PROLONGED RELEASE FORMULATION OF CAFFEINE

Abstract

The present invention relates to a prolonged release formulation of caffeine, which comprises of caffeine embedded in a continuous phase of non-polymeric release controlling carrier. The formulation may be optionally comprised of one or more excipients which are acceptable in nutraceutical and food industry. The invention also relates to a process for preparation; wherein caffeine is uniformly distributed throughout the continuous phase of non-polymeric release controlling carrier to get single-phase granules. The formulation releases caffeine through continuous phase of non-polymeric release controlling carrier, wherein about 20 to 60% of caffeine is released in first hour, followed by about 50-90% of release in 4-8 hours and about 70 to 100% of caffeine release in 8-12 hours. Caffeine formulation can advantageously be administered to a subject for achieving stimulant effect through prolonged release of caffeine over entire day.

Claims

1. A prolonged release caffeine formulation, comprising 20 to 70% by weight of caffeine, embedded in continuous phase of about 20 to 80% by weight of non-polymeric release controlling carrier, and optionally one or more excipients acceptable in nutraceutical and food industry.

2. Prolonged release caffeine formulation of claim 1, wherein the continuous phase is comprised of about 0 to 60% by weight of one or more excipients.

3. Prolonged release caffeine formulation of claim 2, wherein the continuous phase is comprised of about 0 to 50% by weight of one or more excipients.

4. Prolonged release caffeine formulation of claim 1, wherein the non-polymeric release controlling carrier is selected from lipids, fats, fatty acids, fatty alcohols, waxes, oils, their derivatives or the combination thereof.

5. Prolonged release caffeine formulation of claim 4, wherein the non-polymeric release controlling carrier is selected from carnauba wax, beeswax, stearic acid, cetyl alcohol, pegylated fatty acids, glycerol fatty acid esters, monoglycerides, diglycerides, triglycerides, glyceryl behenate, glyceryl monostearate, glyceryl palmitostearate, pegylated vegetable oils, partially hydrogenated oils of soy, cottonseed, palm, sunflower, castor oil, sorbitan esters, polyoxyethylene sorbitan esters, propylene glycol mono- or diesters, phospholipids, glycolipids, glycerolipid, sphingolipid, phosphatides, phosphatic acid, phosphatidylethanolamine, phosphatidylcholine, phosphatidylserine, phosphatidylinositol, glycerophospholipids, cerebrosides, gangliosides, cephalins, sulfatides, sugar esters, sugar ethers, sucrose esters, sterols, polyglycerol esters, ceramide, sterol, fat-soluble vitamins, prenol, saccharolipid, polyketides, their derivatives or the combination thereof.

6. Prolonged release caffeine formulation of claim 1, wherein one or more excipients may be selected from fillers, diluents, disintegrants, lubricants, binders, glidants, anti-caking agents, stabilizers, surfactants, channelizing agents, vehicles, buffers, stabilizers, preservatives, acidifiers, alkalizers, complexing agents, antioxidants, viscosity enhancers, plasticizers, coating materials, sweeteners, colors, flavors or the combination thereof.

7. Prolonged release formulation of claim 1, wherein about 25 to 60% of caffeine is released in first 1 hour, followed by about 50-90% of caffeine release in 4-8 hours and about 70 to 100% of release in 8-12 hours.

8. Process for preparation of prolonged release caffeine formulation, which is comprised of, mixing caffeine with continuous phase of at least one non-polymeric release controlling carrier and optionally one or more excipients to get a blend, subjecting the blend to suitable process of granulation by varying the temperature in the range of 50 to 100° C. to get molten form, processing the molten form to get single-phase granules of desired size, and formulating the granules in suitable dosage form.

9. Process for preparation of claim 8, wherein the granules of caffeine may vary in size ranging from 100 microns to 1500 microns.

10. Process for preparation of claim 8, wherein caffeine granules can be formulated in the form of sachets, mixed in beverages, filled in the capsules, compressed in the tablets, caplets, pills, beads, beadlets, pellets, formulated as chewing gum, gummies and the like.

Description

DETAILED DESCRIPTION

[0024] The invention relates to a prolonged release formulation of caffeine, wherein the active is uniformly distributed in continuous phase of non-polymeric release controlling carrier. Caffeine formulation is non-coated, non-layered and single-phase composition, comprised of at least one non-polymeric release controlling carrier.

[0025] The formulation may be free of any excipients or may be optionally comprised of one or more excipients, which are acceptable in nutraceutical and food industry. The invention also relates to a process for preparation, wherein caffeine is embedded uniformly in the continuous phase of non-polymeric carrier, by suitable process of granulation. Formulation releases caffeine over a prolonged period of 8 to 12 hours and it is useful for delivering the stimulant over day-long time, thus eliminating the need for repeated administration of the active.

[0026] Caffeine as used in this invention is purchased in the form of white crystalline, odorless, bitter powder and having 98 to 101% of active content. Caffeine exhibits good water solubility. It is supplied from a manufacturer, who obtains it from natural source Coffea Robusta, belonging to Rubiaceae family.

[0027] The terminology ‘prolonged release’ as used herein refers to release pattern of the active from continuous phase of non-polymeric release controlling polymer, at desired rate over a period of 6 to 12 hours. The formulation, as described herein, is designed in such a way that about 25 to 60% of caffeine is released in first hour, followed by about 50-90% of release in 4-8 hours and about 70 to 100% of caffeine release in 8-12 hours. Thus the active would be released in the body system for exerting its stimulant action through release of about 25 to 60% of caffeine in initial phase and providing alertness to the subject, followed by about 70 to 100% of release in 8-12 hours, wherein the active would be available in the body system for the entire day as per requirement.

[0028] The terminology ‘continuous phase’ as used herein refers to uniform distribution of active in continuous phase of non-polymeric release controlling carrier. In present invention, the continuous phase may be the mixture of active with non-polymeric release controlling carrier and optionally the excipients, which are acceptable in nutraceutical and food industry. The prolonged release formulation of caffeine, as described herein is non-coated, non-layered and single-phase matrix granules, preferably comprised of one or more non-polymeric release controlling carrier. Caffeine is uniformly dispersed and embedded in the continuous phase of non-polymeric release controlling carrier and optionally the excipients, to form a system through which caffeine releases at a prolonged rate over 6 to 12 hour, when the formulation enters the body system after administration.

[0029] The terminology ‘non-polymeric release controlling carrier’ as used herein relates to the formulation components which are used as continuous phase, for uniformly distributing caffeine for achieving desired prolonged release profile. These components are explicitly responsible for controlling release of caffeine from the formulation. These carriers are insoluble in water. The non-polymeric release controlling carrier may be preferably obtained from natural source, although the carriers may be available from synthetic and semi-synthetic sources.

[0030] As per one important embodiment, the non-polymeric release controlling carrier may be selected from, but not limited to, saturated fatty acids having 12 to 28 carbons, such as stearic acid, fatty alcohols having from 16 to 44 carbons, cetyl alcohol, pegylated fatty acids, glycerol fatty acid esters, monoglycerides, diglycerides, triglycerides, derivatives of mono-diglycerides, glyceryl behenate, glyceryl monostearate, glyceryl palmitostearate, pegylated vegetable oils, partially hydrogenated oils of soy, cottonseed, palm, sunflower, castor oil, sorbitan esters, polyoxyethylene sorbitan esters, propylene glycol mono- or diesters, phospholipids, phosphatides, cerebrosides, gangliosides, cephalins, lipids, glycolipids, sulfatides, sugar esters, sugar ethers, sucrose esters, sterols, polyglycerol esters, glycerolipid, phosphatic acid, phosphatidylethanolamine, phosphatidylcholine, phosphatidylserine, phosphatidylinositol or other glycerophospholipids, ceramide, sphingolipid, sterol, fat-soluble vitamin, prenol, saccharolipid, polyketide, their salts and esters and the combination thereof.

[0031] Non-polymeric release controlling carrier may be selected from the class of, but not limited to lipids, fats, waxes and the combination thereof. Non-polymeric release controlling carrier may also be selected from, but not limited to, beeswax, candelilla wax, carnauba wax, spermaceti, paraffin wax, synthetic waxes and the combination thereof.

[0032] The formulation, as described herein may comprise of about 20 to 70% by weight of caffeine and 20 to 80% by weight of non-polymeric release controlling carrier. The formulation may optionally contain about 0 to 60% by weight of excipients.

[0033] According to one more embodiment of the invention, prolonged release formulation of caffeine may be comprised of about 20 to 70% by weight of caffeine and about 22 to 80% by weight of non-polymeric release controlling carrier and optionally 0 to 50% by weight of excipients.

[0034] According to one embodiment of the invention, the formulation may be comprised of non-polymeric release controlling carrier selected from wax, saturated fatty acid, lipids, oils and the combination thereof.

[0035] As per one embodiment of the invention, continuous phase prolonged release formulation of caffeine may optionally contain 0 to 60% by weight of excipients, which are acceptable in nutraceutical and food industry. Excipients may facilitate the granulation and formulation of caffeine prolonged release formulation, but these do not have any role in controlling release of caffeine from the formulation. These are commonly used ingredient in industry, and are selected from the group of, but not limited to, fillers, diluents, disintegrants, lubricants, binders, glidants, anti-caking agents, stabilizers, surfactants, channelizing agents, vehicles, buffers, stabilizers, preservatives, acidifiers, alkalizers, complexing agents, gum bases, antioxidants, viscosity enhancers, plasticizers, coating materials, sweeteners, colors, flavors and the combination thereof. The excipients may belong to the class such as polymeric, non-polymeric, swelling, non-swelling, pH dependent and pH independent additives, which do not have any role in controlling release of active from the formulation. Prolonged release formulation of caffeine, as described herein, may be comprised of about 0 to 60% by weight of additives, which are selected from natural, semi-synthetic or synthetic sources. More preferably, the formulation may be comprised of about 0 to 50% by weight of excipients. Most preferably, the prolonged release formulation may be comprised of about 0 to 30% by weight of excipients.

[0036] The formulation may be comprised of diluents known in the art, but not limited to microcrystalline cellulose, silicified microcrystalline, cellulose, powdered cellulose, microfine cellulose, corn starch, rice bran extract, calcium phosphate, dibasic calcium phosphate, tribasic calcium phosphate, calcium sulfate, or mixtures thereof. The diluents may also be selected from glucose, lactose, sucrose, dextrose, fructose, compressible sugar, or mixtures thereof.

[0037] The binders may be selected from the group of cellulose derivatives such as hydroxypropylmethyl cellulose (HPMC), hydroxypropyl cellulose (HPC), ethylcellulose, carboxymethylcellulose (CMC), sodium CMC, potassium CMC, calcium CMC, methylcellulose, hydroxyethyl cellulose (HEC), microcrystalline cellulose; polyvinylpyrrolidone (PVP), vinyl pyrrolidone-vinyl acetate copolymer, polyvinyl alcohol, starch, carbomer, gums like xanthan gum, guar gum, acacia, locust bean gum, alginates, or mixtures thereof.

[0038] The disintegrants may be selected from sodium starch glycolate, crospovidone, croscarmellose sodium, croscarmellose calcium, croscarmellose potassium, sodium carbonate, sodium hydrogen carbonate, calcium carbonate, starch, starch 1500, modified starch, pregelatinized starch, crosslinked carboxymethyl starch, sodium hydrogen carbonate, hydroxypropyl cellulose, sodium carboxymethylcellulose or mixtures thereof.

[0039] The lubricants may be selected from magnesium stearate, calcium stearate, sodium benzoate, talc, or mixtures thereof.

[0040] The glidants may be selected from suitable glidants known in the art and commonly used in the industry, selected from the group of stearate, starch, talc and the derivatives.

[0041] According to the important embodiment of the invention, the process for preparation of caffeine formulation may be comprised of mixing caffeine with at least one non-polymeric release controlling carrier and optionally one or more excipients. The blend is subjected to suitable process of granulation such as slugging, dry granulation, direct compression, extrusion spheronization, compaction, compression, melt granulation, melt extrusion, melt solidification, spray-drying, freeze-drying and spray chilling. The formulation of caffeine, as described herein is non-coated, non-layered and continuous phase composition, which provides reliable, reproducible and consistent release of caffeine over prolonged time of 6 to 12 hours.

[0042] As per one more embodiment of the invention, commonly available and easy to use industrial equipment may be used for preparation of prolonged release formulation of caffeine. Suitable parameters of temperature, revolutions and torque may be selected for carrying out melt continuous granulation. The process may be carried out by varying the temperature in the range of 50 to 100° C. and the molten form can be processed to get granules of desired size.

[0043] According to one embodiment of the invention, size of the granules/powder may vary from 100 micron to 1500 micron; preferably from 150 micron to 1000 micron;

[0044] As per one more embodiment, the granules may vary in size from 400 micron to 800 micron. The granules prepared in this way are free flowing in nature.

[0045] Caffeine granules can be used as such, mixed in beverages, filled in the capsules, compressed in the tablets to get final dosage form for oral administration. The granules can also be formulated in chewing gums and gummies. The formulations of the present invention may be granules, tablets, capsules, caplets, pills, beads, beadlets, pellets, and the like.

[0046] The formulations comprising the said caffeine granules embedded in continuous phase of non-polymeric release controlling carrier, may optionally contain one or more excipients suitable for the preparation of the dosage form. These formulations can be manufactured by conventional processes known to a person skilled in the art.

[0047] Prolonged release caffeine formulations can be evaluated for assay, stability as well as cumulative release profile of caffeine over 12-hour time period.

[0048] According to one embodiment of this invention, caffeine formulation releases active over a prolonged period, wherein about 25 to 60% of caffeine is released in first hour, about 50-90% of caffeine release in 4-8 hours and about 70 to 100% of release in 8-12 hours.

[0049] According to one more embodiment of this invention, caffeine formulation preferably releases about 30 to 60% of caffeine in first hour, followed by about 60 to 80% of caffeine release in 4-8 hours and about 75 to 100% of release in 8-12 hours.

[0050] As per important embodiment of the invention, formulation exhibits immediate release of about 20 to 60% of caffeine in first hour, followed by about 65 to 80% of prolonged drug release in 4-8 hours and 75 to 100% release in 8-12 hours, thus providing the prolonged therapeutic effect of the active for 6 to 12 hours, as desired for achieving stimulant action of caffeine over entire day.

[0051] The prolonged release caffeine formulation of the invention can be conveniently administered to the subject for achieving stimulant action and alertness during the start of the day by initial release of active in first hour, followed by prolonged levels of caffeine throughout the day over a period of 6 to 12 hours. Thus, the formulation does not interfere with sleeping hours of the subject. These prolonged release formulations decrease the frequency of administration of the dosage form during the day.

[0052] The invention is now illustrated with non-limiting examples.

Example 1: Composition of Caffeine Formulation-Formula 1

[0053] Caffeine (50%) was mixed with stearic acid (20%), carnauba wax (20%) and maltodextrin (10%) in a blender for 30 minutes at 10 rpm. The mixture was fed in hot melt granulator, while maintaining conditions like feed rate, temperature, and torque. The temperature was varied from 50 to 100° C. The molten form was collected and processed to get granules of Formula 1 in the range of 400 to 1000 micron.

[0054] The formulation was evaluated for dissolution profile using USP Type II (paddle) apparatus at 100 rpm speed, using 900 ml of pH 6.8 phosphate buffer as dissolution medium. Caffeine released from the formulation is measured by using UV spectrophotometer at 274 nm wavelength and the data is provided in Table no. 1.

TABLE-US-00001 TABLE 1 Dissolution profile of Caffeine prolonged release formulation-Formula1 Time (hr.) Cumulative Release profile of Caffeine (%) 1 42 2 57 4 74 6 83 8 89 10 93 12 96

[0055] The dissolution profile of caffeine formulation exhibits prolonged release pattern, wherein about 42% of caffeine is released in first hour and about 70 to 90% of caffeine is released in 4-8 hours, followed by about 100% release in 10-12 hours. The release pattern is achieved from single-phase granules, prepared from use of non-polymeric release controlling carriers. Caffeine formulation with continuous phase of non-polymeric carrier is useful for achieving alertness during the start of the day by initial fast release of active in first hour, followed by prolonged levels of caffeine throughout the day over a period of 10 to 12 hours. Thus the formulation can result in improved performance of the subject, through enhanced focus and alertness throughout the day.

Example 2: Caffeine Formulation with Non-Polymeric Carrier in Various Ratios

[0056]

TABLE-US-00002 TABLE 2 Composition of Caffeine formulations -Formula 2 to Formula 7 Formula 2 Formula 3 Formula 4 Formula 5 Formula 6 Formula 7 Ingredients Percentage Percentage Percentage Percentage Percentage Percentage Caffeine 50 50 50 50 60 70 Stearic acid 15 15 14 12 15 15 Carnauba Wax 15 15 14 12 15 15 Maltodextrin 20 — 12 16 — — Microcrystalline — 20 10 10 10 — cellulose (MCC) Total 100% 100% 100% 100% 100% 100% Particle Size 400 to 800 400 to 800 400 to 800 400 to 800 150 to 250 150 to 250 micron micron micron micron micron micron Time (hr.) Cumulative Release Profile of Caffeine (%) over 12 hours 1 40 27 35 54 58 48 2 45 42 47 70 67 55 4 50 55 61 86 81 63 6 60 72 74 93 88 70 8 67 79 79 96 90 74 10 72 85 85 99 93 77 12 74 89 87 100  95 80

[0057] Process of Formula 1, as described in Example 1 was followed to prepare various caffeine formulations, covered in Table 2. The molten form was collected and processed to get granules in the range of 150 to 1000 micron. The release profile was checked using dissolution apparatus, which is also included in Table 2. The dissolution profile of caffeine formulation indicates prolonged release pattern, wherein about 25-60% of caffeine is released within first one hour and about 50 to 90% of caffeine is released in 4-6 hours, followed by about 75-100% release in 10-12 hours. The release pattern is achieved through use of continuous phase of non-polymeric release controlling carriers.

Example 3: Caffeine Formulations with Non-Polymeric Carrier in Various Ratios

[0058]

TABLE-US-00003 TABLE 3 Composition of Caffeine formulations -Formula 8 to Formula 11 Formula Formula 8 Formula 9 Formula 10 Formula 11 Composition in Percentage Caffeine 50 50 50 58.9 Stearic acid 15 20 20 16.1 Carnauba Wax 15 20 20 16.1 Maltodextrin 10 — 10 — MCC 10 10 — — Shellac — — — 8.9 Total 100% 100% 100% 100% Particle size 400-800 micron 400-800 micron 400-800 micron 400-800 micron Time (hr.) Cumulative Release Profile of Caffeine (%) over 12 hours  1 54 51 42 44  2 70 66 57 57  4 86 80 74 71  6 93 87 83 80  8 99 90 89 85 10 100 93 93 90 12 102 95 96 93

[0059] Process of Formula 1, as described in Example 1 was followed to prepare various caffeine formulations, covered in Table 3. The molten form was collected and processed to get free flowing granules in the range of 400 to 800 micron. The release profile was checked using dissolution apparatus, which is also included in Table 3.

[0060] The dissolution profile of caffeine formulation indicates prolonged release pattern, wherein about 40-60% of caffeine is released within first hour and about 70 to 90% of caffeine is released in 4-6 hours, followed by about 85-100% release in 8-12 hours. The release pattern is achieved through use of continuous phase of non-polymeric release controlling carriers.

Example 4: Caffeine Formulations with Glyceryl Behenate as Non-Polymeric Carrier

[0061]

TABLE-US-00004 TABLE 4 Composition of Caffeine formulations -Formula 12 and 13 Formula Formula 12 Formula 13 Percent Composition Caffeine 20 40 Glyceryl Behenate 80 60 Total 100% 100% Particle Size 400 to 800 micron 400 to 800 micron Cumulative Release Profile of Caffeine (%) over 12 hours Time (hr.) Formula 12 Formula 13  1 23 30  2 32 45  4 67 61  6 74 71  8 81 85 10 89 89 12 97 92

[0062] Process of Formula 1, as described in Example 1 was followed to prepare various caffeine formulations, covered in Table 4. The molten form was collected and processed to get granules in the range of 400 to 800 micron. The release profile was checked using dissolution apparatus, which is also included in Table 4.

[0063] The dissolution profile of caffeine formulation indicates prolonged release pattern, wherein about 25-30% of caffeine is released within first hour and about 60 to 75% of caffeine is released in 4-6 hours, followed by about 80-100% release in 8-12 hours. The release pattern is achieved through use of continuous phase of non-polymeric release controlling carriers.