Hr.

0.1N HCL
2

pH 5.5 Phosphate Buffer
6

pH 7.2 Phosphate Buffer
8

- b) Dissolution medium volume: 900 ml at each stage
- c) Type: USP Type U Paddle
- d) RPM: 75
- e) Temperature: 37° C.+/−0.5° C.
- f) Time: 8 Hrs.
- g) Sampling Interval: As per above table.

Analysis using HPLC at Wavelength 272 nm.

TABLE NO. 06

Dissolution data of caffeine

formulation of Example 3

% Caffeine

Media
Time (Hrs)
Release

0.1N HCl
1
5.9 ± 2

2
10.4 ± 2

pH 5.5 Phosphate
3
28.7 ± 2

Buffer
4
44.3 ± 2

5
51.1 ± 2

6
55.8 ± 2

pH 7.2 Phosphate
7
84.3 ± 2

Buffer
8
96.0 ± 2

(Note:

variation of ±2 is subjected to condition)

Example 4: Pulsed Release Caffeine Formulation

TABLE NO. 07

Composition of example 4

Sr.

Qty. for

No.
Ingredients
100 gm

1
Particulate system I
20

2
Particulate system II
40

3
Particulate system III
40

- A) Procedure:
- a) Particulate system I—As per given in Example 1.
- b) Particulate system II—As per given in Example 2.
- c) Particulate system III—As per given in Example 3.
  - The particulate system I, II and III are blend together to form the pulsed release caffeine formulation.
- B) Dissolution Profile (Total dose was equivalent to 150 mg of Caffeine):
- a) Dissolution medium: 0.1N HCL, 0.25% SLS in pH 5.5 Phosphate Buffer, 0.25% SLS in pH 7.2 Phosphate Buffer

TABLE NO. 08

Dissolution data of caffeine formulation of Example 4

Media
Time points in hour

0.1N HCL
2

0.25% SLS in pH 5.5 Phosphate Buffer
4

0.25% SLS in pH 7.2 Phosphate Buffer
6